Anti-influenza compound as well as preparation method and application thereof

Abstract

The invention relates to an anti-influenza compound as well as a preparation method and application thereof, and the anti-influenza compound has a structure as shown in formula (I): (I) wherein X1 is CR3 or N; x2 is CR4 or N; z is CR5 or N; y1 is CR6 or N; y2 is CR7 or N; y3 is CR8 or N; w is-NH-or-N = CH-; in the formula, R1 is-R < 9 >-COO < 10 >,-(CR < 122 >) < n >-R < 11 >-(CR < 122 >) < n >-O-H,-(CR < 122 >) < m >-O-H,-(CR < 122 >) < h >-COO < 10 > or-R < 11 >-CONR < 13 >-R < 14 >. The compound provided by the invention has strong inhibitory activity on influenza virus, and is subjected to in-vivo antiviral activity test, action mechanism analysis and pharmacokinetic characteristic evaluation at the same time.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically providing an anti-influenza compound, its preparation method, and its application. Background Technology

[0002] Influenza is a seasonal acute respiratory infectious disease caused by the influenza virus. Since the 20th century, there have been numerous influenza pandemics globally, resulting in approximately 60 million deaths and posing a serious threat to human health. Statistics show that about 1 billion people worldwide are infected with seasonal influenza each year, with 3 to 5 million developing severe illness, primarily among children, the elderly, and those with weakened immune systems. This leads to 290,000 to 650,000 deaths from respiratory complications. Although some influenza vaccines are available, their effectiveness is limited due to poor protection in the elderly and those with compromised immune systems, as well as the high rate of genetic recombination and frequent antigenic mutations of the influenza virus, resulting in reduced vaccine efficacy and limited protection. This presents challenges for influenza vaccination and treatment. Therefore, small-molecule antiviral drugs are crucial for the prevention and treatment of influenza and for shortening the course of the disease, especially in populations with poor vaccine responses or during pandemics. This underscores the urgent need to develop novel and effective antiviral drugs to address influenza epidemics.

[0003] PB2 possesses a unique function: it can "steal" the cap structure from the host cell's mRNA. This mechanism allows viruses to deceive host cells, mistaking their RNA for their own mRNA, thereby hijacking the cell's transcription machinery for replication. PB2 not only recognizes and binds to the 5' end of the host's pre-mRNA as a transcription primer, but its cap-binding site is highly conserved, structurally different from other cap-binding proteins, and difficult to mutate, making PB2 an ideal target for developing novel antiviral drugs. Pimodivir, the first oral PB2 inhibitor developed by Vertex, exhibited excellent antiviral activity. However, its Phase III clinical trial was terminated after interim analysis because the combination of pimodir and oseltamivir failed to show additional efficacy compared to the standard of care alone. ZS Biotech has structurally modified pimodir to develop another PB2 inhibitor—Onradivir. This drug exhibits strong antiviral activity against multiple influenza virus strains and can effectively address the resistance issues of oseltamivir and mabaloxavir. It was launched in China in 2025, becoming the world's first approved PB2 inhibitor.

[0004] The successful launch of onradivir demonstrates the significant advantages of the PB2 target in the development of anti-influenza drugs. Therefore, this study aims to develop a novel PB2 inhibitor based on the PB2 target for the treatment of influenza infection. Summary of the Invention

[0005] The purpose of this invention is to provide an anti-influenza compound, its preparation method, and its application. The compound provided by this invention has potent inhibitory activity against influenza virus, and its in vivo antiviral activity, mechanism of action, and pharmacokinetic characteristics have been evaluated.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows: In a first aspect, the present invention provides an anti-influenza compound or its stereoisomers, geometric isomers, tautomers, enantiomers, nitrides, hydrates, solvates, crystalline forms, metabolites, pharmaceutically acceptable salts, prodrugs or isotopic labels thereof, having a structure as shown in formula (I): (I); Among them, X 1 For CR 3 Or N; X 2 For CR 4 Or N; Z is CR 5 Or N; Y 1 For CR 6 Or N; Y 2 For CR 7 Or N; Y 3 For CR 8 Or N; W is -NH- or -N=CH-; R 2 R 3 R 4 R 5 R 6 R 7 R 8 Each of these groups can be independently H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, -OH, -B(OH)2, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkenyl, haloynyl, alkenyl, ynyl, cycloalkyl, heterocyclic, spirocyclic, aryl, or heteroaryl; or R 2 and R 4 Together with the carbon atoms attached to them, they form cycloalkyl, heterocyclic, spirocyclic, aryl, or heteroaryl groups; or R 2 and R 3 Together with the carbon atoms attached to them, they form cycloalkyl, heterocyclic, spirocyclic, aryl, or heteroaryl groups; R 1 -R 9 -COO-R 10 、-(CR 12 2) n -R 11 -(CR 12 2) n -OH, -(CR)12 2) m -OH, -(CR) 12 2) h -COO-R 10 or -R 11 -CONR 13 -R 14 ; n, m, and h are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R 9 R 11 Each independently , , , , , cycloalkyl, heterocyclic, aryl or heteroaryl; R 10 R 12 Each is independently H or alkyl; R 13 R 14 Each is independently H, -CN, -OH, -O(CR) 12 2) m -H or alkyl group; The cycloalkyl, heterocyclic, spirocyclic, aryl, and heteroaryl groups are further mono- or poly-substituted by H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, -OH, -B(OH)2, nitro, or alkyl groups.

[0007] Furthermore, R 2 R 3 R 4 R 5 R 6 R 7 R 8 Each of the following can be independently represented as H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, -OH, -B(OH)2, nitro, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 2-12 Haloalkenyl, C 2-12 Halogenated alkynyl group, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 5-12 Spiral ring, C 6-12 Aryl or C 1-12 heteroaryl; or R 2 and R4 Together with the carbon atoms attached to them, they form C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 5-12 Spiral ring, C 6-12 Aryl or C 1-12 heteroaryl; or R 2 and R 3 Together with the carbon atoms attached to them, they form C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 5-12 Spiral ring, C 6-12 Aryl or C 1-12 Mixed aromatic compounds.

[0008] Furthermore, R 2 R 3 R 4 R 5 R 6 R 7 R 8 Each of the following can be independently represented as H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, -OH, -B(OH)2, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, C 1-6 Alkoxy, difluoromethyl, fluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or ; or R 2 and R 4 Together with the carbon atoms attached to them, they form cyclohexyl groups. ; or R 2 and R 3 Together with the carbon atoms attached to them, they form cyclohexyl groups. .

[0009] Furthermore, R 9 R 11 Each independently , , , , C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 6-12 Aryl or C 1-12 Mixed aromatic compounds.

[0010] Furthermore, R 9 R 11 Each independently , , , , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or .

[0011] Furthermore, R 10 R 12 Each independently is H or C 1-6 alkyl.

[0012] Furthermore, R 10 R 12 Each can be independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, or n-pentyl.

[0013] Furthermore, R 13 R 14 Each is independently H, -CN, -OH, -O(CR) 12 2) m -H or C 1-6 alkyl.

[0014] Furthermore, R 13 R 14 Each is independently H, -CN, -OH, -O(CR) 12 2) m -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, or n-pentyl.

[0015] In some embodiments, the influenza compound of the present invention has one of the following structures: (II) (III) (IV) (V) (VI) (VII) R 1 R 2 R 3 R 4 X 1 X 2 Z, Y 1 Y 2 and Y 3 It has the definition as described in this invention.

[0016] In this invention, X in the same structural formula 1 X 2 Z, Y 1 Y 2 Or Y 3 The selected values ​​can be the same or different, and they do not affect each other.

[0017] Furthermore, the influenza compound of the present invention has one of the following structures: .

[0018] On the other hand, the present invention provides a method for preparing the compound described herein, the specific steps of which are as follows: ; The compound shown in formula (I) is prepared by coupling reaction of the compound shown in formula (I-1) and the compound shown in formula (I-2); R 1 R 2 X 1 X 2 Z, W, Y 1 Y 2 and Y 3 It has the definition as described in this invention.

[0019] On the other hand, the present invention provides pharmaceutical compositions comprising any of the compounds described herein. For example, such pharmaceutical compositions may comprise any one of the compounds of the present invention and pharmaceutically acceptable carriers and / or excipients.

[0020] On the other hand, the present invention provides the use of the compound or pharmaceutical composition described herein in the preparation of a medicament for the prevention, protection or treatment of influenza viruses in animals or human individuals.

[0021] On the other hand, the present invention provides a method for inhibiting the replication of influenza virus in animals or human individuals, the method comprising the step of administering an effective amount of the compound or pharmaceutical composition of the present invention to the animal or human individual.

[0022] On the other hand, the present invention provides a method for reducing the amount of influenza virus in an animal or human individual, the method comprising administering an effective amount of the compound or pharmaceutical composition of the present invention to the animal or human individual.

[0023] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "optionally," whether or not preceding the term "substituted," indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structural formula is substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents described may be, but are not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, etc.

[0024] As used in this invention, the term "alkyl" or "alkyl group" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1-20 carbon atoms. The alkyl group may be optionally and independently substituted by one or more substituents. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms; in some embodiments, the alkyl group contains 1-10 carbon atoms; in other embodiments, the alkyl group contains 1-8 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in other embodiments, the alkyl group contains 1-4 carbon atoms; and in other embodiments, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, and so on. The term "alkyl" and its prefix "alkane" as used herein encompass both straight-chain and branched saturated carbon chains. "alkylene" refers to a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight-chain or branched saturated hydrocarbon. Examples of such groups include, but are not limited to, methylene, ethylene, isopropylene, ethane-1,1-diyl, 2-methoxypropane-1,1-diyl, 2-hydroxypropane-1,1-diyl, 2-methyl-2-hydroxypropane-1,1-diyl, etc.

[0025] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is an sp2 double bond, wherein the alkenyl group may be independently and optionally substituted by one or more substituents described in this invention, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0026] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group with 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents described in this invention, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), etc.

[0027] The term "alkoxy" indicates that an alkyl group is attached to the remainder of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-6 carbon atoms; in some embodiments, the alkoxy group contains 1-4 carbon atoms; and in other embodiments, the alkoxy group contains 1-3 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy, 2-methyl-1-butoxy, etc.

[0028] The terms “haloalkyl” and “haloalkoxy” indicate that an alkyl or alkoxy group is replaced by one or more halogen atoms. Examples of such replacements include, but are not limited to, trifluoromethyl, difluoromethyl, difluoroethyl, trifluoromethoxy, etc.

[0029] The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring, comprising a monocyclic ring of 3-12 carbon atoms or a bicyclic ring of 7-12 carbon atoms. A bicyclic ring with 7-12 atoms can be a bicyclic [4,5], [5,5], [5,6], or [6,6] system, while a bicyclic ring with 9 or 10 atoms can be a bicyclic [5,6] or [6,6] system. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of carbocyclic or cycloalkyl groups further include, but are by no means limited to, 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, and cyclododecyl. Spiro[2.4]heptyl, spiro[4.4]nonyl, hexahydro-furan[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, bicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,2,3,4,4a,5,8,8a-octahydronaphthalene, etc. Furthermore, the cyclic aliphatic group (or "carbocyclic", "carbocyclic", "cycloalkyl") can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, etc. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc.

[0030] The terms “heterocyclic,” “heterocyclic group,” “heterocyclic alicyclic group,” or “heterocyclic” are used interchangeably herein to refer to monocyclic, bicyclic, or tricyclic systems in which one or more atoms on the ring are independently and optionally substituted with heteroatoms. The ring may be fully saturated or contain one or more unsaturations, but is by no means aromatic, and has only one connection point to another molecule. One or more hydrogen atoms on the ring are independently and optionally substituted with one or more substituents described in this invention. Some embodiments of this are that the "heterocyclic," "heterocyclic group," "heterocyclic alicyclic," or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to obtain a group like SO, SO2, PO, PO2, or, when the ring is a three-membered ring, only one heteroatom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to obtain a group like SO, SO2, PO, PO2). The heterocyclic group can be carbon-based or heteroatom-based. "Heterocyclic group" also includes groups formed by the fusion of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiooxaneyl, piperazinyl, homopiperazinyl, azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, homopiperidinyl, epioxypropyl, azirroheptanyl, oxacycloheptanyl, thioheptanyl, oxazolophenyl, diazaphenyl, thioazolophenyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, and dihydrothiophenyl.

[0031] The terms “haloalkyl”, “haloalkenyl”, and “haloalkoxy” refer to alkyl groups, alkenyl groups, or alkoxy groups in which one or more halogen atoms can be substituted. Examples of such groups include, but are not limited to, trifluoromethyl, 2-chloro-vinyl, trifluoromethoxy, etc.

[0032] The term "halogen" refers to F, Cl, Br, or I.

[0033] The term "aryl" refers to a carbocyclic system containing 6-14 membered rings, including monocyclic, bicyclic, and tricyclic systems, wherein at least one ring system is aromatic, and each ring system contains 3-7 membered rings with only one attachment point connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring," as aromatic rings can include phenyl, naphthyl, and anthracene. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linker. Aryl groups can be substituted or unsubstituted.

[0034] The term "heteroaryl" can be used alone or as a part of "heteroarylalkyl" or "heteroarylalkoxy," referring to monocyclic, bicyclic, and tricyclic systems containing 5-14 membered rings, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 membered rings, and has only one attachment point connected to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocycle" or "heteroaromatic compound." Furthermore, the heteroaryl group can be substituted or unsubstituted.

[0035] The terms “comprising” and “including” are open-ended expressions, meaning they include the contents specified in this invention, but do not exclude other aspects.

[0036] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), are within the scope of this invention.

[0037] As used in this invention, the terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can cross low energy barriers and thus interconvert. For example, proton tautomers (i.e., proton shifts) include interconversions via proton migration, such as keto-enol tautomerization and imine-enamine isomerization. Valence tautomers include interconversions via some bonding electron rearrangement.

[0038] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: 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. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name the symbols for the plane polarization rotation of compounds. (-) or l indicates that the compound is levorotatory, while the prefix (+) or d indicates that the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity.

[0039] The terms "tautomer" or "tautomerism form" refer to isomers of different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions via proton transfer, such as isomerization between keto-enol and imine-enamine forms. Valence tautomers include interconversions involving the recombination of bonding electrons.

[0040] As used in this invention, "pharmaceutically acceptable salt" 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 SMBerge et al., J. Pharmaceutical Sciences, 66, 1-19, 1977. 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. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-p-gluconate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, p-pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and N+(C1-4 alkyl)4 salts. This invention also envisions the formation of quaternary ammonium salts from any compound containing an N-group. Water-soluble, oil-soluble, or dispersed products can be obtained via quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. 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, C1-8 sulfonates, and aromatic sulfonates.

[0041] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming 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 by solvent molecules that are water.

[0042] The elements involved in the structure of this invention include all their isotopes. Exemplary isotopes in the compounds of this invention include isotopes of hydrogen (H), carbon (C), nitrogen (N), oxygen (O), phosphorus (P), sulfur (S), fluorine (F), chlorine (Cl), and bromine (Br), such as... 2 H, 3H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F, 37 Cl, Br 81 That is, hydrogen (H) includes 1 H, 2 H, 3 H; Carbon (C) includes 12 C 13 C 14 C; Nitrogen (N) includes 14 N、 15 N; oxygen (O) includes 16 O、 17 O; Phosphorus (P) includes 30 P, 31 P, 32 P; Sulfur (S) includes 32 S, 33 S, 34 S, 36 S; Fluorine (F) includes 18 F, 17 F; Chlorine (Cl) includes 35 Cl、 37 Cl; Bromine (Br) includes Br 79 ,Br 81 .

[0043] The term "isotope-labeled compound" refers to compounds of the present invention labeled with isotopes. They are identical to those compounds described in the present invention except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those of naturally occurring common atoms. Exemplary isotopes may also be introduced in compounds of the present invention, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0044] Compounds of the present invention containing the aforementioned isotopic label and / or other isotopic labels, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this invention. Isotopically labeled compounds of the present invention, such as radioisotope-labeled compounds, are also included. 3 H and 14 The incorporation of tritium into the compounds of this invention can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds, i.e., 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. Additionally, isotopes with higher mass numbers, such as deuterium, are used. 2 H substitution can offer therapeutic advantages such as greater metabolic stability, including increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some situations. Attached Figure Description

[0045] Figure 1 The graph shows the weight change of the BALB / c mouse model in the in vivo experiment of compound 12 in Example 4.

[0046] Figure 2 The graph shows the survival rate changes of the BALB / c mouse model in the in vivo experiment of compound 12 in Example 4.

[0047] Figure 3 The graph shows the weight change of the BALB / c mouse model in the in vivo experiment of compound 33 in Example 4.

[0048] Figure 4 The graph shows the survival rate changes of the BALB / c mouse model in the in vivo experiment of compound 33 in Example 4.

[0049] Figure 5 The image shows the H1N1 copy number in lung tissue of a BALB / c mouse model in in vivo experiments using compound 33 from Example 4. The H1N1 copy number in lung tissue was detected using RT-qPCR, and the titer of H1N1 virus in lung tissue was assessed using plaque assay.

[0050] Figure 6 To demonstrate the efficacy of compound 33 in in vivo experiments in Example 4, RT-qPCR was used to measure the levels of inflammatory and anti-inflammatory cytokines. These inflammatory and anti-inflammatory cytokines included IFN-β, TGF-β, IP-10, IL-6, IL-10, TNF-α, IL-1β, and CCL5.

[0051] Figure 7To demonstrate the efficacy of compound 33 in vivo in Example 4, ELISA was used to measure the levels of inflammatory and anti-inflammatory cytokines. These inflammatory and anti-inflammatory cytokines included IFN-γ, IL-6, IL-10, IL-4, IL-13, TNF-α, and IL-1β. Detailed Implementation

[0052] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0053] One preparation process of the compound of the present invention is as follows: Method 1:

[0054] The compound shown in formula (I) is prepared by coupling reaction of the compound shown in formula (I-1) and the compound shown in formula (I-2); R 1 R 2 X 1 X 2 Z, W, Y 1 Y 2 and Y 3 It has the definition as described in this invention.

[0055] Example 1

[0056] Step 1: Synthesis of compound A-2 Compound A-1 (15.2 g, 0.1 mol) was dissolved in tribromomethane (50 mL) at room temperature, and tert-butyl nitrite (20.6 g, 0.2 mol) was added in portions. The reaction was carried out at 80 °C. o The mixture was stirred at C for 2 h, and TLC was used to confirm that the reaction of the starting material was complete. The reaction temperature was lowered to room temperature, and tribromomethane was removed by vacuum distillation. After adding petroleum ether (50 mL) and ethyl acetate (50 mL), a large amount of solid precipitated. The solid was filtered, and the filter cake was washed three times with ethyl acetate (10 mL × 3). The solid was dried under vacuum to obtain a pale yellow solid A-2 (15.1 g, yield 70%).

[0057] Step 2: Synthesis of compound A-3 Compound A-2 (15.1 g, 0.07 mol) was dissolved in anhydrous DMF (70 mL), and 60% NaH (2.8 g, 0.07 mol) was added in portions under ice bath conditions. The reaction was carried out at 0°C. oAfter stirring at C for 30 min, TrtCl (triphenylmethyl chloride) (22.3 g, 0.08 mol) was added in batches, and the temperature was slowly increased to 55°C. o C. After stirring for 12 h, TLC was used to determine if the reaction of the starting material was complete. The reaction solution was slowly poured into water (50 mL), stirred at room temperature for 1 h, diluted with ethyl acetate (100 mL), washed three times with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 80:1 to 20:1) to give a white solid A-3 (18.3 g, yield 57%).

[0058] Step 3: Synthesis of compound A-4 At room temperature, potassium acetate (11.8 g, 0.12 mol) and DPPF palladium dichloride (1.46 g, 2.0 mmol) were added to a 1,4-dioxane (80 mL) solution of compound A-3 (18.3 g, 0.04 mol) and bis(pinacol) borate (15.2 g, 0.06 mol). The mixture was then incubated at 100 mL under argon protection. o Stir at C for 12 h. Cool the reaction solution to room temperature, filter the crude product through diatomaceous earth, dilute the filtrate with ethyl acetate (150 mL), wash the organic phase twice with saturated brine (50 mL × 2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 40:1 to 10:1) to give a white solid A-4 (15.2 g, yield 75%).

[0059] Example 2

[0060] Step 1: Synthesis of compound B-2 Compound B-1 (3.3 g, 0.02 mol) was dissolved in acetonitrile (50 mL) and water (50 mL) at room temperature, followed by the addition of silver nitrate (3.4 g, 0.02 mol) and cyclopropylformic acid (5.2 g, 0.06 mmol). The reaction solution was then heated to 80 °C. o C, then add dropwise a solution of ammonium persulfate (9.1 g, 0.04 mmol) in 20 mL of water, bringing the reaction solution to 80°C. oStir for 12 hours. Cool the reaction mixture to room temperature and extract three times with ethyl acetate (40 mL × 3). Wash the organic phase with water (30 mL × 3) and brine (30 mL), respectively. Dry the phase with sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 100:1 to 80:1) to give a white solid B-2 (2.0 g, yield 50%).

[0061] Step 2: Synthesis of compound B-3 Compound B-2 (2.0 g, 0.01 mol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and (2... S ,3 S 3-Aminobicyclo[2.2.2]octane-2-carboxylic acid ethyl ester hydrochloride (3.5 g, 0.015 mol) and DIPEA (3.9 g, 0.03 mol), the reaction was carried out at 55 o The mixture was stirred at C for 3 h, and TLC was used to determine if the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (V(petroleum ether):V(ethyl acetate) = 20:1 to 8:1) to give a white solid B-3 (3.4 g, yield 93%).

[0062] Example 3

[0063] Step 1: Synthesis of compound C-2 Compound C-1 (3.0 g, 0.02 mol) was dissolved in acetonitrile (50 mL) and water (50 mL) at room temperature, followed by the addition of silver nitrate (3.4 g, 0.02 mol) and cyclopropylformic acid (5.2 g, 0.06 mmol), respectively. The reaction solution was then heated to 80 °C. o C, then add dropwise a 20 mL solution of ammonium persulfate (9.1 g, 0.04 mmol) in water, and the reaction solution is at 80°C. oStir for 12 hours. Cool the reaction mixture to room temperature and extract three times with ethyl acetate (40 mL × 3). Wash the organic phase with water (30 mL × 3) and brine (30 mL), respectively. Dry the phase with sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (V(petroleum ether):V(ethyl acetate) = 100:1 to 90:1) to give white solid C-2 (2.8 g, yield 75%).

[0064] Step 2: Synthesis of compound C-3 Compound C-2 (2.8 g, 0.015 mol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and (2... S ,3 S 3-Aminobicyclo[2.2.2]octane-2-carboxylic acid ethyl ester hydrochloride (4.7 g, 0.02 mol) and DIPEA (3.9 g, 0.03 mol), the reaction was carried out at 55 o The mixture was stirred at C for 3 h, and TLC was used to determine if the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (30 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 20:1 to 8:1) to give a white solid C-3 (3.5 g, yield 67%).

[0065] Step 3: Synthesis of compound C-4 Compounds C-3 (3.5 g, 10 mmol) and A-4 (7.6 g, 15.0 mmol) were dissolved in 2-methyltetrahydrofuran (40.0 mL) and water (8.0 mL) at room temperature. Potassium phosphate (6.4 g, 30.0 mmol), X-Phos (477 mg, 1.0 mmol), and Pd2(dba)3 (458 mg, 0.5 mmol) were added, respectively. The mixture was then incubated at 80 °C under argon protection. o Stir at C for 12 h. Cool the reaction solution to room temperature and extract three times with ethyl acetate (50 mL × 3). Combine the organic phases and wash three times with saturated brine (50 mL × 3). Dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 10:1 to 5:1) to give white solid C-4 (5.9 g, yield 85%).

[0066] Step 4: Synthesis of compound C-5 Compound C-4 (5.9 g, 8.5 mmol) was dissolved in dichloromethane (40.0 mL) at room temperature, and trifluoroacetic acid (969 mg, 8.5 mmol) and triethylchlorosilane (1.3 g, 8.5 mmol) were added dropwise. The reaction was stirred at room temperature for 4 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 8 with saturated sodium carbonate solution, and the mixture was extracted three times with dichloromethane (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (V(petroleum ether):V(ethyl acetate) = 5:1 to 2:1) to give a white solid C-5 (2.9 g, yield 76%).

[0067] Step 4: Synthesis of Compound 1 Compound C-5 (2.9 g, 6.5 mmol) was dissolved in ethanol (20.0 mL) and water (5.0 mL) at room temperature, and 5 M sodium hydroxide aqueous solution (5.0 mL) was added. The reaction was carried out at 80 °C. o After stirring at C for 1 h, the reaction of the starting material was confirmed by TLC to be complete. The mixture was cooled to room temperature, and the pH was adjusted to 5 with 5M hydrochloric acid. The mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phases were dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and a large amount of solid was precipitated after the addition of petroleum ether (30 mL) and ethyl acetate (10 mL). The solid was filtered, and the filter cake was washed three times with ethyl acetate (5 mL × 3). The solid was dried under vacuum to give compound 1 (1.5 g, yield 54%) as a white solid. 1 H NMR (400 MHz, MeOD) δ 8.62 (s, 1H),8.49 (s, 1H), 6.32 (s, 1H), 2.50 – 2.30 (m, 1H), 2.13 – 2.02 (m, 1H), 1.87 –1.74 (m, 3H), 1.68 – 1.55 (m, 2H), 1.53 – 1.26 (m, 4H), 1.15 – 0.95 (m, 4H). 13 C NMR (151 MHz, DMSO- d 6) δ 178.84, 167.59, 162.34, 159.68, 155.61 (d, J =243.6 Hz), 150.80, 142.31, 139.11 (d, J= 30.5 Hz), 116.71, 114.12, 101.38, 51.00, 50.59, 28.78, 28.68, 26.16, 24.16, 21.63, 19.57, 16.73, 9.09. Example 4

[0068] The difference from Example 3 is that cyclopropylformic acid was replaced with cyclobutylformic acid, and the rest of the steps were the same as in Example 3, to obtain white solid compound 2 (1.6 g, yield 65%). 1 H NMR (600 MHz, MeOD) δ 8.39 (s,1H), 8.30 (s, 1H), 6.42 (s, 1H), 3.55 – 3.48 (m, 1H), 2.55 (d, J = 6.7 Hz, 1H),2.35 – 2.27 (m, 2H), 2.22 – 2.12 (m, 2H), 2.07 – 1.97 (m, 2H), 1.84 (t, J = 9.8Hz, 2H), 1.73 (q, J = 12.8 Hz, 3H), 1.66 – 1.54 (m, 3H), 1.50 – 1.39 (m, 2H). 13 CNMR (151 MHz, MeOD) δ 176.63, 162.83, 159.31 (d, J = 1138.1 Hz), 156.99,155.35, 150.01, 139.64 (d, J = 30.8 Hz), 137.44, 115.69, 113.92 (d, J = 8.2 Hz),100.08, 51.36, 49.56, 37.90, 28.95, 28.73, 27.08, 26.91, 25.40, 23.91, 20.75,18.92, 17.68. Example 5

[0069] The difference from Example 3 is that cyclopropylformic acid was replaced with isobutyric acid, and the rest of the steps were the same as in Example 3, resulting in white solid compound 3 (1.6 g, yield 78%). 1H NMR (600 MHz, MeOD) δ 8.61 (s, 1H), 8.56 (s, 1H), 6.49 (s, 1H), 4.99 (s, 1H), 3.10 – 3.01 (m, 1H), 2.60 (d, J = 6.4 Hz,1H), 2.18 – 2.11 (m, 1H), 1.99 – 1.79 (m, 4H), 1.76 – 1.66 (m, 3H), 1.55 (t, J = 11.6 Hz, 2H), 1.35 (d, J = 6.9 Hz, 6H). 13 C NMR (151 MHz, MeOD) δ 176.02,163.51, 162.90, 156.42 (d, J = 248.1 Hz), 154.07, 149.92, 140.06 (d, J = 31.2Hz), 135.72, 115.22, 113.91, 99.71, 51.69, 48.99, 31.23, 29.05, 28.54, 25.22,23.94, 20.62, 20.06, 18.88. Example 6

[0070] The difference from Example 3 is that cyclopropylformic acid was replaced with cyclopentylformic acid, and the rest of the steps were the same as in Example 3, yielding white solid compound 4 (2.0 g, yield 67%). 1 H NMR (600 MHz, MeOD) δ 8.50 (s, 1H),8.37 (d, J = 8.1 Hz, 1H), 6.62 (s, 1H), 4.96 (d, J = 6.3 Hz, 1H), 3.19 – 3.13 (m,1H), 2.64 (d, J = 6.3 Hz, 1H), 2.16 – 2.08 (m, 2H), 2.06 (q, J = 2.7 Hz, 1H),1.88 (s, 1H), 1.83 – 1.73 (m, 5H), 1.72 – 1.66 (m, 5H), 1.64 – 1.56 (m, 2H),1.52 – 1.42 (m, 2H).13 C NMR (151 MHz, MeOD) δ 175.86, 162.89, 161.77, 156.53(d, J = 248.1 Hz), 154.02, 150.01, 140.17 (d, J = 30.9 Hz), 135.67, 115.32 (d, J =22.0 Hz), 114.01 (d, J = 8.2 Hz), 99.85, 51.68, 48.96, 42.17, 31.86, 29.12,28.56, 25.24, 24.85, 23.98, 20.64, 18.91. Example 7

[0071] The difference from Example 3 is that cyclopropylformic acid was replaced with difluoroacetic acid, and the rest of the steps were the same as in Example 3, yielding white solid compound 5 (1.7 g, yield 64%). 1 H NMR (600 MHz, MeOD) δ 8.48 (d, J = 8.4Hz, 1H), 8.36 (s, 1H), 6.58 (s, 1H), 6.46 (t, J = 55.2 Hz, 1H), 2.46 (d, J = 6.5Hz, 1H), 1.99 (d, J = 4.4 Hz, 1H), 1.93 – 1.85 (m, 1H), 1.84 – 1.75 (m, 1H), 1.68 (q, J = 14.5 Hz, 2H), 1.61 – 1.49 (m, 3H), 1.40 (q, J = 12.9 Hz, 2H). 13 C NMR (151 MHz, MeOD) δ 176.40, 162.95, 159.85, 156.72, 155.10, 139.05 (d, J = 31.0Hz), 116.59 (d, J= 20.8 Hz), 114.38, 113.97, 112.79, 111.20, 100.10, 50.50,49.61, 28.78, 28.56, 25.52, 23.76, 20.77, 18.88. Example 8

[0072] The difference from Example 3 is that cyclopropylformic acid was replaced with spiro[3.3]heptane-2-carboxylic acid, and the rest of the steps were the same as in Example 3, yielding white solid compound 6 (2.0 g, yield 76%). 1 H NMR (600 MHz, MeOD) δ 8.43(s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 3.44 – 3.35 (m, 1H), 2.65 (d, J = 6.2 Hz, 1H), 2.39 (dd, J = 11.5, 8.1 Hz, 2H), 2.20 – 2.03 (m, 5H), 1.91 –1.82 (m, 3H), 1.80 – 1.70 (m, 5H), 1.68 – 1.54 (m, 3H), 1.46 (q, J = 10.2 Hz, 2H). 13 C NMR (151 MHz, MeOD) δ 176.10, 162.78, 160.93, 156.38 (d, J = 248.0 Hz),154.22, 149.92, 140.03 (d, J = 31.0 Hz), 135.89, 115.25 (d, J = 22.0 Hz), 113.90(d, J = 8.4 Hz), 100.13, 51.61, 49.03, 39.77, 39.30, 39.22, 34.47, 33.84,31.66, 29.06, 28.61, 25.27, 23.97, 20.69, 18.93, 15.77. Example 9

[0073] The difference from Example 3 is that cyclopropylcarboxylic acid was replaced with 3,3-dimethylcyclobutanecarboxylic acid, and the rest of the steps were the same as in Example 3, yielding white solid compound 7 (1.9 g, yield 67%). 1 H NMR (600 MHz, MeOD) δ8.50 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 5.00 – 4.92 (m, 1H), 3.62 – 3.53 (m, 1H), 2.62 – 2.58 (m, 1H), 2.21 – 2.15 (m, 2H), 2.07 (q, J = 2.8 Hz, 1H), 1.97 (t, J = 10.2 Hz, 2H), 1.89 (s, 1H), 1.81 – 1.69 (m, 3H), 1.69 – 1.57(m, 3H), 1.48 (t, J = 11.0 Hz, 2H), 1.21 (s, 3H), 1.07 (s, 3H). 13 C NMR (151 MHz, MeOD) δ 175.86, 162.97, 161.48, 156.52 (d, J = 247.9 Hz), 154.35, 150.05,140.13 (d, J = 30.5 Hz), 135.99, 115.43 (d, J = 21.2 Hz), 114.08, 100.10, 51.60,49.08, 39.21, 39.14, 31.56, 30.18, 29.42, 29.11, 28.57, 26.75, 25.27, 23.96,20.63, 18.89. Example 10

[0074] The difference from Example 3 is that cyclopropylformic acid was replaced with tetrahydropyran-4-carboxylic acid, and the rest of the steps were the same as in Example 3, yielding white solid compound 8 (2.2 g, yield 75%). 1 H NMR (600 MHz, MeOD) δ 8.51(s, 1H), 8.32 (dd, J = 8.1, 2.7 Hz, 1H), 6.65 (s, 1H), 4.97 (d,J = 6.3 Hz, 1H), 4.03 – 3.94 (m, 2H), 3.54 – 3.46 (m, 2H), 3.08 – 3.02 (m, 1H), 2.69 (d, J = 6.3Hz, 1H), 2.07 (q, J = 2.8 Hz, 1H), 1.92 – 1.86 (m, 3H), 1.81 – 1.66 (m, 6H), 1.63 – 1.57 (m, 2H), 1.51 – 1.45 (m, 2H). 13 C NMR (151 MHz, MeOD) δ 175.79,162.89, 159.76, 156.56 (d, J = 248.6 Hz), 153.92, 149.96, 140.28 (d, J = 30.7Hz), 135.25 (d, J = 5.1 Hz), 115.13 (d, J = 21.9 Hz), 113.97 (d, J = 8.3 Hz),100.45, 66.95, 51.87, 48.79, 37.69, 30.75 (d, J = 11.6 Hz), 29.12, 28.53,25.21, 24.00, 20.65, 18.94. Example 11

[0075] The difference from Example 3 is that cyclopropylcarboxylic acid was replaced with 4,4-difluorocyclohexanecarboxylic acid, and the rest of the steps were the same as in Example 3, yielding white solid compound 9 (2.5 g, yield 75%). 1 H NMR (600 MHz, MeOD) δ 8.28(d, J = 2.8 Hz, 1H), 8.19 (s, 1H), 6.32 (s, 1H), 4.77 (s, 1H), 2.64 (t, J = 12.4Hz, 1H), 2.56 – 2.43 (m, 1H), 2.05 – 1.96 (m, 3H), 1.92 (d, J= 15.0 Hz, 2H),1.84 – 1.73 (m, 3H), 1.73 – 1.60 (m, 5H), 1.58 – 1.46 (m, 3H), 1.36 (q, J =13.0 Hz, 2H). 13 C NMR (151 MHz, MeOD) δ 176.54, 163.92, 162.74, 156.09, 156.04(d, J = 247.0 Hz), 150.02, 139.55 (d, J = 31.3 Hz), 138.01, 122.56 (t, J = 240.4Hz), 115.77, 113.85, 100.29, 51.18, 49.46, 40.30, 33.03 (t, J = 24.5 Hz), 28.79(d, J = 15.3 Hz), 27.88 – 27.50 (m), 27.44, 25.38, 23.88, 20.75, 18.91. Example 12

[0076] The difference from Example 3 is that compound C-2 was replaced with compound L-1, and the rest of the steps were the same as in Example 3, to obtain white solid compound 10 (1.8 g, yield 66%). 1 H NMR (600 MHz, MeOD) δ 8.80 – 8.56(m, 2H), 8.51 (s, 1H), 2.66 (d, J = 6.7 Hz, 1H), 2.07 (s, 1H), 1.81 (t, J = 11.8Hz, 3H), 1.67 – 1.63 (m, 2H), 1.53 – 1.47 (m, 2H), 1.32 – 1.25 (m, 2H). 13 C NMR (151 MHz, MeOD) δ 176.73 (d, J = 38.2 Hz), 160.50 (d, J = 594.8 Hz), 157.32 (d, J =29.6 Hz), 156.20 (d, J= 244.6 Hz), 149.42, 140.36 (d, J = 57.9 Hz), 138.69 (d, J =30.3 Hz), 129.44, 124.40 (q, J = 269.5 Hz), 116.88 (dd, J = 136.1, 22.1 Hz),114.65, 109.45 (d, J = 45.4 Hz), 51.06, 49.34, 29.16, 28.85 (d, J = 18.9 Hz), 25.50 (d, J = 7.2 Hz), 23.72 (d, J = 25.1 Hz), 20.84, 18.97. Example 13

[0077] The difference from Example 3 is that compound C-1 was replaced with compound L-1, and the rest of the steps were the same as in Example 3, yielding white solid compound 11 (1.9 g, yield 67%). 1 H NMR (400 MHz, MeOD) δ 8.50 (t, J =2.2 Hz, 1H), 8.19 (d, J = 11.3 Hz, 1H), 4.51 (s, 1H), 2.56 (dd, J = 6.8, 2.1 Hz, 1H), 2.31 (d, J = 8.1 Hz, 1H), 2.36 – 2.25 (m, 1H), 1.88 – 1.79 (m, 2H), 1.80 –1.70 (m, 1H), 1.68 – 1.57 (m, 3H), 1.51 – 1.42 (m, 2H), 1.33 – 1.26 (m, 3H),1.12 – 1.03 (m, 2H). 13 C NMR (151 MHz, MeOD) δ 176.71, 173.27 (d, J = 101.0 Hz),161.19, 157.58, 155.84 (d, J = 245.2 Hz), 149.13, 142.34 (d, J= 46.9 Hz), 138.87(d, J = 30.9 Hz), 125.41 (q, J = 271.2 Hz), 115.24 (dd, J = 40.0, 22.1 Hz), 114.06(d, J = 45.9 Hz), 110.68 – 109.20 (m), 50.86, 49.51, 28.80, 25.48, 23.76,20.77, 18.86, 14.69 (d, J = 41.8 Hz), 10.97 (d, J = 58.0 Hz), 10.45 (d, J = 45.9Hz). Example 14

[0078] The difference from Example 3 is that compound C-1 was replaced with compound O-1, and the rest of the steps were the same as in Example 3, yielding white solid compound 13 (1.9 g, yield 67%). 1 H NMR (600 MHz, MeOD) δ 8.55 (dd, J =12.3, 2.9 Hz, 2H), 5.07 (d, J = 6.3 Hz, 1H), 2.67 (d, J = 6.4 Hz, 1H), 2.35 –2.28 (m, 1H), 2.10 (q, J = 2.9 Hz, 1H), 1.99 (q, J = 2.7 Hz, 1H), 1.95 – 1.86 (m,1H), 1.82 – 1.63 (m, 5H), 1.57 – 1.50 (m, 2H), 1.49 – 1.40 (m, 2H), 1.09 (dd, J = 8.0, 3.5 Hz, 2H). 13 C NMR (151 MHz, MeOD) δ 176.72, 170.32, 159.20, 157.98,156.59, 154.96, 150.81, 139.62 (d, J = 31.1 Hz), 125.97 (q, J= 272.5 Hz), 116.02(d, J = 21.5 Hz), 113.71 (d, J = 8.0 Hz), 102.19 (q, J = 30.7 Hz), 50.98, 50.02,28.72, 28.58, 25.36, 23.70, 20.72, 18.99, 14.22 (d, J = 4.9 Hz), 10.23 (d, J =9.5 Hz). Example 15

[0079] Compound P-1 (4.4 g, 10 mmol) was dissolved in dichloromethane (40 mL) at room temperature, and oxalyl chloride (1.3 g, 10 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 1 hour, and the reaction was confirmed to be complete by TLC. The crude product P-2 (4.6 g, 10 mmol) was obtained by concentration under reduced pressure.

[0080] Example 16

[0081] Compound P-2 (459 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL). o When cyanamide (84 mg, 2.0 mmol) and triethylamine (304 mg, 3.0 mmol) are added at temperature C, the reaction proceeds at 0°C. o After stirring at C for 1 h, the reaction mixture was determined to be complete by TLC. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined and washed three times with saturated brine (10 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (V(dichloromethane):V(methanol = 30:1 to 15:1) to give a white solid compound 14 (325 mg, yield 70%). 1 H NMR (600 MHz, DMSO- d 6) δ 14.11 (s, 1H), 11.86 (s, 1H), 8.65 (d, J = 3.2 Hz, 1H), 8.52 – 8.34 (m, 1H), 7.73 – 7.51 (m, 1H), 4.82 (t, J=7.1 Hz, 1H), 3.08 – 2.84 (m, 1H), 2.35 – 2.25 (m, 1H), 1.98 (d, J = 26.2 Hz,2H), 1.90 – 1.70 (m, 3H), 1.66 – 1.34 (m, 5H), 1.25 – 1.03 (m, 4H). 13 C NMR (151 MHz, DMSO-) d 6) δ 175.09, 156.50, 154.89, 152.62 (d, J = 723.8 Hz), 151.96(d, J = 10.3 Hz), 151.23 (d, J = 12.2 Hz), 143.97, 142.28, 140.57 (d, J = 465.3Hz), 116.36, 113.97, 108.89, 49.35, 46.18, 29.52, 28.68, 25.53, 24.12, 20.89,19.31, 9.84, 9.10 (d, J = 10.6 Hz). Example 17

[0082] Step 1: Synthesis of Compound 15 Compound P-2 (459 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL). o When tert-butylamine (146 mg, 2.0 mmol) and triethylamine (304 mg, 3.0 mmol) are added at temperature C, the reaction proceeds at 0°C. o After stirring at C for 1 h, the reaction mixture was determined to be complete by TLC. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined and washed three times with saturated brine (10 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (V(dichloromethane):V(methanol) = 40:1 to 12:1) to give a white solid compound 15 (372 mg, yield 75%). 1 H NMR (600 MHz, DMSO- d 6) δ 14.08 (s, 1H), 8.63 (s, 1H), 8.51 (d, J= 8.7 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.32 (s, 1H), 4.85 (t, J = 6.9Hz, 1H), 2.61 (d, J = 6.7 Hz, 1H), 2.32 – 2.22 (m, 1H), 1.90 (d, J = 12.4 Hz,2H), 1.84 – 1.72 (m, 3H), 1.65 – 1.60 (m, 1H), 1.59 – 1.50 (m, 1H), 1.49 –1.40 (m, 1H), 1.39 – 1.30 (m, 2H), 1.24 (s, 9H), 1.14 (s, 2H), 1.07 (d, J = 8.2Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 173.08, 155.71 (d, J = 243.5 Hz), 155.13,151.69, 151.35 (d, J = 11.7 Hz), 150.18, 143.93, 142.26, 138.92 (d, J = 30.2 Hz), 116.63 (d, J = 20.9 Hz), 114.08 (d, J = 7.6 Hz), 50.45, 49.67, 49.13, 30.27,29.05, 28.96, 25.92, 24.38, 21.11, 19.62, 9.83, 8.97 (d, J = 10.2 Hz). Example 18

[0083] The difference from Example 17 is that tert-butylamine was replaced with O-ethylhydroxylamine, and the rest of the steps were the same as in Example 17, yielding a white solid compound 16 (300 mg, yield 62%). 1 H NMR (600 MHz, MeOD) δ 8.44(s, 1H), 8.33 (s, 1H), 4.88 (s, 1H), 3.87 (q, J= 8.5 Hz, 2H), 2.53 (s, 1H), 2.25 – 2.13 (m, 1H), 1.99 – 1.82 (m, 3H), 1.83 – 1.52 (m, 4H), 1.51 – 1.40(m, 2H), 1.24 (dd, J = 18.2, 9.9 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H), 1.02 (dd, J =8.0, 3.0 Hz, 2H). 13 C NMR (151 MHz, MeOD) δ 172.63, 156.83, 156.38, 154.75,152.12 (d, J = 10.7 Hz), 151.04 (d, J = 11.8 Hz), 143.72, 142.03, 138.95, 116.45,113.44, 71.73, 71.36, 49.58, 30.28, 29.25, 25.84, 24.11, 20.67, 19.03, 12.41(d, J = 4.2 Hz), 9.12, 8.17 (d, J = 13.7 Hz). Example 19

[0084] Step 1: The difference from Example 17 is that tert-butylamine is replaced with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, and the rest of the steps are the same as in Example 17, yielding a white solid Q-1 (415 mg, yield 77%).

[0085] Step 2: Synthesis of Compound 17 Compound Q-1 (415 mg, 0.77 mmol) was dissolved in methanol (5 mL), and p-toluenesulfonic acid (172 mg, 1.0 mmol) was added at room temperature. The reaction was stirred at room temperature for 12 h, and TLC analysis showed that the starting material had reacted completely. Methanol was removed by concentration under reduced pressure, and water (10 mL) was added to the reaction system. The mixture was extracted three times with ethyl acetate (15 mL × 3), and the organic phases were combined and washed three times with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (V(dichloromethane):V(methanol = 30:1 to 15:1) to give a white solid compound 17 (255 mg, 0.56 mmol, yield 73%). 1 H NMR (600 MHz, MeOD) δ 8.50 – 8.30 (m, 2H), 2.51 (s,1H), 2.21 (d, J = 8.2 Hz, 1H), 1.97 (d, J = 8.6 Hz, 2H), 1.92 – 1.72 (m, 4H), 1.67 – 1.54 (m, 2H), 1.55 – 1.40 (m, 2H), 1.22 (s, 2H), 1.03 (d, J = 8.4 Hz, 2H). 13 C NMR (151 MHz, MeOD) δ 172.74, 156.49, 154.86, 152.19 (d, J = 10.7 Hz), 151.99 (d, J = 650.1 Hz), 151.19 (d, J = 11.8 Hz), 143.83, 142.15, 139.01,116.61, 113.59, 67.46, 49.76, 30.20, 29.40, 25.90, 24.10, 20.71, 18.99, 9.05,7.96. Example 20

[0086] Step 1: Synthesis of compound R-2 Compound R-1 (13.9 g, 0.07 mol) was dissolved in anhydrous DMF (70 mL), and 60% NaH (2.8 g, 0.07 mol) was added in portions under ice bath conditions. The reaction was carried out at 0°C. oAfter stirring at C for 30 min, TrtCl (22.3 g, 0.08 mol) was added in batches and the temperature was slowly increased to 55°C. o C. After stirring for 12 h, TLC was used to determine if the reaction of the starting material was complete. The reaction solution was slowly poured into water (100 mL), stirred at room temperature for 1 h, diluted with ethyl acetate (100 mL), washed three times with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 80:1 to 50:1) to obtain a white solid R-2 (17.6 g, yield 57%).

[0087] Step 2: Synthesis of compound R-3 At room temperature, potassium acetate (11.8 g, 0.12 mol) and DPPF palladium dichloride (1.46 g, 2.0 mmol) were added to a 1,4-dioxane (80 mL) solution of compound R-2 (17.6 g, 0.04 mol) and bis(pinacol) borate (15.2 g, 0.06 mol). The mixture was then incubated at 100 mL under argon protection. o Stir at C for 12 h. Cool the reaction solution to room temperature, filter the crude product through diatomaceous earth, dilute the filtrate with ethyl acetate (150 mL), wash the organic phase twice with saturated brine (50 mL × 2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 60:1 to 20:1) to give a white solid R-3 (14.6 g, yield 75%).

[0088] Step 3: Synthesis of compound R-4 Compounds B-3 (3.7 g, 10 mmol) and R-3 (7.3 g, 15.0 mmol) were dissolved in 2-methyltetrahydrofuran (40.0 mL) and water (8.0 mL) at room temperature. Potassium phosphate (6.4 g, 30.0 mmol), X-Phos (477 mg, 1.0 mmol), and Pd2(dba)3 (458 mg, 0.5 mmol) were added, respectively. The mixture was then incubated at 80 °C under argon protection. oStirred at C for 12 h. The reaction solution was cooled to room temperature and extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined and washed three times with saturated brine (50 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 10:1 to 5:1) to give a white solid R-4 (5.9 g, yield 85%).

[0089] Step 4: Synthesis of compound R-5 Compound R-4 (5.9 g, 8.5 mmol) was dissolved in dichloromethane (40.0 mL) at room temperature, and trifluoroacetic acid (969 mg, 8.5 mmol) and triethylchlorosilane (1.3 g, 8.5 mmol) were added dropwise. The reaction was stirred at room temperature for 4 h, and TLC analysis showed that the starting material was completely reacted. The pH was adjusted to 8 with saturated sodium carbonate solution, and the mixture was extracted three times with dichloromethane (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (V(petroleum ether):V(ethyl acetate) = 5:1 to 2:1) to give a white solid R-5 (2.1 g, yield 55%).

[0090] Step 5: Synthesis of Compound 18 Compound R-5 (2.1 g, 4.7 mmol) was dissolved in ethanol (20.0 mL) and water (5.0 mL) at room temperature, and 5 M sodium hydroxide aqueous solution (5.0 mL) was added. The reaction was carried out at 80 °C. o After stirring at C for 1 h, the reaction of the starting material was confirmed by TLC to be complete. The mixture was cooled to room temperature, and the pH was adjusted to 5 with 5M hydrochloric acid. The mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and a large amount of solid was precipitated after the addition of petroleum ether (30.0 mL) and ethyl acetate (10.0 mL). The solid was filtered, and the filter cake was washed three times with ethyl acetate (5 mL × 3). The solid was dried under vacuum to give compound 18 (1.4 g, yield 72%) as a white solid. 1 H NMR (600 MHz, DMSO- d 6) δ 12.97 (s, 2H), 8.69 (d, J = 8.2 Hz, 1H), 8.51 (d, J = 4.3 Hz, 1H), 7.47 (d, J= 7.4 Hz, 1H), 7.24 (dd, J = 8.0, 4.4 Hz, 1H), 4.69 (t, J = 8.1 Hz, 1H), 2.87 (d, J = 8.1 Hz,1H), 2.25 – 2.15 (m, 1H), 1.97 (d, J = 4.8 Hz, 1H), 1.89 (s, 1H), 1.74 – 1.62(m, 3H), 1.55 – 1.45 (m, 2H), 1.44 – 1.31 (m, 2H), 1.30 – 1.21 (m, 1H), 1.11(d, J = 4.8 Hz, 2H), 0.99 (d, J = 8.4 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 176.06,155.38 (d, J = 8.5 Hz), 153.30, 151.65 (d, J = 10.1 Hz), 151.30 (d, J = 11.6 Hz), 149.21, 143.14 (d, J = 254.6 Hz), 141.92, 132.26, 118.03, 114.21, 50.80, 47.92,28.90, 28.79, 25.69, 24.19, 21.59, 19.36, 9.81, 8.98 (d, J = 13.5 Hz). Example 21

[0091] The difference from Example 20 is that compound R-1 was replaced with compound S-1, and the rest of the steps were the same as in Example 20, yielding white solid compound 19 (1.7 g, yield 73%). 1 H NMR (600 MHz, DMSO- d 6) δ 14.25 (s,1H), 12.45 (s, 1H), 9.76 (s, 1H), 9.07 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H), 4.77(t, J= 7.6 Hz, 1H), 2.95 (d, J = 7.1 Hz, 1H), 2.35 – 2.30 (m, 1H), 2.06 (s, 1H), 1.97 – 1.93 (m, 1H), 1.83 – 1.72 (m, 3H), 1.63 – 1.45 (m, 4H), 1.43 – 1.35(m, 1H), 1.22 – 1.18 (m, 2H), 1.14 – 1.07 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ176.02, 155.38, 155.20, 154.70, 154.36, 151.86, 151.39 (d, J = 12.0 Hz), 143.36(d, J = 255.3 Hz), 143.14, 113.00, 50.85, 47.86, 28.86, 28.77, 25.68, 24.25,21.55, 19.39, 9.80, 9.11 (d, J = 14.7 Hz). Example 22

[0092] The difference from Example 20 is that compound R-1 was replaced with compound T-1, and the rest of the steps were the same as in Example 20, to obtain white solid compound 20 (2.2 g, yield 63%). 1 H NMR (600 MHz, MeOD) δ 9.24 (s,1H), 8.81 (s, 1H), 4.96 (s, 1H), 2.77 (d, J = 7.2 Hz, 1H), 2.31 – 2.23 (m, 1H), 2.15 – 2.08 (m, 1H), 1.93 – 1.81 (m, 4H), 1.76 – 1.68 (m, 1H), 1.65 – 1.58(m, 2H), 1.49 (dt, J = 23.1, 11.2 Hz, 2H), 1.30 – 1.27 (m, 2H), 1.08 – 1.00 (m, 2H). 13 C NMR (151 MHz, MeOD) δ 176.61, 153.87, 152.24 (d, J= 11.4 Hz), 151.41(d, J = 12.1 Hz), 145.99 – 145.45 (m), 144.10, 142.41, 131.16 (d, J = 4.2 Hz),125.36, 123.56, 120.47 (q, J = 32.5 Hz), 112.56, 50.50, 48.96, 29.27, 28.89,25.43, 23.77, 20.88, 18.93, 9.11, 7.83 (d, J = 14.0 Hz). Example 23

[0093] The difference from Example 20 is that compound R-1 was replaced with compound U-1, and the rest of the steps were the same as in Example 20, to obtain white solid compound 21 (1.3 g, yield 60%). 1 H NMR (600 MHz, DMSO- d 6) δ 9.15 (s,1H), 8.36 – 8.17 (m, 2H), 7.35 (d, J = 7.0 Hz, 1H), 4.81 (t, J = 7.0 Hz, 1H), 2.69 (d, J = 6.8 Hz, 1H), 2.29 – 2.19 (m, 1H), 2.07 – 2.02 (m, 1H), 1.95 – 1.90(m, 1H), 1.85 – 1.60 (m, 4H), 1.59 – 1.51 (m, 1H), 1.50 – 1.42 (m, 1H), 1.40– 1.27 (m, 2H), 1.15 (s, 2H), 1.09 – 0.99 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ177.83, 155.16 (d, J = 8.5 Hz), 151.46 (d, J = 11.8 Hz), 151.23, 142.96 (d, J=254.4 Hz), 141.65, 139.73, 139.21, 137.07, 125.26, 116.73, 51.90, 50.06,29.11, 29.01, 26.18, 24.49, 21.97, 19.74, 9.80, 8.90 (d, J = 9.7 Hz). Example 24

[0094] The difference from Example 20 is that compound R-1 was replaced with compound V-1, and the rest of the steps were the same as in Example 20, to obtain white solid compound 22 (1.7 g, yield 69%). 1 H NMR (600 MHz, MeOD) δ 8.40 (d, J =2.6 Hz, 1H), 8.33 (s, 1H), 8.19 (d, J = 2.6 Hz, 1H), 4.69 – 4.64 (m, 1H), 2.64(d, J = 6.4 Hz, 1H), 2.19 – 2.11 (m, 1H), 2.07 – 2.03 (m, 1H), 1.96 (q, J = 3.0Hz, 1H), 1.88 – 1.80 (m, 2H), 1.79 – 1.68 (m, 2H), 1.66 – 1.56 (m, 2H), 1.49 – 1.42 (m, 2H), 1.26 – 1.23 (m, 2H), 1.01 (dd, J = 8.2, 2.8 Hz, 2H). 13 C NMR (151MHz, MeOD) δ 177.69, 155.04 (d, J = 8.2 Hz), 151.30 (d, J = 11.5 Hz), 142.76,142.07, 141.10, 138.49, 136.86, 136.61, 133.66, 112.75, 51.17, 50.11, 28.96,28.71, 25.64, 23.83, 20.91, 18.93, 9.09, 7.57 (d, J = 6.4 Hz). Example 25

[0095] The difference from Example 20 is that compound R-1 was replaced with compound W-1, and the rest of the steps were the same as in Example 20, yielding white solid compound 23 (1.3 g, yield 70%). 1 H NMR (600 MHz, DMSO- d 6) δ 12.48 (s,1H), 12.30 (s, 1H), 9.62 (s, 1H), 8.85 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.40(d, J = 6.9 Hz, 1H), 4.67 (t, J = 7.0 Hz, 1H), 2.86 (d, J = 6.8 Hz, 1H), 2.30 –2.21 (m, 1H), 2.02 (d, J = 4.7 Hz, 1H), 1.95 (s, 1H), 1.85 – 1.70 (m, 3H), 1.66 – 1.49 (m, 3H), 1.48 – 1.41 (m, 1H), 1.38 (q, J = 9.3 Hz, 1H), 1.21 – 1.12 (m,2H), 1.07 (dd, J = 8.5, 3.9 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 176.11, 156.76(d, J = 8.4 Hz), 152.47, 151.78, 151.27 (d, J = 10.2 Hz), 151.09 (d, J = 11.9 Hz), 150.88, 142.38 (d, J = 251.8 Hz), 129.14, 116.95, 114.82, 50.82, 48.28, 28.80,28.71, 25.78, 24.29, 21.53, 19.42, 9.64, 8.88 (d, J = 12.1 Hz). Example 26

[0096] Step 1: Synthesis of compound X-2 At room temperature, potassium acetate (11.8 g, 0.12 mol) and DPPF palladium dichloride (1.46 g, 2.0 mmol) were added to a 1,4-dioxane (80 mL) solution of compound X-1 (8.4 g, 0.04 mol) and bis(pinacol) borate (15.2 g, 0.06 mol). The mixture was then incubated at 100 mL under argon protection. o Stirring at C for 12 h. The reaction solution was cooled to room temperature, and the crude product was filtered through diatomaceous earth. The filtrate was diluted with ethyl acetate (150 mL), and the organic phase was washed twice with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 40:1 to 8:1) to give a white solid X-2 (7.7 g, yield 75%).

[0097] Step 2: Synthesis of compound X-3 Compounds B-3 (3.7 g, 10 mmol) and X-2 (3.9 g, 15.0 mmol) were dissolved in 2-methyltetrahydrofuran (40.0 mL) and water (8.0 mL) at room temperature. Potassium phosphate (6.4 g, 30.0 mmol), X-Phos (477 mg, 1.0 mmol), and Pd2(dba)3 (458 mg, 0.5 mmol) were added, respectively. The mixture was then incubated at 80 °C under argon protection. o Stirred at C for 12 h. The reaction solution was cooled to room temperature and extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined and washed three times with saturated brine (50 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 15:1 to 3:1) to give a white solid X-3 (3.9 g, yield 85%).

[0098] Step 3: Synthesis of Compound 24 Compound X-3 (3.9 g, 8.5 mmol) was dissolved in ethanol (20.0 mL) and water (5.0 mL) at room temperature, and 5 M sodium hydroxide aqueous solution (5.0 mL) was added. The reaction was carried out at 80 °C. oAfter stirring at C for 1 h, the reaction of the starting material was confirmed by TLC to be complete. The mixture was cooled to room temperature, and the pH was adjusted to 5 with 5M hydrochloric acid. The mixture was extracted three times with ethyl acetate (20 mL × 3). The organic phases were combined and washed three times with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and a large amount of solid was precipitated after the addition of petroleum ether (30.0 mL) and ethyl acetate (10.0 mL). The solid was filtered, and the filter cake was washed three times with ethyl acetate (5 mL × 3). The solid was dried under vacuum to give compound 24 (1.6 g, yield 44%) as a white solid. 1 H NMR (600 MHz, DMSO- d 6) δ 12.34 (s, 1H), 9.87 (d, J = 2.2 Hz, 1H), 9.16 (d, J = 2.2 Hz, 1H), 9.11 (d, J = 1.8 Hz, 1H), 9.02 (d, J = 3.0 Hz, 1H), 7.74 – 7.65 (m, 1H), 4.76 – 4.68 (m, 1H), 2.90(dd, J = 7.3, 2.0 Hz, 1H), 2.32 – 2.24 (m, 1H), 2.07 – 2.02 (m, 1H), 1.99 –1.94 (m, 1H), 1.93 – 1.68 (m, 4H), 1.68 – 1.53 (m, 2H), 1.53 – 1.34 (m, 2H), 1.26 – 1.18 (m, 2H), 1.11 (dd, J = 8.1, 3.6 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ176.02, 155.00 (d, J = 8.0 Hz), 153.60, 151.78 (d, J = 10.9 Hz), 151.59, 151.30 (d, J = 12.4 Hz), 149.02, 147.74, 143.73 (d, J = 256.2 Hz), 137.57, 136.40,134.65, 51.03, 47.98, 28.79, 28.72, 25.79, 24.38, 21.55, 19.49, 9.77, 9.24(d,J = 17.7 Hz). Example 27

[0099] Step 1: Synthesis of compound Y-1 Compound 18 (845 mg, 2.0 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and oxalyl chloride (254 mg, 2.0 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 1 hour, and the reaction was confirmed by TLC to be complete. The mixture was concentrated under reduced pressure to give crude product Y-1 (882 mg, 2.0 mmol).

[0100] Step 2: Synthesis of Compound 25 Compound Y-1 (441 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL). o When cyanamide (84 mg, 2.0 mmol) and triethylamine (304 mg, 3.0 mmol) are added at temperature C, the reaction proceeds at 0°C. o After stirring at C for 1 h, the reaction mixture was determined to be complete by TLC. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined and washed three times with saturated brine (10 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (V(dichloromethane):V(methanol = 30:1 to 15:1) to give a white solid compound 25 (357 mg, yield 80%). 1 H NMR (600 MHz, DMSO- d 6) δ 13.92 (s, 1H), 11.85 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 7.58 (s, 1H), 7.34 (s, 1H), 4.81 (s, 1H), 2.95(s, 1H), 2.37 – 2.22 (m, 1H), 1.98 (d, J = 18.7 Hz, 2H), 1.88 – 1.70 (m, 3H), 1.62 – 1.35 (m, 5H), 1.18 (s, 2H), 1.09 (d, J = 8.4 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 175.08, 155.36, 153.09, 151.87 (d, J= 10.2 Hz), 151.25 (d, J = 11.9Hz), 149.27, 143.17 (d, J = 254.7 Hz), 142.05, 132.23, 118.14, 114.16, 108.92,49.37, 49.22, 29.51, 28.66, 25.55, 24.10, 20.92, 19.29, 9.85, 9.10 (d, J = 10.5Hz). Example 28

[0101] The difference from Example 27 is that compound 18 was replaced with compound 19, and the rest of the steps were the same as in Example 27, to obtain a white solid compound 12 (380 mg, 0.85 mmol, yield 85%). 1 H NMR (600 MHz, DMSO- d 6) δ 14.31 (s, 1H), 11.83 (s, 1H), 9.73 (s, 1H), 9.05 (s, 1H), 7.68 (s,1H), 4.79 (s, 1H), 2.93 (s, 1H), 2.36 – 2.26 (m, 1H), 2.02 – 1.90 (m, 2H), 1.88 – 1.67 (m, 3H), 1.65 – 1.50 (m, 2H), 1.49 – 1.35 (m, 3H), 1.21 – 1.05 (m, 4H). 13 C NMR (151 MHz, DMSO- d 6) δ 175.07, 155.41, 155.10, 154.60, 154.41,152.10 (d, J = 10.5 Hz), 151.36 (d, J = 12.1 Hz), 143.43 (d, J = 255.5 Hz), 143.22,113.00, 108.91, 49.43, 49.23, 29.51, 28.65, 25.56, 24.17, 20.88, 19.33, 9.83,9.21 (d, J = 10.6 Hz). Example 29 7-Aminotricyclic [3.2.2.0]2,4 Nonane-6-carboxylic acid methyl ester (1-7)

[0102] A solution of cycloheptatriene (10.0 g, 108.62 mm), maleic anhydride (10.64 g, 108.62 mm), and xylene (80 mL) were added to a 250 mL single-necked flask. The mixture was heated to 140 °C under nitrogen protection and refluxed for 12 h. Heating was then stopped, and the mixture was cooled to 0 °C. The mixture was filtered to obtain compounds 1-3 (white solid, 12.80 g, yield 62%). 1 H NMR (600 MHz, Chloroform- d ) δ 5.90-5.88 (m, 2H), 3.47-3.46 (m, 2H), 3.26-3.25 (m, 2H), 1.13-1.11 (m, 2H), 0.35 (q, J = 7.3 Hz, 1H), 0.27-0.25 (m, 1H). Compounds 1-3 (12.80 g, 67.37 mmol) were added to a 25% w / w NaOMe methanol solution (100 mL). The reaction mixture was stirred at room temperature for 3 days to give a white suspension. The reaction mixture was concentrated under vacuum to remove methanol. The pH was adjusted to 1-2 with 2N hydrochloric acid at 0 °C and stirred for 30 minutes. The precipitate was filtered and washed three times with water to give 9.27 g of a grayish-white solid 7-(methoxycarbonyl)tricyclic [3.2.2.0] 2,4] Non-8-ene-6-carboxylic acid (1-4). 1 H NMR (600 MHz, CDCl3) δ 5.91 – 5.86 (m, 1H), 5.74 (ddt, J = 7.9, 6.6, 1.2 Hz, 1H), 3.73 (s,3H), 3.30 (tt, J = 4.2, 1.8 Hz, 1H), 3.27 (dd, J = 5.0, 2.5 Hz, 1H), 3.24 – 3.20(m, 1H), 2.89 (dd, J = 5.1, 2.6 Hz, 1H), 1.06 (qt, J = 7.4, 3.8 Hz, 1H), 0.88(tt, J = 7.6, 3.8 Hz, 1H), 0.15 – 0.08 (m, 2H).

[0103] Compounds 1-4 (9.27 g, 41.74 mmol) were dissolved in tert-butanol (150 mL), and diphenylphosphine hydrazine (12.6 g, 45.91 mmol) and triethylamine (5.06 g, 50.08 mmol) were added. The reaction mixture was heated to 90 °C and reacted for 8 h. The mixture was purified by column chromatography to give a pale yellow oil 1-5 (9.17 g, 75%).

[0104] Compounds 1-5 (9.17 g) were dissolved in 100 mL of dioxane hydrochloride solution. After stirring at room temperature for 8 h, the reaction was stopped. The reaction solution was concentrated under reduced pressure and filtered to obtain compounds 1-6, which were directly used in the next step of the reaction.

[0105] Compounds 1-6 (4.0 g, 17.43 mmol) were dissolved in methanol (50 mL), and 10% Pd / C (1.84 g, 1.74 mmol) was added. The mixture was reacted at 50 °C for 10 h under a hydrogen atmosphere, filtered, and evaporated to dryness to give a pale yellow solid 1-7 (3.55 g, 88%).

[0106] Example 30

[0107] Step 1: Methyl 2-hydroxy-2-methylpropionate compounds 1-8 (10.0 g, 84.70 mmol) were dissolved in DMF (50 mL). NaH (4.1 g, 101.64 mmol) was added at 0 °C, and the reaction was allowed to proceed to room temperature for 1 h. Methyl acrylate compound 1-9 (7.28 g, 84.70 mmol) was then added, and the reaction was continued at room temperature for another 7 h before quenching the reaction. Column chromatography yielded an oily compound 1-10 (3.64 g, 25%). 1 H NMR (600 MHz, CDCl3) δ 4.39 (d, J = 8.5 Hz, 2H), 3.79 (d, J = 2.0Hz, 3H), 3.59 (t, J = 8.5 Hz, 1H), 1.29 (dd, J = 6.5, 1.9 Hz, 6H). Step 2: Compound 1-10 (3.64 g, 21.75 mmol) was dissolved in methanol (50 mL). Ammonium acetate (2.03 g, 26.1 mmol) was added, and the mixture was reacted at room temperature for 10 h. The solvent was evaporated under reduced pressure, extracted, dried, filtered, and evaporated to dryness to obtain oil 1-11 (2.79 g), which was directly used in the next step of the reaction.

[0108] Step 3: Add solid phosgene (2.42 g, 8.15 mmol) and dry DCM (30 mL) to a single-necked flask. Cool the hydrazine to below -78 °C, and add dropwise a solution of compound 1-11 (2.79 g, 16.31 mmol) and triethylamine (9.90 g, 97.86 mmol) in dry dichloromethane (20 mL). After the addition is complete, move the flask to 0 °C and stir for 0.5 h. Then, slowly add 30% ammonia water (9.32 g, 97.86 mmol). After the addition is complete, raise the temperature to 60 °C and react for 8 h. Column chromatography yields a white solid 1-12 (1.14 g, 35%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 11.48 (s, 1H), 11.04 (s, 1H), 4.64 (s, 2H), 1.39 (s, 6H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 160.60, 158.22, 153.16, 105.07,84.38, 68.28, 25.95. Step 4: Compound 1-12 (1.14 g, 6.26 mmol), dried DCE (10 mL), and phosphorus oxychloride (1.15 g, 7.51 mmol) were added to a single-necked flask. The reaction mixture was heated to 90 °C and reacted for 8 h. The mixture was purified by column chromatography to obtain a pale yellow solid 1-13 (0.20 g, 15%).

[0109] Example 31

[0110] Step 1: A solution of ethyl 2-oxocyclopentanecarboxylate 1-14 (10.0 g, 64.10 mmol) and sodium hydride (3.08 g, 76.92 mmol) was added to THF (100 mL) and stirred. The mixture was then reacted at room temperature for 1 hour. Then, 1,2-dibromoethane (14.38 g, 76.92 mmol) was added to the mixture, and the mixture was stirred and reacted at 80°C for 10 hours. Extraction, drying, filtration, and evaporation to dryness yielded an oily substance 1-15 (7.56 g), which was used directly in the next reaction.

[0111] Step 2: A solution of compound 1-15 (7.56 g, 28.85 mmol) and HBr (80 mL) was reacted at 130°C for 3 h. Extraction, drying, filtration, and evaporation to obtain an oily substance 1-16 (3.28 g), which was used directly in the next step of the reaction.

[0112] Step 3: Compound 1-16 (3.28 g, 17.26 mmol) and KOH (1.45 g, 25.89 mmol) in an ethanol (30 mL) solution were reacted at 80°C for 8 h. Extraction, drying, and column chromatography were performed to obtain an oily compound 1-17 (0.47 g, 25%). 1 H NMR (600 MHz, CDCl3) δ 2.30 – 2.28 (m, 2H), 2.00 – 1.92 (m, 4H), 1.11 – 1.04 (m, 2H), 0.82 – 0.79 (m, 2H). Step 4: A solution of compounds 1-17 (10.0 g, 90.90 mmol) and sodium hydride (4.0 g, 99.99 mmol) was added to THF (100 mL) and stirred at room temperature for 1 hour. Then, diethyl carbonate (11.79 g, 99.99 mmol) was added to the mixture, and the mixture was stirred at 80°C for 12 h. Extraction, drying, filtration, and evaporation to dryness yielded an oily compound 1-18 (7.44 g), which was used directly in the next reaction.

[0113] Step 5: According to the preparation process and reaction conditions of Steps 3 and 4 in Example 30, intermediate 1-18 was used as the raw material to replace compound 1-11, and finally white solid 1-21 (0.31 g, 3.6%) was obtained. 1 H NMR (600 MHz, CDCl3)δ 5.22 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 2.60 (dd, J = 8.5, 6.1 Hz, 2H), 1.89(t, J = 7.4 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.92 – 0.88 (m, 2H), 0.79 (t, J =3.3 Hz, 2H). Example 32

[0114] According to the preparation process and reaction conditions of steps 2 to 4 in Example 30, intermediate 1-22 was used as the raw material to replace compound 1-10, and finally white solid 1-25 (0.48 g, 4.0%) was obtained.

[0115] Example 33

[0116] According to the preparation process and reaction conditions of steps 4 to 5 in Example 31, intermediate 1-26 was used as the raw material to replace compound 1-17, and finally white solid 1-30 (0.77 g, 2.0%) was obtained.

[0117] Example 34

[0118] Compound 1-31 (21.6 mL, 155 mmol), ethyl 2-mercaptoacetate (15.6 mL, 142 mmol), and piperidine (2 mL) were added to a 250 mL single-necked flask and heated to 45°C. o C, after 4 h of reaction, TLC monitoring showed that the reaction was complete. 1N HCl (100 mL) was added to adjust the solution to acidity, and the solution was extracted with EA, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless, transparent liquid 1-32. 33 g of the crude product was used directly in the next reaction step.

[0119] Add 80 mL of dichloromethane to a 500 mL single-necked flask and cool to -10 °C. o C. Slowly add titanium tetrachloride (17 mL, 133 mmol), then slowly add isopropanol (11.53 mL, 133 mmol), and stir for 0.5 h. Dissolve crude compound 1-32 (33 g) in DCM (50 mL), then slowly add it to the system, followed by triethylamine (58 mL, 399 mmol), -10 o After reacting at C for 2 h, the reaction was monitored by TLC to indicate completeness. The reaction was quenched by adding 3N HCl (50 mL), and the system was brought to room temperature, extracted with EA, dried over anhydrous sodium sulfate, and concentrated to obtain 27 g of crude compound 1-33, which was directly used in the next reaction.

[0120] The crude product of compound 1-33 (8.0 g) was dissolved in a mixed solvent of methanol and concentrated hydrochloric acid (volume ratio 150 mL:50 mL), urea (72 g) was added, and the mixture was heated to 90°C. o C, the reaction was monitored by TLC after 24 h to indicate complete reaction. The solid was collected by filtration, washed twice with water, and dried to obtain crude compound 1-34 (6.4 g), which was directly used in the next reaction.

[0121] Add 6.4 g of crude compound 1-34 to a 500 mL single-necked flask, then add 100 mL of water and 5.2 g of sodium hydroxide (131 mmol). Heat to 85°C. o After 12 h of reaction at C, TLC monitoring showed the reaction was complete. The system was adjusted to acidity by adding 50 mL of 3N HCl, and the solid produced was collected and dried to give 2.5 g of crude compound 1-35. This was used directly in the next reaction.

[0122] Add crude compound 1-35 (1 g), acetonitrile (60 mL), and phosphorus oxychloride (4.63 g, 30 mmol) to a 100 mL single-necked flask, and heat to 90°C. o After 48 h of reaction at C, TLC monitoring showed that the reaction was complete. After cooling, the reaction solution was poured into ice water (100 mL), the solid was collected, and dried to give compound 1-36 (0.5 g, 30%). 1 H NMR (600 MHz, DMSO- d 6) δ 3.38 (s, 2H), 1.58 (s, 6H). Example 35

[0123] Compound 1-37 (5 g, 22.2 mmol), DCM (50 mL), and DMF (0.16 g, 2.2 mmol) were added to a 500 mL single-necked flask. Oxaloyl chloride (14 g, 111 mmol) was then slowly added dropwise. After 0.5 h, the reaction was monitored by TLC until complete. Most of the DCM was removed by rotary evaporation. THF (40 mL) was added, and the mixture was cooled to 0 °C. o C. Add 50 mL of 30% ammonia solution dropwise. After 0.5 h, TLC monitoring showed that the reaction was complete. Most of the THF was removed by rotary evaporation, and a white solid precipitated. The solid was filtered, collected, and dried to obtain a white solid 1-38 (3.4 g), which was directly used in the next reaction.

[0124] Compound 1-38 (5 g, 26.3 mmol) was dissolved in DCM (50 mL) and cooled to 0 °C. o At C, TFAA (7.2 g, 34.2 mmol) was slowly added dropwise, followed by TEA (6.7 g, 65.8 mmol). The resulting mixture was allowed to react at room temperature for 1.5 hours, and the reaction was monitored by TLC until complete. The reaction solution was added to water (100 mL), extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate to give a white solid 1-39 (3.8 g), which was used directly in the next reaction.

[0125] Compound 1-39 (3 g, 17.4 mmol) was dissolved in n-butanol (20 mL), hydrazine hydrate (16.3 g, 261 mmol) was added, and the mixture was heated to 120 °C. o Under argon protection, the reaction was monitored by TLC for 6 h until complete. The mixture was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate to give a white solid 1-40 (1.5 g), which was used directly in the next step of the reaction.

[0126] Compound 1-40 (2.2 g, 12.9 mmol) was dissolved in tribromomethane (30 mL) and cooled to 0 °C. o C, add tert-butyl nitrite (2.0 g, 19.4 mmol), and heat to 80°C. o C, reacted overnight, and the reaction was monitored by TLC until complete. Most of the tribromomethane was removed by rotary evaporation. PE was added to the reaction solution, and a solid precipitated. The solid was filtered, collected, and dried to give a brown solid compound 1-41 (3 g), which was used directly in the next reaction.

[0127] Compound 1-41 (5 g) was dissolved in DMF (10 mL), and potassium carbonate (6.3 g, 45 mmol) and Trt-Cl (7.7 g, 28 mmol) were added. The reaction was carried out under argon protection for 8 h, and the reaction was monitored by TLC to indicate completion. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, mixed with 10 g silica gel, and purified by PE column chromatography to obtain a white solid 1-42 (6 g, 70%).

[0128] Compound 1-42 (2 g, 1.97 mmol), pinacol diborate (0.55 g, 2.17 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.15 g, 0.20 mmol), and potassium acetate (0.58 g, 5.91 mmol) were dissolved in 15 mL of ultradry THF. The gas was replaced with argon gas by purging three times. The temperature was raised to 100 °C, and the reaction was carried out for 8 hours. After cooling to room temperature, the crude product was filtered through diatomaceous earth. The filtrate was diluted with ethyl acetate (150 mL), and the organic phase was washed twice with saturated brine (50 mL × 2). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (V(petroleum ether):V(ethyl acetate) = 60:1 to 20:1) to obtain compound 1-43. 1 H NMR (400 MHz, DMSO- d 6) δ8.74 (d, J= 2.2 Hz, 1H), 8.56 (dd, J = 2.2 Hz, J = 0.9 Hz, 1H), 7.75 – 6.73 (m,15H). Example 36

[0129] The difference from Example 35 is that compound 1-39 was replaced with compound 1-44, and the rest of the steps were the same as in Example 35, to obtain compound 1-47 (5.0 g, 65%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.38 (d, J =2.4 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 7.41 – 7.17 (m, 15H). Compounds 1-48 were further obtained.

[0130] Example 37

[0131] The difference from Example 35 is that compound 1-39 was replaced with compound 1-49, and the rest of the steps were the same as in Example 35, to obtain compound 1-51 (5.8 g, 71%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.42 (dd, J =2.8, 1.5 Hz, 1H), 8.04 (dd, J = 8.0 Hz, J = 2.7 Hz, 1H), 7.34 – 7.13 (m, 15H). Following the method used to prepare compounds 1-43 from compounds 1-42, compounds 1-52 were further obtained from compounds 1-51.

[0132] Example 38

[0133] The difference from Example 35 is that compound 1-39 was replaced with compound 1-53, and the rest of the steps were the same as in Example 35, to obtain compound 1-54 (4.5 g, 58%). 1H NMR (600 MHz, CDCl3) δ 9.02 (s, 1H), 8.75 (s, 1H), 7.28 – 7.27 (m, 1H), 7.26 – 7.25 (m, 8H), 7.24 – 7.21 (m, 6H). Following the method used to prepare compounds 1-43 from compounds 1-42, compounds 1-55 were further obtained from compounds 1-54.

[0134] Example 39

[0135] The difference from Example 35 is that compound 1-39 was replaced with compound 1-56, and the rest of the steps were the same as in Example 35, to obtain compound 1-57 (4.8 g, 60%). 1 H NMR (600 MHz, CDCl3) δ 8.25 (d, J = 2.3Hz, 1H), 7.86 (d, J = 6.0 Hz, 1H), 7.25 – 7.20 (m, 15H), 7.06 – 7.01 (m, 1H). Following the method used to prepare compounds 1-43 from compounds 1-42, compounds 1-58 were further obtained from compounds 1-57.

[0136] Example 40

[0137] The difference from Example 35 is that compound 1-39 was replaced with compound 1-59, and the rest of the steps were the same as in Example 35, to obtain compound 1-60 (5.0 g, 62%). 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 7.5Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.35 – 7.30 (m, 9H), 7.20 – 7.13 (m, 6H). Following the method used to prepare compounds 1-43 from compounds 1-42, compounds 1-61 were further obtained from compounds 1-60.

[0138] Example 41

[0139] The difference from Example 3 is that compound C-2 was replaced with compound 1-25, and the rest of the steps were the same as in Example 3, to obtain white solid compound 26 (88 mg, 10%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.06 (s,1H), 12.31 (s, 1H), 8.59–8.63 (m, 2H), 6.86 (d, J = 6.7 Hz, 1H), 4.79 (t, J = 7.1Hz, 1H), 2.88 – 2.80 (m, 3H), 2.75 (t, J = 7.5 Hz, 2H), 2.10 – 2.00 (m, 3H), 1.95 – 1.90 (m, 1H), 1.82 – 1.73 (m, 3H), 1.65 – 1.58 (m, 1H), 1.58 – 1.49(m, 2H), 1.49 – 1.42 (m, 1H), 1.34–1.38 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6 ) δ174.38, 162.82, 162.59, 156.73, 155.11, 152.36, 152.13, 130.61, 127.80,122.46, 120.65, 116.30, 114.34, 101.41, 60.22, 53.60, 52.61, 52.06, 51.83,51.30, 50.59, 40.52, 35.67, 35.35, 34.59, 29.42, 29.01, 24.24, 17.24, 14.55,13.96, 10.76, 8.82, 6.31, 5.33, 4.07. HRMS (ESI) calcd for C 22 H 24 FN6O2[M+H] + :423.1867, found 423.1942. Example 41

[0140] The difference from Example 3 is that compound C-2 was replaced with compound 1-30, and the rest of the steps were the same as in Example 3, to obtain white solid compound 27 (66 mg, 7%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.37 (s,1H), 12.37 (s, 1H), 8.67 (d, J = 2.9 Hz, 1H), 8.60 – 8.53 (m, 1H), 7.44 (s,1H), 4.84 (d, J = 7.4 Hz, 1H), 2.92 (d, J = 7.0 Hz, 1H), 2.76 (t, J = 7.2 Hz, 2H), 2.04 (d, J = 3.9 Hz, 1H), 1.96 (t, J = 7.1 Hz, 2H), 1.92 (s, 1H), 1.83 – 1.73 (m,3H), 1.64 – 1.59 (m, 1H), 1.57 – 1.43 (m, 3H), 1.39 – 1.36 (m, 1H), 1.29 (d, J = 6.6 Hz, 6H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 175.99, 159.19, 156.63, 155.01,116.43, 114.14, 66.81, 50.87, 47.94, 44.65, 40.52, 38.72, 29.03, 28.86,26.91, 26.79, 25.71, 25.23, 24.26, 21.56, 19.47. HRMS (ESI) calcd forC 24 H 28 FN6O2[M+H] + : 451.2180, found 451.2261. Example 42

[0141] The difference from Example 3 is that compound C-1 was replaced with compound 1-30 and compound A-4 was replaced with compound 1-55. The remaining steps were the same as in Example 3, yielding a white solid compound 28 (45 mg, 5%). 1 H NMR (600MHz, DMSO- d 6 ) δ 9.83 (s, 1H), 8.84 (s, 1H), 6.59 (d, J = 7.4 Hz, 1H), 4.87 (t, J = 7.2 Hz, 1H), 2.69 – 2.25 (m, 2H), 2.40 (d, J = 6.7 Hz, 1H), 2.02 – 1.98 (m,1H), 1.87 (t, J = 7.2 Hz, 2H), 1.83 – 1.74 (m, 3H), 1.72 – 1.65 (m, 2H), 1.52 –1.41 (m, 2H), 1.32 – 1.26 (m, 2H), 1.23 (s, 3H), 1.21 (s, 3H). 13 C NMR (151MHz, DMSO- d 6 ) δ 178.46, 175.51, 159.66, 159.33, 154.54, 153.75, 143.88,113.74, 112.88, 52.00, 51.55, 44.30, 40.52, 38.68, 29.61, 29.24, 27.24,27.05, 26.57, 25.01, 24.72, 22.17, 19.98. HRMS (ESI) calcd for C 23 H 27 N7O2Na [M+Na] + : 456.2226, found 456.2124. Example 43

[0142] The difference from Example 3 is that compound C-2 was replaced with compound 1-30 and compound A-4 was replaced with compound 1-48. The remaining steps were the same as in Example 3, yielding a white solid compound 29 (48 mg, 5.3%). 1 H NMR (600 MHz, DMSO-)d 6 ) δ 14.55 (s, 1H), 12.43 (s, 1H), 8.81 (d, J J = 8.0 Hz, 1H),8.66 (d, J J = 4.5 Hz, 1H), 7.43 (t, J J = 6.2 Hz, 1H), 4.90 (t, J J = 7.3 Hz, 1H), 2.99(d, J J = 6.8 Hz, 1H), 2.81 (t, J J = 7.4 Hz, 2H), 2.06 (s, 1H), 2.00 (q, J J = 5.2 Hz,3H), 1.93 (s, 1H), 1.80 (d, J J = 9.0 Hz, 2H), 1.76 (t, J J = 12.0 Hz, 1H), 1.63 (td, J J = 12.3, 6.3 Hz, 1H), 1.57 – 1.50 (m, 2H), 1.48 (d, J J = 12.3 Hz, 1H), 1.36 (d, J J = 6.3 Hz, 7H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 175.81, 170.80, 159.50, 153.30,150.23, 131.74, 119.00, 114.20, 60.22, 51.59, 47.53, 45.00, 40.52, 38.88,29.20, 28.73, 26.52, 26.40, 25.63, 24.34, 21.58, 21.23, 19.50, 14.55. HRMS(ESI) calcd for C 24 H 29 N6O2[M+H] + : 433.2274, found 433.2329. Example 44

[0143] The difference from Example 3 is that compound C-2 was replaced with compound 1-74 and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, yielding a white solid compound 30 (50 mg, 5.2%). 1 H NMR (600 MHz, DMSO-) d 6 ) δ 8.67 (d, J = 2.8 Hz, 1H), 8.56 (dd, J = 8.7, 2.8 Hz, 1H), 7.84 (d, J = 7.1 Hz, 1H), 4.89 (t, J = 7.2 Hz, 1H), 2.93 (d, J = 6.9 Hz, 1H), 2.88(q, J = 6.5 Hz, 2H), 2.67 – 2.63 (m, 2H), 2.06 (d, J = 4.2 Hz, 1H), 1.96 (s, 1H), 1.79 (t, J = 11.8 Hz, 3H), 1.67 – 1.61 (m, 1H), 1.58 – 1.45 (m, 3H), 1.41 –1.35 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 175.85, 159.87, 159.83, 157.66,156.65, 155.03, 150.53, 141.51, 139.59, 139.39, 130.50, 128.87, 127.25,118.61, 116.32, 116.18, 114.16, 114.10, 60.21, 51.05, 47.83, 40.51, 33.32,33.16, 33.00, 28.93, 28.78, 28.72, 25.69, 24.23, 22.85, 21.54, 21.22, 19.72,19.49, 14.54, 11.69. HRMS (ESI) calcd for C 22 H 22 F3N6O2[M+H] + : 459.1678, found459.1753. Example 45

[0144] The difference from Example 3 is that compound C-2 was replaced with compound 1-13 and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, yielding a white solid compound 31 (57 mg, 6.0%). 1 H NMR (600 MHz, DMSO-) d 6 ) δ 14.87 (s, 1H), 12.47 (s, 1H), 8.76 (s, 1H), 8.50 (dd, J =8.4, 2.9 Hz, 1H), 5.00 (d, J = 4.5 Hz, 2H), 4.98 – 4.93 (m, 1H), 2.96 (s, 1H), 2.09 – 2.04 (m, 1H), 1.94 (s, 1H), 1.87 – 1.73 (m, 3H), 1.68 – 1.64 (m, 1H),1.54 (d, J = 5.8 Hz, 9H), 1.40 (t, J = 10.2 Hz, 1H). 13 C NMR (151 MHz, DMSO- d 6 ) δ175.65, 157.19, 157.01, 155.38, 150.45, 140.46, 140.26, 115.87, 115.73,114.19, 114.14, 111.38, 84.91, 68.50, 51.68, 47.60, 40.51, 29.09, 28.66,26.42, 26.36, 25.54, 24.30, 21.43, 19.47. HRMS (ESI) calcd for : C 23 H 26 FN6O3[M+H] + : 453.1972, found 453.2074. Example 46

[0145] The difference from Example 3 is that compound C-2 was replaced with compound 1-36 and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, yielding a white solid compound 32 (69 mg, 7.0%). 1 H NMR (600 MHz, DMSO-) d 6 ) δ 14.08 (s, 1H), 12.31 (s, 1H), 8.70 – 8.52 (m, 2H), 6.76 (s, 1H), 4.77 (s, 1H), 3.21 – 3.09 (m, 2H), 2.88 (d, J = 7.0 Hz, 1H), 2.00 (d, J = 6.9 Hz, 2H), 1.91 (d, J = 7.9 Hz, 1H), 1.75 (t, J = 8.8 Hz, 3H), 1.58 (d, J =12.7 Hz, 6H), 1.55 – 1.40 (m, 3H), 1.34 (dt, J = 11.7, 5.4 Hz, 1H), 1.27 – 1.17(m, 1H). Example 47

[0146] The difference from Example 3 is that compound C-2 was replaced with compound 1-21 and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, yielding a white solid compound 33 (37.5 mg, 4.0%). 1 H NMR (600 MHz, DMSO-) d 6 ) δ 8.43 – 8.39 (m, 1H), 8.31 (s, 1H), 6.28 (d, J = 6.9 Hz, 1H), 4.87 (t, J = 7.3 Hz, 1H), 2.79 – 2.81 (m, 2H), 2.27 (d, J = 6.3 Hz, 1H), 2.12 (t, J = 7.6 Hz, 2H), 1.99 (s, 1H), 1.79 (d, J = 13.9 Hz, 3H), 1.68 (t,J =10.2 Hz, 2H), 1.49 – 1.42 (m, 2H), 1.26 (t, J = 12.5 Hz, 2H), 1.15 – 1.11 (m,2H), 0.86 (d, J = 4.0 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 170.41, 157.50,154.45, 152.85, 114.06, 113.43, 111.23, 51.36, 50.84, 39.45, 30.13, 28.97,28.20, 26.52, 25.57, 24.75, 23.67, 21.18, 18.86, 14.01. HRMS (ESI) calcd for: C 24 H 26 FN6O2[M+H] + : 449.1972, found 449.2099. Example 48

[0147] The difference from Example 3 is that compound C-2 was replaced with compound 1-21 and compound A-4 was replaced with compound 1-55. The remaining steps were the same as in Example 3, yielding a white solid compound 34 (33.5 mg, 3.7%). 1 H NMR (600 MHz, DMSO-) d 6 ) δ 9.83 (s, 1H), 9.01 (s, 1H), 6.88 (s, 1H), 4.77 (t, J = 7.1Hz, 1H), 2.85 (t, J = 7.6 Hz, 2H), 2.78 (d, J = 7.1 Hz, 1H), 2.13 – 2.16 (m, 2H), 2.00 (s, 1H), 1.91 (s, 1H), 1.76 (h, J = 10.7 Hz, 3H), 1.56 – 1.59 (m, 2H), 1.48 – 1.51 (m, 1H), 1.43 (d, J = 13.2 Hz, 1H), 1.33 (t, J= 11.3 Hz, 1H), 1.11(s, 2H), 0.91 (d, J = 5.3 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 158.79, 158.37,155.35, 155.05, 115.01, 113.18, 50.80, 48.60, 40.52, 30.97, 28.98, 27.59,25.98, 25.74, 24.29, 21.65, 19.49, 15.44. HRMS (ESI) calcd for : C 23 H 26 N7O2[M+H] + : 432.2070, found 432.2146. Example 49

[0148] The difference from Example 3 is that compound C-2 was replaced with compound 1-21 and compound A-4 was replaced with compound 1-48. The remaining steps were the same as in Example 3, yielding a white solid compound 35 (36.2 mg, 4.0%). 1 H NMR (600 MHz, DMSO-) d 6 ) δ 8.60 (d, J = 2.1 Hz, 1H), 8.49 (d, J = 2.1 Hz, 1H), 6.53 (d, J = 6.8 Hz, 1H), 4.69 (t, J = 7.1 Hz, 1H), 2.89 – 2.78 (m, 2H), 2.39 (d,J = 6.8 Hz, 1H), 2.10 – 2.07 (m, 2H), 1.98 (d, J = 8.6 Hz, 1H), 1.94 (d, J =4.2 Hz, 1H), 1.79 – 1.73 (m, 2H), 1.68 – 1.64 (m, 2H), 1.45 – 1.41 (m, 2H),1.28 – 1.23 (m, 2H), 1.07 (t, J = 3.1 Hz, 2H), 0.84 (d, J = 3.0 Hz, 2H). 13 CNMR (151 MHz, DMSO- d 6) δ 177.58, 170.73, 157.74, 157.50, 146.38, 141.53,140.57, 130.89, 112.80, 50.97, 50.45, 40.18, 39.46, 30.36, 30.05, 28.20,27.88, 26.54, 26.48, 25.65, 24.71, 23.40, 21.93, 21.88, 21.46, 21.05, 18.89,18.68, 18.04, 14.10, 13.56, 13.36, 10.65. HRMS (ESI) calcd for: C 23 H 26 N7O2[M+H] + : 432.2070, found 432.2148. Example 50

[0149] The difference from Example 3 is that compound C-2 was replaced with compound 1-21 and compound A-4 was replaced with compound 1-58. The remaining steps were the same as in Example 3, yielding a white solid compound 36 (34.3 mg, 3.8%). 1 H NMR (600 MHz, DMSO-) d 6 ) δ 14.38 – 13.80 (m, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.52 (d, J = 4.9 Hz, 1H), 7.24 (dd, J = 8.0, 4.4 Hz, 1H), 6.69 – 6.53 (m, 1H), 4.83 (t, J =7.0 Hz, 1H), 2.81 (d, J = 7.2 Hz, 2H), 2.09 – 2.12 (m 2H), 2.00 (d, J = 5.6 Hz,1H), 1.91 (s, 1H), 1.80 – 1.65 (m, 4H), 1.57 – 1.41 (m, 2H), 1.36 – 1.20 (m,3H), 1.10 (s, 2H), 0.86 (d, J = 6.6 Hz, 2H). 13C NMR (151 MHz, DMSO- d 6 ) δ 170.63,158.66, 157.44, 152.30, 148.06, 131.83, 116.62, 113.30, 113.01, 50.89, 49.79,39.46, 30.00, 28.13, 26.52, 25.42, 24.70, 23.48, 21.06, 18.76, 14.16. HRMS(ESI) calcd for : C 24 H 26 N6O2Na [M+Na] + : 453.20117, found 453.2015. Example 51

[0150] The difference from Example 3 is that compound C-2 was replaced with compound 1-21 and compound A-4 was replaced with compound 1-43. The remaining steps were the same as in Example 3, yielding a white solid compound 37 (37.6 mg, 3.7%). 1 H NMR (600 MHz, DMSO-) d 6 ) δ 9.23 (d, J = 2.3 Hz, 1H), 8.91 (d, J = 2.2 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 5.02 (d, J = 7.3 Hz, 1H), 2.85 (d, J = 8.0 Hz, 2H), 2.74 (d, J =5.8 Hz, 1H), 2.36 – 2.38 (m, 1H), 2.22 (t, J = 3.7 Hz, 1H), 2.18 (t, J = 7.6 Hz,2H), 1.50 – 1.53 (m, 2H), 1.38 – 1.31 (m, 1H), 1.11 (d, J = 11.8 Hz, 3H), 1.01– 1.04 (m, 1H), 0.93 (d, J= 6.1 Hz, 3H), 0.70 – 0.74 (m, 1H), 0.45 – 0.40 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 175.09, 171.25, 157.36, 144.85, 129.90,124.87, 123.07, 118.56, 118.35, 113.65, 111.98, 50.19, 48.62, 39.47, 29.90,28.58, 26.56, 25.75, 24.73, 23.07, 16.13, 14.35, 13.14, 9.63, 4.15. HRMS(ESI) calcd for : C 25 H 26 F3N6O2[M+H] + : 499.1991, found 499.2068. Example 52

[0151] The difference from Example 3 is that compound C-2 was replaced with compound 1-21 and compound A-4 was replaced with compound 1-61. The remaining steps were the same as in Example 3, yielding a white solid compound 38 (49.9 mg, 5.0%). 1 H NMR (600 MHz, DMSO-) d 6 ) δ 9.41 (dd, J = 4.2, 2.5 Hz, 1H), 9.08 – 9.04 (m, 1H), 6.44– 6.33 (m, 1H), 4.86 (d, J = 8.1 Hz, 1H), 2.83 (d, J = 15.2 Hz, 2H), 2.40 – 2.34(m, 1H), 2.16 – 2.09 (m, 2H), 1.99 (d, J = 4.4 Hz, 1H), 1.88 – 1.73 (m, 3H), 1.72 – 1.64 (m, 2H), 1.46 – 1.42 (m, 2H), 1.28 (t, J = 12.1 Hz, 2H), 1.16 –1.11 (m, 2H), 0.88 (d, J= 3.8 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 171.56,158.62, 146.10, 113.99, 66.82, 51.75, 51.46, 40.52, 31.12, 29.18, 27.58,26.55, 25.88, 24.60, 22.12, 19.92, 15.18, 15.08. HRMS (ESI) calcd for:C 24 H 26 N7O4[M+H] + : 498.1968, found 476.2049. Example 53

[0152] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with compound 1-6, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 39 (36.69 mg, 3.8%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.08 (s, 1H), 12.42 (s, 1H), 8.64 (d, J = 14.3 Hz, 2H), 6.56 (d, J =6.9 Hz, 1H), 6.06 (t, J = 7.5 Hz, 1H), 5.74 (t, J = 7.2 Hz, 1H), 4.89 (d, J= 6.4Hz, 1H), 3.98 – 3.87 (m, 2H), 3.16–3.19 (m, 2H), 2.77 – 2.70 (m, 1H), 2.63–2.67 (, 1H), 2.58 – 2.51 (m, 1H), 2.39 – 2.25 (m, 2H), 1.84–1.88 (m, 1H), 1.66–1.69 (m, 1H), 1.15 – 1.09 (m, 1H), 0.98–1.02 (m, 1H), 0.22–0.26 (m, 1H), 0.06–0.10 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 173.8, 173.3, 157.6, 155.4,153.8, 129.3, 128.3, 127.6, 126.6, 124.7, 114.0, 111.3, 63.0, 51.7, 49.7,43.2, 41.9, 39.5, 35.9, 34.8, 34.5, 33.6, 33.6, 27.7, 25.2, 20.4, 7.9, 7.8,5.3, 5.2, 3.0. HRMS (ESI) calcd for: C 25 H 24 FN6O2[M+H] + : 459.1968, found459.1942. Example 54

[0153] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 2-carboxylate hydrochloride of 3-aminobicyclo[2.2.2]octane-2-carboxylate was replaced with compounds 1-7, and compound A-4 was replaced with compounds 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 40 (40.6 mg, 4.2%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.63 – 8.55 (m, 2H), 6.75 (s, 1H), 4.94 (d, J = 7.1 Hz, 1H), 2.82(d, J= 7.4 Hz, 2H), 2.57 (s, 1H), 2.41 – 2.36 (m, 1H), 2.31 (s, 1H), 2.11 –2.14 (m, 2H), 1.55 – 1.41 (m, 2H), 1.32 (d, J = 12.5 Hz, 1H), 1.15 – 1.02 (m,4H), 0.97 – 0.99 (m, 1H), 0.89 (s, 2H), 0.66 – 0.69 (m, 1H), 0.41 – 0.44 (m,1H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 170.81, 158.22, 157.36, 155.28, 153.67,115.71, 115.56, 112.96, 51.15, 50.08, 39.46, 29.96, 28.59, 28.30, 26.55,24.69, 23.34, 16.38, 14.29, 14.18, 13.09, 10.20, 4.19. HRMS (ESI) calcd for:C 25 H 26 FN6O2[M+H] + : 461.2023, found 461.2101. Example 55

[0154] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 2-carboxylate hydrochloride of 3-aminobicyclo[2.2.2]octane-2-carboxylate was replaced with compounds 1-7, and compound A-4 was replaced with compounds 1-43. The remaining steps were the same as in Example 3, to obtain white solid compound 41 (42.8 mg, 4.0%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.23 (d, J = 2.3 Hz, 1H), 8.91 (d, J = 2.2 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 5.02 (d, J= 7.3 Hz, 1H), 2.85 (d, J = 8.0 Hz, 2H), 2.74 (d, J = 5.8 Hz, 1H),2.36 – 2.38 (m, 1H), 2.22 (t, J = 3.7 Hz, 1H), 2.18 (t, J = 7.6 Hz, 2H), 1.50 –1.53 (m, 2H), 1.38 – 1.31 (m, 1H), 1.11 (d, J = 11.8 Hz, 3H), 1.01 – 1.04 (m,1H), 0.93 (d, J = 6.1 Hz, 3H), 0.70 – 0.74 (m, 1H), 0.45 – 0.40 (m, 1H). 13 C NMR (151 MHz, DMSO-) d 6 ) δ 175.09, 171.25, 157.36, 144.85, 129.90, 124.87, 123.07,118.56, 118.35, 113.65, 111.98, 50.19, 48.62, 39.47, 29.90, 28.58, 26.56,25.75, 24.73, 23.07, 16.13, 14.35, 13.14, 9.63, 4.15. HRMS (ESI) calcd for:C 26 H 26 F3N6O2[M+H] + : 511.1991, found 511.2072. Example 56

[0155] The difference from Example 3 is that compound C-2 was replaced with compound 1-21 and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, yielding a white solid compound 42 (18.8 mg, 2.0%). 1 H NMR (600 MHz, DMSO-) d 6 ) δ 14.55 (s, 1H), 8.60 – 8.48 (m, 2H), 6.58 (s, 1H), 4.60 (s, 1H), 2.26 (d,J = 6.3 Hz, 1H), 2.14 (dd, J = 10.5, 5.0 Hz, 2H), 1.92 (s, 1H), 1.80 (s, 1H), 1.76 – 1.62 (m, 4H), 1.52 (s, 1H), 1.46 – 1.38 (m, 2H), 1.27 –1.23 (m, 3H), 1.09 (s, 2H), 0.97 – 0.91 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ179.03, 177.90, 175.74, 162.44, 158.70, 158.49, 154.48, 153.13, 150.26,142.67, 138.45, 118.75, 117.84, 116.76, 114.22, 114.17, 52.63, 51.83, 40.47,31.56, 29.19, 28.52, 28.49, 27.31, 26.79, 26.47, 25.24, 24.38, 22.29, 19.93,16.68, 16.49. HRMS (ESI) calcd for: C 24 H 24 FN6O2[MH] - : 447.2023, found447.1951. Example 57

[0156] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S )-3-aminobicyclo[2.2.2]octane-2-carboxylic acid ethyl ester hydrochloride is replaced with D -Valine methyl ester, replacing compound A-4 with compound 1-52, and following the same steps as in Example 3, yielded a white solid compound 43 (30.0 mg, 3.6%). 1 H NMR (600MHz, DMSO- d 6 ) δ 14.55 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 8.7 Hz, 1H), 6.42 (d, J= 7.1 Hz, 1H), 4.26 (s, 1H), 2.86 (t, J = 7.9 Hz, 2H), 2.32 – 2.29 (m, 1H), 2.22 – 2.15 (m, 2H), 1.12 – 1.07 (m, 5H), 0.98 (d, J = 6.7 Hz, 3H), 0.94 – 0.89(m, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 175.57, 171.61, 159.39, 158.37, 156.29,154.68, 138.94, 116.83, 116.69, 114.25, 113.87, 61.72, 40.51, 30.94, 30.91,27.57, 25.11, 20.00, 19.62, 15.50, 15.29. HRMS (ESI) calcd for: C 20 H 20 FN6O2[MH] - : 395.1710, found 395.1635. Example 58

[0157] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with L-isoleucine methyl ester, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 44 (34.5 mg, 4.0%). 1 H NMR (600MHz, DMSO- d 6 ) δ 14.46 (s, 1H), 8.58 (d, J = 2.7 Hz, 1H), 8.47 (dd, J = 8.8, 2.9Hz, 1H), 6.44 (d, J = 6.8 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 2.84 (t, J= 7.5 Hz,2H), 2.22 – 2.13 (m, 2H), 2.03 (dh, J = 11.5, 6.0 Hz, 1H), 1.75 – 1.71 (dm,1H), 1.40 (d, J = 8.8 Hz, 2H), 1.10 (d, J = 3.0 Hz, 2H), 0.94 – 0.89 (m, 8H). 13 CNMR (151 MHz, DMSO- d 6 ) δ 174.96, 171.56, 159.48, 158.15, 156.32, 154.70,116.83, 116.69, 114.16, 113.92, 60.76, 40.52, 37.52, 30.95, 27.59, 26.80,26.49, 25.05, 15.75, 15.46, 15.28, 12.46. HRMS (ESI) calcd for: C 21 H 22 FN6O2[MH] - : 409.1867, found 409.1791. Example 59

[0158] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with methyl 1-aminocyclopropylcarboxylate hydrochloride, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 45 (27.9 mg, 3.5%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.12 (s, 1H), 12.52 (s, 1H), 8.61 (dd, J = 2.8, 1.4Hz, 1H), 8.58 (d, J = 9.4 Hz, 1H), 7.89 (s, 1H), 2.18 (t, J = 7.6 Hz, 2H), 1.59(dd, J= 9.2, 4.0 Hz, 2H), 1.29 (s, 2H), 1.23 (s, 2H), 1.18 (s, 2H), 0.98 –0.94 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 176.13, 156.44, 156.18, 154.83,116.58, 114.28, 60.22, 54.51, 51.63, 50.90, 47.89, 40.52, 30.57, 30.26,28.93, 25.68, 24.21, 21.61, 21.23, 19.43, 14.55. HRMS (ESI) calcd for:C 19 H 18 FN6O2[M+H] + : 381.1397, found 381.1473. Example 60

[0159] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with methyl 1-aminocyclobutylcarboxylate hydrochloride, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 46 (29.8 mg, 3.6%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 13.97 (s, 1H), 12.50 (s, 1H), 8.59 (d, J = 12.1 Hz,2H), 7.52 (s, 1H), 2.89 (t, J = 7.5 Hz, 2H), 2.73 (q, J = 8.7 Hz, 2H), 2.40 (q, J =9.4 Hz, 2H), 2.18 (t, J = 7.5 Hz, 2H), 2.05 – 1.97 (m, 2H), 1.12 (s, 2H), 0.95 – 0.89 (m, 2H). 13C NMR (151 MHz, DMSO- d 6 ) δ 176.15, 172.55, 157.51, 156.50,154.88, 114.87, 58.86, 40.52, 31.46, 31.02, 27.64, 25.67, 15.67, 15.52. HRMS(ESI) calcd for: C 20 H 20 FN6O2[M+H] + : 395.1554, found 395.1628. Example 61

[0160] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with methyl 1-aminocyclopentylcarboxylate hydrochloride, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 47 (27.4 mg, 3.2%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.15 (s, 1H), 12.40 (s, 1H), 8.60 (d, J = 9.7 Hz,2H), 7.21 (s, 1H), 2.90 (t, J = 7.5 Hz, 2H), 2.33 (dt, J = 13.6, 7.7 Hz, 2H),2.28 – 2.24 (m, 2H), 2.19 (t, J = 7.5 Hz, 2H), 1.77 – 1.74 (m, 4H), 1.22 (d, J =11.6 Hz, 2H), 0.98 – 0.94 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 176.77, 157.95,156.61, 155.00, 115.47, 66.52, 40.52, 37.40, 31.14, 27.64, 25.84, 24.84,22.95, 15.84. HRMS (ESI) calcd for: C 21 H 22 FN6O2[M+H] + : 409.1710, found409.1786. Example 62

[0161] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with methyl 3-aminoadamantane-1-carboxylate hydrochloride, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 48 (29.8 mg, 3.0%). 1 H NMR (600 MHz, DMSO- d 6 δ 8.57 (s, 1H), 8.50 (dd, J = 8.8, 2.9 Hz, 1H),5.78 (s, 1H), 2.82 (t, J = 7.6 Hz, 2H), 2.45 (d, J = 11.7 Hz, 2H), 2.18 – 2.12(m, 6H), 2.03 (d, J = 11.6 Hz, 2H), 1.75 (d, J = 3.2 Hz, 4H), 1.71 (d, J = 12.1 Hz, 1H), 1.60 (d, J = 11.9 Hz, 1H), 1.13 (q, J = 3.8 Hz, 2H), 0.94 – 0.90 (m, 2H). 13 CNMR (151 MHz, DMSO- d 6) δ 170.60, 157.80, 157.70, 155.19, 153.58, 115.41,115.27, 113.88, 112.74, 52.43, 43.98, 41.88, 39.91, 39.45, 35.04, 29.80,28.84, 26.52, 24.57, 14.28. HRMS (ESI) calcd for: C 26 H 28 FN6O2[M+H] + : 475.2180, found 475.2259. Example 63

[0162] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with 1-amino-3-methylbut-1-ol hydrochloride, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 49 (36.0 mg, 4.5%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.88 – 14.34 (m, 1H), 8.72 (s, 1H), 8.40 (d, J =8.3 Hz, 1H), 7.82 – 7.40 (m, 1H), 4.28 (s, 1H), 3.72 (d, J = 11.3, 4.2 Hz, 1H), 3.64 (d, J = 11.4, 7.4 Hz, 1H), 2.91 (d, J = 15.9 Hz, 2H), 2.22 (t, J = 7.7 Hz,2H), 2.07 – 2.04 (m, 1H), 1.43 (s, 2H), 1.06 – 1.01 (m, 2H), 0.98 (d, J = 11.7, 6.8 Hz, 7H). 13 C NMR (151 MHz, DMSO- d 6) δ 159.26, 158.60, 158.37, 156.80,155.18, 140.28, 140.07, 117.97, 116.01, 113.97, 61.51, 60.21, 59.27, 40.51,31.49, 29.40, 27.56, 25.77, 21.22, 19.77, 19.67, 16.58, 16.47, 14.54. HRMS(ESI) calcd for: C 20 H 24 FN6O [M+H] + : 383.1917, found 383.1991. Example 64

[0163] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with 1-amino-2-methylprop-2-ol hydrochloride, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 50 (23.2 mg, 3.0%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.59 (s, 1H), 8.70 (dd, J = 2.9, 1.5 Hz, 1H), 8.56– 8.46 (m, 1H), 7.94 (s, 1H), 3.61 (d, J = 6.0 Hz, 2H), 2.95 – 2.84 (m, 2H), 2.22 (t, J = 7.6 Hz, 2H), 1.42 (s, 2H), 1.20 (s, 6H), 1.05 (q, J = 4.2 Hz, 2H). 13 CNMR (151 MHz, DMSO- d 6) δ 159.13, 158.66, 158.43, 158.21, 156.84, 155.21,150.49, 140.28, 140.09, 117.75, 116.40, 116.25, 115.80, 114.03, 113.98,70.56, 51.99, 40.50, 31.42, 28.03, 27.56, 25.62, 16.66. HRMS (ESI) calcd for:C 19 H 22 FN6O [M+H] + : 369.1761, found 369.1837. Example 65

[0164] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with 1-aminocyclopropylmethanol hydrochloride, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 51 (31.5 mg, 4.1%). 1 HNMR (600 MHz, DMSO- d 6 ) δ 14.02 (s, 1H), 8.61 (d, J = 7.9 Hz, 2H), 7.35 (s, 1H), 5.20 (t, J = 5.4 Hz, 1H), 3.68 (d, J = 5.4 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 2.18– 2.14 (m, 2H), 1.15 – 1.11 (m, 2H), 0.95 – 0.91 (m, 4H), 0.85 – 0.81 (m,2H). 13 C NMR (151 MHz, DMSO- d 6) δ 171.44, 158.25, 158.09, 155.39, 153.78,149.19, 141.93, 137.95, 137.75, 116.09, 115.94, 113.69, 113.18, 64.50, 59.16,39.47, 34.77, 33.06, 30.68, 29.92, 28.49, 28.23, 28.09, 27.95, 26.55, 25.97,24.63, 23.89, 21.50, 20.17, 14.44, 13.49, 13.35, 11.37. HRMS (ESI) calcd for:C 19 H 20 FN6O [M+H] + 367.1604, found 367.1680. Example 66

[0165] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with 1-aminomethyloxetane-3-ol hydrochloride, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 52 (28.1 mg, 4.5%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.67 – 8.64 (m, 1H), 8.48 (dd, J = 8.9, 2.7Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 6.3 Hz, 2H), 3.94 (d, J = 5.8 Hz, 2H), 2.87 (t, J = 7.7 Hz, 2H), 2.21 (t, J = 7.6 Hz, 2H), 1.33 (d, J = 8.5 Hz, 2H), 1.24 (d, J = 10.8 Hz, 2H), 1.04 – 0.99 (m, 2H). 13C NMR (151 MHz, DMSO- d 6 ) δ171.31, 159.24, 158.54, 158.32, 157.07, 156.61, 155.44, 154.99, 152.43,150.42, 149.53, 140.97, 140.76, 137.26, 137.22, 118.21, 116.84, 116.49,116.34, 116.24, 115.55, 115.50, 81.68, 74.14, 70.24, 65.27, 64.98, 60.22,55.30, 47.05, 45.72, 40.50, 31.74, 31.12, 30.32, 29.48, 29.28, 28.47, 27.59,27.01, 25.63, 25.51, 22.55, 21.22, 16.82, 16.71, 16.06, 14.54, 14.40. HRMS(ESI) calcd for: C 19 H 20 FN6O2[M+H] + : 383.1554, found 383.1629. Example 67

[0166] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with 1-aminocyclobutane-1-methanol hydrochloride, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 53 (27.9 mg, 3.5%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.01 (s, 1H), 8.60 (d, J = 2.9 Hz, 1H), 8.42 (dd, J =8.6, 2.9 Hz, 1H), 6.79 (s, 1H), 5.25 (t, J = 5.7 Hz, 1H), 3.83 (d, J = 5.4 Hz, 2H), 2.85 (t,J = 7.6 Hz, 2H), 2.31 (t, J = 8.0 Hz, 4H), 2.18 (t, J = 7.6 Hz, 2H),1.92 – 1.89 (m, 1H), 1.84 – 1.80 (m, 1H), 1.15 (d, J = 5.6 Hz, 2H), 0.94 (d, J =3.2 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 171.01, 169.75, 157.97, 156.76,155.30, 153.69, 149.18, 142.07, 142.04, 137.93, 137.73, 115.75, 115.61,113.98, HRMS (ESI) calcd for: C 20 H 22 FN6O [M+H] + 381.1761, found 381.1836. Example 68

[0167] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S The ethyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride was replaced with 1-aminocyclopentyl-1-methanol hydrochloride, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 54 (24.8 mg, 3.0%). 1 HNMR (600 MHz, DMSO- d 6 ) δ 14.03 (s, 1H), 8.60 (d, J = 2.8 Hz, 1H), 8.41 (dd, J =8.7, 2.8 Hz, 1H), 6.17 (s, 1H), 5.43 (t,J = 5.8 Hz, 1H), 3.72 (d, J = 5.7 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.17 (t, J = 7.5 Hz, 2H), 2.12 – 2.09 (m, 2H), 1.93 – 1.89 (m, 2H), 1.79 – 1.75 (m, 2H), 1.62 – 1.59 (m, 2H), 1.15 (t, J = 3.3Hz, 2H), 0.96 – 0.91 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 171.93, 158.89,158.45, 156.36, 154.75, 150.23, 143.11, 143.08, 139.04, 138.84, 116.81,116.67, 115.39, 114.01, 113.96, 66.85, 66.41, 55.38, 40.53, 35.10, 30.84,27.57, 25.72, 24.34, 15.45. HRMS (ESI) calcd for: C 21 H 24 FN6O [M+H] + : 395.1917, found 395.1993. Example 69

[0168] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S )-3-aminobicyclo[2.2.2]octane-2-carboxylic acid ethyl ester hydrochloride is replaced with (1 S , 2 S )-1-aminocyclohexyl-1-ol hydrochloride, replacing compound A-4 with compound 1-52, and the remaining steps were the same as in Example 3, to obtain white solid compound 55 (31.5 mg, 3.8%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 13.98 (s, 1H), 8.60 (d, J= 2.3 Hz, 1H), 8.52(dd, J = 8.8, 2.8 Hz, 1H), 6.64 (s, 1H), 4.76 (d, J = 4.8 Hz, 1H), 3.98 (s, 1H), 3.53 – 3.47 (m, 1H), 2.83 (t, J = 7.7 Hz, 2H), 2.17 (t, J = 7.5 Hz, 2H), 2.06 (d, J = 10.5 Hz, 1H), 1.97 (s, 1H), 1.75 – 1.68 (m, 2H), 1.33 – 1.29 (m, 4H), 1.14 – 1.09 (m, 2H), 0.92 (d, J = 4.1 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 172.59,159.38, 158.35, 157.00, 156.73, 156.46, 154.80, 150.22, 143.02, 138.96,138.76, 117.48, 116.90, 116.77, 115.58, 114.24, 114.05, 113.68, 81.01, 52.64,40.51, 31.60, 30.89, 30.69, 27.58, 25.43, 24.46, 24.05, 15.64, 15.48. HRMS(ESI) calcd for: C 21 H 24 FN6O [M+H] + : 395.1917, found 395.1995. Example 70

[0169] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S )-3-aminobicyclo[2.2.2]octane-2-carboxylic acid ethyl ester hydrochloride is replaced with (1 S , 2 R)-1-aminocyclohexyl-1-ol hydrochloride, replacing compound A-4 with compound 1-52, and the remaining steps were the same as in Example 3, to obtain white solid compound 56 (30 mg, 3.6%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.00 (s, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.43 (dd, J = 8.8, 2.8 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.79 (d, J = 3.8 Hz, 1H), 4.14 (d, J = 10.8 Hz, 1H), 4.04 (s, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.18 (t, J = 7.5 Hz, 2H), 1.80 (t, J = 12.6 Hz, 2H), 1.76 – 1.71 (m, 2H), 1.64 – 1.55 (m, 2H), 1.43 –1.37 (m, 2H), 1.15 – 1.10 (m, 2H), 0.93 (d, J = 3.0 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 171.23, 158.50, 156.91, 155.35, 153.74, 149.17, 142.04, 142.01,137.89, 137.69, 115.78, 115.65, 113.25, 113.20, 113.15, 65.66, 51.93, 39.47,31.53, 29.94, 26.58, 25.68, 24.30, 23.99, 18.69, 14.44, 14.33. HRMS (ESI)calcd for: C 21 H 24 FN6O [M+H] + : 395.1917, found 395.1994. Example 71

[0170] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S )-3-aminobicyclo[2.2.2]octane-2-carboxylic acid ethyl ester hydrochloride is replaced with (1 R , 2 R )-1-aminocyclohexyl-1-ol hydrochloride, replacing compound A-4 with compound 1-52, and the remaining steps were the same as in Example 3, to obtain white solid compound 57 (35 mg, 4.2%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.00 (s, 1H), 8.61 (s, 1H), 8.48 (d, J = 8.8 Hz,1H), 6.98 – 6.92 (m, 1H), 5.11 – 5.06 (m, 1H), 4.54 – 4.45 (m, 1H), 2.83 –2.79 (m, 1H), 2.74 – 2.69 (m, 1H), 2.25 – 2.14 (m, 4H), 2.10 (d, J = 13.5 Hz,1H), 1.88 – 1.82 (m, 1H), 1.78 (d, J = 9.2 Hz, 1H), 1.66 – 1.53 (m, 2H), 1.44 –1.39 (m, 2H), 1.15 – 1.10 (m, 2H), 0.93 (d, J = 3.9 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 172.53, 159.34, 158.35, 157.00, 156.73, 156.45, 156.18, 154.79,150.21, 142.99, 138.96, 138.76, 117.47, 116.89, 116.75, 115.58, 114.23,114.07, 113.68, 111.78, 81.00, 72.12, 60.20, 52.64, 40.51, 31.59, 30.89,30.68, 27.58, 25.43, 25.40, 24.45, 24.05, 21.20, 15.64, 15.49, 14.52. HRMS(ESI) calcd for: C 21 H 24 FN6O [M+H] + : 395.1917, found 395.1993. Example 72

[0171] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S )-3-aminobicyclo[2.2.2]octane-2-carboxylic acid ethyl ester hydrochloride is replaced with (1 s , 3 R , 5 S , 7 s )-4-aminoadamantane-1-ol hydrochloride, replacing compound A-4 with compound 1-52, and the remaining steps were the same as in Example 3, to obtain white solid compound 58 (33.7 mg, 3.6%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.01 (s, 1H), 8.61 (s, 1H), 8.44(d, J = 8.7 Hz, 1H), 6.16 (d, J = 6.2 Hz, 1H), 4.51 (s, 1H), 4.25 (t, J = 4.0 Hz, 1H), 2.93 (t, J = 7.5 Hz, 2H), 2.32 (s, 2H), 2.17 (t, J= 7.6 Hz, 2H), 2.07 –2.00 (m, 3H), 1.88 (d, J = 11.7 Hz, 2H), 1.73 (d, J = 11.6 Hz, 2H), 1.67 (s, 2H), 1.38 (d, J = 12.7 Hz, 2H), 1.13 (s, 2H), 0.95 – 0.91 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 171.33, 158.46, 157.21, 155.37, 153.76, 149.17, 142.00, 137.90,137.70, 115.72, 115.59, 113.69, 113.18, 113.13, 65.12,59.17,54.33,53.47,44.86,44.00,39.48,32.32,29.93,29.43,28.65,26.60,24.45,20.18,14.48,13.50. HRMS (ESI) calcd for: C 25 H 28 FN6O [M+H] + : 447.2230, found 447.2308. Example 73

[0172] The difference from Example 3 is that compound C-2 is replaced with compound 1-21, and (2) S ,3 S )-3-aminobicyclo[2.2.2]octane-2-carboxylic acid ethyl ester hydrochloride is replaced with (1 s , 3 R , 5 S , 7 s )-4-aminoadamantane-1-ol hydrochloride, replacing compound A-4 with compound 1-52, and the remaining steps were the same as in Example 3, to obtain white solid compound 59 (35 mg, 3.7%). 1 H NMR (600 MHz, DMSO- d 6 ) δ 14.02 (s, 1H), 8.60 (s, 1H), 8.48 (dd, J=8.6, 2.9 Hz, 1H), 5.91 (d, J = 5.9 Hz, 1H), 4.54 (s, 1H), 2.83 (t, J = 7.5 Hz,2H), 2.29 – 2.20 (m, 4H), 2.15 (t, J = 7.4 Hz, 2H), 2.12 (d, J = 8.6 Hz, 4H), 1.68 (d, J = 11.5 Hz, 2H), 1.60 (d, J = 10.8 Hz, 3H), 1.51 (d, J = 12.2 Hz, 1H), 1.13 (q, J = 3.8 Hz, 2H), 0.95 – 0.91 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6 ) δ171.85, 158.96, 158.63, 156.34, 154.73, 150.22, 143.39, 143.35, 138.87,138.67, 116.71, 116.57, 115.06, 113.98, 113.93,67.99,60.21,55.00,49.69,44.81,40.52,35.36,30.82,30.72,27.56,25.69,21.22,15.40,14.54. 25 H 28 FN6O [M+H] + : 447.2230, found 447.2307. Example 74

[0173] The difference from Example 3 is that compound C-2 is replaced with compound B-1, and (2) S ,3 S The ethyl 2-carboxylate hydrochloride of 3-aminobicyclo[2.2.2]octane-2-carboxylate was replaced with compound 1-6, and compound A-4 was replaced with compound 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 60 (33 mg, 3.5%). 1 H NMR (600 MHz, DMSO-d 6 ) δ 14.09 (s, 1H), 12.46 (s, 1H), 8.63 (s, 1H), 8.43–8.47 (m, 1H), 7.15 (d, J = 6.9 Hz, 1H), 6.05 (t, J = 7.5 Hz, 1H), 5.74 (t, J = 7.3 Hz, 1H), 4.82 – 4.76(m, 1H), 3.31 – 3.27 (m, 1H), 3.16–3.19(m, 1.7 Hz, 1H), 2.71–2.75 (m, 1H), 2.23–2.27 (m, 1H), 1.12–1.16 (m, 2H), 1.04–1.08 (m, 2H), 0.97–1.02 (m, 1H), 0.22–0.26 (m, 1H), 0.06–0.11 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 174.9,156.5, 154.9, 151.8, 151.1, 151.0, 143.7, 142.0, 130.5, 127.5, 52.9, 50.4,40.5, 35.4, 34.6, 14.5, 9.8, 9.1, 8.9, 6.4, 4.0. HRMS (ESI) calcd for:C 23 H 21 F2N6O2[M+H] + : 451.1616, found 451.1695. Example 75

[0174] The difference from Example 3 is that compound C-2 is replaced with compound 1-25, and (2) S ,3 S The ethyl 2-carboxylate hydrochloride of 3-aminobicyclo[2.2.2]octane-2-carboxylate was replaced with compounds 1-6, and compound A-4 was replaced with compounds 1-52. The remaining steps were the same as in Example 3, to obtain white solid compound 61 (32.7 mg, 3.6%). 1 H NMR (600 MHz, DMSO- d 6) δ 14.43 – 14.17 (m, 1H), 12.51 (s, 1H), 8.65 (d, J = 16.9 Hz, 2H),6.94 – 6.77 (m, 1H), 6.09 (t, J = 7.4 Hz, 1H), 5.75 (t, J = 7.1 Hz, 1H), 4.92 (s,1H), 3.24 – 3.16 (m, 1H), 2.87 (t, J = 7.7 Hz, 2H), 2.77 – 2.60 (m, 3H), 2.03 –2.05 (m, 2H), 1.13 (s, 1H), 1.00 – 1.03 (m, 1H), 0.26 (q, J = 6.7 Hz, 1H), 0.09– 0.11 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6 ) δ 173.76, 157.68, 155.53, 153.92,129.44, 126.48, 114.41, 51.85, 49.59, 39.46, 34.51, 33.64, 32.67, 26.71,20.55, 7.88, 5.33, 2.98. HRMS (ESI) calcd for: C 23 H 22 FN6O2[M+H] + : 433.1710, found 433.1785. Example 1 The anti-influenza virus activity of the compound was detected by the CCK-8 colorimetric method combined with the CPE effect assay. (1) MDCK cells were fed at a rate of 2 × 10⁻⁶ 5 The cells were seeded at a density of 1 cell / mL in 96-well plates and cultured overnight at 37 °C in a 5% CO2 cell culture incubator until the cells grew into a monolayer.

[0175] (2) Discard the cell culture medium and wash twice with autoclaved sterile PBS. Dilute the virus solution (100 TCID50) with FBS-free DMEM medium. 50 ), 100 μL / well was added to the cells, and a blank control group was set up. The cells were incubated at 37 ℃ and 5% CO2 for 1 h.

[0176] (3) Discard the virus solution and serially dilute the compound with DMEM medium containing 0.5 μg / mL TPCK-trypsin without FBS. Add 200 μL / well to the cells and set up a blank control group, a virus control group and a positive drug control group. Continue to incubate in a 37 ℃, 5% CO2 cell culture incubator for 36-48 h.

[0177] (4) Observe the lesions in the virus control group and observe and photograph the CPE effect in the compound treatment group using a microscope.

[0178] (5) Discard the drug-containing culture medium, mix DMEM without FBS and CCK-8 at a ratio of 20:1, add 100 μL / well to the cells, and continue to incubate in a 37 ℃, 5% CO2 cell culture incubator for 1 h.

[0179] (6) After 1 h, the absorbance value was detected at 450 nm using an ELISA reader. The inhibition rate of the compound against influenza A at the corresponding concentration was calculated based on the absorbance value: Inhibition rate (%) = [1 - (A drug group - A blank group) / (A virus group - A blank group)] × 100%.

[0180] The inhibition rate of the compound was analyzed using nonlinear fitting with GraphPad Prism software to obtain the EC50 of the compound. 50 Values. Experimental results are shown in Tables 1-2.

[0181] Table 1. Tests of the anti-H1N1 virus activity of the compounds in MDCK cells.

[0182] Table 2. Inhibitory activity and toxicity of PB2 inhibitors against influenza virus A / WSN / 1933 (H1N1) a

[0183] a EC 50 The value was calculated using GraphPad Prism software. Security Index (SI) = CC 50 / EC 50 . As shown in Tables 1 and 2, based on the molecular structure of Onradivir, the pyrimidine core was modified by replacing the CF bond at position 5 with an N atom and the N atom at position 1 with CH or C-CF3, yielding compounds 1, 10, and 11. Activity tests showed that these compounds exhibited excellent antiviral activity at nanomolar concentrations. Further attempts were made to replace the cyclopropyl group with different hydrophobic groups based on compound 1. Activity results showed that the activity of most compounds decreased by more than 10 times compared to compound 1, suggesting that the cyclopropyl group may be the optimal match for the hydrophobic cavity of this protein and is difficult to be effectively replaced by other hydrophobic fragments. Based on the principle of isosterism, the carboxyl group was replaced with other acidic or neutral groups. Surprisingly, compound 14 showed superior antiviral activity compared to Onradivir. Compound 17, obtained by replacing the carboxyl group with isohydroxamic acid containing a weakly acidic group, showed antiviral activity comparable to Onradivir. For the modification of azidazole, compounds 18 and 19 showed better antiviral activity. Combining the indole cores of compounds 18 and 19 with the key pharmacophore of compound 14 yields compounds 25 and 12, which exhibit antiviral activity comparable to Onradivir. EC50 of compounds 26, 27, 29 to 31, 33, 36 to 38, 42, 48, 56, 57, and 60... 50 The values ​​are all in the nanomolar range, especially compound 33, whose activity is in the subpicomolar range, comparable to that of Onradivir.

[0184] Next, compounds with good activity against H1N1 were selected, and their binding to the PB2 protein was tested. The results are shown in Table 3. The affinity of the compounds for PB2 is consistent with their inhibitory activity against H1N1. Among them, compound 33 has a K... d With a concentration of 0.06 µM, it is superior to K-type Onradivir. d Value: 0.09 µM.

[0185] Table 3. Binding affinity of PB2 inhibitors to PB2 protein

[0186] Based on the above results, the antiviral activity of compounds 33 and 12 against multiple influenza virus strains was further evaluated, as detailed in Table 4.

[0187] Table 4. Inhibitory activities of compounds 33 and 12 against multiple influenza virus strains. a

[0188] a EC50 The value was calculated using GraphPad Prism software. Security Index (SI) = CC 50 / EC 50 . As shown in Table 4, compound 33 exhibits potent antiviral activity against various influenza virus strains, including those resistant to neuraminidase inhibitors and balocimidil, as well as currently circulating H1N1 and H5N1 strains. Most of its antiviral activity is comparable to olativir; however, compound 33 shows limited activity in the CC (Cellular Pathogen Reactivity System). 50 It exhibited superior properties in terms of SI (Self-Induced Influenza) and indicated better safety and efficacy compared to oladivir. These results provide strong support for the potential of compound 33 as an antiviral drug for influenza.

[0189] Compound 12 exhibits potent antiviral activity against various influenza virus strains, including those resistant to neuraminidase inhibitors, as well as currently prevalent H1N1 and H3N2 strains. Most of its antiviral activity is comparable to onradivir; however, compound 12 shows some resistance in CC... 50 It exhibited superior properties in terms of SI, indicating better safety and efficacy compared to onradivir. These results provide strong support for the potential of compound 12 as an antiviral drug for influenza.

[0190] Example 2 FP assay to detect the inhibitory activity of compounds on PB2 protein FP assays were performed in black 96-well plates (Corning) using FITC-labeled m7GTP (EDA-m7GTP-ATTO488; Jena Bioscience) as the detection probe. One PB2cap of influenza A virus was added to a buffer containing 50 mM HEPES (pH 7.2), 0.5 mM EDTA, 100 mM KCl, and 1 mM DTT, followed by the addition of FITC-m7GTP to a final concentration of 20 nM. The mixture was incubated at room temperature for 30 minutes. Subsequently, a small molecule compound dissolved in DMSO was added to the mixture, and incubation was continued at room temperature for another 30 minutes. The total reaction volume was 50 µl, containing 2% DMSO. Finally, fluorescence signals were measured in fluorescence polarization mode using a BioTek Synergy Neo2 multimode microplate reader with excitation at 480 nm and emission at 520 nm. The inhibition rate of the compound was analyzed using nonlinear fitting with GraphPad Prism software to obtain the IC50 of the compound. 50 Values. The experimental results are shown in Table 5.

[0191] Table 5. Inhibitory activity of some compounds against the influenza PB2 target.

[0192] The results in Table 5 show that the inhibitory activity of the newly synthesized compounds against the PB2 target is mostly comparable to that of onradivir, which is consistent with their antiviral activity. Among them, compounds 14, 15, 16, 19, 25, and 12 exhibit superior inhibitory activity against the PB2 target compared to onradivir.

[0193] Example 3: CCK-8 assay for the toxicity of the compound to MDCK cells. The cytotoxicity of the test compounds to MDCK cells was determined using the CCK-8 assay kit. MDCK cells (2.5 × 10⁴ cells per well) were seeded in 96-well plates and incubated overnight at 37 °C with 5% CO₂. The culture medium was then removed, and different concentrations of the test compounds were added, followed by incubation for 2 days. Afterward, 10 µL of CCK-8 reagent was added to each well, and incubation was carried out for 2 hours. The optical density (OD) at 450 nm was measured using a microplate reader, and the 50% cytotoxic concentration (Cd / C) of the test compounds at 1 h and 2 h was calculated. 50 ).

[0194] Table 6. Cytotoxicity of Compounds to MDCK Cells (CC) 50

[0195] The above results show that the compound of this application exhibits micromolar-level effects on MDCK cells and has weak cytotoxicity.

[0196] Example 4 Compound 12 effectively protects mice from influenza virus infection and causes death. Based on their strong in vitro activity and favorable pharmacokinetic properties, we evaluated the in vivo efficacy of compound 12 or compound 33 by gavage administration to BALB / c mice infected with A / WSN / 1933 (H1N1), with Onradivir used as a positive control. Twenty-four hours post-infection, mice were treated twice daily with oral administration of Onradivir (10 mg / kg), compound 12 (3 mg / kg, 10 mg / kg, and 30 mg / kg), or compound 33 (3 mg / kg, 10 mg / kg, and 30 mg / kg), respectively, for four consecutive days. Mice survival and weight changes were monitored and recorded daily. On day 4 post-infection, all mice were euthanized by cervical dislocation, and lung tissue was collected for further analysis.

[0197] like Figure 1 and Figure 2The results showed that mice in the virus group experienced continuous weight loss from infection to day 8 and all died on day 9. Mice treated with compound 12 (3 mg / kg, 10 mg / kg, and 30 mg / kg) had survival rates of 100%, 85.7%, and 85.7%, respectively. Mice treated with onradivir (10 mg / kg) had a survival rate of 57.1%. At the same dosage, compound 12 showed superior protective efficacy against onradivir in mice (85.7% vs. 57.1%). Following infection, mice experienced varying degrees of weight loss, but the weight of mice in the high, medium, and low dose groups of compound 12, as well as the onradivir (10 mg / kg) group, began to gradually recover from day 12.

[0198] Mice treated with compound 33 (3 mg / kg, 10 mg / kg, and 30 mg / kg) had survival rates of 100%, 71.4%, and 42.8%, respectively. Figure 4 Mice treated with onradivir (10 mg / kg) had a survival rate of 57.1%. At the same dose, compound 33 showed superior protective efficacy against onradivir in mice (71.4% vs. 57.1%). Figure 3 As shown, the body weight of mice decreased to varying degrees after infection, but the body weight of mice in the high, medium and low dose groups of compound 33 and the Onradivir (10 mg / kg) group gradually recovered starting from day 12.

[0199] The results of lung index and viral titer analysis showed that the lung index and viral titer in the high, medium, and low dose groups of compound 33 were significantly different from those in the model group, indicating that compound 33 has a good protective effect on the lungs, effectively reducing the influenza virus titer in the lungs of infected mice, and this effect is dose-dependent. At the same dose, the antiviral effect of compound 33 is comparable to that of onradivir. Figure 5 Furthermore, RT-qPCR results showed that compound 33 could inhibit the production of virus-induced inflammatory cytokines while increasing the levels of anti-inflammatory factors. Pro-inflammatory factors including IFN-β, TGF-β, IP-10, IL-6, IL-10, TNF-α, and IL-1β were all significantly inhibited, with the inhibitory effect on CCL5 being superior to that of Onradivir (see...). Figure 6 Correspondingly, the levels of anti-inflammatory factors IL-4 and IL-13 were significantly higher in compound 33 than in the Onradivir group.

[0200] Furthermore, ELISA results showed that compound 33 reduced the release of inflammatory factors in the serum of influenza virus-infected mice and also had some effect on the expression of anti-inflammatory factors, with its activity comparable to that of onradivir (see [link to ELISA results]). Figure 7 ).

[0201] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An anti-influenza compound or its stereoisomers, geometric isomers, tautomers, enantiomers, nitrides, hydrates, solvates, crystalline forms, metabolites, pharmaceutically acceptable salts, prodrugs, or isotopic labels thereof, characterized in that, It has the structure shown in equation (I): （I）； Among them, X 1 For CR 3 Or N; X 2 For CR 4 Or N; Z is CR 5 Or N; Y 1 For CR 6 Or N; Y 2 For CR 7 Or N; Y 3 For CR 8 Or N; W is -NH- or -N=CH-; R 2 R 3 R 4 R 5 R 6 R 7 R 8 Each of these groups can be independently H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, -OH, -B(OH)2, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkenyl, haloynyl, alkenyl, ynyl, cycloalkyl, heterocyclic, spirocyclic, aryl, or heteroaryl; or R 2 and R 4 Together with the carbon atoms attached to them, they form cycloalkyl, heterocyclic, spirocyclic, aryl, or heteroaryl groups; or R 2 and R 3 Together with the carbon atoms attached to them, they form cycloalkyl, heterocyclic, spirocyclic, aryl, or heteroaryl groups; R 1 is -R 9 -COO-R 10 、-(CR 12 2) n -R 11 -(CR 12 2) n -O-H、-(CR 12 2) m -O-H、-(CR 12 2) h -COO-R 10 or -R 11 -CONR 13 -R 14 ; n, m, and h are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R 9 R 11 Each independently , , , , , cycloalkyl, heterocyclic, aryl or heteroaryl; R 10 R 12 Each is independently H or alkyl; R 13 R 14 Each is independently H, -CN, -OH, -O(CR) 12 2) m -H or alkyl group; The cycloalkyl, heterocyclic, spirocyclic, aryl, and heteroaryl groups are further mono- or poly-substituted by H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, -OH, -B(OH)2, nitro, or alkyl groups.

2. The anti-influenza compound according to claim 1, characterized in that, R 2 R 3 R 4 R 5 R 6 R 7 R 8 Each of the following can be independently represented as H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, -OH, -B(OH)2, nitro, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkyl, C 2-12 Haloalkenyl, C 2-12 Halogenated alkynyl group, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 5-12 Spiral ring, C 6-12 Aryl or C 1-12 heteroaryl; or R 2 and R 4 Together with the carbon atoms attached to them, they form C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 5-12 Spiral ring, C 6-12 Aryl or C 1-12 heteroaryl; or R 2 and R 3 Together with the carbon atoms attached to them, they form C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 5-12 Spiral ring, C 6-12 Aryl or C 1-12 Mixed aromatic compounds.

3. The anti-influenza compound according to claim 1, characterized in that, R 2 R 3 R 4 R 5 R 6 R 7 R 8 Each of the following can be independently represented as H, -F, -Cl, -Br, -I, -NH2, -CN, -CHO, -COOH, -OH, -B(OH)2, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, C 1-6 Alkoxy, difluoromethyl, fluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or ; or R 2 and R 4 Together with the carbon atoms attached to them, they form cyclohexyl groups. ; or R 2 and R 3 Together with the carbon atoms attached to them, they form cyclohexyl groups. .

4. The anti-influenza compound according to claim 1, characterized in that, R 9 R 11 Each independently , , , , C 3-12 cycloalkyl, C 2-12 Heterocyclic group, C 6-12 Aryl or C 1-12 Mixed aromatics; Or, R 9 R 11 Each independently , , , , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or .

5. The anti-influenza compound according to claim 1, characterized in that, R 10 R 12 Each independently is H or C 1-6 alkyl; Or, R 10 R 12 Each can be independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, or n-pentyl; Or, R 13 R 14 Each is independently H, -CN, -OH, -O(CR) 12 2) m -H or C 1-6 alkyl; Or, R 13 R 14 Each is independently H, -CN, -OH, -O(CR) 12 2) m -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, or n-pentyl.

6. The anti-influenza compound according to claim 1, characterized in that, The influenza compound of the present invention has one of the following structures: (II)、 (III)、 (IV)、 (V)、 (VI)、 (VII)。 7. The anti-influenza compound according to claim 1, characterized in that, The influenza compound has one of the following structures: 。 8. A method for preparing the compound according to any one of claims 1 to 7, characterized in that, The specific steps are as follows: ； The compound shown in formula (I) is prepared by coupling reaction of the compound shown in formula (I-1) with the compound shown in formula (I-2).

9. A pharmaceutical composition comprising the compound of any one of claims 1 to 7, further comprising a pharmaceutically acceptable carrier and / or excipients.

10. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 9 in the preparation of a medicament for the prevention, protection or treatment of influenza viruses in animals or human individuals.

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