Aza aromatic ring formamide compound and application thereof

Abstract

The invention relates to an aza-aromatic ring formamide compound and application thereof. The aza-aromatic ring formamide compound has the structural characteristics as shown in formula I, and can effectively treat diseases caused by respiratory viruses such as influenza. # imgabs0 #

Description

Technical Field

[0001] The present application relates to the technical field of medicinal chemistry, and in particular to an azaaromatic ring carboxamide compound and application thereof. Background Art

[0002] Influenza (hereinafter referred to as flu) is an acute respiratory infectious disease that seriously endangers human health. It is caused by influenza virus and has the characteristics of high morbidity, widespread prevalence and rapid spread. At present, the main means of treating influenza is to use antiviral chemical small molecule drugs that target key proteins of viral replication, such as M2 ion channel protein inhibitors, hemagglutinin (HA) inhibitors, neuraminidase (NA) inhibitors and RNA-dependent RNA polymerase (RdRP) subunits (PA, PB1, PB2 and their interactions) inhibitors. The anti-influenza virus methods under study include antisense oligonucleotides, ribozymes and deoxyribozymes to inhibit influenza virus replication or RNA expression. The first-line anti-influenza virus drugs in clinical practice are oseltamivir, a neuraminidase inhibitor, and mabaloxavir, a PA inhibitor. The remaining drugs are only used when these two types of drugs fail to work on specific virus strains, specific populations, or against general non-virulent viruses.

[0003] However, the therapeutic window of oseltamivir is narrow, and the drug effect is only apparent when used within 48 hours of infection. In addition, after years of use, a variety of drug-resistant strains have emerged, making it difficult to meet clinical use requirements. Mabaloxavir is the first new anti-influenza drug with a completely new mechanism in nearly 20 years. It was obtained by the Japanese Shionogi Pharmaceutical Company through structural modification of the mother nucleus of dolutegravir. Only one dose of the drug is required for the entire course of the disease to better control the condition. Mabaloxavir can stop viral detoxification within 24 hours of taking it, and effectively relieve influenza symptoms such as high fever and general fatigue. However, when mabaloxavir was used clinically, side effects such as allergic reactions, rashes, urticaria, and vomiting were found, especially when used in pediatric patients, the incidence of drug-resistant strains was higher.

[0004] Therefore, there is a need to develop more drugs that can effectively treat diseases caused by respiratory viruses such as influenza. Summary of the invention

[0005] Based on this, the present application provides an azaaromatic ring carboxamide compound, which can effectively treat diseases caused by respiratory viruses such as influenza.

[0006] In the first aspect of the present application, an azaaromatic ring carboxamide compound having the structural characteristics shown in Formula I or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, or deuterated product thereof is provided:

[0007]

[0008] in,

[0009] m is selected from: 0 or 1;

[0010] X is selected from: N or CH;

[0011] L is selected from: a single bond or a C2-C10 heteroaryl;

[0012] n is selected from: 0, 1, 2 or 3;

[0013] R1 is selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, aldehyde, amino, at least one selected from R S2 Substituents substituted or unsubstituted C1-C5 alkyl, at least one selected from R S1 Substituents substituted or unsubstituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 11 、-N(R 12 R 13 ), amide, sulfonamide, at least one selected from R 12 Substituents substituted or unsubstituted C6-C10 aryl or at least one selected from R 12 R is a substituted or unsubstituted C2-C10 heteroaryl, oxo, -NHC(O)O-C1-C5 alkyl, -C1-C5 alkyl-NHC(O)O-C1-C5 alkyl, 3-8 membered heterocyclic group, -C1-C5 alkyl-C6-C10 aryl, -C1-C5 alkyl-O-C2-C10 heteroaryl or -C(O)-C2-C10 heteroaryl; S1 Including: H, C6-C10 aryl, hydroxyl, halogen, nitro, cyano, C1-C5 alkoxy, C1-C5 alkyl or halogen-substituted C1-C5 alkyl; R 11 , R 12 , R 13 Each independently selected from: C1-C5 alkyl, R 12 With R 13 Ringed or not ringed;

[0014] Y is selected from: CH-R5 or N-R5; R5 is selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, aldehyde, amino, at least one selected from R S2 Substituents substituted or unsubstituted C1-C5 alkyl, at least one selected from R S2 Substituents substituted or unsubstituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 51 、-N(R 52 R 53 ), amide, sulfonamide, at least one selected from R S2 Substituents substituted or unsubstituted C6-C10 aryl or at least one selected from R S2R is a substituted or unsubstituted C2-C10 heteroaryl, oxo, -NHC(O)O-C1-C5 alkyl, -C1-C5 alkyl-NHC(O)O-C1-C5 alkyl, 3-8 membered heterocyclic group, -C1-C5 alkyl-C6-C10 aryl, -C1-C5 alkyl-O-C2-C10 heteroaryl or -C(O)-C2-C10 heteroaryl; S2 Including: H, C6-C10 aryl, hydroxyl, halogen, nitro, cyano, C1-C5 alkoxy, C1-C5 alkyl or halogen-substituted C1-C5 alkyl; R 51 , R 52 , R 53 Each independently selected from: C1-C5 alkyl, R 52 With R 53 Ringed or not ringed;

[0015] Optionally, R5, R1 and the atoms to which they are attached together form a saturated or unsaturated ring, or R1 and Together they form a bridge ring structure;

[0016] R2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C1-C5 alkyl, fluorine-substituted C1-C5 alkyl, C3-C8 cycloalkyl, fluorine-substituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 21 、-N(R 22 R 23 ), amide, sulfonamide, 5-10 membered heterocyclic group, C6-C10 aryl or C2-C10 heteroaryl; R 21 , R 22 , R 23 Each independently selected from: C1-C5 alkyl, R 22 With R 23 The 5- to 10-membered heterocyclic group, C6- to C10 aryl group, and C2- to C10 heteroaryl group are each independently selected from at least one of R S3 The substituents are substituted or unsubstituted, R S3 Including: H, C1~C5 alkyl, -NHC(O)-R 24 , -C(O)NH2 or -C(O)NH2, R 24 Selected from: C1-C5 alkyl;

[0017] R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C1-C5 alkyl, fluorine-substituted C1-C5 alkyl, C3-C8 cycloalkyl, fluorine-substituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 31 、-N(R 32 R 33), amide, sulfonamide, C6-C10 aryl or C2-C10 heteroaryl; R 31 , R 32 , R 33 Each independently selected from: C1-C5 alkyl, R 32 With R 33 Ringed or not ringed;

[0018] R4 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C1-C5 alkyl, fluorine-substituted C1-C5 alkyl, C3-C8 cycloalkyl, fluorine-substituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 41 、-N(R 42 R 43 ), amide, sulfonamide, C6-C10 aryl or C2-C10 heteroaryl; R 41 , R 42 , R 43 Each independently selected from: C1-C5 alkyl, R 42 With R 43 Ringed or not.

[0019] The second aspect of the present application provides a pharmaceutical composition, comprising the azaaromatic ring carboxamide compound or its pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated product described in the first aspect, and a pharmaceutically acceptable carrier.

[0020] The third aspect of the present application provides the use of the nitrogen heteroaromatic ring carboxamide compound or its pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated product described in the first aspect, or the pharmaceutical composition described in the second aspect in the preparation of a drug for treating and / or preventing respiratory viral infections.

[0021] The above-mentioned nitrogen heteroaromatic ring carboxamide compounds can exert good anti-influenza activity through reasonable structural design, especially have anti-influenza virus A / HK / 1 / 68 (H3N2), A / WSN / 33 (H1N1) and influenza B virus strain B / Lee / 40 replication activity. DETAILED DESCRIPTION

[0022] The following is a further detailed description of the azaaromatic ring carboxamide compounds and their applications of the present application in conjunction with specific examples. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thoroughly understood.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0024] The optional scope of the terms "and / or", "or / and", and "and / or" used in this article includes any one of two or more related listed items, and also includes any and all combinations of the related listed items, said any and all combinations include any combination of any two related listed items, any more related listed items, or all related listed items.

[0025] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0026] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0027] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

[0028] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0029] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range of instrument control.

[0030] The room temperature in the present application generally refers to 4°C to 30°C, preferably 20±5°C.

[0031] The term "hydroxyl" as used herein refers to -OH.

[0032] The "aldehyde group" in the present application refers to -C(O)H.

[0033] "Amino" as used herein refers to -NH2.

[0034] "Alkyl" in the present application refers to a monovalent residue formed by the loss of a hydrogen atom from a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Phrases containing this term, for example, "C1-C5 alkyl" refers to an alkyl containing 1 to 5 carbon atoms, and each occurrence may be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl. Suitable examples include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t- Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3).

[0035] "Cycloalkyl" in this application refers to a non-aromatic hydrocarbon containing ring carbon atoms, which can be a monocyclic alkyl, a spirocyclic alkyl, or a bridged cycloalkyl. Phrases containing this term, for example, "C3-C8 cycloalkyl" refers to a cycloalkyl containing 3 to 8 carbon atoms, and each occurrence can be independently C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, C8 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0036] The term "cyano" as used herein refers to -CN.

[0037] The "carboxyl group" in the present application refers to -C(O)OH.

[0038] "Alkoxy" in this application refers to a group with a structure of -O-alkyl, i.e., an alkyl group as defined above is connected to an adjacent group via an oxygen atom. Phrases containing this term, for example, "C1-C5 alkoxy" means that the alkyl portion contains 1 to 5 carbon atoms, and each occurrence can be independently C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy. Suitable examples include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-O-CH2CH3 or -OEt) and tert-butoxy (-OC(CH3)3 or -OtBu).

[0039] The "ester group" in the present application refers to -[RC(O)O-R'], wherein R and R' are each independently selected from non-existent or alkyl, and they are not both non-existent; the alkyl group can be, for example, C1-C5 alkyl.

[0040] The "sulfonyl ester group" in the present application refers to -[RS(O)2-R'], wherein R and R' are each independently selected from non-existent or alkyl, and cannot be both non-existent; the alkyl group can be, for example, C1 to C5 alkyl.

[0041] The "amide group" in the present application refers to -[RC(O)N(R')2], wherein R is selected from non-existent or alkyl, R' is independently selected from non-existent, H or alkyl, and R and R' are not both non-existent, and two R's are not both H; the alkyl group can be, for example, a C1-C5 alkyl group, and optionally, the two R's may form a ring or not, and when forming a ring, they may be directly connected to form a cycloalkyl group, or may form a heterocyclic group together with at least one atom selected from N, O, S, and the cycloalkyl group or heterocyclic group may further include a C1-C2 alkyl group as a substituent.

[0042] The "sulfonamide group" in the present application refers to -[RS(O)2-N(R')2], wherein R is selected from non-existent or alkyl, R' is independently selected from non-existent, H or alkyl, and R and R' are not both non-existent, and the two R's are not both H; the alkyl group can be, for example, a C1-C5 alkyl group, and optionally, the two R's may form a ring or not. When forming a ring, they may be directly connected to form a cycloalkyl group, or they may form a heterocyclic group together with at least one atom selected from N, O, and S. The cycloalkyl group or heterocyclic group may further include a C1-C2 alkyl group as a substituent.

[0043] "Aryl" in this application refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom, which can be a monocyclic aromatic group, a condensed aromatic group, or a polycyclic aromatic group. For polycyclic rings, at least one is an aromatic ring system. For example, "C6-C10 aryl" refers to an aromatic group containing 6 to 10 carbon atoms, and each occurrence can be independently C6 aryl, C7 aryl, C8 aryl, C9 aryl or C10 aryl. Suitable examples include, but are not limited to, benzene, biphenyl, naphthalene, anthracene, phenanthrene, diphenylene, triphenylene and their derivatives.

[0044] In the present application, "heteroaryl" refers to an aryl group in which at least one carbon atom is replaced by a non-carbon atom, and the non-carbon atom may be a N atom, an O atom, an S atom, etc. For example, "C2-C10 heteroaryl" refers to a heteroaryl group containing 2 to 10 carbon atoms, and each occurrence may be independently a C2 heteroaryl group, a C3 heteroaryl group, a C4 heteroaryl group, a C5 heteroaryl group, a C6 heteroaryl group, a C7 heteroaryl group, a C8 heteroaryl group, a C9 heteroaryl group or a C10 heteroaryl group. Suitable examples include, but are not limited to, furanyl, benzofuranyl, thienyl, benzothienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiazolyl, tetrazolyl, indolyl, carbazolyl, pyrroloimidazolyl, pyrrolopyrrolyl, thienopyrrolyl, thienothiphenyl, furopyrrolyl, furofuranyl, thienofuranyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, o-naphthyl, quinoxalinyl, phenanthridinyl, primidinyl, quinazolinyl, and quinazolinonyl.

[0045] The "oxo group" in the present application refers to "=O".

[0046] "Heterocyclyl" in this application means that at least one carbon atom is replaced by a non-carbon atom on the basis of a cycloalkyl group, and the non-carbon atom can be an N atom, an O atom, an S atom, etc., and can be a saturated ring or a partially unsaturated ring. Phrases containing this term, for example, "C4-C9 heterocyclyl" refers to a heterocyclyl group containing 4 to 9 carbon atoms, and each occurrence can be independently C4 heteroalkyl, C5 heteroalkyl, C6 heteroalkyl, C7 heteroalkyl, C8 heteroalkyl or C9 heteroalkyl. Suitable examples include, but are not limited to: dihydropyridyl, tetrahydropyridyl (piperidyl), tetrahydrothienyl, sulfur-oxidized tetrahydrothienyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroindole.

[0047] The term "halogen" or "halo" as used herein refers to F, Cl, Br or I.

[0048] "Nitro" as used herein refers to -NO2.

[0049] The term “at least one” in the present application is not limiting and may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0050] "Pharmaceutically acceptable salt" in this application refers to a salt suitable for use as a drug formed by any compound in the structure shown and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. Among them, one type of salt is a salt formed by the compound of the present invention and an acid. Acids suitable for forming salts include but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another type of salt is a salt formed by a compound of the present invention and a base. Suitable bases for forming salts include but are not limited to alkali metal salts (e.g., sodium salts or potassium salts), alkaline earth metal salts (e.g., magnesium salts or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), for example, methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0051] "Prodrug molecule" in the present application refers to any compound that produces a drug, i.e., an active ingredient, due to a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, a photolysis and / or a metabolic chemical reaction when applied to an organism. Prodrugs are therefore covalently modified analogs or potential forms of therapeutically active compounds. Suitable examples include, but are not limited to, forms such as carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo compound, phosphoramide, glucoside, ether, acetal of the compound.

[0052] In some examples of the present application, an azaaromatic ring carboxamide compound having a structural feature shown in Formula I or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, or deuterated product thereof is provided:

[0053]

[0054] in,

[0055] m is selected from: 0 or 1;

[0056] X is selected from: N or CH;

[0057] L is selected from: a single bond or a C2-C10 heteroaryl;

[0058] n is selected from: 0, 1, 2 or 3;

[0059] R1 is selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, aldehyde, amino, at least one selected from R S2 Substituents substituted or unsubstituted C1-C5 alkyl, at least one selected from R S1 Substituents substituted or unsubstituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 11 、-N(R 12 R 13 ), amide, sulfonamide, at least one selected from R 12 Substituents substituted or unsubstituted C6-C10 aryl or at least one selected from R 12 R is a substituted or unsubstituted C2-C10 heteroaryl, oxo, -NHC(O)O-C1-C5 alkyl, -C1-C5 alkyl-NHC(O)O-C1-C5 alkyl, 3-8 membered heterocyclic group, -C1-C5 alkyl-C6-C10 aryl, -C1-C5 alkyl-O-C2-C10 heteroaryl or -C(O)-C2-C10 heteroaryl; S1 Including: H, C6-C10 aryl, hydroxyl, halogen, nitro, cyano, C1-C5 alkoxy, C1-C5 alkyl or halogen-substituted C1-C5 alkyl; R 11 , R 12 , R 13 Each independently selected from: C1-C5 alkyl, R 12 With R 13 Ringed or not ringed;

[0060] Y is selected from: CH-R5 or N-R5; R5 is selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, aldehyde, amino, at least one selected from R S2 Substituents substituted or unsubstituted C1-C5 alkyl, at least one selected from R S2 Substituents substituted or unsubstituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 51 、-N(R 52 R 53 ), amide, sulfonamide, at least one selected from R S2 Substituents substituted or unsubstituted C6-C10 aryl or at least one selected from R S2 R is a substituted or unsubstituted C2-C10 heteroaryl, oxo, -NHC(O)O-C1-C5 alkyl, -C1-C5 alkyl-NHC(O)O-C1-C5 alkyl, 3-8 membered heterocyclic group, -C1-C5 alkyl-C6-C10 aryl, -C1-C5 alkyl-O-C2-C10 heteroaryl or -C(O)-C2-C10 heteroaryl; S2Including: H, C6-C10 aryl, hydroxyl, halogen, nitro, cyano, C1-C5 alkoxy, C1-C5 alkyl or halogen-substituted C1-C5 alkyl; R 51 , R 52 , R 53 Each independently selected from: C1-C5 alkyl, R 52 With R 53 Ringed or not ringed;

[0061] Optionally, R5, R1 and the atoms to which they are attached together form a saturated or unsaturated ring, or R1 and Together they form a bridge ring structure;

[0062] R2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C1-C5 alkyl, fluorine-substituted C1-C5 alkyl, C3-C8 cycloalkyl, fluorine-substituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 21 、-N(R 22 R 23 ), amide, sulfonamide, 5-10 membered heterocyclic group, C6-C10 aryl or C2-C10 heteroaryl; R 21 , R 22 , R 23 Each independently selected from: C1-C5 alkyl, R 22 With R 23 The 5- to 10-membered heterocyclic group, C6- to C10 aryl group, and C2- to C10 heteroaryl group are each independently selected from at least one of R S3 The substituents are substituted or unsubstituted, R S3 Including: H, C1~C5 alkyl, -NHC(O)-R 24 , -C(O)NH2 or -C(O)NH2, R 24 Selected from: C1-C5 alkyl;

[0063] R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C1-C5 alkyl, fluorine-substituted C1-C5 alkyl, C3-C8 cycloalkyl, fluorine-substituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 31 、-N(R 32 R 33 ), amide, sulfonamide, C6-C10 aryl or C2-C10 heteroaryl; R 31 , R 32 , R 33 Each independently selected from: C1-C5 alkyl, R 32 With R 33 Ringed or not ringed;

[0064] R4 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C1-C5 alkyl, fluorine-substituted C1-C5 alkyl, C3-C8 cycloalkyl, fluorine-substituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 41 、-N(R 42 R 43 ), amide, sulfonamide, C6-C10 aryl or C2-C10 heteroaryl; R 41 , R 42 , R 43 Each independently selected from: C1-C5 alkyl, R 42 With R 43 Ringed or not.

[0065] In some of the examples, the azaaromatic carboxamide compounds have the structural features shown in Formula I-11 or Formula I-12:

[0066]

[0067] In some of the examples, the azaaromatic carboxamide compounds have the structural features shown in Formula I-21 or Formula I-22:

[0068]

[0069] In some examples, the azaaromatic carboxamide compounds have the structural features shown in Formula I-21 or Formula I-22: L is selected from: a single bond or the following groups:

[0070] X1, X2, X3, and X4 are each independently selected from: CH or N.

[0071] Furthermore, the azaaromatic ring carboxamide compound has the structural features shown in Formula I-31 or Formula I-32:

[0072]

[0073] In some of these examples, L is selected from: a single bond or the following groups:

[0074]

[0075] In some examples, R2 is selected from: hydrogen, 5-10 membered heterocyclic group, C6-C10 aryl group or C2-C10 heteroaryl group, wherein the 5-10 membered heterocyclic group, C6-C10 aryl group or C2-C10 heteroaryl group is each independently replaced by at least one selected from R S3 The substituents are substituted or unsubstituted, R S3 Including: H, C1~C5 alkyl, -NHC(O)-R 21, -C(O)NH2 or -C(O)NH2.

[0076] In some examples, R2 is selected from: hydrogen or the following groups:

[0077]

[0078] In some of the examples, R5 and R1 are each independently selected from: hydrogen, aldehyde, -C(O)O-C1~C5 alkyl, oxo, -C(O)NH-C1~C5 alkyl, -NHC(O)O-C1~C5 alkyl, -C1~C5 alkyl-NHC(O)O-C1~C5 alkyl, -C1~C5 alkyl-C(O)O-C1~C5 alkyl, 3~8 membered heterocyclic group, -C1~C5 alkyl-C6~C10 aryl, at least one selected from R S2 Substituents substituted or unsubstituted C1-C5 alkyl, at least one selected from R S2 Substituents substituted or unsubstituted C6-C10 aryl, hydroxyl, at least one selected from R S2 Substituents substituted or unsubstituted C2-C10 heteroaryl, -C1-C5 alkyl-O-C2-C10 heteroaryl, -C(O)-C2-C10 heteroaryl; R S2 Including: H, C6~C10 aryl, hydroxyl, halogen, nitro, cyano, C1~C5 alkoxy, C1~C5 alkyl or halogen-substituted C1~C5 alkyl.

[0079] Furthermore, R5 and R1 are not H at the same time.

[0080] In some of the examples, R1 is selected from: aldehyde, -C(O)O-C1~C5 alkyl, oxo, -C(O)NH-C1~C5 alkyl, -NHC(O)O-C1~C5 alkyl, -C1~C5 alkyl-NHC(O)O-C1~C5 alkyl, -C1~C5 alkyl-C(O)O-C1~C5 alkyl, 3~8 membered heterocyclic group, -C1~C5 alkyl-C6~C10 aryl, at least one selected from R S2 Substituents substituted or unsubstituted C1-C5 alkyl, at least one selected from R S2 Substituents substituted or unsubstituted C6-C10 aryl, hydroxyl, at least one selected from R S2 Substituents substituted or unsubstituted C2-C10 heteroaryl, -C1-C5 alkyl-O-C2-C10 heteroaryl, -C(O)-C2-C10 heteroaryl; R S2 Including: H, C6-C10 aryl, hydroxyl, halogen, nitro, cyano, C1-C5 alkoxy, C1-C5 alkyl or halogen-substituted C1-C5 alkyl;

[0081] R5 is selected from: hydrogen, hydroxyl, aldehyde, at least one selected from R S2 Substituents substituted or unsubstituted C6-C10 aryl, R S2 Includes: Halogen.

[0082] In some of these examples, R5, R1 and the atoms to which they are attached together form a saturated or unsaturated ring, or R1 and Forming a bridged ring structure; the saturated or unsaturated ring includes: at least one selected from R S3 A 3- to 8-membered heterocyclic group substituted or unsubstituted by a substituent, a 3- to 8-membered heterocyclic group substituted or unsubstituted by at least one selected from R S3 Substituents substituted or unsubstituted C2-C10 heteroaryl; the bridged ring structure includes at least one selected from R S3 A 6- to 12-membered heterobridged ring group substituted or unsubstituted with a substituent; R S3 Including: -C(O)O-C1~C5 alkyl or halogen substituted or unsubstituted C1~C5 alkyl.

[0083] In some of these examples, R5, R1 and the atoms to which they are attached together form a saturated or unsaturated ring, or R1 and When a bridge ring structure is formed, Selected from the following groups:

[0084]

[0085] In some examples, R3 and R4 are selected from hydrogen.

[0086] In some examples, the azaaromatic carboxamide compound is selected from one of the following compounds:

[0087]

[0088]

[0089]

[0090] In some other examples of the present application, a pharmaceutical composition is also provided, comprising the above-mentioned azaaromatic ring carboxamide compound or its pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated substance, and a pharmaceutically acceptable carrier.

[0091] Without limitation, a "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are compatible with drug administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch, potato starch and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, etc. Rice oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0092] Some other examples of the present application also provide the use of the above-mentioned nitrogen-aromatic ring carboxamide compounds or their pharmaceutically acceptable salts, stereoisomers, prodrug molecules, deuterated substances, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating and / or preventing respiratory viral infections.

[0093] Furthermore, the viruses in the respiratory virus infection include influenza A virus and / or influenza B virus. Without limitation, the influenza A virus includes A / HK / 1 / 68 (H3N2) and / or A / WSN / 33 (H1N1); the influenza B virus includes B / Lee / 40.

[0094] The dosage form and administration mode of the compound of the present invention or its pharmaceutical composition are not particularly limited. Representative administration modes include but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and local administration.

[0095] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffer. Solid dosage forms such as tablets, sugar pills, capsules, pills and granules may be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that may be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the above-mentioned excipients.

[0096] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, specifically, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices. For example, the suspension may contain a suspending agent, specifically, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methylate and agar or mixtures of these substances.

[0097] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0098] Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants, which are prepared by mixing the active ingredient with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required under sterile conditions.

[0099] As used herein, "drug" includes any agent, compound, composition or mixture that provides physiological and / or pharmacological effects in vivo or in vitro, and often provides beneficial effects. The scope of the physiological and / or pharmacological effects produced by the "drug" in vivo is not particularly limited, and may be systemic effects or may only produce effects locally. The activity of the "drug" is not particularly limited, and may be an active substance that can interact with other substances, or an inert substance that does not interact.

[0100] For experimental parameters not specified in the following specific embodiments, reference is made to the instructions given in the present application document, and reference may also be made to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by manufacturers.

[0101] The raw materials and reagents involved in the following specific examples can be obtained from commercial sources, or can be prepared by those skilled in the art according to known methods.

[0102] Example 1: Synthesis of Compound 1

[0103]

[0104] Synthesis of compound 1:

[0105] 4-Quinolinecarboxylic acid (0.17 g, 1.0 mmol), (S)-pyrrolidine-2-carboxylic acid tert-butyl ester (0.19 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.27 g, 1.5 mmol), 1-hydroxybenzotriazole (0.20 g, 1.5 mmol) and N,N-diisopropylethylamine (0.44 mL, 2.5 mmol) were added to dichloromethane (20 mL) and stirred at room temperature for 24 hours. The mixture was detected by TLC. After the reaction was completed, saturated sodium chloride aqueous solution (20 mL) was added for separation and extraction, ethyl acetate (10 mL) was added to the aqueous phase for extraction and separation three times, the organic phases were combined, the organic phases were washed three times with water (10 mL), the organic phases were dried with magnesium sulfate, the magnesium sulfate was filtered, the filtrate was spin-dried to obtain a concentrate, the concentrate was separated and purified by a 300-400 mesh silica gel column, and eluted with a mobile phase of petroleum ether / ethyl acetate (v / v) = 1 / 1 and ethyl acetate, and finally spin-dried to obtain the target compound 1 as a colorless oil of 0.25 g, with a yield of 77%. MS (ESI) m / z calcd for C 19 H 23 N2O3[M+H] +327.2, found 327.3.

[0106] Example 2: Synthesis of Compound 2

[0107]

[0108] Using 4-quinolinecarboxylic acid and ethyl pyrrolidine-3-carboxylate hydrochloride as raw materials, the synthetic method of Example 1 was used to obtain compound 2, which was a yellow oil (0.26 g) with a yield of 88%. MS (ESI) m / z calcd for C 17 H 19 N2O3[M+H] + 299.1,found299.3.

[0109] Example 3: Synthesis of Compound 3

[0110]

[0111] Using 4-quinolinecarboxylic acid and 2-Boc-2,7-diaza-spiro[4.4]nonane as raw materials, the synthetic method of Example 1 was used to obtain compound 3, which was a yellow oil (0.29 g) with a yield of 77%. MS (ESI) m / z calcd for C 22 H 28 N3O3[M+H] + 382.2, found 382.3.

[0112] Example 4: Synthesis of Compound 4

[0113]

[0114] Using 4-quinolinecarboxylic acid and piperidine-4-carboxylic acid methyl ester as raw materials, the synthetic method of Example 1 was used to obtain compound 4, which was 0.28 g of brown oil with a yield of 96%. 1H NMR(400MHz, CDCl3-d1)δ8.95(d,J=4.4,2.3Hz,1H),8.16(d,J=9.1Hz,1H),7.81(d,1H),7.76(dd,1H) ,7.61(dd,J=12.3,7.5Hz,1H),7.31(d,J=18.8,4.3Hz,1H),4.69(tt,J=14.3,4.3Hz,1H),3.70(s,J=3. 4Hz,3H),3.36(t,J=13.8,4.3,1.4Hz,1H),3.18(t,J=17.1,13.8,11.1,3.2Hz,1H),3.02(t,J=13.6,11 .0,3.2Hz,1H),2.60(t,J=10.3,4.9Hz,1H),2.14(dt,J=14.5,4.4Hz,1H),1.86(dt,2H),1.58(dt,1H).

[0115] Example 5: Synthesis of Compound 5

[0116]

[0117] Using 4-quinolinecarboxylic acid and ethyl piperidine-4-carboxylate as raw materials, the synthetic method of Example 1 was used to obtain compound 5, which was a yellow oil (0.18 g) with a yield of 52%. 1 H NMR (500MHz, CDCl3-d1) δ8.94(d,J=3.9Hz,1H),8.14(d,J=8.4Hz,1H),7.79(dd,J=30.3,8.3Hz,2H),7 .59(dd,J=15.4,7.8Hz,1H),7.30(d,J=25.3,4.2Hz,1H),4.69(t,1H),4.14(t,J=6.8Hz,2H),3.35(dt ,J=13.8,4.7Hz,1H),3.16(dt,J=21.0,10.7Hz,1H),3.01(dt,J=14.0,3.1Hz,1H),2.58(tt,1H),2.12 (t,J=9.4Hz,1H),1.85(t,J=10.4Hz,1H),1.74(t,J=13.9Hz,1H),1.57(dt,1H),1.24(t,J=6.9Hz,3H).

[0118] Example 6: Synthesis of Compound 6

[0119]

[0120] Using 4-quinolinecarboxylic acid and ethyl 3-oxo-4-piperidincarboxylate as raw materials, the synthetic method of Example 1 was used to obtain compound 6, which was a yellow oil (0.24 g) with a yield of 75%. MS (ESI) m / z calcd for C 18 H 19 N2O4[M+H] + 327.1, found 327.3.

[0121] Example 7: Synthesis of Compound 7

[0122]

[0123] Using 4-quinolinecarboxylic acid and piperidine-4-carboxylic acid tert-butyl ester as raw materials, the synthetic method of Example 1 was used to obtain compound 7, which was a yellow oil (0.32 g) with a yield of 98%. MS (ESI) m / z calculated for C 20 H 25 N2O3[M+H] + 341.2, found 341.3.

[0124] Example 8: Synthesis of Compound 8

[0125]

[0126] Synthesis of intermediate 8a:

[0127] In a mixed solvent of water and tetrahydrofuran (4:1, 25 mL), 1-(quinoline-4-carbonyl)piperidine-4-carboxylic acid methyl ester (compound 4) (0.59 g, 2 mmol) and sodium hydroxide (0.16 g, 4 mmol) were added and stirred at room temperature for 12 hours. After TLC inspection, the reaction was completed. Hydrochloric acid was added to adjust the system to acidity, and the intermediate 1-(quinoline-4-carbonyl)piperidine-4-carboxylic acid (8a) was obtained by spin drying as a yellow solid crude product.

[0128] Synthesis of compound 8:

[0129] Using 1-(quinoline-4-carbonyl)piperidine-4-carboxylic acid (8a) and tert-butylamine as raw materials, the synthetic method of Example 1 was used to obtain compound 8 as a white solid (0.27 g) with a yield of 40%. 1H NMR (400MHz, CDCl3-d1) δ8.94(d,J=4.3Hz,1H),8.15(d,J=8.5Hz,1H),7.86(d,J=8.3Hz ,1H),7.76(dd,J=7.9Hz,1H),7.61(dd,J=22.3,7.6Hz,1H),7.33(d,1H),5.28(s,1H),4. 87(t,J=14.3Hz,1H),3.40(t,J=13.6Hz,1H),2.99(t,J=11.2Hz,2H),2.23(tt,1H),1.99 (dt,J=11.5,7.4Hz,1H),1.88(dt,1H),1.61(dt,J=24.9,14.7,7.8Hz,2H),1.33(s,9H).

[0130] Example 9: Synthesis of Compound 9

[0131]

[0132] Compound 9 was obtained using 4-quinolinecarboxylic acid and 4-tert-butyloxycarbonylaminopiperidine as raw materials using the synthesis method of Example 1. The compound 9 was a white solid (0.32 g) with a yield of 91%. MS (ESI) m / z calculated for C 20 H 26 N3O3[M+H] + 356.2, found356.3.

[0133] Example 10: Synthesis of Compound 10

[0134]

[0135] Using 4-quinolinecarboxylic acid and 4-tert-butyloxycarbonylaminopiperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 10, which was a white foamy substance (0.34 g) with a yield of 96%. MS (ESI) m / z calculated for C 20 H 26 N3O3[M+H] + 356.2, found 356.3.

[0136] Example 11: Synthesis of Compound 11

[0137]

[0138] Using 4-quinolinecarboxylic acid and 4-(2-Boc-aminoethyl)piperidine as raw materials, the synthesis method of Example 1 was used to obtain compound 11, which was a white foamy substance (0.38 g) with a yield of 98%. MS (ESI) m / z calculated for C22 H 30 N3O3[M+H] + 384.2, found 384.3.

[0139] Example 12: Synthesis of Compound 12

[0140]

[0141] Using 4-quinolinecarboxylic acid and methyl 4-piperidinylacetate as raw materials, the synthetic method of Example 1 was used to obtain compound 12, which was a colorless oil (0.27 g) with a yield of 86%. 1 H NMR(400MHz, CDCl3-d1)δ8.95(d,J=4.3Hz,1H),8.15(d,J=8.5Hz,1H),7.83(d,1H),7.76 (d,1H),7.60(dd,J=7.7Hz,1H),7.30(dd,J=19.9,4.3Hz,1H),4.91(ttt,J=12.9Hz,1H),3 .67(s,3H),3.32(dt,J=13.6Hz,1H),2.94(d,J=30.3,16.8Hz,2H),2.28(dt,J=15.9,7.2H z,2H),2.10(dt,1H),1.95(t,1H),1.57(t,1H),1.37(t,1H),1.09(t,J=48.5,9.4Hz,1H).

[0142] Example 13: Synthesis of Compound 13

[0143]

[0144] Using 4-quinolinecarboxylic acid and 4-pyrrolidin-1-yl-piperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 13, which was a white foam (0.17 g) with a yield of 55%. 1 H NMR (400MHz, CDCl3-d1) δ8.94(d,J=4.3Hz,1H),8.14(d,J=8.5Hz,1H),7.83(d ,1H),7.75(d,J=7.1Hz,1H),7.57(dd,1H),7.29(dd,J=4.6Hz,1H),4.77(tt,1H ),3.35(t,J=13.5Hz,1H),3.09(t,1H),2.99(t,1H),2.55(t,J=13.2Hz,4H),2 .23(t,1H),2.10(tt,J=15.3Hz,1H),1.79(t,4H),1.70(tt,2H),1.37(tt,1H).

[0145] Example 14: Synthesis of Compound 14

[0146]

[0147] Using 4-quinolinecarboxylic acid and 4-pyrrolidin-1-yl-piperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 14 as a colorless oil (0.26 g) with a yield of 80%. 1 H NMR(400MHz,DMSO-d6)δ8.94(d,J=4.7Hz,1H),8.12(d,J=8.6Hz,1H),7.91(d,1H),7 .82(d,1H),7.72(dd,J=13.2,7.3Hz,1H),7.49(dd,J=36.5Hz,1H),3.36(d,J=10.8Hz ,1H),3.11(dd,J=28.4,13.4Hz,1H),2.98(dd,J=22.2,12.1Hz,1H),2.58(s,5H),2. 10(m,1H),1.76(d,J=14.4Hz,1H),1.63(s,5H),1.48(s,3H),1.31(d,J=16.6Hz,1H).

[0148] Example 15: Synthesis of Compound 15

[0149]

[0150] Using 4-quinolinecarboxylic acid and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate as raw materials, the synthetic method of Example 1 was used to obtain compound 15 as a white foamy substance (0.32 g) with a yield of 80%. 1 H NMR (400MHz, CDCl3-d1) δ8.96(d,J=4.3Hz,1H),8.16(d,J=8.5Hz,1H),7.81(d,1H),7.76(d,J=7.4Hz,1H),7.61(dd,J=7.7Hz,1H),7.3 2(dd,J=4.3Hz,1H),3.96(tt,1H),3.87(t,1H),3.41(t,3H),3.21(t,4H),1.81(d,J=14.5,13.8,7.1Hz,2H),1.75(t,2H),1.56(s,9H).

[0151] Example 16: Synthesis of Compound 16

[0152]

[0153] Using 4-quinolinecarboxylic acid and 4-benzylpiperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 16 as a colorless oil (0.32 g) with a yield of 98%. 1 H NMR (400MHz, CDCl3-d1) δ8.94(d,J=3.2Hz,1H),8.15(d,J=8.4Hz,1H),7.84(dd,1H),7.75(d,J=7.5Hz,1H),7.59 (dd,J=15.6,7.8Hz,1H),7.32(d,1H),7.28(d,2H),7.20(dd,J=7.4Hz,1H),7.12(dd,J=6.7Hz,2H),4.88(tt,J=11 .3Hz,1H),3.31(d,J=13.6Hz,1H),2.94(d,1H),2.82(dt,J=14.4Hz,1H),2.59(dt,1H),2.57(dt,J=7.1Hz,1H),1 .89(dt,J=12.4Hz,1H), 1.83(tt,J=11.4Hz,1H), 1.53(tt,J=17.1Hz,1H), 1.38(tt,J=11.6Hz,1H), 1.08(tt,1H).

[0154] Example 17: Synthesis of Compound 17

[0155]

[0156] Using 4-quinolinecarboxylic acid and diphenyl(piperidin-4-yl)methanol as raw materials, the synthetic method of Example 1 was used to obtain compound 17, which was a white foam (0.38 g) with a yield of 90%. 1 H NMR (400MHz, CDCl3-d1) δ8.91(d,J=4.3Hz,1H),8.12(d,J=8.4Hz,1H),7.77(dd,1H),7.73(d,J=8.0Hz,1H),7. 57(dd,J=7.7Hz,1H),7.48(d,J=7.7Hz,2H),7.41(dd,2H),7.35(dd,J=7.7Hz,2H),7.30(d,J=3.8Hz,2H),7.24 (d,2H),7.15(dd,J=7.4Hz,1H),4.98(s,1H),3.33(tt,J=13.5Hz,1H),3.02(t,J=22.0,11.5Hz,1H),2.89(t,J =14.6,14.2Hz,1H),2.68(t,1H),2.16(t,J=14.0Hz,1H),1.78(dt,1H),1.54(dt,1H),1.37(dt,J=13.4Hz,2H).

[0157] Example 18: Synthesis of Compound 18

[0158]

[0159] Using 4-quinolinecarboxylic acid and 4-phenylpiperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 18, which was a yellow oil (0.30 g) with a yield of 95%. 1 H NMR (400MHz, CDCl3-d1) δ8.96(d,1H),8.16(d,J=8.5Hz,1H),7.90(d,1H),7.77(dd,J=9.2Hz,1H),7. 62(dd,J=15.4,7.6Hz,1H),7.38(d,1H),7.31(d,J=6.7Hz,2H),7.21(dd,J=7.8,7.3Hz,3H),5.08(tt ,J=12.3Hz,1H),3.44(t,J=11.0Hz,1H),3.13(t,1H),2.98(t,J=13.2Hz,1H),2.80(t,J=12.1,3.8Hz ,1H), 2.09(dt,J=25.4Hz,2H), 1.86(dt,J=12.8,8.0,4.5Hz,1H), 1.54(dt,J=46.3,12.5,4.2Hz,1H).

[0160] Example 19: Synthesis of Compound 19

[0161]

[0162] Using 4-quinolinecarboxylic acid and 4-(4-fluorophenyl)piperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 19 as a white solid (0.31 g) with a yield of 93%. 1H NMR (400MHz, CDCl3-d1) δ8.97(d,J=2.8Hz,1H),8.17(d,J=8.5Hz,1H),7.89(d,1H),7.78(d,J=8.6Hz, 1H),7.63(dd,J=15.2,7.7Hz,1H),7.36(dd,J=33.1,4.3Hz,1H),7.16(d,J=7.3Hz,2H),7.01(d,J=7.8 Hz,2H),5.08(t,J=12.3Hz,1H),3.44(t,J=11.4Hz,1H),3.12(t,1H),2.99(t,1H),2.79(tt,J=12.2,3 .7Hz, 1H), 2.07 (td, J = 14.6Hz, 1H), 1.82 (td, J = 12.2, 5.5Hz, 1H), 1.51 (dt, J = 47.3, 12.7, 4.2Hz, 2H).

[0163] Example 20: Synthesis of Compound 20

[0164]

[0165] Using 4-quinolinecarboxylic acid and 4-(4-chlorophenyl)piperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 20 as a white solid (0.28 g) with a yield of 60%. 1 H NMR (400MHz, CDCl3-d1) δ8.97(d,J=4.2Hz,1H),8.17(d,J=8.5Hz,1H),7.89(dd,1H),7.78(s ,1H),7.63(dd,J=14.9,7.6Hz,1H),7.37(d,1H),7.29(d,J=8.2Hz,2H),7.14(d,J=7.7Hz,2H) ,5.08(tt,1H),3.44(t,1H),3.12(t,J=24.6,13.3Hz,1H),2.98(t,J=13.7Hz,1H),2.79(t,1 H), 2.07 (dt, J = 14.2Hz, 1H), 1.79 (dt, 1H), 1.70 (dt, J = 17.5Hz, 1H), 1.44 (dt, J = 12.3Hz, 1H).

[0166] Example 21: Synthesis of Compound 21

[0167]

[0168] Using 4-quinolinecarboxylic acid and 4-(4-bromophenyl)piperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 21 as a white solid (0.23 g) with a yield of 60%.1 H NMR (400MHz, CDCl3-d1) δ8.97(d,J=2.3Hz,1H),8.17(d,J=8.5Hz,1H),7.88(d,1H),7.77(d,J=8 .8Hz,1H),7.63(dd,J=15.0,7.7Hz,1H),7.44(d,J=6.5Hz,2H),7.35(dd,J=33.0,4.2Hz,1H),7. 08(d,J=7.6Hz,2H),5.07(tt,J=12.3Hz,1H),3.45(t,J=13.5Hz,1H),3.11(t,J=23.1,12.7Hz,1 H), 2.97 (t, J = 13.6Hz, 1H), 2.77 (dt, 1H), 2.07 (dt, J = 14.7Hz, 1H), 2.07 (dt, 2H), 1.68 (dt, 1H).

[0169] Example 22: Synthesis of Compound 22

[0170]

[0171] Using 4-quinolinecarboxylic acid and 4-(4-nitrophenyl)piperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 22, which was a white foam (0.23 g) with a yield of 64%. 1 H NMR (400MHz, CDCl3-d1) δ8.98(d,J=4.2Hz,1H),8.21(d,J=2.8Hz,1H),8.18(d,J=4.2Hz,2H),7. 98(dd,1H),7.78(d,J=7.3Hz,1H),7.64(dd,J=15.5,7.8Hz,1H),7.39(d,J=8.8Hz,2H),7.33(d, 1H),5.13(tt,1H),3.49(t,1H),3.15(t,J=23.9,13.1Hz,1H),3.01(t,J=30.0,15.9Hz,2H),2.1 7(dt,J=37.4Hz,1H), 2.05(dt,J=29.7Hz,1H), 1.87(dt,J=13.4Hz,1H), 1.77(dt,J=16.4Hz,1H).

[0172] Example 23: Synthesis of Compound 23

[0173]

[0174] Using 4-quinolinecarboxylic acid and 4-(4-biphenyl)piperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 23 as a yellow oil (0.20 g) with a yield of 99%.1 H NMR (400MHz, CDCl3-d1) δ8.98(d,J=4.2Hz,1H),8.21(d,J=2.8Hz,1H),8.18(d,J=4.2Hz,2H),7. 98(dd,1H),7.78(d,J=7.3Hz,1H),7.64(dd,J=15.5,7.8Hz,1H),7.39(d,J=8.8Hz,2H),7.33(d, 1H),5.13(tt,1H),3.49(t,1H),3.15(t,J=23.9,13.1Hz,1H),3.01(t,J=30.0,15.9Hz,2H),2.1 7(dt,J=37.4Hz,1H), 2.05(dt,J=29.7Hz,1H), 1.87(dt,J=13.4Hz,1H), 1.77(dt,J=16.4Hz,1H).

[0175] Example 24: Synthesis of Compound 24

[0176]

[0177] Using 4-quinolinecarboxylic acid and 4-(3-trifluoromethylphenyl)piperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 24 as a colorless oil (0.34 g) with a yield of 90%. 1 H NMR(400MHz, CDCl3-d1)δ8.97(s,1H),8.17(d,J=8.5Hz,1H),7.90(dd,1H),7.79(d,1H),7.63(dd ,1H),7.50(d,J=7.6Hz,1H),7.45(d,J=5.7Hz,2H),7.41(d,J=3.7Hz,1H),7.36(dd,1H),5.11(tt, J=11.5Hz,1H),3.48(dt,J=14.8Hz,1H),3.13(dt,J=23.5,13.1Hz,1H),3.00(dt,J=13.1Hz,1H),2 .87(dt,1H),2.10(t,J=15.7Hz,1H),1.86(t,J=12.8Hz,1H),1.78(t,J=13.7Hz,1H),1.53(t,1H).

[0178] Example 25: Synthesis of Compound 25

[0179]

[0180] Using 4-quinolinecarboxylic acid and 4-(4-chlorophenyl)piperidin-4-ol as raw materials, the synthetic method of Example 1 was used to obtain compound 25 as a white solid (0.18 g) with a yield of 51%. 1 H NMR (400MHz, DMSO-d6) δ8.97(d,1H),8.10(d,J=8.4Hz,1H),7.84(d,2H),7.70(dd,J=7 .6Hz,1H),7.64(dd,1H),7.55(d,J=11.8Hz,1H),7.50(d,1H),7.39(d,J=8.2Hz,2H),5. 34(s,1H),4.63(t,J=12.6Hz,1H),3.46(t,J=15.1Hz,1H),3.23(t,J=44.6Hz,1H),3.0 7(t,J=13.2Hz,1H),2.10(t,1H),1.68(t,J=65.3,13.8Hz,2H),1.45(t,J=13.2Hz,1H).

[0181] Example 26: Synthesis of Compound 26

[0182]

[0183] Using 4-quinolinecarboxylic acid and 6-fluoro-3-(4-piperidinyl)-1,2-benzimidazole as raw materials, the synthetic method of Example 1 was used to obtain compound 26 as a white foamy product (0.29 g) with a yield of 77%. 1 H NMR (400MHz, CDCl3-d1) δ8.98(s,J=4.3Hz,1H),8.17(d,J=6.4Hz,1H),7.87(d,J=28.6,8.0Hz,1H),7.78( d,J=7.7Hz,1H),7.64(d,J=6.5Hz,1H),7.61(d,1H),7.37(d,J=20.0,4.3Hz,1H),7.28(dd,J=7.9Hz,1H), 7.10(dd,J=8.8,2.2Hz,1H),4.91(tt,J=12.1Hz,1H),3.55(dt,J=14.8Hz,1H),3.40(dt,J=7.6,3.7Hz,1H ),3.32(dt,1H),3.24(dt,J=14.2Hz,1H),2.33(t,J=11.2Hz,1H),2.16(t,1H),1.99(t,1H),1.86(t,1H).

[0184] Example 27: Synthesis of Compound 27

[0185]

[0186] Using 4-quinolinecarboxylic acid and (3S,4R)-3-((benzo[d][1,3]dioxy-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine as raw materials, the synthetic method of Example 1 was used to obtain compound 27 as a white solid (0.32 g) with a yield of 67%. MS (ESI) m / z calcd for C 29 H 26 N2O4[M+H] + 485.2, found 485.2.

[0187] Example 28: Synthesis of Compound 28

[0188]

[0189] Using 4-quinolinecarboxylic acid and 7-bromo-1,2,3,4-tetrahydroisoquinoline as raw materials, the synthesis method of Example 1 was used to obtain compound 28, which was a white foamy substance (0.35 g) with a yield of 95%. MS (ESI) m / z calcd for C 19 H 16 BrN2O[M+H] + 367.0, found 367.2.

[0190] Example 29: Synthesis of Compound 29

[0191]

[0192] Using 4-quinolinecarboxylic acid and N-methylpiperazine as raw materials, the synthesis method of Example 1 was used to obtain compound 29, which was a colorless oil (0.23 g) with a yield of 90%. MS (ESI) m / z calculated for C 15 H 18 N3O[M+H] + 256.1, found 256.2.

[0193] Example 30: Synthesis of Compound 30

[0194]

[0195] Using 4-quinolinecarboxylic acid and N-formylpiperazine as raw materials, the synthesis method of Example 1 was used to obtain compound 30, which was a white foamy substance (0.16 g) with a yield of 60%. MS (ESI) m / z calculated for C 15 H 16 N3O2[M+H] + 270.1, found 270.2.

[0196] Example 31: Synthesis of Compound 31

[0197]

[0198] Using 4-quinolinecarboxylic acid and N-Boc-piperazine as raw materials, the synthesis method of Example 1 was used to obtain compound 31, which was a white foamy substance (0.32 g) with a yield of 94%. MS (ESI) m / z calculated for C 19 H 24 N3O3[M+H] + 342.2, found 342.3.

[0199] Example 32: Synthesis of Compound 32

[0200]

[0201] Using 4-quinolinecarboxylic acid and 6-N-Boc-3,6-diazabicyclo[3.1.1]heptane as raw materials, the synthetic method of Example 1 was used to obtain compound 32, which was a white foamy substance (0.25 g) with a yield of 71%. MS (ESI) m / z calcd for C 20 H 24 N3O3[M+H] + 354.2, found 354.3.

[0202] Example 33: Synthesis of Compound 33

[0203]

[0204] Using 4-quinolinecarboxylic acid and 1-(2-furoyl)piperazine as raw materials, the synthesis method of Example 1 was used to obtain compound 33, which was a white foamy substance (0.32 g) with a yield of 95%. MS (ESI) m / z calcd for C 19 H 18 N3O3[M+H] + 336.1, found 336.3.

[0205] Example 34: Synthesis of Compound 34

[0206]

[0207] Using 4-quinolinecarboxylic acid and 1-phenylpiperazine as raw materials, the synthetic method of Example 1 was used to obtain compound 34 as a yellow oil (0.17 g) with a yield of 54%. 1H NMR (400MHz, CDCl3-d1) δ8.94(d,J=4.3Hz,1H),8.13(d,J=8.1Hz,1H),7.81(d,J= 8.3Hz,1H),7.74(dd,J=8.4,6.9,1.4Hz,1H),7.57(d,J=8.3,6.9,1.3Hz,1H),7.31 (d,J=4.3Hz,1H),7.23(d,2H),6.88(dd,J=7.9,6.3Hz,3H),4.14(t,J=7.1,4.5Hz, 1H), 3.99 (t, J = 8.3Hz, 1H), 3.31 (t, J = 10.2, 6.1Hz, 4H), 3.02 (t, 1H), 2.96 (t, 1H).

[0208] Example 35: Synthesis of Compound 35

[0209]

[0210] Using 4-quinolinecarboxylic acid and 1-(4-fluorophenyl)piperazine as raw materials, the synthetic method of Example 1 was used to obtain compound 35 as a colorless oil (0.31 g) with a yield of 94%. 1 H NMR (400MHz, CDCl3-d1) δ8.99(d,J=4.3Hz,1H),8.19(d,J=8.5Hz,1H),7.86(d,J= 8.4Hz,1H),7.79(dd,J=8.4,6.9,1.4Hz,1H),7.63(dd,J=8.3,6.9,1.3Hz,1H),7.3 6(d,J=4.3Hz,1H),6.98(d,2H),6.88(d,J=9.1,4.5Hz,2H),4.17(t,1H),4.03(s, 1H), 3.35 (t, J = 5.1Hz, 2H), 3.26 (t, J = 10.8, 5.4Hz, 2H), 2.98 (t, 1H), 2.92 (t, 1H).

[0211] Example 36: Synthesis of Compound 36

[0212]

[0213] Using 4-quinolinecarboxylic acid and 1-(4-chlorophenyl)piperazine as raw materials, the synthetic method of Example 1 was used to obtain compound 36 as a colorless oil (0.30 g) with a yield of 87%. 1H NMR (400MHz, CDCl3-d1) δ8.98(d,J=4.3Hz,1H),8.17(d,J=8.5Hz,1H),7.84(d,J=8.4 Hz,1H),7.78(dd,J=8.5,6.9,1.5Hz,1H),7.61(dd,J=8.3,6.9,1.3Hz,1H),7.35(d,J= 4.3Hz,1H),7.22(d,J=9.0Hz,2H),6.82(d,J=9.0Hz,2H),4.16(t,J=7.5,4.7Hz,1H), 4.01(t,J=13.1,7.8Hz,1H), 3.33(t,J=12.5,9.0Hz,4H), 2.99(t,J=24.8,5.5Hz,2H).

[0214] Example 37: Synthesis of Compound 37

[0215]

[0216] Using 4-quinolinecarboxylic acid and 1-(p-tolyl)piperazine as raw materials, the synthetic method of Example 1 was used to obtain compound 37 as a colorless oil (0.28 g) with a yield of 86%. 1 H NMR (400MHz, CDCl3-d1) δ8.98(d,J=4.3Hz,1H),8.18(d,J=8.5Hz,1H),7.85(d,J =8.4Hz,1H),7.78(dd,1H),7.61(dd,J=8.3,6.9,1.2Hz,1H),7.36(d,J=4.3Hz,1H ),7.09(d,J=8.3Hz,2H),6.84(d,J=8.5Hz,2H),4.17(t,1H),4.03(s,1H),3.32( t,J=16.6,5.8Hz,4H),3.02(t,J=5.4Hz,1H),2.94(t,J=6.1Hz,1H),2.28(s,3H).

[0217] Example 38: Synthesis of Compound 38

[0218]

[0219] Using 4-quinolinecarboxylic acid and 1-(4-(trifluoromethyl)phenyl)piperazine as raw materials, the synthetic method of Example 1 was used to obtain compound 38 as a colorless oil (0.18 g) with a yield of 48%. 1H NMR (400MHz, CDCl3-d1) δ8.97(d,J=4.3Hz,1H),8.17(d,J=8.5Hz,1H),7.83(d,J=8 .4Hz,1H),7.77(dd,J=8.4,6.9,1.5Hz,1H),7.60(dd,J=7.6Hz,1H),7.49(d,J=8.5H z,2H),7.34(d,J=4.3Hz,1H),6.90(d,J=8.6Hz,2H),4.17(t,1H),4.00(t,1H),3.4 4(t,J=10.8,5.3Hz,2H), 3.34(t,J=5.0Hz,2H), 3.14(t,J=5.1Hz,1H), 3.08(t,1H).

[0220] Example 39: Synthesis of Compound 39

[0221]

[0222] Using 4-quinolinecarboxylic acid and 4-(piperazine-1-yl)benzonitrile as raw materials, the synthetic method of Example 1 was used to obtain compound 39 as a white solid (0.097 g) with a yield of 28%. 1 H NMR (400MHz, CDCl3-d1) δ8.99(d,J=4.3Hz,1H),8.19(d,J=8.5Hz,1H),7.83(d,J= 8.3Hz,1H),7.79(dd,J=8.4,6.9,1.4Hz,1H),7.62(dd,J=8.2,7.0,1.2Hz,1H),7. 52(d,J=9.0Hz,2H),7.36(d,J=4.2Hz,1H),6.86(d,J=9.0Hz,2H),4.10(t,J=51.4 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H), 3.35 (t, J = 4.4, 3.8 Hz, 2H), 3.19 (d, J = 21.7 Hz, 2H).

[0223] Example 40: Synthesis of Compound 40

[0224]

[0225] Using 4-quinolinecarboxylic acid and 1-(4-nitrophenyl)piperazine as raw materials, the synthetic method of Example 1 was used to obtain compound 40 as a yellow foamy substance (0.30 g) with a yield of 83%. 1H NMR (400MHz, CDCl3-d1) δ9.00(d,J=4.3Hz,1H),8.20(d,J=8.5Hz,1H),8.14(d,J=9.4Hz,2H),7.84(d,J=8.4Hz,1H),7.80(dd,J=8.4,6.9,1.5Hz ,1H),7.63(dd,J=8.3,6.9,1.3Hz,1H),7.37(d,J=4.3Hz,1H),6.83(d,J=9.5Hz,2H),4.11(t,J=44.9Hz,2H),3.62(t,J=4.9Hz,2H),3.32(t,4H).

[0226] Example 41: Synthesis of Compound 41

[0227]

[0228] Using 4-quinolinecarboxylic acid and 4-(piperazine-1-yl)phenol as raw materials, the synthetic method of Example 1 was used to obtain compound 41 as a brown solid (0.26 g) with a yield of 39%. 1 H NMR (400MHz, CDCl3-d1) δ8.97(d,J=4.3Hz,1H),8.18(d,J=8.6Hz,1H),7.86(d,J=8.4Hz ,1H),7.78(dd,J=8.5,6.9,1.5Hz,1H),7.62(dd,J=8.3,6.8,1.3Hz,1H),7.36(d,J=4.3 Hz,1H),6.83(d,J=9.0Hz,2H),6.77(d,J=9.0Hz,2H),5.64(s,1H),4.16(t,1H),4.03(t ,1H),3.34(t,J=5.2Hz,2H),3.21(=t,J=10.6,5.3Hz,2H),2.90(t,J=22.7,6.1Hz,2H).

[0229] Example 42: Synthesis of Compound 42

[0230]

[0231] Using 4-quinolinecarboxylic acid and 1-(4-methoxyphenyl)piperazine as raw materials, the synthetic method of Example 1 was used to obtain compound 42, which was a yellow foam (0.24 g) with a yield of 70%. 1H NMR (500MHz, CDCl3-d1) δ8.97(d,J=4.3Hz,1H),8.16(d,J=8.3Hz,1H),7.85(d,J=8.4,1 .4Hz,1H),7.77(dd,J=8.4,6.9,1.4Hz,1H),7.61(dd,J=8.2,6.8,1.2Hz,1H),7.35(d,J= 4.3Hz,1H),6.88(d,J=9.2Hz,2H),6.84(d,J=9.2Hz,2H),4.21-4.14(t,1H),4.00(t,J=1 0.0Hz, 1H), 3.76 (s, 3H), 3.34 (t, 2H), 3.22 (t, 2H), 2.94 (t, 1H), 2.86 (t, J = 10.8Hz, 1H).

[0232] Example 43: Synthesis of Compound 43

[0233]

[0234] Using 4-quinolinecarboxylic acid and 1-(3-methoxyphenyl)piperazine as raw materials, the synthetic method of Example 1 was used to obtain compound 43 as a yellow oil (0.26 g) with a yield of 77%. 1 H NMR (400MHz, CDCl3-d1) δ8.98(d,J=4.3Hz,1H),8.18(d,J=8.5Hz,1H),7.85(d,J=6.9Hz,1H),7. 78(dd,J=8.4,6.9,1.5Hz,1H),7.61(dd,J=8.3,6.9,1.3Hz,1H),7.36(d,J=4.3Hz,1H),7.19(dd, J=8.2Hz,1H),6.52(d,J=8.3,2.3Hz,1H),6.47(d,J=8.0,2.3Hz,1H),6.44(s,J=2.3Hz,1H),4.16 (t,1H),4.01(t,1H),3.78(s,3H),3.35(t,J=9.7,4.7Hz,4H),3.6(t,1H),3.00(t,J=5.3Hz,1H).

[0235] Example 44: Synthesis of Compound 44

[0236]

[0237] Using 4-quinolinecarboxylic acid and 1-(2-methoxyphenyl)piperazine as raw materials, the synthesis method of Example 1 was used to obtain compound 44, which was a white foamy substance (0.33 g) with a yield of 96%. MS (ESI) m / z calculated for C 21H 22 N3O2[M+H] + 348.2, found 348.3.

[0238] Example 45: Synthesis of Compound 45

[0239]

[0240] Using 4-quinolinecarboxylic acid and 2-(piperazine-1-yl)pyrimidine as raw materials, the synthesis method of Example 1 was used to obtain compound 45, which was a white foamy substance (0.30 g) with a yield of 94%. MS (ESI) m / z calculated for C 18 H 18 N5O[M+H] + 320.2, found 320.3.

[0241] Example 46: Synthesis of Compound 46

[0242]

[0243] Using 4-quinolinecarboxylic acid and 5-ethyl-2-(piperazine-1-yl)pyrimidine as raw materials, the synthetic method of Example 1 was used to obtain compound 46, which was a white foamy substance (0.29 g) with a yield of 83%. MS (ESI) m / z calcd for C 22 H 25 N5O[M+H] + 348.2, found 348.3.

[0244] Example 47: Synthesis of Compound 47

[0245]

[0246] Using 4-quinolinecarboxylic acid and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine as raw materials, the synthetic method of Example 1 was used to obtain compound 47 as a yellow oil (0.25 g) with a yield of 73%. 1 H NMR (400MHz, CDCl3-d1) δ9.03(d,1H),8.24(d,J=8.4Hz,1H),7.83(d,J=8.7Hz,1H),7.74(dd,1H),7.64(dd,J =15.8,7.5Hz,1H),7.39(d,J=12.2Hz,1H),5.37(t,1H),4.66(t,1H),4.38(s,2H),4.04(t,1H),3.69(t,1H).

[0247] Example 48: Synthesis of Compound 48

[0248]

[0249] Synthesis of intermediate (6-chloropyridin-2-yl)(4-methylpiperazin-1-yl)methanone (48a):

[0250] Using 6-chloropyridine-2-carboxylic acid (0.32 g, 2 mmol) and N-methylpiperazine (0.22 g, 2.2 mmol) as raw materials, the synthetic method of Example 1 was used to obtain compound (6-chloropyridin-2-yl)(4-methylpiperazin-1-yl)methanone (48a) as a yellow oil (0.43 g) with a yield of 90%. MS (ESI) m / z calcd for C 11 H 15 ClN3O[M+H] + 240.1, found 240.3.

[0251] Synthesis of compound 48:

[0252] In a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL), (6-chloropyridin-2-yl)(4-methylpiperazin-1-yl)methanone (48a) (0.12 g, 0.5 mmol), (1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (0.10 g, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.04 g, 0.05 mmol) and potassium carbonate (0.17 g) were added. , 1.25mmol), use a microwave reactor to react at 140℃ for 30 minutes, TLC detection reaction is complete, add ethyl acetate (10mL), suck off the water layer, dry the organic layer with magnesium sulfate, filter, spin dry the filtrate, separate and purify by 300-400 mesh silica gel chromatography column (DCM / MeOH=80 / 1,70 / 1,60 / 1,50 / 1,40 / 1,35 / 1 gradient elution), obtain the target compound 48, white solid 0.064g, yield 40%. MS (ESI) m / z calcd for C 18 H 20 N5O[M+H] + 322.2, found 322.4.

[0253] Example 49: Synthesis of Compound 49

[0254]

[0255] Using (6-chloropyridin-2-yl)(4-methylpiperazin-1-yl)methanone (48a) (0.12 g, 0.5 mmol) and (1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 49 as a white solid (0.080 g) with a yield of 50%. MS (ESI) m / z calcd for C 18 H 20 N5O[M+H] + 322.2, found 322.4.

[0256] Example 50: Synthesis of Compound 50

[0257]

[0258] Using 2-chloropyrimidine-4-carboxylic acid (0.32 g, 2 mmol) and tert-butyl piperidine-4-carboxylate (0.41 g, 2.2 mmol) as raw materials, the intermediate compound was obtained using the synthesis method of Example 1, and 0.5 mmol and (1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (0.10 g, 0.6 mmol) were used as raw materials to obtain compound 50 using the synthesis method of Example 48, which was a yellow solid of 0.020 g with a yield of 10%. MS (ESI) m / z calcd for C 22 H 26 N5O3[M+H] + 408.2, found 408.4.

[0259] Example 51: Synthesis of Compound 51

[0260]

[0261] Using 2-chloropyrimidine-4-carboxylic acid (0.32 g, 2 mmol) and tert-butyl piperidine-4-carboxylate (0.41 g, 2.2 mmol) as raw materials, the intermediate compound was obtained using the synthesis method of Example 1, and 0.5 mmol and (1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) were used as raw materials to obtain compound 51 using the synthesis method of Example 48, which was a white foam of 0.16 g with a yield of 80%. MS (ESI) m / z calcd for C 22 H 26 N5O3[M+H] + 408.2, found 408.4.

[0262] Example 52: Synthesis of Compound 52

[0263]

[0264] 6-Chloropyridine-2-carboxylic acid (0.32 g, 2 mmol) and 2-(piperazine-1-yl)pyrimidine (0.36 g, 2.2 mmol) were used as raw materials, and the intermediate compound was obtained using the synthesis method of Example 1. Then, 0.5 mmol and (1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) were used as raw materials, and compound 52 was obtained using the synthesis method of Example 48, which was a white foam of 0.12 g, with a yield of 61%. MS (ESI) m / zcalcd for C 21 H 20 N7O[M+H] + 386.2, found 386.4.

[0265] Example 53: Synthesis of Compound 53

[0266]

[0267] 6-Chloropyridine-2-carboxylic acid (0.32 g, 2 mmol) and 1-(4-methoxyphenyl)piperazine (0.42 g, 2.2 mmol) were used as raw materials, and the intermediate compound was obtained using the synthesis method of Example 1. Then, 0.5 mmol and (1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) were used as raw materials, and compound 53 was obtained using the synthesis method of Example 48, which was 0.14 g of a white solid with a yield of 67%. MS (ESI) m / z calcd for C 24 H 24 N5O2[M+H] + 414.2, found 414.4.

[0268] Example 54: Synthesis of Compound 54

[0269]

[0270] 6-Chloropyridine-2-carboxylic acid (0.32 g, 2 mmol) and 1-(4-methoxyphenyl)piperazine (0.42 g, 2.2 mmol) were used as raw materials, and the intermediate compound was obtained using the synthesis method of Example 1. Then, 0.5 mmol and (1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (0.10 g, 0.6 mmol) were used as raw materials, and compound 54 was obtained using the synthesis method of Example 48, which was a white solid of 0.11 g, with a yield of 53%. MS (ESI) m / z calcd for C 24 H 24 N5O2[M+H] +414.2, found 414.4.

[0271] Example 55: Synthesis of Compound 55

[0272]

[0273] Synthesis of intermediate tert-butyl 1-(2-chloroquinoline-4-formyl)piperidine-4-carboxylate (55a):

[0274] Using 2-chloroquinoline-4-carboxylic acid (0.42 g, 2 mmol) and piperidine-4-carboxylic acid tert-butyl ester (0.41 g, 2.2 mmol) as raw materials, the synthesis method of Example 1 was used to obtain compound 1-(2-chloroquinoline-4-formyl)piperidine-4-carboxylic acid tert-butyl ester (55a) as a brown oil (0.70 g) with a yield of 94%. Synthesis of compound 55:

[0275] 1-(2-chloroquinoline-4-formyl)piperidine-4-carboxylic acid tert-butyl ester (55a) (0.19 g, 0.5 mmol), 1-methylpiperazine (0.06 g, 0.52 mmol) and cesium carbonate (0.13 g, 0.4 mmol) were added to 1,4-dioxane (10 mL). The mixture was reacted at 160 °C for 1 hour. After completion of the reaction, TLC was performed. The system was diluted with ethyl acetate (10 mL) and the concentrate was dried by spin drying. The concentrate was separated and purified by 300-400 mesh silica gel chromatography column (DCM / MeOH=50 / 1, 40 / 1, 35 / 1, 30 / 1, 25 / 1, 20 / 1 gradient elution) to obtain the target compound 55 as a yellow oil (0.11 g) with a yield of 50%. 1 H NMR(400MHz, CDCl3-d1)δ7.71(d,J=7.9Hz,1H),7.57(s,J=7.5Hz,1H),7.51(dd,2H),7.22(dd,1H), 6.88(d,J=17.2Hz,1H),4.65(t,J=24.9,13.5Hz,1H),3.75(t,4H),3.57(t,J=5.3Hz,1H),3.41(t,2 H),3.11(tt,J=35.5,13.6,11.0,3.1Hz,1H),2.98(dt,J=14.1,11.2,3.2Hz,1H),2.55(t,J=4.8Hz, 4H), 2.47 (dt, 1H), 2.40 (dt, J = 10.0, 4.9Hz, 1H), 2.36 (s, 3H), 2.04 (dt, J = 5.5Hz, 1H), 1.44 (s, 9H).

[0276] Example 56: Synthesis of Compound 56

[0277]

[0278] Using tert-butyl 1-(2-chloroquinoline-4-carbonyl)piperidine-4-carboxylate (55a) (0.19 g, 0.5 mmol) and 3-acetamidophenylboronic acid (0.11 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 56 as a red oil (0.10 g) with a yield of 46%. 1 H NMR (400MHz, CDCl3-d1) δ8.22(d,J=24.6Hz,1H),8.17(s,1H),7.86(d,J=6.1Hz,1H),7.81(d,J=1 4.5Hz,1H),7.73(d,J=21.6Hz,2H),7.57(dd,J=14.5,7.5Hz,1H),7.48(dd,J=7.7Hz,1H),7.41(s, 1H),4.70(t,J=30.2,13.4Hz,1H),3.41(t,J=13.7Hz,1H),3.20(t,J=33.7,11.6Hz,1H),3.05(t, 1H), 2.51 (tt, J = 6.8Hz, 1H), 2.22 (s, 3H), 2.10 (td, 2H), 1.86 (dt, 1H), 1.73 (dt, 1H), 1.59 (s, 9H).

[0279] Example 57: Synthesis of Compound 57

[0280]

[0281] Using tert-butyl 1-(2-chloroquinoline-4-carbonyl)piperidine-4-carboxylate (55a) (0.19 g, 0.5 mmol) and (3-carbamoylphenyl)boronic acid (0.11 g, 0.6 mmol) as raw materials, the synthetic method of Example 55 was used to obtain compound 57 as a red foam (0.21 g) with a yield of 91%. 1H NMR (400MHz, CDCl3-d1) δ8.63(s,1H),8.33(d,J=7.0Hz,1H),8.21(d,J=8.6Hz,1H),7.96(dd,J=13.7,7.8H z,1H),7.87(s,1H),7.84(d,J=3.9Hz,1H),7.78(d,J=8.4Hz,1H),7.61(dd,J=14.8,7.5Hz,2H),6.40(s,1H ),5.81(s,1H),4.69(t,J=31.3,13.4Hz,1H),3.40(t,1H),3.24(t,J=23.4,11.0Hz,1H),3.14(t,1H),3.05 (tt,J=11.4,8.2Hz,1H),2.51(td,1H),2.11(td,1H),1.86(td,1H),1.75(td,J=13.8Hz,1H),1.45(s,9H).

[0282] Example 58: Synthesis of Compound 58

[0283]

[0284] Using tert-butyl 1-(2-chloroquinoline-4-carbonyl)piperidine-4-carboxylate (55a) (0.19 g, 0.5 mmol) and (1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 58 as a yellow oil (0.097 g) with a yield of 42%. 1 H NMR (400MHz, CDCl3-d1) δ9.64(s,1H),8.48(s,1H),8.29(d,J=8.0Hz,1H),7.89(d,3H),7.70(dd,J= 5.2,2.9Hz,1H),7.64(dd,1H),7.51(d,J=3.1Hz,1H),7.24(d,J=3.7Hz,1H),4.71(t,J=30.4,13.3Hz ,1H),3.47(t,J=14.2Hz,1H),3.23(t,J=34.1,12.0Hz,1H),3.08(t,J=10.7,10.2Hz,1H),2.52(tt, J=6.6Hz,1H),2.12(td,1H),1.87(td,1H),1.75(s,1H),1.58(td,J=12.6,12.1Hz,1H),1.45(s,9H).

[0285] Example 59: Synthesis of Compound 59

[0286]

[0287] Using tert-butyl 1-(2-chloroquinoline-4-carbonyl)piperidine-4-carboxylate (55a) (0.19 g, 0.5 mmol) and (1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (0.10 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 59 as an orange oil (0.062 g) with a yield of 27%. 1 H NMR (400MHz, CDCl3-d1) δ10.68(s,J=18.5Hz,1H),9.18(s,J=9.2Hz,1H),8.75(s,J=2.1Hz,1H),8.22(s,J=8.8Hz,1H),7.88( d,J=16.6Hz,1H),7.82(d,J=16.1Hz,1H),7.77(d,J=5.6Hz,1H),7.57(dd,J=15.7,7.9Hz,1H),7.45(dd,J=3.6Hz,1H),6.64( d,J=6.5,3.4Hz,1H),4.72(t,J=24.9,13.8Hz,1H),3.47(t,J=12.4Hz,1H),3.22(t,J=28.2,13.6,11.0,3.1Hz,1H),3.08(t, J=10.7,5.3Hz,1H),2.52(tt,J=7.2,3.8Hz,1H),2.11(td,1H),1.93-1.85(td,2H),1.75(td,J=9.1,4.7Hz,1H),1.45(s,9H).

[0288] Example 60: Synthesis of Compound 60

[0289]

[0290] 2-Chloroquinoline-4-carboxylic acid (0.42 g, 2 mmol) and 4-tert-butyloxycarbonylaminopiperidine (0.44 g, 2.2 mmol) were used as raw materials, and the intermediate compound was obtained using the synthesis method of Example 1. Then, 0.5 mmol and (1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) were used as raw materials, and compound 60 was obtained using the synthesis method of Example 48, which was a yellow solid of 0.15 g, with a yield of 63%. MS (ESI) m / z calcd for C 27 H 30 N5O3[M+H]+472.2,found 472.4.

[0291] Example 61: Synthesis of Compound 61

[0292]

[0293] 2-Chloroquinoline-4-carboxylic acid (0.42 g, 2 mmol) and 4-tert-butyloxycarbonylaminopiperidine (0.44 g, 2.2 mmol) were used as raw materials, and the intermediate compound was obtained using the synthesis method of Example 1. Then, 0.5 mmol and (1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (0.10 g, 0.6 mmol) were used as raw materials, and compound 61 was obtained using the synthesis method of Example 48, which was a yellow solid of 0.17 g, with a yield of 70%. MS (ESI) m / z calcd for C 27 H 30 N5O3[M+H] + 472.2, found 472.4.

[0294] Example 62: Synthesis of Compound 62

[0295]

[0296] Using 2-chloroquinoline-4-carboxylic acid (4.2 g, 20 mmol) and 1-(4-methoxyphenyl)piperazine (4.2 g, 22 mmol) as raw materials, the synthesis method of Example 1 was used to obtain the intermediate compound (62a). Then, the intermediate compound (62a) (0.19 g, 0.5 mmol) and 1-methylpiperazine (0.06 g, 0.52 mmol) were used as raw materials and the synthesis method of Example 55 was used to obtain compound 62, which was a yellow oil (0.16 g) with a yield of 72%. 1 H NMR (400MHz, CDCl3-d1) δ7.74(d,J=8.3Hz,1H),7.58(dd,2H),7.26(d,J=7.7Hz,1H),6 .95(s,1H),6.90(d,J=9.2Hz,2H),6.85(d,J=9.2Hz,2H),4.16(t,J=13.4,6.2,3.6Hz, 1H),3.98(t,J=11.1,3.7Hz,1H),3.83(t,J=10.4,4.7Hz,2H),3.78(s,3H),3.74(t,2H ),3.37(t,J=5.2Hz,2H),3.21(t,2H),2.92(t,2H),2.57(t,J=5.0Hz,4H),2.38(s,3H).

[0297] Example 63: Synthesis of Compound 63

[0298]

[0299] Using the intermediate compound (62a) (0.19 g, 0.5 mmol) and 3-acetamidophenylboronic acid (0.11 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 63, which was a brown oil (0.20 g) with a yield of 84%. 1 H NMR (400MHz, CDCl3-d1) δ8.25(s,1H),8.19(d,J=8.5Hz,1H),7.86(d,J=8.7Hz,2H),7.82(s, 1H),7.76(d,J=18.1,8.7Hz,2H),7.58(dd,J=7.0Hz,1H),7.48(dd,2H),6.90(d,J=9.2Hz,2H) ,6.84(d,J=9.1Hz,2H),4.20(s,1H),4.03(t,1H),3.77(s,3H),3.38(t,J=5.1,4.7Hz,2H),3 .28(t,J=5.4Hz,1H),3.22(t,J=6.1Hz,1H),2.98(t,1H),2.89(t,J=6.9Hz,1H),2.21(s,3H).

[0300] Example 64: Synthesis of Compound 64

[0301]

[0302] Using the intermediate compound (62a) (0.19 g, 0.5 mmol) and 3-carbamoylphenylboronic acid (0.11 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 64 as a yellow oil (0.032 g) with a yield of 9.4%. 1 H NMR (400MHz, CDCl3-d1) δ8.66(s,1H),8.34(d,J=7.8Hz,1H),8.24(d,J=8.5Hz,1H),7.94(d,J=7.8 Hz,1H),7.90(s,1H),7.86(d,J=6.8Hz,1H),7.79(dd,J=8.4,6.9,1.4Hz,1H),7.61(dd,J=10.7,5.7 ,3.1Hz,2H),6.90(d,J=9.1Hz,2H),6.84(d,J=9.2Hz,2H),6.48(s,1H),5.93(s,1H),4.22(t,J=14 .5Hz,1H),4.03(t,J=18.5Hz,1H),3.76(s,3H),3.39(t,2H),3.24(t,2H),2.99(t,1H),2.9(t,1H).

[0303] Example 65: Synthesis of Compound 65

[0304]

[0305] Using the intermediate compound (62a) (0.19 g, 0.5 mmol) and (1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 65 as a brown solid (0.11 g) with a yield of 48%. 1 H NMR(400MHz, CDCl3-d1)δ9.59(s,1H),8.50(s,1H),8.31(d,J=8.5Hz,1H),7.97(d,1H),7.91 (d,J=8.3Hz,1H),7.84(dd,J=8.5,6.8,1.4Hz,1H),7.70(d,J=5.0Hz,1H),7.65(dd,J=8.3,6. 9,1.3Hz,1H),7.51(d,J=3.4Hz,1H),7.24(d,J=3.4Hz,1H),6.90(d,2H),6.85(d,2H),4.21( t, 1H), 4.07 (t, 1H), 3.77 (s, 3H), 3.44 (t, J = 5.7Hz, 2H), 3.27 (t, J = 13.6Hz, 2H), 2.96 (t, 2H).

[0306] Example 66: Synthesis of Compound 66

[0307]

[0308] Using the intermediate compound (62a) (0.19 g, 0.5 mmol) and (1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (0.10 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 66 as an orange oil (0.15 g) with a yield of 58%. 1H NMR (400MHz, CDCl3-d1) δ9.89(s,1H),9.17(s,J=2.1Hz,1H),8.76(s,J=2.1Hz,1H),8.24(d,J=8.5Hz, 1H),7.91(s,1H),7.86(m,1H),7.79(dd,J=8.4,6.9,1.5Hz,1H),7.58(dd,J=8.1,6.8,1.2Hz,1H),7.4 2(d,1H),6.90(d,2H),6.85(d,J=9.4,2.8Hz,2H),6.65(d,J=3.6,1.8Hz,1H),4.21(t,1H),4.06(t,1H ), 3.77 (s, 3H), 3.43 (t, J = 6.2Hz, 2H), 3.27 (t, 2H), 2.99 (t, J = 5.9, 4.8Hz, 1H), 2.92 (t, J = 6.2Hz, 1H).

[0309] Example 67: Synthesis of Compound 67

[0310]

[0311] Using the intermediate compound (62a) (0.19 g, 0.5 mmol) and (1H-pyrazolo[3,4-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 67, which was an orange solid (0.16 g) with a yield of 71%. MS (ESI) m / z calcd for C 27 H 25 N6O2[M+H] + 465.2, found 465.4.

[0312] Example 68: Synthesis of Compound 68

[0313]

[0314] Using the intermediate compound (62a) (0.19 g, 0.5 mmol) and (1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (0.11 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 68, which was an orange solid (0.022 g) with a yield of 9%. MS (ESI) m / z calcd for C 28 H 27 N6O2[M+H] + 479.2, found 479.4.

[0315] Example 69: Synthesis of Compound 69

[0316]

[0317] Using the intermediate compound (62a) (0.19 g, 0.5 mmol) and (7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid (0.098 g, 0.6 mmol) as raw materials, the synthetic method of Example 48 was used to obtain compound 69, which was an orange solid (0.12 g) with a yield of 53%. MS (ESI) m / z calcd for C 27 H 24 N6O2[M+H] + 464.2, found 464.4.

[0318] Test example: Influenza virus inhibition experiment

[0319] The basic principle of the inhibitory activity of the compounds of the test examples against influenza virus is that influenza virus infection of MDCK cells can cause pathological changes and lead to cell death. The compounds inhibit the replication of the virus by inhibiting the protease function required for viral replication, thereby inhibiting the occurrence of cell pathological changes and cell death. The activity of the compounds against influenza virus can be reflected by measuring the cell viability by the MTT method.

[0320] Experimental Materials:

[0321] Influenza virus strains: A / HK / 1 / 68 (H3N2), A / WSN / 33 (H1N1) and B / Lee / 40, cells: MDCK passage cells. Culture conditions: routine culture in a 37°C, 5% CO2 incubator. Other reagents: DMEM / F-12 (1:1) medium (Gibco), FBS (Ecocell), PS (Gibco), 0.2% Trypsin-EDTA (Gibco), TPCK trypsin (Sigma Aldrich), PBS buffer (Corning), MTT (Sigma Aldrich).

[0322] Experimental methods:

[0323] 1. In vitro efficacy studies of compounds

[0324] The experiments were conducted in a BSL-2 laboratory.

[0325] The test compound was prepared into a 10mM stock solution with DMSO and stored at 4°C for later use. MDCK cells and DMEM / F-12 medium containing 10% FBS and 1% PS were mixed evenly, the cell density was 1.5×10 5cells / mL, 100μL / well was inoculated in a sterile 96-well plate, and incubated in a conventional incubator at 37°C and 5% CO2 for 24h. At this time, the adherent cells grew to 90% or more, the culture supernatant was discarded, 100μL / well PBS was added for washing, and PBS was discarded. The influenza virus solution stored at -80°C was taken out and diluted to 100TCID50 with DMEM / F-12 medium. The diluted virus solution was added to the experimental group and model group at 100μl / well for attack, and the control group was added with blank DMEM / F-12 medium. After 2 hours of routine culture, the culture medium was discarded, and 100 μL / well of DMEM / F-12 culture medium containing 0.1% TPCK and 1% PS was added. The mother solution of the test object was diluted with DMEM / F-12 culture medium (containing 0.1% TPCK and 1% PS) to obtain 2 times the maximum concentration of the compound to be measured. The dilution of the test object was added to the wells of the experimental group at an amount of 100 μL / well, and the test object was diluted to different concentrations by half dilution method. Seven different concentrations were set for each test object, and each well contained 100 μL of compound culture medium. Three replicate wells were set for each concentration, and the conventional culture was incubated for 48 hours. The culture medium in the well plate was discarded, PBS was added for washing and discarded, and 1 mg / mL of MTT solvent (prepared with PBS) was added to the well plate (100 μL / well), and the supernatant was discarded for 4 hours of routine culture. DMSO 100 μL / well was added, and the absorbance (OD) at a wavelength of 490nm was measured with an enzyme marker. The calculation formula of drug efficacy inhibition rate is:

[0326] Inhibition rate = {[(OD experimental group - OD blank group) - (OD model group - OD blank group)] / [(OD control group - OD blank group) - (OD model group - OD blank group)]} × 100%.

[0327] The half inhibitory concentration (IC50) was calculated using Excel software.

[0328] 2. Drug toxicity test of compounds

[0329] The experiments were conducted in a BSL-2 laboratory.

[0330] The determination of drug toxicity is similar to that of drug efficacy, except that drug toxicity does not require a toxic challenge, and the medium used to dilute the test substance is DMEM / F-12 medium containing 1% PS. The formula for calculating the survival rate of drug toxicity is:

[0331] Survival rate = [(OD experimental group - OD blank group) / (OD control group - OD blank group)] × 100%.

[0332] The CC50 was calculated using Excel software. The efficacy and toxicity experiments of each compound were tested three times in parallel, and the average and standard deviation of the results were calculated.

[0333] The results are shown in Table 1.

[0334] Table 1: Inhibitory effects of compounds on mutant influenza viruses

[0335]

[0336]

[0337] As can be seen from the above table, the compounds of the examples have a high level of inhibitory activity against one or more of the A / HK / 1 / 68 (H3N2), A / WSN / 33 (H1N1) and B / Lee / 40 virus strains. Further, through cytotoxicity evaluation and comparison, most of the compounds of the examples have low cytotoxicity and good drugability.

[0338] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0339] The above-described embodiments only express several implementation methods of the present application, which is convenient for understanding the technical solution of the present application in detail, but it cannot be understood as limiting the scope of protection of the patent application. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several modifications and improvements can be made, which all belong to the scope of protection of the present application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent of this application shall be based on the content of the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. Azaaromatic carboxamide compounds having the structural features shown in Formula I or pharmaceutically acceptable salts, stereoisomers, prodrug molecules, deuterated products thereof: in, m is selected from: 0 or 1; X is selected from: N or CH; L is selected from: a single bond or a C2-C10 heteroaryl; n is selected from: 0, 1, 2 or 3; R1 is selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, aldehyde, amino, at least one selected from R S2 Substituents substituted or unsubstituted C1-C5 alkyl, at least one selected from R S1 Substituents substituted or unsubstituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 11 、-N(R 12 R 13 ), amide, sulfonamide, at least one selected from R 12 Substituents substituted or unsubstituted C6-C10 aryl or at least one selected from R 12 R is a substituted or unsubstituted C2-C10 heteroaryl, oxo, -NHC(O)O-C1-C5 alkyl, -C1-C5 alkyl-NHC(O)O-C1-C5 alkyl, 3-8 membered heterocyclic group, -C1-C5 alkyl-C6-C10 aryl, -C1-C5 alkyl-O-C2-C10 heteroaryl or -C(O)-C2-C10 heteroaryl; S1 Including: H, C6-C10 aryl, hydroxyl, halogen, nitro, cyano, C1-C5 alkoxy, C1-C5 alkyl or halogen-substituted C1-C5 alkyl; R 11 , R 12 , R 13 Each independently selected from: C1-C5 alkyl, R 12 With R 13 Ringed or not ringed; Y is selected from: CH-R5 or N-R5; R5 is selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, aldehyde, amino, at least one selected from R S2 Substituents substituted or unsubstituted C1-C5 alkyl, at least one selected from R S2 Substituents substituted or unsubstituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 51 、-N(R 52 R 53 ), amide, sulfonamide, at least one selected from R S2 Substituents substituted or unsubstituted C6-C10 aryl or at least one selected from R S2 R is a substituted or unsubstituted C2-C10 heteroaryl, oxo, -NHC(O)O-C1-C5 alkyl, -C1-C5 alkyl-NHC(O)O-C1-C5 alkyl, 3-8 membered heterocyclic group, -C1-C5 alkyl-C6-C10 aryl, -C1-C5 alkyl-O-C2-C10 heteroaryl or -C(O)-C2-C10 heteroaryl; S2 Including: H, C6-C10 aryl, hydroxyl, halogen, nitro, cyano, C1-C5 alkoxy, C1-C5 alkyl or halogen-substituted C1-C5 alkyl; R 51 , R 52 , R 53 Each independently selected from: C1-C5 alkyl, R 52 With R 53 Ringed or not ringed; Optionally, R5, R1 and the atoms to which they are attached together form a saturated or unsaturated ring, or R1 and Together they form a bridge ring structure; R2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C1-C5 alkyl, fluorine-substituted C1-C5 alkyl, C3-C8 cycloalkyl, fluorine-substituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 21 、-N(R 22 R 23 ), amide, sulfonamide, 5-10 membered heterocyclic group, C6-C10 aryl or C2-C10 heteroaryl; R 21 , R 22 , R 23 Each independently selected from: C1-C5 alkyl, R 22 With R 23 The 5- to 10-membered heterocyclic group, C6- to C10 aryl group, and C2- to C10 heteroaryl group are each independently selected from at least one of R S3 The substituents are substituted or unsubstituted, R S3 Including: H, C1~C5 alkyl, -NHC(O)-R 24 , -C(O)NH2 or -C(O)NH2, R 24 Selected from: C1-C5 alkyl; R3 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C1-C5 alkyl, fluorine-substituted C1-C5 alkyl, C3-C8 cycloalkyl, fluorine-substituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 31 、-N(R 32 R 33 ), amide, sulfonamide, C6-C10 aryl or C2-C10 heteroaryl; R 31 , R 32 , R 33 Each independently selected from: C1-C5 alkyl, R 32 With R 33 Ringed or not ringed; R4 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C1-C5 alkyl, fluorine-substituted C1-C5 alkyl, C3-C8 cycloalkyl, fluorine-substituted C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 41 、-N(R 42 R 43 ), amide, sulfonamide, C6-C10 aryl or C2-C10 heteroaryl; R 41 , R 42 , R 43 Each independently selected from: C1-C5 alkyl, R 42 With R 43 Ringed or not.

2. The azaaromatic ring carboxamide compound according to claim 1, characterized in that: It has the structural features shown in Formula I-11 or Formula I-12:

3. The azaaromatic ring carboxamide compound according to claim 2, characterized in that: It has the structural features shown in Formula I-21 or Formula I-22:

4. The azaaromatic ring carboxamide compound according to claim 1, characterized in that: L is selected from: a single bond or the following groups: X1, X2, X3, and X4 are each independently selected from: CH or N.

5. The azaaromatic ring carboxamide compound according to claim 4, characterized in that: L is selected from: a single bond or the following groups:

6. The azaaromatic ring carboxamide compound according to any one of claims 1 to 5, characterized in that: R2 is selected from the group consisting of hydrogen, 5-10 membered heterocyclic group, C6-C10 aryl group or C2-C10 heteroaryl group, wherein the 5-10 membered heterocyclic group, C6-C10 aryl group or C2-C10 heteroaryl group is independently substituted by at least one selected from R S3 The substituents are substituted or unsubstituted, R S3 Including: H, C1~C5 alkyl, -NHC(O)-R 21 , -C(O)NH2 or -C(O)NH2.

7. The azaaromatic ring carboxamide compound according to claim 6, characterized in that: R2 is selected from: hydrogen or the following groups:

8. The azaaromatic carboxamide compound according to any one of claims 1 to 5, characterized in that: R5 and R1 are each independently selected from the group consisting of hydrogen, aldehyde, -C(O)O-C1-C5 alkyl, oxo, -C(O)NH-C1-C5 alkyl, -NHC(O)O-C1-C5 alkyl, -C1-C5 alkyl-NHC(O)O-C1-C5 alkyl, -C1-C5 alkyl-C(O)O-C1-C5 alkyl, 3- to 8-membered heterocyclic group, -C1-C5 alkyl-C6-C10 aryl, and at least one selected from R S2 Substituents substituted or unsubstituted C1-C5 alkyl, at least one selected from R S2 Substituents substituted or unsubstituted C6-C10 aryl, hydroxyl, at least one selected from R S2 Substituents substituted or unsubstituted C2~C10 heteroaryl, -C1~C5 alkyl-O-C2~C10 heteroaryl, -C(O)-C2~C10 heteroaryl; R S2 Including: H, C6~C10 aryl, hydroxyl, halogen, nitro, cyano, C1~C5 alkoxy, C1~C5 alkyl or halogen-substituted C1~C5 alkyl.

9. The azaaromatic ring carboxamide compound according to any one of claims 1 to 5, characterized in that: R5, R1 and the atoms to which they are connected together form a saturated or unsaturated ring, or R1 and Forming a bridge ring structure; The saturated or unsaturated ring comprises: S3 A 3- to 8-membered heterocyclic group substituted or unsubstituted by a substituent, a 3- to 8-membered heterocyclic group substituted or unsubstituted by at least one selected from R S3 Substituents substituted or unsubstituted C2-C10 heteroaryl; the bridged ring structure includes at least one selected from R S3 A 6- to 12-membered heterobridged ring group substituted or unsubstituted with a substituent; R S3 Including: -C(O)O-C1~C5 alkyl or halogen substituted or unsubstituted C1~C5 alkyl.

10. The azaaromatic carboxamide compound according to any one of claims 1 to 5, characterized in that: R3 and R4 are selected from the group consisting of: hydrogen.

11. The azaaromatic carboxamide compound according to any one of claims 1 to 5, characterized in that: One of the following compounds:

12. A pharmaceutical composition, characterized in that It comprises the azaaromatic ring carboxamide compound or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated product thereof as described in any one of claims 1 to 11, and a pharmaceutically acceptable carrier.

13. Use of the azaaromatic carboxamide compound or its pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated product according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 12 in the preparation of a drug for treating and / or preventing respiratory viral infections; Optionally, the viruses in the respiratory viral infection include influenza A virus and / or influenza B virus; Further optionally, the influenza A virus includes H3N2 and / or H1N1; Further optionally, the influenza B virus comprises B / Lee / 40.

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