Azaaromatic carboxamides and uses thereof

Abstract

The application relates to a kind of azaheterocyclic ring carboxamide compounds and its application.The azaheterocyclic ring carboxamide compound has the structural characteristics shown in formula I, which can effectively treat diseases caused by respiratory viruses such as influenza.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, in particular to a kind of azaheteroaromatic ring carboxamide compound and its application. BACKGROUND

[0002] Influenza (hereinafter referred to as influenza) is an acute respiratory infectious disease that seriously endangers human health, caused by influenza virus, with high morbidity, widespread and rapid transmission. The main means of treating influenza at present is to use antiviral chemical small molecule drugs targeting 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, etc. The means of anti-influenza virus under research include antisense oligonucleotides, ribozymes and deoxyribozyme to inhibit influenza virus replication or RNA expression, etc. The first-line anti-influenza virus drugs in clinic are neuraminidase inhibitors oseltamivir and PA inhibitors marbovir, and the rest of the drugs are selected for use when the two types of drugs fail to work on specific virus strains, specific population or against general non-severe viruses.

[0003] However, the therapeutic window of oseltamivir is narrow, and the drug efficacy is obvious only within 48 hours of infection, and after years of use, a variety of drug-resistant strains have appeared, making it difficult to meet clinical use. Marbovir is a new anti-influenza drug with a completely new mechanism in the past 20 years, which is obtained by structural modification of the parent nucleus of molnupiravir by Japan's Shionogi Pharmaceutical Company. Only one dose of marbovir is needed throughout the course of the disease to better control the disease. Within 24 hours of taking marbovir, virus shedding can be stopped, effectively relieving symptoms such as high fever and general malaise. However, when marbovir is used in clinic, side effects such as allergic reactions, skin rashes, urticaria and vomiting are found, especially in children, and the incidence of drug-resistant strains is high.

[0004] Therefore, it is necessary to develop more drugs that can effectively treat diseases caused by respiratory viruses such as influenza. SUMMARY

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

[0006] The first aspect of the present application provides an azaheteroaromatic ring carboxamide compound or its pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuteride having the structural characteristics shown in formula I:

[0007]

[0008] wherein,

[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 C2-C10 heteroaryl;

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

[0013] R1is selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, aldehyde, amino, C1-C5 alkyl substituted with at least one substituent selected from R S2 , C3-C8 cycloalkyl substituted with at least one substituent selected from R S1 , cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 11 , -N(R 12 R 13 ), amide, sulfonamide, C6-C10 aryl substituted with at least one substituent selected from R 12 , or C2-C10 heteroaryl substituted with at least one substituent selected from R 12 , oxo, -NHC(O)O-C1-C5 alkyl, -C1-C5 alkyl-NHC(O)O-C1-C5 alkyl, 3-8 membered heterocyclyl, -C1-C5 alkyl-C6-C10 aryl, -C1-C5 alkyl-O-C2-C10 heteroaryl or -C(O)-C2-C10 heteroaryl; R S1 includes: 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 are each independently selected from: C1-C5 alkyl, R 12 and R 13 are cycled or not cycled;

[0014] Y is selected from: CH-R5or N-R5; R5is selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, aldehyde, amino, C1-C5 alkyl substituted with at least one substituent selected from R S2 , C3-C8 cycloalkyl substituted with at least one substituent selected from R S2 , cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 51 , -N(R 52 R 53 ), amide, sulfonamide, C6-C10 aryl substituted with at least one substituent selected from R S2 , or C2-C10 heteroaryl substituted with at least one substituent selected from R S2substituted or unsubstituted C2-C10 heteroaryl, oxo, -NHC(O)O-C1-C5 alkyl, -C1-C5 alkyl-NHC(O)O-C1-C5 alkyl, 3-8 membered heterocyclyl, -C1-C5 alkyl-C6-C10 aryl, -C1-C5 alkyl-O-C2-C10 heteroaryl, or -C(O)-C2-C10 heteroaryl; R S2 comprises 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 are each independently selected from the group consisting of C1-C5 alkyl, R 52 , and R 53 , are cyclic or acyclic;

[0015] Optionally, R5, R1, and the atoms to which they are attached collectively form a saturated or unsaturated ring, or R1and collectively form a bridged ring structure;

[0016] R2is 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 heterocyclyl, C6-C10 aryl, or C2-C10 heteroaryl; R 21 , R 22 , R 23 are each independently selected from the group consisting of C1-C5 alkyl, R 22 , and R 23 , are cyclic or acyclic; the 5-10 membered heterocyclyl, C6-C10 aryl, C2-C10 heteroaryl are each independently substituted with at least one substituent selected from R S3 , or are unsubstituted, R S3 comprises H, C1-C5 alkyl, -NHC(O)-R 24 , -C(O)NH2, or -C(O)NH2, R 24 is selected from the group consisting of C1-C5 alkyl;

[0017] R3is 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 group, sulfonamide group, C6-C10 aryl or C2-C10 heteroaryl; R 31 R 32 R 33 Each is independently selected from: C1 to C5 alkyl groups, R 32 With R 33 Cyclic or non-cyclic;

[0018] R4 is selected from: 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 group, sulfonamide group, C6-C10 aryl or C2-C10 heteroaryl; R 41 R 42 R 43 Each is independently selected from: C1 to C5 alkyl groups, R 42 With R 43 Cyclic or non-cyclic.

[0019] A second aspect of this application provides a pharmaceutical composition comprising the aza-aryl cyclocarboxamide compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated derivative thereof, and a pharmaceutically acceptable carrier.

[0020] A third aspect of this application provides the use of the aza-aryl cyclocarboxamide compounds described in the first aspect or their pharmaceutically acceptable salts, stereoisomers, prodrug molecules, deuterated derivatives, or the pharmaceutical compositions described in the second aspect in the preparation of medicaments for treating and / or preventing respiratory viral infections.

[0021] The aforementioned aza-aryl cyclocarboxamide compounds, through rational structural design, can exhibit good anti-influenza activity, especially against the replication of influenza A (A / HK / 1 / 68(H3N2), A / WSN / 33(H1N1)) and influenza B (B / Lee / 40) virus strains. Detailed Implementation

[0022] The following detailed description, in conjunction with specific embodiments, further illustrates the azirroaryl cyclocarboxamide compounds of this application and their applications. This application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0024] As used herein, the terms "and / or", "or / and", "and / or" are optional ranges that include any one of two or more related listed items, and also include any and all combinations of the related listed items, including any two related listed items, any more related listed items, or all related listed items.

[0025] In this application, the technical features described in an open form include both the closed technical solution consisting of listed features and the open technical solution containing listed features.

[0026] In this application, when referring to a numerical interval, unless otherwise specified, the numerical interval is considered to be continuous and includes the minimum value and the maximum value of the range, as well as every value between the minimum value and the maximum value. Further, when the range refers to integers, every integer between the minimum value and the maximum value of the range is included. In addition, when multiple ranges are provided to describe a feature or a characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges encompassed therein.

[0027] In this application, when referring to a percentage content, unless otherwise specified, it refers to a mass percentage for solid-liquid mixing and solid-solid mixing, and a volume percentage for liquid-liquid mixing.

[0028] In this application, when referring to a percentage concentration, unless otherwise specified, it refers to a final concentration. The final concentration refers to the proportion of the added ingredient in the system after the ingredient is added.

[0029] In this application, unless otherwise specified, the temperature parameter allows both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument.

[0030] In this application, room temperature generally refers to 4℃ to 30℃, preferably 20±5℃.

[0031] In this application, "hydroxyl" refers to -OH.

[0032] In this application, "aldehyde group" refers to -C(O)H.

[0033] In this application, "amino" refers to -NH2.

[0034] "Alkyl" in the present application refers to a saturated hydrocarbon radical derived by the loss of a hydrogen atom from a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing this term, e.g., "C1-C5 alkyl" refers to an alkyl group containing from 1 to 5 carbon atoms, which can be, independently of each other, a C1 alkyl, a C2 alkyl, a C3 alkyl, a C4 alkyl, a C5 alkyl, on each occurrence. 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 the present application refers to a non-aromatic hydrocarbon containing ring carbon atoms, which can be a monocycloalkyl, or a spirocycloalkyl, or a bridged cycloalkyl. Phrases containing this term, e.g., "C3-C8 cycloalkyl" refers to a cycloalkyl group containing from 3 to 8 carbon atoms, which can be, independently of each other, a C3 cycloalkyl, a C4 cycloalkyl, a C5 cycloalkyl, a C6 cycloalkyl, a C7 cycloalkyl, a C8 cycloalkyl, on each occurrence. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0036] "Cyano" in the present application refers to -CN.

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

[0038] As used herein, "alkoxy" refers to a group of structure -O-alkyl, i.e., an alkyl group as defined above attached to the adjacent group through an oxygen atom. Phrases containing this term, e.g., "C1-C5 alkoxy" means that the alkyl portion contains 1-5 carbon atoms, and each occurrence can be, independently of the other, 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 t-butoxy (-O-C(CH3)3 or -OtBu).

[0039] As used herein, "ester" refers to -[R-C(O)O-R'], wherein R and R' are each independently selected from absent or alkyl, and are not simultaneously absent; wherein alkyl can be, for example, C1-C5 alkyl.

[0040] As used herein, "sulfonyl ester" refers to -[R-S(O)2-R'], wherein R and R' are each independently selected from absent or alkyl, and are not simultaneously absent; wherein alkyl can be, for example, C1-C5 alkyl.

[0041] As used herein, "amide" refers to -[R-C(O)N(R')2], wherein R is selected from absent or alkyl, and R' are each independently selected from absent, H or alkyl, and R, R' are not simultaneously absent, and two R' are not simultaneously H; wherein alkyl can be, for example, C1-C5 alkyl, and optionally, two R' are cyclic or acyclic, when cyclic, can be directly connected to form a cycloalkyl, or can form a heterocyclyl group with at least one atom selected from N, O, S, and the cycloalkyl or heterocyclyl group can further include C1-C2 alkyl as a substituent.

[0042] As used herein, "sulfonamide" refers to -[R-S(O)2-N(R')2], wherein R is selected from absent or alkyl, and R' are each independently selected from absent, H or alkyl, and R, R' are not simultaneously absent, and two R' are not simultaneously H; wherein alkyl can be, for example, C1-C5 alkyl, and optionally, two R' are cyclic or acyclic, when cyclic, can be directly connected to form a cycloalkyl, or can form a heterocyclyl group with at least one atom selected from N, O, S, and the cycloalkyl or heterocyclyl group can further include C1-C2 alkyl as a substituent.

[0043] The term "aryl" as used herein refers to an aromatic hydrocarbon group derived from a parent aromatic ring compound by removal of one hydrogen atom. The aryl group can be a monocyclic aryl group, or a fused ring aryl group, or a polycyclic aryl group, wherein at least one ring is an aromatic ring system. For example, "C6-C10 aryl" refers to an aryl group containing 6 to 10 carbon atoms, which can be independently C6 aryl, C7 aryl, C8 aryl, C9 aryl, or C10 aryl at each occurrence. Suitable examples include, but are not limited to, benzene, biphenyl, naphthalene, anthracene, phenanthrene, chrysene, triphenylene, and derivatives thereof.

[0044] The term "heteroaryl" as used herein refers to an aromatic group derived from a parent aromatic ring compound by replacing at least one carbon atom with a non-carbon atom, such as N, O, S, etc. For example, "C2-C10 heteroaryl" refers to a heteroaryl group containing 2 to 10 carbon atoms, which can be independently C2 heteroaryl, C3 heteroaryl, C4 heteroaryl, C5 heteroaryl, C6 heteroaryl, C7 heteroaryl, C8 heteroaryl, C9 heteroaryl, or C10 heteroaryl at each occurrence. 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, thienothienyl, furanopyrrolyl, furanofuranyl, thienofuranyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl, perylenyl, phenanthridinyl, quinazolinyl, and quinazolinonyl.

[0045] The term "oxo" as used herein refers to "=0".

[0046] The term "heterocyclyl" as used herein refers to a saturated or partially unsaturated ring group derived from a parent cycloalkyl group by replacing at least one carbon atom with a non-carbon atom, such as N, O, S, etc. The phrase containing this term, for example, "C4-C9 heterocyclyl" refers to a heterocyclyl group containing 4 to 9 carbon atoms, which can be independently C4 heteroalkyl, C5 heteroalkyl, C6 heteroalkyl, C7 heteroalkyl, C8 heteroalkyl, or C9 heteroalkyl at each occurrence. Suitable examples include, but are not limited to, dihydropyridinyl, tetrahydropyridinyl (piperidinyl), tetrahydrothienyl, sulfoxidized tetrahydrothienyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl.

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

[0048] The term "nitro" as used herein refers to -NO2.

[0049] The "at least one" in the present application, without limitation, can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0050] The "pharmaceutically acceptable salt" in the present application refers to any compound in the structure shown, which is formed with an acid or a base, and is suitable for use as a drug. The pharmaceutically acceptable salt includes inorganic salt and organic salt. Among them, one kind of salt is the salt formed by the compound of the present application and the acid. The acid suitable for forming salt includes but is not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; 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, benzene sulfonic acid, naphthalene sulfonic acid and other organic acids; and proline, phenylalanine, aspartic acid, glutamic acid and other amino acids. Another kind of salt is the salt formed by the compound of the present application and the base, and the base suitable for forming salt includes but is not limited to: alkali metal salt (such as sodium salt or potassium salt), alkaline earth metal salt (such as magnesium salt or calcium salt), ammonium salt (such as lower alkyl ammonium salt and other pharmaceutically acceptable amine salt), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, t-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salt formed by morpholine, piperazine and lysine, respectively.

[0051] The "prodrug molecule" in the present application refers to any compound which, when administered to an organism, produces a drug, i.e. an active ingredient, due to spontaneous chemical reaction, enzyme-catalyzed chemical reaction, photolysis and / or metabolic chemical reaction. The prodrug is thus a covalently modified analogue or latent form of the therapeutically active compound. Suitable examples include but are not limited to: carboxylic acid ester, carbonate ester, phosphate ester, nitrate ester, sulfate ester, sulfone ester, sulfoxide ester, amino compound, carbamate, azo compound, phosphoramidate, glucoside, ether, acetal and the like forms of the compound.

[0052] In some examples of the present application, azaaromatic ring carboxamide compounds having the structural characteristics shown in formula I or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterium thereof are provided:

[0053]

[0054] wherein,

[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 C2-C10 heteroaryl;

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

[0059] R1is selected from the group consisting of: hydrogen, fluoro, chloro, bromo, hydroxyl, aldehydo, amino, C1-C5alkyl substituted with at least one substituent selected from the group consisting of R S2 S1 C3-C8cycloalkyl substituted with at least one substituent selected from the group consisting of R 11 , cyano, carboxyl, C1-C5alkoxy, ester, sulfonyl ester, -NH-R 12 , -N(R 13 ), amido, sulfonamido, C6-C10aryl substituted with at least one substituent selected from the group consisting of R 12 , or C2-C10heteroaryl substituted with at least one substituent selected from the group consisting of R 12 , oxo, -NHC(O)O-C1-C5alkyl, -C1-C5alkyl-NHC(O)O-C1-C5alkyl, 3-8 membered heterocyclyl, -C1-C5alkyl-C6-C10aryl, -C1-C5alkyl-O-C2-C10heteroaryl, or -C(O)-C2-C10heteroaryl; R S1 includes: H, C6-C10aryl, hydroxyl, halogen, nitro, cyano, C1-C5alkoxy, C1-C5alkyl, or halogen substituted C1-C5alkyl; R 11 , R 12 , R 13 are each independently selected from the group consisting of: C1-C5alkyl, R 12 , or R 13 , or R

[0060] Y is selected from the group consisting of: CH-R5or N-R5; R5is selected from the group consisting of: hydrogen, fluoro, chloro, bromo, hydroxyl, aldehydo, amino, C1-C5alkyl substituted with at least one substituent selected from the group consisting of R S2 S2 C3-C8cycloalkyl substituted with at least one substituent selected from the group consisting of R 51 , cyano, carboxyl, C1-C5alkoxy, ester, sulfonyl ester, -NH-R 52 , -N(R 53 ), amido, sulfonamido, C6-C10aryl substituted with at least one substituent selected from the group consisting of R S2 , or C2-C10heteroaryl substituted with at least one substituent selected from the group consisting of R S2 , oxo, -NHC(O)O-C1-C5alkyl, -C1-C5alkyl-NHC(O)O-C1-C5alkyl, 3-8 membered heterocyclyl, -C1-C5alkyl-C6-C10aryl, -C1-C5alkyl-O-C2-C10heteroaryl, or -C(O)-C2-C10heteroaryl; R S2 ​​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 is selected from the group consisting of: C1-C5 alkyl, R 52 , and R 53 , taken together with the atom to which they are attached, form a ring or no ring;

[0061] Optionally, R5, R1, and the atoms to which they are attached, together form a saturated or unsaturated ring, or R1and together form a bridged ring structure;

[0062] R2is 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 heterocyclyl, C6-C10 aryl, or C2-C10 heteroaryl; R 21 , R 22 , R 23 each independently is selected from the group consisting of: C1-C5 alkyl, R 22 , and R 23 , taken together with the atom to which they are attached, form a ring or no ring; said 5-10 membered heterocyclyl, C6-C10 aryl, C2-C10 heteroaryl is each independently substituted with at least one substituent selected from the group consisting of R S3 , or unsubstituted, R S3 includes: H, C1-C5 alkyl, -NHC(O)-R 24 , -C(O)NH2, or -C(O)NH2, R 24 is selected from the group consisting of: C1-C5 alkyl;

[0063] R3is 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 is selected from the group consisting of: C1-C5 alkyl, R 32 , and R 33 , taken together with the atom to which they are attached, form a ring or no ring;

[0064] R4is selected from: hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C1-C5alkyl, fluorine-substituted C1-C5alkyl, C3-C8cycloalkyl, fluorine-substituted C3-C8cycloalkyl, cyano, carboxyl, C1-C5alkoxy, ester, sulfonyl ester, -NH-R 41 , -N(R 42 R 43 ), amide, sulfonamide, C6-C10aryl, or C2-C10heteroaryl; R 41 , R 42 , R 43 are each independently selected from: C1-C5alkyl, R 42 and R 43 form a ring or do not form a ring.

[0065] In some examples, the azaheteroaromatic ring carboxamide compound has the structural features of Formula I-11 or Formula I-12:

[0066]

[0067] In some examples, the azaheteroaromatic ring carboxamide compound has the structural features of Formula I-21 or Formula I-22:

[0068]

[0069] In some examples, the azaheteroaromatic ring carboxamide compound has the structural features of Formula I-21 or Formula I-22: L is selected from: a single bond or the following groups:

[0070] X1, X2, X3, X4are each independently selected from: CH or N.

[0071] Further, the azaheteroaromatic ring carboxamide compound has the structural features of Formula I-31 or Formula I-32:

[0072]

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

[0074]

[0075] In some examples, R2is selected from: hydrogen, 5-10 membered heterocyclyl, C6-C10aryl, or C2-C10heteroaryl, each independently substituted with at least one substituent selected from R S3 , R S3 includes: H, C1-C5alkyl, -NHC(O)-R 21-C(O)NH2, or -C(O)NH2.

[0076] In some examples, R2is selected from: hydrogen or a group:

[0077]

[0078] In some examples, R5, R1are each independently selected from: hydrogen, aldehyde, -C(O)O-C1-C5alkyl, oxo, -C(O)NH-C1-C5alkyl, -NHC(O)O-C1-C5alkyl, -C1-C5alkyl-NHC(O)O-C1-C5alkyl, -C1-C5alkyl-C(O)O-C1-C5alkyl, 3-8 membered heterocyclyl, -C1-C5alkyl-C6-C10aryl, C1-C5alkyl unsubstituted or substituted with at least one substituent selected from R S2 S2 S2 S2 H, C6-C10aryl, hydroxyl, halogen, nitro, cyano, C1-C5alkoxy, C1-C5alkyl, or halogen substituted C1-C5alkyl.

[0079] Further, R5, R1are not simultaneously H.

[0080] In some examples, R1is selected from: aldehyde, -C(O)O-C1-C5alkyl, oxo, -C(O)NH-C1-C5alkyl, -NHC(O)O-C1-C5alkyl, -C1-C5alkyl-NHC(O)O-C1-C5alkyl, -C1-C5alkyl-C(O)O-C1-C5alkyl, 3-8 membered heterocyclyl, -C1-C5alkyl-C6-C10aryl, C1-C5alkyl unsubstituted or substituted with at least one substituent selected from R S2 S2 S2 S2 H, C6-C10aryl, hydroxyl, halogen, nitro, cyano, C1-C5alkoxy, C1-C5alkyl, or halogen substituted C1-C5alkyl.

[0081] ​​​​​​R5 is selected from: hydrogen, hydroxyl group, aldehyde group, and at least one group selected from R. S2 The substituents are substituted or unsubstituted C6-C10 aryl groups, R S2 Includes: halogens.

[0082] In some of these examples, R5, R1, and the atoms they are connected to form saturated or unsaturated rings, or R1 and... Forming a bridge ring structure; the saturated or unsaturated ring comprises: being formed by at least one selected from R S3 The substituents are substituted or unsubstituted 3- to 8-membered heterocyclic groups, and are selected from at least one R S3 The substituents may be substituted or unsubstituted C2-C10 heteroaryl groups; the bridged ring structure includes at least one group selected from R S3 Substituents or unsubstituted 6- to 12-membered heterobridged cyclogroups; R S3 Includes: -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 they are connected to form saturated or unsaturated rings, or R1 and... When forming a bridge ring structure, Selected from the following groups:

[0084]

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

[0086] In some of these examples, the azirrocyclocarboxamide compounds are selected from one of the following compounds:

[0087]

[0088]

[0089]

[0090] Other examples of this application also provide a pharmaceutical composition comprising the azirrocyclocarboxamide compound as described above, or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated derivative thereof, and a pharmaceutically acceptable carrier.

[0091] Without limitation, "pharmaceutically acceptable carrier" means 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, compatible with pharmaceutical administration. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Suitable examples include, but are not limited to: (1) sugars, such as lactose, dextrose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted beta -cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, 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 oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laureate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0092] In some examples of the present application, there is also provided use of an azaheterocyclic carbamide compound as described above, or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated form thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for treating and / or preventing a respiratory viral infection.

[0093] Further, the virus in the respiratory viral infection comprises an influenza A virus and / or an influenza B virus. Without limitation, the influenza A virus comprises A / HK / 1 / 68 (H3N2) and / or A / WSN / 33 (H1N1); the influenza B virus comprises B / Lee / 40.

[0094] The dosage form and mode of administration of the compounds of the present application or pharmaceutical compositions thereof are not particularly limited. Representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous) injection, and topical administration.

[0095] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as binders, (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) humectants, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) moisturizing agents, e.g., glycerol, (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, e.g., paraffin, (f) absoφtion accelerators, e.g., quaternary ammonium compounds, (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate, (h) absorbents, e.g., kaolin, and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents. Solid compositions such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other coatings of

[0096] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof. In addition, the liquid dosage forms can contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and

[0097] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0098] Dosage forms for topical administration of a compound include ointments, powders, patches, sprays, and inhalers. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as can be required.

[0099] As used herein, "drug" includes any agent, compound, composition, or mixture that provides a physiological and / or pharmacological effect in or on a subject, and often provides a beneficial effect. The "drug" is not particularly limited in the range of physiological and / or pharmacological effects it produces in a subject, and can be a systemic effect or can only produce an effect locally. The "drug" is not particularly limited in its activity, and can be an active substance that interacts with other substances, or can be an inert substance that does not interact.

[0100] Experimental parameters not specified in the following specific examples are preferably referred to the guidelines given in this application file, and can also be referred to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by the vendors.

[0101] The starting materials and reagents involved in the following specific examples can be obtained commercially, or can be prepared by one skilled in the art according to known means.

[0102] Example 1: Synthesis of Compound 1

[0103]

[0104] Synthesis of Compound 1:

[0105] To a solution of 4-quinolinecarboxylic acid (0.17 g, 1.0 mmol), (S)-pyrrolidine-2-carboxylic acid tert-butyl ester (0.19 g, 1.1 mmol), l-(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) in dichloromethane (20 mL) was stirred at room temperature for 24 hours. The reaction was monitored by TLC. The reaction mixture was diluted with saturated aqueous sodium chloride solution (20 mL) and extracted with ethyl acetate (10 mL) three times. The combined organic phase was washed with water (10 mL) three times, dried over magnesium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography on 300-400 mesh silica gel, eluting with petroleum ether / ethyl acetate (v / v) = 1 / 1 and ethyl acetate successively to give the target compound 1 as colorless oil 0.25 g in 77% yield. 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 the synthetic method of example 1, starting from 4- quinolinecarboxylic acid and ethyl pyrrolidine-3-carboxylate hydrochloride, compound 2 was obtained as a yellow oil 0.26 g, yield 88%. MS (ESI) m / z calcd for C 17 H 19 N2O3 [M+H] + 299.1, found 299.3.

[0109] Example 3: Synthesis of compound 3

[0110]

[0111] Using the synthetic method of example 1, starting from 4- quinolinecarboxylic acid and 2-Boc-2,7-diaza-spiro[4.4]nonane, compound 3 was obtained as a yellow oil 0.29 g, yield 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 the synthetic method of example 1, starting from 4- quinolinecarboxylic acid and methyl piperidine-4-carboxylate, compound 4 was obtained as a brown oil 0.28 g, yield 96%. 1H NMR (400 MHz, CDC13-dl) δ 8.95 (d, J = 4.4, 2.3 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.81 (d, 1H), 7.76 (dd, 1H), 7.61 (dd, J = 12.3, 7.5 Hz, 1H), 7.31 (d, J = 18.8, 4.3 Hz, 1H), 4.69 (tt, J = 14.3, 4.3 Hz, 1H), 3.70 (s, J = 3.4 Hz, 3H), 3.36 (t, J = 13.8, 4.3, 1.4 Hz, 1H), 3.18 (t, J = 17.1, 13.8, 11.1, 3.2 Hz, 1H), 3.02 (t, J = 13.6, 11.0, 3.2 Hz, 1H), 2.60 (t, J = 10.3, 4.9 Hz, 1H), 2.14 (dt, J = 14.5, 4.4 Hz, 1H), 1.86 (dt, 2H), 1.58 (dt, 1H).

[0115] Example 5: Synthesis of compound 5

[0116]

[0117] Compound 5 was obtained as a yellow oil 0.18 g, yield 52% using the synthetic procedure of example 1 starting from 4-quinolinecarboxylic acid and piperidine-4-carboxylic acid ethyl ester. 1 H NMR (500 MHz, CDC13-dl) δ 8.94 (d, J = 3.9 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 30.3, 8.3 Hz, 2H), 7.59 (dd, J = 15.4, 7.8 Hz, 1H), 7.30 (d, J = 25.3, 4.2 Hz, 1H), 4.69 (t, 1H), 4.14 (t, J = 6.8 Hz, 2H), 3.35 (dt, J = 13.8, 4.7 Hz, 1H), 3.16 (dt, J = 21.0, 10.7 Hz, 1H), 3.01 (dt, J = 14.0, 3.1 Hz, 1H), 2.58 (tt, 1H), 2.12 (t, J = 9.4 Hz, 1H), 1.85 (t, J = 10.4 Hz, 1H), 1.74 (t, J = 13.9 Hz, 1H), 1.57 (dt, 1H), 1.24 (t, J = 6.9 Hz, 3H).

[0118] Example 6: Synthesis of compound 6

[0119]

[0120] Using the synthetic method of Example 1, compound 6 was obtained as yellow oil 0.24 g, yield 75% from 4-quinolinecarboxylic acid and ethyl 3-oxo-4-piperidinecarboxylate. 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 the synthetic method of Example 1, compound 7 was obtained as yellow oil 0.32 g, yield 98% from 4-quinolinecarboxylic acid and piperidine-4-carboxylic acid tert-butyl ester. MS (ESI) m / z calcd 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 mixture solvent of water and tetrahydrofuran (4:1, 25 mL), methyl 1-(quinoline-4- carboxyl)piperidine-4-carboxylate (compound 4) (0.59 g, 2 mmol) and sodium hydroxide (0.16 g, 4 mmol) were added, stirred at room temperature for 12 hours, TLC test showed the reaction was completed, the system was adjusted to be acidic by adding hydrochloric acid, and dried by rotary evaporation to obtain the crude product of intermediate 1-(quinoline-4-carbonyl)piperidine-4-carboxylic acid (8a) as yellow solid.

[0128] Synthesis of compound 8:

[0129] Using the synthetic method of Example 1, compound 8 was obtained as white solid 0.27 g, yield 40% from 1-(quinoline-4-carbonyl)piperidine-4-carboxylic acid (8a) and tert-butylamine. 1H NMR (400 MHz, CDC13-dl) δ 8.94 (d, J = 4.3 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.76 (dd, J = 7.9 Hz, 1H), 7.61 (dd, J = 22.3, 7.6 Hz, 1H), 7.33 (d, 1H), 5.28 (s, 1H), 4.87 (t, J = 14.3 Hz, 1H), 3.40 (t, J = 13.6 Hz, 1H), 2.99 (t, J = 11.2 Hz, 2H), 2.23 (tt, 1H), 1.99 (dt, J = 11.5, 7.4 Hz, 1H), 1.88 (dt, 1H), 1.61 (dt, J = 24.9, 14.7, 7.8 Hz, 2H), 1.33 (s, 9H).

[0130] Example 9: Synthesis of compound 9

[0131]

[0132] Compound 9 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and 4-tert-butoxycarbonylamino piperidine as white solid 0.32 g, yield 91%. MS (ESI) m / z calcd for C 20 H 26 N3O3 [M+H] + 356.2, found 356.3.

[0133] Example 10: Synthesis of compound 10

[0134]

[0135] Compound 10 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and 4-tert-butoxycarbonylamino piperidine as white foam 0.34 g, yield 96%. MS (ESI) m / z calcd for C 20 H 26 N3O3 [M+H] + 356.2, found 356.3.

[0136] Example 11: Synthesis of compound 11

[0137]

[0138] Compound 11 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and 4-(2-Boc-aminoethyl)piperidine as white foam 0.38 g, yield 98%. MS (ESI) m / z calcd for C22 H 30 N3O3[M+H] + 384.2, found 384.3.

[0139] Example 12: Synthesis of compound 12

[0140]

[0141] Compound 12 was obtained as colorless oil 0.27 g, 86% yield using the synthetic method of example 1 starting from 4-quinolinecarboxylic acid and methyl 4-piperidineacetate. 1 H NMR (400 MHz, CDC13-dl) δ 8.95 (d, J = 4.3 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.83 (d, 1H), 7.76 (d, 1H), 7.60 (dd, J = 7.7 Hz, 1H), 7.30 (dd, J = 19.9, 4.3 Hz, 1H), 4.91 (tt, J = 12.9 Hz, 1H), 3.67 (s, 3H), 3.32 (dt, J = 13.6 Hz, 1H), 2.94 (d, J = 30.3, 16.8 Hz, 2H), 2.28 (dt, J = 15.9, 7.2 Hz, 2H), 2.10 (dt, 1H), 1.95 (t, 1H), 1.57 (t, 1H), 1.37 (t, 1H), 1.09 (t, J = 48.5, 9.4 Hz, 1H).

[0142] Example 13: Synthesis of compound 13

[0143]

[0144] Compound 13 was obtained as white foam 0.17 g, 55% yield using the synthetic method of example 1 starting from 4-quinolinecarboxylic acid and 4-pyrrolidin-l-yl-piperidine. 1 H NMR (400 MHz, CDC13-dl) δ 8.94 (d, J = 4.3 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.83 (d, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.57 (dd, 1H), 7.29 (dd, J = 4.6 Hz, 1H), 4.77 (tt, 1H), 3.35 (t, J = 13.5 Hz, 1H), 3.09 (t, 1H), 2.99 (t, 1H), 2.55 (t, J = 13.2 Hz, 4H), 2.23 (t, 1H), 2.10 (tt, J = 15.3 Hz, 1H), 1.79 (t, 4H), 1.70 (tt, 2H), 1.37 (tt, 1H).

[0145] Example 14: Synthesis of compound 14

[0146]

[0147] Using the synthetic method of example 1, starting from 4-quinolinecarboxylic acid and 4-pyrrolidin-1-yl-piperidine, compound 14 was obtained as a colorless oil 0.26 g, yield 80%. 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 4.7 Hz, 1 H), 8.12 (d, J = 8.6 Hz, 1 H), 7.91 (d, 1 H), 7.82 (d, 1 H), 7.72 (dd, J = 13.2, 7.3 Hz, 1 H), 7.49 (dd, J = 36.5 Hz, 1 H), 3.36 (d, J = 10.8 Hz, 1 H), 3.11 (dd, J = 28.4, 13.4 Hz, 1 H), 2.98 (dd, J = 22.2, 12.1 Hz, 1 H), 2.58 (s, 5 H), 2.10 (m, 1 H), 1.76 (d, J = 14.4 Hz, 1 H), 1.63 (s, 5 H), 1.48 (s, 3 H), 1.31 (d, J = 16.6 Hz, 1 H).

[0148] Example 15: Synthesis of compound 15

[0149]

[0150] Using the synthetic method of example 1, starting from 4-quinolinecarboxylic acid and 2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester, compound 15 was obtained as a white foam 0.32 g, yield 80%. 1 H NMR (400 MHz, CDC13-dl) δ 8.96 (d, J = 4.3 Hz, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 7.81 (d, 1 H), 7.76 (d, J = 7.4 Hz, 1 H), 7.61 (dd, J = 7.7 Hz, 1 H), 7.32 (dd, J = 4.3 Hz, 1 H), 3.96 (tt, 1 H), 3.87 (t, 1 H), 3.41 (t, 3 H), 3.21 (t, 4 H), 1.81 (d, J = 14.5, 13.8, 7.1 Hz, 2 H), 1.75 (t, 2 H), 1.56 (s, 9 H).

[0151] Example 16: Synthesis of compound 16

[0152]

[0153] Using the synthetic method of example 1, compound 16 was obtained as colorless oil 0.32 g, yield 98% from 4-quinolinecarboxylic acid and 4-benzylpiperidine. 1 H NMR (400 MHz, CDC13-dl) δ 8.94 (d, J = 3.2 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.84 (dd, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.59 (dd, J = 15.6, 7.8 Hz, 1H), 7.32 (d, 1H), 7.28 (d, 2H), 7.20 (dd, J = 7.4 Hz, 1H), 7.12 (dd, J = 6.7 Hz, 2H), 4.88 (tt, J = 11.3 Hz, 1H), 3.31 (d, J = 13.6 Hz, 1H), 2.94 (d, 1H), 2.82 (dt, J = 14.4 Hz, 1H), 2.59 (dt, 1H), 2.57 (dt, J = 7.1 Hz, 1H), 1.89 (dt, J = 12.4 Hz, 1H), 1.83 (tt, J = 11.4 Hz, 1H), 1.53 (tt, J = 17.1 Hz, 1H), 1.38 (tt, J = 11.6 Hz, 1H), 1.08 (tt, 1H).

[0154] Example 17: Synthesis of compound 17

[0155]

[0156] Using the synthetic method of example 1, compound 17 was obtained as white foam 0.38 g, yield 90% from 4-quinolinecarboxylic acid and diphenyl(piperidin-4-yl)methanol. 1 H NMR (400 MHz, CDC13-dl) δ 8.94 (d, J = 3.2 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.84 (dd, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.59 (dd, J = 15.6, 7.8 Hz, 1H), 7.32 (d, 1H), 7.28 (d, 2H), 7.20 (dd, J = 7.4 Hz, 1H), 7.12 (dd, J = 6.7 Hz, 2H), 4.88 (tt, J = 11.3 Hz, 1H), 3.31 (d, J = 13.6 Hz, 1H), 2.94 (d, 1H), 2.82 (dt, J = 14.4 Hz, 1H), 2.59 (dt, 1H), 2.57 (dt, J = 7.1 Hz, 1H), 1.89 (dt, J = 12.4 Hz, 1H), 1.83 (tt, J = 11.4 Hz, 1H), 1.53 (tt, J = 17.1 Hz, 1H), 1.38 (tt, J = 11.6 Hz, 1H), 1.08 (tt, 1H).

[0157] Example 18: Synthesis of compound 18

[0158]

[0159] Using the synthetic method of example 1, starting from 4-quinolinecarboxylic acid and 4-phenylpiperidine, compound 18 was obtained as a yellow oil 0.30 g, 95% yield. 1 H NMR (400 MHz, CDC13-dl) δ 8.96 (d, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.90 (d, 1H), 7.77 (dd, J = 9.2 Hz, 1H), 7.62 (dd, J = 15.4, 7.6 Hz, 1H), 7.38 (d, 1H), 7.31 (d, J = 6.7 Hz, 2H), 7.21 (dd, J = 7.8, 7.3 Hz, 3H), 5.08 (tt, J = 12.3 Hz, 1H), 3.44 (t, J = 11.0 Hz, 1H), 3.13 (t, 1H), 2.98 (t, J = 13.2 Hz, 1H), 2.80 (t, J = 12.1, 3.8 Hz, 1H), 2.09 (dt, J = 25.4 Hz, 2H), 1.86 (dt, J = 12.8, 8.0, 4.5 Hz, 1H), 1.54 (dt, J = 46.3, 12.5, 4.2 Hz, 1H).

[0160] Example 19: Synthesis of compound 19

[0161]

[0162] Using the synthetic method of example 1, starting from 4-quinolinecarboxylic acid and 4-(4-fluorophenyl)piperidine, compound 19 was obtained as a white solid 0.31 g, 93% yield. 1H NMR (400 MHz, CDC13-dl) δ 8.97 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.89 (d, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.63 (dd, J = 15.2, 7.7 Hz, 1H), 7.36 (dd, J = 33.1, 4.3 Hz, 1H), 7.16 (d, J = 7.3 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 5.08 (t, J = 12.3 Hz, 1H), 3.44 (t, J = 11.4 Hz, 1H), 3.12 (t, 1H), 2.99 (t, 1H), 2.79 (tt, J = 12.2, 3.7 Hz, 1H), 2.07 (td, J = 14.6 Hz, 1H), 1.82 (td, J = 12.2, 5.5 Hz, 1H), 1.51 (dt, J = 47.3, 12.7, 4.2 Hz, 2H).

[0163] Example 20: Synthesis of compound 20

[0164]

[0165] Compound 20 was obtained using the synthetic method of example 1 starting from 4- quinolinecarboxylic acid and 4-(4-chlorophenyl)piperidine as starting materials in 0.28 g, 60% yield as a white solid. 1 H NMR (400 MHz, CDC13-dl) δ 8.97 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.89 (d, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.63 (dd, J = 15.2, 7.7 Hz, 1H), 7.36 (dd, J = 33.1, 4.3 Hz, 1H), 7.16 (d, J = 7.3 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 5.08 (t, J = 12.3 Hz, 1H), 3.44 (t, J = 11.4 Hz, 1H), 3.12 (t, 1H), 2.99 (t, 1H), 2.79 (tt, J = 12.2, 3.7 Hz, 1H), 2.07 (td, J = 14.6 Hz, 1H), 1.82 (td, J = 12.2, 5.5 Hz, 1H), 1.51 (dt, J = 47.3, 12.7, 4.2 Hz, 2H).

[0166] Example 21: Synthesis of compound 21

[0167]

[0168] Compound 21 was obtained using the synthetic method of example 1 starting from 4- quinolinecarboxylic acid and 4-(4-bromophenyl)piperidine as starting materials in 0.23 g, 60% yield as a white solid.1 H NMR (400 MHz, CDC13-dl) δ 8.97 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.88 (d, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.63 (dd, J = 15.0, 7.7 Hz, 1H), 7.44 (d, J = 6.5 Hz, 2H), 7.35 (dd, J = 33.0, 4.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 5.07 (tt, J = 12.3 Hz, 1H), 3.45 (t, J = 13.5 Hz, 1H), 3.11 (t, J = 23.1, 12.7 Hz, 1H), 2.97 (t, J = 13.6 Hz, 1H), 2.77 (dt, 1H), 2.07 (dt, J = 14.7 Hz, 1H), 2.07 (dt, 2H), 1.68 (dt, 1H).

[0169] Example 22: Synthesis of compound 22

[0170]

[0171] Compound 22 was obtained using the synthetic method of example 1 starting from 4- quinolinecarboxylic acid and 4-(4-nitrophenyl)piperidine as starting materials in 0.23 g, 64% yield as a white foam. 1 H NMR (400 MHz, CDC13-dl) δ 8.97 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.88 (d, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.63 (dd, J = 15.0, 7.7 Hz, 1H), 7.44 (d, J = 6.5 Hz, 2H), 7.35 (dd, J = 33.0, 4.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 5.07 (tt, J = 12.3 Hz, 1H), 3.45 (t, J = 13.5 Hz, 1H), 3.11 (t, J = 23.1, 12.7 Hz, 1H), 2.97 (t, J = 13.6 Hz, 1H), 2.77 (dt, 1H), 2.07 (dt, J = 14.7 Hz, 1H), 2.07 (dt, 2H), 1.68 (dt, 1H).

[0172] Example 23: Synthesis of compound 23

[0173]

[0174] Compound 23 was obtained using the synthetic method of example 1 starting from 4- quinolinecarboxylic acid and 4-(4-biphenyl)piperidine as starting materials in 0.20 g, 99% yield as a yellow oil.1 H NMR (400 MHz, CDC13-dl) δ 8.98 (d, J = 4.2 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 4.2 Hz, 2H), 7.98 (dd, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.64 (dd, J = 15.5, 7.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.33 (d, 1H), 5.13 (tt, 1H), 3.49 (t, 1H), 3.15 (t, J = 23.9, 13.1 Hz, 1H), 3.01 (t, J = 30.0, 15.9 Hz, 2H), 2.17 (dt, J = 37.4 Hz, 1H), 2.05 (dt, J = 29.7 Hz, 1H), 1.87 (dt, J = 13.4 Hz, 1H), 1.77 (dt, J = 16.4 Hz, 1H).

[0175] Example 24: Synthesis of compound 24

[0176]

[0177] Using the synthetic method of example 1, starting from 4-quinolinecarboxylic acid and 4-(3-trifluoromethylphenyl)piperidine, compound 24 was obtained as a colorless oil 0.34 g, yield 90%. 1 H NMR (400 MHz, CDC13-dl) δ 8.98 (d, J = 4.2 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 8.18 (d, J = 4.2 Hz, 2H), 7.98 (dd, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.64 (dd, J = 15.5, 7.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.33 (d, 1H), 5.13 (tt, 1H), 3.49 (t, 1H), 3.15 (t, J = 23.9, 13.1 Hz, 1H), 3.01 (t, J = 30.0, 15.9 Hz, 2H), 2.17 (dt, J = 37.4 Hz, 1H), 2.05 (dt, J = 29.7 Hz, 1H), 1.87 (dt, J = 13.4 Hz, 1H), 1.77 (dt, J = 16.4 Hz, 1H).

[0178] Example 25: Synthesis of compound 25

[0179]

[0180] Compound 25 was obtained using the synthetic method of example 1, starting from 4- quinolinecarboxylic acid and 4-(4-chlorophenyl)piperidin-4-ol as starting materials, as a white solid 0.18 g, 51% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (d, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.84 (d, 2 H), 7.70 (dd, J = 7.6 Hz, 1 H), 7.64 (dd, 1 H), 7.55 (d, J = 11.8 Hz, 1 H), 7.50 (d, 1 H), 7.39 (d, J = 8.2 Hz, 2 H), 5.34 (s, 1 H), 4.63 (t, J = 12.6 Hz, 1 H), 3.46 (t, J = 15.1 Hz, 1 H), 3.23 (t, J = 44.6 Hz, 1 H), 3.07 (t, J = 13.2 Hz, 1 H), 2.10 (t, 1 H), 1.68 (t, J = 65.3, 13.8 Hz, 2 H), 1.45 (t, J = 13.2 Hz, 1 H).

[0181] Example 26: Synthesis of compound 26

[0182]

[0183] Compound 26 was obtained using the synthetic method of example 1, starting from 4- quinolinecarboxylic acid and 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole as starting materials, as a white foamy product 0.29 g, 77% yield. 1 H NMR (400 MHz, CDCl3-d1) δ 8.98 (s, J = 4.3 Hz, 1 H), 8.17 (d, J = 6.4 Hz, 1 H), 7.87 (d, J = 28.6, 8.0 Hz, 1 H), 7.78 (d, J = 7.7 Hz, 1 H), 7.64 (d, J = 6.5 Hz, 1 H), 7.61 (d, 1 H), 7.37 (d, J = 20.0, 4.3 Hz, 1 H), 7.28 (dd, J = 7.9 Hz, 1 H), 7.10 (dd, J = 8.8, 2.2 Hz, 1 H), 4.91 (tt, J = 12.1 Hz, 1 H), 3.55 (dt, J = 14.8 Hz, 1 H), 3.40 (dt, J = 7.6, 3.7 Hz, 1 H), 3.32 (dt, 1 H), 3.24 (dt, J = 14.2 Hz, 1 H), 2.33 (t, J = 11.2 Hz, 1 H), 2.16 (t, 1 H), 1.99 (t, 1 H), 1.86 (t, 1 H).

[0184] Example 27: Synthesis of compound 27

[0185]

[0186] Compound 27 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and (3S,4R)-3-((benzo[d][l,3]dioxol-5-yloxy)methyl)-4-(4- fluorophenyl)piperidine as a white solid 0.32 g, 67% yield. 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] Compound 28 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and 7-bromo-l,2,3,4-tetrahydroisoquinoline as a white foam 0.35 g, 95% yield. 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] Compound 29 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and N-methylpiperazine as a colorless oil 0.23 g, 90% yield. MS (ESI) m / z calcd for C 15 H 18 N3O[M+H] + 256.1, found 256.2.

[0193] Example 30: Synthesis of compound 30

[0194]

[0195] Compound 30 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and N-formylpiperazine as a white foam 0.16 g, 60% yield. MS (ESI) m / z calcd for C 15 H 16 N3O2[M+H] + 270.1, found 270.2.

[0196] Example 31: Synthesis of compound 31

[0197]

[0198] Compound 31 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and N-Boc-piperazine as white foamy 0.32 g in 94% yield. MS (ESI) m / z calcd for C 19 H 24 N3O3[M+H] + 342.2, found 342.3.

[0199] Example 32: Synthesis of compound 32

[0200]

[0201] Compound 32 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and 6-N-Boc-3,6-diazabicyclo[3.1.1]heptane as white foamy 0.25 g in 71% yield. 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] Compound 33 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and 1-(2-furancarbonyl)piperazine as white foamy 0.32 g in 95% yield. 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] Compound 34 was obtained using the synthetic method of Example 1 starting from 4- quinolinecarboxylic acid and 1-phenylpiperazine as yellow oil 0.17 g in 54% yield. 1H NMR (400 MHz, CDC13-dl) δ 8.94 (d, J = 4.3 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 (dd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.57 (d, J = 8.3, 6.9, 1.3 Hz, 1H), 7.31 (d, J = 4.3 Hz, 1H), 7.23 (d, 2H), 6.88 (dd, J = 7.9, 6.3 Hz, 3H), 4.14 (t, J = 7.1, 4.5 Hz, 1H), 3.99 (t, J = 8.3 Hz, 1H), 3.31 (t, J = 10.2, 6.1 Hz, 4H), 3.02 (t, 1H), 2.96 (t, 1H).

[0208] Example 35: Synthesis of compound 35

[0209]

[0210] Compound 35 was obtained as a colorless oil 0.31 g, 94% yield using the synthetic method of example 1 starting from 4-quinolinecarboxylic acid and l-(4-fluorophenyl)piperazine. 1 H NMR (400 MHz, CDC13-dl) δ 8.94 (d, J = 4.3 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 (dd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.57 (d, J = 8.3, 6.9, 1.3 Hz, 1H), 7.31 (d, J = 4.3 Hz, 1H), 7.23 (d, 2H), 6.88 (dd, J = 7.9, 6.3 Hz, 3H), 4.14 (t, J = 7.1, 4.5 Hz, 1H), 3.99 (t, J = 8.3 Hz, 1H), 3.31 (t, J = 10.2, 6.1 Hz, 4H), 3.02 (t, 1H), 2.96 (t, 1H).

[0211] Example 36: Synthesis of compound 36

[0212]

[0213] Compound 36 was obtained as a colorless oil 0.30 g, 87% yield using the synthetic method of example 1 starting from 4-quinolinecarboxylic acid and l-(4-chlorophenyl)piperazine. 1H NMR (400 MHz, CDC13-dl) δ 8.98 (d, J = 4.3 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.61 (dd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.35 (d, J = 4.3 Hz, 1H), 7.22 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 4.16 (t, J = 7.5, 4.7 Hz, 1H), 4.01 (t, J = 13.1, 7.8 Hz, 1H), 3.33 (t, J = 12.5, 9.0 Hz, 4H), 2.99 (t, J = 24.8, 5.5 Hz, 2H).

[0214] Example 37: Synthesis of compound 37

[0215]

[0216] Compound 37 was obtained as a colorless oil 0.28 g, 86% yield using the synthetic method of example 1 starting from 4-quinolinecarboxylic acid and l-(p-tolyl)piperazine. 1 H NMR (400 MHz, CDC13-dl) δ 8.98 (d, J = 4.3 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.61 (dd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.35 (d, J = 4.3 Hz, 1H), 7.22 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 4.16 (t, J = 7.5, 4.7 Hz, 1H), 4.01 (t, J = 13.1, 7.8 Hz, 1H), 3.33 (t, J = 12.5, 9.0 Hz, 4H), 2.99 (t, J = 24.8, 5.5 Hz, 2H).

[0217] Example 38: Synthesis of compound 38

[0218]

[0219] Compound 38 was obtained as a colorless oil 0.18 g, 48% yield using the synthetic method of example 1 starting from 4-quinolinecarboxylic acid and l-(4-(trifluoromethyl)phenyl)piperazine. 1H NMR (400 MHz, CDC13-dl) δ 8.97 (d, J = 4.3 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.60 (dd, J = 7.6 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 4.3 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 4.17 (t, 1H), 4.00 (t, 1H), 3.44 (t, J = 10.8, 5.3 Hz, 2H), 3.34 (t, J = 5.0 Hz, 2H), 3.14 (t, J = 5.1 Hz, 1H), 3.08 (t, 1H).

[0220] Example 39: Synthesis of compound 39

[0221]

[0222] Compound 39 was obtained using the synthetic method of example 1 starting from 4- quinolinecarboxylic acid and 4-(piperazin-l-yl)benzonitrile as starting materials in 0.097 g, 28% yield as a white solid. 1 H NMR (400 MHz, CDC13-dl) δ 8.97 (d, J = 4.3 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.60 (dd, J = 7.6 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 4.3 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 4.17 (t, 1H), 4.00 (t, 1H), 3.44 (t, J = 10.8, 5.3 Hz, 2H), 3.34 (t, J = 5.0 Hz, 2H), 3.14 (t, J = 5.1 Hz, 1H), 3.08 (t, 1H).

[0223] Example 40: Synthesis of compound 40

[0224]

[0225] Compound 40 was obtained using the synthetic method of example 1 starting from 4- quinolinecarboxylic acid and l-(4-nitrophenyl)piperazine as starting materials in 0.30 g, 83% yield as a yellow foam. 1H NMR (400 MHz, CDC13-dl) δ 9.00 (d, J = 4.3 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 9.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.63 (dd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.37 (d, J = 4.3 Hz, 1H), 6.83 (d, J = 9.5 Hz, 2H), 4.11 (t, J = 44.9 Hz, 2H), 3.62 (t, J = 4.9 Hz, 2H), 3.32 (t, 4H).

[0226] Example 41: Synthesis of compound 41

[0227]

[0228] Compound 41 was obtained as a brown solid 0.26 g, yield 39% using the synthetic method of example 1 starting from 4-quinolinecarboxylic acid and 4-(piperazin-l-yl)phenol. 1 H NMR (400 MHz, CDC13-dl) δ 9.00 (d, J = 4.3 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 9.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.63 (dd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.37 (d, J = 4.3 Hz, 1H), 6.83 (d, J = 9.5 Hz, 2H), 4.11 (t, J = 44.9 Hz, 2H), 3.62 (t, J = 4.9 Hz, 2H), 3.32 (t, 4H).

[0229] Example 42: Synthesis of compound 42

[0230]

[0231] Compound 42 was obtained as a yellow foam 0.24 g, yield 70% using the synthetic method of example 1 starting from 4-quinolinecarboxylic acid and l-(4-methoxyphenyl)piperazine. 1H NMR (400 MHz, CDC13-dl) δ 8.98 (d, J = 4.3 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.78 (dd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.61 (dd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.36 (d, J = 4.3 Hz, 1H), 7.19 (dd, J = 8.2 Hz, 1H), 6.52 (d, J = 8.3, 2.3 Hz, 1H), 6.47 (d, J = 8.0, 2.3 Hz, 1H), 6.44 (s, J = 2.3 Hz, 1H), 4.16 (t, 1H), 4.01 (t, 1H), 3.78 (s, 3H), 3.35 (t, J = 9.7, 4.7 Hz, 4H), 3.6 (t, 1H), 3.00 (t, J = 5.3 Hz, 1H).

[0232] Example 43: Synthesis of compound 43

[0233]

[0234] Compound 43 was obtained as a yellow oil 0.26 g, 77% yield using the synthetic method of example 1 starting from 4-quinolinecarboxylic acid and l-(3-methoxyphenyl)piperazine. 1 H NMR (400 MHz, CDC13-dl) δ 8.98 (d, J = 4.3 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 6.9 Hz, 1H), 7.78 (dd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.61 (dd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.36 (d, J = 4.3 Hz, 1H), 7.19 (dd, J = 8.2 Hz, 1H), 6.52 (d, J = 8.3, 2.3 Hz, 1H), 6.47 (d, J = 8.0, 2.3 Hz, 1H), 6.44 (s, J = 2.3 Hz, 1H), 4.16 (t, 1H), 4.01 (t, 1H), 3.78 (s, 3H), 3.35 (t, J = 9.7, 4.7 Hz, 4H), 3.6 (t, 1H), 3.00 (t, J = 5.3 Hz, 1H).

[0235] Example 44: Synthesis of compound 44

[0236]

[0237] Compound 44 was obtained as a white foam 0.33 g, 96% yield using the synthetic method of example 1 starting from 4-quinolinecarboxylic acid and l-(2-methoxyphenyl)piperazine. MS (ESI) m / z calcd for C 21H 22 N3O2[M+H] + 348.2, found 348.3.

[0238] Example 45: Synthesis of compound 45

[0239]

[0240] Compound 45 was obtained using the synthetic method of Example 1, starting from 4- quinolinecarboxylic acid and 2-(piperazin-1-yl)pyrimidine as white foamy 0.30 g, yield 94%. MS (ESI) m / z calcd for C 18 H 18 N5O[M+H] + 320.2, found 320.3.

[0241] Example 46: Synthesis of compound 46

[0242]

[0243] Compound 46 was obtained using the synthetic method of Example 1, starting from 4- quinolinecarboxylic acid and 5-ethyl-2-(piperazin-1-yl)pyrimidine as white foamy 0.29 g, yield 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] Compound 47 was obtained using the synthetic method of Example 1, starting from 4- quinolinecarboxylic acid and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine as yellow oil 0.25 g, yield 73%. 1 H NMR (400 MHz, CDC13-dl) δ 9.03 (d, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.74 (dd, 1H), 7.64 (dd, J = 15.8, 7.5 Hz, 1H), 7.39 (d, J = 12.2 Hz, 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 the synthetic method of Example 1, starting from 6-chloropyridine-2-carboxylic acid (0.32 g, 2 mmol) and N-methylpiperazine (0.22 g, 2.2 mmol), compound (6-chloropyridin-2-yl)(4-methylpiperazin-1-yl)methanone (48a) was obtained as a yellow oil 0.43 g, yield 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] To a mixture of (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, 1.25 mmol) in 1,4-dioxane (10 mL) and water (1 mL), a microwave reactor was used for the reaction at 140 °C for 30 min. TLC showed the reaction was completed. Ethyl acetate (10 mL) was added and the water layer was absorbed. The organic layer was dried over magnesium sulfate, filtered and the filtrate was rotary evaporated. The residue was purified by column chromatography on 300-400 mesh silica gel (DCM / MeOH = 80 / 1, 70 / 1, 60 / 1, 50 / 1, 40 / 1, 35 / 1 gradient elution) to give the target compound 48 as a white solid 0.064 g, 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] Starting from (6-chloropyridin-2-yl)(4-methylpiperazin- 1 -yl)methanone (48a) (0.12 g, 0.5 mmol) and (1 H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) using the synthetic method of Example 48 afforded compound 49 as a white solid 0.080 g, 50% yield. 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] Starting from 2-chloropyrimidine-4-carboxylic acid (0.32 g, 2 mmol) and tert-butyl piperidine-4-carboxylate (0.41 g, 2.2 mmol) using the synthetic method of Example 1 to obtain the intermediate compound, then 0.5 mmol with (1 H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (0.10 g, 0.6 mmol) as starting material, using the synthetic method of Example 48 afforded compound 50 as a yellow solid 0.020 g, 10% yield. 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] Starting from 2-chloropyrimidine-4-carboxylic acid (0.32 g, 2 mmol) and tert-butyl piperidine-4-carboxylate (0.41 g, 2.2 mmol) using the synthetic method of Example 1 to obtain the intermediate compound, then 0.5 mmol with (1 H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) as starting material, using the synthetic method of Example 48 afforded compound 51 as a white foam 0.16 g, 80% yield. 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] Using the synthetic method of example 1, intermediate compound was obtained starting from 6-chloropyridine-2-carboxylic acid (0.32 g, 2 mmol) and 2-(piperazin-l- yl)pyrimidine (0.36 g, 2.2 mmol), then 0.5 mmol was used as starting material with (lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) to get compound 52 as white foamy 0.12 g, 61% yield. MS (ESI) m / z calcd for C 21 H 20 N7O[M+H] + 386.2, found 386.4.

[0265] Example 53: Synthesis of compound 53

[0266]

[0267] Using the synthetic method of example 1, intermediate compound was obtained starting from 6-chloropyridine-2-carboxylic acid (0.32 g, 2 mmol) and 1-(4-methoxyphenyl)piperazine (0.42 g, 2.2 mmol), then 0.5 mmol was used as starting material with (lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) to get compound 53 as white solid 0.14 g, 67% yield. 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] Using the synthetic method of example 1, intermediate compound was obtained starting from 6-chloropyridine-2-carboxylic acid (0.32 g, 2 mmol) and 1-(4-methoxyphenyl)piperazine (0.42 g, 2.2 mmol), then 0.5 mmol was used as starting material with (lH-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (0.10 g, 0.6 mmol) to get compound 54 as white solid 0.11 g, 53% yield. 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-carbonyl)piperidine-4- carboxylate (55a):

[0274] Using the synthetic method of example 1, starting from 2-chloroquinoline-4-carboxylic acid (0.42 g, 2 mmol) and tert-butyl piperidine-4-carboxylate (0.41 g, 2.2 mmol), compound tert-butyl 1-(2-chloroquinoline-4-carbonyl)piperidine-4-carboxylate (55a) was obtained as a brown oil 0.70 g, yield 94%. Synthesis of compound 55:

[0275] To tert-butyl 1-(2-chloroquinoline-4-carbonyl)piperidine-4-carboxylate (55a) (0.19 g, 0.5 mmol), 1-methylpiperazine (0.06 g, 0.52 mmol) and cesium carbonate (0.13 g, 0.4 mmol) in 1,4-dioxane (10 mL), using a microwave reactor at 160 °C for 1 h, TLC showed the reaction was completed, the system was diluted with ethyl acetate (10 mL), and concentrated to dryness, the residue was purified by column chromatography on silica gel (300-400 mesh) (DCM / MeOH = 50 / 1, 40 / 1, 35 / 1, 30 / 1, 25 / 1, 20 / 1 gradient elution), to give the target compound 55 as a yellow oil 0.11 g, yield 50%. 1 H NMR (400 MHz, CDC13-dl) δ 7.71 (d, J = 7.9 Hz, 1H), 7.57 (s, J = 7.5 Hz, 1H), 7.51 (dd, 2H), 7.22 (dd, 1H), 6.88 (d, J = 17.2 Hz, 1H), 4.65 (t, J = 24.9, 13.5 Hz, 1H), 3.75 (t, 4H), 3.57 (t, J = 5.3 Hz, 1H), 3.41 (t, 2H), 3.11 (tt, J = 35.5, 13.6, 11.0, 3.1 Hz, 1H), 2.98 (dt, J = 14.1, 11.2, 3.2 Hz, 1H), 2.55 (t, J = 4.8 Hz, 4H), 2.47 (dt, 1H), 2.40 (dt, J = 10.0, 4.9 Hz, 1H), 2.36 (s, 3H), 2.04 (dt, J = 5.5 Hz, 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-acetamidobenzenboronic acid (0.11 g, 0.6 mmol) as starting materials, the synthetic method of example 48 gave compound 56 as a red oil 0.10 g, 46% yield. 1 H NMR (400 MHz, CDC13-dl) δ 8.22 (d, J = 24.6 Hz, 1H), 8.17 (s, 1H), 7.86 (d, J = 6.1 Hz, 1H), 7.81 (d, J = 14.5 Hz, 1H), 7.73 (d, J = 21.6 Hz, 2H), 7.57 (dd, J = 14.5, 7.5 Hz, 1H), 7.48 (dd, J = 7.7 Hz, 1H), 7.41 (s, 1H), 4.70 (t, J = 30.2, 13.4 Hz, 1H), 3.41 (t, J = 13.7 Hz, 1H), 3.20 (t, J = 33.7, 11.6 Hz, 1H), 3.05 (t, 1H), 2.51 (tt, J = 6.8 Hz, 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 starting materials, the synthetic method of example 55 gave compound 57 as a red foam 0.21 g, 91% yield. 1H NMR (400 MHz, CDC13-dl) δ 8.63 (s, 1H), 8.33 (d, J = 7.0 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.96 (dd, J = 13.7, 7.8 Hz, 1H), 7.87 (s, 1H), 7.84 (d, J = 3.9 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 14.8, 7.5 Hz, 2H), 6.40 (s, 1H), 5.81 (s, 1H), 4.69 (t, J = 31.3, 13.4 Hz, 1H), 3.40 (t, 1H), 3.24 (t, J = 23.4, 11.0 Hz, 1H), 3.14 (t, 1H), 3.05 (tt, J = 11.4, 8.2 Hz, 1H), 2.51 (td, 1H), 2.11 (td, 1H), 1.86 (td, 1H), 1.75 (td, J = 13.8 Hz, 1H), 1.45 (s, 9H).

[0282] Example 58: Synthesis of compound 58

[0283]

[0284] Using the synthetic method of example 48, starting from tert-butyl l-(2- chloroquinoline-4-carbonyl)piperidine-4-carboxylate (55a) (0.19 g, 0.5 mmol) and (lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g, 0.6 mmol) gave compound 58 as a yellow oil 0.097 g, 42% yield. 1 H NMR (400 MHz, CDC13-dl) δ 8.63 (s, 1H), 8.33 (d, J = 7.0 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.96 (dd, J = 13.7, 7.8 Hz, 1H), 7.87 (s, 1H), 7.84 (d, J = 3.9 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 14.8, 7.5 Hz, 2H), 6.40 (s, 1H), 5.81 (s, 1H), 4.69 (t, J = 31.3, 13.4 Hz, 1H), 3.40 (t, 1H), 3.24 (t, J = 23.4, 11.0 Hz, 1H), 3.14 (t, 1H), 3.05 (tt, J = 11.4, 8.2 Hz, 1H), 2.51 (td, 1H), 2.11 (td, 1H), 1.86 (td, 1H), 1.75 (td, J = 13.8 Hz, 1H), 1.45 (s, 9H).

[0285] Example 59: Synthesis of compound 59

[0286]

[0287] Using the synthetic method of example 48, starting from 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) afforded compound 59 as an orange oil 0.062 g, 27% yield. 1 H NMR (400 MHz, CDC13-dl) δ 10.68 (s, J = 18.5 Hz, 1H), 9.18 (s, J = 9.2 Hz, 1H), 8.75 (s, J = 2.1 Hz, 1H), 8.22 (s, J = 8.8 Hz, 1H), 7.88 (d, J = 16.6 Hz, 1H), 7.82 (d, J = 16.1 Hz, 1H), 7.77 (d, J = 5.6 Hz, 1H), 7.57 (dd, J = 15.7, 7.9 Hz, 1H), 7.45 (dd, J = 3.6 Hz, 1H), 6.64 (d, J = 6.5, 3.4 Hz, 1H), 4.72 (t, J = 24.9, 13.8 Hz, 1H), 3.47 (t, J = 12.4 Hz, 1H), 3.22 (t, J = 28.2, 13.6, 11.0, 3.1 Hz, 1H), 3.08 (t, J = 10.7, 5.3 Hz, 1H), 2.52 (tt, J = 7.2, 3.8 Hz, 1H), 2.11 (td, 1H), 1.93 - 1.85 (td, 2H), 1.75 (td, J = 9.1, 4.7 Hz, 1H), 1.45 (s, 9H).

[0288] Example 60: Synthesis of compound 60

[0289]

[0290] Using the synthetic method of example 48, starting from 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) afforded compound 59 as an orange oil 0.062 g, 27% yield. 27 H 30 N5O3[M+H]+472.2, found 472.4.

[0291] Example 61: Synthesis of compound 61

[0292]

[0293] Using the synthetic method of example 1, starting from 2-chloroquinoline-4- carboxylic acid (0.42 g, 2 mmol) and 4-tert-butoxycarbonylamino piperidine (0.44 g, 2.2 mmol) to get the intermediate compound, then using the synthetic method of example 48, starting from 0.5 mmol and (1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (0.10 g, 0.6 mmol) to get compound 61 as a yellow solid 0.17 g, 70% yield. 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 the synthetic method of example 1, starting from 2-chloroquinoline-4- carboxylic acid (4.2 g, 20 mmol) and 1-(4-methoxyphenyl)piperazine (4.2 g, 22 mmol) to get the intermediate compound (62a), then using the synthetic method of example 55, starting from intermediate compound (62a) (0.19 g, 0.5 mmol) and 1-methylpiperazine (0.06 g, 0.52 mmol) to get compound 62 as a yellow oil 0.16 g, 72% yield. 1 H NMR (400 MHz, CDC13-dl) δ 7.74 (d, J = 8.3 Hz, 1H), 7.58 (dd, 2H), 7.26 (d, J = 7.7 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J = 9.2 Hz, 2H), 6.85 (d, J = 9.2 Hz, 2H), 4.16 (t, J = 13.4, 6.2, 3.6 Hz, 1H), 3.98 (t, J = 11.1, 3.7 Hz, 1H), 3.83 (t, J = 10.4, 4.7 Hz, 2H), 3.78 (s, 3H), 3.74 (t, 2H), 3.37 (t, J = 5.2 Hz, 2H), 3.21 (t, 2H), 2.92 (t, 2H), 2.57 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H).

[0297] Example 63: Synthesis of compound 63

[0298]

[0299] Using the synthetic method of example 48, starting from intermediate compound (62a) (0.19 g, 0.5 mmol) and 3-acetamidobenzoic acid (0.11 g, 0.6 mmol) gave compound 63 as a brown oil 0.20 g, 84% yield. 1 H NMR (400 MHz, CDC13-dl) δ 8.25 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.82 (s, 1H), 7.76 (d, J = 18.1, 8.7 Hz, 2H), 7.58 (dd, J = 7.0 Hz, 1H), 7.48 (dd, 2H), 6.90 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 9.1 Hz, 2H), 4.20 (s, 1H), 4.03 (t, 1H), 3.77 (s, 3H), 3.38 (t, J = 5.1, 4.7 Hz, 2H), 3.28 (t, J = 5.4 Hz, 1H), 3.22 (t, J = 6.1 Hz, 1H), 2.98 (t, 1H), 2.89 (t, J = 6.9 Hz, 1H), 2.21 (s, 3H).

[0300] Example 64: Synthesis of compound 64

[0301]

[0302] Using the synthetic method of example 48, starting from intermediate compound (62a) (0.19 g, 0.5 mmol) and 3-acetamidobenzoic acid (0.11 g, 0.6 mmol) gave compound 63 as a brown oil 0.20 g, 84% yield. 1 H NMR (400 MHz, CDC13-dl) δ 8.25 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.82 (s, 1H), 7.76 (d, J = 18.1, 8.7 Hz, 2H), 7.58 (dd, J = 7.0 Hz, 1H), 7.48 (dd, 2H), 6.90 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 9.1 Hz, 2H), 4.20 (s, 1H), 4.03 (t, 1H), 3.77 (s, 3H), 3.38 (t, J = 5.1, 4.7 Hz, 2H), 3.28 (t, J = 5.4 Hz, 1H), 3.22 (t, J = 6.1 Hz, 1H), 2.98 (t, 1H), 2.89 (t, J = 6.9 Hz, 1H), 2.21 (s, 3H).

[0303] Example 65: Synthesis of compound 65

[0304]

[0305] Compound 65 was obtained as a brown solid 0.11 g, 48% yield using the synthetic method of example 48, starting from 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). 1 H NMR (400 MHz, CDC13-dl) δ 9.59 (s, 1H), 8.50 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.97 (d, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.84 (dd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.70 (d, J = 5.0 Hz, 1H), 7.65 (dd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.51 (d, J = 3.4 Hz, 1H), 7.24 (d, J = 3.4 Hz, 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 = 5.7 Hz, 2H), 3.27 (t, J = 13.6 Hz, 2H), 2.96 (t, 2H).

[0306] Example 66: Synthesis of compound 66

[0307]

[0308] Compound 66 was obtained as an orange oil 0.15 g, 58% yield using the synthetic method of example 48, starting from 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). 1H NMR (400 MHz, CDC13-dl) δ 9.89 (s, 1H), 9.17 (s, J = 2.1 Hz, 1H), 8.76 (s, J = 2.1 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.91 (s, 1H), 7.86 (m, 1H), 7.79 (dd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.58 (dd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.42 (d, 1H), 6.90 (d, 2H), 6.85 (d, J = 9.4, 2.8 Hz, 2H), 6.65 (d, J = 3.6, 1.8 Hz, 1H), 4.21 (t, 1H), 4.06 (t, 1H), 3.77 (s, 3H), 3.43 (t, J = 6.2 Hz, 2H), 3.27 (t, 2H), 2.99 (t, J = 5.9, 4.8 Hz, 1H), 2.92 (t, J = 6.2 Hz, 1H).

[0309] Example 67: Synthesis of compound 67

[0310]

[0311] Using the synthetic method of Example 48, starting from 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) afforded compound 67 as an orange solid 0.16 g, 71% yield. 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 synthetic method of Example 48, starting from intermediate compound (62a) (0.19 g, 0.5 mmol) and (1-methyl-lH-pyrazolo[3,4-b]pyridin-5-yl)boronic acid (0.11 g, 0.6 mmol) afforded compound 68 as an orange solid 0.022 g, 9% yield. 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 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 material, the synthetic method of Example 48 was used to obtain compound 69 as an orange solid 0.12 g, in 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 this test example for testing the inhibitory activity of the example compounds on influenza virus is that influenza virus infection of MDCK cells can cause cytopathic effects and lead to cell death, and the compounds inhibit the replication of the virus by inhibiting the function of the protease required for viral replication, thereby inhibiting the occurrence of cytopathic effects and cell death. The activity of the compounds against influenza virus can be reflected by determining the viability of the cells 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: cultured routinely at 37°C in a 5% CO2 incubator. Other reagents: DMEM / F-12 (1:1) medium (Gibco), FBS (Invitrogen), PS (Gibco), 0.2% Trypsin-EDTA (Gibco), TPCK trypsin (Sigma Aldrich), PBS buffer (Corning), MTT (Sigma Aldrich).

[0322] Experimental method:

[0323] 1. In vitro efficacy experiment of the compound

[0324] The test was carried out in a BSL-2 laboratory.

[0325] The test compound is configured with DMSO to 10 mM stock solution, 4 ℃ preservation for standby. MDCK cells and DMEM / F-12 culture medium containing 10% FBS and 1% PS are mixed uniformly, the cell density is 1.5×10 5 cells / mL, 100 μL / well is inoculated in a sterile 96-well plate, and is incubated at 37 ℃, 5% CO 2 in a conventional incubator for 24 h. At this time, the adherent cells grow to 90% or more, the culture supernatant is discarded, and 100 μL / well PBS is added and then discarded. The influenza virus liquid stored at -80 ℃ is taken out, diluted with DMEM / F-12 culture medium to 100 TCID 50, and the diluted virus liquid is added to the experimental group and the model group for attack, and the control group is added with blank DMEM / F-12 culture medium. After conventional culture for 2 h, the culture medium is discarded, 100 μL / well of DMEM / F-12 culture medium containing 0.1% TPCK and 1% PS is added, and the stock solution of the test substance is 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 determined. The diluent of the test substance is added to the wells of the experimental group in an amount of 100 μL / well, and the test substance is diluted to different concentrations by half dilution method, 7 different concentrations are set for each test substance, and each well contains 100 μL of compound culture medium. Three replicates are set for each concentration, and conventional culture is incubated for 48 h. The culture medium in the well plate is discarded, washed with PBS and discarded, 1 mg / mL MTT solvent (prepared with PBS) is added to the well plate (100 μL / well), and conventional culture is carried out for 4 h. The supernatant is discarded, 100 μL / well of DMSO is added, and the absorbance (OD) at 490 nm is measured by an enzyme marker. The calculation formula of the 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 maximal inhibitory concentration (IC 50 ) is calculated by excel software.

[0328] 2. Drug toxicity experiment of the compound

[0329] The test is carried out in a BSL-2 laboratory.

[0330] The determination of drug toxicity and the determination method of drug efficacy are basically the same, the difference is that the determination of drug toxicity does not need to be attacked, and the culture medium for diluting the test substance is DMEM / F-12 culture medium containing 1% PS. The calculation formula of 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 by using excel software. The efficacy and toxicity of each compound were determined in triplicate, and the results were calculated as mean and standard deviation.

[0333] The results are shown in Table 1.

[0334] Table 1: Inhibition of variant influenza virus by compounds

[0335]

[0336]

[0337] From the above table, it can be seen that the compounds of the examples have high levels of inhibitory activity against one or more of A / HK / 1 / 68 (H3N2), A / WSN / 33 (H1N1) and B / Lee / 40 virus strains. Further, the compounds of the examples have low cytotoxicity and are good for drug development, as compared by cytotoxicity evaluation.

[0338] Any combination of the technical features of the above-described examples can be made. In order to make the description simple, all possible combinations of the technical features in the above-described examples are not described, however, as long as the combination of the technical features does not exist, it should be considered as the scope of the present disclosure.

[0339] The above-described examples only express several embodiments of the present application, facilitate specific and detailed understanding of the technical solutions of the present application, but should not be understood as a limitation on the scope of patent protection. It should be noted that for ordinary skilled persons in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of the present application. It should be understood that the technical solutions obtained by the skilled person in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present application are within the scope of the appended claims of the present application. Therefore, the scope of patent protection of the present application should be based on the contents of the appended claims, and the specification can be used to explain the contents of the claims.

Claims

1. An azaheteroaromatic ring carboxamide compound having the structural features shown in Formula I: or a pharmaceutically acceptable salt, deuteride thereof. Formula I wherein, L is selected from the group consisting of: a single bond; n is selected from the group consisting of: 1; R1is selected from the group consisting of: hydrogen, hydroxyl, oxo; Y is selected from the group consisting of: CH-R5; R5is selected from the group consisting of: an ester group, an amide group, -NHC(O)O-C1-C5alkyl, -C1-C5alkyl-NHC(O)O-C1-C5alkyl, a 3-8 membered heterocyclyl group; the ester group refers to -[R-C(O)O-R’], the amide group refers to -[R-C(O)N(R’)2], wherein R and R’ are each independently selected from the group consisting of nothing or C1-C5alkyl, and are not simultaneously nothing; or selected from the group consisting of: , R S4 selected from the group consisting of: -C(O)O-C1-C5alkyl; R2is selected from the group consisting of: hydrogen, 5-10 membered heterocyclyl, C6-C10 aryl, or C2-C10 heteroaryl; each of said 5-10 membered heterocyclyl, C6-C10 aryl, C2-C10 heteroaryl is independently substituted with at least one substituent selected from the group consisting of R S3 S3 R is selected from the group consisting of: H, C1-C5 alkyl, -NHC(O)-R 24 or -C(O)NH2, R 24 is selected from the group consisting of: C1-C5 alkyl;​ R3is selected from the group consisting of: hydrogen; R4is selected from the group consisting of: hydrogen.

2. The azaheterocyclic carboxamide compound according to claim 1, wherein R2is selected from the group consisting of: hydrogen, 5-10 membered heterocyclyl, C6-C10 aryl, or C2-C10 heteroaryl, each of said 5-10 membered heterocyclyl, C6-C10 aryl, or C2-C10 heteroaryl being independently substituted with at least one substituent selected from the group consisting of R S3 R S3 is selected from the group consisting of: H, C1-C5 alkyl, -NHC(O)-R 24 or -C(O)NH2.

3. The azaheterocyclic carboxamide compound according to claim 2, wherein R2is selected from the group consisting of: hydrogen or the following group: 。 4. The azaheterocyclic carboxamide compound according to any one of claims 1 to 3, characterized in that, is selected from one of the following compounds: 。 5. A pharmaceutical composition, characterized by, The azaheteroaromatic ring carboxamide compound of any one of claims 1-4, or a pharmaceutically acceptable salt, deuteride thereof, and a pharmaceutically acceptable carrier.

6. Use of the azaheteroaromatic ring carboxamide compound of any one of claims 1-4, or a pharmaceutically acceptable salt, deuteride thereof, or the pharmaceutical composition of claim 5 in the manufacture of a medicament for the treatment and / or prevention of a respiratory viral infection.

7. Use according to claim 6, characterized in that, The virus in the respiratory viral infection is an influenza A virus and / or an influenza B virus.

8. Use according to claim 7, characterized in that, The influenza A virus is H3N2 and / or H1N1.

9. Use according to claim 7, characterized in that, The influenza B virus is B / Lee / 40.

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