Quinoline triazole compound and application thereof

Abstract

The invention relates to a quinoline triazole compound and application thereof. The quinoline triazole compound has the structural characteristics as shown in formula I, and can effectively treat diseases caused by respiratory viruses such as influenza.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry, and in particular to a quinoline triazole compound and its applications. Background Technology

[0002] Influenza (hereinafter referred to as influenza) is an acute respiratory infectious disease that seriously endangers human health. It is caused by the influenza virus and is characterized by high morbidity, widespread prevalence, and rapid transmission. Currently, the main treatment for influenza involves antiviral small-molecule drugs that target key proteins in viral replication, such as M2 ion channel protein inhibitors, hemagglutinin (HA) inhibitors, neuraminidase (NA) inhibitors, and RNA-dependent RNA polymerase (RdRP) subunit (PA, PB1, PB2, and their interactions) inhibitors. Antiviral methods under investigation include inhibiting influenza virus replication or RNA expression using antisense oligonucleotides, ribozymes, and deoxyribozymes. Clinically, first-line antiviral drugs for influenza are the neuraminidase inhibitor oseltamivir and the PA inhibitor mabaloxavir. Other drugs are only used when these two classes of drugs are ineffective against specific viral strains or populations, or when fighting general non-virulent viruses.

[0003] However, oseltamivir has a narrow therapeutic window, requiring administration within 48 hours of infection for its efficacy to be significant. Furthermore, after years of use, multiple resistant strains have emerged, making it difficult to meet clinical needs. Mabaloxavir, on the other hand, is a novel anti-influenza drug with a completely new mechanism of action, developed by Shionogi & Co., Ltd. of Japan through structural modification of the dolutegravir core. It requires only a single dose throughout the course of the illness to effectively control the disease. Viral shedding ceases within 24 hours of taking mabaloxavir, effectively relieving influenza symptoms such as high fever and general weakness. However, clinical use of mabaloxavir has revealed side effects such as allergic reactions, rashes, urticaria, and vomiting, particularly in children where the incidence of 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 of the Invention

[0005] Based on this, this application provides a quinoline triazole compound that can effectively treat diseases caused by respiratory viruses such as influenza.

[0006] The first aspect of this application provides quinoline triazole compounds having the structural features shown in Formula I, or pharmaceutically acceptable salts, stereoisomers, prodrug molecules, or deuterated derivatives thereof:

[0007]

[0008] in,

[0009] R 1 Selected from: C1-C5 alkyl, C3-C8 cycloalkyl, C1-C5 alkenyl, C3-C8 cycloalkenyl, C1-C5 ynyl, C3-C8 cycloalkenyl, at least one R s1 Substituted or unsubstituted C2-C10 heterocyclic group, at least one R s1 Substituted or unsubstituted C6-C10 aryl group or at least one R s1 Substituted or unsubstituted C2-C10 heteroaryl groups; optionally, the C1-C5 alkyl, C1-C5 alkenyl, C3-C8 cycloalkenyl, C1-C5 ynyl, and C3-C8 cycloynyl groups may or may not contain at least one heteroatom selected from N, O, and S.

[0010] R s1 Each is independently selected from: hydrogen, ester group, halogen, C1-C5 alkyl, amide group or C1-C5 alkoxy group;

[0011] Or, R 1 Selected from: by at least one R 11 Substituted -C1 to C3 alkyl groups; R 11 Each is independently selected from: -NHC(O)O-C1~C5 alkyl, at least one R s2 Substituted or unsubstituted C2-C10 heterocyclic group, at least one R s2 Substituted or unsubstituted C6-C10 aryl group, at least one R s2 Substituted or unsubstituted C2-C10 heteroaryl or hydroxyl groups;

[0012] R s2 Each group is independently selected from: hydrogen, ester group, -C1~C5 alkyl-NHC(O)O-C1~C5 alkyl, -NHC(O)O-C1~C5 alkyl, hydroxyl group, halogen, aldehyde group, -C(O)-C2~C8 heteroaryl, -C6~C10 aryl-C1~C5 alkoxy or C2~C10 heteroaryl;

[0013] R 2 Selected from: hydrogen, fluorine, bromine, hydroxyl, amino, C1-C5 alkyl, C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 21 -N(R) 22 R 23 ), amide group, sulfonamide group, C6-C10 aryl or C2-C10 heteroaryl; R 21 R 22 R 23 Each is independently selected from: C1 to C5 alkyl groups, R 22 With R 23Cyclic or non-cyclic; optionally, the C1-C5 alkyl and C3-C8 cycloalkyl contain or do not contain at least one heteroatom selected from N, O, and S, and the C1-C5 alkyl is substituted with 1 to 3 fluorine atoms or is not substituted.

[0014] A second aspect of this application provides a pharmaceutical composition comprising the quinoline triazole compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated derivative thereof, and a pharmaceutically acceptable carrier.

[0015] A third aspect of this application provides the use of the quinoline triazole 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.

[0016] The aforementioned aza-aryl cyclocarboxamide compounds, through rational structural design, can exhibit good anti-influenza activity, especially against influenza A and influenza B viruses. Detailed Implementation

[0017] The quinoline triazole compounds and their applications described in this application are further illustrated below with specific embodiments. This application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0019] In this application, terms such as "first aspect," "second aspect," and "third aspect" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Furthermore, terms such as "first," "second," "third," and "fourth" serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0020] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0021] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0022] Unless otherwise specified, the percentage content mentioned in this application refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures.

[0023] Unless otherwise specified, all percentage concentrations mentioned in this application refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.

[0024] Unless otherwise specified, the temperature parameters in this application may be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows for temperature fluctuations within the precision range controlled by the instrument.

[0025] In this application, room temperature generally refers to 4℃~30℃, and more preferably 20±5℃.

[0026] In this application, "hydroxyl group" refers to -OH.

[0027] In this application, "amino" refers to -NH2.

[0028] In this application, "alkyl" refers to a monovalent residue formed by the loss of a hydrogen atom from a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Phrases containing this term, such as "C1-C5 alkyl," refer to alkyl groups containing 1 to 5 carbon atoms, and each occurrence can be independently referred to as C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, or 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).

[0029] In this application, "cycloalkyl" refers to a non-aromatic hydrocarbon containing a ring of carbon atoms, which can be a monocycloalkyl, spirocycloalkyl, or bridged cycloalkyl. Phrases containing this term, such as "C3-C8 cycloalkyl," refer to cycloalkyl compounds containing 3 to 8 carbon atoms, and each occurrence can independently be C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, or C8-cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0030] In this application, "heterocyclic group" refers to a cycloalkyl group in which at least one carbon atom is replaced by a non-carbon atom. The non-carbon atom can be an N atom, O atom, S atom, etc., and can be a saturated ring or a partially unsaturated ring. Phrases containing this term, such as "C2-C8 heterocyclic group," refer to heterocyclic groups containing 2 to 8 carbon atoms, and each occurrence can independently be a C2 heteroalkyl, C3 heteroalkyl, C4 heteroalkyl, C5 heteroalkyl, C6 heteroalkyl, C7 heteroalkyl, or C8 heteroalkyl. Suitable examples include, but are not limited to: dihydropyridyl, tetrahydropyridyl (piperidinyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and dihydroindolyl.

[0031] In this application, "cyano" refers to -CN.

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

[0033] In this application, "alkoxy" refers to a group with the structure -O-alkyl, i.e., an alkyl group as defined above connected to an adjacent group via an oxygen atom. Phrases containing this term, such as "C1-C5 alkoxy," refer to alkyl moieties containing 1 to 5 carbon atoms, and each occurrence can be independently C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, or 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).

[0034] In this application, "ester group" refers to -[RC(O)O-R'], wherein R and R' are each independently selected from non-existent or alkyl groups, and are not both non-existent; the alkyl group can be, for example, a C1 to C5 alkyl group.

[0035] In this application, "sulfonyl ester group" refers to -[RS(O)2-R'], wherein R and R' are each independently selected from non-existent or alkyl groups, and are not both non-existent; the alkyl group can be, for example, a C1 to C5 alkyl group.

[0036] In this application, "amide group" refers to -[RC(O)N(R')2], wherein R is selected from non-existent or alkyl, and R' is independently selected from non-existent, H or alkyl, and R and R' are not both non-existent, and the two R' are not both H; the alkyl group can be, for example, C1 to C5 alkyl, and optionally, the two R' are cyclic or acyclic. When cyclic, they can be directly linked to form a cycloalkyl group, or they can be combined with at least one atom selected from N, O or S to form a heterocyclic group. The cycloalkyl or heterocyclic group may further include C1 to C2 alkyl groups as substituents.

[0037] In this application, "sulfonamide group" refers to -[RS(O)2-N(R')2], wherein R is selected from non-existent or alkyl, and R' is independently selected from non-existent, H or alkyl, and R and R' are not both non-existent, and the two R' are not both H; the alkyl group can be, for example, C1 to C5 alkyl, and optionally, the two R' are cyclic or acyclic. When cyclic, they can be directly linked to form a cycloalkyl group, or they can be combined with at least one atom selected from N, O, S to form a heterocyclic group. The cycloalkyl or heterocyclic group may further include C1 to C2 alkyl groups as substituents.

[0038] In this application, "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom. It can be a monocyclic aryl, a fused-ring aryl, or a polycyclic aryl. For polycyclic compounds, at least one is an aromatic ring system. For example, "C6-C10 aryl" refers to an aryl group containing 6 to 10 carbon atoms, and each occurrence can be independently C6, C7, C8, C9, or C10 aryl. Suitable examples include, but are not limited to, benzene, biphenyl, naphthalene, anthracene, phenanthrene, dinaphthalene, triphenylene, and their derivatives.

[0039] In this application, "heteroaryl" refers to an aryl group in which at least one carbon atom is replaced by a non-carbon atom, which can be an N atom, an O atom, an S atom, etc. For example, "C2-C10 heteroaryl" refers to a heteroaryl group containing 2 to 10 carbon atoms, and each occurrence can be independently C2 heteroaryl, C3 heteroaryl, C4 heteroaryl, C5 heteroaryl, C6 heteroaryl, C7 heteroaryl, C8 heteroaryl, C9 heteroaryl, or C10 heteroaryl. Suitable examples include, but are not limited to: furanyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrroleyl, pyrazolyl, triazolyl, imidazoyl, oxazolyl, oxadiazolyl, thiazoyl, tetrazolyl, indolyl, carbazoyl, pyrroloimidazoyl, pyrrolopyrroleyl, thiophenolopyrroleyl, thiophenolothiophenyl, furanolopyrroleyl, furanolofuranyl, thiophenolofuranyl, benzoisooxazolyl, benzoisothiazoyl, benzoimidazoyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl, o-diazanaphthyl, quinoxalinyl, phenanthridine, primidinyl, quinazolinyl, and quinazolinoneyl.

[0040] In this application, "halogen" or "halogen group" refers to F, Cl, Br, or I.

[0041] In this application, "aldehyde group" refers to -C(O)H.

[0042] The term "at least one" in this application is not limited to one, two, three, four, five, six, seven, eight, nine, ten, etc.

[0043] In this application, "pharmaceutically acceptable salt" refers to a salt formed by any compound in the indicated structure with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. One type of salt is the salt formed by the compounds of this invention with an acid. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another type of salt is the salt formed by the compounds of the present invention with a base. Suitable bases for forming salts include, but are not limited to: alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0044] In this application, a "prodrug molecule" refers to any compound that, when administered to an organism, produces a drug, i.e., an active ingredient, through spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and / or metabolic chemical reactions. A prodrug is therefore a covalently modified analog or potential form of a therapeutically active compound. Suitable examples include, but are not limited to, carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0045] Some examples of this application provide quinoline triazole compounds having the structural features shown in Formula I, or pharmaceutically acceptable salts, stereoisomers, prodrug molecules, or deuterated derivatives thereof:

[0046]

[0047] in,

[0048] R 1 Selected from: C1-C5 alkyl, C3-C8 cycloalkyl, C1-C5 alkenyl, C3-C8 cycloalkenyl, C1-C5 ynyl, C3-C8 cycloalkenyl, at least one R s1 Substituted or unsubstituted C2-C10 heterocyclic group, at least one R s1 Substituted or unsubstituted C6-C10 aryl group or at least one R s1Substituted or unsubstituted C2-C10 heteroaryl groups; optionally, the C1-C5 alkyl, C1-C5 alkenyl, C3-C8 cycloalkenyl, C1-C5 ynyl, and C3-C8 cycloynyl groups may or may not contain at least one heteroatom selected from N, O, and S.

[0049] R s1 Each is independently selected from: hydrogen, ester group, halogen, C1-C5 alkyl, amide group or C1-C5 alkoxy group;

[0050] Or, R 1 Selected from: by at least one R 11 Substituted -C1 to C3 alkyl groups; R 11 Each is independently selected from: -NHC(O)O-C1~C5 alkyl, at least one R s2 Substituted or unsubstituted C2-C10 heterocyclic group, at least one R s2 Substituted or unsubstituted C6-C10 aryl group, at least one R s2 Substituted or unsubstituted C2-C10 heteroaryl or hydroxyl groups;

[0051] R s2 Each group is independently selected from: hydrogen, ester group, -C1~C5 alkyl-NHC(O)O-C1~C5 alkyl, -NHC(O)O-C1~C5 alkyl, hydroxyl group, halogen, aldehyde group, -C(O)-C2~C8 heteroaryl, -C6~C10 aryl-C1~C5 alkoxy or C2~C10 heteroaryl;

[0052] R 2 Selected from: hydrogen, fluorine, bromine, hydroxyl, amino, C1-C5 alkyl, C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 21 -N(R) 22 R 23 ), amide group, sulfonamide group, C6-C10 aryl or C2-C10 heteroaryl; R 21 R 22 R 23 Each is independently selected from: C1 to C5 alkyl groups, R 22 With R 23 Cyclic or non-cyclic; optionally, the C1-C5 alkyl and C3-C8 cycloalkyl contain or do not contain at least one heteroatom selected from N, O, and S, and the C1-C5 alkyl is substituted with 1 to 3 fluorine atoms or is not substituted.

[0053] In some of these examples, the quinoline triazole compounds have the structural features shown in Formula I-1 or Formula I-2:

[0054]

[0055] In some of these examples, the quinoline triazole compounds have the structural features shown in Formula II, Formula III-1, or Formula III-2:

[0056]

[0057]

[0058] in,

[0059] Ring A is selected from: C2-C8 heterocyclic groups, C6-C10 aryl groups, or C2-C10 heteroaryl groups.

[0060] In some of these examples, ring A in formula II is selected from the following groups:

[0061]

[0062] In some of these examples, in Equation II, R s1 Selected from: hydrogen, -C(O)O-C1~C5 alkyl, halogen, C1~C5 alkyl, -C(O)NH-C1~C5 alkyl, C1~C5 alkoxy or -NHC(O)-C1~C5 alkyl.

[0063] In some of these examples, the quinoline triazole compounds have the structural features shown in Formula III-11, Formula III-12, or Formula III-21:

[0064]

[0065] in,

[0066] R 12 Selected from: C1-C5 alkyl groups;

[0067] Ring B is selected from: C2-C10 heterocyclic group, C6-C10 aryl group, or C2-C10 heteroaryl group.

[0068] In some of these examples, ring B is selected from the following groups:

[0069]

[0070] In some of these examples, R s2 Selected from: hydrogen, -C(O)O-C1~C5 alkyl, -C1~C5 alkyl-NHC(O)O-C1~C5 alkyl, -NHC(O)O-C1~C5 alkyl, hydroxyl, halogen, aldehyde, -C(O)-C2~C8 heteroaryl, -Phenyl-C1~C5 alkoxy or

[0071] In some of these examples, R2 Selected from: Hydrogen.

[0072] In some of these examples, the quinoline triazole compounds are selected from one of the following compounds:

[0073]

[0074]

[0075] Other examples of this application also provide a pharmaceutical composition comprising a quinoline triazole compound as described above, or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated form thereof, and a pharmaceutically acceptable carrier.

[0076] Without limitation, "pharmaceuticalally acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. As used herein, the term "pharmaceuticalally acceptable carrier" includes buffers compatible with drug administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of compatibility with other components in the formulation and harmlessness 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth gum; (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... 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 buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0077] Other examples of this application also provide the use of quinoline triazole compounds as described above, or pharmaceutically acceptable salts, stereoisomers, prodrug molecules, deuterated compounds thereof, or pharmaceutical compositions as described above, in the preparation of medicaments for treating and / or preventing respiratory viral infections.

[0078] Furthermore, the viruses involved in the respiratory viral infection include influenza A virus and / or influenza B virus. Without limitation, the influenza A virus includes A / WSN / 33 (H1N1); the influenza B virus includes B / Lee / 40.

[0079] There are no particular limitations on the dosage form and administration method of the compounds or pharmaceutical compositions thereof of the present invention. Representative administration methods include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and local administration.

[0080] 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 components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl 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 can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound in such compositions may be delayed in a portion of the digestive tract. Examples of encapsulating 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 excipients described above.

[0081] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms 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-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. For example, suspensions may contain suspending agents, specifically, for example, ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures thereof.

[0082] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, as well as 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.

[0083] Dosage forms for topical administration include ointments, powders, patches, sprays, and inhalers. They are prepared by mixing the active ingredient under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0084] 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; it may have systemic effects or only local effects. The activity of the "drug" is not particularly limited; it may be an active substance that can interact with other substances or an inert substance that does not interact with other substances.

[0085] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0086] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods.

[0087] Example 1: Synthesis of Compound 1

[0088]

[0089] Synthesis of intermediate 1a:

[0090] In a mixed solvent of ethanol and water (1 / 1, 40 mL), 4-chloroquinoline (1.64 g, 10 mmol) and sodium azide (2.6 g, 40 mmol) were added, and the mixture was refluxed at 100 °C for 24 h. The reaction was confirmed by TLC. Ethyl acetate (40 mL) was added for extraction, and the aqueous phase was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed three times with water (20 mL) and once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a solid. The solid was slurried with petroleum ether and filtered to obtain crude compound 4-azidoquinoline (1a), which was a brown solid.

[0091] Synthesis of Compound 1:

[0092] An organic phase mixture was prepared by adding 4-azidoquinoline (1a) (0.12 g, 0.67 mmol) and 1-Boc-4-ethynylpiperidine (0.21 g, 1 mmol) to tert-butanol (10 mL). An aqueous phase mixture was prepared by adding copper sulfate pentahydrate (0.05 g, 0.2 mmol) and sodium ascorbate (0.08 g, 0.4 mmol) to water (10 mL). The aqueous phase mixture was added to the organic phase mixture, and the reaction was carried out at room temperature for 24 h. The reaction was monitored by TLC until completion. The mixture was then extracted with dichloromethane (10 mL). The aqueous phase was extracted three times with dichloromethane (10 mL). The organic phases were combined, washed three times with water (10 mL), dried over anhydrous sodium sulfate, filtered, and purified by rotary evaporation and column chromatography to give compound 1 as a yellow oily substance (0.24 g, yield 92%). 1 H NMR (300 MHz, CDCl3-d1) δ9.06 (d, J = 4.6 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.84 (dd, J = 8.4, 6.9, 1.4 Hz,1H),7.77(s,1H),7.65(dd,J=8.3,6.9,1.3 Hz,1H),7.52(d,J=4.6Hz,1H),3.10(tt,J=11.7,3.7 Hz,1H),2.94(t,J=12.8 Hz, 2H), 2.16 (t, J = 13.4 Hz, 2H), 1.73 (dt, J = 12.2, 4.2 Hz, 4H), 1.48 (s, 9H).

[0093] Example 2: Synthesis of Compound 2

[0094]

[0095] Compound 2 was synthesized from 4-azidoquinoline (1a) and phenylacetylene using the method described in Example 1. The compound was a white solid, 0.1 g, with a yield of 74%. MS (ESI) m / z calcd for C 17 H 13 N4[M+H] + 273.1, found 273.3.

[0096] Example 3: Synthesis of Compound 3

[0097]

[0098] Compound 3 was obtained from 4-azidoquinoline (1a) and 4-fluorophenylacetylene using the synthetic method of Example 1. It was a yellow oily substance, 0.034 g in yield, 23%. 1 H NMR (400 MHz, CDCl3-d1) δ9.10 (d, J = 4.3 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.22 (s, 1H), 8.04 (d, J = 7.1 Hz, 1H), 7.96 (d, J = 5.3 Hz, 1H), 7.93 (d, J = 5.3 Hz, 1H), 7.87 (dd, J = 7.0 Hz, 1H), 7.69 (dd, J = 7.1 Hz, 1H), 7.60 (d, J = 4.4 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H).

[0099] Example 4: Synthesis of Compound 4

[0100]

[0101] Compound 4 was obtained as a yellow solid (0.051 g) using the synthetic method of Example 1, with 4-azidoquinoline (1a) and 4-chlorophenylacetylene as raw materials. The yield was 30%. 1 H NMR (400MHz, CDCl3-d1) δ9.01(d,J=4.6Hz,1H),8.25(d,J=8.6Hz,1H),8.03(s,1H),7.82(dd,J=8.4,6.4,2.0Hz,1H) ,7.59(dd,J=8.5Hz,1H),7.55(d,J=9.0Hz,1H),7.29(d,J=4.5Hz,1H),7.22(d,J=8.6Hz,2H),7.06(d,J=8.6Hz,2H).

[0102] Example 5: Synthesis of Compound 5

[0103]

[0104] Compound 5 was obtained from 4-azidoquinoline (1a) and 4-bromophenylacetylene using the synthetic method of Example 35. It was a white solid, 0.041 g, with a yield of 23%. 1 H NMR(400MHz, CDCl3-d1)δ9.02(d,J=4.4Hz,1H),8.26(d,J=8.6Hz,1H),8.04(s,1H),7.83(dd,J=6.5Hz,1H),7.5 9 (dd, J = 8.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 4.3 Hz, 1H), 6.99 (d, J = 8.1 Hz, 2H).

[0105] Example 6: Synthesis of Compound 6

[0106]

[0107] Compound 6 was synthesized from 4-azidoquinoline (1a) and 4-bromophenylacetylene using the method of Example 1. The compound was a white solid, 0.10 g, with a yield of 56%. MS (ESI) m / z calcd for C 17 H 12 BrN4[M+H] + 351.0, found351.2.

[0108] Example 7: Synthesis of Compound 7

[0109]

[0110] Compound 7 was obtained from 4-azidoquinoline (1a) and 1-methyl-4-acetylene using the synthetic method of Example 1. It was an orange solid, 0.11 g, with a yield of 81%. 1 H NMR (400MHz, CDCl3-d1) δ9.10(d,J=4.5Hz,1H),8.29(d,J=8.5Hz,1H),8.22(s,1H),8.07(d,J=7.2Hz,1H),7.89(d,J= 1.4Hz, 1H), 7.85 (d, J = 8.0Hz, 2H), 7.68 (dd, J = 7.1Hz, 1H), 7.61 (dd, J = 4.5Hz, 1H), 7.31 (d, J = 7.8Hz, 2H), 2.43 (s, 3H).

[0111] Example 8: Synthesis of Compound 8

[0112]

[0113] Compound 8 was obtained from 4-azidoquinoline (1a) and 4-propylphenylacetylene using the synthetic method of Example 1. It was a white solid, 0.047 g, with a yield of 30%. 1 H NMR (400MHz, CDCl3-d1) δ9.10(d,J=4.3Hz,1H),8.29(d,J=8.5Hz,1H),8.22(s,1H),8.07(d,J=7.8Hz,1H),7.88(d,2H),7.85(dd,J=1.4Hz,1 H), 7.68 (dd, J = 7.1Hz, 1H), 7.61 (d, J = 4.4Hz, 1H), 7.31 (d, J = 7.9Hz, 2H), 2.66 (t, J = 7.6Hz, 2H), 1.70 (m, J = 7.5Hz, 2H), 0.98 (t, J = 7.4Hz, 3H).

[0114] Example 9: Synthesis of Compound 9

[0115]

[0116] Compound 9 was obtained from 4-azidoquinoline (1a) and methyl 4-ethynylbenzoate using the synthetic method of Example 1. The compound was 0.017 g of orange solid, with a yield of 8.1%. 1 H NMR (300MHz, CDCl3-d1) δ9.11(d,J=4.6Hz,1H),8.35(s,1H),8.28(d,J=8.4Hz,1H),8.18(d, J=8.4Hz,2H),8.05(d,3H),7.88(dd,1H),7.70(dd,1H),7.61(d,J=4.6Hz,1H),3.96(s,3H).

[0117] Example 10: Synthesis of Compound 10

[0118]

[0119] Compound 10 was obtained from 4-azidoquinoline (1a) and 4-ethynylbenzoylmethylamine using the synthetic method of Example 1. The compound was 0.079 g of orange solid, with a yield of 2.4%. 1H NMR (400MHz, DMSO-d6) δ9.41(s,1H),9.18(d,J=4.5Hz,1H),8.54(d,J=4.6Hz,1H),8.25(d,J=8.5Hz,1H),8.10(d,J=8.3Hz,2H), 8.06(d,J=8.5Hz,1H),7.99(d,J=8.2Hz,2H),7.95(dd,J=7.0Hz,1H),7.92(d,J=4.5Hz,1H),7.79(dd,1H),2.82(d,J=4.3Hz,3H).

[0120] Example 11: Synthesis of Compound 11

[0121]

[0122] Compound 11 was obtained using the synthetic method of Example 1, with 0.067 g of a yellow oily substance, yielding 34%, from 4-azidoquinoline (1a) and 4-ethynylbenzoylmethylpiperazine. 1 H NMR (400MHz, CDCl3-d1) δ9.11(d,J=4.5Hz,1H),8.29(d,J=8.6Hz,2H),8.03(d,J=4.8Hz,2H),8.01(s,1H),7.88(dd,J=7.0Hz,1 H), 7.69 (dd, 1H), 7.61 (d, J = 4.5Hz, 1H), 7.56 (d, J = 7.9Hz, 2H), 3.86 (t, 2H), 3.56 (t, 2H), 2.51 (t, J = 34.7Hz, 4H), 2.38 (s, 3H).

[0123] Example 12: Synthesis of Compound 12

[0124]

[0125] Compound 12 was obtained from 4-azidoquinoline (1a) and 4-methoxyphenylacetylene using the synthetic method of Example 1. It was a yellow solid, 0.055 g, with a yield of 36%. 1 H NMR (400MHz, CDCl3-d1) δ9.10(d,J=4.5Hz,1H),8.29(d,J=8.5Hz,1H),8.17(s,1H),8.07(d,J=7.1Hz,1H),7.89(d,J= 8.8Hz, 2H), 7.86 (dd, J = 7.0Hz, 1H), 7.68 (dd, J = 7.1Hz, 1H), 7.60 (d, J = 4.5Hz, 1H), 7.03 (d, J = 8.8Hz, 2H), 3.88 (s, 3H).

[0126] Example 13: Synthesis of Compound 13

[0127]

[0128] Compound 13 was obtained from 4-azidoquinoline (1a) and 4-acetamidophenylacetylene using the synthetic method of Example 1. It was a yellow solid, 0.072 g, with a yield of 21%. 1 H NMR (400MHz, CDCl3-d1) δ9.10(d,J=4.6Hz,1H),8.27(d,J=8.5Hz,1H),8.22(s,1H),8.05(d,J=8.5Hz,1H),7.92(d,J=8.6Hz, 2H), 7.86 (dd, J = 7.0Hz, 1H), 7.69 (dd, J = 7.0Hz, 1H), 7.66 (d, J = 8.6Hz, 2H), 7.60 (d, J = 4.6Hz, 1H), 7.33 (s, 1H), 2.22 (s, 3H).

[0129] Example 14: Synthesis of Compound 14

[0130]

[0131] Compound 14 was obtained as a yellow oil, 0.05 g, with a yield of 36%, using 4-azidoquinoline (1a) and 2-ethynylpyridine as raw materials and the synthetic method of Example 1. 1 H NMR (400MHz, CDCl3-d1) δ9.11(d,J=4.5Hz,1H),8.71(s,1H),8.65(d,J=4.5Hz,1H),8.34(d,J=8.0Hz,1H),8.28(d,J=8.6Hz,1H),8.07(d, J=7.0Hz,1H),7.90(dd,J=7.6Hz,1H),7.86(dd,J=7.1Hz,1H),7.68(dd,J=7.1Hz,1H),7.62(d,J=4.5Hz,1H),7.33(dd,J=6.4,4.9Hz,1H).

[0132] Example 15: Synthesis of Compound 15

[0133]

[0134] Compound 15 was obtained from 4-azidoquinoline (1a) and 3-ethynylpyridine using the synthetic method of Example 1. It was a yellow solid, 0.032 g, with a yield of 23%. 1H NMR (400MHz, CDCl3-d1) δ9.16(s,1H),9.12(d,J=4.4Hz,1H),8.67(d,J=4.8Hz,1H),8.39(d,J=8.2Hz,1H),8.37(s,1H),8.30(d,J=8 .5Hz, 1H), 8.01 (d, J = 8.5Hz, 1H), 7.88 (dd, J = 7.8Hz, 1H), 7.70 (dd, J = 7.8Hz, 1H), 7.61 (d, J = 4.5Hz, 1H), 7.49 (dd, J = 8.0, 4.7Hz, 1H).

[0135] Example 16: Synthesis of Compound 16

[0136]

[0137] Compound 16 was obtained from 4-azidoquinoline (1a) and 2-ethynthiophene using the synthetic method of Example 1. It was a brown oil, 0.1 g, with a yield of 76%. 1 H NMR (400MHz, CDCl3-d1) δ9.10(d,J=4.5Hz,1H),8.29(d,J=8.5Hz,1H),8.17(s,1H),8.05(d,J=7.1Hz,1H),7.87(dd,J=7.0Hz, 1H), 7.69 (dd, J = 7.1Hz, 1H), 7.60 (d, J = 4.5Hz, 1H), 7.55 (d, J = 2.4Hz, 1H), 7.40 (d, J = 3.9Hz, 1H), 7.16 (dd, J = 5.1, 3.5Hz, 1H).

[0138] Example 17: Synthesis of Compound 17

[0139]

[0140] Compound 17 was obtained from 4-azidoquinoline (1a) and 3-alkynylimidazole [1,2-b]pyridazine using the synthetic method of Example 1. The compound was an orange solid, 0.048 g, with a yield of 30%. 1H NMR (400MHz, CDCl3-d1) δ9.12(d,J=4.5Hz,1H),8.80(s,1H),8.45(d,J=3.1Hz,1H),8.31(d,J=8.6Hz,1H),7.98(d,J=7.7Hz,1H),7. 84(dd,J=7.0Hz,1H), 7.56(dd,J=8.0Hz,1H), 7.52(d,J=4.3Hz,1H), 7.42(d,J=8.4Hz,1H), 7.17(dd,J=9.1,4.4Hz,1H), 7.03(s,1H).

[0141] Example 18: Synthesis of Compound 18

[0142]

[0143] Synthesis of intermediate 18a:

[0144] Proprynneamine (0.11 g, 2 mmol), di-tert-butyl dicarbonate (0.65 g, 3 mmol), and triethylamine (0.41 g, 4 mmol) were added to dichloromethane (10 mL) and reacted at room temperature for 24 h. The reaction was completed by TLC. The mixture was then extracted with water (20 mL) and the aqueous phase was extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed three times with water (20 mL), once with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a concentrated solution. The solution was purified by silica gel chromatography (PE / EA = 3 / 1, 1 / 1, EA) to obtain intermediate compound 18a as a white solid, 0.34 g.

[0145] Synthesis of compound 18:

[0146] Compound 18 was obtained from 4-azidoquinoline (1a) and intermediate compound 18a using the synthetic method of Example 1. It was a light brown solid, 0.16 g, with a yield of 75%. 1 H NMR(500MHz, CDCl3-d1)δ9.08(s,1H),8.25(d,J=8.5Hz,1H),8.05(s,1H),7.95(d,J=8.5Hz,1H),7.84(dd,J =7.0Hz,1H),7.63(dd,1H),7.53(d,J=4.3Hz,1H),5.28(d,J=9.2Hz,1H),4.56(d,J=6.1Hz,2H),1.46(s,9H).

[0147] Example 19: Synthesis of Compound 19

[0148]

[0149] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 19 was obtained using the synthesis method of Example 1 with 4-azidoquinoline (1a) and the intermediate as raw materials, as a yellow oily substance of 0.37 g, yield 98%. 1 H NMR(500MHz, CDCl3-d1)δ9.06(d,J=4.6Hz,1H),8.24(d,J=8.0Hz,1H),8.08(s,1H),8.02 (d,J=8.6Hz,1H),7.83(dd,J=8.4,6.8,1.4Hz,1H),7.65(dd,J=8.2,6.9,1.2Hz,1H),7.53 (d,J=4.6Hz,1H),4.19(t,J=13.8Hz,1H),3.99(dt,J=13.8Hz,1H),3.28(s,2H),2.64(dt ,J=8.1Hz,1H),2.17(t,1H),1.94(tt,2H),1.83(t,J=11.8,4.2,3.6Hz,1H),1.43(s,9H).

[0150] Example 20: Synthesis of Compound 20

[0151]

[0152] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 20 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.24 g, with a yield of 56%. 1 H NMR (500MHz, CDCl3-d1) δ9.07(d,J=4.6Hz,1H),8.25(d,J=8.5Hz,1H),7.99(s,1H),7.98(d,J=4 .8Hz,1H),7.84(dd,J=7.7Hz,1H),7.66(dd,J=7.7Hz,1H),7.54(d,J=4.2Hz,1H),3.94(t,2H),3. 38(t,2H),3.31(s,J=10.4Hz,1H),3.23(s,J=14.6,10.5Hz,1H),2.81(t,J=27.9,7.1Hz,2H),2.7 1(s,J=9.4,5.6Hz,1H),2.60(s,J=9.5,5.6Hz,1H),1.87(t,J=5.8Hz,4H),1.43(s,J=5.3Hz,9H).

[0153] Example 21: Synthesis of Compound 21

[0154]

[0155] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 21 was obtained using the synthesis method of Example 1 with 4-azidoquinoline (1a) and the intermediate as raw materials, as a light brown oily substance, 0.1 g, yield 41%. 1 H NMR(300MHz, CDCl3-d1)δ9.07(d,J=4.6Hz,1H),8.25(d,J=8.5Hz,1H),7.84(d d,J=8.4,7.0Hz,1H),7.66(dd,J=8.4,7.0Hz,1H),7.54(d,J=4.6Hz,1H),4.12 (q,2H),3.83(s,2H),3.02(t,2H),2.33(tt,J=11.0,6.9,4.0Hz,1H),2.22(t, J=11.7, 2.8Hz, 2H), 1.89 (dt, J=32.0, 12.0, 3.5Hz, 2H), 1.26 (t, J=7.1Hz, 3H).

[0156] Example 22: Synthesis of Compound 22

[0157]

[0158] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 22 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.38 g, with a yield of 98%. 1 H NMR(500MHz, CDCl3-d1)δ9.06(d,J=4.6Hz,1H),8.24(d,J=8.4Hz,1H),7.99(s, 1H),7.98(d,J=7.9Hz,1H),7.84(dd,J=8.4,6.9,1.4Hz,1H),7.65(dd,J=8.4,6. 9,1.2Hz,1H),7.53(d,J=4.6Hz,1H),3.82(s,2H),2.99(t,J=11.8Hz,2H),2.23 (t,J=8.4,5.1Hz,3H),1.90(dt,2H),1.76(dt,J=11.2,3.7Hz,2H),1.43(s,9H).

[0159] Example 23: Synthesis of Compound 23

[0160]

[0161] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 23 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.19 g, with a yield of 44%. 1 H NMR (500MHz, CDCl3-d1) δ9.07(s,1H),8.26(d,J=8.6Hz,2H),8.01(d,J=8.5Hz,1H),7.85(dd,J=7.6Hz,1H),7.67(dd,J=7.7H z,1H),7.56(d,J=4.5Hz,1H),4.49(s,1H),3.95(s,2H),3.16(t,4H),2.29(t,2H),2.04(ttt,1H),1.79(t,6H),1.44(s,9H).

[0162] Example 24: Synthesis of Compound 24

[0163]

[0164] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 24 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.2 g, with a yield of 92%. 1 H NMR (500MHz, CDCl3-d1) δ9.07(d,J=4.6Hz,1H),8.298.23(m,1H),7.99(d,J=8.6Hz,2H),7.98(s,1H),7.85(dd,J=8.4,6.9,1.4Hz,1H),7.68( dd,J=8.3,6.8,1.3Hz,1H),7.56(d,J=4.6Hz,1H),4.92(s,1H),3.82(s,2H),3.78(tt,J=10.1Hz,1H),2.55(t,4H),1.69(td,4H),1.41(s,9H).

[0165] Example 25: Synthesis of Compound 25

[0166]

[0167] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 25 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.25 g, with a yield of 62%. 1H NMR (500MHz, CDCl3-d1) δ9.07(d,J=4.6Hz,1H),8.26(d,J=9.8Hz,1H),7.99(d,J=7.1Hz,2H),7.97(s,1H),7.85(dd,J=8.4,6.9,1.4Hz,1H),7.68( dd,J=8.3,6.9,1.3Hz,1H),7.56(d,J=4.6Hz,1H),4.91(s,1H),3.82(s,2 H), 3.78 (tt, J = 10.3Hz, 1H), 2.80-2.34 (t, 4H), 1.67 (t, 4H), 1.41 (s, 9H).

[0168] Example 26: Synthesis of Compound 26

[0169]

[0170] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 26 was obtained using the synthesis method of Example 1 with 4-azidoquinoline (1a) and the intermediate as raw materials, as a white solid of 0.17 g, yield 53%. 1 H NMR(500MHz, CDCl3-d1)δ9.07(d,J=4.6Hz,1H),8.97(s,1H),8.25(d,J=7.4Hz,1H), 8.06(d,J=7.2Hz,1H),7.85(dd,J=8.4,6.9,1.4Hz,1H),7.69(dd,J=8.3,6.9,1.2Hz ,1H),7.61(d,J=4.6Hz,1H),4.28(s,2H),4.21(tt,J=4.5Hz,1H),3.80(tt,2H),2.7 3(td,J=15.3Hz,3H), 2.61(td,J=9.0Hz,2H), 2.37(dd,2H), 1.97(dd,J=15.2Hz,2H).

[0171] Example 27: Synthesis of Compound 27

[0172]

[0173] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 27 was obtained using the synthesis method of Example 1 with 4-azidoquinoline (1a) and the intermediate as raw materials, as a brown oily substance, 0.19 g, yield 46%. 1H NMR (500MHz, CDCl3-d1) δ9.08(d,1H),8.26(d,J=8.5Hz,1H),8.07(s,1H),8.00(d,J=8.6Hz,1H),7.85(dd,J=7.6Hz,1H),7. 66(dd,1H),7.55(d,1H),7.24(d,J=2.0Hz,1H),7.19(s,1H),6.98(d,J=8.1Hz,1H),4.03(s,2H),3.78(s,2H),2.90(t,4H).

[0174] Example 28: Synthesis of Compound 28

[0175]

[0176] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 28 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.27 g, with a yield of 84%. 1 H NMR (500MHz, CDCl3-d1) δ9.07(d,J=4.6Hz,1H),8.26(d,J=7.8Hz,1H),8.04(s,1H),7.99(s,1H),7.85(dd,J=8.4,6.9,1.4Hz,1H),7.67(dd,J=8. 3,6.9,1.3Hz,1H),7.54(d,J=4.5Hz,1H),3.89(s,2H),3.62(t,J=5.3Hz, 2H), 3.44(t,J=5.1Hz,2H), 2.66(t,J=5.0Hz,2H), 2.59(t,J=5.2Hz,2H).

[0177] Example 29: Synthesis of Compound 29

[0178]

[0179] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 29 was obtained using the synthesis method of Example 1 with 4-azidoquinoline (1a) and the intermediate as raw materials, as a yellow oily substance, 0.17 g, yield 74%. 1H NMR (500MHz, CDCl3-d1) δ9.08(d,J=4.6Hz,1H),8.27(d,J=8.6,1.2Hz,1H),7.98(s,2H),7.86(dd,J=8.5,6.9,1.4Hz,1H),7.67(dd,J=8.3,6. 8,1.3Hz,1H),7.54(d,J=4.6Hz,1H),4.15(q,J=7.1Hz,2H),3.87(s,2H),3.54(t,J=5.1Hz,4H),2.59(t,J=5.1Hz,4H),1.27(t,J=7.1Hz,3H).

[0180] Example 30: Synthesis of Compound 30

[0181]

[0182] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 30 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.29 g, with a yield of 74%. 1 H NMR (500MHz, CDCl3-d1) δ9.08(d,J=4.6Hz,1H),8.26(d,J=9.5Hz,1H),7.99(s,1H),7.98(d,J=7.1Hz,1H),7.86(dd,J=8.4,6.9,1.4Hz ,1H),7.67(dd,J=8.3,6.9,1.3Hz,1H),7.54(d,J=4.6Hz,1H),3.87(s,2H),3.49(t,J=5.0Hz,4H),2.58(t,J=5.1Hz,4H),1.47(s,9H).

[0183] Example 31: Synthesis of Compound 31

[0184]

[0185] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 31 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.27 g, with a yield of 70%. 1H NMR(500MHz, CDCl3-d1)δ9.07(d,J=4.6Hz,1H),8.26(d,J=8.5Hz,1H),8.00(s, 1H),7.97(d,J=7.3Hz,1H),7.85(dd,J=8.4,6.9,1.4Hz,1H),7.66(dd,J=8.3,6 .8,1.2Hz,1H),7.54(d,J=4.6Hz,1H),7.47(d,J=1.0Hz,1H),7.00(d,J=2.5Hz, 1H), 6.47 (dd, J=3.4, 1.7Hz, 1H), 3.88 (t, J=15.1Hz, 6H), 2.69 (t, J=5.1Hz, 4H).

[0186] Example 32: Synthesis of Compound 32

[0187]

[0188] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 32 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.13 g, with a yield of 34%. 1 H NMR (500MHz, CDCl3-d1) δ9.06(d,J=4.6Hz,1H),8.25(d,J=8.5Hz,1H),8.02(s,1H),7.99(d,J=8.6Hz,1H),7.84(dd,J=8.4,6.9,1.4Hz,1H),7.66(dd,J= 8.2,6.9,1.2Hz,1H),7.54(d,J=4.6Hz,1H),6.90(d,J=9.1Hz,2H),6.83(d, J=9.1Hz,2H),3.92(s,2H),3.76(s,3H),3.14(t,4H),2.80(t,J=4.9Hz,4H).

[0189] Example 33: Synthesis of Compound 33

[0190]

[0191] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 33 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.13 g, with a yield of 34%. 1H NMR(500MHz, CDCl3-d1)δ9.08(d,J=4.6Hz,1H),8.26(d,J=8.0Hz,1H),8.03(s,1H ),8.00(d,J=8.7Hz,1H),7.85(dd,J=8.4,6.9,1.4Hz,1H),7.67(dd,J=8.3,6.8,1. 3Hz,1H),7.55(d,J=4.6Hz,1H),7.01(dd,1H),6.95(d,J=7.9,2.0Hz,1H),6.95(d d,1H),6.86(d,J=6.7Hz,1H),3.96(s,2H),3.86(s,3H),3.15(t,4H),2.85(t,4H).

[0192] Example 34: Synthesis of Compound 34

[0193]

[0194] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 34 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1. The compound was a yellow oil, 0.30 g, with a yield of 83%. 1 H NMR (500MHz, CDCl3-d1) δ9.07(d,J=4.5Hz,1H),8.30(d,J=4.7Hz,2H),8.25(d,J=7.5Hz,1H),8.02(s,1H),7.99(d,J=7.2Hz,1H),7.84(dd,J=8.4,6.8, 1.4Hz,1H),7.66(dd,J=8.3,6.9,1.2Hz,1H),7.55(d,J=4.5Hz,1H),6.49(d d, J=4.7Hz, 1H), 3.90 (s, 2H), 3.88 (t, J=5.1Hz, 4H), 2.69 (t, J=5.1Hz, 4H).

[0195] Example 35: Synthesis of Compound 35

[0196]

[0197] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 35 was obtained using the synthesis method of Example 1 with 4-azidoquinoline (1a) and the intermediate as raw materials, as a yellow foamy substance of 0.34 g, with a yield of 84%. 1HNMR(500MHz,MeOD-d4)δ9.07(d,J=4.7Hz,1H),8.52(s,1H),8.22(d,J=8.1Hz,1H),8.04(d,J=7.3Hz,1H),7.92(dd,1H),7.76(dd,1H),7.74( d,J=4.8Hz,1H),4.08(tt,J=5.9Hz,2H),4.04(s,2H),3.28(d,2H),2.92(d,J=29.4Hz,2H),2.43(dd,1H),1.74(dd,J=8.1Hz,1H),1.37(s,9H).

[0198] Example 36: Synthesis of Compound 36

[0199]

[0200] After obtaining the amino-substituted propargylamine intermediate using the method of Example 18, compound 36 was obtained using 4-azidoquinoline (1a) and the intermediate as raw materials, and synthesized using the method of Example 1, yielding 0.15 g of a yellow solid with a yield of 46%. 1 H NMR (400MHz, CDCl3-d1) δ9.03(d,J=4.6Hz,1H),8.24(d,J=8.5Hz,1H),8.15(s,1H),7.85(d,1H),7.83(d,1H),7.82(s,1H),7.81(d, J=2.4Hz,1H),7.62(dd,J=7.1Hz,1H),7.55(dd,J=6.4,2.7Hz,1H),7.44(d,J=4.5Hz,1H),7.35(dd,1H),7.33(dd,1H),5.69(s,2H).

[0201] Example 37: Synthesis of Compound 37

[0202]

[0203] Compound 37 was obtained as a yellow oil, 0.1 g, with a yield of 75%, using 4-azidoquinoline (1a) and 3-phenyl-1-propyne as raw materials and the synthetic method of Example 1. 1H NMR (400MHz, CDCl3-d1) δ9.03(d,J=4.6Hz,1H),8.24(d,J=8.5Hz,1H),7.98(d,J=7.3Hz,1H),7.83(dd,J=7.0Hz,1H),7.6 6(s,1H),7.63(dd,J=7.0Hz,1H),7.48(d,J=4.6Hz,1H),7.37(s,2H),7.36(dd,J=3.1Hz,2H),7.29(dd,1H),4.26(s,2H).

[0204] Example 38: Synthesis of Compound 38

[0205]

[0206] Compound 38 was obtained from 4-azidoquinoline (1a) and 1-phenyl-2-propyn-1-ol using the synthetic method of Example 1. It was a yellow solid, 0.11 g, with a yield of 74%. 1 H NMR (400MHz, CDCl3-d1) δ9.04(d,J=4.5Hz,1H),8.25(d,J=8.5Hz,1H),7.95(d,J=7.1Hz,1H),7.84(dd,J=7.0Hz,1H),7.79(s,1H),7.65( dd,J=7.1Hz,1H),7.57(d,J=7.0Hz,2H),7.49(d,J=4.5Hz,1H),7.43(dd,J=7.3Hz,2H),7.36(dd,J=7.3Hz,1H),6.21(s,1H),3.02(s,1H).

[0207] Test example: Influenza virus inhibition experiment

[0208] The basic principle behind the inhibitory activity of the compound against influenza virus in this test example is as follows: Influenza virus infection of MDCK cells can cause lesions and lead to cell death. The compound inhibits viral replication by inhibiting the function of the protease required for viral replication, thereby inhibiting cytopathic effects and cell death. Cell viability can be measured using the MTT assay to reflect the compound's anti-influenza virus activity.

[0209] Experimental materials:

[0210] Influenza virus strains: A / WSN / 33 (H1N1) and B / Lee / 40; cells: MDCK passaged cells. Culture conditions: Routine culture at 37°C in a 5% CO2 incubator. Other reagents: DMEM / F-12 (1:1) medium (Gibco), FBS (EcoSyne), PS (Gibco), 0.2% Trypsin-EDTA (Gibco), TPCK trypsin (Sigma Aldrich), PBS buffer (Corning), MTT (Sigma Aldrich).

[0211] Experimental methods:

[0212] 1. In vitro pharmacological effects of compounds

[0213] The experiment was conducted in the BSL-2 laboratory.

[0214] Prepare a 10 mM stock solution of the test compound using DMSO and store at 4°C for later use. Mix MDCK cells with DMEM / F-12 medium containing 10% FBS and 1% PS, and seed 100 μL / well in sterile 96-well plates at a cell density of 1.5 × 10⁵ cells / mL. Incubate at 37°C and 5% CO₂ for 24 h. When the adherent cells reach 90% or more confluence, discard the culture supernatant, wash with 100 μL / well of PBS, and discard the PBS. Take out the influenza virus solution stored at -80°C and dilute it with DMEM / F-12 medium to 100 TCID₅₀. Add 100 μL / well of the diluted virus solution to the experimental and model groups for challenge. The control group is treated 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 medium containing 0.1% TPCK and 1% PS was added. The stock solution of the analyte was diluted with DMEM / F-12 medium (containing 0.1% TPCK and 1% PS) to obtain twice the maximum concentration of the compound to be measured. The diluted analyte solution was added to the wells of the experimental group at a rate of 100 μL / well, and the analyte was diluted to different concentrations using the half-dilution method. Seven different concentrations were set up for each analyte, and each well contained 100 μL of composite medium. Three replicates were set up for each concentration, and the plates were incubated for 48 hours. The culture medium in the plate was then discarded, and the plate was washed with PBS and discarded. 100 μL / well of 1 mg / mL MTT solvent (prepared with PBS) was added to the plate, and the plates were incubated for 4 hours. The supernatant was discarded, and 100 μL / well of DMSO was added. The absorbance (OD) at a wavelength of 490 nm was measured using a microplate reader. The formula for calculating the drug efficacy inhibition rate is:

[0215] 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%.

[0216] The half-maximal inhibitory concentration (IC50) was calculated using Excel software.

[0217] 2. Drug toxicity test of the compound

[0218] The experiment was conducted in the BSL-2 laboratory.

[0219] The methods for determining drug toxicity are largely the same as those for determining drug efficacy. The difference lies in that drug toxicity determination does not require challenge, and the culture medium for diluting the test sample is DMEM / F-12 medium containing 1% PS. The formula for calculating the survival rate of drug toxicity is:

[0220] Survival rate = [(OD experimental group - OD blank group) / (OD control group - OD blank group)] × 100%.

[0221] The median survival concentration (CC50) was calculated using Excel software. The efficacy and toxicity tests for each compound were performed in triplicate, and the mean and standard deviation of the results were calculated.

[0222] The results are shown in Table 1.

[0223] Table 1: Inhibitory effects of some compounds on mutant influenza virus

[0224]

[0225]

[0226] As shown in the table above, the compounds in the examples exhibit high levels of inhibitory activity against one or more of the A / WSN / 33(H1N1) and B / Lee / 40 virus strains. Furthermore, cytotoxicity evaluations showed that all compounds in the examples exhibited low cytotoxicity and good drug-like properties.

[0227] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0228] The embodiments described above are merely illustrative of several implementation methods of this application, intended to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. It should be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. Quinoline triazole compounds having the structural features shown in Formula I, or their pharmaceutically acceptable salts, stereoisomers, prodrug molecules, or deuterated derivatives: in, R 1 Selected from: C1-C5 alkyl, C3-C8 cycloalkyl, C1-C5 alkenyl, C3-C8 cycloalkenyl, C1-C5 ynyl, C3-C8 cycloalkenyl, at least one R s1 Substituted or unsubstituted C2-C10 heterocyclic group, at least one R s1 Substituted or unsubstituted C6-C10 aryl group or at least one R s1 Substituted or unsubstituted C2-C10 heteroaryl groups; optionally, the C1-C5 alkyl, C1-C5 alkenyl, C3-C8 cycloalkenyl, C1-C5 ynyl, and C3-C8 cycloynyl groups may or may not contain at least one heteroatom selected from N, O, and S. R s1 Each is independently selected from: hydrogen, ester group, halogen, C1-C5 alkyl, amide group or C1-C5 alkoxy group; Or, R 1 Selected from: by at least one R 11 Substituted -C1 to C3 alkyl groups; R 11 Each is independently selected from: -NHC(O)O-C1~C5 alkyl, at least one R s2 Substituted or unsubstituted C2-C10 heterocyclic group, at least one R s2 Substituted or unsubstituted C6-C10 aryl group, at least one R s2 Substituted or unsubstituted C2-C10 heteroaryl or hydroxyl groups; R s2 Each group is independently selected from: hydrogen, ester group, -C1~C5 alkyl-NHC(O)O-C1~C5 alkyl, -NHC(O)O-C1~C5 alkyl, hydroxyl group, halogen, aldehyde group, -C(O)-C2~C8 heteroaryl, -C6~C10 aryl-C1~C5 alkoxy or C2~C10 heteroaryl; R 2 Selected from: hydrogen, fluorine, bromine, hydroxyl, amino, C1-C5 alkyl, C3-C8 cycloalkyl, cyano, carboxyl, C1-C5 alkoxy, ester, sulfonyl ester, -NH-R 21 -N(R) 22 R 23 ), amide group, sulfonamide group, C6-C10 aryl or C2-C10 heteroaryl; R 21 R 22 R 23 Each is independently selected from: C1 to C5 alkyl groups, R 22 With R 23 Cyclic or non-cyclic; optionally, the C1-C5 alkyl and C3-C8 cycloalkyl contain or do not contain at least one heteroatom selected from N, O, and S, and the C1-C5 alkyl is substituted with 1 to 3 fluorine atoms or is not substituted.

2. The quinoline triazole compound according to claim 1, characterized in that, It has the structural features shown in Formula II, Formula III-1 or Formula III-2: in, Ring A is selected from: C2-C8 heterocyclic groups, C6-C10 aryl groups, or C2-C10 heteroaryl groups.

3. The quinoline triazole compound according to claim 2, characterized in that, In Formula II, ring A is selected from the following groups:

4. The quinoline triazole compound according to claim 2, characterized in that, It has the structural features shown in Formula III-11, Formula III-12 or Formula III-21: in, R 12 Selected from: C1-C5 alkyl groups; Ring B is selected from: C2-C10 heterocyclic group, C6-C10 aryl group, or C2-C10 heteroaryl group.

5. The quinoline triazole compound according to claim 4, characterized in that, Ring B is selected from the following groups:

6. The quinoline triazole compound according to claim 1, characterized in that, R 2 Selected from: Hydrogen.

7. The quinoline triazole compound according to claim 1, characterized in that, Selected from one of the following compounds:

8. A pharmaceutical composition, characterized in that, This includes the quinoline triazole compounds as described in any one of claims 1 to 7, or their pharmaceutically acceptable salts, stereoisomers, prodrug molecules, deuterated derivatives, and pharmaceutically acceptable carriers.

9. The use of the quinoline triazole compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, deuterated product thereof, or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating and / or preventing respiratory viral infections.

10. The application according to claim 9, characterized in that, The viruses involved in the respiratory viral infection include influenza A virus and / or influenza B virus; Optionally, the influenza A virus includes H1N1; Optionally, the influenza B virus includes B / Lee / 40.

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