Triazole compound and use thereof

Abstract

The present invention belongs to the field of medicines, and specifically relates to a triazole compound, a preparation method therefor and the use thereof, and a compound as shown in formula (I), or a pharmaceutically acceptable salt. The triazole compound of the present invention has a novel structure. The cell activity test proves that the compound of the present invention has a good potential application value in anti-tumor drugs, and can provide a brand-new drug selection for developing anti-tumor and anti-inflammatory drugs.

Description

Triazole compound and use thereof TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular to a triazole compound and use thereof. BACKGROUND

[0002] Malignant tumor is one of the major health problems in the world, and its incidence and mortality rate has been high. With the aging of the population and the change of lifestyle, the incidence and mortality rate of malignant tumor is on the rise, becoming an important focus of current medical research and clinical practice. Developing new anti-tumor drugs has important clinical significance for the treatment of malignant tumor.

[0003] Tumor inflammatory microenvironment as the soil for tumor growth and development plays a key role in the process of tumor occurrence and development. However, there are few reports on the regulation of tumor microenvironment by triazole compounds. Therefore, developing triazole compounds with anti-tumor effect by regulating tumor microenvironment and anti-inflammatory activity has broad application prospects.

[0004] Triazole compounds are five-membered heterocyclic compounds containing three nitrogen atoms. According to the position of the three nitrogen atoms, triazole compounds are divided into 1,2,3-triazole and 1,2,4-triazole. Triazole compounds are used in organic chemistry, organometallic chemistry and material chemistry, such as herbicides, dyes, etc. In the field of pharmaceutical chemistry, they are widely used, such as for inhibiting bacteria, antifungal, anti-allergic, anti-inflammatory, anti-tumor and controlling potassium metabolism balance related to cardiovascular diseases, etc.

[0005] In the medical field, compounds with triazole structure have shown good anti-tumor and anti-inflammatory activities. The granted invention patent CN114805367B discloses a triazolopyrimidine derivative, its preparation method and application; and discloses the following structure compound:

[0006] The compound with the above structure has a significant inhibitory effect on USP28 target and shows high anti-tumor activity.

[0007] The invention patent CN114230557B discloses quinazoline-substituted 1,2,3-triazole derivatives, their pharmaceutical compositions, preparation methods and uses; the structure is as follows:

[0008] The compound with the above structure is also a triazole structure, which has an inhibitory effect on the proliferation of tumor cells, and has an inhibitory effect on the proliferation of human colon cancer (HCT-116) and human lung cancer cell line (A549) cells, and can be used as an anti-tumor drug.

[0009] Invention patent CN114920726B discloses a kind of triazole-isonicotinic acid compound and its preparation method and application protect a variety of triazole compounds, structural formula is as follows:

[0010] Research shows that the compound of the above structure has good effect on breast cancer, gastric cancer, prostate cancer, bone marrow cancer and the like.

[0011] In addition, in the anti-inflammatory field, the published patent CN117447450A-triazole compound and its use as LPAR1 antagonist; Structural formula is as follows:

[0012] Research shows that the compound of the above structure has good therapeutic effect on rheumatoid arthritis, fibrosis and other inflammation-related diseases.In addition, CN116640117A-triazole LPAR1 antagonist and its use, CN102753547B-triazolopyridine derivative and other patents disclose that triazole compounds have good anti-inflammatory effect.Therefore, it is of great significance to study triazole compounds in anti-tumor and anti-inflammatory related diseases, and there are very few drugs in the prior art for regulating tumor inflammatory microenvironment, which has great development value. SUMMARY

[0013] The present application aims to overcome at least one of the above-mentioned deficiencies in the prior art, and provides a triazole compound and its use.

[0014] A triazole compound, characterized in that it has a compound represented by formula (I), or a pharmaceutically acceptable salt,

[0015] R1, R2, R3, R4, R5, R6, R7, R8 are independently selected from hydrogen, deuterium, halogen, cyano, amino, trifluoromethyl, C 1-6 alkanoyl, nitro, C 1-6 alkoxy, carboxyl, alkoxycarbonyl, trifluoromethoxy, acetamido, C 1-6 alkylene sulfenyl, C 1-6- alkylsulfinyl, C 1-6 alkylsulfonyl, trichlorovinyl, trifluoromethylthio, trichloromethylsulfinyl or trifluoromethylsulfonyl; substituted or unsubstituted C1-C6 alkyl, the substituents being selected from methyl, heteroatoms;

[0016] each R9 is independently selected from hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, sulfinyl, sulfonyl, amido, C 1-6 alkyl, C 1-6 alkoxy, C 3-8cycloalkyl, heterocyclyl of 5 to 10 atoms, C 6-10 aryl, heteroaryl of 5 to 10 atoms, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl of 5 to 10 atoms, C 6-10 aryl and heteroaryl of 5 to 10 atoms are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-6 alkyl, C 1-6 alkylamino or C 1-6 alkoxy;

[0017] R 10 independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, cycloalkyl, alkoxy, or cyano;

[0018] R 11 , R 12 independently selected from the group consisting of hydrogen, cycloalkyl, alkoxy, cyano, substituted or unsubstituted C 1-6 alkyl, said substituents being selected from the group consisting of halogen, heteroatom;

[0019] X is independently selected from the group consisting of O, S, SO, SO2, CO, CHCN, substituted or unsubstituted C1-3alkyl, said substituents being halogen; C-R X , R X is hydrogen, C 1-3 alkyl, hydroxy, C 1-3 alkoxy, amino, C l-3 alkylamino, 2-(C 1-3 alkyl)amino, or cyano;

[0020] A ring is C 6-10 aryl or heteroaryl of 5 to 10 atoms or heterocyclyl of 3 to 10 atoms;

[0021] n represents the number of substituents R9on the A ring, and is selected from the group consisting of integers from 0 to 5, and when n is 0, it means that the A ring has no substituents. Further, the present application provides a compound having the formula (I), or a pharmaceutically acceptable salt,

[0022] R1is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl;

[0023] R2is independently selected from the group consisting of hydrogen, deuterium, halogen; substituted or unsubstituted C 1-6alkyl; said substituents are halogen;

[0024] R3is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkynyl, sulfinyl, sulfonyl, amino, cyano; substituted or unsubstituted sulfur, oxygen, carbonyl, C 1-6 alkyl; said substituents are selected from the group consisting of methyl, trifluoromethyl, halogen, heteroatom;

[0025] R4is independently selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 alkyl; said substituents are selected from the group consisting of methyl, heteroatom;

[0026] R5, R6, R7, R8are independently selected from the group consisting of hydrogen, deuterium, halogen;

[0027] A ring is C 6-10 aryl or 5-10 membered heteroaryl or 3-10 membered heterocyclyl;

[0028] each R9is independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, sulfinyl, sulfonyl, amido, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-6 alkyl, C 1-6 alkylamino or C 1-6 alkoxy;

[0029] R 10 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, cycloalkyl, alkoxy, or cyano;

[0030] R 11 , R 12 is independently selected from the group consisting of hydrogen, cycloalkyl, alkoxy, cyano, C 1-6 alkyl;

[0031] wherein represents a double or single bond, when R 13 independently selected from N, O, S; when R 13 independently selected from hydrogen, halogen, hydroxyl.

[0032] Further, R1is independently selected from hydrogen, fluorine, chlorine, bromine, C 1-6 alkyl;

[0033] R2is independently selected from hydrogen, fluorine, chlorine, bromine; substituted or unsubstituted C 1-6 alkyl; said substituents are selected from fluorine, chlorine, bromine; R3is independently selected from hydrogen, fluorine, chlorine, bromine, C 1-6 alkynyl, sulfinyl, sulfonyl, amino, cyano; substituted or unsubstituted sulfur, oxygen, carbonyl, C 1-6 alkyl; said substituents are selected from methyl, fluorine, chlorine, bromine, sulfur, oxygen, nitrogen; R4is independently selected from hydrogen, fluorine, chlorine, bromine; substituted or unsubstituted C 1-6 alkyl; said substituents are selected from methyl, sulfur, oxygen, nitrogen;

[0034] R5is independently selected from hydrogen, fluorine, chlorine, bromine;

[0035] R6is independently selected from hydrogen, fluorine, chlorine, bromine;

[0036] R7is independently selected from hydrogen, fluorine, chlorine, bromine;

[0037] R8is independently selected from hydrogen, fluorine, chlorine, bromine;

[0038] said A ring is phenyl, naphthyl, quinolinyl, purinyl, pyranyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, indolyl, isoindolyl, oxadiazolyl, tetrazolyl, oxatriazolyl.

[0039] R 10 independently selected from hydrogen, halogen, C 1-6 alkyl or cycloalkyl.

[0040] More preferably, R1is independently selected from hydrogen, methyl, chlorine, bromine, fluorine;

[0041] R2is independently selected from hydrogen, trifluoromethyl, chlorine, bromine, fluorine;

[0042] R3is independently selected from hydrogen, chlorine, bromine, fluorine;

[0043] R4is independently selected from hydrogen, methoxy, fluorine, chlorine, bromine;

[0044] R5is independently selected from hydrogen, chlorine, fluorine, bromine;

[0045] R6is independently selected from hydrogen, chloro, fluoro, bromo;

[0046] R7is independently selected from hydrogen, chloro, bromo, fluoro;

[0047] R8is independently selected from hydrogen, chloro, fluoro, bromo;

[0048] R 10 independently selected from hydrogen, chloro, fluoro, bromo, C 1-6 alkyl or cycloalkyl.

[0049] said A ring is phenyl, pyridyl, pyrimidinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, wherein "*" indicates the attachment to the triazole ring. Preferably, each said R9is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C 6-10 aryl, amino, cyano, amido.

[0050] More preferably, each said R9is independently selected from hydrogen, amino, amido, methyl, ethyl, n-butyl, iso-butyl, sec-butyl, t-butyl, fluoro, chloro, bromo, and substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted phenyl; said substituents are halogen, cyano, hydroxyl, amino, deuterium.

[0051] The compounds of the present application are selected from any one of the following structures:

[0052] R9a, R 9b independently selected from hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, sulfinyl, sulfonyl, amido, C 1-6 alkyl, C 1-6 alkyl, C 3-8 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkyl, C 3-8 alkyl, C 1-6 alkyl, C 3-8 alkyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-6 alkyl, C 1-6 alkyl, C1-6 substituted by a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, halo, -ORa, -OC(O)Ra, -OC(O)NRaRa, -SRa, -S(O)Ra, -S(O)2Ra, -CN, -NO2, -NRaRb, -N(Ra)2Rb, -N(Ra)C(O)Rb, -N(Ra)S(O)2Rb, -N(Ra)C(O)NRaRb, -N(Ra)C(O)Ra, -N(Ra)S(O)2Ra, -C(O)Ra, -C(O)NRaRb, -C(O)ORa, -C(O)Ra, -P(O)RaRa, -P(O)(ORa)(ORa), -P(O)(NRaRb)(NRaRb), -P(O)(ORa)(NRaRb), -P(O)(NRaRb)(ORa), -Si(Ra)3, -S(O)2NRaRb, -S(O)2Ra, -N3, =O, =NRa, =N-NO2, and =N-N3;

[0053] when R represents a double bond, R 11 is O; when R represents a single bond, R 11 is independently selected from the group consisting of F, Cl, Br, and I.

[0054] when R represents a double bond, R 11 is O; when R represents a single bond, R 11 is independently selected from the group consisting of F, Cl, Br, and I.

[0055] The present application also provides a triazole compound having one of the following structures, or a stereoisomer, a tautomer, a nitroso, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof:

[0056] In another aspect, the present application provides a pharmaceutical composition comprising the triazole compound of the present application or at least one of a pharmaceutically acceptable carrier, excipient, adjuvant, and vehicle thereof.

[0057] In some embodiments, the dosage form of the pharmaceutical composition comprises an injection, a tablet, a sustained-release tablet, a capsule, a sustained-release agent, a microcapsule, a powder, a liposome, a granule, a paste, a cream, an emulsion, a suspension, a lyophilized agent, a spray, a suppository, an ointment, a cream, an aerosol, a pill, or an oral liquid.

[0058] In another aspect, the present application provides a use of the triazole compound or the pharmaceutical composition in the preparation of an anti-tumor and anti-inflammatory disease drug; the tumor is selected from at least one of a digestive system tumor, a genitourinary system tumor, a nervous system tumor, a circulatory system tumor, a respiratory system tumor, a breast tumor, a skin tumor, and a bone tumor; in particular, the tumor includes the inflammatory disease selected from rheumatoid arthritis, psoriasis and psoriatic arthritis, inflammatory bowel disease, allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, and the like. BRIEF DESCRIPTION OF DRAWINGS

[0059] FIG. 1 is a blood concentration trend graph of compound 25 and compound 31.

[0060] FIG. 2 is a blood concentration trend graph of compound 2, compound 8, compound 12a, compound 18, and compound 23.

[0061] Figure 3 is a graph of blood concentration trends for Compound 36, Compound 39, Compound 40, Compound 41, and Compound 42. DETAILED DESCRIPTION

[0062] Certain embodiments of the application are now described in detail by referring to the following illustrative figures and examples. The application is intended to cover all alternatives, modifications and equivalents thereof that are included within the scope of the application as defined by the claims. One skilled in the art will readily recognize from the disclosure herein, that numerous other methods and materials similar or equivalent to those described herein can be used in the practice of the application. The now recognized present application is not intended to be limited to the methods and materials described herein, but instead includes all alternatives, modifications and equivalents falling within the scope of the appended claims. Where necessary, priority documents are incorporated by reference. Where priority documents are inconsistent with the content of this application, this application shall control. In particular, where the definitions of terms in priority documents are inconsistent with the definitions of terms in the present application, the definitions of terms in this application shall control.

[0063] Unless defined otherwise, 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. All patents and publications referred to in this application are incorporated herein by reference in their entirety.

[0064] Unless defined otherwise, 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. All patents and publications referred to in this application are incorporated herein by reference in their entirety.

[0065] The articles "a", "an", and "the" as used herein mean "one or more" and "at least one" unless otherwise indicated. So as not to be ambiguous, these articles are used in the context of a single embodiment, or in the context of a particular example, subgeneric, or generic class of compounds, as the context indicates. For example, "a group" means one or more groups, i.e., one or more than one group is contemplated, as appropriate for the context.

[0066] As described herein, the compounds of the application can optionally be substituted with one or more substituents, such as described herein for the compounds of the general formula above, or as described in particular examples, subgeneric classes, and generic classes of compounds contained in the application. Unless otherwise indicated, the nomenclature used in this specification is generally in accordance with Benoit's Dictionary of Organic Compounds, 1984, and / or the nomenclature recommendations of the IUPAC Commission on the Nomenclature of Organic Compounds, Pure & Appl. Chem. 1997, 69, 1465- 1479. The practice of the application will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, pharmacology, and pharmacometrical sciences, which are well known to those skilled in the art and as described in such publications as Remington's Pharmaceutical Sciences, 20th Ed. (2000), Mack Publishing Company, Easton, PA; and Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Ed. (2006), McGraw-Hill Companies, Inc. New York, NY.

[0067] In addition, it should be noted that the descriptive terms "each" and "individually" are used interchangeably herein, and are intended to be interpreted broadly, unless otherwise indicated. That is, the terms "each" and "individually" can mean that the recited elements are independent of each other, or that the recited elements are independent of the same element.

[0068] Other embodiments obtained by those skilled in the art without creative work based on the embodiments in the embodiments are within the scope of the application. It should be noted that the raw materials used in the application are ordinary commercially available products, and their sources are not specifically limited. The technical and scientific terms used in the embodiments have the meanings generally understood by those skilled in the art.

[0069] The abbreviations of chemicals and terms involved in the patent are as follows:

[0070] The substituents involved in the embodiments of the application are as follows:

[0071] R1, R2, R3, R4, R5, R6, R7, R8are independently selected from hydrogen, deuterium, halogen, cyano, amino, trifluoromethyl, C 1-6 alkanoyl, nitro, C 1-6 alkoxy, carboxyl, alkoxycarbonyl, trifluoromethoxy, acetamido, C 1-6 alkylene sulfenyl, C 1-6- alkylsulfinyl, C1-6 hydrocarbyl sulfonyl, trichloroethenyl, trifluoromethylthio, trichloromethylsulfinyl or trifluoromethylsulfonyl; substituted or unsubstituted C1-C6alkyl, said substituents being selected from the group consisting of methyl, heteroatom;

[0072] each R9is independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, sulfinyl, sulfonyl, amido, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-6 alkyl, C 1-6 alkylamino or C 1-6 alkoxy, substituted with 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C

[0073] R 10 independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, cycloalkyl, alkoxy, or cyano;

[0074] R 11 , R 12 independently selected from the group consisting of hydrogen, cycloalkyl, alkoxy, cyano, substituted or unsubstituted C1-C6alkyl, said substituents being selected from the group consisting of halogen, heteroatom;

[0075] X is independently selected from the group consisting of O, S, SO, SO2, CO, CHCN, CH2, C=O-R X , R X is hydrogen, C 1-3 alkyl, hydroxyl, C 1-3 alkoxy, amino, C l-3 alkylamino, 2-(C 1-3 alkyl)amino or cyano;

[0076] A ring is C6-10 aryl or 5-10 membered heteroaryl or 3-10 membered heterocyclyl;

[0077] n represents the number of substituents R9on A ring, selected from the group consisting of 0, 1, 2, 3, 4, 5, when n is 0 it means no substituents on A ring.

[0078] wherein represents a double bond or a single bond, when represents a double bond, R 13 is independently selected from N, O, S; when represents a single bond, R 13 is independently selected from hydrogen, halogen.

[0079] Synthetic Scheme I

[0080] for the synthesis of the following structured compounds:

[0081] The bromo-substituted triazole mother nucleus is prepared by Suzuki coupling reaction, and different R9 substituted compounds are obtained by selecting different aryl boron reagents; the synthetic route is as follows:

[0082] The specific method is as follows: the bromo-substituted triazole mother nucleus compound, aryl boron reagent, sodium carbonate, dichlorobis-triphenylphosphine palladium, dioxane, water, and nitrogen protection are placed in the reaction, and the reaction liquid is directly concentrated and column chromatography is carried out to obtain.

[0083] The preparation method of (4-((5-amino-4-bromo-1H-1,2,3-triazol-1-yl)methyl)-2,6-dichlorophenyl)(4-chlorophenyl) methanone (hereinafter referred to as bromide) in the following examples is as follows:

[0084] Carboxamide triazole (CAI) (200 mg, 0.47 mmol), NBS (93 mg, 0.52 mmol) and AIBN (8 mg, 0.047 mmol) were weighed into a reaction bottle, acetonitrile (5 mL) was added, and the reaction was carried out at 80°C for 2h. The reaction was stopped, and the reaction liquid was directly concentrated. The residue was column chromatographed (petroleum ether: ethyl acetate = 5:1-1:1) to obtain 110 mg of yellow solid, with a yield of 47%.

[0085] The bromide is characterized by 1H NMR (500 MHz, DMSO-d6) δ 7.77 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.47 (s, 2H), 6.06 (s, 2H), 5.51 (s, 2H).

[0086] MS (ESI, pos.ion) m / z: 460.92 [M+H] + .

[0087] Examples 1-3 are specific schemes according to the above reaction formula.

[0088] Example 1

[0089] Synthesis of compound 1:

[0090] Bromo compound (92 mg, 0.2 mmol), 4-aminobenzeneboronic acid pinacol ester (46 mg, 0.21 mmol), sodium carbonate (64 mg, 0.6 mmol), dichlorobis(triphenylphosphine)palladium (7 mg, 0.01 mmol), dioxane (2 mL), water (0.5 mL), under nitrogen protection, was placed in 85 °C for 6 h, the reaction was stopped, and the reaction solution was directly concentrated and column chromatography (methanol: dichloromethane = 1:20) to obtain 45 mg of yellow solid, yield 47%.

[0091] 1 H NMR (500 MHz, DMSO) δ 7.76 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.46 (s, 2H), 7.41 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 8.5 Hz, 2H), 5.64 (s, 2H), 5.54 (s, 2H), 5.08 (s, 2H).

[0092] MS (ESI, pos.ion) m / z: 472.55 [M+H] + .

[0093] HPLC: 98.66%.

[0094] Example 2

[0095] Synthesis of compound 2:

[0096] The synthesis method of compound 2 and compound 1 is basically the same, except that the aryl boron reagent in this example is 4-aminocarbonyl benzene boronic acid, and the yield is 46%.

[0097] The characterization results of the compound of the above formula are: 1 H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.50 (s, 2H), 7.32 (s, 1H), 6.18 (s, 2H), 5.59 (s, 2H).

[0098] MS (ESI, pos.ion) m / z: 502.04 [M+H] + .

[0099] HPLC: 96.33%.

[0100] Example 3:

[0101] The synthetic method is basically the same as Example 1, the difference is that the aryl boron reagent in this example is selected as 3-aminocarbonyl phenyl boronic acid to obtain compound 3, the yield is 34%:

[0102] The characterization results of the above structural compounds are as follows: 1 H NMR (500 MHz, DMSO-d6) δ 8.6 (s, 1H), 8.07 (s, 1H), 7.90 (dt, J = 7.8, 1.5 Hz, 1H), 7.80-

[0103] 7.75 (m, 2H), 7.72 (dt, J = 7.8, 1.5 Hz, 1H), 7.69-7.65 (m, 2H), 7.54-7.47 (m, 3H), 7.39 (s, 1H), 6.10 (s, 2H), 5.59 (s, 2H).

[0104] MS (ESI, pos.ion) m / z: 500.59 [M+H] + .

[0105] HPLC: 98.1%.

[0106] Synthetic Scheme Two

[0107] In order to synthesize two structural compounds:

[0108] The synthetic route is as follows:

[0109] The above synthetic route is mainly prepared by Suzuki coupling reaction of bromine-substituted triazole mother nucleus, and the difference from synthetic route one is that, in this route, different pyridine boronic acid reagents are selected to obtain meta- or para- pyridine ring and different R9 substituted compounds; Specifically: weigh the bromine-substituted triazole mother nucleus compound, pyridine boronic acid reagent, dichlorobis (triphenylphosphine) palladium, sodium carbonate, 1, 4-dioxane, water, nitrogen protection, and react overnight. Directly stir the sample and obtain by column chromatography.

[0110] The compounds of Examples 4-10 are prepared according to the method of synthetic route two.

[0111] Example 4

[0112] This example shows the synthetic route of compound 4 as follows:

[0113] The bromide (200 mg, 0.438 mmol), pyridine boronate (101 mg, 0.438 mmol), sodium carbonate (93 mg, 0.875 mmol), bis(triphenylphosphine)palladium dichloride (16 mg, 0.022 mmol), dioxane (4 mL), water (1 mL), under nitrogen protection, was placed in 85 °C for 6 h. The reaction was stopped, and the reaction liquid was directly concentrated and column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound 4: 60 mg, yield 27%, light yellow solid.

[0114] The characterization information is as follows:

[0115] 1 H NMR (500 MHz, DMSO-d6) δ 9.15 (d, J = 1.9 Hz, 1H), 8.31 (dd, J = 8.3, 2.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.52 (s, 2H), 6.56 (s, 2H), 5.60 (s, 2H).

[0116] MS (ESI, pos.ion) m / z: 483.02 [M+H] + .

[0117] Compound 4a can be obtained by oxidizing the cyano group of compound 4 to an amide:

[0118] The characterization is as follows:

[0119] 1 H NMR (500 MHz, DMSO-d6) δ 9.02 (d, J = 1.6 Hz, 1H), 8.28 (dd, J = 8.2, 2.1 Hz, 1H), 8.11–

[0120] 8.00 (m, 2H), 7.77 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.61 (s, 1H), 7.52 (s, 2H), 6.38 (s, 2H), 5.60 (s, 2H).

[0121] MS (ESI, pos.ion) m / z: 501.08 [M+H] + .

[0122] HPLC: 95.70%.

[0123] Example 5

[0124] This example demonstrates a method for synthesizing compound 5, similar to the reaction method of Example 4, except that the pyridine boronic acid reagent used is 4-pyridineboronic acid.

[0125] The characterization results are as follows:

[0126] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 5.2 Hz, 2H), 7.79 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 6.3 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.52 (s, 2H), 6.43 (s, 2H), 5.62 (s, 2H).

[0127] MS (ESI, pos.ion) m / z: 458.02 [M+H] + ;

[0128] HPLC: 94.02%.

[0129] Example 6

[0130] This example demonstrates a method for synthesizing compound 6, similar to the reaction method of Example 4, except that the pyridine boronic acid reagent used is 6-aminopyridineboronic acid,

[0131] The characterization results are as follows:

[0132] 1 H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.74 (dd, J = 8.8, 2.4 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.49 (s, 2H), 6.53 (d, J = 8.6 Hz, 1H), 5.98 (s, 2H), 5.80 (s, 2H), 5.55 (s, 2H).

[0133] MS (ESI, pos.ion) m / z: 473.57 [M+H] + ;

[0134] HPLC: 97.03%.

[0135] Example 7

[0136] This example demonstrates a method for synthesizing compound 7, similar to the reaction method of Example 4, except that the pyridine boronic acid reagent used is 2-aminopyridine-4-boronic acid.

[0137] The characterization results are as follows:

[0138] 1 H NMR (500 MHz, DMSO-d6) δ 7.91 (d, J = 5.7 Hz, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.51 (s, 2H), 7.00 (d, J = 1.5 Hz, 1H), 6.97 (dd, J = 5.7, 1.6 Hz, 1H), 6.30 (s, 2H), 6.23 (s, 2H), 5.60 (s, 2H).

[0139] MS (ESI, pos.ion) m / z: 473.35 [M+H] + ;

[0140] HPLC: 98.95%.

[0141] Example 8

[0142] This example demonstrates the synthesis of compound 8, which is similar to the reaction method of Example 4, except that the pyridine boronic acid reagent used is 2-aminopyridine-3-boronic acid pinacol ester.

[0143] The characterization results are as follows:

[0144] 1 H NMR (500 MHz, DMSO-d6) δ 7.91 (d, J = 5.7 Hz, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.51 (s, 2H), 7.00 (d, J = 1.5 Hz, 1H), 6.97 (dd, J = 5.7, 1.6 Hz, 1H), 6.30 (s, 2H), 6.23 (s, 2H), 5.60 (s, 2H).

[0145] MS (ESI, pos.ion) m / z: 473.33 [M+H] + ;

[0146] HPLC: 96.97%.

[0147] Example 9

[0148] This example demonstrates the synthesis of compound 9, which is similar to the reaction method of Example 4, except that the pyridine boronic acid reagent used is 5-aminopyridine-3-boronic acid pinacol ester.

[0149] The characterization results are as follows:

[0150] 1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.84 (d, J = 2.9 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.70 - 7.65 (m, 2H), 7.50 (s, 2H), 7.35 (t, J = 2.2 Hz, 1H), 6.04 (s, 2H), 5.57 (s, 2H).

[0151] MS (ESI, pos.ion) m / z: 473.05 [M+H] + ;

[0152] HPLC: 96.11%.

[0153] Example 10

[0154] This example shows the synthesis of compound 10, which is similar to the reaction method of Example 4, except that the pyridine boronic acid reagent used is 3-pyridine boronic acid.

[0155] The characterization results are as follows:

[0156] 1 H NMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.46 (d, J = 4.7 Hz, 1H), 8.13 (dd, J = 8.0, 2.0 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.71 - 7.65 (m, 2H), 7.52 (s, 2H), 7.45 (dd, J = 8.0, 4.9 Hz, 1H), 6.22 (s, 2H), 5.60 (s, 2H).

[0157] MS (ESI, pos.ion) m / z: 457.97 [M+H] + ;

[0158] HPLC: 98.63%.

[0159] Synthesis Scheme Three

[0160] For the synthesis of the following structured compounds:

[0161] The synthesis route is as follows:

[0162] The above synthesis route is mainly prepared by 3+2 cycloaddition reaction of azide compound, and the 2-pyridine acetonitrile selected in this route has formed different R9 substituted compounds with different substituents on the pyridine ring;

[0163] Specifically: take the azide compound, add a substituted / unsubstituted 2-pyridine acetonitrile, potassium tert-butoxide, and react overnight at room temperature. Stop the reaction. Column chromatography is used to obtain the product.

[0164] Examples 11-15 are new compounds obtained by using synthesis scheme three.

[0165] Example 11

[0166] The synthesis route of compound 11 is shown in this example as follows:

[0167] Take (4-(azidomethyl)-2,6-dichlorophenyl)(4-chlorophenyl)methanone (632 mg, 1.864 mmol) in a 25 mL single-neck flask, add 2-pyridine acetonitrile (201.0 mg, 1.702 mmol), potassium tert-butoxide (21 mg, 0.187), and react overnight at room temperature. Stop the reaction. Directly stir the sample column chromatography (DCM:MeOH = 10:1) to obtain 300 mg of light yellow solid. Add 6 mL of EA to make compound 11: 60 mg.

[0168] The characterization information is as follows:

[0169] 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 6.4 Hz, 1H), 7.95 (d, J = 9.5 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.52 (s, 2H), 7.25-7.17 (m, 1H), 6.78 (s, 2H).

[0170] MS (ESI, pos.ion) m / z: 458.01 [M+H] + .

[0171] HPLC: 96.74%.

[0172] Example 12

[0173] This example shows the synthesis method of compound 12, which is similar to the reaction method of Example 10, except that 2-pyridine acetonitrile is replaced by bromopyridine.

[0174] The characterization results are as follows:

[0175] 1H NMR (400 MHz, DMSO) δ 7.93 (d, J = 7.9 Hz, 1H), 7.78 (t, J = 8.4 Hz, 3H), 7.67 (d, J = 8.5 Hz, 2H), 7.50 (s, 2H), 7.43 (d, J = 7.8 Hz, 1H), 6.62 (s, 2H), 5.61 (s, 2H).

[0176] Further reducing the Br of compound 12 to amine group to obtain compound 12a:

[0177] The characterization results are as follows:

[0178] 1 H NMR (400 MHz, DMSO) δ 7.76 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 7.48 (s, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.75 (s, 2H), 6.22 (d, J = 8.0 Hz, 1H), 6.08 (s, 2H), 5.56 (s, 2H).

[0179] MS (ESI, pos.ion) m / z: 473.05 [M+H] + .

[0180] HPLC: 98.55%.

[0181] Examples 13-15

[0182] Examples 13-15 are the synthesis of related compounds 13- compound 15 with A ring as pyrimidine ring.

[0183] The synthesis route is as follows:

[0184] Synthesis of intermediate 1:

[0185] CAI (10.0 g, 23.58 mmol) was weighed into a reaction bottle, THF (100 mL), Et3N (8.2 mL, 59.0 mmol) were added, and the temperature was lowered to 0°C, TFAA (6.6 mL, 47.17 mmol) was added, and the reaction was carried out at 0°C for 2.5 h, and then the reaction was stopped. Saturated aqueous sodium bicarbonate solution was added to the reaction, then EA was added for extraction, dried and concentrated, and then column chromatography was carried out (PE:EA = 4:1-1:1) to separate the white crude product, which was added to EA to make a slurry, to obtain 5-amino-1-(3,5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1,2,3-triazole-4-carbonitrile (hereinafter referred to as intermediate 1): 1.27 g, yield 13%.

[0186] Synthesis of Intermediate 2:

[0187] Weighed Intermediate 1 (400 mg, 0.984 mmol) in a reaction flask, added sodium methoxide (32 mg), added methanol (5 mL), reacted at RT for 15 h, the reaction was slow, added THF (2 mL), reacted for 3 h, then added ammonium chloride (95 mg), reacted at RT for 21 h, stopped the reaction. The reaction solution was directly concentrated, column chromatography separation (DCM:MeOH = 40:1-8:1) to obtain 100 mg of white product, which was 5-amino-1-(3,5-dichloro-4-(4-chlorobenzoyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (hereinafter referred to as Intermediate 2), the yield was 24%.

[0188] 1 H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 3H), 7.77 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.55 (s, 2H), 7.46 (s, 2H), 5.65 (s, 2H).

[0189] MS (ESI, pos.ion) m / z: 423.68 [M+H] +

[0190] Synthesis of Compound 13:

[0191] Weighed Intermediate 2 (50 mg, 0.118 mmol) in a reaction flask, added sodium ethoxide (8 mg), ethanol (1 ml), 2-formyl-3-oxo propanoic acid ethyl ester (15 ul, 0.118 mmol), warmed to 80℃ after addition, reacted for 2 h, stopped the reaction. The reaction solution was directly concentrated, column chromatography separation (DCM:MeOH = 60:1-50:1) to obtain Compound 14 (5 mg).

[0192] NMR: 1 H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 2H), 7.78-7.75 (m, 2H), 7.67 (d, J = 6.7 Hz, 2H), 7.53 (s, 2H), 7.19 (s, 2H), 5.63 (s, 2H), 4.40-4.36 (m, 2H), 1.37-1.35 (m, 3H).

[0193] MS (ESI, pos.ion) m / z: 455.62 [M+Na] +

[0194] Synthesis of Compound 14:

[0195] Weigh compound 13 (50 mg, 0.0942 mmol), NaOH (5 mg, 0.113 mmol) into a reaction bottle, add MeOH (1 ml), H2O (0.3 ml), after adding, react at RT for 1 h, stop the reaction. Adjust the PH = 7 of the reaction, concentrate, wash the solid with water, filter dry, get yellow solid product, directly into the next step reaction.

[0196] Synthesis of compound 15

[0197] Weigh compound 14 (0.0942 mmol), EDCI (27 mg, 0.1413 mmol), HOBT (20 mg, 0.151 mmol), NH4Cl (16 mg, 0.306 mmol) into a reaction bottle, add DMSO (1 mL), DIPEA (79 mg), after adding, react at RT for 15 h, stop the reaction. After extraction, column chromatography separation (DCM:MeOH = 30:1-8:1) to get white solid 15 mg.

[0198] 1 H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 2H), 7.77 (d, J = 2.1 Hz, 2H), 7.70-7.64 (m, 2H), 7.53 (s, 2H), 7.20 (s, 2H), 5.63 (s, 2H), 3.91 (s, 2H).

[0199] MS (ESI, pos.ion) m / z: 502.24 [M+H] + .

[0200] Synthetic scheme four

[0201] For the synthesis of compounds related to the structure of A ring being a pyrimidine ring:

[0202] The synthetic route is as follows:

[0203] The above synthetic route is mainly prepared by Suzuki coupling reaction of bromine-substituted triazole mother nucleus, and the difference from synthetic route two is that different pyrimidine boronic acid reagents are selected to obtain different R9-substituted compounds in this route;

[0204] Specifically, weigh the bromine-substituted triazole mother nucleus compound and the pyrimidine boronic acid reagent, bis-triphenylphosphine palladium dichloride, sodium carbonate, dioxane, water, and nitrogen reflux overnight, stop the reaction. Column chromatography to obtain.

[0205] The compound of example 16 is prepared according to the method of synthetic route four.

[0206] Example 16

[0207] This example was prepared by Suzuki coupling reaction of the bromide with 2-aminopyrimidine-5-boronic acid, compound 16 structure and characterization as follows:

[0208] 1 H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J = 1.6 Hz, 2H), 7.78 (d, 2H), 7.68 (d, J = 8.7, 1.8 Hz, 2H), 7.51 (s, 2H), 6.68 (s, 2H), 5.93 (s, 2H), 5.56 (s, 2H).

[0209] MS (ESI, pos.ion) m / z: 473.99 [M+H] + ;

[0210] HPLC: 96.74%.

[0211] Examples 17-18

[0212] This example is the synthesis of compounds with thiazole ring for the A ring.

[0213] Synthesis of 2-(2-aminothiazol-4-yl)acetamide:

[0214] Weigh 2-amino-4-thiazole ethyl acetate (1862 mg, 10 mmol), NH3 / MeOH (10 ml), react at room temperature, reseal the tube reaction, crystallize after cooling, filter to get white solid 1190 mg, yield: 76%.

[0215] 1 H NMR (400 MHz, DMSO-d6) δ 7.21 (s, 1H), 6.88 (d, J = 14.2 Hz, 3H), 6.23 (s, 1H), 3.20 (s, 2H). MS (ESI, pos.ion) m / z: 158.04 [M+H] + .

[0216] Synthesis of 3-(4-(cyanomethyl)thiazol-2-yl)-1,1-dimethylurea:

[0217] Take 2-(2-aminothiazol-4-yl)acetamide (165 mg, 1.05 mmol), DMF (2.5 ml) in a 50 ml flask, nitrogen protection, cooling to 0 °C, adding POCl3(322 mg, 2.10 mmol), stirring for 15 min, then warming to room temperature for 1.5 h, then warming to 80 °C and refluxing for 15 min, adding 1N hydrochloric acid to quench, adding saturated sodium bicarbonate solution to quench, extracting with EA, column chromatography (pure EA) to purify, to obtain 147 mg of orange yellow oily liquid, yield 71%.

[0218] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 6.87 (s, 1H), 3.90 (s, 2H), 3.11 (s, 3H), 2.96 (s, 3H). Synthesis of compound 17:

[0219] Take 3-(4-(cyanomethyl)thiazol-2-yl)-1,1-dimethylurea (134 mg, 0.962 mmol), azide (298 mg, 0.875 mol), tBuOK 10 mg, 0.0875 mmol), a few drops of THF in a 50 ml flask, room temperature reaction overnight, column chromatography (PE:EA = 4:1) to obtain 25 mg of product, yield 6.0%.

[0220] 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.67 (t, J = 7.0 Hz, 3H), 7.46 (s, 2H), 7.04 (s, 1H), 6.11 (s, 2H), 5.57 (s, 2H), 3.13 (s, 3H), 2.98 (s, 3H).

[0221] Synthesis of compound 18:

[0222] Take compound 17 (23 mg, 0.0428 mmol), NaOH (3.4 mg, 0.0857 mmol), H2O (3 ml), EtOH (3 ml) in a 50 ml flask, reflux at 80 °C. Spin off the ethanol and extract with EA, dry, spin dry the solvent, dissolve in DCM, and crystallize with PE, filter to obtain 10 mg of light yellow solid, yield: 49%.

[0223] 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 7.45 (s, 2H), 7.08 (s, 2H), 6.63 (s, 1H), 6.13 (s, 2H), 5.53 (s, 2H).

[0224] MS (ESI, pos.ion) m / z: 481.00 [M+H] + .

[0225] HPLC: 95.7%.

[0226] Examples 19-20

[0227] Examples 19-20 are the synthesis of compound 19 and compound 20 which have a tetrazole as the A ring, the synthesis route is as follows:

[0228] Synthesis of intermediate 1:

[0229] The starting material (5.0 g, 11.8 mmol) was weighed into a reaction bottle, Et3N (4.1 ml, 29.5 mmol), TFAA (3.3 ml, 23.6 mmol) were added, and after stirring for 5 min, the reaction was allowed to proceed at room temperature for 52 h. The reaction was stopped, 10 ml of saturated NaHCO3 aqueous solution was added, and EA was used for extraction. After concentration, column chromatography separation (PE:EA = 5:1-4:1-3:1-2:1-1:1) was used to obtain the white product crude product. The product crude product was added to 2 ml of EA to make a slurry, and 1.0 g of white product was obtained, with a yield of 21%.

[0230] Synthesis of compound 19:

[0231] Intermediate 1 (300 mg, 0.74 mmol) was weighed into a reaction bottle, TMSN3 (192 mg, 1.67 mmol) and TBAF (1M) (0.6 ml, 0.57 mmol) were added to the reaction bottle, and stirring was started. The temperature was raised to 85°C, and the reaction was allowed to proceed for 3 h. The reaction was stopped. DCM was added to the reaction solution, and after concentration, column chromatography separation (EA:PE = 1:1-MeOH:DCM = 1:50-1:40-1:30) was used to obtain 170 mg of white solid, with a yield of 51%.

[0232] 1H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.55 (s, 2H), 6.72 (s, 2H), 5.64 (s, 2H), 4.04 (q, J = 7.1 Hz, 1H).

[0233] MS (ESI, pos.ion) m / z: 449.01 [M+H] + .

[0234] HPLC: 99.25%.

[0235] Synthesis of compound 20:

[0236] Compound 19 (300 mg, 0.67 mmol) was weighed into a reaction bottle, H2SO4 (2 ml) and tert-butyl alcohol (71 ul, 0.74 mmol) were added to the reaction bottle, stirring was started, RT reaction started for 90 min, and the reaction was stopped. The reaction was dropped into ice water, EA was extracted, and saturated NaHCO3 aqueous solution was washed twice, the organic phase was collected, concentrated and column chromatography was separated (EA: PE = 4:1-3:1-2:1-1:1-MeOH: DCM = 1:70) to obtain 100 mg of white solid, with a yield of 30%.

[0237] 1 H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.50 (s, 2H), 6.41 (s, 2H), 5.64 (s, 2H), 1.75 (s, 9H).

[0238] MS (ESI, pos.ion) m / z: 505.6 [M+H] + .

[0239] HPLC: 99.13%.

[0240] Synthesis scheme five

[0241] For the synthesis of compounds with an oxadiazole ring structure in the A ring:

[0242] The synthesis route is as follows:

[0243] The above synthesis route is mainly prepared by condensation ring closure reaction, and then the nitro group is reduced to amine group. Different acyl chloride reagents are selected in this route to obtain different R9 substituted compounds;

[0244] Specifically, the triazole mother nucleus compound in the above formula is weighed into a reaction bottle, pyridine is added for dissolution, and then acyl chloride reagent is dropped, replaced with nitrogen, and refluxed. TLC monitoring shows that a lighter new spot is generated. After treatment, extraction, drying, rotary evaporation, sample mixing, and column chromatography, the intermediate product is obtained, and finally the nitro group is reduced to amine group by Zn powder and ammonium chloride.

[0245] The compounds of examples 21-22 are prepared according to the method of synthesis route five.

[0246] Example 21

[0247] The structure of compound 21 is as follows:

[0248] The acyl chloride reagent selected in compound 21 is benzoyl chloride, and the characterization results are as follows:

[0249] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.25 (m, 2H), 7.87 - 7.73 (m, 2H), 7.73 - 7.65 (m, 4H), 7.54 (s, 3H), 6.66 (s, 2H), 5.66 (s, 2H).

[0250] MS (ESI, pos.ion) m / z: 525.08 [M+H] + ;

[0251] HPLC: 99.18%.

[0252] Example 22

[0253] The structure of compound 22 is as follows:

[0254] The acyl chloride reagent selected in compound 22 is acetyl chloride, and the characterization results are as follows:

[0255] 1H NMR (400 MHz, DMSO-d6) δ 7.82 - 7.76 (m, 2H), 7.72 - 7.66 (m, 2H), 7.52 (s, 2H), 6.52 (d, J = 2.4 Hz, 2H), 5.62 (s, 2H), 2.67 (s, 3H).

[0256] MS (ESI, pos.ion) m / z: 463.04 [M+H] + .

[0257] HPLC: 98.50%.

[0258] Example 23

[0259] This example is also for the synthesis of compounds with oxadiazole ring structure as the A ring, and the synthesis of compound 23 is as follows:

[0260] Synthesis of 1-(3,5-dichloro-4-(4-chlorobenzoyl)benzyl)-5-nitro-1H-1,2,3- triazole-4-carbonitrile: Weigh 1-(3,5-dichloro-4-(4-chlorobenzoyl)benzyl)-5-nitro-1H-1,2,3- triazole-4-carboxamide (500 mg, 1.10 mmol) into a reaction flask, add DCM (10 mL), Et3N (278 mg, 2.75 mmol), cool to 0 °C, add TFAA (306 uL, 2.20 mmol), stir for 5 min, remove to room temperature, react for 1.5 h, stop the reaction. Add saturated aqueous sodium bicarbonate solution to the reaction, then extract with EA, dry and concentrate, separate by column chromatography (PE:EA = 5:1-4:1) to obtain 420 mg of product.

[0261] Synthesis of 1-(3,5-dichloro-4-(4-chlorobenzoyl)benzyl)-N-hydroxy-5-nitro-1H-1,2,3- triazole-4-carboximide: Weigh 1-(3,5-dichloro-4-(4-chlorobenzoyl)benzyl)-5-nitro-1H-1,2,3- triazole-4-carbonitrile (420 mg, 1.03 mmol), hydroxylamine hydrochloride (180 mg, 2.59 mmol), sodium carbonate (164 mg, 1.55 mmol) into a reaction flask, add H2O (4 mL), EtOH (8 mL), warm to 80 °C, react for 2 h, stop the reaction. Add EA and water to the reaction, extract, dry and concentrate, directly input into the next step reaction.

[0262] Synthesis of (4-chlorophenyl)(2,6-dichloro-4-((5-nitro-4-(1,2,4-oxadiazol-3-yl)-1H-1,2,3- triazol-1-yl)methyl)phenyl)methanone: Weigh 1-(3,5-dichloro-4-(4-chlorobenzoyl)benzyl)-N- hydroxy-5-nitro-1H-1,2,3-triazole-4-carboximide (600 mg, 1.28 mmol), orthoformic acid trimethyl ester (8 mL) into a reaction flask, add TsOH·H2O (24 mg, 0.68 mmol), warm to 90 °C, react for 1 h, stop the reaction. Extract the reaction, separate by column chromatography (PE:EA = 6:1-4:1) to obtain 220 mg of white solid product.

[0263] Synthesis of compound 23: Weigh (4-chlorophenyl) (2,6-dichloro-4-((5-nitro-4-(1,2,4-oxadiazol-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)methanone (290 mg, 0.604 mmol), zinc powder (395 mg, 6.04 mmol) into a reaction bottle, add THF (5 mL), then weigh NH4Cl (65 mg) dissolved in 2.5 mL of water, add to the reaction, react for 2 h at RT, stop the reaction. Add EA and water to the reaction, dry and concentrate the organic phase after extraction, separate by column chromatography (PE:EA = 3:1-1:2), get 170 mg of white solid, EA beating, get 90 mg of product.

[0264] The characterization results of compound 23 are as follows:

[0265] 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.53 (s, 2H), 6.59 (s, 2H), 5.64 (s, 2H).

[0266] MS (ESI, pos.ion) m / z: 451.02 [M+H] + .

[0267] HPLC: 96.18%.

[0268] Example 24

[0269] This example is also for the synthesis of compounds with oxadiazole ring structure in ring A, the synthesis of compound 24 is as follows:

[0270] Take cyan compound (61.5 mg, 0.5 mmol), azide (186 mg, 0.55 mmol), drop two drops of THF, then add potassium tert-butoxide (5.5 mg, 0.05 mmol), react for ten minutes at room temperature, stop the reaction, add water and ethyl acetate, separate, concentrate the organic phase, the residue is separated by column chromatography (PE:EA = 1:3) to get 50 mg of white solid, yield 22%. The characterization results of compound 24 are as follows:

[0271] 1 H NMR (400 MHz, DMSO) δ 7.77 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.51 (s, 2H), 6.77 (s, 2H), 5.61 (s, 2H), 2.56 (s, 3H).

[0272] MS (ESI, pos.ion) m / z: 461.05 [M+H] + .

[0273] HPLC: 98.52%.

[0274] Examples 25-28 are directed to the synthesis of compounds with a pyrazole ring in the A ring.

[0275] Example 25

[0276] The synthetic route for compound 25 is as follows:

[0277] Synthesis of 2-(l-methyl-lH-pyrazol-5-yl)acetonitrile: To a 250 ml flask, charged with p-toluenesulfonylmethyl isocyanide (3.90 g, 20 mmol) in THF (dry, 10 ml) under nitrogen protection, cooled to -60 °C, added tBuOK (4.49 g, 20 mmol) in THF (25 ml), -60 °C for 15 min, added l-methyl-lH-pyrazole-5-carboxaldehyde (1.10 g, 10 mmol) in THF (7.0 ml), stirred for 1.5 h, added methanol (10 ml) and refluxed for 1.5 h, after the solvent was removed, column chromatography (dichloromethane:methanol = 80: 1) to get 442 mg yellow liquid, yield 36%.

[0278] Synthesis of compound 25: To a 50 ml flask, charged with azide (887 mg, 2.607 mmol), 2-(l-methyl-lH-pyrazol-5-yl)acetonitrile (347 mg, 2.864 mmol), tBuOK (29 mg, 0.260 mmol) at room temperature overnight, column chromatography (dichloromethane:methanol = 60: 1) to get 143 mg product, yield: 6%.

[0279] The characterization results of compound 25 are as follows:

[0280] 1 H NMR (400 MHz, DMSO-d6) δ 7.82 - 7.74 (m, 2H), 7.71 - 7.64 (m, 2H), 7.52 - 7.46 (m, 3H), 6.50 (d, J = 1.9 Hz, 1H), 6.06 (s, 2H), 5.57 (s, 2H), 3.99 (s, 3H).

[0281] MS (ESI, pos.ion) m / z: 461.05 [M+H] + .

[0282] HPLC: 97.81%.

[0283] Example 26

[0284] The synthetic route for compound 26 is as follows:

[0285] Synthesis of compound 26: Bromide (184.2 mg, 0.4 mmol), l-ethylpyrazole-5- boronic acid pinacol ester (97.7 mg, 2.4 mmol), dichlorobis(triphenylphosphine)palladium (14 mg, 0.02 mmol), sodium carbonate (84.8 mg, 0.8 mmol), dioxane (4 ml), water (1 ml), 100 °C overnight under nitrogen protection, but TLC monitoring showed that the amount of new spot did not increase over time, and a large amount of starting material remained. Work-up: direct spin dry, sample stirring, column chromatography (PE:EA = 4:1 ~ 1:2), to get 30 mg of white solid, the yield was 7.8%. The characterization results of compound 26 are as follows:

[0286] 1 H NMR (400 MHz, DMSO-d6) d 7.79 - 7.76 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.50 (s, 1H), 7.48 (s, 2H), 6.49 (s, 1H), 6.03 (s, 2H), 5.58 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.33 (d, J = 7.0 Hz, 3H).

[0287] MS (ESI, pos.ion) m / z: 475.03 [M+H] + .

[0288] HPLC: 95.7%.

[0289] Example 27

[0290] The synthetic route for compound 27 is as follows:

[0291] Synthesis of 2-(l-methyl-lH-pyrazol-3-yl)acetonitrile: Potassium tert-butoxide (2.9 g, 26 mmol) was dissolved in DME (11 ml) under nitrogen protection and cooled to -60 °C. Then p-toluenesulfonylmethyl isocyanide (2.9 g, 15 mmol) was dissolved in DME (9 ml) and slowly added into the reaction solution. The temperature of the reaction system should be controlled between -60 °C and -55 °C during the addition. The addition time was about 60 min. After the addition was completed, the solution was stirred for 30 min. Then l-methyl-lH-pyrazole-3-carboxaldehyde (1.1 g, 10 mmol) was dissolved in DME (7 ml) and slowly added into the reaction solution. After the addition was completed, the solution was stirred at -55 °C for 1.5 h. Then MeOH (11 ml) was slowly added into the reaction solution. After the solution was stirred for 10 min, it became a brown clear solution. The solution was stirred at room temperature until the reaction temperature returned to room temperature. Then the solution was refluxed at 85 °C for 1 h. The solution was still a brown clear solution at this time. The reaction was completed. Work-up: The reaction solution was directly rotary evaporated. Then 50 ml water and 1 ml acetic acid were added into the solution. The solution was stirred for 10 min. Then 50 ml EA was added into the solution. The solution was extracted, separated, rotary evaporated, mixed, and column chromatographed (PE:EA = 5:1 to 1:2) to obtain 1.02 g of yellow oily liquid. The yield was 84.3%.

[0292] Synthesis of compound 27: The azide in the above formula (408.0 mg, 1.2 mmol), 2-(l-methyl-lH-pyrazol-3-yl)acetonitrile (160.0 mg, 1.32 mmol), and THF (3 drops) were stirred at room temperature. Then potassium tert-butoxide (13.4 mg, 0.6 mmol) was slowly added into the reaction solution. After the solution was stirred at room temperature for 0.5 h, TLC monitoring showed that a new spot appeared. The reaction was carried out at room temperature overnight. Work-up: 10 ml water and 10 ml EA were added into the solution. The solution was extracted, rotary evaporated, mixed, and column chromatographed (PE:EA = 5:1 to 1:2) to obtain 26 mg of white solid. The yield was 4.6%. The characterization results of compound 27 are as follows:

[0293] 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.75 (s, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.45 (s, 1H), 6.50 (d, J = 2.2 Hz, 2H), 6.01 (s, 2H), 5.57 (s, 2H), 3.87 (s, 3H). MS (ESI, pos.ion) m / z: 461. [M+H] + .

[0294] HPLC: 96.5%.

[0295] Example 28

[0296] The synthetic route for compound 28 is as follows:

[0297] The cyan compound (244 mg, 2 mmol), azide compound (746 mg, 2.2 mmol) were weighed, 0.3 mL THF was added dropwise, followed by the addition of potassium tert-butoxide (23 mg, 0.2 mmol), and the reaction was stopped after 1 h of reaction at room temperature. Water and ethyl acetate were added for extraction, the liquid was separated, and the organic phase was concentrated. The residue was column chromatographed (DCM:MeOH = 20:1) to obtain 20 mg of white solid, with a yield of 3%. The characterization results of compound 28 are as follows:

[0298] 1 H NMR (400 MHz, DMSO) δ 8.01 (s, 1H), 7.77 (s, 1H), 7.76 (d, J = 4.9 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.45 (s, 2H), 5.71 (s, 2H), 5.53 (s, 2H), 3.86 (s, 3H).

[0299] MS (ESI, pos.ion) m / z: 461.02 [M+H] + .

[0300] HPLC: 97.52%.

[0301] Example 29

[0302] This example is directed to the synthesis of a compound with an imidazole ring as the A ring structure. In other embodiments of the present application, by replacing the methyl group on the cyan compound with other R9groups, the following reaction formula is also applicable, and is within the scope of protection of the present application.

[0303] Synthesis of compound 29: The 2-(1-methyl-1H-imidazol-2-yl)acetonitrile (36.3 mg, 0.3 mmol), azide compound (111 mg, 0.33 mmol) were weighed, 2 drops of THF were added dropwise, followed by the addition of potassium tert-butoxide (3.3 mg, 0.03 mmol), and the reaction was stopped after 10 min of reaction at room temperature. Water and ethyl acetate were added for extraction, the liquid was separated, and the organic phase was concentrated. The residue was column chromatographed (PE:EA = 1:1) to obtain 130 mg of yellowish solid, with a yield of 71%.

[0304] 1H NMR (500 MHz, DMSO) δ 7.76 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.49 (s, 2H), 7.15 (d, J = 1.0 Hz, 1H), 6.97 (d, J = 1.0 Hz, 1H), 6.55 (s, 2H), 5.59 (s, 2H), 4.01 (s, 3H).

[0305] MS (ESI, pos.ion) m / z: 447.08 [M+H] + .

[0306] HPLC: 99.52%.

[0307] Example 30

[0308] This example is a preparation method of compound 30, the preparation step 1 is similar to that of example 25, and the reaction formula is as follows:

[0309] The synthesis principle of intermediate 1 in the above formula is similar to that of compound 25, except that 2-(1-methyl-1H-pyrazol-5-yl)acetonitrile is replaced by raw material 2.

[0310] Synthesis of compound 30:

[0311] Intermediate 1 (150 mg, 0.28 mmol) was weighed, dissolved in 2 mL of methanol and 2 mL of tetrahydrofuran, and concentrated hydrochloric acid (2.8 mmol) was added. After 30 min, it was directly concentrated and column chromatographed (PE:EA = 1:1-1:4) to obtain 46 mg of product, with a yield of 36%.

[0312] 1 H NMR (500 MHz, DMSO-d6) δ 7.81-7.76 (m, 2H), 7.71-7.65 (m, 2H), 7.53-7.46 (m, 3H), 6.51 (d, J = 2.0 Hz, 1H), 6.05 (s, 2H), 5.58 (s, 2H).

[0313] MS (ESI, pos.ion) m / z: 447.08 [M+H] + .

[0314] HPLC: 95.39%.

[0315] Example 31

[0316] This example is a preparation method of compound 31, and the reaction formula is as follows:

[0317] Step 1: synthesis of intermediate 1 in the above formula:

[0318] Take raw materials 1 (2.52g, 20mmol), cesium carbonate (9.75g, 30mmol) in a reaction bottle, add DMF (20mL), deuterated methyl iodide (3.19g, 22mmol), react at room temperature overnight, add water and EA extraction, separate, concentrate the organic phase, column chromatography (PE:EA = 12:1-10:1), get the product 1.1g, yield 39%.

[0319] MS (ESI, pos.ion) m / z: 144.08 [M+H] + .

[0320] Step 2: synthesis of intermediate 2 in the formula above

[0321] Take intermediate 1 (1.1g, 7.69mmol), dissolve in 20mL tetrahydrofuran, add lithium aluminum hydride (350.5mg, 9.23mmol) at 0℃, react at room temperature for 12h, stop the reaction, quench with water, EA extraction, concentrate to get 480mg of crude product, which is directly used in the next step. MS (ESI, pos.ion) m / z: 116.10 [M+H] + .

[0322] Step 3: synthesis of intermediate 3 in the formula above

[0323] Take intermediate 2 (480mg, 4.17mmol), dissolve in DCM (6mL), add a drop of DMF, add dichlorosulfoxide (993mg, 8.34mmol) at 0℃, stir for 20min, turn to room temperature and react for 6h, quench with water, dichloromethane extraction, get 302mg of crude product, which is directly used in the next step.

[0324] Step 4: synthesis of intermediate 4 in the formula above

[0325] Dissolve intermediate 3 (302mg, 2.26mmol) in dioxane (5mL), add zinc cyanide (159.3mg, 1.35mmol), tetrabutylammonium chloride (942mg, 3.39mmol), under nitrogen protection, reflux at 100℃ for 4h, rotary evaporation to remove the solvent, add water and EA extraction, rotary evaporation, concentrate the organic phase, column chromatography purification (PE:EA = 4:1-1:1) to get 90mg of product, yield 32%.

[0326] MS (ESI, pos.ion) m / z: 125.10 [M+H] + .

[0327] Step 5: The synthesis of compound 31 was carried out according to the principle of Example 25, except that 2-(1-methyl-1H-pyrazol-5-yl)acetonitrile was replaced by the above intermediate 4. The characterization results of compound 31 are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.82 - 7.79 (m, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.54 - 7.48 (m, 3H), 6.53 (d, J = 2.0 Hz, 1H), 6.08 (s, 2H), 5.60 (s, 2H).

[0328] MS (ESI, pos.ion) m / z: 464.08 [M+H] + .

[0329] HPLC: 98.52%.

[0330] Example 32

[0331] This example provides a method for preparing compound 35. The preparation process is the same as that of Example 25, and the reaction formula is as follows:

[0332] The characterization results of compound 35 are as follows:

[0333] 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.51 (s, 2H), 6.30 (s, 1H), 6.05 (s, 2H), 5.58 (s, 2H), 3.92 (s, 3H), 2.52 (s, 3H).

[0334] MS (ESI, pos.ion) m / z: 477.12 [M+H] + .

[0335] HPLC: 96.56%.

[0336] Example 33

[0337] This example provides a method for preparing compound 36. The reaction formula is as follows:

[0338] Step 1: Synthesis of intermediate 2 in the above reaction formula

[0339] Into a flask, was placed the starting material 1 (2 g, 6.87 mmol) from the above structure, anhydrous THF (20 mL) was added under nitrogen protection, 2.5 M n-butyllithium solution in n-hexane (2.8 mL, 7.07 mmol) was added dropwise slowly at -70 °C, and the mixture was stirred for 0.5 h. Then p-fluorobenzoyl chloride (1.10 g, 6.96 mmol) was dissolved in 5 mL of anhydrous THF and added dropwise to the reaction system, and the mixture was stirred for 1 h. TLC showed that there was no starting material left and a product spot appeared. 5 mL of saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, 4 mL of concentrated hydrochloric acid was added to the above THF solution, and the mixture was stirred for 2 h. After the reaction was completed, 10 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed once with water, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (PE:EA = 4:1) to give 1.6 g of white solid with a yield of 78%.

[0340] 1H NMR (500 MHz, DMSO-d6) δ 7.88 - 7.81 (m, 2H), 7.56 (s, 2H), 7.42 (t, J = 8.8 Hz, 2H), 5.59 (t, J = 5.8 Hz, 1H), 4.61 (d, J = 5.7 Hz, 2H).

[0341] MS (ESI, pos.ion) m / z: 299.00 [M+H] + .

[0342] Step 2: Synthesis of intermediate 3

[0343] Into a flask, was placed intermediate 2 (1.5 g, 5.00 mmol) dissolved in 5 mL of DMF, and at 0 °C, thionyl chloride (1.18 g, 11.0 mmol) was added dropwise to the reaction system, and the mixture was reacted at room temperature for 1 h. Then potassium carbonate (4.50 g, 32.5 mmol) was added to quench the reaction. 100 mL of water was added to the reaction system, and the mixture was extracted with EA. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and 1.11 g of yellow oily liquid was obtained with a yield of 70%.

[0344] Step 3: Synthesis of intermediate 4

[0345] Into a flask, was placed intermediate 3 (1.04 g, 3.28 mmol) dissolved in 15 mL of acetonitrile, and under stirring, n-butyl azide (0.93 g, 3.28 mmol) was added, and the mixture was reacted at room temperature for 1 h. TLC showed that there was no starting material left and a product spot appeared. The mixture was extracted with ethyl acetate and water to obtain the organic phase, which was dried over anhydrous sodium sulfate. The residue was purified by column chromatography (PE:EA = 8:1) to give 0.79 g of product with a yield of 75%.

[0346] 1H NMR (500 MHz, DMSO-d6) δ 7.88 - 7.82 (m, 2H), 7.67 (s, 2H), 7.48 - 7.37 (m, 2H), 4.62 (s, 2H).

[0347] MS (ESI, POS. ion) m / z: 324.01 [M+H] + .

[0348] Step 4: Synthesis of compound 36

[0349] The reaction method is similar to that of Example 25, except that the azide reagent used is ((4-(azidomethyl)-2,6-dichlorophenyl)(4-fluorophenyl)methanone. The characterization results are as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 8.7, 5.5 Hz, 2H), 7.64 - 7.59 (m, 1H), 7.49 (s, 3H), 7.42 (t, J = 8.6 Hz, 2H), 7.33 (d, J = 6.5 Hz, 1H), 6.52 (s, 1H), 5.58 (s, 2H), 3.99 (s, 3H).

[0350] MS (ESI, POS. ion) m / z: 445.07 [M+H] + .

[0351] HPLC: 96.53%.

[0352] Example 34

[0353] This example provides a method for preparing compound 38, which has the same principle as the preparation of compound 36 (Example 33), except that the reactant p-fluorobenzoyl chloride is replaced by p-bromobenzoyl chloride. The reaction formula is as follows:

[0354] The characterization results of compound 38 are as follows:

[0355] 1 1H NMR (400 MHz, DMSO-d6) δ 7.82 - 7.74 (m, 2H), 7.71 - 7.64 (m, 2H), 7.52 - 7.46 (m, 3H), 6.50 (d, J = 1.9 Hz, 1H), 6.06 (s, 2H), 5.57 (s, 2H), 3.99 (s, 3H).

[0356] MS (ESI, POS. ion) m / z: 507.20 [M+H] + .

[0357] HPLC: 97.55%.

[0358] Example 35

[0359] This example provides a method for preparing compound 39, the preparation process is the same as the principle of preparing compound 36 (Example 33), the main difference is that the reactant p-fluorobenzoyl chloride is changed to benzoyl chloride, and the reaction formula is as follows:

[0360] The characterization results of compound 39 are as follows:

[0361] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 7.8 Hz, 3H), 7.61 (dd, J = 8.7, 6.7 Hz, 2H), 7.54 - 7.46 (m, 3H), 6.53 (d, J = 2.0 Hz, 1H), 6.07 (s, 2H), 5.60 (s, 2H), 4.01 (s, 3H).

[0362] MS (ESI, pos.ion) m / z: 427.08 [M+H] + .

[0363] HPLC: 98.03%.

[0364] Example 36

[0365] This example provides a method for preparing compound 40, and the reaction formula is as follows:

[0366] Step 1: synthesis of intermediate 1

[0367] Weigh the raw material 1 (2.00 g, 12.9 mmol) into a single-mouth bottle, add chlorobenzene (5 mL), and add aluminum chloride at room temperature in four batches, 500 mg each time, and then heat to 80°C and stir for 12 h. Stop the reaction, add the reaction solution dropwise into ice water to quench the reaction, then add 50 mL of ethyl acetate for extraction, dry the organic phase, concentrate, add 15 mL of petroleum ether at room temperature, stir for 0.5 h, filter, and dry the filter cake to obtain a light yellow solid 2.00 g, with a yield of 67%.

[0368] 1 H NMR (500 MHz, CDCl3) δ 7.77 - 7.71 (m, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.48 - 7.42 (m, 2H), 7.29 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H).

[0369] MS (ESI, pos.ion) m / z: 231.06 [M+H] + .

[0370] Step 2: Synthesis of Intermediate 2

[0371] Intermediate 1 (746 mg, 3.23 mmol), NBS (632 mg, 3.55 mmol), AIBN (26.5 mg, 0.16 mmol) were weighed into a 50 mL reaction flask, acetonitrile (10 mL) was added, the reaction was stopped after refluxing for 5 h, most of the reaction solution was removed by concentration, 20 mL water and 30 mL ethyl acetate were added for extraction, the organic phase was dried, and concentrated to obtain a crude product which was directly used in the next step without further purification.

[0372] MS (ESI, pos.ion) m / z: 308.97 [M+H] + .

[0373] Step 3: Synthesis of Intermediate 3

[0374] Intermediate 2 (3.23 mmol), tetrabutylammonium azide (919 mg, 3.23 mmol) were weighed into a reaction flask, acetonitrile (7 mL) was added, and the reaction was carried out at room temperature for 0.5 h. Most of the solvent was removed by concentration, 20 mL water and 20 mL ethyl acetate were added, stirred for 2 min, and the organic phase was concentrated. Column chromatography gave 569 mg of white solid with a yield of 65%.

[0375] MS (ESI, pos.ion) m / z: 272.06 [M+H] + .

[0376] Step 4: Synthesis of Compound 40

[0377] 1 H NMR (400 MHz, DMSO-d6) δ 7.81 - 7.73 (m, 4H), 7.68 - 7.61 (m, 2H), 7.49 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 6.50 (d, J = 1.9 Hz, 1H), 6.00 (s, 2H), 5.62 (s, 2H), 4.00 (s, 3H). MS (ESI, pos.ion) m / z: 393.16 [M+H] + .

[0378] HPLC: 99.10%.

[0379] Example 37

[0380] This example is a method for preparing Compound 41, and the reaction formula is as follows:

[0381] Step 1: Synthesis of Intermediate 1

[0382] Take raw material 2 (248 mg, 1.72 mmol) in a two-necked flask, add anhydrous THF (3 mL) under nitrogen protection, slowly drop butyllithium (0.71 mL, 2.5 M) at -70°C, maintain low temperature stirring for 0.5 h after adding, then dissolve raw material 1 (300 mg, 1.72 mmol) in 1 mL of anhydrous tetrahydrofuran and slowly drop into the reaction system, stop the reaction after stirring at -40°C for 1 h. Add 10 mL of saturated aqueous ammonium chloride solution to quench the reaction, extract with ethyl acetate (10 mL*2), wash the organic phase with water, dry over anhydrous sodium sulfate, concentrate to give a crude product, add 5 mL of PE, stir at -10°C for 10 min, filter and dry the filter cake to obtain a light yellow solid 280 mg, yield 58%.

[0383] 1 H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.10 (s, 1H), 6.92 (d, J = 9.4 Hz, 1H), 2.41 (s, 3H).

[0384] Step 2: Synthesis of Intermediate 2

[0385] Take intermediate 1 (1.47 g, 5.21 mmol), NBS (1.02 g, 5.73 mmol), AIBN (43 mg, 0.26 mmol) in a 100 mL reaction flask, add acetonitrile (20 mL), reflux for 5 h, stop the reaction, concentrate to remove most of the reaction liquid, add 20 mL of water and 30 mL of ethyl acetate for extraction, dry the organic phase, concentrate to give a crude product which is used directly for the next step without further purification.

[0386] Step 3: Synthesis of Intermediate 3

[0387] Take tetrabutylammonium azide (1.25 g, 4.40 mmol) in the above reaction flask containing the raw material, add acetonitrile (10 mL), react at room temperature for 0.5 h. Concentrate to remove most of the solvent, add 20 mL of water and 30 mL of ethyl acetate, stir for 2 min and separate, dry the organic phase over anhydrous sodium sulfate, concentrate the residue and purify by column chromatography (PE:EA = 50:1-20:1) to obtain white solid product 900 mg, total yield of two steps 53%.

[0388] 1H NMR (400 MHz, CDC13) δ 7.77 (t, J = 6.8 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.26 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 4.44 (s, 2H).

[0389] Step 4: The synthesis of compound 41 was carried out in a similar manner as compound 25 by reacting intermediate 3 with 2-(1-methyl-1H-pyrazol-5-yl)acetonitrile to give compound 41, which was characterized as follows:

[0390] 1 H NMR (400 MHz, CDC13) δ 7.77 (t, J = 6.8 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.26 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 4.44 (s, 2H).

[0391] MS (ESI, pos.ion) m / z: 445.11 [M+H] + .

[0392] HPLC: 95.80%.

[0393] Example 38

[0394] This example is a method for preparing compound 42, which was prepared in a similar manner as compound 41 in Example 37, and the reaction scheme is as follows:

[0395] The characterization results of compound 42 are as follows:

[0396] 1 H NMR (400 MHz, CDC13) δ 7.77 (t, J = 6.8 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.26 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 4.44 (s, 2H).

[0397] MS (ESI, pos.ion) m / z: 445.11 [M+H] + .

[0398] HPLC: 95.80%.

[0399] Example 39

[0400] This example is a preparation method of compound 43, which has the same principle as the preparation of compound 36 (Example 33), and the main difference is that the reactant p-fluorobenzoyl chloride is changed to 3-chlorobenzoyl chloride, and the reaction formula is as follows:

[0401] The characterization results of compound 43 are as follows:

[0402] 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (ddd, J = 7.6, 2.2, 1.4 Hz, 1H), 7.81 (t, J = 1.9 Hz, 1H), 7.74 - 7.62 (m, 2H), 7.51 (d, J = 10.5 Hz, 3H), 6.53 (d, J = 1.9 Hz, 1H), 6.08 (s, 2H), 5.60 (s, 2H), 4.01 (s, 3H).

[0403] MS (ESI, pos.ion) m / z: 461.10 [M+H] + ;

[0404] HPLC: 99.12%.

[0405] Example 40

[0406] This example is a preparation method of compound 48, which has the same principle as the preparation of compound 36 (Example 33), and the main difference is that the reactant p-fluorobenzoyl chloride is changed to 3-methylbenzoyl chloride, and the reaction formula is as follows:

[0407] The characterization results of compound 48 are as follows:

[0408] 1 H NMR (500 MHz, DMSO-d6) δ 7.53 - 7.46 (m, 2H), 7.44 (s, 2H), 7.43 (d, J = 1.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 6.50 (d, J = 1.9 Hz, 1H), 6.41 (s, 2H), 5.53 (s, 2H), 3.93 (s, 3H), 2.38 (s, 3H). MS (ESI, pos.ion) m / z: 441.10 [M+H] + .

[0409] HPLC: 97.23%.

[0410] Example 41

[0411] This example is a preparation method of compound 50, which is the same as the principle of preparing compound 36 (Example 33), the main difference is that the reactant p-fluorobenzoyl chloride is changed to 4-cyclohexylbenzoyl chloride, and the reaction formula is as follows:

[0412] The characterization results of compound 50 are as follows:

[0413] 1 H NMR (400 MHz, DMSO-d6) δ 7.80-7.72 (m, 2H), 7.70-7.62 (m, 2H), 7.50-7.43 (m, 3H), 6.52 (d, J = 1.9 Hz, 1H), 6.08 (s, 2H), 5.55 (s, 2H), 3.96 (s, 3H), 2.71-2.66 (m, 1H), 1.90-1.41 (m, 10H).

[0414] MS (ESI, pos.ion) m / z: 509.20 [M+H] + .

[0415] HPLC: 97.55%.

[0416] Example 42

[0417] This example is a preparation method of compound 55, which is the same as the principle of preparing compound 36 (Example 33), the main difference is that the reactant p-fluorobenzoyl chloride is changed to p-chlorobenzoyl chloride, and the reaction formula is as follows:

[0418] The characterization results of compound 55 are as follows:

[0419] 1 H NMR (500 MHz, DMSO-d6) δ 7.84-7.73 (m, 2H), 7.72-7.63 (m, 2H), 7.50-7.43 (m, 3H), 6.52 (d, J = 1.9 Hz, 1H), 6.45 (s, 2H), 5.78 (q, J = 6.9 Hz, 1H), 3.95 (s, 3H), 1.92 (d, J = 7.0 Hz, 3H). MS (ESI, pos.ion) m / z: 475.08 [M+H] + .

[0420] HPLC: 98.50%.

[0421] Example 43

[0422] This example is a preparation method of compound 62, and the reaction formula is as follows:

[0423] Step 1 : Synthesis of Intermediate 1

[0424] Take raw material 1 (3.00 g, 8.98 mmol) in a 250 mL single-necked flask, add THF (30 mL), anhydrous ethanol (30 mL), and then add NaBH4 (1.02 g, 26.9 mmol) at room temperature. Stir the reaction at room temperature for 3 h, then quench the reaction by slowly adding 5 mL of water at room temperature. Concentrate most of the solvent, add 30 mL of water and 50 mL of EA, stir for 2 min, separate the layers, concentrate the organic phase, and purify the residue by column chromatography (PE:EA = 30:1-10:1) to obtain 2.00 g of an oil, with a yield of 66%.

[0425] 1 H NMR (500 MHz, CDC13) δ 7.49 (s, 1H), 7.39 (s, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 6.58 (d, J = 10.5 Hz, 1H), 4.51 (s, 2H), 3.28 (d, J = 10.5 Hz, 1H).

[0426] Step 2: Synthesis of Intermediate 2

[0427] Take Intermediate 1 (0.30 g, 0.90 mmol) in a 50 mL reaction flask, add DCM (5 mL), then slowly add 0.14 g of DAST (0.14 g, 0.90 mmol) to the reaction system at -30°C. React the methane at -30°C for 1 h, then stop the reaction, quench the reaction with 10 mL of aqueous sodium bicarbonate solution, spin off the organic solvent, extract with EA (10 mL x 2), combine the organic phases and dry, concentrate, and purify the residue by column chromatography (PE:EA = 30:1-10:1) to obtain 230 mg of a white solid, with a yield of 76%. 1 H NMR (500 MHz, DMSO-d6) δ 7.69 (s, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 45.0 Hz, 1H), 4.80 (s, 2H).

[0428] Step 3: Synthesis of Intermediate 3

[0429] Take Intermediate 2 (0.20 g, 0.60 mmol) in a 50 mL reaction flask, add acetonitrile (3 mL), then add tetrabutylammonium azide (0.23 g, 0.78 mmol) at room temperature. React at room temperature for 0.5 h, then stop the reaction, and directly concentrate the reaction liquid and purify by column chromatography to obtain 155 mg of Intermediate 3, with a yield of 75%.

[0430] Step 4: Synthesis of Compound 62

[0431] Intermediate 3 (445 mg, 1.29 mmol), raw material 22 (191 mg, 1.42 mmol), DMSO (3 mL) were weighed into a 25 ml single-necked flask, triethylamine was added at room temperature for 15 min, sodium tert-butoxide (99 mg, 1.03 mmol) was added in batches at room temperature, and the reaction was carried out at room temperature for 1.5 h. Add water, extract with EA, wash with water, dry over sodium sulfate, and column chromatography (100% EA) to obtain 105 mg of light yellow solid, yield: 17%.

[0432] 1H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J = 5.3, 3.3 Hz, 3H), 7.42 (s, 2H), 7.33 - 7.18 (m, 3H), 6.49 (d, J = 1.7 Hz, 1H), 6.05 (s, 2H), 5.52 (s, 2H), 3.98 (s, 3H).

[0433] MS (ESI, pos.ion) m / z: 467.13 [M+H] + .

[0434] HPLC: 95.35%.

[0435] Example 44

[0436] This example is a preparation method of compound 63, and the reaction formula is as follows:

[0437] The above raw material 1 is compound 29, and the preparation method is described in detail in Example 29.

[0438] Raw material 1 (138 mg, 0.3 mmol) was dissolved in DMF (3 mL), sodium hydride (6 mg, 0.15 mmol) was added at 0°C, and the reaction was carried out for 30 min. Methyl iodide (21.3 mg, 0.15 mmol) was added, the reaction was stopped after 30 min, water and ethyl acetate were added for extraction, the liquid was separated, and then concentrated and purified by column chromatography to obtain the product as a white solid 25 mg, yield 18%.

[0439] 1 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.71 - 7.67 (m, 2H), 7.60 (s, 2H), 5.73 (s, 2H), 5.69 (s, 1H), 4.11 (s, 3H), 2.91 (s, 3H).

[0440] MS (ESI, pos.ion) m / z: 475.06 [M+H] + .

[0441] HPLC: 96.88%.

[0442] Example 45

[0443] This example is a preparation method of compound 66, the preparation process is similar to the reaction principle of example 25, and the reaction formula is as follows:

[0444] The characterization results of compound 66 are as follows:

[0445] 1 H NMR (400 MHz, DMSO) δ 7.75 (d, J = 8.5 Hz, 2H), 7.68 (s, 3H), 7.63 (d, J = 8.5 Hz, 2H), 6.75 (s, 2H), 5.60 (s, 2H), 2.53 (s, 3H).

[0446] MS (ESI, pos.ion) m / z: 462.03 [M+H] + .

[0447] HPLC: 98.58%.

[0448] Example 46

[0449] This example is a preparation method of compound 68, the preparation process is similar to example 25, and the reaction formula is as follows:

[0450] The characterization results of compound 68 are as follows:

[0451] 1 H NMR (400 MHz, DMSO) δ 7.73 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.51 (s, 2H), 7.30 (s, 1H), 6.72 (s, 2H), 5.58 (s, 2H), 2.51 (s, 3H).

[0452] MS (ESI, pos.ion) m / z: 488.03 [M+H] + .

[0453] HPLC: 97.58%.

[0454] Example 47

[0455] This example is a preparation method of compound 70, the preparation process is similar to example 25, and the reaction formula is as follows:

[0456] The characterization results of compound 70 are as follows:

[0457] 1H NMR (400 MHz, DMSO-d6) 8.18 (s, 1H), 7.83-7.75 (m, 2H), 7.73-7.66 (m, 2H), 7.55 (s, 2H), 6.05 (s, 2H), 5.56 (s, 2H), 3.95 (s, 3H).

[0458] MS (ESI, pos.ion) m / z: 462.05 [M+H] + .

[0459] HPLC: 97.88%.

[0460] Pharmacodynamic experiment

[0461] I. Anti-tumor pharmacodynamic experiment:

[0462] The above compounds were investigated for significant inhibition of various tumor cells; this experiment was a CCK8 experiment for the above compounds to inhibit the proliferation of A549 cells, A498 cells, MCF-7 cells, and HUH-7 cells.

[0463] A549 (human lung cancer cells), A498 (human kidney cancer cells), MCF-7 (human breast cancer cells), and HUH-7 (human liver cancer cells) were inoculated into 96-well microplates (3000-5000 cells / well), and cultured in a 37°C, 5% CO2 incubator until the cells were 80% confluent, then drug treatment was performed; 100 μL of different concentrations (final concentration of 20, 10, 5, 1, and 0.1 μg / mL) of carboxamide triazole single crystal DMSO solution was added as the test group, and 100 μL of control solution was used for the normal control group; after incubation for 72 hours, 10 μL of CCK8 reagent was added, and after incubation at 37°C for 4 hours, the absorbance of each well was measured using a microplate reader, and the IC50 was calculated.

[0464] II. Anti-inflammatory pharmacodynamic experiment:

[0465] This experiment mainly investigated the effect of the above compounds 1-68 on inflammatory mediator TNF-α. The test method was as follows: LPS-induced RAW264.7 cells: RAW264.7 cells in the logarithmic growth phase were collected, and 1×10 6The cells were seeded in 24-well plates at a density of wells. After the cells adhered, they were divided into a DMSO+blank control (DMEM) group, a DMSO+LPS group, and a compound 1-68+LPS group. LPS (1 μg / ml) was used to induce for 4 h, and then the drugs were added and incubated for 2 h. The supernatant was collected, centrifuged at 2000 x g for 10 min, and the content of TNF-a in the cell-free supernatant was determined using a mouse TNF-a ELISA kit. The inhibition rate (%) of TNF-a was calculated. The intensity of the TNF-a inhibition rate I was divided into different grades, wherein grade A: 0≤I<15%; grade B: 15%≤I<30%; grade C: 30%≤I<60%; and grade D: I≥60%.

[0466] The above in vitro experiments show that the triazole compounds of the present application have good anti-tumor and anti-inflammatory activities, and are expected to be developed into a new generation of anti-tumor and anti-inflammatory drugs.

[0467] III. Pharmacokinetic study

[0468] The rats were randomly divided into groups, with 3 rats in each group. The animals were fasted for 12 h before the experiment and allowed to drink water freely. The solution of the compound prepared in the above examples was prepared using PEG400 and was used for gavage administration to animals before the experiment. The experiment used a continuous blood sampling method. The rats were gavaged, and 200 μL of blood was taken from the orbital venous plexus at 5, 15, 30 min, 1, 2, 4, 8, 12, 24, 36, and 48 h. The blood was placed on ice, centrifuged, and 50 μL of plasma was separated and stored at -20°C. 50 μL of plasma sample was taken at each time point, and the content of the compound in the plasma was determined according to the established analysis method.

[0469] The experimental data were analyzed by non-compartment model, and the plasma pharmacokinetic parameters were calculated using WinNonLin software.

[0470] Experimental results

[0471] The above experimental results show that the exposure amount of compound 25 is the highest, and the AUC(0-∞) thereof is 153855.1 h*ng / mL; the exposure amounts of compound 31, compound 36, compound 41, compound 42, compound 23, compound 18 and compound 40 are relatively high, and the AUC(0-∞) thereof are 117522.5 h*ng / mL, 79236.4 h*ng / mL, 32411.8 h*ng / mL, 31888.2 h*ng / mL, 17542.2 h*ng / mL, 10302.4 h*ng / mL and 10312.6 h*ng / mL, respectively; the exposure amounts of compound 39, compound 2, compound 12a and compound 8 are relatively low, and the AUC(0-∞) thereof are 9784.2 h*ng / mL, 3802.5 h*ng / mL, 1790.7 h*ng / mL and 4391.8 h*ng / mL, respectively; and the blood drug concentrations thereof are shown in FIG. 1, FIG. 2 and FIG. 3.

[0472] The above embodiments are only used to illustrate the technical solutions of the present application but not limit the present application. Although the present application has been described in detail with reference to the above preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the spirit and scope of the present application. Those skilled in the art can also make other changes and the like in the design of the present application within the spirit of the present application, as long as the changes do not deviate from the technical effects of the present application. These changes made in the spirit of the present application should be included in the scope of the present application.

Claims

1. A triazole compound, characterized in that A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, R1, R2, R3, R4, R5, R6, R7, R8 are independently selected from hydrogen, deuterium, halogen, cyano, amino, trifluoromethyl, C 1-6 Alkanoyl, nitro, C 1-6 Alkoxy, carboxyl, alkoxycarbonyl, trifluoromethoxy, acetamido, C 1-6 Alkylenethio, C 1-6- Alkylsulfinyl, C 1-6 Alkylsulfonyl, trichlorovinyl, trifluoromethylthio, trichloromethylsulfinyl or trifluoromethylsulfonyl; substituted or unsubstituted C1-C6 alkyl, wherein the substituent is selected from methyl and heteroatoms; Each R9 is independently selected from hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, sulfinyl, sulfonyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, heterocyclic group composed of 5-10 atoms, C 6-10 Aryl, heteroaryl composed of 5-10 atoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl-C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclic group composed of 5-10 atoms, C 6-10 Aryl and 5-10 atoms of heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Alkylamino or C 1-6 substituted by an alkoxy substituent; R 10 independently selected from hydrogen, halogen, C 1-6 Alkyl, cycloalkyl, alkoxy or cyano; R 11 、R 12 independently selected from hydrogen, cycloalkyl, alkoxy, cyano, substituted or unsubstituted C 1-6 Alkyl, wherein the substituent is selected from halogen and heteroatom; X is independently selected from O, S, SO, SO2, CO, CHCN, substituted or unsubstituted C1-3 alkyl, wherein the substituent group is halogen; CR X , R X It is hydrogen, C 1-3 Alkyl, hydroxyl, C 1-3 Alkoxy, amino, C l-3 Alkylamino, 2-(C 1-3 alkyl)amino or cyano; A ring is C 6-10 Aryl or heteroaryl composed of 5-10 atoms or heterocyclic group composed of 3-10 atoms; n represents the number of substituents R9 on ring A, and is an integer selected from 0 to 5. When n is 0, it means that there is no substituent on ring A.

2. The triazole compound according to claim 1, wherein A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, R1 is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl; R2 is independently selected from hydrogen, deuterium, halogen; substituted or unsubstituted C 1-6 Alkyl; the substituent is halogen; R3 is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkynyl, sulfinyl, sulfonyl, amino, cyano; substituted or unsubstituted sulfur, oxygen, carbonyl, C 1-6 Alkyl; the substituent is selected from methyl, trifluoromethyl, halogen, heteroatom; R4 is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl; the substituent is selected from methyl, heteroatom; R5, R6, R7, and R8 are independently selected from hydrogen, deuterium, and halogen; A ring is C 6-10 Aryl or heteroaryl composed of 5-10 atoms or heterocyclic group composed of 3-10 atoms; Each R9 is independently selected from hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, sulfinyl, sulfonyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, heterocyclic group composed of 5-10 atoms, C 6-10 Aryl, heteroaryl composed of 5-10 atoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl-C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclic group composed of 5-10 atoms, C 6-10 Aryl and 5-10 atoms of heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Alkylamino or C 1-6 substituted by an alkoxy substituent; R 10 independently selected from hydrogen, halogen, C 1-6 an alkyl group, a cycloalkyl group, an alkoxy group or a cyano group; R 11 、R 12 independently selected from hydrogen, cycloalkyl, alkoxy, cyano, C 1-6 alkyl; in Indicates a double bond or a single bond. When it represents a double bond, R 13 are independently selected from N, O, S; when When it represents a single bond, R 13 Independently selected from hydrogen, halogen, and hydroxy.

3. The triazole compound according to claim 1, wherein R1 is independently selected from hydrogen, fluorine, chlorine, bromine, C 1-6 alkyl; R2 is independently selected from hydrogen, fluorine, chlorine, bromine; substituted or substituted C 1-6 Alkyl; the substituent is fluorine, chlorine, or bromine; R3 is independently selected from hydrogen, fluorine, chlorine, bromine, C 1-6 Alkynyl, sulfinyl, sulfonyl, amino, cyano; substituted or unsubstituted sulfur, oxygen, carbonyl, C 1-6 Alkyl; the substituent is selected from methyl, trifluoromethyl, fluorine, chlorine, bromine, sulfur, oxygen, and nitrogen; R4 is independently selected from hydrogen, fluorine, chlorine, bromine; substituted or unsubstituted C 1-6 Alkyl; said substituent is selected from methyl, sulfur, oxygen, nitrogen; R5 is independently selected from hydrogen, fluorine, chlorine, bromine; R6 is independently selected from hydrogen, fluorine, chlorine, bromine; R7 is independently selected from hydrogen, fluorine, chlorine, bromine; R8 is independently selected from hydrogen, fluorine, chlorine, bromine; The A ring is phenyl, naphthyl, quinolyl, purinyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, indolyl, isoindolyl, oxadiazolyl, tetrazolyl, or oxatriazolyl. R 10 independently selected from hydrogen, halogen, C 1-6 Alkyl or cycloalkyl.

4. The triazole compound according to claim 1, wherein R1 is independently selected from hydrogen, methyl, chlorine, bromine, fluorine; R2 is independently selected from hydrogen, trifluoromethyl, chlorine, bromine, fluorine; R3 is independently selected from hydrogen, chlorine, bromine, fluorine; R4 is independently selected from hydrogen, methoxy, fluorine, chlorine, bromine; R5 is independently selected from hydrogen, chlorine, fluorine, bromine; R6 is independently selected from hydrogen, chlorine, fluorine, bromine; R7 is independently selected from hydrogen, chlorine, bromine, fluorine; R8 is independently selected from hydrogen, chlorine, fluorine, bromine; R 10 independently selected from hydrogen, chlorine, fluorine, bromine, C 1-6 Alkyl or cycloalkyl. The A ring is phenyl, pyridyl, pyrimidinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, Wherein "*" indicates connection with a trinitrogen ring.

5. The triazole compound according to claim 1, wherein Each of the R9 is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 Aryl, amino, cyano, amide.

6. The triazole compound according to claim 5, characterized in that Each of the R9 is independently selected from hydrogen, amino, amide, methyl, ethyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluorine, chlorine, bromine and substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted phenyl; the substituent is halogen, cyano, hydroxyl, amino, or deuterium.

7. The triazole compound according to claim 1, characterized in that The compound is selected from any of the following structures: R9a、R 9b independently selected from hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, sulfinyl, sulfonyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, heterocyclic group composed of 5-10 atoms, C 6-10 Aryl, heteroaryl composed of 5-10 atoms, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl-C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclic group composed of 5-10 atoms, C 6-10 Aryl and 5-10 atoms of heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Alkylamino or C 1-6 The alkoxy group is substituted by a substituent; n is an integer selected from 0 to 3. when When it represents a double bond, R 11 is O; when When it represents a single bond, R 11 Independently selected from F, Cl, Br, I.

8. A triazole compound having one of the following structures, or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or at least one of its pharmaceutically acceptable carriers, excipients, adjuvants and vehicles.

10. The pharmaceutical composition according to claim 9, characterized in that The dosage forms of the pharmaceutical composition include injections, tablets, sustained-release tablets, capsules, sustained-release agents, microcapsules, powders, liposomes, granules, ointments, creams, emulsions, suspensions, lyophilized agents, sprays, suppositories, ointments, creams, aerosols, pills or oral solutions.

11. Use of the triazole compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 8 in the preparation of anti-tumor and anti-inflammatory disease drugs; the tumor is selected from at least one of digestive system tumors, genitourinary system tumors, nervous system tumors, circulatory system tumors, respiratory system tumors, breast tumors, skin tumors, and bone tumors; and the inflammatory disease is selected from rheumatoid arthritis, psoriasis, and inflammatory bowel disease.

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