Heteroarylamide CYP1B1 enzyme inhibitor as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a heteroaryl amide derivative and a preparation method thereof, and an application of the heteroaryl amide derivative as a CYP1B1 inhibitor in antitumor drugs. The structure of the compound is shown in general formulas I and II, wherein A, B, C, X, Y, Z, R1, R2, R3, R4, R5, R6, R7 and R8 are defined in the specification. The heteroaryl amide small molecule compounds have an efficient inhibition effect on CYP1B1 enzyme, and IC50 of part of the compounds is less than 1nM; besides, the invention also constructs an efficient and convenient chemical synthesis method of the multi-substituted five-membered ring small molecule compound, and the method has the characteristics of wide substrate adaptability, simple reaction operation, low cost, mild reaction conditions and simple purification method. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to heteroaromatic amide derivatives and preparation methods. The derivatives prepared by the present invention have strong inhibitory activity and high selectivity on the CYP1B1 enzyme. The present invention also relates to the use of the derivatives in preparing anti-tumor drugs with drug resistance caused by the CYP1B1 enzyme, and are used for preparing drugs for treating and / or preventing cancer (lung cancer, breast cancer, colorectal cancer, etc.). Background Art

[0002] Among the cytochrome CYP450 enzymes, the three families responsible for drug metabolism are CYP1, CYP2 and CYP3. Unlike other families, the CYP1 family contains only three members: CYP1A1, CYP1B1 and CYP1A2, of which the sequence similarity between CYP1B1 and CYP1A1 / 1A2 is about 38% and 37%, while the similarity between CYP1A1 and CYP1A2 is more than 72%. Studies have shown that the CYP1B1 enzyme is highly expressed in tumor tissues and cells including breast cancer, kidney cancer and ovarian cancer, but is almost undetectable in normal tissue cells.

[0003] The expression of CYP1 gene is mainly regulated by aryl hydrocarbon receptor (AhR). Polycyclic aromatic hydrocarbon procarcinogens such as tetrachlorodibenzo-p-dioxin (TCDD) and halogenated hydrocarbons can bind to AHR after entering cells, then enter the nucleus to form dimers with aryl hydrocarbon receptor nuclear transporter (ARNT), and then bind to xenobiotic effector elements (XREs) to regulate the expression of CYP1B1 target genes. Overexpressed CYP1B1 further metabolizes and activates polycyclic aromatic hydrocarbons and other substances, promoting the transformation of procarcinogens into carcinogens. It can be inferred that when procarcinogens appear, that is, in the early stage of the lesion, CYP1B1 will be induced to express in cells and the expression level will increase rapidly with the development of the tumor. In addition, many studies have shown that CYP1B1 enzymes participate in the development of drug resistance by accelerating the degradation of several chemotherapy drugs such as paclitaxel and tamoxifen in breast cancer cells. CYP1B1 is not only involved in the occurrence and development of tumors, but also closely related to the drug resistance of tumor cells. The combination of CYP1B1 inhibitor α-naphthoflavone (ANF) can effectively sensitize chemotherapy drugs. CYP1A1 is only specifically expressed in certain tumor tissues, but it still participates in the metabolism of a small amount of drugs. CYP1A2, as the main metabolic enzyme in the liver, is very important for drug metabolism and detoxification. Therefore, when developing inhibitors targeting CYP1B1, it is crucial to study the selectivity of CYP1A1 and CYP1A2.

[0004] In summary, the study of new CYP1B1 inhibitors that are both selective and active is crucial for the clinical treatment of cancer patients and reversing multidrug resistance to chemotherapy drugs. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides a novel heteroaromatic amide derivative, as well as a preparation method of the derivative and the use of the derivative as a CYP1B1 enzyme inhibitor in anti-tumor drugs.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is:

[0007] The present invention provides heteroaromatic amide derivatives having CYP1B1 enzyme inhibitory effect, and the structural formulas of the derivatives are shown in the following general formulas I and II.

[0008]

[0009] wherein said A, B, C, X, Y or Z is selected from C, N, NH or S;

[0010] The R1, R2, R3, R4, R5, R6, R7, and R8 are selected from hydrogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C 1- C6 alkyl, substituted or unsubstituted C 3- C7 cycloalkyl, substituted or unsubstituted C2-C6 olefin, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, etc.; the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, nitro, hydroxyl, amino, alkoxy, alkyl, ester, amide, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, trifluoroacetyl, trifluoromethanesulfonyl, cycloalkyl, olefin, alkynyl, aryl, heteroaryl, etc.;

[0011] The halogen is fluorine, chlorine, bromine or iodine; alkyl refers to a straight-chain or branched alkyl; alkoxy refers to an oxygen-containing straight-chain or branched alkoxy; alkylene refers to a straight-chain or branched alkylene; aryl refers to a phenyl or naphthyl group with no substituent or with a substituent; heteroaryl refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, and S; the ring system is aromatic, such as imidazolyl, benzimidazolyl, pyridyl, pyrrolyl, pyrazolyl, furanyl, thienyl, thiazolyl, benzothiazolyl, oxazolyl, benzoxazolyl, quinolyl, and the like.

[0012] The preparation methods of heteroaromatic amide derivatives of the general formula I and II are shown in the following routes A, B, C, D, E and F.

[0013] Route A:

[0014]

[0015] Route B:

[0016]

[0017] Route C:

[0018]

[0019] Route D:

[0020]

[0021] Route E:

[0022]

[0023] Route F:

[0024]

[0025] Route G:

[0026]

[0027] Route H:

[0028]

[0029] The reaction steps using route A are as follows:

[0030] (1) Preparation of intermediate A-2: A-2 is obtained by reacting aldehydes with different substitutions with sodium p-toluenesulfinate in the presence of an alkaline reagent and an acid reagent. The reaction solvent is selected from one of triethylamine, ethylenediamine, acetamide, and formamide. The acid is selected from one or more of hydrochloric acid, formic acid, acetic acid, propionic acid, sulfuric acid, p-toluenesulfonic acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid. The amount of the acid is 1.0-8.0 times (M / M molar ratio) of the amount of sodium p-toluenesulfinate. The reaction temperature is 30-100° C. and the reaction time is 5-24 h.

[0031] (2) Preparation of intermediate A-3: A-2 is reacted with phosphorus oxychloride under alkaline reagent conditions to obtain A-3, wherein the base is selected from one or more of triethylamine, ethylenediamine, acetamide, and formamide; the amount of the base used is 1.0-4.0 times the amount of phosphorus oxychloride used (M / M molar ratio), the reaction temperature is -10-40°C, and the reaction time is 0.5-5h;

[0032] (3) Preparation of intermediate A-5: A-3 and A-4 react under the action of a strong base to obtain compound A-5, the base reagent selected is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium bicarbonate, sodium methoxide, potassium tert-butoxide, potassium phosphate, and the amount of the base reagent is 1.0-8.0 times the amount of A-4 (M / M molar ratio); the solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, acetone, dimethylformamide, propylene glycol; the reaction temperature is 30-100°C, and the reaction time is 1-12h;

[0033] (4) Preparation of intermediate A-6: A-5 is hydrolyzed under acidic or alkaline conditions, and the acid catalyst selected is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, etc.; the base catalyst selected is one or more of sodium hydroxide, potassium hydroxide, etc.; the amount of the alkaline reagent used is 1.0-5.0 times the amount of A-5 (M / M molar ratio); the solvent is one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, water; the reaction temperature is 30-100°C, and the reaction time is 1-12h;

[0034] (5) Preparation of A-Ⅰ: A-6 is reacted with different substituted amines to form amides to obtain A-Ⅰ. The reaction reagents used are oxalyl chloride, N,N-dimethylformamide, dichlorothionyl, carbonyldiimidazole (CDI), methanesulfonyl chloride (MsCl), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-N,N-dimethylpyridine (DMAP). , O-(7-azabenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), etc.; the solvent is one or more of dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide; the reaction temperature is 0-100°C, and the reaction time is 1-12h.

[0035] The reaction steps using route B are as follows:

[0036] (1) Preparation of intermediate B-2: B-1 is reacted with amines of different substitutions to form amides to obtain B-2. The specific steps are the same as step (5) in route A.

[0037] (2) Preparation of B-Ⅰ: B-2 is coupled with differently substituted boronic acids or boronic esters to obtain B-Ⅰ. The coupling catalyst selected is tetrakis(triphenylphosphine)palladium, palladium acetate, diphenylphosphinocene palladium dichloride, ditriphenylphosphine palladium dichloro, di(tri-tert-butylphosphine)palladium, etc.; the alkaline reagent selected is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, potassium tert-butoxide, potassium phosphate, etc.; the amount of differently substituted boronic acids or boronic esters used is 1.0-4.0 times the amount of B-2 (M / M molar ratio); the solvent is one or more of water, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, dimethyl sulfoxide, etc.; the reaction temperature is 80-150°C, and the reaction time is 1-12h.

[0038] The reaction steps using route C are as follows:

[0039] (1) Preparation of intermediate C-2: C-1 and C-2 undergo a cyclization reaction and then add an alkaline reagent for hydrolysis to obtain C-3. The alkaline reagent selected is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, potassium tert-butoxide, 1,8-diazabicycloundec-7-ene, and potassium phosphate. The solvent is one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, dimethyl sulfoxide, etc. The reaction temperature is 50-100°C and the reaction time is 1-24h.

[0040] (2) Preparation of C-Ⅰ: C-3 is reacted with an amine to obtain C-Ⅰ. The specific steps are the same as step (5) in route A.

[0041] The reaction steps using route D are as follows:

[0042] (1) Preparation of intermediate D-2: D-1 is subjected to a cyclization reaction with thiooxamic acid and then an alkaline reagent is added for hydrolysis to obtain D-2. The specific steps are the same as step (1) in route C;

[0043] (2) Preparation of D-Ⅱ: D-2 is reacted with an amine to obtain D-Ⅱ, and the specific steps are the same as step (5) in route A.

[0044] The reaction steps using route E are as follows:

[0045] (1) Preparation of intermediate E-2: E-1 is reacted with an amine to obtain E-2, and the specific steps are the same as step (5) in route A;

[0046] (2) Preparation of E-Ⅱ: E-2 is coupled with different substituted boronic acids or boronic esters to obtain E-Ⅱ. The specific steps are the same as step (2) in route B.

[0047] The reaction steps using route F are as follows:

[0048] (1) Preparation of intermediate F-2: F-1 is reacted with an amine to obtain F-2, and the specific steps are the same as step (5) in route A;

[0049] (2) Preparation of F-Ⅱ: F-2 is coupled with different substituted boronic acids or boronic esters to obtain E-Ⅱ. The specific steps are the same as step (2) in route B.

[0050] The reaction steps using route G are as follows:

[0051] (1) Preparation of intermediate G-2: G-1 is reacted with trimethylsilyl bromide to obtain G-2. The solvent used is one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, dimethyl sulfoxide, etc. The reaction temperature is 0-100°C and the reaction time is 1-24h.

[0052] (2) Preparation of intermediate G-3: G-2 is oxidized to G-3, and the oxidant selected is one of Dess-Martin reagent, manganese dioxide, hydrogen peroxide, oxygen, pyridinium dichromate, pyridinium chlorochromate, diacetate iodobenzene, sodium hypochlorite, iodine, dichloroiodobenzene, etc.; the catalyst is selected from tetraacetonitrile copper hexafluorophosphate, tetra(acetonitrile)tetrafluoroborate copper (I), (2,2,6,6-tetramethylpiperidin-1-yl)oxyl free radical, 4-acetylamino-2,2,6,6-tetramethylpiperidin-1-oxyl free radical, etc.; the molar amount of the oxidant is 1.0-6.0 times that of compound 3; the reaction solvent is acetonitrile, tetrahydrofuran, dichloromethane, acetone, dioxane, toluene, dimethylformamide, etc. or a mixture of two or more thereof; the reaction temperature is 0°C-80°C, and the reaction time is 1-12h.

[0053] (3) Preparation of intermediate G-4: G-3 is subjected to cyclization reaction with ethyl thiooxamate and then an alkali reagent is added for hydrolysis to obtain G-4. The specific steps are the same as step (1) in route C.

[0054] (4) Preparation of intermediate G-II: G-4 is reacted with amine to obtain G-II. The specific steps are the same as step (5) in route A.

[0055] The reaction steps using route H are as follows:

[0056] (1) Preparation of intermediate H-2: H-1 is hydrolyzed under acidic or alkaline conditions to obtain H-2, and the specific steps are the same as step (4) in route A;

[0057] (2) Preparation of intermediate H-3: H-2 is reacted with an amine to obtain H-3, and the specific steps are the same as step (5) in route A;

[0058] (3) Preparation of intermediate H-Ⅱ: H-3 is coupled with boronic acids or boronic esters of different substitutions to obtain H-Ⅱ. The specific steps are the same as step (2) in route B.

[0059] Beneficial effects of the present invention:

[0060] The novel heteroaromatic amide derivatives described in the present invention have potent inhibitory activity and high selectivity against CYP1B1 enzymes. When used in combination with other commonly used clinical anti-tumor drugs, they can increase the sensitivity of commonly used clinical anti-tumor drugs and achieve the effect of reversing drug resistance. They can be used to prepare drugs for treating and / or preventing cancer (lung cancer, breast cancer, colorectal cancer, etc.). DETAILED DESCRIPTION

[0061] The present invention will be further described in detail below in conjunction with embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several changes and improvements can also be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0062] All chemicals and solvents were from commercial suppliers and used as received. All reagents were analytically pure or chemically pure. Unless otherwise specified, all reagents were not purified. NMR measurements were performed using a Bruker Avance III-600 NMR spectrometer, TMS was used as the internal standard, and the test solvent was DMSO-d6 or CDCl3.

[0063] Table 1

[0064]

[0065]

[0066]

[0067] The following describes the process for synthesizing the above 170 compounds, wherein Examples 1-15 are prepared using Route A, Examples 16-17 are prepared using Route B, Examples 18-114 are prepared using Route D, Examples 115-132 are prepared using Route E, Examples 133-158 are prepared using Route C, Example 159 is prepared using Route F, Examples 160-167 are prepared using Route G, and Examples 168-170 are prepared using Route H.

[0068] The experimental steps for preparing Route A of Examples 1-15 (Scheme A) are as follows:

[0069] (1) Different substituted aldehydes, sodium p-toluenesulfinate, formic acid and formamide are added to a reaction flask and reacted at 40°C to 90°C for 8 to 16 hours. After the reaction is complete, a large amount of solids are precipitated, which are filtered to obtain intermediate A-2. The molar ratio of the reactants is sodium p-toluenesulfinate: substituted aldehyde: formic acid: formamide = 1: 2-5: 2-5: 4-8.

[0070] (2) Add A-2 and phosphorus oxychloride to a reaction flask, add a solvent, dropwise add an alkaline reagent triethylamine, react at 0°C to 30°C for 0.5 to 3 hours, after the reaction is complete, add water to quench, extract with ethyl acetate, concentrate the organic layer under reduced pressure to obtain a yellow solid, and slurry with ethanol to obtain A-3. The molar ratio of the reactants is A-2:phosphorus oxychloride:triethylamine=1:2-5:2-6.

[0071] (3) Add A-3 and A-4 to a reaction flask, add a solvent, and then add sodium hydride in batches to react at 0°C to 40°C for 0.5 to 2 hours. After the reaction is complete, add water to quench, and a large amount of solid precipitates. The crude product is filtered to obtain a slurry with a mixed solvent of ethyl acetate and petroleum ether to obtain A-5. The molar ratio of the reactants is A-3: A-4: sodium hydride = 1: 1: 1-6.

[0072] (4) A-5 is added to a reaction flask, and after adding a solvent to dissolve, sodium hydroxide is added, and the reaction is carried out at 40°C to 90°C for 1 to 12 hours. After the reaction is complete, the solvent is concentrated under reduced pressure to obtain a solid, and water is added and stirred until the solid is dissolved. The pH is adjusted to be acidic, a large amount of solid is precipitated, and a crude product is obtained by suction filtration, and ethanol is used to slurry to obtain A-6. The molar ratio of the reactants is A-5: sodium hydroxide = 1: 1-5.

[0073] (5) After A-6 is dissolved in a solvent, oxalyl chloride is added, and the reaction is carried out for 0.5 to 2 hours. After the reaction is complete, the mixture is concentrated under reduced pressure, and then a solvent is added, and different substituted amines are added, and the reaction is carried out at room temperature to 60°C for 1 to 8 hours. After the reaction is complete, extraction is performed, and A-I is obtained by separation and purification. The molar ratio of the reactants is A-6: oxalyl chloride: substituted amine = 1: 1-5: 0.9-1.5.

[0074] The structures of the compounds of Examples 1-15 are shown in Table 1.

[0075] Example 1 was synthesized according to process A to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ11.57(s,1H),9.35(s,1H),7.73(ddd,J=16.7,8.4,1.3Hz,4H),7.48–7.39(m,3H), 7.35–7.30(m,2H),7.26–7.20(m,1H),7.05(td,J=7.3,3.7Hz,1H),3.78(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 16 N2O2Na,315.1109; found,315.1114.

[0076] Example 2 was synthesized according to process A to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.65–11.62(m,1H),9.69(s,1H),7.87(d,J=1.9Hz,2H),7.74(dd,J=8.0,1.3Hz,2H ),7.46(d,J=3.8Hz,1H),7.42(t,J=7.7Hz,2H),7.27–7.20(m,2H),3.77(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcd forHRMS(ESI-TOF)m / z:[M+Na]+calcd for C 18 H 14 N2O2Cl2Na,383.0433; found,383.0440.

[0077] Example 3 was synthesized according to process A to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ11.65(d,J=4.6Hz,1H),9.72(s,1H),7.77–7.72(m,2H),7.56–7.50(m,2H),7.4 7–7.40(m,3H),7.26–7.20(m,1H),6.88(tt,J=9.3,2.4Hz,1H),3.77(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 18 H 14 N2O2F2Na,351.0921; found,351.0928.

[0078] Example 4 was synthesized according to process A to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ11.40(s,1H),9.35(s,1H),7.73–7.65(m,3H),7.42(d,J=3.7Hz,1H),7.38(ddd,J=11.5,9.3,2.6Hz ,1H),7.32(dd,J=8.4,7.3Hz,2H),7.20(td,J=8.5,2.4Hz,1H),7.08–7.02(m,1H),3.72(s,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 14 N2O2F2Na,351.0921; found,351.0925.

[0079] Example 5 was synthesized according to process A to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.65(d,J=4.6Hz,1H),9.66(s,1H),8.54(d,J=8.9Hz,1H),7.72–7.64(m,2H),7. 45(dd,J=8.9,2.5Hz,1H),7.44–7.38(m,2H),7.25–7.19(m,1H),3.68(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 12 N2O2F2Cl2Na,419.0235; found,419.0231.

[0080] Example 6 was synthesized according to process A to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ11.23(s,0H),10.26(s,0H),9.35–9.31(m,0H),8.34–8.27(m,0H),7.97(d,J=8.5Hz,0H) ,7.93(d,J=2.8Hz,0H),7.68–7.61(m,1H),7.59(dd,J=8.6,2.5Hz,0H),4.29(s,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 12 N2O2F2Cl2Na,419.0235; found,419.0238.

[0081] Example 7 was synthesized according to process A to obtain a white solid.1 H NMR (600MHz, DMSO-d6) δ11.47(d,J=3.8Hz,1H),9.70(s,1H),7.87(d,J=1.9Hz,2H),7.68(td,J=8.7,6.6Hz,1H),7.50(d,J=3.7Hz,1 H),7.36(ddd,J=11.4,9.2,2.6Hz,1H),7.23(q,J=1.6Hz,1H),7.19(td,J=8.5,2.6Hz,1H),3.71(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 12 N2O2F2Cl2Na,419.0235; found,419.0231.

[0082] Example 8 was synthesized according to process A to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.55(d,J=4.3Hz,1H),9.67(s,1H),8.17–8.13(m,1H),7.69(td,J=8.6,6.5Hz,1H),7.41(ddd,J=10.4,9.3,2.6Hz,1H),7.3 4–7.30(m,1H),7.26–7.19(m,1H),7.00–6.96(m,1H),6.61–6.56(m,1H),3 .87(d,J=0.7Hz,3H),3.71(s,3H),3.67(s,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 20 H 18 N2O4F2Na,411.1234; found,411.1237.

[0083] Example 9 was synthesized according to process A to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ11.48(d,J=4.5Hz,1H),9.43(s,1H),8.29(d,J=8.8Hz,1H),7.69(td,J=8.6,6.5Hz,1H),7.40(ddd,J=11.3,9.4,2.6Hz,1 H),7.29(d,J=3.6Hz,1H),6.67(d,J=2.9Hz,1H),6.52(dd,J=8.9,2.6Hz,1H),3.90(s,3H),3.75(s,3H),3.66(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 20 H 18 N2O4F2Na,411.1234; found,411.1238.

[0084] Example 10 was synthesized according to process A to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.41(d,J=3.6Hz,1H),9.30(s,1H),7.68(td,J=8.7,6.6Hz,1H),7.42(d,J=3.7Hz,1H),7.37(ddd,J=11.0,9.3,2 .6Hz,1H),7.19(td,J=8.4,2.3Hz,1H),7.00(d,J=2.3Hz,2H),6.22(t,J=2.3Hz,1H),3.73(s,6H),3.71(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 20 H 18 N2O4F2Na,411.1234; found,411.1240.

[0085] Example 11 was synthesized according to process A to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.64(s,1H),9.69(s,1H),7.87(d,J=1.9Hz,2H),7.76–7.72(m ,2H),7.47(d,J=3.8Hz,1H),7.44–7.40(m,2H),3.77(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 19 H 13 N3O2F2Na,376.0970; found,376.0972.

[0086] Example 12 was synthesized according to process A to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ11.48–11.45(m,1H),9.56(s,1H),7.84–7.79(m,2H),7.74(td,J=8.7,6.6Hz,1H ),7.49(d,J=3.7Hz,1H),7.47–7.40(m,3H),7.29–7.23(m,1H),3.77(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 18 H 13 N2O2F2ClNa,385.0631; found,385.0636.

[0087] Example 13 was synthesized according to process A to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.42–11.39(m,1H),9.46(s,1H),7.72–7.62(m,3H),7.59–7.55(m,2H),7.43(d,J= 3.7Hz,1H),7.37(ddd,J=11.4,9.3,2.6Hz,1H),7.23–7.17(m,1H),3.70(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 13 N2O2F2INa,476.9990; found,476.9989.

[0088] Example 14 was synthesized according to process A to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ11.25(s,1H),7.95(t,J=6.1Hz,1H),7.66(td,J=8.7,6.6Hz,1H),7.39–7.29(m,5H),7 .28–7.21(m,2H),7.18(td,J=8.3,2.3Hz,1H),4.46(d,J=6.1Hz,2H),3.62(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 19 H 16 N2O2F2Na,365.1078; found,365.1076.

[0089] Example 15 was synthesized according to process A to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.16(s,1H),9.77(s,2H),8.37–8.23(m,2H),8.02–7.95(m,4H),7.90(t,J= 1.9Hz,2H),7.68–7.58(m,4H),7.16(tt,J=9.2,2.4Hz,2H),4.29(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 18 H 12 N2O2F4Na,387.0834; found,387.0838.

[0090] The experimental steps for preparing Route B of Examples 16-17 (Scheme B) are as follows:

[0091] (1) After B-1 is dissolved in a solvent, oxalyl chloride is added, and the reaction is carried out for 0.5 to 2 hours. After the reaction is complete, the mixture is concentrated under reduced pressure, and then a solvent is added, and aniline is added. The mixture is reacted at room temperature to 60° C. for 1 to 8 hours. After the reaction is complete, the mixture is extracted, separated and purified to obtain B-2. The molar ratio of the reactants is B-1: oxalyl chloride: aniline = 1: 1-5: 0.9-1.1.

[0092] (2) Add B-2, phenylboronic acid and potassium carbonate to a reaction flask, add a solvent, then add a palladium catalyst, stir under a nitrogen atmosphere, react at 80°C to 110°C for 1 to 10 hours, and after the reaction is complete, filter, extract, separate and purify to obtain B-I. The molar ratio of the reactants is B-2: phenylboronic acid: potassium carbonate: palladium catalyst = 1: 2: 1-5: 0.01-0.2.

[0093] Example 16 was synthesized according to process B to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.83(s,1H),9.58(s,1H),7.78–7.74(m,2H),7.73–7.60(m,3H),7.40(t,J=7.8Hz,2H),7. 34–7.29(m,2H),7.23(td,J=7.3,1.3Hz,1H),7.10(t,J=2.2Hz,1H),7.06–7.01(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 14 N2ONa,285.1004; found,285.1010.

[0094] Example 17 was synthesized according to process B to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.27(s,1H),8.49(d,J=1.5Hz,1H),8.19(d,J=1.4Hz,1H),7.75(ddt,J=6.3,5.1,1.3Hz,4H ),7.48(t,J=7.8Hz,2H),7.37(dtd,J=14.1,7.3,1.6Hz,3H),7.13(tt,J=7.3,1.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 13 NONaS,302.0616; found,302.0616.

[0095] The experimental procedure for preparing Route D of Examples 18-114 (Scheme D) is as follows:

[0096] (1) D-1 and ethyl thiooxamate are added to a reaction flask, and a solvent is added. The reaction is carried out at 50°C to 100°C for 1 to 10 hours. After the reaction is complete, sodium hydroxide is added and the reaction is continued for 2 to 6 hours. After the reaction is complete, the solvent is concentrated under reduced pressure to obtain a solid, and water is added and stirred until the solid is dissolved. The pH is adjusted to be acidic, and a large amount of solid is precipitated. The crude product is filtered and slurried with ethanol to obtain D-2. The molar ratio of the reactants is D-1:ethyl thiooxamate:sodium hydroxide = 1:1-1.5:1-5.

[0097] (2) After D-2 is dissolved in a solvent, oxalyl chloride is added, and the reaction is carried out for 0.5 to 2 hours. After the reaction is complete, the mixture is concentrated under reduced pressure, and then a solvent is added. Different substituted amines are added, and the reaction is carried out at room temperature to 60° C. for 1 to 8 hours. After the reaction is complete, extraction is performed, and separation and purification are performed to obtain D-II. The molar ratio of the reactants is D-2: oxalyl chloride: substituted amine = 1: 1-5: 0.9-1.5.

[0098] Example 18 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.62(s,1H),8.51(s,1H),8.20–8.16(m,2H),7.90–7.86(m,2H),7.52(t, J=7.7Hz,2H),7.42(dt,J=8.6,7.5Hz,3H),7.18(tt,J=7.3,1.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H 12N2ONaS,303.0568; found,303.0574.

[0099] Example 19 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.51(s,1H),8.51(s,1H),8.20–8.16(m,2H),7.52(dd,J=8.3,7.1Hz,2H),7. 45–7.39(m,1H),7.20(d,J=2.3Hz,2H),6.33(t,J=2.3Hz,1H),3.77(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 18 H 16 N2O3NaS,363.0779; found,363.0779.

[0100] Example 20 was synthesized according to Scheme D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.48(s,1H),8.49(s,1H),8.20–8.15(m,2H),7.55(d,J=2.4Hz,1H),7.54–7.46 (m,3H),7.45–7.39(m,1H),6.98(d,J=8.7Hz,1H),3.79(s,3H),3.77(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 18 H 16 N2O3NaS,363.0779; found,363.0773.

[0101] Example 21 was synthesized according to Scheme D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.48(s,1H),8.49(s,1H),8.20–8.15(m,2H),7.56(d,J=2.4Hz,1H),7.53–7.4 7(m,3H),7.45–7.40(m,1H),6.98(d,J=8.7Hz,1H),3.78(d,J=13.1Hz,6H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 18 H 16 N2O3NaS,363.0779; found,363.0780.

[0102] Example 22 was synthesized according to Scheme D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ9.78(s,1H),8.46(s,1H),8.18–8.14(m,2H),7.50(t,J=7.7Hz,2H),7.44– 7.38(m,1H),7.30(t,J=8.4Hz,1H),6.75(d,J=8.5Hz,2H),3.76(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 18 H 16 N2O3NaS,363.0779; found,363.0783.

[0103] Example 23 was synthesized according to Scheme D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ9.73(s,1H),8.50(s,1H),8.10–8.06(m,2H),7.95(d,J=8.7Hz,1H),7.52(t,J=7.7Hz,2H),7.46 –7.40(m,1H),6.73(d,J=2.6Hz,1H),6.60(dd,J=8.8,2.7Hz,1H),3.92(s,3H),3.79(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 16 N2O3NaS,363.0779; found,363.0784.

[0104] Example 24 was synthesized according to Scheme D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.50(s,1H),8.51(s,1H),8.20–8.16(m,2H),7.52(dd,J=8.3,7.1H z,2H),7.46–7.39(m,1H),7.36(s,2H),3.80(s,6H),3.67(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 19 H 18 N2O4NaS,393.0885; found,393.0884.

[0105] Example 25 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ9.24(t,J=6.3Hz,1H),8.43(s,1H),8.13–8.08(m,2H),7.49(dd,J=8.4,7.1Hz,2H),7.43–7.37(m ,1H),6.96–6.91(m,1H),6.84–6.79(m,2H),4.49(d,J=6.2Hz,2H),3.80(s,3H),3.67(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 19 H 18 N2O3NaS,377.0936; found,377.0932.

[0106] Example 26 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ9.43(t,J=6.4Hz,1H),8.42(s,1H),8.12–8.07(m,2H),7.49(dd,J=8.4,7.1Hz,2H),7.43–7.3 7(m,1H),6.53(d,J=2.3Hz,2H),6.41(t,J=2.3Hz,1H),4.45(d,J=6.4Hz,2H),3.73(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 19 H 18 N2O3NaS,377.0936; found,377.0937.

[0107] Example 27 was synthesized according to Scheme D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ9.86(s,1H),8.53(s,1H),8.19(dd,J=7.9,1.6Hz,1H),8.07(d,J=8.1Hz,1H),7.53(t,J=7.6 Hz,2H),7.47–7.41(m,1H),7.23–7.14(m,2H),7.03(td,J=7.5,1.5Hz,1H),3.96(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 14 N2O2NaS,333.0674; found,333.0677.

[0108] Example 28 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.53(s,1H),8.48(s,1H),8.19–8.15(m,2H),7.81–7.75(m,2H),7.51(dd ,J=8.3,7.1Hz,2H),7.45–7.39(m,1H),7.01–6.95(m,2H),3.77(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 14 N2O2NaS,333.0674; found,333.0679.

[0109] Example 29 was synthesized according to Scheme D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.90(s,1H),8.55(s,1H),8.19–8.15(m,2H),8.04(d,J= 1.9Hz,2H),7.52(t,J=7.7Hz,2H),7.46–7.39(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 10 N2ONaSCl2,370.9789; found,370.9782.

[0110] Example 30 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.35(s,1H),8.55(s,1H),8.13–8.08(m,3H),7.64(d,J=8.6Hz,1H),7. 52(t,J=7.7Hz,2H),7.45–7.40(m,1H),7.35(dd,J=8.6,2.5Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H 10 N2ONaSCl2,370.9789; found,370.9786.

[0111] Example 31 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.36(d,J=8.4Hz,1H),8.55(s,1H),8.11(d,J=7.6Hz,2H),7.98 (d,J=8.7Hz,1H),7.78(s,1H),7.47(dt,J=55.4,7.6Hz,4H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 10 N2ONaSCl2,370.9789; found,370.9786.

[0112] Example 32 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ9.56(t,J=6.3Hz,1H),8.45(s,1H),8.12–8.08(m,2H),7.53 –7.47(m,3H),7.45–7.38(m,3H),4.53(d,J=6.3Hz,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 12 N2ONaSCl2,384.9945; found,384.9945.

[0113] Example 33 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.71(s,1H),8.53(s,1H),8.20–8.15(m,2H),7.68(t,J=1.8Hz,1H),7.5 6–7.46(m,3H),7.46–7.38(m,1H),6.85(t,J=2.1Hz,1H),3.81(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 13 N2O2NaSCl,367.0284; found,367.0287.

[0114] Example 34 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.44(s,1H),8.53(s,1H),8.17–8.12(m,2H),7.77(td,J=7.8,1.7Hz,1H),7.52(dd,J= 8.4,7.1Hz,2H),7.47–7.38(m,1H),7.40–7.30(m,2H),7.28(td,J=7.6,1.7Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 11 N2ONaSF,321.0474; found,321.0476.

[0115] Example 35 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.80(s,1H),8.53(s,1H),8.20–8.15(m,2H),7.82(dt,J=11.6,2.3Hz,1H),7.7 5–7.71(m,1H),7.52(t,J=7.7Hz,2H),7.48–7.40(m,2H),7.04–6.98(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H 11 N2ONaSF,321.0474; found,321.0470.

[0116] Example 36 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.71(s,1H),8.51(s,1H),8.19–8.15(m,2H),7.93–7.88(m,2H) ,7.52(t,J=7.7Hz,2H),7.45–7.40(m,1H),7.29–7.22(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 11 N2ONaSF,321.0474; found,321.0477.

[0117] Example 37 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.95(s,1H),8.51(s,1H),8.16–8.14(m,2H),7.67(d,J=7.3Hz,1H ),7.52(t,J=7.7Hz,2H),7.45–7.40(m,1H),7.04–6.96(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 10 N2OF2NaS,339.0380; found,339.0375.

[0118] Example 38 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ9.53(t,J=6.4Hz,1H),8.44(s,1H),8.12–8.07(m,2H),7.49(dd,J=8.4,7.0Hz,2H), 7.43–7.36(m,2H),7.23–7.16(m,2H),7.13–7.07(m,1H),4.54(d,J=6.3Hz,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 13 N2ONaSF,335.0630; found,335.0630.

[0119] Example 39 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.79(s,1H),8.53(s,1H),8.20–8.16(m,2H),8.05(t,J=2.1Hz,1H),7.88(ddd,J=8.2,2.1,0.9Hz, 1H),7.52(dd,J=8.3,7.1Hz,2H),7.44(q,J=7.6,7.1Hz,2H),7.24(ddd,J=8.0,2.1,0.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 11 N2ONaSCl,337.0178; found,337.0175.

[0120] Example 40 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.77(s,1H),8.52(s,1H),8.20–8.15(m,2H),7.96–7.90(m,2H) ,7.52(t,J=7.7Hz,2H),7.49–7.46(m,2H),7.44–7.41(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 11 N2ONaSCl,337.0178; found,337.0180.

[0121] Example 41 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.26(s,1H),8.57(s,1H),8.16–8.12(m,2H),7.97(dd,J=7.9,1.4Hz,1H),7.93(dd,J= 8.1,1.5Hz,1H),7.55–7.45(m,3H),7.46–7.40(m,1H),7.06(td,J=7.6,1.6Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 11 N2ONaSI,428.9534; found,428.9535.

[0122] Example 42 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.70(s,1H),8.53(s,1H),8.33(t,J=1.9Hz,1H),8.20–8.16(m,2H),7.94(dd,J= 8.3,2.1Hz,1H),7.56–7.49(m,3H),7.45–7.40(m,1H),7.21(t,J=8.0Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H 11 N2ONaSI,428.9534; found,428.9533.

[0123] Example 43 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.72(s,1H),8.52(s,1H),8.19–8.15(m,2H),7.78–7. 71(m,4H),7.51(t,J=7.7Hz,2H),7.45–7.39(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 11 N2ONaSI,428.9534; found,428.9539.

[0124] Example 44 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),8.56(s,1H),8.19–8.15(m,2H),8.13–8.08(m,2H),7. 91–7.86(m,2H),7.52(dd,J=8.3,7.1Hz,2H),7.46–7.37(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N3ONaS,328.0521; found,328.0517.

[0125] Example 45 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.80(s,1H),8.53(s,1H),8.20–8.16(m,2H),7.99–7.87(m,4H) ),7.52(t,J=7.6Hz,2H),7.43(t,J=7.3Hz,1H),7.32(s,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 13 N3O2NaS,346.0626; found,346.0629.

[0126] Example 46 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ9.83(s,1H),8.55(s,1H),8.09–8.04(m,2H),8.03–7.99(m,2H),7.94(d,J=8.3Hz,1 H),7.53(d,J=7.6Hz,1H),7.51(d,J=3.3Hz,1H),7.45–7.42(m,1H),3.95(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 13 N2O2NaSI,458.9640; found,458.9645.

[0127] Example 47 was synthesized according to Scheme D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.72(s,1H),8.51(s,1H),8.19–8.15(m,2H),7.94–7.88(m,2H),7.54–7.4 9(m,2H),7.45–7.39(m,1H),7.26–7.22(m,2H),7.22(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 12 N2O2NaSF2,369.0485; found,369.0486.

[0128] Example 48 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.82(s,1H),8.53(s,1H),8.19–8.15(m,2H),8.03–7.98(m ,2H),7.52(t,J=7.6Hz,2H),7.43(dd,J=8.2,4.0Hz,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2O2NaSF3,387.0391; found,387.0394.

[0129] Example 49 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.83(s,1H),8.53(s,1H),8.20–8.16(m,2H),8.03(d,J=8.3Hz,2H),7.67–7.6 0(m,2H),7.52(t,J=7.7Hz,2H),7.46–7.37(m,1H),7.03(t,J=56.1Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 12 N2OF2NaS,353.0536; found,353.0541.

[0130] Example 50 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.95(s,1H),8.55(s,1H),8.21–8.17(m,2H),8.14(d,J=8.4Hz,2H) ,7.79(d,J=8.5Hz,2H),7.53(t,J=7.7Hz,2H),7.46–7.38(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2OF3NaS,371.0442; found,371.0446.

[0131] Example 51 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.81(s,1H),8.53(s,1H),8.27(s,1H),8.19(d,2H),8.04(d,2H),7.76(s,1H ),7.74–7.69(m,2H),7.53(t,J=7.6Hz,2H),7.46–7.41(m,1H),7.13(s,1H).HRMS(ESI-TOF)m / z:[M+H] + calcdforC 19 H 15 N4OS,347.0967; found,347.0970.

[0132] Example 52 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.66(s,1H),8.50(s,1H),8.19–8.14(m,2H),7.88–7.83(m,2H),7.77(t,J=1.1Hz,1H),7.51(t,J=7.7Hz ,2H),7.45–7.39(m,1H),7.33–7.28(m,2H),7.21(d,J=1.3Hz,1H),6.92(t,J=1.1Hz,1H),5.19(s,2H).HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 20 H 17 N4OS,361.1123; found,361.1123.

[0133] Example 53 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.49(s,1H),8.49(s,1H),8.20–8.15(m,2H),7.77–7.73(m,2H),7.51(t,J=7.7Hz, 2H),7.45–7.39(m,1H),7.03–6.98(m,2H),3.28–3.23(m,4H),3.08–3.04(m,4H).HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 20 H 21 N4OS,365.1436; found,365.1440.

[0134] Example 54 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.46(s,1H),8.47(s,1H),8.19–8.15(m,2H),7.77–7.71(m,2H),7.51(t,J=7.7Hz, 2H),7.45–7.39(m,1H),7.00–6.96(m,2H),3.77–3.72(m,4H),3.13–3.08(m,4H).HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 20 H 20 N3O2S,366.1276; found,366.1277.

[0135] Example 55 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.54(s,1H),8.49(s,1H),8.18–8.14(m,2H),7.54–7.48(m,3H),7.44–7.39 (m,1H),7.34(dd,J=8.4,2.1Hz,1H),6.95(d,J=8.4Hz,1H),6.04(s,2H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 12 N2O3NaS,347.0466; found,347.0470.

[0136] Example 56 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ11.05(s,1H),8.97(dd,J=4.1,1.6Hz,1H),8.55(s,1H ),8.43(dt,J=8.5,1.3Hz,1H),8.24–8.19(m,2H),8.02(dt,J=8.5,1.1Hz,1H) ,7.84(dd,J=8.4,7.4Hz,1H),7.79(dd,J=7.3,1.2Hz,1H),7.60(dd,J=8.6,4. 1Hz,1H),7.53(t,J=7.7Hz,2H),7.46–7.40(m,1H).HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 19 H 14 N3OS,332.0858; found,332.0857.

[0137] Example 57 was synthesized according to Scheme D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ7.94–7.88(m,2H),7.86(s,1H),7.52–7.45(m,2H),7.44–7.37(m,1 H),3.68–3.61(m,2H),3.59–3.48(m,2H),1.91(p,J=1.9Hz,4H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 14 H 14 N2ONaS,281.0725; found,281.0729.

[0138] Example 58 was synthesized according to Process D to obtain a white solid.1 H NMR(600MHz,DMSO-d6)δ7.94–7.88(m,2H),7.86(s,1H),7.52–7.45(m,2H),7.44 –7.37(m,1H),3.76–3.64(m,6H),3.65–3.58(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 14 H 14 N2O2NaS,297.0674; found,297.0679.

[0139] Example 59 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz, DMSO-d6)δ10.88(s,1H),8.50(s,1H),8.24–8.17(m,2H),8.00(d,J=1.9Hz,1H),7.41–7.30(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2OFNaSCl2,388.9694; found,388.9693.

[0140] Example 60 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.89(s,1H),8.60(s,1H),8.23–8.17(m,2H),8.02(d,J= 1.8Hz,2H),7.61–7.56(m,2H),7.39(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2ONaSCl3,404.9399; found,404.9398.

[0141] Example 61 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.90(s,1H),8.61(s,1H),8.17–8.11(m,2H),8.02(d,J= 1.8Hz,2H),7.74–7.63(m,2H),7.40(t,J=1.8Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16H9N2ONaSCl2Br,448.8894; found,448.8891.

[0142] Example 62 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.90(d,J=2.6Hz,1H),8.62–8.59(m,1H),8.01(t,J=1.4Hz,2H),8. 00–7.95(m,2H),7.95–7.86(m,2H),7.40(dd,J=2.4,1.4Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2ONaSCl2I,496.8755; found,496.8758.

[0143] Example 63 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.92(s,1H),8.68(s,1H),8.28–8.24(m,2H),8.09(s,1H) ,8.05–8.00(m,4H),7.46(s,1H),7.41(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N3O2NaSCl2,413.9847; found,413.9846.

[0144] Example 64 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.92(s,1H),8.44(td,J=8.0,1.9Hz,1H),8.37(d,J=2.2Hz,1H) ,8.02(d,J=1.9Hz,2H),7.56–7.45(m,1H),7.43–7.36(m,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2OFNaSCl2,388.9694; found,388.9683.

[0145] Example 65 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz, CDCl3)δ9.06(s,1H),7.74(d,J=1.5Hz,1H),7.65(d,J=1.8Hz,2H),7.64–7.56(m,2H),7.37(t dd,J=7.8,5.8,1.5Hz,1H),7.11(q,J=1.8Hz,1H),7.04(tt,J=8.4,2.0Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2OFNaSCl2,388.9694; found,388.9693.

[0146] Example 66 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.99(s,1H),8.49(s,1H),8.07(dd,J=7.5,2.0Hz,1H),8.01(d,J=1.9Hz,2H ),7.63(dd,J=7.8,1.5Hz,1H),7.54–7.45(m,2H),7.38(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H9N2ONaSCl3,404.9399; found,404.9397.

[0147] Example 67 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.90(s,1H),8.68(s,1H),8.29(t,J=1.9Hz,1H),8.12(dt,J=7.7,1.3Hz,1H),8.02(d,J= 1.9Hz,2H),7.54(t,J=7.8Hz,1H),7.48(dt,J=8.1,1.4Hz,1H),7.40(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2ONaSCl3,404.9399; found,404.9398.

[0148] Example 68 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.95(s,1H),8.62–8.57(m,2H),8.33(dt,J=7.9,1.4Hz,1H),8.11–7.99(m,3H),7.91 (dt,J=7.9,1.4Hz,1H),7.61(t,J=7.7Hz,1H),7.52(s,1H),7.41(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N3O2NaSCl2,413.9847; found,413.9839.

[0149] Example 69 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.55(s,1H),8.47(td,J=8.0,2.0Hz,1H),8.33(d,J=2.3Hz,1H),7.52–7.46(m,1H ),7.43–7.36(m,2H),7.19(d,J=2.3Hz,2H),6.34(t,J=2.3Hz,1H),3.77(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 15 N2O3FNaS,381.0685; found,381.0681.

[0150] Example 70 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.53(s,1H),8.61(s,0H),8.08(ddd,J=10.5,2.7,1.6Hz,1H),8.01(ddd,J=7.8,1.6,0.9Hz,1H),7.56( td,J=8.0,6.1Hz,1H),7.29–7.22(m,1H),7.19(d,J=2.3Hz,2H),6.34(t,J=2.3Hz,1H),3.77(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 15 N2O3FNaS,381.0685; found,381.0688.

[0151] Example 71 was synthesized according to Process D to obtain a white solid.1 H NMR(600MHz,DMSO-d6)δ10.52(s,1H),8.49(d,J=0.9Hz,1H),8.27–8.20(m,2H),7.39–7.33( m,2H),7.20(d,J=2.3Hz,2H),6.34(t,J=2.3Hz,1H),3.77(s,5H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 15 N2O3FNaS,381.0685; found,381.0688.

[0152] Example 72 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.42(s,1H),8.39(d,J=2.2Hz,1H),8.32(t,J=7.8Hz,1H),7.93(d,J=8. 6Hz,1H),7.79(d,J=2.3Hz,1H),7.56–7.46(m,2H),7.43–7.37(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H9N2OFNaSCl2,388.9694; found,388.9690.

[0153] Example 73 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.45(s,1H),8.45(s,3H),7.99–7.90(m,9H),7.61(s,3H),7.53(td, J=8.0,6.0Hz,3H),7.39–7.35(m,3H),7.22(td,J=8.5,2.6Hz,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2OFNaSCl2,388.9694; found,388.9695.

[0154] Example 74 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, CDCl3) δ9.76 (s, 1H), 8.47 (d, J = 8.9Hz, 1H), 7.89–7.83 (m, 2H), 7.67 (s, 1H), 7.40 ( d,J=2.3Hz,1H),7.25(dd,J=8.9,2.4Hz,1H),7.10(t,J=8.6Hz,2H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H9N2OFNaSCl2,388.9694; found,388.9696.

[0155] Example 75 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.70(s,1H),8.47–8.42(m,1H),8.34(d,J=2.2Hz,1H),7.88–7.83(m,3H),7.49(tdd,J=7.6,5.2 ,1.7Hz,1H),7.42–7.36(m,2H),7.32(d,J=8.2Hz,2H),7.25(s,1H),6.97(s,1H),5.20(s,2H).HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 20 H 16 N4OSF,379.1029; found,379.1033.

[0156] Example 76 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.66(s,1H),8.49(s,1H),8.22(dd,J=8.5,5.5Hz,2H),7.84(d,J=8.2Hz,2H),7.77(d,J=1.3Hz,1H),7. 36(t,J=8.7Hz,2H),7.30(d,J=8.3Hz,2H),7.20(d,J=1.3Hz,1H),6.92(d,J=1.3Hz,1H),5.18(s,2H).HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 20 H 16 N4OSF,379.1029; found,379.1034.

[0157] Example 77 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.67(s,1H),8.61(s,1H),8.07(dt,J=10.3,2.0Hz, 1H),8.02–7.98(m,1H),7.87–7.82(m,2H),7.77(d,J=1.2Hz,1H),7.55(td,J =8.0,6.1Hz,1H),7.31(d,J=8.3Hz,2H),7.25(td,J=8.5,2.7Hz,1H),7.21(d ,J=1.2Hz,1H),6.92(t,J=1.1Hz,1H),5.19(s,2H).HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 20 H 16 N4OFS,379.1029; found,379.1033.

[0158] Example 78 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.75(s,1H),8.44(td,J=8.0,1.9Hz,1H),8.35(d,J=2.2Hz,1H ),7.78–7.70(m,4H),7.52–7.46(m,1H),7.42–7.36(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 10 N2OFSINa,446.9440; found,446.9444.

[0159] Example 79 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.72(s,1H),8.50(s,1H),8.24–8.19(m,2H),7.74(q,J=8.9Hz,4H),7.36(t,J=8.8Hz,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 10 N2OFNaSI,446.9440; found,446.9444.

[0160] Example 80 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.72(s,1H),8.63(s,1H),8.07(ddd,J=10.5,2.7,1.6Hz,1H),8.00(dt,J=7.7,1 .2Hz,1H),7.78–7.70(m,4H),7.56(td,J=8.0,6.1Hz,1H),7.29–7.22(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H 10 N2OFNaSI,446.9440; found,446.9442.

[0161] Example 81 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.76(s,1H),8.45(td,J=8.1,2.0Hz,1H),8.34(d,J=2.2Hz,1H),7.93–7.89(m,2H),7.49(t dd,J=7.4,5.2,1.9Hz,1H),7.43–7.36(m,2H),7.26–7.23(m,2H),7.22(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2O2F3NaS,387.0391; found,387.0395.

[0162] Example 82 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.73(s,1H),8.50(s,1H),8.25–8.19(m,2H),7.93–7.88(m,2H), 7.40–7.31(m,2H),7.25–7.22(m,2H),7.16(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2O2F3NaS,387.0391; found,387.0396.

[0163] Example 83 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.73(s,1H),8.62(d,J=1.1Hz,1H),8.08(ddd,J=10.5,2.8,1.5Hz,1H),8.01(dd,J=7.8,1.6Hz ,1H),7.93–7.89(m,2H),7.59–7.53(m,1H),7.28–7.23(m,3H),7.16(t,J=74.3,1.1Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2O2F3NaS,387.0391; found,387.0395.

[0164] Example 84 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.98(s,1H),8.46(td,J=8.0,2.0Hz,1H),8.38(d,J=2.2Hz,1H),8.12(d,J= 8.5Hz,2H),7.79(d,J=8.6Hz,2H),7.53–7.47(m,1H),7.44–7.37(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 10 N2OF4NaS,389.0348; found,389.0353.

[0165] Example 85 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.95(s,1H),8.53(s,1H),8.26–8.21(m,2H),8.12(d,J= 8.5Hz,2H),7.79(d,J=8.7Hz,2H),7.40–7.34(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 10 N2OF4NaS,389.0348; found,389.0345.

[0166] Example 86 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.95(s,1H),8.66(s,1H),8.14–8.06(m,3H),8.02(d,J=7.7Hz,1H),7.79(d ,J=8.5Hz,2H),7.57(td,J=7.9,5.9Hz,1H),7.27(td,J=8.4,2.6Hfz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 10 N2OF4NaS,389.0348; found,389.0349.

[0167] Example 87 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.79(s,1H),8.45(s,1H),8.07(dd,J=7.6,1.9Hz,1H),7.92–7.82(m,2H),7.63(dd,J =7.8,1.5Hz,1H),7.53–7.46(m,2H),7.22(d,J=6.6Hz,2H),7.15(t,J=72.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2O2F2NaSCl,403.0096; found,403.0099.

[0168] Example 88 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.76(s,1H),8.65(s,1H),8.30(s,1H),8.12(d,J=7.7Hz,1H),7.91(d,J=8.6Hz,2H),7. 55(t,J=7.8Hz,1H),7.50–7.46(m,1H),7.24(d,J=8.8Hz,2H),7.22(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2O2F2NaSCl,403.0096; found,403.0101.

[0169] Example 89 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.74(s,1H),8.57(s,1H),8.20(d,J=8.5Hz,2H),7.91(d,J=9.0Hz,2H), 7.59(d,J=8.5Hz,2H),7.24(d,J=8.9Hz,2H),7.16(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 11 N2O2F2NaSCl,403.0096; found,403.0096.

[0170] Example 90 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.03(s,1H),8.49(s,1H),8.13–8.06(m,3H),7.77(d,J=8. 5Hz,2H),7.63(dd,J=7.8,1.5Hz,1H),7.55–7.39(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 10 N2OF3NaSCl,405.0052; found,405.0057.

[0171] Example 91 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.98(s,1H),8.68(s,1H),8.32(t,J=1.9Hz,1H),8.13(ddd,J=8.5,3.4,2.0Hz,3H) ,7.79(d,J=8.5Hz,2H),7.55(t,J=7.9Hz,1H),7.49(ddd,J=8.0,2.2,1.0Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 10 N2OF3NaSCl,405.0052; found,405.0052.

[0172] Example 92 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.97(s,1H),8.61(s,1H),8.24–8.19(m,2H),8.12(d,J= 8.5Hz,2H),7.79(d,J=8.6Hz,2H),7.64–7.57(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 10 N2OF3NaSCl,405.0052; found,405.0045.

[0173] Example 93 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.56(s,1H),8.63(t,J=1.8Hz,1H),8.31(t,J=1.9Hz,1H),8.13(dt,J=7.8,1.3Hz,1H),7.54(td,J =7.9,1.8Hz,1H),7.50–7.46(m,1H),7.21(d,J=2.3Hz,2H),6.35(t,J=2.2Hz,1H),3.78(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 15 N2O3NaSCl,397.0390; found,397.0387.

[0174] Example 94 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.54(s,1H),8.57(s,1H),8.24–8.19(m,2H),7.58(dd,J=8.6,1.8H z,2H),7.19(d,J=2.2Hz,2H),6.33(t,J=2.3Hz,1H),3.77(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 15 N2O3NaSCl,397.0390; found,397.0391.

[0175] Example 95 was synthesized according to Process D to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.76(s,1H),8.59(t,J=1.8Hz,1H),8.57(s,1H),8.32(dt,J=7.9,1.3Hz,1H),8.07(s,1H),7.94 –7.88(m,3H),7.60(t,J=7.7Hz,1H),7.51(s,1H),7.26–7.21(m,2H),7.22(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 13 N3O3F2NaS,412.0543; found,412.0547.

[0176] Example 96 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.76(s,1H),8.64(s,1H),8.08(s,1H),8.04–8.00(m,2H),7.94–7.8 9(m,2H),7.45(s,1H),7.27–7.23(m,2H),7.22(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 13 N3O3F2NaS,412.0543; found,412.0547.

[0177] Example 97 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.75(s,1H),8.59(t,J=1.8Hz,1H),8.57(s,1H),8.32(dt,J=7.8,1.4Hz,1H),8.06(s,1H ),7.90(dt,J=7.8,1.4Hz,1H),7.76–7.71(m,4H),7.60(t,J=7.7Hz,1H),7.51(s,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 12 N3O2NaSI,471.9593; found,471.9597.

[0178] Example 98 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.76(s,1H),8.66(s,1H),8.28–8.24(m,2H),8.11(s,1H) ),8.05–8.01(m,2H),7.79–7.71(m,4H),7.45(s,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 12 N3O2NaSI,471.9593; found,471.9595.

[0179] Example 99 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.00(s,1H),8.61(d,J=2.4Hz,2H),8.34(dt,J=7.8,1.4Hz,1H),8.13(d,J=8.5Hz,2H),8.08(s ,1H),7.91(dt,J=7.7,1.4Hz,1H),7.79(d,J=8.6Hz,2H),7.61(t,J=7.7Hz,1H),7.52(s,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 12 N3O2NaSF3,414.0500; found,414.0505.

[0180] Example 100 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.98(s,1H),8.68(s,1H),8.29–8.25(m,2H),8.13(d,J=8.5Hz,2H),8 .08(s,1H),8.04–8.00(m,2H),7.79(d,J=8.5Hz,2H),7.46(s,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 18 H 12 N3O2F3NaS,414.0500; found,414.0503.

[0181] Example 101 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.75(s,1H),8.58(s,1H),8.16–8.11(m,2H),8.01–7.88(m,2H), 7.75–7.70(m,2H),7.25–7.22(m,2H),7.22(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2O2F2NaSBr,446.9590; found,446.9588.

[0182] Example 102 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.74(s,1H),8.57(s,1H),8.00–7.95(m,2H),7.89(dd,J=9. 3,7.4Hz,3H),7.25–7.22(m,2H),7.22(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2O2F2NaSI,494.9452; found,494.9457.

[0183] Example 103 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.97(s,1H),8.62(s,1H),8.17–8.09(m,4H),7.79(d,J=8.5Hz,2H),7.76–7.67(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 10 N2O2F3NaSBr,448.9547; found,448.9539.

[0184] Example 104 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.96(s,1H),8.61(s,1H),8.11(d,J=8.5Hz,2H),8.03–7 .96(m,2H),7.92–7.87(m,2H),7.79(d,J=8.6Hz,2H).HRMS(ESI-TOF)m / z:[M+Na] +Calculate for C 17 H 10 N2O2F3NaSI,496.9408; found,496.9411.

[0185] Example 105 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.83(s,1H),8.01–7.98(m,2H),7.74–7.70(m,1H),7.69–7.65(m,1H),7.57(q,J =7.5Hz,1H),7.38(q,J=1.6Hz,1H),7.29(td,J=8.6,2.7Hz,1H),2.69(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2OFNaSCl2,402.9851; found,402.9855.

[0186] Example 106 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.88(s,1H),8.00(d,J=1.9Hz,2H),7.83–7.77(m,2H),7.39– 7.33(m,3H),3.02(q,J=7.5Hz,2H),1.31(t,J=7.5Hz,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 13 N2OFNaSCl2,417.0007; found,417.0011.

[0187] Example 107 was synthesized according to Process D to obtain a white solid. 1 HNMR(600MHz,DMSO-d6)δ11.00(s,1H),8.02(d,J=1.9Hz,2H),7.63–7.57(m,2H),7.48–7.38(m,6H),7.28–7.21(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 22 H 13 N2OFNaSCl2,465.0007; found,465.0010.

[0188] Example 108 was synthesized according to Process D to obtain a white solid.1 H NMR(600MHz,DMSO-d6)δ10.86(s,1H),8.00(d,J=1.9Hz,2H),7.89–7.84(m,2H),7.39–7.33(m,3H),2.64(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2OFNaSCl2,402.9851; found,402.9854.

[0189] Example 109 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.43(s,1H),7.90–7.85(m,2H),7.42–7.28(m,2H),7.17(d,J= 2.3Hz,2H),6.30(t,J=2.3Hz,1H),3.74(s,6H),2.64(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 19 H 17 N2O3FNaS,395.0842; found,395.0845.

[0190] Example 110 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.29(s,1H),7.90(d,J=8.7Hz,1H),7.78(d,J=2.4Hz,1H),7.70–7.63(m,2H),7.58(t d,J=8.0,6.1Hz,1H),7.51(dd,J=8.7,2.4Hz,1H),7.32–7.25(m,1H),2.70(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2OFNaSCl2,402.9851; found,402.9855.

[0191] Example 111 was synthesized according to Process D to obtain a white solid. 1HNMR(600MHz,DMSO-d6)δ10.65(s,1H),7.91–7.86(m,2H),7.73(ddd,J=10.4,2.7,1.6Hz,1H),7.67(dt,J=7.8,1.2Hz,1H) ,7.57(td,J=8.0,6.1Hz,1H),7.31–7.26(m,1H),7.23–7.21(m,2H),7.14(t,1H),2.68(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 13 N2O2F3NaS,401.0548; found,401.0551.

[0192] Example 112 was synthesized according to Process D to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.65(s,1H),7.99–7.76(m,4H),7.39–7.33(m,2H),7.23–7.17(m,2H),7.20(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 13 N2O2F3NaS,401.0548; found,401.0553.

[0193] Example 113 was synthesized according to Process D to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),8.09(d,J=8.5Hz,2H),7.79–7.74(m,3H),7.73(dd,J=2.7,1.6Hz,1H),7.6 8(dt,J=7.8,1.3Hz,1H),7.58(td,J=8.0,6.1Hz,1H),7.32–7.26(m,1H),2.70(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 12 N2OF4NaS,403.0504; found,403.0508.

[0194] Example 114 was synthesized according to Process D to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.90(s,1H),8.10(d,J=8.5Hz,2H),7.96(t,J=1.9Hz,1H),7.82–7.72(m,3H ),7.56(t,J=7.8Hz,1H),7.52(ddd,J=8.1,2.2,1.1Hz,1H),2.69(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 18 H 12 N2OF3NaSCl,419.0209; found,419.0213.

[0195] The experimental procedure for preparing Route E of Examples 115-132 (Scheme E) is as follows:

[0196] (1) After dissolving E-1 in a solvent, add oxalyl chloride, react for 0.5 to 2 hours, concentrate under reduced pressure after the reaction is complete, add solvent again, add different substituted amines, react for 1 to 8 hours at room temperature to 60°C, extract, separate and purify to obtain E-2. The molar ratio of the reactants is E-2: oxalyl chloride: substituted amine = 1: 1-5: 0.9-1.5.

[0197] (2) Add E-2, substituted boronic acid and inorganic base to a reaction bottle, add solvent, then add palladium catalyst, stir under nitrogen atmosphere, react at 80°C to 110°C for 1 to 10 hours, and after the reaction is complete, filter, extract, separate and purify to obtain E-II. The molar ratio of the reactants is E-2: substituted boronic acid: inorganic base: palladium catalyst

[0198] =1∶1.5-3∶1-5∶0.01-0.2.

[0199] Example 115 was synthesized according to Process E to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.76(s,1H),8.72(s,1H),8.69(d,J=1.8Hz,1H),8.49(dt,J=8.0,1.5Hz,1H),7.93 –7.87(m,3H),7.74(t,J=7.8Hz,1H),7.27–7.22(m,2H),7.23(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 11 N3O2F2NaS,394.0438; found,394.0433.

[0200] Example 116 was synthesized according to Process E to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.78(s,1H),8.77(s,1H),8.40–8.36(m,2H),8.05–7.98(m,2H), 7.93–7.84(m,2H),7.26–7.23(m,2H),7.22(t,J=74.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 11 N3O2F2NaS,394.0438; found,394.0439.

[0201] Example 117 was synthesized according to Process E to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.96(s,1H),8.75(s,1H),8.70(d,J=1.7Hz,1H),8.51(dt,J=8.0,1.4Hz,1H),8.12(d,J= 8.5Hz,2H),7.90(dt,J=7.7,1.3Hz,1H),7.80(d,J=8.6Hz,2H),7.75(t,J=7.8Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 10 N3ONaSF3,396.0394; found,396.0391.

[0202] Example 118 was synthesized according to Process E to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),8.80(d,J=1.3Hz,1H),8.39(d,J=8.1Hz,2H),8.1 2(d,J=8.4Hz,2H),8.04–8.00(m,2H),7.79(d,J=8.4Hz,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 11 N3OF3S,374.0575; found,374.0573.

[0203] Example 119 was synthesized according to Process E to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.88(s,1H),8.48(s,1H),8.09–8.04(m,2H),8.04(d,J=1.9Hz,2 H),7.40(t,J=1.9Hz,1H),7.32(d,J=7.9Hz,2H),2.37(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 12 N2ONaSCl2,384.9945; found,384.9946.

[0204] Example 120 was synthesized according to Process E to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),8.48(d,J=1.1Hz,1H),8.07(d,J=8.2Hz,2H),8.04(d,J=1.9Hz ,2H),7.42–7.36(m,3H),2.96(hept,J=6.9Hz,1H),1.25(d,J=6.9Hz,6H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 19 H 16 N2ONaSCl2,413.0258; found,413.0256.

[0205] Example 121 was synthesized according to Process E to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.94(s,1H),8.61(s,1H),8.28–8.25(m,2H),8.05(d,J=1.9Hz,2H),7.85 –7.81(m,2H),7.82–7.72(m,2H),7.53–7.48(m,2H),7.49–7.38(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 22 H 14 N2ONaSCl2,447.0102; found,447.0101.

[0206] Example 122 was synthesized according to Process E to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.84(s,1H),9.74(s,1H),8.29(s,1H),8.03(d,J=1.9Hz,2H), 8.01–7.96(m,2H),7.40(t,J=1.9Hz,1H),6.90–6.86(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 10 N2O2NaSCl2,386.9738; found,386.9739.

[0207] Example 123 was synthesized according to Process E to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.87(s,1H),8.39(s,1H),8.14–8.07(m,2H),8.03(d,J=1.9Hz ,2H),7.40(t,J=1.9Hz,1H),7.09–7.04(m,2H),3.83(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 12 N2O2NaSCl2,400.9894; found,400.9893.

[0208] Example 124 was synthesized according to Process E to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.97(s,1H),8.87(s,1H),8.46–8.42(m,2H),8.40–8.37 (m,2H),8.01(d,J=1.9Hz,2H),7.42(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N3O3NaSCl2,415.9639; found,415.9631.

[0209] Example 125 was synthesized according to Process E to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.79(s,1H),8.13(s,1H),8.04(d,J=1.9Hz,2H),7.86–7.81(m ,2H),7.39(t,J=1.9Hz,1H),6.68–6.63(m,2H),5.41(s,2H).HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 16 H 12 N3OSCl2,364.0078; found,364.0075.

[0210] Example 126 was synthesized according to Process E to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.93(s,1H),8.80(s,1H),8.39–8.35(m,2H),8.03–7.99(m,4H),7.42–7.39(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H9N3ONaSCl2,395.9741; found,395.9741.

[0211] Example 127 was synthesized according to Process E to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.87–10.84(m,1H),10.10(s,1H),8.41(d,J=1.3Hz,1H),8.11–8.07(m,2H),8 .03(d,J=1.9Hz,2H),7.78–7.70(m,2H),7.40(q,J=1.7Hz,1H),2.08(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 18 H 13 N3O2NaSCl2,428.0003; found,428.0002.

[0212] Example 128 was synthesized according to Process E to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.95(s,1H),8.20(d,J=1.4Hz,1H),8.02(d,J=1.9Hz,2H),7. 70(dd,J=7.6,1.3Hz,1H),7.42–7.28(m,4H),2.45(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 12 N2ONaSCl2,384.9945; found,384.9950.

[0213] Example 129 was synthesized according to Process E to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.89(s,1H),8.52(d,J=1.2Hz,1H),8.04(d,J=1.9Hz,2H),7.99(s,1H),7.9 5(d,J=7.8Hz,1H),7.42–7.37(m,2H),7.24(d,J=7.5Hz,1H),2.41(s,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 12 N2ONaSCl2,384.9945; found,384.9939.

[0214] Example 130 was synthesized according to Process E to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.91(s,1H),9.42(dd,J=2.3,0.9Hz,1H),8.71(d,J=0.8Hz,1H),8.63(dd,J=4.8,1.6Hz,1H),8.50(dt,J= 8.0,2.0Hz,1H),8.03(d,J=1.9Hz,2H),7.56(ddd,J=8.0,4.8,0.9Hz,1H),7.42(td,J=1.9,1.0Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 15 H9N3ONaSCl2,371.9843; found,371.9841.

[0215] Example 131 was synthesized according to Process E to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.94(s,1H),8.87(d,J=1.0Hz,1H),8.73(d,J=5.0Hz,2H),8.1 8–8.11(m,2H),8.02(d,J=1.9Hz,2H),7.42(q,J=1.8Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 15 H9N3ONaSCl2,371.9843; found,371.9848.

[0216] Example 132 was synthesized according to Process E to obtain a white solid. 1 H NMR(600MHz, DMSO-d6)δ10.87(s,1H),9.07(d,J=2.6Hz,1H),8.73–8.64(m,2H),8.00(d,J=1.9Hz,2H),7.41–7.32(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 15 H8N3OFNaSCl2,389.9647; found,389.9646.

[0217] The experimental procedure for preparing Route C of Examples 133-158 (Scheme C) is as follows:

[0218] (1) Add C-1 and C-2 to a reaction flask, add a solvent, react at 50°C to 100°C for 1 to 10 hours, add sodium hydroxide after the reaction is complete, and react for another 2 to 6 hours. After the reaction is complete, concentrate the solvent under reduced pressure to obtain a solid, add water and stir until the solid is dissolved, adjust the pH to acidic, precipitate a large amount of solid, filter to obtain a crude product, and slurry with ethanol to obtain C-3. The molar ratio of the reactants is C-1: C-2: sodium hydroxide = 1: 1-1.1: 1-5.

[0219] (2) After C-3 is dissolved in a solvent, oxalyl chloride is added, and the reaction is carried out for 0.5 to 2 hours. After the reaction is complete, the mixture is concentrated under reduced pressure, and then a solvent is added. Different substituted amines are added, and the reaction is carried out at room temperature to 60°C for 1 to 8 hours. After the reaction is complete, extraction is performed, and C-I is obtained by separation and purification. The molar ratio of the reactants is C-3: oxalyl chloride: substituted amine = 1: 1-5: 0.9-1.5.

[0220] Example 133 was synthesized according to Process C to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.24(s,1H),8.49(s,1H),8.21–8.14(m,2H),7.89–7.85(m,2H),7. 62–7.51(m,3H),7.42–7.36(m,2H),7.15(tt,J=7.4,1.2Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 12 N2ONaS,303.0568; found,303.0568.

[0221] Example 134 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.57(s,1H),8.56(d,J=1.4Hz,1H),8.17(dt,J=6.8,1.7Hz,2H),8.13( d,J=8.4Hz,2H),7.79–7.74(m,2H),7.57(dq,J=4.9,2.9,2.5Hz,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 11 N2OF3NaS,371.0442; found,371.0446.

[0222] Example 135 was synthesized according to Process C to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.34(s,1H),8.49(s,1H),8.19–8.14(m,2H),7.94–7 .88(m,2H),7.61–7.52(m,3H),7.35–7.07(m,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 12 N2O2F2NaS,369.0485; found,369.0488.

[0223] Example 136 was synthesized according to Process C to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.34(s,1H),8.50(d,J=0.8Hz,1H),8.18–8.14(m,2H),7.73(s,4H),7.57(qd,J=4.6,1.5Hz,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 11 N2ONaSI,428.9534; found,428.9539.

[0224] Example 137 was synthesized according to Process C to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.14(s,1H),8.48(s,1H),8.19–8.15(m,2H),7.60–7.53(m,3H) ),7.20(d,J=2.2Hz,2H),6.30(t,J=2.3Hz,1H),3.76(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 16 N2O3NaS,363.0779; found,363.0781.

[0225] Example 138 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.55(s,1H),8.56(s,1H),8.21–8.14(m,2H),8.06(d,J=1.9H z,2H),7.57(qd,J=3.9,1.6Hz,3H),7.36(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 10 N2ONaSCl2,370.9789; found,370.9785.

[0226] Example 139 was synthesized according to Process C to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.13(s,1H),8.58(s,1H),8.20(d,J=8.8Hz,1H),8.11–8.03(m,2H),7. 78(d,J=2.4Hz,1H),7.61–7.56(m,3H),7.52(dd,J=8.7,2.4Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H 10 N2ONaSCl2,370.9789; found,370.9791.

[0227] Example 140 was synthesized according to Process C to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.57(s,1H),8.55(d,J=0.6Hz,1H),8.27–8.21(m,2H),8.11( d,J=8.5Hz,2H),7.76(d,J=8.6Hz,2H),7.46–7.35(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 10 N2ONaSF4,389.0348; found,389.0353.

[0228] Example 141 was synthesized according to Process C to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.35(s,1H),8.48(s,1H),8.27–8.20(m,2H),7.93–7 .87(m,2H),7.45–7.39(m,2H),7.35–7.07(m,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2O2F3NaS,387.0391; found,387.0394.

[0229] Example 142 was synthesized according to Process C to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.34(s,1H),8.49(s,1H),8.25–8.19(m,2H),7.72(s,4H),7.45–7.35(m,2H).HRMS(ESI-TOF)m / z:[M+Na] +Calculate for C 16 H 10 N2OFNaSI,446.9440; found,446.9442.

[0230] Example 143 was synthesized according to Process C to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.14(s,1H),8.47(s,1H),8.27–8.20(m,2H),7.45–7.37(m,2H ),7.18(d,J=2.2Hz,2H),6.30(t,J=2.3Hz,1H),3.76(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 15 N2O3FNaS,381.0685; found,381.0685.

[0231] Example 144 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.53(s,1H),8.54(s,1H),8.26–8.20(m,2H),8.03(d,J= 1.8Hz,2H),7.46–7.39(m,2H),7.36(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2OFNaSCl2,388.9694; found,388.9694.

[0232] Example 145 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.12(s,1H),8.56(s,1H),8.19–8.11(m,3H),7.77(d,J=2.4H z,1H),7.51(dd,J=8.8,2.4Hz,1H),7.42(t,J=8.7Hz,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2OFNaSCl2,388.9694; found,388.9698.

[0233] Example 146 was synthesized according to Process C to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.59(s,1H),8.58(s,1H),8.22–8.18(m,2H),8.11(d,J= 8.5Hz,2H),7.76(d,J=8.5Hz,2H),7.67–7.63(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 10 N2OF3NaSCl,405.0052; found,405.0055.

[0234] Example 147 was synthesized according to Process C to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.51(s,1H),8.22–8.16(m,2H),7.93–7 .87(m,2H),7.67–7.62(m,2H),7.35–7.07(m,3H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H 11 N2O2F2NaSCl,403.0096; found,403.0100.

[0235] Example 148 was synthesized according to Process C to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.36(s,1H),8.52(s,1H),8.21–8.16(m,2H),7.72(d,J=0.7Hz,4H),7.69–7.61(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 10 N2ONaSCI,462.9145; found,462.9145.

[0236] Example 149 was synthesized according to Process C to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.16(s,1H),8.50(s,1H),8.22–8.17(m,2H),7.67–7.62(m,2H) ),7.18(d,J=2.3Hz,2H),6.30(t,J=2.3Hz,1H),3.76(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C18 H 15 N2O3NaSCl,397.0390; found,397.0394.

[0237] Example 150 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.54(s,1H),8.57(s,1H),8.21–8.16(m,2H),8.03(d,J= 1.9Hz,2H),7.67–7.62(m,2H),7.36(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2ONaSCl3,404.9399; found,404.9399.

[0238] Example 151 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.13(s,1H),8.59(s,1H),8.14(d,J=8.8Hz,1H),8.12–8.07(m,2H),7. 77(d,J=2.4Hz,1H),7.67–7.62(m,2H),7.51(dd,J=8.7,2.4Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H9N2ONaSCl3,404.9399; found,404.9398.

[0239] Example 152 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.61(s,1H),8.61(s,1H),8.34(t,J=1.9Hz,1H),8.13(d,J=8.4Hz,2H), 8.07(dt,J=7.5,1.4Hz,1H),7.77(d,J=8.6Hz,2H),7.66–7.56(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 10 N2ONaSCLF3,405.0052; found,405.0055.

[0240] Example 153 was synthesized according to Process C to obtain a white solid. 1H NMR (600MHz, DMSO-d6) δ10.39(s,1H),8.54(s,1H),8.33(t,J=1.9Hz,1H),8.06(dt,J=7.5,1. 4Hz,1H),7.93–7.88(m,2H),7.65–7.56(m,2H),7.39–7.03(m,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 11 N2O2F2NaSCl,403.0096; found,403.0101.

[0241] Example 154 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.38(s,1H),8.55(s,1H),8.32(t,J=1.9Hz,1H),8.06(d t,J=7.5,1.4Hz,1H),7.73(s,4H),7.65–7.57(m,2H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 10 N2ONaSCI,462.9145; found,462.9146.

[0242] Example 155 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.19(s,1H),8.53(s,1H),8.32(t,J=1.9Hz,1H),8.07(dt,J=7.5,1.4Hz,1H),7 .66–7.55(m,2H),7.19(d,J=2.3Hz,2H),6.31(t,J=2.3Hz,1H),3.76(s,6H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 15 N2O3NaSCl,397.0390; found,397.0393.

[0243] Example 156 was synthesized according to Process C to obtain a white solid. 1H NMR(600MHz,DMSO-d6)δ10.55(s,1H),8.60(s,1H),8.31(t,J=1.9Hz,1H),8.10–8 .02(m,3H),7.65–7.56(m,2H),7.37(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2ONaSCl3,404.9399; found,404.9401.

[0244] Example 157 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.19(s,1H),8.61(s,1H),8.18(d,J=2.0Hz,1H),8.07–7.98(m,2H),7. 78(d,J=2.4Hz,1H),7.65–7.57(m,2H),7.52(dd,J=8.7,2.4Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H9N2ONaSCl3,404.9399; found,404.9403.

[0245] Example 158 was synthesized according to Process C to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.52(s,1H),8.60(s,1H),8.11(ddd,J=10.0,2.7,1.6Hz,1H),8.04(d,J=1.9Hz,2H),7.96(ddd, J=7.7,1.6,0.9Hz,1H),7.62(td,J=8.0,5.9Hz,1H),7.44–7.39(m,1H),7.37(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2ONaSCl2F,388.9694; found,388.9698.

[0246] The experimental procedure for preparing Route F of Example 159 (Scheme F) is as follows:

[0247] (1) After dissolving F-1 in a solvent, add oxalyl chloride and react for 0.5 to 2 hours. After the reaction is complete, concentrate under reduced pressure, add solvent, add aniline, and react for 1 to 8 hours at room temperature to 60°C. After the reaction is complete, extract, separate and purify to obtain F-2. The molar ratio of the reactants is F-2: oxalyl chloride: aniline = 1: 4: 0.9.

[0248] (2) Add F-2, phenylboronic acid and potassium carbonate to a reaction flask, add a solvent, then add a palladium catalyst, stir under a nitrogen atmosphere, react at 80° C. to 110° C. for 1 to 10 hours, and after the reaction is complete, filter, extract, separate and purify to obtain F-II. The molar ratio of the reactants is F-2: phenylboronic acid: potassium carbonate: palladium catalyst = 1: 2: 3: 0.02.

[0249] Example 159 was synthesized according to Process F to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.47(s,1H),8.69(s,1H),8.06–8.00(m,2H),7.75–7.70(m,2H),7 .56(qd,J=4.3,1.6Hz,3H),7.41–7.35(m,2H),7.17–7.12(m,1H).HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 16 H 13 N2OS,281.0749; found,281.0742.

[0250] The experimental procedure for Route G (Scheme G) used to prepare Examples 160-167 is as follows:

[0251] (1) Add G-1 and trimethylsilyl bromide to a reaction bottle, react at room temperature to 60°C for 4 to 10 hours, and after the reaction is complete, separate and purify using a silica gel column to obtain G-2. The molar ratio of the reactants is G-1: trimethylsilyl bromide = 1: 1-5.

[0252] (2) Add G-2 to a reaction flask, add a solvent to dissolve it, then add pyridinium dichromate in batches, and react at room temperature for 3 to 8 hours. After the reaction is complete, separate and purify it on a silica gel column to obtain G-3. The molar ratio of the reactants is G-2:pyridinium dichromate = 1:1.5-3.

[0253] (3) G-3 and ethyl thiooxamate are added to a reaction flask, and a solvent is added. The reaction is carried out at 50°C to 100°C for 1 to 10 hours. After the reaction is complete, sodium hydroxide is added and the reaction is continued for 2 to 6 hours. After the reaction is complete, the solvent is concentrated under reduced pressure to obtain a solid, and water is added and stirred until the solid is dissolved. The pH is adjusted to be acidic, and a large amount of solid is precipitated. The crude product is filtered and slurried with ethanol to obtain G-4. The molar ratio of the reactants is G-3:ethyl thiooxamate:sodium hydroxide = 1:1-1.5:1-5.

[0254] (4) After G-4 is dissolved in a solvent, oxalyl chloride is added, and the reaction is carried out for 0.5 to 2 hours. After the reaction is complete, the mixture is concentrated under reduced pressure, and then a solvent is added. Different substituted amines are added, and the reaction is carried out at room temperature to 60° C. for 1 to 8 hours. After the reaction is complete, extraction is performed, and separation and purification are performed to obtain G-II. The molar ratio of the reactants is G-4: oxalyl chloride: substituted amine = 1: 1-5: 0.9-1.5.

[0255] Example 160 was synthesized according to Process G to obtain a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.79(s,1H),8.52(s,1H),7.90–7.86(m,2H),7.83(dd,J=7.2,1.8Hz,2H),7.51(d d,J=8.4,6.8Hz,2H),7.48–7.43(m,1H),7.41–7.35(m,2H),7.18–7.12(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 12 N2ONaS,303.0568; found,303.0573.

[0256] Example 161 was synthesized according to Process G to obtain a white solid. 1 HNMR(600MHz,DMSO-d6)δ11.18(s,1H),8.55(s,1H),8.02(d,J=1.9Hz,2H),7.86–7.82(m,2H),7.5 1(td,J=7.2,6.2,1.4Hz,2H),7.48–7.43(m,1H),7.38(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 16 H 10 N2ONaSCl2,370.9789; found,370.9791.

[0257] Example 162 was synthesized according to Process G to obtain a white solid.1 H NMR(600MHz,DMSO-d6)δ10.29(s,1H),8.55(s,1H),7.96(d,J=8.6Hz,1H),7.91–7.75(m,3H),7.49(dt,J=31.8,7.7Hz,4H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H 10 N2ONaSCl2,370.9789; found,370.9792.

[0258] Example 163 was synthesized according to Process G to obtain a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.92(s,1H),8.52(s,1H),7.95–7.89(m,2H),7.85–7.79(m,2H),7.51 (td,J=7.3,6.4,1.3Hz,2H),7.48–7.41(m,1H),7.35–7.07(m,3H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 12 N2O2NaSF2,369.0485; found,369.0488.

[0259] Example 164 was synthesized according to Process G to obtain a white solid. 1 HNMR(600MHz,DMSO-d6)δ11.20(s,1H),8.62(s,1H),8.01(d,J=1.9Hz,2H),7.80 –7.76(m,2H),7.56–7.50(m,2H),7.33–7.27(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2OFNaSCl2,388.9694; found,388.9691.

[0260] Example 165 was synthesized according to Process G to obtain a white solid. 1HNMR (600MHz, DMSO-d6) δ11.19(s,1H),8.63(s,1H),8.01(d,J=1.9Hz,2H),7.79(ddd,J=10.1,2.6,1.7Hz,1H),7.66(ddd, J=7.8,1.8,0.9Hz,1H),7.55(td,J=8.0,6.1Hz,1H),7.37(t,J=1.9Hz,1H),7.33–7.27(m,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2OFNaSCl2,388.9694; found,388.9691.

[0261] Example 166 was synthesized according to Process G to obtain a white solid. 1 HNMR(600MHz,DMSO-d6)δ11.21(s,1H),8.66(s,1H),8.00(dd,J=10.7,1.4Hz,3H),7. 81–7.74(m,1H),7.56–7.49(m,2H),7.38(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2ONaSCl3,404.9399; found,404.9395.

[0262] Example 167 was synthesized according to Process G to obtain a white solid. 1 HNMR(600MHz,DMSO-d6)δ11.19(s,1H),8.59(s,1H),8.01(d,J=1.9Hz,2H),7.89– 7.82(m,2H),7.60–7.55(m,2H),7.38(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 16 H9N2ONaSCl3,404.9399; found,404.9395.

[0263] The experimental procedure for Route H (Scheme H) used to prepare Examples 168-170 is as follows:

[0264] (1) Add H-1 to a reaction flask, add a solvent to dissolve it, then add sodium hydroxide, react at 60°C for 1 to 12 hours, after the reaction is complete, concentrate the solvent under reduced pressure to obtain a solid, add water and stir until the solid is dissolved, adjust the pH to acidic, precipitate a large amount of solid, filter to obtain a crude product, and slurry with ethanol to obtain H-2. The molar ratio of the reactants is H-1: sodium hydroxide = 1: 1-5.

[0265] (2) After H-2 is dissolved in a solvent, oxalyl chloride is added, and the reaction is carried out for 0.5 to 2 hours. After the reaction is complete, the mixture is concentrated under reduced pressure, and then a solvent is added. Different substituted amines are added, and the reaction is carried out at room temperature to 60° C. for 1 to 8 hours. After the reaction is complete, extraction is performed, and H-3 is obtained by separation and purification. The molar ratio of the reactants is H-2: oxalyl chloride: substituted amine = 1: 1-5: 0.9-1.5.

[0266] (3) Add H-3, substituted boronic acid and inorganic base to a reaction bottle, add solvent, then add palladium catalyst, stir under nitrogen atmosphere, react at 80°C to 110°C for 1 to 10 hours, and after the reaction is complete, filter, extract, separate and purify to obtain H-II. The molar ratio of the reactants is H-2: substituted boronic acid: inorganic base: palladium catalyst

[0267] =1∶1.5-3∶1-5∶0.01-0.2.

[0268] Example 168 was synthesized according to Scheme H to obtain a white solid. 1 HNMR (600MHz, DMSO-d6) δ11.23(s,1H),8.72(s,1H),8.43(t,J=1.8Hz,1H),8.15(ddd,J=8.0,2.0,1.1Hz,1H),8.02(d ,J=1.9Hz,2H),7.91(dt,J=7.8,1.3Hz,1H),7.71(t,J=7.8Hz,1H),7.39(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 17 H9N3ONaSCl2,395.9741; found,395.9738.

[0269] Example 169 was synthesized according to Scheme H to obtain a white solid. 1 HNMR(600MHz,DMSO-d6)δ11.25(s,1H),8.75(s,1H),8.08–8.05(m,2H),8.02(d,J =1.9Hz,2H),8.00–7.95(m,2H),7.39(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na]+ Calculate for C 17 H9N3ONaSCl2,395.9741; found,395.9734.

[0270] Example 170 was synthesized according to Scheme H to obtain a white solid. 1 HNMR(600MHz,DMSO-d6)δ11.22(s,1H),8.66(s,1H),8.10(s,1H),8.02(d,J=1.9Hz,2H),8.01– 7.97(m,2H),7.96–7.91(m,2H),7.49(s,1H),7.38(t,J=1.9Hz,1H).HRMS(ESI-TOF)m / z:[M+Na] + calcdforC 17 H 11 N3O2NaSCl2,413.9847; found,413.9848.

[0271] Pharmacological study on some heteroaromatic amide derivatives prepared by the present invention

[0272] In vitro enzyme activity assay of compounds

[0273] The EROD test is used to evaluate the inhibitory activity of the target compound on human recombinant CYP1B1, CYP1A1 and CYP1A2 enzymes. The test uses 7-ethoxyresorufin (ERF) as the reaction substrate, which can be metabolized by three enzymes to resorufin with greater fluorescence intensity under certain conditions. Therefore, the difference in fluorescence intensity reflects the inhibitory effect of the target compound on CYP1B1 enzyme activity.

[0274] In vitro enzyme activity assay steps:

[0275] (1) Dilute the target compound according to the experimental requirements;

[0276] (2) Pipette 144 μL of phosphate buffer saline (PBS) and add it to a black 96-well plate;

[0277] (3) Pipette 8 μL MgCl2 into a black 96-well plate to make a final concentration of 3.2 mM;

[0278] (3) Pipette 5 μL of ERF solution and add it to a black 96-well plate to make the final concentration 2 μM;

[0279] (4) Pipette 2 μL of target compound into a black 96-well plate;

[0280] (5) Pipette 1 μL of the recombinant enzyme into a black 96-well plate to a final concentration of 5 pM;

[0281] (6) Pipette 40 μL of reduced nicotinamide adenine dinucleotide phosphate (NADPH) into a black 96-well plate to a final concentration of 1 mM to start the reaction;

[0282] (7) After NADPH was added, the cells were incubated at 37°C in the dark for 30 min and the fluorescence value was measured using a multifunctional microplate reader at an excitation wavelength of 544 nm and an emission wavelength of 590 nm.

[0283] The enzyme inhibition test results of some compounds in Examples 1-170 are shown in Table 2, wherein A < 1 nM, B = 1 ~ 10 nM, C = 10 ~ 100 nM, D = 0.1 ~ 1 μM, E = 1 ~ 10 μM, F > 10 μM.

[0284] Table 2

[0285]

[0286]

[0287] The above results show that the compounds of the present invention have good CYP1B1 inhibitory activity, and most of the compounds are more active than the positive drug α-naphthoflavone (ANF) and have better selectivity, which suggests that the compounds of the present invention can be used as potent and selective CYP1B1 inhibitors.

[0288] In vitro cell activity assay of compounds

[0289] A549, A549 / paclitaxel-resistant strains and HUVEC cells in the logarithmic growth phase were collected and cultured at 3.0×10 3 Cells / well were inoculated in a 96-well cell culture plate and cultured overnight. After the cells were stably attached to the wall, the original culture medium was aspirated the next day, and 100 μL of the test drug solution containing different concentrations and combinations was added to each well, and at least 3 replicates were set for each group. After culturing in a 37°C, 5% CO2 cell culture incubator for 72 hours, the supernatant was discarded, 100 μL of PBS was added to each well for washing once, and then 100 μL of 0.5 mg / mL MTT was added to each well. After culturing for 3-5 hours, the supernatant was removed, 100 μL of DMSO was added to each well, and after oscillation and dissolution for 3 minutes, the absorbance was detected at 492 nm on an ELISA reader to indirectly reflect the number of living cells. The data were recorded, and the cells treated with the solvent control were used as the control group to calculate the cell survival rate.

[0290] The cell activity test results of some compounds in Examples 1-170 are shown in Table 3, wherein A < 1 μM, B = 1-10 μM, C = 10-20 μM, D = 20-40 μM, and E > 40 μM.

[0291] Table 3

[0292]

[0293] The above results show that the inhibitory activity of the compound of the present invention on normal cells HUVEC is weak, and the compound has good safety; it has no inhibitory effect on A549 cells, but shows obvious inhibitory effect on the drug-resistant cells A549 / paclitaxel-resistant strain added with low concentration of paclitaxel, which suggests that the compound of the present invention can reduce the survival rate of cells by inhibiting the activity of CYP1B1 in cells, thereby reversing the drug resistance effect of paclitaxel, increasing the sensitivity of the drug to drug-resistant cells, and thus achieving the purpose of tumor treatment.

[0294] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A heteroaromatic amide derivative having CYP1B1 enzyme inhibitory effect or a pharmaceutically acceptable salt thereof, characterized in that: The structural formula of the derivative is shown in the following general formula I: Wherein, A, B or C is selected from C, N, NH or S; The R1 is selected from substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C 1- C6 alkyl, substituted or unsubstituted C 3- C7 cycloalkyl, substituted or unsubstituted C2-C6 olefin, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3- to 15-membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, alkoxy, alkyl, ester, amide, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, trifluoroacetyl, trifluoromethanesulfonyl, cycloalkyl, olefin, alkynyl, aryl, heteroaryl or heterocyclyl; The R2 is selected from substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C 1- C6 alkyl, substituted or unsubstituted C 3- C7 cycloalkyl, substituted or unsubstituted C2-C6 olefin, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3- to 15-membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, alkoxy, alkyl, ester, amide, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, trifluoroacetyl, trifluoromethanesulfonyl, cycloalkyl, olefin, alkynyl, aryl, heteroaryl or heterocyclyl; The R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C 1- C6 alkyl, substituted or unsubstituted C 3- C7 cycloalkyl, substituted or unsubstituted C2-C6 olefin, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3- to 15-membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, alkoxy, alkyl, ester, amide, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, trifluoroacetyl, trifluoromethanesulfonyl, cycloalkyl, olefin, alkynyl, aryl, heteroaryl or heterocyclyl; The R4 is selected from hydrogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C 1- C6 alkyl, substituted or unsubstituted C 3- C7 cycloalkyl, substituted or unsubstituted C2-C6 alkene, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3- to 15-membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the following group: halogen, cyano, nitro, hydroxyl, amino, alkoxy, alkyl, ester, amide, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, trifluoroacetyl, trifluoromethanesulfonyl, cycloalkyl, alkene, alkynyl, aryl, heteroaryl or heterocyclyl.

2. A heteroaromatic amide derivative or a pharmaceutically acceptable salt thereof having a CYP1B1 enzyme inhibitory effect, characterized in that: The structural formula of the derivative is shown in the following general formula II: Wherein, X, Y or Z is selected from C, N, NH or S; The R5 is selected from substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C 1- C6 alkyl, substituted or unsubstituted C 3- C7 cycloalkyl, substituted or unsubstituted C2-C6 olefin, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3- to 15-membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, alkoxy, alkyl, ester, amide, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, trifluoroacetyl, trifluoromethanesulfonyl, cycloalkyl, olefin, alkynyl, aryl, heteroaryl or heterocyclyl; The R6 is selected from hydrogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C 1- C6 alkyl, substituted or unsubstituted C 3- C7 cycloalkyl, substituted or unsubstituted C2-C6 olefin, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3- to 15-membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, alkoxy, alkyl, ester, amide, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, trifluoroacetyl, trifluoromethanesulfonyl, cycloalkyl, olefin, alkynyl, aryl, heteroaryl or heterocyclyl; The R7 is selected from hydrogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C 1- C6 alkyl, substituted or unsubstituted C 3- C7 cycloalkyl, substituted or unsubstituted C2-C6 olefin, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3- to 15-membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, alkoxy, alkyl, ester, amide, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, trifluoroacetyl, trifluoromethanesulfonyl, cycloalkyl, olefin, alkynyl, aryl, heteroaryl or heterocyclyl; The R8 is selected from hydrogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C 1- C6 alkyl, substituted or unsubstituted C 3- C7 cycloalkyl, substituted or unsubstituted C2-C6 alkene, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3- to 15-membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the following group: halogen, cyano, nitro, hydroxyl, amino, alkoxy, alkyl, ester, amide, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, trifluoroacetyl, trifluoromethanesulfonyl, cycloalkyl, alkene, alkynyl, aryl, heteroaryl or heterocyclyl.

3. The heteroaromatic amide derivative or a pharmaceutically acceptable salt thereof according to claim 1 or claim 2, characterized in that: The halogen is fluorine, chlorine, bromine or iodine; alkyl refers to a straight-chain or branched alkyl; alkoxy refers to an oxygen-containing straight-chain or branched alkoxy; alkylene refers to a straight-chain or branched alkylene; aryl refers to a phenyl or naphthyl group with no substituent or with a substituent; heteroaryl refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O or S; the ring system is aromatic, such as imidazolyl, benzimidazolyl, pyridyl, pyrrolyl, pyrazolyl, (1,2,3)- and (1,2,4)-triazolyl, furanyl, thienyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolyl and isoquinolyl.

4. The method for preparing the heteroaromatic amide derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The structural formula of the derivative is shown in the following general formula I: The method is prepared by route A, route B or route C, wherein when B and C are C (carbon) and R4 is hydrogen, route A is adopted; when A is NH or S, B is N or C (carbon), and R3 and R4 are hydrogen, route B is adopted; when A is S, B is N, and C is C (carbon), route C is adopted, which specifically comprises the following steps: Route A: Route B: Route C: Route A: (1) Preparation of intermediate A-2: A-2 is obtained by reacting aldehydes with different substitutions with sodium p-toluenesulfinate in the presence of an alkaline reagent and an acid reagent. The reaction solvent is selected from one of triethylamine, ethylenediamine, acetamide or formamide. The acid is selected from one or more of hydrochloric acid, formic acid, acetic acid, propionic acid, sulfuric acid, p-toluenesulfonic acid, nitric acid, phosphoric acid, hydrofluoric acid or hydrobromic acid. The amount of the acid is 1.0-8.0 times (M / M molar ratio) of the amount of sodium p-toluenesulfinate. The reaction temperature is 30-100° C. and the reaction time is 5-24 h. (2) Preparation of intermediate A-3: A-2 is reacted with phosphorus oxychloride under alkaline reagent conditions to obtain A-3, wherein the base is selected from one or more of triethylamine, ethylenediamine, acetamide or formamide; the amount of the base used is 1.0-4.0 times the amount of phosphorus oxychloride used (M / M molar ratio), the reaction temperature is -10-40°C, and the reaction time is 0.5-5h; (3) Preparation of intermediate A-5: A-3 and A-4 react under the action of a strong base to obtain compound A-5, the base reagent selected is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium bicarbonate, sodium methoxide, potassium tert-butoxide, 1,8-diazabicycloundec-7-ene or potassium phosphate, and the amount of the base reagent used is 1.0-8.0 times the amount of A-4 (M / M molar ratio); the solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, acetone, dimethylformamide or propylene glycol; the reaction temperature is 30-100°C, and the reaction time is 1-12h; (4) Preparation of intermediate A-6: A-5 is hydrolyzed under acidic or alkaline conditions, the acid catalyst selected is one or more of sulfuric acid, hydrochloric acid or phosphoric acid; the base catalyst selected is sodium hydroxide or potassium hydroxide; the amount of the alkaline reagent used is 1.0-5.0 times the amount of A-5 (M / M molar ratio); the solvent is one or more of methanol, ethanol, acetonitrile, tetrahydrofuran or water; the reaction temperature is 30-100°C, and the reaction time is 1-12h; (5) Preparation of A-Ⅰ: A-6 is reacted with different substituted amines to form amides to obtain A-Ⅰ. The reaction reagents used are oxalyl chloride, N,N-dimethylformamide, thionyl chloride, phosphorus oxychloride, ethyl chloroformate or isobutyl chloroformate, carbonyldiimidazole (CDI), dimethyl trifluoromethanesulfonate (CBMIT), di-tert-butyl dicarbonate (Boc2O), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride (NsCl), dicyclohexylcarbodiimide (DCC), diisopropylcarbonate, diimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-N,N-dimethylpyridine (DMAP), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine or diisopropylethylamine (DIEA, Hunigbase), O-(7-azabenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (H BTU), O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate (TBTU), O-(N-succinimidyl)-bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarbodiimide)-bis(dimethylamino)carbonium tetrafluoroborate (TNTU), benzotriazol-1-yloxy - one or more of tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA), thiodimethylphosphoryl azide (MPTA) or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl); the solvent is one or more of dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the reaction temperature is 0-100°C, and the reaction time is 1-12h; Route B: (1) Preparation of intermediate B-2: B-1 is reacted with different substituted amines to form amides to obtain B-2. The reaction reagents used are oxalyl chloride, N,N-dimethylformamide, dichlorothionyl, phosphorus oxychloride, ethyl chloroformate or isobutyl ester, carbonyldiimidazole (CDI), dimethyl trifluoromethanesulfonate (CBMIT), di-tert-butyl dicarbonate (Boc2O), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride (NsCl), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-N,N-dimethylpyridine (DMAP), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine or diisopropylethylamine (DIEA, Hunig base), O-(7-azabenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HBTU), O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate (TBTU), O-(N-succinimidyl)-bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarbonyl) One or more of diimide)-bis(dimethylamino)carbonium tetrafluoroborate (TNTU), benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA), thiodimethylphosphoryl azide (MPTA) or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl); the solvent is one or more of dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the reaction temperature is 0-100°C, and the reaction time is 1-12h; (2) Preparation of B-Ⅰ: B-2 is coupled with a different substituted boronic acid or boronic ester to obtain B-Ⅰ. The coupling catalyst selected is tetrakis(triphenylphosphine)palladium, palladium acetate, diphenylphosphinocene palladium dichloride, ditriphenylphosphine palladium dichloro, di(tri-tert-butylphosphine)palladium or dba (dibenzylideneacetone) (such as Pd(dba)2 and Pd2(dba)3, etc.); the alkaline reagent selected is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, potassium tert-butoxide or potassium phosphate; the amount of the different substituted boronic acid or boronic ester used is 1.0-4.0 times the amount of B-2 (M / M molar ratio); the solvent is one or more of water, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane or dimethyl sulfoxide; the reaction temperature is 80-150°C, and the reaction time is 1-12h; Route C: (1) Preparation of intermediate C-2: C-1 and C-2 undergo a cyclization reaction and then add an alkaline reagent for hydrolysis to obtain C-3. The alkaline reagent selected is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, potassium tert-butoxide, 1,8-diazabicycloundec-7-ene or potassium phosphate. The solvent is one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane or dimethyl sulfoxide. The reaction temperature is 50-100°C and the reaction time is 1-24h. (2) Preparation of C-Ⅰ: C-3 is reacted with different substituted amines to form amides to obtain C-Ⅰ. The reaction reagents used are oxalyl chloride, N,N-dimethylformamide, thionyl chloride, phosphorus oxychloride, ethyl chloroformate or isobutyl chloroformate, carbonyldiimidazole (CDI), dimethyl trifluoromethanesulfonate (CBMIT), di-tert-butyl dicarbonate (Boc2O), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride (NsCl), dicyclohexylcarbodiimide (DCC), diisopropylcarbonate diimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-N,N-dimethylpyridine (DMAP), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine or diisopropylethylamine (DIEA, Hunigbase), O-(7-azabenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (H BTU), O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate (TBTU), O-(N-succinimidyl)-bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarbodiimide)-bis(dimethylamino)carbonium tetrafluoroborate (TNTU), benzotriazol-1-yloxy -tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA, thiodimethylphosphoryl azide (MPTA) or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl) or more; the solvent is one or more of dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the reaction temperature is 0-100°C, and the reaction time is 1-12h.

5. The method for preparing the heteroaromatic amide derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The structural formula of the derivative is shown in the following general formula II: The method is prepared by route D, route E, route F, route G or route H, wherein when X is C (carbon), Y is S, and Z is N, route D, E, G or H is adopted; when X is N, Y is S, and Z is C (carbon), route F is adopted, which specifically comprises the following steps: Route D: Route E: Route F: Route G: Route H: Route D: (1) Preparation of intermediate D-2: D-1 is subjected to a cyclization reaction with ethyl thiooxamate and then an alkaline reagent is added for hydrolysis to obtain D-2. The alkaline reagent selected is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, potassium tert-butoxide, 1,8-diazabicycloundec-7-ene or potassium phosphate. The solvent is one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane or dimethyl sulfoxide. The reaction temperature is 50-100°C and the reaction time is 1-24h. (2) Preparation of D-Ⅱ: D-2 is reacted with different substituted amines to form amides to obtain D-Ⅱ. The reaction reagents used are oxalyl chloride, N,N-dimethylformamide, dichlorothionyl, phosphorus oxychloride, ethyl chloroformate or isobutyl ester, carbonyldiimidazole (CDI), dimethyl trifluoromethanesulfonate (CBMIT), di-tert-butyl dicarbonate (Boc2O), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride (NsCl), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-N,N-dimethylpyridine (DMAP), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine or diisopropylethylamine (DIEA, Hunig base), O-(7-azabenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HBTU), O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate (TBTU), O-(N-succinimidyl)-bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarbonyl) One or more of diimide)-bis(dimethylamino)carbonium tetrafluoroborate (TNTU), benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA), thiodimethylphosphoryl azide (MPTA) or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl); the solvent is one or more of dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the reaction temperature is 0-100°C, and the reaction time is 1-12h; Route E: (1) Preparation of intermediate E-2: E-1 is reacted with different substituted amines to form amides to obtain E-2. The reaction reagents used are oxalyl chloride, N,N-dimethylformamide, dichlorothionyl, phosphorus oxychloride, ethyl chloroformate or isobutyl ester, carbonyldiimidazole (CDI), dimethyl trifluoromethanesulfonate (CBMIT), di-tert-butyl dicarbonate (Boc2O), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride (NsCl), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-N,N-dimethylpyridine (DMAP), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine or diisopropylethylamine (DIEA, Hunig base), O-(7-azabenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HBTU), O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate (TBTU), O-(N-succinimidyl)-bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-di one or more of di(dimethylamino)carbonium tetrafluoroborate (TNTU), benzotriazol-1-yloxy-tri(tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), diethylphosphorocyanide (DECP), diphenylphosphoryl azide (DPPA, thiodimethylphosphoryl azide (MPTA) or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl); the solvent is one or more of dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the reaction temperature is 0-100°C, and the reaction time is 1-12h; (2) Preparation of E-Ⅱ: E-2 is coupled with a different substituted boronic acid or boronic ester to obtain E-Ⅱ. The coupling catalyst selected is tetrakis(triphenylphosphine)palladium, palladium acetate, diphenylphosphinocene palladium dichloride, ditriphenylphosphine palladium dichloro, di(tri-tert-butylphosphine)palladium or dba (dibenzylideneacetone) (such as Pd(dba)2 and Pd2(dba)3, etc.); the alkaline reagent selected is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, potassium tert-butoxide or potassium phosphate; the amount of the different substituted boronic acid or boronic ester used is 1.0-4.0 times the amount of E-2 (M / M molar ratio); the solvent is one or more of water, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane or dimethyl sulfoxide; the reaction temperature is 80-150°C, and the reaction time is 1-12h; Route F: (1) Preparation of intermediate F-2: F-1 is reacted with different substituted amines to form amides to obtain F-2. The reaction reagents used are oxalyl chloride, N,N-dimethylformamide, dichlorothionyl, phosphorus oxychloride, ethyl chloroformate or isobutyl ester, carbonyldiimidazole (CDI), dimethyl trifluoromethanesulfonate (CBMIT), di-tert-butyl dicarbonate (Boc2O), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride (NsCl), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-N,N-dimethylpyridine (DMAP), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine or diisopropylethylamine (DIEA, Hunig base), O-(7-azabenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HBTU), O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate (TBTU), O-(N-succinimidyl)-bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarbonyl) One or more of diimide)-bis(dimethylamino)carbonium tetrafluoroborate (TNTU), benzotriazol-1-yloxy-tris(tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA), thiodimethylphosphoryl azide (MPTA) or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl); the solvent is one or more of dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the reaction temperature is 0-100°C, and the reaction time is 1-12h; (2) Preparation of F-Ⅱ: F-2 is coupled with a different substituted boronic acid or boronic ester to obtain E-Ⅱ. The coupling catalyst selected is tetrakis(triphenylphosphine)palladium, palladium acetate, diphenylphosphinocene palladium dichloride, ditriphenylphosphine palladium dichloro, di(tri-tert-butylphosphine)palladium or dba (dibenzylideneacetone) (such as Pd(dba)2 and Pd2(dba)3, etc.); the alkaline reagent selected is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, potassium tert-butoxide or potassium phosphate, etc.; the amount of the different substituted boronic acid or boronic ester used is 1.0-4.0 times the amount of F-2 (M / M molar ratio); the solvent is one or more of water, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane or dimethyl sulfoxide; the reaction temperature is 80-150°C, and the reaction time is 1-12h; Route G: (1) Preparation of intermediate G-2: G-1 is reacted with trimethylsilyl bromide to obtain G-2, and the solvent used is one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane or dimethyl sulfoxide; the reaction temperature is 0-100°C, and the reaction time is 1-24h; (2) Preparation of intermediate G-3: G-2 is oxidized to G-3, and the oxidant selected is one or more of Dess-Martin reagent, manganese dioxide, hydrogen peroxide, oxygen, pyridinium dichromate, pyridinium chlorochromate, diacetate iodobenzene, sodium hypochlorite, iodine, dichloroiodobenzene, iodosobenzene or trichloroisocyanuric acid; the catalyst is selected from tetraacetonitrile copper hexafluorophosphate, tetra(acetonitrile)tetrafluoroborate copper (I), tetra(acetonitrile)trifluoromethanesulfonate, (2,2,6,6-tetramethyl 4-Acetylpiperidin-1-yl)oxyl free radical, 4-acetylamino-2,2,6,6-tetramethylpiperidin-1-oxyl free radical, 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl free radical, 4-methacryloyloxy-2,2,6,6-tetramethylpiperidin-1-oxyl free radical, 4-oxo-2,2,6,6-tetramethyl-1-piperidinoxyl free radical, 4-amino-2,2,6,6-tetramethylpiperidin-1-oxyl free radical, 4 -Carboxy-2,2,6,6-tetramethylpiperidinyl 1-oxyl free radical, 4-hydroxy-2,2,6,6-tetramethylpiperidinyl 1-oxyl benzoate, 4-(2-iodoacetamide)-2,2,6,6-tetramethyl-1-piperidinyloxy free radical, 4-maleimido-2,2,6,6-tetramethyl-1-piperidinyloxy free radical, 4-isothiocyanate-2,2,6,6-tetramethylpiperidinyl 1-oxyl free radical, 4-methoxy-2,2 ,6,6-tetramethyl-1-piperidinyloxy free radical or 4-phosphoryloxy-2,2,6,6-tetramethyl-1-piperidinyloxy free radical; the molar amount of the oxidant is 1.0-6.0 times that of compound 3; the reaction solvent is acetonitrile, tetrahydrofuran, dichloromethane, acetone, dioxane, toluene, ethyl acetate, methanol, dimethylformamide, dimethyl sulfoxide or a mixture of two or more thereof; the reaction temperature is 0°C-80°C, and the reaction time is 1-24h; (3) Preparation of intermediate G-4: G-3 is subjected to a cyclization reaction with ethyl thiooxamate and then an alkaline reagent is added for hydrolysis to obtain G-4, wherein the alkaline reagent is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, potassium tert-butoxide, 1,8-diazabicycloundec-7-ene or potassium phosphate, and the solvent is one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane or dimethyl sulfoxide; the reaction temperature is 50-100°C, and the reaction time is 1-24h; (4) Preparation of intermediate G-Ⅱ: G-4 is reacted with amines of different substitutions to form amides to obtain G-Ⅱ. The reaction reagents used are oxalyl chloride, DMF, thionyl chloride, phosphorus oxychloride, ethyl chloroformate, isobutyl ester, carbonyldiimidazole (CDI), dimethyl trifluoromethanesulfonate (CBMIT), di-tert-butyl dicarbonate (Boc2O), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride (NsCl), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide ( DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-N,N-dimethylpyridine (DMAP), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine or diisopropylethylamine (DIEA, Hunigbase), O-(7-azabenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HBTU ), O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate (TBTU), O-(N-succinimidyl)-bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarbodiimide)-bis(dimethylamino)carbonium tetrafluoroborate (TNTU), benzotriazol-1-yloxy-tri(2-nitro-1-ol)-bis ​​... One or more of (tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA), thiodimethylphosphoryl azide (MPTA) or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl); the solvent is one or more of dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the reaction temperature is 0-100°C, and the reaction time is 1-12h; Route H: (1) Preparation of intermediate H-2: H-1 is hydrolyzed under acidic or alkaline conditions to obtain H-2, the acid catalyst selected is one or more of sulfuric acid, hydrochloric acid or phosphoric acid; the base catalyst selected is sodium hydroxide or potassium hydroxide; the amount of the alkaline reagent used is 1.0-5.0 times the amount of H-1 (M / M molar ratio); the solvent is one or more of methanol, ethanol, acetonitrile, tetrahydrofuran or water; the reaction temperature is 30-100°C, and the reaction time is 1-6h; (2) Preparation of intermediate H-3: H-2 is reacted with different substituted amines to form amides to obtain H-3. The reaction reagents used are oxalyl chloride, DMF, thionyl chloride, phosphorus oxychloride, ethyl chloroformate or isobutyl chloroformate, carbonyl diimidazole (CDI), dimethyl trifluoromethanesulfonate (CBMIT), di-tert-butyl dicarbonate (Boc2O), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride (NsCl), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide ( DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-N,N-dimethylpyridine (DMAP), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine or diisopropylethylamine (DIEA, Hunigbase), O-(7-azabenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HBTU ), O-(5-chlorobenzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate (HCTU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate (TBTU), O-(N-succinimidyl)-bis(dimethylamino)carbonium tetrafluoroborate (TSTU), O-(N-endo-5-norbornene-2,3-dicarbodiimide)-bis(dimethylamino)carbonium tetrafluoroborate (TNTU), benzotriazol-1-yloxy-tri(2-nitro-1-ol)-bis ​​... One or more of (tetrahydropyrrolyl)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA), thiodimethylphosphoryl azide (MPTA) or bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOP-Cl); the solvent is one or more of dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide; the reaction temperature is 0-100°C, and the reaction time is 1-12h; (3) Preparation of intermediate H-Ⅱ: H-3 is coupled with differently substituted boronic acids or boronic esters to obtain H-Ⅱ. The coupling catalyst selected is tetrakis(triphenylphosphine)palladium, palladium acetate, diphenylphosphinocene palladium dichloride, ditriphenylphosphine palladium dichloro, di(tri-tert-butylphosphine)palladium or dba (dibenzylideneacetone) (such as Pd(dba)2 and Pd2(dba)3, etc.); the alkaline reagent selected is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium methoxide, potassium tert-butoxide or potassium phosphate; the amount of differently substituted boronic acids or boronic esters used is 1.0-4.0 times (M / M molar ratio) of the amount of E-2 used; the solvent is one or more of water, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane or dimethyl sulfoxide; the reaction temperature is 80-150°C, and the reaction time is 1-12h.

6. The heteroaromatic amide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The heteroaromatic amide derivatives or pharmaceutically acceptable salts thereof have potent inhibitory activity and high selectivity on the CYP1B1 enzyme, and can inhibit the conversion of pro-carcinogens metabolized by the CYP1B1 enzyme into carcinogens.

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the heteroaromatic amide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 6 and a pharmaceutically acceptable carrier.

8. Use of the heteroaromatic amide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 6 in the preparation of a CYP1B1 enzyme inhibitor.

9. Use of the heteroaromatic amide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 6 in the preparation of an anti-tumor drug resistant to CYP1B1 enzyme, characterized in that: The heteroaromatic amide derivative or a pharmaceutically acceptable salt thereof is used in combination with other anti-tumor drugs to increase the sensitivity of the other anti-tumor drugs.

10. Use of the heteroaromatic amide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 6 in the preparation of antitumor drugs.

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