A novel synthetic method for TDMQ molecules

Abstract

This invention belongs to the field of chemical synthesis technology and discloses a novel synthetic method for TDMQ molecules. Given the previous development of a series of novel tetradentate chelating agents with specific recognition of copper ions, referred to as TDMQ, TDMQ20 was selected as a preferred candidate drug from the TDMQ series. To meet the requirements of regulatory compliance in preclinical and clinical trials, large-scale synthesis of this candidate drug is crucial. However, previously disclosed synthetic routes and processes for TDMQ20 and its analogues cannot meet the requirements for large-scale production. Therefore, this application develops a novel synthetic process route using commercially available quinoline derivatives as starting materials, sequentially proceeding through reduction, optional amino protection, methyl oxidation to formyl, olefination to construct a carbon-carbon double bond, side chain addition, deprotection, and salt formation to prepare the target compound. This route follows the core principles of green chemistry and features high yields in each step and a small number of synthetic steps.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis technology and relates to a novel synthetic method for TDMQ molecules. Background Technology

[0002] This invention relates to the field of Wilson's disease (WD) and Alzheimer's disease (AD), and the subject matter of this invention is protected in the applicant's previously granted patents. This technology is based on "a novel tetradentate ligand for metal modulation in neurodegenerative diseases," for which the following patents have been granted:

[0003] Y. LIU, XG LIU, W. HUANG, D. WANG, M. NGUYEN, A. ROBERT, B.MEUNIER.

[0004] Chinese invention patent application: 201610369550.X, application date May 27, 2016, grant date May 21, 2018.

[0005] PCT International Application: PCT / CN2017 / 085886, application date May 25, 2017.

[0006] US Patent: US 10807957 B2, granted on October 20, 2020.

[0007] Canadian Patent: 3025406, granted on June 1, 2021.

[0008] Japanese Patent: 6889825, granted on May 26, 2021.

[0009] European Patent: EP3466931, granted on January 10, 2024.

[0010] Following the publication of the aforementioned patents in the TDMQ series, the inventors of this application reported a method for synthesizing such copper chelators in the journal ChemMedChem (Reference 1); at the same time, they also published several papers on the pharmacological activity of the preferred candidate drug TDMQ20, including references 2 and 3 on Alzheimer's disease (AD) and references 4 and 5 on Wilson's disease (WD).

[0011] Alzheimer's disease (AD) is an age-related disease whose pathogenesis is associated with multiple factors, including dysregulation of copper homeostasis in the brain and the accumulation of amyloid peptides. When the copper-amyloid complex is reduced by endogenous reducing agents, reactive oxygen species (ROS) are generated, which in turn damage neurons. The inventors of this application have reported this in detail in the review in Reference 6.

[0012] Wilson's disease (WD) is a genetic disorder caused by a mutation in the Atp7b gene, which encodes a copper transporter responsible for removing excess copper from the liver. Globally, this autosomal recessive disorder of copper metabolism affects approximately 1 in 30,000 people. The ATP7b protein transports excess copper from the liver into bile, from which it is then excreted in feces. When this copper transporter malfunctions, excess copper is released into the bloodstream and slowly excreted in urine, leading to copper accumulation in the liver and eventually chronic hepatitis and cirrhosis. Ultimately, excess copper is detected in the brain, resulting in neurological disorders (see reference 7 for a related review).

[0013] References.

[0014] 1.Preparation of new tetradentate copper chelators as potential anti-Alzheimer agents.Weixin ZHANG, Daya HUANG, Meijie HUANG, Ju HUANG, Dean WANG, Xingguo LIU, Michel NgUYEN, Laure VENDIER, Serge MAZÈRES, Anne ROBERT YanLIU, Bernard MEUNIER. ChemMedChem., 13, 684-704 (2018).

[0015] 2.TDMQ20, a specific copper chelator, reduces memory impairments inAD mouse models.Jie ZHAO, Qihui SHI, Hongda TIAN, Youzhi LI, Yan LIU, ZhenXU, Anne ROBERT, Quiong LIU, Bernard MEUNIER. ACS Chem. Neurosc., 12, 140-149(2021).

[0016] 3.Proteomics evidences of the role of TDMQ20 in the cholinergicsystem and synaptic transmission in a mouse model of Alzheimer’sdisease.Fanfan SUN, Jie ZHIAO, Huajie ZHANG, Qihui SHI, Yan LIU, Anne ROBERT,Qiong LIU, Bernard MEUNIER. ACS Chem. Neurosci. 13, 3093-3107 (2022).

[0017] 4.The Specific Copper(II) Chelator TDMQ20 Is Efficient for theTreatment of Wilson’s Disease in Mice. Yingshan ZHU, Ying TANG, Lan HUANG,Michel NGUYEN, Yan LIU, Anne ROBERT, Bernard MEUNIER. Pharmaceuticals, 15, 2719(2023).

[0018] 5.TDMQ20 as drug candidate for Wilson's disease: comparison with D-penicillamine, trientine and tetrathiomolybdate in vitro and in mice. YingshanZHU, Weiling PENG, Guangwei LIU, Longxi LI, Zikang ZHOU, Michel NGUYEN, AnneROBERT, Yan LIU, Bernard MEUNIER. Pharmaceuticals,17 , 1237 (2025).

[0019] 6. Metal ions in Alzheimer's disease: a key role or not? Yan LIU, Michel NGUYEN, Anne ROBERT, Bernard MEUNIER. Acc. Chem. Res., 52 , 2026-2035(2019).

[0020] 7.Wilson's disease: revisiting an old friend.Ana LUCENA-VALERO and al., World J. Hepatol., 13, 634-649 (2021). Summary of the Invention

[0021] To adhere to green chemistry principles (i.e., reducing chemical waste through high-yield synthetic routes), the applicant has improved the synthetic methods for TDMQ20 and its analogues. To this end, this application discloses three different synthetic routes for the candidate drug TDMQ20. The applicant has successfully applied these three different routes to other TDMQ examples, and therefore believes that such routes are applicable to all possible different molecules in the TDMQ series.

[0022] In the optimal synthesis scheme, the applicant achieved an overall yield of 50.4%, compared to only 12.2% in the aforementioned reference 1 (ChemMedChem, 2018). Under conditions of complete conversion of the 1-gram starting material TDMQ20-NO2, the separation yield of the first step in the synthetic route was only 20% (see the reaction below); when the scale was increased to 5 grams, under the same complete conversion conditions, the yield dropped sharply to below 10%, and further increased to 50 grams, the yield fell below 5% (the synthetic route based on the oxidation of potassium persulfate to synthesize the core intermediate is difficult to industrialize). Therefore, the first step of this synthetic route is a key bottleneck restricting the overall process yield and the feasibility of industrial scale-up.

[0023]

[0024] In contrast, the newly developed synthetic route in this application has excellent linearity for scale-up. When performing a 100-gram scale-up synthesis, the yield remains stable without decreasing, as shown in the following specific embodiments and their scale-up verification.

[0025] The three synthetic routes described in this invention have stable process performance and are all suitable for industrial-scale production.

[0026] Accordingly, the present invention provides an alternative solution to the predicament of the inability to industrialize TDMQ20 and related compounds on a large scale, the solution comprising:

[0027] A method for preparing TDMQ20 or a pharmaceutically acceptable salt thereof, wherein TDMQ20 has the following structural formula:

[0028] The method includes the following steps:

[0029] (a) The compound 5,7-dichloro-2-methyl-8-nitroquinoline was reduced to give 8-amino-5,7-dichloro-2-methylquinoline;

[0030] (b) Optionally, the amino group in 8-amino-5,7-dichloro-2-methylquinoline is protected by a protecting group selected from acetyl, diacetyl, or pivaloyl; or, the subsequent reaction is carried out directly without amino protection.

[0031] (c) Oxidize the methyl group at the 2-position of the quinoline ring of the compound obtained in step (b) to a formyl group;

[0032] (d) Converting the formyl group to a vinyl group via any of the following reactions:

[0033] i) Peterson olefination reaction;

[0034] ii) Wittig reaction;

[0035] iii) The Grignard addition reaction is followed by a dehydration elimination reaction;

[0036] (e) The vinyl group of the compound obtained in step (d) is reacted with N,N-dimethylethylenediamine to introduce a side chain;

[0037] (f) If the amino group was protected in step (b), then remove the protecting group;

[0038] (g) The resulting compound is converted into a pharmaceutically acceptable salt of TDMQ20.

[0039] Preferably, the pharmaceutically acceptable salt is selected from hydrochloride or sulfate.

[0040] Preferably, in step (d), the reaction that converts the formyl group to the vinyl group is a Peterson olefination reaction.

[0041] Preferably, the protecting group used in step (b) is an acetyl group, including the following steps of route A-1:

[0042] (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline;

[0043] (b) Acetylation of the amino group with acetyl chloride to prepare N-(5,7-dichloro-2-methylquinoline-8-yl)acetamide;

[0044] (c) N-(5,7-dichloro-2-aldehydequinoline-8-yl)acetamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80 ℃~90 ℃;

[0045] (d) Reaction with (trimethylsilyl)methylmagnesium chloride to prepare N-(5,7-dichloro-2-(1-hydroxy-2-(trimethylsilyl)ethyl)quinoline-8-yl)acetamide;

[0046] (e) N-(5,7-dichloro-2-vinylquinoline-8-yl)acetamide was prepared by treatment with trimethylsilyl trifluoromethanesulfonate at 45 ℃~55 ℃;

[0047] (f) N-(5,7-dichloro-2-(2-((2-(dimethylamino)ethyl)amino)ethyl)quinoline-8-yl)acetamide was prepared by reacting N,N-dimethylethylenediamine in the presence of potassium carbonate, with 1,4-dioxane as solvent, at 80 ℃~90 ℃.

[0048] (g) TDMQ20 trihydrochloride was prepared by treating with hydrochloric acid in ethanol at 80℃~90℃ to remove protection and form salt.

[0049] Preferably, the protecting group in step (b) is a pivaloyl group, and the method includes the following steps of route A-2:

[0050] (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline;

[0051] (b) In the presence of triethylamine, N-(5,7-dichloro-2-methylquinoline-8-yl)pentylamide was prepared by reacting it with pentyl chloride.

[0052] (c) N-(5,7-dichloro-2-aldehydequinoline-8-yl)pentylamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80℃~90℃;

[0053] (d) Reaction with (trimethylsilyl)methylmagnesium chloride to prepare N-(5,7-dichloro-2-(1-hydroxy-2-(trimethylsilyl)ethyl)quinoline-8-yl)pentanamide;

[0054] (e) N-(5,7-dichloro-2-vinylquinoline-8-yl) terpentamide was prepared by treatment with trimethylsilyl trifluoromethanesulfonate at 45℃~55℃;

[0055] (f) N-(5,7-dichloro-2-(2-((2-(dimethylamino)ethyl)amino)ethyl)quinoline-8-yl)pentanamide was prepared by reacting N,N-dimethylethylenediamine in the presence of potassium carbonate and 1,4-dioxane at 80-90°C.

[0056] (g) TDMQ20 trihydrochloride was prepared by treating it with hydrochloric acid at 80℃~90℃ in 1,4-dioxane to remove protection and form a salt.

[0057] Preferably, in step (d), the reaction that converts the formyl group to the vinyl group is the Wittig reaction.

[0058] Preferably, the protecting group in step (b) is an acetyl group, including the following steps of route B-1:

[0059] (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline;

[0060] (b) Acetylating the amino group with acetyl chloride to prepare N-(5,7-dichloro-2-methylquinoline-8-yl)acetamide;

[0061] (c) N-(5,7-dichloro-2-formylquinoline-8-yl)acetamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80-90°C;

[0062] (d) N-(5,7-dichloro-2-vinylquinoline-8-yl)acetamide was prepared by reacting methyltriphenylphosphonium bromide with tetrahydrofuran in the presence of potassium carbonate;

[0063] (e) N-(5,7-dichloro-2-(2-((2-(dimethylamino)ethyl)amino)ethyl)quinoline-8-yl)acetamide was prepared by reacting N,N-dimethylethylenediamine in the presence of potassium carbonate and in 1,4-dioxane at 80°C to 90°C;

[0064] (f) TDMQ20 trihydrochloride was prepared by treating it with hydrochloric acid in ethanol at 80℃~90℃ to remove protection and form salt.

[0065] Preferably, the protecting group in step (b) is a pivaloyl group, including the following steps of route B-2:

[0066] (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline;

[0067] (b) In the presence of triethylamine, the amino group reacts with pivaloyl chloride to prepare N-(5,7-dichloro-2-methylquinoline-8-yl)pivalamide;

[0068] (c) N-(5,7-dichloro-2-formylquinoline-8-yl)pentylamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80℃~90℃;

[0069] (d) N-(5,7-dichloro-2-vinylquinoline-8-yl)pentanamide was prepared by reacting methyltriphenylphosphonium bromide with tetrahydrofuran in the presence of potassium carbonate;

[0070] (e) N-(5,7-dichloro-2-(2-((2-(dimethylamino)ethyl)amino)ethyl)quinoline-8-yl)pentanamide was prepared by reacting N,N-dimethylethylenediamine in the presence of potassium carbonate and 1,4-dioxane at 80°C to 90°C.

[0071] (f) TDMQ20 trihydrochloride was prepared by treating it with hydrochloric acid at 80℃~90℃ in 1,4-dioxane to remove protection and form a salt.

[0072] Preferably, the method includes the steps of route B-3 and does not require prior protection of the amino group:

[0073] (a) 5,7-dichloro-8-nitroquinoline-2-carboxaldehyde was prepared by oxidizing 5,7-dichloro-2-methyl-8-nitroquinoline with selenium dioxide in 1,4-dioxane at 100℃~110℃.

[0074] (b) 8-amino-5,7-dichloroquinoline-2-carboxaldehyde was prepared by reduction with iron powder and acetic acid in ethanol at 80-90°C.

[0075] (c) In the presence of potassium carbonate and in tetrahydrofuran, methyltriphenylphosphonium bromide was reacted with phosphonium bromide to prepare 8-amino-5,7-dichloro-2-vinylquinoline;

[0076] (d) In the presence of potassium carbonate and 1,4-dioxane at 80-90°C, the compound obtained in step (c) was reacted with N,N-dimethylethylenediamine to prepare N. 1 -(2-(8-amino-5,7-dichloroquinoline-2-yl)ethyl)-N 2 N 2 -Dimethylethane-1,2-diamine;

[0077] (e) TDMQ20 trihydrochloride was prepared by salting in ethanol with hydrochloric acid.

[0078] Preferably, in step (d), the reaction that converts the formyl group to the vinyl group is a Grignard addition reaction followed by a dehydration elimination reaction.

[0079] Preferably, the protecting group in step (b) is a diacetyl group, and the method includes the following steps of route C-1:

[0080] (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline;

[0081] (b) In the presence of N,N-diisopropylethylamine, N-acetyl-N-(5,7-dichloro-2-methylquinoline-8-yl)acetamide was prepared by reaction with acetyl chloride.

[0082] (c) N-acetyl-N-(5,7-dichloro-2-aldehydequinoline-8-yl)acetamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80-90°C;

[0083] (d) N-(5,7-dichloro-2-(1-hydroxyethyl)quinoline-8-yl)acetamide was prepared by reacting methylmagnesium bromide in tetrahydrofuran;

[0084] (e) 8-amino-5,7-dichloro-2-vinylquinoline was prepared by dehydration with sulfuric acid at 120°C to 140°C;

[0085] (f) N,N-dimethylethylenediamine was reacted with 1,4-dioxane at 40-50°C to prepare N 1 -(2-(8-amino-5,7-dichloroquinoline-2-yl)ethyl)-N 2 N 2 -Dimethylethane-1,2-diamine;

[0086] (g) TDMQ20 trihydrochloride was prepared by salting in ethanol with hydrochloric acid.

[0087] Preferably, the protecting group in step (b) is an acetyl group, and the method includes the following steps of route C-2:

[0088] (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline;

[0089] (b) N-(5,7-dichloro-2-methylquinoline-8-yl)acetamide was prepared by acetyl chloride-p-aminoacetylation;

[0090] (c) N-(5,7-dichloro-2-aldehydequinoline-8-yl)acetamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80-90°C;

[0091] (d) N-(5,7-dichloro-2-(1-hydroxyethyl)quinoline-8-yl)acetamide was prepared by reacting methylmagnesium bromide in tetrahydrofuran;

[0092] (e) 8-amino-5,7-dichloro-2-vinylquinoline was prepared by dehydration with sulfuric acid at 120°C to 140°C.

[0093] (f) N,N-dimethylethylenediamine was reacted with 1,4-dioxane at 40-50°C to prepare N 1 -(2-(8-amino-5,7-dichloroquinoline-2-yl)ethyl)-N 2 N 2 -Dimethylethane-1,2-diamine;

[0094] (g) TDMQ20 trihydrochloride was prepared by salting in ethanol with hydrochloric acid.

[0095] Preferably, the protecting group in step (b) is a pivaloyl group, and the method includes the following steps of route C-3:

[0096] (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline;

[0097] (b) In the presence of triethylamine, N-(5,7-dichloro-2-methylquinoline-8-yl)pentylamide was prepared by reacting it with pentyl chloride.

[0098] (c) N-(5,7-dichloro-2-formylquinoline-8-yl) terpentamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80-90°C;

[0099] (d) N-(5,7-dichloro-2-(1-hydroxyethyl)quinoline-8-yl)pentanamide was prepared by reacting methylmagnesium bromide in tetrahydrofuran;

[0100] (e) 8-amino-5,7-dichloro-2-vinylquinoline was prepared by dehydration with sulfuric acid at 120°C to 140°C.

[0101] (f) N,N-dimethylethylenediamine was reacted with 1,4-dioxane at 40-50°C to prepare N 1 -(2-(8-amino-5,7-dichloroquinoline-2-yl)ethyl)-N 2 N 2 -Dimethylethane-1,2-diamine;

[0102] (g) TDMQ20 trihydrochloride was prepared by salting in ethanol with hydrochloric acid.

[0103] Preferably, the method includes the steps of route C-4 and does not require prior protection of the amino group:

[0104] (a) 5,7-dichloro-8-nitroquinoline-2-carboxaldehyde was prepared by oxidizing 5,7-dichloro-2-methyl-8-nitroquinoline with selenium dioxide in 1,4-dioxane at 110℃~120℃.

[0105] (b) 8-amino-5,7-dichloroquinoline-2-carboxaldehyde was prepared by reduction in ethanol using iron powder and acetic acid;

[0106] (c) Reacting an aldehyde with methyl magnesium bromide in tetrahydrofuran to prepare 1-(8-amino-5,7-dichloroquinoline-2-yl)ethanol-1-ol;

[0107] (d) The alcohol was treated with sulfuric acid at 120°C to 140°C to prepare 8-amino-5,7-dichloro-2-vinylquinoline;

[0108] (e) The vinyl compound is reacted with N,N-dimethylethylenediamine in 1,4-dioxane at 40°C to 50°C to obtain N 1 -(2-(8-amino-5,7-dichloroquinoline-2-yl)ethyl)-N 2 N 2 -Dimethylethane-1,2-diamine;

[0109] (f) TDMQ20 trihydrochloride was prepared by salting in ethanol with hydrochloric acid.

[0110] Compared with the prior art, the beneficial effects of the present invention are:

[0111] 1. Significantly improved overall synthesis yield: The existing public route (ChemMedChem 2018) has an overall yield of only 12.2%, and the yield drops sharply after scale-up: only 20% for 1 gram, less than 10% for 5 grams, and less than 5% for 50 grams; the new process routes developed in this invention have an optimal overall yield of up to 50.4%, and the other routes can reach 29.3%, 30.3%, 45.0%, etc., with the yield increased several times, significantly reducing raw material costs and the generation of waste.

[0112] 2. The process has good stability for scale-up and is suitable for large-scale industrial production: Existing processes cannot be scaled up, and the yield drops precipitously after scale-up, which does not meet the needs of industrial production; The synthesis route of this invention has no significant decrease in yield under scale-up conditions of 5 to 100 grams, excellent process linearity, good reaction repeatability, and mild conditions, which is fully suitable for kilogram-level industrial production and solves the bottleneck of existing technologies that cannot be prepared on a large scale.

[0113] 3. Multiple synthetic routes with greater process tolerance and substitution potential: This invention simultaneously develops three major synthetic routes: Peterson olefination, Wittig reaction, and Grignard addition-dehydration. Production can switch routes based on raw materials, equipment conditions, and reagent availability, avoiding the risk of being limited by a single process, and has a wider coverage and stronger production practicality.

[0114] 4. Adhering to green chemistry principles, the reaction conditions are mild: conventional organic solvents (1,4-dioxane, tetrahydrofuran, ethanol, etc.) are used throughout the process, and the reaction temperature is concentrated between 40 and 140°C. There are no extreme high temperatures or pressures, and no highly toxic or hazardous reagents. Each step of the reaction has high selectivity, few side reactions, and simple post-processing, reducing separation and purification costs, lowering environmental protection pressure, and meeting the requirements of green pharmaceutical production.

[0115] 5. High versatility and can be extended to other quinoline drug candidates: The process of this invention is not limited to TDMQ20, but can also be directly applied to the synthesis of molecules with the same parent nucleus, such as TDMQ22, TDMQ29, and TDMQ60; one process system can cover the research and development and production of multiple candidate compounds, which greatly saves research and development time and process development costs.

[0116] 6. Enables short-route synthesis without protecting groups, with more streamlined steps: This invention also designs a synthetic route that does not require amino protection, eliminating the two-step protection and deprotection reactions, shortening the synthesis process, reducing reagent consumption and process time, further improving synthesis efficiency and reducing production costs. Attached Figure Description

[0117] Figure 1 is a chemical reaction route diagram for the synthesis of TDMQ20 in route A-1 of the present invention;

[0118] Figure 2 is a chemical reaction route diagram for the synthesis of TDMQ20 in route A-2 of the present invention;

[0119] Figure 3 is a chemical reaction route diagram for the synthesis of TDMQ22 in route A-2 of the present invention;

[0120] Figure 4 is a chemical reaction route diagram for the synthesis of TDMQ29 in route A-2 of the present invention;

[0121] Figure 5 is a chemical reaction route diagram for the synthesis of TDMQ60 in route A-2 of the present invention;

[0122] Figure 6 is a chemical reaction route diagram for the synthesis of TDMQ20 in route B-1 of the present invention;

[0123] Figure 7 is a chemical reaction route diagram for the synthesis of TDMQ20 in route B-2 of the present invention;

[0124] Figure 8 is a chemical reaction route diagram for the synthesis of TDMQ20 in route B-3 of the present invention;

[0125] Figure 9 is a chemical reaction route diagram for the synthesis of TDMQ22 in route B-3 of the present invention;

[0126] Figure 10 is a chemical reaction route diagram for the synthesis of TDMQ29 in route B-3 of the present invention;

[0127] Figure 11 is a chemical reaction route diagram for the synthesis of TDMQ60 in route B-3 of the present invention;

[0128] Figure 12 is a chemical reaction route diagram for the synthesis of TDMQ20 in route C-1 of the present invention;

[0129] Figure 13 is a chemical reaction route diagram for the synthesis of TDMQ20 in route C-2 of the present invention;

[0130] Figure 14 is a chemical reaction route diagram for the synthesis of TDMQ20 in route C-3 of the present invention;

[0131] Figure 15 is a chemical reaction route diagram for the synthesis of TDMQ20 in route C-4 of the present invention;

[0132] Figure 16 is a chemical reaction route diagram for the synthesis of TDMQ22 in route C-3 of the present invention;

[0133] Figure 17 is a chemical reaction route diagram for the synthesis of TDMQ29 in route C-3 of the present invention;

[0134] Figure 18 is a chemical reaction route diagram for the synthesis of TDMQ60 in route C-3 of the present invention. Detailed Implementation

[0135] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise specified, the experimental methods used in the embodiments of the present invention are conventional methods; the materials and reagents used, unless otherwise specified, are commercially available reagents and materials.

[0136] Example 1 - Route A - TDMQ20 Synthesis Route Based on Peterson Olelation Reaction (Intermediate B2 - TDMQ20 - NAc)

[0137] Route A-1: ​​The overall yield of TDMQ20 synthesis was 41.3% (see Figure 1).

[0138] 8-Amino-5,7-dichloro-2-methylquinoline (TDMQ20-NH2): Iron powder (3.26 g, 58.35 mmol) and acetic acid (45 mL) were added to an ethanol (125 mL) solution of 5,7-dichloro-2-methyl-8-nitroquinoline (TDMQ20-NO2, 5 g, 19.45 mmol). The mixture was stirred at 80 °C for 1 hour, and then the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (300 mL) and extracted with dichloromethane (3 × 250 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 50 / 1, v / v) to give a yellow solid compound TDMQ20-NH2 (4.4 g, 99%). 1 H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 8.7 Hz, 1 H), 7.39 (s, 1 H), 7.32 (d, J = 8.7 Hz, 1 H), 5.30 (s, 2 H), 2.71 (s, 3 H). 13 C NMR (101 MHz, CDCl3): d = 157.81, 139.59, 138.04, 133.15,126.52, 123.41, 122.91, 117.84, 113.57, 25.16 ppm.

[0139] 5,7-Dichloro-2-methyl-8-( N (-Acetyl)aminoquinoline (TDMQ20-NAc): Acetyl chloride (2.5 mL, 35.2 mmol) was added to an ultradry dichloromethane (15 mL) solution of compound TDMQ20-NH2 (1 g, 4.4 mmol) under an argon atmosphere. The mixture was stirred at room temperature for 8 hours, and then the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted with dichloromethane (3 × 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give a white solid compound TDMQ20-NAc (1.15 g, 97%). 1 H NMR (400 MHz, CDCl3): d = 8.37 (s, 1 H), 8.32 (d, J= 8.6 Hz, 1 H), 7.58 (s, 1 H), 7.36 (d, J = 8.6 Hz, 1 H), 2.72 (s, 3 H), 2.31 (s, 3 H). 13 C NMR (126 MHz, CDCl3): d = 169.00, 160.41, 143.36,133.31, 130.64, 130.45, 129.01, 127.36, 123.52, 123.28, 25.39, 23.74 ppm.

[0140] 5,7-Dichloro-2-aldehyde-8-( N (-Acetyl)aminoquinoline (A-TDMQ20-NAc): Selenium dioxide (821 mg, 17.4 mmol) was added to a 1,4-dioxane (15 mL) solution of compound TDMQ20-NAc (1 g, 3.7 mmol). The mixture was heated to 80 °C and stirred for 20 min. The reaction mixture was filtered through diatomaceous earth and eluted with ethyl acetate. The filtrates were combined and distilled under reduced pressure until dry. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give the orange solid compound A-TDMQ20-NAc (982 mg, 94%). 1 H NMR (500 MHz, DMSO- d 6 ): d = 10.26 (s, 1 H), 10.13 (s, 1 H), 8.78 (d, J = 8.7 Hz, 1 H), 8.20 (s, 1 H), 8.15 (d, J = 8.7 Hz, 1 H), 2.19 (s, 3 H). 13 C NMR (126 MHz, DMSO- d 6 ): d =193.10, 168.68, 152.85, 144.55, 135.24, 133.47, 132.94, 129.93, 128.95,126.65, 118.85, 22.81 ppm.

[0141] 5,7-Dichloro-2-(1-hydroxy-2-(trimethylsilyl)ethyl)-8-( N(-acetyl)aminoquinoline (B2-TDMQ20-NAc): Under an argon atmosphere, (trimethylsilyl)methylmagnesium chloride (4.4 mL) was added dropwise to a solution of compound A-TDMQ20-NAc (200 mg, 0.71 mmol) in dichloromethane (10 mL). M (in THF, 5.68 mmol). The reaction mixture was stirred at 0 °C for 10 min, then transferred to room temperature and stirred for 5 h. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (3 × 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give a white solid compound B2-TDMQ20-NAc (189 mg, 72%). 1 H NMR (400 MHz, CDCl3): d = 8.30 (d, J = 8.7Hz, 1 H), 8.17 (s, 1 H), 7.56 (s, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 4.95 (dd, J = 9.5, 4.9 Hz, 1 H), 4.21 (s, 1 H), 2.26 (s, 3 H), 1.19 (dd, J = 14.4, 4.9Hz, 1H), 1.05 (dd, J = 14.5, 9.6 Hz, 1 H), 0.03 (s, 9 H). 13 C NMR (101 MHz, CDCl3): d = 169.22, 166.05, 142.36, 133.99, 131.70, 130.64, 129.50, 127.73,124.26, 119.52, 71.79, 53.55, 27.21, 23.42, -0.63 ppm.

[0142] 5,7-Dichloro-2-vinyl-8-( N(-acetyl)aminoquinoline (C-TDMQ20-NAc): At 0 °C, trimethylsilyl trifluoromethanesulfonate (0.1 mL, 0.58 mmol) was added dropwise to dichloromethane (2 mL) containing compound B2-TDMQ20-NAc (130 mg, 0.35 mmol), and the mixture was stirred for 10 minutes. The reaction mixture was heated to 45 °C and reacted for 3 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (3 × 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give a yellow solid compound C-TDMQ20-NAc (353 mg, 90%). 1 H NMR (500 MHz, DMSO- d 6 ): d =10.00 (s, 1 H), 8.49 (d, J = 8.8 Hz, 1 H), 7.93 (d, J = 8.8 Hz,1 H), 7.92 (s, 1 H), 7.02 (dd, J = 17.6, 10.8 Hz, 1 H), 6.54 (d, J = 17.5 Hz, 1 H), 5.78 (d, J = 11.9 Hz, 1 H), 2.15 (s, 3 H). 13 C NMR (126 MHz, DMSO- d 6 ): d =168.63, 156.62, 144.58, 136.79, 133.49, 132.52, 132.04, 128.67, 126.99,124.07, 122.70, 120.82, 22.75 ppm.

[0143] 5,7-Dichloro-2-(2'-( N,N -dimethylethylenediamine))ethyl)-8-( N (-acetyl)aminoquinoline (D-TDMQ20-NAc): Add to a mixture of compound C-TDMQ20-NAc (80 mg, 0.28 mmol) and potassium carbonate (47 mg, 0.34 mmol) in 2 mL of 1,4-dioxane. N , N-Dimethylethylenediamine (0.061 mL, 0.56 mmol). The reaction mixture was reacted at 80 °C for 3 hours. The reaction mixture was poured into a saturated aqueous sodium carbonate solution (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / isopropanol / ammonia, 10 / 1 / 0.5, v / v / v) to give a yellow oily compound D-TDMQ20-NAc (89 mg, 86%). 1 H NMR (500 MHz, CDCl3): d = 9.01 (s, 1 H), 8.33 (d, J = 8.6 Hz, 1 H), 7.56 (s, 1 H), 7.35 (d, J = 8.6 Hz, 1 H), 3.20 (s, 1 H), 3.14 (t, J = 6.3 Hz, 2 H), 3.07 (t, J = 6.3 Hz, 2 H), 2.70 (t, J = 5.9Hz, 2 H), 2.43 (t, J = 5.9 Hz, 2 H), 2.27 (s, 3 H), 2.09 (s, 6 H). 13 C NMR (126 MHz, CDCl3): d = 169.15, 162.35, 143.62, 133.54, 131.39, 131.14, 129.27,127.40, 123.80, 122.85, 58.88, 48.58, 46.72, 45.39, 37.33, 23.48ppm.

[0144] TDMQ20: 6.3 mL of 12 M hydrochloric acid was added to a 3 mL ethanol solution of compound D-TDMQ20-NAc (280 mg, 0.76 mmol). The mixture was stirred at 80 °C for 12 hours. Subsequently, 3 mL of diethyl ether was added at 0 °C and the mixture was stirred for 5 hours to precipitate a yellow solid. The reaction suspension was centrifuged (10000 r / min, 5 min), the supernatant was discarded, and the yellow solid was washed with diethyl ether (3 × 30 mL) and dried under vacuum to obtain the yellow solid compound TDMQ20 3HCl (205 mg, 82%). 1H NMR (400 MHz, D2O): d = 8.21 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1 H), 7.41 (s, 1 H), 3.78 (t, J = 7.1 Hz, 2 H),3.70-3.56 (m, 4 H), 3.47 (t, J = 7.1 Hz, 2 H), 3.00 (s, 6 H). 13 C NMR (101MHz, D2O): d = 156.90, 137.86, 134.43, 133.97, 126.77, 123.53, 123.02,122.60, 119.27, 52.38, 46.32, 43.39, 41.93, 33.14 ppm.

[0145] Route A-2: The overall yield of TDMQ20 synthesis was 50.4% (see Figure 2).

[0146] 8-Amino-5,7-dichloro-2-methylquinoline (TDMQ20-NH2): Iron powder (3.26 g, 58.35 mmol) and acetic acid (45 mL) were added to an ethanol (125 mL) solution of 5,7-dichloro-2-methyl-8-nitroquinoline (TDMQ20-NO2, 5 g, 19.45 mmol). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (300 mL) and extracted with dichloromethane (3 × 250 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 50 / 1, v / v) to give a yellow solid compound TDMQ20-NH2 (4.4 g, 99%). 1 H NMR (400 MHz, CDCl3): d = 8.27 (d, J =8.7 Hz, 1 H), 7.39 (s, 1 H), 7.32 (d, J = 8.7 Hz, 1 H), 5.30 (s, 2 H), 2.71 (s, 3 H). 13 C NMR (101 MHz, CDCl3): d= 157.81, 139.59, 138.04, 133.15,126.52, 123.41, 122.91, 117.84, 113.57, 25.16 ppm.

[0147] 5,7-Dichloro-2-methyl-8-( N (-Pivaloyl)aminoquinoline (TDMQ20-Bu): Under an argon atmosphere, triethylamine (1.3 mL, 8.8 mmol) was added to a solution of compound TDMQ20-NH2 (1 g, 4.4 mmol) in dichloromethane (20 mL), followed by the dropwise addition of pentanoyl chloride (1.7 mL, 13.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours, then the reaction mixture was poured into water (200 mL) and extracted with dichloromethane (3 × 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give a yellow solid compound TDMQ20-Bu (1.33 g, 93%). 1 H NMR (400 MHz, CDCl3): d =8.55 (s, 1 H), 8.35 (d, J = 8.7 Hz, 1 H), 7.60 (s, 1 H), 7.37 (d, J = 8.6 Hz, 1 H), 2.72 (s, 3 H), 1.45 (s, 9 H). 13 C NMR (126 MHz, CDCl3): d = 176.79,159.89, 143.07, 133.14, 130.98, 129.63, 128.15, 127.33, 123.25, 123.03,40.06, 27.73, 25.45 ppm.

[0148] 5,7-Dichloro-2-aldehyde-8-( N(-Pentavaloyl)aminoquinoline (A-TDMQ20-Bu): Selenium dioxide (535 mg, 4.8 mmol) was added to a 1,4-dioxane (6.4 mL) solution of compound TDMQ20-Bu (500 mg, 1.6 mmol). After stirring at 80 °C for 1 hour, the reaction mixture was filtered through diatomaceous earth and eluted with ethyl acetate. The filtrates were combined and distilled under reduced pressure until dry. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give a yellow solid compound A-TDMQ20-Bu (508 mg, 98%). 1 H NMR (400 MHz, CDCl3): d = 10.15(d, J = 0.9 Hz, 1 H), 8.67 (dd, J = 8.6, 0.9 Hz, 1 H), 8.42 (s, 1 H), 8.11(d, J = 8.7 Hz, 1 H), 7.81 (s, 1 H), 1.47 (s, 9 H). 13 C NMR (101 MHz, CDCl3): d = 192.47, 176.74, 152.30, 143.57, 135.18, 132.43, 131.60, 130.79, 128.76,126.98, 118.37, 40.12, 27.72 ppm.

[0149] 5,7-Dichloro-2-(1-hydroxy-2-(trimethylsilyl)ethyl)-8-( N (-Pentavaloyl)aminoquinoline (B2-TDMQ20-Bu): Under an argon atmosphere, (trimethylsilyl)methylmagnesium chloride (2.86 mL 1.3 M inTHF, 3.72 mmol) was added dropwise to a solution of compound A-TDMQ20-Bu (200 mg, 0.62 mmol) in dichloromethane (1 mL) and tetrahydrofuran (3 mL). The reaction mixture was stirred at 0 °C for 10 min, then transferred to room temperature and stirred for 6 h. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (3 × 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give a white solid compound B2-TDMQ20-Bu (213 mg, 83%). 1H NMR (400 MHz, CDCl3): d =8.38 (d, J = 8.8 Hz, 1 H), 8.16 (s, 1 H), 7.60 (s, 1 H), 7.43 (d, J = 8.7 Hz,1 H), 4.99 (m, 1 H), 3.99 (s, 1 H), 1.43 (s, 9 H), 1.23 (dd, J = 14.5, 4.8Hz, 1H), 1.07 (dd, J = 14.5, 9.6 Hz, 1 H), 0.03 (s, 9 H). 13 C NMR (126 MHz, CDCl3): d = 176.78, 165.89, 142.46, 134.22, 131.43, 130.89, 129.14, 127.81,124.38, 119.58, 71.88, 39.94, 27.81, 27.36, -0.41 ppm.

[0150] 5,7-Dichloro-2-vinyl-8-( N (-Pentavaloyl)aminoquinoline (C-TDMQ20-Bu): Trimethylsilyl trifluoromethanesulfonate (5.5 mL, 32.4 mmol) was added dropwise to a solution of compound B2-TDMQ20-Bu (895 mg, 2.16 mmol) in dichloromethane (20 mL) at 0 °C, and the mixture was stirred for 10 minutes. The reaction mixture was heated to 45 °C and reacted for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (150 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 30 / 1, v / v) to give a yellow solid, C-TDMQ20-Bu (606 mg, 87%). 1 H NMR (400MHz, CDCl3): d = 8.56 (s, 1 H), 8.44 (d, J = 8.8 Hz, 1 H), 7.61 (d, J = 8.4Hz, 2 H), 6.96 (dd, J = 17.6, 10.8 Hz, 1 H), 6.39 (d,J = 16.5 Hz, 1 H), 5.70(d, J = 9.8 Hz, 1 H), 1.45 (s, 9 H). 13 C NMR (126 MHz, CDCl3): d = 176.62,155.98, 143.30, 136.90, 133.76, 131.41, 130.05, 128.18, 128.01, 124.29,121.39, 120.30, 40.11, 27.79 ppm.

[0151] 100g-scale synthesis of the core intermediate 5,7-dichloro-2-vinyl-8-(N-pevaleroyl)aminoquinoline (C-TDMQ20-Bu):

[0152] At 0 °C, trimethylsilyl trifluoromethanesulfonate (636.6 mL, 3.75 mol) was added dropwise to a solution of compound B2-TDMQ20-Bu (103.6 g, 0.25 mol) in dichloromethane (2.3 L), and the mixture was stirred for 30 minutes. The reaction mixture was heated to 45 °C and reacted for 12 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (150 mL) and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized to give a yellow solid compound C-TDMQ20-Bu (69.4 g, 86%).

[0153] 5,7-Dichloro-2-(2'-( N,N -dimethylethylenediamine))ethyl)-8-( N (-Pentavalloyl)aminoquinoline (D-TDMQ20-Bu): To a mixture of compound C-TDMQ20-Bu (606 mg, 1.87 mmol) and potassium carbonate (309 mg, 2.24 mmol) in 1,4-dioxane (5 mL), add N,N -Dimethylethylenediamine (2 mL, 18.7 mmol). The reaction mixture was reacted at 80 °C for 5 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (150 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / isopropanol / ammonia, 15 / 1 / 0.5, v / v / v) to give a yellow oily compound D-TDMQ20-Bu (689 mg, 89%). 1H NMR (500 MHz, CDCl3): d = 8.57 (s, 1 H), 8.37 (d, J = 8.6 Hz, 1 H), 7.59 (s, 1 H), 7.40 (d, J = 8.6 Hz, 1 H), 3.16 (m, 4 H), 2.72(t, J = 6.1 Hz, 2 H), 2.41 (t, J = 6.1 Hz, 2 H), 2.14 (s, 6 H), 1.43 (s, 9H). 13 C NMR (126 MHz, CDCl3): d = 176.87, 160.93, 143.39, 133.50, 131.13,130.55, 128.57, 127.42, 123.71, 122.89, 57.90, 47.87, 46.50, 45.21, 39.84,37.70, 27.71 ppm.

[0154] TDMQ20: 2 mL of concentrated hydrochloric acid (24 mmol) was added to 2 mL of 1,4-dioxane (2 mL) of compound D-TDMQ20-Bu (200 mg, 0.49 mmol). The mixture was heated to 80 °C and reacted for 12 hours. Subsequently, 4 mL of diethyl ether was added at 0 °C and the mixture was stirred for 5 hours to precipitate a yellow solid. The reaction suspension was centrifuged (10000 r / min, 5 min), the supernatant was discarded, and the yellow solid was washed with diethyl ether (3 × 30 mL) and dried under vacuum to obtain the yellow solid compound TDMQ20 3HCl (139 mg, 87%). 1 H NMR (400 MHz, D2O): d = 8.21 (d, J = 8.7Hz, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.41 (s, 1 H), 3.78 (t, J = 7.1 Hz, 2H), 3.70-3.56 (m, 4 H), 3.47 (t, J = 7.1 Hz, 2 H), 3.00 (s, 6 H). 13 C NMR (101MHz, D2O): d= 156.90, 137.86, 134.43, 133.97, 126.77, 123.53, 123.02,122.60, 119.27, 52.38, 46.32, 43.39, 41.93, 33.14 ppm.

[0155] Application of Route A-2 in the synthesis of TDMQ22 (see Figure 3).

[0156] 8-Amino-6-trifluoromethyl-2-methylquinoline (E-TDMQ16): Iron powder (958 mg, 17.1 mmol) and glacial acetic acid (29 mL) were added to an ethanol (95 mL) solution of 6-trifluoromethyl-2-methyl-8-nitroquinoline (D-TDMQ16, 1.47 g, 5.7 mmol). The mixture was stirred at 80 °C for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (300 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give a yellow solid compound E-TDMQ16 (1.16 g, 89%). 1 H NMR (400 MHz, CDCl3): d = 7.90 (d, J = 8.4 Hz, 1 H), 7.35 (dd, J = 2.0, 1.0 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 6.98 (d, J = 1.9 Hz, 1 H), 5.18 (s, 2 H), 2.71 (s, 3 H). 13 C NMR (101 MHz, CDCl3): d = 158.44, 144.32, 138.65, 136.82, 128.16 (q, J = 31.9 Hz), 125.80, 124.49 (q, J = 272.3 Hz), 123.24, 113.05 (q, J = 4.7 Hz), 104.91 (q, J = 3.2Hz), 25.21 ppm.

[0157] 6-Trifluoromethyl-2-methyl-8-( N (-Pivaloyl)aminoquinoline (TDMQ22-Bu): Under an argon atmosphere, triethylamine (0.8 mL, 6 mmol) was added to a solution of compound E-TDMQ16 (679 mg, 3.0 mmol) in dichloromethane (10 mL), followed by dropwise addition of pentanoyl chloride (1.1 mL, 9 mmol) at 0 °C. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give the white solid compound TDMQ22-Bu (954 mg, 100%). 1 H NMR (400 MHz, CDCl3): d = 10.32 (s, 1 H), 8.97 (s, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.65 (s, 1 H), 7.35 (d, J = 8.3 Hz, 1 H), 2.74 (s, 3 H), 1.42 (s, 9 H). 13 C NMR (101 MHz, CDCl3): d =177.57, 159.60, 139.11, 137.35, 135.09, 128.41 (d, J = 32.3 Hz), 125.05, 124.18 (d, J = 272.7 Hz), 123.61, 118.60 (q, J = 4.6 Hz), 111.96 (d, J = 3.4 Hz), 40.56, 27.73, 25.65 ppm.

[0158] 6-Trifluoromethyl-2-methyl-8-( N(-Pentavaloyl)aminoquinoline (A-TDMQ22-Bu): Selenium dioxide (2.36 g, 21.3 mmol) was added to a 29 mL solution of 1,4-dioxane (2.2 g, 7.09 mmol) of the phase compound TDMQ22-Bu. The reaction mixture was heated to 101 °C and stirred for 12 hours. The reaction mixture was filtered through diatomaceous earth and the product was eluted with ethyl acetate. The filtrates were combined and distilled under reduced pressure until dry. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give a yellow solid compound A-TDMQ22-Bu (1.86 g, 81%). 1 H NMR (400MHz, CDCl3): d = 10.22 (s, 1 H), 10.21 (s, 1 H), 9.10 (d, J = 1.9 Hz, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 7.83 (s, 1 H), 1.45 (s, 9 H). 13 C NMR (101 MHz, CDCl3): d = 192.27, 177.62, 151.66, 139.18, 139.10,136.58, 132.10 (q, J = 32.8 Hz), 129.04, 123.64 (d, J = 273.2 Hz), 118.89,118.59 (q, J = 4.6 Hz), 112.90 (d, J = 3.3 Hz), 40.68, 27.66 ppm.

[0159] 6-Trifluoromethyl-2-(1-hydroxy-2-(trimethylsilyl)ethyl)-8-( N (-Pentavalloyl)aminoquinoline (B2-TDMQ22-Bu): Under an argon atmosphere, (trimethylsilyl)methylmagnesium chloride (5.5 mL) was added dropwise to dichloromethane (10 mL) containing compound A-TDMQ22-Bu (400 mg, 1.2 mmol). MThe reaction mixture was stirred at 0 °C for 15 min, then transferred to room temperature and stirred for 12 h. The reaction mixture was poured into water (150 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give a yellow oily compound B2-TDMQ22-Bu (414 mg, 83%). 1 H NMR (500 MHz, CDCl3): d =10.11 (s, 1 H), 8.94 (d, J = 2.0 Hz, 1 H), 8.18 (d, J = 8.6 Hz, 1 H), 7.71 (s, 1 H), 7.66 (d, J =8.5 Hz, 1 H), 5.11 (dd, J = 8.4, 6.2 Hz, 1 H), 3.41 (s, 1 H), 1.42 (s, 9 H), 1.32 (dd, J = 14.5, 6.3 Hz, 1H), 1.25 (dd, J = 14.5, 8.4 Hz, 1 H), -0.02 (s,9 H). 13 C NMR (126 MHz, CDCl3): d = 177.51, 165.82, 138.39, 137.91, 135.04,128.93 (q, J = 32.3 Hz) 126.07, 124.00 (q, J = 272.8 Hz), 120.28, 118.83 (q, J = 4.5 Hz), 112.40 (q, J = 3.5 Hz), 73.04, 40.56, 27.70, 27.56, -0.80 ppm.

[0160] 6-Trifluoromethyl-2-vinyl-8-( N(-Pentavaloyl)aminoquinoline (C-TDMQ22-Bu): Trimethylsilyl trifluoromethanesulfonate (1 mL, 6 mmol) was added dropwise to a solution of compound B2-TDMQ22-Bu (414 mg, 1 mmol) in dichloromethane (10 mL) at 0 °C, and the mixture was stirred for 15 minutes. The reaction mixture was heated to 45 °C and reacted for 5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give a yellow solid, C-TDMQ22-Bu (299 mg, 92%). 1 H NMR (400 MHz, CDCl3): d =10.34 (s, 1 H), 9.00 (d, J = 2.1 Hz, 1 H), 8.14 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J = 8.6 Hz, 1 H), 6.98 (dd, J = 17.6, 10.8 Hz, 1H), 6.39 (d, J = 18.5 Hz, 1 H), 5.72 (d, J = 10.8 Hz, 1 H), 1.44 (s, 9 H). 13 CNMR (101 MHz, CDCl3): d = 177.48, 155.60, 139.23, 137.82, 136.98, 135.56,129.03 (q, J = 32.3 Hz), 126.13, 124.10 (d, J = 272.5 Hz), 121.24, 120.73,118.54 (q, J = 4.4 Hz), 112.19 (q, J = 3.1 Hz), 40.58, 27.74 ppm.

[0161] 6-Trifluoromethyl-2-(2'-( N,N -dimethylethylenediamine))ethyl)-8-( N(-Pentavalloyl)aminoquinoline (D-TDMQ22-Bu): Add to a mixture of compound C-TDMQ22-Bu (200 mg, 0.62 mmol) and potassium carbonate (103 mg, 0.74 mmol) in 1,4-dioxane (5 mL) N,N -Dimethylethylenediamine (0.7 mL, 6.2 mmol). The reaction mixture was reacted at 101 °C for 12 h. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / isopropanol / ammonia, 20 / 1 / 0.5, v / v / v) to give a yellow oily compound D-TDMQ22-Bu (244 mg, 96%). 1 H NMR (400 MHz, CDCl3): d = 10.28 (s, 1 H), 8.93 (s, 1 H), 8.07 (dd, J = 8.4, 4.0 Hz, 1 H), 7.66 (s, 1 H), 7.40 (dd, J =8.4, 3.4 Hz, 1 H), 3.17 (d, J = 3.7 Hz, 4H), 2.74-2.66 (m, 2 H), 2.39-2.30(m, 2 H), 2.11 (s, 6 H), 1.93 (s, 1 H), 1.37 (s, 9 H). 13 C NMR (101 MHz, CDCl3): d = 177.33, 161.23, 138.95, 137.46, 135.07, 128.38 (d, J = 32.3 Hz), 125.28, 124.02 (d, J = 272.5 Hz), 123.44, 118.51 (q, J = 4.8 Hz), 111.81 (q, J = 4.5 Hz), 59.05, 48.82, 47.33, 45.48, 40.39, 39.13, 27.62 ppm.

[0162] TDMQ22: 12 M hydrochloric acid (5 mL, 60 mmol) was added to a 2 mL solution of 1,4-dioxane (245 mg, 0.6 mmol) of compound D-TDMQ22-Bu. The mixture was reacted at 80 °C for 12 h, followed by cooling to room temperature. The reaction mixture was poured into water (50 mL), and the pH was adjusted to 13 by adding 25% ammonia. After extraction with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. At 0 °C, 3 mL of 10 M HCl-EtOH solution was added to an ethanol (3 mL) solution of the crude product, and the mixture was stirred for 12 h to precipitate a yellow solid. The reaction suspension was centrifuged (10000 r / min, 5 min), the supernatant was discarded, the yellow solid was washed with diethyl ether (3 × 3 mL), and dried under vacuum to obtain a yellow solid compound TDMQ22 3HCl (193 mg, 74%). 1 H NMR (400 MHz, D2O): d = 8.45(d, J = 8.7 Hz, 1 H), 8.27 (s, 1 H), 7.92 (d, J = 2.0 Hz, 1 H), 7.69 (d, J =8.6 Hz, 1 H), 3.85 (t, J = 6.8 Hz, 2 H), 3.72-3.67 (m, 2 H), 3.67-3.61 (m, 2H), 3.59 (t, J = 6.8 Hz, 2 H), 3.02 (s, 6 H). 13 C NMR (101 MHz, D2O): d =159.96, 140.57, 138.91, 130.62, 127.35 (d, J = 33.4 Hz), 126.83, 124.87 (q, J = 4.8 Hz), 124.35, 123.37 (d, J = 271.8 Hz), 117.34 (q, J = 3.4 Hz), 52.34, 46.17, 43.41, 41.99, 33.39 ppm.

[0163] Application of Route A-2 in TDMQ29 synthesis (see Figure 4).

[0164] 2-Methyl-8-aminoquinoline (E-TDMQ4): Iron powder (4.45 g, 79.71 mmol) and glacial acetic acid (30 mL) were added to an ethanol (85 mL) solution of 2-methyl-8-nitroquinoline (D-TDMQ4, 5 g, 26.57 mmol). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (1000 mL) and extracted with dichloromethane (3 × 250 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 30 / 1, v / v) to give a yellow solid compound E-TDMQ4 (3.76 g, 89%). 1 H NMR (500 MHz, CDCl3): d = 7.95 (d, J = 8.4 Hz, 1 H), 7.31-7.26 (m, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.13 (dd, J = 8.1, 1.3 Hz, 1 H), 6.91 (dd, J = 7.5, 1.3 Hz, 1 H), 5.00 (s, 2 H), 2.73 (s, 3 H). 13 C NMR (126MHz, CDCl3): d = 156.16, 143.45, 137.87, 136.10, 126.91, 126.36, 122.17,115.89, 110.15, 25.27 ppm.

[0165] 2-Methyl-8-( N(-Pivaloyl)aminoquinoline (TDMQ29-Bu): Under an argon atmosphere, triethylamine (6.6 mL, 47.52 mmol) was added to a solution of compound E-TDMQ4 (3.76 g, 23.76 mmol) in dichloromethane (55 mL), followed by the dropwise addition of pentanoyl chloride (8.7 mL, 71.28 mmol) at 0 °C. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water (200 mL) and extracted with dichloromethane (3 × 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give a yellow solid compound TDMQ29-Bu (6.83 g, 100%). 1 H NMR (400 MHz, CDCl3): d =10.35 (s, 1 H), 8.74 (dd, J = 7.3, 1.7 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H),7.46-7.41 (m, 1 H), 7.39 (dd, J = 8.2, 1.7 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1H), 2.71 (s, 3 H), 1.43 (s, 9 H). 13 C NMR (101 MHz, CDCl3): d = 177.13,157.01, 138.16, 136.42, 134.10, 126.42, 126.04, 122.29, 121.02, 116.14,40.42, 27.77, 25.43 ppm.

[0166] 2-Aldehyde-8-( N (-Pentavaloyl)aminoquinoline (A-TDMQ29-Bu): Selenium dioxide (1.66 g, 15.0 mmol) was added to 1,4-dioxane (20 mL) of compound TDMQ29-Bu (1.2 g, 5.0 mmol). The reaction mixture was heated to 101 °C and stirred for 24 hours. The reaction mixture was filtered through diatomaceous earth and the product was eluted with ethyl acetate. The filtrates were combined and distilled under reduced pressure until dry. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give a yellow solid compound A-TDMQ29-Bu (1.0 g, 80%).1 H NMR (500 MHz, CDCl3): d =10.24 (s, 1 H), 10.20 (s, 1 H), 8.87 (d, J = 9.1 Hz, 1 H), 8.32 (d, J = 8.1Hz, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.56 (d, J =9.6 Hz, 1 H), 1.45 (s, 9 H). 13 C NMR (126 MHz, CDCl3): d =192.99, 177.41,150.14, 138.34, 137.96, 135.58, 130.77, 130.05, 121.28, 117.82, 117.24,40.63, 27.80 ppm.

[0167] 2-(1-Hydroxy-2-(Trimethylsilyl)ethyl)-8-( N (-Pentavaloyl)aminoquinoline (B2-TDMQ29-Bu): Under an argon atmosphere, (trimethylsilyl)methylmagnesium chloride (9 mL 1.3 M in THF, 11.7 mmol) was added dropwise to a solution of compound A-TDMQ29-Bu (500 mg, 1.95 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at 0 °C for 15 min, then transferred to room temperature and stirred for 20 h. The reaction mixture was poured into water (150 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give a yellow oily compound B2-TDMQ29-Bu (582 mg, 86%). 1 H NMR (500 MHz, CDCl3): d = 10.09 (s, 1 H), 8.75 (dd, J = 6.7, 2.4 Hz, 1 H), 8.13 (d, J = 8.5 Hz, 1 H), 7.50 (d, J= 5.7 Hz, 1 H),7.48 (m, 1 H), 7.46 (m, 1 H), 5.10 (dd, J = 8.4, 6.0 Hz, 1 H), 1.42 (s, 9 H), 1.35 (dd, J = 14.5, 6.0 Hz, 1 H), 1.21 (m, 1 H), -0.01 (s, 9 H). 13 C NMR (126MHz, CDCl3): d = 177.15, 162.99, 137.62, 136.94, 134.11, 127.23, 127.20,121.42, 119.04, 116.90, 72.65, 40.50, 27.82, 27.52, -0.72 ppm.

[0168] 2-Vinyl-8-( N (-Pentavaloyl)aminoquinoline (C-TDMQ29-Bu): At 0 °C, trimethylsilyl trifluoromethanesulfonate (4.6 mL, 27.06 mmol) was added dropwise to a solution of compound B2-TDMQ29-Bu (1.55 g, 4.51 mmol) in dichloromethane (30 mL), and the mixture was stirred for 10 minutes. The reaction mixture was heated to 45 °C and reacted for 5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted with dichloromethane (3 × 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 30 / 1, v / v) to give a yellow oily compound C-TDMQ29-Bu (1.09 g, 95%). 1 H NMR (400 MHz, CDCl3): d = 10.35 (s, 1 H), 8.76 (dd, J = 7.5, 1.6 Hz, 1 H), 8.06 (d, J = 8.6Hz, 1 H), 7.52 (d, J = 8.6 Hz, 1 H), 7.46 (t, J = 7.9 Hz, 1 H), 7.41 (dd, J =8.3, 1.6 Hz, 1 H), 6.97 (dd, J= 17.6, 10.8 Hz, 1 H), 6.34 (dd, J = 17.5, 1.1Hz, 1H), 5.63 (dd, J = 10.8, 1.1 Hz, 1 H), 1.44 (s, 9 H). 13 C NMR (101 MHz, CDCl3): d = 177.10, 153.51, 138.29, 137.40, 136.83, 134.62, 127.29, 127.20,121.03, 119.60, 119.53, 116.45, 40.47, 27.79 ppm.

[0169] 2-(2'-( N,N -dimethylethylenediamine))ethyl)-8-( N (-Pentavalloyl)aminoquinoline (D-TDMQ29-Bu): Add to a mixture of compound C-TDMQ29-Bu (218 mg, 0.86 mmol), potassium carbonate (595 mg, 4.3 mmol), and 18-crown ether-6 (1.14 g, 4.3 mmol) in 1,4-dioxane (10 mL) N,N -Dimethylethylenediamine (0.94 mL, 8.6 mmol). The reaction mixture was stirred at 101 °C for 24 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / isopropanol / ammonia, 20 / 1 / 0.5, v / v / v) to give a yellow oily compound D-TDMQ29-Bu (261 mg, 88%). 1 H NMR (400 MHz, CDCl3): d = 10.24 (s, 1 H), 8.67 (dd, J = 6.8, 2.2 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H),7.43-7.32 (m, 2 H), 7.27 (d, J = 8.4 Hz, 1 H), 3.16 (s, 4 H), 2.72 (t, J =6.2 Hz, 2 H), 2.38 (t, J= 6.2 Hz, 2 H), 2.12 (s, 6 H), 1.36 (s, 9 H). 13 C NMR (101 MHz, CDCl3): d = 176.92, 158.30, 138.00, 136.63, 134.03, 126.55, 126.30,122.13, 121.00, 116.14, 58.57, 48.62, 46.95, 45.30, 40.26, 38.47, 27.67 ppm.

[0170] TDMQ29: 12 M hydrochloric acid (1.2 mL, 14.5 mmol) was added to a 4.8 mL solution of compound D-TDMQ29-Bu (496 mg, 1.45 mmol) in 1,4-dioxane. The mixture was heated to 80 °C and reacted for 12 hours, then cooled to room temperature. The reaction mixture was poured into water (50 mL). The pH of the mixture was adjusted to 13 by adding 25% ammonia. After extraction with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in ethanol (5 mL), and 10 M HCl-EtOH solution (6.6 mL) was added at 0 °C. The mixture was stirred for 12 hours to precipitate a yellow solid. The reaction suspension was centrifuged (10000 r / min, 5 min), the supernatant was discarded, the yellow solid was washed with ether (3 × 3 mL), and dried under vacuum to obtain the yellow solid compound TDMQ29 3HCl (391 mg, 73%). 1 H NMR (400 MHz, D2O): d = 8.24 (d, J = 8.5 Hz, 1 H), 7.86 (dd, J = 8.3, 1.3 Hz, 1 H), 7.75(dd, J = 7.5, 1.3 Hz, 1 H), 7.54 (dd, J =8.3, 7.5 Hz 1 H), 7.49 (d, J = 8.5Hz, 1 H), 3.78 (t, J = 6.8 Hz, 2 H), 3.67 – 3.62 (m, 2 H), 3.62-3.57 (m, 2H), 3.48 (t, J = 6.8 Hz, 2 H), 2.96 (s, 6 H).13 C NMR (101 MHz, D2O): d =157.97, 139.47, 138.19, 128.70, 127.46, 126.19, 126.15, 123.62, 123.26,52.35, 46.29, 43.43, 42.03, 33.13 ppm.

[0171] Application of Route A-2 in TDMQ60 synthesis (see Figure 5).

[0172] 8-Amino-5,7-difluoro-2-methylquinoline (E-TDMQ6): Iron powder (749 mg, 13.4 mmol) and acetic acid (22 mL) were added to an ethanol (74 mL) solution of 5,7-difluoro-2-methyl-8-nitroquinoline (D-TDMQ6, 1.0 g, 4.5 mmol). The mixture was stirred at 80 °C for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give a yellow solid compound E-TDMQ6 (820 mg, 95%). 1 H NMR (400 MHz, CDCl3): d = 8.14 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1 H), 6.96 (dd, J = 10.9, 9.8 Hz, 1 H), 4.63 (s, 2H), 2.70 (s, 3 H). 13 C NMR (101 MHz, CDCl3): d = 158.48, 149.32 (dd, J =246.1, 13.6 Hz), 147.16 (dd, J = 237.5, 12.7 Hz), 138.18 (dd, J = 10.2, 3.9Hz), 129.44 (t, J = 2.8 Hz), 126.29 (dd, J = 12.5, 4.8 Hz), 121.29 (t, J=2.7 Hz), 114.12 (dd, J = 17.3, 1.6 Hz), 101.25 (dd, J = 26.6, 24.4 Hz), 25.38ppm.

[0173] 5,7-Difluoro-2-methyl-8-( N (-Pivaloyl)aminoquinoline (TDMQ60-Bu): Under an argon atmosphere, triethylamine (1.1 mL, 8.24 mmol) was added to a solution of compound E-TDMQ6 (800 mg, 4.1 mmol) in dichloromethane (14 mL). Subsequently, pentovaleyl chloride (1.5 mL, 12.4 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give a yellow solid compound TDMQ60-Bu (1.14 g, 100%). 1 H NMR (500 MHz, CDCl3): d = 8.37 (s, 1 H), 8.12 (d, J = 8.5 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 6.99(t, J = 10.0 Hz, 1 H), 2.67 (s, 3 H), 1.41 (s, 9 H). 13 C NMR (126 MHz, CDCl3): d =176.91, 160.33, 155.07 (dd, J = 254.7, 13.9 Hz), 154.22 (dd, J = 254.3, 13.2 Hz), 142.11 (dd, J = 8.8, 4.7 Hz), 129.47, 121.56 (d, J = 2.9 Hz), 116.17 (dd, J = 12.4, 5.5 Hz), 113.89 (d, J = 17.2 Hz), 101.93 (dd, J= 28.5,24.1 Hz), 39.79, 27.75, 25.56 ppm.

[0174] 5,7-Difluoro-2-aldehyde-8-( N (-Pentavaloyl)aminoquinoline (A-TDMQ60-Bu): Selenium dioxide (3.08 g, 27.78 mmol) was added to a solution of compound TDMQ60-Bu (2.58 g, 9.26 mmol) in 1,4-dioxane (30 mL). The reaction mixture was heated to 80 °C and stirred for 1 hour. The reaction mixture was filtered through diatomaceous earth and the product was eluted with ethyl acetate. The filtrates were combined and distilled under reduced pressure until dry. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give a yellow solid compound A-TDMQ60-Bu (2.48 g, 92%). 1 H NMR (400MHz, CDCl3): d = 10.15 (d, J = 0.9 Hz, 1 H), 8.54 (dd, J = 8.6, 0.9 Hz, 1 H),8.30 (s, 1 H), 8.04 (d, J = 8.6 Hz, 1 H), 7.33-7.23 (m, 1 H), 1.45 (s, 9 H). 13 C NMR (101 MHz, CDCl3): d = 192.67, 176.94, 155.32 (dd, J = 257.7, 12.7 Hz), 155.06 (dd, J = 257.0, 13.5 Hz), 152.77, 142.62 (dd, J = 8.8, 4.7 Hz), 131.71(d, J = 5.2 Hz), 118.14-117.68 (m), 117.07 (t, J = 2.6 Hz), 105.93 (d, J =24.1 Hz), 105.65 (d, J = 23.8 Hz), 39.97, 27.84 ppm.

[0175] 5,7-Difluoro-2-(1-hydroxy-2-(trimethylsilyl)ethyl)-8-(N-petaloyl)aminoquinoline (B2-TDMQ60-Bu):

[0176] Under an argon atmosphere, (trimethylsilyl)methylmagnesium chloride (3.1 mL 1.3 M in THF, 4.08 mmol) was added dropwise to a solution of compound A-TDMQ60-Bu (200 mg, 0.68 mmol) in dichloromethane (2.5 mL). The reaction mixture was stirred at 0 °C for 15 min, then transferred to room temperature and stirred for 6 h. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give a yellow solid compound B2-TDMQ60-Bu (216 mg, 84%). 1 H NMR (500 MHz, CDCl3): d = 8.29 (d, J = 8.7 Hz, 1H), 8.05 (s, 1 H), 7.41 (d, J = 8.7 Hz, 1 H), 7.08 (t, J = 9.9 Hz, 1 H), 5.00(dd, J = 9.5, 4.9 Hz, 1 H), 4.04 (s, 1 H), 1.42 (s, 9 H), 1.24 (dd, J = 14.5,4.9 Hz, 1 H), 1.08 (dd, J = 14.5, 9.5 Hz, 1 H), 0.02 (s, 9 H). 13 C NMR (126MHz, CDCl3): d = 177.05, 166.38, 155.69 (dd, J =255.9 Hz, 12.9 Hz), 155.63(dd, J = 256.2, 14.2 Hz), 141.58 (q, J = 5.0 Hz), 130.75, 118.24, 116.27 (dt, J = 12.1 Hz, 6.2 Hz), 115.09 (d, J= 16.9 Hz), 102.68 (dd, J = 28.4, 24.1Hz), 71.97, 39.80, 27.89, 27.34, -0.65 ppm.

[0177] 5,7-Difluoro-2-vinyl-8-( N (-Pentavaloyl)aminoquinoline (C-TDMQ60-Bu): At 0 °C, trimethylsilyl trifluoromethanesulfonate (1.6 mL, 9.6 mmol) was added dropwise to a solution of compound B2-TDMQ60-Bu (600 mg, 1.6 mmol) in dichloromethane (5 mL), and the mixture was stirred for 10 minutes. The reaction mixture was heated to 45 °C and stirred for 4 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (150 mL) and extracted with dichloromethane (3 × 75 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to give a yellow solid, C-TDMQ60-Bu (372 mg, 80%). 1 H NMR (400 MHz, CDCl3): d = 8.38 (s, 1 H), 8.25 (d, J = 8.7 Hz, 1 H), 7.50 (d, J = 8.7 Hz, 1H), 7.05 (t, J = 10.0 Hz, 1 H), 6.93 (dd, J = 17.6, 10.8 Hz, 1 H), 6.38 (d, J = 18.6 Hz, 1 H), 5.68 (d, J = 11.7 Hz, 1 H), 1.44 (s, 9 H). 13 C NMR (101 MHz, CDCl3): d = 176.79, 156.38, 156.06 (dd, J = 254.9, 13.9 Hz), 154.53 (dd, J =254.9, 13.2 Hz), 142.40 (dd, J = 9.2, 4.8 Hz), 137.06, 130.18 (t, J= 2.1Hz), 121.24, 118.90 (t, J = 2.8 Hz), 116.74 (dd, J = 12.5, 5.5 Hz), 115.02(d, J = 17.6 Hz), 102.76 (dd, J = 28.6, 24.2 Hz), 39.91, 27.87 ppm.

[0178] 5,7-Difluoro-2-(2'-( N,N -dimethylethylenediamine))ethyl)-8-( N (-Pentavalloyl)aminoquinoline (D-TDMQ60-Bu): Add to a mixture of compound C-TDMQ60-Bu (200 mg, 0.69 mmol) and potassium carbonate (115 mg, 0.83 mmol) in 2.5 mL of 1,4-dioxane. N,N -Dimethylethylenediamine (1.05 mL, 9.66 mmol). The reaction mixture was stirred at 80 °C for 23 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3 × 75 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / isopropanol / ammonia, 20 / 1 / 0.5, v / v / v) to give a yellow oily compound D-TDMQ60-Bu (232 mg, 88%). 1 H NMR (400 MHz, CDCl3): d =8.37 (s, 1 H), 8.20 (d, J = 8.6 Hz, 1 H), 7.29 (d, J = 8.6 Hz, 1 H), 7.01 (t, J = 10.0 Hz, 1H), 3.13-3.09 (m, 4 H), 2.68 (t, J = 6.1 Hz, 2 H), 2.35 (t, J = 6.2 Hz, 2 H), 2.11 (s, 6 H), 1.38 (s, 9 H). 13 C NMR (126 MHz, CDCl3): d =176.85, 162.09,155.19 (dd, J= 255,1, 13.8 Hz), 154.53 (dd, J =254.9, 13.2 Hz), 142.33 (dd, J = 8.8, 4.8 Hz), 129.85 (t, J = 2.1 Hz), 121.48 (t, J = 2.8 Hz), 116.38 (dd, J = 12.5, 5.5 Hz), 114.36 (dd, J = 17.4, 1.7 Hz), 102.18 (dd, J = 28.6, 23.8Hz), 59.05, 48.75, 47.26, 45.50, 39.75, 39.04, 27.8 ppm.

[0179] TDMQ60: 12 M hydrochloric acid (5 mL, 61 mmol) was added to a 2 mL solution of compound D-TDMQ60-Bu (232 mg, 0.61 mmol) in 1,4-dioxane. The mixture was heated to 80 °C and stirred for 12 hours, then cooled to room temperature. The reaction mixture was poured into water (50 mL). The pH was adjusted to 13 by adding 25% ammonia. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in ethanol (3 mL), and 10 M HCl-EtOH solution (1.95 mL) was added at 0 °C, followed by stirring for 12 hours to precipitate a yellow solid. The reaction suspension was centrifuged (10000 r / min, 5 min), the supernatant was discarded, the yellow solid was washed with ether (3 × 3 mL), and dried under vacuum to obtain the yellow solid compound TDMQ60 3HCl (158 mg, 64%). 1 H NMR (400 MHz, D2O): d =8.49 (d, J = 8.7 Hz, 1 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.43-7.33 (m, 1 H), 3.84 (t, J = 6.8 Hz, 2 H), 3.72-3.66 (m, 2 H), 3.66-3.60 (m, 2 H), 3.56 (t, J = 6.8 Hz, 2 H), 3.02 (s, 6 H).13 C NMR (101 MHz, D2O): d = 159.97, 156.53 (dd, J = 257.3, 14.5 Hz), 154.40 (dd, J = 250.9, 13.9 Hz), 140.45 (dd, J = 6.8, 5.3 Hz), 131.39 (dd, J =3.6, 1.9 Hz), 122.55 (t, J = 2.6 Hz), 115.19 (dd, J =18.1, 1.3 Hz), 110.90 (dd, J = 13.4, 5.3 Hz), 102.40 – 101.64 (m), 52.35, 46.19, 43.41, 41.99, 33.50 ppm.

[0180] Example 2 - Route B: TDMQ20 Synthetic Route Based on Wittig Reaction (Intermediate: C-TDMQ20-NAc)

[0181] Route B-1: The overall yield of TDMQ20 synthesis was 29.3% (see Figure 6).

[0182] 5,7-Dichloro-2-methyl-8-aminoquinoline (TDMQ20-NH2): Reduced iron powder (3.26 g, 58.35 mmol) and acetic acid (45 mL) were added to a 125 mL ethanol solution of TDMQ20-NO2 (5 g, 19.45 mmol). The mixture was stirred at 80 °C for 1 hour. The mixture was added dropwise to a saturated aqueous sodium bicarbonate solution to adjust the pH to 7, and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give a pale yellow solid compound TDMQ20-NH2 (4.4 g, 99%). 1 H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 8.7 Hz, 1 H), 7.39 (s, 1 H), 7.32 (d, J = 8.7 Hz, 1 H), 5.30 (s, 2 H), 2.71 (s, 3 H); 13C NMR (101 MHz, CDCl3): d = 157.81, 139.59, 138.04, 133.15, 126.52, 123.41, 122.91, 117.84,113.57, 25.16 ppm.

[0183] 5,7-Dichloro-2-methyl-8-( N (-Acetyl)aminoquinoline (TDMQ20-NAc): Acetyl chloride (2.5 mL) was added dropwise to an ultradry dichloromethane (15 mL) solution of TDMQ20-NH2 (1.0 g, 4.4 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 8 hours. The mixture was slowly added to a saturated aqueous sodium bicarbonate solution, the pH was adjusted to 7, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 2, v / v) to give a pale yellow solid compound TDMQ20-NAc (1.15 g, 97%). 1 HNMR (400 MHz, CDCl3): d = 8.37 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 7.58 (s,1H), 7.36 (d, J = 8.6 Hz, 1H), 2.72 (s, 3H), 2.31 (s, 3H); 13 C NMR (126 MHz, CDCl3): d = 169.00, 160.41, 143.36, 133.31, 130.64, 130.45, 129.01, 127.36,123.52, 123.28, 25.39, 23.74 ppm.

[0184] 5,7-Dichloro-2-aldehyde-8-( N(-Acetyl)aminoquinoline (A-TDMQ20-NAc): Selenium dioxide (821 mg, 7.4 mmol) was added to a solution of TDMQ20-NAc (1.0 g, 3.7 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 80 °C for 30 min. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 2, v / v) to give a white solid compound A-TDMQ20-NAc (982 mg, 94%). 1 H NMR (500MHz, DMSO- d 6): d = 10.26 (s, 1H), 10.13 (s, 1H), 8.78 (d, J = 8.7 Hz, 1H),8.20 (s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 2.19 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6): d = 193.10, 168.68, 152.85, 144.55, 135.24, 133.47, 132.94, 129.93,128.95, 126.65, 118.85, 22.81 ppm.

[0185] 5,7-Dichloro-2-vinyl-8-( N (-acetyl)aminoquinoline (C-TDMQ20-NAc): Potassium carbonate (774 mg, 5.6 mmol) and methyltriphenylphosphine bromide (1.5 g, 4.2 mmol) were suspended in an ultradry tetrahydrofuran solution (4 mL). The mixture was stirred at room temperature for 30 min under an argon atmosphere. An ultradry tetrahydrofuran solution (6 mL) containing A-TDMQ20-NAc (200 mg, 0.7 mmol) was added to the mixture, and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 5, v / v) to give a white solid compound C-TDMQ20-NAc (88 mg, 45%). 1 H NMR (500 MHz, DMSO- d 6 ): d= 9.96 (s, 1H), 8.46 (d, J = 8.8 Hz, 1H), 7.93-7.87 (m, 2H), 6.98 (dd, J = 17.6, 10.8 Hz, 1H), 6.50(d, J = 17.6 Hz, 1H), 5.75 (d, J = 10.8 Hz, 1H), 2.12 (s, 3H); 13 C NMR (126MHz, DMSO- d 6 ): d = 169.12, 157.11, 145.07, 137.28, 133.98, 133.01, 132.53,129.16, 127.48, 124.56, 123.18, 121.31, 23.24 ppm.

[0186] 5,7-Dichloro-2-(2'-( N,N -Dimethylethylenediamine)ethyl)-8-(N-acetyl)aminoquinoline (D-TDMQ20-NAc): Add to a mixture of 1,4-dioxane containing C-TDMQ20-NAc (150 mg, 0.53 mmol) and potassium carbonate (89 mg, 0.64 mmol) N,N -Dimethyl-1,2-ethylenediamine (0.4 mL). The mixture was stirred at 80 °C for 24 hours, and the reaction was quenched with saturated brine. The pH of the mixture was adjusted to 13 by adding 25% ammonia. Extraction was performed with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / 25% ammonia, 50 / 1, v / v) to give a pale yellow solid compound D-TDMQ20-NAc (174 mg, 88%). 1 HNMR (500 MHz, CDCl3): d = 9.01 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.56 (s,1H), 7.35 (d, J = 8.6 Hz, 1H), 3.20 (s, 1H), 3.14 (t, J = 6.3 Hz, 2H), 3.07(t, J = 6.3 Hz, 2H), 2.69 (t, J= 5.9 Hz, 2H), 2.43 (t, J = 5.9 Hz, 2H), 2.27(s, 3H), 2.09 (s, 6H). 13 C NMR (126 MHz, CDCl3): d = 169.15, 162.35, 143.62,133.54, 131.39, 131.14, 129.27, 127.40, 123.80, 122.85, 58.88, 48.58, 46.72,45.39, 37.33, 23.48ppm.

[0187] TDMQ20: 12 M hydrochloric acid (6.3 mL, 76 mmol) was added dropwise to an ethanol solution (3 mL) of D-TDMQ20-NAc (280 mg, 0.76 mmol). The mixture was stirred at 80 °C for 12 hours, then cooled to room temperature. 3 mL of diethyl ether was added to the reaction mixture, and the mixture was stirred at 0 °C for 5 hours to precipitate a yellow solid. The reaction suspension was centrifuged, the supernatant was discarded, the yellow solid was washed with diethyl ether, and dried under vacuum to obtain the yellow solid compound TDMQ20 3HCl (205 mg, 82%). 1 HNMR (400 MHz, D2O): d =8.21 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H),7.41 (s, 1H), 3.78 (t, J = 7.1 Hz, 2H), 3.70-3.56 (m, 4H), 3.47 (t, J = 7.1Hz, 2H), 3.00 (s, 6H). 13 C NMR (101 MHz, D2O): δ = 156.90, 137.86, 134.43,133.97, 126.77, 123.53, 123.02, 122.60, 119.27, 52.38, 46.32, 43.39, 41.93,33.14 ppm.

[0188] Route B-2: The overall yield of TDMQ20 synthesis was 39.1% (see Figure 7).

[0189] 5,7-Dichloro-2-methyl-8-aminoquinoline (TDMQ20-NH2): Reduced iron powder (3.26 g, 58.35 mmol) and acetic acid (45 mL) were added to a solution of TDMQ20-NO2 (5 g, 19.45 mmol) in ethanol (125 mL). The mixture was stirred at 80 °C for 1 hour. The mixture was added dropwise to a saturated aqueous solution of sodium bicarbonate to adjust the pH to 7, and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give a pale yellow solid compound TDMQ20-NH2 (4.4 g, 99%). 1 H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 8.7 Hz, 1 H), 7.39 (s, 1 H), 7.32 (d, J = 8.7 Hz, 1 H), 5.30 (s, 2 H), 2.71 (s, 3 H); 13 C NMR (101 MHz, CDCl3): d = 157.81, 139.59, 138.04, 133.15, 126.52, 123.41, 122.91, 117.84,113.57, 25.16 ppm.

[0190] 5,7-Dichloro-2-methyl-8-( N (-Pivaloyl)aminoquinoline (TDMQ20-Bu): Under an argon atmosphere, dried triethylamine (1.3 mL) and pentivaloyl chloride (1.7 mL) were added to an ultradry solution of TDMQ20-NH2 (1.0 g, 4.4 mmol) in 20 mL of dichloromethane. The reaction mixture was stirred at 0 °C for 15 min, then heated to room temperature and stirred for 12 h. Water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 10, v / v) to give a white solid compound TDMQ20-Bu (1.3 g, 93%). 1 H NMR (400 MHz, CDCl3) d = 8.55 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 7.60 (s, 1H), 7.37 (d, J= 8.6 Hz, 1H), 2.72 (s, 3H), 1.45 (s, 9H). 13 C NMR (126 MHz, CDCl3): d = 176.79, 159.89, 143.07, 133.14,130.98, 129.63, 128.15, 127.33, 123.25, 123.03, 40.06, 27.73, 25.45 ppm.

[0191] 5,7-Dichloro-2-aldehyde-8-( N (-Pentavalloyl)aminoquinoline (A-TDMQ20-Bu): Selenium dioxide (535 mg, 4.8 mmol) was added to a solution of TDMQ20-Bu (500 mg, 1.6 mmol) in 1,4-dioxane (6.4 mL). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 10, v / v) to give a white solid compound A-TDMQ20-Bu (508 mg, 98%). 1 H NMR (400 MHz, CDCl3): d = 10.15(d, J = 0.9 Hz, 1H), 8.67 (dd, J = 8.6, 0.9 Hz, 1H), 8.42 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.81 (s, 1H), 1.47 (s, 9H). 13 C NMR (101 MHz, CDCl3): d =192.47, 176.74, 152.30, 143.57, 135.18, 132.43, 131.60, 130.79, 128.76,126.98, 118.37, 40.12, 27.72 ppm.

[0192] 5,7-Dichloro-2-vinyl-8-( N(-Pentavaloyl)aminoquinoline (C-TDMQ20-Bu): Under argon protection, a mixture of potassium carbonate (497 mg, 3.6 mmol) and methyltriphenylphosphine bromide (857 mg, 2.4 mmol) in tetrahydrofuran was stirred at room temperature for 30 minutes. A solution of tetrahydrofuran (6 mL) containing A-TDMQ20-Bu (200 mg, 0.6 mmol) was added to this mixture, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 30, v / v) to give a white solid compound C-TDMQ20-Bu (111 mg, 56%). 1 HNMR (400 MHz, CDCl3): d = 8.54 (s, 1H), 8.37 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 9.3 Hz, 2H), 6.93 (dd, J = 17.5, 10.8 Hz, 1H), 6.37 (dd, J = 17.5, 1.0 Hz, 1H), 5.69 (dd, J = 10.8, 1.0 Hz, 1H), 1.45 (s, 9H). 13 C NMR (126 MHz, CDCl3): d = 176.62, 155.98, 143.30, 136.90, 133.76, 131.41, 130.05, 128.18, 128.01,124.29, 121.39, 120.30, 40.11, 27.79 ppm.

[0193] 5,7-Dichloro-2-(2'-( N,N -dimethylethylenediamine))ethyl-8-( N (-Pentavalloyl)aminoquinoline (D-TDMQ20-Bu): Add to a mixture of C-TDMQ20-Bu (606 mg, 1.87 mmol) and potassium carbonate (309 mg, 2.24 mmol) in 5 mL of 1,4-dioxane. N,N-Dimethyl-1,2-ethylenediamine (2 mL). The mixture was stirred at 80 °C for 5 hours and then quenched with saturated brine. 25% ammonia was added to the mixture to adjust the pH to 13. Extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / 25% ammonia, 50 / 1, v / v) to give a pale yellow solid compound D-TDMQ20-Ac (689 mg, 89%). 1 H NMR (500MHz, CDCl3): d = 8.57 (s, 1H), 8.37 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.40(d, J = 8.6 Hz, 1H), 3.16 (dd, J = 9.4, 4.9 Hz, 4H), 2.72 (t, J = 6.1 Hz, 2H), 2.41 (t, J = 6.1 Hz, 2H), 2.14 (s, 6H), 1.43 (s, 9H). 13 C NMR (126 MHz, CDCl3): d = 176.87, 160.93, 143.39, 133.50, 131.13, 130.55, 128.57, 127.42,123.71, 122.89, 57.90, 47.87, 46.50, 45.21, 39.84, 37.70, 27.71 ppm.

[0194] TDMQ20: 12 M hydrochloric acid (2 mL, 24.3 mmol) was added dropwise to a solution of D-TDMQ20-Bu (200 mg, 0.49 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at 80 °C for 12 hours, then cooled to room temperature. Ether was added to the mixture, and the mixture was stirred at 0 °C for 5 hours to precipitate a yellow solid. The reaction suspension was centrifuged, the supernatant was discarded, and the yellow solid was washed three times with ether and dried under vacuum to obtain the yellow solid compound TDMQ20 3HCl (139 mg, 87%). 1 H NMR (400 MHz, D2O): d = 8.21 (d, J = 8.7 Hz, 1H), 7.46 (d, J= 8.7 Hz, 1H), 7.41 (s, 1H), 3.78 (t, J = 7.1 Hz, 2H), 3.70-3.56 (m, 4H), 3.47 (t, J = 7.1 Hz, 2H), 3.00 (s, 6H). 13 C NMR (101 MHz, D2O): d = 156.90,137.86, 134.43, 133.97, 126.77, 123.53, 123.02, 122.60, 119.27, 52.38, 46.32,43.39, 41.93, 33.14 ppm.

[0195] Route B-3: The overall yield of TDMQ20 synthesis was 45.0% (see Figure 8).

[0196] 5,7-Dichloro-2-aldehyde-8-nitroquinoline (A-TDMQ20-NO2): Under argon protection, selenium dioxide (2.59 g, 23.34 mmol) was added to a solution of TDMQ20-NO2 (2.0 g, 7.78 mmol) in 30 mL of 1,4-dioxane. The mixture was stirred at 101 °C for 18 h. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give an orange solid compound A-TDMQ20-NO2 (1.39 g, 66%). 1 H NMR (500 MHz, CDCl3): d = 10.13(s, 1H), 8.77 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 7.85 (s, 1H). 13 CNMR (126 MHz, CDCl3): d = 191.96, 154.48, 146.16, 140.24, 135.21, 134.25,129.38, 127.08, 126.84, 119.83 ppm.

[0197] 5,7-Dichloro-2-aldehyde-8-aminoquinoline (A-TDMQ20-NH2): Reduced iron powder (618 mg, 11 mmol) and acetic acid (8.5 mL) were added to a 24 mL ethanol solution of A-TDMQ20-NO2 (1 g, 3.69 mmol). The mixture was stirred at 80 °C for 1 hour. The mixture was added dropwise to a saturated aqueous solution of sodium bicarbonate to adjust the pH to 7, and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give an orange solid compound A-TDMQ20-NH2 (879 mg, 98%). 1 H NMR (400 MHz, DMSO- d 6 ): d = 10.13 (s, 1H), 8.58 (d, J = 8.7 Hz, 1H), 7.83 (s, 2H), 6.61 (s, 2H). 13 C NMR (126 MHz, DMSO- d 6 ): d = 192.92, 150.09,142.23, 136.83, 134.28, 130.29, 126.45, 118.48, 114.54, 112.19 ppm.

[0198] 5,7-Dichloro-2-vinyl-8-aminoquinoline (C-TDMQ20-NH2): Under argon protection, a mixture of potassium carbonate (2.4 g, 17.4 mmol) and methyltriphenylphosphine bromide (4.1 g, 11.6 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 30 minutes. A solution of A-TDMQ20-NH2 (700 mg, 2.9 mmol) in tetrahydrofuran (10 mL) was added to this mixture, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 100, v / v) to give a yellow solid compound C-TDMQ20-NH2 (572 mg, 82%). 1 H NMR (400 MHz, CDCl3): d = 8.35 (d, J = 8.8 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.42 (s, 1H), 6.98 (dd, J = 17.6, 10.9 Hz, 1H), 6.32 (dd, J =17.7, 0.9 Hz, 1H), 5.66 (dd, J = 10.9, 1.0 Hz, 1H), 5.35 (s, 2H). 13 C NMR (101MHz, CDCl3): d = 154.41, 140.08, 138.07, 137.25, 133.52, 127.23, 124.39,120.31, 119.62, 117.76, 113.74 ppm.

[0199] 100g-scale synthesis of the core intermediate 5,7-dichloro-2-vinyl-8-aminoquinoline (C-TDMQ20-Bu):

[0200] Under argon protection, a mixture of potassium carbonate (480 g, 3.48 mol) and methyltriphenylphosphine bromide (840 g, 2.32 mol) in tetrahydrofuran (2 L) was stirred at room temperature for 30 minutes. A solution of A-TDMQ20-NH2 (140 g, 0.58 mol) in tetrahydrofuran (500 mL) was added to this mixture, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude product was recrystallized to give a yellow solid compound C-TDMQ20-NH2 (118.6 g, 85%).

[0201] 5,7-Dichloro-2-(2'-( N,N 1,4-Dimethylethylenediamine)ethyl)-8-aminoquinoline (D-TDMQ20-NH2): A 2 M hydrochloric acid-ethyl acetate solution (10 mL) of C-TDMQ20-NH2 (106 mg, 0.44 mmol) was stirred overnight at room temperature and concentrated under reduced pressure. The resulting orange solid solution of 1,4-dioxane (1.5 mL) was slowly added... N,N Dimethyl-1,2-ethylenediamine (0.58 mL) was stirred at 40 °C for 42 hours, followed by quenching with saturated brine. 25% ammonia was added to the reaction mixture to adjust the pH to 13. Extraction was performed with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / 25% ammonia, 50 / 1, v / v) to give a yellow oily compound D-TDMQ20-NH2 (123 mg, 85%).1 H NMR (400 MHz, CDCl3): d = 8.24 (d, J = 8.6 Hz,1H), 7.35 (s, 1H), 7.30 (d, J = 8.6 Hz, 1H), 5.37 (s, 2H), 3.19-3.06 (m, 4H), 2.75 (dd, J = 6.6, 5.4 Hz, 2H), 2.51 (s, 2H), 2.43 (t, J = 6.0 Hz, 2H), 2.20(s, 6H). 13 C NMR (126 MHz, CDCl3): d = 159.45, 139.62, 137.75, 133.11, 126.49,123.51, 122.54, 117.43, 113.33, 58.94, 48.65, 47.12, 45.55, 38.22 ppm.

[0202] TDMQ20: 4.3 mL of 10 M hydrochloric acid-ethanol solution (43 mmol) was added to a 10 mL ethanol solution of D-TDMQ20-NH2 (280 mg, 0.85 mmol). The reaction mixture was stirred overnight at room temperature to precipitate a yellow solid. The reaction suspension was centrifuged, and the supernatant was discarded. The yellow solid was washed three times with diethyl ether and dried under vacuum to quantitatively obtain the yellow solid compound TDMQ20 3HCl (quant.). 1 H NMR (400 MHz, D2O): d = 8.21 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.41 (s, 1H), 3.78 (t, J = 7.1 Hz, 2H), 3.70-3.56 (m, 4H), 3.47 (t, J = 7.1 Hz, 2H), 3.00 (s, 6H). 13 C NMR (101 MHz, D2O): d= 156.90, 137.86, 134.43, 133.97, 126.77, 123.53, 123.02, 122.60, 119.27,52.38, 46.32, 43.39, 41.93, 33.14 ppm.

[0203] Application of Route B-3 in TDMQ22 synthesis (see Figure 9).

[0204] 6-Trifluoromethyl-2-aldehyde-8-nitroquinoline (B-TDMQ22): Selenium dioxide (998 mg, 9 mmol) was added to a solution of A-TDMQ22 (768 mg, 3 mmol) in 1,4-dioxane (10 mL), and the mixture was stirred at 80 °C for 4 hours. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, and the combined organic phases were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 3, v / v) to give a yellow solid compound B-TDMQ22 (401 mg, 50%). 1 H NMR (400 MHz, CDCl3): d = 10.14 (s, 1H), 8.51 (d, J = 8.5 Hz, 1H),8.40-8.36 (m, 1H), 8.24-8.16 (m, 2H).; 13 C NMR (101 MHz, CDCl3): d = 192.21,155.22, 149.12, 140.12, 138.80, 129.99 (q, J = 34.5 Hz), 129.93, 129.32 (q, J = 4.2 Hz), 122.51 (q, J = 273.0 Hz), 120.51 (q, J = 3.1 Hz), 120.11 ppm.

[0205] 6-Trifluoromethyl-2-aldehyde-8-aminoquinoline (C-TDMQ22): Reduced iron powder (94 mg, 1.6 mmol) and acetic acid (1 mL) were added to an ethanol solution (3 mL) of B-TDMQ22 (150 mg, 0.56 mmol). The mixture was stirred at 80 °C for 3 hours. The mixture was added dropwise to a saturated aqueous solution of sodium bicarbonate to adjust the pH to 5-6, and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 20, v / v) to give a yellow solid compound C-TDMQ22 (113 mg, 84%). 1 HNMR (400 MHz, CDCl3): d = 10.19 (s, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.46 (s, 1H), 7.10 (s, 1H), 5.40 (s, 2H). 13 C NMR (101 MHz, CDCl3): d = 193.00, 151.18, 145.82, 138.26, 135.21, 132.02 (d, J = 32.3 Hz), 129.94, 124.61 (d, J = 273.0 Hz), 118.51, 112.61 (q, J = 3.8 Hz), 105.52 (q, J = 3.1 Hz) ppm.

[0206] 6-Trifluoromethyl-2-vinyl-8-aminoquinoline (D-TDMQ22): Under argon protection, potassium carbonate (578 mg, 3.7 mmol) and methyltriphenylphosphine bromide (892 mg, 2.5 mmol) were suspended in tetrahydrofuran (10 mL) and stirred at room temperature for 30 minutes. This mixture was then added to a tetrahydrofuran (10 mL) solution of C-TDMQ22 (200 mg, 1.16 mmol) and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give a yellow solid compound D-TDMQ22 (145 mg, 98%). 1 H NMR (400 MHz, CDCl3): d = 8.07 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.38 (dd, J = 2.0, 1.0 Hz, 1H), 7.06-6.94 (m, 2H), 6.32 (dd, J = 17.6, 0.9Hz, 1H), 5.66 (dd, J = 10.9, 0.9 Hz, 1H), 5.20 (s, 2H). 13 C NMR (101 MHz, CDCl3): d = 155.06, 144.87, 138.82, 137.62, 137.30, 128.99 (d, J = 32.1 Hz), 127.01, 124.40 (d, J = 272.3 Hz), 120.13, 120.03, 113.04 (q, J = 4.7 Hz), 105.21 (q, J = 3.2 Hz) ppm.

[0207] 6-Trifluoromethyl-2-(2'-( N , N -Dimethylethylenediamine))ethyl)-8-aminoquinoline (E-TDMQ22): Add to a mixture of D-TDMQ22 (119 mg, 0.5 mmol), potassium carbonate (83 mg, 0.6 mmol), and crown ether (159 mg, 0.6 mmol) in 2 mL of 1,4-dioxane. N,N -Dimethyl-1,2-ethylenediamine (0.44 mL). The reaction mixture was stirred at reflux for 12 hours, followed by quenching with saturated brine. 25% ammonia was added to the mixture to adjust the pH to 13. Extraction was performed with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / 25% ammonia, 25 / 1, v / v) to give a yellow oily compound E-TDMQ22 (160 mg, 96%). 1 H NMR (400 MHz, CDCl3): d = 7.88 (d, J = 8.4 Hz, 1H), 7.31-7.17 (m, 2H), 6.88 (d,J = 1.9 Hz, 1H), 5.22 (s, 2H), 3.07 (dd, J = 7.7, 4.3 Hz, 4H), 2.68(t, J = 6.1 Hz, 2H), 2.35 (t, J = 6.0 Hz, 2H), 2.11 (s, 6H). 13 C NMR (101 MHz, CDCl3): d = 160.15, 144.58, 138.54, 137.04, 128.34 (d, J = 31.9 Hz), 126.78 (d, J = 217.1 Hz), 126.15, 123.03, 112.75 (q, J = 4.7 Hz), 104.86 (q, J = 3.2Hz), 58.96, 48.71, 47.19, 45.55, 38.41 ppm.

[0208] TDMQ22: To a 5 mL ethanol solution of E-TDMQ22 (80 mg, 0.24 mmol), 10 M hydrochloric acid-ethanol solution (1.2 mL, 12 mmol) was added, and the mixture was stirred overnight at room temperature to precipitate a yellow solid. The reaction suspension was centrifuged. The yellow solid was washed three times with diethyl ether and dried under vacuum to quantitatively obtain the yellow solid compound TDMQ22 3HCl (quant.). 1 H NMR (400 MHz, D2O): d = 8.45 (d, J = 8.6 Hz, 1H), 8.27 (dd, J =2.0, 1.1 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 3.85(t, J = 6.8 Hz, 2H), 3.67 (ttd, J = 9.2, 4.7, 1.9 Hz, 4H), 3.59 (t, J = 6.8Hz, 2H), 3.02 (s, 6H). 13 C NMR (101 MHz, D2O): d =159.96, 140.57, 138.91,130.62, 127.35 (d, J = 33.4 Hz), 126.83, 124.87 (q, J = 4.8 Hz), 124.35, 123.37 (d, J = 271.8 Hz), 117.34 (q, J = 3.4 Hz), 52.34, 46.17, 43.41, 41.99,33.39 ppm.

[0209] Application of Route B-3 in TDMQ29 synthesis (see Figure 10 ).

[0210] 2-Aldehyde-8-nitroquinoline (B-TDMQ29): Selenium dioxide (3.5 g, 31.86 mmol) was added to a solution of A-TDMQ29 (2 g, 10.6 mmol) in 24 mL of 1,4-dioxane, and the mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The combined organic phases were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 5, v / v) to give the brown solid compound B-TDMQ29 (1.8 g, 84%). 1 HNMR (400 MHz, CDCl3): d = 10.15 (d, J = 0.9 Hz, 1H), 8.43 (dd, J = 8.5, 0.9Hz, 1H), 8.16-8.07 (m, 3H), 7.81 -7.72 (m, 1H). 13 C NMR (101 MHz, CDCl3): d =192.94, 153.85, 148.74, 139.19, 137.84, 131.97, 130.52, 128.01, 124.57,119.02 ppm.

[0211] 2-Aldehyde-8-aminoquinoline (C-TDMQ29): Reduced iron powder (419 mg, 7.5 mmol) and acetic acid (5 mL) were added to a 13 mL ethanol solution of B-TDMQ29 (506 mg, 2.5 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to a saturated aqueous solution of sodium bicarbonate, and the pH was adjusted to 5-6. The mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 25, v / v) to give a yellow solid compound C-TDMQ29 (163 mg, 38%). 1 H NMR (400MHz, CDCl3): d = 10.18 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.5Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.19 (dd, J = 8.2, 1.2 Hz, 1H), 6.99 (dd, J = 7.7, 1.2 Hz, 2H), 5.20 (s, 2H). 13 C NMR (101 MHz, CDCl3): d = 193.68,149.94, 145.25, 137.79, 137.21, 130.99, 130.77, 117.60, 115.77, 110.66 ppm.

[0212] 2-Vinyl-8-aminoquinoline (D-TDMQ29): Under argon protection, potassium carbonate (962 mg, 6.9 mmol) and methyltriphenylphosphine bromide (1.6 g, 4.6 mmol) were suspended in tetrahydrofuran (5 mL) and stirred at room temperature for 30 min. A solution of C-TDMQ29 (200 mg, 1.16 mmol) in tetrahydrofuran (5 mL) was added to the mixture, and the mixture was stirred at 70 °C for 28 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give a yellow oily compound D-TDMQ29 (92 mg, 46%). 1 H NMR (400MHz, CDCl3): d = 8.02 (d, J= 8.6 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.11 (dd, J = 8.1, 1.3 Hz, 1H), 7.00 (dd, J = 17.7, 10.9 Hz,1H), 6.91 (dd, J = 7.5, 1.3 Hz, 1H), 6.27 (dd, J = 17.6, 1.1 Hz, 1H), 5.59(dd, J = 10.8, 1.1 Hz, 1H), 5.01 (s, 2H). 13 C NMR (101 MHz, CDCl3): d =153.25, 144.13, 138.13, 137.99, 136.41, 128.13, 127.33, 118.91, 118.70,115.92, 110.35 ppm.

[0213] 2-(2'-( N,N 1,4-Dioxane (E-TDMQ29): Add to a mixture of D-TDMQ29 (128 mg, 0.75 mmol), potassium carbonate (687 mg, 3.75 mmol), and crown ether (991 mg, 3.75 mmol) in 3 mL of 1,4-dioxane. N,N -Dimethyl-1,2-ethylenediamine (0.7 mL). The mixture was stirred at reflux for 24 hours, followed by quenching with saturated brine. A 25% ammonia solution was added to the reaction mixture to adjust the pH to 13. Extraction was performed with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / 25% ammonia, 25 / 1, v / v) to give a yellow oily compound E-TDMQ29 (38 mg, 20%). 1 HNMR (400 MHz, CDCl3): d = 77.94 (d, J = 8.4 Hz, 1H), 7.26-7.18 (m, 2H), 7.07(dd, J = 8.2, 1.3 Hz, 1H), 6.87 (dd, J= 7.5, 1.2 Hz, 1H), 3.18 (s, 4H), 2.80(t, J = 6.0 Hz, 2H), 2.46 (t, J = 6.0 Hz, 2H), 2.19 (s, 6H). 13 C NMR (101 MHz, CDCl3): d = 157.68, 143.69, 137.78, 136.63, 127.46, 126.81, 122.02, 115.99,110.49, 58.46, 48.47, 46.82, 45.65, 37.44 ppm.

[0214] TDMQ29: To a 3 mL ethanol solution of E-TDMQ29 (40 mg, 0.15 mmol), 0.75 mL of 10 M hydrochloric acid-ethanol solution (7.5 mmol) was added dropwise, and the mixture was stirred overnight at room temperature to precipitate a yellow solid. The reaction suspension was centrifuged. The yellow solid was washed three times with diethyl ether and dried under vacuum to quantitatively obtain the yellow solid compound TDMQ29 3HCl (quant.). 1 H NMR (400 MHz, D2O): d = 8.24 (d, J = 8.5 Hz, 1H), 7.86 (dd, J =8.3, 1.3 Hz, 1H), 7.75 (dd, J = 7.5, 1.3 Hz, 1H), 7.54 (dd, J = 8.3, 7.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 3.78 (t, J = 6.8 Hz, 2H), 3.67-3.62 (m, 2H), 3.62-3.57 (m, 2H), 3.48 (t, J = 6.8 Hz, 2H), 2.96 (s, 6H). 13 C NMR (101 MHz, D2O): d = 157.97, 139.47, 138.19, 128.70, 127.46, 126.19, 126.15, 123.62,123.26, 52.35, 46.29, 43.43, 42.03, 33.13 ppm.

[0215] Application of Route B-3 in TDMQ60 synthesis (see Figure 11).

[0216] 5,7-Difluoro-2-aldehyde-8-nitroquinoline (B-TDMQ60): Selenium dioxide (738 mg, 6.6 mmol) was added to a 5 mL solution of A-TDMQ60 (497 mg, 2.2 mmol) in 1,4-dioxane, and the mixture was stirred at reflux for 4 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The combined organic phases were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 3, v / v) to give a yellow solid compound B-TDMQ60 (396 mg, 70%). 1 H NMR (400 MHz, CDCl3): d = 10.18 (d, J = 0.9 Hz, 1H), 8.69(dd, J = 8.6, 0.9 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 7.38 (t, J = 9.1 Hz, 1H). 13 C NMR (101 MHz, CDCl3): d = 192.07, 158.57 (dd, J = 266.0, 13.6 Hz),155.06, 154.10 (dd, J = 263.6, 13.9 Hz), 140.41 (t, J = 5.0 Hz), 131.76 (dd, J = 3.7, 2.1 Hz), 126.75 (d, J = 12.5 Hz), 118.59 (t, J = 2.6 Hz), 117.94 (d, J = 17.5 Hz), 104.45 (dd, J = 26.5, 25.5 Hz) ppm.

[0217] 5,7-Difluoro-2-aldehyde-8-aminoquinoline (C-TDMQ60): Reduced iron powder (176 mg, 3.15 mmol) and acetic acid (2 mL) were added to an ethanol solution (6 mL) of B-TDMQ60 (250 mg, 1.05 mmol). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was added dropwise to a saturated aqueous solution of sodium bicarbonate and the pH was adjusted to 5–6. The mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give a yellow solid compound C-TDMQ60 (170 mg, 77%). 1 H NMR (400 MHz, CDCl3): d = 10.13 (d, J = 0.9 Hz, 1H), 8.41 (dd, J = 8.6, 0.9Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.18-7.11 (m, 1H), 4.81 (s, 2H). 13 C NMR (126 MHz, CDCl3): d = 193.02, 151.21, 148.52 (dd, J = 247.3, 13.5 Hz), 147.02 (dd, J = 240.6, 11.7 Hz),134.25, 131.02 (t, J = 2.7 Hz), 129.50, 128.22 (dd, J = 12.8, 4.9 Hz), 117.63 (dd, J = 17.1, 1.9 Hz), 105.13 (dd, J = 26.3, 24.4Hz) ppm.

[0218] 5,7-Difluoro-2-vinyl-8-aminoquinoline (D-TDMQ60): Under argon protection, a mixture of potassium carbonate (299 mg, 2.1 mmol) and methyltriphenylphosphine bromide (515 mg, 1.44 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 30 minutes. This mixture was added to a solution of C-TDMQ60 (75 mg, 0.36 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 36 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give a yellow solid compound D-TDMQ60 (66 mg, 89%). 1 H NMR (400MHz, CDCl3): d = 8.25 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.05-6.93 (m, 2H), 6.33 (d, J = 17.7 Hz, 1H), 5.66 (d, J = 10.8 Hz (1H), 4.68 (s, 2H). 13 C NMR (101 MHz, CDCl3): d = 155.05, 149.20 (dd, J = 245.9, 13.4 Hz), 147.24 (dd, J = 238.1, 12.5 Hz), 138.22 (dd, J = 10.0, 4.0 Hz), 137.56,129.90 (t, J = 2.8 Hz), 126.92 (d, J = 17.2 Hz), 120.33, 118.08 (t, J = 2.8Hz), 115.09 (d, J = 17.1 Hz), 102.07 (dd, J = 26.5, 24.3 Hz) ppm.

[0219] 5,7-Difluoro-2-(2'-( N , N1,4-Dioxane (E-TDMQ60): Add to a mixture of D-TDMQ60 (123 mg, 0.6 mmol), potassium carbonate (550 mg, 3.0 mmol), and crown ether (793 mg, 3.0 mmol) in 24 mL of 1,4-dioxane. N, N -Dimethyl-1,2-ethylenediamine (0.53 mL). The mixture was stirred at 80 °C for 24 hours, followed by quenching with saturated brine. 25% ammonia was added to the reaction mixture to adjust the pH to 13, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / 25% ammonia, 25 / 1, v / v) to give a yellow oily compound E-TDMQ60 (145 mg, 82%). 1 HNMR (400 MHz, CDCl3): d = 8.19 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.98 (dd, J = 10.9, 9.7 Hz, 1H), 4.72 (s, 2H), 3.17 (dt, J = 10.3, 5.4 Hz, 4H), 2.78 (t, J = 6.0 Hz, 2H), 2.45 (t, J = 6.0 Hz, 2H), 2.21 (s, 6H). 13 C NMR (101 MHz, CDCl3): d = 160.34, 149.20 (dd, J = 246.0, 13.5 Hz), 147.20 (dd, J =237.6, 12.6 Hz), 138.08 (dd, J = 10.3, 4.0 Hz), 129.78 (t, J = 2.8 Hz), 126.60 (dd, J = 12.4, 4.7 Hz), 121.19 (t, J = 2.8 Hz), 114.52 (dd, J = 17.2, 1.4 Hz), 101.52 (dd, J= 26.5, 24.3 Hz), 59.03, 48.72, 47.29, 45.73, 38.40ppm.

[0220] TDMQ60: To a 5 mL ethanol solution of E-TDMQ60 (95 mg, 0.32 mmol), 10 M hydrochloric acid-ethanol solution (1.6 mL, 16 mmol) was added, and the mixture was stirred overnight at room temperature to precipitate a yellow solid. The reaction suspension was centrifuged. The resulting yellow solid was washed three times with diethyl ether and dried under vacuum to quantitatively obtain the yellow solid compound TDMQ603HCl (quant.). 1 H NMR (400 MHz, D2O): d = 8.49 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.43-7.33 (m, 1H), 3.84 (t, J = 6.8 Hz, 2H), 3.72-3.66 (m,2H), 3.66-3.60 (m, 2H), 3.56 (t, J = 6.8 Hz, 2H), 3.02 (s, 6H). 13 C NMR (101MHz, D2O): d = 159.97, 156.53 (dd, J = 257.3, 14.5 Hz), 154.40 (dd, J =250.9, 13.9 Hz). 140.45 (dd, J = 6.8, 5.3 Hz), 131.39(dd, J = 3.6, 1.9 Hz), 122.55 (t, J = 2.6 Hz), 115.19 (dd, J = 18.1, 1.3 Hz), 111.90 (dd, J = 13.4,5.3 Hz), 102.40-101.64 (m), 52.35, 46.19, 43.41, 41.99, 33.50 ppm.

[0221] Example 3: Route C - TDMQ20 Synthesis Route Based on Grignard Reactions

[0222] Route C-1: The overall yield of TDMQ20 synthesis was 8.2% (see Figure 12).

[0223] 5,7-Dichloro-2-methyl-8-aminoquinoline (TDMQ20-NH2): Iron powder (3.2 g, 58.2 mmol) and acetic acid (45 mL) were added to an ethanol (125 mL) solution of 5,7-dichloro-2-methyl-8-nitroquinoline (TDMQ20-NO2, 5.0 g, 19.4 mmol), and the mixture was stirred under reflux for 1 hour. The reaction mixture was added dropwise to a saturated aqueous solution of sodium bicarbonate, and the pH was adjusted to 13 with ammonia. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:50, v / v) to give a pale yellow solid compound TDMQ20-NH2 (4.4 g, 99%). 1 H NMR (400 MHz, CDCl3): d = 8.27 (d, J =8.7 Hz, 1H), 7.39 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 5.30 (s, 2H), 2.71 (s, 3H). 13 C NMR (101 MHz, CDCl3): d = 157.81, 139.59, 138.04, 133.15, 126.52,123.41, 122.91, 117.84, 113.57, 25.16 ppm.

[0224] 5,7-Dichloro-2-methyl-8-( N , N (-Diacetyl)aminoquinoline (TDMQ20-2Ac): Under argon protection, acetyl chloride (0.63 mL) was added to an ultra-dry dichloromethane (7 mL) solution of compound TDMQ20-NH2 (500 mg, 2.2 mmol) and... N , N -Diisopropylethylamine (3.45 mL). The reaction mixture was stirred at 0 °C for 15 min, then heated to room temperature and stirred for 14 h. The organic solvent in the mixture was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:50, v / v) to give the pale yellow solid compound TDMQ20-2Ac (499 mg, 73%). 1H NMR (500 MHz, CDCl3): d = 8.41 (d, J = 8.6 Hz, 1H), 7.69 (s, 1H), 7.41 (d, J =8.7 Hz, 1H), 2.70 (s, 3H), 2.29 (s, 6H). 13 C NMR (101 MHz, CDCl3): d = 172.57,162.39, 145.00, 134.28, 133.56, 133.32, 133.01, 126.65, 124.47, 123.73,26.18, 25.76 ppm.

[0225] 5,7-Dichloro-2-aldehyde-8-( N , N (-Diacetyl)aminoquinoline (A-TDMQ20-2Ac): Selenium dioxide (533 mg, 4.8 mmol) was added to a 6 mL solution of TDMQ20-2Ac (500 mg, 1.6 mmol) in 1,4-dioxane, and the mixture was stirred at 85 °C for 8 h. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The combined organic phases were concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give a pale yellow solid compound A-TDMQ20-2Ac (220 mg, 42%). 1 H NMR (400 MHz, CDCl3): d = 10.13 (d, J =0.9 Hz, 1H), 8.76 (dd, J = 8.7, 0.9 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.92(s, 1H), 2.32 (s, 6H). 13 C NMR (126 MHz, CDCl3): d = 192.68, 172.22, 154.03,145.24, 135.93, 135.63, 134.82, 133.43, 130.02, 127.93, 119.01, 26.23 ppm.

[0226] 5,7-Dichloro-2-(1-hydroxyethyl)-8-( N(-Acetyl)aminoquinoline (B-TDMQ20-NAc): Under argon protection, a solution of methyl magnesium bromide in tetrahydrofuran (3 M, 1 mL) was slowly added dropwise to a dry tetrahydrofuran solution (6 mL) of compound A-TDMQ20-2Ac (200 mg, 0.62 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then heated to room temperature and stirred for 28 h. A saturated aqueous solution of ammonium chloride (2.5 mL) and a saturated aqueous solution of sodium chloride (6 mL) were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:1, v / v). After evaporation of the eluent, a pale yellow solid, compound B-TDMQ20-NAc (95 mg, 51%), was given. 1 H NMR (400 MHz, CDCl3): d = 8.37 (d, J =8.7 Hz, 1H), 8.19 (s, 1H), 7.59 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 4.98 (q, J = 6.6 Hz, 1H), 4.45 (s, 1H), 2.27 (s, 3H), 1.53 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3): d = 178.66, 164.68, 142.52, 134.35, 131.92, 130.55, 129.71,127.83, 124.52, 119.32, 69.34, 29.71, 23.90 ppm.

[0227] 5,7-Dichloro-2-vinyl-8-aminoquinoline (C-TDMQ20-NH2): Compound B-TDMQ20-NAc (180 mg, 0.6 mmol) was dissolved in 85% sulfuric acid (1.2 mL) and stirred at 130 °C for 16 hours. The reaction mixture was added dropwise to ice water, followed by the addition of saturated sodium bicarbonate solution and ammonia water to adjust the pH to 13. The mixture was extracted three times with ethyl acetate. The organic phases were combined, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:100). v / v), yielded a yellow solid compound C-TDMQ20-NH2 (90 mg, 63%). 1H NMR (400 MHz, CDCl3): d = 8.35 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.42 (s, 1H), 6.98 (dd, J = 17.6,10.9 Hz, 1H), 6.32 (dd, J = 17.7, 0.9 Hz, 1H), 5.66 (dd, J = 10.9, 0.9 Hz,1H), 5.35 (s, 1H). 13 C NMR (101 MHz, CDCl3): d = 154.41, 140.08, 138.07,137.25, 133.52, 127.23, 124.39, 120.31, 119.62, 117.76, 113.74 ppm.

[0228] 5,7-Dichloro-2-(2'-( N , N C-TDMQ20-NH2 (106 mg, 0.44 mmol) was dissolved in 2 M ethyl chloride-ethyl acetate solution (10 mL) and stirred overnight at room temperature. After concentration under reduced pressure, the solution was slowly added to a solution of 1,4-dioxane (1.5 mL) containing an orange solid. N , N -Dimethylethylenediamine (580 μL, 5.28 mmol). The mixture was incubated at 40 °C and stirred for 42 hours. A saturated aqueous sodium chloride solution and ammonia were added to the reaction mixture to adjust the pH to 8, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / isopropanol / 25% ammonia, 8:1:0.5). v / v), yielded a pale yellow oily compound D-TDMQ20-NH2 (123 mg, 85%). 1 H NMR (400 MHz, CDCl3): d = 8.24 (d, J = 8.6 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J= 8.6 Hz, 1H), 5.37 (s,2H), 3.19-3.06 (m, 4H), 2.75 (dd, J = 6.6, 5.4 Hz, 2H), 2.51 (s, 2H), 2.43(t, J = 6.0 Hz, 2H), 2.20 (s, 6H). 13 C NMR (126 MHz, CDCl3): d = 159.45,139.62, 137.75, 133.11, 126.49, 123.51, 122.54, 117.43, 113.33, 58.94, 48.65,47.12, 45.55, 38.22 ppm.

[0229] TDMQ20: To an anhydrous ethanol solution of D-TDMQ20-NH2 (108 mg, 0.33 mmol), 10 M hydrogen chloride-ethanol solution (1.6 mL) was slowly added dropwise, and the mixture was stirred overnight at room temperature to precipitate a solid. The precipitate was filtered, washed with ether, and dried under reduced pressure to quantitatively obtain a yellow solid powder TDMQ20 3HCl (quant.). 1 H NMR (400 MHz, D2O): d = 8.21 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.41 (s, 1H), 3.78 (t, J = 7.1 Hz, 2H), 3.70-3.56 (m, 4H), 3.47 (t, J = 7.1 Hz, 2H), 3.00 (s, 6H). 13 C NMR (101 MHz, D2O): d = 156.90, 137.86, 134.43, 133.97, 126.77,123.53, 123.02, 122.60, 119.27, 52.38, 46.32, 43.39, 41.93, 33.14 ppm.

[0230] Route C-2: The overall yield of TDMQ20 synthesis was 27.0% (see Figure 13).

[0231] 5,7-Dichloro-2-methyl-8-aminoquinoline (TDMQ20-NH2): Iron powder (3.2 g, 58.2 mmol) and acetic acid (45 mL) were added to an ethanol (125 mL) solution of 5,7-dichloro-2-methyl-8-nitroquinoline (TDMQ20-NO2, 5.0 g, 19.4 mmol), and the mixture was stirred under reflux for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the pH was adjusted to 13 with ammonia. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:50, v / v) to give a pale yellow solid compound TDMQ20-NH2 (4.4 g, 99%). 1 H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 8.7 Hz,1H), 7.39 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 5.30 (s, 2H), 2.71 (s, 3H). 13 CNMR (101 MHz, CDCl3): d = 157.81, 139.59, 138.04, 133.15, 126.52, 123.41,122.91, 117.84, 113.57, 25.16 ppm.

[0232] 5,7-Dichloro-2-methyl-8-( N (-Acetyl)aminoquinoline (TDMQ20-NAc): Under argon protection, acetyl chloride (2.5 mL) was added to an ultradry dichloromethane (15 mL) solution of compound TDMQ20-NH2 (500 mg, 2.2 mmol), and the mixture was stirred at 0 °C for 15 min. The mixture was then heated to room temperature and stirred for 8 h. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, and the pH was adjusted to 8. The mixture was extracted three times with dichloromethane. The organic phases were combined, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:3, v / v) to give a pale yellow solid, TDMQ20-NAc (1.15 g, 97%). 1 H NMR (400 MHz, CDCl3): d = 8.37 (s, 1H), 8.32 (d, J = 8.6 Hz,1H), 7.58 (s, 1H), 7.36 (d,J = 8.6 Hz, 1H), 2.72 (s, 3H), 2.31 (s, 3H). 13 CNMR (126 MHz, CDCl3): d = 169.00, 160.41, 143.36, 133.31, 130.64, 130.45,129.01, 127.36, 123.52, 123.28, 25.39, 23.74 ppm.

[0233] 5,7-Dichloro-2-carboxyl-8-(N-acetyl)aminoquinoline (A-TDMQ20-NAc): Selenium dioxide (821 mg, 7.4 mmol) was added to a 1,4-dioxane solution (1.0 g, 3.7 mmol) of TDMQ20-NAc (1.0 g, 3.7 mmol) in 1,4-dioxane (15 mL). The mixture was stirred at 80 °C, and the reaction was monitored by TLC. The starting material was completely converted after 20 min. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 3, v / v) to obtain a pale yellow solid compound A-TDMQ20-NAc (982 mg, 94%). 1 H NMR (500 MHz, DMSO- d 6 ): d = 10.26 (s, 1H), 10.13 (s, 1H), 8.78 (d, J = 8.7 Hz, 1H), 8.20(s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 2.19 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6 ): d = 193.10, 168.68, 152.85, 144.55, 135.24, 133.47, 132.94, 129.93, 128.95,126.65, 118.85, 22.81 ppm.

[0234] 5,7-Dichloro-2-(1-hydroxyethyl)-8-( N(-Acetyl)aminoquinoline (B-TDMQ20-NAc): Under argon protection, a methylmagnesium bromide-tetrahydrofuran solution (3 M, 11 mL) was slowly added dropwise to a dry tetrahydrofuran solution of A-TDMQ20-NAc (600 mg, 2.12 mmol) at 0 °C, and stirred for 1 h. The mixture was then heated to 40 °C and stirred for 18 h. A saturated ammonium chloride aqueous solution (17 mL) and a saturated sodium chloride aqueous solution (21 mL) were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 1, v / v) to give a pale yellow solid compound B-TDMQ20-NAc (353 mg, 56%). 1 H NMR (400 MHz, CDCl3): d = 8.37 (d, J = 8.7 Hz, 1H), 8.19 (s, 1H), 7.59(s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 4.98 (q, J = 6.6 Hz, 1H), 4.45 (s, 1H), 2.27 (s, 3H), 1.53 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3): d = 178.66,164.68, 142.52, 134.35, 131.92, 130.55, 129.71, 127.83, 124.52, 119.32,69.34, 29.71, 23.90 ppm.

[0235] 5,7-Dichloro-8-amino-2-vinylquinoline (C-TDMQ20-NH2): Compound B-TDMQ20-NAc (180 mg, 0.6 mmol) was dissolved in 1.2 mL of 85% sulfuric acid and heated to 130 °C with stirring for 16 hours. The reaction mixture was added dropwise to ice water, followed by the addition of saturated sodium bicarbonate solution and ammonia to adjust the pH to 13. The mixture was extracted three times with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:100). v / v), yielded a yellow solid compound C-TDMQ20-NH2 (90 mg, 63%). 1H NMR (400 MHz, CDCl3): d = 8.35 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.42 (s, 1H), 6.98 (dd, J = 17.6,10.9 Hz, 1H), 6.32 (dd, J = 17.7, 0.9 Hz, 1H), 5.66 (dd, J = 10.9, 0.9 Hz,1H), 5.35 (s, 1H). 13 C NMR (101 MHz, CDCl3): d = 154.41, 140.08, 138.07,137.25, 133.52, 127.23, 124.39, 120.31, 119.62, 117.76, 113.74 ppm.

[0236] 5,7-Dichloro-2-(2'-( N,N C-Dimethylethylenediamine)ethyl)-8-aminoquinoline (D-TDMQ20-NH2): Compound C-TDMQ20-NH2 (106 mg, 0.44 mmol) was dissolved in a solution of hydrogen chloride and ethyl acetate (2 M, 10 mL) and stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure. The resulting orange solid solution of 1,4-dioxane (1.5 mL) was slowly added... N,N -Dimethylethylenediamine (580 μL, 5.28 mmol) was stirred at 40 °C for 42 hours. A saturated aqueous sodium chloride solution and ammonia were added to the reaction mixture to adjust the pH to 8, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / isopropanol / 25% ammonia, 8:1:0.5). v / v), yielded a pale yellow oily compound D-TDMQ20-NH2 (123 mg, 85%). 1 H NMR (400 MHz, CDCl3): d =8.17 (d, J = 8.6 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 5.30 (s,2H), 3.10-3.05 (m, 2H), 3.02 (dd,J = 7.7, 3.9 Hz, 2H), 2.66 (t, J = 6.0 Hz,2H), 2.59 (s, 1H), 2.34 (t, J = 6.0 Hz, 2H), 2.11 (s, 6H). 13 C NMR (101 MHz, CDCl3): d = 159.49, 139.65, 137.80, 133.15, 126.52, 123.55, 122.57, 117.47,113.37, 58.96, 48.67, 47.14, 45.55, 38.26 ppm.

[0237] TDMQ20: To an anhydrous ethanol solution of D-TDMQ20-NH2 (108 mg, 0.33 mmol), a hydrogen chloride-ethanol solution (10 M, 1.6 mL) was slowly added dropwise, and the mixture was stirred overnight at room temperature to precipitate a solid. The precipitate was filtered, washed with diethyl ether, and dried under reduced pressure to quantitatively obtain the yellow solid compound TDMQ20 3HCl (quant.). 1 H NMR (400 MHz, D2O): d = 8.21 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.41 (s, 1H), 3.78 (t, J = 7.1 Hz, 2H), 3.70-3.56 (m, 4H), 3.47 (t, J = 7.1 Hz, 2H), 3.00 (s, 6H). 13 C NMR (101 MHz, D2O): d = 156.90, 137.86, 134.43, 133.97, 126.77,123.53, 123.02, 122.60, 119.27, 52.38, 46.32, 43.39, 41.93, 33.14 ppm.

[0238] Route C-3: The overall yield of TDMQ20 synthesis was 30.3% (see Figure 14).

[0239] 5,7-Dichloro-2-methyl-8-aminoquinoline (TDMQ20-NH2): Iron powder (3.2 g, 58.2 mmol) and acetic acid (45 mL) were added to an ethanol (125 mL) solution of 5,7-dichloro-2-methyl-8-nitroquinoline (TDMQ20-NO2, 5.0 g, 19.4 mmol), and the mixture was stirred under reflux for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, the pH was adjusted to 13 with ammonia, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:50, v / v) to give a pale yellow solid compound TDMQ20-NH2 (4.4 g, 99%). 1 H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 8.7Hz, 1H), 7.39 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 5.30 (s, 2H), 2.71 (s, 3H). 13 C NMR (101 MHz, CDCl3): d = 157.81, 139.59, 138.04, 133.15, 126.52, 123.41,122.91, 117.84, 113.57, 25.16 ppm.

[0240] 5,7-Dichloro-2-methyl-8-( N (-Pterovaleryl)aminoquinoline (TDMQ20-Bu): Under argon protection, triethylamine (1.3 mL) and tert-butyl chloroformate (1.7 mL) were added to an ultradry dichloromethane (20 mL) solution of compound TDMQ20-NH2 (1.0 g, 4.4 mmol) at 0 °C, and the mixture was stirred at room temperature for 12 hours. After removing the solvent under reduced pressure, the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:30, v / v) to give a white solid compound TDMQ20-Bu (1.3 g, 93%). 1 H NMR (400 MHz, CDCl3): d = 8.55 (s, 1H), 8.35 (d, J =8.7 Hz, 1H), 7.60 (s, 1H), 7.37 (d, J= 8.6 Hz, 1H), 2.72 (s, 3H), 1.45 (s, 9H). 13 C NMR (126 MHz, CDCl3): d = 176.79, 159.89, 143.07, 133.14, 130.98,129.63, 128.15, 127.33, 123.25, 123.03, 40.06, 27.73, 25.45 ppm.

[0241] 5,7-Dichloro-2-carboxaldehyde-8-( N (-Pentavaloyl)aminoquinoline (A-TDMQ20-Bu): Selenium dioxide (535 mg, 4.8 mmol) was added to a 6.4 mL solution of TDMQ20-Bu (500 mg, 1.6 mmol) in 1,4-dioxane, and the mixture was stirred at 80 °C for 45 min. The reaction mixture was filtered through diatomaceous earth, and the product was eluted with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 30, v / v) to give a pale yellow solid compound A-TDMQ20-Bu (508 mg, 98%). 1 H NMR (400 MHz, CDCl3): d = 10.15 (d, J =0.9 Hz, 1H), 8.67 (dd, J = 8.6, 0.9 Hz, 1H), 8.42 (s, 1H), 8.11 (d, J = 8.7Hz, 1H), 7.81 (s, 1H), 1.47 (s, 9H). 13 C NMR (101 MHz, CDCl3): d = 192.47,176.74, 152.30, 143.57, 135.18, 132.43, 131.60, 130.79, 128.76, 126.98,118.37, 40.12, 27.72 ppm.

[0242] 5,7-Dichloro-2-(1-hydroxyethyl)-8-( N(-Pentavaloyl)aminoquinoline (B-TDMQ20-Bu): Under argon protection, a methyl magnesium bromide-tetrahydrofuran solution (3 M, 5.3 mL) was slowly added dropwise to an ultradry tetrahydrofuran solution (520 mg, 1.6 mmol) of A-TDMQ20-Bu (16 mL) at 0 °C, and stirred for 1 h, followed by stirring at room temperature for 30 h. A saturated ammonium chloride aqueous solution (17 mL) and a saturated sodium chloride aqueous solution (21 mL) were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 10, v / v) to give a pale yellow solid compound B-TDMQ20-Bu (395 mg, 72%). 1 H NMR (400 MHz, CDCl3): d = 8.50 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.67 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 5.04 (q, J = 6.6 Hz, 1H), 4.23 (s, 1H), 1.57 (d, J = 6.6 Hz, 3H), 1.45 (s, 9H). 13 C NMR (101 MHz, CDCl3): d = 176.82, 164.52,142.62, 134.59, 131.75, 130.92, 129.33, 128.01, 124.64, 119.39, 69.43, 39.97,27.84, 23.96 ppm.

[0243] 5,7-Dichloro-8-amino-2-vinylquinoline (C-TDMQ20-NH2): Compound B-TDMQ20-Bu (157 mg, 0.46 mmol) was dissolved in 85% sulfuric acid (1 mL), heated to 130 °C, and stirred for 18 hours. The reaction mixture was added dropwise to ice water, followed by the addition of saturated sodium bicarbonate solution and ammonia to adjust the pH to 13. The mixture was extracted three times with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:100). v / v), yielded a yellow solid compound C-TDMQ20-NH2 (65 mg, 55%). 1 H NMR (400 MHz, CDCl3): d = 8.35 (d, J = 8.8Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.42 (s, 1H), 6.98 (dd, J = 17.6, 10.9 Hz,1H), 6.32 (dd, J = 17.7, 0.9 Hz, 1H), 5.66 (dd, J = 10.9, 0.9 Hz, 1H), 5.35(s, 1H). 13 C NMR (101 MHz, CDCl3): d = 154.41, 140.08, 138.07, 137.25, 133.52,127.23, 124.39, 120.31, 119.62, 117.76, 113.74 ppm.

[0244] 5,7-Dichloro-2-(2'-( N , N C-Dimethylethylenediamine)ethyl-8-aminoquinoline (D-TDMQ20-NH2): Compound C-TDMQ20-NH2 (106 mg, 0.44 mmol) was dissolved in a solution of hydrogen chloride and ethyl acetate (2 M, 10 mL), stirred overnight at room temperature, and concentrated under reduced pressure. The resulting orange solid solution of 1,4-dioxane (1.5 mL) was slowly added... N,N -Dimethylethylenediamine (580 μL, 5.28 mmol) was stirred at 40 °C for 42 hours. A saturated aqueous sodium chloride solution and ammonia were added to the reaction mixture to adjust the pH to 8, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / isopropanol / 25% ammonia, 8:1:0.5). v / v), yielded a pale yellow oily compound D-TDMQ20-NH2 (123 mg, 85%). 1 H NMR (400 MHz, CDCl3): d = 8.17 (d, J = 8.6Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 5.30 (s, 2H), 3.10-3.05 (m,2H), 3.02 (dd, J= 7.7, 3.9 Hz, 2H), 2.66 (t, J = 6.0 Hz, 2H), 2.59 (s, 1H), 2.34 (t, J = 6.0 Hz, 2H), 2.11 (s, 6H). 13 C NMR (101 MHz, CDCl3): d = 159.49,139.65, 137.80, 133.15, 126.52, 123.55, 122.57, 117.47, 113.37, 58.96, 48.67,47.14, 45.55, 38.26 ppm.

[0245] TDMQ20: To an anhydrous ethanol solution of D-TDMQ20-NH2 (108 mg, 0.33 mmol), 10 M hydrogen chloride-ethanol solution (1.6 mL) was slowly added dropwise, and the mixture was stirred overnight at room temperature. The precipitate was filtered, washed with ether, and dried under reduced pressure to quantitatively obtain the yellow solid compound TDMQ20 3HCl (quant.). 1 H NMR (400 MHz, D2O): d =8.21 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.41 (s, 1H), 3.78 (t, J = 7.1 Hz, 2H), 3.70-3.56 (m, 4H), 3.47 (t, J = 7.1 Hz, 2H), 3.00 (s, 6H). 13 CNMR (101 MHz, D2O): d = 156.90, 137.86, 134.43, 133.97, 126.77, 123.53,123.02, 122.60, 119.27, 52.38, 46.32, 43.39, 41.93, 33.14 ppm.

[0246] Route C-4: The overall yield of TDMQ20 synthesis was 10.7% (see Figure 15 below).

[0247] 5,7-Dichloro-2-aldehyde-8-nitroquinoline (A-TDMQ20-NO2): Selenium dioxide (2.59 g, 23.34 mmol) was added to a 1,4-dioxane solution (58 mL) of TDMQ20-NO2 (2.0 g, 7.78 mmol), and the mixture was stirred at 110 °C for 18 h. The reaction mixture was filtered through diatomaceous earth and eluted with industrial-grade ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 100, v / v) to give a pale yellow solid compound A-TDMQ20-NO2 (1.39 g, 66%). 1 H NMR (500 MHz, CDCl3): d = 10.13 (s, 1H), 8.77 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 7.85 (s, 1H). 13 C NMR (126 MHz, CDCl3): d = 191.96, 154.48, 146.16, 140.24, 135.21, 134.25, 129.38, 127.08,126.84, 119.83 ppm.

[0248] 5,7-Dichloro-8-amino-2-carboxylquinoline (A-TDMQ20-NH2): Reduced iron powder (618 mg, 11.0 mmol) and glacial acetic acid (8.5 mL) were added to a solution of A-TDMQ20-NO2 (1.0 g, 3.69 mmol) in anhydrous ethanol (24 mL), and the mixture was stirred under reflux for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and the pH was adjusted to 13 with ammonia. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 100, v / v) to give a pale yellow solid compound A-TDMQ20-NH2 (879 mg, 98%). 1 H NMR (400 MHz, DMSO- d 6 ): d = 10.13 (s, 1H), 8.58 (d, J = 8.7 Hz, 1H), 7.83 (s, 2H), 6.61 (s, 4H). 13C NMR (126 MHz, DMSO- d 6 ): d = 192.92, 150.09, 142.23, 136.83, 134.28, 130.29, 126.45, 118.48, 114.54,112.19 ppm.

[0249] 5,7-Dichloro-8-amino-2-(1-hydroxyethyl)quinoline (B-TDMQ20-NH2): Under argon protection, a 3 mol / L solution of magnesium methyl bromide in tetrahydrofuran (1.7 mL) was slowly added dropwise to an ultradry tetrahydrofuran solution (5 mL) of A-TDMQ20-NH2 (121 mg, 0.5 mmol) at 0 °C, and stirred for 1 h, followed by stirring at room temperature for 24 h. Subsequently, a saturated aqueous solution of ammonium chloride (4 mL) and a saturated aqueous solution of sodium chloride (5 mL) were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 30, v / v) to give a white solid compound B-TDMQ20-NH2 (33 mg, 26%). 1 H NMR (500 MHz, CDCl3): d = 8.38 (dd, J = 8.6, 2.2 Hz, 1H), 7.50-7.41 (m, 2H), 5.25(s, 2H), 5.06 (q, J = 6.6 Hz, 1H), 4.15 (s, 1H), 1.60-1.55 (m, 3H). 13 C NMR (126 MHz, CDCl3): d = 162.29, 139.46, 136.63, 134.38, 127.32, 124.45, 119.07,118.06, 114.45, 69.59, 24.22 ppm.

[0250] 5,7-Dichloro-8-amino-2-vinylquinoline (C-TDMQ20-NH2): Compound B-TDMQ20-NH2 (41 mg, 0.16 mmol) was dissolved in 0.5 mL of 85% sulfuric acid, heated to 130 °C, and stirred for 24 hours. The reaction mixture was added dropwise to ice water, followed by the addition of saturated sodium bicarbonate solution, and the pH was adjusted to 13 with ammonia. The resulting mixture was extracted three times with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:100). v / v), yielded a yellow solid compound C-TDMQ20-NH2 (29 mg, 75%). 1 H NMR (400 MHz, CDCl3): d =8.35 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.42 (s, 1H), 6.98 (dd, J = 17.6, 10.9 Hz, 1H), 6.32 (dd, J = 17.7, 0.9 Hz, 1H), 5.66 (dd, J = 10.9,0.9 Hz, 1H), 5.35 (s, 1H). 13 C NMR (101 MHz, CDCl3): d = 154.41, 140.08,138.07, 137.25, 133.52, 127.23, 124.39, 120.31, 119.62, 117.76, 113.74 ppm.

[0251] 5,7-Dichloro-2-(2'-( N , N C-TDMQ20-NH2 (106 mg, 0.44 mmol) was dissolved in 2 M hydrogen chloride-ethyl acetate solution (10 mL), stirred overnight at room temperature, and then concentrated under reduced pressure. The resulting orange solid was dissolved in 1,4-dioxane (1.5 mL) and slowly added... N,N-Dimethylethylenediamine (580 μL, 5.28 mmol). The reaction mixture was heated to 40 °C and stirred for 42 hours. A saturated sodium chloride aqueous solution was added to the reaction mixture, and the pH was adjusted to 8 with ammonia. The resulting mixture was extracted three times with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / isopropanol / 25% ammonia, 8:1:0.5). v / v), yielded a pale yellow oily compound D-TDMQ20-NH2 (123 mg, 85%). 1 H NMR (400MHz, CDCl3): d = 8.17 (d, J = 8.6 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 8.5 Hz,1H), 5.30 (s, 2H), 3.10-3.05 (m, 2H), 3.02 (dd, J = 7.7, 3.9 Hz, 2H), 2.66(t, J = 6.0 Hz, 2H), 2.59 (s, 1H), 2.34 (t, J = 6.0 Hz, 2H), 2.11 (s, 6H). 13 CNMR (101 MHz, CDCl3): d = 159.49, 139.65, 137.80, 133.15, 126.52, 123.55,122.57, 117.47, 113.37, 58.96, 48.67, 47.14, 45.55, 38.26 ppm.

[0252] TDMQ20: To an anhydrous ethanol solution of D-TDMQ20-NH2 (108 mg, 0.33 mmol), 10 M hydrogen chloride-ethanol solution (1.6 mL) was slowly added dropwise, and the mixture was stirred overnight at room temperature. The precipitate was filtered, washed with ether, and dried under reduced pressure to quantitatively obtain a yellow solid mixture of TDMQ20 3HCl (quant.). 1 H NMR (400 MHz, D2O): d =8.21 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.41 (s, 1H), 3.78 (t, J= 7.1 Hz, 2H), 3.70-3.56 (m, 4H), 3.47 (t, J = 7.1 Hz, 2H), 3.00 (s, 6H). 13 CNMR (101 MHz, D2O): d = 156.90, 137.86, 134.43, 133.97, 126.77, 123.53,123.02, 122.60, 119.27, 52.38, 46.32, 43.39, 41.93, 33.14 ppm.

[0253] Application of Route C-3 in TDMQ22 synthesis (see Figure 16 )

[0254] 6-Trifluoromethyl-2-methyl-8-aminoquinoline (TDMQ22-NH2): Reduced iron powder (958 mg, 17.1 mmol) and glacial acetic acid (29 mL) were added to a 95 mL ethanol solution of TDMQ22-NO2 (1.47 g, 5.7 mmol), and the mixture was stirred at reflux for 3 h. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, the pH was adjusted to 13 with ammonia, and then extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 100, v / v) to give a pale yellow solid compound TDMQ22-NH2 (1.16 g, 89%). 1 H NMR (400 MHz, CDCl3): d = 7.90 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 2.0, 1.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 1.9 Hz, 1H), 5.18 (s, 2H), 2.71 (s, 3H). 13 C NMR (101 MHz, CDCl3): d = 158.44, 144.32, 138.65,136.82, 128.16 (q, J = 31.9 Hz), 125.80, 124.49 (d, J = 272.3 Hz), 123.24,113.05 (q,J = 4.7 Hz), 104.91 (q, J = 3.2 Hz), 25.21 ppm.

[0255] 6-Trifluoromethyl-2-methyl-8-( N (-Pivanoyl)aminoquinoline (TDMQ22-Bu): Under argon protection, triethylamine (0.8 mL) and pivanoyl chloride (1.1 mL) were added to an anhydrous dichloromethane (10 mL) solution of TDMQ22-NH2 (679 mg, 3.0 mmol) at 0 °C, and the mixture was stirred for 12 h. After removing the solvent under reduced pressure, the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 100, v / v) to give the pale yellow solid compound TDMQ22-Bu (954 mg, 100%). 1 HNMR (400 MHz, CDCl3): d = 10.32 (s, 1H), 8.97 (s, 1H), 8.01 (d, J = 8.4 Hz,1H), 7.65 (s, 1H), 7.35 (d, J = 8.3 Hz, 1H), 2.74 (s, 3H), 1.42 (s, 9H). 13 CNMR (101 MHz, CDCl3): d = 177.57, 159.60, 139.11, 137.35, 135.09, 128.41 (d, J = 32.3 Hz), 125.05, 124.18 (d, J = 272.7 Hz), 123.61, 118.60 (q, J = 4.6Hz), 111.96 (q, J = 3.0 Hz), 40.56, 27.73, 25.65 ppm.

[0256] 6-Trifluoromethyl-2-carboxaldehyde-8-( N(-Pentavaloyl)aminoquinoline (A-TDMQ22-Bu): Selenium dioxide (2.4 g, 21.3 mmol) was added to a 29 mL solution of TDMQ22-Bu (2.2 g, 7.0 mmol) in 1,4-dioxane. The mixture was heated to reflux at 101 °C and stirred for 12 h. The reaction mixture was filtered through diatomaceous earth, and the product was washed with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 20). v / v), yielding a pale yellow solid compound A-TDMQ22-Bu (1.9 g, 81%). 1 H NMR (400 MHz, CDCl3): d = 10.22(s, 1H), 10.21 (s, 1H), 9.10 (d, J = 1.9 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 1.45 (s, 9H). 13 C NMR (101 MHz, CDCl3): d = 192.27, 177.62, 151.66, 139.18, 139.10, 136.58, 132.10 (q, J =32.8 Hz), 129.04, 123.64 (d, J = 273.2 Hz), 118.89, 118.59 (q, J = 4.6 Hz), 112.90 (q, J = 3.3 Hz), 40.68, 27.66 ppm.

[0257] 6-Trifluoromethyl-2-(1-hydroxyethyl)-8-( N(-Pentavaloyl)aminoquinoline (B-TDMQ22-Bu): Under argon protection, at 0°C, a 3 M magnesium bromide-tetrahydrofuran solution (2 mL) was slowly added dropwise to a dry tetrahydrofuran solution of A-TDMQ22-Bu (124 mg, 0.4 mmol) at 0°C, stirred for 1 h, followed by stirring at room temperature for 28 h. A saturated ammonium chloride aqueous solution (3 mL) and a saturated sodium chloride aqueous solution (4 mL) were added to the reaction mixture. The resulting mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 10). v / v), yielded a pale yellow oily compound B-TDMQ22-Bu (79 mg, 61%). 1 H NMR (500 MHz, CDCl3): d = 10.11 (s, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.24 (d, J =8.5 Hz, 1H), 7.77 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 5.13 (q, J = 6.6 Hz, 1H), 1.65 (d, J = 6.6 Hz, 3H), 1.43 (s, 9H). 13 C NMR (126 MHz, CDCl3): d =177.50, 164.42, 138.58, 138.10, 135.10, 129.61, 126.16, 125.13-122.65 (m),120.00, 118.85 (d, J = 4.2 Hz), 112.63 (q, J = 3.9 Hz), 70.27, 40.59, 29.82,27.74 ppm.

[0258] 6-Trifluoromethyl-8-amino-2-vinylquinoline (C-TDMQ22-NH2): Compound B-TDMQ22-Bu (326 mg, 0.9 mmol) was dissolved in 98% concentrated sulfuric acid (2 mL), and the mixture was heated to 130 °C and stirred for 4 h. The reaction mixture was added dropwise to ice water, followed by the addition of saturated sodium bicarbonate, and the pH was adjusted to 13 with ammonia. The resulting mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 100, v / v) to give a yellow solid compound C-TDMQ22-NH2 (167 mg, 73%). 1 H NMR (400 MHz, CDCl3): d = 8.07 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.38 (dd, J = 2.0, 1.0 Hz, 1H), 7.06-6.94 (m, 2H), 6.32 (dd, J = 17.6, 0.9Hz, 1H), 5.66 (dd, J = 10.9, 0.9 Hz, 1H), 5.20 (s, 2H). 13 C NMR (101 MHz, CDCl3): d = 155.06, 144.87, 138.82, 137.62, 137.30, 128.99 (d, J = 32.1 Hz), 127.01, 124.40 (d, J = 272.3 Hz), 120.13, 120.03, 113.04 (q, J = 4.7 Hz), 105.21 (d, J = 3.2 Hz) ppm.

[0259] 6-Trifluoromethyl-2-(2'-( N , N -Dimethylethylenediamine))ethyl)-8-aminoquinoline (D-TDMQ22-NH2): Add dropwise to a mixture of C-TDMQ22-NH2 (119 mg, 0.5 mmol), potassium carbonate (83 mg, 0.6 mmol), 18-crown ether-6 (159 mg, 0.6 mmol), and 1,4-dioxane (2 mL) as directed.N , N -Dimethylethylenediamine (440 μL, 4.0 mmol). The reaction mixture was heated to 101 °C and stirred under reflux for 12 h. Ammonia was added to adjust the pH to 13. The resulting mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / ammonia, 100:1, v / v) to give a pale yellow oily compound D-TDMQ22-NH2 (160 mg, 98%). 1 H NMR (400 MHz, CDCl3): d = 7.88 (d, J = 8.4 Hz, 1H), 7.31-7.17 (m, 2H), 6.88 (d, J = 1.9 Hz, 1H), 5.22 (s, 2H), 3.07 (dd, J = 7.7, 4.3 Hz, 4H), 2.68(t, J = 6.1 Hz, 2H), 2.35 (t, J = 6.0 Hz, 2H), 2.11 (s, 6H). 13 C NMR (101 MHz, CDCl3): d = 160.15, 144.58, 138.54, 137.04, 128.34 (d, J = 31.9 Hz), 126.78 (d, J = 217.1 Hz), 126.15, 123.03, 112.75 (d, J = 4.7 Hz), 104.86 (d, J = 3.2Hz), 58.96, 48.71, 47.19, 45.55, 38.41 ppm.

[0260] TDMQ22: To an anhydrous ethanol solution of compound D-TDMQ22-NH2 (136 mg, 0.42 mmol), 10 M hydrogen chloride-ethanol solution (0.25 mL) was added, and the mixture was stirred overnight at room temperature. The precipitate was filtered, washed with diethyl ether, and dried under reduced pressure to quantitatively obtain the white solid compound TDMQ22 3HCl (quant.). 1 H NMR (400 MHz, D2O): d =8.45 (d, J= 8.7 Hz, 1H), 8.27 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 3.85 (t, J = 6.8 Hz, 2H), 3.72-3.67 (m, 2H), 3.67-3.61 (m,2H), 3.59 (t, J = 6.8 Hz, 2H), 3.02 (s, 6H). 13 C NMR (101 MHz, D2O): d =159.96, 140.57, 138.91, 130.62, 127.35 (d, J = 33.4 Hz), 126.83, 124.87 (d, J = 4.8 Hz), 124.35, 123.37 (d, J = 271.8 Hz), 117.34 (q, J = 3.4 Hz), 52.34, 46.17, 43.41, 41.99, 33.39 ppm.

[0261] Application of Route C-3 in TDMQ29 synthesis (see Figure 17)

[0262] 2-Methyl-8-aminoquinoline (TDMQ29-NH2): Iron powder (4.45 g, 79.71 mmol) and acetic acid (30 mL) were added to an ethanol (85 mL) solution of 2-methyl-8-nitroquinoline TDMQ29-NO2 (5.0 g, 26.57 mmol). The mixture was stirred under reflux for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, the pH was adjusted to 13 with ammonia, and then extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1:50, v / v) to give a pale yellow solid compound TDMQ29-NH2 (3.76 g, 89%). 1 H NMR (400 MHz, CDCl3): d = 7.95 (d, J = 8.4 Hz, 1H), 7.31-7.26(m, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.13 (dd,J = 8.1, 1.3 Hz, 1H), 6.91 (dd, J = 7.5, 1.3 Hz, 1H), 5.00 (s, 1H), 2.73 (s, 3H). 13 C NMR (101 MHz, CDCl3): d = 156.16, 143.45, 137.87, 136.10, 126.91, 126.36, 122.17, 115.89, 110.15,25.27 ppm.

[0263] 2-Methyl-8-( N (-Pivanoyl)aminoquinoline (TDMQ29-Bu): Under argon protection, triethylamine (6.6 mL) and pivanoyl chloride (8.7 mL) were added to an ultradry dichloromethane (55 mL) solution of TDMQ29-NH2 (3.76 g, 23.76 mmol) at 0 °C, and the mixture was stirred for 12 hours. After removing the solvent under reduced pressure, the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give the pale yellow solid compound TDMQ29-Bu (6.82 g, 100%). 1 H NMR (400 MHz, CDCl3): d = 10.35 (s, 1H), 8.74 (dd, J = 7.3, 1.7 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.46-7.41 (m, 1H), 7.39 (dd, J = 8.2, 1.7 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 2.71 (s, 3H), 1.43 (s, 9H). 13 C NMR (101 MHz, CDCl3): d =177.13, 157.01, 138.16, 136.42, 134.10, 126.42, 126.04, 122.29, 121.02,116.14, 40.42, 27.77, 25.43 ppm.

[0264] 2-Aldehyde-8-( N(-Pentavaloyl)aminoquinoline (A-TDMQ29-Bu): Selenium dioxide (1.66 g, 15.0 mmol) was added to a 20 mL solution of TDMQ29-Bu (1.2 g, 5.0 mmol) in 1,4-dioxane, and the mixture was heated under reflux for 24 h. The reaction mixture was filtered through diatomaceous earth, and the product was eluted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 100). v / v), yielding a yellow solid compound A-TDMQ29-Bu (1.0 g, 80%). 1 H NMR (500 MHz, CDCl3): d = 10.24 (s, 1H), 10.20 (s, 1H), 8.87 (d, J = 9.1 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 9.6 Hz, 1H), 1.45 (s, 9H). 13 C NMR (126 MHz, CDCl3): d = 192.99, 177.41, 150.14, 138.34, 137.96, 135.58, 130.77, 130.05,121.28, 117.82, 117.24, 40.63, 27.80 ppm.

[0265] 2-(1-hydroxyethyl)-8-( N (-Pentavaloyl)aminoquinoline (B-TDMQ29-Bu): Under argon protection, a 3 M magnesium bromide-tetrahydrofuran solution (7.5 mL) was slowly added dropwise to a dry tetrahydrofuran solution (15 mL) of A-TDMQ29-Bu (384 mg, 1.5 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, followed by stirring at room temperature for 18 h. A saturated ammonium chloride aqueous solution (10 mL) and a saturated sodium chloride aqueous solution (15 mL) were added to the reaction mixture, and the resulting mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 20). v / v), yielded a pale yellow oily compound B-TDMQ29-Bu (388 mg, 95%). 1 HNMR (400 MHz, CDCl3): d = 10.05 (s, 1H), 8.62 (p, J = 4.3 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 4.5 Hz, 2H), 5.03 (q, J = 6.6 Hz, 1H), 4.24 (s, 1H), 1.58 (d, J = 6.6 Hz, 3H), 1.35 (s, 9H). 13 C NMR (101 MHz, CDCl3): d = 177.01, 162.23, 137.27, 136.94, 133.82, 126.90, 126.86,121.25, 118.60, 116.61, 70.11, 40.28, 27.61, 23.74 ppm.

[0266] 2-Vinyl-8-aminoquinoline (C-TDMQ29-NH2): The mixture B-TDMQ29-Bu (355 mg, 1.1 mmol) was dissolved in 98% concentrated sulfuric acid (4 mL), and the solution was heated to 130 °C and stirred for 5 hours. The reaction mixture was added dropwise to ice water, followed by saturated sodium bicarbonate solution, and the pH was adjusted to 13 with ammonia. The resulting mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 100, v / v) to give a yellow solid compound C-TDMQ29-NH2 (158 mg, 52%). 1 H NMR (400 MHz, CDCl3): d = 8.02 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.28 (t, J =7.8 Hz, 1H), 7.11 (dd, J = 8.1, 1.3 Hz, 1H), 7.00 (dd,J = 17.7, 10.9 Hz,1H), 6.91 (dd, J = 7.5, 1.3 Hz, 1H), 6.27 (dd, J = 17.6, 1.1 Hz, 1H), 5.59(dd, J = 10.8, 1.1 Hz, 1H), 5.01 (s, 2H). 13 C NMR (101 MHz, CDCl3): d =153.25, 144.13, 138.13, 137.99, 136.41, 128.13, 127.33, 118.91, 118.70,115.92, 110.35 ppm.

[0267] 2-(2'-( N , N -Dimethylethylenediamine))ethyl)-8-aminoquinoline (D-TDMQ29-NH2): To a mixture of compound C-TDMQ29-NH2 (128 mg, 0.75 mmol), potassium carbonate (687 mg, 3.7 mmol), 18-crown ether-6 (991 mg, 3.7 mmol), and 1,4-dioxane (3.0 mL), 1,4-dioxane was slowly added dropwise. N , N -Dimethylethylenediamine (0.7 mL, 6.0 mmol). The reaction mixture was heated to 101 °C and stirred under reflux for 24 hours. Ammonia was added to the mixture to adjust the pH to 13, and the resulting mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / ammonia, 50:1, v / v) to give a pale yellow oily compound D-TDMQ29-NH2 (38 mg, 20%). 1 H NMR (400 MHz, CDCl3): d = 7.94 (d, J = 8.4 Hz, 1H), 7.25-7.19 (m, 2H), 7.07 (dd, J = 8.2, 1.3 Hz, 1H), 6.87 (dd, J = 7.5, 1.2 Hz, 1H), 3.18 (s, 4H), 2.80 (t, J = 6.0 Hz, 2H), 2.46 (t, J= 6.0 Hz, 2H), 2.19 (s, 6H). 13 C NMR (101 MHz, CDCl3): d = 157.68, 143.69, 137.78, 136.63, 127.46,126.81, 122.02, 115.99, 110.49, 58.46, 48.47, 46.82, 45.65, 37.44 ppm.

[0268] TDMQ29: To an anhydrous ethanol solution of D-TDMQ29-NH2 (26 mg, 0.1 mmol), 0.5 mL of 10 M hydrogen chloride-ethanol solution was slowly added dropwise, and the mixture was stirred overnight at room temperature. The precipitate was filtered, washed with ether, and dried under reduced pressure to quantitatively obtain the yellow solid compound TDMQ29 3HCl (quant.). 1 H NMR (400 MHz, D2O): d =8.24 (d, J = 8.5 Hz, 1H), 7.86 (dd, J = 8.3, 1.3 Hz, 1H), 7.75 (dd, J = 7.5, 1.3 Hz, 1H), 7.54 (dd, J = 8.3, 7.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 3.78(t, J = 6.8 Hz, 2H), 3.67-3.62 (m, 2H), 3.62-3.57 (m, 2H), 3.48 (t, J = 6.8Hz, 2H), 2.96 (s, 6H). 13 C NMR (101 MHz, D2O): d = 157.97, 139.47, 138.19,128.70, 127.46, 126.19, 126.15, 123.62, 123.26, 52.35, 46.29, 43.43, 42.03,33.13 ppm.

[0269] Application of Route C-3 in TDMQ60 synthesis (see Figure 18)

[0270] 5,7-Difluoro-2-methyl-8-aminoquinoline (TDMQ60-NH2): Reduced iron powder (749 mg, 13.4 mmol) and glacial acetic acid (22 mL) were added to a solution of TDMQ60-NO2 (1.0 g, 4.5 mmol) in anhydrous ethanol (74 mL), and the mixture was refluxed and stirred for 3 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and the pH was adjusted to 13 with ammonia. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 50, v / v) to give a pale yellow solid compound TDMQ60-NH2 (820 mg, 95%). 1 HNMR (400 MHz, CDCl3): d = 8.14 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.96 (dd, J = 10.9, 9.8 Hz, 1H), 4.63 (s, 2H), 2.70 (s, 3H). 13 C NMR (101 MHz, CDCl3): d = 158.48, 149.32 (dd, J = 246.1, 13.6 Hz), 147.16 (dd, J = 237.5, 12.7 Hz), 138.18 (dd, J = 10.2, 3.9 Hz), 129.44 (t, J = 2.8 Hz), 126.29 (dd, J = 12.5, 4.8 Hz), 121.29 (t, J = 2.7 Hz), 114.12 (dd, J = 17.3, 1.6 Hz), 101.25 (dd, J = 26.6, 24.4 Hz), 25.38 ppm.

[0271] 5,7-Difluoro-2-methyl-8-( N(-Pivanoyl)aminoquinoline (TDMQ60-Bu): Under argon protection, triethylamine (1.1 mL) and pivanoyl chloride (1.5 mL) were added to an ultradry dichloromethane (14 mL) solution of TDMQ60-NH2 (800 mg, 4.1 mmol) at 0 °C, and the mixture was stirred at room temperature for 12 h. After removing the solvent under reduced pressure, the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 10, v / v) to give a pale yellow solid compound TDMQ60-Bu (1.14 g, 100%). 1 H NMR (500 MHz, CDCl3): d = 8.37 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.23 (d, J =8.5 Hz, 1H), 6.99 (t, J = 10.0 Hz, 1H), 2.67 (s, 3H), 1.41 (s, 9H). 13 C NMR (126 MHz, CDCl3): d = 176.91, 160.33, 155.07 (dd, J = 254.7, 13.9 Hz), 154.22(dd, J = 254.3, 13.2 Hz), 142.11 (dd, J = 8.8, 4.7 Hz), 129.47, 121.56 (d, J = 2.9 Hz), 116.17 (dd, J = 12.4, 5.5 Hz), 113.89 (d, J = 17.2 Hz), 101.93(dd, J = 28.5, 24.1 Hz), 39.79, 27.75, 25.56 ppm.

[0272] 5,7-Difluoro-2-aldehyde-8-( N(-Pentavaloyl)aminoquinoline (A-TDMQ60-Bu): Selenium dioxide (3.08 g, 27.78 mmol) was added to a 30 mL solution of TDMQ60-Bu (2.58 g, 9.26 mmol) in 1,4-dioxane, and the mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the product was eluted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 10). v / v), yielding a yellow solid compound A-TDMQ60-Bu (2.48 g, 92%). 1 H NMR (400 MHz, CDCl3): d = 10.15 (d, J =0.9 Hz, 1H), 8.54 (dd, J = 8.6, 0.9 Hz, 1H), 8.30 (s, 1H), 8.04 (d, J = 8.6Hz, 1H), 7.33-7.23 (m, 1H), 1.45 (s, 9H). 13 C NMR (101 MHz, CDCl3): d =192.67, 176.94, 155.32 (dd, J = 257.7, 12.7 Hz), 155.06 (dd, J = 257.0, 13.5Hz), 152.77, 142.62 (dd, J = 8.8, 4.7 Hz), 131.71 (d, J = 5.2 Hz), 118.14-117.68 (m), 117.07 (t, J = 2.6 Hz), 105.93 (d, J = 24.1 Hz), 105.65 (d, J =23.8 Hz), 39.97, 27.84 ppm.

[0273] 5,7-Difluoro-2-(1-hydroxyethyl)-8-( N(-Pentavaloyl)aminoquinoline (B-TDMQ60-Bu): Under argon protection, at 0 °C, 15 mL of 3 M methylmagnesium bromide-tetrahydrofuran solution was slowly added dropwise to an ultra-dry tetrahydrofuran (30 mL) solution of A-TDMQ60-Bu (880 mg, 3.0 mmol). The mixture was stirred at 0 °C for 1 hour, followed by stirring at room temperature for 12 hours. A saturated ammonium chloride aqueous solution (20 mL) and a saturated sodium chloride aqueous solution (30 mL) were added to the reaction mixture, and the resulting mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 5). v / v), yielded a pale yellow oily compound B-TDMQ60-Bu (644 mg, 70%). 1 H NMR (400 MHz, CDCl3): d = 8.25 (d, J = 8.7 Hz, 1H), 8.06 (s, 1H), 7.39(d, J = 8.7 Hz, 1H), 7.02 (t, J = 9.8 Hz, 1H), 4.96 (s, 1H), 4.37 (s, 1H), 1.52 (d, J = 6.6 Hz, 3H), 1.39 (s, 9H). 13 C NMR (101 MHz, CDCl3): d = 177.21,165.12, 155.74 (dd, J = 255.7, 10.9 Hz), 155.60 (dd, J = 255.7, 11.7 Hz), 141.68 (d, J = 8.4 Hz), 130.80-130.57 (m), 117.90 (t, J = 2.7 Hz), 116.33(dd, J = 12.7, 5.5 Hz), 115.07 (dd, J = 17.2, 1.7 Hz), 102.56 (dd, J = 28.3,24.1 Hz), 69.54, 39.73, 27.80, 23.79 ppm.

[0274] 5,7-Difluoro-2-vinyl-8-aminoquinoline (C-TDMQ60-NH2): Compound B-TDMQ60-Bu (355 mg, 1.1 mmol) was dissolved in 98% concentrated sulfuric acid (2.3 mL), and the mixture was heated to 130 °C and stirred for 5 hours. The reaction mixture was added dropwise to ice water, followed by the addition of saturated sodium bicarbonate, and the pH was adjusted to 13 with ammonia. The resulting mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 100, v / v) to give a yellow solid compound C-TDMQ60-NH2 (138 mg, 58%). 1 H NMR (400 MHz, CDCl3): d = 8.25 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H),7.05-6.93 (m, 2H), 6.33 (d, J = 17.7 Hz, 1H), 5.66 (d, J = 10.8 Hz, 1H), 4.68 (s, 2H). 13 C NMR (101 MHz, CDCl3): d = 155.05, 149.20 (dd, J = 245.9, 13.4Hz), 147.24 (d, J = 250.5 Hz), 138.22 (dd, J = 10.0, 4.0 Hz), 137.56, 129.90(t, J = 2.8 Hz), 126.92 (d, J = 17.2 Hz), 120.33, 118.08 (t, J = 2.8 Hz), 115.09 (d, J = 17.1 Hz), 102.07 (dd, J = 26.5, 24.3 Hz) ppm.

[0275] 5,7-Difluoro-2-(2'-( N , N-Dimethylethylenediamine))ethyl)-8-aminoquinoline (D-TDMQ60-NH2): Add dropwise to a mixture of C-TDMQ60-NH2 (124 mg, 0.6 mmol), potassium carbonate (550 mg, 3.0 mmol), 18-crown ether-6 (793 mg, 3.0 mmol), and 1,4-dioxane (2.4 mL). N , N -Dimethylethylenediamine (530 μL, 4.8 mmol). The mixture was heated to 80 °C and stirred for 24 hours. Ammonia was added to adjust the pH to 13, and the resulting mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / ammonia, 50:1, v / v) to give a pale yellow oily compound D-TDMQ60-NH2 (145 mg, 82%). 1 H NMR (400 MHz, CDCl3): d = 8.19 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.6Hz, 1H), 6.98 (dd, J = 10.9, 9.7 Hz, 1H), 4.72 (s, 2H), 3.17 (dt, J = 10.3, 5.4 Hz, 4H), 2.78 (t, J = 6.0 Hz, 2H), 2.45 (t, J = 6.0 Hz, 2H), 2.21 (s, 6H). 13 C NMR (101 MHz, CDCl3): d = 160.34, 149.20 (dd, J = 246.0, 13.5 Hz), 147.20 (dd, J = 237.6, 12.6 Hz), 138.08 (dd, J = 10.3, 4.0 Hz), 129.78 (t, J = 2.8 Hz), 126.60 (dd, J = 12.4, 4.7 Hz), 121.19 (t, J = 2.8 Hz), 114.52 (dd, J = 17.2, 1.4 Hz), 101.52 (dd,J = 26.5, 24.3 Hz), 59.03, 48.72, 47.29, 45.73, 38.40 ppm.

[0276] TDMQ60: To an anhydrous ethanol solution of D-TDMQ60-NH2 (121 mg, 0.41 mmol), 10 M hydrogen chloride-ethanol solution (2.0 mL) was slowly added dropwise, and the mixture was stirred overnight at room temperature. The precipitate was filtered, washed with ether, and dried under reduced pressure to quantitatively obtain the yellow solid compound TDMQ60 3HCl (quant.). 1 H NMR (400 MHz, D2O): d =8.49 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.43-7.33 (m, 1H), 3.84(t, J = 6.8 Hz, 2H), 3.72-3.66 (m, 2H), 3.66-3.60 (m, 2H), 3.56 (t, J = 6.8Hz, 2H), 3.02 (s, 6H). 13 C NMR (101 MHz, D2O): d = 159.97, 156.53 (dd, J =257.3, 14.5 Hz), 154.40 (dd, J = 250.9, 13.9 Hz). 140.45 (dd, J = 6.8, 5.3Hz), 131.39(dd, J = 3.6, 1.9 Hz), 122.55 (t, J = 2.6 Hz), 115.19 (dd, J =18.1, 1.3 Hz), 111.90 (dd, J = 13.4, 5.3 Hz), 102.40-101.64 (m), 52.35, 46.19, 43.41, 41.99, 33.50 ppm.

[0277] Obviously, the specific implementation schemes described above are merely a further detailed explanation of the purpose, technical solution and beneficial effects of the present invention. It should be understood that the above descriptions are only specific examples of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing TDMQ20 or a pharmaceutically acceptable salt thereof, wherein TDMQ20 has the following structural formula: ； The method includes the following steps: (a) 5,7-dichloro-2-methyl-8-nitroquinoline was reduced to give 8-amino-5,7-dichloro-2-methylquinoline; (b) Optionally, the amino group in 8-amino-5,7-dichloro-2-methylquinoline is protected by a protecting group selected from acetyl, diacetyl, or pivaloyl; or, the subsequent reaction is carried out directly without amino protection. (c) Oxidize the methyl group at the 2-position of the quinoline ring of the compound obtained in step (b) to a formyl group; (d) Converting the formyl group to a vinyl group via any of the following reactions: i) Peterson olefination reaction; ii) Wittig reaction; iii) The Grignard addition reaction is followed by a dehydration elimination reaction; (e) The vinyl group of the compound obtained in step (d) is introduced into the side chain by an addition reaction with N,N-dimethylethylenediamine; (f) If the amino group was protected in step (b), then remove the protecting group; (g) The resulting compound is converted into a pharmaceutically acceptable salt of TDMQ20.

2. The method according to claim 1, characterized in that, The pharmaceutically acceptable salt is selected from hydrochloride or sulfate.

3. The method according to claim 1, characterized in that, In step (d), the reaction that converts the formyl group to the vinyl group is the Peterson olefination reaction.

4. The method according to claim 3, characterized in that, The protecting group used in step (b) is an acetyl group, including the following steps in route A-1: (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline; (b) Acetylation of the amino group with acetyl chloride to prepare N-(5,7-dichloro-2-methylquinoline-8-yl)acetamide; (c) N-(5,7-dichloro-2-aldehydequinoline-8-yl)acetamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80 ℃~90 ℃; (d) Reaction with (trimethylsilyl)methylmagnesium chloride to prepare N-(5,7-dichloro-2-(1-hydroxy-2-(trimethylsilyl)ethyl)quinoline-8-yl)acetamide; (e) N-(5,7-dichloro-2-vinylquinoline-8-yl)acetamide was prepared by treatment with trimethylsilyl trifluoromethanesulfonate at 45 ℃~55 ℃; (f) N-(5,7-dichloro-2-(2-((2-(dimethylamino)ethyl)amino)ethyl)quinoline-8-yl)acetamide was prepared by reacting N,N-dimethylethylenediamine in the presence of potassium carbonate, with 1,4-dioxane as solvent, at 80 ℃~90 ℃. (g) TDMQ20 trihydrochloride was prepared by treating with hydrochloric acid in ethanol at 80℃~90℃ to remove protection and form salt.

5. The method according to claim 3, characterized in that, In step (b), the protecting group is pivaloyl, and the method includes the following steps of route A-2: (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline; (b) In the presence of triethylamine, N-(5,7-dichloro-2-methylquinoline-8-yl)pentylamide was prepared by reacting it with pentyl chloride. (c) N-(5,7-dichloro-2-aldehydequinoline-8-yl)pentylamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80℃~90℃; (d) Reaction with (trimethylsilyl)methylmagnesium chloride to prepare N-(5,7-dichloro-2-(1-hydroxy-2-(trimethylsilyl)ethyl)quinoline-8-yl)pentanamide; (e) N-(5,7-dichloro-2-vinylquinoline-8-yl) terpentamide was prepared by treatment with trimethylsilyl trifluoromethanesulfonate at 45℃~55℃; (f) N-(5,7-dichloro-2-(2-((2-(dimethylamino)ethyl)amino)ethyl)quinoline-8-yl)pentanamide was prepared by reacting N,N-dimethylethylenediamine in the presence of potassium carbonate and 1,4-dioxane at 80-90°C. (g) TDMQ20 trihydrochloride was prepared by treating it with hydrochloric acid at 80℃~90℃ in 1,4-dioxane to remove protection and form a salt.

6. The method according to claim 1, characterized in that, In step (d), the reaction that converts the formyl group to the vinyl group is called the Wittig reaction.

7. The method according to claim 6, characterized in that, In step (b), the protecting group is an acetyl group, including the following steps in route B-1: (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline; (b) Acetylating the amino group with acetyl chloride to prepare N-(5,7-dichloro-2-methylquinoline-8-yl)acetamide; (c) N-(5,7-dichloro-2-formylquinoline-8-yl)acetamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80-90°C; (d) N-(5,7-dichloro-2-vinylquinoline-8-yl)acetamide was prepared by reacting methyltriphenylphosphonium bromide with tetrahydrofuran in the presence of potassium carbonate; (e) N-(5,7-dichloro-2-(2-((2-(dimethylamino)ethyl)amino)ethyl)quinoline-8-yl)acetamide was prepared by reacting N,N-dimethylethylenediamine in the presence of potassium carbonate and in 1,4-dioxane at 80°C to 90°C; (f) TDMQ20 trihydrochloride was prepared by treating it with hydrochloric acid in ethanol at 80℃~90℃ to remove protection and form salt.

8. The method according to claim 6, characterized in that, In step (b), the protecting group is pivaloyl, including the following steps of route B-2: (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline; (b) In the presence of triethylamine, the amino group reacts with pivaloyl chloride to prepare N-(5,7-dichloro-2-methylquinoline-8-yl)pivalamide; (c) N-(5,7-dichloro-2-formylquinoline-8-yl)pentylamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80℃~90℃; (d) N-(5,7-dichloro-2-vinylquinoline-8-yl)pentanamide was prepared by reacting methyltriphenylphosphonium bromide with tetrahydrofuran in the presence of potassium carbonate; (e) N-(5,7-dichloro-2-(2-((2-(dimethylamino)ethyl)amino)ethyl)quinoline-8-yl)pentanamide was prepared by reacting N,N-dimethylethylenediamine in the presence of potassium carbonate and 1,4-dioxane at 80°C to 90°C. (f) TDMQ20 trihydrochloride was prepared by treating it with hydrochloric acid at 80℃~90℃ in 1,4-dioxane to remove protection and form a salt.

9. The method according to claim 6, characterized in that, The method includes the steps of route B-3 and does not require prior protection of the amino group: (a) 5,7-dichloro-8-nitroquinoline-2-carboxaldehyde was prepared by oxidizing 5,7-dichloro-2-methyl-8-nitroquinoline with selenium dioxide in 1,4-dioxane at 100℃~110℃. (b) 8-amino-5,7-dichloroquinoline-2-carboxaldehyde was prepared by reduction with iron powder and acetic acid in ethanol at 80-90°C. (c) In the presence of potassium carbonate and in tetrahydrofuran, methyltriphenylphosphonium bromide was reacted with phosphonium bromide to prepare 8-amino-5,7-dichloro-2-vinylquinoline; (d) In the presence of potassium carbonate and 1,4-dioxane at 80-90°C, the compound obtained in step (c) was reacted with N,N-dimethylethylenediamine to prepare N. 1 -(2-(8-amino-5,7-dichloroquinoline-2-yl)ethyl)-N 2 N 2 -Dimethylethane-1,2-diamine; (e) TDMQ20 trihydrochloride was prepared by salting in ethanol with hydrochloric acid.

10. The method according to claim 1, characterized in that, In step (d), the reaction that converts the formyl group to the vinyl group is a Grignard addition reaction followed by a dehydration elimination reaction.

11. The method according to claim 10, characterized in that, In step (b), the protecting group is a diacetyl group, and the method includes the following steps of route C-1: (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline; (b) In the presence of N,N-diisopropylethylamine, N-acetyl-N-(5,7-dichloro-2-methylquinoline-8-yl)acetamide was prepared by reaction with acetyl chloride. (c) N-acetyl-N-(5,7-dichloro-2-aldehydequinoline-8-yl)acetamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80-90°C; (d) N-(5,7-dichloro-2-(1-hydroxyethyl)quinoline-8-yl)acetamide was prepared by reacting methylmagnesium bromide in tetrahydrofuran; (e) 8-amino-5,7-dichloro-2-vinylquinoline was prepared by dehydration with sulfuric acid at 120°C to 140°C; (f) N,N-dimethylethylenediamine was reacted with 1,4-dioxane at 40-50°C to prepare N 1 -(2-(8-amino-5,7-dichloroquinoline-2-yl)ethyl)-N 2 N 2 -Dimethylethane-1,2-diamine; (g) TDMQ20 trihydrochloride was prepared by salting in ethanol with hydrochloric acid.

12. The method according to claim 10, characterized in that, In step (b), the protecting group is an acetyl group, and the method includes the following steps of route C-2: (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline; (b) N-(5,7-dichloro-2-methylquinoline-8-yl)acetamide was prepared by acetyl chloride-p-aminoacetylation; (c) N-(5,7-dichloro-2-aldehydequinoline-8-yl)acetamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80-90°C; (d) N-(5,7-dichloro-2-(1-hydroxyethyl)quinoline-8-yl)acetamide was prepared by reacting methylmagnesium bromide in tetrahydrofuran; (e) 8-amino-5,7-dichloro-2-vinylquinoline was prepared by dehydration with sulfuric acid at 120°C to 140°C. (f) N,N-dimethylethylenediamine was reacted with 1,4-dioxane at 40-50°C to prepare N 1 -(2-(8-amino-5,7-dichloroquinoline-2-yl)ethyl)-N 2 N 2 -Dimethylethane-1,2-diamine; (g) TDMQ20 trihydrochloride was prepared by salting in ethanol with hydrochloric acid.

13. The method according to claim 10, characterized in that, In step (b), the protecting group is pivaloyl, and the method includes the following steps of route C-3: (a) Reduction of 5,7-dichloro-2-methyl-8-nitroquinoline to prepare 8-amino-5,7-dichloro-2-methylquinoline; (b) In the presence of triethylamine, N-(5,7-dichloro-2-methylquinoline-8-yl)pentylamide was prepared by reacting it with pentyl chloride. (c) N-(5,7-dichloro-2-formylquinoline-8-yl) terpentamide was prepared by oxidation with selenium dioxide in 1,4-dioxane at 80-90°C; (d) N-(5,7-dichloro-2-(1-hydroxyethyl)quinoline-8-yl)pentanamide was prepared by reacting methylmagnesium bromide in tetrahydrofuran; (e) 8-amino-5,7-dichloro-2-vinylquinoline was prepared by dehydration with sulfuric acid at 120°C to 140°C. (f) N,N-dimethylethylenediamine was reacted with 1,4-dioxane at 40-50°C to prepare N 1 -(2-(8-amino-5,7-dichloroquinoline-2-yl)ethyl)-N 2 N 2 -Dimethylethane-1,2-diamine; (g) TDMQ20 trihydrochloride was prepared by salting in ethanol with hydrochloric acid.

14. The method according to claim 10, characterized in that, The method includes the steps of route C-4 and does not require prior protection of the amino group: (a) 5,7-dichloro-8-nitroquinoline-2-carboxaldehyde was prepared by oxidizing 5,7-dichloro-2-methyl-8-nitroquinoline with selenium dioxide in 1,4-dioxane at 110℃~120℃. (b) 8-amino-5,7-dichloroquinoline-2-carboxaldehyde was prepared by reduction in ethanol using iron powder and acetic acid; (c) Reacting an aldehyde with methyl magnesium bromide in tetrahydrofuran to prepare 1-(8-amino-5,7-dichloroquinoline-2-yl)ethanol-1-ol; (d) The alcohol was treated with sulfuric acid at 120°C to 140°C to prepare 8-amino-5,7-dichloro-2-vinylquinoline; (e) The vinyl compound is reacted with N,N-dimethylethylenediamine in 1,4-dioxane at 40°C to 50°C to obtain N 1 -(2-(8-amino-5,7-dichloroquinoline-2-yl)ethyl)-N 2 N 2 -Dimethylethane-1,2-diamine; (f) TDMQ20 trihydrochloride was prepared by salting in ethanol with hydrochloric acid.

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