Sulfonamide compound, preparation method and application thereof, derivative of sulfonamide compound, application of derivative, pharmaceutical composition and application of pharmaceutical composition

Abstract

The invention provides a sulfonamide compound, a preparation method and application thereof, a derivative of the sulfonamide compound, application of the derivative, a pharmaceutical composition and application of the pharmaceutical composition, and relates to the technical field of medicines. The sulfonamide compound with the structure shown in the formula I contains sulfonamide groups, can independently and efficiently inhibit drug resistance generated after EGFR mutation of cancer (such as lung cancer), especially drug resistance generated after EGFR / del19, EGFR / del19 / T790M, EGFR / L858R / T790M, EGFR / del19 / T790M / C797S and EGFR / L858R / T790M / C797S mutation, and has a good application prospect in preparation of novel drugs capable of efficiently inhibiting drug resistance of different EGFRs.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly relates to sulfonamide compounds and their preparation methods and applications, derivatives of sulfonamide compounds and their applications, pharmaceutical compositions and their applications. Background Art

[0002] Cancer is a major disease that seriously endangers people's health and lives. The pathogenesis of cancer is complex and is regulated by multiple signaling pathways. Among them, the epidermal growth factor receptor (EGFR) is related to cell proliferation, survival, adhesion, migration and differentiation, and is over-activated or highly expressed in various tumors such as lung cancer, breast cancer, prostate cancer, etc. For example, in non-small cell lung cancer cases, approximately 60% of non-small cell lung cancer patients have over-expression of EGFR. Therefore, EGFR has always been one of the popular targets in the research and development of innovative drugs.

[0003] The first-generation small molecule EGFR inhibitors Gefitinib and Erlotinib were approved for marketing in 2003 and 2004 respectively for the treatment of advanced non-small cell lung cancer. Although the first-generation small molecule EGFR inhibitors have achieved significant clinical effects in non-small cell lung cancer patients carrying EGFR sensitive mutations, most patients will develop drug resistance after about one year of use because more than 50% of the patients have the EGFR / T790M mutation. Different from the first-generation EGFR inhibitors that reversibly bind to the target, the second-generation EGFR inhibitor, the representative drug afatinib, is an irreversible inhibitor and shows better anti-tumor effects in clinical studies, but lacks selectivity for wild-type EGFR and has greater toxic side effects. The third-generation EGFR inhibitor is represented by osimertinib, which has an acrylamide group in the molecule and can covalently bind to the T790M mutation site of the EGFR sensitive mutation, effectively inhibiting tumor drug resistance caused by the T790M mutation. The advent of osimertinib has brought good survival benefits to more lung cancer patients, and its sales volume has been among the top 200 drugs globally in recent years. However, after 9-14 months of treatment with the third-generation targeted drug represented by osimertinib, drug resistance has occurred again. The drug resistance mechanism of the third-generation EGFR inhibitor is relatively complex, among which, the target protein EGFR / C797S mutation and c-Met amplification are two main reasons. The literature reports the research results of using the FDA-approved lung cancer drug brigatinib alone and the combination of brigatinib and EGFR antibody to inhibit the EGFR / C797S mutation.

[0004] There are many research reports on fourth-generation EGFR inhibitors targeting EGFR (del19 / T790M / C797S and L858R / T790M / C797S) mutations at home and abroad. Most of the fourth-generation EGFR inhibitors under current research are reversible inhibitors. Although they have good effects on EGFR / C797S mutations at the kinase and cellular levels, in in vivo anti-tumor or clinical trials, they generally need to be used in combination with osimertinib and others to achieve good effects. Therefore, it is of great significance to develop a highly effective new drug that can act alone to inhibit EGFR drug resistance. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a sulfonamide compound, its preparation method and application, derivatives of the sulfonamide compound and their applications, a pharmaceutical composition and its application. The sulfonamide compound provided by the present invention has the effect of inhibiting EGFR drug resistance alone and highly effectively.

[0006] To achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0007] The present invention provides a sulfonamide compound having the structure shown in Formula I:

[0008]

[0009] Wherein, R 1 and R 2 independently include hydrogen, deuterium, unsubstituted or substituted C1-C4 alkyl;

[0010] R 3 includes hydrogen or halogen;

[0011] R 4 includes hydrogen, unsubstituted or substituted alkoxy;

[0012] R 5 includes N-methyl-N-(2-(N,N-dimethylamino)ethylamino), N-methylhomopiperazinyl or N-methylpiperazinyl;

[0013] R 6 includes hydrogen, deuterium, unsubstituted or substituted alkyl.

[0014] Preferably, the substituents in the substituted C1-C4 alkyl include one or more of deuterium, hydroxyl, amino and halogen;

[0015] the substituents in the substituted alkyl include one or more of deuterium, hydroxyl, amino and halogen;

[0016] the substituents in the substituted alkoxy include deuterium and / or halogen.

[0017] The present invention also provides a method for preparing the sulfonamide compound described in the above technical solution, comprising the following steps:

[0018] Perform a nucleophilic substitution reaction on intermediate 3 and intermediate 7 to obtain the sulfonamide compound;

[0019]

[0020] Preferably, when intermediate 3 does not contain deuterium, the preparation method of intermediate 3 comprises the following steps:

[0021] Perform a nucleophilic substitution reaction on intermediate 2 and reagent 1 to obtain intermediate 3;

[0022] When intermediate 3 contains deuterium, the preparation method of intermediate 3 comprises the following steps:

[0023] Perform a nucleophilic substitution reaction on reagent 5 and reagent 1 to obtain intermediate 8;

[0024] Perform a nucleophilic substitution reaction on the intermediate 8 and reagent 6 to obtain intermediate 9. When one of R 1 and R 2 is hydrogen, the intermediate 9 is intermediate 3;

[0025] When neither R 1 nor R 2 is hydrogen, perform a nucleophilic substitution reaction on the intermediate 9 and reagent 7 to obtain intermediate 3;

[0026]

[0027] Preferably, the preparation method of intermediate 7 comprises the following steps:

[0028] Perform a nucleophilic substitution reaction on reagent 2 and Boc anhydride to obtain reagent 2-1;

[0029] Perform a nucleophilic substitution reaction on the reagent 2-1 and reagent 3 to obtain reagent 3-1;

[0030] Perform a reduction reaction on the reagent 3-1 using a reducing agent to obtain reagent 3-2;

[0031] Perform a nucleophilic substitution reaction on the reagent 3-2 and reagent 4 to obtain reagent 3-3;

[0032] Perform a deprotection reaction on the reagent 3-3 to obtain intermediate 7;

[0033]

[0034] The present invention also provides a method for preparing the sulfonamide compound described in the above technical solution, comprising the following steps:

[0035] The intermediate 6 is subjected to a nucleophilic substitution reaction with reagent 4 to obtain the sulfonamide compound;

[0036]

[0037] Preferably, the method for preparing the intermediate 6 includes the following steps:

[0038] The intermediate 3 is subjected to a nucleophilic substitution reaction with reagent 2 to obtain intermediate 4;

[0039] The intermediate 4 is subjected to a nucleophilic substitution reaction with reagent 3 to obtain intermediate 5;

[0040] The intermediate 5 is subjected to a reduction reaction using a reducing agent to obtain intermediate 6;

[0041]

[0042] The present invention also provides a derivative of a sulfonamide compound, including a pharmaceutically acceptable salt or solvate of the sulfonamide compound described in the above technical solution.

[0043] The present invention also provides a pharmaceutical composition, including an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient includes one or more of a sulfonamide compound, a pharmaceutically acceptable salt and solvate of the sulfonamide compound; the sulfonamide compound is the sulfonamide compound described in the above technical solution; the pharmaceutically acceptable salt and solvate of the sulfonamide compound are the pharmaceutically acceptable salt and solvate of the sulfonamide compound described in the above technical solution.

[0044] The present invention also provides the use of the sulfonamide compound described in the above technical solution, the derivative of the sulfonamide compound described in the above technical solution or the pharmaceutical composition described in the above technical solution in the preparation of a drug for treating EGFR-mediated diseases.

[0045] The sulfonamide compound having the structure shown in Formula I provided by the present invention contains a sulfonamide group and can independently and efficiently inhibit the drug resistance generated after EGFR mutation in cancer (such as lung cancer), especially the drug resistance after EGFR / del19, EGFR / del19 / T790M, EGFR / L858R / T790M, EGFR / del19 / T790M / C797S and EGFR / L858R / T790M / C797S mutations, and has good application prospects in the preparation of new drugs that can efficiently inhibit different EGFR drug resistances.

[0046] The sulfonamide compounds provided by the present invention, through kinase profiling analysis, show that in addition to having the same target EGFR as the representative third-generation EGFR inhibitor osimertinib, they also have excellent inhibitory activities against other tumor-related targets with very low activity of osimertinib, such as kinases like JAK3, IGF1R, ITK, BMX, FGFR1, AXL, KDR, etc. This is of great significance for inhibiting the drug resistance phenomenon that occurs after the use of third-generation EGFR inhibitors such as osimertinib for a period of time.

[0047] The fourth-generation EGFR inhibitor targeting EGFR triple mutations generally has lower anti-tumor activity than osimertinib in EGFR double-mutant animals, while the sulfonamide compounds provided by the present invention show comparable effects to osimertinib in the EGFR double-mutant animal model.

[0048] The anti-tumor activity experiment of the sulfonamide compounds provided by the present invention in animals modeled with EGFR triple-mutant tumor cells (such as Baf3) resistant to osimertinib is superior to the effect of brigatinib.

[0049] The present invention also provides a preparation method of the sulfonamide compounds described in the above technical solution. The preparation method provided by the present invention has simple process, simple operation, high yield, low production cost, and is suitable for industrial production. Description of the Drawings

[0050] Figure 1 For the results of the anti-tumor activity test of the target compound 1 prepared in Example 1 in nude mice. Among them, A is the curve graph of the change in tumor volume of H1975 cells inhibited by the target compound 1 and osimertinib at the dosing doses of 10 mg / kg or 20 mg / kg; B is the curve graph of the tumor tissue weight of H1975 cells inhibited by the target compound 1 and osimertinib at the dosing doses of 10 mg / kg or 20 mg / kg; C is the curve graph of the change in tumor volume of Baf3 cells inhibited by the target compound 1 and brigatinib at the dosing dose of 50 mg / kg; D is the curve graph of the tumor tissue weight of Baf3 cells inhibited by the target compound 1 and brigatinib at the dosing dose of 50 mg / kg. Detailed Embodiments

[0051] The present invention provides a sulfonamide compound having the structure shown in Formula I:

[0052]

[0053] In the present invention, the R 1 and R 2Independently include hydrogen, deuterium, unsubstituted or substituted C1-C4 alkyl groups, more preferably hydrogen or deuterium; the C1-C4 alkyl groups preferably include methyl, ethyl, propyl or butyl; the propyl group preferably includes n-propyl or isopropyl; the butyl group preferably includes n-butyl, isobutyl, sec-butyl or tert-butyl. In the present invention, the substituents in the substituted C1-C4 alkyl groups include one or more of deuterium, hydroxyl, amino and halogen, and the halogen preferably includes fluorine, chlorine, bromine or iodine. In the present invention, the R 1 and R 2 can be the same or different.

[0054] In the present invention, the R 3 includes hydrogen or halogen; the halogen preferably includes fluorine, chlorine, bromine or iodine, and more preferably chlorine.

[0055] In the present invention, the R 4 includes hydrogen, unsubstituted or substituted alkoxy groups; the alkoxy groups preferably include C1-C4 alkoxy groups, more preferably include methoxy, ethoxy, isopropoxy, cyclopropoxy, trifluoroethoxy or 2,2-difluoroethoxy; the substituents in the substituted alkoxy groups include deuterium and / or halogen, and the halogen preferably includes fluorine, chlorine, bromine or iodine.

[0056] In the present invention, the R 5 includes N-methyl N-(2-(N,N-dimethylamino)ethylamino, N-methyl homopiperazinyl or N-methyl piperazinyl.

[0057] In the present invention, the R 6 includes hydrogen, deuterium, unsubstituted or substituted alkyl groups; the substituents in the substituted alkyl groups preferably include one or more of deuterium, hydroxyl, amino and halogen, and the halogen preferably includes fluorine, chlorine, bromine or iodine; the alkyl groups preferably include C1-C4 alkyl groups, more preferably methyl; the substituted alkyl groups preferably include N,N-dimethylaminomethyl.

[0058] The present invention also provides a preparation method of the sulfonamide compound according to the above technical solution, including the following steps: performing a nucleophilic substitution reaction (denoted as the first nucleophilic substitution reaction) on intermediate 3 and intermediate 7 to obtain the sulfonamide compound;

[0059]

[0060] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0061] In the present invention, the first nucleophilic substitution reaction is preferably: mixing intermediate 3, intermediate 7, a first organic solvent and an acidic catalyst, and performing the first nucleophilic substitution reaction.

[0062] In the present invention, the molar ratio of the intermediate 7 to the intermediate 3 is preferably 1:1 to 1.3, and in specific embodiments, it can be 1:1, 1:1.1, 1:1.2, or 1:1.3.

[0063] In the present invention, the acidic catalyst preferably includes one or more of p-toluenesulfonic acid, trifluoroacetic acid, and hydrochloric acid. In the present invention, the molar ratio of the intermediate 7 to the acidic catalyst is preferably 1:1.5 to 2.2, and in specific embodiments, it can be 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, or 1:2.2.

[0064] In the present invention, the first organic solvent preferably includes one or more of alcohol solvents, amide solvents, and sulfone solvents, and in specific embodiments, it can be one or more of 2-butanol, n-butanol, isopropanol, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). In the present invention, the molar amount of the intermediate 7 to the volume of the first organic solvent is preferably 1 mol:5 to 15 L, and in specific embodiments, it can be 1 mol:5 L, 1 mol:6 L, 1 mol:8 L, 1 mol:10 L, 1 mol:12 L, or 1 mol:15 L.

[0065] In the present invention, the temperature of the first nucleophilic substitution reaction is preferably 105 to 115 °C, and in specific embodiments, it can be 105 °C, 108 °C, 110 °C, 112 °C, or 115 °C; the time of the first nucleophilic substitution reaction is preferably 4 to 7 h, and in specific embodiments, it can be 4 h, 5 h, 6 h, or 7 h; the first nucleophilic substitution reaction is preferably carried out under a protective atmosphere, and the protective atmosphere preferably includes nitrogen, argon, or helium.

[0066] After completing the first nucleophilic substitution reaction, the present invention preferably further includes: cooling the reaction solution obtained from the first nucleophilic substitution reaction to room temperature, removing the solvent under reduced pressure, adding dichloromethane to the residue for extraction, washing the organic phase successively with saturated sodium bicarbonate solution and brine, drying over anhydrous sodium sulfate, filtering to remove, removing the solvent from the filtrate under reduced pressure, and purifying by silica gel column to obtain the sulfonamide compound. In the present invention, the eluent used for silica gel column purification is preferably a mixed solvent of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 80:1 to 40:1.

[0067] In the present invention, when the intermediate 3 does not contain deuterium, the preparation method of the intermediate 3 preferably includes the following steps: performing a nucleophilic substitution reaction on the intermediate 2 with the reagent 1 (denoted as the second nucleophilic substitution reaction) to obtain the intermediate 3;

[0068]

[0069] In the present invention, the second nucleophilic substitution reaction is preferably: mixing intermediate 2, an inorganic basic reagent, reagent 1 and a second organic solvent, and carrying out the second nucleophilic substitution reaction.

[0070] In the present invention, the molar ratio of intermediate 2 to reagent 1 is preferably 1:1.2 to 1.6, and in specific embodiments, it can be 1:1.2, 1:1.3, 1:1.4, 1:1.5 or 1:1.6.

[0071] In the present invention, the second organic solvent preferably includes one or more of amide solvents, ketone solvents, sulfone solvents, nitrile solvents and ether solvents, and more preferably includes one or more of dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile and tetrahydrofuran.

[0072] In the present invention, the inorganic basic reagent preferably includes one or more of alkali metal hydrides, alkali metal carbonates, and alkali metal hydroxides, and in specific embodiments, it can be one or more of NaH, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide. In the present invention, the molar ratio of intermediate 2 to the inorganic basic reagent is preferably 1:1.5 to 2.2, and in specific embodiments, it can be 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1 or 1:2.2.

[0073] In the present invention, the mixing is preferably: dissolving intermediate 2 in a part of the second organic solvent to obtain an intermediate 2 solution, dissolving reagent 1 in the remaining second organic solvent to obtain a reagent 1 solution, adding the inorganic basic reagent to the intermediate 2 solution under low temperature conditions, and dropwise adding the reagent 1 solution after stirring. In the present invention, the temperature of the low temperature conditions is preferably 0 to 5 °C, and in specific embodiments, it can be 0 °C, 1 °C, 2 °C, 3 °C, 4 °C or 5 °C. In the present invention, the dropping time is preferably 10 to 15 min, and in specific embodiments, it can be 10 min, 12 min or 15 min. In the present invention, the concentration of the intermediate 2 solution is preferably 0.1 to 0.3 mol / L, and in specific embodiments, it can be 0.1 mol / L, 0.15 mol / L, 0.1875 mol / L, 0.2 mol / L, 0.25 mol / L or 0.3 mol / L. In the present invention, the concentration of the reagent 1 solution is preferably 2.25 to 4.5 mol / L, and in specific embodiments, it can be 2.25 mol / L, 2.5 mol / L, 3 mol / L, 3.5 mol / L, 4 mol / L or 4.5 mol / L.

[0074] In the present invention, the temperature of the second nucleophilic substitution reaction is preferably 60 to 70 °C, and in specific embodiments, it can be 60 °C, 63 °C, 65 °C, 68 °C or 70 °C; the time of the second nucleophilic substitution reaction is preferably 40 to 50 h, and in specific embodiments, it can be 40 h, 42 h, 45 h, 48 h or 50 h; the second nucleophilic substitution reaction is preferably carried out under a protective atmosphere, and the protective atmosphere preferably includes nitrogen, argon or helium.

[0075] After completing the second nucleophilic substitution reaction, the present invention preferably further includes: adding the reaction solution obtained from the second nucleophilic substitution reaction to ice water and ethyl acetate, separating the organic phase, washing the obtained organic phase with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate and purifying by silica gel column chromatography to obtain intermediate 3. In the present invention, the eluent used for the silica gel column chromatography purification is preferably a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 20:1 to 5:1.

[0076] In the present invention, when deuterium is contained in the intermediate 3, the preparation method of the intermediate 3 preferably includes the following steps:

[0077] Performing a nucleophilic substitution reaction on reagent 5 and reagent 1 (denoted as the third nucleophilic substitution reaction) to obtain intermediate 8;

[0078] Performing a nucleophilic substitution reaction on the intermediate 8 and reagent 6 (denoted as the fourth nucleophilic substitution reaction) to obtain intermediate 9. When one of R 1 and R 2 is hydrogen, the intermediate 9 is the intermediate 3;

[0079] When neither R 1 nor R 2 is hydrogen, performing a nucleophilic substitution reaction on the intermediate 9 and reagent 7 (denoted as the fifth nucleophilic substitution reaction) to obtain intermediate 3;

[0080]

[0081] The present invention performs a nucleophilic substitution reaction on reagent 5 and reagent 1 (denoted as the third nucleophilic substitution reaction) to obtain intermediate 8.

[0082] In the present invention, the third nucleophilic substitution reaction is preferably: mixing reagent 5, reagent 1, a basic reagent and a third organic solvent, and performing the third nucleophilic substitution reaction.

[0083] In the present invention, the molar ratio of reagent 5 to reagent 1 is preferably 1:1.1 to 1.3, and in specific embodiments, it can be 1:1.1, 1:1.2 or 1:1.3.

[0084] In the present invention, the basic reagent preferably includes an organic base and / or an inorganic basic reagent. The organic base preferably includes one or more of organic amines, nitrogen-containing aromatic heterocycles, and alkali metal alcoholates, and may be one or more of diisopropylethylamine, pyridine, triethylamine, potassium tert-butoxide, and sodium tert-butoxide in specific embodiments; the inorganic basic reagent preferably includes one or more of alkali metal carbonates, alkali metal hydroxides, and alkali metal hydrides, and may be one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride in specific embodiments. In the present invention, the molar ratio of the reagent 5 to the basic reagent is preferably 1:1.8 to 2.4, and may be 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, or 1:2.4 in specific embodiments.

[0085] In the present invention, the third organic solvent preferably includes one or more of alcohol solvents, ester solvents, ether solvents, and aromatic hydrocarbon solvents, and may be one or more of isopropyl alcohol, n-butanol, sec-butanol, and tert-butanol, ethyl acetate, isopropyl acetate, dioxane, and toluene in specific embodiments. In the present invention, the ratio of the amount of substance of the reagent 5 to the volume of the third organic solvent is preferably 1 mol: 2 to 6 L, and may be 1 mol: 2 L, 1 mol: 3 L, 1 mol: 4 L, 1 mol: 5 L, or 1 mol: 6 L in specific embodiments.

[0086] In the present invention, the temperature of the third nucleophilic substitution reaction is preferably room temperature, and the time of the third nucleophilic substitution reaction is preferably 2 to 4 h, and may be 2 h, 3 h, or 4 h in specific embodiments; the third nucleophilic substitution reaction is preferably carried out under a protective atmosphere, and the protective atmosphere preferably includes nitrogen, argon, or helium.

[0087] After completing the third nucleophilic substitution reaction, the present invention preferably further includes: removing the solvent from the reaction solution obtained by the third nucleophilic substitution reaction under reduced pressure and purifying it by silica gel column to obtain intermediate 3. In the present invention, the eluent used for silica gel column purification is preferably a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 5:1 to 2:1.

[0088] After obtaining intermediate 8, the present invention performs a nucleophilic substitution reaction (denoted as the fourth nucleophilic substitution reaction) on the intermediate 8 and reagent 6 to obtain intermediate 9. When one of R 1 and R 2 is hydrogen, the intermediate 9 is intermediate 3.

[0089] In the present invention, the fourth nucleophilic substitution reaction is preferably: mixing the intermediate 8, reagent 6, inorganic basic reagent, and fourth organic solvent to carry out the fourth nucleophilic substitution reaction.

[0090] In the present invention, the molar ratio of the intermediate 8 to the reagent 6 is preferably 1:0.9 to 1.1, and in specific embodiments, it can be 1:0.9, 1:1 or 1:1.1.

[0091] In the present invention, the inorganic basic reagent preferably includes one or more of alkali metal hydrides, alkali metal carbonates, and alkali metal hydroxides, and in specific embodiments, it can be one or more of NaH, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide. In the present invention, the molar ratio of the intermediate 8 to the inorganic basic reagent is preferably 1:2.4 to 2.6, and in specific embodiments, it can be 1:2.4, 1:2.5 or 1:2.6.

[0092] In the present invention, the fourth organic solvent preferably includes one or more of amide solvents, ketone solvents, sulfone solvents, and nitrile solvents, and in specific embodiments, it can be one or more of dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and acetonitrile; the fourth organic solvent is preferably an anhydrous organic solvent. In the present invention, the ratio of the amount of substance of the intermediate 8 to the volume of the fourth organic solvent is preferably 1 mol:5 to 7 L, and in specific embodiments, it can be 1 mol:5 L, 1 mol:6 L or 1 mol:7 L.

[0093] In the present invention, the mixing is preferably as follows: the intermediate 8 is dissolved in the fourth organic solvent, and under low-temperature conditions, an inorganic basic reagent is added and stirred, and then the reagent 6 is added for mixing. In the present invention, the temperature of the low-temperature conditions is preferably 0 to 5 °C, and in specific embodiments, it can be 0 °C, 1 °C, 2 °C, 3 °C, 4 °C or 5 °C. In the present invention, the stirring time is preferably 30 to 60 min, and in specific embodiments, it can be 30 min, 40 min, 50 min or 60 min.

[0094] In the present invention, the temperature of the fourth nucleophilic substitution reaction is preferably room temperature; the time of the fourth nucleophilic substitution reaction is preferably 2 to 4 h, and in specific embodiments, it can be 2 h, 3 h or 4 h.

[0095] After completing the fourth nucleophilic substitution reaction, the present invention preferably further includes: adding a certain amount of water to the reaction solution obtained from the fourth nucleophilic substitution reaction to quench the reaction, then adding water, extracting with ethyl acetate, washing the obtained organic phase with water, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and purifying the obtained filtrate by silica gel column chromatography (the eluent is petroleum ether / ethyl acetate, 8:1 to 4:1) to obtain the intermediate 3. In the present invention, the eluent used for silica gel column chromatography is preferably a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 8:1 to 4:1.

[0096] When the R1 and R 2 When neither of them is hydrogen, the present invention performs a nucleophilic substitution reaction (denoted as the fifth nucleophilic substitution reaction) on the intermediate 9 with the reagent 7 to obtain the intermediate 3. In the present invention, the preparation conditions of the intermediate 3 are the same as those of the intermediate 9, which will not be elaborated herein.

[0097] In the present invention, the preparation method of the intermediate 2 preferably includes the following steps:

[0098] React 2-nitrobenzenesulfonyl chloride with R 1 NHR 2 to perform a nucleophilic substitution reaction (denoted as the sixth nucleophilic substitution reaction) to obtain the intermediate 1;

[0099] Use a reducing agent (denoted as the first reducing agent) to perform a reduction reaction (denoted as the first reduction reaction) on the intermediate 1 to obtain the intermediate 2.

[0100]

[0101] The present invention reacts 2-nitrobenzenesulfonyl chloride with R 1 NHR 2 to perform a nucleophilic substitution reaction (denoted as the sixth nucleophilic substitution reaction) to obtain the intermediate 1.

[0102] In the present invention, the sixth nucleophilic substitution reaction is preferably: mixing 2-nitrobenzenesulfonyl chloride, R 1 NHR 2 , an organic base and a fifth organic solvent, and performing the sixth nucleophilic substitution reaction.

[0103] In the present invention, the molar ratio of the 2-nitrobenzenesulfonyl chloride to R 1 NHR 2 is preferably 1:1.1 to 1.4, and in specific embodiments, it can be 1:1.1, 1:1.2, 1:1.3 or 1:1.4.

[0104] In the present invention, the organic base preferably includes organic amines, more preferably includes one or more of triethylamine, N,N-diisopropylethylamine, 4-(N,N-dimethyl)aminopyridine, 1,4-diazabicyclo[2.2.2]octane and tetramethylethylenediamine. In the present invention, the molar ratio of the 2-nitrobenzenesulfonyl chloride to the organic amine is preferably 1:1.8 to 2.3, and in specific embodiments, it can be 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2 or 1:2.3.

[0105] In the present invention, the fifth organic solvent preferably includes chloroalkane solvents and / or ether solvents, and may be one or more of dichloromethane, tetrahydrofuran, and dioxane in specific embodiments. In the present invention, the mass ratio of 2-nitrobenzenesulfonyl chloride to the volume of the fifth organic solvent is preferably 1 g: 25-35 mL, and may be 1 g: 25 mL, 1 g: 28 mL, 1 g: 30 mL, 1 g: 32 mL, or 1 g: 35 mL in specific embodiments.

[0106] In the present invention, the mixing preferably comprises: mixing R 1 NHR 2 , an organic base, and a fifth organic solvent to obtain a mixed solution, and adding 2-nitrobenzenesulfonyl chloride to the mixed solution in batches under low-temperature conditions. In the present invention, the temperature of the low-temperature conditions is preferably 0-5 °C, and may be 0 °C, 1 °C, 2 °C, 3 °C, 4 °C, or 5 °C in specific embodiments.

[0107] In the present invention, the temperature of the sixth nucleophilic substitution reaction is preferably room temperature; the sixth nucleophilic substitution reaction preferably takes 4-6 h, and may be 4 h, 5 h, or 6 h in specific embodiments.

[0108] After completing the sixth nucleophilic substitution reaction, the present invention preferably further comprises: diluting the reaction solution obtained from the sixth nucleophilic substitution reaction with water to obtain an organic phase and an aqueous phase respectively, extracting the aqueous phase once with dichloromethane to obtain a dichloromethane phase, combining the organic phase and the dichloromethane phase, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying by silica gel column chromatography to obtain intermediate 1. In the present invention, the eluent used for silica gel short column purification is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 10:1-5:1.

[0109] After obtaining intermediate 1, the present invention uses a reducing agent (denoted as the first reducing agent) to carry out a reduction reaction (denoted as the first reduction reaction) on intermediate 1 to obtain intermediate 2.

[0110] In the present invention, the first reduction reaction preferably comprises: mixing intermediate 1, the first reducing agent, and a sixth organic solvent to carry out the first reduction reaction.

[0111] In the present invention, the first reducing agent preferably includes stannous chloride. In the present invention, the molar ratio of intermediate 1 to the first reducing agent is preferably 1:5-6, and may be 1:5, 1:5.2, 1:5.5, 1:5.8, or 1:6 in specific embodiments.

[0112] In the present invention, the sixth organic solvent preferably includes an ester solvent and / or an alcohol solvent, and may be one or more of ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, n-butanol, sec-butanol, and tert-butanol in a specific embodiment. In the present invention, the molar ratio of the amount of substance of Intermediate 1 to the volume of the sixth organic solvent is preferably 1 mol: 5-10 L, and may be 1 mol: 5 L, 1 mol: 6 L, 1 mol: 7 L, 1 mol: 8 L, 1 mol: 9 L, or 1 mol: 10 L in a specific embodiment.

[0113] In the present invention, the first reduction reaction is preferably carried out under heating and reflux conditions, and the time of the first reduction reaction is preferably 16-20 h, and may be 16 h, 17 h, 18 h, 19 h, or 20 h in a specific embodiment.

[0114] After completing the first reduction reaction, the present invention preferably further includes: cooling the reaction solution obtained from the first reduction reaction to room temperature, adding saturated sodium carbonate solution, filtering with diatomaceous earth, washing the diatomaceous earth with ethyl acetate, washing the organic phase with water, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate to remove the solvent to obtain Intermediate 2, and Intermediate 2 is directly used in the subsequent reaction without purification.

[0115] In the present invention, the preparation method of Intermediate 7 preferably includes the following steps:

[0116] Carry out a nucleophilic substitution reaction (denoted as the seventh nucleophilic substitution reaction) between Reagent 2 and Boc anhydride to obtain Reagent 2-1;

[0117] Carry out a nucleophilic substitution reaction (denoted as the eighth nucleophilic substitution reaction) between the Reagent 2-1 and Reagent 3 to obtain Reagent 3-1;

[0118] Use a reducing agent (denoted as the second reducing agent) to carry out a reduction reaction (denoted as the second reduction reaction) on the Reagent 3-1 to obtain Reagent 3-2;

[0119] Carry out a nucleophilic substitution reaction (denoted as the ninth nucleophilic substitution reaction) between the Reagent 3-2 and Reagent 4 to obtain Reagent 3-3;

[0120] Carry out a deprotection reaction on the Reagent 3-3 to obtain Intermediate 7;

[0121]

[0122] In the present invention, the preparation route of Intermediate 7 is as follows:

[0123]

[0124] In the present invention, a nucleophilic substitution reaction (denoted as the seventh nucleophilic substitution reaction) is carried out between Reagent 2 and Boc anhydride to obtain Reagent 2-1.

[0125] In the present invention, the seventh nucleophilic substitution reaction is preferably as follows: reagent 2, Boc anhydride, organic amine and a seventh organic solvent are mixed for an amino protection reaction.

[0126] In the present invention, the molar ratio of reagent 2 to Boc anhydride ((Boc) 2 ) is preferably 1:1 to 1.2, and in specific embodiments, it can be 1:1, 1:1.1 or 1:1.2.

[0127] In the present invention, the organic amine preferably includes one or more of 4-(N,N-dimethyl)aminopyridine (DMAP), triethylamine and N,N-diisopropylethylenediamine. In the present invention, the molar ratio of reagent 2 to the organic amine is preferably 1:0.1 to 0.2, and in specific embodiments, it can be 1:0.1, 1:0.12, 1:0.15, 1:0.18 or 1:0.2.

[0128] In the present invention, the seventh organic solvent preferably includes one or more of chloroalkanes, oxacycloalkanes and nitrile solvents, and in specific embodiments, it can be one or more of dichloromethane, tetrahydrofuran and acetonitrile. In the present invention, the ratio of the amount of substance of reagent 2 to the volume of the seventh organic solvent is preferably 1 mol:5 to 7 L, and in specific embodiments, it can be 1 mol:5 L, 1 mol:5.5 L, 1 mol:6 L, 1 mol:6.5 L or 1 mol:7 L.

[0129] In the present invention, the temperature of the seventh nucleophilic substitution reaction is preferably 0 to 25 °C, and in specific embodiments, it can be 0 °C, 5 °C, 10 °C, 15 °C, 20 °C or 25 °C; the time of the seventh nucleophilic substitution reaction is preferably 4 to 18 h, and in specific embodiments, it can be 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h or 18 h.

[0130] After completing the seventh nucleophilic substitution reaction, the present invention preferably further includes: washing the reaction solution obtained from the seventh nucleophilic substitution reaction with an HCl solution, drying with anhydrous sodium sulfate, filtering, subjecting the obtained filtrate to solvent removal under reduced pressure and then purifying by silica gel column chromatography to obtain reagent 2-1. In the present invention, the concentration of the HCl solution is preferably 1 to 2.5 mol / L, and in specific embodiments, it can be 1 mol / L, 1.5 mol / L, 2 mol / L or 2.5 mol / L. In the present invention, the eluent used for silica gel column purification is preferably a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 10:1 to 6:1.

[0131] After obtaining reagent 2-1, the present invention conducts a nucleophilic substitution reaction between the reagent 2-1 and reagent 3 (denoted as the eighth nucleophilic substitution reaction) to obtain reagent 3-1.

[0132] In the present invention, the eighth nucleophilic substitution reaction is preferably: mixing reagent 2-1, reagent 3, an inorganic basic reagent, and an eighth organic solvent, and conducting the eighth nucleophilic substitution reaction.

[0133] In the present invention, the molar ratio of reagent 2-1 to reagent 3 is preferably 1:1.2 to 1.6, and in specific embodiments, it can be 1:1.2, 1:1.3, 1:1.4, 1:1.5, or 1:1.6. In the present invention, reagent 3 preferably includes N,N,N'-trimethylethylenediamine.

[0134] In the present invention, the inorganic basic reagent preferably includes one or more of alkali metal carbonates, alkali metal alcoholates, alkali metal hydrides, and alkali metal hydroxides, and in specific embodiments, it can be one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium hydroxide, and potassium hydroxide. In the present invention, the molar ratio of reagent 2-1 to the inorganic basic reagent is preferably 1:1.8 to 2.2, and in specific embodiments, it can be 1:1.8, 1:1.9, 1:2, 1:2.1, or 1:2.2.

[0135] In the present invention, the eighth organic solvent preferably includes amide solvents, ketone solvents, sulfone solvents, and nitrile solvents, and in specific embodiments, it can be one or more of dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and acetonitrile. In the present invention, the ratio of the amount of substance of reagent 2-1 to the volume of the eighth organic solvent is preferably 1 mol:4 to 6 L, and in specific embodiments, it can be 1 mol:4 L, 1 mol:4.5 L, 1 mol:5 L, 1 mol:5.5 L, or 1 mol:6 L.

[0136] In the present invention, the temperature of the eighth nucleophilic substitution reaction is preferably 80 to 100 °C, and in specific embodiments, it can be 80 °C, 85 °C, 90 °C, 95 °C, or 100 °C; the time of the eighth nucleophilic substitution reaction is preferably 4 to 8 h, and in specific embodiments, it can be 4 h, 5 h, 6 h, 7 h, or 8 h.

[0137] After completing the eighth nucleophilic substitution reaction, the present invention preferably further includes: cooling the reaction solution obtained from the eighth nucleophilic substitution reaction to room temperature. Adding ethyl acetate, separating the organic phase, extracting the aqueous phase with ethyl acetate, combining the organic phases, washing with water, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to remove the solvent, and purifying by silica gel column to obtain reagent 3-1. In the present invention, the eluent used for the silica gel column purification is preferably a mixed solvent of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 40:1 to 20:1.

[0138] After obtaining reagent 3-1, the present invention uses a reducing agent (denoted as the second reducing agent) to perform a reduction reaction (denoted as the second reduction reaction) on the reagent 3-1 to obtain reagent 3-2.

[0139] In the present invention, the second reducing agent preferably includes hydrogen, and the pressure of the hydrogen is preferably 0.10 to 0.30 MPa, and can be 0.1 MPa, 0.15 MPa, 0.2 MPa, 0.25 MPa or 0.3 MPa in specific embodiments.

[0140] In the present invention, the second reduction reaction is preferably: mixing the reagent 3-1, a catalyst and a ninth organic solvent, and introducing hydrogen to perform the second reduction reaction.

[0141] In the present invention, the catalyst preferably includes Pd / C, and the mass fraction of palladium in the Pd / C is preferably 5 to 10%, and can be 5%, 6%, 7%, 8%, 9% or 10% in specific embodiments.

[0142] In the present invention, the molar ratio of the amount of substance of the reagent 3-1 to the mass of the catalyst is preferably 1 mol: 21 to 43 g, and can be 1 mol: 21 g, 1 mol: 25 g, 1 mol: 30 g, 1 mol: 35 g, 1 mol: 40 g or 1 mol: 43 g in specific embodiments.

[0143] In the present invention, the ninth organic solvent preferably includes one or more of alcohol solvents, ester solvents, aromatic hydrocarbon solvents, ether solvents and nitrile solvents, and can be one or more of methanol, ethanol, ethyl acetate, toluene, dioxane and acetonitrile in specific embodiments. In the present invention, the molar ratio of the amount of substance of the reagent 3-1 to the volume of the ninth organic solvent is preferably 1 mol: 6 to 10 L, and can be 1 mol: 6 L, 1 mol: 7 L, 1 mol: 8 L, 1 mol: 9 L or 1 mol: 10 L in specific embodiments.

[0144] In the present invention, the temperature of the second reduction reaction is preferably room temperature, and the time of the second reduction reaction is preferably 2 to 4 h, which can be 2 h, 2.5 h, 3 h, 3.5 h or 4 h in specific embodiments.

[0145] After completing the second reduction reaction, the present invention preferably further includes: filtering the reaction solution obtained from the second reduction reaction to obtain a filtrate and a filter cake respectively, washing the filter cake with methanol to obtain a washing solution, combining the filtrate and the washing solution, and concentrating under reduced pressure to remove the solvent to obtain reagent 3-2, which is directly used in the next reaction without purification.

[0146] After obtaining reagent 3-2, the present invention carries out a nucleophilic substitution reaction (denoted as the ninth nucleophilic substitution reaction) between reagent 3-2 and reagent 4 to obtain reagent 3-3.

[0147] In the present invention, the ninth nucleophilic substitution reaction is preferably: mixing reagent 3-2, reagent 4, an organic base and a tenth organic solvent, and carrying out the ninth nucleophilic substitution reaction.

[0148] In the present invention, reagent 3-2 preferably includes acryloyl chloride. In the present invention, the molar ratio of reagent 3-2 to reagent 4 is preferably 1:1.1 to 1.3, which can be 1:1.1, 1:1.2 or 1:1.3 in specific embodiments.

[0149] In the present invention, the organic base preferably includes an organic amine, which can be one or more of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and triethylenediamine in specific embodiments. In the present invention, the molar ratio of reagent 3-2 to the organic base is preferably 1:1.8 to 2.3, which can be 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2 or 1:2.3 in specific embodiments.

[0150] In the present invention, the tenth organic solvent preferably includes one or more of chloroalkanes, oxaalkanes, aromatic alkanes and alcohol solvents, which can be one or more of dichloromethane, tetrahydrofuran, methyl tert-butyl ether, toluene and isopropanol in specific embodiments. In the present invention, the ratio of the amount of substance of reagent 3-2 to the volume of the tenth organic solvent is preferably 1 mol:5 to 9 L, which can be 1 mol:5 L, 1 mol:6 L, 1 mol:7 L, 1 mol:8 L or 1 mol:9 L in specific embodiments.

[0151] In the present invention, the mixing is preferably: mixing the tenth organic solvent of reagent 3-2 with the organic base, and adding reagent 4 for mixing under low temperature conditions. In the present invention, the temperature of the low temperature conditions is preferably 0 to 5 °C, which can be 0 °C, 1 °C, 2 °C, 3 °C, 4 °C or 5 °C in specific embodiments.

[0152] In the present invention, the temperature of the ninth nucleophilic substitution reaction is preferably 0 to 25 °C, and in specific embodiments, it can be 0 °C, 5 °C, 10 °C, 15 °C, 20 °C or 25 °C; the time of the ninth nucleophilic substitution reaction is preferably 4 to 7 h, and in specific embodiments, it can be 4 h, 5 h, 6 h or 7 h; the ninth nucleophilic substitution reaction is preferably carried out under a protective atmosphere, and the protective atmosphere preferably includes nitrogen, argon or helium.

[0153] After completing the ninth nucleophilic substitution reaction, the present invention preferably further includes: washing the reaction solution obtained from the ninth nucleophilic substitution reaction successively with saturated sodium bicarbonate aqueous solution and brine, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure and purifying by silica gel column to obtain reagent 3-3. In the present invention, the eluent used for the silica gel column purification is preferably a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 5:1 to 2:1.

[0154] After obtaining reagent 3-3, the present invention performs a deprotection reaction on the reagent 3-3 to obtain intermediate 7.

[0155] In the present invention, the deprotection reaction is preferably: mixing the reagent 3-3, the eleventh organic solvent and the deprotection reagent to carry out the deprotection reaction.

[0156] In the present invention, the deprotection reagent preferably includes an acid, and the acid preferably includes one or more of trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid and methanesulfonic acid. In the present invention, the molar ratio of the reagent 3-3 to the deprotection reagent is preferably 1:8 to 11, and in specific embodiments, it can be 1:8, 1:9, 1:10 or 1:11.

[0157] In the present invention, the eleventh organic solvent preferably includes one or more of chloroalkanes, ester solvents, alcohol solvents, water and ether solvents, and in specific embodiments, it can be one or more of dichloromethane, ethyl acetate, methanol, ethanol, water and dioxane. In the present invention, the molar amount of the reagent 3-3 and the volume ratio of the eleventh organic solvent are preferably 1 mol: 4 to 7.5 L, and in specific embodiments, it can be 1 mol: 4 L, 1 mol: 5 L, 1 mol: 6 L, 1 mol: 7 L or 1 mol: 7.5 L.

[0158] In the present invention, the mixing is preferably: dissolving the reagent 3-3 in the eleventh organic solvent to obtain a reagent 3-3 solution, and dropping the deprotection reagent into the reagent 3-3 solution under ice bath conditions.

[0159] In the present invention, the temperature of the deprotection reaction is preferably 0 to 60 °C, and in specific embodiments, it can be 0 °C, 10 °C, 20 °C, 25 °C, 30 °C, 40 °C, 50 °C or 60 °C; the time of the deprotection reaction is preferably 4 to 6 h, and in specific embodiments, it can be 4 h, 5 h or 6 h.

[0160] After completing the deprotection reaction, the present invention preferably further includes: adding water to the reaction solution obtained from the deprotection reaction, adjusting the pH value to 7.5 to 9 with saturated potassium carbonate solution, extracting with dichloromethane, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, removing the solvent from the obtained filtrate under reduced pressure, and purifying by silica gel column to obtain intermediate 7. In the present invention, the pH value can be 7.5, 8, 8.5 or 9. In the present invention, the eluent used for silica gel column purification is preferably a mixed solvent of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 100:1 to 80:1.

[0161] The present invention also provides a method for preparing the sulfonamide compound described in the above technical solution, including the following steps: performing a nucleophilic substitution reaction (denoted as the tenth nucleophilic substitution reaction) on intermediate 6 and reagent 4 to obtain the sulfonamide compound;

[0162]

[0163] In the present invention, the tenth nucleophilic substitution reaction is preferably: mixing intermediate 6, reagent 4, an inorganic basic reagent and a mixed solvent, and performing the tenth nucleophilic substitution reaction.

[0164] In the present invention, the molar ratio of intermediate 6 to reagent 4 is preferably 1:1.2 to 1.6, and in specific embodiments, it can be 1:1.2, 1:1.3, 1:1.4, 1:1.5 or 1:1.6.

[0165] In the present invention, the inorganic basic reagent preferably includes one or more of alkali metal carbonates, alkali metal bicarbonates and alkali metal hydroxides, and in specific embodiments, it can be one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and sodium hydroxide. In the present invention, the molar ratio of intermediate 6 to the inorganic basic reagent is preferably 1:1.5 to 2.1, and in specific embodiments, it can be 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2 or 1:2.1.

[0166] In the present invention, the mixed solvent preferably comprises an organic solvent and water. The organic solvent preferably comprises one or more of chloroalkanes, ether solvents, ketone solvents, and alcohol solvents, and may be one or more of dichloromethane, tetrahydrofuran (THF), dioxane, acetone, and isopropanol in specific embodiments; the volume ratio of the organic solvent to water in the mixed solvent is preferably 4 to 6:1, and may be 4:1, 5:1, or 6:1 in specific embodiments. In the present invention, the molar amount of intermediate 6 to the volume of the mixed solvent is preferably 1 mol: 2.5 to 10 L, and may be 1 mol: 2.5 L, 1 mol: 3 L, 1 mol: 4 L, 1 mol: 5 L, 1 mol: 6 L, 1 mol: 7 L, 1 mol: 8 L, 1 mol: 9 L, or 1 mol: 10 L in specific embodiments.

[0167] In the present invention, the mixing preferably comprises: mixing intermediate 6, an inorganic basic reagent, and the mixed solvent, and then dropwise adding reagent 4.

[0168] In the present invention, the temperature of the tenth nucleophilic substitution reaction is preferably 0 to 5 °C, and may be 0 °C, 1 °C, 2 °C, 3 °C, 4 °C, or 5 °C in specific embodiments; the time of the tenth nucleophilic substitution reaction is preferably 0.5 to 1.5 h, and may be 0.5 h, 1 h, or 1.5 h in specific embodiments.

[0169] After completing the tenth nucleophilic substitution reaction, the present invention preferably further comprises: adding ethyl acetate and water to the reaction solution obtained from the tenth nucleophilic substitution reaction, drying the obtained organic layer with anhydrous sodium sulfate, concentrating to remove the solvent, and purifying by silica gel column chromatography to obtain the sulfonamide compound. In the present invention, the eluent used for silica gel flash column chromatography purification is preferably a mixed solvent of petroleum ether - ethyl acetate or a mixed solvent of petroleum ether - ethyl acetate - triethylamine; the volume ratio of petroleum ether to ethyl acetate in the mixed solvent of petroleum ether - ethyl acetate is preferably 2:1 to 1:1; the volume ratio of petroleum ether, ethyl acetate, and triethylamine in the mixed solvent of petroleum ether - ethyl acetate - triethylamine is preferably 2:1:0.05 to 1:1:0.05.

[0170] In the present invention, the preparation method of intermediate 6 preferably comprises the following steps:

[0171] Carrying out a nucleophilic substitution reaction (denoted as the eleventh nucleophilic substitution reaction) between intermediate 3 and reagent 2 to obtain intermediate 4;

[0172] Carrying out a nucleophilic substitution reaction (denoted as the twelfth nucleophilic substitution reaction) between intermediate 4 and reagent 3 to obtain intermediate 5;

[0173] The intermediate 5 is subjected to a reduction reaction (denoted as the third reduction reaction) using a reducing agent (denoted as the third reducing agent) to obtain intermediate 6;

[0174]

[0175] In the present invention, the preparation routes of the intermediate 3, intermediate 6 and sulfonamide compounds are as follows:

[0176]

[0177] In the present invention, the intermediate 3 is subjected to a nucleophilic substitution reaction (denoted as the eleventh nucleophilic substitution reaction) with reagent 2 to obtain intermediate 4.

[0178] In the present invention, the tenth nucleophilic substitution reaction is preferably: the intermediate 3, reagent 2, an acidic catalyst and a twelfth organic solvent are mixed to carry out the eleventh nucleophilic substitution reaction.

[0179] In the present invention, the molar ratio of the intermediate 3 to reagent 2 is preferably 1:1.1 - 1.3, and in specific embodiments, it can be 1:1.1, 1:1.2 or 1:1.3.

[0180] In the present invention, the acidic catalyst preferably includes one or more of p-toluenesulfonic acid, hydrochloric acid, trifluoroacetic acid and methanesulfonic acid. In the present invention, the molar ratio of the intermediate 3 to the acidic catalyst is preferably 1:1.8 - 2.2, and in specific embodiments, it can be 1:1.8, 1:1.9, 1:2, 1:2.1 or 1:2.2.

[0181] In the present invention, the twelfth organic solvent preferably includes one or more of alcohol solvents, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO); the alcohol solvents preferably include one or more of 2-butanol, isopropanol and n-butanol. In the present invention, the molar amount of the intermediate 3 and the volume ratio of the twelfth organic solvent are preferably 1 mol:5 - 15 L, and in specific embodiments, it can be 1 mol:5 L, 1 mol:8 L, 1 mol:10 L, 1 mol:1 L or 1 mol:15 L.

[0182] In the present invention, the temperature of the eleventh nucleophilic substitution reaction is preferably 105 - 115 °C, and in specific embodiments, it can be 105 °C, 108 °C, 110 °C, 112 °C or 115 °C; the eleventh nucleophilic substitution reaction is preferably 4 - 6 h, and in specific embodiments, it can be 4 h, 5 h or 6 h; the eleventh nucleophilic substitution reaction is preferably carried out under a protective atmosphere, and the protective atmosphere preferably includes nitrogen, argon or helium.

[0183] After completing the eleventh nucleophilic substitution reaction, the present invention preferably further includes: cooling the reaction solution obtained from the eleventh nucleophilic substitution reaction to room temperature, filtering, washing the obtained solid component with acetonitrile, washing with water, and drying to obtain Intermediate 4. The present invention has no special limitation on the temperature and time of the drying, and it can be dried to constant weight.

[0184] After obtaining Intermediate 4, the present invention conducts a nucleophilic substitution reaction between Intermediate 4 and Reagent 3 (denoted as the twelfth nucleophilic substitution reaction) to obtain Intermediate 5.

[0185] In the present invention, the twelfth nucleophilic substitution reaction is preferably: mixing Intermediate 4, Reagent 3, and a thirteenth organic solvent, and conducting the twelfth nucleophilic substitution reaction.

[0186] In the present invention, the molar ratio of Intermediate 4 to Reagent 3 is preferably 1:5 to 7, and in specific embodiments, it can be 1:5.5, 1:6, 1:6.5, or 1:7.

[0187] In the present invention, the thirteenth organic solvent preferably includes one or more of ether solvents, amide solvents, and nitrile solvents, and in specific embodiments, it can be one or more of 1,4-dioxane, N,N-dimethylformamide, and acetonitrile. In the present invention, the molar amount of Intermediate 4 and the volume ratio of the thirteenth organic solvent are preferably 1 mol: 2 to 6 L, and in specific embodiments, it can be 1 mol: 2 L, 1 mol: 3 L, 1 mol: 4 L, 1 mol: 5 L, or 1 mol: 6 L.

[0188] In the present invention, the temperature of the twelfth nucleophilic substitution reaction is preferably 80 to 110 °C, and in specific embodiments, it can be 80 °C, 90 °C, 100 °C, or 110 °C; the time of the twelfth nucleophilic substitution reaction can be 4 to 7 h, and in specific embodiments, it can be 4 h, 5 h, 6 h, or 7 h.

[0189] After completing the twelfth nucleophilic substitution reaction, the present invention preferably further includes: cooling the reaction solution obtained from the twelfth nucleophilic substitution reaction to room temperature, adding water, extracting with dichloromethane 2 to 4 times, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate under reduced pressure to remove the solvent, and purifying by silica gel column to obtain Intermediate 5. In the present invention, the eluent used for the silica gel column purification is preferably a mixed solvent of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 80:1 to 30:1.

[0190] After obtaining Intermediate 5, the present invention uses a reducing agent (denoted as the third reducing agent) to conduct a reduction reaction on Intermediate 5 (denoted as the third reduction reaction) to obtain Intermediate 6.

[0191] In the present invention, the third reduction reaction is preferably as follows: the intermediate 5, a third reducing agent, concentrated hydrochloric acid and a fourteenth organic solvent are mixed to carry out the third reduction reaction.

[0192] In the present invention, the third reducing agent preferably includes one or more of stannous chloride, reduced iron powder and zinc powder. In the present invention, the molar ratio of the intermediate 5 to the third reducing agent is preferably 1:5 to 6, and in specific embodiments, it can be 1:5, 1:5.2, 1:5.5, 1:5.8 or 1:6.

[0193] In the present invention, the molar ratio of the intermediate 5 to concentrated hydrochloric acid is preferably 1:5 to 6, and in specific embodiments, it can be 1:5, 1:5.2, 1:5.5, 1:5.8 or 1:6. The present invention has no special limitation on the concentration of the concentrated hydrochloric acid, and the concentrated hydrochloric acid well-known to those skilled in the art can be used.

[0194] In the present invention, the temperature of the third reduction reaction is preferably 45 to 65 °C, and in specific embodiments, it can be 45 °C, 50 °C, 55 °C, 60 °C or 65 °C; the time of the third reduction reaction is preferably 4 to 6 h, and in specific embodiments, it can be 4 h, 5 h or 6 h.

[0195] After completing the third reduction reaction, the present invention preferably further includes: adjusting the pH value of the reaction solution obtained from the third reduction reaction to 7 with a saturated Na 2 CO 3 solution, filtering, extracting with ethyl acetate, washing the obtained organic phase with water, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating the obtained filtrate to remove the solvent, obtaining intermediate 6, and directly using it in the subsequent reaction without purification.

[0196] The present invention also provides a derivative of a sulfonamide compound, including a pharmaceutically acceptable salt or solvate of the sulfonamide compound described in the above technical solution. In the present invention, the pharmaceutically acceptable salt preferably includes inorganic acid salts or organic acid salts, and in specific embodiments, it can be one or more of chlorides, methanesulfonates, fumarates, maleates, p-toluenesulfonates, sulfates, succinates, acetates, phosphates and citrates. In the present invention, the solvate preferably includes hydrates.

[0197] The present invention also provides a pharmaceutical composition, including an active ingredient and a pharmaceutically acceptable excipient, and the active ingredient includes the sulfonamide compound described in the above technical solution and / or the derivative of the sulfonamide compound described in the above technical solution.

[0198] The present invention has no special limitation on the pharmaceutically acceptable excipient, and the pharmaceutically acceptable excipient well-known to those skilled in the art can be used.

[0199] For the dosage form of the pharmaceutical composition of the present invention, it preferably includes injection, tablet, capsule, pill, suspension or emulsion.

[0200] In the present invention, the administration routes of the pharmaceutical composition preferably include oral administration, spraying, transdermal, intravenous or intramuscular injection.

[0201] The present invention also provides the use of the sulfonamide compound, the derivative of the sulfonamide compound or the pharmaceutical composition described in the above technical solution in the preparation of a drug for treating EGFR-mediated diseases.

[0202] In the present invention, the EGFR-mediated diseases preferably include one or more of cancer and immune diseases. The cancer preferably includes one or more of lung cancer, breast cancer, prostate cancer, colorectal cancer, esophageal cancer, ovarian cancer, melanoma and brain cancer; the lung cancer preferably includes non-small cell lung cancer; the cancer preferably includes drug-resistant cancer; the drug-resistant cancer preferably includes drug resistance generated after EGFR mutation, and in specific embodiments, it can be drug resistance after EGFR / del19, EGFR / del19 / T790M, EGFR / L858R / T790M, EGFR / del19 / T790M / C797S and EGFR / L858R / T790M / C797S mutations.

[0203] To further illustrate the present invention, the sulfonamide compound provided by the present invention, its preparation method and application, the derivative of the sulfonamide compound and its application, and the pharmaceutical composition and its application will be described in detail below with reference to examples, but they should not be construed as limiting the protection scope of the present invention.

[0204] In the following examples, the temperature without special description is room temperature.

[0205] Example 1

[0206] (1) Synthesis of Intermediate 1

[0207]

[0208] At 0 °C, 2-nitrobenzenesulfonyl chloride (10.0 g, 45.2 mmol) was added portionwise to a solution of ethylamine (1.2 equiv, 54.2 mmol) and triethylamine (2.0 equiv, 90.2 mmol) in dichloromethane (300 mL). The reaction mixture was warmed to room temperature, stirred for 4 h, diluted with water, and the organic layer was separated. The aqueous phase was extracted once with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate volume ratio = 10:1 - 5:1) to give Intermediate 1, a colorless solid, 9.34 g, with a yield of 90.4%. ESI-MS m / z: 253.04 [M+Na] + . 1 H-NMR(400MHz,CDCl 3 )δ8.20 - 8.08(m,1H),7.90 - 7.83(m,1H),7.79 - 7.68(m,2H),3.17(qd,J=7.2,5.9Hz,2H),1.17(t,J=7.3Hz,3H).

[0209] (2) Synthesis of Intermediate 2

[0210]

[0211] With stirring, stannous chloride dihydrate (200.0 mmol, 5 equiv) was added to a solution of Intermediate 1 (40 mmol) in ethyl acetate (400 mL). The mixture was heated under reflux for 18 h and then cooled to room temperature. Saturated sodium carbonate solution was added, and the mixture was filtered through diatomaceous earth. The diatomaceous earth was washed with ethyl acetate. The resulting organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to a constant weight to give Intermediate 2, a pale yellow oily liquid, 7.6 g, with a yield of 95%. Thin layer silica gel plate monitoring showed no other impurities formed in Intermediate 2. ESI-MS m / z: 201.09 [M+H] + . 1 H NMR(400MHz,CDCl3)δ7.71(dd,J=8.0,1.6Hz,1H),7.32(ddd,J=8.1,7.3,1.6Hz,1H),6.86 - 6.73(m,2H),4.90(s,2H),4.71(s,1H),2.94(qd,J=7.3,6.1Hz,2H),1.07(t,J=7.2Hz,3H).

[0212] (3) Synthesis of Intermediate 3

[0213]

[0214] At 0 °C, NaH (2 equivalents, 30 mmol) was added to a solution of intermediate 2 (1 equivalent, 15 mmol) in DMF (80 mL). After stirring for 10 minutes, a solution of 2,4,5-trichloropyrimidine (1.5 equivalents, 22.5 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature naturally and stirred for 3 h. Then, ice water and ethyl acetate were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate volume ratio = 20:1 - 5:1) to obtain intermediate 3, a colorless solid, 2.39 g, with a yield of 46.1%. 1 H-NMR(400MHz,CDCl 3 )δ9.63(s,1H),8.52(dd,J=8.5,1.2Hz,1H),8.27(s,1H),7.95(dd,J=8.0,1.6Hz,1H),7.66(ddd,J=8.7,7.4,1.6Hz,1H),7.33-7.23(m,1H),4.74(t,J=6.0Hz,1H),3.03(qd,J=7.2,6.0Hz,2H),1.10(t,J=7.2Hz,3H).

[0215] (4) Preparation of reagent 2-1

[0216]

[0217] 4-(N,N-Dimethyl)aminopyridine (1.100 g, 9.0 mmol) and Boc anhydride (14.405 g, 66 mmol) were added to a solution of reagent 2 (11.169 g, 60 mmol) in dichloromethane (300 mL). The mixture was stirred for 8 h, washed with 2 mol / L HCl solution, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate volume ratio = 10:1 - 6:1) to obtain reagent 2-1, a yellow solid, 14.20 g, with a yield of 82.7%. 1 H-NMR(400MHz,d 6 -DMSO)δ8.52(d,J=11.3Hz,2H),7.28(d,J=13.4Hz,1H),3.94(s,3H),1.47(s,9H).

[0218] (5) Preparation of reagent 3-1

[0219]

[0220] At room temperature, reagent 2-1 (12.88 g, 45 mmol), N,N,N'-trimethylethylenediamine (6.897 g, 67.5 mmol), and potassium carbonate (12.438 g, 90 mmol) were added to dry DMF (240 mL). The reaction mixture was stirred at 85 °C for 6 h. After the reaction was completed as monitored by TLC, it was cooled to room temperature. Ethyl acetate was added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with pure water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent. It was purified by silica gel column chromatography (the eluent was dichloromethane:methanol volume ratio = 40:1 to 20:1) to obtain reagent 3-1, an orange solid, 15.06 g, with a yield of 90.9%. 1 H-NMR(400MHz,CDCl 3 )δ8.57(s,1H),6.62(s,1H),3.92(s,3H),3.27-3.17(m,2H),2.84(s,3H),2.56-2.48(m,2H),2.24(s,6H),1.52(s,9H).

[0221] (6) Preparation of reagent 3-2

[0222]

[0223] 10 wt% Pd / C (1.23 g) was added to a methanol solution (300 mL) of reagent 3-1 (14.728 g, 40 mmol). It was stirred at room temperature under a hydrogen atmosphere for 3 h. After the raw materials had basically disappeared as monitored by TLC, it was filtered to obtain the filtrate and the filter cake respectively. The filter cake was washed with methanol to obtain the washing solution. The filtrate and the washing solution were combined and concentrated under reduced pressure to constant weight to obtain reagent 3-2, 13.26 g, with a yield of 98%. There were no other impurities generated in reagent 3-2 as monitored by thin-layer silica gel plates.

[0224] (7) Preparation of reagent 3-3

[0225]

[0226] Triethylamine (7.344 g, 72 mmol) was added to a dichloromethane (240 mL) solution of reagent 3-2 (12.18 g, 36 mmol), and it was cooled to 0 °C. Acryloyl chloride (3.910 g, 43.2 mmol) was added. After stirring at room temperature for 5 h under nitrogen protection, it was washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (the eluent was petroleum ether:ethyl acetate volume ratio = 5:1 to 2:1) to obtain reagent 3-3, a colorless solid, 8.49 g, with a yield of 60.1%.

[0227] (8) Preparation of intermediate 7

[0228]

[0229] Under an ice bath, trifluoroacetic acid (22.81 g, 200 mmol) was slowly added to a solution of reagent 3-3 (7.850 g, 20 mmol) in dichloromethane (100 mL). The mixture was allowed to warm to room temperature naturally and stirred for 5 h. Water (200 mL) was added, and the pH was adjusted to 8 with saturated potassium carbonate solution. The mixture was extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol volume ratio = 100:1 to 80:1) to obtain 4.95 g of intermediate 7 with a yield of 84.7%. 1 H-NMR(400MHz,d 6 -DMSO)δ1H NMR(400MHz,DMSO)δ9.56(d,J=22.3Hz,1H),7.48(d,J=12.2Hz,1H),6.75(s,1H),6.20(dd,J=16.9,2.3Hz,1H),5.76(s,1H),5.65(dd,J=9.9,2.3Hz,1H),4.64(s,2H),3.77(d,J=7.2Hz,3H),3.12(d,J=12.4Hz,5H),2.67(d,J=9.0Hz,6H),2.50(s,2H).

[0230] (9) Preparation of target compound 1 (R 1 = hydrogen, R 2 = ethyl, R 3 = chlorine, R 4 = methoxy, R 6 = hydrogen)

[0231]

[0232] To a solution of intermediate 7 (1 equiv, 1.0 mmol) in 2-butanol (5 mL), intermediate 3 (1.2 equiv, 1.2 mmol) and p-toluenesulfonic acid (2 equiv, 2.0 mmol) were added. The reaction was stirred at 110 °C for 5 h under nitrogen protection. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was extracted with dichloromethane, and the organic phase was washed successively with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol volume ratio = 80:1 to 40:1) to obtain 0.30 g of target compound 1 as an off-white solid with a yield of 50.2%. HRMS(ESI)(m / z)[M+H] + calcd for C27 H 36 ClN 8 O 4 S, 603.22688; found, 603.22898. Purity: 98.3122% (HPLC). 1 H-NMR (400 MHz, CDCl 3 ) δ 10.04 (s, 1H), 9.09 (s, 1H), 8.95 (s, 1H), 8.42 - 8.24 (m, 1H), 8.13 (s, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 - 7.28 (m, 2H), 7.11 - 6.92 (m, 1H), 6.76 (s, 1H), 6.40 - 5.97 (m, 2H), 5.66 (dd, J = 9.4, 2.5 Hz, 1H), 5.47 (s, 1H), 3.85 (s, 3H), 3.06 (q, J = 7.3 Hz, 2H), 2.91 - 2.77 (m, 2H), 2.68 (s, 3H), 2.33 - 2.28 (m, 2H), 2.27 (s, 6H), 1.07 (t, J = 7.2 Hz, 3H). 13 C-NMR (101 MHz, CDCl 3 ) δ 162.86, 157.50, 155.61, 155.14, 145.35, 136.58, 136.27, 133.02, 132.14, 129.45, 129.04, 128.94, 125.94 (d, J = 9.5 Hz), 124.71, 123.18, 112.56, 105.90, 104.62, 57.42, 56.57, 56.00, 45.45, 43.44, 38.22, 15.32.

[0233] Example 2

[0234] Synthesis of target compound 2 (R 1 = ethyl, R 2 = ethyl, R 3 = chlorine, R 4 = methoxy, R 6 = hydrogen)

[0235]

[0236] The target compound 2 was prepared according to the method of Example 1, with the difference from Example 1 being that diethylamine was used instead of ethylamine in the preparation process of intermediate 1.

[0237] Target compound 2, colorless solid, yield 56.7%. HRMS (ESI) (m / z) [M+H] + calcd for C 29 H 40 ClN 8 O 4 S, 631.25818; found, 631.25792. Purity: 96.02% (by HPLC). 1 H NMR (600 MHz, d 6 -DMSO) δ 10.67 (s, 1H), 9.85 (s, 1H), 9.27 (s, 1H), 8.45 (d, J = 8.4 Hz, 2H), 8.23 (s, 1H), 8.19 (s, 1H), 7.78 (dd, J = 7.9, 1.6 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.20 (s, 1H), 6.90 (s, 1H), 6.17 (dd, J = 17.0, 2.2 Hz, 1H), 5.66 (dd, J = 10.1, 2.2 Hz, 1H), 3.80 (s, 3H), 3.21 (m, 4H), 3.06 (q, J = 7.4 Hz, 4H), 2.72 (s, 6H), 2.59 (s, 3H), 0.98 (t, J = 7.1 Hz, 6H). 13 C-NMR (151 MHz, d 6 -DMSO) δ 163.97, 156.54 (d, J = 3.0 Hz), 149.02 (d, J = 9.9 Hz), 142.24 - 141.84 (m), 140.75, 136.40, 134.20, 133.02, 129.70, 127.74, 126.35, 125.63, 124.56, 123.55, 123.16, 119.47, 104.73, 56.32, 53.88, 49.42, 45.81, 43.17, 41.60, 14.05。

[0238] Example 3

[0239] Synthesis of target compound 3 (R 1 = hydrogen, R 2 = propyl, R 3 = chlorine, R 4 = methoxy, R 6 = hydrogen)

[0240]

[0241] The target compound 3 was prepared according to the method of Example 1, with the difference from Example 1 being only that propylamine was used instead of ethylamine in the preparation process of Intermediate 1.

[0242] Target compound 2, off-white solid, yield 58.0%. HRMS (ESI) (m / z) [M + H] + calcd for C 28 H 38 ClN 8 O 4 S, 617.24253; found, 617.24441. Purity: 97.8701% (HPLC). 1 1H-NMR (400 MHz, CDCl 3 ) δ 10.05 (s, 1H), 9.07 (s, 1H), 8.91 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.14 (s, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 - 7.32 (m, 2H), 7.14 - 6.94 (m, 1H), 6.75 (s, 1H), 6.34 - 6.00 (m, 2H), 5.66 (dd, J = 9.2, 2.6 Hz, 1H), 5.47 (s, 1H), 3.85 (s, 3H), 2.97 (q, J = 6.5 Hz, 2H), 2.86 (dd, J = 6.7, 4.4 Hz, 2H), 2.68 (s, 3H), 2.28 (m, 8H), 1.45 (m, 2H), 0.80 (t, J = 7.4 Hz, 3H). 13 13C-NMR (101 MHz, CDCl 3 ) δ 162.87, 157.48, 155.67, 155.18, 145.26, 136.50, 136.20, 132.99, 132.11, 129.47, 129.22, 129.02, 126.07, 125.91, 124.95, 123.29, 112.46, 105.85, 104.56, 57.37, 56.53, 55.98, 45.42, 44.90, 43.48, 23.13, 11.00.

[0243] Example 4

[0244] Synthesis of target compound 4 (R 1 = hydrogen, R 2 = -CD 2 CD 3 R 3 = chlorine, R 4 = methoxy, R 6= hydrogen)

[0245]

[0246] Step 1. To a solution of 2-aminobenzenesulfonamide (1.72 g, 10 mmol) in isopropanol (50 mL), diisopropylethylamine (2.58 g, 20 mmol) and 2,4,5-trichloropyrimidine (2.17 g, 12 mmol) were added. The reaction was carried out at 63 °C for 48 h under nitrogen protection. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 - 2:1) to obtain 2-(3,6-dichloropyrimidinyl)aminobenzenesulfonamide with a yield of 62.5%.

[0247] Step 2. 2-(3,6-Dichloropyrimidinyl)aminobenzenesulfonamide (1.56 g, 5 mmol) was dissolved in 30 mL of anhydrous DMF. After cooling in an ice bath, sodium hydride (2.5 equiv, 12.5 mmol) was added, and the mixture was stirred for 0.5 h. Then deuterated ethyl p-toluenesulfonate (5 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched by adding water, and then 100 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed successively with pure water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8:1 - 4:1) to obtain deuterated intermediate 3-d5 with a yield of 80.9%.

[0248] Step 3. According to the method of step (9) in Example 1, intermediate 3-d5 was reacted with intermediate 6 to obtain the target compound 4, a yellow solid, with a yield of 42.4%. HRMS (ESI) (m / z) + calcd for C 27 H 30 D 5 ClN 8 O 4 S, 607.25043; found, 608.27154. 1 H-NMR (400 MHz, CDCl 3)δ10.03(s,1H),9.09(s,1H),8.93(s,1H),8.30(dd,J=8.3,1.1Hz,1H),8.14(s,1H),7.89(dd,J=7.9,1.6Hz,1H),7.47 - 7.36(m,1H),7.34(s,1H),7.08(td,J=7.7,1.2Hz,1H),6.75(s,1H),6.36 - 6.17(m,2H),5.73 - 5.57(m,1H),5.30(s,1H),3.85(s,3H),2.87(t,J=5.6Hz,2H),2.68(s,3H),2.30(m,8H). 13 C-NMR(101MHz,CDCl 3 )δ162.96,157.48,155.62,155.20,145.31,136.55,136.24,133.06,132.10,129.47,128.97,126.11,125.90,124.74,123.26,112.58,105.91,104.50,57.30,56.31,55.98,45.36,43.49,14.13。

[0249] Example 5

[0250] Synthesis of target compound 5 (R 1 =-CD 2 CD 3 , R 2 =-CD 2 CD 3 , R 3 =chloro, R 4 =methoxy, R 6 =hydrogen)

[0251]

[0252] The target compound 5 was prepared according to the method of Example 4, with the difference from Example 4 being that: the amount of deuterated ethyl p-toluenesulfonate in step 2 was 10 mmol to obtain intermediate 3-d10, and intermediate 3-d10 was reacted with intermediate 6 to obtain the target compound 5, a pale yellow solid, with a yield of 38.0%.

[0253] Example 6

[0254] Synthesis of target compound 6 (R 1 =ethyl, R 2 =ethyl, R 3 =fluoro, R 4 =methoxy, R 6 = hydrogen)

[0255]

[0256] The target compound 6 was prepared according to the method of Example 1, with the difference from Example 1 being only that: in the preparation process of Intermediate 1, diethylamine was used to replace ethylamine; in the preparation process of Intermediate 3, 2,4-dichloro-5-fluoropyrimidine was used to replace 2,4,5-trichloropyrimidine.

[0257] The target compound 6, a colorless solid, had a yield of 59.4%. HRMS(ESI)(m / z)[M+H] + calcd for C 29 H 40 FN 8 O 4 S, 615.28773; found, 615.28819. Purity: 99.63% (by HPLC). 1 1H NMR(600MHz, d 6 -DMSO)δ 1H NMR(600MHz, DMSO-d6)δ 1H NMR(600MHz, DMSO-d6)δ 1H NMR(600MHz, DMSO-d6)δ 10.63(s, 1H), 9.87(s, 1H), 9.18(d, J = 3.0Hz, 1H), 8.52(d, J = 8.4Hz, 1H), 8.33 - 8.17(m, 3H), 7.79(dd, J = 8.0, 1.6Hz, 1H), 7.60 - 7.51(m, 1H), 7.24 - 7.15(m, 2H), 6.90(s, 1H), 6.18(dd, J = 17.0, 2.1Hz, 1H), 5.67(dd, J = 10.2, 2.2Hz, 1H), 3.82(s, 3H), 3.33 - 3.24(m, 4H), 3.19(q, J = 7.1Hz, 4H), 2.73(s, 6H), 2.58(s, 3H), 0.99(t, J = 7.1Hz, 6H). 13 13C-NMR(151MHz, d 6 -DMSO)δ 163.94, 159.00, 155.84, 155.01, 149.51, 141.41, 136.40, 133.93, 133.02, 129.64, 129.13, 127.79, 126.33, 125.65, 123.89, 123.63, 120.46, 104.86, 104.40, 56.28, 53.84, 45.81, 43.07, 41.51, 14.01.

[0258] Example 7

[0259] Synthesis of target compound 7 (R 1 = hydrogen, R 2 = ethyl, R 3 = fluoro, R 4 = methoxy, R 6 = hydrogen)

[0260]

[0261] The target compound 7 was prepared according to the method of Example 1, and the difference from Example 1 was only that: in the preparation process of intermediate 3, 2,4-dichloro-5-fluoropyrimidine was used instead of 2,4,5-trichloropyrimidine.

[0262] Target compound 7, colorless solid, yield 45.7%. HRMS (ESI) (m / z) [M + H] + calcd for C 27 H 36 F N 8 O 4 S, 587.2564; found, 587.2536. Purity: 98.0020% (HPLC). 1 1H-NMR (400 MHz, CDCl 3 ) δ 10.10 (s, 1H), 9.20 (s, 1H), 8.94 - 8.78 (m, 1H), 8.40 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 2.9 Hz, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.32 (s, 1H), 7.08 (m, 1H), 6.76 (s, 1H), 6.39 - 6.10 (m, 2H), 5.66 (dd, J = 9.1, 2.6 Hz, 1H), 5.51 (s, 1H), 3.86 (s, 3H), 3.05 (q, J = 7.2 Hz, 2H), 2.90 - 2.80 (m, 2H), 2.69 (s, 3H), 2.27 (s, 6H), 2.09 (d, J = 33.9 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H). 13 13C-NMR (101 MHz, CDCl 3)δ162.96,155.27,155.24,149.45,149.35,145.10,142.40,141.81,141.61,139.92,136.18,136.11,133.38,132.17,129.50,129.15,127.98,126.37,126.00,123.64,122.84,111.78,104.61,57.39,56.59,55.99,45.44,43.53,38.21,15.19.

[0263] Example 8

[0264] Synthesis of target compound 8 (R 1 = hydrogen, R 2 = ethyl, R 3 = bromine, R 4 = methoxy, R 6 = hydrogen)

[0265]

[0266] The target compound 8 was prepared according to the method of Example 1, with the difference from Example 1 being only that: in the preparation of intermediate 3, 2,4-dichloro-5-bromopyrimidine was used instead of 2,4,5-trichloropyrimidine. The target compound 8, a light yellow solid, with a yield of 41.8%. HRMS (ESI) (m / z) [[M+H]] + calcd for C 27 H 36 BrN 8 O 4 S, 647.17636; found, 647.17680. Purity: 98.6456% (HPLC). 1 1H-NMR (400 MHz, CDCl 3 )δ10.05 (s, 1H), 9.06 (s, 1H), 8.77 (d, J = 9.0 Hz, 1H), 8.31 - 8.16 (m, 2H), 7.89 (m, 1H), 7.48 - 7.27 (m, 2H), 7.08 (t, J = 5.5 Hz, 1H), 6.74 (s, 1H), 6.39 - 6.05 (m, 2H), 5.73 - 5.57 (m, 1H), 5.20 (d, J = 79.2 Hz, 1H), 3.84 (s, 3H), 3.30 - 2.94 (m, 2H), 2.93 - 2.72 (m, 2H), 2.68 (s, 3H), 2.28 (m, 8H), 1.07 (t, J = 7.2 Hz, 3H). 13 13C-NMR (101 MHz, CDCl3 )δ162.87,158.13,158.00,156.39,145.24,136.51,136.36,132.94,132.08,129.53,129.42,129.02,126.10,125.88,125.21,123.40,112.48,104.53,57.35,56.55,55.97,45.40,43.50,38.23,15.44。

[0267] Example 9

[0268] Synthesis of target compound 9 (R 1 = hydrogen, R 2 = propyl, R 3 = bromine, R 4 = methoxy, R 6 = hydrogen)

[0269]

[0270] Prepare target compound 9 according to the method of Example 1, the difference from Example 1 is only that: in the preparation of intermediate 1, propylamine is used instead of ethylamine. Target compound 9, light yellow solid, yield 55.3%. HRMS (ESI) (m / z) [M + H] + calcd for C 28 H 38 BrN 8 O 4 S, 661.19201; found, 661.19409. Purity: 99.5655% (HPLC). 1 1H-NMR (400 MHz, CDCl 3 ) δ 10.05 (s, 1H), 9.05 (s, 1H), 8.74 (s, 1H), 8.24 (s, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.89 (dd, J = 7.9, 1.6 Hz, 1H), 7.52 - 7.32 (m, 2H), 7.07 (m, 1H), 6.74 (s, 1H), 6.39 - 6.07 (m, 2H), 5.67 (dd, J = 9.7, 2.1 Hz, 1H), 5.37 (s, 1H), 3.84 (s, 3H), 2.98 (m, 2H), 2.90 - 2.79 (m, 2H), 2.68 (s, 3H), 2.27 (m, 8H), 1.45 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H). 13 13C-NMR (101 MHz, CDCl 3)δ162.82, 158.06, 157.97, 156.43, 145.22, 136.49, 136.30, 132.86, 132.09, 129.64, 129.50, 129.02, 126.10, 125.86, 125.38, 123.43, 112.45, 104.55, 94.51, 57.37, 56.54, 55.97, 45.41, 44.89, 43.49, 23.18, 10.98。

[0271] Example 10

[0272] Synthesis of target compound 10 (R 1 = hydrogen, R 2 = ethyl, R 3 = hydrogen, R 4 = methoxy, R 6 = hydrogen)

[0273]

[0274] Prepare target compound 10 according to the method of Example 1, the difference from Example 1 is only that: in the preparation of intermediate 3, 2,4-dichloropyrimidine is used instead of 2,4,5-trichloropyrimidine. Target compound 10, colorless solid, yield is 60.8%. HRMS(ESI)(m / z)[M + H] + calcd for C 27 H 37 N 8 O 4 S, 569.26585; found, 569.26754. Purity: 98.1214% (HPLC). 1 H NMR(400MHz, CDCl 3 )δ10.30(s, 1H), 9.68 - 9.42(m, 1H), 8.23 - 8.06(m, 2H), 8.00(m, 1H), 7.80(dd, J = 8.1, 3.0Hz, 1H), 7.48(d, J = 8.8Hz, 3H), 7.13(m, 1H), 6.77(s, 1H), 6.53 - 6.00(m, 3H), 5.72(dt, J = 9.8, 2.2Hz, 1H), 3.86(s, 3H), 2.99(t, J = 7.3, 2H), 2.90 - 2.82(m, 2H), 2.69(s, 3H), 2.26(m, 8H), 1.03(t, J = 7.2Hz, 3H). 13 C NMR(101MHz, CDCl 3)δ163.70,159.91,159.77,158.21,144.89,137.18,135.55,133.26,132.33,130.65,129.39,129.11,126.67,126.16,122.73,122.34,111.43,104.64,96.41,57.35,56.54,56.05,45.38,43.73,37.71,15.10。

[0275] Example 11

[0276] Synthesis of target compound 11 (R 1 =H, R 2 =ethyl, R 3 =methyl, R 4 =methoxy, R 6 =hydrogen)

[0277]

[0278] Prepare target compound 11 according to the method of Example 1, the difference from Example 1 is only that: in the preparation of intermediate 3, 2,4-dichloro-5-methylpyrimidine is used instead of 2,4,5-trichloropyrimidine. Target compound 11, light yellow solid, yield 50.6%. HRMS(ESI)(m / z)[M+H] + calcd for C 28 H 39 N 8 O 4 S, 583.28150; found, 583.28398. Purity: 98.4306% (HPLC). 1 1H-NMR(400MHz, CDCl 3 )δ10.00(s, 1H), 9.12(d, J = 14.0Hz, 1H), 8.52(s, 1H), 8.36(dd, J = 8.4, 1.1Hz, 1H), 7.91 - 7.87(m, 1H), 7.85(dd, J = 7.9, 1.6Hz, 1H), 7.45 - 7.31(m, 1H), 7.24(s, 2H), 7.04 - 6.94(m, 1H), 6.75(s, 1H), 6.22(d, J = 5.9Hz, 2H), 5.67 - 5.60(m, 1H), 3.87(s, 3H), 3.10 - 3.01(m, 2H), 2.93 - 2.84(m, 2H), 2.69(m, 2H), 2.31(br, 9H), 2.08(s, 3H), 1.13 - 1.08(m, 3H). 13C-NMR(101MHz,CDCl 3 ) δ 162.75, 158.72, 157.85, 156.48, 145.10, 137.31, 135.75, 132.94, 132.29, 129.30, 129.01, 127.75, 126.64, 125.71, 124.28, 122.16, 112.36, 106.82, 104.49, 57.39, 56.03, 45.39, 43.62, 38.34, 15.22, 13.14。

[0279] Example 12

[0280] Prepare intermediate 3 according to Example 1.

[0281] (1) Preparation of intermediate 4

[0282]

[0283] Dissolve intermediate 3 (10 mmol, 1 equivalent) in 2-butanol (60 mL), add 2-methoxy-4-fluoro-5-nitroaniline (Reagent 2, 1.2 equivalents, 12 mmol) and p-toluenesulfonic acid (2 equivalents, 20 mmol). After stirring and reacting at 110 °C for 5 h, cool to room temperature, filter, wash the obtained solid component with acetonitrile and water, and dry to constant weight to obtain intermediate 4, a yellow solid, 3.74 g, with a yield of 79.3%. 1 HNMR(400MHz,d 6 -DMSO) δ 9.37 (s, 1H), 8.58 (d, J = 6.1 Hz, 2H), 8.38 (d, J = 8.3 Hz, 1H), 8.32 (s, 1H), 7.92 (m, 1H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 7.48 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.34 (d, J = 13.4 Hz, 1H), 7.30 - 7.21 (m, 1H).

[0284] (2) Preparation of intermediate 6

[0285]

[0286] Potassium carbonate (14 mmol, 2 equiv) and reagent 3 (8.4 mmol, 1.2 equiv) were added to a DMF solution (60 mL) of intermediate 4 (7 mmol, 1 equiv), and the mixture was stirred at 100 °C for 5 h. After cooling to room temperature, water and dichloromethane were added for extraction. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and purified by silica gel column chromatography (DCM / MeOH volume ratio = 80:1 - 30:1) to obtain intermediate 5, 3.79 g, with a yield of 98%.

[0287] At 0 °C, stannous chloride dihydrate (30 mmol, 5 equiv) and concentrated hydrochloric acid (30 mmol, 5 equiv) were added to ethyl acetate (60 mL) of the obtained intermediate 5 (6 mmol, 1 equiv), and the mixture was stirred at 50 °C for 5 h. The pH value was adjusted to 7 with saturated Na 2 CO 3 solution, cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate. The organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to remove the solvent to obtain intermediate 6, 2.95 g, with a yield of 94%.

[0288] (4) Preparation of target compound 12 (R 1 = H, R 2 = deuterated ethyl, R 3 = chlorine, R 4 = hydrogen, R 6 = hydrogen)

[0289]

[0290] To a solution of intermediate 6 (2 mmol, 1 equiv) in THF / H 2 O (v / v = 5 / 1, 18 mL) and Na 2 CO 3 (4 mmol, 2 equiv), reagent 4 (3 mmol, 1.5 equiv) was added dropwise. The mixture was stirred at 0 °C for 1 h, ethyl acetate and water were added, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and purified by silica gel column (eluent: petroleum ether:ethyl acetate:triethylamine volume ratio = 2:1:0.05 - 1:1:0.05) to obtain the target compound 12. Off-white solid, with a yield of 50.5%. HRMS (ESI) (m / z) [M + H] + calcd for C 26 H 28 D 5 ClN 8 O 3 S, 577.2399; found, 577.2386. Purity: 98.9964% (HPLC). 1H-NMR(400MHz,CDCl 3 )δ9.89(s,1H),8.78(s,1H),8.76(s,1H),8.40(d,J=8.3Hz,2H),7.99(d,J=2.9Hz,1H),7.91(d,J=8.0Hz,1H),7.52(m,1H),7.27(s,2H),7.15(m,2H),6.64(d,J=11.8Hz,2H),2.99(m,2H),2.70(m,2H),2.59(s,3H),2.30(s,6H). 13 C-NMR(101MHz,CDCl 3 )δ163.06,157.50,155.64,155.26,145.30,136.51,136.26,133.13,132.07,129.53,128.98,126.23,125.96,124.78,123.33,105.93,104.42,55.97,45.18,43.52,38.24,31.94,22.71,15.38。

[0291] Example 13

[0292] Synthesis of target compound 13 (R 1 = hydrogen, R 2 = ethyl, R 3 = chlorine, R 4 = methoxy, R 6 = hydrogen)

[0293]

[0294] The target compound 13 was prepared according to the preparation method of Example 1, and the difference from Example 1 was only that: in the preparation process of intermediate 7, N-methylpiperazine was used instead of N,N,N'-trimethylethylenediamine. The target compound 13 was a pale yellow solid with a yield of 56.0%. HRMS(ESI)(m / z)[M+H] + calcd for C 27 H 34 ClN 8 O 4 S, 601.21123; found, 601.20786. Purity: 97.4060% (HPLC). 1 H NMR(400MHz,CDCl 3)δ9.09(s,1H),9.01(s,1H),8.38 - 8.30(m,2H),8.14(s,1H),7.90(dd,J=8.0,1.6Hz,1H),7.46 - 7.37(m,1H),7.31(d,J=31.5Hz,1H),7.13 - 7.07(m,1H),6.75(s,1H),6.25 - 6.23(m,1H),6.22 - 6.12(m,1H),5.84 - 5.60(m,1H),5.32(m,1H),3.85(s,3H),3.07(q,J=7.2Hz,2H),2.91(m,4H),2.63(m,4H),2.41(s,3H),1.08(t,J=7.2Hz,3H). 13 C-NMR(101MHz,CDCl 3 )δ162.35,157.38,155.53,155.14,145.30,136.25,133.17,131.88,129.47,128.60,127.75,126.63,126.36,125.76,124.38,123.22,112.14,106.10,103.34,55.99,55.89,52.25,46.07,38.28,26.92,15.27。

[0295] Example 14

[0296] Synthesis of target compound 14 (R 1 = hydrogen, R 2 = ethyl, R 3 = chlorine, R 4 = hydrogen, R 6 = hydrogen)

[0297]

[0298] The target compound 14 was prepared according to the method of Example 1, with the difference from Example 1 only being that in the preparation of reagent 2-1, 3-nitro-4-fluoroaniline was used instead of reagent 2 (2-methoxy-4-fluoro-5-nitroaniline). Pale yellow solid, yield 28.4%. HRMS(ESI)(m / z)[M + H] + calcd for C 26 H 34 ClN 8 O 3 S,573.21631; found,573.26832.Purity:99.7517%(HPLC). 11H NMR (400 MHz, CDCl 3 ) δ 10.23 (s, 1H), 9.12 (s, 1H), 8.48 (d, J = 8.3 Hz, 1H), 8.35 (d, J = 2.6 Hz, 1H), 8.09 (s, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.44 (s, 1H), 7.17 (m, 1H), 7.11 (d, J = 8.7 Hz, 1H), 6.42 (dd, J = 17.1, 1.7 Hz, 1H), 6.29 (dd, J = 17.0, 10.0 Hz, 1H), 5.72 (dd, J = 10.0, 1.7 Hz, 1H), 3.03 - 2.93 (m, 2H), 2.84 (t, J = 5.5 Hz, 2H), 2.68 (s, 3H), 2.37 - 2.19 (m, 8H), 1.01 (t, J = 7.3 Hz, 3H). 13 13C - NMR (101 MHz, CDCl 3 ) δ 163.86, 157.63, 155.60, 154.87, 136.98, 136.76, 136.41, 135.89, 133.22, 131.81, 129.55, 128.44, 126.97, 124.09, 123.20, 122.40, 115.23, 111.49, 106.30, 57.39, 56.63, 45.54, 43.29, 38.20, 15.08。

[0299] Example 15

[0300] Synthesis of target compound 15 (R 1 = H, R 2 = ethyl, R 3 = bromo, R 4 = H, R 6 = H)

[0301]

[0302] The target compound 15 was prepared according to the method of Example 1, with the difference from Example 1 only being that: in the preparation of intermediate 3, 2,4 - dichloro - 5 - bromopyrimidine was used instead of 2,4,5 - trichloropyrimidine, and in the preparation of reagent 2 - 1, 3 - nitro - 4 - fluoroaniline was used instead of reagent 2 (2 - methoxy - 4 - fluoro - 5 - nitroaniline). The target compound 15 is a pale yellow solid with a yield of 25.9%. HRMS (ESI) (m / z) [M + H] + calcd for C 26 H 34 BrN8 O 3 S, 617.16580; found, 617.22546. Purity: 99.6683% (HPLC). 1 H-NMR (400 MHz, CDCl 3 ) δ 10.20 (s, 1H), 8.96 (s, 1H), 8.42 - 8.36 (m, 2H), 8.21 (s, 1H), 7.94 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 (m, 2H), 7.34 (s, 1H), 7.21 - 7.15 (m, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.41 (dd, J = 17.0, 1.7 Hz, 1H), 6.28 (dd, J = 17.0, 10.1 Hz, 1H), 5.71 (dd, J = 10.1, 1.7 Hz, 1H), 2.97 (t, J = 7.2 Hz, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.68 (s, 3H), 2.30 - 2.24 (m, 8H), 1.00 (t, J = 7.2 Hz, 3H). 13 C-NMR (101 MHz, CDCl 3 ) δ 163.80, 158.17, 157.90, 156.34, 136.99, 136.71, 136.52, 135.94, 133.12, 131.85, 129.54, 128.81, 126.86, 124.55, 123.34, 122.38, 115.25, 111.48, 94.98, 57.45, 56.71, 45.60, 45.53, 38.20, 15.14.

[0303] Example 16

[0304] Synthesis of target compound 16 (R 1 = hydrogen, R 2 = ethyl, R 3 = chlorine, R 4 = hydrogen, R 6 = hydrogen)

[0305]

[0306] The target compound 16 was prepared according to the method of Example 1, with the difference from Example 1 being only that N-methylhomopiperazine was used instead of N,N,N'-trimethylethylenediamine in the preparation of reagent 3-1. The target compound 16 is a pale yellow solid with a yield of 13.5%. HRMS (ESI) (m / z) [M + H] + calcd for C 27 H34 ClN 8 O 3 S,585.21631; found,585.27477.Purity:99.8288%(HPLC). 1 H-NMR(400MHz,d6-DMSO)δ9.43(s,1H),9.37(s,1H),9.18(s,1H),8.71-8.53(m,1H),8.25(s,1H),8.12(s,1H),7.81(dd,J=8.0,1.6Hz,1H),7.57(ddd,J=8.7,7.3,1.6Hz,1H),7.40(dd,J=8.7,2.6Hz,1H),7.27-7.19(m,1H),7.09(d,J=8.8Hz,1H),6.68-6.51(m,1H),6.22(dd,J=17.0,1.9Hz,1H),5.95-5.67(m,1H),3.12-2.98(m,4H),2.84(q,J=7.2Hz,2H),2.75-2.62(m,4H),2.34(s,3H),1.91-1.78(m,2H),0.96(t,J=7.2Hz,3H). 13 C-NMR(101MHz,d6-DMSO)δ163.41,158.24,155.43,155.33,141.05,136.68,135.82,133.60,132.71,132.23,129.16,128.30,126.96,123.39,121.66,117.25,115.12,105.38,58.41,57.12,54.80,54.11,47.09,37.97,28.19,15.24.

[0307] Example 17

[0308] Synthesis of target compound 17 (R 1 = hydrogen, R 2 = ethyl, R 3 = bromine, R 4 = hydrogen, R 6 = hydrogen)

[0309]

[0310] The target compound 17 was prepared according to the method of Example 1, with the difference from Example 1 being only that: in the preparation of intermediate 3, 2,4-dichloro-5-bromopyrimidine was used instead of 2,4,5-trichloropyrimidine, and in the preparation of reagent 3-1, N-methylhomopiperazine was used instead of N,N,N-trimethylethylenediamine. The target compound 17 had a yield of 12.5%. HRMS(ESI)(m / z)[M+H] + calcd forC 27 H 34 BrN 8 O 3 S,629.16580;found,629.22860.Purity:99.7358%(HPLC). 1 1H-NMR(400MHz,CDCl 3 )δ9.03(s,1H),8.97(s,1H),8.38(d,J=8.3Hz,1H),8.29(d,J=2.6Hz,1H),8.19(s,1H),7.94(dd,J=7.9,1.6Hz,1H),7.53-7.44(m,2H),7.39(s,1H),7.19(t,J=7.6Hz,1H),7.06(d,J=8.6Hz,1H),6.45-6.28(m,2H),5.77(dd,J=9.8,1.7Hz,1H),5.26(d,J=25.5Hz,1H),3.09(m,4H),2.99(q,J=7.2Hz,2H),2.78(t,J=5.9Hz,2H),2.74(t,J=6.4Hz,2H),2.46(s,3H),1.01(t,J=7.2Hz,3H). 13 13C-NMR(101MHz,CDCl 3 )δ163.37,158.14,157.89,156.31,138.76,136.48,136.37,133.86,133.14,131.81,129.54,128.78,127.21,124.53,123.40,122.81,115.51,111.14,94.94,59.46,55.80,55.01,47.48,47.39,38.22,28.90,15.09.

[0311] Test Example 1

[0312] Inhibitory activity of the target compound against EGFR double mutant, single mutant and wild-type non-small cell lung cancer cells

[0313] The anti-proliferative activities of the target compounds prepared in the examples against EGFR double-mutant tumor cells (H1975), EGFR single-mutant tumor cells (PC9), and EGFR wild-type tumor cells (A549) were tested by the MTT method, and osimertinib was used as a positive drug control. The specific experimental steps are as follows. Tumor cells H1975 and PC9 were cultured in RPMI 1640 medium containing 10% (v / v) FBS, 1% (v / v) penicillin, and streptomycin; A549 cells were cultured in high-glucose DMEM medium containing 10% (v / v) FBS, 1% (v / v) penicillin, and streptomycin, and placed in an incubator at 37 °C and 5% CO 2 saturated humidity for culturing, and the fresh culture medium was changed every other day. When the cells grew to cover 80%-90% of the bottom wall of the culture flask, they were digested with 0.25% trypsin and passaged at a ratio of 1:2 to 1:3. Logarithmic-phase cells were collected, the cell suspension concentration was adjusted, and they were inoculated into a 96-well plate at 8×10 3 cells / well and continued to be cultured in a carbon dioxide incubator at 37 °C and 5% for 12 h. After the cells adhered to the wall, the old culture medium was aspirated and discarded, and the medium containing 1% FBS was added; six concentration gradients were set for each compound, and three replicates were set for each concentration. After adding, they were cultured for 72 h, and then 10 μL of MTT solution was added to each well in the dark and incubated in the carbon dioxide incubator for another 4 h. The absorbance (OD value) at 570 nM was measured with an enzyme-linked immunosorbent assay reader. Finally, data statistics were performed, and the inhibition rate calculation formula at each concentration was as follows: Inhibition rate = 1 - (OD value of the drug-added group - OD value of the blank group) / (OD value of the control group - OD value of the blank group) × 100%.

[0314] The half-maximal inhibitory concentration (IC50) was calculated using the software IBM SPSS15.0. Each group of experiments was independently repeated three times and the average value was taken to obtain the final data, and the results are shown in Table 1.

[0315] Table 1 Inhibitory activities of the compounds in the examples against EGFR mutant and wild-type tumor cells (IC 50 , μM)

[0316] Example H1975 (EGFR double mutation) PC9 (EGFR single mutation) A549 (EGFR wild type) Example 1 0.0006 0.004 0.853 Example 2 0.0057 0.013 0.430 Example 3 0.0083 0.012 1.33 Example 4 0.001 0.006 0.865 Example 5 0.007 0.006 0.526 Example 6 0.0013 0.029 0.511 Example 7 0.0036 0.004 1.395 Example 8 0.0063 0.007 0.955 Example 9 0.018 0.012 0.869 Example 10 0.047 0.025 0.951 Example 11 0.045 0.066 3.368 Example 12 0.04 0.048 6.45 Example 13 0.031 0.037 0.629 Example 14 0.001 0.019 0.56 Example 15 0.005 0.0021 0.73 Example 16 0.0057 0.026 0.59 Example 17 0.0013 0.0065 1.35 Osimertinib 0.016 0.019 1.41

[0317] The data in Table 1 show that the target compounds provided by the present invention showed excellent effects in the anti-proliferative activity tests of PC9 tumor cells with EGFR single mutation and H1975 tumor cells with EGFR double mutation, and most of the target compounds showed better results than osimertinib. At the same time, there was also good selectivity between EGFR wild-type and EGFR mutant tumor cells.

[0318] Test Example 2

[0319] Inhibitory activity test of the target compound 1 prepared in Example 1 against 80 kinases

[0320] To explore the anti-tumor mechanism of the target compound provided by the present invention, the inhibitory activity of the target compound 1 against 80 kinases was measured.

[0321] The experimental steps are as follows: Transfer 250 nl of a 20 μM solution of the compound to each well of a 384-well reaction plate for standby. Add 250 nl of 100% DMSO to the negative control well and the blank well respectively. Prepare a kinase solution at 2.5 times the final concentration with 1×Kinase buffer. Add 10 μL of the kinase solution at 2.5 times the final concentration to the compound well and the positive control well respectively; add 10 μL of 1×Kinase buffer to the negative control well. Centrifuge at 1000 rpm for 30 seconds, mix well by oscillation, and incubate at room temperature for 10 minutes. Prepare a mixed solution of ATP and Kinase substrate 2 at 25 / 15 times the final concentration with 1×Kinase buffer. Add 15 μL of the mixed solution of ATP and substrate at 25 / 15 times the final concentration to initiate the reaction. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, mix well by oscillation, and incubate at room temperature for 60 minutes. Add 30 μL of the termination detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and mix well by oscillation. Read the conversion rate with a Caliper EZ Reader II (microfluidic chip instrument II). Each kinase has duplicate wells, and the calculation formula for the inhibition rate of each well is as follows: Inhibition rate = (conversion rate of the compound well - conversion rate of the blank) / (conversion rate of the negative control well - conversion rate of the blank) × 100%. Table 2 shows the kinases with an inhibition rate of more than 70% of the compound in Example 1 against kinases, and lists the results in the literature published by the original company of the positive drug osimertinib for comparison.

[0322] Table 2 Comparison of the inhibitory activities of the target compound 1 and the third-generation EGFR representative drug osimertinib against various kinases

[0323]

[0324] *Data are from the literature of the original company of osimertinib (J. Med. Chem. 2014, 57, 8249 - 8267), and are the inhibition rates of osimertinib against various kinases at a concentration of 1.0 μM (selecting those with an inhibition rate of more than 70%).

[0325] **Data are the inhibition rates of the target compound 1 prepared in Example 1 against various kinases at a concentration of 0.1 μM (selecting those with an inhibition rate of more than 70%).

[0326] The data in Table 2 show that the positive drug osimertinib and the representative target compound 1 of the present invention both have excellent inhibitory activities against the EGFR kinase, but their inhibitory activities against other targets are very different. The compound of Example 1 shows significantly better activities than osimertinib against tumor-related kinases such as JAK3, insulin-like growth factor 1 receptor (IGF1R), IL2-induced T-cell kinase (ITK), and bone marrow X-linked kinase (BMX), which is worthy of further study.

[0327] Test Example 3

[0328] Antitumor Activity Test of Target Compound 1 (Example 1, Test Code 23 or D23) in Nude Mice

[0329] To further study the antitumor effect of the compounds of the present invention, the present invention conducted an antitumor activity study in animals. The experimental steps are as follows: BALB / c nude mice (3 - 5 weeks old, 18 - 20 g) were used. Non-small cell lung cancer H1975 (EGFR / L858 / T790M) cells in the logarithmic growth phase cultured for 3 - 5 passages, and murine Baf3 tumor cells with EGFR / L858 / T790M / C797S mutation were taken. After digestion with trypsin, they were prepared into a cell suspension with a concentration of 1.0×10 7 cells / ml using serum-free medium. The cells were subcutaneously injected into the right axilla of nude mice to establish nude mouse models of EGFR double-mutant non-small cell lung cancer H1975 and EGFR triple-mutant Baf3 tumor xenografts. When the tumor volume of the H1975 model reached 100 - 150 mm 3 and the tumor volume of the Baf3 model reached 50 - 100 mm 3 , the mice were randomly divided into four groups (control group, positive drug group, Example 1 group (experimental code 23)), with six mice in each group. Among them, the positive drug for the H1975 model experiment was osimertinib; the positive drug for the Baf3 mouse model experiment was brigatinib, an EGFR triple-mutation inhibitor commonly used in the literature. The test compound was orally administered once a day at a set dose for 14 consecutive days. The changes in tumor volume of each group of mice are as Figure 1As shown, where A is a graph showing the change in tumor volume of H1975 cells inhibited by target compound 1 and osimertinib at a dosing dose of 10 mg / kg or 20 mg / kg, B is a graph showing the tumor tissue weight of H1975 cells inhibited by target compound 1 and osimertinib at a dosing dose of 10 mg / kg or 20 mg / kg, C is a graph showing the change in tumor volume of Baf3 cells inhibited by target compound 1 and brigatinib at a dosing dose of 50 mg / kg, and D is a graph showing the tumor tissue weight of Baf3 cells inhibited by target compound 1 and brigatinib at a dosing dose of 50 mg / kg. For the H1975 model, the tumor growth inhibition rate TGI (calculated by volume) of target compound 1 at a dose of 20 mg / kg was 97.2%, and the TGI of osimertinib at the same dose was 98.3%, which were comparable. For the EGFR triple mutant model resistant to osimertinib, the tumor growth inhibition rate TGI (calculated by volume) of target compound 1 at a dose of 50 mg / kg was 65.26%; the TGI of brigatinib at the same dose was 33.11%. During the entire experiment, there were no significant changes in the body weights of the mice in the control group and group 11b, and the behavior of the mice was normal.

[0330] The above experimental results show that in the animal experiment of modeling EGFR double mutant tumor cells, target compound 1 exhibited tumor growth inhibitory activity comparable to that of the representative third-generation EGFR inhibitor osimertinib, and also had good inhibitory activity against tumors with EGFR / C797S mutations (EGFR / L858 / T790M / C797S Baf3 model) after the use of osimertinib, which was superior to the EGFR triple mutant inhibitor brigatinib.

[0331] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A sulfonamide compound, characterized in that: It has the structure shown in Formula I: wherein R1 and R2 independently include hydrogen, deuterium, unsubstituted or substituted C1-C4 alkyl; R3 includes hydrogen or halogen; R4 includes hydrogen, unsubstituted or substituted alkoxy; R5 includes N-methyl N-(2-(N,N-dimethylamino)ethylamino, N-methylhomopiperazinyl or N-methylpiperazinyl; R6 includes hydrogen, deuterium, and unsubstituted or substituted alkyl.

2. The sulfonamide compound according to claim 1, characterized in that The substituents in the substituted C1-C4 alkyl group include one or more of deuterium, hydroxyl, amino and halogen; The substituents in the substituted alkyl group include one or more of deuterium, hydroxyl, amino and halogen; The substituents in the substituted alkoxy group include deuterium and / or halogen.

3. The method for preparing the sulfonamide compound according to claim 1 or 2, characterized in that: The following steps are involved: The intermediate 3 and the intermediate 7 are subjected to a nucleophilic substitution reaction to obtain the sulfonamide compound; 4. The preparation method according to claim 3, characterized in that: When the intermediate 3 does not contain deuterium, the preparation method of the intermediate 3 comprises the following steps: Intermediate 2 is subjected to a nucleophilic substitution reaction with reagent 1 to obtain intermediate 3; When the intermediate 3 contains deuterium, the preparation method of the intermediate 3 comprises the following steps: Reagent 5 is subjected to a nucleophilic substitution reaction with reagent 1 to obtain intermediate 8; The intermediate 8 is subjected to a nucleophilic substitution reaction with the reagent 6 to obtain the intermediate 9. When one of the R1 and R2 is hydrogen, the intermediate 9 is the intermediate 3; When neither R1 nor R2 is hydrogen, the intermediate 9 is subjected to a nucleophilic substitution reaction with the reagent 7 to obtain the intermediate 3; 5. The preparation method according to claim 3, characterized in that: The preparation method of the intermediate 7 comprises the following steps: Reagent 2 is subjected to a nucleophilic substitution reaction with Boc anhydride to obtain reagent 2-1; The reagent 2-1 is subjected to a nucleophilic substitution reaction with the reagent 3 to obtain the reagent 3-1; Using a reducing agent to reduce the reagent 3-1 to obtain a reagent 3-2; The reagent 3-2 is subjected to a nucleophilic substitution reaction with the reagent 4 to obtain the reagent 3-3; The reagent 3-3 is subjected to a deprotection reaction to obtain an intermediate 7; 6. The method for preparing the sulfonamide compound according to claim 1 or 2, characterized in that: The following steps are involved: The intermediate 6 is subjected to a nucleophilic substitution reaction with the reagent 4 to obtain the sulfonamide compound; 7. The preparation method according to claim 6, characterized in that: The preparation method of the intermediate 6 comprises the following steps: Intermediate 3 is subjected to a nucleophilic substitution reaction with reagent 2 to obtain intermediate 4; The intermediate 4 is subjected to a nucleophilic substitution reaction with the reagent 3 to obtain the intermediate 5; Using a reducing agent to reduce the intermediate 5 to obtain an intermediate 6; 8. A derivative of a sulfonamide compound, characterized in that: A pharmaceutically acceptable salt or solvate of the sulfonamide compound according to claim 1 or 2.

9. A pharmaceutical composition, characterized in that The invention comprises an active component and a pharmaceutically acceptable excipient, wherein the active component comprises one or more of a sulfonamide compound, a pharmaceutically acceptable salt and a solvate of the sulfonamide compound; the sulfonamide compound is the sulfonamide compound described in claim 1; the pharmaceutically acceptable salt and solvate of the sulfonamide compound are the pharmaceutically acceptable salt and solvate of the sulfonamide compound described in claim 8.

10. Use of the sulfonamide compound according to claim 1 or 2, the derivative of the sulfonamide compound according to claim 8, or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating EGFR-mediated diseases.

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