A sulfonamide compound, a preparation method and application thereof, and a pharmaceutical composition

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a sulfonamide compound, a preparation method and application thereof, and a pharmaceutical composition. The sulfonamide compound provided by the application has the structure shown in formula I: wherein A is methyl or deuterated methyl; R is or wherein R1 and R2 are independently first C 1～4 alkyl, heteroarylalkyl, or R1 and R2 together with the N atom to which they are attached form a heterocyclyl, which is a substituted or unsubstituted five- or six-membered heterocyclyl, which contains 1-2 heteroatoms selected from N, O or S; when the heterocyclyl is a substituted heterocyclyl, the substituents in the substituted heterocyclyl are second C 1～4 alkyl, oxo, phenyl and acetyl. The sulfonamide compound provided by the application has good inhibitory activity on the activity of FAK kinase, and can well inhibit the proliferation and growth of tumor cells.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a sulfonamide compound, a preparation method and application thereof, and a pharmaceutical composition. BACKGROUND

[0002] Focal adhesion kinase (FAK) is a kind of cytoplasmic non-receptor protein tyrosine kinase (PTKs) belonging to the protein tyrosine kinase superfamily. FAK plays an important role in cell signal transduction, and is a central point of signals in and out of cells, mediating multiple signaling pathways. FAK can accept signals from integrins, growth factors and mechanical stimulation, activate intracellular PI3K / Akt, Ras / MAPK and other signaling pathways, and regulate cell growth. In addition, FAK is also related to embryonic development and tumor occurrence and migration. Therefore, FAK is considered as a potential new type of anti-cancer drug target.

[0003] Recent studies have found that FAK can be activated by various factors, including integrins, G protein-coupled receptors, etc. At the same time, FAK regulates intracellular P53, PI3K-AKT-mTOR and other signaling pathways through kinase-dependent and non-kinase-dependent two pathways, and participates in the biological processes of tumor cell survival, proliferation, metastasis, etc. The initial attempt is to down-regulate the expression of FAK in tumor cells to achieve the purpose of inhibiting tumors. By transfecting FAK with carboxy-terminal inactivation (FAK-CD), FAK is silenced, cell adhesion and proliferation are reduced, and the growth of breast cancer cells is inhibited in vivo experiments. By transfecting a plasmid containing FAK-silenced RNA (FAK-siRNA), cancer is inhibited in vivo. Simultaneous inhibition of the expression of FAK and FAK downstream signaling molecules (such as SRC) can enhance the anti-tumor effect.

[0004] Considering the important function of FAK in tumor cells, the reliability of gene transfection and the safety of viral vectors, small molecule inhibitors based on FAK signaling pathways have begun to appear, and good results have been achieved in recent years. At present, there are various FAK inhibitors as anti-tumor drugs in the preclinical research or clinical trial stage. It has been reported (Research Progress of Adhesion Focal Kinase FAK and Its Inhibitors as Anti-tumor New Targets, Chen Ying et al.) that TAE226, also known as NVP-226, can inhibit the activity of FAK by blocking the connection site of FAK and ATP and the Y397 and Y861 phosphorylation sites of FAK. However, there is still a need in the art to develop FAK inhibitors with better inhibitory activity or better pharmacokinetic properties. SUMMARY

[0005] Therefore, the application provides a sulfonamide compound, a preparation method and application thereof, and a pharmaceutical composition.

[0006] To solve the above technical problems, the application provides a sulfonamide compound having a structure shown in Formula I.

[0007]

[0008] A is methyl or deuterated methyl;

[0009] R is R1 and R2 are independently a first C 1～4 alkyl, heteroarylalkyl or R1 and R2 together with the N atom to which they are attached form a heterocyclyl, the heterocyclyl being a substituted or unsubstituted five- or six-membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S; when the heterocyclyl is a substituted heterocyclyl, the substituents in the substituted heterocyclyl are one or more of a second C 1～4 alkyl, oxo, phenyl and acetyl.

[0010] Preferably, the first C 1～4 alkyl is methyl, ethyl, propyl or allyl;

[0011] the heteroarylalkyl is pyridylmethyl;

[0012] the heterocyclyl is piperazinyl, morpholinyl, tetrahydropyrrolyl, piperidinyl or thiomorpholinyl;

[0013] the second C 1～4 alkyl is methyl or isopropyl.

[0014] Preferably, the substituted heterocyclyl is 2,6-dimethylmorpholinyl, methylpiperazinyl, isopropylpiperazinyl, acetyl piperazinyl, 2-piperazinonyl or tetrahydroisoquinolinyl.

[0015] Preferably, the sulfonamide compound has any one of structures shown in Formulas I-1 to I-23.

[0016]

[0017]

[0018]

[0019] The application further provides a preparation method of the sulfonamide compound.

[0020] 2,4,5-trichloropyrimidine, and N,N-diisopropylethylamine were dissolved in isopropanol to perform a nucleophilic substitution reaction to obtain compound 1;

[0021] Compound 1, 2-methoxy-4-nitroaniline, potassium phosphate, Xantphos ligand and a catalyst were dissolved in N,N-dimethylformamide to perform a C-N coupling reaction to obtain compound 2;

[0022] Compound 2, iron powder and ammonium chloride were dissolved in an ethanol / water solution to perform a nitro reduction reaction to obtain compound 3;

[0023] Compound 3 was dissolved in dichloromethane and mixed with chloroethylsulfonyl chloride and N-methylmorpholine to perform a sulfonamidation reaction to obtain compound 4;

[0024] When R is , compound 4 and R1R2NH were dissolved in a mixed solvent of dichloromethane and methanol to perform a first Michael addition reaction to obtain

[0025] When R is , R1R2NH, carbon disulfide and triethylamine were dissolved in N,N-dimethylformamide to perform a nucleophilic reaction and then mixed with compound 4 to perform a second Michael addition reaction to obtain

[0026] Compound 1 is Compound 2 is Compound 3 is Compound 4 is

[0027] Preferably, the molar ratio of the 2,4,5-trichloropyrimidine and N,N-diisopropylethylamine is 1:1 to 1.1; and the molar ratio of the 2,4,5-trichloropyrimidine and N,N-diisopropylethylamine is 1:1.05 to 1.2.

[0028] The temperature of the nucleophilic substitution reaction is 80 to 90°C, and the time is 5.5 to 6.5h.

[0029] Preferably, the catalyst is palladium acetate.

[0030] The temperature of the C-N coupling reaction is 115 to 125°C, and the time is 22 to 24h.

[0031] The present application also provides a pharmaceutical composition comprising a pharmaceutically active component and a pharmaceutically acceptable carrier or excipient; the pharmaceutically active component is the sulfonamide compound or its pharmaceutically acceptable salt as described in the above technical solution or the sulfonamide compound prepared by the preparation method as described in the above technical solution.​

[0032] The application also provides application of the sulfonamide compound or the pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating catalytic activity of protein kinase.

[0033] Preferably, the protein kinase is focal adhesion kinase.

[0034] The medicament for regulating catalytic activity of protein kinase is a medicament for treating or preventing cancer.

[0035] The application provides a sulfonamide compound having the structure shown in Formula I.

[0036] wherein A is methyl or deuterated methyl; R is wherein R1 and R2 are independently first C 1～4 alkyl, heteroarylalkyl, or R1 and R2 together with the N atom to which they are attached form a heterocyclyl group, which is a substituted or unsubstituted five- or six-membered heterocyclyl group, the heterocyclyl group containing 1-2 heteroatoms selected from N, O or S; when the heterocyclyl group is a substituted heterocyclyl group, the substituents in the substituted heterocyclyl group are one or more of second C 1～4 alkyl, oxo, phenyl and acetyl. The sulfonamide compound provided by the application has good inhibitory activity on FAK kinase and can well inhibit the proliferation and growth of tumor cells. DETAILED DESCRIPTION

[0037] The application provides a sulfonamide compound having the structure shown in Formula I.

[0038]

[0039] In the application, A is methyl or deuterated methyl, preferably methyl.

[0040] In the application, R is preferably In the application, R1 and R2 are independently first C 1～4 alkyl, heteroarylalkyl, or R1 and R2 together with the N atom to which they are attached form a heterocyclyl group, which is a substituted or unsubstituted five- or six-membered heterocyclyl group, the heterocyclyl group containing 1-2 heteroatoms selected from N, O or S; when the heterocyclyl group is a substituted heterocyclyl group, the substituents in the substituted heterocyclyl group are one or more of second C 1～4 alkyl, oxo, phenyl and acetyl.

[0041] In the application, the first C 1～4The alkyl group is preferably a methyl group, an ethyl group, a propyl group, or an allyl group. In the present application, the heteroarylalkyl group is preferably a pyridylmethyl group. In the present application, the heterocyclic group is preferably a piperazinyl group, a morpholinyl group, a tetrahydropyrrolyl group, a piperidinyl group, or a thiomorpholinyl group. In the present application, the second C 1～4 The alkyl group is a methyl group or an isopropyl group. In the present application, the substituted heterocyclic group is preferably a 2,6-dimethylmorpholinyl group, a methylpiperazinyl group, an isopropylpiperazinyl group, an acetyl piperazinyl group, a 2-piperazinonyl group, or a tetrahydroisoquinolinyl group.

[0042] In the present application, the sulfonamide compound preferably has a structure represented by any one of formulas I-1 to I-23:

[0043]

[0044]

[0045]

[0046] The present application also provides a preparation method of the sulfonamide compound according to the above technical solution, which comprises the following steps:

[0047] dissolving 2,4,5-trichloropyrimidine, and N,N-diisopropylethylamine in isopropanol to perform a nucleophilic substitution reaction, thereby obtaining compound 1;

[0048] dissolving the compound 1, 2-methoxy-4-nitroaniline, potassium phosphate, a Xantphos ligand, and a catalyst in N,N-dimethylformamide to perform a C-N coupling reaction, thereby obtaining compound 2;

[0049] dissolving the compound 2, iron powder, and ammonium chloride in an ethanol / water solution to perform a nitro reduction reaction, thereby obtaining compound 3;

[0050] dissolving the compound 3 in dichloromethane and mixing with chloroethylsulfonyl chloride and N-methylmorpholine to perform a sulfonamidation reaction, thereby obtaining compound 4;

[0051] when R is dissolving the compound 4 and R1R2NH in a mixed solvent of dichloromethane and methanol to perform a first Michael addition reaction, thereby obtaining

[0052] when R is dissolving R1R2NH, carbon disulfide, and triethylamine in N,N-dimethylformamide to perform a nucleophilic reaction, and then mixing with the compound 4 to perform a second Michael addition reaction, thereby obtaining

[0053] The compound 1 is Compound 2 is Compound 3 is Compound 4 is

[0054] The present application dissolves 2,4,5-trichloropyrimidine, and N,N-diisopropyl ethylamine in isopropyl alcohol to carry out a nucleophilic substitution reaction to obtain compound 1. In the present application, the molar ratio of the 2,4,5-trichloropyrimidine and is preferably 1:1-1.1, and more preferably 1:1.05-1.1. In the present application, the molar ratio of the 2,4,5-trichloropyrimidine and N,N-diisopropyl ethylamine (DIPEA) is preferably 1:1.05-1.2, and more preferably 1:1.05-1.1. The present application does not have special requirements for the amount of isopropyl alcohol, as long as it can completely dissolve the materials.

[0055] In the present application, the temperature of the nucleophilic substitution reaction is preferably 80-90℃, and more preferably 83-95℃; and the time of the nucleophilic substitution reaction is preferably 5.5-6.5h, and more preferably 6h.

[0056] In the present application, the equation of the nucleophilic substitution reaction is shown in formula 1:

[0057]

[0058] In the present application, after the nucleophilic substitution reaction, it preferably further comprises: mixing the nucleophilic substitution reaction system after cooling with water, carrying out solid-liquid separation on the mixed system, and sequentially washing and drying the solid obtained by the solid-liquid separation to obtain the compound 1. In the present application, the temperature after cooling is preferably room temperature, and the temperature of the room temperature is preferably 20-35℃, and more preferably 25-30℃. In the present application, the volume ratio of the nucleophilic substitution reaction system after cooling and water is preferably 1:4-6, and more preferably 1:4.5-5.2. The present application does not have special requirements for the mixing as long as it can be uniformly mixed. The present application will precipitate light yellow solid after mixing the nucleophilic substitution reaction system after cooling with water. In the present application, the solid-liquid separation is preferably suction filtration. In the present application, the washing solvent is preferably water. In the present application, the drying is preferably reduced pressure drying. The present application does not have special requirements for the reduced pressure drying, and the conventional method in the art can be used.

[0059] After obtaining compound 1, the present application dissolves compound 1, 2-methoxy-4-nitroaniline, potassium phosphate, Xantphos ligand and catalyst in N,N-dimethylformamide to perform C-N coupling reaction to obtain compound 2. In the present application, the catalyst is preferably palladium acetate. In the present application, the molar ratio of compound 2 and 2-methoxy-4-nitroaniline is preferably 1:1-1.1, more preferably 1:1.05-1.1. In the present application, the molar ratio of 2-methoxy-4-nitroaniline and potassium phosphate is preferably 1:2-2.5, more preferably 1:2-2.1. In the present application, the molar ratio of 2-methoxy-4-nitroaniline and Xantphos ligand is preferably 1:0.13-0.15, more preferably 1:0.14-0.15. The present application does not have special limitation on the amount of N,N-dimethylformamide (DMF) as long as the material can be completely dissolved.

[0060] In the present application, the temperature of C-N coupling reaction is preferably 115-125°C, more preferably 120°C; the time of C-N coupling reaction is preferably 22-24h, more preferably 23h. In the present application, the C-N coupling reaction is preferably performed under protective atmosphere, which is preferably nitrogen or argon, more preferably argon.

[0061] In the present application, the equation of C-N coupling reaction is shown in formula 2:

[0062]

[0063] In the present application, the C-N coupling reaction preferably further comprises the following steps after C-N coupling reaction: filtering the system after C-N coupling reaction, mixing the filtrate and water to perform crystallization, then performing solid-liquid separation, drying the solid obtained by solid-liquid separation to obtain compound 2. The present application does not have special requirement on the filtering, which can be performed by conventional method in the art. The present application preferably washes the solid obtained by filtering with acetone. The present application does not have special limitation on the crystallization, which can be performed by conventional method in the art. In the present application, the solid-liquid separation is preferably filtering. In the present application, the drying is preferably reduced pressure drying.

[0064] After obtaining compound 2, the present application dissolves compound 2, iron powder and ammonium chloride in an ethanol / water solution to perform a nitro reduction reaction to obtain compound 3. In the present application, the mass concentration of the ethanol / water solution is preferably 70-80%, more preferably 75-78%. In the present application, the molar ratio of compound 2, iron powder and ammonium chloride is preferably 1:1.3-1.5:2.8-3.2, more preferably 1:1.4:3. In the present application, the temperature of the nitro reduction reaction is preferably 85-95°C, more preferably 90°C; the time of the nitro reduction reaction is preferably 21-23h, more preferably 22h. In the present application, the nitro reduction reaction is preferably accompanied by reflux.

[0065] In the present application, the equation of the nitro reduction reaction is shown in formula 3:

[0066]

[0067] In the present application, after the nitro reduction reaction, preferably further comprises: cooling the system after the nitro reduction reaction, filtering through diatomite, mixing the filtrate and water to perform crystallization, performing solid-liquid separation, drying the solid obtained by the solid-liquid separation to obtain compound 3. The present application has no special requirements for the filtering, which can be performed by using conventional methods in the art. The present application preferably washes the solid obtained by the filtering with methyl ketone. The present application has no special limitation for the crystallization, which can be performed by using conventional methods in the art. In the present application, the solid-liquid separation is preferably suction filtration. In the present application, the drying is preferably vacuum drying, the temperature of the vacuum drying is preferably 38-42°C, more preferably 40°C; the time of the vacuum drying is preferably 7.5-8.5h, more preferably 8h.

[0068] After obtaining compound 3, the present application dissolves compound 3 in dichloromethane, mixes with chloroethylsulfonyl chloride and N-methylmorpholine to perform a sulfonamidation reaction to obtain compound 4. The present application has no special limitation for the amount of dichloromethane, as long as the material can be completely dissolved. In the present application, the mixing preferably comprises the following steps: first mixing N-methylmorpholine and compound 3 in a dichloromethane system to obtain a first mixed solution; adding chloroethylsulfonyl chloride dropwise to the mixed solution. In the present application, the molar ratio of compound 3 and N-methylmorpholine is preferably 1:2.8-3.2, more preferably 1:3. In the present application, the molar ratio of compound 3 and chloroethylsulfonyl chloride is preferably 1:1-1.5, more preferably 1:1.1-1.3. In the present application, the temperature of the dropwise addition is preferably 0°C, and the rate of the dropwise addition is preferably 4-6s per drop, more preferably 5s per drop.

[0069] In the present application, the temperature of the sulfonylating reaction is preferably room temperature, and the temperature of the room temperature is preferably 20-35°C, more preferably 25-30°C; the time of the sulfonylating reaction is preferably 5.5-6.5h, more preferably 6h. In the present application, the time of the sulfonylating reaction is preferably calculated from the completion of the dropwise addition of chloroethylsulfonyl chloride.

[0070] In the present application, the equation of the sulfonylating reaction is shown in Formula 4:

[0071]

[0072] In the present application, the sulfonylating reaction preferably further comprises, after the sulfonylating reaction, mixing the sulfonylating reaction system with water, extracting with dichloromethane, washing the organic phase obtained by the extraction with saturated brine, drying, and column chromatography separation and purification of the dried product to obtain compound 4. In the present application, the number of extractions is preferably 2-4, more preferably 3. In the present application, the drying is preferably mixing the washed product with anhydrous sodium sulfate. In the present application, the column chromatography uses a mixture of ethyl acetate and petroleum ether in a volume ratio of 2:1 as the eluent.

[0073] When R is , the present application dissolves compound 4 and R1R2NH in a mixed solvent of dichloromethane and methanol to perform a first Michael addition reaction to obtain In the present application, the volume percentage of dichloromethane in the mixed solvent of dichloromethane and methanol is preferably 60-70%, more preferably 65-67%. In the present application, the molar ratio of compound 4 to R1R2NH is preferably 1:1.5-2.5, more preferably 1:2. In the present application, the temperature of the first Michael addition reaction is preferably room temperature, and the temperature of the room temperature is preferably 20-35°C, more preferably 25-30°C; the time of the first Michael addition reaction is preferably 3.5-4.5h, more preferably 4h.

[0074] In the present application, the equation of the first Michael addition reaction is shown in Formula 5:

[0075]

[0076] In the present application, the first Michael addition reaction preferably further comprises, after the first Michael addition reaction, concentrating the system and performing column chromatography separation and purification. The present application does not have a special limitation on the method of concentration, as long as the solvent in the system can be removed. In the present application, the column chromatography uses a combination of ethyl acetate and petroleum ether as the eluent.

[0077] When R is The present application dissolves R1R2NH, carbon disulfide and triethylamine in N, N-dimethylformamide, and then carries out a second Michael addition reaction with compound 4 after a nucleophilic reaction to obtain In the present application, the molar ratio of R1R2NH, carbon disulfide and triethylamine is preferably 1:1.4-1.6:1.8-2.2, and more preferably 1:1.5:2. In the present application, the molar ratio of R1R2NH and compound 4 is preferably 1:0.4-0.6, and more preferably 1:0.5.

[0078] In the present application, the temperature of the nucleophilic reaction is preferably room temperature, and the temperature of the room temperature is preferably 20-35°C, and more preferably 25-30°C. The time of the nucleophilic reaction is preferably 0.4-0.6h, and more preferably 0.5h. In the present application, the temperature of the second Michael addition reaction is preferably room temperature, and the temperature of the room temperature is preferably 20-35°C, and more preferably 25-30°C. The time of the second Michael addition reaction is preferably 5.5-6.5h, and more preferably 6h.

[0079] In the present application, the equations of the nucleophilic reaction and the second Michael addition reaction are shown in formula 6:

[0080]

[0081] In the present application, after the second Michael addition reaction, preferably further comprising: mixing the system after the second Michael addition reaction with water, and then carrying out extraction with dichloromethane, washing the organic phase obtained by the extraction with saturated brine, drying, and then carrying out column chromatography separation and purification of the dried product to obtain In the present application, the number of extractions is preferably 2-4 times, and more preferably 3 times. In the present application, the drying is preferably mixing the washed product with anhydrous sodium sulfate.

[0082] The application further provides a pharmaceutical composition comprising a pharmaceutically active component and a pharmaceutically acceptable carrier or excipient; the pharmaceutically active component is the sulfamide compound or the pharmaceutically acceptable salt thereof as described in the above technical solution or the sulfamide compound prepared by the preparation method as described in the above technical solution. In the application, the pharmaceutically acceptable salt is a salt generated by the reaction of the sulfamide compound with an inorganic acid or an organic acid. In the application, the inorganic acid is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid or phosphoric acid; and the organic acid is preferably citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetyloxybenzoic acid or isethionic acid.

[0083] The application does not have special requirements for the carrier and the excipient, which can be selected according to the form of the medicine. In the application, the form of the pharmaceutical composition is preferably solid, semi-solid, liquid or gaseous; and the dosage form of the pharmaceutical composition is preferably tablet, pill, lozenge, sugar-coated pill, capsule, powder, granule, paste, emulsion, suspension, solution, suppository, injection, inhaler, gel, microsphere or aerosol.

[0084] The application does not have special requirements for the preparation method of the pharmaceutical composition, which can be prepared by the conventional method in the art, specifically mixing method, dissolving method, granulation method, sugar-coated pill preparation method, grinding method, emulsification method or freeze-drying method.

[0085] The solid oral pharmaceutical composition of the present application is preferably prepared by a conventional mixing, filling or tableting method. For example, it can be obtained by mixing the pharmaceutical active ingredient with solid excipients and obtaining a pharmaceutical composition by milling. In the present application, an auxiliary agent can be preferably added during the mixing process to prepare a granular pharmaceutical composition. The granular pharmaceutical composition of the present application is processed to obtain a tablet or a sugar-coated agent. In the present application, the auxiliary agent preferably includes a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetening agent or a flavoring agent. In the present application, the auxiliary agent is particularly preferably microcrystalline cellulose, a glucose solution, gum arabic, a gelatin solution, sucrose, a starch paste, talc, starch, magnesium stearate, calcium stearate, stearic acid, lactose, sucrose, starch, mannitol, sorbitol, dicalcium phosphate, silicon dioxide, sodium croscarmellose, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl cellulose or cross-linked polyvinyl pyrrolidone. The granular pharmaceutical composition of the present application is preferably coated; the coating method of the present application is not particularly limited and a conventional method in the art can be used, and the coating is preferably an enteric coating.

[0086] In the present application, the pharmaceutical composition can also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product for parenteral administration.

[0087] In the present application, the administration route of the pharmaceutical composition preferably includes oral administration, rectal administration, transmucosal administration, enteral administration or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0088] The present application also provides the use of the sulfamide compound or a pharmaceutically acceptable salt thereof according to the above technical solution or the sulfamide compound prepared by the preparation method according to the above technical solution in the preparation of a medicament for regulating the catalytic activity of a protein kinase. In the present application, the protein kinase is preferably a focal adhesion kinase; the medicament for regulating the catalytic activity of a protein kinase is preferably a medicament for treating or preventing cancer; the cancer is preferably colon cancer, cervical cancer, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer, osteosarcoma, melanoma, kidney cancer, gastric cancer, liver cancer, bladder cancer, thyroid cancer or large intestine cancer.

[0089] In order to further illustrate the present application, the technical solutions provided by the present application are described in detail below in conjunction with examples, but they should not be understood as limiting the scope of protection of the present application.

[0090] Example 1

[0091] 2-amino-N-methylbenzamide (1.58 g, 10 mmol) and 2,4,5-trichloropyrimidine (1.83 g, 10 mmol) were dissolved in 20 mL of isopropanol, DIPEA (N,N-diisopropylethylamine) (2 mL, 12 mmol) was added, and the system was heated to reflux (nucleophilic substitution reaction) at 85°C for 6 h; after the nucleophilic substitution reaction, the system was cooled to room temperature, 100 mL of water was added, a light yellow solid was precipitated, and the solid was filtered, washed with water, and dried under reduced pressure to obtain 2-((2,5-dichloropyrimidin-4-yl)amino)-N-methylbenzamide as a light yellow solid 2.64 g, yield 88%. 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.87 (d, J = 4.4 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.46 (s, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.62-7.58 (m, 1H), 7.22 (t, J = 7.4 Hz, 1H), 2.84 (d, J = 4.4 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 168.69, 156.62, 156.13, 155.26, 138.30, 131.82, 128.10, 123.07, 120.96, 120.78, 114.92, 26.34;

[0092] 2-methoxy-4-nitroaniline (1.59 g, 9.45 mmol) and 2-((2,5-dichloropyrimidin-4-yl)amino)-N-methylbenzamide (2.68 g, 9 mmol), potassium phosphate (3.82 g, 18 mmol), Xantphos (0.78 g, 1.35 mmol), and Pd(OAc)2(0.30 g, 1.35 mmol) were dissolved in DMF (25 mL), and a C-N coupling reaction was carried out at 120°C under the protection of argon for 23 h; the system after the C-N coupling reaction was filtered, the filter cake was washed with acetone, the filtrate and the washing liquid were added to 200 mL of water, and a large amount of light yellow solid was precipitated; the solid was filtered, washed with water, and dried under reduced pressure to obtain 2-((5-chloro-2-((2-methoxy-4-nitrophenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide as a light yellow solid 3.25 g, yield 84%;

[0093] Into a 100 mL round bottom flask, 2-((5-chloro-2-((2-methoxy-4- nitrophenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (3.22 g, 7.5 mmol), NH4Cl (0.57 g, 10.5 mmol) and iron powder (1.26 g, 22.5 mmol) were added, 30 mL of ethanol and 10 mL of water were added, and the reaction was refluxed at 90 °C for 22 h (nitro reduction reaction). After the nitro reduction reaction, the system was cooled to room temperature, filtered through diatomite, and the filter cake was washed with methanol. The filtrate and washing liquid were added to 200 mL of water, and a light green solid was precipitated. The filter cake was filtered under suction, washed with water, and the filter cake was dried under vacuum at 40 °C for 8 h to obtain 2-((2-((4-amino-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-N- methylbenzamide as a light green solid. 1.50 g, 50% yield;

[0094] Into a 100 mL round bottom flask, 2-((5-chloro-2-((2-methoxy-4- nitrophenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (3.22 g, 7.5 mmol), NH4Cl (0.57 g, 10.5 mmol) and iron powder (1.26 g, 22.5 mmol) were added, 30 mL of ethanol and 10 mL of water were added, and the reaction was refluxed at 90 °C for 22 h (nitro reduction reaction). After the nitro reduction reaction, the system was cooled to room temperature, filtered through diatomite, and the filter cake was washed with methanol. The filtrate and washing liquid were added to 200 mL of water, and a light green solid was precipitated. The filter cake was filtered under suction, washed with water, and the filter cake was dried under vacuum at 40 °C for 8 h to obtain 2-((2-((4-amino-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-N- methylbenzamide as a light green solid. 1.53 g, 56% yield; 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.90 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.74 (dd, J = 7.8, 1.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.85 - 6.75 (m, 2H), 6.14 (d, J = 16.4 Hz, 1H), 6.04 (d, J = 10.0 Hz, 1H), 3.76 (s, 3H), 2.81 (d, J = 4.4 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.91, 158.46, 154.95, 154.67, 151.76, 139.41, 136.31, 134.16, 131.34, 127.90, 127.53, 124.64, 124.48, 121.70, 121.09, 120.40, 111.96, 104.70, 104.21, 55.48, 26.30;

[0095] Michael addition was carried out by dissolving 2-((5-chloro-2-((2-methoxy-4- (vinylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (0.25 g, 0.5 mmol) in 4 mL of dichloromethane and 2 mL of methanol, and adding morpholine (87 mg, 1 mmol) at room temperature for 4 h; after the reaction was completed, the reaction system was concentrated, and column chromatography (eluent: ethyl acetate-petroleum ether) was used for separation and purification to obtain 2-((5-chloro-2-((2-methoxy-4-((2-morpholinoethyl)sulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide as a gray solid 0.15 g, yield 52%. 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.69 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.74-7.72 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.0 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 8.4, 2.0 Hz, 1H), 3.77 (s, 3H), 3.50-3.48 (m, 4H), 3.30-3.26 (m, 2H), 2.80 (d, J = 4.4 Hz, 3H), 2.73-2.69 (m, 2H), 2.32 (s, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 168.88, 158.47, 154.94, 154.68, 154.68, 151.95, 139.42, 134.58, 131.27, 127.88, 124.63, 124.58, 121.58, 121.04, 120.37, 111.85, 104.69, 104.16, 65.95, 55.50, 52.87, 51.91, 47.74, 26.28; HRMS m / z: C 25 H 31CIN7O5S calcd for [M+H] 336.0307; found: 336.0307. + :576.1796; found: 576.1785.

[0096] Example 2

[0097] 2-((5-chloro-2-((2-methoxy-4-((2-(piperidin-l-yl)ethyl)sulfonamido)phenyl)amino)pyrimidin-4- yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that piperidine is used instead of morpholine as the starting material, with a yield of 59%. 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.68 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.73 (dd, J = 7.8, 1.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 8.4, 2.0 Hz, 1H), 3.76 (s, 3H), 3.26 - 3.22 (m, 2H), 2.80 (d, J = 4.4 Hz, 3H), 2.70 - 2.67 (m, 2H), 2.28 (s, 4H), 1.43 - 1.40 (m, 4H), 1.32 (d, J = 4.8 Hz, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 158.45, 154.94, 154.67, 151.85, 139.44, 134.55, 131.26, 127.87, 124.64, 124.55, 121.63, 121.02, 120.33, 111.91, 104.68, 104.22, 55.48, 53.58, 52.20, 47.85, 26.27, 25.36, 23.69; HRMS m / z: C 26 H 33 CIN7O4S calcd for [M+H] 336.0307; found: 336.0307. + :574.2003; found: 574.1993.

[0098] Example 3

[0099] 2-((5-chloro-2-((2-methoxy-4-((2-(4-methylpiperazin-l-yl)ethyl)sulfonamido)phenyl)amino)pyrimidin-4- yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that 1 -methylpiperazine is used instead of raw material morpholine, and the yield is 47%. 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.70 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.74-7.73 (m, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 8.6, 2.2 Hz, 1H), 3.77 (s, 3H), 3.27-3.23 (m, 2H), 2.81 (d, J = 4.4 Hz, 3H), 2.72-2.69 (m, 2H), 2.33 (s, 4H), 2.24 (s, 4H), 2.10 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 168.88, 158.44, 154.95, 154.67, 151.80, 139.43, 134.50, 131.27, 127.88, 124.67, 124.49, 121.66, 121.05, 120.37, 111.94, 104.70, 104.26, 55.50, 54.44, 52.30, 51.50, 47.97, 45.61, 26.28; HRMS m / z: C 26 H 34 ClN8O4S calcd for [M+H] + : 589.2112; found: 589.2101.

[0100] Example 4

[0101] 2-((5-chloro-2-((4-((2-(4-isopropylpiperazin-l-yl)ethyl)sulfonamido)-2- methoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that 1 -isopropylpiperazine is used instead of raw material morpholine, and the yield is 42%. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.67 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 8.4, 2.0 Hz, 1H), 3.77 (s, 3H), 3.27 - 3.24 (m, 2H), 2.80 (d, J = 4.4 Hz, 3H), 2.72 - 2.69 (m, 2H), 2.37 (s, 9H), 0.96 (s, 3H), 0.94 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 168.86, 158.44, 154.94, 154.66, 151.81, 139.43, 134.53, 131.28, 127.87, 124.64, 124.48, 121.66, 121.02, 120.33, 111.89, 104.71, 104.19, 55.49, 51.42, 47.93, 47.64, 47.28, 40.70, 26.27, 17.87; HRMS m / z: [M+H] C 28 H 38 ClN8O4S calcd for [M+H] + : 617.2425; found: 617.2411.

[0102] Example 5

[0103] 2-((5-chloro-2-((4-((2-(dimethylamino)ethyl)sulfonamido)-2- methoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that dimethylamine 2M in tetrahydrofuran solution was used instead of the starting material morpholine, with a yield of 59%. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.69 (s, 1H), 8.73 (s, 1H), 8.57 (d, J = 6.4 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.37 (s, 1H), 7.10 (s, 1H), 6.95 (s, 1H), 6.83 (d, J = 7.6 Hz, 1H), 3.78 (s, 3H), 3.24 (s, 2H), 2.81 (s, 3H), 2.68 (s, 2H), 2.11 (s, 6H); 13 C NMR (101 MHz, DMSO-d6) δ 168.89, 158.45, 154.95, 154.67, 151.83, 139.41, 134.51, 131.27, 127.89, 124.71, 124.53, 121.66, 121.04, 120.37, 112.03, 104.70, 104.34, 55.49, 52.63, 48.14, 44.73, 26.28; HRMS m / z: [M+H] C 23 H 29 ClN7O4S calcd for [M+H] + : 534.1690; found: 534.1681.

[0104] Example 6

[0105] 2-((5-Chloro-2-((4-((2-(diethylamino)ethyl)sulfonamido)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that diethylamine was used instead of morpholine as the starting material, with a yield of 64%. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.68 (s, 1H), 8.73 (d, J = 3.6 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.95 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.21 - 3.17 (m, 2H), 2.87 - 2.81 (m, 5H), 2.39 (dd, J = 14.0, 6.8 Hz, 4H), 0.89 (t, J = 7.0 Hz, 6H); 13 C NMR (100 MHz, DMSO-d6) δ 168.88, 158.43, 154.95, 154.67, 151.79, 139.43, 134.52, 131.26, 127.88, 124.68, 124.45, 121.64, 121.02, 120.35, 111.83, 104.71, 104.13, 55.47, 47.44, 46.14, 45.78, 26.28, 11.79; HRMS m / z: [M+H] C 25 H 33 ClN7O4S calcd for [M+H] + : 562.2003; found: 562.1993.

[0106] Example 7

[0107] 2-((5-chloro-2-((2-methoxy-4-((2-(pyrrolidin-l- yl)ethyl)sulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that pyrrolidine is used instead of morpholine as starting material, with a yield of 60%. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 2.0 Hz, 1H), 3.77 (s, 3H), 3.28 - 3.25 (m, 2H), 2.83 - 2.79 (m, 5H), 2.39 (s, 4H), 1.63 (s, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 168.89, 158.47, 154.95, 154.68, 151.87, 139.44, 134.61, 131.27, 127.88, 124.62, 124.57, 121.63, 121.03, 120.36, 111.80, 104.69, 104.13, 55.48, 53.31, 49.39, 49.19, 26.28, 23.10; HRMS m / z: C 25 H 31 ClN7O4Scalcd for [M+H] + : 560.1847; found: 560.1837.

[0108] Example 8

[0109] 2-((5-chloro-2-((2-methoxy-4-((2- thiomorpholinoethyl)sulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N- methylbenzamide was prepared according to the procedure of Example 1 The difference is that thiomorpholine is used instead of the starting material morpholine, with a yield of 64%. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.68 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 8.6, 2.2 Hz, 1H), 3.77 (s, 3H), 3.33 - 3.25 (m, 2H), 2.81 (d, J = 4.4 Hz, 3H), 2.78 - 2.75 (m, 2H), 2.59 - 2.58 (m, 4H), 2.53 - 2.52 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 168.88, 158.45, 154.94, 154.67, 151.83, 139.43, 134.53, 131.26, 127.88, 124.64, 124.53, 121.66, 121.03, 120.37, 111.81, 104.71, 104.15, 55.50, 54.08, 52.27, 47.51, 26.97, 26.28; HRMS m / z: C 25 H 31 ClN7O4S2 calcd for [M+H] + : 592.1567; found: 592.1559.

[0110] Example 9

[0111] 2-((5-chloro-2-((4-((2-((2S,6R)-2,6-dimethylmorpholino)ethyl)sulfonamido)-2- methoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that cis-2,6-dimethylmorpholine was used instead of morpholine as starting material, with a yield of 56%. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.70 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.76-7.74 (m, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.85 (dd, J = 8.6, 2.2 Hz, 1H), 3.79 (s, 3H), 3.47-3.43 (m, 2H), 3.31-3.28 (m, 2H), 2.82 (d, J = 4.4 Hz, 3H), 2.72-2.68 (m, 2H), 2.62 (d, J = 10.4 Hz, 2H), 1.58 (t, J = 10.6 Hz, 2H), 0.97 (d, J = 6.4 Hz, 6H); 13 C NMR (100 MHz, DMSO-d6) δ 168.89, 158.45, 154.96, 154.65, 151.80, 139.48, 134.55, 131.28, 127.89, 124.61, 124.49, 121.65, 121.04, 120.33, 111.72, 104.75, 104.00, 70.79, 58.55, 55.49, 51.47, 47.64, 26.30, 18.81; HRMS m / z: [M+H] C 27 H 35 ClN7O5S calcd for [M+H] + : 604.2109; found: 604.2098.

[0112] Example 10

[0113] 2-((5-chloro-2-((4-((2-(di-n-propylamino)ethyl)sulfonamido)-2- methoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 except that di-n-propylamine was used instead of morpholine, in 61% yield. 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.68 (s, 1H), 8.73 (d, J = 4.0 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H), 3.21 - 3.18 (m, 2H), 2.87 - 2.81 (m, 5H), 2.25 (t, J = 7.0 Hz, 4H), 1.29 (dt, J = 14.4, 7.2 Hz, 4H), 0.75 (t, J = 7.4 Hz, 6H); 13 C NMR (100 MHz, DMSO-d6) δ 168.88, 158.41, 154.95, 154.66, 151.76, 139.47, 134.51, 131.25, 127.88, 124.70, 124.40, 121.63, 121.01, 120.22, 111.73, 104.74, 104.04, 55.46, 54.95, 47.17, 46.78, 26.28, 19.89, 11.56; HRMS m / z: C 27 H 37 ClN7O4S calcd for [M+H] + : 590.2316; found: 590.2307.

[0114] Example 11

[0115] 2-((5-chloro-2-((4-((2-(diallylamino)ethyl)sulfonamido)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that diallylamine was used instead of morpholine as starting material, in a yield of 54%. 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.69 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.93 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.78 - 5.68 (m, 2H), 5.13 - 5.06 (m, 4H), 3.78 (s, 3H), 3.26 - 3.22 (m, 2H), 3.00 (d, J = 6.0 Hz, 4H), 2.87 - 2.81 (m, 5H); 13 C NMR (100 MHz, DMSO-d6) δ 168.89, 158.44, 154.96, 154.66, 151.76, 139.46, 135.26, 134.47, 131.29, 127.89, 124.65, 124.42, 121.65, 121.04, 120.34, 117.65, 111.77, 104.73, 104.05, 55.93, 55.48, 47.59, 46.30, 26.29; HRMS m / z: C 27 H 33 ClN7O4S calcd for [M+H] + : 586.2003; found: 586.1993.

[0116] Example 12

[0117] 2-((5-chloro-2-((4-((2-(3,4-dihydroisoquinolin-2(lH)-yl)ethyl)sulfonamido)-2- methoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that tetrahydroisoquinoline was used instead of morpholine as starting material, with a yield of 51%. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.72 (s, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.09 - 7.06 (m, 4H), 6.96 - 6.92 (m, 2H), 6.83 (dd, J = 8.6, 2.2 Hz, 1H), 3.72 (s, 3H), 3.53 (s, 2H), 3.40 - 3.36 (m, 2H), 2.92 - 2.89 (m, 2H), 2.80 (d, J = 4.4 Hz, 3H), 2.74 (t, J = 5.4 Hz, 2H), 2.64 (t, J = 5.6 Hz, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 168.86, 158.45, 154.94, 154.66, 151.82, 139.43, 134.51, 134.36, 133.79, 131.28, 128.32, 127.85, 126.28, 125.93, 125.40, 124.67, 124.48, 121.63, 121.01, 120.32, 111.92, 104.65, 104.27, 55.42, 54.91, 51.32, 50.05, 48.10, 28.40, 26.27; HRMS m / z: C 30 H 33 ClN7O4Scalcdfor[M+H] + : 622.2003; found: 622.1991.

[0118] Example 13

[0119] 2-((5-chloro-2-((2-methoxy-4-((2-(methyl(piperidin-4-ylmethyl)amino)ethyl)sulfonyl)amino)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that N-methyl-3-piperidin-4-ylmethylamine was used instead of the starting material morpholine, with a yield of 49%. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.69 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.44 (dd, J = 4.6, 1.4 Hz, 2H), 8.28 (s, 1H), 8.16 (s, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.64 - 7.60 (m, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.29 (dd, J = 7.6, 4.8 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.4, 2.4 Hz, 1H), 3.75 (s, 3H), 3.49 (s, 2H), 3.32 - 3.30 (m, 2H), 2.81 - 2.78 (m, 5H), 2.08 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 168.87, 158.45, 154.94, 154.67, 151.82, 149.91, 148.30, 139.41, 136.38, 133.70, 131.28, 127.87, 124.70, 124.51, 123.30, 121.66, 121.02, 120.36, 111.90, 104.70, 104.23, 57.80, 55.46, 50.30, 47.96, 41.37, 26.27; HRMS m / z: [M+H] C 28 H 32 ClN8O4S calcd for [M+H] + : 611.1956; found: 611.1943.

[0120] Example 14

[0121] 2-((2-((4-((2-(4-acetylpiperazin-l-yl)ethyl)sulfonamido)-2-methoxyphenyl)amino)-5- chloropyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that 1-acetylpiperazine was used instead of morpholine as starting material, with a yield of 49%. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.69 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 8.4, 2.0 Hz, 1H), 3.77 (s, 3H), 3.29 - 3.27 (m, 6H), 2.81 (d, J = 4.4 Hz, 3H), 2.76 - 2.73 (m, 2H), 2.34 - 2.27 (m, 4H), 1.95 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 168.88, 168.05, 158.47, 154.94, 154.67, 151.88, 139.42, 134.56, 131.27, 127.87, 124.63, 124.59, 121.67, 121.03, 120.37, 111.83, 104.70, 104.12, 55.50, 52.49, 52.01, 51.42, 47.81, 45.43, 40.59, 26.28, 21.08; HRMS m / z: [M+H] C 27 H 34 ClN8O5S calcd for [M+H] + : 617.2061; found: 617.2049.

[0122] Example 15

[0123] 2-((5-chloro-2-((2-methoxy-4-((2-(3-oxopiperazin-l-yl)ethyl)sulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 The difference is that 2-piperazinone was used instead of the starting material morpholine, with a yield of 49%. 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.69 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.73 (d, J = 6.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 8.6, 2.2 Hz, 1H), 3.77 (s, 3H), 3.33 - 3.29 (m, 4H), 3.06 (s, 2H), 2.93 (s, 2H), 2.81 - 2.77 (m, 5H); 13 CNMR (100 MHz, DMSO-d6) δ 168.89, 167.33, 158.45, 154.94, 154.68, 151.81, 139.38, 134.47, 131.29, 127.88, 124.68, 124.48, 121.69, 121.07, 120.43, 111.94, 104.70, 104.29, 56.27, 55.49, 50.52, 48.34, 47.82, 26.28; HRMS m / z: C 25 H 30 ClN8O5S calcd for [M+H] + : 589.1748; found: 589.1736.

[0124] Example 16

[0125] 2-((5-chloro-2-((2-methoxy-4-(vinylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N- methylbenzamide was prepared according to the procedure of Example 1;

[0126] Sulfur (0.11 g, 1 mmol) was dissolved in 10 mL of N,N-dimethylformamide, triethylamine (0.29 mL, 2 mmol) and carbon disulfide (0.12 g, 1.5 mmol) were added, and the reaction was allowed to proceed at room temperature for 0.5 h. 2-((5-chloro-2-((2-methoxy-4-(vinylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (0.25 g, 0.5 mmol) was added, and the reaction was allowed to proceed at room temperature for 6 h. After the reaction was completed, 100 mL of water was added to the reaction solution, and the mixture was extracted with 15 mL of dichloromethane three times. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then column chromatography was performed to isolate and purify the product, thereby obtaining 2-(N-(4-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)sulfamoyl)ethyl-thiomorpholine-4-carbodithioate as a light yellow solid

[0127] 0.18 g, 53% yield.

[0128] 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.90 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 8.4, 2.0 Hz, 1H), 4.46 (s, 2H), 4.15 (s, 2H), 3.78 (s, 3H), 3.66-3.62 (m, 2H), 3.50-3.46 (m, 2H), 2.81 (d, J = 4.4 Hz, 3H), 2.70-2.67 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 193.58, 168.86, 158.35, 154.93, 154.63, 151.59, 139.38, 134.08, 131.29, 127.84, 124.78, 124.19, 121.65, 121.07, 120.37, 112.20, 104.73, 104.43, 55.51, 52.94, 52.80, 49.93, 29.48, 26.26; HRMS m / z: [M+H] C 26 H 31 CIN7O4S4 calcd for [M+H] +: 668.1009; found: 668.1000.

[0129] Example 17

[0130] Example 16 was followed to prepare 2-(N-(4-((5-chloro-4-((2- (methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-3- methoxyphenyl)sulfamoyl)ethyl-3,4-dihydroisoquinoline-2(lH)-carbodithioate The difference is that tetrahydroisoquinoline is used instead of starting material thiomorpholine, and the yield is 60%. 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.90 (s, 1H), 8.72 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.21 (s, 4H), 7.08 (t, J = 7.4 Hz, 1H), 6.97 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.22 (s, 1H), 4.97 (s, 1H), 4.27 (s, 1H), 3.97 (s, 1H), 3.78 (s, 3H), 3.69-3.65 (m, 2H), 3.52-3.48 (m, 2H), 2.93 (s, 2H), 2.81 (d, J = 4.4 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 193.23, 168.85, 158.32, 154.92, 154.60, 151.53, 139.35, 134.49, 134.05, 132.62, 131.28, 127.83, 127.71, 127.01, 126.38, 124.79, 124.11, 124.01, 121.64, 121.06, 120.37, 112.24, 104.74, 104.45, 55.50, 53.27, 51.01, 49.91, 47.80, 28.12, 26.25; HRMS m / z: C 31 H 33 ClN7O4S3 calcd for [M+H] + : 698.1445; found: 698.1434.

[0131] Example 18

[0132] Prepared according to the procedure of Example 16. Yield: 59%. The difference is that diethylamine is used instead of the starting material thiomorpholine. Yield: 59%. 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.88 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.8, 2.1 Hz, 1H), 3.91 (q, J = 6.8 Hz, 2H), 3.78 (s, 3H), 3.68 (dd, J = 14.0, 6.8 Hz, 2H), 3.61 - 3.57 (m, 2H), 3.48 - 3.44 (m, 2H), 2.81 (d, J = 4.4 Hz, 3H), 1.19 - 1.12 (m, 6H); 13 CNMR (100 MHz, DMSO-d6) δ 192.36, 168.88, 158.38, 154.94, 154.67, 151.38, 139.40, 134.13, 131.31, 127.85, 124.78, 124.25, 121.66, 121.08, 120.37, 112.21, 104.71, 104.44, 55.51, 50.03, 49.14, 46.56, 29.40, 26.27, 12.28, 11.25; HRMS m / z: C 26 H 33 ClN7O4S3 calcd for [M+H] + : 638.1445; found: 638.1432.

[0133] Example 19

[0134] Prepared according to the procedure of Example 16. Yield: 59%. The difference is that cis-2,6-dimethylmorpholine is used instead of the starting material thiomorpholine. Yield: 67%.1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.89 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.4, 2.0 Hz, 1H), 5.17 (s, 1H), 4.26 (s, 1H), 3.77 (s, 3H), 3.65 - 3.61 (m, 2H), 3.52 - 3.44 (m, 4H), 2.97 (s, 1H), 2.80 (d, J = 4.4 Hz, 4H), 1.11 (d, J = 6.0 Hz, 6H); 13 CNMR (100 MHz, DMSO-d6) δ 193.79, 168.87, 158.35, 154.94, 154.65, 151.58, 124.80, 124.17, 121.67, 121.07, 120.36, 112.20, 104.74, 104.44, 70.65, 55.52, 54.68, 49.90, 29.26, 26.27, 18.29; HRMS m / z: C 28 H 35 ClN7O5S3 calcd for [M+H] + : 680.1550; found: 680.1537.

[0135] Example 20

[0136] 2-(N-(4-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-3- methoxyphenyl)sulfamoyl)ethyl-morpholine-4-carbodithioate was prepared according to the procedure of Example 16 The difference is that morpholine was used instead of thiomorpholine as starting material, and the yield was 73%. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.90 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.17 (s, 2H), 3.85 (s, 2H), 3.78 (s, 3H), 3.63 (s, 6H), 3.49-3.46 (m, 2H), 2.81 (d, J = 4.0 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 194.04, 168.86, 158.35, 154.93, 154.64, 151.58, 139.38, 134.07, 131.31, 127.85, 124.80, 124.20, 121.67, 121.08, 120.38, 112.23, 104.74, 104.46, 65.38, 55.52, 51.08, 49.96, 29.25, 26.27; HRMS m / z: [M+H] C 26 H 31 ClN7O5S3 calcd for [M+H] + : 652.1237; found: 652.1226.

[0137] Example 21

[0138] 2-((2,5-dichloropyrimidin-4-yl)amino)-N-methylbenzamide was prepared according to the procedure of Example 1 with the exception that 2-amino-N-methylbenzamide was replaced with 2-amino-N- deuteromethylbenzamide; in 92% yield, 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.84 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.46 (s, 1H), 7.82 (dd, J = 7.8, 1.0 Hz, 1H), 7.62-7.58 (m, 1H), 7.24-7.21 (m, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 168.73, 156.63, 156.14, 155.28, 138.30, 131.83, 128.11, 123.08, 121.00, 120.79, 114.92;

[0139] 2-((5-chloro-2-((2-methoxy-4-nitrophenyl)amino)pyrimidin-4-yl)amino)-N- deuteriomethylbenzamide was prepared according to the procedure of Example 1 The difference is that 2-((2,5-dichloropyrimidin-4-yl)amino)-N-deuteriomethylbenzamide was used as the starting material; the yield was 94%;

[0140] 2-((2-((4-amino-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-N- deuteriomethylbenzamide was prepared according to the procedure of Example 1 The difference is that 2-((5-chloro-2-((2-methoxy-4-nitrophenyl)amino)pyrimidin-4-yl)amino)-N- deuteriomethylbenzamide was used as the starting material; the yield was 90%;

[0141] 2-((5-chloro-2-((2-methoxy-4-(vinylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N- deuteriomethylbenzamide was prepared according to the procedure of Example 1 The difference is that 2-((2-((4-amino-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-N- deuteriomethylbenzamide was used as the starting material; the yield was 63%; 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.90 (s, 1H), 8.72 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.86 - 6.76 (m, 1H), 6.15 (d, J = 16.4 Hz, 1H), 6.05 (d, J = 10.0 Hz, 1H), 3.77 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 168.96, 158.46, 154.97, 154.68, 151.75, 139.43, 136.31, 134.16, 131.34, 127.91, 127.54, 124.65, 124.47, 121.70, 121.10, 120.40, 111.97, 104.73, 104.21, 55.48;

[0142] Prepared according to the procedure of Example 1 using 2-((5-chloro-2-((2- methoxy-4-((2-morpholinoethyl)sulfonamido)phenyl)amino)pyrimidin-4-yl)amino)- N-methylbenzamide instead of 2-((5-chloro-2-((2-methoxy-4- (vinylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide in 67% yield. The difference is that thiomorpholine is used instead of morpholine as starting material, and 2-((5-chloro-2-((2-methoxy-4-(vinylsulfonamido)phenyl)amino)pyrimidin-4- yl)amino)-N-deuteromethylbenzamide is used instead of 2-((5-chloro-2-((2-methoxy-4- (vinylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide in 67% yield. 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.67 (s, 1H), 8.70 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 8.4, 2.0 Hz, 1H), 3.77 (s, 1H), 3.28 - 3.22 (m, 2H), 2.78 - 2.74 (m, 2H), 2.58 (d, J = 4.8 Hz, 2H), 2.52 - 2.50 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 168.91, 158.44, 154.95, 154.66, 151.81, 139.44, 134.53, 131.26, 127.88, 124.64, 124.49, 121.66, 121.04, 120.38, 111.82, 104.72, 104.16, 55.50, 54.09, 52.28, 47.52, 26.98; HRMS m / z: [M+H] C 25 H 28 C3H12D3ClN7O4S2 calcd for [M+H] + : 595.1756; found: 595.1745.

[0143] Example 22

[0144] Prepared according to the procedure of Example 21 using 2-((5-chloro-2-((4-((2-((2S,6R)- 2,6-dimethylmorpholino)ethyl)sulfonamido)-2-methoxyphenyl)amino)pyrimidin-4- yl)amino)-N-methylbenzamide instead of 2-((5-chloro-2-((2-methoxy-4- (vinylsulfonamido)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide in 67% yield. The difference is that cis-2,6-dimethylmorpholine is used instead of thiomorpholine, with a yield of 69%. 1 H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.68 (s, 1H), 8.69 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.6, 2.2 Hz, 1H), 3.77 (s, 3H), 3.47 - 3.40 (m, 2H), 3.29 - 3.26 (m, 2H), 2.69 (t, J = 7.4 Hz, 1H), 2.61 (d, J = 10.4 Hz, 2H), 1.57 (t, J = 10.6 Hz, 2H), 0.96 (s, 3H), 0.95 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 168.93, 158.45, 154.97, 154.65, 151.78, 139.49, 134.55, 131.28, 127.89, 124.62, 124.46, 121.65, 121.04, 120.34, 111.72, 104.76, 104.01, 70.79, 58.55, 55.50, 51.48, 47.65, 18.81; HRMS m / z: [M+H] C 27 H 32 D3ClN7O5S calcd for [M+H] + : 607.2297; found: 607.2288.

[0145] Example 23

[0146] 2-(N-(4-((5-chloro-4-((2-(dime thylaminoformyl)phenyl)amino)pyrimidin-2-yl)amino)-3- methoxyphenyl)sulfamoyl)ethyl-morpholine-4-carbodithioate was prepared according to the procedure of Example 21 The difference is that morpholine is used instead of thiomorpholine, with a yield of 67%. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.89 (s, 1H), 8.70 (s, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.73 (dd, J = 7.8, 1.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.4, 2.0 Hz, 1H), 4.16 - 3.84 (m, 4H), 3.77 (s, 3H), 3.66 - 3.62 (m, 6H), 3.49 - 3.45 (m, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 194.06, 168.91, 158.36, 154.95, 154.66, 151.60, 139.40, 134.09, 131.32, 127.87, 124.81, 124.21, 121.68, 121.09, 120.39, 112.25, 104.75, 104.48, 65.45, 55.53, 50.46, 49.97, 29.26; HRMS m / z: [M+H] C 26 H 28 D3ClN7O5S3 calcd for [M+H] + : 655.1426; found: 655.1417.

[0147] Evaluation of FAK kinase inhibitory activity

[0148] Experimental method:

[0149] 5 μL per well in 384-well plate, including 2 μL FAK protein (2.6 ng dissolved in buffer), 2 μL mixture of ATP and substrate (ATP final concentration 25 μM dissolved in buffer, substrate final concentration 0.4 μg / μL dissolved in buffer), 1 μL DMSO or different concentrations of drug-containing DMSO, incubated at room temperature for 1 h, 5 μL ADP-Glo TM Reagent was added, incubated at room temperature for 40 min, then 10 μL Kinase Detection Reagent was added, incubated at room temperature for 30 min, then the value of chemiluminescence was read by microplate reader (integration time = 500 ms);

[0150] Blank and control groups were set, blank group: buffer instead of FAK kinase; control group: only DMSO. Other reagents were unchanged.

[0151] Inhibition rate = (Rc-R) / (Rc-Rb) x 100%

[0152] Wherein, R is the light emission value of the administration group, Rc is the light emission value of the control group, and Rb is the light emission value of the blank group.

[0153] According to the inhibition rate, IC50value is calculated by graphpad 50 The results are listed in Table 1.

[0154] Table 1 Inhibition of FAK kinase by compounds of Examples 1-23 and positive drug TAE226

[0155] Example IC 50 (nM) Example IC 50 (nM) 1 0.55±0.21 13 0.62±0.02 2 0.57±0.33 14 0.54±0.16 3 0.68±0.19 15 0.55±0.08 4 0.77±0.30 16 2.21±0.45 5 0.42±0.03 17 6.01±0.07 6 0.46±0.15 18 2.49±0.68 7 0.40±0.02 19 2.09±0.88 8 0.61±0.12 20 0.87±0.35 9 0.27±0.09 21 0.29±0.02 10 1.44±0.59 22 0.39±0.01 11 0.76±0.64 23 0.80±0.00 12 1.05±0.33 TAE226 0.51±0.10

[0156] As can be seen from Table 1, the sulfonamide compounds provided by the present application have excellent inhibitory activity on FAK, and the inhibitory activity of the compounds prepared in Examples 5, 6, 7, 9, 21 and 22 on FAK is significantly better than that of the positive drug TAE226.

[0157] Cell activity evaluation

[0158] Experimental method:

[0159] Cell strain: HCT116 colon cancer cells, A549 human non-small cell lung cancer cells, MDA-MB-231 human breast cancer cells, and HeLa human cervical cancer cells.

[0160] The cells recovered and cultured for two generations were inoculated in a 96-well cell culture plate at 2000 cells / 100 μL of medium per well, and incubated in a 37°C, 5% CO2incubator for 24 h; a blank control group without drug and a drug administration group were set up for each 96-well plate. Six concentration gradients were set up for each compound in the drug administration group, with three replicates. After drug administration, the cells were incubated together for 72 h. Finally, MTS reagent was added for detection. The color development principle of MTS method is that MTS can be reduced to water-soluble formazan by active cells under the action of phenazine methosulfate (PMS), and the OD value at 490 nm is proportional to the number of active cells. MTS method is more convenient and more accurate than MTT method. The specific detection method is as follows: MTS is prepared into a 2 mg / mL stock solution, PMS is prepared into a 0.92 mg / mL stock solution, and the two stock solutions are mixed at a volume ratio of 20:1, filtered and added to the 96-well plate to be detected, 20 μL per well, and incubated in the cell culture incubator for 3 h. The OD value is measured at a wavelength of 490 nm by an enzyme-labeled instrument, and the cell proliferation inhibition rate is calculated according to the following formula: Proliferation inhibition rate = (OD 空白对照组 -OD 给药组 ) / (OD 空白对照组 -OD 背景) x 100%. The corresponding inhibition rate was inputted into Graphpad Prism and the IC 50 values were calculated, the results of which are listed in Table 2.

[0161] Table 2 Test results of Examples 1-23 and positive drug TAE226 on different cell activities

[0162]

[0163] As can be seen from the results of Table 2, the sulfonamide compounds provided by the present application have significant proliferation inhibition effects on HCT116 colon cancer cells, A549 human non-small cell lung cancer cells, MDA-MB-231 human breast cancer cells, and HeLa human cervical cancer cells; among them, the proliferation inhibition effect on HCT116 colon cancer cells is the most obvious, and the IC 50 values of most compounds on the proliferation of HCT116 colon cancer cells are less than 1 μM.

[0164] Although the above examples have made a detailed description of the present application, it is only a part of the embodiments of the present application, but not all the embodiments, and people can also obtain other embodiments according to the present embodiments without creativity, which all belong to the protection scope of the present application.

Claims

1. A sulfonamide compound, characterized in that, It has the structure shown in Equation I: Wherein, A is methyl or deuterated methyl; R is Where R1 and R2 are independently the first C 1～4 Alkyl groups, heteroarylalkyl groups, or R1 and R2 together with the N atom to which they are attached form a heterocyclic group; the heteroarylalkyl group is pyridinemethyl; The heterocyclic group is a substituted or unsubstituted five- or six-membered heterocyclic group; when the heterocyclic group is a substituted heterocyclic group, the substituent in the substituted heterocyclic group is a second C. 1～4 One or more of alkyl, oxo, phenyl, and acetyl groups, wherein the second C 1～4 The alkyl group is methyl or isopropyl; The heterocyclic group is piperazinyl, morpholinyl, tetrahydropyrroleyl, piperidinyl, or thiomorpholinyl.

2. The sulfonamide compound according to claim 1, characterized in that, The first C 1～4 The alkyl group is methyl, ethyl, propyl or allyl.

3. The sulfonamide compound according to claim 2, characterized in that, The substituted five- or six-membered heterocyclic group is 2,6-dimethylmorpholino, methylpiperazino, isopropylpiperazino, acetylpiperazino, 2-piperazinoneo, or tetrahydroisoquinolino.

4. The sulfonamide compound according to claim 1, characterized in that, The sulfonamide compounds have any of the structures shown in formulas I-1 to I-23:

5. A method for preparing the sulfonamide compound according to any one of claims 1 to 4, comprising the following steps: 2,4,5-trichloropyrimidine, N,N-diisopropylethylamine was dissolved in isopropanol and subjected to a nucleophilic substitution reaction to give compound 1; Compound 1, 2-methoxy-4-nitroaniline, potassium phosphate, Xantphos ligand and catalyst were dissolved in N,N-dimethylformamide and subjected to CN coupling reaction to obtain compound 2; Compound 2, iron powder, and ammonium chloride were dissolved in an ethanol / water solution and subjected to a nitro reduction reaction to obtain compound 3. Compound 3 was dissolved in dichloromethane and then mixed with chloroethylsulfonyl chloride and N-methylmorpholine to undergo a sulfonation reaction to obtain compound 4. When R is Then, compound 4 and R1R2NH were dissolved in a mixed solvent of dichloromethane and methanol to carry out the first Michael addition reaction, yielding... When R is R1R2NH, carbon disulfide, and triethylamine were dissolved in N,N-dimethylformamide and subjected to a nucleophilic reaction. Following this, the mixture was combined with compound 4 to undergo a second Michael addition reaction to obtain... Compound 1 is Compound 2 is Compound 3 is Compound 4 is 6. The preparation method according to claim 5, characterized in that, The 2,4,5-trichloropyrimidine and The molar ratio of 2,4,5-trichloropyrimidine to N,N-diisopropylethylamine is 1:1 to 1.1; the molar ratio of 2,4,5-trichloropyrimidine to N,N-diisopropylethylamine is 1:1.05 to 1.

2. The nucleophilic substitution reaction is carried out at a temperature of 80–90 °C for 5.5–6.5 h.

7. The preparation method according to claim 5, characterized in that, The catalyst is palladium acetate; The CN coupling reaction was carried out at a temperature of 115–125°C for 22–24 hours.

8. A pharmaceutical composition, characterized in that, It includes a pharmaceutically active ingredient and a pharmaceutically acceptable carrier or excipient; the pharmaceutically active ingredient is a sulfonamide compound as described in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

9. Use of the sulfonamide compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating the catalytic activity of protein kinases.

10. The application according to claim 9, characterized in that, The protein kinase is a local adhesion kinase; The drug used to regulate the catalytic activity of protein kinases is a drug used to treat or prevent cancer.

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