3-sulfamoylbenzamide compound, and preparation method therefor and use thereof

Abstract

The present application belongs to the technical field of pharmaceutical chemistry, and specifically relates to a 3-sulfamoylbenzamide compound, and a preparation method therefor and the use thereof. The 3-sulfamoylbenzamide compound has a structure represented by formula I. In formula I, X is chloro or trifluoromethyl; R1 and R2 are independently C1-4 alkyl, or R1 and R2, together with the N atom to which they are attached, form heterocyclyl, wherein the heterocyclyl is substituted or unsubstituted five- or six-membered heterocyclyl; and when the heterocyclyl is substituted heterocyclyl, the substituent in the substituted heterocyclyl is one or more of C1-4 alkyl, phenyl and acetyl. The 3-sulfamoylbenzamide compound of the present application exhibits a significant inhibitory effect on the proliferation of HCT116 colon cancer cells, HeLa human cervical cancer cells, MDA-MB-231 human breast cancer cells, and A375 human malignant melanoma cells.

Description

A 3-aminosulfonylbenzamide compound, its preparation method and application

[0001] This application claims priority to Chinese Patent Application No. CN202510099419.5, filed on January 22, 2025, entitled "A 3-aminosulfonylbenzamide compound and its preparation method and application", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application belongs to the field of medicinal chemistry technology, specifically relating to a 3-aminosulfonylbenzamide compound, its preparation method, and its application. Background Technology

[0003] Local adhesion kinase (FAK) is a non-receptor protein tyrosine kinase (nPTK) belonging to the protein tyrosine kinase superfamily. FAK plays an important role in cell signal transduction, serving as a central hub for intracellular and extracellular signal transduction and mediating multiple signaling pathways. FAK is mainly activated by the accumulation of integrin on the cell membrane surface, and the intracellular domain of its β subunit can promote FAK phosphorylation.

[0004] The main physiological functions of FAK are: 1) Participation in cell adhesion and migration: During cell spreading and movement, FAK participates in the formation and regulation of focal adhesion, helping cells attach to the extracellular matrix and promoting cell migration; 2) Regulation of cell proliferation and survival: Activation of FAK can initiate a series of signaling pathways, promoting cell cycle progression and enabling cells to smoothly enter the S phase from the G0 / G1 phase or the M phase from the G2 / M phase, thereby promoting cell proliferation. At the same time, FAK can also inhibit apoptosis, playing an important role in cell survival; 3) Mediating signal transduction: As a convergence point of multiple intracellular signaling pathways, FAK can integrate various signals such as those from the extracellular matrix and growth factors, activating intracellular signaling pathways such as PI3K / Akt and Ras / MAPK, thereby regulating various physiological functions such as cell growth and differentiation.

[0005] However, FAK is overexpressed in various tumors, such as head and neck cancer, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer, cervical cancer, melanoma, thyroid cancer, and ovarian cancer, and is highly correlated with the invasive phenotype of tumors. Inhibiting FAK signaling can reduce the invasion of glioblastoma and ovarian cancer cells. Therefore, FAK has become an important target for the development of anti-tumor and anti-metastatic drugs. However, current drugs targeting this target have poor inhibitory effects on tumor cell proliferation. Summary of the Invention

[0006] In view of this, the purpose of this application is to provide a 3-aminosulfonylbenzamide compound, its preparation method, and its application. The 3-aminosulfonylbenzamide compound provided in this application exhibits good inhibitory activity against FAK and significant inhibitory effect on tumor cell proliferation.

[0007] This application provides a 3-aminosulfonylbenzamide compound or a pharmaceutically acceptable salt thereof, said 3-aminosulfonylbenzamide compound having the structure shown in Formula I:

[0008] In Formula I, X is chloro or trifluoromethyl;

[0009] R1 and R2 are independently C 1～4 Alkyl groups, or R1 and R2, together with the N atoms attached to them, form a heterocyclic group. This heterocyclic group can be substituted or unsubstituted, and can be a five- or six-membered heterocyclic group. When the heterocyclic group is substituted, the substituent in the substituted heterocyclic group is a C atom. 1～4 One or more of alkyl, phenyl, and acetyl groups.

[0010] Preferably, R1 and R2 are ethyl groups.

[0011] Preferably, the heterocyclic group further contains 1 to 2 heteroatoms selected from N or O.

[0012] Preferably, the heterocyclic group is a substituted or unsubstituted piperazine, morpholino, tetrahydropyrrole, or piperidinyl group.

[0013] Preferably, the substituted heterocyclic group is 2,6-dimethylmorpholino, methylpiperazino, acetylpiperazino, or tetrahydroisoquinolino.

[0014] Preferably, the 3-aminosulfonylbenzamide compound has a structure shown in any one of formulas I-1 to I-11:

[0015] This application also provides a method for preparing the 3-aminosulfonylbenzamide compounds described in the above technical solution, comprising the following steps:

[0016] A mixture of 3-aminosulfonylbenzoic acid compounds having the structure shown in Formula II, N,N-dimethylformamide, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine was subjected to carboxyl activation, and then mixed with 2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide having the structure shown in Formula III or 2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide having the structure shown in Formula IV was subjected to an amidation reaction to obtain the 3-aminosulfonylbenzoamide compounds.

[0017] In Equation II, R1 and R2 are defined in the same way as in Equation I.

[0018] This application also provides a pharmaceutical composition comprising a pharmaceutically active component and a pharmaceutically acceptable carrier or excipient;

[0019] The active pharmaceutical ingredient is a 3-aminosulfonylbenzamide compound or a pharmaceutically acceptable salt thereof as described in the above technical solution.

[0020] This application also provides the use of the 3-aminosulfonylbenzamide compounds or their pharmaceutically acceptable salts described in the above-described technical solutions, or the pharmaceutical compositions described in the above-described technical solutions, in the preparation of drugs that inhibit FAK activity.

[0021] Preferably, the drug that inhibits FAK activity is a drug used to treat and / or prevent cancer.

[0022] Compared with the prior art, this application has the following beneficial effects:

[0023] This application provides a 3-aminosulfonylbenzamide compound or a pharmaceutically acceptable salt thereof, wherein the 3-aminosulfonylbenzamide compound has the structure shown in Formula I. The 3-aminosulfonylbenzamide compound provided in this application is a FAK inhibitor, exhibiting good inhibitory activity against FAK activity and effectively inhibiting the proliferation and growth of tumor cells. Example data show that the 3-aminosulfonylbenzamide compound of this application has significant inhibitory effects on the proliferation of HCT116 colon cancer cells, HeLa human cervical cancer cells, MDA-MB-231 human breast cancer cells, and A375 human malignant melanoma cells. Detailed Implementation

[0024] This application provides a 3-aminosulfonylbenzamide compound or a pharmaceutically acceptable salt thereof, said 3-aminosulfonylbenzamide compound having the structure shown in Formula I:

[0025] In Formula I, X is chloro or trifluoromethyl;

[0026] R1 and R2 are independently C 1～4 Alkyl groups, or R1 and R2, together with the N atoms attached to them, form a heterocyclic group. This heterocyclic group can be substituted or unsubstituted, and can be a five- or six-membered heterocyclic group. When the heterocyclic group is substituted, the substituent in the substituted heterocyclic group is a C atom. 1～4 One or more of alkyl, phenyl, and acetyl groups.

[0027] In this application, X is preferably trifluoromethyl.

[0028] In this application, R1 and R2 are preferably ethyl.

[0029] In this application, the heterocyclic group preferably contains one or two heteroatoms selected from N or O, in addition to the N linked by the sulfonyl group.

[0030] In this application, the heterocyclic group is preferably a substituted or unsubstituted piperazine, morpholino, tetrahydropyrrole, or piperidinyl group. The C in the substituted heterocyclic group... 1～4 The alkyl group is preferably methyl. When the substituent in the substituted heterocyclic group is phenyl, the phenyl group may be cyclically fused with the heterocyclic group. The substituted heterocyclic group is preferably 2,6-dimethylmorpholino, methylpiperazino, acetylpiperazino, or tetrahydroisoquinolino.

[0031] In this application, the 3-aminosulfonylbenzamide compound preferably has the structure shown in any one of formulas I-1 to I-11:

[0032] This application also provides a method for preparing the 3-aminosulfonylbenzamide compounds described in the above technical solution, comprising the following steps:

[0033] A mixture of 3-aminosulfonylbenzoic acid compounds having the structure shown in Formula II, N,N-dimethylformamide, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine was subjected to carboxyl activation, and then mixed with 2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide having the structure shown in Formula III or 2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide having the structure shown in Formula IV was subjected to an amidation reaction to obtain the 3-aminosulfonylbenzoamide compounds.

[0034] In Equation II, R1 and R2 are defined in the same way as in Equation I.

[0035] Unless otherwise specified, all materials and equipment used in this application are commercially available products in the field.

[0036] In this application, the carboxyl activation temperature is preferably 10–30°C (room temperature), specifically 25°C, and the activation time is preferably 15–30 min. The preferred ratio of the 3-aminosulfonylbenzoic acid compound, N,N-dimethylformamide, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine is 0.24 mmol:10 mL:0.3 mmol:1 mmol.

[0037] In this application, the amidation reaction is preferably carried out at room temperature and overnight. The molar ratio of the 3-aminosulfonylbenzoic acid compound to 2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide or 2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide is preferably 0.24:0.2.

[0038] The amidation reaction preferably further includes: mixing the obtained reaction solution with water, extracting with dichloromethane, washing and drying the obtained organic phase, and purifying it by column chromatography. In this invention, the washing preferably uses saturated brine, the drying preferably uses anhydrous sodium sulfate, and the eluent for column chromatography is preferably a mixture of ethyl acetate and methanol, with the volume ratio of ethyl acetate to methanol preferably being 20–40:1.

[0039] When X is chlorine:

[0040] This application involves mixing a 3-sulfonylbenzoic acid compound, N,N-dimethylformamide, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine, activating their carboxyl groups, and then subjecting them to an amidation reaction with 2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)N-methylbenzamide having the structure shown in Formula III, to obtain the 3-aminosulfonylbenzoamide compound.

[0041] In this application, 2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide having the structure shown in Formula III is preferably prepared by a method comprising the following steps:

[0042] A first nucleophilic substitution reaction was carried out on a mixture of 2,4,5-trichloropyrimidine, 2-amino-N-methylbenzamide, N,N-diisopropylethylamine and isopropanol to give compound A;

[0043] Compound A, 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester, trifluoroacetic acid and sec-butanol were mixed and subjected to a first CN coupling reaction to obtain compound B;

[0044] Compound B, dichloromethane, and trifluoroacetic acid were mixed and subjected to a first deBoc reaction to obtain 2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)N-methylbenzamide having the structure shown in Formula III;

[0045] The structural formulas of compounds A and B are shown below:

[0046] The preferred molar ratio of 2,4,5-trichloropyrimidine to 2-amino-N-methylbenzamide is 1:1 to 1.1, and the structural formula of 2-amino-N-methylbenzamide is shown below:

[0047] The molar ratio of 2,4,5-trichloropyrimidine to N,N-diisopropylethylamine is preferably 1:1.05–1.2; the temperature of the first nucleophilic substitution reaction is preferably 80–90°C, specifically 85°C, and the time is preferably 5.5–6.5 h, specifically 6 h. Preferably, after the first nucleophilic substitution reaction, the reaction mixture is cooled and mixed with water to precipitate a solid; the solid and liquid are separated; and the obtained solid is washed and dried.

[0048] The structural formula of the 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester is shown below:

[0049] The preferred temperature for the first CN coupling reaction is 75–85°C, specifically 80°C, and the preferred time is 11–13 hours, specifically 12 hours. Preferably, the reaction mixture after the first CN coupling reaction further includes: cooling the resulting reaction solution and mixing it with water, extracting it with dichloromethane, washing and drying the resulting organic phase, and purifying it using column chromatography; the washing preferably uses saturated brine, the drying preferably uses anhydrous sodium sulfate, and the column chromatography purification preferably uses a mixture of ethyl acetate and petroleum ether, with the volume ratio of ethyl acetate to petroleum ether preferably being 1:1.

[0050] The first Boc removal reaction preferably includes: mixing compound B, dichloromethane, and trifluoroacetic acid with a first stirring, performing vacuum distillation, and mixing the resulting residue with dichloromethane and triethylamine with a second stirring; the first stirring is preferably performed at room temperature for 6 hours, and the second stirring is preferably performed at room temperature for 1-3 hours, specifically 2 hours. The first Boc removal reaction preferably further includes: mixing the resulting reaction solution with water, extracting with dichloromethane, washing and drying the resulting organic phase, and purifying it using column chromatography; the washing preferably uses saturated brine, the drying preferably uses anhydrous sodium sulfate, and the column chromatography purification preferably uses a mixture of ethyl acetate and methanol, with the volume ratio of ethyl acetate to methanol preferably being 3:2.

[0051] When X is trifluoromethyl:

[0052] This application involves mixing a 3-aminosulfonylbenzoic acid compound having the structure shown in Formula II, N,N-dimethylformamide, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine, activating their carboxyl groups, and then mixing them with 2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide having the structure shown in Formula IV, and performing an amidation reaction to obtain the 3-aminosulfonylbenzoamide compound.

[0053] In this application, 2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide having the structure shown in Formula IV is preferably prepared by a method comprising the following steps:

[0054] A second nucleophilic substitution reaction was carried out in a mixture of 2,4-dichloro-5-trifluoromethylpyrimidine, tert-butanol and 1,2-dichloroethane, a catalyst, tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate and N,N-diisopropylethylamine to give compound C;

[0055] Compound C, 2-amino-N-methylbenzamide, trifluoroacetic acid, and sec-butanol were mixed and subjected to a second CN coupling reaction to obtain compound D;

[0056] The compound D, dichloromethane, and trifluoroacetic acid were mixed and subjected to a second deBoc reaction to give 2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide having the structure shown in Formula IV;

[0057] In this application, the catalyst preferably comprises zinc bromide or zinc chloride; the volume ratio of 1,2-dichloroethane to tert-butanol in the mixed solvent of tert-butanol and 1,2-dichloroethane is preferably 1:1; the second nucleophilic substitution reaction preferably comprises an ice bath reaction and a room temperature reaction, the ice bath reaction time is preferably 30 min, and the room temperature reaction time is preferably 24 h. The second nucleophilic reaction preferably further includes: concentrating the obtained reaction solution and then performing column chromatography for purification; the column chromatography purification preferably uses a mixture of ethyl acetate and petroleum ether, the volume ratio of ethyl acetate to petroleum ether is preferably 1:2.

[0058] In this application, the temperature of the second CN coupling reaction is preferably 95–105°C, specifically 100°C, and the time is preferably 16–18 h, specifically 17 h. The second CN coupling reaction preferably further includes: mixing the obtained reaction solution with water, extracting with dichloromethane, washing and drying the obtained organic phase, and purifying it by column chromatography; the washing preferably uses saturated brine, the drying preferably uses anhydrous sodium sulfate, and the column chromatography purification preferably uses a mixture of ethyl acetate and petroleum ether, with the volume ratio of ethyl acetate to petroleum ether preferably being 2:3.

[0059] In this application, the second Boc removal reaction preferably includes: mixing the compound D, dichloromethane, and trifluoroacetic acid with a first stirring, performing vacuum distillation, and mixing the resulting residue with dichloromethane and triethylamine with a second stirring; the first stirring is preferably performed at room temperature for 6 hours, and the second stirring is preferably performed at room temperature for 1 to 3 hours, specifically 2 hours. The second Boc removal reaction preferably further includes: mixing the resulting reaction solution with water, extracting with dichloromethane, washing and drying the resulting organic phase, and purifying it using column chromatography; the washing preferably uses saturated brine, the drying preferably uses anhydrous sodium sulfate, and the column chromatography purification preferably uses a mixture of ethyl acetate and methanol, with the volume ratio of ethyl acetate to methanol preferably being 1:1.

[0060] This application also provides a pharmaceutical composition comprising a pharmaceutically active component and a pharmaceutically acceptable carrier or excipient; wherein the pharmaceutically active component is a 3-aminosulfonylbenzamide compound or a pharmaceutically acceptable salt thereof as described in the above technical solution.

[0061] In this application, the pharmaceutically acceptable salt is a salt formed by the reaction of a 3-aminosulfonylbenzamide compound with an inorganic or organic acid. The inorganic acid is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, or phosphoric acid; 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, pyric acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, or hydroxyethanesulfonic acid.

[0062] This application does not have special requirements for the carrier and excipients; they can be selected according to the form of the drug. The form of the drug composition is preferably solid, semi-solid, liquid, or gaseous; the dosage form of the drug composition is preferably tablet, pill, lozenge, sugar-coated tablet, capsule, powder, granule, ointment, emulsion, suspension, solution, suppository, injection, inhalation, gel, microsphere, or aerosol.

[0063] This application does not specify any particular method for preparing the pharmaceutical composition; any method commonly used in the art may be employed, such as mixing, dissolving, granulation, sugar-coated pill preparation, grinding, emulsification, or freeze-drying.

[0064] This application preferably uses conventional mixing, filling, or tableting methods to prepare solid oral pharmaceutical compositions. For example, it can be obtained by mixing the active pharmaceutical ingredient with a solid excipient and then milling the mixture to obtain the pharmaceutical composition. Preferably, an excipient may also be added during the mixing process to prepare a granular pharmaceutical composition.

[0065] This application describes a process that can yield tablets or sugar-coated pharmaceutical compositions. The excipients preferably include binders, diluents, disintegrants, lubricants, flow aids, sweeteners, or flavoring agents. Specifically, the excipients are preferably microcrystalline cellulose, glucose solution, gum arabic, gelatin solution, sucrose, starch paste, talc, starch, magnesium stearate, calcium stearate, stearic acid, lactose, sucrose, starch, mannitol, sorbitol, dicalcium phosphate, silicon dioxide, croscarmellose sodium, precrossyl starch, sodium starch glycolate, alginate, corn starch, potato starch, methylcellulose, agar, carboxymethyl cellulose, or croscarmellose.

[0066] Preferably, the granular pharmaceutical composition can also be coated. The coating method is not particularly required and can be any conventional method in the art. The coating is preferably enteric coating.

[0067] In this application, the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products.

[0068] In this application, the preferred routes of administration for the pharmaceutical composition include oral administration, rectal administration, transmucosal administration, enteral administration, or local, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0069] This application also provides the use of the 3-aminosulfonylbenzamide compounds or their pharmaceutically acceptable salts described in the above-described technical solutions, or the pharmaceutical compositions described in the above-described technical solutions, in the preparation of drugs that inhibit FAK (local adhesion kinase) activity.

[0070] In this application, the drug that inhibits FAK activity is preferably a drug for treating and / 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, leukemia, osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer, or colorectal cancer.

[0071] To further illustrate this application, the following detailed description of the 3-aminosulfonylbenzamide compounds, their preparation methods, and applications provided in this application is provided in conjunction with the embodiments, but these descriptions should not be construed as limiting the scope of protection of this application.

[0072] Example 1

[0073] 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, and DIPEA (N,N-diisopropylethylamine) (2 mL, 12 mmol) was added. The mixture was heated under reflux at 85 °C for 6 h (nucleophilic substitution reaction). After cooling the system to room temperature, 100 mL of water was added, and a pale yellow solid precipitated. The solid was filtered, the filter cake was washed with water, and the filter cake was dried under reduced pressure to give 2.64 g of the pale yellow solid 2-((2,5-dichloropyrimidine-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are as follows), with a yield of 88%.

[0074] 1H NMR (400MHz, DMSO-d6) δ12.25(s,1H),8.87(d,J=4.4Hz,1H),8.54(d,J=8.4Hz,1H),8.46(s, 1H),7.82(d,J=6.8Hz,1H),7.62-7.58(m,1H),7.22(t,J=7.4Hz,1H),2.84(d,J=4.4Hz,3H); 13 C NMR (100MHz, DMSO-d6) δ168.69,156.62,156.13,155.26,138.30,131.82,128.10,123.07,120.96,120.78,114.92,26.34;

[0075] 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (2.84 g, 9.23 mmol), 2-((2,5-dichloropyrimidin-4-yl)amino)-N-methylbenzamide (2.29 g, 7.69 mmol), and trifluoroacetic acid (685 μL, 9.23 mmol) were dissolved in sec-butanol (20 mL) and reacted at 80 °C for 12 h. The reaction mixture was cooled, and 50 mL of water was added to the resulting solution. The solution was then precipitated with 15 mL of tert-butyl ester. Extracted three times with dichloromethane, the organic layers were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate: petroleum ether = 1:1, V / V) to give 2.22 g of pale yellow solid 1-piperazincarnate tert-butyl ester-4-(4-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl (structural formula and NMR data are as follows), yield 50%;

[0076] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.72(s,1H),8.61(s,1H),8.11(d,J=8.4Hz,2H),7.72(d,J=7.6Hz,1H),7.48(d,J=8.4Hz,1H),7.33(d,J=7 .2Hz,1H),7.08(t,J=7.4Hz,1H),6.68(s,1H),6.50(d,J=8.4Hz,1H),3. 78(s,3H),3.48(s,4H),3.10(s,4H),2.81(d,J=4.4Hz,3H),1.43(s,9H); 13C NMR(100MHz,DMSO-d6)δ168.97,158.88,154.93,154.66,153.87,152.48,148.89,139.60,131.43,127.8 5,125.06,121.54,120.99,120.69,120.16,107.36,104.15,100.81,78.96,55.45,49.18,28.07,26.31;

[0077] 1-Piperazine carboxylate tert-butyl ester-4-(4-((5-chloro-4-((2-(methylcarbamoyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl) (1.38 g, 2.42 mmol) was dissolved in 6 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 6 h, and the solvent and excess trifluoroacetic acid were removed by vacuum distillation. The residue was dissolved in 6 mL of dichloromethane, and 3 mL of triethylamine was added. The mixture was stirred at room temperature for 2 h, and the reaction mixture was then added to the final solution. Add 50 mL of water, extract three times with 15 mL of dichloromethane, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, and purify by column chromatography (ethyl acetate:methanol = 3:2, V / V) to give 0.97 g of pale yellow solid 2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)N-methylbenzamide (structural formula and NMR data are as follows), with a yield of 85%;

[0078] 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),8.73(s,1H),8.59(s,1H),8.15(s,1H),8.09(s,1H),7.71(d,J=7.6Hz,1H),7.39(d,J=8.4Hz,1H) ,7.31(s,1H),7.07(t,J=7.4Hz,1H),6.62(s,1H),6.46(d,J=8.4Hz,1H),3.75(s,2H),3.04(s,4H),2.85(s,4H),2.79(d,J=4.0Hz,3H); 13 C NMR(100MHz,DMSO-d6)δ168.89,159.06,154.90,154.69,150.78,149.89,139.61,131.39,127.8 6,125.49,121.50,120.94,120.10,119.89,106.60,103.89,99.96,55.37,50.07,45.69,26.31;

[0079] Dissolve 3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid (68 mg, 0.24 mmol) in 10 mL of DMF, add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (114 mg, 0.3 mmol) and N,N-diisopropylethylamine (158 μL, 1 mmol), and stir at room temperature for 15 min; add 2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)N-methylbenzamide (94 mg, 0.2 mmol), and react overnight at room temperature. Add 50 mL of the reaction mixture to the final solution. Water was extracted three times with 15 mL of dichloromethane. The organic layers were combined, washed with saturated brine, and dried with anhydrous sodium sulfate. The mixture was then purified by column chromatography (ethyl acetate:methanol = 20:1, V / V) to give 75 mg of a pale yellow solid 2-((5-chloro-2-((2-methoxy-4-(4-(3-(((4-methylpiperazin-1-yl)sulfonyl)benzoyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are as follows), with a yield of 51%.

[0080] 1 H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.70(s,1H),8.63(s,1H),8.13(s,1H),8.10(s,1H), 7.92(s,1H),7.81(s,1H),7.77(s,2H),7.70(d,J=7.8Hz,1H),7.46(d,J=8.2Hz,1H),7.33( d,J=6.6Hz,1H),7.11-7.07(m,1H),6.68(s,1H),6.50(d,J=8.2Hz,1H),3.75(s,3H),3.52( s,6H),3.31(s,5H),3.16(s,1H),2.92(s,2H),2.88(s,2H),2.79(s,3H),1.95-1.91(m,3H); 13C NMR(100MHz,DMSO-d6)δ168.90,168.31,167.21,158.68,154.82,154.59,148.56,139.51,137.16,135.23,131.71,131.33,130.13,128.15 ,127.46,125.68,125.24,121.43,120.69,120.58,120.31,107.22,104.21,100.59,56.17,48.12,46.49,45.78,45.23,25.38,22.42; HRMS m / z:C 35 H 41 ClN9O5S calcd for [M+H] + :734.2640; found:734.2653.

[0081] Example 2

[0082] 2-((5-chloro-2-((2-methoxy-4-(4-(3-(morpholinosulfonyl)benzoyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are shown below) was prepared according to the method of Example 1, except that 3-(morpholinosulfonyl)benzoic acid was used instead of the starting material 3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid, with a yield of 45%.

[0083] 1 H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.73(s,1H),8.61(s,1H),8.17(s,1H),8.11(s,1H),7.9 6(s,1H),7.84(s,1H),7.79(s,2H),7.72(d,J=7.6Hz,1H),7.48(d,J=8.0Hz,1H),7.34(d,J=6.4 Hz,1H),7.10-7.06(m,1H),6.70(s,1H),6.52(d,J=8.4Hz,1H),3.77(s,3H),3.64(s,3H),3.49( s,2H),3.36(s,1H),3.28(s,2H),3.17(s,2H),2.90(d,J=7.6Hz,4H),2.80(s,3H),2.73(s,3H); 13C NMR(100MHz,DMSO-d6)δ168.97,167.32,162.32,158.94,154.93,154.68,152.57,139.58,137.08,134.85,131.79,131.43,129.99,12 8.64,127.86,125.98,121.58,120.98,120.70,120.14,107.34,104.06,100.80,65.30,55.48,49.13,45.92,35.79,30.77,26.32; HRMS m / z:C 34 H 38 ClN8O6S calcd for [M+H] + :721.2324; found:721.2304.

[0084] Example 3

[0085] 2-((5-chloro-2-((4-(4-(3-((((2R,6S)-2,6-dimethylmorpholine)sulfonyl)benzoyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are shown below) was prepared according to the method of Example 1, except that 3-(((2R,6S)-2,6-dimethylmorpholine)sulfonyl)benzoic acid was used instead of the starting material 3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid, with a yield of 54%.

[0086] 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.73(s,1H),8.60(s,1H),8.17(s,1H),8.11(s,1H),7.95-7.82(m ,2H),7.78(t,J=7.4Hz,2H),7.72(d,J=8.0Hz,1H),7.47(d,J=8.0Hz,1H),7.34(s,1H),7.08(t,J=7.2Hz ,1H),6.69(s,1H),6.51(d,J=8.4Hz,1H),3.77(s,3H),3.62-3.56(m,4H),3.47(s,2H),3.35(s,2H),3.1 6(s,2H),2.89(s,1H),2.80(d,J=4.4Hz,3H),2.73(s,1H),1.87(t,J=10.6Hz,2H),1.06(d,J=6.0Hz,6H); 13C NMR(100MHz,DMSO-d6)δ168.95,167.35,162.26,158.89,154.92,154.69,152.58,148.60,139.55,137.09,135.00,131.69,131.44,130.06 ,128.50,127.85,125.78,121.56,120.92,120.67,120.15,107.32,104.04,100.68,70.67,55.46,50.52,49.08,35.78,26.31,18.41; HRMS m / z:C 36 H 42 ClN8O6Scalcd for [M+H] + :749.2637; found:749.2616.

[0087] Example 4

[0088] 2-((5-chloro-2-((4-(4-(3-((3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)benzoyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are shown below) was prepared according to the method of Example 1, except that 3-((3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)benzoic acid was used instead of the starting material 3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid, with a yield of 58%.

[0089] 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.73(s,1H),8.61(s,1H),8.18(s,1H),8.11(s,1H) ,7.94(d,J=8.8Hz,1H),7.86(s,1H),7.79-7.71(m,3H),7.47(d,J=8.0Hz,1H),7.34(s,1H) ,7.15-7.06(m,5H),6.69(s,1H),6.51(d,J=8.4Hz,1H),4.27(s,2H),3.77(s,3H),3.37(d ,J=8.8Hz,6H),3.11(s,2H),2.89(s,1H),2.85(s,1H),2.80(d,J=4.0Hz,3H),2.73(s,2H); 13C NMR(100MHz,DMSO-d6)δ168.96,167.34,162.32,158.87,154.93,154.55,152.60,1 48.69,139.58,137.04,136.47,132.94,131.55,131.45,129.92,128.69,128.40,12 7.87,127.30,126.69,126.41,126.13,125.64,121.58,120.97,120.70,120.16,10 7.35,104.13,100.78,55.47,49.07,47.20,43.52,35.79,30.77,27.81,26.32; HRMS m / z:C 39 H 40 ClN8O5Scalcd for [M+H] + :767.2531; found:767.2509.

[0090] Example 5

[0091] 2-((5-chloro-2-((4-(4-(3-(N,N-diethylaminosulfonyl)benzoyl)piperazin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are shown below) was prepared according to the method of Example 1, except that 3-(N,N-diethylaminosulfonyl)benzoic acid was used instead of the starting material 3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid, with a yield of 61%.

[0092] 1 H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.74(s,1H),8.61(s,1H),8.18(s,1H),8.11(s,1 H),7.96-7.83(m,3H),7.75-7.70(m,2H),7.47(d,J=8.0Hz,1H),7.33(d,J=6.8Hz,1H), 7.08(t,J=7.6Hz,1H),6.70(s,1H),6.52(d,J=8.8Hz,1H),3.77(s,3H),3.37(s,4H),3. 28-3.18(m,4H),2.89(s,2H),2.80(d,J=4.0Hz,3H),2.73(s,2H),1.06(t,J=7.0Hz,6H); 13C NMR (100MHz, DMSO-d6) δ168.97,167.45,162.33,158.86,154.94,154.66,152.62,148.60,140.14,139.58,138.61,136.99,131.01,129.91 ,127.86,127.66,125.04,121.60,120.98,120.71,120.17,107.24,104.50,100.78,55.47,49.14,41.92,35.79,30.78,26.31,14.11; HRMS m / z:C 34 H 40 ClN8O5S calcd for [M+H] + :707.2531; found:707.2511.

[0093] Example 6

[0094] 2-((5-chloro-2-((2-methoxy-4-(4-(3-(piperidin-1-ylsulfonyl)benzoyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are shown below) was prepared according to the method of Example 1, except that 3-(piperidin-1-ylsulfonyl)benzoic acid was used instead of the starting material 3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid, with a yield of 52%.

[0095] 1 H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.74(s,1H),8.63(s,1H),8.17(s,1H),8.12(s,1 H),7.85-7.73(m,5H),7.51(d,J=8.0Hz,1H),7.35(d,J=6.0Hz,1H),7.05(t,J=7.2Hz,1 H),6.71(s,1H),6.52(d,J=8.4Hz,1H),3.79(s,3H),3.44(s,4H),3.28-3.17(m,4H),2. 93(s,2H),2.81(s,3H),1.54(s,4H),1.38(s,2H),1.22-1.16(m,1H),0.84-0.80(m,1H); 13C NMR(100MHz,DMSO-d6)δ169.04,167.48,158.87,155.01,154.65,152.50,148.67,139.61,136.98,136.07,131.51,131.44,129.91,128.43 ,127.92,125.77,125.04,121.67,121.07,120.78,120.26,107.40,104.23,100.82,55.50,49.18,46.66,35.82,26.36,24.76,22.86; HRMS m / z:C 35 H 40 ClN8O5S calcd for [M+H] + :719.2531; found:719.2508.

[0096] Example 7

[0097] 2-((5-chloro-2-((2-methoxy-4-(4-(3-(pyrrolidine-1-ylsulfonyl)benzoyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are shown below) was prepared according to the method of Example 1, except that 3-(pyrrolidine-1-ylsulfonyl)benzoic acid was used instead of the starting material 3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid, with a yield of 60%.

[0098] 1 H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.74(s,1H),8.61(s,1H),8.18(s,1H),8.11(s,1H), 7.92(d,J=6.0Hz,1H),7.85(s,1H),7.79-7.71(m,3H),7.47(d,J=8.0Hz,1H),7.33(d,J=7.2 Hz,1H),7.08(t,J=7.6Hz,1H),6.70(s,1H),6.52(d,J=8.4Hz,1H),3.77(s,3H),3.46(s,2H) ,3.35(s,1H),3.28(s,2H),3.19-3.17(m,7H),2.80(d,J=4.0Hz,3H),1.66(d,J=6.4Hz,4H); 13C NMR (100MHz, DMSO-d6) δ168.95,167.40,158.89,154.91,154.67,152.58,148.66,139.57,136.97,136.63,131.45,131.34,129.89, 128.24,127.85,125.53,125.17,121.55,120.96,120.72,120.14,107.35,104.10,100.80,55.47,49.19,47.90,26.30,24.76; HRMS m / z:C 34 H 38 ClN8O5S calcd for [M+H] + :705.2374; found:705.2349.

[0099] Example 8

[0100] 2-((2-((4-(4-(3-(((4-acetylpiperazin-1-yl)sulfonyl)benzoyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are shown below) was prepared according to the method of Example 1, except that 3-((4-acetylpiperazin-1-yl)sulfonyl)benzoic acid was used instead of the raw material 3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid, with a yield of 54%.

[0101] 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.75(s,1H),8.61(s,1H),8.17(s,1H), 8.11(s,1H),7.84-7.71(m,5H),7.47(d,J=7.6Hz,1H),7.34(s,1H),7.10-7.0 6(m,1H),6.70(s,1H),6.52(d,J=8.4Hz,1H),3.77(s,3H),3.51(s,6H),3.36( s,5H),3.15(s,1H),2.97(s,2H),2.91(s,2H),2.80(s,3H),1.95-1.91(m,3H); 13CNMR(100MHz,DMSO-d6)δ168.95,168.39,167.28,158.88,154.92,154.69,148.64,139.57,137.06,135.28,131.78,131.45,130.02,128.5 2,127.86,125.86,125.15,121.57,120.96,120.71,120.14,107.33,1 04.11,100.78,55.47,49.12,45.94,45.73,44.93,26.31,21.12; HRMS m / z:C 36 H 41 ClN9O6S calcd for [M+H] + :762.2589; found:762.2571.

[0102] Example 9

[0103] 2,4-Dichloro-5-trifluoromethylpyrimidine (1.44 g, 6 mmol) was dissolved in a 1,2-dichloroethane:tert-butanol mixture (10 mL, v / v) of 1,2-dichloroethane and tert-butanol. Zinc bromide (1.35 g, 6 mmol) was added, and the mixture was stirred at room temperature until the zinc bromide was completely dissolved. The reaction solution was then cooled in an ice bath, and 1.85 g, 6 mmol, of 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.85 g, 6 mmol) and 1,2-dichloroethane:tert-butanol mixture (10 mL, v / v) of 1,2-dichloroethane and tert-butanol were added dropwise. A solution of N,N-diisopropylethylamine (2 mL, 12 mmol) dissolved in butanol at a volume ratio of 1:1 (10 mL) was reacted for 30 min under ice bath conditions, then reacted at room temperature for 24 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:2, V / V) to give 1.25 g of a pale yellow solid 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (structural formula and NMR data are as follows), with a yield of 42%.

[0104] 1 H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.61(s,1H),7.22-7.16(m,1H),6.65(s,1 H),6.51(d,J=8.4Hz,1H),3.75(s,3H),3.46(s,4H),3.13(s,4H),1.42(s,9H); 13C NMR(100MHz,DMSO-d6)δ162.12,157.97,154.12,153.83,150.56,126.96,124.5 2,121.84,117.96,117.88,107.27,100.70,78.98,55.57,48.63,48.33,28.05;

[0105] 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.25 g, 2.56 mmol), 2-amino-N-methylbenzamide (0.46 g, 3.07 mmol), and trifluoroacetic acid (228 μL, 3.07 mmol) were dissolved in sec-butanol (15 mL) and refluxed (100 °C) for 17 h. The reaction solution was cooled, and 100 mL of water was added to the resulting system. The extract was extracted three times with 15 mL of dichloromethane. The organic layers were combined, washed with saturated brine, and dried with anhydrous sodium sulfate. The mixture was then purified by column chromatography (ethyl acetate: petroleum ether = 2:3, V / V) to give 0.78 g of a pale yellow solid, 4-(3-methoxy-4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester (structural formula and NMR data are as follows), with a yield of 50%.

[0106] 1 H NMR (400MHz, DMSO-d6) δ11.48(s,1H),8.71(s,2H),8.32(s,2H),7.68(d,J=7.2Hz,1H),7.31(s,2H),7.07(s,1H) ,6.69(s,1H),6.49(d,J=8.4Hz,1H),3.76(s,3H),3.48(s,4H),3.13(s,4H),2.78(d,J=4.0Hz,3H),1.44(s,9H); 13 CNMR(100MHz,DMSO-d6)δ168.89,162.10,155.97,153.81,153.50,149.79,139.11,131.16,127.69,126.59,1 26.14,123.46,123.46,122.19,121.94,121.00,119.48,107.29,100.69,78.97,55.43,48.96,28.06,26.23;

[0107] 0.63 g (1.04 mmol) of 4-(3-methoxy-4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in 4 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 6 h. The solvent and excess trifluoroacetic acid were removed by vacuum distillation. The residue was dissolved in 6 mL of dichloromethane, and 3 mL of triethylamine was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was then added to the final solution. Add 50 mL of water, extract three times with 15 mL of dichloromethane, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, and purify by column chromatography (ethyl acetate:methanol = 1:1, V / V) to give 0.40 g of pale yellow solid 2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are as follows), yield 76%;

[0108] 1 H NMR (400MHz, DMSO-d6) δ11.45(s,1H),8.77(s,1H),8.69(s,1H),8.31(s,2H),7.68(d,J=7.2Hz,1H),7.28(s ,2H),7.06(s,2H),6.63(s,2H),6.45(d,J=8.4Hz,2H),3.75(s,3H),3.06(s,4H),2.86(s,4H),2.77(s,3H); 13 C NMR(100MHz,DMSO-d6)δ168.88,162.20,156.00,155.78,153.54,150.64,131.08,127.72,126.6 3,126.21,123.53,122.22,121.81,121.02,118.81,106.59,99.86,55.36,49.90,45.67,26.22;

[0109] 3-(morpholinosulfonyl)benzoic acid (65 mg, 0.24 mmol) was dissolved in 10 mL of LMF, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (114 mg, 0.3 mmol) and N,N-diisopropylethylamine (158 μL, 1 mmol) were added. The mixture was stirred at room temperature for 15 min. Then, 2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (100 mg, 0.2 mmol) was added. The reaction was carried out overnight at room temperature. 50 mL of water was added to the reaction mixture, and the mixture was extracted three times with 15 mL of dichloromethane. The organic layers were combined, washed with saturated brine, and dried with anhydrous sodium sulfate. The mixture was then purified by column chromatography (ethyl acetate:methanol = 40:1, V / V) to give 65 mg of a pale yellow solid 2-((2-((2-methoxy-4-(4-(3-(morpholinylsulfonyl)benzoyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are as follows), with a yield of 43%.

[0110] 1 H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.71(s,2H),8.32(s,1H),7.84-7.66(m,6H),7.30(s,2H),7.07(s,1H),6.70(s, 1H),6.51(d,J=8.8Hz,1H),3.76(s,3H),3.64(s,4H),3.48(s,2H),3.35(s,4H),3.18(s,2H),2.91(s,4H),2.78(s,3H); 13 C NMR(100MHz,DMSO-d6)δ168.87,167.30,162.07,155.94,153.52,149.53,139.09,137.05,134.85,131.78,131.15,129.98,128.62,127 .68,126.68,126.12,125.94,123.44,122.15,121.96,120.96,119.51,107.27,100.66,65.28,55.45,48.96,47.02,45.90,26.23; HRMS m / z:C 35 H 38 F3N8O6S calcd for [M+H] + :755.2587; found:755.2562.

[0111] Example 10

[0112] 2-((2-((2-methoxy-4-(4-(3-(pyrrolidine-1-ylsulfonyl)benzoyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are as follows) was prepared according to the method of Example 9, except that 3-(pyrrolidine-1-ylsulfonyl)benzoic acid was used instead of the starting material 3-(morpholinosulfonyl)benzoic acid, with a yield of 62%;

[0113] 1 H NMR (400MHz, DMSO-d6) δ11.47(s,1H),8.72(s,2H),8.32(s,1H),7.92(d,J=7. 6Hz,1H),7.85(s,1H),7.81-7.73(m,2H),7.68(d,J=7.6Hz,1H),7.32(s,2H), 7.08(s,1H),6.71(s,1H),6.51(d,J=8.4Hz,1H),3.82(s,2H),3.76(s,3H),3. 47(s,2H),3.35-3.31(m,2H),3.19(s,6H),2.78(d,J=4.0Hz,3H),1.67(s,4H); 13 C NMR(100MHz,DMSO-d6)δ168.87,167.42,162.14,155.95,155.86,153.61,149.46,139.09,136.96,136.65,131.34,131.18,129.89, 128.24,127.68,126.65,126.12,125.54,122.16,121.97,120.96,119.52,107.28,100.69,55.45,48.94,47.90,26.23,24.76; m / z:C 35 H 38 F3N8O5S calcd for [M+H] + :739.2638; found:739.2613.

[0114] Example 11

[0115] 2-((2-((4-(4-(3-(((4-acetylpiperazin-1-yl)sulfonyl)benzoyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (structural formula and NMR data are as follows) was prepared according to the method of Example 9, except that 3-((4-acetylpiperazin-1-yl)sulfonyl)benzoic acid was used instead of the starting material 3-(morpholinesulfonyl)benzoic acid, and the yield was 47%.

[0116] 1 H NMR(400MHz,DMSO-d6)δ11.49(s,1H),8.73(s,2H),8.41-8.34(m,2H),7.85-7.7 6(m,4H),7.70(d,J=7.2Hz,1H),7.36-7.29(m,2H),7.09(s,1H),6.72(s,1H),6. 52(d,J=7.6Hz,1H),3.86(s,1H),3.84(s,1H),3.78(s,3H),3.54(s,6H),3.38-3 .32(m,3H),3.19(s,2H),2.99-2.94(m,4H),2.79(d,J=3.2Hz,3H),1.96(s,3H); 13 C NMR(100MHz,DMSO-d6)δ168.89,168.39,167.31,162.07,155.98,153.43 ,149.50,139.11,137.06,135.33,131.77,131.18,130.01,128.53,127.7 0,126.57,126.14,125.89,123.46,122.20,121.99,121.00,119.56,107. 28,100.66,55.45,53.56,48.92,45.94,45.73,44.94,26.24,21.09; HRMS m / z:C 37 H 41 F3N9O6S calcd for [M+H] + :796.2853; found:796.2831.

[0117] 1. Evaluation of FAK kinase inhibitory activity

[0118] Experimental methods:

[0119] The system, consisting of 2 μL of LFAK protein (2.6 ng dissolved in buffer), 2 μL of a mixture of ATP and substrate (ATP final concentration 25 μM dissolved in buffer, substrate final concentration 0.4 μg / μL dissolved in buffer), and 1 μL of DMSO or drug-containing DMSO of different concentrations, was incubated at room temperature for 1 h. Then, 5 μL of ADP-Glo™ Reagent was added, and the mixture was incubated at room temperature for 40 min. Finally, 10 μL of Kinase Detection Reagent was added, and the mixture was incubated at room temperature for 30 min. The chemiluminescence values ​​were then read using a microplate reader (integration time = 500 ms).

[0120] Set up a blank control group and a control group. The blank control group used buffer instead of FAK kinase; the control group used only DMSO. Other reagents remained unchanged.

[0121] Inhibition rate = (Rc-R) / (Rc-Rb) × 100%

[0122] Where R is the luminescence value of the drug treatment group, Rc is the luminescence value of the control group, and Rb is the luminescence value of the blank group.

[0123] IC is calculated using GraphPad based on the inhibition rate. 50 The values ​​are listed in Table 1.

[0124] Table 1. Inhibitory effects of Examples 1-11 and the positive control drug TAE226 on FAK kinase.

[0125] As can be seen from Table 1, the 3-aminosulfonylbenzamide compounds provided in this application have excellent inhibitory activity against FAK, and the compounds prepared in Examples 1, 7, 10 and 11 have inhibitory activity against FAK comparable to that of the positive control drug TAE226.

[0126] 2. Evaluation of cell viability

[0127] Experimental methods:

[0128] Cell lines: HCT116 colon cancer cells, HeLa human cervical cancer cells, MDA-MB-231 human breast cancer cells, and A375 human malignant melanoma cells.

[0129] Cells, after being revived and cultured for two generations, were seeded into 96-well cell culture plates at 2000 cells / 100 μL of medium per well and incubated at 37°C with 5% CO2 for 24 h. Each 96-well plate included a blank control group (no drug administered) and a drug-treated group. For each compound administered, six concentration gradients were set up in three replicates. Cells were incubated together for 72 h after drug administration. Finally, MTS reagent was added for detection. The colorimetric principle of the MTS method is that MTS can be reduced to water-soluble formazan by living cells under the action of phenazine methyl sulfate (PMS). This substance absorbs at 490 nm, and its OD value is directly proportional to the number of living cells. The MTS method is simpler and more accurate than the MTT method. The specific detection method is as follows: Prepare a 2 mg / mL stock solution of MTS and a 0.92 mg / mL stock solution of PMS. Mix the two stock solutions at a volume ratio of 20:1, filter, and add 20 μL to each well of a 96-well plate. Incubate in a cell culture incubator for 3 hours. Measure the OD value at a wavelength of 490 nm using a microplate reader. Calculate the cell proliferation inhibition rate using the following formula: Proliferation inhibition rate = (OD value / 0.92 mg / mL) 空白对照 组 -OD 给药组 ) / (OD 空白对照组 -OD 背景 )×100%. Input the corresponding inhibition rate into Graphpad Prism and calculate IC. 50 The values ​​are listed in Table 2.

[0130] Table 2 shows the test results of Examples 1-11 and the positive control drug TAE226 on different cell activities.

[0131] As shown in Table 2, the 3-aminosulfonylbenzamide compounds provided in this application have significant inhibitory effects on the proliferation of HCT116 colon cancer cells, HeLa human cervical cancer cells, MDA-MB-231 human breast cancer cells, and A375 human malignant melanoma cells. Among them, most of the compounds have better inhibitory activity on the proliferation of MDA-MB-231 human breast cancer cells and A375 human malignant melanoma cells than the positive control drug TAE226.

[0132] Although the above embodiments have provided a detailed description of this application, they are only some embodiments of this application, not all embodiments. People can obtain other embodiments based on the embodiments of this application without creative effort, and these embodiments all fall within the protection scope of this application.

Claims

1. A 3-aminosulfonylbenzamide compound or a pharmaceutically acceptable salt thereof, characterized in that, The 3-aminosulfonylbenzamide compounds have the structure shown in Formula I: In Formula I, X is chloro or trifluoromethyl; R1 and R2 are independently C 1～4 Alkyl groups, or R1 and R2 together with the N atoms attached to them, form a heterocyclic group, which can be a substituted or unsubstituted heterocyclic group, and can be a five- or six-membered heterocyclic group; when the heterocyclic group is a substituted heterocyclic group, the substituent in the substituted heterocyclic group is C. 1～4 One or more of alkyl, phenyl, and acetyl groups.

2. The 3-aminosulfonylbenzamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 and R2 are ethyl groups.

3. The 3-aminosulfonylbenzamide compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The heterocyclic group also contains 1 to 2 heteroatoms selected from N or O.

4. The 3-aminosulfonylbenzamide compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The heterocyclic group is a substituted or unsubstituted piperazine, morpholino, tetrahydropyrrole, or piperidinyl group.

5. The 3-aminosulfonylbenzamide compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The C in the substituted heterocyclic group 1～4 The alkyl group is methyl.

6. The 3-aminosulfonylbenzamide compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The substituted heterocyclic group is 2,6-dimethylmorpholino, methylpiperazino, acetylpiperazino, or tetrahydroisoquinolino.

7. The 3-aminosulfonylbenzamide compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The 3-aminosulfonylbenzamide compounds have any of the structures shown in formulas I-1 to I-11:

8. The 3-aminosulfonylbenzamide compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salt is a salt formed by the reaction of the 3-aminosulfonylbenzamide compound with an inorganic or organic acid; the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, or phosphoric acid; the organic acid is 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, pyric acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, or hydroxyethanesulfonic acid.

9. A method for preparing the 3-aminosulfonylbenzamide compound according to any one of claims 1 to 8, characterized in that, Includes the following steps: A mixture of 3-aminosulfonylbenzoic acid compounds having the structure shown in Formula II, N,N-dimethylformamide, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine was subjected to carboxyl activation, and then mixed with 2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide having the structure shown in Formula III or 2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide having the structure shown in Formula IV was subjected to an amidation reaction to obtain the 3-aminosulfonylbenzoamide compounds; In Equation II, R1 and R2 are defined in the same way as in Equation I.

10. The preparation method according to claim 9, characterized in that, The carboxyl group is activated at a temperature of 10–30°C for 15–30 min.

11. The preparation method according to claim 9, characterized in that, The amidation reaction further includes: mixing the obtained reaction solution with water, extracting with dichloromethane, washing and drying the obtained organic phase, and separating and purifying it using column chromatography.

12. A pharmaceutical composition, characterized in that, This includes the active pharmaceutical ingredient and a pharmaceutically acceptable carrier or excipient; The active pharmaceutical ingredient is a 3-aminosulfonylbenzamide compound as described in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

13. The use of the 3-aminosulfonylbenzamide compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12, in the preparation of a medicament for inhibiting FAK activity.

14. The use of the 3-aminosulfonylbenzamide compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12, in the preparation of a medicament for treating and / or preventing cancer.

15. The application according to claim 14, characterized in that, The cancers mentioned are 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, leukemia, osteosarcoma, melanoma, kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer, or colorectal cancer.

16. A method for treating and / or preventing cancer, characterized in that, Treatment and / or prevention are performed by administering the 3-aminosulfonylbenzamide compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12.

Images