CN111057021B - s-triazine compound and its preparation method and use - Google Patents

Abstract

The invention discloses a class of s-triazine compounds and pharmaceutically acceptable salts thereof. Experiments have proved that the compounds can treat or prevent diseases related to protein kinase activity such as leukemia, Lymphoma.

Description

S-triazine compounds and preparation methods and uses thereof

Technical Field

The present invention relates to a compound and a preparation method and application thereof, in particular to an s-triazine compound and a preparation method and application thereof.

Background Art

With the gradual increase in the incidence and mortality of leukemia and lymphoma, the study of the pathogenesis of leukemia and lymphoma and their clinical treatment have attracted great attention. Studies have shown that the disorder of the B-cell receptor (BCR) signaling pathway is one of the main causes of B-cell leukemia and lymphoma. In malignant B cells, the BCR pathway is abnormally active, inhibiting the normal differentiation and apoptosis of B cells and promoting abnormal proliferation of B cells, thereby leading to the occurrence of a variety of diseases, such as Acute Lymphocytic Leukemia (ALL), Waldenstrom's Macroglobulinemia (WM), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin’s Lymphoma (NHL). Bruton’s tyrosine kinase (Btk) is an important member of the TEC family (TFKs). It is expressed at all developmental stages of B lymphocytes and is a key regulator in the BCR signaling pathway, which has an important impact on the differentiation, proliferation and apoptosis of B cells. Therefore, BTK has become an important therapeutic target for B cell lineage-related diseases.

Given the important role that BTK plays in the occurrence and progression of B-cell tumors, research on small molecule inhibitors targeting BTK has attracted much attention. In recent years, two irreversible BTK inhibitors have been launched. Ibrutinib has been approved by the FDA for the treatment of MCL, CLL, SLL and cGVHD, and Acalabrutinib has been approved for the treatment of CLL. However, despite the great success of Ibrutinib in clinical practice, its drug resistance is still inevitable. Studies have shown that this may be because Ibrutinib impairs tumor adhesion and metastasis, but does not directly cause tumor cell death. The second-generation more selective Btk inhibitor Acalabrutinib will also quickly develop drug-resistant mutations after use. Compared with irreversible inhibitors, reversible inhibitors form weaker forces with BTK molecules in the Btk-specific H3 cavity through hydrogen bonds, van der Waals forces, hydrophobic interactions, etc., have better kinase selectivity, are conducive to reducing toxicity and risks, and make reversible inhibitors more suitable for long-term use. However, reversible inhibitors also have some disadvantages, such as insufficient inhibition strength, short inhibition time, and resistance caused by mutations in the H3 region. Therefore, the development of new BTK inhibitors is of great significance.

Summary of the invention

Purpose of the invention: The purpose of the present invention is to provide an s-triazine compound, and this series of compounds all have an s-triazine mother nucleus. Another purpose of the present invention is to disclose a method for preparing the compound, which method is highly operable and relatively efficient. Another purpose of the present invention is to disclose the use of the compound in the preparation of Bruton's tyrosine kinase inhibitors and the use of the compound in the preparation of drugs for treating or preventing leukemia and lymphoma.

Technical solution: The s-triazine compounds and pharmaceutically acceptable salts thereof of the present invention comprise compounds having a structure as shown in general formula (I) or general formula (II):

Wherein, n = 1-2;

Ring A is selected from aryl groups;

X is selected from C, N, O;

R is selected from H, Cl, NH ₂ ;

R ₂ is selected from substituted or unsubstituted aryl, heteroaryl, R ₅ O-, CH ₃ O(CH2)n-, R ₆ CO-, R ₇ NHCO-; wherein, when R ₂ is selected from heteroaryl, the heteroaryl contains at least one N atom, and the substituent is C1-C3 alkyl, halogen, methoxy or trifluoromethoxy; when R ₂ is selected from R ₅ O-, R ₅ is substituted or unsubstituted phenyl, and the substituent is selected from methyl and methoxy; when R ₂ is selected from CH ₃ O(CH2)n-, n=1-4; when R ₂ is selected from R ₆ CO-, R ₆ is a five-membered or six-membered unsaturated heterocycle; when R ₂ is selected from R ₇ NHCO-, R ₇ is substituted or unsubstituted aryl or heteroaryl, and the heteroaryl contains at least one heteroatom, and the heteroatom is selected from N, O, S, and the substituent is selected from C1-C4 alkyl, halogen, methoxy, trifluoromethoxy;

R ₃ is selected from H, C1-C3 alkyl;

R ₄ is selected from R ₈ CONH-, wherein R ₈ is selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, saturated five-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N, and S;

The halogen is selected from F, Cl, Br, and I.

The compound and its pharmaceutically acceptable salt:

wherein ring A is selected from phenyl;

R ₂ is selected from substituted or unsubstituted pyridine, R ₅ O-, CH ₃ O(CH2)n-, R ₆ CO-, R ₇ NHCO-; wherein, when R ₂ is selected from substituted or unsubstituted pyridine, the substituent is methyl, halogen, methoxy or trifluoromethoxy; when R ₂ is selected from R ₅ O-, R ₅ is substituted or unsubstituted phenyl, wherein the substituent is selected from methyl and methoxy; when R ₂ is selected from CH ₃ O(CH2)n-, n=1-4; when R ₂ is selected from R ₆ CO-, wherein R ₆ is tetrahydropyrrole, morpholine, piperidine; when R ₂ is selected from R ₇ NHCO-, wherein R ₇ is substituted or unsubstituted aryl or heteroaryl, wherein the heteroaryl contains at least one heteroatom selected from N, O, S, and the substituent is selected from methyl, halogen, methoxy, trifluoromethoxy;

R ₃ is selected from H, CH ₃ .

The compound and its pharmaceutically acceptable salt are selected from the following compounds:

N-(3-((4-amino-6-((4-phenoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-amino-6-((4-(2-methoxyethoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-chloro-6-((4-phenoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-chloro-6-((4-(2-methoxyethoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-((4-phenoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-((4-(2-methoxyethoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-((4-(2-methoxyphenoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-((4-(morpholine-4-carbonyl)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-((4-(piperidine-1-carbonyl)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

4-((4-((3-Acrylamidophenyl)amino)-1,3,5-triazin-2-yl)amino)-N-(pyridin-2-yl)benzamide;

4-((4-((3-Acrylamidophenyl)amino)-1,3,5-triazin-2-yl)amino)-N-(5-methylpyridin-2-yl)benzamide;

N-(3-((4-((4-(pyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-((4-(6-methylpyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-((4-(6-methoxypyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-((4-(6-fluoropyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(3-((4-((4-(6-chloropyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

N-(2-methyl-5-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;

(E)-N-(3-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)but-2-enamine;

1-(6-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)indolin-1-yl)prop-2-en-1-one;

1-(3-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)but-2-yn-1-one;

N-(3-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)thiophene-2-carboxamide.

A pharmaceutical composition comprising any of the above compounds and pharmaceutically acceptable salts thereof.

The composition is prepared by adding pharmaceutically acceptable excipients to any of the above-mentioned compounds and pharmaceutically acceptable salts thereof.

The method for preparing the compound and its pharmaceutically acceptable salt comprises the following steps:

Reaction conditions: (a) Michael acceptor, sodium carbonate, acetone, 0°C, 1h; (b) ammonia, tetrahydrofuran, 36°C, 3h; (c) aromatic amine, palladium acetate, 1,1'-bis(diphenylphosphino)ferrocene, cesium carbonate, dioxane, 110°C; (d) aromatic amine, sodium carbonate, acetone, 60°C, 4h;

or:

Reaction conditions: (e) Michael acceptor, N,N-diisopropylpropylamine, dioxane, room temperature, 5 min; (f) aromatic amine, palladium acetate, 1,1'-bis(diphenylphosphino)ferrocene, cesium carbonate, dioxane, 110°C, 5 h.

The compound and pharmaceutically acceptable salts thereof are used in preparing drugs for inhibiting Bruton's tyrosine kinase.

The compound and pharmaceutically acceptable salts thereof are used in preparing drugs for treating or preventing leukemia.

The compound and pharmaceutically acceptable salts thereof are used in preparing drugs for treating or preventing lymphoma.

In some embodiments, the compound is selected from the following compounds

The codes of the compounds in the pharmacological experiments and experimental examples are equivalent to the structures of the compounds corresponding to the above codes.

Beneficial effects: The s-triazine compounds and pharmaceutically acceptable salts thereof of the present invention can be used to prepare Bruton's tyrosine kinase inhibitors to treat or prevent diseases related to the activity of the kinase, such as leukemia and malignant lymphoma, by inhibiting Btk.

DETAILED DESCRIPTION

1H-NMR nuclear magnetic resonance was measured by a Bruker AV300 (300HZ) nuclear magnetic resonance instrument (TMS as internal standard), and mass spectra were measured by a Shimadzu GC/MS-QP2010 mass spectrometer (EI-MS) and an Agilent 100LC-MDS-Trans/SL mass spectrometer (EI-MS), respectively.

The silica gel for column chromatography was 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel (Qingdao Ocean Chemical Plant), and the eluent was petroleum ether-ethyl acetate system or dichloromethane-methanol system. Thin layer chromatography (TLC) used GF254 thin layer chromatography plate (Yantai Jiangyou Silica Gel Development Co., Ltd.); the TLC development system was petroleum ether-ethyl acetate system or dichloromethane-methanol system; TLC was irradiated and displayed under ZF7 three-purpose UV analyzer (Henan Gongyi Yuhua Instrument Co., Ltd.). The purity of some compounds was detected by Shimadzu HPLC at 254nm, and the mobile phase was methanol/water system.

Synthetic route

Route 1

Reaction conditions: (a) Michael acceptor, sodium carbonate, acetone, 0℃, 1h; (b) ammonia water, tetrahydrofuran, 36℃, 3h; (c) aromatic amine, palladium acetate, 1,1'-bis(diphenylphosphino)ferrocene, cesium carbonate, dioxane, 110℃; (d) aromatic amine, sodium carbonate, acetone, 60℃, 4h.

Route 2:

Reaction conditions: (e) Michael acceptor, N,N-diisopropylpropylamine, dioxane, room temperature, 5 min; (f) aromatic amine, palladium acetate, 1,1'-bis(diphenylphosphino)ferrocene, cesium carbonate, dioxane, 110°C, 5 h.

Example 1

Synthesis of Intermediate N-(3-aminophenyl)acrylamide

Add m-nitroaniline (3 g, 21.70 mmol) and sodium bicarbonate (5.02 g, 32.60 mmol) to 20 ml acetonitrile and mix well. Add acryloyl chloride (1 eq) dropwise under ice bath, stir for 30 min at room temperature, precipitate with water, and filter to obtain a white solid (3.94 g, 94.47%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ10.49 (s, 1H), 8.57 (q, J＝2.0 Hz, 1H), 7.88–7.73 (m, 2H), 7.49 (td, J＝8.2, 1.5 Hz, 1H), 6.38–6.13 (m, 2H), 5.70 (td, J＝9.8, 1.9 Hz, 1H).

N-(3-nitrophenyl)acrylamide (0.5 g, 2.60 mmol), reduced iron powder (0.44 g, 7.80 mmol), ammonium chloride (0.42 g, 7.80 mmol) were placed in a 10 ml mixed solvent of ethanol and water (1:1), and reacted at 85°C for 1 h. Filtered, the filter cake was washed with ethyl acetate, separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure, and a yellow solid (0.37 g, 87.84%) was obtained by column chromatography. ¹ H NMR(300MHz, DMSO-d ₆ )δ9.78(s,1H),7.08–6.84(m,2H),6.76(d,J＝8.0Hz,1H),6.42(dd,J＝17.0,10.0Hz,1H),6.34–6.12(m,2H),5.75–5.60(m,1H),5.0 5(s,2H).

Example 2

Synthesis of Intermediate N-(3-amino-4-methylphenyl)acryloyl chloride

The synthesis method was the same as that of Example 1, and 0.47 g of a white solid was obtained by column chromatography with a yield of 80.82%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.08 (s, 1H), 6.70 (d, J=8.1 Hz, 1H), 6.62 (s, 1H), 6.37 (dd, J=17.0, 10.0 Hz, 1H), 6.19 (dd, J=8.1, 2.3 Hz, 1H), 6.07 (dd, J=17.0, 2.1 Hz, 1H), 5.56 (dd, J=10.1, 2.2 Hz, 1H), 4.75 (s, 2H), 1.89 (s, 3H).

Example 3

Synthesis of Intermediate (E)-N-(3-aminophenyl)butyl-2-enamide

The synthesis method was the same as that of Example 1, and 0.16 g of yellow oil was obtained by column chromatography, with a yield of 93.51%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.66 (s, 1H), 7.01 (s, 1H), 6.95 (d, J = 15.7 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 6.29 (d, J = 8.0 Hz, 1H), 6.15 (d, J = 15.2 Hz, 1H), 5.09 (s, 2H), 1.89 (d, J = 6.9 Hz, 3H).

Example 4

Synthesis of Intermediate N-(3-aminophenyl)butyl-2-ynamide

The synthesis method was the same as that in Example 1, and 0.83 g of yellow solid was obtained by column chromatography, with a yield of 97.23%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ10.25 (s, 1H), 6.94-6.86 (m, 2H), 6.65 (d, J＝7.9 Hz, 1H), 6.26 (dd, J＝7.8, 2.2 Hz, 1H), 5.07 (s, 2H), 2.01 (s, 3H).

Example 5

Synthesis of Intermediate N-(3-aminophenyl)thiophene-2-carboxamide

The synthesis method was the same as that of Example 1, and a yellow solid was obtained by column chromatography with a yield of 43.8%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.95 (s, 1H), 8.02 (d, J = 3.8 Hz, 1H), 7.84 (d, J = 5.0 Hz, 1H), 7.22 (t, J = 4.3 Hz, 1H), 7.00 (dd, J = 16.6, 8.7 Hz, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.54-6.10 (m, 1H), 5.13 (s, 1H), 3.39 (s, 1H).

Example 6

Synthesis of Intermediate 1-(6-aminoindol-1-yl)propyl-2-en-1-one

The synthesis method was the same as that of Example 1, and a white solid was obtained by column chromatography with a yield of 46.20%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.38 (s, 1H), 6.71 (d, J=7.7 Hz, 1H), 6.56 (s, 1H), 6.10 (dd, J=9.2, 3.7 Hz, 2H), 5.67-5.56 (m, 1H), 4.89-4.77 (m, 2H), 3.96 (s, 2H), 2.79 (s, 2H).

Example 7

Synthesis of Intermediate 4-(2-methoxyethoxy)aniline

Add p-fluoronitrobenzene (0.5 g, 3.54 mmol), ethylene glycol methyl ether (0.335 ml, 4.25 mmol), and potassium hydroxide (0.3 g, 5.31 mmol) into 10 ml of dimethyl sulfoxide, stir at 60°C overnight, precipitate with water, and filter to obtain 0.537 g of a yellow solid. The yield is 76.9%.

Example 8

Synthesis of Intermediate 4-(Morpholinecarbonyl)aniline

Under ice bath, p-nitrobenzoyl chloride (1 g, 5.39 mmol) was added in batches to an anhydrous tetrahydrofuran solution containing morpholine (0.7 g, 8.08 mmol) and triethylamine (1.5 eq). The mixture was reacted for 1 h, extracted with ethyl acetate, and the solvent was dried to obtain 1.3 g of a white solid with a yield of 100%.

The above product, reduced iron powder (3eq), and ammonium chloride (3eq) were placed in a 10ml mixed solvent of ethanol and water (1:1) and reacted at 85°C for 1h. Filter, wash the filter cake with ethyl acetate, separate the liquids, wash with saturated brine, and dry over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure, and a light yellow solid was obtained by column chromatography with a yield of 82.1%. ¹ H NMR (300MHz, DMSO-d ₆ )δ6.99(d, J＝8.4Hz,2H),6.41(d, J＝8.4Hz,2H),5.40(s,2H),3.44(m, J＝4.3Hz,4H),3.38–3.28(m,4H).

Example 9

Synthesis of Intermediate 4-(Piperidinyl)aniline

The synthesis method was the same as that of Example 8, and a yellow solid was obtained by column chromatography with a yield of 84.0%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.09 (d, J=8.5 Hz, 2H), 6.54 (d, J=8.5 Hz, 2H), 5.47 (s, 2H), 3.56-3.37 (m, 4H), 1.60 (dt, J=11.1, 5.7 Hz, 2H), 1.48 (q, J=10.9, 8.9 Hz, 4H).

Example 10

Synthesis of Intermediate 4-Amino-N-(pyridin-2-yl)benzamide

The synthesis method was the same as that of Example 8, and a yellow solid was obtained by column chromatography with a yield of 89.9%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.80 (m, J = 8.5 Hz, 3H), 7.22-7.01 (m, 1H), 6.60 (d, J = 8.6 Hz, 2H), 5.84 (s, 2H).

Embodiment 11

Synthesis of Intermediate 4-Amino-N-(5-methylpyridin-2-yl)benzamide

The synthesis method was the same as that of Example 8, and a yellow solid was obtained by column chromatography with a yield of 89.9%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.61 (dd, J = 8.5, 1.8 Hz, 1H), 6.59 (d, J = 8.5 Hz, 2H), 5.82 (s, 2H), 2.27 (s, 3H).

Example 12

Synthesis of Intermediate 4-(Pyridin-3-yl)aniline

Add p-bromonitrobenzene (2 g, 9.9 mmol), pyridine-3-boric acid (1 eq), bistriphenylphosphine palladium chloride (0.1 eq) and potassium carbonate (2 eq) to anhydrous dioxane, protect with nitrogen, react at 80°C for 10 h, precipitate with water, filter and perform column chromatography to obtain a yellow solid (1.4 g, 70%).

The above product, reduced iron powder (3eq), and ammonium chloride (3eq) were placed in a 10ml mixed solvent of ethanol and water (1:1), and reacted at 85°C for 1h. Filter, wash the filter cake with ethyl acetate, separate the liquids, wash with saturated brine, and dry over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure, and a yellow solid was obtained by column chromatography with a yield of 92.4%. ¹ H NMR (300MHz, DMSO-d ₆ )δ8.80(s,1H),8.43(d,J＝4.6Hz,1H),7.93(d,J＝7.9Hz,1H),7.45(s,1H),7.42(s,1H),7.39(dd,J＝8.0,4.8Hz,1H),6.66(s,2H),5.37(s,2H).

Example 13

Synthesis of Intermediate 4-(6-methylpyridin-3-yl)aniline

The synthesis method was the same as that of Example 12, and a yellow solid was obtained by column chromatography with a yield of 79.8%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 8.94 (d, J = 10.5 Hz, 1H), 8.52 (d, J = 8.4 Hz, 2H), 8.37 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 4.52 (s, 2H), 3.60 (s, 3H).

Embodiment 14

Synthesis of Intermediate 4-(6-methoxypyridin-3-yl)aniline

The synthesis method was the same as that of Example 12, and a yellow solid was obtained by column chromatography with a yield of 82.1%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.18 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 11.1 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.6 Hz, 1H), 6.49 (d, J = 8.4 Hz, 2H), 5.07 (s, 1H), 3.70 (s, 3H).

Embodiment 15

Synthesis of Intermediate 4-(6-fluoropyridin-3-yl)aniline

The synthesis method was the same as that of Example 12, and a yellow solid was obtained by column chromatography with a yield of 86.3%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ8.34 (s, 1H), 8.06 (td, J=8.3, 2.6 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.11 (dd, J=8.5, 3.0 Hz, 1H), 6.77-6.43 (m, 2H), 5.29 (s, 2H).

Example 16

Synthesis of Intermediate 4-(6-chloropyridin-3-yl)aniline

The synthesis method was the same as that of Example 12, and a yellow solid was obtained by column chromatography with a yield of 81.4%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.55 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 8.4, 2.5 Hz, 1H), 7.39 (dd, J = 13.1, 8.5 Hz, 3H), 6.61 (d, J = 8.4 Hz, 2H), 5.37 (s, 3H).

Embodiment 17

Synthesis of Intermediate N-(3-((4,6-dichloro-1,3,5-triazine-2-yl)amino)phenyl)acrylamide

Cyanuric chloride (4.67 g, 21.6 mmol) was dissolved in acetone, and an acetone solution containing acrylamide (1 eq) was slowly added dropwise under ice bath, and the temperature was maintained for 3.5 h. After precipitation, 8.3 g of white solid was obtained by suction filtration, with a yield of 78.5%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.77 (s, 1H), 10.22 (s, 1H), 8.64 (s, 1H), 7.97 (s, 1H), 7.50 (d, J = 5.9 Hz, 1H), 7.42–7.21 (m, 2H), 6.57–6.36 (m, 1H), 6.27 (d, J = 16.5 Hz, 1H), 5.86–5.65 (d, J = 10.1 Hz, 1H).

Embodiment 18

Synthesis of Intermediate N-(3-((4-amino-6-chloro-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

N-(3-((4,6-dichloro-1,3,5-triazine-2-yl)amino)phenyl)acrylamide (1 g, 3.22 mmol) and 30% aqueous ammonia (1 eq) were added to a tetrahydrofuran solution, reacted at 60° C. for 4 h, precipitated with water, and filtered to obtain 0.89 g of a white solid with a yield of 89%. ¹ HNMR (300MHz, DMSO-d ₆ ) δ10.05(s,1H),9.88(s,1H),7.64(s,1H),7.52(m,2H),7.37(d,J＝8.5Hz,2H),7.17(t,J＝8.1Hz,1H),6.39(dd,J＝16.9,10.1Hz,1 H),6.18(d,J＝17.1Hz,1H),5.76–5.61(d,J＝10.3Hz,1H).

Embodiment 19

Synthesis of Intermediate N-(3-((4-chloro-1,3,5-triazine-2-yl)amino)phenyl)acrylamide

2,4-Dichloro-s-triazine (1 g, 6.7 mmol) was dissolved in dioxane solution, 4-aminophenylacrylamide (1 eq) and DIPEA (1.1 eq) were slowly added dropwise at room temperature, reacted for 5 min, precipitated with water, and filtered to obtain 1.6 g of white solid with a yield of 80.4%. ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 10.79 (s, 1H), 10.24 (s, 1H), 8.64 (s, 1H), 7.97 (d, J = 26.7 Hz, 1H), 7.50 (s, 1H), 7.43–7.10 (m, 2H), 6.47 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (d, J = 18.9 Hz, 1H), 5.76 (d, J = 12.0 Hz, 1H).

Embodiment 20

Synthesis of Intermediate N-(5-((4-chloro-1,3,5-triazine-2-yl)amino)-2-methylphenyl)acrylamide

The synthesis method was the same as that of Example 19, and a white solid was obtained by water precipitation with a yield of 73%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 8.93 (s, 1H), 8.47 (s, 1H), 7.47 (s, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.12 (dd, J = 7.5, 1.6 Hz, 1H), 6.39 (dd, J = 16.8, 10.1 Hz, 1H), 5.90 (dd, J = 10.1 Hz, 3.1 Hz, 1H), 5.87-5.80 (m, 1H), 1.89 (s, 3H).

Embodiment 21

Intermediate (E)-N-(3-((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)but-2-enamine

The synthesis method was the same as that of Example 19, with a yield of 78.8%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.92 (s, 1H), 9.20 (s, 1H), 8.47 (s, 1H), 7.67 (s, 0H), 7.31 (d, J = 7.5 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 5.9 Hz, 1H), 6.89-6.78 (m, 1H), 6.11 (d, J = 16.1 Hz, 1H), 1.99 (s, 3H).

Example 22

Intermediate 1-(6-((4-chloro-1,3,5-triazine-2-yl)amino)indolin-1-yl)acrylamide

The synthesis method was the same as that of Example 19, with a yield of 78.2%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.47 (s, 1H), 7.49 (s, 1H), 7.22 (s, 1H), 7.00 (s, 1H), 6.32 (dd, J = 16.8, 10.1 Hz, 1H), 6.01–5.53 (m, 2H), 4.30 (m, J = 7.1 Hz, 2H), 3.36–3.09 (m, 2H).

Embodiment 23

Synthesis of Intermediate N-(3-((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)but-2-ynylamide

The synthesis method was the same as that of Example 19, with a yield of 76.4%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.78 (s, 1H), 10.71 (s, 1H), 8.64 (s, 1H), 7.95 (s, 1H), 7.56–6.93 (m, 3H), 3.54 (s, 3H).

Embodiment 24

Synthesis of Intermediate N-(3-((4-chloro-1,3,5-triazine-2-yl)amino)phenyl)thiophene-2-amide

The synthesis method was the same as that of Example 19, with a yield of 74.2%. ¹ H NMR (300 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.35 (s, 1H), 8.67 (s, 1H), 8.07 (d, J = 3.7 Hz, 2H), 7.88 (d, J = 5.0 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.46-7.32 (m, 1H), 7.25 (t, J = 4.4 Hz, 1H).

Embodiment 25

Synthesis of N-(3-((4-amino-6-((4-phenoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (A1)

4-aminodiphenyl ether (1 eq) and DIPEA (4 eq) were added to an acetone solution containing N-(3-((4-amino-6-chloro-1,3,5-triazine-2-yl)amino)phenyl)acrylamide, reacted at 80°C for 24 h, extracted with ethyl acetate, and the solvent was dried by spin drying. A white solid was obtained by column chromatography with a yield of 46.4%. ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.05(s,1H),9.11(s,1H),9.09(s,1H),7.82(s,2H),7.79(s,1H),7.59(s,1H),7.36(t,J＝9.2Hz,3H),7.20(t,J＝7.3Hz,1H),7.09(t,J＝7.3Hz,1H) ¹³ C NMR(75MHz,-d6)δ167.31,165.05,164.85,163.51,158.28,150.78,140.87,139.32,136.87,132.43,130.34,128.91,127.10,123.09,121.95,119.8 4,117.91,116.70.HRMS(ESI)m/z calcd for C ₂₄ H ₂₁ N ₇ O ₂ [M+H] ⁺ 440.1836, found 440.1790.

Embodiment 26

Synthesis of N-(3-((4-amino-6-((4-(2-methoxyethoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (A2)

The synthesis method is the same as that of Example 25, with a yield of 40.4%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.07 (s, 1H), 9.09 (s, 1H), 8.89 (s, 1H), 7.81 (s, 1H), 7.65 (d, J = 8.4Hz, 3H), 7.36 (d, J = 7.9Hz, 1H), 7.21 (t, J = 8.1Hz, 1H), 6.82 ( d,J＝8.8Hz,2H),6.62–6.40(m,3H),6.27(d,J＝18.6Hz,1H),5.76(d,J＝8.7Hz,1H),4.15–3.95(m,2H),3.71–3.55(m,2H),3.31(s,3H). ¹³ C NMR (101MHz, DM SO-d ₆ )δ167.30,165.04,164.86,163.48,153.96,140.96,139.28,133.88,132.46,128.92,127.20,122.06,116.63,114.55,70.95,67.44,58.63.HRMS(ES I)m/z calcd for C ₂₁ H ₂₃ N ₇ O ₃ [M+H] ⁺ 422.1938, found 422.1896.

Embodiment 27

Synthesis of N-(3-((4-chloro-6-((4-phenoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (A3)

4-aminodiphenyl ether (1 eq) was added in batches to an acetone solution containing N-(3-((4,6-dichloro-1,3,5-triazine-2-yl)amino)phenyl)acrylamide at room temperature, and triethylamine (2 eq) was added at the same time. The mixture was reacted at room temperature for 2 h, extracted with ethyl acetate, and the solvent was dried by spin drying. A white solid was obtained by column chromatography with a yield of 62.1%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 10.17 (s, 1H), 7.90 (s, 2H), 7.67 (s, 3H), 7.48–7.17 (m, 1H), 7.10 (m, J = 7.4 Hz, 3H), 7.05–6.77 (m, 1H), 6.40 (s, 1H), 6.23 (s, 1H), 5.69 (d, J = 24.4 Hz, 1H). ¹³ C NMR(75MHz,-d6)δ167.42,165.01,164.82,163.51,157.81,150.78,139.84,139.32,136.87,132.43,131.15,128.90,127.20,123.09,120.31,119.8 9,117.91,114.89.HRMS(ESI)m/z calcd for C ₂₄ H ₁₉ ClN ₆ O ₂ [M+H] ⁺ 459.1333, found 459.1229.

Embodiment 28

Synthesis of N-(3-((4-chloro-6-((4-(2-methoxyethoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (A4)

The synthesis method is the same as that of Example 27, with a yield of 57.2%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.25(s,1H),10.18(s,1H),10.13(s,1H),7.82(s,1H),7.71(s,1H),7.52(s,2H),7.41(s,1H),7.28(t,J＝7.6Hz,1H),6.88(d ,J＝36.1Hz,2H),6.47(dt,J＝18.7,9.4Hz,1H),6.28(d,J＝16.9Hz,1H),5.77(d,J＝10.0Hz,1H),4.03(s,2H),3.64(s,2H),3.38(s,3H). ¹³ C NMR (101MHz, DMSO -d ₆ )δ168.53,164.58,163.59,155.18,139.56,132.32,131.68,129.22,127.42,123.05,114.71,70.87,67.49,58.64.HRMS(ESI)m/z calcd for C ₂₁ H ₂₁ ClN ₆ O ₃ [M+H] ⁺ 441.1450, found 441.1334.

Embodiment 29

Synthesis of N-(3-((4-((4-phenoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (A5)

N-(3-((4-chloro-1,3,5-triazine-2-yl)amino)phenyl)acrylamide (1 eq), 4-aminodiphenyl ether (1 eq), cesium carbonate (1.5 eq), palladium acetate (0.08 eq) and 1,1'-bis(diphenylphosphino)ferrocene (0.6 eq) were added to a dioxane solution, reacted at 90°C for 6 h, the dioxane was removed by rotary evaporation, and a white solid was obtained by column chromatography with a yield of 42.4%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.14(s,1H),9.81(s,2H),8.35(s,1H),7.92(s,1H),7.75(s,2H),7.37(t,J＝7.9Hz,3H),7.25(t,J＝8.1Hz,1H),7.10(t,J＝7. 4Hz, 1H), 6.97 (d, J = 7.8Hz, 4H), 6.59–6.28 (m, 1H), 6.23 (d, J = 18.5Hz, 1H), 5.70 (d, J = 9.8Hz, 1H). ¹³ C NMR (75MHz, DMSO-d ₆ )δ166.57,164.06,163.80,163.62,158.01,151.75,139.53,135.55,132.29,130.40,130.16,129.15,127.33,123.31,122.59,119.86,118.12,1 16.89.HRMS(ESI)m/z calcdfor C ₂₄ H ₂₀ N ₆ O ₂ [M+H] ⁺ 425.1726,found 425.1681.

Embodiment 30

Synthesis of N-(3-((4-((4-(2-methoxyethoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (A6)

The synthesis method is the same as that of Example 29, with a yield of 45.1%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.17 (s, 1H), 9.78 (s, 1H), 9.68 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.64 (d, J = 7.0Hz, 2H), 7.43 (d, J = 7.2Hz, 1H), 7.28 (t, J = 8.0 Hz,1H),6.89(d,J＝7.7Hz,2H),6.51(dd,J＝16.9,10.0Hz,1H),6.30(d,J＝16.7Hz,1H),5.91–5.62(m,1H),4.06(s,2H),3.76–3.58(m,2H),3.41(s,3H). ¹³ C NMR (75MHz, DMSO-d ₆ )δ166.46,164.74–163.90(m),163.66,154.74,139.81,139.43,132.53,132.30,129.15,127.46,122.72,115.89–112.59(m),70.89,67.47,5 8.62.HRMS(ESI)m/zcalcd for C ₂₂ H ₂₂ N ₆ O ₃ [M+H] ⁺ 407.1826, found 407.1787.

Embodiment 31

Synthesis of N-(3-((4-((4-(2-methoxyphenoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (B1)

The synthesis method was the same as that of Example 29, with a yield of 41.6%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 9.78 (s, 2H), 8.34 (s, 1H), 7.93 (s, 1H), 7.70 (s, 2H), 7.40 (d, J = 6.9 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.95 (s, 4H), 6.89 (d, J = 7.8 Hz, 2H), 6.45 (dd, J = 19.2, 7.4 Hz, 1H), 6.25 (d, J = 16.8 Hz, 1H), 5.72 (d, J = 9.5 Hz, 1H), 3.75 (s, 3H). ¹³ C NMR (101 MHz, DMSO-d ₆ )δ166.52,164.05,163.79,163.58,155.72,153.40,150.79,139.52,134.70,132.32,129.10,127.26,122.70,120.29,118.41,115.45,55.86.HRMS (ESI)m/z calcd for C ₂₅ H ₂₂ N ₆ O ₃ [M+H] ⁺ 455.1827,found 455.1787.

Embodiment 32

Synthesis of N-(3-((4-((4-(morpholine-4-carbonyl)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (B2)

The synthesis method was the same as that of Example 29, with a yield of 39.8%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 10.00 (s, 1H), 9.90 (s, 1H), 8.42 (s, 1H), 7.97 (s, 2H), 7.89 (s, 2H), 7.62–7.20 (m, 3H), 6.50 (dd, J=16.7, 10.1 Hz, 1H), 6.29 (d, J=16.9 Hz, 1H), 5.93–5.59 (m, 1H), 3.62 (s, 4H), 3.52 (s, 4H). ¹³ C NMR (75 MHz, DMSO-d ₆ )δ169.51,166.69,164.10,163.87,163.63,141.11,139.59,132.36,129.52,129.18,128.36,127.35,120.01,66.60.HRMS(ESI)m/z calcd forC ₂₃ H ₂₃ N ₇ O ₃ [M+H] ⁺ 446.1937,found 446.1896.

Embodiment 33

Synthesis of N-(3-((4-((4-(piperidine-1-carbonyl)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (B3)

The synthesis method was the same as that of Example 29, with a yield of 42.8%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.97 (s, 1H), 9.88 (s, 1H), 8.40 (s, 1H), 7.94 (s, 1H), 7.83 (s, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 8.0 Hz, 3H), 6.48 (dd, J = 16.9, 10.1 Hz, 1H), 6.27 (d, J = 18.7 Hz, 1H), 5.75 (d, J = 11.9 Hz, 1H), 1.56 (d, J = 47.3 Hz, 6H). ¹³ C NMR (75 MHz, DMSO-d ₆ )δ169.29,166.66,164.08,163.86,163.59,140.77,140.75,139.59,132.36,130.58,129.15,127.90,127.30,120.04,26.27,24.58.HRMS(ESI)m/z calc d for C ₂₄ H ₂₅ N ₇ O ₂ [M+H] ⁺ 444.2134,found 444.2103.

Embodiment 34

Synthesis of 4-((4-((3-acrylamidephenyl)amino)-1,3,5-triazine-2-yl)amino)-N-(pyridin-2-yl)benzamide (B4)

The synthesis method is the same as that of Example 29, with a yield of 29.4%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.63(s,1H),10.13(s,1H),9.98(s,1H),8.47(s,1H),8.41(s,1H),8.23(d,J＝8.1Hz,1H),8.00(d,J＝13.1Hz,5H ),7.86(t,J＝7.2Hz,1H),7.55(s,1H),7.46(d,J＝7.2Hz,1H),7.37(d,J＝7.5Hz,1H),7.18(s,1H),6.62–6.37(m,1H),6.29(d,J＝16.8Hz,1H),5.75(d,J＝9 .6Hz,1H). ¹³ C NMR (75MHz, DMSO-d ₆ ) δ166.75,165.84,164.11,163.90,163.66,152.84,148.34,143.31,139.65,138.52,132.36,129.24,127.88,127.33,120.08,1 19.53,115.14.HRMS(ESI)m/z calcd for C ₂₄ H ₂₀ N ₈ O ₂ [M+H] ⁺ 453.1779, found 453.1743.

Embodiment 35

Synthesis of 4-((4-((3-acrylamidephenyl)amino)-1,3,5-triazine-2-yl)amino)-N-(5-methylpyridin-2-yl)benzamide (B5)

The synthesis method was the same as in Example 29, with a yield of 30.6%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.54(s,1H),10.18(s,1H),10.11(s,1H),9.97(s,1H),8.45(s,1H),8.21(s,1H),8.12(d,J＝8.4Hz,1H),8.01(d,J＝7.9Hz,2H),7.95(s,2H),7.64( d,J＝10.7Hz,1H),7.54(s,1H),7.45(d,J＝8.0Hz,1H),7.33(t,J＝8.0Hz,1H),6.49(dd,J＝16.9,10.1Hz,1H),6.27(d,J＝16.9Hz,1H),5.72(s,1H),2.28(s ,3H). ¹³ C NMR (101MHz, DMSO-d ₆ ) δ166.73,165.60,164.10,163.89,163.64,150.65,148.03,143.20,139.66,138.86,132.37,129.21,129.15,128.96,127.98, 127.29,119.51,114.71,17.78.HRMS(ESI)m/z calcd for C ₂₅ H ₂₂ N ₈ O ₂ [M+H] ⁺ 467.1943,found467.1899.

Embodiment 36

Synthesis of N-(3-((4-((4-(pyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (B6)

The synthesis method is the same as that of Example 29, with a yield of 37.4%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.22(s,1H),9.93(s,1H),8.91(s,1H),8.57(s,1H),8.43(s,1H),8.05(d,J＝7.6Hz,1H),7.95(d, ^J ＝6.7Hz,3H),7 ... d ₆ )δ166.65,164.11,163.85,163.60,148.42,147.76,139.89,139.69,139.54,135.68,134.00,132.35,131.43,129.22,127.37,124.28,121.15.H RMS(ESI)m/z calcdfor C ₂₃ H ₁₇ N ₇ O[M+H] ⁺ 410.1731, found 410.1685.

Embodiment 37

Synthesis of N-(3-((4-((4-(6-methylpyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (B7)

The synthesis method was the same as that of Example 29, with a yield of 32.1%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.23 (s, 1H), 9.96 (d, J = 12.9 Hz, 2H), 8.76 (s, 1H), 8.42 (s, 1H), 7.99 (s, 1H), 7.92 (d, J = 7.7 Hz, 3H), 7.63 (d, J = 7.3 Hz, 2H), 7.46 (d, J = 7.7 Hz, 1H), 7.33 (dt, J = 7.9, 3.9 Hz, 1H), 6.50 (dd, J = 16.9, 10.0 Hz, 1H), 6.29 (d, J = 16.9 Hz, 1H), 5.86-5.60 (m, 1H). ¹³ C NMR (75 MHz, DMSO-d ₆ )δ166.63,164.09,163.83,163.59,156.76,146.94,139.53,134.27,132.80,132.33,131.59,129.22,127.39,127.07,123.55,121.17,24.13.HRMS (ESI)m/z calcd for C ₂₄ H ₂₁ N ₇ O[M+H] ⁺ 424.1882,found 424.1841.

Embodiment 38

Synthesis of N-(3-((4-((4-(6-methoxypyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (B8)

The synthesis method is the same as that of Example 29, with a yield of 34.8%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.20 (s, 1H), 9.89 (s, 2H), 8.48 (s, 1H), 8.41 (s, 1H), 7.98 (d, J = 6.9Hz, 2H), 7.89 (d, J = 7.2Hz, 2H), 7.59 (d, J = 7.3Hz, 2H), 7.45 ( ¹³ C NMR(75MHz,DMSO-d ₆ )δ166.62,164.12,163.84,163.64,163.22,144.65,139.52,139.10,137.60,132.33,131.58,129.51,129.21,127.37,126.76,121.25,110.97,5 3.70.HRMS(ESI)m/z calcd for C ₂₄ H ₂₁ N ₇ O ₂ [M+H] ⁺ 440.1831,found 440.1790.

Embodiment 39

Synthesis of N-(3-((4-((4-(6-fluoropyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (B9)

The synthesis method was the same as that of Example 29, with a yield of 47.2%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 9.99 (s, 1H), 9.94 (s, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 8.25 (t, J = 9.0 Hz, 1H), 8.07–7.83 (m, 3H), 7.65 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H), 7.38–7.20 (m, 1H), 6.49 (dd, J = 16.9, 10.0 Hz, 1H), 6.31 (s, 1H), 5.75 (d, J = 10.5 Hz, 1H). ¹³ C NMR (75 MHz, DMSO-d ₆ )δ166.65,164.30,164.09,163.84,163.59,161.18,145.41,145.21,140.27,139.52,134.31,132.33,130.25,129.23,127.37,121.11,110.27,1 09.78.HRMS(ESI)m/z calcd for C ₂₃ H ₁₈ FN ₇ O[M+H] ⁺ 428.1631, found 428.1590.

Embodiment 40

Synthesis of N-(3-((4-((4-(6-chloropyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (B10)

The synthesis method was the same as that of Example 29, with a yield of 46.6%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 9.98 (d, J = 19.4 Hz, 2H), 8.74 (s, 1H), 8.43 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 7.97 (s, 3H), 7.69 (s, 2H), 7.59 (d, J = 7.9 Hz, 1H), 7.55-7.40 (m, 2H), 7.35 (d, J = 6.9 Hz, 1H), 6.69-6.36 (m, 1H), 6.29 (d, J = 16.7 Hz, 1H), 5.75 (d, J = 9.1 Hz, 1H). ¹³ C NMR (75 MHz, DMSO-d ₆ )δ166.65,164.10,163.85,163.59,149.12,147.77,140.25,139.54,137.56,135.12,132.36,129.90,129.22,127.42,124.73,121.10.HRMS(ESI)m/z calcd for C ₂₃ H ₁₈ ClN ₇ O[M+H] ⁺ 444.1339,found444.1232.

Embodiment 41

Synthesis of N-(2-methyl-5-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide (C1)

The synthesis method was the same as that of Example 29, with a yield of 39.7%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.98 (s, 1H), 9.84 (s, 1H), 9.59 (s, 1H), 8.40 (s, 1H), 7.83 (s, 3H), 7.54 (s, 1H), 7.33 (d, J = 7.4 Hz, 2H), 7.20 (d, J = 7.9 Hz, 1H), 6.79-6.37 (m, 1H), 6.39-6.06 (m, 1H), 5.76 (d, J = 9.7 Hz, 1H), 2.01 (d, J = 6.8 Hz, 3H) 1.58 (m, J = 31.4 Hz, 6H). ¹³ C NMR (75 MHz, DMSO-d ₆ )δ169.33,166.58,163.94,163.87,163.72,140.75,137.32,136.50,132.18,130.59,127.97,127.05,119.93,26.19,24.58,17.89.HRMS(ESI)m/z calcd for C ₂₅ H ₂₇ N ₇ O ₂ [M+H] ⁺ 458.2301, found 458.2260.

Embodiment 42

Synthesis of (E)-N-(3-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)but-2-enamine (C2)

The synthesis method was the same as that of Example 29, with a yield of 41.0%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.99 (s, 2H), 9.88 (s, 1H), 8.41 (s, 1H), 7.95 (s, 1H), 7.86 (d, J = 6.7 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H), 7.34-7.15 (m, 3H), 6.83 (dq, J = 13.8, 7.3, 6.9 Hz, 1H), 6.18 (d, J = 16.4 Hz, 1H), 1.89 (d, J = 6.8 Hz, 3H), 1.57 (d, J = 30.7 Hz, 6H). ¹³ C NMR (75 MHz, DMSO-d ₆ )δ169.34,166.66,164.11,163.96,163.87,140.75,140.30,139.87,139.56,130.56,129.07,127.90,126.51,120.03,56.53,24.58,17.98.HRMS(ES I)m/z calcd for C ₂₅ H ₂₇ N ₇ O ₂ [M+H] ⁺ 458.2305,found458.2260.

Embodiment 43

Synthesis of 1-(6-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)indolin-1-yl)prop-2-en-1-one (C3)

The synthesis method was the same as that of Example 29, with a yield of 37.8%. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.97 (s, 1H), 9.74 (s, 1H), 8.56 (s, 1H), 7.84 (s, 3H), 7.50 (s, 1H), 7.33 (d, J = 7.4 Hz, 2H), 7.27 (d, J = 7.9 Hz, 1H), 6.74-6.37 (m, 1H), 6.51-6.21 (d, 1H), 5.79 (d, J = 9.7 Hz, 1H), 1.58 (m, J = 31.4 Hz, 8H). ¹³ C NMR (101 MHz, DMSO-d ₆ )δ169.34,166.55,164.10,163.85(d,J＝2.1Hz),143.49,140.76,130.43,127.92,124.67,119.97,68.17,58.52,48.55,35.85,27.42,24.59.HRMS(ES I)m/z calcd for C ₂₆ H ₂₇ N ₇ O ₂ [M+H] ⁺ 470.2304, found 470.2270.

Embodiment 44

Synthesis of 1-(3-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)but-2-yn-1-one (C4)

The synthesis method was the same as that of Example 29, with a yield of 44.1%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 9.97 (s, 1H), 9.87 (s, 1H), 8.38 (s, 1H), 7.86 (d, J = 25.8 Hz, 4H), 7.29 (d, J = 15.3 Hz, 4H), 2.04 (s, 3H), 1.56 (d, J = 41.0 Hz, 6H). ¹³ C NMR (101 MHz, DMSO-d ₆ )δ169.32,166.66,164.08,163.84,151.01,139.09,130.59,129.11,127.90,120.01,84.65,76.37,24.59,3.69.HRMS(ESI)m/z calcd for C ₂₅ H ₂₅ N ₇ O ₂ [ M+H] ⁺ 456.2140, found 456.2103.

Embodiment 45

Synthesis of N-(3-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)thiophene-2-carboxamide (C5)

The synthesis method was the same as that of Example 29, with a yield of 48.8%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.29 (s, 1H), 9.96 (d, J = 26.8 Hz, 2H), 8.41 (s, 1H), 8.06 (d, J = 3.4 Hz, 2H), 7.85 (d, J = 4.4 Hz, 3H), 7.45 (d, J = 7.7 Hz, 1H), 7.34 (s, 0H), 7.32 (s, 1H), 7.31-7.25 (m, 2H), 7.25-7.17 (m, 1H), 1.51 (d, J = 48.2 Hz, 6H). ¹³ C NMR (101 MHz, DMSO-d ₆ )δ169.24,166.69,164.12,163.88,160.37,140.55,139.27,132.32,130.58,129.59,129.05,128.54,127.88,120.01,24.56.HRMS(ESI)m/zcalcd for C ₂₇ H ₂₇ N ₇ O ₂ S[M+H] ⁺ 500.1868, found 500.1824.

Embodiment 46

Some pharmacological tests and results

1. CCK-8 method to test Raji cell proliferation experiment

Raji cells were cultured in RPMI1640 medium containing 10% fetal bovine serum. Cells in logarithmic growth phase were used for experiments. The cell density was adjusted to 8×10 ⁴ cells/mL and 100 μl/well was inoculated in a 96-well plate. After 4 hours of culture, 100 μl/well of drug-containing culture medium was added. The final concentrations of the samples were 50×10 ^-5 mol/L, 2×10 ^-5 mol/L, 1×10 ^-5 mol/L and 1×10 ^-6 mol/L. Three replicates were used for each concentration. The same volume of culture medium was used instead of the test drug as the control group. After further culture for 48 hours, 10 μl/well CCK-8 was added. After 4 hours of culture, the absorbance (A) value of each well was measured at a wavelength of 450 nm using an enzyme-labeled detector. The cell proliferation inhibition rate was calculated according to the formula: inhibition rate = (control group A value - experimental group A value) / (control group A value - blank group A value) × 100%, and the IC ₅₀ was calculated.

2. CCK-8 method to test Ramos cell proliferation experiment

Ramos cells were cultured in RPMI1640 medium containing 10% fetal bovine serum. Cells in logarithmic growth phase were used for experiments. The cell density was adjusted to 8×10 ⁴ cells/mL and 100 μl/well were inoculated in 96-well plates. After 4 hours of culture, 100 μl/well of drug-containing culture medium was added. The final concentrations of the samples were 50×10 ^-5 mol/L, 2×10 ^-5 mol/L, 1×10 ^-5 mol/L and 1×10 ^-6 mol/L. Three replicates were used for each concentration. The same volume of culture medium was used instead of the test drug as the control group. After further culture for 48 hours, 10 μl/well CCK-8 was added. After 4 hours of culture, the absorbance (A) value of each well was measured at a wavelength of 450 nm using an enzyme-labeled detector. The cell proliferation inhibition rate was calculated according to the formula: inhibition rate = (control group A value - experimental group A value) / (control group A value - blank group A value) × 100%, and the IC ₅₀ was calculated.

3.Btk enzyme activity inhibition test

Based on the principle that ATP can phosphorylate Btk to form ADP, the ADP-GloTM kinase system can convert the generated ADP into fluorescently labeled ATP belonging to ATP tyrosine kinase, thereby measuring the activity of the kinase. Its brief steps are: 1. Enzyme inhibition reaction, that is, adding the tested inhibitor to the kinase reaction solution containing the enzyme substrate, and then adding ATP, reacting for 60 minutes; 2. Adding ADP-GloTM reagent to terminate the kinase reaction and remove the remaining ATP; 3. Incubating at room temperature for 40 minutes; 4. Adding detection reagent and luciferase to convert ADP into fluorescently labeled ATP; 5. Incubating at room temperature for 30 minutes; 6. Detecting fluorescence and calculating the inhibition rate.

Some pharmacological test results of the compounds of the present invention:

The synthetic s-triazine compounds were subjected to Raji cell and Ramos antiproliferation experiments using the Btk inhibitor Ibrutinib as a positive control. The results showed that most of the compounds showed good inhibitory activity against Raji cells. In the Btk enzyme inhibition experiment using Ibrutinib as a control, most of the compounds had a good inhibitory effect on Btk. Therefore, this class of compounds can be used as Btk inhibitors for the treatment of leukemia or lymphoma.

Claims (6)

1. A s-triazine compound and a pharmaceutically acceptable salt thereof, characterized in that said compound is selected from the following compounds: N-(3-((4-amino-6-((4-phenoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide; N-(3-((4-amino-6-((4-(2-methoxyethoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)propene amides; N-(3-((4-chloro-6-((4-phenoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide; N-(3-((4-chloro-6-((4-(2-methoxyethoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)propene amides; N-(3-((4-((4-phenoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide; N-(3-((4-((4-(2-methoxyethoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide; N-(3-((4-((4-(2-methoxyphenoxy)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide; N-(3-((4-((4-(morpholine-4-carbonyl)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide; N-(3-((4-((4-(piperidine-1-carbonyl)phenylamino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide; 4-((4-((3-acrylamidophenyl)amino)-1,3,5-triazin-2-yl)amino)-N-(pyridin-2-yl)benzamide; 4-((4-((3-acrylamidophenyl)amino)-1,3,5-triazin-2-yl)amino)-N-(5-methylpyridin-2-yl)benzamide ; N-(3-((4-((4-(pyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide; N-(3-((4-((4-(6-methylpyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide ; N-(3-((4-((4-(6-methoxypyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)propene amides; N-(3-((4-((4-(6-fluoropyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide; N-(3-((4-((4-(6-chloropyridin-3-yl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide; N-(2-methyl-5-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl) Acrylamide; (E)-N-(3-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)butyl -2-enamine; 1-(6-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)indoline-1-yl) prop-2-en-1-one; 1-(3-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)but-2-yne -1-one; N-(3-((4-((4-(piperidine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)thiophene-2-methyl amides. 2. A pharmaceutical composition, characterized in that it comprises the compound according to any one of claim 1 and a pharmaceutically acceptable salt thereof. 3. The pharmaceutical composition according to claim 2, characterized in that the composition is prepared from the compound of claim 1 and a pharmaceutically acceptable salt thereof by adding pharmaceutically acceptable adjuvants. 4. The compound as claimed in claim 1 and the pharmaceutically acceptable salt thereof are used in the preparation of the medicine for inhibiting Bruton's tyrosine kinase. 5. The application of the compound as claimed in claim 1 and the pharmaceutically acceptable salt thereof in the preparation of a medicine for treating or preventing leukemia. 6. The application of the compound as claimed in claim 1 and the pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing lymphoma.