2-amino-4-anilino pyrimidines, processes for their preparation and use

Abstract

The application discloses a 2-amino-4-anilino pyrimidine compound and a preparation method and application thereof. The compound has a strong inhibiting effect on EGFR gene mutation targets and c-MET and has a strong inhibiting effect on osimertinib drug-resistant cells. Moreover, the compound can inhibit the proliferation of various tumor cells, and provides an excellent application prospect for the treatment of EGFR gene mutation and MET amplification malignant tumors.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of 2-amino-4-anilino pyrimidines compound, also relates to the preparation method of the above-mentioned compound and its application in the preparation of antitumor drugs. BACKGROUND

[0002] Abnormal activation of epidermal growth factor receptor (EGFR) is a key molecular event driving the occurrence and development of various solid tumors, especially non-small cell lung cancer (NSCLC). As the third generation of EGFR tyrosine kinase inhibitors, osimertinib forms a covalent bond with the C797 site of the EGFR kinase domain through its acrylamide domain, showing excellent efficacy on EGFR sensitive mutations (such as exon 19 deletion) and T790M drug-resistant mutations, and has become the standard first-line treatment. However, the development of acquired drug resistance eventually limits its clinical benefits.

[0003] The mechanisms of resistance to osimertinib are complex and diverse, among which EGFR C797S point mutation and abnormal activation of c-MET signaling pathway are the most common and crucial. First, C797S mutation makes osimertinib unable to form a covalent bond with the target, directly leading to a sharp decline in its binding affinity and inhibitory efficiency. Second, the abnormal activation of c-MET (including its gene amplification or overexpression of the ligand hepatocyte growth factor) can bypass the pathway inhibited by EGFR TKI by activating its downstream signaling mediators, forming "bypass activation", thereby maintaining the survival and proliferation of tumor cells.

[0004] Further exploration of its biological basis shows that although EGFR and c-MET are different receptors, their downstream signaling networks have high cross and redundancy, and converge on core pro-survival / proliferation pathways such as PI3K-AKT-mTOR and RAS-RAF-MEK-ERK. This feature means that even if a tumor cell only exhibits a single EGFR C797S drug-resistant mutation, its survival can still rely on the compensation of c-MET-mediated basic signal flow. Therefore, while inhibiting mutant EGFR, combined inhibition of c-MET can produce a synergistic blocking effect, more thoroughly disrupting the signaling network of tumor cells, thereby overcoming drug resistance caused by insufficient inhibition of a single target. For complex drug-resistant models with c-MET amplification, this strategy can achieve dual suppression of the main and bypass signals.

[0005] Based on the above mechanism, the development of a dual inhibitor that can simultaneously target EGFR C797S mutant and c-MET kinase is expected to overcome the drug resistance bottleneck of osimertinib through synergistic effect, providing a more promising treatment strategy for clinical use. SUMMARY

[0006] Invention purposes: In order to solve the problem of drug resistance caused by target point mutation of osimertinib, the application provides a 2-amino-4-anilino pyrimidine compound which has strong inhibitory effect on EGFR gene mutation target point and c-MET and strong inhibitory effect on osimertinib drug-resistant cells, and also provides a preparation method of the compound and application of the compound in preparation of an antitumor drug.

[0007] Technical scheme: The 2-amino-4-anilino pyrimidine compound of the application has a structure as shown in formula I:

[0008]

[0009] Among them, R1 is selected from , , , , , , , , , , , , , , ;

[0010] R2 is selected from hydrogen, C1-C3 alkyl, alkoxy, halogen, trifluoromethyl, substituted phenyl, ; R3 is selected from hydrogen, C1-C3 alkyl; R4 is selected from methyl, ethyl, isopropyl; R5 is selected from hydrogen, C1-C3 alkyl, alkoxy, halogen, trifluoromethyl, nitro; R6 is selected from hydrogen, C1-C3 alkyl, , , ; R7 is selected from C1-C3 alkyl; R8 is selected from hydrogen, C1-C3 alkyl; R9 is selected from hydrogen, C1-C3 alkyl, acetyl; R 10 is selected from hydrogen, C1-C3 alkyl, acetyl; R 11 is selected from hydrogen, C1-C3 alkyl, acetyl.

[0011] Further preferably, R1 is selected from , , , , , , , , , , , , , , ; R2is selected from the group consisting of hydrogen, C1-C3alkyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, , ; R3is selected from the group consisting of C1-C3alkyl; R4is selected from the group consisting of methyl, ethyl, isopropyl; R5is selected from the group consisting of hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, nitro; R6is selected from the group consisting of hydrogen, C1-C3alkyl, , , ; R7is selected from the group consisting of C1-C3alkyl; R8is selected from the group consisting of hydrogen, C1-C3alkyl; R9is selected from the group consisting of hydrogen, C1-C3alkyl, acetyl; R 10 is selected from the group consisting of hydrogen, C1-C3alkyl, acetyl; R 11 is selected from the group consisting of hydrogen, C1-C3alkyl, acetyl.

[0012] Further preferred is: R1is selected from the group consisting of , , , , , , , , , , , , , , ; R2is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, , ; R3is selected from the group consisting of methyl, ethyl, isopropyl; R4is selected from the group consisting of methyl, ethyl, isopropyl; R5is selected from the group consisting of hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, nitro; R6is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, , , ; R7is selected from the group consisting of methyl, ethyl, isopropyl; R8is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl; R9is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, acetyl; R 10 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, acetyl; R 11 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, acetyl.

[0013] Further preferred is: R1is selected from the group consisting of , , , , , , , , , , , 、 、 、 ; R2 is selected from hydrogen, methyl, methoxy, chloro, trifluoromethyl, 、 ; R3 is selected from methyl, ethyl, isopropyl; R4 is selected from methyl, ethyl, isopropyl; R5 is selected from hydrogen, methyl, methoxy, fluorine, chloro, bromo, trifluoromethyl, nitro; R6 is selected from hydrogen, methyl, 、 、 ; R7 is selected from methyl, ethyl; R8 is selected from hydrogen, methyl; R9 is selected from hydrogen, methyl, ethyl, isopropyl, acetyl; R 10 is selected from hydrogen, methyl, ethyl, isopropyl, acetyl; R 11 is selected from hydrogen, methyl, ethyl, isopropyl, acetyl.

[0014] The compound is selected from the compounds shown in formula (C-1) to formula (C-50): .

[0015] The compound also includes pharmaceutically acceptable salts thereof, the salt is an acid addition salt of the compound of formula I, the acid used for salification includes inorganic acid and organic acid, the inorganic acid includes hydrochloric acid, phosphoric acid, sulfuric acid, the organic acid includes trifluoroacetic acid, acetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid and tartaric acid.

[0016] The preparation method of the compound, comprising the following steps:

[0017]

[0018] Dissolve A and B in n-butanol, add trifluoroacetic acid, react at 110-130 DEG C for 10-15 hours, after the reaction is completed, concentrate the reaction mixture, and separate and purify by column chromatography to obtain.

[0019] The application further discloses a pharmaceutical composition, which comprises the compound shown in formula I or a pharmaceutically acceptable salt or optical isomer thereof, and a pharmaceutically acceptable carrier.

[0020] The 2-amino-4-anilino pyrimidine compound can be applied to the preparation of an EGFR and c-MET dual-target inhibitor drug.

[0021] The 2-amino-4-anilino pyrimidine compound can be applied to the preparation of an anti-tumor drug.

[0022] The application also discloses a preparation method of the compound and a pharmaceutical composition containing the compound.

[0023] The tumor is an EGFR gene mutation and MET amplification malignant tumor, including lung cancer, gastric cancer, liver cancer, prostate cancer, breast cancer, testicular cancer, ovarian cancer, colon cancer, leukemia, pancreatic cancer, multiple myeloma, melanoma, glioma, brain glioma, pituitary tumor, various solid tumors and blood tumors.

[0024] Invention principle: The application is based on a 2-amino-4-anilino pyrimidine compound designed by structure, which realizes double inhibition through high complementarity of the core pyrimidine ring to the ATP binding pocket of EGFR and c-MET kinase: the 2-amino pyrimidine skeleton forms a key hydrogen bond network with the hinge region of the kinase, and the flexible aniline at the 4-position is deeply inserted into the hydrophobic cavity through a system-optimized substitution mode (especially the nitrogen heterocyclic structure at the R1 site) to establish a stable non-covalent interaction with the EGFR C797S mutant, effectively overcoming the covalent binding failure caused by cysteine-serine mutation; meanwhile, the molecular skeleton maintains high affinity to c-MET kinase through a conserved spatial conformation, realizes synchronous blocking of the cross signal pathways downstream of EGFR and c-MET, and through synergistic effect, the signal compensation mechanism of tumor cells is broken down, thereby comprehensively overcoming the osimertinib resistance problem.

[0025] Beneficial effects: Compared with the prior art, the 2-amino-4-anilino pyrimidine compound of the application has the following remarkable advantages: the 2-amino-4-anilino pyrimidine compound of the application exhibits excellent EGFR C797S mutant and c-MET double-target point inhibition activity. Specifically, a representative compound (such as C-15) has an IC L858R / T790M / C797S of less than 100 nM for the EGFR 50 triple mutant kinase, while maintaining equivalent inhibition intensity (IC 50 of less than 100 nM) for the c-MET kinase, realizing double-target point synergistic blocking. At the cellular level, the compound shows strong anti-proliferation activity on the osimertinib-resistant H1975TM cell strain, and the IC 50 values of multiple compounds (such as C-15 and C-20) are less than 250 nM, which is significantly better than the control drug. In vivo efficacy experiments further confirm that the compound C-15 has an inhibition rate of 65.7% on H1975TM transplanted tumors at a dose of 40 mg / kg, and no obvious toxic reactions are observed. The application provides an efficient and low-toxicity solution for overcoming osimertinib resistance through the unique mechanism of simultaneously inhibiting double targets by a single molecule. DETAILED DESCRIPTION

[0026] The technical solutions of the present application are further described below in combination with examples. The test materials used in the examples can be purchased through conventional channels.

[0027] Synthesis of intermediate reactants

[0028] (1) Synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N- methylmethanesulfonamide (A-1):

[0029]

[0030] Step one, synthesis of N-methyl-N-(2-nitrophenyl)methanesulfonamide (A-1-1): Dissolve 1-fluoro-2-nitrobenzene (1 eq, 100 mmol) and N-methylmethanesulfonamide (1.1 eq, 110 mmol) in 250 mL of acetonitrile, add cesium carbonate (3 eq, 300 mmol), and react overnight at 80 °C. After the reaction is complete, filter and concentrate the filtrate to obtain a solid, wash the solid with water, and dry again to obtain A-1-1 with a yield of 86%. 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J = 8.1, 1.4 Hz, 1H), 7.85 - 7.75 (m, 2H), 7.66 - 7.58 (m, 1H), 3.28 (s, 3H), 3.05 (s, 3H). Step two, synthesis of N-(2-aminophenyl)-N-methylmethanesulfonamide (A-1-2): Dissolve A-1-1 (1 eq, 50 mmol) in 100 mL of a DMF and methanol mixture (1:1), add 1.1 g of Pd / C, and stir for 24 hours under a hydrogen atmosphere. After the reaction is complete, filter out the Pd / C and concentrate the filtrate to obtain A-1-2 with a yield of 95%. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (dd, J = 7.9, 1.5 Hz, 1H), 7.11 – 6.98 (m, 1H), 6.74 (dd, J = 8.1, 1.5Hz, 1H),6.64 – 6.51 (m, 1H),5.12 (s, 2H),3.07 (s, 3H),3.04 (s, 3H). Step three, synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (A-1): A-1-2 (1 eq, 20mmol) was dissolved in 50 mL of isopropanol, 2,4,5-trichloropyrimidine (1 eq, 20 mmol) and N,N-diisopropylethylamine (3 eq, 60 mmol) were added, and the reaction was carried out at 90 °C for 12 hours. The reaction was concentrated, and a large amount of solid was precipitated. The solid was suction filtered and washed with cold methanol, and dried to obtain compound A-1 with a yield of 84%. 1 H NMR (400 MHz, Chloroform-d) δ 8.69 (s,1H), 8.34 (dd, J = 8.3, 1.4 Hz, 1H), 8.23 (s, 1H), 7.50 – 7.43 (m, 1H), 7.34(dd, J = 8.0, 1.6 Hz, 1H), 7.26 – 7.22 (m, 1H), 3.29 (s, 3H), 2.99 (s, 3H).

[0031] (2) Synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5-methylphenyl)-N- methylmethanesulfonamide (A-2):

[0032]

[0033] Step one, synthesis of N-methyl-N-(5-methyl-2-nitrophenyl)methanesulfonamide (A-2-1): Refer to the synthesis of A-1-1, yield 90%. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.3 Hz, 1H), 7.62 (d, J= 1.2 Hz, 1H), 7.41 (dd, J = 8.2, 1.0 Hz, 1H), 3.27 (s, 3H), 3.05 (s, 3H),2.43 (s, 3H). Step two, synthesis of N-(2-amino-5-methylphenyl)-N-methylmethanesulfonamide (A-2-2): Refer to the synthesis of A-1-2, yield 97%. 1H NMR (400 MHz, DMSO-d6) δ 7.01 (d, J = 2.0 Hz, 1H), 6.85(dd, J = 8.1, 2.0 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 4.88 (s, 2H), 3.06 (s,3H), 3.04 (s, 3H), 2.15 (s, 3H). Step three, synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5-methylphenyl)-N-methylmethanesulfonamide (A-2): refer to the synthesis of A-1, yield 85%. 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.41 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 2.1Hz, 1H), 7.26 (dd, J = 8.8, 1.6 Hz, 1H), 3.17 (s, 3H), 3.04 (s, 3H), 2.36 (s,3H).

[0034] (3) Synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5-methoxyphenyl)-N-methylmethanesulfonamide (A-3):

[0035]

[0036] Step one, synthesis of N-(5-methoxy-2-nitrophenyl)-N-methylmethanesulfonamide (A-3-1): refer to the synthesis of A-1-1, yield 92%. 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 9.1 Hz, 1H), 7.30 (d,J = 2.7 Hz, 1H), 7.12 (dd, J = 9.1, 2.7 Hz, 1H), 3.91 (s, 3H), 3.29 (s, 3H),3.05 (s, 3H). Step two, synthesis of N-(2-amino-5-methoxyphenyl)-N-methylmethanesulfonamide (A-3-2): refer to the synthesis of A-1-2, yield 96%. 1H NMR (400 MHz, Chloroform-d) δ 6.78 - 6.74 (m, 2H), 6.72 (dd, J = 2.1, 1.2 Hz, 1H), 3.74 (s, 3H), 3.21 (s, 3H), 2.96 (s, 3H). Step three, synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5- methoxyphenyl)-N-methylmethanesulfonamide (A-3): refer to the synthesis of A-1, yield 82%. 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.38 (s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 2.9 Hz, 1H), 7.05 (dd, J = 9.0, 2.9 Hz, 1H), 3.83 (s, 3H), 3.17 (s, 3H), 3.04 (s, 3H).

[0037] (4) Synthesis of N-(5-chloro-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N- methylmethanesulfonamide (A-4):

[0038]

[0039] Step one, synthesis of N-(5-chloro-2-nitrophenyl)-N-methylmethanesulfonamide (A-4-1): refer to the synthesis of A-1-1, yield 88%. 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 2.3 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.71 (dd, J = 8.7, 2.2 Hz, 1H), 3.30 (s, 3H), 3.08 (s, 3H). Step two, synthesis of N-(2-amino-5-chlorophenyl)-N-methylmethanesulfonamide (A-4-2): dissolve A-4-1 (1 eq, 10 mmol) in 50 mL of 75% ethanol, add zinc powder and ammonium chloride, react at room temperature for 5 hours, filter off the solid, collect the filtrate and concentrate, purify by column chromatography to obtain A-4-2, yield 85%. 1H NMR (400 MHz, Chloroform-d) δ 7.14 - 7.07 (m, 2H), 6.76 - 6.72 (m, 1H), 4.17 (s, 2H), 3.22 (s, 3H), 2.98 (s, 3H). Step 3. Synthesis of N-(5-chloro-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N- methylmethanesulfonamide (A-4): Refer to the synthesis of A-1, yield 84%. 1 H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.46 (s, 1H), 7.89 - 7.78 (m, 2H), 7.55 (dd, J = 8.8, 2.4 Hz, 1H), 3.20 (s, 3H), 3.07 (s, 3H).

[0040] (5) Synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5- (trifluoromethyl)phenyl)-N-methylmethanesulfonamide (A-5):

[0041]

[0042] Step 1. Synthesis of N-methyl-N-(2-nitro-5-(trifluoromethyl)phenyl) methanesulfonamide (A-5-1): Refer to the synthesis of A-1-1, yield 86%. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 1.9 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.03 (dd, J = 8.5, 1.9 Hz, 1H), 3.34 (s, 3H), 3.10 (s, 3H). Step 2. Synthesis of N-(2-amino-5-(trifluoromethyl)phenyl)-N- methylmethanesulfonamide (A-5-2): Refer to the synthesis of A-1-2, yield 94%. 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 1.4 Hz, 1H), 7.35 (dd, J = 8.7, 2.0 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 5.91 (s, 2H), 3.10 (s, 3H), 3.08 (s, 3H). Step 3. Synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5- (trifluoromethyl)phenyl)-N-methylmethanesulfonamide (A-5): Refer to the synthesis of A-1, yield 90%. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.54 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.13 - 8.08 (m, 1H), 7.92 - 7.80 (m, 1H), 3.26 (s, 3H), 3.11 (s, 3H).

[0043] (6) Synthesis of N-(4-((2,5-dichloropyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-N- methylmethanesulfonamide (A-6):

[0044]

[0045] Step one, synthesis of N-(5-bromo-2-nitrophenyl)-N-methylmethanesulfonamide (A-6-1): Refer to the synthesis of A-1-1, yield 91%. 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.54 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.13 - 8.08 (m, 1H), 7.92 - 7.80 (m, 1H), 3.26 (s, 3H), 3.11 (s, 3H). 1 H NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.5, 2.0 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.54 - 7.43 (m, 3H), 3.36 (s, 3H), 3.06 (s, 3H). 1H NMR (400 MHz, DMSO-d6) δ 7.57 (dd, J = 8.3, 1.2 Hz, 2H), 7.52 (d, J = 2.2 Hz, 1H), 7.45 - 7.36 (m, 3H), 7.25 (t, J = 7.3 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.15 (s, 3H), 3.10 (s, 3H). Step four, synthesis of N-(4-((2,5-dichloropyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)-N- methylmethanesulfonamide (A-6): refer to the synthesis of A-1, yield 89%. 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.47 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.86 - 7.72 (m, 3H), 7.50 (t, J = 7.5 Hz, 2H), 7.47 - 7.36 (m, 1H), 3.28 (s, 3H), 3.13 (s, 3H).

[0046] (7) Synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-4- yl)phenyl)-N-methylmethanesulfonamide (A-7):

[0047]

[0048] Step one, synthesis of N-methyl-N-(5-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl) methanesulfonamide (A-7-1): refer to the synthesis of A-6-2, yield 73%. 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.10 (s, 1H), 8.00 - 7.91 (m, 2H), 7.76 (dd, J = 8.4, 1.8 Hz, 1H), 3.90 (s, 3H), 3.33 (s, 3H), 3.08 (s, 3H). Step two, synthesis of N-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-N- methylmethanesulfonamide (A-7-2): refer to the synthesis of A-1-2, yield 93%. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.24 (dd, J= 8.3, 2.1 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.10 (s, 2H), 3.82 (s, 3H),3.11 (s, 3H), 3.08 (s, 3H). Step three, synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-N-methylmethanesulfonamide (A-7): refer to the synthesis of A-1, yield 87%. 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.24 (dd, J= 8.3, 2.1 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.10 (s, 2H), 3.82 (s, 3H),3.11 (s, 3H), 3.08 (s, 3H). Step three, synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-N-methylmethanesulfonamide (A-7): refer to the synthesis of A-1, yield 87%.

[0049] (8) Synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-methylethanesulfonamide (A-8):

[0050]

[0051] Step one, synthesis of N-(2-nitrophenyl)ethanesulfonamide (A-8-1): refer to the synthesis of A-1-1, yield 91%. 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.00 (dd, J = 8.2, 1.5 Hz, 1H), 7.72(ddd, J = 8.7, 7.4, 1.5 Hz, 1H), 7.62 (dd, J = 8.2, 1.3 Hz, 1H), 7.40 (ddd, J= 8.5, 7.3, 1.3 Hz, 1H), 3.26 (q, J = 7.3 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H). Step two, synthesis of N-methyl-N-(2-nitrophenyl)ethanesulfonamide (A-8-2): Dissolve A-8-1 (1 eq, 10 mmol) in 20 mL of DMF, add iodomethane (1.1 eq, 11 mmol) and potassium carbonate (3 eq, 30 mmol), react at 80 °C overnight. After the reaction is completed, remove the potassium carbonate by filtration, concentrate the filtrate to obtain a solid, wash with water and dry to obtain compound A-8-2 in 89% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 8.0 Hz, 1H), 7.85 – 7.72 (m,2H), 7.71 – 7.55 (m, 1H), 3.30 (s, 3H), 3.21 (q, J = 7.4 Hz, 2H), 1.21 (t, J= 7.3 Hz, 3H). Step three, synthesis of N-(2-aminophenyl)-N-methylethanesulfonamide (A-8-3): Refer to the synthesis of A-1-2, yield 97%. 1 H NMR (400 MHz, Chloroform-d) δ 7.17 – 7.09 (m, 2H), 6.84 – 6.67(m, 2H), 3.25 (s, 3H), 3.15 (q, J = 7.4 Hz, 2H), 1.44 (t, J = 7.4 Hz, 3H). Step four, synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N- methylethanesulfonamide (A-8): Refer to the synthesis of A-1, yield 86%. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.44 (s, 1H), 7.79 (dd, J = 8.1, 1.5 Hz, 1H), 7.65 (dd, J = 8.0, 1.5 Hz, 1H), 7.46 (td, J = 7.8, 1.5 Hz, 1H), 7.36 (td, J = 7.7, 1.6 Hz, 1H), 3.27 - 3.17 (m, 5H), 1.20 (t, J = 7.4 Hz, 3H).

[0052] (9) Synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N- methylpropane-2-sulfonamide (A-9):

[0053]

[0054] Step one, synthesis of N-(2-nitrophenyl)propane-2-sulfonamide (A-9-1): refer to the synthesis of A-1-1, yield 88%. 1 H NMR (400 MHz, Chloroform-d) δ 9.66 (s, 1H), 8.25 (dd, J = 8.5, 1.6 Hz, 1H), 7.97 (dd, J = 8.5, 1.3 Hz, 1H), 7.65 (ddd, J = 8.7, 7.2, 1.6 Hz, 1H), 7.20 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 3.46 - 3.32 (m, 1H), 1.43 (d, J = 6.8 Hz, 6H). Step two, synthesis of N-methyl-N-(2-nitrophenyl)propane-2-sulfonamide (A-9-2): refer to the synthesis of A-8-2, yield 90%. 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (dd, J = 8.0, 1.4 Hz, 1H), 7.85 - 7.71 (m, 2H), 7.61 (ddd, J = 8.0, 7.0, 1.9 Hz, 1H), 3.47 - 3.38 (m, 1H), 3.34 (s, 3H), 1.25 (d, J = 6.8 Hz, 6H). Step three, synthesis of N-(2-aminophenyl)-N-methylpropane-2-sulfonamide (A-9-3): refer to the synthesis of A-1-2, yield 96%. 1H NMR (400 MHz, Chloroform-d) δ 7.18 – 7.10 (m, 2H), 6.83 – 6.68 (m, 2H), 3.44 (p, J = 6.9 Hz, 1H), 3.27 (s, 3H), 1.45 (d, J = 6.9 Hz, 6H). Step four, synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-methylpropane-2- sulfonamide (A-9): Refer to the synthesis of A-1, yield 83%. 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.44 (s, 1H), 7.72 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (dd, J = 7.9, 1.5 Hz, 1H), 7.46 (td, J = 7.7, 1.6 Hz, 1H), 7.37 (td, J = 7.6, 1.6 Hz, 1H), 3.59 – 3.43 (m, 1H), 3.21 (s, 3H), 1.24 (d, J = 6.8 Hz, 6H).

[0055] (10) Synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N- ethylmethanesulfonamide (A-10):

[0056]

[0057] Step one, synthesis of N-(2-nitrophenyl)methanesulfonamide (A-10-1): Refer to the synthesis of A-1-1, yield 92%. 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.03 (dd, J = 8.2, 1.5 Hz, 1H), 7.74 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.64 (dd, J = 8.2, 1.4 Hz, 1H), 7.41 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 3.15 (s, 3H). Step two, synthesis of N-ethyl-N-(2-nitrophenyl)methanesulfonamide (A-10-2): Refer to the synthesis of A-8-2, yield 85%. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J =8.0 Hz, 1H), 7.79 (d, J = 4.0 Hz, 2H), 7.68 - 7.59 (m, 1H), 3.74 (q, J = 7.2 Hz, 2H), 3.03 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H). Step three, synthesis of N-(2-aminophenyl)-N-ethylmethanesulfonamide (A-10-3): refer to the synthesis of A-1-2, yield 97%. 1 H NMR (400 MHz, DMSO-d6) δ 7.14 (dd, J = 7.9, 1.5 Hz, 1H), 7.05 (ddd, J = 8.5, 7.3, 1.5 Hz, 1H), 6.75 (dd, J = 8.1, 1.5 Hz, 1H), 6.57 (td, J = 7.6, 1.5 Hz, 1H), 5.10 (s, 2H), 3.60 - 3.41 (m, 2H), 3.01 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H). Step four, synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N-ethylmethanesulfonamide (A-10): refer to the synthesis of A-1, yield 83%. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.52 (s, 1H), 8.16 (dd, J = 8.3, 1.5 Hz, 1H), 7.66 (dd, J = 8.0, 1.5 Hz, 1H), 7.52 (td, J = 7.9, 1.5 Hz, 1H), 7.35 (td, J = 7.7, 1.5 Hz, 1H), 3.83 - 3.48 (m, 2H), 3.12 (s, 3H), 0.93 (t, J = 7.1 Hz, 3H).

[0058] (11) Synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N- isopropylmethanesulfonamide (A-11):

[0059]

[0060] Step one, synthesis of N-isopropyl-N-(2-nitrophenyl)methanesulfonamide (A-11-1): refer to the synthesis of A-8-2, yield 83%. 1H NMR (400 MHz, Chloroform-d) δ 7.88 (dd, J = 8.0, 1.7 Hz, 1H), 7.65 (td, J = 7.7, 1.7 Hz, 1H), 7.56 (td, J = 7.8, 1.5 Hz, 1H), 7.50 (dd, J = 7.9, 1.5 Hz, 1H), 4.37 - 4.24 (m, 1H), 3.14 (s, 3H), 1.31 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H). Step two, synthesis of N-(2-aminophenyl)-N-isopropylmethanesulfonamide (A-11-2): refer to the synthesis of A-1-2, yield 93%. 1 H NMR (300 MHz, Chloroform-d) δ 7.18 (ddd, J = 8.1, 7.3, 1.5 Hz, 1H), 7.07 (dd, J = 7.9, 1.5 Hz, 1H), 6.81 (dd, J = 8.1, 1.5 Hz, 1H), 6.73 (ddd, J = 7.9, 7.3, 1.5 Hz, 1H), 4.66 - 4.48 (m, 1H), 2.98 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). Step three, synthesis of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)-N- isopropylmethanesulfonamide (A-11): refer to the synthesis of A-1, yield 86%. 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 8.36 (dd, J = 8.3, 1.3 Hz, 1H), 8.22 (s, 1H), 7.52 (ddd, J = 8.5, 6.9, 2.0 Hz, 1H), 7.33 - 7.20 (m, 2H), 4.77 - 4.55 (m, 1H), 3.03 (s, 3H), 1.28 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H).

[0061] (12) Synthesis of N-(2-((2-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (A-12):

[0062]

[0063] Reference the synthesis of A-1, yield 71%. 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.13(d, J = 5.9 Hz, 1H), 7.69 (dd, J = 8.0, 1.5 Hz, 1H), 7.59 (dd, J = 8.0, 1.5Hz, 1H), 7.44 - 7.37 (m, 1H), 7.30 (td, J = 7.7, 1.6 Hz, 1H), 6.81 (d, J =5.9 Hz, 1H), 3.17 (s, 3H), 3.01 (s, 3H).

[0064] (13) Synthesis of N-(2-((2-chloro-5-methylpyrimidin-4-yl)amino)phenyl)-N- methylmethanesulfonamide (A-13):

[0065]

[0066] Reference the synthesis of A-1, yield 68%. 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.09(d, J = 1.0 Hz, 1H), 7.87 (dd, J = 8.1, 1.5 Hz, 1H), 7.63 (dd, J = 8.0, 1.5Hz, 1H), 7.48 - 7.41 (m, 1H), 7.30 (td, J = 7.7, 1.5 Hz, 1H), 3.18 (s, 3H),3.04 (s, 3H), 2.15 (s, 3H).

[0067] (14) Synthesis of N-(2-((2-chloro-5-methoxypyrimidin-4-yl)amino)phenyl)-N- methylmethanesulfonamide (A-14):

[0068]

[0069] Reference the synthesis of A-1, yield 62%. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.15(dd, J = 8.3, 1.5 Hz, 1H), 8.02 (s, 1H), 7.64 (dd, J = 8.0, 1.5 Hz, 1H), 7.45(ddd, J = 8.5, 7.5, 1.5 Hz, 1H), 7.26 (td, J = 7.7, 1.5 Hz, 1H), 3.96 (s,3H), 3.20 (s, 3H), 3.08 (s, 3H).

[0070] (15) Synthesis of N-(2-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)-N- methylmethanesulfonamide (A-15):

[0071]

[0072] Referring to the synthesis of A-1, yield 86%. 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.34(d, J = 3.3 Hz, 1H), 7.65 (td, J = 7.7, 1.5 Hz, 2H), 7.44 (td, J = 7.7, 1.6Hz, 1H), 7.36 (td, J = 7.6, 1.6 Hz, 1H), 3.18 (s, 3H), 3.00 (s, 3H).

[0073] (16) Synthesis of N-(2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)-N- methylmethanesulfonamide (A-16):

[0074]

[0075] Referring to the synthesis of A-1, yield 82%. 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.54(s, 1H), 7.94 (dd, J = 8.2, 1.5 Hz, 1H), 7.67 (dd, J = 8.0, 1.5 Hz, 1H), 7.47(td, J = 7.8, 1.5 Hz, 1H), 7.35 (td, J = 7.7, 1.5 Hz, 1H), 3.20 (s, 3H), 3.07(s, 3H).

[0076] (17) Synthesis of N-(2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-N- methylmethanesulfonamide (A-17):

[0077]

[0078] Referring to the synthesis of A-1, yield 55%. 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.65(d, J = 1.0 Hz, 1H), 7.78 (dd, J = 8.0, 1.6 Hz, 1H), 7.67 (dd, J = 7.9, 1.6Hz, 1H), 7.47 (td, J = 7.7, 1.6 Hz, 1H), 7.40 (td, J = 7.7, 1.6 Hz, 1H), 3.17(s, 3H), 3.03 (s, 3H).

[0079] (18) Synthesis of N-(2-((2-chloro-5-nitropyrimidin-4-yl)amino)phenyl)-N- methylmethanesulfonamide (A-18):

[0080]

[0081] Referring to the synthesis of A-1, yield 65%. 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.24(s, 1H), 8.07 (dd, J = 8.2, 1.4 Hz, 1H), 7.71 (dd, J = 8.0, 1.5 Hz, 1H), 7.52(td, J = 7.8, 1.5 Hz, 1H), 7.41 (td, J = 7.7, 1.5 Hz, 1H), 3.21 (s, 3H), 3.11(s, 3H).

[0082] Example 1

[0083] Synthesis of N-(2-((2-((1H-indol-5-yl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N- methylmethanesulfonamide (C-1):

[0084]

[0085] A-1 (1 eq, 1 mmol) and B-6 (1.1 eq, 1.1 mmol) were dissolved in 10 mL of n-butanol, trifluoroacetic acid (1.5 eq, 1.5 mmol) was added, and the reaction was carried out at 120 °C for 10 hours. After the reaction was completed, the reaction mixture was concentrated, and C-1 was obtained by column chromatography separation and purification with a yield of 73%. 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.34(s, 1H), 8.42 (s, 1H), 8.38 (d, J = 7.9 Hz, 1H), 8.18 (s, 1H), 7.82 (d, J =2.0 Hz, 1H), 7.62 (dd, J = 7.9, 1.6 Hz, 1H), 7.39 – 7.13 (m, 5H), 6.32 (s,1H), 3.19 (s, 3H), 3.11 (s, 3H).

[0086] Example 2

[0087] Synthesis of N-(2-((5-chloro-2-((1-methyl-1H-indol-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-2):

[0088]

[0089] Referring to the synthesis of C-1, the yield was 80%. 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.41(d, J = 8.1 Hz, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.62 (dd, J =7.9, 1.5 Hz, 1H), 7.36 – 7.19 (m, 5H), 6.30 (d, J = 3.0 Hz, 1H), 3.77 (s,3H), 3.19 (s, 3H), 3.11 (s, 3H).

[0090] Example 3

[0091] Synthesis of N-(2-((5-chloro-2-((1-(2-(dimethylamino)ethyl)-1H-indol-5- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-3):

[0092]

[0093] Reference to the synthesis of C-1, yield 83%. 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.41(d, J = 8.1 Hz, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.63 (dd, J =8.0, 1.5 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.43 – 7.20 (m, 4H), 6.39 (d, J =3.1 Hz, 1H), 4.62 (t, J = 7.2 Hz, 2H), 3.43 (t, J = 7.2 Hz, 2H), 3.20 (s,3H), 3.11 (s, 3H), 2.76 (s, 6H).

[0094] Example 4

[0095] Synthesis of N-(2-((5-chloro-2-((1-(2-(diethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-4):

[0096]

[0097] Reference to the synthesis of C-1, yield 85%. 1 H NMR (400 MHz, Chloroform-d) δ 8.41 (dd, J =8.3, 1.4 Hz, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.22(dd, J = 8.1, 6.3 Hz, 3H), 7.15 – 7.09 (m, 2H), 7.09 – 7.03 (m, 2H), 6.34 (d,J = 2.9 Hz, 1H), 4.15 (t, J = 7.3 Hz, 2H), 3.20 (s, 3H), 2.92 (s, 3H), 2.77(t, J = 7.3 Hz, 2H), 2.54 (q, J = 7.1 Hz, 4H), 0.97 (t, J = 7.1 Hz, 6H).

[0098] Example 5

[0099] Synthesis of N-(2-((5-chloro-2-((l-(2-morpholinoethyl)-lH-indol-5- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-5):

[0100]

[0101] Refer to the synthesis of C-1, yield 84%. 1 H NMR (400 MHz, Chloroform-d) δ 8.48 (dd, J = 8.4, 1.4 Hz, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.34 - 7.26 (m, 3H), 7.22 - 7.10 (m, 3H), 7.06 (s, 1H), 6.42 (d, J = 3.1 Hz, 1H), 4.26 (t, J = 6.9 Hz, 2H), 3.75 - 3.67 (m, 4H), 3.28 (s, 3H), 3.00 (s, 3H), 2.77 (t, J = 6.9 Hz, 2H), 2.50 (t, J = 4.6 Hz, 4H).

[0102] Example 6

[0103] Synthesis of N-(2-((5-chloro-2-((2-methyl-2H-indazol-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-6):

[0104]

[0105] Refer to the synthesis of C-1, yield 88%. 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.40 (s, 1H), 8.38 - 8.27 (m, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.65 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.37 - 7.27 (m, 2H), 4.14 (s, 3H), 3.19 (s, 3H), 3.11 (s, 3H).

[0106] Example 7

[0107] Synthesis of N-(2-((5-chloro-2-((2-ethyl-2H-indazol-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-7):

[0108]

[0109] Refer to the synthesis of C-1, yield 86%. 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.39(s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.99 (s, 1H),7.65 (dd, J = 7.9, 1.5 Hz, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.46 – 7.39 (m,1H), 7.38 – 7.24 (m, 2H), 4.42 (q, J = 7.3 Hz, 2H), 3.19 (s, 3H), 3.11 (s,3H), 1.50 (t, J = 7.3 Hz, 3H).

[0110] Example 8

[0111] Synthesis of N-(2-((5-chloro-2-((2-ethyl-2H-indazol-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-7):

[0112]

[0113] Refer to the synthesis of C-1, yield 82%. 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.47(s, 1H), 8.25 (s, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.66 (dd, J =8.0, 1.5 Hz, 1H), 7.51 – 7.40 (m, 2H), 7.30 (td, J = 7.7, 1.5 Hz, 1H), 7.24(d, J = 8.6 Hz, 1H), 3.70 (t, J = 7.8 Hz, 2H), 3.19 (s, 3H), 3.17 (s, 1H),3.10 (s, 5H).

[0114] Example 9

[0115] Synthesis of N-(2-((5-chloro-2-((l-methylindolin-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-9):

[0116]

[0117] Refer to the synthesis of C-1, yield 87%. 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (dd, J = 8.6, 1.5 Hz, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 7.34 - 7.27 (m, 3H), 7.17 - 7.04 (m, 2H), 6.86 (s, 1H), 6.44 (d, J = 8.3 Hz, 1H), 3.35 - 3.21 (m, 5H), 2.99 (s, 3H), 2.93 (t, J = 8.1 Hz, 2H), 2.76 (s, 3H).

[0118] Example 10

[0119] Synthesis of N-(2-((5-chloro-2-(isoindolin-5-ylamino)pyrimidin-4-yl)amino)phenyl)- N-methylmethanesulfonamide (C-10):

[0120]

[0121] Refer to the synthesis of C-1, yield 80%. 1 H NMR (400 MHz, Chloroform-d) δ 8.39 - 8.31 (m, 2H), 8.09 (s, 1H), 7.59 (s, 1H), 7.42 - 7.32 (m, 2H), 7.24 - 7.13 (m, 3H), 7.05 (s, 1H), 4.26 (d, J = 10.7 Hz, 4H), 3.29 (s, 3H), 3.00 (s, 3H).

[0122] Example 11

[0123] Synthesis of N-(2-((5-chloro-2-((2-methyl-2,3,3a,7a-tetrahydro-lH-isoindol-5- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-11):

[0124]

[0125] Compound C-10 (1 eq, 1 mmol) was dissolved in 10 mL of DMF, DIPEA (3 eq, 3 mmol) and iodomethane (1.2 eq, 1.2 mmol) were added, and the reaction was carried out at 80 °C overnight. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate was extracted 3 times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. Compound C-11 was separated by column chromatography, and the yield was 53%. 1 H NMR (400 MHz, Chloroform-d) δ 8.41 – 8.32 (m, 2H), 8.07 (s, 1H), 7.50 (s, 1H), 7.39 – 7.31 (m, 2H), 7.27 – 7.16 (m, 3H), 7.09 (d, J = 8.0 Hz, 1H), 3.90 (d, J = 7.6 Hz, 4H), 3.28 (s, 3H), 2.99 (s, 3H), 2.62 (s, 3H).

[0126] Example 12

[0127] Synthesis of N-(2-((5-chloro-2-((2-ethylisoindolin-5-yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-12):

[0128]

[0129] Referring to the synthesis of C-11, the yield was 55%. 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.05 (s, 1H), 8.82 (s, 1H), 8.32 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 8.0, 1.4 Hz, 1H), 7.62 (s, 1H), 7.55 - 7.49 (m, 1H), 7.45 (dd, J = 8.3, 1.9 Hz, 1H), 7.36 (td, J = 7.7, 1.5 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 4.66 - 4.54 (m, 2H), 4.40 - 4.32 (m, 2H), 3.37 (p, J = 7.0, 6.5 Hz, 2H), 3.17 (s, 3H), 3.09 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).

[0130] Example 13

[0131] Synthesis of N-(2-((5-chloro-2-((2-isopropylisoindolin-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-13):

[0132]

[0133] Referring to the synthesis of C-11, yield 60%. 1 H NMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H), 7.88 - 7.81 (m, 1H), 7.72 - 7.66 (m, 1H), 7.56 - 7.49 (m, 2H), 7.47 (d, J = 1.8 Hz, 1H), 7.43 - 7.30 (m, 2H), 4.84 - 4.80 (m, 1H), 4.75 - 4.44 (m, 3H), 3.78 (hept, J = 6.5 Hz, 1H), 3.21 (s, 3H), 3.00 (s, 3H), 1.48 (dd, J = 6.6, 3.5 Hz, 6H).

[0134] Example 14

[0135] Synthesis of N-(2-((2-((2-acetylisindolin-5-yl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-14):

[0136]

[0137] Compound C-10 (1 eq, 1 mmol) was dissolved in 10 mL of DCM, triethylamine (3 eq, 3 mmol) and acetyl chloride (1.2 eq, 1.2 mmol) were added, and the reaction was allowed to proceed at room temperature for 3 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench the reaction, and DCM was added for extraction three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. Compound C-14 was isolated by column chromatography in a yield of 81%. 1 H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 8.31 (ddd, J = 16.1, 8.2, 1.5 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J = 27.6 Hz, 1H), 7.45 – 7.27 (m, 3H), 7.26 – 7.07 (m, 3H), 4.89 – 4.61 (m, 4H), 3.29 (d, J = 2.3 Hz, 3H), 3.00 (d, J = 3.3 Hz, 3H), 2.18 (s, 3H).

[0138] Example 15

[0139] Synthesis of N-(2-((5-chloro-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-15):

[0140]

[0141] Referring to the synthesis of C-1, the yield was 73%. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.38(s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 8.20 (s, 1H), 7.64 (dd, J = 8.0, 1.5 Hz,1H), 7.44 – 7.34 (m, 2H), 7.33 – 7.19 (m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 3.80(s, 2H), 3.20 (s, 3H), 3.17 (s, 1H), 3.11 (s, 3H), 2.94 (t, J = 5.8 Hz, 2H),2.60 (t, J = 5.9 Hz, 2H).

[0142] Example 16

[0143] Synthesis of N-(2-((5-chloro-2-((2-methyl-l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-16):

[0144]

[0145] Refer to the synthesis of C-11, yield 57%. 1 H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1H),8.35 (dd, J = 8.3, 1.4 Hz, 1H), 8.09 (s, 1H), 7.44 – 7.39 (m, 2H), 7.35 (dd,J = 8.0, 1.5 Hz, 1H), 7.26 – 7.17 (m, 2H), 7.01 – 6.92 (m, 2H), 3.89 (s, 2H),3.29 (s, 3H), 3.04 (s, 4H), 3.00 (s, 3H), 2.68 (s, 3H).

[0146] Example 17

[0147] Synthesis of N-(2-((5-chloro-2-((2-ethyl-l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-17):

[0148]

[0149] Refer to the synthesis of C-11, yield 52%. 1H NMR (400 MHz, Chloroform-d) δ 8.38 - 8.32 (m, 2H), 8.08 (s, 1H), 7.47 - 7.41 (m, 2H), 7.35 (dd, J = 8.0, 1.5 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.24 - 7.18 (m, 1H), 7.14 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.01 (s, 2H), 3.28 (s, 3H), 3.20 - 3.13 (m, 2H), 3.09 - 3.03 (m, 2H), 3.00 (s, 5H), 1.43 (t, J = 7.2 Hz, 3H).

[0150] Example 18

[0151] Synthesis of N-(2-((5-chloro-2-((2-isopropyl-l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-18):

[0152]

[0153] Refer to the synthesis of C-11, yield 59%. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.09 (s, 1H), 8.93 (s, 1H), 8.35 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 (td, J = 7.8, 1.4 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.38 - 7.32 (m, 2H), 7.09 (d, J = 8.5 Hz, 1H), 4.32 - 4.20 (m, 2H), 3.64 - 3.53 (m, 2H), 3.25 - 3.16 (m, 5H), 3.09 (s, 3H), 2.83 - 2.69 (m, 1H), 1.36 (t, J = 6.8 Hz, 6H).

[0154] Example 19

[0155] Synthesis of N-(2-((2-((2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- chloropyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-19):

[0156]

[0157] Referring to the synthesis of C-14, yield 89%. 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 6.3 Hz, 1H), 8.40 (s, 1H), 8.28 (t, J = 7.0 Hz, 1H), 8.21 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.46 - 7.34 (m, 2H), 7.31 - 7.24 (m, 1H), 7.04 (d, J = 8.3 Hz, 1H), 4.62 - 4.47 (m, 2H), 3.62 (t, J = 5.9 Hz, 2H), 3.19 (s, 3H), 3.10 (s, 3H), 2.78 - 2.58 (m, 2H), 2.08 (s, 3H).

[0158] Example 20

[0159] Synthesis of N-(2-((5-chloro-2-((l,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-20):

[0160]

[0161] Referring to the synthesis of C-l, yield 77%. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.43(s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.23 (s, 1H), 7.66 (dd, J = 8.0, 1.5 Hz,1H), 7.50 – 7.43 (m, 2H), 7.40 (dd, J = 8.3, 2.2 Hz, 1H), 7.28 (td, J = 7.7,1.5 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.05 (s, 2H), 3.28 (t, J = 6.2 Hz,2H), 3.20 (s, 3H), 3.11 (s, 3H), 2.87 (t, J = 6.2 Hz, 2H).

[0162] Example 21

[0163] Synthesis of N-(2-((5-chloro-2-((2-methyl-l,2,3,4-tetrahydroisoquinolin-7- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-21):

[0164]

[0165] Referring to the synthesis of C-11, yield 56%. 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H),10.23 (s, 1H), 9.07 (s, 1H), 8.36 (s, 1H), 8.04 (d, J = 7.0 Hz, 1H), 7.69 (d,J = 7.2 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.45 – 7.31 (m, 3H), 7.10 (d, J=8.2 Hz, 1H), 4.14 – 4.03 (m, 2H), 3.65 – 3.53 (m, 1H), 3.32 – 3.17 (m, 2H),3.16 (s, 3H), 3.08 (s, 3H), 2.96 – 2.89 (m, 1H), 2.86 (d, J = 4.7 Hz, 3H).

[0166] Example 22

[0167] Synthesis of N-(2-((5-chloro-2-((2-ethyl-l,2,3,4-tetrahydroisoquinolin-7- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-22):

[0168]

[0169] Refer to the synthesis of C-11, yield 55%. 1 H NMR (400 MHz, Chloroform-d) δ 8.38 - 8.33 (m, 2H), 8.07 (s, 1H), 7.40 (ddd, J = 8.5, 7.4, 1.5 Hz, 1H), 7.36 - 7.33 (m, 2H), 7.19 (ddd, J = 10.6, 7.9, 2.0 Hz, 2H), 7.02 (d, J = 7.2 Hz, 2H), 3.67 (s, 2H), 3.28 (s, 3H), 3.00 (s, 3H), 2.96 - 2.83 (m, 4H), 2.70 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0170] Example 23

[0171] Synthesis of N-(2-((5-chloro-2-((2-isopropyl-l,2,3,4-tetrahydroisoquinolin-7- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-23):

[0172]

[0173] Refer to the synthesis of C-11, yield 58%. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.89(s, 1H), 8.76 (s, 1H), 8.30 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.68 (dd, J =8.0, 1.4 Hz, 1H), 7.55 – 7.46 (m, 2H), 7.43 – 7.29 (m, 2H), 7.12 (d, J = 8.4Hz, 1H), 4.29 – 4.05 (m, 2H), 3.66 – 3.57 (m, 2H), 3.19 (s, 5H), 3.09 (s,3H), 2.98 – 2.88 (m, 1H), 1.36 (t, J = 6.1 Hz, 6H).

[0174] Example 24

[0175] Synthesis of N-(2-((5-chloro-2-((2-acetyl-l,2,3,4-tetrahydroisoquinolin-7- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-24):

[0176]

[0177] Refer to the synthesis of C-14, yield 86%. 1 H NMR (400 MHz, Chloroform-d) δ 8.44 – 8.28(m, 2H), 8.09 (d, J = 7.8 Hz, 1H), 7.51 – 7.34 (m, 3H), 7.26 – 7.13 (m, 2H),7.06 (dd, J = 10.4, 8.2 Hz, 2H), 4.67 – 4.51 (m, 2H), 3.85 – 3.63 (m, 2H),3.29 (d, J = 3.8 Hz, 3H), 3.00 (d, J = 4.3 Hz, 3H), 2.89 – 2.77 (m, 2H), 2.18(d, J = 5.4 Hz, 3H).

[0178] Example 25

[0179] Synthesis of N-(2-((5-chloro-2-((l-methyl-lH-indol-4-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-25):

[0180]

[0181] Refer to the synthesis of C-1, yield 88%. 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (dd, J =8.3, 1.4 Hz, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.34(dd, J = 14.0, 7.2 Hz, 2H), 7.23 (s, 1H), 7.17 (t, J = 7.8 Hz, 2H), 7.07 (d,J = 8.2 Hz, 1H), 7.03 (d, J = 3.1 Hz, 1H), 6.50 (d, J = 2.9 Hz, 1H), 3.80 (s,3H), 3.28 (s, 3H), 2.99 (s, 3H).

[0182] Example 26

[0183] Synthesis of N-(2-((5-chloro-2-((l,3-dihydroisobenzofuran-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-26):

[0184]

[0185] Refer to the synthesis of C-1, yield 86%. 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.42(s, 1H), 8.22 (s, 2H), 7.65 (d, J = 6.0 Hz, 2H), 7.49 – 7.35 (m, 2H), 7.30(t, J = 7.1 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 4.92 (d, J = 14.1 Hz, 4H),3.18 (s, 3H), 3.10 (s, 3H).

[0186] Example 27

[0187] Synthesis of N-(2-((5-chloro-2-((2,3-dihydro-lH-inden-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-27):

[0188]

[0189] Refer to the synthesis of C-1, yield 89%.1 H NMR (400 MHz, Chloroform-d) δ 8.41 (dd, J =8.3, 1.4 Hz, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.46 (s, 1H), 7.39 – 7.30 (m,2H), 7.20 – 7.11 (m, 3H), 6.97 (s, 1H), 3.28 (s, 3H), 2.99 (s, 3H), 2.87 (t,J = 7.4 Hz, 4H), 2.08 (p, J = 7.4 Hz, 2H).

[0190] Example 28

[0191] Synthesis of N-(2-((5-chloro-2-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-28):

[0192]

[0193] Refer to the synthesis of C-1, yield 91%. 1 H NMR (400 MHz, Chloroform-d) δ 8.42 (dd, J =8.3, 1.4 Hz, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.42 – 7.30 (m, 2H), 7.23 –7.10 (m, 3H), 7.02 – 6.88 (m, 2H), 3.28 (s, 3H), 2.99 (s, 3H), 2.79 – 2.66(m, 4H), 1.82 – 1.76 (m, 4H).

[0194] Example 29

[0195] Synthesis of N-(2-((5-chloro-2-((2-methyl-l-oxoisoindolin-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-29):

[0196]

[0197] Refer to the synthesis of C-1, yield 82%. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.52(s, 1H), 8.29 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.68 (dd, J =8.0, 1.4 Hz, 1H), 7.60 - 7.44 (m, 3H), 7.36 (t, J = 7.2 Hz, 1H), 4.31 (s,2H), 3.18 (s, 3H), 3.10 (s, 3H), 3.04 (s, 3H).

[0198] Example 30

[0199] Synthesis of N-(2-((5-chloro-2-((3-oxo-l,3-dihydroisobenzofuran-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-31):

[0200]

[0201] Refer to the synthesis of C-1, yield 85%. 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.54(s, 1H), 8.36 (s, 1H), 8.31 - 8.18 (m, 2H), 7.97 (dd, J = 8.3, 2.0 Hz, 1H),7.67 (dd, J = 8.2, 1.8 Hz, 2H), 7.57 - 7.46 (m, 1H), 7.31 (td, J = 7.7, 1.5Hz, 1H), 3.21 (s, 3H), 3.11 (s, 3H), 3.00 (s, 3H).

[0202] Example 31

[0203] Synthesis of N-(2-((5-chloro-2-((3-oxo-l,3-dihydroisobenzofuran-5-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-31):

[0204]

[0205] Refer to the synthesis of C-1, yield 83%. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.78(s, 1H), 8.36 (s, 1H), 8.25 – 8.11 (m, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.65(dd, J = 8.0, 1.5 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.45 (td, J = 7.8, 1.4Hz, 1H), 7.30 (td, J = 7.7, 1.5 Hz, 1H), 5.36 (s, 2H), 3.19 (s, 3H), 3.10 (s,3H).

[0206] Example 32

[0207] Synthesis of N-(2-((5-chloro-2-(isoquinoline-6-ylamino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-32):

[0208]

[0209] The synthesis was based on C-1, with a yield of 86%. 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.21(s, 1H), 8.81 (s, 1H), 8.77 (dd, J = 7.5, 1.7 Hz, 1H), 8.29 (d, J = 9.2 Hz,1H), 8.23 ​​(s, 1H), 8.12 (dd, J = 8.1, 1.4 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.74 (dd, J = 8.0, 1.4 Hz, 1H), 7.59 (td, J = 7.8, 1.4 Hz, 1H), 7.44 (td, J =7.7, 1.5 Hz, 1H), 7.33 (dd, J = 9.1, 2.0 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 3.22 (s, 3H), 3.11 (s, 3H).

[0210] Example 33

[0211] Synthesis of N-(2-((5-chloro-2-((1,2,3,4-tetrahydroquinolin-7-yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-33):

[0212]

[0213] Refer to the synthesis of C-1, yield 78%. 1 H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.26(s, 2H), 8.34 (s, 1H), 8.20 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H),7.48 – 7.44 (m, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.05 (d,J = 8.5 Hz, 1H), 4.17 (s, 2H), 3.32 (s, 2H), 3.15 (s, 3H), 3.09 (s, 3H), 2.83(t, J = 6.3 Hz, 2H), 2.37 (s, 3H).

[0214] Example 34

[0215] Synthesis of N-(2-((5-chloro-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)-5-methylphenyl)-N-methylmethanesulfonamide (C-34):

[0216]

[0217] Refer to the synthesis of C-1, yield 71%. 1 H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.26(s, 2H), 8.34 (s, 1H), 8.20 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H),7.48 – 7.44 (m, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.05 (d,J = 8.5 Hz, 1H), 4.17 (s, 2H), 3.32 (s, 2H), 3.15 (s, 3H), 3.09 (s, 3H), 2.83(t, J = 6.3 Hz, 2H), 2.37 (s, 3H).

[0218] Example 35

[0219] Synthesis of N-(2-((5-chloro-2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)-5-methoxyphenyl)-N-methylmethanesulfonamide (C-35):

[0220]

[0221] Refer to the synthesis of C-1, yield 73%. 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.36 (s, 2H), 8.26 (s, 1H), 8.16 (s, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.49 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 7.09 - 6.98 (m, 2H), 4.15 (s, 2H), 3.84 (s, 3H), 3.31 (s, 2H), 3.15 (s, 3H), 3.08 (s, 3H), 2.80 (t, J = 6.3 Hz, 2H).

[0222] Example 36

[0223] Synthesis of N-(5-chloro-2-((5-chloro-2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-36):

[0224]

[0225] Refer to the synthesis of C-1, yield 74%. 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.23 (s, 1H), 8.44 (s, 1H), 8.24 (s, 2H), 7.83 (d, J = 2.4 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 4.18 (s, 2H), 3.35 - 3.32 (m, 2H), 3.19 (s, 3H), 3.13 (s, 3H), 2.85 (t, J = 6.2 Hz, 2H).

[0226] Example 37

[0227] Synthesis of N-(2-((5-chloro-2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)-5-(trifluoromethyl)phenyl)-N-methylmethanesulfonamide (C-37):

[0228]

[0229] Referring to the synthesis of C-1, yield 77%. 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.93(s, 1H), 8.60 (s, 2H), 8.31 (d, J = 1.2 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 8.9, 2.1 Hz, 1H), 7.51 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.09(d, J = 8.5 Hz, 1H), 4.23 – 4.08 (m, 2H), 3.26 (s, 5H), 3.16 (s, 3H), 2.85(t, J = 6.0 Hz, 2H).

[0230] Example 38

[0231] Synthesis of N-(4-((5-chloro-2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)-[l,l'-biphenyl]-3-yl)-N-methylmethanesulfonamide (C-38):

[0232]

[0233] Referring to the synthesis of C-1, yield 77%. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.58(s, 2H), 9.07 (s, 1H), 8.38 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.98 (d, J =2.1 Hz, 1H), 7.82 - 7.74 (m, 3H), 7.53 (t, J = 7.6 Hz, 2H), 7.44 (dd, J =13.3, 5.9 Hz, 2H), 7.33 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.25 -4.05 (m, 2H), 3.24 (s, 3H), 3.15 (s, 5H), 2.79 (t, J = 6.4 Hz, 2H).

[0234] Example 39

[0235] Synthesis of N-(2-((5-chloro-2-((l,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)-5-(l-methyl-lH-pyrazol-4-yl)phenyl)-N-methylmethanesulfonamide (C-39):

[0236]

[0237] Referring to the synthesis of C-1, yield 74%. 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.62(s, 2H), 9.09 (s, 1H), 8.36 (d, J = 4.7 Hz, 2H), 8.03 (s, 1H), 7.94 (d, J =8.4 Hz, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.65 (dd, J = 8.4, 2.0 Hz, 1H), 7.44(s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.28 - 4.09 (m,2H), 3.91 (s, 3H), 3.19 (s, 5H), 3.11 (s, 3H), 2.75 (t, J = 6.2 Hz, 2H).

[0238] Example 40

[0239] Synthesis of N-(2-((5-chloro-2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylpropane-2-sulfonamide (C-41):

[0240]

[0241] Referring to the synthesis of C-1, yield 79%. 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 9.42(s, 2H), 8.45 (s, 1H), 8.23 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.64 (dd, J =7.9, 1.5 Hz, 1H), 7.53 – 7.37 (m, 3H), 7.29 (td, J = 7.5, 1.2 Hz, 1H), 7.05(d, J = 8.5 Hz, 1H), 4.16 (s, 2H), 3.34 – 3.23 (m, 4H), 3.20 (s, 3H), 2.86(t, J = 6.3 Hz, 2H), 1.25 (t, J = 7.4 Hz, 3H).

[0242] Example 41

[0243] Synthesis of N-(2-((5-chloro-2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylpropane-2-sulfonamide (C-41):

[0244]

[0245] Referring to the synthesis of C-1, yield 79%. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.40(s, 2H), 8.46 (s, 1H), 8.22 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.62 (dd, J =7.9, 1.5 Hz, 1H), 7.46 (td, J = 7.9, 7.0, 2.6 Hz, 2H), 7.41 – 7.26 (m, 2H),7.02 (d, J = 8.5 Hz, 1H), 4.14 (s, 2H), 3.59 – 3.50 (m, 1H), 3.31 (s, 2H),3.19 (s, 3H), 2.81 (t, J = 5.9 Hz, 2H), 1.28 (d, J = 6.8 Hz, 6H).

[0246] Example 42

[0247] Synthesis of N-(2-((5-chloro-2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-ethylmethanesulfonamide (C-42):

[0248]

[0249] Refer to the synthesis of C-1, yield 75%. 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.44(s, 2H), 8.39 (d, J = 8.1 Hz, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 7.64 (dd, J =7.9, 1.5 Hz, 1H), 7.54 (s, 1H), 7.48 (ddd, J = 8.5, 7.5, 1.4 Hz, 1H), 7.43(dd, J = 8.5, 2.1 Hz, 1H), 7.28 (td, J = 7.7, 1.5 Hz, 1H), 7.09 (d, J = 8.4Hz, 1H), 4.18 (s, 2H), 3.39 (s, 2H), 3.34 (d, J = 5.8 Hz, 2H), 3.13 (s, 3H),2.90 (t, J = 6.3 Hz, 2H), 0.93 (t, J = 7.1 Hz, 3H).

[0250] Example 43

[0251] Synthesis of N-(2-((5-chloro-2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-isopropylmethanesulfonamide (C-43):

[0252]

[0253] Refer to the synthesis of C-1, yield 76%. 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.43(s, 2H), 8.33 (d, J = 8.2 Hz, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 7.59 – 7.47(m, 3H), 7.43 (dd, J = 8.5, 2.2 Hz, 1H), 7.27 (td, J = 7.7, 1.5 Hz, 1H), 7.08(d, J = 8.5 Hz, 1H), 4.51 – 4.37 (m, 1H), 4.17 (s, 2H), 3.31 (s, 2H), 3.16(s, 3H), 2.96 – 2.78 (m, 2H), 1.19 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.7 Hz,3H).

[0254] Example 44

[0255] Synthesis of N-methyl-N-(2-((2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (C-44):

[0256]

[0257] Refer to the synthesis of C-1, yield 76%. 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.23(s, 1H), 9.47 (s, 2H), 8.05 (d, J = 7.0 Hz, 1H), 7.72 (dd, J = 7.8, 1.7 Hz,1H), 7.63 (dd, J = 7.8, 1.7 Hz, 1H), 7.49 – 7.37 (m, 2H), 7.32 (s, 1H), 7.27(d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 6.7 Hz, 1H), 4.19(s, 2H), 3.36 – 3.28 (m, 2H), 3.11 (s, 3H), 3.03 (s, 3H), 2.80 (t, J = 6.2Hz, 2H).

[0258] Example 45

[0259] Synthesis of N-methyl-N-(2-((5-methyl-2-((1,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (C-45):

[0260]

[0261] Referring to the synthesis of C-1, yield 71%. 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.69(s, 2H), 9.54 (s, 1H), 8.03 (s, 1H), 7.68 (td, J = 7.3, 2.1 Hz, 2H), 7.57 –7.44 (m, 2H), 7.20 (s, 1H), 7.14 (dd, J = 8.4, 2.2 Hz, 1H), 7.05 (d, J = 8.4Hz, 1H), 4.15 (s, 2H), 3.33 – 3.23 (m, 2H), 3.06 (s, 3H), 3.02 (s, 3H), 2.73(t, J = 6.2 Hz, 2H), 2.17 (s, 3H).

[0262] Example 46

[0263] Synthesis of N-(2-((5-methoxy-2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-46):

[0264]

[0265] Referring to the synthesis of C-1, yield 76%. 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.75(s, 2H), 9.59 (s, 1H), 7.99 – 7.91 (m, 2H), 7.69 (d, J = 7.2 Hz, 1H), 7.50(t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.30 (s, 1H), 7.21 (dd, J =8.4, 1.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.20 – 4.15 (m, 2H), 3.92 (s,3H), 3.34 – 3.27 (m, 2H), 3.15 (s, 3H), 3.05 (s, 3H), 2.84 (t, J = 6.3 Hz,2H).

[0266] Example 47

[0267] Synthesis of N-(2-((5-fluoro-2-((l,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (C-47):

[0268]

[0269] Referring to the synthesis of C-1, yield 76%. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 2H), 9.32(s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.24 - 8.07 (m, 2H), 7.64 (dd, J = 8.0,1.5 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.28 (td, J =7.7, 1.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 4.14 (s, 2H), 3.31 (t, J = 6.3Hz, 2H), 3.19 (s, 3H), 3.07 (s, 3H), 2.87 (t, J = 6.3 Hz, 2H).

[0270] Example 48

[0271] Synthesis of N-(2-((5-bromo-2-((l,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4- yl)amino)phenyl)-N-methylmethanesulfonamide (C-48):

[0272]

[0273] Refer to the synthesis of C-1, yield 77%. 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.43(s, 2H), 8.38 (s, 1H), 8.30 (s, 2H), 7.65 (dd, J = 8.0, 1.5 Hz, 1H), 7.51 (s,1H), 7.49 - 7.38 (m, 2H), 7.27 (td, J = 7.7, 1.5 Hz, 1H), 7.08 (d, J = 8.5Hz, 1H), 4.17 (s, 2H), 3.35 - 3.29 (m, 2H), 3.20 (s, 3H), 3.12 (s, 3H), 2.89(t, J = 6.3 Hz, 2H).

[0274] Example 49

[0275] Synthesis of N-methyl-N-(2-((2-((l,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (C-49):

[0276]

[0277] Refer to the synthesis of C-1, yield 70%. 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.52(s, 2H), 8.44 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.66 (dd, J = 8.0, 1.5 Hz,1H), 7.57 – 7.26 (m, 4H), 7.06 (d, J = 8.4 Hz, 1H), 4.17 (s, 2H), 3.34 – 3.28(m, 2H), 3.15 (s, 3H), 3.07 (s, 3H), 2.84 (s, 2H).

[0278] Example 50

[0279] Synthesis of N-methyl-N-(2-((5-nitro-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (C-50):

[0280]

[0281] Refer to the synthesis of C-1, yield 76%. 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.59(s, 1H), 9.53 (s, 2H), 9.14 (s, 1H), 8.16 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H),7.53 – 7.32 (m, 4H), 7.13 (d, J = 5.4 Hz, 1H), 4.21 (s, 2H), 3.33 (s, 2H),3.18 (s, 3H), 3.11 (s, 3H), 2.84 (s, 2H)。

[0282] The compounds prepared in Examples 1-50 were subjected to biological evaluation experiments:

[0283] (1) EGFR in vitro enzyme activity assay: add 0.5 μL EGFR or c-MET kinase and 5 μL compound prepared in Examples 1-50 in a 384 plate, incubate at room temperature for 5 minutes; add 0.5 μL polyE4Y1 (0.2 μg / μL, SIGMA, P0275) / ATP (1 μM, Promega, V915B) mixture, incubate at room temperature for 60 minutes in the dark; add 6 μL ADP-Glo™ Reagent (Promega, V912B), incubate at room temperature for 40 minutes; add 12 μL Kinase Detection Reagent (Promega, V913B), incubate at room temperature for 30 minutes, read the plate on a microplate reader, record the luminescence, and calculate the IC 50 values of each compound on enzyme activity using analysis software GraphPad Prism.

[0284] The results are shown in Tables 1 and 2, wherein the IC 50 According to the classification instructions: "A" indicates that the IC 50 value is less than or equal to 100 nM; "B" indicates that the IC 50 value is less than or equal to 500 nM and greater than 100 nM; "C" indicates that the IC 50 value is less than or equal to 1 μM and greater than 500 nM, and "D" indicates that the IC

[0285] Table 1, the inhibitory activity of the compounds of the present application on EGFR L858R / T790M / C797S and c-MET

[0286]

[0287] From the experimental results, it can be seen that the compounds C-1-C-50 prepared in the examples of the present application exhibit significant inhibitory activity on EGFR L858R / T790M / C797S and c-MET. Among them, a plurality of compounds achieve the best dual inhibition effect: such as C-15, C-16, C-20, C-24, C-34, C-35, etc., the IC L858R / T790M / C797S values of EGFR 50 and c-MET all reach the nanomolar level (IC 50 <100 nM), and at the same time, they also exhibit the strongest anti-proliferation activity (IC 50<250nM). These highly potent compounds share the common structural feature that their R1 substituent is a benzo-saturated nitrogen heterocycle (especially 1,2,3,4-tetrahydroisoquinoline), and the sulfonamide group ortho to the benzene ring maintains an N-methyl methanesulfonamide structure, which combination shows the optimal target binding properties. It is worth noting that even for compounds with relatively slightly inferior inhibitory activity against c-MET, such as C-27, C-28 (rated as "D" level), their inhibitory activity against EGFR L858R / T790M / C797S 50 =100-500 nM) is still significantly superior to the inhibitory effect of existing single-target inhibitors against the same mutant. In addition, compounds such as C-25, although relatively weak against c-MET, still have nanomolar inhibitory activity against EGFR L858R / T790M / C797S , showing their development potential as high-selectivity EGFR C797S mutant inhibitors. Through systematic structure-activity relationship studies, the present application has successfully constructed a compound library with high dual-target inhibitory activity and optimized selectivity, providing a multi-level, multi-mechanism solution to overcome osimertinib resistance.

[0288] (2) In vitro cell activity determination: the inhibitory effect of the compounds on the proliferation of various cancer cells was determined according to the CCK-8 method, and the half inhibitory concentration IC 50 value of the cell proliferation activity of the compounds was obtained. Logarithmic growth phase cells were seeded at 3000-5000 cells / well in a 96-well plate and incubated at 37 °C, 5% CO2 for 24 hours; 100 μL of different concentrations of test compound solution was added to the culture plate, and the culture plate was incubated in a 37 °C, 5% CO2 incubator for 72 hours; 4 hours before the end of incubation, 10 μL of CCK-8 solution (5 mg / mL) was added to each well. After incubation, the OD 450 was determined by a microplate reader, and the inhibition rate was calculated as (control group OD value-experimental group OD value) / control group OD value x 100%; after obtaining the data, GraphPad Prism was used to fit the IC 50 .

[0289] "++++" indicates that the IC 50 determination value is less than or equal to 250 nM. "+++" indicates that the IC 50 determination value is less than or equal to 500 nM and greater than 250 nM. "++" indicates that the IC 50 determination value is less than or equal to 1 μM and greater than 500 nM. "+" indicates that the IC 50 determination value is greater than 1 μM. "-" indicates that the IC 50 was not determined.

[0290] Table 2, the inhibitory activity of the compounds of the present application against EGFR L858R / T790M / C797S ​Antiproliferative activity of mutant cell H1975TM

[0291]

[0292] EGFR L858R / T790M / C797S Antiproliferative activity of mutant H1975TM cell. From the experimental results, it can be seen that the compounds of the present application exhibit significant differences in efficacy, highlighting their structure-activity relationship. Preferred compounds such as C-2, C-6, C-15, C-20, C-34, etc. exhibit excellent antiproliferative potency, with IC 50 values reaching the nanomolar level (≤250 nM), far exceeding the activity of osimertinib, with a clear advantage. At the same time, some compounds such as C-1, C-8 and C-30 (IC 50 =500-1000 nM) have relatively moderate activity in this model, but still demonstrate their basic activity based on the dual-target inhibition mechanism, and are significantly superior to existing single-target inhibitors in inhibiting the same mutant. This data clearly shows that through the structural optimization of the present application, a series of potent candidate compounds that far exceed the effects of existing technologies at the cellular level have been successfully obtained.

[0293] (3) In vivo antitumor (H1975TM (EGFR L858R / T790M / C797S ) activity determination:

[0294] The drug is the compound (C-15) prepared in Example 15; the cell strain is human lung adenocarcinoma H1975TM cells; the test animals are SPF BALB / c nude mice (Changzhou Kavens Experimental Animal Co., Ltd.); female; 6 in each group, a total of 18; the drug dose settings are as shown in Table 3.

[0295] Table 3, drug dose configuration

[0296]

[0297] Experimental method: Take the tumor in the vigorous growth period, under sterile conditions, human lung adenocarcinoma H1975-TM cells were inoculated into the right axillary subcutaneous of 25 BALB / c nude mice, and the cell inoculation amount was 5×10 6 . The diameter of the transplanted tumor of the nude mice was measured with a vernier caliper, and when the tumor grew to 85 mm 3The tumor-bearing nude mice in good growth state and with uniform tumor size were selected, and 18 of them were divided into 3 groups, 6 in each, i.e. (1) model group, (2) low-dose test drug group, and (3) high-dose test drug group, and dosing was performed according to the dose setting table. The anti-tumor effect of the test substance was dynamically observed by measuring the tumor diameter. The tumor diameter was measured once every other day, and the body weight of the nude mice was measured at the same time. The nude mice were euthanized after 21 days of dosing, and the tumor mass was surgically stripped and weighed. The tumor inhibition rate (%) was calculated according to the tumor mass weight. Tumor inhibition rate (%) = (tumor weight of the model group - tumor weight of the dosing group) / tumor weight of the model group x 100%.

[0298] Table 4, Effect of the test sample on the growth of human lung adenocarcinoma H1975TM transplanted tumor in nude mice

[0299]

[0300] The experimental results are shown in Table 4: the test drug Example 15 had a significant inhibitory effect on tumor growth, and the inhibitory effect of the high-dose group (40 mg / kg) was better than that of the low-dose group (20 mg / kg), and the tumor inhibition rates of the high-dose and low-dose groups were 65.7% and 52.6%, respectively. The dosing groups and the model control group had no significant effect on the body weight of the animals.

Claims

1. A 2-amino-4-phenylaminopyrimidine compound, characterized in that, The structure of the compound is shown in Formula I: ； Wherein, R1 is selected from , , , , , , ; R2 is selected from hydrogen, C1-C3 alkyl, methoxy, halogen, trifluoromethyl, , ; R3 is selected from hydrogen and C1-C3 alkyl groups; R4 is selected from methyl, ethyl, and isopropyl. R5 is selected from hydrogen, C1-C3 alkyl, methoxy, halogen, trifluoromethyl, and nitro; R8 is selected from C1-C3 alkyl groups; R9 is selected from hydrogen, C1-C3 alkyl, and acetyl groups; R 10 Selected from hydrogen, C1-C3 alkyl, and acetyl groups; R 11 Selected from hydrogen, C1-C3 alkyl, and acetyl groups.

2. The compound according to claim 1, characterized in that, R1 is selected from , , , , , , ; R2 is selected from hydrogen, C1-C3 alkyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, , ; R3 is selected from C1-C3 alkyl groups; R4 is selected from methyl, ethyl, and isopropyl. R5 is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, and nitro. R8 is selected from C1-C3 alkyl groups; R9 is selected from hydrogen, C1-C3 alkyl, and acetyl groups; R 10 Selected from hydrogen, C1-C3 alkyl, and acetyl groups; R 11 Selected from hydrogen, C1-C3 alkyl, and acetyl groups.

3. The compound according to claim 1, characterized in that, R1 is selected from , , , , , , ; R2 is selected from hydrogen, methyl, ethyl, isopropyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, etc. , ; R3 is selected from methyl, ethyl, and isopropyl. R4 is selected from methyl, ethyl, and isopropyl. R5 is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, and nitro. R8 is selected from methyl, ethyl, and isopropyl. R9 is selected from hydrogen, methyl, ethyl, isopropyl, and acetyl. R 10 Selected from hydrogen, methyl, ethyl, isopropyl, and acetyl; R 11 Selected from hydrogen, methyl, ethyl, isopropyl, and acetyl.

4. The compound according to claim 1, characterized in that, R1 is selected from , , , , , , ; R2 is selected from hydrogen, methyl, methoxy, chlorine, trifluoromethyl, , ; R3 is selected from methyl, ethyl, and isopropyl. R4 is selected from methyl, ethyl, and isopropyl. R5 is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, and nitro. R8 is selected from methyl; R9 is selected from hydrogen, methyl, ethyl, isopropyl, and acetyl. R 10 Selected from hydrogen, methyl, ethyl, isopropyl, and acetyl; R 11 Selected from hydrogen, methyl, ethyl, isopropyl, and acetyl.

5. The compound according to claim 1, characterized in that, The compounds are selected from those represented by formulas (C-1) to (C-50): 。 6. The compound according to claim 1, characterized in that, The compound also includes its pharmaceutically acceptable salt, which is an acid addition salt of the compound of formula I. The acid used for salt formation includes inorganic acids and organic acids, wherein the inorganic acids include hydrochloric acid, phosphoric acid, and sulfuric acid, and the organic acids include trifluoroacetic acid, acetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid, and tartaric acid.

7. A method for preparing the compound according to claim 1, characterized in that, Includes the following steps: ； Dissolve A and B in n-butanol, add trifluoroacetic acid, and react at 110-130 °C for 10-15 hours. After the reaction is complete, concentrate the reaction mixture and purify it by column chromatography. The substituents R1 to R5 are consistent with those defined in claim 1.

8. The use of the 2-amino-4-aniline pyrimidine compound of claim 1 in the preparation of a dual-target inhibitor of EGFR and c-MET.

9. The use of the 2-amino-4-phenylaminopyrimidine compound of claim 1 in the preparation of an antitumor drug.

10. The application according to claim 8, characterized in that, The tumors mentioned are malignant tumors with EGFR gene mutations and MET amplification, including lung cancer, gastric cancer, liver cancer, prostate cancer, breast cancer, testicular cancer, ovarian cancer, colon cancer, leukemia, pancreatic cancer, multiple myeloma, melanoma, glioma, brain glioma, pituitary adenoma, and various solid tumors and hematologic malignancies.

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