CN107098887B - Pyrimidines - Google Patents

Abstract

The invention belongs to the field of drug synthesis, and relates to pyrimidine compounds, their preparation method and application, a pharmaceutical composition containing them as active ingredients, and their application in the preparation of antitumor drugs. The invention discloses a pyrimidine compound having a structure shown in formula I, wherein W is NH, R ₁ is a nitrogen-containing five-membered heterocyclic ring, and R ₂ is a nitrogen-containing basic group; the pyrimidine compound of the present invention can be Inhibit a variety of tumor cells, especially can selectively act on EGFRL858R/T790M lung cancer cells. Compared with wild-type cells, the IC50 of this type of compound is 10-100 times higher. This type of compound can overcome the resistance of existing EGFR inhibitors.

Description

Pyrimidines

technical field

The invention belongs to the field of drug synthesis, and relates to pyrimidine compounds, in particular to a pyrimidine compound containing a pseudocycle, a preparation method and application thereof. The pyrimidine compound of the present invention can inhibit various tumor cells, especially can selectively act on EGFR L858R/T790M lung cancer cells, and this type of compound can overcome drug resistance of existing EGFR inhibitors.

Background technique

According to statistics, about one-third of the deaths caused by cancer worldwide are due to lung cancer, 80% of which are non-small cell lung cancer. Surgical treatment is currently the first choice and main treatment for lung cancer, but about 70% of patients will have secondary disease and metastasis. Significant progress has been made in the development of small molecule tyrosine kinase inhibitors (TKIs), and a variety of small molecule drugs are on the market.

EGFR is a member of the ErbB tyrosine kinase receptor family, and this signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. Studies have shown that EGFR is highly expressed or abnormally expressed in many tumors.

EGFR is widely distributed in mammalian epithelial cells and consists of three parts: the cell-based ligand binding region, the hydrophobic transmembrane domain and the intracellular kinase region. When the tyrosine protein kinase is overexpressed, it will hinder the programmed death of the cell, make the growth regulation of the cell out of control, always be in a state of proliferation, and develop into a malignant tumor. Clinical studies have shown that many types of solid tumors such as glioma, breast cancer, lung cancer, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, gastric cancer, etc. have high levels of expression.

It is disclosed in the prior art that tyrosine kinase inhibitors are one of the most widely studied small molecule inhibitors, which block the autophosphorylation of intramolecular tyrosine by competitively binding to extracellular ligand binding sites, and inhibit tyrosine kinase inhibitors. Activation of amino acid kinases, thereby blocking the cell cycle and accelerating apoptosis.

The EGFR T790M mutation is the most important drug resistance mechanism of EGFR inhibitors. The current EGFR inhibitors still cannot completely solve the clinical limitations caused by drug resistance, and most of the existing drugs use quinazoline as the basic core of EGFR reversible or Irreversible inhibitors have unavoidable side effects due to their poor selectivity to wild-type EGFR (EGFR WT). Therefore, there is an urgent need for selective novel framework compounds to solve the problem of drug resistance caused by EGFR T790M.

Contents of the invention

The technical problem mainly solved by the present invention is to provide a new pyrimidine compound, especially a pyrimidine compound containing a pseudocycle, its preparation method and application. The compound can inhibit the growth of tumor cells.

In order to solve the above technical problems, a technical solution adopted by the present invention is to provide a pyrimidine compound containing a pseudocycle, characterized in that, the compound has a structure of formula I:

Wherein W is NH, R ₁ is a nitrogen-containing five-membered heterocyclic ring, and R ₂ is a nitrogen-containing basic group.

In a preferred embodiment of the present invention, the structure of the nitrogen-containing five-membered heterocyclic ring is:

In a preferred embodiment of the present invention, said R ₂ is:

In a preferred embodiment of the present invention, the pyrimidine compound is used in the preparation of a drug for treating tumors and a pharmaceutical composition thereof.

In a preferred embodiment of the present invention, the tumor is any one of non-small cell lung cancer, small cell lung cancer, pancreatic cancer, and nasopharyngeal cancer.

The beneficial effects of the present invention are:

The pyrimidine compounds containing pseudocycles of the present invention can inhibit various tumor cells, especially can selectively act on EGFR L858R/T790M lung cancer cells. Compared with wild-type cells, the IC50 of this type of compound is 10-100 times higher. A class of compounds is a new class of tyrosine kinase inhibitors that can overcome the drug resistance of existing EGFR inhibitors and have selectivity.

Detailed ways

The technical solutions in the embodiments of the present invention will be described below, and the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

The following are definitions of terms used in the present invention. Unless otherwise indicated, the initial definition of a group or term provided herein applies in this specification alone or as part of another group.

"Substituted heterocycle" and "substituted heterocyclic" mean that one or more positions in the heterocycle or heterocyclic group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following substituents such as hydrogen, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, cycloalkyl.

Compounds represented by the particularly preferred general formula (I) of the present invention include

In one embodiment, the present invention provides a method for preparing the above-mentioned compound of the present invention.

The above-mentioned compounds of the present invention can be synthesized by the methods described in the following schemes and/or other techniques known to those of ordinary skill in the art, but are not limited to the following methods.

For convenience, the present invention uses well-known abbreviations to represent various compounds, including but not limited to DMF: N,N-dimethylformamide; THF: tetrahydrofuran; DIPEA: N,N-diisopropylethylamine Reaction scheme:

Reaction steps:

Example 1

The preparation of step 1 intermediate 2a

2-Nitroacetophenone (100mg, 0.6mmol) was dissolved in DMF-DMA, heated (100°C) and stirred overnight. After cooling, the solvent was evaporated to dryness to obtain Intermediate 1. It was directly used in the next reaction without purification. 220.9[M+H] ⁺

Step 2 Preparation of Intermediate 3a

Intermediate 1 (114 mg, 0.6 mmol) was mixed with ethanol as a solvent, about two equivalents of hydrazine hydrate was added, and the reaction was stirred for several hours until intermediate 1 disappeared. After cooling, the solvent was evaporated to dryness to obtain 90 mg of intermediate 2, yield 90%, 190 [M+H] ⁺ .

Step 3 Preparation of intermediate 4a

Intermediate 2 (90mg, 0.5mmol) was dissolved in THF, NaH (40mg, 1mmol) was added under ice-cooling condition, and iodomethane (31Ul, 0.5MMOL) was added after stirring for one hour. The reaction was stirred at room temperature for several hours until the disappearance of intermediate 2. The reaction system was concentrated and subjected to column chromatography to obtain 168 mg of intermediate 3 with a yield of 62%, 204[M+H] ⁺ .

Step 4 Preparation of intermediate 5a

Intermediate 4 (168mg, 0.8mmol) was dissolved in methanol, Pd/C was added, hydrogen was pressurized, and reacted overnight at room temperature. After filtration and concentration, 44 mg of intermediate 4 was obtained, which was directly used in the next reaction, 173.9 [M+H] ⁺ .

Example 2

Preparation of Intermediate 9a

Dissolve intermediate 5a (60mg, 0.3mmol) in 2-butanol, add 2,6-dichloropyrimidine (44mg, 0.3mmol), DIPEA (110uL, 0.6MMOL), heat and stir overnight, cool, evaporate the solvent to dryness, Purified by column chromatography (mobile phase 90:10 Hexane/EtOAc) to obtain 66 mg of intermediate 9a, yield 73%, 286 [M+H] ⁺ .

Example 3

Intermediate 9a (57 mg, 0.2 mmol) was mixed with intermediate 4-fluoro-2-methoxy-5-nitroaniline (50 mg, 0.2 mmol), 2-pentanol was added, and p-toluenesulfonic acid ( 19mg, 0.07mmol) was heated and stirred overnight, cooled, and a solid precipitated out, filtered to obtain 26mg of intermediate 10a, which was directly used in the next step without purification, 436[M+H] ⁺ .

Example 4 N ² -(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)-N ⁴ -(2-(1 -methyl-1H-pyrazole-3-yl)phenyl)pyrimidine-2,4-diamine (11a)

Intermediate 10a (56mg, 0.13mmol) was dissolved in DMF, DIPEA (6uL, 0.036mmol), N,N,N-trimethylethylenediamine (13mg, 0.13mmol) were added, heated and stirred for two hours, and the solvent was evaporated to dryness. Purified by column chromatography (mobile phase 1:15 methanol/dichloromethane) to obtain 28 mg of intermediate 11a.

¹ H NMR (400MHz, Chloroform-d) δ10.56(s, 1H), 9.05(s, 1H), 8.26(d, J=8.3Hz, 1H), 8.05(d, J=5.8Hz, 1H), 7.63(dd, J=7.8,1.5Hz,1H),7.40(d,J=2.3Hz,1H),7.34(s,1H),7.33–7.28(m,1H),7.09(t,J=7.6Hz ,1H),6.65(s,1H),6.58(d,J=2.3Hz,1H),6.31(d,J=5.8Hz,1H),4.01(s,3H),3.95(s,3H),3.24 (t, J=7.2Hz, 2H), 2.86(s, 3H), 2.56(t, J=7.2Hz, 2H), 2.27(s, 6H). ¹³ C NMR (150MHz, CDCl ₃ ) δ161.8, 160.7, 159.4, 156.9, 152.0, 143.5, 142.2, 137.9, 136.6, 129.8, 128.6, 124.8, 122.5, 120.6, 118.6, 116.3, 102.1, 56.2, 55.9, 55.3, 55.2, 52.5, 52.46.3, 52.2, ESI) (m/z): [M+H] ⁺ calcd for C ₂₆ H ₃₂ N ₉ O ₃ 518.2550; found 518.2548. Mp. 110-112°C.

Example 5 N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-((2-(1-methyl-1H-pyrazole -3-yl)phenyl)amino)pyrimidine-2-yl)phenyl-1,2,4-triazole (12a)

Intermediate 11a (28mg, 0.05mmol) was dissolved in methanol, and Pd/C was added for catalytic hydrogenation to obtain Intermediate 12a. After filtration, the solvent was evaporated to dryness, and it was directly used in the next reaction without purification.

¹ H NMR (400MHz, Chloroform-d) δ10.50(s, 1H), 8.50(d, J=8.3Hz, 1H), 8.03(d, J=5.7Hz, 1H), 8.01(s, 1H), 7.64(dd, J=7.7,1.4Hz,1H),7.44(s,1H),7.41(d,J=2.4Hz,1H),7.37(t,J=7.9Hz,1H),7.08(t,J =7.5Hz,1H),6.68(s,1H),6.59(d,J=2.3Hz,1H),6.19(d,J=5.8Hz,1H),4.01(s,3H),3.82(s,3H ), 2.96(t, J=6.9Hz, 2H), 2.66(s, 3H), 2.42(t, J=6.9Hz, 2H), 2.27(s, 6H). ¹³ C NMR(150MHz, CDCl ₃ ) δ160 .4, 159.7, 157.2, 141.1, 135.2, 135.0, 135.0, 132.4, 131.3, 129.8, 128.2, 126.5, 124.0, 123.4, 123.2, 107.1, 104.1, 98.8, 62.8, 56.9, 51.2, 41.0, 28 m/z): [M+H] ⁺ calcd for C ₂₆ H ₃₄ N ₉ O 488.2886; found 488.2870.

Example 6 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-((2-(1-methyl-1H -pyrazole-3-yl)phenyl)amino)pyrimidine-2-yl)amino)phenyl)acrylamide (13a)

Intermediate 12a (17mg, 0.035mmol) was dissolved in dichloromethane, ice-bathed, DIPEA (7L, 0.038mmol), acryloyl chloride (3L, 0.035mmol) were added, the solvent was evaporated to dryness after half an hour of reaction, and column chromatography (flow (phase 1:15 methanol/dichloromethane) was purified to obtain 17 mg of the target product with a yield of 53%.

¹ H NMR (400MHz, Chloroform-d) δ10.37(s,1H),10.07(s,1H),9.49(s,1H),8.41(d,J＝8.3Hz,1H),8.11(d,J =5.7Hz,1H),7.72–7.55(m,1H),7.39(s,0H),7.35(s,1H),7.02(t,J=7.6Hz,1H),6.76(s,1H),6.57 (d,J=2.4Hz,1H),6.47–6.26(m,1H),6.22(d,J=5.8Hz,1H),5.66(dd,J=9.5,2.4Hz,1H),3.99(s, 3H), 3.85(s, 3H), 2.88(t, J=5.6Hz, 2H), 2.69(s, 3H), 2.27(s, 6H). ¹³ C NMR(150MHz, CDCl ₃ ) δ163.24, 161.09, 159.92 ,156.61,151.11,145.25,137.22,135.68,132.57,130.95,129.47,128.10,128.05,127.15,125.92,122.20,121.71,121.63,112.36,104.68,104.48,99.48,57.51,56.16,45.56,43.80,39.27,29.84 .HRMS(ESI)(m/z):[M+H] ⁺ calcd for C29H36N9O2542.2992; found542.2990.

Example 7 N ² -(4-(2-(Dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-N ⁴ -(2-(1-methyl-1H- Pyrazole-3-yl)phenyl)pyrimidine-2,4-diamine (11b)

Step is with embodiment 4.

1H NMR (400MHz, Chloroform-d) δ10.53(s,1H),8.51(d,J=8.3Hz,1H),8.02(d,J=5.8Hz,1H),8.00(s,1H),7.64 (dd, J=7.8,1.6Hz,1H),7.41(d,J=2.3Hz,1H),7.40–7.32(m,2H),7.08(d,J=1.2Hz,0H),6.59(d, J＝2.3Hz, 1H), 6.54(s, 1H), 6.17(d, J＝5.7Hz, 1H), 4.09(s, 1H), 4.00(s, 3H), 3.81(s, 3H), 2.75( s,1H),2.38(s,6H).13C NMR(150MHz,CDCl3)δ160.8,159.8,156.4,151.2,141.2,140.6,137.2,131.0,130.7,128.1,127.9,124.4,122.2,121.9,121.34,108 ,104.4,100.3,99.1,68.0,58.6,57.0,45.8,39.3.HRMS(ESI)(m/z):[M+H] ⁺ calcd for C ₂₅ H ₃₆ N ₈ O ₄ 505.2312;

Example 8 N ² -(5-amino-4-(2-(dimethylamino)ethoxy)-2-methoxyphenyl)-N ⁴ -(2-(1-methyl-1H-pyridine Azole-3-phenyl)pyrimidine-2,4-diamine (12b)

Step is with embodiment 5

1H NMR (400MHz, Chloroform-d) δ10.57(s,1H),9.22(s,1H),8.24(d,J=8.3Hz,1H),8.06(d,J=5.8Hz,1H),7.64 (dd, J=7.8,1.5Hz,1H),7.41(d,J=2.3Hz,1H),7.34(s,1H),7.30(td,J=8.3,7.9,1.6Hz,1H),7.09( td,J=7.6,1.2Hz,1H),6.61(s,1H),6.59(d,J=2.3Hz,1H),6.33(d,J=5.8Hz,1H),4.20(t,J=5.8 Hz, 2H), 4.01(s, 3H), 3.97(s, 3H), 2.82(t, J=5.8Hz, 2H), 2.38(s, 6H).13C NMR(150MHz, CDCl3) δ161.0, 159.5, 156.6 ,152.7,151.0,148.8,136.7,133.1,131.0,128.3,128.1,123.7,122.7,121.7,121.3,116.2,104.4,99.6,98.4,69.7,58.2,56.4,46.2,39.3. z): [M+H] ⁺ calcd for C ₂₅ H ₃₁ N ₈ O ₂ 475.2570; found 475.2569.

Example 9 N-(2-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-((2-(1-methyl-1H-pyrazole -3-phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide (13b)

Step is with embodiment 6.

1H NMR (400MHz, Chloroform-d) δ10.39(s, 1H), 9.78(s, 1H), 9.34(s, 1H), 8.41(d, J=8.3Hz, 1H), 8.09(d, J= 5.8Hz, 1H), 7.61(dd, J=7.8, 1.6Hz, 1H), 7.40(d, J=2.4Hz, 1H), 7.24(t, J=4.0Hz, 2H), 7.02(t, J= 7.6Hz, 1H), 6.61(s, 1H), 6.57(d, J=2.3Hz, 1H), 6.42(d, J=1.8Hz, 0H), 6.38(d, J=1.8Hz, 1H), 6.29 (d,J=10.1Hz,1H),6.24(d,J=10.0Hz,0H),6.21(d,J=5.8Hz,1H),5.68(dd,J=10.0,1.8Hz,1H),4.11 (t,J=5.2Hz,2H),4.00(s,3H),3.85(s,3H),2.62–2.50(m,2H),2.36(s,6H).13C NMR(150MHz,CDCl3)δ163. 3,161.1,160.0,156.6,151.1,145.7,142.8,137.2,132.1,130.9,128.1,128.0,126.3,125.0,124.40,122.1,121.3,113.9,104.4,1055.8,99.4,72.1,72.3 29.8. HRMS (ESI) (m/z): [M+H] ⁺ calcd for C ₂₈ H ₃₁ N ₈ O ₃ 529.2676; found 529.2680.

Example 10 N ² -(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)-N ⁴ -(2-(1-methyl -1H-pyrazol-3-yl)phenyl)pyrimidine-2,4-diamine (11c)

Step is with embodiment 4.

1H NMR (400MHz, Chloroform-d) δ10.62(s,1H),9.15(s,1H),8.27(d,J=8.2Hz,1H),8.04(d,J=5.8Hz,1H),7.76 (d,J=8.1Hz,1H),7.62(dd,J=7.8,1.6Hz,1H),7.40(d,J=2.3Hz,1H),7.33–7.25(m,1H),7.17(d, J＝7.9Hz, 1H), 7.07(td, J＝7.5, 1.2Hz, 1H), 6.57–6.56(m, 2H), 6.30(d, J＝5.8Hz, 1H), 3.98(s, 3H), 3.92(s,3H),3.31(d,J=11.7Hz,2H),2.89–2.75(m,3H),2.00(d,J=11.9Hz,2H),1.83-1.81(m,1H).13C NMR (150MHz, Chloroform-d) δ160.8, 159.2, 156.3, 151.9, 150.8, 142.2, 141.9, 140.1, 136.6, 136.4, 131.0, 128.8, 128.1, 128.0, 125.8, 124.8, 122.5, 121.4, 101 102.4, 62.4, 56.1, 51.7, 46.1, 40.5, 39.1, 27.3, 21.3. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₈ H ₃₄ N ₉ O ₃ 544.2779; found 544.2786.

Example 11 N ² -(5-amino-4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N ⁴ -(2-(1-methyl- 1H-pyrazol-3-yl)phenyl)pyrimidine-2,4-diamine (12c)

Step is with embodiment 5.

1H NMR (400MHz, Chloroform-d) δ10.53(s, 1H), 8.53(d, J=8.3Hz, 1H), 8.05(t, J=2.9Hz, 2H), 7.66(dd, J=7.8, 1.5Hz, 1H), 7.48–7.34(m, 3H), 7.28(d, J＝0.9Hz, 1H), 7.11(td, J＝7.6, 1.2Hz, 1H), 6.67–6.59(m, 2H), 6.20(d, J=5.7Hz, 1H), 4.03(s, 3H), 3.83(s, 3H), 3.22(d, J=11.6Hz, 2H), 2.70–2.59(m, 2H), 2.46(s ,6H),2.02(d,J=12.4Hz,2H),1.73(dd,J=11.8,3.7Hz,2H).13C NMR(150MHz,MeOD)δ163.0,151.3,143.5,141.7,133.0,129.8,129.5 , _{129.1,126.9,125.9,125.2,105.9,105.7,100.2,65.0,57.1,51.2,40.5,39.1,28.3,21.3.HRMS} (ESI)(m/z):[M+H]+calcd for C ₃₆ N ₉ O, 514.3037; found 514.3040.

Example 12 N-(2-(4-(dimethylamino)piperidin-1-yl)-4-methoxy-5-((4-((2-(1-methyl-1H-pyrazole -3-yl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide (13c)

Step is with embodiment 6.

1H NMR (400MHz, Chloroform-d) δ10.37(s, 1H), 9.41(s, 1H), 8.51(s, 1H), 8.38(d, J=8.3Hz, 1H), 8.10(d, J= 5.8Hz, 1H), 7.62(dd, J=7.8, 1.6Hz, 1H), 7.40(d, J=2.3Hz, 1H), 7.32(s, 1H), 7.04(t, J=7.6Hz, 1H) ,6.72(s,1H),6.58(d,J=2.3Hz,1H),6.41–6.25(m,2H),6.23(d,J=6.0Hz,1H),5.72(d,J=9.8Hz, 1H), 3.99(s, 3H), 3.86(s, 3H), 3.04(d, J=11.6Hz, 2H), 2.71(t, J=11.4Hz, 2H), 2.38(s, 6H), 2.30- 2.28(m,2H),2.20-2.15(m,1H).13C NMR(150MHz,MeOD)δ162.8,161.1,159.8,156.5,151.0,145.2,137.1,135.9,132.3,130.9,128.1,128.0,126.7,126.6 ,126.4,122.3,121.7,112.1,104.4,103.2,99.5,62.1,56.1,52.4,42.0,39.2,30.0.HRMS(ESI)(m/z):[M+H]+calcd for C ₃₁ H ₃₈ N ₉ O ₂ , 568.3134, found 568.3137.

Example 13 N ² -(2-methoxy-4-(4-methylpiperidin-1-yl)-5-5-nitrophenyl)-N ⁴ -(2-(1-methyl- 1H-pyrazol-3-yl)phenyl)pyrimidine-2,4-diamine (11d)

Step is with embodiment 4.

¹ H NMR (400MHz, Chloroform-d) δ10.59(s, 1H), 9.20(s, 1H), 8.25(d, J=8.3Hz, 1H), 8.06(d, J=5.8Hz, 1H), 7.64(dd, J=7.8,1.5Hz,1H),7.47–7.38(m,2H),7.35–7.25(m,2H),7.09(td,J=7.6,1.2Hz,1H),6.64(s, 1H), 6.59(d, J=2.3Hz, 1H), 6.33(d, J=5.8Hz, 1H), 3.99(s, 3H), 3.97(s, 3H), 3.25(t, J=4.7Hz, 4H), 2.88(t, J=4.6Hz, 4H), 2.54(s, 3H). ¹³ C NMR (150MHz, CDCl3) δ161.8, 160.7, 159.4, 156.9, 152.0, 143.5, 142.2, 137.9, 136.6, 129.8, 128.6,124.8,122.5,120.6,118.6,116.3,102.1,56.2,55.9,55.3,55.2,52.7,52.3,52.2,46.1,36.5.Mp.110-113HRMS(ESI)(m/z):[M+H ]+calcd for C ₂₆ H ₃₀ N ₉ O ₃ , 516.2472, found 5516.2468.

Example 14 N ² -(5-amino-2-methoxy-4-(4-methylpiperidin-1-yl)-5-5-nitrophenyl)-N ⁴ -(2-(1 -Methyl-1H-pyrazol-3-yl)phenyl)pyrimidine-2,4-diamine (12d)

Step is with embodiment 5.

¹ H NMR (400MHz, Chloroform-d) δ10.55(s, 1H), 9.17(s, 1H), 8.24(d, J=8.2Hz, 1H), 8.05(d, J=5.8Hz, 1H), 7.63(dd, J=7.8,1.5Hz,1H),7.40(d,J=2.1Hz,2H),7.33–7.28(m,1H),7.13–7.06(m,1H),6.61(s,1H) ,6.58(d,J=2.2Hz,1H),6.32(d,J=5.8Hz,1H),4.00(s,3H),3.96(s,3H),3.09(t,J=4.7Hz,4H) ,2.62(t,J＝4.7Hz,4H). ¹³ C NMR(150MHz,CDCl ₃ )δ162.1,160.7,159.7,156.6,143.3,141.3,138.3,135.3,132.3,129.6,128.5,126.7,122.1,121.7, 118.3, 107.2, 104.3, 99.4, 56.9, 56.0, 51.4, 46.3, 36.5, 29.8; HRMS (ESI) (m/z): [M+Na]+calcd for C ₂₆ H ₃₁ N ₉ ONa, 508.2544, found 508.2541 ..

Example 15 N-(4-methoxy-5-((4-((2-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyrimidin-2-yl)amino) Phenyl)-2-(4-methylpiperidin-1-yl)phenyl)acrylamide (13d)

Step is with embodiment 6.

1H NMR (400MHz, Chloroform-d) δ10.52(s, 1H), 9.42(s, 1H), 8.55(s, 1H), 8.42(d, J=8.2Hz, 1H), 8.17(d, J= 5.8Hz, 1H), 7.76(d, J=8.1Hz, 1H), 7.62(dd, J=7.8, 1.6Hz, 1H), 7.40(d, J=2.3Hz, 1H), 7.33–7.25(m, 1H), 7.17(d, J=7.9Hz, 1H), 7.07(td, J=7.5, 1.2Hz, 1H), 6.57–6.56(m, 2H), 6.30(d, J=5.8Hz, 1H), 4.01(s,3H),3.85(s,3H),2.95-2.89(m,4H),2.60-2.58(m,4H),2.38(s,3H). ¹³ C NMR(150MHz,CDCl ₃ )δ162. 1,160.7,159.8,156.6,143.3,141.3,138.4,135.4,132.2,129.7,128.5,126.8,122.1,121.7,118.4,107.3,104.3,99.4,56.9,56.0,51.3,45.2,36 /z): [M+H]+calcd for C ₂₉ H ₃₄ N ₉ O ₂ , 540.2830; found 540.2835.

Example 16 N ² -(2-methoxy-4-morpholine-5-nitrophenyl)-N ⁴ -(2-(1-methyl-1H-pyrazol-3-yl)phenyl) Pyrimidine-2,4-diamine (11e)

Step is with embodiment 4.

1H NMR (400MHz, Chloroform-d) δ10.55(s,1H),9.18(s,1H),8.05(s,2H),7.63(dd,J=7.8,1.6Hz,1H),7.43–7.39( m,2H),7.30(td,J=8.3,7.8,1.6Hz,1H),7.09(td,J=7.6,1.3Hz,1H),6.60(s,1H),6.58(d,J=2.3Hz ,1H),6.32(d,J=5.8Hz,1H),4.00(s,3H),3.97(s,3H),3.89–3.84(m,4H),3.07–3.02(m,4H).13C NMR (151MHz,MeOD)δ161.0,159.4,156.5,151.9,151.0,141.7,137.2,136.7,131.0,128.3,128.1,125.3,122.7,121.7,121.3,116.1,104.4,106.1,56.7,757,3 , 52.9, 45.4, 40.6, 39.0. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₅ H ₂₇ N ₈ O ₄ , 503.2150, found 503.2155.

Example 17 N ² -(5-amino-2-methoxy-4-morpholinephenyl)-N ⁴ -(2-(1-methyl-1H-pyrazol-3-yl)phenyl)pyrimidine -2,4-diamine (12e)

Step is with embodiment 5.

¹ H NMR (400MHz, Chloroform-d) δ10.53(s, 1H), 8.52(d, J=8.3Hz, 1H), 8.07(t, J=4.2Hz, 2H), 8.04(s, 0H), 7.66(dd, J=7.8,1.6Hz,1H),7.48(s,1H),7.44(d,J=2.4Hz,1H),7.38(t,J=8.1Hz,1H),7.11(t,J =7.6Hz,1H),6.66(s,1H),6.62(d,J=2.5Hz,1H),6.21(d,J=5.7Hz,1H),4.03(s,3H),3.87(t,J =4.5Hz, 4H), 3.85(s, 3H), 2.92(t, J=4.6Hz, 4H). ¹³ C NMR (151MHz, MeOD) δ161.0, 160.8, 159.7, 156.4, 151.2, 141.3, 137.2, 135.3, 132.0,131.0,128.1,127.8,127.0,122.2,122.0,121.5,107.3,104.5,104.2,99.3,67.9,67.3,66.6,56.9,52.0,45.9,40.7,39.3.HRMS(ESI)(m/z): [M+H]+calcd for C ₂₅ H ₂₉ N ₈ O ₂ , 573.2408; found 473.2411.

Example 18 N-(4-methoxy-5-((4-((2-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyrimidin-2-yl)amino) -2-morpholinephenyl)acrylamide (13e)

Step is with embodiment 6.

¹ H NMR (400MHz, Chloroform-d) δ10.40(s,1H),9.46(s,1H),8.53(s,1H),8.39(d,J＝8.3Hz,1H),8.10(d,J =5.7Hz,1H),8.06(s,1H),7.64–7.61(m,1H),7.40(d,J=2.5Hz,2H),7.25(d,J=7.4Hz,1H),7.04(t ,J=7.5Hz,1H),6.74(s,1H),6.58(d,J=2.3Hz,1H),6.41–6.26(m,2H),6.23(d,J=5.9Hz,1H),5.74 (d, J=9.9Hz, 1H), 4.00(s, 3H), 3.88-3.85(m, 7H), 2.88(t, J=4.5Hz, 4H). ¹³ C NMR (151MHz, MeOD) δ162.7, 161.0 ,160.9,159.8,156.4,151.0,145.3,137.1,135.0,132.2,130.9,128.1,128.0,127.2,126.8,126.6,122.3,121.6,112.2,104.4,103.8,99.67,67.6,2 , 45.5, 40.7, 39.2. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₈ H ₃₁ N ₈ O ₃ , 527.2514, found 527.2516.

Example 19 N ² -(4-((2-(methylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)-N ⁴ -(2-(1- Methyl-1H-1,2,4-triazole-3-yl)phenyl)pyrimidine-2,4-diamine (11n)

Step is with embodiment 4.

¹ H NMR(400MHz,Chloroform-d)δ10.72(s,1H),9.12(s,1H),8.22(s,1H),8.20(s,2H),8.09(d,J＝5.8Hz,1H ), 7.41(t, J=7.9Hz, 1H), 7.36(s, 1H), 7.12(t, J=7.6Hz, 1H), 6.66(s, 1H), 6.42(d, J=5.8Hz, 1H ),4.04(s,3H),3.96(s,3H),3.29–3.23(m,2H),2.87(s,3H),2.57(t,J＝7.2Hz,2H),2.28(s,6H) . ¹³ C NMR (150MHz, CDCl ₃ ) δ162.0, 160.8, 159.6, 157.0, 152.2, 143.5, 142.4, 138.0, 135.1, 129.9, 128.7, 123.4, 122.5, 120.6, 118.7, 11556.5, 102.2, 99.1 54.2, 45.9, 41.5, 36.5. HRMS (ESI) (m/z): [M+H] ⁺ calcd for C25H31N10O3 519.2581; found 519.2584.

Example 20 N ¹ -(2-(dimethylamino)ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -(4-((2-(1-methyl-1H-1, 2,4-triazol-3-yl)phenyl)amino)pyrimidin-2-yl)amino)phenyl-1,2,4-triamine (12n)

Step is with embodiment 5.

¹ H NMR (400MHz, Chloroform-d) δ10.74(s, 1H), 8.46(d, J=8.3Hz, 1H), 8.19(dd, J=7.9, 1.6Hz, 1H), 8.15(s, 1H ),7.99(d,J＝5.9Hz,1H),7.90(s,1H),7.48–7.39(m,1H),7.19–7.10(m,1H),6.62(s,1H),6.25(d, J＝5.9Hz, 1H), 4.01(s, 3H), 3.81(s, 3H), 3.47(s, 2H), 3.30(t, J＝6.0Hz, 2H), 3.06(t, J＝6.2Hz, 2H), 2.82(s, 6H). ¹³ C NMR (150MHz, CDCl ₃ ) δ161.9, 160.8, 158.6, 143.4, 141.6, 137.8, 137.3, 130.4, 129.8, 129.7, 128.6, 127.4, 122.8, 121.6, 1178.7, 1 , 105.4, 99.5, 57.0, 55.6, 51.1, 50.8, 43.6, 43.4, 36.6. HRMS (ESI) (m/z): [M+H] ⁺ calcd for C25H33N10O 489.2839;

Example 21 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-((2-(1-methyl-1H -1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide (13n)

Step is with embodiment 6.

¹ H NMR (600MHz, Chloroform-d) δ10.52(s,1H),10.03(s,1H),9.45(s,1H),8.44(d,J＝8.3Hz,1H),8.16(d,J =7.8Hz,1H),8.13(s,1H),8.13(s,2H),7.54(d,J=8.6Hz,1H),7.37(d,J=12.3Hz,2H),7.33(t,J =7.8Hz,1H),7.14–7.12(m,1H),7.05(t,J=7.6Hz,1H),6.76(s,1H),4.00(s,3H),3.86(s,3H),2.89 (t, J=5.6Hz, 2H), 2.69(s, 3H), 2.32(t, J=5.8Hz, 2H), 2.28(s, 6H). ¹³ C NMR (15MHz, CDCl ₃ ) δ163.3, 162.1, 160.9, 159.9, 156.8, 145.3, 143.4, 138.3, 135.8, 132.6, 129.8, 129.3, 128.4, 127.0, 125.9, 124.8, 121.9, 121.1, 118.3, 104.6, 99.5, 56.1, 45.HR, 36.4, 43 (m/z): [M+H] ⁺ calcd for C ₂₈ H ₃₅ N ₁₀ O ₂ 543.2944; found 543.2950.

Example 22

Dissolve o-nitrochlorobenzene (3g, 19mmol) in DMF, add pyrazole (1.5g, 22.8mmol), potassium carbonate (3.1g, 22.8mmol), CuI (36mg, 0.19mmol), react overnight at 110°C, filter, Concentration gave 1.9 g of yellow solid.

Example 23

Operation is with embodiment 2.. 273[M+H] ⁺ .

Example 24

The operation is the same as in Example 3. 422[M+H] ⁺ .

Example 25 N ⁴ -(2-(1H-pyrazol-1-yl)phenyl)-N ² -(4-((2-(dimethylamino)ethyl)(methyl)amino)-2- Methylamino-5-nitrophenyl)pyrimidine-2,4-diamine (11f)

Operation is the same as embodiment 4.

¹ H NMR (400MHz, Chloroform-d) δ9.55(s, 1H), 8.93(s, 1H), 8.20(dd, J＝8.2, 1.4Hz, 1H), 8.05(d, J＝5.8Hz, 1H ),7.86(d,J=1.9Hz,1H),7.80(d,J=2.4Hz,1H),7.40–7.32(m,4H),7.16(td,J=7.7,1.4Hz,1H),6.64 (s,1H),6.49(t,J=2.2Hz,1H),6.18(d,J=5.8Hz,1H),3.94(s,4H),3.26–3.22(m,2H),2.86(s, 4H), 2.55(dd, J=8.0, 6.4Hz, 3H), 2.27(s, 6H). ¹³ C NMR (150MHz, MeOD) δ160.5, 159.4, 157.0, 152.1, 142.3, 141.2, 135.1, 132.5, 130.2, 130.2, 128.1, 123.5, 123.5, 123.2, 123.1, 116.4, 107.1, 102.1, 99.2, 57.0, 56.1, 54.2, 45.8, 41.4.

Example 26 N ⁴ -(4-((2-(1H-pyrazol-1-yl)phenyl)amino)pyrimidin-2-yl)-N ¹ -(2-(dimethylamino)ethyl)- 5-Methoxy-N ¹ -methylphenyl-1,2,4-triazole (12f)

Same as Example 5

¹ H NMR (400MHz, Chloroform-d) δ9.35(s, 1H), 8.36(dd, J=8.3, 1.3Hz, 1H), 8.02(d, J=5.7Hz, 1H), 7.92(s, 1H ),7.81(dd,J＝9.8,2.2Hz,2H),7.49–7.39(m,2H),7.36(dd,J＝8.0,1.5Hz,1H),7.21–7.12(m,1H),6.67( s,1H),6.48(t,J=2.2Hz,1H),6.09(d,J=5.7Hz,1H),3.80(s,3H),2.96(dd,J=7.6,6.1Hz,2H), 2.65(s,3H),2.42(dd,J＝7.6,6.1Hz,2H),2,27(s,6H). ¹³ C NMR(150MHz,MeOD)δ155.7,155.0,152.3,136.5,136.4,131.8, 128.3, 127.7, 125.7, 125.6, 123.0, 122.0, 119.5, 118.9, 118.5, 102.4, 102.2, 100.4, 94.1, 53.1, 52.2, 50.1, 41.2, 38.1.

Example 27 N-(5-((4-((2-(1H-pyrazol-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino ) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (13f)

Operation is the same as embodiment 6.

¹ H NMR (400MHz, Chloroform-d) δ10.07(s,1H),9.42(s,1H),9.20(s,1H),8.25(d,J＝8.1Hz,1H),8.09(d,J =5.7Hz,1H),7.82(d,J=1.9Hz,1H),7.78(d,J=2.5Hz,1H),7.32(q,J=3.5,3.0Hz,3H),7.13–7.06(m ,1H),6.75(s,1H),6.50–6.42(m,1H),6.42–6.28(m,2H),6.11(d,J=5.8Hz,1H),5.68(dd,J=9.2,2.6 Hz, 1H), 3.84(s, 3H), 2.88(t, J=5.6Hz, 2H), 2.69(s, 3H), 2.29(s, 9H). ¹³ C NMR(150MHz, CDCl3) δ163.2, 160.6, 159.8, 157.2, 145.2, 141.2, 135.8, 132.9, 132.5, 130.6, 130.3, 129.3, 127.9, 126.8, 126.0, 123.8, 123.7, 123.2, 112.3, 107.1, 104.6, 98.6, 544.5, 5.6, 5 HRMS (ESI) (m/z): [M+H]+calcd for C ₂₈ H ₃₄ N ₉ O ₂ , 528.2830; found 528.2828.

Example 28 N ⁴ -(2-(1H-pyrazol-1-yl)-N ² -(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5- Nitrophenyl)pyrimidine-2,4-diamine (11g)

Operation is the same as embodiment 4.

¹ H NMR (400MHz, Chloroform-d) δ9.56(s, 1H), 9.03(s, 1H), 8.18(d, J=8.1Hz, 1H), 8.04(d, J=5.8Hz, 1H), 7.85(d,J=1.9Hz,1H),7.79(d,J=2.5Hz,1H),7.38–7.32(m,3H),7.18–7.12(m,1H),6.56(s,1H),6.47 (t,J=2.3Hz,1H),6.18(d,J=5.8Hz,1H),3.93(s,3H),3.32(d,J=11.7Hz,2H),2.79(td,J=11.7, 2.3Hz, 2H), 2.34(s, 6H), 1.91-1.89(m, 2H), 1.91-1.77(m, 1H). ¹³ C NMR(150MHz, CDCl3) δ160.5, 159.3, 157.0, 151.9, 142.6, 141.3 ,141.2,136.3,132.5,130.2,130.2,128.0,124.2,123.6,123.4,123.3,116.4,107.1,102.2,99.3,62.0,56.1,52.2,41.6,28.4. M+H]+calcd for C ₂₇ H ₃₂ N ₉ O ₃ , 530.2623; found 530.2628.

Example 29 N-(5-((4-((2-(1H-pyrazol-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(dimethylamino) Piperidin-1-yl)-4-methoxyphenyl)acrylamide (12g)

Operation is the same as embodiment 5.

¹ H NMR (400MHz, Chloroform-d) δ9.36 (s, 1H), 8.06–8.00 (m, 2H), 7.94 (s, 1H), 7.81 (dd, J＝8.3, 2.1Hz, 2H), 7.49 –7.32(m,3H),7.21–7.12(m,1H),6.63(s,1H),6.49(t,J=2.2Hz,1H),6.08(d,J=5.7Hz,1H),4.40( ddd,J=15.7,4.8,2.3Hz,2H),3.80(s,3H),3.69-3.63(m,2H),3.17(d,J=11.5Hz,2H),3.07(td,J=12.6, ¹³ C NMR (150MHz, CDCl ₃ ) δ160.5, 160.2, 159.5, 156.8, 140.9, 140.9, 135.0, 132.8, 130.4, 130.1, 127.5, 126.1, 124.1, 123.4, 123.1, 107.0, 106.8, 103.9, 132.6, 2 51.4, 44.9, 41.7, 41.5, 38.6, 29.3, 29.0, 27.4. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₇ H ₃₄ N ₉ O, 500.2881; found 500.2877.

Example 30 N-(5-((4-((2-(1H-pyrazol-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(dimethylamino) Piperidin-1-yl)-4-methoxyphenyl)acrylamide (13g)

Step is with embodiment 6.

¹ H NMR (400MHz, Chloroform-d) δ9.36(s,1H),9.25(s,1H),8.44(s,1H),8.24(d,J＝8.2Hz,1H),8.08(d,J =5.8Hz,1H),7.82(d,J=1.8Hz,1H),7.78(d,J=2.4Hz,1H),7.36–7.28(m,3H),7.10(t,J=7.6Hz,1H ),6.70(s,1H),6.47(t,J=2.2Hz,1H),6.41–6.29(m,2H),6.13(d,J=5.8Hz,1H),5.74(d,J=9.8Hz ,1H),5.30(s,1H),3.85(s,3H),3.05(d,J＝11.6Hz,2H),2.77–2.66(m,2H),2.46(s,6H),2.08(d, J＝12.4Hz, 2H), 1.78-1.74(m, 1H). ¹³ CNMR (150MHz, CDCl3) δ160.6, 159.8, 157.2, 141.2, 132.9, 132.3, 130.5, 130.3, 127.9, 126.6, 126.5, 123.6, 123.3, _{Found _ _ _} 554.2981.

Example 31 N ⁴ -(2-(1H-pyrazol-1-yl)phenyl)-N ² -(2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitro Phenyl)pyrimidine-2,4-diamine (11h)

With embodiment 4.

¹ H NMR (400MHz, Chloroform-d) δ9.58(s, 1H), 9.07(s, 1H), 8.23–8.17(m, 1H), 8.07(d, J=5.8Hz, 1H), 7.87(d ,J=1.9Hz,1H),7.82(d,J=2.5Hz,1H),7.41–7.35(m,2H),7.18(td,J=7.6,1.3Hz,1H),6.62(s,1H) ,6.50(t,J=2.2Hz,1H),6.21(d,J=5.8Hz,1H),3.97(s,3H),3.11(t,J=4.8Hz,4H),2.66(t,J= 4.7Hz,4H),2.40(s,3H). ¹³ C NMR(150MHz,MeOD)δ160.5,159.3,157.0,151.89,141.9,141.2,136.9,132.5,130.2,130.2,128.0,124.7,123.6,123.5,123.3 ,116.2,107.1,102.2,99.4,56.2,55.2,52.3,46.1.HRMS(ESI)(m/z):[M+H]+calcd for C ₂₅ H ₂₈ N ₉ O ₃ ,502.2310;

found 502.2306..

Example 32 N ⁴ -(2-(1H-pyrazol-1-yl)phenyl)-N ² -(5-amino-2-methoxy-4-(4-methylpiperazin-1-yl) ) phenyl) pyrimidine-2,4-diamine (12h)

With embodiment 5.

¹ H NMR (400MHz, Chloroform-d) δ9.35(s, 1H), 8.37(dd, J＝8.3, 1.4Hz, 1H), 8.03(t, J＝2.8Hz, 2H), 7.95(s, 1H ),7.82(d,J=1.9Hz,1H),7.80(d,J=2.5Hz,1H),7.47–7.40(m,2H),7.36(dd,J=8.0,1.5Hz,1H),7.16 (td,J=7.7,1.4Hz,1H),6.66(s,1H),6.49(t,J=2.2Hz,1H),6.09(d,J=5.7Hz,1H),3.80(s,3H) ,3.43–3.36(m,4H),2.44–2.39(m,4H),2.32(s,6H). ¹³ C NMR(150MHz,MeOD)δ160.8,160.4,159.6,157.0,141.2,135.2,133.0,132.3, HRMS(ESI)(m/z): [M+H]+calcd for C ₂₅ H ₃₀ N ₉ O, 472.2568; found 472.2565.

Example 33 N-(5-((4-((2-(1H-pyrazol-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4 -Methylpiperazin-1-yl)phenyl)acrylamide (13h)

With embodiment 6.

¹ H NMR (400MHz, Chloroform-d) δ10.55(s,1H),9.45(s,1H),8.60–8.55(m,1H),8.45(d,J＝8.4Hz,1H),8.25–8.12 (m,4H),8.04(s,0H),7.37(d,J＝8.0Hz,2H),7.08(t,J＝7.4Hz,1H),6.79(s,1H),6.39–6.29(m, 2H), 5.76(d, J=9.7Hz, 1H), 4.03(s, 3H), 3.88(s, 3H), 2.99-2.94(m, 4H), 2.63-2.61(m, 4H), 2.41(s ,3H). ¹³ C NMR (151MHz, CDCl3) δ162.7, 160.6, 159.8, 157.2, 145.1, 141.2, 135.3, 132.9, 132.3, 130.5, 130.2, 127.9, 126.8, 126.7, 126.4, 123.6, 123.9, 101.9, 10 107.1, 103.5, 98.7, 56.1, 56.1, 52.5, 46.2. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₈ H ₃₂ N ₉ O ₂ , 526.2673; found 526.2669.

Example 34 N ⁴ -(2-(1H-pyrazol-1-yl)phenyl)-N ² -(2-methoxy-4-morpholine-5-nitrophenyl)pyrimidine-2,4 - Diamine (11i)

Step is with embodiment 4.

¹ H NMR (400MHz, Chloroform-d) δ9.58(s, 1H), 9.07(s, 1H), 8.18(d, J=8.2Hz, 1H), 8.06(d, J=5.8Hz, 1H), 7.86(d, J=1.9Hz, 1H), 7.80(d, J=2.5Hz, 1H), 7.37(dd, J=15.1, 7.5Hz, 3H), 7.17(td, J=7.6, 1.4Hz, 1H ),6.59(s,1H),6.49(t,J=2.2Hz,1H),6.21(d,J=5.8Hz,1H),3.96(s,3H),3.91–3.83(m,4H),3.07 –3.00(m,4H). ¹³ C NMR(151MHz,CDCl3)δ160.5,159.3,157.0,151.8,141.7,141.2,137.2,132.5,130.3,130.2,128.0,125.1,123.6,123.5,123.3,1176.1,1 102.1, 99.4, 67.1, 56.2, 52.9. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₄ H ₂₅ N ₈ O ₄ , 489.1993; found 489.1987.

Example 35 N ⁴ -(2-(1H-pyrazol-1-yl)phenyl)-N ² -(5-amino-2-methoxy-4-morpholinephenyl)pyrimidine-2,4- Diamine (12i)

Step is with embodiment 5.

¹ H NMR (400MHz, Chloroform-d) δ9.38(s, 1H), 8.38(d, J=8.4Hz, 1H), 8.03(d, J=5.7Hz, 1H), 7.97(s, 1H), 7.83(d,J=1.9Hz,1H),7.80(d,J=2.4Hz,1H),7.49(s,1H),7.46–7.40(m,1H),7.36(dd,J=8.1,1.5Hz ,1H),7.26(d,J=0.9Hz,3H),7.17(t,J=7.8Hz,1H),6.64(s,1H),6.50(t,J=2.2Hz,1H),6.10(d , J=5.7Hz, 1H), 3.85(t, J=4.5Hz, 4H), 3.82(s, 3H), 2.90(t, J=4.5Hz, 4H). ¹³ C NMR (151MHz, CDCl3) δ160. 4,159.6,156.9,141.3,141.2,135.3,133.1,132.1,130.5,130.3,127.7,126.8,124.2,123.5,123.2,107.2,107.1,104.2,98.9,67.9,56.9,52.0.

Example 36 N-(5-((4-((pyrazol-1-yl)phenyl)amino)pyrimidin-2yl)amino)-4-methoxy-2-morpholine phenyl)acrylamide ( 13i)

Step is with embodiment 6.

¹ H NMR (400MHz, Chloroform-d) δ9.41(s,1H),9.27(s,1H),8.50(s,1H),8.23(d,J＝8.2Hz,1H),8.09(d,J =5.8Hz,1H),7.82(d,J=1.9Hz,1H),7.78(d,J=2.4Hz,1H),7.38–7.27(m,3H),7.10(t,J=7.6Hz,1H ),6.72(s,1H),6.46(t,J=2.2Hz,1H),6.42–6.24(m,2H),6.14(d,J=5.8Hz,1H),5.80–5.71(m,1H) ,3.86-3.79(m,7H),2.86(t,J=4.5Hz,4H). ¹³ C NMR(150MHz,CDCl3)δ162.7,160.6,159.7,157.1,145.1,141.2,135.0,132.8,132.2,130.5, 130.2, 127.8, 126.9, 126.7, 126.5, 123.6, 123.3, 112.1, 107.1, 103.4, 98.8, 67.8, 56.1, 52.9...

Example 37

The operation is the same as in Example 3. 422.9 [M+H] ⁺ .

Example 38 N ⁴ -(2-(2H-1,2,3-triazol-2-yl)phenyl)-N ² -(4-((2-(dimethylamino)ethyl)(methyl )amino)-2-methoxy-5-nitrophenyl)pyrimidine-2,4-diamine (11j)

Step is with embodiment 4.

¹ H NMR (400MHz, Chloroform-d) δ9.82(s, 1H), 9.01(s, 1H), 8.16(d, J=8.3Hz, 1H), 8.08(d, J=5.8Hz, 1H), 7.99(dd,J=8.4,1.7Hz,1H),7.93(s,2H),7.43–7.35(m,2H),7.23–7.17(m,1H),6.65(s,1H),6.31(d, J=5.8Hz, 1H), 3.94(s, 4H), 3.26(t, J=7.2Hz, 2H), 2.86(s, 3H), 2.58(t, J=7.2Hz, 2H). ¹³ C NMR ( 150MHz, CDCl3) δ160.5, 159.4, 157.3, 152.2, 142.5, 135.1, 135.0, 135.0, 131.0, 129.7, 128.5, 123.5, 123.4, 123.1, 122.8, 116.5, 102.1, 95.7, 54.0, 4.8, 56.0 HRMS (ESI) (m/z): [M+H]+calcd for C ₂₄ H ₂₉ N ₁₀ O ₃ , 505.2419; found 505.2418.

Example 39 N ⁴ -(4-((2-(2H-1,2,3-triazol-2-yl)phenyl)amino)pyrimidin-2-yl)-N ¹ -(2-(dimethyl Amino)ethyl)-5-methoxy-N ¹ -methylphenyl-1,2,4-triamine (12j)

Step is with embodiment 5.

¹ H NMR (400MHz, Chloroform-d) δ9.63(s, 1H), 8.40(d, J=8.3Hz, 1H), 8.07(d, J=5.7Hz, 1H), 8.01(s, 1H), 7.95–7.88(m,5H),7.52–7.43(m,2H),7.22(t,J=7.7Hz,1H),6.67(s,1H),6.18(d,J=5.7Hz,1H),3.81 (s,3H),2.96(t,J=6.6Hz,2H),2.66(s,3H),2.42(dd,J=8.6,5.1Hz,2H),2.29(s,3H),2.28(s, 3H). ¹³ C NMR (150MHz, MeOD) δ160.4, 159.7, 157.2, 141.1, 135.2, 135.0, 135.0, 132.4, 131.3, 129.8, 128.2, 126.5, 124.0, 123.4, 123.2, 1056.1, 104.1, 98.8 , 51.2, 41.0, 28.6. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₄ H ₃₁ N ₁₀ O, 475.2677; found 475.2674.

Example 40 N-(5-((4-((2-(2H-1,2,3-triazol-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(( 2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (13j)

Step is with embodiment 6.

¹ H NMR (400MHz, Chloroform-d) δ10.09(s,1H),9.67(s,1H),9.48(s,1H),8.24(d,J＝8.2Hz,1H),8.13(d,J =5.6Hz,1H),7.95(dd,J=8.2,1.6Hz,1H),7.91(s,2H),7.39–7.31(m,2H),7.17–7.11(m,1H),6.76(s, 1H), 6.26(d, J=5.8Hz, 1H), 5.71–5.66(m, 1H), 3.85(s, 3H), 2.88(t, J=5.6Hz, 2H), 2.69(s, 3H), 2.33–2.26(m,9H) ^.13C NMR(150MHz,CDCl3)δ163.2,160.6,159.9,157.5,145.1,135.8,135.0,134.9,132.6,131.4,129.9,129.4,128.4,126.8,1235.33,123 , 123.1, 112.3, 104.6, 98.4, 57.5, 56.1, 45.5, 43.7. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₇ H ₃₃ N ₁₀ O ₂ , 529.2782; found 529.2780.

Example 41 N ⁴ -(2-(2H-1,2,3-triazol-2-yl)phenyl)-N ² -(4-(4-(dimethylamino)piperidin-1-yl) -2-methoxy-5nitrophenyl)pyrimidine-2,4-diamine (11k)

Step is with embodiment 4.

¹ H NMR (400MHz, Chloroform-d) δ9.82(s, 1H), 9.11(s, 1H), 8.15(d, J=8.1Hz, 1H), 8.08(d, J=5.8Hz, 1H), 8.01–7.97(m,2H),7.93(s,2H),7.43–7.36(m,2H),7.21(ddd,J＝8.5,7.3,1.4Hz,1H),6.56(s,1H),6.31( d,J=5.8Hz,1H),3.94(s,3H),3.34(d,J=11.6Hz,2H),2.80(m,2H),2.40-2.36(m,2H),2.34(s,6H ),1.90-1.88(m,2H),1.78(m,1H). ¹³ C NMR(150MHz,MeOD)δ160.5,159.3,157.3,152.1,142.9,135.9,135.2,135.1,135.0,130.9,129.7,128.5, 124.0, 123.6, 123.4, 122.8, _116.5 , 102.0, 98.7, 61.9, 56.2, 56.1, 52.2, 41.6, 41.5, 41.4, 28.3. H ₃₁ N ₁₀ O ₃ , 531.2575; found 531.2570.

Example 42 N ⁴ -(2-(2H-1,2,3-triazol-2-yl)phenyl)-N ² -(5-amino-4-(4-(dimethylamino)piperidine- 1-yl)-2-methoxyphenyl)pyrimidine-2,4-diamine (12k)

Step is with embodiment 5.

¹ H NMR (400MHz, Chloroform-d) δ9.62(s, 1H), 8.38(d, J=8.0Hz, 1H), 8.05(d, J=5.7Hz, 1H), 8.00(d, J=7.1 Hz, 1H), 7.92(s, 1H), 7.90(s, 2H), 7.49–7.43(m, 3H), 7.21(t, J=7.7Hz, 1H), 6.60(s, 1H), 6.17(d ,J＝5.7Hz,1H),3.80(s,3H),3.2-3.18(m,2H),2.65-2.59(m,2H),2.50(s,6H),2.07-2.04(m,2H), 1.76(m,2H) ^.13C NMR(150MHz,MeOD)δ160.4,159.7,157.2,141.1,135.2,135.0,135.0,132.4,131.3,129.8,128.2,126.5,124.0,123.4,123.2,108.1,98.10 , 62.8, 56.9, 51.2, 41.0, 28.6. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₆ H ₃₃ N ₁₀ O, 501.2833; found 501.2835.

Example 43 N-(5-((4-((2-(2H-1,2,3-triazol-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4 -(Dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide (13k)

Step is with embodiment 6.

¹ H NMR (400MHz, Chloroform-d) δ9.67(s,1H),9.41(s,1H),8.49(s,1H),8.22(d,J＝8.2Hz,1H),8.12(d,J =5.7Hz,1H),7.96(d,J=9.3Hz,1H),7.91(s,2H),7.38–7.31(m,2H),7.16(t,J=7.7Hz,1H),6.71(s ,1H),6.39–6.29(m,1H),6.27(d,J＝5.7Hz,1H),5.77–5.72(m,1H),3.85(s,3H),3.05(d,J＝11.4Hz, 2H), 2.78–2.68(m,2H), 2.43(s,6H), 2.39-2.35(m,2H), 2.09-2.01(m,2H), ^1.79–1.65 (m,2H). 150MHz, CDCl3) δ162.8, 160.6, 159.9, 157.4, 135.1, 132.3, 131.4, 129.9, 128.2, 126.7, 126.4, 123.4, 123.3, 112.0, 103.2, 98.4, 62.2, 56.2, 52.3, 41.8 MS(HR) (m/z): [M+H]+calcd for C ₂₉ H ₃₅ N ₁₀ O ₂ , 555.2939; found 555.2928.

Example 44 N ⁴ -(2-(2H-1,2,3-triazol-2-yl)phenyl)-N ² -(2-methoxy-4-(4-methylpiperidine-1 -yl)-5-nitrophenyl)pyrimidine-2,4-diamine (11l)

Step is with embodiment 4.

¹ H NMR (400MHz, Chloroform-d) δ9.82(s, 1H), 9.13(s, 1H), 8.15(d, J=8.3Hz, 1H), 8.10(d, J=6.2Hz, 1H), 8.02–7.98(m,1H),7.93(s,1H),7.43–7.36(m,2H),7.22(t,J=7.8Hz,1H),6.60(s,1H),6.32(d,J= 5.8Hz, 1H), 3.96(s, 3H), 3.10(t, J＝4.7Hz, 5H), 2.63(t, J＝4.6Hz, 5H), 2.38(s, 3H). ¹³ C NMR (150MHz, CDCl3) δ160.5, 159.4, 157.3, 152.0, 142.2, 136.7, 135.1, 135.1, 130.9, 129.8, 128.5, 124.6, 123.6, 123.5, 122.9, 116.3, 102.1, 98.9, 56.2, 55.3HR, 246.3MS (ESI.3MS) (m/z): [M+H]+calcd for C ₂₄ H ₂₇ N ₁₀ O ₃ , 503.2262; found 503.2263.

Example 45 N ⁴ -(2-(2H-1,2,3-triazol-2-yl)phenyl)-N ² -(5-amino-2-methoxy-4-(4-methyl) piperidin-1-yl)phenyl)pyrimidine-2,4-diamine (12l)

Step is with embodiment 5.

¹ H NMR (400MHz, Chloroform-d) δ9.63(s, 1H), 8.39(dd, J＝8.4, 1.4Hz, 1H), 8.07(d, J＝5.7Hz, 1H), 8.01(dd, J =8.1,1.6Hz,1H),7.95(s,1H),7.91(s,2H),7.50(s,1H),7.46(td,J=8.4,7.8,1.6Hz,1H),7.22(ddd, J=8.5,7.3,1.3Hz,1H),6.66(s,1H),6.19(d,J=5.7Hz,1H),3.82(s,3H),3.07(t,J=4.9Hz,4H), 2.54(s,3H) ^.13C NMR(151MHz,CDCl3)δ160.5,159.7,157.1,141.3,135.1,135.08,131.4,129.9,128.2,127.0,124.0,123.4,123.2,107.1,104.3,98.9,5 , 50.4, 45.5. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₄ H ₂₉ N ₁₀ O, 473.2520; found 573.2524.

Example 46 N-(5-((4-((2-(2H-1,2,3-triazol-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy Base-2-(4-methylpiperidin-1-yl)phenyl)pyrimidine-2,4-diamine (13l)

Step is with embodiment 6.

¹ H NMR (400MHz, Chloroform-d) δ9.69(s,1H),9.43(s,1H),8.50(s,1H),8.22(d,J＝8.3Hz,1H),8.12(d,J =5.8Hz,1H),7.96(dd,J=8.1,1.5Hz,1H),7.91(s,2H),7.45(s,1H),7.34(t,J=7.8Hz,1H),7.16(t ,J=7.7Hz,1H),6.76(s,1H),6.37(d,J=1.7Hz,1H),6.32(d,J=9.9Hz,1H),6.27(d,J=5.8Hz,1H ), 5.75(d, J＝10.0Hz, 1H), 3.85(s, 3H), 2.95-2.90(m, 4H), 2.74-2.63(m, 4H) 2.46(s, 3H). ¹³ C NMR (151MHz , CDCl3) δ162.7, 160.7, 159.7, 157.1, 135.1, 132.3, 131.3, 129.9, 128.4, 126.8, 126.5, 123.4, 123.3, 112.0, 103.6, 98.5, 56.1, 55.9, 52.2, 45.9.HRMS (ESI z): [M+H]+calcd for C ₂₇ H ₃₁ N ₁₀ O ₂ , 527.2626; found 527.2626.

Example 47 N ⁴ -(2-(2H-1,2,3-triazol-2-yl)phenyl)-N ² -(2-methoxy-4-morpholine-5-nitrophenyl ) pyrimidine-2,4-diamine (11m)

Step is with embodiment 4.

¹ H NMR (400MHz, Chloroform-d) δ9.82(s, 1H), 9.16(s, 1H), 8.15(d, J=8.3Hz, 1H), 8.10(d, J=5.8Hz, 1H), 8.00(dd,J=8.2,1.5Hz,1H),7.94(s,2H),7.44–7.37(m,2H),7.22(ddd,J=8.4,7.4,1.3Hz,1H),6.60(s, 1H), 6.34(d, J=5.8Hz, 1H), 5.30(s, 0H), 3.98(s, 3H), 3.92–3.82(m, 4H), 3.13–3.01(m, 4H). ¹³ C NMR (151MHz, CDCl3) δ160.6, 159.4, 157.4, 151.9, 141.9, 137.0, 135.1, 130.9, 129.9, 128.5, 125.0, 123.7, 123.5, 122.9, 116.3, 102.1, 99.0, 67.2, 56.2, 52.9 (HRMS (ESI) m/z): [M+H]+calcd for C ₂₃ H ₂₄ N ₉ O ₄ , 490.1946; found 490.1943.

Example 48 N ⁴ -(2-(2H-1,2,3-triazol-2-yl)phenyl)-N ² -(5-amino-2-methoxy-4-(4-methyl) piperidin-1-yl)phenyl)pyrimidine-2,4-diamine (12m)

Step is with embodiment 5.

¹ H NMR (400MHz, Chloroform-d) δ9.64(s, 1H), 8.41(d, J=8.3Hz, 1H), 8.07(d, J=5.7Hz, 1H), 8.01(dd, J=8.2 ,1.4Hz,1H),7.96(s,1H),7.91(s,1H),7.52–7.42(m,2H),7.22(t,J＝8.0Hz,1H),6.64(s,1H),6.19 (d, J=5.7Hz, 1H), 3.86(t, J=4.5Hz, 4H), 3.83(s, 3H), 2.94–2.87(m, 4H). ¹³ C NMR(151MHz, CDCl3) δ160.5, 159.7 ,157.2,141.3,135.4,135.0,132.2,131.4,129.9,128.2,126.7,124.0,123.4,123.2,107.1,104.2,98.9,67.9,56.9,52.0.HRMS(ESI)(m/z):[M+ H]+calcd for C ₂₃ H ₂₆ N ₉ O ₂ , 460.2204; found 460.2206.

Example 49 N-(5-((4-((2-(2H-1,2,3-triazol-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy yl-2-morpholinephenyl)acrylamide (13m)

Step is with embodiment 6.

¹ H NMR (400MHz, Chloroform-d) δ9.69(s,1H),9.47(s,1H),8.53(s,1H),8.21(d,J＝8.4Hz,11H),8.13(d,J =5.8Hz,11H),7.97(dd,J=8.1,1.4Hz,10H),7.92(d,J=0.9Hz,19H),7.34(t,J=7.6Hz,9H),7.16(t,J ＝7.7Hz, 11H), 6.74(s, 11H), 6.43–6.29(m, 18H), 6.28(d, J＝6.0Hz, 14H), 5.76(d, J＝10.0Hz, 10H), 5.30(s ,10H),2.88(t,J=4.5Hz,47H). ¹³ C NMR(151MHz,CDCl ₃ )δ160.7,135.1,132.3,128.4,126.5,123.4,103.5,98.5,67.8,56.2,53.5,53.0,29.8 , 29.4. HRMS (ESI) (m/z): [M+H]+calcd for C ₂₆ H ₂₈ N ₉ O ₃ , 514.2310; found 514.2314.

Embodiment 50 pharmaceutical experiment

1) Kinase inhibitory activity test of pyrimidine derivatives

To detect the inhibitory activity of the compounds of the present invention on kinases, the method is Enzyme-Linked Immunosorbent Assay (Enzyme-Linked Immunosorbent Assay, ELISA) to detect the ability of phosphorylated substrates of kinases, and calculate the inhibitory effect of compounds on kinase activity. Bac-to- ^BacTM baculovirus expression system (Invitrogen, Carlsbad, CA, USA) was used to express the kinase region of wild-type EGFR and EGFRT790M/L858R mutation, and purified by nickel column (QIAGEN Inc., Valencia, CA, USA) .

The main steps of ELISA are as follows: Enzyme reaction substrate Poly( _Glu,Tyr ) 4:1 was diluted to 20μg/mL with PBS without potassium ion (10mM sodium phosphate buffer, 150mMNaCl, pH 7.2-7.4), and reacted at 37℃ for 12- Coat the ELISA plate for 16h, then wash the plate with PBS (T-PBS) containing 0.1% Tween-20, add reaction buffer (50mM HEPES pH 7.4, 50mMMgCl ₂ , 0.5mM MnCl ₂ , 0.2mM Na ₃ VO ₄ , 1 mM DTT) diluted ATP (final concentration 5 μM) solution was added with different concentrations of the test compound or solvent control, and then the corresponding kinase was added to start the reaction, and the reaction was carried out at 37° C. for 1 h on a shaking table. The plate was washed three times with T-PBS, and 100 μL/well of antibody PY99 (diluted with T-PBS containing BSA) was added to react on a shaker at 37° C. for 0.5 h. After washing the plate with T-PBS, add horseradish peroxidase-labeled goat anti-mouse IgG 100μL/well (diluted with T-PBS containing BSA), react on a shaker at 37°C for 0.5h, and wash the plate again, add 2mg /mL of OPD chromogenic solution 100 μL/well, react at 25°C in the dark for 1-10min. The reaction was terminated by adding 2M H ₂ SO ₄ , and read with a wavelength-tunable microplate microplate reader SPECTRAMAX 190 at a wavelength of 492 nm. _IC50 values were obtained from inhibition curves.

Table 1 Inhibitory activity of test compounds on kinases (IC ₅₀ , nM)

The experimental results show that the tested compounds have strong inhibitory activity on EGFR T790M/L858R, and weak inhibitory activity on wild-type EGFR, showing good selectivity. Among them, compounds 13a, 13f and 13n have strong inhibitory activity on EGFR T790M/L858R kinase The inhibitory activity is slightly stronger than that of the reference compound AZD9291, and the selectivity is better than that of AZD9291;

2) In vitro human tumor cell proliferation inhibition experiment of pyrimidine derivatives

The method used to detect the inhibitory activity of the compound of the present invention on the proliferation of human tumor cells in vitro is the sulforhodamine B (sulforodamine B, SRB) method.

Human epidermal cell carcinoma A431 cell line containing wild-type EGFR and human non-small cell lung cancer NCI-H1975 cell line containing EGFR T790M/L858R mutation (both purchased from ATCC) were selected for detection. Cells were seeded in a 96-well plate at a certain density, adhered to the wall overnight, added different concentrations of compounds for 72 hours, fixed with pre-cooled 10% trichloroacetic acid at 4°C for 1 hour, washed with distilled water and dried, and used 4 mg/mL SRB solution (dissolved in 1% acetic acid) was stained at room temperature for 15 minutes, washed off excess staining solution, and dried at room temperature. Before using a microplate reader to detect, add 10mmol/L Tris 100μL per well. After about 15 minutes, SRB was completely dissolved and used The absorption wavelength of 515nm was measured by a multifunctional microplate reader (VERSAmax, Molecular Devices), and the inhibition rate was calculated as: [1-(A515 _treated /A515 _control )]×100%.

Table 2 Inhibitory activity of test compounds on cell proliferation (IC ₅₀ , μM)

The results showed that the test compounds 13a, 13f and 13n had strong inhibitory activity on the in vitro growth of NCI-H1975 cells containing EGFR T790M/L858R mutation, which was comparable to the activity of the control compound AZD9291, and compounds 13a and 13f had strong inhibitory activity on the growth of NCI-H1975 cells containing wild-type EGFR The anti-proliferation activity of A431 cells is weak, and its selectivity is better than that of AZD9291; other compounds also have strong inhibitory activity.

The above-mentioned embodiments only express several implementation modes of the present invention, and the description thereof is relatively specific and detailed, but should not be construed as limiting the patent scope of the present invention. It should be pointed out that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.

Claims (9)

1. the pyrimidines of Formulas I structure,

Wherein, W NH, R₁For nitrogenous five-ring heterocycles, R₂For nitrogen-containing basic group.

2. pyrimidines according to claim 1, which is characterized in that the nitrogenous five-ring heterocycles are in following structures One kind:

The R₂For one of following structures:

3. pyrimidines according to claim 2, which is characterized in that the R₂For

4. pyrimidines according to claim 1, the compound is one of following compounds:

5. pyrimidines according to claim 4, the compound is one of following compounds:

6. pyrimidines according to claim 4, the compound is one of following compounds:

7. application of the pyrimidines described in claim 1 in the drug for being used to prepare treatment tumour.

8. application according to claim 7, which is characterized in that the tumour is non-small cell lung cancer, Small Cell Lung Cancer, pancreas Any one of gland cancer or nasopharyngeal carcinoma.

9. a kind of pharmaceutical composition, the composition includes the pyrimidine according to any one of claims 1 to 6 of therapeutically effective amount Class compound.