CN107098887B - Pyrimidines - Google Patents

Pyrimidines Download PDF

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Publication number
CN107098887B
CN107098887B CN201610095126.0A CN201610095126A CN107098887B CN 107098887 B CN107098887 B CN 107098887B CN 201610095126 A CN201610095126 A CN 201610095126A CN 107098887 B CN107098887 B CN 107098887B
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Prior art keywords
nmr
phenyl
amino
pyrimidines
pyrimidine
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CN107098887A (en
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李英霞
丁健
闫琪
耿美玉
谢华
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Fudan University
Shanghai Institute of Materia Medica of CAS
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Fudan University
Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The invention belongs to pharmaceutical synthesis fields, are related to pyrimidines, preparation method and application, contain their pharmaceutical compositions and its application in preparation of anti-tumor drugs as active constituent.The invention discloses a kind of pyrimidines with structure shown in Formulas I, and wherein W is NH, R1For nitrogenous five-ring heterocycles, R2For nitrogen-containing basic group；Pyrimidines of the invention, it can inhibit kinds of tumor cells, more particularly to selectively acting in EGFRL858R/T790M lung carcinoma cell, compare wild-type cell, the IC50 high 10-100 times order of magnitude difference of such compound, such compound can overcome existing EGFR inhibitor drug resistance.

Description

Pyrimidines
Technical field
The invention belongs to pharmaceutical synthesis fields, are related to pyrimidines more particularly to a kind of miazines containing false ring Object is closed, and its preparation method and application.Pyrimidines of the invention can inhibit kinds of tumor cells, more particularly to select Selecting property acts on EGFR L858R/T790M lung carcinoma cell, such compound can overcome existing EGFR inhibitor drug resistance.
Background technique
It shows according to statistics, in the global death as caused by cancer, about one third dies of lung cancer, and 80% belongs among these In non-small cell lung cancer.Surgical intervention is current lung cancer first choice and most important treatment method, but about 70% patient It will appear secondary disease and transfer.The development of small molecule tyrosine kinase inhibitors (TKIs) makes remarkable progress, more Kind small-molecule drug listing.
EGFR is one of ErbB tyrosine kinase receptor family member, and the signal path is to the growth of cell, increment and divides The physiology courses such as change play an important role.Studies have shown that the expression of EGFR height or unconventionality expression in many tumours.
EGFR is distributed widely in the epithelial cell of mammal, the ligand binding domain that is by cell, hydrophobic transmembrane domain It is formed with intracellular kinases area three parts.When tyrosine protein kinase over-expresses, meeting block cell programmed cell death makes cell Adjusting and controlling growth it is out of control, always be in proliferative state, develop into malignant tumour.Clinical research shows the essence of many types Property tumour such as neurogliocytoma, breast cancer, lung cancer, oophoroma, G. cephalantha, cervical carcinoma, gastric cancer etc. has high-level table It reaches.
It is one of most commonly used micromolecular inhibitor of research prior art discloses tyrosine kinase inhibitor, passes through The extracellular ligand binding site of competitive binding, the autophosphorylation of tyrosine in blocker molecule, inhibits tyrosine kinase activation, from And the cell cycle is blocked, accelerate Apoptosis.
EGFR T790M mutation is EGFR inhibitor resistance mechanism the most main, and current EGFR inhibitor still cannot be complete Complete solution determine clinic caused by Drug-resistant limitation, and existing drug mostly with quinazoline be basic parent nucleus EGFR it is reversible or Irreversible inhibitor, it is inevitable to toxic side effect caused by Wild type EGFR (EGFR WT) poor selectivity.Therefore urgent Selective novel framework compound is needed to solve drug resistance problems caused by EGFR T790M.
Summary of the invention
The invention mainly solves the technical problem of providing new pyrimidines more particularly to a kind of containing false ring Pyrimidines, and its preparation method and application.The compound can inhibit growth of tumour cell.
In order to solve the above technical problems, one technical scheme adopted by the invention is that: a kind of pyrimidine containing false ring is provided Class compound, which is characterized in that the structure that the compound has is Formulas I:
Wherein W is NH, R1For nitrogenous five-ring heterocycles, R2For nitrogen-containing basic group.
The structure of the nitrogenous five-ring heterocycles in a preferred embodiment of the present invention are as follows:
In a preferred embodiment of the present invention, the R2Are as follows:
In a preferred embodiment of the present invention, the pyrimidines are used to prepare the drug and its medicine for the treatment of tumour In compositions.
In a preferred embodiment of the present invention, the tumour is non-small cell lung cancer, Small Cell Lung Cancer, cancer of pancreas, nose Any one of pharynx cancer.
The beneficial effects of the present invention are:
Pyrimidines containing false ring of the invention, can inhibit kinds of tumor cells, more particularly to selective work For EGFR L858R/T790M lung carcinoma cell, wild-type cell, the IC50 high 10-100 times order of magnitude of such compound are compared Difference, such compound are a new class of existing EGFR inhibitor drug resistance and selective tyrosine kinases can be overcome to press down Preparation.
Specific embodiment
Technical solution in the embodiment of the present invention is described below, described embodiment is only one of the invention Point embodiment, rather than whole embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art are not making wound Every other embodiment obtained under the premise of the property made labour, shall fall within the protection scope of the present invention.
Following is the definition of term used in the present invention.Unless otherwise noted, group or term provided herein is initial fixed Justice is individually or as a part of using in this manual of other groups.
" substituted heterocycle " and " substituted heterocycle " refers to that one or more positions in heterocycle or heterocyclic group are substituted, especially It is 1-4 substituent group, upper in any position can be replaced.It is typical to replace including but not limited to one or more is following to replace Base: such as hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, naphthenic base.
Logical formula (I) compound represented specifically preferred according to the invention includes
In one embodiment, the present invention provides the preparation methods of aforementioned present invention compound.
Above compound of the present invention can use method described in following processes and/or those of ordinary skill in the art Other technologies for knowing synthesize, but are not limited only to following methods.
For convenience, the present invention represents multiple compounds, including but not limited to DMF:N using well-known abbreviation, Dinethylformamide；THF: tetrahydrofuran；DIPEA:N, N- diisopropylethylamine reaction route:
Reaction step:
Embodiment 1
The preparation of step 1 intermediate 2a
2- nitro-acetophenone (100mg, 0.6mmol) is dissolved in DMF-DMA, heating (100 DEG C) is stirred to react overnight.It is cold But, solvent evaporated obtains intermediate 1.It is directly used in the next step without further purification.220.9[M+H]+
The preparation of step 2 intermediate 3a
Intermediate 1 (114mg, 0.6mmol) is mixed with quantity of solvent ethyl alcohol, about two equivalent hydrazine hydrates are added, are stirred to react A few hours to intermediate 1 disappears.Cooling, solvent evaporated obtains 90mg intermediate 2, yield 90%, 190 [M+H]+。
The preparation of step 3 intermediate 4a
Intermediate 2 (90mg, 0.5mmol) is dissolved in THF, NaH (40mg, 1mmol) is added under condition of ice bath, stirring one is small When after be added iodomethane (31Ul, 0.5MMOL).Reaction a few hours to intermediate 2 is stirred at room temperature to disappear, reaction system, column is concentrated Chromatography, obtains 168mg intermediate 3, yield 62%, 204 [M+H]+。
The preparation of step 4 intermediate 5a
Intermediate 4 (168mg, 0.8mmol) is dissolved in methanol, Pd/C is added, pressurized with hydrogen, room temperature reaction is overnight.Filtering, Concentration, obtains 44mg intermediate 4, is directly used in the next step, 173.9 [M+H]+。
Embodiment 2
The preparation of intermediate 9a
Intermediate 5a (60mg, 0.3mmol) is dissolved in 2- butanol, is added 2,6- dichloro pyrimidine (44mg, 0.3mmol), DIPEA (110uL, 0.6MMOL), heating stirring is overnight, cooling, solvent evaporated, through column chromatographic purifying (mobile phase 90: 10Hexane/EtOAc) obtain 66mg intermediate 9a, yield 73%, 286 [M+H]+。
Embodiment 3
By intermediate 9a (57mg, 0.2mmol) and the fluoro- 2- methoxyl group -5- nitroaniline of intermediate 4- (50mg, It 0.2mmol) mixes, 2- amylalcohol is added, it is overnight to be added at one time p-methyl benzenesulfonic acid (19mg, 0.07mmol) heating stirring, and it is cooling, Solid is precipitated, filtering obtains 26mg intermediate 10a, do not purify and be directly used in the next step, 436 [M+H]+。
4 N of embodiment2(4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N4- (2- (1- methyl-1 H- pyrazoles -3-yl) phenyl) pyrimidine -2,4- diamines (11a)
Intermediate 10a (56mg, 0.13mmol) is dissolved in DMF, is added DIPEA (6uL, 0.036mmol), N, N, N- trimethyl Ethylenediamine (13mg, 0.13mmol), heating stirring two hours, solvent evaporated chromatographed (mobile phase 1:15 methanol/dichloromethane through column Alkane) purify to obtain 28mg intermediate 11a.
1H NMR (400MHz, Chloroform-d) δ 10.56 (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)13C 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.HRMS(ESI)(m/z):[M+H]+calcd for C26H32N9O3518.2550；found 518.2548.Mp.110-112℃.
5 N of embodiment1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4(4- ((2- (1- methyl-1 H- pyrrole Azoles -3-yl) phenyl) amino) pyrimidine -2-yl) phenyl -1,2,4- triazole (12a)
Intermediate 11a (28mg, 0.05mmol) is dissolved in methanol, and Pd/C is added, and catalytic hydrogenation obtains intermediate 12a.Filtering is steamed Dry solvent, is directly used in the next step without further purification.
1H NMR (400MHz, Chloroform-d) δ 10.50 (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)13C NMR(150MHz,CDCl3)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, 104.1,98.8,62.8,56.9,51.2,41.0,28.6.HRMS(ESI)(m/z):[M+H]+calcd for C26H34N9O 488.2886；found 488.2870..
6 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- ((2- (1- first Base -1H- pyrazoles -3-yl) phenyl) amino) pyrimidine -2-yl) amino) phenyl) acrylamide (13a)
Intermediate 12a (17mg, 0.035mmol) is dissolved in methylene chloride, and ice bath is added DIPEA (7L, 0.038mmol), third Alkene acyl chlorides (3L, 0.035mmol) reacts solvent evaporated after half an hour, pure through column chromatography (mobile phase 1:15 ethanol/methylene) Change to obtain target product 17mg, yield 53%.
1H 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).13C NMR(150MHz,CDCl3)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；found 542.2990.。
7 N of embodiment2(4- (2- (dimethylamino) ethyoxyl) -2- methoxyl group -5- nitrobenzophenone)-N4(2- (1- methyl- 1H- pyrazoles -3-yl) phenyl) pyrimidine -2,4- diamines (11b)
Step is the same as embodiment 4.
1H NMR (400MHz, Chloroform-d) δ 10.53 (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, 124.4,122.2,121.9,121.4,108.3,104.4,100.3,99.1,68.0,58.6,57.0,45.8,39.3.HRMS (ESI)(m/z):[M+H]+calcd for C25H36N8O4505.2312；found 505.2315..
8 N of embodiment2(5- amino -4- (2- (dimethylamino) ethyoxyl) -2- methoxyphenyl)-N4(2- (1- methyl- 1H- pyrazoles -3- phenyl) pyrimidine -2,4- diamines (12b)
Step is the same as embodiment 5
1H NMR (400MHz, Chloroform-d) δ 10.57 (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=5.8Hz, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 2.82 (t, J=5.8Hz, 2H), 2.38 (s, 6H) .13C NMR (150MHz, CDCl3) δ 161.0,159.5,156.6,152.7, 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.HRMS(ESI)(m/z):[M+H]+calcd for C25H31N8O2475.2570；found 475.2569..
9 N- of embodiment (2- (2- (2- (dimethylamino) ethyoxyl) -4- methoxyl group -5- ((4- ((2- (1- methyl-1 H- pyrrole Azoles -3- phenyl) amino) pyrimidine -2-base) amino) phenyl) acrylamide (13b)
Step is the same as 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, 125.0,124.40,122.1,121.3,113.9,104.4,101.8,99.4,70.3,58.1,56.2,45.3,39.2, 29.8.HRMS(ESI)(m/z):[M+H]+calcd for C28H31N8O3529.2676；found 529.2680.
10 N of embodiment2(4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyl group -5- nitrobenzophenone)-N4-(2-(1- Methyl-1 H- pyrazole-3-yl) phenyl) pyrimidine -2,4- diamines (11c)
Step is the same as embodiment 4.
1H NMR (400MHz, Chloroform-d) δ 10.62 (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, 131.0,128.8,128.1,128.0,125.8,124.8,122.5,121.4,121.0,115.9,104.2,102.4,62.4, 56.1,51.7,46.1,40.5,39.1,27.3,21.3.HRMS(ESI)(m/z):[M+H]+calcd for C28H34N9O3544.2779；found 544.2786.
11 N of embodiment2(5- amino -4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyl)-N4-(2-(1- Methyl-1 H- pyrazole-3-yl) phenyl) pyrimidine -2,4- diamines (12c)
Step is the same as embodiment 5.
1H NMR (400MHz, Chloroform-d) δ 10.53 (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) δ 163.0,151.3,143.5,141.7,133.0, 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 C28H36N9O,514.3037；found 514.3040。
12 N- of embodiment (2- (4- (dimethylamino) piperidin-1-yl) -4- methoxyl group -5- ((4- ((2- (1- methyl-1 H- Pyrazole-3-yl) phenyl) amino) pyrimidine -2-base) amino) phenyl) acrylamide (13c)
Step is the same as 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 C31H38N9O2,568.3134, found 568.3137.。
13 N of embodiment2(2- methoxyl group -4- (4- methyl piperidine -1- base) -5-5- nitrobenzophenone)-N4(2- (1- methyl- 1H- pyrazole-3-yl) phenyl) pyrimidine -2,4- diamines (11d)
Step is the same as embodiment 4.
1H NMR (400MHz, Chloroform-d) δ 10.59 (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) .13C 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 C26H30N9O3, 516.2472,found 5516.2468.。
14 N of embodiment2(5- amino -2- methoxyl group -4- (4- methyl piperidine -1- base) -5-5- nitrobenzophenone)-N4-(2- (1- methyl-1 H- pyrazole-3-yl) phenyl) pyrimidine -2,4- diamines (12d)
Step is the same as embodiment 5.
1H NMR (400MHz, Chloroform-d) δ 10.55 (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)13C NMR (150MHz,CDCl3)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 C26H31N9ONa,508.2544,found 508.2541.。
15 N- of embodiment (4- methoxyl group -5- ((4- ((2- (1- methyl-1 H- pyrazole-3-yl) phenyl) amino) pyrimidine -2- Base) amino) phenyl) -2- (4- methyl piperidine -1- base) phenyl) acrylamide (13d)
Step is the same as 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).13C NMR(150MHz,CDCl3)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, 107.3,104.3,99.4,56.9,56.0,51.3,46.2,36.5.HRMS(ESI)(m/z):[M+H]+calcd for C29H34N9O2,540.2830；found540.2835..
16 N of embodiment2(2- methoxyl group -4- morpholine -5- nitrobenzophenone)-N4(2- (1- methyl-1 H- pyrazole-3-yl) benzene Base) pyrimidine -2,4- diamines (11e)
Step is the same as 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, 121.3,116.1,104.4,102.1,99.7,67.3,67.2,66.5,56.2,52.9,45.4,40.6,39.0.HRMS (ESI)(m/z):[M+H]+calcd for C25H27N8O4,503.2150,found 503.2155.。
17 N of embodiment2(5- amino -2- methoxyl group -4- morpholinyl phenyl)-N4(2- (1- methyl-1 H- pyrazole-3-yl) benzene Base) pyrimidine -2,4- diamines (12e)
Step is the same as embodiment 5.
1H NMR (400MHz, Chloroform-d) δ 10.53 (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).13C 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 C25H29N8O2,573.2408；found 473.2411..
18 N- of embodiment (4- methoxyl group -5- ((4- ((2- (1- methyl-1 H- pyrazole-3-yl) phenyl) amino) pyrimidine -2- Base) amino) -2- morpholinyl phenyl) acrylamide (13e)
Step is the same as embodiment 6.
1H 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)13C 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, 121.6,112.2,104.4,103.8,99.6,67.8,67.3,66.5,56.2,52.9,45.5,40.7,39.2.HRMS (ESI)(m/z):[M+H]+calcd for C28H31N8O3,527.2514,found 527.2516.。
19 N of embodiment2(4- ((2- (methylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone)-N4- (2- (1- methyl-1 H-1,2,4- triazole -3-yl) phenyl) pyrimidine -2,4- diamines (11n)
Step is the same as embodiment 4.
1H 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)13C NMR(150MHz,CDCl3)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, 116.5,102.2,99.0,57.1,56.2,54.2,45.9,41.5,36.5.HRMS(ESI)(m/z):[M+H]+calcd for C25H31N10O3519.2581；found 519.2584..
20 N of embodiment1(2- (dimethylamino) ethyl) -5- methoxyl group-N1Methyl-N4(4- ((2- (1- methyl-1 H- 1,2,4- triazole -3- base) phenyl) amino) pyrimidine -2-base) amino) phenyl -1,2,4- triamine (12n)
Step is the same as embodiment 5.
1H NMR (400MHz, Chloroform-d) δ 10.74 (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)13C NMR(150MHz,CDCl3)δ 161.9,160.8,158.6,143.4,141.6,137.8,137.3,130.4,129.8,129.7,128.6,127.4, 122.8,121.6,118.7,107.7,105.4,99.5,57.0,55.6,51.1,50.8,43.6,43.4,36.6.HRMS (ESI)(m/z):[M+H]+calcd for C25H33N10O 489.2839；found 489.2840..
21 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- ((2- (1- first Base -1H-1,2,4- triazole -3- base) phenyl) amino) pyrimidine -2-base) amino) phenyl) acrylamide (13n)
Step is the same as embodiment 6.
1H 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)13C NMR(15MHz,CDCl3)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, 121.1,118.3,104.6,99.5,56.1,45.4,43.8,36.5.HRMS(ESI)(m/z):[M+H]+calcd for C28H35N10O2543.2944；found 543.2950..
Embodiment 22
O-nitrochlorobenzene (3g, 19mmol) is dissolved in DMF, is added pyrazoles (1.5g, 22.8mmol), potassium carbonate (3.1g, 22.8mmol), CuI (36mg, 0.19mmol), 110 DEG C of reactions overnight, are filtered, and concentration obtains 1.9g yellow solid.
Embodiment 23
Operation is the same as embodiment 2..273[M+H]+。
Embodiment 24
Operation is the same as embodiment 3.422[M+H]+。
25 N of embodiment4(2- (1H- pyrazol-1-yl) phenyl)-N2(4- ((2- (dimethylamino) ethyl) (methyl) ammonia Base) -2- methylamino -5- nitrobenzophenone) pyrimidine -2,4- diamines (11f)
Operation is the same as embodiment 4.
1H NMR (400MHz, Chloroform-d) δ 9.55 (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).13C 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.。
26 N of embodiment4(4- ((2- (1H- pyrazol-1-yl) phenyl) amino) pyrimidine -2-base)-N1(2- (dimethylamino) Ethyl) -5- methoxyl group-N1Aminomethyl phenyl -1,2,4- triazole (12f)
With embodiment 5
1H NMR (400MHz, Chloroform-d) δ 9.35 (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).13C 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.。
27 N- of embodiment (5- ((4- ((2- (1H- pyrazol-1-yl) phenyl) amino) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) acrylamide (13f)
Operation is the same as embodiment 6.
1H 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=9.2,2.6Hz, 1H), 3.84 (s, 3H), 2.88 (t, J=5.6Hz, 2H),2.69(s,3H),2.29(s,9H).13C 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, 123.2,112.3,107.1,104.6,98.6,57.4,56.4,56.1,45.5,43.7.HRMS(ESI)(m/z):[M+H]+ calcd for C28H34N9O2,528.2830；found 528.2828..
28 N of embodiment4(2- (1H- pyrazol-1-yl)-N2(4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyl group - 5- nitrobenzophenone) pyrimidine -2,4- diamines (11g)
Operation is the same as embodiment 4.
1H NMR (400MHz, Chloroform-d) δ 9.56 (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).13C 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.HRMS(ESI)(m/z):[M+H]+calcd for C27H32N9O3, 530.2623；found 530.2628..
29 N- of embodiment (5- ((4- ((2- (1H- pyrazol-1-yl) phenyl) amino) pyrimidine -2-base) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4- methoxyphenyl) acrylamide (12g)
Operation is the same as embodiment 5.
1H 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=12.6,3.0Hz, 2H), 2.44-2.36 (m, 2H),2.37(s,3H),2.34-2.31(m,2H),2.29(s,6H),1.68-1.62(m,3H).13C NMR(150MHz, CDCl3)δ160.5,160.2,159.5,156.8,140.9,140.9,135.0,132.8,130.4,130.1,127.5, 126.1,124.1,123.4,123.1,107.0,106.8,103.9,98.5,62.1,62.0,56.7,51.4,44.9,41.7, 41.5,38.6,29.3,29.0,27.4.HRMS(ESI)(m/z):[M+H]+calcd for C27H34N9O,500.2881； found 500.2877.。
30 N- of embodiment (5- ((4- ((2- (1H- pyrazol-1-yl) phenyl) amino) pyrimidine -2-base) amino) -2- (4- (dimethylamino) piperidin-1-yl) -4- methoxyphenyl) acrylamide (13g)
Step is the same as embodiment 6.
1H 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)13C NMR(150MHz,CDCl3)δ160.6,159.8,157.2,141.2,132.9,132.3,130.5,130.3,127.9, 126.6,126.5,123.6,123.3,112.2,107.1,103.25,98.7,62.3,56.1,52.3,41.8,29.8, 29.6.HRMS(ESI)(m/z):[M+H]+calcd for C30H36N9O2,554.2986；found 554.2981.
31 N of embodiment4(2- (1H- pyrazol-1-yl) phenyl)-N2(2-methoxy-4- (4- methylpiperazine-1-yl)- 5- nitrobenzophenone) pyrimidine -2,4- diamines (11h)
With embodiment 4.
1H 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)13C 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 C25H28N9O3,502.2310；
found 502.2306.。
32 N of embodiment4(2- (1H- pyrazol-1-yl) phenyl)-N2(5- amino -2- methoxyl group -4- (4- methyl piperazine - 1- yl) phenyl) pyrimidine -2,4- diamines (12h)
With embodiment 5.
1H NMR (400MHz, Chloroform-d) δ 9.35 (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).13C NMR(150MHz,MeOD)δ160.8,160.4,159.6,157.0,141.2,135.2,133.0, 132.3,130.4,130.3,127.7,126.6,124.2,123.5,123.2,107.1,107.0,104.2,98.8,56.8, 56.0,55.5,54.3,51.5,46.3,46.2,45.6,39.99.HRMS(ESI)(m/z):[M+H]+calcd for C25H30N9O,472.2568；found 472.2565..
33 N- of embodiment (5- ((4- ((2- (1H- pyrazol-1-yl) phenyl) amino) pyrimidine -2-base) amino) -4- methoxy Base -2- (4- methylpiperazine-1-yl) phenyl) acrylamide (13h)
With embodiment 6.
1H 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).13C 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, 126.7,126.4,123.6,123.3,111.9,107.1,107.1,103.5,98.7,56.1,56.1,52.5,46.2.HRMS (ESI)(m/z):[M+H]+calcd for C28H32N9O2,526.2673；found 526.2669..
34 N of embodiment4(2- (1H- pyrazol-1-yl) phenyl)-N2(2- methoxyl group -4- morpholine -5- nitrobenzophenone) is phonetic Pyridine -2,4- diamines (11i)
Step is the same as embodiment 4.
1H NMR (400MHz, Chloroform-d) δ 9.58 (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)13C 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, 125.1,123.6,123.5,123.3,116.1,107.1,102.1,99.4,67.1,56.2,52.9.HRMS(ESI)(m/z): [M+H]+calcd for C24H25N8O4,489.1993；found489.1987..
35 N of embodiment4(2- (1H- pyrazol-1-yl) phenyl)-N2(5- amino -2- methoxyl group -4- morpholinyl phenyl) is phonetic Pyridine -2,4- diamines (12i)
Step is the same as embodiment 5.
1H NMR (400MHz, Chloroform-d) δ 9.38 (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)13C 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.。
36 N- of embodiment (5- (- 2 base of (4- ((pyrazol-1-yl) phenyl) amino) pyrimidine) amino) -4- methoxyl group -2- Quinoline phenyl) acrylamide (13i)
Step is the same as embodiment 6.
1H 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) .13C 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.。
Embodiment 37
Operation is the same as embodiment 3.422.9[M+H]+。
38 N of embodiment4(2- (2H-1,2,3- triazole -2- base) phenyl)-N2(4- ((2- (dimethylamino) ethyl) (first Base) amino) -2- methoxyl group -5- nitrobenzophenone) pyrimidine -2,4- diamines (11j)
Step is the same as embodiment 4.
1H NMR (400MHz, Chloroform-d) δ 9.82 (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)13C 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, 116.5,102.1,98.7,57.0,56.1,54.0,45.8,41.4.HRMS(ESI)(m/z):[M+H]+calcd for C24H29N10O3,505.2419；found 505.2418..
39 N of embodiment4(4- ((2- (2H-1,2,3- triazole -2- base) phenyl) amino) pyrimidine -2-base)-N1(2- (two Methylamino) ethyl) -5- methoxyl group-N1Aminomethyl phenyl -1,2,4- triamine (12j)
Step is the same as embodiment 5.
1H NMR (400MHz, Chloroform-d) δ 9.63 (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)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, 107.1,104.1,98.8,62.8,56.9,51.2,41.0,28.6.HRMS(ESI)(m/z):[M+H]+calcd for C24H31N10O,475.2677；found 475.2674..
40 N- of embodiment (5- ((4- ((2- (2H-1,2,3- triazole -2- base) phenyl) amino) pyrimidine -2-base) amino) - 2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) acrylamide (13j)
Step is the same as embodiment 6.
1H 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, 129.4,128.4,126.8,125.9,123.3,123.3,123.1,112.3,104.6,98.4,57.5,56.1,45.5, 43.7.HRMS(ESI)(m/z):[M+H]+calcd for C27H33N10O2,529.2782；found 529.2780.
41 N of embodiment4(2- (2H-1,2,3- triazole -2- base) phenyl)-N2(4- (4- (dimethylamino) piperidines -1- Base) -5 nitrobenzophenone of -2- methoxyl group) pyrimidine -2,4- diamines (11k)
Step is the same as embodiment 4.
1H NMR (400MHz, Chloroform-d) δ 9.82 (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) .13C 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.HRMS(ESI)(m/z):[M+H]+calcd for C26H31N10O3,531.2575； found 531.2570.。
42 N of embodiment4(2- (2H-1,2,3- triazole -2- base) phenyl)-N2(5- amino -4- (4- (dimethylamino) piperazine Pyridine -1- base) -2- methoxyphenyl) pyrimidine -2,4- diamines (12k)
Step is the same as embodiment 5.
1H NMR (400MHz, Chloroform-d) δ 9.62 (s, 1H), 8.38 (d, J=8.0Hz, 1H), 8.05 (d, J= 5.7Hz, 1H), 8.00 (d, J=7.1Hz, 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, 123.4,123.2,107.1,104.1,98.8,62.8,56.9,51.2,41.0,28.6.HRMS(ESI)(m/z):[M+H]+ calcd for C26H33N10O,501.2833；found501.2835..
43 N- of embodiment (5- ((4- ((2- (2H-1,2,3- triazole -2- base) phenyl) amino) pyrimidine -2-base) amino) - 2- (4- (dimethylamino) piperidin-1-yl) -4- methoxyphenyl) acrylamide (13k)
Step is the same as embodiment 6.
1H 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).13C NMR(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, 103.2,98.4,62.2,56.2,52.3,41.8,29.8.HRMS(ESI)(m/z):[M+H]+calcd for C29H35N10O2, 555.2939；found 555.2928..
44 N of embodiment4(2- (2H-1,2,3- triazole -2- base) phenyl)-N2(2- methoxyl group -4- (4- methyl piperidine -1- Base) -5- nitrobenzophenone) pyrimidine -2,4- diamines (11l)
Step is the same as embodiment 4.
1H NMR (400MHz, Chloroform-d) δ 9.82 (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)13C 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, 102.1,98.9,56.2,55.2,52.3,46.1.HRMS(ESI)(m/z):[M+H]+calcd for C24H27N10O3, 503.2262；found 503.2263..
45 N of embodiment4(2- (2H-1,2,3- triazole -2- base) phenyl)-N2(5- amino -2- methoxyl group -4- (4- methyl Piperidin-1-yl) phenyl) pyrimidine -2,4- diamines (12l)
Step is the same as embodiment 5.
1H NMR (400MHz, Chloroform-d) δ 9.63 (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)δ 160.5,159.7,157.1,141.3,135.1,135.08,131.4,129.9,128.2,127.0,124.0,123.4, 123.2,107.1,104.3,98.9,56.9,55.6,50.4,45.5.HRMS(ESI)(m/z):[M+H]+calcd for C24H29N10O,473.2520；found 573.2524..
46 N- of embodiment (5- ((4- ((2- (2H-1,2,3- triazole -2- base) phenyl) amino) pyrimidine -2-base) amino) - 4- methoxyl group -2- (4- methyl piperidine -1- base) phenyl) pyrimidine -2,4- diamines (13l)
Step is the same as embodiment 6.
1H 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).13C 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)(m/z):[M+H]+calcd for C27H31N10O2,527.2626；found 527.2626.。
47 N of embodiment4(2- (2H-1,2,3- triazole -2- base) phenyl)-N2(2- methoxyl group -4- morpholine -5- nitrobenzene Base) pyrimidine -2,4- diamines (11m)
Step is the same as embodiment 4.
1H NMR (400MHz, Chloroform-d) δ 9.82 (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).13C 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 C23H24N9O4, 490.1946；found 490.1943.
48 N of embodiment4(2- (2H-1,2,3- triazole -2- base) phenyl)-N2(5- amino -2- methoxyl group -4- (4- methyl Piperidin-1-yl) phenyl) pyrimidine -2,4- diamines (12m)
Step is the same as embodiment 5.
1H NMR (400MHz, Chloroform-d) δ 9.64 (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).13C 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 C23H26N9O2,460.2204；found 460.2206..
49 N- of embodiment (5- ((4- ((2- (2H-1,2,3- triazole -2- base) phenyl) amino) pyrimidine -2-base) amino) - 4- methoxyl group -2- morpholinyl phenyl) acrylamide (13m)
Step is the same as embodiment 6.
1H 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) .13C NMR(151MHz,CDCl3)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 C26H28N9O3,514.2310； found 514.2314.。
50 pharmaceutical test of embodiment
1) the kinase inhibiting activity test of pyrimidine derivatives
The compounds of this invention is detected to the inhibitory activity of kinases, uses method for enzyme linked immunosorbent assay (Enzyme- Linked ImmunosorbentAssay, ELISA) detection tyrosine phosphorylation substrate ability, calculate compound to kinase activity Inhibiting effect.Using Bac-to-BacTMBaculovirus expression system (Invitrogen, Carlsbad, CA, USA) carries out wild The kinases area expression of raw type EGFR and EGFRT790M/L858R mutation, through nickel column (QIAGEN Inc., Valencia, CA, USA) Purifying.
ELISA key step is as follows: enzyme reaction substrate Poly (Glu,Tyr) the no potassium ion of 4:1 PBS (10mM sodium phosphate Buffer, 150mMNaCl, pH 7.2-7.4) 20 μ g/mL are diluted to, in 37 DEG C of reaction 12-16h coated elisa plates, then with containing PBS (T-PBS) board-washing of 0.1%Tween-20, every hole, which is added, uses reaction buffer (50mM HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mM Na3VO4, 1mM DTT) and diluted ATP (5 μM of final concentration) solution, various concentration is added Untested compound or solvent control, are then respectively adding respective kinase starting reaction, and 37 DEG C of shaking tables react 1h.T-PBS board-washing three It is secondary, the hole antibody PY99100 μ L/ (being diluted with the T-PBS containing BSA) is added in 37 DEG C of shaking tables and reacts 0.5h.After T-PBS board-washing, add Enter 100 hole μ L/ IgG (being diluted with the T-PBS containing BSA) of the sheep anti mouse of horseradish peroxidase-labeled, 37 DEG C of shaking table reactions Again after board-washing, 100 hole μ L/ of OPD developing solution of 2mg/mL is added, 25 DEG C are protected from light 1-10min in 0.5h.2M H is added2SO4 Terminate reaction, with wavelengthtunable decline orifice plate microplate reader SPECTRAMAX 190 read, wavelength 492nm.IC50Value is by inhibiting bent Line obtains.
Inhibitory activity (IC of 1 test-compound of table to kinases50,nM)
The experimental results showed that test-compound has stronger inhibitory activity to EGFR T790M/L858R, to wild type EGFR inhibitory activity is weaker, shows preferable selectivity, wherein compound 13a, and 13f and 13n are to EGFR T790M/L858R Kinase inhibiting activity be slightly stronger than control compound AZD9291, and selectivity is better than AZD9291；
2) the external human tumor cells increment Inhibition test of pyrimidine derivatives
The compounds of this invention is detected to external human tumor cells proliferation inhibition activity, the method used is Sulforhodamine B (sulforodamine B, SRB) method.
Select the cancer A431 cell strain of human epidermal cell containing Wild type EGFR and the mutant human of T790M/L858R containing EGFR non-small Cell lung cancer NCI-H1975 cell strain (being purchased from ATCC) is detected.Cell is inoculated in 96 orifice plates, adherent mistake with certain density Various concentration compound effects 72h is added in night, and with 10% trichloroacetic acid of pre-cooling in 4 DEG C of fixed 1h, distilled water washes away fixer After dry, dyed 15 minutes using SRB solution (the being dissolved in 1% acetic acid) room temperature of 4mg/mL, wash away excess stain liquid, room temperature is dried It is dry, the 100 every hole μ L 10mmol/L Tris is added before detecting using microplate reader, after about 15 minutes, SRB is completely dissolved, and is used Multi-function microplate reader (VERSAmax, Molecular Devices) measures the absorbing wavelength of 515nm, and inhibiting rate calculates Gongwei: [1–(A515treated/A515control)] × 100%.
Increment inhibitory activity (IC of 2 test-compound of table to cell50,μM)
The result shows that the NCI-H1975 that test-compound 13a, 13f and 13n are mutated T790M/L858R containing EGFR is thin The growth in vitro of born of the same parents has very strong inhibitory activity, suitable with control compound AZD9291 activity, and compound 13a and 13f pairs The proliferation inhibition activity of A431 cell containing Wild type EGFR is weak, and selectivity is better than AZD9291；Other compounds also have it There is stronger inhibitory activity.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention Protect range.Therefore, the scope of protection of the patent of the invention shall be subject to 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.
CN201610095126.0A 2016-02-22 2016-02-22 Pyrimidines Expired - Fee Related CN107098887B (en)

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WO2021104305A1 (en) * 2019-11-26 2021-06-03 上海翰森生物医药科技有限公司 Nitrogen-containing polycyclic derivative inhibitor, preparation method therefor and application thereof
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