CN113683596B - Pyrimidine tankyrase 2 inhibitor and preparation method and application thereof - Google Patents

Pyrimidine tankyrase 2 inhibitor and preparation method and application thereof Download PDF

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CN113683596B
CN113683596B CN202110943449.1A CN202110943449A CN113683596B CN 113683596 B CN113683596 B CN 113683596B CN 202110943449 A CN202110943449 A CN 202110943449A CN 113683596 B CN113683596 B CN 113683596B
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pyrimidine
tankyrase
morpholine
inhibitor
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CN113683596A (en
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庞婉
李堂
刘运力
王杰
赵泽圣
张孝礼
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Shanghai Institute of Technology
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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a pyrimidine tankyrase 2 inhibitor, a preparation method and an application thereof, wherein the inhibitor has the following structure:
Figure DDA0003216005230000011
compared with the prior art, the preparation method is simple, and the synthesized compound has a novel structure and better activity of inhibiting tankyrase 2.

Description

Pyrimidine tankyrase 2 inhibitor and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a pyrimidine tankyrase 2 inhibitor as well as a preparation method and application thereof.
Background
Tankyrase is a multifunctional protein translation modifying enzyme, a member of the polyadenylic diphosphoribose polymerase family, and its main domain is ankyrin repeat. The enzyme can be combined with a telomere repetitive sequence factor, and can also be combined with a highly conserved structural domain of a carboxyl terminal of an axial inhibitory protein, so that the inhibition effect on the telomere enzyme is realized, and an extracellular factor (Wnt)/beta-catenin (beta-catenin) signal path is adjusted, so that the proliferation and the growth of tumor cells are inhibited. A tankyrase inhibitor XAV939 reported in Nature in 2009 is directly synthesized based on the crystal structure of tankyrase 1/2, and can selectively block the activation of a Wnt/beta-catenin signaling pathway through the expression of a stable axis inhibiting protein, so as to limit the proliferation and growth of tumor cells. The tankyrase 2 inhibitors known at present can be classified into inhibitors acting on the active site of nicotinamide, inhibitors acting on the adenosine binding site, and inhibitors acting on the binding sites of nicotinamide and adenosine, depending on the active site. However, the semi-Inhibitory Concentration (IC) of the tankyrase 2 inhibitor GK-007 has been reported 50 ) The larger, i.e. the lower sensitivity,there is therefore a need to develop novel inhibitors of tankyrase 2.
Disclosure of Invention
The invention aims to provide a pyrimidine tankyrase 2 inhibitor with better activity, a preparation method and application thereof.
With the continuous development of computer technology, virtual screening technology has played an increasingly important role in the field of new drug discovery. In the invention, 350000 small molecule compounds in a ZINC database are screened layer by comprehensively utilizing molecular docking and molecular dynamics simulation technologies to finally obtain a compound with the terminal anchor polymerase 2 inhibition activity theoretically, then the compound is subjected to group modification to design two more ideal compound structures and a synthetic route, and finally the terminal anchor polymerase 2 inhibition activity is tested and compared with the reported inhibition activity (IC) of a terminal anchor polymerase 2 inhibitor GK-007 50 =0.035 uM).
The purpose of the invention is realized by the following technical scheme:
the invention provides a pyrimidine tankyrase 2 inhibitor, which has a structure shown in a formula I:
Figure BDA0003216005210000021
wherein R is selected from
Figure BDA0003216005210000022
Figure BDA0003216005210000023
Any one of them.
Preferably, R is selected from:
Figure BDA0003216005210000024
the second aspect of the present invention provides a preparation method of the pyrimidine tankyrase 2 inhibitor, comprising the following steps:
(1): 2,4,6-trichloropyrimidine reacts with morpholine in an organic solvent under the condition of adding alkali to prepare 4- (2,6-dichloropyrimidin-4-yl) morpholine;
(2): reacting 4- (2,6-dichloropyrimidin-4-yl) morpholine with 2-hydroxyethyl pyridine in an organic solvent under the condition of adding alkali to obtain 4- (6-chloro-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine;
(3): reacting 4- (6-chloro-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine with hydrazine hydrate in an organic solvent to obtain an intermediate 4- (6-hydrazino-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine;
(4): 4- (6-hydrazino-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine and an acid corresponding to the R group are subjected to condensation reaction in an organic solvent under the conditions that a uronium salt is used as a condensing agent and a base is added to obtain the pyrimidine terminal-anchored polymerase 2 inhibitor.
In the preparation method of the pyrimidine tankyrase 2 inhibitor, the reaction equation is as follows:
Figure BDA0003216005210000031
preferably, in the step (1), the mole ratio of 2,4,6-trichloropyrimidine to morpholine is 1:1 to 2:1.
preferably, in the step (1), the base is any one selected from sodium hydroxide, potassium carbonate, triethylamine, sodium carbonate and sodium bicarbonate.
Preferably, in the step (1), the organic solvent is selected from any one of methanol, ethanol, DCM and THF.
Preferably, in the step (1), the reaction temperature of the reaction is-20 ℃ to 30 ℃.
Preferably, in step (2), the molar ratio of 4- (2,6-dichloropyrimidin-4-yl) morpholine to 2-hydroxyethyl pyridine is 1:1 to 2:1.
preferably, in the step (2), the base is selected from any one of sodium hydroxide, potassium hydroxide, sodium hydride and sodium tert-butoxide.
Preferably, in the step (2), the organic solvent is selected from any one of DMF and THF.
Preferably, in the step (2), the reaction temperature of the reaction is-20 ℃ to 30 ℃.
Preferably, in the step (3), the molar ratio of the 4- (6-chloro-2- (2- (pyridin-2-yl) ethoxy) pyrimidin-4-yl) morpholine to the hydrazine hydrate is 1:1 to 1:3.
preferably, in step (3), the organic solvent is 1,4-dioxane.
Preferably, in the step (3), the reaction temperature of the reaction is 70-130 ℃.
Preferably, in step (4), the molar ratio of 4- (6-hydrazino-2- (2- (pyridin-2-yl) ethoxy) pyrimidin-4-yl) morpholine to the corresponding acid in group R is 1:1 to 2:1.
preferably, in the step (4), the base is any one of DIPEA, DIEA, TEA and NMM;
preferably, in the step (4), the organic solvent is any one selected from DMF, DCM, 1,4-dioxane and THF.
Preferably, in the step (4), the condensing agent is any one selected from HATU, HBTU, HCTU, TBTU, TSTU and TNTU.
Preferably, in the step (4), the reaction temperature of the reaction is 0-50 ℃.
Preferably, in step (4), the acid corresponding to the R group has the formula:
Figure BDA0003216005210000041
wherein R is 1 Is selected from
Figure BDA0003216005210000042
Figure BDA0003216005210000043
Any one of the above;
that is, the formula of the acid corresponding to the R group is:
Figure BDA0003216005210000044
Figure BDA0003216005210000045
any one of them.
Further preferably, R 1 Is selected from
Figure BDA0003216005210000046
The third aspect of the invention provides an application of the pyrimidine tankyrase 2 inhibitor in preparation of a drug for inhibiting tankyrase 2.
Compared with the prior art, the invention has the following beneficial effects:
(1) The pyrimidine tankyrase 2 inhibitor synthesized by the invention has good effect, wherein the IC of two preferable compounds 50 Value (to determine IC) 50 0.027uM and 0.018uM, respectively) compared to the positive control, GK-007 (IC) 50 =0.035 uM), higher sensitivity and better biological activity.
(2) The compound synthesized by the invention has a novel structure, and is reported for the first time.
(3) The preparation method is simple.
Drawings
FIG. 1 shows nuclear magnetic resonance of a compound of formula IV 1 H NMR chart (CDCl) 3 )；
FIG. 2 shows NMR of a compound of formula IV 13 C NMR chart (CDCl) 3 )；
FIG. 3 shows NMR of a compound of formula V 1 H NMR chart (CDCl) 3 )；
FIG. 4 shows NMR of a compound of formula V 13 C NMR chart (CDCl) 3 )；
FIG. 5 shows NMR of the objective product obtained in example 1 1 H NMR graph (DMSO);
FIG. 6 shows NMR of the objective product obtained in example 1 13 C NMR charts (DMSO);
FIG. 7 is an HRMS chart ([ M + Na ] s) of the target product obtained in example 1] + (CH 3 OH))；
FIG. 8 shows NMR of target product obtained in example 2 1 H NMR graph (DMSO);
FIG. 9 shows NMR of target product obtained in example 2 13 C NMR charts (DMSO);
FIG. 10 is the HRMS pattern ([ M + Na ] for the target product obtained in example 2] + (CH 3 OH))。
Detailed Description
A pyrimidine tankyrase 2 inhibitor having the structure shown in formula I:
Figure BDA0003216005210000051
wherein R is selected from
Figure BDA0003216005210000052
Figure BDA0003216005210000061
Any one of them.
In some embodiments, R is further preferably selected from:
Figure BDA0003216005210000062
the preparation method of the pyrimidine tankyrase 2 inhibitor comprises the following steps:
(1): 2,4,6-trichloropyrimidine reacts with morpholine in an organic solvent under the condition of adding alkali to prepare 4- (2,6-dichloropyrimidin-4-yl) morpholine;
(2): reacting 4- (2,6-dichloropyrimidin-4-yl) morpholine with 2-hydroxyethyl pyridine in an organic solvent under the condition of adding alkali to obtain 4- (6-chloro-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine;
(3): reacting 4- (6-chloro-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine with hydrazine hydrate in an organic solvent to obtain an intermediate 4- (6-hydrazino-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine;
(4): 4- (6-hydrazino-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine and acid corresponding to the R group are subjected to condensation reaction in an organic solvent under the conditions that uronium salts are used as a condensing agent and alkali is added to obtain the pyrimidine telotrague polymerase 2 inhibitor.
The reaction equation is as follows:
Figure BDA0003216005210000063
in some embodiments, the molar ratio of 2,4,6-trichloropyrimidine to morpholine in step (1) is 1:1 to 2:1.
in some embodiments, the base in step (1) is selected from any one of sodium hydroxide, potassium carbonate, triethylamine, sodium carbonate and sodium bicarbonate.
In some embodiments, the organic solvent in step (1) is selected from any one of methanol, ethanol, DCM, and THF.
In some embodiments, the reaction temperature of the reaction in step (1) is from-20 ℃ to 30 ℃.
In some embodiments, the molar ratio of 4- (2,6-dichloropyrimidin-4-yl) morpholine to 2-hydroxyethylpyridine in step (2) is 1:1 to 2:1.
in some embodiments, the base in step (2) is selected from any one of sodium hydroxide, potassium hydroxide, sodium hydride, and sodium tert-butoxide.
In some embodiments, the organic solvent in step (2) is selected from any one of DMF and THF.
In some embodiments, the reaction temperature of the reaction in step (2) is from-20 ℃ to 30 ℃.
In some embodiments, the molar ratio of 4- (6-chloro-2- (2- (pyridin-2-yl) ethoxy) pyrimidin-4-yl) morpholine to hydrazine hydrate in step (3) is 1:1 to 1:3.
in some embodiments, the organic solvent in step (3) is 1,4-dioxane.
In some embodiments, the reaction temperature of the reaction in step (3) is from 70 ℃ to 130 ℃.
In some embodiments, the molar ratio of 4- (6-hydrazino-2- (2- (pyridin-2-yl) ethoxy) pyrimidin-4-yl) morpholine to the corresponding acid of the R group in step (4) is 1:1 to 2:1.
in some embodiments, the base in step (4) is any one of DIPEA, DIEA, TEA and NMM;
in some embodiments, the organic solvent in step (4) is selected from any one of DMF, DCM, 1,4-dioxane, and THF.
In some embodiments, the condensing agent in step (4) is selected from any one of HATU, HBTU, HCTU, TBTU, TSTU and TNTU.
In some embodiments, the reaction temperature of the reaction in step (4) is from 0 ℃ to 50 ℃.
In some embodiments, the acid corresponding to the R group in step (4) has the formula:
Figure BDA0003216005210000071
wherein R is 1 Is selected from
Figure BDA0003216005210000072
Figure BDA0003216005210000081
Any one of the above;
that is, the formula of the acid corresponding to the R group is:
Figure BDA0003216005210000082
Figure BDA0003216005210000083
any one of them.
In some embodiments, R 1 Further preferably selected from:
Figure BDA0003216005210000084
the pyrimidine tankyrase 2 inhibitor is applied to preparation of a drug for inhibiting tankyrase 2.
The invention is described in detail below with reference to the figures and specific embodiments.
Preparation of a target product:
step (1)
Figure BDA0003216005210000085
2,4,6-trichloropyrimidine (4.5g, 25mmol) was dissolved in 25ml ethanol, morpholine (1.9g, 22mmol) and triethylamine (5g, 50mmol) were added to the 2,4,6-trichloropyrimidine solution in ethanol with stirring under ice-bath conditions, the temperature was slowly raised to room temperature, and stirring was continued at room temperature for 5h until morpholine reaction was complete. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the content of Na was determined by using water and 10% 2 CO 3 And washing with brine. Purification by flash silica gel chromatography (petroleum ether/ethyl acetate = 4:1) afforded the product. To obtain the product of formula III.
Step (2)
Figure BDA0003216005210000091
4- (2,6-dichloropyrimidin-4-yl) morpholine (3.5 g, 15mmol) was dissolved in 10ml THF, 2-hydroxyethylpyridine (1.5g, 12mmol) and sodium hydride (0.6 g, 30mmol) were added to a THF solution containing 4- (2,6-dichloropyrimidin-4-yl) morpholine under ice-bath conditions with stirring, and stirring was continued for 2h under ice-bath conditions until the 2-hydroxyethylpyridine reaction was complete. After completion of the reaction, the reaction mixture was poured into ice water to precipitate a white solid, and the solid was purified by water, 10% by weight of Na 2 CO 3 And washing with brine. To obtain the product of formula IV.
Step (3)
Figure BDA0003216005210000092
4- (6-chloro-2- (2- (pyridin-2-yl) ethoxy) pyrimidin-4-yl) morpholine (2.5 g, 7.8mmol) was dissolved in 10ml1,4-Dioxane (1,4-Dioxane), and N was added with stirring 2 H 4 ·H 2 O (750mg, 15mmol) was added to a 1,4-Dioxane (1,4-Dioxane) solution containing 4- (2,6-dichloropyrimidin-4-yl) morpholine, the temperature was slowly raised to 100 ℃, and stirring was continued at 100 ℃ for 5h until the reaction of 4- (6-chloro-2- (2- (pyridin-2-yl) ethoxy) pyrimidin-4-yl) morpholine was complete. After completion of the reaction, 1,4-Dioxane (1,4-Dioxane) was vacuum spin-dried at 40 ℃ and 20mL of ethyl acetate was added to the residue to precipitate a white solid, which was then treated with water and 10% Na 2 CO 3 And washing with brine. To obtain the product of formula V.
Step (4)
Figure BDA0003216005210000093
The acid corresponding to the R group (0.5 mmol) was dissolved in 10ml of DMF and HATU (230mg, 0.6 mmol) and DIPEA (130mg, 1mmol) were added to a solution of DMF containing the acid corresponding to the R group with stirring under ice bath, slowly warmed to room temperature, and after 15 minutes 4- (6-hydrazino-2- (2- (pyridin-2-yl) ethoxy) pyrimidin-4-yl) morpholine (200mg, 0.6 mmol) was added. Stirring was continued at room temperature for 6h until the corresponding acid reaction was complete. After completion of the reaction, the reaction solution was poured into ice water. Precipitating solid, collecting solid, adding water, and adding Na 2 CO 3 Saline and ethanol ultrasonic washing. Purification of the solid by flash silica gel chromatography (petroleum ether/ethyl acetate = 2:1) afforded the product. To obtain the product of formula IV.
Testing of inhibitory activity of pyrimidine tankyrase:
the inhibitory activity of the compounds on TNKS2 was determined by enzymatic reactions. Dissolving a compound to be detected in a DMSO solution to prepare a solution with an initial concentration of 200 mu M/L, diluting the solution 5 times each time according to a proportion, and configuring 7 concentration gradients to obtain a solution concentration range of each compound to be detected of 0.0128 mu M/L to 200 mu M/L. The enzymatic reaction was carried out in 96-well plates (Greiner bio-one U-shaped blackboard) at room temperature. TNKS2 at 5nM was incubated with compound and 500nM NAD' in assay buffer (50mM HEPES pH 7.0, 1mM CHAPS) for 1 hour, with four parallel experimental groups being set up simultaneously per concentration gradient. Then, a detection buffer (0.1% of 50mM HEPES in BSA, 0.8M KF and 20mM EDTA) was added thereto, and the reaction was carried out at room temperature for 1 hour. Finally, 20mL of 20% acetophenone ethanol solution and 20mL of 2M KOH are added to terminate the reaction, unreacted NAD' is chemically converted into a fluorescent substance, and the fluorescence intensity is read under the conditions of an excitation wavelength of 355nm and an absorption wavelength of 450 nm. According to the formula: inhibition = (sample fluorescence intensity-blank)/(enzyme value fluorescence intensity-blank) the corresponding inhibition for each inhibitor was calculated and then fitted to the half-effective inhibitory concentration using Graph Pad Prism software.
The structural formulas of formula IV and formula V are as follows:
Figure BDA0003216005210000101
1 H NMR(501MHz,CDCl 3 )δ8.47(d,J＝4.9Hz,1H),7.53(td,J＝7.8,1.9Hz,1H),7.20(d,J＝7.7Hz,1H),7.06(dd,J＝7.4,4.9Hz,1H),6.08(s,1H),4.61(t,J＝6.8Hz,2H),3.67(t,J＝4.9Hz,4H),3.58–3.48(m,4H),3.19(t,J＝6.8Hz,2H). 13 C NMR(126MHz,CDCl 3 )δ164.25,164.10,161.09,158.22,149.32,136.38,123.72,121.53,95.28,66.67,66.31,44.45,37.59.
Figure BDA0003216005210000111
1 H NMR(501MHz,CDCl 3 )δ8.52(d,J＝4.4Hz,1H),7.57(td,J＝7.6,1.9Hz,1H),7.23(d,J＝7.8Hz,1H),7.10(dd,J＝7.5,4.9Hz,1H),6.39(s,1H),5.51(s,1H),4.61(t,J＝6.9Hz,2H),3.72(t,J＝4.9Hz,4H),3.57–3.48(m,4H),3.23(t,J＝6.9Hz,2H). 13 C NMR(126MHz,CDCl 3 )δ168.29,164.77,164.43,158.80,149.35,136.38,123.64,121.45,75.14,66.59,65.74,44.66,37.90.
the following examples were prepared and tested for inhibitory activity according to the above preparation methods and inhibitory activity test methods.
Example 1
Figure BDA0003216005210000112
1 H NMR(400MHz,DMSO)δ10.11(s,1H),8.62(s,1H),8.49(d,J＝4.8Hz,1H),7.70(t,J＝7.7Hz,1H),7.31(d,J＝7.7Hz,1H),7.25–7.16(m,3H),6.93(d,J＝8.7Hz,1H),5.26(s,1H),4.69(s,2H),4.50(t,J＝6.6Hz,2H),3.62(t,J＝4.8Hz,4H),3.38–3.28(m,4H),3.11(t,J＝6.8Hz,2H),2.21(s,3H). 13 C NMR(101MHz,DMSO)δ167.97,167.11,164.83,164.46,158.89,155.33,149.59,136.96,130.58,129.31,126.84,124.91,123.93,122.10,113.25,76.46,66.96,66.29,65.44,44.62,37.53,16.42.
IC 50 The value was 0.027uM.
Example 2
Figure BDA0003216005210000113
1 H NMR(400MHz,DMSO)δ10.44(s,1H),8.70(s,1H),8.48(d,J＝4.9Hz,1H),7.68(t,J＝7.6Hz,1H),7.28(d,J＝10.1Hz,3H),7.23–7.19(m,1H),5.44(s,1H),4.50(t,J＝6.9Hz,2H),3.85(s,3H),3.82(s,6H),3.60(t,J＝4.8Hz,4H),3.40–3.36(m,4H),3.10(t,J＝6.8Hz,2H). 13 C NMR(101MHz,DMSO)δ166.13,165.89,164.92,164.59,158.92,153.29,149.62,140.98,136.99,128.16,123.99,122.16,105.52,76.34,66.39,65.54,60.68,56.57,44.73,37.60.
IC 50 The value was 0.018uM.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (10)

1. A pyrimidine tankyrase 2 inhibitor having the structure shown in formula i:
Figure FDA0003907901170000011
wherein R is selected from
Figure FDA0003907901170000012
Figure FDA0003907901170000013
Any one of them.
2. The pyrimidine tankyrase 2 inhibitor of claim 1, wherein R is selected from the group consisting of:
Figure FDA0003907901170000014
3. a method for preparing the pyrimidine tankyrase 2 inhibitor of claim 1, comprising the steps of:
(1): 2,4,6-trichloropyrimidine reacts with morpholine in an organic solvent under the condition of adding alkali to prepare 4- (2,6-dichloropyrimidin-4-yl) morpholine;
(2): reacting 4- (2,6-dichloropyrimidin-4-yl) morpholine with 2-hydroxyethyl pyridine in an organic solvent under the condition of adding alkali to obtain 4- (6-chloro-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine;
(3): reacting 4- (6-chloro-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine with hydrazine hydrate in an organic solvent to obtain an intermediate 4- (6-hydrazino-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine;
(4): 4- (6-hydrazino-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine and an acid corresponding to the R group are subjected to condensation reaction in an organic solvent under the conditions that a uronium salt is used as a condensing agent and a base is added to obtain the pyrimidine terminal-anchored polymerase 2 inhibitor.
4. The method for preparing the pyrimidine tankyrase 2 inhibitor according to claim 3, wherein the step (1) comprises one or more of the following conditions:
(i) The molar ratio of 2,4,6-trichloropyrimidine to morpholine is 1:1 to 2:1;
(ii) The alkali is selected from any one of sodium hydroxide, potassium carbonate, triethylamine, sodium carbonate and sodium bicarbonate;
(iii) The organic solvent is selected from any one of methanol, ethanol, DCM and THF;
(iv) The reaction temperature is-20 ℃ to 30 ℃.
5. The method for preparing a pyrimidine tankyrase 2 inhibitor according to claim 3, wherein the step (2) comprises one or more of the following conditions:
(i) The mol ratio of the 4- (2,6-dichloropyrimidin-4-yl) morpholine to the 2-hydroxyethyl pyridine is 1:1 to 2:1;
(ii) The alkali is selected from any one of sodium hydroxide, potassium hydroxide, sodium hydride and sodium tert-butoxide;
(iii) The organic solvent is selected from any one of DMF and THF;
(iv) The reaction temperature is-20 ℃ to 30 ℃.
6. The method for preparing the pyrimidine tankyrase 2 inhibitor according to claim 3, wherein the step (3) comprises one or more of the following conditions:
(i) The molar ratio of the 4- (6-chloro-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine to the hydrazine hydrate is 1:1 to 1:3;
(ii) The organic solvent is 1,4-dioxane;
(iii) The reaction temperature of the reaction is 70-130 ℃.
7. The method for preparing the pyrimidine tankyrase 2 inhibitor according to claim 3, wherein the step (4) comprises one or more of the following conditions:
(i) The molar ratio of the 4- (6-hydrazino-2- (2- (pyridine-2-yl) ethoxy) pyrimidine-4-yl) morpholine to the corresponding acid of the R group is 1:1 to 2:1;
(ii) The alkali is any one of DIPEA, DIEA, TEA and NMM;
(iii) The organic solvent is selected from any one of DMF, DCM, 1,4-dioxane and THF;
(iv) The condensing agent is selected from any one of HATU, HBTU, HCTU, TBTU, TSTU and TNTU;
(v) The reaction temperature of the reaction is 0-50 ℃.
8. The method for preparing pyrimidine tankyrase 2 inhibitor according to claim 3 or 7, wherein in step (4), the acid corresponding to the R group has the structural formula:
Figure FDA0003907901170000031
wherein R is 1 Is selected from
Figure FDA0003907901170000032
Figure FDA0003907901170000033
Any one of them.
9. The method for preparing pyrimidine tankyrase 2 inhibitor according to claim 8A process for preparing R 1 Is selected from
Figure FDA0003907901170000034
10. Use of a pyrimidine tankyrase 2 inhibitor as claimed in claim 1 or claim 2 in the manufacture of a medicament for inhibiting tankyrase 2.
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