CN113135900B - Indole pyrimidine compound and synthesis method and application thereof - Google Patents
Indole pyrimidine compound and synthesis method and application thereof Download PDFInfo
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Abstract
The invention discloses an indole pyrimidine compound, which has a structural formula shown in a formula (I):
wherein L is selected from any one of H, OH, halogen, alkoxy, halogenated alkyl, aryl and pyridine, Q is O, S or NH, X is NH or-CONH, N is a natural number, R is N (CH)3)2Or
T is selected from at least one of H, OH, halogen, alkoxy, halogenated alkyl, aryl and pyridine. The indole pyrimidine compound provided by the invention can effectively inhibit the differentiation of fat cells, and has a good lipid-lowering effect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an indole pyrimidine compound and a synthesis method and application thereof.
Background
Today in the 21 st century, with the rapid development of economy and the improvement of the living standard of people, the number of obesity patients worldwide is increasing year by year, obesity is associated with various diseases such as: diabetes, cardiovascular disease, cancer, etc. And a huge burden is added to global public health. In the current clinical drug treatment of obesity, fewer drugs can be selected. Therefore, the ideal anti-obesity drug is deficient, and new drugs are urgently needed to be created.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention provides an indole pyrimidine compound, and the structural formula of the indole pyrimidine compound is shown as the formula (I):
wherein L is at least one selected from H, OH, halogen, alkoxy, halogenated alkyl, aryl and pyridine,
q is O, S or NH, and the formula is shown in the specification,
x is NH or-CONH, n is a natural number,
r is N (CH)3)2Or
T is selected from at least one of H, OH, halogen, alkoxy, halogenated alkyl, aryl and pyridine.
The indole pyrimidine compound provided by the embodiment of the invention has at least the following beneficial effects:
the indole pyrimidine compound provided by the invention has the advantages of novel chemical structure, good water solubility and moderate fat solubility. In cells and animal models, the differentiation of fat cells can be effectively inhibited under low concentration, a better lipid-lowering effect is achieved, and the indole pyrimidine compounds also have the curative effect of treating non-alcoholic steatohepatitis.
According to some embodiments of the invention, the alkyl group is a C1-C4 alkyl group.
According to some embodiments of the invention, the haloalkyl is fluoroalkyl; preferably, the halogenated alkyl is C1-C3 fluorinated alkyl; more preferably, the haloalkyl is CF3。
According to some embodiments of the invention, the halogen is fluorine.
According to some embodiments of the invention, the aryl group is phenyl.
According to some embodiments of the invention, the indole pyrimidines are selected from any one of the following compounds:
in a second aspect of the present invention, there is provided a method for synthesizing the indole pyrimidines, comprising the following steps:
(1) will be provided with
And
in the presence of K2CO3In a solvent system of
(2) To be generated
And
generated under the action of catalyst
Wherein W is a protecting group;
(3) to be generated
Removing W protecting group to generate
(4) To be generated
With POCl3Reaction to form
In a second aspect of the present invention, there is provided an application of the indole pyrimidine compounds or the indole pyrimidine compounds synthesized by the above synthesis method in preparing lipid lowering drugs and drugs for treating non-alcoholic steatohepatitis.
According to some embodiments of the invention, the lipid-lowering drug or the drug for treating non-alcoholic steatohepatitis further comprises a pharmaceutically acceptable salt or a carrier.
Drawings
The invention is further described with reference to the following figures and examples, in which:
FIG. 1 is a graph showing the effect of reducing blood lipid using indole pyrimidines provided in some embodiments of the present invention;
FIG. 2 is a graph showing the results of half maximal effect concentration of an indole pyrimidine compound MY2 prepared in example 16;
FIG. 3 is a graph showing the effect of a mouse taking an indole pyrimidine compound MY2 in an effect example of the invention;
FIG. 4 is a graph showing the effect of metabolic indexes related to glycolipid metabolism in blood of a mouse after the mouse takes an indole pyrimidine compound MY2 in an effect example of the invention;
FIG. 5 is a graph showing the effect of liver protection index of mice taking indole pyrimidine compound MY2 in the present invention.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
Example 1
This example provides an indole pyrimidine compound
The synthetic route is as follows:
the specific synthesis steps are as follows:
(1) 2, 4-dichloropyrimidine (297.9mg, 2.0mmol), 15mL of N, N-dimethylformamide, potassium carbonate (276.4mg, 2.0eq) and N, N-dimethyl-1, 3-diaminopropane (302. mu.L, 1.2eq) were successively charged into a 50mL eggplant-shaped bottle, and the reaction was stirred at room temperature for 5 hours. To the system was added 15mL of water, followed by extraction with ethyl acetate (30 mL. times.3) and the combined organic phases, which were washed successively with saturated brine (30 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to give 295mg of intermediate WD-R17-1.
The nuclear magnetic data of the intermediate WD-R17-1 are:1H NMR(400MHz,DMSO-d6)δ7.99(s,1H),7.87(d,J＝5.9Hz,1H),6.50(d,J＝6.0Hz,1H),2.63(t,J＝6.5Hz,2H),2.55(d,J＝6.2Hz,4H),1.71(p,J＝3.0Hz,6H).
(2) WD-R17-1(214.7mg, 1.0mmol), 1-Boc-indole-2-boronic acid (313.3mg, 1.2eq), K2CO3(276.4mg, 2.0eq) and tetrakis (triphenylphosphine) palladium (57.8mg, 0.05eq) were put in a 50mL round bottom flask, then water (1mL) and 1, 4-dioxane (15mL) were added, argon gas was replaced (three times), and the mixture was heated to 90 ℃ to reflux and reacted for 8 hours. After the reaction is finished, filtering the reaction solution by using kieselguhr, concentrating the filtrate under reduced pressure, and separating and purifying by silica gel column chromatography to obtain 298mg of a light yellow intermediate WD-R17-2; ESI-MS: m/z 396.2[ M + l [ ]]+。
(3) Trifluoroacetic acid (1mL), WD-R17-2(158.4mg, 0.4mmol) and 1, 2-dichloroethane (15mL) were sequentially added to a 50mL eggplant-shaped bottle, and the temperature was raised to 50 ℃ to react for 2 hours. After the reaction is finished, concentrating the reaction solution under reduced pressure to remove most of the solvent, then adding sodium bicarbonate to adjust the pH value to be neutral, extracting an aqueous phase (20mL multiplied by 3) by using ethyl acetate, combining organic phases, then adding anhydrous sodium sulfate to dry, then concentrating the organic phases under reduced pressure, and separating and purifying by silica gel column chromatography to obtain a 110mg intermediate WD-R17-3; ESI-MS: m/z is 296.2[ M + l ] +
(4) While stirring in ice bath, DMF (0.5mL,6.5mmol) was slowly added dropwise to POCl in a 50mL eggplant-shaped bottle3(0.5ml, 5.4mmol) for 30 min. Then, 1, 2-dichloroethane solution of WD-R17-3(88.9mg, 0.3mmol) is slowly added, the temperature is raised to 50 ℃ for reaction for 4 hours, after the reaction is finished, the reaction solution is decompressed and concentrated to remove most of the solvent, then sodium bicarbonate is added to adjust the pH value to be neutral, the ethyl acetate is used for extracting the aqueous phase, the organic phases are combined, anhydrous sodium sulfate is added for drying, then the organic phase is decompressed and concentrated, and the mixture is separated and purified by silica gel column chromatography to obtain 75mg of light yellow product WD-R17. The calculated yield is: 77 percent.
1H NMR(400MHz,Methanol-d4)δ11.08(s,1H),8.29(d,J＝7.9Hz,1H),8.14(s,1H),7.53(d,J＝8.1Hz,1H),7.28(t,J＝7.6Hz,1H),7.22(t,J＝7.5Hz,1H),6.43(d,J＝5.8Hz,1H),3.51(s,2H),2.45–2.40(m,2H),2.23(s,6H),1.85–1.79(m,2H).
13C NMR(101MHz,Methanol-d4)δ192.33,163.78,159.27,154.96,145.24,137.09,130.83,127.76,125.78,124.01,123.51,117.75,113.25,58.17,45.47,39.71,28.02.
HRMS[ESI]:calcd for(M+H)+(C18H21N5O)requires m/z 324.1812,found 324.1819.
Example 2
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) 2, 4-dichloro-5-methylpyrimidine (326.1, 2.0mmol) was used instead of 2, 4-dichloropyrimidine in example 1, step (1). 310.4mg of intermediate JJ-R17-1 are obtained
The nuclear magnetic data of the intermediate JJ-R17-1 is:1H NMR(400MHz,Chloroform-d)δ7.81(s,1H),7.73(s,1H),3.59(td,J＝6.0,4.6Hz,2H),2.58–2.54(m,2H),2.32(s,6H),1.92(s,3H),1.82–1.77(m,2H).
(2) JJ-R17-1(228.7mg, 1.0mmol) was used in place of WD-R17-1 in example 1, step (2). 193mg of a pale yellow intermediate JJ-R17-2 are obtained
ESI-MS：m/z＝410.2[M+l]+。
(3) JJ-R17-2(163.7mg, 0.4mmol) was used in place of WD-R17-2 in example 1, step (3). 110mg of intermediate JJ-R17-3 are obtained
ESI-MS：m/z＝310.2[M+l]+。
(4) JJ-R17-3(92.8mg,0.3mmol) was used in place of WD-R17-3 in example 1, step (4). 61mg of JJ-R17 were obtained as a pale yellow solid.
1H NMR(500MHz,Methanol-d4)δ11.12(s,1H),8.32(d,J＝7.9Hz,1H),8.07(s,1H),7.56(d,J＝8.1Hz,1H),7.31(t,J＝7.6Hz,1H),7.25(t,J＝7.5Hz,1H),3.66(t,J＝7.1Hz,2H),2.49(t,J＝7.5Hz,2H),2.28(s,6H),2.12(s,3H),1.90(t,J＝7.3Hz,2H).
13C NMR(101MHz,Methanol-d4)δ192.28，162.20,157.15,153.75,145.57,136.93,127.80,125.56,123.86,123.43,117.37,115.04,113.16,58.40,45.46,40.43,27.78,13.91.
HRMS[ESI]:calcd for(M+H)+(C19H23N5O)requires m/z 338.1975,found 338.1970.
Example 3
This example is an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) 5-Ethyluracil (700.5mg, 5mmol) and phosphorus oxychloride (15mL) were added sequentially to a 20mL pressure tube. Heating to 100 ℃, and stirring in a sealed way for reaction for 5 hours. After the reaction is finished, cooling to room temperature, pouring the system into ice, adding saturated aqueous bicarbonate solution, and adjusting the pH value to be neutral. Then extracted with ethyl acetate (50mL x3) and the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Separating and purifying by silica gel column chromatography to obtain 725mg of 2, 4-dichloro-5-ethyl pyrimidine.
The nuclear magnetic data for 2, 4-dichloro-5-ethylpyrimidine is:1H NMR(400MHz,Chloroform-d)δ8.40(s,1H),2.73(q,J＝7.5Hz,2H),1.27(t,J＝7.6Hz,3H).
2, 4-dichloro-5-ethylpyrimidine (354.5mg, 2.0mmol) was used in place of 2, 4-dichloropyrimidine in example 1, step (1). 406mg of intermediate E2-1 are obtained
1H NMR(500MHz,Methanol-d4)δ7.70(s,1H),3.48(t,J＝6.7Hz,2H),2.41(dt,J＝14.1,7.1Hz,4H),2.27(s,6H),1.81(p,J＝8.2,7.5Hz,2H),1.18(t,J＝7.4Hz,3H).
(2) E2-1(242.8mg, 1.0mmol) was used in place of WD-R17-1 in example 1, step (2). 300mg of pale yellow intermediate E2-2 are obtained
ESI-MS：m/z＝424.2[M+l]+。
(3) E2-2(163.7mg, 0.4mmol) was used instead of WD-R17-2 in example 1, step (3). Yield 130mg of intermediate E2-3
ESI-MS：m/z＝324.2[M+l]+。
(4) E2-3(97.1mg,0.3mmol) was used instead of WD-R17-3 in example 1, step (4). 81mg of yellowish product E2 are obtained. The calculated yield is: 77 percent.
1H NMR(400MHz,Methanol-d4)δ11.14(s,1H),8.34(d,J＝7.8Hz,1H),8.11(s,1H),7.59(d,J＝8.1Hz,1H),7.34(t,J＝7.6Hz,1H),7.27(t,J＝7.5Hz,1H),3.69(t,J＝6.9Hz,2H),2.82–2.76(m,2H),2.55(d,J＝3.6Hz,2H),2.52(s,6H),2.01(p,J＝7.2Hz,2H),1.31(d,J＝7.5Hz,3H).
13C NMR(101MHz,Chloroform-d)δ190.44,160.20,155.71,150.96,142.59,134.72,126.77,124.54,123.00,122.78,118.70,116.78,111.25,58.42,44.72,41.24,24.20,20.99,11.86.
HRMS[ESI]:calcd for(M+H)+(C20H25N5O)requires m/z 352.2132,found 352.2134.
Example 4
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) 5, 6-Dimethyluracil (700.5mg, 5mmol) and phosphorus oxychloride (15mL) were added sequentially to a 20mL pressure tube. Heating to 100 ℃, and stirring in a sealed way for reaction for 5 hours. After the reaction is finished, cooling to room temperature, pouring the system into ice, adding saturated aqueous bicarbonate solution, and adjusting the pH value to be neutral. Then extracted with ethyl acetate (50mL x3) and the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The column chromatography of silica gel is used for separating and purifying to obtain 699mg of yellow white solid 2, 4-dichloro-5, 6-dimethylpyrimidine. The nuclear magnetic data for 2, 4-dichloro-5, 6-dimethylpyrimidine is: 1H NMR (500MHz, Methanol-d4) delta 2.55(s,3H),2.37(s,3H).
2, 4-dichloro-5, 6-dimethylpyrimidine (354.5, 2.0mmol) was used in place of 2, 4-dichloropyrimidine in example 1, step (1). 380mg of intermediate J3-1 are obtained
1H NMR(500MHz,Methanol-d4)δ3.47(t,J＝6.7Hz,2H),2.44(t,J＝7.2Hz,2H),2.29(s,9H),1.99(s,3H),1.82(q,J＝7.2Hz,2H)
(2) J3-1(242.8mg, 1.0mmol) was used in place of WD-R17-1 in example 1, step (2). Yield 316mg of intermediate J3-2
ESI-MS：m/z＝424.2[M+l]+。
(3) J3-2(163.7mg, 0.4mmol) was used instead of WD-R17-2 in example 1, step (3). Yield 130mg of intermediate J3-3
Characterization data for intermediate J3-3 was as follows:
ESI-MS：m/z＝324.2[M+l]+
1H NMR(500MHz,Methanol-d4)δ7.59(d,J＝7.8Hz,1H),7.48(d,J＝8.1Hz,1H),7.22(s,1H),7.17(t,J＝7.5Hz,1H),7.03(t,J＝7.3Hz,1H),3.76(t,J＝6.0Hz,2H),2.93(t,J＝7.0Hz,2H),2.58(d,J＝2.0Hz,6H),2.41(s,3H),2.08(s,3H),2.05–1.98(m,2H).
13C NMR(101MHz,Methanol-d4)δ161.74,160.58,156.63,137.79,137.24,129.41,123.26,121.43,119.96,112.01,109.14,103.19,57.73,44.72,39.50,27.59,20.55,10.75.
(4) j3-3(97.1mg,0.3mmol) was used instead of WD-R17-3 in example 1, step (4). 87mg of J3 were obtained as a pale yellow solid. Calculated, the yield is: 92 percent. Characterization data for intermediate J3 was as follows:
H NMR(400MHz,Methanol-d4)δ11.15(s,1H),8.33(d,J＝7.8Hz,1H),7.58(d,J＝8.0Hz,1H),7.33(t,J＝7.5Hz,1H),7.27(t,J＝7.5Hz,1H),3.63(t,J＝6.9Hz,2H),2.71–2.64(m,2H),2.45(s,3H),2.44(s,6H),2.08(s,3H),1.99–1.92(m,2H).
13C NMR(101MHz,Methanol-d4)δ191.68,161.70,161.13,155.14,145.21,136.32,127.15,124.92,123.26,122.74,116.73,112.55,111.29,57.51,44.37,39.74,26.84,21.19,10.91.
HRMS[ESI]:calcd for(M+H)+(C20H25N5O)requires m/z 352.2132,found 352.2133.
example 5
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) 2, 4-dichloro-6-methylpyrimidine (326.1, 2.0mmol) was used instead of 2, 4-dichloropyrimidine in example 1, step (1). 294mg of intermediate 6JJ-R17-1 are obtained as a pale yellow oil
The nuclear magnetic data of the intermediate 6JJ-R17-1 is as follows: 1H NMR (400MHz, Methanol-d4) δ 6.27(s,1H),3.43(s,2H),2.45(t, J ═ 7.8Hz,2H),2.31(s,6H),2.26(s,3H), 1.86-1.78 (m,2H).
(2) 6JJ-R17-1 (228) was used.7mg, 1.0mmol) was substituted for WD-R17-1 in example 1, step (2). This gave 289mg of intermediate as a pale yellow solid, 6JJ-R17-2
ESI-MS：m/z＝410.2[M+l]+。
(3) 6JJ-R17-2(163.7mg, 0.4mmol) was used in place of WD-R17-2 in example 1, step (3). 96mg of 6JJ-R17-3 are obtained as a yellow solid
Characterization data for the yellow solid 6JJ-R17-3 are as follows:
ESI-MS：m/z＝310.2[M+l]++
1H NMR(400MHz,Methanol-d4)δ7.58(d,J＝8.0Hz,1H),7.46(d,J＝8.2Hz,1H),7.25(s,1H),7.16(d,J＝7.2Hz,1H),7.04–7.00(m,1H),6.20(s,1H),3.61(s,2H),2.80(t,J＝7.3Hz,2H),2.51(s,6H),2.33(s,3H),1.97–1.90(m,2H).
(4) 6JJ-R17-3(92.8mg,0.3mmol) was used in place of WD-R17-3 in example 1, step (4). 89mg of 6JJ-R17 was obtained as a pale yellow solid. The calculated yield was 88%. Characterization data for product 6JJ-R17 are as follows:
1H NMR(500MHz,Methanol-d4)δ11.12(s,1H),8.32(d,J＝7.9Hz,1H),7.56(d,J＝8.1Hz,1H),7.31(t,J＝7.6Hz,1H),7.25(t,J＝7.5Hz,1H),6.32(s,1H),3.53(s,2H),2.68(t,J＝13.6,7.2Hz,2H),2.45(s,6H),2.37(s,3H),1.94–1.87(m,2H).
13C NMR(126MHz,Methanol-d4)δ191.06,163.86,163.01,157.46,143.94,135.62,126.34,124.36,122.62,122.07,116.31,111.87,103.34,56.42,43.50,26.05,22.33.
example 6
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) 5-bromo-2, 4-dichloropyrimidine (911.5mg, 4.0mmol) was used in place of 2, 4-dichloropyrimidine in example 1, step (1). 997mg of MY1-1 are obtained as a pale white solid
Characterization data for MY1-1 are as follows:
ESI-MS：m/z＝293.2[M+l]+
1H NMR(500MHz,Methanol-d4)δ8.12(s,1H),3.53(t,J＝7.3Hz,2H),2.67(t,J＝7.4Hz,2H),2.47(s,6H),1.92–1.86(m,2H).
(2) mixing MY1-1(587.2mg, 2.0mmol), phenylboronic acid (243.8mg, 1.0eq), and K2CO3(552.8mg, 2.0eq) and tetrakis (triphenylphosphine) palladium (115.6mg, 0.05eq) were put in a 50mL round bottom flask, then water (1mL) and 1, 4-dioxane (15mL) were added, argon gas was replaced (three times), and the mixture was heated to 90 ℃ for reflux reaction for 8 hours. After the reaction is finished, the reaction solution is filtered by diatomite, the filtrate is decompressed and concentrated, and then the 521mg light yellow intermediate MY1-2 is obtained by silica gel column chromatography separation and purification
Characterization data for MY1-2 are as follows:
ESI-MS：m/z＝291.3[M+l]+
1H NMR(400MHz,Methanol-d4)δ7.72(s,1H),7.49(d,J＝7.5Hz,2H),7.47–7.42(m,1H),7.38–7.35(m,2H),3.45(t,J＝6.7Hz,2H),2.37(t,J＝6.9Hz,2H),2.11(s,6H),1.77–1.70(m,2H).。
(3) MY1-2(290.8mg, 1.0mmol) was used instead of WD-R17-1 in example 1, step (2). 353mg of MY1-3 was obtained as a dark red solid
ESI-MS：m/z＝472.2[M+l]+。
(4) MY1-3(188.5mg, 0.4mmol) was used instead of WD-R17-2 in example 1, step (3). 121mg of MY1-4 are obtained as a pale yellow solid
Characterization data for product MY1-4 are as follows:
ESI-MS：m/z＝372.2[M+l]+
1H NMR(400MHz,Methanol-d4)δ7.92(s,1H),7.58(d,J＝8.0Hz,1H),7.52–7.46(m,3H),7.44–7.39(m,3H),7.25(s,1H),7.17(t,J＝7.6Hz,1H),7.02(t,J＝7.1Hz,1H),3.70(t,J＝6.7Hz,2H),2.44(t,J＝6.9Hz,2H),2.16(s,6H),1.85–1.77(m,2H)。
(5) MY1-4(111.4mg,0.3mmol) was used instead of WD-R17-3 in example 1, step (4). 99mg of MY1 are obtained as a pale yellow solid. The calculated yield was 83%. Characterization data for product MY1 are as follows:
1H NMR(500MHz,Methanol-d4)δ11.14(s,1H),8.32(d,J＝7.9Hz,1H),8.03(s,1H),7.55(d,J＝8.1Hz,1H),7.50(t,J＝7.3Hz,2H),7.46–7.40(m,3H),7.29(t,J＝8.1Hz,1H),7.23(t,J＝7.5Hz,1H),3.54(t,J＝6.7Hz,2H),2.41(t,J＝7.0Hz,2H),2.14(s,6H),1.77(p,J＝6.8Hz,2H).
13C NMR(126MHz,Methanol-d4)δ192.27,161.02,158.13,154.28,144.98,137.10,135.58,130.37,129.95,129.52,127.81,125.80,124.01,123.54,120.35,117.86,113.25,58.76,45.22,41.13,26.95.
HRMS[ESI]:calcd for(M+H)+(C24H25N5O)requires m/z 400.2132,found 400.2132.
example 7
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) prepared according to the method of step (1) in example 6
Mixing MY1-1(587.2mg, 2.0mmol), pyridine-3-boric acid (245.8mg, 2.0mmol), and K2CO3(552.8mg, 2.0eq) and tetrakis (triphenylphosphine) palladium (115.6mg, 0.05eq) were put in a 50mL round bottom flask, then water (1mL) and 1, 4-dioxane (15mL) were added, argon gas was replaced (three times), and the mixture was heated to 90 ℃ for reflux reaction for 8 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography to obtain 507mg of dark brown solid MY19-1
1H NMR(400MHz,Methanol-d4)δ8.60(dd,J＝5.0,1.6Hz,1H),8.56(dd,J＝2.3,0.9Hz,1H),7.88(ddd,J＝7.8,2.2,1.6Hz,1H),7.79(s,1H),7.56(ddd,J＝7.8,5.0,0.9Hz,1H),3.44(t,J＝6.7Hz,2H),2.35(t,J＝6.9Hz,2H),2.09(s,6H),1.78–1.70(m,2H).
(2) MY19-1(291.8mg, 1.0mmol) was used instead of WD-R17-1 in example 1, step (2). 351mg of MY19-2 are obtained as a brown solid
ESI-MS：m/z＝473.2[M+l]+。
(3) Replacement of WD-R17-2 in example 1, step (3) with MY19-2(189.3mg, 0.4mmol) gave 125mg of MY19-3 as a pale yellow solid
ESI-MS：m/z＝373.2[M+l]+
(4) Substitution of MY19-3(112.0mg, 0.3mmol) for example 1, step (4) WD-R17-3 gave 109mg of MY19 as a pale yellow solid, calculated as 91% yield
1H NMR(400MHz,Methanol-d4)δ11.16(s,1H),8.65–8.60(m,2H),8.31(d,J＝7.9Hz,1H),8.10(s,1H),7.94(dt,J＝7.9,1.8Hz,1H),7.60–7.54(m,2H),7.33–7.28(m,1H),7.25–7.21(m,1H),3.58(t,J＝6.7Hz,2H),2.43(t,J＝7.0Hz,2H),2.16(s,6H),1.85–1.77(m,2H).
13C NMR(101MHz,Methanol-d4)δ191.80,160.77,158.57,154.69,149.82,149.51,144.20,138.52,136.77,132.19,127.39,125.52,125.34,123.68,123.16,117.65,116.16,112.88,58.39,44.86,40.79,26.53.
HRMS[ESI]:calcd for(M+H)+(C24H25N5O)requires m/z 401.2084,found 401.2083.
Example 8
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) prepared according to the method of step (1) in example 6
Mixing MY1-1(587.2mg, 2.0mmol), 4-tert-butylboronic acid (356.1mg, 2.0mmol), K2CO3(552.8mg, 2.0eq) and tetrakis (triphenylphosphine) palladium (115.6mg, 0.05eq) were put in a 50mL round bottom flask, then water (1mL) and 1, 4-dioxane (15mL) were added, argon gas was replaced (three times), and the mixture was heated to 90 ℃ for reflux reaction for 8 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography to obtain 470mg of dark brown solid MY15-1
1H NMR(500MHz,Methanol-d4)δ7.72(s,1H),7.56(d,J＝7.1Hz,2H),7.31(d,J＝7.1Hz,2H),3.47(t,J＝6.7Hz,2H),2.37(t,J＝5.6Hz,2H),2.09(s,6H),1.77–1.70(m,2H),1.36(s,9H).
(2) MY15-1(346.9mg, 1.0mmol) was used instead of WD-R17-1 in example 1, step (2). 351mg of MY15-2 are obtained as a brown solid
ESI-MS：m/z＝528.3[M+l]+。
(3) Replacement of WD-R17-2 in example 1, step (3) with MY15-2(211.1mg, 0.4mmol) gave 150mg of MY15-3 as a pale yellow solid
ESI-MS：m/z＝428.3[M+l]+。
1H NMR(500MHz,Methanol-d4)δ7.93(s,1H),7.60(d,J＝8.1Hz,1H),7.56(d,J＝7.7Hz,2H),7.50(d,J＝8.2Hz,1H),7.37(d,J＝7.8Hz,2H),7.26(s,1H),7.18(t,J＝7.6Hz,1H),7.04(t,J＝7.5Hz,1H),3.72(t,J＝6.6Hz,2H),2.49(t,J＝7.0Hz,2H),2.20(s,6H),1.87–1.81(m,2H),1.37(s,9H).
(4) MY15-3(128.3mg, 0.3mmol) was used instead of example 1, step (4) WD-R17-3. 118mg of MY15 was obtained as a pale yellow solid, calculated in 88% yield.
1H NMR(400MHz,Chloroform-d)δ11.32(s,1H),10.58(s,1H),8.50(d,J＝7.4Hz,1H),8.07(s,1H),7.52(d,J＝8.1Hz,3H),7.36–7.28(m,4H),7.13(s,1H),3.68(t,J＝5.9Hz,2H),2.56(t,J＝6.4Hz,2H),2.15(s,6H),1.87–1.80(m,2H),1.38(s,9H).
13C NMR(101MHz,Chloroform-d)δ191.08,160.39,157.17,153.20,152.05,142.76,135.56,131.53,128.99,127.36,126.68,125.37,123.65,123.54,119.42,117.75,112.14,58.56,44.79,35.19,31.76,30.15,25.31.
HRMS[ESI]:calcd for(M+H)+(C28H33N5O)requires m/z 456.2758,found 456.2759.
Example 9
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) 2-chloro-4-pyrimidinecarboxylic acid (792.5, 5.0mmol) was added to a 50mL eggplant-shaped bottle and dissolved in 20mL of N, N-dimethylformamide. N, N-diisopropylethylamine (1239.1. mu.L, 1.5eq) and HATU (2850mg, 1.5eq) were added in this order, and stirred for 30min, and N, N-dimethyl-1, 3-diaminopropane (628.7. mu.L, 1.2eq) was added and stirred at room temperature for reaction for 6 hours. TLC monitored the starting material reaction was complete. Adding 30mL of water into the system, extracting the system with ethyl acetate (50mL x3), combining organic phases, washing the organic phase with supersaturated sodium chloride solution, drying with anhydrous sodium sulfate, and separating and purifying by silica gel column chromatography to obtain 1016.4mg of yellow white solid XA-R17-1
(2) Instead of WD-R17-1 in example 1, step (2), XA-R17-1(242.7mg, 1.0mmol) was used. 228mg of intermediate XA-R17-2 are obtained
ESI-MS：m/z＝424.2[M+l]+。
(3) Instead of WD-R17-2 in example 1, step (3), XA-R17-2(163.7mg, 0.4mmol) was used. 121mg of intermediate XA-R17-3 are obtained
ESI-MS：m/z＝324.2[M+l]+
1H NMR(400MHz,Methanol-d4)δ8.97(d,J＝4.9Hz,1H),7.80(d,J＝4.9Hz,1H),7.63(d,J＝8.0Hz,1H),7.46(d,J＝8.3Hz,1H),7.43(s,1H),7.23(t,J＝7.4,6.8Hz,1H),7.06(t,J＝7.5Hz,1H),3.55(t,J＝6.8Hz,2H),2.82(t,J＝7.7Hz,2H),2.58(s,6H),2.03–1.96(m,2H).
(4) QZ-3(97.1mg,0.3mmol) was used in place of WD-R17-3 in example 1, step (4). 92mg of XA-R17 were obtained as a pale yellow solid. Calculated, the yield is: 87 percent.
1H NMR(500MHz,Methanol-d4)δ11.03(s,1H),8.95(s,1H),8.22(d,J＝7.6Hz,1H),7.84(s,1H),7.45(d,J＝7.7Hz,1H),7.30(t,J＝6.4Hz,1H),7.19(t,J＝6.7Hz,1H),3.51(t,2H),2.45(t,2H),2.28(s,6H),1.94–1.86(m,2H).
13C NMR(126MHz,Methanol-d4)δ191.37,164.24,160.79,158.63,157.44,141.55,137.02,127.42,126.22,124.03,123.62,118.59,117.61,112.70,57.80,45.13,38.69,27.90.
HRMS[ESI]:calcd for(M+H)+(C24H24N4O2)requires m/z 401.1972,found 401.1971.
Example 10
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) the 2, 4-dichloropyrimidine in example 1, step (1) was replaced with 2, 4-dichloro-5-fluoro-pyrimidine (333.9mg, 2.0 mmol). 382mg of a pale yellow product F-R17-1 are obtained
1H NMR(400MHz,Methanol-d4)δ7.90(d,J＝3.5Hz,1H),3.52(t,J＝7.0Hz,2H),2.47(t,J＝7.3Hz,2H),2.32(s,6H),1.91–1.84(m,2H).
(2) F-R17-1(232.7mg, 1.0mmol) was used in place of WD-R17-1 in example 1, step (2). 310mg of intermediate F-R17-2 are obtained
ESI-MS：m/z＝414.2[M+l]+。
(3) F-R17-2(165.3mg, 0.4mmol) was used in place of WD-R17-2 in example 1, step (3). 105mg of intermediate F-R17-3 are obtained
ESI-MS：m/z＝314.2[M+l]+。
(4) F-R17-3(94.0mg,0.3mmol) was used in place of WD-R17-3 in example 1, step (4). 86mg of F-R17 were obtained as a pale yellow solid. The calculated yield was 84%.
1H NMR(500MHz,Methanol-d4)δ11.05(s,1H),8.29(d,J＝7.9Hz,1H),8.11(d,J＝3.4Hz,1H),7.53(d,J＝8.2Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝7.6Hz,1H),3.60(t,J＝7.1Hz,2H),2.45(t,J＝7.6Hz,2H),2.26(s,6H),1.87(p,J＝7.2Hz,2H).
13C NMR(126MHz,Methanol-d4)δ191.75,154.38(d,J＝7.0Hz),153.41(d,J＝11.8Hz),147.38,145.32,143.80,138.43(d,J＝19.5Hz),136.54,127.19,124.39(d,J＝220.5Hz),122.98,116.96,112.69,57.67,44.94,39.40,27.35.
HRMS[ESI]:calcd for(M+H)+(C18H20N5OF)requires m/z 342.1725,found 342.1727.
Example 11
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) 2, 4-dichloro-5-trifluoromethyl-pyrimidine (433.9mg, 2.0mmol) was used instead of 2, 4-dichloropyrimidine in example 1, step (1). 487mg of pale yellow product CF3-R17-1 are obtained
1H NMR(400MHz,Methanol-d4)δ8.48(d,J＝27.0Hz,1H),3.48(q,J＝6.6Hz,2H),2.50–2.44(m,2H),2.32(s,6H),1.88–1.80(m,2H).
(2) The WD-R17-1 in example 1, step (2) was replaced with CF3-R17-1(282.7mg, 1.0 mmol). 320mg of intermediate CF3-R17-2 are obtained
ESI-MS：m/z＝464.2[M+l]+。
(3) The WD-R17-2 in example 1, step (3) was replaced with CF3-R17-2(185.3mg, 0.4 mmol). To yield 129mg of intermediate CF3-R17-3
ESI-MS：m/z＝364.2[M+l]+。
(4) CF3-R17-3(108.0mg,0.3mmol) was used in place of WD-R17-3 in example 1, step (4). 103mg of CF3-R17 are obtained as a pale yellow solid. The calculated yield was 88%.
1H NMR(400MHz,Methanol-d4)δ9.77(d,J＝13.5Hz,1H),8.66(d,J＝27.2Hz,1H),8.21(d,J＝7.0Hz,1H),7.48(d,J＝7.1Hz,1H),7.29(dt,J＝14.4,6.5Hz,2H),3.51–3.37(m,2H),2.44(dd,J＝18.8,7.6Hz,2H),2.26(d,J＝22.5Hz,6H),1.86–1.75(m,2H).
13C NMR(126MHz,Methanol-d4)δ186.96(d,J＝9.2Hz),163.64,157.92(d,J＝9.5Hz),144.20(d,J＝39.0Hz),137.15,125.58(d,J＝5.5Hz),125.29,δ124.91(q,J＝270.2Hz),123.73,122.22,117.19,113.68(d,J＝5.9Hz),113.43(d,J＝6.5Hz),112.66,57.40(d,J＝11.5Hz),44.62(d,J＝11.7Hz),39.98,27.06.
HRMS[ESI]:calcd for(M+H)+(C19H20N5OF3)requires m/z 392.1693,found 392.1694.
Example 12
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) 2, 4-dichloropyrimidine (297.9mg, 2.0mmol), 15mL of N, N-dimethylformamide, potassium carbonate (276.4mg, 2.0eq) and 1- (2-aminoethyl) pyrrolidine (304. mu.L, 2.4mmol) were sequentially added to a 50mL eggplant-shaped bottle, and the reaction was stirred at room temperature for 5 hours. Adding 15mL of water into the system, extracting with ethyl acetate (30 mL. times.3), combining the organic phases, washing the organic phase with saturated saline (30 mL. times.3) in sequence, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying by silica gel column chromatography,378mg of a pale yellow solid WD-3d-1 were obtained
1H NMR(400MHz,Chloroform-d)δ7.99(s,1H),6.28(s,1H),6.17(s,1H),2.79(s,2H),2.65(s,4H),2.18(d,J＝24.6Hz,2H),1.84(s,4H).
(2) WD-3d-1(226.7mg, 1.0mmol) was used in place of WD-R17-1 in example 1, step (2). 336mg of intermediate WD-3d-2 are obtained
ESI-MS：m/z＝408.2[M+l]+。
(3) WD-3d-2(168.9mg, 0.4mmol) was used in place of WD-R17-2 in example 1, step (3). 108mg of intermediate WD-3d-3 are obtained
ESI-MS：m/z＝308.2[M+l]+。
1H NMR(400MHz,Methanol-d4)δ8.10(d,J＝6.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.52(d,J＝8.3Hz,1H),7.28(s,1H),7.22(t,J＝7.6Hz,1H),7.07(t,J＝7.5Hz,1H),6.38(d,J＝6.0Hz,1H),3.79(s,2H),2.85(t,J＝7.0Hz,2H),2.75(d,J＝6.0Hz,4H),1.91(t,J＝3.6Hz,4H).
(4) WD-3d-3(92.5mg,0.3mmol) was used in place of WD-R17-3 in example 1, step (4). 90mg of WD-3d are obtained as a pale yellow solid. The yield was calculated to be 90%.
1H NMR(400MHz,Methanol-d4)δ11.13(s,1H),8.35(d,J＝7.9Hz,1H),8.25(d,J＝5.9Hz,1H),7.60(d,J＝8.1Hz,1H),7.35(t,J＝8.2Hz,1H),7.28(t,J＝7.1Hz,1H),6.53(d,J＝6.0Hz,1H),3.81(s,2H),3.08(t,J＝6.5Hz,2H),2.99(s,4H),1.99–1.92(m,4H).
13C NMR(101MHz,Methanol-d4)δ190.70,184.46,162.37,157.86,154.18,143.53,135.71,126.34,124.47,122.67,122.12,116.46,111.89,54.20,53.88,38.04,22.73.
HRMS[ESI]:calcd for(M+H)+(C19H21N5O)requires m/z 336.1819,found 336.1814.
Example 13
This example provides an indole pyrimidineCompounds of the class
The specific synthesis steps are as follows:
(1) 2, 4-dichloro-5-methylpyrimidine (326.1, 2.0mmol), 15mL of N, N-dimethylformamide, potassium carbonate (276.4mg, 2.0eq), and 1- (2-aminoethyl) pyrrolidine (304. mu.L, 2.4mmol) were sequentially added to a 50mL eggplant-shaped bottle and the reaction was stirred at room temperature for 5 hours. 15mL of water was added to the system, followed by extraction with ethyl acetate (30 mL. times.3) and combination of the organic phases, which were washed successively with saturated saline (30 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to give 410mg of JJ-3d-1 as a pale yellow solid
1H NMR(400MHz,Chloroform-d)δ7.77(d,J＝1.1Hz,1H),5.80(s,1H),3.63–3.54(m,2H),2.77(t,J＝5.9Hz,2H),2.62(t,J＝2.7Hz,4H),2.00(d,J＝1.0Hz,3H),1.82(t,J＝3.6Hz,4H).
(2) Using JJ-3d-1(240.7, 1.0mmol) instead of WD-R17-1 in example 1, step (2), 351mg of JJ-3d-2 were obtained as a pale yellow solid
ESI-MS：m/z＝422.2[M+l]+。
(3) Using JJ-3d-2(168.6, 0.4mmol) instead of WD-R17-2 in example 1, step (3), 105mg of JJ-3d-3 as a pale yellow solid
ESI-MS：m/z＝322.2[M+l]+
1H NMR(500MHz,Methanol-d4)δ7.96(s,1H),7.58(d,J＝8.0Hz,1H),7.47(d,J＝8.3Hz,1H),7.20(s,1H),7.17(t,J＝7.7Hz,1H),7.02(t,J＝7.5Hz,1H),3.96(t,J＝6.5Hz,2H),3.21(t,J＝6.5Hz,2H),3.12(s,4H),2.10(s,3H),1.97(p,J＝3.2Hz,4H).
13C NMR(126MHz,Methanol-d4)δ162.02,157.97,153.48,138.11,136.91,129.47,123.70,121.67,120.28,113.01,112.22,103.65,55.50,54.86,38.55,23.54,13.16.
(4) JJ-3d-3(92.5mg,0.3mmol) was used in place of WD-R17-3 in example 1, step (4). 89mg of JJ-3d was obtained as a pale yellow solid. The calculated yield was 85%.
1H NMR(400MHz,Methanol-d4)δ11.11(s,1H),8.32(d,J＝7.9Hz,1H),8.06(s,1H),7.57(d,J＝8.1Hz,1H),7.32(t,J＝7.5Hz,1H),7.25(t,J＝7.5Hz,1H),3.78(t,J＝7.0Hz,2H),2.79(t,J＝7.0Hz,2H),2.66(d,J＝6.1Hz,4H),2.11(s,3H),1.86(q,J＝3.5Hz,4H).
13C NMR(101MHz,Methanol-d4)δ191.61,161.89,156.76,153.97,144.94,136.61,127.32,125.26,123.55,122.99,117.03,115.15,112.83,55.21,54.86,39.10,23.67,13.42.
HRMS[ESI]:calcd for(M+H)+(C20H23N5O)requires m/z 350.1975,found 350.1966.
Example 14
This example provides an indole pyrimidine compound
The specific synthesis steps are as follows:
(1) 2, 4-dichloro-5-ethylpyrimidine (354.5mg, 2.0mmol), 15mL of N, N-dimethylformamide, potassium carbonate (276.4mg, 2.0eq), and 1- (2-aminoethyl) pyrrolidine (304. mu.L, 2.4mmol) were sequentially added to a 50mL eggplant-shaped bottle, and the reaction was stirred at room temperature for 5 hours. 15mL of water was added to the system, followed by extraction with ethyl acetate (30 mL. times.3) and combination of the organic phases, which were washed successively with saturated brine (30 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 423mg of a pale yellow solid E1-1
1H NMR(400MHz,Methanol-d4)δ7.70(s,1H),3.62(t,J＝6.9Hz,2H),2.73(t,J＝6.9Hz,2H),2.67–2.62(m,4H),2.40(q,J＝7.5Hz,2H),1.81(p,J＝3.2Hz,4H),1.17(t,J＝7.5Hz,3H).
(2) Replacement of WD-R17-1 in example 1, step (2) with E1-1(254.8mg, 1.0mmol) gave 372mg of E1-2 as a pale yellow solid
ESI-MS：m/z＝436.2[M+l]+。
(3) Replacement of WD-R17-2 in example 1, step (3) with E1-2(174.6, 0.4mmol) gave 116mg of E1-3 as a pale yellow solid
ESI-MS：m/z＝336.2[M+l]+
1H NMR(500MHz,Methanol-d4)δ7.95(s,1H),7.57(d,J＝7.8Hz,1H),7.47(d,J＝8.1Hz,1H),7.20(s,1H),7.16(t,J＝7.5Hz,1H),7.02(t,J＝7.3Hz,1H),3.92(t,J＝5.9Hz,2H),3.15(d,J＝6.9Hz,2H),3.05(s,4H),2.48(p,J＝6.6,5.6Hz,2H),1.93(s,4H),1.23(t,J＝7.4Hz,3H).
(4) E1-3(100mg,0.3mmol) was used instead of WD-R17-3 in example 1, step (4). 90mg of E1 were obtained as a pale yellow solid. The calculated yield was 83%.
1H NMR(500MHz,Methanol-d4)δ11.08(s,1H),8.30(d,J＝7.5Hz,1H),8.05(s,1H),7.55(d,J＝7.6Hz,1H),7.30(t,J＝7.0Hz,1H),7.23(t,J＝6.6Hz,1H),3.80(t,J＝5.3Hz,2H),2.97–2.91(m,2H),2.84(s,4H),2.49(q,J＝6.2,5.2Hz,2H),1.90(s,4H),1.25(t,J＝6.2Hz,3H).
13C NMR(101MHz,Methanol-d4)δ191.41,161.13,156.50,152.42,144.78,136.44,127.12,125.06,123.35,122.79,120.08,116.88,112.58,55.10,54.64,39.25,23.52,21.03,11.88.
HRMS[ESI]:calcd for(M+H)+(C21H25N5O)requires m/z 364.2132,found 364.2134.
Example 15
This example provides an indole pyrimidine compound 6JJ-3d
The synthetic route is as follows:
(1) 2, 4-dichloro-6-methylpyrimidine (326.2mg, 2.0mmol) was used instead of 2, 4-dichloropyrimidine in example 12, step (1). 360mg of a pale yellow solid 6JJ-3d-1 are obtained
1H NMR(400MHz,Methanol-d4)δ6.26(s,1H),3.60–3.52(m,2H),2.74(t,J＝6.7Hz,2H),2.67(s,4H),2.23(s,3H),1.84(t,J＝3.6Hz,4H)。
(2) Replacement of WD-R17-1 in example 1, step (2) with 6JJ-3d-1(240.7mg, 1.0mmol) gave 372mg of 6JJ-3d-2 as a pale yellow solid
ESI-MS：m/z＝422.2[M+l]+。
(3) Using 6JJ-3d-2(168.6, 0.4mmol) instead of WD-R17-2 in example 1, step (3), 116mg of 6JJ-3d-3 as a pale yellow solid
ESI-MS：m/z＝322.2[M+l]+
1H NMR(400MHz,Methanol-d4)δ7.58(d,J＝8.0Hz,1H),7.47(d,J＝8.2Hz,1H),7.27(s,1H),7.17(t,J＝7.6Hz,1H),7.02(t,J＝7.5Hz,1H),6.24(s,1H),3.82(s,2H),3.11(t,J＝6.3Hz,2H),3.04(s,4H),2.35(s,3H),1.94(s,4H).
13C NMR(126MHz,Methanol-d4)δ164.89,163.86,159.69,138.13,136.92,129.42,123.81,121.77,120.27,112.26,104.24,102.59,55.54,54.82,38.52,23.56,22.86.
(4) 6JJ-3d-3(96.4mg,0.3mmol) was used in place of WD-R17-3 in example 1, step (4). 71mg of 6JJ-3d as a pale yellow solid were obtained. The calculated yield is 68 percent
1H NMR(500MHz,Methanol-d4)δ11.12(s,1H),8.32(d,J＝7.9Hz,1H),7.57(d,J＝8.1Hz,1H),7.31(t,J＝7.4Hz,1H),7.25(t,J＝7.4Hz,1H),6.36(s,1H),3.76(s,2H),3.04(t,J＝6.8Hz,2H),2.96(s,4H),2.39(s,3H),1.94(s,4H).
13C NMR(126MHz,DMSO-d6)δ189.59,163.37,162.32,157.13,142.62,135.45,126.05,124.26,122.59,121.84,116.07,112.91,103.69,59.74,54.91,53.27,37.49,23.49,22.83.
HRMS[ESI]:calcd for(M+H)+(C20H23N5O)requires m/z 350.1975,found 350.1975.
Example 16
This example provides an indole pyrimidine compound MY2
The specific synthesis steps are as follows:
(1) 5-bromo-2, 4-dichloropyrimidine (911.5mg, 4.0mmol) was used in place of 2, 4-dichloropyrimidine in example 1, step (1). 970mg of MY2-1 as a pale white solid are obtained
1H NMR(500MHz,Methanol-d4)δ8.24(s,1H),3.88(t,J＝5.8Hz,2H),3.47(t,J＝5.9Hz,2H),3.21(q,J＝7.3Hz,4H),2.12(s,4H).
(2) Mixing MY2-1(611.2mg, 2.0mmol), phenylboronic acid (243.8mg, 1.0eq), and K2CO3(552.8mg, 2.0eq) and tetrakis (triphenylphosphine) palladium (115.6mg, 0.05eq) were charged in a 50mL round bottom flask, then water (1mL) and 1, 4-dioxane (15mL) were added, argon was replaced (three times), the temperature was raised to 90 ℃ and the reaction was refluxed for 8 hours. After the reaction is finished, the reaction solution is filtered by diatomite, the filtrate is decompressed and concentrated, and then 342mg of light yellow intermediate MY2-2 is obtained by silica gel column chromatography separation and purification
1H NMR(400MHz,Methanol-d4)δ7.76(s,1H),7.52–7.47(m,2H),7.44(d,J＝7.1Hz,1H),7.41–7.38(m,2H),3.57(t,J＝6.7Hz,2H),2.68(t,J＝6.8Hz,2H),2.59(s,4H),1.81–1.76(m,4H).
(3) MY2-2(302.8mg, 1.0mmol) was used instead of WD-R17-1 in example 1, step (2). 353mg of MY2-3 was obtained as a dark red solid
ESI-MS：m/z＝484.2[M+l]+
(4) MY2-3(193.3mg, 0.4mmol) was used instead of WD-R17-2 in example 1, step (3). 126mg of a pale yellow solid QZ6-4 were obtained
1H NMR(500MHz,Methanol-d4)δ7.95(s,1H),7.58(d,J＝8.0Hz,1H),7.50–7.46(m,3H),7.42(d,J＝7.4Hz,3H),7.27(s,1H),7.17(t,J＝7.3Hz,1H),7.02(t,J＝7.5Hz,1H),3.77(t,J＝7.0Hz,2H),2.77(t,J＝7.0Hz,2H),2.67(s,4H),1.82(s,4H).
(5) MY2-4(114.9mg,0.3mmol) was used in place of WD-R17-3 in example 1, step (4). This gave 81mg of MY2 as a pale yellow solid. The calculated yield is 66 percent
11H NMR(400MHz,Methanol-d4)δ11.09(s,1H),8.28(d,J＝7.9Hz,1H),8.03(s,1H),7.52(d,J＝8.1Hz,1H),7.49–7.45(m,2H),7.43–7.38(m,3H),7.26(t,J＝7.3Hz,1H),7.19(t,J＝7.5Hz,1H),3.67(t,J＝6.8Hz,2H),2.79(t,J＝6.8Hz,2H),2.71–2.67(m,4H),1.82–1.78(m,4H).
13C NMR(101MHz,Methanol-d4)δ191.55,160.26,157.44,154.08,144.09,136.51,134.65,129.79,129.26,129.00,127.16,125.20,123.40,122.90,119.77,117.28,112.66,54.81,54.44,39.51,23.54.
HRMS[ESI]:calcd for(M+H)+(C25H25N5O)requires m/z 412.2132,found 412.2132.
Example 17
This example provides an indole pyrimidine compound QZ17, which is synthesized as follows:
the specific preparation process is as in example 1, and the QZ17 characterization data obtained by the preparation method are as follows: HRMS [ ESI ]: calcd for (M + H) + (C19H20N5OF) requires M/z 354.1725, found 354.1724.
Example 18
This example provides an indole pyrimidine compound QZ18, which is synthesized as follows:
Effect example 1: activity measurement of indole pyrimidine compounds
1.1 Effect of indole pyrimidines on triglyceride levels in adipocytes
3T3-L1 preadipocytes in logarithmic growth phase and 5.0 x 104 cells/hole are evenly inoculated to a 48-hole plate, a cell culture box is used for standing culture, and the culture solution is replaced every two days. When the cells are fused at a growth rate of 80%, the culture medium is replaced, the cells are cultured for 2 days until the cells are completely fused (Day 0), the DMEM complete culture medium containing the differentiation inducing liquid I (the DMEM culture medium containing 10% FBS and 1% double antibody) is replaced, and the temperature is 37 ℃ and the CO content is 5%2The cells were cultured for 3 days (Day 3). After 3 days, the culture was continued for 3 days by replacing the DMEM complete medium containing the differentiation-inducing liquid II (Day 6). For the drug intervention group, DMEM complete culture medium containing differentiation-inducing solution was used as a diluent to dilute the drug solution to a certain concentration, and Day 0 and Day 3 were added together. The blank control group and the differentiation control group are added with DMSO solutions with equal volumes respectively. At Day 6, photographs were taken of oil red O staining and triglyceride content analysis. 500mM IBMX stock: 1g of IBMX powder was dissolved in 9mL of DMSO solution and dispensed, and stored at-20 ℃.
(1) Preparation of differentiation-inducing liquid
Differentiation-inducing liquid i: contains 500 μ M3-isobutyl-1-methyl-xanthine, 100ng/mL dexamethasone, 2 μ g/mL pancreas
DMEM complete culture solution of insulin
Differentiation-inducing liquid ii: DMEM complete medium containing 2. mu.M insulin containing the elicitor.
(2) Oil red O dyeing
When the cells are induced to differentiate to Day 6, the cells are rinsed for 1 time by precooled PBS, and 4% frozen paraformaldehyde fixing solution is used at room temperature
Fixing for 60 min. Dyeing is carried out for 30min at room temperature by using 0.3% oil red O dyeing working solution. Deionized water rinsing 2-3 times at room temperature and photographing by an inverted microscope (40 times). And respectively adding 300uL of isopropanol solution into each hole, gently shaking a shaking table to extract the oil red O dye at room temperature for 30min, and respectively transferring 100 mu M dye solution to perform absorbance detection at 510 nm.
(3) Analysis of triglyceride content
After cell differentiation was complete, pre-chilled PBS was rinsed 2 times to remove PBS, and deionization with 0.2% Triton X-100 was added
Standing the solution at room temperature for 1h, collecting cell suspension, performing ultrasonic disruption for 10min to fully crack cells, centrifuging to collect supernatant, and determining the content of triglyceride according to the specification of the triglyceride detection kit.
(4) Analysis of results
Triglyceride content analysis was expressed by differentiation control as "triglyceride containing control", i.e. compound triglyceride content/differentiation control content 100%. The experimental results are the average of three independent experiments, and the results are statistically analyzed according to the average +/-standard deviation.
(5) Results of the experiment
FIG. 1 is a graph showing the lipid-lowering effect of indole pyrimidines provided in some embodiments of the present invention, wherein A represents the lipid-lowering activity of the indole pyrimidines, and B represents the oil red O staining pattern after the indole pyrimidines act. As shown in figure 1, compounds such as WD-R17, JJ-R17, E2, J3, 6JJ-R17, MY2 and the like can effectively inhibit the maturation process of fat cells at the concentration of 1 mu M and reduce the content of lipid in the cells (A in figure 1), which indicates that the indole pyrimidine compounds provided by the embodiment of the invention have better lipid-lowering effect at low concentration; the oil red O staining result shows that compared with a differentiated control group cell, the content of lipid in the cell of the indole pyrimidine compound treated group prepared by the embodiment of the invention is obviously reduced (B in figure 1), and the experimental result shows that the indole pyrimidine compound provided by the application has a good lipid-lowering effect.
FIG. 2 is a graph showing the results of half maximal effect concentration of the indole pyrimidine compound MY2 prepared in example 16. As shown in figure 2, compared with the differentiated control group cells, the indole pyrimidine compound MY2 can reduce the intracellular lipid content level in a concentration gradient-dependent manner, and the half effective concentration of the indole pyrimidine compound MY2 is 0.041 mu M.
1.2 effects of MY2 on the high-fat high-cholesterol diet-induced body weight and associated glycolipid metabolic syndrome in obese mice
(1) Constructing and identifying an obese mouse model: male C57BL/6 mice (18-20 g in weight) at 8 weeks of age were fed either high fat high cholesterol (HFC, containing 60% fat and 1.2% cholesterol, purchased from Research die, usa under cat number D12492) or normal Diet (supplied by the university of zhongshan at eastern school district laboratory animals center) for 10 weeks. When the body weight of the HFC diet mouse is 1.2 times of that of the normal diet mouse, the establishment of the obese mouse model is considered to be successful.
(2) Aspartic acid: preparing MY2 solution with the concentration of 1mg/mL by using physiological saline;
(3) MY2 intervention treatment: the HFC diet mice were randomly divided into two groups (HFC control group and MY2 dosing group), with 10 mice per group. Normal diet mice continued to be fed with normal diet, and HFC group and MY2 group mice continued to be fed with HFC diet. Wherein, MY2 group is administered by intragastric administration MY2 solution at 10mg/kg dose. Mice were treated every two days, and food intake and body weight were observed and recorded. After 3 weeks of administration, mice were tested for glucose tolerance. The mice are fasted for 6 hours, glucose solution (2g/L) is injected into the abdominal cavity, and the blood sugar change of the mice is detected at 0, 15, 30, 60, 90 and 120 minutes after the injection; after 5 weeks of administration, mice were tested for insulin resistance. The mice are fasted for 6 hours, insulin solution (0.6U/kg) is injected into the abdominal cavity, and the blood sugar change of the mice is detected at 0, 15, 30, 60, 90 and 120 minutes after the injection; all mice were bled at 7 weeks of anaesthesia after dosing and sacrificed and dissected by cervical dislocation and the weight of each group of mice, liver and adipose tissue was recorded.
(4) Centrifuging the blood sample of the mouse for 10min at 3000 r, taking the supernatant, and detecting indexes such as glucose, fatty acid, triglyceride and the like in the serum. Liver tissue specimens from mice were histopathologically analyzed to assess the protection of MY2 treatment for non-alcoholic steatohepatitis.
FIG. 3 is a graph showing the effect of a mouse administered an indole pyrimidine compound MY2, wherein A represents the weight change curve of the mouse during administration, B represents the weight of the mouse at the end of administration, and C represents the content of white adipose tissue and the total amount of white adipose in the main part of the mouse. As can be seen in fig. 3, oral administration of MY2 in mice was effective in inhibiting the development of long-term HFC diet-induced obesity in mice (a in fig. 3). After 7 weeks of administration, mice in the MY2 group lost approximately 29.6% of body weight compared to control mice (B in fig. 3). The quantification of white adipose tissue in vivo shows that MY2 can significantly reduce the total amount of white adipose tissue (tWAT) and the content of white adipose tissue in various parts, such as subcutaneous white adipose tissue (sWAT), gonadal white adipose tissue (iWAT), perirenal white adipose tissue (pWAT), abdominal white adipose tissue (eWAT), and the like.
As can be seen from fig. 4, glucose (a in fig. 4), insulin (B in fig. 4), triglycerides (C in fig. 4), free fatty acids (D in fig. 4), and high density lipoprotein/low density lipoprotein ratio (E in fig. 4) were decreased in blood of mice of MY2 group compared to mice of HFC control group; in contrast, the MY2 group mice had increased glucose tolerance (F in fig. 4) and insulin sensitivity (G in fig. 4); MY2 is indicated to treat obesity-related glycolipid metabolism syndrome.
As can be seen from fig. 5, MY2 significantly improved mouse liver size (a in fig. 5), reduced liver lipid content (B in fig. 5) compared to HFC control mice; serum AST (glutamic-oxaloacetic transaminase) and ALT (glutamic-pyruvic transaminase) assays indicated that MY2 could significantly ameliorate obesity-induced liver injury (C and D in fig. 5). The eosin/hematoxylin staining and the oil red O staining prove that MY2 can protect the liver and reduce the lipid drop content of the liver; the detection result of interleukin 6 shows that MY2 can treat liver inflammation; results of dyeing experiments of sirius red and masson show that MY2 can treat liver fibrosis of mice (E in FIG. 5). The results show that MY2 can treat nonalcoholic steatohepatitis.
The MY2 compound is used in the examples of the effect of treating nonalcoholic steatohepatitis, and the indole pyrimidines provided by the application all have the same mother ring structure
According to the research results, the volume of the T group and the electron donating group/electron donating group only have certain influence on the electron cloud density of the pyrimidine ring, but the indole pyrimidine parent nucleus of the compound has the same structure and the same contribution to the activity, so other compounds can also realize the effect of treating nonalcoholic steatohepatitis.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (9)
1. An indole pyrimidine compound is characterized in that the structural formula of the indole pyrimidine compound is shown as the formula (I):
wherein L is at least one selected from H, halogen and alkyl,
q is NH, and the catalyst is the reaction product of the catalyst,
x is NH or-CONH, n is 2 or 3,
r is N (CH)3)2Or
T is selected from at least one of H, OH, halogen, halogenated alkyl, aryl and pyridine,
the alkyl is C1-C4 alkyl, the aryl is phenyl, and the halogenated alkyl is C1-C4 halogenated alkyl.
2. An indole pyrimidine compound according to claim 1, wherein the haloalkyl group is a fluoroalkyl group.
3. The indole pyrimidine compound according to claim 2, wherein the haloalkyl group is a C1-C3 fluoroalkyl group.
4. An indole pyrimidine compound according to claim 3, wherein the haloalkyl group is a haloalkyl groupIs CF3。
5. An indole pyrimidine compound according to claim 1, wherein the halogen is fluorine.
6. An indole pyrimidine compound, which is selected from any one of the following compounds:
7. the method for synthesizing indole pyrimidines as claimed in claim 1 or 6, which comprises the following steps:
(1) will be provided with
And
in the presence of K2CO3In a solvent system of
(2) To be generated
And
generated under the action of catalyst
Wherein W is a protecting group;
(3) to be generated
Removing W protecting group to generate
(4) To be generated
With POCl3Reaction to form
8. Use of an indole pyrimidine according to any one of claims 1 to 6 or synthesized according to the synthesis process of claim 7 in the preparation of a lipid lowering medicament and a medicament for the treatment of non-alcoholic steatohepatitis.
9. The use of claim 8, wherein the lipid-lowering agent or the agent for the treatment of non-alcoholic steatohepatitis further comprises a pharmaceutically acceptable salt or carrier.
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