CN113563310B - 4- (1-methylindol-3-yl) pyrimidine derivative and application thereof - Google Patents

4- (1-methylindol-3-yl) pyrimidine derivative and application thereof Download PDF

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CN113563310B
CN113563310B CN202110709318.7A CN202110709318A CN113563310B CN 113563310 B CN113563310 B CN 113563310B CN 202110709318 A CN202110709318 A CN 202110709318A CN 113563310 B CN113563310 B CN 113563310B
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张兴贤
陈田朋
朱高扬
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Abstract

The invention takes 4-indolyl-2-aryl amino pyrimidine as a skeleton, reasonably designs and prepares a series of 4- (1-methyl indole-3-yl) pyrimidine derivatives, and in vitro anti-inflammatory activity test results show that most compounds of the invention have better inhibition capability on inflammatory cytokines IL-6 and IL-8, and experimental results show that most compounds have inhibition effects on IL-6 and IL-8 induced by LPS in different degrees, and are basically superior to 4-indolyl-2-amino pyrimidine. The invention provides a certain research basis for further obtaining the anti-ALI micromolecules with good anti-inflammatory activity and high bioavailability.

Description

4- (1-methylindol-3-yl) pyrimidine derivative and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to 4- (1-methylindol-3-yl) pyrimidine derivatives and a medical application thereof in preparing medicines for treating inflammatory diseases such as acute lung injury and the like.
Background
Acute Lung Injury (ALI) is a common complication after sepsis in intensive care unit patients, and despite existing treatment strategies such as fluid management and protective ventilation, the mortality rate is still high due to the lack of effective drugs. It has been reported that proinflammatory and anti-inflammatory cytokines, including IL-1, IL-6, IL-8 and TNF- α, play a major role in the pathogenesis of inflammatory lung injury such as sepsis, pneumonia, aspiration and shock. Therefore, the development of novel, highly effective anti-inflammatory drugs for the treatment of acute lung injury is still imminent.
The inventor obtains a series of 4- (1-methylindol-3-yl) pyrimidine derivatives based on previous research, and biological experiments show that the compounds have certain anti-inflammatory activity and can be used for treating inflammatory diseases such as acute lung injury caused by over-expression of IL-6 or IL-8.
Disclosure of Invention
The invention provides a series of 4- (1-methylindol-3-yl) pyrimidine derivatives with anti-inflammatory activity and application thereof in preparing medicaments for treating inflammatory diseases such as acute lung injury and the like.
In order to achieve the purpose, the technical scheme of the invention is as follows:
in a first aspect, the invention provides a 4- (1-methylindol-3-yl) pyrimidine derivative shown as a formula (I) and pharmaceutically acceptable salts thereof,
Figure GDA0003763074410000011
in the formula (I), R is selected from C 1 -C 6 Alkyl, unsubstituted or substituted five-or six-membered aromatic heterocycle, unsubstituted or substituted aromatic ring; the substituted five-membered or six-membered aromatic heterocycle is C 1 -C 4 Alkyl, halogen, C 1 -C 4 Alkoxy, cyano or trifluoromethyl substituted five-or six-membered aromatic heterocycle; the substituted aromatic ring is a benzene ring substituted by one or more of amino, halogen, alkoxy, alkyl, cyano and trifluoromethyl.
Preferably, in the formula (I), C is 1 -C 6 The alkyl is selected from n-butyl, isopropyl, cyclopropyl and cyclohexyl.
Preferably, in formula (I), the substituted or unsubstituted five-or six-membered aromatic heterocycle is selected from pyrimidinyl, pyridinyl, methyl-substituted pyrazolyl.
Preferably, the structure of the 4- (1-methylindol-3-yl) pyrimidine derivative is selected from any one of the following formulas:
Figure GDA0003763074410000023
specifically, the method is one of the following steps:
Figure GDA0003763074410000022
Figure GDA0003763074410000031
in a second aspect, the invention also provides application of the 4- (1-methylindol-3-yl) pyrimidine derivative shown in the formula (I) and pharmaceutically acceptable salts thereof in preparing medicines for treating inflammation-related diseases.
Preferably, the 4- (1-methylindol-3-yl) pyrimidine derivative is a compound 3a1, 3a2, 3a3, 3a4, 2a6, 2a7, 2a8 or 2a9.
More preferably, the 4- (1-methylindol-3-yl) pyrimidine derivative is a compound 3a2.
The 4- (1-methylindol-3-yl) pyrimidine derivatives and pharmaceutically acceptable salts thereof have anti-inflammatory activity, but some compounds (when R is an amino group-containing benzene ring) have poor solubility, and the solubility can be increased by using the salts.
The pharmaceutically acceptable salt of the 4- (1-methylindol-3-yl) pyrimidine derivative shown in the formula (I) is formed by salifying the 4- (1-methylindol-3-yl) pyrimidine derivative and acid, wherein the acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid and succinic acid. Preferably, the pharmaceutically acceptable salt of the 4- (1-methylindol-3-yl) pyrimidine derivative shown in the formula (I) is a hydrochloride compound of the 4- (1-methylindol-3-yl) pyrimidine derivative shown in the formula (I).
Preferably, the invention provides the application of the 4- (1-methylindol-3-yl) pyrimidine derivatives and pharmaceutically acceptable salts thereof in preparing medicines for treating inflammation-related diseases through inhibiting the release of IL-6 or IL-8.
Specifically, the etiology of the inflammation-related disease is at least partially caused by inflammation, and particularly, the inflammation-related disease is caused by inflammation. Such inflammation-related disorders include, but are not limited to, the following: sepsis, pneumonia, hepatitis, rheumatoid arthritis, systemic lupus erythematosus, asthma, viral myocarditis, acute respiratory distress syndrome, pancreatitis, systemic inflammatory response syndrome, septicemia, ulcerative colitis, bronchitis, infectious endocarditis, and autoimmune diseases.
Preferably, the inflammation-related disease includes: sepsis, pneumonia, hepatitis, rheumatoid arthritis, asthma, acute respiratory distress syndrome, pancreatitis, systemic inflammatory response syndrome, sepsis, autoimmune disease.
In a third aspect, the 4- (1-methylindol-3-yl) pyrimidine derivatives and the pharmaceutically acceptable salts thereof are prepared by the following method:
A.R is C 1 -C 6 Process for preparing alkyl 4- (1-methylindol-3-yl) pyrimidine derivatives
Figure GDA0003763074410000051
Cesium carbonate (1.5mmol, 1.5equiv.), the compound of formula 1 (1.0mmol, 1.0equiv.), tris (dibenzylideneacetone) dipalladium (0.05mmol, 0.05equiv.), BINAP (0.1mmol, 0.1equiv.), and NH at room temperature 2 R (1.2 mmol,1.2 equiv.) in 1,4-dioxane (10 mL) in N 2 Heating to 110 ℃ under protection and reacting for 12h; cooling the obtained reaction liquid to room temperature, adding water for dilution, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (using dichloromethane/methanol with the volume ratio of 35-40; wherein R is C 1 -C 6 An alkyl group.
B.R is unsubstituted or substituted 4- (1-methylindol-3-yl) pyrimidine derivatives of five-membered or six-membered aromatic heterocyclic ring
Figure GDA0003763074410000052
Cesium carbonate (1.5mmol, 1.5equiv.), 1 (1.2mmol, 1.2equiv.), tris (dibenzylideneacetone) dipalladium (0.05mmol, 0.05equiv.), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.1mmol, 0.1equiv.), and NH at room temperature 2 R (1.0mmol, 1.0equiv.) in 1,4-dioxane (10 mL), N 2 Heating to 110 ℃ under protection and reacting for 12h; cooling the obtained reaction liquid to room temperature, adding water for dilution, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (eluting by using dichloromethane/methanol with a volume ratio of 15-20 as an eluent), collecting eluent containing the target compound, and concentrating under reduced pressure to obtain a yellow solid 6 (the compound shown in the formula (I)), wherein R is unsubstituted or substituted five-membered or six-membered aromatic heterocycle.
Process for the preparation of 4- (1-methylindol-3-yl) pyrimidine derivatives wherein R is an unsubstituted or substituted phenyl ring (R1 is not amino)
Figure GDA0003763074410000061
Compound 1 (1.0mmol, 1.0equiv.) was added to 1,4-dioxane (20 mL) at room temperature, and stirred to dissolve, and NH was added 2 R (1.0 mmol,1.0 equiv.), 4-methylbenzenesulfonic acid hydrate or acetic acid (1.2 mmol,1.2 equiv.), and the resulting mixture was stirred at 105 ℃ for 4 hours; and carrying out aftertreatment on the obtained reaction liquid to obtain a yellow solid 2 (the compound shown in the formula (I)), wherein R is an unsubstituted or substituted benzene ring.
The post-treatment is generally: cooling the reaction solution to room temperature, performing suction filtration, and using dichloromethane for a filter cake: ethyl acetate =1:3 (V/V =1:3, 20 mL) and dried to give yellow solid 2.
The post-treatment method for the reaction solution with less solid precipitation comprises the following steps: diluting with water, extracting with dichloromethane, and extracting the organic layer with anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, purifying by silica gel column chromatography (eluting with dichloromethane/methanol at a volume ratio of 20: 1), collecting the eluate containing the target compound, and concentrating under reduced pressure to obtain target product 2.
D.R is a preparation method of 4- (1-methylindol-3-yl) pyrimidine derivatives containing amino substituted benzene ring and pharmaceutically acceptable salts thereof:
Figure GDA0003763074410000062
compound 2 (0.5mmol, 1.0equiv.) was purified by reaction with ethanol: water =3:1 (V/V =3:1, 16 mL) was stirred and dissolved, iron powder (3.0 mmol,6.0 equiv.) and ammonium chloride (0.38mmol, 0.75 equiv.) were added, the reaction solution reacted at 100 ℃ for 6h, the tlc detection reaction was complete, cooled to room temperature, the iron powder was removed by suction filtration, the filter cake was washed with dichloromethane (20 mL), the ethanol was removed by concentration under reduced pressure, water (10 mL) was added, dichloromethane was extracted, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (eluting with dichloromethane/methanol at a volume ratio of 20.
Dissolving the product 3 in dichloromethane (15 mL) at room temperature, adding excess saturated hydrogen chloride in ethanol until the pH is 2-3, stirring at room temperature until the TLC detection reaction is complete, and spin-drying to obtain a yellow solid 4.
Other salt forms can be prepared according to methods well known in the art.
Compared with the prior art, the invention has the beneficial effects that:
the invention takes 4-indolyl-2-aryl aminopyrimidine as a skeleton, reasonably designs and prepares a series of 4- (1-methyl-indolyl-3-yl) pyrimidine derivatives, and in vitro anti-inflammatory activity test results show that most of the compounds of the invention have better inhibition capability on inflammatory cytokines IL-6 and IL-8, and experimental results show that most of the compounds have inhibition effects of different degrees on IL-6 and IL-8 induced by LPS, and are basically superior to 4-indolyl-2-amino pyrimidine 2a26, the inhibition rates of 7 derivatives on IL-6 and IL-8 are both greater than 50% when the administration concentration is 5 mu M, and the inhibition activities of 12 derivatives on IL-6 and IL-8 are both superior to indomethacin contrast. 3a1, 3a2, 3a3, 3a4, 2a6, 2a7, 2a8 and 2a9 show stronger anti-inflammatory activity, and the inhibition rates of IL-6 and IL-8 are respectively 54-76% and 56-77%. Among them, 3a2 shows the best anti-inflammatory activity, and the inhibition rates of IL-6 and IL-8 at 5 mu M respectively reach 86% and 87%, which are both obviously higher than that of indomethacin serving as a positive control drug. Therefore, compound 3a2, as a head-of-shoot compound, is worth further optimization of its structure. The invention provides a certain research basis for further obtaining the anti-ALI micromolecules with good anti-inflammatory activity and high bioavailability.
Drawings
FIG. 1 shows the nuclear magnetic hydrogen spectrum of compound 3a2 obtained in example 2;
FIG. 2 is a nuclear magnetic carbon spectrum of Compound 3a2 obtained in example 2;
FIG. 3 is a graph of the biological activity of example 27 in inhibiting the release of the proinflammatory cytokine IL-6: * p <0.05, p <0.01, p <0.001, p <0.0001vs. The ordinate is the relative amount of cytokine (% compared to LPS)
FIG. 4 is a graph of the biological activity of example 27 in inhibiting the release of the proinflammatory cytokine IL-8: * p <0.05, p <0.01, p <0.001, p <0.0001vs. The ordinate is the relative amount of cytokine (% compared to LPS)
Detailed Description
In order to better illustrate the present invention, a specific synthetic route for the 4- (1-methylindol-3-yl) pyrimidine derivatives of the present invention is given in the following detailed description. It will be appreciated by those skilled in the art that the invention may be practiced using certain other synthetic routes, utilizing the structures of the claimed compounds, and that the following examples do not limit the scope of the invention. The examples do not show specific conditions, and the raw materials are conventional products commercially available, and the raw materials are not shown in manufacturers and manufacturers.
The route for synthesizing the 4- (1-methylindol-3-yl) pyrimidine derivatives is as follows:
Figure GDA0003763074410000081
example 1: synthesis of Compound 4a1
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added and dissolved with stirring, 3-nitro-4-chloroaniline (0.173g, 1.0mmol,1.0 equiv.), 4-methylbenzenesulfonic acid hydrate (0.207g, 1.2mmol, 1.2equiv.) were added, and the resulting mixture was stirred at 105 ℃ for 4 hours. Cooling to room temperature, suction filtering, and adding dichloromethane to a filter cake: ethyl acetate =1:3 (V/V =1:3, 20 mL) and dried to give 0.327g of yellow solid 2a1 with a yield of 86%.
Compound 2a1 (0.190g, 0.5mmol,1.0 equiv.) was added to a 50mL round bottom flask at room temperature, and the mixture was purified by ethanol: water =3:1 (V/V =3:1, 16 mL) was dissolved with stirring, and iron powder (0.168g, 3.0mmol,6.0 equiv.) and ammonium chloride (0.020g, 0.38mmol, 0.75equiv.) were added. The reaction solution was reacted at 100 ℃ for 6 hours. The reaction was completed by TLC, cooled to room temperature, and then iron powder was removed by suction filtration, the filter cake was washed with dichloromethane (20 mL), and then concentrated under reduced pressure to remove ethanol, water (10 mL) was added, and then extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (using dichloromethane/methanol at a volume ratio of 20.
The product 3a1 is added into a 50mL round-bottom flask at room temperature, dissolved by 15mL dichloromethane, added with excess saturated hydrogen chloride ethanol solution until the pH is 2-3, the solution becomes turbid, stirred at room temperature until the TLC detection reaction is complete, and dried by spinning to obtain 0.143g yellow solid 4a1 with the yield of 99%.
Figure GDA0003763074410000091
4-Chloro-N 1 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benz ene-1,3-diamine(3a1):yellow oil； 1 H NMR(400MHz, DMSO-d 6 )δ9.32(s,1H),8.65(d,J＝7.8Hz,1H),8.33(d,J＝ 5.4Hz,1H),8.29(s,1H),7.52(d,J＝8.0Hz,1H),7.43(d,J＝ 2.4Hz,1H),7.29-7.21(m,2H),7.18(d,J＝5.4Hz,1H),7.12(d, J＝8.7Hz,1H),7.07(dd,J＝8.7,2.4Hz,1H),5.27(s,2H),3.88(s,3H). 13 C NMR (100MHz,DMSO-d 6 )δ162.6,160.5,157.2,144.9,140.9,138.1,133.3,129.0,126.0, 122.9,122.7,121.4,113.0,110.8,110.4,109.4,107.7,106.4,33.5.
Example 2: synthesis of Compound 4a2
Compound 1 (0.244g, 1.0mmol,1.0 equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added thereto and dissolved with stirring, 4-methyl 3-nitroaniline (0.152g, 1.0mmol,1.0 equiv.), 4-methylbenzenesulfonic acid hydrate (0.207g, 1.2mmol,1.2 equiv.) were added, and the resulting mixture was stirred at 105 ℃ for 4 hours. Cooling to room temperature, suction filtering, and adding dichloromethane to a filter cake: ethyl acetate =1:3 (V/V =1:3, 20 mL) and oven dried to give 0.323g yellow solid 2a2, 90% yield.
Compound 2a2 (0.180g, 0.5mmol,1.0 equiv.) was added to a 50mL round bottom flask at room temperature, and the mixture was purified by ethanol: water =3:1 (V/V =3:1, 16 mL) was dissolved with stirring, and iron powder (0.168g, 3.0mmol,6.0 equiv.) and ammonium chloride (0.020g, 0.38mmol, 0.75equiv.) were added. The reaction solution was reacted at 100 ℃ for 6 hours. The reaction was completed by TLC, cooled to room temperature, and then iron powder was removed by suction filtration, the filter cake was washed with dichloromethane (20 mL), and then concentrated under reduced pressure to remove ethanol, water (10 mL) was added, and then extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (using dichloromethane/methanol at a volume ratio of 20.
The product 3a2 is added into a 50mL round-bottom flask at room temperature, dissolved by 15mL dichloromethane, added with excess saturated hydrogen chloride ethanol solution until the pH is 2-3, the solution becomes turbid, stirred at room temperature until the TLC detection reaction is complete, and dried by spinning to obtain 0.148g yellow solid 4a2 with the yield of 99%.
Figure GDA0003763074410000092
4-Methyl-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benze ne-1,3-diamine(3a2):yellow oil； 1 H NMR(400MHz, Chloroform-d)δ8.53(dd,J＝6.6,2.3Hz,1H),8.34(d,J＝5.3Hz, 1H),7.74(s,1H),7.52(s,1H),7.38-7.36(m,1H),7.34-7.29(m, 3H),7.04(d,J＝8.0Hz,1H),7.00(d,J＝5.3Hz,1H),6.93(dd,J＝8.0,2.2Hz,1H), 3.80(s,3H),3.63(s,2H),2.19(s,3H). 13 C NMR(100MHz,Chloroform-d)δ162.4, 160.4,157.1,145.0,138.9,138.0,131.3,130.6,126.1,122.6,122.2,121.3,116.5, 114.1,110.2,109.8,107.7,106.7,33.3,16.9.
Example 3: synthesis of Compound 4a3
Compound 1 (0.244g, 1.0mmol,1.0 equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added thereto and dissolved with stirring, and 4-nitroaniline (0.166g, 1.2mmol,1.2 equiv.), acetic acid (0.300g, 5.0mmol,5.0 equiv.) were added. The reaction mixture was stirred at 110 ℃ for 16h. Cooled to room temperature, filtered, the filter cake washed with 15mL ethyl acetate and dried to give 0.224g of yellow solid 2a3 in 65% yield.
Compound 2a3 (0.173g, 0.5mmol,1.0 equiv.) was added to a 50mL round bottom flask at room temperature, quenched with ethanol: water =3:1 (V/V =3:1, 16 mL) was dissolved with stirring, and iron powder (0.168g, 3.0mmol,6.0 equiv.) and ammonium chloride (0.020g, 0.38mmol, 0.75equiv.) were added. The reaction solution was reacted at 100 ℃ for 6 hours. The reaction was completed by TLC, cooled to room temperature, and then iron powder was removed by suction filtration, the filter cake was washed with dichloromethane (20 mL), and then concentrated under reduced pressure to remove ethanol, water (10 mL) was added, and then dichloromethane was extracted, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (using dichloromethane/methanol at a volume ratio of 20.
The product 3a3 is added into a 50mL round-bottom flask at room temperature, dissolved by 15mL dichloromethane, added with excess saturated hydrogen chloride ethanol solution until the pH is 2-3, the solution becomes turbid, stirred at room temperature until the TLC detection reaction is complete, and dried by spinning to obtain 0.131g yellow solid 4a3 with the yield of 98%.
Figure GDA0003763074410000101
N 1 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,4- diamine(3a3):yellow solid；mp 164-166℃； 1 H NMR(400 MHz,DMSO-d 6 )δ8.90(s,1H),8.59(d,J＝8.0Hz,1H),8.23 (d,J＝5.9Hz,2H),7.50(d,J＝8.2Hz,1H),7.42(d,J＝8.6 Hz,2H),7.27-7.23(m,1H),7.18-7.14(m,1H),7.05(d,J＝ 5.3Hz,1H),6.59(d,J＝8.6Hz,2H),4.80(s,2H),3.86(s,3H). 13 C NMR(100MHz, DMSO-d 6 )δ162.4,161.1,157.3,144.1,138.0,132.9,130.5,126.1,123.1,122.59, 122.3,121.1,114.4,113.2,110.7,106.5,33.4.
Example 4: synthesis of Compound 4a4
Cesium carbonate (0.489g, 1.5mmol,1.5equ v.), 1 (0.293g, 1.2mmol,1.2equ v.), tris (dibenzylideneacetone) dipalladium (0.046 g,0.05mmol, 0.05equ v.), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.058g, 0.11mmol, 0.1equ v.) and 2-nitroaniline (0.058g, 1.0mmol,1.0equ v.) were charged to a25 mL round-bottomed flask at room temperature. 1,4-dioxane (10 mL), N was added 2 Protecting, and heating to 110 ℃ for reaction for 12h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 40.
Compound 2a4 (0.173g, 0.5mmol,1.0 equiv.) was added to a 50mL round bottom flask at room temperature, and the mixture was quenched with ethanol: water =3:1 (V/V =3:1, 16 mL) was dissolved with stirring, and iron powder (0.168g, 3.0mmol, 6.0equiv.) and ammonium chloride (0.020g, 0.38mmol, 0.75equiv.) were added. The reaction solution was reacted at 100 ℃ for 6 hours. The reaction was completed by TLC, cooled to room temperature, and then iron powder was removed by suction filtration, the filter cake was washed with dichloromethane (20 mL), and then concentrated under reduced pressure to remove ethanol, water (10 mL) was added, and then extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (using dichloromethane/methanol at a volume ratio of 20.
The product 3a4 is added into a 50mL round-bottom flask at room temperature, dissolved by 15mL dichloromethane, added with excess saturated hydrogen chloride ethanol solution until the pH is 2-3, the solution becomes turbid, stirred at room temperature until the TLC detection reaction is complete, and dried by spinning to obtain 0.115g yellow solid 4a4 with the yield of 99%.
Figure GDA0003763074410000111
N 1 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2-diam ine(3a4):yellow solid；mp 220-222℃； 1 H NMR(400MHz, DMSO-d 6 )δ8.45(d,J＝7.8Hz,1H),8.37(d,J＝2.9Hz,1H), 8.24-8.21(m,2H),7.49-7.42(m,2H),7.22(t,J＝7.3Hz,1H), 7.10-7.05(m,2H),6.93(t,J＝7.6Hz,1H),6.81-6.79(m,1H),6.64 (t,J＝7.6Hz,1H),4.89(s,2H),3.85(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ 162.7,161.7,157.5,142.8,138.0,133.0,126.2,126.2,126.1,125.2,123.3,122.6, 121.1,116.7,116.2,113.1,110.6,106.7,33.5.
Example 5: synthesis of Compound 2a5
Compound 1 (0.244g, 1.0mmol,1.0 equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added thereto and stirred to dissolve, and 2-methoxyaniline (0.148g, 1.2mmol,1.2 equiv.), acetic acid (0.300g, 5.0mmol,5.0 equiv.) were added. The reaction mixture was stirred at 110 ℃ for 16h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 30.
Figure GDA0003763074410000112
N-(2-methoxyphenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-a mine(2a5):white solid；mp 106-109℃； 1 H NMR(400MHz, DMSO-d 6 )δ8.48-8.45(m,1H),8.34(d,J＝5.4Hz,1H),8.29(d,J ＝7.1Hz,2H),7.99(s,1H),7.52(d,J＝8.3Hz,1H),7.29-7.25(m, 1H),7.22(d,J＝5.5Hz,1H),7.19-7.17(m,1H),7.07-6.99(m, 3H),3.88(s,3H),3.88(s,3H). 13 C NMR(125MHz,Chloroform-d)δ162.3,160.2, 157.2,148.0,138.0,131.4,129.8,126.0,122.6,121.9,121.4,121.3,120.8,118.9, 114.1,110.0,109.8,108.1,55.7,33.3.
Example 6: synthesis of Compound 2a6
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added thereto and dissolved with stirring, and 4-fluoroaniline (0.133g, 1.2mmol, 1.2equiv.), acetic acid (0.300g, 5.0mmol, 5.0equiv.) were added. The reaction mixture was stirred at 110 ℃ for 16h. Cooled to room temperature, filtered, the filter cake washed with 15mL ethyl acetate and dried to give 0.277g of a yellow solid 2a6 in 87% yield.
Figure GDA0003763074410000121
N-(4-fluorophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine(2a6):yellow solid；mp 194-196℃； 1 H NMR(400MHz,DMSO-d 6 )δ9.45(s, 1H),8.61(d,J＝7.9Hz,1H),8.34(d,J＝5.3Hz,1H),8.28(s, 1H),7.86(dd,J＝9.0,4.9Hz,2H),7.53(d,J＝8.0Hz,1H), 7.30-7.15(m,5H),3.88(s,3H). 13 C NMR(100MHz,DMSO-d 6 ) δ162.7,160.5,157.5(J C-F ＝236.0Hz),157.3,138.1,137.8(J C-F ＝2.4Hz),133.3, 126.0,122.8,122.7,121.3,121.2(J C-F ＝7.5Hz),115.3(J C-F ＝21.9Hz),113.0,110.8, 107.8,33.5.
Example 7: synthesis of Compound 2a7
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added and dissolved with stirring, 4-chloroaniline (0.153g, 1.2mmol, 1.20equiv.), acetic acid (0.300g, 5.0mmol, 5.0equiv.) were added. The reaction mixture was stirred at 110 ℃ for 16h. Cooled to room temperature, filtered, the filter cake washed with 20mL ethyl acetate and dried to give 0.208g of a yellow solid 2a7 in 62% yield.
Figure GDA0003763074410000122
N-(4-chlorophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ami ne(2a7):yellow solid；mp 176-178℃； 1 H NMR(400MHz, DMSO-d 6 )δ9.92(s,1H),8.52(d,J＝7.9Hz,1H),8.42(s,1H), 8.34(d,J＝5.7Hz,1H),7.86-7.82(m,2H),7.55(d,J＝8.1Hz, 1H),7.43-7.39(m,2H),7.31-7.27(m,2H),7.24-7.20(m,1H), 3.89(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ163.8,158.6,154.4,139.4,138.2, 134.8,128.9,126.1,126.0 123.0,122.75,122.0,121.8,112.7,111.1,107.8,33.7.
Example 8: synthesis of Compound 2a8
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added and dissolved with stirring, 4-methoxyaniline (0.148g, 1.2mmol,1.2 equiv.), acetic acid (0.300g, 5.0mmol, 5.0equiv.) were added. The reaction mixture was stirred at 110 ℃ for 16h. Cooled to room temperature, filtered, the filter cake washed with 20mL ethyl acetate and dried to give 0.271g of yellow solid 2a8 in 82% yield.
Figure GDA0003763074410000123
N-(4-methoxyphenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin -2-amine(2a8):yellow solid；mp 113-115℃； 1 H NMR(400 MHz,DMSO-d 6 )δ10.15(s,1H),8.55(s,1H),8.38(s,1H), 8.24(d,J＝5.5Hz,1H),7.58(d,J＝8.0Hz,2H),7.53(d,J＝ 7.9Hz,1H),7.30-7.26(m,2H),7.16(t,J＝7.4Hz,1H),7.00(d,J＝8.1Hz,2H), 3.88(s,3H),3.79(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ165.3,156.6,156.5, 150.0,138.3,136.6,131.6,125.9,124.2,123.4,123.0,122.2,114.5,112.5,111.3, 106.6,55.8,33.9.
Example 9: synthesis of Compound 2a9
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added and dissolved with stirring, and 4-trifluoromethylaniline (0.193g, 1.2mmol,1.2 equiv.), acetic acid (0.300g, 5.0mmol, 5.0equiv.) were added. The reaction mixture was stirred at 110 ℃ for 16h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 30.
Figure GDA0003763074410000131
4-(1-Methyl-1H-indol-3-yl)-N-(4-(trifluoromethyl)phenyl)py rimidin-2-amine(2a9):white solid；mp 192-194℃； 1 H NMR (400MHz,DMSO-d 6 )δ9.89(s,1H),8.63(d,J＝7.2Hz,1H), 8.41(d,J＝5.4Hz,1H),8.34(s,1H),8.11(d,J＝8.5Hz,2H), 7.67(d,J＝8.5Hz,2H),7.54(dd,J＝7.7,1.2Hz,1H), 7.31-7.22(m,3H),3.89(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ162.8,160.1 157.3,145.2,138.2,133.6,126.2(J C-F ＝3.7Hz),125.3(J C-F ＝269.1Hz),126.0, 122.8,122.7,121.4,121.2(J C-F ＝31.4Hz),118.7,112.8,110.9,108.7,33.5.
Example 10: synthesis of Compound 2a10
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added and dissolved with stirring, and 3-chloroaniline (0.153g, 1.2mmol, 1.2equiv.), acetic acid (0.300g, 5.0mmol, 5.0equiv.) were added. The reaction mixture was stirred at 110 ℃ for 16h. Cooled to room temperature, filtered, the filter cake washed with 20mL ethyl acetate and dried to give 0.131g of yellow solid 2a10 in 39% yield.
Figure GDA0003763074410000132
N-(3-Chlorophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ami ne(2a10):yellow solid；mp 172-173℃； 1 H NMR(400MHz, DMSO-d 6 )δ9.69(s,1H),8.65(d,J＝7.8Hz,1H),8.39(d,J＝5.4 Hz,1H),8.33(s,1H),8.20(s,1H),7.70(d,J＝7.8Hz,1H),7.54(d, J＝7.9Hz,1H),7.35-7.21(m,4H),7.01(d,J＝7.8Hz,1H),3.89(s, 3H). 13 C NMR(100MHz,DMSO-d 6 )δ162.8,160.2,157.2,143.0,138.1,133.6, 133.5,130.5,126.0,122.8,121.5,121.0,118.6,117.7,112.8,110.9,108.3,33.6.
Example 11: synthesis of Compound 2a11
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added and dissolved with stirring, and 3-cyanoaniline (0.142g, 1.2mmol,1.2 equiv.), acetic acid (0.300g, 5.0mmol, 5.0equiv.) were added. The reaction mixture was stirred at 110 ℃ for 16h. Cooling to room temperature, diluting with water, extracting with dichloromethane, combining the organic phases, concentrating, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 25:1 as eluent), collecting the eluate containing the target compound, and concentrating under reduced pressure to obtain 0.068g of white solid 2a11 with a yield of 21%.
Figure GDA0003763074410000141
3-((4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)benzonitrile (2a11):white solid；mp 187-189℃； 1 H NMR(400MHz,DMSO-d 6 ) δ9.83(s,1H),8.62(d,J＝7.2Hz,1H),8.49(t,J＝1.9Hz,1H),8.41 (d,J＝5.4Hz,1H),8.33(s,1H),8.04-8.01(m,1H),7.56-7.50(m, 2H),7.40(d,J＝7.7Hz,1H),7.31-7.23(m,3H),3.89(s,3H). 13 C NMR(100MHz, DMSO-d 6 )δ162.8,160.1,157.3,142.3,138.1,133.7,130.3,126.0,124.8,123.8, 122.8,122.6,121.6,121.5,119.7,112.8,111.8,110.9,108.6,33.6.
Example 12: synthesis of Compound 2a12
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added thereto and dissolved with stirring, and 3-fluoroaniline (0.133g, 1.2mmol, 1.2equiv.), acetic acid (0.300g, 5.0mmol, 5.0equiv.) were added. The reaction mixture was stirred at 110 ℃ for 16h. Cooled to room temperature, filtered, the filter cake washed with 20mL ethyl acetate and dried to give 0.134g of yellow solid 2a12 in 42% yield.
Figure GDA0003763074410000142
N-(3-Fluorophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amin e(2a12):yellow solid；mp 228-230℃； 1 H NMR(400MHz, DMSO-d 6 )δ10.98(s,1H),8.69(s,1H),8.33(d,J＝6.8Hz,2H), 7.68-7.64(m,1H),7.56(d,J＝8.2Hz,1H),7.51-7.45(m,1H),7.41 (d,J＝7.0Hz,2H),7.30(t,J＝7.6Hz,1H),7.16(t,J＝7.8Hz,1H),7.08-7.03(m, 1H),3.89(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ166.5,162.7(J C-F ＝240.9Hz), 154.2,147.0,139.7(J C-F ＝10.5Hz),138.6,138.4,131.0(J C-F ＝9.4Hz),125.8,123.8, 122.7,122.6,118.3(J C-F ＝2.8Hz),112.3,111.6,111.3,109.5(J C-F ＝25.2Hz),107.4, 34.1.
Example 13: synthesis of Compound 2a13
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added and dissolved with stirring, 4-methoxyaniline (0.148g, 1.2mmol,1.2 equiv.), acetic acid (0.300g, 5.0mmol, 5.0equiv.) were added. The reaction mixture was stirred at 110 ℃ for 16h. Cooled to room temperature, filtered, the filter cake washed with 20mL ethyl acetate and dried to give 0.264g of yellow solid 2a13 with a yield of 80%.
Figure GDA0003763074410000143
N-(3-methoxyphenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-a mine(2a13):yellow solid；mp 143-146℃； 1 H NMR(400MHz, DMSO-d 6 )δ10.82(s,1H),8.59(s,1H),8.31(d,J＝8.0Hz,1H), 8.27(d,J＝6.5Hz,1H),7.46(d,J＝8.2Hz,1H),7.35-7.28(m, 3H),7.25(t,J＝7.6Hz,1H),7.18(dd,J＝7.9,1.9Hz,1H),7.11(t,J＝7.5Hz,1H), 6.79(dd,J＝8.3,2.5Hz,1H),3.82(s,3H),3.76(s,3H). 13 C NMR(100MHz, DMSO-d 6 )δ166.3,160.2,154.3,146.8,139.0,138.4,138.1,130.1,125.7,123.6, 122.9,122.5,114.7,112.4,111.3,110.3,108.5,106.9,55.6,33.9.
Example 14: synthesis of Compound 2a14
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added and dissolved with stirring, 3-trifluoromethylaniline (0.161g, 1.0mmol,1.0 equiv.), 4-methylbenzenesulfonic acid hydrate (0.207g, 1.2mmol, 1.2equiv.) were added, and the resulting mixture was stirred at 105 ℃ for 4 hours. Cooling to room temperature, suction filtering, and adding dichloromethane to a filter cake: ethyl acetate =1:3 (20 mL) and dried to give 0.192g of white solid 2a14 in 52% yield.
Figure GDA0003763074410000151
4-(1-Methyl-1H-indol-3-yl)-N-(3-(trifluoromethyl)phenyl)pyrimi din-2-amine(2a14):white solid；mp 164-165℃； 1 H NMR(400 MHz,DMSO-d 6 )δ9.83(s,1H),8.61(d,J＝8.0Hz,1H),8.38(d,J ＝31.1Hz,3H),8.03(t,J＝15.2Hz,1H),7.62-7.38(m,2H), 7.38-6.92(m,4H),3.89(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ162.8,160.2, 157.4,142.3,138.1,133.6,130.0,129.8(J C-F ＝31.0Hz),126.0,124.9(J C-F ＝270.7 Hz),122.8,122.72,122.68,121.4,117.6(J C-F ＝3.9Hz),115.0(J C-F ＝3.5Hz),112.8, 110.9,108.5,33.6.
Example 15: synthesis of Compound 2a15
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added and dissolved with stirring, p-aminobenzoic acid (0.137g, 1.0mmol,1.0 equiv.), 4-methylbenzenesulfonic acid hydrate (0.207g, 1.2mmol, 1.2equiv.) were added, and the resulting mixture was stirred at 105 ℃ for 4 hours. Cooling to room temperature, suction filtering, and adding dichloromethane to a filter cake: ethyl acetate =1:3 (20 mL) and dried to give 0.207g of yellow solid 2a15 in 60% yield.
Figure GDA0003763074410000152
3-((4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)benzoic acid(2a15):yellow solid；mp 230-232℃； 1 H NMR(400MHz, DMSO-d 6 )δ11.08(s,1H),8.70(s,1H),8.32(d,J＝6.1Hz,2H), 8.22(d,J＝8.0Hz,1H),7.83(t,J＝7.4Hz,2H),7.59(t,J＝7.9 Hz,1H),7.54(d,J＝8.2Hz,1H),7.41(d,J＝6.7Hz,1H),7.28(t,J＝7.7Hz,1H), 7.11(t,J＝7.6Hz,1H),3.88(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ167.5,166.8, 153.8,146.2,138.8,138.5,137.9,132.1,129.7,127.1,126.0,125.7,123.8,122.9, 122.7,112.3,111.5,107.1,34.1.
Example 16: synthesis of Compound 2a16
Compound 1 (0.244g, 1.0mmol, 1.0equiv.) was added to a 50mL round-bottomed flask at room temperature, 20mL of 1, 4-dioxane was added and dissolved with stirring, p-aminophenylacetic acid (0.151g, 1.0mmol,1.0 equiv.), 4-methylbenzenesulfonic acid hydrate (0.207g, 1.2mmol, 1.2equiv.) were added, and the resulting mixture was stirred at 105 ℃ for 4 hours. Cooling to room temperature, suction filtration, filtration of the filter cake with dichloromethane: ethyl acetate =1:3 (20 mL) was washed and dried to give 0.287g of yellow solid 2a16 in 80% yield.
Figure GDA0003763074410000161
2-(3-((4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)pheny l)acetic acid(2a16):yellow solid；mp 245-248℃； 1 H NMR(400 MHz,DMSO-d 6 )δ9.54(s,1H),8.62(d,J＝7.8Hz,1H),8.35(d, J＝5.4Hz,1H),8.30(s,1H),7.91(t,J＝1.9Hz,1H),7.72-7.69 (m,1H),7.53-7.51(m,1H),7.31-7.26(m,2H),7.26-7.23(m,1H),7.21(d,J＝5.4Hz, 1H),6.94-6.91(m,1H),3.87(s,3H),3.61(s,2H). 13 C NMR(100MHz,DMSO-d 6 )δ 173.3,162.7,160.2,156.9,141.2,138.2,135.7,133.6,128.9,126.0,122.9,122.8, 122.7,121.4,120.5,118.1,113.0,110.9,107.7,41.7,33.5.
Example 17: synthesis of Compound 2a17
Cesium carbonate (0.489g, 1.5mmol,1.5equ v.), 1 (0.293g, 1.2mmol,1.2equ v.), tris (dibenzylideneacetone) dipalladium (0.046 g,0.05mmol, 0.05equ v.), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.058g, 0.1mmol,0.1equ v.) and 3-aminopyridine (0.094g, 1.0mmol,1.0equ v.) were charged to a25 mL round-bottomed flask at room temperature. 1,4-dioxane (10 mL), N was added 2 Protecting, and heating to 110 ℃ for reaction for 12h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 15.
Figure GDA0003763074410000162
4-(1-Methyl-1H-indol-3-yl)-N-(pyridin-3-yl)pyrimidin-2-amine (2a17):yellow solid；mp 181-183℃； 1 H NMR(400MHz, DMSO-d 6 )δ9.66(s,1H),9.00(d,J＝2.6Hz,1H),8.61(d,J＝7.9 Hz,1H),8.37(d,J＝5.4Hz,1H),8.35-8.32(m,1H),8.30(s,1H), 8.19(dd,J＝4.7,1.5Hz,1H),7.52(d,J＝8.0Hz,1H),7.35(dd,J＝8.4,4.6Hz,1H), 7.30-7.16(m,3H),3.87(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ162.8,160.4, 157.3,142.4,141.4,138.12,138.09,133.4,126.0,123.8,122.8,122.7,121.4,112.8, 110.9,108.3,33.5.
Example 18: synthesis of Compound 2a18
Cesium carbonate (0.489g, 1.5mmol, 1.5equiv.), 1 (0.293g, 1.2mmol, 1.2equiv.), tris (dibenzylideneacetone) dipalladium (0.046 g,0.05mmol, 0.05 equiv.), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.058g, 0.18mmol, 0.1equiv.) and 2-aminopyridine (0.094g, 1.0mmol, 1.0v.) were added to a25 mL round bottom flask at room temperature.0 equiv.). 1,4-dioxane (10 mL), N was added 2 Protecting, and heating to 110 ℃ for reaction for 12h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 15.
Figure GDA0003763074410000171
4-(1-Methyl-1H-indol-3-yl)-N-(pyridin-2-yl)pyrimidin-2-amine (2a18):yellow solid；mp 181-183℃； 1 H NMR(400MHz,DMSO-d 6 ) δ10.03(s,1H),8.71(d,J＝7.9Hz,1H),8.45(d,J＝5.4Hz,1H), 8.42(dd,J＝8.5,1.1Hz,1H),8.39-8.37(m,1H),8.33(s,1H),7.81 -7.77(m,1H),7.52(d,J＝8.3Hz,1H),7.31-7.26(m,2H),7.23-7.19(m,1H), 7.02-6.99(m,1H),3.88(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ162.8,159.7, 157.3,154.0,148.4,138.1,138.0,133.6,126.0,123.2,122.8,121.5,117.6,113.3, 112.8,110.8,108.7,33.5.
Example 19: synthesis of Compound 2a19
Cesium carbonate (0.489g, 1.5mmol,1.5equ v.), 1 (0.293g, 1.2mmol,1.2equ v.), tris (dibenzylideneacetone) dipalladium (0.046 g,0.05mmol, 0.05equ v.), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.058g, 0.1mmol,0.1equ v.) and 2-aminopyrimidine (0.095g, 1.0mmol,1.0equ v.) were charged into a25 mL round-bottomed flask at room temperature. 1,4-dioxane (10 mL), N was added 2 Protecting, and heating to 110 ℃ for reaction for 12h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 15.
Figure GDA0003763074410000172
4-(1-Methyl-1H-indol-3-yl)-N-(pyrimidin-2-yl)pyrimidin-2-amine (2a19):yellow solid；mp 245-247℃； 1 H NMR(400MHz,DMSO-d 6 ) δ10.28(s,1H),9.26-8.96(m,1H),8.69(d,J＝4.8Hz,2H),8.43(d, J＝5.4Hz,1H),8.35(s,1H),7.51(d,J＝7.9Hz,1H),7.38(d,J＝ 5.4Hz,1H),7.28-7.20(m,2H),7.09(t,J＝4.8Hz,1H),3.88(s,3H). 13 C NMR(100 MHz,DMSO-d 6 )δ162.8,159.5,159.2,158.6,157.3,138.0,133.3,126.3,124.0, 122.8,121.4,115.3,112.9,110.5,109.7,33.5.
Example 20: synthesis of Compound 2a20
Cesium carbonate (0.489g, 1.5mmol,1.5equ v.), 1 (0.293g, 1.2mmol,1.2equ v.), tris (dibenzylideneacetone) dipalladium (0.046 g,0.05mmol, 0.05equ v.), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.058g, 0.1mmol,0.1equ v.) and N-methyl 3-aminopyrazole (0.097g, 1.0mmol,1.0equ v.) were charged at room temperature into a25 mL round-bottomed flask. 1,4-dioxane (10 mL), N was added 2 Protecting, and heating to 110 ℃ for reaction for 12h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 20 as an eluent), collecting the eluate containing the target compound, and concentrating under reduced pressure to obtain 0.198g of yellow solid 2a20 with a yield of 65%.
Figure GDA0003763074410000181
4-(1-Methyl-1H-indol-3-yl)-N-(1-methyl-1H-pyrazol-3-yl) pyrimidin-2-amine(2a20):yellow solid；mp 211-213℃； 1 H NMR(400MHz,DMSO-d 6 )δ9.67(s,1H),8.69(d,J＝ 8.0Hz,1H),8.31(d,J＝5.3Hz,1H),8.26(s,1H),7.59(d,J ＝2.2Hz,1H),7.51(d,J＝8.2Hz,1H),7.28-7.24(m,1H), 7.20-7.16(m,1H),7.14(d,J＝5.4Hz,1H),6.65(d,J＝2.2 Hz,1H),3.87(s,3H),3.80(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ162.6,160.3, 157.4,149.0,138.1,133.0,131.1,126.1,123.2,122.6,121.23,113.2,110.7,107.2, 97.4,38.8,33.5.
Example 21: synthesis of Compound 2a21
Cesium carbonate (0.489g, 1.5mmol,1.5equ v.), 1 (0.293g, 1.2mmol,1.2equ v.), tris (dibenzylideneacetone) dipalladium (0.046 g,0.05mmol, 0.05equ v.), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.058g, 0.1mmol,0.1equ v.) and 1-methyl-5 aminopyrazole (0.097g, 1.0mmol,1.0equ v.) were charged at room temperature into a25 mL round-bottomed flask. Adding 1,4-dioxane (10 mL), N 2 Protecting, and heating to 110 ℃ for reaction for 12h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 20 as eluent), collecting the eluate containing the target compound, and concentrating under reduced pressure to obtain 0.243g of yellow solid 2a21 with a yield of 80%.
Figure GDA0003763074410000182
4-(1-Methyl-1H-indol-3-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimi din-2-amine(2a21):yellow solid；mp>250℃； 1 H NMR(400 MHz,DMSO-d 6 )δ9.14(s,1H),8.46-8.05(m,3H),7.49(d,J＝8.2 Hz,1H),7.42(d,J＝1.9Hz,1H),7.26-7.20(m,2H),7.13-7.09(m, 1H),6.24(d,J＝1.9Hz,1H),3.85(s,3H),3.70(s,3H). 13 C NMR(100MHz, DMSO-d 6 )δ163.0,161.1,157.6,139.1,138.1,137.7,133.3,126.1,122.9,122.7, 121.3,112.8,110.7,107.8,100.1,35.9,33.5.HRMS(ESI):calcd.for C 17 H 17 N 6 [M+H] + 305.1509；found 305.1506.
Example 22: synthesis of Compound 2a22
Cesium carbonate (0.489g, 1.5mmol,1.5equ v.), 1 (0.244g, 1.0mmol,1.0equ v.), tris (dibenzylideneacetone) dipalladium (0.046 g,0.05mmol, 0.05equ v.), BINAP (0.062g, 0.1mmol,0.1equ v.), and n-butylamine (0.88g, 1.2mmol,1.2equ v.) were added to a25 mL round bottom flask at room temperature. 1,4-dioxane (10 mL), N was added 2 Protecting, and heating to 110 ℃ for reaction for 12h. Cooling to room temperature, addingDilution with water, extraction with dichloromethane, drying over anhydrous sodium sulfate, concentration under reduced pressure, purification by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 35:1 as eluent), collection of the eluate containing the target compound, and concentration under reduced pressure gave 0.084g of yellow solid 2a22 in 30% yield.
Figure GDA0003763074410000183
N-butyl-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine(2a22): yellow solid；mp 145-147℃； 1 H NMR(400MHz,Chloroform-d)δ8.48(d,J＝7.6 Hz,1H),8.23(d,J＝5.3Hz,1H),7.75(s,1H),7.39-7.27(m,3H),6.88(d,J＝5.3Hz, 1H),5.19(s,1H),3.85(s,3H),3.56(q,J＝6.7Hz,2H),1.74-1.67(m,2H),1.56-1.46 (m,2H),1.01(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ163.0,162.5, 157.4,138.0,132.6,126.3,122.8,122.5,121.0,113.4,110.7,105.1,41.0,33.4,31.9, 20.3,14.3.
Example 23: synthesis of Compound 2a23
Cesium carbonate (0.489g, 1.5mmol,1.5equ v.), 1 (0.244g, 1.0mmol,1.0equ v.), tris (dibenzylideneacetone) dipalladium (0.046 g,0.05mmol, 0.05equ v.), BINAP (0.062g, 0.1mmol,0.1equ v.), and isopropylamine (0.071g, 1.2mmol,1.2equ v.) were added to a25 mL round bottom flask at room temperature. 1,4-dioxane (10 mL), N was added 2 Protecting, and heating to 110 ℃ for reaction for 12h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 35.
Figure GDA0003763074410000191
N-isopropyl-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine(2a23): yellow solid；mp 159-162℃； 1 H NMR(400MHz,DMSO-d 6 )δ8.66 (s,1H),8.27-8.02(m,2H),7.48(d,J＝7.8Hz,1H),7.27-7.20(m,2H), 6.90(dd,J＝17.3,6.6Hz,2H),4.23(s,1H),3.83(s,3H),1.25(d,J＝ 6.6Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ162.6,162.3,157.4,138.0,132.7, 126.3,122.8,122.5,121.1,113.3,110.7,105.0,42.5,33.4,23.1.
Example 24: synthesis of Compound 2a24
Cesium carbonate (0.489g, 1.5mmol,1.5equ v.), 1 (0.244g, 1.0mmol,1.0equ v.), tris (dibenzylideneacetone) dipalladium (0.046 g,0.05mmol, 0.05equ v.), BINAP (0.062g, 0.1mmol,0.1equ v.), and cyclopropylamine (0.06g, 1.2mmol,1.2equ v.) were added to a25 mL round bottom flask at room temperature. 1,4-dioxane (10 mL), N was added 2 Protecting, and heating to 110 ℃ for reaction for 12h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 35.
Figure GDA0003763074410000192
N-cyclopropyl-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (2a24):yellow solid；mp 183-184℃； 1 H NMR(400MHz,DMSO-d 6 ) δ8.71(d,J＝7.9Hz,1H),8.21(s,1H),8.17(d,J＝5.3Hz,1H),7.50 (d,J＝8.0Hz,1H),7.27-7.23(m,1H),7.20-7.15(m,2H),6.99(d,J＝ 5.4Hz,1H),3.86(s,3H),2.83(tt,J＝7.1,3.6Hz,1H),0.77-0.73(m,2H),0.57-0.53 (m,2H). 13 C NMR(100MHz,DMSO-d 6 )δ163.9,162.5,157.3,138.0,132.6,126.4, 123.1,122.5,121.1,113.3,110.6,105.7,33.4,24.5,7.0.
Example 25: synthesis of Compound 2a25
Cesium carbonate (0.489g, 1.5mmol,1.5equ v.), 1 (0.244g, 1.0mmol,1.0equ v.), tris (dibenzylideneacetone) dipalladium (0.046 g,0.05mmol, 0.05equ v.), BINAP (0.062g, 0.1mmol,0.1equ v.) and cyclohexylamine (0.119g, 1.2mm, 1.5 mm.) were added to a25 mL round bottom flask at room temperatureol,1.2 equiv.). 1,4-dioxane (10 mL), N was added 2 Protecting, and heating to 110 ℃ for reaction for 12h. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, purifying by silica gel column chromatography (with dichloromethane/methanol at a volume ratio of 40.
Figure GDA0003763074410000201
N-cyclohexyl-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (2a25):yellow solid；mp 163-165℃； 1 H NMR(400MHz,DMSO-d 6 ) δ8.62(s,1H),8.21(s,1H),8.13(d,J＝5.3Hz,1H),7.50(d,J＝8.1 Hz,1H),7.27-7.23(m,1H),7.20-7.16(m,1H),6.91(d,J＝5.3Hz, 1H),6.83(d,J＝7.8Hz,1H),3.86(s,3H),2.01(s,2H),1.78(d,J＝12.3Hz,2H), 1.67-1.64(m,1H),1.39-1.17(m,6H). 13 C NMR(100MHz,DMSO-d 6 )δ162.5, 162.2,157.4,138.0,132.7,126.3,122.8,122.5,121.0,113.3,110.7,104.9,50.1,33.4, 33.1,26.0,25.5.
Comparative example 1:
to a15 mL sealed tube, compound 1 (0.292g, 1.20mmol, 1.00equiv.), aqueous ammonia (2 mL) and isopropanol (4 mL) were added, and the resulting mixture was refluxed for 36h. The cooled mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated NaCl and anhydrous Na 2 SO 4 After drying and concentration under reduced pressure to remove the solvent, the mixture was purified by silica gel column chromatography (using dichloromethane/methanol at a volume ratio of 10.
Figure GDA0003763074410000202
4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-amine(2a26):white solid；mp 216-218℃； 1 H NMR(400MHz,DMSO-d 6 )δ8.60(d,J＝7.8Hz,1H), 8.19(s,1H),8.12(d,J＝5.4Hz,1H),7.50(d,J＝8.2Hz,1H),7.27-7.23 (m,1H),7.20-7.16(m,1H),6.95(d,J＝5.3Hz,1H),6.44(s,2H),3.86 (s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ164.0,162.7,157.6,138.0,132.6,126.2, 123.0,122.5,121.0,113.1,110.7,105.6,33.4.
Example 27:
this example describes the inhibitory activity of a series of 4- (1-methylindol-3-yl) pyrimidine derivatives prepared in examples 1 to 26 on the release of inflammatory factors by Lipopolysaccharide (LPS) stimulation of human airway epithelial (HBE) cells.
The anti-inflammatory activity of the synthesized derivatives was evaluated using the LPS-induced HBE cell inflammation model. The specific method comprises the following steps: 3.5X 10 5 HBE cells were inoculated per mL in 1640 medium containing 10% FBS, cultured at 37 ℃ for 24 hours, the culture was refreshed, and the test compound (final concentration: 5. Mu.M) was added for pretreatment for 30min. Then continuously treating the mixture for 24 hours by using 100 mu g/mL LPS, collecting culture solution, and detecting the content of IL-6 and IL-8 by using an ELISA method; collecting cells to detect total protein concentration, and dividing the ELISA result by the corresponding total protein concentration to calibrate the ELISA result, wherein the content of IL-6 and IL-8 in the LPS control group is calibrated to be 100; each compound was tested in duplicate 3 times and the mean and error values were calculated.
The inhibitory activity of the tested compounds on IL-6 and IL-8 release is shown in figure 3 and figure 4, the comparative example 2a26 has no inhibitory activity on IL6 and IL-8, while most effective compounds have inhibitory effect on IL-6 and IL-8 release stimulated by LPS, 3a1, 3a2, 3a3, 3a4, 2a6, 2a7, 2a8 and 2a9 show stronger anti-inflammatory activity, and the inhibitory rate on IL-6 and IL-8 is 54-76% and 56-77% respectively. Among them, 3a2 shows the best anti-inflammatory activity, and the inhibition rates of IL-6 and IL-8 at 5 mu M respectively reach 86% and 87%, so that the compound has the potential of becoming a new anti-inflammatory drug.
The above detailed description is specific to possible embodiments of the invention, and the embodiments are not intended to limit the scope of the invention, and all equivalent implementations or modifications that do not depart from the scope of the invention should be construed as being included within the scope of the invention.

Claims (5)

1. A 4- (1-methylindol-3-yl) pyrimidine derivative and pharmaceutically acceptable salts thereof,
the structure of the 4- (1-methylindol-3-yl) pyrimidine derivative is
Figure DEST_PATH_IMAGE002
。
2. The use of the 4- (1-methylindol-3-yl) pyrimidine derivatives and their pharmaceutically acceptable salts according to claim 1 for the preparation of medicaments for the treatment of inflammatory related diseases.
3. The use of claim 2, wherein: the inflammation-related disease refers to a disease caused by inflammation.
4. The use of claim 2, wherein: the inflammation-related disease is sepsis, pneumonia, hepatitis, rheumatoid arthritis, systemic lupus erythematosus, asthma, viral myocarditis, acute respiratory distress syndrome, pancreatitis, systemic inflammatory response syndrome, septicemia, ulcerative colitis, bronchitis, or infectious endocarditis.
5. The use according to claim 2, characterized in that the use is: the 4- (1-methylindol-3-yl) pyrimidine derivative is applied to preparation of medicines for treating inflammation related diseases by inhibiting release of IL-6 or IL-8.
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