Triazine ring derivatives, processes for their preparation, their use and pdgfr kinase inhibitors

Abstract

The present application relates to the technical field of compound preparation, in particular to a triazine ring derivative, a preparation method and application thereof and a PDGFR kinase inhibitor. The structural formula of the triazine ring derivative is shown in the following: wherein R1 and R2 are respectively selected from substituted phenyl. The triazine ring derivative has an inhibiting effect on PDGFR kinase, can be used as a PDGFR kinase inhibitor, and also has an inhibiting effect on related tumors.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of compound preparation, in particular to a triazine ring derivative, a preparation method and application thereof and a PDGFR kinase inhibitor. BACKGROUND

[0002] Platelet-derived growth factor receptors (PDGFs) target malignant cells (such as glioblastoma, breast cancer, non-small cell cancer, acute leukemia, prostate cancer, etc.), vascular cells and stromal cells to regulate tumor growth, metastasis and tumor microenvironment. PDGFR inhibitors can be divided into two categories from the mechanism of action. One is an ATP competitive inhibitor, which targets the ATP binding site of PDGFR kinase and blocks the phosphorylation process. The other is a PDGF antagonist. This type of inhibitor is similar in structure to the PDGF subtypes and inhibits the binding of PDGF to PDGFR. Most PDGFR inhibitors have multi-target characteristics, leading to off-target effects in multiple cancers, and the low activity of PDGFR inhibitors also hinders their clinical research.

[0003] In view of this, the present application is proposed. SUMMARY

[0004] The present application aims to provide a triazine ring derivative, a preparation method and application thereof and a PDGFR kinase inhibitor. The triazine ring derivative provided by the embodiments of the present application has an inhibitory effect on PDGFR kinase, can be used as a PDGFR kinase inhibitor, and also has an inhibitory effect on related tumors.

[0005] The present application is implemented as follows:

[0006] In a first aspect, the present application provides a triazine ring derivative, which has the following structural formula:

[0007] wherein R1 and R2 are each selected from a substituted phenyl group.

[0008] In an optional embodiment, R1 is a monosubstituted phenyl group or a disubstituted phenyl group.

[0009] In an optional embodiment, when R1 is a monosubstituted phenyl group, the substituent group is located at the para position of the connecting bond, and the connecting bond is the position where R1 is connected to the triazine ring.

[0010] Preferably, when R1 is a monosubstituted phenyl group, the substituent group of the monosubstituted phenyl group is selected from a hydroxyl group or an alkenyl group.

[0011] Preferably, when R1 is a disubstituted phenyl group, the substituent groups are located at the para position and the meta position of the connecting bond, and the connecting bond is the position where R1 is connected to the triazine ring.

[0012] Preferably, when R1 is di-substituted phenyl, the substituents of the di-substituted phenyl are selected from the group consisting of hydroxyl and C1-C3 alkyl.

[0013] In an alternative embodiment, R1 is selected from any one of the following groups:

[0014]

[0015] In an alternative embodiment, R2 is mono-substituted phenyl;

[0016] Preferably, the substituents of R2 are located at the para position of the connecting bond, which is the position where R2 is connected to the triazine ring.

[0017] Preferably, the substituents of the mono-substituted phenyl of R2 are selected from the group consisting of halogen, aldehyde, alkoxy, amino and C1-C3 substituted alkyl, wherein the substituents of the C1-C3 substituted alkyl are selected from the group consisting of amino and hydroxyl.

[0018] In an alternative embodiment, R2 is selected from any one of the following groups:

[0019]

[0020] In a second aspect, the present application provides a method for preparing the triazine ring derivative as described in the preceding embodiments, which is synthesized by referring to the following synthesis path:

[0021]

[0022] Preferably, the step of step a comprises mixing 4,6-dichloro-1,3,5-triazine-2-amine and an aniline compound at 80-90°C to react.

[0023] Preferably, the molar ratio of 4,6-dichloro-1,3,5-triazine-2-amine to the aniline compound is 1:1.1-1.3.

[0024] Preferably, the step of step b comprises mixing the product of step a, palladium on carbon and a boronic acid compound or a boronic ester compound at 100-120°C to react.

[0025] Preferably, the molar ratio of the product of step a, the palladium on carbon and the boronic acid compound or the boronic ester compound is 1:(0.01-0.02):(1.2-1.5).

[0026] In a third aspect, the present application provides a PDGFR kinase inhibitor, which comprises the triazine ring derivative as described in the preceding embodiments.

[0027] Fourthly, the present invention provides the application of the triazine ring derivative described in the foregoing embodiments in the preparation of an antitumor drug, wherein the tumor includes breast cancer, lung adenocarcinoma, and glioma.

[0028] The present invention has the following beneficial effects: The embodiments of the present invention provide a triazine ring derivative, which has an inhibitory effect on PDGFR kinase, can be used as a PDGFR kinase inhibitor, and also has an inhibitory effect on related tumors, and can be used as a drug for treating tumors. Attached Figure Description

[0029] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0030] Fig. 1 The 1H NMR spectrum of the triazine ring derivative provided in Example 1 of this invention;

[0031] Fig. 2 The carbon NMR spectrum of the triazine ring derivative provided in Example 1 of this invention;

[0032] Fig. 3 The mass spectrum of the triazine ring derivative provided in Example 1 of this invention;

[0033] Fig. 4 The 1H NMR spectrum of the triazine ring derivative provided in Example 3 of this invention;

[0034] Fig. 5 The carbon NMR spectrum of the triazine ring derivative provided in Example 3 of this invention;

[0035] Fig. 6 This is the mass spectrum of the triazine ring derivative provided in Example 3 of the present invention. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0037] In a first aspect, the present invention provides a triazine ring derivative, the structural formula of which is shown below:

[0038] R1 and R2 are selected from substituted phenyl groups, respectively.

[0039] Specifically, R1 is a monosubstituted phenyl or a disubstituted phenyl. When it is a monosubstituted phenyl, the substituent is located at the para position of the linking bond, where the linking bond is the position where R1 is connected to the triazine ring; in this case, the substituent of the monosubstituted phenyl is selected from hydroxyl or alkenyl groups.

[0040] When it is a disubstituted phenyl, the substituents are located at the para and meta positions of the linking bond, which is the position where R1 is connected to the triazine ring; in this case, the substituents of the disubstituted phenyl are selected from hydroxyl and C1-C3 alkyl, such as methyl, ethyl and propyl.

[0041] For example, R1 is selected from any of the groups shown in the following structural formulas:

[0042]

[0043] It should be noted that the dashed lines in the above groups represent sites that are connected to the triazine ring.

[0044] Further, R2 is a monosubstituted phenyl group; the substituent of R2 is located at the para position of the linking bond, wherein the linking bond is the position where R2 is connected to the triazine ring. In this case, the substituent of the substituted phenyl group is selected from any one of halogen, aldehyde, alkoxy, amino, and C1-C3 substituted alkyl groups, wherein the substituent in the C1-C3 substituted alkyl groups is selected from amino or hydroxyl groups.

[0045] For example, R2 is selected from any of the groups shown in the following structural formulas:

[0046]

[0047] Furthermore, the triazine ring derivative is selected from any one of the compounds shown in the following structural formulas:

[0048]

[0049] The numerical designations below the above structural formulas correspond to the compound designations and structural formulas of the compounds in subsequent embodiments.

[0050] Secondly, the present invention provides a method for preparing the triazine ring derivative described in the foregoing embodiments, wherein the synthesis is carried out according to the following synthetic route:

[0051]

[0052] Specifically, step a is performed as follows: Weigh 2g of 4,6-dichloro-1,3,5-triazinecyclo-2-amine (12.2 mmol, 1 equivalent) into a reaction flask, add 2 equivalents of DIPEA and 1.1-1.2 equivalents of the corresponding aniline compound, and add anhydrous DMF solvent to dissolve the raw material. React at 80-90℃, and monitor the reaction process with TLC. The developing solvent is dichloromethane (DCM):methanol (MeOH) = 20:1. After the reaction is complete, water is added and a precipitate is formed. The filter cake obtained by vacuum filtration is washed with methanol in small amounts several times to obtain a solid product, which is then stored in a refrigerator at 4℃.

[0053] Step b is performed as follows: Weigh 1 equivalent of the product from step a into a reaction flask, and add 1.2-1.5 equivalents of a boric acid or borate ester compound, 0.01-0.02 equivalents of [1,1'-bis(diphenyltenyl)ferrocene]palladium dichloride, and 2 equivalents of potassium carbonate. Use a mixed solution of dimethyl sulfoxide and water (dimethyl sulfoxide:water = 3:1) as the solvent, and purge the reaction flask with nitrogen gas multiple times for protection. Then, place the flask at 110°C and stir the reaction. Monitor the reaction process with TLC, using DCM:MeOH = 15:1 as the developing solvent. After the reaction is complete, quench the reaction with water, extract the reaction solution multiple times with ethyl acetate, back-extract with saturated brine, remove water with anhydrous sodium sulfate, filter, add silica gel to the filtrate and evaporate to dryness, and separate the final product by silica gel column chromatography. The yield is 40%–90%.

[0054] Thirdly, the present invention provides a PDGFR kinase inhibitor comprising the triazine ring derivative described in the foregoing embodiments.

[0055] Fourthly, the present invention provides the application of the triazine ring derivative described in the foregoing embodiments in the preparation of an antitumor drug, wherein the tumor includes breast cancer, lung adenocarcinoma, and glioma.

[0056] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0057] Example 1

[0058] This invention provides a method for preparing a triazine ring derivative (compound B2), which is synthesized according to the following synthetic route:

[0059]

[0060] Specifically,

[0061] Step a:

[0062] 2 g of 4,6-dichloro-1,3,5-triazinecyclo-2-amine (12.2 mmol, 1 equivalent) was weighed into a reaction flask, and 2 equivalents of DIPEA and 1.2 equivalents of 4-aminophenol were added. Anhydrous DMF was added to dissolve the starting material. The reaction was carried out at 90 °C, and the reaction was monitored by TLC with dichloromethane:methanol = 20:1 as the developing solvent. After the reaction was complete, water was added, and a precipitate formed. The precipitate was obtained by vacuum filtration and washed with methanol in small amounts several times to obtain a solid product, which was stored at 4 °C. The yield was 70%.

[0063] Step b:

[0064] One equivalent of intermediate I was weighed and placed in a reaction flask, along with 1.5 equivalents of 4-methoxyborate pinacol ester, 0.02 equivalents of [1,1'-bis(diphenyltenyl)ferrocene]palladium dichloride, and 2 equivalents of potassium carbonate. A mixed solution of dimethyl sulfoxide and water (DMSO:water = 3:1) was used as the solvent, and nitrogen gas was repeatedly purged into the reaction flask for protection. The flask was then placed at 110°C with stirring. The reaction was monitored by TLC, with DCM:MeOH = 15:1 as the developing solvent. After the reaction was complete, water was added to quench the reaction, and the reaction solution was extracted multiple times with ethyl acetate. The solution was then back-extracted with saturated brine, and dehydrated with anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness with silica gel, and the final product B1 was obtained by silica gel column chromatography. The yield was 65%.

[0065] The characterization spectrum of compound B2 can be found in [reference needed]. Figs. 1-3 The specific data is represented as follows:

[0066] 1 H NMR(400MHz, DMSO-d6)δ9.12(d,J=18.1Hz,2H),8.36-8.15(m,2H),7.54(d,J=8.6H z,2H),7.15-6.88(m,2H),6.71(d,J=8.7Hz,2H),3.83(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 16 H 15 N5O2:310.1304; found:310.1301.

[0067] 13 C NMR (151MHz, DMSO-d6) δ170.14, 167.58, 164.96, 162.37, 153.18, 131.93, 129.87 (d, J = 44.2Hz), 122.57, 115.38, 114.06, 55.76.

[0068] Examples 2-18

[0069] Examples 2-18 each provide a triazine ring derivative, prepared using the same method as in Example 1, except that the corresponding raw materials are replaced to attach the corresponding chemical groups to the triazine ring. The characterization data of the triazine ring derivatives synthesized in Examples 2-18 are as follows:

[0070] Example 2—B1: 4-((4-amino-6-(4-chlorophenyl)-1,3,5-triazine-2-yl)amino)phenol

[0071] 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),9.13(s,1H),8.39(t,J=8.0Hz,1H),8.28(d,J=8.4Hz,1H),7.81(ddd,J= 11.6,8.8,2.7Hz,2H),7.55(td,J=11.7,10.1,7.3Hz,4H),6.72(dd,J=8.8,3.9Hz,2H).HRMS(ESI)m / z:(M+H) + calcd for C 15 H 12 ClN5O:314.0808; found:314.0809.

[0072] 13 C NMR (151MHz, DMSO) δ167.66,165.02,164.97,153.37,153.30,139.15,138.69,136.59,136.54,136.44,13 6.28,131.83,131.80,131.67,129.97,129.46,129.43,129.02,128.96,127.94,127.84,127.66,126.97.

[0073] Example 3—B3: 4-((4-amino-6-(4-(hydroxymethyl)phenyl)-1,3,5-triazine-2-yl)amino)phenol

[0074] The characterization spectrum of compound B3 is shown in [reference]. Figs. 4-6 The specific analysis is as follows: 1H NMR (400MHz, DMSO-d6) δ9.21(s,1H),9.11(s,1H),8.25(d,J=8.1Hz,2H),7.55(d,J=8.6Hz,2H),7.43(d,J=8.1 Hz,2H),6.97(s,2H),6.71(d,J=8.5Hz,2H),5.30(t,J=5.7Hz,1H),4.58(d,J=5.5Hz,2H).HRMS(ESI)m / z:(M+H) + calcd for C 16 H 15 N5O2:310.1304; found:310.1306.

[0075] 13 C NMR (151MHz, DMSO-d6) δ170.45,167.66,165.02,153.24,146.46,135.86,131.86,128.12,126.56,122.62,115.40,63.13.

[0076] Example 4—B4: 4-(4-amino-6-((4-hydroxyphenyl)amino)-1,3,5-triazin-2-yl)benzaldehyde

[0077] 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),9.36(s,1H),9.14(s,1H),8.47(d,J=8.1Hz,2H),8.12- 7.99(m,2H),7.55(d,J=8.5Hz,2H),7.14(s,2H),6.73(d,J=8.4Hz,2H).HRMS(ESI)m / z:(M+H) + calcd for C 16 H 13 N5O2:310.1304; found:308.1137.

[0078] 13 C NMR (151MHz, DMSO-d6) δ193.53,169.59,167.65,164.96,153.41,142.76,138.39,131.56,129.94,128.79,122.78,115.44.

[0079] Example 5—B5: 4-((4-amino-6-(4-aminophenyl)-1,3,5-triazine-2-yl)amino)phenol

[0080] 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.98 (s, 1H), 8.02 (d, J = 8.3Hz, 2H), 7.55 (d ,J=8.6Hz,2H),6.65(dd,J=46.4,8.4Hz,6H),5.66(s,2H).HRMS(ESI)m / z:(M+H) + calcdfor C 15 H 14 N6O:295.1307; found:295.1306.

[0081] 13 C NMR (151MHz, DMSO-d6) δ170.62,167.45,164.89,152.97,132.20,129.98,124.21,122.38,115.37,113.31.

[0082] Example 6—B6: 4-((4-amino-6-(4-(aminomethyl)phenyl)-1,3,5-triazine-2-yl)amino)phenol

[0083] 1 H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 8.24 (d, J = 7.9Hz, 2H), 7.50 (dd, J = 40.5, 8. 2Hz,5H),6.97(s,3H),6.71(t,J=8.3Hz,3H),3.80(s,2H).HRMS(ESI)m / z:(M+H) + calcd for C 16 H 16 N6O:309.1464; found:309.1457.

[0084] 13 C NMR (151MHz, DMSO-d6) δ170.65 (d, J=62.3Hz), 167.66, 165.02, 153.35, 135.59, 131.81, 128.15, 127.42, 122.60, 115.42, 45.66.

[0085] Example 7—B7: 4-((4-amino-6-(4-chlorophenyl)-1,3,5-triazin-2-yl)amino)-2-methylphenol

[0086] 1H NMR (400MHz, DMSO-d6) δ9.18(s,1H),9.00(s,1H),8.33(dd,J=40.5,8.3Hz,2H),7.57(dd,J=8.6,6.6Hz,2H ),7.41(d,J=13.8Hz,2H),7.02(s,2H),6.72(d,J=7.3Hz,1H),2.13(d,J=4.9Hz,3H).HRMS(ESI)m / z:(M+H) + calcd for C 16 H 14 ClN5O:328.0965; found:328.0959.

[0087] 13 C NMR(151MHz,DMSO-d6)δ170.83–164.51(m),151.45(d,J=9.4Hz),137.16–135.75(m),131.45(d,J=20.1Hz),129.97, 129.46, 128.92 (dd, J = 23.3, 12.0Hz), 126.96, 124.08 (d, J = 7.4Hz), 120.01 (d, J = 9.9Hz), 114.80, 16.70 (d, J = 5.4Hz).

[0088] Example 8—B8: 4-((4-amino-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl)amino)-2-methylphenol

[0089] 1 H NMR(400MHz,DMSO-d6)δ9.01(d,J=33.4Hz,2H),8.35-8.11(m,2H),7.44-7.30(m,2H),7 .12-6.98(m,2H),6.70(d,J=8.4Hz,1H),3.83(s,3H),2.13(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 17 H 17 N5O2:324.1460; found:324.1457.

[0090] 13C NMR (151MHz, DMSO-d6) δ170.12, 167.53, 164.94, 161.90 (d, J = 145.4Hz), 151.29, 136.32, 129. 81 (d, J = 65.0Hz), 124.01 (d, J = 15.6Hz), 119.87, 114.77, 113.75 (d, J = 93.4Hz), 55.77, 16.70.

[0091] Example 9—B9: 4-((4-amino-6-(4-(hydroxymethyl)phenyl)-1,3,5-triazin-2-yl)amino)-2-methylphenol

[0092] 1 H NMR (400MHz, DMSO-d6) δ9.10(d,J=16.9Hz,1H),8.98(s,1H),8.25(d,J=8.0Hz,2H),7.51-7.30(m,4H),6.95( s,2H),6.71(d,J=8.5Hz,1H),5.30(t,J=5.7Hz,1H),4.58(d,J=5.7Hz,2H),2.13(s,3H).HRMS(ESI)m / z:(M+H) + calcd for C 17 H 17 N5O2:324.1382; found:324.1458.

[0093] 13 C NMR (151MHz, DMSO-d6) δ 170.41, 167.63, 165.01, 151.36, 146.42, 135.83, 128.12, 126.57, 124.02 (d, J = 5.7Hz), 119.92, 114.78, 63.12, 16.72.

[0094] Example 10—B10: 4-(4-amino-6-((4-hydroxy-3-methylphenyl)amino)-1,3,5-triazin-2-yl)benzaldehyde

[0095] 1 H NMR (400MHz, DMSO-d6) δ10.10(s,1H),9.27(s,1H),9.03(s,1H),8.47(d,J=8.0Hz,2H),8.21-7.93 (m,2H),7.57-7.32(m,2H),7.11(s,2H),6.73(d,J=8.3Hz,1H),2.14(s,3H).HRMS(ESI)m / z:(M+H) +calcd for C 17 H 15 N5O2:322.1304; found:322.1300.

[0096] 13 C NMR(151MHz,DMSO-d6)δ193.52,169.56,167.66,164.98,151.57,142.81,13 8.39, 131.35, 129.95, 128.78, 124.10 (d, J = 10.9Hz), 120.09, 114.80, 16.72.

[0097] Example 11—B11: 4-((4-amino-6-(4-aminophenyl)-1,3,5-triazin-2-yl)amino)-2-methylphenol

[0098] 1 H NMR(400MHz,DMSO-d6)δ8.90(d,J=10.0Hz,2H),8.05-7.95(m,2H),7.45-7.3 6(m,2H),6.77-6.49(m,5H),5.66(s,2H),2.13(s,3H).HRMS(ESI)m / z:(M+H) + calcd forC 16 H 16 N6O:309.1464; found:309.1457.

[0099] 13 C NMR (151MHz, DMSO-d6) δ170.56,167.44,164.89,152.47,151.09,132.00,129.96,124.99-122.98(m),119.64,114.76,113.29,16.77.

[0100] Example 12—B12: 4-((4-amino-6-(4-(aminomethyl)phenyl)-1,3,5-triazin-2-yl)amino)-2-methylphenol

[0101] 1 H NMR (400MHz, DMSO-d6) δ9.12 (s, 1H), 8.24 (d, J = 7.9Hz, 2H), 7.55-7.28 (m, 5H), 7.23 -6.82(m,3H),6.72(d,J=8.4Hz,2H),3.81(s,2H),2.13(s,3H).HRMS(ESI)m / z:(M+H) +calcd for C 17 H 18 N6O:323.1620; found:323.1617.

[0102] 13 C NMR(151MHz,DMSO-d6)δ172.76–168.92(m),167.66,165.02,151.45,146.94,135.71 ,131.60,129.83–126.07(m),123.96,119.89,115.15(d,J=110.2Hz),45.50,16.77.

[0103] Example 13—B13: 4-(4-amino-6-((4-vinylphenyl)amino)-1,3,5-triazin-2-yl)chlorobenzene

[0104] 1 H NMR (400MHz, DMSO-d6) δ9.67(s,1H),8.36-8.26(m,2H),7.83(d,J=8.3Hz,2H),7.64-7.53(m,2H),7.42(d,J=8.4 Hz,2H),7.22(s,2H),6.69(dd,J=17.7,11.0Hz,1H),5.78-5.69(m,1H),5.19-5.12(m,1H).HRMS(ESI)m / z:(M+H) + calcd for C 17 H 14 ClN5:323.1620; found:324.1009.

[0105] 13 C NMR (151MHz, DMSO-d6) δ169.78,167.63,164.99,140.14,136.74,136.11,131.56,130.05,128.97,126.85,112.66.

[0106] Example 14—B14: 4-(4-amino-6-((4-vinylphenyl)amino)-1,3,5-triazine-2-yl)anisole

[0107] 1H NMR (400MHz, DMSO-d6) δ9.55 (s, 1H), 8.43-8.11 (m, 2H), 7.93-7.74 (m, 2H), 7.42 (d, J = 8.4Hz, 2H), 7.13-6.99 (m, 4H ),6.84-6.58(m,1H),5.73(dd,J=17.8,1.2Hz,1H),5.15(dd,J=10.9,1.1Hz,1H),3.84(s,3H).HRMS(ESI)m / z:(M+H) + calcd forC 18 H 17 N5O:320.1511; found:320.1508.

[0108] 13 C NMR(151MHz,DMSO-d6)δ170.39,167.59,164.98,162.52,140.39,136.84,131.33,12 9.82 (d, J = 85.4Hz), 126.83, 120.23, 115.63 (d, J = 169.6Hz), 114.14, 112.52, 55.79.

[0109] Example 15—B15: 4-(4-amino-6-((4-vinylphenyl)amino)-1,3,5-triazin-2-yl)benzyl alcohol

[0110] 1 H NMR (400MHz, DMSO-d6) δ9.60(s,1H),8.29(d,J=8.1Hz,2H),7.85(d,J=8.5Hz,2H),7.63(d,J=7.8Hz,1H),7.44(dd,J=14.4,8.3Hz,3H),7.13( s,2H),6.69(dd,J=17.6,10.9Hz,1H),5.76(s,1H),5.31(t,J=5.6Hz,1H),5.16(d,J=11.0Hz,1H),4.59(d,J=5.7Hz,2H).HRMS(ESI)m / z:(M+H) + calcd for C 18 H 17 N5O:320.1511; found:320.1506.

[0111] 13C NMR(151MHz,DMSO-d6)δ170.70,167.63,165.00,136.77,135.59,134.62(d,J=49.9Hz) ,131.47,128.20,126.74(d,J=32.7Hz),126.05(d,J=44.8Hz),120.29,112.66,63.10.

[0112] Example 16—B16: 4-(4-amino-6-((4-vinylphenyl)amino)-1,3,5-triazin-2-yl)benzaldehyde

[0113] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),9.74(s,1H),8.50(d,J=8.2Hz,2H),8.06(d,J=8.2Hz,2H),7.84(d,J=8.4Hz,2H),7.43( d,J=8.4Hz,2H),7.31(s,2H),6.70(dd,J=17.7,10.9Hz,1H),5.94-5.61(m,1H),5.15(t,J=12.0Hz,1H).HRMS(ESI)m / z:(M+H) + calcd for C 18 H 15 N5O:318.1355; found:318.1353.

[0114] 13 C NMR (151MHz, DMSO-d6) δ193.61,169.86,167.63,164.96,142.47,139.92,138.50,136.72,131.73,130.00,128.88,126.89,120.46,112.87.

[0115] Example 17—B17: 4-(4-amino-6-((4-vinylphenyl)amino)-1,3,5-triazine-2-yl)aniline

[0116] 1H NMR (400MHz, DMSO-d6) δ9.37(s,1H),8.04(d,J=8.7Hz,2H),7.83(d,J=8.6Hz,2H),7.40(d,J=8.5Hz,2H),6.85(s,2H ),6.60(d,J=8.6Hz,2H),6.51(d,J=8.3Hz,1H),5.72(t,J=8.9Hz,3H),5.14(d,J=11.1Hz,1H).HRMS(ESI)m / z:(M+H) + calcd forC 17 H 16 N6:305.1514; found:305.1505.

[0117] 13 C NMR (151MHz, DMSO-d6) δ170.84,167.42,164.85,152.66,140.49,136.80,136.42,131.16,130.09,126.83,123.88,120.08,113.45,112.49.

[0118] Example 18—B18: 4-(4-amino-6-((4-vinylphenyl)amino)-1,3,5-triazin-2-yl)benzylamine

[0119] 1 H NMR (400MHz, DMSO-d6) δ9.60(s,1H),8.29(d,J=8.1Hz,2H),7.85(d,J=8.4Hz,2H),7.46(dd,J=34.3,8.2Hz,5H),7.12(d,J=1 8.7Hz,3H),6.69(dd,J=17.6,11.0Hz,1H),5.73(d,J=17.7Hz,1H),5.16(d,J=11.0Hz,1H),3.88(s,2H).HRMS(ESI)m / z:(M+H) + calcd for C 18 H 18 N6:319.1671; found:319.1663.

[0120] 13 C NMR (151MHz, DMSO-d6) δ 170.77 (d, J = 28.8Hz), 167.66, 165.03, 140.31, 136.81, 135.61, 131.43, 128.26, 127.72, 126.85, 120.28, 112.60, 45.28.

[0121] Experimental Example 1

[0122] The PDGFR in vitro activity screening experiments of the triazine ring derivatives of Examples 1-18 are as follows:

[0123] Cellular drug administration: This experiment included a control group, an doxorubicin hydrochloride group, and a drug administration group. 1 μL of the prepared compound solution was added to an EP tube containing 999 μL of complete culture medium, mixed thoroughly, and labeled. The original culture medium in the 96-well plate was aspirated. 100 μL of the compound solution was added to each well of the positive control group and the drug administration group, while fresh complete culture medium was added to the control group. Each compound was administered in triplicate. After drug administration, the 96-well plate was placed in a cell culture incubator for further incubation.

[0124] Add CCK-8 reagent: After incubating the drug and cells together for 48 hours, remove the original culture medium, and then add 90 μL of complete culture medium and 10 μL of CCK-8 mixed solution to each well. Continue to incubate in the incubator for 2 hours, and then take it out to detect its absorbance.

[0125] Measurement of optical density (OD): The 96-well plate was placed in a microplate reader and the absorbance was measured at a wavelength of 450 nm. Cell viability was calculated as shown in formula (1).

[0126] Cell viability (%) = [OD experimental group - OD blank group] / [OD positive control group - OD blank group] × 100% Formula (1)

[0127] Preliminary cell viability screening: Following the procedures in the cell viability testing section, the synthesized compound was administered to four different cell types at a concentration of 10 μM and the results were measured. Compounds with a preliminary inhibition rate greater than 50% were subjected to IC50 assay. 50 test.

[0128] IC 50 Assay: Compounds with an initial inhibition rate greater than 50% were prepared at five concentrations: 10 μM, 5.0 μM, 2.50 μM, 1.25 μM, and 0.625 μM. These compounds and positive control drugs were then administered to the corresponding cells according to the above procedure, and the results were measured. Each group of experiments was performed in triplicate. The results are shown in Table 1 below.

[0129] Table 1. In vitro anti-tumor cell proliferation activity

[0130]

[0131]

[0132] As shown in Table 1 above, B2, B4, B6, B9, B10, B12, and B18 have varying degrees of inhibitory effects on the four cell types, with their IC50 values... 50 All values ​​are less than 10 μM. Among them, compound B10 has an IC50 of 131 nm for U251.

[0133] Experimental Example 2

[0134] The PDGFR kinase inhibitory effects of the triazine ring derivatives in Examples 1-18 were detected.

[0135] The kinase detection method used was ADP-Glo TM This method detects ADP formed during a kinase reaction, which is then converted into ATP, and finally, ATP is reacted with Ultra-Glo. TM Luciferase converts light into a signal, and the light emission signal is directly proportional to the kinase activity. The specific method is as follows:

[0136] Prepare 2×ATP / substrate solution and 2×kinase solution using kinase reaction buffer.

[0137] Transfer 50 nL of the compound dilution to a 384 detection plate using an Echo 655; centrifuge and add 2.5 μL of 2× kinase solution to the 384 detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0138] Add 2.5 μL of 2× substrate and ATP solution to a 384 detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes (PDGFR).

[0139] Prepare 2×XL665 and antibody detection reagents using detection buffer.

[0140] Add 5 μL of kinase assay reagent to the test plate and incubate at 25°C. Centrifuge at 1000 rpm for 1 minute and incubate at 25°C for 1 hour.

[0141] Fluorescence signals on the BMG were read at 620 nm (Cryptate) and 665 nm (XL665).

[0142] The test results are shown in Table 2 below.

[0143] Table 2 shows the inhibition rate of the compounds against PDGFR at a concentration of 10 μM.

[0144]

[0145] As shown in Table 2, triazine cyclic PDGFR inhibitors have a good inhibitory effect on PDGFRα kinase.

[0146] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A triazine ring derivative, characterized in that, Its structural formula is shown below: In this case, R1 is a disubstituted phenyl group, where the substituents are located at the para and meta positions of the linking bond; the linking bond is the position where R1 is connected to the triazine ring; the substituents in the disubstituted phenyl group of R1 are selected from hydroxyl and C1-C3 alkyl groups; R2 is a monosubstituted phenyl group; the substituent of R2 is located at the para position of the linking bond, which is the position where R2 is connected to the triazine ring; the substituent of the substituted phenyl group of R2 is selected from any one of formaldehyde group, amino group and C1-C3 substituted alkyl group, wherein the substituent in the C1-C3 substituted alkyl group is selected from amino group or hydroxyl group.

2. The triazine ring derivative according to claim 1, characterized in that, R1 is selected from any one of the groups shown in the following structural formulas: 。 3. The triazine ring derivative according to claim 1, characterized in that, R2 is selected from any one of the groups shown in the following structural formulas: , , and .

4. A triazine ring derivative, characterized in that, The triazine ring derivative is selected from any one of the compounds shown in the following structural formulas: 。 5. A method for preparing the triazine ring derivative according to claim 1, characterized in that, Perform the synthesis according to the following synthesis path: R1 and R2 refer to the groups shown in the triazine ring derivatives of claim 1 or claim 4.

6. The preparation method according to claim 5, characterized in that, Step a includes: mixing 4,6-dichloro-1,3,5-triazine-2-amine with an aniline compound and reacting the mixture at 80-90°C; The molar ratio of 4,6-dichloro-1,3,5-triazine-2-amine to aniline compounds is 1:1.1-1.3; Step b includes: mixing the product of step a, palladium on carbon, and borate or borate ester compounds and reacting them at 100-120°C; The molar ratio of the product of step a, the palladium on carbon, and the borate compound or borate ester compound is 1:(0.01-0.02):(1.2-1.5).

7. A PDGFR kinase inhibitor, characterized in that, It includes the triazine ring derivative as described in claim 1.

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