CN111057021B - S-triazine compound, preparation method and application thereof - Google Patents
S-triazine compound, preparation method and application thereof Download PDFInfo
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- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
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- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a s-triazine compound and pharmaceutically acceptable salts thereof, and experiments prove that the compound can treat or prevent diseases related to protein kinase activity, such as leukemia and lymphoma, by inhibiting Btk.
Description
Technical Field
The invention relates to a compound, a preparation method and application thereof, in particular to a s-triazine compound, a preparation method and application thereof.
Background
With the gradual increase of the morbidity and mortality of leukemia and lymphoma, great attention is paid to the research on the pathogenesis of leukemia and lymphoma and the clinical treatment thereof. Studies have shown that B-cell Receptor (BCR) signaling pathway disorders are one of the major causes of B-cell line leukemias and lymphomas. In malignant B cells, BCR pathways are abnormally active, inhibit normal differentiation and apoptosis of B cells, promote abnormal proliferation of B cells, and thus cause occurrence of various diseases such as acute lymphoblastic leukemia (Acute Lymphocytic Leukemia, ALL), waldenstrom's macroglobulinemia (Waldenstrom's Macroglobulinemia, WM), mantle cell Lymphoma (Mantle Cell Lymphoma, MCL), chronic lymphoblastic leukemia (Chronic Lymphocytic Leukemia, CLL), non-Hodgkin's lymphomas, NHL, and the like. Bruton's tyrosine kinase, btk) is an important member of the TEC Family (TFKs), expressed at various stages of B lymphocytes, a key regulator in BCR signaling pathways, and has an important impact on B cell differentiation, proliferation and apoptosis. Thus, BTK has become an important therapeutic target for B cell line related diseases.
In view of the important roles played by BTK in the development and progression of B-cell tumors, research on small molecule inhibitors targeting BTK has been attracting attention. In recent years, two irreversible BTK inhibitors have been marketed, ibutinib has been approved by the FDA for the treatment of MCL, CLL, SLL and cGVHD, and Acalabrutinib for the treatment of CLL. However, despite the great clinical success of ibutinib, its resistance remains unavoidable. It is thought that this may be because ibutinib impairs tumor adhesion and metastasis, but does not directly cause tumor cell death. Whereas the second generation of the more selective Btk inhibitor Acalabrutinib also shows drug resistance mutation soon after use. Compared with the irreversible inhibitor, the reversible inhibitor forms weaker acting force with BTK molecules in Btk specific H3 cavity through hydrogen bond, van der Waals force, hydrophobic action and the like, has better kinase selectivity, is beneficial to reducing toxicity and risk, and is more suitable for long-term administration. However, reversible inhibitors have some disadvantages such as insufficient inhibition strength, short inhibition time, resistance to H3 region mutation, etc. Therefore, the development of novel BTK inhibitors is of great significance.
Disclosure of Invention
The invention aims to: the invention aims to provide a s-triazine compound, which has a s-triazine mother nucleus. Another object of the present invention is to disclose a process for the preparation of such compounds, which is highly operable and efficient. The invention also aims to disclose the application of the compounds in preparing Bruton tyrosine kinase inhibitors and the application of the compounds in preparing medicines for treating or preventing leukemia and lymphoma.
The technical scheme is as follows: the s-triazine compound and pharmaceutically acceptable salt thereof comprise a compound with a structure shown as a general formula (I) or a general formula (II):
wherein n=1-2;
ring a is selected from aryl;
x is selected from C, N, O;
r is selected from H, cl, NH 2 ；
R 2 Selected from substituted or unsubstituted aryl, heteroaryl, R 5 O-、CH 3 O(CH2)n-、R 6 CO-、R 7 NHCO-; wherein when R is 2 Selected from heteroaryl, heteroaryl contains at least one N atom, and substituent is C1-C3 alkyl, halogen, methoxy or trifluoromethoxy; when R is 2 Selected from R 5 O-，R 5 Is a substituted or unsubstituted phenyl group, wherein the substituents are selected from methyl, methoxy; when R is 2 Selected from CH 3 O (CH 2) n-, n=1 to 4; when R is 2 Selected from R 6 CO-, wherein R 6 Is a five-membered or six-membered unsaturated heterocycle; when R is 2 Selected from R 7 NHCO-, where R 7 Is a substituted or unsubstituted aryl or heteroaryl group, wherein the heteroaryl group contains at least one heteroatom selected from N, O, S and the substituents are selected from C1-C4 alkyl, halogen, methoxy, trifluoromethoxy;
R 3 selected from H, C-C3 alkyl;
R 4 selected from R 8 CONH-, wherein R 8 Selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, saturated five-membered heterocycle, said heterocycle contains 1-3 hetero atoms selected from O, N, S;
the halogen is selected from F, cl, br, I.
The compound and pharmaceutically acceptable salts thereof:
wherein ring A is selected from phenyl;
R 2 selected from substituted or unsubstituted pyridines, R 5 O-、CH 3 O(CH2)n-、R 6 CO-、R 7 NHCO-; wherein when R is 2 Selected from substituted or unsubstituted pyridines, the substituents being methyl, halogen, methoxy or trifluoromethoxy; when R is 2 Selected from R 5 O-，R 5 Is a substituted or unsubstituted phenyl group, wherein the substituents are selected from methyl, methoxy; when R is 2 Selected from CH 3 O (CH 2) n-, n=1 to 4; when R is 2 Selected from R 6 CO-, wherein R 6 Is tetrahydropyrrole, morpholine and piperidine; when R is 2 Selected from R 7 NHCO-, where R 7 Is a substituted or unsubstituted aryl or heteroaryl group, wherein the heteroaryl group contains at least one heteroatom selected from N, O, S, and the substituents are selected from methyl, halogen, methoxy, trifluoromethoxy;
R 3 selected from H, CH 3 。
The compound and pharmaceutically acceptable salts thereof, wherein the compound is selected from the following compounds:
n- (3- ((4-amino-6- ((4-phenoxyphenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4-amino-6- ((4- (2-methoxyethoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4-chloro-6- ((4-phenoxyphenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4-chloro-6- ((4- (2-methoxyethoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4-phenoxyphenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (2-methoxyethoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (2-methoxyphenoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (morpholine-4-carbonyl) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (piperidine-1-carbonyl) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
4- ((4- ((3-acrylamidophenyl) amino) -1,3, 5-triazin-2-yl) amino) -N- (pyridin-2-yl) benzamide;
4- ((4- ((3-acrylamidophenyl) amino) -1,3, 5-triazin-2-yl) amino) -N- (5-methylpyridin-2-yl) benzamide;
n- (3- ((4- ((4- (pyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (6-methylpyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (6-methoxypyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (6-fluoropyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (6-chloropyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (2-methyl-5- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
(E) -N- (3- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) but-2-enamine;
1- (6- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) indolin-1-yl) prop-2-en-1-one;
1- (3- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) but-2-yn-1-one;
n- (3- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) thiophene-2-carboxamide.
A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims and pharmaceutically acceptable salts thereof.
The composition is prepared from the compound and pharmaceutically acceptable salt thereof according to any one of the above, and pharmaceutically acceptable auxiliary materials.
The preparation method of the compound and the pharmaceutically acceptable salt thereof comprises the following steps:
reaction conditions: (a) Michael acceptor, sodium carbonate, acetone, 0 ℃,1h; (b) ammonia water and tetrahydrofuran at 36 ℃ for 3 hours; (c) Aromatic amine, palladium acetate, 1' -bis (diphenylphosphine) ferrocene, cesium carbonate, dioxane, 110 ℃; (d) aromatic amine, sodium carbonate, acetone, 60 ℃ for 4 hours;
or:
reaction conditions: (e) Michael acceptor, N-diisopropylalanin, dioxane, room temperature, 5min; (f) Aromatic amine, palladium acetate, 1' -bis (diphenylphosphine) ferrocene, cesium carbonate, dioxane, 110 ℃ for 5h.
The application of the compound and the pharmaceutically acceptable salt thereof in preparing medicines for inhibiting Bruton tyrosine kinase.
The application of the compound and the pharmaceutically acceptable salt thereof in preparing medicines for treating or preventing leukemia.
The application of the compound and the pharmaceutically acceptable salt thereof in preparing medicaments for treating or preventing lymphoma.
In some embodiments, the compound is selected from the group consisting of
The codes of the compounds in the pharmacological experiments and experimental examples are equivalent to the structures of the compounds corresponding to the codes.
The beneficial effects are that: the s-triazine compound and the pharmaceutically acceptable salt thereof can be used for preparing a Bruton tyrosine kinase inhibitor and treating or preventing diseases related to the kinase activity. Diseases associated with protein kinase activity, such as leukemia, malignant lymphoma, are treated or prevented, for example, by inhibiting Btk.
Detailed Description
The 1H-NMR was measured by Bruker AV300 type (300 HZ) NMR (TMS is an internal standard), and the mass spectra were measured by Shimadzu GC/MS-QP2010 type mass spectrometer (EI-MS) and Agilent 100LC-MDS-Trans/SL type mass spectrometer (EI-MS), respectively.
The column chromatography silica gel is 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel (Qingdao ocean chemical plant), and the eluent is petroleum ether-ethyl acetate system or dichloromethane-methanol system. Thin Layer Chromatography (TLC) was performed using GF254 thin layer chromatography plates (smoke table Jiang You silica gel development limited); the TLC developing system is a petroleum ether-ethyl acetate system or a methylene dichloride-methanol system; TLC was shown by irradiation under a ZF7 three-purpose uv analyzer (henna, inc.). Some of the compound purities were measured at 254nm using Shimadzu HPLC, with a methanol/water system as the mobile phase.
Synthetic route
Route one
Reaction conditions: (a) Michael acceptors, sodium carbonate, acetone, 0deg.C, 1h; (b) ammonia water, tetrahydrofuran, 36 ℃ for 3 hours; (c) Aromatic amine, palladium acetate, 1' -bis (diphenylphosphine) ferrocene, cesium carbonate, dioxane, 110 ℃; (d) aromatic amine, sodium carbonate, acetone, 60 ℃ for 4h.
Route two:
reaction conditions: (e) Michael acceptor, N-diisopropylalanin, dioxane, room temperature, 5min; (f) Aromatic amine, palladium acetate, 1' -bis (diphenylphosphine) ferrocene, cesium carbonate, dioxane, 110 ℃ for 5h.
Example 1
Synthesis of intermediate N- (3-aminophenyl) acrylamide
M-nitroaniline (3 g,21.70 mmol) and sodium bicarbonate (5.02 g,32.60 mmol) were added to 20ml acetonitrile and mixed well. Acryloyl chloride (1 eq) was added dropwise under ice bath, stirred at ambient temperature for 30min, water out, suction filtered to give a white solid (3.94 g, 94.47%). 1 H NMR(300MHz,DMSO-d 6 )δ10.49(s,1H),8.57(q,J＝2.0Hz,1H),7.88–7.73(m,2H),7.49(td,J＝8.2,1.5Hz,1H),6.38–6.13(m,2H),5.70(td,J＝9.8,1.9Hz,1H)。
N- (3-nitrophenyl) acrylamide (0.5 g,2.60 mmol), reduced iron powder (0.44 g,7.80 mmol), and ammonium chloride (0.42 g,7.80 mmol) were placed in a mixed solvent of 10ml ethanol and water (1:1), and reacted at 85℃for 1h. The mixture was filtered, and the cake was washed with ethyl acetate, separated, washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure, and a yellow solid (0.37 g, 87.84%) was obtained by column chromatography. 1 H NMR(300MHz,DMSO-d 6 )δ9.78(s,1H),7.08–6.84(m,2H),6.76(d,J＝8.0Hz,1H),6.42(dd,J＝17.0,10.0Hz,1H),6.34–6.12(m,2H),5.75–5.60(m,1H),5.05(s,2H)。
Example 2
Synthesis of intermediate N- (3-amino-4-methylphenyl) acryloyl chloride
The synthesis was carried out in the same manner as in example 1 and column chromatography gave 0.47g of a white solid in 80.82% yield. 1 H NMR(300MHz,DMSO-d 6 )δ9.08(s,1H),6.70(d,J＝8.1Hz,1H),6.62(s,1H),6.37(dd,J＝17.0,10.0Hz,1H),6.19(dd,J＝8.1,2.3Hz,1H),6.07(dd,J＝17.0,2.1Hz,1H),5.56(dd,J＝10.1,2.2Hz,1H),4.75(s,2H),1.89(s,3H)。
Example 3
Synthesis of intermediate (E) -N- (3-aminophenyl) butyl-2-enamide
The synthesis was carried out in the same manner as in example 1 and the separation by column chromatography gave 0.16g of a yellow oil in 93.51% yield. 1 H NMR(300MHz,DMSO-d 6 )δ9.66(s,1H),7.01(s,1H),6.95(d,J＝15.7Hz,1H),6.80(d,J＝8.4Hz,2H),6.29(d,J＝8.0Hz,1H),6.15(d,J＝15.2Hz,1H),5.09(s,2H),1.89(d,J＝6.9Hz,3H)。
Example 4
Synthesis of intermediate N- (3-aminophenyl) butyl-2-alkynylamide
The synthesis was carried out in the same manner as in example 1 and the yellow solid was separated by column chromatography to obtain 0.83g in 97.23% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.25(s,1H),6.94–6.86(m,2H),6.65(d,J＝7.9Hz,1H),6.26(dd,J＝7.8,2.2Hz,1H),5.07(s,2H),2.01(s,3H)。
Example 5
Synthesis of intermediate N- (3-aminophenyl) thiophene-2-carboxamide
The synthesis was carried out in the same manner as in example 1 and column chromatography gave a yellow solid with a yield of 43.8%. 1 H NMR(300MHz,DMSO-d 6 )δ9.95(s,1H),8.02(d,J＝3.8Hz,1H),7.84(d,J＝5.0Hz,1H),7.22(t,J＝4.3Hz,1H),7.00(dd,J＝16.6,8.7Hz,2H),6.85(d,J＝8.0Hz,1H),6.54–6.10(m,1H),5.13(s,1H),3.39(s,1H).
Example 6
Synthesis of intermediate 1- (6-aminoindol-1-yl) propyl-2-en-1-one
The synthesis was carried out in the same manner as in example 1 and column chromatography gave a white solid with a yield of 46.20%. 1 H NMR(300MHz,DMSO-d 6 )δ7.38(s,1H),6.71(d,J＝7.7Hz,1H),6.56(s,1H),6.10(dd,J＝9.2,3.7Hz,2H),5.67–5.56(m,1H),4.89–4.77(m,2H),3.96(s,2H),2.79(s,2H)。
Example 7
Synthesis of intermediate 4- (2-methoxyethoxy) aniline
Parafluoronitrobenzene (0.5 g,3.54 mmol), ethylene glycol methyl ether (0.335 ml,4.25 mmol), potassium hydroxide (0.3 g,5.31 mmol) were added to 10ml dimethyl sulfoxide, stirred overnight at 60 ℃, water separated out, suction filtered to give 0.537g of a yellow solid with a yield of 76.9%.
Example 8
Synthesis of intermediate 4- (morpholinyl) aniline
Paranitrobenzoyl chloride (1 g,5.39 mmol) was added portionwise to an anhydrous tetrahydrofuran solution containing morpholine (0.7 g,8.08 mmol), triethylamine (1.5 eq) under ice bath, reacted for 1h, extracted with ethyl acetate and the solvent was dried to give 1.3g of a white solid in 100% yield.
The above product, reduced iron powder (3 eq) and ammonium chloride (3 eq) were placed in a mixed solvent of 10ml ethanol and water (1:1) and reacted at 85℃for 1h. The mixture was filtered, and the cake was washed with ethyl acetate, separated, washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure, and the pale yellow solid was separated by column chromatography, with a yield of 82.1%. 1 H NMR(300MHz,DMSO-d 6 )δ6.99(d,J＝8.4Hz,2H),6.41(d,J＝8.4Hz,2H),5.40(s,2H),3.44(m,J＝4.3Hz,4H),3.38–3.28(m,4H).
Example 9
Synthesis of intermediate 4- (piperidyl) aniline
The synthesis was carried out in the same manner as in example 8 and column chromatography gave a yellow solid with a yield of 84.0%. 1 H NMR(400MHz,DMSO-d 6 )δ7.09(d,J＝8.5Hz,2H),6.54(d,J＝8.5Hz,2H),5.47(s,2H),3.56–3.37(m,4H),1.60(dt,J＝11.1,5.7Hz,2H),1.48(q,J＝10.9,8.9Hz,4H).
Example 10
Synthesis of intermediate 4-amino-N- (pyridin-2-yl) benzamide
The synthesis was carried out in the same manner as in example 8 and column chromatography gave a yellow solid in 89.9% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.19(s,1H),8.35(d,J＝5.7Hz,1H),8.18(d,J＝8.4Hz,1H),7.80(m,J＝8.5Hz,3H),7.22–7.01(m,1H),6.60(d,J＝8.6Hz,2H),5.84(s,2H).
Example 11
Synthesis of intermediate 4-amino-N- (5-methylpyridin-2-yl) benzamide
The synthesis was carried out in the same manner as in example 8 and column chromatography gave a yellow solid in 89.9% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.11(s,1H),8.18(s,1H),8.08(d,J＝8.5Hz,1H),7.81(d,J＝8.5Hz,2H),7.61(dd,J＝8.5,1.8Hz,1H),6.59(d,J＝8.5Hz,2H),5.82(s,2H),2.27(s,3H).
Example 12
Synthesis of intermediate 4- (pyridin-3-yl) anilines
P-bromonitrobenzene (2 g,9.9 mmol), pyridine-3-boronic acid (1 eq), bis-triphenylphosphine palladium chloride (0.1 eq), potassium carbonate (2 eq) were added to anhydrous dioxane, nitrogen protected, reacted at 80℃for 10h, water out, suction filtered, column chromatography gave a yellow solid (1.4 g, 70%).
The above product, reduced iron powder (3 eq) and ammonium chloride (3 eq) were placed in a mixed solvent of 10ml ethanol and water (1:1) and reacted at 85℃for 1h. The mixture was filtered, and the cake was washed with ethyl acetate, separated, washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure, and the yellow solid was separated by column chromatography, with a yield of 92.4%. 1 H NMR(300MHz,DMSO-d 6 )δ8.80(s,1H),8.43(d,J＝4.6Hz,1H),7.93(d,J＝7.9Hz,1H),7.45(s,1H),7.42(s,1H),7.39(dd,J＝8.0,4.8Hz,1H),6.66(s,2H),5.37(s,2H).
Example 13
Synthesis of intermediate 4- (6-methylpyridin-3-yl) aniline
The synthesis was carried out in the same manner as in example 12 and column chromatography gave a yellow solid with a yield of 79.8%. 1 H NMR(300MHz,DMSO-d 6 )δ9.78(s,1H),8.94(d,J＝10.5Hz,1H),8.52(d,J＝8.4Hz,2H),8.37(d,J＝8.1Hz,1H),7.80(d,J＝8.4Hz,2H),4.52(s,2H),3.60(s,3H).
Example 14
Synthesis of intermediate 4- (6-methoxypyridin-3-yl) aniline
The synthesis method is the same asExample 12, column chromatography gave a yellow solid in 82.1% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.18(d,J＝2.4Hz,1H),7.69(d,J＝11.1Hz,1H),7.16(d,J＝8.4Hz,2H),6.66(d,J＝8.6Hz,1H),6.49(d,J＝8.4Hz,2H),5.07(s,1H),3.70(s,3H).
Example 15
Synthesis of intermediate 4- (6-fluoropyridin-3-yl) aniline
The synthesis was carried out in the same manner as in example 12 and column chromatography gave a yellow solid with a yield of 86.3%. 1 H NMR(300MHz,DMSO-d 6 )δ8.34(s,1H),8.06(td,J＝8.3,2.6Hz,1H),7.33(d,J＝8.4Hz,2H),7.11(dd,J＝8.5,3.0Hz,1H),6.77–6.43(m,2H),5.29(s,2H).
Example 16
Synthesis of intermediate 4- (6-chloropyridin-3-yl) aniline
The synthesis was carried out in the same manner as in example 12 and column chromatography gave a yellow solid in a yield of 81.4%. 1 H NMR(300MHz,DMSO-d 6 )δ8.55(d,J＝2.4Hz,1H),7.94(dd,J＝8.4,2.5Hz,1H),7.39(dd,J＝13.1,8.5Hz,3H),6.61(d,J＝8.4Hz,2H),5.37(s,3H).
Example 17
Synthesis of intermediate N- (3- ((4, 6-dichloro-1, 3, 5-triazin-2-yl) amino) phenyl) acrylamide
Cyanuric chloride (4.67 g,21.6 mmol) was dissolved in acetone, an acetone solution containing acrylamide (1 eq) was slowly added dropwise under ice bath, the temperature was maintained for reaction for 3.5h, water was separated out, and a white solid was obtained by suction filtration in a yield of 8.3g, 78.5%. 1 H NMR(300MHz,DMSO-d 6 )δ10.77(s,1H),10.22(s,1H),8.64(s,1H),7.97(s,1H),7.50(d,J＝5.9Hz,1H),7.42–7.21(m,2H),6.57–6.36(m,1H),6.27(d,J＝16.5Hz,1H),5.86–5.65(d,J＝10.1Hz,1H).
Example 18
Synthesis of intermediate N- (3- ((4-amino-6-chloro-1, 3, 5-triazin-2-yl) amino) phenyl) acrylamide
N- (3- ((4, 6-dichloro-1, 3, 5-triazin-2-yl) amino) phenyl) acrylamide (1 g,3.22 mmol) and 30% aqueous ammonia (1 eq) were added to a tetrahydrofuran solution and reacted at 60℃for 4h, water out and suction filtration to give 0.89g of a white solid in 89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.05(s,1H),9.88(s,1H),7.64(s,1H),7.52(m,2H),7.37(d,J＝8.5Hz,2H),7.17(t,J＝8.1Hz,1H),6.39(dd,J＝16.9,10.1Hz,1H),6.18(d,J＝17.1Hz,1H),5.76–5.61(d,J＝10.3Hz,1H).
Example 19
Synthesis of intermediate N- (3- ((4-chloro-1, 3, 5-triazin-2-yl) amino) phenyl) acrylamide
2, 4-dichloro-s-triazine (1 g,6.7 mmol) was dissolved in dioxane solution, and 4-aminophenylacrylamide (1 eq) and DIPEA (1.1 eq) were slowly added dropwise at room temperature, reacted for 5min, water separated out, and suction filtered to give 1.6g of white solid with a yield of 80.4%. 1 H NMR(400MHz,DMSO-d 6 )δ10.79(s,1H),10.24(s,1H),8.64(s,1H),7.97(d,J＝26.7Hz,1H),7.50(s,1H),7.43–7.10(m,2H),6.47(dd,J＝17.0,10.1Hz,1H),6.27(d,J＝18.9Hz,1H),5.76(d,J＝12.0Hz,1H).
Example 20
Synthesis of intermediate N- (5- ((4-chloro-1, 3, 5-triazin-2-yl) amino) -2-methylphenyl) acrylamide
The synthesis was carried out in the same manner as in example 19 and a white solid was obtained by water separation in 73% yield. 1 H NMR(300MHz,DMSO-d 6 )δ9.17(s,1H),8.93(s,1H),8.47(s,1H),7.47(s,1H),7.30(d,J＝7.5Hz,1H),7.12(dd,J＝7.5,1.6Hz,1H),6.39(dd,J＝16.8,10.1Hz,1H),5.90(dd,J＝10.1Hz,3.1Hz,1H),5.87–5.80(m,1H),1.89(s,3H).
Example 21
Intermediate (E) -N- (3- ((4-chloro-1, 3, 5-triazin-2-yl) amino) phenyl) but-2-enamine
The synthesis was carried out in the same manner as in example 19 and the yield was 78.8%. 1 H NMR(300MHz,DMSO-d 6 )δ9.92(s,1H),9.20(s,1H),8.47(s,1H),7.67(s,0H),7.31(d,J＝7.5Hz,1H),7.24(t,J＝7.5Hz,1H),7.04(d,J＝5.9Hz,1H),6.89–6.78(m,1H),6.11(d,J＝16.1Hz,1H),1.99(s,3H).
Example 22
Intermediate 1- (6- ((4-chloro-1, 3, 5-triazin-2-yl) amino) indolin-1-yl) acrylamide
The synthesis was carried out in the same manner as in example 19 and the yield was 78.2%. 1 H NMR(300MHz,DMSO-d 6 )δ8.92(s,1H),8.47(s,1H),7.49(s,1H),7.22(s,1H),7.00(s,1H),6.32(dd,J＝16.8,10.1Hz,1H),6.01–5.53(m,2H),4.30(m,J＝7.1Hz,2H),3.36–3.09(m,2H).
Example 23
Synthesis of intermediate N- (3- ((4-chloro-1, 3, 5-triazin-2-yl) amino) phenyl) but-2-ynyl amide
The synthesis was carried out in the same manner as in example 19 and the yield was 76.4%. 1 H NMR(300MHz,DMSO-d 6 )δ10.78(s,1H),10.71(s,1H),8.64(s,1H),7.95(s,1H),7.56–6.93(m,3H),3.54(s,3H).
Example 24
Synthesis of intermediate N- (3- ((4-chloro-1, 3, 5-triazin-2-yl) amino) phenyl) thiophene-2-amide
The synthesis was carried out in the same manner as in example 19 and the yield was 74.2%. 1 H NMR(300MHz,DMSO-d6)δ10.83(s,1H),10.35(s,1H),8.67(s,1H),8.07(d,J＝3.7Hz,2H),7.88(d,J＝5.0Hz,1H),7.52(d,J＝7.7Hz,1H),7.46–7.32(m,1H),7.25(t,J＝4.4Hz,1H).
Example 25
Synthesis of N- (3- ((4-amino-6- ((4-phenoxyphenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (A1)
4-aminodiphenyl ether (1 eq), DIPEA (4 eq) was added to an acetone solution containing N- (3- ((4-amino-6-chloro-1, 3, 5-triazin-2-yl) amino) phenyl) acrylamide, reacted at 80 ℃ for 24h, extracted with ethyl acetate, dried with solvent, and column chromatographed to give a white solid with a yield of 46.4%. 1 H NMR(300MHz,DMSO-d 6 )δ10.05(s,1H),9.11(s,1H),9.09(s,1H),7.82(s,2H),7.79(s,1H),7.59(s,1H),7.36(t,J＝9.2Hz,3H),7.20(t,J＝7.3Hz,1H),7.09(t,J＝7.3Hz,1H),6.94(t,J＝7.4Hz,4H),6.54(s,2H),6.49–6.34(m,1H),6.24(d,J＝13.5Hz,1H),5.71(d,J＝12.6Hz,1H). 13 C NMR(75MHz,-d6)δ167.31,165.05,164.85,163.51,158.28,150.78,140.87,139.32,136.87,132.43,130.34,128.91,127.10,123.09,121.95,119.84,117.91,116.70.HRMS(ESI)m/z calcd for C 24 H 21 N 7 O 2 [M+H] + 440.1836,found 440.1790.
Example 26
Synthesis of N- (3- ((4-amino-6- ((4- (2-methoxyethoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (A2)
The synthesis was carried out in the same manner as in example 25 and the yield was 40.4%. 1 H NMR(400MHz,DMSO-d 6 )δ10.07(s,1H),9.09(s,1H),8.89(s,1H),7.81(s,1H),7.65(d,J＝8.4Hz,3H),7.36(d,J＝7.9Hz,1H),7.21(t,J＝8.1Hz,1H),6.82(d,J＝8.8Hz,2H),6.62–6.40(m,3H),6.27(d,J＝18.6Hz,1H),5.76(d,J＝8.7Hz,1H),4.15–3.95(m,2H),3.71–3.55(m,2H),3.31(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ167.30,165.04,164.86,163.48,153.96,140.96,139.28,133.88,132.46,128.92,127.20,122.06,116.63,114.55,70.95,67.44,58.63.HRMS(ESI)m/z calcd for C 21 H 23 N 7 O 3 [M+H] + 422.1938,found 422.1896.
Example 27
Synthesis of N- (3- ((4-chloro-6- ((4-phenoxyphenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (A3)
4-Aminodiphenyl ether (1 eq) was added in portions to an acetone solution containing N- (3- ((4, 6-dichloro-1, 3, 5-triazin-2-yl) amino) phenyl) acrylamide at room temperature, triethylamine (2 eq) was added at the same time, the mixture was reacted at room temperature for 2 hours, extracted with ethyl acetate, the solvent was dried by spinning, and column chromatography was carried out to give a white solid, the yield was 62.1%. 1 H NMR(400MHz,DMSO-d 6 )δ10.31(s,1H),10.17(s,1H),7.90(s,2H),7.67(s,3H),7.48–7.17(m,1H),7.10(m,J＝7.4Hz,3H),7.05–6.77(m,1H),6.40(s,1H),6.23(s,1H),5.69(d,J＝24.4Hz,1H). 13 C NMR(75MHz,-d6)δ167.42,165.01,164.82,163.51,157.81,150.78,139.84,139.32,136.87,132.43,131.15,128.90,127.20,123.09,120.31,119.89,117.91,114.89.HRMS(ESI)m/z calcd for C 24 H 19 ClN 6 O 2 [M+H] + 459.1333,found 459.1229.
Example 28
Synthesis of N- (3- ((4-chloro-6- ((4- (2-methoxyethoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (A4)
The synthesis was carried out in the same manner as in example 27 and the yield was 57.2%. 1 H NMR(400MHz,DMSO-d 6 )δ10.25(s,1H),10.18(s,1H),10.13(s,1H),7.82(s,1H),7.71(s,1H),7.52(s,2H),7.41(s,1H),7.28(t,J＝7.6Hz,1H),6.88(d,J＝36.1Hz,2H),6.47(dt,J＝18.7,9.4Hz,1H),6.28(d,J＝16.9Hz,1H),5.77(d,J＝10.0Hz,1H),4.03(s,2H),3.64(s,2H),3.38(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ168.53,164.58,163.59,155.18,139.56,132.32,131.68,129.22,127.42,123.05,114.71,70.87,67.49,58.64.HRMS(ESI)m/z calcd for C 21 H 21 ClN 6 O 3 [M+H] + 441.1450,found 441.1334.
Example 29
Synthesis of N- (3- ((4- ((4-phenoxyphenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (A5)
N- (3- ((4-chloro-1, 3, 5-triazin-2-yl) amino) phenyl) acrylamide (1 eq), 4-aminodiphenyl ether (1 eq), cesium carbonate (1.5 eq), palladium acetate (0.08 eq) and 1,1' -bis (diphenylphosphorus) ferrocene (0.6 eq) were added to a dioxane solution and reacted at 90℃for 6h, dioxane was removed by rotary evaporation, and column chromatography gave a white solid in 42.4% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),9.81(s,2H),8.35(s,1H),7.92(s,1H),7.75(s,2H),7.37(t,J＝7.9Hz,3H),7.25(t,J＝8.1Hz,1H),7.10(t,J＝7.4Hz,1H),6.97(d,J＝7.8Hz,4H),6.59–6.28(m,1H),6.23(d,J＝18.5Hz,1H),5.70(d,J＝9.8Hz,1H). 13 C NMR(75MHz,DMSO-d 6 )δ166.57,164.06,163.80,163.62,158.01,151.75,139.53,135.55,132.29,130.40,130.16,129.15,127.33,123.31,122.59,119.86,118.12,116.89.HRMS(ESI)m/z calcd for C 24 H 20 N 6 O 2 [M+H] + 425.1726,found 425.1681.
Example 30
Synthesis of N- (3- ((4- ((4- (2-methoxyethoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (A6)
The synthesis was carried out in the same manner as in example 29 and the yield was 45.1%. 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.78(s,1H),9.68(s,1H),8.34(s,1H),7.93(s,1H),7.64(d,J＝7.0Hz,2H),7.43(d,J＝7.2Hz,1H),7.28(t,J＝8.0Hz,1H),6.89(d,J＝7.7Hz,2H),6.51(dd,J＝16.9,10.0Hz,1H),6.30(d,J＝16.7Hz,1H),5.91–5.62(m,1H),4.06(s,2H),3.76–3.58(m,2H),3.41(s,3H). 13 C NMR(75MHz,DMSO-d 6 )δ166.46,164.74–163.90(m),163.66,154.74,139.81,139.43,132.53,132.30,129.15,127.46,122.72,115.89–112.59(m),70.89,67.47,58.62.HRMS(ESI)m/z calcd for C 22 H 22 N 6 O 3 [M+H] + 407.1826,found 407.1787.
Example 31
Synthesis of N- (3- ((4- ((4- (2-methoxyphenoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (B1)
The synthesis was carried out in the same manner as in example 29 and the yield was 41.6%. 1 H NMR(400MHz,DMSO-d 6 )δ10.13(s,1H),9.78(s,2H),8.34(s,1H),7.93(s,1H),7.70(s,2H),7.40(d,J＝6.9Hz,1H),7.25(t,J＝8.0Hz,1H),6.95(s,4H),6.89(d,J＝7.8Hz,2H),6.45(dd,J＝19.2,7.4Hz,1H),6.25(d,J＝16.8Hz,1H),5.72(d,J＝9.5Hz,1H),3.75(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ166.52,164.05,163.79,163.58,155.72,153.40,150.79,139.52,134.70,132.32,129.10,127.26,122.70,120.29,118.41,115.45,55.86.HRMS(ESI)m/z calcd for C 25 H 22 N 6 O 3 [M+H] + 455.1827,found 455.1787.
Example 32
Synthesis of N- (3- ((4- ((4- (morpholine-4-carbonyl) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (B2)
The synthesis was carried out in the same manner as in example 29 and the yield was 39.8%. 1 H NMR(300MHz,DMSO-d 6 )δ10.19(s,1H),10.00(s,1H),9.90(s,1H),8.42(s,1H),7.97(s,2H),7.89(s,2H),7.62–7.20(m,3H),6.50(dd,J＝16.7,10.1Hz,1H),6.29(d,J＝16.9Hz,1H),5.93–5.59(m,1H),3.62(s,4H),3.52(s,4H). 13 C NMR(75MHz,DMSO-d 6 )δ169.51,166.69,164.10,163.87,163.63,141.11,139.59,132.36,129.52,129.18,128.36,127.35,120.01,66.60.HRMS(ESI)m/z calcd for C 23 H 23 N 7 O 3 [M+H] + 446.1937,found 446.1896.
Example 33
Synthesis of N- (3- ((4- ((4- (piperidine-1-carbonyl) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (B3)
The synthesis was carried out in the same manner as in example 29 and the yield was 42.8%. 1 H NMR(400MHz,DMSO-d 6 )δ10.17(s,1H),9.97(s,1H),9.88(s,1H),8.40(s,1H),7.94(s,1H),7.83(s,2H),7.43(d,J＝8.0Hz,2H),7.28(t,J＝8.0Hz,3H),6.48(dd,J＝16.9,10.1Hz,1H),6.27(d,J＝18.7Hz,1H),5.75(d,J＝11.9Hz,1H),1.56(d,J＝47.3Hz,6H). 13 C NMR(75MHz,DMSO-d 6 )δ169.29,166.66,164.08,163.86,163.59,140.77,140.75,139.59,132.36,130.58,129.15,127.90,127.30,120.04,26.27,24.58.HRMS(ESI)m/z calcd for C 24 H 25 N 7 O 2 [M+H] + 444.2134,found 444.2103.
Example 34
Synthesis of 4- ((4- ((3-acrylamidophenyl) amino) -1,3, 5-triazin-2-yl) amino) -N- (pyridin-2-yl) benzamide (B4)
The synthesis was carried out in the same manner as in example 29 and the yield was 29.4%. 1 H NMR(300MHz,DMSO-d 6 )δ10.63(s,1H),10.20(s,1H),10.13(s,1H),9.98(s,1H),8.47(s,1H),8.41(s,1H),8.23(d,J＝8.1Hz,1H),8.00(d,J＝13.1Hz,5H),7.86(t,J＝7.2Hz,1H),7.55(s,1H),7.46(d,J＝7.2Hz,1H),7.37(d,J＝7.5Hz,1H),7.18(s,1H),6.62–6.37(m,1H),6.29(d,J＝16.8Hz,1H),5.75(d,J＝9.6Hz,1H). 13 C NMR(75MHz,DMSO-d 6 )δ166.75,165.84,164.11,163.90,163.66,152.84,148.34,143.31,139.65,138.52,132.36,129.24,127.88,127.33,120.08,119.53,115.14.HRMS(ESI)m/z calcd for C 24 H 20 N 8 O 2 [M+H] + 453.1779,found 453.1743.
Example 35
Synthesis of 4- ((4- ((3-acrylamidophenyl) amino) -1,3, 5-triazin-2-yl) amino) -N- (5-methylpyridin-2-yl) benzamide (B5)
The synthesis was carried out in the same manner as in example 29 and the yield was 30.6%. 1 H NMR(400MHz,DMSO-d 6 )δ10.54(s,1H),10.18(s,1H),10.11(s,1H),9.97(s,1H),8.45(s,1H),8.21(s,1H),8.12(d,J＝8.4Hz,1H),8.01(d,J＝7.9Hz,2H),7.95(s,2H),7.64(d,J＝10.7Hz,1H),7.54(s,1H),7.45(d,J＝8.0Hz,1H),7.33(t,J＝8.0Hz,1H),6.49(dd,J＝16.9,10.1Hz,1H),6.27(d,J＝16.9Hz,1H),5.72(s,1H),2.28(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ166.73,165.60,164.10,163.89,163.64,150.65,148.03,143.20,139.66,138.86,132.37,129.21,129.15,128.96,127.98,127.29,119.51,114.71,17.78.HRMS(ESI)m/z calcd for C 25 H 22 N 8 O 2 [M+H] + 467.1943,found 467.1899.
Example 36
Synthesis of N- (3- ((4- ((4- (pyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (B6)
The synthesis was carried out in the same manner as in example 29 and the yield was 37.4%. 1 H NMR(300MHz,DMSO-d 6 )δ10.22(s,1H),9.99(s,1H),9.93(s,1H),8.91(s,1H),8.57(s,1H),8.43(s,1H),8.05(d,J＝7.6Hz,1H),7.95(d,J＝6.7Hz,3H),7.67(d,J＝7.1Hz,3H),7.47(dd,J＝10.3,6.3Hz,3H),7.33(t,J＝7.9Hz,1H),6.50(dd,J＝16.8,10.1Hz,1H),6.38–6.18(m,1H),5.76(s,1H). 13 C NMR(75MHz,DMSO-d 6 )δ166.65,164.11,163.85,163.60,148.42,147.76,139.89,139.69,139.54,135.68,134.00,132.35,131.43,129.22,127.37,124.28,121.15.HRMS(ESI)m/z calcd for C 23 H 17 N 7 O[M+H] + 410.1731,found 410.1685.
Example 37
Synthesis of N- (3- ((4- ((4- (6-methylpyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (B7)
The synthesis was carried out in the same manner as in example 29 and the yield was 32.1%. 1 H NMR(300MHz,DMSO-d 6 )δ10.23(s,1H),9.96(d,J＝12.9Hz,2H),8.76(s,1H),8.42(s,1H),7.99(s,1H),7.92(d,J＝7.7Hz,3H),7.63(d,J＝7.3Hz,2H),7.46(d,J＝7.7Hz,1H),7.33(dt,J＝7.9,3.9Hz,1H),6.50(dd,J＝16.9,10.0Hz,1H),6.29(d,J＝16.9Hz,1H),5.86–5.60(m,1H). 13 C NMR(75MHz,DMSO-d 6 )δ166.63,164.09,163.83,163.59,156.76,146.94,139.53,134.27,132.80,132.33,131.59,129.22,127.39,127.07,123.55,121.17,24.13.HRMS(ESI)m/z calcd for C 24 H 21 N 7 O[M+H] + 424.1882,found 424.1841.
Example 38
Synthesis of N- (3- ((4- ((4- (6-methoxypyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (B8)
The synthesis was carried out in the same manner as in example 29 and the yield was 34.8%. 1 H NMR(300MHz,DMSO-d 6 )δ10.20(s,1H),9.89(s,2H),8.48(s,1H),8.41(s,1H),7.98(d,J＝6.9Hz,2H),7.89(d,J＝7.2Hz,2H),7.59(d,J＝7.3Hz,2H),7.45(d,J＝7.9Hz,2H),7.33(t,J＝8.0Hz,1H),6.92(d,J＝8.6Hz,1H),6.50(dd,J＝16.9,10.1Hz,1H),6.36–6.14(m,3H),5.75(d,J＝9.9Hz,1H),3.92(s,3H). 13 C NMR(75MHz,DMSO-d 6 )δ166.62,164.12,163.84,163.64,163.22,144.65,139.52,139.10,137.60,132.33,131.58,129.51,129.21,127.37,126.76,121.25,110.97,53.70.HRMS(ESI)m/z calcd for C 24 H 21 N 7 O 2 [M+H] + 440.1831,found 440.1790.
Example 39
Synthesis of N- (3- ((4- ((4- (6-fluoropyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (B9)
The synthesis was carried out in the same manner as in example 29 and the yield was 47.2%. 1 H NMR(300MHz,DMSO-d 6 )δ10.21(s,1H),9.99(s,1H),9.94(s,1H),8.54(s,1H),8.42(s,1H),8.25(t,J＝9.0Hz,1H),8.07–7.83(m,3H),7.65(d,J＝7.6Hz,2H),7.45(d,J＝7.8Hz,2H),7.38–7.20(m,1H),6.49(dd,J＝16.9,10.0Hz,1H),6.31(s,1H),5.75(d,J＝10.5Hz,1H). 13 C NMR(75MHz,DMSO-d 6 )δ166.65,164.30,164.09,163.84,163.59,161.18,145.41,145.21,140.27,139.52,134.31,132.33,130.25,129.23,127.37,121.11,110.27,109.78.HRMS(ESI)m/z calcd for C 23 H 18 FN 7 O[M+H] + 428.1631,found 428.1590.
Example 40
Synthesis of N- (3- ((4- ((4- (6-chloropyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (B10)
The synthesis was carried out in the same manner as in example 29 and the yield was 46.6%. 1 H NMR(300MHz,DMSO-d 6 )δ10.21(s,1H),9.98(d,J＝19.4Hz,2H),8.74(s,1H),8.43(s,1H),8.12(d,J＝6.8Hz,1H),7.97(s,3H),7.69(s,2H),7.59(d,J＝7.9Hz,1H),7.55–7.40(m,2H),7.35(d,J＝6.9Hz,1H),6.69–6.36(m,1H),6.29(d,J＝16.7Hz,1H),5.75(d,J＝9.1Hz,1H). 13 C NMR(75MHz,DMSO-d 6 )δ166.65,164.10,163.85,163.59,149.12,147.77,140.25,139.54,137.56,135.12,132.36,129.90,129.22,127.42,124.73,121.10.HRMS(ESI)m/z calcd for C 23 H 18 ClN 7 O[M+H] + 444.1339,found 444.1232.
Example 41
Synthesis of N- (2-methyl-5- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide (C1)
The synthesis was carried out in the same manner as in example 29 and the yield was 39.7%. 1 H NMR(300MHz,DMSO-d 6 )δ9.98(s,1H),9.84(s,1H),9.59(s,1H),8.40(s,1H),7.83(s,3H),7.54(s,1H),7.33(d,J＝7.4Hz,2H),7.20(d,J＝7.9Hz,1H),6.79–6.37(m,1H),6.39–6.06(m,1H),5.76(d,J＝9.7Hz,1H),2.01(d,J＝6.8Hz,3H)1.58(m,J＝31.4Hz,6H). 13 C NMR(75MHz,DMSO-d 6 )δ169.33,166.58,163.94,163.87,163.72,140.75,137.32,136.50,132.18,130.59,127.97,127.05,119.93,26.19,24.58,17.89.HRMS(ESI)m/z calcd for C 25 H 27 N 7 O 2 [M+H] + 458.2301,found 458.2260.
Example 42
(E) Synthesis of (E) -N- (3- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) but-2-enamine (C2)
The synthesis was carried out in the same manner as in example 29 and the yield was 41.0%. 1 H NMR(300MHz,DMSO-d 6 )δ9.99(s,2H),9.88(s,1H),8.41(s,1H),7.95(s,1H),7.86(d,J＝6.7Hz,2H),7.42(d,J＝7.8Hz,2H),7.34–7.15(m,3H),6.83(dq,J＝13.8,7.3,6.9Hz,1H),6.18(d,J＝16.4Hz,1H),1.89(d,J＝6.8Hz,3H),1.57(d,J＝30.7Hz,6H). 13 C NMR(75MHz,DMSO-d 6 )δ169.34,166.66,164.11,163.96,163.87,140.75,140.30,139.87,139.56,130.56,129.07,127.90,126.51,120.03,56.53,24.58,17.98.HRMS(ESI)m/z calcd for C 25 H 27 N 7 O 2 [M+H] + 458.2305,found 458.2260.
Example 43
Synthesis of 1- (6- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) indolin-1-yl) prop-2-en-1-one (C3)
The synthesis method is the same as that of the solidExample 29, yield 37.8%. 1 H NMR(300MHz,DMSO-d 6 )δ9.97(s,1H),9.74(s,1H),8.56(s,1H),7.84(s,3H),7.50(s,1H),7.33(d,J＝7.4Hz,2H),7.27(d,J＝7.9Hz,1H),6.74–6.37(m,1H),6.51–6.21(d,1H),5.79(d,J＝9.7Hz,1H),1.58(m,J＝31.4Hz,8H). 13 C NMR(101MHz,DMSO-d 6 )δ169.34,166.55,164.10,163.85(d,J＝2.1Hz),143.49,140.76,130.43,127.92,124.67,119.97,68.17,58.52,48.55,35.85,27.42,24.59.HRMS(ESI)m/z calcd for C 26 H 27 N 7 O 2 [M+H] + 470.2304,found 470.2270.
Example 44
Synthesis of 1- (3- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) but-2-yn-1-one (C4)
The synthesis was carried out in the same manner as in example 29 and the yield was 44.1%. 1 H NMR(400MHz,DMSO-d 6 )δ10.63(s,1H),9.97(s,1H),9.87(s,1H),8.38(s,1H),7.86(d,J＝25.8Hz,4H),7.29(d,J＝15.3Hz,4H),2.04(s,3H),1.56(d,J＝41.0Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ169.32,166.66,164.08,163.84,151.01,139.09,130.59,129.11,127.90,120.01,84.65,76.37,24.59,3.69.HRMS(ESI)m/z calcd for C 25 H 25 N 7 O 2 [M+H] + 456.2140,found 456.2103.
Example 45
Synthesis of N- (3- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) thiophene-2-carboxamide (C5)
The synthesis was carried out in the same manner as in example 29 and the yield was 48.8%. 1 H NMR(400MHz,DMSO-d 6 )δ10.29(s,1H),9.96(d,J＝26.8Hz,2H),8.41(s,1H),8.06(d,J＝3.4Hz,2H),7.85(d,J＝4.4Hz,3H),7.45(d,J＝7.7Hz,1H),7.34(s,0H),7.32(s,1H),7.31–7.25(m,2H),7.25–7.17(m,1H),1.51(d,J＝48.2Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ169.24,166.69,164.12,163.88,160.37,140.55,139.27,132.32,130.58,129.59,129.05,128.54,127.88,120.01,24.56.HRMS(ESI)m/z calcd for C 27 H 27 N 7 O 2 S[M+H] + 500.1868,found 500.1824.
Example 46
Partial pharmacological test and results
CCK-8 method for testing Raji cell proliferation experiment
Raji cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, and logarithmic growth phase cells were used for experiments to adjust cell density to 8×10 4 Inoculating 100 μl/well into 96-well plate, culturing for 4 hr, adding 100 μl/well of medicated culture medium, and concentrating to 50×10 -5 mol/L、2×10 -5 mol/L、1×10 -5 mol/L and 1X 10 -6 mol/L, 3 compound holes of each concentration, using the culture medium with the same volume to replace the test drug as a control group, adding 10 mu L/hole CCK-8 after culturing for 48 hours, measuring absorbance (A) value of each hole at a wavelength of 450nm by using an enzyme-labeled detector after culturing for 4 hours, and calculating the cell proliferation inhibition rate according to a formula: inhibition ratio = (control group a value-experimental group a value)/(control group a value-blank group a value) ×100%, and IC was calculated 50 。
CCK-8 assay for Ramos cell proliferation assay
Ramos cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, and cells in logarithmic growth phase were used for experiments to adjust cell density to 8×10 4 Inoculating 100 μl/well into 96-well plate, culturing for 4 hr, adding 100 μl/well of medicated culture medium, and concentrating to 50×10 -5 mol/L、2×10 -5 mol/L、1×10 -5 mol/L and 1X 10 -6 mol/L, 3 compound holes of each concentration, using the culture medium with the same volume to replace the test drug as a control group, adding 10 mu L/hole CCK-8 after culturing for 48 hours, measuring absorbance (A) value of each hole at a wavelength of 450nm by using an enzyme-labeled detector after culturing for 4 hours, and calculating the cell proliferation inhibition rate according to a formula: inhibition ratio = (control group a value-experimental group a value)/(control group a value-blank group a value) ×100%, and IC was calculated 50 。
Btk enzyme Activity inhibition assay
The ADP-GloTM kinase system can determine kinase activity by converting the generated ADP to fluorescently labeled ATP, which is an ATP tyrosine kinase, according to the principle that ATP can phosphorylate Btk to form ADP. The method comprises the following steps: 1. enzyme inhibition reaction, namely adding a tested inhibitor into kinase reaction liquid containing enzyme substrates, then adding ATP, and reacting for 60 min; 2. adding ADP-GloTM reagent to stop kinase reaction and clear residual ATP;3. incubating for 40 minutes at room temperature; 4. adding a detection reagent and a fluorogenic enzyme to convert ADP into fluorescent-labeled ATP;5. incubating for 30mins at room temperature; 6. fluorescence was detected and the inhibition was calculated.
Results of partial pharmacological experiments of the compounds of the invention:
raji cells and Ramos antiproliferation experiments were performed on the synthesized s-triazine compounds using the Btk inhibitor Ibrutinib as a positive control. The research results show that most of the compounds show better inhibition activity on Raji cells. In the Btk enzyme inhibition experiment using Ibrutinib as a control, most of the compounds have better inhibition effect on Btk. Therefore, the compounds can be used as Btk inhibitors for treating leukemia or lymphoma.
Claims (6)
1. S-triazine compound and pharmaceutically acceptable salts thereof, characterized in that the compound is selected from the following compounds:
n- (3- ((4-amino-6- ((4-phenoxyphenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4-amino-6- ((4- (2-methoxyethoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4-chloro-6- ((4-phenoxyphenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4-chloro-6- ((4- (2-methoxyethoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4-phenoxyphenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (2-methoxyethoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (2-methoxyphenoxy) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (morpholine-4-carbonyl) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (piperidine-1-carbonyl) phenylamino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
4- ((4- ((3-acrylamidophenyl) amino) -1,3, 5-triazin-2-yl) amino) -N- (pyridin-2-yl) benzamide;
4- ((4- ((3-acrylamidophenyl) amino) -1,3, 5-triazin-2-yl) amino) -N- (5-methylpyridin-2-yl) benzamide;
n- (3- ((4- ((4- (pyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (6-methylpyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (6-methoxypyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (6-fluoropyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (3- ((4- ((4- (6-chloropyridin-3-yl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
n- (2-methyl-5- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) acrylamide;
(E) -N- (3- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) but-2-enamine;
1- (6- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) indolin-1-yl) prop-2-en-1-one;
1- (3- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) but-2-yn-1-one;
n- (3- ((4- ((4- (piperidine-1-carbonyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) phenyl) thiophene-2-carboxamide.
2. A pharmaceutical composition comprising a compound according to any one of claims 1 and pharmaceutically acceptable salts thereof.
3. The pharmaceutical composition according to claim 2, characterized in that the composition is formulated from a compound according to claim 1 and its pharmaceutically acceptable salts with pharmaceutically acceptable excipients.
4. The use of a compound as claimed in claim 1 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for inhibiting bruton's tyrosine kinase.
5. The use of a compound as claimed in claim 1 and a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of leukemia.
6. The use of a compound as claimed in claim 1 and a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of lymphoma.
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