CN111057021A - S-triazine compound and its preparing method and use - Google Patents

S-triazine compound and its preparing method and use Download PDF

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CN111057021A
CN111057021A CN201911263133.7A CN201911263133A CN111057021A CN 111057021 A CN111057021 A CN 111057021A CN 201911263133 A CN201911263133 A CN 201911263133A CN 111057021 A CN111057021 A CN 111057021A
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amino
phenyl
triazin
acrylamide
pharmaceutically acceptable
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CN111057021B (en
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向华
滕雨
李振邦
肖茂旭
任胜楠
哈斯
童超
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • 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
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • 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
    • C07D251/14—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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • 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
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
    • C07D251/50—Two nitrogen atoms with a halogen atom attached to the third ring carbon atom
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    • C07D401/00—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
    • C07D401/02—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
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—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
    • 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 s-triazineExperiments prove that the compounds can treat or prevent diseases related to the activity of protein kinase, such as leukemia and lymphoma, by inhibiting Bruton's tyrosine kinase Btk.

Description

S-triazine compound and its preparing method and use
Technical Field
The invention relates to a compound, a preparation method and application thereof, in particular to an s-triazine compound, and 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 of leukemia and lymphoma. Studies have shown that B-cell Receptor (BCR) signaling pathway disorders are one of the major causes of B-cell line leukemia and lymphoma. Among malignant B cells, BCR pathway is abnormally active, inhibits normal differentiation and apoptosis of B cells, promotes abnormal proliferation of B cells, and thus causes the development of various diseases, such as Acute Lymphocytic Leukemia (act Lymphocytic Leukemia, ALL), Waldenstrom's Macroglobulinemia (WM), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (Chronic Lymphocytic Leukemia, CLL), Non-Hodgkin's Lymphoma (NHL), and the like. Bruton's tyrosine kinase (Btk) is an important member of the TEC Family (TFKs), is expressed at various developmental stages of B lymphocytes, is a key regulator in the BCR signaling pathway, and has important effects on differentiation, proliferation, and apoptosis of B cells. Therefore, BTK has become an important therapeutic target for B cell line-related diseases.
In view of the important role BTK plays in the development and progression of B cell tumors, the research of BTK-targeted small molecule inhibitors is of great interest. In recent years, two irreversible BTK inhibitors have been marketed, Ibrutinib has been successively approved by the FDA for the treatment of MCL, CLL, SLL and cGVHD, and acaraburtinib has been approved for the treatment of CLL. However, despite the great clinical success of Ibrutinib, its resistance is still inevitable. It is thought that this is probably due to the fact that ibbrutinib impairs tumor adhesion and metastasis, but does not directly cause tumor cell death. The second generation of the more selective Btk inhibitor, acarabretinib, also develops drug resistance mutations soon after use. Compared with an irreversible inhibitor, the reversible inhibitor forms weaker acting force with BTK molecules in a Btk-specific H3 cavity through hydrogen bonds, van der Waals force, hydrophobic effect and the like, has better kinase selectivity, is favorable for reducing toxicity and risks, and is more suitable for long-term administration. However, reversible inhibitors have some disadvantages, such as insufficient inhibition strength, short inhibition time, drug resistance due to mutation in the H3 region, and the like. Therefore, the development of novel BTK inhibitors is of great interest.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a series of s-triazine compounds, wherein the series of compounds all have s-triazine parent nucleus. The invention also aims to disclose a preparation method of the compound, which has strong operability and high efficiency. The invention also discloses the application of the compounds in preparing Bruton tyrosine kinase inhibitors and the application thereof in preparing medicaments for treating or preventing leukemia and lymphoma.
The technical scheme is as follows: the s-triazine compound and the pharmaceutically acceptable salt thereof comprise a compound with a structure shown as a general formula (I) or a general formula (II):
Figure BDA0002312120780000021
wherein n is 1-2;
ring A is selected from aryl;
x is selected from C, N, O;
r is selected from H, Cl and NH2；
R2Selected from substituted or unsubstituted aryl, heteroaryl, R5O-、CH3O(CH2)n-、R6CO-、R7NHCO-; wherein when R is2Selected from heteroaryl, the heteroaryl at least contains one N atom, and the substituent is C1-C3 alkyl and halogenA hormone, methoxy or trifluoromethoxy; when R is2Is selected from R5O-，R5Is substituted or unsubstituted phenyl, wherein the substituents are selected from methyl, methoxy; when R is2Is selected from CH3O (CH2) n-, wherein n is 1-4; when R is2Is selected from R6CO-, wherein R6Is a five-membered or six-membered unsaturated heterocycle; when R is2Is selected from R7NHCO-, wherein R7Is substituted or unsubstituted aryl or heteroaryl, wherein heteroaryl contains at least one heteroatom selected from N, O, S, and the substituents are selected from C1-C4 alkyl, halogen, methoxy, trifluoromethoxy;
R3selected from H, C1-C3 alkyl;
R4is selected from R8CONH-wherein R8Selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and saturated five-membered heterocycle, wherein the heterocycle contains 1-3 heteroatoms selected from O, N, S;
the halogen is selected from F, Cl, Br and I.
The compounds and pharmaceutically acceptable salts thereof:
wherein ring a is selected from phenyl;
R2selected from substituted or unsubstituted pyridine, R5O-、CH3O(CH2)n-、R6CO-、R7NHCO-; wherein when R is2Selected from substituted or unsubstituted pyridine, the substituent is methyl, halogen, methoxy or trifluoromethoxy; when R is2Is selected from R5O-，R5Is substituted or unsubstituted phenyl, wherein the substituents are selected from methyl, methoxy; when R is2Is selected from CH3O (CH2) n-, wherein n is 1-4; when R is2Is selected from R6CO-, wherein R6Is tetrahydropyrrole, morpholine and piperidine; when R is2Is selected from R7NHCO-, wherein R7Is substituted or unsubstituted aryl or heteroaryl, wherein heteroaryl contains at least one heteroatom selected from N, O, S, and the substituents are selected from methyl, halogen, methoxy, trifluoromethoxy;
R3selected from H, CH3。
The compound and pharmaceutically acceptable salts thereof, 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 of any of the foregoing and pharmaceutically acceptable salts thereof.
The composition is prepared from the compound and the pharmaceutically acceptable salt thereof in 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:
Figure BDA0002312120780000041
reaction conditions are as follows: (a) michael acceptor, sodium carbonate and acetone at 0 ℃ for 1 h; (b) ammonia water and tetrahydrofuran at 36 ℃ for 3 h; (c) aromatic amine, palladium acetate, 1' -bis (diphenylphosphino) ferrocene, cesium carbonate, dioxane, 110 ℃; (d) aromatic amine, sodium carbonate and acetone at 60 ℃ for 4 h;
or:
Figure BDA0002312120780000042
reaction conditions are as follows: (e) michael acceptor, N-diisopropylalanine, dioxane, room temperature, 5 min; (f) aromatic amine, palladium acetate, 1' -bis (diphenylphosphino) ferrocene, cesium carbonate and dioxane at 110 ℃ for 5 h.
The compound and the pharmaceutically acceptable salt thereof are applied to the preparation of the drug for inhibiting Bruton's tyrosine kinase.
The compound and the pharmaceutically acceptable salt thereof are applied to the preparation of drugs for treating or preventing leukemia.
The compound and the pharmaceutically acceptable salt thereof are applied to the preparation of the drugs for treating or preventing lymphoma.
In some embodiments, the compound is selected from the group consisting of
Figure BDA0002312120780000043
Figure BDA0002312120780000044
Figure BDA0002312120780000051
Figure BDA0002312120780000052
Figure BDA0002312120780000053
The code of the compound in the pharmacological experiment and experimental examples is equal to the structure of the compound corresponding to the code.
Has the advantages 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. For example, by inhibiting Btk, to treat or prevent diseases associated with protein kinase activity, such as leukemia, malignant lymphoma.
Detailed Description
1H-NMR nuclear magnetic resonance was measured by a Bruker AV300 type (300HZ) nuclear magnetic resonance apparatus (TMS is an internal standard substance), and 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) using GF254 thin layer chromatography plate (tai jiang friend silica gel development ltd); the TLC development system is a petroleum ether-ethyl acetate system or a dichloromethane-methanol system; TLC was illuminated under model ZF7 three-way uv analyzer (henan consortium seoul instruments ltd). Some of the compound purities were checked using Shimadzu HPLC at 254nm with the mobile phase being a methanol/water system.
Synthetic route
Route one
Figure BDA0002312120780000061
Reaction conditions are as follows: (a) michael acceptor, sodium carbonate, acetone, 0 ℃,1 h; (b) ammonia water and tetrahydrofuran at 36 ℃ for 3 h; (c) aromatic amine, palladium acetate, 1,1' -bis (diphenylphosphino) ferrocene, cesium carbonate, dioxane, 110 ℃; (d) aromatic amine, sodium carbonate, acetone, 60 ℃ and 4 h.
And a second route:
Figure BDA0002312120780000062
reaction conditions are as follows: (e) michael acceptor, N, N-diisopropylalanine, dioxane, room temperature, 5 min; (f) aromatic amine, palladium acetate, 1,1' -bis (diphenylphosphino) ferrocene, cesium carbonate, dioxane, 110 ℃ and 5 h.
Example 1
Synthesis of intermediate N- (3-aminophenyl) acrylamide
M-nitroaniline (3g, 21.70mmol), sodium bicarbonate (5.02g, 32.60mmol) was added to 20ml acetonitrile and mixed well. Acryloyl chloride (1eq) was added dropwise in an ice bath, stirred at room temperature for 30min, decanted, and filtered with suction to give a white solid (3.94g, 94.47%).1H NMR(300MHz,DMSO-d6)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 (0.5g, 2.60mmol), reduced iron powder (0.44g, 7.80mmol) and ammonium chloride (0.42g, 7.80mmol) were placed in a mixed solvent of 10ml ethanol and water (1:1) and reacted at 85 ℃ for 1 hour. The mixture was filtered, and the filter 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 column chromatography was performed to give a yellow solid (0.37g, 87.84%).1H NMR(300MHz,DMSO-d6)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 method is the same as example 1, and the column chromatography is carried out to obtain 0.47g of white solid with the yield of 80.82%.1H NMR(300MHz,DMSO-d6)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 method is the same as example 1, and the yellow oily matter is obtained by column chromatography separation and the yield is 93.51%.1H NMR(300MHz,DMSO-d6)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 method is the same as example 1, and the yellow solid is obtained by column chromatography separation, with the yield of 97.23%.1H NMR(300MHz,DMSO-d6)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-formamide
The synthesis method is the same as example 1, and column chromatography is carried out to obtain yellow solid with the yield of 43.8%.1H NMR(300MHz,DMSO-d6)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 method is the same as example 1, and the white solid is obtained by column chromatography, and the yield is 46.20%.1H NMR(300MHz,DMSO-d6)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
P-fluoronitrobenzene (0.5g, 3.54mmol), ethylene glycol monomethyl ether (0.335ml, 4.25mmol) and potassium hydroxide (0.3g, 5.31mmol) were added to 10ml of dimethyl sulfoxide, stirred at 60 ℃ overnight, elutriated in water and filtered to give 0.537g of yellow solid with a yield of 76.9%.
Example 8
Synthesis of intermediate 4- (morpholinoformyl) aniline
P-nitrobenzoyl chloride (1g,5.39mmol) was added in portions to an anhydrous tetrahydrofuran solution containing morpholine (0.7g, 8.08mmol) and triethylamine (1.5eq) under ice-bath, reacted for 1h, extracted with ethyl acetate, and the solvent was spin-dried to give 1.3g of a white solid with a yield of 100%.
The product, reduced iron powder (3eq) and ammonium chloride (3eq) are put into a mixed solvent of 10ml ethanol and water (1:1) and react for 1h at 85 ℃. The mixture was filtered, and the filter 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 column chromatography separation was carried out to obtain a pale yellow solid with a yield of 82.1%.1H NMR(300MHz,DMSO-d6)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- (piperidinecarbonyl) aniline
The synthesis method is the same as example 8, and column chromatography is carried out to obtain yellow solid with the yield of 84.0%.1H NMR(400MHz,DMSO-d6)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 method is the same as example 8, and column chromatography is carried out to obtain yellow solid with the yield of 89.9%.1H NMR(300MHz,DMSO-d6)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 method is the same as example 8, and column chromatography is carried out to obtain yellow solid with the yield of 89.9%.1H NMR(300MHz,DMSO-d6)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) aniline
Adding p-bromonitrobenzene (2g, 9.9mmol), pyridine-3-boric acid (1eq), bis-triphenylphosphine palladium chloride (0.1eq) and potassium carbonate (2eq) into anhydrous dioxane, reacting at 80 ℃ for 10h under the protection of nitrogen, performing water precipitation, performing suction filtration and performing column chromatography to obtain a yellow solid (1.4g, 70%).
The product, reduced iron powder (3eq) and ammonium chloride (3eq) are put into a mixed solvent of 10ml ethanol and water (1:1) and react for 1h at 85 ℃. The mixture was filtered, and the filter 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 was obtained by column chromatography with a yield of 92.4%.1H NMR(300MHz,DMSO-d6)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 method is the same as example 12, and the yellow solid is obtained by column chromatography, and the yield is 79.8%.1H NMR(300MHz,DMSO-d6)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 as example 12, and column chromatography is carried out to obtain yellow solid with the yield of 82.1%.1H NMR(300MHz,DMSO-d6)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 method is the same as example 12, and column chromatography is carried out to obtain yellow solid with the yield of 86.3%.1H NMR(300MHz,DMSO-d6)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 method is the same as example 12, and column chromatography is carried out to obtain yellow solid with the yield of 81.4%.1H NMR(300MHz,DMSO-d6)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
Dissolving cyanuric chloride (4.67g, 21.6mmol) in acetone, slowly adding dropwise acetone solution containing acrylamide (1eq) under ice bath, maintaining the temperature, reacting for 3.5h, water separating, and vacuum filtering to obtain white pigment8.3g of a colored solid, yield 78.5%.1H NMR(300MHz,DMSO-d6)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 (1g, 3.22mmol) and 30% ammonia (1eq) were added to a tetrahydrofuran solution, reacted at 60 ℃ for 4 hours, dialyzed with water, and filtered to obtain 0.89g of a white solid with a yield of 89%.1HNMR(300MHz,DMSO-d6)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
Dissolving 2, 4-dichloros-triazine (1g, 6.7mmol) in dioxane solution, slowly adding 4-aminophenylacrylamide (1eq) and DIPEA (1.1eq) dropwise at room temperature, reacting for 5min, performing elutriation, and performing suction filtration to obtain a white solid 1.6g with the yield of 80.4%.1HNMR(400MHz,DMSO-d6)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 method is the same as example 19, and a white solid is obtained by water precipitation, with the yield of 73%.1H NMR(300MHz,DMSO-d6)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 method is the same as example 19, and the yield is 78.8%.1H NMR(300MHz,DMSO-d6)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 method is the same as example 19, and the yield is 78.2%.1H NMR(300MHz,DMSO-d6)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-ynylamide
The synthesis method is the same as example 19, and the yield is 76.4%.1H NMR(300MHz,DMSO-d6)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 method is the same as example 19, and the yield is 74.2%.1H 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)
Adding 4-aminodiphenyl ether (1eq) and DIPEA (4eq) into an acetone solution containing N- (3- ((4-amino-6-chloro-1, 3, 5-triazin-2-yl) amino) phenyl) acrylamide, reacting for 24 hours at 80 ℃, extracting with ethyl acetate, spin-drying the solvent, and carrying out column chromatography to obtain a white solid with the yield of 46.4%.1H NMR(300MHz,DMSO-d6)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).13C 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 C24H21N7O2[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 method is the same as example 25, and the yield is 40.4%.1H NMR(400MHz,DMSO-d6)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).13C NMR(101MHz,DMSO-d6)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 C21H23N7O3[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)
Adding 4-aminodiphenyl ether (1eq) into an acetone solution containing N- (3- ((4, 6-dichloro-1, 3, 5-triazin-2-yl) amino) phenyl) acrylamide in batches at room temperature, simultaneously adding triethylamine (2eq), reacting at room temperature for 2 hours, extracting with ethyl acetate, spin-drying the solvent, and carrying out column chromatography to obtain a white solid with the yield of 62.1%.1H NMR(400MHz,DMSO-d6)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).13C 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 C24H19ClN6O2[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 method is the same as example 27, and the yield is 57.2%.1H NMR(400MHz,DMSO-d6)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).13C NMR(101MHz,DMSO-d6)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 C21H21ClN6O3[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)
Adding N- (3- ((4-chloro-1, 3, 5-triazin-2-yl) amino) phenyl) acrylamide (1eq), 4-aminodiphenyl ether (1eq), cesium carbonate (1.5eq), palladium acetate (0.08eq) and 1,1' -bis (diphenylphosphino) ferrocene (0.6eq) into a dioxane solution, reacting at 90 ℃ for 6 hours, removing dioxane by rotary evaporation, and performing column chromatography to obtain a white solid with the yield of 42.4%.1H NMR(400MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 calcdfor C24H20N6O2[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 method is the same as example 29, and the yield is 45.1%.1H NMR(300MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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/zcalcd for C22H22N6O3[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 method is the same as example 29, and the yield is 41.6%.1H NMR(400MHz,DMSO-d6)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).13C NMR(101MHz,DMSO-d6)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 C25H22N6O3[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 method is the same as example 29, and the yield is 39.8%.1H NMR(300MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 forC23H23N7O3[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 method is the same as example 29, and the yield is 42.8%.1H NMR(400MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 C24H25N7O2[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 method is the same as example 29, and the yield is 29.4%.1H NMR(300MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 C24H20N8O2[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 method is the same as example 29, and the yield is 30.6%.1H NMR(400MHz,DMSO-d6)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).13C NMR(101MHz,DMSO-d6)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 C25H22N8O2[M+H]+467.1943,found467.1899.
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 method is the same as example 29, and the yield is 37.4%.1H NMR(300MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 calcdfor C23H17N7O[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 method is the same as example 29, and the yield is 32.1%.1H NMR(300MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 C24H21N7O[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 method is the same as example 29, and the yield is 34.8%.1H NMR(300MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 C24H21N7O2[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 method is the same as example 29, and the yield is 47.2%.1H NMR(300MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 C23H18FN7O[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 method is the same as example 29, and the yield is 46.6%.1H NMR(300MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 C23H18ClN7O[M+H]+444.1339,found444.1232.
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 method is the same as example 29, and the yield is 39.7%.1H NMR(300MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 C25H27N7O2[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 method is the same as example 29, and the yield is 41.0%.1H NMR(300MHz,DMSO-d6)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).13C NMR(75MHz,DMSO-d6)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 C25H27N7O2[M+H]+458.2305,found458.2260.
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 example 29, and the yield is 37.8%.1H NMR(300MHz,DMSO-d6)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).13C NMR(101MHz,DMSO-d6)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 C26H27N7O2[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 method is the same as example 29, and the yield is 44.1%.1H NMR(400MHz,DMSO-d6)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).13C NMR(101MHz,DMSO-d6)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 C25H25N7O2[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 method is the same as example 29, and the yield is 48.8%.1H NMR(400MHz,DMSO-d6)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).13C NMR(101MHz,DMSO-d6)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/zcalcd for C27H27N7O2S[M+H]+500.1868,found 500.1824.
Example 46
Partial pharmacological test and results
Experiment for testing Raji cell proliferation by CCK-8 method
Culturing Raji cells in RPMI1640 culture medium containing 10% fetal calf serum, taking logarithmic growth phase cells for experiment, adjusting cell density to 8 × 104Inoculating 100 μ l/well of the culture medium into a 96-well plate, culturing for 4 hr, adding 100 μ l/well of the culture medium containing the drug, and obtaining a final sample concentration of 50 × 10-5mol/L、2×10-5mol/L、1×10-5mol/L and 1X 10-6And (3) mol/L, replacing the test drug with a culture medium with the same volume as the control group for 3 multiple wells, continuing culturing for 48 hours, adding 10 mu L/well CCK-8, culturing for 4 hours, measuring the absorbance (A) value of each well at the wavelength of 450nm by using an enzyme-labeled detector, and calculating the cell proliferation inhibition rate according to the formula: the inhibition rate (control a value-experimental a value)/(control a value-blank a value) × 100%, and IC was calculated50。
Experiment for testing Ramos cell proliferation by CCK-8 method
Ramos cells are cultured in RPMI1640 culture medium containing 10% fetal calf serum, cells in logarithmic growth phase are taken for experiment, and the cell density is adjusted to 8 multiplied by 104Inoculating 100 μ l/well of the culture medium into a 96-well plate, culturing for 4 hr, adding 100 μ l/well of the culture medium containing the drug, and obtaining a final sample concentration of 50 × 10-5mol/L、2×10-5mol/L、1×10-5mol/L and 1X 10-6mol/L, each concentratedRepeating 3 wells, using culture medium with the same volume to replace test drugs as a control group, continuously culturing for 48 hours, adding 10 mu l/well of CCK-8, culturing for 4 hours, measuring the absorbance (A) value of each well at the wavelength of 450nm by using an enzyme-labeled detector, and calculating the cell proliferation inhibition rate according to the formula: the inhibition rate (control a value-experimental a value)/(control a value-blank a value) × 100%, and IC was calculated50。
Btk enzyme activity inhibition assay
Based on the principle that ATP can phosphorylate Btk to form ADP, the ADP-GloTM kinase system can convert ADP generated into fluorescence labeled ATP belonging to ATP tyrosine kinase, thereby measuring the activity of the kinase. The method comprises the following steps: 1. enzyme inhibition reaction, namely adding a tested inhibitor into a kinase reaction solution containing an enzyme substrate, then adding ATP, and reacting for 60 mins; 2. adding ADP-GloTM reagent to stop kinase reaction and eliminate residual ATP; 3. incubation at room temperature for 40 minutes; 4. adding a detection reagent and a fluorescent enzyme to convert ADP into fluorescence labeled ATP; 5. incubating for 30mins at room temperature; 6. fluorescence was detected and inhibition was calculated.
Partial pharmacological test results for the compounds of the invention:
Figure BDA0002312120780000181
Figure BDA0002312120780000191
the Btk inhibitor Ibrutinib is used as a positive control, and Raji cell and Ramos antiproliferation experiments are carried out on the synthesized s-triazine compounds. Research results show that most compounds show better inhibitory activity on Raji cells. In Btk enzyme inhibition experiments with Ibrutinib as a control, most compounds have better Btk inhibition effect. Therefore, the compounds can be used as Btk inhibitors and used for treating leukemia or lymphoma.

Claims (9)

1. An s-triazine compound and pharmaceutically acceptable salts thereof are characterized by comprising a compound with a structure shown as a general formula (I) or a general formula (II):
Figure FDA0002312120770000011
wherein n is 1-2;
ring A is selected from aryl;
x is selected from C, N, O;
r is selected from H, Cl and NH2；
R2Selected from substituted or unsubstituted aryl, heteroaryl, R5O-、CH3O(CH2)n-、R6CO-、R7NHCO-; wherein when R is2Is selected from heteroaryl, the heteroaryl at least contains one N atom, and the substituent is C1-C3 alkyl, halogen, methoxyl or trifluoromethoxy; when R is2Is selected from R5O-，R5Is substituted or unsubstituted phenyl, wherein the substituents are selected from methyl, methoxy; when R is2Is selected from CH3O (CH2) n-, wherein n is 1-4; when R is2Is selected from R6CO-, wherein R6Is a five-membered or six-membered unsaturated heterocycle; when R is2Is selected from R7NHCO-, wherein R7Is substituted or unsubstituted aryl or heteroaryl, wherein heteroaryl contains at least one heteroatom selected from N, O, S, and the substituents are selected from C1-C4 alkyl, halogen, methoxy, trifluoromethoxy;
R3selected from H, C1-C3 alkyl;
R4is selected from R8CONH-wherein R8Selected from C2-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and saturated five-membered heterocycle, wherein the heterocycle contains 1-3 heteroatoms selected from O, N, S;
the halogen is selected from F, Cl, Br and I.
2. The compound according to claim 1 and pharmaceutically acceptable salts thereof, characterized in that:
wherein ring a is selected from phenyl;
R2selected from substituted or unsubstituted pyridine, R5O-、CH3O(CH2)n-、R6CO-、R7NHCO-; it is composed ofIn when R is2Selected from substituted or unsubstituted pyridine, the substituent is methyl, halogen, methoxy or trifluoromethoxy; when R is2Is selected from R5O-，R5Is substituted or unsubstituted phenyl, wherein the substituents are selected from methyl, methoxy; when R is2Is selected from CH3O (CH2) n-, wherein n is 1-4; when R is2Is selected from R6CO-, wherein R6Is tetrahydropyrrole, morpholine and piperidine; when R is2Is selected from R7NHCO-, wherein R7Is substituted or unsubstituted aryl or heteroaryl, wherein heteroaryl contains at least one heteroatom selected from N, O, S, and the substituents are selected from methyl, halogen, methoxy, trifluoromethoxy;
R3selected from H, CH3。
3. Compound according to claim 1, characterized in that it 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.
4. A pharmaceutical composition characterized by comprising a compound according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof.
5. The pharmaceutical composition according to claim 4, wherein the composition is prepared from the compound and the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and pharmaceutically acceptable auxiliary materials.
6. A process for the preparation of a compound according to claim 1 and pharmaceutically acceptable salts thereof, comprising the steps of:
Figure FDA0002312120770000031
reaction conditions are as follows: (a) michael acceptor, sodium carbonate and acetone at 0 ℃ for 1 h; (b) ammonia water and tetrahydrofuran at 36 ℃ for 3 h; (c) aromatic amine, palladium acetate, 1' -bis (diphenylphosphino) ferrocene, cesium carbonate, dioxane, 110 ℃; (d) aromatic amine, sodium carbonate and acetone at 60 ℃ for 4 h;
or:
Figure FDA0002312120770000032
reaction conditions are as follows: (e) michael acceptor, N-diisopropylalanine, dioxane, room temperature, 5 min; (f) aromatic amine, palladium acetate, 1' -bis (diphenylphosphino) ferrocene, cesium carbonate and dioxane at 110 ℃ for 5 h.
7. Use of a compound according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for inhibiting bruton's tyrosine kinase.
8. Use of a compound according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prophylaxis of leukaemia.
9. Use of a compound according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prevention of lymphoma.
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