CN105801582A - Novel dihydro pteridinone derivative, preparing method thereof and application to medicine - Google Patents

Novel dihydro pteridinone derivative, preparing method thereof and application to medicine Download PDF

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CN105801582A
CN105801582A CN201610229124.6A CN201610229124A CN105801582A CN 105801582 A CN105801582 A CN 105801582A CN 201610229124 A CN201610229124 A CN 201610229124A CN 105801582 A CN105801582 A CN 105801582A
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compound
ethyl acetate
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methyl
cyclopenta
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廖晨钟
杨洋
涂正超
张兴星
倪勇
郑敏
许涵菲
肖炫
詹美苗
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Hefei University of Technology
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Hefei University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems

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Abstract

The invention discloses a novel dihydro pteridinone derivative, a preparing method thereof and application to medicine.The novel dihydro pteridinone derivative is characterized in that the structure general formula is shown in the formula (I) or (II) (see the formulas in the description).The dihydro pteridinone derivative can be used in a drug for treating cell proliferation diseases.The dihydro pteridinone derivative is simple in preparing method and greatly improves selectivity in Plk family while keeping good kinase inhibitory activity to Plk1 to improve selectivity to most kinds of kinase, targeting ability of the drug is improved, and toxic and side effects as well as untoward effects are reduced while the pharmacological effect is kept.

Description

One novel dihydropteridine ketones derivant of class and preparation method thereof and in purposes pharmaceutically
Technical field
The present invention relates to medicine synthesis technique neck, be specifically related to novel dihydropteridine ketones derivant of class and preparation method thereof and the medicinal usage as Plks inhibitors of kinases.
Background technology
Protein kinase is that high energy donor molecule (such as ATP) is shifted the phosphate group enzyme to certain target molecules by a class, they are signaling molecules important in Cell signal propagation pathways, play pivotal role in regulating cell DNA replication dna, period run, energy metabolism and growth and differentiation etc..Polo sample kinases (Polo-likekinases, Plks) is the serine/threonine kinase of a class formation high conservative, has five kinds of hypotypes in human cell, is Plk1-5 respectively.They all play a significant role (JournalofCellScience.2005,118 (21): 5101-5108.) in the regulation and control in Growth of Cells and cell mitogen cycle.Research shows, multiple committed steps of Plk1 regulating cell propagation M phase, including the formation of bipolar spindle, chromosome separation, promotion complex regulation and control, and stage (JournalofCellScience.2005,118 (21): 5101-5108) such as cytokinesis.Plk1 excessively expresses in the human tumor of about 80%, including breast carcinoma, colorectal carcinoma, carcinoma of prostate, cancer of pancreas, nonsmall-cell lung cancer, ovarian cancer etc., but in normal human tissue, seldom express (JournalofBiologicalChemistry.2005,280 (52): 42994-42999).
Up to now, all kinds of reports have been disclosed many dihydropteridine ketones derivants as Plk1 inhibitor, and this compounds is respectively provided with antiproliferative activity.Such as, patent WO01/019825 discloses the preparation method of pteridinone analog derivative and for treating the purposes of tumor and virus disease in drug regimen, and the compound such as MLN0905, BI2536, HMN-214, BI6727, NMS-P937, Ro5203280 and GSK461364 all shows to treat and is characterized as excessively or the purposes of the disease of abnormal cell proliferation subsequently.
Although there being some Plk1 inhibitors of kinases to be disclosed, the restriction of the aspects such as but its application is additionally subjected to medicine generation at present, medicine moves, especially the puzzlement of the problem such as selectivity in the drug resistance of various dissimilar tumors and kinase families thereof, also there is not long-acting medicine, therefore in the urgent need to developing the improved Plk1 inhibitors of kinases of character such as efficient, low toxicity, pharmacokinetics.
Summary of the invention
In order to overcome the deficiencies in the prior art part, present invention aim at design, synthesize a kind of novel dihydropteridine ketones derivant, it is intended to while making it that Plk1 is kept good kinase inhibiting activity, Plk family internal selectivity is greatly improved.
This invention address that technical problem, adopt the following technical scheme that
The dihydropteridine ketones derivant of the present invention, shown in general structure such as formula I or formula II:
In formula: R1Selected from-H ,-CH3、-CH2OCH3Or-CH2CH2OH；R2Selected from-CH3、-OCH3、-CH2CH2OH、-OCH2CH2OH、-OCH2CH2OCH3Or-OCH2C6H5；R3Selected from-CH2CH2CH3、-CH2CH2CH2CH3、-Ar、-CH2CH2N(CH3)2, 1-cyclohexyl-4-cyclopropane methyl-piperazine, 4-ethyl morpholine, 1-methyl-4-ethyl piperazidine, 1-methyl-pi, 1-isopropyl-piperidines, alkyl, the alkyl replaced by heterocyclic radical, five-membered ring, hexatomic ring or the hexatomic ring that replaced by alkyl substituent；R4Selected from-CH2CH2OH、-CH2CH2CH2OH、-CH3、-CH2CH2CH3、-CH2CH2CH2CH3,-Ar, (R)-7-ethyl-2-chloro-8-cyclopenta chloro-5 hydrogen of-5-methyl-7,8-two-dish pyridine-6-ketone, alkyl, the alkyl replaced by heterocyclic radical, five-membered ring, hexatomic ring or the hexatomic ring that replaced by alkyl substituent；R5It is selected from
Preferably, the dihydropteridine ketones derivant of the present invention, shown in its structural formula such as formula (1), formula (2) ... or formula (56):
The feature of the preparation method of dihydropteridine ketones derivant of the present invention is: with 2-dicyclohexyl phosphine-2', 4', 6'-tri isopropyl biphenyl or 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene is part, adopts Pd based metal catalysts and polar non-solute, by arylamine with virtue halogen under the alkali condition of anhydrous and oxygen-free, with 60 DEG C of-140 DEG C of coupling reactions 8～24 hours, obtain product；When product structure formula is such as shown in formula I, shown in reaction equation such as formula (A), when product structure formula is such as shown in formula II, shown in reaction equation such as formula (B)；
Wherein, described Pd based metal catalysts is Palladous chloride., palladium, three (dibenzalacetone) two palladium or tetrakis triphenylphosphine palladium；Described polar non-solute is dioxane, dimethyl sulfoxide, N,N-dimethylformamide or acetone；Described alkali condition is provided by cesium carbonate.Preferably, described Pd based metal catalysts is three (dibenzalacetone) two palladium；Described polar non-solute is dioxane；Described part is the double; two diphenylphosphine-9,9-dimethyl xanthene of 4,5-；The temperature of coupling reaction is 100 DEG C-120 DEG C, the time is 12～18 hours.
In addition, the dihydropteridine ketones derivant of the present invention can also be adopted and be prepared with the following method: with BTA-N, N, N', N'-tetramethylurea hexafluorophosphate is catalyst, adopt dichloromethane make solvent, by (R)-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-benzoic acid and primary amine under anhydrous alkali condition, with room temperature reaction 12 hours, obtain product；Shown in reaction equation such as formula (A), alkali condition is provided by diisopropylamine.
The present invention further discloses the application in the medicine for the treatment of cell proliferation class disease of the above-mentioned dihydropteridine ketones derivant.Wherein said cell proliferation class disease includes: breast carcinoma, adenocarcinoma of lung, cervical cancer, hepatocarcinoma, early children's grain leukemia, colon cancer, chronic myelocytic leukemia, epidermal carcinoma, nonsmall-cell lung cancer, carcinoma of prostate, acute lymphoblastic leukemia, lymphoma, cancer of pancreas, acute leukemia, carcinoma of prostate, tumor of head and neck, cutaneous melanoma, ovarian cancer, sarcoma etc..
Beneficial effects of the present invention is embodied in: the dihydropteridine ketones derivant of the present invention, preparation method is simple, and while Plk1 is kept good kinase inhibiting activity, Plk family internal selectivity is greatly improved, thereby improve most kinase whose selectivitys, thus improving the targeting of medicine, reach, while keeping drug effect, to reduce toxic and side effects and untoward reaction.
Accompanying drawing explanation
Fig. 1 is the reaction scheme figure of embodiment 1；Fig. 2 is the reaction scheme figure of embodiment 2；Fig. 3 is the reaction scheme figure of embodiment 3；Fig. 4 is the reaction scheme figure of embodiment 4；Fig. 5 is the reaction scheme figure of embodiment 5；Fig. 6 is the reaction scheme figure of embodiment 6；Fig. 7 is the reaction scheme figure of embodiment 7；Fig. 8 is the reaction scheme figure of embodiment 8；Fig. 9 is the reaction scheme figure of embodiment 9；Figure 10 is the reaction scheme figure of embodiment 10；Figure 11 is the reaction scheme figure of embodiment 11；Figure 12 is the reaction scheme figure of embodiment 12；Figure 13 is the reaction scheme figure of embodiment 13；Figure 14 is the reaction scheme figure of embodiment 14；Figure 15 is the reaction scheme figure of embodiment 15；Figure 16 is the reaction scheme figure of embodiment 16；Figure 17 is the reaction scheme figure of embodiment 17；Figure 18 is the reaction scheme figure of embodiment 18；Figure 19 is the reaction scheme figure of embodiment 19；Figure 20 is the reaction scheme figure of embodiment 20；Figure 21 is the reaction scheme figure of embodiment 21；Figure 22 is the reaction scheme figure of embodiment 22；Figure 23 is the reaction scheme figure of embodiment 23；Figure 24 is the reaction scheme figure of embodiment 24；Figure 25 is the reaction scheme figure of embodiment 25；Figure 26 is the reaction scheme figure of embodiment 26；Figure 27 is the reaction scheme figure of embodiment 27.
Detailed description of the invention
In the following embodiments, the structure of compound is determined by nuclear magnetic resonance, NMR (NMR) and mass spectrum (MS).NMR displacement provides with the unit of 1/1000000th (ppm).The mensuration of NMR with Agilent company of U.S. VNMRS600 nuclear magnetic resonance spectrometer VNMRS400 nuclear magnetic resonance spectrometer, mensuration solvent is deuterochloroform, deuterated dimethyl sulfoxide, deuterated acetone, is inside designated as tetramethylsilane (TMS).The mensuration of MS ACQUITYUPLCLCTPremierXE (ESI) mass spectrograph.
Kinases and cancerous cell IC50Mensuration with NovoStar microplate reader (Germany BMG company)
Tlc silica gel plate uses Qingdao GF254 silica gel plate, and specification is 0.15mm-0.2mm, and the specification that thin layer chromatography separation purified product adopts is 0.4mm-0.5mm.It is carrier that column chromatography for separation is generally adopted 200-300 order silica gel.
The initiation material of the present invention is all bought from market, buys from companies such as splendid remote science and technology (Shanghai) Co., Ltd., lark prestige Science and Technology Ltd., Aladdin Reagent Company, this Reagent Company of Adama.
Nitrogen atmosphere refers to that reaction unit connects the nitrogen balloon of an about 1L volume, and substitutes nitrogen more than three times.
Without specified otherwise in following embodiment, the temperature of reaction is room temperature, reaction dissolvent is dichloromethane.
Embodiment 1, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino)-3-hydroxy-benzoyIamide (compound 1), reaction scheme as shown in Figure 1:
The first step, (R)-2-amino-butyric acid methyl ester (compound 1b)
Under ice bath, take (R)-2-amino-butyric acid (compound 1a) (10g, 96.9mmol) be dissolved in 120mL methanol, it is slowly added dropwise thionyl chloride (16mL, 0.22mol), return stirring reacts 2 hours, is cooled to room temperature, concentrating under reduced pressure reactant liquor, give light yellow oil, add 100mL t-butyl methyl ether to stir 0.5 hour, precipitate out white solid, sucking filtration, dried in vacuum overnight, obtain compound 1b (10.5g, white solid, productivity 93%).1HNMR (600MHz, CDCl3) δ 8.78 (s, 2H), 4.15 (d, J=5.2Hz, 1H), 3.82 (s, 3H), 2.14 (q, J=7.4Hz, 2H), 1.12 (t, J=7.5Hz, 3H).
Second step, (R)-2-cyclopenta-amino-butyric acid methyl ester (compound 1c)
Take compound 1b (10.5g, 89.7mmol) and Ketocyclopentane (7.9mL, 89.7mmol) is dissolved in dichloromethane, react 0.5 hour.Sodium acetate (7.36g, 89.7mmol) and sodium triacetoxy borohydride (20.3g, 101mmol) is added under ice bath, rise to room temperature subsequently, after stirring reaction 16h, add saturated sodium carbonate, with dichloromethane extraction (100mL × 3), merge organic facies, clean with saturated aqueous common salt, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, obtain light yellow oil, it is compound 1c, is direct plungeed into next step.1HNMR(600MHz,CDCl3) δ 3.73 (s, 3H), 3.25 (t, J=6.7Hz, 1H), 3.03 2.97 (m, 1H), 1.83-1.77 (m, 2H), 1.69 (dd, J=17.8,10.8Hz, 4H), 1.55 1.46 (m, 2H), 1.38-1.33 (m, 2H), 0.92 (t, J=7.5Hz, 3H).
3rd step, (R)-2-{ (2-chloro-5-nitro-pyrimidin-4-base)-cyclopenta-amino }-methyl butyrate (compound 1d)
Take Compound Compound 1c (8.5g, 45.9mmol) and potassium carbonate (8.25g, 60.0mmol) join in acetone, under ice bath, add 2,4-bis-chloro-5-nitro-pyrimidine (10.7g, 55.1mmol), 60 DEG C are reacted 16 hours, and reduce pressure distillation and concentration, and residue with Ethyl acetate extracts, and clean with saturated aqueous common salt, merging organic facies, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, compound 1d (8.5g, yellow solid, productivity 27.6%) is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=10:1) separating-purifying.1HNMR(400MHz,CDCl3) δ 8.66 (s, 1H), 3.78 3.71 (m, 4H), 3.60 3.50 (m, 1H), 2.41 (tt, J=14.5,7.4Hz, 1H), 2.26 2.15 (m, 1H), 2.09 1.98 (m, 1H), 1.98 1.88 (m, 1H), 1.84 1.66 (m, 3H), 1.66 1.45 (m, 3H), 1.05 (t, J=7.5Hz, 3H).
4th step, (R)-7-ethyl-2-chloro-5 hydrogen of chloro-8-cyclopenta-7,8-two-dish pyridine-6-ketone (compound 1e)
Take compound 1d (8.5g, 24.9mmol) to be dissolved in glacial acetic acid.At 40 DEG C, add 200mg iron powder, react 1 hour.At 50 DEG C, add 200mg iron powder, react 1 hour.At 60 DEG C, add 200mg iron powder, react 1 hour, filtered by kieselguhr while hot, filtrate reduced in volume, with saturated sodium carbonate tune pH to alkalescence, extraction into ethyl acetate (100mL × 3), then use saturated common salt water washing, merge organic facies, anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, obtain compound 1e (2.5g with column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying, brown solid, productivity 35.9%).1HNMR(600MHz,DMSO-d6) δ 10.82 (s, 1H), 7.54 (s, 1H), 4.21 (dd, J=6.7,3.1Hz, 1H), 4.09 (p, J=8.2Hz, 1H), 1.90 (dd, J=15.6,8.4Hz, 2H), 1.86 1.75 (m, 5H), 1.69 (tt, J=14.5,7.3Hz, 1H), 1.57 1.44 (m, 2H), 0.75 (t, J=7.4Hz, 3H).
5th step, (R)-7-ethyl-2-chloro-8-cyclopenta chloro-5 hydrogen of-5-methyl-7,8-two-dish pyridine-6-ketone (compound 1f)
Take Compound Compound 1e (2.5g, 8.9mmol) it is dissolved in acetone, add p-methyl benzenesulfonic acid methyl ester (2.42g, 13.3mmol) and potassium carbonate (6.9g, 17.8mmol), return stirring reacts 2 hours, it is cooled to room temperature, reactant liquor decompression distillation, extract by ethyl acetate, saturated aqueous common salt rinse (100mL × 3), merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, compound 1f (1.5g is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying, white solid, productivity 57.3%).1HNMR(600MHz,DMSO-d6) δ 7.66 (s, 1H), 4.33 (dd, J=8.9,8.2Hz, 1H), 4.25 (dd, J=7.5,3.6Hz, 1H), 3.31 (s, 3H), 2.10 2.03 (m, 1H), 1.99 1.82 (m, 5H), 1.80 1.68 (m, 2H), 1.68 1.59 (m, 2H), 0.85 (s, 3H).
6th step, 4-((tertbutyloxycarbonyl) amino)-3-((tertbutyloxycarbonyl) oxygen base) benzoic acid (compound 1h)
Take compound 1g (1g, 6.5mmol) with Bis(tert-butoxycarbonyl)oxide (4.48mL, 19.5mmol), triethylamine (2.7mL, 19.5mmol) be dissolved in dioxane, room temperature reaction 16 hours, reactant liquor adds distilled water, extraction into ethyl acetate (100mL × 3), organic facies uses saturated common salt water washing again, merges organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, obtain compound 1h (1.5g with column chromatography chromatogram method (petroleum ether: ethyl acetate=2:1) separating-purifying, white solid, productivity 61.6%).1HNMR(600MHz,CDCl3) δ 8.27 (d, J=8.3Hz, 1H), 7.95 (d, J=8.9Hz, 2H), 6.99 (s, 1H), 1.59 (s, 9H), 1.54 (s, 9H).
7th step, (R)-N-cyclopenta-4-((tertbutyloxycarbonyl) amino)-3-((tertbutyloxycarbonyl) oxygen base) Benzoylamide (compound 1i)
Take compound 1h (1.5g, 4.2mmol), BTA-N, N, N', N'-tetramethylurea hexafluorophosphate (HBTU) (2.07g, 5.46mmol) it is dissolved in DMF, room temperature reaction 0.5 hour, add Aminocyclopentane (497.3 μ l, 5.04mmol) with diisopropylamine (1.18mL, 8.4mmol), room temperature reaction 12 hours.Reactant liquor adds distilled water, with dichloromethane extraction (100mL × 3), saturated common salt water washing, merging organic facies, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, compound 1i (1.12g, white solid, productivity 63%) is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=3:1) separating-purifying.1HNMR(600MHz,CDCl3) δ 8.17 (d, J=7.0Hz, 1H), 7.66 (d, J=1.9Hz, 1H), 7.51 (dd, J=8.6,1.8Hz, 1H), 6.85 (s, 1H), 6.00 (s, 1H), 4.41 4.31 (m, 1H), 2.08 (tt, J=14.8,7.3Hz, 2H), 1.76 1.70 (m, 2H), 1.69 1.62 (m, 2H), 1.58 (s, 9H), 1.53 (s, 9H), 1.51 1.45 (m, 2H).
8th step, (R)-N-cyclopenta-4-amino-3-hydroxy-benzoyIamide (compound 1j)
Take compound 1i (1.12g, 2.67mmol) be dissolved in trifluoroacetic acid and in the solution of dichloromethane (1:1), reaction 2 hour be stirred at room temperature.Reactant liquor decompression distillation, dropping saturated sodium carbonate solution, it is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merges organic facies, and anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains compound 1j (500mg, brown solid, productivity 85%).1HNMR(600MHz,DMSO-d6) δ 9.16 (s, 1H), 7.74 (t, J=26.6Hz, 1H), 7.18 (s, 1H), 7.14 (d, J=8.1Hz, 1H), 6.53 (d, J=8.1Hz, 1H), 4.99 (s, 2H), 4.16 (dt, J=13.5,6.9Hz, 1H), 1.88 1.77 (m, 2H), 1.66 (s, 2H), 1.56 1.42 (m, 4H).
9th step, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-hydroxy-benzoyIamide (compound 1)
Under nitrogen atmosphere, take compound 1j (400mg, 1.82mmol), compound 1f (500mg, 1.70mmol), three (dibenzalacetone) two palladium (155.7mg, 0.17mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (196.7mg, 0.34mmol) and cesium carbonate (830mg, 2.55mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (203.3mg, light yellow solid, productivity 25%).1HNMR(600MHz,Acetone-d6null)δ7.95(s,1H),7.83(d,J=8.4Hz,1H),7.74(s,1H),7.47(d,J=1.9Hz,1H),7.40(d,J=7.1Hz,1H),7.35(dd,J=8.4,2.0Hz,1H),4.40(dd,J=16.4,8.6Hz,1H),4.37–4.32(m,1H),4.22(dd,J=7.7,3.6Hz,1H),3.31(s,3H),2.12–2.06(m,1H),2.00–1.93(m,4H),1.90–1.80(m,4H),1.77–1.68(m,4H),1.66–1.53(m,7H),0.85–0.80(m,3H).MS(ESI):479.0251(C26H34N6O3,[M+H]+).
Embodiment 2, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy) Benzoylamide (compound 2)
As shown in Figure 2, take compound 1 (100mg, 0.209mmol), ethylene bromohyrin (26.7 μ l, 0.376mmol) with potassium carbonate (57.8mg, 0.418mmol) it is dissolved in acetone, 60 DEG C are reacted 12 hours, reaction is cooled to room temperature after terminating, reactant liquor concentrating under reduced pressure, add distilled water, extraction into ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (55mg, light yellow solid, productivity 47.6%).1HNMR(600MHz,CDCl3null)δ8.39(d,J=8.5Hz,1H),7.54(s,1H),7.40(d,J=1.1Hz,1H),7.26(dd,J=8.5,1.7Hz,1H),6.19(d,J=6.8Hz,1H),4.50(dd,J=15.9,7.8Hz,1H),4.38(dt,J=14.1,7.0Hz,1H),4.26(dd,J=7.7,3.6Hz,1H),4.20(dd,J=10.4,6.1Hz,2H),4.06–4.02(m,1H),3.28(s,3H),2.20–2.14(m,1H),2.13–2.06(m,2H),2.03–1.95(m,1H),1.93–1.78(m,4H),1.77–1.61(m,7H),1.55–1.47(m,2H),0.86(t,J=6.0Hz,3H).MS(ESI):523.3035(C28H38N6O4,[M+H]+).
Embodiment 3, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-methoxy ethoxy) Benzoylamide (compound 3)
Such as Fig. 3, take compound 1 (100mg, 0.209mmol), 2-bromo-ethyl-methyl ether (35.3 μ l, 0.376mmol) with potassium carbonate (57.8mg, 0.418mmol) it is dissolved in acetone, 60 DEG C are reacted 12 hours, reaction is cooled to room temperature after terminating, reactant liquor concentrating under reduced pressure, add distilled water, extraction into ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (45mg, red brown solid, productivity 40%).1HNMR(600MHz,CDCl3null)δ8.54(d,J=8.4Hz,1H),7.74(s,1H),7.68(s,1H),7.45(s,1H),7.26(d,J=8.5Hz,1H),6.07(d,J=7.2Hz,1H),4.45–4.36(m,1H),4.29–4.26(m,1H),4.22(dd,J=7.7,3.5Hz,1H),3.83–3.79(m,1H),3.47(s,1H),3.32(s,1H),2.13–2.07(m,1H),2.04–1.95(m,1H),1.88(dd,J=19.5,8.9Hz,1H),1.79–1.63(m,3H),1.50(td,J=13.5,6.9Hz,1H),0.87(t,J=7.5Hz,1H).MS(ESI):537.3188(C29H40N6O4,[M+H]+).
Embodiment 4, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(benzyloxy) Benzoylamide (compound 4)
Such as Fig. 4, take compound 1 (100mg, 0.209mmol), cylite (44.6 μ l, 0.376mmol) with potassium carbonate (57.8mg, 0.418mmol) it is dissolved in acetone, 60 DEG C are reacted 12 hours, reaction is cooled to room temperature after terminating, reactant liquor concentrating under reduced pressure, add distilled water, extraction into ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (53mg, light yellow solid, productivity 45%).1HNMR(600MHz,CDCl3null)δ8.56(d,J=8.4Hz,1H),7.66(s,1H),7.64(s,1H),7.53(s,1H),7.47(d,J=7.3Hz,1H),7.40(t,J=7.3Hz,1H),7.36(d,J=7.2Hz,1H),7.27(d,J=6.4Hz,1H),6.09(d,J=7.1Hz,1H),5.19(s,1H),2.08(dd,J=19.0,12.8Hz,1H),1.95(t,J=11.2Hz,1H),1.91–1.84(m,1H),1.79(d,J=22.1Hz,1H),1.76–1.69(m,1H),1.67(dd,J=19.9,5.5Hz,1H),1.53–1.43(m,1H),0.86(t,J=7.4Hz,1H).MS(ESI):569.3243(C33H40N6O3,[M+H]+).
Embodiment 5, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino)-3-(methoxyl group)-Benzoylamide (compound 5), reaction scheme as shown in Figure 5:
The first step, 4-((tertbutyloxycarbonyl) amino)-3-(methoxyl group)-benzoic acid (compound 5b)
Take compound 5a (1g, 5.98mmol) with Bis(tert-butoxycarbonyl)oxide (2.75mL, 11.9mmol), triethylamine (1.66mL, 11.9mmol) be dissolved in dioxane, room temperature reaction 16 hours, reactant liquor adds distilled water, extraction into ethyl acetate (100mL × 3), organic facies uses saturated common salt water washing again, merges organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, obtain compound 5b (1.3g with column chromatography chromatogram method (petroleum ether: ethyl acetate=2:1) separating-purifying, white solid, productivity 81.4%).
Second step, (R)-N-cyclopenta-4-((tertbutyloxycarbonyl) amino)-3-(methoxyl group)-Benzoylamide (compound 5c)
Take compound 5b (1.3g, 4.87mmol), BTA-N, N, N', N'-tetramethylurea hexafluorophosphate (HBTU) (2.4g, 6.33mmol) it is dissolved in DMF, room temperature reaction 0.5h, add Aminocyclopentane (576 μ l, 5.84mmol) with diisopropylamine (1.37mL, 9.74mmol), room temperature reaction 12 hours.Reactant liquor adds distilled water, with dichloromethane extraction (100mL × 3), saturated common salt water washing, merging organic facies, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, compound 5c (1.1g, white solid, productivity 71.5%) is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=3:1) separating-purifying.1HNMR(600MHz,CDCl3) δ 8.10 (d, J=8.0Hz, 1H), 7.45 (s, 1H), 7.22 (s, 1H), 7.17 (dd, J=8.4,1.6Hz, 1H), 6.11 (d, J=5.6Hz, 1H), 4.38 (dd, J=13.8,6.9Hz, 1H), 3.92 (s, 3H), 2.09 (dt, J=12.4,6.3Hz, 2H), 1.73 (dd, J=8.8,6.8Hz, 2H), 1.69 1.61 (m, 2H), 1.53 (s, 9H), 1.52 1.46 (m, 2H).
3rd step, (R)-N-cyclopenta-4-amino-3-(methoxyl group)-Benzoylamide (compound 5d)
Take compound 5c (1.1g, 3.42mmol) to be dissolved in the solution that trifluoroacetic acid is 1:1 with dichloromethane ratio, reaction 2 hour is stirred at room temperature.Reactant liquor decompression distillation, dropping saturated sodium carbonate solution, it is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merges organic facies, and anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 5d (600mg, brown solid, productivity 75%)
4th step, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(methoxyl group)-Benzoylamide (compound 5)
Under nitrogen atmosphere, take compound 5d (73mg, 0.31mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (51.9mg, light yellow solid, productivity 34%).1HNMR(600MHz,CDCl3null)δ8.41(d,J=8.2Hz,1H),7.90-8.10(m,1H),7.61(s,1H),7.43(s,1H),7.23(d,J=8.4Hz,1H),6.08(d,J=7.1Hz,1H),4.53–4.45(m,1H),4.40(dd,J=14.0,7.0Hz,1H),4.24(dd,J=7.6,3.4Hz,1H),3.97(s,3H),3.32(s,3H),2.17–2.08(m,3H),2.03–1.96(m,1H),1.91–1.85(m,1H),1.81(d,J=4.8Hz,3H),1.77–1.71(m,4H),1.70–1.65(m,4H),1.51(dd,J=12.6,6.5Hz,2H),0.88(t,J=7.4Hz,3H).MS(ESI):493.2922(C27H36N6O3,[M+H]+).
Embodiment 6, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(methoxyl group)-Benzoylamide (compound 6)
As shown in Figure 6, under nitrogen atmosphere, take compound 5d (73mg, 0.31mmol), compound 1e (95mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4,5-double; two diphenylphosphine-9,9-dimethyl xanthene (40mg, 0.068mmol) with cesium carbonate (166mg, 0.51mmol) putting in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (53.3mg, light yellow solid, productivity 36%).1HNMR(600MHz,Acetone-d6) δ 9.52 (s, 1H), 8.58 (d, J=8.1Hz, 1H), 7.69 (s, 1H), 7.51 (m, 3H), 7.46 (d, J=5.8Hz, 1H), 4.49 4.41 (m, 1H), 4.39 4.32 (m, 1H), 4.15 (d, J=4.1Hz, 1H), 3.96 (s, 3H), 2.11 (d, J=7.7Hz, 1H), 2.01-1.93 (s, 4H), 1.92-1.81 (s, 4H), 1.80 1.64 (m, 5H), 1.61-1.52 (s, 4H), 0.89 (t, J=7.1Hz, 3H) .MS (ESI): 479.2774 (C26H34N6O3,[M+H]+).
Embodiment 7, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-(2-ethoxy)-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(methoxyl group)-Benzoylamide (compound 7), reaction scheme as shown in Figure 7:
The first step, (R)-7-ethyl-2-chloro-8-cyclopenta-5-(2-ethoxy) chloro-5 hydrogen of-7,8-two-dish pyridine-6-ketone (compound 7a)
Take compound 1e (100mg, 0.357mmol), ethylene bromohyrin (46.7 μ l, 0.643mmol) with potassium carbonate (98.7mg, 0.714mmol) it is dissolved in acetone, 60 DEG C are reacted 12 hours, reaction is cooled to room temperature after terminating, reactant liquor concentrating under reduced pressure, add distilled water, extraction into ethyl acetate (50mL × 2), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=2:1) separating-purifying obtains title product compound 7a (76.1mg, light yellow solid, productivity 65.8%).1HNMR(600MHz,CDCl3)δ7.99(s,1H),4.39–4.32(m,1H),4.30–4.22(m,2H),3.96–3.89(m,2H),3.89–3.81(m,1H),3.53(s,1H),2.11–2.05(m,1H),2.00–1.94(m,1H),1.92–1.81(m,4H),1.78–1.70(m,2H),1.68–1.61(m,2H),0.90–0.86(m,3H).
Second step, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-(2-ethoxy)-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(methoxyl group)-Benzoylamide (compound 7)
Under nitrogen atmosphere, take compound 5d (73mg, 0.31mmol), compound 7a (110mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains target product (58.6mg, light yellow solid, productivity 33%).1HNMR(600MHz,CDCl3null)δ8.39(d,J=8.4Hz,1H),7.98(s,1H),7.42(s,1H),7.23(d,J=8.4Hz,1H),6.16(d,J=7.2Hz,1H),4.50(dd,J=15.7,7.7Hz,1H),4.39(dd,J=14.2,7.1Hz,1H),4.28(dt,J=14.1,4.9Hz,1H),4.23(dd,J=7.9,3.6Hz,1H),3.96(s,3H),3.92(t,J=5.4Hz,2H),3.88–3.82(m,1H),2.11(td,J=12.5,6.7Hz,3H),2.00(dd,J=15.1,8.8Hz,1H),1.89–1.78(m,4H),1.70(ddd,J=23.9,13.5,5.9Hz,8H),1.55–1.48(m,2H),0.92–0.86(m,3H).MS(ESI):523.3591(C28H38N6O4,[M+H]+).
Embodiment 8, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-(methoxy)-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(methoxyl group)-Benzoylamide (compound 8), reaction scheme as shown in Figure 8:
The first step, (R)-7-ethyl-2-chloro-8-cyclopenta-5-(2-methoxy) chloro-5 hydrogen of-7,8-two-dish pyridine-6-ketone (compound 8a)
Take compound 1e (100mg, 0.357mmol), bromomethyl methyl ether (52.5 μ l, 0.643mmol) with potassium carbonate (98.7mg, 0.714mmol) it is dissolved in acetone, 60 DEG C are reacted 12 hours, reaction is cooled to room temperature after terminating, reactant liquor concentrating under reduced pressure, add distilled water, extraction into ethyl acetate (50mL × 2), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=2:1) separating-purifying obtains title product compound 8a (41mg, light yellow solid, productivity 35.4%).1HNMR(600MHz,CDCl3) δ 8.00 (s, 1H), 5.64 (d, J=10.7Hz, 1H), 4.88 (d, J=10.7Hz, 1H), 4.47 4.36 (m, 1H), 4.22 (dd, J=8.3,3.8Hz, 1H), 3.39 (s, 3H), 2.08 (tdd, J=13.5,8.7,4.7Hz, 1H), 1.99 (ddd, J=16.6,8.1,3.7Hz, 1H), 1.93 1.78 (m, 4H), 1.78 1.69 (m, 2H), 1.64 (tt, J=9.3,6.0Hz, 2H), 0.93 (t, J=7.5Hz, 3H).
Second step, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-(methoxy)-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(methoxyl group)-Benzoylamide
Under nitrogen atmosphere, take compound 5d (73mg, 0.31mmol), compound 8a (110mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains target product (61.5mg, light yellow solid, productivity 38%).1HNMR(600MHz,CDCl3null)δ7.91(s,1H),7.42(s,1H),7.24(dd,J=8.4,1.4Hz,1H),6.14–6.08(m,1H),5.65(d,J=10.6Hz,1H),4.85–4.82(m,1H),4.56–4.49(m,1H),4.40(dd,J=14.1,7.0Hz,1H),4.23(d,J=4.9Hz,1H),3.98(s,3H),3.39(s,3H),2.17–2.07(m,2H),2.03–1.85(m,2H),1.85–1.61(m,12H),1.55–1.46(m,2H),0.95(t,J=7.5Hz,3H).MS(ESI):523.3696(C28H38N6O4,[M+H]+).
Embodiment 9, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino) benzsulfamide (compound 9), reaction scheme as shown in Figure 9:
The first step, N-cyclopenta-4-acetamido-benzsulfamide (compound 9b)
Under ice bath, take Aminocyclopentane (345 μ l, 3.5mmol) with triethylamine (970 μ l, 7mmol) it is dissolved in dichloromethane, compound 9a (800mg, 3.43mmol) it is slowly added in reaction bulb in batches, room temperature reaction 3 hours, add excessive distilled water, extract with dichloromethane (100mL × 2) again, saturated common salt water washing, merges organic facies, and anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains compound 9b (725mg, white solid, productivity 75%).1HNMR(400MHz,DMSO-d6) δ 10.31 (s, 1H), 7.74 (q, J=8.4Hz, 4H), 7.50 (d, J=6.9Hz, 1H), 3.36 (d, J=5.8Hz, 1H), 2.09 (s, 3H), 1.54 (d, J=3.5Hz, 4H), 1.36 (s, 2H), 1.26 (d, J=5.6Hz, 2H).
Second step, N-cyclopenta-4-amido-benzsulfamide (compound 9c)
Take compound 9b (725mg, 2.57mmol) it is dissolved in mass fraction and is about in the concentrated hydrochloric acid solution of 20%, back flow reaction 2 hours, it is cooled to room temperature, the sodium hydroxide solution of dropping mass fraction 40%, extract by ethyl acetate (100mL × 3), saturated common salt water washing is associated with machine phase, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 9c (420mg, white solid, productivity 68%)
3rd step, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino) benzsulfamide
Under nitrogen atmosphere, take compound 9c (76.8mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (70.3mg, light yellow solid, productivity 44%).1HNMR(600MHz,CDCl3null)δ7.78(td,J=9.0,1.9Hz,4H),7.66(s,1H),7.62(d,J=8.1Hz,1H),5.19(d,J=7.0Hz,1H),4.50–4.43(m,1H),4.26(dd,J=7.8,3.6Hz,1H),3.61–3.55(m,1H),3.33(s,3H),2.14(tt,J=18.3,9.0Hz,1H),2.00(dt,J=12.4,5.1Hz,1H),1.92–1.65(m,10H),1.63–1.57(m,2H),1.51–1.43(m,2H),1.37(td,J=13.5,6.8Hz,2H),0.88(t,J=7.5Hz,3H).MS(ESI):499.2491(C25H34N6O3S,[M+H]+).
Embodiment 10, (R)-N-phenyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino) benzsulfamide (compound 10), reaction scheme as shown in Figure 10:
The first step, N-phenyl-4-acetamido-benzsulfamide (compound 10b)
Under ice bath, take aniline (319 μ l, 3.5mmol) with triethylamine (970 μ l, 7mmol) it is dissolved in dichloromethane, compound 10a (850mg, 3.64mmol) it is slowly added in reaction bulb in batches, room temperature reaction 3 hours, add excessive distilled water, extract with dichloromethane (100mL × 2) again, saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 10b (801mg, white solid, productivity 79%).
Second step, N-phenyl-4-amido-benzsulfamide (compound 10c)
Take compound 10b (801mg, 2.77mmol) it is dissolved in mass fraction and is about in the concentrated hydrochloric acid solution of 20%, back flow reaction 2 hours, it is cooled to room temperature, the sodium hydroxide solution of dropping mass fraction 40%, extract by ethyl acetate (100mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 10c (439mg, white solid, yield 64%).
3rd step, (R)-N-phenyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino) benzsulfamide
Under nitrogen atmosphere, take compound 10c (79.4mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (63.2mg, light yellow solid, productivity 39%).1HNMR(600MHz,CDCl3null)δ8.07(s,1H),7.72(s,1H),7.71–7.67(m,4H),7.62(s,1H),7.21(t,J=7.9Hz,2H),7.12–7.09(m,2H),7.07(t,J=7.4Hz,1H),4.45–4.38(m,1H),4.26(dd,J=7.8,3.6Hz,1H),3.30(s,3H),2.13–2.06(m,1H),1.99–1.92(m,1H),1.90–1.75(m,4H),1.69(tt,J=12.1,6.1Hz,2H),1.66–1.59(m,2H),0.87(t,J=7.5Hz,3H).MS(ESI):507.2177(C26H30N6O3S,[M+H]+).
Embodiment 11, (R)-N-methyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino) benzsulfamide (compound 11), reaction scheme as shown in figure 11:
The first step, N-methyl-4-acetamido-benzsulfamide (compound 11b)
Under ice bath, take methylamine (165 μ l, 3.5mmol) with triethylamine (970 μ l, 7mmol) it is dissolved in dichloromethane, compound 11a (850mg, 3.64mmol) it is slowly added in reaction bulb in batches, room temperature reaction 3 hours, add excessive distilled water, extract with dichloromethane (100mL × 2) again, saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 11b (654mg, white solid, productivity 82%).
Second step, N-methyl-4-amido-benzsulfamide (compound 11c)
Take compound 11b (654mg, 2.87mmol) it is dissolved in mass fraction and is about in the concentrated hydrochloric acid solution of 20%, back flow reaction 2 hours, it is cooled to room temperature, the sodium hydroxide solution of dropping mass fraction 40%, extract by ethyl acetate (100mL × 3), saturated common salt water washing is associated with machine phase, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 11c (378mg, white solid, productivity 71%).
3rd step, (R)-N-methyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino) benzsulfamide
Under nitrogen atmosphere, take compound 11c (60mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (65.4mg, light yellow solid, productivity 46%).1HNMR(600MHz,CDCl3) δ 7.78 (s, 4H), 7.66 (s, 1H), 7.48 (d, J=37.4Hz, 1H), 4.91 (d, J=61.4Hz, 1H), 4.51 4.43 (m, 1H), 4.26 (dd, J=7.7,3.4Hz, 1H), 3.33 (s, 3H), 2.65 (s, 3H), 2.15 (d, J=8.1Hz, 1H), 1.99 (dd, J=14.6,8.2Hz, 1H), 1.92 1.79 (m, 4H), 1.77 1.64 (m, 4H), 0.88 (t, J=7.5Hz, 3H) .MS (ESI): 444.1954 (C21H28N6O3S,[M+H]+).
Embodiment 12, (R)-N-(3-hydroxypropyl)-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino) benzsulfamide (compound 12), reaction scheme as shown in figure 12:
The first step, N-hydroxypropyl-4-acetamido-benzsulfamide (compound 12b)
Under ice bath, take Propanolamine (268 μ l, 3.5mmol) with triethylamine (970 μ l, 7mmol) it is dissolved in dichloromethane, compound 12a (850mg, 3.64mmol) it is slowly added in reaction bulb in batches, room temperature reaction 3 hours, add excessive distilled water, extract with dichloromethane (100mL × 2) again, saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 12b (638mg, white solid, productivity 67%).
Second step, N-hydroxypropyl-4-amido-benzsulfamide (compound 12c)
Take compound 12b (638mg, 2.35mmol) it is dissolved in mass fraction and is about in the concentrated hydrochloric acid solution of 20%, back flow reaction 2 hours, it is cooled to room temperature, the sodium hydroxide solution of dropping mass fraction 40%, extract by ethyl acetate (100mL × 3), saturated common salt water washing is associated with machine phase, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 12c (405mg, white solid, productivity 75%).
3rd step, (R)-N-hydroxypropyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino) benzsulfamide
Under nitrogen atmosphere, take compound 12c (73.6mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (62.5mg, light yellow solid, productivity 40%).1HNMR(600MHz,Acetone-d6null)δ8.64(s,1H),8.00(d,J=8.7Hz,2H),7.82(s,1H),7.73(d,J=8.7Hz,2H),6.25(t,J=5.9Hz,1H),4.49–4.42(m,1H),4.23(dd,J=7.9,3.5Hz,1H),3.62(s,1H),3.58(t,J=5.5Hz,2H),3.32(s,3H),3.00(q,J=6.7Hz,2H),2.15–2.06(m,1H),2.00(dt,J=10.5,6.2Hz,1H),1.91(dt,J=17.2,6.8Hz,1H),1.88–1.79(m,4H),1.74–1.60(m,5H),0.82(t,J=7.5Hz,3H).MS(ESI):489.2284(C23H32N6O4S,[M+H]+).
Embodiment 13, (R)-N-butyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino) benzsulfamide (compound 13), reaction scheme as shown in figure 13:
The first step, N-normal-butyl-4-acetamido-benzsulfamide (compound 13b)
Under ice bath, take n-butylamine (341 μ l, 3.5mmol) with triethylamine (970 μ l, 7mmol) it is dissolved in dichloromethane, compound 13a (850mg, 3.64mmol) it is slowly added in reaction bulb in batches, room temperature reaction 3 hours, add excessive distilled water, extract with dichloromethane (100mL × 2) again, saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 13b (707mg, white solid, productivity 75%).
Second step, N-normal-butyl-4-amido-benzsulfamide (compound 13c)
Take compound 13b (707mg, 2.63mmol) it is dissolved in mass fraction and is about in the concentrated hydrochloric acid solution of 20%, back flow reaction 2 hours, it is cooled to room temperature, the sodium hydroxide solution of dropping mass fraction 40%, extract by ethyl acetate (100mL × 3), saturated common salt water washing is associated with machine phase, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains target product compound 13c (438mg, white solid, productivity 73%).
3rd step, (R)-N-normal-butyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino) benzsulfamide
Under nitrogen atmosphere, take compound 13c (73mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (68.5mg, light yellow solid, productivity 44%).1HNMR(600MHz,CDCl3null)δ7.93–7.85(m,1H),7.78(q,J=8.9Hz,4H),7.65(s,1H),4.94(t,J=6.1Hz,1H),4.50–4.43(m,1H),4.28(dd,J=7.7,3.5Hz,1H),3.33(s,3H),2.97–2.91(m,2H),2.18–2.12(m,1H),2.03–1.96(m,1H),1.95–1.87(m,1H),1.86–1.79(m,3H),1.77–1.64(m,4H),1.49–1.42(m,2H),1.33–1.27(m,2H),0.87(dt,J=17.6,7.4Hz,6H).MS(ESI):487.2495(C24H34N6O3S,[M+H]+).
Embodiment 14, N-((S)-8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base)-4-((R)-8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino) benzsulfamide (compound 14), reaction scheme as shown in figure 14:
The first step, N-amino-4-acetamido-benzsulfamide (compound 14b)
Under ice bath, take ammonia (269.6 μ l, 7mmol) with triethylamine (970 μ l, 7mmol) it is dissolved in dichloromethane, compound 14a (850mg, 3.64mmol) it is slowly added in reaction bulb in batches, room temperature reaction 3 hours, add excessive distilled water, extract with dichloromethane (100mL × 2) again, saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 14b (483mg, white solid, productivity 62%).
Second step, N-amino-4-amido-benzsulfamide (compound 14c)
Take compound 14b (483mg, 2.26mmol) it is dissolved in mass fraction and is about in the concentrated hydrochloric acid solution of 20%, back flow reaction 2 hours, it is cooled to room temperature, the compound 14c sodium hydroxide solution of dropping mass fraction 40%, extract by ethyl acetate (100mL × 3), saturated common salt water washing is associated with machine phase, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product (311mg, white solid, productivity 80%).
3rd step, N-((S)-8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base)-4-((R)-8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino) benzsulfamide
Under nitrogen atmosphere, take compound 14c (55mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (35.6mg, light yellow solid, yield 16%).1HNMR(600MHz,CDCl3null)δ7.88(d,J=8.6Hz,2H),7.72–7.66(m,3H),7.62(s,1H),4.49(dd,J=16.0,8.0Hz,1H),4.31–4.24(m,2H),4.21–4.16(m,1H),3.33(s,3H),3.23(s,3H),2.15(d,J=8.7Hz,1H),2.08(d,J=7.9Hz,1H),1.99(s,1H),1.95–1.85(m,2H),1.83(dd,J=22.0,3.9Hz,3H),1.77–1.70(m,5H),1.68–1.58(m,5H),1.52(dd,J=19.9,9.4Hz,1H),1.44–1.36(m,1H),0.89(t,J=7.5Hz,3H),0.80(t,J=7.5Hz,3H).MS(ESI):688.3328(C33H44N10O4S,[M+H]+).
Embodiment 15, (R)-N-isobutyl group-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino)-N-iso-butyl-benzenesulfonamide (compound 15), reaction scheme as shown in figure 15:
The first step, N-isobutyl group-4-acetamido-benzsulfamide (compound 15b)
Under ice bath, take isobutyl amine (353 μ l, 3.5mmol) with triethylamine (970 μ l, 7mmol) it is dissolved in dichloromethane, compound 15a (850mg, 3.64mmol) it is slowly added in reaction bulb in batches, room temperature reaction 3 hours, add excessive distilled water, extract with dichloromethane (100mL × 2) again, saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 15b (718mg, white solid, productivity 76%).
Second step, N-isobutyl group-4-amido-benzsulfamide (compound 15c)
Take compound 15b (718mg, 2.66mmol) it is dissolved in mass fraction and is about in the concentrated hydrochloric acid solution of 20%, back flow reaction 2 hours, it is cooled to room temperature, the sodium hydroxide solution of dropping mass fraction 40%, extract by ethyl acetate (100mL × 3), saturated common salt water washing is associated with machine phase, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 15c (437mg, white solid, productivity 72%).
3rd step, (R)-N-isobutyl group-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-N-isobutyl-benzene sulfonamide
Under nitrogen atmosphere, take compound 15c (73mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (69mg, light yellow solid, productivity 45%).1HNMR(400MHz,DMSO-d6) δ 9.53 (s, 1H), 7.97 7.83 (m, 3H), 7.64 (d, J=8.6Hz, 2H), 7.35 (t, J=5.9Hz, 1H), 4.50 4.37 (m, 1H), 4.24 (d, J=4.2Hz, 1H), 3.26 (s, 3H), 1.96 (dd, J=50.3,20.4Hz, 3H), 1.65 (dd, J=39.4,32.7Hz, 10H), 0.78 (dd, J=15.1,7.0Hz, 9H) .MS (ESI): 487.2495 (C24H34N6O3S,[M+H]+).
Embodiment 16, (R)-N-n-pro-pyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino)-N-n-pro-pyl-benzsulfamide (compound 16), reaction scheme as shown in figure 14:
The first step, N-n-pro-pyl-4-acetamido-benzsulfamide (compound 16b)
Under ice bath, take n-propylamine (287 μ l, 3.5mmol) with triethylamine (970 μ l, 7mmol) it is dissolved in dichloromethane, compound 16a (850mg, 3.64mmol) it is slowly added in reaction bulb in batches, room temperature reaction 3 hours, add excessive distilled water, extract with dichloromethane (100mL × 2) again, saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 16b (725mg, white solid, productivity 81%).
Second step, N-n-pro-pyl-4-amido-benzsulfamide (compound 16c)
Take compound 16b (725mg, 2.84mmol) it is dissolved in mass fraction and is about in the concentrated hydrochloric acid solution of 20%, back flow reaction 2 hours, it is cooled to room temperature, the sodium hydroxide solution of dropping mass fraction 40%, extract by ethyl acetate (100mL × 3), saturated common salt water washing is associated with machine phase, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 16c (425mg, white solid, productivity 70%).
3rd step, (R)-N-n-pro-pyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-N-iso-butyl-benzenesulfonamide
Under nitrogen atmosphere, take compound 16c (69mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (70mg, light yellow solid, productivity 46%).1HNMR(600MHz,CDCl3null)δ7.85(s,1H),7.78(q,J=8.9Hz,4H),7.65(s,1H),5.04(d,J=5.1Hz,1H),4.50–4.43(m,1H),4.27(dd,J=7.7,3.5Hz,1H),3.33(s,3H),2.91(dd,J=13.5,6.7Hz,2H),2.18–2.11(m,1H),1.99(dd,J=15.0,7.4Hz,1H),1.93–1.86(m,1H),1.86–1.78(m,3H),1.77–1.65(m,4H),1.53–1.45(m,2H),0.91–0.84(m,6H).MS(ESI):473.2339(C23H32N6O3S,[M+H]+).
Embodiment 17, (R)-N-butyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino)-N-(2-ethoxy) benzsulfamide (compound 17), reaction scheme as shown in figure 17:
The first step, N-ethoxy-4-acetamido-benzsulfamide (compound 17b)
Under ice bath, take ethanolamine (210 μ l, 3.5mmol) with triethylamine (970 μ l, 7mmol) it is dissolved in dichloromethane, compound 17a (850mg, 3.64mmol) it is slowly added in reaction bulb in batches, room temperature reaction 3 hours, add excessive distilled water, extract with dichloromethane (100mL × 2) again, saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 17b (578mg, white solid, productivity 64%).
Second step, N-ethoxy-4-amido-benzsulfamide (compound 17c)
Take compound 17b (578mg, 2.24mmol) it is dissolved in mass fraction and is about in the concentrated hydrochloric acid solution of 20%, back flow reaction 2 hours, it is cooled to room temperature, the sodium hydroxide solution of dropping mass fraction 40%, extract by ethyl acetate (100mL × 3), saturated common salt water washing is associated with machine phase, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product compound 17c (353mg, white solid, yield 73%).1HNMR(600MHz,DMSO-d6) δ 7.40 (t, J=5.6Hz, 2H), 7.02 (t, J=6.0Hz, 1H), 6.63 6.58 (m, 2H), 5.90 (s, 2H), 4.61 (t, J=5.7Hz, 1H), 3.36 3.32 (m, 4H), 2.70 (q, J=6.4Hz, 2H).
3rd step, (R)-N-ethoxy-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-N-iso-butyl-benzenesulfonamide
Under nitrogen atmosphere, take compound 17c (69mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains target product (74mg, light yellow solid, productivity 49%).1HNMR(600MHz,Acetone-d6null)δ8.65(s,1H),8.00(d,J=8.7Hz,2H),7.82(s,1H),7.74(d,J=8.8Hz,2H),6.24(t,J=6.0Hz,1H),4.52–4.40(m,1H),4.23(dd,J=7.9,3.5Hz,1H),3.83(s,1H),3.57(d,J=4.9Hz,2H),3.32(s,3H),3.01–2.94(m,2H),2.12(dd,J=15.4,7.6Hz,1H),2.03–1.97(m,1H),1.92(dt,J=16.5,6.6Hz,1H),1.84(ddd,J=11.1,9.2,5.4Hz,4H),1.75–1.61(m,3H),0.82(t,J=7.5Hz,3H).MS(ESI):475.2125(C22H30N6O4S,[M+H]+).
Embodiment 18, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-methyl-benzamide
The first step, N-cyclopenta-3-methyl-4-nitrobenzamide (compound 18b)
Take compound 18a (800mg, 4.42mmol), BTA-N, N, N', N'-tetramethylurea hexafluorophosphate (HBTU) (2.17g, 5.75mmol) it is dissolved in DMF, room temperature reaction 0.5 hour, add Aminocyclopentane (522 μ l, 5.31mmol) with diisopropylamine (1.25mL, 8.84mmol), room temperature reaction 12 hours.Reactant liquor adds distilled water, it is extracted with ethyl acetate (100mL × 3), saturated common salt water washing, merging organic facies, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, title product compound 18b (600mg, white solid, productivity 55%) is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=5:1) separating-purifying.1HNMR(600MHz,CDCl3) δ 7.98 7.94 (m, 1H), 7.73 (s, 1H), 7.66 (d, J=8.4Hz, 1H), 6.28 (s, 1H), 4.38 (dt, J=14.0,6.9Hz, 1H), 2.62 (d, J=2.6Hz, 3H), 2.15 2.07 (m, 2H), 1.78 1.71 (m, 2H), 1.71 1.62 (m, 2H), 1.52 (td, J=13.7,7.1Hz, 2H).
Second step, N-cyclopenta-3-methyl-4-aminobenzamide (compound 18c)
Take compound 18b (600mg, 2.42mmol) and be dissolved in glacial acetic acid, at 40 DEG C, add 100mg iron powder, react 1 hour.At 50 DEG C, add 100mg iron powder, react 1 hour.At 60 DEG C, add 100mg iron powder, react 1 hour, filtered by kieselguhr while hot, filtrate reduced in volume, with saturated sodium carbonate tune pH to alkalescence, extraction into ethyl acetate (100mL × 2), then use saturated common salt water washing, merge organic facies, anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, obtain title product compound 18c (370mg with column chromatography chromatogram method (petroleum ether: ethyl acetate=3:1) separating-purifying, light yellow solid, productivity 70%).1HNMR(600MHz,CDCl3) δ 7.49 (s, 1H), 7.44 (d, J=8.2Hz, 1H), 6.61 (d, J=8.2Hz, 1H), 6.08 (s, 1H), 4.41 4.30 (m, 1H), 3.87 (d, J=46.3Hz, 2H), 2.14 (s, 3H), 2.04 (td, J=12.5,6.7Hz, 2H), 1.74 1.66 (m, 2H), 1.65 1.56 (m, 2H), 1.51 1.41 (m, 2H).
3rd step, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-methyl-benzamide
Under nitrogen atmosphere, take compound 18c (70mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains target product (79mg, light yellow solid, productivity 52%).1HNMR(600MHz,CDCl3null)δ8.31(d,J=8.4Hz,1H),7.64(s,1H),7.59(d,J=11.9Hz,2H),6.89(s,1H),6.03(d,J=7.3Hz,1H),4.48–4.35(m,2H),4.22(dd,J=7.8,3.6Hz,1H),3.32(s,3H),2.36(s,3H),2.13–2.05(m,3H),1.97(dd,J=13.9,6.0Hz,1H),1.90–1.76(m,4H),1.75–1.60(m,8H),1.49(td,J=13.7,7.0Hz,2H),0.88(t,J=7.4Hz,3H).MS(ESI):477.2980(C27H36N6O2,[M+H]+).
Embodiment 19, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino)-3-(2-ethoxy) Benzoylamide (compound 19), reaction scheme as shown in figure 19:
The first step, 3-ethoxy-4-nitro-benzoic acid methyl ester (compound 19b)
Take compound 19a (2g, 10.3mmol), sodium bicarbonate (400mg, 4.76mmol) it is dissolved in dimethyl sulfoxide with paraformaldehyde (400mg), 60 DEG C are reacted 12 hours, reaction stops, it is cooled to room temperature, add excessive distilled water, be extracted with ethyl acetate (100mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=3:1) separating-purifying obtains title product compound 19b (330mg, light yellow solid, productivity 15%).1HNMR(600MHz,Acetone-d6) δ 7.98 7.94 (m, 1H), 7.74 7.73 (m, 1H), 7.66 (d, J=0.9Hz, 1H), 3.68 3.66 (m, 5H), 2.77 (t, J=0.7Hz, 2H).
Second step, 3-ethoxy-4-Nitro-benzoic acid (compound 19c)
Take compound 19b (330mg, 1.47mmol) it is dissolved in the sodium hydroxide solution of mass fraction 50%, room temperature reaction 3 hours, reactant liquor dropping concentrated hydrochloric acid, it is extracted with ethyl acetate (100mL × 2), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains title product compound 19c (263mg, light yellow solid, productivity 85%).
3rd step, N-cyclopenta-3-ethoxy-4-nitro-benzamide (compound 19d)
Take compound 19c (263mg, 1.25mmol), BTA-N, N, N', N'-tetramethylurea hexafluorophosphate (HBTU) (615mg, 1.63mmol) are dissolved in N, in dinethylformamide, room temperature reaction 0.5 hour, adds Aminocyclopentane (148 μ l, 1.5mmol) and diisopropylamine (352 μ l, 2.5mmol), room temperature reaction 12 hours.Reactant liquor adds distilled water, it is extracted with ethyl acetate (100mL × 2), saturated common salt water washing, merging organic facies, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, title product compound 19d (205mg, white solid, productivity 60%) is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying.1HNMR (600MHz, Acetone-d6) δ 7.86 (s, 1H), 7.82 7.75 (m, 3H), 4.29 4.20 (m, 1H), 3.86 (s, 1H), 3.68 (d, J=6.0Hz, 2H), 2.97 (dd, J=8.6,4.4Hz, 2H), 1.90 1.83 (m, 2H), 1.60 (d, J=10.2Hz, 2H), 1.51 1.43 (m, 4H).
4th step, N-cyclopenta-3-ethoxy-4-Amino-benzamide (compound 19e)
Take compound 19d (250mg, 0.899mmol) and be dissolved in glacial acetic acid, at 40 DEG C, add 50mg iron powder, react 1 hour.At 50 DEG C, add 50mg iron powder, react 1 hour.At 60 DEG C, add 50mg iron powder, react 1 hour, filtered by kieselguhr while hot, filtrate reduced in volume, with saturated sodium carbonate tune pH to alkalescence, extraction into ethyl acetate (100mL × 2), then use saturated common salt water washing, merge organic facies, anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, obtain title product compound 19e (121mg with column chromatography chromatogram method (petroleum ether: ethyl acetate=3:1) separating-purifying, light yellow solid, productivity 55%).1HNMR(600MHz,DMSO-d6) δ 7.75 (d, J=7.3Hz, 1H), 7.47 (s, 1H), 7.45 (d, J=8.3Hz, 1H), 6.57 (d, J=8.3Hz, 1H), 5.35 (s, 2H), 4.64 (t, J=5.1Hz, 1H), 4.21 4.13 (m, 1H), 3.59 (dd, J=12.1,6.7Hz, 2H), 2.62 (t, J=6.9Hz, 2H), 1.88 1.80 (m, 2H), 1.72 1.62 (m, 2H), 1.55 1.44 (m, 4H).
5th step, (R)-N-cyclopenta-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-ethoxy) Benzoylamide
Under nitrogen atmosphere, take compound 19e (79mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product (78mg, light yellow solid, productivity 48%).1HNMR(600MHz,CDCl3null)δ8.54(s,1H),8.06(d,J=8.5Hz,1H),7.62(s,1H),7.56(d,J=8.5Hz,1H),7.51(s,1H),6.09(d,J=7.4Hz,1H),4.43–4.33(m,2H),4.19(dd,J=7.8,3.5Hz,1H),4.01–3.94(m,2H),3.27(s,3H),2.99–2.91(m,2H),2.08(ddd,J=28.4,17.0,7.5Hz,3H),1.92(dd,J=8.0,4.3Hz,1H),1.84(ddt,J=22.3,16.3,7.9Hz,1H),1.79–1.55(m,10H),1.49(td,J=13.6,6.9Hz,2H),0.87(t,J=7.5Hz,3H).MS(ESI):507.3804(C28H38N6O3,[M+H]+).
Embodiment 20, (R)-N-n-pro-pyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide (compound 20), its reaction scheme as shown in figure 20:
The first step, N-propyl group-3-hydroxyl-4-nitro-benzamide (compound 20b)
Take compound 20a (1g, 5.46mmol), BTA-N, N, N', N'-tetramethylurea hexafluorophosphate (HBTU) (2.69g, 7.1mmol) it is dissolved in DMF, room temperature reaction 0.5 hour, add n-propylamine (538 μ l, 6.55mmol) with diisopropylamine (1.54mL, 10.9mmol), room temperature reaction 12 hours.Reactant liquor adds distilled water, it is extracted with ethyl acetate (100mL × 3), saturated common salt water washing, merging organic facies, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, title product compound 20b (800mg, white solid, productivity 65%) is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=5:1) separating-purifying.1HNMR(600MHz,CDCl3) δ 10.56 (s, 1H), 8.17 (d, J=8.7Hz, 1H), 7.51 (d, J=1.6Hz, 1H), 7.35 (dd, J=8.7,1.6Hz, 1H), 6.26 (s, 1H), 3.43 (dd, J=13.5,6.7Hz, 2H), 1.70 1.62 (m, 2H), 1.00 (t, J=7.4Hz, 3H).
Second step, N-propyl group-3-(2-hydroxy ethoxy)-4-nitro-benzamide (compound 20c)
Take compound 20b (800mg, 3.57mmol), ethylene bromohyrin (456 μ l, 6.42mmol) with potassium carbonate (985mg, 7.14mmol) it is dissolved in acetone, 60 DEG C are reacted 12 hours, reaction is cooled to room temperature after terminating, reactant liquor concentrating under reduced pressure, add distilled water, extraction into ethyl acetate (100mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains title product compound 20c (315mg, light yellow solid, productivity 33%).1HNMR(600MHz,CDCl3) δ 7.83 (d, J=8.3Hz, 1H), 7.58 (s, 1H), 7.30 (t, J=9.0Hz, 1H), 6.61 (s, 1H), 4.29 4.24 (m, 2H), 3.99 3.95 (m, 2H), 3.44 3.38 (m, 2H), 1.70 1.60 (m, 2H), 0.99 (t, J=7.4Hz, 3H).
3rd step, N-propyl group-3-(2-hydroxy ethoxy)-4-Amino-benzamide (compound 20d)
Take compound 20d (315mg, 1.17mmol) and be dissolved in glacial acetic acid, at 40 DEG C, add 50mg iron powder, react 1 hour.At 50 DEG C, add 50mg iron powder, react 1 hour.At 60 DEG C, add 50mg iron powder, react 1 hour, filtered by kieselguhr while hot, filtrate reduced in volume, with saturated sodium carbonate tune pH to alkalescence, extraction into ethyl acetate (100mL × 2), then use saturated common salt water washing, merge organic facies, anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, obtain title product compound 20d (153mg with column chromatography chromatogram method (petroleum ether: ethyl acetate=3:1) separating-purifying, light yellow solid, productivity 55%).1HNMR(600MHz,CDCl3) δ 7.30 (s, 1H), 7.13 (d, J=8.1Hz, 1H), 6.60 (d, J=8.1Hz, 1H), 6.41 (s, 1H), 4.04 4.01 (m, 2H), 3.89 3.86 (m, 2H), 3.36 (dd, J=13.4,6.7Hz, 2H), 1.63 1.55 (m, 2H), 0.95 (t, J=7.4Hz, 3H).
4th step, (R)-N-n-pro-pyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide
Under nitrogen atmosphere, take compound 20d (76mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains target product (60mg, light yellow solid, productivity 38%).1HNMR(400MHz,Acetone-d6null)δ8.60(t,J=8.5Hz,1H),7.83–7.77(m,1H),7.56(dd,J=10.8,2.4Hz,2H),4.43(p,J=8.4Hz,1H),4.23(dd,J=8.1,3.7Hz,3H),4.00–3.93(m,2H),3.38–3.29(m,5H),2.16–2.11(m,1H),2.02–1.96(m,2H),1.93–1.80(m,4H),1.77–1.65(m,3H),1.60(dd,J=14.5,7.3Hz,2H),0.93(t,J=7.4Hz,3H),0.82(t,J=7.5Hz,3H).MS(ESI):497.2878(C26H36N6O4,[M+H]+).
Embodiment 21, (R)-N-butyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino)-3-(2-hydroxy ethoxy) Benzoylamide (compound 21), reaction scheme as shown in figure 21:
The first step, N-butyl-3-hydroxyl-4-nitro-benzamide (compound 21b)
Take compound 21a (1g, 5.46mmol), BTA-N, N, N', N'-tetramethylurea hexafluorophosphate (HBTU) (2.69g, 7.1mmol) it is dissolved in DMF, room temperature reaction 0.5 hour, add n-butylamine (637 μ l, 6.55mmol) with diisopropylamine (1.54mL, 10.9mmol), room temperature reaction 12 hours.Reactant liquor adds distilled water, it is extracted with ethyl acetate (100mL × 3), saturated common salt water washing, merging organic facies, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, title product compound 21b (805mg, white solid, productivity 62%) is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=5:1) separating-purifying
Second step, N-butyl-3-(2-hydroxy ethoxy)-4-nitro-benzamide (compound 21c)
Take compound 21b (805mg, 3.38mmol), ethylene bromohyrin (432 μ l, 6.08mmol) with potassium carbonate (932mg, 6.76mmol) it is dissolved in acetone, 60 DEG C are reacted 12 hours, reaction is cooled to room temperature after terminating, reactant liquor concentrating under reduced pressure, add distilled water, extraction into ethyl acetate (100mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains title product compound 21c (276mg, light yellow solid, productivity 29%)
3rd step, N-butyl-3-(2-hydroxy ethoxy)-4-Amino-benzamide (compound 21d)
Take compound 21c (276mg, 0.98mmol) and be dissolved in glacial acetic acid, at 40 DEG C, add 50mg iron powder, react 1 hour.At 50 DEG C, add 50mg iron powder, react 1 hour.At 60 DEG C, add 50mg iron powder, react 1 hour, filtered by kieselguhr while hot, filtrate reduced in volume, with saturated sodium carbonate tune pH to alkalescence, extraction into ethyl acetate (100mL × 2), then use saturated common salt water washing, merge organic facies, anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, obtain title product compound 21d (120mg with column chromatography chromatogram method (petroleum ether: ethyl acetate=3:1) separating-purifying, red brown solid, productivity 49%).1HNMR(600MHz,Acetone-d6) δ 7.63 (s, 1H), 7.43 (s, 1H), 7.36 (dd, J=8.1,1.6Hz, 1H), 6.67 (d, J=8.1Hz, 1H), 5.05 (s, 2H), 4.37 (s, 1H), 4.05 (dt, J=9.1,4.6Hz, 2H), 3.86 (t, J=10.1Hz, 2H), 3.34 (dd, J=12.9,6.8Hz, 2H), 1.56 1.50 (m, 2H), 1.38 1.31 (m, 2H), 0.94 0.84 (m, 3H).
4th step, (R)-N-butyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide
Under nitrogen atmosphere, take compound 21d (80mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains title product (47.2mg, light yellow solid, productivity 29%).1HNMR(400MHz,Acetone-d6null)δ8.60(d,J=8.4Hz,1H),7.88(s,1H),7.80(s,1H),7.67(s,1H),7.55(dd,J=11.0,2.5Hz,2H),4.48–4.39(m,1H),4.23(dd,J=9.3,4.5Hz,3H),4.00–3.94(m,2H),3.38(dd,J=12.9,7.0Hz,2H),3.32(s,3H),2.12(ddd,J=11.4,5.7,3.2Hz,1H),2.03–1.95(m,2H),1.94–1.81(m,4H),1.70(ddd,J=19.2,14.5,7.6Hz,3H),1.57(dt,J=14.8,7.4Hz,2H),1.39(dd,J=14.5,6.8Hz,2H),0.93(t,J=7.3Hz,3H),0.83(t,J=7.5Hz,3H).MS(ESI):511.3034(C27H38N6O4,[M+H]+).
Embodiment 22, (R)-N-(tetrahydrochysene-2 hydrogen-pyrans-4-base) 4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide (compound 22), reaction scheme as shown in figure 22:
The first step, N-(tetrahydrochysene-2 hydrogen-pyrans-4-base)-3-hydroxyl-4-nitro-benzamide (compound 22b)
Take compound 22a (1g, 5.46mmol), BTA-N, N, N', N'-tetramethylurea hexafluorophosphate (HBTU) (2.69g, 7.1mmol) it is dissolved in DMF, room temperature reaction 0.5 hour, add 4-amino-Pentamethylene oxide. (687 μ l, 6.55mmol) with diisopropylamine (1.54mL, 10.9mmol), room temperature reaction 12 hours.Reactant liquor adds distilled water, it is extracted with ethyl acetate (100mL × 3), saturated common salt water washing, merging organic facies, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, title product compound 22b (1g, white solid, productivity 71%) is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=5:1) separating-purifying
Second step, N-butyl-3-(2-hydroxy ethoxy)-4-nitro-benzamide (compound 22c)
Take compound 22b (1g, 3.88mmol), ethylene bromohyrin (496 μ l, 6.98mmol) with potassium carbonate (1g, 7.76mmol) it is dissolved in acetone, 60 DEG C are reacted 12 hours, reaction is cooled to room temperature after terminating, reactant liquor concentrating under reduced pressure, add distilled water, extraction into ethyl acetate (100mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains title product compound 22c (372mg, light yellow solid, productivity 31%).1HNMR(600MHz,CDCl3) δ 7.90 (d, J=8.3Hz, 1H), 7.62 (s, 1H), 7.30 (d, J=8.4Hz, 1H), 6.06 (d, J=7.4Hz, 1H), 4.32 (t, J=4.3Hz, 2H), 4.24 4.17 (m, 1H), 4.02 (dd, J=11.6,7.5Hz, 4H), 3.55 (t, J=11.5Hz, 2H), 2.02 (d, J=10.8Hz, 2H), 1.63 1.55 (m, 2H).
3rd step, N-butyl-3-(2-hydroxy ethoxy)-4-Amino-benzamide (compound 22d)
Take compound 22c (372mg, 1.2mmol) and be dissolved in glacial acetic acid, at 40 DEG C, add 50mg iron powder, react 1 hour.At 50 DEG C, add 50mg iron powder, react 1 hour.At 60 DEG C, add 50mg iron powder, react 1 hour, filtered by kieselguhr while hot, filtrate reduced in volume, with saturated sodium carbonate tune pH to alkalescence, extraction into ethyl acetate (100mL × 2), then use saturated common salt water washing, merge organic facies, anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, obtain title product compound 22d (147mg with column chromatography chromatogram method (petroleum ether: ethyl acetate=3:1) separating-purifying, red brown solid, productivity 44%).1HNMR(600MHz,DMSO-d6) δ 7.82 (d, J=7.7Hz, 1H), 7.30 7.22 (m, 2H), 6.56 (d, J=8.1Hz, 1H), 5.34 (s, 2H), 4.91 (s, 1H), 3.93 (dd, J=10.5,5.8Hz, 3H), 3.86 3.81 (m, 2H), 3.70 (d, J=3.9Hz, 2H), 3.32 (d, J=11.7Hz, 2H), 1.69 (dd, J=12.5,1.9Hz, 2H), 1.52 (qd, J=12.3,4.3Hz, 2H).
4th step, (R)-N-normal-butyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide
Under nitrogen atmosphere, take compound 22d (89mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains target product (53.6mg, light yellow solid, productivity 32%).1HNMR(400MHz,DMSO-d6null)δ8.41(d,J=8.1Hz,1H),8.14(d,J=7.7Hz,2H),7.85(s,1H),7.50(s,2H),4.34(d,J=7.6Hz,1H),4.26(s,1H),4.13(s,2H),4.02(s,1H),3.89(d,J=9.1Hz,2H),3.80(s,2H),3.39(t,J=11.2Hz,2H),3.26(s,3H),2.01(s,1H),1.90(s,2H),1.77(d,J=11.2Hz,6H),1.61(s,5H),0.77(s,3H).MS(ESI):539.2986(C28H38N8O5,[M+H]+).
Embodiment 23, (R)-N-(2-morpholinoethyl)-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide (compound 23), reaction scheme as shown in figure 23:
The first step, N-(2-morpholinoethyl)-3-hydroxyl-4-nitro-benzamide (compound 23b)
Take compound 23a (1g, 5.46mmol), BTA-N, N, N', N'-tetramethylurea hexafluorophosphate (HBTU) (2.69g, 7.1mmol) it is dissolved in DMF, room temperature reaction 0.5 hour, add 2-morpholinoethyl amine (880 μ l, 6.55mmol) with diisopropylamine (1.54mL, 10.9mmol), room temperature reaction 12 hours.Reactant liquor adds distilled water, it is extracted with ethyl acetate (100mL × 3), saturated common salt water washing, merging organic facies, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, title product compound 23b (950mg, white solid, productivity 59%) is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=5:1) separating-purifying.
Second step, N-(2-morpholinoethyl)-3-(2-hydroxy ethoxy)-4-nitro-benzamide (compound 23c)
Take compound 23b (950mg, 3.22mmol), ethylene bromohyrin (411 μ l, 5.79mmol) with potassium carbonate (830mg, 6.44mmol) it is dissolved in acetone, 60 DEG C are reacted 12 hours, reaction is cooled to room temperature after terminating, reactant liquor concentrating under reduced pressure, add distilled water, extraction into ethyl acetate (100mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, filter, filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:2) separating-purifying obtains title product compound 23c (382mg, light yellow solid, productivity 35%)
3rd step, N-(2-morpholinoethyl)-3-(2-hydroxy ethoxy)-4-Amino-benzamide (compound 23d)
Take compound 23c (382mg, 1.12mmol) and be dissolved in glacial acetic acid, at 40 DEG C, add 50mg iron powder, react 1 hour.At 50 DEG C, add 50mg iron powder, react 1 hour.At 60 DEG C, add 50mg iron powder, react 1 hour, filtered by kieselguhr while hot, filtrate reduced in volume, with saturated sodium carbonate tune pH to alkalescence, extraction into ethyl acetate (100mL × 2), then use saturated common salt water washing, merge organic facies, anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, obtain title product compound 23d (128mg with column chromatography chromatogram method (petroleum ether: ethyl acetate=3:1) separating-purifying, red brown solid, productivity 37%).
4th step, (R)-N-normal-butyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide
Under nitrogen atmosphere, take compound 21d (98mg, 0.32mmol), compound 1f (100mg, 0.34mmol), three (dibenzalacetone) two palladium (31mg, 0.034mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (40mg, 0.068mmol) and cesium carbonate (166mg, 0.51mmol) put in pressure pipe, solvent is dioxane, reacts 12 hours at 120 DEG C.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying obtains target product (50.8mg, light yellow solid, productivity 28%).1HNMR(400MHz,Acetone-d6null)δ8.65–8.56(m,1H),7.85(s,1H),7.80(s,1H),7.65(t,J=5.0Hz,1H),7.56(d,J=1.8Hz,1H),7.51(dd,J=8.5,1.8Hz,1H),4.42(dd,J=16.5,8.2Hz,1H),4.23(dd,J=8.2,3.3Hz,3H),4.01–3.94(m,2H),3.63(dd,J=10.9,6.3Hz,4H),3.51(dd,J=12.3,6.5Hz,2H),3.32(d,J=4.8Hz,3H),2.55(t,J=6.7Hz,2H),2.47(s,4H),2.17–2.08(m,1H),2.00(dd,J=13.8,7.8Hz,2H),1.94–1.80(m,4H),1.78–1.63(m,3H),0.82(t,J=7.5Hz,3H).MS(ESI):568.3242(C29H41N7O5,[M+H]+).
Embodiment 24, (R)-N-2-(dimethylamino) ethyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide (C15) (compound 24), reaction scheme as shown in figure 24:
The first step, 3-(2-hydroxy ethoxy)-4-nitro-benzoic acid methyl ester (compound 24b)
Compound 24a (2g, 10.15mol), triphenylphosphine (3.46g, 13.2mol), ethylene glycol (733 μ l, 13.2mol) puts in 100mL round-bottomed flask, and anhydrous tetrahydro furan (heavily steaming) selected by solvent.Separately tert-butyl azodicarboxylate (DBAD) (3.04g, 13.2mol) is dissolved in 20mL anhydrous tetrahydro furan, is slowly added dropwise to round-bottomed flask, room temperature reaction 48 hours.Reactant liquor concentrating under reduced pressure, obtains title product (1.91g, light yellow solid, productivity 78%) with column chromatography chromatogram method (petroleum ether: ethyl acetate=2:1) separating-purifying.1HNMR(600MHz,CDCl3) δ 7.87 (d, J=8.4Hz, 1H), 7.77 (s, 1H), 7.72 (d, J=8.4Hz, 1H), 4.33 4.30 (m, 2H), 4.03 4.00 (m, 2H), 3.97 (s, 3H).
Second step, 3-(2-hydroxy ethoxy)-4-amino-benzoic acid methyl ester (compound 24c)
By compound 24b1.91g, 150mg palladium carbon (10%) put into methanol as solvent round-bottomed flask, react 2 hours under atmosphere of hydrogen, reacting liquid filtering, filtrate reduced in volume, title product (1.42g is obtained with column chromatography chromatogram method (petroleum ether: ethyl acetate=1:1) separating-purifying, yellow solid, productivity 85%).
3rd step, (R)-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-essence of Niobe (compound 24d)
Under nitrogen atmosphere, take compound 24c (1.4g, 6.72mmol), compound 1f (2.1g, 7.14mmol), three (dibenzalacetone) two palladium (651mg, 0.714mmol), 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (840mg, 1.428mmol) and cesium carbonate (3.48g, 10.71mmol) put in pressure pipe, solvent is dioxane, 100 DEG C-120 DEG C Gradient temperature reactions 12 hours.It is cooled to room temperature, filter, filtrate adds distilled water, is extracted with ethyl acetate (100mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (pure ethyl acetate) separating-purifying obtains title product (945mg, yellow solid, productivity 30%).
4th step, (R)-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-benzoic acid (compound 24e)
Upper step product 945mg, puts in 20% sodium hydroxide solution, and namely liquid react end from muddiness reaction to transparent clarification stops, and period can strengthen naoh concentration or reacting by heating.With dilute hydrochloric acid tune PH to faintly acid, it is extracted with ethyl acetate (50mL × 3), saturated common salt water washing, merge organic facies, anhydrous sodium sulfate dries, and filters, and filtrate reduced in volume column chromatography chromatogram method (ethyl acetate: methanol=20:1) separating-purifying obtains title product (762mg, yellow solid, productivity 83%).
5th step, (R)-N-2-(dimethylamino) ethyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide
Take compound 24e (100mg, 0.22mmol), BTA-N, N, N', N'-tetramethylurea hexafluorophosphate (HBTU) (108mg, 0.29mmol) it is dissolved in dichloromethane, room temperature reaction 0.5 hour, add N, N-dimethyl ethane-hydrazine (29.1mg, 0.33mmol) with diisopropylamine (61.9 μ l, 0.44mmol), room temperature reaction 12 hours.Reactant liquor repeatedly adds excessive dichloromethane, concentrating under reduced pressure, analyses chromatography (dichloromethane: methanol=5:1) separating-purifying with thin layer and obtain title product (50mg, light yellow solid, productivity 43%).1HNMR(400MHz,Acetone-d6null)δ8.59(d,J=8.5Hz,1H),7.79(s,1H),7.57(t,J=2.9Hz,1H),7.54(dd,J=8.5,1.8Hz,1H),4.42(p,J=8.5Hz,1H),4.25–4.17(m,3H),3.97–3.91(m,2H),3.54–3.48(m,2H),3.31(m,3H),2.57(t,J=6.5Hz,2H),2.29(s,6H),2.09–2.03(m,2H),1.97(dt,J=10.2,5.1Hz,2H),1.92–1.79(m,3H),1.77–1.59(m,3H),0.82(t,J=7.5Hz,3H).MS(ESI):526.3141(C27H39N7O4,[M+H]+).
Embodiment 25, (R)-N-1-methyl piperidine-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysenes-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide (compound 25), reaction scheme as shown in figure 25:
The preparation of reference compound 24, substitutes N, N-dimethyl ethane-hydrazine by identical rate of charge compound 4-amino-1-methyl piperidine and obtains title product (62mg, light yellow solid, productivity 51%).1HNMR(600MHz,DMSO-d6null)δ8.43(d,J=8.3Hz,1H),8.13(d,J=7.7Hz,1H),8.02(s,1H),7.85(s,1H),7.50(d,J=8.8Hz,2H),4.38–4.32(m,1H),4.24(dd,J=7.5,3.3Hz,1H),4.13(t,J=4.4Hz,2H),3.80–3.77(m,2H),3.76–3.72(m,1H),3.26(s,3H),2.79(d,J=11.2Hz,2H),2.17(s,3H),2.04–1.99(m,1H),1.90(d,J=3.8Hz,2H),1.79(dd,J=36.5,15.2Hz,6H),1.67–1.56(m,5H),0.77(t,J=7.4Hz,3H).MS(ESI):552.3294(C29H41N7O4,[M+H]+).
Embodiment 26, (R)-N-2-(4-methyl piperazine)-1-ethyl-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide (compound 26), reaction scheme as shown in figure 26:
The preparation of reference compound 24, substitutes N, N-dimethyl ethane-hydrazine by identical rate of charge compound 4-methyl piperazine-1-ethylamine and obtains title product (72mg, light yellow solid, productivity 57%).1HNMR(600MHz,DMSO-d6null)δ8.43(d,J=8.4Hz,1H),8.34(t,J=5.4Hz,1H),8.05(s,1H),7.85(s,1H),7.48(s,1H),7.46(d,J=8.5Hz,1H),4.34(dd,J=16.8,8.3Hz,1H),4.25(dd,J=7.4,3.2Hz,1H),4.11(t,J=4.2Hz,2H),3.79(d,J=4.1Hz,2H),3.40–3.33(m,3H),3.25(s,3H),3.12(dd,J=12.9,6.5Hz,1H),2.46–2.42(m,2H),2.31–2.28(m,2H),2.13(d,J=3.8Hz,4H),2.07–1.96(m,2H),1.90(d,J=6.5Hz,2H),1.85–1.74(m,5H),1.66–1.57(m,3H),0.76(t,J=7.4Hz,3H).MS(ESI):581.3564(C30H44N8O4,[M+H]+).
Embodiment 27, (R)-N-1-isopropanol piperidines-4-(8-cyclopenta-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydrochysene-pteridine-2-base amino)-3-(2-hydroxy ethoxy)-Benzoylamide (C18) (compound 27), reaction scheme as shown in figure 27:
The preparation of reference compound 24, substitutes N, N-dimethyl ethane-hydrazine by identical rate of charge compound 4-amino-1-isopropyl piperidines and obtains title product (61mg, light yellow solid, productivity 48%).1HNMR(600MHz,DMSO-d6null)δ8.42(d,J=8.2Hz,1H),8.12(dd,J=42.5,7.6Hz,1H),8.00(s,1H),7.85(s,1H),7.48(d,J=8.4Hz,2H),4.39–4.30(m,1H),4.25–4.20(m,1H),4.14–4.09(m,2H),4.03(dd,J=14.3,7.2Hz,1H),3.78(d,J=3.4Hz,2H),3.73(d,J=6.7Hz,1H),3.25(s,3H),2.79(d,J=9.8Hz,2H),2.72–2.63(m,2H),2.16(t,J=11.1Hz,2H),2.01(s,1H),1.90(s,2H),1.79(s,3H),1.70–1.49(m,6H),0.95(dd,J=17.6,5.7Hz,6H),0.77(t,J=7.3Hz,3H).MS(ESI):580.3611(C31H45N7O4,[M+H]+).
Biological assessment test case
Test case 1, the compounds of this invention mensuration to Plks kinase inhibiting activity
External Plks kinase activity is tested by following method:
This kinase assay, Plk1 adopt recombinant human (1-603 residue) as nitrogen end, with the fusion protein of the spike-glutathione transferase (GST) carrying baculovirus expression system, and glutathione-sepharose is used to be purified by affinity chromatograph chromatography.The Plk2 of recombinant human is obtained by commercially available test kit.The mankind Plk3 (19-301 residue) of restructuring merges the fusion protein of His6 spike as nitrogen end.Choose 1.00 × 10 successively respectively-5mol/L、3.33×10-6mol/L、1.11×10-6mol/L、3.70×10-7mol/L、1.23×10-7mol/L、4.12×10-8mol/L、1.37×10-8mol/L、4.57×10-9mol/L、1.52×10-9mol/L、5.08×10-10The compound of mol/L10 group gradient concentration carries out the enzymatic activity experiment of Plk1, Plk2, Plk3 respectively with the casein in 20ng restructuring kinases, 10 μ g milk as substrate.The mixture (15mMMgCl2,25mMMOPS [pH7.0], 1mMDTT, 1%DMSO, 7.5mMATP, 0.3 μ Ci γ-33P-ATP) that final volume is 60 μ L carries out kinase reaction 45 minutes at 30 DEG C.The 5%TCA adding 125 μ L frosts terminates reaction.Precipitate is transferred on the cellulosic multi-screen screen plate of mixed ester, uses 1%TCA to rinse brassboard, then utilizes radioactivity to measure.Draw dose-effect curve, and calculate IC50Value.
The IC that the compounds of this invention records50Value, between 1～1000nM, is mostly between 1～500nM, and the inhibitory activity of Plk1 has been surmounted positive control BI2536 by part of compounds, and their selectivity within Plk family has respectively obtained and has been greatly improved.
Test case 2, the compounds of this invention mensuration to multiple cancer cell in vitro strain inhibitory activity
Result according to kinases test, selectively carries out mtt assay cell experiment to the compound of the present invention in following human breast carcinoma MCF-7, human lung adenocarcinoma A549, cervical cancer Hela, hepatocarcinoma Huh-7, chronic myelocytic leukemia K562 cell strain, epidermal carcinoma A431, Non-small cell lung carcinoma H1975, carcinoma of prostate DU145 totally 8 kinds of cell strains.
First tumor cell is cultured in the medium exponential phase, after 0.25% trypsinization, makes single cell suspension.With complete medium by cell dilution to 2 × 104After/mL, the cell suspending liquid obtained is seeded in the hole of 96 orifice plates.At 37 DEG C, 5%CO2Incubator in cultivate 24h.Compound to be measured and positive control BI2536 and paclitaxel DMSO are configured to 1.00 × 10-5mol/L、3.33×10-6mol/L、1.11×10-6mol/L、3.70×10-7mol/L、1.23×10-7mol/L、4.12×10-8mol/L、1.37×10-8mol/L、4.57×10-9mol/L、1.52×10-9mol/L、5.08×10-1The solution of mol/L10 Concentraton gradient, adds cultivation 48h in 96 orifice plates, then adds the MTT solution of the 2.5mg/mL of 40 μ L PBS preparations in each hole.Supernatant in hole is discarded after 4h, add 150 μ L/ hole DMSO to dissolve first a ceremonial jade-ladle, used in libation, vibrate gently to crystal and be completely dissolved, its absorbance (OD value) at 578nm wavelength place is detected by microplate reader, suppression ratio with the variable concentrations of medicine and to cell is mapped and can be obtained cuing open quantitative response curve, therefrom obtains the half-inhibition concentration of medicine.Experiment repeats three groups.
Conclusion: the compound activity showing the growth of good anticancer to various JEG-3 in the present invention.Part of compounds is better than positive control BI2536.

Claims (6)

1. a novel dihydropteridine ketones derivant of class, it is characterised in that shown in general structure such as formula I or formula II:
In formula: R1Selected from-H ,-CH3、-CH2OCH3Or-CH2CH2OH；R2Selected from-CH3、-OCH3、-CH2CH2OH、-OCH2CH2OH、-OCH2CH2OCH3Or-OCH2C6H5；R3Selected from-CH2CH2CH3、-CH2CH2CH2CH3、-Ar、-CH2CH2N(CH3)2, 1-cyclohexyl-4-cyclopropane methyl-piperazine, 4-ethyl morpholine, 1-methyl-4-ethyl piperazidine, 1-methyl-pi, 1-isopropyl-piperidines, alkyl, the alkyl replaced by heterocyclic radical, five-membered ring, hexatomic ring or the hexatomic ring that replaced by alkyl substituent；R4Selected from-CH2CH2OH、-CH2CH2CH2OH、-CH3、-CH2CH2CH3、-CH2CH2CH2CH3,-Ar, (R)-7-ethyl-2-chloro-8-cyclopenta chloro-5 hydrogen of-5-methyl-7,8-two-dish pyridine-6-ketone, alkyl, the alkyl replaced by heterocyclic radical, five-membered ring, hexatomic ring or the hexatomic ring that replaced by alkyl substituent；R5It is selected from
2. dihydropteridine ketones derivant according to claim 1, it is characterised in that shown in structural formula such as formula (1), formula (2) ... or formula (56):
3. the preparation method of the dihydropteridine ketones derivant described in a claim 1, it is characterised in that:
With 2-dicyclohexyl phosphine-2', 4', 6'-tri isopropyl biphenyl or 4, the double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene is part, adopts Pd based metal catalysts and polar non-solute, by arylamine with virtue halogen under the alkali condition of anhydrous and oxygen-free, with 60 DEG C of-140 DEG C of coupling reactions 8～24 hours, obtain product；When product structure formula is such as shown in formula I, shown in reaction equation such as formula (A), when product structure formula is such as shown in formula II, shown in reaction equation such as formula (B)；
4. preparation method according to claim 3, it is characterised in that: described Pd based metal catalysts is Palladous chloride., palladium, three (dibenzalacetone) two palladium or tetrakis triphenylphosphine palladium；Described polar non-solute is dioxane, dimethyl sulfoxide, N,N-dimethylformamide or acetone；Described alkali condition is provided by cesium carbonate.
5. preparation method according to claim 4, it is characterised in that: described Pd based metal catalysts is three (dibenzalacetone) two palladium；Described polar non-solute is dioxane；Described part is the double; two diphenylphosphine-9,9-dimethyl xanthene of 4,5-；The temperature of coupling reaction is 100 DEG C-120 DEG C, the time is 12～18 hours.
6. the application in the medicine for the treatment of cell proliferation class disease of the dihydropteridine ketones derivant described in a claim 1.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106543185A (en) * 2016-11-10 2017-03-29 吉林大学 A kind of compound of targeting ubiquitination degraded PLK1 and BRD4 albumen and its application
CN110343109A (en) * 2019-08-21 2019-10-18 郑州大学 A kind of dihydro pteridinone-sulfonic acid amide derivatives and its pharmaceutically acceptable salt, preparation method and its application
WO2019209757A1 (en) * 2018-04-24 2019-10-31 Vertex Pharmaceuticals Incorporated Pteridinone compounds and uses thereof
WO2020073906A1 (en) * 2018-10-12 2020-04-16 中国科学院合肥物质科学研究院 Mst1 kinase inhibitor and use thereof
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1745081A (en) * 2003-02-26 2006-03-08 贝林格尔英格海姆法玛两合公司 Dihydropteridinones, method for the production and use thereof in the form of drugs
CN101541800A (en) * 2006-10-25 2009-09-23 色品疗法有限公司 Pteridine derivatives as polo-like kinase inhibitors useful in the treatment of cancer
WO2015117055A1 (en) * 2014-01-31 2015-08-06 Dana-Farber Cancer Institute, Inc. Dihydropteridinone derivatives and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1745081A (en) * 2003-02-26 2006-03-08 贝林格尔英格海姆法玛两合公司 Dihydropteridinones, method for the production and use thereof in the form of drugs
CN101541800A (en) * 2006-10-25 2009-09-23 色品疗法有限公司 Pteridine derivatives as polo-like kinase inhibitors useful in the treatment of cancer
WO2015117055A1 (en) * 2014-01-31 2015-08-06 Dana-Farber Cancer Institute, Inc. Dihydropteridinone derivatives and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIJIA CHEN ET AL.: "BRD4 Structure−Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536", 《ACS MEDICINAL CHEMISTRY》 *

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