CN103435608A - Pyridino-miazines PLK1 (Polo-like kinase 1) inhibitor and application thereof - Google Patents
Pyridino-miazines PLK1 (Polo-like kinase 1) inhibitor and application thereof Download PDFInfo
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Abstract
The invention relates to the field of medicinal chemistry, and particularly relates to pyridino-miazines compounds, preparation methods of the pyridino-miazines compounds, medicinal compositions containing the compounds, and medicinal applications of the pyridino-miazines compounds and the medicinal compositions, especially applications of the pyridino-miazines compounds and the medicinal compositions serving as Polo-like kinase 1 inhibitors.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to pyridopyrimidines derivatives, their preparation method, the medicinal compositions that contains these compounds and their medical use, particularly as the purposes of Polo sample kinases 1 (Polo-like kinase1, PLKl) inhibitor.
Background technology
In recent years, tumour has surmounted cardiovascular disorder, becomes the first dead disease in the whole world, and antitumor drug research has important science and realistic meaning.
Research finds, all be obstructed, abnormal apoptosis is relevant by, differentiation out of control with the Growth of Cells that the cell cycle disorder causes for nearly all tumour.Tumour cell division frequency compared with normal cell is fast, and various regulation and control microtubule polymerizations, centrosome copy, spindle body forms and the usually overexpression of the albumen of division of cytoplasm, and increased activity.A class important in traditional antineoplastic chemotherapy medicine is exactly by acting on tubulin, make tubulin polymerization or depolymerization, thereby reach the interference tumour cell division, suppress the purpose of tumor growth, as clinical widely used vinca medicine and taxanes medicine.But tubulin also has extremely important effect in normal cell, also participate in the conduction of nerve synapse signal, therefore there is larger toxic side effect in traditional tubulin agent interfering, as taxol has obvious toxicity to peripheral nervous system, their absorption distribution performance is also not ideal in addition.So now people turn one's attention to those overexpressions and can regulate and control the tubulin function, affect the specific proteins of spindle body effect, as microtubule kinesin (kinesin), Aurora A, Polo sample kinases etc. in tumour cell.
PLKs is the serine/threonine kinases, and in multiple organism, structure is conservative.Comprise altogether 3 members that are closely related in the human cell, be that PLK1, PLK2 are (also referred to as Serum-Inducible Kinase, Snk), PLK3 is (also referred to as Fibroblast Growth Factor-Inducible Kinase, Fnk or Prk), also has in addition a member relatively far away, it is PLK4 (claiming again SNK akin Kinase, Sak).Usually PLKs has N terminal filament/Serineprotein kinase territory (approximately 252 amino-acid residues) of high conservative, simultaneously according to the hypotype difference, comprising 1 (PLK4) or 2 (PLK1-3) is positioned at C and holds conservative phospho-peptide combining site--and polo-box (60-70 residue), two polo-box that are together in series have formed polo-box domain (PBD).To the most study of PLK1, its function and regulatory mechanism are comparatively clear so far.
PLK1 mainly participates in regulating centrosome maturation; Activation CDK1-cyclin B, to enter mitotic division; Raise γ tubulin cyclic compounds, promote that bipolar spindle body forms, sister chromosome separates; Promote mixture (anaphase-promoting complex/cyclosome, APC/C) anaphase of phosphorylation, suppress early stage mitotic division and suppress son (early mitotic inhibitor, EMI-1), drive the mitotic division process.The research discovery, PLK1 can promote that in somatoblast, film forms, phosphorylation kinesin sample dynein MKLP1 and nuclear distribution gene C (NUDC) participate in division of cytoplasm.In fact the anaphase PLK1 can promote Rho GTP enzyme exchange factor Ect2 to be positioned to spindle body middle part, start division of cytoplasm, Ect2 activates RhoA at cell cortex place, RhoA triggers the gathering of actomyosin shrunk ring, promotes the contracting of hanging of cell intermediate recess simultaneously.The subcellular area positioning experiment shows, PLK1 is positioned centrosome, equatorial plate, kinetochore and division of cytoplasm place at different times.Arrive S between the phase in the G0 phase, expression amount and the activity of PLK1 rest on lower level, from the G2 phase, start to rise, and in the M phase, reach peak.But PLK1 is not the necessary factor from the G2 phase to prophase, and PLK1 can extend (prometaphase) the required time in prometaphase that is transitioned into while being suppressed largely.
Many evidences show, PLK1 is a very attractive antineoplaston target.At first, PLK1 is all overexpressions in kinds of tumors (mammary cancer, ovarian cancer, colorectal carcinoma, carcinoma of the pancreas, lung cancer, carcinoma of endometrium, cerebral tumor, skin carcinoma, head and neck cancer, esophagus cancer, cancer of the stomach, prostate cancer), its expression is one of sign of poor prognosis in specific tumors, and in normal cell, the expression level of (except the growing multiplications such as placenta, spleen, ovary, testis extracellular faster) PLK1 is very low, sometimes even can't measure.The composition activation of the second, PLK1 can be induced the fibroblastic vicious transformation of NIH3T3.The 3rd, PLK1 phosphorylation p53, make the latter lose short apoptosis of tumor cells effect.The 4th, no matter be wild-type or inactivation type (Lys82Met mutant), the overexpression of PLK1 all causes multinucleation.The 5th, the expression of high reactivity PLK1 (Thr210Asp mutant) can be crossed because DNA damage causes the G2 phase cell and is stagnated inspection.Importantly, many scholars' work shows, knocks out PLK1 in tumour cell with antisense technology, siRNA technology or micromolecular inhibitor and can cause the bipolar spindle body of oncocyte to form to be obstructed, growth-inhibiting, even apoptosis.Inject the dazed and confused propagation that specific antibody can obviously suppress cell in the Hela cell, somatoblast is near monopolar spindle phenomenon (referring to that karyomit(e) forms a single centronucleus being gathered in the centrosome that shows separation), make the dominant negative gene of expressing viral PLK1 in 10 kinds of clones, can cause two kinds of clones " mitotic division disaster " occurs.In contrast, knocking out PLK1 in normal cell system does not show the obvious cell cycle and is obstructed and growth-inhibiting, only show as poor growth as expressed dominant negative PLK1 in normal epithelium cell, but centrosome maturation is normal, less trigger cell apoptosis, in addition, suppressing the PLK1 activity can form population of cells by inhibition tumor cell on soft agar, and the tumour that can also suppress mouse tumour deformity grafting model generates.
At present, many companies have all carried out the inhibitor research for PLK1, the companies such as Cyclacel, GlaxoSmithKline, Onconova, Boehringer Ingelheim, SuperGen and Nippon Shinyaku Co., Ltd. (JP) Tokyo To, Japan have all developed the PLK1 inhibitor of controlling oneself, and wherein BI2536 and BI6727 have entered the clinical II phase and study.In a word, PLKI gets more and more people's extensive concerning as the kinases relevant to mitotic division, its cell cycle carry out smoothly and vital effect is all being brought into play in the regulation and control of Periodic correlation check point.Take PLK1 as target, find the antitumor drug of determined curative effect from gene, protein level, will become the new breakthrough point of oncotherapy.
Summary of the invention
The object of the invention is to, provide a class to there is PLK1 and suppress active small molecules organic compound or its pharmacy acceptable salt.
Another object of the present invention is to provide the preparation method of above-claimed cpd.
Another purpose of the present invention is to provide the pharmaceutical composition that comprises above-claimed cpd or its pharmacy acceptable salt.
An also purpose of the present invention is, the medical use of above-claimed cpd or its pharmaceutically-acceptable salts and medicinal compositions thereof is provided, especially in prevention, delay or treat PLK1 separately or both purposes in simultaneously participating in the medicine of the disease, particularly tumour that mediate.
For achieving the above object, the invention provides compound or its pharmacy acceptable salt with structure shown in general formula I:
Wherein, R
1expression-H, methyl.
Wherein, R
2or R
3mean independently 1-methyl piperidine-4-amino, morpholinyl the third amino, 4-methylpiperazine-1-yl, 4-(pyrrolidin-1-yl) fourth amino, 3-diethylin the third amino, 3-methoxy propyl amino, adjacent amino phenyl amino.
Wherein, R
4mean sec.-propyl, cyclopentyl.
According to the present invention, pharmacy acceptable salt comprises the acid salt that compound of Formula I and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, toxilic acid or succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid, tussol.The acid salt that comprises in addition mineral alkali, as: basic metal positively charged ion, alkaline earth metal cation, ammonium cation salt contained.
The compound of above-mentioned general formula I can be:
8-sec.-propyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-1)
8-sec.-propyl-2-[3-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-2)
8-sec.-propyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-3)
N-methyl-8-sec.-propyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-4)
N-methyl-8-sec.-propyl-2-[3-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-5)
N-methyl-8-sec.-propyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-6)
8-sec.-propyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-7)
8-sec.-propyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-8)
8-sec.-propyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-9)
N-methyl-8-sec.-propyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-10)
N-methyl-8-sec.-propyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-11)
N-methyl-8-sec.-propyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-12)
8-cyclopentyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-13)
8-cyclopentyl-2-[3-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-14)
8-cyclopentyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-15)
N-methyl-8-cyclopentyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-16)
N-methyl-8-cyclopentyl-2-[3-(1-methyl piperidine 4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-17)
N-methyl-8-cyclopentyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-18)
8-cyclopentyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-19)
8-cyclopentyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-20)
8-cyclopentyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-21)
N-methyl-8-cyclopentyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-22)
N-methyl-8-cyclopentyl-2-[4-(1-methyl piperidine 4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-23)
N-methyl-8-cyclopentyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-24)
Compounds process for production thereof of the present invention is as follows:
Reagents?and?conditions:
(i)DIPEA,n-buthanol,rt,9h;(ii)t-BuOK,toluene,rt,2h;(iii)Bt
2,Et
3N,DCM,rt,7h;(iv)m-CPBA,DCM,rt,5h;(v)THF,p-TSA,50℃,16h;(vi)R
1NH
2,MeOH,rt,12~24h.
The compounds of this invention can prepare by above-mentioned or similar above-mentioned preparation method, according to the difference of substituent difference and substituting group position, selects corresponding raw material to get final product.
The biological activity test result shows, compound of Formula I provided by the present invention and pharmacy acceptable salt thereof have the PLK1 inhibition, the growth of tumor cell line are had to certain restraining effect simultaneously.The compounds of this invention can be used for treating various parenchymatous organ's cancers, comprising melanoma, liver cancer, kidney, lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, carcinoma of testis, osteocarcinoma, the cancer of the brain, the esophageal carcinoma, gastrointestinal cancer, soft-tissue tumor, leukemia, lymphatic cancer etc., can be wherein the cancer by the PLK1 mediation, can be also the cancer that does not rely on above-mentioned mechanism.Therefore, the present invention proposes, and the compounds of this invention and pharmacy acceptable salt thereof can be used for the preparation of cancer therapy drug.
The pharmacology test of compound is as follows:
1.PLK1 inhibition active testing
The I experiment material
PLK1 (Invitrogen, USA), Z-lyte Ser/Thr16Phospho-peptide (Invitrogen, USA), 5 * kinase buffer (Invitrogen, USA), ATP (Invitrogen, USA), Development Reagent A (Invitrogen, USA), Development Buffer (Invitrogen, USA), Stop Reagent (Invitrogen, USA), 384 hole black microwell plates (Corning, USA).
The II experimental procedure
First every hole adds 2.5 μ L compound solutions, more every hole adds 5 μ L2 * substrates and 2 * ATP mixing solutions.Add 5 μ L buffer simultaneously, 5 μ L2 * substrates contrast, add 5 μ Lbuffer with 2 * ATP mixed solution as 0% phosphorylation, and 5 μ L2 * phospho-peptide solution (100%phosphorylation control) suppresses in contrast as 100% phosphorylation and 0%.Rocker 30s, room temperature (20-25 ℃) is hatched 1h.Every hole adds 5 μ LDevelopment Solution, rocker 30s, and room temperature (20-25 ℃) is hatched 1h.Every hole adds 5 μ LStop Reagent, rocker 30s, stopped reaction.Excitation wavelength is 400nm, and at λ em=445nm, plate is read respectively at the 520nm place, calculates inhibiting rate (n=3).
The III part of test results
(in table, the compound code name is corresponding to the compound code name of front)
2. tumor cell in vitro suppresses active testing
The compounds of this invention is in vitro to the inhibition activity of tumor cell line.
The I experiment material
96 porocyte culture plates (Corning, USA), T25 Tissue Culture Flask (Corning, USA), T75 Tissue Culture Flask (Corning, USA), centrifuge tube (Corning, USA), transfer pipet (Corning, USA)
dyestuff (Invitrogen, USA), 3%SDS phosphate buffered saline buffer (Invitrogen, USA), the black wall culture plate (Corning, USA) in 384 holes, rifle head (Axygen, USA), Multidrop sample injector (Thermo, USA), Janus liquid processing system (Perkinelmer, USA), the long microwell plate plate reading of Safire2 all-wave (Tecan, Switzerland).
The II experimental procedure
Before detecting, cell is processed 24~72 hours with testing compound,
add in cell culture medium 5%CO according to ten times of Dilution ratios
2with 37 ℃, lucifuge is hatched 1-4 hour.Adopt the long microwell plate plate reading of all-wave (Safire2, Switzerland) to detect fluorescent value, instrument setting: excitation wavelength (excitaion)=540nm, wavelength of transmitted light (emission)=585nm.Adopt inhibiting rate and the IC of Prism5.0 (Graphpad Software, USA) statistical analysis software computerized compound
50value.
Part of compounds is as shown in the table to the activity data of human colon cancer cell strain HCT116, human lung carcinoma cell line A549, human oophoroma cell line Hela and acute myeloid leukemia cells in children strain HL60:
(in table, the compound code name is corresponding to the compound code name of front)
Embodiment
Fusing point is measured with b shape melting point tube, and medium is methyl-silicone oil, and thermometer is not proofreaied and correct;
1for HNMR, JEOL FX90Q type fourier transform NMR instrument, BRUKER ACF-300 type nuclear magnetic resonance analyser and BRUKER AM-500 type nuclear magnetic resonance analyser complete (mark in TMS); MS measures with Nicolet2000 type Fourier transform mass spectrometer and MAT-212 type mass spectrograph.
Embodiment 1
4-[sec.-propyl (3-methoxyl group-3-oxopropyl) amino]-2-methylthiopyrimidine-5 ethyl formate (M1)
Add compound 3-isopropylamino methyl propionate 0.579g in 25ml in reaction flask, DIPEA5 drips, propyl carbinol 12ml, after stirring in ice bath cooling 5min, slowly add 2-methyl-6-chloropyrimide-5-ethyl formate 0.928g, ice bath stirs 10min, normal-temperature reaction 9h.Remove solvent under reduced pressure, in residue, add water 10ml, ethyl acetate extraction (10ml * 3), organic phase is with anhydrous magnesium sulfate drying, concentrated rear column chromatography (PE:EA=30:1), obtain white solid 0.9g, productive rate 66.1%, MS[M+H]
+342.1.
Embodiment 2
4-[cyclopentyl (3-methoxyl group-3-oxopropyl) amino]-2-methylthiopyrimidine-5 ethyl formate (M2)
The preparation method is similar to M1, obtains sample 1.2g, productive rate 61.5%, MS[M+H]
+368.2.
Embodiment 3
8-sec.-propyl-2-methylthio group-5-oxo-5,6,7,8-tetrahydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M3)
Add compound M10.36g in the 25ml reaction flask, toluene 3ml, t-BuOK is a small amount of, reacts yellowing at once, add frozen water 20ml after 2h, DCM extracts (15ml * 3), removes solvent under reduced pressure, concentrated rear column chromatography, obtain yellow crystals 0.14g, productive rate 44.9%, MS[M+H]
+296.1.
Embodiment 4
8-cyclopentyl-2-methylthio group-5-oxo-5,6,7,8-tetrahydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M4)
The preparation method is similar to M3, obtains sample 0.22g, productive rate 43.8%, MS[M+H]
+322.1.
Embodiment 5
8-sec.-propyl-2-methylthio group-5-oxo-5,8-tetrahydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M5)
Add compound M31.4g in the 50ml reaction flask, DCM20ml, slow dropping liquid Br under argon atmospher
20.025ml, drip a little Et
3n, normal-temperature reaction 7h.Remove solvent under reduced pressure, DCM extracts (20ml * 3), concentrated rear column chromatography (PE:EA=5:1+Et
3n), obtain white solid 0.42g, productive rate 30.2%.
1HNMR(300MHz?DMSO-d6)δ:9.17(1H,s,pyrimidine),8.58(1H,s,=CH-),5.50(1H,m,isopropyl),4.24(2H,q,-COOC
H 2CH
3),2.63(3H,s,-SCH
3),1.66(6H,d,isopropyl),1.29(3H,t,-COOCH
2C
H 3).MS[M+H]
+294.1.
Embodiment 6
8-cyclopentyl-2-methylthio group-5-oxo-5,8-tetrahydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M6)
The preparation method is similar to M5, obtains sample 0.60g, productive rate 30.1%, MS[M+H]
+320.1.
Embodiment 7
8-sec.-propyl-2-methylsulfonyl-5-oxo-5,8-tetrahydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M7)
Add compound M50.15g in the 25ml reaction flask, DCM5ml adds 1 equivalent m-CPBA, normal-temperature reaction 5h in batches after stirring.To the Na that adds 10% in reaction system
2s
2o
4solution, stir 30min, adds saturated Na
2cO
3solution 5ml, with DCM extraction (10ml * 3), anhydrous magnesium sulfate drying, column chromatography after concentrating under reduced pressure (PE:EA=2:1), obtain white solid 0.113g, productive rate 67.9%, MS[M+H]
+326.1.
Embodiment 8
8-cyclopentyl-2-methylsulfonyl-5-oxo-5,8-tetrahydropyridine [2,3-a] pyrimidine-6-methyl-formiate (M8)
The preparation method is similar to M7, obtains sample 0.15g, productive rate 72.0%.
1HNMR(300MHz?DMSO-d6)δ:9.57(1H,s,pyrimidine),8.74(1H,s,=CH-),5.50(1H,m,cyclopentane),4.27(2H,q,-CO
2C
H 2CH
3),3.52(3H,s,-SO
2CH
3),1.72-2.21(8H,m,cyclopentane),1.30(3H,t,-CO
2CH
2C
H 3).MS[M+H]
+352.1.
Embodiment 9
8-sec.-propyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M9)
Add compound M70.055g in the 25ml reaction flask, 3-(4-methylpiperazine-1-yl) aniline 0.1g, p-TSA0.003g, THF10ml, be heated to 50 ℃, reaction 16h.Remove solvent under reduced pressure, in residue, add water 10ml, regulate PH to 9, ethyl acetate extraction (15ml * 3), organic phase is closed with anhydrous magnesium sulfate drying, column chromatography (PE:EA=1:4+Et after concentrating under reduced pressure
3n), obtain the about 0.06g of yellow solid, productive rate 45.1%, MS[M+H]
+437.2.
Embodiment 10
8-sec.-propyl-2-[3-(1-methyl piperidine 4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M10)
The preparation method is similar to M9, obtains white solid 0.049g, productive rate 46.2%, MS[M+H]
+451.2.
Embodiment 11
8-sec.-propyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M11)
The preparation method is similar to M9, obtains white solid 0.05g, productive rate 43%, MS[M+H]
+481.3.
Embodiment 12
N-methyl-8-sec.-propyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M12)
The preparation method is similar to M9, obtains white solid 0.11g, productive rate 37.9%, MS[M+H]
+437.2.
Embodiment 13
N-methyl-8-sec.-propyl-2-[3-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M13)
The preparation method is similar to M9, obtains white solid 0.073g, productive rate 42.5%, MS[M+H]
+451.2.
Embodiment 14
N-methyl-8-sec.-propyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M14)
The preparation method is similar to M9, obtains white solid 0.06g, productive rate 41.3%, MS[M+H]
+481.3.
Embodiment 15
8-sec.-propyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M15)
The preparation method is similar to M9, obtains white solid 0.074g, productive rate 43.8%, MS[M+H]
+437.2.
Embodiment 16
8-sec.-propyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M16)
The preparation method is similar to M9, obtains white solid 0.05g, productive rate 42.0%, MS[M+H]
+451.2.
Embodiment 17
8-sec.-propyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M17)
The preparation method is similar to M9, obtains white solid 0.24g, productive rate 37.9%, MS[M+H]
+481.2.
Embodiment 18
N-methyl-8-sec.-propyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M18)
The preparation method is similar to M9, obtains white solid 0.08g, productive rate 69.4%, MS[M+H]
+437.2.
Embodiment 19
N-methyl-8-sec.-propyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-a] pyrimidine-6-methyl-formiate (M19)
The preparation method is similar to M9, obtains white solid 0.07g, productive rate 69%, MS[M+H]
+451.2.
Embodiment 20
N-methyl-8-sec.-propyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-a] pyrimidine-6-methyl-formiate (M20)
The preparation method is similar to M9, obtains white solid 0.14g, productive rate 72.8%, MS[M+H]
+481.3.
Embodiment 21
8-cyclopentyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M21)
The preparation method is similar to M9, obtains white solid 0.04g, productive rate 43.5%, MS[M+H]
+463.2.
Embodiment 22
8-cyclopentyl-2-[3-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M22)
The preparation method is similar to M9, obtains white solid 0.05g, productive rate 42%, MS[M+H]
+477.3.
Embodiment 23
8-cyclopentyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M23)
The preparation method is similar to M9, obtains white solid 0.061g, productive rate 43.4%, MS[M+H]
+507.3.
Embodiment 24
N-methyl-8-cyclopentyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M24)
The preparation method is similar to M9, obtains white solid 0.061g, productive rate 67.3%, MS[M+H]
+463.2.
Embodiment 25
N-methyl-8-cyclopentyl-2-[3-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M25)
The preparation method is similar to M9, obtains white solid 0.15g, productive rate 74.8%, MS[M+H]
+477.2.
Embodiment 26
N-methyl-8-cyclopentyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M26)
The preparation method is similar to M9, obtains white solid 0.15g, productive rate 74.8%, MS[M+H]
+507.3.
Embodiment 27
8-cyclopentyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M27)
The preparation method is similar to M9, obtains white solid 0.08g, productive rate 45.7%, MS[M+H]
+463.2.
Embodiment 28
8-cyclopentyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M28)
The preparation method is similar to M9, obtains white solid 0.06g, productive rate 43.8%, MS[M+H]
+477.3.
Embodiment 29
8-cyclopentyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M29)
The preparation method is similar to M9, obtains white solid 0.045g, productive rate 40.8%, MS[M+H]
+507.3.
Embodiment 30
N-methyl-8-cyclopentyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M30)
The preparation method is similar to M9, obtains white solid 0.075g, productive rate 70%, MS[M+H]
+463.2.
Embodiment 31
N-methyl-8-cyclopentyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M31)
The preparation method is similar to M9, obtains white solid 0.08g, productive rate 72%, MS[M+H]
+477.3.
Embodiment 32
N-methyl-8-cyclopentyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methyl-formiate (M32)
The preparation method is similar to M9, obtains white solid 0.08g, productive rate 65.5%, MS[M+H]
+507.3.
Embodiment 33
8-sec.-propyl-2-[3-(4-methylpiperazine-1-yl) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-1)
Add compound M90.02g in the 25ml reaction flask, saturated ammonia methanol solution 10ml, stirring at normal temperature 13h, react complete, column chromatography (EA:MeOH=100:1+Et
3n), obtain yellow solid 12mg, productive rate 62.1%, mp.275~277 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.28(1H,s,-NH-),9.21(1H,s,pyridinone),9.01(1H,s,-CONH),8.68(1H,s,pyrimidine),7.59(1H,s,-CONH),7.43(1H,s,ArH),7.17(2H,d,ArH),6.69(1H,d,ArH),5.55(1H,m,isopropyl),3.17(4H,s,-CH
2-×2),2.57(4H,s,-CH
2-×2),2.48(3H,s,-CH
3),1.68(6H,d,isopropyl).MS[M+H]
+422.2.
Embodiment 34
8-sec.-propyl-2-[3-(1-methyl piperidine-4-base amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-2)
The preparation method is similar to I-1, obtains faint yellow solid 20mg, productive rate 63.7%, mp.271~272 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.28(1H,s,-NH-),9.22(1H,s,pyridinone),9.02(1H,s,-CONH
2),8.68(1H,s,pyrimidine),8.08(1H,s,-NH-),7.60(1H,s,-CONH
2),7.39(1H,s,ArH),7.15(2H,d,ArH),6.70(1H,d,ArH),5.54(1H,m,isopropyl),4.02(1H,m,piepridine),2.73(2H,br.s,piepridine),2.19(3H,s,-CH
3),2.06(2H,m,piepridine),1.88(2H,m,piepridine),1.68(6H,d,isopropyl),1.48(2H,m,piepridine).MS[M+H]
+436.2.
Embodiment 35
8-sec.-propyl-2-[3-(morpholinyl propyl group amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-3)
The preparation method is similar to I-1, obtains faint yellow solid 32mg, productive rate 56.1%, mp.264~266 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.27(1H,s,-NH-),9.21(1H,s,pyridinone),9.02(1H,s,-CONH
2),8.69(1H,s,pyrimidine),8.10(1H,s,-NH-),7.58(1H,s,-CONH
2),7.38(1H,s,ArH),7.15(2H,d,ArH),6.72(1H,d,ArH),5.55(1H,m,isopropyl),3.55(4H,m,-CH
2-×2),3.04(2H,m,-CH
2-),2.33(6H,m,-CH
2-×3),1.73(2H,quint,-CH
2-),1.68(6H,d,isopropyl).MS[M+H]
+466.3.
Embodiment 36
N-methyl-8-sec.-propyl-2-[3-(4-methylpiperazine-1-yl) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-4)
The preparation method is similar to I-1, obtains faint yellow solid 26mg, productive rate 66.5%, mp.273~275 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.27(1H,s,-NH-),9.52(1H,s,pyridinone),9.15(1H,s,-CONH),8.64(1H,s,pyrimidine),7.43(1H,s,ArH),7.17(2H,d,ArH),6.69(1H,d,ArH),5.41(1H,m,isopropyl),3.09(4H,s,-CH
2-×2),2.82(3H,d,-CONHCH
3),2.46(4H,t,-CH
2-×2),2.21(3H,d,-CH
3).MS[M+H]
+436.2.
Embodiment 37
N-methyl-8-sec.-propyl-2-[3-(1-methyl piperidine-4-base amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-5)
The preparation method is similar to I-1, obtains faint yellow solid 33mg, productive rate 70.2%, mp.268~270 ℃.
1HNMR(300MNz?DMSO-d6)δ:10.28(1H,s,-NH-),9.51(1H,s,pyridinone),9.16(1H,s,-CONH),8.64(1H,s,pyrimidine),7.45(1H,s,ArH),7.16(2H,d,ArH),6.67(1H,d,ArH),5.40(1H,m,isopropyl),4.02(1H,m,piepridine),2.81(3H,d,-CONHCH
3),2.73(2H,br.s,piepridine),2.19(3H,s,-CH
3),2.07(2H,m,piepridine),1.90(2H,m,piepridine),1.69(6H,d,isopropyl),1.45(2H,m,piepridine).MS[M+H]
+450.3.
Embodiment 38
N-methyl-8-sec.-propyl-2-[3-(morpholinyl propyl group amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-6)
The preparation method is similar to I-1, obtains faint yellow solid 18mg, productive rate 65.3%, mp.261~263 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.28(1H,s,-NH-),9.20(1H,s,pyridinone),9.03(1H,s,-CONH
2),8.69(1H,s,pyrimidine),8.10(1H,s,-NH-),7.58(1H,s,-CONH
2),7.38(1H,s,ArH),7.15(2H,d,ArH),6.74(1H,d,ArH),5.51(1H,m,isopropyl),3.54(4H,m,-CH
2-×2),3.05(2H,m,-CH
2-),2.83(3H,d,-CONHCH
3),2.30(6H,m,-CH
2-×3),1.72(2H,quint,-CH
2-),1.69(6H,d,isopropyl).MS[M+H]
+480.3.
Embodiment 39
8-sec.-propyl-2-[4-(4-methylpiperazine-1-yl) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-7)
The preparation method is similar to I-1, obtains white solid 37mg, productive rate 58.5%, mp.270~272 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.24(1H,s,-NH-),9.15(1H,s,pyridinone),9.03(1H,s,-CONH),8.65(1H,s,pyrimidine),7.57(3H,s,ArH?and-CONH),6.93(2H,d,ArH),5.45(1H,s,isopropyl),3.09(4H,s,-CH
2-×2),2.46(4H,t,-CH
2-×2),2.21(3H,s,-CH
3),1.67(6H,d,isopropyl).MS[M+H]
+421.2.
Embodiment 40
8-sec.-propyl-2-[4-(1-methyl piperidine-4-base amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-8)
The preparation method is similar to I-1, obtains faint yellow solid 19mg, productive rate 59.8%, mp.275~277 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.26(1H,s,-NH-),9.15(1H,s,pyridinone),9.02(1H,s,-CONH),8.66(1H,s,pyrimidine),8.01(1H,s,-NH-),7.59(3H,s,ArH?and-CONH),6.92(2H,d,ArH),5.41(1H,s,isopropyl),3.09(4H,s,-CH
2-×2),2.44(4H,t,-CH
2-×2),2.22(3H,s,-CH
3),1.68(6H,d,isopropyl).MS[M+H]
+436.2.
Embodiment 41
8-sec.-propyl-2-[4-(morpholinyl propyl group amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-9)
The preparation method is similar to I-1, obtains faint yellow solid 42mg, productive rate 67.4%, mp.267~269 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.28(1H,s,-NH-),9.20(1H,s,pyridinone),9.03(1H,s,-CONH
2),8.69(1H,s,pyrimidine),8.10(1H,s,-NH-),7.58(3H,s,ArH?and-CONH),6.95(2H,d,ArH),5.48(1H,m,isopropyl),3.54(4H,m,-CH
2-×2),3.05(2H,m,-CH
2-),2.30(6H,m,-CH
2-×3),1.72(2H,m,-CH
2-),1.68(6H,d,isopropyl).MS[M+H]
+466.3.
Embodiment 42
N-methyl-8-sec.-propyl-2-[4-(4-methylpiperazine-1-yl) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-10)
The preparation method is similar to I-1, obtains faint yellow solid 55mg, productive rate 70.1%, mp.276~278 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.27(1H,s,-NH-),9.52(1H,s,pyridinone),9.15(1H,s,-CONH),8.64(1H,s,pyrimidine),7.58(2H,s,ArH),6.93(2H,s,ArH),5.41(1H,m,cyclopentane),3.09(4H,s,-CH
2-×2),2.82(3H,d,-CONHCH
3),2.46(4H,t,-CH
2-×2),2.21(3H,d,-CH3),2.17(2H,s,-CH
2-),1.74-1.97(6H,m,-CH
2×3).MS[M+H]
+436.3.
Embodiment 43
N-methyl-8-sec.-propyl-2-[4-(1-methyl piperidine-4-base amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-11)
The preparation method is similar to I-1, obtains white solid 55mg, productive rate 68%, mp.273~274 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.26(1H,s,-NH-),9.15(1H,s,pyridinone),9.02(1H,s,-CONH),8.66(1H,s,pyrimidine),8.01(1H,s,-NH-),7.59(2H,d,ArH),6.92(2H,d,ArH),5.41(1H,s,isopropyl),3.09(4H,s,-CH
2-×2),2.82(3H,d,-CONHCH
3),2.44(4H,t,-CH
2-×2),2.22(3H,s,-CH
3),1.68(6H,d,isopropyl).MS[M+H]
+450.3.
Embodiment 44
N-methyl-8-sec.-propyl-2-[4-(morpholinyl propyl group amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-12)
The preparation method is similar to I-1, obtains white solid 26mg, productive rate 71.4%, mp.264~265 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.27(1H,s,-NH-),9.18(1H,s,pyridinone),9.05(1H,s,-CONH
2),8.69(1H,s,pyrimidine),8.10(1H,s,-NH-),7.59(2H,d,ArH),6.92(2H,d,ArH),5.49(1H,m,isopropyl),3.54(4H,m,-CH
2-×2),3.05(2H,m,-CH
2-),2.83(3H,d,-CONHCH
3),2.30(6H,m,-CH
2-×3),1.73(2H,m,-CH
2-),1.69(6H,d,isopropyl).MS[M+H]
+480.3.
Embodiment 45
8-cyclopentyl-2-[3-(4-methylpiperazine-1-yl) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-13)
The preparation method is similar to I-1, obtains white solid 22mg, productive rate 60%, mp.272~274 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.28(1H,s,-NH-),9.21(1H,s,pyridinone),9.01(1H,s,-CONH),8.68(1H,s,pyrimidine)),7.59(1H,s,-CONH),7.43(1H,s,ArH),7.17(2H,d,ArH),6.69(1H,d,ArH),5.55(1H,m,cyclopentane),3.17(4H,s,-CH
2-×2),2.57(4H,s,-CH
2-×2),2.48(3H,s,-CH
3),2.18(2H,d,-CH
2-),1.69-1.85(6H,m,-CH
2-×3).MS[M+H]
+448.2.
Embodiment 46
8-cyclopentyl-2-[3-(1-methyl piperidine-4-base amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-14)
The preparation method is similar to I-1, obtains white solid 25mg, productive rate 62%, mp.268~270 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.27(1H,s,-NH-),9.21(1H,s,pyridinone),9.02(1H,s,-CONH),8.69(1H,s,pyrimidine)),7.56(1H,s,-CONH),7.46(1H,s,ArH),7.18(2H,d,ArH),6.70(1H,d,ArH),5.53(1H,m,cyclopentane),2.97(4H,s,-CH
2-×2),2.57(4H,s,-CH
2-×2),2.50(3H,s,-CH
3),1.67-2.11(8H,m,-CH
2-×4).MS[M+H]
+462.2.
Embodiment 47
8-cyclopentyl-2-[3-(morpholinyl propyl group amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-15)
The preparation method is similar to I-1, obtains white solid 17mg, productive rate 64.9%, mp.265~266 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.28(1H,s,-NH-),9.19(1H,s,pyridinone),9.04(1H,s,.CONH
2),8.69(1H,s,pyrimidine3,8.09(1H,s,-NH-),7.58(1H,s,-CONH
2),7.38(1H,s,ArH),7.16(2H,d,ArH),6.72(1H,d,ArH),5.54(1H,m,cyclopentane),3.56(4H,m,-CH
2-×2),3.24(2H,m,-CH
2-),1.68-2.33(16H,m,-CH
2-×8).MS[M+H]
+492.3.
Embodiment 47
N-methyl-8-cyclopentyl-2-[3-(4-methylpiperazine-1-yl) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-16)
The preparation method is similar to I-1, obtains white solid 34mg, productive rate 74.6%, mp.264~265 ℃.
1HNMR(300MHZ?DMSO-d6)δ:10.28(1H,s,-NH-),9.52(1H,s,pyridinone),9.15(1H,s,-CONH),8.64(1H,s,pyrimidine),7.42(1H,s,ArH),7.16(2H,d,ArH),6.70(1H,d,ArH),5.42(1H,m,cyclopentane),3.19(4H,s,-CH
2-×2),2.81(3H,d,-CONHCH
3),2.40(4H,t,-CH
2-×2),1.73-2.21(8H,m,-CH
2-×4).MS[M+H]
+462.3.
Embodiment 47
N-methyl-8-cyclopentyl-2-[3-(1-methyl piperidine-4-base amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-17)
The preparation method is similar to I-1, obtains white solid 31mg, productive rate 70.1%, mp.261~262 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.28(1H,s,-NH-),9.50(1H,s,pyridinone),9.16(1H,s,-CONH),8.64(1H,s,pyrimidine),7.46(1H,s,ArH),7.16(2H,d,ArH),6.66(1H,d,ArH),5.40(1H,m,cyclopentane),4.08(1H,m,piepridine),2.82(3H,d,-CONHCH
3),2.73(2H,m,piepridine),2.34(3H,s,-CH
3),1.73-2.20(14H,m,-CH
2-×7).MS[M+H]
+476.3.
Embodiment 48
N-methyl-8-cyclopentyl-2-[3-(morpholinyl propyl group amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-18)
The preparation method is similar to I-1, obtains white solid 33mg, productive rate 68.5%, mp.248~252 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.27(1H,s,-NH-),9.18(1H,s,pyridinone),9.03(1H,s,-CONH
2),8.69(1H,s,pyrimidine),8.10(1H,s,-NH-),7.58(1H,s,-CONH
2),7.38(1H,s,ArH),7.15(2H,d,ArH),6.74(1H,d,ArH),5.51(1H,m,cyclopentane),3.64(4H,m,-CH
2-×2),3.35(2H,m,-CH
2-),2.93(5H,m,-CH
2-),2.82(3H,d,-CONHCH
3),1.19-2.25(11H,m,-CH
2-).MS[M+H]
+506.3.
Embodiment 49
8-cyclopentyl-2-[4-(4-methylpiperazine-1-yl) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-19)
The preparation method is similar to I-1, obtains white solid 17mg, productive rate 48.1%, mp.261~262 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.24(1H,s,-NH-),9.15(1H,s,pyridinone),9.03(1H,s,-CONH),8.65(1H,s,pyrimidine),7.57(3H,s,ArH?and-CONH),6.93(2H,d,ArH),5.49(1H,s,cyclopentane),,3.17(4H,s,-CH
2-×2),2.57(4H,s,-CH
2-×2),2.48(3H,s,-CH
3),2.18(2H,d,-CH
2-),1.69-1.85(6H,m,-CH
2-×3).MS[M+H]
+448.2.
Embodiment 50
8-cyclopentyl-2-[4-(1-methyl piperidine-4-base amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-20)
The preparation method is similar to I-1, obtains white solid 23mg, productive rate 54.2%, mp.264~266 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.26(1H,s,-NH-),9.15(1H,s,pyridinone),9.02(1H,s,-CONH),8.66(1H,s,pyrimidine),8.01(1H,s,-NH-),7.59(3H,s,ArH?and-CONH),6.92(2H,d,ArH),5.41(1H,s,cyclopentane),3.09(4H,s,-CH
2-×2),2.51(3H,s,-CH
3),2.59(4H,s,-CH
2-×2),1.69-2.13(8H,m,-CH
2-×4).MS[M+H]
+462.3.
Embodiment 51
8-cyclopentyl-2-[4-(morpholinyl propyl group amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-21)
The preparation method is similar to I-1, obtains white solid 20mg, productive rate 61.8%, mp.256~258 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.28(1H,s,-NH-),9.20(1H,s,pyridinone),9.03(1H,s,-CONH
2),8.69(1H,s,pyrimidine),8.10(1H,s,-NH-),7.58(3H,s,ArH?and-CONH),6.95(2H,d,ArH),5.48(1H,m,cyclopentane),3.56(4H,m,-CH
2-×2),3.24(2H,m,-CH
2-),1.68-2.33(16H,m,-CH
2-×8).MS[M+H]
+492.3.
Embodiment 52
N-methyl-8-cyclopentyl-2-[4-(4-methylpiperazine-1-yl) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-22)
The preparation method is similar to I-1, obtains white solid 21mg, productive rate 55%, mp.267~268 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.27(1H,s,-NH-),9.52(1H,s,pyridinone),9.15(1H,s,-CONH),8.64(1H,s,pyrimidine),7.58(2H,s,ArH),6.93(2H,s,ArH),5.41(1H,m,cyclopentane),3.09(4H,s,-CH
2-×2),2.82(3H,d,-CH3),2.46(4H,t,-CH
2-×2),2.21(3H,d,-CONHCH
3),2.17(2H,s,-CH
2-),1.74-1.97(6H,m,-CH
2×3).MS[M+H]
+462.3.
Embodiment 53
N-methyl-8-cyclopentyl-2-[4-(1-methyl piperidine-4-base amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-23)
The preparation method is similar to I-1, obtains white solid 21mg, productive rate 55%, mp.264~265 ℃.
1HNMR(300MHZ?DMSO-d6)δ:10.26(1H,s,-NH-),9.15(1H,s,pyridinone),9.02(1H,s,-CONH),8.66(1H,s,pyrimidine),8.01(1H,s,-NH-),7.59(2H,d,ArH),6.92(2H,d,ArH),5.41(1H,s,cyclopentane),4.08(1H,m,piepridine),2.82(3H,d,-CONHCH
3),2.73(2H,m,piepridine),2.34(3H,s,-CH
3),1.73-2.20(14H,m,-CH
2-×7).MS[M+H]
+476.3.
Embodiment 54
N-methyl-8-cyclopentyl-2-[4-(morpholinyl propyl group amino) phenyl]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-24)
The preparation method is similar to I-1, obtains white solid 21mg, productive rate 55%, mp.257~258 ℃.
1HNMR(300MHz?DMSO-d6)δ:10.27(1H,s,-NH-),9.18(1H,s,pyridinone),9.05(1H,s,-CONH
2),8.69(1H,s,pyrimidine),8.10(1H,s,-NH-),7.59(2H,d,ArH),6.92(2H,d,ArH),5.49(1H,m,cyclopentane),3.56(4H,m,-CH
2-×2),3.24(2H,m,-CH
2-),1.68-2.33(16H,m,-CH
2-×8).MS[M+H]
+492.3.
Claims (6)
2. the compound of claim 1, its structure is:
8-sec.-propyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-pyridinium hydroxide [2,3-d] pyrimidine-6-methane amide (I-1)
8-sec.-propyl-2-[3-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-pyridinium hydroxide [2,3-d] pyrimidine-6-methane amide (I-2)
8-sec.-propyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-3)
N-methyl-8-sec.-propyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-4)
N-methyl-8-sec.-propyl-2-[3-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-5)
N-methyl-8-sec.-propyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-6)
8-sec.-propyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-7)
8-sec.-propyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-8)
8-sec.-propyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-9)
N-methyl-8-sec.-propyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-10)
N-methyl-8-sec.-propyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-11)
N-methyl-8-sec.-propyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-12)
8-cyclopentyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-bis-dihydropyridines [2,3-d] pyrimidine-6-methane amide (I-13)
8-cyclopentyl-2-[3-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-14)
8-cyclopentyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-15)
N-methyl-8-cyclopentyl-2-[3-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-16)
N-methyl-8-cyclopentyl-2-[3-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-17)
N-methyl-8-cyclopentyl-2-[3-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-18)
8-cyclopentyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-19)
8-cyclopentyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-20)
8-cyclopentyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-21)
N-methyl-8-cyclopentyl-2-[4-(4-methylpiperazine-1-yl) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-22)
N-methyl-8-cyclopentyl-2-[4-(1-methyl piperidine-4-base amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-23)
N-methyl-8-cyclopentyl-2-[4-(morpholinyl propyl group amino) phenyl amino]-5-oxo-5,8-dihydropyridine [2,3-d] pyrimidine-6-methane amide (I-24)
3. the compound of claim 1 or its pharmacy acceptable salt, wherein pharmacy acceptable salt comprises the acid salt that general formula (I) compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, toxilic acid or Phenylsulfonic acid, succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid or tussol.
4. a pharmaceutical composition, wherein contain general formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
5. the compound of the general formula of claim 1 (I) or its pharmacy acceptable salt purposes in the medicine for the preparation of prevention or the treatment disease relevant with Polo sample kinases 1 inhibitor.
6. the purposes of claim 5, wherein the relevant clinical disease of Polo sample kinases 1 inhibitor is melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, mesothelioma.
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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 |
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CN101305000A (en) * | 2005-09-14 | 2008-11-12 | 詹森药业有限公司 | 5-oxo-5,8-dihydro-pyrido-pyrimidines as inhibitors of C-FMS kinase |
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 |
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CN101305000A (en) * | 2005-09-14 | 2008-11-12 | 詹森药业有限公司 | 5-oxo-5,8-dihydro-pyrido-pyrimidines as inhibitors of C-FMS kinase |
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 |
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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 |
CN106543185B (en) * | 2016-11-10 | 2017-12-15 | 吉林大学 | A kind of compound for targetting ubiquitination degraded PLK1 and BRD4 albumen and its application |
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