CN103435594A - 2-amino-quinazolines PLK1 (Polo-like kinase1) inhibitor and application thereof - Google Patents
2-amino-quinazolines PLK1 (Polo-like kinase1) inhibitor and application thereof Download PDFInfo
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Abstract
The invention relates to the field of medicinal chemistry, and particularly relates to 2-amino-quinazolines compounds, preparation methods of the 2-amino-quinazolines compounds, medicinal compositions containing the compounds, and medical applications of the 2-amino-quinazolines compounds and the medicinal compositions, especially applications of the 2-amino-quinazolines compounds and the medicinal compositions serving as Polo-like kinase1 inhibitors.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to 2-amino quinazoline derivative, 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, PLK1) 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-like kinases (PLKs) 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 DNA damage and be caused that the G2 phase stagnates 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 for the research of the inhibitor of PLK1, and increasing to the Research Literature of the Molecular biological function of PLKs, Patents also constantly occurs.The companies such as Cyclacel, GlaxoSmithKline, Onconova, Boehringer Ingelheim, SuperGen and Nippon Shinyaku Co., Ltd. (JP) Tokyo To, Japan have all developed own PLK1 inhibitor, and wherein BI2536 and BI6727 have entered the clinical II phase and study.In a word, PLK1 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 oncotherapy new breakthrough point.
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
1mean methyl, ethyl, sec.-propyl; R
2expression-H, methyl, methoxyl group, trifluoromethoxy.
Wherein, X means C or N.
Wherein, L means
Wherein, R
3, R
4mean independently piperidines-4-amino, 1-methyl piperidine-4-amino, morpholinyl the third amino, piperazinyl, 4-methylpiperazine-1-yl, 4-(pyrrolidin-1-yl) fourth amino, 3-diethylin the third amino, 3-methoxy propyl amino.
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:
N-(piperidin-4-yl)-3-methyl-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-1)
N-(piperidin-4-yl)-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-2)
N-(piperidin-4-yl)-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-3)
N-(piperidin-4-yl)-3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-4)
N-(1-methyl piperidine-4-yl)-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-5)
N-(1-methyl piperidine-4-yl)-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-6)
N-(1-methyl piperidine-4-yl)-3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-7)
N-(3-morpholine propyl group)-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-8)
N-(3-morpholine propyl group)-4-[(8-methyl quinazoline-2-yl) amino] benzamide (1-9)
N-(3-morpholine propyl group)-3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-10)
3-methyl-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-11)
4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-12)
3-methoxyl group-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-13)
3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-14)
4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-15)
3-methoxyl group-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-16)
3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-17)
N-(piperidin-4-yl)-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-18)
N-(piperidin-4-yl)-4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-19)
N-(1-methyl piperidine-4-yl)-4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-20)
N-(1-methyl piperidine-4-yl)-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-21)
N-(3-morpholine propyl group)-4-trifluoromethoxy-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-22)
4-methoxyl group-3-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-23)
3-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-24)
4-methoxyl group-3-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-25)
N-[4-(pyrrolidin-1-yl) butyl]-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-26)
N-[4-(pyrrolidin-1-yl) butyl]-4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-27)
N-[3-(diethylin) propyl group]-3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-28)
N-(3-methoxy-propyl)-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-29)
N-(3-methoxy-propyl)-4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-30)
N-[3-(diethylin) propyl group]-4-trifluoromethoxy-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-31)
N-(piperidin-4-yl)-3-methyl-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-32)
N-(piperidin-4-yl)-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-33)
N-(piperidin-4-yl)-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-34)
N-(piperidin-4-yl)-3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-35)
N-(1-methyl piperidine-4-yl)-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-36)
N-(1-methyl piperidine-4-yl)-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-37)
N-(1-methyl piperidine-4-yl)-3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-38)
N-(morpholinyl propyl group)-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-39)
N-(1-methyl piperidine-4-yl)-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-40)
N-(morpholinyl propyl group)-3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-41)
3-methyl-4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-42)
4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-43)
3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-44)
3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-45)
4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-46)
3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-47)
3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-48)
N-(piperidin-4-yl)-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-49)
N-(piperidin-4-yl)-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-50)
N-(1-methyl piperidine-4-yl)-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-51)
N-(1-methyl piperidine-4-yl)-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-52)
N-(3-morpholine propyl group)-4-trifluoromethoxy-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-53)
4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-piperazine-1-yl) ketone (I-54)
3-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-55)
4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-56)
N-[4-(pyrrolidin-1-yl) butyl]-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-57)
N-[4-(pyrrolidin-1-yl) butyl]-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-58)
N-[3-(diethylin) propyl group]-3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-59)
N-(3-methoxy-propyl)-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-60)
N-(3-methoxy-propyl)-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-61)
N-[3-(diethylin) propyl group]-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-62)
N-(piperidin-4-yl)-3-methyl-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-63)
N-(piperidin-4-yl)-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-64)
N-(piperidin-4-yl)-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-65)
N-(piperidin-4-yl)-3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-66)
N-(1-methyl piperidine-4-yl)-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-67)
N-(1-methyl piperidine-4-yl)-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-68)
N-(1-methyl piperidine-4-yl)-3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-69)
N-(3-morpholine propyl group)-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-70)
N-(3-morpholine propyl group)-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-71)
N-(3-morpholine propyl group)-3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-72)
3-methyl-4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-73)
4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-74)
3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-75)
3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-76)
4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-77)
3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-78)
3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-79)
N-(piperidin-4-yl)-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-80)
N-(piperidin-4-yl)-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-81)
N-(1-methyl piperidine-4-yl)-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-82)
N-(1-methyl piperidine-4-yl)-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-83)
N-(3-morpholine propyl group)-4-trifluoromethoxy-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-84)
4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-85)
3-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-86)
4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-87)
N-[4-(pyrrolidin-1-yl) butyl]-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-88)
N-[4-(pyrrolidin-1-yl) butyl]-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-89)
N-[3-(diethylin) propyl group]-3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-90)
N-(3-methoxy-propyl)-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-91)
N-(3-methoxy-propyl)-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-92)
N-[3-(diethylin) propyl group]-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-93)
N-(1-methyl piperidine-4-yl)-5-[(8-methyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-94)
6-methyl-5-[(8-sec.-propyl quinazoline-2-yl) and amino] pyridine-2-yl } (piperazine-1-yl) ketone (I-95)
N-(3-morpholine propyl group)-6-methoxyl group-5-[(8-methyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-96)
6-trifluoromethoxy-5-[(8-sec.-propyl quinazoline-2-yl) and amino] pyridine-2-yl } (4-methylpiperazine-1-yl) ketone (I-97)
N-(1-methyl piperidine-4-yl)-5-[(8-sec.-propyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-98)
N-(3-morpholine propyl group)-6-methoxyl group-5-[(8-sec.-propyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-99)
N-(1-methyl piperidine-4-yl)-6-methoxyl group-5-[(8-ethyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-100)
6-trifluoromethoxy-5-[(8-sec.-propyl quinazoline-2-yl) and amino] pyridine-2-yl } (4-methylpiperazine-1-yl) ketone (I-101)
N-(3-morpholine propyl group)-5-[(8-ethyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-102)
N-(3-methoxy-propyl)-6-methoxyl group-5-[(8-ethyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-103)
N-(1-methyl piperidine-4-yl)-6-methoxyl group-5-[(8-sec.-propyl quinazoline-2-yl) amino] pyridine-3-carboxamide (I-104)
N-(3-diethylin propyl group)-6-trifluoromethoxy-5-[(8-sec.-propyl quinazoline-2-yl) amino] pyridine-3-carboxamide (I-105)
Part of compounds preparation method of the present invention is as follows:
Reagents and conditions：
(i)Cl
3CH(OH)
2，Na
2SO
4，NH
2OH·HCl，reflex，8min；(ii)H
2SO4，80℃，2h；(iii)H
2O
2，NaOH，40℃，30min；
(iv)Urea，130℃，3.5h；(v)POCl
3，N，N-dimethylaniline，reflux，4h；(vi)NaCl，NH
3，H
2O，Zn，40℃；(vii)n-Butanol，Et
3N，118℃；(viii)KOH，EtOH，H
2O，reflux；(ix)NH
2R
2，HATU，DIPEA，DMF，rt，12h.
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 part of compounds is as follows:
1.PLK1 inhibition active testing
The I experiment material
PLK1 (Invitrogen, USA), Z-lyte Ser/Thr 16 Phospho-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 L buffer with 2 * ATP mixed solution as 0% phosphorylation, and 5 μ L 2 * phospho-peptide solution (100%phosphorylation control) suppress in contrast as 100% phosphorylation and 0%.Rocker 30s, room temperature (20-25 ℃) is hatched 1h.Every hole adds 5 μ L Development Solution, rocker 30s, and room temperature (20-25 ℃) is hatched 1h.Every hole adds 5 μ L Stop Reagent, rocker 30s, stopped reaction.Excitation wavelength is 400nn, 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 hour 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 lung carcinoma cell line A549:
(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 Nicolet 2000 type Fourier transform mass spectrometer and MAT-212 type mass spectrograph.
Embodiment 1
N-(2-isopropyl phenyl)-2-oximino ethanamide (M1)
In the 50m1 three-necked bottle, first by Na
2sO
45.14g (36.2mmol) be dissolved in H
2in O (20ml), then add Chloral Hydrate 0.98g (5.9mmol), oxammonium hydrochloride 1.25g (17.9mmol), in the 50ml eggplant-shape bottle, adds HCl 1ml, H
2o3ml, drip o-isopropyl aniline 0.73g (5.4mmol), becomes muddy, hot a little, until clarification; The clarification that all becomes in three-necked bottle and eggplant-shape bottle, pour solution in eggplant-shape bottle in three-necked bottle into, and mechanical stirring, be rapidly heated to 100 ℃, and solution is clarified gradually by muddy shape, keeps about 8 minutes; Be cooled to rapidly 20 ℃, occur the thick solid of brown in solution; Thick solid is dissolved in to EA, and mother liquor is with EA extraction (30ml * 3), column chromatography (PE: EA=5: 1), obtain the 0.41g product, productive rate 36%, mp.105-108 ℃.
Embodiment 2
N-(2-aminomethyl phenyl)-2-oximino ethanamide (M2)
The preparation method is similar to M1, obtains sample 0.60g, productive rate 40%, mp.119～120 ℃.
Embodiment 3
N-(2-ethylphenyl)-2-oximino ethanamide (M3)
The preparation method is similar to M1, obtains sample 0.68g, productive rate 38%, mp.109～111 ℃.
Embodiment 4
7-isopropyl indole-2,3-diketone (M4)
In the 25ml three-necked bottle, add vitriol oil 5ml, be preheated to 50 ℃, add compound M1 1g (4.8mmol), in controlling, temperature is no more than 50 ℃, finishes in batches, be warming up to 80 ℃, reaction 2h, complete, be cooled to room temperature, in impouring frozen water-EA mixed solution, be red solution, stir 30min, extraction, column chromatography (PE: EA=200: 1); Obtain 0.3g safran solid, productive rate 32%, mp.195～196 ℃, MS[M+H]
+1901.
Embodiment 5
7-skatole-2,3-diketone (M5)
The preparation method is similar to M4, obtains sample 0.47g, productive rate 33%, mp.270～271 ℃, MS[M+H]
+162.1.
Embodiment 6
7-ethylindole-2,3-diketone (M6)
The preparation method is similar to M4, obtains sample 0.80g, productive rate 35%, mp.193～194 ℃, MS[M+H]
+176.1.
Embodiment 7
2-amino-3-isopropyl acid (M7)
Add compound M4 0.3g (1.6mmol) in the 25ml eggplant-shape bottle, the NaOH solution 8ml of 1M, it is brown that solution is, and slowly drips 30%H
2o
20.6ml solution becomes brown, is warming up to 40 ℃.After 30min, stop.Regulate PH to 6, extraction (10ml * 3), be spin-dried for, and obtains grey powder 0.26g.Productive rate 90%, mp.95-98 ℃, MS[M+H]
+180.1.
Embodiment 8
2-amino-3-tolyl acid (M8)
The preparation method is similar to M7, obtains faint yellow solid 1.1g, productive rate 92%, mp.175～177 ℃, MS[M+H]
+152.1.
Embodiment 9
2-amino-3-ethyl benzoate (M9)
The preparation method is similar to M7, obtains faint yellow solid 1.4g, productive rate 90%, mp.158～159 ℃, MS[M+H]
+166.1.
Embodiment 10
8-sec.-propyl quinazoline-2,4 (1H, 3H)-diketone (M10)
Add compound M7 2.38g (13.3mmol) and urea 3.99g (66.4mmol) in pressure bottle, mix rear sealing, be warming up to 150 ℃ (130 ℃ the time, the raw material solid thing starts to melt, and all melts to 140 ℃ of raw materials), after 3.5h, react complete, be down to normal temperature, add water, have solid to separate out, filter, drying, obtain the 2.23g brown solid, productive rate 83%.MS[M+H]
+205.1.
Embodiment 11
8-methyl quinazoline-2,4 (1H, 3H)-diketone (M11)
The preparation method is similar to M10, obtains gray solid 1.7g, productive rate 81%, mp.285～287 ℃, MS[M+H]
+178.1.
Embodiment 12
8-ethyl quinazoline-2,4 (1H, 3H)-diketone (M12)
The preparation method is similar to M10, obtains white solid 1.0g, productive rate 85%, mp.199～200 ℃, MS[M+H]
+191.1.
Embodiment 13
The chloro-8-sec.-propyl of 2,4-bis-quinazoline (M13)
Add compound M102.89g (14.2mmol) in the 50ml reaction flask, POCl
310ml, add N after stirring, and N '-xylidene(s) 0.6ml refluxes, and the 4h reaction is complete; Reaction solution is poured in trash ice, separated out a large amount of gray solid, suction filtration, mother liquor is with EA extraction (30ml * 3), and organic phase concentrates rear and filter cake merging, column chromatography (PE: EA=100: 1), obtain yellow solid 1.13g, productive rate 33%, MS[M+H]
+242.0.
1HNMR(300MHz CDCl
3-d6)δ：8.11(1H，q，ArH)，7.88(1H，d，ArH)，7.69(1H，t，ArH)，4.16(1H，m，-C
H(CH
3)
2)，1.37(6H，d，CH(C
H 3)
2).
Embodiment 14
The chloro-8-methyl of 2,4-bis-quinazoline (M14)
The preparation method is similar to M13, obtains yellow solid 0.9g, productive rate 23%, MS[M+H]
+214.0.
1HNMR(300MHz CDCl
3-d6)δ：7.65-7.68(2H，m，ArH)，7.46(1H，t，ArH)，4.30(3H，s，-CH
3).
Embodiment 15
2,4-, bis-chloro-8-ethyl quinazolines (M15)
The preparation method is similar to M13, obtains yellow solid 1.0g, productive rate 30%, MS[M+H]
+228.0.
1HNMR(300MHz CDCl
3-d6)δ：7.74(1H，d，ArH)，7.66(1H，d，ArH)，7.53(1H，m，ArH)，4.24(2H，q，-C
H 2CH
3)1.36(3H，t，-CH
2C
H 3).
Embodiment 16
The chloro-8-sec.-propyl of 2-quinazoline (M16)
Add compound M13 0.9g (3.7mmol) in the reaction flask of 25ml, DCM10ml, add saturated NaCl (9% ammoniacal liquor) 10ml successively after stirring, and excessive Zn powder, be heated to 40 ℃, the solution colour flavescence, and 1h is complete in reaction; Filter, extraction (15ml * 3), column chromatography (PE: EA=150: 1), obtain faint yellow solid 0.42g, productive rate 54%, MS[M+H]
+207.1.
Embodiment 17
The chloro-8-methyl of 2-quinazoline (M17)
The preparation method is similar to M16, obtains faint yellow solid 0.56g, productive rate 52%, MS[M+H]
+179.0.
Embodiment 18
The chloro-8-methyl of 2-quinazoline (M18)
The preparation method is similar to M16, obtains faint yellow solid 2.1g, productive rate 55%, MS[M+H]
+193.1.
Embodiment 19
4-[(8-sec.-propyl quinazoline-2-yl) amino] ethyl benzoate (M19)
Add compound M16 0.1g (0.5mmol) in the reaction flask of 25ml, parathesin 0.083g (0.5mmol) and primary isoamyl alcohol 10ml, reflux under argon atmospher.After 24h, reaction finishes.Reaction solution is poured in large water gaging, standing, separate out solid, suction filtration, drying, obtain yellow powder shape product 1.15g, productive rate is 30%, MS[M+H]
+336.2.
1HNMR(300MHz CDCl
3-d6)δ：10.32(1H，s，-NH-)，9.36(1H，s，pyrimidine)，7.41-8.20(7H，m，ArH)，4.31(2H，m，-OC
H 2CH
3)，4.00(1H，m，-C
H(CH
3)
2)，1.38(6H，d，-CH(C
H 3)
2).
Embodiment 20
4-[(8-methyl quinazoline-2-yl) amino] ethyl benzoate (M20)
The preparation method is similar to M19, obtains yellow powder shape product 1.3g, productive rate 31%, MS[M+H]
+308.1.
1HNMR(300MHz CDCl
3-d6)δ：10.33(1H，s，-NH-)，9.35(1H，s，pyrimidine)，7.40-8.21(7H，m，ArH)，4.31(2H，m，-OC
H 2CH
3)，4.06(3H，s，CH
3).
Embodiment 21
4-[(8-ethyl quinazoline-2-yl) amino] ethyl benzoate (M21)
The preparation method is similar to M19, obtains faint yellow solid 1.2g, productive rate 33%, MS[M+H]
+322.1.
1HNMR(300MHz CDCl
3-d6)δ：10.33(1H，s，-NH-)，9.36(1H，s，pyrimidine)，7.41-8.22(7H，m，ArH)，4.30(2H，m，-OC
H 2CH
3)，4.02(2H，q，-C
H 2CH
3)，1.32(3H，t，-CH
2C
H 3).
Embodiment 22
3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] ethyl benzoate (M22)
The preparation method is similar to M19, obtains white solid 1.0g, productive rate 43%, MS[M+H]
+366.2.
Embodiment 23
3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] ethyl benzoate (M23)
The preparation method is similar to M19, obtains off-white color solid 1.1g, productive rate 35%, MS[M+H]
+338.1.
Embodiment 24
3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] ethyl benzoate (M24)
The preparation method is similar to M19, obtains off-white color solid 0.8g, productive rate 36%, MS[M+H]
+352.2.
Embodiment 25
3-methyl-4-[(8-sec.-propyl quinazoline-2-yl) amino] ethyl benzoate (M25)
The preparation method is similar to M19, obtains white solid 0.3g, productive rate 43%, MS[M+H]
+350.2.
Embodiment 26
3-methyl-4-[(8-methyl quinazoline-2-yl) amino] ethyl benzoate (M26)
The preparation method is similar to M19, obtains white solid 0.6g, productive rate 50%, MS[M+H]
+322.2.
Embodiment 27
3-methyl-4-[(8-ethyl quinazoline-2-yl) amino] ethyl benzoate (M27)
The preparation method is similar to M19, obtains pale solid 1.0g, productive rate 42%, MS[M+H]
+336.2.
Embodiment 28
3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] ethyl benzoate (M28)
The preparation method is similar to M19, obtains faint yellow solid 0.3g, productive rate 26%, MS[M+H]
+420.2.
Embodiment 29
3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) amino] ethyl benzoate (M29)
The preparation method is similar to M19, obtains faint yellow solid 0.8g, productive rate 34%, MS[M+H]
+392.1.
Embodiment 30
3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] ethyl benzoate (M30)
The preparation method is similar to M19, obtains faint yellow solid 0.8g, productive rate 30%, MS[M+H]
+406.1.
Embodiment 31
3-[(8-sec.-propyl quinazoline-2-yl) amino] ethyl benzoate (M31)
The preparation method is similar to M19, obtains light brown solid 0.8g, productive rate 35%, MS[M+H]
+336.2.
Embodiment 32
3-[(8-methyl quinazoline-2-yl) amino] ethyl benzoate (M32)
The preparation method is similar to M19, obtains light brown solid 1.0g, productive rate 38%, MS[M+H]
+308.1.
Embodiment 33
3-[(8-ethyl quinazoline-2-yl) amino] ethyl benzoate (M33)
The preparation method is similar to M19, obtains light brown solid 1.0g, productive rate 38%, MS[M+H]
+322.1.
Embodiment 34
4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] ethyl benzoate (M34)
The preparation method is similar to M19, obtains white solid 0.8g, productive rate 27%, MS[M+H]
+366.2.
Embodiment 35
4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] ethyl benzoate (M35)
The preparation method is similar to M19, obtains white solid 0.5g, productive rate 28%, MS[M+H]
+338.1.
Embodiment 36
4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] ethyl benzoate (M36)
The preparation method is similar to M19, obtains white solid 0.6g, productive rate 27%, MS[M+H]
+352.2.
Embodiment 37
4-methyl-3-[(8-sec.-propyl quinazoline-2-yl) amino] ethyl benzoate (M37)
The preparation method is similar to M19, obtains white solid 0.2g, productive rate 30%, MS[M+H]
+350.2.
Embodiment 38
4-methyl-3-[(8-methyl quinazoline-2-yl) amino] ethyl benzoate (M38)
The preparation method is similar to M19, obtains white solid 0.4g, productive rate 32%, MS[M+H]
+322.1.
Embodiment 39
4-methyl-3-[(8-ethyl quinazoline-2-yl) amino] ethyl benzoate (M39)
The preparation method is similar to M19, obtains white solid 0.8g, productive rate 28%, MS[M+H]
+336.2.
Embodiment 40
4-trifluoromethoxy-3-[(8-sec.-propyl quinazoline-2-yl) amino] ethyl benzoate (M40)
The preparation method is similar to M19, obtains white solid 0.5g, productive rate 33%, MS[M+H]
+420.2.
Embodiment 41
4-trifluoromethoxy-3-[(8-methyl quinazoline-2-yl) amino] ethyl benzoate (M41)
The preparation method is similar to M19, obtains white solid 1.2g, productive rate 37%, MS[M+H]
+392.1.
Embodiment 42
4-trifluoromethoxy-3-[(8-ethyl quinazoline-2-yl) amino] ethyl benzoate (M42)
The preparation method is similar to M19, obtains white solid 1.0g, productive rate 36%, MS[M+H]
+406.1.
Embodiment 43
4-[(8-sec.-propyl quinazoline-2-yl) amino] phenylformic acid (M43)
In the eggplant-shape bottle of 50ml, add compound M190.15g (0.45mmol), KOH0.05g (1.25mmol), ethanol 1ml, H
2o5ml, be warming up to backflow, reaction 3h.Adjust PH to acid, separate out solid, suction filtration, drying, obtain the 0.1g white solid, productive rate 71%, MS[M+H]
+308.2.
Embodiment 44
4-[(8-methyl quinazoline-2-yl) amino] phenylformic acid (M44)
The preparation method is similar to M43, obtains white solid 0.2g, productive rate 72%, MS[M+H]
+280.1.
Embodiment 45
4-[(8-ethyl quinazoline-2-yl) amino] phenylformic acid (M45)
The preparation method is similar to M43, obtains white solid 0.25g, productive rate 70%, MS[M+H]
+294.1.
Embodiment 46
3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] phenylformic acid (M46)
The preparation method is similar to M43, obtains white solid 0.25g, productive rate 70%, MS[M+H]
+338.2.
Embodiment 47
3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] phenylformic acid (M47)
The preparation method is similar to M43, obtains white solid 0.3g, productive rate 83%, MS[M+H]
+310.1.
Embodiment 48
3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] phenylformic acid (M48)
The preparation method is similar to M43, obtains white solid 0.47g, productive rate 65%, MS[M+H]
+324.1.
Embodiment 49
3-methyl-4-[(8-sec.-propyl quinazoline-2-yl) amino] phenylformic acid (M49)
The preparation method is similar to M43, obtains white solid 0.18g, productive rate 80%, MS[M+H]
+322.1.
Embodiment 50
3-methyl-4-[(8-methyl quinazoline-2-yl) amino] phenylformic acid (M50)
The preparation method is similar to M43, obtains white solid 0.6g, productive rate 79%, MS[M+H]
+294.1.
Embodiment 51
3-methyl-4-[(8-ethyl quinazoline-2-yl) amino] phenylformic acid (M51)
The preparation method is similar to M43, obtains white solid 0.52g, productive rate 77%, MS[M+H]
+308.1.
Embodiment 52
3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] phenylformic acid (M52)
The preparation method is similar to M43, obtains white solid 0.66g, productive rate 85%, MS[M+H]
+392.1.
Embodiment 53
3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) amino] phenylformic acid (M53)
The preparation method is similar to M43, obtains white solid 0.5g, productive rate 80%, MS[M+H]
+364.1.
Embodiment 54
3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] phenylformic acid (M54)
The preparation method is similar to M43, obtains white solid 0.3g, productive rate 86%, MS[M+H]
+378.1.
Embodiment 55
3-[(8-sec.-propyl quinazoline-2-yl) amino] phenylformic acid (M55)
The preparation method is similar to M43, obtains white solid 0.66g, productive rate 85%, MS[M+H]
+392.1.
Embodiment 56
3-[(8-methyl quinazoline-2-yl) amino] phenylformic acid (M56)
The preparation method is similar to M43, obtains white solid 0.54g, productive rate 81%, MS[M+H]
+280.1.
Embodiment 57
3-[(8-ethyl quinazoline-2-yl) amino] phenylformic acid (M57)
The preparation method is similar to M43, obtains white solid 0.49g, productive rate 88%, MS[M+H]
+294.1.
Embodiment 58
4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] phenylformic acid (M58)
The preparation method is similar to M43, obtains white solid 1.2g, productive rate 70%, MS[M+H]
+338.2.
Embodiment 59
4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] phenylformic acid (M59)
The preparation method is similar to M43, obtains white solid 1.0g, productive rate 70%, MS[M+H]
+310.1.
Embodiment 60
4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] phenylformic acid (M60)
The preparation method is similar to M43, obtains white solid 1.0g, productive rate 70%, MS[M+H]
+324.1.
Embodiment 61
4-methyl-3-[(8-sec.-propyl quinazoline-2-yl) amino] phenylformic acid (M61)
The preparation method is similar to M43, obtains white solid 0.8g, productive rate 69%, MS[M+H]
+322.2.
Embodiment 62
4-methyl-3-[(8-methyl quinazoline-2-yl) amino] phenylformic acid (M62)
The preparation method is similar to M43, obtains white solid 0.19g, productive rate 62%, MS[M+H]
+294.1.
Embodiment 63
4-methyl-3-[(8-ethyl quinazoline-2-yl) amino] phenylformic acid (M63)
The preparation method is similar to M43, obtains white solid 0.3g, productive rate 77%, MS[M+H]
+308.1.
Embodiment 64
4-trifluoromethoxy-3-[(8-sec.-propyl quinazoline-2-yl) amino] phenylformic acid (M64)
The preparation method is similar to M43, obtains white solid 0.15g, productive rate 86%, MS[M+H]
+392.1.
Embodiment 65
4-trifluoromethoxy-3-[(8-methyl quinazoline-2-yl) amino] phenylformic acid (M65)
The preparation method is similar to M43, obtains white solid 0.6g, productive rate 85%, MS[M+H]
+364.1.
Embodiment 66
4-trifluoromethoxy-3-[(8-ethyl quinazoline-2-yl) amino] phenylformic acid (M66)
The preparation method is similar to M43, obtains white solid 0.4g, productive rate 83%, MS[M+H]
+378.1.
Embodiment 67
N-(1-methyl piperidine-4-yl)-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-68)
Add M43137mg (0.45mmol) in the eggplant-shape bottle of 25ml, 1-methyl piperidine-4-amine 62mg (0.54mmol), DMF8ml, add HATU0.26g (0.68mmol) after stirring, drip a DIPEA, normal-temperature reaction 10h.Remove solvent under reduced pressure, add water, adjust PH to alkalescence, extraction, column chromatography (EA: PE=20: 1+Et
3n), obtain white powder product 93mg, productive rate 52%, mp.212～214 ℃.
1HNMR(300MHz DMSO-d6)δ：10.14(1H，s，-CONH)，9.33(1H，s，-NH-)，8.11(2H，d，ArH)，8.06(1H，d，ArH)，7.87(2H，d，ArH)，7.76(2H，m，ArH)，7.40(1H，t，ArH)，4.04(1H，m，piperidine)，3.73(1H，m，-C
H(CH
3)
2)，2.77(2H，d，piperidine)，2.17(3H，s，-CH
3)，1.95(2H，m，piperidine)，1.76(2H，d，piperidine)，1.60(2H，m，piperidine)，1.38(6H，d，-CH(C
H 3)
2).MS[M+H]
+404.3。
Embodiment 68
N-(piperidin-4-yl)-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-3)
The preparation method is similar to I-68, obtains white solid 400mg, productive rate 53%, mp.226～227 ℃.
1HNMR(300MHz DMSO-d6)δ：10.17(1H，s，-CONH)，9.35(1H，s，-NH-)，8.11(2H，d，ArH)，8.05(1H，d，ArH)，7.87(1H，d，ArH)，7.76-7.40(4H，m，ArH)，4.04(1H，m，piperidine)，2.79(2H，d，piperidine)，2.53(2H，m，piperidine)，1.89(2H，d，piperidine)，1.64(2H，m，piperidine).MS[M+H]
+362.2。
Embodiment 69
N-(1-methyl piperidine-4-yl)-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-5)
The preparation method is similar to I-68, obtains faint yellow solid 800mg, productive rate 72%, mp.193～194 ℃.
1HNMR(300MHz DMSO-d6)δ：9.35(1H，s，-CONH)，8.85(1H，d，-NH-)，8.34(2H，s，ArH)，7.80(2H，q，ArH)，7.64(1H，d，ArH)，7.55(1H，s，ArH)，7.44(1H，t，ArH)，4.02(5H，m，-OCH
3and piperidine)，3.48(2H，m，piperidine)，2.80(3H，s，-CH
3)，2.05(2H，d，piperidine)，1.77(2H，d，piperidine)，1.38(3H，s，-C
H 3).MS406.2[M+H]
+.
Embodiment 70
N-(1-methyl piperidine-4-yl)-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-6)
The preparation method is similar to I-68, obtains faint yellow solid 200mg, productive rate 55%, mp.164～166 ℃.
1HNMR(300MHz DMSO-d6)δ：10.02(1H，s，-CONH)，9.36(1H，s，-NH-)，8.11(2H，d，ArH)，8.05(1H，d，ArH)，7.89(1H，d，ArH)，7.74-7.41(4H，m，ArH)，4.03(1H，m，piperidine)，2.79(2H，d，piperidine)，2.52(2H，m，piperidine)，1.90(2H，d，piperidine)，1.66(2H，m，piperidine).MS376.2[M+H]
+.
Embodiment 71
N-(3-morpholine propyl group)-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-8)
The preparation method is similar to I-68, obtains white solid 280mg, productive rate 50%, mp.140～141 ℃.
1HNMR(300MHz DMSO-d6)δ：9.08(2H，m，-CONH and-NH-)，8.19(1H，s，pyrimidine)，8.07(1H，s，ArH)，7.26-7.71(5H，m，ArH)，4.03(3H，s，-OCH
3)，3.84(3H，s，-CH
3)，3.60(2H，m，-CH
2)，2.64(5H，s，-CH
3and-CH
2-)，1.25-1.87(10H，m，-CH
2×5)，1.38(6H，s，-CH
3).MS[M+H]
+436.2.
Embodiment 72
3-methyl-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-11)
The preparation method is similar to I-68, obtains white solid 100mg, productive rate 63%, mp.172～174 ℃.
1HNMR(300MHz DMSO-d6)δ：9.08(1H，s，-NH-)，8.20(1H，s，pyrimidine)，8.08(1H，s，ArH)，7.26-7.72(5H，m，ArH)，3.84(3H，s，-CH
3)，3.14(3H，s，-CH
3)，2.88(4H，m，-CH
2-)，2.37(4H，m，-CH
2-)，2.12(1H，s，-NH-).MS[M+H]
+362.2.
Embodiment 73
3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (1-17)
The preparation method is similar to I-68, obtains white solid 130mg, productive rate 46%, mp.235～236 ℃.
1HNMR(300MHz DMSO-d6)δ：9.34(1H，s，-NH-)，8.22(1H，s，pyrimidine)，8.08(1H，m，ArH)，7.30-7.72(5H，m，ArH)，3.84(3H，s，-CH
3)，2.40(3H，s，-CH
3)，2.88(4H，m，-CH
2-)，2.31(4H，m，-CH
2-).MS[M+H]
+446.2.
Embodiment 74
N-(1-methyl piperidine-4-yl)-4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-20)
The preparation method is similar to I-68, obtains white solid 130mg, productive rate 46%, mp.172～173 ℃.
1HNMR(300MHz DMSO-d6)δ：9.35(1H，s，-CONH)，8.85(1H，d，-NH-)，8.34(2H，s，ArH)，7.80(2H，q，ArH)，7.60(1H，d，ArH)，7.55(1H，s，ArH)，7.49(1H，t，ArH)，4.02(5H，m，-OCH
3and piperidine)，3.48(2H，m，piperidine)，2.80(3H，s，-CH
3)，2.05(2H，d，piperidine)，1.77(2H，d，piperidine)，1.38(3H，s，-C
H 3).MS[M+H]
+406.2.
Embodiment 75
N-(piperidin-4-yl)-3-methyl-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-32)
The preparation method is similar to I-68, obtains white solid 50mg, productive rate 55%, mp.202～203 ℃.
1HNMR(300MHz DMSO-d6)δ：10.17(1H，s，-CONH)，9.35(1H，s，-NH-)，8.11(2H，d，ArH)，8.05(1H，d，ArH)，7.87(1H，d，ArH)，7.56-7.37(3H，m，ArH)，4.04(1H，m，piperidine)，3.78(2H，q，-CH
2CH
3)，2.88(3H，s，-CH
3)，2.79(2H，d，piperidine)，2.53(2H，m，piperidine)，1.89(2H，d，piperidine)，1.65(5H，m，piperidine and -CH
3).MS[M+H]
+390.2.
Embodiment 76
N-(1-methyl piperidine-4-yl)-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-36)
The preparation method is similar to I-68, obtains white solid 58mg, productive rate 45%, mp.218～220 ℃.
1HNMR(300MHz DMSO-d6)δ：9.35(1H，s，-CONH)，8.85(1H，d，-NH-)，8.34(2H，s，ArH)，7.80(2H，q，ArH)，7.64(1H，d，ArH)，7.55(1H，s，ArH)，7.44(1H，t，ArH)，4.02(6H，m，-OCH
3and-C
H 2CH
3and piperidine)，3.48(2H，m，piperidine)，2.80(3H，s，-CH
3)，2.05(2H，d，piperidine)，1.77(2H，d，piperidine)，1.38(3H，t，-CH
2C
H 3).MS[M+H]
+420.2.
Embodiment 77
N-(morpholinyl propyl group)-3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-41)
The preparation method is similar to I-68, obtains white solid 86mg, productive rate 64%, mp.136～138 ℃.
1HNMR(300MHz DMSO-d6)δ：9.36(1H，s，-CONH)，8.90(1H，d，-NH-)，8.34(2H，s，ArH)，7.71-7.90(3H，m，ArH)，7.58(1H，s，ArH)，7.50(1H，t，ArH)，4.10(2H，q，-C
H 2CH
3)，3.65(2H，m，-CH
2-)，3.3(2H，m，-CH
2-)，2.5(2H，m，-CH
2-)，2.5(4H，m，-CH
2-)，2.5(2H，m，-CH
2-)，1.6(2H，q，-CH
2-)，1.35(3H，t，-CH
2C
H 3).MS[M+H]
+504.2.
Embodiment 78
N-(1-methyl piperidine-4-yl)-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (1-51)
The preparation method is similar to I-68, obtains white solid 36mg, productive rate 56%, mp.167～168 ℃.
1HNMR(300MHz DMSO-d6)δ：9.57(1H，s，-CONH)，8.71(1H，d，-NH-)，8.33(1H，d，ArH)，7.61-7.80(4H，m，ArH)，7.55(1H，m，ArH)，7.50(1H，m，ArH)，3.92-4.10(7H，m，-CH
2-and-OCH
3and piperidine)，3.48(2H，m，piperidine)，2.78(3H，s，-CH
3)，2.05(2H，d，piperidine)，1.77(2H，d，piperidine)，1.38(3H，s，-C
H 3).MS[M+H]
+420.2.
Embodiment 79
N-[4-(pyrrolidin-1-yl) butyl]-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-57)
The preparation method is similar to I-68, obtains white solid 40mg, productive rate 37%, mp.149～151 ℃.
1HNMR(300MHz DMSO-d6)δ：9.35(1H，s，-CONH)，8.85(1H，d，-NH-)，8.34(2H，s，ArH)，7.80(2H，q，ArH)，7.60(1H，d，ArH)，7.55(1H，s，ArH)，7.49(1H，t，ArH)，3.94-3.96(5H，m，-OCH
3and-CH
2-)，1.50-2.42(16H，m，-CH
2×8)，1.38(3H，s，-CH
3).MS[M+H]
+448.3.
Embodiment 80
N-(3-methoxy-propyl)-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-60)
The preparation method is similar to I-68, obtains white solid 100mg, productive rate 62%, mp.163～165 ℃.
1HNMR(300MHz DMSO-d6)δ：9.35(1H，s，-CONH)，8.85(1H，d，-NH-)，8.34(2H，s，ArH)，7.80(2H，q，ArH)，7.60(1H，d，ArH)，7.55(1H，s，ArH)，7.49(1H，t，ArH)，3.94-3.96(5H，m，-OCH
3and-CH
2-)，3.48(2H，m，-CH
2-)，3.35(3H，s，-OCH
3)，2.38(2H，m，-CH
2-)，1.88(2H，m，-CH
2-)，1.38(3H，s，-CH
3).MS[M+H]
+395.2.
Embodiment 81
N-(1-methyl piperidine-4-yl)-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-67)
The preparation method is similar to I-68, obtains pale yellow crystals 63mg, productive rate 49%, mp.267～269 ℃.
1HNMR(300MHz DMSO-d6)δ：9.35(1H，s，-CONH)，8.85(1H，d，-NH-)，8.34(2H，s，ArH)，7.80(2H，q，ArH)，7.64(1H，d，ArH)，7.55(1H，s，ArH)，7.44(1H，t，ArH)，4.02(5H，m，-OCH
3and-C
H(CH
3)
2and piperidine)，3.48(2H，m，piperidine)，2.80(3H，s，-CH
3)，2.05(2H，d，piperidine)，1.77(2H，d，piperidine)，1.38(6H，d，-CH(C
H 3)
2).MS[M+H]
+434.3.
Embodiment 82
N-(3-morpholine propyl group)-3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-72)
The preparation method is similar to I-68, obtains light yellow solid 55mg, productive rate 50%, mp.260～262 ℃.
1HNMR(300MHz DMSO-d6)δ：9.08(2H，m，-CONH and-NH-)，8.19(1H，s，pyrimidine)，8.07(1H，s，ArH)，7.31-7.80(5H，m，ArH)，4.12(1H，m，-CH(CH
3)
2)，3.84(3H，s，-CH
3)，3.60(2H，m，-CH
2)，2.64(5H，s，-CH
3and-CH
2-)，1.25-1.87(10H，m，-CH
2×5).MS[M+H]
+518.2.
Embodiment 83
4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-77)
The preparation method is similar to I-68, obtains light yellow solid 63mg, productive rate 45%, mp.149～151 ℃.
1HNMR(300MHz DMSO-d6)δ：9.34(1H，s，-NH-)，8.22(1H，s，pyrimidine)，8.08(1H，m，ArH)，7.20-7.61(6H，m，ArH)，4.02(1H，m，-C
H(CH
3)
2)，2.40(3H，s，-CH
3)，2.88(4H，m，-CH
2-)，2.31(4H，m，-CH
2-)，1.36(6H，d，-CH(C
H 3)
2).MS[M+H]
+390.2.
Embodiment 84
N-(3-methoxy-propyl)-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-92)
The preparation method is similar to I-68, obtains white solid 25mg, productive rate 45%, mp.171～172 ℃.
1HNMR(300MHz DMSO-d6)δ：9.35(1H，s，-CONH)，8.85(1H，d，-NH-)，8.34(2H，s，ArH)，7.80(2H，q，ArH)，7.60(1H，d，ArH)，7.55(1H，s，ArH)，7.49(1H，t，ArH)，3.94-3.96(5H，m，-OCH
3and-CH(CH
3)
2)，3.48(2H，m，-CH
2-)，3.35(3H，s，-OCH
3)，2.38(2H，m，-CH
2-)，1.88(2H，m，-CH
2-)，1.38(6H，d，-CH
3).MS[M+H]
+ 409.2.
Embodiment 85
N-(1-methyl piperidine-4-yl)-5-[(8-methyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-94)
The preparation method is similar to I-68, obtains white solid 74mg, productive rate 53%, mp.203～205 ℃.
1HNMR(300MHz DMSO-d6)δ：9.35(1H，s，-CONH)，8.85(1H，d，-NH-)，8.34(2H，s，ArH)，8.20-8.28(2H，m，ArH)，7.80(1H，d，ArH)，7.65(1H，s，ArH)，7.59(1H，t，ArH)，3.93(3H，s，-CH
3)，3.48(2H，m，-CH
2-)，2.82(3H，s，-CH
3)，2.38(2H，m，-CH
2-)，1.88(2H，m，-CH
2-)，1.76(2H，m，-CH
2-).MS[M+H]
+377.2.
Embodiment 86
N-(1-methyl piperidine-4-yl)-6-methoxyl group-5-[(8-ethyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-100)
The preparation method is similar to I-68, obtains white solid 66mg, productive rate 57%, mp.235～236 ℃.
1HNMR(300MHz DMSO-d6)δ：9.34(1H，s，-CONH)，8.87(1H，s，-NH-)，8.34-8.36(3H，m，ArH)，7.80-8.02(2H，m，ArH)，7.65(1H，d，ArH)，3.93(3H，q，-CH
2-)，3.48(2H，m，-CH
2-)，2.81(3H，s，-CH
3)，2.36(2H，m，-CH
2-)，1.89(2H，m，-CH
2-)，1.76(2H，m，-CH
2-)，1.37(3H，t，-CH
3).MS[M+H]
+421.2.
Embodiment 87
N-(3-diethylin propyl group)-6-trifluoromethoxy-5-[(8-sec.-propyl quinazoline-2-yl) amino] pyridine-3-carboxamide (I-105)
The preparation method is similar to I-68, obtains white solid 35mg, productive rate 50%, mp.241～243 ℃.
1HNMR(300MHz DMSO-d6)δ：9.34(1H，s，-CONH)，8.88(1H，s，-NH-)，8.34-8.38(3H，m，ArH)，7.80-8.02(2H，m，ArH)，7.67(1H，d，ArH)，4.02(1H，m，-C
H(CH
3)
2)，3.31(4H，m，-CH
2×2)，2.69-2.89(6H，m，-CH
2×3)，1.38(6H，d，-CH
3)，1.08-1.20(6H，m，-CH
3×2).MS[M+H]
+505.3。
Claims (6)
1. the compound of general formula (I) or its pharmacy acceptable salt:
Wherein, R
1mean methyl, ethyl, sec.-propyl; R
2expression-H, methyl, methoxyl group, trifluoromethoxy.
Wherein, X means C or N.
Wherein, L means
Wherein, R
3, R
4mean independently piperidines-4-amino, 1-methyl piperidine-4-amino, morpholinyl the third amino, piperazinyl, 4-methylpiperazine-1-yl, 4-(pyrrolidin-1-yl) fourth amino, 3-diethylin the third amino, 3-methoxy propyl amino.
2. the compound of claim 1, its structure is:
N-(piperidin-4-yl)-3-methyl-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-1)
N-(piperidin-4-yl)-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-2)
N-(piperidin-4-yl)-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-3)
N-(piperidin-4-yl)-3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-4)
N-(1-methyl piperidine-4-yl)-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-5)
N-(1-methyl piperidine-4-yl)-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-6)
N-(1-methyl piperidine-4-yl)-3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-7)
N-(3-morpholine propyl group)-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-8)
N-(3-morpholine propyl group)-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-9)
N-(3-morpholine propyl group)-3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-10)
3-methyl-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-11)
4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-12)
3-methoxyl group-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-13)
3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-14)
4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-15)
3-methoxyl group-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-16)
3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-17)
N-(piperidin-4-yl)-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-18)
N-(piperidin-4-yl)-4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-19)
N-(1-methyl piperidine-4-yl)-4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-20)
N-(1-methyl piperidine-4-yl)-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-21)
N-(3-morpholine propyl group)-4-trifluoromethoxy-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-22)
4-methoxyl group-3-[(8-methyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-23)
3-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-24)
4-methoxyl group-3-[(8-methyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-25)
N-[4-(pyrrolidin-1-yl) butyl]-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-26)
N-[4-(pyrrolidin-1-yl) butyl]-4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-27)
N-[3-(diethylin) propyl group]-3-trifluoromethoxy-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-28)
N-(3-methoxy-propyl)-3-methoxyl group-4-[(8-methyl quinazoline-2-yl) amino] benzamide (I-29)
N-(3-methoxy-propyl)-4-methoxyl group-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-30)
N-[3-(diethylin) propyl group]-4-trifluoromethoxy-3-[(8-methyl quinazoline-2-yl) amino] benzamide (I-31)
N-(piperidin-4-yl)-3-methyl-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-32)
N-(piperidin-4-yl)-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-33)
N-(piperidin-4-yl)-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-34)
N-(piperidin-4-yl)-3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-35)
N-(1-methyl piperidine-4-yl)-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-36)
N-(1-methyl piperidine-4-yl)-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-37)
N-(1-methyl piperidine-4-yl)-3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-38)
N-(morpholinyl propyl group)-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-39)
N-(1-methyl piperidine-4-yl)-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-40)
N-(morpholinyl propyl group)-3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-41)
3-methyl-4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-42)
4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-43)
3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-44)
3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-45)
4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-46)
3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-47)
3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-48)
N-(piperidin-4-yl)-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-49)
N-(piperidin-4-yl)-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-50)
N-(1-methyl piperidine-4-yl)-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-51)
N-(1-methyl piperidine-4-yl)-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-52)
N-(3-morpholine propyl group)-4-trifluoromethoxy-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-53)
4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-piperazine-1-yl) ketone (I-54)
3-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-55)
4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-56)
N-[4-(pyrrolidin-1-yl) butyl]-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-57)
N-[4-(pyrrolidin-1-yl) butyl]-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-58)
N-[3-(diethylin) propyl group]-3-trifluoromethoxy-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-59)
N-(3-methoxy-propyl)-3-methoxyl group-4-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-60)
N-(3-methoxy-propyl)-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-61)
N-[3-(diethylin) propyl group]-4-methoxyl group-3-[(8-ethyl quinazoline-2-yl) amino] benzamide (I-62)
N-(piperidin-4-yl)-3-methyl-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-63)
N-(piperidin-4-yl)-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-64)
N-(piperidin-4-yl)-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-65)
N-(piperidin-4-yl)-3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-66)
N-(1-methyl piperidine-4-yl)-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-67)
N-(1-methyl piperidine-4-yl)-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-68)
N-(1-methyl piperidine-4-yl)-3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-69)
N-(3-morpholine propyl group)-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-70)
N-(3-morpholine propyl group)-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-71)
N-(3-morpholine propyl group)-3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-72)
3-methyl-4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-73)
4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-74)
3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-75)
3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-76)
4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-77)
3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-78)
3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-79)
N-(piperidin-4-yl)-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-80)
N-(piperidin-4-yl)-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-81)
N-(1-methyl piperidine-4-yl)-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-82)
N-(1-methyl piperidine-4-yl)-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-83)
N-(3-morpholine propyl group)-4-trifluoromethoxy-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-84)
4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (piperazine-1-yl) ketone (I-85)
3-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-86)
4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) and amino] phenyl } (4-methylpiperazine-1-yl) ketone (I-87)
N-[4-(pyrrolidin-1-yl) butyl]-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-88)
N-[4-(pyrrolidin-1-yl) butyl]-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-89)
N-[3-(diethylin) propyl group]-3-trifluoromethoxy-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-90)
N-(3-methoxy-propyl)-3-methoxyl group-4-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-91)
N-(3-methoxy-propyl)-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-92)
N-[3-(diethylin) propyl group]-4-methoxyl group-3-[(8-sec.-propyl quinazoline-2-yl) amino] benzamide (I-93)
N-(1-methyl piperidine-4-yl)-5-[(8-methyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-94)
6-methyl-5-[(8-sec.-propyl quinazoline-2-yl) and amino] pyridine-2-yl } (piperazine-1-yl) ketone (I-95)
N-(3-morpholine propyl group)-6-methoxyl group-5-[(8-methyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-96)
6-trifluoromethoxy-5-[(8-sec.-propyl quinazoline-2-yl) and amino] pyridine-2-yl } (4-methylpiperazine-1-yl) ketone (I-97)
N-(1-methyl piperidine-4-yl)-5-[(8-sec.-propyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-98)
N-(3-morpholine propyl group)-6-methoxyl group-5-[(8-sec.-propyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-99)
N-(1-methyl piperidine-4-yl)-6-methoxyl group-5-[(8-ethyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-100)
6-trifluoromethoxy-5-[(8-sec.-propyl quinazoline-2-yl) and amino] pyridine-2-yl } (4-methylpiperazine-1-yl) ketone (I-101)
N-(3-morpholine propyl group)-5-[(8-ethyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-102)
N-(3-methoxy-propyl)-6-methoxyl group-5-[(8-ethyl quinazoline-2-yl) amino] pyridine-2-carboxamide (I-103)
N-(1-methyl piperidine-4-yl)-6-methoxyl group-5-[(8-sec.-propyl quinazoline-2-yl) amino] pyridine-3-carboxamide (I-104)
N-(3-diethylin propyl group)-6-trifluoromethoxy-5-[(8-sec.-propyl quinazoline-2-yl) amino] pyridine-3-carboxamide (I-105).
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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106278918A (en) * | 2016-08-12 | 2017-01-04 | 合肥久诺医药科技有限公司 | A kind of bromfenac sodium contamination levels product 2 amino 3 (4 benzoyl bromide) benzoic synthetic method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2226315A1 (en) * | 2007-12-28 | 2010-09-08 | Carna Biosciences Inc. | 2-aminoquinazoline derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2226315A1 (en) * | 2007-12-28 | 2010-09-08 | Carna Biosciences Inc. | 2-aminoquinazoline derivative |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106278918A (en) * | 2016-08-12 | 2017-01-04 | 合肥久诺医药科技有限公司 | A kind of bromfenac sodium contamination levels product 2 amino 3 (4 benzoyl bromide) benzoic synthetic method |
| CN106278918B (en) * | 2016-08-12 | 2018-05-11 | 合肥久诺医药科技有限公司 | A kind of synthetic method of bromfenac sodium contamination levels product 2- amino -3- (4- benzoyl bromides) benzoic acid |
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