CN103408540A - 2-imidazole ring-substituted thiophene PLK1 (Polo-like kinase 1) inhibitors and applications thereof - Google Patents

2-imidazole ring-substituted thiophene PLK1 (Polo-like kinase 1) inhibitors and applications thereof Download PDF

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CN103408540A
CN103408540A CN2013103728340A CN201310372834A CN103408540A CN 103408540 A CN103408540 A CN 103408540A CN 2013103728340 A CN2013103728340 A CN 2013103728340A CN 201310372834 A CN201310372834 A CN 201310372834A CN 103408540 A CN103408540 A CN 103408540A
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thiophene
anilino
amino
isoxzzole
carboxamide derivatives
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CN103408540B (en
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卢帅
张亮
刘海春
郭晓星
孙善亮
陈亚东
陆涛
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention relates to the field of medicinal chemistry, and in particular relates to 2-imidazole ring-substituted thiophene PLK1 (Polo-like kinase 1) inhibitors, a preparation method for the inhibitors, a medicinal composition containing the compounds, and medical applications for the compounds, and in particular an application for the compounds as Polo-like kinase 1 (PLK1) inhibitors.

Description

2-azoles ring substituted thiophene class PLK1 inhibitor and uses thereof
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to 2-azoles ring substituted thiophene class PLK1 inhibitor, 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
Tumour is that a class be take Growth of Cells and proliferation out of control and is the disease of principal character, and cell is in abnormal generation and the development that has all participated in tumour aspect propagation, differentiation and apoptosis, and wherein the cell cycle disorder is the mechanism that tumour is wanted.In the whole regulated and control network of cell cycle, each quasi-molecule abnormal all likely causes the generation of tumour.Tumour cell division frequency compared with normal cell is fast, and regulation and control microtubule polymerization, centrosome copy, spindle body forms and the usually overexpression of various 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, peripheral nervous system is had to obvious toxicity, and their ADME character is also not ideal in addition.So people turn one's attention to those overexpressions in tumour cell, and can regulate and control the tubulin function, affect the specific proteins of spindle body effect, as KSP (kinesin spindle protein), Aurora A, Polo-like kinases (polo-like kinases, PLKs), CENPE (centromeric protein E) etc., wish to affect special and efficiently the function of microtubule in tumour cell, spindle body etc., do not disturb simultaneously the morphology and function of the tubulin in normal cell, thereby reduce the toxic side effect of medicine.
Suppress can realize by several different methods with the protein kinase of disease-related, but the attack that is subject to ribozyme due to synthetic antisense oligonucleotide is degraded, there are the problems such as security, stability and the effect of missing the target in the RNA perturbation technique, so the investigator starts to attempt from chemical micromolecular inhibitor the chemical small molecules of organic synthesis or natural product.Conservative serine/threonine kinases PLK has received great concern, and it mainly concentrates on take ATP pocket and PDB phospho-peptide land and be the strategy of micromolecular compound in conjunction with territory, all has more inhibitor to come out.Wherein, kinases territory inhibitor mainly comprises dihydropteridine ketone (BI2536, BI6727), benzyl styrene Sulfone class (ON01910), thiophene-based (GSK461364), the assorted stibene class (HMN-176, HMN-214) of N-, 2-amido virtue heterocyclic, 4,5-dihydro-1H-quinazoline [4,3-h] pyrazoles (NMS-P937), benzo hexanolactam class, benzodiazepine
Figure BSA0000094270520000011
(RO3280, TAK-960), β-carboline class; PBD is away from catalysis region, can avoid also can causing the problems such as drug resistance and cross action because with ATP, competing the accumulation that causes the variation of tumour cell ATP domain structure, this direction mainly comprises micromolecular inhibitor and some peptide classes or the class peptide inhibitors such as thymoquinone at present.
In recent years, the research of antitumor drug is at a tremendous pace, the progress of a large amount of new techniques such as molecular biology and Computer-Aided Drug Design, and the development of automatic high-speed medicament sifting motion system, make the mankind be more readily understood pharmaceutically-active pattern, this is very helpful for drug development.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.The PLK1 of take is target, from gene, protein level, finds the antitumor drug of determined curative effect, will become oncotherapy new breakthrough point.
Summary of the invention
The present invention, having studied on the basis that has in a large number PLK1 micromolecular inhibitor optionally, according to the crystal structure model of PLK1, has designed and synthesized the compound of a series of 2-of take azoles ring substituted thiophenes as the brand new of parent nucleus.
The object of the invention is to, provide a class to have PLK1 and suppress active small molecules organic compound or its pharmacy acceptable salt.It 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.
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 independent or both purposes in participating in simultaneously the medicine of the disease, particularly tumour that mediate of PLK1.
For achieving the above object, the invention provides compound or its pharmacy acceptable salt of the structure shown in (I) that has general formula:
Figure BSA0000094270520000021
Wherein, R 1Expression-H, cyano group, amide group; R 2Expression-H, cyano group, amide group.
Wherein, X means O, N or-NH-; Y mean O, S ,-CH 2-.
Wherein, R 3Expression-H, methoxyl group or trifluoromethoxy.
Wherein, R 4, R 5Mean 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; Perhaps mean independently
Figure BSA0000094270520000031
The compound of general formula I is following structural compounds preferably:
5-{5-[4-(4-methyl piperidine-1-yl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-1)
5-{5-[4-(N-amino piperidine-1-base amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-2)
5-{5-[4-(3-(diethylamino) Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-3)
5-{5-[4-(morpholinyl Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-4)
5-{5-[2-methoxyl group-4-(4-methyl piperidine-1-yl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-5)
5-{5-[2-methoxyl group-4-(N-amino piperidine-1-base amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-6)
5-{5-[2-methoxyl group-4-(3-(diethylamino) Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-7)
5-{5-[2-methoxyl group-4-(morpholinyl Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-8)
5-{5-[4-(4-methyl piperidine-1 carbonyl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-9)
4-{[3-(5-cyano-thiophene-2-yl)-1H-pyrazoles-5-yl] amino }-N-(1-methyl piperidine-4-yl) benzamide (I-10)
4-{[3-(5-cyano-thiophene-2-yl)-1H-pyrazoles-5-yl] amino }-N-[3-(diethylamino) propyl group] benzamide (I-11)
4-{[3-(5-cyano-thiophene-2-yl)-1H-pyrazoles-5-yl] amino }-the N-[3 morpholinyl propyl] benzamide (I-12)
5-{5-[4-(4-methyl piperidine-1-yl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-13)
5-{5-[4-(1-methyl piperidine-4-base amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-14)
5-{5-[4-(3-(diethylamino) Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-15)
5-{5-[4-(morpholinyl amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-16)
5-{5-[2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-17)
5-{5-[2-methoxyl group-4-(1-methyl piperidine-4-base amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-18)
5-{5-[2-methoxyl group-4-(3-(diethylamino) Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-19)
5-{5-[2-methoxyl group-4-(morpholinyl amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-20)
5-{5-[4-(4-methylpiperazine-1-carbonyl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-21)
5-{5-[4-(1-methyl piperidine-4-base carbamyl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-22)
5-{5-[4-(3-(diethylamino) Propylamino carbonyl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-23)
5-{5-[4-(morpholinyl Propylamino carbonyl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-24)
5-{5-[4-(4-methylpiperazine-1-yl) anilino] isoxzzole-3-yl } thiophene-2-formonitrile HCN (I-25)
5-{5-[4-(1-methyl piperidine-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-formonitrile HCN (I-26)
5-{5-[4-(3-(diethylamino)-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-formonitrile HCN (I-27)
5-{5-[4-(morpholinyl amino) anilino] isoxzzole-3-yl } thiophene-2-formonitrile HCN (I-28)
5-{5-[4-(4-methylpiperazine-1-carbonyl) anilino] isoxzzole-3-yl } thiophene-2-formonitrile HCN (I-29)
4-[3-(5-cyano-thiophene-2-yl) isoxzzole-5-base amino]-N-(1-methyl piperidine-4-yl) benzamide (I-30)
4-[3-(5-cyano-thiophene-2-yl) isoxzzole-5-base amino]-the N-[(3-diethylamino) propyl group] benzamide (I-31)
4-[3-(5-cyano-thiophene-2-yl) isoxzzole-5-base amino]-N-(morpholinyl propyl group) benzamide (I-32)
5-{5-[4-(4-methylpiperazine-1-yl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-33)
5-{5-[4-(1-methyl piperidine-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-34)
5-{5-[4-(3-(diethylamino)-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-35)
5-{5-[4-(morpholinyl amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-36)
5-{5-[2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-37)
5-{5-[2-methoxyl group-4-(1-methyl piperidine-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-38)
5-{5-[2-methoxyl group-4-(3-(diethylamino)-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-39)
5-{5-[2-methoxyl group-4-(morpholinyl amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-40)
5-{5-[4-(4-methylpiperazine-1-carbonyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-41)
5-{5-[4-(1-methyl piperidine-4-base carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-42)
5-{5-[4-(3-(diethylamino) propyl group carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-43)
5-{5-[4-(morpholinyl propyl group carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-44)
5-{5-[2-methoxyl group-4-(4-methylpiperazine-1-carbonyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-45)
5-{5-[[2-methoxyl group-4-(1-methyl piperidine-4-base carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-46)
5-{5-[[2-methoxyl group-4-(3-(diethylamino) propyl group carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-47)
5-{5-[[2-methoxyl group-4-(morpholinyl propyl group carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-48)
5-{5-[4-(4-methylpiperazine-1-yl) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-49)
5-{5-[4-(1-methyl piperidine-4-base amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-50)
5-{5-[4-(3-(diethylamino) propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-51)
5-{5-[4-(morpholinyl propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-52)
5-{5-[4-(4-methylpiperazine-1-yl) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-53)
5-{5-[4-(1-methyl piperidine-4-base amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-54)
5-{5-[4-(3-(diethylamino) propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-55)
5-{5-[4-(morpholinyl propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-56)
5-{5-[3-(4-methylpiperazine-1-yl) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-57)
5-{5-[3-(1-methyl piperidine-4-base amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-58)
5-{5-[3-(3-(diethylamino) propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-59)
5-{5-[3-(morpholinyl propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-60)
5-{5-[3-(4-methylpiperazine-1-yl) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-61)
5-{5-[3-(1-methyl piperidine-4-base amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-62)
5-{5-[3-(3-(diethylamino) propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-63)
5-{5-[3-(morpholinyl propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-64)
5-{5-[4-(4-methylpiperazine-1-yl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-65)
5-{5-[4-(1-methyl piperidine-1-base amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-66)
5-{5-[4-(3-(diethylamino) propyl group amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-67)
5-{5-[4-(morpholinyl propyl group amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-68)
5-{5-[4-(4-methylpiperazine-1-yl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-69)
5-{5-[4-(1-methyl piperidine-1-base amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-70)
5-{5-[4-(3-(diethylamino) propyl group amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-71)
5-{5-[4-(morpholinyl propyl group amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-72)
5-{5-[4-(4-methylpiperazine-1-carbonyl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-73)
5-{5-[4-(1-methyl piperidine-4-base carbamyl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-74)
5-{5-[4-(3-(diethylamino) propyl group carbamyl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-75)
5-{5-[4-(morpholinyl propyl group carbamyl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-76)
Part of compounds preparation method of the present invention is as follows:
Method one
Figure BSA0000094270520000061
Figure BSA0000094270520000062
Figure BSA0000094270520000063
Figure BSA0000094270520000064
ents?and?conditions：
(i)Br 2，AlCl 3，CCl 4，-30℃→rt；(ii)CuCN，reflux，5h；(iii)1-methylpiperazine，TEA，N，N-dimethylaniline，3.5h；(iv)H 2，Pd/C，rt，overnight；(v)CSCl 2，DCM，NaHCO 3，H 2O，0℃；(vi)NaH，THF，Reflux；(vii)NH 2NH 2.H 2O，EtOH，Reflux，3h；(viii)NaOH，30％H 2O 2，EtOH，DMSO，80℃，12h.
Method two
Figure BSA0000094270520000071
Figure BSA0000094270520000073
Reagents?and?conditions：
(i)SOCl 2，MeOH，reflux，2h；(ii)CuCN，reflux，5h；(iii)NH 2NH 2.H 2O，EtOH，50℃，3h；(iv)1-methylpiperazine，TEA，N，N-dimethylaniline，3.5h；(v)H 2，Pd/C，rt，overnight；(vi)CSCl 2，DCM，NaHCO 3，H 2O，0℃；(vii)Pyridine，EtOH，Reflux；(viii)Hg(OAc) 2，EtOH，reflux；(ix)NaOH，30％H 2O 2，EtOH，DMSO，80℃，12h.
The compounds of this invention can prepare by above-mentioned or similar above-mentioned preparation method, selects corresponding raw material to get final product according to the difference of substituent difference and substituting group position.
The biological activity test result shows, compound of Formula I provided by the present invention and pharmacy acceptable salt thereof have the PLK1 inhibition, simultaneously the growth of tumor cell line are had to certain restraining effect.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/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 simultaneously 5 μ Lbuffer, 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
Figure BSA0000094270520000081
Figure BSA0000094270520000091
2. tumor cell in vitro suppresses active testing
The compounds of this invention is in the external activity of inhibition to 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)
Figure BSA0000094270520000095
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,
Figure BSA0000094270520000094
According to ten times of Dilution ratios, add in cell culture medium 5%CO 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 leukemia cell line HL60:
Figure BSA0000094270520000093
Figure BSA0000094270520000101
(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; 1HNMR completes (mark in TMS) by JEOL FX90Q type fourier transform NMR instrument, BRUKER ACF-300 type nuclear magnetic resonance analyser and BRUKER AM-500 type nuclear magnetic resonance analyser; MS measures with Nicolet2000 type Fourier transform mass spectrometer and MAT-212 type mass spectrograph.
Embodiment 1
2-ethanoyl-4-bromothiophene (M-1)
In the mono-neck bottle of 250ml, add 2-acetyl thiophene 3.00g (23.81mmol), Aluminum chloride anhydrous 9.53g (71.43mmol) and tetracol phenixin 80ml, be cooled to-40 ℃, after stablizing 10min, slowly drip the carbon tetrachloride solution (20ml) of bromine 3.81g (23.81mmol), 0.5h drip, finish stirring at normal temperature.After 12h, TLC shows that raw material is without residue.By the mixture of the saturated NaOH solution of reaction system impouring and trash ice, ethyl acetate extraction (75ml * 3), merge organic phase, with the saturated aqueous common salt washed twice, and anhydrous MgSO 4Dry.Concentrating under reduced pressure rear pillar layer (PE: EA=500: 1), obtain pale yellow oily liquid body 2.74g, yield 72.6%.
1HNMR(300MHz?DMSO-d 6)δ：7.65(1H，d，ArH)，6.91(1H，d，ArH)，2.57(3H，s，-COC H 3).MS[M+H] +205.2，207.1.
Embodiment 2
2-ethanoyl-4-cyano-thiophene (M-2)
In the 100ml pressure piping, add M-10.5g (2.45mmol), cuprous cyanide 0.66g (3.68mmol), potassiumiodide 0.04g (0.245mmol) and dry DMF 10ml.Under the protection of inert gas condition, be warming up to 190 ℃, after 3h, TLC shows that raw material is without residue.By the mixture of reaction system impouring ammoniacal liquor and trash ice, ethyl acetate extraction (20ml * 3), merge organic phase, with the saturated aqueous common salt washed twice, and anhydrous MgSO 4Drying, (the PE: EA=100: 1), obtain faint yellow solid 0.23g, yield 62.2% of column chromatography after concentrating under reduced pressure.Mp.112～114 ℃ (document mp.111～113 ℃).
Embodiment 3
1-methyl-4-(4-oil of mirbane) piperidines (M-3)
In the mono-neck bottle of 50ml, add p-fluoronitrobenzene 1.41g (10.00mmol), 1-methylpiperazine 1.01g (10.00mmol), triethylamine 1.01g (10.00mmol) and dry DMF 25ml, room temperature reaction, after 24h, TLC shows that raw material is without residue.Remove solvent under reduced pressure, add frozen water, regulate PH to 8 with saturated sodium carbonate solution, ethyl acetate extraction (40ml * 3), merge organic phase, with the saturated aqueous common salt washed twice, and anhydrous MgSO 4Dry.(the PE: EA=1: 1) obtain orange-yellow needle-like crystal 1.38g, yield 85.3%, mp.35～38 ℃ of column chromatography after concentrating under reduced pressure.
MS[M+H] +222.3.
Embodiment 4
4-(4-methyl piperidine) aniline (M-4)
In the mono-neck bottle of 50ml, add M-30.60g (0.27mmol), ammonium chloride 0.46g (1.34mmol) and 70% ethanol 25ml add reduced iron powder 0.46g (0.80mmol), reflux in batches after stirring.After 5h, TLC shows that raw material is without residue.Suction filtration, remove filtrate under reduced pressure while hot, adds water, and ethyl acetate extraction (15ml * 3) merges organic phase, with the saturated aqueous common salt washed twice, and anhydrous MgSO 4Dry.(the PE: EA=1: 1) obtain light brown liquid 0.47g, yield 91.1% of column chromatography after concentrating under reduced pressure.
MS[M+H] +192.3.
Embodiment 5
1-(4-thiocyanogen phenyl)-4-methyl piperidine (M-5)
In the mono-neck bottle of 50ml, add sodium bicarbonate 1.20g (14.28mmol) and water 10ml, under condition of ice bath, stir 10min, again the dichloromethane solution of M-40.40g (2.65mmol) (10ml) is slowly added to single neck bottle, finally the dichloromethane solution of thiophosgene 0.58g (3.97mmol) (10ml) is slowly splashed into to single neck bottle, 0.5h drip, finish, after 4h, TLC shows that raw material is without residue.Dichloromethane extraction (20ml * 7), merge organic phase, with the saturated aqueous common salt washed twice, and anhydrous MgSO 4Dry.Concentrating under reduced pressure except after desolventizing with the sherwood oil recrystallization, obtain white solid 0.34g, yield 87.3%, mp.73～75 ℃.
MS[M+H] +234.1，MS[M-H] -232.2.
Embodiment 6
3-(4-cyano-thiophene-2-yl)-N-(4-(4-methyl piperidine-1-yl) phenyl)-3-oxo rosickyite acid amides (M-6)
Under condition of ice bath, in the mono-neck bottle of 100ml, add M-50.54g (2.65mmol), sodium hydride 0.16g (3.98mmol) and anhydrous tetrahydro furan 25ml, after stirring 10min, slowly splash into the tetrahydrofuran solution (5ml) of M-5 (2.65mmol), room temperature reaction.After 3h, TLC shows that raw material is without residue.Remove solvent under reduced pressure, add frozen water, regulate pH to 7～8 with Glacial acetic acid, separate out solid, suction filtration, dry orange/yellow solid 0.8g, yield 69.1%, mp.121～125 ℃ of obtaining.
Embodiment 7
5-{5-[4-(4-methyl piperidine-1-yl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-1)
In the mono-neck bottle of 100ml, add M-60.25g (0.57mmol), hydrazine hydrate 40mg (0.68mmol) and dehydrated alcohol 25ml, back flow reaction, after 6h, TLC shows that raw material is without residue.Remove solvent under reduced pressure, add water, regulate pH to 9～10 with triethylamine solution, ethyl acetate extraction (40ml * 3), merge organic phase, with the saturated aqueous common salt washed twice, and anhydrous MgSO 4Drying, (the DCM: MeOH=20: 1), obtain faint yellow solid 90mg, yield 37.8%, mp.137～139 ℃ of column chromatography after concentrating under reduced pressure.
1H-NMR(300MHz?DMSO-d 6)δ：12.39-12.15(1H，d，-NH-，Pyrazole)，8.10-8.03(1H，d，-NH-)，7.22(3H，s，ArH)，6.85-6.82(3H，br.s，ArH)，6.12-5.99(1H，d，Pyrazo-le)，3.31-2.43(8H，m，piperazine)，2.21(3H，m，-N-CH3).MS[M+H] +365.1，MS[M-H] -363.2.
Embodiment 8
5-{5-[4-(N-amino piperidine-1-base amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-2)
The preparation method is similar to (I-1), obtains sample 100mg, yield 33.5%.mp：134-136℃。
1H-NMR(300MHz?DMSO-d 6)δ：12.66-12.34(1H，d，-NH-，Pyrazole)，8.21-8.13(1H，d，-NH-)，7.30(3H，s，ArH)，7.02-6.9l(3H，br.s，ArH)，6.80-6.71(1H，d，-N H-CH-)，6.29-6.27(1H，d?Pyrazole)，3.72-3.74(1H，m，-CH-N H-)，2.73-2.72(2H，d，piperidin)，2.19-2.06(3H，s，-N-C H 3)，2.06-2.05(2H，d，piperidin)，1.90-1.87(2H，m，piperidin)，1.49-1.48(2H，m，piperidin).MS[M+H] +379.1，401.3.
Embodiment 9
5-{5-[4-(3-(diethylamino) Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-3)
The preparation method is similar to (I-1), obtains sample 28mg, yield 23.2%.mp：139-142℃。
1H-NMR(300MHz?DMSO-d 6)δ：12.46-12.44(1H，d，-NH-，Pyrazole)，9.21-9.13(1H，d，-NH-)，7.51(3H，s，ArH)，6.72-6.41(3H，br.s，ArH)，6.30-6.29(1H，m，-N H-CH 2-)，6.21-6.20(1H，d，Pyrazole)，3.12-3.04(2H，m，-C H 2-NH-)，2.53-2.52(6H，m，-C H 2-N-)，1.65-1.56(2H，m，-CH 2-C H 2-CH 2)，0.98-0.93(6H，t，-CH 2-C H 3).MS[M+H] +395.4，MS[M-H] -393.2.
Embodiment 10
5-{5-[4-(morpholinyl Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-4)
The preparation method is similar to (I-1), obtains sample 61mg, yield 33.4%.mp：142-145℃。
1H-NMR(300MHz?DMSO-d 6)δ：12.36-12.32(1H，d，-NH-，Pyrazole)，9.61-9.53(1H，d，-NH-)，7.61(3H，s，ArH)，7.02-6.91(3H，br.s，ArH)，6.43-6.39(1H，m，-N H-CH 2-)，6.31-6.26(1H，d，Pyrazole)，3.78-3.74(4H，m，-C H 2-O-C H 2-)，3.33-3.21(2H，m，-C H 2-NH-)，2.35-2.30(6H，m，-C H 2-N-)，1.73-1.66(2H，m，-CH 2-C H 2-CH 2).MS[M+H] +409.2，MS[M-H] -407.3.
Embodiment 11
The bromo-2-thiophenecarboxylate of 4-(M-7)
In the mono-neck bottle of 100ml, add the bromo-2-thiophenic acid of 4-2.07g (10mmol), thionyl chloride 1.19g (10mmol) and dehydrated alcohol 25ml, back flow reaction, after 6h, TLC shows that raw material is without residue.Underpressure distillation goes out desolventizing, adds frozen water, regulates pH to 9～10 with saturated sodium carbonate solution, and ethyl acetate extraction (40ml * 3) merges organic phase, with the saturated aqueous common salt washed twice, and anhydrous MgSO 4Drying, obtain pale yellow oily liquid body 2.02g, yield 91.4%.
MS[M+H] +221.02，223.13.
Embodiment 12
4-itrile group-2-thiophenecarboxylate (M-8)
In the 60ml pressure piping, add M-72.21g (10mmol), cuprous cyanide 5.3g (30mmol), potassiumiodide 0.16g (1mmol) and dry DMF 6ml.Under the protection of inert gas condition, be warming up to 190 ℃, after 4h, TLC shows that raw material is without residue.By the mixture of reaction system impouring ammoniacal liquor and trash ice, ethyl acetate extraction (20ml * 3), merge organic phase, with the saturated aqueous common salt washed twice, and anhydrous MgSO 4Drying, (the PE: EA=80: 1), obtain white solid 0.95g, yield 56.8% of column chromatography after concentrating under reduced pressure.
MS[M+H] +168.11，MS[M-H] -166.20.
Embodiment 13
4-itrile group-2-thenoyl hydrazine (M-9)
In the mono-neck bottle of 100ml, add M-81.67g (10mmol), hydrazine hydrate 1.19g (10mmol) and dehydrated alcohol 25ml, 45 ℃ of reactions, after 10h, TLC shows that raw material is without residue.Underpressure distillation is except desolventizing, and 95% ethyl alcohol recrystallization, obtain white crystal 1.45g, yield 86.8%.
MS[M+H] +168.21，MS[M-H] -166.30.
Embodiment 14
2-(4-cyano-thiophene-2-carbonyl)-N-[4-(4-methyl piperidine-1-yl) phenyl] thiosemicarbazide (M-10)
In the mono-neck bottle of 50ml, add M-90.17g (1mmol), M-50.26g (1.1mmol), pyridine 0.79mg (0.01mmol) and dehydrated alcohol 10ml, back flow reaction, after 1h, the TLC demonstration remains without raw material.Underpressure distillation is except desolventizing, and 95% ethyl alcohol recrystallization, obtain faint yellow solid 0.21g, yield 52.5%.
MS[M+H] +401.14，MS[M-H] -399.06.
Embodiment 15
5-{5-[4-(4-methylpiperazine-1-yl) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-49)
In the mono-neck bottle of 50ml, add M-100.4g (1mmol), mercuric acetate 0.35g (1.1mmol) and dehydrated alcohol 15ml, back flow reaction, after 3h, TLC shows without raw material residue, filtered while hot.Underpressure distillation is except desolventizing, and column chromatography (DCM: MeOH: TEA=40: 2: 1), obtain white solid 95mg, yield 25.9%.mp：255-257℃。
1H-NMR(300MHz?DMSO-d 6)δ：10.50(1H，s，-NH-)，8.77-8.76(1H，d，J＝1.23，Thiophene)，7.97-7.96(1H，d，J＝1.23，Thiophene)，7.46-7.43(2H，d，Benzene)，6.97-6.94(2H，d，Benzene)，3.09-3.06(4H，m，-N-C H 2-)，2.51-2.46(4H，m，-C H 2-N-CH 3)，2.24(3H，s，-N-C H 3).MS[M+H] +367.2.
Embodiment 16
5-{5-[4-(1-methyl piperidine-4-base amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-50)
The preparation method is similar to (I-49), obtains sample 61mg, yield 23.4%.mp：250-251℃。
1H-NMR(300MHz?DMSO-d 6)δ：10.52(1H，s，-NH-)，8.75-8.73(1H，d，J＝1.44，Thiophene)，8.07-8.05(1H，d，J＝1.44，Thiophene)，7.36-7.33(2H，d，Benzene)，7.08-7.04(2H，d，Benzene)，6.81-6.79(1H，m，- NH-CH-)，3.11-3.10(1H，m，piperidine)，2.63-2.61(2H，m，piperidine)，2.21(3H，m，piperidine)，2.04-2.03(2H，m，piperidine)，1.90-1.89(2H，m，piperidine)，1.51-1.49(2H，m.piperidine).MS[M+H] +381.1.
Embodiment 17
5-{5-[4-(3-(diethylamino) propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-51)
The preparation method is similar to (I-49), obtains sample 43mg, yield 15.4%.mp：259-261℃。
1H-NMR(300MHz?DMSO-d 6)δ：10.65(1H，s，-NH-)，8.45-8.44(1H，d，J＝1.46，Thiophene)，8.11-8.07(1H，d，J＝1.46，Thiophene)，7.38-7.35(2H，d，Benzene)，7.10-7.08(2H，d，Benzene)，6.71-6.69(1H，m，- NH-CH 2-)，3.35-3.32(2H，m，-NH-C H 2-)，3.03-3.00(6H，m，-C H 2-N-)，1.63-1.61(2H，m，-CH 2-C H 2-CH 2-)，1.00-0.98(6H，m，-CH 2-C H 3).MS[M+H] +397.4.
Embodiment 18
5-{5-[4-(morpholinyl propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-52)
The preparation method is similar to (I-49), obtains sample 37mg, yield 19.3%.mp：259-262℃。
1H-NMR(300MHz?DMSO-d 6)δ：10.65(1H，s，-NH-)，8.43-8.42(1H，d，J＝1.45，Thiophene)，8.13-8.12(1H，d，J＝1.45，Thiophene)，7.36-7.34(2H，d，Benzene)，7.10-7.07(2H，d，Benzene)，6.43-6.42(1H，m，- NH-CH 2-)，3.65-3.63(4H，m，Morpholine)，3.35-3.32(2H，m，-NH-C H 2-)，2.46-2.43(6H，m，-C H 2-N-)，1.63-1.61(2H，m，-CH 2-C H 2-CH 2-).MS[M+H] +411.4.
Embodiment 19
5-{5-[4-(4-methylpiperazine-1-yl) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-53)
In the mono-neck bottle of 50ml, add I-490.37g (1mmol), 30%H 2O 20.35g (1.1mmol) with dehydrated alcohol 15ml, back flow reaction, after 3h, TLC shows without raw material residue, filtered while hot.Underpressure distillation is except desolventizing, and column chromatography (DCM: MeOH: TEA=40: 2: 1), obtain white solid 95mg, yield 25.9%.mp：270-272℃。
1H-NMR(300MHz?DMSO-d 6)δ：10.50(1H，s，-NH-)，8.37-8.36(1H，d，J＝1.43，Thiophene)，7.94-7.92(1H，s，-CON H 2-)，7.77-7.76(1H，d，J＝1.43，Thiophene)，7.36-7.33(2H，d，Benzene)，6.98-6.96(2H，d，Benzene)，6.84-6.82(1H，s，-CON H 2-)，3.09-3.06(4H，m，-N-C H 2-)，2.51-2.46(4H，m，-C H 2-N-CH 3)，2.24(3H，s，-N-C H 3).MS[M+H] +385.2.
Embodiment 20
5-{5-[4-(1-methyl piperidine-4-base amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-54)
The preparation method is similar to (I-53), obtains sample 57mg, yield 25.3%.mp：269-270℃。
1H-NMR(300MHz?DMSO-d 6)δ：10.5(1H，s，-NH-)，8.81-8.80(1H，d，J＝1.43，Thiophene)，7.84-7.82(1H，s，-CON H 2-)，7.78-7.77(1H，d，J＝1.43，Thiophene)，7.46-7.43(2H，d，Benzene)，7.18-7.16(2H，d，Benzene)，6.91-6.89(1H，s，-CON H 2-)，6.36-6.34(1H，m，-N H-)，3.11-3.10(1H，m，piperidine)，2.63-2.61(2H，m，piperidine)，2.21(3H，m，piperidine)，2.04-2.03(2H，m，piperidine)，1.90-1.89(2H，m，piperidine)，1.51-1.49(2H，m.piperidine).MS[M+H] +399.2.
Embodiment 21
5-{5-[4-(3-(diethylamino) propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-55)
The preparation method is similar to (I-53), obtains sample 23mg, yield 14.3%.mp：265-267℃。
1H-NMR(300MHz?DMSO-d 6)δ：10.65(1H，s，-NH-)，8.45-8.44(1H，d，J＝1.46，Thiophene)，8.11-8.07(1H，d，J＝1.46，Thiophene)，7.88-7.85(1H，s，-CON H 2-)，7.38-7.35(2H，d，Benzene)，7.10-7.08(2H，d，Benzene)，6.91-6.89(1H，s，-CON H 2-)，6.70-6.65(1H，m，- NH-CH 2-)，3.33-3.31(2H，m，-NH-C H 2-)，3.01-3.00(6H，m，-C H 2N-)，1.60-1.56(2H，m，-CH 2-C H 2-CH 2-)，1.00-0.95(6H，m，-CH 2-C H 3).MS[M+H] +415.4.
Embodiment 22
5-{5-[4-(morpholinyl propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-56)
The preparation method is similar to (I-53), obtains sample 23mg, yield 14.3%.mp：263-264℃。
1H-NMR(300MHz?DMSO-d 6)δ：10.52(1H，s，-NH-)，8.81-8.78(1H，d，J＝1.45，Thiophene)，8.13-7.92(2H，m，Thiophene?and-CON H 2-)，7.36-7.34(2H，d，Benzene)，7.10-7.04(3H，m，Benzene?and-CON H 2-)，6.40-6.39(1H，m，- NH-CH 2-)，3.60-3.58(4H，m，Morpholine)，3.35-3.33(2H，m，-NH-C H 2-)，2.47-2.45(6H，m，-C H 2N-)，1.63-1.61?(2H，m，-CH 2-C H 2-CH 2-).MS[M+H] +429.4，MS[M-H] -427.2。

Claims (6)

1. the compound of general formula (I) or its pharmacy acceptable salt:
Figure FSA0000094270510000011
Wherein, R 1Expression-H, cyano group, amide group; R 2Expression-H, cyano group, amide group.
Wherein, X means O, N or-NH-; Y mean O, S ,-CH 2-.
Wherein, R 3Expression-H, trifluoromethoxy or methoxyl group.
Wherein, R 4, R 5Mean 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; Perhaps mean independently
Figure FSA0000094270510000012
2. under the compound of claim 1, its structure be:
5-{5-[4-(4-methyl piperidine-1-yl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-1)
5-{5-[4-(N-amino piperidine-1-base amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-2)
5-{5-[4-(3-(diethylamino) Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-3)
5-{5-[4-(morpholinyl Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-4)
5-{5-[2-methoxyl group-4-(4-methyl piperidine-1-yl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-5)
5-{5-[2-methoxyl group-4-(N-amino piperidine-1-base amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-6)
5-{5-[2-methoxyl group-4-(3-(diethylamino) Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-7)
5-{5-[2-methoxyl group-4-(morpholinyl Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-8)
5-{5-[4-(4-methyl piperidine-1 carbonyl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-9)
4-{[3-(5-cyano-thiophene-2-yl)-1H-pyrazoles-5-yl] amino }-N-(1-methyl piperidine-4-yl) benzamide (I-10)
4-{[3-(5-cyano-thiophene-2-yl)-1H-pyrazoles-5-yl] amino }-N-[3-(diethylamino) propyl group] benzamide (I-11)
4-{[3-(5-cyano-thiophene-2-yl)-1H-pyrazoles-5-yl] amino }-the N-[3 morpholinyl propyl] benzamide (I-12)
5-{5-[4-(4-methyl piperidine-1-yl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-13)
5-{5-[4-(1-methyl piperidine-4-base amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-14)
5-{5-[4-(3-(diethylamino) Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-15)
5-{5-[4-(morpholinyl amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-16)
5-{5-[2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-17)
5-{5-[2-methoxyl group-4-(1-methyl piperidine-4-base amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-18)
5-{5-[2-methoxyl group-4-(3-(diethylamino) Propylamino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-19)
5-{5-[2-methoxyl group-4-(morpholinyl amino) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-20)
5-{5-[4-(4-methylpiperazine-1-carbonyl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-21)
5-{5-[4-(1-methyl piperidine-4-base carbamyl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-22)
5-{5-[4-(3-(diethylamino) Propylamino carbonyl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-23)
5-{5-[4-(morpholinyl Propylamino carbonyl) anilino]-the 1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-24)
5-{5-[4-(4-methylpiperazine-1-yl) anilino] isoxzzole-3-yl } thiophene-2-formonitrile HCN (I-25)
5-{5-[4-(1-methyl piperidine-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-formonitrile HCN (I-26)
5-{5-[4-(3-(diethylamino)-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-formonitrile HCN (I-27)
5-{5-[4-(morpholinyl amino) anilino] isoxzzole-3-yl } thiophene-2-formonitrile HCN (I-28)
5-{5-[4-(4-methylpiperazine-1-carbonyl) anilino] isoxzzole-3-yl } thiophene-2-formonitrile HCN (I-29)
4-[3-(5-cyano-thiophene-2-yl) isoxzzole-5-base amino]-N-(1-methyl piperidine-4-yl) benzamide (I-30)
4-[3-(5-cyano-thiophene-2-yl) isoxzzole-5-base amino]-the N-[(3-diethylamino) propyl group] benzamide (I-31)
4-[3-(5-cyano-thiophene-2-yl) isoxzzole-5-base amino]-N-(morpholinyl propyl group) benzamide (I-32)
5-{5-[4-(4-methylpiperazine-1-yl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-33)
5-{5-[4-(1-methyl piperidine-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-34)
5-{5-[4-(3-(diethylamino)-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-35)
5-{5-[4-(morpholinyl amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-36)
5-{5-[2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-37)
5-{5-[2-methoxyl group-4-(1-methyl piperidine-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-38)
5-{5-[2-methoxyl group-4-(3-(diethylamino)-4-base amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-39)
5-{5-[2-methoxyl group-4-(morpholinyl amino) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-40)
5-{5-[4-(4-methylpiperazine-1-carbonyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-41)
5-{5-[4-(1-methyl piperidine-4-base carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-42)
5-{5-[4-(3-(diethylamino) propyl group carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-43)
5-{5-[4-(morpholinyl propyl group carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-44)
5-{5-[2-methoxyl group-4-(4-methylpiperazine-1-carbonyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-45)
5-{5-[[2-methoxyl group-4-(1-methyl piperidine-4-base carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-46)
5-{5-[[2-methoxyl group-4-(3-(diethylamino) propyl group carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-47)
5-{5-[[2-methoxyl group-4-(morpholinyl propyl group carbamyl) anilino] isoxzzole-3-yl } thiophene-2-carboxamide derivatives (I-48)
5-{5-[4-(4-methylpiperazine-1-yl) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-49)
5-{5-[4-(1-methyl piperidine-4-base amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-50)
5-{5-[4-(3-(diethylamino) propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-51)
5-{5-[4-(morpholinyl propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-52)
5-{5-[4-(4-methylpiperazine-1-yl) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-53)
5-{5-[4-(1-methyl piperidine-4-base amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-54)
5-{5-[4-(3-(diethylamino) propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-55)
5-{5-[4-(morpholinyl propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-56)
5-{5-[3-(4-methylpiperazine-1-yl) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-57)
5-{5-[3-(1-methyl piperidine-4-base amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-58)
5-{5-[3-(3-(diethylamino) propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-59)
5-{5-[3-(morpholinyl propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-60)
5-{5-[3-(4-methylpiperazine-1-yl) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-61)
5-{5-[3-(1-methyl piperidine-4-base amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-62)
5-{5-[3-(3-(diethylamino) propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-63)
5-{5-[3-(morpholinyl propyl group amino) anilino]-1,3,4-oxadiazole-2-yl } thiophene-3-methane amide (I-64)
5-{5-[4-(4-methylpiperazine-1-yl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-65)
5-{5-[4-(1-methyl piperidine-1-base amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-66)
5-{5-[4-(3-(diethylamino) propyl group amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-67)
5-{5-[4-(morpholinyl propyl group amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-68)
5-{5-[4-(4-methylpiperazine-1-yl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-69)
5-{5-[4-(1-methyl piperidine-1-base amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-70)
5-{5-[4-(3-(diethylamino) propyl group amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-71)
5-{5-[4-(morpholinyl propyl group amino) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-72)
5-{5-[4-(4-methylpiperazine-1-carbonyl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-73)
5-{5-[4-(1-methyl piperidine-4-base carbamyl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-74)
5-{5-[4-(3-(diethylamino) propyl group carbamyl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-75)
5-{5-[4-(morpholinyl propyl group carbamyl) anilino]-1,3,4-thiadiazoles-2-yl } thiophene-3-methane amide (I-76).
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. 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 1, wherein the disease relevant with 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, gastrointestinal cancer or mesothelioma.
CN201310372834.0A 2013-08-22 2013-08-22 2-azoles ring substituted thiophene class PLK1 inhibitor and uses thereof and uses thereof Expired - Fee Related CN103408540B (en)

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