CN103242341B - Thieno-2,4 substituted pyrimidines compounds and pharmaceutical composition thereof and application - Google Patents

Thieno-2,4 substituted pyrimidines compounds and pharmaceutical composition thereof and application Download PDF

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CN103242341B
CN103242341B CN201310138125.6A CN201310138125A CN103242341B CN 103242341 B CN103242341 B CN 103242341B CN 201310138125 A CN201310138125 A CN 201310138125A CN 103242341 B CN103242341 B CN 103242341B
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thieno
pyrimidine
pyrazoles
isophthalic acid
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CN103242341A (en
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蔡倩
涂正超
刘丹
罗金凤
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Guangzhou Institute of Biomedicine and Health of CAS
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Guangzhou Institute of Biomedicine and Health of CAS
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Abstract

The invention discloses a kind of general formula is (I), (II), (III), thieno-2, the 4 substituted pyrimidines compounds of (IV) or its pharmacy acceptable salt or steric isomer or prodrugs and pharmaceutical composition thereof and application.Above-mentioned thieno-2,4 substituted pyrimidines compounds effectively can suppress the unconventionality expression of Aurora A, special restraining effect is had to Aurora-A and Aurora-B, can be applicable to the frontier of molecular targeted therapy, for excessively proliferative disease, particularly to uterine cervix oncocyte, human macrophage system leukemia cell, human T lymphocyte system cancer cells has stronger inhibit activities.

Description

Thieno-2,4 substituted pyrimidines compounds and pharmaceutical composition thereof and application
Technical field
The present invention relates to chemical medicine, particularly relate to thieno-2,4 substituted pyrimidines compounds and pharmaceutical composition thereof and application.
Background technology
Tumor cells targeted therapy is a kind of methods for the treatment of based on passing through chemistry or biological means selective killing tumour cell to the closely-related key molecule of tumor growth.The feature of targeted therapy is: specificity is high, and selectivity is strong, and toxic side effect is lighter; During combined utilization, it can strengthen the curative effect of classic chemotherapy, radiotherapy, reduces postoperative recurrence, and with Gleevec(STI571, imatinib, commodity are called imatinib mesylate) for the targeted drug of representative be that chemotherapy of tumors has started a New Times.Neoplasm targeted therapy obtains in recent years and develops rapidly.The appearance of neoplasm targeted therapy has been formed convenient administration idea and pattern to be impacted, and such as, because toxic side effect is little, targeted drug often cannot reach dose-limiting toxicity and maximum tolerated dose in I clinical trial phase; When using target therapeutic agent, without the need to can satisfactory effect be reached with maximum tolerated dose.Therefore, neoplasm targeted therapy is focus and the development trend of oncotherapy.
Aurora A is that the Serine of one group of three kinds of very high homology--Serineprotein kinase plays important regulating effect in mitotic division process.Aurora family is divided into AuroraA, AuroraB and AuroraC.Be found to from nineteen ninety-five the observation that first time was applied to human canceration's tissue expression in 1998, these kinases become oncology industry science and produce ambilateral nervous target of investication and study.This effort achieves great successes, and up to the present, more than 10 plant Aurora A inhibitor have passed early clinic evaluation.These mixtures with characteristic feature have good selectivity for other most kinases, most cross reaction in them and a kinase whose small setting relevant with oncobiology, this wherein the most significantly representative be Abl and Flt-3 kinases.
Aurora A inhibitor can be sub-divided into three general kinds again: have to the selectivity of the Aurora-A selectivity more than Aurora-B, have to the selectivity of the Aurora-B selectivity more than Aurora-A, the third protein inhibitor then has the selectivity to Aurora-A and Aurora-B simultaneously.
Aurora A and mitotic division
Aurora-A:Aurora-A is included in the adjustment of mitotic division early ambulant, also comprises participation mitotic division.Protein expression and kinase activity the cell cycle G2 stage rising and reach peak (people such as Meraldi, 2004 in early days in mitotic division; CarmenaandEarnshaw, 2003; The people such as Andrew, 2003).Find to the frequent observation of monopolar spindle, the consumption of Aurora-A causes participating in mitotic delay, and indicates the division of spindle body.At molecular level, the effect that Aurora-A plays in all the other processes of mitotic division is fully elucidated; But some data helps to differentiate its special biomarker to the forbidding of Aurora-A to have some conclusive discoveries can help to explain.
Aurora-B:Aurora-B is the moiety catalyzing and synthesizing chromosomal passenger complex (CPC), determines mitoticly carry out continuously and complete.This mixture is made up of four kinds of protein, i.e. Aurora-B, Survivin (survivin), INCENP and borealin.The non-catalytic component of this mixture then partly plays the effect regulating limitation and activate Aurora-B.The consumption of any component of this mixture, can have a negative impact to other components, and destroys and mitoticly to carry out continuously.Survivin (survivin), INCENP and borealin is the known base of Aurora-B, although Survivin (survivin) and borealin are on the impact of phosphorylation or unknown, but with regard to INCENP, seem to be serve positive effect (people such as Andrew, 2003 in feedback loop; CarmenaandEarnshaw, 2003; The people such as Meraldi, 2004).
Aurora-C:Aurora-C be study in Aurora A minimum, and the definition that its concrete effect in mitotic division is clear and definite.The performance of Aurora-C in most of somatic tissues of lower level, obviously not as good as Aurora-A or Aurora-B.It is unique exception that the height of Aurora-C in testis tissue is expressed.Express spectra is consistent therewith, contrasts mouse experiment determine its keying action in nucleus reduction division by homozygote and heterozygote.These mouse show a very normal physiological function, but the also infertility (ZhouH, KuangJ, ZhongL, et.al, Nat.Gent, 1998,20 (2): 189-193 that cause of defectiveness sperm; LittlepayLE, WuH, AndressonT, et.al, ProcNatlAcadSciUSA, 2002,99 (24): 15440-15445), these and aberrant chromosomal condense relevant with polyploidy.
Aurora A and cancer cells
Since finding from the nineties in 20th century, abundant science and clinical data show already Aurora A and human cancer be in progress between strong connection.
Aurora-A has 20q13.2(ZhouH, KuangJ, ZhongL, et.al, Nat.Gent, 1998,20 (2): 189-193) namely genome area has the gene mapping be closely connected with human cancer.The Aurora-A albumen of overexpression is observed in many cancer cells middle periods.The multiple cancer cells feature such as such as Centrosomal Amplification, aneuploid, chromosome instability are fixed, lengthening of telomeres that Aurora-A dystopy overexpression in vitro causes cell to show.Observe and find, Aurora-A oneself expression, or activate the people such as partner TPX-2(Hirota, 2003; The people such as Bayliss, 2003; EyersandMaller, 2004; The people such as Kufer, 2002; The people such as Satinover, 2004), fixed relevant with human cancer cell's chromosome instability.In addition, Aurora-A is relevant with the decisive main cause of tumor suppression and this is produced to negative adjustment.Perhaps wherein the most noticeable is p53, degenerates because Aurora-A promotes mdm2-mediated and suppresses its transcriptional activity.In any case Aurora-A does not adhere to that cell conversion in vitro and overexpression position be not in common active tumor cell, therefore not a conventional protein.In general, these observations show that Aurora-A requires that other random oncogene are converted usually.This potential impact is, the selective inhibitory of Aurora-A may only to specific cancer cells display antitumour activity or with other drug in conjunction with time just can reach best result of use.Remove Aurora-A in aforesaid consume research and often cause mitotic division significant deficiency, seem and which form striking contrast.Occur that the reason of this species diversity may be because the JEG-3 quantity of these research uses is relatively less.Probably the real impact of Aurora-A inhibitor is only appeared once Selective depression and has then been widely used in cancer cells.
Consistent with hypothesis, the Aurora-A possible benefit that suppresses to combine with other therapies has had some team to make explanation, the cytotoxic effect that Aurora-A has consumption to produce as taxanes, cis-platinum and ionizing rays etc. due to chemotherapeutics for responsive cancer cells.
Aurora-B changes (ZengWF, NavaratneK, PraysonRA, et.al, JClinPathol, 2007,60 (2): 218-221) at the gene mapping of 17p13.1 genome area in some human cancer region.The mRNA of Aurora-B and protein this in cancer and have at protein expression and some report type serious disease tumour on frequent overexpression.Between Aurora-B and cancer except these are contacted directly, more should be noted that CPC protein, itself and Aurora-B cooperation show, or are regulated by Aurora-B, are also often overexpressed or are exaggerated as cancer.Although the key of cancer and Aurora-B contacting very closely in fission process, it is not transcribed in vitro and generally can't form tumour in vivo.An important exception is in the tumorigenic behavior of the formal overexpression of p53 cell mutation (ManfrediMG, EcsedyJA, MeetzeKA, ProcNatlAcadSciUSA, 2007,104 (10): 4106-4111.) at Aurora-B.Show from these experimental results, although Aurora-B itself is not oncogene, it can serve as the affiliate that other oncogenic mutation form tumour.Concept consistent is therewith, Aurora-B can strengthen the conversion of Ras-mediated, but Aurora-B and short consume of restrainting RNA can suppress the transformation of Ras.As the target of an important cancer-resisting substance, further research is also needed for Aurora-B, comprises the therapy of Aurora-B consume for responsive cancer cells, the cytotoxicity of such as alkylating agent and ionizing rays.
Nearest data show, in many mitotic division processes, the effect of Aurora-B and Aurora-C is overlapping.Although Aurora-C quantitatively observes in human cancer cell's strain, Aurora-C not yet determines in the saying with obvious effect of tumour.
Aurora A micromolecular inhibitor is as chemical probe
The consumption of Aurora A activity uses the Expression Skill of such as siRNA and kinase-dead albumen, contribute to the biometric profile (MorrowCJ predicting Aurora inhibitor, TigheA, JohnsonVL, et.al, JCellSci, 2005,118(16): 3639-3652) inhibitor is required.It is below the chemical structural formula of disclosed Aurora inhibitor (mixture 1-6).
The double inhibitor of Aurora-A and Aurora-B.In 2003, first Aurora micromolecular inhibitor disclosed (ZM4474391 and Hesperidin 2).Mixture 1 can than other uncorrelated kinases (not comprising closely-related Aurora-C with it) more effective suppression Aurora-A and Aurora-B(IC 50respectively at 110nm and 130nm place) (MorlockAA, KeenNJ, JungFH, et.al, WO0121596 [P], 2001-03-29).This selectivity is the support energetically it being widely used in chemical probe.Mixture 2 it is said it is a kind of to Aurora-B(IC 50at 250nm place) inhibitor, have antagonism other six kinds of kinases (not having data to show this comprising Aurora-A or Aurora-C) important cross reaction.In two, inhibitor all shows similar entirely dominant on polyploid cell: inhibition of histone H3 phosphorylation (Ser10) and lack fissional endoreduplication people such as (, 2002) Ota.Reach in the giant cells case of 32 DNA replication dnas can observe at some.Certain experiment shows a cell G1 and is blocked in mixture 1 and has failed cytokinesis.Under these conditions, enter and exit mitotic division and normally carry out, but cell cannot divide.These two kinds of enzyme inhibitorss cause obvious karyomit(e) to lack of proper care, and normal and karyomit(e) is connected on the main shaft of non-both sexes kinetochore microtubule side by side.Although there are these to distort, the separation of two sister strands still exists.The two unification, all strong the showing of these activities, suppresses Aurora A activity that the abolishment of spindle body check position and karyomit(e) dirt settling can be caused to exit mitotic division in the appropriate case.The performance of this covering mitotic blockade that mixture is caused by taxanes microtubule stabilizer in two confirms this point.More detailed analysis shows, it is all unfixed that the component of many spindle body check positions comprises BurR1, Mad2 and CENP-E.Milli is N/R, and observed finding by defective type mitotic division, the cell viability processed by mixture 1 declines.
The sign of potential Aurora A inhibitor in mixture 3 pairs of bodies is disclosed first in 2004.Mixture 3(MK-0457(VX-680)) be a kind of to the effective strong inhibitor of all three kinds of Aurora As, to other kinases, there is selectivity (HarringtonEA simultaneously, BebbingtonD, MooreJ, et.al, Nat.Med, 2004,10 (3): 262-267).Consistent with Aurora-A and Aurora-B double inhibitor (mixture 1 and 2), mixture 3 is induced polyploidy rapidly and is blocked hyperplasia.It should be noted that most that the random mitotic division mediated by Aurora is enough to cause apoptosis.This case comprises cancerous cell line, non-cancerous cells system and primary tumors cells sampling the whole cell cycle processed through mixture 3.What the cell death mechanism of cell cycle was corresponding therewith is observe the cell found within non-period not lose viability.In human cancer rodent model, the very effective obstruction tumor growth of mixture 3 even causes some lump to restore (WilkinsonRW, OdedraR, HcatonSP, et.al, ClinCancerRes, 2007,13 (12): 3682-3688).The immunohistochemical analysis of mixture 3 demonstrates obvious Tumor suppression treatment phosphorylated histone H3, suppresses consistent, significantly can reduce apoptosis with Aurora-B.Mixture 3 tolerance of effective dose is good, but observes the remarkable reversible minimizing (>50% is reduced to lower-most point) of discovery neutrophil count.Clinical observation finds, in non-cancer cell cycle mechanism with on the basis of form, Aurora A has restraining effect to general neutrophil leucocyte.Mixture 3 can cause can induced synthesis monopolar spindle, and a kind of phenotype is the surrogate of Aurora-A and the Aurora-B double inhibitor mixture 1 consuming and not have report along with Aurora-A.Therefore, mixture 3 can suppress the specific Aurora-A matrix phosphorylation except Aurora-B matrix histone H 3.Therefore, mixture 3 can suppress Aurora-A and Aurora-B in mitotic division and cell viability simultaneously.
Although its Aurora A inhibitor can cause Mitotic abnomality and block cycle inner cell propagation to be reported widely, many research organizations prove that the final destiny of cell is seemingly relevant with genetic background now.In the cell that mixture 1 or 3 processes, the cell lacking p53 gene function lacks cytokine, and then apoptosis after breeding with a large amount of endoreduplication.On the other hand, the cell of p53 complete function is then less carries out endoreduplication.This result indicates the effect of p53 at G1 tetraploid check position.Can this will make people be interested in by clinical observation to this situation.
The appearance of this mechanism will cause chemotherapy of tumors leptin suppression often to occur.In many cases, resistance is relevant with the expression of Teat pipette, but can observe in the sudden change middle period of drug targeting itself.Observe the polymorphism of a small amount of mankind Aurora gene, although these are on kinase activity or on the impact of drug susceptibility and atypia.A nearest research shows, the cancer cells cultivated under the long-term existence of mixture 1 can produce the vegetative propagation of this mixture by resistant function.Detailed analysis shows, this resistance is because the Aurora-B albumen of certain number produces sudden change.The impact of expression on cell of these sudden changes Aurora-B albumen has exceeded mixture 1 at phosphorylated histone H3, cell cycle and spindle body check position.What this was perfectly clear show mixture 1 is but not Aurora-A relevant with suppression Aurora-B on antimitotic impact.The formation of mixture 3 at cell cycle and bacterium colony has also been blocked in the sudden change of these Aurora-B.The anticancer property that show again mixture 3 is relevant with the suppression of Aurora-B instead of Aurora-A or Aurora-C.This affect antimitotic with the consumption of Aurora-A compared with some is unexpected.This shows in this test, can not suppress Aurora-A completely, suppress the catalytic activity of Aurora-A in other words with mixture 1 and 3, only on himself there being faint impact.These data resultss observed are added up discovery, and Aurora-A can not transform or anti-tumor usually, conclusion be when Aurora-A and other cancer therapies in conjunction with time may produce best curative effect.Certainly the more important thing is, the clinical resistance that this research makes Aurora A inhibitor potential is more outstanding, and this is subject to more harsh monitoring by making Aurora A inhibitor by clinical.
Except individual drugs is on the impact of Aurora A double inhibitor, some groups show, these mixtures can make cell more sharp to other treatment method.When with Aurora-A/B double inhibitor joint assessment, the effect of dexamethasone, Streptomycin sulphate, Etoposide, vincristine(VCR), daunomycin and ionizing rays strengthens (YangJ all to some extent, IkezoeT, NishiokaC, et.al, Blood, 2007,110 (6): 2034-2040).Wherein some combined effect can attribution be the suppression of Aurora A to crucial mitotic division process, and in other situations, viewed synergistic mechanism is still not clear.But, these clinical observations are designed with very large effect likely to clinical study.
Recently, illustrating of the biological function of Aurora A in normal cell and cancer cells makes micromolecular inhibitor obtain very fast development.Clinical PRELIMINARY RESULTS that is front and clinical trial shows, although the molecular mechanism of Aurora A inhibitor inducing cancer cell growth retardation and apoptosis needs to explain further, this kind of material gets a good chance of for the treatment of cancer.Therefore, in the process of future therapeutic cancer .Aurora kinase inhibitor needs to confirm further as strong anticancer strategy, and many clinical trials will provide answer in the near future.
Miazines is known as kinase whose inhibitor usually, the substituted uracil such as having non-aromatic group at 4 is described in international patent application WO021096888 and WO031032997 as the activeconstituents with antitumous effect, 2, the 4-diamino-pyrimidines being and for example used as Aurora inhibitor are described in international patent application WO2007/003596.In fact, current Aurora A inhibitor series antineoplastic medicament also exists the sudden change of drug-induced drug resistance gene mostly, and is faced with the problems such as the clinical scope of application is narrower.Therefore, develop more novel protein Aurora A inhibitor to overcome existing drug resistance and to improve clinical effectiveness, be significant.
Summary of the invention
Based on this, the present invention has expanded the scope of pyrimidines, synthesizes more how novel active compound for disease that to prevent and/or treat with excessive or abnormal cell proliferation be feature.The object of this invention is to provide and a kind ofly can be used for preventing and/or treating with excessive or abnormal cell proliferation new active substance-thieno-2, the 4 substituted pyrimidines compounds being feature.
A kind of thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or prodrugs, general formula is:
Wherein, X 1, X 2be O, S, S (O), S (O) simultaneously or independently 2or NR 5, wherein R 5for H or C 1-6alkyl;
X 3, X 4be O, N, CH, m, n, o, p are the integer between 1-4 simultaneously or independently;
R 1, R 2simultaneously or be independently selected from following groups:
To be substituted or unsubstituted
Wherein, dotted line represents and X 1, X 2the key connected;
A is the integer between 0-3, and X, Y, Z are N, CH simultaneously or independently;
R 61, R 62, R 63be hydrogen, C simultaneously or independently 1-5alkyl, halogen, nitro, cyano group, amino or hydroxyl;
R 3, R 4simultaneously or be independently selected from following groups:
Hydrogen, C 1-5alkyl, C 3-8cycloalkyl or R 6cOR 7; Wherein, R 6for C 1-3alkyl or C 1-3alkyl phenyl, R 7for C 1-5alkoxyl group, halogen, amino, hydroxyl, C 1-5phenyl, C that alkyl replaces 1-5the heterocyclic aryl that alkyl replaces.
In above-mentioned thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or prodrugs, " alkyl " mean to comprise the side chain with particular carbon atom number with the saturated fatty alkyl of straight chain.Such as, " C 1-5alkyl " in " C 1-5" definition comprise with straight or branched arrangement the group with 1,2,3,4 or 5 carbon atom.Such as, " C 1-5alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group.Term " cycloalkyl " refers to the monocycle saturated fatty alkyl with particular carbon atom number.Such as " cycloalkyl " comprises cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyI-cyclopentyl, cyclohexyl etc.
" heterocycle " or " heterocyclic radical " refers to heteroatomic 5 yuan of-6 yuan of aromaticity or the non-aromatic heterocyclic rings that are selected from O, N and S containing 1-4, and comprises bicyclic radicals." heterocyclic radical " comprises heteroaryl, also comprises its dihydro and tetrahydro-analogue." heterocyclic radical " further example includes but not limited to: imidazolyl, indyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl (oxetanyl), pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinoxalinyl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl, l, 4-alkyl dioxin, pyrrolidyl, glyoxalidine base, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyl, dihydro-oxazole base, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydro tetrazyl, thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl, and N-oxide compound.The connection of heterocyclic substituent realizes by carbon atom or by heteroatoms.
" halogen " means to comprise chlorine, fluorine, bromine and iodine.
Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituent can be unsubstituted or replacement.Such as, C 1-5h atom on alkyl or cycloalkyl can by one, substituting group that two or three are selected from hydroxyl, halogen, alkoxyl group, dialkyl amido or heterocyclic radical such as morpholinyl, piperidyl etc. replaces.
In above-mentioned thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or prodrugs, as any variable (such as R 1, R 2deng) occur exceeding once in any component, then its definition at every turn occurred is independent of other each definition occurred.Equally, the combination of substituting group and variable is allowed, as long as this combination makes stability of compounds.Be appreciated that this area, those of ordinary skill can be selected the substituting group of the compounds of this invention and substitution pattern and provide chemically stable, and is easy to the compound that synthesizes from the raw material that can easily obtain by the method for art technology and following proposition.Replace if substituting group self is exceeded group, should understand these groups can in identical carbon atoms or on different carbon atom, as long as make Stability Analysis of Structures.
The present invention includes formula I, II, III, the free form of IV compound, also comprise its pharmacy acceptable salt and steric isomer.
The pharmacy acceptable salt of the compounds of this invention comprises the conventional non-toxic salts of the compounds of this invention formed by the compounds of this invention and inorganic or organic acid reaction.Such as, conventional non-toxic salt comprises the salt deriving from mineral acid such as hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc., also comprises from organic acid such as acetic acid, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, flutters the salt of the preparations such as acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2-acetoxy-benzoic, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid.
Berg etc. describe the preparation of pharmacy acceptable salt mentioned above and other typical pharmacy acceptable salt in detail in PharmaceuticalSalts, J.Pharm.Sci.1977,66:1-19.
Wherein in an embodiment, described in ring hydrogen atom has at least 1 H atom to be substituted with a substituent, and described substituting group is C 1-5alkyl, C 1-3alkoxyl group, halogen, aryl, saturated or unsaturated heterocycle base, described saturated heterocyclyl is morpholinyl, thio-morpholinyl, pyrrolidyl, piperazinyl, piperidyl, imidazolidyl or pyrazolidyl; Described aryl, saturated or unsaturated heterocycle base are and are connected with 1 or two and are selected from following substituent group: hydroxyl, halogen, C 1-3alkyl, C 1-3alkoxyl group, C 1-3alkanoyloxy, trifluoromethyl, cyano group, amino, nitro, C 1-4alkoxy carbonyl.
Wherein in an embodiment, described C 1-5alkyl or C 3-8cycloalkyl is have a H atom at least by hydroxyl, fluorine atom or the amino C replaced 1-5alkyl or C 3-8cycloalkyl.
Wherein in an embodiment, described X 1with described X 2be NH or NCH simultaneously or independently 3.
Wherein in an embodiment, described R 1, R 2simultaneously or be independently selected from having structure:
Wherein, e, f are the integer between 0-3.
Wherein in an embodiment, described R 1, R 2simultaneously or be independently
Wherein in an embodiment, described X 1with described X 2be N, X 3, X 4be N, O or CH simultaneously or independently, described R 1, R 2simultaneously or be independently selected from having structure:
Wherein, g is the integer between 0-3.
Wherein in an embodiment, be selected from one of following compound:
N 2-(the fluoro-3-of 4-(trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(3-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(the bromo-2-luorobenzyl of 4-)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
2-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) ethyl ketone;
N 2-diphenyl-methyl-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(1-benzyl piepridine-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-((2-chloropyridine-4-replaces) methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(benzo [d] [1,3] dioxolane-5-substituent methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
(3-chloro-phenyl-) (4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperazine-1-replaces) ketone;
N 2-(4-chlorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(the chloro-6-luorobenzyl of 2-)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(2,6-dichloro benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-(trifluoromethyl) benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(4-chlorobenzene ethyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(2,4 difluorobenzene base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
(4-chloro-phenyl-)-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperidines-1-replaces) ketone;
(the chloro-2-fluorophenyl of 5-)-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperidines-1-replaces) ketone;
2-(2-chloro-phenyl-)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) ethyl ketone;
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperidines-1-replaces) (1-cyclo-propane base) ketone;
N 2-(3-bromophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
(4-bromophenyl)-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperidines-1-replaces) ketone;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-morpholine base propyl group) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(xenyl-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(3-methylpiperazine-1-replaces) thieno-[3,2-d] pyrimidine-4-amine;
N 2-(the chloro-3-(trifluoromethyl of 4-) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(4-bromine-3-fluorophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(the fluoro-5-(trifluoromethyl of 3-) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-replaces) thieno-[3,2-d] pyrimidine-4-amine;
N 2-(2,6-diethyl phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperazine-1-replaces) (pyridine-2-replaces) ketone;
N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(4-(4-methylpiperazine-1-replaces) piperidines-1-replaces) thieno-[3,2-d] pyrimidine-4-amine;
N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-4-morpholine base thieno-[3,2-d] pyrimidine-2-amine;
4-(4-(2-(5-fluoro-2-methylbenzene amine) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replaces) ethyl benzoate;
N 4-methyl-N 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 4-tolylthiophene is [3,2-d] pyrimidine-2,4-diamines also;
N 2, N 4-dimethyl-N 2, N 4-diphenyl thiophene is [3,2-d] pyrimidine-2,4-diamines also;
4,4 '-(thieno-[3,2-d] pyrimidine-2,4-bis-replaces) two morpholines;
(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) ethyl benzoate;
4-(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) ethyl benzoate;
N 2-(3,4-Dimethoxyphenyl)-N 4-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(4-fluoro-2-methylbenzene base)-N 4-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2,4-diamines;
N-(3,4-Dimethoxyphenyl)-4-morpholine base thieno-[3,2-d] pyrimidine-2-amine;
N 4-(4-morpholine base phenyl)-N 2-(pyridine-2-substituent methyl) thieno-[3,2-d] pyrimidine-2,4-diamines;
N-methyl-4-morpholine base-N-tolylthiophene also [3,2-d] pyrimidine-2-amine;
4-(4-(Cvclopropvlmethvl) piperazine-1-replaces)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2-amine;
4-(4-(2-(5-methyl isophthalic acid H-pyrazoles-3-substituted amido) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replaces) ethyl benzoate;
N 4-(4-fluoro-2-methylbenzene base)-N 2-(pyridine-3-substituent methyl) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 4-(4-fluoro-2-methylbenzene base)-N 2-methyl-N 2-tolylthiophene is [3,2-d] pyrimidine-2,4-diamines also;
2-(2,6-Dimethoxyphenyl)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-4-amine;
N 2, N 4-two (4-fluoro-2-methylbenzene base) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 4-phenyl-N 2-(5-fluoro-2-methylbenzene base) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamine hydrochloride;
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperazine-1-replaces) (pyridine-4-replaces) methanone hvdrochloric acid salt;
2-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) ethyl ketone mesylate;
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines mesylate.
Present invention also offers a kind of pharmaceutical composition being used for the treatment of tumour, described composition is made up of above-mentioned thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or prodrugs and pharmaceutically acceptable carrier.
Above-mentioned thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or prodrugs preparing anti-tumor drugs targeting, prevent and/or treat cancer, infection, inflammation and autoimmune disease pharmaceutical composition in application.
Described disease comprises: virus infection (such as HIV and kaposi's sarcoma); Inflammatory and autoimmune disease (such as colitis, sacroiliitis, alzheimer's disease, glomerulonephritis and wound healing); Bacterium, fungi and or parasitize; Leukemia, lymphoma and solid tumor (such as cancer and sarcoma); Dermatosis (such as psoriasis); Be characterised in that the proliferative disease (such as inoblast, liver cell, bone and medullary cell, cartilage or smooth muscle cell or epithelial cell (such as endometrial hyperplasia)) that cell number increases; Osteopathia and cardiovascular disorder (such as restenosis and hypertrophy).
Above-mentioned thieno-2, 4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or prodrugs effectively can suppress the unconventionality expression of Aurora A, special restraining effect is had to Aurora-A and Aurora-B, particularly can significantly suppress human cervical cancer 1 oncocyte, human macrophage system leukemia cell, human T lymphocyte system cancer cells, human fibrosarcoma cell, human skin basal cell cancer cells, non-small cell lung cancer cell, people's breast duct oncocyte, the propagation of breast cancer cell etc., can be applicable to the frontier of molecular targeted therapy or the medicine for the preparation of overmedication proliferative disease.
Embodiment
Below in conjunction with specific embodiment, invention is further elaborated.
Except standard method that is known or illustration in experimental arrangement in the literature, the reaction shown in the scheme of following embodiment can be adopted to prepare the compounds of this invention.Therefore, following illustrative approach be for illustrate object instead of be confined to listed compound or any specific substituting group.The substituting group number shown in scheme must not meet number used in claim, and for clarity sake, show monosubstituted base and be connected to and allow on the compound of multi-substituent under the definition of formula (I), (II), (III), (IV).
English abbreviation in following examples represents following reagent or reaction conditions:
(1) DCM: methylene dichloride; (2) DMF:N, dinethylformamide; (3) TFA: trifluoroacetic acid; (4) HATU:2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester; (5) DIPEA:N, N-diisopropylethylamine; (6) POCl 3: phosphorus oxychloride; (7) rt: room temperature.
The nuclear magnetic resonance spectrometer used and mass spectrograph as follows:
(1), nuclear magnetic resonance spectrometer model: VANCEAV400MHz, manufacturer: Bruker company of Switzerland; Solvent is deuterated dimethyl sulfoxide-d 6if use other solvents, have in an embodiment and clearly mention; Chemical shift carries out reference with the tetramethylsilane of standard (δ=0.00ppm);
The multiplicity at peak is expressed as follows: s: unimodal; D: doublet; Dd: two doublets; T: triplet; Q: quartet; Qu: quintet; M: multiplet; Brs: wide unimodal.
(2), mass spectrograph model: Agilent1200/MSD, manufacturer: Agilent company; ESI: electron spray ionisation.
Embodiment 1N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2the preparation (LD4484) of-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2the synthetic route of-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines is as follows:
Specifically comprise the following steps:
(1), the synthesis of thieno-[3,2-d] pyrimidine-2,4-diketone, its chemical structural formula is: synthesis step is:
In round-bottomed flask, add 3-amine pyrimidine-2-methyl-formiate (50g, 0.318mol) and urea (110g, 1.96mol), be heated to 150 DEG C of backflows 8 hours.Be cooled to 90 DEG C of stirrings that add water to spend the night, suction filtration vacuum-drying obtains white solid, is thieno-[3,2-d] pyrimidine-2,4-diketone (50.2g, productive rate: 94%).
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ11.22(t，J=8Hz，2H)，8.04(m，J=6.8Hz，1H)，6.90(m，J=6.4Hz，1H)。
MS(ESI)，m/z:169(M ++H +)。
(2), the synthesis of 2,4-dichloro-thiophenes also [3,2-d] pyrimidine, chemical structural formula is: synthesis step is:
Thieno-[3,2-d] pyrimidine-2,4-diketone (50.2g .298mol) is added, POCl in round-bottomed flask 3(300ml, 3.2mol), 130 DEG C of backflows, until react completely.Question response liquid slowly inclines after being cooled to room temperature and solvent, with a small amount of washed with dichloromethane remaining solid, then in remaining solid, mixture of ice and water and ethyl acetate is added, separatory after solid all dissolves, organic phase is merged after being extracted with ethyl acetate aqueous phase, washing organic phase is also dry, concentrates to obtain white solid.Silica gel column chromatography is separated, and the white solid of gained is 2,4-dichloro-thiophene also [3,2-d] pyrimidine (54.1g, productive rate: 89%).
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ6.90(m，J=6.4Hz，1H)，8.04(m，J=6.8Hz，1H)。
MS(ESI)，m/z:205(M ++H +)。
(3), the synthesis of the chloro-N-of 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-4-amine, chemical structural formula is: synthesis step is:
At room temperature, by 2,4-dichloro-thiophene also [3,2-d] pyrimidine (10g, 49mmol) and 5-methyl isophthalic acid H-pyrazoles-3-amine (5.5g, 56.7mmol) be dissolved in 30mL dimethyl formamide, add N again, N-diisopropyl ethyl amine 9.8ml, stirring reaction, until react completely.Stir in reaction solution impouring water, leach solid, dry, then use washed with diethylether 3-4 time, dry namely white solid obtains the chloro-N-of 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-4-amine (12.5g, productive rate 96%).
1HNMR(400MHz，d-DMSO)，δ12.35(s，1H)，10.53(s，1H)，8.20(d，J=5.6Hz，1H)，7.34(d，J=5.2Hz，1H)，6.34(s，1H)，2.27(s，3H)。
MS(ESI)，m/z:265(M ++H +)。
(4), N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2the synthesis of-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines, chemical structural formula is: synthesis step is:
At room temperature, the chloro-N-of 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3 is added in reaction tubes, 2-d] pyrimidine-4-amine (0.30g, 1.13mmol) with o-methyl-benzene ethamine (0.411g, 3.39mmol), tube sealing 140 DEG C reaction, until react completely.After having reacted, be spin-dried for solvent, add EtOAc and water extraction, organic phase saturated common salt is washed, anhydrous Na 2sO 4drying, silica gel column chromatography is separated to obtain white solid, i.e. N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines (0.356g, productive rate: 90%).
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.00(br，1H)，9.58(br，1H)，7.95(d，J=4Hz，1H)，7.18(d，J=136.8Hz，6H)，4.50(d，J=6Hz，2H)，2.23(d，J=30Hz，6H)。
MS(ESI)，m/z：351(M ++H +)。
Embodiment 2N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4481)
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
H 1NMR(400MHz，d-DMSO)，δ12.26(br，1H)，10.31(br，1H)，8.06(s，1H)，7.98(br，1H)，7.56(s，1H)，7.42(d，J=7.6Hz，1H)，7.35(t，J=14Hz，1H)，7.28(t，J=15.2Hz，1H)，7.16(d，J=5.2Hz，1H)，6.21(br，1H)，4.58(t，J=6Hz，2H)，2.20(s，3H)。
MS(ESI)，m/z:416(M ++H +)。
Embodiment 3N 2-(the bromo-2-luorobenzyl of 4-)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4478)
N 2-(the bromo-2-luorobenzyl of 4-)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.12(br，1H)，9.69(br，1H)，7.91(d，J=3.6Hz，1H)，7.69(t，J=10.4Hz，2H)，7.43(m，J=71.6Hz，1H)，7.186(brs，1H)，7.05(d，J=3.6Hz，1H)，4.52(d，J=6Hz，2H)，2.17(s，3H)。
MS(ESI)，m/z：434(M ++H +)。
Embodiment 4N 2-diphenyl-methyl-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4413)
N 2-diphenyl-methyl-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
H 1NMR(400MHz，d-DMSO)，δ12.01(br，1H)，9.651(br，1H)，8.16(s，1H)，7.93(d，J=30.4Hz，1H)，7.39(d，J=7.2Hz，4H)，7.31(s，4H)，7.22(d，J=6Hz，2H)，7.06(d，J=22.4Hz，1H)，6.38(s，1H)，2.20(d，J=36.4Hz，3H)。
MS(ESI)，m/z:413(M ++H +)。
Embodiment 5N 2-(1-benzyl piepridine-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation; (LD4430)
N 2-(1-benzyl piepridine-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
H 1NMR(400MHz，d-DMSO)，δ12.01(s，1H)，9.63(d，J=41.2Hz，1H)，7.90(t，J=32.8Hz，1H)，7.32(t，J=14，5H)，7.13(m，J=105.6Hz，1H)，6.47(d，J=62.8Hz，1H)，3.72(d，J=2.8Hz，1H)，3.48(s，2H)，2.80(s，2H)，2.23(s，2H)，2.14(s，3H)，1.88(d，J=7.2Hz，2H)，1.49(d，J=10.8Hz，2H)。
MS(ESI)，m/z:420(M ++H +)。
Embodiment 6N 2-((2-chloropyridine-4-replaces) methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4443)
N 2-((2-chloropyridine-4-replaces) methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
H 1NMR(400MHz，d-DMSO)，δ12.05(br，1H)，9.62(br，1H)，8.38(s，1H)，7.89(s，2H)，7.80(d，J=7.2Hz，1H)，7.43(d，J=8Hz，1H)，7.19(s，1H)，7.03(s，1H)，4.51(d，J=4.8Hz，2H)，2.19(s，3H)。
MS(ESI)，m/z:372(M ++H +)。
Embodiment 7N 2-(benzo [d] [1,3] dioxolane-5-substituent methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4442)
N 2-(benzo [d] [1,3] dioxolane-5-substituent methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
H 1NMR(400MHz，d-DMSO)，δ12.01(br，1H)，9.59(br，1H)，7.87(s，1H)，7.02(s，1H)，6.91(s，1H)，6.76(s，2H)，5.94(s，2H)，4.42(d，J=6Hz，2H)，2.18(d，J=20.4Hz，3H)。
MS(ESI)，m/z:381(M ++H +)。
Embodiment 8N 2-(2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4445)
N 2-(2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
H 1NMR(400MHz，d-DMSO)，δ12.08(br，1H)，9.63(br，1H)，7.92(d，J=30.4Hz，1H)，7.20(m，J=133.6Hz，6H)，6.28(br，1H)，4.57(d，J=5.6Hz，2H)，2.16(s，3H)。
MS(ESI)，m/z:355(M ++H +)。
Embodiment 9N 2-(4-chlorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4476)
N 2-(4-chlorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
H 1NMR(400MHz，d-DMSO)，δ12.10(br，1H)，10.17(br，1H)，7.94(s，1H)，7.36(s，5H)，7.06(s，1H)，4.52(d，J=6.4Hz，2H)，2.18(s，3H)。
MS(ESI)，m/z:371(M ++H +)。
Embodiment 10N 2-(the chloro-6-luorobenzyl of 2-)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4483)
N 2-(the chloro-6-luorobenzyl of 2-)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
H 1NMR(400MHz，d-DMSO)，δ12.29(d，J=221.2Hz，1H)，9.97(d，J=269.2Hz，1H)，7.95(d，J=43.6Hz，1H)，7.27(m，J=162Hz，5H)，6.68(d，J=51.6Hz，1H)，4.63(d，J=3.6Hz，2H)，2.13(d，J=32.8Hz3H)。
MS(ESI)，m/z:389(M ++H +)。
Embodiment 11N 2-(2,6-dichloro benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4479)
N 2-(2,6-dichloro benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.29(d，J=222.8Hz，1H)，9.99(d，J=272.8Hz，1H)，7.96(d，J=40Hz，1H)，7.44(d，J=47.6Hz，4H)，7.15(d，J=41.6Hz，1H)，6.67(s，1H)，4.72(d，J=4.4Hz，2H)，2.17(d，J=28.8Hz，3H)。
MS(ESI)，m/z:406(M ++H +).
Embodiment 12N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-(trifluoromethyl) benzyl) preparation (LD4485) of thieno-[3,2-d] pyrimidine-2,4-diamines
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-(trifluoromethyl) benzyl) chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.03(s，1H)，9.64(s，1H)，7.89(s，1H)，7.66(d，J=7.6Hz，2H)，7.56(s，2H)，7.25(s，1H)，7.02(s，1H)，4.75(s，2H)，2.16(s，3H)。
MS(ESI)，m/z:405(M ++H +)。
Embodiment 13N 2-(4-chlorobenzene ethyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4480)
N 2-(4-chlorobenzene ethyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.07(br，1H)，9.60(br，1H)，7.94(d，J=32Hz，1H)，7.34(m，J=46.4Hz，4H)，7.03(s，1H)，6.62(s，1H)，6.51(s，1H)，3.51(s，2H)，2.87(m，J=20.4Hz，2H)，2.21(s，3H)。
MS(ESI)，m/z:386(M ++H +)。
Embodiment 14N 2-(2,4 difluorobenzene base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4473)
N 2-(2,4 difluorobenzene base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.43(br，1H)，10.18(br，1H)，8.46(s，1H)，8.16(s，1H)，7.79(s，1H)，7.28(m，J=22.4Hz，1H)，7.14(s，1H)，7.06(t，J=16.4Hz，1H)，6.22(m，J=83.6Hz，1H)，2.17(s，3H)。
MS(ESI)，m/z:359(M ++H +)。
Embodiment 15N 2-(3-bromophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4420)
N 2-(3-bromophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.15(br，1H)，9.85(s，1H)，9.26(s，1H)，8.15(d，J=23.24Hz，1H)，8.02(d，J=5.2Hz，1H)，7.77(d，J=7.2Hz，1H)，7.23(m，J=59.6Hz，2H)，7.05(t，J=23.6Hz，1H)，6.51(s，1H)，2.27(s，3H)。
MS(ESI)，m/z:402(M ++H +)。
Embodiment 16N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2the preparation (LD4419) of-(3-morpholine base propyl group) thieno-[3,2-d] pyrimidine-2,4-diamines
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2the chemical structural formula of-(3-morpholine base propyl group) thieno-[3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.03(br，1H)，9.75(br，1H)，7.84(t，J=22.8Hz，1H)，7.03(m，J=20.4Hz，1H)，6.58(s，1H)，3.57(t，J=8.8Hz，4H)，3.30(s，2H)，2.23(s，6H)，2.21(s，3H)，1.71(m，J=27.6Hz，2H)。
MS(ESI)，m/z:374(M ++H +)。
Embodiment 17N 2-(xenyl-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4407)
N 2-(xenyl-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ9.78(br，1H)，7.89(br，1H)，7.58(t，J=52Hz，5H)，7.34(t，J=31.2Hz，5H)，7.25(m，J=21.2Hz，2H)，6.56(br，4H)，2.21(s，3H)。
MS(ESI)，m/z:399(M ++H +)。
Embodiment 18N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(3-methylpiperazine-1-replaces) preparation (LD4421) of thieno-[3,2-d] pyrimidine-4-amine
N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(3-methylpiperazine-1-replaces) chemical structural formula of thieno-[3,2-d] pyrimidine-4-amine is its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.09(s，1H)，9.63(s，1H)，7.90(d，J=33.2Hz，1H)，7.06(d，J=4.8Hz，1H)，6.314(s，1H)，4.47(t，J=20Hz，2H)，4.1(d，J=4.4Hz，1H)，3.16(d，J=4.4Hz，2H)，2.90(d，J=10Hz，1H)，2.76(t，J=24Hz，1H)，2.63(t，J=20Hz，2H)，2.40(t，J=22.4Hz，1H)，2.24(s，3H)，1.01(m，J=6Hz，3H)。
MS(ESI)，m/z:330(M ++H +)。
Embodiment 19N 2-(the chloro-3-(trifluoromethyl of 4-) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4422)
N 2-(the chloro-3-(trifluoromethyl of 4-) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.17(br，1H)，9.92(br，1H)，9.54(s，1H)，8.35(s，
1H)，8.25(d，J=7.6Hz，1H)，8.04(d，J=5.6Hz，1H)，7.55(d，J=8.8Hz，1H)，7.20(d，J=5.2Hz，1H)，6.54(d，J=22Hz，1H)，2.26(s，3H)。
MS(ESI)，m/z:425(M ++H +)。
Embodiment 20N 2-(4-bromine-3-fluorophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4424)
N 2-(4-bromine-3-fluorophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.20(br，1H)，9.87(s，1H)，9.46(br，1H)，8.19(d，J=12.8Hz，1H)，8.04(s，1H)，7.36(s，2H)，7.00(s，1H)，2.27(s，3H)。
MS(ESI)，m/z:420(M ++H +)。
Embodiment 21N 2-(the fluoro-5-(trifluoromethyl of 3-) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4432)
N 2-(the fluoro-5-(trifluoromethyl of 3-) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.20(br，1H)，9.65(br，1H)，9.68(s，1H)，8.32(d，J=12Hz，1H)，8.06(d，J=4.8Hz，1H)，7.23(d，J=5.2Hz，1H)，7.04(d，J=8Hz，1H)，6.48(s，1H)，2.27(s，3H)。
MS(ESI)，m/z:409(M ++H +)。
Embodiment 22N 2-(2,6-diethyl phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4437)
N 2-(2,6-diethyl phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ11.80(br，1H)，9.69(br，1H)，8.08(s，1H)，8.66(s，1H)，7.18(d，J=6Hz，1H)，7.13(d，J=6.8Hz，2H)，7.03(s，1H)，2.52(t，J=19.6Hz，4H)，2.04(d，J=9.6Hz，3H)，1.06(m，J=24.4Hz，6H)。
MS(ESI)，m/z:379(M ++H +)。
Embodiment 23N 2-methyl-N 4the preparation (LD1140) of-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N2-tolylthiophene also [3,2-d] pyrimidine-2,4-diamines
N 2-methyl-N 4the chemical structural formula of-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N2-tolylthiophene also [3,2-d] pyrimidine-2,4-diamines is its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ11.87(s，1H)，9.80(s，1H)，7.95(d，J=4Hz，1H)，7.42(t，J=14.8Hz，2H)，7.33(d，J=7.6Hz，2H)，7.24(t，J=13.6Hz，1H)，7.14(d，J=4.4Hz，1H)，5.75(s，1H)，3.7(s，3H)，2.04(s，3H)。
MS(ESI)，m/z:337(M ++H +)。
Embodiment 24N 2-(5-fluoro-2-methylbenzene base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD1148)
N 2-(5-fluoro-2-methylbenzene base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.08(br，1H)，9.87(br，1H)，8.14(s，1H)，8.02(s，1H)，7.73(s，1H)，7.19(t，J=15.2Hz，2H)，6.80(m，J=16.4Hz，1H)，6.30(br，1H)，2.25(s，3H)，2.18(s，3H)。
MS(ESI)，m/z:355(M ++H +)。
Embodiment 25N 2-(3,5-bis-(trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4486)
N 2-(3,5-bis-(trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.03(br，1H)，9.75(br，1H)，7.96(t，J=56.4Hz，4H)，7.39(d，J=52.4Hz，1H)，7.01(s，1H)，6.28(m，J=130Hz，1H)，4.67(s，1H)，2.17(s，3H)。
MS(ESI)，m/z:473(M ++H +)。
Embodiment 264-(4-(2-(5-methyl isophthalic acid H-pyrazoles-3-substituted amido) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replaces) preparation (LD1192) of ethyl benzoate
4-(4-(2-(5-methyl isophthalic acid H-pyrazoles-3-substituted amido) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replaces) chemical structural formula of ethyl benzoate is its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.09(s，1H)，9.74(s，1H)，7.94(d，J=5.6Hz，1H)，7.8(d，J=8.8Hz，2H)，7.10(d，J=5.6Hz，1H)，7.04(d，J=8.8Hz，2H)，6.38(s，1H)，4.23(m，J=26Hz，2H)，3.87(t，J=10Hz，4H)，3.43(t，J=10Hz，4H)，2.26(s，3H)，1.29(t，J=14Hz，3H)。
MS(ESI)，m/z:464(M ++H +)。
Embodiment 272-(4-methyl isophthalic acid, 4-Diazesuberane-1-replaces)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) preparation (LD4415) of thieno-[3,2-d] pyrimidine-4-amine
2-(4-methyl isophthalic acid, 4-Diazesuberane-1-replaces)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) chemical structural formula of thieno-[3,2-d] pyrimidine-4-amine is its synthesis step is with embodiment 1.
1HNMR(400MHz，d-DMSO)，δ12.05(s，1H)，9.64(s，1H)，7.88(d，J=5.2Hz，1H)，7.05(d，J=5.2Hz，1H)，6.37(s，1H)，3.84(d，J=4Hz，2H)，3.76(t，J=12Hz，2H)，2.62(d，J=4.4Hz，2H)，2.46(d，J=5.2Hz，2H)，2.24(d，J=8.4Hz，6H)，1.89(d，J=5.2Hz，2H)。
MS(ESI)，m/z:344(M ++H +)。
Embodiment 28N 2, N 4the preparation (LD4428) of-two (5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines
N 2, N 4-two (5-methyl isophthalic acid H-pyrazoles-3-replaces) chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines is its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ11.80(br，1H)，10.36(br，1H)，9.81(br，1H)，8.89(br，1H)，8.06(s，1H)，7.19(s，1H)，5.92(br，1H)，5.31(s，1H)，2.19(d，J=34Hz，6H)。
MS(ESI)，m/z:327(M ++H +)。
The preparation (LD4487) of embodiment 29N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(4-(4-methylpiperazine-1-replaces) piperidines-1-replaces) thieno-[3,2-d] pyrimidine-4-amine
The chemical structural formula of N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(4-(4-methylpiperazine-1-replaces) piperidines-1-replaces) thieno-[3,2-d] pyrimidine-4-amine is its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.09(s，1H)，9.62(s，1H)，7.90(d，J=5.2Hz，1H)，7.05(d，J=5.2Hz，1H)，6.31(s，1H)，4.67(d，J=12.8Hz，2H)，3.35(m，J=21.6Hz，2H)，3.16(s，1H)，2.82(t，J=23.6Hz，2H)，2.41(m，J=11.2Hz，4H)，2.24(s，3H)，2.13(s，3H)，1.8(d，J=10.8Hz，2H)，1.31(m，J=23.2Hz，2H)。
MS(ESI)，m/z:413(M ++H +)。
Embodiment 30N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) preparation (LD1142) of-4-morpholine base thieno-[3,2-d] pyrimidine-2-amine
N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) chemical structural formula of-4-morpholine base thieno-[3,2-d] pyrimidine-2-amine is: its synthesis step is with embodiment 1.
1HNMR(400MHz，d-DMSO)，δ11.83(s，1H)，8.77(s，1H)，8.04(s，1H)，7.18(s，1H)，3.85(d，J=4.4Hz，4H)，3.75(d，J=4.8Hz，4H)，2.19(s，3H)。
MS(ESI)，m/z:317(M ++H +)。
Embodiment 314-(4-(2-(5-fluoro-2-methylbenzene amine) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replaces) preparation (LD1193) of ethyl benzoate
4-(4-(2-(5-fluoro-2-methylbenzene amine) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replaces) chemical structural formula of ethyl benzoate is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，CDCl3)，δ8.19(m，J=14.8Hz，1H)，7.97(d，J=9.2Hz，2H)，7.69(d，J=5.6Hz，1H)，7.09(t，J=15.2Hz，1H)，6.89(d，J=8.8Hz，2H)，6.70(s，1H)，6.64(m，J=19.2Hz，2H)，4.34(m，J=21.2Hz，2H)，4.15(m，J=20.4Hz，4H)，3.54(m，J=10.4Hz，4H)，2.32(t，J=14.8Hz，3H)，1.25(t，J=14Hz，3H)。
MS(ESI)，m/z:492(M ++H +)。
Embodiment 32N 4-methyl-N 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 4the preparation (LD1145) of-tolylthiophene also [3,2-d] pyrimidine-2,4-diamines
N 4-methyl-N 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 4the chemical structural formula of-tolylthiophene also [3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(500MHz，d-DMSO)，δ11.73(s，1H)，8.08(s，1H)，7.73(s，1H)，7.52(m，J=35.6Hz，3H)，7.45(s，1H)，7.43(s，1H)，3.53(s，3H)，2.20(d，J=4.8Hz，3H)。
MS(ESI)，m/z:337(M ++H +)。
Embodiment 33N 2, N 4-dimethyl-N 2, N 4the preparation (LD1133) of-diphenyl thiophene also [3,2-d] pyrimidine-2,4-diamines
N 2, N 4-dimethyl-N 2, N 4the chemical structural formula of-diphenyl thiophene also [3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ7.70(d，J=5.2Hz，1H)，7.42(m，J=54.0Hz，8H)，7.14(m，J=14.0Hz，1H)，6.99(d，J=5.2Hz，1H)，3.53(s，3H)，3.32(s，3H)。
MS(ESI)，m/z:347(M ++H +)。
Embodiment 344, the preparation (LD1134) of 4 '-(thieno-[3,2-d] pyrimidine-2,4-bis-replaces) two morpholines
The chemical structural formula of 4,4 '-(thieno-[3,2-d] pyrimidine-2,4-bis-replaces) two morpholines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，CDCl 3)，δ7.61(d，J=5.2Hz，1H)，3.94(d，J=4.4Hz，4H)，3.86(m，J=29.2Hz，4H)，3.79(s，8H)。
MS(ESI)，m/z:307(M ++H +)。
Embodiment 35(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) preparation (LD1179) of ethyl benzoate
(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) chemical structural formula of ethyl benzoate is: its synthesis step is with embodiment 1.
1HNMR(400MHz，d-DMSO)，δ8.03(d，J=5.6Hz，1H)，7.80(d，J=8.8Hz，2H)，7.16(d，J=5.6Hz，1H)，7.02(d，J=9.2Hz，2H)，4.25(m，J=24Hz，2H)，3.84(d，J=3.6Hz，8H)，3.74(t，J=9.2Hz，4H)，3.41(t，J=10Hz，4H)，1.29(t，J=14.4Hz，3H)。
MS(ESI)，m/z:454(M ++H +)。
Embodiment 364-(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) preparation (LD1178) of ethyl benzoate
4-(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) chemical structural formula of ethyl benzoate is: its synthesis step is with embodiment 1.
1HNMR(400MHz，d-DMSO)，δ9.22(s，1H)，7.96(d，J=5.2Hz，1H)，7.80(d，J=9.2Hz，2H)，7.55(d，J=9.2Hz，2H)，7.12(d，J=5.2Hz，1H)，7.03(d，J=9.2Hz，2H)，6.96(d，J=9.2Hz，2H)，4.24(m，J=21.2Hz，2H)，3.84(t，J=10Hz，4H)，3.75(t，J=9.6Hz，4H)，3.41(t，J=9.6Hz，4H)，3.10(t，J=9.6Hz，4H)，1.29(t，J=14Hz，3H)。
MS(ESI)，m/z:545(M ++H +)。
Embodiment 37N 2-(3,4-Dimethoxyphenyl)-N 4the preparation (LD1175) of-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2,4-diamines
N 2-(3,4-Dimethoxyphenyl)-N 4the chemical structural formula of-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ9.20(s，1H)，8.79(s，1H)，7.99(d，J=5.2Hz，1H)，7.58(d，J=8Hz，2H)，7.47(d，J=2Hz，1H)，7.31(t，J=8.8Hz，1H)，7.15(d，J=5.6Hz，1H)，6.93(d，J=9.2Hz，2H)，6.80(d，J=8.8Hz，1H)，3.76(t，J=9.6Hz，4H)，3.70(s，3H)，3.63(s，3H)。
MS(ESI)，m/z:464(M ++H +)。
Embodiment 38N 2-(4-fluoro-2-methylbenzene base)-N 4the preparation (LD1167) of-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2,4-diamines
N 2-(4-fluoro-2-methylbenzene base)-N 4the chemical structural formula of-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ10.76(brs，1H)，9.73(brs，1H)，8.28(brs，1H)，7.5(m，J=8.4Hz，1H)，7.43(d，J=6.8Hz，2H)，7.31(t，J=14.8Hz，2H)，7.03(d，J=6.4Hz1H)，6.91(d，J=7.2Hz，2H)，3.75(t，J=8.4Hz，4H)，3.11(s，4H)，2.25(s，3H)。
MS(ESI)，m/z:436(M ++H +)。
Embodiment 39N-(3,4-Dimethoxyphenyl) preparation (LD1174) of-4-morpholine base thieno-[3,2-d] pyrimidine-2-amine
N-(3,4-Dimethoxyphenyl) chemical structural formula of-4-morpholine base thieno-[3,2-d] pyrimidine-2-amine is: its synthesis step is with embodiment 1.
The characterization data of this compound is: 1hNMR (400MHz, d-DMSO), δ 8.97 (s, 1H), 8.08 (d, J=5.2Hz, 1H), 7.50 (s, 1H), 7.19 (d, J=6Hz, 2H), 6.85 (d, J=8.4Hz, 1H), 3.88 (s, 4H), 3.73 (t, J=21.6Hz, 14H).
MS(ESI)，m/z:373(M ++H +)。
Embodiment 40N 4-(4-morpholine base phenyl)-N 2the preparation (LD1182) of-(pyridine-2-substituent methyl) thieno-[3,2-d] pyrimidine-2,4-diamines
N 4-(4-morpholine base phenyl)-N 2the chemical structural formula of-(pyridine-2-substituent methyl) thieno-[3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ9.05(s，1H)，8.51(d，J=4.4Hz，1H)，7.90(d，J=5.6Hz，1H)，7.69(m，J=17.2Hz，1H)，7.51(s，2H)，7.31(d，J=8Hz，1H)，7.21(m，J=12Hz，1H)，7.05(t，J=18.4Hz，1H)，6.84(d，J=6.4Hz，2H)，4.58(d，J=6.4Hz，2H)，3.74(t，J=9.2Hz，4H)，3.06(t，J=9.2Hz，4H)。
MS(ESI)，m/z:419(M ++H +)。
The preparation (LD1147) of embodiment 41N-methyl-4-morpholine base-N-tolylthiophene also [3,2-d] pyrimidine-2-amine
The chemical structural formula of N-methyl-4-morpholine base-N-tolylthiophene also [3,2-d] pyrimidine-2-amine is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ8.03(d，J=5.2Hz，1H)，7.35(m，J=10.8Hz，4H)，7.14(m，J=20.4Hz，2H)，3.71(t，J=5.2Hz，4H)，3.67(d，J=4.8Hz，4H)，3.32(s，3H)。
MS(ESI)，m/z:327(M ++H +)。
The preparation (LD1186) of embodiment 424-(4-(Cvclopropvlmethvl) piperazine-1-replaces)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2-amine
The chemical structural formula of 4-(4-(Cvclopropvlmethvl) piperazine-1-replaces)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2-amine is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ11.72(s，1H)，8.74(s，1H)，8.02(d，J=4.8Hz，1H)，7.17(s，1H)，6.41(s，1H)，3.88(s，4H)，2.57(t，J=9.2Hz，4H)，2.32(s，3H)，2.21(t，J=16.8Hz，2H)，0.86(m，J=38.8Hz，1H)，0.47(m，J=9.2Hz，2H)，0.08(d，J=4.64Hz，2H)。
MS(ESI)，m/z:370(M ++H +)。
Embodiment 434-(4-(2-(5-methyl isophthalic acid H-pyrazoles-3-substituted amido) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replaces) preparation (LD1190C) of ethyl benzoate
4-(4-(2-(5-methyl isophthalic acid H-pyrazoles-3-substituted amido) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replaces) chemical structural formula of ethyl benzoate is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ8.26(d，J=5.6Hz，1H)，7.82(d，J=8.4Hz，2H)，7.46(d，J=5.6Hz，1H)，7.00(d，J=8.8Hz，2H)，6.66(s，2H)，5.24(s，1H)，4.24(m，J=20.8Hz，2H)，4.16(s，4H)，3.62(s，4H)，2.08(s，3H)，1.29(t，J=14.4Hz，3H)。
MS(ESI)，m/z:464(M ++H +)。
Embodiment 44N 4-(4-fluoro-2-methylbenzene base)-N 2the preparation (LD46018) of-(pyridine-3-substituent methyl) thieno-[3,2-d] pyrimidine-2,4-diamines
N 4-(4-fluoro-2-methylbenzene base)-N 2the chemical structural formula of-(pyridine-3-substituent methyl) thieno-[3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ8.94(s，1H)，8.46(d，J=4Hz，1H)，7.89(d，J=5.6Hz，1H)，7.66(m，J=16.8Hz，1H)，7.23(m，J=46Hz，4H)，7.01(m，J=24.4Hz，3H)，4.51(dJ=6Hz，2H)，2.14(s，3H)。
MS(ESI)，m/z:366(M ++H +)。
Embodiment 45N 4-(4-fluoro-2-methylbenzene base)-N 2-methyl-N 2the preparation (LD46017) of-tolylthiophene also [3,2-d] pyrimidine-2,4-diamines
N 4-(4-fluoro-2-methylbenzene base)-N 2-methyl-N 2the chemical structural formula of-tolylthiophene also [3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ8.92(s，1H)，7.97(d，J=5.6Hz，1H)，7.25(m，J=49.2Hz，5H)，7.14(d，J=5.6Hz，1H)，7.03(d，J=53.2Hz，1H)，6.94(m，J=16.8Hz，1H)，3.41(s，3H)，2.15(s，3H)。
MS(ESI)，m/z:365(M ++H +)。
Embodiment 462-(2,6-Dimethoxyphenyl)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) preparation (LD46016) of thieno-[3,2-d] pyrimidine-4-amine
2-(2,6-Dimethoxyphenyl)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) chemical structural formula of thieno-[3,2-d] pyrimidine-4-amine is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.23(s，1H)，9.84(s，1H)，8.1(d，J=4.8Hz，1H)，7.33(t，J=16.8Hz，2H)，6.72(d，J=8.4Hz，2H)，6.18(s，1H)，3.64(s，6H)，2.21(s，3H)。
MS(ESI)，m/z:368(M ++H +)。
Embodiment 47N 2, N 4the preparation (LD46011) of-two (4-fluoro-2-methylbenzene base) thieno-[3,2-d] pyrimidine-2,4-diamines
N 2, N 4the chemical structural formula of-two (4-fluoro-2-methylbenzene base) thieno-[3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ10.99(s，1H)，9.82(s，1H)，8.34(d，J=4.8Hz，1H)，7.45(d，J=8.8Hz，1H)，7.37(t，J=12.4Hz，2H)，7.31(m，J=12Hz，1H)，7.35(t，J=14.8Hz，1H)，7.17(t，J=6.4Hz，1H)，6.91(t，J=14.4Hz，1H)，2.25(s，3H)，2.18(s，3H)。
MS(ESI)，m/z:383(M ++H +)。
Embodiment 48N 4-phenyl-N 2the preparation (LD1149) of-(5-fluoro-2-methylbenzene base) thieno-[3,2-d] pyrimidine-2,4-diamines
N 4-phenyl-N 2the chemical structural formula of-(5-fluoro-2-methylbenzene base) thieno-[3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ8.38(s，1H)，7.76(t，J=12Hz，2H)，7.30(m，J=22.8Hz，1H)，7.19(m，J=38.4Hz，7H)，4.67(s，J=6Hz，2H)，2.20(s，3H)。
MS(ESI)，m/z:365(M ++H +)。
The preparation (LD4490) of embodiment 492-(4-(3-chloro-phenyl-) piperazine-1-replaces)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-4-amine
The chemical structural formula of 2-(4-(3-chloro-phenyl-) piperazine-1-replaces)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-4-amine is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.12(s，1H)，9.72(s，1H)，7.93(d，J=5.2Hz，1H)，7.22(t，J=16.4Hz，1H)，7.09(d，J=5.2Hz，1H)，7.01(d，J=1.6Hz，1H)，6.96(m，J=10Hz，1H)，6.35(s，1H)，3.85(t，J=9.6Hz，4H)，3.26(t，J=10Hz，4H)，2.27(s，3H)。
MS(ESI)，m/z:427(M ++H +)。
Embodiment 50N 2-(the fluoro-3-of 4-(trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4491)
N 2-(the fluoro-3-of 4-(trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.02(br，1H)，9.61(br，1H)，7.90(br，1H)，7.73(t，J=24.8Hz，2H)，7.43(t，J=19.6Hz，1H)，7.22(br，1H)，7.04(br，1H)，6.34(br，1H)，4.56(d，J=5.2Hz，2H)，2.18(s，3H)。
MS(ESI)，m/z:423(M ++H +)。
Embodiment 51N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2the preparation (LD4494) of-(4-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2the chemical structural formula of-(4-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines is: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.00(br，1H)，9.74(br，1H)，8.21(br，1H)，7.89(br，1H)，7.35(d，J=8Hz，2H)，7.23(d，J=6Hz，2H)，7.04(br，1H)，6.40(br，1H)，4.49(d，J=6Hz，2H)，2.25(s，3H)，2.18(s，3H)。
MS(ESI)，m/z:351(M ++H +)。
Embodiment 52N 2-(3-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines preparation (LD4497)
N 2-(3-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines was: its synthesis step is with embodiment 1.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.06(br，1H)，9.58(br，1H)，7.89(s，1H)，7.35(m，J=39.2Hz，1H)，7.07(m，J=64Hz，4H)，6.61(br，1H)，6.51(br，1H)，3.54(d，J=6.4Hz，2H)，2.20(s，3H)。
MS(ESI)，m/z:355(M ++H +)。
The fluoro-N-(4-of embodiment 534-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces amine) phenyl) preparation (LD4489) of benzamide
The fluoro-N-(4-of 4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces amine) phenyl) synthetic route of benzamide is as follows:
Specifically comprise the following steps:
(1), N 2-(4-aminophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines, its chemical structural formula is: synthesis step is:
In reaction tubes, add the chloro-N-of 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-4-amine (0.3g, 1.13mmol) and benzene-Isosorbide-5-Nitrae-diamines (0.367g, 3.39mmol), react at tube sealing 145 DEG C, until react completely.After having reacted, be spin-dried for solvent, add EtOAc and water extraction, organic phase saturated common salt is washed, anhydrous Na 2sO 4drying, silica gel column chromatography is separated white solid is N 2-(4-aminophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines (0.36g, productive rate: 95%).
The characterization data of this compound is:
MS(ESI)，m/z:338(M ++H +)。
(2), the fluoro-N-(4-of 4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces amine) phenyl) synthesis of benzamide, chemical structural formula is: synthesis step is:
By N 2-(4-aminophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines (150mg, 0.445mmol), 4-fluorobenzoic acid (68mg, 0.485mmol), HATU (183mg, 0.48mmol), DIPEA (1.85g, 0.25ml) be dissolved in (1.0mL) in DMF, stirred at ambient temperature is until react completely.Reaction solution DCM extracts, washing, merges organic phase, concentrated.Obtaining white solid after column chromatography is the fluoro-N-(4-of 4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces amine) phenyl) benzamide (0.18g, productive rate 88%).
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.13(br，1H)，10.13(br，1H)，9.76(s，1H)，9.02(s，1H)，8.02(m，J=22.4Hz，3H)，7.80(d，J=8.8Hz，2H)，7.63(s，2H)，7.36(m，J=28.4Hz，2H)，7.17(s，1H)，6.56(br，1H)，2.28(s，3H)。
MS(ESI)，m/z:460(M ++H +)。
Embodiment 54N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-replaces) preparation (LD4429) of thieno-[3,2-d] pyrimidine-4-amine
N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-replaces) synthetic route of thieno-[3,2-d] pyrimidine-4-amine is as follows:
Specifically comprise the following steps:
(1), 4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-tertbutyloxycarbonyl, its chemical structural formula is: synthesis step is:
The chloro-N-of 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3 is added in reaction tubes, 2-d] pyrimidine-4-amine (0.3g, 1.13mmol) and piperazine-1-tert-butylformamide (0.633g, 3.39mmol), react at tube sealing 140 DEG C, until react completely.After having reacted, be spin-dried for solvent, add EtOAc and water extraction, organic phase saturated common salt is washed, anhydrous Na 2sO 4drying, silica gel column chromatography is separated white solid is 4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-tertbutyloxycarbonyl (0.32g, productive rate: 90%).
The characterization data of this compound is:
MS(ESI)，m/z:416(M ++H +).
(2), N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-replaces) synthesis of thieno-[3,2-d] pyrimidine-4-amine, chemical structural formula is: synthesis step is:
By 4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-tert-butylformamide (0.32g, 0.77mmol), TFA(0.7g, 0.5ml) be dissolved in methylene dichloride (5ml).After stirred at ambient temperature 2h, be spin-dried for solvent, adding saturated sodium bicarbonate solution adjusts PH to alkalescence, filter, vacuum-drying obtains white solid and is N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-and replaces) thieno-[3,2-d] pyrimidine-4-amine (0.22g, productive rate: 92%).
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.10(brs，1H)，9.64(brs，1H)，7.89(t，J=16.4Hz，1H)，7.05(m，J=20.4Hz，1H)，6.28(s，1H)，3.63(t，J=9.6Hz，4H)，2.73(t，J=2.73Hz，4H)，2.23(s，3H)。
MS(ESI)，m/z:316(M ++H +)。
Embodiment 552-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) preparation (LD4456) of ethyl ketone
2-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) synthetic route of ethyl ketone is as follows:
Specifically comprise the following steps:
(1), synthesis N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-replace) thieno-[3,2-d] pyrimidine-4-amine, step is with embodiment 54;
(2), N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-is replaced) thieno-[3,2-d] pyrimidine-4-amine (100mg, 0.317mmol), 2-(4-fluorophenyl) acetic acid (54mg, 0.35mmol), HATU (145mg, 0.38mmol), DIPEA (1.48g, 0.2ml) is dissolved in (2.0mL) in the mixed solvent of DMF/DCM=1, and stirred at ambient temperature is until react completely.Reaction solution DCM extracts, washing, merges organic phase, concentrated.Obtaining white solid after column chromatography is that 2-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) ethyl ketone (0.122g, productive rate 85%).
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.11(s，1H)，9.71(s，1H)，7.93(d，J=5.2Hz，1H)，7.36(d，J=8.4Hz，2H)，7.27(d，J=8.4Hz，2H)，7.08(d，J=5.2Hz，1H)，6.3(s，1H)，3.78(s，2H)，3.69(s，4H)，3.58(t，J=12.8Hz，4H)，2.25(s，3H)。
MS(ESI)，m/z:452(M ++H +)。
Embodiment 56 (3-chloro-phenyl-) (4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) preparation (LD4449) of ketone
(3-chloro-phenyl-) (4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperazine-1-replaces) chemical structural formula of ketone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.10(s，1H)，9.72(s，1H)，7.94(d，J=5.2Hz，1H)，7.51(m，J=30.8Hz，3H)，7.41(d，J=7.6Hz，1H)，7.09(d，J=5.2Hz，1H)，6.29(s，1H)，3.78(m，J=38.4Hz，8H)，2.23(s，3H)。
MS(ESI)，m/z:454(M ++H +)。
Embodiment 57 (4-chloro-phenyl-)-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) preparation (LD4455) of ketone
(4-chloro-phenyl-)-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperidines-1-replaces) chemical structural formula of ketone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.09(s，1H)，9.72(s，1H)，7.94(d，J=1.2Hz，1H)，7.51(m，J=28.8Hz，4H)，7.09(d，J=5.2Hz，1H)，6.3(s，1H)，3.81(s，2H)，3.74(s，4H)，3.43(s，2H)，2.23(s，3H)。
MS(ESI)，m/z:454(M ++H +)。
Embodiment 58 (the chloro-2-fluorophenyl of 5-)-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) preparation (LD4463) of ketone
(the chloro-2-fluorophenyl of 5-)-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperidines-1-replaces) chemical structural formula of ketone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.10(s，1H)，9.74(s，1H)，7.94(d，J=5.2Hz，1H)，7.58(m，J=15.6Hz，2H)，7.39(m，J=18Hz，1H)，7.09(d，J=5.2Hz，1H)，6.29(s，1H)，3.82(d，J=5.6Hz，2H)，3.73(s，4H)，3.31(s，2H)，2.23(s，3H)。
MS(ESI)，m/z:473(M ++H +)。
Embodiment 592-(2-chloro-phenyl-)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) preparation (LD4469) of ethyl ketone
2-(2-chloro-phenyl-)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) chemical structural formula of ethyl ketone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.11(s，1H)，9.74(s，1H)，7.94(d，J=5.2Hz，1H)，7.42(m，J=8.8Hz，1H)，7.30(m，J=26.8Hz，3H)，7.1(d，J=5.2Hz，1H)，6.31(s，1H)，3.88(s，2H)，3.76(d，J=21.2Hz，4H)，3.62(d，J=29.2Hz，4H)，2.25(s，3H)。
MS(ESI)，m/z:469(M ++H +)。
Embodiment 60(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) preparation (LD4474) of (1-cyclo-propane base) ketone
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperidines-1-replaces) chemical structural formula of (1-cyclo-propane base) ketone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.12(s，1H)，9.75(s，1H)，8.16(s，1H)，7.93(d，J=5.2Hz，1H)，7.32(t，J=15.2Hz，2H)，7.20(t，J=14.8Hz，2H)，7.06(d，J=14.8Hz，1H)，6.22(s，1H)，3.63(m，J=36.4Hz，4H)，3.32(s，4H)，3.13(m，J=26.4Hz，2H)，2.23(s，3H)，1.25(m，J=36.4Hz，2H)。
MS(ESI)，m/z:460(M ++H +)。
Embodiment 61 (4-bromophenyl)-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) preparation (LD4454) of ketone
(4-bromophenyl)-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperidines-1-replaces) chemical structural formula of ketone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.09(s，1H)，9.73(s，1H)，7.94(d，J=5.2Hz，1H)，7.67(d，J=8.4Hz，1H)，7.41(d，J=8Hz，2H)，7.09(d，J=5.6Hz，1H)，6.29(s，1H)，3.81(s，2H)，3.80(s，4H)，3.42(s，2H)，2.23(s，3H)。
MS(ESI)，m/z:499(M ++H +)。
Embodiment 62(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) preparation (LD4446) of (pyridine-2-replaces) ketone
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperazine-1-replaces) chemical structural formula of (pyridine-2-replaces) ketone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.10(s，1H)，9.72(s，1H)，8.62(d，J=4.8Hz，1H)，7.72(m，J=56.8Hz，2H)，7.61(d，J=8Hz，1H)，7.50(m，J=12.4Hz，1H)，7.09(d，J=5.6Hz，1H)，6.30(s，1H)，3.84(s，2H)，3.74(s，4H)，3.64(s，4H)，2.23(s，3H)。
MS(ESI)，m/z:421(M ++H +)。
Embodiment 631-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) preparation (LD4448) of-3-phenyl-1-acetone
1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) chemical structural formula of-3-phenyl-1-acetone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.13(s，1H)，9.75(s，1H)，7.94(d，J=5.2Hz，1H)，7.27(m，J=19.6Hz，4H)，7.17(m，J=17.2Hz，1H)，7.09(d，J=5.2Hz，1H)，6.29(s，1H)，3.67(s，4H)，3.52(d，J=16.4Hz，4H)，2.84(t，J=15.6Hz，2H)，22.68(t，J=15.6Hz，2H)，2.25(s，3H)。
MS(ESI)，m/z:448(M ++H +)。
Embodiment 64(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) preparation (LD4450) of (pyridine-4-replaces) ketone
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperazine-1-replaces) chemical structural formula of (pyridine-4-replaces) ketone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.10(s，1H)，9.72(s，1H)，8.68(m，J=5.6Hz，2H)，7.96(d，J=5.6Hz，2H)，7.43(m，J=6Hz，2H)，7.09(d，J=5.2Hz，1H)，6.28(s，1H)，3.84(s，1H)，3.73(s，4H)，3.08(m，J=22Hz，4H)，2.22(s，1H)。
MS(ESI)，m/z:421(M ++H +)。
The preparation (LD4447) of embodiment 65 (4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) (pyrazine-2-replaces) ketone
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) chemical structural formula of (pyrazine-2-replaces) ketone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.11(s，1H)，9.73(s，1H)，8.88(d，J=1.2Hz，1H)，8.76(d，J=2.4Hz，1H)，8.70(d，J=3.6Hz，2H)，7.94(d，J=5.6Hz，1H)，7.09(d，J=5.2Hz，1H)，6.30(s，1H)，3.86(d，J=5.2Hz，2H)，3.76(s，4H)，3.53(s，2H)，2.23(s，3H)。
MS(ESI)，m/z:422(M ++H +)。
Embodiment 661-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) preparation (LD4459) of propane-1-ketone
1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) chemical structural formula of propane-1-ketone is: its synthesis step is with embodiment 55.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ12.12(s，1H)，9.73(s，1H)，9.62(s，1H)，7.94(d，J=5.2Hz，1H)，7.09(d，J=5.2Hz，1H)，6.31(s，1H)，3.72(d，J=23.6Hz，4H)，3.53(s，4H)，2.37(m，J=22Hz，2H)，2.25(s，3H)，0.93(m，J=49.2Hz，3H)。
MS(ESI)，m/z:372(M ++H +)。
Embodiment 67N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2the preparation (LD4484 hydrochloride) of-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamine hydrochloride
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2the chemical structural formula of-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamine hydrochloride is: synthesis step is:
By N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines (0.351g, 1mmol) is placed in 100mL there-necked flask, adds 20mL dehydrated alcohol, stirs lower dropping 6mol/L aqueous hydrochloric acid, treats that raw material all dissolves, be spin-dried for obtain white solid, be i.e. N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamine hydrochloride (0.405g, productive rate 90%).
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ8.00(br，4H)，7.43(t，1H)，7.20(d，1H)，6.96～7.10(m，6H)，5.00(d，1H)，4.59(s,2H)，2.34(s，3H)，1.71(d,3H)。
MS(ESI)，m/z：351(M ++H +)。
Embodiment 68(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replaces) preparation (LD4450 hydrochloride) of (pyridine-4-replaces) methanone hvdrochloric acid salt
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine), thieno-[3,2-d] pyrimidine-2-replaced) piperazine-1-replaces) chemical structural formula of (pyridine-4-replaces) methanone hvdrochloric acid salt is: its synthesis step is with embodiment 67.
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ8.89(d，2H)，8.0(br，3H)，7.92(d，2H)，7.20(d，1H)，7.0(br，3H)，6.96(d，1H)，5.0(s，1H)，4.07(s，8H)，1.71(d，3H)。
MS(ESI)，m/z:421(M ++H +)。
Embodiment 692-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) preparation (LD4456 mesylate) of ethyl ketone mesylate
2-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) chemical structural formula of ethyl ketone mesylate is: synthesis step is:
2-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-is replaced amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replaces) ethyl ketone (0.451g, 1mmol) be placed in 100mL single port bottle, add 30mL dehydrated alcohol, stir lower dropping 384mg methylsulfonic acid (4mmol), be heated to boil, system becomes clarification, backflow 4h, be cooled to room temperature, adularescent solid is separated out, and filters, filter residue ethanol washes three times, and vacuum-drying obtains light yellow solid 0.750g(90%).
The characterization data of this compound is:
1HNMR(400MHz，d-DMSO)，δ8.00(br，3H)，7.34(m，2H)，7.20(d，1H)，7.12(m，2H)，7.0(br，3H)，6.96(ds，1H)，5.00(d，1H)，4.07(s，8H)，3.66(s，2H)，2.84(s，12H)，1.71(d,3H)。
MS(ESI)，m/z：452(M ++H +)。
Embodiment 70N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines mesylate preparation (LD4481 mesylate)
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces), the chemical structural formula of thieno-[3,2-d] pyrimidine-2,4-diamines mesylate was: its synthesis step is with embodiment 69.
The characterization data of this compound is:
H 1NMR(400MHz，d-DMSO)，δ8.00(br，4H)，7.22～7.41(m，3H)，7.17～7.20(m，2H)，7.00(br，2H)，6.96(d，1H)，5.00(d，1H)，4.59(s，2H)，2.84(s，9H)，1.71(d，3H)。
MS(ESI)，m/z:416(M ++H +)。
Embodiment 71 vitro kinase activity detects
Kinase activity detects and adopts Fluorescence Resonance Energy transfer (FRET) Z-LYTE method.Medicine carries out gradient dilution (from 10 μMs 3 times of dilutions), and add kinases (AuroraA is about 0.1-0.01U/mL or AuroraB and is about 0.1-0.01U/mL) and two ends indicate coumarin(fluorogenic donor respectively) and fluorophores(fluorescent receptor) substrate (20 μMs) is in the reaction system of 10ul, adding final concentration is room temperature reaction 2 hours after 10uMATP; Add the Development solution of 5ul again in reaction system, room temperature reaction is after 1 hour, and then the stop buffer adding 5ul, microplate reader detects.Under the excitation wavelength of 400nm, the ratio detecting the emission wavelength gained at utilizing emitted light 460nm and 535nm place respectively, through GraphpadPrism5.0 Fitting Analysis, obtains the IC of sieved medicine 50.Each compound is to the kinase whose half-inhibition concentration IC of AuroraA or AuroraB 50value is described by table 1.Compound used therefor is selected from the compound prepared by embodiment 1-66 respectively.
The compound of table 1. embodiment 1-66 is to the IC of AuroraA, B kinase activity 50(nM)
(ND：NotDetected，NR:NotReported)
Vitro kinase activity data in the chemical structure of the compound in conjunction with the embodiments prepared by 1-66 and table 1, can analyze and obtain thieno-2,4 substituted pyrimidines compounds have remarkable structure activity relationship to AuroraA kinases and AuroraB kinases.Its feature is as follows: 1) work as X 2for NH or NCH 3time, R 2during for 5-methyl isophthalic acid H-pyrazolyl, its activity is better than other molecules; 2) X is worked as 2for NH or NCH 3time, R 2for 5-methyl isophthalic acid H-pyrazolyl, and X 1for NH or NCH 3time, R 1for replace phenyl or benzyl time, its activity is better than other molecules; 3) size of phenyl or benzyl substituent affects the activity of compound, and universal law is that few substituting group activity is better than multi-substituent, and small-substituent activity is better than large-substituent; 4) X is worked as 1for NH or NCH 3time, R 1during for 5-methyl isophthalic acid H-pyrazolyl, it suppresses Aurora A activity all very poor; 5) in substituting group, alkyl chain is longer, and it suppresses Aurora A activity poorer; 6) the active order of its suppression Aurora A of compound of four kinds of structural formulas is generally formula I >(III) >(II) >(IV); 7) X is worked as 3, X 4for compound during N, it suppresses Aurora A activity to be better than X 3, X 4for the compound of O and CH.
The structure of active compound is preferably as follows:
LD4484 chemical structure is: lD4481 chemical structure is:
LD4478 chemical structure is: lD4456 chemical structure is:
Embodiment 72 cell in vitro Activity determination
Thieno-2, the cell growth inhibiting activity of 4 substituted pyrimidines compounds uses the method described in CCK-8 test kit to assess.After cell (3000-10000/hole) being inoculated in 96 porocyte culture plate upper 24 hours, the compound solution of 100 μ L different concns joins in each culture hole, hatch 72 hours, 10 μ LCCK-8 solution join in each culture hole, hatch 2-3 hour again, measure the light absorption value of 450nm and 650nm by microplate reader.In Excel form, process raw data, obtain the cell survival rate of each disposal hole.Then use survival rate data on GraphPadPrism software, use nonlinear regression model (NLRM) to calculate IC 50value.Found that, part thieno-2,4 substituted pyrimidines compounds significantly can suppress Hela(human cervical cancer 1 oncocyte), HT1080(human fibrosarcoma cell), MCF-7(breast cancer cell), A431(human skin basal cell cancer cells), H1975(non-small cell lung cancer cell), BT474(people's breast duct oncocyte), U937(human macrophage system leukemia oncocyte), MOLT-4(human T lymphocyte system oncocyte) etc. propagation, its half-inhibition concentration IC 50positive correlation is become with drug level.Compound used therefor is respectively the compound prepared by embodiment 1-66, and result is as shown in table 2.
The compound of table 2. embodiment 1-66 is to the IC of different tumour cell 50(uM)
Compound chemical structure in conjunction with the embodiments prepared by 1-66 and the cell in vitro activity data given by table 2, can analyze and obtain thieno-2, and structure activity relationship and the embodiment 67 of 4 substituted uracil Compounds in vitro cell activity are basically identical.Part of compounds is to Hela(tumor of cervix cell as can be seen from Table 2), U937(human macrophage system leukemia cell), MoLT-4(human T lymphocyte system cancer cells) and there is stronger inhibit activities more.
Can infer from table 2 and draw that there is thieno-2,4 substituted uracil compounds-treatable people or other mammiferous mammary cancer of described structure shown in formula I, respiratory cancer, the cancer of the brain, male, the tumour digestive tract tumor of female reproductive organ, tumor of urethra, liver cancer, skin carcinoma, head and neck cancer, lymphoma, sarcoma and leukemia, including, but not limited to breast cancer as infiltrating ductal carcinoma, mucinous carcinoma, leaflet infiltrating cancer, tubular carcinoma, adenocystic carcinoma, papillary carcinoma, SCBC (oat-cell carcinoma), non-small cell bronchogenic carcinoma is as plateepithelial cancer, gland cancer, maxicell bronchogenic carcinoma, pleura lung parent cell cancer, brain stem and now neurospongioma, cerebellum and cerebral astrocytoma, ependymoma and neuroderm and pine nut knurl body, prostate gland and carcinoma of testis are as spermocytoma, nonseminoma, carcinoma of endometrium, cervical cancer, ovarian cancer is as mucinous, endometrial sex, or serumal cancer, carcinoma of vagina, carcinoma vulvae and intrauterine knurl, anus cancer, colorectal carcinoma, colon straight way cancer, esophagus cancer, cancer of the stomach, the carcinoma of the pancreas rectum cancer, carcinoma of small intestine or glandula cancer, bladder cancer, penile cancer, kidney, carcinoma of renal pelvis, carcinoma of ureter or urethral carcinoma, intraocular melanoma and retinocytoma, hepatoma (there is or do not have the stem cell cancer of fiberboard change), the hepatocellular cholangiocarcinoma of cholangiocarcinoma (intrahepatic cholangiocarcinoma) and mixing, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merck Schwann Cells skin carcinoma and non-melanoma cells cancer, larynx, swallow, nasopharynx, oropharynx cancer and lip and oral carcinoma, AIDS associated lymphoma, non Hodgkin lymphoma, cutaneous T cell lymphoma, He Jiesen disease and central nervous system lymphoma, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma and rhabdosarcoma, acute myeloid leukemia, acute woods chronic myeloid leukemia, chronic lymphocyte leukemia, chronic lymphocytic leukemia and hairy cell leukemia.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Claims (6)

1. general formula is thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt of (I):
Wherein, X 1, X 2be O, S, S (O), S (O) simultaneously or independently 2or NR 5, wherein R 5for H or C 1-6alkyl;
R 1, R 2simultaneously or be independently selected from following groups:
Wherein, f is the integer between 0-3, and dotted line represents and X 1, X 2the key connected;
R 61, R 62, R 63be hydrogen, C simultaneously or independently 1-5alkyl, halogen, nitro, cyano group, amino or hydroxyl.
2. thieno-2,4 substituted pyrimidines compounds according to claim 1 or its pharmacy acceptable salt, is characterized in that, described X 1with described X 2be NH or NCH simultaneously or independently 3.
3. thieno-2,4 substituted pyrimidines compounds according to claim 1 or its pharmacy acceptable salt, is characterized in that, described R 1, R 2simultaneously or be independently
4. thieno-2,4 substituted pyrimidines compounds according to claim 1 or its pharmacy acceptable salt, is characterized in that, be selected from one of following compound:
N 2-(the fluoro-3-of 4-(trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(3-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(the bromo-2-luorobenzyl of 4-)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-((2-chloropyridine-4-replaces) methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(4-chlorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(the chloro-6-luorobenzyl of 2-)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(2,6-dichloro benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-(trifluoromethyl) benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(4-chlorobenzene ethyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(2,4 difluorobenzene base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(3-bromophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(xenyl-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(the chloro-3-of 4-(trifluoromethyl) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(4-bromine-3-fluorophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(the fluoro-5-of 3-(trifluoromethyl) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
N 2-(2,6-diethyl phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines;
2-(2,6-Dimethoxyphenyl)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-4-amine;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamine hydrochloride;
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2,4-diamines mesylate.
5. be used for the treatment of a pharmaceutical composition for tumour, it is characterized in that, be made up of arbitrary described thieno-2, the 4 substituted pyrimidines compounds of claim 1-4 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
6. according to arbitrary described thieno-2, the 4 substituted pyrimidines compounds of claim 1-4 or its pharmacy acceptable salt preparing anti-tumor drugs targeting, prevent and/or treat cancer, infection, inflammation and autoimmune disease pharmaceutical composition in application.
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