CN103242341A - Thieno 2,4-substituted pyrimidine compound, and pharmaceutical composition and application thereof - Google Patents

Thieno 2,4-substituted pyrimidine compound, and pharmaceutical composition and application thereof Download PDF

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CN103242341A
CN103242341A CN2013101381256A CN201310138125A CN103242341A CN 103242341 A CN103242341 A CN 103242341A CN 2013101381256 A CN2013101381256 A CN 2013101381256A CN 201310138125 A CN201310138125 A CN 201310138125A CN 103242341 A CN103242341 A CN 103242341A
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thieno
pyrimidine
replaces
pyrazoles
isophthalic acid
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CN103242341B (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 thieno 2,4-substituted pyrimidine compound of which the general formulas are (I), (II), (III) and (IV), or pharmaceutically acceptable salt or stereisomer or a prodrug molecule, and a pharmaceutical composition and application thereof. The thieno 2,4-substituted pyrimidine compound can effectively restrain abnormal expression of Aurora kinase, has specific inhibited effect on Aurora-A and Aurora-B, can be applied to a novel field of molecular targeting treatment, and has strong inhibitory activity on an excessive hyperplasia disease, especially cervical tumor cells, human macrophage line leukemia cell, and human t-lymphocyte line cancer cell.

Description

Thieno-2,4 substituted pyrimidines compounds and pharmaceutical composition and application
Technical field
The present invention relates to chemical field of medicaments, particularly relate to thieno-2,4 substituted pyrimidines compounds and pharmaceutical composition and application.
Background technology
The molecular targeted treatment of tumour is based on a kind of methods for the treatment of of the closely-related key molecule of tumor growth by chemistry or biological means selective killing tumour cell.The characteristics of targeted therapy are: the specificity height, and selectivity is strong, and toxic side effect is lighter; During combined utilization, it can strengthen the curative effect of traditional 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 been started a New Times.Neoplasm targeted therapy has obtained developing rapidly in recent years.The appearance of neoplasm targeted therapy constitutes impact to traditional administration idea and pattern, and for example, because toxic side effect is little, targeted drug often can't reach dose-limiting toxicity and maximum tolerated dose in the I clinical trial phase; When using target therapeutic agent, need not to reach satisfactory effect with maximum tolerated dose.Therefore, neoplasm targeted therapy is focus and the development trend of oncotherapy.
The Aurora kinases be one group three kinds the height homologies Serine--Serineprotein kinase plays important regulatory role in the mitotic division process.Aurora family is divided into AuroraA, AuroraB and AuroraC.Be found to the observation that was applied to for the first time human canceration's tissue expression in 1998 from nineteen ninety-five, these kinases become the oncology industry academic with produce ambilateral nervous target of investication and study.This effort has obtained great successes, and up to the present, kind of an Aurora kinase inhibitor has been passed through early stage clinical evaluation surplus in the of 10.These mixtures that have characteristic feature have good selectivity for other most kinases, most cross reaction among them is that a kinase whose small setting is relevant with oncobiology, this wherein the most significant representative be Abl and Flt-3 kinases.
The Aurora kinase inhibitor can be sub-divided into three general kinds again: what have surpasses the selectivity of Aurora-B to the selectivity of Aurora-A, what have surpasses the selectivity of Aurora-A to the selectivity of Aurora-B, and the third protein inhibitor then has the selectivity to Aurora-A and Aurora-B simultaneously.
Aurora kinases and mitotic division
Aurora-A:Aurora-A is included in the adjusting of mitotic division early ambulant, also comprises participation mitotic division.Protein expression and kinase activity are in the rising in cell cycle G2 stage and reach peak (people such as Meraldi, 2004 in early days in the mitotic division; Carmena and Earnshaw, 2003; People such as Andrew, 2003).Find that from the frequent observation to monopolar spindle the consumption of Aurora-A causes participating in mitotic delay, and indicate the division of spindle body.At molecular level, the effect that Aurora-A plays in all the other processes of mitotic division is illustrated fully; Yet, have some conclusive discoveries can help to explain that some data is to the forbidding of Aurora-A and its special biomarker of help discriminating.
Aurora-B:Aurora-B is the moiety that catalyzes and synthesizes karyomit(e) passenger complex body (CPC), has determined mitoticly to carry out continuously and finish.This mixture is made up of four kinds of protein, i.e. Aurora-B, Survivin (survivin), INCENP and borealin.The on-catalytic component of this mixture then part plays the effect of regulating limitation and activating Aurora-B.The consumption of any component of this mixture can both have a negative impact to other components, and destroys and mitoticly carry out continuously.Survivin (survivin), INCENP and borealin are the known base of Aurora-B, although the influence of Survivin (survivin) and the phosphorylation of borealin or the unknown, but with regard to INCENP, as if be to have played positive effect (people such as Andrew, 2003 in feedback loop; Carmena and Earnshaw, 2003; People such as Meraldi, 2004).
Aurora-C:Aurora-C is that research is minimum in the Aurora kinases, and its concrete effect in mitotic division does not have clear and definite definition.The performance of Aurora-C in most of somatic tissues of lower level is obviously not as good as Aurora-A or Aurora-B.It is unique exception that the height of Aurora-C in testis tissue expressed.Express spectra is consistent therewith, has determined its keying action in nucleus reduction division by homozygote and heterozygote contrast mouse experiment.These mouse show a very normal physiological function, but the also infertility (Zhou H, Kuang J, Zhong L, et.al, Nat.Gent, 1998,20 (2): 189-193 that cause of defectiveness sperm; Littlepay LE, Wu H, Andresson T, et.al, Proc Natl Acad SciUSA, 2002,99 (24): 15440-15445), these condense relevant with polyploidy with distortion karyomit(e).
Aurora kinases and cancer cells
Since the discovery nineties in 20th century, abundant science and clinical data have shown contacting strongly between Aurora kinases and the human cancer progress already.
Aurora-A has 20q13.2(Zhou H, Kuang J, and Zhong L, et.al, Nat.Gent, 1998,20 (2): 189-193) namely there is the gene mapping that is closely connected in the genome field with human cancer.Observe the Aurora-A albumen of overexpression in many cancer cells middle period.Aurora-A causes cell to show such as multiple cancer cells features such as centrosome amplification, aneuploid, karyomit(e) instability, telomere prolongations at external dystopy overexpression.Observe and find, the Aurora-A oneself expression perhaps activates people such as partner TPX-2(Hirota, 2003; People such as Bayliss, 2003; Eyers and Maller, 2004; People such as Kufer, 2002; People such as Satinover, 2004), relevant with human cancer cell's karyomit(e) instability.In addition, Aurora-A is relevant with the decisive main cause of tumor suppression and this is produced negative adjusting.Perhaps wherein the most noticeable is p53, owing to Aurora-A promotes mdm2-mediated to degenerate and suppresses its transcriptional activity.In any case Aurora-A does not adhere to that cell does not enliven in the tumour cell common in external conversion and overexpression position, not the protein of a routine therefore.In general, these observations show that Aurora-A requires other random oncogene to be transformed usually.This potential impact is that the selective inhibitory of Aurora-A may only show antitumour activity or just can reach best result of use when other drug is combined specific cancer cells.Remove Aurora-A in the aforesaid consume research and often cause the mitotic division significant deficiency, as if formed striking contrast therewith.The reason that this species diversity occurs may be because the JEG-3 quantity that these researchs are used is less relatively.The real influence of Aurora-A inhibitor is only appeared once that the selectivity inhibition then is widely used in the cancer cells probably.
Consistent with hypothesis, the Aurora-A possible benefit that suppresses to combine with other therapies has had some team to make explanation, and Aurora-A consumption is arranged for responsive cancer cells because the cytotoxic effect of generations such as chemotherapeutics such as taxanes, cis-platinum and ionizing rays.
Aurora-B is in the gene mapping of 17p13.1 genome area change in some human cancer zone (Zeng WF, Navaratne K, Prayson RA, et.al, J Clin Pathol, 2007,60 (2): 218-221).This has frequent overexpression on the serious disease tumour of reporting type in cancer with at protein expression and some mRNA of Aurora-B and protein.Except these are contacted directly, more should be noted that CPC protein between Aurora-B and the cancer, itself and Aurora-B cooperation show, or are regulated by Aurora-B, also often are cancer by overexpression or by exaggeration.Although the key of cancer and Aurora-B contacting in fission process is very not tight, it is not in in-vitro transcription and can't generally form tumour in vivo.An important exception is in the tumorigenic behavior of the formal overexpression of p53 cell mutation (Manfredi MG, Ecsedy JA, Meetze KA, Proc Natl Acad Sci USA, 2007,104 (10): 4106-4111.) at Aurora-B.Show that from these experimental results though Aurora-B itself is not oncogene, it can serve as the affiliate that other oncogene sudden changes form tumour.Yi Zhi concept is therewith, and Aurora-B can strengthen the conversion of Ras-mediated, but the consume of Aurora-B and short bundle RNA can suppress the transformation of Ras.Also need further research for Aurora-B as the target of an important cancer-resisting substance, comprise that the Aurora-B consume is for the therapy of responsive cancer cells, for example cytotoxicity of alkylating agent and ionizing rays.
Nearest data show that in many mitotic division processes, the effect of Aurora-B and Aurora-C is overlapping.Though Aurora-C quantitatively observes in human cancer cell's strain, Aurora-C does not determine as yet in the saying with obvious effect of tumour.
Aurora kinases micromolecular inhibitor is as chemical probe
The expression skill such as siRNA and kinases inactivating protein is used in the consumption of Aurora kinase activity, helps to predict biometric profile (Morrow CJ, the Tighe A of Aurora inhibitor, Johnson VL, et.al, J CellSci, 2005,118(16): 3639-3652) inhibitor is essential.It below is the chemical structural formula of disclosed Aurora inhibitor (mixture 1-6).
Figure BDA00003074279900041
The double inhibitor of Aurora-A and Aurora-B.In 2003, first Aurora micromolecular inhibitor disclosed (ZM447439 1 and Hesperidin 2).Mixture 1 can be than other uncorrelated kinases (not comprising closely-related Aurora-C with it) more effective inhibition Aurora-A and Aurora-B(IC 50Respectively at 110nm and 130nm place) (Morlock AA, Keen NJ, Jung FH, et.al, WO 0121596[P], 2001-03-29).This selectivity is the support energetically that it is widely used in chemical probe.Mixture 2 it is said it is a kind of to Aurora-B(IC 50At the 250nm place) inhibitor, have the antagonism other six kinds of kinases (not having data to show that this is comprising Aurora-A or Aurora-C) important cross reaction.Inhibitor has all shown similar full dominance at polyploid cell in two: inhibition of histone H3 phosphorylation (Ser10) and lack fissional endoreduplication people such as (, 2002) Ota.Nearly can observe in the giant cells case of 32 dna replication dnas at some.Certain experiment has shown that a cell G1 is blocked in the mixture 1 and fails to finish cytokinesis.Under this condition, enter and withdraw from mitotic division and normally carry out, but cell can't divide.These two kinds of enzyme inhibitorss cause tangible karyomit(e) imbalance, and normal and karyomit(e) is connected on the main shaft of non-both sexes kinetochore microtubule side by side.Although these distortion are arranged, the separation of two sister strands still exists.The two unification, these activities are strong showing all, suppresses the Aurora kinase activity and can cause the abolishment of spindle body check position and karyomit(e) dirt settling suitably withdrawing from mitotic division under the situation.The performance of this covering mitotic division retardance that mixture is caused by the taxanes microtubule stabilizer in two has confirmed this point.More detailed analysis revealed, the component of many spindle body check positions comprises that BurR1, Mad2 and CENP-E are unfixed.Strange not, observe discovery by defective type mitotic division, the cell viability of being handled by mixture 1 descends.
Disclosed the sign of potential Aurora kinase inhibitor in 3 pairs of bodies of mixture first in 2004.Mixture 3(MK-0457(VX-680)) be a kind of to the effective strong inhibitor of all three kinds of Aurora kinases, simultaneously other kinases had selectivity (Harrington EA, Bebbington D, Moore J, et.al, Nat.Med, 2004,10 (3): 262-267).With Aurora-A consistent with the 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 by the Aurora mediation is enough to cause apoptosis.This case is to comprise cancerous cell line, non-cancerous cell line and primary tumor cell sample through the whole cell cycle that mixture 3 is handled.What the necrocytosis of cell cycle mechanism was corresponding therewith is to observe the cell of finding in non-period not lose viability.Mixture 3 very effective obstruction tumor growths even cause that some lumps restores (Wilkinson RW, Odedra R, Hcaton SP, et.al, Clin Cancer Res, 2007,13 (12): 3682-3688) in the human cancer rodent model.The immunohistochemical analysis of mixture 3 demonstrates obvious suppression oncotherapy histone H 3 phosphorylation, suppresses consistent with Aurora-B, can significantly reduce apoptosis.Mixture 3 tolerances of effective dose are good, find that the neutrophilic granulocyte remarkable reversible minimizing of quantity (〉 50% is reduced to lower-most point but observe).Clinical observation finds that on the basis of non-cancer cell circulative metabolism and form, the Aurora kinases has restraining effect to general neutrophil leucocyte.Mixture 3 can cause can induce the formation monopolar spindle, and a kind of phenotype is along with Aurora-A consumption and does not have the Aurora-A of report and the surrogate of Aurora-B double inhibitor mixture 1.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 aspect mitotic division and the cell viability simultaneously.
Though its Aurora kinase inhibitor can cause unusual the propagation with retardance cycle inner cell of mitotic division to be reported widely, many research organizations prove that now the final destiny of cell is seemingly relevant with genetic background.In mixture 1 or 3 cells of handling, lack cytokine after the cell process breeding of shortage p53 gene function and a large amount of endoreduplication, and then cell becomes feeble and die.On the other hand, the cell of p53 complete function is then less carries out endoreduplication.This result has shown 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 opposing phenomenon 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.Observed the polymorphism of a spot of human Aurora gene, although these are to kinase activity or to influence and the atypia of drug susceptibility.Nearest one studies show that the cancer cells of cultivating can produce the vegetative propagation of this mixture by resistant function under the long-term existence of mixture 1.Detail analysis shows that this resistance is because the Aurora-B albumen of certain number produces sudden change.The influence that is expressed on the cell of these sudden changes Aurora-B albumen has surpassed mixture 1 at histone H 3 phosphorylation, cell cycle and spindle body check position.This is perfectly clear shows 1 pair of antimitotic influence of mixture and suppresses the relevant but not Aurora-A of Aurora-B.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 mixture 3 has been described again is relevant with the inhibition of Aurora-B rather than Aurora-A or Aurora-C.This influences antimitotic with the consumption of Aurora-A and compares that some is unexpected.This shows in this test, can not complete inhibition Aurora-A with mixture 1 and 3, suppress the catalytic activity of Aurora-A in other words, only to faint influence is arranged himself.The data results of these observations is added up discovery, and Aurora-A can not transform or tumourization usually, and conclusion is may produce best curative effect as Aurora-A when other cancer therapies are combined.Certainly the more important thing is that this research makes the potential clinical resistance of Aurora kinase inhibitor more outstanding, this will make the Aurora kinase inhibitor be subjected to more harsh monitoring by clinical.
Except the influence of individual drug to Aurora kinases double inhibitor, some groups show that these mixtures can make cell more sharp to the 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 all strengthens (Yang J, Ikezoe T to some extent, Nishioka C, et.al, Blood, 2007,110 (6): 2034-2040).Wherein some combined effect can attribution be the Aurora kinases to the inhibition of crucial mitotic division process, viewed synergistic mechanism is still indeterminate under other situations.But, these clinical observations might have very big effect to the design of clinical study.
Recently, illustrating of the biological function of Aurora kinases in normal cell and cancer cells makes micromolecular inhibitor obtain very fast development.The PRELIMINARY RESULTS that reaches clinical trial before clinical shows, although the molecular mechanism of Aurora kinase inhibitor inducing cancer cell growth retardation and apoptosis awaits to explain that further this class material gets a good chance of for treatment for cancer.Therefore, treat in future that the .Aurora kinase inhibitor needs to confirm that further many clinical trials will provide answer in the near future as strong anticancer strategy in the process of cancer.
Miazines is known as kinase whose inhibitor usually, for example be described among International Patent Application WO 021096888 and the WO 031032997 as the activeconstituents with antitumous effect at 4 substituted uracils with non-aromatic group, and for example as 2 of Aurora inhibitor, 4-diamino-pyrimidines is described in the International Patent Application WO 2007/003596.In fact, present Aurora kinase inhibitor series antineoplastic medicament exists the sudden change of drug-induced drug resistance gene mostly, and is faced with problems such as the clinical scope of application is narrower.Therefore, develop more novel protein Aurora kinase 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, and having synthesized how novel active compound is the disease of feature for preventing and/or treating with excessive or unusual cell proliferation.The purpose of this invention is to provide that a kind of to can be used for preventing and/or treating with excessive or unusual cell proliferation be new active substance-thieno-2,4 substituted pyrimidines compounds of feature.
A kind of thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or prodrugs, general formula is:
Figure BDA00003074279900061
Wherein, X 1, X 2Be O, S, S (O), S (O) simultaneously or independently 2Or NR 5, R wherein 5Be H or C 1-6Alkyl;
X 3, X 4Be O, N, CH simultaneously or independently, m, n, o, p are the integer between the 1-4;
R 1, R 2Simultaneously or independently be selected from following groups:
Be substituted or unsubstituted
Wherein, dotted line is represented and X 1, X 2The key that connects;
A is the integer between the 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 independently be selected from following groups:
Hydrogen, C 1-5Alkyl, C 3-8Cycloalkyl or R 6COR 7Wherein, R 6Be C 1-3Alkyl or C 1-3Alkyl phenyl, R 7Be 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 the prodrugs, " alkyl " means and comprises saturated fatty alkyl side chain and straight chain with particular carbon atom number.For example, " C 1-5Alkyl " in " C 1-5" definition comprise the group of arranging with straight or branched with 1,2,3,4 or 5 carbon atom.For example, " C 1-5Alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group.Term " cycloalkyl " refers to have the monocycle saturated fatty alkyl of particular carbon atom number.For example " cycloalkyl " comprises cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl etc.
" heterocycle " or " heterocyclic radical " refers to contain 1-4 heteroatomic 5 yuan of-6 yuan of aromaticity or non-aromaticity heterocycle that is selected from O, N and S, 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 oxadiazole base oxazolyl, oxetanyl (oxetanyl), pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl quinoxalinyl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl, l, the 4-alkyl dioxin, pyrrolidyl, the glyoxalidine base, the dihydro-isoxazole base, dihydro isothiazolyl Er Qing oxadiazole base dihydro-oxazole base, the dihydro pyrazinyl, the pyrazoline base, the dihydropyridine base, the dihydro-pyrimidin base, the pyrrolin base, the dihydro tetrazyl, the thiodiazoline base, dihydro-thiazolyl, the dihydro-thiophene base, the dihydro triazolyl, the dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl, and N-oxide compound.The connection of heterocyclic substituent can realize by carbon atom or by heteroatoms.
" halogen " means and comprises chlorine, fluorine, bromine and iodine.
Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical substituting group can be unsubstituted or replacement.For example, C 1-5H atom on the alkyl or cycloalkyl can by one, two or three be selected from hydroxyl, halogen, alkoxyl group, dialkyl amido or heterocyclic radical for example the substituting group of morpholinyl, piperidyl etc. replace.
In above-mentioned thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or the prodrugs, as any variable (R for example 1, R 2Deng) in any component, occur surpassing once, then its each definition that occurs is independent of other each definition that occurs.Equally, allow the combination of substituting group and variable, as long as this combination makes compound stable.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 can be easy to synthetic compound from the raw material that can obtain easily by the method for art technology and following proposition.Replace if substituting group self is exceeded a group, should understand these groups can be on the identical carbon atoms or on the different carbon atom, as long as make Stability Analysis of Structures.
The present invention includes the free form of formula I, II, III, IV compound, also comprise its pharmacy acceptable salt and steric isomer.
The pharmacy acceptable salt of The compounds of this invention comprises by The compounds of this invention and conventional the non-toxic salt inorganic or The compounds of this invention that organic acid reaction forms.For example, conventional non-toxic salt comprises and derives from for example salt of hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc. of mineral acid, also comprise from organic acid for example acetic acid, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, pounce on the salt of preparations such as acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2-acetoxyl group-phenylformic acid, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid.
Berg etc. are at Pharmaceutical Salts, and J.Pharm.Sci.1977 describes the preparation of pharmacy acceptable salt mentioned above and other typical pharmacy acceptable salt in detail among the 66:1-19.
Among embodiment, described therein
Figure BDA00003074279900081
The ring hydrogen atom has at least 1 H atom to be substituted the base replacement, 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.
Therein among embodiment, described C 1-5Alkyl or C 3-8Cycloalkyl is to have a H atom at least by hydroxyl, fluorine atom or the amino C that replaces 1-5Alkyl or C 3-8Cycloalkyl.
Therein among embodiment, described X 1With described X 2Be NH or NCH simultaneously or independently 3
Therein among embodiment, described R 1, R 2Simultaneously or independently be selected from down array structure:
Wherein, e, f are the integer between the 0-3.
Therein among embodiment, described R 1, R 2Simultaneously or independently be
Figure BDA00003074279900092
Therein among 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 independently be selected from down array structure:
Figure BDA00003074279900093
Wherein, g is the integer between the 0-3.
Among embodiment, be selected from one of following compound therein:
N 2-(4-fluoro-3-(trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(3-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(4-bromo-2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
2-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replacement) piperidines-1-replacement) ethyl ketone;
N 2-diphenyl-methyl-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(1-benzyl piepridine-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-((2-chloropyridine-4-replaces) methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(benzo [d] [1,3] dioxolane-5-substituent methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 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-benzyl chloride base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(2-chloro-6-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(2,6-dichloro benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-(trifluoromethyl) benzyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(4-chlorobenzene ethyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(2,4 difluorobenzene base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 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;
(5-chloro-2-fluorophenyl)-(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-replacement) piperidines-1-replacement) ethyl ketone;
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replacement) (1-benzyl ring propyl) ketone;
N 2-(3-bromophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 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, the 4-diamines;
N 2-(xenyl-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(3-methylpiperazine-1-replacement) thieno-[3,2-d] pyrimidine-4-amine;
N 2-(4-chloro-3-(trifluoromethyl) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(4-bromo-3-fluorophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(3-fluoro-5-(trifluoromethyl) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 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-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replacement) (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-aminotoluene) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replacement) ethyl benzoate;
N 4-methyl-N 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 4-phenyl thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2, N 4-dimethyl-N 2, N 4-diphenyl thiophene is [3,2-d] pyrimidine-2 also, the 4-diamines;
4,4 '-(thieno-[3,2-d] pyrimidine-2,4-two replaces) two morpholines;
(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replacement) ethyl benzoate;
4-(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replacement) ethyl benzoate;
N 2-(3,4-Dimethoxyphenyl)-N 4-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(4-fluoro-2-aminomethyl phenyl)-N 4-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N-(3, the 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, the 4-diamines;
N-methyl-4-morpholine base-N-phenyl thieno-[3,2-d] pyrimidine-2-amine;
4-(4-(cyclopropyl methyl) 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-aminomethyl phenyl)-N 2-(pyridine-3-substituent methyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-(4-fluoro-2-aminomethyl phenyl)-N 2-methyl-N 2-phenyl thieno-[3,2-d] pyrimidine-2, the 4-diamines;
2-(2, the 6-Dimethoxyphenyl)-N-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-4-amine;
N 2, N 4-two (4-fluoro-2-aminomethyl phenyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-phenyl-N 2-(5-fluoro-2-aminomethyl phenyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the 4-diamine hydrochloride;
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replacement) (pyridine-4-replaces) ketone hydrochloride;
2-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replacement) piperidines-1-replacement) the ethyl ketone mesylate;
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2,4-diamines mesylate.
The present invention also provides a kind of pharmaceutical composition that is used for the treatment of tumour, and described composition is by above-mentioned thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or prodrugs and pharmaceutically acceptable carrier composition.
Above-mentioned thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or prodrugs at preparation targeting anti-tumor medicine, prevent and/or treat the application in the pharmaceutical composition of cancer, infection, inflammation and autoimmune disease.
Described disease comprises: virus infection (for example HIV and kaposi's sarcoma); Inflammatory and autoimmune disease (for example colitis, sacroiliitis, alzheimer's disease, glomerulonephritis and wound healing); Bacterium, fungi and or parasitize; Leukemia, lymphoma and solid tumor (for example cancer and sarcoma); Dermatosis (for example psoriasis); Be characterised in that the proliferative disease (for example inoblast, liver cell, bone and medullary cell, cartilage or smooth muscle cell or epithelial cell (for example endometrial hyperplasia)) that cell number increases; Osteopathia and cardiovascular disorder (for example restenosis and hypertrophy).
Above-mentioned thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or prodrugs can effectively suppress the kinase whose unconventionality expression of Aurora, Aurora-A and Aurora-B there is special restraining effect, particularly can significantly suppress the human cervical cancer 1 oncocyte, human macrophage is the leukemia cell, the human T lymphocyte is cancer cells, the human fibrosarcoma cell, human skin basal cell cancer cells, non-small cell lung cancer cell, people's mammary gland conduit oncocyte, the propagation of breast cancer cell etc., can be applicable to molecular targeted treatment frontier or for the preparation of the treatment excessively proliferative disease medicine.
Embodiment
Below in conjunction with specific embodiment invention is further elaborated.
Except standard method known or illustration in experimental arrangement in the literature, can adopt the prepared in reaction The compounds of this invention that shows in the scheme of following embodiment.Therefore, following illustrative approach is for illustrative purposes rather than is confined to listed compound or any specific substituting group.The substituting group number that shows in the scheme must not meet number used in the claim, and for clarity sake, shows that single substituting group is connected under the definition of formula (I), (II), (III), (IV) to allow on the compound of multi-substituent.
The english abbreviation following reagent of representative or reaction conditions in following examples:
(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, the N-diisopropylethylamine; (6) POCl 3: phosphorus oxychloride; (7) rt: room temperature.
Nuclear magnetic resonance spectrometer and the mass spectrograph used are as follows:
(1), nuclear magnetic resonance spectrometer model: VANCE AV400MHz, manufacturer: Switzerland Bruker company; Solvent is deuterated dimethyl sulfoxide-d 6If, use other solvents, have clearly in an embodiment and mention; (δ=0.00ppm) carries out reference with the tetramethylsilane of standard in chemical shift;
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: electronic spraying ionization.
Embodiment 1 N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4484)
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the synthetic route of 4-diamines is as follows:
Figure BDA00003074279900121
Figure BDA00003074279900131
Specifically may further comprise the steps:
(1), thieno-[3,2-d] pyrimidine-2,4-diketone synthetic, 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), is heated to 150 ℃ of backflows 8 hours.Be cooled to 90 ℃ and add water and stir and to spend the night, suction filtration vacuum-drying gets white solid, is thieno-[3,2-d] pyrimidine-2,4-diketone (50.2g, productive rate: 94%).
The characterization data of this compound is:
1H?NMR(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), 2, the 4-dichloro-thiophene is [3,2-d] pyrimidine synthetic also, chemical structural formula is:
Figure BDA00003074279900133
Synthesis step is:
In round-bottomed flask, add thieno-[3,2-d] pyrimidine-2, and the 4-diketone (50.2g .298mol), POCl 3(300ml, 3.2mol), 130 ℃ of backflows are until reacting completely.Question response liquid is cooled to slowly to incline after the room temperature and solvent, with a small amount of washed with dichloromethane remaining solid, in remaining solid, add mixture of ice and water and ethyl acetate then, treat that solid all dissolves the back separatory, with merging organic phase behind the ethyl acetate extraction water, the washing organic phase is also dry, concentrate white solid.Silica gel column chromatography separates, and the white solid of gained is also [3,2-d] pyrimidine (54.1g, productive rate: 89%) of 2,4-dichloro-thiophene.
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), 2-chloro-N-(5-methyl isophthalic acid H-pyrazoles-3-replace) thieno-[3,2-d] pyrimidine-4-amine synthetic, chemical structural formula is:
Figure BDA00003074279900134
Synthesis step is:
At room temperature, with 2,4-dichloro-thiophene [3,2-d] pyrimidine (10g also, 49mmol) (5.5g 56.7mmol) is dissolved in the 30mL dimethyl formamide, adds N again with 5-methyl isophthalic acid H-pyrazoles-3-amine, N-diisopropyl ethyl amine 9.8ml, stirring reaction is until reacting completely.With stirring in the reaction solution impouring water, leach solid, oven dry again with ether washing 3-4 time, is dried to such an extent that white solid namely gets 2-chloro-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-4-amine (12.5g, productive rate 96%).
1H?NMR(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 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2,4-diamines synthetic, chemical structural formula is:
Figure BDA00003074279900141
Synthesis step is:
At room temperature, (0.30g, 1.13mmol) (0.411g, 3.39mmol), 140 ℃ of reactions of tube sealing are until reacting completely with o-methyl-benzene ethamine for thieno-[3,2-d] pyrimidine-4-amine to add 2-chloro-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) in reaction tubes.After reaction is finished, be spin-dried for solvent, add the extraction of EtOAc and water, organic phase is washed with saturated common salt, anhydrous Na 2SO 4Drying, silica gel column chromatography separate 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:
1H?NMR(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 2 N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4481)
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900142
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 3 N 2-(4-bromo-2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4478)
N 2-(4-bromo-2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is
Figure BDA00003074279900151
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 4 N 2-diphenyl-methyl-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4413)
N 2-diphenyl-methyl-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900152
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 5 N 2-(1-benzyl piepridine-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines; (LD4430)
N 2-(1-benzyl piepridine-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900153
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 6 N 2-((2-chloropyridine-4-replaces) methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4443)
N 2-((2-chloropyridine-4-replaces) methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900161
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 7 N 2-(benzo [d] [1,3] dioxolane-5-substituent methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4442)
N 2-(benzo [d] [1,3] dioxolane-5-substituent methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900162
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 8 N 2-(2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4445)
N 2-(2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900163
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 9 N 2-(4-benzyl chloride base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4476)
N 2-(4-benzyl chloride base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900171
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 10 N 2-(2-chloro-6-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4483)
N 2-(2-chloro-6-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900172
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=32.8Hz?3H)。
MS(ESI)，m/z:389(M ++H +)。
Embodiment 11 N 2-(2,6-dichloro benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4479)
N 2-(2,6-dichloro benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900173
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 12 N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-(trifluoromethyl) benzyl) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4485)
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-(trifluoromethyl) benzyl) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900181
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 13 N 2-(4-chlorobenzene ethyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4480)
N 2-(4-chlorobenzene ethyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900182
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 14 N 2-(2,4 difluorobenzene base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4473)
N 2-(2,4 difluorobenzene base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900183
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 15 N 2-(3-bromophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4420)
N 2-(3-bromophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900191
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 16 N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-morpholine base propyl group) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4419)
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-morpholine base propyl group) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900192
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 17 N 2-(xenyl-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4407)
N 2-(xenyl-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is
Figure BDA00003074279900193
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 18 N-(5-methyl isophthalic acid H-pyrazoles-3-replace)-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:
1H?NMR(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 19 N 2-(4-chloro-3-(trifluoromethyl) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4422)
N 2-(4-chloro-3-(trifluoromethyl) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is
Figure BDA00003074279900202
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 20 N 2-(4-bromo-3-fluorophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4424)
N 2-(4-bromo-3-fluorophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is 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 21 N 2-(3-fluoro-5-(trifluoromethyl) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4432)
N 2-(3-fluoro-5-(trifluoromethyl) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is
Figure BDA00003074279900211
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 22 N 2-(2,6-diethyl phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4437)
N 2-(2,6-diethyl phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is
Figure BDA00003074279900212
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 23 N 2-methyl-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N2-phenyl thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD1140)
N 2-methyl-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N2-phenyl thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is
Figure BDA00003074279900213
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 24 N 2-(5-fluoro-2-aminomethyl phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD1148)
N 2-(5-fluoro-2-aminomethyl phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is
Figure BDA00003074279900221
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 25 N 2-(3,5-two (trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4486)
N 2-(3,5-two (trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is
Figure BDA00003074279900222
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 26 4-(4-(2-(5-methyl isophthalic acid H-pyrazoles-3-substituted amido) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replacement) 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-replacement) chemical structural formula of ethyl benzoate is
Figure BDA00003074279900231
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 27 2-(4-methyl isophthalic acids, 4-Diazesuberane-1-replaces)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) preparation (LD4415) of thieno-[3,2-d] pyrimidine-4-amine
The 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
Figure BDA00003074279900232
Its synthesis step is with embodiment 1.
1H?NMR(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 28 N 2, N 4-two (5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4428)
N 2, N 4-two (5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is
Figure BDA00003074279900233
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 29 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
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:
1H?NMR(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 30 N-(5-methyl isophthalic acid H-pyrazoles-3-replace)-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:
Figure BDA00003074279900242
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 31 4-(4-(2-(5-fluoro-2-aminotoluenes) preparation (LD1193) of ethyl benzoate thieno-[3,2-d] pyrimidine-4-replacement) piperazine-1-replacement)
4-(4-(2-(5-fluoro-2-aminotoluene) thieno-[3,2-d] pyrimidine-4-replacement) piperazine-1-replacement) chemical structural formula of ethyl benzoate is:
Figure BDA00003074279900243
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 32 N 4-methyl-N 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 4-phenyl thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD1145)
N 4-methyl-N 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 4-phenyl thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900251
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 33 N 2, N 4-dimethyl-N 2, N 4-diphenyl thiophene is [3,2-d] pyrimidine-2 also, the preparation of 4-diamines (LD1133)
N 2, N 4-dimethyl-N 2, N 4-diphenyl thiophene is [3,2-d] pyrimidine-2 also, and the chemical structural formula of 4-diamines is:
Figure BDA00003074279900252
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 34 4,4 '-preparation (LD1134) of (thieno-[3,2-d] pyrimidine-2,4-two replace) two morpholines
4,4 '-chemical structural formula of (thieno-[3,2-d] pyrimidine-2,4-two replace) 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-replacement) piperazine-1-replacement) preparation (LD1179) of ethyl benzoate
(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replacement) piperazine-1-replacement) chemical structural formula of ethyl benzoate is: Its synthesis step is with embodiment 1.
1H?NMR(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 36 4-(4-(4-(4-morpholine base anilinos) preparation (LD1178) of ethyl benzoate thieno-[3,2-d] pyrimidine-2-replacement) piperazine-1-replacement)
4-(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replacement) piperazine-1-replacement) chemical structural formula of ethyl benzoate is:
Figure BDA00003074279900262
Its synthesis step is with embodiment 1.
1H?NMR(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 37 N 2-(3,4-Dimethoxyphenyl)-N 4-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD1175)
N 2-(3,4-Dimethoxyphenyl)-N 4-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900263
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 38 N 2-(4-fluoro-2-aminomethyl phenyl)-N 4-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD1167)
N 2-(4-fluoro-2-aminomethyl phenyl)-N 4-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900271
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 39 N-(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:
Figure BDA00003074279900272
Its synthesis step is with embodiment 1.
The characterization data of this compound is: 1H NMR (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 40 N 4-(4-morpholine base phenyl)-N 2-(pyridine-2-substituent methyl) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD1182)
N 4-(4-morpholine base phenyl)-N 2-(pyridine-2-substituent methyl) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is: Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 41 N-methyl-4-morpholine base-N-phenyl thieno-[3,2-d] pyrimidine-2-amine
The chemical structural formula of N-methyl-4-morpholine base-N-phenyl thieno-[3,2-d] pyrimidine-2-amine is:
Figure BDA00003074279900282
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 42 4-(4-(cyclopropyl methyl) 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-(cyclopropyl methyl) piperazine-1-replaces)-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-2-amine is:
Figure BDA00003074279900283
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 43 4-(4-(2-(5-methyl isophthalic acid H-pyrazoles-3-substituted amido) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replacement) 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-replacement) chemical structural formula of ethyl benzoate is:
Figure BDA00003074279900291
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 44 N 4-(4-fluoro-2-aminomethyl phenyl)-N 2-(pyridine-3-substituent methyl) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD46018)
N 4-(4-fluoro-2-aminomethyl phenyl)-N 2-(pyridine-3-substituent methyl) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900292
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 45 N 4-(4-fluoro-2-aminomethyl phenyl)-N 2-methyl-N 2-phenyl thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD46017)
N 4-(4-fluoro-2-aminomethyl phenyl)-N 2-methyl-N 2-phenyl thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900293
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 46 2-(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:
Figure BDA00003074279900301
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 47 N 2, N 4-two (4-fluoro-2-aminomethyl phenyl) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD46011)
N 2, N 4-two (4-fluoro-2-aminomethyl phenyl) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900302
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 48 N 4-phenyl-N 2-(5-fluoro-2-aminomethyl phenyl) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD1149)
N 4-phenyl-N 2-(5-fluoro-2-aminomethyl phenyl) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is: Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 49 2-(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:
Figure BDA00003074279900311
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 50 N 2-(4-fluoro-3-(trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4491)
N 2-(4-fluoro-3-(trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900312
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 51 N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4494)
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900313
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 52 N 2-(3-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines (LD4497)
N 2-(3-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines is:
Figure BDA00003074279900321
Its synthesis step is with embodiment 1.
The characterization data of this compound is:
1H?NMR(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 +)。
Embodiment 53 4-fluoro-N-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces amine) phenyl) preparation (LD4489) of benzamide
4-fluoro-N-(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:
Figure BDA00003074279900322
Specifically may further comprise the steps:
(1), N 2-(4-aminophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines, its chemical structural formula is:
Figure BDA00003074279900323
Synthesis step is:
(0.3g, 1.13mmol) and benzene-1, (0.367g, 3.39mmol), tube sealing reacts down for 145 ℃ the 4-diamines, until reacting completely to add 2-chloro-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-4-amine in reaction tubes.After reaction is finished, be spin-dried for solvent, add the extraction of EtOAc and water, organic phase is washed with saturated common salt, anhydrous Na 2SO 4Drying, silica gel column chromatography are separated to such an extent that white solid is N 2-(4-aminophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) 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), 4-fluoro-N-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces amine) phenyl) benzamide synthetic, chemical structural formula is:
Figure BDA00003074279900331
Synthesis step is:
With N 2-(4-aminophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 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) among the DMF, stir until reacting completely under the room temperature.Reaction solution extracts with DCM, and washing merges organic phase, concentrates.Obtaining white solid after the column chromatography is 4-fluoro-N-(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:
1H?NMR(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 54 N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-replacement) preparation (LD4429) of thieno-[3,2-d] pyrimidine-4-amine
N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-replacement) synthetic route of thieno-[3,2-d] pyrimidine-4-amine is as follows:
Specifically may further comprise the steps:
(1), 4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replace) piperazine-1-tertbutyloxycarbonyl, its chemical structural formula is:
Figure BDA00003074279900333
Synthesis step is:
In reaction tubes, add 2-chloro-N-(5-methyl isophthalic acid H-pyrazoles-3-replaces) thieno-[3,2-d] pyrimidine-4-amine (0.3g, 1.13mmol) and piperazine-1-tert-butylformamide (0.633g, 3.39mmol), tube sealing reacts down for 140 ℃, until reacting completely.After reaction is finished, be spin-dried for solvent, add the extraction of EtOAc and water, organic phase is washed with saturated common salt, anhydrous Na 2SO 4Drying, silica gel column chromatography are separated to such an extent that 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-replace)-2-(piperazine-1-replaces) thieno-[3,2-d] pyrimidine-4-amine synthetic, chemical structural formula is:
Figure BDA00003074279900341
Synthesis step is:
(0.32g 0.77mmol), TFA(0.7g, 0.5ml) is dissolved in the methylene dichloride (5ml) with 4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replace) piperazine-1-tert-butylformamide.After stirring 2h under the room temperature, be spin-dried for solvent, add saturated sodium bicarbonate solution and transfer PH to alkalescence, filter, vacuum-drying gets white solid and is N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-replacement) thieno-[3,2-d] pyrimidine-4-amine (0.22g, productive rate: 92%).
The characterization data of this compound is:
1H?NMR(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 55 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) 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:
Figure BDA00003074279900342
Specifically may further comprise the steps:
(1), synthetic N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(piperazine-1-replaces) 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), (1.48g 0.2ml) is dissolved in the mixed solvent of DMF/DCM=1 (2.0mL) DIPEA, stirs until reacting completely under the room temperature.Reaction solution extracts with DCM, and washing merges organic phase, concentrates.Obtaining white solid after the 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-replacement) piperidines-1-replacement) ethyl ketone (0.122g, productive rate 85%).
The characterization data of this compound is:
1H?NMR(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-replacement) piperazine-1-replacement) 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:
Figure BDA00003074279900351
Its synthesis step is with embodiment 55.
The characterization data of this compound is:
1H?NMR(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-replacement) piperidines-1-replacement) 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:
Figure BDA00003074279900352
Its synthesis step is with embodiment 55.
The characterization data of this compound is:
1H?NMR(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 (5-chloro-2-fluorophenyl)-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replacement) piperidines-1-replacement) preparation (LD4463) of ketone
(5-chloro-2-fluorophenyl)-(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:
Figure BDA00003074279900361
Its synthesis step is with embodiment 55.
The characterization data of this compound is:
1H?NMR(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 59 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) 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:
Figure BDA00003074279900362
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-replacement) piperidines-1-replacement) preparation (LD4474) of (1-benzyl ring propyl) ketone
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replacement) piperidines-1-replacement) chemical structural formula of (1-benzyl ring propyl) ketone is: Its synthesis step is with embodiment 55.
The characterization data of this compound is:
1H?NMR(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-replacement) piperidines-1-replacement) 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:
Figure BDA00003074279900371
Its synthesis step is with embodiment 55.
The characterization data of this compound is:
1H?NMR(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-replacement) piperazine-1-replacement) preparation (LD4446) of (pyridine-2-replaces) ketone
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replacement) piperazine-1-replacement) chemical structural formula of (pyridine-2-replaces) ketone is:
Figure BDA00003074279900372
Its synthesis step is with embodiment 55.
The characterization data of this compound is:
1H?NMR(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 63 1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replace 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-replacement) piperazine-1-replacement) preparation (LD4450) of (pyridine-4-replaces) ketone
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replacement) piperazine-1-replacement) chemical structural formula of (pyridine-4-replaces) ketone is:
Figure BDA00003074279900381
Its synthesis step is with embodiment 55.
The characterization data of this compound is:
1H?NMR(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:
Figure BDA00003074279900382
Its synthesis step is with embodiment 55.
The characterization data of this compound is:
1H?NMR(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 66 1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replace 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:
Figure BDA00003074279900391
Its synthesis step is with embodiment 55.
The characterization data of this compound is:
1H?NMR(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 67 N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamine hydrochloride (LD4484 hydrochloride)
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamine hydrochloride is:
Figure BDA00003074279900392
Synthesis step is:
With N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines (0.351g 1mmol) places the 100mL there-necked flask, adds the 20mL dehydrated alcohol, stirs to drip the 6mol/L aqueous hydrochloric acid down, treats that raw material all dissolves, be spin-dried for 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-diamine hydrochloride (0.405g, productive rate 90 %).
The characterization data of this compound is:
1H?NMR(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-replacement) piperazine-1-replacement) preparation (LD4450 hydrochloride) of (pyridine-4-replaces) ketone hydrochloride
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replacement) piperazine-1-replacement) chemical structural formula of (pyridine-4-replaces) ketone hydrochloride is:
Figure BDA00003074279900393
Its synthesis step is with embodiment 67.
The characterization data of this compound is:
1H?NMR(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 69 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) 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-replacement) piperidines-1-replacement) (0.451g 1mmol) places 100mL single port bottle to ethyl ketone, add the 30mL dehydrated alcohol, stir down and drip 384mg methylsulfonic acid (4mmol), be heated to and boil, system becomes clarification, backflow 4h, be cooled to room temperature, the adularescent solid is separated out, and filters, filter residue is given a baby a bath on the third day after its birth inferior with ethanol, vacuum-drying gets light yellow solid 0.750g(90%).
The characterization data of this compound is:
1H?NMR(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 70 N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the preparation of 4-diamines mesylate (LD4481 mesylate)
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the chemical structural formula of 4-diamines mesylate is: 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 activities detect
Kinase activity detects fluorescent energy resonance transfer (FRET) the Z-LYTE method that adopts.Medicine carries out gradient dilution (since 3 times of dilutions of 10 μ M), and add kinases (the about 0.1-0.01U/mL of AuroraA or the about 0.1-0.01U/mL of AuroraB) and two ends and indicate coumarin(fluorescence donor respectively) and the fluorophores(fluorescent receptor) substrate (20 μ M) is in the reaction system of 10ul, the adding final concentration is room temperature reaction 2 hours behind the 10uM ATP; Add the Development solution of 5ul again in reaction system, room temperature reaction added the stop buffer of 5ul then after 1 hour, detected in microplate reader.Under the excitation wavelength of 400nm, detect the ratio process Graphpad Prism5.0 Fitting Analysis of the emission wavelength gained at emission light 460nm and 535nm place respectively, obtain the IC of the medicine that sieves 50Each compound is to AuroraA or the kinase whose half-inhibition concentration IC of AuroraB 50The value such as table 1 description.Compound used therefor is selected from the prepared compound into embodiment 1-66 respectively.
The compound of table 1. embodiment 1-66 is to the IC of AuroraA, B kinase activity 50(nM)
Figure BDA00003074279900411
(ND：Not?Detected，NR:Not?Reported)
The chemical structure of the prepared compound of 1-66 and the vitro kinase activity data in the table 1 in conjunction with the embodiments can be analyzed and obtain thieno-2,4 substituted pyrimidines compounds AuroraA kinases and AuroraB kinases are had remarkable structure activity relationship.Its feature is as follows: 1) work as X 2Be NH or NCH 3The time, R 2During for 5-methyl isophthalic acid H-pyrazolyl, its activity is better than other molecules; 2) work as X 2Be NH or NCH 3The time, R 2Be 5-methyl isophthalic acid H-pyrazolyl, and X 1Be NH or NCH 3The time, R 1During for the phenyl that replaces or benzyl, its activity is better than other molecules; 3) the substituent size of phenyl or benzyl influences the activity of compound, and universal law is that few substituting group activity is better than multi-substituent, and the small-substituent activity is better than large-substituent; 4) work as X 1Be NH or NCH 3The time, R 1During for 5-methyl isophthalic acid H-pyrazolyl, it is all very poor that it suppresses the Aurora kinase activity; 5) alkyl chain is more long in the substituting group, and it is more poor that it suppresses the Aurora kinase activity; 6) its inhibition of the compound of four kinds of structural formulas Aurora kinase activity is generally formula I in proper order〉(III)〉(II)〉(IV); 7) work as X 3, X 4Compound during for N, it suppresses the Aurora kinase activity and is better than X 3, X 4Compound for O and CH.
The structure of active compound preferably is as follows:
The LD4484 chemical structure is:
Figure BDA00003074279900421
The LD4481 chemical structure is:
Figure BDA00003074279900422
The LD4478 chemical structure is:
Figure BDA00003074279900423
The LD4456 chemical structure is:
Figure BDA00003074279900424
Embodiment 72 cell in vitro are active to be detected
The cell growth inhibiting activity of thieno-2,4 substituted pyrimidines compounds uses the method for describing in the CCK-8 test kit to assess.(3000-10000/hole) is inoculated in 96 porocyte culture plates after last 24 hour with cell, the compound solution of 100 μ L different concns joins in each culture hole, hatched 72 hours, 10 μ L CCK-8 solution join in each culture hole, hatched again 2-3 hour, and measured the light absorption value of 450nm and 650nm with microplate reader.In the Excel form, handle raw data, respectively handled the cell survival rate in hole.Use survival rate data to use nonlinear regression model (NLRM) to calculate IC at GraphPad Prism software then 50Value.Found that, part thieno-2,4 substituted pyrimidines compounds can significantly suppress Hela(human cervical cancer 1 oncocyte), the HT1080(human fibrosarcoma cell), the MCF-7(breast cancer cell), A431(human skin basal cell cancer cells), the H1975(non-small cell lung cancer cell), BT474(people's mammary gland conduit oncocyte), the U937(human macrophage is the leukemia oncocyte), the MOLT-4(human T lymphocyte is oncocyte) etc. propagation, its half-inhibition concentration IC 50Become positive correlation with drug level.Compound used therefor is respectively the prepared compound of embodiment 1-66, and the result is as shown in table 2.
The compound of table 2. embodiment 1-66 is to the IC of different tumour cells 50(uM)
Figure BDA00003074279900425
Figure BDA00003074279900431
Figure BDA00003074279900441
Prepared compound chemical structure and the given cell in vitro activity data of table 2 of 1-66 can be analyzed and obtain thieno-2,4 substituted pyrimidines compounds to cell in vitro structure activity relationship study and embodiment 67 basically identicals in conjunction with the embodiments.Part of compounds is to Hela(tumor of cervix cell as can be seen from Table 2), the U937(human macrophage is the leukemia cell), the MoLT-4(human T lymphocyte is cancer cells) have a stronger inhibition activity more.
Can infer from table 2 and to draw, thieno-2 with described formula I structure, 4 substituted pyrimidines compounds can be treated people or other mammiferous mammary cancer, respiratory cancer, the cancer of the brain, male, female reproductive organ's tumour digestive tract tumor, tumor of urethra, liver cancer, skin carcinoma, head and neck cancer, lymphoma, sarcoma and leukemia are including, but not limited to breast cancer such as infiltrating ductal carcinoma, mucinous carcinoma, the leaflet infiltrating cancer, tubular carcinoma, adenocystic carcinoma, papillary carcinoma, SCBC (oat-cell carcinoma), non-small cell bronchogenic carcinoma such as plate epithelial cancer, gland cancer, the maxicell bronchogenic carcinoma, pleura lung parent cell cancer, brain stem and neurospongioma now, cerebellum and big cerebral astrocytoma, ependymoma and neuroderm and pine nut knurl body, prostate gland and carcinoma of testis such as spermocytoma, nonseminoma, carcinoma of endometrium, cervical cancer, ovarian cancer such as Saliva Orthana, uterine endometrium, perhaps serum 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 (having or do not have the stem cell cancer that fiberboard changes), cholangiocarcinoma (stones in intrahepatic bile duct cancer) and the liver cell property cholangiocarcinoma that mixes, squamous cell carcinoma, Kaposi, malignant melanoma, Merck Schwann Cells skin carcinoma and non-melanoma cells cancer, larynx, swallow, nasopharynx, oropharynx cancer and lip and oral carcinoma, the AIDS lymphoma of being correlated with, 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 has only expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to claim of the present invention.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 (10)

1. general formula is thieno-2,4 substituted pyrimidines compounds or its pharmacy acceptable salt or steric isomer or the prodrugs of (I), (II), (III), (IV):
Figure FDA00003074279800011
Wherein, X 1, X 2Be O, S, S (O), S (O) simultaneously or independently 2Or NR 5, R wherein 5Be H or C 1-6Alkyl;
X 3, X 4Be O, N, CH simultaneously or independently, m, n, o, p are the integer between the 1-4;
R 1, R 2Simultaneously or independently be selected from following groups:
Be substituted or unsubstituted
Figure FDA00003074279800013
Wherein, dotted line is represented and X 1, X 2The key that connects;
A is the integer between the 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 independently be selected from following groups:
Hydrogen, C 1-5Alkyl, C 3-8Cycloalkyl or R 6COR 7Wherein, R 6Be C 1-3Alkyl or C 1-3Alkyl phenyl, R 7Be C 1-5Alkoxyl group, halogen, amino, hydroxyl, C 1-5Phenyl, C that alkyl replaces 1-5The heterocyclic aryl that alkyl replaces.
2. thieno-2,4 substituted pyrimidines compounds according to claim 1 or its pharmacy acceptable salt or steric isomer or prodrugs is characterized in that, and be described The ring hydrogen atom has at least 1 H atom to be substituted the base replacement, 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.
3. thieno-2,4 substituted pyrimidines compounds according to claim 1 and 2 or its pharmacy acceptable salt or steric isomer or prodrugs is characterized in that described C 1-5Alkyl or C 3-8Cycloalkyl is to have a H atom at least by hydroxyl, fluorine atom or the amino C that replaces 1-5Alkyl or C 3-8Cycloalkyl.
4. thieno-2,4 substituted pyrimidines compounds according to claim 3 or its pharmacy acceptable salt or steric isomer or prodrugs is characterized in that described X 1With described X 2Be NH or NCH simultaneously or independently 3
5. thieno-2,4 substituted pyrimidines compounds according to claim 4 or its pharmacy acceptable salt or steric isomer or prodrugs is characterized in that described R 1, R 2Simultaneously or independently be selected from down array structure:
Figure FDA00003074279800021
Wherein, e, f are the integer between the 0-3.
6. thieno-2,4 substituted pyrimidines compounds according to claim 1 or its pharmacy acceptable salt or steric isomer or prodrugs is characterized in that described X 1With described X 2Be N, X 3, X 4Be N, O or CH simultaneously or independently, described R 1, R 2Simultaneously or independently be selected from down array structure:
Figure FDA00003074279800031
Wherein, g is the integer between the 0-3.
7. thieno-2,4 substituted pyrimidines compounds according to claim 1 or its pharmacy acceptable salt or steric isomer or prodrugs is characterized in that described R 1, R 2Simultaneously or independently be
Figure FDA00003074279800032
8. thieno-2,4 substituted pyrimidines compounds according to claim 1 or its pharmacy acceptable salt or steric isomer or prodrugs is characterized in that, are selected from one of following compound:
N 2-(4-fluoro-3-(trifluoromethyl) benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(3-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(4-bromo-2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
2-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replacement) piperidines-1-replacement) ethyl ketone;
N 2-diphenyl-methyl-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(1-benzyl piepridine-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-((2-chloropyridine-4-replaces) methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(benzo [d] [1,3] dioxolane-5-substituent methyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(2-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 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-benzyl chloride base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(2-chloro-6-luorobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(2,6-dichloro benzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(4-(trifluoromethyl) benzyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(4-chlorobenzene ethyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(2,4 difluorobenzene base)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 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;
(5-chloro-2-fluorophenyl)-(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-replacement) piperidines-1-replacement) ethyl ketone;
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperidines-1-replacement) (1-benzyl ring propyl) ketone;
N 2-(3-bromophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 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, the 4-diamines;
N 2-(xenyl-4-replaces)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-2-(3-methylpiperazine-1-replacement) thieno-[3,2-d] pyrimidine-4-amine;
N 2-(4-chloro-3-(trifluoromethyl) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(4-bromo-3-fluorophenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(3-fluoro-5-(trifluoromethyl) phenyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2, the 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-replacement) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replacement) (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-aminotoluene) thieno-[3,2-d] pyrimidine-4-replaces) piperazine-1-replacement) ethyl benzoate;
N 4-methyl-N 2-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 4-phenyl thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2, N 4-dimethyl-N 2, N 4-diphenyl thiophene is [3,2-d] pyrimidine-2 also, the 4-diamines;
4,4 '-(thieno-[3,2-d] pyrimidine-2,4-two replaces) two morpholines;
(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replacement) ethyl benzoate;
4-(4-(4-(4-morpholine base anilino) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replacement) ethyl benzoate;
N 2-(3,4-Dimethoxyphenyl)-N 4-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 2-(4-fluoro-2-aminomethyl phenyl)-N 4-(4-morpholine base phenyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N-(3, the 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, the 4-diamines;
N-methyl-4-morpholine base-N-phenyl thieno-[3,2-d] pyrimidine-2-amine;
4-(4-(cyclopropyl methyl) 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-aminomethyl phenyl)-N 2-(pyridine-3-substituent methyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-(4-fluoro-2-aminomethyl phenyl)-N 2-methyl-N 2-phenyl thieno-[3,2-d] pyrimidine-2, the 4-diamines;
2-(2, the 6-Dimethoxyphenyl)-N-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-4-amine;
N 2, N 4-two (4-fluoro-2-aminomethyl phenyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-phenyl-N 2-(5-fluoro-2-aminomethyl phenyl) thieno-[3,2-d] pyrimidine-2, the 4-diamines;
N 4-(5-methyl isophthalic acid H-pyrazoles-3-replaces)-N 2-(3-methyl-benzyl) thieno-[3,2-d] pyrimidine-2, the 4-diamine hydrochloride;
(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replaces) piperazine-1-replacement) (pyridine-4-replaces) ketone hydrochloride;
2-(4-fluorophenyl)-1-(4-(4-(5-methyl isophthalic acid H-pyrazoles-3-replaces amine) thieno-[3,2-d] pyrimidine-2-replacement) piperidines-1-replacement) the ethyl ketone mesylate;
N 2-(3-bromobenzyl)-N 4-(5-methyl isophthalic acid H-pyrazoles-3-replacement) thieno-[3,2-d] pyrimidine-2,4-diamines mesylate.
9. a pharmaceutical composition that is used for the treatment of tumour is characterized in that, by arbitrary described thieno-2, the 4 substituted pyrimidines compounds of claim 1-8 or its pharmacy acceptable salt or steric isomer or prodrugs and pharmaceutically acceptable carrier composition.
According to arbitrary described thieno-2, the 4 substituted pyrimidines compounds of claim 1-8 or its pharmacy acceptable salt or steric isomer or prodrugs at preparation targeting anti-tumor medicine, prevent and/or treat the application in the pharmaceutical composition of cancer, infection, inflammation and autoimmune disease.
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