CN101730703B - Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof - Google Patents

Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof Download PDF

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CN101730703B
CN101730703B CN2008800159294A CN200880015929A CN101730703B CN 101730703 B CN101730703 B CN 101730703B CN 2008800159294 A CN2008800159294 A CN 2008800159294A CN 200880015929 A CN200880015929 A CN 200880015929A CN 101730703 B CN101730703 B CN 101730703B
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amino
methyl
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CN101730703A (en
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李庶心
刘永学
赵砚瑾
韩春光
匡先照
黄琳仪
肖文松
孙小梅
邓晓东
薛阳
叶清泉
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Institute of Radiation Medicine of CAMMS
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Abstract

Novel benzamide derivatives of formula I, wherein the definition of substituents Het, G1, G2, G3, Y, X1, X2, X3 and X4 see also in the description. Preparation processes for these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds as active ingredients in medicament for the treatment of diseases associated with proliferation, such as leukaemia and solid tumor.

Description

Benzamide derivatives and medicinal prepns thereof with antiproliferative activity
Technical field
The present invention relates to a kind of compound that is used to treat and breeds relative disease, more particularly, relate to a kind of new benzamide derivatives and preparation method thereof, the salt of this verivate and the medicine that is activeconstituents with this compound or its salt class.
Background technology
The malignant tumour serious threat human life with healthy.According to World Health Organization statistics, the whole world has 6,300,000 people to die from malignant tumour every year approximately, and China has 1,500,000 people to die from cancer every year approximately, and at present domestic newly-increased tumour patient every year is up to more than 1,800,000.Because the factors such as change of environmental pollution, mode of life, China's malignant tumour death toll is ascendant trend year by year, and cancer prevention and treatment task are very arduous.Pharmacological agent occupies an important position in three big main treat-ment of malignant tumour, and tempo is very fast.In recent years, chemotherapy of tumors had been obtained sizable progress, and the tumour patient survival time obviously prolongs, but the most serious most of treating malignant tumor of harm humans life and health is still failed to reach satisfied effect.
Traditional chemotherapeutics often produces comparatively serious toxic side effects in default of the selectivity of action target, has greatly restricted the performance of clinical effectiveness.In recent years, the progress of pharmacogenomics, proteomics and molecular pharmacology is progressively illustrated the pathogenesis of tumour; The medicament research and development process has been quickened in large-scale virtual screening, combinatorial chemistry, engineered application, and the research and development of antitumor drug have got into a brand-new era.Pharmacy man and oncologist more and more profoundly recognize the curative effect that will improve oncotherapy, must start with from the mechanism of tumor development, just can make a breakthrough, and fundamentally prevent and treat cancer.Therefore, antitumor drug is just from traditional cytotoxic drug, to the new type antineoplastic medicine development of the too many levels effect molecular target that is directed against mechanism.For example the anti-non-small cell lung cancer drug ZD1939 (Gefitinib) of listing is exactly the specificity protein kinase to the tumour cell signal transduction system recently; Show good curative effect and lower toxic side effects, the discovery of this quasi-molecule targeted drug and clinical use make Internal Medicine-Oncology treat from palliative therapy to the radical cure transition.
With the generation of tumour with to shift relevant albumen of a great variety, and the growth of tumour cell factor is regulated and control to have the albumen of general biological significance, just most possibly become the action target of wide spectrum low toxicity antitumor drug.A kind of so just albumen of histon deacetylase (HDAC) (HDAC) is one of novel targets of antitumor action.Because of its mechanism of action, cause domestic and international researchist's very big concern based on the gene level uniqueness.
Chromatin is made up of DNA, histone and nonhistones.Nucleosome is chromatinic basic repeating unit, eight aggressiveness that are made up of histone H 3, H4, H2A, H2B and be positioned at the outside histone h1 of nucleosome and be wrapped in its outer DNA that contains 146 base pairs and constitute.The acetylize state of histone has the important regulating and controlling effect for genetic transcription; Research shows that the ε-Methionin of histone in its nucleosome of the high position of transcriptional activity is in high acetylize state, transcribes the histone that is in static relatively position and then is low acetylize state.The acetylize state of histone is regulated and control by two fermentoids; Be acetylation of histone transferring enzyme (histone acetyltransferases; HAT) and histon deacetylase (HDAC) (histonedeacetylase, HDAC), the acetylize of several kinds of histone components of HAT catalysis specifically H1, H2A, H2B, H3, H4 N-terminal lysine residue; HDAC is the deacetylation of catalysis histone then; Cause that the corresponding gene expression descends, under the normal physiological state, this two fermentoid is in equilibrium state to the regulation and control of acetylation.And cell is taking place under the state that transforms, and the active of HDAC obviously strengthens.Make that original genetic expression equilibrium state is broken, the developed by molecule that causes some to influence cell proliferation and cell cycle regulation is unbalance, and then causes malignant change of cell.
Present research confirms that histone is low acetylize state mostly in tumour cell, and the generation of the unbalance and tumour of acetylation of histone state is closely related.The best illustration of relation was in the research to acute promyelocytic leukemia between low acetylize of histone and tumour took place.Retinoid receptor (RAR) is the important transcriptional regulator of medullary system differentiation, and RAR α and RAR form heterodimer, goes up retinoic acid response element with DNA and combines.Under the situation of retinoic acid deficiency, can raise SIN3/HDAC3 with the reticent regulon of vitamin A acid thryoid receptor through examining common inhibition, thereby inhibition is transcribed.
HAT extensively is present in from the cell of yeast to mammal biology, has found the active protein molecular of multiple HAT, according to 26S Proteasome Structure and Function multiple sorting technique can be arranged.Mammiferous HDAC says from molecular level, can be divided into 3 types: I/II type HDAC is Zn 2+Dependent form, III type HDAC is Reduced nicotinamide-adenine dinucleotide (NAD) dependent form.The I type comprises HDAC1,2,3,8,11, all is positioned at nuclear, and its relative molecular weight is 42000～55000.The II type comprises HDAC4,5,6,7,9, is large molecular weight protein relatively, and relative molecular weight is 120000～130000.Mainly be positioned at tenuigenin, but can between nucleus and tenuigenin, shuttle back and forth.III type HDAC and yeast Sir2 family have homology; In mammlian system, do not carry out as yet broad research (Liu Liu Bing likes Liao of army the morning bell etc. " sulfoamido hydroximic acid hdac inhibitor 3D-QSAR ". " Acta PhySico-Chimica Sinica " .2005,21 (3): 333-337).
Research shows that histon deacetylase (HDAC) (HDAC) suppressor factor can suppress growth of tumour cell, promotes differentiation, cell death inducing.Compare with the traditional antineoplastic thing; The treatment advantage of hdac inhibitor will be mainly reflected in two aspects: (1) can directly act on this key link of gene abnormal expression; Thereby the hyper-proliferative, escape apoptosis, the differentiation capability that suppress and correct tumour cell reduce; This will be different from the traditional antineoplastic thing only to the excessive single phenotype of cell proliferation, to the more weak shortcoming of other phenotype effect because of abnormal gene expression caused; Experiment in vitro confirms; Hdac inhibitor has antitumor action widely; Tumour cell to many swollen sources; Comprise that bladder, bone, mammary gland, uterus, cns, oesophagus, lung, ovary, pancreas, prostate gland etc. show good fragmentation effect, after hdac inhibitor was handled, tangible apoptosis, propagation inhibition, cell-cycle arrest appearred in these cells.Experimentation on animals is the result show, hdac inhibitor can suppress and kill and wound the tumour cell of tumor animal effectively, and without tangible untoward reaction.This type medicine has changed the mode that traditional chemotherapeutics hits all quick splitted cells comprehensively, and is to the treatment that the transgenation or the abnormal gene expression of tumour cell carries out, less to Normocellular influence.(2) can be to common resistance problem in patient's chemotherapy; Hdac inhibitor not only can increase the selectivity of antitumour drug species, also can be significant with medication combined application, antagonism drug resistance of tumor and the final tumour patient survival rate that improves of different effects mechanism.Hdac inhibitor and multiple chemotherapy drugs in combination medication also show good synergistic therapeutic effect.For example, use TSA or SAHA, can increase the susceptibility of tumour cell the chemotherapeutics Zuyeyidal of target DNA or topoisomerase II at the treatment initial stage.With SAHA and imatinib mesylate drug combination, can make the chronic myelocytic leukemia cell that imatinib mesylate has been tolerated possess susceptibility again.The VEGF suppressor factor uses with hdac inhibitor LAQ824 can suppress 51% endothelial cells cultured (being the twice of the effect when using two kinds of medicines separately).In mouse model, this associating can be controlled 60% neovascularization, and is 50% when using separately.The inhibiting rate of suffering from the tumor growth in the prostate cancer mouse is respectively 35% and 75%.During drug combination, inhibiting rate is 85%.These two kinds of suppressor factor are respectively 54% and 60% to the tumor control rate of mammary cancer mouse, and tumor growth has slowed down 80% when using and unite.
Known hdac inhibitor has: (1) short chain fatty acid, like butyric acid, benzenebutanoic acid; (2) hydroximic acid is like SAHA, Scriptaid; (3) comprise the ring four phthalein structures of epoxy ketone group, like TrapoxinB, HC-Toxin etc.; (4) do not contain the cyclic tetrapeptide structure of epoxy ketone group, like FK228; (5) benzamides, as MS-275 (EP0847992A1, US2002/0103192A1, WO02/26696A1, WO01/18171A2).These compounds have all shown the potential anti-tumor activity; At present existing valproic acid (in July, 2005) and SAHA (in October, 2006) go on the market through drugs approved by FDA.
But there is following shortcoming in these medicines: (1) curative effect is low, and short chain fatty acid is like anti-knurl weak effects such as butyric acid; (2) spinoff is big, and hydroximic acid compound is with Zn 2+For combining target, many Zn of containing are arranged in the known organism body 2+Albumen, so the hydroximic acid compound spinoff is bigger; (3) cost is high, comprises the ring four phthalein structures of epoxy ketone group, reaches the cyclic tetrapeptide structure that does not contain the epoxy ketone group and need adopt the biological method preparation, pass through the performance liquid chromatography separation and purification, is not suitable for macro preparation, and production cost is higher; As adopt chemical method to prepare that then cost is higher.(4) poor stability, benzamides is because of containing the phenylenediamine structure, and its physico-chemical property is unstable.MS-275 is that first is proved to be the histon deacetylase (HDAC) inhibition that has oral antitumour activity in animal body, and at present, MS-275 is just carrying out the clinical study of white blood disease and solid tumor in the U.S..Yet the compound that better performance is arranged that some are new still remains to be developed, in the hope of obtaining antitumour activity height, the little and more stable hdac inhibitor of spinoff.
Summary of the invention
An object of the present invention is to provide new benzamide derivatives, have structure:
Or the salt of pharmaceutical acceptable acid, here, each substituent definition sees following specifying for details in the formula.
Another object of the present invention provides the pharmaceutical composition that contains above-claimed cpd or pharmaceutical acceptable acid salt.
Another object of the present invention provides the preparation method of above-claimed cpd or its pharmaceutical acceptable acid salt.
Another object of the present invention provides the purposes of above-claimed cpd or its pharmaceutical acceptable acid salt.
The invention provides new benzamide derivatives, have formula (I) structure:
Figure GPA00000632129500032
Or the salt of its pharmaceutical acceptable acid,
Wherein:
Het is aryl, heterocyclic aromatic base, naphthenic base or heterocyclic radical; These groups can be by any replacement; Each group can condense arbitrarily with one or more aryl or heterocyclic aryl, or with one or more saturated or unsaturated naphthenic base of part or heterocyclic fused, each ring can be by any replacement;
G 1Be selected from chemical bond, T, L-T, T-L or a T-L-T;
Wherein under the situation that L exists, L is S, O, C=O or N (R 1), R here 1Be selected from hydrogen, alkyl, hydroxyalkyl and tertbutyloxycarbonyl;
T is C under situation about existing 1-C 4Alkylene;
G 2Be arylidene or heterocycle arylidene, each group all can be by any replacement;
G 3Be vinylidene, or not exist (be G 2Group directly with formula I in-C=O links to each other);
Y is NH 2Or OH;
X 1, X 2, X 3, X 4Be selected from hydrogen, halogen (can be preferably fluorine, chlorine, bromine or iodine), C independently of one another 1-C 4Alkyl or C 1-C 4Alkoxyl group, and regulation X 1, X 2, X 3, X 4In at least one is not a hydrogen.
The preferred formula I compound of the present invention, wherein X 2Be selected from fluorine, C 1-C 4Alkoxyl group, X 1, X 3, X 4Be selected from hydrogen, fluorine, chlorine, bromine, iodine, C independently of one another 1-C 4Alkyl or C 1-C 4Alkoxyl group.
The preferred formula I compound of the present invention, wherein X 2Be fluorine, C 1-C 4Alkoxyl group, X 1, X 3, X 4All be hydrogen.
The preferred formula I compound of the present invention, wherein G 3Be not exist.
The preferred formula I compound of the present invention, wherein G 2Be penylene, and
Het-G 1Be
Figure GPA00000632129500041
The preferred formula of the present invention (I) compound has the structure shown in the formula (IA):
Figure GPA00000632129500042
Wherein:
L is S, O or N (R 1), R wherein 1Be hydrogen or C 1-C 4Alkyl;
R 2Be hydrogen or C 1-C 4Alkyl;
Y is-NH 2Or-OH;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
Het is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, benzothiazolyl, benzimidazolyl-or benzotriazole base, and each group can be by any replacement.
The preferred formula of the present invention (IA) compound has formula (IA-1) structure:
Figure GPA00000632129500051
Wherein: L is NH or S;
P, Q, M, G and U are CH or N and M, Q independently of one another, U can not be N simultaneously, is N as long as be no more than 2 among P, Q, M, G and the U, in the ring that contains P, Q, M, G and U, the S of a ring or O not with another ring on S or O adjacent;
R 2Be hydrogen or C 1-C 4Alkyl;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
Group A and B can be identical or different and be independently selected from hydrogen, halogen, C 1-C 4Alkyl, arbitrarily substituted alkoxy comprise aminoalkoxy, halogen alkoxyl group, heteroaryl alkoxyl group, alkoxyalkyl, alkylhalide group, amino, nitro, alkylthio, amido, carbamyl or
Figure GPA00000632129500052
Figure GPA00000632129500061
Figure GPA00000632129500071
The preferred formula of the present invention (IA) compound has formula (IA-2) structure:
Wherein:
L is S or NH;
R 2Be hydrogen or C 1-C 4Alkyl;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
A, B is suc as formula defining in (IA-1) compound.
The preferred formula of the present invention (IA) compound has the structure shown in the formula (IA-3):
Figure GPA00000632129500073
Wherein:
L is S or NH;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
A, B are suc as formula defining in (IA-1) compound.
The preferred formula of the present invention (IA) compound has the structure shown in the formula (IA-4):
Figure GPA00000632129500074
Wherein:
L is S or NH;
D is N-R3 or S;
E is N or C-A;
R 2And R 3Be respectively hydrogen or C independently 1-C 4Alkyl;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
A, B is suc as formula defining in (IA-1) compound.
The preferred formula of the present invention (IA) compound has the structure shown in the formula (IA-5):
Figure GPA00000632129500081
Wherein:
L is NH;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
A, B is suc as formula defining in (IA-1) compound.
The preferred formula of the present invention (I) compound has the structure shown in the formula (IA-6):
Wherein:
A is hydrogen or C 1-C 4Alkyl;
B is suc as formula defining in (IA-1) compound;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
The preferred formula of the present invention (I) compound has the structure shown in the formula (IA-7):
Wherein:
P is CH, N;
B is suc as formula defining in (IA-1) compound;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
The preferred formula of the present invention (I) compound has the structure shown in the formula (IB):
Figure GPA00000632129500084
Wherein:
G 1Be T, L-T or T-L, L is S, O or NH here; T is-CH 2-;
Z 1Be O, S, NH or CH 2
Z 2Be N or CH;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
Het is selected from phenyl, pyridyl, pyrimidyl or benzothiazolyl, can by A and 1 or B replace; A, B are suc as formula defining in (IA-1) compound; Het also can be replaced arbitrarily by 1,2 or 3 groups, and these groups are independently selected from any substituted phenyl of alkoxyl group, halogenated alkoxy, acyl group, morphine quinoline base or alkoxyl group.
The preferred formula of the present invention (I) compound has the structure shown in the formula (IC):
Figure GPA00000632129500091
Wherein:
G 1Be T, L-T or T-L;
L is S, O or NH;
T is-CH 2-;
Z 2Be N or CH;
Z 1Be O, S, NH or CH 2
X 2Be selected from fluorine or, C 1-C 4Alkoxyl group;
Het is selected from phenyl, pyridyl, pyrimidyl or benzothiazolyl, can be replaced by A and/or B, and A, B is suc as formula defining in (IA-1) compound; Het also can be replaced arbitrarily by 1,2 or 3 groups, and these groups are independently selected from any substituted phenyl of alkoxyl group, halogen alkoxyl group, acyl group, morphine quinoline base or alkoxyl group.
The preferred formula of the present invention (I) compound has the structure shown in the formula (ID):
Figure GPA00000632129500092
Wherein:
Het is:
Figure GPA00000632129500093
X 2Be selected from fluorine or C 1-C 4Alkoxyl group.
The preferred formula of the present invention (I) compound has the structure shown in the formula (IE):
Figure GPA00000632129500101
Wherein:
Y is-OH or-NH 2
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
Het is heterocycle or heteroaryl, and each ring contains the part of at least one nitrogen-atoms as ring, and can be by any replacement.
In the preferred formula of the present invention (IE) compound, Y is-NH 2X 2Be fluorine or C 1-C 4Alkoxyl group;
Het is heterocycle or heteroaryl, and each ring contains the part of at least one nitrogen-atoms as ring, and can be replaced arbitrarily by 1 or 2 substituting group, and these substituting groups are selected from A or B, and A, B are suc as formula defining in (IA-1) compound.
In the preferred formula of the present invention (IE) compound, Het can be replaced arbitrarily by 1 or 2 substituting group, and these groups are independently selected from:
Figure GPA00000632129500102
In the preferred formula of the present invention (I) compound, G 3Be not exist; G 2Be penylene, indyl or indolinyl, each can be by any replacement, G 1Be chemical bond ,-CH 2-,-O-CH 2-,-S-CH 2-,-S-CH (CH 3)-or-N (R 1)-CH 2-.
In preferred formula (I) compound, G 2Be indyl or indolinyl; G 1Be-CH 2-or-N (R 1)-CH 2-;
Het is:
Figure GPA00000632129500103
In preferred formula (I) compound, G 3Be not exist;
G 2It is penylene;
G 1Be-S-CH 2-or-S-C (CH 3) (H)-;
Het is:
Figure GPA00000632129500104
Wherein:
J is selected from following groups:
Figure GPA00000632129500111
The preferred formula of the present invention (I) compound has the structure shown in the formula (IF):
Figure GPA00000632129500112
Wherein:
Y is-OH or-NH 2
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
Het is heterocycle or heteroaryl, and wherein each group can be by any replacement, and each ring contains at least one nitrogen-atoms.
In the preferred formula of the present invention (IF) compound, Het is:
Figure GPA00000632129500113
The preferred formula of the present invention (IF) compound has the structure shown in the formula (IF-1):
Wherein:
Y is-NH 2
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
A defines suc as formula (IA-1) structure.
The preferred formula of the present invention (I) compound has the structure shown in the formula (IG):
Figure GPA00000632129500115
Wherein:
Het, G 1, Y suc as formula in (I) structure define X 2Be selected from fluorine or C 1-C 4Alkoxyl group.
The preferred formula of the present invention (I) compound has the structure shown in the formula (IH):
Figure GPA00000632129500121
Wherein:
L be S, O or-NH-;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
A, B are suc as formula defining in (IA-1) structure.
In preferred formula (IH) compound, A is any substituted pyridine or any substituted phenyl; B is a hydrogen or halogen.
The preferred formula of the present invention (I) compound has the structure shown in the formula (I-I):
Wherein:
L be S, O or-NH;
X 2Be selected from fluorine or C 1-C 4Alkoxyl group;
R 4Be hydrogen or C 1-C 6Alkyl.
The present invention also provides new benzamide derivatives, has formula II structure:
Figure GPA00000632129500123
Or the salt of pharmaceutical acceptable acid.
Het1 is aryl or heteroaryl, can be by any replacement, each group can with one or more aryl or heterocyclic radical arbitrarily and close, or with one or more saturated or unsaturated naphthenic base of part or heterocycles, each ring can be by any replacement;
X 1, X 2, X 3, X 4, Y defines suc as formula (I);
G 1Be covalent linkage C 0-C 4Alkyl, C 0-C 4-alkyl-(CO)-C 0-C 4-alkyl, C 0-C 4-alkyl-(NR5)-C 0-C 4-alkyl, C 0-C 4-alkyl-(S)-C 0-C 4-alkyl, C 0-C 4-alkyl-(O)-C 0-C 4-alkyl, C 0-C 4-alkyl-(SO)-C 0-C 4-alkyl, C 0-C 4-alkyl-(SO)-C 0-C 4-alkyl, C 0-C 4-alkyl-(NH)-(CO)-C 0-C 4-alkyl, C 0-C 4-alkyl-(CO)-(NH)-C 0-C 4-alkyl ,-NH-CO-NH-,-NH-CS-NH-,-O-CO-O-,-O-CS-O-,-NH-C (NH)-NH-,-S (O) 2-N (R 5)-,-N (R 5)-S (O) 2-,-NH-C (O)-O-, or-O-C (O)-NH-, wherein R5 possibly be hydrogen, C 1-C 5Alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic aryl, SO 2-alkyl, SO 2-aryl, CO-alkyl, CO-aryl, CO-NH-alkyl, CO-NH-aryl, CO-O-alkyl or CO-O-aryl;
N possibly be 0,1,2,3 or 4;
Z is N or CH;
Y is NH 2Or OH.
The compounds of this invention contain basic group can with sour salify, adopt common means can form the salt of verivate.
Common salt has organic acid salt, inorganic acid salt etc.Usually organic acid salt relatively more commonly used has citrate, fumarate, oxalate, malate, lactic acid salt, camsilate, tosilate, mesylate etc.; Inorganic acid salt has halogen acid salt, vitriol, phosphoric acid salt, nitrate salt etc.
For example, with low alkyl group sulfonic acid, can form mesylate, fluoroform sulphonate like methylsulfonic acid, trifluoromethanesulfonic acid etc.; With aryl sulfonic acid, can form tosilate, benzene sulfonate like Phenylsulfonic acid or tosic acid etc.; With organic carboxyl acid, can form corresponding salt like acetate, fumaric acid, tartrate, oxalic acid, toxilic acid, oxysuccinic acid, succsinic acid or Hydrocerol A etc.; With amino acid, can form glutaminate or aspartate like L-glutamic acid or aspartic acid.With mineral acid, also can form corresponding salt like haloid acid (like hydrofluoric acid, Hydrogen bromide, hydroiodic acid HI, spirit of salt), nitric acid, carbonic acid, sulfuric acid or phosphoric acid etc.
The solvolyte of benzamide derivatives of the present invention also belongs to protection scope of the present invention, and its solvent is preferably water, ethanol or methyl alcohol.
The present invention also provides the preparation method of benzamide derivatives of the present invention.
The preparation method of formula I compound of the present invention comprises formula III compound and formula IV compound reacted and obtains product that its reaction formula is following in solvent:
Figure GPA00000632129500131
Wherein, Het, G in the formula III compound 1, G 2, G 3Definition identical with formula I compound, Y is-NH2 or OH in the formula IV compound, X 1, X 2, X 3, X 4Be selected from hydrogen, halogen (can be preferably fluorine, chlorine, bromine or iodine), C independently of one another 1-C 4Alkyl or C 1-C 4Alkoxyl group, and regulation X 1, X 2, X 3, X 4In at least one is not a hydrogen.
Starting raw material formula III compound according to or with reference to the preparation of the disclosed method of WO2005092899.
Compound IV can be buied in market or obtained with ordinary method is synthetic.
The solvent that above-mentioned preparation method selected for use has multiple choices, all can select for use like chloroform, methylene dichloride, THF, dioxane, 1,2-glycol dimethyl ether, YLENE, toluene, methyl-sulphoxide, triethylamine, etc. organic solvent; Its temperature of reaction is at-30-+80 ℃; Alkali such as sodium hydroxide, triethylamine, pyridine etc. be can add in case of necessity, sour example hydrochloric acid, acetic acid, trifluoracetic acid etc. added.
Het, G in the formula III compound 1, G 2, G 3Or the amino of formula IV compound (if any words), hydroxyl (if any words) protection of available corresponding protection base, after obtaining containing the formula I compound of protection base, deprotection obtains formula I compound again.These protection bases and introducing thereof or the method for sloughing are known by one of skill in the art.
The described compound of general formula I can adopt common separation method to carry out purifying, like column chromatography, recrystallization etc.
In like manner, according to the method for synthesizing amide, can prepare formula (II) compound:
Wherein, Het1, G 1, Z, n, X 1, X 2, X 3, X 4, or the definition of Y identical with formula (II) compound.
The present invention also provides the pharmaceutical composition that contains benzamide compound of the present invention or its esters or solvolyte.
In aforementioned pharmaceutical compositions, can also contain one or more pharmaceutically acceptable carriers, said carrier comprises the conventional thinner of pharmaceutical field, vehicle, weighting agent; Tackiness agent, wetting agent, disintegrating agent; Absorption enhancer, tensio-active agent, absorption carrier; Lubricants etc. can also add flavouring agent, sweeting agent etc. in case of necessity.Medicine of the present invention can be processed tablet, pulvis, and granula, capsule, various ways such as oral liquid and injecting drug use, the medicine of above-mentioned each formulation all can be according to the ordinary method preparation of pharmaceutical field.Wherein best with the oral administration mode clinically.Dosage is 0.0001-200mg/kg body weight every day.
The present invention also provides benzamide compound of the present invention or its esters or solvolyte as the application of treatment with propagation relative disease such as leukemia and solid tumor.
The inventor is through experiment confirm, and compound disclosed by the invention shows sure retarding effect to tumor cell proliferation, and antitumor activity obviously is superior to positive control medicine MS-275, and The compounds of this invention is lower than MS-275 to normal cytotoxicity.
Compound disclosed by the invention is more stable than positive control medicine MS-275 and the disclosed compound physico-chemical property of WO2005092899 in addition.
Preferred forms of the present invention
Through embodiment exploitativeness of the present invention is described below, is it will be understood by those of skill in the art that instruction, the corresponding techniques characteristic is made amendment or replaced, still belong in the scope of requirement protection of the present invention according to prior art.
Figure GPA00000632129500151
Reaction formula 1
Embodiment 1. synthetic N-(2-amino-5-fluorophenyl)-4 ((4-(pyridin-3-yl) pyrimidine-2-is amino) methyl) BM (compound 1)
Step 1. synthesizes 3,3-dimethylamino-1-pyridin-3-yl-acrylketone
The 2g 3-acetylpyridine is dissolved in the anhydrous N of 5ml, in the dinethylformamide, in solution, adds 5ml N, dinethylformamide two acetals again; Finish, be heated to 110 ℃ of reactions 3 hours, thin-layer chromatography shows that reaction finishes reclaim under reduced pressure N; Dinethylformamide, debris places refrigerator overnight, separates out yellow solid; Suction filtration, ethyl acetate/petroleum ether is washed at 1: 1, gets yellow solid 2.05g.
M.p.82-83 ℃ of product fusing point;
Step 2. is synthesized 4-guanidine radicals methyl-phenylformic acid
The 2g methyl-isourea is dissolved in the 10ml 1mol/L aqueous sodium hydroxide solution, slowly drips 2.15g4-aminomethyl phenyl formic acid under the ice bath, finish, stirring reaction spends the night under the room temperature, separates out white solid, filters, and drying gets white solid 2.56g.
Step 3. is synthesized 4-[(4-pyridin-3-yl-pyrimidine-2-base-amino)-methyl] phenylformic acid
1.57g step 1 product and 1.88g step 2 product are dissolved in the 10ml Virahol, add 1.26g salt of wormwood simultaneously, finish, temperature rising reflux 12h, thin-layer chromatography demonstration reaction finishes, and cooling is filtered, and drying gets white solid 1.87g.
M.p.219.5-221 ℃ of product fusing point;
Step 4. is synthesized N-(2-amino-5-fluorophenyl)-4 ((4-(pyridine-3 base) pyrimidine-2-is amino) methyl) BM (compound 1)
With 1g step 3 product, 0.54g N, N-phosphinylidyne diimidazole is dissolved in the 8ml anhydrous tetrahydro furan, 45 ℃ of reaction 1.5h, cooling, subsequent use.Get another dry 100ml three-necked bottle, under nitrogen protection, with 0.52g 4-fluoro-1, the 2-phenylenediamine is dissolved in the 7ml anhydrous tetrahydro furan; Drip the 0.38g trifluoroacetic acid, drip subsequent use reaction solution again, stirred overnight at room temperature, thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue is crossed silica gel and is leant on, and ethyl acetate/petroleum ether/ethanol is washed at 2: 1: 2; Elutriant concentrates, and crystallization gets white solid 0.28g.
M.p.180-181.5 ℃ of product fusing point;
1HNMR(DMSO-d 6)(δppm)：4.640-4.654(d，2H)，5.212(s，2H)，6.338-6.354(m，1H)，6.506-6.541(dd，1H)，7.069-7.107(t，1H)，7.262-7.274(d，1H)，7.492-7.531(m，3H)，7.910-8.044(m，3H)，8.407-8.420(d，2H)，8.680-8.690(d，1H)，9.246(s，1H)，9.515-9.532(d，1H)。
Following compound 2～4,9～17,51～55,125～126 synthesis step is as embodiment 1 (compound 1) N-(2-amino-5-fluorophenyl)-4 ((4-(pyridine-2-yl) pyrimidine-2-is amino) methyl) BM (compound 2)
M.p.206-207 ℃ of product fusing point;
1HNMR(DMSO-d 6)(δppm)：4.653-4.667(d，2H)，5.208(s，2H)，6.337-6.344(m，1H)，6.503-6.539(dd，1H)，7.066-7.104(t，1H)，7.494-7.520(m，4H)，7.908-7.997(m，4H)，8.317-8.337(d，1H)，8.442-8.455(d，1H)，8.692-8.703(d，1H)，9.525(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(pyridin-4-yl) pyrimidine-2-is amino) methyl) BM (compound 3)
M.p.206-207 ℃ of product fusing point;
1HNMR(DMSO-d 6)(δppm)：4.647-4.662(d，2H)，5.192(s，2H)，6.324-6.367(m，1H)，6.508-6.543(dd，1H)，7.073-7.111(m，1H)，7.284-7.297(d，1H)，7.486-7.494(d，2H)，0.89(t，3H)，7.909-8.074(m，5H)，8.460-8.472(d，1H)，8.720-8.734(d，2H)9.510(s，1H)。
N-(2-amino-5-fluorophenyl)-4-(4-(4-p-methoxy-phenyl) pyrimidine-2-is amino) methyl) BM (compound 4)
M.p.209-209.5 ℃ of product fusing point;
1HNMR(DMSO-d 6)(δppm)：3.831(s，3H)，4.676(s，2H)，6.349-6.392(m，1H)，6.528-6.563(dd，1H)，7.049-7.220(m，4H)，7.484-7.503(d，2H)，7.916-7.936(d，2H)，8.081-8.110(dd，2H)，8.318-8.331(d，1H)，9.539(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-bromophenyl) pyrimidine-2-is amino) methyl) BM (compound 9)
1HNMR(DMSO-d 6)(δppm)：4.632-4.645(d，2H)，5.223(s，2H)，6.330-6.367(m，1H)，6.514-6.549(dd，1H)，7.075-7.112(t，1H)，7.186-7.200(d，1H)，7.481(s，2H)，7.698-7.717(d，2H)，7.912-8.050(m，5H)，8.372-8.384(d，1H)，9.540(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(3, the 4-difluorophenyl) pyrimidine-2-is amino) methyl) benzamide (compound 10)
1HNMR(DMSO-d 6)(δppm)：4.631-4.654(d，2H)，5.189(s，2H)，6.337-6.344(m，1H)，6.507-6.542(dd，1H)，7.071-7.108(t，1H)，7.218-7.230(d，1H)，7.487-7.579(m，3H)，7.904-7.974(m，4H)，8.120-(s，1H)，8.381-8.393(d，1H)，9.509(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(2,4-dimethylthiazole-5-yl) pyrimidine-2-is amino) methyl) BM (compound 11)
1HNMR(DMSO-d 6)(δppm)：2.614(s，6H)，4.558-4.574(d，2H)，5.192(s，2H)，6.326-6.361(m，1H)，6.509-6.544(dd，1H)，6.826-6.839(d，1H)，7.075-7.112(t，1H)，7.440-7.459(d，2H)，7.899-7.919(d，3H)，8.317-8.329(d，1H)，9.507(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-((2-(piperidines-1-yl) oxyethyl group) phenyl) pyrimidine-2-is amino) methyl) BM (compound 12)
1HNMR(DMSO-d 6)(δppm)：1.525-1.759(m，6H)，3.155-3.601(m，6H)，4.359-4.372(t，2H)，4.626-4.614(d，2H)，5.188(s，2H)，6.340-6.368(m，1H)，6.511-6.540(dd，1H)，7.072-7.129(m，4H)，7.464-7.483(d，2H)，7.802(t，1H)，7.903-7.923(d，2H)，8.068-8.090(d，2H)，8.300-8.321(d，1H)，9.512(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(3-fluoro-4-(methylthio group) phenyl) pyrimidine-2-is amino) methyl) BM (compound 13)
1HNMR(DMSO-d 6)(δppm)：2.505(s，3H)，4.625-4.640(d，2H)，5.188(s，2H)，6.337-6.366(m，1H)，6.507-6.542(dd，1H)，7.072-7.110(q，1H)，7.199-7.212(d，1H)，7.423-7.485(m，3H)，7.904-7.966(m，5H)，8.354-8.366(d，1H)，9.508(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(3-fluoro-4-(methoxyl group) phenyl) pyrimidine-2-is amino) methyl) BM (compound 14)
1HNMR(DMSO-d 6)(δppm)：3.904(s，3H)，4.621-4.635(d，2H)，5.213(s，2H)，6.326-6.369(m，1H)，6.508-6.543(dd，1H)，7.070-7.107(t，1H)，7.161-7.173(d，1H)，7.254-7.296(t，1H)，7.483(s，2H)，7.908-7.928(m，5H)，8.316-8.329(d，1H)，9.534(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(pyrazine-2-yl) pyrimidine-2-is amino) methyl) BM (compound 15)
1HNMR(DMSO-d 6)(δppm)：4.673(d，2H)，5.215(s，2H)，6.338-6.35(m，1H)，6.503-6.538(dd，1H)，7.065-7.101(t，1H)，7.451-7.531(m，3H)，7.915-7.935(dd，2H)，8.159(s，1H)，8.503-8.515(d，1H)，8.785(s，2H)，9.451(s，1H)，9.539(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-(thiene-3-yl-)) pyrimidine-2-is amino) methyl) BM (compound 16)
1HNMR(DMSO-d 6)(δppm)：4.602-4.618(d，2H)，5.190(s，2H)，6.337-6.366(m，1H)，6.514-6.542(dd，1H)，7.045-7.094(t，2H)，7.498(d，2H)，7.639-7.918(m，5H)，8.287-8.306(d，2H)，9.503(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-methylthio group phenyl) pyrimidine-2-is amino) methyl) BM (compound 17)
1HNMR(DMSO-d 6)(δppm)：2.511(s，3H)，4.627-4.642(d，2H)，5.192(s，2H)，6.325-6.367(m，1H)，6.518-6.546(dd，1H)，7.090-7.149(m，2H)，7.344-7.488(q，4H)，7.832-8.040(m，5H)，8.320-8.333(d，1H)，9.508(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-(2-morpholine oxyethyl group) phenyl) pyrimidine-2-is amino) methyl) BM (compound 51)
MS(FAB)：543(M+1)
N-(2-amino-5-fluorophenyl)-4 ((4-(4-ethoxyl phenenyl) pyrimidine-2-is amino) methyl) BM (compound 52)
1HNMR(DMSO-d6)(δppm)：1.33-1.36(m，3H)，4.07-4.10(q，2H)，4.63-4.64(d，2H)，5.19(s，2H)，6.33-6.37(q，1H)，6.51-6.55(dd，1H)，7.01-7.11(q，4H)，7.47-7.49(d，2H)，7.76-7.79(m，1H)，7.90-7.92(d，2H)，8.03-8.05(d，2H)，8.28-8.29(d，1H)，9.51(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-butoxy phenyl) pyrimidine-2-is amino) methyl) BM (compound 53)
1HNMR(DMSO-d6)(δppm)：0.92-0.96(m，3H)，1.43-1.45(q，2H)，1.70-1.71(q，2H)，4.02-4.05(m，2H)，4.62-4.63(d，2H)，5.21(s，2H)，6.34-6.35(q，1H)，6.50-6.54(dd，1H)，7.02-7.11(q，4H)，7.46-7.48(q，2H)，7.80-7.83(m，1H)，7.90-7.92(d，2H)，8.03-8.05(d，2H)，8.28-8.29(d，1H)，9.53(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-phenyl) pyrimidine-2-is amino) methyl) BM (compound 54)
1HNMR(DMSO-d6)(δppm)：4.64-4.65(d，2H)，5.21(s，2H)，6.33-6.36(q，1H)，6.51-6.54(dd，1H)，7.07-7.11(m，1H)，7.17-7.19(d，1H)，7.50(s，5H)，7.91-7.93(m，3H)，8.08-8.09(d，2H)，8.35-8.37(d，1H)，9.53(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-cyclopentyloxy phenyl) pyrimidine-2-is amino) methyl) BM (compound 55)
1HNMR(DMSO-d6)(δppm)：1.59-1.71(q，6H)，1.94-1.99(q，2H)，4.62-4.63(d，2H)，4.88-4.91(m，1H)，5.21(s，2H)，6.34-6.37(q，1H)，6.51-6.53(dd，1H)，6.98-7.10(q，4H)，7.46-7.48(d，2H)，7.79-7.82(q，1H)，7.90-7.92(d，2H)，8.02-8.04(d，2H)，8.28-8.29(d，1H)，9.53(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(3-p-methoxy-phenyl) pyrimidine-2-is amino) methyl) BM (compound 125)
1HNMR(DMSO-d6)(δppm)：3.814(s，3H)，4.623-4.638(d，2H)，5.187(s，2H)，6.322-6.343(m，1H)，6.512-6.541(dd，1H)，7.059-7.179(m，3H)，7.382-7.647(m，5H)，7.877-7.921(t，3H)，8.345-8.358(d，1H)，9.504(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(3, the 4-methylenedioxyphenyl) pyrimidine-2-is amino) methyl) BM (compound 126)
1HNMR(DMSO-d6)(δppm)：4.615-4.630(d，2H)，5.190(s，2H)，6.096(s，2H)，6.336-6.344(m，1H)，6.506-6.541(dd，1H)，7.077-7.111(m，3H)，7.457-7.477(d，2H)，7.625-7.620(m，5H)，8.282-8.295(d，1H)，9.507(s，1H)。
Figure GPA00000632129500191
R 1=H R 2=OCH 3R 3=H R 4=H R 5=H compound 5
R 1=H R 2=OCH 3R 3=OCH 3R 4=H R 5=H compound 6
R 1=OCH 3R 2=OCH 3R 3=OCH 3R 4=H R 5=H compound 7
R 1=H R 2=OCF 3R 3=H R 4=H R 5=H compound 18
R 1, R 2=
Figure GPA00000632129500192
R 3=H R 4=H R 5=H compound 19
R 1=CH 3R 2=H R 3=H R 4=H R 5=H compound 82
R 1=H R 2=H R 3=H R 4=H R 5=H compound 83
R 1=H R 2=CH 3R 3=H R 4=H R 5=H compound 84
R 1=H R 2=OC 2H 5R 3=H R 4=H R 5=H compound 85
R 1=H R 2=Cl R 3=H R 4=H R 5=H compound 86
R 1=H R 2=Br R 3=H R 4=H R 5=H compound 87
R 1=H R 2=H R 3=CF 3R 4=H R 5=H compound 88
R 1=H R 2=H R 3=H R 4=CH 3R 5=H compound 89
R 1=H R 2=H R 3=H R 4=Cl R 5=CH 3Compound 90
Reaction formula 2
Embodiment 2. synthetic N-(2-amino-5-fluorophenyl)-4-((the 4-p-methoxy-phenyl is amino) methyl) BM (compound 5)
Step 1. is synthesized the terephthalaldehydic acid methyl esters
The 2.0g terephthalaldehydic acid is dissolved in the 20ml methyl alcohol, under ice bath, slowly drips the 1.81ml thionyl chloride, finish, behind the temperature rising reflux 3h, thin-layer chromatography shows that reaction finishes, decompression and solvent recovery, and cooling is filtered, and obtains faint yellow solid 2.13g.
M.p.59-61 ℃ of product fusing point;
Step 2. is synthesized 4-((the 4-p-methoxy-phenyl is amino) methyl) oil of Niobe hydrochloride
1.59g is dissolved in the 15ml methyl alcohol aminoanisole and 2.13g step 1 product, adds 3.07gNaBH under the ice bath in batches 4, and dropping Glacial acetic acid min. 99.5 maintenance reaction solution PH 5～6, thin-layer chromatography shows that reaction finishes, and decompression desolventizes, and residue is allocated in ETHYLE ACETATE/water, is adjusted to acidity with 2N hydrochloric acid, separates out a large amount of white solids, filters, and drying gets white solid 2.89g.
Step 3. is synthesized 4-((the 4-p-methoxy-phenyl is amino) methyl) phenylformic acid
2.67g step 2 product is suspended in 8ml THF/8ml water, adds the 0.53g Lithium Hydroxide MonoHydrate, stirred overnight at room temperature, thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue adds the 20ml water dissolution, and using 1N hydrochloric acid to transfer PH is about 5; Leave standstill, filter, promptly get white solid 2.17g.
M.p.178-180.5 ℃ of product fusing point;
Step 4. is synthesized N-(2-amino-5-fluorophenyl)-4-((the 4-p-methoxy-phenyl is amino) methyl) BM (compound 5)
With step 3 product 2.17g, N, N-phosphinylidyne diimidazole 1.39g is dissolved in the 10ml anhydrous tetrahydro furan, 45 ℃ of reaction 1.5h, cooling, subsequent use.Get another three-necked bottle, under nitrogen protection, with 1.34g 4-fluoro-1, the 2-phenylenediamine is dissolved in the anhydrous tetrahydro furan; Drip the 0.98g trifluoroacetic acid, drip subsequent use reaction solution again, the stirring at room reaction is spent the night, and thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue is crossed silicagel column, and ethyl acetate/petroleum ether is washed at 1: 2; Elutriant concentrates, and crystallization gets white solid 1.05g.
M.p.205.5-206 ℃ of product fusing point;
1HNMR(DMSO-d6)(δppm)：3.603(s，3H)，4.284-4.299(d，2H)，5.214(s，2H)，5.939-5.969(t，1H)，6.329-6.372(m，1H)，6.496-6.539(m，3H)，6.660-6.683(d，2H)，7.073-7.111(q，1H)，7.448-7.469(d，2H)，7.900-7.920(d，2H)，9.529(s，1H)。
Following compound 6～7,18～19,82～90 synthesis step is as embodiment 2 (compound 5).
N-(2-amino-5-fluorophenyl)-4-((3,4-Dimethoxyphenyl amino methyl) BM (compound 6)
M.p.135.5-136.5 ℃ of product fusing point;
1HNMR(DMSO-d6)(δppm)：3.589(s，3H)，3.659(s，3H)，4.292-4.306(d，2H)，5.192(s，2H)，5.968-6.009(m，2H)，6.324-6.352(m，2H)，6.517-6.665(m，2H)，7.081-7.118(t，1H)，7.460-7.480(d，2H)，7.097-7.790(d，2H)，9.521(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((3,4, the 5-trimethoxyphenyl is amino) methyl) BM (compound 7)
M.p.166-167 ℃ of product fusing point;
1HNMR(DMSO-d6)(δppm)：3.495(s，3H)，3.624(s，3H)，3.643(s，3H)，4.313-4.328(d，2H)，5.229(s，2H)，5.882(s，2H)，6.332-6.375(m，2H)，6.512-6.548(dd，1H)，7.075-7.097(q，1H)，7.479-7.499(d，2H)，7.919-7.939(d，2H)，9.551(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((the 4-Trifluoromethoxyphen-l is amino) methyl) benzamide (compound 18)
1HNMR(DMSO-d6)(δppm)：4.408-4.423(d，2H)，5.234(s，2H)，6.333-6.375(m，1H)，6.514-6.542(dd，1H)，6.797-6.894(m，4H)，7.076-7.266(m，2H)，7.465-7.486(d，2H)，7.931-7.951(d，2H)，9.562(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((3, the 4-methylenedioxyphenyl is amino) methyl) BM (compound 19)
1HNMR(DMSO-d 6)(δppm)：4.277-4.292(d，2H)，5.230(s，2H)，5.804(s，2H)，5.956-5.979(dd，1H)，6.016-6.137(t，1H)，6.257-6.262(d，1H)，6.336-6.374(m，1H)，6.512-6.627(m，2H)，7.090-7.112(q，1H)，7.445-7.465(d，2H)，7.907-7.928(d，2H)，9.543(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((the 3-aminomethyl phenyl is amino) methyl) BM (compound 82)
1HNMR(DMSO-d 6)(δppm)：3.047(s，3H)，4.641(s，2H)，5.229(s，2H)，6.327-6.370(q，1H)，6.507-6.542(dd，1H)，6.598-6.634(q，1H)，6.698-6.719(d，2H)，7.069-7.165(q，3H)，7.305-7.325(d，2H)，7.902-7.923(d，2H)，9.541(s，1H)。
N-(2-amino-5-fluorophenyl)-4-(phenylamino methyl) BM (compound 83)
1HNMR(DMSO-d 6)(δppm)：4.336-4.351(d，2H)，5.220(s，2H)，6.343-6.381(q，2H)，6.506-6.560(q，4H)，7.009-7.110(q，3H)，7.454-7.475(d，2H)，7.908-7.928(d，2H)，9.535(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((the 4-aminomethyl phenyl is amino) methyl) BM (compound 84)
1HNMR(DMSO-d 6)(δppm)：2.111(s，3H)，4.305-4.320(d，2H)，5.222(s，2H)，6.142-6.174(m，1H)，6.330-6.372(q，1H)，6.451-6.472(d，2H)，6.509-6.554(dd，1H)，6.831-6.852(d，2H)，7.070-7.107(t，1H)，7.898-7.918(d，2H)，9.535(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((the 4-ethoxyl phenenyl is amino) methyl) BM ((compound 85)
1HNMR(DMSO-d 6)(δppm)：1.223-1.258(q，3H)，3.817-3.851(q，2H)，4.279-4.295(d，2H)，5.226(s，2H)，5.946-5.997(m，1H)，6.331-6.373(q，1H)，6.479-6.539(q，3H)，6.649-6.671(d，2H)，7.071-7.109(t，1H)，7.449-7.484(m，2H)，7.903-7.923(d，2H)，9.541(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((the 4-chloro-phenyl-is amino) methyl) BM (compound 86)
1HNMR(DMSO-d 6)(δppm)：4.335-4.350(d，2H)，5.225(s，2H)，6.331-6.374(q，2H)，6.512-6.585(q，4H)，7.046-7.089(q，3H)，7.437-7.457(d，2H)，7.913-7.933(d，2H)，9.543(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((the 4-bromophenyl is amino) methyl) BM (compound 87)
1HNMR(DMSO-d 6)(δppm)：4.332-4.348(d，2H)，5.229(s，2H)，6.345-6.353(q，1H)，6.501-6.546(q，3H)，6.609-6.625(m，1H)，7.072-7.109(t，1H)，7.158-7.180(q，2H)，7.432-7.453(d，2H)，7.912-7.932(d，2H)，9.547(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((the 3-trifluoromethyl is amino) methyl) BM (compound 88)
1HNMR(DMSO-d 6)(δppm)：4.363-4.379(d，2H)，5.189(s，2H)，6.302-6.330(q，1H)，6.467-6.495(dd，1H)，6.752-6.850(q，4H)，7.029-7.067(t，1H)，7.182-7.222(m，1H)，7.420-7.441(d，2H)，7.884-7.905(d，2H)，9.515(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((the 2-aminomethyl phenyl is amino) methyl) BM (compound 89)
1HNMR(DMSO-d 6)(δppm)：2.175(s，3H)，4.419-4.435(d，2H)，5.220(s，2H)，5.749-5.779(m，1H)，6.292-6.349(q，2H)，6.441-6.475(q，1H)，6.507-6.543(dd，H)，6.845-6.884(m，1H)，6.956-6.973(d，1H)，7.070-7.107(t，1H)，7.451-7.472(d，2H)，7.894-7.915(d，2H)，9.524(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((2-chloro-4-aminomethyl phenyl is amino) methyl) BM (compound 90)
1HNMR(DMSO-d 6)(δppm)：2.250(s，3H)，4.363-4.403(m，2H)，5.200(s，2H)，6.324-6.367(q，1H)，6.518-6.546(dd，1H)，6.731-6.769(q，1H)，7.003-7.156(q，3H)，7.422-7.457(m，2H)，7.811-7.894(m，2H)，9.517(s，1H)。
Figure GPA00000632129500221
Reaction formula 3
Embodiment 3. synthetic 4-(((styroyl) (2-hydroxyethyl) amino) methyl)-N-(2-amino-5-fluorophenyl) BMs (compound 8)
Step 1. is synthesized 4-((benzene ethylamino) methyl) oil of Niobe hydrochloride
With phenylethylamine 1.43ml, terephthalaldehydic acid methyl esters 1.46g is dissolved in the 10ml methyl alcohol, adds the 2.5g Peng Qinghuana under the ice bath in batches; And drip Glacial acetic acid min. 99.5 maintenance reaction solution PH 5～6, and thin-layer chromatography shows that reaction finishes, decompression desolventizes; Residue is allocated in ETHYLE ACETATE/water, is adjusted to acidity with 2N hydrochloric acid, separates out a large amount of white solids; Filter, drying promptly gets white solid 2.06g.
Step 2. is synthesized 4-(((2-(tertiary butyl dimethyl Si base) ethyl) (styroyl) amino) methyl) oil of Niobe
Get the dry three-necked bottle of 100ml, in the drying nitrogen protection down, 2.06g4-((benzene ethylamino) methyl) oil of Niobe hydrochloride is dissolved in the 20ml anhydrous dimethyl sulphoxide, under the stirring at room; And add 2.87ml anhydrous triethylamine free salt hydrochlorate, and treat the solid dissolving, add 3.91g (2-bromine oxethyl) (tertiary butyl) dimethylsilane again; Be warming up to 60 ℃, isothermal reaction 24h, thin-layer chromatography show that reaction finishes; Reaction solution is allocated in ETHYLE ACETATE/water, collects methacrylate layer, decompression and solvent recovery; Liquid concentrator is crossed silicagel column, and 1: 6 wash-out of ethyl acetate/petroleum ether, elutriant concentrating under reduced pressure get faint yellow oily thing 1.53g.
Step 3. is synthesized 4-(((2-(tertiary butyl dimethyl Si base) ethyl) (styroyl) amino) methyl) phenylformic acid (IV)
Get 1.53g step 2 product and be dissolved in the 6mlTHF/6ml water, add the 0.32g Lithium Hydroxide MonoHydrate, stirred overnight, thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue is soluble in water, and using 1N hydrochloric acid carefully to transfer PH is 6.5; Filter, drying gets white solid 1.02g.
M.p.246-248.5 ℃ of product fusing point;
Step 4. is synthesized 4-(((2-(tertiary butyl dimethyl Si base) ethyl) (styroyl) amino) methyl)-N-(2-amino-5-fluorophenyl) BM (compound 8)
With 1.02g step 3 product, 0.44g N, N-phosphinylidyne diimidazole is dissolved in the 7ml anhydrous tetrahydro furan, 45 ℃ of reaction 1.5h, cooling, subsequent use.Get the dry three-necked bottle of another 100ml, under nitrogen protection, with 0.35g4-fluoro-1, the 2-phenylenediamine is dissolved in the 5ml anhydrous tetrahydro furan; Drip the 0.26g trifluoroacetic acid, drip subsequent use reaction solution again, stirred overnight at room temperature, thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue is crossed silicagel column, ETHYLE ACETATE: sherwood oil is washed at 1: 2; Elutriant concentrates, and crystallization gets white solid 0.34g
Step 5. is synthesized 4-(((styroyl) (2-hydroxyethyl) amino) methyl)-N-(2-amino-5-fluorophenyl) BM (compound 8)
Get the dry three-necked bottle of a 100ml, feed drying nitrogen, under-20 ℃, add 0.34g step 4 product; The dissolving of 5ml anhydrous tetrahydro furan slowly drips 0.17g tetrabutyl fluoride amine again, finishes, and slowly rises to room temperature; Stirring reaction spends the night, and thin-layer chromatography shows that reaction finishes, decompression and solvent recovery, and residue is crossed silicagel column; 1: 4 wash-out of ethyl acetate/petroleum ether, elutriant concentrates, and crystallization gets white solid 0.102g
M.p.100.0-101.5 ℃ of product fusing point;
1HNMR(DMSO-d 6)(δppm)：2.593-2.746(m，6H)，3.611-3.750(q，4H)，5.182(s，2H)，6.317-6.359(m，1H)，6.502-6.537(dd，1H)，7.063-7.391(m，8H)，7.873-7.893(d，2H)，9.521(s，1H)。
The synthesis step of following compound 20～21 is as embodiment 3 (compound 8).
4-(((4-mehtoxybenzyl) (2-hydroxyethyl) amino) methyl)-N-(2-amino-5-fluorophenyl) BM (compound 20)
11HNMR(DMSO-d 6)(δppm)：2.498-2.508(t，2H)，3.487-3.523(d，4H)，3.601-3.634(t，2H)，3.730(s，3H)，5.234(s，2H)，6.333-6.376(m，1H)，6.513-6.548(dd，1H)，6.879-6.901(d，2H)，7.077-7.115(q，1H)，7.263-7.285(d，2H)，7.469-7.490(m，2H)，7.922-7.943(d，2H)，9.563(s，1H)。
4-(((3,4-difluoro phenmethyl) (2-hydroxyethyl) amino) methyl)-N-(2-amino-5-fluorophenyl) BM (compound 21)
11HNMR(DMSO-d 6)(δppm)：2.500-2.509(t，2H)，3.387-3.423(d，4H)，3.594-3.603(t，2H)，5.235(s，2H)，6.333-6.379(m，1H)，6.520-6.552(dd，1H)，7.095-7.108(q，1H)，7.231-7.233(d，1H)，7.368-7.395(d，1H)，7.487-7.539(m，3H)，7.930-7.951(d，2H)，9.569(s，1H)。
Figure GPA00000632129500241
Reaction formula 4
Embodiment 4. synthetic 4-(2-fluorine benzyl is amino)-N-(2-amino-5-fluorophenyl) BMs (compound 22)
Step 1. is synthesized 4-(2-fluorine benzyl is amino) phenylformic acid
1.59g2-fluorobenzaldehyde and 2.13g4-benzaminic acid are dissolved in the 15ml methyl alcohol, add 3.07gNaBH under the ice bath in batches 4, and drip Glacial acetic acid min. 99.5 maintenance reaction solution PH 5～6, and thin-layer chromatography shows that reaction finishes, and decompression desolventizes, and residue adds suitable quantity of water, is adjusted to acidity with 2N hydrochloric acid, separates out a large amount of white solids, filters, and drying gets white solid 2.89g.
M.p.178-180.5 ℃ of product fusing point;
Step 2. is synthesized N-(2-amino-5-fluorophenyl)-4-((the 4-p-methoxy-phenyl is amino) methyl) benzamide (compound 22)
With step 1 product 2.17g, N, N-phosphinylidyne diimidazole 1.39g is dissolved in the 10ml anhydrous tetrahydro furan, 45 ℃ of reaction 1.5h, cooling, subsequent use.Get another three-necked bottle, under nitrogen protection, with 1.34g 4-fluoro-1, the 2-phenylenediamine is dissolved in the anhydrous tetrahydro furan; Drip the 0.98g trifluoroacetic acid, drip subsequent use reaction solution again, the stirring at room reaction is spent the night, and thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue is crossed silicagel column, and ethyl acetate/petroleum ether is washed at 1: 2; Elutriant concentrates, and crystallization gets white solid 1.05g
1HNMR(DMSO-d 6)(δppm)：4.385-4.400(d，2H)，5.113(s，2H)，6.317-6.360(m，1H)，6.504-6.644(m，3H)，6.807-6.837(t，1H)，7.044-7.081(q，1H)，7.155-7.227(m，2H)，7.301-7.395(m，2H)，7.727-7.749(d，2H)，9.190(s，1H)。
The synthesis step of following compound 23～31,56～62 is as embodiment 4 (compound 22).
4-(4-fluorine benzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 23)
1HNMR(DMSO-d 6)(δppm)：4.329-4.344(d，2H)，5.136(s，2H)，6.318-6.339(m，1H)，6.507-6.615(m，3H)，6.908-7.184(m，4H)，7.371-7.405(t，2H)，7.710-7.731(d，2H)，9.207(s，1H)。
4-(the 4-benzyl chloride is amino)-N-(2-amino-5-fluorophenyl) BM (compound 24)
1HNMR(DMSO-d 6)(δppm)：4.343-4.358(d，2H)，5.110(s，2H)，6.316-6.358(m，1H)，6.504-6.607(m，3H)，6.897-6.927(t，1H)，7.041-7.079(q，1H)，7.354-7.404(m，4H)，7.709-7.731(d，2H)，9.178(s，1H)。
N-(2-amino-5-fluorophenyl)-4-(pyridin-3-yl-methylamino-) BM (compound 25)
1HNMR(DMSO-d 6)(δppm)：4.388-4.401(d，2H)，5.115(s，2H)，6.313-6.353(m，1H)，6.507-6.648(m，3H)，6.906-7.130(m，2H)，7.338-7.368(t，1H)，7.726-7.743(d，3H)，8.446-8.456(d，1H)，8.590(s，1H)，9.194(s，1H)。
4-(the 4-methoxybenzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 26)
1HNMR(DMSO-d 6)(δppm)：3.722(s，3H)，4.259-4.274(d，2H)，5.121(s，2H)，6.318-6.360(m，1H)，6.501-6.614(m，3H)，6.804-6.903(m，3H)，7.037-7.058(q，1H)，7.263-7.285(d，2H)，7.702-7.723(d，2H)，9.184(s，1H)。
4-(4-N, N-dimethylamino benzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 27)
1HNMR(DMSO-d 6)(δppm)：3.000(s，6H)，4.727(s，2H)，5.105(s，2H)，6.111-6.140(m，1H)，6.278-6.313(m，1H)，6.409-6.430(m，1H)，6.593-6.701(m，2H)，6.821-6.842(d，2H)，7.160-7.204(m，1H)，7.698-7.720(d，1H)，7.963-7.986(m，2H)，9.161(s，1H)。
4-(3,4-(methylenedioxy) benzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 28)
1HNMR(DMSO-d 6)(δppm)：4.242-4.257(d，2H)，5.111(s，2H)，5.971(s，2H)，6.316-6.359(m，1H)，6.502-6.615(m，3H)，6.792-6.906(m，4H)，7.043-7.080(q，1H)，7.706-7.728(d，2H)，9.171(s，1H)。4-(3,4-difluoro benzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 29)
1HNMR(DMSO-d 6)(δppm)：4.34-4.358(d，2H)，5.135(s，2H)，6.318-6.361(m，1H)，6.500-6.530(dd，1H)，6.595-6.617(d，2H)，6.940-6.962(t，1H)，7.033-7.070(q，1H)，7.209(s，1H)，7.365-7.413(m，2H)，7.718-7.739(d，2H)，9.212(s，1H)。
4-(the 2-benzyl chloride is amino)-N-(2-amino-5-fluorophenyl) BM (compound 30)
1HNMR(DMSO-d 6)(δppm)：4.408-4.423(d，2H)，5.137(s，2H)，6.320-6.363(m，1H)，6.501-6.530(dd，1H)，6.580-6.602(d，2H)，6.915-6.945(q，1H)，7.289-7.490(m，4H)，7.731-7.753(d，2H)，9.217(s，1H).
4-(2, the 4-dichloro benzyl amino)-N-(2-amino-5-fluorophenyl) BM (compound 31)
1HNMR(DMSO-d 6)(δppm)：4.388-4.403(d，2H)，5.138(s，2H)，6.320-6.363(m，1H)，6.503-6.538(dd，1H)，6.568-6.591(d，2H)，6.936-6.967(t，1H)，7.038-7.076(q，1H)，7.342-7.363(d，1H)，7.401-7.428(dd，1H)，7.649-7.655(d，1H)，7.735-7.757(d，2H)，9.226(s，1H)。
4-(the 2-methoxy-benzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 56)
1HNMR(DMSO-d 6)(δppm)：3.846(s，3H)，4.285-4.299(d，2H)，5.109(s，2H)，6.316-6.359(q，1H)，6.503-6.695(q，4H)，6.884-7.252(q，5H)，7.710-7.732(d，2H)，9.172(s，1H)。
4-(the 3-methoxy-benzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 57)
1HNMR(DMSO-d 6)(δppm)：3.73(s，3H)，4.31-4.33(d，2H)，5.13(s，2H)，6.32-6.36(q，1H)，6.50-6.54(dd，1H)，6.60-6.62(d，2H)，6.79-6.81(m，1H)，6.88-6.93(q，2H)，7.04-7.7.0(t，1H)，7.22-7.26(m，1H)，7.71-7.73(d，2H)，9.19(s，1H)。
4-(the 4-ethoxy benzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 58)
1HNMR(DMSO-d 6)(δppm)：1.29-1.32(m，3H)，3.96-3.99(t，2H)，4.25-4.27(d，2H)，5.13(s，2H)，6.31-6.36(q，1H)，6.50-6.54(dd，1H)，6.59-6.61(d，2H)，6.81-6.84(m，1H)，6.86-6.89(d，2H)，7.04-7.07(t，1H)，7.25-7.27(d，2H)，7.70-7.72(d，2H)，9.19(s，1H)。
4-(the 2-ethoxy benzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 59)
1HNMR(DMSO-d 6)(δppm)：1.36-1.40(m，3H)，4.09-4.11(t，2H)，4.29-4.31(d，2H)，5.13(s，2H)，6.32-6.36(q，1H)，6.50-6.54(dd，1H)，6.57-6.60(d，2H)，6.71-6.74(m，1H)，6.85-6.89(m，1H)，6.98-7.00(d，1H)，7.04-7.07(t，1H)，7.19-7.22(m，2H)，7.71-7.73(d，2H)，9.20(s，1H)。
4-(2, the 4-dimethoxy-benzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 60)
1HNMR(DMSO-d 6)(δppm)：3.73(d，6H)，4.252-4.266(d，2H)，5.131(s，2H)，6.334-6.363(q，1H)，6.505-6.533(dd，1H)，6.607-6.629(d，2H)，6.812-6.886(q，3H)，6.977-6.980(m，1H)，7.055-7.061(t，1H)，7.713-7.734(d，2H)，9.200(s，1H)。
4-(2-methoxyl group-4-ethoxy benzyl is amino)-N-(2-amino-5-fluorophenyl) BM (compound 61)
1HNMR(DMSO-d 6)(δppm)：1.28-1.32(m，3H)，3.72-3.74(m，3H)，3.95-3.97(t，2H)，4.25-4.26(d，2H)，5.13(s，2H)，6.33-6.34(q，1H)，6.50-6.54(dd，1H)，6.61-6.63(d，2H)，6.80-7.07(q，5H)，7.71-7.73(d，2H)，9.20(s，1H)。
4-(4-(cyclopentyl oxygen) benzylamino)-N-(2-amino-5-fluorophenyl) BM (compound 62)
1HNMR(DMSO-d 6)(δppm)：1.57-1.68(q，6H)，1.88-1.89(q，2H)，3.95-3.97(t，2H)，4.24-4.26(d，2H)，4.77(m，1H)，5.11(s，2H)，6.32-6.36(q，1H)，6.50-6.54(dd，1H)，6.60-6.62(d，2H)，6.76-6.79(m，1H)，6.84-6.86(d，2H)，7.04-7.08(t，1H)，7.23-7.25(d，2H)，7.71-7.73(d，2H)，9.17(s，1H)。
Figure GPA00000632129500271
Reaction formula 5
Embodiment 5. synthetic N-(2-amino-5-fluorophenyl)-4 ((4-(3, the 4-difluorophenyl) pyrimidine-2-sulfenyl) methyl) BMs (compound 32)
Step 1. synthesizes 3,3-dimethylamino-1-(3, the 4-difluorophenyl)-acrylketone
With 2g 3, the 4-difluoro acetophenone is dissolved in the 5ml dry DMF, in solution, adds 2.56ml DMAPDMA again; Finish, be heated to 110 ℃ of reactions 3 hours, TCL shows that reaction finishes; Reclaim under reduced pressure DMF, debris places refrigerator overnight, separates out yellow solid; Suction filtration, ethyl acetate/petroleum ether is washed at 1: 1, gets yellow solid 1.86g.
M.p.79-81 ℃ of product fusing point;
Step 2. is synthesized 4-(3, the 4-difluorophenyl) pyrimidine-2-mercaptan
0.17g sodium is dissolved in the 20ml absolute ethyl alcohol, adds the 0.58g thiocarbamide again, 1.60g step 1 product finishes; Temperature rising reflux 4h, TCL show that reaction finishes, and decompression and solvent recovery, residue add the suitable quantity of water dissolving; Transfer the pH slightly acidic with 1N hydrochloric acid, separate out a large amount of yellow solids, filter, be drying to obtain.
Step 3. is synthesized 4-((4-(3, the 4-difluorophenyl) pyrimidine-2-sulfenyl)-methyl) oil of Niobe
The 0.22g sodium hydride is suspended in the 20ml dry DMF, adds 1.40g step 1 product, after half a hour; Add 1.16g 4-chloromethyl benzoic acid methyl esters again, room temperature reaction 6h, TCL show that reaction finishes; In reaction flask, add suitable quantity of water; Promptly separate out a large amount of solids, filter, be drying to obtain look solid 1.76g.
M.p.102.5-104 ℃ of product fusing point;
Step 4. is synthesized 4-((4-(3, the 4-difluorophenyl) pyrimidine-2-sulfenyl)-methyl) phenylformic acid
1.5g step 3 product is suspended in the 15ml methyl alcohol 15/ml water, adds the 0.52g Lithium Hydroxide MonoHydrate, stirred overnight at room temperature, thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue adds the 20ml water dissolution, and using 1N hydrochloric acid to transfer PH is about 5; Leave standstill, filter, promptly get solid 1.29g.
Step 5. is synthesized N-(2-amino-5-fluorophenyl)-4 ((4-(3, the 4-difluorophenyl) pyrimidine-2-sulfenyl) methyl) BM (compound 32)
With 1g step 4 product, 0.46gN, N-phosphinylidyne diimidazole is dissolved in the 8ml anhydrous tetrahydro furan, 45 ℃ of reaction 1.5h, cooling, subsequent use.Get another dry 100ml three-necked bottle, under nitrogen protection, with 0.42g4-fluoro-1, the 2-phenylenediamine is dissolved in the 7ml anhydrous tetrahydro furan; Drip the 0.32g trifluoroacetic acid, drip subsequent use reaction solution again, stirred overnight at room temperature, TCL shows that reaction finishes; Decompression and solvent recovery, residue is crossed silica gel and is leant on, and ethyl acetate/petroleum ether is washed at 2: 1; Elutriant concentrates, and crystallization gets white solid 0.29g.
1HNMR(DMSO-d 6)(δppm)：4.573-4.587(d，2H)，5.221(s，2H)，6.324-6.367(m，1H)，6.508-6.536(dd，1H)，7.071-7.093(q，1H)，7.849-7.929(m，3H)，8.104-8.291(m，2H)，8.737-8.750(d，1H)，9.530(s，1H)。
The synthesis step of following compound 33～38,63～69 is as embodiment 5 (compound 32).
N-(2-amino-5-fluorophenyl)-4 ((4-(3-fluoro-4-methoxyphenyl) pyrimidine-2-sulfenyl) methyl) BM (compound 33)
1HNMR(DMSO-d 6)(δppm)：3.934(s，3H)，4.575(s，2H)，5.205(s，2H)，6.495-6.515(m，1H)，6.712-6.741(dd，1H)，7.152-7.189(q，1H)，7.317-7.361(t，1H)，7.600-7.621(d，2H)，7.774-8.076(m，5H)，8.654-8.668(d，1H)，9.528(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-methylthio group phenyl) pyrimidine-2-sulfenyl) methyl) BM (compound 34)
1HNMR(DMSO-d 6)(δppm)：2.550(s，3H)，4.571-4.954(s，2H)，5.202(s，2H)，6.335-6.363(m，1H)，6.504-6.532(dd，1H)，7.069-7.090(q，1H)，7.406-7.428(d，2H)，7.587-7.608(d，2H)，7.766-7.923(m，3H)，8.140-8.162(d，2H)，8.659-8.672(d，1H)，9.522(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(thiene-3-yl-) pyrimidine-2-sulfenyl) methyl) BM (compound 35)
1HNMR(DMSO-d 6)(δppm)：4.557(S，2H)，5.232(s，2H)，6.321-6.364(m，1H)，6.499-6.535(dd，1H)，7.061-7.099(q，1H)，7.593-7.614(d，2H)，7.672-7.686(d，1H)，7.735-7.755(q，1H)，7.841-7.920(m，3H)，8.552-8.560(m，1H)，8.647-8.660(d，1H)，9.548(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-bromophenyl) pyrimidine-2-sulfenyl) methyl) BM (compound 36)
1HNMR(DMSO-d 6)(δppm)：4.574(s，2H)，5.168(s，2H)，6.361-6.395(m，1H)，6.531-6.566(dd，1H)，7.086-7.102(d，1H)，7.602-7.621(d，2H)，7.772-7.792(d，3H)，7.898-7.914(d，2H)，8.129-8.145(d，2H)，8.710-8.723(d，1H)，9.580(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(pyridine-2-yl) pyrimidine-2-sulfenyl) methyl) BM (compound 37)
1HNMR(DMSO-d 6)(δppm)：4.609(s，2H)，5.203(s，2H)，6.315-6.365(m，1H)，6.501-6.536(dd，1H)，7.066-7.103(q，1H)，7.580-7.631(m，3H)，7.905-8.096(m，4H)，8.458-8.478(d，1H)，8.763-8.811(d，2H)，9.522(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(pyridin-3-yl) pyrimidine-2-sulfenyl) methyl) BM (compound 38)
1HNMR(DMSO-d 6)(δppm)：4.598(s，2H)，5.207(s，2H)，6.322-6.365(m，1H)，6.510-6.541(dd，1H)，7.071-7.093(q，1H)，7.590-7.617(m，3H)，7.902-7.914(m，3H)，8.541-8.562(m，1H)，8.764-8.776(m，2H)，9.360-9.365(t，1H)，9.529(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(pyridin-4-yl) pyrimidine-2-sulfenyl) methyl) BM (compound 63)
1HNMR(DMSO-d 6)(δppm)：4.607(s，2H)，5.227-5.259(q，1H)，5.840-5.820(d，1H)，6.496-6.503(q，1H)，6.708-6.731(dd，1H)，7.145-7.166(t，1H)，7.615-7.635(d，2H)，7.912-7.957(q，3H)，8.134-8.149(d，2H)，8.801-8.833(q，3H)，9.522(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-phenyl pyrimidine-2-sulfenyl) methyl) BM (compound 64)
1HNMR(DMSO-d 6)(δppm)：4.59(s，2H)，5.23(s，2H)，6.33-6.37(q，1H)，6.51-6.54(dd，1H)，7.07-7.11(q，1H)，7.57-7.62(q，5H)，7.81-7.93(q，3H)，8.20-8.22(q，2H)，8.71-8.72(d，1H)，9.55(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-fluoro-3-methylthio group phenyl) pyrimidine-2-sulfenyl) methyl) BM (compound 65)
1HNMR(DMSO-d 6)(δppm)：2.503-2.572(s，3H)，4.580(s，2H)，5.226(s，2H)，6.332-6.365(q，1H)，6.501-6.537(dd，1H)，7.063-7.101(t，1H)，7.484-7.525(m，1H)，7.592-7.613(d，2H)，7.839-7.852(d，1H)，7.907-7.928(d，2H)，8.013-8.047(dd，1H)，8.102-8.106(dd，1H)，9.548(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-p-methoxy-phenyl) pyrimidine-2-sulfenyl) methyl) BM (compound 66)
1HNMR(DMSO-d 6)(δppm)：3.832-3.849(s，3H)，4.568(s，2H)，5.231(s，2H)，6.325-6.368(q，1H)，6.506-6.541(dd，1H)，7.089-7.119(q，3H)，7.591-7.745(q，3H)，7.908-7.928(d，2H)，8.182-8.205(q，2H)，8.621-8.635(d，1H)，9.550(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-(cyclopentyl oxygen) phenyl) pyrimidine-2-sulfenyl) methyl) BM (compound 67)
1HNMR(DMSO-d 6)(δppm)：1.72-1.73(q，6H)，1.96-1.99(q，2H)，4.56(s，2H)，4.91-4.93(q，1H)，5.23(s，2H)，6.34-6.37(q，1H)，6.51-6.54(dd，1H)，7.05-7.10(q，3H)，7.59-7.73(q，3H)，7.91-7.97(q，2H)，8.12-8.17(q，2H)，8.61-8.62(d，1H)，9.55(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-ethoxyl phenenyl) pyrimidine-2-sulfenyl) methyl) BM (compound 68)
1HNMR(DMSO-d 6)(δppm)：1.34-1.38(m，3H)，4.10-4.13(t，2H)，4.56(s，2H)，，6.32-6.36(q，1H)，6.50-6.54(dd，1H)，7.07-7.11(q，3H)，7.58-7.60(q，3H)，7.90-7.92(d，2H)，8.16-8.18(d，2H)，8.61-8.63(d，1H)，9.52(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((4-(4-n-butoxy phenyl) pyrimidine-2-sulfenyl) methyl) BM (compound 69)
1HNMR(DMSO-d 6)(δppm)：0.93-0.96(m，3H)，1.44-1.46(q，2H)，1.71-1.73(q，2H)，4.05-4.08(q，2H)，4.56(s，2H)，5.23(s，2H)，6.34-6.37(q，1H)，6.50-6.54(dd，1H)，7.06-7.10(q，3H)，7.59-7.74(q，3H)，7.90-7.92(q，2H)，8.16-8.18(q，2H)，8.61-8.63(d，1H)，
Figure GPA00000632129500301
R 1=H R 2=OCH 3R 3=H compound 39
R 1=H R 2=OCH 3R 3=OCH 3Compound 40
R 1=OCH 3R 2=OCH 3R 3=OCH 3Compound 41
R 1=H R 2=H R 3=H compound 70
R 1=H R 2=F R 3=H compound 71
R 1=H R 2=Cl R 3=H compound 72
R 1=H R 2=H R 3=CH 3Compound 73
R 1=H R 2=CF 3R 3=H compound 74
R 1=H R 2=OCF 3R 3=H compound 75
Reaction formula 6
Embodiment 6. synthetic N-(2-amino-5-fluorophenyl)-3-(4-((the 4-anisole is amino) methyl) Phenyl Acrylamide (compound 39)
Step 1. is synthesized 3-(4-((the 4-p-methoxy-phenyl is amino) methyl) phenyl) methyl acrylate hydrochloride
2g is dissolved in the 15ml methyl alcohol aminoanisole and 3.09g 4-aldehyde radical cinnamic acid methyl esters, adds 3.07g NaBH under the ice bath in batches 4, and dropping Glacial acetic acid min. 99.5 maintenance reaction solution PH 5～6, thin-layer chromatography shows that reaction finishes, and decompression desolventizes, and residue is allocated in ETHYLE ACETATE/water, is adjusted to acidity with 2N hydrochloric acid, separates out a large amount of white solids, filters, and drying gets white solid 3.10g.
Step 2. is synthesized 3-(4-((the 4-p-methoxy-phenyl is amino) methyl) phenyl) vinylformic acid
3.10g step 2 product is suspended in the 8mlTHF/8ml water, adds the 0.66g Lithium Hydroxide MonoHydrate, stirred overnight at room temperature, thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue adds the 20ml water dissolution, and using 1N hydrochloric acid to transfer PH is about 5; Leave standstill, filter, promptly get white solid 2.99g.
M.p.176.5-178.5 ℃ of product fusing point;
Step 3. is synthesized N-(2-amino-5-fluorophenyl)-3-(4-((the 4-anisole is amino) methyl) Phenyl Acrylamide (compound 39)
With step 3 product 2.50g, N, N-phosphinylidyne diimidazole 1.44g is dissolved in the 10ml anhydrous tetrahydro furan, 45 ℃ of reaction 1.5h, cooling, subsequent use.Get another three-necked bottle, under nitrogen protection, with 1.33g4-fluoro-1, the 2-phenylenediamine is dissolved in the anhydrous tetrahydro furan; Drip the 1.01g trifluoroacetic acid, drip subsequent use reaction solution again, the stirring at room reaction is spent the night, and thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue is crossed silicagel column, and ethyl acetate/petroleum ether is washed at 1: 2; Elutriant concentrates, and crystallization gets white solid 1.57g
1HNMR(DMSO-d 6)(δppm)：3.605(s，3H)，4.238-4.276(d，2H)，5.238(s，2H)，6.325-6.367(m，1H)，6.496-6.532(m，4H)，6.675-6.691(d，2H)，6.800-6.840(d，1H)，7.257-7.294(q，1H)，7.390-7.421(d，2H)，7.497-7.607(m，3H)，7.445-7.465(d，2H)，7.907-7.928(d，2H)，9.543(s，1H)。
The synthesis step of following compound 40～41,70～75 is as embodiment 6 (compound 39).
N-(2-amino-5-fluorophenyl)-3-(4-((3,4-dimethoxy phenylamino) methyl) Phenyl Acrylamide (compound 40)
1HNMR(DMSO-d 6)(δppm)：3.592(s，3H)，3.655(s，3H)，4.239-4.254(d，2H)，5.261(s，2H)，5.905-5.935(t，1H)，5.994-6.022(dd，1H)，6.320-6.370(m，2H)，6.502-6.538(dd，1H)，6.653-6.675(d，1H)，6.803-6.843(d，1H)，7.256-7.293(q，1H)，7.410-7.430(d，2H)，7.500-7.572(m，3H)，9.319(s，1H)。
N-(2-amino-5-fluorophenyl)-3-(4-((2,3,4-trimethoxy phenylamino) methyl) Phenyl Acrylamide (compound 41)
1HNMR(DMSO-d 6)(δppm)：3.504(s，3H)，3.644(s，6H)，4.263-4.274(d，2H)，5.274(s，2H)，5.887(s，2H)，6.070-6.084(t，1H，6.324-6.369(m，1H)，6.502-6.534(dd，1H)，6.807-6.846(d，1H)，7.254-7.292(q，1H)，7.425-7.446(d，2H)，7.502-7.582(q，3H)，9.328(s，1H)。
N-(2-amino-5-fluorophenyl)-3-(4-phenylamino methyl) Phenyl Acrylamide (compound 70)
1HNMR(DMSO-d 6)(δppm)：4.28-4.30(d，2H)，5.27(s，2H)，6.29-6.37(q，2H)，6.49-6.57(q，4H)，6.80-6.84(d，1H)，7.02-7.06(t，2H)，7.25-7.29(t，1H)，7.41-7.58(q，5H)，9.33(s，1H)。
N-(2-amino-5-fluorophenyl)-3-(4-(4-fluoroanilino) methyl) Phenyl Acrylamide (compound 71)
1HNMR(DMSO-d 6)(δppm)：4.26-4.27(d，2H)，5.25(s，2H)，6.20-6.23(m，1H)，6.33-6.37(q，1H)，6.53-6.57(q，3H)，6.80-6.96(q，3H)，7.26-7.29(t，1H)，7.40-7.42(d，2H)，7.50-7.57(q，3H)，9.31(s，1H)。
N-(2-amino-5-fluorophenyl)-3-(4-(the 4-chlorobenzene is amino) methyl) Phenyl Acrylamide (compound 72)
1HNMR(DMSO-d 6)(δppm)：4.28-4.30(d，2H)，5.27(s，2H)，6.34-6.37(q，1H)，6.53-6.57(q，4H)，6.80-6.84(d，1H)，7.05-7.07(d，2H)，7.25-7.29(t，1H)，7.39-7.41(d，2H)，7.50-7.58(q，3H)，9.34(s，1H)。
N-(2-amino-5-fluorophenyl)-3-(4-(the 3-methylbenzene is amino) methyl) Phenyl Acrylamide (compound 73)
1HNMR(DMSO-d 6)(δppm)：2.12(s，3H)，4.25-4.27(d，2H)，5.25(s，2H)，6.04-6.07(m，1H)，6.32-6.53(q，4H)，6.80-6.86(q，3H)，7.26-7.56(q，6H)，9.31(s，1H)。
N-(2-amino-5-fluorophenyl)-3-(4-(4-trifluoromethyl phenylamino) methyl) Phenyl Acrylamide (compound 74)
1HNMR(DMSO-d 6)(δppm)：4.35-4.37(d，2H)5.26(s，2H)，6.33-6.37(q，1H)，6.50-6.53(dd，1H)，6.80-6.85(q，5H)，7.23-7.29(t，2H)，7.41-7.43(d，2H)，7.50-7.59(q，3H)，9.33(s，1H)。
N-(2-amino-5-fluorophenyl)-3-(4-(4-trifluoromethoxy phenylamino) methyl) Phenyl Acrylamide (compound 75)
1HNMR(DMSO-d 6)(δppm)：4.30-4.31(d，2H)，5.27(s，2H)，6.33-6.37(q，1H)，6.50-6.63(q，4H)，6.81-6.85(d，1H)，7.03-7.05(d，2H)，7.25-7.29(q，1H)，7.41-7.43(d，2H)，7.50-7.59(q，3H)，9.34(s，1H)。
Figure GPA00000632129500321
Reaction formula 7
Embodiment 7. synthetic 6-(4-methoxybenzyl ammonia)-N-(2-amino-5-fluorophenyl)-nicotinic acid amides (compound 42)
Step 1. is synthesized 6-(4-methoxybenzylamine) nicotinic acid
With 1g 6-chlorine nicotinic acid, 1.26g is to emilium tosylate, 1.3g K 2CO 3, the 20ml dry DMF adds in the reaction flask, is warming up to 150 ℃, reaction 6h; Thin-layer chromatography shows that reaction finishes, and in reaction flask, adds suitable quantity of water, and with ethyl acetate extraction once, water layer is transferred PH6～7 with 1N hydrochloric acid; Separate out a large amount of white solids, filter, drying promptly gets 1.67g.
M.p.221-223 ℃ of product fusing point;
Step 2. is synthesized 6-(4-methoxybenzyl ammonia)-N-(2-amino-5-fluorophenyl)-nicotinic acid amide (compound 42)
With 1g step 1 product, 0.64gN, N-phosphinylidyne diimidazole is dissolved in the 8ml anhydrous tetrahydro furan, 45 ℃ of reaction 1.5h, cooling, subsequent use.Get another dry 100ml three-necked bottle, under nitrogen protection, with 0.6g4-fluoro-1, the 2-phenylenediamine is dissolved in the 7ml anhydrous tetrahydro furan; Drip the 0.44g trifluoroacetic acid, drip subsequent use reaction solution again, stirred overnight at room temperature, thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue is crossed silica gel and is leant on, and ethyl acetate/petroleum ether is washed at 3: 2; Elutriant concentrates, and crystallization gets white solid 0.31g.
1HNMR(DMSO-d 6)(δppm)：3.715(S，3H)，4.529-4.543(d，2H)，5.266(s，2H)，6.302-6.345(m，1H)，6.487-6.522(dd，1H)，6.623-6.654(q，1H)，6.862-6.883(d，2H)，7.011-7.049(q，1H)，7.248-7.269(d，2H)，8.191-8.207(m，2H)，8.516(t，1H)，9.554(s，1H)。
The synthesis step of following compound 43～44,76 is as embodiment 7 (compound 42)
N-(2-amino-5-fluorophenyl)-6-((3, the 4-methylenedioxyphenyl) methylamino) nicotinic acid amide (compound 43)
1HNMR(DMSO-d 6)(δppm)：4.512-4.526(d，2H)，5.253(s，2H)，5.961(s，2H)，6.305-6.348(m，1H)，6.491-6.656(m，2H)，6.814-7.059(m，4H)，8.187-8.203(m，2H)，8.491-8.519(t，1H)，9.543(s，1H)。
N-(2-amino-5-fluorophenyl)-6-(2-(1H-indol-3-yl) ethylamino) nicotinic acid amide (compound 44)
1HNMR(DMSO-d 6)(δppm)：2.964-2.983(t，2H)，3.690-3.704(q，2H)，5.222(s，2H)，6.316-6.359(m，1H)，6.498-6.620(m，2H)，6.964-7.172(m，4H)，7.313-7.333(d，1H)，7.573-7.593(d，1H)，8.114-8.288(m，3H)，9.486(s，1H)，10.796(s，1H)。
6-(2-benzyl) ethylamino-N-(2-amino-5-fluorophenyl)-nicotinic acid amide (compound 76)
1HNMR(DMSO-d 6)(δppm)：2.853-2.871(m，2H)，3.633-3.648(t，2H)，5.28(s，2H)，6.331-6.334(q，1H)，6.599-6.630(q，2H)，7.253-7.285(q，6H)，8.213-8.225(q，3H)，9.499(s，1H)。
Figure GPA00000632129500331
Reaction formula 8
Embodiment 8. synthetic N-(2-amino-5-fluorophenyl)-5-((3, the 4-methylene dioxy phenyl group) methylamino)-benzofuran-2-carboxamides (compound 45)
Step 1. is synthesized 5-nitrobenzofuran-2-ethyl formate
With 1.0g 2-hydroxyl-5-nitrobenzaldehyde and 1.65 gram K 2CO 3Be dissolved in 20mlN, in the dinethylformamide, behind the stirring reaction 1h, slowly drip 0.67 METHYL BROMOACETATE again under the room temperature; Finish and be warming up to 80 ℃ of reaction 3h, thin-layer chromatography shows that reaction finishes, cooling; The thin up reaction solution filters, and obtains yellow-gray solid 1.53g.
The amino cumarone of the synthetic 5-of step 2.-2-ethyl formate
1.40 gram iron powders and 0.51 gram NaCl are added in the three-necked bottle of 100ml, and add 6.63ml H 2O and 0.15ml30%HCl finish, and are warming up to 100 ℃ of backflow 1h.Keep adding 1.51g 5-nitrobenzofuran-2-ethyl formate (step 1 product) under this temperature, continue backflow 3h, thin-layer chromatography shows that reaction finishes, and cooling is filtered, washing, and ETHYLE ACETATE is washed, and collects ethyl acetate layer, anhydrous MgSO 4Drying is filtered, and reclaim under reduced pressure ETHYLE ACETATE gets synthetic 5-((3, the 4-methylene dioxy phenyl group) methylamino) the coumarilic acid carbethoxy hydrochloride of faint yellow oily thing 1.16g step 3.
With 1.10g3,4-(methylenedioxy) phenyl aldehyde and 1.50g step 2 product are dissolved in the 15ml methyl alcohol, add 3.07g NaBH under the ice bath in batches 4, and dropping Glacial acetic acid min. 99.5 maintenance reaction solution pH 5～6, thin-layer chromatography shows that reaction finishes, and decompression desolventizes, and residue is allocated in ETHYLE ACETATE/water, is adjusted to acidity with 5N hydrochloric acid, separates out a large amount of white solids, filters, and drying gets white solid 1.96g
Step 4. is synthesized 5-((3, the 4-methylene dioxy phenyl group) methylamino) coumarilic acid
1.56g step 3 product is suspended in 8ml THF/8ml water, adds the 0.53g Lithium Hydroxide MonoHydrate, stirred overnight at room temperature, thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue adds the 20ml water dissolution, and using 1N hydrochloric acid to transfer PH is about 5; Leave standstill, filter, promptly get white solid 1.30g.
Step 5. is synthesized N-(2-amino-5-fluorophenyl)-5-((3, the 4-methylene dioxy phenyl group) methylamino)-benzofuran-2-carboxamides (compound 45)
With step 4 product 0.68g, N, N-phosphinylidyne diimidazole 0.358g is dissolved in the 10ml anhydrous tetrahydro furan, 45 ℃ of reaction 1.5h, cooling, subsequent use.Get another three-necked bottle, under nitrogen protection, with 0.331g 4-fluoro-1, the 2-phenylenediamine is dissolved in the anhydrous tetrahydro furan; Drip the 0.36g trifluoroacetic acid, drip subsequent use reaction solution again, the stirring at room reaction is spent the night, and thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue is crossed silicagel column, and ethyl acetate/petroleum ether is washed at 1: 2; Elutriant concentrates, and crystallization gets white solid 0.38g
M.p.205.5-206 ℃ of product fusing point;
1HNMR(DMSO-d 6)(δppm)：4.195-4.210(d，2H)，5.253(s，2H)，5.971(s，2H)，6.150-6.180(t，1H)，6.338-6.381(m，1H)，6.520-6.556(dd，1H)，6.727-6.733(d，1H)，6.848-6.874(m，3H)，6.953-6.955(d，1H)，7.099-7.137(q，1H)，7.376-7.398(d，1H)，7.422(s，1H)，9.656(s，1H)。
The synthesis step of following compound 46～50,77～81 is as embodiment 8 (compound 45)
N-(2-amino-5-fluorophenyl)-5-(4-(dimethylamino) aminotoluene base)-benzofuran-2-carboxamides (compound 46)
11HNMR(DMSO-d 6)(δppm)：2.854(s，6H)，4.145-4.159(d，2H)，5.250(s，2H)，6.007-6.035(t，1H)，6.338-6.373(m，1H)，6.521-6.549(dd，1H)，6.686-6.738(q，3H)，6.855-6.883(dd，1H)，7.101-7.224(m，3H)，7.362-7.384(d，1H)，7.439(s，1H)，9.649(s，1H)。
N-(2-amino-5-fluorophenyl)-5-(4-fluorobenzene methylamino-)-benzofuran-2-carboxamides (compound 47)
HNMR(DMSO-d 6)(δppm)：4.280-4.294(d，2H)，5.253(s，2H)，6.221-6.251(t，1H)，6.338-6.380(m，1H)，6.521-6.556(dd，1H)，6.726-6.731(d，1H)，6.856-6.885(dd，1H)，7.099-7.175(m，3H)，7.382-7.448(m，4H)，9.657(s，1H)。
N-(2-amino-5-fluorophenyl)-5-(2-fluorobenzene methylamino-)-benzofuran-2-carboxamides (compound 48)
1HNMR(DMSO-d 6)(δppm)：4.34-4.35(d，2H)，5.25(s，2H)，6.17-6.20(t，1H)，6.35-6.38(m，1H)，6.52-6.55(dd，1H)，6.75-6.76(d，1H)，6.88-6.90(dd，1H)，7.11-7.45(m，7H)，9.66(s，1H)。
N-(2-amino-5-fluorophenyl)-5-(2-chlorobenzene methylamino-)-benzofuran-2-carboxamides (compound 49)
1HNMR(DMSO-d 6)(δppm)：4.37-4.38(d，2H)，5.25(s，2H)，6.29-6.36(m，2H)，6.52-6.55(dd，1H)，6.67-6.20(d，1H)，6.87-6.89(dd，1H)，7.11-7.13(q，1H)，7.28-7.48(m，6H)，9.66(s，1H)。
N-(2-amino-5-fluorophenyl)-5-(2,4 dichloro benzene methylamino-)-benzofuran-2-carboxamides (compound 50)
1HNMR(DMSO-d 6)(δppm)：4.35-4.36(d，2H)，5.25(s，2H)，6.33-6.38(m，2H)，6.52-6.67(m，2H)，6.86-6.88(dd，1H)，7.10-7.14(q，1H)，7.41-7.45(m，4H)，7.63-7.64(d，1H)，9.67(s，1H)。
N-(2-amino-5-fluorophenyl)-5-(3,4-difluoro aminotoluene base)-benzofuran-2-carboxamides (compound 77)
1HNMR(DMSO-d 6)(δppm)：4.292-4.306(d，2H)，5.271(s，2H)，6.317-6.377(q，2H)，6.513-6.548(dd，1H)，6.714-6.720(d，1H)，6.847-6.875(dd，1H)，7.086-7.123(t，1H)，7.248(s，1H)，7.378-7.450(q，4H)，9.688(s，1H)。
N-(2-amino-5-fluorophenyl)-5-(2-anisole methylamino-)-benzofuran-2-carboxamides (compound 78)
1HNMR(DMSO-d 6)(δppm)：3.853(s，3H)，4.246-4.261(d，2H)，5.250(s，2H)，6.024-6.054(m，1H)，6.339-6.381(q，1H)，6.522-6.557(dd，1H)，6.687-6.692(d，1H)，6.859-6.902(q，2H)，7.002-7.022(d，1H)，7.100-7.138(t，1H)，7.212-7.296(q，2H)，7.379-7.441(q，2H)，9.658(s，1H).
N-(2-amino-5-fluorophenyl)-5-(4-anisole methylamino-)-benzofuran-2-carboxamides (compound 79)
1HNMR(DMSO-d 6)(δppm)：3.724(s，3H)，4.207-4.222(d，2H)，5.275(s，2H)，6.150-6.179(m，1H)，6.338-6.381(q，1H)，6.518-6.553(dd，1H)，6.723-6.728(d，1H)，6.855-6.909(q，3H)，7.092-7.130(t，1H)，7.307-7.443(q，4H)，9.686(s，1H)。
N-(2-amino-5-fluorophenyl)-5-(3,4-dimethoxy benzene methylamino-)-benzofuran-2-carboxamides (compound 80)
1HNMR(DMSO-d 6)(δppm)：3.737(s，6H)，4.201-4.215(d，2H)，5.276(s，2H)，6.156-6.157(m，1H)，6.352-6.359(q，1H)，6.515-6.550(dd，1H)，6.740-6.745(d，1H)，6.885-6.911(q，3H)，7.015-7.016(d，1H)，7.090-7.128(t，1H)，7.379-7.451(q，2H)，9.687(s，1H)。
N-(2-amino-5-fluorophenyl)-5-(pyridin-3-yl-methylamino)-benzofuran-2-carboxamides (compound 81)
1HNMR(DMSO-d 6)(δppm)：4.332-4.347(d，2H)，5.276(s，2H)，6.309-6.358(q，2H)，6.513-6.549(dd，1H)，6.764-6.770(d，1H)，6.868-6.898(dd，1H)，7.087-7.125(t，1H)，7.356-7.451(q，3H)，7.780-7.800(q，1H)，8.443-8.455(dd，1H)，8.622-8.627(d，1H)，9.694(s，1H).
Figure GPA00000632129500351
Reaction formula 9
Embodiment 9. synthetic N-(2-amino-5-methoxyphenyl)-4 ((4-(pyridine-3 base) pyrimidine-2-is amino) methyl) benzamide (compound 97)
Step 1. synthesizes 3,3-dimethylamino-1-pyridin-3-yl-acrylketone
The 2g3-acetylpyridine is dissolved in the 5ml dry DMF, in solution, adds 5ml DMAPDMA again, finish; Be heated to 110 ℃ of reactions 3 hours, thin-layer chromatography shows that reaction finishes reclaim under reduced pressure DMF; Debris places refrigerator overnight, separates out yellow solid, suction filtration; Ethyl acetate/petroleum ether is washed at 1: 1, gets yellow solid 2.05g.
M.p.82-83 ℃ of MS of product fusing point (FAB);
Step 2. is synthesized 4-guanidine radicals methyl-phenylformic acid
The 2g methyl-isourea is dissolved in the 10ml 1mol/LNaOH aqueous solution, slowly drips 2.15g 4-aminomethyl phenyl formic acid under the ice bath, finish, stirring reaction spends the night under the room temperature, separates out white solid, filters, and drying gets white solid 2.56g.
Step 3. is synthesized 4-[(4-pyridin-3-yl-pyrimidine-2-base-amino)-methyl] phenylformic acid
1.57g step 1 product and 1.88g step 2 product are dissolved in the 10ml Virahol, add 1.26gK2CO3 simultaneously, finish, temperature rising reflux 12h, thin-layer chromatography demonstration reaction finishes, and cooling is filtered, and drying gets white solid 1.87g.
M.p.219.5-221 ℃ of product fusing point;
Step 4. is synthesized N-(2-amino-5-fluorophenyl)-4 ((4-(pyridine-3 base) pyrimidine-2-is amino) methyl) benzamide (compound 1)
With 1g step 3 product, 0.54gN, N-phosphinylidyne diimidazole is dissolved in the 8ml anhydrous tetrahydro furan, 45 ℃ of reaction 1.5h, cooling, subsequent use.Get another dry 100ml three-necked bottle, under nitrogen protection, with 0.52g4-fluoro-1, the 2-phenylenediamine is dissolved in the 7ml anhydrous tetrahydro furan; Drip the 0.38g trifluoroacetic acid, drip subsequent use reaction solution again, stirred overnight at room temperature; Thin-layer chromatography shows that reaction finishes, decompression and solvent recovery, and residue is crossed silica gel and is leant on, and ethyl acetate/petroleum ether/ethanol is washed at 2: 1: 2; Elutriant concentrates, and crystallization gets white solid 0.28g.
M.p.165-167 ℃ of product fusing point;
1HNMR(DMSO-d6)(ppm)：3.641-3.670(d，3H)，4.636-4.649(d，2H)，5.212(s，2H)，6.150-6.178(dd，1H)，6.330-6.337(d，1H)，δ6.969-6.991(d，1H)，7.262-7.274(d，1H)，7.492-7.531(m，3H)，7.901-8.045(m，3H)，8.407-8.420(d，2H)，8.680-8.690(d，1H)，9.246(s，1H)，9.475(d，1H)
Embodiment 98-102 compound is pressed the step of embodiment 9 and is synthesized
N-(2-amino-5-methoxyphenyl)-4 ((4-(4-ethoxyl phenenyl) pyrimidine-2-is amino) methyl) benzamide (compound 98)
M.p.215-217 ℃ of product fusing point;
1HNMR(DMSO-d 6)(δppm)：1.328-1.363(m，3H)，3.670(s，3H)，4.066-4.101(dd，2H)，4.620-4.634(d，2H)，4.877(s，2H)，6.159-6.180(dd，1H)，6.334-6.340(d，1H)，6.997-7.104(m，4H)，7.453-7.473(d，2H)，7.751-8.048(m，5H)，8.277-8.289(d，1H)，9.443(s，1H)。
N-(2-amino-5-methoxyphenyl)-4 ((4-(4-p-methoxy-phenyl) pyrimidine-2-is amino) methyl) benzamide (compound 99)
M.p.183-186 ℃ of product fusing point;
1HNMR(DMSO-d 6)(δppm)：3.562-3.670(m，3H)，3.818(s，3H)，4.620-4.632(d，2H)，4.899(s，2H)，6.158-6.180(dd，1H)，6.333-6.339(d，1H)，7.028-7.117(m，4H)，7.460-7.475(d，2H)，7.815-7.917(m，3H)，8.046-8.067(d，2H)，8.283-8.296(d，2H)，9.469(s，1H)。
N-(2-amino-5-methoxyphenyl)-4 ((4-(4-methoxyl group-5-fluorophenyl) pyrimidine-2-is amino) methyl) benzamide (compound 100)
M.p.219-222 ℃ of product fusing point;
1HNMR(DMSO-d 6)(δppm)：4.361-3.670(s，3H)，3.903(s，3H)，4.616-4.631(d，2H)，4.901(s，2H)，6.151-6.180(dd，1H)，6.330-6.337(d，1H)，6.968-6.990(d，1H)，7.162-7.277(m，2H)，7.474(m，2H)，7.898-7.944(m，5H)，8.315-8.328(d，1H)，9.474(s，1H)。
N-(2-amino-5-methoxyphenyl)-4 ((4-(4, the 5-difluorophenyl) pyrimidine-2-is amino) methyl) benzamide (compound 101)
1HNMR(DMSO-d 6)(δppm)：3.63-3.672(s，3H)，4.629-4.644(d，2H)，4.879(s，2H)，6.154-6.182(dd，1H)，6.334-6.341(d，1H)，6.974-6.996(d，1H)，7.217-7.230(d，1H)，7.457-7.580(m，3H)，7.900-7.967(m，4H)，8.121(m，1H)，8.381-8.393(d，1H)，9.450(s，1H)。
N-(2-amino-5-methoxyphenyl)-4 ((4-(4-bromophenyl) pyrimidine-2-is amino) methyl) benzamide (compound 102)
M.p.212-215 ℃ of product fusing point;
1HNMR(DMSO-d 6)(δppm)：3.565-3.673(s，3H)，4.629-4.644(d，2H)，4.833(s，2H)，6.156-6.184(dd，1H)，6.339-6.345(d，1H)，6.980-7.001(dd，1H)，7.177-7.191(d，1H)，7.460-7.77(d，2H)，7.69-7.714(d，2H)，7.900-7.942(m，3H)，8.024-8.045(d，2H)，8.369-8.382(d，1H)，9.451(s，1H)。
Figure GPA00000632129500381
Reaction formula 10
Embodiment 10. synthetic N-(2-amino-5-methoxyphenyl)-4 ((6-phenyl pyrimidine-4-is amino) methyl) BM (compound 91)
Step 1. is synthesized the paraaminomethyl benzoic acid methyl ester hydrochloride
Take by weighing the 2g paraaminomethyl benzoic acid and be suspended in the 100ml methyl alcohol, ice bath slowly drips the 2ml thionyl chloride down, finishes; Continued stirring reaction under the room temperature 3 hours, 50 ℃ of back flow reaction are 3 hours again, and the reaction of some plate is complete basically; Ethyl acetate extraction; Saturated sodium carbonate is washed, dried over mgso, and condensing crystal gets the 2.05g white solid.
Step 2. is synthesized 4-((6-chloropyrimide-4-is amino) methyl) oil of Niobe
With 9.5g paraaminomethyl benzoic acid methyl ester hydrochloride be dissolved in 250mlTHF/DMF (=5: in the mixing solutions 1), drip the 20ml triethylamine, treat into suspendible after; Add 4 of 7g, the 6-dichloro pyrimidine, 70 ℃ of following stirring and refluxing were reacted 15 hours; Separate out white solid and separate out, filter, washing; Drying gets white solid 13.8g.
Step 3. is synthesized 4-((6-phenyl pyrimidine-4-is amino) methyl) phenylformic acid
Take by weighing the 0.2836g triphenyl phosphorus and the 0.1214g palladium is dissolved in 10ml1, in the 4-dioxane, under the nitrogen protection in 80 ℃ of reactions 1 hour, after the some plate reacts completely; Add 50ml second cyanogen/water (=3: mixed solvent 2), and adding 1.5g4-((6-chloropyrimide-4-is amino) methyl) oil of Niobe, 1.12g salt of wormwood and 0.1g Sodium Bromide, reaction under 90 ℃; After half a hour, add the 0.79g phenylo boric acid, reaction is spent the night; The point plate reacts completely, and puts and is chilled to 60 ℃, suction filtration; The outstanding steaming transfers PH=5-6 a large amount of solids to occur with hydrochloric acid, and suction filtration is drying to obtain.
Step 4. is synthesized N-(2-amino-5-methoxyphenyl)-4 ((6-phenyl pyrimidine-4-is amino) methyl) BM
With 0.3g4-((6-phenyl pyrimidine-4-is amino) methyl) phenylformic acid and 0.16g N, N-phosphinylidyne diimidazole is dissolved in the 8ml anhydrous tetrahydro furan, 50 ℃ of back flow reaction 1.5h, and cooling, subsequent use.Get another dry 100ml three-necked bottle, under nitrogen protection, with 0.14g4-methoxyl group-1, the 2-phenylenediamine is dissolved in the 7ml anhydrous tetrahydro furan; Drip the 0.12g trifluoroacetic acid, drip subsequent use reaction solution again, stirred overnight at room temperature, TCL shows that reaction finishes; Decompression and solvent recovery, residue is crossed silica gel and is leant on, and ETHYLE ACETATE/ethanol is washed at 7: 1; Elutriant concentrates, and crystallization gets white solid 0.15g.
1HNMR(DMSO-d 6)(δppm)：3.650-3.677(s，3H)，4.633-4.675(d，2H)，4.895(s，2H)，6.168-6.189(dd，1H)，6.344-6.350(d，1H)，6.989-7.026(d，2H)，7.050-7.502(m，6H)，7.926-8.060(m，6H)，8.515(s，1H)，9.477(s，1H)。
Following compound 92～96,103～119,123～124 synthesis step is as embodiment 10 (compound 91).
N-(2-amino-5-methoxyphenyl)-4 ((6-(3-p-methoxy-phenyl) pyrimidine-4-is amino) methyl) BM (compound 92)
1HNMR(DMSO-d 6)(δppm)：3.647-3.674(s，3H)，3.821(s，3H)，4.655-4.669(d，2H)，4.892(s，2H)，6.165-6.186(dd，1H)，6.339-6.346(d，1H)，6.984-7.038(m，3H)，7.388-7.564(m，5H)，7.919-8.032(m，3H)，8.506(s，1H)，9.471(s，1H)。
N-(2-amino-5-methoxyphenyl)-4 ((6-(4-p-methoxy-phenyl) pyrimidine-4-is amino) methyl) BM (compound 93)
1HNMR(DMSO-d 6)(δppm)：3.674(s，3H)，3.815(s，3H)，4.644-4.656(d，2H)，4.892(s，2H)，6.165-6.186(dd，1H)，6.339-6.346(d，1H)，6.983-7.052(m，4H)，7.39-7.59(d，2H)，7.917-7.980(dd，5H)，8.460(s，1H)，9.496(s，1H)。
N-(2-amino-5-methoxyphenyl)-4 ((6-(3-pyridyl) pyrimidine-4-is amino) methyl) BM (compound 94)
1HNMR(DMSO-d 6)(δppm)：3.647-3.674(s，3H)，4.667-4.681(d，2H)，4.892(s，2H)，6.165-6.187(dd，1H)，6.339-6.346(d，1H)，6.984-7.096(m，2H)，7.449-7.527(m，3H)，7.922-7.943(d，2H)，8.130-8.162(t，1H)，8.334-8.353(d，1H)，8.544-8.678(m，2H)，9.196(s，1H)，9.473(s，1H)。
N-(2-amino-5-methoxyphenyl)-4 ((6-(3, the 4-methylenedioxyphenyl) pyrimidine-4-is amino) methyl) BM (compound 95)
1HNMR(DMSO-d 6)(δppm)：3.647-3.674(s，3H)，4.641-4.653(d，2H)，4.890(s，2H)，6.092(s，2H)，6.164-6.186(dd，1H)，6.338-6.345(s，1H)，7.004-7.031(m，3H)，7.435-7.541(m，4H)，7.915-7.935(m，3H)，8.450(s，1H)，9.468(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((6-phenyl pyrimidine-4-is amino) methyl) BM (compound 103)
1HNMR(DMSO-d 6)(δppm)：4.665-4.667(s，2H)，5.205(s，2H)，6.330-6.373(m，1H)，6.516-6.551(dd，1H)，7.026(s，1H)，7.085-7.122(t，1H)，7.478-7.502(m，6H)，7.930-8.066(m，6H)，8.514(s，1H)，9.535(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((6-(3-p-methoxy-phenyl) pyrimidine-4-is amino) methyl) BM (compound 104)
1HNMR(DMSO-d 6)(δppm)：3.821(s，3H)，4.661-4.673(s，2H)，5.226(s，2H)，6.330-6.373(m，1H)，6.517-6.546(dd，1H)，7.041-7.097(m，3H)，7.392-7.469(m，3H)，7.548-7.567(s，2H)，7.928-7.949(d，2H)，8.057-8.088(t，1H)，8.506(s，1H)，9.556(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((6-(4-p-methoxy-phenyl) pyrimidine-4-is amino) methyl) BM (compound 105)
1HNMR(DMSO-d 6)(δppm)：3.815(s，3H)，4.646-4.660(s，2H)，5.203(s，2H)，6.328-6.371(m，1H)，6.513-6.548(dd，1H)，6.942-7.119(m，4H)，7.448-7.468(d，2H)，7.924-7.981(m，5H)，8.458-8.3460(s，1H)，9.531(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((6-(3-pyridyl) pyrimidine-4-is amino) methyl) BM (compound 106)
1HNMR(DMSO-d 6)(δppm)：4.669-4.682(s，2H)，5.202(s，2H)，6.342-6.349(m，1H)，6.511-6.547(dd，1H)，7.079-7.117(t，2H)，7.454-7.535(m，3H)，7.927-7.948(d，2H)，8.135-8.165(t，1H)，8.334-8.354(d，1H)，8.544-8.674(m，2H)，9.170(s，1H)，9.532(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((6-(3, the 4-methylenedioxyphenyl) pyrimidine-4-is amino) methyl) BM (compound 107)
1HNMR(DMSO-d 6)(δppm)：4.643-4.825(d，2H)，5.201(s，2H)，6.093(s，2H)，6.328-6.371(m，1H)，6.512-6.547(dd，1H)，6.924-7.118(m，3H)，7.446-7.586(m，5H)，7.921-7.974(m，4H)，8.450(s，1H)，9.527(s，1H)。
N-(2-amino-5-fluorophenyl)-4 ((6-(2, the 4-Dimethoxyphenyl) pyrimidine-4-is amino) methyl) BM (compound 108)
1HNMR(DMSO-d 6)(δppm)：3.818-.083(d，6H)，4.607(s，2H)，5.201(s，2H)，6.330-6.373(m，1H)，6.514-6.655(m，3H)，7.084-7.121(q，2H)，7.436-7.457(d，2H)，7.913-7.964(m，4H)，8.432(s，1H)，9.533(s，1H)。
N-(2-amino-5-p-methoxy-phenyl)-4 ((2-methyl-6-phenyl pyrimidine-4-is amino) methyl) BM (compound 109)
1HNMR(DMSO-d 6)(δppm)：2.416-2.505(s，3H)，3.674(s，3H)，4.658(s，2H)，4.892(s，2H)，6.158-6.186(dd，1H)，6.339-6.346(d，1H)，6.822(s，1H)，6.984-7.005(d，1H)，7.463-7.474(m，5H)，7.923-7.993(m，5H)，9.473(s，1H)。
N-(2-amino-5-p-methoxy-phenyl)-4 ((6-(3-p-methoxy-phenyl)-2-methylpyrimidine-4-is amino) methyl) BM (compound 110)
1HNMR(DMSO-d 6)(δppm)：2.412(s，3H)，3.674(s，3H)，3.815(s，3H)，4.645-4.655(s，2H)，4.890(s，2H)，6.158-6.186(dd，1H)，6.339-6.345(d，1H)，6.813(d，1H)，6.982-7.046(m，2H)，7.388-7.548(m，5H)，7.883-7.941(t，3H)，9.472(s，1H)。
N-(2-amino-5-p-methoxy-phenyl)-4 ((2-methyl-6-(3, the 4-methylenedioxyphenyl) pyrimidine-4-is amino) methyl) BM (compound 113)
1HNMR(DMSO-d 6)(δppm)：2.401(s，3H)，3.674(s，3H)，4.638(s，2H)，4.890(s，2H)，6.082-6.185(m，3H)，6.338-6.345(d，1H)，6.729(s，1H)，6.982-7.010(q，2H)，7.445-7.576(m，4H)，7.810-7.936(t，3H)，9.467(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((2-methyl-6-phenyl pyrimidine-4-is amino) methyl) BM (compound 96)
1HNMR(DMSO-d 6)(δppm)：2.415(s，3H)，4.652(s，2H)，5.201(s，2H)，6.349(m，1H)，6.511-6.546(dd，1H)，6.781-6.822(s，1H)，7.079-7.117(t，1H)，7.413-7.480(d，6H)，7.905-7.992(m，5H)，9.532(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((6-(3-p-methoxy-phenyl)-2-methylpyrimidine-4-is amino) methyl) BM (compound 111)
1HNMR(DMSO-d 6)(δppm)：2.496(s，3H)，3.815(s，3H)，4.646-4.658(s，2H)，5.202(s，2H)，6.328-6.371(m，1H)，6.511-6.546(dd，1H)，6.824-6.835(s，1H)，7.019-7.100(m，2H)，7.369-7.548(m，5H)，7.888-7.947(ds，3H)，9.532(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((6-(4-p-methoxy-phenyl)-2-methylpyrimidine-4-is amino) methyl) BM (compound 112)
1HNMR(DMSO-d 6)(δppm)：2.497(s，3H)，3.808(s，3H)，4.632(d，2H)，5.200(s，2H)，6.328-6.370(m，1H)，6.511-6.546(dd，1H)，6.742(s，1H)，7.010-7.166(m，3H)，7.432-7.476(m，2H)，7.924-7.962(t，5H)，9.529(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((2-methyl-6-(3-pyridyl) pyrimidine-4-is amino) methyl) BM (compound 114)
1HNMR(DMSO-d 6)(δppm)：2.497(s，3H)，4.664(s，2H)，5.601(s，2H)，6.328-6.370(m，1H)，6.511-6.546(dd，1H)，6.903(s，1H)，7.080-7.166(t，3H)，7.466-7.513(m，3H)，7.929-8.005(sd，3H)，8.314-8.33(d，1H)，8.643-8.655(dd，1H)，9.144(s，1H)，9.534(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((6-(3, the 4-methylenedioxyphenyl)-2-methylpyrimidine-4-is amino) methyl) BM (compound 115)
1HNMR(DMSO-d 6)(δppm)：2.492(s，3H)，4.629-4.639(s，2H)，5.200(s，2H)，6.083-6.097(s，2H)，6.321-6.370(m，1H)，6.511-6.546(dd，1H)，6.728(s，1H)，6.990-7.116(td，2H)，7.453-7.576(td，4H)，7.818-7.942(ds，3H)，9.526(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((6-(2, the 4-Dimethoxyphenyl)-2-methylpyrimidine-4-is amino) methyl) BM (compound 116)
1HNMR(DMSO-d 6)(δppm)：2.365(s，3H)，3.810(s，6H)，4.592(s，2H)，5.201(s，2H)，6.331-6.374(m，1H)，6.515-6.551(dd，1H)，6.601-6.633(q，2H)，7.084-7.121(q，2H)，7.444-7.465(d，2H)，7.766-7.780(t，1H)，7.919-7.952(m，3H)，9.537(s，1H)。
N-(2-amino-5-p-methoxy-phenyl)-4-((6-(2, the 4-Dimethoxyphenyl) pyrimidine-4-is amino) methyl) BM (compound 123)
1HNMR(DMSO-d 6)(δppm)：3.674(s，3H)，3.818-3.856(s，6H)，4.628(s，2H)，4.923(s，2H)，6.158-6.186(dd，1H)，6.337-6.344(d，1H)，6.625-6.658(m，2H)，6.979-7.001(d，1H)，7.229(s，1H)，7.427-7.447(d，2H)，7.924-7.970(m，4H)，8.434(s，1H)，9.510(s，1H)。
Figure GPA00000632129500421
Reaction formula 11
N-(2-amino-5-fluorophenyl)-4-((6-(4-p-methoxy-phenyl) pyrazine-2-is amino) methyl) BM (compound 117)
1HNMR(DMSO-d 6)(δppm)：3.799(s，3H)，4.648-4.663(d，2H)，5.196(s，2H)，6.325-6.361(m，1H)，6.511-6.539(dd，1H)，7.011-7.097(td，3H)，7.503-7.523(d，2H)，7.727-7.756(t，1H)，7.899-7.968(m，5H)，8.246(s，1H)，9.521(s，1H)。
N-(2-amino-5-methoxyphenyl)-4-((6-(4-p-methoxy-phenyl) pyrazine-2-is amino) methyl) BM (compound 118)
1HNMR(DMSO-d 6)(δppm)：3.670-3.677(s，3H)，3.799(s，3H)，4.642-4.657(d，2H)，4.882(s，2H)，6.159-6.188(dd，1H)，6.334-6.341(d，1H)，6.975-7.023(t，3H)，7.491-7.511(d，2H)，7.718-7.748(t，1H)，7.894-7.966(m，5H)，8.242(s，1H)，9.457(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((6-(3, the 4-methylenedioxyphenyl) pyrazine-2-is amino) methyl) BM (compound 119)
1HNMR(DMSO-d 6)(δppm)：4.638-4.653(d，2H)，5.193(s，2H)，6.066(s，2H)，6.323-6.365(m，1H)，6.507-6.535(dd，1H)，6.978-7.110(m，2H)，7.491-7.535(m，4H)，7.746-7.775(t，1H)，7.909-7.941(t，3H)，8.239(s，1H)，9.519(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((6-phenyl pyrazines-2-is amino) methyl) BM (compound 124)
1HNMR(DMSO-d 6)(δppm)：4.662-4.676(d，2H)，5.224(s，2H)，6.324-6.366(m，1H)，6.503-6.531(dd，1H)，7.080-70102(q，1H)，7.436-7.529(m，5H)，7.928-8.018(m，6H)，8.315(s，1H)，9.550(s，1H)。
Reaction formula 12
Embodiment 12. synthetic N-(2-amino-5-p-methoxy-phenyl)-4-((6,7-dimethoxyquinazoline-4-is amino) methyl) BM (compound 120)
Step 1. is synthesized the paraaminomethyl benzoic acid methyl ester hydrochloride
Compound method is as the step 1 of embodiment 10
Step 2. Synthetic 2-amino-4, the 5-dimethoxy p-methyl
With 15g 4,5 dimethoxys-2-nitrobenzoic acid acid methyl esters, the 0.86g iron trichloride, the 3g dry activated carbon adds in the ethanol of 150ml; Under nitrogen protection, be heated to 80 ℃ of backflow 0.5h, temperature is reduced to 60 ℃, in reaction solution, slowly drips 10ml Hydrazine Hydrate 80 (85%), drips Bi Jixu backflow 3h; Thin-layer chromatography shows that reaction finishes, and reacting liquor while hot is filtered, and filtrate decompression concentrates removes most of ethanol; There is faint yellow solid to separate out after the debris cooling, filters, the dry faint yellow solid 8.6g that gets.
Step 3. synthesizes 6,7-dimethoxy-3H quinazoline-4-one
With 7.2g step 2 product, 7.2g acetic acid first miaow adds in the 100ml ethanol, and heating reflux reaction 4h, thin-layer chromatography show that reaction finishes, and the reaction solution cooled and filtered gets white solid
Step 4. synthesizes 6,7-dimethoxy-4 '-chloro-quinazoline
With 5.4g step 3 product, the mixing solutions of thionyl chloride (30ml) and DMF (2.5ml) stirs and is heated to 50 ℃ of reaction 5h, and thin-layer chromatography shows that reaction finishes, and thionyl chloride is removed in decompression, and the gained solid is washed with ethanol, is drying to obtain.
Step 5. is synthesized 4-((6,7-dimethoxyquinazoline-4-is amino) methyl) oil of Niobe
With 5.0g step 4 product, 4.4g step 1 product, triethammonia 8.6ml adds among the 50mlDMF, and mixed solution is in 80 ℃ of back flow reaction 18h under nitrogen protection; Thin-layer chromatography shows that reaction finishes, and reaction solution is poured in the 100ml water, transfers ph=7 with hydrochloric acid (2N); Separate out solid, filter, be drying to obtain.
Step 6. is synthesized 4-((6,7-dimethoxyquinazoline-4-is amino) methyl) phenylformic acid formic acid
With 6.4g step 5 product, the 2.3g Lithium Hydroxide MonoHydrate, the mixing solutions of 40mlTHF and 20ml water is in 30 ℃ of stirring reaction 4h; Thin-layer chromatography shows that reaction finishes, and concentrating under reduced pressure is removed THF, and residual solution is transferred ph=3 with hydrochloric acid (2N); The adularescent solid is separated out, and filtration drying promptly gets.
Step 7. is synthesized (2-amino-5-p-methoxy-phenyl)-4-((6,7-dimethoxyquinazoline-4-is amino) methyl) BM
With 0.4 step 6 product, 0.19gN, N-phosphinylidyne diimidazole is dissolved in the 10ml dry DMF, 45 ℃ of reaction 1.5h, cooling, subsequent use.Get another dry 100ml three-necked bottle, under nitrogen protection, with 0.19g4-methoxyl group-1, the 2-phenylenediamine is dissolved in the 7ml anhydrous tetrahydro furan; Drip the 0.44g trifluoroacetic acid, drip subsequent use reaction solution again, stirred overnight at room temperature, thin-layer chromatography shows that reaction finishes; Decompression and solvent recovery, residue is crossed silica gel and is leant on, 5: 1 wash-outs of ETHYLE ACETATE/ethanol; Elutriant concentrates, and crystallization gets white solid 0.28g.
1HNMR(DMSO-d 6)(δppm)：3.672(s，3H)，3.902(s，6H)，4.834-4.848(d，2H)，4.915(s，2H)，6.163-6.178(m，1H)，6.335-6.342(dd，1H)，6.999-7.115(m，2H)，7.448-7.469(d，2H)，7.674(s，1H)，7.908-7.929(t，2H)，8.320(s，1H)，8.557-8.589(t，1H)，9.497(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((6,7-dimethoxyquinazoline-4-is amino) methyl) BM (compound 121)
1HNMR(DMSO-d 6)(δppm)：：3.902(s，6H)，.835-4.850(d，2H)，5.195(s，2H)，6.343-6.350(m，1H)，6.512-6.547(dd，1H)，7.082-7.112(m，2H)，7.458-7.478(d，2H)，7.684(s，1H)，7.912-7.952(t，2H)，8.317(s，1H)，8.536-8.566(t，1H)，9.520(s，1H)。
Figure GPA00000632129500441
Reaction formula 13
Embodiment 13. synthetic N-(2-amino-5-fluorophenyl)-4-((2,4-dioxo-1,2-dihydroquinazoline-3 (4H)-yl) methyl) BMs (compound 122)
Step 1. is synthesized 4-((2-nitrobenzoyl amido) methyl) oil of Niobe
The 1.6g o-Carboxynitrobenzene is suspended in 15ml heavily steams in the methylene dichloride, under ice bath, slowly add 1.28gN in batches, N '-NSC 57182 adds the 0.66g N-hydroxy-succinamide again, catalytic amount 4-Dimethylamino pyridine, and stirring at room, subsequent use; Get another reaction flask, add 2g aminomethyl phenyl methyl-formiate hydrochloride, 1.47ml triethylamine, 10ml heavily steam methylene dichloride, after half a hour; Slowly be added dropwise to subsequent use reaction solution again, stirring at room is after two hours, and TLC shows and reacts completely stopped reaction; Filter, collect filtrating, wash 3 times with sour water earlier, wash 3 times with saturated sodium carbonate again; Collected organic layer, anhydrous magnesium sulfate drying filters, and concentrating under reduced pressure promptly gets white solid 1.46g.
Step 2. is synthesized 4-((2-nitrobenzoyl amido) methyl) phenylformic acid
1.15g step 1 product, 0.67g sodium hydroxide are suspended in 10ml THF/10ml water mixed liquid, stirred overnight at room temperature, decompression desolventizes, and in residue, adds suitable quantity of water, and using Hydrogen chloride to transfer PH is 5～6, filters, and drying promptly gets white solid 0.94g.
Step 3. is synthesized 4-((2-aminobenzoic amido) methyl) phenylformic acid
With 0.8g step 2 product, 0.13g iron trichloride, 0.24g dry activated carbon, be suspended in the 20ml absolute ethyl alcohol, reflux stops heating after half a hour; Slowly drip the 0.4ml Hydrazine Hydrate 80, continue backflow 2h, TLC shows and reacts completely filtered while hot; Collect filtrating, decompression desolventizes, and in residue, adds suitable quantity of water; Transferring PH is about 7, filters, and is drying to obtain white solid 0.68g
Step 4. is synthesized 4-((2-(ethoxycarbonyl) benzamido-) methyl) phenylformic acid
0.62g step 3 product is dissolved in the 15ml pyridine, under ice bath, slowly drips the 0.24ml Vinyl chloroformate, after continuing to stir 2h; TLC shows and reacts completely, and in reaction solution, adds an amount of sour water and makes the PH slant acidity, with dichloromethane extraction for several times; Merge organic layer, anhydrous magnesium sulfate drying filters; Concentrating under reduced pressure promptly gets light yellow solid, gets white solid 0.63g with ethyl ester/ethyl alcohol recrystallization.
Step 5. is synthesized 4-((2,4-dioxo-1,2-dihydroquinazoline-3 (4H)-yl) methyl) phenylformic acid
0.50g step 3 product is suspended in 10ml methyl alcohol/10ml water mixed liquid, adds 0.074gNaOH again, behind the reflux 12h, TLC shows and reacts completely; Filter, collect filtrating, decompression desolventizes, and in residue, adds suitable quantity of water; Transferring PH is about 5～6, filters, and drying promptly gets white solid 0.46g.
Step 6. is synthesized N-(2-amino-5-fluorophenyl)-4-((2,4-dioxo-1,2-dihydroquinazoline-3 (4H)-yl) methyl) BM
With 0.43g step 5 product and 0.24gN, N-phosphinylidyne diimidazole is dissolved in the 8ml anhydrous tetrahydro furan, 50 ℃ of back flow reaction 1.5h, and cooling, subsequent use.Get another dry 100ml three-necked bottle, under nitrogen protection, with 0.23g4-fluoro-1, the 2-phenylenediamine is dissolved in the 7ml anhydrous tetrahydro furan; Drip the 0.165g trifluoroacetic acid, drip subsequent use reaction solution again, stirred overnight at room temperature, TCL shows that reaction finishes; Decompression and solvent recovery, residue is crossed silica gel and is leant on, 10: 1 wash-outs of ETHYLE ACETATE/ethanol; Elutriant concentrates, and crystallization gets white solid 0.25g.
1HNMR(DMSO-d 6)(δppm)：5.131(s，2H)，5.295(s，2H)，6.942-7.112(m，3H)，7.215-7.348(m，4H)，7.669-7.706(t，1H)，7.845-7.964(m，3H)，9.520(s，1H)，11.425(s，1H)。
The synthesis step of following compound 127,128 is as embodiment 13 (compound 122).
N-(2-amino-5-fluorophenyl)-4-((1-(2-(dimethylamino) ethyl)-2,4-dioxo-1,2-dihydroquinazoline-3 (4H)-yl) methyl) BM (compound 127)
1HNMR(DMSO-d 6)(δppm)：2.271(s，6H)，5.134(s，2H)，5.301(s，2H)，6.944-7.113(m，3H)，7.216-7.350(m，4H)，7.670-7.706(t，1H)，7.853-7.969(m，3H)，9.532(s，1H)。
N-(2-amino-5-fluorophenyl)-4-((1-(2-morpholine ethyl)-2,4-dioxo-1,2-dihydroquinazoline-3 (4H)-yl) methyl) BM (compound 128)
1HNMR(DMSO-d 6)(δppm)：2.389-2.401(t，4H)，3.671-3.680(t，4H)，5.131(s，2H)，5.295(s，2H)，6.942-7.112(m，3H)，7.215-7.348(m，4H)，7.669-7.706(t，1H)，7.845-7.964(m，3H)，9.522(s，1H)。
Embodiment 9. compounds disclosed by the invention are to the growth-inhibiting effect of tumour cell
Mtt assay detects, and treats to carry out when culturing cell is in good condition experiment.Cell preparation is become uniform suspension-s, be inoculated in 96 orifice plates according to certain density.Every hole adds 100 μ L cell suspensions, makes that cell count is 10000-50000/hole in every hole.0～500 μ M different pharmaceutical concentration group is set, and other establishes blank group and solvent control group.Three repeating holes of each concentration, every hole add 10 μ L medicines, and medicine adds according to concentration from low to high successively, during dosing necessarily with the medicine mixing.Seal 96 orifice plates, stay next little convection current sealing, reduce the error that causes owing to the cell culture fluid volatilization.Dosing detects cell proliferation with mtt assay after stimulating 48h.Detect absorbance in the 570nm wavelength, GI is tried to achieve in the statistical study of the line number of going forward side by side reason 50Value (cell growth suppresses 50% compound concentration).
Table 2 compound is to the proliferation inhibition activity of tumour cell
Figure GPA00000632129500461
Figure GPA00000632129500471
* positive control medicine: N-(2-aminophenyl)-4-((3, the 4-Dimethoxyphenyl) amino methyl) BM (the disclosed compound of WO2005092899, we synthesize by its disclosed method)
The cell source:
SMMC-7721: human liver cancer cell HepG2: human liver cancer cell
MCF-7: human breast cancer cell MDA-MB-231: human breast cancer cell
HL-60: human myeloid leukemia cell Jurkat: human T lymphocyte's white blood disease
CCD-1059SK: normal fibroblast
The result shows that compound disclosed by the invention has remarkable antitumour activity, and particularly to human breast cancer cell MDA-MB-231, MCF-7, compound 6 is than high respectively 29,13 times of MS-275; To leukemia cell HL60, Jurkat, compound 6 is than high respectively 3,2 times of MS-275; To human liver cancer cell SMMC-7721, HepG2, compound 6 is than high respectively 5,1 times of MS-275.The proliferation inhibition activity and the MS-275 of 4 pairs of tumour cells of compound are suitable.Compound disclosed by the invention is lower than MS-275 or positive control medicine (YX) to normal cytotoxicity.
3. preliminarily stabilised property test
A. high temperature test
Get each 2 parts of prerun compound samples, an amount of, put in the weighing bottle, be paved into the thin layer of 5mm, placed 60 ℃ of thermostat containers 10 days, respectively at sampling in 5,10 days, investigate outward appearance, related substance and content, the result sees table 3.
Table 3, compound thimble test be table as a result
Conclusion: MS-275 high temperature is after 10 days, and appearance white becomes redness property powder, and content, related substance considerable change show that these article are unstable to high temperature; Behind strong illumination compound 6-10 days, outward appearance, content, related substance do not have considerable change, show that these article are to high-temperature stable.
B. strong illumination test
It is an amount of to get the prerun compound, is paved into the thick thin layer of 5mm, places under the condition of illumination 4500Lx ± 500Lx illumination 10 days, respectively at sampling in 5,10 days, investigates outward appearance, related substance and the content of sample, and the result sees table 4.
Table 4, prerun compound strong illumination stability test result
Figure GPA00000632129500482
Figure GPA00000632129500491
Conclusion: the reference substance strong illumination is after 10 days, and appearance white becomes redness property powder, and content, related substance considerable change show that reference substance is unstable to illumination; Compound 6 strong illuminations are after 10 days, and outward appearance, content, related substance do not have considerable change, show that these article are more stable than reference substance (the disclosed compound of WO2005092899) to illumination.
* N-(2-aminophenyl)-4-((3,4, the 5-trimethoxyphenyl is amino) methyl) BM (reference substance) is the disclosed compound of WO2005092899, and we synthesize by its disclosed method: fusing point m.p.164.5-165 ℃; 1HNMR (DMSO-d6) (δ ppm): 3.646 (s, 6H), 3.500 (s, 3H), 4.313-4.327 (d, 2H); 5.186-5.206 (d, 2H), 5.887 (s, 2H), 6.138-6.169 (t, 1H); 6.331-6.374 (m, 1H), 6.515-6.550 (dd, 1H), 7.082-7.103 (dd, 1H); 7.477-7.498 (d, 2H), 7.917-7.938 (d, 2H), 9.529 (s, 1H).
Industrial applicibility
The inventor is through experiment confirm, and compound disclosed by the invention shows sure retarding effect to tumor cell proliferation, and antitumor activity obviously is superior to positive control medicine MS-275, and The compounds of this invention is lower than MS-275 to normal cytotoxicity.Compound disclosed by the invention is more stable than positive control medicine MS-275 and the disclosed compound physico-chemical property of WO2005092899 in addition.

Claims (8)

1. the salt of following formula: compound, or its pharmaceutical acceptable acid,
Figure FSB00000784343600011
Here, Ar is:
Figure FSB00000784343600012
2. the salt of following formula: compound, or its pharmaceutical acceptable acid,
Figure FSB00000784343600013
Here, Ar is:
Figure FSB00000784343600014
3. the salt of following formula: compound, or its pharmaceutical acceptable acid,
Here, Ar is:
Figure FSB00000784343600016
4. the salt of following formula: compound, or its pharmaceutical acceptable acid:
Figure FSB00000784343600017
Wherein,
Figure FSB00000784343600018
Figure FSB00000784343600021
5. the salt of following formula: compound, or its pharmaceutical acceptable acid:
Figure FSB00000784343600022
wherein
Figure FSB00000784343600023
6. compound is shown below:
Or the salt of its pharmaceutical acceptable acid, wherein:
R 1＝H?R 2＝OCH 3?R 3＝OCH 3?R 4＝H?R 5＝H。
7. a pharmaceutical composition contains the said compound of arbitrary claim among one or more claims 1-6, and pharmaceutically acceptable carrier.
8. the application of the described compound of arbitrary claim in the medicine of relevant psoriasis, leukemia or solid tumor of preparation treatment human or animal cell proliferative among the claim 1-6.
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