CN105646371B - The 2,4- diaryl-amine yl pyrimidines analog derivative of the segment containing hydroxamic acid and preparation and application - Google Patents

The 2,4- diaryl-amine yl pyrimidines analog derivative of the segment containing hydroxamic acid and preparation and application Download PDF

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CN105646371B
CN105646371B CN201610034158.XA CN201610034158A CN105646371B CN 105646371 B CN105646371 B CN 105646371B CN 201610034158 A CN201610034158 A CN 201610034158A CN 105646371 B CN105646371 B CN 105646371B
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amino
base
compound
phenyl
hydrochloride
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CN105646371A (en
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俞永平
罗婧
陈文腾
舒可
刘星雨
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Abstract

The present invention provides 2 of the segment containing hydroxamic acid as shown in formula I and formula II; 4- diaryl-amine yl pyrimidines analog derivative; mainly with 2, the 4- diaryl-amine yl pyrimidines containing carboxy fragment for parent nucleus, target compound is obtained by the condensation of one step of azanol and relevant modification protected to THP.Experiments have shown that; in cellular level pair tumour cell relevant to EGFR tyrosine kinase activity (human lung adenocarcinoma cell line H1975 drug resistant to Gefitinib, the people's epidermis cancer cell line A431 for being overexpressed EGFR) and to tumour cells such as human cervical carcinoma cell lines Hela relevant with HDAC acetylation of histone enzymatic activity, human mouth epidermoid carcinoma cell strain KB, the early young grain acute leukemia cells strain HL60 of people, HepG2 cell lines, human colon cancer cell strain SW620; with significant inhibited proliferation, corresponding antitumor cell drug can be prepared.General structure is as follows:

Description

The 2,4- diaryl-amine yl pyrimidines analog derivative of the segment containing hydroxamic acid and preparation and application
Technical field
The invention belongs to pharmaceutical field, it is related to the 2 of a kind of segment containing hydroxamic acid, 4- diaryl-amine pyrimidine derivatives and its system Preparation Method and application.
Background technique
The study found that be more than 60% malignant tumour in all there is the mutation of one or more EGFR family receptors or mistake Expression.Tyrosine kinase plays important regulating and controlling effect in the growth of cell, proliferation and apoptotic process.Small molecule EGFR tyrosine Kinase inhibitor and ATP competitive binding inhibit EGFR from process phosphoric acid and downstream to be blocked to believe to EGFR intracellular region phosphorylation site Number access achievees the purpose that inhibit tumour cell.First generation reversible EGFR inhibitor including Gefitinib is to non-small Cell lung cancer patients have a better effect, however, occurring acquired resistance in clinical use.Because first generation inhibitor is to skin There is stronger inhibiting effect with the Wild type EGFR of enteron aisle, so causing the side effects such as dermatitis, diarrhea, makes patient receiving treatment Quality of life decline.The therapeutic strategy of irreversible EGFR inhibitor targeting EGFR T790M obtains certain achievement, with Afatinib is that the irreversible EGFR inhibitor of the second generation of representative can be used for by first generation reversible EGFR inhibitor Gefitinib Caused drug resistance patient treatment.But the irreversible EGFR inhibitor of the second generation is selected between Wild type EGFR and T790M saltant type Selecting property is not strong, causes to cause the side effects such as dermatitis, diarrhea to the high inhibition effect of Wild type EGFR.AZD9291, trade name tower lattice Rui Si (Tagrisso or Osimertinib) is the non-reversible mutation of the third generation of Astrazeneca AB (AstraZeneca) research and development Selection type EGFR inhibitor, the NSCLC patient being mutated to existing EGFR-TKI resistance and T790M have good therapeutic effect. WZ4002 is most to look for the non-reversible Catastrophic selection type EGFR inhibitor of the third generation of report, Wild type EGFR and mutant egf R it Between have good selectivity.But the C797S that the non-reversible Catastrophic selection type EGFR inhibitor of the third generation also can cause EGFR new is prominent Become.How resistance problems are solved, at the research hotspot of EGFR inhibitor.
It is thin that histon deacetylase (HDAC) (Histone Deacetylase, HDAC) is that one kind is widely present in eucaryote Protease in born of the same parents, histon deacetylase (HDAC) forms activated centre by chelated zinc ions, and then catalyzing hydrolysis histone relies Acetamide on histidine residue, makes DNA methylase inhibitor.All exist during Several Kinds of Malignancy occurs and develops HDAC unconventionality expression.In recent years, research finds to inhibit the activity of HDACs, makes HATs level is opposite to improve, histone can be improved and go Acetylation Level achievees the purpose that antitumor to promote tumor cell differentiation.
Hdac inhibitor is able to suppress the enzymatic activity of histon deacetylase (HDAC), plays cell-cycle arrest, induction tumour The purpose of cell differentiation or apoptosis.It can be six classes: short-chain fat class, hydroxyl by HDACs points according to the difference of Zinc Ions Chelated group Oxime acids, cyclic tetrapeptide class, benzamides, mercaptan and electrophilic ketone and miscellaneous molecule class.It wherein studies most extensive, active stronger Be hydroximic acid inhibitor.Vorinostat (SAHA) is the hdac inhibitor of first listing.Many clinical researches become now It is combined in by HDACIs and other anti-tumor drugs, to obtain better therapeutic effect.Wherein, hdac inhibitor SAHA with Proteasome inhibitor Bortezomib drug combination treats glioblastoma, recurrent lymthoma, Huppert's disease etc. Clinical II, III phase research is carrying out.Also have in recent clinical research and is combined hdac inhibitor and EGFR inhibitor, to Resistance problems are able to solve, the drug effect segment hydroxamic acid of hdac inhibitor is connected to EGFR inhibitor quinazoline by existing research Parent nucleus designs EGFR/HDAC multiple target point drug, and CUDC-101 comes into clinicalⅰstage conceptual phase, the multiple target point inhibitor pair The inhibitory effect of drug-resistant cell strain is better than the EGFR inhibitor of single target spot.The bis- target spot inhibitor of EGFR/HDAC are expected to become one Kind effective antitumour drug.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of 2,4- diaryl-amine miazines of segment containing hydroxamic acid to spread out Biology is a kind of and the entirely different pyridine derivatives of the prior art, has preferable anti-tumor activity, has simultaneously EGFR/HDAC inhibitory activity.
The 2 of a kind of segment containing hydroxamic acid provided by the invention, 4- diaryl-amine pyridine derivatives, general structure such as formula I It is shown:
Wherein:
R1For hydrogen atom or chlorine atom；
R2For hydrogen atom or methoxyl group.
The 2 of a kind of segment containing hydroxamic acid provided by the invention, 4- diaryl-amine pyridine derivatives, general structure such as formula II It is shown:
Wherein:
X is ehter bond (- O-), amido bondPiperazinylOr N, N '-dimethyl ethylenediamine base
N is 1~5；
R1For hydrogen atom, chlorine atom or trifluoromethyl；
R2For hydrogen atom, methoxyl group, halogen and methyl.
Chemical compounds I of the present invention is following any compound:
N1(3- ((2- ((4- (4- acetyl group-piperazine -1- base) -2- methoxyphenyl) amino) -5- chlorine pyrimidine-4-yl) Amino) phenyl)-N4Hydroxyl maleic amide hydrochloride (compound 1)；
N1(3- ((2- ((4- (4- acetyl group-piperazine -1- base)-phenyl) amino) -5- chlorine pyrimidine-4-yl) amino) benzene Base)-N4Hydroxyl maleic amide hydrochloride (compound 2).
The compound ii is following any compound:
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino)-phenyl) piperazine Piperazine -1- base)-N- hydroxyl acetamide hydrochloride (compound 3)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyl group Phenyl) piperazine -1- base)-N- hydroxyl acetamide hydrochloride (compound 4)；
(((the chloro- 2- of 5- ((4- (4- (2- (hydroxyl amino) -2- oxoethyl) piperazine -1- base) phenyl) amino) is phonetic by 3- by N- Pyridine -4- base) oxo) phenyl) acrylamide hydrochloride (compound 5)；
(((the chloro- 2- of 5- ((3- (4- (2- (hydroxyl amino) -2- oxoethyl) piperazine -1- base) phenyl) amino) is phonetic by 3- by N- Pyridine -4- base) amino) phenyl) acrylamide hydrochloride (compound 6)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- trifluoromethvl-Dvrimidin -2- base) amino)-benzene Base) piperazine -1- base)-N- hydroxyl acetamide hydrochloride (compound 7)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyl group Phenyl) piperazine -1- base)-N- hydroxypropanamide hydrochloride (compound 8)；
4- (4- (4- ((4- ((3- acetvlaminophenvl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) piperazine -1- Base)-N- hydroxybutyramide hydrochloride (compound 9)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyl group Phenyl) piperazine -1- base)-N- hydroxybutyramide hydrochloride (compound 10)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyl group Phenyl) piperazine -1- base)-N- hydroxypentanoyl amine hydrochlorate (compound 11)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyl group Phenyl) piperazine -1- base)-N- hydroxyl hexanamide hydrochloride (compound 12)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -2- fluorophenyl) Piperazine -1- base)-N- hydroxyl hexanamide hydrochloride (compound 13)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- fluorophenyl) Piperazine -1- base)-N- hydroxybutyramide hydrochloride (compound 14)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -2- fluorophenyl) Piperazine -1- base)-N- hydroxybutyramide hydrochloride (compound 15)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- fluorophenyl) Piperazine -1- base)-N- hydroxyl hexanamide hydrochloride (compound 16)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) piperazine - 1- yl)-N- hydroxyl hexanamide hydrochloride (compound 17)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -2- methylbenzene Base) piperazine -1- base)-N- hydroxyl hexanamide hydrochloride (compound 18)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -2- chlorphenyl) Piperazine -1- base)-N- hydroxyl hexanamide hydrochloride (compound 19)；
N1(4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl)-N5Hydroxyl Base glutaramide hydrochloride (compound 20)；
N1(4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl)-N8Hydroxyl Base suberamide hydrochloride (compound 21)；
N1(4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxybenzene Base)-N5Hydroxyl glutaramide hydrochloride (compound 22)；
4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) pyrimidine -2-base) amino) phenoxy group)-N- hydroxyl penta Amide hydrochloride (compound 23)；
4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) pyrimidine -2-base) amino) phenoxy group)-N- hydroxyl oneself Amide hydrochloride (compound 24)；
4- (3- ((4- ((3- acryloyl group-amino-phenyl) amino) pyrimidine -2-base) amino) phenoxy group)-N- hydroxyl fourth Amide hydrochloride (compound 25)；
4- (4- ((4- ((3- aminophenyl) amino) pyrimidine -2-base) amino) phenoxy group)-N- hydroxybutyramide hydrochloride (compound 26)；
4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenoxy group)-N- hydroxyl Base butanamide hydrochloride (compound 27)；
6- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) the chloro- 2- pyrimidine radicals of -5-) amino) -3- methoxyl group-benzene Oxygroup)-N- ((tetrahydro -2H- pyrans -2- base) oxo) acetamide (compound 28)；
4- ((2- ((4- ((4- ((3- Acryloyl amino phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) (first Base) amino-ethyl) (methyl) amino)-N- hydroxybutyramide hydrochloride (compound 29)；
4- ((2- ((4- ((4- ((3- Acryloyl amino phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) (first Base) amino-ethyl) (methyl) amino)-N- hydroxyl hexanamide hydrochloride (compound 30).
It is a further object to provide the preparation methods of the chemical compounds I, are realized by following steps:
With 2,4- dichloro pyrimidine (compound A) and tert-butyl (3- aminophenyl) carbamate for starting material, low temperature Under the conditions of reaction generate tert-butyl (3- ((2- chlorine pyrimidine-4-yl) amino) phenyl) carbamate (compound B), compound B Midbody compound C is generated with all kinds of substituted arylamine reactions, compound C takes off protecting group in acid condition and generates 2- (4- (N4- acetylpiperazinyl)-aminophenyl) -4- (3- amino) aminophenyl) -3- chlorine pyrimidine (compound D), compound D with it is suitable Anhydride maleique reacts under the conditions of N,N-dimethylformamide (DMF) generates intermediate 4- oxo -2- butenoic acid (compound E), the azanol condensation of midbody compound E and THP protection generates compound F, and final compound F takes off guarantor in acid condition It protects base and generates target compound I, reaction equation is as follows:
Reagent and reaction condition: a) n,N-diisopropylethylamine, sec-butyl alcohol, 0 DEG C, 1 hour；B) sec-butyl alcohol, reflux, 5 is small When；C) trifluoroacetic acid, methylene chloride, room temperature, 30 minutes；D) n,N-Dimethylformamide, 50 DEG C, 3 hours；E) 1- (3- diformazan Aminopropyl) -3- ethyl-carbodiimide hydrochloride, 1- hydroxy benzo triazole, n,N-Dimethylformamide: methylene chloride=1: 2,45 DEG C, 5 hours；F) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour；Wherein the definition of each substituent group is as described above.
It is also another object of the present invention to provide the preparation methods of the compound ii, are realized by following steps:
It is anti-under cryogenic conditions with 2,4- dichloro pyrimidine a and tert-butyl (3- aminophenyl) carbamate for starting material Tert-butyl (3- ((2- chlorine pyrimidine-4-yl) amino) phenyl) carbamate b, b should be generated and all kinds of substituted arylamine reactions are raw At intermediate c, c takes off protecting group in acid condition and generates 2- (4- (4- ((4- ((3- aminophenyl) amino) -2- pyrimidine radicals) Amino) phenyl)) ethyl acetate d, d and acryloyl chloride generate e under cryogenic, intermediate e hydrolyzes generation under alkaline condition The azanol condensation of f, intermediate f and O- (tetrahydro -2H- pyrans -2- base) hydroxylamine (THP) protection generates compound g, and last g exists Protecting group is taken off under acid condition and generates target compound II, and reaction route is as follows:
Reagent and reaction condition: 1) sec-butyl alcohol, 0 DEG C, 4 hours；2) sec-butyl alcohol, reflux, 4 hours；3) trifluoroacetic acid (TFA), methylene chloride (DCM), 1 hour；4) acryloyl chloride, methylene chloride, -5 DEG C to 0 DEG C, 30 minutes to 1 hour；5) tetrahydro Furans: water=1:1,1 hour；6) methylene chloride: N, N- dimethyl formyl=2:1,1- (3- dimethylamino-propyl) -3- ethyl carbon Diimmonium salt hydrochlorate, 1- hydroxy benzo triazole, 45 DEG C, 5 hours；7) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour； Wherein, the definition of each substituent group is as described above.
Raw material and intermediate according to the present invention, the literature method system that can directly buy or be referred to according to embodiment part It is standby.
II compound of formula I described in preparation method of the present invention and formula can use organic synthesis and field of medicinal chemistry or skill A variety of method preparations, can be used method described above to prepare the compound of the present invention, allusion quotation can be used known to art personnel Type or preferred process condition (i.e. reaction temperature, time, the molar ratio of reactant and solvent etc.), can also use Other process conditions, unless otherwise indicated.Optimum reaction condition can change with specific reactant used or solvent, but These conditions should be determined by those skilled in the art by routine optimization process.In general, above-mentioned reaction road can be used Line and technique prepare the compounds of this invention, but are not limited to the reagent in reaction condition and solvent.
The 2,4- diaryl-amine miazines that fourth object of the present invention is to provide a kind of segment containing hydroxamic acid spreads out Biological application in preparation of anti-tumor drugs, the tumour cell refer to be overexpressed EGFR people's epidermis cancer cell line A431, Human lung adenocarcinoma cell line H1975 drug resistant to Gefitinib, to thin to the relevant tumour of acetylation of histone enzyme (HDAC) activity Born of the same parents (human cervical carcinoma cell lines Hela, human mouth epidermoid carcinoma cell strain KB, the early young grain acute leukemia cells strain HL60 of people, people Hepatoma H22 cells, human colon cancer cell strain SW620).Its pharmacodynamics embodiment experimental data is shown, in cellular level There is significant inhibited proliferation to tumour cell relevant to EGFR, HDAC activity, corresponding anti-tumor drug can be prepared.
The present invention provides the 2 of a kind of completely new segment containing hydroxamic acid, 4- diaryl-amine pyridine derivatives are therein different Hydroximic acid segment can be used as the Zinc Ions Chelated group of HDAC.Its pharmacodynamics embodiment experimental data is shown, in cellular level pair Tumour cell relevant to EGFR (is overexpressed people's epidermis cancer cell line A431 of EGFR, to the drug resistant human lung adenocarcinoma of Gefitinib Cell strain H1975) and to the relevant tumour cell of acetylation of histone enzyme (HDAC) activity (human cervical carcinoma cell lines Hela, Human mouth epidermoid carcinoma cell strain KB, the early young grain acute leukemia cells strain HL60 of people, HepG2 cell lines, people's colon Cancer cell line SW620) there is significant inhibited proliferation.Especially there is preferable inhibitory effect to drug-resistant cell strain H1975, The bis- target spot inhibitor of the drug resistant EGFR/HDAC of Gefitinib can be overcome to provide possibility for design is novel.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range, in the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient The selection of product specification.
Embodiment 1N1(((2- ((4- (4- acetyl group-piperazine -1- base) -2- methoxyphenyl) amino) -5- chlorine is phonetic by 3- Pyridine -4- base) amino) phenyl)-N4Hydroxyl maleic amide hydrochloride
Reagent and reaction condition: a) n,N-Dimethylformamide, 50 DEG C, 3 hours；B) 1- (3- dimethylamino-propyl) -3- Ethyl-carbodiimide hydrochloride, 1- hydroxy benzo triazole, n,N-Dimethylformamide: methylene chloride=1:2,45 DEG C, 5 is small When；C) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour.
Step 1:(Z) -4- ((2 ((2- ((4- (4- acetylpiperazine base) -2- methoxyl group) amino) -5- chlorine pyrimidine) amino) benzene Base) amino) -4- oxo -2- butenoic acid preparation
Raw material 1:2- ((2- methoxyl group -4- (N4Acetylpiperazinyl)-aminophenyl) -4- (3- amino) aminophenyl) - 5- chlorine pyrimidine is prepared according to Nature, the method for 2009,462,1070-1074.
By 2- ((2- methoxyl group -4- (N4Acetylpiperazinyl)-aminophenyl) -4- (3- amino) aminophenyl) -5- chlorine Pyrimidine (1mmol) and maleic anhydride (1.2mmol) are dissolved in 15mL dichloroethanes, and reaction overnight, after reaction, subtracts Pressure is spin-dried for, and can obtain brown solid with acetone recrystallization.
Brown solid；m.p.:120.5–120.9℃；1HNMR(500MHz,DMSO-d6)δ10.44(s,1H),9.53 (s, 1H), 7.91-7.86 (m, 3H), 7.68 (s, 1H), 7.44 (d, J=8.6Hz, 1H), 7.28-6.91 (m, 4H), 6.48 (d, J=12.1Hz, 1H), 6.35 (d, J=12.1Hz, 1H), 6.29-6.27 (m, 1H), 6.13 (s, 1H), 3.58-3.57 (m, 4H),3.10–3.04(m,4H),2.04(s,1H),1.23(s,3H).HRMS(ESI)calcd.for C27H29ClN7O5[M+H]+ =566.1913, found 566.1914.
Step 2:N1(3- ((2- ((4- (4- Acetylpiperazine -1- base) -2- anisyl) amino) -5- chlorine pyrimidine -4- Base) amino) phenyl)-N4The preparation of ((tetrahydro -2H- pyrans -2- base) oxo) Malaysia acid diamine
By 2- ((2- methoxyl group -4- (N4Acetylpiperazinyl)-aminophenyl) -4- (3- amino) aminophenyl) -5- chlorine Pyrimidine (1mmol) and O- (tetrahydro -2H- pyrans -2- base) azanol (1.2mmol) are dissolved into and are dissolved in 12mL methylene chloride and 4mL In n,N-Dimethylformamide mixed solution, 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide salt is added into reaction solution Hydrochlorate (1.32mmol), 1- hydroxy benzo triazole (1.32mmol) are placed in 40 DEG C and are stirred to react 4 hours, after reaction, to In reaction solution plus 30mL water three times with the extraction of 20mL methylene chloride merges organic phase, and organic phase is spin-dried for, through column chromatographic purifying (stream Dynamic phase methylene chloride: methanol=90:1) yellow solid.
Yellow solid；m.p.:150.2–150.9℃；1HNMR(500MHz,DMSO-d6)δ9.35(s,1H), 7.80-7.66 (m, 3H), 7.48 (s, 1H), 7.40 (d, J=8.5Hz, 1H), 7.21-6.81 (m, 4H), 6.58 (d, J= 11.9Hz, 1H), 6.33 (d, J=11.9Hz, 1H), 6.27-6.24 (m, 1H), 6.10 (s, 1H), 4.08-3.87 (m, 2H), 3.80–3.76(m,2H),3.75–3.71(m,2H),3.15(s,2H),3.09–2.96(m,4H),2.70–2.66(m,3H), 1.88–1.79(m,4H),1.61–1.47(m,4H).HRMS(ESI)calcd.for C32H38ClN8O6[M+H]+= 566.2597,found 566.2597。
Step 3:N1(3- ((2- ((4- (4- acetyl group-piperazine -1- base) -2- methoxyphenyl) amino) -5- chlorine pyrimidine - 4- yl) amino) phenyl)-N4The preparation of hydroxyl maleic amide hydrochloride
By N1(3- ((2- ((4- (4- Acetylpiperazine -1- base) -2- anisyl) amino) -5- pyrimidine-4-yl) ammonia Base) phenyl)-N4((tetrahydro -2H- pyrans -2- base) oxo) Malaysia acid diamine (1mmol) is added in 25mL three-necked flask, and The dichloroethanes of 8mL is added.Ether (3.4mL) solution that 1M hydrochloric acid is instilled under condition of ice bath, low-temp reaction 1 hour, has reacted Cheng Houyou solid is precipitated, and decompression filters, and obtains yellow solid.
Brown solid；m.p.:217.9–218.3℃；1H NMR(500MHz,DMSO-d6)δ10.60(s,3H), 7.65 (d, J=8.5Hz, 1H), 7.50-7.44 (m, 2H), 7.40 (s, 1H), 7.31-7.18 (m, 4H), 6.87 (d, J= 12.1Hz, 1H), 6.72 (d, J=12.1Hz, 1H), 6.28 (s, 1H), 3.82 (s, 3H), 3.80 (s, 1H), 3.72-3.64 (m, 4H), 3.44 (q, J=7.0Hz, 4H), 2.08 (s, 3H), 1.91 (s, 1H) .HRMS (ESI) calcd.for C27H30ClN8O5[M +H]+=581.2022, found 581.2025.
Embodiment 2:N1(3- ((2- ((4- (4- acetyl group-piperazine -1- base)-phenyl) amino) -5- chlorine pyrimidine-4-yl) Amino) phenyl)-N4Hydroxyl maleic amide hydrochloride
Referring to the method for embodiment 1, only by (Z) -4- ((2 ((2- ((4- (4- acetylpiperazine base) -2- first in step 1 Oxygroup) amino) -5- chlorine pyrimidine) amino) phenyl) amino) -4- oxo -2- butenoic acid changes (Z) -4- ((2 ((2- ((4- (4- second into Acyl piperazinyl) amino) -5- chlorine pyrimidine) amino) phenyl) amino) -4- oxo -2- butenoic acid, by 2- ((the 2- methoxy in step 2 Base -4- (N4Acetylpiperazinyl)-aminophenyl) -4- (3- amino) aminophenyl) -5- chlorine pyrimidine changes 2- ((4- (N into4Second Acyl piperazine base)-aminophenyl) -4- (3- amino) aminophenyl) -5- chlorine pyrimidine, by the N in step 31-(3-((2-((4- (4- Acetylpiperazine -1- base) -2- anisyl) amino) -5- pyrimidine-4-yl) amino) phenyl)-N4((tetrahydro -2H- pyrrole Mutter -2- base) oxo) Malaysia acid diamine changes N into1(((2- ((4- (4- Acetylpiperazine -1- base) phenyl) amino) -5- is phonetic by 3- Pyridine -4- base) amino) phenyl)-N4((tetrahydro -2H- pyrans -2- base) oxo) Malaysia acid diamine.
Brown solid；m.p.:220.6-221.1℃；1H NMR(500MHz,DMSO-d6)δ10.08(s,3H), 7.65 (d, J=8.5Hz, 1H), 7.50-7.44 (m, 2H), 7.40 (s, 1H), 7.31-7.18 (m, 4H), 6.87 (d, J= 11.8Hz, 1H), 6.72 (d, J=11.8Hz, 1H), 6.28 (s, 1H), 3.80 (s, 1H), 3.72-3.68 (m, 4H), 3.44 (q, J=7.0Hz, 4H), 2.08 (s, 3H), 1.91 (s, 1H) .HRMS (ESI) calcd.for C26H28ClN8O4[M+H]+= 551.1917,found 551.1917。
Embodiment 3:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - Phenyl) piperazine -1- base)-N- hydroxyl acetamide hydrochloride
Reagent and reaction condition: 1) sec-butyl alcohol, reflux, 4 hours；3) trifluoroacetic acid, methylene chloride, 1 hour；4) acryloyl Chlorine, methylene chloride, -5-0 DEG C, 30 minutes to 1 hour；5) tetrahydrofuran: water=1:1,1 hour；6) methylene chloride: N, N- diformazan Base formyl=2:1,1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, 1- hydroxy benzo triazole, 45 DEG C, 5 is small When；7) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour.
Step 1:2- ((2- methoxyl group -4- (N4Acetylpiperazinyl)-aminophenyl) -4- (3- amino) aminophenyl) - The preparation of 3- chlorine pyrimidine.
Raw material 1:4- ((the chloro- 4- pyrimidine radicals of 2,5- bis-) amino) phenyl) t-butyl carbamate is according to Cancer It is prepared by the method for diacovery, 2013,3,1404-1415.
By 4- ((the chloro- 4- pyrimidine radicals of 2,5- bis-) amino) phenyl) t-butyl carbamate (1.0mmol) and 2- (4- (4- ammonia Base phenyl) piperazine -1- base) ethyl acetate (1.0mmol) is added in 50mL three-necked flask, and 200 microlitres of 1N dilute hydrochloric acid are added It with the sec-butyl alcohol of 10mL, is heated to reflux, is stirred to react mixture 4 hours.It is cooled to room temperature after reaction, decompression is spin-dried for. Obtain brown solid.Obtained brown solid (1.0mmol) is added in 50mL three-necked flask, and 10mL trifluoro second is added Acid reacts half an hour.Trifluoroacetic acid is spin-dried under reduced pressure as far as possible, obtains brown oil.Again toward system under condition of ice bath In middle dropwise addition saturated sodium bicarbonate and remaining trifluoroacetic acid three times with the coextraction of 80mL ethyl acetate merges organic phase, organic It after phase anhydrous sodium sulfate drying, then depressurizes and is spin-dried for solvent, obtain yellow solid.
m.p.:214.5–214.8℃；1HNMR(500MHz,DMSO-d6)δ8.36(s,1H),7.96(s,1H),7.68– 7.59 (m, 2H), 6.88-6.85 (m, 2H), 6.69 (d, J=7.9Hz, 1H), 6.59 (d, J=2.4Hz, 1H), 6.38 (dd, J =8.8,2.4Hz, 1H), 6.26 (dd, J=7.9,1.3Hz, 1H), 4.90 (s, 2H), 3.73 (s, 3H), 3.53-3.50 (m, 4H),3.07–2.96(m,4H),1.99(s,3H).HRMS(ESI)calcd.for C23H27ClN7O2[M+H]+=468.1909, found 468.1912。
Step 2:2- (4- (4- ((4- ((3- acrylamido phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) piperazine Piperazine -1- base) ethyl acetate preparation
By 2- ((2- methoxyl group -4- (N4Acetylpiperazinyl)-aminophenyl) -4- (3- amino) aminophenyl) -3- chlorine Pyrimidine (1.0mmol) is added in 25mL three-necked flask, and the methylene chloride of triethylamine (4.0mmol) and 10mL is added, will be anti- Bottle is answered to be placed in ice bath, by interior temperature control system at -5 DEG C to -10 DEG C.It is slow added into acryloyl chloride (1.0mmol), stirs mixture Mix reaction 30 minutes.After reaction, 20mL water is added into reaction solution, three times with the extraction of 20mL methylene chloride, merges organic phase, Organic phase is spin-dried for, and obtains yellow solid.
m.p.:214.5–214.8℃；1HNMR(500MHz,DMSO-d6)δ8.36(s,1H),7.96(s,1H),7.68– 7.59 (m, 2H), 6.88-6.85 (m, 2H), 6.69 (d, J=7.9Hz, 1H), 6.59 (d, J=2.4Hz, 1H), 6.48 (dd, J =8.8,2.4Hz, 1H), 6.26 (s, 1H), 6.20-6.13 (m, 3H), 4.90 (s, 1H), 3.73 (s, 3H), 3.53-3.50 (m, 4H),3.07–2.96(m,4H),1.99(s,3H).HRMS(ESI)calcd.for C27H30ClN7O3[M+H]+=536.2171, found536.2171。
Step 3:2- (4- (4- ((4- ((3- acrylamido phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) piperazine Piperazine -1- base) acetic acid preparation
By 2- (4- (4- ((4- ((3- acrylamido phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) piperazine - 1- yl) ethyl acetate (1.0mmol) and lithium hydroxide (10mmol) are added in 25mL three-necked flask, and the tetrahydro of 8mL is added The water of furans and 8mL reacts 1 hour.After fully reacting, reaction system PH is adjusted to 7 or so with hydrochloric acid, faint yellow yellow is precipitated Solid.
Yellow solid；m.p.:216.3–216.9℃；1H NMR (500MHz, DMSO-d6) δ 10.01 (s, 1H), 8.07–7.94(m,2H),7.54(s,1H),7.35–7.29(m,2H),7.09(s,1H),6.54–6.21(m,3H),5.76– 5.74 (m, 1H), 5.29 (s, 1H), 5.02 (d, J=24.5Hz, 1H), 4.06-3.87 (m, 2H), 3.85-3.82 (m, 2H), 3.67-3.64 (m, 2H), 3.17 (s, 2H), 3.14 (dd, J=12.9,8.5Hz, 4H), 2.73-2.67 (m, 3H) .HRMS (ESI)calcd.for C25H27ClN7O3[M+H]+=508.1858, found 508.1859.
Step 4:N- (3- ((the chloro- 2- of 5- ((4- (4- (2- oxo -2- (((tetrahydro -2H- pyrans -2- base) oxo) amino) Ethoxy acyl group) -1- piperazinyl) phenyl) amino) -4- pyrimidine radicals) amino) phenyl) and acrylamide preparation
By 2- (4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) the chloro- 2- pyrimidine radicals of -5-) amino)-phenyl) - 1- piperazinyl)-acetic acid (1mmol) and O- (tetrahydro -2H- pyrans -2- base) azanol (1.2mmol) be dissolved into and be dissolved in 12mL dichloro In ethane and 4mL n,N-Dimethylformamide mixed solution, 1- (3- dimethylamino-propyl) -3- ethyl is added into reaction solution Carbodiimide hydrochloride (1.32mmol), 1- hydroxy benzo triazole (1.32mmol) are placed in 40 DEG C and are stirred to react 4 hours.Instead After answering, into reaction solution plus 30mL water three times with the extraction of 20mL methylene chloride merges organic phase, organic phase is spin-dried for, through column Chromatographic purifying (mobile phase dichloromethane: methanol=90:1) obtains the solid of yellow.
Yellow solid；m.p.:230.1–230.4℃；1H NMR(500MHz,DMSO-d6)δ9.49(s,1H), 8.07–7.94(m,2H),7.54(s,1H),7.35–7.29(m,2H),7.09(s,1H),6.54–6.21(m,3H),5.76– 5.73 (m, 1H), 5.29 (s, 1H), 5.02 (d, J=24.5Hz, H), 4.06-3.87 (m, 2H), 3.85-3.82 (m, 2H), 3.67-3.65 (m, 2H), 3.17 (s, 2H), 3.14 (dd, J=12.9,8.5Hz, 4H), 1.89-1.78 (m, 4H), 1.63 (m, 4H).HRMS(ESI)calcd.for C30H36ClN8O4[M+H]+=607.2454, found 607.2455.
Step 5:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino)-benzene Base) piperazine -1- base)-N- hydroxyl acetamide hydrochloride preparation.
By N- (3- ((the chloro- 2- of 5- ((4- (4- (2- oxo -2- (((tetrahydro -2H- pyrans -2- base) oxo) amino) ethoxy Acyl group) -1- piperazinyl) phenyl) amino) -4- pyrimidine radicals) amino) phenyl) acrylamide (1mmol) is added to tri- mouthfuls of 25mL burnings In bottle, and the dichloroethanes of 8mL is added.Ether (3.4mL) solution of instillation 1M hydrochloric acid under condition of ice bath, low-temp reaction 1 hour. There is solid precipitation after the reaction was completed, decompression filters, and obtains yellow solid.
Yellow solid；m.p.:218.3–218.8℃；1H NMR(500MHz,DMSO-d6)δ11.09(s,1H), 10.28 (d, J=8.9Hz, 1H), 8.31 (d, J=35.0Hz, 2H), 7.23-7.03 (m, 9H), 6.62 (d, J=16.6Hz, 1H), 6.25 (d, J=8.5Hz, 1H), 5.70 (d, J=8.5Hz, 1H), 3.20-3.07 (m, 4H), 2.75-2.71 (m, 4H), 2.16–1.93(m,4H),2.46(s,2H).HRMS(ESI)calcd.for C25H28ClN8O3[M+H]+=523.1967, found 523.1967。
Following compound is prepared using different material according to 1 same procedure of embodiment.
Embodiment 4:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 3- methoxyphenyl) piperazine -1- base)-N- hydroxyl acetamide hydrochloride
Yellow solid；m.p.:170.8–171.3℃；1H NMR(500MHz,DMSO-d6)δ11.14(s,1H), 10.38 (d, J=8.9Hz, 1H), 8.31 (d, J=35.0Hz, 2H), 7.23-7.02 (m, 9H), 6.62 (d, J=16.6Hz, 1H), 6.25 (d, J=8.7Hz, 1H), 5.73 (d, J=8.7Hz, 1H), 3.73 (s, 3H), 3.20-3.07 (m, 4H), 2.75- 2.70(m,4H),2.16–1.93(m,4H),2.46(s,2H).HRMS(ESI)calcd.for C25H27ClN7O4[M+H]+= 524.1813,found524.1815。
Embodiment 5:N- (3- ((the chloro- 2- of 5- ((4- (4- (2- (hydroxyl amino) -2- oxoethyl) piperazine -1- base) phenyl) Amino) pyrimidine-4-yl) oxo) phenyl) acrylamide hydrochloride
Its structural formula are as follows:
Yellow solid；m.p.:218.3–218.8℃；1H NMR(500MHz,DMSO-d6)δ11.03(s,1H), 10.14 (d, J=8.9Hz, 1H), 8.35 (d, J=35.0Hz, 2H), 7.37-7.28 (m, 9H), 6.78 (d, J=16.4Hz, 1H), 6.23 (d, J=8.7Hz, 1H), 5.75 (d, J=8.7Hz, 1H), 3.20-3.12 (m, 2H), 2.75-2.70 (m, 4H), 2.16–1.93(m,4H),2.46(s,2H).HRMS(ESI)calcd.for C25H27ClN7O4[M+H]+=524.1808, found 524.1809。
Embodiment 6:N- (3- ((the chloro- 2- of 5- ((3- (4- (2- (hydroxyl amino) -2- oxoethyl) piperazine -1- base) phenyl) Amino) pyrimidine-4-yl) amino) phenyl) acrylamide hydrochloride
Its structural formula are as follows:
Yellow solid；m.p.:218.3–218.8℃；1H NMR(500MHz,DMSO-d6)δ11.01(s,1H), 10.02 (d, J=8.9Hz, 1H), 8.37 (d, J=35.0Hz, 2H), 7.32-7.25 (m, 9H), 6.76 (d, J=16.0Hz, 1H), 6.25 (d, J=9.5Hz, 1H), 5.70 (d, J=9.5Hz, 1H), 3.20-3.07 (m, 4H), 2.75-2.71 (m, 4H), 2.16–1.93(m,4H),2.46(s,2H).HRMS(ESI)calcd.for C25H28ClN8O3[M+H]+=523.1967, found 523.1969。
Embodiment 7:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- trifluoromethvl-Dvrimidin -2- base) Amino)-phenyl) piperazine -1- base)-N- hydroxyl acetamide hydrochloride
Its structural formula are as follows:
Yellow solid；m.p.:192.3–192.8℃；1H NMR(500MHz,DMSO-d6)δ11.04(s,1H), 10.35 (d, J=8.9Hz, 1H), 8.31 (d, J=35.0Hz, 2H), 7.23-6.98 (m, 9H), 6.62 (d, J=16.1Hz, 1H), 6.25 (d, J=9.5Hz, 1H), 5.73 (d, J=9.5Hz, 1H), 3.20-3.07 (m, 4H), 2.70-2.67 (m, 4H), 2.16–1.93(m,4H),2.49(s,2H).HRMS(ESI)calcd.for C26H28F3N8O3[M+H]+=557.2231, found 557.2233。
Embodiment 8:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 3- methoxyphenyl) piperazine -1- base)-N- hydroxypropanamide hydrochloride
Its structural formula are as follows:
Yellow solid；m.p.:187.8–188.2℃；1H NMR(500MHz,DMSO-d6)δ10.77(s,1H), 10.68 (s, 1H), 10.32 (s, 1H), 7.99 (t, J=6.4Hz, 3H), 7.68 (s, 1H), 7.34-7.30 (m, 3H), 6.82- 6.41 (m, 2H), 6.30-6.17 (d, J=5.7Hz, 1H), 5.75 (d, J=5.7Hz, 1H), 3.79 (s, 3H), 3.56-3.32 (m, 4H), 3.08-3.02 (m, 4H), 2.73 (d, J=4.9Hz, 4H), 2.65 (s, 1H), 1.91 (s, 1H) .HRMS (ESI) calcd.for C27H32ClN8O4[M+H]+=567.2230, found 567.2234.
Embodiment 9:4- (4- (4- ((4- ((3- acetvlaminophenvl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) Piperazine -1- base)-N- hydroxybutyramide hydrochloride
Its structural formula are as follows:
Brown solid；m.p.:239.2–240.1℃；1H NMR(500MHz,DMSO-d6)δ11.01(s,1H), 10.47 (d, J=8.9Hz, 1H), 8.31 (d, J=35.0Hz, 2H), 7.23-7.18 (m, 9H), 6.62 (d, J=16.6Hz, 1H), 6.25 (d, J=8.2Hz, 1H), 5.73 (d, J=8.2Hz, 1H), 3.20-3.07 (m, 4H), 2.75-2.71 (m, 4H), 2.16–1.93(m,4H),1.39–1.36(m,2H).HRMS(ESI)calcd.for C27H32ClN8O3[M+H]+= 551.2280,found 551.2283。
Embodiment 10:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 3- methoxyphenyl) piperazine -1- base)-N- hydroxybutyramide hydrochloride
Its structural formula are as follows:
Brown solid；m.p.:194.2–194.4℃；1H NMR(500MHz,DMSO-d6)δ8.12(s,1H),8.01 (s, 1H), 7.84 (s, 2H), 7.54 (d, J=14.4Hz, 1H), 7.40 (d, J=7.7Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.25 (s, 1H), 7.16 (s, 1H), 7.05 (d, J=10.0Hz, 1H), 6.84 (t, J=9.0Hz, 1H), 6.46 (d, J= 9.0Hz, 1H), 6.33-6.29 (m, 1H), 5.78 (d, J=10.0Hz, 1H), 3.79 (s, 3H), 3.69 (s, 4H), 3.10 (s, 4H), 2.34 (t, J=7.5Hz, 2H), 2.06 (s, 1H), 1.69-1.60 (m, 2H), 1.39-1.37 (m, 2H) .HRMS (ESI) calcd.for C28H34ClN8O4[M+H]+=581.2386, found 581.2388.
Embodiment 11:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 3- methoxyphenyl) piperazine -1- base)-N- hydroxypentanoyl amine hydrochlorate
Its structural formula are as follows:
Brown solid；m.p.:211.5–212.2℃；1H NMR(500MHz,DMSO-d6)δ8.12(s,1H),8.01 (s, 1H), 7.84 (s, 2H), 7.54 (d, J=14.4Hz, 1H), 7.40 (d, J=7.7Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.25 (s, 1H), 7.16 (s, 1H), 7.05 (d, J=10.0Hz, 1H), 6.84 (t, J=9.0Hz, 1H), 6.46 (d, J= 9.0Hz, 1H), 6.33-6.30 (m, 1H), 5.78 (d, J=10.0Hz, 1H), 3.79 (s, 3H), 3.69 (s, 4H), 3.10 (s, 4H), 2.73 (s, 2H), 2.34 (t, J=7.5Hz, 2H), 2.06 (s, 1H), 1.69-1.65 (m, 2H), 1.50-1.46 (m, 2H).
13CNMR(125MHz,DMSO-d6)δ163.8,161.0,139.8,137.5,132.6,132.4,129.1, 127.3,123.9,123.1,118.2,107.5,107.4,100.8,100.8,56.4,56.3,54.3,51.6,45.8, 19.0,17.2.HRMS(ESI)calcd.for C29H35ClFN8O3[M+H]+=597.2499, found 597.2503.
Embodiment 12:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 3- methoxyphenyl) piperazine -1- base)-N- hydroxyl hexanamide hydrochloride
Its structural formula are as follows:
Brown solid；m.p.:206.5–206.8℃；1H NMR(500MHz,DMSO-d6)δ9.12(s,1H),9.01 (s, 1H), 8.84 (s, 2H), 7.54 (d, J=14.4Hz, 1H), 7.40 (d, J=7.7Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.25 (s, 1H), 7.16 (s, 1H), 7.05 (d, J=10.0Hz, 1H), 6.84 (t, J=9.7Hz, 1H), 6.46 (d, J= 9.7Hz, 1H), 6.33-6.30 (m, 1H), 5.78 (d, J=10.0Hz, 1H), 3.79 (s, 3H), 3.69 (s, 4H), 3.10 (s, 4H), 2.73 (s, 2H), 2.34 (t, J=7.5Hz, 2H), 2.08 (s, 2H), 2.06 (s, 1H), 1.69-1.65 (m, 2H), 1.39–1.35(m,2H).HRMS(ESI)calcd.for C29H35ClFN8O3[M+H]+=597.2499, found 597.2503。
Embodiment 13:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 2- fluorophenyl) piperazine -1- base)-N- hydroxyl hexanamide hydrochloride
Its structural formula are as follows:
Brown solid；m.p.:75.6–76.2℃；1H NMR(500MHz,DMSO-d6)δ8.12(s,1H),8.01 (s, 1H), 7.84 (s, 2H), 7.54 (d, J=14.4Hz, 1H), 7.40 (d, J=7.7Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.25 (s, 1H), 7.16 (s, 1H), 7.05 (d, J=10.0Hz, 1H), 6.84 (t, J=8.7Hz, 1H), 6.46 (d, J= 8.7Hz, 1H), 6.33-6.31 (m, 1H), 5.78 (d, J=10.0Hz, 1H), 3.69 (s, 4H), 3.10 (s, 4H), 2.73 (s, 2H), 2.34 (t, J=7.5Hz, 2H), 2.08 (s, 2H), 2.06 (s, 1H), 1.69-1.65 (m, 2H), 1.57-1.54 (m, 2H).HRMS(ESI)calcd.for C29H35ClFN8O3[M+H]+=597.2499, found 597.2503.
Embodiment 14:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 3- fluorophenyl) piperazine -1- base)-N- hydroxybutyramide hydrochloride
Its structural formula are as follows:
Yellow solid；m.p.:197.7–198.2℃；1H NMR(500MHz,DMSO-d6)δ8.22(s,1H), 8.01 (s, 1H), 7.74 (s, 2H), 7.51 (d, J=14.4Hz, 1H), 7.47 (d, J=7.7Hz, 1H), 7.30 (t, J= 8.0Hz, 1H), 7.25 (s, 1H), 7.16 (s, 1H), 7.09 (d, J=10.0Hz, 1H), 6.87 (t, J=9.0Hz, 1H), 6.43 (d, J=9.0Hz, 1H), 6.33-6.31 (m, 1H), 5.78 (d, J=10.0Hz, 1H), 3.69 (s, 4H), 3.10 (s, 4H), 2.73(s,2H),2.34–2.32(m,2H),1.57–1.55(m,2H).HRMS(ESI)calcd.for C27H31ClFN8O3[M+ H]+=569.2192, found569.2192.
Embodiment 15:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 2- fluorophenyl) piperazine -1- base)-N- hydroxybutyramide hydrochloride
Its structural formula are as follows:
Yellow solid；M.p. 250 DEG C of >；1H NMR(500MHz,DMSO-d6)δ8.22(s,1H),8.01(s, 1H), 7.74 (s, 2H), 7.55 (d, J=14.4Hz, 1H), 7.40 (d, J=7.7Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.25 (s, 1H), 7.16 (s, 1H), 7.05 (d, J=10.0Hz, 1H), 6.84 (t, J=9.0Hz, 1H), 6.46 (d, J= 9.0Hz, 1H), 6.33-6.31 (m, 1H), 5.78 (d, J=10.0Hz, 1H), 3.69 (s, 4H), 3.10 (s, 4H), 2.73 (s, 2H),2.34–2.30(m,2H),1.57–1.54(m,2H).HRMS(ESI)calcd.for C27H31ClFN8O3[M+H]+= 569.2192,found 569.2192。
Embodiment 16:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 3- fluorophenyl) piperazine -1- base)-N- hydroxyl hexanamide hydrochloride
Its structural formula are as follows:
Yellow solid；m.p.:90.6–91.2℃；1H NMR(500MHz,DMSO-d6)δ8.12(s,1H),8.01 (s, 1H), 7.84 (s, 2H), 7.54 (d, J=14.4Hz, 1H), 7.40 (d, J=7.7Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 7.05 (d, J=10.0Hz, 1H), 6.84 (t, J=9.7Hz, 1H), 6.46 (d, J= 9.7Hz, 1H), 6.33-6.30 (m, 1H), 5.78 (d, J=10.0Hz, 1H), 3.69 (s, 4H), 3.10 (s, 4H), 2.73 (s, 2H), 2.34 (t, J=7.5Hz, 2H), 2.08 (s, 2H), 2.06 (s, 1H), 1.69-1.65 (m, 2H), 1.57-1.53 (m, 2H).HRMS(ESI)calcd.for C29H35ClFN8O3[M+H]+=597.2499, found 597.2503.
Embodiment 17:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) Phenyl) piperazine -1- base)-N- hydroxyl hexanamide hydrochloride
Its structural formula are as follows:
Yellow solid；m.p.:179.6–179.9℃；1H NMR(500MHz,DMSO-d6)δ8.11(s,1H), 8.00 (s, 1H), 7.84 (s, 2H), 7.57-7.54 (m, 1H), 7.40 (d, J=7.7Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 7.05 (d, J=10.0Hz, 1H), 6.84 (t, J=8.0Hz, 1H), 6.46 (d, J= 8.0Hz, 1H), 6.33-6.31 (m, 2H), 5.78 (d, J=10.0Hz, 1H), 3.69 (s, 4H), 3.10 (s, 4H), 2.73 (s, 2H), 2.34 (t, J=7.5Hz, 2H), 2.08 (s, 2H), 2.06 (s, 1H), 1.69-1.65 (m, 2H), 1.57-1.55 (m, 2H).HRMS(ESI)calcd.for C29H35ClFN8O3[M+H]+=597.2499, found 597.2503.
Embodiment 18:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 2- aminomethyl phenyl) piperazine -1- base)-N- hydroxyl hexanamide hydrochloride
Its structural formula are as follows:
Brown solid；m.p.:135.7-136.5℃；1H NMR(500MHz,DMSO-d6)δ8.42(s,1H),8.31 (s, 1H), 7.93 (s, 2H), 7.56 (d, J=14.4Hz, 1H), 7.45 (d, J=7.7Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.26 (s, 1H), 7.16 (s, 1H), 7.03 (d, J=10.0Hz, 1H), 6.87 (t, J=9.0Hz, 1H), 6.40 (d, J= 9.0Hz, 1H), 6.33 (m, 1H), 5.79 (d, J=10.0Hz, 1H), 3.70 (s, 4H), 3.28 (s, 3H), 3.10 (s, 4H), 2.73 (s, 2H), 2.34 (t, J=7.5Hz, 2H), 2.08 (s, 2H), 2.06 (s, 1H), 1.69-1.65 (m, 2H), 1.37- 1.33(m,2H).HRMS(ESI)calcd.for C30H38ClN8O3[M+H]+=593.2750, found 593.2750.
Embodiment 19:6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 2- chlorphenyl) piperazine -1- base)-N- hydroxyl hexanamide hydrochloride
Its structural formula are as follows:
Brown solid；m.p.:135.7-136.5℃；1H NMR(500MHz,DMSO-d6)δ8.45(s,1H),8.31 (s, 1H), 7.93 (s, 2H), 7.90 (d, J=14.4Hz, 1H), 7.78 (d, J=7.7Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.16 (s, 1H), 7.10 (s, 1H), 7.03 (d, J=10.0Hz, 2H), 6.87 (t, J=9.0Hz, 1H), 6.40 (d, J= 9.0Hz, 1H), 6.33-6.31 (m, 1H), 5.79 (d, J=10.0Hz, 1H), 3.70 (s, 4H), 3.10 (s, 4H), 2.73 (s, 2H), 2.34 (t, J=7.5Hz, 2H), 2.08 (s, 2H), 2.06 (s, 1H), 1.69-1.65-1.63 (m, 2H), 1.37-1.35 (m,2H).HRMS(ESI)calcd.for C29H35Cl2N8O3[M+H]+=613.2209, found 613.2210.
Embodiment 20:N1(4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) benzene Base)-N5Hydroxyl glutaramide hydrochloride
Its structural formula are as follows:
Brown solid；m.p.:113.4-114.1℃；1H NMR(500MHz,DMSO-d6)δ11.05(s,1H), 10.01 (d, J=16.5Hz, 2H), 9.97 (d, J=9.2Hz, 2H), 8.38-8.35 (m, 2H), 8.17-8.15 (m, 1H), 7.59 (d, J=8.5Hz, 2H), 7.33-7.11 (m, 7H), 6.75-6.70 (m, 1H), 6.24 (d, J=3.8Hz, 1H), 5.78 (d, J=3.8Hz, 1H), 2.12-2.08 (m, 6H) .HRMS (ESI) calcd.for C24H25ClN7O4[M+H]+= 510.1651,found 510.1655。
Embodiment 21:N1(4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) benzene Base)-N8Hydroxyl suberamide hydrochloride
Its structural formula are as follows:
Brown solid；m.p.:97.6–98.0℃；1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),10.56 (d, J=16.8Hz, 2H), 9.98 (d, J=9.2Hz, 2H), 8.34-8.29 (m, 2H), 8.07 (d, J=52.7Hz, 1H), 7.58 (d, J=8.3Hz, 2H), 7.33-7.01 (m, 7H), 6.55-6.50 (m, 1H), 6.24 (d, J=3.9Hz, 1H), 5.75 (d, J=3.9Hz, 1H), 3.30-3.14 (m, 2H), 2.08-2.02 (m, 6H), 1.53-1.44 (m, 2H), 1.26 (s, 2H) .HRMS(ESI)calcd.for C27H31ClN7O4[M+H]+=552.2121, found 552.2124.
Embodiment 22:N1(4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) - 3- methoxyphenyl)-N5Hydroxyl glutaramide hydrochloride
Its structural formula are as follows:
Brown solid；m.p.:1153.9–154.4℃；1H NMR(500MHz,DMSO-d6)δ10.09(s,1H), 9.58 (d, J=16.5Hz, 2H), 8.91 (d, J=9.2Hz, 2H), 8.54-8.50 (m, 2H), 8.19-8.16 (m, 1H), 7.60 (d, J=8.1Hz, 2H), 7.34-7.16 (m, 7H), 6.75-6.55 (m, 1H), 6.24 (d, J=3.9Hz, 1H), 5.78 (d, J =3.9Hz, 1H), 3.75 (s, 3H), 2.33-218 (m, 6H) .HRMS (ESI) calcd.for C25H27ClN7O5[M+H]+= 540.1757,found 540.1755。
Embodiment 23:4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) pyrimidine -2-base) amino) phenoxy group)- N- hydroxypentanoyl amine hydrochlorate
Its structural formula are as follows:
White solid；m.p.:130.0–130.4℃；1H NMR(500MHz,DMSO-d6)δ10.98(s,1H), 10.63(s,1H),10.46(s,1H),8.30–7.78(m,2H),7.49–7.24(m,4H),6.93(s,2H),6.71–6.36 (m, 2H), 6.26 (d, J=2.3Hz, 1H), 5.81-5.71 (d, J=2.3Hz, 1H), 3.95-3.86 (m, 4H), 3.38 (q, J =7.0Hz, 1H), 2.14 (t, J=7.4Hz, 2H), 2.00-1.84 (m, 2H), 1.09 (t, J=7.0Hz, 1H).
13CNMR(125MHz,DMSO-d6)δ169.7,164.1,158.5,157.8,156.4,140.2,137.9, 132.7,130.6,129.8,129.6,127.7,121.1,121.0,118.0,117.1,115.3,108.8,68.1,32.7, 29.0,22.6.HRMS(ESI)calcd.for C23H25N6O4[M+H]+=449.1932, found 449.1932.
Embodiment 24:4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) pyrimidine -2-base) amino) phenoxy group)- N- hydroxyl hexanamide hydrochloride
Its structural formula are as follows:
White solid；m.p.:146.5–146.9℃；1H NMR (500MHz, DMSO) δ 10.54 (d, J=11.9Hz, 2H), 10.21 (s, 1H), 8.34 (s, 1H), 8.03 (s, 1H), 7.58 (d, J=6.5Hz, 1H), 7.32-7.22 (m, 4H), 6.76 (s, 2H), 6.55 (dd, J=16.9,10.2Hz, 1H), 6.26 (dd, J=16.9,1.7Hz, 1H), 5.76 (dd, J= 10.2,1.8Hz, 1H), 3.88 (s, 2H), 2.01 (t, J=6.9Hz, 2H), 1.74-1.48 (m, 4H) .HRMS (ESI) calcd.for C24H26ClN6O4[M+H]+=497.1699, found 497.1699.
Embodiment 25:4- (3- ((4- ((3- acryloyl group-amino-phenyl) amino) pyrimidine -2-base) amino) phenoxy group)- N- hydroxybutyramide hydrochloride
Its structural formula are as follows:
White solid；m.p.:156.2–156.6℃；1H NMR(500MHz,DMSO-d6)δ10.68(s,1H), 10.22(s,1H),10.06(s,1H),8.33–7.58(m,2H),7.50–7.22(m,4H),6.90(s,2H),6.71–6.41 (m, 2H), 6.26 (d, J=2.3Hz, 1H), 5.81-5.70 (d, J=2.3Hz, 1H), 3.95-3.86 (m, 4H), 3.38 (q, J =7.0Hz, 1H), 2.14 (t, J=7.4Hz, 2H), 2.00-1.84 (m, 2H), 1.09 (t, J=7.0Hz, 1H) .HRMS (ESI) calcd.for C23H25N6O4[M+H]+=449.1932, found 449.1932.
Embodiment 26:4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) benzene Oxygroup)-N- hydroxybutyramide hydrochloride
Its structural formula are as follows:
White solid；m.p.:130.0-130.4℃；1H NMR(500MHz,DMSO-d6)δ10.98(s,1H), 10.63(s,1H),10.46(s,1H),8.30–7.78(m,2H),7.49–7.24(m,4H),6.93(s,2H),6.71–6.36 (m, 2H), 6.26 (d, J=2.3Hz, 1H), 5.81 (d, J=2.3Hz, 1H), 3.95-3.86 (m, 4H), 3.38 (q, J= 7.0Hz, 1H), 2.14 (t, J=7.4Hz, 2H), 2.00-1.84 (m, 2H), 1.09 (t, J=7.0Hz, 1H) .HRMS (ESI) calcd.for C23H25N6O4[M+H]+=483.1542, found 483.1542.
Embodiment 27:4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) benzene Oxygroup)-N- hydroxybutyramide hydrochloride
Its structural formula are as follows:
White solid；m.p.:130.0-130.4℃；1H NMR(500MHz,DMSO-d6)δ10.98(s,1H), 10.63(s,1H),10.46(s,1H),8.30–7.78(m,1H),7.49–7.24(m,4H),6.93(s,2H),6.71–6.36 (m, 2H), 6.26 (d, J=2.3Hz, 1H), 5.81 (d, J=2.3Hz, 1H), 3.95-3.89 (m, 4H), 3.38 (q, J= 7.0Hz, 1H), 2.14 (t, J=7.4Hz, 2H), 2.00-1.84 (m, 2H), 1.09 (t, J=7.0Hz, 1H) .HRMS (ESI) calcd.for C23H25N6O4[M+H]+=483.1542, found 483.1542.
Embodiment 28:6- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) the chloro- 2- pyrimidine radicals of -5-) amino) -3- Difluoro-phenoxy)-N- ((tetrahydro -2H- pyrans -2- base) oxo) acetamide
Its structural formula are as follows:
White solid；m.p.:145.3-145.9℃；1H NMR(500MHz,DMSO-d6)δ10.09(s,1H), 10.01(s,1H),9.98(s,1H),8.30–7.73(m,2H),7.49–7.24(m,4H),6.89(s,2H),6.77–6.30 (m, 2H), 6.27 (d, J=2.2Hz, 1H), 5.85 (d, J=2.2Hz, 1H), 3.92-3.83 (m, 4H), 3.39 (q, J= 7.0Hz, 1H), 2.15 (t, J=7.4Hz, 2H), 2.00-1.84 (m, 2H), 1.19 (t, J=7.0Hz, 1H) .HRMS (ESI) calcd.for C23H25N6O4[M+H]+=483.1542, found 483.1542.
Embodiment 29:4- ((2- ((4- ((4- ((3- Acryloyl amino phenyl) amino) -5- chlorine pyrimidine -2-base) amino) Phenyl) (methyl) amino-ethyl) (methyl) amino)-N- hydroxybutyramide hydrochloride
Its structural formula are as follows:
Yellow solid；m.p.:110.5–112.1℃；1H NMR(500MHz,DMSO)δ9.25(s,1H),8.79 (s, 1H), 7.95 (d, J=8.4Hz, 4H), 7.65 (d, J=8.3Hz, 4H), 7.49-7.46 (m, 4H), 7.39-7.35 (m, 4H), 6.25 (d, J=12.1Hz, 1H), 5.74 (d, J=12.1Hz, 1H), 3.58 (d, J=2.8Hz, 2H), 2.93 (s, 3H), 2.44-2.23 (m, 2H), 2.01 (s, 2H), 1.79-1.61 (m, 3H), 1.18 (t, J=7.1Hz, 2H) .HRMS (ESI) calcd.for C27H34ClN8O3[M+H]+=553.2442, found 553.2443.
Embodiment 30:4- ((2- ((4- ((4- ((3- Acryloyl amino phenyl) amino) -5- chlorine pyrimidine -2-base) amino) Phenyl) (methyl) amino-ethyl) (methyl) amino)-N- hydroxyl hexanamide hydrochloride
Its structural formula are as follows:
Yellow solid；m.p.:163.8-164.5℃；1H NMR(500MHz,DMSO)δ9.15(s,1H),8.78 (s, 1H), 7.94 (d, J=8.4Hz, 4H), 7.65 (d, J=8.3Hz, 4H), 7.49-7.46 (m, 4H), 7.39-7.35 (m, 4H), 6.25 (d, J=12.0Hz, 1H), 5.74 (d, J=12.0Hz, 1H), 4.03 (q, J=7.1Hz, 2H), 3.58 (d, J= 2.8Hz, 2H), 2.93 (s, 3H), 2.75 (t, J=27.4Hz, 4H), 2.41-2.21 (m, 2H), 1.99 (s, 2H), 1.78- 1.61 (m, 3H), 1.18 (t, J=7.1Hz, 2H) .HRMS (ESI) calcd.for C29H38ClN8O3[M+H]+=581.2755, found581.2755。
Embodiment 31: compound is to A431, H1975, HeLa cell inhibitory effect determination of activity
This example is thin for EGFR wild type overexpression cell line A431, T790M point mutation for measuring the compounds of this invention The proliferation inhibition activity of born of the same parents' strain H1975, human cervical carcinoma cell lines Hela, the inhibitory activity of compound on intracellular proliferation are pressed down with half Concentration IC processed50To indicate.Testing program is as follows: EGFR wild type overexpression cell line A431, T790M point mutation cell strain H1975 cell and human cervical carcinoma cell lines Hela are purchased from ATCC, with suitable cell concentration (A431:20000 cell/ml Culture medium；H1975:15000 cell/ml culture medium) by cell inoculation on 96 well culture plates of white clear；It later will be thin Born of the same parents are placed in 37 DEG C, 5%CO2Environment in cultivated, after 24 hours, be added into the cell culture medium of culture a series of dense The drug for spending gradient, is typically chosen 10 concentration, puts back in former culture environment cell continue culture 48 hours later, press later According to the method for CellTiter-Glo Luminescent Cell Viability Assay, measure test-compound to A431 and The influence of H1975, HeLa cell Proliferation, and the inhibitory activity of the compound on intracellular proliferation of various concentration is calculated, CellTiter-Glo Luminescent Cell Viability Assay detection reagent is purchased from Promega.Later to difference A431, H1975, HeLa cell inhibitory effect activity carry out four parameter fittings, test-compound of the present invention under the compound of concentration IC50 data be shown in Table 1.
Table 1
Embodiment 32: part of compounds is to SW620, KB, HepG2, HL60 cell inhibitory effect determination of activity
This example is for measuring the compounds of this invention for HepG2 cell lines, human colon cancer cell strain SW620, people The proliferation inhibition activity of oral cavity epidermoid carcinoma cell strain KB, people in loop strain HL60, compound on intracellular proliferation Inhibitory activity half-inhibitory concentration IC50To indicate.Testing program such as embodiment 31.Part test-compound of the present invention IC50Data such as the following table 2.
Table 2
Conclusion: there is novelty in the compounds of this invention structure, synthesize 2 of the segment containing hydroxamic acid, 4- diaryl-amine for the first time Pyrimidines.Bioactivity evaluation result is shown simultaneously, and the compound of the present invention is to the people's epidermis for being overexpressed EGFR Cancer cell line A431, human lung adenocarcinoma cell line H1975 drug resistant to Gefitinib and Human cervical carcinoma cell line HeLa have obvious Inhibit proliferaton activity, part of compounds is suitable with positive WZ4002 and SAHA.Gefitinib drug resistance is overcome for design is novel EGFR inhibitor provides mentality of designing.

Claims (4)

1. the 2 of a kind of segment containing hydroxamic acid as shown in formula II, 4- diaryl-amine yl pyrimidines analog derivative, general structure are as follows:
Wherein:
X is
N is 1~5,
R1For hydrogen, chlorine atom or trifluoromethyl,
R2For hydrogen atom, methoxyl group, halogen or methyl.
2. the hydrochloride of the 2 of a kind of segment containing hydroxamic acid, 4- diaryl-amine yl pyrimidines analog derivative, which is characterized in that selected from such as Under any compound:
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino)-phenyl) piperazine -1- Base)-N- hydroxyl acetamide hydrochloride (compound 3)；
N- (3- ((the chloro- 2- of 5- ((4- (4- (2- (hydroxyl amino) -2- oxoethyl) piperazine -1- base) phenyl) amino) pyrimidine -4- Base) oxo) phenyl) acrylamide hydrochloride (compound 5)；
N- (3- ((the chloro- 2- of 5- ((3- (4- (2- (hydroxyl amino) -2- oxoethyl) piperazine -1- base) phenyl) amino) pyrimidine -4- Base) amino) phenyl) acrylamide hydrochloride (compound 6)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- trifluoromethvl-Dvrimidin -2- base) amino)-phenyl) Piperazine -1- base)-N- hydroxyl acetamide hydrochloride (compound 7)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyl) Piperazine -1- base)-N- hydroxypropanamide hydrochloride (compound 8)；
4- (4- (4- ((4- ((3- acetvlaminophenvl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) piperazine -1- base) - N- hydroxybutyramide hydrochloride (compound 9)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyl) Piperazine -1- base)-N- hydroxybutyramide hydrochloride (compound 10)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyl) Piperazine -1- base)-N- hydroxypentanoyl amine hydrochlorate (compound 11)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyl) Piperazine -1- base)-N- hydroxyl hexanamide hydrochloride (compound 12)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- fluorophenyl) piperazine Piperazine -1- base)-N- hydroxybutyramide hydrochloride (compound 14)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -2- fluorophenyl) piperazine Piperazine -1- base)-N- hydroxybutyramide hydrochloride (compound 15)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) piperazine -1- Base)-N- hydroxyl hexanamide hydrochloride (compound 17)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -2- aminomethyl phenyl) piperazine Piperazine -1- base)-N- hydroxyl hexanamide hydrochloride (compound 18)；
6- (4- (4- ((4- ((3- acryloyl group-aminophenyl) amino) -5- chlorine pyrimidine -2-base) amino) -2- chlorphenyl) piperazine Piperazine -1- base)-N- hydroxyl hexanamide hydrochloride (compound 19)；
N1(4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl)-N5Hydroxyl penta Diamides hydrochloride (compound 20)；
N1(4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) -3- methoxyphenyl) - N5Hydroxyl glutaramide hydrochloride (compound 22)；
4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) pyrimidine -2-base) amino) phenoxy group)-N- hydroxyvaleramide Hydrochloride (compound 23)；
4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) pyrimidine -2-base) amino) phenoxy group)-N- hydroxyl hexanamide Hydrochloride (compound 24)；
4- (3- ((4- ((3- acryloyl group-amino-phenyl) amino) pyrimidine -2-base) amino) phenoxy group)-N- hydroxybutyrate amide Hydrochloride (compound 25)；
4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenoxy group)-N- hydroxyl fourth Amide hydrochloride (compound 26)；
4- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenoxy group)-N- hydroxyl fourth Amide hydrochloride (compound 27)；
6- (4- ((4- ((3- acryloyl group-amino-phenyl) amino) the chloro- 2- pyrimidine radicals of -5-) amino) -3- methoxyl group-benzene oxygen Base)-N- ((tetrahydro -2H- pyrans -2- base) oxo) acetamide (compound 28)；
4- ((2- ((4- ((4- ((3- Acryloyl amino phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) (methyl) ammonia Base ethyl) (methyl) amino)-N- hydroxybutyramide hydrochloride (compound 29)；
4- ((2- ((4- ((4- ((3- Acryloyl amino phenyl) amino) -5- chlorine pyrimidine -2-base) amino) phenyl) (methyl) ammonia Base ethyl) (methyl) amino)-N- hydroxyl hexanamide hydrochloride (compound 30).
3. the preparation method of II compound of formula according to claim 1, which is characterized in that realized by following steps:
Wherein X, R1、R2Definition with n is the same as claim 1；
Reagent and reaction condition: 1) sec-butyl alcohol, 0 DEG C, 4 hours；2) sec-butyl alcohol, reflux, 4 hours；3) trifluoroacetic acid, dichloromethane Alkane, 1 hour；4) acryloyl chloride, methylene chloride, -5-0 DEG C, 30 minutes to 1 hour；5) tetrahydrofuran: water=1:1,1 hour；6) Methylene chloride: N, N- dimethyl formyl=2:1,1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, 1- hydroxy benzenes And triazole, 45 DEG C, 5 hours；7) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour.
4. II compound of formula according to claim 1 is preparing the application in antitumor cell drug, which is characterized in that institute It states tumour cell and refers to people's epidermis cancer cell line A431 of overexpression EGFR, to the drug resistant human lung adenocarcinoma cell line of Gefitinib H1975, tumour cell relevant to HDAC acetylation of histone enzymatic activity；It is wherein described with HDAC acetylation of histone enzyme activity Property relevant tumour cell be Human cervical carcinoma cell line HeLa, human mouth epidermoid carcinoma cell strain KB, the acute white blood of the early young grain of people Disease cell line HL60, HepG2 cell lines, human colon cancer cell strain SW620.
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