CN105646371A - 2,4-diarylamine pyrimidine derivatives containing hydroxamic acid fragments and preparation and application - Google Patents

2,4-diarylamine pyrimidine derivatives containing hydroxamic acid fragments and preparation and application Download PDF

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CN105646371A
CN105646371A CN201610034158.XA CN201610034158A CN105646371A CN 105646371 A CN105646371 A CN 105646371A CN 201610034158 A CN201610034158 A CN 201610034158A CN 105646371 A CN105646371 A CN 105646371A
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amino
base
compound
phenyl
chloropyrimide
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CN105646371B (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 invention provides 2,4-diarylamine pyrimidine derivatives containing hydroxamic acid fragments shown in formulas I and II. 2,4-diarylamine pyrimidine containing carboxyl fragments is mainly used as a parent nucleus and is subjected to single-step condensation and related modification with hydroxylamine protected by THP to obtain a target compound. An experiment proves that the remarkable anti-proliferative effect is achieved for tumor cells (a human lung adenocarcinoma cell line H1975 and an overexpression EGFR human epidermal carcinoma cell line A431) related to EGFR tyrosine kinase activity on the cellular level, and a human cervical carcinoma cell line Hela, a human oral epidermoid carcinoma cell line KB, a human promyelocytic acute leukemia cell line HL60, a human hepatoma cell line HepG2, a human colon cancer cell line SW620 and other tumor cells related to the HDAC histone acetylase activity, and the corresponding medicine for resisting cancer cells can be prepared. The general structural formula is shown in the description.

Description

2,4-diaryl-amine yl pyrimidines analog derivative containing hydroxamic acid fragment and preparation and application
Technical field
The invention belongs to pharmaceutical field, relate to a kind of 2,4-diaryl-amine pyrimidine derivatives containing hydroxamic acid fragment and its preparation method and application.
Background technology
Research finds, all there is the sudden change of one or more EGFR family receptors or process LAN in more than the malignant tumor of 60%. Tyrosine kinase plays important regulating and controlling effect in the growth of cell, propagation and apoptotic process. Small molecule EGFR tyrosine inhibitors of kinases and ATP competition binding to EGFR intracellular region phosphorylation site, it is suppressed that EGFR is from process phosphoric acid and blocks downstream signaling pathway, reach to suppress the purpose of tumor cell. Patients with Non-small-cell Lung is had good curative effect by the first generation reversible EGFR inhibitor including gefitinib, but, Clinical practice occurs acquired drug-resistance. Because the Wild type EGFR of skin and intestinal is had stronger inhibitory action by first generation inhibitor, so causing the side effect such as dermatitis, diarrhoea, making to connect subject patients ' life quality and declining. The therapeutic strategy of irreversible EGFR inhibitor targeting EGFR T790M obtains certain achievement, can be used for, with the Afatinib irreversible EGFR inhibitor of the second filial generation being representative, the drug resistance patient treatment that caused by first generation reversible EGFR inhibitor gefitinib. But the irreversible EGFR inhibitor of second filial generation selectivity between Wild type EGFR and T790M saltant type is not strong, the high inhibition effect of Wild type EGFR is caused the initiation side effect such as dermatitis, diarrhoea. AZD9291, trade name tower gires (Tagrisso or Osimertinib), being the non-reversible Catastrophic selection type EGFR inhibitor of the third generation that Astrazeneca AB (AstraZeneca) researches and develops, the NSCLC patient that existing EGFR-TKI resistance and T790M are suddenlyd change has good therapeutic effect. WZ4002 is the non-reversible Catastrophic selection type EGFR inhibitor of the third generation looking for report most, has good selectivity between Wild type EGFR and mutant egf R. But the third generation non-reversible Catastrophic selection type EGFR inhibitor also can cause C797S new for EGFR to suddenly change.How to solve resistance problems, become the study hotspot of EGFR inhibitor.
Histon deacetylase (HDAC) (HistoneDeacetylase; HDAC) it is the class protease that is widely present in eukaryotic cells; histon deacetylase (HDAC) forms active center by chelated zinc ions; and then the acetamide on catalyzing hydrolysis istone lysine residue, make DNA methylase inhibitor. Occur at Several Kinds of Malignancy and the process of development all exists HDAC unconventionality expression. In recent years, research finds to suppress the activity of HDACs, making HATs level of relative improve, can improve DNA methylase inhibitor level, thus promoting tumor cell differentiation, reaching antineoplastic purpose.
Hdac inhibitor can the enzymatic activity of inhibition of histone deacetylase, play the purpose of cell cycle arrest, inducing tumor cell differentiation or apoptosis. HDACs can be divided into six classes by the difference according to Zinc Ions Chelated group: short-chain fat class, hydroximic acid, cyclic tetrapeptide class, benzamides, mercaptan and electrophilic ketone and assorted molecule class. Wherein study the most extensively, activity stronger be hydroximic acid inhibitor. Vorinostat (SAHA) is the hdac inhibitor of first listing. A lot of clinical researches now trend towards the HDACIs antitumor drug coupling with other, to obtain better therapeutic effect. Wherein, clinical II, the III phase research such as hdac inhibitor SAHA and proteasome inhibitor Bortezomib drug combination treatment glioblastoma multiforme, recurrent lymphoma, multiple myeloma carries out. Recent clinical research also have by hdac inhibitor and EGFR inhibitor coupling, to can solve the problem that resistance problems, the drug effect fragment hydroxamic acid of hdac inhibitor is connected to EGFR inhibitor quinazoline parent nucleus design EGFR/HDAC Mutiple Targets medicine by existing research, CUDC-101 comes into clinical?stage conceptual phase, and this Mutiple Targets inhibitor is better than the EGFR inhibitor of single target spot to the inhibition of drug-resistant cell strain. The double; two target spot inhibitor of EGFR/HDAC is expected to become a kind of effective antitumour medicine.
Summary of the invention
The technical problem to be solved is to provide a kind of containing the 2 of hydroxamic acid fragment, 4-diaryl-amine pyridine derivatives, it is a kind of and the diverse pyridine derivatives of prior art, there is preferably anti-tumor activity, there is EGFR/HDAC inhibitory activity simultaneously.
A kind of 2,4-diaryl-amine pyridine derivatives containing hydroxamic acid fragment provided by the invention, general structure is such as shown in formula I:
Wherein:
R1For hydrogen atom or chlorine atom;
R2For hydrogen atom or methoxyl group.
A kind of 2,4-diaryl-amine pyridine derivatives containing hydroxamic acid fragment provided by the invention, general structure is such as shown in formula II:
Wherein:
X is ehter bond (-O-), amido linkPiperazinylOr N, N '-dimethyl ethylenediamine base
N is 1��5;
R1For hydrogen atom, chlorine atom or trifluoromethyl;
R2For hydrogen atom, methoxyl group, halogen and methyl.
Compounds I of the present invention is following arbitrary compound:
N1-(3-((2-((4-(4-acetyl group-piperazine-1-base)-2-methoxyphenyl) amino)-5-chloropyrimide-4-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 1);
N1-(3-((2-((4-(4-acetyl group-piperazine-1-base)-phenyl) amino)-5-chloropyrimide-4-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 2).
Described compound ii is following arbitrary compound:
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-phenyl) piperazine-1-base)-N-glycoloyl amine hydrochlorate (compound 3);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-glycoloyl amine hydrochlorate (compound 4);
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 hydrochlorate (compound 5);
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 hydrochlorate (compound 6);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-trifluoromethvl-Dvrimidin-2-base) amino)-phenyl) piperazine-1-base)-N-glycoloyl amine hydrochlorate (compound 7);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxypropanamide hydrochlorate (compound 8);
4-(4-(4-((4-((3-acetvlaminophenvl) amino)-5-chloropyrimide-2-base) amino) phenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 9);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 10);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxypentanoyl amine hydrochlorate (compound 11);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 12);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-fluorophenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 13);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-fluorophenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 14);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-fluorophenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 15);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-fluorophenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 16);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 17);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-aminomethyl phenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 18);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-chlorphenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 19);
N1-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl)-N5-hydroxyl glutaramide hydrochlorate (compound 20);
N1-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl)-N8-hydroxyl suberamide hydrochlorate (compound 21);
N1-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl)-N5-hydroxyl glutaramide hydrochlorate (compound 22);
4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) pyrimidine-2-base) amino) phenoxy group)-N-hydroxypentanoyl amine hydrochlorate (compound 23);
4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) pyrimidine-2-base) amino) phenoxy group)-N-hydroxyl hexanamide hydrochlorate (compound 24);
4-(3-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) pyrimidine-2-base) amino) phenoxy group)-N-hydroxybutyramide 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-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenoxy group)-N-hydroxybutyramide hydrochloride (compound 27);
6-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) the chloro-2-pyrimidine radicals of-5-) amino)-3-Difluoro-phenoxy)-N-((tetrahydrochysene-2H-pyrans-2-base) oxo) acetamide (compound 28);
4-((2-((4-((4-((3-Acryloyl amino phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) (methyl) amino-ethyl) (methyl) amino)-N-hydroxybutyramide hydrochloride (compound 29);
4-((2-((4-((4-((3-Acryloyl amino phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) (methyl) amino-ethyl) (methyl) amino)-N-hydroxyl hexanamide hydrochlorate (compound 30).
The preparation method that it is a further object to provide described compounds I, is realized by following steps:
With 2, 4-dichloro pyrimidine (compound A) and the tert-butyl group (3-aminophenyl) carbamate are initiation material, under cryogenic conditions, reaction generates the tert-butyl group (3-((2-chloropyrimide-4-base) amino) phenyl) carbamate (compound B), the arylamine reaction of compound B and all kinds of replacements generates midbody compound C, compound C takes off protection base in acid condition and generates 2-(4-(N4-acetylpiperazinyl)-aminophenyl)-4-(3-amino) aminophenyl)-3-chloropyrimide (compound D), compound D and maleic anhydride are at N, under dinethylformamide (DMF) condition, reaction generates intermediate 4-oxo-2-butylene acid (compound E), the azanol condensation of midbody compound E and THP protection generates compound F, final compound F takes off protection base in acid condition and generates target compound I, reaction equation is as follows:
Reagent and reaction condition: a) DIPEA, sec-butyl alcohol, 0 DEG C, 1 hour; B) sec-butyl alcohol, backflow, 5 hours; C) trifluoroacetic acid, dichloromethane, room temperature, 30 minutes; D) DMF, 50 DEG C, 3 hours; E) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, DMF: dichloromethane=1:2,45 DEG C, 5 hours; F) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour; Wherein described in the definition of each substituent group all ditto.
The preparation method that it is also another object of the present invention to provide described compound ii, is realized by following steps:
With 2, 4-dichloro pyrimidine a and the tert-butyl group (3-aminophenyl) carbamate are initiation material, under cryogenic conditions, reaction generates the tert-butyl group (3-((2-chloropyrimide-4-base) amino) phenyl) carbamate b, the arylamine reaction of b and all kinds of replacements generates intermediate c, c takes off protection base 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 is hydrolyzed generation f in the basic conditions, the azanol condensation that intermediate f and O-(tetrahydrochysene-2H-pyrans-2-base) hydroxylamine (THP) is protected generates compound g, last g takes off protection base in acid condition and generates target compound II, reaction scheme is as follows:
Reagent and reaction condition: 1) sec-butyl alcohol, 0 DEG C, 4 hours;2) sec-butyl alcohol, backflow, 4 hours; 3) trifluoroacetic acid (TFA), dichloromethane (DCM), 1 hour; 4) acryloyl chloride, dichloromethane ,-5 DEG C to 0 DEG C, 30 minutes to 1 hour; 5) oxolane: water=1:1,1 hour; 6) dichloromethane: N, N-dimethyl formyl=2:1,1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, 45 DEG C, 5 hours; 7) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour; Wherein, described in the definition of each substituent group all ditto.
Raw material involved in the present invention and intermediate, can directly buy or prepared by the literature method mentioned according to embodiment part.
Formula I described in preparation method of the present invention and formula II compound, prepared by available organic synthesis and medicinal chemistry art or multiple method known by the technical staff, method described above can be used to prepare the compound of the present invention, typical or preferred process condition (i.e. the mol ratio and solvent etc. of reaction temperature, time, reactant) can be used, other process conditions can also be used, except as otherwise noted. Optimum reaction condition can change with concrete reactant used or solvent, but these conditions should be determined by routine optimization process by those skilled in the art. Generally, above-mentioned reaction scheme and technique can be used to prepare the compounds of this invention, but be not limited to the reagent in reaction condition and solvent.
4th purpose of the present invention is to provide described a kind of containing the 2 of hydroxamic acid fragment, the application in preparing antitumor drug of the 4-diaryl-amine pyridine derivatives, described tumor cell refers to the people epidermal carcinoma cell strain A431 of process LAN EGFR, human lung adenocarcinoma cell line H1975 to Gefitinib drug resistance, to tumor cell (the human cervical carcinoma cell lines Hela relevant to acetylation of histone enzyme (HDAC) activity, human mouth epidermoid carcinoma cell strain KB, people is children grain acute leukemia cells strain HL60 early, HepG2 cell lines, human colon cancer cell strain SW620). its pharmacodynamics embodiment experimental data shows, it has significant inhibited proliferation at cellular level pair and EGFR, tumor cell that HDAC activity is relevant, can prepare corresponding antitumor drug.
The invention provides 2, the 4-diaryl-amine pyridine derivatives containing hydroxamic acid fragment that a class is brand-new, hydroxamic acid fragment therein can as the Zinc Ions Chelated group of HDAC. Its pharmacodynamics embodiment experimental data shows, has significant inhibited proliferation at the cellular level pair tumor cell (the people epidermal carcinoma cell strain A431 of process LAN EGFR, the human lung adenocarcinoma cell line H1975 to Gefitinib drug resistance) relevant to EGFR with to the tumor cell (human cervical carcinoma cell lines Hela, human mouth epidermoid carcinoma cell strain KB, people early children grain acute leukemia cells strain HL60, HepG2 cell lines, human colon cancer cell strain SW620) relevant with acetylation of histone enzyme (HDAC) activity. Particularly drug-resistant cell strain H1975 there is good inhibition, it is possible to provide possible for designing the novel double; two target spot inhibitor of EGFR/HDAC overcoming Gefitinib drug resistance.
Detailed description of the invention
Mode by the examples below further illustrates the present invention, but therefore do not limit the present invention among described scope of embodiments, the experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Embodiment 1N1-(3-((2-((4-(4-acetyl group-piperazine-1-base)-2-methoxyphenyl) amino)-5-chloropyrimide-4-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate
Reagent and reaction condition: a) DMF, 50 DEG C, 3 hours;B) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, DMF: dichloromethane=1:2,45 DEG C, 5 hours; C) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour.
Step 1:(Z) preparation of-4-((2 ((2-((4-(4-acetylpiperazine base)-2-methoxyl group) amino)-5-chloropyrimide) amino) phenyl) amino)-4-oxo-2-butylene acid
Raw material 1:2-((2-methoxyl group-4-(N4-acetylpiperazinyl)-aminophenyl)-4-(3-amino) aminophenyl)-5-chloropyrimide prepared according to the method for Nature, 2009,462,1070-1074.
By 2-((2-methoxyl group-4-(N4-acetylpiperazinyl)-aminophenyl)-4-(3-amino) aminophenyl)-5-chloropyrimide (1mmol) and maleic anhydride (1.2mmol) be dissolved in 15mL dichloroethanes; reaction is overnight; after reaction terminates; decompression is spin-dried for, and can obtain brown solid with acetone recrystallization.
Brownsolid; M.p.:120.5 120.9 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.44 (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.forC27H29ClN7O5[M+H]+=566.1913, found566.1914.
Step 2:N1-(3-((2-((4-(4-Acetylpiperazine-1-base)-2-anisyl) amino)-5-chloropyrimide-4-base) amino) phenyl)-N4The preparation of-((tetrahydrochysene-2H-pyrans-2-base) oxo) maleic acid diamidogen
By 2-((2-methoxyl group-4-(N4-acetylpiperazinyl)-aminophenyl)-4-(3-amino) aminophenyl)-5-chloropyrimide (1mmol) and O-(tetrahydrochysene-2H-pyrans-2-base) azanol (1.2mmol) be dissolved into and be dissolved in 12mL dichloromethane and 4mLN, in dinethylformamide mixed solution, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.32mmol) is added in reactant liquor, 1-hydroxy benzo triazole (1.32mmol), it is placed in 40 DEG C of stirring reactions 4 hours, after reaction terminates, 30mL water is added in reactant liquor, with 20mL dichloromethane extraction three times, merge organic facies, organic facies is spin-dried for, the solid of yellow is obtained through column chromatography purification (mobile phase dichloromethane: methanol=90:1).
Yellowsolid; M.p.:150.2 150.9 DEG C;1HNMR (500MHz, DMSO-d6) �� 9.35 (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.forC32H38ClN8O6[M+H]+=566.2597, found566.2597.
Step 3:N1-(3-((2-((4-(4-acetyl group-piperazine-1-base)-2-methoxyphenyl) amino)-5-chloropyrimide-4-base) amino) phenyl)-N4The preparation of-hydroxyl maleic amide hydrochlorate
By N1-(3-((2-((4-(4-Acetylpiperazine-1-base)-2-anisyl) amino)-5-pyrimidine-4-yl) amino) phenyl)-N4-((tetrahydrochysene-2H-pyrans-2-base) oxo) maleic acid diamidogen (1mmol) joins in 25mL there-necked flask, and adds the dichloroethanes of 8mL.Instilling ether (3.4mL) solution of 1M hydrochloric acid, low-temp reaction 1 hour under condition of ice bath, have solid to precipitate out after having reacted, reduce pressure sucking filtration, obtains yellow solid.
Brownsolid; M.p.:217.9 218.3 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.60 (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.forC27H30ClN8O5[M+H]+=581.2022, found581.2025.
Embodiment 2:N1-(3-((2-((4-(4-acetyl group-piperazine-1-base)-phenyl) amino)-5-chloropyrimide-4-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate
Method with reference to embodiment 1, (Z)-4-((2 ((2-((4-(4-acetylpiperazine base)-2-methoxyl group) amino)-5-chloropyrimide) amino) phenyl) amino)-4-oxo-2-butylene acid in step 1 simply changes into (Z)-4-, and ((2 ((2-((4-(4-acetylpiperazine base) amino)-5-chloropyrimide) amino) phenyl) amino)-4-oxo-2-butylene acid, by the 2-((2-methoxyl group-4-(N in step 24-acetylpiperazinyl)-aminophenyl)-4-(3-amino) aminophenyl)-5-chloropyrimide changes 2-((4-(N into4-acetylpiperazinyl)-aminophenyl)-4-(3-amino) aminophenyl)-5-chloropyrimide, by the N in step 31-(3-((2-((4-(4-Acetylpiperazine-1-base)-2-anisyl) amino)-5-pyrimidine-4-yl) amino) phenyl)-N4-((tetrahydrochysene-2H-pyrans-2-base) oxo) maleic acid diamidogen changes N into1-(3-((2-((4-(4-Acetylpiperazine-1-base) phenyl) amino)-5-pyrimidine-4-yl) amino) phenyl)-N4-((tetrahydrochysene-2H-pyrans-2-base) oxo) maleic acid diamidogen.
Brownsolid; M.p.:220.6-221.1 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.08 (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.forC26H28ClN8O4[M+H]+=551.1917, found551.1917.
Embodiment 3:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-phenyl) piperazine-1-base)-N-glycoloyl amine hydrochlorate
Reagent and reaction condition: 1) sec-butyl alcohol, backflow, 4 hours; 3) trifluoroacetic acid, dichloromethane, 1 hour; 4) acryloyl chloride, dichloromethane ,-5-0 DEG C, 30 minutes to 1 hour; 5) oxolane: water=1:1,1 hour; 6) dichloromethane: N, N-dimethyl formyl=2:1,1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, 45 DEG C, 5 hours; 7) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour.
Step 1:2-((2-methoxyl group-4-(N4-acetylpiperazinyl)-aminophenyl)-4-(3-amino) aminophenyl) preparation of-3-chloropyrimide.
Raw material 1:4-((the chloro-4-pyrimidine radicals of 2,5-bis-) amino) phenyl) t-butyl carbamate prepared according to the method for Cancerdiacovery, 2013,3,1404-1415.
By 4-((2, the chloro-4-pyrimidine radicals of 5-bis-) amino) phenyl) t-butyl carbamate (1.0mmol) and 2-(4-(4-aminophenyl) piperazine-1-base) ethyl acetate (1.0mmol) join in 50mL there-necked flask, and add the sec-butyl alcohol of 200 microlitre 1N dilute hydrochloric acid and 10mL, it is heated to reflux, makes mixture stirring reaction 4 hours.Reaction is cooled to room temperature after terminating, and decompression is spin-dried for. Obtain brown solid. The brown solid (1.0mmol) obtained is joined in 50mL there-necked flask, and adds 10mL trifluoroacetic acid, react half an hour. It is spin-dried for trifluoroacetic acid under reduced pressure as far as possible, obtains brown oil. Dripping in saturated sodium bicarbonate again under condition of ice bath in system and remaining trifluoroacetic acid, with 80mL ethyl acetate coextraction three times, merge organic facies, organic facies is dried with anhydrous sodium sulfate, then decompression is spin-dried for solvent, obtains yellow solid.
M.p.:214.5 214.8 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.36 (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.forC23H27ClN7O2[M+H]+=468.1909, found468.1912.
The preparation of step 2:2-(4-(4-((4-((3-acrylamido phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) piperazine-1-base) ethyl acetate
By 2-((2-methoxyl group-4-(N4-acetylpiperazinyl)-aminophenyl)-4-(3-amino) aminophenyl)-3-chloropyrimide (1.0mmol) joins in 25mL there-necked flask; and add the dichloromethane of triethylamine (4.0mmol) and 10mL; reaction bulb is placed in ice bath, by interior temperature control at-5 DEG C to-10 DEG C. It is slow added into acryloyl chloride (1.0mmol), makes mixture stirring reaction 30 minutes. Reaction adds 20mL water after terminating in reactant liquor, with 20mL dichloromethane extraction three times, merges organic facies, and organic facies is spin-dried for, and obtains yellow solid.
M.p.:214.5 214.8 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.36 (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.forC27H30ClN7O3[M+H]+=536.2171, found536.2171.
The preparation of step 3:2-(4-(4-((4-((3-acrylamido phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) piperazine-1-base) acetic acid
2-(4-(4-((4-((3-acrylamido phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) piperazine-1-base) ethyl acetate (1.0mmol) and Lithium hydrate (10mmol) are joined in 25mL there-necked flask, and add the oxolane of 8mL and the water of 8mL, react 1 hour. After reacting completely, with hydrochloric acid, reaction system PH is adjusted to about 7, precipitates out faint yellow yellow solid.
Yellowsolid; M.p.:216.3 216.9 DEG C;1HNMR (500MHz, DMSO-d6) �� 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.forC25H27ClN7O3[M+H]+=508.1858, found508.1859.
The preparation of step 4:N-(3-((the chloro-2-of 5-((4-(4-(2-oxo-2-(((tetrahydrochysene-2H-pyrans-2-base) oxo) amino) ethoxy acyl group)-1-piperazinyl) phenyl) amino)-4-pyrimidine radicals) amino) phenyl) acrylamide
2-(4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) the chloro-2-pyrimidine radicals of-5-) amino)-phenyl)-1-piperazinyl)-acetic acid (1mmol) and O-(tetrahydrochysene-2H-pyrans-2-base) azanol (1.2mmol) are dissolved into and are dissolved in 12mL dichloroethanes and 4mLN; in dinethylformamide mixed solution; 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.32mmol) is added in reactant liquor; 1-hydroxy benzo triazole (1.32mmol), is placed in 40 DEG C of stirring reactions 4 hours. Reaction adds 30mL water after terminating in reactant liquor, with 20mL dichloromethane extraction three times, merges organic facies, and organic facies is spin-dried for, through column chromatography purification (mobile phase dichloromethane: methanol=90:1) the solid of yellow.
Yellowsolid; M.p.:230.1 230.4 DEG C;1HNMR (500MHz, DMSO-d6) �� 9.49 (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.forC30H36ClN8O4[M+H]+=607.2454, found607.2455.
The preparation of step 5:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-phenyl) piperazine-1-base)-N-glycoloyl amine hydrochlorate.
N-(3-((the chloro-2-of 5-((4-(4-(2-oxo-2-(((tetrahydrochysene-2H-pyrans-2-base) oxo) amino) ethoxy acyl group)-1-piperazinyl) phenyl) amino)-4-pyrimidine radicals) amino) phenyl) acrylamide (1mmol) is joined in 25mL there-necked flask, and adds the dichloroethanes of 8mL. Ether (3.4mL) solution of 1M hydrochloric acid, low-temp reaction 1 hour is instilled under condition of ice bath. Having solid to precipitate out after having reacted, reduce pressure sucking filtration, obtains yellow solid.
Yellowsolid; M.p.:218.3 218.8 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.09 (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.forC25H28ClN8O3[M+H]+=523.1967, found523.1967.
According to embodiment 1 same procedure, adopt different material, prepare following compound.
Embodiment 4:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-glycoloyl amine hydrochlorate
Yellowsolid; M.p.:170.8 171.3 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.14 (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.forC25H27ClN7O4[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 hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:218.3 218.8 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.03 (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.forC25H27ClN7O4[M+H]+=524.1808, found524.1809.
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 hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:218.3 218.8 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.01 (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.forC25H28ClN8O3[M+H]+=523.1967, found523.1969.
Embodiment 7:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-trifluoromethvl-Dvrimidin-2-base) amino)-phenyl) piperazine-1-base)-N-glycoloyl amine hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:192.3 192.8 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.04 (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.forC26H28F3N8O3[M+H]+=557.2231, found557.2233.
Embodiment 8:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxypropanamide hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:187.8 188.2 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.77 (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.forC27H32ClN8O4[M+H]+=567.2230, found567.2234.
Embodiment 9:4-(4-(4-((4-((3-acetvlaminophenvl) amino)-5-chloropyrimide-2-base) amino) phenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride
Its structural formula is:
Brownsolid; M.p.:239.2 240.1 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.01 (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.forC27H32ClN8O3[M+H]+=551.2280, found551.2283.
Embodiment 10:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride
Its structural formula is:
Brownsolid; M.p.:194.2 194.4 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.12 (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.forC28H34ClN8O4[M+H]+=581.2386, found581.2388.
Embodiment 11:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxypentanoyl amine hydrochlorate
Its structural formula is:
Brownsolid; M.p.:211.5 212.2 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.12 (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)��163.8,161.0,139.8,137.5,132.6,132.4,129.1,127.3,123.9,123.1,118.2,107.5,107.4,100.8,100.8,56.4,56.3,54.3,51.6,45.8,19.0,17.2.HRMS(ESI)calcd.forC29H35ClFN8O3[M+H]+=597.2499, found597.2503.
Embodiment 12:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate
Its structural formula is:
Brownsolid; M.p.:206.5 206.8 DEG C;1HNMR (500MHz, DMSO-d6) �� 9.12 (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.forC29H35ClFN8O3[M+H]+=597.2499, found597.2503.
Embodiment 13:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-fluorophenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate
Its structural formula is:
Brownsolid; M.p.:75.6 76.2 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.12 (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.forC29H35ClFN8O3[M+H]+=597.2499, found597.2503.
Embodiment 14:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-fluorophenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride
Its structural formula is:
Yellowsolid; M.p.:197.7 198.2 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.22 (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.forC27H31ClFN8O3[M+H]+=569.2192, found569.2192.
Embodiment 15:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-fluorophenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride
Its structural formula is:
Yellowsolid; M.p. > 250 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.22 (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.forC27H31ClFN8O3[M+H]+=569.2192, found569.2192.
Embodiment 16:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-fluorophenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:90.6 91.2 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.12 (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.forC29H35ClFN8O3[M+H]+=597.2499, found597.2503.
Embodiment 17:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:179.6 179.9 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.11 (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.forC29H35ClFN8O3[M+H]+=597.2499, found597.2503.
Embodiment 18:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-aminomethyl phenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate
Its structural formula is:
Brownsolid; M.p.:135.7-136.5 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.42 (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.forC30H38ClN8O3[M+H]+=593.2750, found593.2750.
Embodiment 19:6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-chlorphenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate
Its structural formula is:
Brownsolid; M.p.:135.7-136.5 DEG C;1HNMR (500MHz, DMSO-d6) �� 8.45 (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.forC29H35Cl2N8O3[M+H]+=613.2209, found613.2210.
Embodiment 20:N1-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl)-N5-hydroxyl glutaramide hydrochlorate
Its structural formula is:
Brownsolid; M.p.:113.4-114.1 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.05 (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.forC24H25ClN7O4[M+H]+=510.1651, found510.1655.
Embodiment 21:N1-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl)-N8-hydroxyl suberamide hydrochlorate
Its structural formula is:
Brownsolid; M.p.:97.6 98.0 DEG C;1HNMR (500MHz, DMSO-d6) �� 11.51 (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.forC27H31ClN7O4[M+H]+=552.2121, found552.2124.
Embodiment 22:N1-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl)-N5-hydroxyl glutaramide hydrochlorate
Its structural formula is:
Brownsolid;M.p.:1153.9 154.4 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.09 (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.forC25H27ClN7O5[M+H]+=540.1757, found540.1755.
Embodiment 23:4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) pyrimidine-2-base) amino) phenoxy group)-N-hydroxypentanoyl amine hydrochlorate
Its structural formula is:
Whitesolid; M.p.:130.0 130.4 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.98 (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)��169.7,164.1,158.5,157.8,156.4,140.2,137.9,132.7,130.6,129.8,129.6,127.7,121.1,121.0,118.0,117.1,115.3,108.8,68.1,32.7,29.0,22.6.HRMS(ESI)calcd.forC23H25N6O4[M+H]+=449.1932, found449.1932.
Embodiment 24:4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) pyrimidine-2-base) amino) phenoxy group)-N-hydroxyl hexanamide hydrochlorate
Its structural formula is:
Whitesolid; M.p.:146.5 146.9 DEG C;1HNMR (500MHz, DMSO) �� 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.forC24H26ClN6O4[M+H]+=497.1699, found497.1699.
Embodiment 25:4-(3-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) pyrimidine-2-base) amino) phenoxy group)-N-hydroxybutyramide hydrochloride
Its structural formula is:
Whitesolid; M.p.:156.2 156.6 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.68 (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.forC23H25N6O4[M+H]+=449.1932, found449.1932.
Embodiment 26:4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenoxy group)-N-hydroxybutyramide hydrochloride
Its structural formula is:
Whitesolid; M.p.:130.0-130.4 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.98 (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.forC23H25N6O4[M+H]+=483.1542, found483.1542.
Embodiment 27:4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenoxy group)-N-hydroxybutyramide hydrochloride
Its structural formula is:
Whitesolid; M.p.:130.0-130.4 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.98 (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.forC23H25N6O4[M+H]+=483.1542, found483.1542.
Embodiment 28:6-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) the chloro-2-pyrimidine radicals of-5-) amino)-3-Difluoro-phenoxy)-N-((tetrahydrochysene-2H-pyrans-2-base) oxo) acetamide
Its structural formula is:
Whitesolid; M.p.:145.3-145.9 DEG C;1HNMR (500MHz, DMSO-d6) �� 10.09 (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.forC23H25N6O4[M+H]+=483.1542, found483.1542.
Embodiment 29:4-((2-((4-((4-((3-Acryloyl amino phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) (methyl) amino-ethyl) (methyl) amino)-N-hydroxybutyramide hydrochloride
Its structural formula is:
Yellowsolid; M.p.:110.5 112.1 DEG C;1HNMR (500MHz, DMSO) �� 9.25 (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.forC27H34ClN8O3[M+H]+=553.2442, found553.2443.
Embodiment 30:4-((2-((4-((4-((3-Acryloyl amino phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) (methyl) amino-ethyl) (methyl) amino)-N-hydroxyl hexanamide hydrochlorate
Its structural formula is:
Yellowsolid; M.p.:163.8-164.5 DEG C;1HNMR (500MHz, DMSO) �� 9.15 (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.forC29H38ClN8O3[M+H]+=581.2755, found581.2755.
Embodiment 31: compound is to A431, H1975, HeLa cell inhibitory effect determination of activity
This example is used for measuring the compounds of this invention proliferation inhibition activity for EGFR wild type overexpression cell line A431, T790M point mutation cell strain H1975, human cervical carcinoma cell lines Hela, the inhibitory activity half-inhibition concentration IC of compound on intracellular propagation50Represent.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 all purchased from ATCC, with suitable cell concentration (A431:20000 cell/ml culture medium; H1975:15000 cell/ml culture medium) cell is inoculated on 96 well culture plates of white clear; Afterwards cell is positioned over 37 DEG C, 5%CO2Environment in cultivate, after 24 hours, the medicine of a series of Concentraton gradient is added in cultured cells culture medium, it is typically chosen 10 concentration, afterwards cell is put back to and former culture environment continues cultivate 48 hours, afterwards according to the method for CellTiter-GloLuminescentCellViabilityAssay, measure the test-compound impact on A431 and H1975, HeLa cell proliferation, and the inhibitory activity that the compound on intracellular calculating variable concentrations is bred, CellTiter-GloLuminescentCellViabilityAssay detectable is purchased from Promega. Afterwards A431, H1975, HeLa cell inhibitory effect activity under the compound of variable concentrations being carried out four parameter fittings, the IC50 data of test-compound of the present invention are in Table 1.
Table 1
Embodiment 32: part of compounds is to SW620, KB, HepG2, HL60 cell inhibitory effect determination of activity
This example for measure the compounds of this invention for HepG2 cell lines, human colon cancer cell strain SW620, human mouth epidermoid carcinoma cell strain KB, people in loop strain HL60 proliferation inhibition activity, compound on intracellular propagation inhibitory activity half-inhibition concentration IC50Represent. Testing program is embodiment 31 such as. The IC of part test-compound of the present invention50Data are table 2 below such as.
Table 2
Conclusion: have novelty in the compounds of this invention structure, synthesizes 2, the 4-diaryl-amine pyrimidines containing hydroxamic acid fragment first. Bioactivity evaluation result shows simultaneously, the compound of the present invention people epidermal carcinoma cell strain A431 to process LAN EGFR, the human lung adenocarcinoma cell line H1975 to Gefitinib drug resistance and Human cervical carcinoma cell line HeLa have obvious Inhibit proliferaton activity, and part of compounds is suitable with positive WZ4002 and SAHA. Mentality of designing is provided for designing the novel Gefitinib of overcoming drug resistance EGFR inhibitor.

Claims (8)

1. 2, the 4-diaryl-amine yl pyrimidines analog derivatives containing hydroxamic acid fragment as shown in formula I, its general structure is:
Wherein:
R1For hydrogen atom or chlorine atom,
R2For hydrogen atom or methoxyl group.
2. 2, the 4-diaryl-amine yl pyrimidines analog derivatives containing hydroxamic acid fragment as shown in formula II, its general structure is:
Wherein:
X is ehter bond, amido link, piperazinyl or N, N '-dimethyl ethylenediamine base;
N is 1��5,
R1For hydrogen, chlorine atom or trifluoromethyl,
R2For hydrogen atom, methoxyl group, halogen or methyl.
3. 2, the 4-diaryl-amine yl pyrimidines analog derivatives containing hydroxamic acid fragment according to claim 1, it is characterised in that described type I compound is following arbitrary compound:
N1-(3-((2-((4-(4-acetyl group-piperazine-1-base)-2-methoxyphenyl) amino)-5-chloropyrimide-4-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 1);
N1-(3-((2-((4-(4-acetyl group-piperazine-1-base)-phenyl) amino)-5-chloropyrimide-4-base) amino) phenyl)-N4-hydroxyl maleic amide hydrochlorate (compound 2).
4. 2, the 4-diaryl-amine yl pyrimidines analog derivatives containing hydroxamic acid fragment according to claim 2, it is characterised in that described formula II compound is following arbitrary compound:
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-phenyl) piperazine-1-base)-N-glycoloyl amine hydrochlorate (compound 3);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-glycoloyl amine hydrochlorate (compound 4);
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 hydrochlorate (compound 5);
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 hydrochlorate (compound 6);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-trifluoromethvl-Dvrimidin-2-base) amino)-phenyl) piperazine-1-base)-N-glycoloyl amine hydrochlorate (compound 7);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxypropanamide hydrochlorate (compound 8);
4-(4-(4-((4-((3-acetvlaminophenvl) amino)-5-chloropyrimide-2-base) amino) phenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 9);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 10);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxypentanoyl amine hydrochlorate (compound 11);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 12);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-fluorophenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 13);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-fluorophenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 14);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-fluorophenyl) piperazine-1-base)-N-hydroxybutyramide hydrochloride (compound 15);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-3-fluorophenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 16);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 17);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-aminomethyl phenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 18);
6-(4-(4-((4-((3-acryloyl group-aminophenyl) amino)-5-chloropyrimide-2-base) amino)-2-chlorphenyl) piperazine-1-base)-N-hydroxyl hexanamide hydrochlorate (compound 19);
N1-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl)-N5-hydroxyl glutaramide hydrochlorate (compound 20);
N1-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl)-N8-hydroxyl suberamide hydrochlorate (compound 21);
N1-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino)-3-methoxyphenyl)-N5-hydroxyl glutaramide hydrochlorate (compound 22);
4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) pyrimidine-2-base) amino) phenoxy group)-N-hydroxypentanoyl amine hydrochlorate (compound 23);
4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) pyrimidine-2-base) amino) phenoxy group)-N-hydroxyl hexanamide hydrochlorate (compound 24);
4-(3-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) pyrimidine-2-base) amino) phenoxy group)-N-hydroxybutyramide hydrochloride (compound 25);
4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenoxy group)-N-hydroxybutyramide hydrochloride (compound 26);
4-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino)-5-chloropyrimide-2-base) amino) phenoxy group)-N-hydroxybutyramide hydrochloride (compound 27);
6-(4-((4-((3-acryloyl group-methanesulfonylamino-phenyl) amino) the chloro-2-pyrimidine radicals of-5-) amino)-3-Difluoro-phenoxy)-N-((tetrahydrochysene-2H-pyrans-2-base) oxo) acetamide (compound 28);
4-((2-((4-((4-((3-Acryloyl amino phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) (methyl) amino-ethyl) (methyl) amino)-N-hydroxybutyramide hydrochloride (compound 29);
4-((2-((4-((4-((3-Acryloyl amino phenyl) amino)-5-chloropyrimide-2-base) amino) phenyl) (methyl) amino-ethyl) (methyl) amino)-N-hydroxyl hexanamide hydrochlorate (compound 30).
5. the preparation method of the type I compound according to claim 1 or 3, it is characterised in that realized by following steps:
With 2, 4-dichloro pyrimidine A and the tert-butyl group (3-aminophenyl) carbamate are initiation material, under cryogenic conditions, reaction generates the tert-butyl group (3-((2-chloropyrimide-4-base) amino) phenyl) carbamate B, the arylamine reaction of B and all kinds of replacements generates intermediate C, C takes off protection base in acid condition and generates 2-(4-(N4-acetylpiperazinyl)-aminophenyl)-4-(3-amino) aminophenyl)-3-chloropyrimide D, D and maleic anhydride react generation 4-oxo-2-butylene acid E when DMF, intermediate E generates compound F with the THP azanol condensation protected, last F takes off protection base in acid condition and generates target compound I, reagent and reaction condition: a) DIPEA, sec-butyl alcohol, 0 DEG C, 1 hour, b) sec-butyl alcohol, backflow, 5 hours, c) trifluoroacetic acid, dichloromethane, room temperature, 30 minutes, d) DMF, 50 DEG C, 3 hours, e) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 1-hydroxy benzo triazole, DMF: dichloromethane=1:2,45 DEG C, 5 hours, f) 1M ethereal HCI solution, 0 DEG C, 30 minutes to 1 hour, reaction equation is:
Wherein substituent R1And R2Definition with claim 1.
6. the preparation method of the formula II compound according to claim 2 or 4, it is characterised in that realized by following steps:
With 2, 4-dichloro pyrimidine a and the tert-butyl group (3-aminophenyl) carbamate are initiation material, under cryogenic conditions, reaction generates the tert-butyl group (3-((2-chloropyrimide-4-base) amino) phenyl) carbamate b, the arylamine reaction of b and all kinds of replacements generates intermediate c, c takes off protection base 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 is hydrolyzed generation f in the basic conditions, the azanol condensation of intermediate f and O-(tetrahydrochysene-2H-pyrans-2-base) hydroxylamine protection generates compound g, last g takes off protection base in acid condition and generates target compound II,Reagent and reaction condition: 1) sec-butyl alcohol, 0 DEG C, 4 hours; 2) sec-butyl alcohol, backflow, 4 hours; 3) trifluoroacetic acid, dichloromethane, 1 hour; 4) acryloyl chloride, dichloromethane ,-5-0 DEG C, 30 minutes to 1 hour; 5) oxolane: water=1:1,1 hour; 6) dichloromethane: N, N-dimethyl formyl=2:1,1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 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 substituent group was with claim 2; Reaction scheme is as follows:
Wherein X, R1��R2Definition with n is with claim 2.
7. formula I according to claim 1 and 2 or the application in preparing antitumor cell and targeting EGFR/HDAC medicine of the formula II compound; it is characterized in that, described tumor cell refers to the people epidermal carcinoma cell strain A431 of process LAN EGFR, the tumor cell that human lung adenocarcinoma cell line H1975 and the HDAC acetylation of histone enzymatic activity of Gefitinib drug resistance is relevant.
8. application according to claim 7; it is characterized in that, the described tumor cell relevant to HDAC acetylation of histone enzymatic activity is Human cervical carcinoma cell line HeLa, human mouth epidermoid carcinoma cell strain KB, people early children grain acute leukemia cells strain HL60, HepG2 cell lines, human colon cancer cell strain SW620.
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Publication number Priority date Publication date Assignee Title
CN106243044A (en) * 2016-06-30 2016-12-21 浙江大学 Pyridine derivatives containing halo acrylamide side chain and preparation and application
CN115286583A (en) * 2022-08-10 2022-11-04 山东大学 Diphenylaminopyrimidine-containing compound, preparation and application thereof as HDACs enzyme inhibitor
CN115304551A (en) * 2022-07-25 2022-11-08 南通大学 2- ((4-morpholinyl phenyl) amino) pyrimidine amino acid derivative and preparation method and application thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1625400A (en) * 2002-02-01 2005-06-08 里格尔药品股份有限公司 2,4-pyrimidinediamine compounds and their uses
WO2011084991A2 (en) * 2010-01-08 2011-07-14 President And Fellows Of Harvard College Fluorinated hdac inhibitors and uses thereof
CN103906732A (en) * 2011-10-28 2014-07-02 株式会社钟根堂 Hydroxamate derivatives for hdac inhibitor, and the pharmaceutical composition comprising thereof
WO2015158310A1 (en) * 2014-04-18 2015-10-22 山东轩竹医药科技有限公司 Tyrosine kinase inhibitor and uses thereof
CN105188371A (en) * 2013-02-08 2015-12-23 西建阿维拉米斯研究公司 Erk inhibitors and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1625400A (en) * 2002-02-01 2005-06-08 里格尔药品股份有限公司 2,4-pyrimidinediamine compounds and their uses
WO2011084991A2 (en) * 2010-01-08 2011-07-14 President And Fellows Of Harvard College Fluorinated hdac inhibitors and uses thereof
CN103906732A (en) * 2011-10-28 2014-07-02 株式会社钟根堂 Hydroxamate derivatives for hdac inhibitor, and the pharmaceutical composition comprising thereof
CN105188371A (en) * 2013-02-08 2015-12-23 西建阿维拉米斯研究公司 Erk inhibitors and uses thereof
WO2015158310A1 (en) * 2014-04-18 2015-10-22 山东轩竹医药科技有限公司 Tyrosine kinase inhibitor and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
刘燊: "EGFR酪氨酸激酶抑制剂的设计、合成及生物活性筛选和类药性化合物库的构建", 《中国博士学位论文全文数据库 医药卫生科技辑》 *
齐维兴: "克服耐药的非可逆EGFR抑制剂的设计合成和生物活性筛选", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106243044A (en) * 2016-06-30 2016-12-21 浙江大学 Pyridine derivatives containing halo acrylamide side chain and preparation and application
CN115304551A (en) * 2022-07-25 2022-11-08 南通大学 2- ((4-morpholinyl phenyl) amino) pyrimidine amino acid derivative and preparation method and application thereof
CN115286583A (en) * 2022-08-10 2022-11-04 山东大学 Diphenylaminopyrimidine-containing compound, preparation and application thereof as HDACs enzyme inhibitor
CN115286583B (en) * 2022-08-10 2024-01-30 山东大学 Diphenylamino pyrimidine-containing compound, preparation and application thereof as HDACs enzyme inhibitor

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