CN103159742A - 5-Chloropyrimidine compound and application of 5-Chloropyrimidine compound serving as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor - Google Patents
5-Chloropyrimidine compound and application of 5-Chloropyrimidine compound serving as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor Download PDFInfo
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Abstract
The invention discloses an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and the structural formula of the inhibitor is shown as in the formula (I). The invention further discloses an application of any compound shown as in the formula (I) and pharmacy-acceptable salt of the compound. The invention further provides a medicine compound for curing, and the medicine compound comprises the compound shown as in the formula (I) and an EGFR modifier.
Description
Technical field
The present invention relates to field of medicaments, particularly EGFR tyrosine kinase inhibitor and application thereof.
Background technology
Cancer claims again malignant tumour, has become the second largest disease of serious harm human life and health.According to statistics, in 6,600,000,000 populations of the whole world, annual new tumour patient approximately 1,000 ten thousand, approximately more than 500 ten thousand people die from cancer, and such numeral is also presenting ever-increasing trend.China Ministry of Health " Cancer in China prevention and control planning outline (2004-2010) " regulation, 8 kinds of cancers such as lung cancer, liver cancer, cancer of the stomach, the esophageal carcinoma, colorectal cancer, mammary cancer, cervical cancer and nasopharyngeal carcinoma add up to and account for more than 80% of the cancer cause of the death, are that China is from now on the main cancer of keypoint control.
Research finds in the generation of most of tumours, development, the overactive phenomenon of protein tyrosine kinase (PTK) signal path is arranged all.Reach by suppressing tyrosine kinase activity the medicinal design that the inhibition tumor cell hyper-proliferative carries out, the appearance of tyrosine kinase inhibitor (TKI) becomes the landmark progress in anticancer field.Especially the research of targeting epidermal growth factor receptor (EGFR) Tyrosylprotein kinase, obtained considerable progress in the past few decades.
The EGFR signal transduction pathway plays an important role at the aspects such as propagation, injury repairing, invasion and attack and new vessel formation of tumour cell.EGFR is a kind of transmembrane receptor, and EGF is incorporated into ectodomain, and acceptor generation dimerization also activates tyrosine kinase domain in born of the same parents, causes the phosphorylation of kinases autophosphorylation and downstream molecules, activates the various kinds of cell function that comprises propagation and survival.According to the different positions of drug effect at EGFR, mainly formed two kinds of strategies, a kind of is to act on extracellular region, is mainly the monoclonal antibodies medicine; Another kind is to act on catalysis region in born of the same parents, thereby disturbs ATP in conjunction with stoping functional protein to carry out the micromolecular inhibitor of phosphorylation.
lung cancer is the very high class malignant tumour of lethality rate, on histology, lung cancer is divided into small cell lung cancer (SCLC) and nonsmall-cell lung cancer (NSCLC), the latter comprises gland cancer, squamous cell carcinoma and large cell carcinoma etc., account for the 80-85% of lung cancer sum, approximately 65% such patient has belonged to late period (IIIB/IV) when making a definite diagnosis this disease, at this moment, cancer cells has been invaded important organ or has been shifted, can't take operative treatment, can only consider chemotherapy, radiotherapy or Chinese medicine expectant treatment, current First-line chemotherapy is take the two medicine chemotherapy regimens that contain platinum medicine as main, but remission rate is less than 30%, use rhuMAb-VEGF (vascular epidermis growth factor antibodies) even add, total survival median is still less than 12 months.Although docetaxel and pemetrexed have been used as the second line treatment of advanced NSCLC, often prognosis mala.
In recent years, molecular targeted therapy has become the new tool of oncotherapy, and it has efficiently, the specific killing tumour cell, and the little characteristics of normal tissue and cell injury.To in the understanding in depth of the molecule parting of lung cancer, to continuous three extensive random contrast clinical study: IPASS, the WJTOG3405 of the NSCLC of EGFR sudden change and NEJ002, confirmed that a line uses the curative effect of EGF-R ELISA-tyrosine kinase inhibitor (EGFR-TKI) Gefitinib to be better than traditional platiniferous two medicine chemotherapy regimens in the NSCLC patient of EGFR sudden change.EGFR-TKI Gefitinib and Tarceva have gone through to play an important role in the treatment of EGFR mutant NSCLC late as the NSCLC patient of a line platinum-based chemotherapy failure.People observe from the clinical trial of Gefitinib and Tarceva, and they only treat sensitivity (Paez et al Scinece 2004 to the crowd of EGFR mutant NSCLC; Lynch et al.NEJM 2004; Pao et al.PNAS 2004), it is the L858R sudden change of exons 19 disappearances (E19del) and exon 21 that this sudden change surpasses 90%, such case is common in Asia, non-smoking, female patient, and gland cancer is the EGFR mutation rate high (Shigematsu et al.JNCI 2005) of bronchovesicular cancer and the high NSCLC of differentiation degree especially.
Studies show that, approximately 75% EGFR mutant patient is responsive to EGFR-TKI, and all the other insensitive sudden changes as the insertion mutation of extron 20, are observed in 5% NSCLC case.In addition, at the NSCLC that uses Gefitinib or Tarceva treatment EGFR-TKI responsive type, the Secondary cases resistance all appears in 6-12 after the month, wherein about 50% T790M sudden change (the Kosaka et al.CCR 2006 that comprises by the extron 20 coding; Balak et al.CCR2006 and Engelman et al.Science), other sudden change (as D761Y, L747S, T845A) only accounts for less than 5%; In addition, also having an appointment 20% comprises the resistance that MET oncogene amplification causes, and wherein half is also and depositing the T790M sudden change.More than studies show that, the T790M sudden change is the major cause (Kobayashi et al.N.Engl.J.Med) to the EGFR-TKIs resistance.In addition, research is found, contains KRAS sudden change (accounting for 15-25%) in NSCLC, and BRAF sudden change (accounting for 2-3%) or ALK sudden change (accounting for 5%) are also insensitive to EGFR-TKI.
The EGFR of the EGFR contrast L858R single mutation of the two sudden changes of L858R-T790M, ATP had higher avidity, be the usefulness (Yun CH et al.PNAS) that the T790M sudden change has weakened the ATP competitive inhibitors such as Gefitinib and Tarceva, the appearance of resistance has also obtained explanation so.In order to overcome because the T90M sudden change causes EGFR, the binding ability of ATP is recovered caused sudden change, developing the emulative irreversible inhibitor of non ATP, be called s-generation EGFR-TKI, this class has HKI-272 at the compound that grinds, BIBW2992, PF-00299804 etc., they can form covalent linkage with the Cys797 at the ATP binding pocket place of EGFR, all demonstrate the anti-T790M mutation effect that is better than Gefitinib and Tarceva in vivo with in experiment in vitro.But clinical trial shows, the amplification that produces immediately or high expression level T790M sudden change will cause the resistance to these irreversible inhibitors; On the other hand, owing to being subject to pharmacokinetics character, they are difficult to clinically reach and can suppress the required concentration of T790M sudden change.WZ4002 is that a kind of anilino-pyrimidine that adopts of report in 2009 is the new E GFR irreversible inhibitor (Wenjun Zhou et al.Nature) of parent nucleus, also referred to as third generation EGFR-TKI.In vivo with experiment in vitro in, its inhibition to EGFR two sudden change E19del-T790M and L858R-T790M is better than independent medicaments insensitive sudden change (E19del or L858R) and Wild type EGFR, therefore can greatly reduce because Wild type EGFR in the inhibition nonneoplastic tissue produces the toxic side effect such as fash and diarrhoea.Another kind of strategy for resistance is the inhibitor that share other signal path of target, as unites and use Mammals rapamycin target protein (mTOR) inhibitor everolimus, and in addition, the multiple dosage regimen of share has begun to prepare to carry out clinical trial.
Summary of the invention
The present invention has found the irreversible inhibitor of a class EGFR Catastrophic selection, and experiment in vitro shows that it can suppress the propagation of the two mutant clone H1975 of L858R-T790M under nanomolar concentration; Simultaneously, EGFR susceptibility mutant clone HCC827 (Del E746_A750) is also had very high inhibition strength, to the inhibition of Wild type EGFR cell strain A431 relatively a little less than.Therefore, this class formation not only can be used for the treatment of EGFR responsive type sudden change cancer, also is applicable to produce in present EGFR-TKI treatment the case of Secondary cases resistance; Simultaneously, its Catastrophic selection has reduced the toxic side effect that produces because suppressing Wild type EGFR greatly, is the desirable surrogate of first-generation EGFR-TKI.
An object of the present invention is to provide the irreversible inhibitor of a class EGFR Catastrophic selection, be compound or its pharmacy acceptable salt of formula (I), solvate or prodrug:
Wherein, X is selected from O, NR
8Or disappearance;
M is selected from 1 or 2;
N is selected from 1,2 or 3;
A ring and B ring are independently selected from C
5-8Aryl or heteroaryl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl, 8-14 unit condensed ring, and can not be substituted or by one or more nitros, halogen, cyano group, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
1-6Alkoxyl group, the C that halogen replaces
1-6Alkoxyl group replaces;
R
1Be selected from hydrogen, N (R
4) (R
5), N (R
4) CO (R
5), N (R
4) SO
2(R
5), N (R
4) SO (R
5), C (O) OR
4, C (O) N (R
4) (R
5), SO
2R
4, SOR
4, SR
4, SO
2NR
4R
5, OR
4, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl, C
5-8Aryl, C
5-8Heteroaryl, C
3-8Heterocyclylalkyl-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-SO
2-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C
1-6Alkyl-C
5-8Aryl, heteroaryl or C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-C
5-8Aryl or heteroaryl, C
3-8Heterocyclylalkyl-CO-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C (O) N-C
1-6Alkyl or C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-CO
2-C
1-6Alkyl, C
3-8Heterocyclylalkyl-CO-C
3-8Cycloalkyl or Heterocyclylalkyl, above each group can not be substituted or by one or more halogens, cyano group, amino, C
1-6The amido that alkyl replaces, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
1-6Alkoxyl group, the C that halogen replaces
1-6Alkoxyl group replaces;
R
2Be selected from
R
3Be selected from hydrogen, C
1-6Alkyl, CO-C
1-6Alkyl, CO-C
2-6Thiazolinyl, CO-C
2-6Alkynyl, the C that halogen replaces
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl
R
4And R
5Be independently selected from hydrogen C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl, C
5-8Aryl or heteroaryl, C
1-6Alkyl-C
3-8Heterocyclylalkyl, C
1-6Alkyl-C
5-8Aryl or heteroaryl, C
3-8Heterocyclylalkyl-C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-C
5-8Aryl or heteroaryl.Wherein, R
4And R
5Also can be connected to form 5-8 unit Heterocyclylalkyl, can not be substituted on ring or by one or more halogens, cyano group, amido, C
1-6The amido that alkyl replaces, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
1-6Alkoxyl group, the C that halogen replaces
1-6Alkoxyl group replaces;
R
6And R
7Be independently selected from hydrogen halogen, C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl, C
5-8Aryl or heteroaryl also can be connected to form C
3-8Heterocyclylalkyl or cycloalkyl;
R
8Be selected from hydrogen, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl.
As preferably, compound provided by the invention or its pharmacy acceptable salt, solvate or prodrug, wherein compound is selected from formula (II):
Wherein A ring and B ring is independently selected from hexa-atomic virtue (mixing) and encircles, and can not be substituted or by one or more nitros, halogen, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group replaces;
R
1Be selected from hydrogen, N (R
4) (R
5), C (O) N (R
4) (R
5), C
3-8Heterocyclylalkyl-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-SO
2-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C
1-6Alkyl-C
5-8Aryl, heteroaryl or C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-C
5-8Aryl or heteroaryl, C
3-8Heterocyclylalkyl-CO-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C (O) N-C
1-6Alkyl or C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-CO
2-C
1-6Alkyl, C
3-8Heterocyclylalkyl-CO-C
3-8Cycloalkyl or Heterocyclylalkyl, above each group can not be substituted or by one or more halogens, cyano group, amino, C
1-6The amido that alkyl replaces, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
1-6Alkoxyl group, the C that halogen replaces
1-6Alkoxyl group replaces;
R
2Be selected from
R
3Be selected from hydrogen, methyl;
R
4And R
5Be independently selected from hydrogen C
1-6Alkyl-C
3-8Heterocyclylalkyl, R
4And R
5Also can be connected to form 5-8 unit Heterocyclylalkyl, can not be substituted on ring or by one or more halogens, cyano group, amido, C
1-6The amido that alkyl replaces, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
1-6Alkoxyl group, the C that halogen replaces
1-6Alkoxyl group replaces.
Preferred, described compound or its pharmacy acceptable salt, solvate or prodrug, wherein compound is selected from formula (III)
X is selected from O, NH or disappearance;
M is selected from 1 or 2;
N is selected from 1 or 2; And if only if, and m is 1 o'clock, and n is selected from 1,2 or 3;
K is selected from 1,2 or 3;
J is selected from 0,1 or 2;
R
9Be selected from C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl, C
5-8Aryl or heteroaryl, CO-C
1-6Alkyl, CO-C
3-8Cycloalkyl, SO
2-C
1-6Alkyl, C
1-6Alkyl-C
5-8Aryl or heteroaryl, CONH-C
1-6Alkyl, CONH-C
3-8Cycloalkyl, COO-C
1-6Alkyl, COO-C
3-8Cycloalkyl.
In specific embodiments of the invention, the compound that provides or its pharmacy acceptable salt or solvate, described structural formula of compound is selected from:
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-N-(the basic piperazine of 1--4-yl) benzamide
1-(3-(3-(5-chloro-2-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) third-2-alkene-1-ketone
1-(4-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-ethyl piperazidine-1-yl)-2-anisole amido) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-yl) third-2-alkene-1-ketone
7-(4-(3-(1-acryl azetidine-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-ketone
1-(3-(3-(5-chloro-2-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(3,4-lupetazin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-ethyl piperazidine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-morpholine anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-parathiazan anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(3-fluoro-4-(4-methyl piperidine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-(methylsulfonyl) piperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-(2-(dimethylamine) ethyl) piperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(2-(4-(4-acetylpiperazine-1-yl) anilino)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(2-(4-(4-benzyl diethylenediamine-1-yl) anilino)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-phenylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(2,6-dimethylated morpholinyl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(piperidin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-(cyclopropane carbonyl) piperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(3,5-lupetazin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl amido) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(2-(4-methylpiperazine-1-yl) ethylamino-) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(piperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
4-(4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido) phenyl)-NEP-1-carboxamide
6-(4-(3-(acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-3,4-dihydronaphthalene-1 (2H)-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl amido) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino)-N, N-dimethyl azetidin-1-carboxamide
(E)-1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) but-2-ene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl)-3-methyl but-2-ene-1-ketone
Tertiary butyl 4-(4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido) phenylpiperazine-1-manthanoate
1-(3-(3-(2-(3-bromobenzene amido)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
The cell growth inhibition test demonstration, in the present invention, part embodiment compound shows stronger inhibition activity to the EGFR mutant cell, and the EGFR wild-type cell is shown the weak activity that suppresses, so the EGFR Mutant Cells is had selectivity preferably; In cytotoxicity experiment, the Hs-27 human skin fibroblast there is extremely weak restraining effect, therefore show lower cytotoxicity; The experiment of EGFR kinase inhibition shows, the contrast Wild type EGFR, and part embodiment has higher inhibition selectivity to mutant egf R kinases; Stability study demonstration in hepatomicrosome, compound of the present invention show good microsome stability.For example the residue per-cent of the compound of embodiment 2 and embodiment 19 after hatching 60 minutes is more than 50%; Part embodiment compound in the present invention all only has faint inhibition or unrestraint to various CYP enzymes, its half-inhibition concentration all higher than or near 20 μ M.Compound of the present invention shows good bioavailability simultaneously.
The present invention also provides medicinal compositions, comprises the described compound of above-mentioned any one or pharmacologically acceptable salts, solvate or prodrug and pharmaceutically acceptable carrier.
Another object of the present invention be disclose the described compound of above-mentioned any one or its pharmacy acceptable salt, solvate or prodrug in the medicine of preparation regulation and control EGFR tyrosine kinase activity purposes or in the purposes of the medicine of preparation treatment EGFR relative disease, as preferably, described EGFR relative disease is cancer, diabetes, disease of immune system, nerve degenerative diseases or cardiovascular disorder.
As preferably, described cancer is nonsmall-cell lung cancer, head and neck cancer, mammary cancer, kidney, carcinoma of the pancreas, cervical cancer, esophagus cancer, carcinoma of the pancreas, prostate cancer, bladder cancer, colorectal carcinoma, ovarian cancer, cancer of the stomach, brain cancer comprises glioblastoma etc., or their any combination.
The present invention also provides above-mentioned arbitrary compound or pharmaceutically acceptable salt thereof, solvate or the prodrug purposes in preparing the disease for the treatment of the EGFR unconventionality expression or the disease that has acquired resistance during use EGFR modulators for treatment.
Described acquired resistance is the resistance that is caused by the T790 sudden change that the EGFR extron 20 is encoded, as T790M.
In the present invention, the EGFR conditioning agent refers to the small molecule tyrosine kinase inhibitors of targeting EGFR, as Gefitinib, and Tarceva, Conmana, lapatinibditosylate.
the present invention also provides a kind of medicinal compositions, comprise the described compound of above-mentioned any one or its pharmacy acceptable salt, solvate or prodrug and be selected from: Gefitinib, Tarceva, Conmana, lapatinibditosylate, XL647, NVP-AEE-788, ARRY-334543, EKB-569, BIBW2992, HKI272, BMS-690514, CI-1033, ZD6474, PF00299804, WZ4002, Cetuximab, Herceptin, the Pa Ni monoclonal antibody of dashing forward, the horse trastuzumab, Buddhist nun's trastuzumab, prick Shandong wood monoclonal antibody, the handkerchief trastuzumab, MDX-214, CDX-110, IMC-11F8, Zemab, Her2 vaccine PX 1041 and HSP90 inhibitor, CNF2024, KOS-953, Ah's Spiramycin Base, IPI-504, the combination of one or more of SNX-5422 and NVP-AUY922, the disease that is used for the treatment of the EGFR unconventionality expression, as cancer, diabetes, disease of immune system, nerve degenerative diseases or cardiovascular disorder.
Formula one compound as therepic use usually can be with the form administration of pharmaceutical composition.
On the one hand, the invention provides formula (I) compound or its pharmacologically acceptable salts as medicine.On the other hand, the present invention also provides pharmaceutical composition, and it comprises formula (I) compound, pharmacologically acceptable salts and pharmaceutically acceptable carrier.
Usually, the compounds of this invention or its pharmacologically acceptable salts can form suitable formulation with one or more pharmaceutical carriers and use.That these formulations are applicable to is oral, rectal administration, topical, mouthful in administration and other parenteral routes use (for example, subcutaneous, muscle, vein etc.).For example, the formulation of suitable oral administration comprises capsule, tablet, granule and syrup etc.The compound of the present invention that comprises in these preparations can be pressed powder or particle; Solution in water-based or non-aqueous liquid or suspension; Water-in-oil or oil-in-water emulsion etc.Above-mentioned formulation can be made via general practice of pharmacy by active compound and one or more carriers or auxiliary material.Above-mentioned carrier need to be compatible with active compound or other auxiliary materials.For solid preparation, non-toxic carrier commonly used includes but not limited to N.F,USP MANNITOL, lactose, starch, Magnesium Stearate, Mierocrystalline cellulose, glucose, sucrose etc.The carrier that is used for liquid preparation comprises water, physiological saline, D/W, ethylene glycol and polyoxyethylene glycol etc.Active compound can form solution or suspension with above-mentioned carrier.
Concrete administering mode and formulation depend on the physico-chemical property of compound itself and the severity of the disease of using etc.
Compound of the present invention in some disease can with the other drug combined utilization, to reach the result for the treatment of of expection.The example of a combined utilization is to treat advanced NSCLC.For example, compound shown in formula of the present invention (I) can with mTOR inhibitors coupling (for example rapamycin); With Met inhibitor (comprising Met antibody MetMAb and Met micromolecular inhibitor PF02341066) coupling; With the coupling of IGF1R inhibitor (for example OSI-906); With heat shock protein inhibitors coupling etc.
On the one hand, compound of the present invention or formulation are applicable to warm blooded animal; On the other hand, compound of the present invention and formulation are applicable to Mammals, such as the mankind.
Composition of the present invention is prepared in the mode that meets the medical practice standard, quantitative and administration.The factors such as the target spot of cause, medicine of " significant quantity " of compound individuality by the concrete illness that will treat, treatment, illness and administering mode that give determine.Usually, general dosage through the gi tract external administration is 1-100mg/kg.The formulation of oral administration can contain 1-500mg/kg compound of the present invention.
Term definition:
" alkyl " as group or the part of other groups, for example alkyl that replaces of halogen, the alkyl that hydroxyl replaces, can be straight chain or side chain.For example, the C1-6 alkyl represents the alkyl of 1 to 6 carbon, includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl.
" alkoxyl group " refers to the generation group after alkyl and Sauerstoffatom link, and includes but not limited to methoxyl group, oxyethyl group, isopropoxy, ring propoxy-etc.
" halogen " refers to fluorine, chlorine, bromine and iodine.Particularly preferably be fluorine and chlorine.
" aryl " refers to comprise the monocycle of six to ten carbon atoms or the aromatic ring that condenses (for example phenyl and naphthyl).
" heteroaryl " refers to any condensing or the aromatic ring system of non-condensed, wherein at least one ring be contain 1-4 be selected from nitrogen, oxygen and sulphur heteroatomic five to octatomic ring, preferably at least one heteroatoms is selected from nitrogen.Heteroaryl includes but not limited to thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzimidazolyl-, benzopyrazoles base, indyl etc.
" cycloalkyl " refers to comprise saturated or the undersaturated monocycle of part, condensed ring or the bridged ring of the carbon atom that specifies number.For example, the C3-8 cycloalkyl refers to the cycloalkyl of three to eight carbon, comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
" Heterocyclylalkyl " refers to defined cycloalkyl in the present invention, the carbon atom on wherein one or more rings by oxygen, nitrogen ,-NR-, sulphur, carbonyl ,-S (O)-or-groups such as S (O) 2 replace; Heterocyclylalkyl includes but not limited to morpholinyl, piperazinyl, piperidyl, thio-morpholinyl etc.
" pharmacy acceptable salt " comprises the acceptable acid salt of pharmacy and the acceptable base addition salt of pharmacy." pharmaceutically acceptable acid salt " refer to keep free alkali biological effectiveness and without other side effects, with mineral acid or the formed salt of organic acid.Inorganic acid salt includes but not limited to hydrochloride, hydrobromate, vitriol, phosphoric acid salt etc.; Organic acid salt includes but not limited to formate, acetate, propionic salt, glycollate, gluconate, lactic acid salt, oxalate, maleate, succinate, fumarate, tartrate, Citrate trianion, glutaminate, aspartate, benzoate, mesylate, tosilate and salicylate etc.These salt can be by the known method preparation of this specialty.
The acceptable base addition salt of pharmacy includes but not limited to salt such as the sodium salt of mineral alkali, sylvite, calcium salt and magnesium salts etc.Include but not limited to the salt of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginic acid salt etc.These salt can be by the known method preparation of this specialty.
Inhibitor: refer to can and receptors bind (such as EGFR), and suppress the compound of this receptor performance physiological action.
Medicinal combination: refer to a kind of combination, comprise at least a compound of the present invention and at least a acceptable auxiliary material of pharmacy or carrier.Medicinal combination can be by the known method preparation of this specialty.
Treatment effective dose: refer to produce the active compound of physiology or pharmacological action or the amount of medicinal combination in the animals or humans body.The effective dose produce an effect generally includes prophylactic generation, suppresses the progress of disease or the symptom of alleviation disease.Effective dose is usually by the investigator, and doctor or other healthcare givers decide.
Some formula (I) compound can exist more than a kind of crystal formation, the present invention includes various crystal formations and composition thereof.
" solvate " mentioned in the present invention refers to the title complex that compound of the present invention and solvent form.They or in solvent reaction or from solvent Precipitation or crystallize out.For example, a title complex that forms with water is called " hydrate ".Within the solvate of formula (I) compound belongs to the scope of the invention.
Compound shown in formula of the present invention (I) can contain one or more chiral centres, and exists with different optical activity forms.When compound contained a chiral centre, compound comprised enantiomer.The present invention includes the mixture of these two kinds of isomer and isomer, as racemic mixture.Enantiomer can split by the known method of this specialty, methods such as crystallization and chiral chromatography.When formula one compound contains more than a chiral centre, can there be diastereomer.The present invention includes the optically pure specific isomer that split and the mixture of diastereomer.Diastereomer can be split by this professional currently known methods, such as crystallization and preparative chromatography.
The present invention includes the prodrug of above-claimed cpd.Prodrug comprises known amino protecting group and carboxyl-protecting group, is hydrolyzed or discharges via enzyme reaction to obtain parent compound under physiological condition.Concrete front medicament preparation can be with reference to (Saulnier, M.G.; Frennesson, D.B.; Deshpande, M.S.; Hansel, S.B and Vysa, D.M.Bioorg.Med.Chem Lett.1994,4,1985-1990.Greenwald, R.B.; Choe, Y.H.; Conover, C.D.; Shum, K.; Wu, D.; Royzen, M.J.Med.Chem.2000,43,475.).
Embodiment
The invention discloses preparation method, ingredients and the treatment plan of a compounds and compound, those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is, all similarly replace and change apparent to those skilled in the art, and they all are deemed to be included in the present invention.Product of the present invention, method and application are described by preferred embodiment, the related personnel obviously can change methods and applications as herein described within not breaking away from content of the present invention, spirit and scope or suitably change and combination, realizes and use the technology of the present invention.
The present invention has set forth a compounds, and they cross the cancer of expression to EGFR dependent, have therapeutic efficiency.In addition, the preparation method of these compounds, ingredients and treatment plan are also described.
In order to make those skilled in the art understand better technical scheme of the present invention, the present invention is described in further detail below in conjunction with specific embodiment.
Syntheti c route
Compound in the present invention can easily prepare by multiple synthetic operation, and these operations are that one of ordinary skill in the art grasp when skilled.The specific preparation method of these compounds includes, but is not limited to flow process hereinafter described.
Flow process 1
The chlorine that pyrimidine is 2 replaces with amine, needs at a certain temperature, uses suitable catalyzer and suitable solvent just can carry out.Use acid catalysis, catalyzer can be but be not limited to TFA or tosic acid.Use Buchwald-Hartwig amination method, palladium catalyst used can be but be not limited to Pd
2(dba)
3, part used can be but be not limited to BINAP, alkali used can be but be not limited to potassium tert.-butoxide.
Flow process 2
4 derivative and azacycloalkyl ketones that replace with arylamine of pyrimidine carry out the ammonification reduction reaction, and the original reagent of going back used can be but be not limited to the acetic acid sodium borohydride, need use the ice bath temperature control during use.Further alkylation, optional corresponding halohydrocarbon, acyl chlorides etc. are as raw material, and prerequisite is to guarantee R
2Upper without sensitive group participation reaction.
Flow process 3
This nitro-compound is converted into corresponding amino-complex and can under acidic conditions, reduces with metal (can be but be not limited to iron powder, zinc powder).
Flow process 4
Be starting raw material with 2,4,5-trichloropyrimidine, can introduce multiple functional group with different conditions at its 4.Phenol and arylamine can under acid binding agent (can be but be not limited to DIEA) exists, be realized transforming in alcohol.Phenols at room temperature can be completed reaction smoothly, and the introducing of arylamine generally need to be carried out at a certain temperature.4 of pyrimidines are direct substitution with aromatic ring, can adopt Suzuki linked reaction condition, carry out coupling with corresponding phenylo boric acid, and catalyzer can be but be not limited to tetrakis triphenylphosphine palladium.
Flow process 5
Nitro to this compounds reduces, and can realize by catalytic hydrogenation.
Flow process 6
To nitro halobenzene and ring secondary amine, under proper temperature (heating or microwave), solvent condition, carry out substitution reaction.Alternative method also has Buchwald-Hartwig amination method.
Flow process 7
The azacycloalkyl ketone of Boc protection removes Boc under acidic conditions, form hydrochloride, under alkaline condition, can be condensed into acid amides with corresponding acyl chlorides, and this conversion need to be completed in suitable solvent.
The preparation of embodiment 1, compound
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1:3-(2,5-dichloro pyrimidine-4-base oxygen base) aniline
With 2,4,5-trichloropyrimidine (3.67g, 20mmol), a hydroxyl oil of mirbane (2.78g, 20mmol) and diisopropyl ethyl amine (7mL, 40mmol) join respectively in the 30mL dehydrated alcohol.Stir under room temperature, it is muddy that system becomes gradually, visible a large amount of rice white Precipitations, and after 2 hours, the thin-layer chromatography monitoring shows that raw material transforms substantially fully.Decompress filter, filter cake normal hexane washed twice obtains 5.32g (93%) rice white solid after drying.
this white solid all is dissolved in the 30mL tetrahydrofuran (THF), add zinc powder (6g, 93mmol), water (8mL) and ammonium chloride (5g, 93mmol) reflux is 5 hours, the thin-layer chromatography monitoring shows without the raw material point, let cool, remove by filter the excessive solid residues such as zinc powder, filtrate decompression is concentrated adds the 50mL acetic acid ethyl dissolution except after organic solvent, with the saturated aqueous common salt washed twice, tell organic layer, after anhydrous sodium sulfate drying, concentrated, the white solid product 4.0g (84.2%) of decompression column chromatography purifying (n-hexane/ethyl acetate=6/1).MS(m/z)256.1(M+1)。
2:1-acryl azetidin-3-ketone
With 1-tertbutyloxycarbonyl azetidin-3-ketone (3.66g, 21.4mmol) be dissolved in the 20mL dioxane, slowly passed into hydrogen chloride gas 2 hours, filter to get white solid, with a small amount of normal hexane washing, get white solid 2.07g (90.2%) after drying.
This white solid (1g, 9.3mmol) is dissolved in the mixing solutions of tetrahydrofuran (THF) (15mL) and water (10ml), slowly adds sodium bicarbonate (1.72g, 20.5mmol).Under ice bath, drip the tetrahydrofuran solution (20mL) of acrylate chloride (756 μ L, 9.3mmol) in 30 minutes.Ice bath.After reaction 5h, decompression steams organic solvent, adds ethyl acetate dilution, after a small amount of salt solution washing, organic layer with anhydrous sodium sulfate drying after, the concentrated yellow oil product 1.1g (94.5%) that to get, this purity can be directly used in next step reaction.
3:1-(3-(3-(2,5-dichloro pyrimidine-4-base oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
With 3-(2; 5-dichloro pyrimidine-4-base oxygen base) aniline (2.25g; 8.8mmol); 1-acryl azetidin-3-ketone and anhydrous sodium sulphate (6.24g; 44.0mmol) be dissolved in 15mL acetic acid, slowly add acetic acid sodium borohydride (2.05g, 9.7mmol) under the ice-water bath temperature control; keep temperature below 10 ℃, reaction is spent the night.After decompression steams most of acetic acid, system adds water 15mL dilution, be neutralized to pH as 7 left and right take saturated sodium bicarbonate aqueous solution, with ethyl acetate extraction (3 * 15mL), merge organic phase, with anhydrous sodium sulfate drying, concentrated rear normal pressure column chromatography is separated (methylene chloride/methanol=50/1) and is got white solid 2.68g (83.8%).MS(m/z)365.2(M+1)，387.1(M+23)。
4:4-(4-methylpiperazine-1-yl) aniline
With parachloronitrobenzene (20g, 127mmol) with methylpiperazine (25.4g, 254mmol) mix, stirring makes solid all after dissolving, in reaction under 90 ℃ after 4 hours, with the reaction solution impouring approximately in the 200mL frozen water, separate out a large amount of yellow solids, suction filtration, filter cake washes with water, gets yellow solid 27.9g (99.3%) after drying.
This yellow solid (100mg, 0.45mmol) is dissolved in methyl alcohol (15mL), adds 10% palladium carbon (10mg), reaction is 2 hours under hydrogen atmosphere, substrate transforms substantially fully, removes by filter palladium carbon, and the filtrate evaporate to dryness concentrates to get yellow liquid 89mg (100%).MS(m/z)192.0(M+1)。
5:1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
((3-(2 for 3-with 1-, 5-dichloro pyrimidine-4-base oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone (170mg, 0.465mmol), 4-(4-methylpiperazine-1-yl) aniline (89mg, 0.465mmol), join in 2-butanols (15mL), add the rear backflow of trifluoroacetic acid (104 μ L, 1.395mmol) 20 hours.After system is neutralized to neutrality with saturated sodium bicarbonate, thin up, with ethyl acetate extraction (2 * 15mL), after merging organic phase, with the saturated common salt water washing, after anhydrous sodium sulfate drying, concentrated, often compression leg chromatogram preliminary purification (methylene chloride/methanol=15/1) is rear with high-efficient liquid phase chromatogram purification, gets white solid 42.77mg (17.7%).
1HNMR?300MHz(CDCl
3)δ8.15(s，1H)，7.28-7.32(m，1H)，7.16(d，J＝8.7Hz，2H)，6.70(d，J＝8.7Hz，2H)，6.57(dd，J＝1.5Hz，J＝14.1Hz，1H)，6.62(d，J＝8.1Hz，1H)，6.31(d，J＝17.1Hz，1H)，6.15(s，1H)，6.10(dd，J＝14.1Hz，J＝10.2Hz，1H)，5.68(dd，J＝1.5Hz，J＝10.2Hz，1H)，4.45(t，J＝8.1Hz，J＝15.9Hz，1H)，4.31-4.36(m，1H)，4.17-4.20(m，1H)，3.73-3.83(m，2H)，3.59-3.61(m，2H)，3.40-3.41(m，4H)，3.07-3.09(m，2H)，2.88(s，3H).MS(m/z)：520.3(M+1)。
The preparation of embodiment 2, compound
4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-N-(the basic piperazine of 1--4-yl) benzamide
1:4-amido-N-(1-methyl piperidine-4-yl) benzamide
With 1-methyl piperidine-4-amine (228mg, 2mmol), p-nitrobenzoic acid (335mg, 2mmol) and diisopropyl ethyl amine (1.04mL, 6mmol) are dissolved in N, in N-N,N-DIMETHYLACETAMIDE (10mL), after separately HATU (1.14g, 3.0mml) being dissolved in N,N-dimethylacetamide (10mL), join in above-mentioned reaction solution, under room temperature, reaction is 3 hours.Decompression steams N, the N-N,N-DIMETHYLACETAMIDE, add saturated sodium bicarbonate aqueous solution (100mL), remove by filter insolubles, water is with in 2N hydrochloric acid and afterwards with dichloromethane extraction, organic phase is used and the saturated common salt water washing, and after anhydrous sodium sulfate drying, normal pressure column chromatography purifying gets light yellow solid 500mg (95.0%).
Light yellow solid obtained above (500mg) is dissolved in methyl alcohol (25mL), add 10% palladium carbon (50mg), reaction is 2 hours under hydrogen atmosphere, and substrate transforms substantially fully, remove by filter palladium carbon, the filtrate evaporate to dryness concentrates to get yellow liquid 440mg (99.3%).MS(m/z)234.0(M+1)。
2:4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-N-(the basic piperazine of 1--4-yl) benzamide
((3-(2 for 3-with 1-, 5-dichloro pyrimidine-4-base oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone (186mg, 0.51mmol), 4-amido-N-(1-methyl piperidine-4-yl) benzamide (120mg, 0.51mmol), join in 2-butanols (15mL), add the rear backflow of trifluoroacetic acid (76 μ L, 1.02mmol) 20 hours.After system is neutralized to neutrality with saturated sodium bicarbonate, thin up, with ethyl acetate extraction (2 * 15mL), after merging organic phase, with the saturated common salt water washing, after anhydrous sodium sulfate drying, concentrated, often compression leg chromatogram preliminary purification (methylene chloride/methanol=15/1) is rear with high-efficient liquid phase chromatogram purification, gets white solid 10.4mg (3.6%).
1HNMR?300MHz(CDCl
3)δ8.43(s，1H)，8.25(s，1H)，7.53(d，J＝8.4Hz，2H)，7.32(m，2H)，6.71(d，J＝6.6Hz，1H)，6.67(d，J＝7.8Hz，1H)，6.59(dd，J＝1.8Hz，J＝17.1Hz，1H)，6.28(s，1H)，6.25(m，1H)，6.09(dd，J＝10.2Hz，J＝17.1Hz，1H)，5.67(dd，J＝1.8Hz，J＝10.2Hz，1H)，4.46-4.52(m，1H)，4.35-4.38(m，1H)，4.23-4.25(m，2H)，3.83-3.90(m，2H)，3.62(d，J＝11.2Hz，2H)，2.84-2.85(m，2H)，2.83(s，3H)，2.29-2.33(m，2H)，2.16-2.21(m，2H).MS(m/z)：562.5(M+1).
Embodiment 3, cell growth inhibition test
1. materials and methods
Cell growth medium: RPMI1640 (Gibco, 22400089) adds 10%FBS (Gibco, 10099141)
Detection kit: CCK-8 detection reagent (DojinDo, CK04-20)
Clone: A431 (EGFR WT, Chinese Academy of Sciences's Shanghai cell bank), NCI-H1975 (EGFR L858R/T790M, Chinese Academy of Sciences's Shanghai cell bank), HCC827 (EGFR Del E746_A750,
Korea S S. Korea and the USA medicine), Hs-27 (human skin fibroblast, Korea S S. Korea and the USA medicine)
The TECANIF200 microplate reader
Invitrogen Countess cell counter (C10227)
2. cell inoculation
Cell with 0.25% trysinization logarithmic phase.Be made into single cell suspension with the RPMI1640 substratum that contains 10%FBS.Invitrogen Countess carries out cell counting.A431, NCI-H1975, HCC827 and Hs-27 all are inoculated in 96 orifice plates (brassboard and control board) with 5000 cells/well/100uL.The blank group adds the 100uL substratum.Culture plate is put in incubator, 37 ℃, 5%CO
2Overnight incubation.
3. the control board Growth of Cells is measured
Take out control board in incubator, discard substratum in the hole, add the fresh culture that contains 10%CCK-8, the 100uL/ hole.After adding, 96 orifice plates are put back in incubator, continued to cultivate 1-4h, until present significantly orange red.450nm measures absorbance value, is the front OD value of drug treating.
4. drug treating
Each testing sample is from 10uM, and 10 times of dilutions arrange 6 drug levels, and each concentration is done the test of multiple hole.For A431, NCI-1975, HCC827 clone is used to contain the substratum gradient dilution testing sample of 0.1% foetal calf serum, and is 2 times of final concentration.For the Hs-27 cell, be 2 times of final concentration with the substratum dilution that contains 10% foetal calf serum.Take out brassboard and add the substratum that contains 2 times of medicine final concentrations to be measured, 100uL/ takes out brassboard in the hole, discards substratum in the hole, adds the fresh substratum 100uL/ hole that contains 0.1% foetal calf serum; Add again the substratum that contains 2 times of medicine final concentrations to be measured, the 100uL/ hole.96 orifice plates are put back to incubator, 37 ℃, 5%CO
2Act on 72 hours.Control group adds the substratum that does not contain medicine.
5. develop the color and GI
50Calculating
After effect in 72 hours is complete, take out 96 orifice plates in incubator, discard substratum in the hole, add the fresh culture that contains 10%CCK-8, the 100uL/ hole.After adding, 96 orifice plates are put back in incubator, continued to cultivate 1-4h (consistent with the control board developing time).450nm measures photoabsorption.Cell growth rate %=[(administration group OD value-brassboard blank OD value)-(OD value before drug treating-control board blank OD value)]/[(control group OD value-brassboard blank group OD value)-(OD value before drug treating-control board blank OD value)] * 100.Carry out the logistic match with origin8, calculate the GI of counter sample
50Value, GI
50Lower explanation medicine is more obvious to the growth-inhibiting of cell.
GI in the # table
50Being worth residing interval is represented by the number of asterisk: 1nM≤GI
50≤ 10nM:**** (activity is very strong); 10nM＜GI
50≤ 100nM:*** (activity is stronger); 100nM＜GI
50≤ 1000nM:** (active medium); 1000nM＜GI
50≤ 10000nM:* (activity is weak).
Carry out cytotoxicity experiment according to above-mentioned experimental technique, investigate the compound of the embodiment of the present invention to the growth-inhibiting effect of normal people's skin flbroblast Hs-27.Wherein, part embodiment compound shows lower cytotoxicity, the compound of embodiment 1, embodiment 2 and embodiment 19 for example, their GI to the Hs-27 cell
50Be respectively 1032,1584 and 1992nM.
Embodiment 4, kinase inhibition test
Concentration shown in following table is adopted in the kinase inhibition test:
#The Km value equals enzymatic reaction speed and reaches the maximum reaction velocity one corresponding concentration of substrate of half, and the same enzyme is also different from different substrate reactions Km values.The avidity size of the reaction enzyme-to-substrate that the Km value can be similar to: the Km value is large, shows that avidity is little; The Km value is little, shows that avidity is large.
1. with distilled water, compound being carried out serial dilution is 4 times of final concentration.
2. the required solution of preparation test (1X RB:40mM Tris, 7.5; 20mM MgCl
20.1mg/ml BSA; 2mM MnCl
2, 50 μ M DTT).
3. composition that control group adds:
CK-：10uL?ddH
2O+5uL?4X?R.B.(EGFR)+ATP&S(EGFR)
CK+：5uL?ddH
2O+10uL?2X?EGFR(WT)in?2X?R.B.+ATP&S(EGFR)
4. adding with the distilled water dilution is the compound 5uL/ hole of 4 times of final concentrations.
5.2X EGFR (WT/T790M/T790M﹠amp; L858R/L858R) in 2X R.B., at room temperature hatched after mixing 10 minutes in the 10uL/ hole.
6.4X ATP+S.in 1X ddH
2O, 5uL/ is hatched respectively 60 minutes (WT, T790M) and 120min (T790M/L858R, L858R) under room temperature
7. add ADP-Glo reagent, after mixing, hatched under room temperature 40 minutes in the 20uL/ hole.
8. add kinase assay reagent, hatched under room temperature 40 minutes after mixing in the 40uL/ hole.
9. survey the luciferase value.
According to above experimental technique, in the present invention, part of compounds demonstrates EGFR Catastrophic selection inhibition preferably.
IC in table
50Be worth littlely, represent that relative inhibition ability is stronger.
Embodiment 5, the compound stability study in hepatomicrosome
1. testing compound is dissolved in acetonitrile, makes the storing solution that concentration is 0.5mM.
2.2 μ L storing solution adds in the 1.5mL centrifuge tube, then adds 148 μ L phosphoric acid buffers (100mM, pH7.4) and 10 μ L hepatomicrosomes (protein concentration is 20mg/mL) suspension; Control group adds 158 μ L phosphoric acid buffers (100mM, pH 7.4).
3. the mixed system for preparing in step 2 was incubated 3 minutes in 37 ℃ of water-baths in advance, then added 40 μ LNADPH that system occurs and (contained NADP
+: 6.5mM, Glucose-6-phosphate:16.5mM, MgCl
2: 16.5mM, Glucose-6-phosphate dehydrogenase:2U/mL) start reaction, and hatched 1 hour in 37 ℃ of water-baths.
4. after reaction is carried out 1 hour, centrifuge tube is taken out from water-bath, and add 400 μ L acetonitrile termination reactions, then vortex concussion is 3 minutes, and centrifugal (13000rpm, 4 ℃) 5 minutes are at last got supernatant liquor and detected residual drug concentration C r with HPLC.
5. 0 of parallel preparation minute response sample preparation method: the mixed system for preparing in step 2, take out incubate in advance 3 minutes in 37 ℃ of water-baths after, add 400 μ L acetonitriles, then add 40 μ L NADPH that systems occur.Mediate concussion after 3 minutes, and centrifugal (13000rpm, 4 ℃) 5 minutes get supernatant liquor HPLC detection of drugs concentration C 0.
6. after hatching in 60 minutes, the residue per-cent of medicine in incubation system calculates according to the following formula:
Medicine residue (%)=Cr ÷ C0 * 100%
According to above-mentioned experimental technique, the part embodiment compound in the present invention shows good microsome stability.For example the residue per-cent (% successively in the hepatomicrosome enzyme of people/rat/dog/mouse) of the compound of embodiment 2 and embodiment 19 after hatching 60 minutes is respectively: 76.24/84.67/48.33/67.67 and 79.2/87.55/62.54/61.82.
Embodiment 6, assessing compound are to the CYP enzyme inhibition
Method: this experiment uses the CYP Inhibitor Screening Kit test kit of BD Gentest company to complete.All experimental implementation are carried out according to the product instruction in test kit.Experimental procedure is as follows:
1. be preheated to 37 ℃ in deionized water and buffering brine bath.
2. prepare the NADPH generation systems.
3. the first row of black 96 orifice plates adds the NADPH generation systems 144 μ L of step 2 preparation.
4. according to the instruction of test kit, prepare cofactor-ACN solution.
5.96 the secondary series to the of orifice plate 12 row add the cofactor-ACN for preparing in 100 μ L steps 4.
6.6uL positive inhibitor, testing compound are added to the first hole of test set separately.After using volley of rifle fire piping and druming to mix, 50 μ L serial dilution to the eight row.The 8th row take out 50 μ L solution and abandon after piping and druming mixes.
7. 96 orifice plates are sealed with the shrouding film, hatched 10min for 37 ℃.
8. prepare the enzyme-substrate mixture according to the instruction of test kit.
9. hatch 96 orifice plates of 10min in step 7, first row to the ten is listed as every hole and adds 100 μ L enzyme-substrate mixtures (adding speed slightly fast, to guarantee abundant mixing solutions).
10. again build the shrouding film, hatch certain hour (different CYP hypotype incubation times is different) according to 37 ℃ of the instructions of test kit.
11. 96 orifice plates after hatching, every hole adds 75 μ L reaction terminating liquids.
12.96 the 11 row of orifice plate and the 12 row add 100 μ L enzyme-substrate mixtures.
13. according to the instruction of test kit, detect the fluorescence intensity in every hole with microplate reader, and calculate IC
50
According to above-mentioned experimental technique, the part embodiment compound in the present invention all only has faint inhibition or unrestraint to various CYP enzymes.For example the compound of embodiment 2 and embodiment 19 to the half-inhibition concentration of various CYP hypotypes (1A2,2D6,2C9,2C19,3A4) all higher than or near 20 μ M.
The pharmacokinetics research in the rat body of embodiment 7, compound
1. after male SD rat is bought in, raised 7 days in this laboratory adaptability.
2.6 only the SD rat is divided into 2 groups at random, 3 every group, one group is used for gastric infusion, and another group is used for the tail vein injection administration.Need overnight fast before the rat of gastric infusion group, administration.
3. after the rat administration, adopt the method for eye socket venous plexus blood sampling at following time point blood sample collection: 0min (before administration), 5min, 15min, 30min, 1h, 2h, 3h, 5h, 7h, 24h.Each blood sampling time point blood sampling volume is about 300 μ L.
4. then the blood sample that gathers gathers the upper plasma sample at 4 ℃ of centrifugal 5min of the rotating speed with 12000rpm, and preserves to be measured in-20 ℃ of refrigerators.
5. experimental implementation is summed up and is seen the following form:
6. use the LC-MS/MS in this laboratory to detect compound concentration in blood plasma.
7. use the pharmacokinetics professional software WinNonlin in this laboratory to calculate pharmacokinetic parameter.
According to above-mentioned experimental technique, compound of the present invention shows good bioavailability, shows 5.7% bioavailability as the compound of embodiment 1.
The above is only the preferred embodiment of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (13)
1. the compound of formula (I) or its pharmacy acceptable salt, solvate or prodrug:
Wherein, X is selected from O, NR
8Or disappearance;
M is selected from 1 or 2;
N is selected from 1,2 or 3;
A ring and B ring are independently selected from C
5-8Aryl or heteroaryl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl, 8-14 unit condensed ring, and can not be substituted or by one or more nitros, halogen, cyano group, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
1-6Alkoxyl group, the C that halogen replaces
1-6Alkoxyl group replaces;
R
1Be selected from hydrogen, N (R
4) (R
5), N (R
4) CO (R
5), N (R
4) SO
2(R
5), N (R
4) SO (R
5), C (O) OR
4, C (O) N (R
4) (R
5), SO
2R
4, SOR
4, SR
4, SO
2NR
4R
5, OR
4, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl, C
5-8Aryl, C
5-8Heteroaryl, C
3-8Heterocyclylalkyl-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-SO
2-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C
1-6Alkyl-C
5-8Aryl, heteroaryl or C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-C
5-8Aryl or heteroaryl, C
3-8Heterocyclylalkyl-CO-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C (O) N-C
1-6Alkyl or C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-CO
2-C
1-6Alkyl, C
3-8Heterocyclylalkyl-CO-C
3-8Cycloalkyl or Heterocyclylalkyl, above each group can not be substituted or by one or more halogens, cyano group, amino, C
1-6The amido that alkyl replaces, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
1-6Alkoxyl group, the C that halogen replaces
1-6Alkoxyl group replaces;
R
2Be selected from
R
3Be selected from hydrogen, C
1-6Alkyl, CO-C
1-6Alkyl, CO-C
2-6Thiazolinyl, CO-C
2-6Alkynyl, the C that halogen replaces
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl
R
4And R
5Be independently selected from hydrogen C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl, C
5-8Aryl or heteroaryl, C
1-6Alkyl-C
3-8Heterocyclylalkyl, C
1-6Alkyl-C
5-8Aryl or heteroaryl, C
3-8Heterocyclylalkyl-C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-C
5-8Aryl or heteroaryl.Wherein, R
4And R
5Also can be connected to form 5-8 unit Heterocyclylalkyl, can not be substituted on ring or by one or more halogens, cyano group, amido, C
1-6The amido that alkyl replaces, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
1-6Alkoxyl group, the C that halogen replaces
1-6Alkoxyl group replaces;
R
6And R
7Be independently selected from hydrogen halogen, C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl, C
5-8Aryl or heteroaryl also can be connected to form C
3-8Heterocyclylalkyl or cycloalkyl;
R
8Be selected from hydrogen, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl.
2. the described compound of claim 1 or its pharmacy acceptable salt, solvate or prodrug, wherein compound is selected from formula (II):
Wherein A ring and B ring is independently selected from hexa-atomic virtue (mixing) and encircles, and can not be substituted or by one or more nitros, halogen, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group replaces;
R
1Be selected from hydrogen, N (R
4) (R
5), C (O) N (R
4) (R
5), C
3-8Heterocyclylalkyl-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-SO
2-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C
1-6Alkyl-C
5-8Aryl, heteroaryl or C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-C
5-8Aryl or heteroaryl, C
3-8Heterocyclylalkyl-CO-C
1-6Alkyl, C
3-8Heterocyclylalkyl-C (O) N-C
1-6Alkyl or C
3-8Heterocyclylalkyl, C
3-8Heterocyclylalkyl-CO
2-C
1-6Alkyl, C
3-8Heterocyclylalkyl-CO-C
3-8Cycloalkyl or Heterocyclylalkyl, above each group can not be substituted or by one or more halogens, cyano group, amino, C
1-6The amido that alkyl replaces, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
1-6Alkoxyl group, the C that halogen replaces
1-6Alkoxyl group replaces;
R
2Be selected from
R
3Be selected from hydrogen, methyl;
R
4And R
5Be independently selected from hydrogen C
1-6Alkyl-C
3-8Heterocyclylalkyl, R
4And R
5Also can be connected to form 5-8 unit Heterocyclylalkyl, can not be substituted on ring or by one or more halogens, cyano group, amido, C
1-6The amido that alkyl replaces, C
1-6Alkyl, the C that halogen replaces
1-6Alkyl, C
1-6Alkoxyl group, the C that halogen replaces
1-6Alkoxyl group replaces.
3. the described compound of claim 2 or its pharmacy acceptable salt, solvate or prodrug, wherein compound is selected from formula (III)
X is selected from O, NH or disappearance;
M is selected from 1 or 2;
N is selected from 1 or 2; And if only if, and m is 1 o'clock, and n is selected from 1,2 or 3;
K is selected from 1,2 or 3;
J is selected from 0,1 or 2;
R
9Be selected from C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl, C
5-8Aryl or heteroaryl, CO-C
1-6Alkyl, CO-C
3-8Cycloalkyl, SO
2-C
1-6Alkyl, C
1-6Alkyl-C
5-8Aryl or heteroaryl, CONH-C
1-6Alkyl, CONH-C
3-8Cycloalkyl, COO-C
1-6Alkyl, COO-C
3-8Cycloalkyl.
4. the described compound of claim 1-3 any one or its pharmacy acceptable salt or solvate, is characterized in that, described structural formula of compound is selected from:
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-N-(the basic piperazine of 1--4-yl) benzamide
1-(3-(3-(5-chloro-2-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) third-2-alkene-1-ketone
1-(4-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) piperidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-ethyl piperazidine-1-yl)-2-anisole amido) pyrimidine-4-yl oxygen base) anilino) pyrroles-1-yl) third-2-alkene-1-ketone
7-(4-(3-(1-acryl azetidine-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-4,5-dihydro-1H-benzo [b] azatropylidene-2 (3H)-ketone
1-(3-(3-(5-chloro-2-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(3,4-lupetazin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-ethyl piperazidine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-morpholine anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-parathiazan anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(3-fluoro-4-(4-methyl piperidine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-(methylsulfonyl) piperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-(2-(dimethylamine) ethyl) piperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(2-(4-(4-acetylpiperazine-1-yl) anilino)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(2-(4-(4-benzyl diethylenediamine-1-yl) anilino)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-phenylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(2,6-dimethylated morpholinyl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(piperidin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-(cyclopropane carbonyl) piperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(3,5-lupetazin-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl amido) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(2-(4-methylpiperazine-1-yl) ethylamino-) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(piperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
4-(4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido) phenyl)-NEP-1-carboxamide
6-(4-(3-(acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido)-3,4-dihydronaphthalene-1 (2H)-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl amido) anilino) azetidin-1-yl) third-2-alkene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone
3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino)-N, N-dimethyl azetidin-1-carboxamide
(E)-1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl) but-2-ene-1-ketone
1-(3-(3-(5-chloro-2-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl oxygen base) anilino) azetidin-1-yl)-3-methyl but-2-ene-1-ketone
Tertiary butyl 4-(4-(4-(3-(1-acryl azetidin-3-base amido) phenoxy group)-5-chloropyrimide-2-base amido) phenylpiperazine-1-manthanoate
1-(3-(3-(2-(3-bromobenzene amido)-5-chloropyrimide-4-base oxygen base) anilino) azetidin-1-yl) third-2-alkene-1-ketone.
5. medicinal compositions, comprise the described compound of claim 1-4 any one or pharmacologically acceptable salts, solvate or prodrug and pharmaceutically acceptable carrier.
6. the described compound of any one or its pharmacy acceptable salt, solvate or the prodrug purposes in the medicine of preparation regulation and control EGFR tyrosine kinase activity in claim 1-4.
7. in claim 1-4, the described compound of any one or its pharmacy acceptable salt, solvate or prodrug are treated the purposes of the medicine of EGFR relative disease in preparation.
8. purposes claimed in claim 7, is characterized in that, described EGFR relative disease is the disease of EGFR unconventionality expression, as cancer, and diabetes, disease of immune system, nerve degenerative diseases or cardiovascular disorder.
9. purposes claimed in claim 8, is characterized in that, described cancer is nonsmall-cell lung cancer, head and neck cancer, mammary cancer, kidney, carcinoma of the pancreas, cervical cancer, esophagus cancer, carcinoma of the pancreas, prostate cancer, bladder cancer, colorectal carcinoma, ovarian cancer, cancer of the stomach, brain cancer comprises glioblastoma etc., or their any combination.
10. purposes claimed in claim 7, is characterized in that, described EGFR relative disease also comprises and uses the disease that has acquired resistance during the EGFR modulators for treatment.
11. purposes claimed in claim 10 is characterized in that, described acquired resistance be by or comprise the T790 sudden change of EGFR extron 20 coding, as T790M, caused.
12. purposes claimed in claim 10 is characterized in that, described EGFR conditioning agent is the small molecule tyrosine kinase inhibitors of targeting EGFR, as from Gefitinib, and Tarceva, Conmana, lapatinibditosylate.
13. medicinal compositions, comprise the described compound of any one or its pharmacy acceptable salt in claim 1-4, solvate or prodrug and be selected from: Gefitinib, Tarceva, Conmana, lapatinibditosylate, XL647, NVP-AEE-788, ARRY-334543, EKB-569, BIBW2992, HKI272, BMS-690514, CI-1033, ZD6474, PF00299804, WZ4002, Cetuximab, Herceptin, the Pa Ni monoclonal antibody of dashing forward, the horse trastuzumab, Buddhist nun's trastuzumab, prick Shandong wood monoclonal antibody, the handkerchief trastuzumab, MDX-214, CDX-110, IMC-11F8, Zemab, Her2 vaccine PX 1041 and HSP90 inhibitor, CNF2024, KOS-953, Ah's Spiramycin Base, IPI-504, the combination of one or more of SNX-5422 and NVP-AUY922.
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