CN102643272B - Novel thieno [3, 2-d] pyrimidine compound - Google Patents

Novel thieno [3, 2-d] pyrimidine compound Download PDF

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CN102643272B
CN102643272B CN201210111946.6A CN201210111946A CN102643272B CN 102643272 B CN102643272 B CN 102643272B CN 201210111946 A CN201210111946 A CN 201210111946A CN 102643272 B CN102643272 B CN 102643272B
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base
pyrimidine
thieno
morpholine
diazanyl
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CN102643272A (en
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宫平
刘亚婧
赵燕芳
翟鑫
朱五福
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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Abstract

The invention relates to a thieno [3, 2-d] pyrimidine compound shown in the formula I, a stereomer thereof and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein substituent groups R1 and R2 have the meanings given in the specification. The invention also relates to the usage of the compound shown in the formula I in preparing drugs for treating and/or preventing cancer and other poliferative diseases.

Description

New thieno-[3,2-d] pyrimidines
Technical field
The present invention relates to new thieno-[3,2 -d] pyrimidines, its geometrical isomer and pharmacy acceptable salt, hydrate, solvate or prodrug, their preparation method and the pharmaceutical composition containing described compound.The invention still further relates to thieno-[3,2 -d] pyrimidines is for the preparation of the purposes treated and/or prevented in the medicine of cancer and other proliferative disease.
Background technology
Malignant tumour is a kind of disease of serious harm human life health, along with the change of the extraneous factors such as environmental pollution, whole world pathogenesis of cancer number rises year by year, add up according to the World Health Organization (WHO), 1,000 ten thousand tumour patients are about diagnosed out in the current whole world every year, 7000000 people die from the relative disease caused by tumour, and therefore malignant tumour has become the large killer of mankind's Equations of The Second Kind being only second to cardiovascular disorder.
Cancer is the disease caused because control growth and proliferation of cell mechanism is not normal, and the essence of cell carcinogenesis is the imbalance of cell signaling system, thus result in quick growth and the infinite multiplication of cancer cells.By phosphinositides-3-kinases (phosphoinositide 3-kinase, PI3K) and the PI3K-Akt-mTOR path that forms of the protein kinase B in its downstream (PKB/Akt), rapamycin target body albumen (mTOR) referred to as PI3K path, in the generation and development of tumour, have important effect, the micromolecular inhibitor being target spot with key molecule in PI3K/Akt signal path has become the focus of current antineoplastic medicine research.
The cyclopean family that PI3K is made up of lipid and serine/threonine kinases, comprise the protein kinase of several phosphinositides kinases and DNA dependence as ATM, ATR and DNA-PK etc., it can make the 3rd di of phosphatidylinositols, produces inositol fat material---the phosphatidylinositols-3-phosphoric acid ester (PIP3) with second messenger's effect.Second messenger PIP3 can make the effector (particularly Akt) in PI3K and downstream match to combine, thus causes film to be raised and phosphorylation.Research shows: numerous processes such as PI3K family transports to cell proliferation, anti-apoptotic, cell migration, film bubble, cell cancerous transformation are relevant, these biological effects are mainly by " anchor " molecule 3-phosphoinositide fat (PIP that PI3K catalysis is formed, PIP2, PIP3) mediate.Research finds; in extensive human tumor spectrum, PI3K path is generally lacked of proper care; dysfunction in this path caused by some transgenation or disappearance can cause normal cell turnover, promote tumor cell proliferation and survive and the invasion and attack of mediate tumor cell and migration; therefore be the favourable effects target position of micromolecular inhibitor, for the treatment of cancer provides chance.
Related to inhibiting patent (WO2009055730/WO2009036082) and relevant report (the Journal of Medicinal Chemistry of PI3K in recent years, 2008, 51 (18): 5522-5532, Drugs of the Future, 2007, 32 (6): 537-547.) sharply increase, have been found that multiple kinase whose micromolecular inhibitor in this signal path at present, as the PI3K inhibitor that natural product wortmannin (Wortmannin) and Mongolian oak flavin compound L Y294002 are two kinds of widespread uses, the former can be combined with the multiple hypotype of PI3K, inhibitor 1L-6-hydroxymethyl-chiro-inositol 2-(the R)-2-O-methyl-3-O-octadecylcarbonate of Akt, the IC of its Selective depression Akt 50value is approximately 5 μMs, is significantly less than the IC that it suppresses PI3K 50be worth 90 μMs, p70S6K is another feasibility target spot of PI3K-Akt signal path, immunosuppressor Rapamycin (RPM) is widely used in clinical organ transplantation, research finds, RPM can make p70S6K dephosphorylation and suppress this kinase whose activity, thus the growth of inhibition tumor cell, in the human tumour cell line that multiple PTEN suddenlys change or PI3K-Akt pathway activity raises, observe the selectivity anti-tumor activity of RPM at present.
In PI3K family, I type PI3K can activate by extracellular signal, be therefore study a class the most widely so far in numerous PI3K hypotype.At present, the compound of many target I type PI3K enters clinical investigation phase, as: natural product wortmannin, PX-866, LY-294002, TGX-115, TGX-155, PI-103, GDC-0941 etc., wherein major part is PI3K-mTOR double inhibitor.
The GDC-0941 (Fig.1) of bibliographical information belongs to thienopyrimidines, is the oral PI3K inhibitor developed by Genentech company, has completed I clinical trial phase at present.GDC-0941 is to the IC of p110 α and δ 50value all reaches 3 nM, is 10 times and 25 times of p110 β, γ, has good selectivity.Preclinical study shows, GDC-0941 shows significant Inhibit proliferaton effect, its IC to various human tumor cell line (comprising glioblastoma multiforme, breast cancer cell, prostate cancer cell etc.) 50value reaches 0.009ug/mL.In nude mouse in Anticancer Activities, when oral dosage is 75 mg/kg, the growth inhibition rate of tumour is reached to more than 80%.
The present inventor on the basis of reference, a series of new thieno-[3,2 of design and synthesis -d] pyridine derivatives, carry out antitumor activity screening through external to various tumor cell strains, result shows to have anti-tumor activity.
summary of the invention:
The present invention relates to general formula ishown thieno-[3,2 -d] pyrimidines, its geometrical isomer and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein:
R 1be selected from H,
N is 0,1 or 2;
R 3, R 4identical or different, be separately selected from (C 1-C 6) alkyl, (C 3-C 6) cycloalkyl; Or R 3and R 4form 5-10 unit saturated heterocyclyl together with the nitrogen-atoms connected with them, described saturated heterocyclyl except with R 3and R 4outside the nitrogen-atoms connected, the optional heteroatoms being selected from O, N and S containing 1-3, optionally by 1 ~ 3 identical or different R 5replace;
R 5for (C 1-C 4) alkyl, methyl sulphonyl;
R 2structural formula be selected from:
M is CH or N;
R 7for hydrogen, trifluoromethyl, (C 1-C 4) alkyl, (C 1-C 4) alkyl acyl, (C 3-C 6) cycloalkyl ,-CH 2r 8,-C (O) R 8,-S (O) 2r 8;
R 8for 6-10 unit aryl, 6-10 unit aryl (C 1-C 4) alkyl, (C 3-C 6) cycloalkyl, (C 1-C 4) alkyl, 5-10 unit heteroaryl, 5-10 unit heteroaryl (C 1-C 4) heterocyclic radical (C of the saturated or fractional saturation of alkyl, the heterocyclic radical of the saturated or fractional saturation of 5-10 unit, 5-10 unit 1-C 4) alkyl, described heteroaryl and heterocyclic radical contain the heteroatoms that 1-3 is selected from O, N and S, and R 8an optional 1-3 R 9replace;
R 6, R 9be 1 ~ 3 independently and identical or different be selected from hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido-, nitro, cyano group, sulfydryl, (C 1-C 4) alkyl, (C 3-C 6) cycloalkyl, (C 1-C 4) thiazolinyl, (C 1-C 4) alkynyl, (C 1-C 4) alkoxyl group, (C 1-C 4) alkylthio, allyl group, (2-methyl) allyl group, (C 1-C 4) alkoxy methyl, (C 1-C 4) alkyl acyl, (C 1-C 3) substituting group of alkylenedioxy group.
The present invention preferably relates to the compound of the formula I be defined as follows, its geometrical isomer and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein:
R 1be selected from H,
N is 1 or 2;
R 5for (C 1-C 4) alkyl, methyl sulphonyl;
R 2structural formula be selected from:
M is CH, N;
R 7for hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkyloyl, (C 3-C 6) cycloalkyl ,-CH 2r 8,-C (O) R 8,-S (O) 2r 8;
R 8for the heterocyclic radical of 6-10 unit aryl, 5-10 unit heteroaryl, the saturated or fractional saturation of 5-10 unit, described heteroaryl and heterocyclyl contain the heteroatoms that 1-3 is selected from O, N and S, and R 8an optional 1-3 R 9replace;
R 6, R 9be 1 ~ 3 independently and identical or different be selected from hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido-, nitro, cyano group, sulfydryl, (C 1-C 4) alkyl, (C 3-C 6) cycloalkyl, (C 1-C 4) thiazolinyl, (C 1-C 4) alkynyl, (C 1-C 4) alkoxyl group, (C 1-C 4) alkylthio, allyl group, (2-methyl) allyl group, (C 1-C 4) alkoxy methyl, (C 1-C 4) alkyl acyl, (C 1-C 3) substituting group of alkylenedioxy group.
The present invention also preferably relates to the compound of the formula I be defined as follows, its geometrical isomer and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein
R 1be selected from H,
R 2structural formula be selected from:
Wherein M is CH or N;
R 7for hydrogen ,-CH 2r 8;
R 8for phenyl, and R 8an optional 1-3 R 9replace;
R 6, R 9be 1 ~ 3 independently and identical or different be selected from hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido-, nitro, cyano group, sulfydryl, (C 1-C 4) alkyl, (C 3-C 6) cycloalkyl, (C 1-C 4) thiazolinyl, (C 1-C 4) alkynyl, (C 1-C 4) alkoxyl group, (C 1-C 4) alkylthio, allyl group, (2-methyl) allyl group, (C 1-C 4) alkoxy methyl, (C 1-C 4) alkyl acyl, (C 1-C 3) substituting group of alkylenedioxy group.
The present invention particularly preferably relates to the compound of the formula I be defined as follows, its geometrical isomer and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein
R 2structural formula be selected from:
R 6, R 9be 1 ~ 3 independently and identical or different be selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido-, nitro, cyano group, sulfydryl, methyl, ethyl, n-propyl, cyclopropyl, the tertiary butyl, vinyl, propenyl, 2-methylpropenyl, ethynyl, methoxyl group, oxyethyl group, ring propoxy-, tert.-butoxy, methylthio group, ethylmercapto group, allyl group, (2-methyl) allyl group, methoxymethyl, ethoxyl methyl, i-propoxymethyl, formyl radical, ethanoyl, propionyl, ring propionyl, butyryl radicals, 2, 3-methylenedioxy, 2, the substituting group of 3-ethylidene dioxy base.
The present invention also preferably relates to the compound of the formula I be defined as follows, its geometrical isomer and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein:
R 1for
R 5for (C 1-C 4) alkyl, methyl sulphonyl;
R 2structural formula be selected from:
M is CH or N;
R 7for hydrogen ,-CH 2r 8;
R 8for phenyl, and R 8an optional 1-3 R 9replace;
R 6, R 9be 1 ~ 3 independently and identical or different be selected from hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido-, nitro, cyano group, sulfydryl, (C 1-C 4) alkyl, (C 3-C 6) cycloalkyl, (C 1-C 4) thiazolinyl, (C 1-C 4) alkynyl, (C 1-C 4) alkoxyl group, (C 1-C 4) alkylthio, allyl group, (2-methyl) allyl group, (C 1-C 4) alkoxy methyl, (C 1-C 4) alkyl acyl, (C 1-C 3) substituting group of alkylenedioxy group.
The present invention particularly preferably relates to the compound of the formula I be defined as follows, its geometrical isomer and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein:
R 1for
R 2structural formula be selected from:
R 6, R 9be 1 ~ 3 independently and identical or different be selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido-, nitro, cyano group, sulfydryl, methyl, ethyl, n-propyl, cyclopropyl, the tertiary butyl, vinyl, propenyl, 2-methylpropenyl, ethynyl, methoxyl group, oxyethyl group, ring propoxy-, tert.-butoxy, methylthio group, ethylmercapto group, allyl group, (2-methyl) allyl group, methoxymethyl, ethoxyl methyl, i-propoxymethyl, formyl radical, ethanoyl, propionyl, ring propionyl, butyryl radicals, 2, 3-methylenedioxy, 2, the substituting group of 3-ethylidene dioxy base.
Compound of Formula I of the present invention, its geometrical isomer and the preferred following compound of pharmacy acceptable salt, hydrate, solvate or prodrug thereof, but these compounds do not mean that any limitation of the invention:
( e)-4-[2-[2-[1-(3-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-t-butylbenzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(3,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[[2-[1-(4-trifluoromethyl benzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-3-[3-[2-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base hydrazono-] methyl]-1 h-indoles-1-ylmethyl cyanobenzene;
( e)-4-[2-[2-[1-(2-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(2,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-3-[3-[2-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl-4-morpholine thieno-[3,2- d] pyrimidine-2-base] methylene radical]-1 h-indoles-1-base] methyl benzonitrile;
( e)-4-[2-[2-(1-benzyl-1 h-indol-3-yl) methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(2,3-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(2,6-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(3,4-dichloro benzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(3,4-dichloro benzyl)-1 h-pyrroles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(3-luorobenzyl)-1 h-pyrroles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-chlorobenzyl)-1 h-pyrroles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(3-chlorobenzyl)-1 h-pyrroles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-3-[3-[2-[6-(4-Nmethanesulphonylpiperazine-1-ylmethyl)-4-morpholine thieno-[3,2- d] pyrimidine-2-base] diazanyl methyl]-1 h-indoles-1-base] methyl benzonitrile;
( e)-4-[2-[2-[1-(4-luorobenzyl)-1 h-pyrroles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-t-butylbenzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-methyl-benzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(2,3-dichloro benzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(2-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-(1-benzyl-1 h-benzo [ d] imidazoles-2-base) methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(3-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-2,4-di-t-butyl-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] methylphenol;
( e) the fluoro-3-of-5-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] indol-2-one;
( e)-4-[2-[2-(1 h-indazole-3-base) methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-3-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] indol-2-one;
( e)-4-[2-[2-(1 h-indazole-3-base) methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-2-allyl group-4-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] methylphenol;
( e) the bromo-3-of-5-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] indol-2-one
( e)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[2-(3,4,5-trimethoxy benzal base) diazanyl] thiophene [3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[2-(2,3,4-trimethoxy benzal base) diazanyl] thiophene [3,2- d] pyrimidine-4-yl morpholine;
( e)-2-allyl group-4-the tertiary butyl-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] methylphenol;
( e)-2-(2-methacrylic)-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] methylphenol;
( e) the chloro-2-of-5-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] methylphenol;
( e)-2-allyl group-4-methyl-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] methylphenol;
( e)-4-[2-(2-benzo [ d] [1,3] dioxol-5-base methene base) diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[2-[4-(trifluoromethoxy) benzal base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-2,6-bis-bromo-4-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] methylphenol;
( e)-4-[2-[2-(2-chloro-4-fluorine benzyl) pitches base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[6-(4-Nmethanesulphonylpiperazine-1-ylmethyl)-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] methyl benzonitrile;
( e)-1-[2-[6-(4-Nmethanesulphonylpiperazine-1-ylmethyl)-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-] methyl-beta naphthal.
Compound of Formula I of the present invention, its geometrical isomer and pharmacy acceptable salt, hydrate, solvate or prodrug be preferred following compound also, but these compounds do not mean that any limitation of the invention:
( e)-4-[2-[2-[1-(4-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(2-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(2,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(2-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-(1-benzyl-1 h-indol-3-yl) methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(3,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[3-[2-(4-morpholine thieno-[3,2- d] pyrimidine-2-base) hydrazonomethyl]-1 h-indoles-1-base] methyl benzonitrile;
( e)-4-[2-[2-[1-(3-trifluoromethyl) benzyl]-6,7-dihydros-1 h-indol-3-yl] methene base diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-methyl-benzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-3-[3-[2-(4-morpholine thieno-[3,2- d] pyrimidine-2-base) hydrazonomethyl]-1 h-indoles-1-base] methyl benzonitrile;
( e)-4-[2-[2-[1-(3-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(3-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-t-butylbenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(2,3-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2- d] pyrimidine-6-base-2-propyl alcohol;
( e)-4-[2-[2-[1-(3-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2- d] pyrimidine-6-base-2-propyl alcohol;
( e)-4-[2-[2-[1-(3-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2- d] pyrimidine-6-base-2-propyl alcohol;
( e)-4-[2-[2-[1-(2-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2- d] pyrimidine-6-base-2-propyl alcohol;
( e)-4-[3-[2-[6-(2-hydroxypropyl)-2-base-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-]-1 h-indoles-1-base] methyl benzonitrile;
( e)-3-[3-[2-[6-(2-hydroxypropyl)-2-base-4-morpholine thieno-[3,2- d] pyrimidine-2-base] hydrazono-]-1 h-indoles-1-base] methyl benzonitrile;
( e)-4-[2-[2-[1-(2,3-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholinyl thieno-[3,2- d] pyrimidine-6-base-2-propyl alcohol;
( e)-4-[2-[2-[1-(2,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholinyl thieno-[3,2- d] pyrimidine-6-base-2-propyl alcohol;
( e)-4-[2-[2-[1-(3,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholinyl thieno-[3,2- d] pyrimidine-6-base-2-propyl alcohol;
( e)-4-[2-[2-[1-(4-t-butylbenzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-(1-benzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[1-(2-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-t-butylbenzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-methyl-benzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(3-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(2,3-dichloro benzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine;
( e)-4-[2-[2-[1-(4-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2- d] pyrimidine-4-yl morpholine.
And, according to some usual methods in field belonging to the present invention, above formula in the present invention ithieno-[3,2 -d] pyridine derivatives can generate pharmacy acceptable salt with acid.Pharmaceutically acceptable additive salt comprises mineral acid and organic acid addition salt, is particularly preferred: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, toxilic acid, citric acid, fumaric acid, oxalic acid, tartrate, phenylformic acid etc. with the salt of following sour addition.
In addition, the present invention also comprises the prodrug of derivative of the present invention.The prodrug of derivative of the present invention is general formula iderivative, they self may have more weak activity and even not have activity, but upon administration, (such as by metabolism, solvolysis or other mode) is converted to corresponding biologically active form in physiological conditions.
In the present invention, " halogen " refers to fluorine, chlorine, bromine or iodine generation; " alkyl " refers to the alkyl of straight or branched; " alkylidene group " refers to the alkylidene group of straight or branched; " cycloalkyl " refers to substituted or unsubstituted cycloalkyl; " aryl " refers to unsubstituted or is connected with the cyclic aromatic system of substituent monocycle or many rings; " heteroaryl " refers to that ring-type system is aromaticity containing one or more ring-type system being selected from the heteroatomic monocycle of N, O, S or many rings, as imidazolyl, pyridyl, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, furyl, thienyl, pyrryl, thiazolyl, benzothiazolyl oxazolyl ， isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl-, benzoxazolyl etc.; The heterocyclic radical of fractional saturation " saturated or " refers to and is selected from the heteroatomic monocycle of N, O, S or the ring-type system of many rings, as pyrrolidyl, morpholinyl, piperazinyl, piperidyl, pyrazolidyl, imidazolidyl and thiazolinyl etc. containing one or more.
The present invention can contain the thieno-[3,2 of above formula I -d] pyridine derivatives, and pharmacy acceptable salt, hydrate or solvate are as active ingredient, composition is mixed with into pharmaceutically acceptable carrier or excipient, and being prepared into acceptable formulation clinically, above-mentioned pharmaceutically acceptable excipient refers to any thinner, auxiliary and/or the carrier that can be used for pharmaceutical field.Derivative of the present invention can combinationally use with other active ingredients, such as, as long as they do not produce other disadvantageous effect, anaphylaxis.
The thieno-[3,2 of above formula I of the present invention -d] pyridine derivatives is used for the clinical dosage of patient can basis: the age of activeconstituents therapeutic efficiency in vivo and bioavailability, their metabolism and discharge rate and patient, sex, disease phase suitably adjust, but every per daily dose of adult generally should be 10-500mg, is preferably 50-300mg.Therefore, when pharmaceutical composition of the present invention is made into unit dosage, consider above-mentioned effective dose, per unit preparation should contain the thieno-[3,2 of 10-500mg above formula I -d] pyridine derivatives, be preferably 50-300mg.According to the guidance of doctor or pharmacist, these preparations can divide several times administration (being preferably to six time) at certain intervals.
Medicinal compositions of the present invention can be mixed with several formulation, wherein containing some conventional vehicle in pharmaceutical field.Several formulation as above can adopt the drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Carrier for pharmaceutical composition of the present invention is available common type in pharmaceutical field, comprising: tackiness agent, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives, sanitas, solubilizing agent and matrix etc.Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable under stomach condition, can be mixed with enteric coated tablets.
Active compound of the present invention or its pharmacologically acceptable salt and solvate thereof can be used as unique anti-proliferate medicine and are used alone, or can with the anti-proliferate Drug combination now gone on the market, be used for the treatment of and/or prevent proliferative disease, as psoriasis, benign prostatauxe, atherosclerosis and restenosis.
We have found that the compounds of this invention is external and have had growth inhibitory activity to tumor cell, therefore, it can be used as the medicine that preparation treats and/or prevents cancer, as cancer and leukemia, the neuroblastoma etc. of mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate gland, bladder, uterus, pancreas, marrow, testis, ovary, lymph, soft tissue, neck, Tiroidina, esophagus.
By vitro inhibition lung carcinoma cell H460, colon cancer cell HT-29, human breast cancer cell MDA-MB-231, people's malignant glioblastoma cell U87MG, human lung carcinoma cell H1975 and Liver cancer cell SMMC-7721 activity test, the compounds of this invention has remarkable restraining effect to lung carcinoma cell, colon cancer cell and liver cancer cell, is used in particular for preparing the medicine treating and/or preventing lung cancer and liver cancer.
By finding the test of PI3K α enzymic activity, it is active that the compounds of this invention has the significant PI3K alpha kinase that suppresses, and has stronger restraining effect, be used in particular for preparing the medicine treating and/or preventing lung cancer to the lung carcinoma cell, glioblast etc. of PI3K high expression level.
Active compound of the present invention or its pharmacologically acceptable salt and solvate thereof can be used as unique antitumor drug and are used alone, or can with the antitumor drug now gone on the market (as platinum medicine cis-platinum, camptothecine irinotecan, vinca alkaloids medicine nvelbine, deoxidation born of the same parents former times class medicine gemcitabine, etoposide, taxol etc.) conbined usage.Combination therapy by by each treatment component simultaneously, order or separate administration to realize.
The embodiment hereinafter provided and preparation example are illustrated further and are illustrated the compounds of this invention and preparation method thereof.Should be appreciated that the scope of following example and preparation example and limit the scope of the invention never in any form.
Synthetic route below describes the preparation of formula I derivative of the present invention, and all raw materials are all modes by describing in these schematic diagram, prepared by the method known by organic chemistry filed those of ordinary skill or commercially available.All final derivatives of the present invention are all methods by describing in these schematic diagram or are prepared by similar method, and these methods are that organic chemistry filed those of ordinary skill is known.The whole variable factors applied in these schematic diagram are as definition hereafter or as the definition in claim.
According to formula I derivative of the present invention, can according to route 1 method by compound V, aldehyde A, B, C, D, E, F condensation of VII, XII and replacement prepares; Wherein A, B, C, D are obtained by reacting by corresponding aldehyde and the different benzyl chloride replaced, and formula 3-aminothiophene-2-ethyl formate and urea etc. obtain compound V through series reaction, VII, XII;
The substituting group of its Chinese style II ~ formula XII and the substituent R of formula A ~ formula B 1, R 2the same generalformulaⅰcompound of definition.Compound shown in formula E and formula F can be known by organic chemistry filed those of ordinary skill method preparation or commercially available.
embodiment:
Embodiment is intended to set forth instead of limit the scope of the invention.The proton nmr spectra of derivative measures with Bruker ARX-600, and mass spectrum Agilent 1100 LC/MSD measures; Agents useful for same is analytical pure or chemical pure.
Structural formula
Embodiment 1:( e) -4-[2-[2-[1-(4-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine;
steps A 1 h-thiophene [3,2 -d] synthesis of pyrimidine-2,4-diketone (II)
100g (0.64mol) 3-amino-2-thiophenecarboxylate and 191g (3.2mol) urea are placed in 1L three-necked bottle, 190 DEG C of reaction 5h.React complete, poured into by reactant in the sodium hydroxide solution of 20%, stir, suction filtration, the salt acid for adjusting pH 3 of filtrate 2N, separates out a large amount of white solid, suction filtration, filter cake 500mL water washing, and dry 24h at 45 DEG C, obtains white solid 103.4g, yield 96.1%; Purity 88%.
step B 2,4-dichloro-thiophen also [3,2 -d] synthesis of pyrimidine (III)
By 50g (0.30mol) intermediate iIbe placed in 87mL (0.60mol) triethylamine, ice bath borehole cooling to 0 DEG C, keep 0 DEG C and slowly drip 300mL (3.29mol) phosphorus oxychloride, 2h finishes, and is warming up to back flow reaction 6h.Reacted rear concentration of reaction solution to 150mL, by residue impouring 1000g frozen water under stirring, separate out a large amount of white solid, suction filtration, filter cake massive laundering is washed, dry 24h at 45 DEG C, obtains white flock crystallization 50.3g, yield 81.7%; Purity 99.7%; Fusing point 142-144 DEG C.
the chloro-4-of step C 2-(morpholine-4-base)-thieno-[3,2 -d] synthesis of pyrimidine (IV)
By 50g (0.24mol) intermediate iIIbe placed in 200mL methyl alcohol, (0.54mol morpholine, 15min adds, and at room temperature reacts 1h after dripping slowly to drip 47mL under room temperature.Reacted rear suction filtration, filter cake 200mL water washing, dry 24h at 45 DEG C, obtains crude white solid 60.3g.Total recovery 93.6%; Purity 99.9%; Fusing point 204-205 DEG C.MS(ESI), m/z(%): 255.9(M ++1), 277.6(M ++23)。
step D 4-(2-diazanyl thieno-[3,2 -d] pyrimidine-4-yl) synthesis of morpholine (V)
By 58.4g intermediate iVbe placed in 1000mL three-necked bottle, add the hydrazine hydrate that 584mL massfraction is 80%, at 90 DEG C, react 5h, be cooled to 0 DEG C, stir 1h, suction filtration, 100mL cold wash 2 times, dry white solid 39.0g.
the synthesis (B) of step e N-benzylindole-3-formaldehyde
Successively by indole-3-formaldehyde (14.5g, 0.1mol), benzyl chloride (15.1g, 0.12mol), salt of wormwood (16.6g, 0.12mol) is added in 200mLDMF solution the about 5h that refluxes.Reaction solution is cooled to room temperature, pours in 250mL frozen water and stirs 0.5h, and suction filtration is dry obtains white solid 20.3g.
According to method indazole-3-formaldehyde, the pyrrole-2-aldehyde replacement indole-3-formaldehyde of step e, obtained difference replaces respectively n-benzyl-indazole-3-formaldehyde and n-benzyl-pyrrole-2-aldehyde.
step F ( e)-4-[2-[2-[1-(4-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine (embodiment 1)
Successively by 0.1g (0.4mmol) intermediate v, 0.1g (0.44mmol) n-benzylindole-3-formaldehyde is added in 15mL ethanol, instills 1 Glacial acetic acid, back flow reaction 6h, and white solid is separated out, suction filtration, dry 0.152g target compound ( e) -4-[2-[2-[1-(4-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine.
ESI-MS [M+H] (m/z): 504.1; m.p.:221-223℃; 1H NMR (300 MHz, DMSO) δ 10.51 (s, 1H), 8.48 (d, J= 7.5 Hz, 1H), 8.27 (s, 1H), 8.06 (d, J= 5.5 Hz, 1H), 7.81 (s, 1H), 7.47 (d, J= 7.7 Hz, 1H), 7.38 (d, J= 8.2 Hz, 2H), 7.19 (m, 6H), 5.44 (s, 2H), 3.97 (s, 4H), 3.80 (s, 4H)。
According to the method for embodiment 1, the benzyl chloride first replaced with difference to obtain replacement respectively with indole-3-formaldehyde, pyrrole-2-aldehyde, indazole-3-formaldehyde reaction n-benzylindole-3-formaldehyde, n-benzyl-indazole-3-formaldehyde and n-benzyl-pyrrole-2-aldehyde derivative; Afterwards again with intermediate vcondensation reaction is carried out, respectively obtained embodiment 2-19 compound according to the method for step F.
Embodiment 2:( e) -4-[2-[2-[1-(2-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 504.1; m.p.:247-249℃； 1H NMR (300 MHz, DMSO) δ 10.58 (s, 1H), 8.53 (d, J= 7.1 Hz, 1H), 8.33 (s, 1H), 8.06 (d, J= 5.5 Hz, 1H), 7.74 (s, 1H), 7.52 (d, J= 7.8 Hz, 1H), 7.41 (d, J= 8.1 Hz, 1H), 7.38-7.12 (m, 5H), 6.78 (d, J= 7.5 Hz, 1H), 5.53 (s, 2H), 3.98 (s, 4H), 3.81 (d, J= 4.3 Hz, 4H)。
Embodiment 3:( e) -4-[2-[2-[1-(2,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 537.46; m.p.:138-140℃； 1H NMR (300 MHz, DMSO) δ 10.54 (s, 1H), 8.53 (d, J=7.1Hz, 1H), 8.27 (s, 1H), 8.06 (d, J= 5.5 Hz, 1H), 7.81-7.63 (m, 2H), 7.41 (d, J= 7.3 Hz, 1H), 7.34 (dd, J= 8.4, 2.1 Hz, 1H), 7.27-7.09 (m, 3H), 6.75 (d, J= 8.4 Hz, 1H), 5.55 (s, 2H), 3.97 (d, J= 4.4 Hz, 4H), 3.81 (d, J= 4.6 Hz, 4H)。
Embodiment 4:( e)-4-[2-[2-[1-(4-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 487.56; m.p.:134-136℃; 1H NMR (300 MHz, DMSO) δ 10.49 (s, 1H), 8.48 (d, J= 7.5 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J= 5.5 Hz, 1H), 7.81 (s, 1H), 7.49 (d, J= 7.9 Hz, 1H), 7.31 (dd, J= 8.5, 5.6 Hz, 2H), 7.17 (dt, J= 15.1, 7.1 Hz, 5H), 5.42 (s, 2H), 3.96 (d, J= 4.7 Hz, 4H), 3.80(d, J= 4.6 Hz,4H)。
Embodiment 5:( e)-4-[2-[2-[1-(2-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 487.56; m.p.:134-135℃; 1H NMR (300 MHz, DMSO) δ 10.51 (s, 1H), 8.49 (d, J= 7.4 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J= 5.5 Hz, 1H), 7.75 (s, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.41-7.27 (m, 1H), 7.32-6.87 (m, 6H), 5.50 (s, 2H), 3.94 (d , J= 4.5 Hz, 4H), 3.81 (d, J= 4.7 Hz, 4H)。
Embodiment 6:( e)-4-[2-[2-(1-benzyl-1 h-indol-3-yl) methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 469.57; m.p.:256-258℃; 1H NMR (300 MHz, DMSO) δ 10.51 (s, 1H), 8.49 (d, J= 7.6 Hz, 1H), 8.28 (s, 1H), 8.04 (t, J= 6.7 Hz, 1H), 7.81 (s, 1H), 7.48 (d, J= 7.8 Hz, 1H), 7.37-7.07 (m, 8H), 5.43 (s, 2H), 3.97 (d, J= 4.5 Hz, 4H), 3.80 (d , J=4.7Hz, 4H)。
Embodiment 7:( e)-4-[2-[2-[1-(3,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 538.46; m.p.:208-210℃; 1H NMR (300 MHz, DMSO) δ 10.54 (s, 1H), 8.49 (d, J= 7.4 Hz, 1H), 8.28 (s, 1H), 8.06 (d, J= 5.5 Hz, 1H), 7.85 (s, 1H), 7.66-7.54 (m, 2H), 7.50 (d, J= 7.9 Hz, 1H), 7.34-7.10 (m, 4H), 5.46 (s, 2H), 3.98 (s, 4H), 3.81 (s, 4H)。
Embodiment 8:( e)-4-[3-[2-(4-morpholine thieno-[3,2 -d] pyrimidine-2-base) hydrazono-] methyl isophthalic acid h-indoles-1-base] methyl benzonitrile
ESI-MS [M+H] (m/z): 494.58; m.p.:248-250℃; 1H NMR (300 MHz, DMSO) δ 10.54 (s, 1H), 8.53 (d, J= 7.1 Hz, 1H), 8.28 (s, 1H), 8.06 (d, J= 5.5 Hz, 1H), 7.91 (d, J= 7.3 Hz, 1H), 7.77 (s, 1H), 7.61 (t, J= 7.4 Hz, 1H), 7.47 (dd, J= 12.2, 7.5 Hz, 2H), 7.35-7.09 (m, 3H), 6.96 (d, J= 7.7 Hz, 1H), 5.72 (s, 2H), 3.98 (s, 4H), 3.81 (s, 4H)。
Embodiment 9:( e)-4-[2-[2-[1-(3-trifluoromethyl) benzyl]-6,7-dihydros-1 h-indol-3-yl] methene base] diazanyl thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 539.59; m.p.:136-137℃; 1H NMR (300 MHz, DMSO) δ 10.59 (s, 1H), 8.50 (d, J= 7.3 Hz, 1H), 8.29 (s, 1H), 8.07 (d, J= 5.4 Hz, 1H), 7.92 (s, 1H), 7.79-7.38 (m, 5H), 7.35-7.02 (m, 3H), 5.56 (s, 2H), 3.98 (s, 4H), 3.80 (s, 4H)。
Embodiment 10:( e)-4-[2-[2-[1-(4-methyl-benzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 483.60; m.p.:224-226℃; 1H NMR (300 MHz, DMSO) δ 10.50 (s, 1H), 8.47 (d, J= 7.5 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J= 5.5 Hz, 1H), 7.78 (s, 1H), 7.46 (d, J= 7.9 Hz, 1H), 7.22-6.97 (m, 7H), 5.76 (s, 1H), 5.37 (s, 2H), 3.96 (d, J= 4.4 Hz, 3H), 3.80 (d, J= 4.6 Hz, 4H), 2.24 (s, 3H)。
Embodiment 11:( e)-3-[3-[2-(4-morpholine thieno-[3,2 -d] pyrimidine-2-base) hydrazonomethyl]-1 h-indoles-1-ylmethyl] cyanobenzene
ESI-MS [M+H] (m/z): 494.58; m.p.:227-229℃; 1H NMR (300 MHz, DMSO) δ 10.53 (s, 1H), 8.50 (d, J= 7.5 Hz, 1H), 8.28 (s, 1H), 8.05 (d, J= 5.5 Hz, 1H), 7.86 (s, 1H), 7.82-7.65 (m, 2H), 7.62-7.42 (m, 3H), 7.31-7.01 (m, 3H), 5.50 (s, 2H), 3.98 (s, 4H), 3.81 (s, 4H)。
Embodiment 12:( e)-4-[2-[2-[1-(3-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 487.56; m.p.:248-250℃; 1H NMR (300 MHz, DMSO) δ 10.55 (s, 1H), 8.49 (d, J= 7.3 Hz, 1H), 8.28 (s, 1H), 8.06 (d, J= 5.4 Hz, 1H), 7.84 (s, 1H), 7.49 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 7.2 Hz, 1H), 7.30-6.91 (m, 6H), 5.45 (s, 2H), 3.97 (s, 4H), 3.80 (s, 4H)。
Embodiment 13:( e)-4-[2-[2-[1-(3-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 504.02; m.p.:238-240℃; 1H NMR (300 MHz, DMSO) δ 10.53 (s, 1H), 8.50 (d, J= 7.3 Hz, 1H), 8.28 (s, 1H), 8.05 (d, J= 5.5 Hz, 1H), 7.84 (s, 1H), 7.49 (d, J= 7.9 Hz, 1H), 7.34 (dd, J= 12.2, 6.1 Hz, 3H), 7.27-7.06 (m, 4H), 5.45 (s, 2H), 3.98 (s, 4H), 3.81 (d, J= 4.4 Hz, 4H)。
Embodiment 14:( e)-4-[2-[2-[1-(4-t-butylbenzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 525.68; m.p.:143-145℃; 1H NMR (300 MHz, DMSO) δ 10.50 (s, 1H), 8.48 (d, J= 7.8 Hz, 1H), 8.31 (s, 1H), 8.09 (d , J= 5.4 Hz, 1H), 7.80 (s, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.32 (d, J= 8.1 Hz, 2H), 7.28-7.03 (m, 5H), 5.41 (s, 2H), 4.00 (s, 4H), 3.81 (s, 4H), 1.22 (s, 9H)。
Embodiment 15:( e)-4-[2-[2-[1-(2,3-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 538.46; m.p.:266-269℃。
Embodiment 16:( e)-4-[2-[2-(1-benzyl-1 h-indazole-3-base) methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 468。
Embodiment 17:( e)-4-[2-[2-[1-(4-chlorobenzyl)-1 h-indazole-3-base] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 470。
Embodiment 18:( e)-4-[2-[2-[1-(3-methyl-benzyl)-1 h-indazole-3-base] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 476。
Embodiment 19:( e)-4-[2-[2-(1-benzyl-1 h-pyrroles-2-base) methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 470。
Embodiment 20:( e)-4-[2-[2-[1-(3-methyl-benzyl)-1 h-pyrroles-2-base] methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 470。
According to the method for embodiment 1, replace with different substituted benzaldehyde, dihydroindole ketone nthe indole-3-formaldehyde that-benzyl replaces and intermediate vcarry out condensation reaction, obtained embodiment 21-30 chemical combination.
Embodiment 21:( e)-4-[2-(2-benzene methylene fork base) diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z):340。
Embodiment 22:( e)-4-[2-[2-(benzo [ d] [1,3] dioxy-l, 5-yl) methene base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z):384。
Embodiment 23:( e)-4-[2-[2-(4-aminomethyl phenyl) methylene fork base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z):340。
Embodiment 24:( e)-4-[2-[2-(3,4-difluorophenyl) methylene fork base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z):376。
Embodiment 25:( e)-4-[2-[2-(2,4 difluorobenzene base) methylene fork base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z):376。
Embodiment 26:( e)-4-[2-[2-(2-trifluoromethyl) methylene fork base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z):408。
Embodiment 27:( e) the chloro-3-of-5-[2-(4-morpholine thieno-[3,2 -d] pyrimidine-2-base) diazanyl] indole-2-ketone ESI-MS [M+H] (m/z): 415.
Embodiment 28:( e)-5,6-bis-fluoro-3-[2-(4-morpholine thieno-[3,2 -d] pyrimidine-2-base) diazanyl] indole-2-ketone
ESI-MS [M+H] (m/z):417。
Embodiment 29:( e) the fluoro-3-of-5-[2-(4-morpholine thieno-[3,2 -d] pyrimidine-2-base) diazanyl] indole-2-ketone
ESI-MS [M+H] (m/z):399。
Embodiment 30:( e)-5-methoxyl group-3-[2-(4-morpholine thieno-[3,2 -d] pyrimidine-2-base) diazanyl] indole-2-ketone
ESI-MS [M+H] (m/z):340。
Embodiment 31:( e)-4-[2-[2-(1-benzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
the synthesis of step G:N-benzyl-(benzo) imidazoles
Add in the DMF of 50mL by Anhydrous potassium carbonate (0.11 mol), benzoglyoxaline (0.1 mol), stirring at room temperature 20 minutes, adds PhCH 2cl (0.11 mol), is warming up to 50 DEG C of reaction 2h.Be cooled to room temperature, poured into by reaction solution in 250mL water, stir 0.5h, suction filtration, repeatedly, dry 1-substituted benzyl benzoglyoxaline, can be directly used in next step reaction in washing.
Add in the DMF of 50mL by Anhydrous potassium carbonate (0.11 mol), imidazoles (0.1 mol), stirring at room temperature 20 minutes, adds ArCH 2cl (0.11 mol), is warming up to 50 DEG C of reaction 2h.Be cooled to room temperature, poured into by reaction solution in 250mL water, stir 0.5h, dichloromethane extraction, repeatedly, saturated common salt water washing, anhydrous sodium sulfate drying, removes the 1-substituted benzyl imidazoles that solvent obtains oily under reduced pressure, can be directly used in next step reaction in washing.
the synthesis of step H:N-benzyl-(benzo) imidazoles-2-formaldehyde
1-substituted benzyl benzoglyoxaline or 1-substituted benzyl imidazoles (0.03mol) are dissolved in the tetrahydrofuran (THF) that 60mL heavily steams; under nitrogen protection; be cooled to less than-78 DEG C; slow dropping n-Butyl Lithium (0.04 mol); keep temperature of reaction not higher than-78 DEG C; drip and finish, rise to-60 DEG C of reaction 1h.Again be cooled to less than-78 DEG C, drip dry DMF (0.1mol), keep temperature of reaction not higher than-78 DEG C, drip and finish, insulation reaction 10 minutes 1h, rise to room temperature reaction 2h.Saturated aqueous ammonium chloride 50mL is added in reaction solution, stir 1h, ether extraction, successively with water, saturated common salt washing, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent, crude product petrol ether/ethyl acetate column chromatography for separation, obtains 1-substituted benzyl-benzimidazolyl-2 radicals-formaldehyde or 1-substituted benzyl-imidazoles-2-formaldehyde.
step I:( e ) -4-[2-[2-(1-benzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical diazanyl] thieno-[3,2 -d] synthesis of pyrimidine-4-yl morpholine (embodiment 31)
With reference to the method for embodiment 1 step F, successively by 0.1g (0.4mmol) intermediate v, 0.1g (0.44mmol) N-benzyl benzimidazole-2-formaldehyde is added in 15mL ethanol, instills 1 Glacial acetic acid, back flow reaction 6h, and white solid is separated out, suction filtration, dry 0.102g target compound ( e)-4-[2-[2-(1-benzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine.
ESI-MS [M+H] (m/z): 470.50; m.p.:268-270℃。
According to the method for embodiment 31, the benzyl chloride first replaced with difference obtains n-benzyl-(benzo) imidazoles-2-formaldehyde; Condensation reaction is carried out according to the method for step F more afterwards, respectively obtained embodiment 32-37 chemical combination with intermediate V.
Embodiment 32:( e)-4-[2-[1-(2 chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 505.01; m.p.:280-283℃。
Embodiment 33:4-[2-[2-[1-(4-t-butylbenzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical]] diazanyl thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 526.91; m.p.:257-260℃。
Embodiment 34:4-[2-[1-(4-methyl-benzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 484.5.10; m.p.:268-270℃。
Embodiment 35:4-[2-[1-(3-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z):505.0; m.p.:266-268℃。
Embodiment 36:4-[2-[1-(2,3-dichloro benzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 539.40; m.p.:296-298℃。
Embodiment 37:4-[2-[1-(4-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methylene radical] diazanyl thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 505.50; m.p.:265-267℃。
Embodiment 38:( e)-4-[2-[2-[1-(4-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2 -d] pyrimidine-6-base-2-propyl alcohol
step J:2-(2-chloro-4-morpholine thieno-[3,2 -d] pyrimidine-6-base) synthesis of-2-propyl alcohol (VI)
20g (0.078mol) intermediate compound IV is added in 300mLTHF, is cooled to lower than-78 DEG C in cold hydrazine.The hexane solution 56mL (0.14mol) of slow instillation 2.5M n-Butyl Lithium, temperature controls lower than-70 DEG C.Be cooled to-78 DEG C after dropwising and stir 3h.Slow dropping absolute acetone 17mL, and control temperature is not higher than-70 DEG C.Drip off rear stirring reaction 1h, be placed to room temperature.Stir while in impouring 100mL1mol/l hydrochloric acid and 600mL ice.A large amount of white solid is had to separate out.Use 200mL water washing after suction filtration, at 45 DEG C, dry 24 h, obtain white solid 20g, yield 83%; Purity 96.03%; Fusing point 173-177 DEG C.MS(ESI), m/z(%): 313.9(M ++1), 335.6(M ++23).1H NMR (300 MHz, DMSO) δ 7.22 (s, 1H,), 5.93 (s, 1H),3.89 (m, 4H), 3.75 (m, 4H), 1.56 (s, 6H)。
With trifluoromethyl acetone for acetone obtained 2-(2-chloro-4-morpholine thieno-[3,2 according to the method described above replaced by raw material -d] pyrimidine-6-base)-1,1,1-trifluoro propyl-2-alcohol (VI ')
With reference to the step D of embodiment 1, the method for F, with 2-(2-chloro-4-morpholine thieno-[3,2 -d] pyrimidine-6-base)-2-propyl alcohol (VI) is raw material, through hydrazinolysis, obtains white solid, yield 80% with the condensation reaction of 4-chlorobenzyl indole-3-formaldehyde.
ESI-MS [M+H] (m/z): 562.10; m.p.:251-252℃; 1H NMR (300 MHz, DMSO) δ 10.45 (s, 1H), 8.49 (d, J= 7.5 Hz, 1H), 8.26 (s, 1H), 7.80 (s, 1H), 7.46 (d, J= 7.7 Hz, 1H), 7.38 (d, J= 8.3 Hz, 2H), 7.26 (d, J= 8.2 Hz, 2H), 7.22-7.07 (m, 2H), 7.00 (s, 1H), 5.75 (s, 1H), 5.43 (s, 2H), 3.95 (s, 4H), 3.79 (s, 4H), 1.56 (s, 6H)。
With reference to the method for embodiment 38, with 2-(2-chloro-4-morpholine thieno-[3,2 -d] pyrimidine-6-base)-2-propyl alcohol (VI) and 2-(2-chloro-4-morpholine thieno-[3,2 -d] pyrimidine-6-base)-1,1,1-trifluoro propyl-2-alcohol (VI ') be raw material, through hydrazinolysis, obtain embodiment 39-49 from the benzylindole-3-formaldehyde reaction of different replacement.
Embodiment 39:( e) -4-[2-[2-[1-(3-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2 -d] pyrimidine-6-base-2-propyl alcohol
ESI-MS [M+H] (m/z): 562.10; m.p.:233-234℃; 1H NMR (300 MHz, DMSO) δ 10.47 (s, 1H), 8.50 (d, J= 7.6 Hz, 1H), 8.26 (s, 1H), 7.82 (s, 1H), 7.49 (d, J= 8.0 Hz, 1H), 7.34 (dd, J= 13.2, 7.1 Hz, 3H), 7.27-7.09 (m, 3H), 7.00 (s, 1H), 5.75 (s, 1H), 5.45 (s, 2H), 3.96 (s, 4H), 3.80 (d, J= 4.3 Hz, 4H), 1.91 (s, 3H), 1.56 (s, 6H)。
Embodiment 40:( e)-4-[2-[2-[1-(3-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2 -d] pyrimidine-6-base-2-propyl alcohol
ESI-MS [M+H] (m/z): 545.64; m.p.:243-244℃; 1H NMR (300 MHz, DMSO) δ 10.46 (s, 1H), 8.50 (d, J= 7.4 Hz, 1H), 8.27 (s, 1H), 7.82 (s, 1H), 7.49 (d, J= 8.0 Hz, 1H), 7.36 (dd, J= 14.0, 8.1 Hz, 1H), 7.26-7.03 (m, 5H), 7.01 (s, 1H), 5.75 (s, 1H), 5.46 (s, 2H), 3.96 (s, 4H), 3.80 (s, 4H), 1.57 (s, 6H)。
Embodiment 41:( e)-4-[2-[2-[1-(2-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2 -d] pyrimidine-6-base-2-propyl alcohol
ESI-MS [M+H] (m/z): 545.64; m.p.:218-220℃; 1H NMR (300 MHz, DMSO) δ 10.51 (s, 1H), 8.51 (d, J= 7.4 Hz ,1H), 8.28 (s, 1H), 7.86 (s, 1H), 7.53 (d, J= 21.6 Hz, 3H), 7.20 (d, J= 8.4 Hz, 4H), 7.03 (s, 1H), 5.79 (s, 1H), 5.46 (s, 2H), 3.96 (s, 4H), 3.80 (s, 4H)。
Embodiment 42:( e)-4-[3-[2-[6-(2-hydroxypropyl)-2-base]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base hydrazono-]-1 h-indoles-1-base] methyl benzonitrile
ESI-MS [M+H] (m/z): 552.66; m.p.:156-158℃; 1H NMR (300 MHz, DMSO) δ 10.48 (s, 1H), 8.54 (d, J= 7.2 Hz, 1H), 8.27 (s, 1H), 7.91 (d, J= 7.5 Hz, 1H), 7.75 (s, 1H), 7.61 (t, J= 7.6 Hz, 1H), 7.47 (dd, J= 13.8, 7.3 Hz, 2H), 7.31-7.10 (m, 2H), 7.07-6.88 (m, 2H), 5.75 (s, 1H), 5.68 (s, 2H), 3.96 (s 4H), 3.81 (s, 4H), 1.57 (s, 6H)。
Embodiment 43:( e)-3-[3-[2-[6-(2-hydroxypropyl)-2-base]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazono-]-1 h-indoles-1-ylmethyl cyanobenzene
ESI-MS [M+H] (m/z): 552.66; m.p.:232-234℃; 1H NMR (300 MHz, DMSO) δ 10.47 (s, 1H), 8.51 (d, J= 7.5 Hz, 1H), 8.28 (s, 1H), 7.84 (s, 1H), 7.75 (d, J= 7.8 Hz, 2H), 7.63-7.40 (m, 3H), 7.28-7.08 (m, 2H), 7.01 (s, 1H), 5.75 (s, 1H), 5.50 (s, 2H), 3.96 (s, 4H), 3.80 (s, 4H), 1.57 (s, 6H)。
Embodiment 44:( e)-4-[2-[2-[1-(2,3-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholinyl thieno-[3,2 -d] pyrimidine-6-base-2-propyl alcohol
ESI-MS [M+H] (m/z): 596.54; m.p.:243-245℃; 1H NMR (300 MHz, DMSO) δ 10.48 (s, 1H), 8.54 (d, J= 7.0 Hz, 1H), 8.26 (s, 1H), 7.73 (s, 1H), 7.58 (d, J= 7.8 Hz, 1H), 7.41 (d, J= 7.4 Hz, 1H), 7.28-7.15 (m, 3H), 7.01 (s, 1H), 6.60 (d, J= 7.6 Hz, 1H), 5.75 (s, 1H), 5.58 (s, 2H), 3.96 (d, J= 4.2 Hz, 4H), 3.81 (d, J= 4.3 Hz, 4H), 1.57 (s, 6H)。
Embodiment 45:( e)-4-[2-[2-[1-(2,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholinyl thieno-[3,2 -d] pyrimidine-6-base-2-propyl alcohol
ESI-MS [M+H] (m/z): 596.54; m.p.:231-233℃; 1H NMR (300 MHz, DMSO) δ 10.47 (s, 1H), 8.53 (d, J= 6.7 Hz, 1H), 8.26 (s, 1H), 7.70 (d, J= 5.5 Hz, 2H), 7.41 (d, J= 7.6 Hz, 1H), 7.34 (d, J= 8.3 Hz, 1H), 7.27-7.11 (m, 2H), 7.01 (s, 1H), 6.75 (d, J= 8.4 Hz, 1H), 5.75 (s, 1H), 5.51 (s, 2H), 3.96 (s, 4H), 3.80 (s, 4H), 1.57 (s, 6H)。
Embodiment 46:( e)-4-[2-[2-[1-(3,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholinyl thieno-[3,2 -d] pyrimidine-6-base-2-propyl alcohol
ESI-MS [M+H] (m/z): 596.54; m.p.:225-227℃; 1H NMR (300 MHz, DMSO) δ 10.45 (s, 1H), 8.49 (d, J= 7.6 Hz, 1H), 8.25 (s, 1H), 7.73 (s, 1H), 7.50 (d, J= 8.1 Hz, 1H), 7.40-7.06 (m, 6H), 7.00 (s, 1H), 5.74 (s, 1H), 5.49 (s, 2H), 3.94 (s, 4H), 3.80 (s, 4H), 1.56 (s, 6H)。
The fluoro-2-of embodiment 47:1,1,1-tri-[2-[2-[1-(3-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-4-morpholinyl thieno-[3,2 -d] pyrimidine-6-base-2-propyl alcohol
ESI-MS [M+H] (m/z): 598.61;。
Embodiment 48:3-[3-[2-[4-morpholinyl-6-(1,1,1-tri-fluoro-2-hydroxypropyl-2 base) thieno-[3,2 -d] pyrimidine-2-base] hydrazono-] methyl]-1 h-indoles-1-base-methyl benzonitrile
ESI-MS [M+H] (m/z): 605.63。
Embodiment 49:2-[2-[2-[1-(3-chloro-phenyl-)-1 h-indol-3-yl] methylene radical] diazanyl]-4-morpholinyl thieno-[3,2 -d] pyrimidine-6-base-1,1,1-Trifluoro-2-propanol
ESI-MS [M+H] (m/z): 615.07。
Embodiment 50:( e)-2,4-di-t-butyl-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazono-] methylphenol
the chloro-4-of step K: 2-(morpholine-4-base)-thieno-[3,2 -d] synthesis of pyrimidine-6-formaldehyde (VIII)
By 50g (0.20mol) intermediate iVbe placed in 300mL tetrahydrofuran (THF), N 2protection borehole cooling is to-78 DEG C, and maintain the temperature at the hexane solution that less than-60 DEG C slowly drip 94mL (0.23mol) n-Butyl Lithium, 1.5h adds.After dripping, be cooled to-78 DEG C, slowly drip 22.7mL (0.29mol) DMF after stirring 0.5h, 0.5h adds.Continue stirring reaction 1h at-78 DEG C after dripping, be then slowly warming up to 0 DEG C and continue stirring reaction 1h, then be warming up to 25 DEG C of continuation reaction 2h.After having reacted, under vigorous stirring, be poured into by reaction solution in 1000mL 0.25mol/L aqueous hydrochloric acid and 400g ice, separate out a large amount of yellow solid, suction filtration, filter cake massive laundering is washed, and dry 24h at 45 DEG C, obtains buff powder 49.1g, yield 88.5%; Purity 97.5%; Fusing point 235-243 DEG C. 1H NMR (300 MHz, DMSO) δ 10.21(s, 1H), 8.29(s, 1H), 3.95(t, 4H), 3.77(t, 4H,)。
step L:2-chlorine -6-methylol -4-(morpholine -4-base )-thieno- [3,2 -d] pyrimidine (IX)synthesis
By 25g (0.09mol) intermediate vIIIjoin in 200mL anhydrous methanol, be placed in cryosel bath and be cooled to-10 DEG C, keep temperature to divide 10 batches to add 4g (0.1mol) sodium borohydride, after adding, at-10 DEG C, continue reaction 1h.After having reacted, concentration response, to 50mL, is poured under stirring in 500mL water, separates out a large amount of white solid, suction filtration, filter cake 100mL water washing twice, and dry 24h at 45 DEG C, obtains white powder 23.2g, yield 92.1%; Purity 95.7%; Fusing point 184-186 DEG C.MS(ESI), m/z(%): 285.8(M ++1), 307.9(M ++23), 324.0(M ++39)。
step M:2-chlorine -6-chloromethyl -4-(morpholine -4-base )-thieno- [3,2 -d] pyrimidine (X)synthesis
By 33.2g (0.12mol) intermediate under room temperature iXbe added in the mixed solution of 232mL sulfur oxychloride and 1.66mLDMF, be warming up to back flow reaction 1h.After having reacted, reaction solution is concentrated into 60mL, by residue impouring 500mL frozen water under stirring, separates out a large amount of yellow solid, suction filtration, obtain pale yellow powder 34.4g, yield 97.3%; Purity 97.4%. 1H NMR (300 MHz, DMSO) δ 7.48(s, 1H), 5.17(s, 2H,), 3.89(t, J=4.2Hz, J=5.4, 4H), 3.75(t, J=5.4Hz, J=4.2, 4H)。
step N:2-chlorine -6-[(4-methylsulfonyl -piperazine -1-base) methyl ]-4-(morpholine -4-base )-thieno- [3,2 -d] pyrimidine (XI)synthesis
By 29.1g (0.096mol) intermediate x, 38.4g (0.19mol) 4-methylsulfonyl piperazine and 37.1g (0.29mol) DIPEA join in 200mL Virahol, is warming up to back flow reaction 11h.After having reacted, let cool by reaction solution, suction filtration, filter cake 300mL washes, and then wash with 100mL ethanol, at 45 DEG C, dry 24h, obtains off-white powder 39.5g, yield 95.6%; Purity 92.1%. 1H NMR (300 MHz, DMSO) δ 7.31(s, 1H), 3.91-3.84(q, 6H), 3.75(t, J=4.5, J=3.9, 4H), 3.14(s, 4H,), 2.90(s, 3H,), 2.57(s, 4H)。
step O:4-[2-diazanyl-6-[(4-methylsulfonyl piperazine-1-base) methyl] thieno-[3,2 -d] pyrimidine-4-yl] morpholine (XII) synthesis
It is faint yellow solid that method with reference to embodiment 1 step D obtains intermediate X II.
step P:4-[2-diazanyl-6-[(4-methylsulfonyl piperazine-1-base) methyl] thieno-[3,2 -d] pyrimidine-4-yl] morpholine (embodiment 50) synthesis
With reference to the method for embodiment 1 step F, with intermediate xIIreplace vfaint yellow solid (embodiment 50) is obtained with phenyl aldehyde back flow reaction in ethanolic soln
ESI-MS [M+H] (m/z): 644.8 ; m.p.: 248-250℃。
First the benzyl chloride replaced with difference according to the method for embodiment 1, embodiment 50 obtains the N-benzylindole-3-formaldehyde of replacement, N-benzyl-indazole-3-formaldehyde and N-benzyl-pyrrole-2-aldehyde derivative, N-benzyl-(benzo) imidazoles-2-formaldehyde respectively with indole-3-formaldehyde, pyrrole-2-aldehyde, indazole-3-formaldehyde reaction; Afterwards again with intermediate vcondensation reaction is carried out, respectively obtained embodiment 51-84 compound according to the method for step F.
Embodiment 51:( e)-4-[2-[2-(1 h-indazole-3-base) methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 556.2 ; m.p.:249-251℃。
Embodiment 52:( e)-4-[2-[2-(1 h-indol-3-yl) methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 555.0 ; m.p.: 256-257℃。
Embodiment 53:( e)-2-allyl group-4-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazono-] methylphenol
ESI-MS [M+H] (m/z): 572.54 ; m.p.:185-187℃。
Embodiment 54:( e)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[2-(3,4,5-trimethoxy benzal base) diazanyl] thiophene [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z]: 606.1 ; m.p.:265-266℃。
Embodiment 55:( e]-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[2-(2,3,4-trimethoxy benzal base) diazanyl] thiophene [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 606.2 ; m.p.:184-185℃。
Embodiment 56:( e)-2-allyl group-4-the tertiary butyl-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazono-] methylphenol
ESI-MS [M+H] (m/z): 628.3 ; m.p.:273-273℃。
Embodiment 57:( e)-2-(2-methacrylic)-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazono-] methylphenol
ESI-MS [M+H] (m/z): 586.54 ; m.p.:265-265℃。
Embodiment 58:( e) the chloro-2-of-5-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazono-] methylphenol
ESI-MS [M+H] (m/z): 567.1 ; m.p.:251-251℃。
Embodiment 59:( e)-2-allyl group-4-methyl-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazono-] methylphenol
ESI-MS [M+H] (m/z): 586.5; m.p.:195-196℃。
Embodiment 60:( e)-4-[2-[2-(benzo [ d] [1,3] dioxol-5-base) methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 560.2 ; m.p.:200-202℃。
Embodiment 61:( e)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[2-[4-(trifluoromethoxy) benzal base] diazanyl] thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 601 ; m.p.:240-241℃。
Embodiment 62:( e)-2,6-bis-bromo-4-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazono-] methylphenol
ESI-MS [M+H] (m/z): 690.0 ; m.p.:210-211℃。
Embodiment 63:( e)-4-[2-[2-(2-chloro-4-fluorine benzal base)] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 569.2 ; m.p.:237-238℃。
Embodiment 64:( e)-4-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazono-] methyl benzonitrile
ESI-MS [M+H] (m/z): 541.1 ; m.p.:266-267℃。
Embodiment 65:( e)-1-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazono-] methyl-beta naphthal
ESI-MS [M+H] (m/z): 582.7; m.p.:>300℃。
Embodiment 66:( e)-4-[2-[2-[1-(3-luorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 663.8; m.p.: 199-201℃。
Embodiment 67:( e)-4-[2-[2-[1-(4-t-butylbenzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 702; m.p.: 253-255℃。
Embodiment 68:( e)-4-[2-[2-[1-(3,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 715; m.p.: 272-273℃。
Embodiment 69:( e)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[2-[1-(4-trifluoromethyl benzyl)-1 h-indol-3-yl] methene base] diazanyl thieno-[3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 714.8; m.p.:283-284℃。
Embodiment 70:( e)-3-[3-[2-[6-(4-Nmethanesulphonylpiperazine-1-ylmethyl)-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazonomethyl]-1 h-indoles-1-base] methyl benzonitrile
ESI-MS [M+H] (m/z): 671; m.p.: 266-268℃。
Embodiment 71:( e)-4-[2-[2-[1-(2-chlorobenzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 680.8; m.p.:279-281℃。
Embodiment 72:( e)-4-[2-[2-[1-(2,4-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 715.8; m.p.:245-246℃。
Embodiment 73:( e)-3-[3-[2-[6-(4-Nmethanesulphonylpiperazine-1-ylmethyl)-4-morpholine thieno-[3,2 -d] pyrimidine-2-base] hydrazonomethyl]-1 h-indoles-1-base] methyl benzonitrile
ESI-MS [M+H] (m/z): 671.8; m.p.: 264-265℃。
Embodiment 74:( e)-4-[2-[2-(1-benzyl-1 h-indol-3-yl) methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 645.6; m.p.:267-268℃。
Embodiment 75:( e)-4-[2-[2-[1-(2,3-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 715.8; m.p.:287-288℃。
Embodiment 76:( e)-4-[2-[2-[1-(2,6-dichloro benzyl)-1 h-indol-3-yl] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 715.2; m.p.:275-276℃。
Embodiment 77:( e)-4-[2-[2-[1-(3,4-dichloro benzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 715.8。
Embodiment 78:( e)-4-[2-[2-[1-(4-t-butylbenzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 703.0; m.p.:252-254℃。
Embodiment 79:( e)-4-[2-[2-[1-(4-methyl-benzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 661.8; m.p.: 281-282℃。
Embodiment 80:( e)-4-[2-[2-[1-(2,3-dichloro benzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 715.4; m.p.:279-281℃。
Embodiment 81:( e)-4-[2-[2-[1-(2-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 682.3; m.p.:255-257℃。
Embodiment 82:( e)-4-[2-[2-(1-benzyl-1 h-benzo [ d] imidazoles-2-base) methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 646.6; m.p.:254-256℃。
Embodiment 83 ( e)-4-[2-[2-[1-(4-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 681.9; m.p.:253-255℃。
Embodiment 84:( e)-4-[2-[2-[1-(3-chlorobenzyl)-1 h-benzo [ d] imidazoles-2-base] methene base] diazanyl]-6-(4-Nmethanesulphonylpiperazine-1-base) thiotolene also [3,2 -d] pyrimidine-4-yl morpholine
ESI-MS [M+H] (m/z): 681.7; m.p.:253-255℃。
The pharmacological research of product of the present invention
in vitro cytotoxic effect
To the thieno-[3,2 according to above formula I of the present invention -d] pyridine derivatives carried out vitro inhibition lung carcinoma cell H460, colon cancer cell HT-29, human breast cancer cell MDA-MB-231, people's malignant glioblastoma cell U87MG, human lung carcinoma cell H1975 and Liver cancer cell SMMC-7721 screening active ingredients, reference substance GDC-0941 is according to document (J. Med. Chem., 2008,51 (18), pp 5522 – 5532) described method prepares.
1) cell recovery and go down to posterity 2-3 time stable after, make it digest bottom culturing bottle with trypsin solution (0.25%).Cell dissociation buffer is poured into after in centrifuge tube, add nutrient solution afterwards to stop digestion.By centrifuge tube centrifugal 10min under 800r/min, add 5 mL nutrient solutions after abandoning supernatant, piping and druming mixing cell, draws 10 μ L cell suspensions and adds in cell counting count board and count, and adjustment cell concn is 10 4individual/hole.Except A1 hole is that blank well does not add extracellular in 96 orifice plates, all the other all add 100 μ L cell suspensions.96 orifice plates are put into incubator and cultivates 24 h.
2) with 50 μ L dmso solution given the test agent, then add appropriate nutrient solution, make sample dissolution become 2 mg/mL liquids, be then 20,4 by diluted sample in 24 orifice plates, 0.8,0.16,0.032 μ g/mL.
Each concentration adds 3 holes, and wherein around two row two row cell growing ways are affected by environment comparatively large, only and be the use of blanc cell hole.96 orifice plates are put into incubator and cultivates 72 h.
3) will medicine nutrient solution in 96 orifice plates, be with to discard, with phosphate buffer solution (PBS), cell is rinsed twice, add after MTT (tetrazole) (0.5 mg/mL) 100 μ L puts into incubator 4 h in every hole, discard MTT solution, add dimethyl sulfoxide (DMSO) 100 μ L.On magnetic force vibrator, vibration makes survivaling cell and MTT reaction product first abundant dissolving, puts into microplate reader measurement result.Medicine IC can be obtained by Bliss method 50value.
Suppression lung carcinoma cell H460, the colon cancer cell HT-29 of compound, human breast cancer cell MDA-MB-231, people's malignant glioblastoma cell U87MG, human lung carcinoma cell H1975 and Liver cancer cell SMMC-7721 Activity Results are in table 1.
α enzymic activity is tested
1, solution preparation
1) testing compound adds 1mL DMSO, is made into 10mM storage solutions.Positive compound GDC-0941 storage liquid concentration is that 10mM(is dissolved in DMSO), the storage liquid concentration of positive compound cis-platinum is that 2mM(is dissolved in DMSO).
2) by DMSO diluted compounds storage liquid, 2mM solution (100X) is made into.
3) get 2 μ L 2mM solution, add 18 μ L reaction solution diluted compounds to 200 μM (10X) solution.
4) in working plate, add the above-mentioned solution of 2 μ L and 18 μ L reaction solutions, be made into 10X solution.
5) get with solution in upper plate 1 μ L to check-out console.
6) the full suppression of check-out console contrasts and adds 1 μ L kinase reaction liquid in null suppression control wells, makes the concentration of DMSO be 10%.
2, experimental procedure
1) layout of orifice plate
384 orifice plates are experimentally needed to arrange, wherein:
A) HPE(suppresses contrast entirely): do not add kinases and compound, add ATP, substrate and 1%DMSO.
B) ZPE(null suppression contrast): do not add compound, add kinases, ATP, substrate and 1%DMSO.
C) positive reference compound hole: add kinases, ATP, substrate and different concns positive compound.
D) testing compound hole: add kinases, ATP, substrate and testing compound.
2) agents useful for same preparation
4XATP: ATP is diluted to 4X with reaction solution.
4X substrate solution: substrate is diluted to 4X with reaction solution.
2.5X kinase solution: with reaction solution by kinase dilution to 2.5X.
3) kinase reaction
A) add 1 μ L10X compound (testing compound or various kinase whose positive control) solution according to the every hole of layout, full contrast and the null suppression control wells of suppressing adds 1 μ L reaction solution.
B) 4 μ L2.5X kinase solution are added according to the every hole of layout.Full suppression control wells adds 4 μ L reaction solutions.
C) by centrifugal for check-out console 1000rpm with mixing.
D) 4XATP solution is mixed with 4X substrate solution equal-volume, obtain 2XATP-substrate solution.
E) 5 μ L above-mentioned 2X ATP-substrate solution is added according to the every hole of layout.
F) by centrifugal for check-out console 1000rpm with mixing.
G) check-out console is placed in 30 DEG C of reactions 1 hour.
H) every hole adds 10 μ L Kinase glo plus or ADP-Glo reaction reagents, places 20 minutes for 27 DEG C.
I) every hole adds 20 μ L Kinase Detection reagent, places 30 minutes for 27 DEG C.
J) Envision reads fluorescence values.
Attention: Kinase glo plus, ADP-Glo and Kinase Detection reagent needs preset room temperature half an hour before using.
4) primary data analysis
Prism5.0 analyzes raw data.
According to the IC of Bliss method computerized compound 50
Table 1 target compound anti tumor activity in vitro and enzymic activity
Can clearly be seen that from above-mentioned test-results, the compound of the claimed formula I of the present invention, has good anti tumor activity in vitro, quite or be better than the antitumor drug cis-platinum that gone on the market.
The compound of formula of I of the present invention can be used separately, but normally give with pharmaceutical carrier mixture, the selection of described pharmaceutical carrier will according to required route of administration and standard pharmaceutical practice, below respectively with the various pharmaceutical dosage forms of this compounds, the such as preparation method of tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment, illustrates its new opplication in pharmacy field.
Embodiment 85: tablet
With compound (for embodiment 12 compound) 10 g containing compound in claim 1, after adding auxiliary material 20 g mixing according to the general pressed disc method of pharmaceutics, be pressed into 100, every sheet weighs 300 mg.
Embodiment 86: capsule
With compound (for embodiment 76 compound) 10 g containing compound in claim 1, after being mixed by auxiliary material 20 g according to the requirement of pharmaceutics capsule, load Capsules, each capsule weighs 300 mg.
Embodiment 87: injection
With compound (for embodiment 1 compound) 10 g containing compound in claim 1, according to pharmaceutics ordinary method, carry out charcoal absorption, after 0.65 μm of filtering with microporous membrane, insert nitrogen pot and make hydro-acupuncture preparation, often only fill 2 mL, filling 100 bottles altogether.
Embodiment 88: aerosol
With compound (for embodiment 22 compound) 10 g containing compound in claim 1, after dissolving with appropriate propylene glycol, after adding distilled water and other spoke material, make the settled solution of 500 mL and get final product.
Embodiment 89: suppository
With compound (for embodiment 19 compound) 10 g containing compound in claim 1, it porphyrize is added glycerine in right amount, add the glycogelatin melted after grinding well, evenly, impouring has been coated with in the model of lubricant in grinding, obtained suppository 50
Embodiment 90: film
With compound (for embodiment 58 compound) 10 g containing compound in claim 1, polyvinyl alcohol, medicinal glycerin, water etc. are stirred expansion post-heating dissolve, 80 eye mesh screens filter, again embodiment 18 compound is joined stirring and dissolving in filtrate, film applicator masking 100.
Embodiment 91: pill
With compound (for embodiment 17 compound) 10 g containing compound in claim 1, after mixing with the matrix 50 g heat fused such as gelatin, in instillation cryogenic liquid paraffin, obtained dripping pill 1000 ball altogether.
Embodiment 92: externally-applied liniment
With compound (for embodiment 31 compound) 10 g containing compound in claim 1, the conveniently auxiliary material such as practice of pharmacy and emulsifying agent 2.5 g mixed grinding, then adding distil water to 200 mL obtains.
Embodiment 93: ointment
With compound (for embodiment 47 compound) 10 g containing compound in claim 1, grind well obtained with oleaginous base 500 g such as Vaseline after porphyrize.
Although describe the present invention by particular, amendment and equivalent variations are obvious for the technician being proficient in this field, and they are included within the scope of the invention.

Claims (8)

1. the compound of formula I and pharmacy acceptable salt thereof,
Wherein:
R 1be selected from H,
R 2structural formula be selected from:
R 6, R 9be 1 ~ 3 independently and identical or different be selected from hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano group, (C 1-C 4) alkyl, (C 3-C 6) cycloalkyl, (C 1-C 4) thiazolinyl, (C 1-C 4) alkoxyl group, allyl group, (2-methyl) allyl group, (C 1-C 4) alkoxy methyl, (C 1-C 3) substituting group of alkylenedioxy group.
2. the compound of the formula I of claim 1 and pharmacy acceptable salt thereof,
Wherein
R 1be selected from H, .
3. the compound of the formula I of claim 2 and pharmacy acceptable salt thereof,
R 6, R 9be 1 ~ 3 independently and identical or different be selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano group, methyl, ethyl, n-propyl, cyclopropyl, the tertiary butyl, vinyl, propenyl, 2-methylpropenyl, methoxyl group, oxyethyl group, ring propoxy-, tert.-butoxy, allyl group, (2-methyl) allyl group, methoxymethyl, ethoxyl methyl, i-propoxymethyl, 2, the substituting group of 3-methylenedioxy, 2,3-ethylidene dioxy bases.
4. the compound of following formula I and pharmacy acceptable salt thereof,
(E)-4-[2-[2-[1-(3-luorobenzyl)-1H-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-t-butylbenzyl)-1H-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(3,4-dichloro benzyl)-1H-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[[2-[1-(4-trifluoromethyl benzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-3-[3-[2-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base hydrazono-] methyl]-1H-indoles-1-ylmethyl cyanobenzene;
(E)-4-[2-[2-[1-(2-chlorobenzyl)-1H-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(2,4-dichloro benzyl)-1H-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-3-[3-[2-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl-4-morpholine thieno-[3,2-d] pyrimidine-2-base] methylene radical]-1H-indoles-1-base] methyl benzonitrile;
(E)-4-[2-[2-(1-benzyl-1H-indol-3-yl) methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(2,3-dichloro benzyl)-1H-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(2,6-dichloro benzyl)-1H-indol-3-yl] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(3,4-dichloro benzyl)-1H-benzo [d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(3,4-dichloro benzyl)-1H-pyrroles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(3-luorobenzyl)-1H-pyrroles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-chlorobenzyl)-1H-pyrroles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(3-chlorobenzyl)-1H-pyrroles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-3-[3-[2-[6-(4-Nmethanesulphonylpiperazine-1-ylmethyl)-4-morpholine thieno-[3,2-d] pyrimidine-2-base] diazanyl methyl]-1H-indoles-1-base] methyl benzonitrile;
(E)-4-[2-[2-[1-(4-luorobenzyl)-1H-pyrroles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-t-butylbenzyl)-1H-benzo [d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-methyl-benzyl)-1H-benzo [d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(2,3-dichloro benzyl)-1H-benzo [d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(2-chlorobenzyl)-1H-benzo [d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-(1-benzyl-1H-benzo [d] imidazoles-2-base) methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-chlorobenzyl)-1H-benzo [d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(3-chlorobenzyl)-1H-benzo [d] imidazoles-2-base] methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-2,4-di-t-butyl-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] methylphenol;
(E) the fluoro-3-of-5-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] indol-2-one;
(E)-4-[2-[2-(1H-indazole-3-base) methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-3-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] indol-2-one;
(E)-4-[2-[2-(1H-indazole-3-base) methene base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-2-allyl group-4-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] methylphenol;
(E) the bromo-3-of-5-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] indol-2-one
(E)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[2-(3,4,5-trimethoxy benzal base) diazanyl] thiophene [3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[2-(2,3,4-trimethoxy benzal base) diazanyl] thiophene [3,2-d] pyrimidine-4-yl morpholine;
(E)-2-allyl group-4-the tertiary butyl-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] methylphenol;
(E)-2-(2-methacrylic)-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] methylphenol;
(E) the chloro-2-of-5-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] methylphenol;
(E)-2-allyl group-4-methyl-6-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] methylphenol;
(E)-4-[2-(2-benzo [d] [1,3] dioxol-5-base methene base) diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[6-(4-Nmethanesulphonylpiperazine-1-base) methyl]-2-[2-[4-(trifluoromethoxy) benzal base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-2,6-bis-bromo-4-[2-[6-[(4-Nmethanesulphonylpiperazine-1-base) methyl]-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] methylphenol;
(E)-4-[2-[2-(2-chloro-4-fluorine benzyl) pitches base] diazanyl]-6-[(4-Nmethanesulphonylpiperazine-1-base) methyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[6-(4-Nmethanesulphonylpiperazine-1-ylmethyl)-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] methyl benzonitrile;
(E)-1-[2-[6-(4-Nmethanesulphonylpiperazine-1-ylmethyl)-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-] methyl-beta naphthal.
5. the compound of following formula I and pharmacy acceptable salt thereof,
(E)-4-[2-[2-[1-(4-chlorobenzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(2-chlorobenzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(2,4-dichloro benzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-luorobenzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(2-luorobenzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-(1-benzyl-1H-indol-3-yl) methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(3,4-dichloro benzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[3-[2-(4-morpholine thieno-[3,2-d] pyrimidine-2-base) hydrazonomethyl]-1H-indoles-1-base] methyl benzonitrile;
(E)-4-[2-[2-[1-(3-trifluoromethyl) benzyl]-6,7-dihydro-1H-indol-3-yls] methene base diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-methyl-benzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-3-[3-[2-(4-morpholine thieno-[3,2-d] pyrimidine-2-base) hydrazonomethyl]-1H-indoles-1-base] methyl benzonitrile;
(E)-4-[2-[2-[1-(3-luorobenzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(3-chlorobenzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-t-butylbenzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(2,3-dichloro benzyl)-1H-indol-3-yl] methene base] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-chlorobenzyl)-1H-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2-d] pyrimidine-6-base-2-propyl alcohol;
(E)-4-[2-[2-[1-(3-chlorobenzyl)-1H-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2-d] pyrimidine-6-base-2-propyl alcohol;
(E)-4-[2-[2-[1-(3-luorobenzyl)-1H-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2-d] pyrimidine-6-base-2-propyl alcohol;
(E)-4-[2-[2-[1-(2-luorobenzyl)-1H-indol-3-yl] methene base] diazanyl]-4-morpholine thieno-[3,2-d] pyrimidine-6-base-2-propyl alcohol;
(E)-4-[3-[2-[6-(2-hydroxypropyl)-2-base-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-]-1H-indoles-1-base] methyl benzonitrile;
(E)-3-[3-[2-[6-(2-hydroxypropyl)-2-base-4-morpholine thieno-[3,2-d] pyrimidine-2-base] hydrazono-]-1H-indoles-1-base] methyl benzonitrile;
(E)-4-[2-[2-[1-(2,3-dichloro benzyl)-1H-indol-3-yl] methene base] diazanyl]-4-morpholinyl thieno-[3,2-d] pyrimidine-6-base-2-propyl alcohol;
(E)-4-[2-[2-[1-(2,4-dichloro benzyl)-1H-indol-3-yl] methene base] diazanyl]-4-morpholinyl thieno-[3,2-d] pyrimidine-6-base-2-propyl alcohol;
(E)-4-[2-[2-[1-(3,4-dichloro benzyl)-1H-indol-3-yl] methene base] diazanyl]-4-morpholinyl thieno-[3,2-d] pyrimidine-6-base-2-propyl alcohol;
(E)-4-[2-[2-[1-(4-t-butylbenzyl)-1H-benzo [d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-(1-benzyl)-1H-benzo [d] imidazoles-2-base] methylene radical diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[1-(2-chlorobenzyl)-1H-benzo [d] imidazoles-2-base] methylene radical diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-t-butylbenzyl)-1H-benzo [d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-methyl-benzyl)-1H-benzo [d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(3-chlorobenzyl)-1H-benzo [d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(2,3-dichloro benzyl)-1H-benzo [d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine;
(E)-4-[2-[2-[1-(4-chlorobenzyl)-1H-benzo [d] imidazoles-2-base] methylene radical] diazanyl] thieno-[3,2-d] pyrimidine-4-yl morpholine.
6. a medicinal compositions, to comprise in claim 1-5 any one compound and pharmacy acceptable salt thereof as activeconstituents and pharmaceutically acceptable vehicle.
7. in claim 1-5, any one compound and pharmacy acceptable salt thereof are preparing the application treated and/or prevented in the medicine of cancer.
8. in claim 1-5, any one compound and pharmacy acceptable salt thereof are preparing the application treated and/or prevented in the medicine of lung cancer, liver cancer, cancer of the stomach, colorectal carcinoma, mammary cancer.
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