CN100354278C - Quinazoline derivatives as SRC tyrosine kinase inhibitors - Google Patents
Quinazoline derivatives as SRC tyrosine kinase inhibitors Download PDFInfo
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- CN100354278C CN100354278C CNB2003801081947A CN200380108194A CN100354278C CN 100354278 C CN100354278 C CN 100354278C CN B2003801081947 A CNB2003801081947 A CN B2003801081947A CN 200380108194 A CN200380108194 A CN 200380108194A CN 100354278 C CN100354278 C CN 100354278C
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Abstract
The invention concerns quinazoline derivatives of Formula (I): (A chemical formula should be inserted here - please see paper copy enclosed herewith) wherein Z is an O, S, SO, SO2, N(R<2>) or C(R<2>)2 group wherein each R<2 >group is hydrogen or (1-8C) alkyl, m is 0, 1, 2 or 3, each R<1> group is selected from halogeno, (1-8C) alkyl, (1-6C) alkoxy and any of the other meanings defined in the description, n is 0, 1, 2 or 3, and each R<3> group is selected from halogeno, (1-8C) alkyl, (1-6C) alkoxy and any of the other meanings defined in the description, or pharmaceutically-acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
Description
The present invention relates to some new quinazoline derivant or its pharmacy acceptable salt, these compounds have anti-tumor activity, therefore can be used for the treatment of in the method for human or animal body.The invention still further relates to method, the pharmaceutical composition that contains these derivatives and their purposes in methods of treatment of the described quinazoline derivant of preparation, as the purposes of medicine of the noumenal tumour disease that is used for prevention or treatment warm-blooded animal (as the people) in preparation.
The scheme of present multiple treatment cell hyperplastic disease such as psoriasis and cancer has all adopted inhibition DNA synthetic compound.These compounds are all toxic to various cells, but they may be useful for the toxic action of quick noble cells such as tumour cell.Developmental function mechanism is not to suppress the selectivity that DNA synthetic antitumor drug can the raising effect.
In recent years, it is found that, after the part in the cell DNA is converted into oncogene, can make cell produce carinogenicity, the formation (Bradshaw, Mutagenesis, 1986,1,91) of inducing malignant tumor cell after described oncogene is activated.Several these type of oncogene are produced as the polypeptide of growth factor receptors.The growth factor receptors complex body activates the increase that causes cell proliferation subsequently.People are known, as, several oncogene coding Tyrosylprotein kinases, and some growth factor receptors also is Tyrosylprotein kinase (Yarden etc., Ann.Rev.Biochem., 1988,57,443; Larsen etc., Ann.Reports in Med.Chem., 1989, Chpt.13).Have the 1st group of Tyrosylprotein kinase to be identified by viral oncogene (as pp60
V-SrcTyrosylprotein kinase perhaps is known as v-Src) and normal cell in corresponding Tyrosylprotein kinase (as pp60
C-SrcTyrosylprotein kinase perhaps is known as c-Src) produce.
In the biochemical signals that activated cell duplicates was transmitted, these receptor tyrosine kinases played an important role.These enzymes are the macromole enzyme, their cross over cytolemma and have born of the same parents of somatomedin (as Urogastron EGF) outer in conjunction with the territory, and have in the tyrosine amino acid phosphorylation in albumen and be used as part in the kinase whose born of the same parents, so these endonuclease capables influence cell proliferation.Different based on the family of different receptor tyrosine kinase bonded somatomedin, and the known various types of receptor tyrosine kinases of people (Wilks, Advances in CancerResearch, 1993,60,43-73).Classification comprises following all kinds of: I receptoroid Tyrosylprotein kinase, the EGF family that comprises receptor tyrosine kinase, as EGF, TGF α, Neu and erbB acceptor, II receptoroid Tyrosylprotein kinase comprises the Regular Insulin family of receptor tyrosine kinase, as Regular Insulin and IGFI acceptor and Regular Insulin associated receptor (IRR), III receptoroid Tyrosylprotein kinase comprises thrombocyte class somatomedin (PDGF) family of receptor tyrosine kinase, as PDGF α, PDGF β and colony-stimulating factor 1 (CSF1) acceptor.
People are also known, and some Tyrosylprotein kinase belongs to the nonreceptor tyrosine kinase class, and they are positioned at cell, and relevant with the transmission of biochemical signals, described signal has for example influences the tumour cell motility, signal (Ullrich etc., the Cell of diffusion and intrusion and metastases growth subsequently, 1990,61,203-212, Bolen etc., FASEB J., 1992,6,3403-3409, Brickell etc., Critical Reviews in Oncogenesis, 1992,3,401-406, Bohlen etc., Oncogene, 1993,8,2025-2031, Courtneidge etc., Semin.CancerBiol., 1994,5,239-246, Lauffenburger etc., Cell, 1996,84,359-369, Hanks etc., BioEssays, 1996,19,137-145, Parsons etc., Current Opinionin Cell Biology, 1997,9,187-192, Brown etc., Biochimica et BiophysicaActa, 1996,1287,121-149 and Schlaepfer etc., Progress in Biophysics andMolecular Biology.1999,71,435-478).The known various types of nonreceptor tyrosine kinases of people comprise Src family (as Src, Lyn and Yes Tyrosylprotein kinase), Abl family (as Abl and Arg) and Jak family (as Jak1 and Tyk2).
People are known, and the Src family of nonreceptor tyrosine kinase is subjected to highly regulation and control in normal cell, and is in the non-activity state when acellular external stimulue exists.But, the member of some Src family, as the c-Src Tyrosylprotein kinase at common human cancer such as gastrointestinal cancer (as colorectal carcinoma, the rectum cancer and cancer of the stomach) (Cartwright etc., Proc.Natl.Acad.Sci.USA, 1990,87,558-562 and Mao etc., Oncogene, 1997,15,3083-3090) and mammary cancer (Muthuswamy etc., Oncogene, 1995,11, usually significantly activated (comparing) in 1801-1810) with the normal cell level.(NSCLCs comprises gland cancer and squamous cell lung carcinoma (Mazurenko etc., European Journalof Cancer at other common human cancer such as nonsmall-cell lung cancer, 1992,28,372-7), bladder cancer (Fanning etc., Cancer Research, 1992,52,1457-62), the esophageal carcinoma (Jankowski etc., Gut, 1992,33,1033-8), prostate cancer, ovarian cancer (Wiener etc., Clin.Cancer Research, 1999,5,2164-70) and carcinoma of the pancreas (Lutz etc., Biochem.and Biophys.Res.Comm., 1998,243, also found the Src family of nonreceptor tyrosine kinase in 503-8).Along with the detection to the Src family of nonreceptor tyrosine kinase in other people's tumor tissues, people expect that the popularity of this family will be established.
People are also known, and the main effect of c-Src nonreceptor tyrosine kinase is to regulate the assembling of adhesion plaque complex body (focal adhesion kinase) by interacting with multiple cytoplasmic protein (comprising as focal adhesion kinase and paxillin).In addition, c-Src can also with the signal path coupling of modulate actin cytoskeleton, described cytoskeleton helps the motility of cell.Equally, c-Src, c-Yes and the c-Fyn nonreceptor tyrosine kinase (Owens etc. that in 6 integrin-mediated signal path and cell-cell of relying on the calcium attachment proteins link to each other destruction, also play an important role, Molecular Biology of the Cell, 2000,11,51-64 and Klinghoffer etc., EMBOJournal, 1999,18,2459-2471).The cell motility enters blood circulation, invades its hetero-organization and produce the metastases growth by diffusion for local tumor is essential.For example, colon tumor is that invasive transfer disease and the c-Src nonreceptor tyrosine kinase activity that spreads has certain relation (Brunton etc., Oncogene by the locality disease progression, 1997,14,283-293, Fincham etc., EMBO J, 1998,17,81-92 and Verbeek etc., Exp.Cell Research, 1999,248,531-537).
Therefore, people recognize that this type of nonreceptor tyrosine kinase inhibitor should also can suppress the growth of metastatic tumour as the selective depressant of malignant cancer cellular invasion and intrusion thus as the selective depressant of tumour cell motility.Particularly, this type of nonreceptor tyrosine kinase inhibitor should be as the inhibition of noumenal tumour disease and/or the anti-intrusion agent in the treatment.
At present, the applicant has found that some has the quinazoline derivant of astonishing anti-tumor activity.Although do not wish compound disclosed by the invention only is defined as by a kind of single bioprocess of influence and play pharmacological action, but, the applicant thinks that compound provided by the invention is to play antitumor action by suppressing one or more nonreceptor tyrosine kinase-specificity protein kinases, and described kinases is relevant with the signal conduction step of invasive that causes tumour cell and transfer motility ability.Specifically, the applicant thinks that compound of the present invention is by the Src family that suppresses nonreceptor tyrosine kinase, for example produces antitumor action by suppressing one or more c-Src, c-Yes and c-Fyn.
People are also known, control relevant (Soriano etc., Cell, 1991,64, the 693-702 of the bone resorption that c-Src nonreceptor tyrosine kinase and osteoclast drive; Boyce etc., J.Clin.Invest., 1992,90,1622-1627; Yoneda etc., J.Clin.Invest., 1993,91,2791-2795 and Missbach etc., Bone, 1999,24,437-49).Therefore, c-Src nonreceptor tyrosine kinase inhibitor can be used for prevention and treatment osteopathia, as osteoporosis, paget's abscess, bone and metastatic disease inductive hypercalcemia.
Compound of the present invention can also be used to suppress the cell proliferation out of control that various nonmalignant diseases cause, as inflammatory diseases (such as rheumatoid arthritis and inflammatory bowel disease), fibrosis disease (as liver cirrhosis and pulmonary fibrosis), glomerulonephritis, multiple sclerosis, psoriasis, skin allergy, vascular conditions (as atherosclerosis and restenosis), allergic asthma, insulin-dependent diabetes, diabetes type retinopathy and diabetic nephropathy.
Usually, although compound of the present invention has less inhibition activity to other Tyrosylprotein kinase such as receptor tyrosine kinase (as EGF receptor tyrosine kinase and/or vegf receptor tyrosine kinase), but they but have effective inhibition activity to nonreceptor tyrosine kinase Src family, and for example they can suppress c-Src and/or c-Yes.
And with respect to the inhibition for vegf receptor tyrosine kinase, some compound of the present invention shows the significant more activity that suppresses to the Src family (as c-Src and/or c-Yes) of nonreceptor tyrosine kinase.This compounds has enough inhibition activity to nonreceptor tyrosine kinase Src family (as c-Src and/or c-Yes), therefore they can with to as c-Src and/or c-Yes have the active amount use of enough inhibition, although they also show little inhibition activity to vegf receptor tyrosine kinase.The vegf receptor tyrosine kinase inhibition activity that reduces some compound to greatest extent is favourable, has found that this activity works as potassium channel antagonists, for example in the potassium channel of people's ether-a-go-go-genes involved (hERG) coding is analyzed.Such activity can produce the change of electrocardiogram(ECG (ECG) in vivo.
Hereinafter the anticancer therapy of Xian Dinging can be used as that independent therapy is used or (except that quinazoline derivant of the present invention) can also comprise operation or the radiotherapy or the chemotherapy of routine.As everyone knows, nearly all medicine all has metabolism to a certain degree in human body, and normally fat-soluble lower compound is easier of renal excretion.The enzyme of many drug metabolisms is found in (it forms microsome through homogenize) in the hepatocellular endoplasmic reticulum.Liver is the main place of drug metabolism, because liver cell (liver cell) contains the drug metabolism enzyme of special high density.The isozyme family of Cytochrome P450 in the microsome of liver, finding.6 specific specificity P450 isozymes are responsible for most of common drugs, i.e. the metabolism of P450 1A2,2C9,2C19,2D6,2E1 and 3A4.If one or more component drug of combination are by Cytochrome P450 3A4 (hereinafter referred to as CYP 3A4) metabolism, then combination chemotherapy is debatable.Such component can be the substrate of CYP3A4 or primer or the inhibitor that it can be isozyme.Such effect can influence the pharmacokinetics of other component of conjoint therapy.
We confirm that some compound of the present invention has and are not subject to such P450 isozyme, the particularly advantageous feature of the metabolic effect of CYP 3A4.Therefore, unite with anti-cancer therapies that to give such compound be possible with bigger security.
We confirm that also some compound of the present invention has two-fold advantage, even promptly they have that to suppress showing than low activity and their of vegf receptor tyrosine kinase few fully not by P450 isozyme such as the metabolic trend of CYP 3A4.
International Patent Application WO 01/94341 has been described the scope that quinazoline derivant is used for the treatment of cancer.Described compound is described to have the inhibition activity to the Src family of non--receptor tyrosine kinase.Wherein disclose the quinazoline derivant that some 5-replaces, comprised 4-(2, the 3-methylene-dioxy phenylamino) quinazoline that some 5-replaces.But wherein unexposed any 4-(2,3-methylene-dioxy pyridin-4-yl amino) quinazoline derivant.
International Patent Application WO 02/16352 has been described 4-(2,3-methylene-dioxy phenylamino) quinazoline derivant and has been used for the treatment of the scope of cancer.Described compound is described to have the inhibition activity to non--receptor tyrosine kinase Src family.But wherein unexposed any 4-(2,3-methylene-dioxy pyridin-4-yl amino) quinazoline derivant.
According to an aspect of the present invention, the invention provides quinazoline derivant or its pharmacy acceptable salt of formula I:
Wherein Z is O, S, SO, SO
2, N (R
2) or C (R
2)
2Group, wherein each R
2Group can be identical or different, is hydrogen or (1-8C) alkyl;
M is 0,1,2 or 3;
Each R
1Group can be identical or different; be selected from: halo; trifluoromethyl; cyano group; isocyano-; nitro; hydroxyl; sulfydryl; amino; formyl radical; carboxyl; formamyl; (1-8C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkyloyl; (2-6C) alkyloyl oxygen base; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); (3-6C) alkenoyl amino; the alkenoyl amino of N-(1-6C) alkyl-(3-6C); (3-6C) alkynes acyl amino; the alkynes acyl amino of N-(1-6C) alkyl-(3-6C); N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the group of following formula:
Q
1-X
1-
X wherein
1Directly for key or be selected from: O, S, SO, SO
2, N (R
4), CO, CH (OR
4), CON (R
4), N (R
4) CO, SO
2N (R
4), N (R
4) SO
2, OC (R
4)
2, SC (R
4)
2And N (R
4) C (R
4)
2, R wherein
4Be hydrogen or (1-8C) alkyl, and Q
1Be the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C) alkyl, perhaps (R
1)
mBe (1-3C) alkylene dioxo base,
And R wherein
1Adjacent carbons in arbitrary (2-6C) alkylidene chain in the substituting group is optional to be inserted into the following group of being selected from of this chain separately: O, S, SO, SO
2, N (R
5), CO, CH (OR
5), CON (R
5), N (R
5) CO, SO
2N (R
5), N (R
5) SO
2, CH=CH and C ≡ C, wherein R
5Be hydrogen or (1-8C) alkyl, perhaps when the group that inserts be N (R
5) time, R
5Also can be (2-6C) alkyloyl,
And R wherein
1Arbitrary CH in the substituting group
2The optional CH endways of=CH-or HC ≡ C-group
2=or HC ≡ position have and be selected from following substituting group: halo, carboxyl, formamyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N; alkyl and two-[(1-6C) alkyl] of the alkyl of N-two-[(1-6C) alkyl] formamyl, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl, perhaps be selected from the group of following formula:
Q
2-X
2-
X wherein
2Directly for key or be selected from CO and N (R
6) CO, wherein R
6Be hydrogen or (1-8C) alkyl, and Q
2Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at described CH
2Or CH
3Have one or more halos or (1-8C) alkyl substituent or be selected from following substituting group on each of group: hydroxyl; cyano group; amino; carboxyl; formamyl; oxo; sulfo-; (1-6C) alkoxyl group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkyloyl; (2-6C) alkyloyl oxygen base; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the group of following formula:
-X
3-Q
3：
X wherein
3Directly for key or be selected from: O, S, SO, SO
2, N (R
7), CO, CH (OR
7), CON (R
7), N (R
7) CO, SO
2N (R
7), N (R
7) SO
2, C (R
7)
2O, C (R
7)
2S and N (R
7) C (R
7)
2, R wherein
7Be hydrogen or (1-8C) alkyl, and Q
3Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)
And R wherein
1Arbitrary aryl in the substituting group; heteroaryl and heterocyclic radical are optional to have 1; 2 or 3 substituting groups; these substituting groups can be identical or different; be selected from: halo; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-8C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkyloyl; (2-6C) alkyloyl oxygen base; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) alkane sulfuryl amino; alkane sulfuryl amino of N-(1-6C) alkyl-(1-6C) and (1-3C) alkylenedioxy group perhaps are selected from the group of following formula:
-X
4-R
8
X wherein
4Directly for key or be selected from O and N (R
9), R wherein
9Be hydrogen or (1-8C) alkyl, and R
8For alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of alkyl, (2-6C) alkanoylamino-(1-6C) or (1-6C) alkyl of alkoxycarbonyl amino-(1-6C), perhaps be selected from the group of following formula:
-X
5-Q
4
X wherein
5Directly for key or be selected from: O, N (R
10) and CO, wherein R
10Be hydrogen or (1-8C) alkyl, and Q
4Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), it is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: halo, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxyl group
And R wherein
1Arbitrary heterocyclic radical in the substituting group is optional to have 1 or 2 oxos or sulfo-substituting group;
N is 0,1,2 or 3; And
Each R
3Group can be identical or different; be selected from halo; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-8C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkyloyl; (2-6C) alkyloyl oxygen base; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); (3-6C) alkenoyl amino; the alkenoyl amino of N-(1-6C) alkyl-(3-6C); (3-6C) alkynes acyl amino; the alkynes acyl amino of N-(1-6C) alkyl-(3-6C); N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the group of following formula:
-X
6-R
11
X wherein
6Directly for key or be selected from O and N (R
12), R wherein
12Be hydrogen or (1-8C) alkyl, and R
11For alkyl or two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl, perhaps be selected from the group of following formula:
-X
7-Q
5
X wherein
7Directly for key or be selected from: O, S, SO, SO
2, N (R
13), CO, CH (OR
13), CON (R
13), N (R
13) CO, SO
2N (R
13), N (R
13) SO
2, C (R
13)
2O, C (R
13)
2S and N (R
13) C (R
13)
2, R wherein
13Be hydrogen or (1-8C) alkyl, and Q
5Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), it is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: halo, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxyl group, and Q
5In arbitrary heterocyclic radical optional have 1 or 2 oxos or a sulfo-substituting group.
According to another aspect of the present invention, the invention provides quinazoline derivant or its pharmacy acceptable salt of formula I as defined above:
Wherein Z is O, S, SO, SO
2, CH
2Or NH;
Wherein m is 0,1,2 or 3;
Each R
1Group can be identical or different; be selected from: halo; trifluoromethyl; cyano group; isocyano-; nitro; hydroxyl; sulfydryl; amino; formyl radical; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkyloyl; (2-6C) alkyloyl oxygen base; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); (3-6C) alkenoyl amino; the alkenoyl amino of N-(1-6C) alkyl-(3-6C); (3-6C) alkynes acyl amino; the alkynes acyl amino of N-(1-6C) alkyl-(3-6C); N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the group of following formula:
Q
1-X
1-
X wherein
1Directly for key or be selected from: O, S, SO, SO
2, N (R
4), CO, CH (OR
4), CON (R
4), N (R
4) CO, SO
2N (R
4), N (R
4) SO
2, OC (R
4)
2, SC (R
4)
2And N (R
4) C (R
4)
2, R wherein
4Be hydrogen or (1-6C) alkyl, and Q
1Be the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C) alkyl, perhaps (R
1)
mBe (1-3C) alkylene dioxo base,
And R wherein
1Adjacent carbons in arbitrary (2-6C) alkylidene chain in the substituting group is optional to be inserted into the following group of being selected from of this chain separately: O, S, SO, SO
2, N (R
5), CO, CH (OR
5), CON (R
5), N (R
5) CO, SO
2N (R
5), N (R
5) SO
2, CH=CH and C ≡ C, wherein R
5Be hydrogen or (1-6C) alkyl, perhaps when the group that inserts be N (R
5) time, R
5Also can be (2-6C) alkyloyl,
And R wherein
1Arbitrary CH in the substituting group
2The optional CH endways of=CH-or HC ≡ C-
2=or HC ≡ position have and be selected from following substituting group: halo, carboxyl, formamyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N; alkyl and two-[(1-6C) alkyl] of the alkyl of N-two-[(1-6C) alkyl] formamyl, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl, perhaps be selected from the group of following formula:
Q
2-X
2-
X wherein
2Directly for key or be selected from: CO and N (R
6) CO, wherein R
6Be hydrogen or (1-6C) alkyl, Q
2Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at described CH
2Or CH
3Have one or more halos or (1-6C) alkyl substituent or be selected from following substituting group on each of group: hydroxyl; cyano group; amino; carboxyl; formamyl; oxo; sulfo-; (1-6C) alkoxyl group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkyloyl; (2-6C) alkyloyl oxygen base; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the group of following formula:
-X
3-Q
3：
X wherein
3Directly for key or be selected from: O, S, SO, SO
2, N (R
7), CO, CH (OR
7), CON (R
7), N (R
7) CO, SO
2N (R
7), N (R
7) SO
2, C (R
7)
2O, C (R
7)
2S and N (R
7) C (R
7)
2, R wherein
7Be hydrogen or (1-6C) alkyl, and Q
3Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)
And R wherein
1Arbitrary aryl on the substituting group; heteroaryl and heterocyclic radical are optional to have 1; 2 or 3 substituting groups; these substituting groups can be identical or different; be selected from: halo; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkyloyl; (2-6C) alkyloyl oxygen base; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) alkane sulfuryl amino; alkane sulfuryl amino of N-(1-6C) alkyl-(1-6C) and (1-3C) alkylenedioxy group perhaps are selected from the group of following formula:
-X
4-R
8
X wherein
4Directly for key or be selected from O and N (R
9), R wherein
9Be hydrogen or (1-6C) alkyl, and R
8For alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of alkyl, (2-6C) alkanoylamino-(1-6C) or (1-6C) alkyl of alkoxycarbonyl amino-(1-6C), perhaps be selected from the group of following formula:
-X
5-Q
4
X wherein
5Directly for key or be selected from: O, N (R
10) and CO, wherein R
10Be hydrogen or (1-6C) alkyl, and Q
4Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), it is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: halo, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxyl group
And R wherein
1On substituting group in arbitrary heterocyclic radical optional have 1 or 2 oxos or a sulfo-substituting group;
N is 0,1,2 or 3; And
Each R
3Group can be identical or different; be selected from halo; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkyloyl; (2-6C) alkyloyl oxygen base; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); (3-6C) alkenoyl amino; the alkenoyl amino of N-(1-6C) alkyl-(3-6C); (3-6C) alkynes acyl amino; the alkynes acyl amino of N-(1-6C) alkyl-(3-6C); N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the group of following formula:
-X
6-R
11
X wherein
6Directly for key or be selected from O and N (R
12), R wherein
12Be hydrogen or (1-6C) alkyl, and R
11For alkyl or two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl, perhaps be selected from the group of following formula:
-X
7-Q
5
X wherein
7Directly for key or be selected from: O, S, SO, SO
2, N (R
13), CO, CH (OR
13), CON (R
13), N (R
13) CO, SO
2N (R
13), N (R
13) SO
2, C (R
13)
2O, C (R
13)
2S and N (R
13) C (R
13)
2, R wherein
13Be hydrogen or (1-6C) alkyl, and Q
5Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), it is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: halo, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxyl group, and Q
5In arbitrary heterocyclic radical optional have 1 or 2 oxos or a sulfo-substituting group.
In this specification sheets, generic term " alkyl " comprises straight chain and branched-chain alkyl, as propyl group, sec.-propyl and the tertiary butyl, also comprise (3-7C) cycloalkyl, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, and comprise (3-7C) cycloalkyl-(1-2C) alkyl such as cyclopropyl methyl, 2-cyclopropyl ethyl, cyclobutylmethyl, 2-cyclobutyl ethyl, cyclopentyl-methyl, 2-cyclopentyl ethyl, cyclohexyl methyl and 2-cyclohexyl ethyl.Yet, when mentioning the independent alkyl such as " propyl group ", only be to refer in particular to the straight chain variant, and when mentioning the independent branched-chain alkyl such as " sec.-propyl ", only be to refer in particular to chain variants, and when mentioning independent cycloalkyl such as " cyclopentyl ", only refer in particular to 5 yuan of rings.Similar convention is used for other generic term, for example (1-6C) alkoxyl group comprises (3-6C) cycloalkyloxy and (3-5C) alkoxyl group, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, cyclo propyl methoxy, 2-cyclopropyl oxyethyl group, cyclobutyl methoxy base, 2-cyclobutyl oxyethyl group and the cyclopentyl methoxyl group of cycloalkyl-(1-2C); (1-6C) alkylamino comprises (3-6C) cycloalkyl amino and (3-5C) alkylamino, for example methylamino-, ethylamino, third amino, cyclopropylamino, ring fourth amino, hexamethylene amino, cyclopropyl methylamino-, 2-cyclopropyl ethylamino, cyclobutylmethyl amino, 2-cyclobutyl ethylamino and the cyclopentyl methylamino-of cycloalkyl-(1-2C); Comprise two-[(3-6C) cycloalkyl] amino and two-[(3-5C) cycloalkyl-(1-2C) alkyl] amino, for example dimethylamino, diethylin, dipropyl amino, N-cyclopropyl-N-methylamino-, N-cyclobutyl-N-methylamino-, N-cyclohexyl-N-ethylamino, N-cyclopropyl methyl-N-methylamino-, N-(2-cyclopropyl ethyl)-N-methylamino-and N-cyclopentyl-methyl-N-methylamino-with two-[(1-6C) alkyl] amino.
Should be appreciated that, more than the isomer of Ding Yi some formula I compound is owing to have one or more unsymmetrical carbon, therefore can exist with optically active or racemic form, the present invention comprises any such optically active or racemic form in its definition, they have above-mentioned activity.By standard technique of organic chemistry well known in the art, for example, can carry out the synthetic of optically active form by fractionation synthetic from the optically active raw material or by racemic form.Similarly, use the standard laboratory technology of indication hereinafter, can estimate above-mentioned activity.
Suitable group in the above-mentioned general group comprises those that list below.
As arbitrary " Q " group (Q
1-Q
5) when being aryl, promptly the aryl in " Q " group is suitably for, as phenyl or naphthyl, preferred phenyl.
As arbitrary " Q " group (Q
1Or Q
3) when being (3-7C) cycloalkyl, promptly (3-7C) cycloalkyl in " Q " group is suitably for, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or dicyclo [2.2.1] heptyl, as arbitrary " Q " group (Q
1Or Q
3) when being (3-7C) cycloalkenyl group, promptly (3-7C) cycloalkenyl group in " Q " group is suitably for, as cyclobutene base, cyclopentenyl, cyclohexenyl or cycloheptenyl.
As arbitrary " Q " group (Q
1-Q
5) when being heteroaryl, promptly the heteroaryl in " Q " group is suitably for, as aromatics 5-or 6-unit monocycle, it perhaps is 9-or 10-unit dicyclo, can have 5 of as many as and be selected from following ring hetero atom: oxygen, nitrogen and sulphur, furyl for example, pyrryl, thienyl, azoles base, different azoles base, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, the di azoly, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3, the 5-triazinyl, benzofuryl, indyl, benzothienyl, the benzoxazol base, benzimidazolyl-, benzothiazolyl, indazolyl, benzo furazan base, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, cinnolines base or naphthyridine base.
As arbitrary " Q " group (Q
1-Q
5) when being heterocyclic radical, promptly the heterocyclic radical in " Q " group is suitably for, first monocycle of 3-10 saturated as non-aromatics or fractional saturation or dicyclo, can have 5 of as many as and be selected from following heteroatoms: oxygen, nitrogen and sulphur, Oxyranyle for example, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, oxepane alkyl (oxepanyl), tetrahydro-thienyl, 1,1-dioxo tetrahydro-thienyl, tetrahydro thiapyran base, 1,1-dioxo tetrahydro thiapyran base, azetidinyl, pyrrolinyl, pyrrolidyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, 1,1-dioxo tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl (homopiperidinyl), piperazinyl, high piperazinyl (homopiperazinyl), the dihydropyridine base, tetrahydro pyridyl, dihydro-pyrimidin base or tetrahydro-pyrimidine base, preferred tetrahydrofuran base, THP trtrahydropyranyl, pyrrolidyl, morpholinyl, 1,1-dioxo tetrahydrochysene-4H-1, the 4-thiazinyl, piperidyl or piperazinyl.Having 1 or 2 oxos or substituent this type of group of sulfo-is suitably for as 2-oxo-pyrrolidine base, 2-sulfo-pyrrolidyl, 2-oxo-imidazole alkyl, 2-thiocarbamoyl imidazole alkyl, 2-oxo-piperidine base, 2,5-dioxo pyrrolidyl, 2,5-dioxo alkyl imidazole base or 2,6-dioxopiperidine base.
When " Q " group was the alkyl of heteroaryl-(1-6C), it was suitably for as heteroaryl methyl, 2-heteroaryl ethyl and 3-heteroaryl propyl group.The present invention includes corresponding " Q " group that is fit to, for example when " Q " group is not the alkyl of heteroaryl-(1-6C), can also there be the alkyl of alkyl of the alkyl of the alkyl of aryl-(1-6C), (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group-(1-6C) or heterocyclic radical-(1-6C).
Should be appreciated that in structural formula I, all to have hydrogen atom on 2 of described quinazoline ring.Therefore, described R
1Substituting group only can be positioned at 5,6,7 or 8 of quinazoline ring, and promptly 2 are not substituted.Be further appreciated that 2 among the structural formula I, the R that exists on the 3-methylene-dioxy pyridyl
3Group can be positioned on its 5-or the 6-unit ring position, i.e. R
3Group can be positioned at 2, on the pyridine ring or methylene radical in the 3-methylene-dioxy pyridyl.For example, R
3Group can be to be positioned at 2, and the methyl on the methylene moiety in the 3-methylene-dioxy pyridyl promptly carries ethylenedioxy on the 2-of pyridyl and the 3-position.Preferably, 2 of structural formula I, any R that exists in the 3-methylene-dioxy pyridyl
3Group is positioned on its pyridine ring.Be also to be understood that when there being a plurality of R
3During group, R
3Group can be identical or different.
" R " group (R
1-R
13) or R
1Or R
3Various groups in the substituting group are suitably for:
For halo, be fluoro base, chloro base, bromo base and iodo base;
For (1-8C) alkyl: be methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, cyclobutyl, cyclopentyl and 2-cyclopropyl ethyl;
For (1-6C) alkyl: methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl;
For (2-8C) alkenyl: vinyl, pseudoallyl, allyl group and but-2-ene base;
For (2-8C) alkynyl: ethynyl, 2-propynyl and fourth-2-alkynyl;
For (1-6C) alkoxyl group: methoxyl group, oxyethyl group, propoxy-, isopropoxy and butoxy;
For (2-6C) alkenyl oxy: vinyloxy group and allyl group oxygen base;
For (2-6C) alkynyloxy base: ethynyl oxygen base and 2-propynyl oxygen base;
For (1-6C) alkylthio: methylthio group, ethylmercapto group and rosickyite base;
For (1-6C) alkyl sulphinyl: methylsulfinyl and ethyl sulfinyl;
For (1-6C) alkyl sulphonyl: methyl sulphonyl and ethylsulfonyl;
For (1-6C) alkylamino: methylamino-, ethylamino, third amino, isopropylamino and fourth amino;
For two-[(1-6C) alkyl] amino: dimethylamino, diethylamino, N-ethyl-N-methylamino-and diisopropylaminoethyl;
For (1-6C) alkoxy carbonyl: methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl and tert-butoxycarbonyl;
For N-(1-6C) alkyl-carbamoyl: N-methylamino formyl radical, N-ethylamino formyl radical and N-propyl group formamyl;
For N, N-two-[(1-6C) alkyl] formamyl: N, N-formyl-dimethylamino, N-ethyl-N-methylamino formyl radical and N, N-diethylamino formyl radical;
For (2-6C) alkyloyl: ethanoyl, propionyl and isobutyryl;
For (2-6C) alkyloyl oxygen base: acetoxyl group and propionyl oxygen base;
For (2-6C) alkanoylamino: kharophen and propionamido;
For the alkanoylamino of N-(1-6C) alkyl-(2-6C): N-methyl kharophen and N-methyl-prop amido;
For N-(1-6C) alkylsulfamoyl group: N-methyl sulfamyl and N-ethyl sulfamyl;
For N, N-two-[(1-6C) alkyl] sulfamyl: N, N-dimethylamino alkylsulfonyl;
For (1-6C) alkane sulfuryl amino: methylsulfonyl amino and ethylsulfonylamino;
For the alkane sulfuryl amino of N-(1-6C) alkyl-(1-6C): the amino and N-methyl ethylsulfonylamino of N-methyl methylsulfonyl;
For (3-6C) alkenoyl amino: acrylamido, methacrylamido and crotonoyl amino;
For the alkenoyl amino of N-(1-6C) alkyl-(3-6C): N-methacrylamido and N-methyl butene amido;
For (3-6C) alkynes acyl amino: propiolyl amino;
For the alkynes acyl amino of N-(1-6C) alkyl-(3-6C): N-methyl propine amido;
For amino-(1-6C) alkyl: amino methyl, 2-amino-ethyl, 1-amino-ethyl and 3-aminopropyl;
For the alkyl of (1-6C) alkylamino-(1-6C): methylamino-methyl, ethylamino methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, 2-ethylamino ethyl and 3-methylamino-propyl group;
For two-[(1-6C) alkyl] amino-(1-6C) alkyl: dimethylamino methyl, diethylamino methyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylamino-propyl;
For the alkyl of halo-(1-6C): chloromethyl, 2-fluoro ethyl, 2-chloroethyl, 1-chloroethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3,3-two fluoropropyls and 3,3,3-trifluoro propyl;
For the alkyl of hydroxyl-(1-6C): hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl;
For the alkyl of (1-6C) alkoxyl group-(1-6C): methoxymethyl, ethoxyl methyl, 1-methoxy ethyl, 2-methoxy ethyl, 2-ethoxyethyl group and 3-methoxy-propyl;
For the alkyl of cyano group-(1-6C): cyano methyl, 2-cyano ethyl, 1-cyano ethyl and 3-cyano group propyl group;
For the alkyl of (2-6C) alkanoylamino-(1-6C): acetylamino methyl, propionamido methyl and 2-kharophen ethyl; And
For the alkyl of (1-6C) alkoxycarbonyl amino-(1-6C): methoxycarbonyl amino methyl, ethoxy carbonyl amino methyl, tert-butoxycarbonyl amino methyl and 2-methoxycarbonyl amino-ethyl.
As (R
1)
mDuring for (1-3C) alkylene dioxo base or for R
1(1-3C) alkylene dioxo base in the substituting group, its value that is fit to be, as methylene-dioxy, ethylenedioxy, isopropylidene dioxy base or ethylene dioxy base and as described in Sauerstoffatom occupy the ortho position of ring.
As previously mentioned, work as R
1Group forms formula Q
1-X
1-group, and X
1For as OC (R
4)
2During linking group, be this OC (R so
4)
2The carbon atom of linking group rather than Sauerstoffatom link to each other with the quinazoline ring, and described Sauerstoffatom and Q
1Link to each other.Equally, work as R
1Group in the substituting group such as CH
3Have formula-X
3-Q
3Group, and X
3For as C (R
7)
2During the O linking group, be this C (R so
7)
2The carbon atom of O linking group rather than Sauerstoffatom and CH
3Link to each other, and described Sauerstoffatom and Q
3Link to each other.Similarly convention also is applicable to formula Q
2-X
2-and-X
7-Q
5The connection of group.
As previously mentioned, R
1Adjacent carbons in arbitrary (2-6C) alkylidene chain in the substituting group can be chosen wantonly and be inserted into the following group of being selected from of this chain separately, and described group is just like O, CON (R
5) or C ≡ C.For example, in the ethylidene chain of 2-morpholino oxyethyl group, insert C ≡ C group, obtain 4-morpholino fourth-2-alkynyloxy base thus, and in the ethylidene chain of 3-methoxy propoxy, insert, obtain oxyethyl group as 2-(2-methoxyl group kharophen) as the CONH group.
As previously mentioned, work as R
1Arbitrary CH in the substituting group
2The optional CH endways of=CH-or HC ≡ C-group
2=or HC ≡ position have for example formula Q
2X
2During the substituting group of-group, in the formula, X
2For as NHCO, and Q
2Be the alkyl of heterocyclic radical-(1-6C), the R that is fit to that so so forms
1Substituting group comprises, as the alkyl of N-[heterocyclic radical-(1-6C)] alkyl of formamyl vinyl (for example N-(2-tetramethyleneimine-1-base ethyl) formamyl vinyl) or N-[heterocyclic radical-(1-6C)] formamyl ethynyl (for example N-(2-tetramethyleneimine-1-base ethyl) formamyl ethynyl).
As previously mentioned, work as R
1Arbitrary CH in the substituting group
2Or CH
3Group is at described CH
2Or CH
3Optional on the group have one or more halos or (1-6C) during alkyl substituent, so at each described CH
2Be fit to have 1 or 2 halos or (1-6C) alkyl substituent on the group, and at each described CH
3Be fit to have 1 on the group, 2 or 3 these type of substituting groups.
As previously mentioned, work as R
1Arbitrary CH in the substituting group
2Or CH
3Group is at each described CH
2Or CH
3Choose when having the substituting group of aforementioned definitions the R that is fit to that so so forms on the group wantonly
1Substituting group comprises, for example the alkoxyl group (as 2-hydroxyl-3-piperidino-(1-position only) propoxy-and 2-hydroxyl-3-morpholino propoxy-) of the heterocyclic radical of hydroxyl-replacement-(1-6C); the alkoxyl group (as 3-amino-2-hydroxyl propoxy-) of the amino of hydroxyl-replacement-(2-6C); the alkoxyl group (as 2-hydroxyl-3-methylamino-propoxy-) of (1-6C) alkylamino of hydroxyl-replacement-(2-6C); two of hydroxyl-replacement-[(1-6C) alkyl] be amino-(2-6C) alkoxyl group (as 3-dimethylamino-2-hydroxyl propoxy-); the alkylamino of the heterocyclic radical of hydroxyl-replacement-(1-6C) (as 2-hydroxyl-3-piperidino-(1-position only) third amino and 2-hydroxyl-3-morpholino third amino); the alkylamino (as 3-amino-2-hydroxyl third amino) of the amino of hydroxyl-replacement-(2-6C); the alkylamino (as 2-hydroxyl-3-methylamino-third amino) of (1-6C) alkylamino of hydroxyl-replacement-(2-6C); two of hydroxyl-replacement-[(1-6C) alkyl] be amino-(2-6C) alkylamino (as 3-dimethylamino-2-hydroxyl third amino); (1-6C) alkoxyl group (as the 2-hydroxyl-oxethyl) of hydroxyl-replacement; (1-6C) (1-6C) alkoxyl group of alkoxyl group-replacement (as 2-methoxy ethoxy and 3-oxyethyl group propoxy-); (1-6C) alkyl of (1-6C) alkylamino of (1-6C) alkoxyl group of alkyl sulphonyl-replacement (as 2-sulfonyloxy methyl base oxethyl) and heterocyclic radical-replacement-(1-6C) is (as 2-morpholino ethylamino methyl; 2-piperazine-1-base ethylamino methyl and 3-morpholino third amino methyl).
Should be appreciated that, as R as defined above
1Any CH in the substituting group
2Or CH
3Group is at each described CH
2Or CH
3Optional when carrying as defined above substituting group on the group, the CH of so optional substituting group in may reside in substituting group scope as defined above
2Or CH
3On the group, described substituting group can be for being present in R
1On aryl in the substituting group, heteroaryl or the heterocyclic radical.For example, if R
1Comprise the aryl or the heteroaryl that are replaced by (1-8C) alkyl, the CH that then described (1-8C) alkyl can be therein
2Or CH
3Optionally on the group replaced as one of substituting group of preceding definition by it.For example, if R
1When comprising the heteroaryl that is replaced by the alkyl of for example (1-6C) alkylamino-(1-6C), the terminal CH of (1-6C) alkylamino then
3Group can by for example (1-6C) alkyl sulphonyl or (2-6C) alkyloyl further replace.For example, R
1Group can be the thienyl of heteroaryl as being replaced by N-(2-methyl sulphonyl ethyl) amino methyl, so that R
1Be for example 5-[N-(2-methyl sulphonyl ethyl) amino methyl] thiophene-2-base group.In addition, for example, if R
1Comprise piperidyl or the piperazinyl of heterocyclic radical, then the terminal CH of (2-6C) alkyloyl as on its nitrogen-atoms, being replaced by for example (2-6C) alkyloyl
3Group can further be replaced by for example two-[(1-6C) alkyl] amino.For example, R
1Group can be N-(2-dimethylamino ethanoyl) piperidin-4-yl or 4-(2-dimethylamino ethanoyl) piperazine-1-base.
The pharmacy acceptable salt that is fit to of formula I compound is, suc as formula the acid salt of I compound, and the acid salt that is become with mineral acid or organic acid for example, described acid comprises example hydrochloric acid, Hydrogen bromide, sulfuric acid, trifluoroacetic acid, citric acid or toxilic acid; Perhaps, for example, when the salt of formula I compound has enough when acid, for these compounds as basic metal or alkaline earth salt (as calcium salt or magnesium salts) or be their ammonium salt, perhaps be the salt that these compounds and organic bases such as methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine form.
Concrete new compound of the present invention comprises, suc as formula quinazoline derivant or its pharmacy acceptable salt of I, and wherein except that specializing, Z, m, R
1, n and R
3In each have meaning defined in front or following (a) to (o) section:
(a) Z is O, S, SO, SO
2, CH
2Or NH;
(b) Z is O;
(c) Z is NH;
(d) m is 1 or 2, and each R
1Group can be identical or different; be selected from: halo; trifluoromethyl; hydroxyl; amino; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyloxy base; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; N-(1-6C) alkyl-carbamoyl; N; N-two [(1-6C) alkyl] formamyl; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); (3-6C) alkenoyl amino; the alkenoyl amino of N-(1-6C) alkyl-(3-6C); (3-6C) the alkynes acyl amino of alkynes acyl amino and N-(1-6C) alkyl-(3-6C) perhaps is selected from the group of following formula:
Q
1-X
1-
X wherein
1Directly for key or be selected from: O, N (R
4), CON (R
4), N (R
4) CO and OC (R
4)
2, R wherein
4Be hydrogen or (1-6C) alkyl, and Q
1Be the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), cycloalkyl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),
And R wherein
1The adjacent carbons of arbitrary (2-6C) alkylidene chain in the substituting group is optional to be inserted into the following group of being selected from of this chain separately: O, N (R
5), CON (R
5), N (R
5) CO, CH=CH and C ≡ C, wherein R
5Be hydrogen or (1-6C) alkyl, perhaps when described insertion group be N (R
5) time, R
5Also can be (2-6C) alkyloyl,
And R wherein
1Arbitrary CH in the substituting group
2The optional CH endways of=CH-or HC ≡ C-group
2=or HC ≡ position have and be selected from following substituting group: formamyl, N-(1-6C) alkyl-carbamoyl, N, alkyl and two-[(1-6C) alkyl] of the alkyl of N-two-[(1-6C) alkyl] formamyl, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl or form the group of following formula:
Q
2-X
2-
X wherein
2It directly is key or for CO or N (R
6) CO, wherein R
6Be hydrogen or (1-6C) alkyl, and Q
2Be the alkyl of heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at each described CH
2Or CH
3Carry one or more halogeno-groups on the group or be selected from following substituting group: the alkanoylamino of hydroxyl, amino, oxo, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (2-6C) alkyloyl oxygen base, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C) perhaps is selected from the group of following formula:
-X
3-Q
3-
X wherein
3Directly for key or be selected from: O, N (R
6), CON (R
7), N (R
7) CO and C (R
7)
2O, wherein R
7Be hydrogen or (1-6C) alkyl, and Q
3Be the alkyl of heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),
And R wherein
1On substituting group in arbitrary aryl, heteroaryl or heterocyclic radical optional have 1,2 or 3 substituting group; they can be identical or different; be selected from: halo; trifluoromethyl, hydroxyl, amino, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, N-(1-6C) alkyl-carbamoyl, N; N-two-[(1-6C) alkyl] formamyl, (2-6C) alkyloyl and (1-3C) alkylenedioxy group, or optionally have 1 substituting group that is selected from following formula:
-X
4-R
8
X wherein
4Directly for key or be selected from: O and N (R
9), R wherein
9Be hydrogen or (1-6C) alkyl, R
8For alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of alkyl, (2-6C) alkanoylamino-(1-6C) or (1-6C) alkyl of alkoxycarbonyl amino-(1-6C), perhaps be selected from the group of following formula:
-X
5-Q
4
X wherein
5Directly for key or be selected from: O, N (R
10) and CO, wherein R
10Be hydrogen or (1-6C) alkyl, and Q
4Be the alkyl of heterocyclic radical or heterocyclic radical-(1-6C), it is optional to have 1 or 2 substituting group, and described substituting group can be identical or different, is selected from: halo, (1-6C) alkyl and (1-6C) alkoxyl group,
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 oxo substituting group;
(e) m is 1 or 2, and each R
1Group can be identical or different; be selected from: the fluoro base; the chloro base; trifluoromethyl; hydroxyl; amino; formamyl; methyl; ethyl; propyl group; butyl; vinyl; allyl group; fourth-3-thiazolinyl; penta-4-thiazolinyl; oneself-the 5-thiazolinyl; ethynyl; 2-propynyl; fourth-3-alkynyl; penta-4-alkynyl; oneself-the 5-alkynyl; methoxyl group; oxyethyl group; propoxy-; isopropoxy; butoxy; allyloxy; fourth-3-thiazolinyl oxygen base; penta-4-thiazolinyl oxygen base; oneself-5-thiazolinyl oxygen base; ethynyl; 2-propynyl oxygen base; fourth-3-alkynyloxy base; penta-4-alkynyloxy base; oneself-5-alkynyloxy base; methylamino-; ethylamino; third amino; dimethylamino; diethylin; dipropyl amino; the N-methyl-carbamoyl; N; N-dimethylamino formyl radical; kharophen; propionamido; acrylamido and propiolyl amino perhaps are selected from the group of following formula:
Q
1-X
1
X wherein
1Directly for key or be selected from: O, NH, CONH, NHCO and OCH
2, and Q
1Be phenyl, benzyl, the cyclopropyl methyl, the 2-thienyl, the 1-imidazolyl, 1,2, the 3-triazol-1-yl, 1,2, the 4-triazol-1-yl, 2-, 3-or 4-pyridyl, 2-imidazoles-1-base ethyl, 3-imidazoles-1-base propyl group, 2-(1,2, the 3-triazolyl) ethyl, 3-(1,2, the 3-triazolyl) propyl group, 2-(1,2, the 4-triazolyl) ethyl, 3-(1,2, the 4-triazolyl) propyl group, 2-, 3-or 4-pyridylmethyl, 2-(2-, 3-or 4-pyridyl) ethyl, 3-(2-, 3-or 4-pyridyl) propyl group, tetrahydrofuran base-3-base, 3-or 4-THP trtrahydropyranyl, 1-, 2-or 3-pyrrolidyl, morpholino, 1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-base, piperidino-(1-position only), piperidines-3-base, piperidin-4-yl, 1-, 3-or 4-homopiperidinyl, piperazine-1-base, high piperazine-1-base, 1-, 2-or 3-pyrrolidyl methyl, the morpholino methyl, the piperidino-(1-position only) methyl, 3-or 4-piperidino methyl, 1-, 3-or 4-homopiperidinyl methyl, 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-2-base propyl group, tetramethyleneimine-2-ylmethyl, 2-tetramethyleneimine-2-base ethyl, 3-tetramethyleneimine-1-base propyl group, 4-tetramethyleneimine-1-base butyl, 2-morpholino ethyl, 3-morpholino propyl group, 4-morpholino butyl, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) ethyl, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propyl group, 2-piperidino-(1-position only) ethyl, 3-piperidino-(1-position only) propyl group, 4-piperidino-(1-position only) butyl, 2-piperidines-3-base ethyl, 3-piperidines-3-base propyl group, 2-piperidin-4-yl ethyl, 3-piperidin-4-yl propyl group, the high piperidines of 2--1-base ethyl, the high piperidines of 3--1-base propyl group, 2-(1,2,3,6-tetrahydropyridine-1-yl) ethyl, 3-(1,2,3,6-tetrahydropyridine-1-yl) propyl group, 4-(1,2,3,6-tetrahydropyridine-1-yl) butyl, 2-piperazine-1-base ethyl, 3-piperazine-1-base propyl group, 4-piperazine-1-base butyl, the high piperazine of 2--1-base ethyl or the high piperazine of 3--1-base propyl group
And R wherein
1Adjacent carbons in arbitrary (2-6C) alkylidene chain in the substituting group is optional to be inserted into the following group of being selected from of this chain separately: O, NH, N (Me), CONH, and NHCO, CH=CH and C ≡ C,
And R wherein
1Arbitrary CH in the substituting group
2The optional CH endways of=CH-or HC ≡ C-group
2=or HC ≡ position have and be selected from following substituting group: formamyl, N-methyl-carbamoyl, N-ethylamino formyl radical, N-third formamyl, N; the amino butyl of N-dimethylamino formyl radical, amino methyl, 2-amino-ethyl, 3-aminopropyl, 4-, methylamino-methyl, 2-methylamino-ethyl, 3-methylamino-propyl group, 4-methylamino-butyl, dimethylamino methyl, 2-dimethylaminoethyl, 3-dimethylamino-propyl or 4-dimethylamino butyl perhaps are selected from the group of following formula:
Q
2-X
2-
X wherein
2Directly be key or for CO, NHCO or N (Me) CO, and Q
2Be pyridyl, pyridylmethyl, 2-pyridyl ethyl, tetramethyleneimine-1-base, tetramethyleneimine-2-base, morpholino, piperidino-(1-position only), piperidines-3-base, piperidin-4-yl, piperazine-1-base, tetramethyleneimine-1-ylmethyl, 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-1-base propyl group, 4-tetramethyleneimine-1-base butyl, tetramethyleneimine-2-ylmethyl, 2-tetramethyleneimine-2-base ethyl, 3-tetramethyleneimine-2-base propyl group, the morpholino methyl, 2-morpholino ethyl, 3-morpholino propyl group, 4-morpholino butyl, the piperidino-(1-position only) methyl, 2-piperidino-(1-position only) ethyl, 3-piperidino-(1-position only) propyl group, 4-piperidino-(1-position only) butyl, piperidines-3-ylmethyl, 2-piperidines-3-base ethyl, the piperidin-4-yl methyl, 2-piperidin-4-yl ethyl, piperazine-1-ylmethyl, 2-piperazine-1-base ethyl, 3-piperazine-1-base propyl group or 4-piperazine-1-base butyl
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at described CH
2Or CH
3Carry one or more fluoro or chloro group on the group or be selected from following substituting group: hydroxyl, amino, oxo, methoxyl group, methylsulfonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino-, N-sec.-propyl-N-methylamino-, N-methyl-N-third amino, acetoxyl group, kharophen and N-methyl kharophen or be selected from the group of following formula:
-X
3-Q
3
X wherein
3Directly for key or be selected from: O, NH, CONH, NHCO and CH
2O, and Q
3Be pyridyl, pyridylmethyl, tetramethyleneimine-1-base, tetramethyleneimine-2-base, morpholino, piperidino-(1-position only), piperidines-3-base, piperidin-4-yl, piperazine-1-base, 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-1-base propyl group, tetramethyleneimine-2-ylmethyl, 2-tetramethyleneimine-2-base ethyl, 3-tetramethyleneimine-2-base propyl group, 2-morpholino ethyl, 3-morpholino propyl group, 2-piperidino-(1-position only) ethyl, 3-piperidino-(1-position only) propyl group, piperidines-3-ylmethyl, 2-piperidines-3-base ethyl, the piperidin-4-yl methyl, 2-piperidin-4-yl ethyl, 2-piperazine-1-base ethyl or 3-piperazine-1-base propyl group
And R wherein
1Arbitrary aryl, heteroaryl and heterocyclic radical in the substituting group chosen wantonly has 1,2 or 3 substituting group; described substituting group can be identical or different; be selected from: fluoro base, chloro base, trifluoromethyl, hydroxyl, amino, formamyl, methyl, ethyl, allyl group, 2-propynyl, methoxyl group, methyl sulphonyl, N-methylamino formyl radical, N; N-formyl-dimethylamino, ethanoyl, propionyl, isobutyryl, methylene-dioxy, ethylenedioxy and isopropylidene dioxy base, or optional have 1 substituting group that is selected from the following formula group:
-X
4-R
8
X wherein
4Directly for key or be selected from: O and NH, R
8Be 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2, the 2-trifluoroethyl, 3-fluoro propyl group, 3,3-two fluoropropyls, 3,3, the 3-trifluoro propyl, the 2-hydroxyethyl, the 3-hydroxypropyl, the 2-methoxy ethyl, the 3-methoxy-propyl, cyano methyl, amino methyl, the 2-amino-ethyl, the 3-aminopropyl, the methylamino-methyl, 2-methylamino-ethyl, 3-methylamino-propyl group, 2-ethylamino ethyl, 3-ethylamino propyl group, dimethylamino methyl, the 2-dimethylaminoethyl, the 3-dimethylamino-propyl, acetylamino methyl, the methoxycarbonyl amino methyl, ethoxy carbonyl amino methyl or tert-butoxycarbonyl amino methyl and be selected from the group of following formula:
-X
5-Q
4
X wherein
5Directly for key or be selected from: O, NH and CO, and Q
4Be tetramethyleneimine-1-ylmethyl, 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-1-base propyl group, morpholino methyl, 2-morpholino ethyl, 3-morpholino propyl group, piperidino-(1-position only) methyl, 2-piperidino-(1-position only) ethyl, 3-piperidino-(1-position only) propyl group, piperazine-1-ylmethyl, 2-piperazine-1-base ethyl or 3-piperazine-1-base propyl group, in these groups each is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: fluoro base, chloro base, methyl and methoxyl group
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 oxo substituting group;
(f) m is 1, R
1Group is positioned at 5-, 6-or 7-position, and perhaps m is 2, each R
1Group can be identical or different, is positioned at 5-and 7 or is positioned at 6-and 7 and each R
1Group is selected from: hydroxyl, amino, methyl, ethyl, propyl group, butyl, vinyl, ethynyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, pentyloxy, fourth-3-thiazolinyl oxygen base, penta-4-thiazolinyl oxygen base, oneself-5-thiazolinyl oxygen base, fourth-3-alkynyloxy base, penta-4-alkynyloxy base, oneself-5-alkynyloxy base, methylamino-, ethylamino, dimethylamino, diethylin, kharophen, propionamido, cyclopentyloxy, cyclohexyl oxygen base, phenoxy group, benzyloxy, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-3-base oxygen base, tetrahydropyran-4-base oxygen base, cyclo propyl methoxy, 2-imidazoles-1-base oxethyl, 3-imidazoles-1-base propoxy-, 2-(1,2, the 3-triazol-1-yl) oxyethyl group, 3-(1,2, the 3-triazol-1-yl) propoxy-, 2-(1,2, the 4-triazol-1-yl) oxyethyl group, 3-(1,2, the 4-triazol-1-yl) propoxy-, pyridine-2-ylmethoxy, the pyridin-3-yl methoxyl group, the pyridin-4-yl methoxyl group, 2-pyridine-2-base oxethyl, 2-pyridin-3-yl oxyethyl group, 2-pyridin-4-yl oxyethyl group, 3-pyridine-2-base propoxy-, 3-pyridin-3-yl propoxy-, 3-pyridin-4-yl propoxy-, tetramethyleneimine-1-base, morpholino, piperidino-(1-position only), piperazine-1-base, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 4-tetramethyleneimine-1-base butoxy, tetramethyleneimine-3-base oxygen base, tetramethyleneimine-2-ylmethoxy, 2-tetramethyleneimine-2-base oxethyl, 3-tetramethyleneimine-2-base propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 4-morpholino butoxy, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 4-piperidino-(1-position only) butoxy, piperidines-3-base oxygen base, piperidin-4-yl oxygen base, piperidines-3-ylmethoxy, the piperidin-4-yl methoxyl group, 2-piperidines-3-base oxethyl, 3-piperidines-3-base propoxy-, 2-piperidin-4-yl oxyethyl group, 3-piperidin-4-yl propoxy-, the high piperidines of 2--1-base oxethyl, the high piperidines of 3--1-base propoxy-, 2-(1,2,3,6-tetrahydropyridine-1-yl) oxyethyl group, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 4-(1,2,3,6-tetrahydropyridine-1-yl) butoxy, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, 4-piperazine-1-base butoxy, the high piperazine of 2--1-base oxethyl, the high piperazine of 3--1-base propoxy-, 2-tetramethyleneimine-1-base ethylamino, 3-tetramethyleneimine-1-base third amino, 4-tetramethyleneimine-1-base butyl amino, tetramethyleneimine-3-base is amino, tetramethyleneimine-2-base methylamino-, 2-tetramethyleneimine-2-base ethylamino, 3-tetramethyleneimine-2-base third amino, 2-morpholino ethylamino, 3-morpholino third amino, 4-morpholino butyl amino, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) ethylamino, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) third amino, 2-piperidino-(1-position only) ethylamino, 3-piperidino-(1-position only) third amino, 4-piperidino-(1-position only) butyl amino, piperidines-3-base is amino, piperidin-4-yl amino, piperidines-3-base methylamino-, 2-piperidines-3-base ethylamino, the piperidin-4-yl methylamino-, 2-piperidin-4-yl ethylamino, the high piperidines of 2--1-base ethylamino, the high piperidines of 3--1-base third amino, 2-piperazine-1-base ethylamino, 3-piperazine-1-base third amino, 4-piperazine-1-base butyl amino, the high piperazine of 2--1-base ethylamino or the high piperazine of 3--1-base third amino
And R wherein
1Adjacent carbons in arbitrary (2-6C) alkylidene chain in the substituting group is optional to be inserted into the following group of being selected from of this chain separately: O, NH, N (Me), CH=CH and C ≡ C,
And work as R
1During for vinyl or ethynyl, R
1The optional CH endways of substituting group
2=or HC ≡ position have and be selected from following substituting group: N-(2-dimethylaminoethyl) formamyl, N-(3-dimethylamino-propyl) formamyl, methylamino-methyl, 2-methylamino-ethyl, 3-methylamino-propyl group, 4-methylamino-butyl, dimethylamino methyl, 2-dimethylaminoethyl, 3-dimethylamino-propyl and 4-dimethylamino butyl, perhaps be selected from the group of following formula:
Q
2-X
2-
X wherein
2Directly be key or for NHCO or N (Me) CO, and Q
2Be imidazolyl methyl, 2-imidazolyl ethyl, 3-imidazolyl propyl group, pyridylmethyl, 2-pyridyl ethyl, 3-pyridyl propyl group, tetramethyleneimine-1-ylmethyl, 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-1-base propyl group, 4-tetramethyleneimine-1-base butyl, tetramethyleneimine-2-ylmethyl, 2-tetramethyleneimine-2-base ethyl, 3-tetramethyleneimine-2-base propyl group, the morpholino methyl, 2-morpholino ethyl, 3-morpholino propyl group, 4-morpholino butyl, the piperidino-(1-position only) methyl, 2-piperidino-(1-position only) ethyl, 3-piperidino-(1-position only) propyl group, 4-piperidino-(1-position only) butyl, piperidines-3-ylmethyl, 2-piperidines-3-base ethyl, the piperidin-4-yl methyl, 2-piperidin-4-yl ethyl, piperazine-1-ylmethyl, 2-piperazine-1-base ethyl, 3-piperazine-1-base propyl group or 4-piperazine-1-base butyl
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at described CH
2Or CH
3Carry one or more fluoro bases or chloro base on the group or be selected from following substituting group: hydroxyl, oxo, amino, methoxyl group, methylsulfonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino-, N-sec.-propyl-N-methylamino-, N-methyl-N-third amino, acetoxyl group, kharophen and N-methyl kharophen
And R wherein
1Arbitrary phenyl, imidazolyl, triazolyl, pyridyl or heterocyclic radical in the substituting group chosen wantonly has 1 or 2 substituting group; described substituting group can be identical or different; be selected from: fluoro base, chloro base, trifluoromethyl, hydroxyl, amino, formamyl, methyl, ethyl, methoxyl group, oxyethyl group, N-methylamino formyl radical, N; N-formyl-dimethylamino, methylene-dioxy, ethylenedioxy and isopropylidene dioxy base, and R
1Tetramethyleneimine in the substituting group-2-base; piperidines-3-base; piperidin-4-yl; piperazine-1-base or high piperazine-the 1-base is optional to be replaced by following groups N-: allyl group; 2-propynyl; methyl sulphonyl; ethylsulfonyl; ethanoyl; propionyl; isobutyryl; 2-fluoro ethyl; 2; 2-two fluoro ethyls; 2; 2; the 2-trifluoroethyl; 3-fluoro propyl group; 3; 3-two fluoropropyls; 3; 3; the 3-trifluoro propyl; the 2-methoxy ethyl; the 3-methoxy-propyl; cyano methyl; the 2-amino-ethyl; the 3-aminopropyl; 2-methylamino-ethyl; 3-methylamino-propyl group; the 2-dimethylaminoethyl; the 3-dimethylamino-propyl; 2-tetramethyleneimine-1-base ethyl; 3-tetramethyleneimine-1-base propyl group; 2-morpholino ethyl; 3-morpholino propyl group; 2-piperidino-(1-position only) ethyl; 3-piperidino-(1-position only) propyl group; 2-piperazine-1-base ethyl or 3-piperazine-1-base propyl group; in back 8 in these substituting groups each is optional have 1 or 2 can be identical or different be selected from following substituting group: the fluoro base; the chloro base; methyl and methoxyl group
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 oxo substituting group;
(g) m is 1, and R
1It is 2 that group is positioned at 7 or m, and each R
1Group can be identical or different, is positioned at 6-and 7 and each R
1Group is selected from: hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, methylamino-, ethylamino, dimethylamino, diethylin, kharophen, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 4-tetramethyleneimine-1-base butoxy, tetramethyleneimine-3-base oxygen base, tetramethyleneimine-2-ylmethoxy, 2-tetramethyleneimine-2-base oxethyl, 3-tetramethyleneimine-2-base propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 4-morpholino butoxy, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 4-piperidino-(1-position only) butoxy, piperidines-3-base oxygen base, piperidin-4-yl oxygen base, piperidines-3-ylmethoxy, 2-piperidines-3-base oxethyl, the piperidin-4-yl methoxyl group, 2-piperidin-4-yl oxyethyl group, the high piperidines of 2--1-base oxethyl, the high piperidines of 3--1-base propoxy-, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, the high piperazine of 2--1-base oxethyl or the high piperazine of 3--1-base propoxy-
And R wherein
1The optional chain that is selected from following groups that is inserted into of adjacent carbons in arbitrary (2-6C) alkylidene chain in the substituting group separates: O, NH, CH=CH and C ≡ C,
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at each described CH
2Or CH
3Carry one or more chloro groups on the group or be selected from following substituting group: hydroxyl, oxo, amino, methoxyl group, methylsulfonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino-, N-sec.-propyl-N-methylamino-and acetoxyl group,
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: fluoro base, chloro base, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene-dioxy, ethylenedioxy and isopropylidene dioxy base, and R
1Tetramethyleneimine in the substituting group-2-base, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are chosen wantonly and are replaced by following groups N-: methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; 2-trifluoroethyl or cyano methyl
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 oxo substituting group;
(h) m is 1 and R
1It is 2 that group is positioned at 5 or m, and each R
1Group can be identical or different, is positioned at 5-and 7 and each R
1Group is selected from: hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, methylamino-, ethylamino, dimethylamino, diethylin, kharophen, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-4-base oxygen base, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 4-tetramethyleneimine-1-base butoxy, tetramethyleneimine-3-base oxygen base, tetramethyleneimine-2-ylmethoxy, 2-tetramethyleneimine-2-base oxethyl, 3-tetramethyleneimine-2-base propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 4-morpholino butoxy, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 4-piperidino-(1-position only) butoxy, 3-piperidyl oxygen base, 4-piperidyl oxygen base, piperidines-3-ylmethoxy, the piperidin-4-yl methoxyl group, 2-piperidines-3-base oxethyl, 2-piperidin-4-yl oxyethyl group, the high piperidines of 2--1-base oxethyl, the high piperidines of 3--1-base propoxy-, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, the high piperazine of 2--1-base oxethyl, the high piperazine of 3--1-base propoxy-, cyclobutoxy group, cyclopentyloxy and cyclohexyl oxygen base
And R wherein
1Adjacent carbons in arbitrary (2-6C) alkylidene chain in the substituting group is optional to be inserted into the following group of being selected from of this chain separately: O, NH, CH=CH and C ≡ C,
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at each described CH
2Or CH
3Carry one or more chloro groups on the group or be selected from following substituting group: hydroxyl, oxo, amino, methoxyl group, methylsulfonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino-, N-sec.-propyl-N-methylamino-and acetoxyl group,
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: fluoro base, chloro base, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene-dioxy, ethylenedioxy and isopropylidene dioxy base, and R
1Tetramethyleneimine in the substituting group-2-base, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are chosen wantonly and are replaced by following groups N-: methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; 2-trifluoroethyl or cyano methyl
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 oxo substituting group;
(i) m is 2, and each R
1Group can be identical or different, and be positioned at 6-and 7, the R of 6-position
1Group is selected from: hydroxyl, methoxyl group, oxyethyl group and propoxy-, and the R of 7-position
1Group is selected from: methoxyl group, oxyethyl group, propoxy-, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 4-tetramethyleneimine-1-base butoxy, tetramethyleneimine-3-base oxygen base, tetramethyleneimine-2-ylmethoxy, 2-tetramethyleneimine-2-base oxethyl, 3-tetramethyleneimine-2-base propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 4-morpholino butoxy, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 4-piperidino-(1-position only) butoxy, piperidines-3-base oxygen base, piperidin-4-yl oxygen base, piperidines-3-ylmethoxy, 2-piperidines-3-base oxethyl, the piperidin-4-yl methoxyl group, 2-piperidin-4-yl oxyethyl group, the high piperidines of 2--1-base oxethyl, the high piperidines of 3--1-base propoxy-, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, the high piperazine of 2--1-base oxethyl and the high piperazine of 3--1-base propoxy-
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at each described CH
2Or CH
3Carry one or more chloro groups on the group or be selected from following substituting group: hydroxyl, oxo, amino, methoxyl group, methylsulfonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino-, N-sec.-propyl-N-methylamino-and acetoxyl group;
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: fluoro base, chloro base, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene-dioxy, ethylenedioxy and isopropylidene dioxy base, and R
1Tetramethyleneimine in the substituting group-2-base, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are chosen wantonly and are replaced by following groups N-: methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; 2-trifluoroethyl or cyano methyl
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 oxo substituting group;
(j) m is 2, and each R
1Group can be identical or different, is positioned at 5-and 7 and the R of 5-position
1Group is selected from methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-4-base oxygen base, tetramethyleneimine-3-base oxygen base, tetramethyleneimine-2-ylmethoxy, 3-pyrrolidyl oxygen base, 4-piperidyl oxygen base, piperidines-3-ylmethoxy, piperidin-4-yl methoxyl group, cyclobutoxy group, cyclopentyloxy and cyclohexyloxy, and the R of 7-position
1Group is selected from: hydroxyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 4-tetramethyleneimine-1-base butoxy, 2-tetramethyleneimine-2-base oxethyl, 3-tetramethyleneimine-2-base propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 4-morpholino butoxy, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 4-piperidino-(1-position only) butoxy, 2-piperidines-3-base oxethyl, 2-piperidin-4-yl oxyethyl group, the high piperidines of 2--1-base oxethyl, the high piperidines of 3--1-base propoxy-, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, the high piperazine of 2--1-base oxethyl or the high piperazine of 3--1-base propoxy-
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at each described CH
2Or CH
3Carry one or more chloro groups on the group or be selected from following substituting group: hydroxyl, oxo, amino, methoxyl group, methylsulfonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino-, N-sec.-propyl-N-methylamino-and acetoxyl group,
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: fluoro base, chloro base, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene-dioxy, ethylenedioxy and isopropylidene dioxy base, and R
1Tetramethyleneimine in the substituting group-2-base, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are chosen wantonly and are replaced by following groups N-: methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; 2-trifluoroethyl or cyano methyl
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 oxo substituting group;
(k) n is 0;
(l) n is 1 or 2, and each R
3Group can be identical or different, is positioned at 2,5 and/or 6 of 3-methylene-dioxy pyridin-4-yl, and being selected from: halo, trifluoromethyl, cyano group, hydroxyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxyl group;
(m) n is 1 or 2, and each R
3Group can be identical or different, be positioned at 2,5 and/or 6 of 3-methylene-dioxy pyridin-4-yl, and be selected from: fluoro base, chloro base, bromo base, iodo base, trifluoromethyl, cyano group, hydroxyl, methyl, ethyl, vinyl, allyl group, pseudoallyl, ethynyl, 1-proyl, 2-propynyl, methoxyl group and oxyethyl group;
(n) n be 0 or n be 1, and R
3Group is positioned at 2, the 5-of 3-methylene-dioxy pyridin-4-yl or 6, and particularly 5, and be selected from: fluoro base, chloro base, bromo base, trifluoromethyl, cyano group, hydroxyl, methyl, ethyl, methoxyl group and oxyethyl group; With
(o) n is 1, and R
3Group is positioned at 2,5 of 3-methylene-dioxy pyridin-4-yl, and be selected from: fluoro base, chloro base, bromo base, trifluoromethyl, cyano group, hydroxyl, methyl, ethyl, methoxyl group and oxyethyl group.
New compound more particularly of the present invention comprises, for example, and the quinazoline derivant of formula I or its pharmacy acceptable salt, wherein, except as otherwise noted, each Z, m, R
1, n and R
3Have the meaning of any aforementioned qualification, prerequisite is:
(A) R
1Substituting group can only be positioned at 5-, 6-and/or the 7-position of quinazoline ring, and promptly 2-and 8-position are not substituted yet; Or
(B) R
1Substituting group can only be positioned at the 6-and/or the 7-position of quinazoline ring, and promptly 2-, 5-and 8-position are not substituted yet.
The quinazoline derivant that specilization compound of the present invention is formula I or its pharmaceutically-acceptable acid addition, wherein:
Z is O or NH;
M is 1 and R
1It is 2 and R that group is positioned at 5-, 6-or 7-position or m
1Group, it can be identical or different, and be positioned at 5-and 7-position or be positioned at 6-and the 7-position, and each R
1Be selected from hydroxyl, amino, methyl, ethyl, propyl group, butyl, vinyl, ethynyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, pentyloxy, fourth-3-thiazolinyl oxygen base, penta-4-thiazolinyl oxygen base, oneself-5-thiazolinyl oxygen base, fourth-3-alkynyloxy base, penta-4-alkynyloxy base, oneself-5-alkynyloxy base, methylamino, ethylamino, dimethylamino, diethylamino, kharophen, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy group, benzyloxy, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-3-base oxygen base, tetrahydropyran-4-base oxygen base, cyclo propyl methoxy, 2-imidazoles-1-base oxethyl, 3-imidazoles-1-base propoxy-, 2-(1,2, the 3-triazol-1-yl) oxyethyl group, 3-(1,2, the 3-triazol-1-yl) propoxy-, 2-(1,2, the 4-triazol-1-yl) oxyethyl group, 3-(1,2, the 4-triazol-1-yl) propoxy-, pyridine-2-ylmethoxy, the pyridin-3-yl methoxyl group, the pyridin-4-yl methoxyl group, 2-pyridine-2-base oxethyl, 2-pyridin-3-yl oxyethyl group, 2-pyridin-4-yl oxyethyl group, 3-pyridine-2-base propoxy-, 3-pyridin-3-yl propoxy-, 3-pyridin-4-yl propoxy-, tetramethyleneimine-1-base, morpholino, piperidino-(1-position only), piperazine-1-base, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 4-tetramethyleneimine-1-base butoxy, tetramethyleneimine-3-base oxygen base, tetramethyleneimine-2-ylmethoxy, 2-tetramethyleneimine-2-base oxethyl, 3-tetramethyleneimine-2-base propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 4-morpholino butoxy, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 4-piperidino-(1-position only) butoxy, piperidines-3-base oxygen base, piperidin-4-yl oxygen base, piperidines-3-ylmethoxy, the piperidin-4-yl methoxyl group, 2-piperidines-3-base oxethyl, 3-piperidines-3-base propoxy-, 2-piperidin-4-yl oxyethyl group, 3-piperidin-4-yl propoxy-, the high piperidines of 2--1-base oxethyl, the high piperidines of 3--1-base propoxy-, 2-(1,2,3,6-tetrahydropyridine-1-yl) oxyethyl group, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 4-(1,2,3,6-tetrahydropyridine-1-yl) butoxy, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, 4-piperazine-1-base butoxy, the high piperazine of 2--1-base oxethyl, the high piperazine of 3--1-base propoxy-, 2-tetramethyleneimine-1-base ethylamino, 3-tetramethyleneimine-1-base propyl group amino, 4-tetramethyleneimine-1-base butyl amino, tetramethyleneimine-3-base is amino, tetramethyleneimine-2-ylmethyl amino, 2-tetramethyleneimine-2-base ethylamino, 3-tetramethyleneimine-2-base propyl group amino, 2-morpholino ethylamino, 3-morpholino propyl group amino, 4-morpholino butyl amino, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) ethylamino, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propyl group amino, 2-piperidino-(1-position only) ethylamino, 3-piperidino-(1-position only) propyl group amino, 4-piperidino-(1-position only) butyl amino, piperidines-3-base is amino, piperidin-4-yl amino, piperidines-3-ylmethyl amino, 2-piperidines-3-base ethylamino, the piperidin-4-yl methylamino, 2-piperidin-4-yl ethylamino, the high piperidines of 2--1-base ethylamino, the high piperidines of 3--1-base propyl group amino, 2-piperazine-1-base ethylamino, 3-piperazine-1-base propyl group amino, 4-piperazine-1-base butyl amino, the high piperazine of 2--1-base ethylamino or the high piperazine of 3--1-base propyl group amino
And wherein at R
1Contiguous carbon atom on any (2-6C) alkylidene chain in the substituting group is chosen on chain the group that is selected from O, NH, N (Me), CH=CH and C ≡ C by insertion wantonly and is separated,
And work as R
1During for vinyl or ethynyl, R
1The optional CH endways of substituting group
2=or HC ≡ position have and be selected from following substituting group: N-(2-dimethylaminoethyl) formamyl, N-(3-dimethylamino-propyl) formamyl, methylamino-methyl, 2-methylamino-ethyl, 3-methylamino-propyl group, 4-methylamino-butyl, dimethylamino methyl, 2-dimethylaminoethyl, 3-dimethylamino-propyl and 4-dimethylamino butyl, perhaps be selected from the group of following formula:
Q
2-X
2-
X wherein
2Directly be key or for NHCO or N (Me) CO, and Q
2Be imidazolyl methyl, 2-imidazolyl ethyl, 3-imidazolyl propyl group, pyridylmethyl, 2-pyridyl ethyl, 3-pyridyl propyl group, tetramethyleneimine-1-ylmethyl, 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-1-base propyl group, 4-tetramethyleneimine-1-base butyl, tetramethyleneimine-2-ylmethyl, 2-tetramethyleneimine-2-base ethyl, 3-tetramethyleneimine-2-base propyl group, the morpholino methyl, 2-morpholino ethyl, 3-morpholino propyl group, 4-morpholino butyl, the piperidino-(1-position only) methyl, 2-piperidino-(1-position only) ethyl, 3-piperidino-(1-position only) propyl group, 4-piperidino-(1-position only) butyl, piperidines-3-ylmethyl, 2-piperidines-3-base ethyl, the piperidin-4-yl methyl, 2-piperidin-4-yl ethyl, piperazine-1-ylmethyl, 2-piperazine-1-base ethyl, 3-piperazine-1-base propyl group or 4-piperazine-1-base butyl
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at each described CH
2Or CH
3Carry one or more fluoro bases or chloro base on the group or be selected from following substituting group: hydroxyl, oxo, amino, methoxyl group, methylsulfonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino-, N-sec.-propyl-N-methylamino-, N-methyl-N-third amino, acetoxyl group, kharophen and N-methyl kharophen
And R wherein
1Arbitrary phenyl, imidazolyl, triazolyl, pyridyl or heterocyclic radical in the substituting group chosen wantonly has 1 or 2 substituting group; described substituting group can be identical or different; be selected from: fluoro base, chloro base, trifluoromethyl, hydroxyl, amino, formamyl, methyl, ethyl, methoxyl group, oxyethyl group, N-methylamino formyl radical, N; N-formyl-dimethylamino, methylene-dioxy, ethylenedioxy and isopropylidene dioxy base, and R
1Tetramethyleneimine in the substituting group-2-base; piperidines-3-base; piperidin-4-yl; piperazine-1-base or high piperazine-the 1-base is optional to be replaced by following groups N-: allyl group; 2-propynyl; methyl sulphonyl; ethylsulfonyl; ethanoyl; propionyl; isobutyryl; 2-fluoro ethyl; 2; 2-two fluoro ethyls; 2; 2; the 2-trifluoroethyl; 3-fluoro propyl group; 3; 3-two fluoropropyls; 3; 3; the 3-trifluoro propyl; the 2-methoxy ethyl; the 3-methoxy-propyl; cyano methyl; the 2-amino-ethyl; the 3-aminopropyl; 2-methylamino-ethyl; 3-methylamino-propyl group; the 2-dimethylaminoethyl; the 3-dimethylamino-propyl; 2-tetramethyleneimine-1-base ethyl; 3-tetramethyleneimine-1-base propyl group; 2-morpholino ethyl; 3-morpholino propyl group; 2-piperidino-(1-position only) ethyl; 3-piperidino-(1-position only) propyl group; 2-piperazine-1-base ethyl or 3-piperazine-1-base propyl group; in back 8 in these substituting groups each is optional have 1 or 2 can be identical or different be selected from following substituting group: the fluoro base; the chloro base; methyl and methoxyl group
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 oxo substituting group;
N be 0 or n be 1, and R
3Group is positioned at 2, the 5-of 3-methylene-dioxy pyridin-4-yl or 6, and be selected from: fluoro base, chloro base, bromo base, trifluoromethyl, cyano group, hydroxyl, methyl, ethyl, methoxyl group and oxyethyl group.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 2, each R
1Group can be identical or different, and be positioned at 6-and 7 and the R of 6-position
1Group is selected from: hydroxyl, methoxyl group, oxyethyl group and propoxy-, and the R of 7-position
1Group is selected from: methoxyl group, oxyethyl group, propoxy-, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 4-tetramethyleneimine-1-base butoxy, tetramethyleneimine-3-base oxygen base, tetramethyleneimine-2-ylmethoxy, 2-tetramethyleneimine-2-base oxethyl, 3-tetramethyleneimine-2-base propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 4-morpholino butoxy, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 4-piperidino-(1-position only) butoxy, piperidines-3-base oxygen base, piperidin-4-yl oxygen base, piperidines-3-ylmethoxy, 2-piperidines-3-base oxethyl, the piperidin-4-yl methoxyl group, 2-piperidin-4-yl oxyethyl group, the high piperidines of 2--1-base oxethyl, the high piperidines of 3--1-base propoxy-, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, the high piperazine of 2--1-base oxethyl and the high piperazine of 3--1-base propoxy-
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at each described CH
2Or CH
3Carry one or more chloro groups on the group or be selected from following substituting group: hydroxyl, oxo, amino, methoxyl group, methylsulfonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino-, N-sec.-propyl-N-methylamino-and acetoxyl group;
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: fluoro base, chloro base, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene-dioxy, ethylenedioxy and isopropylidene dioxy base, and R
1Tetramethyleneimine in the substituting group-2-base, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are chosen wantonly and are replaced by following groups N-: methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; 2-trifluoroethyl or cyano methyl
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 oxo substituting group;
N be 0 or n be 1, and R
3Group is positioned at 2, the 5-of 3-methylene-dioxy pyridin-4-yl or 6, and be selected from: chloro base, bromo base, trifluoromethyl, cyano group, hydroxyl, methyl, ethyl, methoxyl group and oxyethyl group.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 2, and first R
1Group is the 6-methoxyl group, and described second R
1Group is positioned at 7 and be selected from: 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 2-piperidines-3-base oxethyl, 2-(N-methyl piperidine-3-yl) oxyethyl group, 3-piperidines-3-base propoxy-, 3-(N-methyl piperidine-3-yl) propoxy-, 2-piperidin-4-yl oxyethyl group, 2-(N-methyl piperidine-4-yl) oxyethyl group, 3-piperidin-4-yl propoxy-, 3-(N-methyl piperidine-4-yl) propoxy-, 2-(1,2,3,6-tetrahydropyridine-1-yl) oxyethyl group, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-(4-hydroxy piperidine-1-yl) oxyethyl group, 3-(4-hydroxy piperidine-1-yl) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, 4-piperazine-1-base butoxy, 2-(4-methylpiperazine-1-yl) oxyethyl group, 3-(4-methylpiperazine-1-yl) propoxy-, 4-(4-methylpiperazine-1-yl) butoxy, 2-(4-allyl group piperazine-1-yl) oxyethyl group, 3-(4-allyl group piperazine-1-yl) propoxy-, 2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-, 2-(4-methyl sulphonyl piperazine-1-yl) oxyethyl group, 3-(4-methyl sulphonyl piperazine-1-yl) propoxy-, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 3-(4-ethanoyl piperazine-1-yl) propoxy-, 4-(4-ethanoyl piperazine-1-yl) butoxy, 2-(4-isobutyryl piperazine-1-yl) oxyethyl group, 3-(4-isobutyryl piperazine-1-yl) propoxy-, 4-(4-isobutyryl piperazine-1-yl) butoxy, 2-[4-(2-fluoro ethyl) piperazine-1-yl] oxyethyl group, 3-[4-(2-fluoro ethyl) piperazine-1-yl] propoxy-, 2-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] oxyethyl group, 3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-, 2-(4-cyano methyl piperazine-1-yl) oxyethyl group, 3-(4-cyano methyl piperazine-1-yl) propoxy-, 2-[2-(4-methylpiperazine-1-yl) oxyethyl group] oxyethyl group, 2-chloro oxyethyl group, 3-chloro propoxy-, 4-chloro butoxy, 2-sulfonyloxy methyl base oxethyl, 3-methyl sulphonyl propoxy-, 2-(2-methoxy ethoxy) oxyethyl group, 2-(4-pyridyl oxygen base) oxyethyl group, 3-pyridyl methoxyl group and 2-cyanopyridine-4-ylmethoxy; With
N be 0 or n be 1, and R
3Group is positioned at 2, the 5-of 3-methylene-dioxy pyridin-4-yl or 6-position and be selected from fluoro base, chloro base, bromo base, trifluoromethyl and cyano group.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 2 and first R
1Group is the 6-methoxyl group, and second R
1Group is positioned at the 7-position and is selected from 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 2-(4-methylpiperazine-1-yl) oxyethyl group, 3-(4-methylpiperazine-1-yl) propoxy-, 2-(4-allyl group piperazine-1-yl) oxyethyl group, 3-(4-allyl group piperazine-1-yl) propoxy-, 2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 3-(4-ethanoyl piperazine-1-yl) propoxy-, 2-(4-isobutyryl piperazine-1-yl) oxyethyl group, 3-(4-isobutyryl piperazine-1-yl) propoxy-, 2-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] oxyethyl group and 3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-; With
N is 1 and R
3Group is positioned at 2, the 6-position of 3-methylene-dioxy pyridin-4-yl and be selected from the chloro base and the bromo base.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 2 and each R
1Group can be identical or different, and be positioned at 5-and 7 and the R of 5-position
1Group is selected from: methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-4-base oxygen base, tetramethyleneimine-3-base oxygen base, tetramethyleneimine-2-ylmethoxy, 3-piperidyl oxygen base, 4-piperidyl oxygen base, piperidines-3-ylmethoxy, piperidin-4-yl methoxyl group, cyclobutyl oxygen base, cyclopentyloxy and cyclohexyloxy, and the R of 7-position
1Group is selected from: hydroxyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 4-tetramethyleneimine-1-base butoxy, 2-tetramethyleneimine-2-base oxethyl, 3-tetramethyleneimine-2-base propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 4-morpholino butoxy, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 4-piperidino-(1-position only) butoxy, 2-piperidines-3-base oxethyl, 2-piperidin-4-yl oxyethyl group, the high piperidines of 2--1-base oxethyl, the high piperidines of 3--1-base propoxy-, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, the high piperazine of 2--1-base oxethyl and the high piperazine of 3--1-base propoxy-
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at described CH
2Or CH
3Carry one or more chloro groups on the group or be selected from following substituting group: hydroxyl, oxo, amino, methoxyl group, methylsulfonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino-, N-sec.-propyl-N-methylamino-and acetoxyl group;
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: fluoro base, chloro base, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene-dioxy, ethylenedioxy and isopropylidene dioxy base, R
1Tetramethyleneimine in the substituting group-2-base, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are chosen wantonly and are replaced by following groups N-: methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; 2-trifluoroethyl or cyano methyl
And R wherein
1On substituting group in arbitrary heterocyclic radical optional have 1 or 2 oxo substituting group;
N be 0 or n be 1, and R
3Group is positioned at 2, the 5-of 3-methylene-dioxy pyridin-4-yl or 6, and be selected from: fluoro base, chloro base, bromo base, trifluoromethyl, cyano group, hydroxyl, methyl, ethyl, methoxyl group and oxyethyl group.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 1 and R
1Group is positioned at the 5-position and is selected from oxyethyl group; propoxy-; isopropoxy; butoxy; tetrahydrofuran (THF)-3-base oxygen base; tetrahydropyran-4-base oxygen base; tetramethylene sulfide-3-base oxygen base; 1; 1-dioxo tetramethylene sulfide-3-base oxygen base; tetrahydric thiapyran-4-group oxygen base; 1; 1-dioxo tetrahydric thiapyran-4-group oxygen base; N-methyl azetidine-3-base oxygen base; N-ethyl azetidine-3-base oxygen base; N-sec.-propyl azetidine-3-base oxygen base; tetramethyleneimine-3-base oxygen base; N-methylpyrrolidin-3-base oxygen base; tetramethyleneimine-2-ylmethoxy; 3-piperidyl oxygen base; N-methyl piperidine-3-base oxygen base; 4-piperidyl oxygen base; N-methyl piperidine-4-base oxygen base; N-allyl group piperidin-4-yl oxygen base; N-Propargyl piperidin-4-yl oxygen base; N-ethanoyl piperidin-4-yl oxygen base; N-methyl sulphonyl piperidin-4-yl oxygen base; N-(2-methoxyl group) piperidin-4-yl oxygen base; piperidines-3-ylmethoxy; N-methyl piperidine-3-ylmethoxy; the piperidin-4-yl methoxyl group; N-methyl piperidine-4-ylmethoxy; cyclobutyl oxygen base; cyclopentyloxy and cyclohexyloxy
Or m is 2 and first R
1Group is positioned at the 5-position and is selected from the listed substituting group of the preceding paragraph, and second R
1Group is positioned at the 7-position and is selected from 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 2-piperidines-3-base oxethyl, 2-(N-methyl piperidine-3-yl) oxyethyl group, 3-piperidines-3-base propoxy-, 3-(N-methyl piperidine-3-yl) propoxy-, 2-piperidin-4-yl oxyethyl group, 2-(N-methyl piperidine-4-yl) oxyethyl group, 3-piperidin-4-yl propoxy-, 3-(N-methyl piperidine-4-yl) propoxy-, 2-(1,2,3,6-tetrahydropyridine-1-yl) oxyethyl group, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-(4-hydroxy piperidine-1-yl) oxyethyl group, 3-(4-hydroxy piperidine-1-yl) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, 4-piperazine-1-base butoxy, 2-(4-methylpiperazine-1-yl) oxyethyl group, 3-(4-methylpiperazine-1-yl) propoxy-, 4-(4-methylpiperazine-1-yl) butoxy, 2-(4-allyl group piperazine-1-yl) oxyethyl group, 3-(4-allyl group piperazine-1-yl) propoxy-, 2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-, 2-(4-methyl sulphonyl piperazine-1-yl) oxyethyl group, 3-(4-methyl sulphonyl piperazine-1-yl) propoxy-, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 3-(4-ethanoyl piperazine-1-yl) propoxy-, 4-(4-ethanoyl piperazine-1-yl) butoxy, 2-(4-isobutyryl piperazine-1-yl) oxyethyl group, 3-(4-isobutyryl piperazine-1-yl) propoxy-, 4-(4-isobutyryl piperazine-1-yl) butoxy, 2-[4-(2-fluoro ethyl) piperazine-1-yl] oxyethyl group, 3-[4-(2-fluoro ethyl) piperazine-1-yl] propoxy-, 2-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] oxyethyl group, 3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-, 2-(4-cyano methyl piperazine-1-yl) oxyethyl group, 3-(4-cyano methyl piperazine-1-yl) propoxy-, 2-[2-(4-methylpiperazine-1-yl) oxyethyl group] oxyethyl group, 2-chloro oxyethyl group, 3-chloro propoxy-, 4-chloro butoxy, 2-sulfonyloxy methyl base oxethyl, 3-methyl sulphonyl propoxy-, 2-(2-methoxy ethoxy) oxyethyl group, 2-(4-pyridyl oxygen base) oxyethyl group, 3-pyridyl methoxyl group and 2-cyanopyridine-4-ylmethoxy;
N be 0 or n be 1 and R
3Group is positioned at 2, the 5-of 3-methylene-dioxy pyridin-4-yl or 6-position and be selected from chloro base, bromo base, trifluoromethyl, cyano group, hydroxyl, methyl, ethyl, methoxyl group and oxyethyl group.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 1 and R
1Group is positioned at the 5-position and is selected from propoxy-; isopropoxy; tetrahydrofuran (THF)-3-base oxygen base; tetrahydropyran-4-base oxygen base; tetramethyleneimine-3-base oxygen base; N-methylpyrrolidin-3-base oxygen base; tetramethyleneimine-2-ylmethoxy; 3-piperidyl oxygen base; N-methyl piperidine-3-base oxygen base; 4-piperidyl oxygen base; N-methyl piperidine-4-base oxygen base; N-allyl group piperidin-4-yl oxygen base; N-Propargyl piperidin-4-yl oxygen base; N-ethanoyl piperidin-4-yl oxygen base; N-methyl sulphonyl piperidin-4-yl oxygen base; piperidines-3-ylmethoxy; N-methyl piperidine-3-ylmethoxy; the piperidin-4-yl methoxyl group; N-methyl piperidine-4-ylmethoxy; cyclobutyl oxygen base; cyclopentyloxy and cyclohexyloxy
Or m is 2 and first R
1Group is positioned at the 5-position and is selected from the listed substituting group of the preceding paragraph, and second R
1Group is positioned at the 7-position and is selected from 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 2-piperidines-3-base oxethyl, 2-(N-methyl piperidine-3-yl) oxyethyl group, 3-piperidines-3-base propoxy-, 3-(N-methyl piperidine-3-yl) propoxy-, 2-piperidin-4-yl oxyethyl group, 2-(N-methyl piperidine-4-yl) oxyethyl group, 3-piperidin-4-yl propoxy-, 3-(N-methyl piperidine-4-yl) propoxy-, 2-(1,2,3,6-tetrahydropyridine-1-yl) oxyethyl group, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-(4-hydroxy piperidine-1-yl) oxyethyl group, 3-(4-hydroxy piperidine-1-yl) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, 4-piperazine-1-base butoxy, 2-(4-methylpiperazine-1-yl) oxyethyl group, 3-(4-methylpiperazine-1-yl) propoxy-, 4-(4-methylpiperazine-1-yl) butoxy, 2-(4-allyl group piperazine-1-yl) oxyethyl group, 3-(4-allyl group piperazine-1-yl) propoxy-, 2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-, 2-(4-methyl sulphonyl piperazine-1-yl) oxyethyl group, 3-(4-methyl sulphonyl piperazine-1-yl) propoxy-, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 3-(4-ethanoyl piperazine-1-yl) propoxy-, 4-(4-ethanoyl piperazine-1-yl) butoxy, 2-(4-isobutyryl piperazine-1-yl) oxyethyl group, 3-(4-isobutyryl piperazine-1-yl) propoxy-, 4-(4-isobutyryl piperazine-1-yl) butoxy, 2-[4-(2-fluoro ethyl) piperazine-1-yl] oxyethyl group, 3-[4-(2-fluoro ethyl) piperazine-1-yl] propoxy-, 2-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] oxyethyl group, 3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-, 2-(4-cyano methyl piperazine-1-yl) oxyethyl group, 3-(4-cyano methyl piperazine-1-yl) propoxy-, 2-[2-(4-methylpiperazine-1-yl) oxyethyl group] oxyethyl group, 2-chloro oxyethyl group, 3-chloro propoxy-, 4-chloro butoxy, 2-sulfonyloxy methyl base oxethyl, 3-methyl sulphonyl propoxy-, 2-(2-methoxy ethoxy) oxyethyl group, 2-(4-pyridyl oxygen base) oxyethyl group, 3-pyridyl methoxyl group and 2-cyanopyridine-4-ylmethoxy;
N be 0 or n be 1 and R
3Group is positioned at 2, the 5-of 3-methylene-dioxy pyridin-4-yl or 6-position and be selected from chloro base, bromo base, trifluoromethyl, cyano group, hydroxyl, methyl, ethyl, methoxyl group and oxyethyl group.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 1 and R
1Group is positioned at the 5-position and is selected from propoxy-, isopropoxy, tetrahydropyran-4-base oxygen base, 4-piperidyl oxygen base and N-methyl piperidine-4-base oxygen base,
Or m be 2 and first R1 group be positioned at the 5-position and be selected from the listed substituting group of the preceding paragraph, and second R1 group is positioned at the 7-position and is selected from 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, 4-piperazine-1-base butoxy, 2-(4-methylpiperazine-1-yl) oxyethyl group, 3-(4-methylpiperazine-1-yl) propoxy-, 2-(4-allyl group piperazine-1-yl) oxyethyl group, 3-(4-allyl group piperazine-1-yl) propoxy-, 2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 3-(4-ethanoyl piperazine-1-yl) propoxy-, 2-(4-isobutyryl piperazine-1-yl) oxyethyl group, 3-(4-isobutyryl piperazine-1-yl) propoxy-, 2-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] oxyethyl group and 3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-; With
N be 0 or n be 1, and R
3Group is positioned at 2, the 5-of 3-methylene-dioxy pyridin-4-yl or 6-position and be selected from fluoro base, chloro base, bromo base, trifluoromethyl and cyano group.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 2 and first R
1Group is positioned at the 5-position and is selected from isopropoxy and tetrahydropyran-4-base oxygen base, and second R
1Group is positioned at the 7-position and is selected from 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, 2-(4-methylpiperazine-1-yl) oxyethyl group, 3-(4-methylpiperazine-1-yl) propoxy-, 2-(4-allyl group piperazine-1-yl) oxyethyl group, 3-(4-allyl group piperazine-1-yl) propoxy-, 2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 3-(4-ethanoyl piperazine-1-yl) propoxy-, 2-(4-isobutyryl piperazine-1-yl) oxyethyl group, 3-(4-isobutyryl piperazine-1-yl) propoxy-, 2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group, 3-[4-(2-hydroxyethyl) piperazine-1-yl] propoxy-, 2-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] oxyethyl group, 3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-, 2-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] oxyethyl group and 3-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] propoxy-; With
N is 1 and R
3Group is positioned at 2, the 5-position of 3-methylene-dioxy pyridin-4-yl and be selected from the chloro base and the bromo base.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 2 and first R
1Group is positioned at the 5-position and is selected from isopropoxy and tetrahydropyran-4-base oxygen base, and second R
1Group is positioned at the 7-position and is selected from 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 2-(4-methylpiperazine-1-yl) oxyethyl group, 3-(4-methylpiperazine-1-yl) propoxy-, 2-(4-allyl group piperazine-1-yl) oxyethyl group, 3-(4-allyl group piperazine-1-yl) propoxy-, 2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 3-(4-ethanoyl piperazine-1-yl) propoxy-, 2-(4-isobutyryl piperazine-1-yl) oxyethyl group, 3-(4-isobutyryl piperazine-1-yl) propoxy-, 2-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] oxyethyl group and 3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-; With
N is 1 and R
3Group is positioned at 2, the 5-position of 3-methylene-dioxy pyridin-4-yl and be selected from the chloro base and the bromo base.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 2 and first R
1Group is positioned at the 5-position and is selected from isopropoxy and tetrahydropyran-4-base oxygen base, and second R
1Group is positioned at the 7-position and is selected from 2-tetramethyleneimine-1-base oxethyl, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-piperidino-(1-position only) oxyethyl group, 2-piperazine-1-base oxethyl, 2-(4-methylpiperazine-1-yl) oxyethyl group, 2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group and 2-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] oxyethyl group; With
N is 1 and R
3Group is positioned at 2, the 5-position of 3-methylene-dioxy pyridin-4-yl and be the chloro group.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 2 and first R
1Group is positioned at the 5-position and is selected from isopropoxy and tetrahydropyran-4-base oxygen base, and second R
1Group is positioned at the 7-position and is selected from 2-tetramethyleneimine-1-base oxethyl, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 2-morpholino oxyethyl group, 2-piperidino-(1-position only) oxyethyl group, 2-piperazine-1-base oxethyl, 2-(4-methylpiperazine-1-yl) oxyethyl group, 2-(4-Propargyl piperazine-1-yl) oxyethyl group, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group and 2-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] oxyethyl group; With
N is 1 and R
3Group is positioned at 2, the 5-position of 3-methylene-dioxy pyridin-4-yl and be the chloro group.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 2 and first R
1Group is a 5-isopropoxy group, and second R
1Group is positioned at the 7-position and is selected from 2-tetramethyleneimine-1-base oxethyl, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 2-morpholino oxyethyl group, 2-piperidino-(1-position only) oxyethyl group, 2-piperazine-1-base oxethyl, 2-(4-methylpiperazine-1-yl) oxyethyl group, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group and 2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group; With
N is 1 and R
3Group is positioned at 2, the 5-position of 3-methylene-dioxy pyridin-4-yl and be the chloro group.
Special more compound of the present invention is quinazoline derivant or its pharmaceutically-acceptable acid addition of formula I, wherein:
Z is NH;
M is 2 and first R
1Group is a 5-isopropoxy group, and second R
1Group is positioned at the 7-position and is selected from 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 2-piperazine-1-base oxethyl, 2-(4-methylpiperazine-1-yl) oxyethyl group, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group and 2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group; With
N is 1 and R
3Group is positioned at 2, the 5-position of 3-methylene-dioxy pyridin-4-yl and be the chloro group.
Particular compound of the present invention is, for example, and the quinazoline derivant of disclosed formula I in after this embodiment 3 and embodiment 6 (1)-6 (7).
Particular compound of the present invention is for example, to be selected from the quinazoline derivant of following formula I:
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group-7-[3-(4-Propargyl piperazine-1-yl) propoxy-] quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-[3-(4-isobutyryl piperazine-1-yl) propoxy-]-6-methoxyl group quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group-7-{3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-quinazoline and
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group-7-[2-(4-Propargyl piperazine-1-yl) oxyethyl group] quinazoline;
Or its pharmaceutically-acceptable acid addition.
Special more compound of the present invention is for example, to be selected from the quinazoline derivant of following formula I:
7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-tetrahydropyran-4-base oxygen base quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-{2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group }-5-tetrahydropyran-4-base oxygen base quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-[2-(4-Propargyl piperazine-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-[3-(4-Propargyl piperazine-1-yl) propoxy-]-5-tetrahydropyran-4-base oxygen base quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(2-morpholino oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline and
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-morpholino propoxy-)-5-tetrahydropyran-4-base oxygen base quinazoline;
Or its pharmaceutically-acceptable acid addition.
Special more compound of the present invention is for example, to be selected from the quinazoline derivant of following formula I:
7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(2-piperazine-1-base oxethyl) quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-{2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group }-5-isopropoxy quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(2-tetramethyleneimine-1-base oxethyl) quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(2-piperidino-(1-position only) oxyethyl group) quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(2-morpholino oxyethyl group) quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(3-morpholino propoxy-) quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-[2-(4-Propargyl piperazine-1-yl) oxyethyl group] quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-[2-(4-methylpiperazine-1-yl) oxyethyl group] quinazoline and
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-{2-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] oxyethyl group }-5-isopropoxy quinazoline;
Or its pharmaceutically-acceptable acid addition.
Can be according to known quinazoline derivant or its pharmacy acceptable salt that is used to prepare any suitable method preparation formula I of the relevant compound of chemistry.When being used for the quinazoline derivant of preparation formula I, these methods have constituted another aspect of the present invention, and these methods can be described with the alternative of exemplary process described below, and except that specializing, that adopts in these methods meets m, R
1, Z, n and R
3Having the front limits in all senses.Necessary raw material can adopt the organic chemistry standard method to obtain.In conjunction with the alternative of following exemplary process and the embodiment that provides, the applicant also is described the preparation of this type of raw material.Perhaps, also can adopt with the similar method of described method and obtain required raw material, these methods are in the those of ordinary skill ken of organic chemistry filed.
(a) Z is O, S or N (R in order to prepare wherein
2) those formulas I compound of group, make the quinazoline of formula II:
In formula II, L is a displaceable group, and m and R
1Have the aforementioned meaning that limits, but where necessary any functional group is protected, and the compound reaction of formula III:
Wherein Z is O, S or N (R
2), and n, R
2And R
3Have the aforementioned meaning that limits, but where necessary any functional group is protected, after this remove any blocking group of existence by ordinary method.
This method is convenient carries out in the presence of suitable sour or suitable alkali.Suitable acid is as mineral acid, such as hydrogenchloride or hydrogen bromide.Suitable alkali is as organic amine alkali, such as pyridine, 2, and 6-lutidine, collidine, 4-Dimethylamino pyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.4.0] 11 carbon-7-alkene; Perhaps be carbonate or oxyhydroxide, such as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide as basic metal or alkaline-earth metal; Perhaps be as alkali metal ammonia compound, hexamethyldisilane base ammonification sodium (sodium hexamethyldisilazane) for example, perhaps for example, alkalimetal hydride, for example sodium hydride.
Suitable displaceable group L is, as halo, alkoxyl group, aryloxy or alkylsulfonyl oxygen base, such as chloro base, bromo base, methoxyl group, phenoxy group, penta fluoro benzene oxygen base, methylsulfonyl oxygen base or toluene-4-alkylsulfonyl oxygen base.This reaction is carried out in the presence of suitable inert solvent or thinner respectively, and described solvent or thinner are as alcohol or ester, such as methyl alcohol, ethanol, Virahol or ethyl acetate; Halogenated solvent such as methylene dichloride, chloroform or tetracol phenixin; Ester such as tetrahydrofuran (THF) or 1, the 4-dioxane; Aromatic solvent such as toluene, or dipolar aprotic solvent such as N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO).This reaction is respectively temperature such as 0-250 ℃, preferably carry out in 0-120 ℃ of scope.
Usually, can pass through at aprotic solvent such as N, there is down, is preferably in alkali in dinethylformamide as in the presence of salt of wormwood or hexamethyldisilane base ammonification sodium and temperature such as 0-150 ℃, preferably in 0-70 ℃ of temperature range, and the quinazoline of formula II and formula III compound are reacted.
The quinazoline derivant of the formula I that is obtained by this method can be free alkali form, also can for the form of the salt of the acid of formula H-L, in formula H-L, L has the meaning that the front limits.When needs obtain free alkali by described salt, can be with this salt with suitable alkali such as organic amine alkali (such as pyridine, 2,6-lutidine, collidine, 4-Dimethylamino pyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.4.0] 11 carbon-7-alkene), perhaps use carbonate or oxyhydroxide (such as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide) processing to obtain as basic metal or alkaline-earth metal.
Generally speaking, blocking group can be selected from any group that is suitable for protecting functional group to be protected that describe in the document or well known by persons skilled in the art, and can adopt ordinary method to introduce blocking group.Remove blocking group according to any method easily that is suitable for removing blocking group to be removed that describe in the document or well known by persons skilled in the art; these class methods are selected, and principle is that this method can remove described blocking group and simultaneously to the minimum that influences of the group of other positions in the related molecule.
For simplicity, provide the example of concrete blocking group below, wherein " rudimentary " (as in low alkyl group) representative preferably has the group of 1-4 carbon atom.Be appreciated that these examples are not to enumerate one by one.The concrete example of the method that removes blocking group that provides equally, below is not to enumerate one by one yet.The using method and the removal methods thereof that it will be appreciated, of course, that the blocking group of specifically not mentioning are also included within the scope of the invention.
Carboxy protective group can be the aliphatic series of formation ester or the residue of aromatic grease group alcohol, is the residue that forms the silanol of ester perhaps, and described pure and mild silanol preferably has 1-20 carbon atom.The example of carboxy protective group comprises straight chain and side chain (1-12C) alkyl (as the sec.-propyl and the tertiary butyl); Lower alkoxy-low alkyl group (as methoxymethyl, ethoxyl methyl and isobutoxy methyl); Low-grade acyloxy-low alkyl group (as acetoxy-methyl, propionyl oxygen ylmethyl, butyryl radicals oxygen ylmethyl and valeryl oxygen ylmethyl); Elementary alkoxy carbonyl oxygen base-low alkyl group (as 1-methoxycarbonyl oxygen base ethyl and 1-ethoxy carbonyl oxygen base ethyl); Aryl lower alkyl (as benzyl, 4-methoxy-benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-methyl and phthalidyl); Three (low alkyl group) silyl (as trimethyl silyl and tert-butyl dimetylsilyl); Three (low alkyl group) silyl-low alkyl group (as the trimethyl silyl ethyl); And (2-6C) alkenyl (as allyl group).The method that is particularly suitable for removing carboxy protective group comprises, as acid-, alkali-, metal-or enzyme-catalytic scission reaction.
The example of hydroxy-protective group comprises low alkyl group (as tert-butyl), low-grade alkenyl (as allyl group); Low-grade alkane acidyl (as ethanoyl); Elementary alkoxy carbonyl (as uncle-butoxy carbonyl); Low-grade alkenyl oxygen base carbonyl (as allyl group oxygen base carbonyl); The aryl-lower alkoxy carbonyl is (as benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro benzyloxycarbonyl and 4-; The nitro benzyloxycarbonyl); Three (low alkyl group) silyl (as trimethyl silyl and tert-butyl dimetylsilyl) and aryl lower alkyl (as benzyl).
The example of amido protecting group comprises formyl radical, aryl lower alkyl (as benzyl, 4-methoxy-benzyl, the 2-nitrobenzyl and 2 of benzyl and replacement, 4-dimethoxy-benzyl and trityl group); Two-4-anisyl methyl and furyl methyl; Elementary alkoxy carbonyl (as uncle-butoxy carbonyl); Low-grade alkenyl oxygen base carbonyl (as allyl group oxygen base carbonyl); Aryl-lower alkoxy carbonyl (as benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro benzyloxycarbonyl and 4-nitro benzyloxycarbonyl); Trialkylsilkl (as trimethyl silyl and tert-butyl dimetylsilyl); The benzylidene of alkylidene group (as methylene radical) and benzylidene and replacement.
The appropriate means that removes hydroxyl and amido protecting group comprise as acid-, alkali-, metal-or the hydrolysis reaction (as the hydrolysis reaction of 2-nitro benzyloxycarbonyl) of enzyme-catalytic group, the photolysis of the hydrogenation of group such as benzyl and group such as 2-nitro benzyloxycarbonyl.
About the guide of reaction conditions and reagent, the reader can be referring to Advanced OrganicChemistry, the 4th edition, is edited by J.March, by John Wiley ﹠amp; Sons publishes in 1992, and about the general guide of blocking group, then can be referring to Protective Groups inOrganic Synthesis, the 2nd edition, by editors such as T.Green, by John Wiley﹠amp; Son publishes.
The quinazoline raw material of formula II can adopt ordinary method, obtains as those disclosed method in No. 02/16352, International Patent Application WO 01/94341 and WO.For example, make 1 of formula IV, 4-dihydroquinazoline-4-ketone:
Wherein m and R
1Have the meaning that the front limits, but when needing, any functional group protected, can with the mixture reaction of halogenating agent such as thionyl chloride, phosphoryl chloride or tetracol phenixin and triphenyl phosphine, after this, adopt ordinary method to remove the blocking group of existence.
When needing, by suitable alkali such as salt of wormwood and appropriate solvent as, N, dinethylformamide exist down and react with Pentafluorophenol, can make the 4-chloro-quinazoline that so obtains be converted into 4-penta fluoro benzene oxygen base quinazoline.
4-amino-2,3-(methylenedioxy) yl pyridines starting raw material (formula III is for example when Z is NH) can obtain by the ordinary method as explanation in an embodiment.Corresponding 4-hydroxyl-and 4-sulfydryl-2,3-(methylenedioxy) yl pyridines starting raw material (formula III is when Z is respectively O or S) can obtain by ordinary method.
(b) prepare wherein at least one R
1Group is Q
1-X
1-those compounds of formula I the time, in the formula, Q
1Be the alkyl of the alkyl of the alkyl of the alkyl of aryl-(1-6C), (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group-(1-6C), heteroaryl-(1-6C) or heterocyclic radical-(1-6C) alkyl or the optional alkyl that replaces, and X
1Be Sauerstoffatom, make the quinazoline of following formula V:
Wherein m, R
1, Z, n and R
3Have the meaning that the front limits, when still needing functional group is protected, be preferably in suitable dewatering agent and exist down and suitable pure coupling, when needing any functional group in the alcohol is protected, after this remove any blocking group of existence by ordinary method.
Suitable dewatering agent is as carbodiimide reagent, such as dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide or be the mixture of azo-compound (as diethylazodicarboxylate or azo-2-carboxylic acid's di-tert-butyl) and phosphine (triphenyl phosphine).This reaction is preferably in suitable inert solvent or thinner and exists down, carries out at temperature such as 10-150 ℃ (preferably at room temperature or near room temperature), and described inert solvent or thinner are as halogenated solvent, such as methylene dichloride, chloroform or tetracol phenixin.
Above-mentioned reaction is preferably in suitable inert solvent or thinner and exists down, carries out at temperature such as 10-150 ℃ (preferably at room temperature or near room temperature), and described inert solvent or thinner are as halogenated solvent, such as methylene dichloride, chloroform or tetracol phenixin.
(c) in order to prepare that R1 group wherein has (1-6C) alkoxy base of (1-6C) alkoxyl group or replacement or (1-6C) during the formula I compound of (1-6C) alkylamino of alkylamino or replacement, the suitable alkali that is preferably in as preceding definition exists down, makes the quinazoline derivant of formula VI:
Wherein L is displaceable group and Z, n and the R as preceding definition
3Meaning with any aforementioned qualification except protecting any functional group in case of necessity, with suitable alcohol or amine reaction, is after this removed any blocking group of existence by conventional methods.
This reaction is preferably in the suitable inert diluent of aforementioned definitions or carrier exists down, in temperature 10-150 ℃ (preferably 50 ℃ or near 50 ℃ temperature under) carry out.
(d) in order to prepare wherein R
1Be those formulas I compound of (1-6C) alkoxy base (as 2-(4-methylpiperazine-1-yl) oxyethyl group or 3-dimethylamino propoxy group) of amino-replacement, make the compound (R wherein of formula I
1(1-6C) alkoxy base for halo-replacement) with nitrogen heterocyclic ring based compound or suitable amine reaction.
This reaction is preferably in as the suitable inert diluent of preceding definition or carrier and exists down, in 10-180 ℃ temperature range, preferably carries out in 60-120 ℃ of scope.
(e) in order to prepare wherein R
1Those formulas I compound for amino-hydroxyl-dibasic (1-6C) alkoxy base (as 2-hydroxyl-3-tetramethyleneimine-1-base propoxy-or 3-[N-allyl group-N-methylamino]-2-hydroxyl propoxy-) makes wherein R
1Group contains compound group and heterocyclyl compounds or the suitable amine reaction of the formula I of epoxy-replacement (1-6C) alkoxyl group.
This reaction is preferably in as the suitable inert diluent of preceding definition or carrier and exists down, and (under the preferred room temperature or near the room temperature) carries out in 10-150 ℃ temperature range.
(f) Z is SO or SO in order to prepare wherein
2Those formulas I compound of group, oxidation wherein Z are the formula I compound of S group.
The oxygenant and the reaction conditions of routine that is used for so partially or completely oxidation of sulphur atom is that the organic chemist knows.
(g) in order to prepare wherein R
1Group contains those formulas I compound of the heterocyclic radical of N-acidylate, and the suitable alkali that is preferably in as preceding definition exists down, and acidylate is R wherein
1Group contains the quinazoline derivant of the formula I of the heterocyclic radical with unsubstituted NH group.
Suitable acidylate base is well known to those skilled in the art, and the example has description in an embodiment.For example, R wherein
1Group contains the formula I compound of piperidyl with unsubstituted NH group or piperazinyl can be under normal condition and optional carboxylic acid or its activity derivatives reaction that replaces.
The suitable reactive derivative of the optional carboxylic acid that replaces is, for example, and carboxylic acid halides; Carboxylic acid amide; Mixed acid anhydrides, for example acid anhydrides of carboxylic acid and carbonochloridic acid ester such as carbonochloridic acid isobutyl reaction formation; The reaction product of carboxylic acid and carbodiimide such as dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide; The reaction product of the mixture of the azodicarboxylate of carboxylic acid and azo-compound such as diethyl or two-tertiary butyl and phosphine such as triphenyl phosphine; Or carboxylic acid and urea salt such as 2-(7-azepine benzo triazol-1-yl)-1,1,3, the reaction product of 3-tetramethyl-urea hexafluorophosphate (V).For example, the carboxylic acid of suitable amino-replacement is N, and N-N-methylsarcosine and its suitable reactive derivative are 2-dimethylamino Acetyl Chloride 98Min..
This reaction is preferably in as the suitable inert diluent of preceding definition or carrier and exists down, and (under the preferred room temperature or near the room temperature) carries out in 10-150 ℃ temperature range.
When needs, the pharmacy acceptable salt of the quinazoline derivant of formula I, acid salt for example, it can adopt ordinary method for example to pass through, and makes described quinazoline derivant and suitable acid-respons and obtains.
Many intermediates of this paper definition are new, thereby provide as additional features of the present invention.For example, many formula III compounds are new compound:
Wherein Z is O, S or N (R
2) and n, R
3And R
2Meaning with any aforementioned qualification.For example, though 4-amino-2,3-(methylenedioxy) yl pyridines starting raw material (formula III, for example when Z is NH) can obtain by ordinary method as explanation in an embodiment, compound such as 4-amino-5-chloro-2,3-(methylenedioxy) yl pyridines is new compound, and it provides as additional features of the present invention.
Biology is measured
Below measuring method can be used for detecting compound of the present invention as the c-Src tyrosine kinase inhibitor, as the inhibitor of the fibroblast proliferation of external c-Src transfection, as the inhibitor of external A549 human lung cancer cell migration, organize heterograft inhibitor in the body that nude mice grows as A549, and be used for usefulness at the potassium channel of vitro inhibition hERG-coding.
(a) vitro enzyme is measured
Adopt conventional Elisa assay method, estimate test-compound and suppress the ability that the c-Src kinases makes the peptide substrate phosphorylation that contains tyrosine.
With substrate solution [100 μ l, 20 μ g/ml amino acids Poly (Glu, Tyr) phosphate buffered saline buffer (PBS) solution of 4:1 (SigmaCatalogue No.P0275), contain the 0.2mg/ml sodiumazide] add in each hole of a plurality of Nunc 96 hole immunization test boards (Catalogue No.439454), seal described plate and placed 16 hours in 4 ℃.Discard excessive substrate solution, each equal portions bovine serum albumin (BSA, the PBS solution of 150 μ l 5%) is transferred in each mensuration hole of substrate bag quilt, under room temperature, hatch 1 hour with the blocking-up non-specific binding.With each hole of PBS (PBST) that contains 0.05%v/v Tween 20 and Hepes pH7.4 damping fluid (50mM, 300 μ l/ holes) washing assay plate, blot then successively.
Test-compound is dissolved in the dimethyl sulfoxide (DMSO), is serial dilutions (100 μ M-0.001 μ M) with distilled water diluting.In each hole of the assay plate of washing, add various test-compound diluent equal portions liquid (25 μ l).Contain the DMSO of dilution in " fully " control wells, and do not contain test-compound.To all equal portions liquid (25 μ l) that is subjected to add in the prospect hole magnesium chloride brine (80mM) that contains adenosine-5 '-triphosphoric acid (ATP, 40 μ M), contain magnesium chloride solution in " blank " control wells, and do not contain ATP.
With at once preceding, with the active people c-Src of 1: 10000 usefulness enzyme diluted kinases (at the recombinase of Sf9 expressed in insect cells, derive from Upstate Biotechnology Inc.product14-117), described enzyme diluent contains 100mM Hepes pH7.4 damping fluid, 0.2mM sodium orthovanadate, 2mM dithiothreitol (DTT) and 0.02%BSA.The equal portions liquid (50 μ l) that adds the enzyme of new dilution in each hole starts reaction, with assay plate in incubated at room 20 minutes.Discard the supernatant liquor in each hole, wash each hole twice with PBST.With 1: 6000 proportion factor, the PBST dilution anti-phosphotyrosine antibody of mouse IgG (UpstateBiotechnology Inc.product 05-321,100 μ l) with containing 0.5%w/v BSA added in each hole then.Each assay plate was hatched under room temperature 1 hour.Abandoning supernatant is washed each Kong Sici (* 4) with PBST.With 1: 500 proportion factor, PBST dilution horseradish peroxidase (the HRP)-bonded sheep anti-mouse Ig antibody (Amersham Catalogue No.NXA 931,100 μ l) with containing 0.5%w/v BSA added in each hole then.Each assay plate was hatched under room temperature 1 hour.Abandoning supernatant is washed each Kong Sici (* 4) with PBST.
(Sigma Catalogue No.P4922) is dissolved in the distilled water (100ml) with the PCSB capsule, obtains containing the damping fluid (50mM) of the phosphate-citrate salts pH5 of 0.03% Sodium peroxoborate.With the equal portions liquid (50ml) and 2 of 50mg/ sheet of this damping fluid, two (3-ethyl benzo thiazole phenanthroline-6-sulfonic acid) (ABTS, Boehringer Catalogue No.1204 521) are mixed for 2 '-azine.The equal portions liquid (100 μ l) that in each hole, adds the solution that obtains.Then plate was hatched under room temperature 20-60 minute, read the plate spectrophotometer till the optical density value of measuring " fully " control wells under the 405nm is about 1.0 until employing." blank " (no ATP) and " fully " (no compound) control value are used for measuring the dilution range of the test compounds that provides the inhibition of 50% enzymic activity.
(b) the NIH 3T3 of external c-Src transfection (c-src 3T3) fibroblast proliferation is measured
This measure to detect the ability that test-compound suppresses National Institute of Health (NIH) mouse 3T3 fibroblast proliferation, chosen activation mutant (Y530F) stable transfection of c-Src of described inoblast.
Adopt with Shalloway etc. at Cell, 1987,49, similar method described in the 65-73, activation mutant (Y530F) the transfection NIH 3T3 cell of personnel selection c-Src.Generally be that the c-Src 3T3 cell that will produce is with every hole 1.5 * 10
4Respectively containing in each hole of measuring substratum of the limpid mensuration culture plate (Costar) that individual cell inoculation is handled in 96 hole tissue culture mediums, described mensuration substratum comprises Eagle nutrient solution (DMEM, Sigma)+0.5% foetal calf serum (FCS), 2mM glutamine, 100 units/ml penicillin and the solution of 0.1mg/ml Streptomycin sulphate in 0.9% sodium chloride aqueous solution of Dulbecco improvement.With assay plate under 37 ℃, at humidifying (7.5%CO
2: overnight incubation in the incubator 95% air).
Test-compound is dissolved among the DMSO, is prepared as the 10mM storing solution.Dilute each equal portions storing solution and add in each suitable hole with above-mentioned DMEM nutrient solution.Carry out serial dilution to obtain the test-compound of finite concentration scope.In each assay plate, be provided with the control wells that does not contain test-compound.With assay plate under 37 ℃, at humidifying (7.5%CO
2: overnight incubation in the incubator 95% air).
With 1: 100 ratio factor, with the reagent (Boehringer Mannheim Catalogue No.647 229) of the DMEM nutrient solution dilution BrdU mark that contains 0.5%FCS, get 20 μ l equal portions test solutions and add in each hole, making final concentration is 10 μ M.Each plate was hatched 2 hours in 37 ℃.Discard nutrient solution.In each hole, add denaturing soln (FixDenat solution, BoehringerMannheim Catalogue No.647 229; 50 μ l), Jiang Geban places last 45 minute of oscillator plate under the room temperature.Abandoning supernatant is washed each hole with PBS (the every hole of 200 μ l/).Ratio factor with 1: 100, with containing 1%BSA and 0.025% dried skim-milk (Marvel (registered trademark), Premier Beverages, Stafford, GB) PBS dilution resists-BrdU-superoxide enzyme solution (Boehringer Mannheim Catalogue No.647 229), adds the equal portions test solution (100 μ l) of the solution that obtains in each hole.Each plate is placed last 90 minute of oscillator plate under the room temperature.With each hole of PBS thorough washing 5 times to guarantee to remove unconjugated antibody conjugates.Blot each plate, in each hole, add tetramethyl benzidine substrate solution (Boehringer MannheimCatalogue No.647 229,100 μ l).Jolting flat board gently on oscillator plate produced color simultaneously in 10-20 minute.Measure the absorption value in each hole in the 690nm place.Calculate the inhibition degree of each test-compound on cell proliferation in being tried concentration range and calculate antiproliferative IC thus
50Value,
(c) external droplet migration is measured
This measures the ability that test-compound suppresses adhesion mammal cell line such as human tumor cell line A549 migration that detects.
The RPMI nutrient solution (Sigma) that will contain 10%FCS, 1%L-glutamine and 0.3% agarose (Difco CatalogueNo.0142-01) is warmed to 37 ℃ in water-bath.The storing solution of the 2% agar equal portions aqueous solution is carried out autoclaving and in 42 ℃ of storages.With at once preceding, in RPMI nutrient solution (10ml), add the equal portions liquid of 1.5ml agar-agar soln.With A549 cell (preserving number ATCC CCL185) with 2 * 10
7The concentration of individual cell/ml is suspended in the nutrient solution, in 37 ℃ of preservations.
Get 2 μ l cell/agarose mixtures with dropper and be transferred to flat each the hole central authorities of microdetermination plate (Bibby Sterilin Catalogue No.642000) in a plurality of 96 holes without tissue culture medium's processing.Each plate is placed fast the gelling that contains the drop of agarose on ice with acceleration.The equal portions liquid (90 μ l) that will be cooled to 4 ℃ nutrient solution subsequently is transferred in each hole, and droplet is not disturbed in careful adding.According to above-mentioned DMSO storing solution with RPMI nutrient solution dilution 10mM test-compound.In each hole, add the equal portions liquid (10 μ l) of the test-compound of dilution, and note not disturbing droplet.With each plate in 37 ℃, humidifying (7.5%CO
2: 95% air) hatch about 48 hours in the incubator.
Visual assessment migration is measured as the distance of migration with the distance of agar drop edge.By will on average moving and the concentration of the test-compound IC that migration suppresses that derives that maps
50
(d) A549 xenotransplantation growth measurement in the body
This test detection compound suppresses the ability of A549 people's cancer growth, described cancer in nude mouse (Alderley Park nu/nu strain) as tumor growth.Be injected at total about 5 * 10 among the matrigel (Beckton Dickinson Catalogue No.40234) by subcutaneous at the left rib that is respectively tried mouse
6Individual A549 cell makes about 14 days of the tumor growth of formation.Adopt vernier callipers to measure tumour size twice and theory of computation volume weekly.Select animal, make the mean tumour volume of control group and treatment group approximately equal.Test-compound is prepared as the ball milling suspension of 1% polysorbate solvent, every day per os give 1 time about 28 days.Assessing compound is to the effect of tumor growth.
(e) the potassium channel analysis of hERG-coding
This assay determination test compound suppresses the ability of tail current by the potassium channel of hERG-coding.
Make human embryo kidney (HEK) (HEK) cell of the passage of expressing the hERG-coding grow in Eagle ' s minimum essential medium (EMEM; Sigma-Aldrich classification number M2279), this culture medium supplemented has 10% foetal calf serum (Labtech International; Production number 4-101-500), 10%M1 serum-free fill-in (Egg Technologies; Production number 70916) and 0.4mg/ml GeneticinG418 (Sigma-Aldrich classification number G7034).Test the day before yesterday or two days each, adopt the normal structure cultural method, cell is broken away from from tissue culture flasks with Accutase (TCS Biologicals).Then they are positioned on the cover glass that rests on each hole on 12 orifice plates and and cover with the 2ml growth medium.
For every hole of record, under room temperature (about 20 ℃), the cover glass that will contain cell places the bottom (seeing below) of containing the Perspex chamber (chamber) of bathing solution (bath solution).This chamber is fixed on the platform of inverted phase contrast microscope.After being positioned over cover plate on the chamber,, will bathe solution immediately from gravity filling storage storehouse in the flood chamber 2 minutes with about 2ml/ minute speed.After this, stop to inject.
Use P-97 micropipet Bottle stopper puller (Sutter Instrument Co.), transfer pipet solution (seeing below) is filled into the diaphragm transfer pipet of making by borosilicate glass tube (patchpipette) (GC120F, Harvard Apparatus).Transfer pipet is connected to the head of patch clamp amplifier (amplifier) (Axopatch 200B, Axon Instruments) by silver/silver chloride pipeline.The bottom (ground) of head is connected in the earth polar.This is made up of the silver/silver chloride pipeline that is embedded in 3% agar, and described agar is made up of 0.85% sodium-chlor.
Cell record is in the full cell table shape at patch clamping technique." cutting off (break in) ", promptly keeping-voltage (through the amplifier setting) of 80mV, and carry out after the control of the suitable adjustment of series resistance and electric capacity, adopt electrophysiology software (Clampex, Axon Instruments) to keep voltage (80mV) and the transfer overvoltage scheme with setting.Used this scheme in per 15 seconds, and by 1 second step to+40mV, then formed to-50mV in 1 second.Current-responsive to each voltage schemes that applies is low filtering by the amplifier of 1kHz.Then by making and the filterable excessively signal of online acquisition from this analog signal digital of amplifier with analog digital transmodulator.On the computer (Axon Instruments) of operation Clampex software, catch digitized signal then.Keeping voltage and stepping (step to) during+40mV, in the 1kHz sampling current.To remaining voltage schemes, sampling rate is arranged on 5kHz then.
Composition, pH and the infiltration volumetric molar concentration of bath and transfer pipet solution are listed as follows.
| Salt | Transfer pipet liquid (mM) | Body lotion (mM) |
| Sodium-chlor | - | 137 |
| Repone K | 130 | 4 |
| Magnesium chloride | 1 | 1 |
| Calcium chloride | - | 1.8 |
| HEPES | 10 | 10 |
| Glucose | - | 10 |
| Na 2ATP | 5 | - |
| EGTA | 5 | - |
| Parameter | Transfer pipet liquid | Body lotion |
| pH | 7.18-7.22 | 7.40 |
| PH regulator | 1M potassium hydroxide | 1M sodium hydroxide |
| Infiltration volumetric molar concentration (mOsm) | 275-285 | 285-295 |
After the stepping from+40mV to-50mV, the amplitude of the potassium channel tail current of hERG-coding is through Clampex software (Axon Instruments) online record.Behind the tail current amplitude stabilization, will contain the vectorial body lotion that is useful on substances and be applied to cell.Condition is that vectorial application does not act on the tail current amplitude is significant, makes up the cumulative concentration effect curve to described compound then.
By in the presence of the test compound of given concentration, the tail current magnitudes table is shown there is vectorial percentage ratio, the effect of the test compound of each concentration is carried out quantitatively.Adopt normal data-match software package, make the percentage inhibiting value of formation concentration-effect carry out match to four Parameter H ill equations, the effectiveness (IC of confirmed test compound
50).If the inhibition level of being found when the highest experimental concentration is no more than 50%, then can not obtains the effectiveness value and limit the percentage inhibiting value of this concentration.
The Cytochrome P450 isozyme is measured and can be carried out by conventional methods.
Although the pharmacological properties of formula I compound changes with structural changes as expected, usually, one or more plant above test (a) and (b), (c) and (d) in, under following concentration or dosage, susceptible of proof formula I compound has activity:
Test (a) :-IC in 0.001-10 μ M scope for example
50
Test (b) :-IC in 0.01-20 μ M scope for example
50
Test (c) :-for example have activity in the 0.1-25 μ M scope
Test (d) :-for example have activity in 1-200mg/kg/ days the dosage range
In general, one or more plant above test (a) and (b), (c) and (d) in, under following concentration or dosage, can have activity as the many special formula I compound that after this provides in an embodiment:
Test (a) :-IC in 0.001-0.1 μ M scope for example
50
Test (b) :-IC in 0.01-1 μ M scope for example
50
Test (c) :-for example have activity in the 0.1-1 μ M scope
Test (d) :-for example have activity in 1-200mg/kg/ days the dosage range
Under the effective dose of test-compound of the present invention, in test (d), do not observe unacceptable toxicity on the physiology.Therefore, when formula I compound that gives aforementioned definitions with the dosage range that after this limits or pharmacy acceptable salt, expection can not produce the toxic action of trouble.
According to another aspect of the present invention, the invention provides medicinal compositions, this medicinal compositions comprises quinazoline derivant or its pharmacy acceptable salt and the pharmaceutically acceptable diluent or carrier of the formula I of definition as mentioned.
Composition of the present invention can (for example be tablet for the form that is applicable to oral administration, lozenge, hard or soft capsule, water-based or oily suspensions, emulsion, but dispersion powder or granule, syrup or elixir), the form that is applicable to topical is (as creme, paste, jelling agent, water-based or oily solution or suspension), be applicable to the form (as fine powder or liquid aerosol) of inhalation, be applicable to the form (as pulvis subtilis) that is blown into administration or be the form that is applicable to parenterai administration (for example sterile aqueous or oily solution, can be used for vein, subcutaneous, intramuscular administration is perhaps as the suppository that is used for rectal administration).
Can adopt various conventional pharmaceutical excipient well known in the art to prepare composition of the present invention through conventional method.Therefore, being used for liquid preparations for oral administration can contain just like one or more tinting materials, sweeting agent, correctives and/or sanitas.
Combine with one or more vehicle and must adjust according to host who is treated and concrete route of administration with the amount of the active ingredient that obtains single formulation.For example, the preparation that is used for the human oral administration contains usually just like 0.5mg-0.5g active ingredient (be more suitable for being 0.5-100mg, as be 1-30mg), and also contains an amount of vehicle in the said preparation, and the amount of vehicle can be about 5%-98% of composition total weight.
Certainly, according to the known principle of medical field, when being used for the treatment of or prevent, the dosage size of formula I compound should change according to the character of animal or patient's disease and severity, age and sex and route of administration.
When formula I compound being used for the treatment of or preventing, generally be administration by this way, be the 0.1mg/kg-75mg/kg body weight promptly as the per daily dose scope, can divide administration for several times in case of necessity.Usually, when adopting the parenteral administration, should give lower dosage.Based on this principle, when intravenously administrable, the dosage range that adopts is as 0.1 mg/kg-30mg/kg body weight usually.Similarly, when inhalation, the dosage range that adopts is as the 0.05mg/kg-25mg/kg body weight usually.But the preferred oral administration is particularly with the form oral administration of tablet.Generally speaking, contain the 0.5mg-0.5g that has an appointment compound of the present invention in the unit dosage.
According to a further aspect of the invention, the invention provides quinazoline derivant or the purposes of its pharmacy acceptable salt in the method for treatment human or animal body of the formula I of aforementioned definitions.
As mentioned above, the main effect of the known c-Src nonreceptor tyrosine kinase of people is a motility of regulating cell, and this kind motility enters blood circulation, invades its hetero-organization and produce the metastases growth by diffusion phase for local tumor is essential.The applicant also finds, quinazoline derivant of the present invention has the effective antitumour activity, and think that these activity are owing to due to one or more non-receptor tyrosine-specificity protein kinases such as the kinase whose restraining effect of c-Src, described specificity kinases is relevant with the signal conduction step that causes intrusion of metastatic tumour cell and transport property.
Therefore, quinazoline derivant of the present invention can be used as antitumour drug, particularly can be used as the selective depressant of mammalian cancer cells motility, diffusion and intrusion, thereby can suppress the growth of metastatic tumo(u)r.Particularly, quinazoline derivant of the present invention can be as anti-intrusion agent when suppressing and/or treat the noumenal tumour disease.Specifically, expect that compound of the present invention can be used to prevent or treat those many (multiple) nonreceptor tyrosine kinases (as the c-Src kinases) to one or more be suppressed responsive tumour, described kinases is relevant with the signal conduction step that causes intrusion of metastatic tumour cell and transport property.And, expect that compound of the present invention can also be used for prevention or the more such tumours of treatment, be that these tumours are separately or are mediated by the restraining effect to enzyme c-Src on part, that is to say that compound of the present invention can be used for the warm-blooded animal of this kind of needs treatment the c-Src enzyme being produced restraining effect.Particularly, expect that compound of the present invention can be used for effectively prevention or treatment noumenal tumour disease.
So, according to this aspect of the invention, the invention provides quinazoline derivant or its pharmacy acceptable salt of the formula I of aforementioned definitions, it is used as the anti-agent of invading in the inhibition of noumenal tumour disease and/or treatment.
So, according to another aspect of the present invention, the invention provides the quinazoline derivant of formula I of aforementioned definitions or its pharmacy acceptable salt and in the inhibition of noumenal tumour disease and/or treatment, be used as purposes in the anti-drug manufacture of invading agent.
Another feature according to this aspect of the present invention, by suppressing and/or treat the noumenal tumour disease to produce the method for anti-intrusion, this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described treatment of animals significant quantity among warm-blooded animal that the invention provides in this type of treatment of needs such as the people.
According to a further aspect of the invention, the invention provides quinazoline derivant or the purposes of its pharmacy acceptable salt in the drug manufacture of prevention or treatment warm-blooded animal such as people's noumenal tumour disease of the formula I of aforementioned definitions.
Another one feature according to this aspect of the present invention, the method of prevention or treatment noumenal tumour disease among warm-blooded animal that the invention provides in this type of treatment of needs such as the people, this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described treatment of animals significant quantity.
According to also aspect of the present invention, the invention provides the quinazoline derivant of formula I of aforementioned definitions or its pharmacy acceptable salt in prevention or treat purposes in the drug manufacture of such tumour, be that these tumours are suppressed sensitivity to nonreceptor tyrosine kinase (as the c-Src kinases), described kinases is relevant with the signal conduction step that causes intrusion of metastatic tumour cell and transport property.
The another one feature of this aspect according to the present invention, the invention provides prevention or treatment are suppressed responsive tumour to nonreceptor tyrosine kinase (as the c-Src kinases) method, described kinases is relevant with the signal conduction step that causes intrusion of metastatic tumour cell and transport property, and this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described treatment of animals significant quantity.
According to a further aspect of the invention, the invention provides the quinazoline derivant of formula I of aforementioned definitions or its pharmacy acceptable salt are used for providing the medicine of c-Src kinase inhibiting activity in production purposes.
The anticancer therapy effect of aforementioned definitions can be used separately as the single therapy method, perhaps except that quinazoline derivant of the present invention, can also combine with therapeutic method of surgery, radiotherapy or the chemical therapeutic method of routine.This type of chemical therapeutic method can comprise one or more following all kinds of antitumour drugs:
(i) other anti-intrusion agent (as inhibitors of metalloproteinase (as Marimastat) and bird kinases Profibrinolysin activator function of receptors inhibitor);
(ii) antiproliferative/antitumour drug that adopts in medical oncology and combination thereof is as alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and Nitrosourea); Antimetabolite (as anti-folic acid class (antifolates), for example fluoropyrimidines (as 5 FU 5 fluorouracil and Tegafur), Raltitrexed, methotrexate, cytarabin and hydroxyurea; Antitumor antibiotics (as anthracyclines, as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, darubicin, Mitomycin-C, actinomycin and duomycin); Antimitotic agent (as vinca alkaloids, as vincristin, vinblastine, vindesine and vinorelbine, and taxoids, as taxol and taxotere); And topoisomerase enzyme inhibitor (as the Etoposide class, as Etoposide and teniposide, amsacrine, the special willing and camptothecine of topology);
(iii) cytostatics, as anti-estrogens (as tamoxifen, fulvestrant, Toremitene, raloxifene, droloxifene and iodoxyfene), anti-androgens (as bicalutamide, flutamide, Nilutamide and acetate cyproterone), lhrh antagonist or LHRH agonist (as goserelin, Leuprolide and buserelin), progestogens (as the acetate megestrol), arimedex (as Anastrozole, letrozole, fluorine chlorazol (vorazole) and Exemestane) and 5 inhibitor are as finasteride;
(iv) the somatomedin depressant of functions is drawn together growth factor antibodies, growth factor receptor antibody (for example, anti--erbB2 antibody trastuzumab [Herceptin as this type of inhibitor packages
TM] and anti--erbB1 antibody Cetuximab [C225]), farnesyl tranfering enzyme inhibitor, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, for example the inhibitor of epidermal growth factor family is (as the tyrosine kinase inhibitor N-of EGFR family (3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (gehtinib, ZD 1839), N-(3-ethynyl phenyl)-6, two (2-methoxy ethoxy) quinazolines of 7--4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), the inhibitor of the inhibitor of thrombocyte-deutero-growth factor family and pHGF family for example;
(v) anti-angiogenic agent (for example resists-vascular endothelial growth factor antibody rhuMAb-VEGF [Avastin as those medicines that suppress the vascular endothelial growth factor effect
TM], those disclosed compound in International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 for example) and those compounds that work by other mechanism (as linomide, beta 2 integrin alpha v β 3 depressant of functions and angiostatin).
(vi) blood vessel injury agent such as combretastatin A4 and, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213 disclosed compound in International Patent Application WO 99/02166;
(vii) antisense therapy agent for example relates to those therapeutical agents of top listed target, as ISIS2503, anti--agent of ras antisense therapy;
(viii) gene therapy approach, comprise the approach that for example replaces aberrant gene such as unusual p53 or unusual BRCA1 or BRCA2, GDEPT (gene-pacemaker enzyme prodrug therapy) approach as those approach of using Isocytosine deaminase, thymidine kinase or bacterium nitroreductase and increase the patient to chemotherapy or radiotherapy as approach to the tolerance of the drug-fast gene therapy of multiple medicine; With
(ix) immunotherapy approach, comprise approach in the immunogenic external and body that for example increases the patient tumors cell, as using cytokine transfection such as interleukin-22, interleukin 4 or granulocyte-macrophage colony stimutaing factor, reduce the anergic approach of T-cell, use the approach of the dendritic cell of transfection immunocyte such as cytokine-transfection, use cytokine-transfection tumor cell line approach and use anti--Te to answer the approach of antibody.
By simultaneously, order or each component of separately treating, can carry out this type of combination therapy.This type of joint product can use compound of the present invention in aforesaid dosage range, other medical active agent are also in the amount ranges of its approval.
According to an aspect of the present invention, the invention provides medicinal product, this product comprises the quinazoline derivant of formula I of aforementioned definitions and other antitumour drugs that are used for the aforementioned definitions of cancer combination therapy.
Although formula I compound mainly is the medicine as warm-blooded animal (comprising the people), when needing, they also can be used to suppress the effect of c-Src.Therefore, these compounds can also be as new biological test exploitation and the pharmaceutical standards product in the new pharmacology drug research.
In the following embodiments, the present invention is further specified, in the ordinary course of things, in these embodiments:
(i) except that specializing, all operations is under room temperature (promptly at 17-25 ℃), carries out in rare gas element (as argon gas) environment;
(ii) adopt rotary evaporation to evaporate in a vacuum, filtration is carried out post-processing step after removing residual solids;
(iii) column chromatography (rapid method) and medium pressure liquid chromatography (MPLC) adopt available from E.Merck, Darmstadt, the Merck Kieselgel silica gel (Art.9385) of Germany or Merck Lichroprep RP-18 (Art.9303) reverse phase silica gel carry out, perhaps high pressure liquid chromatography (HPLC) (HPLC) adopts the C18 reverse phase silica gel to carry out, as adopting Dynamax C-1860 preparation property reversed-phase column;
(iv) output (or productive rate) if provide, is not obtainable maximum value yet;
(v) generally speaking, formula I end product all has gratifying trace analysis result, and their structure is through nucleus magnetic resonance (NMR) and/or mass-spectrometric technique checking; Adopt the Platform spectrophotometer to obtain fast atom bombardment (FAB) mass-spectrometric data, and if suitable, can collect positively charged ion data or negatively charged ion data; [proton NMR spectrum adopts Jeol JNM EX 400 spectrophotometers to measure under the 400MHz field intensity to the nmr chemical shift value with the δ value representation, perhaps adopt Varian Gemini 2000 spectrophotometers under the 300MHz field intensity, to measure, perhaps adopt Bruker AM300 spectrophotometer under the 300MHz field intensity, to measure]; Adopt following abbreviation: s representative unimodal; The d representative is bimodal; T represents triplet; Q represents quartet; M represents multimodal; Br represents broad peak;
(vi) generally speaking, intermediate is not identified fully, adopted thin-layer chromatography, HPLC, infrared (IR) and/or NMR assay determination purity;
(vii) fusing point is not calibrated, adopts the automatic fusing point test device of Mettler SP62 or adopts oil bath device to measure fusing point; Make end product crystallization from conventional organic solvent such as ethanol, methyl alcohol, acetone, ether or hexane or their mixture of formula I, and then measure their fusing point;
(viii) wherein some compound can be used as acid salt, for example a hydrochloride or dihydrochloride obtain, the stechiometry of described salt can be based upon on the basis of the quantity of basic group of compound and character, the precise chemical structure measurement Law of described salt is not generally passed through, and for example ultimate analysis data are determined;
(xi) when the substituting group on the amino of the quinazoline ring 4-position in description following examples, chemical name principle below claims of specification sheets and this specification sheets partly adopt, ' 2,3-methylene-dioxy pyridin-4-yl ' often be described to ' 2,3-methylene-dioxy pyridin-4-yl '; For avoiding any query, should be appreciated that each such term relates to the group of following formula:
(x) adopt following abbreviation:
DMF represents N, dinethylformamide
DMSO represents dimethyl sulfoxide (DMSO)
THF represents tetrahydrofuran (THF)
DMA represents N,N-dimethylacetamide
Embodiment 1
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-chloro propoxy-)-6-methoxyl group quinazoline
With hexamethyldisilane base ammonification sodium (the THF solution of 1M; 0.734ml) join the 4-amino-5-chloro-2 that is cooled to 0 ℃, in DMF (4ml) solution of 3-(methylenedioxy) yl pyridines (0.12g), this mixture was stirred 15 minutes.Add a (0.1g) 4-chloro-7-(3-chloro propoxy-)-6-methoxyl group quinazoline, stir the mixture that obtains, make to be warming up to room temperature.Under room temperature, stirred this mixture 16 hours.Evaporation reaction mixture is allocated between methylene dichloride and the saturated aqueous ammonium chloride residue.Water and salt water washing organic phase are through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, and the cumulative polar compound of using methylene dichloride and ethyl acetate is then used the cumulative polar compound wash-out of methylene dichloride and acetonitrile as elutriant.So obtain to be the title compound (0.11g) of white foam thing; NMR spectrum: (DMSOd
6And CD
3CO
2D) 2.3 (m, 2H), 3.8 (m, 2H), 4.05 (s, 3H), 4.4 (t, 2H), 6.3 (s, 2H), 7.4 (s, 1H), 7.9 (s, 1H), 8.15 (s, 1H), 8.95 (s, 1H); Mass spectrum: M+H
+423 and 425.
As the 4-amino-5-chloro-2 of starting raw material, 3-(methylenedioxy) yl pyridines is prepared as follows:
(20ml) joins 5-chloro-2 with the bromo methyl chloride, in the mixture of 3-dihydroxy-pyridine (30g), cesium carbonate (100g) and DMF (300ml), this mixture stirred and is heated to 90 ℃ 3.5 hours.This mixture is cooled to room temperature and filtration.Evaporated filtrate, residue use methylene dichloride as elutriant through purification by silica gel column chromatography.So obtain 5-chloro-2,3-(methylenedioxy) yl pyridines is white solid (4.7g); NMR spectrum: (DMSOd
6) 6.25 (s, 2H), 7.5 (s, 1H), 7.65 (s, 1H).
The mixture of diisopropylamine (8.2ml) and THF (100ml) is cooled to-70 ℃, be added dropwise to n-Butyl Lithium (hexane solution of 2.5 M, 24ml).This mixture was stirred other 20 minutes in-70 ℃.With 10 minutes adding 5-chloros-2, THF (40ml) solution of 3-(methylenedioxy) yl pyridines (4.2g) stirred this compound of reaction 1 hour in-70 ℃.Exsiccant carbon dioxide bubbling was fed in the reaction mixture 30 minutes.Make the reaction mixture that obtains be warming up to room temperature.Add entry (20ml), the evaporation organic solvent.By adding the 1N aqueous hydrochloric acid residue is acidified to pH2.Separate the solid that obtains, water and ether wash in proper order, in 40 ℃ of vacuum-dryings.So obtain 5-chloro-2,3-(methylenedioxy) yl pyridines-4-carboxylic acid (3.6g); 13C NMR spectrum: (DMSOd
6) 103,120,121,138,140,158,163.
With raw material, diphenyl phosphoryl azide (3.6ml), anhydrous tertiary butanol (13.5ml), the triethylamine (4.2ml) and 1 that so obtains, the stirring of the mixture of 4-dioxane (63ml) and be heated to 100 ℃ 3 hours.Evaporate this mixture, residue is distributed between ethyl acetate and water.Organic phase washes with water, through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, with the mixture of 9: 1 methylene dichloride and ethyl acetate as elutriant.So obtain 5-chloro-2,3-methylene-dioxy pyridin-4-yl carboxylamine tertiary butyl ester (3.8g); NMR spectrum: (DMSOd
6) 1.45 (s, 9H), 6.2 (s, 2H), 7.7 (s, 1H), 9.2 (s, 1H).
The raw material of acquisition like this is dissolved in the methylene dichloride (35ml), this solution is cooled to 0 ℃.Add trifluoroacetic acid (15ml), this mixture was stirred 3 hours in 0 ℃.Make this mixture be warming up to room temperature, stirred 16 hours.Evaporating solvent dilutes residue with frozen water, is neutralized to pH7 by adding the 2N aqueous sodium hydroxide solution, keeps this mixture simultaneously in 0 ℃ temperature.With the mixture that dichloromethane extraction obtains, extract is through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, with the mixture of 19: 1 methylene dichloride and ether as elutriant.So obtain 4-amino-5-chloro-2,3-(methylenedioxy) yl pyridines (2 g); NMR spectrum: (DMSOd
6) 6.1 (s, 2H), 6.2 (s, 2H), 7.45 (s, 1H);
13C NMR spectrum: (DMSOd
6) 100,112,125,136,138,157; Mass spectrum: M+H
+173.
4-chloro-7-(3-chloro propoxy-)-6-methoxyl group quinazoline as starting raw material is prepared as follows:
With 1.25 hours ammonium formiate (45g) is joined 7-benzyloxy-6-methoxyl group-3 in batches, 4-dihydroquinazoline-4-ketone (International Patent Application WO 02/16352, embodiment 1; 20g), in the stirred mixture of 10% palladium on carbon catalyst (3.3g) and DMF (530ml), reaction mixture was stirred other 30 minutes.Remove by filter catalyzer, evaporating solvent. so obtain 7-hydroxyl-6-methoxyl group-3,4-dihydroquinazoline-4-ketone (8.65g); NMR spectrum: (DMSOd
6) 3.9 (s, 3H), 7.0 (s, 1H), 7.45 (s, 1H), 7.9 (s, 1H).
With the mixture heating up to 100 of the raw material, diacetyl oxide (63ml) and the pyridine (7.5ml) that so obtain ℃ 4.5 hours.Make the mixture that obtains place envrionment temperature following 16 hours.In stir the mixture (400ml) with this mixture impouring ice and water.Separate the precipitation that generates, vacuum-drying.Analyzing the hydrolysis that shows the acetate group on the quinazoline 4-position does not finish.Therefore, in 90 ℃ with water (150ml) and pyridine (several) hydrolysis 15 minutes again of this mixture.Make the mixture that obtains be cooled to the room temperature solid collected by filtration, wash vacuum-drying with water.So obtain 7-acetoxyl group-6-methoxyl group-3,4-dihydroquinazoline-4-ketone (7.4g); NMR spectrum: (DMSOd
6) 2.3 (s, 3H), 3.9 (s, 3H), 7.45 (s, 1H), 7.65 (s, 1H), 8.05 (s, 1H).
The mixture of a (2g) raw material, thionyl chloride (32ml) and DMF (5) that obtains like this is stirred and is heated to backflow 1.5 hours.Make this mixture be cooled to room temperature, evaporate excessive thionyl chloride.Toluene is joined in this residue evaporation.The residue that obtains is with methylene dichloride (15ml) dilution, adds the mixture (80ml) of 10: 1 methyl alcohol and saturated ammonium hydroxide aqueous solution.The mixture that stirring obtains and be heated to 80 ℃ 10 minutes.Make this mixture be cooled to room temperature, evaporation.Water is joined in the residue, by adding diluted hydrochloric acid aqueous solution this mixture that neutralizes.Filter and collect the precipitation that produces, in 35 ℃ of vacuum-dryings 16 hours. so obtain 4-chloro-7-hydroxyl-6-methoxyl group quinazoline (1.65g); NMR spectrum: (DMSOd
6) 4.0 (s, 3H), 7.25 (s, 1H), 7.4 (s, 1H), 8.8 (s, 1H).
With several minutes azo-2-carboxylic acid's di-t-butyl ester (2.3g) is joined in the stirring the mixture of 4-chloro-7-hydroxyl-6-methoxyl group quinazoline (1.65g), 3-chloro propyl alcohol (0.7ml), triphenylphosphine (2.6g) and methylene dichloride (100ml) in batches, stirred reaction mixture is 2 hours under room temperature.By evaporating the volume that this mixture is concentrated into about 30ml, residue is through purification by silica gel column chromatography, and the cumulative polar compound of using sherwood oil (b.p 40-60 ℃) and ethyl acetate is as elutriant.So obtain 4-chloro-7-(3-chloro propoxy-)-6-methoxyl group quinazoline, be white solid (2g); NMR spectrum: (DMSOd
6) 2.3 (m, 2H), 3.8 (m, 2H), 4.05 (s, 3H), 4.4 (m, 2H), 7.45 (s, 1H), 7.55 (s, 1H), 8.9 (s, 1H).
Embodiment 2
7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group quinazoline
Adopt and the similar method of method described in the embodiment 1, make 4-chloro-7-(2-chloro oxyethyl group)-6-methoxyl group quinazoline and 4-amino-5-chloro-2, the reaction of 3-(methylenedioxy) yl pyridines obtains title compound with 92% yield; NMR spectrum: (DMSOd
6And CD
3CO
2D) 4.05 (s, 3H), 4.1 (t, 2H), 4.55 (t, 2H), 6.3 (s, 2H), 7.4 (s, 1H), 7.9 (s, 1H), 8.15 (s, 1H), 8.95 (s, 1H); Mass spectrum: M+H
+409 and 411.
4-chloro-7-(2-chloro oxyethyl group)-6-methoxyl group quinazoline as starting raw material is prepared as follows:
With l, 2-ethylene dichloride (400ml) joins 7-hydroxyl-6-methoxyl group-3-oxy acid methyl neopentyl-3, and 4-dihydroquinazoline-4-ketone (International Patent Application WO 02/16352, embodiment 2, its note [4]; 85g), in the stirring the mixture of salt of wormwood (77g) and DMF (400ml), with this compound of reaction be heated to 70 ℃ 16 hours.This compound of reaction is cooled to room temperature and filtration.Evaporated filtrate, so the solid that obtains washes with water, in 50 ℃ through the Vanadium Pentoxide in FLAKES drying.So the raw material that obtains is through purification by silica gel column chromatography, and the cumulative polar compound of using methylene dichloride and ethyl acetate is as elutriant.So obtain 7-(2-chloro oxyethyl group)-6-methoxyl group-3-valeryl oxygen ylmethyl-3,4-dihydroquinazoline-4-ketone is white solid (65.6 g); NMR spectrum: (CDCl
3) 1.2 (s, 9H), 3.9 (t, 2H), 4.0 (s, 3H), 4.4 (t, 2H), 5.95 (s, 2H), 7.1 (s, 1H), 7.7 (s, 1H), 8.2 (s, 1H); Mass spectrum: M+H
+369 and 371.
The mixture of the methanol solution (1.6L) of the raw material that so obtains and saturated ammonia was stirred under room temperature 2 days.By evaporation solvent is concentrated into the about 1/4th of original volume, filters collecting precipitation, wash with ether.So obtain 7-(2-chloro oxyethyl group)-6-methoxyl group-3,4-dihydroquinazoline-4-ketone is white solid (44 g); NMR spectrum: (DMSOd
6) 3.9 (s, 3H), 4.05 (t, 2H), 4.4 (t, 2H), 7.15 (s, 1H), 7.45 (s, 1H), 8.0 (s, 1H); Mass spectrum: M+H
+255 and 257.
The mixture stirring of raw material, thionyl chloride (28ml) and DMF (0.7ml) that a (5g) so obtained and be heated to 80 ℃ 1.5 hours.Evaporate excessive thionyl chloride, add toluene, evaporation.Make the residue solid suspension in the mixture of ice and water,, add saturated sodium bicarbonate aqueous solution then and alkalize to pH7.5 by adding the 2N aqueous sodium hydroxide solution.The solid that filter to collect generates, water and ether washing, under the vacuum through the Vanadium Pentoxide in FLAKES drying.So the raw material that obtains is through purification by silica gel column chromatography, with the cumulative mixture of the polarity of methylene dichloride and acetonitrile as elutriant.So obtain 4-chloro-7-(2-chloro oxyethyl group)-6-methoxyl group quinazoline (3.06g); NMR spectrum: (CDCl
3) 3.95 (t, 2H), 4.1 (s, 3H), 4.5 (t, 2H), 7.35 (s, 1H), 7.45 (s, 1H), 8.9 (s, 1H); Mass spectrum: M+H
+273 and 275.
Embodiment 3
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group-7-[3-(4-Propargyl piperazine-1-yl) propoxy-] quinazoline
The mixture of 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-chloro propoxy-)-6-methoxyl group quinazoline (0.08g), 1-Propargyl piperazine (0.047g), salt of wormwood (0.01g) and DMA (2ml) stirred and is heated to 80 ℃ 3.5 hours.Evaporating solvent and residue is allocated between methylene dichloride and the saturated aqueous ammonium chloride.Organic phase is through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, and the mixture of ammonia solution of successively using the methylene dichloride of 19: 1 methylene dichloride and methanol mixture and 9: 1 and saturated methyl alcohol is as elutriant.The jelly that obtains grinds with ether.So obtain to be solid title compound (0.066g); NMR spectrum: (DMSOd
6And CF
3CO
2D) 2.3 (m, 2H), 3.2-3.6 (br m, 10H), 3.75 (s, 1H), 3.95 (br s, 2H), 4.0 (s, 3H), 4.35 (m, 2H), 6.3 (s, 2H), 7.4 (s, 1H), 7.9 (s, 1H), 8.15 (s, 1H), 8.95 (s, 1H); Mass spectrum: M+H
+511 and 513.
1-Propargyl piperazine as starting raw material is prepared as follows:
In 10 minutes with propargyl bromide (80% toluene solution; 40ml) be added drop-wise in the stirring the mixture of the 1-tert-butoxycarbonyl piperazine (50g), salt of wormwood (74.2g) and the acetonitrile (2L) that are cooled to 0 ℃.This mixture was stirred 1.5 hours, make to be warming up to room temperature.Filter this mixture, evaporated filtrate.Residue is through purification by silica gel column chromatography, and the cumulative polar compound of using methylene dichloride and ethyl acetate is as elutriant.So obtain 4-Propargyl piperazine-1-formic acid tertiary butyl ester, be oily matter (45.5g); NMR spectrum: (CDCl
3) 1.4 (s, 9H), 2.2 (s, 1H), 2.45 (m, 4H), 3.3 (s, 2H), 3.45 (m, 4H).
The dichloromethane solution (100ml) of the raw material that so obtains is slowly joined 1 of hydrogen chloride gas, the 4-dioxane solution (4M, 450ml) in.This reaction is slight exothermic reaction, and when carbon dioxide took place, precipitation formed.Under room temperature, stirred this mixture 1 hour.The mixture that evaporation obtains is suspended in the methylene dichloride residue.(7M 110ml), stirred this mixture 15 minutes to the methanol solution of adding ammonia under room temperature.Filter this mixture, evaporated filtrate.Obtain oily matter, it is through leaving standstill crystallization.So obtain 1-Propargyl piperazine (23g); NMR spectrum: (CDCl
3) 2.2 (s, 1H), 2.5 (br s, 4H), 2.85 (m, 4H), 3.25 (s, 2H).
Embodiment 4
7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-tetrahydropyran-4-base oxygen base quinazoline
Adopt and the similar method of method described in the embodiment 1, make 4-chloro-7-(2-chloro oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline and 4-amino-5-chloro-2, the reaction of 3-(methylenedioxy) yl pyridines obtains title compound with 37% yield; NMR spectrum: (CDCl
3) 2.0 (m, 2H), 2.3 (m, 2H), 3.65 (m, 2H), 3.9 (m, 2H), 4.1 (m, 2H), 4.4 (m, 2H), 4.8 (m, 1H), 6.2 (s, 2H), 6.65 (s, 1H), 6.9 (s, 1H), 7.8 (s, 1H), 8.6 (s, 1H), 9.5 (s, 1H); Mass spectrum: M+H
+479 and 481.
4-chloro-7-(2-chloro oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline as starting raw material is prepared as follows:
With azo-2-carboxylic acid's di-t-butyl ester (0.338g) join 4-chloro-7-hydroxyl-5-tetrahydropyran-4-base oxygen base quinazoline (International Patent Application WO 01/94341, embodiment 15, its note [10]; 0.25g), in the stirring the mixture of 2-chloro ethanol (0.073ml), triphenylphosphine (0.385g) and methylene dichloride (15ml), stirred reaction mixture is 1 hour under room temperature.By evaporating the volume that this mixture is concentrated into about 5ml, residue is through purification by silica gel column chromatography, and the cumulative polar compound of using sherwood oil (b.p 40-60 ℃) and ethyl acetate is as elutriant.So obtain 4-chloro-7-(2-chloro oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline, be a kind of solid (0.17g); NMR spectrum: (CDCl
3) 2.0 (m, 2H), 2.15 (m, 2H), 3.7 (m, 2H), 3.95 (t, 2H), 4.1 (m, 2H), 4.4 (t, 2H), 4.8 (m, 1H), 6.7 (s, 1H), 6.95 (s, 1H), 8.85 (s, 1H).
Embodiment 5
7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline
Adopt and the similar method of method described in the embodiment 1, make 4-chloro-7-(2-chloro oxyethyl group)-5-isopropoxy quinazoline and 4-amino-5-chloro-2, the reaction of 3-(methylenedioxy) yl pyridines obtains title compound with 86% yield; NMR spectrum: (CDCl
3) 1.55 (d, 6H), 3.9 (t, 2H), 4.4 (t, 2H), 4.9 (m, 1H), 6.2 (s, 2H), 6.6 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.65 (s, 1H); Mass spectrum: M+H
+437 and 439.
4-chloro-7-(2-chloro oxyethyl group)-5-isopropoxy quinazoline as starting raw material is prepared as follows:
Azo-2-carboxylic acid's di-t-butyl ester (28.9g) is joined the 7-benzyloxy-5-hydroxyl-3-valeryl oxygen ylmethyl-3 that is cooled to 0 ℃, and 4-dihydroquinazoline-4-ketone (International Patent Application WO 01/94341, embodiment 15, its note [8]; 30g), in the stirring the mixture of Virahol (7.3ml), triphenylphosphine (32.95g) and methylene dichloride (350ml).Make this reaction mixture be warming up to room temperature, stirred 1.5 hours.Evaporate this mixture and residue through purification by silica gel column chromatography, with the cumulative polar compound of methylene dichloride and methyl alcohol as elutriant. so obtain 7-benzyloxy-5-isopropoxy-3,4-dihydroquinazoline-4-ketone is a kind of solid (23.8g); NMR spectrum: (DMSOd
6) 7.89 (s, 1H), 7.5-7.3 (m, 5H), 6.75 (s, 1H), 6.62 (s, 1H), 5.24 (s, 2H), 4.65 (m, 1H), 1.29 (d, 6H).
Ammonium formiate (48.4g) is joined 7-benzyloxy-5-isopropoxy-3, in the stirring the mixture of 4-dihydroquinazoline-4-ketone (23.8g), 10% palladium on carbon catalyst (2.8g) and DMF (300ml), under room temperature, stirred the mixture that obtains 2 hours.Filter this mixture, evaporated filtrate.The raw material that so obtains is ground in the presence of water, its pH value is adjusted to pH7.Filter to collect the solid that so obtains, water and ether washing, under the vacuum through the Vanadium Pentoxide in FLAKES drying.So obtain 7-hydroxyl-5-isopropoxy-3,4-dihydroquinazoline-4-ketone is white solid (15.9g); NMR spectrum: (DMSOd
6) 1.3 (d, 6H), 4.57 (m, 1H), 6.42 (s, 1H), 6.5 (s, 1H), 7.8 (s, 1H).
With the mixture heating up to 70 of the raw material, diacetyl oxide (34ml) and the pyridine (0.62ml) that so obtain ℃ 30 minutes.Make this reaction mixture be cooled to room temperature, the evaporation excessive acetic anhydride via.So the white solid that obtains join hot water (80 ℃, 250ml) in, this mixture of vigorous stirring, be heated to 80 ℃ 20 minutes.Make this mixture be cooled to room temperature, separate solid is through the Vanadium Pentoxide in FLAKES drying.So obtain 7-acetoxyl group-5-isopropoxy-3,4-dihydroquinazoline-4-ketone (17.86g); NMR spectrum: (DMSOd
6) 7.97 (s, 1H), 6.91 (s, 1H), 6.85 (s, 1H), 4.65 (m, 1H), 2.32 (s, 3H), 1.33 (d, 6H).
With raw material, triphenylphosphine (10.8g), the tetracol phenixin (12ml) and 1 that a (5.4g) so obtains, the stirring of the mixture of 2-ethylene dichloride (50ml) and be heated to 70 ℃ 2 hours.Make this mixture be cooled to room temperature and evaporating solvent.Make residue be dissolved in 1 of 0.5M ammonia, in the 4-dioxane solution (250ml), with this mixture heating up to 70 ℃ 10 minutes.Evaporating solvent cools off residue in ice-water bath.Add methylene dichloride and water, water layer is adjusted to pH7 by adding diluted hydrochloric acid aqueous solution.Filter this mixture.Organic phase obtains 4-chloro-7-hydroxyl-5-isopropoxy quinazoline through dried over mgso and evaporation, is the foam thing, and it need not be further purified and use.
Azo-2-carboxylic acid's di-t-butyl ester (7.9g) is joined in the stirring the mixture of 4-chloro-7-hydroxyl-5-isopropoxy quinazoline, 2-chloro ethanol (1.5ml), triphenylphosphine (8g) and methylene dichloride (200ml) of acquisition like this, stirred reaction mixture is 4 hours under room temperature.By this mixture of evaporation concentration, residue is through purification by silica gel column chromatography, and the cumulative polar compound of using sherwood oil (b.p 40-60 ℃) and ethyl acetate is as elutriant.So obtain 4-chloro-7-(2-chloro oxyethyl group)-5-isopropoxy quinazoline (2.5g); NMR spectrum: (CDCl
3) 1.45 (d, 6H), 3.9 (t, 2H), 4.4 (t, 2H), 4.75 (m, 1H), 6.65 (s, 1H), 6.9 (s, 1H), 8.8 (s, 1H).
Embodiment 6
The similar method of describing among employing and the embodiment 3 of method makes suitable 7-halogenated alkoxy quinazoline and suitable heterogeneous ring compound reaction, the compound that obtains describing in the Table I.Except as otherwise noted, each compound of describing in the Table I obtains as free alkali.
Table I
| Compound number and note | (R 1) m | (R 3) n |
| [1] | 6-methoxyl group-7-[3-(4-isobutyryl piperazine-1-yl) propoxy-] | The 5-chloro |
| [2] | 6-methoxyl group-7-{3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-} | The 5-chloro |
| [3] | 6-methoxyl group-7-[2-(4-Propargyl piperazine-1-yl) oxyethyl group] | The 5-chloro |
| [4] | 5-tetrahydropyran-4-base oxygen base-7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group] | The 5-chloro |
| [5] | 5-tetrahydropyran-4-base oxygen base-7-{2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group } | The 5-chloro |
| [6] | 5-isopropoxy-7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group] | The 5-chloro |
| [7] | 5-isopropoxy-7-{2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group } | The 5-chloro |
| [8] | 6-(2-morpholino oxyethyl group)-7-methoxyl group | The 5-chloro |
| [9] | 6-[2-(4-methylpiperazine-1-yl) oxyethyl group]-the 7-methoxyl group | The 5-chloro |
| [10] | 6-(2-tetramethyleneimine-1-base oxethyl)-7-methoxyl group | The 5-chloro |
| [11] | 6-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-the 7-methoxyl group | The 5-chloro |
| [12] | 6-{2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group }-the 7-methoxyl group | The 5-chloro |
| [13] | 6-(3-tetramethyleneimine-1-base propoxy-)-7-methoxyl group | The 5-chloro |
| [14] | 6-(3-morpholino propoxy-)-7-methoxyl group | The 5-chloro |
| [15] | 6-[3-(4-ethanoyl piperazine-1-yl) propoxy-]-the 7-methoxyl group | The 5-chloro |
| [16] | 6-[3-(4-methylpiperazine-1-yl) propoxy-]-the 7-methoxyl group | The 5-chloro |
| [17] | 6-{3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-}-the 7-methoxyl group | The 5-chloro |
| [18] | 5-tetrahydropyran-4-base oxygen base-7-[2-(4-Propargyl piperazine-1-yl) oxyethyl group] | The 5-chloro |
| [19] | 5-tetrahydropyran-4-base oxygen base-7-(2-morpholino oxyethyl group) | The 5-chloro |
| [20] | 5-tetrahydropyran-4-base oxygen base-7-(3-morpholino propoxy-) | The 5-chloro |
| [21] | 5-tetrahydropyran-4-base oxygen base-7-[3-(4-Propargyl piperazine-1-yl) propoxy-] | The 5-chloro |
| [22] | 5-isopropoxy-7-(2-piperazine-1-base oxethyl) | The 5-chloro |
| [23] | 5-isopropoxy-7-{2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group } | The 5-chloro |
| [24] | 5-isopropoxy-7-(2-tetramethyleneimine-1-base oxethyl) | The 5-chloro |
| [25] | 5-isopropoxy-7-(2-piperidino-(1-position only) oxyethyl group) | The 5-chloro |
| [26] | 5-isopropoxy-7-(2-morpholino oxyethyl group) | The 5-chloro |
| [27] | 5-isopropoxy-7-[2-(4-Propargyl piperazine-1-yl) oxyethyl group] | The 5-chloro |
| [28] | 5-isopropoxy-6-{2-[(3RS, 4SR)-3,4-dimethoxy tetramethyleneimine-1-yl] oxyethyl group } | The 5-chloro |
| [29] | 6-{2-[(3RS, 4SR)-3,4-ethylidene dioxy base tetramethyleneimine-1-yl] oxyethyl group }-the 5-isopropoxy | The 5-chloro |
| [30] | 5-isopropoxy-7-[2-(4-methylpiperazine-1-yl) oxyethyl group] | The 5-chloro |
| [31] | 5-isopropoxy-7-(3-morpholino propoxy-) | The 5-chloro |
| [32] | 7-(3-morpholino propoxy-) | The 5-chloro |
| [33] | 7-[3-(4-ethanoyl piperazine-1-yl) propoxy-] | The 5-chloro |
| [34] | 6-methoxyl group-7-[2-(4-Propargyl piperazine-1-yl) oxyethyl group] | Hydrogen |
| [35] | 6-methoxyl group-7-[3-(4-Propargyl piperazine-1-yl) propoxy-] | Hydrogen |
Explain [1]
Reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-chloro propoxy-)-6-methoxyl group quinazoline and 1-isobutyryl piperazine.With this compound of reaction be heated to 120 ℃ 3 hours.Through column chromatography purification (Waters Symmetrycolumn, 5 microns silica gel, 19mm diameter, 100mm length), the polar compound decrescence of water and acetonitrile (containing 1% acetate) is as elutriant on C18 reverse phase silica gel post for reaction product.The raw material that so obtains is dissolved in the methylene dichloride, adds ion exchange resin (diethylamino polystyrene resin, 4 equivalents), this mixture was stirred 30 minutes.Filter this mixture, evaporated filtrate.The residue that obtains grinds under pentane, obtains required product with 51% yield, and it has following characteristic; NMR spectrum: (CDCl
3) 1.1 (d, 6H), 2.1 (m, 2H), 2.45 (m, 4H), 2.55 (m, 2H), 2.75 (m, 1H), 3.5 (m, 2H), 3.6 (m, 2H), 4.0 (s, 3H), 4.25 (t, 2H), 6.1 (s, 2H), 7.1 (br s, 1H), 7.3 (s, 1H), 7.75 (s, 1H), 8.7 (br s, 1H); Mass spectrum: M+H
+543 and 545.
1-isobutyryl piperazine as starting raw material is prepared as follows:
Isobutyryl chloride (3.25ml) is added drop-wise in the stirring the mixture of the 1-benzyl diethylenediamine (5g), triethylamine (4.35ml) and the methylene dichloride (75ml) that are cooled to 0 ℃.Make this reaction mixture be warming up to room temperature and stirred 1 hour.This mixture is allocated between methylene dichloride and the water.Water and salt water washing organic phase are through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, and 3: 2 mixtures using methylene dichloride and ethyl acetate are as elutriant.So obtain 1-benzyl-4-isobutyryl piperazine (5.95g), be oily matter; NMR spectrum: (CDCl
3) 1.1 (d, 6H), 245 (m, 4H), 2.8 (m, 1H), 3.5 (m, 4H), 3.65 (m, 2H), 7.3 (m, 5H); Mass spectrum: M+H
+247.
With raw material, hexanaphthene (70ml), the palladous oxide C catalyst (20% that so obtains; 1.1g) and the mixture of ethanol (120ml) stir and be heated to 80 ℃ 3 hours.Remove by filter catalyzer, evaporating solvent obtains 1-isobutyryl piperazine (3.7g), is solid; NMR spectrum: (CDCl
3) 1.05 (d, 6H), 2.75 (m, 1H), 2.8 (m, 4H), 3.45 (m, 2H), 3.55 (m, 2H).
[2] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-chloro propoxy-)-6-methoxyl group quinazoline and 1-(2,2, the 2-trifluoroethyl) piperazine.With this compound of reaction be heated to 120 ℃ 3 hours.Reaction product makes the polar compound decrescence of water and acetonitrile (containing 1% acetate) as elutriant through column chromatography purification (Waters Symmetry column, 5 microns silica gel, 19mm diameter, 100mm length) on C18 reverse phase silica gel post.The raw material that so obtains is dissolved in the methylene dichloride, adds ion exchange resin (diethylamino polystyrene resin, 4 equivalents), this mixture was stirred 30 minutes.Filter this mixture, evaporated filtrate.The residue that obtains grinds under pentane, obtains required product with 72% yield, and it has following characteristic; NMR spectrum: (CDCl
3) 2.1 (m, 2H), 2.5 (m, 6H), 2.7 (m, 4H), 2.95 (q, 2H), 4.05 (s, 3H), 4.25 (t, 2H), 6.1 (s, 2H), 7.1 (br s, 1H), 7.3 (s, 1H), 7.75 (s, 1H), 8.35 (br s, 1H); Mass spectrum: M+H
+555 and 557; Ultimate analysis: measured value C, 51.8; H, 5.0; N, 14.8; C
24H
26ClF
3N
6O
4Calculated value C, 51.9; H, 4.7; N, 15.1%.
1-(2,2, the 2-trifluoroethyl) piperazine as starting raw material is prepared as follows:
With trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (8.2g) joins in the stirring the mixture of 1-tert-butoxycarbonyl piperazine (6g), salt of wormwood (5.77g) and acetonitrile (30ml), the mixture that stirring obtains under room temperature 16 hours.Filter this mixture, evaporated filtrate.Residue is through purification by silica gel column chromatography, and the cumulative polar compound of using sherwood oil (b.p 40-60 ℃) and ethyl acetate is as elutriant.(2,2,2-trifluoroethyl piperazine-1-formic acid tertiary butyl ester is a kind of solid (8.1g) so to obtain 4-; NMR spectrum: (CDCl
3) 1.45 (s, 9H), 2.6 (m, 4H), 2.95 (q, 2H), 3.4 (m, 4H).
In 1.5 hours, with the hydrogen chloride gas bubbling feed 4-(2,2, in ethyl acetate (50ml) solution of 2-trifluoroethyl piperazine-1-formic acid tertiary butyl ester (8g).When carbon dioxide took place, precipitation formed.Filter collecting precipitation, with ethyl acetate washing, vacuum-drying.So obtain 1-(2,2, the 2-trifluoroethyl) piperazine hydrochloride (7g); NMR spectrum: (DMSOd
6And CF
3CO
2D) 2.85 (m, 4H), 3.1 (m, 4H), 3.35 (q, 2H).
The raw material of acquisition like this is suspended in the methylene dichloride, adds saturated methyl alcohol system ammonia solution (20ml).The mixture that stirring obtains under room temperature 20 minutes.Filter this mixture, reduction vaporization filtrate under room temperature.So obtain 1-(2,2, the 2-trifluoroethyl) piperazine, it need not any further purifying and use.
[3] reactant is 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group quinazoline and 1-Propargyl piperazine.Yield with 52% obtains required product, and obtains following characteristic; NMR spectrum: (DMSOd
6And CF
3CO
2D) 3.3 (brs, 4H), 3.6 (br s, 4H), 3.75 (br s, 3H), 3.95 (s, 2H), 4.05 (s, 3H), 4.65 (t, 2H), 6.3 (s, 2H), 7.5 (s, 1H), 7.9 (s, 1H), 8.2 (s, 1H), 9.0 (s, 1H); Mass spectrum: M+H ' 497 and 499; Ultimate analysis: measured value C, 56.3; H, 5.4; N, 16.2; C
24H
25ClN
6O
40.7H
2O calculated value C, 56.6; H, 5.2; N, 16.5%.
[4] reactant is 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-tetrahydropyran-4-base oxygen base quinazoline and 1-ethanoyl piperazine.With this compound of reaction be heated to 80 ℃ 3 hours, be heated to then 110 ℃ 5 hours.Through column chromatography purification (Waters Symmetry column, 5 microns silica gel, 19mm diameter, 100mm length), the polar compound decrescence of water and acetonitrile (containing 1% acetate) is as elutriant on C18 reverse phase silica gel post for reaction product.The evaporation organic solvent is with the pH regulator to 7.5 of water.With this solution of dichloromethane extraction, organic phase is through dried over mgso and evaporation.The residue that obtains grinds under ether, obtains required product with 45% yield, and it has following characteristic; NMR spectrum: (CDCl
3) 2.0 (m, 2H), 2.1 (s, 3H), 2.3 (m, 2H), 2.6 (m, 4H), 2.95 (m, 2H), 3.55 (m, 2H), 3.65 (m, 4H), 4.1 (m, 2H), 4.3 (m, 2H), 4.8 (m, 1H), 6.2 (s, 2H), 6.6 (s, 1H), 6.9 (s, 1H), 7.8 (s, 1H), 8.65 (s, 1H), 9.5 (s, 1H); Mass spectrum: M+H
+571 and 573; Ultimate analysis: measured value C, 55.3; H, 5.4; N, 13.9; C
27H
31ClN
6O
61H
2O calculated value C, 55.1; H, 5.7; N, 14.3.
[5] reactant be 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-tetrahydropyran-4-base oxygen base quinazoline and (3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine.With this compound of reaction be heated to 80 ℃ 3 hours, be heated to then 110 ℃ 5 hours.Reaction product makes the polar compound decrescence of water and acetonitrile (containing 1% acetate) as elutriant through column chromatography purification (Waters Symmetrycolumn, 5 microns silica gel, 19mm diameter, 100mm length) on C18 reverse phase silica gel post.The evaporation organic solvent is with the pH regulator to 7.5 of water.With this solution of dichloromethane extraction, organic phase is through dried over mgso and evaporation.The residue that obtains grinds under ether, obtains required product with 69% yield, and it has following characteristic; NMR spectrum: (CDCl
3) 2.0 (m, 2H), 2.3 (m, 2H), 2.4 (m, 2H), 2.3 (t, 2H), 3.3 (d, 2H), 3.55 (m, 2H), 4.1 (m, 2H), 4.3 (t, 2H), 4.65 (m, 2H), 4.8 (m, 1H), 4.9 (s, 1H), 5.2 (s, 1H), 6.2 (s, 2H), 6.6 (s, 1H), 6.9 (s, 1H), 7.8 (s, 1H), 8.65 (s, 1H), 9.5 (s, 1H); Mass spectrum: M+H
+558 and 560; Ultimate analysis: measured value C, 56.5; H, 5.3; N, 12.5; C
26H
28ClN
5O
70.2Et
2O calculated value C, 56.2; H, 5.3; N, 12.2%.
As starting raw material (3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine is prepared as follows:
With two dimethyl dicarbonate butyl ester (Boc
2O, ethyl acetate 78.95g) (125ml) drips of solution is added to 3-pyrroline (25g; 65% purity contains tetramethyleneimine) and ethyl acetate (125ml) be cooled in 0 ℃ the stirring the mixture.During the adding, reaction mixture is maintained 5-10 ℃.Make the reaction mixture that obtains be warming up to ambient temperature overnight.Reaction mixture water, 0.1N aqueous hydrochloric acid, water, saturated sodium bicarbonate aqueous solution and salt solution wash in proper order, through dried over mgso and evaporation.So obtain (62g) 3-pyrroline-1-formic acid tertiary butyl ester (NMR) of colorless oil: (CDCl
3) 1.45 (s, 9H), 4.1 (d, 4H), 6.75 (m, 2H)) and tetramethyleneimine-1-formic acid tertiary butyl ester (NMR): (CDCl
3) 1.5 (s, 9H), 1.8 (br s, 4H), 2: 1 mixtures of 3.3 (br s, 4H)).
Acetone (500ml) drips of solution of the raw mix that so obtains is added in the mixture of N-methylmorpholine-N-oxide compound (28.45g), perosmic anhydride (1g) and water (500ml), keeps temperature of reaction to be lower than 25 ℃ simultaneously.Stirred reaction mixture 5 hours under room temperature then.Evaporating solvent distributes residue between ethyl acetate and water.Organic phase salt water washing is through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, with sherwood oil (b.p.40-60 ℃) and ethyl acetate cumulative polar compound as elutriant, again through silica gel column chromatography, the cumulative polar compound wash-out of usefulness methylene dichloride and methyl alcohol.So obtain (3RS, 4SR)-3,4-dihydroxy pyrrolidine-1-formic acid tertiary butyl ester is oily matter (34.6g); NMR spectrum: (CDCl
3) 1.45 (s, 9H), 2.65 (m, 2H), 3.35 (m, 2H), 3.6 (m, 2H), 4.25 (m, 2H).
Will (3RS, 4SR)-3, the DMF solution (400ml) of 4-dihydroxy pyrrolidine-1-formic acid tertiary butyl ester (34.6g) is cooled to 0-5 ℃, and (60% is scattered in the mineral oil, 0.375mol) to be added dropwise to sodium hydride.This compound of reaction was stirred 1 hour in 5 ℃.Add methylene bromide (15.6ml), this compound of reaction was stirred 30 minutes in 5 ℃.Make this reaction mixture be warming up to room temperature, stirred 16 hours.Evaporation DMF distributes residue between ethyl acetate and water.Water and salt water washing organic phase are through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, with sherwood oil (b.p.40-60 ℃) and ethyl acetate cumulative polar compound as elutriant.So obtain (3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-formic acid tertiary butyl ester is colorless oil (19.77g); NMR spectrum: (CDCl
3) 1.45 (s, 9H), 3.35 (m, 2H), 3.75 (br s, 2H), 4.65 (m, 2H), 4.9 (s, 1H), 5.1 (s, 1H).
The aqueous isopropanol (150ml) of refrigerative 5M hydrogenchloride is joined (3RS, 4SR)-3, the methylene dichloride (500ml) of 4-methylene-dioxy tetramethyleneimine-1-formic acid tertiary butyl ester (19.7g) on ice bath in the refrigerative solution.Make this reaction mixture be warming up to room temperature, stirred 4 hours.Evaporating solvent, residue grinds under ether.Filter collecting precipitation, with ether washing and dry.So obtain (3RS, 4SR)-3,4-methylene-dioxy pyrrolidine hydrochloride is beige solid (13.18g); NMR spectrum: (DMSOd
6) 3.15 (m, 2H), 3.35 (m, 2H), 4.65 (s, 1H), 4.8 (m, 2H), 5.1 (s, 1H).
The raw material of acquisition like this is suspended in the ether, adds saturated methyl alcohol system ammonia solution.The mixture that stirring obtains under room temperature 10 minutes.Filter this mixture, vacuum evaporating solvent under room temperature.So obtain (3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine, it need not any further purifying and use.
[6] reactant is 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline and 1-ethanoyl piperazine.With this compound of reaction be heated to 85 ℃ 8 hours.Reaction product is through purification by silica gel column chromatography, and the cumulative polar compound of using methylene dichloride and methyl alcohol is as elutriant.Obtain product with 89% yield, and obtain following characteristic; M.p.208-210 ℃; NMR spectrum: (CDCl
3) 1.55 (d, 6H), 2.1 (s, 3H), 2.6 (m, 4H), 2.9 (t, 2H), 3.5 (t, 2H), 3.7 (t, 2H), 4.25 (t, 2H), 4.85 (m, 1H), 6.15 (s, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+529 and 531; Ultimate analysis: measured value C, 57.0; H, 5.7; N, 15.7; C
25H
29ClN
6O
5Calculated value C, 56.8; H, 5.5; N, 15.9%.
[7] reactant be 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline and (3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine.With this compound of reaction be heated to 95 ℃ 3 hours.Through column chromatography purification (Waters Symmetry column, 5 microns silica gel, 19mm diameter, 100mm length), the polar compound decrescence that makes water and acetonitrile (containing 1% acetate) is as elutriant on C18 reverse phase silica gel post for reaction product.The evaporation organic solvent is with the pH regulator to 7 of water.With this solution of dichloromethane extraction, organic phase is through dried over mgso and evaporation.The residue that obtains grinds under ether, obtains required product with 64% yield, and it has following characteristic; NMR spectrum: (CDCl
3) 1.55 (d, 6H), 2.35 (m, 2H), 2.9 (t, 2H), 3.25 (d, 2H), 4.25 (t, 2H), 4.6 (m, 2H), 4.85 (m, 1H), 4.9 (s, 1H), 5.15 (s, 1H), 6.15 (s, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+516 and 518; Ultimate analysis: measured value C, 54.7; H, 5.2; N, 13.2; C
24H
26ClN
5O
60.5H
2O calculated value C, 54.9; H, 5.2; N, 13.3%.
[8] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-(2-chloro oxyethyl group)-7-methoxyl group quinazoline (its preparation be described in hereinafter embodiment 7 in) and morpholine.With this compound of reaction be heated to 120 ℃ 16 hours.Obtain required product with 69% yield, and obtain following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) 3.3 (m, 4H), 3.5 (t, 2H), 3.95 (m, 4H), 4.05 (s, 3H), 4.6 (t, 2H), 6.15 (s, 2H), 7.6 (s, 1H), 7.8 (s, 2H), 8.6 (s, 1H); Mass spectrum: M+H
+460 and 462; Ultimate analysis: measured value C, 53.45; H, 4.8; N, 14.5; C
21H
22ClN
5O
50.55H
2O calculated value C, 53.7; H, 5.0; N, 14.9%.
[9] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-(2-chloro oxyethyl group)-7-methoxyl group quinazoline and 1-methylpiperazine.With this compound of reaction be heated to 120 ℃ 16 hours.Reaction product Waters X-Terra silicagel column (C18 is anti-phase, 5 microns, 19mm diameter, 100mm length; Waters Inc., Milford, MA01757 is USA) through column chromatography purification, with the polar compound wash-out decrescence of volatile salt damping fluid (2g/L is in water) and acetonitrile.Collect suitable part, the evaporation organic solvent is allocated between ethyl acetate and the saturated sodium bicarbonate aqueous solution mixture that obtains.Organic phase is through dried over mgso and evaporation.So obtain required product, yield 29%, it has following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) 2.7 (s, 3H), 3.25-3.35 (br m, 10H), 4.05 (s, 3H), 4.45 (t, 2H), 6.15 (s, 2H), 7.55 (s, 1H), 7.7 (s, 1H), 7.8 (s, 1H), 8.65 (s, 1H); Mass spectrum: M+H
+473 and 475; Ultimate analysis: measured value C, 54.9; H, 5.3; N, 17.1; C
22H
25ClN
6O
40.4H
2O calculated value C, 55.0; H, 5.4; N, 17.5%.
[10] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-(2-chloro oxyethyl group)-7-methoxyl group quinazoline and tetramethyleneimine.With this compound of reaction be heated to 120 ℃ 16 hours.Obtain required product with 41% yield, and obtain following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) 2.15 (m, 4H), 3.3-3.6 (br s, 4H), 3.7 (t, 2H), 4.05 (s, 3H), 4.65 (t, 2H), 6.15 (s, 2H), 7.65 (s, 1H), 7.8 (s, 1H), 7.9 (s, 1H), 8.65 (s, 1H); Mass spectrum: M+H
+444 and 446; Ultimate analysis: measured value C, 55.0; H, 5.0; N, 14.9; C
21H
22ClN
5O
40.7H
2O calculated value C, 55.25; H, 5.2; N, 15.3%.
[11] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-(2-chloro oxyethyl group)-7-methoxyl group quinazoline and 1-ethanoyl piperazine.With this compound of reaction be heated to 120 ℃ 16 hours.Obtain required product with 51% yield, and obtain following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) 2.15 (s, 3H), 3.1 (m, 2H), 3.2 (m, 2H), 3.4 (t, 2H), 3.75 (m, 2H), 3.85 (m, 2H), 4.0 (s, 3H), 4.55 (t, 2H), 6.15 (s, 2H), 7.6 (s, 1H), 7.7 (s, 1H), 7.8 (s, 1H), 8.6 (s, 1H); Mass spectrum: M+H
+501 and 503.
[12] reactant be 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-(2-chloro oxyethyl group)-7-methoxyl group quinazoline and (3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine.With this compound of reaction be heated to 120 ℃ 16 hours.Obtain required product with 73% yield, and obtain following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) 2.95 (m, 2H), 3.45 (t, 2H), 3.65 (d, 2H), 4.05 (s, 3H), 4.55 (t, 2H), 4.8 (m, 3H), 5.2 (s, 1H), 6.15 (s, 2H), 7.6 (s, 1H), 7.75 (s, 1H), 7.8 (s, 1H), 8.65 (s, 1H); Mass spectrum: M+H
+488 and 490.
[13] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-(3-chloro propoxy-)-7-methoxyl group quinazoline (its preparation be described in hereinafter embodiment 8 in) and tetramethyleneimine.With this compound of reaction be heated to 120 ℃ 16 hours.Obtain required product with 50% yield, and obtain following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) 2.1 (m, 4H), 2.4 (m, 2H), 3.0-3.8 (br s, 4H), 3.4 (t, 2H), 4.05 (s, 3H), 4.35 (t, 3H), 6.1 (s, 2H), 7.6 (s, 1H), 7.75 (s, 1H), 7.8 (s, 1H), 8.65 (s, 1H); Mass spectrum: M+H
+458 and 460; Ultimate analysis: measured value C, 57.3; H, 5.4; N, 14.5; C
22H
24ClN
5O
40.15H
2O calculated value C, 57.4; H, 5.3; N, 15.2%.
[14] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-(3-chloro propoxy-)-7-methoxyl group quinazoline and morpholine.With this compound of reaction be heated to 120 ℃ 16 hours.Obtain required product with 72% yield, and obtain following characteristic; NMR spectrum: (CDCl
3) 2.1 (m, 2H), 2.5 (m, 4H), 2.6 (t, 2H), 3.7 (m, 4H), 4.05 (s, 3H), 4.25 (t, 2H), 6.1 (s, 2H), 7.05 (s, 1H), 7.15 (s, 1H), 7.3 (s, 1H), 7.75 (s, 1H), 8.7 (s, 1H); Mass spectrum: M+H
+474 and 476.
[15] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-(3-chloro propoxy-)-7-methoxyl group quinazoline and 1-ethanoyl piperazine.With this compound of reaction be heated to 120 ℃ 16 hours.Obtain required product with 39% yield, and obtain following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) 2.15 (s, 3H), 2.35 (m, 2H), 3.15-3.3 (m, 6H), 3.8 (m, 2H), 3.9 (m, 2H), 4.0 (s, 3H), 4.3 (t, 2H), 6.15 (s, 2H), 7.6 (s, 1H), 7.65 (s, 1H), 7.8 (s, 1H), 8.65 (s, 1H); Mass spectrum: M+H
+515 and 517.
[16] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-(3-chloro propoxy-)-7-methoxyl group quinazoline and 1-ethanoyl piperazine.With this compound of reaction be heated to 120 ℃ 16 hours.Obtain required product with 27% yield, and obtain following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) 2.3 (m, 2H), 2.7 (s, 3H), 3.3 (t, 2H), 3.4 (m, 4H), 3.5 (m, 4H), 4.0 (s, 3H), 4.3 (t, 2H), 6.15 (s, 2H), 7.6 (s, 1H), 7.65 (s, 1H), 7.8 (s, 1H), 8.65 (s, 1H); Mass spectrum: M+H
+487 and 489.
[17] reactant be 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-(3-chloro propoxy-)-7-methoxyl group quinazoline and (3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine.With this compound of reaction be heated to 95 ℃ 3 hours.Reaction product on C18 reverse phase silica gel post (WatersSymmetry post, 5 microns silica gel, 19mm diameter, 100mm length) through column chromatography purification, the polar compound decrescence of water and acetonitrile (containing 1% acetate) is as elutriant.The evaporation organic solvent is with the pH regulator to 7 of water.With this solution of dichloromethane extraction, organic phase is through dried over mgso and evaporation.The residue that obtains grinds under ether, obtains required product with 57% yield, and it has following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) 2.3 (m, 2H), 3.3 (m, 2H), 3.4 (t, 2H), 3.6 (d, 2H), 4.0 (s, 3H), 4.3 (t, 2H), 4.8 (m, 3H), 5.2 (s, 1H), 6.15 (s, 2H), 7.55 (s, 1H), 7.6 (s, 1H), 7.8 (s, 1H), 8.6 (s, 1H); Mass spectrum: M+H
+502 and 504.
[18] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(2-chloro oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline and 1-Propargyl piperazine.With this compound of reaction be heated to 80 ℃ 3 hours, be heated to then 110 ℃ 5 hours.Reaction product at Waters X-Terra silicagel column (C18 is anti-phase, 5 microns, 19mm diameter, 100mm length) through column chromatography purification, with the polar compound wash-out decrescence of volatile salt damping fluid (2g/L is in water) and acetonitrile.Collect suitable part, the evaporation organic solvent is allocated between ethyl acetate and the saturated sodium bicarbonate aqueous solution mixture that obtains.Organic phase is through dried over mgso and evaporation.So obtain required product, yield 54%, it has following characteristic; NMR spectrum: (DMSOd
6And CD
3CO
2D) 1.85 (m, 2H), 2.15 (m, 2H), 2.5-3.0 (m, 10H), 3.15 (s, 1H), 3.3 (s, 2H), 3.55 (t, 2H), 3.9 (m, 2H), 4.3 (m, 2H), 5.05 (m, 1H), 6.2 (s, 2H), 6.9 (s, 2H), 7.8 (s, 1H), 8.5 (s, 1H); Mass spectrum: M+H
+567 and 569; Ultimate analysis: measured value C, 55.9; H, 5.6; N, 14.0; C
28H
31ClN
6O
52H
2O calculated value C, 55.8; H, 5.85; N, 13.9%.
[19] adopt the condition of explaining detailed description in [18] at the preceding paragraph, make 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-and 7-(2-chloro oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline and morpholine reaction, obtain required product with 48% yield, it has following characteristic; NMR spectrum: (DMSOd
6And CD
3CO
2D) 1.8 (m, 2H), 2.15 (m, 2H), 2.55 (m, 4H), 2.8 (m, 2H), 3.5 (m, 2H), 3.6 (m, 4H), 3.9 (m, 2H), 4.3 (t, 2H), 5.1 (m, 1H), 6.2 (s, 2H), 6.9 (m, 2H), 7.8 (s, 1H), 8.45 (s, 1H); Mass spectrum: M+H
+530 and 532; Ultimate analysis: measured value C, 51.8; H, 5.8; N, 12.1; C
25H
28ClN
5O
62.5H
2O calculated value C, 52.2; H, 5.8; N, 12.2%.
[20] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-chloro propoxy-)-5-tetrahydropyran-4-base oxygen base quinazoline (be described in hereinafter embodiment 9 in) and morpholine.Obtain required product with 30% yield, and obtain following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) 2.05 (m, 2H), 2.35 (m, 4H), 3.15 (m, 2H), 3.45 (m, 2H), 3.75 (m, 4H), 3.9 (m, 2H), 4.2 (m, 6H), 5.0 (m, 1H), 6.3 (s, 2H), 6.85 (s, 1H), 7.0 (s, 1H), 7.9 (s, 1H), 8.7 (s, 1H); Mass spectrum: M+H
+544 and 546.
[21] reactant is 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-chloro propoxy-)-5-tetrahydropyran-4-base oxygen base quinazoline and 1-Propargyl piperazine.Reaction product on C18 reverse phase silica gel post (Waters Symmetry post, 5 microns silica gel, 19mm diameter, 100mm length) through column chromatography purification, the polar compound decrescence of water and acetonitrile (containing 1% acetate) is as elutriant.The evaporation organic solvent is with the pH regulator to 9 of water.With this solution of dichloromethane extraction, organic phase is through dried over mgso and evaporation.The residue that obtains grinds under pentane, obtains required product, yield 48%, and it has following characteristic; NMR spectrum: (DMSOd
6And CD
3CO
2D) 1.85 (m, 2H), 2.0 (m, 2H), 2.15 (m, 2H), 2.5-2.8 (br m, 10H), 3.15 (s, 1H), 3.3 (s, 2H), 3.55 (t, 2H), 3.9 (m, 2H), 4.2 (t, 2H), 5.05 (m, 1H), 6.2 (s, 2H), 6.85 (s, 1H), 6.9 (s, 1H), 7.8 (s, 1H), 8.45 (s, 1H); Mass spectrum: M+H
+581 and 583.
[22] reactant is 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline and piperazine.Obtain required product with 30% yield, and obtain following characteristic; NMR spectrum: (CDCl
3) 1.55 (d, 6H), 2.6 (m, 4H), 2.85 (t, 2H), 2.95 (m, 4H), 4.25 (t, 2H), 4.85 (m, 1H), 6.15 (s, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+487 and 489; Ultimate analysis: measured value C, 55.4; H, 5.5; N, 16.4; C
23H
27ClN
6O
40.1Et
2O 0.6H
2O calculated value C, 55.65; H, 5.8; N, 16.6%.
[23] reactant is 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline and 1-(2-hydroxyethyl) piperazine.With this compound of reaction be heated to 85 ℃ 8 hours.Reaction product is through purification by silica gel column chromatography, and the cumulative polar compound of using methylene dichloride and methyl alcohol is as elutriant.The raw material that obtains grinds under ether, obtains required product, yield 67%, and it has following characteristic; NMR spectrum: (CDCl
3) 1.5 (d, 6H), 2.5-2.7 (br m, 12H), 3.65 (t, 2H), 4.25 (t, 2H), 4.8 (m, 1H), 6.15 (s, 2H), 6.6 (s, 1H), 6.85 (s, 1H), 7.25 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+531 and 533; Ultimate analysis: measured value C, 55.4; H, 6.05; N, 15.2; C
25H
31ClN
6O
50.1Et
2O 0.5H
2O calculated value C, 55.7; H, 6.1; N, 15.35%.
[24] reactant is 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline and tetramethyleneimine.With this compound of reaction be heated to 80 ℃ 4 hours.Reaction product on C18 reverse phase silica gel post (Waters Symmetry post, 5 microns silica gel, 19mm diameter, 100mm length) through column chromatography purification, the polar compound decrescence of water and acetonitrile (containing 1% acetate) is as elutriant.The evaporation organic solvent is with the pH regulator to 9 of water.With this solution of dichloromethane extraction, organic phase is through dried over mgso and evaporation.The residue that obtains grinds under pentane, obtains required product with 62% yield, and it has following characteristic; NMR spectrum: (CDCl
3) 1.55 (d, 6H), 1.85 (m, 4H), 2.6 (m, 4H), 2.95 (t, 2H), 4.25 (t, 2H), 4.85 (m, 1H), 6.15 (s, 2H), 6.6 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+472 and 474; Ultimate analysis: measured value C, 58.3; H, 5.4; N, 14.7; C
23H
26ClN
5O
4Calculated value C, 58.5; H, 5.55; N, 14.8%.
[25] adopt the condition of explaining [24] detailed description at the preceding paragraph, make 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-and 7-(2-chloro oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline and piperidines reaction, obtain required product with 52% yield, it has following characteristic; NMR spectrum: (CDCl
3) 1.45 (m, 2H), 1.55 (d, 6H), 1.65 (m, 4H), 2.5 (m, 4H), 2.85 (t, 2H), 4.25 (t, 2H), 4.85 (m, 1H), 6.15 (s, 2H), 6.6 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+486 and 488; Ultimate analysis: measured value C, 59.3; H, 5.9; N, 14.4; C
24H
28ClN
5O
4Calculated value C, 59.3; H, 5.8; N, 14.4%.
[26] adopt the above condition that [24] are described in detail of explaining, make 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-and 7-(2-chloro oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline and morpholine reaction, obtain required product with 57% yield, it has following characteristic; NMR spectrum: (CDCl
3) 1.55 (d, 6H), 2.6 (m, 4H), 2.85 (t, 2H), 3.75 (m, 4H), 4.25 (t, 2H), 4.85 (m, 1H), 6.15 (s, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+488 and 490; Ultimate analysis: measured value C, 56.6; H, 5.4; N, 14.2; C
23H
26ClN
5O
5Calculated value C, 56.6; H, 5.4; N, 14.35%.
[27] adopt the above condition that [24] are described in detail of explaining, make 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(2-chloro oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline and the reaction of 1-Propargyl piperazine, obtain required product with 41% yield, it has following characteristic; NMR spectrum: (CDCl
3) 1.55 (d, 6H), 2.25 (s, 1H), 2.65 (br m, 8H), 2.9 (t, 2H), 3.3 (s, 2H), 4.25 (t, 2H), 4.85 (m, 1H), 6.15 (s, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+525 and 527; Ultimate analysis: measured value C, 59.3; H, 5.4; N, 15.85; C
26H
29ClN
6O
4Calculated value C, 59.5; H, 5.6; N, 16.0%.
[28] reactant be 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline and (3RS, 4SR)-3,4-dimethoxy tetramethyleneimine.Obtain required product with 78% yield, and obtain following characteristic; NMR spectrum: (DMSOd
6And CD
3CO
2D) 1.45 (d, 6H), 2.7 (m, 2H), 3.0 (m, 2H), 3.15 (m, 2H), 3.3 (s, 6H), 3.75 (m, 2H), 4.25 (t, 2H), 5.5 (m, 1H), 6.2 (s, 2H), 6.8 (s, 1H), 6.85 (s, 1H), 7.8 (s, 1H), 8.45 (s, 1H); Mass spectrum: M+H
+532 and 534; Ultimate analysis: measured value C, 56.0; H, 5.6; N, 12.85; C
25H
30ClN
5O
60.3H
2O calculated value C, 56.25; H, 5.7; N, 13.1%.
Following acquisition as starting raw material (3RS, 4SR)-3,4-dimethoxy tetramethyleneimine:
Will (3RS, 4SR)-3, the DMF solution (20 ml) of 4-dihydroxy pyrrolidine-1-formic acid tertiary butyl ester (1g) is cooled to 0-5 ℃, and (60% is scattered in the mineral oil, 0.433g) to be added dropwise to sodium hydride.This compound of reaction was stirred 1 hour in 5 ℃.Add methyl-iodide (0.675ml), make this reaction mixture be warming up to room temperature, stirred 16 hours.Evaporation DMF is allocated between ether and the water residue.Water and salt water washing organic phase are through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, with sherwood oil (b.p.40-60 ℃) and ethyl acetate cumulative polar compound as elutriant.So obtain (3RS, 4SR)-3,4-dimethoxy tetramethyleneimine-1-formic acid tertiary butyl ester is oily matter (1.06g); NMR spectrum: (CDCl
3) 1.45 (s, 9H), 3.35 (m, 1H), 3.45 (s, 6H), 3.5 (m, 2H), 3.55 (m, 1H), 3.85 (m, 2H).
The aqueous isopropanol (3ml) of refrigerative 5M hydrogenchloride is joined (3RS, 4SR)-3, the methylene dichloride (25ml) of 4-dimethoxy tetramethyleneimine-1-formic acid tertiary butyl ester (1g) on ice bath in the refrigerative solution.Make this reaction mixture be warming up to room temperature, stirred 16 hours.Evaporating solvent.So obtain (3RS, 4SR)-3,4-dimethoxy pyrrolidine hydrochloride is oily matter (0.72g); NMR spectrum: (DMSOd
6) 3.1 (m, 2H), 3.25 (m, 2H), 3.35 (s, 6H), 4.0 (m, 2H), 9.3 (br s, 1H), 9.5 (br s, 1H).
The raw material of acquisition like this is dissolved in the methylene dichloride, adds 7M methyl alcohol system ammonia solution (0.2ml).The mixture that stirring obtains under room temperature 5 minutes.Filter this mixture, vacuum evaporating solvent under room temperature.So obtain (3RS, 4SR)-3,4-dimethoxy tetramethyleneimine, it need not any further purifying and use.
[29] adopt the condition that describes in detail above note [24], except product grinds under ether, rather than outside under pentane, grinding, make 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(2-chloro oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline with (3RS, 4SR)-3,4-ethylidene dioxy base tetramethyleneimine reaction, obtain required product with 67% yield, it has following characteristic; NMR spectrum: (CDCl
3) 1.45 (d, 3H), 1.55 (d, 6H), 2.3 (d, 2H), 2.95 (m, 2H), 3.25 (d, 2H), 4.25 (t, 2H), 4.55 (m, 2H), 4.8 (m, 1H), 5.0 (m, 1H), 6.15 (s, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+530 and 532; Ultimate analysis: measured value C, 56.7; H, 5.5; N, 12.9; C
25H
28ClN
5O
60.1Et
2O calculated value C, 56.8; H, 5.4; N, 13.0%.
Following acquisition as starting raw material (3RS, 4SR)-3,4-ethylidene dioxy base tetramethyleneimine:
With (3RS, 4SR)-3, the dichloromethane solution (15ml) of 4-dihydroxy pyrrolidine-1-formic acid tertiary butyl ester (0.5g) is cooled to 0-5 ℃, adds dimethylacetal (0.782ml) and 4-toluenesulphonic acids (0.025g) successively.Under room temperature, stirred this reaction mixture 2 hours.The mixture that obtains of evaporation, residue be through purification by silica gel column chromatography, with sherwood oil (b.p.40-60 ℃) and ethyl acetate cumulative polar compound as elutriant.So obtain (3RS, 4SR)-3,4-ethylidene dioxy base tetramethyleneimine-1-formic acid tertiary butyl ester is oily matter (0.484 g); NMR spectrum: (CDCl
3) 1.4 (d, 3H), 1.45 (s, 9H), 3.3 (m, 2H), 3.8 (m, 2H), 4.6 (m, 2H), 5.0 (q, 1H).
The aqueous isopropanol (4ml) of refrigerative 5M hydrogenchloride is joined (3RS, 4SR)-3, the methylene dichloride (25ml) of 4-ethylidene dioxy base tetramethyleneimine-1-formic acid tertiary butyl ester (0.475g) on ice bath in the refrigerative solution.Make this reaction mixture be warming up to room temperature, stirred 2 hours.Evaporating solvent, residue grinds under ether.Filter collecting precipitation, with ether washing and dry.So obtain (3RS, 4SR)-3,4-ethylidene dioxy base pyrrolidine hydrochloride (0.28g); NMR spectrum: (DMSOd
6And CD
3CO
2D) 1.35 (d, 3H), 3.1 (d, 2H), 3.4 (d, 2H), 4.75 (s, 2H), 4.9 (q, 1H).
The raw material of acquisition like this is dissolved in the methylene dichloride, adds 7M methyl alcohol system ammonia solution (0.2ml).The mixture that stirring obtains under room temperature 5 minutes.Filter this mixture, vacuum evaporating solvent under room temperature.So obtain (3RS, 4SR)-3,4-ethylidene dioxy base tetramethyleneimine, it need not any further purifying and use.
[30] reactant is 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino) quinazoline and 1-methylpiperazine.Obtain required product with 74% yield, and obtain following characteristic; NMR spectrum: (CDCl
3And CD
3CO
2D) mass spectrum: M+H
+501 and 503; Ultimate analysis: measured value C, 57.5; H, 6.5; N, 16.0; C
24H
29ClN
6O
40.23H
2O calculated value C, 57.8; H, 6.1; N, 16.2%.
[31] reactant is 7-(3-chloro propoxy-)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline (its preparation be described in hereinafter embodiment 12 in) and morpholine.Obtain required product with 39% yield, and obtain following characteristic; NMR spectrum: (CDCl
3) 1.55 (d, 6H), 2.05 (m, 2H), 2.45 (m, 4H), 2.55 (t, 2H), 3.7 (m, 4H), 4.15 (t, 2H), 4.85 (m, 1H), 6.15 (s, 2H), 6.5 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+502 and 504; Ultimate analysis: measured value C, 57.3; H, 5.65; N, 13.6; C
24H
28ClN
5O
5Calculated value C, 57.4; H, 5.6; N, 13.95%.
[32] reactant is 7-(3-chloro propoxy-)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino) quinazoline (its preparation be described in hereinafter embodiment 13 in) and morpholine.Obtain required product with 45% yield, and obtain following characteristic; NMR spectrum: (DMSOd
6And CF
3CO
2D) 2.3 (m, 2H), 3.15 (m, 2H), 3.35 (m, 2H), 3.5 (m, 2H), 3.7 (m, 2H), 4.05 (m, 2H), 4.35 (m, 2H), 6.3 (s, 2H), 7.35 (s, 1H), 7.6 (d, 1H), 7.9 (s, 1H), 8.7 (d, 1H), 9.05 (s, 1H); Mass spectrum: M+H
+444 and 446; Ultimate analysis: measured value C, 57.0; H, 5.1; N, 15.7; C
21H
22ClN
5O
4Calculated value C, 56.8; H, 5.0; N, 15.8%.
[33] reactant is 7-(3-chloro propoxy-)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino) quinazoline and 1-ethanoyl piperazine.Obtain required product with 34% yield, and obtain following characteristic; NMR spectrum: (DMSOd
6And CF
3CO
2D) 2.05 (s, 3H), 2.3 (s, 2H), 3.0 (m, 2H), 3.15 (m, 1H), 3.3-3.4 (m, 4H), 3.6 (m, 2H), 4.05 (m, 1H), 4.35 (m, 2H), 4.5 (m, 1H), 6.3 (s, 2H), 7.35 (s, 1H), 7.6 (d, 1H), 7.9 (s, 1H), 8.7 (d, 1H), 9.0 (s, 1H); Mass spectrum: M+H485 and 487; Ultimate analysis: measured value C, 56.9; H, 5.4; N, 16.6; C
23H
25ClN
6O
40.15Et
2O calculated value C, 57.1; H, 5.4; N, 16.9%.
[34] reactant is 7-(2-chloro oxyethyl group)-4-(2,3-methylene-dioxy pyridin-4-yl amino) quinazoline (its preparation be described in hereinafter embodiment 14 in) and 1-Propargyl piperazine.After the reaction mixture, evaporating solvent, residue grind in the presence of water, filter the precipitation that generates, water and ether washing, drying.With 60% yield, obtain required product, and obtain following characteristic; NMR spectrum: (CDCl
3) 2.26 (s, 1H), 2.8-2.6 (m, 8H), 2.97 (t, 2H), 3.3 (s, 2H); 4.03 (s, 3H), 4.33 (t, 2H), 6.14 (s, 2H), 6.98 (s, 1H), 7.12 (br s, 1H), 7.30 (s, 1H), 7.73 (d, 1H), 8.08 (d, 1H), 8.76 (s, 1H); Mass spectrum: M+H
+463.
[35] reactant is 7-(3-chloro propoxy-)-4-(2,3-methylene-dioxy pyridin-4-yl amino) quinazoline (its preparation be described in hereinafter embodiment 15 in) and 1-Propargyl piperazine.Obtain required product with 57% yield, and obtain following characteristic; NMR spectrum: (CDCl
3) 2.13 (m, 2H), 2.26 (s, 1H), 2.6 (m, 10H), 3.31 (s, 2H), 4.04 (s, 3H), 4.26 (t, 2H), 6.14 (s, 2H), 6.98 (s, 1H), 7.12 (br s, 1H), 7.31 (s, 1H), 7.72 (d, 1H), 8.08 (d, 1H), 8.76 (s, 1H); Mass spectrum: M+H
+477.
Embodiment 7
6-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-methoxyl group quinazoline
Adopt and the similar method of method described in the embodiment 1, make 4-chloro-6-(2-chloro oxyethyl group)-7-methoxyl group quinazoline and 4-amino-5-chloro-2, the reaction of 3-(methylenedioxy) yl pyridines obtains title compound with 59% yield; NMR spectrum: (CDCl
3) 3.95 (t, 2H), 4.05 (s, 3H), 4.4 (t, 2H), 6.1 (s, 2H), 7.05 (s, 1H), 7.2 (s, 1H), 7.35 (s, 1H), 7.75 (s, 1H), 8.75 (s, 1H); Mass spectrum: M+H
+409 and 411.
Be prepared as follows 4-chloro-6-(2-chloro oxyethyl group)-7-methoxyl group quinazoline as starting raw material:
With 6-acetoxyl group-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (International Patent Application WO 96/15118, embodiment 39; 8g), the mixture of thionyl chloride (80ml) and DMF (0.8ml) stir and be heated to 80 ℃ 1.5 hours.Make this mixture be cooled to room temperature, the evaporation thionyl chloride.The raw material of acquisition like this is suspended in the toluene, is evaporated to dried (twice).The residue that obtains dilutes with methylene dichloride (5ml), adds 10: 1 mixtures (290ml) of methyl alcohol and saturated ammonium hydroxide aqueous solution.The mixture that stirring obtains and be heated to 80 ℃ 5 minutes.Evaporating solvent suspends in water solid residue.By adding diluted hydrochloric acid aqueous solution the alkalescence of this mixture is adjusted to pH7.Filter and collect the solid that generates, wash vacuum-drying on five phosphorus oxide with water.So obtain 4-chloro-6-hydroxyl-7-methoxyl group quinazoline (6.08g), it need not be further purified and use; NMR spectrum: (DMSOd
6) 4.05 (s, 3H), 7.4 (s, 1H), 7.45 (s, 1H), 8.8 (s, 1H).
In the mixture with the 4-chloro-6-hydroxyl-7-methoxyl group quinazoline (1g), 2-chloro ethanol (0.382ml), triphenylphosphine (1.74g) and the methylene dichloride (30ml) that azo-2-carboxylic acid's di-t-butyl ester (1.53ml) were added drop-wise in several minutes stirring, stirred reaction mixture is 2 hours under room temperature.Evaporate this mixture and residue through purification by silica gel column chromatography, the cumulative polar compound of using methylene dichloride and ethyl acetate is as elutriant.So obtain 4-chloro-6-(2-chloro oxyethyl group)-7-methoxyl group quinazoline, be white solid (1.06g); NMR spectrum: (CDCl
3) 3.95 (t, 2H), 4.05 (s, 3H), 4.45 (t, 2H), 7.35 (s, 1H), 7.4 (s, 1H), 8.9 (s, 1H).
Embodiment 8
6-(3-chloro propoxy-)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-methoxyl group quinazoline
Adopt and the similar method of method described in the embodiment 1, make 4-chloro-6-(3-chloro propoxy-)-7-methoxyl group quinazoline and 4-amino-5-chloro-2, the reaction of 3-(methylenedioxy) yl pyridines obtains title compound with 58% yield; NMR spectrum: (CDCl
3) 2.4 (m, 2H), 3.8 (t, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 6.15 (s, 2H), 7.05 (s, 1H), 7.2 (s, 1H), 7.3 (s, 1H), 7.75 (s, 1H), 8.7 (s, 1H); Mass spectrum: M+H
+423 and 425.
Be prepared as follows 4-chloro-6-(3-chloro propoxy-)-7-methoxyl group quinazoline as starting raw material:
In the mixture with the 4-chloro-6-hydroxyl-7-methoxyl group quinazoline (1.2g), 3-chloro propyl alcohol (0.572ml), triphenylphosphine (2.1g) and the methylene dichloride (30ml) that azo-2-carboxylic acid's di-t-butyl ester (1.84g) were added drop-wise in several minutes stirring, stirred reaction mixture is 3 hours under room temperature.Evaporate this mixture, residue is through purification by silica gel column chromatography, with the cumulative mixed solution of the polarity of methylene dichloride and ethyl acetate as elutriant.The raw material that so obtains is ground under ether.Separate the solid that obtains, vacuum-drying.So obtain 4-chloro-6-(3-chloro propoxy-)-7-methoxyl group quinazoline, be white solid (0.84g); NMR spectrum: (CDCl
3) 2.4 (m, 2H), 3.8 (t, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 7.35 (s, 1H), 7.45 (s, 1H), 8.9 (s, 1H).
Embodiment 9
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-chloro propoxy-)-5-tetrahydropyran-4-base oxygen base quinazoline
Adopt and the similar method of method described in the embodiment 1, make 4-chloro-7-(3-chloro propoxy-)-5-tetrahydropyran-4-base oxygen base quinazoline and 4-amino-5-chloro-2, the reaction of 3-(methylenedioxy) yl pyridines obtains title compound with 78% yield; Mass spectrum: M+H
+493 and 495.
Be prepared as follows 4-chloro-7-(3-chloro propoxy-)-5-tetrahydropyran-4-base oxygen base quinazoline as starting raw material:
Adopt and relate to the similar method of the method for describing in the part that prepare starting raw material, 4-chloro-7-hydroxyl-5-tetrahydropyran-4-base oxygen base quinazoline (2.5 g) and 3-chloro propyl alcohol are reacted at embodiment 4.So obtain required starting raw material, yield 21%; NMR spectrum: (DMSOd
6And CF
3CO
2D) 1.7 (m, 2H), 2.0 (m, 2H), 2.25 (m, 2H), 3.55 (m, 2H), 3.8 (t, 2H), 3.9 (m, 2H), 4.3 (t, 2H), 4.95 (m, 1H), 6.8 (s, 1H), 6.9 (s, 1H), 9.2 (s, 1H).
Embodiment 10
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(2,4-dimethoxy benzyloxy)-5-isopropoxy quinazoline
Adopt and the similar method of method described in the embodiment 1, make 4-chloro-7-(2,4-dimethoxy benzyloxy)-5-isopropoxy quinazoline and 4-amino-5-chloro-2, the reaction of 3-(methylenedioxy) yl pyridines obtains title compound with 75% yield; NMR spectrum: (CDCl
3) 1.55 (d, 6H), 3.8 (s, 3H), 3.85 (s, 3H), 4.8 (m, 1H), 5.15 (s, 2H), 6.15 (s, 2H), 6.5 (m, 2H), 6.6 (s, 1H), 7.0 (s, 1H), 7.35 (d, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+525 and 527.
Be prepared as follows 4-chloro-7-(2,4-dimethoxy benzyloxy)-5-isopropoxy quinazoline as starting raw material:
(60% is scattered in the mineral oil with sodium hydride; 40g) DMF (500ml) that in batches joins Virahol (30g) has been cooled in 5 ℃ the solution.Make this mixture be warming up to room temperature, stirred 60 minutes.Add 5,7-two fluoro-3,4-dihydroquinazoline-4-ketone (International Patent Application WO 01/94341; 90g), under room temperature, stirred this mixture 3 hours.In this mixture impouring water (1 liter), under the vigorous stirring, add Glacial acetic acid, so that this mixture is acidified to pH5.Separate the solid that obtains, water and ether washing, vacuum-drying.So obtain 7-fluoro-5-isopropoxy-3,4-dihydroquinazoline-4-ketone (79g); NMR spectrum: (DMSOd
6) 1.31 (s, 6H), 4.73 (m, 1H), 6.89 (m, 1H), 6.95 (m, 1H), 7.96 (s, 1H); Mass spectrum: M+H
+223.
With 7-fluoro-5-isopropoxy-3,4-dihydroquinazoline-4-ketone (61g), 2, the mixture of 4-dimethoxy-benzyl alcohol (138g), potassium tert.-butoxide (185g) and THF (1.5 liters) stir and are heated to and refluxed 18 hours.After the cooling, evaporating solvent, the mixture of adding methylene dichloride (400ml) and water (600ml).Cooling down, by adding 2N aqueous hydrochloric acid this 2-phase mixed solution that neutralizes.Filter this mixture, separate organic phase, through dried over mgso and evaporation.Residue grinds under ether.So obtain 7-(2,4-dimethoxy benzyloxy)-5-isopropoxy-3,4-dihydroquinazoline-4-ketone (68g); NMR spectrum: (DMSOd
6) 1.28 (s, 6H), 3.78 (s, 3H), 3.82 (s, 3H), 4.63 (m, 1H), 5.06 (s, 2H), 6.55 (m, 2H), 6.62 (s, 1H), 6.71 (s, 1H), 7.33 (d, 1H), 7.88 (s, 1H); Mass spectrum: M+H
+371.
The mixture stirring of raw material (4g), phosphoryl chloride (1.98g), diisopropylethylamine (3.6g) and the methylene dichloride (100ml) that portion is so obtained and be heated to 75 ℃ 3 hours.Cool off this mixture, evaporation.Vacuum-drying residue 1 hour, through purification by silica gel column chromatography, 20: 3 mixtures using methylene dichloride and ethyl acetate are as elutriant.So obtain 4-chloro-7-(2,4-dimethoxy benzyloxy)-5-isopropoxy quinazoline, be a kind of solid (2.63g); NMR spectrum: (CDCl
3) 1.46 (s, 3H), 1.47 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 4.68 (m, 1H), 5.16 (s, 2H), 6.52 (m, 2H), 6.65 (s, 1H), 7.06 (s, 1H), 7.33 (d, 1H), 8.78 (s, 1H); Mass spectrum: M+H
+389.
Embodiment 11
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-hydroxyl-5-isopropoxy quinazoline
Trifluoroacetic acid (4.5ml) is joined 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(2,4-dimethoxy benzyloxy)-methylene dichloride (9ml) solution of 5-isopropoxy quinazoline (0.53g) in, stirred reaction mixture is 30 minutes under room temperature.Evaporating solvent obtains the two-trifluoroacetate (0.618g) of required compound.A such salt is dissolved in the methylene dichloride (2ml), adds 7M methyl alcohol system ammonia solution.Filter this mixture, evaporated filtrate.So obtain title compound; Mass spectrum: M+H
+375 and 377.
Embodiment 12
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-chloro propoxy-)-5-isopropoxy quinazoline
With 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-hydroxyl-5-isopropoxy quinazoline two-trifluoroacetate (0.615g), 1, the mixture of 3-dichloro-propane (0.38ml), salt of wormwood (0.56g) and DMF (6ml) stir and be heated to 80 ℃ 5 hours.After the cooling, filtering solid, evaporated filtrate.Residue is through purification by silica gel column chromatography, and 24: 1 mixtures using methylene dichloride and methyl alcohol are as elutriant.So obtain title compound (0.32g); NMR spectrum: (CDCl
3) 1.55 (d, 6H), 2.3 (m, 2H), 3.8 (t, 2H), 4.25 (t, 2H), 4.9 (m, 1H), 6.15 (s, 2H), 6.5 (s, 1H), 6.9 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H).
Embodiment 13
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-chloro propoxy-) quinazoline
Adopt and the similar method of method described in the embodiment 1, make 4-chloro-7-(3-chloro propoxy-) quinazoline and 4-amino-5-chloro-2,3-(methylenedioxy) yl pyridines obtains title compound with 89% yield; NMR spectrum: (DMSOd
6And CF
3CO
2D) 2.25 (m, 2H), 3.8 (t, 2H), 4.35 (t, 2H), 6.25 (s, 2H), 7.35 (s, 1H), 7.6 (d, 1H), 7.9 (s, 1H), 8.7 (d, 1H), 9.0 (s, 1H).
Be prepared as follows 4-chloro-7-(3-chloro propoxy-) quinazoline as starting raw material:
(60% was scattered in the mineral oil with sodium hydride with 45 minutes; 2.92g) being added drop-wise to 1 of stirring, ammediol (5.3ml) and DMF (20ml) have been cooled in 0 ℃ the mixed solution.The mixture that stirring obtains under room temperature 1 hour is heated to 60 ℃ then.Add 7-fluoro-3, and 4-dihydroquinazoline-4-ketone (International Patent Application WO 01/04102, embodiment 2, its note [12]; 2g), this compound of reaction is stirred and is heated to 115 ℃ 3.5 hours.Make reaction mixture be cooled to 0 ℃, add entry (50ml).With the 2N aqueous hydrochloric acid this mixture is acidified to pH5.9.Filter and collect the precipitation that produces, wash with water, in 40 ℃ of vacuum-dryings on five phosphorus oxide.With the solid that the ether washing so obtains, vacuum-drying once more.So obtain 7-(3-hydroxyl propoxy-)-3,4-dihydroquinazoline-4-ketone (2.1g); NMR spectrum: (DMSOd
6) 1.9 (m, 2H), 3.6 (m, 2H), 4.15 (m, 2H), 4.6 (br s, 2H), 7.1 (m, 2H), 8.05 (m, 2H); Mass spectrum: M+H
+221.
With 7-(3-hydroxyl propoxy-)-3,4-dihydroquinazoline-4-ketone (1g), 1, the mixture of 2-ethylene dichloride (50ml), triphenylphosphine (5.24g) and tetracol phenixin (2.9ml) stir and be heated to 70 ℃ 2 hours.Evaporating solvent, residue be through purification by silica gel column chromatography, use earlier methylene dichloride, and the solvent of mixed solution of following the methylene dichloride up to 9: 1 that increases gradually with polarity and methyl alcohol is as elutriant.So obtain 4-chloro-7-(3-chloro propoxy-) quinazoline (1.23g; Contain 0.6 mole of triphenylphosphine oxidation thing/every product of moles); Mass spectrum: M+H
+393 and 395.
Embodiment 14
7-(2-chloro oxyethyl group)-4-(2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group quinazoline
With hexamethyldisilane base ammonification sodium (the THF solution of 1M; 2ml) be added drop-wise to 4-amino-2,3-(methylenedioxy) yl pyridines (0.138g), 4-chloro-7-(2-chloro oxyethyl group)-6-methoxyl group quinazoline (0.272g) and THF (5ml) have been cooled in 0 ℃ the mixture.This mixture was stirred 1 hour in 0 ℃.Make the mixture that obtains be warming up to room temperature, stirred 2 hours.By adding Glacial acetic acid (0.12ml) quencher reaction.Evaporating solvent is allocated between methylene dichloride and the ammonium hydroxide aqueous solution residue.Collected organic layer is concentrated into small volume.Add ether, form precipitation.Separate the solid that obtains, with ether washing and dry.So obtain title compound (0.245g); NMR spectrum: (DMSOd
6) 3.97 (s, 3H), 4.04 (m, 2H), 4.45 (m, 2H), 6.12 (s, 2H), 7.13 (br d, 1H), 7.25 (s, 1H), 7.60 (d, 1H), 7.83 (s, 1H), 8.47 (s, 1H), 9.87 (br s, 1H); Mass spectrum: M+H
+375.
Be prepared as follows 4-amino-2,3-(methylenedioxy) yl pyridines as starting raw material:
Two bromo methane (31.5ml) are joined 2, in the mixture of 3-dihydroxy-pyridine (33g), salt of wormwood (62g) and NMP (200ml), this mixture stirred and is heated to 90 ℃ 16 hours.This mixture is cooled to room temperature and filtration.Make filtrate distribution in ether (5 * 100ml) and water (200ml) between.Merge organic extraction, vacuum concentration is to the volume of about 20ml.Add (b.p 40-60 ℃ of sherwood oil; 300ml), with the salt water washing of this solution.Separate organic layer, evaporation.So obtain 2,3-(methylenedioxy) yl pyridines is liquid (5.1g); NMR spectrum: (CDCl
3) 6.05 (s, 2H), 6.76 (m, 1H), 6.99 (d, 1H), 7.65 (d, 1H).
Adopt and relate to preparation starting raw material 4-amino-5-chloro-2 at embodiment 1, the similar method of describing in part second paragraph of 3-(methylenedioxy) yl pyridines of method, make 2,3-(methylenedioxy) yl pyridines and carbon dioxide gas precursor reactant, obtain 2 with 80% yield, 3-(methylenedioxy) yl pyridines-4-carboxylic acid; NMR spectrum: (DMSOd
6) 6.24 (s, 2H), 7.13 (d, 1H); 7.63 (d, 1H).
Adopt and relate to the similar method of describing in part the 3rd paragraph for preparing starting raw material of method at embodiment 1, make 2,3-(methylenedioxy) yl pyridines-4-carboxylic acid and diphenyl phosphoryl azide and anhydrous tertiary butanol reaction, obtain 2 with 62% yield, 3-methylene-dioxy pyridin-4-yl carboxylamine tertiary butyl ester; Mass spectrum: M+H
+239.
Adopt and relate to the similar method of describing in the part final stage for preparing starting raw material of method at embodiment 1, make 2,3-methylene-dioxy pyridin-4-yl carboxylamine tertiary butyl ester and trifluoroacetic acid reaction obtain 4-amino-2 with 80% yield, 3-(methylenedioxy) yl pyridines; NMR spectrum: (CDCl
3) 3.98 (m, 2H), 5.98 (s, 2H), 6.24 (d, 1H), 7.44 (d, 1H); Mass spectrum: M+H
+139.
Embodiment 15
7-(3-chloro propoxy-)-4-(2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group quinazoline
Adopt and the similar method of describing in embodiment 14 of method, make 4-chloro-7-(3-chloro propoxy-)-6-methoxyl group quinazoline and 4-amino-2, the reaction of 3-(methylenedioxy) yl pyridines obtains title compound with 68% yield; NMR spectrum: (DMSOd
6) 2.26 (m, 2H), 3.83 (m, 2H), 3.96 (s, 3H), 4.28 (m, 2H), 6.12 (s, 2H), 7.15 (br d, 1H), 7.25 (s, 1H), 7.61 (d, 1H), 7.81 (s, 1H), 8.49 (s, 1H), 9.79 (br s, 1H); Mass spectrum: M+H+389.
Embodiment 16
7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-4-(2,3-methylene-dioxy pyridin-4-yl amino)-5-tetrahydropyran-4-base oxygen base quinazoline
Adopt and the similar method of method described in the embodiment 1, make 7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-4-chloro-5-tetrahydropyran-4-base oxygen base quinazoline (0.113g) and 4-amino-2,3-(methylenedioxy) yl pyridines (0.036g) reaction.With Glacial acetic acid (0.031g) quencher reaction mixture, dilute with methyl alcohol.Evaporate this mixture, residue is gone up through column chromatography purification at C18 reverse phase silica gel post (WatersSymmetry post, 5 microns silica gel, 20mm diameter, 100mm length), and the polar compound decrescence of water and acetonitrile (containing 1% acetate) is as elutriant.So the raw material that obtains dilutes with 7M methyl alcohol system ammonia solution.Evaporate this mixture, the raw material of acquisition is dissolved in the methylene dichloride.This solution obtains title compound through dried over mgso and evaporation, is the foam thing, yield 53%; NMR spectrum: (CDCl
3) 2.02 (m, 2H), 2.1 (s, 3H), 2.22 (m, 2H), 2.6 (m, 4H), 2.9 (m, 2H), 3.51 (m, 2H), 3.6 (m, 2H), 3.66 (m, 2H), 4.1 (m, 2H), 4.25 (m, 2H), 4.73 (m, 1H), 6.13 (s, 2H), 6.59 (s, 1H), 6.9 (s, 1H), 7.7 (d, 1H), 8.36 (d, 1H), 8.66 (s, 1H); Mass spectrum: M+H
+537.
Be prepared as follows 7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group as starting raw material]-4-chloro-5-tetrahydropyran-4-base oxygen base quinazoline:
(60% is scattered in the mineral oil with sodium hydride; 0.6g) DMF (10ml) that in batches joins 4-hydroxy tetrahydro pyrans (0.78g) has been cooled in 5 ℃ the solution.Make this mixture be warming up to room temperature, stirred 15 minutes.Add 5,7-two fluoro-3,4-dihydroquinazoline-4-ketone (International Patent Application WO 01/94341; 0.9g), under room temperature, stirred this mixture 30 minutes.With this mixture impouring water (100ml), under the vigorous stirring, add Glacial acetic acid so that this mixture is acidified to pH5.Separate the solid that obtains, water and ether washing, vacuum-drying.So obtain 7-fluoro-5-tetrahydropyran-4-base oxygen base-3,4-dihydroquinazoline-4-ketone (1.1g); NMR spectrum: (DMSOd
6) 1.6-1.75 (m, 2H), 1.9-2.0 (m, 2H), 3.5-3.6 (m, 2H), 3.85-3.95 (m, 2H), 4.8 (m, 1H), 6.9 (m, 1H), 7.05 (m, 1H), 8.0 (s, 1H); Mass spectrum: M+H265.
After repeating previous reaction, with 7-fluoro-5-tetrahydropyran-4-base oxygen base-3, the mixture of 4-dihydroquinazoline-4-ketone (5.3g), 2-piperazine-1-base ethanol (3.9g), potassium tert.-butoxide (6.7g) and THF (200ml) stirs and is heated to and refluxed 3 hours.Add second part of (6.7g) potassium tert.-butoxide, with this mixture heating up to refluxing other 12 hours.This mixture is cooled to room temperature and filtration.Evaporated filtrate, residue are through purification by silica gel column chromatography, and the mixed solution of using cumulative methylene dichloride of polarity and 7M methyl alcohol system ammonia solution is as elutriant.The raw material that obtains grinds under ether.So obtain 7-(2-piperazine-1-base oxethyl)-5-tetrahydropyran-4-base oxygen base-3,4-dihydroquinazoline-4-ketone (5.2g); NMR spectrum: (DMSOd
6And CF
3CO
2D) 1.75 (m, 2H), 2.03 (m, 2H), 3.2-4.0 (m, 14H), 4.59 (m, 2H), 4.92 (m, 1H), 6.88 (s, 1H), 6.9 (s, 1H), 9.28 (s, 1H); Mass spectrum: M+H
+375.
Diacetyl oxide (1.51ml) is added drop-wise to 7-(2-piperazine-1-the base oxethyl)-5-tetrahydropyran-4-base oxygen base-3 of stirring, in the mixture of 4-dihydroquinazoline-4-ketone (5g) and water (20ml), under room temperature, stirred the mixture that obtains 10 minutes.Evaporation reaction mixture, residue grinds under ether.Separate the solid that obtains, with ether washing, vacuum-drying.So obtain 7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base-3,4-dihydroquinazoline-4-ketone (5.5g); NMR spectrum: (DMSOd
6And CF
3CO
2D) 1.75 (m, 2H), 2.03 (m, 2H), 2.08 (s, 3H), 3.0-4.2 (m, 13H), 4.56 (m, 3H), 4.94 (m, 1H), 6.84 (s, 1H), 6.9 (s, 1H), 9.21 (s, 1H); Mass spectrum: M+H
+417.
With raw material (0.416g), triphenylphosphine (0.655g), the tetracol phenixin (0.34ml) and 1 that portion so obtains, the stirring of the mixture of 2-ethylene dichloride (20ml) and be heated to 70 ℃ 1.5 hours.Evaporate this mixture, residue is through purification by silica gel column chromatography, with the mixed solution of cumulative methylene dichloride of polarity and 7M methyl alcohol system ammonia solution (a kind of gradient solvent that contains the ammonia solution of 1%-3% methyl alcohol) as elutriant.So obtain 7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-4-chloro-5-tetrahydropyran-4-base oxygen base quinazoline, be a kind of solid (0.35 g); NMR spectrum: (CDCl
3) 2.0 (m, 2H), 2.1 (s, 3H), 2.12 (m, 2H), 2.58 (m, 4H), 2.9 (m, 2H), 3.51 (m, 2H), 3.68 (m, 4H), 4.05 (m, 2H), 4.25 (m, 2H), 4.75 (m, 1H), 6.62 (s, 1H), 6.94 (s, 1H), 8.82 (s, 1H); Mass spectrum: M+H
+435 and 437.
Embodiment 17
7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-4-(2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline
Adopt and the similar method of method described in the embodiment 16, make 7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-4-chloro-5-isopropoxy quinazoline and 4-amino-2, the reaction of 3-(methylenedioxy) yl pyridines obtains title compound with 55% yield; NMR spectrum: (CDCl
3) 1.55 (s, 3H), 1.56 (s, 3H), 2.1 (s, 3H), 2.59 (m, 4H), 2.89 (m, 2H), 3.51 (m, 2H), 3.67 (m, 2H), 4.24 (m, 2H), 4.85 (m, 1H), 6.13 (s, 2H), 6.57 (s, 1H), 6.85 (s, 1H), 7.71 (d, 1H), 8.41 (d, 1H), 8.66 (s, 1H); Mass spectrum: M+H
+495.
Adopt with embodiment 16 in relate to the similar method of method described in the part for preparing starting raw material, being prepared as follows need be as 7-[2-(the 4-ethanoyl piperazine-1-yl) oxyethyl group of starting raw material]-4-chloro-5-isopropoxy quinazoline.
Make 5,7-two fluoro-3,4-dihydroquinazoline-4-ketone and isopropanol reaction obtains 7-fluoro-5-isopropoxy-3 with 73% yield, 4-dihydroquinazoline-4-ketone; NMR spectrum: (DMSOd
6) 1.31 (s, 6H), 4.73 (m, 1H), 6.89 (m, 1H), 6.95 (m, 1H), 7.96 (s, 1H); Mass spectrum: M+H
+223.
Make the raw material and the 2-piperazine-1-base ethanol synthesis of acquisition like this, obtain 5-isopropoxy-7-(2-piperazine-1-base oxethyl)-3,4-dihydroquinazoline-4-ketone with 63% yield; NMR spectrum: (CDCl
3) 1.45 (s, 3H), 1.46 (s, 3H), 2.4-3.0 (m, 10H), 4.2 (t, 2H), 4.62 (m, 1H), 6.51 (s, 1H), 6.72 (s, 1H), 7.9 (s, 1H).
Make the raw material and the excessive acetic anhydride via reaction of acquisition like this, but be to use methylene fluoride rather than water as reaction solvent.Under room temperature, stirred this reaction mixture 15 minutes.This mixture is allocated between methylene dichloride and the saturated sodium bicarbonate aqueous solution.Water and salt water washing organic layer are through dried over mgso and evaporation.Residue grinds with the mixed solution of acetonitrile and ether.So obtain 7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-5-isopropoxy-3,4-dihydroquinazoline-4-ketone, 70% yield; NMR spectrum: (CDCl
3) 1.46 (s, 3H), 1.47 (s, 3H), 2.1 (s, 3H), 2.58 (m, 4H), 2.87 (t, 2H), 3.5 (m, 2H), 3.66 (m, 2H), 4.21 (t, 2H), 4.63 (m, 1H), 6.51 (s, 1H), 6.72 (s, 1H), 7.9 (s, 1H), 9.9 (br s, 1H); Mass spectrum: M+H
+375.
Make raw material and the tetracol phenixin and the triphenylphosphine reaction of acquisition like this, obtain 7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group with 68% yield]-4-chloro-5-isopropoxy quinazoline, it need not be further purified and use.
Embodiment 18
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-{2-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] oxyethyl group }-5-isopropoxy quinazoline
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(2-piperazine-1-base oxethyl) quinazoline (0.2 g) is joined being cooled in 0 ℃ the mixture of 2-methylamino acetyl chloride hydrochloride (0.097g), triethylamine (0.15ml) and methylene dichloride (5ml) of stirring.Make this reaction mixture be warming up to room temperature and stirred 2 hours.Add second part of 2-dimethylamino acetyl chloride hydrochloride (0.097g) and triethylamine (0.057ml) respectively, this reactant is stirred under room temperature spent the night in 16 hours.Add methylene dichloride (50ml), this compound of reaction is extracted twice with saturated sodium bicarbonate aqueous solution.Organic phase is through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, with the cumulative solvent mixture of polarity, promptly begins the mixed solution with 9: 1 methylene dichloride and methyl alcohol, uses 90: 8: 2 the methylene dichloride, methyl alcohol and the mixed solution wash-out of saturated methyl alcohol system ammonia solution at last.So obtain title compound, be foam thing (0.155g); NMR spectrum: (CDCl
3) 1.55 (d, 6H), 2.3 (s, 6H), 2.6 (m, 4H), 2.9 (t, 2H), 3.1 (s, 2H), 3.65 (m, 4H), 4.25 (t, 2H), 4.85 (s, 1H), 6.15 (s, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass spectrum: M+H
+572 and 574; Ultimate analysis: measured value C, 55.1; H, 6.1; N, 16.8; C
27H
34ClN
7O
50.75H
2O calculated value C, 55.4; H, 6.1; N, 16.7%.
Embodiment 19
7-(N-tert-butoxycarbonyl piperidin-4-yl methoxyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group quinazoline
Adopt and the similar method of method described in the embodiment 1, with 4-amino-5-chloro-2, DMF (2ml) solution of 3-(methylenedioxy) yl pyridines (0.193g) joins the sodium hydride of stirring, and (60% is scattered in the mineral oil, 0.048g) in the suspension in DMF (2ml), under room temperature, stirred this mixture 15 minutes.Add 7-(N-tert-butoxycarbonyl piperidin-4-yl methoxyl group)-4-chloro-6-methoxyl group quinazoline [International Patent Application WO 02/16352 (note in the embodiment 2 [24]; 0.38g] DMF (4ml) solution, under room temperature, stirred the mixture obtain 1 hour.Reaction mixture is allocated between ethyl acetate and the salt solution.Organic phase is through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, with 49: 1 mixed solution wash-outs of methylene dichloride and methyl alcohol.So obtain to be solid title compound (0.24g); NMR spectrum: (DMSOd
6) 1.29 (m, 2H), 1.45 (s, 9H), 1.8 (m, 2H), 2.04 (m, 1H), 2.83 (m, 2H), 4.0 (m, 7H), 8.12 (br s, 2H), 7.17 (br s, 1H), 7.72 (m, 2H), 8.37 (br s, 1H), 9.37 (br s, 1H); Mass spectrum: M+H
+544 and 546.
Embodiment 20
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group-7-(piperidin-4-yl methoxyl group) quinazoline
Trifluoroacetic acid (1ml) is joined 7-(N-tert-butoxycarbonyl piperidin-4-yl methoxyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-methylene dichloride (10ml) solution of 6-methoxyl group quinazoline (0.253g) in, stirred reaction mixture is 1 hour under room temperature.Evaporate this reaction mixture.Toluene is joined in this residue, evaporate this mixture.Residue uses 7M methyl alcohol system ammonia solution as elutriant through silicagel column (Isolute SCX post) chromatography purification.So obtain to be solid title compound (0.187g); NMR spectrum: (DMSOd
6) 1.25 (m, 2H), 1.75 (d, 2H), 1.93 (m, 1H), 2.54 (m, 2H), 3.0 (d, 2H), 3.93 (s, 3H), 3.98 (d, 2H), 6.17 (s, 2H), 7.15 (s, 1H), 7.76 (s, 1H), 7.78 (s, 1H), 8.23 (s, 1H); Mass spectrum: M+H
+444 and 446.
Embodiment 21
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-[N-(2-dimethylamino ethanoyl) piperidin-4-yl methoxyl group]-6-methoxyl group quinazoline
Diisopropylethylamine (0.118ml) is joined 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-6-methoxyl group-7-(piperidin-4-yl methoxyl group) quinazoline (0.15g), N, N-N-methylsarcosine (0.042g), 2-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate (V) is (0.154g) and in the mixture of DMF (3ml), and stirred reaction mixture is 16 hours under room temperature.Dilute this mixture with ethyl acetate, use the salt water washing.Organic solution is through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, and 100: 3 mixed solutions using methylene dichloride and 7M methyl alcohol system ammonia solution are as elutriant.So obtain to be solid title compound (0.051g); NMR spectrum: (DMSOd
6) 1.11-1.36 (m, 2H), 1.83 (d, 2H), 2.11 (m, 1H), 2.19 (s, 6H), 2.61 (t, 1H), 3.03 (m, 2H), 3.12 (d, 1H), 3.93 (s, 3H), 4.06 (m, 3H), 4.4 (d, 1H), 6.19 (br s, 2H), 7.19 (br s, 1H), 7.78 (m, 2H), 8.39 (br s, 1H), 9.71 (br s, 1H); Mass spectrum: M+H
+529 and 531.
Embodiment 22
7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline
The mixture of 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline (24g), 1-ethanoyl piperazine (21g), potassiumiodide (18g) and DMA (500ml) stirred and is heated to 100 ℃ 4 hours.Evaporating solvent is allocated between methylene dichloride (1 liter) and the water (500ml) residue.Use the dichloromethane extraction waterbearing stratum.Merge organic solution, use the salt water washing, through dried over mgso and evaporation.Residue is through purification by silica gel column chromatography, with the cumulative methylene dichloride of polarity and methanol mixture (from 20: 1 mixtures to 10: 1 mixture) as elutriant.Behind the evaporating solvent, the raw material that so obtains is ground under ether.So obtain title compound, be white solid (26.2g); M.p.208-210 ℃.
Following acquisition is used as 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl the amino)-5-isopropoxy quinazoline of starting raw material:
With 1 hour with hexamethyldisilane base ammonification sodium (the THF solution of 1M, 164ml) be added drop-wise to ice-cooled 4-chloro-7-(2,4-dimethoxy benzyloxy)-5-isopropoxy quinazoline (32g), 4-amino-5-chloro-2, in the mixture of 3-(methylenedioxy) yl pyridines (15.6g) and THF (430ml), the temperature of keeping reaction mixture simultaneously is at about 3 ℃.After adding is finished, make this reaction mixture be warming up to room temperature, stirred 2.5 hours.Make reaction mixture be cooled to 0 ℃, add the mixture of acetate (9.4ml) and water (250ml).Evaporate this mixture, residue is allocated between methylene dichloride and the water, the alkalescence of water is adjusted to 7.5 by adding the 3N aqueous hydrochloric acid.Separate organic phase, with methylene dichloride with aqueous extraction 3 times.Merge organic layer, use the salt water washing, through dried over mgso and evaporation.The solid that obtains grinds with ethyl acetate.So obtain 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(2,4-dimethoxy benzyloxy)-5-isopropoxy quinazoline, be white solid (38g); Mass spectrum: M+H
+525 and 527.
Successively triethyl silicane (70ml) and trifluoroacetic acid (48ml) are joined ice-cooled 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(2,4-dimethoxy benzyloxy)-methylene dichloride (560ml) solution of 5-isopropoxy quinazoline (37.7g) in, under room temperature, stirred the reaction mixture that obtains 1 hour.Evaporating solvent under the high vacuum.The solid that obtains grinds with ethyl acetate.Separate the raw material that so obtains, with the ethyl acetate washing, dry under high vacuum.So obtain the two-trifluoroacetate (37.4g) of 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-hydroxyl-5-isopropoxy quinazoline, it need not be further purified and use.
Salt of wormwood (34.6g) is joined 4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-hydroxyl-5-isopropoxy quinazoline two-trifluoroacetate (49g), 1, in the mixture of 2-ethylene dichloride (440ml) and DMF (245ml), this mixture stirred and is heated to 90 ℃ 3.5 hours.Add another part (7g) salt of wormwood, with this mixture in 90 ℃ of restir 1 hour.Make this reaction mixture be cooled to room temperature, the filtering solid is used washed with dichloromethane.Merging filtrate and washing lotion, evaporation.The residue that obtains is through purification by silica gel column chromatography, with the cumulative methylene dichloride of polarity and methanol mixture (from 50: 1 mixtures to 20: 1 mixture) as elutriant.So obtain 7-(2-chloro oxyethyl group)-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline, be white solid (37.1g); Mass spectrum: M+H
+437 and 439.
Claims (10)
1. the quinazoline derivant of a formula I or its pharmaceutically-acceptable acid addition:
Wherein:
Z is NH;
M is 2 and each R
1Group can be identical or different, and be positioned at 5-and 7 and the R of 5-position
1Group is selected from: methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-4-base oxygen base, tetramethyleneimine-3-base oxygen base, tetramethyleneimine-2-ylmethoxy, 3-piperidyl oxygen base, 4-piperidyl oxygen base, piperidines-3-ylmethoxy, piperidin-4-yl methoxyl group, cyclobutyl oxygen base, cyclopentyloxy and cyclohexyloxy, and the R of 7-position
1Group is selected from: hydroxyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 4-tetramethyleneimine-1-base butoxy, 2-tetramethyleneimine-2-base oxethyl, 3-tetramethyleneimine-2-base propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 4-morpholino butoxy, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 4-piperidino-(1-position only) butoxy, 2-piperidines-3-base oxethyl, 2-piperidin-4-yl oxyethyl group, the high piperidines of 2--1-base oxethyl, the high piperidines of 3--1-base propoxy-, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, the high piperazine of 2--1-base oxethyl and the high piperazine of 3--1-base propoxy-
And R wherein
1Arbitrary CH in the substituting group
2Or CH
3Group is chosen wantonly at described CH
2Or CH
3Carry one or more chloro groups on the group or be selected from following substituting group: hydroxyl, oxo, amino, methoxyl group, methylsulfonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino-, N-sec.-propyl-N-methylamino-and acetoxyl group;
And R wherein
1Arbitrary heterocyclic radical in the substituting group is chosen wantonly has 1 or 2 substituting group, described substituting group can be identical or different, be selected from: fluoro base, chloro base, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene-dioxy, ethylenedioxy and isopropylidene dioxy base, and R
1Tetramethyleneimine in the substituting group-2-base, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base is optional to be replaced by following groups N-: methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl,
2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl or cyano methyl,
And R wherein
1On substituting group in arbitrary heterocyclic radical optional have 1 or 2 oxo substituting group;
N be 0 or n be 1, and R
3Group is positioned at 2, the 5-of 3-methylene-dioxy pyridin-4-yl or 6, and be selected from: fluoro base, chloro base, bromo base, trifluoromethyl, cyano group, hydroxyl, methyl, ethyl, methoxyl group and oxyethyl group.
2. quinazoline derivant or its pharmaceutically-acceptable acid addition according to the formula I of claim 1, wherein:
Z is NH;
M is 1 and R
1Group is positioned at the 5-position and is selected from propoxy-; isopropoxy; tetrahydrofuran (THF)-3-base oxygen base; tetrahydropyran-4-base oxygen base; tetramethyleneimine-3-base oxygen base; N-methylpyrrolidin-3-base oxygen base; tetramethyleneimine-2-ylmethoxy; 3-piperidyl oxygen base; N-methyl piperidine-3-base oxygen base; 4-piperidyl oxygen base; N-methyl piperidine-4-base oxygen base; N-allyl group piperidin-4-yl oxygen base; N-Propargyl piperidin-4-yl oxygen base; N-ethanoyl piperidin-4-yl oxygen base; N-methyl sulphonyl piperidin-4-yl oxygen base; piperidines-3-ylmethoxy; N-methyl piperidine-3-ylmethoxy; the piperidin-4-yl methoxyl group; N-methyl piperidine-4-ylmethoxy; cyclobutyl oxygen base; cyclopentyloxy and cyclohexyloxy
Perhaps m is 2 and first R
1Group is positioned at the 5-position and is selected from the listed substituting group of the preceding paragraph, and second R
1Group be positioned at the 7-position and be selected from 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-,
2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group,
3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-, 2-morpholino oxyethyl group,
3-morpholino propoxy-, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group,
3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group,
3-piperidino-(1-position only) propoxy-, 2-piperidines-3-base oxethyl, 2-(N-methyl piperidine-3-yl) oxyethyl group,
3-piperidines-3-base propoxy-, 3-(N-methyl piperidine-3-yl) propoxy-, 2-piperidin-4-yl oxyethyl group,
2-(N-methyl piperidine-4-yl) oxyethyl group, 3-piperidin-4-yl propoxy-, 3-(N-methyl piperidine-4-yl) propoxy-, 2-(1,2,3,6-tetrahydropyridine-1-yl) oxyethyl group, 3-(1,2,3,6-tetrahydropyridine-1-yl) propoxy-, 2-(4-hydroxy piperidine-1-yl) oxyethyl group, 3-(4-hydroxy piperidine-1-yl) propoxy-,
2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, 4-piperazine-1-base butoxy,
2-(4-methylpiperazine-1-yl) oxyethyl group, 3-(4-methylpiperazine-1-yl) propoxy-, 4-(4-methylpiperazine-1-yl) butoxy, 2-(4-allyl group piperazine-1-yl) oxyethyl group, 3-(4-allyl group piperazine-1-yl) propoxy-,
2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-,
2-(4-methyl sulphonyl piperazine-1-yl) oxyethyl group, 3-(4-methyl sulphonyl piperazine-1-yl) propoxy-,
2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 3-(4 ethanoyl piperazine-1 base) propoxy-, 4-(4-ethanoyl piperazine-
The 1-yl) butoxy, 2-(4-isobutyryl piperazine-1-yl) oxyethyl group, 3-(4-isobutyryl piperazine-1-yl) propoxy-,
4-(4-isobutyryl piperazine-1-yl) butoxy, 2-[4-(2-fluoro ethyl) piperazine-1-yl] oxyethyl group,
3-[4-(2-fluoro ethyl) piperazine-1 base] propoxy-, 2-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] oxyethyl group,
3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-, 2-(4-cyano methyl piperazine-1-yl) oxyethyl group,
3-(4-cyano methyl piperazine-1-yl) propoxy-, 2-[2-(4-methylpiperazine-1-yl) oxyethyl group] oxyethyl group,
2-chloro oxyethyl group, 3-chloro propoxy-, 4-chloro butoxy, 2-sulfonyloxy methyl base oxethyl,
3-methyl sulphonyl propoxy-, 2-(2-methoxy ethoxy) oxyethyl group, 2-(4-pyridyl oxygen base) oxyethyl group,
3-pyridyl methoxyl group and 2-cyanopyridine-4-ylmethoxy;
N be 0 or n be 1 and R
3Group is positioned at 2, and the 5-of 3-methylene-dioxy pyridin-4-yl or 6-position also are selected from chloro base, bromo base, trifluoromethyl, cyano group, hydroxyl, methyl, ethyl, methoxyl group and oxyethyl group.
3. quinazoline derivant according to the formula I of claim 1, or its pharmaceutically-acceptable acid addition, wherein:
Z is NH;
M is 2 and first R
1Group is positioned at the 5-position and is selected from isopropoxy and tetrahydropyran-4-base oxygen base, and second R
1Group be positioned at the 7-position and be selected from 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-,
2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group,
3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-, 2-morpholino oxyethyl group,
3-morpholino propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 2-piperazine-1-base oxethyl,
3-piperazine-1-base propoxy-, 2-(4-methylpiperazine-1-yl) oxyethyl group, 3-(4-methylpiperazine-1-yl) propoxy-, 2-(4-allyl group piperazine-1-yl) oxyethyl group, 3-(4-allyl group piperazine-1-yl) propoxy-,
2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-,
2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 3-(4-ethanoyl piperazine-1-yl) propoxy-,
2-(4-isobutyryl piperazine-1-yl) oxyethyl group, 3-(4-isobutyryl piperazine-1-yl) propoxy-,
2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group, 3-[4-(2-hydroxyethyl) piperazine-1-yl] propoxy-,
2-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] oxyethyl group, 3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-, 2-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] oxyethyl group and
3-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] propoxy-; With
N is 1 and R
3Group is positioned at 2, and the 5-position of 3-methylene-dioxy pyridin-4-yl also is selected from the chloro base and the bromo base.
4. quinazoline derivant or its pharmaceutically-acceptable acid addition according to the formula I of claim 1, wherein:
Z is NH;
M is 2 and first R
1Group is positioned at the 5-position and is selected from isopropoxy and tetrahydropyran-4-base oxygen base, and second R
1Group be positioned at the 7-position and be selected from 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-,
2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group,
3-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] propoxy-,
2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, 2-(4-methylpiperazine-1-yl) oxyethyl group,
3-(4-methylpiperazine-1-yl) propoxy-, 2-(4-allyl group piperazine-1-yl) oxyethyl group,
3-(4-allyl group piperazine-1-yl) propoxy-, 2-(4-Propargyl piperazine-1-yl) oxyethyl group,
3-(4-Propargyl piperazine-1-yl) propoxy-, 2-(4-ethanoyl piperazine-1-yl) oxyethyl group,
3-(4-ethanoyl piperazine-1-yl) propoxy-, 2-(4-isobutyryl piperazine-1-yl) oxyethyl group,
3-(4-isobutyryl piperazine-1-yl) propoxy-, 2-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] oxyethyl group and
3-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] propoxy-; With
N is 1 and R
3Group is positioned at 2, and the 5-position of 3-methylene-dioxy pyridin-4-yl also is selected from the chloro base and the bromo base.
5. quinazoline derivant or its pharmaceutically-acceptable acid addition according to the formula I of claim 1, wherein:
Z is NH;
M is 2 and first R
1Group is positioned at the 5-position and is selected from isopropoxy and tetrahydropyran-4-base oxygen base, and second R
1Group is positioned at the 7-position and is selected from 2-tetramethyleneimine-1-base oxethyl, 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-piperidino-(1-position only) oxyethyl group,
2-piperazine-1-base oxethyl, 2-(4-methylpiperazine-1-yl) oxyethyl group,
2-(4-Propargyl piperazine-1-yl) oxyethyl group, 3-(4-Propargyl piperazine-1-yl) propoxy-,
2-(4-ethanoyl piperazine-1-yl) oxyethyl group, 2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group and
2-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] oxyethyl group; With
N is 1 and R
3Group is positioned at 2, and the 5-position of 3-methylene-dioxy pyridin-4-yl is the chloro base also.
6. quinazoline derivant or its pharmaceutically-acceptable acid addition according to the formula I of claim 1, wherein:
Z is NH;
M is 2 and first R
1Group is the 5-isopropoxy, and second R
1Group is positioned at the 7-position and is selected from 2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group, 2-piperazine-1-base oxethyl, 2-(4-methylpiperazine-1-yl) oxyethyl group,
2-(4-ethanoyl piperazine-1-yl) oxyethyl group and 2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group; With
N is 1 and R
3Group is positioned at 2, the 5-position of 3-methylene-dioxy pyridin-4-yl and be the chloro group.
7. quinazoline derivant according to the formula I of claim 1, it is selected from:
7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-tetrahydropyran-4-base oxygen base quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-{2-[(3RS, 4SR)-3,4-methylene-dioxy tetramethyleneimine-1-yl] oxyethyl group }-5-tetrahydropyran-4-base oxygen base quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-[2-(4-Propargyl piperazine-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-[3-(4-Propargyl piperazine-1-yl) propoxy-]-5-tetrahydropyran-4-base oxygen base quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(2-morpholino oxyethyl group)-5-tetrahydropyran-4-base oxygen base quinazoline and
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-(3-morpholino propoxy-)-5-tetrahydropyran-4-base oxygen base quinazoline;
Or its pharmaceutically-acceptable acid addition.
8. quinazoline derivant according to the formula I of claim 1, it is selected from:
7-[2-(4-ethanoyl piperazine-1-yl) oxyethyl group]-4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(2-piperazine-1-base oxethyl) quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-{2-[4-(2-hydroxyethyl) piperazine-1-yl] oxyethyl group }-5-isopropoxy quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(2-tetramethyleneimine-1-base oxethyl) quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(2-piperidino-(1-position only) oxyethyl group) quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(2-morpholino oxyethyl group) quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-(3-morpholino propoxy-) quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-[2-(4-Propargyl piperazine-1-yl) oxyethyl group] quinazoline,
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-5-isopropoxy-7-[2-(4-methylpiperazine-1-yl) oxyethyl group] quinazoline and
4-(5-chloro-2,3-methylene-dioxy pyridin-4-yl amino)-7-{2-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] oxyethyl group }-5-isopropoxy quinazoline;
Or its pharmaceutically-acceptable acid addition.
9. pharmaceutical composition, it comprises according to the quinazoline derivant of the formula I of claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier.
According to the quinazoline derivant of the formula I of claim 1 or its pharmacy acceptable salt in preparation as the purposes in the medicine of the inhibition of noumenal tumour disease and/or the anti-intrusion agent in the treatment.
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| EP02292736.2 | 2002-11-04 | ||
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| TWI577671B (en) * | 2011-11-14 | 2017-04-11 | Sunshine Lake Pharma Co Ltd | Aminoquinazoline derivatives and salts thereof and methods of use thereof |
| CN103788085B (en) * | 2012-10-31 | 2016-09-07 | 复旦大学 | 2-(quinazoline-4-amino)-5-thiazole carboxamides analog derivative and bio-pharmaceutical purposes thereof |
| CN105294718B (en) * | 2015-11-18 | 2018-01-23 | 乳源瑶族自治县大众药品贸易有限公司 | The maleate and its crystal formation of a kind of amino quinazoline derivative |
| CN105294715B (en) * | 2015-11-18 | 2017-12-22 | 乳源瑶族自治县大众药品贸易有限公司 | The fumarate and its crystal formation of a kind of amino quinazoline derivative |
| CN108078990B (en) * | 2016-11-23 | 2023-06-02 | 山东轩竹医药科技有限公司 | New application of quinazoline derivative tyrosine kinase inhibitor |
| CN110357858B (en) * | 2018-04-09 | 2022-02-18 | 威尚（上海）生物医药有限公司 | 5-substituted difluoropiperidine compounds having blood-brain barrier crossing capability |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995015758A1 (en) * | 1993-12-10 | 1995-06-15 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit csf-1r receptor tyrosine kinase |
| WO1997003069A1 (en) * | 1995-07-13 | 1997-01-30 | Glaxo Group Limited | Heterocyclic compounds and pharmaceutical compositions containing them |
| WO2002016352A1 (en) * | 2000-08-21 | 2002-02-28 | Astrazeneca Ab | Quinazoline derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995015758A1 (en) * | 1993-12-10 | 1995-06-15 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit csf-1r receptor tyrosine kinase |
| WO1997003069A1 (en) * | 1995-07-13 | 1997-01-30 | Glaxo Group Limited | Heterocyclic compounds and pharmaceutical compositions containing them |
| WO2002016352A1 (en) * | 2000-08-21 | 2002-02-28 | Astrazeneca Ab | Quinazoline derivatives |
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