CN101437810A - Quinazoline derivatives - Google Patents

Abstract

The invention concerns quinazoline derivatives of Formula (I) or a pharmaceutically-acceptable salt thereof, wherein each of X1, p, R<1>, q, R<2>, R<3>, R<4>, R<5>, Ring A, r and R<6> has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.

Description

Quinazoline derivant

The present invention relates to some novel quinazoline quinoline derivant or its pharmacy acceptable salt, these compounds have antitumour 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 the medicine of the cancer (comprise prevention or treatment solid tumor disease) that is used for prevention or treatment warm-blooded animal (as the people) in preparation.

The scheme of the abnormal cell growth that exists in the present multiple treatment cell proliferation disorders (as psoriatic and cancer) all adopts and suppresses DNA synthetic compound.The general pair cell of this compounds is toxic, but they may be useful for the toxic action of quick noble cells such as tumour cell.Has the usefulness that presents the enhanced selectively acting by suppressing the alternative cancer therapy drug that the mechanism of DNA outside synthetic plays a role.

Eukaryotic cell is constantly made response to many different extracellular signals, and these signals can make between intravital each cell of machine and link up.Physical responses widely in these Signal Regulation cells comprises propagation, differentiation, apoptosis and mobile.The extracellular signal adopts the form of various soluble factor, comprises somatomedin and paracrine factor, the autocrine factor and endocrine factor.By combining with the specificity transmembrane receptor, the somatomedin part interrelates extracellular signal and the interior signal pathway of cell, thereby individual cells pair cell external signal is made a response.The transduction process of many these signals is utilized the reversing process (comprising specificity kinases and Phosphoric acid esterase) of protein phosphorylation.

Because phosphorylation is important regulation mechanism like this in the signal transduction process, therefore the distortion in this process causes that unusual cytodifferentiation, conversion and growth are just not at all surprising.For example, have found that section of DNA owing to cell self is converted into oncogene and makes this cell be carcinous.Several these type of oncogene encoded protein matter all are the acceptor of somatomedin, for example Tyrosylprotein kinase.Tyrosylprotein kinase also can sport the constitutive activity form, and this causes the various human cell transformation.Perhaps, the overexpression of normal Tyrosylprotein kinase also can cause abnormal cell proliferation.

Tyrosylprotein kinase can be divided into two groups: receptor tyrosine kinase and nonreceptor tyrosine kinase.Identified about 90 kinds of Tyrosylprotein kinases in human genome, wherein about 60 kinds is receptor type, and about 30 kinds is non-receptor type.These Tyrosylprotein kinases can be divided into 20 kinds of receptor tyrosine kinase subfamilies (according to the family of their bonded somatomedins) and 10 kinds of nonreceptor tyrosine kinase subfamilies (Robinson etc., Oncogene, 2000, 19, 5548-5557).Classification comprises the receptor tyrosine kinase of EGF family, for example EGF, TGF α, Neu and erbB acceptor; The receptor tyrosine kinase of Regular Insulin family, for example Regular Insulin and IGF1 acceptor and Regular Insulin dependency acceptor (IRR); And the receptor tyrosine kinase of Class III family, for example Thr6 PDGF BB (PDGF) receptor tyrosine kinase, for example PDGF α acceptor and PDGF beta receptor, STEM CELL FACTOR receptor tyrosine kinase (SCF RTK (being commonly referred to c-Kit), fms-dependency Tyrosylprotein kinase 3 (Flt3) receptor tyrosine kinases and colony-stimulating factor 1 acceptor (CSF-1R) Tyrosylprotein kinase.

Have found that these sudden changes and the Tyrosylprotein kinase of overexpression form are present in the common human cancer of major part, for example leukemia, mammary cancer, prostate cancer, comprise the nonsmall-cell lung cancer (NSCLC) of gland cancer and squamous cell lung cancer, the gastrointestinal cancer that comprises colon, rectum and cancer of the stomach, bladder cancer, esophagus cancer, ovarian cancer and carcinoma of the pancreas.Along with detecting mankind tumor tissue more, people expect that the popularity of Tyrosylprotein kinase and importance will further be established.For example, shown already that the EGFR Tyrosylprotein kinase suddenlys change and/or overexpression, was included in lung, neck, gi tract, mammary gland, esophagus, ovary, uterus, bladder and the thyroid tumour in several human cancers.

Thr6 PDGF BB (PDGF) is the main mitogen of phoirocyte and other cell type.Pdgf receptor (comprising PDGF α and PDGF beta receptor isozyme) is the performance enhanced activity in vascular disease (for example atherosclerosis and restenosis, for example in the restenosis process of sacculus angioplasty and heart arter bypass secondary).Enhanced pdgf receptor kinase activity is also observed in other cell proliferation disorders like this, for example fibrotic disease (for example renal fibrosis, liver cirrhosis, pulmonary fibrosis and polycystic Kidney dysplasia), glomerulonephritis, inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel), multiple sclerosis disease, psoriatic, skin hypersusceptibility, atopic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.

Pdgf receptor also can be by the cell transformation in autocrine stimulation cell growth cancer and the leukemia.Shown already that pdgf receptor kinase suddenlyd change and/or overexpression in several human cancers, be included in lung tumors (nonsmall-cell lung cancer and small cell lung cancer), gastrointestinal tumor (colon for example, rectum and gastric tumor), tumor of prostate, breast tumor, tumor of kidney, liver tumor, cerebral tumor (for example glioblastoma), esophageal tumor, ovarian tumor, in pancreatic neoplasm and the dermatoma (for example dermatofibrosarcoma protuberans) and at leukemia and lymphoma (chronic granulocytic leukemia (CML) for example, chronic grain monocytic leukemia (CMML), acute lymphoblastic leukemia (ALL) and multiple myeloma) in.Strengthen cell signal by the pdgf receptor Tyrosylprotein kinase and can facilitate various cytological effects, comprise that cell proliferation, cell move and invasion and attack, Premeabilisation of cells and apoptosis.

Therefore, people expect that the activity of antagonism pdgf receptor kinase helps treating a large amount of cell proliferation disorders (for example cancer), are particularly conducive to suppress tumor growth and transfer and suppress the leukemia progress.

In addition, PDGF relates to the angiogenesis that forms neovascularity, and described vasculogenesis is very crucial to the tumour continued growth.Usually, vasculogenesis plays a significant role in the process of for example fetal development, wound healing and a few part female reproductive functions.Yet vasculogenesis bad or pathology is relevant with a large amount of diseases, comprises diabetic retinopathy, psoriatic, cancer, rheumatoid arthritis, atheroma, Kaposi sarcoma and vascular tumor.By promoting endothelial cell growth to stimulate vasculogenesis.Identified already and severally have vitro endothelial cell growth and promote active polypeptide, comprised acid and Prostatropin (aFGF and bFGF) and vascular endothelial growth factor (VEGF).Because the expression of vegf receptor is limited,, endotheliocyte is relative specificity so the growth factor activity of VEGF and aFGF and bFGF's is opposite.Evidence suggests that recently VEGF generates for normal and pathological angiogenesis and vascular permeability all is important stimulant.Induction of vascular bud shape growth phenotype then causes kapillary to form to this cytokine by inducing endothelial cell propagation, proteolytic enzyme expression and migration, and kapillary promotes hypertonicity, immature vasoganglion to form, and this is the feature that pathological angiogenesis generates.Comprise receptor KDR (being also referred to as Flk-1), fms sample tyrosine kinase receptor Flt-1 and the fms sample tyrosine kinase receptor Flt-4 that contains kinases insertion territory with VEGF bonded receptor tyrosine kinase (RTK) subfamily.Shown already that be called Flt-1 and KDR among these relevant RTK two kinds combined with the VEGF high-affinity.

Therefore, people expect that the activity of antagonism VEGF can help treatment a large amount of and vasculogenesis and/or vascular permeability increase diseases associated, and for example cancer is particularly conducive to the inhibition tumor development.

Known severally have pdgf receptor kinase and suppress active compound and carrying out clinical development.Shown the 2-anilino-pyrimidine derivative (STI571 that is called imatinib already; Nature Reviews, 2002, 1, 493-502; Cancer Research, 1996, 56, 100-104) suppress the pdgf receptor kinase activity, but being based on it, its present clinical application is used for the treatment of CML as the other activity of BCR-ABL kinase inhibitor.STI571 suppress by will people's glioblastoma strain U343 and U87 inject the glioblastoma that forms in the nude mouse brain growth ( Cancer Research, 2000, 60, 5143-5150).This compound also suppress growth in the body of knuckle shape dermatofibrosarcoma cell culture ( Cancer Research, 2001, 61, 5778-5783).Pdgf receptor kinase based on this compound suppresses active, is carrying out the clinical trial to glioblastoma and prostate cancer.Studying several other pdgf receptor kinase inhibitors, comprise quinoline, quinazoline and quinoxaline derivatives ( Cytokine ﹠amp; Growth Factor Reviews, 2004, 15, 229-235).

Some aryl and heteroaryl compound suppress EGF and/or pdgf receptor Tyrosylprotein kinase as can be known from International Patent Application WO 92/20642.Wherein disclose some quinazoline derivant, but wherein specifically do not mentioned 2-(2-pyridyl) acetamide derivative; Specifically, wherein specifically do not mention 2-(2-pyridyl) acetamide derivative that quinazoline-4-base oxygen base replaces.

In many disclosed patent applications (for example International Patent Application WO 96/09294), disclose 4-anilinoquinazoline, 4-aryloxy quinazoline, 4-anilino quinoline or 4-aryloxy quinoline and had the tyrosine-kinase enzyme inhibition activity.Yet, wherein specifically do not mention 2-(2-pyridyl) acetamide compound of quinazoline-4-base oxygen base-replacement.

The 2-phenyl-acetamides compound of thienopyridine-replacement suppresses vegf receptor tyrosine kinase as can be known from International Patent Application WO 2005/021554, and blood vessel formation against function is provided.Embodiment 87 wherein discloses the 2-phenyl-acetamides of single quinolyl-4 oxygen base-replacement, i.e. compound N-(5-chloropyridine-2-yl)-2-[4-(7-methoxy quinoline-4-base oxygen base) phenyl] ethanamide.

Another of hyperproliferative disease (for example cancer) is characterised in that the cellular pathways of damage control cell cycle development, and the described cell cycle relates to the orderly cascade of protein phosphorylation in normal eukaryotic cell.As for signal transduction mechanism, it seems that the protein kinase of several families plays a significant role in the cell cycle cascade.Research is cell cycle protein dependent kinase family (CDK) the most widely in these Cycle Regulation agent.Specific CDK is very important for startup and the development of coordination cell cycle in the activity of specified time.For example, CDK4 albumen enters the cell cycle (G0-G1-S transformations) by making retinoblastoma gene product pRb phosphorylation control, and this stimulates pRb release transcription factor E2F, and this is used to again increase and enters essential gene transcription of S phase.By combine the catalytic activity that stimulates CDK4 with mating-type protein cyclin D.Increase in view of in many human tumors, observing cyclin D1 gene amplification and cyclin D protein level, prove cancer and contacting directly between the cell cycle first.

Recently, identified the protein kinase that structurally is different from CDK family, it played a significant role in the adjusting cell cycle, and it seems in tumour generates also very important.They comprise fruit bat (Drosophila) aurora and the proteic human homologue of yeast saccharomyces cerevisiae (S.cerevisiae) Ipll.Three-type-person's class homologue Aurora-A, Aurora-B and the serine-threonine protein kinase enzyme of Aurora-C coding and regulating cell cycle of these genes, these kinases demonstrate peak value and express and kinase activity through G2 and mitotic division the time.Observe the human aurora albumen of hint and cancer implication, particularly Aurora-A and Aurora-B for several.Cause cell cycle arrest and bring into play antiproliferative effect with abolishment Aurora-A expression of antisense oligonucleotide processing human tumor cell line and function.In addition, the micromolecular inhibitor that had proved Aurora-A and Aurora-B already has antiproliferative effect in the human tumor cell.

International Patent Application WO 01/21597 is open, and some quinazoline derivant that for example has the heteroaryl that is connected with the 4-position of quinoline ring by NH or O group has the Aurora kinase inhibiting activity.Wherein specifically do not mention 2-(2-pyridyl) acetamide derivative; Specifically, wherein specifically do not mention 2-(2-pyridyl) acetamide derivative of quinazoline-replacement.

International Patent Application WO 01/21594 and WO 01/21596 is open, and some has the anilino that is connected with the 4-position of quinazoline ring or the quinazoline derivant of phenoxy group has the Aurora kinase inhibiting activity.Wherein specifically do not mention 2-(2-pyridyl) acetamide derivative; Specifically, wherein specifically do not mention 2-(2-pyridyl) acetamide derivative quinazoline-replacement or that quinoline replaces.

International Patent Application WO 01/55116, WO 02/00649, WO 03/055491, WO04/058752, WO 04/058781, WO 04/094410, WO 04/105764 and WO04/113324 are open, and some quinazoline derivant that for example has the first heteroaryl of 5-that is connected with the 4-position of quinazoline ring by NH or O group has the Aurora kinase inhibiting activity.Wherein not mentioned 2-(2-pyridyl) acetamide derivative; Specifically, wherein specifically do not mention 2-(2-pyridyl) acetamide derivative of quinazoline-replacement.

We find that now 2-(2-pyridyl) acetamide compound of some novel quinazoline quinoline-4-base oxygen base-replacement has the effective active of inhibition of cell proliferation disease surprisingly.Only do not hint that by influencing one or both bioprocesss compound disclosed by the invention has pharmacologically active although do not wish, but it is generally acknowledged that described compound is by suppressing the effect of pdgf receptor Tyrosylprotein kinase, can be cell proliferation disorders and provide the treatment of usefulness, antitumor action for example is provided.Specifically, it is generally acknowledged that The compounds of this invention by suppressing the effect of PDGF α and/or PDGF beta receptor Tyrosylprotein kinase, can be used for treating cell proliferation disorders.

Chemical compound lot of the present invention has effective inhibition activity to pdgf receptor family Tyrosylprotein kinase (for example PDGF α and/or PDGF beta receptor Tyrosylprotein kinase), and to other Tyrosylprotein kinase (for example one or more other Class III family receptors Tyrosylprotein kinase, for example Flt3 receptor tyrosine kinase and CSF-1R Tyrosylprotein kinase; The EGF receptor tyrosine kinase; Or vegf receptor tyrosine kinase, for example KDR and Flt-1) have a less inhibition activity.And some The compounds of this invention significantly is better than effectiveness to EGF receptor tyrosine kinase or vegf receptor tyrosine kinase (for example KDR) to the effectiveness of pdgf receptor Family Tyrosine Kinases (particularly PDGF beta receptor Tyrosylprotein kinase).Such compound has enough usefulness makes them to show less active amount use to EGF receptor tyrosine kinase or vegf receptor tyrosine kinase (for example KDR) to be enough to suppress pdgf receptor family Tyrosylprotein kinase (particularly PDGF beta receptor Tyrosylprotein kinase).

Quinazoline derivant or its pharmacy acceptable salt of formula I are provided according to an aspect of the present invention,

X wherein ¹Be O or N (R ⁷), R wherein ⁷Be hydrogen or (1-8C) alkyl;

P is 0,1,2 or 3;

Each R ¹Group can be identical or different; be selected from halo; trifluoromethyl; cyano group; hydroxyl; sulfydryl; amino; carboxyl; (1-6C) alkoxy carbonyl; formamyl; (1-8C) alkyl; (2-8C) thiazolinyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) chain oxy-acetylene; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (2-6C) alkyloyl; (2-6C) alkanoylamino of alkanoylamino and N-(1-6C) alkyl-(2-6C), or be selected from the group of following formula:

Q ¹-X ²-

X wherein ²Be selected from O, S, SO, SO ₂, N (R ⁸), CO, CON (R ⁸), N (R ⁸) CO, OC (R ⁸) ₂And N (R ⁸) C (R ⁸) ₂, each R wherein ⁸Be hydrogen or (1-8C) alkyl, Q ¹Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-8C) cycloalkyl, (3-8C) cycloalkyl-(1-6C), (3-8C) cycloalkenyl group, (3-8C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)

And wherein at R ¹Any aryl in the substituting group; (3-8C) cycloalkyl; (3-8C) cycloalkenyl group; heteroaryl or heterocyclic radical are optional to carry 1; 2 or 3 substituting groups; described substituting group can be identical or different; be selected from halo; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; urea groups; (1-8C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkene oxygen base; (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; (2-6C) alkyloyl; (2-6C) alkanoyloxy; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); N-(1-6C) alkyl urea groups; the alkyl urea groups of N '-(1-6C); N '; N '-two-[(1-6C) alkyl] urea groups; N; N '-two-[(1-6C) alkyl] urea groups; N; N '; N '-three-[(1-6C) alkyl] urea groups; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C), or be selected from the group of following formula:

-X ³-R ⁹

X wherein ³For direct key or be selected from O and N (R ¹⁰), R wherein ¹⁰Be hydrogen or (1-8C) alkyl, R ⁹Be the alkyl of halo-(1-6C); the alkyl of hydroxyl-(1-6C); the alkyl of sulfydryl-(1-6C); (1-6C) alkyl of alkoxyl group-(1-6C); (1-6C) alkyl of alkylthio-(1-6C); (1-6C) alkyl of alkyl sulphinyl-(1-6C); (1-6C) alkyl of alkyl sulphonyl-(1-6C); the alkyl of cyano group-(1-6C); amino-(1-6C) alkyl; (1-6C) alkyl of alkylamino-(1-6C); two-[(1-6C) alkyl] amino-(1-6C) alkyl; (2-6C) alkyl of alkanoylamino-(1-6C); the alkyl of the alkanoylamino of N-(1-6C) alkyl-(2-6C)-(1-6C); (1-6C) alkyl of alkoxycarbonyl amino-(1-6C); the alkyl of urea groups-(1-6C); the alkyl of N-(1-6C) alkyl urea groups-(1-6C); the alkyl of the alkyl urea groups of N '-(1-6C)-(1-6C); N '; the alkyl of N '-two-[(1-6C) alkyl] urea groups-(1-6C); N; N '-two-[(1-6C) alkyl] urea groups-(1-6C) alkyl or N; N '; the alkyl of N '-three-[(1-6C) alkyl] urea groups-(1-6C), or be selected from the group of following formula:

-X ⁴-Q ²

X wherein ⁴For direct key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen or (1-8C) alkyl, Q ²Be the optional alkyl of the alkyl of 1 or 2 substituent aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C) that carries, described substituting group can be identical or different, be selected from halo, hydroxyl, (1-8C) alkyl and (1-6C) alkoxyl group

And wherein at R ¹Optional (1-3C) alkylenedioxy group that carries of any aryl, heteroaryl or heterocyclic radical in the last substituting group,

And wherein at R ¹Optional 1 or 2 oxo or the sulfo-substituting group of carrying of any heterocyclic radical in the substituting group,

And wherein at R ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halos or (1-8C) alkyl substituent and/or be selected from following substituting group of carrying on the group: hydroxyl; sulfydryl; amino; cyano group; carboxyl; formamyl; urea groups; (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) alkanoyloxy; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); N-(1-6C) alkyl urea groups; the alkyl urea groups of N '-(1-6C); N '; N '-two-[(1-6C) alkyl] urea groups; N; N '-two-[(1-6C) alkyl] urea groups; N; N '; N '-three-[(1-6C) alkyl] urea groups; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C)

And wherein at R ¹Adjacent carbons on any in the substituting group (2-6C) alkylidene chain is optional to be inserted into the following group of being selected from of this chain and to separate: O, S, SO, SO2, N (R ¹²), CO, CH (OR ¹²), CON (R ¹²), N (R ¹²) CO, N (R ¹²) CON (R ¹²), SO ₂N (R ¹²), N (R ¹²) SO ₂, CH=CH and C ≡ C, wherein R ¹²Be hydrogen or (1-8C) alkyl, maybe when the group that inserts be N (R ¹²) time, R ¹²Also can be (2-6C) alkyloyl;

Q is 0,1 or 2;

Each R ²Group can be identical or different, be selected from halo, trifluoromethyl, cyano group, carboxyl, hydroxyl, amino, formamyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyl, the alkyl of halo-(1-6C), the alkyl of hydroxyl-(1-6C), (1-6C) alkyl of alkoxyl group-(1-6C), the alkyl of cyano group-(1-6C), the alkyl of carboxyl-(1-6C), (1-6C) alkyl of alkoxy carbonyl-(1-6C), amino-(1-6C) alkyl, (1-6C) alkyl of alkylamino-(1-6C), two-[(1-6C) alkyl] amino-(1-6C) alkyl, the alkyl of formamyl-(1-6C), the alkyl of N-(1-6C) alkyl-carbamoyl-(1-6C), N, the alkyl of N-two-[(1-6C) alkyl] formamyl-(1-6C), (2-6C) alkyl of the alkanoylamino of alkyl of alkanoylamino-(1-6C) and N-(1-6C) alkyl-(2-6C)-(1-6C);

R ³Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl or (2-8C) alkynyl;

R ⁴Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, the alkyl of halo-(1-6C), the alkyl of hydroxyl-(1-6C), (1-6C) alkyl of alkoxyl group-(1-6C), the alkyl of cyano group-(1-6C), the alkyl of carboxyl-(1-6C), amino-(1-6C) alkyl, (1-6C) alkyl of alkylamino-(1-6C), two-[(1-6C) alkyl] amino-(1-6C) alkyl, the alkyl of formamyl-(1-6C), the alkyl of N-(1-6C) alkyl-carbamoyl-(1-6C), N, the alkyl of N-two-[(1-6C) alkyl] formamyl-(1-6C), (1-6C) alkyl of alkoxy carbonyl-(1-6C), (2-6C) alkyl of the alkanoylamino of alkyl of alkanoylamino-(1-6C) or N-(1-6C) alkyl-(2-6C)-(1-6C);

Or R ³And R ⁴The carbon atom that connects with them forms (3-8C) cycloalkyl;

R ⁵Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl or (2-8C) group of alkynyl or following formula:

-X ⁵-R ¹³

X wherein ⁵For direct key or be selected from O and N (R ¹⁴), R wherein ¹⁴Be hydrogen or (1-8C) alkyl, R ¹³Be the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C) or cyano group-(1-6C);

Ring A is 6-unit's monocycle or 10-unit's two cyclophane rings or 5-or 6-unit's monocycle or 9-or 10-unit two ring hetero-aromatic rings, and described hetero-aromatic ring contains 3 ring hetero atoms that are selected from oxygen, nitrogen and sulphur at the most;

R is 0,1,2 or 3; With

Each R ⁶Group can be identical or different; be selected from halo; trifluoromethyl; cyano group; hydroxyl; sulfydryl; amino; carboxyl; formamyl; sulfamyl; urea groups; (1-8C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (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; (2-6C) alkyloyl; (2-6C) alkanoyloxy; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); the alkyl urea groups of N '-(1-6C); N '; N '-two-[(1-6C) alkyl] urea groups; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C), or be selected from the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶For direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-8C) alkyl, R ¹⁵Be the alkyl of halo-(1-6C); the alkyl of hydroxyl-(1-6C); the alkyl of sulfydryl-(1-6C); (1-6C) alkyl of alkoxyl group-(1-6C); (1-6C) alkyl of alkylthio-(1-6C); (1-6C) alkyl of alkyl sulphinyl-(1-6C); (1-6C) alkyl of alkyl sulphonyl-(1-6C); the alkyl of cyano group-(1-6C); amino-(1-6C) alkyl; (1-6C) alkyl of alkylamino-(1-6C); two-[(1-6C) alkyl] amino-(1-6C) alkyl; (2-6C) alkyl of alkanoylamino-(1-6C); the alkyl of the alkanoylamino of N-(1-6C) alkyl-(2-6C)-(1-6C); the alkyl of carboxyl-(1-6C); (1-6C) alkyl of alkoxy carbonyl-(1-6C); the alkyl of formamyl-(1-6C); the alkyl of N-(1-6C) alkyl-carbamoyl-(1-6C); N; the alkyl of N-two-[(1-6C) alkyl] formamyl-(1-6C); the alkyl of sulfamyl-(1-6C); the alkyl of N-(1-6C) alkylsulfamoyl group-(1-6C); N; the alkyl of N-two-[(1-6C) alkyl] sulfamyl-(1-6C); the alkyl of urea groups-(1-6C); the alkyl of N-(1-6C) alkyl urea groups-(1-6C); the alkyl of the alkyl urea groups of N '-(1-6C)-(1-6C); N '; the alkyl of N '-two-[(1-6C) alkyl] urea groups-(1-6C); N; the alkyl of N '-two-[(1-6C) alkyl] urea groups-(1-6C); N; N '; the alkyl of N '-three-[(1-6C) alkyl] urea groups-(1-6C); (1-6C) alkyl of the alkanesulfonyl amino of alkyl of alkanesulfonyl amino-(1-6C) or N-(1-6C) alkyl-(1-6C)-(1-6C), or be selected from the group of following formula:

-X ⁷-Q ³

X wherein ⁷For direct key or be selected from O, S, SO, SO ₂, N (R ¹⁷), CO, CH (OR ¹⁷), CON (R ¹⁷), N (R ¹⁷) CO, N (R ¹⁷) CON (R ¹⁷), SO ₂N (R ¹⁷), N (R ¹⁷) SO ₂, C (R ¹⁷) ₂O, C (R ¹⁷) ₂S and C (R ¹⁷) ₂N (R ¹⁷), each R wherein ¹⁷Be hydrogen or (1-8C) alkyl, Q ³Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-8C) cycloalkyl, (3-8C) cycloalkyl-(1-6C), (3-8C) cycloalkenyl group, (3-8C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)

Perhaps two R ⁶Group forms span together on ring A be the divalent group of adjacent ring position, and described divalent group is selected from OC (R ¹⁸) ₂O, OC (R ¹⁸) ₂C (R ¹⁸) ₂O, OC (R ¹⁸) ₂C (R ¹⁸) ₂, C (R ¹⁸) ₂OC (R ¹⁸) ₂, C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂, C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂, OC (R ¹⁸) ₂N (R ¹⁹), N (R ¹⁹) C (R ¹⁸) ₂N (R ¹⁹), N (R ¹⁹) C (R ¹⁸) ₂C (R ¹⁸) ₂, N (R ¹⁹) C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂, OC (R ¹⁸) ₂C (R ¹⁸) ₂N (R ¹⁹), C (R ¹⁸) ₂N (R ¹⁹) C (R ¹⁸) ₂, CO.N (R ¹⁸) C (R ¹⁸) ₂, N (R ¹⁸) CO.C (R ¹⁸) ₂, N (R ¹⁹) C (R ¹⁸) ₂CO, CO.N (R ¹⁸) CO, N (R ¹⁹) N (R ¹⁸) CO, N (R ¹⁸) CO.N (R ¹⁸), O.CO.N (R ¹⁸), O.CO.C (R ¹⁸) ₂And CO.OC (R ¹⁸) ₂, each R wherein ¹⁸Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl or (2-8C) alkynyl, and R wherein ¹⁹Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl or (2-6C) alkyloyl,

And wherein at R ⁶Any aryl in the group; (3-8C) cycloalkyl; (3-8C) cycloalkenyl group; heteroaryl or heterocyclic radical are optional to carry 1; 2 or 3 substituting groups; described substituting group can be identical or different; be selected from halo; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; urea groups; (1-8C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkene oxygen base; (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; (2-6C) alkyloyl; (2-6C) alkanoyloxy; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); the alkyl urea groups of N '-(1-6C); N '; N '-two-[(1-6C) alkyl] urea groups; N-(1-6C) alkyl urea groups; N; N '-two-[(1-6C) alkyl] urea groups; N; N '; N '-three-[(1-6C) alkyl] urea groups; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C), or be selected from the group of following formula:

-X ⁸-R ²⁰

X wherein ⁸For direct key or be selected from O and N (R ²¹), R wherein ²¹Be hydrogen or (1-8C) alkyl, R ²⁰Be the alkyl of halo-(1-6C); the alkyl of hydroxyl-(1-6C); the alkyl of sulfydryl-(1-6C); (1-6C) alkyl of alkoxyl group-(1-6C); (1-6C) alkyl of alkylthio-(1-6C); (1-6C) alkyl of alkyl sulphinyl-(1-6C); (1-6C) alkyl of alkyl sulphonyl-(1-6C); the alkyl of cyano group-(1-6C); amino-(1-6C) alkyl; (1-6C) alkyl of alkylamino-(1-6C); two-[(1-6C) alkyl] amino-(1-6C) alkyl; (2-6C) alkyl of the alkanoylamino of alkyl of alkanoylamino-(1-6C) or N-(1-6C) alkyl-(2-6C)-(1-6C), or be selected from the group of following formula:

-X ⁹-Q ⁴

X wherein ⁹For direct key or be selected from O, CO and N (R ²²), R wherein ²²Be hydrogen or (1-8C) alkyl, Q ⁴Be the optional alkyl of the alkyl of 1 or 2 substituent aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C) that carries, described substituting group can be identical or different, be selected from halo, hydroxyl, (1-8C) alkyl and (1-6C) alkoxyl group

And wherein at R ⁶Optional (1-3C) alkylenedioxy group that carries of any aryl, heteroaryl or heterocyclic radical in the group,

And wherein at R ⁶Optional 1 or 2 oxo or the sulfo-substituting group of carrying of any heterocyclic radical in the group,

And wherein at R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halos or (1-8C) alkyl substituent and/or be selected from following substituting group of carrying on the group: hydroxyl; sulfydryl; amino; cyano group; carboxyl; formamyl; urea groups; (2-8C) alkenyl; (2-8C) alkynyl; (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) alkanoyloxy; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); the alkyl urea groups of N '-(1-6C); N '; N '-two-[(1-6C) alkyl] urea groups; N-(1-6C) alkyl urea groups; N; N '-two-[(1-6C) alkyl] urea groups; N; N '; N '-three-[(1-6C) alkyl] urea groups; N-(1-6C) alkylsulfamoyl group; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C)

And wherein at R ⁶Adjacent carbons on any (2-6C) alkylidene chain in the group is optional to be inserted into the following group of being selected from of this chain and to separate: O, S, SO, SO ₂, N (R ²³), N (R ²³) CO, CON (R ²³), N (R ²³) CON (R ²³), CO, CH (OR ²³), N (R ²³) SO ₂, SO ₂N (R ²³), CH=CH and C ≡ C, wherein R ²³Be hydrogen or (1-8C) alkyl, maybe when the group that inserts be N (R ²³) time, R ²³Also can be (2-6C) alkyloyl.

In this manual, generic term " (1-8C) alkyl " comprise straight chain and branched-chain alkyl the two, as propyl group, sec.-propyl and the tertiary butyl, also comprise (3-8C) cycloalkyl, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, and also comprise the alkyl of (3-6C) cycloalkyl-(1-2C), as cyclopropyl methyl, 2-cyclopropyl ethyl, cyclobutylmethyl, 2-cyclobutyl ethyl, cyclopentyl-methyl, 2-cyclopentyl ethyl, cyclohexyl methyl and 2-cyclohexyl ethyl.Yet, when relating to the independent alkyl such as " propyl group ", only be to refer in particular to linear form, when relating to the independent branched-chain alkyl such as " sec.-propyl ", only be to refer in particular to the side chain form, and when mentioning independent cycloalkyl such as " cyclopentyl ", only refer in particular to 5-unit ring.Similarly convention is applicable to other generic term, for example (1-6C) alkoxyl group comprises (3-6C) cycloalkyl oxy 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, cyclopropyl amino, cyclobutyl amino, cyclohexyl amino, cyclopropyl methylamino-, 2-cyclopropyl ethylamino, cyclobutylmethyl amino, 2-cyclobutyl ethylamino and the cyclopentyl methylamino-of cycloalkyl-(1-2C); With two-[(1-6C alkyl] amino comprises 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.

Should be appreciated that, some formula I compound defined above is owing to have one or more unsymmetrical carbons, therefore can exist with optically active or racemic form, the present invention comprises any have above-mentioned active such optically active or racemic form in its definition.By standard 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 starting raw material or by racemic form.Similarly, use the standard laboratory technology of mentioning hereinafter, can estimate activity mentioned above.

Should be appreciated that some formula I compound defined above can demonstrate tautomerism.Specifically, tautomerism may influence the hetero-aromatic ring in the ring A definition or carry 1 or 2 oxo or the substituent R of sulfo- ¹And R ⁶Heterocyclic radical in the group.Should be appreciated that, the present invention comprises any such tautomeric form or its mixture in its definition, described form has activity mentioned above, and any tautomeric form that is not limited only to be adopted in structural formula figure or name in an embodiment.For example, ring A can be pyrazolyl.For example, be connected to 3 CON (R when this pyrazolyl ⁵) N atomic time of group, can there be the tautomerism mixture of the compound that contains 1H-pyrazole-3-yl and 1H-pyrazoles-5-base.Generally speaking, name any such tautomeric form wherein only among the embodiment later, perhaps wherein any such tautomeric form is present among hereinafter any dependency structure figure.

In structural formula I, should be appreciated that on the 2-position of quinazoline ring has hydrogen atom.Therefore should be appreciated that R ¹Substituting group can only be positioned at 5-, 6-, 7-or the 8-position of quinazoline ring, and promptly the 2-position keeps not being substituted.Aptly, R ¹Substituting group can only be positioned at 5-, 6-or the 7-position of quinazoline ring.Ground preferably, R ¹Substituting group can only be positioned at the 6-and/or the 7-position of quinazoline ring.

In structural formula I, should also be appreciated that any R that may be present on the pyridyl of center ²Group can be positioned on any available position.Aptly, there is not R ²Group (q=0).Perhaps, there is single R ²Group.Ground preferably exists to be positioned at 2 (with respect to C (R ³) (R ⁴) group) and single R ²Group.

In structural formula I, should be appreciated that any R ⁶Group can be positioned on any available position of ring A.For example, when ring A is 6-unit ring, R ⁶Group can be positioned at 3-or 4-position (with respect to CON (R ⁵) group), perhaps for example when ring A be 5-when ring unit, it can be positioned at the 3-position (with respect to CON (R ⁵) group).

The desired value of above-mentioned general group comprises those that hereinafter list.

When ' Q ' group is aryl, R ¹Or R ⁶Any one ' Q ' group (Q in the group ¹-Q ⁴) or any ' Q ' group in the desired value of aryl be for example phenyl or naphthyl, preferred phenyl.

When ' Q ' group is (3-8C) cycloalkyl, R ¹Or R ⁶Any one ' Q ' group (Q in the group ¹Or Q ³) or any ' Q ' group in the desired value of (3-8C) cycloalkyl be for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two ring [2.2.1] heptyl or ring octyl group.

Work as R ³And R ⁴When the carbon atom that connects with their formed (3-8C) cycloalkyl, the desired value of described (3-8C) cycloalkyl was for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl.

When ' Q ' group is (3-8C) cycloalkenyl group, R ¹Or R ⁶Any one ' Q ' group (Q in the group ¹Or Q ³) or any ' Q ' group in the fit value of (3-8C) cycloalkenyl group be for example cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctene base.

When ' Q ' group is heteroaryl, R ¹Or R ⁶Any one ' Q ' group (Q in the group ¹-Q ⁴) or any ' Q ' group in the desired value of heteroaryl be for example aromatics 5-or 6-unit's monocycle or 9-or 10-unit two rings, contain at the most 5 and be selected from oxygen, the ring hetero atom of nitrogen and sulphur, furyl for example, pyrryl, thienyl oxazolyl isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3, the 5-triazenyl, benzofuryl, indyl, benzothienyl benzoxazolyl, benzimidazolyl-, benzothiazolyl, indazolyl, benzo furazan base, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, cinnolines base or naphthyridine base.

When ' Q ' group is heterocyclic radical, R then ¹Or R ⁶Any one ' Q ' group (Q in the group ¹-Q ⁴) or any ' Q ' group in the fit value of heterocyclic radical be the 3-10 unit's monocycle or two rings of the saturated or fractional saturation of for example non-aromatics, contain at the most 5 and be selected from oxygen, the heteroatoms of nitrogen and sulphur, Oxyranyle for example, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, the oxepane alkyl, tetrahydro-thienyl, 1,1-dioxo tetrahydro-thienyl, tetrahydro thiapyran base, 1,1-dioxo tetrahydro thiapyran base, the azacyclopropane base, azetidinyl, pyrrolinyl, pyrrolidyl, imidazolinyl, imidazolidyl, pyrazolinyl, pyrazolidyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, 1,1-dioxo tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, 2-azabicyclic [2.2.1] heptyl, quinuclidinyl, chromanyl, the isochroman base, indolinyl, iso-dihydro-indole-group, the dihydropyridine base, tetrahydro pyridyl, dihydro-pyrimidin base or tetrahydro-pyrimidine base, preferred tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro thiapyran base, pyrrolinyl, pyrrolidyl, morpholinyl, piperidyl, piperazinyl, indolinyl or iso-dihydro-indole-group.The fit value that carries the substituent such group of 1 or 2 oxo or sulfo-is for example 2-oxo-pyrrolidine base, 2-sulfo-pyrrolidyl, 2-oxo-imidazole alkyl, 2-thiocarbamoyl imidazole alkyl, 2-oxo-piperidine base, 4-oxo-1,4-dihydropyridine base, 2,5-dioxo pyrrolidyl, 2,5-dioxo alkyl imidazole base or 2,6-dioxopiperidine base.

When any ' Q ' group was the alkyl of heteroaryl-(1-6C), its fit value was for example heteroaryl methyl, 2-heteroaryl ethyl and 3-heteroaryl propyl group.For ' Q ' group, the present invention includes corresponding fit value, for example when ' Q ' group is not the alkyl of heteroaryl-(1-6C), there is the alkyl of alkyl of the alkyl of the alkyl of aryl-(1-6C), (3-8C) cycloalkyl-(1-6C), (3-8C) cycloalkenyl group-(1-6C) or heterocyclic radical-(1-6C).

When ring A is 6-unit monocycle or 10-unit's two cyclophane rings or contains at the most 3 and be selected from oxygen, when the 5-of the ring hetero atom of nitrogen and sulphur or 6-unit's monocycle or 9-or 10-unit two ring hetero-aromatic rings, the fit value of described ring A is for example phenyl, naphthyl, furyl, pyrryl, thienyl oxazolyl isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl oxadiazole base, thiadiazolyl group, triazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3, the 5-triazenyl, benzofuryl, indyl, benzothienyl benzoxazolyl, benzimidazolyl-, benzothiazolyl, indazolyl, benzo furazan base, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, cinnolines base or naphthyridine base.Aptly, ring A is phenyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazine basic ring.Ground preferably, ring A is phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazine basic ring.When ring A is that the fit value of described ring A is for example furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group or triazolyl when containing at the most the 5-unit monocycle hetero-aromatic ring of 3 ring hetero atoms that are selected from oxygen, nitrogen and sulphur.Aptly, ring A is oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring.

For any ' R ' group (R ¹-R ²³) or R ¹, R ²Or R ⁶Various groups in the substituting group, suitable value comprises:

For halo: fluoro, chloro, bromo and iodo;

For (1-8C) alkyl: methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl,

Cyclobutyl, cyclohexyl, cyclohexyl methyl and 2-ring third

The base ethyl;

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) alkene oxygen base: vinyloxy group and allyloxy;

For (2-6C) alkynyloxy group: second alkynyloxy group and 2-third alkynyloxy group;

For (1-6C) alkylthio: methylthio group, ethylmercapto group and rosickyite base;

For (1-6C) alkyl sulfenyl methylsulfinyl and ethyl sulfinyl;

Base:

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] ammonia dimethylaminos, diethylin, N-ethyl-N-methyl ammonia

Base: base and diisopropylaminoethyl;

For (1-6C) alkoxy carbonyl: methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl

And tert-butoxycarbonyl;

For N-(1-6C) alkylamino N-methylamino formyl radical, N-ethylamino formyl radical and

Formyl radical: N-propyl group formamyl;

For N, N-two-[(1-6C) alkane N, N-formyl-dimethylamino, N-ethyl-N-methyl

Base] formamyl: formamyl 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 N-(1-6C) alkyl N-methyl kharophen and N-methyl-prop amido;

-(2-6C) alkanoylamino:

For N '-(1-6C) alkyl urea N '-methyl urea groups and N '-ethyl urea groups;

Base:

For N ', N '-two-[(1-6C) alkane N ', N '-dimethyl urea groups and N '-methyl-N '-ethyl carbamide

Base] urea groups: base;

For N-(1-6C) alkyl urea N-methyl urea groups and N-ethyl urea groups;

Base:

For N, N '-two-[(1-6C) alkane N, N '-dimethyl urea groups, N-methyl-N '-ethyl urea groups and

Base] urea groups: N-ethyl-N '-methyl urea groups;

For N, N ', N '-three-[(1-6C) N, N ', N '-trimethylammonium urea groups, N-ethyl-N ', N '-diformazan

Alkyl] urea groups: basic urea groups and N-methyl-N ', N '-diethyl urea groups;

For N-(1-6C) alkyl ammonia sulphur N-methyl sulfamyl and N-ethyl sulfamyl;

Acyl group:

For N, N-two-[(1-6C) alkane N, N-dimethylamino alkylsulfonyl;

Base] sulfamyl:

For (1-6C) alkanesulfonyl methylsulfonyl amino and ethylsulfonylamino;

Amino:

Amino and the N-methyl ethylsulfonyl for N-(1-6C) alkyl N-methyl methylsulfonyl

-(1-6C) alkanesulfonyl ammonia amino;

Base:

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-trifluoropropyl

Base;

For the alkyl of hydroxyl-(1-6C): methylol, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl;

For the alkyl of sulfydryl-(1-6C): thiopurine methyltransferase, 2-mercapto ethyl, 1-mercapto ethyl and 3-mercapto propyl group;

For (1-6C) alkoxyl group methoxy ylmethyl, ethoxyl methyl, 1-methoxy ethyl,

-(1-6C) alkyl: 2-methoxy ethyl, 2-ethoxyethyl group and 3-methoxyl group

Propyl group;

For (1-6C) alkylthio methylthiomethyl, ethylmercapto group methyl, 2-methylmercaptoethyl,

-(1-6C) alkyl: 1-methylmercaptoethyl and 3-methylthio group propyl group;

For (1-6C) alkyl sulfenyl methylsulfinyl methyl, ethyl sulfinyl methyl,

Base-(1-6C) alkyl: 2-methylsulfinyl ethyl, 1-methylsulfinyl second

Base and 3-methylsulfinyl propyl group;

For (1-6C) alkyl sulphonyl sulfonyloxy methyl ylmethyl, ethylsulfonyl methyl, 2-

-(1-6C) alkyl: methyl sulphonyl ethyl, 1-methyl sulphonyl ethyl and

3-methyl sulphonyl propyl group;

For the alkyl of cyano group-(1-6C): cyano methyl, 2-cyano ethyl, 1-cyano ethyl and 3-

The cyano group propyl group;

For amino-(1-6C) alkyl: amino methyl, 2-amino-ethyl, 1-amino-ethyl,

3-aminopropyl, 1-aminopropyl and 5-amino third

Base;

For (1-6C) alkylamino methylamino-methyl, ethylamino methyl, 1-methylamino-second

-(1-6C) alkyl: base, 2-methylamino-ethyl, 2-ethylamino ethyl and 3-

The methylamino-propyl group;

For two-[(1-6C) alkyl] ammonia dimethylamino methyls, diethylin methyl, 1-two

Base-(1-6C) alkyl: methylamino-ethyl, 2-dimethylaminoethyl and 3-diformazan ammonia

The base propyl group;

For (2-6C) alkanoylamino acetylamino methyl, propionamido methyl, 2-acetyl ammonia

-(1-6C) alkyl: basic ethyl and 1-kharophen ethyl;

For N-(1-6C) alkyl N-methyl acetylamino methyl, N-methyl-prop amido

-(2-6C) alkanoylamino methyl, 2-(N-methyl kharophen) ethyl and 1-(N-

-(1-6C) alkyl: the ethyl methyl kharophen);

For (1-6C) alkoxy carbonyl methoxycarbonyl amino methyl, ethoxy carbonyl amino

Amino-(1-6C) alkyl: methyl, tert-butoxycarbonyl amino methyl and 2-methoxy

Base carbonylamino ethyl;

For the alkyl of urea groups-(1-6C): urea groups methyl, 2-urea groups ethyl and 1-urea groups ethyl;

For the alkyl urea groups N '-methyl urea groups methyl of N '-(1-6C), 2-(N '-methyl urea groups) ethyl

-(1-6C) alkyl: and 1-(N '-the methyl urea groups) ethyl;

For N ', N '-two-[(1-6C) alkane N ', and N '-dimethyl urea ylmethyl, 2-(N ', N '-dimethyl

Base] alkyl of urea groups-(1-6C): ethyl and 1-(N ', N '-dimethyl urea groups) ethyl urea groups);

For N-(1-6C) alkyl urea groups N-methyl urea groups methyl, 2-(N-methyl urea groups) ethyl and

-(1-6C) alkyl: 1-(N-methyl urea groups) ethyl;

For N, N '-two-[(1-6C) alkane N, N '-dimethyl urea ylmethyl, 2-(N, N '-dimethyl urea

Base] alkyl of urea groups-(1-6C): ethyl and 1-(N, N '-dimethyl urea groups) ethyl base);

For N, N ', N '-three-[(1-6C) N, N ', N '-trimethyl-urea ylmethyl, 2-(N, N ', N '-three

Alkyl] alkyl of urea groups-(1-6C): ethyl and 1-(N, N ', the N '-trimethyl-urea methyl urea groups)

Base) ethyl;

For the alkyl of carboxyl-(1-6C): carboxyl methyl, 1-carboxy ethyl, 2-carboxy ethyl, 3-

Carboxyl propyl group and 4-carboxybutyl;

For (1-6C) alkoxy carbonyl methoxycarbonyl methyl, ethoxy carbonyl methyl, uncle

-(1-6C) alkyl: butoxy carbonyl methyl, 1-methoxycarbonyl ethyl, 1-

Ethoxy carbonyl ethyl, 2-methoxycarbonyl ethyl, 2-

Ethoxy carbonyl ethyl, 3-methoxycarbonyl propyl group and

The 3-ethoxycarbonyl propyl;

For formamyl-(1-6C) carbamyl ylmethyl, 1-formamyl ethyl, 2-

Alkyl: formamyl ethyl and 3-formamyl propyl group;

For N-(1-6C) alkylamino N-methylamino formyl radical methyl, N-ethylamino formyl

The alkyl of formyl radical-(1-6C): ylmethyl, N-propyl group carbamyl ylmethyl, 1-(N-

The methylamino formyl radical) ethyl, 1-(N-ethylamino formyl

Base) ethyl, 2-(N-methylamino formyl radical) ethyl,

2-(N-ethylamino formyl radical) ethyl and 3-(N-methyl ammonia

The base formyl radical) propyl group;

For N, N-two-[(1-6C) alkane N, N-formyl-dimethylamino methyl, N-ethyl-N-

Base] formamyl-(1-6C) methylamino formyl radical methyl, N, the N-diethylacbamazine

Alkyl: acyl group methyl, 1-(N, N-formyl-dimethylamino) second

Base, 1-(N, N-diethylamino formyl radical) ethyl,

2-(N, N-formyl-dimethylamino) ethyl, 2-(N, N-

The diethylamino formyl radical) ethyl, 3-(N, N-dimethyl

Formamyl) propyl group and 4-(N, N-dimethylamino

Formyl radical) butyl;

For sulfamyl-(1-6C) alkane sulfamyl methyl, 1-sulfamyl ethyl, 2-ammonia sulphur

Base: acyl group ethyl and 3-sulfamyl propyl group;

For N-(1-6C) alkyl ammonia sulphur N-methyl sulfamyl methyl, 1-(N-methyl sulphonamide

The alkyl of acyl group-(1-6C): base) ethyl, 2-(N-methyl sulfamyl) ethyl and

3-(N-methyl sulfamyl) propyl group;

For N, N-two-[(1-6C) alkane N, N-dimethylamino alkylsulfonyl methyl, 1-(N, N-diformazan

Base] alkylsulfamoyl group of sulfamyl-(1-6C)) ethyl, 2-(N, N-dimethylamino sulphonyl

Base: ethyl and 3-(N, N-dimethylamino alkylsulfonyl) propyl group base);

For (1-6C) alkanesulfonyl methylsulfonyl amino methyl, 2-(methylsulfonyl amino) second

Amino-(1-6C) alkyl: base and 1-(methylsulfonyl amino) ethyl; With

For N-(1-6C) alkyl N-methyl methylsulfonyl amino methyl, 2-(N-methyl first

-(1-6C) alkanesulfonyl amino-sulfonyl amino) ethyl and 1-(N-methyl methylsulfonyl

-(1-6C) alkyl: ethyl amino).

May appear at R ¹Or R ⁶The fit value of (1-3C) alkylenedioxy group in the group is for example methylene-dioxy, second-1-subunit dioxy base, isopropylidene dioxy base or ethylenedioxy, and the Sauerstoffatom on it occupies the adjacent ring position.

As preceding definition, work as R ¹Group forms formula Q ¹-X ²-group and X ²Be for example OC (R ⁸) ₂During linking group, be this OC (R so ⁸) ₂The carbon atom of linking group rather than Sauerstoffatom are connected with the quinazoline ring, and Sauerstoffatom is connected in Q ¹Group.Similarly, as preceding definition, work as R ⁶Group forms formula-X ⁷-Q ³Group and X ⁷Be for example C (R ¹⁷) ₂During the O linking group, be C (R ¹⁷) ₂The Sauerstoffatom of O linking group is connected in Q ³Group.

R ¹Or R ⁶(2-6C) alkylidene chain suitable in the group is for example ethylidene chain, trimethylene chain, tetramethylene chain or five methene chain.

As preceding definition, at R ¹Or R ⁶Adjacent carbons on any in the group (2-6C) alkylidene chain can be chosen wantonly on chain by inserting for example O, CON (R ¹²) or CON (R ²³) (respectively) and C ≡ C group and separate.For example, on the alkylidene chain of 4-methoxyl group butoxy, insert Sauerstoffatom and obtain for example 2-(2-methoxy ethoxy) oxyethyl group, for example obtain 4-hydroxyl fourth-2-alkynyloxy base and for example insert the CONH group on the ethylidene chain in the 3-methoxy propoxy obtaining for example 2-(2-methoxyl group kharophen) oxyethyl group inserting C ≡ C group on the ethylidene chain of 2-hydroxyl-oxethyl.

As preceding definition, work as R ¹Or R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optionally on the group carry one or more halos or (1-8C) during alkyl substituent, on each described CH group, be fit to have 1 halo or (1-8C) alkyl substituent so, at each described CH ₂Be fit to have 1 or 2 this type of substituting group on the group, and at each described CH ₃Be fit to have 1,2 or 3 this type of substituting group on the group.

As preceding definition, work as R ¹Or R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃On the group during the optional substituting group that carries as preceding definition, the R that is fit to that so so forms ¹Or R ⁶Group comprises that for example (1-8C) alkyl of hydroxyl-replacement is (as methylol, 1-hydroxyethyl and 2-hydroxyethyl), (1-6C) alkoxyl group of hydroxyl-replacement (as 2-hydroxyl propoxy-and 3-hydroxyl propoxy-), (1-6C) (1-6C) alkoxyl group of alkoxyl group-replacement (as 2-methoxy ethoxy and 3-oxyethyl group propoxy-), 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 (as 3-amino-2-hydroxypropyl amino) of the amino of hydroxyl-replacement-(2-6C), two-[(1-6C) alkyl] amino-(2-6C) alkylamino (as 3-dimethylamino-2-hydroxypropyl amino) of the alkylamino (as 2-hydroxyl-3-methylamino-propyl group amino) of (1-6C) alkylamino of hydroxyl-replacement-(2-6C) and hydroxyl-replacement.

As preceding definition, work as R ¹Or R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃On the group during the optional substituting group that carries as preceding definition, the R that is fit to that so so forms ¹Or R ⁶Group also comprises, for example two-[(1-6C) alkyl] of the alkyl (as 2-hydroxyl-3-methylamino-propyl group and 2-hydroxyl ethylamino methyl) of (1-6C) alkylamino of hydroxyl-replacement-(1-6C) and hydroxyl-replacement is amino-and (1-6C) alkyl (as 3-dimethylamino-2-hydroxypropyl and 2-(2-hydroxyethyl) amino methyl).

As preceding definition, be also to be understood that and work as R ¹Or R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃During the optional substituting group that carries as preceding definition, so optional substituting group can be present in as the CH in the substituting group of preceding definition, CH on the group ₂Or CH ₃On the group, described substituting group can be present in R ¹Or R ⁶On aryl in the group, heteroaryl or the heterocyclic radical.For example, if R ¹Or R ⁶Group comprises aryl or the heteroaryl that is replaced by (1-8C) alkyl, so should (1-8C) alkyl can be therein CH, CH ₂Or CH ₃Chosen wantonly replacement by its substituting group on the group as preceding definition.For example, if R ¹Or R ⁶Group comprises the heteroaryl that is replaced by the alkyl of for example (1-6C) alkylamino-(1-6C), terminal CH that so should (1-6C) alkylamino ₃Group can by for example (1-6C) alkyl sulphonyl or (2-6C) alkyloyl further replace.In addition, for example, if R ¹Or R ⁶Group comprises heterocyclic radical as piperidyl or piperazinyl (as described in heterocyclic radical replaced by for example (2-6C) alkyloyl) on its nitrogen-atoms, terminal CH that so should (2-6C) alkyloyl ₃Group can further be replaced by for example two-[(1-6C) alkyl] amino.For example, R ¹Or R ⁶Group can comprise N-(2-dimethylamino ethanoyl) piperidin-4-yl or 4-(2-dimethylamino ethanoyl) piperazine-1-base.In addition, for example, if R ¹Or R ⁶Group comprises heterocyclic radical as azetidinyl, piperidyl or piperazinyl (as described in heterocyclic radical replaced by (2-6C) alkyloyl for example) on its nitrogen-atoms, CH that so should (2-6C) alkyloyl ₂Group can further be replaced by for example hydroxyl.For example, R ¹Or R ⁶Group can comprise N-(2-hydroxyl propionyl) piperidin-4-yl.

As preceding definition, two R ⁶Group can form span together on ring A be the divalent group of adjacent ring position, for example OC (R ¹⁸) ₂O.As ring A during for phenyl for example, so the suitable group of formation is 2,3-methylenedioxyphenyl or 3,4-methylenedioxyphenyl.When there being another optional R ⁶During group (for example halogeno-group), so the suitable group that forms is for example 6-fluoro-2,3-methylenedioxyphenyl.And A is for example phenyl and two R when ring ⁶Group forms for example OC (R together ¹⁸) ₂C (R ¹⁸) ₂During group, so the suitable group that forms is for example 2, and 3-Dihydrobenzofuranes-5-is basic or 2,3-Dihydrobenzofuranes-6-base.And A is for example phenyl and two R when ring ⁶Group forms for example N (R together ¹⁹) C (R ¹⁸) ₂C (R ¹⁸) ₂During group, so the suitable group that forms is for example indoline-5-base or indoline-6-base.And A is for example phenyl and two R when ring ⁶Group forms for example N (R together ¹⁸) CO.C (R ¹⁸) during 2 groups, so the suitable group that forms is for example 2-oxoindoline-5-base or 2-oxoindoline-6-base.

The suitable pharmacy acceptable salt of formula I compound is the acid salt of formula I compound for example, for example the acid salt that forms with inorganic or organic acid (example hydrochloric acid, Hydrogen bromide, sulfuric acid, trifluoroacetic acid or citric acid); Or for example have the salt of enough tart formula I compounds, as basic metal or alkaline earth salt (as calcium salt or magnesium salts), or ammonium salt, or the salt that forms with organic bases (as methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine).The suitable pharmacy acceptable salt of formula I compound also has, for example the salt that forms in human or animal body behind the giving construction I compound.

What it is also understood that is that the suitable pharmaceutically acceptable solvent of formula I compound also constitutes one aspect of the present invention.Suitable pharmaceutically acceptable solvent is for example hydrate, as semihydrate, monohydrate, dihydrate or trihydrate or its optional amount.

What it is also understood that is that the suitable pharmaceutically acceptable prodrug of formula I compound also constitutes one aspect of the present invention.Therefore, The compounds of this invention can adopt the prodrug forms administration, and described prodrug is cracking and discharge the compound of The compounds of this invention in human or animal body.Prodrug can be used for changing the physical property and/or the pharmacokinetic properties of The compounds of this invention.When The compounds of this invention contains the suitable group that can be connected with the modification group or substituting group, can form prodrug.The example of prodrug comprises the amide derivatives of cleavable in the ester derivative of cleavable in the body and the body, and described ester derivative can form on the carboxyl of formula I compound or hydroxyl, and described amide derivatives can form on the carboxyl of formula I compound or amino.

Therefore, but but when as those formulas I compound of preceding definition by the organic synthesis time spent with pass through its prodrug cracking time spent in human or animal body, the present invention includes described compound.Therefore, the present invention includes those formulas I compound that produces with methodology of organic synthesis, be also included within this compounds that produces by the precursor compound metabolism in the human or animal body, described precursor compound is to can be the compound of synthetic generation or the formula I compound of the compound that metabolism produces.

The suitable pharmaceutically acceptable prodrug of formula I compound is based on the medicine that rational medicine is judged, is fit to deliver medicine to human or animal body, invariably active the and no abnormal toxicity of good medicine reason.

Various forms of prodrugs are described, for example in following file:

A) Methods in Enzymology, 42Volume, the 309-396 page or leaf is by editors (Academic Press, 1985) such as K.Widder;

B) Design of Pro-drugs is edited by H.Bundgaard, (Elsevier, 1985);

C) A Textbook of Drug Design and Development is edited by Krogsgaard-Larsen and H.Bundgaard, the 5th chapter " Design andApplication of Pro-drugs ", H.Bundgaard, 113-191 (1991);

d)H.Bundgaard， Advanced?Drug?Delivery?Reviews， 8，1-38(1992)；

E) H.Bundgaard etc., Journal of Pharmaceutical Sciences, 77, 285 (1988);

F) N.Kakeya etc., Chem.Pharm.Bull., 32, 692 (1984);

G) T.Higuchi and V.Stella, " Pro-Drugs as Novel Delivery Systems ", A.C.S.Symposium Series, 14 volumes; With

H) E.Roche (editor), " Bioreversible Carriers in Drug Design ", Pergamon Press, 1987.

Pharmaceutically acceptable prodrug with suitable formula I compound of carboxyl is, for example the ester of cleavable in its body.The ester that contains cleavable in the body of formula I compound of carboxyl is, for example cracking produces the pharmaceutically acceptable ester of parent acid in human or animal body.For carboxyl, suitable pharmaceutically acceptable ester comprises that (1-6C) alkyl ester is (as methyl esters, the ethyl ester and the tert-butyl ester), (1-6C) alkoxyl group methyl esters (as the methoxyl group methyl esters), (1-6C) the alkanoyloxy methyl esters is (as the new pentane acyloxy methyl esters, 3-2-benzo [C] furanonyl ester), (3-8C) alkyl ester (as cyclopentylcarbonyl oxygen base methyl esters and 1-cyclohexyl-carbonyl oxygen base ethyl ester) of naphthene base carbonyl oxygen base-(1-6C), 2-oxo-1,3-dioxa cyclopentenyl (dioxolenyl) methyl esters (as 5-methyl-2-oxo-1,3-Dioxol-4-yl methyl esters) and (1-6C) alkyl ester (as methoxycarbonyl oxygen base methyl esters and 1-methoxycarbonyl oxygen base ethyl ester) of alkoxy-carbonyl oxy-(1-6C).

Pharmaceutically acceptable prodrug with suitable formula I compound of hydroxyl is, for example the ester or the ether of cleavable in its body.The ester or the ether that contain cleavable in the body of formula I compound of hydroxyl is, for example cracking produces the pharmaceutically acceptable ester or the ether of parent hydroxy compound in the humans and animals body.For hydroxyl, suitable pharmaceutically acceptable one-tenth ester group comprises for example phosphoric acid ester (comprising the phosphoramidic acid cyclic ester) of inorganic ester.For hydroxyl; suitable pharmaceutically acceptable one-tenth ester group also comprises (1-10C) alkyloyl (as the benzoyl and the phenylacetyl of ethanoyl, benzoyl, phenylacetyl and replacement), (1-10C) alkoxy carbonyl (as ethoxy carbonyl, N, N-[two-(1-4C) alkyl] formamyl, 2-dialkyl amido ethanoyl and 2-carboxyl ethanoyl).The example of ring substituents comprises amino methyl, N-alkylamino methyl, N on phenylacetyl and the benzoyl, N-dialkyl amino ylmethyl, morpholino methyl, piperazine-1-ylmethyl and 4-(1-4C) alkylpiperazine-1-ylmethyl.For hydroxyl, suitable pharmaceutically acceptable one-tenth ether group comprises the alpha-acyloxy alkyl, for example acetoxy-methyl and oxy acid methyl neopentyl.

Pharmaceutically acceptable prodrug with suitable formula I compound of carboxyl is, the acid amides of cleavable in its body for example is for example with acid amides or its ester of alkylamine (as benzylamine) of the alkylamine (as the 2-methoxyethyl amine) of amine (as ammonia), (1-4C) alkylamine (as methylamine), two-(1-4C) alkylamines (as dimethylamine, N-ethyl-N-methylamine or diethylamine), (1-4C) alkoxyl group-(2-4C), phenyl-(1-4C) and amino acid (as glycine) formation.

Pharmaceutically acceptable prodrug with amino suitable formula I compound is, for example the amide derivatives of cleavable in its body.The suitable pharmaceutically acceptable acid amides that is formed by amino comprises, for example the acid amides that forms with (1-10C) alkyloyl (as the benzoyl and the phenylacetyl of ethanoyl, benzoyl, phenylacetyl and replacement).The example of ring substituents comprises amino methyl, N-alkylamino methyl, N on phenylacetyl and the benzoyl, N-dialkyl amino ylmethyl, morpholino methyl, piperazine-1-ylmethyl and 4-(1-4C) alkylpiperazine-1-ylmethyl.

By one or more meta-bolitess that in human or animal body, form behind the giving construction I compound, can partly bring into play the vivo effect of formula I compound.As previously mentioned, also can pass through the vivo effect of the metabolism performance formula I compound of precursor compound (prodrug).

Concrete novel The compounds of this invention comprises for example quinazoline derivant or its pharmacy acceptable salt of formula I, except as otherwise noted, otherwise each X wherein ¹, p, R ¹, q, R ², R ³, R ⁴, R ⁵, ring A, r and R ⁶Have any implication that in paragraph (a)-(iii) above or hereinafter, limits:

(a) X ¹Be O or NH;

(b) X ¹Be O;

(c) X ¹Be NH;

(d) p is 1,2 or 3, each R of existence ¹Group is selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, carboxyl, (1-6C) alkoxy carbonyl, formamyl, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy, (2-6C) chain oxy-acetylene, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N; N-two-[(1-6C) alkyl] formamyl, or be selected from the group of following formula:

Q ¹-X ²-

X wherein ²Be selected from O, N (R ⁸), CO, CON (R ⁸), N (R ⁸) CO and OC (R ⁸) ₂, R wherein ⁸Be hydrogen or (1-8C) alkyl, Q ¹Be the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-8C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

And R wherein ¹Any aryl in the last substituting group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried 1,2 or 3 substituting group; described substituting group can be identical or different, be selected from halo, trifluoromethyl, hydroxyl, amino, formamyl, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (2-6C) alkyloyl, N-(1-6C) alkyl-carbamoyl, N, NThe alkanoylamino of-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C), or be selected from the group of following formula:

-X ³-R ⁹

X wherein ³For direct key or be selected from O and N (R ¹⁰), R wherein ¹⁰Be hydrogen or (1-8C) alkyl, R ⁹For alkyl, two-[(1-6C) alkyl] of the 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), (1-6C) alkyl sulphonyl-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of the alkanoylamino of the alkyl of alkyl, (2-6C) alkanoylamino-(1-6C) or N-(1-6C) alkyl-(2-6C)-(1-6C), or be selected from the group of following formula:

-X ⁴-Q ²

X wherein ⁴For direct key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen or (1-8C) alkyl, Q ²Be the optional alkyl of 1 or 2 substituent heterocyclic radical or heterocyclic radical-(1-6C) that carries, described substituting group can be identical or different, is selected from halo, (1-8C) alkyl and (1-6C) alkoxyl group,

And R wherein ¹On substituting group in optional (1-3C) alkylenedioxy group that carries of any heterocyclic radical,

And R wherein ¹On substituting group in any heterocyclic radical optional carry 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halos or (1-8C) alkyl and/or be selected from following substituting group of carrying on the group: hydroxyl; amino; cyano group; carboxyl; formamyl; urea groups; (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) 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 alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C)

And R wherein ¹Adjacent carbons in any in the substituting group (2-6C) alkylidene chain is optional to be inserted into the following group of being selected from of this chain and to separate: O, N (R ¹²), CON (R ¹²), N (R ¹²) CO, CH=CH and C ≡ C, wherein R ¹²Be hydrogen or (1-8C) alkyl, maybe when the group that inserts be N (R ¹²) time, R ¹²Also can be (2-6C) alkyloyl;

(e) p is 1 or 2, and the R1 group is positioned at 6-and/or 7-position, the R in the 6-position ¹Group is selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, carboxyl, (1-6C) alkoxy carbonyl, formamyl, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy, (2-6C) chain oxy-acetylene, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N; N-two-[(1-6C) alkyl] formamyl, the R in the 7-position ¹Group is selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, carboxyl, (1-6C) alkoxy carbonyl, formamyl, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy, (2-6C) chain oxy-acetylene, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N; N-two-[(1-6C) alkyl] formamyl, or be selected from the group of following formula:

Q ¹-X ²-

X wherein ²Be selected from O, N (R ⁸), CO, CON (R ⁸), N (R ⁸) CO and OC (R ⁸) ₂, R wherein ⁸Be hydrogen or (1-8C) alkyl, Q ¹Be the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-8C) cycloalkyl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

And R wherein ¹Any aryl in the last substituting group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried 1,2 or 3 substituting group; described substituting group can be identical or different, be selected from halo, trifluoromethyl, hydroxyl, amino, formamyl, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (2-6C) alkyloyl, N-(1-6C) alkyl-carbamoyl, N, NThe alkanoylamino of-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C), or be selected from the group of following formula:

-X ³-R ⁹

X wherein ³For direct key or be selected from O and N (R ¹⁰), R wherein ¹⁰Be hydrogen or (1-8C) alkyl, R ⁹For alkyl, two-[(1-6C) alkyl] of the 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), (1-6C) alkyl sulphonyl-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of the alkanoylamino of the alkyl of alkyl, (2-6C) alkanoylamino-(1-6C) or N-(1-6C) alkyl-(2-6C)-(1-6C), or be selected from the group of following formula:

-X ⁴-Q ²

X wherein ⁴For direct key or be selected from O, CO and N (R ¹1), R wherein ¹1 is hydrogen or (1-8C) alkyl, Q ²Be the optional alkyl of 1 or 2 substituent heterocyclic radical or heterocyclic radical-(1-6C) that carries, described substituting group can be identical or different, is selected from halo, (1-8C) alkyl and (1-6C) alkoxyl group,

And R wherein ¹On substituting group in optional (1-3C) alkylenedioxy group that carries of any heterocyclic radical,

And R wherein ¹On substituting group in any heterocyclic radical optional carry 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halos or (1-8C) alkyl and/or be selected from following substituting group of carrying on the group: hydroxyl; amino; cyano group; carboxyl; formamyl; urea groups; (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) 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 alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C)

And wherein at R ¹Adjacent carbons on any in the substituting group (2-6C) alkylidene chain is optional to be inserted into the following group of being selected from of this chain and to separate: O, N (R ¹²), CON (R ¹²), N (R ¹²) CO, CH=CH and C ≡ C, wherein R ¹²Being hydrogen or (1-8C) alkyl, be N (R when inserting group perhaps ¹²) time, R ¹²Can also be (2-6C) alkyloyl;

(f) p is 1,2 or 3,1 R ¹Group is a 3-cyano group, arbitrarily other R ¹Group can be positioned at 5-, 6-or 7-position, or 5-and 7-position, or 6-and 7-position, each other R ¹Group is selected from fluoro; chloro; trifluoromethyl; cyano group; hydroxyl; amino; carboxyl; methoxycarbonyl; ethoxy carbonyl; formamyl; methyl; ethyl; propyl group; butyl; vinyl; allyl group; fourth-3-thiazolinyl; ethynyl; 2-propynyl; fourth-3-alkynyl; methoxyl group; oxyethyl group; propoxy-; isopropoxy; butoxy; allyloxy; fourth-3-thiazolinyl oxygen base; the second alkynyloxy group; 2-third alkynyloxy group; fourth-3-alkynyloxy base; methylamino-; ethylamino; third amino; dimethylamino; diethylin; dipropyl amino; N-methylamino formyl radical; N-ethylamino formyl radical; N; N-formyl-dimethylamino and N; N-diethylamino formyl radical, or be selected from the group of following formula:

Q ¹-X ²-

X wherein ²Be selected from O, NH, CO, CONH, NHCO and OCH ₂, 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 (THF)-3-base, 3-or 4-THP trtrahydropyranyl, 1-, 2-or 3-pyrrolidyl, morpholino, 1,1-dioxo tetrahydrochysene-4 H-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-4 H-1,4-thiazine-4-yl) ethyl, 3-(1,1-dioxo tetrahydrochysene-4 H-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 ¹Any aryl in the last substituting group; (3-8C) cycloalkyl; heteroaryl or heterocyclic radical are optional to carry 1; 2 or 3 substituting groups; described substituting group can be identical or different; be selected from fluoro; chloro; trifluoromethyl; hydroxyl; amino; formamyl; methyl; ethyl; allyl group; 2-propynyl; methoxyl group; methyl sulphonyl; methylamino-; dimethylamino; ethanoyl; propionyl; isobutyryl; N-methylamino formyl radical; N; the N-formyl-dimethylamino; methylene radical dioxy base; ethylidene dioxy base and isopropylidene dioxy base, or choose wantonly and carry 1 substituting group that is selected from the following formula group:

-X ³-R ⁹

X wherein ³For direct key or be selected from O and NH, R ⁹Be 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-two fluoropropyls, 3,3,3-trifluoro propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxy ethyl, 3-methoxy-propyl, cyano methyl, amino methyl, 2-amino-ethyl, 3-aminopropyl, methylamino-methyl, 2-methylamino-ethyl, 3-methylamino-propyl group, 2-ethylamino ethyl, 3-ethylamino propyl group, dimethylamino methyl, 2-dimethylaminoethyl, 3-dimethylamino-propyl, acetamidomethyl or N-methylacetamide ylmethyl and be selected from the group of following formula:

-X ⁴-Q ²

X wherein ⁴For direct key or be selected from O, CO and NH, Q ²Be 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, it is chosen wantonly separately and carries 1 or 2 substituting group, described substituting group can be identical or different, be selected from fluoro, chloro, methyl and methoxyl group

And R wherein ¹On substituting group in any heterocyclic radical optional carry 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Choose wantonly on the group and carry one or more fluoro, chloro or methyl or be selected from following substituting group: hydroxyl, amino, cyano group, methoxyl group, methyl sulphonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino, N-sec.-propyl-N-methylamino, ethanoyl, acetamido and N-methylacetamide base

And wherein at R ¹Adjacent carbons on any in the substituting group (2-6C) alkylidene chain is optional to be inserted into the following group of being selected from of this chain and to separate: O, NH, N (Me), N (COMe), CONH, NHCO, CH=CH and C ≡ C;

(g) p is 2, and R ¹Group is positioned at 5-and 7-position, or is positioned at 6-and 7-position, R ¹Group can be identical or different; be selected from cyano group; hydroxyl; amino; carboxyl; methoxycarbonyl; ethoxy carbonyl; formamyl; methyl; ethyl; propyl group; butyl; vinyl; ethynyl; methoxyl group; oxyethyl group; propoxy-; isopropoxy; butoxy; fourth-3-thiazolinyl oxygen base; methylamino-; ethylamino; dimethylamino; diethylin; N-methylamino formyl radical; N-ethylamino formyl radical; N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; cyclopentyloxy; cyclohexyloxy; phenoxy group; benzyl oxygen base; 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; tetramethyleneimine-1-base carbonyl; morpholino carbonyl; the piperidino-(1-position only) carbonyl; piperazine-1-base carbonyl; 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-4 H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4 H-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-base methylamino-, 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-4 H-1,4-thiazine-4-yl) ethylamino, 3-(1,1-dioxo tetrahydrochysene-4 H-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-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 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 ¹Any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclic radical in the last substituting group chosen wantonly and carried 1 or 2 substituting group; described substituting group can be identical or different; be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, formamyl, methyl, ethyl, methoxyl group, oxyethyl group, N-methylamino formyl radical, N; N-formyl-dimethylamino, methylene radical dioxy base, ethylidene dioxy base and isopropylidene dioxy base are at R ¹Tetramethyleneimine in the substituting group-2-base; piperidines-3-base; piperidin-4-yl; piperazine-1-base or high piperazine-1-base are randomly replaced by following groups N-: allyl group; 2-propynyl; methyl sulphonyl; ethylsulfonyl; ethanoyl; propionyl; isobutyryl; the 2-fluoro ethyl; 2; 2-two fluoro ethyls; 2; 2; the 2-trifluoroethyl; the 3-fluoropropyl; 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; the 8 kinds of substituting groups in back are chosen wantonly separately and are carried 1 or 2 substituting group; described substituting group can be identical or different; be selected from fluoro; chloro; methyl and methoxyl group

And wherein at R ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Choose wantonly on the group and carry one or more fluoro, chloro or methyl or be selected from following substituting group: hydroxyl, amino, methoxyl group, methyl sulphonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino, N-sec.-propyl-N-methylamino, N-methyl-N-propyl group amino, kharophen and N-methyl kharophen

And R wherein ¹Adjacent carbons on any in the substituting group (2-6C) alkylidene chain is optional to be inserted into the following group of being selected from of this chain and to separate: O, NH, N (Me), CH=CH and C ≡ C;

(h) p is 2, and R ¹Group is positioned at 6-and 7-position, R ¹Group can be identical or different; be selected from cyano group; hydroxyl; amino; methoxycarbonyl; ethoxy carbonyl; formamyl; methyl; ethyl; methoxyl group; oxyethyl group; propoxy-; isopropoxy; butoxy; methylamino-; ethylamino; dimethylamino; diethylin; N-methylamino formyl radical; N-ethylamino formyl radical; N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; tetramethyleneimine-1-base carbonyl; morpholino carbonyl; the piperidino-(1-position only) carbonyl; piperazine-1-base carbonyl; 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-4 H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4 H-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 wherein at R ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 substituting group, described substituting group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene radical dioxy base, ethylidene dioxy base 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 selected from following group N-replacement: 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 wherein at R ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Choose wantonly on the group and carry one or more chloro bases or be selected from following substituting group: hydroxyl, amino, methoxyl group, methyl sulphonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino and N-sec.-propyl-N-methylamino,

And R wherein ¹Adjacent carbons on any in the substituting group (2-6C) alkylidene chain is optional to be inserted into the following group of being selected from of this chain and to separate: O, NH, CH=CH and C ≡ C;

(i) p is 2, and R ¹Group is positioned at 6-and 7-position, R ¹Group can be identical or different; be selected from hydroxyl; amino; methoxycarbonyl; ethoxy carbonyl; formamyl; methyl; ethyl; methoxyl group; oxyethyl group; propoxy-; isopropoxy; butoxy; methylamino-; ethylamino; dimethylamino; diethylin; N-methylamino formyl radical; N-ethylamino formyl radical; N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; tetramethyleneimine-1-base carbonyl; morpholino carbonyl; the piperidino-(1-position only) carbonyl; piperazine-1-base carbonyl; 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-4 H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4 H-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 and the high piperazine of 3--1-base propoxy-

And wherein at R ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 substituting group, described substituting group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene radical dioxy base, ethylidene dioxy base 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 selected from following group N-replacement: 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 wherein at R ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Choose wantonly on the group and carry one or more chloro bases or be selected from following substituting group: hydroxyl, amino, methoxyl group, methyl sulphonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino and N-sec.-propyl-N-methylamino,

And R wherein ¹Adjacent carbons on any in the substituting group (2-6C) alkylidene chain is optional to be inserted into the following group of being selected from of this chain and to separate: O, NH, CH=CH and C ≡ C;

(j) p is 2, and R ¹Group is positioned at 6-and 7-position, is positioned at 6 R ¹Group is selected from cyano group, hydroxyl, methoxycarbonyl, ethoxy carbonyl, formamyl, methoxyl group, oxyethyl group, propoxy-, N-methylamino formyl radical, N-ethylamino formyl radical, N; N-formyl-dimethylamino, N; N-diethylamino formyl radical, tetramethyleneimine-1-base carbonyl, morpholino carbonyl, piperidino-(1-position only) carbonyl and piperazine-1-base carbonyl are positioned at 7 R ¹Group be 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-4 H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4 H-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 wherein at R ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 substituting group, described substituting group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene radical dioxy base, ethylidene dioxy base 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 selected from following group N-replacement: 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 wherein at R ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Choose wantonly on the group and carry one or more chloro bases or be selected from following substituting group: hydroxyl, amino, methoxyl group, methyl sulphonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino and N-sec.-propyl-N-methylamino;

(k) q is 0;

(l) q is 1 or 2, each R ²Group can be identical or different, be selected from halo, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N, N-two-[(1-6C) alkyl] formamyl;

(m) q is 1 or 2, each R ²Group can be identical or different, is selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino and two-[(1-6C) alkyl] amino;

(n) q is 1 or 2, each R ²Group can be identical or different, is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino;

(o) q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is (1-6C) alkoxyl group;

(p) q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, methyl, methoxyl group, methylamino-, dimethylamino, N-methylamino formyl radical and N, N-formyl-dimethylamino;

(q) q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino;

(r) q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, cyano group, methyl and methoxyl group;

(s) q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is a methoxyl group;

(t) R ³Be hydrogen, methyl or ethyl;

(u) R ³Be hydrogen;

(v) R ⁴Be hydrogen, methyl, ethyl, propyl group, the 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2, the 2-trifluoroethyl, the 3-fluoropropyl, 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, the 2-cyano ethyl, 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, acetamidomethyl or N-methylacetamide ylmethyl;

(w) R ⁴Be hydrogen, methyl or ethyl;

(x) R ⁴Be hydrogen;

(y) R ³And R ⁴The carbon atom that connects with them forms cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(z) R ⁵Be hydrogen, methyl, ethyl, propyl group, allyl group, 2-propynyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-two fluoropropyls, 3,3,3-trifluoro propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxy ethyl, 3-methoxy-propyl, cyano methyl, 2-cyano ethyl or 3-cyano group propyl group;

(aa) R ⁵Be methyl or ethyl;

(bb) R ⁵Be hydrogen;

(cc) ring A is 6-unit's monocyclic aromatic rings or contains 3 5-or 6-unit monocycle hetero-aromatic rings that are selected from the ring hetero atom of oxygen, nitrogen and sulphur at the most;

(dd) ring A is a phenyl ring;

(ee) ring A is a 6-unit monocycle hetero-aromatic ring, contains 3 nitrogen heteroatoms at the most;

(ff) ring A contains 3 5-unit monocycle hetero-aromatic rings that are selected from the ring hetero atom of oxygen, nitrogen and sulphur at the most;

(gg) ring A is phenyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, pyridyl, pyrimidyl, pyrazinyl or pyridazine basic ring;

(hh) ring A is phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazine basic ring;

(ii) encircling A is furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring;

(jj) be 6-unit ring and have 1 or 2 R as ring A ⁶During group, 1 R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group);

(kk) be 5-unit ring and have 1 or 2 R as ring A ⁶During group, 1 R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group);

(ll) ring A is for carrying 1 or 2 R ⁶The phenyl of group, pyridyl, pyrimidyl, pyrazinyl or pyridazine basic ring, 1 R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group);

(mm) ring A is for carrying 1 or 2 R ⁶The furyl of group, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring, 1 R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group);

(nn) ring A is 9-or 10-unit two ring hetero-aromatic rings, contains 3 ring hetero atoms that are selected from oxygen, nitrogen and sulphur at the most;

(oo) ring A is benzofuryl, indyl, benzothienyl, benzoxazolyl, benzimidazolyl-, benzothiazolyl, indyl, benzotriazole base, 1H-pyrrolo-[3,2-b] pyridyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl or naphthyridine basic ring;

(pp) r is 0,1,2 or 3, each R of existence ⁶Group can be identical or different, is selected from that halo, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C) alkanoylamino;

(qq) r is 1 or 2, each R ⁶Group can be identical or different, is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin;

(rr) r is 1, R ⁶Group is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin;

(ss) r is 1,2 or 3, and 1 R ⁶Group is the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶For direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-8C) alkyl, R ¹⁵Be the alkyl of halo-(1-6C); the alkyl of hydroxyl-(1-6C); the alkyl of sulfydryl-(1-6C); (1-6C) alkyl of alkoxyl group-(1-6C); (1-6C) alkyl of alkylthio-(1-6C); (1-6C) alkyl of alkyl sulphinyl-(1-6C); (1-6C) alkyl of alkyl sulphonyl-(1-6C); the alkyl of cyano group-(1-6C); amino-(1-6C) alkyl; (1-6C) alkyl of alkylamino-(1-6C); two-[(1-6C) alkyl] amino-(1-6C) alkyl; (2-6C) alkyl of alkanoylamino-(1-6C); the alkyl of the alkanoylamino of N-(1-6C) alkyl-(2-6C)-(1-6C); the alkyl of carboxyl-(1-6C); (1-6C) alkyl of alkoxy carbonyl-(1-6C); the alkyl of formamyl-(1-6C); N-(1-6C) alkyl-carbamoyl-(1-6C) alkyl or N; the alkyl of N-two-[(1-6C) alkyl] formamyl-(1-6C), prerequisite is to work as X ⁶Be O or N (R ¹⁶) time, at X ⁶With R ¹⁵Have 2 carbon atoms between any heteroatoms in the group at least,

And any other R that exists ⁶Group is selected from that halo, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, the alkanoylamino of (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C)

And wherein at R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halos or (1-8C) alkyl substituent and/or be selected from following substituting group of carrying on the group: hydroxyl, amino, cyano group, carboxyl, formamyl, urea groups, (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, the alkanoylamino of N-two-[(1-6C) alkyl] formamyl, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C);

(tt) r is 1,2 or 3 and 1 R ⁶Group is the group of following formula:

-X ⁷-Q ³

X wherein ⁷For direct key or be selected from O, N (R ¹⁷), CON (R ¹⁷), N (R ¹⁷) CO and C (R ¹⁷) ₂O, wherein each R ¹⁷Be hydrogen or (1-8C) alkyl, Q ³Be the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-8C) cycloalkyl, (3-8C) cycloalkyl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), prerequisite is to work as X ⁷Be selected from O, N (R ¹⁷), CON (R ¹⁷) or C (R ¹⁷) ₂During O, at X ⁷With the Q in hetero-aromatic ring not ³In any heteroatoms between have 2 carbon atoms at least,

And any other R that exists ⁶Group is selected from that halo, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, the alkanoylamino of (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C)

And wherein at R ⁶Any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried 1,2 or 3 substituting group; described substituting group can be identical or different; be selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, carboxyl, formamyl, urea groups, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino and two-[(1-6C) alkyl] amino, or be selected from the group of following formula:

-X ⁸-R ²⁰

X wherein ⁸For direct key or be selected from O and N (R ²¹), R wherein ²¹Be hydrogen or (1-8C) alkyl, R ²⁰For 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

R wherein ⁶Any heterocyclic radical in the group randomly carries 1 or 2 oxo or sulfo-substituting group,

And wherein at R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halos or (1-8C) alkyl substituent and/or be selected from following substituting group of carrying on the group: hydroxyl, amino, cyano group, carboxyl, formamyl, urea groups, (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, the alkanoylamino of N-two-[(1-6C) alkyl] formamyl, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C);

(uu) r is 1,2 or 3,1 R ⁶Group is the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶For direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-8C) alkyl, R ¹⁵Be the alkyl of hydroxyl-(1-6C); (1-6C) alkyl of alkoxyl group-(1-6C); (1-6C) alkyl of alkylthio-(1-6C); (1-6C) alkyl of alkyl sulphinyl-(1-6C); (1-6C) alkyl of alkyl sulphonyl-(1-6C); the alkyl of cyano group-(1-6C); amino-(1-6C) alkyl; (1-6C) alkyl of alkylamino-(1-6C); two-[(1-6C) alkyl] amino-(1-6C) alkyl; (2-6C) alkyl of alkanoylamino-(1-6C); the alkyl of the alkanoylamino of N-(1-6C) alkyl-(2-6C)-(1-6C); aryl; the alkyl of aryl-(1-6C); (3-8C) cycloalkyl; (3-8C) alkyl of cycloalkyl-(1-6C); heteroaryl; the alkyl of heteroaryl-(1-6C); the alkyl of heterocyclic radical or heterocyclic radical-(1-6C), prerequisite is to work as X ⁶Be O or N (R ¹⁶) time, at X ⁶With R ¹⁶Have 2 carbon atoms between any heteroatoms of group at least,

And any other R that exists ⁶Group is selected from that halo, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, the alkanoylamino of (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C)

And R wherein ⁶Any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried 1 or 2 substituting group, described substituting group can be identical or different, be selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (1-6C) alkoxyl group, (1-6C) alkylamino and two-[(1-6C) alkyl] amino, or be selected from the group of following formula:

-X ⁸-R ²⁰

X wherein ⁸Be direct key, R ²⁰For 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

And wherein at R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional 1,2 or 3 halo or (1-8C) alkyl substituent and/or be selected from following substituting group of carrying on the group: hydroxyl, amino, cyano group, (3-8C) thiazolinyl, (3-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C) alkanoylamino;

(vv) r is 1,2 or 3,1 R ⁶Group is the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶For direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-8C) alkyl, R ¹⁵For alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of alkyl, heterocyclic radical or the heterocyclic radical of the alkyl of the alkyl of alkyl, aryl, aryl-(1-6C), (3-8C) cycloalkyl, (3-8C) cycloalkyl-(1-6C), heteroaryl, heteroaryl-(1-6C)-(1-6C), prerequisite is to work as X ⁶Be O or N (R ¹⁶) time, at X ⁶With R ¹⁵Have 2 carbon atoms between any heteroatoms of group at least,

And any other R that exists ⁶Group is selected from that halo, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, the alkanoylamino of (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C)

And R wherein ⁶Any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried 1 or 2 substituting group, described substituting group can be identical or different, be selected from that halo, trifluoromethyl, hydroxyl, amino, (1-8C) alkyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, hydroxyl-(1-6C) alkyl and two-[(1-6C) alkyl] of the alkyl of alkyl, amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl;

(ww) r is 1 or 2,1 R ⁶Group is the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶For direct key or be selected from O, NH and N (Me), R ¹⁵Be methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 1-hydroxyl-1-methylethyl, the 3-hydroxypropyl, methoxymethyl, the 1-methoxy ethyl, the 2-methoxy ethyl, 1-methoxyl group-1-methylethyl, the 3-methoxy-propyl, cyano methyl, the 1-cyano ethyl, the 2-cyano ethyl, 1-cyano group-1-methylethyl, 3-cyano group propyl group, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, 1-amino-1-methylethyl, the 3-aminopropyl, the methylamino-methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, 1-methylamino--1-methylethyl, 3-methylamino-propyl group, the ethylamino methyl, 1-ethylamino ethyl, 2-ethylamino ethyl, 1-ethylamino-1-methylethyl, 3-ethylamino propyl group, the sec.-propyl amino methyl, 1-sec.-propyl amino-ethyl, dimethylamino methyl, the 1-dimethylaminoethyl, the 2-dimethylaminoethyl, 1-dimethylamino-1-methylethyl, the 3-dimethylamino-propyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, thienyl oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro thiapyran base, pyrrolinyl, pyrrolidyl, imidazolinyl, pyrazolinyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, indolinyl, iso-dihydro-indole-group, the pyrrolinyl methyl, the pyrrolidyl methyl, 2-pyrrolidyl ethyl, 3-pyrrolidyl propyl group, the imidazolinyl methyl, the pyrazolinyl methyl, the morpholinyl methyl, 2-(morpholinyl) ethyl, 3-(morpholinyl) propyl group, tetrahydrochysene-1,4-thiazinyl methyl, 2-(tetrahydrochysene-1, the 4-thiazinyl) ethyl, 3-(tetrahydrochysene-1, the 4-thiazinyl) propyl group, piperidino methyl, 2-(piperidyl) ethyl, 3-(piperidyl) propyl group, the homopiperidinyl methyl, the piperazinyl methyl, 2-(piperazinyl) ethyl, 3-(piperazinyl) propyl group or high piperazinyl methyl, prerequisite is to work as X ⁶During for O, NH or N (Me), at X ⁶With R ¹⁵Have 2 carbon atoms between any heteroatoms of group at least,

And R wherein ⁶Any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried 1 or 2 substituting group, described substituting group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, dimethylamine, methylol, the 2-hydroxyethyl, the 3-hydroxypropyl, amino methyl, the 2-amino-ethyl, the 3-aminopropyl, the methylamino-methyl, 2-methylamino-ethyl, 3-methylamino-propyl group, dimethylamino methyl, 2-dimethylaminoethyl and 3-dimethylamino-propyl

And any other R that exists ⁶Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino;

(xx) r is 1 or 2, first R ⁶Group is the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or O, R ¹⁵Be methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, the 3-hydroxypropyl, methoxymethyl, the 1-methoxy ethyl, the 2-methoxy ethyl, 1-methoxyl group-1-methylethyl, the 3-methoxy-propyl, cyano methyl, the 1-cyano ethyl, the 2-cyano ethyl, 3-cyano group propyl group, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the 3-aminopropyl, the methylamino-methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, 3-methylamino-propyl group, the ethylamino methyl, 1-ethylamino ethyl, 2-ethylamino ethyl, 1-ethylamino-1-methylethyl, 3-ethylamino propyl group, the sec.-propyl amino methyl, 1-sec.-propyl amino-ethyl, dimethylamino methyl, the 1-dimethylaminoethyl, the 2-dimethylaminoethyl, the 3-dimethylamino-propyl, phenyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl group, pyrrolidyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, the pyrrolidyl methyl, 2-(pyrrolidyl) ethyl, 3-(pyrrolidyl) propyl group, the morpholinyl methyl, 2-(morpholinyl) ethyl, 3-(morpholinyl) propyl group, piperidino methyl, 2-(piperidyl) ethyl, 3-(piperidyl) propyl group, the homopiperidinyl methyl, the piperazinyl methyl, 2-(piperazinyl) ethyl, 3-(piperazinyl) propyl group or high piperazinyl methyl, prerequisite is to work as X ⁶During for O, at X ⁶With R ¹⁵Have 2 carbon atoms between any heteroatoms of group at least,

And R wherein ⁶Optional the carrying of any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical is selected from following substituting group: fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino, R ⁶Optional also the carrying of any such aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical is selected from following substituting group: methylol, cyano methyl, amino methyl, methylamino-methyl and dimethylamino methyl,

Any second R that exists ⁶Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino;

(yy) r is 1 or 2, first R ⁶Group is selected from methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, methoxymethyl, the 1-methoxy ethyl, the 2-methoxy ethyl, cyano methyl, the 1-cyano ethyl, the 2-cyano ethyl, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the methylamino-methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, the ethylamino methyl, 1-ethylamino ethyl, 2-ethylamino ethyl, the sec.-propyl amino methyl, 1-sec.-propyl amino-ethyl, 2-sec.-propyl amino-ethyl, dimethylamino methyl, the 1-dimethylaminoethyl, the 2-dimethylaminoethyl, phenyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl group, pyrrolidyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, the pyrrolidyl methyl, 2-(pyrrolidyl) ethyl, the morpholinyl methyl, 2-(morpholinyl) ethyl, piperidino methyl, 2-(piperidyl) ethyl, the homopiperidinyl methyl, the piperazinyl methyl, 2-(piperazinyl) ethyl and high piperazinyl methyl

And R wherein ⁶Optional the carrying of any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical is selected from following substituting group: fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino, R ⁶Optional also the carrying of any such aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical is selected from following substituting group: methylol, cyano methyl, amino methyl, methylamino-methyl and dimethylamino methyl,

And any second R that exists ⁶Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino;

(zz) r is 1 or 2, first R ⁶Group is selected from fluoro; chloro; cyano group; hydroxyl; amino; methyl; ethyl; propyl group; sec.-propyl; butyl; the second month in a season-butyl; isobutyl-; the tertiary butyl; cyclopropyl; cyclobutyl; cyclopentyl; methoxyl group; oxyethyl group; methylamino-; ethylamino; propyl group amino; sec.-propyl amino; cyclopropyl amino; the 2-hydroxyethylamino; 2-methoxyl group ethylamino; dimethylamino; N-cyclopropyl-N-methylamino; ethanoyl; methylol; the 1-hydroxyethyl; amino methyl; the methylamino-methyl; the ethylamino methyl; the propyl group amino methyl; the sec.-propyl amino methyl; the cyclopropyl amino methyl; 2-hydroxyl ethylamino methyl; dimethylamino methyl; the diethylin methyl; N-ethyl-N-methylamino methyl; the cyclopropyl amino methyl; N-cyclopropyl-N-methylamino methyl; furyl methylamino-methyl; pyrryl methylamino-methyl; pyridyl methylamino-methyl; phenyl; furyl; thienyl; imidazolyl oxazolyl; thiazolyl; pyrrolidyl; morpholinyl; piperidyl; homopiperidinyl; piperazinyl; high piperazinyl; the azetidine ylmethyl; the pyrrolidyl methyl; the morpholinyl methyl; piperidino methyl; the homopiperidinyl methyl; piperazinyl methyl and high piperazinyl methyl

And R wherein ⁶Optional the carrying of any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical is selected from following substituting group: fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-, dimethylamino, methylol, cyano methyl, amino methyl, methylamino-methyl and dimethylamino methyl

And any second R that exists ⁶Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino;

(aaa) r is 1, R ⁶Group is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylol, 2-hydroxyethyl, methoxymethyl, 2-methoxy ethyl, methylamino-methyl, ethylamino methyl, sec.-propyl amino methyl, cyclopropyl amino methyl, dimethylamino methyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin;

(bbb) two R ⁶Group forms span together on ring A be the divalent group of adjacent ring position, and described divalent group is selected from OC (R ¹⁸) ₂O, OC (R ¹⁸) ₂C (R ¹⁸) ₂O, OC (R ¹⁸) ₂C (R ¹⁸) ₂, C (R ¹⁸) ₂OC (R ¹⁸) ₂, C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂, C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂, OC (R ¹⁸) ₂N (R ¹⁹), N (R ¹⁹) C (R ¹⁸) ₂N (R ¹⁹), N (R ¹⁹) C (R ¹⁸) ₂C (R ¹⁸) ₂, N (R ¹⁹) C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂And C (R ¹⁸) ₂N (R ¹⁹) C (R ¹⁸) ₂, R wherein ¹⁸And R ¹⁹Respectively do for oneself hydrogen, (1-8C) alkyl, (2-8C) thiazolinyl or (2-8C) alkynyl;

(ccc) two R ⁶Group forms span together on ring A be the divalent group of adjacent ring position, and described divalent group is selected from OC (R ¹⁸) ₂O, OC (R ¹⁸) ₂C (R ¹⁸) ₂O, C (R ¹⁸) ₂OC (R ¹⁸) ₂, OC (R ¹⁸) ₂N (R ¹⁹), N (R ¹⁹) C (R ¹⁸) ₂N (R ¹⁹), N (R ¹⁹) C (R ¹⁸) ₂C (R ¹⁸) ₂, N (R ¹⁹) C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂And C (R ¹⁸) ₂N (R ¹⁹) C (R ¹⁸) ₂, R wherein ¹⁸And R ¹⁹Respectively do for oneself hydrogen, methyl, ethyl or propyl group;

(ddd) two R ⁶Group forms span together on ring A be the divalent group of adjacent ring position, and described divalent group is selected from OCH ₂O, OCH ₂CH ₂O, OCH ₂NH, NHCH ₂CH ₂And NHCH ₂CH ₂CH ₂

(eee) two R ⁶Group forms span together on ring A be the divalent group of adjacent ring position, and described divalent group is selected from OCH ₂O and OCH ₂CH ₂O;

(fff) p be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position; be selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, formamyl, (1-6C) alkoxy carbonyl, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy, (2-6C) chain oxy-acetylene, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N; N-two-[(1-6C) alkyl] formamyl; q is 1, R ²Group is positioned at the 2-position (with respect to C (R ³) (R ⁴) group), be selected from halo, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N, N-two-[(1-6C) alkyl] formamyl;

(ggg) p be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position; be selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, formamyl, methoxycarbonyl, ethoxy carbonyl, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, dimethylamino, N-methylamino formyl radical and N; the N-formyl-dimethylamino; q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, dimethylamino, N-methylamino formyl radical and N, N-formyl-dimethylamino;

(hhh) p be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position, is selected from fluoro, chloro, cyano group, formamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, the N-formyl-dimethylamino, and q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from formamyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, N-formyl-dimethylamino; With

(iii) p be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position, is selected from fluoro, cyano group, formamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, the N-formyl-dimethylamino, and q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from methoxyl group and oxyethyl group.

The quinazoline derivant that a kind of particular compound of the present invention is formula I or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2, R ¹Group is positioned at 6-and 7-position, the R in the 6-position ¹Group is selected from cyano group, hydroxyl, methoxycarbonyl, ethoxy carbonyl, formamyl, methoxyl group, oxyethyl group, propoxy-, N-methylamino formyl radical, N-ethylamino formyl radical, N; N-formyl-dimethylamino, N; N-diethylamino formyl radical, tetramethyleneimine-1-base carbonyl, morpholino carbonyl, piperidino-(1-position only) carbonyl and piperazine-1-base carbonyl, the R in the 7-position ¹Group be 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-4 H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4 H-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 ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 substituting group, described substituting group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene radical dioxy base, ethylidene dioxy base 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 randomly 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 ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is chosen wantonly at each described CH, CH ₂Or CH ₃Carry one or more chloro groups on the group or be selected from following substituting group: hydroxyl, amino, methoxyl group, methyl sulphonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino and N-sec.-propyl-N-methylamino;

Q be 0 or q be 1, be positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazine basic ring; With

R be 0 or r be 1 or 2,1 R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group), each R ⁶Group can be identical or different, is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino,

Perhaps r is 1 or 2,1 R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group), be the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or O, R ¹⁵Be methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, the 3-hydroxypropyl, methoxymethyl, the 1-methoxy ethyl, the 2-methoxy ethyl, 1-methoxyl group-1-methylethyl, the 3-methoxy-propyl, cyano methyl, the 1-cyano ethyl, the 2-cyano ethyl, 3-cyano group propyl group, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the 3-aminopropyl, the methylamino-methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, 3-methylamino-propyl group, the ethylamino methyl, 1-ethylamino ethyl, 2-ethylamino ethyl, 1-ethylamino-1-methylethyl, 3-ethylamino propyl group, the sec.-propyl amino methyl, 1-sec.-propyl amino-ethyl, dimethylamino methyl, the 1-dimethylaminoethyl, the 2-dimethylaminoethyl, the 3-dimethylamino-propyl, phenyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl group, pyrrolidyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, the pyrrolidyl methyl, 2-(pyrrolidyl) ethyl, 3-(pyrrolidyl) propyl group, the morpholinyl methyl, 2-(morpholinyl) ethyl, 3-(morpholinyl) propyl group, piperidino methyl, 2-(piperidyl) ethyl, 3-(piperidyl) propyl group, the homopiperidinyl methyl, the piperazinyl methyl, 2-(piperazinyl) ethyl, 3-(piperazinyl) propyl group or high piperazinyl methyl, prerequisite is to work as X ⁶During for O, at X ⁶And R ¹⁵Between any heteroatoms in the group at least 2 carbon atoms are arranged,

And R wherein ⁶Optional the carrying of any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical is selected from following substituting group: fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino, R ⁶Optional also the carrying of any such aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical is selected from following substituting group: methylol, cyano methyl, amino methyl, methylamino-methyl and dimethylamino methyl,

And any second R of Cun Zaiing wherein ⁶Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino.

The quinazoline derivant that another particular compound of the present invention is formula I or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2, first R ¹Group is positioned at the 6-position, is selected from cyano group, formamyl, methoxyl group, N-methylamino formyl radical and N, N-formyl-dimethylamino, second R ¹Group is positioned at the 7-position; be selected from methoxyl group, oxyethyl group, 2-methoxy ethoxy, 3-methoxy propoxy, 2-sulfonyloxy methyl base oxethyl, 3-methyl sulphonyl propoxy-, 2-(2-methoxy ethoxy) oxyethyl group, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 2-[(3RS; 4SR)-3; 4-methylene radical dioxy base tetramethyleneimine-1-yl] oxyethyl group, 3-[(3RS; 4SR)-3; 4-methylene radical dioxy base tetramethyleneimine-1-yl] and propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-(1,1-dioxo tetrahydrochysene-4 H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4 H-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-(4-pyridyl oxygen base) oxyethyl group, 3-pyridyl methoxyl group and 2-cyanopyridine-4-ylmethoxy;

Q be 0 or q be 1, be positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, cyano group, methyl and methoxyl group;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen or methyl;

Ring A is phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazine basic ring; With

R be 0 or r be 1 or 2,1 R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group), each R ⁶Group can be identical or different, is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino,

Perhaps r is 1 or 2,1 R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group), be selected from methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, methoxymethyl, the 1-methoxy ethyl, the 2-methoxy ethyl, cyano methyl, the 1-cyano ethyl, the 2-cyano ethyl, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the methylamino-methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, the ethylamino methyl, 1-ethylamino ethyl, 2-ethylamino ethyl, the sec.-propyl amino methyl, 1-sec.-propyl amino-ethyl, 2-sec.-propyl amino-ethyl, dimethylamino methyl, the 1-dimethylaminoethyl, the 2-dimethylaminoethyl, the pyrrolidyl methyl, the morpholinyl methyl, piperidino methyl and piperazinyl methyl

And R wherein ⁶Optional the carrying of any heterocyclic radical in the group is selected from following substituting group: fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino,

And any second R that exists ⁶Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino.

The quinazoline derivant that another particular compound of the present invention is formula I or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2, R ¹Group can be identical or different, be positioned at 6-and 7-position, be selected from cyano group, methoxyl group, oxyethyl group, propoxy-, 2-hydroxyl-oxethyl, 3-hydroxyl propoxy-, 2-methoxy ethoxy, 3-methoxy propoxy, 2-sulfonyloxy methyl base oxethyl, 3-methyl sulphonyl propoxy-and 2-(2-methoxy ethoxy) oxyethyl group;

Q be 0 or q be 1, be positioned at 2-or 3-position (with respect to C (R ³) (R ⁴) group) and R ²Group is fluoro, chloro, methyl or methoxy;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is a phenyl; With

R is 1 or 2, first R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group), be selected from fluoro, chloro, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino, cyclopropyl amino, N-cyclopropyl-N-methylamino, methylol, amino methyl, the methylamino-methyl, the ethylamino methyl, the sec.-propyl amino methyl, the cyclopropyl amino methyl, dimethylamino methyl, the diethylin methyl, N-ethyl-N-methylamino methyl, N-cyclopropyl-N-methylamino methyl, the azetidine ylmethyl, the pyrrolidyl methyl, the morpholinyl methyl, piperidino methyl, the homopiperidinyl methyl, piperazinyl methyl and high piperazinyl methyl

And any second R that exists ⁶Group is selected from fluoro, chloro, methyl, ethyl, methoxyl group and oxyethyl group,

And R wherein ⁶Optional methyl, ethyl or the methylol substituting group of carrying of any heterocyclic radical in the group.

The quinazoline derivant that another particular compound of the present invention is formula I or its pharmacy acceptable salt, solvate or prodrug, wherein:

X ¹Be O;

P is 2, first R ¹Group is 6-cyano group or 6-methoxyl group, second R ¹Group is positioned at the 7-position, is selected from methoxyl group, oxyethyl group, 2-hydroxyl-oxethyl and 2-methoxy ethoxy;

Q be 0 or q be 1, R ²Group is a fluorine;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is a phenyl; With

R is 1 or 2, first R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group), be selected from fluoro, chloro, methoxyl group, methylamino-, ethylamino, dimethylamino, cyclopropyl amino, methylol, amino methyl, the methylamino-methyl, the ethylamino methyl, the propyl group amino methyl, the sec.-propyl amino methyl, the cyclopropyl amino methyl, dimethylamino methyl, the diethylin methyl, N-ethyl-N-methylamino methyl, N-cyclopropyl-N-methylamino methyl, azetidine-1-ylmethyl, tetramethyleneimine-1-ylmethyl, the morpholino methyl, piperidino-(1-position only) methyl and piperazine-1-ylmethyl

And any second R that exists ⁶Group is selected from fluoro, chloro, methyl, ethyl, methoxyl group and oxyethyl group,

And R wherein ⁶Optional methyl, ethyl or the methylol substituting group of carrying of any heterocyclic radical in the group.

The quinazoline derivant that another particular compound of the present invention is formula I or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2, R ¹Group can be identical or different, be positioned at 6-and 7-position, be selected from cyano group, methoxyl group, oxyethyl group, propoxy-, 2-hydroxyl-oxethyl, 3-hydroxyl propoxy-, 2-methoxy ethoxy, 3-methoxy propoxy, 2-sulfonyloxy methyl base oxethyl, 3-methyl sulphonyl propoxy-and 2-(2-methoxy ethoxy) oxyethyl group;

Q be 0 or q be 1, R ²Group is fluoro, chloro, methyl or methoxy;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; With

R is 0,1 or 2, each R of existence ⁶Group is selected from fluoro; chloro; trifluoromethyl; cyano group; methyl; ethyl; propyl group; sec.-propyl; the tertiary butyl; cyclopropyl; cyclobutyl; cyclopentyl; methoxyl group; oxyethyl group; methylamino-; ethylamino; propyl group amino; sec.-propyl amino; cyclopropyl amino; the 2-hydroxyethylamino; 2-methoxyl group ethylamino; dimethylamino; N-cyclopropyl-N-methylamino; ethanoyl; methylol; amino methyl; the methylamino-methyl; the ethylamino methyl; the propyl group amino methyl; the sec.-propyl amino methyl; the cyclopropyl amino methyl; dimethylamino methyl; the diethylin methyl; N-ethyl-N-methylamino methyl; N-cyclopropyl-N-methylamino methyl; tetramethyleneimine-1-base; piperidino-(1-position only); morpholino; piperazine-1-base; tetramethyleneimine-1-ylmethyl; the morpholino methyl; piperidino-(1-position only) methyl and piperazine-1-ylmethyl

And R wherein ⁶Optional methyl or the ethyl substituting group of carrying of any heterocyclic radical in the group.

The quinazoline derivant that another particular compound of the present invention is formula I or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2, first R ¹Group is 6-cyano group or 6-methoxyl group, second R ¹Group is positioned at the 7-position, is selected from methoxyl group, oxyethyl group, 2-hydroxyl-oxethyl and 2-methoxy ethoxy;

Q be 0 or q be 1, R ²Group is fluoro, chloro, methyl or methoxy;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl; With

R be 0 or r be 1 or 2, any first R of existence ⁶Group is selected from methylamino-, ethylamino, propyl group amino, sec.-propyl amino, cyclopropyl amino, 2-hydroxyethylamino, 2-methoxyl group ethylamino, dimethylamino, N-cyclopropyl-N-methylamino, tetramethyleneimine-1-base, piperidino-(1-position only), morpholino and piperazine-1-base, any second R of existence ⁶Group is selected from fluoro, chloro, methyl, ethyl, methoxyl group and oxyethyl group,

And R wherein ⁶Optional methyl or the ethyl substituting group of carrying of any heterocyclic radical group in the group.

The quinazoline derivant that a kind of particular compound of the present invention is formula I or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2, R ¹Group is positioned at 6-and 7-position, the R in the 6-position ¹Group is selected from cyano group, hydroxyl, methoxycarbonyl, ethoxy carbonyl, formamyl, methoxyl group, oxyethyl group, propoxy-, N-methylamino formyl radical, N-ethylamino formyl radical, N; N-formyl-dimethylamino, N; N-diethylamino formyl radical, tetramethyleneimine-1-base carbonyl, morpholino carbonyl, piperidino-(1-position only) carbonyl and piperazine-1-base carbonyl, the R in the 7-position ¹Group be 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-4 H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4 H-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 ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 substituting group, described substituting group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene radical dioxy base, ethylidene dioxy base 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 optional by following substituting group N-replacement: 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 ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is carried 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Choose wantonly on the group and carry one or more chloro groups or be selected from following substituting group: hydroxyl, amino, methoxyl group, methyl sulphonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino and N-sec.-propyl-N-methylamino;

Q be 0 or q be 1, R ²Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring; With

R be 0 or r be 1 or 2,1 R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group), each R ⁶Group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin

Perhaps r is 1 or 2,1 R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group), be the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or O, R ¹⁵Be methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, the 3-hydroxypropyl, methoxymethyl, the 1-methoxy ethyl, the 2-methoxy ethyl, 1-methoxyl group-1-methylethyl, the 3-methoxy-propyl, cyano methyl, the 1-cyano ethyl, the 2-cyano ethyl, 3-cyano group propyl group, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the 3-aminopropyl, the methylamino-methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, 3-methylamino-propyl group, the ethylamino methyl, 1-ethylamino ethyl, 2-ethylamino ethyl, 1-ethylamino-1-methylethyl, 3-ethylamino propyl group, the sec.-propyl amino methyl, 1-sec.-propyl amino-ethyl, dimethylamino methyl, the 1-dimethylaminoethyl, the 2-dimethylaminoethyl, the 3-dimethylamino-propyl, phenyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl group, pyrrolidyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, the pyrrolidyl methyl, 2-(pyrrolidyl) ethyl, 3-(pyrrolidyl) propyl group, the morpholinyl methyl, 2-(morpholinyl) ethyl, 3-(morpholinyl) propyl group, piperidino methyl, 2-(piperidyl) ethyl, 3-(piperidyl) propyl group, the homopiperidinyl methyl, the piperazinyl methyl, 2-(piperazinyl) ethyl, 3-(piperazinyl) propyl group or high piperazinyl methyl, prerequisite is to work as X ⁶During for O, at X ⁶And R ¹⁵Between any heteroatoms of group at least 2 carbon atoms are arranged,

And R wherein ⁶Optional the carrying of any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical is selected from following substituting group: fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino, R ⁶Optional also the carrying of any such aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical is selected from following substituting group: methylol, cyano methyl, amino methyl, methylamino-methyl and dimethylamino methyl,

And any second R that exists ⁶Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino.

The quinazoline derivant that another particular compound of the present invention is formula I or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2, first R ¹Group is positioned at the 6-position, is selected from cyano group, formamyl, methoxyl group, N-methylamino formyl radical and N, N-formyl-dimethylamino, second R ¹Group is positioned at the 7-position; be selected from methoxyl group, oxyethyl group, 2-methoxy ethoxy, 3-methoxy propoxy, 2-sulfonyloxy methyl base oxethyl, 3-methyl sulphonyl propoxy-, 2-(2-methoxy ethoxy) oxyethyl group, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, 2-[(3RS; 4SR)-3; 4-methylene radical dioxy base tetramethyleneimine-1-yl] oxyethyl group, 3-[(3RS; 4SR)-3; 4-methylene radical dioxy base tetramethyleneimine-1-yl] and propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-(1,1-dioxo tetrahydrochysene-4 H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4 H-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-(4-pyridyl oxygen base) oxyethyl group, 3-pyridyl methoxyl group and 2-cyanopyridine-4-ylmethoxy;

Q be 0 or q be 1, be positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, cyano group, methyl and methoxyl group;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen or methyl;

Ring A is oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring; With

R be 0 or r be 1 or 2,1 R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group), each R ⁶Group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin

Perhaps r is 1 or 2,1 R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group), be selected from methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, methoxymethyl, the 1-methoxy ethyl, the 2-methoxy ethyl, cyano methyl, the 1-cyano ethyl, the 2-cyano ethyl, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the methylamino-methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, the ethylamino methyl, 1-ethylamino ethyl, 2-ethylamino ethyl, the sec.-propyl amino methyl, 1-sec.-propyl amino-ethyl, 2-sec.-propyl amino-ethyl, dimethylamino methyl, the 1-dimethylaminoethyl, the 2-dimethylaminoethyl, the pyrrolidyl methyl, the morpholinyl methyl, piperidino methyl and piperazinyl methyl

And R wherein ⁶Optional the carrying of any heterocyclic radical in the group is selected from following substituting group: fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino,

And any second R that exists ⁶Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino.

The quinazoline derivant that another particular compound of the present invention is formula I or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2, first R ¹Group is positioned at the 6-position, is selected from cyano group, formamyl, methoxyl group, N-methylamino formyl radical and N, N-formyl-dimethylamino, second R ¹Group is positioned at the 7-position, is selected from methoxyl group, oxyethyl group, propoxy-, 2-hydroxyl-oxethyl, 3-hydroxyl propoxy-, 2-methoxy ethoxy, 3-methoxy propoxy, 2-sulfonyloxy methyl base oxethyl, 3-methyl sulphonyl propoxy-and 2-(2-methoxy ethoxy) oxyethyl group;

Q be 0 or q be 1, be positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, cyano group, methyl and methoxyl group;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen or methyl;

Ring A Xuan Zi oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base and thiadiazolyl group; With

R is 0,1 or 2, each R of existence ⁶Group is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylol, 2-hydroxyethyl, methoxymethyl, 2-methoxy ethyl, methylamino-methyl, ethylamino methyl, sec.-propyl amino methyl, cyclopropyl amino methyl, dimethylamino methyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin.

The quinazoline derivant that another particular compound of the present invention is formula I or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2, first R ¹Group is positioned at the 6-position, is selected from cyano group, formamyl, methoxyl group, N-methylamino formyl radical and N, N-formyl-dimethylamino, second R ¹Group is positioned at the 7-position, is selected from methoxyl group, oxyethyl group, 2-hydroxyl-oxethyl and 2-methoxy ethoxy;

Q be 0 or q be 1, be positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, cyano group, methyl and methoxyl group;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen or methyl;

Ring A is 2-oxazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isothiazolyl, 5-isothiazolyl, 1,2,4-oxadiazole-5-base and 1,3,4-oxadiazole-5-base; With

R is 1 or 2, each R of existence ⁶Group is selected from methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, cyclopropyl, methylol, 2-hydroxyethyl, methoxymethyl, 2-methoxy ethyl, methylamino-methyl, ethylamino methyl, sec.-propyl amino methyl, cyclopropyl amino methyl, dimethylamino methyl, amino, methylamino-, ethylamino, dimethylamino and diethylin.

Generally speaking, belong to effectiveness that the compound of following compound definition of the present invention has pdgf receptor family tyrosine kinase, especially PDGF beta receptor Tyrosylprotein kinase and significantly be better than effectiveness vegf receptor tyrosine kinase such as KDR.

The concrete novel cpd of this aspect of the present invention is quinazoline derivant or its pharmacy acceptable salt of formula I, wherein:

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position; be selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, formamyl, (1-6C) alkoxy carbonyl, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy, (2-6C) chain oxy-acetylene, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N; N-two-[(1-6C) alkyl] formamyl and

Q is 1, R ²Group is positioned at the 2-position (with respect to C (R ³) (R ⁴) group), be selected from halo, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N, N-two-[(1-6C) alkyl] formamyl;

X ¹, R ³, R ⁴, R ⁵, ring A, r and R ⁶Has any implication defined above separately.

Another concrete novel cpd of this aspect of the present invention is quinazoline derivant or its pharmacy acceptable salt of formula I, wherein:

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position; be selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, formamyl, methoxycarbonyl, ethoxy carbonyl, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, dimethylamino, N-methylamino formyl radical and N; the N-formyl-dimethylamino and

Q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, dimethylamino, N-methylamino formyl radical and N, N-formyl-dimethylamino;

X ¹, R ³, R ⁴, R ⁵, ring A, r and R ⁶Has any implication defined above separately.

Another concrete novel cpd of this aspect of the present invention is quinazoline derivant or its pharmacy acceptable salt of formula I, wherein:

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position, is selected from fluoro, chloro, cyano group, formamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, the N-formyl-dimethylamino and

Q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from formamyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, N-formyl-dimethylamino;

X ¹, R ³, R ⁴, R ⁵, ring A, r and R ⁶Has any implication defined above separately.

Another concrete novel cpd of this aspect of the present invention is quinazoline derivant or its pharmacy acceptable salt of formula I, wherein:

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position, is selected from fluoro, cyano group, formamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, the N-formyl-dimethylamino and

Q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from methoxyl group and oxyethyl group;

X ¹, R ³, R ⁴, R ⁵, ring A, r and R ⁶Has any implication defined above separately.

Another particular compound of this aspect of the present invention is quinazoline derivant or its pharmacy acceptable salt of formula I, wherein:

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position; be selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, formamyl, (1-6C) alkoxy carbonyl, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy, (2-6C) chain oxy-acetylene, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N; N-two-[(1-6C) alkyl] formamyl

Q is 1, R ²Group is positioned at the 2-position (with respect to C (R ³) (R ⁴) group), be selected from halo, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N, N-two-[(1-6C) alkyl] formamyl;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen;

Ring A contains 3 5-unit monocycle hetero-aromatic rings that are selected from the ring hetero atom of oxygen, nitrogen and sulphur at the most; With

R is 0,1,2 or 3, each R of existence ⁶Group can be identical or different, is selected from that halo, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C) alkanoylamino.

Another particular compound of this aspect of the present invention is quinazoline derivant or its pharmacy acceptable salt of formula I, wherein:

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position; be selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, formamyl, methoxycarbonyl, ethoxy carbonyl, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, dimethylamino, N-methylamino formyl radical and N; the N-formyl-dimethylamino

Q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, dimethylamino, N-methylamino formyl radical and N, N-formyl-dimethylamino;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen;

Ring A is furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring; With

R is 1 or 2, each R ⁶Group can be identical or different, is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin.

Another particular compound of this aspect of the present invention is quinazoline derivant or its pharmacy acceptable salt of formula I, wherein:

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position, is selected from fluoro, chloro, cyano group, formamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, the N-formyl-dimethylamino,

Q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from formamyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, N-formyl-dimethylamino;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen;

Ring A is furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring, and it carries 1 or 2 R ⁶Group, 1 R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group); With

R is 1 or 2, each R ⁶Group can be identical or different, is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin.

Another particular compound of this aspect of the present invention is quinazoline derivant or its pharmacy acceptable salt of formula I, wherein:

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position, is selected from fluoro, cyano group, formamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, the N-formyl-dimethylamino,

Q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from methoxyl group and oxyethyl group;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen;

Ring A is furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring, and it carries 1 or 2 R ⁶Group, 1 R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group); With

R is 1 or 2, each R ⁶Group can be identical or different, is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin.

A kind of concrete compound of this aspect of the present invention is quinazoline derivant or its pharmacy acceptable salt of formula I, wherein:

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position, is selected from fluoro, cyano group, formamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, the N-formyl-dimethylamino,

Q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from methoxyl group and oxyethyl group;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen or methyl;

Ring A is 2-oxazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isothiazolyl, 5-isothiazolyl, 1,2,4-oxadiazole-5-base and 1,3,4-oxadiazole-5-base; With

R is 1 or 2, each R of existence ⁶Group is selected from methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, cyclopropyl, methylol, 2-hydroxyethyl, methoxymethyl, 2-methoxy ethyl, methylamino-methyl, ethylamino methyl, sec.-propyl amino methyl, cyclopropyl amino methyl, dimethylamino methyl, amino, methylamino-, ethylamino, dimethylamino and diethylin.

Another particular compound of this aspect of the present invention is quinazoline derivant or its pharmacy acceptable salt of formula I, wherein:

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position, is selected from fluoro, cyano group, formamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, the N-formyl-dimethylamino,

Q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is a methoxyl group;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen;

Ring A is 2-oxazolyl, 3-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl and 2-thiazolyl; With

R is 1 or 2, each R of existence ⁶Group is selected from methyl, ethyl, propyl group and sec.-propyl.

Particular compound of the present invention is the quinazoline derivant of disclosed formula I among the embodiment that for example hereinafter states.

For example, particular compound of the present invention is to be selected from following formula I quinazoline derivant or its pharmacy acceptable salt:

N-(4,5-dimethylthiazole-2-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide,

N-(the 5-methyl-isoxazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide,

N-(1-ethyl-1H-pyrazoles-4-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide,

N-(1-sec.-propyl-1H-pyrazoles-4-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide,

N-(5-ethyl-1H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide and N-(1,5-dimethyl-1H-pyrazole-3-yl)-and 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide.

For example, other particular compound of the present invention is to be selected from following formula I quinazoline derivant or its pharmacy acceptable salt:

N-(1-ethyl-1H-pyrazoles-4-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-and 3-Methoxy Pyridine-2-yl] ethanamide and N-(1-sec.-propyl-1H-pyrazoles-4-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide.

For example, other particular compound of the present invention is quinazoline derivant or its pharmacy acceptable salt that is selected from following formula I:

N-(1-methyl isophthalic acid H-pyrazoles-4-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1,3-dimethyl-1H-pyrazoles-4-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1-ethyl-3-methyl isophthalic acid H-pyrazoles-4-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1-methyl isophthalic acid H-pyrazoles-4-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1-ethyl-1H-pyrazoles-4-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1-sec.-propyl-1H-pyrazoles-4-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1,3-dimethyl-1H-pyrazoles-4-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1-ethyl-3-methyl isophthalic acid H-pyrazoles-4-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1-methyl isophthalic acid H-pyrazoles-4-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1-ethyl-1H-pyrazoles-4-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1-sec.-propyl-1H-pyrazoles-4-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1,3-dimethyl-1H-pyrazoles-4-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(1-ethyl-3-methyl isophthalic acid H-pyrazoles-4-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-ethyl-1H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-sec.-propyl-1H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4-ethyl-1H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4,5-dimethyl-1H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-ethyl-4-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4-ethyl-5-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-cyclopropyl-1H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4,5-trimethylene-1H-pyrazole-3-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-ethyl-1H-pyrazole-3-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-sec.-propyl-1H-pyrazole-3-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4-ethyl-1H-pyrazole-3-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4,5-dimethyl-1H-pyrazole-3-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-ethyl-4-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4-ethyl-5-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-cyclopropyl-1H-pyrazole-3-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4,5-trimethylene-1H-pyrazole-3-yl)-2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-ethyl-1H-pyrazole-3-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-sec.-propyl-1H-pyrazole-3-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4-ethyl-1H-pyrazole-3-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4,5-dimethyl-1H-pyrazole-3-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-ethyl-4-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(4-ethyl-5-methyl isophthalic acid H-pyrazole-3-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide,

N-(5-cyclopropyl-1H-pyrazole-3-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide and

N-(4,5-trimethylene-1H-pyrazole-3-yl)-2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide.

The quinazoline derivant of formula I or its pharmacy acceptable salt can prepare with the known any method of the chemical related compounds of preparation that is applicable to.These methods are another feature provided by the invention when being used for the quinazoline derivant of preparation formula I, and the alternative by following exemplary process illustrates such method: wherein, and except as otherwise noted, otherwise X ¹, p, R ¹, q, R ², R ³, R ⁴, R ⁵, ring A, r and R ⁶Has any implication that above limits separately.Essential starting raw material can adopt the organic chemistry standard method to obtain.The preparation of describing this type of starting raw material in conjunction with the alternative and the accessory embodiment of following exemplary process.Perhaps, required starting raw material can be by obtaining with the similar method of described method, and these methods are in general technique of organic chemistry personnel's ken.

(a) make the quinazoline of formula II

Wherein L is a displaceable group, p and R ¹Has any implication that above limits, except protecting any functional group where necessary, with 2-(2-pyridyl) the ethanamide reaction of formula III

X wherein ¹, q, R ², R ³, R ⁴, R ⁵, ring A, r and R ⁶Have any implication that above limits, except protecting any functional group where necessary, remove any blocking group of existence then.

Reaction can be carried out in the presence of suitable sour or suitable alkali easily.Suitable acid is, for example mineral acid (example hydrochloric acid or Hydrogen bromide).Suitable alkali is, for example organic amine alkali is (as pyridine, 2, the 6-lutidine, trimethylpyridine, the 4-Dimethylamino pyridine, triethylamine, morpholine, N-methylmorpholine or diazabicylo [5.4.0] 11 carbon-7-alkene), perhaps for example basic metal or alkaline earth metal carbonate or oxyhydroxide (as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide), perhaps alkali metal ammonia compound (alkali metal amide) (as hexamethyldisilazane base sodium (sodium hexamethyldisilazane)) for example, perhaps alkalimetal hydride (as sodium hydride) for example.

Suitable displaceable group L is, for example halo, alkoxyl group, aryloxy or alkylsulfonyl oxygen base are as chloro, bromo, methoxyl group, phenoxy group, penta fluoro benzene oxygen base, methylsulfonyl oxygen base or toluene-4-alkylsulfonyl oxygen base.Be reflected at suitable inert solvent or thinner, for example alcohol or ester (as methyl alcohol, ethanol, Virahol or ethyl acetate), halogenated solvent (as methylene dichloride, chloroform or tetracol phenixin), ether are (as tetrahydrofuran (THF) or 1, the 4-dioxane), aromatic solvent (as toluene) or dipolar aprotic solvent are (as N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)) exist down and carry out easily.Described for example being reflected at carried out under 0-250 ℃ of scope temperature interior, preferably 0-120 ℃ of scope easily.

Usually, easily in 0-150 ℃ of scope for example, in the temperature range of preference such as 0-70 ℃ of scope, in the presence of alkali (as salt of wormwood or hexamethyldisilazane base sodium), at aprotic solvent (as N, dinethylformamide) exists down, can make the compound reaction of quinazoline and the formula III of formula II.

Can obtain the formula I quinazoline derivant of free alkali form in this way, the perhaps acid of available formula H-L (wherein L has the implication that above limits) obtains the formula I quinazoline derivant of salt form.When needs obtain free alkali with salt, this salt can be with suitable alkaline purification, for example organic amine alkali is (as pyridine, 2,6-lutidine, trimethylpyridine, 4-Dimethylamino pyridine, triethylamine, morpholine, N-methylmorpholine or diazabicylo [5.4.0] 11 carbon-7-alkene), perhaps for example basic metal or alkaline earth metal carbonate or oxyhydroxide (as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide).

Generally speaking, blocking group can be selected from describe in the document or the known any group that is suitable for protecting group to be protected of chemical technology personnel, and can adopt ordinary method to introduce blocking group.Blocking group can remove according to any method easily of describing in the document; perhaps can remove according to the known any method that makes things convenient for that is suitable for removing blocking group to be removed of chemical technology personnel; these class methods are selected, so that the described blocking group of effective elimination and simultaneously to the minimum that influences of other group of intramolecularly.

For simplicity, provide the specific examples of blocking group hereinafter, wherein " rudimentary " (as in low alkyl group) representative preferably has the group of 1-4 carbon atom.Be appreciated that these examples and non exhaustive.The specific examples of the method that removes blocking group that provides equally, hereinafter is also also non exhaustive.The use and the removal methods thereof of the blocking group of certainly, specifically not mentioning are included in the scope of the present invention.

Carboxy protective group can be the aliphatic series of formation ester or the residue of aromatic grease group alcohol, perhaps is the residue (described alcohol or silanol preferably contain 1-20 carbon atom) that forms the silanol of ester.The example of carboxy protective group comprises straight or branched (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 acyloxy methyl and oxy acid methyl neopentyl); 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 t-butyldimethylsilyl); Three (low alkyl group) silyl-low alkyl group (as the trimethyl silyl ethyl); (2-6C) alkenyl (as allyl group).The method that is particularly suitable for removing carboxy protective group comprises, for example acid-, alkali-, metal-or enzyme-catalytic scission reaction.

The example of hydroxy-protective group comprises low alkyl group (as the tertiary butyl), low-grade alkenyl (as allyl group); Low-grade alkane acidyl (as ethanoyl); Elementary alkoxy carbonyl (as tert-butoxycarbonyl); Rudimentary allyloxycarbonyl (as allyloxy carbonyl); Aryl-lower alkoxy carbonyl (as benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro benzyloxycarbonyl and 4-nitro benzyloxycarbonyl); Three (low alkyl group) silyl (as trimethyl silyl and t-butyldimethylsilyl) 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 tert-butoxycarbonyl); Rudimentary allyloxycarbonyl (as allyloxy 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 t-butyldimethylsilyl); The benzylidene of alkylidene group (as methylene radical) and benzylidene and replacement.

The proper method that removes hydroxyl and amido protecting group comprise as acid-, alkali-, metal-or the hydrolysis reaction of enzyme-catalytic group (as 2-nitro benzyloxycarbonyl), the hydrogenation of group (as benzyl) and photolysis of group (as 2-nitro benzyloxycarbonyl).

About the general 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 in OrganicSynthesis, the 2nd edition by editors such as T.Green, also is by John Wiley ﹠amp; Son publishes.

The quinazoline starting raw material of formula II can adopt for example those disclosed ordinary method acquisition in International Patent Application WO 01/94341, WO 02/00649, WO 02/16352 and WO 03/055491.For example, can make 1 of formula IV, 4-dihydroquinazoline-4-ketone

Wherein p and R ¹Have any implication (except protecting any functional group where necessary) that above limits,, remove any blocking group of existence then with halogenating agent (as the mixture of thionyl chloride, phosphoryl chloride or tetracol phenixin and triphenyl phosphine) reaction.

If desired, can in the presence of suitable alkali (as salt of wormwood), exist down, by making thus obtained 4-chloro quinazoline be converted into 4-penta fluoro benzene oxygen base quinazoline with the Pentafluorophenol reaction at suitable solvent (as N, dinethylformamide).

The 2-of formula III (2-pyridyl) ethanamide starting raw material can obtain with ordinary method.For example, can make the acetate of formula V

Or its reactive derivatives, wherein X ¹, q, R ², R ³And R ⁴Has any implication (except protecting any functional group where necessary) that above limits, with the amine reaction of formula VI

R wherein ⁵, ring A, r and R ⁶Have any implication (except protecting any functional group where necessary) that above limits, remove any blocking group of existence then.

The suitable reactive derivatives of formula V acetate is for for example, carboxylic acid halides, and for example acid is reacted formed acyl chlorides with inorganic acyl chlorides (for example thionyl chloride); Mixed acid anhydride, for example acid is reacted formed acid anhydrides with chloro-formic ester (for example isobutyl chlorocarbonate); Active ester, for example acid with phenol (for example Pentafluorophenol), with ester (for example trifluoroacetic acid pentafluorophenyl group ester) or with alcohol (for example methyl alcohol, ethanol, Virahol, butanols or N-hydroxybenzotriazole) react formed ester; Acyl azide, for example acid is reacted formed trinitride with trinitride (for example diphenyl phosphoryl azide); Acyl cyanide, for example acid is reacted formed prussiate with prussiate (for example diethyl phosphoryl prussiate); Or the product of acid and carbodiimide (for example dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide) reaction, or acid and carbamide compound (2-(7-azepine benzo triazol-1-yl)-1 for example, 1,3,3-tetramethyl-urea hexafluorophosphate (V) or 2-(benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate) product of reaction.

Be reflected at suitable inert solvent or thinner, for example carry out easily under the existence of alcohol or ester (as methyl alcohol, ethanol, Virahol or ethyl acetate), halogenated solvent (as methylene dichloride, chloroform or tetracol phenixin), ether (as tetrahydrofuran (THF) or 1, the 4-dioxane), aromatic solvent (as toluene).Being reflected at dipolar aprotic solvent (for example N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)) exists down and carries out easily.For example be reflected in the 0-120 ℃ of scope, preferably carry out easily in envrionment temperature or under near the temperature of envrionment temperature.

The amine of the acetogenin of formula V and formula VI can obtain with ordinary method, those disclosed method among the embodiment that for example lists hereinafter.

(b) in the presence of suitable alkali, can make the quinazoline of formula VII

Or its reactive derivatives that above limits, wherein p, R ¹, X ¹, q, R ², R ³And R ⁴Has above any implication (except protecting any functional group where necessary) that limits, easily with the amine coupling of formula VI

R wherein ⁵, ring A, r and R ⁶Have any implication (except protecting any functional group where necessary) that above limits, remove any blocking group of existence then.

Suitable alkali is, for example organic amine alkali is (as pyridine, 2,6-lutidine, trimethylpyridine, 4-Dimethylamino pyridine, triethylamine, morpholine, N-methylmorpholine or diazabicylo [5.4.0] 11 carbon-7-alkene), perhaps for example basic metal or alkaline earth metal carbonate or oxyhydroxide (as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide, perhaps alkali metal ammonia compound (as hexamethyldisilazane base sodium) for example, perhaps alkalimetal hydride (as sodium hydride) for example.

Be reflected at suitable inert solvent or thinner, for example carry out easily under the existence of alcohol or ester (as methyl alcohol, ethanol, Virahol or ethyl acetate), halogenated solvent (as methylene dichloride, chloroform or tetracol phenixin), ether (as tetrahydrofuran (THF) or 1, the 4-dioxane), aromatic solvent (as toluene).Be reflected under the existence of dipolar aprotic solvent (as N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)) and carry out easily.For example be reflected in the 0-120 ℃ of scope, preferably carry out easily in envrionment temperature or under near the temperature of envrionment temperature.

The amine of the quinazoline derivant of formula VII and formula VI can obtain with ordinary method, those disclosed method among the embodiment that for example lists hereinafter.

(c) for producing wherein at least one R ¹Group is those formulas I compound of following formula group:

Q ¹-X ²-

Q wherein 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, X ²Be Sauerstoffatom, in the presence of suitable dewatering agent, make the quinazoline of formula VIII

Wherein p, R ¹, X ¹, q, R ², R ³, R ⁴, R ⁵, ring A, r and R ⁶Have any implication (except protecting any functional group where necessary) that above limits separately,, remove any blocking group of existence then with suitable alcohol (wherein protecting any functional group where necessary) coupling.

Suitable dewatering agent is, for example the mixture of carbodiimide reagent (as dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide) or azo-compound (as diethylazodicarboxylate or azo-2-carboxylic acid's di tert butyl carbonate) and phosphine (as triphenyl phosphine).Be reflected under the existence of suitable inert solvent or thinner (for example halogenated solvent (as methylene dichloride, chloroform or tetracol phenixin)), in 10-150 ℃ of scope for example, preferably carry out easily in envrionment temperature or under near the temperature of envrionment temperature.

The quinazoline derivant of formula VIII can obtain with ordinary method.

(d) for producing wherein R ⁶Group is formula-X ⁶-R ¹⁵Group (X wherein ⁶Has any implication that above limits, R ¹⁵(1-6C) alkyl (as dimethylamino methyl, 2-dimethylaminoethyl or 4-methylpiperazine-1-ylmethyl) for amino-replacement) those formulas I compound, formula I compound (R wherein ⁶Group is formula-X ⁶-R ¹⁵Group, R wherein ¹⁵(1-6C) alkyl for halo-replacement) can in the presence of the suitable alkali that above limits, carry out easily with suitable amine or with the reaction of nitrogen heterocyclic ring based compound.

Be reflected under the existence of suitable inert solvents as defined above or thinner, in for example 10-180 ℃ of scope, aptly 20-120 ℃ of scope, preferably carry out easily in envrionment temperature or under near the temperature of envrionment temperature.

The compound of formula I (R wherein ⁶Group is formula-X ⁶-R ¹⁵Group, R wherein ¹⁵(1-6C) alkyl for halo-replacement) can be by the alternative (a) and (b) of above-described any exemplary process or (c) acquisition.

(e) for producing wherein R ⁶Group is formula-X ⁶-R ¹⁵Group (X wherein ⁶Has any implication that above limits, R ¹⁵(1-6C) alkyl (as methylamino-methyl, 2-methylamino-ethyl or 2-hydroxyl ethylamino methyl) for amino-replacement) those formulas I compound makes formula I compound (R wherein ⁶Group is formula-X ⁶-R ¹⁵Group, R wherein ¹⁵Be formyl radical or (2-6C) alkyloyl) reductive amination.

The appropriate reductant that is used for the reductive amination reaction is for example hydride reducer, for example alkali metal aluminum hydride such as lithium aluminum hydride, or preferred as alkali hydroborate such as sodium borohydride, sodium cyanoborohydride, triethyl-boron sodium hydride, trimethoxy sodium borohydride and sodium triacetoxy borohydride.Be reflected in suitable inert solvent or the thinner and carry out easily, for example tetrahydrofuran (THF) and ether are used to render a service stronger reductive agent (for example lithium aluminum hydride), and for example methylene dichloride or protonic solvent (as methyl alcohol and ethanol) are used to render a service more weak reductive agent (as sodium triacetoxy borohydride and sodium cyanoborohydride).For example be reflected in the 10-80 ℃ of scope, carry out in envrionment temperature or under easily near the temperature of envrionment temperature.

The compound of formula I (R wherein ⁶Group is formula-X ⁶-R ¹⁵Group, R wherein ¹⁵Be formyl radical or (2-6C) alkyloyl) the alternative (a) and (b) of above-mentioned any exemplary process that can be by conventional reorganization or (c) obtain.

(f) for producing wherein R ⁵Be those formulas I compound of (1-8C) alkyl, in the presence of suitable as defined above alkali, make formula I compound (R wherein with the alkylating agent that suits easily ⁵Be hydrogen) alkylation.

Be reflected under the existence of suitable inert solvents as defined above or thinner, for example-10 ℃ to 180 ℃ of scopes, easily 0-100 ℃ of scope, carry out easily in envrionment temperature or under more easily near the temperature of envrionment temperature.Suitable alkylating agent is connected to the compound of suitable leavings group (for example chloro, bromo, iodo, methoxyl group, phenoxy group, penta fluoro benzene oxygen base, methoxyl group alkylsulfonyl oxygen base, methylsulfonyl oxygen base or toluene-4-alkylsulfonyl oxygen base) for (1-8C) alkyl for example wherein.

(g) for producing wherein R ¹Be those formulas I compound of carboxyl, in the presence of suitable as defined above alkali, make things convenient for ground cleave to separate formula I compound (R wherein ¹Be (1-6C) alkoxy carbonyl).

The method that is suitable for cracking (1-6C) alkoxy carbonyl comprise for example acid-, alkali, metal-or enzymatic hydrolysis.This is reflected under the existence of suitable inert solvents as defined above or thinner,, carries out easily in envrionment temperature or under near the temperature of envrionment temperature easily ℃ to 100 ℃ of scopes for example-10.For example, the cracking of base catalysis can use alkali metal hydroxide (as lithium hydroxide) to realize in alcohol (as methyl alcohol) in room temperature.

When the pharmacy acceptable salt that needs formula I quinazoline derivant (for example acid salt), it can obtain by for example making described quinazoline derivant and suitable acid-respons.

When needing the pharmaceutically acceptable prodrug forms of formula I quinazoline derivant, its available ordinary method obtains.For example, the ester of cleavable can followingly obtain in the body of formula I quinazoline derivant: by for example carboxylic formula I compound and pharmaceutically acceptable alcohol reaction, perhaps the formula I compound of hydroxyl and pharmaceutically acceptable carboxylic acid reaction.For example, the acid amides of cleavable can followingly obtain in the body of formula I quinazoline derivant: by for example carboxylic formula I compound and pharmaceutically acceptable amine reaction, perhaps contain amino formula I compound and pharmaceutically acceptable carboxylic acid reaction.

The intermediate of many this paper definition all is new, and these intermediates provide as another feature of the present invention.For example, the compound of many formula IIIs, VI and VII is a novel cpd.

Can use above-described any method to obtain at the compound of above just having described.Essential starting raw material can obtain by standard organic chemistry method.For example, can in above-described alternative (a), use 4-chloro-quinazoline or 4-chloro-6-fluquinconazole quinoline (International Patent Application WO 96/16960; In embodiment 3).

Biology is measured

Below measure and can be used for determining that The compounds of this invention is as PDGFR α, PDGFR β and KDR tyrosine kinase inhibitor, as the inhibitor that is expressed in the external phosphorylation of PDGFR on the MG63 osteosarcoma cell, as the inhibitor that is expressed in the external phosphorylation of KDR on the Human umbilical vein endothelial cells (HUVEC), inhibitor as MG63 osteosarcoma cell in-vitro multiplication, the effect of the inhibitor of in heteroplastic nude mouse body, growing as the inhibitor of HUVEC in-vitro multiplication and as people's tumor tissues (as CaLu-6 and Colo205).

(a) Vitro enzyme is measured

Suppress Tyrosylprotein kinase PDGFR α, PDGFR β and KDR ability with conventional ELISA assay method assessment test compounds to the phosphorylation of the peptide substrate that contains tyrosine.

The DNA of coding PDGFR α, PDGFR β or KDR acceptor cytosolic domain can be synthetic by full gene ( International Biotechnology Lab., 1987, 5(3), 19-25) or the clone obtain.Dna fragmentation is expressed on the appropriate expression system, to obtain to have the polypeptide of tyrosine kinase activity.For example, by recombinant protein PDGFR α, PDGFR β that expressed in insect cells obtains and KDR acceptor cytosolic domain can be used for showing have in the activity of Tyrosylprotein kinase.For vegf receptor KDR (Genbank accession number L04947), the dna fragmentation of the most of cytosolic domain of coding (from methionine(Met) 806 beginning and comprise terminator codon) can be cloned in that [for example pAcYM1 is (referring to The Baculovirus ExpressionSystem:A Laboratory Guide in the baculovirus replacement vector, L.A.King and R.D.Possee, Chapman and Hall, 1992) or pAc360 or pBlueBacHis (deriving from Invitrogen Corporation)].This recombinant precursor and viral DNA (as Pharmingen BaculoGold) cotransfection can be gone into insect cell [as the greedy noctuid 9 (Sf9) of greedy noctuid 21 (Sf21) in meadow or meadow], with the baculovirus of preparation reorganization.The detailed method of recombinant DNA molecules combination and preparation and use recombinant baculovirus can be consulted standard textbook, Sambrook etc. for example, 1989, Molecular cloning-ALaboratory Manual, the 2nd edition, Cold Spring Harbour Laboratory Press and O ' Reilly etc., 1992, Baculovirus Expression Vectors-A Laboratory Manual, W.H.Freeman and Co, New York.

In order to express, the Sf9 cell with no spot KDR recombinant virus infection, is collected after 48 hours.The cell of collecting (is contained the 10mM sodium phosphate with freezing phosphate buffered salt solution (PBS), the pH74 damping fluid, 138mM sodium-chlor and 2.7mM Repone K) washing, per 1,000 ten thousand cells (contain 20mM HepespH7.5 damping fluid with its resuspending in freezing cell dilution agent with the 1ml cell diluent, 150mM sodium-chlor, 10% (volume/volume) glycerine, 1% (volume/volume) triton X100,1.5mM magnesium chloride, 1mM ethylene glycol-two (the amino ether of β) N, N, N ', N '-tetraacethyl (EGTA) and 1mM PMSF (phenylmethylsulfonyl fluoride)) in [add immediately use before in methyl alcohol freshly prepared 100mM PMSF solution].4 ℃ with 13,000rpm was with centrifugal 10 minutes of suspension.Take out supernatant liquor (stocking enzyme solution) and store with aliquots containig at-70 ℃.

[100 μ l, 2 μ g/ml gather-amino acid poly-(Glu, Ala, Tyr) 6:3:1 (Sigma-Aldrich Company Ltd., Poole, Dorset with substrate solution; Production number P3899) phosphate buffered saline (PBS) (PBS) solution] a large amount of Nunc96-of adding hole MaxiSorp immunity dull and stereotyped (Nunc, Roskilde, Denmark; Production number 439454) in each hole, seal plate was also stored 16 hours at 4 ℃.Remove excessive substrate solution, use PBS (to contain 0.05% (volume/volume) polysorbas20 (PBST successively; 300 μ l/ holes)) wash each hole, with Hepes pH7.4 damping fluid (50mM, 300 μ l/ holes) washing 2 times, absorption dehydration then.

Every kind of test compounds is dissolved among the DMSO, and the distilled water solution dilution with 10% DMSO obtains a series of diluents (40 μ M-0.0012 μ M).Every kind of test compounds diluent of aliquots containig (25 μ l) is transferred in each hole in the washed assay plate." maximum " control wells contains the DMSO rather than the compound of dilution.The Manganous chloride tetrahydrate aqueous solution (40mM) (containing adenosine-5 '-triphosphoric acid (ATP)) of aliquots containig (25 μ l) is added in whole test holes, contain except " blank " control wells of the Manganous chloride tetrahydrate that has or not ATP.For PDGFR α enzyme, used ATP concentration is 14 μ M; For PDGFR β enzyme, used ATP concentration is 2.8 μ M, and for the KDR enzyme, used ATP concentration is 8 μ M.

The active people PDGFR α and the PDGFR β recombinase that have been expressed in the Sf9 insect cell derive from Upstate Biotechnology Inc., Milton Keynes, UK (product 14-467 is used for PDGFR α, and product 14-463 is used for PDGFR β).Active people KDR recombinase is expressed in the Sf9 insect cell.

Before use, use every kind of kinases of enzyme thinner (containing 100mM Hepes pH7.4 damping fluid, 0.1mM sodium orthovanadate, 0.1% triton x-100 and 0.2mM dithiothreitol (DTT)) dilution immediately.The freshly prepared enzyme of aliquots containig (50 μ l) is added in each hole, at ambient temperature flat board was stirred 20 minutes.Remove the solution in each hole, wash each hole 2 times with PBST.Mouse IgG is resisted-phosphotyrosine antibody (Upstate Biotechnology Inc.; Product 05-321; 100 μ l) with the PBST that contains 0.5% weight/volume bovine serum albumin (BSA) with the 1:3667 dilution proportion, aliquots containig is added in each hole.At ambient temperature flat board was stirred 1.5 hours.Remove supernatant liquor, wash each hole 2 times with PBST.Goat-anti-mouse Ig antibody (Amersham Pharmacia Biotech, Chalfont St Giles, Buckinghamshire, the UK that will put together horseradish peroxidase (HRP); Production number NXA 931; 100 μ l) with the PBST that contains 0.5% weight/volume BSA with the 1:550 dilution proportion and add in each hole.At ambient temperature flat board was stirred 1.5 hours.Remove supernatant liquor, wash each hole 2 times with PBST.Make Sodium peroxoborate (PCSB) capsule (Sigma-Aldrich Company Ltd., Poole, Dorset, UK; Production number P4922) is dissolved in the distilled water (100ml), obtains containing the phosphate-citrate salts pH5 damping fluid (50mM) of 0.03% Sodium peroxoborate.Make this damping fluid and the 50mg 2 of aliquots containig (50ml), 2 '-azino two (3-ethyl benzo thiazole phenanthroline-6-sulfonic acid) (ABTS; Roche Diagnostics Ltd., Lewes, East Sussex, UK; Production number 1,204 521) tablet mixes.The gained solution of aliquots containig (100 μ l) is added in each hole.At ambient temperature with dull and stereotyped stir about 20 minutes, until with read the plate spectrophotometer 405nm place measurement " maximum " control wells optical density(OD) be about 1.0." blank " (no ATP) and " maximum " (no compound) control value are used for determining the dilution range of test compounds, obtain 50% inhibiting value of enzymic activity.

(b) External phosphoric acid-Tyr751PDGFR β ELISA measures

This mensuration determines that with conventional ELISA method test compounds suppresses the ability of tyrosine phosphorylation among the PDGFR β.

Routinely at 7.5% CO ₂With 37 ℃ under make MG63 osteosarcoma cell line [American type culture collection (ATCC) CCL 1427] be kept at Dulbecco ' s improvement Eagle ' s growth medium (DMEM; Sigma-Aldrich; Production number D6546) in, this substratum contains 10% foetal calf serum (FCS; Sigma-Aldrich; Production number F7524) and 2mM L-glutaminate (Invitrogen Ltd., Paisley, UK; Production number 25030-024).

In order to measure, with cell trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA) mixture (Invitrogen Ltd.; Production number 15400-054) separates from culturing bottle, be resuspended in the test media (Sigma-Aldrich that contains no phenol red DMEM; Production number D5921) in, this substratum contains (stripped) foetal calf serum (FCS) (Sigma-Aldrich of 1% carbon absorption; Production number F7524, by under continuously stirring with the activated carbon of dextran-Bao quilt 55 ℃ of incubations 30 minutes, follow and centrifugally remove carbon elimination and filtration sterilization is adsorbed) and 2mM L-glutaminate (Invitrogen Ltd., production number 25030-024), obtain 6 * 10 ⁴Individual cell/ml.Aliquots containig (100 μ l) is seeded in transparent 96 hole tissue culturing plates (Corning Life Sciences, Koolhovenlaan, The Netherlands; Production number 3595) 2-12 row (except that the 1st row) and B-G capable (except that A and H are capable) obtain the density of about 6000 cells/well.Substratum is placed on outer hole makes the fringing effect minimum with aliquots containig (100 μ l).Make cell at 37 ℃ and 7.5%CO ₂Following overnight incubation adheres to cell and hole.

Test compounds is prepared into 10mM DMSO stock solution, uses the DMSO serial dilution as required, obtain a series of concentration.The aliquots containig (3 μ l) of every kind of compound concentration is added test media (300 μ l), produce second dilution range.The every kind of compound concentration that obtains of aliquots containig (16 μ l) is added in the cell in each hole." maximum " control cells is only accepted the DMSO diluent and is added test media." minimum " control cells is accepted reference PDGFR inhibitor (16 μ l).Make cell at 37 ℃ and 7.5% CO ₂Cultivated 90 minutes.

Use PDGF in accordance with the following methods _BBStimulate the gained cell.Make cryodesiccated PDGF _BBPowder (Sigma-Aldrich; Production number P4306) mixes with sterilized water, obtain the PDGF of 10 μ g/ml _BBStock solution.This stock solution is obtained 182ng/ml PDGF with the test media dilution _BBSolution.Cell and " maximum " control cells of its aliquots containig (44 μ l) being added compound treatment." minimum " control cells is only accepted nutrient solution.Make cell at 37 ℃ and 7.5% CO ₂Cultivated 5 minutes.Solution in the cleaning hole, add 120 μ l/ hole RIPA damping fluids and make cytolysis, described damping fluid contains 60mM three (methylol) aminomethane hydrochloride (Tris-HCl), 150mM sodium-chlor, 1mM EDTA, 1% (volume/volume) Igepal CA-630,0.25% sodium deoxycholate, 1% (volume/volume) inhibitors of phosphatases mixture, 1 P2850,1% inhibitors of phosphatases mixture, 2 P5726 and 0.5% (volume/volume) proteinase inhibitor mixture P8340 (all chemical reagent and inhibitor mixture all derive from Sigma-Aldrich Company Ltd.).Make gained tissue culturing plate vibrate 5 minutes at ambient temperature to guarantee whole dissolvings, freezing then standby at-20 ℃.

With MaxiSorp ELISA flat board (Nunc; Production number 439454) with PDGF β antibody (R﹠amp; D Systems, Abingdon, Oxfordshire, UK; Production number AF385 contains useful 100 μ l PBS and is prepared as the lyophilize antibody that final concentration is 100 μ l/ml) the bag quilt.Make antibody be diluted in carbonate-bicarbonate buffer (Sigma-Aldrich with 1:40; Production number C3041; One capsules is dissolved in the 100ml distilled water) in, 2.5 μ g/ml solution obtained.(50 μ l) adds in each hole with aliquots containig, and be dull and stereotyped 4 ℃ of placements 16 hours.5 times (at every turn soaking 1 minute) washed with 300 μ l PBST/ holes in each hole.At ambient temperature the 3%BSA/PBST of each hole with 50 μ l handled 1 hour, then with 300 μ l PBST/ holes washing 2 times.

Allow the tissue culturing plate that freezing cellular lysate is housed be warmed to 0 ℃.The MG63 cellular lysate of aliquots containig (50 μ l) is added in the elisa plate.Make every kind of sample on independent flat board by carrying out in duplicate.At ambient temperature elisa plate was stirred 2 hours.Wash each hole 2 times with 300 μ l PBST/ holes.With 1% BSA/PBST preparation phosphoric acid PDGFR β antibody (Cell Signaling Technology, Beverley, MA, USA; Production number 3161) 1:1000 diluent.Aliquots containig (50 μ l) antibody-solutions is added in each hole.At ambient temperature flat board was stirred 1 hour.With dull and stereotyped 2 times of 300 μ l PBST/ holes washing.With 1% BSA/PBST preparation anti--second kind of antibody (Cell Signaling Technology that the rabbit horseradish peroxidase is puted together; Production number 7074) 1:2000 diluent.Aliquots containig (50 μ l) gained diluent is added in each hole, at ambient temperature flat board was stirred 1 hour.With dull and stereotyped 5 times of 300 μ l PBST/ holes washing.Prepare chemical luminous substrate (Pierce Biotechnology Inc., Rockford IL, USA according to manufacturer specification; Production number 34080).The chemical luminous substrate solution of aliquots containig (50 μ l) is added in each hole, flat board was stirred 2 minutes, (Berkshire reads on UK) luminous for TecanUK Ltd., Reading to read the plate device at SpectraFluor Plus.Following finishing: determine the ratio of ' phosphoric acid antibody ' plate reading of every kind of specimen, draw, determine the IC of every kind of test compounds with these ratios to ' total antibody ' plate reading to analysis to every kind of compound ₅₀Value.

(c) External phosphoric acid-KDR ELISA measures

This mensuration uses conventional ELISA method to determine that test compounds suppresses the ability of the tyrosine phosphorylation among the KDR (VEGFR2).

Human umbilical vein endothelial cells (HUVEC; PromoCell) containing MCDB 131 (Gibco production number 10372-019 routinely; In 500ml) ' growth medium ' in 37 ℃ and 7.5%CO ₂Cultivate, described substratum contains L-glutaminate (Sigma production number G3126; 0.848 μ g), 1% penicillin streptomycin (Gibco production number 15140-122) and foetal calf serum (PAALaboratories production number A15-043; 50ml).

In order to measure, use trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA) mixture (InvitrogenLtd.; Production number 15400-054) cell is separated with culturing bottle, and be resuspended in contain MCDB131 ' test media ' (500ml) in, this substratum contains L-glutaminate (0.848g), 1% penicillin streptomycin and foetal calf serum (10ml).(the Corning Life Sciences of 24 hole tissue culturing plates is gone in aliquots containig (1ml) inoculation; Production number 3527) in each hole, obtains the density of about 3.5 * 104 cells/well.With cell in 37 ℃ with 7.5% CO ₂Incubated overnight is to allow to adhere to hole surface.Inclining second day morning the mensuration substratum, ' serum free medium ' that contain MCDB 131 that add aliquots containig (0.5ml) to each hole (500ml), this substratum contains L-glutaminate (0.848g) and 1% penicillin streptomycin.With flat board in 37 ℃ of incubations 2.5 hours.

Test compounds is prepared into 10mM DMSO stock solution, uses the DMSO serial dilution as required.The aliquots containig (3 μ l) of every kind of test compounds concentration is diluted with ' serum free medium ' (300 μ l).The every kind of compound concentration that obtains of aliquots containig (50 μ l) is added in the cell in each hole." maximum " control cells is only accepted the DMSO diluent.And reference KDR inhibitor is accepted in " minimum " contrast, obtains 1 μ M final concentration.Make cell at 37 ℃ and 7.5% CO ₂Cultivated 90 minutes.

Stimulate the gained cell with VEGF in accordance with the following methods.Make cryodesiccated VEGF powder (Sigma-Aldrich; Production number V7259) mixes with the PBS (0.1% BSA/PBS) of the BSA that contains 0.1% Sterile Filtration, obtain the VEGF stock solution of 10 μ g/ml.This stock solution dilution is obtained 1000ng/ml VEGF solution for ' serum free medium '.Institute is porose with its aliquots containig (50 μ l) adding.Make cell at 37 ℃ and 7.5% CO ₂Cultivated 5 minutes.Solution in the cleaning hole, add 100 μ l/ hole RIPA damping fluids and make cytolysis, described damping fluid contains 60mMTris-HCl, 150mM sodium-chlor, 1mM EDTA, 1% (volume/volume) IgepalCA-630,0.25% sodium deoxycholate, 1% (volume/volume) inhibitors of phosphatases mixture 1P2850,1% inhibitors of phosphatases mixture, 2 P5726 and 0.5% (volume/volume) proteinase inhibitor mixture P8340.Made gained tissue culturing plate vibration at ambient temperature 5 minutes, to guarantee whole dissolvings, then-20 ℃ freezing on dry ice, when needs.

With MaxiSorp ELISA flat board (Nunc; Production number 439454) with phosphoric acid-VEGFR2 capture antibody (R﹠amp; D Systems, Abingdon, Oxfordshire, UK; People phosphoric acid-VEGFR2ELISA, production number DYC1766) the bag quilt.Make antibody with 8 μ g/ml concentration dilutions in PBS, (100 μ l) adds in each hole with aliquots containig, dull and stereotyped stores 16 hours in envrionment temperature.3 times (at every turn soaking 1 minute) washed with 300 μ l PBST/ holes in each hole.At ambient temperature with PBS solution (1% BSA/PBS of each hole with the BSA that contains 1% Sterile Filtration; 200 μ l) handled 1 hour, then with 300 μ l PBST/ holes washing 3 times.

Make the tissue culturing plate that freezing cellular lysate is housed be warmed to 0 ℃.The HUVEC cellular lysate that adds aliquots containig (100 μ l) stirs elisa plate 3 hours at ambient temperature.Wash each hole 3 times with 300 μ l PBST/ holes.Tris buffered saline solution (containing 0.05% (volume/volume) polysorbas20 (TBST)) with 0.1% BSA dilutes anti-phosphoric acid-tyrosine-HRP detection antibody (R﹠amp; D Systems; People's phosphoric acid-VEGFR2 ELISA, production number DYC1766) diluent is to produce the working concentration of 600ng/ml.The gained diluent of aliquots containig (100 μ l) is added in each hole, at ambient temperature flat board was stirred 2 hours.With dull and stereotyped 4 times of 300 μ lPBST/ holes washing.Prepare chemical luminous substrate (PierceBiotechnology Inc., Rockford IL, USA according to manufacturer specification; Production number 34080).The chemical luminous substrate solution of aliquots containig (50 μ l) is added in each hole, flat board was stirred 2 minutes, read to read on the plate device (Tecan UK Ltd.) luminous at SpectraFluor Plus.Analyze the data that obtain, to determine the IC of every kind of test compounds ₅₀Value.

(d) External MG63 osteosarcoma proliferation assay

This is measured and determines that test compounds suppresses the ability of MG63 osteosarcoma cell (ATCC CCL 1427) propagation.

With the MG63 cell with 1.5 * 10 ³Individual cells/well is seeded to assay plate (the Corning Life Sciences that 96-hole hyaline tissue substratum is handled; Production number 3595) in, in this plate, added 60 μ l/ hole test media (containing no phenol red DMEM, the FCS and the 2mM glutamine of 1% carbon absorption), made cell at 37 ℃ and 7.5% CO ₂Overnight incubation.

Test compounds is dissolved in obtains the 10mM stock solution among the DMSO.With the stock solution of above-described test media dilution aliquots containig, in the hole that every kind of diluent adding of 20 μ l aliquots containigs is suitable.Carry out serial dilution to obtain a series of test concentrations.All comprise the control wells that only adds DMSO solution on each flat board.Each flat board duplicates in duplicate.Make cryodesiccated PDGF _BBPowder mixes with 4mM hydrochloric acid soln (BSA that contains 0.1% filtration sterilization), obtains 10 μ g/ml PDGF _BBStock solution.This stock solution dilution for test media, is obtained 250ng/ml PDGF _BBSolution.Its aliquots containig (20 μ l) is added one group of control wells, obtain " maximum " contrast.Its aliquots containig (20 μ l) is added the flat board of one group of compound-processing of duplicating, and be called " PDGF _BBStimulate " flat board.The flat board of second group of compound-processing of duplicating is only accepted substratum, and these plates are called " base " plate.Substratum is only accepted in " minimum " contrast.Make dull and stereotyped at 37 ℃ and 7.5% CO ₂Cultivated 72 hours.

Make BrdU labelled reagent (Roche Diagnostics Ltd., Lewes, East Sussex, UK; Production number 647 229) with the dilution proportion of 1:100 in the DMEM substratum of the FCS that contains the absorption of 1% carbon, (10 μ l) adds each hole with aliquots containig, obtaining final concentration is 10 μ M.Dull and stereotyped 37 ℃ of cultivations 2 hours.Pour out substratum.With denaturing soln (FixDenat solution, Roche Diagnostics Ltd.; Production number 647 229; 200 μ l) add in each hole, at ambient temperature flat board was stirred 30 minutes.Pour out supernatant liquor, wash each hole (200 μ l/ hole) with PBS.To resist-BrdU-superoxide enzyme solution (Roche Diagnostics Ltd.; Production number 647229) with the dilution proportion of 1:100 in antibody dilution agent (Roche Diagnostics Ltd., production number 647229), 100 μ l gained solution are added in each hole.At ambient temperature flat board was stirred 90 minutes.Each hole is washed (* 3 with PBS; 300 μ l), to guarantee to remove unconjugated antibody conjugates.Make dull and stereotyped absorption dehydration, with tetramethyl benzidine substrate solution (Roche DiagnosticsLtd.; Production number 647229; 100 μ l) add in each hole.On oscillator plate, stir flat board gently, develop the color simultaneously 10-20 minute time period.With aliquots containig sulfuric acid (1M; 50 μ l) add in the suitable hole,, measure the absorbancy in each hole at 450nm to stop any further reaction.Determine the inhibition degree of every kind of test compounds on cell proliferation in concentration range, and derive antiproliferative IC ₅₀Value.

(e) External HUVEC proliferation assay

This measures the ability of the propagation of the factors stimulated growth of determining test compounds inhibition Human umbilical vein endothelial cells (HUVEC).

HUVEC is separated in MCDB 131 (Gibco BRL) and 7.5% (volume/volume) foetal calf serum (FCS), in the mixture of MCDB 131,2% (volume/volume) FCS, 3 μ g/ml heparin and 1 μ g/ml hydrocortisone, the concentration in 96 orifice plates is 1000 cells/well in tiling (2-8 generation).After minimum 4 hours, add suitable somatomedin (for example VEGF) and test compounds to cell.With culture at 37 ℃ and 7.5% CO ₂Under cultivated 4 days.At the 4th day,, and cultivated 4 hours with 1 μ Ci/ hole tritiated thymidine (Amersham product TRA 61) pulse cell culture medium.With 96-hole flat panel collector (Tomtek) collecting cell, measure the tritium that adds with β plate count device.Add intracellular radioactivity with count per minute (cpm) expression, be used for determining the restraining effect of every kind of test compounds the cell proliferation of factors stimulated growth.

(f) Solid tumor disease model in the body

This test determines that compound suppresses the ability of solid tumor growth.

By with 1 * 10 ⁶The culture medium solution of 50% (volume/volume) Matrigel/ serum-free of individual CaLu-6 cell/mouse subcutaneous injection 100 μ l is set up the CaLu-6 tumor xenogeneic graft in the flank portion of female athymia Swiss nu/nu mouse.After the Transplanted cells 10 days, mouse is distributed by every group of 8-10 animal, every treated animal has mean tumour volume in the comparable group.Use the vernier caliper measurement tumour, use the following formula volume calculated

(lxw)x√(lxw)x(π/6)

Wherein l is the longest diameter, and w is the diameter perpendicular to longest diameter.The orally give test compounds is at least 21 days once a day, and control animal is only accepted diluted chemical compound liquid.Measure tumour weekly 2 times.Use Student ' s T check and/or Mann-Whitney rank test, the mean tumour volume by compare group and treatment group calculates growth inhibiting level.

Although the pharmacological properties of formula I compound changes with structural changes as expected, but usually, at one or more above-mentioned test (a) and (b), (c), (d), (e) with (f), in following concentration or dosage, the activity that susceptible of proof formula I compound has:

Test (a): in 0.1nM-5 μ M scope for example to the IC of PDGFR α Tyrosylprotein kinase ₅₀

In 0.1nM-5 μ M scope for example to the IC of PDGFR β Tyrosylprotein kinase ₅₀

Test (b): in 0.1nM-1 μ M scope for example to the phosphoric acid-Tyr751 among the PDGFR β

The IC that forms ₅₀

Test (c): in 1nM-5 μ M scope for example, the phosphoric acid among the KDR-tyrosine is formed

IC ₅₀；

Highly selective suppresses to live and have more to the pdgf receptor Family Tyrosine Kinases

The property those compounds right to the scope at 100nM for example greater than 5 μ M

The IC that phosphoric acid among the KDR-tyrosine forms ₅₀

Test (d): in 1nM-5 μ M scope for example to the IC of MG63 osteosarcoma propagation ₅₀

Test (e): in 1nM-5 μ M scope for example to the IC of HUVEC propagation ₅₀

Test (f): the heterograft activity in 1-200mg/kg/ days scopes for example

For example, the activity that disclosed quinazoline compound has in test (b) among the embodiment 1 is with respect to the IC of the phosphoric acid among the PDGFR β-Tyr751 formation ₅₀Be about 5nM; The IC that the activity that has in test (c) forms with respect to the phosphoric acid among the KDR-tyrosine ₅₀Be about 2nM.

For example, the IC that forms with respect to the phosphoric acid among the PDGFR β-Tyr751 of the activity that has in (b) in test as the 5th the disclosed quinazoline compound of in the Table I of embodiment 2, listing of compound ₅₀Be about 25nM; The IC that the activity that has in test (c) forms with respect to the phosphoric acid among the KDR-tyrosine ₅₀Be about 0.3 μ M.

For example, the IC that forms with respect to the phosphoric acid among the PDGFR β-Tyr751 of the activity that has in (b) in test as the 1st the disclosed quinazoline compound of in the Table II of embodiment 4, listing of compound ₅₀Be about 25nM.

For example, the activity that disclosed quinazoline compound has in test (b) in embodiment 7 is with respect to the IC of the phosphoric acid among the PDGFR β-Tyr751 formation ₅₀Be about 10nM; The IC that the activity that has in test (c) forms with respect to the phosphoric acid among the KDR-tyrosine ₅₀For greater than 3 μ M.

For example, the activity that disclosed quinazoline compound has in test (b) in embodiment 8 is with respect to the IC of the phosphoric acid among the PDGFR β-Tyr751 formation ₅₀Be about 5nM; The IC that the activity that has in test (c) forms with respect to the phosphoric acid among the KDR-tyrosine ₅₀For greater than 5 μ M.

When the formula I compound that above limits or its pharmacy acceptable salt during, expect no bad toxicological effect with the dosage range administration that hereinafter limits.

According to another aspect of the invention, provide a kind of medicinal compositions, it comprises above formula I quinazoline derivant or its pharmacy acceptable salt that limits, and the pharmaceutically acceptable diluent or carrier of blended with it.

Composition of the present invention can adopt and be fit to oral form (tablet for example, lozenge, hard or soft capsule, water or oil suspension, emulsion, dispersible pulvis or granula, syrup or elixir), be fit to the local form of using (creme for example, ointment, gelifying agent or water or oily solution or suspension), the form (for example pulvis of fine dispersion or liquid aerosol) that is fit to inhalation, the form (for example pulvis of fine dispersion) or the form of suitable parenteral admin that are fit to be blown into administration (for example are used for intravenously, subcutaneous, the sterilized water of intraperitoneal or intramuscular administration or oily solution or be used for the suppository of rectal administration).

Composition of the present invention can obtain through conventional method with conventional pharmaceutical excipient well known in the art.Therefore, the composition that is intended to orally use can comprise, for example one or more tinting materials, sweeting agent, correctives and/or sanitas.

The amount that forms the activeconstituents of single formulation with one or more excipient composition will change on demand, depend on treatment main body and concrete route of administration.For example, the preparation that is intended to the orally give people will contain usually, and for example with 1mg-1g (being more suitable for being 1-250mg, for example 1-100mg) activeconstituents suitable and the convenient mixed with excipients of measuring, described vehicle can account for about 5% to about 98% of total composition weight.

The big young pathbreaker of dosage of formula I compound who is used for the treatment of or prevents purpose is usually according to character and severity, animal or patient's age and the sex and the route of administration of disease, according to the Physical alterations of well-known medical science principle.

Formula I compound is when being used for the treatment of or prevent purpose, and it is to accept the per daily dose administration in the 1mg/kg-100mg/kg weight range for example, graded administration if desired usually.In general, when adopting the parenteral approach, will give than low dosage.Therefore, for example during intravenous administration, with the dosage of using usually in the 1mg/kg-25mg/kg weight range for example.Equally, will use dosage in the 1mg/kg-25mg/kg weight range for example during inhalation.Yet the tablet form oral administration is particularly adopted in the preferred oral administration.More effective compound is usually to accept the day oral dosage administration in the 1mg/kg-25mg/kg weight range for example.Compounds effective is usually to accept the day oral dosage administration in the 1mg/kg-15mg/kg weight range for example.Usually, unit dosage will comprise about 10mg-0.5g The compounds of this invention.

As mentioned above, the activity of antagonism pdgf receptor kinase, particularly suppress PDGF α and/or PDGF beta receptor Tyrosylprotein kinase, expection helps treating a large amount of cell proliferation disorders (as cancer), is particularly conducive to suppress tumor growth and transfer and suppress the leukemia progress.

We have now found that new quinazoline derivant described herein has the effective active of inhibition of cell proliferation disease.It is generally acknowledged that described compound provides effective treatment of on cell proliferation disease by the restraining effect to the pdgf receptor Tyrosylprotein kinase, for example provides antitumor action.In addition, as indicated above, PDGF relates to the angiogenesis that forms neovascularity, and described vasculogenesis is very crucial for the tumour continued growth.Therefore think, expect that compound of the present invention helps treating the relevant disease (as cancer) of vascular permeability numerous and vasculogenesis and/or increase, be particularly advantageous in the development that suppresses tumour.

According to another aspect of the invention, provide the formula I quinazoline derivant or its pharmacy acceptable salt that above limit, as being used for for example people's medicine of warm-blooded animal.

According to another aspect of the invention, provide the formula I quinazoline derivant or its pharmacy acceptable salt that above limit, be used for the treatment of (or prevention) cell proliferation disorders or treatment (or prevention) and vasculogenesis and/or vascular permeability diseases associated.

According to another aspect of the invention, provide above purposes in the formula I quinazoline derivant or its pharmacy acceptable salt that limit be used for the treatment of (or prevention) cell proliferation disorders or treatment (or prevention) and vasculogenesis and/or vascular permeability diseases associated in preparation the medicine.

According to this aspect of the invention, also be provided at the method for treatment in the warm-blooded animal that needs this treatment (or prevention) (or prevention) cell proliferation disorders, or the method for treatment in the warm-blooded animal of this treatment of needs (or prevention) (or prevention) and vasculogenesis and/or vascular permeability diseases associated, described method comprises the formula I quinazoline derivant or its pharmacy acceptable salt that above limit that gives described animal effective dose.

Suitable cell proliferation disorders comprises the knurl disease, lung cancer (nonsmall-cell lung cancer for example, small cell lung cancer and bronchovesicular cancer), gastrointestinal cancer is (as colon, rectum and gastric tumor), prostate cancer, mammary cancer, kidney, liver cancer, the cancer of the brain (as glioblastoma), cholangiocarcinoma, osteocarcinoma, bladder cancer, head and neck cancer, the esophageal carcinoma, ovarian cancer, carcinoma of the pancreas, carcinoma of testis, thyroid carcinoma, cervical cancer and carcinoma vulvae and skin carcinoma (as dermatofibrosarcoma protuberans), and leukemia and lymphoma are (as chronic lymphocytic leukemia (CML), chronic grain monocytic leukemia (CMML), acute lymphoblastic leukemia (ALL), chronic neutrophilic leukemia (CNL), acute myelogenous leukemia (AML) and multiple myeloma).

According to this aspect of the invention, also be provided at the method for the treatment of cell proliferation disorders (for example solid tumor disease) in the warm-blooded animal that needs this treatment, described method comprises the formula I quinazoline derivant or its pharmacy acceptable salt that above limit that gives described animal effective dose.

Other suitable cell proliferation disorders comprises nonmalignant disease, vascular disease (, for example being secondary to the restenosis process of sacculus angioplasty and heart arter bypass) for example as atherosclerosis and restenosis, fibrotic disease is (as renal fibrosis, liver cirrhosis, pulmonary fibrosis and multicystic dysplastic kidney), glomerulonephritis, benign prostatauxe, inflammatory diseases (as rheumatoid arthritis and inflammatory bowel), multiple sclerosis, psoriatic, the skin hypersusceptibility, atopic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.

Suitable comprises with vasculogenesis and/or vascular permeability diseases associated, for example is found in diabetic retinopathy, psoriatic, cancer, rheumatoid arthritis, atheroma, Kaposi and angiomatous bad or pathological angiogenesis generation.

According to another aspect of the invention, be provided for the formula I quinazoline derivant or its pharmacy acceptable salt that above limit of those tumours of treatment (or prevention), described tumour is to the inhibition sensitivity of pdgf receptor enzyme (as PDGF α and/or PDGF beta receptor Tyrosylprotein kinase), and described enzyme relates to the signal transduction step that causes tumor cell proliferation, survival, invasion and attack and transfer ability.

The another feature of this respect according to the present invention, purposes in the formula I quinazoline derivant or its pharmacy acceptable salt that limit be used for the treatment of (or prevention) those tumours in preparation the medicine is provided above, described tumour is to the inhibition sensitivity of pdgf receptor enzyme (as PDGF α and/or PDGF beta receptor Tyrosylprotein kinase), and described enzyme relates to the signal transduction step that causes tumor cell proliferation, survival, invasion and attack and transfer ability.

The another feature of this respect according to the present invention, provide treatment (or prevention) to suffer from the method for the warm-blooded animal of tumour, described tumour is to the inhibition sensitivity of pdgf receptor enzyme (as PDGF α and/or PDGF beta receptor Tyrosylprotein kinase), described enzyme relates to the signal transduction step that causes tumor cell proliferation, survival, invasion and attack and transfer ability, and described method comprises the formula I quinazoline derivant or its pharmacy acceptable salt that above limit that gives described animal effective dose.

According to another aspect of the invention, provide the formula I quinazoline derivant or its pharmacy acceptable salt that above limit, be used to provide pdgf receptor enzyme inhibition (as PDGF α and/or PDGF beta receptor tyrosine kinase inhibitory activity).

The another feature of this respect according to the present invention, the formula I quinazoline derivant or the purposes of its pharmacy acceptable salt in the preparation medicine that above limit are provided, and described medicine is used to provide pdgf receptor enzyme inhibition (as PDGF α and/or PDGF beta receptor tyrosine kinase inhibitory activity).

According to another aspect of the invention, also provide the method that suppresses pdgf receptor enzyme (as PDGF α and/or PDGF beta receptor Tyrosylprotein kinase), described method comprises the formula I quinazoline derivant or its pharmacy acceptable salt that above limit that gives significant quantity.

Above the anticancer therapy of Xian Dinging can be used as the use of single therapy method, perhaps except that quinazoline derivant of the present invention, also can comprise routine operation or radiotherapy or chemotherapy.Such chemotherapy can comprise the antitumour drug of one or more following classifications:

(i) other antiproliferative/antitumour drug and the combination thereof adopted in medical oncology are as alkylating agent (for example cis-platinum, Oxalipratin, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan, Temozolomide and nitrosourea); Antimetabolite (as antifol, for example fluorinated pyrimidine class (as 5 FU 5 fluorouracil and Tegafur), Raltitrexed, methotrexate, cytarabin, hydroxyurea and gemcitabine); Antitumor antibiotics (as anthracyclines, as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, darubicin, Mitomycin-C, gengshengmeisu and Plicamycin); Antimitotic agent (as vinca alkaloids, as vincristin, vinealeucoblastine(VLB), vindesine and vinorelbine, and Taxan such as taxol and taxotere and polo kinase inhibitor); And topoisomerase enzyme inhibitor (as epipodophyllotoxin, as Etoposide and teniposide, amsacrine, Hycamtin and camptothecine);

(ii) cytostatics is as anti-estrogens (as tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and idoxifene (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 such as finasteride;

(iii) anti-invasion agent (as c-Src kinases man group inhibitor, for example 4-(6-chloro-2,3-methylene dioxo group aniline base)-7-[2-(4-methylpiperazine-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base quinazoline (AZD0530; International Patent Application WO 01/94341) and bosutinib (bosutinib) (SKI-606), and inhibitors of metalloproteinase is as Marimastat, and the inhibitor of urokinase plasminogen activator function of receptors];

(iv) somatomedin depressant of functions: for example this type of inhibitor comprises growth factor antibodies and growth factor receptor antibody [for example, anti--erbB2 antibody Herceptin and anti--erbB1 antibody Cetuximab [C225] and handkerchief Buddhist nun monoclonal antibody (panitumumab)]; This type of inhibitor also comprises, for example tyrosine kinase inhibitor is [as the epidermal growth factor family inhibitor (as EGFR family tyrosine kinase inhibitor, as Gefitinib (gefitinib, ZD 1839), erlotinib (erlotinib, OSI-774) and CI 1033), with erbB2 tyrosine kinase inhibitor such as lapatinibditosylate (lapatinib)), pHGF man group inhibitor, the insulin-like growth factor acceptor inhibitor, growth factor family inhibitor that other is platelet-derived and/or bcr/abl kinases, imatinib (imatinib) for example, Dasatinib (dasatinib) (BMS-354825) and nilotinib (nilotinib) (AMN107), pass through MEK, AKT, PI3, c-kit, Flt3, the kinase whose cell signal inhibitor of CSF-1R and/or aurora]; This type of inhibitor also comprises, cell cycle protein dependent kinase inhibitor comprises CDK2 and CDK4 inhibitor; This type of inhibitor also comprises, for example serine/threonine kinase inhibitor (for example Ras/Raf signal suppressing agent, farnesyl transferase inhibitor for example, for example Xarelto (sorafenib) (BAY 43-9006), for pyrrole method Buddhist nun (tipifarnib) (R115777) and Luo Nafani (lonafarnib) (SCH66336);

(v) anti-angiogenic agent [for example resists-vascular endothelial growth factor antibody, as rhuMAb-VEGF [Avastin as those medicines that suppress the vascular endothelial growth factor effect ^TM], or vegf receptor tyrosine kinase inhibitor for example, as ZD6474 (vandetanib) (ZD6474), Wa Talani (vatalanib) (PTK787), Sutent (sunitinib) (SU11248), A Xi for Buddhist nun (axitinib) (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(the basic propoxy-of 3-tetramethyleneimine-1-) quinazoline (AZD2171; Embodiment 240 among the WO00/47212); Or the compound that for example works (for example three carboxyl quinolylamines, beta 2 integrin alpha v β 3 depressant of functions and angiostatin)] by other mechanism;

(vi) blood vessel injury agent, as combretastatin A4 and in International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213 disclosed compound;

(vii) antisense therapy agent for example relates to above those therapeutical agents of listed target, as ISIS2503, anti--agent of ras antisense therapy;

(viii) gene therapy approach, comprise the approach, GDEPT (gene-pacemaker enzyme prodrug therapy) approach that for example replace aberrant gene (as unusual p53 or unusual BRCA1 or BRCA2), as use those approach of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, and increase the approach of patient to the tolerance of chemotherapy or radiotherapy (as to the drug-fast gene therapy of multiple medicine); With

(ix) immunotherapy approach, comprise for example increase the patient tumors cell immunogenic in vitro with body in approach, as using cytokine (as interleukin-22, interleukin 4 or granulocyte-macrophage colony stimutaing factor) transfection, 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, sequential or each component of separately treating, can realize this type of combination therapy.This type of joint product uses other interior medical active agent of amount ranges of interior The compounds of this invention of aforementioned dosage range and approval.

According to this aspect of the invention, provide the combination that is applicable to treatment cell proliferation disorders (for example solid tumor disease), this combination comprises quinazoline derivant and other antitumour drug defined above of formula I defined above.

According to this aspect of the invention, provide medicament production, other antitumour drug defined above that this product comprises the quinazoline derivant of formula I defined above and is used for the cancer combination therapy.

Specifically, anticancer disease treatment defined above can comprise quinazoline derivant of the present invention together with the angiogenesis inhibitor medicine, for example anti-vascular endothelial cell growth factor antibody (for example rhuMAb-VEGF) and/or vegf receptor tyrosine kinase inhibitor (for example ZD6474 (vandetanib), Wa Talani (vatalanib), Sutent (sunitinib) or AZD2171).

According to this aspect of the invention, provide the combination that is applicable to treatment cell proliferation disorders (for example solid tumor disease), this combination comprises quinazoline derivant and the angiogenesis inhibitor medicine defined above of formula I defined above.

According to this aspect of the invention, also provide medicament production, the angiogenesis inhibitor medicine defined above that this product comprises the quinazoline derivant of formula I defined above and is used for the cancer combination therapy.

Anticancer disease treatment defined above can comprise quinazoline derivant of the present invention together with the anti-medicine of invading, for example c-Src kinases man group inhibitor, for example AZD0530 or bosutinib.

According to this aspect of the invention, provide the combination that is applicable to treatment cell proliferation disorders (for example solid tumor disease), this combination comprises quinazoline derivant and the anti-intrusion medicine defined above of formula I defined above.

According to this aspect of the invention, also provide medicament production, the defined above anti-intrusion medicine that this product comprises the quinazoline derivant of formula I defined above and is used for the cancer combination therapy.

Anticancer disease treatment defined above can also comprise that quinazoline derivant of the present invention is together with the angiogenesis inhibitor medicine, anti-vascular endothelial cell growth factor antibody (for example rhuMAb-VEGF) and/or vegf receptor tyrosine kinase inhibitor (for example ZD6474 (vandetanib), Wa Talani (vatalanib), Sutent (sunitinib) or AZD2171) for example, with the anti-medicine of invading, c-Src kinases man group inhibitor, for example AZD0530 or bosutinib for example.

According to this aspect of the invention, provide the combination that is applicable to treatment cell proliferation disorders (for example solid tumor disease), this combination comprises the quinazoline derivant of formula I defined above, angiogenesis inhibitor medicine defined above and anti-intrusion medicine defined above.

According to this aspect of the invention, also provide medicament production, angiogenesis inhibitor medicine defined above and anti-intrusion medicine defined above that this product comprises the quinazoline derivant of formula I defined above and is used for the cancer combination therapy.

In above-described any cancer combination therapy, randomly can also there be the biphosphonate compound.

The biphosphonate compound is the bis phosphoric acid derivative that can regulate metallic cation (especially calcium) processing in warm-blooded animal such as people.Therefore, biphosphonate can be used for preventing or treats disease such as osteoporosis and molten bone osteopathy, for example the molten bone damage that can take place with metastatic cancer (for example kidney, thyroid carcinoma and lung cancer, especially breast cancer and prostate cancer).Suitable biphosphonate comprises tiludronic acid (tiludronic acid), Ibandronic acid (ibandronic acid), ineadronic acid (incadronic acid), Zoledronic acid (zoledronic acid), clodronic acid (clodronic acid), neridronic acid (neridronic acid), pamidronic acid (pamidronic acid) and clinic effect of alendronate (alendronic acid).

Though mainly as the medicine of warm-blooded animal (comprising the people), when needed, they also can be used to suppress the effect of pdgf receptor Tyrosylprotein kinase to formula I compound.Therefore, these compounds can be as new biological test exploitation and the pharmaceutical standards product in the new pharmacology drug research.

The present invention will be described by following examples now, wherein, and in general:

(i) except as otherwise noted, be to carry out at ambient temperature otherwise operate, promptly in 17-25 ℃ temperature range and under rare gas element (as nitrogen or argon gas) atmosphere, carry out;

The reaction of (ii) carrying out under microwave radiation is used such as the equipment of " Smith Synthesiser " (300 kilowatts) and is implemented under normal or high configuration, and this equipment use temperature transmitter is adjusted microwave power automatically, so that keep desired temperature; Perhaps can use " Emrys Optimizer " microwave equipment;

(iii) in general, follow thin-layer chromatography (TLC) and/or analysis high pressure liquid chromatography (HPLC) after the reaction process; Not necessarily accessible minimum value of the reaction times that provides;

(iv) in case of necessity, organic solution is through anhydrous magnesium sulfate drying, and post-processing step carries out behind the residual solid of filtering, and evaporation is carried out with vacuum rotary evaporator;

(v) productive rate (if exist) not necessarily accessible maximum value, in case of necessity, more substantial if desired reaction product is reaction repeated then;

(vi) in general, the structure of the end product of formula I is confirmed by nucleus magnetic resonance (NMR) and/or mass-spectrometric technique; The electrospray mass-spectrometric data obtains with for example Waters ZMD or Waters ZQ LC/ mass spectrograph, obtains two kinds of data of positive ion and negative ion, the general only report ion relevant with parent's structure; Proton N MR ( ¹H NMR) chemical displacement value is measured with for example BrukerSpectrospin DPX300 spectrometer on the δ scale, operates in the 300MHz field intensity; Use following abbreviation: s, unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; Br, broad peak;

(vii) except as otherwise noted, otherwise the compound that contains asymmetric carbon and/or sulphur atom do not split;

(viii) intermediate is not necessarily wanted complete purifying, but with TLC, analysis HPLC, infrared rays (IR) and/or their structure of NMR analysis and evaluation and purity;

(ix) column chromatography (rapid method) and medium pressure liquid chromatography (MPLC) carry out on silica gel, for example use Merk Kieselgel silica gel (Art.9385) or use post from Armen Instrument (56890-Saint Ave, France);

(x) preparation HPLC carries out on the C18 reverse phase silica gel, for example at Waters ' Xterra ' preparation reversed-phase column (5 microns silica gel, 19mm diameter, 100mm length) carry out for eluent with falling polar solvent mixture (for example polar compound that falls of 1% acetic acid solution or 1% ammonium hydroxide aqueous solution (d=0.88) and acetonitrile) or on Novasep SAS ' Prochrom DAC ' the preparation reversed-phase column;

(xi) when obtaining the compound of some acid salt (for example mono-hydrochloric salts or dihydrochloride) form, the stoichiometric calculation of this salt is based on the number and the character of base in the compound; In general, do not obtain the precise chemical structure calculating that the ultimate analysis data are determined this salt;

(xii) use following abbreviation:

DMF N, dinethylformamide

The DMA N,N-dimethylacetamide

The DMSO dimethyl sulfoxide (DMSO)

Embodiment 1

N-(4,5-dimethylthiazole-2-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide

With triethylamine (0.245ml) and 2-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea phosphofluoric acid ester (V) (0.236g) adds 2-[5-(6 successively, 7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] acetate (0.2g), 2-amino-4, in the stirring the mixture of 5-dimethylthiazole (0.083g) and DMF (2ml), stirred institute's mixture that obtains 40 minutes in envrionment temperature.The mixture that adds saturated sodium bicarbonate aqueous solution (5ml) and saturated aqueous sodium carbonate (5ml) stirred institute's mixture that obtains 1 hour in envrionment temperature.Precipitation separation, and under ether, grind.Under vacuum in 40 ℃ of dry institute solids that obtain 16 hours.Obtain to be solid title compound (0.185g) thus; ¹ H NMR: (DMSOd ₆) 2.1 (s, 3H), 2.2 (s, 3H), 4.0 (m, 8H), 7.4 (s, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.5 (m, 1H), 8.55 (s, 1H); Mass spectrum:M-H ^-450.

Be prepared as follows 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl as starting raw material] acetate:

Stir the mixture of 5-hydroxy-2-methyl pyridine (100g), benzyl chloride (116ml), salt of wormwood (177.2g) and DMA (1.5 liters), and be heated to 90 ℃ and reach 5 hours.Filtering mixt, and vacuum-evaporation filtered solution.The residue silica gel chromatography is an eluent with polar solvent gradient (95:5 to the 1:1) mixture that increases of sherwood oil and ethyl acetate.Obtain 5-benzyloxy-2-picoline (135.6g) thus; ¹ H NMR:(CDCl ₃) 2.5 (s, 3H), 5.1 (s, 2H), 7.05 (d, 1H), 7.15 (m, 1H), 7.4 (m, 5H), 8.25 (d, 1H).

Stir the mixture 1 hour of the material, 3-chlorine peroxybenzoic acid (184.3g) and the methylene dichloride (2 liters) that so obtain in envrionment temperature.Use 5% aqueous sodium carbonate and water washing mixture successively, through dried over mgso, and evaporation.Obtain 5-benzyloxy-2-PICOLINE N-OXIDES (135g) thus; ¹ H NMR:(CDCl ₃) 2.45 (s, 3H), 5.05 (s, 2H), 6.9 (d, 1H), 7.1 (d, 1H), 7.4 (m, 5H), 8.1 (d, 1H).

The material that so obtains is added the diacetyl oxide (296ml) of stirring in batches, be heated to 135 ℃ (bath temperatures), in this temperature mixture that restir obtains 30 minutes.In mixture impouring mixture of ice and water, stirred 1.5 hours.Add sodium-chlor,, use the ethyl acetate extraction mixture with saturated water.Organic phase is through dried over mgso and evaporation.The crude product silica gel chromatography is an eluent with the polar solvent mixture (100:0 to 11:9) that increases of methylene dichloride and ether.Obtain 2-acetoxy-methyl-5-benzyloxy pyridine (119g) thus; Mass spectrum: M+H ⁺258.

Methyl alcohol (330ml) solution that the material that so obtains is added in batches the potassium hydroxide (32.9g) of stirring.With obtaining mixture heating up to refluxing 1 hour.By the most of solvent of evaporative removal, residue is distributed between ether and the water.Organic phase is through dried over mgso and evaporation.Obtain 5-benzyloxy-2-4-hydroxymethylpiperidine (93.7g) thus; Mass spectrum: M+H ⁺216.

The material dissolves that so obtains in methylene dichloride (700ml), is cooled to 0 ℃ with solution.Add thionyl chloride (34.8ml) in batches, mixture is cooled to 0 ℃ simultaneously.Make the mixture that obtains be warming up to envrionment temperature, mixture was stirred 1 hour.Evaporating solvent, residual solid is ground under ether.Solid that filtering separation obtains.Obtain 5-benzyloxy-2-chloromethyl pyridine hydrochloride (115.6g) thus; Mass spectrum: M+H ⁺234.

The material that so obtains is suspended in the ethanol (450ml), and adds potassiumiodide (1.5g), water (150ml) and potassium cyanide (55.6g) successively.Stirred reaction mixture, and be heated to backflow 4 hours.Obtaining mixture is cooled to envrionment temperature.Add saturated sodium bicarbonate aqueous solution, use the dichloromethane extraction mixture.Organic phase water and salt water washing are through dried over mgso and evaporation.So the solid that obtains grinds under ether.Institute's solid by filtration that obtains is collected, and obtains 2-(5-benzyloxy pyridine-2-yl) acetonitrile (85.1g); ¹ H NMR:(CDCl ₃) 3.9 (s, 2H), 5.1 (s, 2H), 7.4 (m, 7H), 8.3 (d, 1H).

With the material dissolves that so obtains in methyl alcohol.Add 25% aqueous sodium hydroxide solution (170ml), with mixture heating up to refluxing 18 hours.Mixture is cooled to envrionment temperature, evaporating solvent.Be dissolved in the water residue and filtration.Filtered solution is cooled to 0 ℃, and is acidified to pH4.7 by adding the 6N aqueous hydrochloric acid.Separate the precipitation that obtains, wash with water, and under ether, grind.The solid vacuum-drying that obtains.Obtain 2-(5-benzyloxy pyridine-2-yl) acetate (84.1g) thus; Mass spectrum: M+H ⁺244.

With the 2-tertiary butyl-1,3-di-isopropyl isourea [629g; By DIC (496ml), the trimethyl carbinol (303ml) and cuprous chloride (4.71g) were reacted 48 hours under argon gas in envrionment temperature, and filtering mixt, obtain as liquid] add the stirred suspension of 2-(5-benzyloxy pyridine-2-yl) acetate (84.1g) in methylene dichloride (1.4 liters), stirred the mixture 48 hours in envrionment temperature.Obtain precipitation by removing by filter, the vacuum concentration filtered solution.The residue silica gel chromatography is an eluent with the polar solvent mixture (100:0 to 19:1) that increases of methylene dichloride and ethyl acetate.Obtain 2-(5-benzyloxy pyridine-2-yl) tert.-butyl acetate (63.7g) thus, it is crystalline oily matter when leaving standstill; ¹ H NMR:(DMSOd ₆) 1.4 (s, 9H), 3.65 (s, 2H), 5.2 (s, 2H), 7.25 (d, 1H), 7.4 (m, 6H), 8.25 (d, 1H).

Carbon is carried palladium hydroxide catalyzer (10g; The Pearlman catalyzer that contains have an appointment 20% palladium and about 50% water) adds stirring the mixture of 2-(5-benzyloxy pyridine-2-yl) tert.-butyl acetate (58.7g), 1 (200ml) and ethanol (1 liter).With obtaining mixture heating up to refluxing 2 hours.Mixture is cooled to envrionment temperature, by removing by filter catalyzer.The evaporation filtered solution.Residue grinds under ether.Separate the solid that obtains.Obtain to be the 2-of white solid (5-pyridone-2-yl) tert.-butyl acetate (39.6g) thus; ¹ H NMR:(DMSOd ₆) 1.4 (s, 9H), 3.6 (s, 2H), 7.1 (m, 2H), 8.05 (d, 1H), 9.8 (br s, 1H).

Stir 4-chlorine 6,7-dimethoxyquinazoline (European Patent Application No. 0566226, embodiment 1; 0.95g), the mixture of (5-pyridone-2-yl) tert.-butyl acetate (0.93g), salt of wormwood (0.7g) and DMA (30ml), and be heated to 95 ℃ and reach 2.5 hours.Filter the mixture that obtains, and the evaporation filtered solution.The residue silica gel chromatography is an eluent with the polar solvent mixture (by 100:0 to 19:1) that increases of methylene dichloride and methyl alcohol.Obtain pyridine-2-yl thus for solid 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)] tert.-butyl acetate (1.29g); Mass spectrum: M+H ⁺398.

With hydrogenchloride 1,6M solution in the 4-diox (5ml) adds 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] in the stirring the mixture of tert.-butyl acetate (1.2g) and methylene dichloride (5ml), stirred the mixture 4 hours in envrionment temperature.Evaporating solvent, residue grinds under the mixture of ether and methylene dichloride.Separate residual solid, and vacuum-drying.Obtain 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl thus] acetate (0.965g); Matter Spectrum: M+H ⁺342.

Embodiment 2

Use with in similar method described in the embodiment 1, make suitable 2-pyridine-2-guanidine-acetic acid (0.2g) and suitable amine reaction, obtain at the compound described in the Table I.Except as otherwise noted, otherwise every kind of amine all is commercially available material.

Table I

Numbering and note	(R 1) p	(R 2) q	R
				[1]	6, the 7-dimethoxy	H	4-methylthiazol-2-base
[2]	6, the 7-dimethoxy	H	5-methylthiazol-2-base
				[3]	6, the 7-dimethoxy	H	5-methoxy thiazole-2-base
[4]	6, the 7-dimethoxy	H	4,5-Er Jia Ji oxazole-2-base
				[5]	6, the 7-dimethoxy	H	5-methyl-isoxazole-3-base
[6]	6, the 7-dimethoxy	H	1-sec.-propyl pyrazoles-4-base
				[7]	6, the 7-dimethoxy	H	5-Dimethylamino pyridine-2-base
[8]	6, the 7-dimethoxy	H	1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-5-base

ExplainThe yield and the characteristic of every kind of product are as follows.

[1]0.108g； ¹ H?NMR：(DMSOd ₆)2.2(s，3H)，3.9(s，2H)，3.99(s，3H)，4.0(s，3H)，

6.55 (br s, 1H), 7.4 (s, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.5 (m, 1H), 8.55 (s, 1H); Mass spectrum: M-H ^-436.

[2] 0.111g; ¹ H NMR: (DMSOd ₆) 2.35 (s, 3H), 4.0 (m, 8H), 7.15 (s, 1H), 7.4 (s, 1H), 7.55 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.5 (m, 1H), 8.55 (s, 1H); Mass spectrum: M+H ⁺438.

[3] 0.134g; ¹ H NMR: (DMSOd ₆) 3.85 (s, 3H), 4.0 (m, 8H), 6.85 (s, 1H), 7.4 (s, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.5 (m, 1H), 8.55 (s, 1H), 12.5 (s, 1H); Mass spectrum: M-H ^-452.

Be prepared as follows 2-amino-5-methoxy thiazole as starting raw material:

Sodium methylate (0.724g) is added the 2-amino-solution (6ml) of 5-bromo thiazole (0.6g) in methyl alcohol, and institute's mixture that obtains stirred 12 hours in envrionment temperature.Evaporating mixture, the residue silica gel chromatography is an eluent with the polar compound that increases of methylene dichloride and ethyl acetate.Obtain required starting raw material (0.132g) thus; ¹H NMR:(CDCl ₃) 3.82 (s, 3H), 4.53 (br s, 2H), 6.41 (s, 1H).

[4] 0.036g; ¹ H NMR: (DMSOd ₆) 1.95 (s, 3H), 2.2 (s, 3H), 3.9 (m, 2H), 3.99 (s, 3H), 4.0 (s, 3H), 7.4 (s, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.5 (m, 1H), 8.55 (s, 1H), 11.2 (br s, 1H); Mass spectrum: M-H ^-434.

Be prepared as follows 2-amino-4,5-Er Jia Ji oxazole as starting raw material:

The mixture of cyanamide (0.96ml), 3-hydroxyl fourth-2-ketone (1g) and water (100ml) is warming up to 50 ℃ gradually, until dissolving fully takes place.The temperature of reaction mixture is remained in 45 ℃ reach 30 minutes.Reaction mixture is cooled to envrionment temperature, alkalizes to pH 10 by adding the 2N aqueous sodium hydroxide solution, and use extracted with diethyl ether.Organic solution obtains the 2-amino-4 into oily matter, 5-Er Jia Ji oxazole (0.66g) through dried over mgso and evaporation.

[5] 0.11g; ¹ H NMR: (DMSOd ₆) 2.35 (s, 3H), 3.95 (s, 2H), 3.98 (s, 3H), 4.0 (s, 3H), 6.6 (s, 1H), 7.4 (s, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.5 (m, 1H), 8.55 (s, 1H), 11.2 (s, 1H); Mass spectrum: M+H ⁺422.

[6] 0.132g; ¹ H NMR: (DMSOd ₆) 1.35 (d, 6H), 3.8 (s, 2H), 3.99 (s, 3H), 4.0 (s, 3H), 4.45 (m, 1H), 7.4 (s, 1H), 7.45 (s, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 7.9 (s, 1H), 8.5 (s, 1H), 8.55 (s, 1H), 10.3 (s, 1H); Mass spectrum: M+H ⁺449.

Be prepared as follows 4-amino-1-sec.-propyl-1H-pyrazoles as starting raw material:

The 4-nitropyrazole is by N.D.Zelinsky Institute, Organic Chemistry, and Leninskyprospect 47,117913Moscow B-334, Russia buys.This compound can also be prepared as follows:

Nitrosonitric acid (9.5ml) is dropped to the stirred solution of pyrazoles (13.6g) in glacial acetic acid (51ml), and this solution has used cryosel to bathe and has been cooled to-10 ℃.Form a large amount of precipitations.Drip diacetyl oxide (27ml), stirred institute's mixture that obtains 2.5 hours in envrionment temperature.Mixture is poured on ice, the acidity of mixture is reduced to pH 5 by adding salt of wormwood.Precipitate by filtering separation.Obtaining solid is dissolved in the water aqueous solution extracted with diethyl ether.Organic solution is through dried over mgso and filtration.To by evaporation concentration to the filtered solution of about 50ml volume adding sherwood oil (boiling point 60-80 ℃, 50ml).The precipitation that forms is passed through filtering separation.This solid is considered to 1-nitropyrazole (20.6g); ¹ H NMR: (DMSOd ₆) 6.71 (s, 1H), 7.88 (s, 1H), 8.81 (s, 1H).This compound may be volatile, the care should be used to operation.

1-nitropyrazole (20.3g) sample drop that stirs to refrigerative in ice bath adds the vitriol oil (80ml).Stirred institute's mixture that obtains 16 hours, and made it be warming up to envrionment temperature.Mixture is poured onto on ice, and stirred 20 minutes.Separate the solid that obtains, and wash with water.Filtered solution neutralizes by adding salt of wormwood, and uses extracted with diethyl ether.The solid that reclaims is added diethyl ether solution,,, and filter through dried over mgso with the saturated sodium-chloride water solution washing solution that obtains.Sherwood oil (boiling point 60-80 ℃) is added by the filtered solution of evaporation concentration to about 50ml volume.The precipitation that forms is passed through filtering separation.Obtain 4-nitropyrazole (16g) thus; ¹ H NMR: (DMSOd ₆+ CF ₃CO ₂H) 8.57 (s, 2H).

Stir the mixture of 4-nitropyrazole (1.13g), isopropyl iodide (1ml), salt of wormwood (1.38g) and DMF (30ml), and be heated to 70 ℃ and reach 2 hours.Obtaining mixture is poured onto in the water, and precipitation separation washes with water, and vacuum-drying.Obtain 1-sec.-propyl-4-nitro-1H-pyrazoles (0.845g) thus; ¹ H NMR: (DMSOd ₆) 1.44 (d, 6H), 4.59 (m, 1H), 8.26 (s, 1H), 8.93 (s, 1H).

The mixture of mixing part (0.8g) so obtains under 3 hydrogen gas pressure material, platinum oxide (0.1g), ethyl acetate (10ml) and ethanol (30ml) 2 hours.By removing by filter catalyzer, the evaporation filtered solution.Obtain to be the required starting raw material (0.607g) of colorless oil thus; ¹ H NMR: (DMSOd ₆) 1.31 (d, 6H), 3.76 (br s, 2H), 4.27 (m, 1H), 6.88 (s, IH), 7.03 (s, 1H).

[7] 0.169g; ¹ H NMR: (DMSOd ₆) 2.9 (s, 6H), 3.95 (s, 2H), 3.99 (s, 3H), 4.0 (s, 3H), 7.2 (m, 1H), 7.4 (s, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 7.85 (m, 1H), 7.9 (d, 1H), 8.5 (m, 1H), 8.55 (s, 1H), 10.45 (s, 1H); Matter Spectrum: M+H ⁺461.

Be prepared as follows 2-amino-5-Dimethylamino pyridine as starting raw material:

To the stirred suspension of 5-bromo-2-nitropyridine (6.1g) in ethanol (60ml) add dimethylamine agueous solution (40%, 11.3ml), with obtaining mixture heating up to refluxing 16 hours.Mixture is cooled to envrionment temperature, and separate solid washes with water, vacuum-drying.Obtain 5-dimethylamino-2-nitropyridine (4g) thus; ¹ H NMR: (CDCl ₃) 3.16 (s, 6H), 6.98 (m, 1H), 7.96 (m, 1H), 8.17 (m, 1H); Mass spectrum: M+H ⁺168.

The mixture of the material, platinum-oxide catalyst (0.27g), ethanol (60ml) and the ethyl acetate (60ml) that so obtain was stirred 3 hours under 5 hydrogen gas pressure.Filtration catalizer, the evaporation filtered solution.Obtain 2-amino-5-Dimethylamino pyridine (3g) thus; ¹H NMR:(CDCl ₃) 2.83 (s, 6H), 4.08 (br s, 2H), 6.49 (m, 1H), 7.08 (m, 1H), 7.67 (m, 1H); Mass spectrum: M+H ⁺138.

[8]0.19g； ¹ H?NMR：(DMSOd ₆)3.8(s，3H)，4.0(m，8H)，6.4(m，1H)，7.4(s，1H)，7.6(m，3H)，7.8(m，1H)，7.9(m，1H)，7.95(m，1H)，8.55(m，1H)，8.6(s，1H)，10.6(s，1H)。

Be prepared as follows 5-amino-1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine as starting raw material:

(60% dispersion liquid in oil 0.093g) adds the N that stirs with sodium hydride ¹, N ¹-dimethyl-N ²-(1H-pyrrolo-[3,2-b] pyridine-5-yl) carbonamidine ( J.Med.Chem., 2003, 46, 3060; 0.418g) and the mixture of DMF (8ml), reaction mixture stirred 10 minutes in envrionment temperature.Add methyl-iodide (0.138ml), reaction mixture stirred 16 hours in envrionment temperature.Add entry, use the dichloromethane extraction mixture.Organic phase water and salt water washing, through dried over mgso, and evaporation.Obtain N thus ¹, N ¹-dimethyl-N ²-[1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine-5-yl] carbonamidine (0.212g); ¹ H NMR: (DMSOd ₆) 2.95 (s, 3H), 3.1 (s, 3H), 3.85 (s, 3H), 6.3 (d, 1H), 6.7 (d, 1H), 7.4 (d, 1H), 7.7 (d, 1H), 8.45 (s, 1H).

Stir the mixture of the material, potassium hydroxide (0.12g), water (0.5ml) and the methyl alcohol (2ml) that so obtain, and be heated to 75 ℃ and reach 24 hours.The mixture dilute with water that obtains is with methylene dichloride and methanol mixture extraction.Organic phase water and salt water washing are through dried over mgso and evaporation.Obtain the 2:3 mixture (0.16g) of reacted and 5-amino-1-methyl isophthalic acid H-pyrrolo-[3,2-b] pyridine thus; ¹ H NMR: (DMSOd ₆) 3.7 (s, 3H), 5.35 (br s, 2H), 6.1 (d, 1H), 6.35 (d, 1H), 7.25 (d, 1H), 7.5 (d, 1H).

Embodiment 3

N-(5-cyano thiazole-2-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide

Successively 2 hydroxy pyrimidine N-oxide compound (0.053g) and triethylamine (0.184ml) are added 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl in envrionment temperature] stirred mixture of acetate (0.15g), 2-amino-5-cyano thiazole (0.6g), 1-(3-dimethylamino-propyl)-3-ethyl hydrochloric acid carbodiimide (0.095g) and DMF (2ml).Stir the mixture that obtains, and be heated to 45 ℃ and reach 4 hours.Reaction mixture uses Waters ' β Basic Hypersil ' reversed-phase column (5 μ m silica gel, 30mm diameter, 250mm length) by preparation HPLC purifying, and what make water (containing 0.2% volatile salt) and acetonitrile falls polar compound as eluent.Obtain title compound (0.034g) thus; ¹ H NMR: (DMSOd ₆) 3.99 (s, 3H), 4.0 (s, 3H), 4.1 (s, 2H), 7.4 (s, 1H), 7.55 (m, 2H), 7.8 (m, 1H), 8.4 (s, 1H), 8.55 (d, 1H), 8.6 (s, 1H), 13.2 (s, 1H); Mass spectrum: M-H ^-447.

Embodiment 4

Use is similar to embodiment 3 described methods, makes suitable 2-pyridine-2-guanidine-acetic acid and suitable amine reaction, obtains at the compound described in the Table II.Except as otherwise noted, otherwise every kind of amine all is commercially available material.

Except as otherwise noted, otherwise every kind of reaction product is all used Waters ' β BasicHypersil ' reversed-phase column (5 μ m silica gel, the 30mm diameter, 250mm length) by preparation HPLC purifying, what make water (containing 0.2% volatile salt) and acetonitrile falls polar compound as eluent.

Table II

Numbering and note	(R 1) p	(R 2) q	R
				[1]	6, the 7-dimethoxy	H	1-ethyl pyrazoles-4-base
[2]	6, the 7-dimethoxy	H	5-ethyl pyrazole-3-yl
				[3]	6, the 7-dimethoxy	H	1-ethyl pyrazole-3-yl
[4]	6, the 7-dimethoxy	H	1,5-dimethyl pyrazole-3-base
				[5]	6-methoxyl group-7-(2-tetramethyleneimine-1-base oxethyl)	H	5-Dimethylamino pyridine-2-base
[6]	6-methoxyl group-7-(2-tetramethyleneimine-1-base oxethyl)	H	The 3-p-methoxy-phenyl

ExplainThe every kind of relevant 2-pyridine-weight of 2-guanidine-acetic acid starting raw material and the yield and the characteristic of every kind of product are as follows.

[1] starting raw material (0.2g) produces product (0.17g); ¹ H NMR: (DMSOd ₆) 1.3 (t, 3H), 3.85 (s, 2H), 3.99 (s, 3H), 4.0 (s, 3H), 4.1 (q, 2H), 7.4 (s, 1H), 7.45 (s, 1H), 7.5 (d, 1H), 7.55 (s, 1H), 7.80 (m, 1H), 7.9 (s, 1H), 8.5 (d, 1H), 8.55 (s, 1H); Mass spectrum: M+H ⁺435.

Be prepared as follows 4-amino-1-ethyl-1H-pyrazoles as starting raw material:

With ethyl sulfate (5.23ml) slowly adding be warming up to 30 ℃ the stirred solution of 4-nitropyrazole (2.26g) in 1N aqueous sodium hydroxide solution (22ml), institute's mixture that obtains stirred 48 hours in this temperature.Mixture is cooled to envrionment temperature, and precipitation separation is used cold water washing, vacuum-drying.Obtain 1-ethyl-4-nitro-1H-pyrazoles (1.71g) thus; ¹ H NMR: (DMSOd ₆) 1.4 (t, 3H), 4.2 (q, 2H), 8.25 (s, 1H), 8.9 (s, 1H).

Partly the mixture of (0.8g) material, platinum oxide (0.1g), ethyl acetate (10ml) and ethanol (30ml) that obtains like this stirred 2 hours under 3 hydrogen gas pressure.By removing by filter catalyzer, the evaporation filtered solution.Obtain required starting raw material with 89% yield thus; ¹ H NMR: (DMSOd ₆) 1.27 (t, 3H), 3.77 (br s, 2H), 3.92 (q, 2H), 6.87 (s, 1H), 7.01 (s, 1H).

[2] starting raw material (0.2g) obtains product (0.058g); ¹ H NMR: (DMSOd ₆) 1.15 (t, 3H), 2.55 (q, 2H), 3.9 (s, 2H), 3.99 (s, 3H), 4.0 (s, 3H), 6.30 (br s, 1H), 7.4 (s, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.5 (d, 1H), 8.6 (s, 1H), 10.55 (s, 1H); Mass spectrum: M-H ^-433.

Be prepared as follows 5-amino-3-ethyl-1H-pyrazoles as starting raw material:

Acetonitrile (1.17ml) is dropped to the n-Butyl Lithium that is cooled to-78 ℃, and (mixture stirred 1 hour in this temperature for the hexane solution of 1.6M, stirred solution 14.06ml).Drip ethyl propionate (1.5ml), make reaction medium be warming up to-45 ℃, stirred 2 hours in this temperature.By adding the 2N aqueous hydrochloric acid obtaining mixture is acidified to pH 2, and passes through evaporation concentration.The residue dichloromethane extraction, organic extract is through dried over mgso and evaporation.Obtain 3-oxo valeronitrile with 80% yield thus; ¹ H NMR: (CDCl ₃) 1.14 (t, 3H), 2.66 (q, 2H), 3.46 (s, 2H).

The mixture heating up to 70 of material, hydrazine hydrate (0.28ml) and the ethanol (45ml) that will part (0.6g) so obtains ℃ reaches 12 hours.Evaporating solvent, the residue silica gel chromatography is an eluent with the 19:1 mixture of methylene dichloride and methyl alcohol.Obtain required starting raw material with 51% yield thus; ¹ H NMR: (DMSOd ₆) 1.04 (t, 3H), 2.41 (q, 2H), 4.4 (br s, 2H).

[3] starting raw material (0.2g) obtains product (0.18g); ¹ H NMR: (DMSOd ₆) 1.3 (t, 3H), 3.85 (s, 2H), 3.99 (s, 3H), 4.0 (s, 3H), 4.1 (q, 2H), 7.4 (s, 1H), 7.45 (s, 1H), 7.5 (d, 1H), 7.55 (s, 1H), 7.8 (m, 1H), 7.9 (s, 1H), 8.5 (d, 1H), 8.55 (s, 1H); Mass spectrum: M+H ⁺435.

3-amino-1-ethyl-1H-pyrazoles as starting raw material is described in ChemicalAbstracts, and 1975, 82, 156172 and International Patent Application WO 2005/060970.

[4] starting raw material (0.2g) obtains product (0.175g); ¹ H NMR: (DMSOd ₆) 2.2 (s, 3H), 3.6 (s, 3H), 3.85 (s, 2H), 3.95 (s, 3H), 4.0 (s, 3H), 6.3 (s, 1H), 7.4 (s, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.5 (d, 1H), 8.55 (s, 1H); Matter Spectrum: M+H ⁺435.

As the 3-amino-1 of starting raw material, 5-dimethyl-1H-pyrazoles is described in J. Heterocyclic Chem., 1982, 19, 1267.

[5] starting raw material (0.16g) obtains product (0.035g); ¹ H NMR: (DMSOd ₆) 1.7 (m, 4H), 2.55 (m, 4H), 2.9 (m, 8H), 3.95 (s, 2H), 4.0 (s, 3H), 4.3 (t, 2H), 7.2 (m, 1H), 7.45 (s, 1H), 7.55 (d, 1H), 7.6 (s, 1H), 7.8 (d, 1H), 7.85 (d, 1H), 7.9 (d, 1H), 8.53 (d, 1H), 8.56 (s, 1H); Mass spectrum: M+H ⁺544.

Be prepared as follows 2-{5-[6-methoxyl group-7-(2-tetramethyleneimine-1-base oxethyl) quinazoline-4-base oxygen base as starting raw material] pyridine-2-yl } acetate:

Stir 4-chloro-6-methoxyl group-7-(2-tetramethyleneimine-1-base oxethyl) quinazoline (International Patent Application WO 97/42187, embodiment 28 wherein, 0.45g), the mixture of 2-(5-pyridone-2-yl) tert.-butyl acetate (0.322g), salt of wormwood (0.242g) and DMA (10ml), and be heated to 95 ℃ and reach 2.5 hours.Filter the mixture that obtains, and the evaporation filtered solution.The residue silica gel chromatography is an eluent with the polar solvent mixture (by 10:0 to 17:3) that increases of methylene dichloride and methyl alcohol.Obtain to be foamed 2-{5-[6-methoxyl group-7-(2-tetramethyleneimine-1 base oxethyl) quinazoline-4-base oxygen base thus] pyridine-2-yl } tert.-butyl acetate (0.593g); Mass spectrum: M+H ⁺481.

The material dissolves that so obtains in methylene dichloride (2ml), is added 4M hydrogenchloride 1, the solution in the 4-diox (3ml).Stirred the mixture 12 hours in envrionment temperature.Evaporating solvent, residue grinds under ether.Separate the solid that obtains, and vacuum-drying.Obtain 2-{5-[6-methoxyl group-7-(2-tetramethyleneimine-1-base oxethyl) quinazoline-4-base oxygen base thus] pyridine-2-yl } acetic acid hydrochloride (0.58g); Mass spectrum: M+H ⁺425.

[6] starting raw material (0.07g) obtains product (0.026g); ¹ H NMR: (DMSOd ₆) 1.7 (m, 4H), 2.55 (m, 4H), 2.9 (t, 2H), 3.7 (s, 3H), 3.9 (s, 2H), 4.0 (s, 3H), 4.3 (t, 2H), 6.65 (m, 1H), 7.2 (m, 2H), 7.35 (s, 1H), 7.4 (s, 1H), 7.55 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.55 (d, 1H), 8.6 (s, 1H); Mass spectrum: M+H ⁺530.

Embodiment 5

N-(6-indolinyl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide

Successively 2 hydroxy pyrimidine N-oxide compound (0.102g) and triethylamine (0.245ml) are added 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl in envrionment temperature] the stirring the mixture of acetate (0.3g), the amino indoline of 6--1-t-butyl formate (0.206g), 1-(3-dimethylamino-propyl)-3-ethyl hydrochloric acid carbodiimide (0.182g) and DMF (3ml).Stir the mixture that obtains, and be heated to 45 ℃ and reach 3 hours.Add entry (10ml), separate the solid that obtains, and under ether, grind.So the solid that obtains was in 40 ℃ of vacuum-dryings 16 hours.Obtain N-[1-(N-tert-butoxycarbonyl) indoline-6-yl thus]-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide (0.368g), it need not to be further purified and can use.

Stir 1 of material that obtains like this and 7M hydrogenchloride, the mixture of 4-dioxane solution (6ml) 3 hours in envrionment temperature.Separate the solid that obtains, and be resuspended in the methylene dichloride (5ml).Add the saturated solution of ammonium in methyl alcohol, to obtain this solid lysate.Evaporating mixture, so solid water (5ml) that obtains and ether (5ml) washing, and in 40 ℃ of vacuum-dryings 16 hours.Obtain title compound (0.15g) thus; ¹ H NMR: 2.85 (t, 2H), 3.4 (t, 2H), 3.85 (s, 2H), 3.99 (s, 3H), 4.0 (s, 3H), 5.55 (s, 1H), 6.7 (m, 1H), 6.9 (m, 2H), 7.4 (s, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.5 (m, 1H), 8.55 (s, 1H); Mass spectrum: M+H ⁺458.

Be prepared as follows as the amino indoline of the 6-of starting raw material-1-t-butyl formate:

With the mixture of tert-Butyl dicarbonate (7.2g) adding 6-nitro indoline (4.92g) and methylene dichloride (50ml), mixture stirred 1 hour in envrionment temperature.Add 4-Dimethylamino pyridine (0.37g), in envrionment temperature stirred reaction mixture 16 hours.The evaporation mixture that obtains, the residue silica gel chromatography is an eluent with the polar compound that increases of sherwood oil (boiling point 40-60 ℃) and ethyl acetate.Obtain to be solid 6-nitro indoline-1-t-butyl formate (5.45g) thus; ¹ H NMR: (CDCl ₃) 1.6 (s, 9H), 3.2 (t, 2H), 4.1 (t, 2H), 7.2 (d, 1H), 7.85 (d, 1H), 8.3 (br s, 0.5H), 8.7 (br s, 0.5H).

Partly the mixture of (2.64g) material, 10% carbon-containing palladium catalyst (0.5g) and ethyl acetate (200ml) that obtains like this stirred 5 hours under 2.7 hydrogen gas pressure.Filter the mixture that obtains, the evaporation filtered solution.The residue silica gel chromatography is an eluent with the polar compound that increases of sherwood oil (boiling point 40-60 ℃) and ethyl acetate.Obtain the amino indoline of 6--1-t-butyl formate (1.5g) thus. ¹ H?NMR：(CDCl ₃)2.95(m，2H)，3.9(m，2H)，6.3(d，1H)，6.9(d，1H)，7.25(s，1H)。

Embodiment 6

N-(1,2,3,4-tetrahydroquinoline-7-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] ethanamide

Stir 2-[5-(6 in envrionment temperature, 7-dimethoxyquinazoline-4-base oxygen base) pyridine-2-yl] acetate (0.187g), 7-amino-1,2,3,4-tetrahydroquinoline (0.09g), diisopropylethylamine (0.116ml), 2-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate (V) (0.255g) and the mixture of DMF (5ml) 2 hours.Evaporating solvent.(15.7M 0.155ml), stirred the mixture 30 minutes in envrionment temperature to add entry (20ml) and spissated ammonium hydroxide aqueous solution to residue.Remove water, wash the colloid residue with water, and vacuum-drying.So the material silica gel chromatography that obtains is an eluent with the methylene dichloride of 100:0 to 19:1 solvent gradient and the mixture of 3.5M methanol ammonia solution.So the material that obtains grinds under ether.Obtain to be solid title compound (0.03g) thus; ¹ H NMR: (DMSOd ₆) 1.75 (m, 2H), 2.6 (t, 2H), 3.15 (m, 2H), 3.85 (s, 2H), 4.0 (s, 3H), 4.05 (s, 3H), 5.65 (s, 1H), 6.6 (m, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 7.4 (s, 1H), 7.55 (d, 1H), 7.6 (s, 1H), 7.8 (m, 1H), 8.5 (d, 1H), 8.55 (s, 1H), 9.9 (s, 1H); Mass spectrum: M+H ⁺472.

Be prepared as follows 7-amino-1,2,3, the 4-tetrahydroquinoline as starting raw material:

In 15 minutes, drip the mixture of the vitriol oil (12.03ml) and concentrated nitric acid (4.9ml) to 1,2,3,4 tetrahydroquinolines (6.66g) and the stirring the mixture of the vitriol oil (118ml) that are cooled to 0 ℃.Adding speed makes the temperature of reaction mixture remain on below 5 ℃.Institute's mixture that obtains stirred 15 minutes in 5 ℃.Mixture is poured on the ice (300ml), and by adding the solid sodium carbonate neutralization.The aqueous mixture ethyl acetate extraction, organic phase water and salt water washing are through dried over mgso and evaporation.The residue silica gel chromatography is an eluent with the polar compound that increases of sherwood oil (boiling point 40-60 ℃) and ethyl acetate.Obtain to be the 7-nitro-1,2 of oily matter, 3,4 tetrahydroquinolines (6.14g) thus; ¹ H NMR: (CDCl ₃) 1.95 (m, 2H), 2.8 (t, 2H), 3.35 (t, 2H), 7.05 (d, 1H), 7.3 (s, 1H), 7.4 (d, 1H).

Partly the mixture of (1.2g) material, 10% carbon-containing palladium catalyst (0.12g) and ethanol (20ml) that obtains like this stirred 30 minutes under 1 hydrogen gas pressure.Filter the mixture that obtains, and the evaporation filtered solution.Obtain 7-amino-1,2,3 thus, 4-tetrahydroquinoline (1g); ¹ H NMR: (CDCl ₃) 1.9 (m, 2H), 2.65 (m, 2H), 3.25 (m, 2H), 3.4 (br s, 2H), 3.7 (br s, 1H), 5.85 (d, 1H), 6.0 (m, 1H), 6.7 (d, 1H).

Embodiment 7

N-(1-ethyl-1H-pyrazoles-4-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide

Successively with diisopropylethylamine (0.263ml) and 2-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate (V) (0.186g) adds 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-and 3-Methoxy Pyridine-2-yl] in the stirring the mixture of acetate (0.14g), 4-amino-1H-1-ethyl pyrazoles (0.072g) and DMF (1.5ml), institute's mixture that obtains was in envrionment temperature stirring 18 hours.Institute's mixture that obtains is by evaporation concentration, and residue uses Waters ' Xterra ' reversed-phase column (5 μ m silica gel, 19mm diameter, 10mm length) by preparation HPLC purifying, and what make water (containing 0.2% volatile salt) and acetonitrile falls polar compound as eluent.Obtain title compound (0.085g) thus; ¹ H NMR: (DMSOd ₆) 1.33 (t, 3H), 3.78 (s, 2H), 3.8 (s, 3H), 3.99 (s, 3H), 4.0 (s, 3H), 4.06 (q, 2H), 7.41 (d, 1H), 7.54 (d, 1H), 7.58 (s, 1H), 7.86 (s, 1H), 8.11 (d, 1H), 8.59 (s, 1H), 10.13 (br s, 1H); Mass spectrum: M+H ⁺465.

Be prepared as follows 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl as starting raw material] acetate:

Under argon atmospher, to the 5-bromo-2-chloro-3-Methoxy Pyridine (International Patent Application WO 01/81347, the embodiment 10 wherein that are cooled to 18 ℃; 8g), stirring the mixture of acetonitrile (4.1ml) and THF (80ml) drips THF (80ml) solution of 1M hexamethyldisilazane lithium.Acetonitrile of Jia Ruing (4.1ml) and 1M hexamethyldisilazane lithium solution (80ml) successively.Make reaction mixture be warming up to envrionment temperature, and be poured onto in the stirring the mixture of water (300ml) and ether (300ml).The water extracted with diethyl ether.Merge organic phase, through dried over mgso and evaporation.The residue silica gel chromatography is an eluent with the sherwood oil and the ether of 4:1 to 1:1 solvent gradient.Obtain 2-(5-bromo-3-Methoxy Pyridine-2-yl) acetonitrile (4.8g) thus; ¹ H NMR: (CDCl ₃) 3.85 (s, 2H), 3.91 (s, 3H), 7.35 (d, 1H), 8.25 (d, 1H); Mass spectrum: M+H ⁺227 and 229.

Trimethylchlorosilane (21.55ml) is added stirring the mixture of 2-(5-bromo-3-Methoxy Pyridine-2-yl) acetonitrile (6.6g) and methyl alcohol (70ml).Obtaining mixture heating up to 50 ℃ is reached 12 hours.Mixture is dissolved in residue in the ether by evaporation concentration.Add saturated sodium bicarbonate aqueous solution, stop until gas evolution.Separate the water that obtains, and use extracted with diethyl ether.Merge organic phase, through dried over mgso and evaporation.Residue is by silica gel (70g), and the 1:1 mixture that uses sherwood oil and ether is as elutriant.Obtain 2-(5-bromo-3-Methoxy Pyridine-2-yl) methyl acetate (7.1g) thus; ¹ H NMR: (CDCl ₃) 3.71 (s, 3H), 3.83 (s, 2H), 3.85 (s, 3H), 7.3 (d, 1H), 8.21 (d, 1H); Mass spectrum: M+H ⁺260 and 262.

Under argon atmospher, successively with two valeryl two boron (8.23g), with methylene dichloride 1:1 compound [1,1 '-two (diphenylphosphino) ferrocene] dichloro palladium (II) (0.661g) and salt of wormwood (8.21g) add 2-(5-bromo-3-Methoxy Pyridine-2-yl) methyl acetate (7.02g) and 1, in the stirring the mixture of 4-diox (300ml).Stir the mixture that obtains, and be heated to 90 ℃ and reach 6 hours.Mixture is cooled to envrionment temperature, and concentrates by evaporation section.Residue dilutes with methylene dichloride, and water and salt solution is purging compound successively.Reclaim organic phase, through dried over mgso and evaporation.Obtain thus for the 2-[3-methoxyl group-5-of dark oily matter (4,4,5,5-tetramethyl--1,3, the pyridine-2-yl of 2-dioxane pentaborane-2-yl)] methyl acetate (16.8g), its contain some 1, the 4-diox; ¹ H NMR: (CDCl ₃) 1.35 (s, 6H), 3.69 (s, 3H), 3.87 (s, 3H), 3.92 (s, 2H), 7.5 (d, 1H), 8.49 (d, 1H); Mass spectrum: M+H ⁺308.

With the material dissolves that so obtains in methylene dichloride (300ml).(30%, 15ml), institute's mixture that obtains was in envrionment temperature vigorous stirring 2 hours to add aqueous hydrogen peroxide solution.Separate two-phase.The water dichloromethane extraction.Merge organic phase, use the salt water washing, through sal epsom and evaporation.The residue silica gel chromatography is an eluent with the polar compound that increases of ether and ethyl acetate.Obtain 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate (3.2g) thus; ¹ H NMR: (DMSOd ₆) 3.58 (s, 3H), 3.63 (s, 2H), 3.74 (s, 3H), 6.8 (d, 1H), 7.63 (d, 1H); Mass spectrumM+H ⁺198.

Under argon gas atmosphere, stir 4-chloro-6, the mixture of 7-dimethoxyquinazoline (0.552g), 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate (0.5g), cesium carbonate (2.41g) and DMF (5ml), and be heated to 90 ℃ and reach 1.5 hours.Mixture is cooled to envrionment temperature, and water (30ml) dilution.Institute obtains precipitation by filtered and recycled, washes with water, in 50 ℃ of vacuum-dryings.Obtain 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl thus] methyl acetate (0.823g); ¹ H NMR: (CDCl ₃) 3.74 (s, 3H), 3.87 (s, 3H), 3.93 (s, 2H), 4.08 (s, 3H), 7.17 (d, 1H), 7.36 (s, 1H), 7.54 (s, 1H), 8.17 (d, 1H), 8.63 (s, 1H); Mass spectrum: M+H ⁺386.

Stir the mixture 1.5 hours of the material, lithium hydroxide (0.103g), water (8ml) and the THF (8ml) that so obtain in envrionment temperature.Filtering mixt is by adding 1N aqueous hydrochloric acid (2.35ml) acidifying filtered solution.Separate the precipitation that obtains, water and ethyl acetate washing successively, and vacuum-drying.Obtain 3-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl thus] acetate (0.781g); ¹ H NMR: 3.73 (s, 2H), 3.81 (s, 3H), 3.98 (s, 3H), 4.0 (s, 3H), 7.42 (s, 1H), 7.55 (d, 1H), 7.58 (s, 1H), 8.11 (d, 1H), 8.6 (s, 1H); Mass spectrum: M+H ⁺372.

Embodiment 8

N-(1-sec.-propyl-1H-pyrazoles-4-yl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide

Use is similar to the method described in the embodiment 7, makes 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate and 4-amino-1H-1-sec.-propyl pyrazoles reaction, obtain title compound with 44% yield; ¹ H NMR: 1.37 (d, 6H), 3.78 (s, 2H), 3.81 (s, 3H), 3.99 (s, 3H), 4.0 (s, 3H), 4.44 (m, 1H), 7.41 (d, 1H), 7.54 (d, 1H), 7.58 (s, 1H), 7.87 (s, 1H), 8.11 (d, 1H), 8.59 (s, 1H), 10.13 (s, 1H); Mass spectrum: M+H ⁺479.

Embodiment 9

N-(3-dimethylamino methyl-5-aminomethyl phenyl)-2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide

Use is similar to the method described in the embodiment 7, makes 2-[5-(6,7-dimethoxyquinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate and 3-dimethylamino methyl-5-monomethylaniline reaction, obtain title compound with 56% yield; ¹ H NMR: 2.13 (s, 6H), 2.26 (s, 3H), 3.81 (s, 3H), 3.85 (s, 2H), 3.99 (s, 3H), 4.0 (s, 3H), 6.78 (s, 1H), 7.35 (m, 2H), 7.42 (s, 1H), 7.55 (d, 1H), 7.59 (s, 1H), 8.12 (d, 1H), 8.59 (s, 1H), 10.06 (s, 1H); Mass spectrum: M+H ⁺518.

Be prepared as follows 3-dimethylamino methyl-5-monomethylaniline as starting raw material:

Stir 1, the mixture of 3-dimethyl-5-oil of mirbane (15.15g), N-bromine succinimide (2g), benzoyl peroxide (0.484g) and tetracol phenixin (250ml), and be heated to backflow.Reaction mixture to heating in 4 hours adds more part of N-bromine succinimide (21g altogether) in batches.Mixture is cooled to envrionment temperature.Add sherwood oil (boiling point 60-80 ℃).Filtering mixt, the evaporation filtered solution obtains oily matter (25g), and it analyzes the mixture that is shown as 3-methyl-5-nitro bromotoluene (76%), unreacted starting raw material (about 19%) and 3-brooethyl-5-nitrobenzyl bromine (about 15%) through NMR.This mixture is used for next step.

Part (2.3g) oily matter that obtains like this is dissolved in the ethanol (5ml), adds dimethylamine (6 equivalent), in batches so that prevent remarkable heat release.Institute's reaction mixture that obtains stirred 12 hours in envrionment temperature.Evaporating mixture, the residue silica gel chromatography is an eluent with the polar compound that increases of methylene dichloride and ether.Obtain N thus, N-dimethyl-N-(3-methyl-5-nitro benzyl) amine (0.98g); ¹ H NMR: (DMSOd ₆) 2.17 (s, 6H), 2.43 (s, 3H), 3.48 (s, 2H), 7.58 (s, 1H), 7.94 (m, 2H); Mass spectrum: M+H ⁺195.

With N, the mixture of N-dimethyl-N-(3-methyl-5-nitro benzyl) amine (0.98g), platinum oxide (0.01g) and ethyl acetate (5ml) stirred 20 minutes under 1.8 hydrogen gas pressure.Remove by filter catalyzer, the evaporation filtered solution.So the material that obtains was in envrionment temperature vacuum-drying 2 hours.Obtain 3-dimethylamino methyl-5-monomethylaniline with 94% yield thus; ¹ H NMR: (DMSOd ₆) 2.09 (s, 6H), 2.12 (s, 3H), 3.16 (s, 2H), 4.87 (s, 2H), 6.24 (s, 2H), 6.31 (s, 1H).

Starting raw material

Except as otherwise noted, otherwise every kind of amine all is the commercially available material that gets.

(1) be prepared as follows 4-amino-1-methyl isophthalic acid H-pyrazoles:

With 4-nitropyrazole (2g) the stirred solution in 1N aqueous sodium hydroxide solution (20ml) of the slow adding of methyl-sulfate (5ml) temperature to 30 ℃, institute's mixture that obtains stirred 48 hours in this temperature.Mixture is cooled to envrionment temperature, precipitation separation, with the cold water dilution, and vacuum-drying.Obtain 1-methyl-4-nitro-1H-pyrazoles (1.5g) thus; ¹ H NMR: (DMSOd ₆) 3.91 (s, 1H), 8.24 (s, 1H), 8.85 (s, 1H).

Partly the mixture of (0.7g) material, platinum oxide (0.05g), ethyl acetate (5ml) and ethanol (15ml) that obtains like this stirred 2 hours under 3 hydrogen gas pressure.Remove by filter catalyzer, and the evaporation filtered solution.Obtain required starting raw material (0.6g) thus; ¹ H NMR: (DMSOd ₆) 3.64 (s, 3H), 6.86 (s, 1H), 6.97 (s, 1H).

(2) as the 4-amino-1 of starting raw material, 3-dimethyl-1H-pyrazoles can be by Sigma-Aldrich, Gillingham, and SP8 4XT UK) is purchased.This compound can also be according at Chemical Abstracts94 volume, summary numbers 103228 ( Zhurnal Obshchei Khimii, 1980, 50, 2106-9) middle disclosed method preparation.

(3) be prepared as follows 3-amino-5-sec.-propyl pyrazoles:

(hexane solution of 1.6M 14.06ml) adds acetonitrile (1.17ml) in batches, and mixture stirred 1 hour in this temperature to the n-butyllithium solution that is cooled to-78 ℃.Be added dropwise to ethyl isobutyrate (1.5ml), make reaction mixture be warming up to-45 ℃, stirred 2 hours in this temperature.By adding the 2N aqueous hydrochloric acid obtaining mixture is acidified to pH 2, and passes through evaporation concentration.Residue dichloromethane extraction, organic extract are through dried over mgso, and evaporation.Obtain 4-methyl-3-oxo valeronitrile (1.22g) thus; ¹ H NMR: (CDCl ₃) 1.18 (d, 6H), 2.82 (m, 1H), 3.52 (s, 2H).

The mixture heating up to 70 of material, hydrazine hydrate (0.288ml) and the ethanol (45ml) that will part (0.6g) so obtains ℃ reaches 12 hours.Evaporating solvent, residue are by silica gel chromatography, and the 19:1 mixture that uses methylene dichloride and methyl alcohol is as eluent.Obtain required starting raw material (0.574g) thus; ¹ H NMR: (DMSOd ₆) 1.13 (d, 6H), 2.76 (m, 1H), 4.31 (br s, 2H), 5.17 (br s, 1H), 11.05 (br s, 1H); Mass spectrum: M+H ⁺126.

(4) 3-amino-4-methyl isophthalic acid H-pyrazoles is described in J.Amer.Chem.Soc., 1992, 114, 7695 Hes J.Het.Chem., 1982, 19, 1267.

(5) be prepared as follows 5-amino-1-tertiary butyl-4-ethyl pyrazoles:

Under argon atmospher, the mixture solution in THF (4ml) is added dropwise to the stirred suspension of uncle's fourth potassium oxide (6.18g) in THF (40ml) with butyronitrile (2.18ml) and ethyl formate (2.11ml), and institute's mixture that obtains stirred 16 hours in envrionment temperature.Evaporating solvent, institute's solid suspension that obtains by filtering separation, washs with ether in ether.Solid is dissolved in the water, by adding the 2N aqueous hydrochloric acid solution is acidified to pH 4, and uses dichloromethane extraction.Organic extract is through dried over mgso.Obtain 2-formyl radical butyronitrile (1g) thus, it need not to be further purified and can use.

Ethanol (10ml) solution that successively 1-tertiary butyl hydrazine hydrate (1.72g) and acetate (0.59ml) is added 2-formyl radical butyronitrile (1g), with obtaining mixture heating up to refluxing 5 hours.Evaporating mixture adds saturated sodium bicarbonate aqueous solution.With the 2N aqueous sodium hydroxide solution mixture is alkalized to pH9, and use dichloromethane extraction.Organic extract is through dried over mgso and evaporation.Residue is by silica gel chromatography, use methylene dichloride to the solvent gradient of the 1:1 mixture of methylene dichloride and ethyl acetate as eluent.Obtain 5-amino-1-tertiary butyl-4-ethyl pyrazoles thus; ¹ H NMR: (CDCl ₃) 1.17 (t, 3H), 1.64 (s, 9H), 2.28 (q, 2H), 3.28 (br s, 2H), 7.15 (s, 1H); Mass spectrum: M+H ⁺168.

Use is similar in the method described in the embodiment 1, makes this amine and suitable acetate coupling, and institute's acid amides that obtains uses methyl-phenoxide and trifluoroacetic acid in 90 ℃ of processing, and the 1-tertiary butyl blocking group on the pyrazoles is split.

(6) be prepared as follows 5-amino-1-tertiary butyl-3, the 4-dimethyl pyrazole:

1-tertiary butyl hydrazine hydrochloride (1.55g) is added the 2-methyl-stirred solution of 3-oxo butyronitrile (1g) in ethanol (10ml), obtaining mixture heating up to 85 ℃ is reached 5 hours.Evaporation concentrated mixture, residue be by silica gel chromatography, use methylene dichloride to the solvent gradient of the 7:3 mixture of methylene dichloride and ethyl acetate as eluent.Obtain required amine (0.87g) thus; ¹ H NMR: (DMSOd ₆) 1.47 (s, 9H), 1.72 (s, 3H), 1.9 (s, 3H), 4.32 (br s, 2H); Mass spectrum: M+H ⁺168.

Use is similar to the method described in the embodiment 1, makes this amine and suitable acetate coupling, and institute's acid amides that obtains uses methyl-phenoxide and trifluoroacetic acid in 90 ℃ of processing, and the 1-tertiary butyl blocking group on the pyrazoles is split.

(7) be prepared as follows 5-amino-1-tertiary butyl-4-ethyl-3-methylpyrazole:

Under argon atmospher, the mixture solution in THF (40ml) is added dropwise to the stirred suspension of uncle's fourth potassium oxide (56.67g) in THF that is cooled to 15 ℃ with butyronitrile (20ml) and methyl acetate (23.54ml).Institute's mixture that obtains stirred 16 hours in envrionment temperature.Evaporating solvent, residue grinds under ether.Separate solid.Add entry (200ml), mixture is acidified to pH 4 by adding the 12N aqueous hydrochloric acid.Use the dichloromethane extraction aqueous mixture, organic extract is through dried over mgso and evaporation.Obtain 2-ethyl-3-oxo butyronitrile (6.8g) thus; ¹ H NMR: (CDCl ₃) 1.11 (t, 3H), 1.93 (m, 2H), 2.39 (s, 3H), 3.37 (m, 1H).

Hydrochloric acid 1-tertiary butyl hydrazine (5.11g) is added the 2-ethyl-stirred solution of 3-oxo butyronitrile (3.4g) in ethanol (35ml), with obtaining mixture heating up to refluxing 12 hours.Evaporating mixture.Add saturated sodium bicarbonate aqueous solution.With the 2N aqueous sodium hydroxide solution mixture is alkalized to pH 9.Use the ethyl acetate extraction mixture.Organic phase salt water washing is through dried over mgso and evaporation.Residue is by silica gel chromatography, use methylene dichloride to the solvent gradient of the 3:2 mixture of methylene dichloride and ethyl acetate as eluent.Obtain 5-amino-1-tertiary butyl-4-ethyl-3-methylpyrazole (2.95g) thus; ¹ H NMR: (CDCl ₃) 1.06 (t, 3H), 1.62 (s, 9H), 2.14 (s, 3H), 2.25 (q, 2H), 3.28 (br s, 2H).

Use is similar to the method described in the embodiment 1, makes this amine and suitable acetate coupling, and institute's acid amides that obtains uses methyl-phenoxide and trifluoroacetic acid in 90 ℃ of processing, and the 1-tertiary butyl blocking group on the pyrazoles is split.

(8) be prepared as follows the 5-amino-1-tertiary butyl-3-ethyl-4-methylpyrazole:

Under argon atmospher, to the stirred solution of Diisopropylamine (17.52ml) in THF (100ml) that is cooled to-78 ℃ slowly add n-Butyl Lithium (hexane solution of 2.5M, 50ml).The solution that obtains remains in-78 ℃, slowly adds propionitrile (8.92ml).Mixture stirred 30 minutes in-78 ℃.Drip methyl propionate (6ml), mixture stirred 2 hours in-78 ℃.Make reaction mixture be warming up to 0 ℃, and add ice.Institute's solution that obtains passes through evaporation concentration, and is distributed between ether and the water.By adding the 6N aqueous hydrochloric acid aqueous solution is acidified to pH 2, and uses extracted with diethyl ether.Institute's organic phase that obtains is through dried over mgso and evaporation.Obtain 2-methyl-3-oxo valeronitrile (5.8g) thus; ¹ H NMR: (CDCl ₃) 1.35 (t, 3H), 1.51 (d, 3H), 2.69 (m, 1H), 2.82 (m, 1H), 3.48 (m, 1H).

Use has been similar to just the above method described in the paragraph (7), makes 1-tertiary butyl hydrazine hydrochloride and 2-methyl-3-oxo valeronitrile (5.8g) reaction.Obtain 5-amino-1-tertiary butyl-3-ethyl-4-methylpyrazole (6.64g) thus; ¹ H NMR: (CDCl ₃) 1.05 (t, 3H), 1.48 (s, 9H), 1.74 (s, 3H), 2.31 (q, 2H), 4.29 (br s, 2H); Mass spectrum: M+H ⁺182.

Use is similar to the method described in the embodiment 1, makes this amine and suitable acetate coupling, and institute's acid amides that obtains uses methyl-phenoxide and trifluoroacetic acid in 90 ℃ of processing, and the 1-tertiary butyl blocking group on the pyrazoles is split.

(9) be prepared as follows 3-amino-5-cyclopropyl pyrazoles:

Use is similar to the above method described in the paragraph (3), makes cyclopropane-1-ethyl formate and acetonitrile reaction, obtains cyclopropyl cyano group ketone, and it reacts with hydrazine hydrate again, obtains required starting raw material.

(10) be prepared as follows 5-amino-1-tertiary butyl-3,4-trimethylene pyrazoles:

Under nitrogen atmosphere, add 1-tertiary butyl hydrazine hydrochloride (1.5g) to the stirred solution of 2-oxo-cyclopentane-1-nitrile (1.09g) in ethanol (20ml), with obtaining mixture heating up to refluxing 2 hours.Evaporation concentrated mixture.Add entry to residue, then add the sodium bicarbonate aqueous solution of capacity, until stopping gas evolution.The institute's mixture that obtains extracted with diethyl ether, through dried over mgso, and evaporation.Obtain 5-amino-1-tertiary butyl-3 thus, 4-trimethylene pyrazoles (1.6g); ¹ H NMR: (CDCl ₃) 1.64 (s, 9H), 2.35 (m, 1H), 2.48 (m, 2H), 2.67 (m, 2H), 3.47 (br s, 2H); Matter Spectrum: M+H ⁺180.

Use is similar to the method described in the embodiment 1, makes this amine and suitable acetate coupling, and institute's acid amides that obtains uses methyl-phenoxide and trifluoroacetic acid in 90 ℃ of processing, and the 1-tertiary butyl blocking group on the pyrazoles is split.

(11) be prepared as follows 2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate:

Diethyl azodiformate (0.673ml) is added 4-chloro-7-hydroxyl-6-methoxyl group quinazoline (International Patent Application WO 03/064413, embodiment 4 wherein; 0.6g), the stirring the mixture of ethanol (0.182ml), triphenyl phosphine (1.12g) and methylene dichloride (12ml), institute's mixture that obtains stirred 10 minutes in envrionment temperature.Evaporating mixture, the residue silica gel chromatography is that the methylene dichloride of 17:3 to 4:1 and the mixture of ethyl acetate are eluent with the solvent gradient.Obtain to be solid 4-chloro-7-oxyethyl group-6-methoxyl group quinazoline (0.391g) thus; ¹ H NMR: (CDCl ₃) 1.58 (t, 3H), 4.07 (s, 3H), 4.29 (q, 2H), 7.32 (s, 1H), 7.39 (s, 1H), 8.86 (s, 1H).

Use is similar among the embodiment 7 and relevant last 2 methods that paragraph is partly described of preparation starting raw material, make the reaction of 4-chloro-7-oxyethyl group-6-methoxyl group quinazoline and 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate, obtained product lithium hydroxide hydrolysis.Obtain 2-[5-(7-oxyethyl group-6-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl thus] acetate.

(12) can following acquisition 2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate:

Use is similar among the embodiment 7 and relevant last 2 methods that paragraph is partly described of preparation starting raw material, make 4-chloro-6-oxyethyl group-7-methoxyl group quinazoline (Application No. 2006/0019975) and the reaction of 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate, obtained product lithium hydroxide hydrolysis.Obtain 2-[5-(6-oxyethyl group-7-methoxyl group quinazoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl thus] acetate.

Claims (11)

1. the quinazoline derivant of a formula I or its pharmacy acceptable salt:

X wherein ¹Be O or N (R ⁷), R wherein ⁷Be hydrogen or (1-8C) alkyl;

P is 0,1,2 or 3;

Each R ¹Group can be identical or different; be selected from halo; trifluoromethyl; cyano group; hydroxyl; sulfydryl; amino; carboxyl; (1-6C) alkoxy carbonyl; formamyl; (1-8C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkene oxygen base; (2-6C) alkynyloxy group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (2-6C) alkyloyl; (2-6C) alkanoylamino of alkanoylamino and N-(1-6C) alkyl-(2-6C)

Or be selected from the group of following formula:

Q ¹-X ²-

X wherein ²Be selected from O, S, SO, SO ₂, N (R ⁸), CO, CON (R ⁸), N (R ⁸) CO, OC (R ⁸) ₂And N (R ⁸) C (R ⁸) ₂, each R wherein ⁸Be hydrogen or (1-8C) alkyl, Q ¹Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-8C) cycloalkyl, (3-8C) cycloalkyl-(1-6C), (3-8C) cycloalkenyl group, (3-8C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)

And wherein at R ¹Any aryl in the substituting group; (3-8C) cycloalkyl; (3-8C) cycloalkenyl group; heteroaryl or heterocyclic radical are optional to carry 1; 2 or 3 substituting groups; described substituting group can be identical or different; be selected from halo; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; urea groups; (1-8C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkene oxygen base; (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; (2-6C) alkyloyl; (2-6C) alkanoyloxy; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); N-(1-6C) alkyl urea groups; the alkyl urea groups of N '-(1-6C); N '; N '-two-[(1-6C) alkyl] urea groups; N; N '-two-[(1-6C) alkyl] urea groups; N; N '; N '-three-[(1-6C) alkyl] urea groups; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C), or be selected from the group of following formula:

-X ³-R ⁹

X wherein ³For direct key or be selected from O and N (R ¹⁰), R wherein ¹⁰Be hydrogen or (1-8C) alkyl, R ⁹Be the alkyl of halo-(1-6C); the alkyl of hydroxyl-(1-6C); the alkyl of sulfydryl-(1-6C); (1-6C) alkyl of alkoxyl group-(1-6C); (1-6C) alkyl of alkylthio-(1-6C); (1-6C) alkyl of alkyl sulphinyl-(1-6C); (1-6C) alkyl of alkyl sulphonyl-(1-6C); the alkyl of cyano group-(1-6C); amino-(1-6C) alkyl; (1-6C) alkyl of alkylamino-(1-6C); two-[(1-6C) alkyl] amino-(1-6C) alkyl; (2-6C) alkyl of alkanoylamino-(1-6C); the alkyl of the alkanoylamino of N-(1-6C) alkyl-(2-6C)-(1-6C); (1-6C) alkyl of alkoxycarbonyl amino-(1-6C); the alkyl of urea groups-(1-6C); the alkyl of N-(1-6C) alkyl urea groups-(1-6C); the alkyl of the alkyl urea groups of N '-(1-6C)-(1-6C); N '; the alkyl of N '-two-[(1-6C) alkyl] urea groups-(1-6C); N; N '-two-[(1-6C) alkyl] urea groups-(1-6C) alkyl or N; N '; the alkyl of N '-three-[(1-6C) alkyl] urea groups-(1-6C), or be selected from the group of following formula:

-X ⁴-Q ²

X wherein ⁴For direct key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen or (1-8C) alkyl, Q ²Be the optional alkyl of the alkyl of 1 or 2 substituent aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C) that carries, described substituting group can be identical or different, be selected from halo, hydroxyl, (1-8C) alkyl and (1-6C) alkoxyl group

And wherein at R ¹Optional (1-3C) alkylenedioxy group that carries of any aryl, heteroaryl or heterocyclic radical in the last substituting group,

And wherein at R ¹Optional 1 or 2 oxo or the sulfo-substituting group of carrying of any heterocyclic radical in the substituting group,

And wherein at R ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halos or (1-8C) alkyl substituent and/or be selected from following substituting group of carrying on the group: hydroxyl; sulfydryl; amino; cyano group; carboxyl; formamyl; urea groups; (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) alkanoyloxy; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); N-(1-6C) alkyl urea groups; the alkyl urea groups of N '-(1-6C); N '; N '-two-[(1-6C) alkyl] urea groups; N; N '-two-[(1-6C) alkyl] urea groups; N; N '; N '-three-[(1-6C) alkyl] urea groups; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C)

And wherein at R ¹Adjacent carbons on any in the substituting group (2-6C) alkylidene chain is optional to be inserted into the following group of being selected from of this chain and to separate: O, S, SO, SO ₂, N (R ¹²), CO, CH (OR ¹²), CON (R ¹²), N (R ¹²) CO, N (R ¹²) CON (R ¹²), SO ₂N (R ¹²), N (R ¹²) SO ₂, CH=CH and C ≡ C, wherein R ¹²Be hydrogen or (1-8C) alkyl, maybe when the group that inserts be N (R ¹²) time, R ¹²Also can be (2-6C) alkyloyl;

Q is 0,1 or 2;

Each R ²Group can be identical or different, be selected from halo, trifluoromethyl, cyano group, carboxyl, hydroxyl, amino, formamyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyl, the alkyl of halo-(1-6C), the alkyl of hydroxyl-(1-6C), (1-6C) alkyl of alkoxyl group-(1-6C), the alkyl of cyano group-(1-6C), the alkyl of carboxyl-(1-6C), (1-6C) alkyl of alkoxy carbonyl-(1-6C), amino-(1-6C) alkyl, (1-6C) alkyl of alkylamino-(1-6C), two-[(1-6C) alkyl] amino-(1-6C) alkyl, the alkyl of formamyl-(1-6C), the alkyl of N-(1-6C) alkyl-carbamoyl-(1-6C), N, the alkyl of N-two-[(1-6C) alkyl] formamyl-(1-6C), (2-6C) alkyl of the alkanoylamino of alkyl of alkanoylamino-(1-6C) and N-(1-6C) alkyl-(2-6C)-(1-6C);

R ³Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl or (2-8C) alkynyl;

R ⁴Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, the alkyl of halo-(1-6C), the alkyl of hydroxyl-(1-6C), (1-6C) alkyl of alkoxyl group-(1-6C), the alkyl of cyano group-(1-6C), the alkyl of carboxyl-(1-6C), amino-(1-6C) alkyl, (1-6C) alkyl of alkylamino-(1-6C), two-[(1-6C) alkyl] amino-(1-6C) alkyl, the alkyl of formamyl-(1-6C), the alkyl of N-(1-6C) alkyl-carbamoyl-(1-6C), N, the alkyl of N-two-[(1-6C) alkyl] formamyl-(1-6C), (1-6C) alkyl of alkoxy carbonyl-(1-6C), (2-6C) alkyl of the alkanoylamino of alkyl of alkanoylamino-(1-6C) or N-(1-6C) alkyl-(2-6C)-(1-6C);

Or R ³And R ⁴The carbon atom that connects with them forms (3-8C) cycloalkyl;

R ⁵Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl or (2-8C) group of alkynyl or following formula:

-X ⁵-R ¹³

X wherein ⁵For direct key or be selected from O and N (R ¹⁴), R wherein ¹⁴Be hydrogen or (1-8C) alkyl, R ¹³Be the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C) or cyano group-(1-6C);

Ring A is 6-unit's monocycle or 10-unit's two cyclophane rings or 5-or 6-unit's monocycle or 9-or 10-unit two ring hetero-aromatic rings, and described hetero-aromatic ring contains 3 ring hetero atoms that are selected from oxygen, nitrogen and sulphur at the most;

R is 0,1,2 or 3; With

Each R ⁶Group can be identical or different; be selected from halo; trifluoromethyl; cyano group; hydroxyl; sulfydryl; amino; carboxyl; formamyl; sulfamyl; urea groups; (1-8C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (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; (2-6C) alkyloyl; (2-6C) alkanoyloxy; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); the alkyl urea groups of N '-(1-6C); N '; N '-two-[(1-6C) alkyl] urea groups; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C), or be selected from the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶For direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-8C) alkyl, R ¹⁵Be the alkyl of halo-(1-6C); the alkyl of hydroxyl-(1-6C); the alkyl of sulfydryl-(1-6C); (1-6C) alkyl of alkoxyl group-(1-6C); (1-6C) alkyl of alkylthio-(1-6C); (1-6C) alkyl of alkyl sulphinyl-(1-6C); (1-6C) alkyl of alkyl sulphonyl-(1-6C); the alkyl of cyano group-(1-6C); amino-(1-6C) alkyl; (1-6C) alkyl of alkylamino-(1-6C); two-[(1-6C) alkyl] amino-(1-6C) alkyl; (2-6C) alkyl of alkanoylamino-(1-6C); the alkyl of the alkanoylamino of N-(1-6C) alkyl-(2-6C)-(1-6C); the alkyl of carboxyl-(1-6C); (1-6C) alkyl of alkoxy carbonyl-(1-6C); the alkyl of formamyl-(1-6C); the alkyl of N-(1-6C) alkyl-carbamoyl-(1-6C); N; the alkyl of N-two-[(1-6C) alkyl] formamyl-(1-6C); the alkyl of sulfamyl-(1-6C); the alkyl of N-(1-6C) alkylsulfamoyl group-(1-6C); N; the alkyl of N-two-[(1-6C) alkyl] sulfamyl-(1-6C); the alkyl of urea groups-(1-6C); the alkyl of N-(1-6C) alkyl urea groups-(1-6C); the alkyl of the alkyl urea groups of N '-(1-6C)-(1-6C); N '; the alkyl of N '-two-[(1-6C) alkyl] urea groups-(1-6C); N; the alkyl of N '-two-[(1-6C) alkyl] urea groups-(1-6C); N; N '; the alkyl of N '-three-[(1-6C) alkyl] urea groups-(1-6C); (1-6C) alkyl of the alkanesulfonyl amino of alkyl of alkanesulfonyl amino-(1-6C) or N-(1-6C) alkyl-(1-6C)-(1-6C), or be selected from the group of following formula:

-X ⁷-Q ³

X wherein ⁷For direct key or be selected from O, S, SO, SO ₂, N (R ¹⁷), CO, CH (OR ¹⁷), CON (R ¹⁷), N (R ¹⁷) CO, N (R ¹⁷) CON (R ¹⁷), SO ₂N (R ¹⁷), N (R ¹⁷) SO ₂, C (R ¹⁷) ₂O, C (R ¹⁷) ₂S and C (R ¹⁷) ₂N (R ¹⁷), each R wherein ¹⁷Be hydrogen or (1-8C) alkyl, Q ³Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-8C) cycloalkyl, (3-8C) cycloalkyl-(1-6C), (3-8C) cycloalkenyl group, (3-8C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)

Perhaps two R ⁶Group forms span together on ring A be the divalent group of adjacent ring position, and described divalent group is selected from OC (R ¹⁸) ₂O, OC (R ¹⁸) ₂C (R ¹⁸) ₂O, OC (R ¹⁸) ₂C (R ¹⁸) ₂, C (R ¹⁸) ₂OC (R ¹⁸) ₂, C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂, C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂, OC (R ¹⁸) ₂N (R ¹⁹), N (R ¹⁹) C (R ¹⁸) ₂N (R ¹⁹), N (R ¹⁹) C (R ¹⁸) ₂C (R ¹⁸) ₂, N (R ¹⁹) C (R ¹⁸) ₂C (R ¹⁸) ₂C (R ¹⁸) ₂, OC (R ¹⁸) ₂C (R ¹⁸) ₂N (R ¹⁹), C (R ¹⁸) ₂N (R ¹⁹) C (R ¹⁸) ₂, CO.N (R ¹⁸) C (R ¹⁸) ₂, N (R ¹⁸) CO.C (R ¹⁸) ₂, N (R ¹⁹) C (R ¹⁸) ₂CO, CO.N (R ¹⁸) CO, N (R ¹⁹) N (R ¹⁸) CO, N (R ¹⁸) CO.N (R ¹⁸), O.CO.N (R ¹⁸), O.CO.C (R ¹⁸) ₂And CO.OC (R ¹⁸) ₂, each R wherein ¹⁸Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl or (2-8C) alkynyl, and R wherein ¹⁹Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl or (2-6C) alkyloyl,

And wherein at R ⁶Any aryl in the group; (3-8C) cycloalkyl; (3-8C) cycloalkenyl group; heteroaryl or heterocyclic radical are optional to carry 1; 2 or 3 substituting groups; described substituting group can be identical or different; be selected from halo; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; urea groups; (1-8C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkene oxygen base; (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; (2-6C) alkyloyl; (2-6C) alkanoyloxy; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); the alkyl urea groups of N '-(1-6C); N '; N '-two-[(1-6C) alkyl] urea groups; N-(1-6C) alkyl urea groups; N; N '-two-[(1-6C) alkyl] urea groups; N; N '; N '-three-[(1-6C) alkyl] urea groups; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C), or be selected from the group of following formula:

-X ⁸-R ²⁰

X wherein ⁸For direct key or be selected from O and N (R ²¹), R wherein ²¹Be hydrogen or (1-8C) alkyl, R ²⁰Be the alkyl of halo-(1-6C); the alkyl of hydroxyl-(1-6C); the alkyl of sulfydryl-(1-6C); (1-6C) alkyl of alkoxyl group-(1-6C); (1-6C) alkyl of alkylthio-(1-6C); (1-6C) alkyl of alkyl sulphinyl-(1-6C); (1-6C) alkyl of alkyl sulphonyl-(1-6C); the alkyl of cyano group-(1-6C); amino-(1-6C) alkyl; (1-6C) alkyl of alkylamino-(1-6C); two-[(1-6C) alkyl] amino-(1-6C) alkyl; (2-6C) alkyl of the alkanoylamino of alkyl of alkanoylamino-(1-6C) or N-(1-6C) alkyl-(2-6C)-(1-6C), or be selected from the group of following formula:

-X ⁹-Q ⁴

X wherein ⁹For direct key or be selected from O, CO and N (R ²²), R wherein ²²Be hydrogen or (1-8C) alkyl, Q ⁴Be the optional alkyl of the alkyl of 1 or 2 substituent aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C) that carries, described substituting group can be identical or different, be selected from halo, hydroxyl, (1-8C) alkyl and (1-6C) alkoxyl group

And wherein at R ⁶Optional (1-3C) alkylenedioxy group that carries of any aryl, heteroaryl or heterocyclic radical in the group,

And wherein at R ⁶Optional 1 or 2 oxo or the sulfo-substituting group of carrying of any heterocyclic radical in the group,

And wherein at R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halos or (1-8C) alkyl substituent and/or be selected from following substituting group of carrying on the group: hydroxyl; sulfydryl; amino; cyano group; carboxyl; formamyl; urea groups; (2-8C) alkenyl; (2-8C) alkynyl; (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) alkanoyloxy; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); the alkyl urea groups of N '-(1-6C); N '; N '-two-[(1-6C) alkyl] urea groups; N-(1-6C) alkyl urea groups; N; N '-two-[(1-6C) alkyl] urea groups; N; N '; N '-three-[(1-6C) alkyl] urea groups; N-(1-6C) alkylsulfamoyl group; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) the alkanesulfonyl amino of amino and N-(1-6C) alkyl of alkanesulfonyl-(1-6C)

And wherein at R ⁶Adjacent carbons on any (2-6C) alkylidene chain in the group is optional to be inserted into the following group of being selected from of this chain and to separate: O, S, SO, SO ₂, N (R ²³), N (R ²³) CO, CON (R ²³), N (R ²³) CON (R ²³), CO, CH (OR ²³), N (R ²³) SO ₂, SO ₂N (R ²³), CH=CH and C ≡ C, wherein R ²³Be hydrogen or (1-8C) alkyl, maybe when the group that inserts be N (R ²³) time, R ²³Also can be (2-6C) alkyloyl.

2. quinazoline derivant or its pharmacy acceptable salt according to the formula I of claim 1, wherein:

X ¹Be O;

P is 2, R ¹Group is positioned at 6 and 7, in 6 R ¹Group is selected from cyano group, hydroxyl, methoxycarbonyl, ethoxy carbonyl, formamyl, methoxyl group, oxyethyl group, propoxy-, N-methylamino formyl radical, N-ethylamino formyl radical, N; N-formyl-dimethylamino, N; N-diethylamino formyl radical, tetramethyleneimine-1-base carbonyl, morpholino carbonyl, piperidino-(1-position only) carbonyl and piperazine-1-base carbonyl are in 7 R 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 ¹Any heterocyclic radical in the last substituting group randomly carries 1 or 2 substituting group, described substituting group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene radical dioxy base, ethylidene dioxy base 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 randomly by 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 N-replace

And R wherein ¹Any heterocyclic radical in the last substituting group all randomly carries 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is all at each described CH, CH ₂Or CH ₃Randomly carry one or more cl radicals on the group or be selected from following substituting group: hydroxyl, amino, methoxyl group, methyl sulphonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino and N-sec.-propyl-N-methylamino;

Q be 0 or q be 1, and be positioned at 2 (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazine basic ring; With

R be 0 or r be 1 or 2,1 R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group), each R ⁶Group can be identical or different, is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino,

Perhaps r is 1 or 2,1 R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group), and be the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or O, R ¹⁵Be methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, the 3-hydroxypropyl, methoxymethyl, the 1-methoxy ethyl, the 2-methoxy ethyl, 1-methoxyl group-1-methylethyl, the 3-methoxy-propyl, cyano methyl, the 1-cyano ethyl, the 2-cyano ethyl, 3-cyano group propyl group, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the 3-aminopropyl, the methylamino-methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, 3-methylamino-propyl group, the ethylamino methyl, 1-ethylamino ethyl, 2-ethylamino ethyl, 1-ethylamino-1-methylethyl, 3-ethylamino propyl group, the sec.-propyl amino methyl, 1-sec.-propyl amino-ethyl, dimethylamino methyl, the 1-dimethylaminoethyl, the 2-dimethylaminoethyl, the 3-dimethylamino-propyl, phenyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl group, pyrrolidyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, the pyrrolidyl methyl, 2-(pyrrolidyl) ethyl, 3-(pyrrolidyl) propyl group, the morpholinyl methyl, 2-(morpholinyl) ethyl, 3-(morpholinyl) propyl group, piperidino methyl, 2-(piperidyl) ethyl, 3-(piperidyl) propyl group, the homopiperidinyl methyl, the piperazinyl methyl, 2-(piperazinyl) ethyl, 3-(piperazinyl) propyl group or high piperazinyl methyl, prerequisite is to work as X ⁶During for O, at X ⁶And R ¹⁵Between any heteroatoms of group at least 2 carbon atoms are arranged,

And R wherein ⁶Any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical all randomly carry and are selected from following substituting group: fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino, and R ⁶Any such aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical randomly carry the further substituting group that is selected from methylol, cyano methyl, amino methyl, methylamino-methyl and dimethylamino methyl in the group,

And any second R that exists ⁶Group all is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino.

3. quinazoline derivant or its pharmacy acceptable salt according to the formula I of claim 1, wherein:

Ring A contains 3 5-unit monocycle hetero-aromatic rings that are selected from the ring hetero atom of oxygen, nitrogen and sulphur at the most; And

X ¹, p, R ¹, q, R ², R ³, R ⁴, R ⁵, r and R ⁶Has any implication that limits in the claim 1 separately.

4. quinazoline derivant or its pharmacy acceptable salt according to the formula I of claim 1, wherein:

X ¹Be O;

P is 2, and R ¹Group is positioned at 6-and 7-position, at 6 R ¹Group is selected from cyano group, hydroxyl, methoxycarbonyl, ethoxy carbonyl, formamyl, methoxyl group, oxyethyl group, propoxy-, N-methylamino formyl radical, N-ethylamino formyl radical, N; N--formyl-dimethylamino, N; N-diethylamino formyl radical, tetramethyleneimine-1-base carbonyl, morpholino carbonyl, piperidino-(1-position only) carbonyl and piperazine-1-base carbonyl, and at 7 R ¹Group be 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-4 H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4 H-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 ¹Any heterocyclic radical in the last substituting group all randomly carries 1 or 2 substituting group, described substituting group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, ethyl, methoxyl group, methylene radical dioxy base, ethylidene dioxy base 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 randomly by 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 N-replace

And R wherein ¹On substituting group in any heterocyclic radical group all randomly carry 1 or 2 oxo substituting group,

And R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is all at each described CH, CH ₂Or CH ₃Randomly carry one or more cl radicals on the group or be selected from following substituting group: hydroxyl, amino, methoxyl group, methyl sulphonyl, methylamino-, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino and N-sec.-propyl-N-methylamino;

Q be 0 or q be 1, R ²Group is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring; With

R be 0 or r be 1 or 2,1 R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group), each R ⁶Group can be identical or different, be selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin

Perhaps r is 1 or 2,1 R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group), and be the group of following formula:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or O, R ¹⁵Be methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, the 3-hydroxypropyl, methoxymethyl, the 1-methoxy ethyl, the 2-methoxy ethyl, 1-methoxyl group-1-methylethyl, the 3-methoxy-propyl, cyano methyl, the 1-cyano ethyl, the 2-cyano ethyl, 3-cyano group propyl group, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the 3-aminopropyl, the methylamino-methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, 3-methylamino-propyl group, the ethylamino methyl, 1-ethylamino ethyl, 2-ethylamino ethyl, 1-ethylamino-1-methylethyl, 3-ethylamino propyl group, the sec.-propyl amino methyl, 1-sec.-propyl amino-ethyl, dimethylamino methyl, the 1-dimethylaminoethyl, the 2-dimethylaminoethyl, the 3-dimethylamino-propyl, phenyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl group, pyrrolidyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, the pyrrolidyl methyl, 2-(pyrrolidyl) ethyl, 3-(pyrrolidyl) propyl group, the morpholinyl methyl, 2-(morpholinyl) ethyl, 3-(morpholinyl) propyl group, piperidino methyl, 2-(piperidyl) ethyl, 3-(piperidyl) propyl group, the homopiperidinyl methyl, the piperazinyl methyl, 2-(piperazinyl) ethyl, 3-(piperazinyl) propyl group or high piperazinyl methyl, prerequisite is to work as X ⁶During for O, at X ⁶And R ¹⁵Between any heteroatoms of group at least 2 carbon atoms are arranged,

And R wherein ⁶Any aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical all randomly carry and are selected from following substituting group: fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino, and R ⁶Any such aryl in the group, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical group all randomly carry and are selected from following further substituting group: methylol, cyano methyl, amino methyl, methylamino-methyl and dimethylamino methyl,

And any second R that exists ⁶Group all is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino.

5. quinazoline derivant or its pharmacy acceptable salt according to the formula I of claim 1, wherein:

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position; be selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, formamyl, (1-6C) alkoxy carbonyl, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy, (2-6C) chain oxy-acetylene, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N; N-two-[(1-6C) alkyl] formamyl and

Q is 1, R ²Group is positioned at the 2-position (with respect to C (R ³) (R ⁴) group), be selected from halo, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N, N-two-[(1-6C) alkyl] formamyl;

And X ¹, R ³, R ⁴, R ⁵, ring A, r and R ⁶Has any implication that in claim 1, limits separately.

6. quinazoline derivant or its pharmacy acceptable salt according to the formula I of claim 1, wherein:

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position; be selected from halo, trifluoromethyl, cyano group, hydroxyl, amino, formamyl, (1-6C) alkoxy carbonyl, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy, (2-6C) chain oxy-acetylene, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N; N-two-[(1-6C) alkyl] formamyl

Q is 1, R ²Group is positioned at the 2-position (with respect to C (R ³) (R ⁴) group), be selected from halo, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N, N-two-[(1-6C) alkyl] formamyl;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen;

Ring A contains 3 5-unit monocycle hetero-aromatic rings that are selected from the ring hetero atom of oxygen, nitrogen and sulphur at the most; And

R is 0,1,2 or 3, each R of existence ⁶Group can be identical or different, is selected from that halo, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C) alkanoylamino.

7. quinazoline derivant or its pharmacy acceptable salt according to the formula I of claim 1, wherein:

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position; be selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, formamyl, methoxycarbonyl, ethoxy carbonyl, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, dimethylamino, N-methylamino formyl radical and N; the N-formyl-dimethylamino

Q is 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from fluoro, chloro, trifluoromethyl, cyano group, formamyl, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, dimethylamino, N-methylamino formyl radical and N, N-formyl-dimethylamino;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen;

Ring A is furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring; And

R is 1 or 2, each R ⁶Group can be identical or different, is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino and diethylin.

8. quinazoline derivant or its pharmacy acceptable salt according to the formula I of claim 1, wherein:

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group is positioned at 6-and/or 7-position, and is selected from fluoro, cyano group, formamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methylamino formyl radical and N, N-formyl-dimethylamino;

Q is 1, and is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is a methoxyl group;

R ³And R ⁴The hydrogen of respectively doing for oneself;

R ⁵Be hydrogen;

Ring A is the different phonetic azoles base of 2-oxazolyl, 3-, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl and 2-thiazolyl; And

R is 1 or 2, and each R that exists ⁶Group is selected from methyl, ethyl, propyl group and sec.-propyl.

9. one kind prepares according to the quinazoline derivant of the formula I of claim 1 or the method for its pharmacy acceptable salt, and described method comprises:

(a) make the quinazoline of formula II

Wherein L is a displaceable group, p and R ¹Has any implication that in claim 1, limits, except protecting any functional group where necessary, with 2-(2-pyridyl) the ethanamide reaction of formula III

X wherein ¹, q, R ², R ³, R ⁴, R ⁵, ring A, r and R ⁶Have any implication that in claim 1, limits, except protecting any functional group where necessary, remove any blocking group of existence then;

(b) make the quinazoline of formula VII

Or its reactive derivatives, wherein p, R ¹, X ¹, q, R ², R ³And R ⁴Has any implication that in claim 1, limits, except protecting any functional group where necessary, with the amine coupling of formula VI

R wherein ⁵, ring A, r and R ⁶Have any implication that in claim 1, limits, except protecting any functional group where necessary, remove any blocking group of existence then;

(c) for preparing wherein at least one R ¹Group is those formulas I compound of following formula group

Q ¹-X ²-

Q wherein 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 ²Be Sauerstoffatom, make the quinazoline of formula VIII

Wherein p, R ¹, X ¹, q, R ², R ³, R ⁴, R ⁵, ring A, r and R ⁶Have any implication that in claim 1, limits separately, except protecting any functional group where necessary,, wherein except protecting any functional group where necessary, remove any blocking group of existence then with suitable pure coupling;

(d) for preparing wherein R ⁶Group is formula-X ⁶-R ¹⁵Those formulas I compound of group, wherein X ⁶Have any implication and the R that in claim 1, limit ¹⁵(1-6C) alkyl for amino-replacement makes such formula I compound: R wherein ⁶Group is formula-X ⁶-R ¹⁵Group, wherein R ¹⁵Be (1-6C) alkyl of halo-replacement, with suitable amine or the reaction of nitrogen heterocyclic ring based compound;

(e) for preparing wherein R ⁶Group is formula-X ⁶-R ¹⁵Those formulas I compound of group, X wherein ⁶Have any implication and the R that in claim 1, limit ¹⁵(1-6C) alkyl for amino-replacement makes wherein R ⁶Group is formula-X ⁶-R ¹⁵The formula I compound of group, wherein R ¹⁵For formyl radical or (2-6C) alkyloyl, carry out reductive amination;

(f) for preparing wherein R ⁵Be those formulas I compound of (1-8C) alkyl, make wherein R with the alkylating agent that is fit to ⁵Formula I alkylation for hydrogen; Or

(g) for preparing wherein R ¹Those formulas I compound for carboxyl cuts wherein R ¹Formula I compound for (1-6C) alkoxy carbonyl;

And when needing the pharmacy acceptable salt of formula I quinazoline derivant, can obtain by the reaction of described quinazoline derivant and suitable acid.

10. medicinal compositions, it comprises according to the formula I quinazoline derivant of claim 1 or its pharmacy acceptable salt, and the pharmaceutically acceptable diluent or carrier of blended with it.