CN101432276A - Quinoline derivatives - Google Patents

Abstract

The invention concerns quinoline derivatives of Formula (I) or a pharmaceutically-acceptable salt thereof, wherein each of X<1>, 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

Quinoline

The present invention relates to some new quinoline or its pharmacy acceptable salt, it has antitumour activity, therefore can be used for treating the method for human or animal body.The invention still further relates to the preparation described quinoline method, comprise the medicinal compositions of described derivative and the purposes in methods of treatment thereof, for example be used for preventing or treat the purposes of medicine of warm-blooded animal such as people's cancer, comprise being used for prevention or treatment solid tumor disease in preparation.

For the abnormal cell growth that occurs in cell proliferation disorders such as psoriatic and the cancer, present many treatment plans use and suppress DNA synthetic compound.This compounds pair cell generally has toxicity, but its toxic action to quick somatoblast such as tumour cell can be useful.Has the potential that strengthens selectively acting by the alternative route that suppresses the anticarcinogen that the mechanism of DNA outside synthetic plays a role.

Eukaryotic cell is constantly to replying the multiple different extracellular signal that can link up between each cell in the organism.Multiple somatic reaction in these Signal Regulation cells comprises propagation, differentiation, apoptosis and migration.The extracellular signal adopts multiple different soluble factor form, comprises somatomedin and paracrine, autocrine and endocrine factor.By combining with the specificity transmembrane receptor, the somatomedin part is conveyed to signal pathway in the cell with the extracellular signal, thereby causes individual cells pair cell external signal to be replied.Many these signal transduction processes are utilized the reversibility process of protein (comprising specificity kinases and Phosphoric acid esterase) phosphorylation.

Since phosphorylation is important regulatory mechanism like this in the signal transduction process, so this process distortion causes abnormal cells differentiation, conversion and growth also not at all surprising.For example, have been found that this cell becomes carcinous because the part of cell DNA is converted into oncogene.Several these type of oncogene encoded protein matter are growth factor receptorses, as Tyrosylprotein kinase.Tyrosylprotein kinase also can sport the composition activated form, 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 the people's gene group, wherein about 60 kinds is receptor type, and about 30 kinds is non-receptor type.According to they bonded growth factor families, with these kinases be divided into 20 kinds of receptor tyrosine kinase subfamilies and 10 kinds of nonreceptor tyrosine kinase subfamilies (Robinson etc., Oncogene, 2000,19,5548-5557).Classification comprises the EGF family such as the EGF of receptor tyrosine kinase, TGF α, Neu and erbB acceptor, the Regular Insulin family of receptor tyrosine kinase such as Regular Insulin and IGF1 acceptor and Regular Insulin associated receptor (IRR), III class family such as Thr6 PDGF BB (PDGF) receptor tyrosine kinase with receptor tyrosine kinase, as PDGF α and PDGF beta receptor, STEM CELL FACTOR receptor tyrosine kinase (SCF RTK is 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 been found that this type of sudden change and the Tyrosylprotein kinase of overexpression form are present in the common human cancer of major part, as leukemia, mammary cancer, prostate cancer, comprise the nonsmall-cell lung cancer (NSCLC) of adenocarcinoma of lung and squamous cell lung carcinoma, the gastrointestinal cancer that comprises colorectal carcinoma, the rectum cancer and cancer of the stomach, bladder cancer, the esophageal carcinoma, ovarian cancer and carcinoma of the pancreas.When the more people's tumor tissues of test, the rate that is widely current and the dependency of Tyrosylprotein kinase will be further established in expection.For example, be presented at EGFR tyrosine-kinase enzyme mutant and/or overexpression in several human cancers, described cancer comprises lung, neck, gi tract, mammary gland, oesophagus, ovary, uterus, bladder and thyroid tumour.

Thr6 PDGF BB (PDGF) is the main mitogen of phoirocyte and other cell type.Pdgf receptor (comprising PDGF α and PDGF beta receptor) isozyme shows the enhanced activity in vascular disease (for example atherosclerosis and restenosis, as the restenosis process of sacculus angioplasty and heart arter bypass secondary).This type of enhanced pdgf receptor kinase activity also sees other cell proliferation disorders such as fibrotic disease (as renal fibrosis, liver cirrhosis, pulmonary fibrosis and multicystic dysplastic kidney), glomerulonephritis, inflammatory diseases (as rheumatoid arthritis and inflammatory bowel), multiple sclerosis, psoriatic, skin hypersensitivity, atopic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.

Pdgf receptor also can promote cancer and leukemic cell transformation by the autocrine stimulation of cell growth.Shown that pdgf receptor kinase suddenlys change and/or overexpression in several human cancers, the tumour that comprises lung (nonsmall-cell lung cancer and small cell lung cancer), stomach and intestine (as colon, rectum and gastric tumor), prostate gland, mammary gland, kidney, liver, brain (as glioblastoma), oesophagus, ovary, pancreas and skin (as dermatofibrosarcoma), and leukemia and lymphoma such as chronic granulocytic leukemia (CML), chronic Myelomonocyte leukemia (CMML), acute lymphoblastic leukemia (ALL) and multiple myeloma.Mode by the pdgf receptor Tyrosylprotein kinase strengthens cell signal and can promote the various kinds of cell effect, comprises cell proliferation, cell migration and invasion and attack, Premeabilisation of cells and apoptosis.

Therefore, the expection of the activity of antagonism pdgf receptor kinase can help treating various kinds of cell proliferative disease such as cancer, particularly suppresses tumor growth and transfer and suppresses leukemic progress.

In addition, PDGF relates to vasculogenesis, and this is the process to the very crucial formation neovascularity of tumor growth.Usually, vasculogenesis plays a significant role in as fetal development, wound healing and female reproductive function several sections.Yet bad or pathologic vessels generates and multiple disease-related, comprises diabetic retinopathy, psoriatic, cancer, rheumatoid arthritis, sebaceous cyst, Kaposi ' s sarcoma and vascular tumor.By promoting the growth-stimulating vasculogenesis of endotheliocyte.Identified that having vitro endothelial cell growth promotes active a few peptide species, comprised acid and Prostatropin (aFGF and bFGF) and vascular endothelial growth factor (VEGF).By limiting its receptor expression, to compare with bFGF with aFGF, the growth factor activity of VEGF is relative specificity to endotheliocyte.Up-to-date evidence shows that VEGF generates normal and pathologic vessels and the blood vessel infiltration all is important stimulant.This cytokine is expressed by inducing endothelial cell propagation, proteolytic enzyme and migration induction of vascular bud is planted phenotype, then causes forming kapillary, promotes to form high infiltration, jejune blood vessel network, and this is the feature that pathologic vessels 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.Known two kinds of these relevant RTK are that Flt-1 and KDR combine with the VEGF high-affinity.

Therefore, the expection of the activity of antagonism VEGF can help treating with vasculogenesis and/or vascular permeability increases relevant multiple disorders such as cancers, particularly suppresses tumor development.

Known severally have pdgf receptor kinase and suppress active compound and will be used for clinical development.The known 2-phenylamino pyrimidine derivatives (STI571 that is called imatinib; Nature Reviews, 2002, 1, 493-502; Cancer Research, 1996, 56, 100-104) can suppress the pdgf receptor kinase activity, but its present clinical application is according to its other activity as the BCR-ABL kinase inhibitor, to treat CML.STI571 suppress with people's glioblastoma be U343 and the U87 growth of injecting the glioblastoma that the nude mouse brain produces ( Cancer Research, 2000, 60, 5143-5150).This compound also suppress growth in the body of dermatofibrosarcoma cell culture ( Cancer Research, 2001, 61, 5778-5783).Pdgf receptor kinase according to compound suppresses active, is just carrying out the clinical trial about 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).

Suppress EGF and/or pdgf receptor Tyrosylprotein kinase from International Patent Application WO 92/20642 known some aryl and heteroaryl compound.Wherein disclose some quinoline, but wherein specifically do not mention 2-(2-pyridyl) acetamide derivative; Particularly, wherein specifically do not mention 2-(2-pyridyl) acetamide derivative of quinolyl-4 oxygen base-replacement.

Many disclosed patent applications such as International Patent Application WO 96/09294 open 4-phenylamino quinazoline, 4-aryloxy quinazoline, 4-phenylamino quinoline or 4-aryloxy quinoline have the tyrosine-kinase enzyme inhibition activity.Yet, wherein specifically do not mention 2-(2-pyridyl) acetamide compound of quinolyl-4 oxygen base-replacement.

For example, can suppress the MEK receptor tyrosine kinase from International Patent Application WO 02/36570 and WO 02/44166 known some aryl and heteroaryl compound.Wherein disclose some quinoline, but wherein specifically do not mention 2-(2-pyridyl) acetamide derivative; Particularly, wherein specifically do not mention 2-(2-pyridyl) acetamide derivative of quinolyl-4 oxygen base-replacement.

For example, suppress jak kinase from International Patent Application WO 02/092571 known some 3-carbamyl quinoline compound.Wherein disclose the 2-phenyl-acetamides derivative of some quinolyl-4 amino-replacement, but wherein specifically do not mention 2-(2-pyridyl) acetamide derivative; Particularly, wherein specifically do not mention N-aryl-or N-heteroaryl-2-(2-pyridyl) acetamide derivative.

Suppress vegf receptor tyrosine kinase from the 2-phenyl-acetamides compound of International Patent Application WO 2005/021554 known thienopyridine-replacement, blood vessel formation against function is provided.Wherein disclosed embodiment 87 is single 2-phenyl-acetamides of planting quinolyl-4 oxygen base-replacement, i.e. compound N-(5-chloropyridine-2-yl)-2-[4-(7-methoxy quinoline-4-base oxygen base) phenyl] ethanamide.

Our 2-(2-pyridyl) acetamide compound that has been surprised to find some new quinolyl-4 oxygen base-replacement has the effective active of inhibition of cell proliferation disease now.Think that described compound by suppressing the pdgf receptor Tyrosylprotein kinase, can be used for treating cell proliferation disorders, as antitumor action is provided.

Another feature of height proliferative disease such as cancer is the cellular pathways of damage control cell cycle progress, and the cell cycle relates to the orderly cascade of protein phosphorylation in normal eukaryotic cell.As for signal transduction mechanism, several protein kinase family all brings into play keying action in the cell cycle cascade.That broad research is cell cycle protein dependent kinase family (CDK) in these Cycle Regulation agent.Specific CDK is very important in the startup and the adjustment of the active cell cycle progress of specified time.For example, CDK4 albumen is by making retinoblastoma gene product pRb phosphorylation, and control enters the cell cycle (G0-G1-S transition), and described phosphorylation stimulates pRb to discharge transcription factor E2F, enters transcribing of S phase indispensable gene then increase.The catalytic activity of CDK4 obtains stimulating by combining with chaperone Cyclin D.One of cancer and best evidence of contacting directly between the cell cycle are to observe Cyclin D1 gene amplification and Cyclin D protein level increases in many human tumors.

Recently, identified the protein kinase different with the CDK family structure, described protein kinase is brought into play keying action in the adjusting cell cycle, and is also very important in tumour generates.They comprise Drosophila aurora and the proteic human homology's thing of S.cerevisiae Ipl1.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, it shows by G2 and mitotic expression and kinase activity peak.Observe the prompting cancer for several and relate to human aurora albumen, particularly Aurora-A and Aurora-B.By abolish expression and the function of Aurora-A with antisense oligonucleotide handler tumor cell line, cause cell cycle arrest, the performance antiproliferative effect.In addition, the micromolecular inhibitor that has proved Aurora-A and Aurora-B can have antiproliferative effect to human tumor cells.

International Patent Application WO 01/21594, WO 01/21596 and WO 01/21597 disclose some quinazoline derivant and have the Aurora kinase inhibiting activity, and described derivative carries phenylamino or the phenoxy group that is connected with the 4-position of quinazoline ring.Wherein specifically do not mention 2-(2-pyridyl) acetamide derivative; Particularly, wherein specifically do not mention 2-quinazoline-replacement or quinoline-replacement (2-pyridyl) acetamide derivative.

International Patent Application WO 01/55116 discloses some quinoline and has the Aurora kinase inhibiting activity, and described derivative carries the heteroaryl that is connected with the 4-position of quinoline ring by for example NH or O group.Wherein specifically do not mention 2-(2-pyridyl) acetamide derivative; Particularly, wherein specifically do not mention 2-(2-pyridyl) acetamide derivative of quinoline-replacement.

International Patent Application WO 02/00649, WO 03/055491, WO 04/058752, WO 04/058781 and WO 04/094410 disclose some quinazoline derivant and have the Aurora kinase inhibiting activity, and described derivative carries the 5-unit heteroaryl that is connected with the 4-position of quinazoline ring by for example NH or O group.Wherein do not mention 2-(2-pyridyl) acetamide derivative; Particularly, wherein specifically do not mention 2-(2-pyridyl) acetamide derivative of quinazoline-replacement.

As mentioned above, our 2-(2-pyridyl) acetamide compound that has been surprised to find some new quinolyl-4 oxygen base-replacement has the effective active of inhibition of cell proliferation disease now.Although do not wish to hint that compound disclosed by the invention only has pharmacological activity by the effect to one or both biological procedureses, but think that described compound can be used for treating cell proliferation disorders by the restraining effect of pdgf receptor Tyrosylprotein kinase, as antitumor action is provided.Specifically, think that compound of the present invention passes through the restraining 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 of anti-pdgf receptor family's Tyrosylprotein kinase such as PDGF α and/or PDGF beta receptor Tyrosylprotein kinase, but the active effect of inhibition of anti-other Tyrosylprotein kinase is lower, as anti-one or more other III class family receptors Tyrosylprotein kinase such as Flt3 receptor tyrosine kinase and CSF-1R Tyrosylprotein kinases, anti-EGF receptor tyrosine kinase, the active effect of inhibition of perhaps anti-vegf receptor tyrosine kinase such as KDR and Flt-1 is lower.And the effect of the pdgf receptor family particularly anti-PDGF beta receptor Tyrosylprotein kinase of the anti-Tyrosylprotein kinase of some compound of the present invention obviously is better than the effect of anti-EGF receptor tyrosine kinase or vegf receptor tyrosine kinase such as KDR.This compounds has enough effects, so that they can be with the pdgf receptor family of enough inhibition Tyrosylprotein kinases PDGF beta receptor Tyrosylprotein kinase particularly, the amount that the activity of anti-simultaneously EGF receptor tyrosine kinase or anti-vegf receptor tyrosine kinase such as KDR is very little is used.

Quinoline 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 halogeno-group; trifluoromethyl; cyano group; hydroxyl; sulfydryl; amino; carboxyl; (1-6C) alkoxy carbonyl; carbamyl; (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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; 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) perhaps is selected from the following formula group:

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 ¹It is 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)

R wherein 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 halogeno-group; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; carbamyl; 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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; (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 alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the group of following formula:

-X ³-R ⁹

X wherein ³Be direct key or be selected from O and N (R ¹⁰), R wherein ¹⁰Be hydrogen or (1-8C) alkyl, R ⁹It is the alkyl of halogeno-group-(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) perhaps is selected from the following formula group:

-X ⁴-Q ²

X wherein ⁴Be direct key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen or (1-8C) alkyl, Q ²It is 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 halogeno-group, hydroxyl, (1-8C) alkyl and (1-6C) alkoxyl group

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

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

R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halogeno-groups or (1-8C) alkyl substituent and/or be selected from hydroxyl of carrying on the group; sulfydryl; amino; cyano group; carboxyl; carbamyl; 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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; (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) substituting group of alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C)

R wherein ¹Adjacent carbons in the substituting group in any (2-6C) alkylidene chain is inserted into intrachain and is selected from 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 optional separation of group, R wherein ¹²Be hydrogen or (1-8C) alkyl, perhaps when the group that inserts be N (R ¹²) time, R ¹²It can also be (2-6C) alkyloyl;

Q is 0,1 or 2;

Each R ²Group can be identical or different, be selected from halogeno-group, trifluoromethyl, cyano group, carboxyl, amino, carbamyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylcarbamoyl group, N, N-two-[(1-6C) alkyl] carbamyl, 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 carbamyl-(1-6C), the alkyl of N-(1-6C) alkylcarbamoyl group-(1-6C), N, the alkyl of N-two-[(1-6C) alkyl] carbamyl-(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 halogeno-group-(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 carbamyl-(1-6C), the alkyl of N-(1-6C) alkylcarbamoyl group-(1-6C), N, the alkyl of N-two-[(1-6C) alkyl] carbamyl-(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);

Perhaps 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) alkynyl or following formula group:

-X ⁵-R ¹³

X wherein ⁵Be direct key or be selected from O and N (R ¹⁴), R wherein ¹⁴Be hydrogen or (1-8C) alkyl, R ¹³It is the alkyl of alkyl of the alkyl of the alkyl of halogeno-group-(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 dicyclo aromatic ring or 5-or 6-unit's monocycle or 9-or 10-unit dicyclo hetero-aromatic ring, has 3 ring hetero atoms that are selected from oxygen, nitrogen and sulphur at the most;

R is 0,1,2 or 3; And

Each R ⁶Group can be identical or different; be selected from halogeno-group; trifluoromethyl; cyano group; hydroxyl; sulfydryl; amino; carboxyl; carbamyl; 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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; (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 alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the following formula group:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-8C) alkyl, R ¹⁵It is the alkyl of halogeno-group-(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 carbamyl-(1-6C); the alkyl of N-(1-6C) alkylcarbamoyl group-(1-6C); N; the alkyl of N-two-[(1-6C) alkyl] carbamyl-(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 alkane sulfuryl amino of alkyl of alkane sulfuryl amino-(1-6C) or N-(1-6C) alkyl-(1-6C)-(1-6C) perhaps is selected from the following formula group:

-X ⁷-Q ³

X wherein ⁷Be 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 ³It is 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 together crosses over the upward divalent group of adjacent ring position of ring A, 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, wherein R ¹⁹Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl or (2-6C) alkyloyl,

R wherein 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 halogeno-group; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; carbamyl; 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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; (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 alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the following formula group:

-X ⁸-R ²⁰

X wherein ⁸Be direct key or be selected from O and N (R ²¹), R wherein ²¹Be hydrogen or (1-8C) alkyl, R ²⁰It is the alkyl of halogeno-group-(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) perhaps is selected from the following formula group:

-X ⁹-Q ⁴

X wherein ⁹Be direct key or be selected from O, CO and N (R ²²), R wherein ²²Be hydrogen or (1-8C) alkyl, Q ⁴It is the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), it is optional carry 1 or 2 can be identical or different substituting group, be selected from halogeno-group, hydroxyl, (1-8C) alkyl and (1-6C) alkoxyl group

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

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

R wherein ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halogeno-groups or (1-8C) alkyl substituent and/or be selected from hydroxyl of carrying on the group; sulfydryl; amino; cyano group; carboxyl; carbamyl; 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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; (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) substituting group of alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C)

R wherein ⁶Adjacent carbons is inserted into intrachain and is selected from O, S, SO, SO in interior any (2-6C) alkylidene chain of group 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), optional separation of group of CH=CH and C ≡ C, wherein R ²³Be hydrogen or (1-8C) alkyl, perhaps when the group that inserts be N (R ²³) time, R ²³It can also be (2-6C) alkyloyl.

In this manual, generic term " (1-8C) alkyl " comprises straight chain and branched-chain alkyl such as propyl group, sec.-propyl and the tertiary butyl, also comprise (3-8C) cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, also comprise (3-6C) cycloalkyl-(1-2C) alkyl such as cyclopropyl methyl, 2-cyclopropyl ethyl, cyclobutylmethyl, 2-cyclobutyl ethyl, cyclopentyl-methyl, 2-cyclopentyl ethyl, cyclohexyl methyl and 2-cyclohexyl ethyl.But when mentioning individual alkyl, only refer in particular to straight chain type, when mentioning individual branched-chain alkyl, only refer in particular to branched chain type, when mentioning individual cycloalkyl, only refer in particular to 5-unit ring as " cyclopentyl " as " sec.-propyl " as " propyl group ".Similar convention is applicable to other generic term, comprise (3-6C) cycloalkyl oxy and (3-5C) alkoxyl group of cycloalkyl-(1-2C) as (1-6C) alkoxyl group, as 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 cyclopentyl methoxyl group; (1-6C) alkylamino comprises (3-6C) cycloalkyl amino and (3-5C) alkylamino of cycloalkyl-(1-2C), as methylamino, ethylamino, propyl group amino, cyclopropyl amino, cyclobutyl amino, cyclohexyl amino, cyclopropyl methylamino, 2-cyclopropyl ethylamino, cyclobutylmethyl amino, 2-cyclobutyl ethylamino and cyclopentyl-methyl amino; That two-[(1-6C alkyl] amino comprise is two-[(3-6C) cycloalkyl] amino and two-[(3-5C) cycloalkyl-(1-2C) alkyl] amino, and as dimethylamino, diethylamino, 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 understand owing to there are one or more unsymmetrical carbons, above some formula I compound of Xian Dinging can exist opticity or racemic form, and definition of the present invention comprises having above-mentioned active any this type of opticity or racemic form.Available organic chemistry standard technique well known in the art is synthesized the opticity form, for example by the synthetic or resolution of racemic form with the opticity raw material.Similarly, the available above-mentioned activity of hereinafter mentioning of standard laboratory technical evaluation.

Should understand some the formula I compound that above limits and to have tautomerism.Particularly, tautomerism can influence the hetero-aromatic ring in the ring A definition or carry 1 or 2 oxo or the substituent R of sulfo- ¹Or R ⁶Heterocyclic radical in the group.Should understand definition of the present invention and comprise having above-mentioned active any this type of tautomeric form or its mixture, be not limited only to any tautomeric form of naming among interior use of general formula or the embodiment.For example, ring A can be a pyrazolyl.For example, when this type of pyrazolyl at 3-position and CON (R ⁵) when the N atom of group connects, can there be the compound tautomerism mixture that comprises 1H-pyrazole-3-yl and 1H-pyrazoles-5-base.Usually, only name any of this type of tautomeric form hereinafter among the embodiment, any in this type of tautomeric form perhaps only is provided in any relevant general formula hereinafter.

In structural formula I, should understand on the 2-position of quinoline ring has hydrogen atom.Should understand R thus ¹Substituting group is 3-, 5-, 6-, 7-or the 8-position to be positioned at the quinoline ring only, and promptly the 2-position keeps not being substituted.Usually, the 3-position of quinoline ring also keeps not being substituted, and perhaps the R1 substituting group of 3-position is a cyano group on the quinoline ring.More commonly, R ¹Substituting group is only to be positioned at 5-, 6-or the 7-position on the quinoline ring.Also more commonly, R ¹Substituting group is 6-and/or the 7-position to be positioned at the quinoline ring only.

In formula I structure, that will also be understood that is any R that can be present on the pyridyl of center ²Group can be positioned at any effective position.Normally, there is not R ²Group (q=0).Perhaps, there is single R ²Group.More generally, single R ²Group is positioned at 2-position (relative C (R ³) (R ⁴) group).

In structural formula I, should understand any R ⁶Group can be in ring A and go up any active position.For example, R when ring A is 6-unit ring ⁶Group can be positioned at 3-or 4-position (with respect to CON (R ⁵) group), for example, when being 5-unit ring, ring A can be positioned at the 3-position (with respect to CON (R ⁵) group).

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

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

When ' R when Q ' group is (3-8C) cycloalkyl ¹Or R ⁶In the group any one ' Q ' group (Q ¹Or Q ³) or any ' Q ' group in the desired value of (3-8C) cycloalkyl be for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, dicyclo [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, (3-8C) cycloalkyl of formation was, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl.

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

When ' R when Q ' group is heteroaryl ¹Or R ⁶In the group any one ' Q ' group (Q ¹-Q ⁴) or ' desired value of heteroaryl in Q ' group is, for example have at the most 5 and be selected from oxygen, the aromatics 5-of the ring hetero atom of nitrogen and sulphur or 6-unit's monocycle or 9-or 10-unit dicyclo, as furyl, 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 naphthyridinyl.

When ' R when Q ' group is heterocyclic radical ¹Or R ⁶In the group any one ' Q ' group (Q ¹-Q ⁴) or any ' Q ' group in the desired value of heterocyclic radical be, for example, have at the most 5 and be selected from oxygen, the heteroatomic non-aromatics of nitrogen and sulphur first monocycle of 3-10 saturated or fractional saturation or dicyclo, as epoxy ethyl, epoxypropyl, tetrahydrofuran base, THP trtrahydropyranyl, the epoxy heptyl, tetrahydro-thienyl, 1,1-dioxo tetrahydro-thienyl, tetrahydro thiapyran base, 1,1-dioxo tetrahydro thiapyran base, the nitrogen heterocyclic propyl group, azelidinyl, 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-azabicyclo [2.2.1] heptyl, quinuclidinyl, chromanyl, different chromanyl, 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 desired value that carries 1 or 2 oxo or substituent this type of group of 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 desired value was for example heteroaryl methyl, 2-heteroaryl ethyl and 3-heteroaryl propyl group.When there not being the alkyl of heteroaryl-(1-6C), but when for example having the alkyl of the 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), the present invention includes ' the corresponding desired value of Q ' group.

When ring A is 6-unit monocycle or 10-unit's dicyclo aromatic ring or has 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 dicyclo hetero-aromatic ring, it is phenyl for example, 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 naphthyridinyl.Usually, ring A is phenyl ring, furan nucleus, pyrrole ring, thiphene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazoles ring, thiazole ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring.Usually, ring A is phenyl ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring.When ring A is when having at the most the 5-unit monocycle hetero-aromatic ring of 3 ring hetero atoms that are selected from oxygen, nitrogen and sulphur, be for example furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group or triazolyl.Usually, ring A Shi oxazole ring, isoxazole ring, imidazole ring, pyrazoles ring, thiazole ring, isothiazole Huan, oxadiazole ring or thiadiazoles ring.

Any ' R ' group (R ¹-R ²³) or R ¹, R ²Or R ⁶The desired value of various groups comprises in the substituting group :-

For halogeno-group: fluoro, chloro, bromo and iodo;

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

Cyclobutyl, cyclohexyl, cyclohexyl methyl and 2-cyclopropyl 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 sulphinyl: methylsulfinyl and ethyl sulfinyl;

For (1-6C) alkyl sulphonyl: methylsulfonyl and ethylsulfonyl;

For (1-6C) alkylamino: methylamino, ethylamino, propyl group amino, sec.-propyl amino and butyl amino;

Two-[(1-6C) alkyl] amino: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylaminoethyl;

For (1-6C) alkoxy carbonyl: methoxycarbonyl, ethoxycarbonyl, third oxygen carbonyl and the tertbutyloxycarbonyl;

For N-(1-6C) alkyl carboxamide N-methyl carbamyl, N-ethyl carbamyl and N-

Base: propyl group carbamyl;

For N, N-two-[(1-6C) alkyl] N, N-dimethylamino formyl radical, N-ethyl-N-methyl ammonia

Carbamyl: formyl radical and N, N-diethyl amino formyl radical;

For (2-6C) alkyloyl: ethanoyl, propionyl and isobutyryl;

For (2-6C) alkanoyloxy: acetoxyl group and propionyloxy;

For (2-6C) alkanoylamino: kharophen and propionamido;

For N-(1-6C) alkyl-(2-6C) N-methyl kharophen and N-methyl-prop amido;

Alkanoylamino:

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

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

Urea groups: base;

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

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

Urea groups: and N-ethyl-N '-methyl urea groups;

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

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

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

Base:

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

Sulfamyl:

For (1-6C) alkane Herbicidal sulphonylamino methylsulfonyl amino and ethylsulfonylamino;

Base:

Amino and the N-methyl second sulphonyl for the N-methyl methylsulfonyl of N-(1-6C) alkyl-(1-6C)

The alkane sulfuryl amino: base is amino;

For the alkyl of halogeno-group-(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, the 3-trifluoro propyl;

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

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

For (1-6C) alkoxyl group-(1-6C) methoxymethyl, ethoxyl methyl, 1-methoxyl group second

Alkyl: base, 2-methoxy ethyl, 2-ethoxyethyl group and 3-methoxy-propyl;

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

Alkyl: base, 1-methylmercaptoethyl and 3-methylthio group propyl group;

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

-(1-6C) alkyl: 2-methylsulfinyl ethyl, 1-methylsulfinyl ethyl 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-cyano group propyl group;

For amino-(1-6C) alkyl: amino methyl, 2-amino-ethyl, 1-amino-ethyl, 3-aminopropyl, 1-aminopropyl and 5-aminopropyl;

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

-(1-6C) alkyl: amino-ethyl, 2-methylamino ethyl, 2-ethylamino ethyl and 3-methylamino propyl group;

For two-[(1-6C) alkyl] amino dimethylaminomethyls, diethylamino methyl, 1-

-(1-6C) alkyl: dimethyl aminoethyl, 2-dimethyl aminoethyl and 3-dimethylaminopropyl;

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

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

For N-(1-6C) alkyl-(2-6C) N-methyl acetylamino methyl, N-methyl-prop amido

The alkyl of alkanoylamino-(1-6C): methyl, 2-(N-methyl kharophen) ethyl and 1-(N-methyl kharophen) ethyl;

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

Base-(1-6C) alkyl: methyl, tert-butoxycarbonyl amino methyl and 2-methoxycarbonyl amino-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) alkyl] N ', N '-dimethyl urea ylmethyl, 2-(N ', N '-dimethyl

The 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) alkyl] N, N '-dimethyl urea ylmethyl, 2-(N, N '-dimethyl urea

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

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

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

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 3-ethoxycarbonyl propyl;

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

For N-(1-6C) alkyl carboxamide N-methyl carbamyl methyl, N-ethyl carbamyl

Base-(1-6C) alkyl: methyl, N-propyl group carbamyl methyl, 1-(N-methyl carbamyl) ethyl, 1-(N-ethyl carbamyl) ethyl, 2-(N-methyl carbamyl) ethyl, 2-(N-ethyl carbamyl) ethyl and 3-(N-methyl carbamyl) propyl group;

For N, N-two-[(1-6C) alkyl] N, N-dimethylamino formyl radical methyl, N-ethyl-N-

The alkyl of carbamyl-(1-6C): methyl carbamyl methyl; N; N-diethyl amino formyl radical methyl; 1-(N; N-dimethylamino formyl radical) ethyl; 1-(N; N-diethyl amino formyl radical) ethyl; 2-(N; N-dimethylamino formyl radical) ethyl; 2-(N; N-diethyl amino formyl radical) ethyl; 3-(N, N-dimethylamino formyl radical)

Propyl group and 4-(N, N-dimethylamino formyl radical) butyl;

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

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

Base-(1-6C) alkyl: base) ethyl, 2-(N-methyl sulfamyl) ethyl and 3-(N-methyl sulfamyl) propyl group;

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

The alkyl of sulfamyl-(1-6C): basic sulfamyl) ethyl, 2-(N, N-dimethylamino alkylsulfonyl) ethyl and 3-(N, N-dimethylamino alkylsulfonyl) propyl group;

For (1-6C) alkane Herbicidal sulphonylamino methylsulfonyl amino methyl, 2-(methylsulfonyl amino)

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

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

The alkane sulfuryl amino of alkane sulfuryl amino-(1-6C)) ethyl and 1-(N-methyl methylsulfonyl

Base: ethyl amino).

Can be present in R ¹Or R ⁶The desired value of (1-3C) alkylenedioxy group in the group is, for example methylene radical dioxy base, ethylidene dioxy base, isopropylidene dioxy base or ethylidene dioxy base, and its Sauerstoffatom is positioned at adjacent ring position.

Limit as mentioned, work as R ¹Group forms formula Q ¹-X ²-group and for example X be OC (R ⁸) ₂During linking group, be OC (R ⁸) ₂The carbon atom of linking group rather than Sauerstoffatom are connected with the quinoline ring, and Sauerstoffatom connects Q ¹Group.Similarly, limit as mentioned, work as R ⁶Group forms formula-X ⁷-Q ³Group and X for example ⁷Be C (R ¹⁷) ₂During the O linking group, be C (R ¹⁷) ₂The Sauerstoffatom of O linking group and Q ³Group connects.

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

Limit R as mentioned ¹Or R ⁶Adjacent carbons in the group in any (2-6C) alkylidene chain can be inserted into intrachain group such as O, CON (R ¹²) or CON (R ²³) and the optional respectively separation of C ≡ C.For example, the alkylidene chain that the O atom inserts in the 4-methoxyl group butoxy produces for example 2-(2-methoxy ethoxy) oxyethyl group, for example, the ethylidene chain that C ≡ C group inserts in the 2-hydroxyl-oxethyl produces 4-hydroxyl fourth-2-alkynyloxy base, for example, the CONH group inserts the interior ethylidene chain of 3-methoxy propoxy and produces for example 2-(2-methoxyl group kharophen) oxyethyl group.

Limit as mentioned, 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 halogeno-groups or (1-8C) during alkyl substituent, be fit to have 1 halogeno-group or (1-8C) alkyl substituent be present on each described CH group, be fit to have 1 or 2 this type of substituting group to be present in each described CH ₂On the group, be fit to have 1,2 or 3 this type of substituting group to be present in each described CH ₃On the group.

Limit as mentioned, work as R ¹Or R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Choose wantonly on the group when carrying the substituting group that limits as mentioned, thus the suitable R of Xing Chenging ¹Or R ⁶Group comprises that for example (1-8C) alkyl of hydroxyl-replacement is (as hydroxymethyl, 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 of (1-6C) alkylamino of hydroxyl-replacement-(2-6C) (as the amino propoxy-of 2-hydroxy-3-methyl), 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) the alkylamino group (as 3-dimethylamino-2-hydroxypropyl amino) of the alkylamino (as 2-hydroxy-3-methyl amino propyl amino) of (1-6C) alkylamino of hydroxyl-replacement-(2-6C) and hydroxyl-replacement.

Limit as mentioned, work as R ¹Or R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Choose wantonly on the group when carrying the substituting group that limits as mentioned, thus the suitable R of Xing Chenging ¹Or R ⁶Group also comprises, for example two-[(1-6C) alkyl] of the alkyl (as 2-hydroxy-3-methyl aminopropyl and 2-hydroxyethyl amino 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 two-(2-hydroxyethyl) amino methyl).

Will also be understood that as mentioned to limit, work as R ¹Or R ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Choose wantonly on the group when carrying the substituting group that limits as mentioned, the examples of such optional substituting group can be present in the be present in R that above limits ¹Or R ⁶CH, CH in the substituting group on aryl, heteroaryl or the heterocyclic radical in the group ₂Or CH ₃On the group.For example, if R ¹Or R ⁶When group comprises the aryl that replaced by (1-8C) alkyl or heteroaryl, (1-8C) CH, the CH that groups can be therein ₂Or CH ₃A kind of substituting group that is above limited on the group is optional to be replaced.For example, if R ¹Or R ⁶Group comprises the heteroaryl that is replaced by the alkyl of for example (1-6C) alkylamino-(1-6C), the then terminal CH of (1-6C) alkylamino ₃Group can be further by for example (1-6C) alkyl sulphonyl or (2-6C) alkyloyl replacement.And, for example, if R ¹Or R ⁶Group comprises heterocyclic radical, for example piperidyl or the piperazinyl that is replaced by for example (2-6C) alkyloyl on its nitrogen-atoms, the then terminal CH of (2-6C) alkyloyl ₃Group can be further by for example two-[(1-6C) alkyl] amino replacements.For example, R ¹Or R ⁶Group can comprise N-(2-dimethylamino ethanoyl) piperidin-4-yl or 4-(2-dimethylamino ethanoyl) piperazine-1-base.And, for example, if R ¹Or R ⁶Group comprises heterocyclic radical, for example azelidinyl, piperidyl or the piperazinyl that is replaced by for example (2-6C) alkyloyl on its nitrogen-atoms, the then CH of (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.

Limit two R as mentioned ⁶Group can form divalent group such as OC (R together ¹⁸) ₂O strides across the adjacent ring position on the ring A.When ring A is for example during phenyl, the proper group of Xing Chenging is 2 thus, 3-methylenedioxyphenyl base or 3,4-methylenedioxyphenyl base.When there being other optional R ⁶When group such as halogeno-group, the proper group of Xing Chenging is a 6-fluoro-2 for example thus, 3-methylenedioxyphenyl base.And A is for example phenyl and two R when ring ⁶Group forms for example OC (R together ¹⁸) ₂C (R ¹⁸) ₂During group, the proper group of Xing Chenging is for example 2 thus, 3-Dihydrobenzofuranes-5-base 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, the proper group of Xing Chenging for example is thus, 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) ₂During group, the proper group of Xing Chenging is for example 2-oxoindoline-5-base or 2-oxoindoline-6-base thus.

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

Will also be understood that the suitable pharmaceutically acceptable solvate of formula I compound also forms an aspect of of the present present invention.Suitable pharmaceutically acceptable solvate for example is, hydrate such as semihydrate, monohydrate, dihydrate or trihydrate or its be amount (alternative quantity) alternately.

Will also be understood that the suitable pharmaceutically acceptable prodrug of formula I compound also forms an aspect of of the present present invention.Therefore, can give the The compounds of this invention of prodrug forms, just in human or animal body, decompose the compound that discharges The compounds of this invention.Available prodrug changes the physicals and/or the pharmacokinetics feature of The compounds of this invention.When comprising suitable group or substituting group (connectivity can be regulated group), The compounds of this invention can form prodrug.The example of prodrug comprise can the carboxyl of formula I compound or hydroxyl form can body in the cracked ester derivative and can the carboxyl of formula I compound or amino form can body in the cracked amide derivatives.

Therefore, the present invention includes those formulas I compound that limits as mentioned that obtains or in human or animal body, obtain by its prodrug cracking by organic synthesis.Therefore, the present invention includes those formulas I compound that produces by methodology of organic synthesis, also comprise this compounds that in human or animal body, produces by the precursor compound metabolism, that is to say that formula I compound can be the compound that synthetic compound that produces or metabolism produce.

The suitable pharmaceutically acceptable prodrug of formula I compound is to be fit to give human or animal body according to rational medical judgment, and good medicine is learned the prodrug of active and excessive toxicity invariably.

Various forms of prodrugs have been described in for example following document :-

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

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

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 page or leaf (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.

The suitable pharmaceutically acceptable prodrug of formula I compound with carboxyl is the ester of cleavable in its body for example.Comprise that the cleavable ester is in the body of formula I compound of carboxyl, for example cracking produces the pharmaceutically acceptable ester of parent acid in human or animal body.Suitable pharmaceutically acceptable carboxyl ester comprises that (1-6C) alkyl ester is (as methyl; the ethyl and the tertiary butyl); (1-6C) alkoxy methyl ester (as the methoxyl group methyl esters); (1-6C) the alkanoyloxymethyl ester is (as the pivaloyl group methyl ester; 3-phthalidyl ester); (3-8C) alkyl ester (as cyclopentylcarbonyl oxygen ylmethyl and 1-cyclohexyl-carbonyl oxygen base ethyl ester) of naphthene base carbonyl oxygen base-(1-6C); 2-oxo-1; 3-dioxa cyclopentenyl methyl ester (as 5-methyl-2-oxo-1,3-Dioxol-4-yl methyl ester) and (1-6C) alkyl ester (as methoxycarbonyl oxygen ylmethyl and 1-methoxycarbonyl oxygen base ethyl ester) of alkoxy-carbonyl oxy-(1-6C).

The suitable pharmaceutically acceptable prodrug of formula I compound with hydroxyl is the ester or the ether of for example interior cleavable of its body.Comprising in the body of formula I compound of hydroxyl cleavable ester or ether is, for example cracking produces the pharmaceutically acceptable ester or the ether of parent hydroxy compound in human or animal body.The pharmaceutically acceptable one-tenth ester group that is fit to hydroxyl comprises inorganic ester such as phosphoric acid ester (comprising phosphoramidic acid cyclic ester (phosphoramidic cyclic ester)).Other the pharmaceutically acceptable one-tenth ester group that is fit to hydroxyl 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] carbamyl, 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.The pharmaceutically acceptable one-tenth ether group that is fit to hydroxyl comprises alpha-acyloxy alkyl such as acetoxy-methyl and pivaloyl oxygen ylmethyl.

The suitable pharmaceutically acceptable prodrug of formula I compound with carboxyl is the acid amides of cleavable in its body for example, as with the acid amides of the alkylamine (as benzene methanamine) 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) or the formation of its ester.

It is suitable that to have the amino pharmaceutically acceptable prodrug of formula I compound be the amide derivatives of cleavable in its body for example.The pharmaceutically acceptable acid amides from amino that is fit to comprises, for example with the benzoyl of (1-10C) alkyloyl such as ethanoyl, benzoyl, phenylacetyl and replacement and the acid amides of phenylacetyl formation.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.

Can partly act in the body by one or more metabolite performance formulas I compound that in human or animal body, forms behind the giving construction I compound.As noted above, also can bring into play the interior effect of body of formula I compound by the metabolism of precursor compound (prodrug).

Concrete new The compounds of this invention comprises for example quinoline or its pharmacy acceptable salt of formula I, wherein unless otherwise noted, otherwise X ¹, p, R ¹, q, R ², R ³, R ⁴, R ⁵, ring A, r and R ⁶Have above or any implication that following paragraph (a)-(iii) limits :-

(a) X ¹Be O or NH;

(b) X ¹Be O;

(c) X ¹Be NH;

(d) p is 0,1,2 or 3, each R of existence ¹Group is selected from halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, carboxyl, (1-6C) alkoxy carbonyl, carbamyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylcarbamoyl group and N; N-two-[(1-6C) alkyl] carbamyl perhaps is selected from the following formula group:

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),

R wherein ¹Any aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried 1,2 or 3 substituting group in the last substituting group; described substituting group can be identical or different, be selected from halogeno-group, trifluoromethyl, hydroxyl, amino, carbamyl, (1-8C) alkyl, (2-8C) alkenyl, (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) alkylcarbamoyl group, N, NThe alkanoylamino of-two-[(1-6C) alkyl] carbamyls, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C) perhaps is selected from the following formula group:

-X ³-R ⁹

X wherein ³Be direct key or be selected from O and N (R ¹⁰), R wherein ¹⁰Be hydrogen or (1-8C) alkyl, R ⁹Be alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogeno-group-(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), perhaps be selected from the following formula group:

-X ⁴-Q ²

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

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

R wherein ¹On substituting group in any heterocyclic radical is optional carries 1 or 2 oxo substituting group,

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

R wherein ¹Adjacent carbons in the substituting group in any (2-6C) alkylidene chain is inserted into the optional separation of intrachain group, and described group is selected from O, N (R ¹²), CON (R ¹²), N (R ¹²) CO, CH=CH and C ≡ C, wherein R ¹²Be hydrogen or (1-8C) alkyl, perhaps when the group that inserts be N (R ¹²) time, R ¹²It also can be (2-6C) alkyloyl;

(e) p is 1 or 2, R ¹Group is positioned at 6-and/or 7-position, is positioned at the R of 6-position ¹Group is selected from halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, carboxyl, (1-6C) alkoxy carbonyl, carbamyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylcarbamoyl group and N; N-two-[(1-6C) alkyl] carbamyl is positioned at the R of 7-position ¹Group is selected from halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, carboxyl, (1-6C) alkoxy carbonyl, carbamyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylcarbamoyl group and N; N-two-[(1-6C) alkyl] carbamyl perhaps is selected from the following formula group:

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),

R wherein ¹Any aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried 1,2 or 3 substituting group in the last substituting group; described substituting group can be identical or different, be selected from halogeno-group, trifluoromethyl, hydroxyl, amino, carbamyl, (1-8C) alkyl, (2-8C) alkenyl, (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) alkylcarbamoyl group, N, NThe alkanoylamino of-two-[(1-6C) alkyl] carbamyls, (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C) perhaps is selected from the following formula group:

-X ³-R ⁹

X wherein ³Be direct key or be selected from O and N (R ¹⁰), R wherein ¹⁰Be hydrogen or (1-8C) alkyl, R ⁹Be alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogeno-group-(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), perhaps be selected from the following formula group:

-X ⁴-Q ²

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

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

R wherein ¹On substituting group in any heterocyclic radical is optional carries 1 or 2 oxo substituting group,

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

R wherein ¹Adjacent carbons in the substituting group in any (2-6C) alkylidene chain is inserted into the optional separation of intrachain group, and described group is selected from O, N (R ¹²), CON (R ¹²), N (R ¹²) CO, CH=CH and C ≡ C, wherein R ¹²Be hydrogen or (1-8C) alkyl, perhaps when the group that inserts be N (R ¹²) time, R ¹²It also can be (2-6C) alkyloyl;

(f) p is 1,2 or 3, one R ¹Group is a 3-cyano group, any 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; carbamyl; 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; propyl group amino; dimethylamino; diethylin; dipropyl amino; N-methyl carbamyl; N-ethyl carbamyl; N; N-dimethylamino formyl radical and N; N-diethyl amino formyl radical perhaps is selected from the following formula group:

Q ¹-X ²-

X wherein ²Be selected from O, NH, CO, CONH, NHCO and OCH ₂, Q ¹It is phenyl, phenmethyl, 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

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; carbamyl; methyl; ethyl; allyl group; 2-propynyl; methoxyl group; methyl sulphonyl; methylamino; dimethylamino; ethanoyl; propionyl; isobutyryl; N-methyl carbamyl; N; N-dimethylamino formyl radical; methylene radical dioxy base; ethylidene dioxy base and isopropylidene dioxy base, perhaps choose wantonly and carry 1 substituting group that is selected from following formula:

-X ³-R ⁹

X wherein ³Be direct key or be selected from O and NH, R ⁹It is 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, 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, dimethylaminomethyl, the 2-dimethyl aminoethyl, the 3-dimethylaminopropyl, acetylamino methyl or N-methyl acetylamino methyl are selected from the following formula group:

-X ⁴-Q ²

X wherein ⁴Be 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

R wherein ¹On substituting group in any heterocyclic radical is optional carries 1 or 2 oxo substituting group,

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, kharophen and N-methyl kharophen

R wherein ¹Adjacent carbons in the substituting group in any (2-6C) alkylidene chain is inserted into the optional separation of intrachain group, and described group is selected from O, NH, N (Me), N (COMe), CONH, NHCO, CH=CH and C ≡ C;

(g) p is 2, R ¹Group is positioned at 5-and 7-position or 6-and 7-position, R ¹Group can be identical or different; be selected from cyano group; hydroxyl; amino; carboxyl; methoxycarbonyl; ethoxy carbonyl; carbamyl; methyl; ethyl; propyl group; butyl; vinyl; ethynyl; methoxyl group; oxyethyl group; propoxy-; isopropoxy; butoxy; fourth-3-thiazolinyl oxygen base; methylamino; ethylamino; dimethylamino; diethylamino; N-methyl carbamyl; N-ethyl carbamyl; N; N-dimethylamino formyl radical; N; N-diethyl amino formyl radical; cyclopentyloxy; cyclohexyl oxygen base; phenoxy group; benzyloxy; tetrahydrofuran (THF)-3-base oxygen base; tetrahydropyran-3-base oxygen base; tetrahydropyran-4-base oxygen base; cyclo propyl methoxy; 2-imidazoles-1-base oxethyl; 3-imidazoles-1-base propoxy-; 2-(1; 2; the 3-triazol-1-yl) oxyethyl group; 3-(1; 2; the 3-triazol-1-yl) propoxy-; 2-(1; 2; the 4-triazol-1-yl) oxyethyl group; 3-(1; 2; the 4-triazol-1-yl) propoxy-; pyridine-2-ylmethoxy; the pyridin-3-yl methoxyl group; the pyridin-4-yl methoxyl group; 2-pyridine-2-base oxethyl; 2-pyridin-3-yl oxyethyl group; 2-pyridin-4-yl oxyethyl group; 3-pyridine-2-base propoxy-; 3-pyridin-3-yl propoxy-; 3-pyridin-4-yl propoxy-; tetramethyleneimine-1-base; morpholino; piperidino-(1-position only); piperazine-1-base; 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-ylmethyl amino, 2-tetramethyleneimine-2-base ethylamino, 3-tetramethyleneimine-2-base propyl group amino, 2-morpholino ethylamino, 3-morpholino propyl group amino, 4-morpholino butyl amino, 2-(1,1-dioxo tetrahydrochysene-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-ylmethyl amino, 2-piperidines-3-base ethylamino, the piperidin-4-yl methylamino, 2-piperidin-4-yl ethylamino, the high piperidines of 2--1-base ethylamino, the high piperidines of 3--1-base propyl group amino, 2-piperazine-1-base ethylamino, 3-piperazine-1-base propyl group amino, 4-piperazine-1-base butyl amino, the high piperazine of 2--1-base ethylamino or the high piperazine of 3--1-base propyl group amino

R wherein ¹Any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclic radical are chosen wantonly and are carried 1 or 2 substituting group in the last substituting group; described substituting group can be identical or different; be selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, carbamyl, methyl, ethyl, methoxyl group, oxyethyl group, N-methyl carbamyl, N; N-dimethylamino formyl radical, methylene radical dioxy base, ethylidene dioxy base and isopropylidene dioxy base, R ¹Tetramethyleneimine-2-base in the substituting group; piperidines-3-base; piperidin-4-yl; piperazine-1-base or high piperazine-1-base are by 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-dimethyl aminoethyl; the 3-dimethylaminopropyl; 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-optional N-of 1-base propyl group replaces; wherein back 8 kinds of substituting groups are optional separately carry 1 or 2 can be identical or different be selected from fluoro; chloro; the substituting group of methyl and methoxyl group

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

R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃The optional substituting group that carries one or more fluoro bases, chloro base or methyl or be selected from 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 on the group

R wherein ¹Adjacent carbons in the alkylidene chain of substituting group inherence any (2-6C) is inserted into optional separation of group that intrachain is selected from O, NH, N (Me), CH=CH and C ≡ C;

(h) p is 2, 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; carbamyl; methyl; ethyl; methoxyl group; oxyethyl group; propoxy-; isopropoxy; butoxy; methylamino; ethylamino; dimethylamino; diethylamino; N-methyl carbamyl; N-ethyl carbamyl; N; N-dimethylamino formyl radical; N; N-diethyl amino 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-

R wherein ¹On substituting group in any heterocyclic radical is optional 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-2-base in the substituting group, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are by methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2; 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; the optional N-of 2-trifluoroethyl or cyano methyl replaces

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

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

R wherein ¹Adjacent carbons in the alkylidene chain of substituting group inherence any (2-6C) is inserted into optional separation of group that intrachain is selected from O, NH, CH=CH and C ≡ C;

(i) p is 2, R ¹Group is positioned at 6-and 7-position; the R1 group can be identical or different; be selected from hydroxyl; amino; methoxycarbonyl; ethoxy carbonyl; carbamyl; methyl; ethyl; methoxyl group; oxyethyl group; propoxy-; isopropoxy; butoxy; methylamino; ethylamino; dimethylamino; diethylamino; N-methyl carbamyl; N-ethyl carbamyl; N; N-dimethylamino formyl radical; N; N-diethyl amino 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-

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-2-base in the substituting group, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are by methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; the optional N-of 2-trifluoroethyl or cyano methyl replaces

R wherein ¹On substituting group in any heterocyclic radical is optional carries 1 or 2 oxo substituting group,

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

R wherein ¹Adjacent carbons in the substituting group in any (2-6C) alkylidene chain is inserted into optional separation of group that intrachain is selected from O, NH, CH=CH and C ≡ C;

(j) p is 2, R ¹Group is positioned at 6-and 7-position, is positioned at the R of 6-position ¹Group is selected from cyano group, hydroxyl, methoxycarbonyl, ethoxy carbonyl, carbamyl, methoxyl group, oxyethyl group, propoxy-, N-methyl carbamyl, N-ethyl carbamyl, N; N-dimethylamino formyl radical, N; N-diethyl amino formyl radical, tetramethyleneimine-1-base carbonyl, morpholino carbonyl, piperidino-(1-position only) carbonyl and piperazine-1-base carbonyl is positioned at the R of 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-

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-2-base in the substituting group, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are by methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; the optional N-of 2-trifluoroethyl or cyano methyl replaces

R wherein ¹On substituting group in any heterocyclic radical is optional carries 1 or 2 oxo substituting group,

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

(k) q is 0;

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

(m) q is 1 or 2, each R ²Group can be identical or different, is selected from halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) alkenyl, (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, carbamyl, hydroxyl, amino, methyl, methoxyl group, methylamino and dimethylamino, N-methyl carbamyl and N, N-dimethylamino formyl radical;

(q) 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) 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, dimethylaminomethyl, the 2-dimethyl aminoethyl, the 3-dimethylaminopropyl, acetylamino methyl or N-methyl acetylamino methyl;

(w) R ⁴Be hydrogen, methyl or ethyl;

(s) 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 has 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 has the 6-unit monocycle hetero-aromatic ring of 3 nitrogen heteroatoms at the most;

(ff) ring A has 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 ring, furan nucleus, pyrrole ring, thiphene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazoles ring, thiazole ring, isothiazole Huan, oxadiazole ring, thiadiazoles ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring;

(hh) ring A is phenyl ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring;

(ii) encircling A is furan nucleus, pyrrole ring, thiphene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazoles ring, thiazole ring, isothiazole Huan, oxadiazole ring or thiadiazoles ring;

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

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

(ll) ring A is phenyl ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring, and described ring carries one or two R ⁶Group and a R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group);

(mm) ring A is furan nucleus, pyrrole ring, thiphene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazoles ring, thiazole ring, isothiazole Huan, oxadiazole ring or thiadiazoles ring, and described ring carries one or two R ⁶Group and a R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group);

(nn) ring A has 3 9-or 10-unit dicyclo hetero-aromatic rings that are selected from the ring hetero atom of oxygen, nitrogen and sulphur at the most;

(oo) ring A is cumarone ring, indole ring, thionaphthene ring, benzoxazole ring, benzoglyoxaline ring, benzothiazole ring, indazole ring, benzotriazole ring, 1H-pyrrolo-[3,2-b] pyridine ring, quinoline ring, isoquinoline 99.9 ring, quinazoline ring, quinoxaline ring or naphthyridines ring;

(pp) r is 0,1,2 or 3, each R of existence ⁶Group can be identical or different, is selected from that halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) alkenyl, (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, sec-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino, ethylamino, dimethylamino and diethylamino;

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

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

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-8C) alkyl, R ¹⁵It is the alkyl of halogeno-group-(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 carbamyl-(1-6C); N-(1-6C) alkylcarbamoyl group-(1-6C) alkyl or N; the alkyl of N-two-[(1-6C) alkyl] carbamyl-(1-6C), prerequisite is to work as X ⁶Be O or N (R ¹⁶) time, at X ⁶With R ¹⁵Have two carbon atoms between any heteroatoms of group at least,

Any other R that exists ⁶Group is selected from that halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) alkenyl, (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)

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

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

-X ⁷-Q ³

X wherein ⁷Be 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 that is not positioned at hetero-aromatic ring ³In any heteroatoms between have two carbon atoms at least,

Any other R that exists ⁶Group is selected from that halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) alkenyl, (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)

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

-X ⁸-R ²⁰

X wherein ⁸Be direct key or be selected from O and N (R ²¹), R wherein ²¹Be hydrogen or (1-8C) alkyl, R ²⁰Be alkyl or two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogeno-group-(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 ⁶Optional 1 or 2 oxo or the sulfo-substituting group of carrying of any heterocyclic radical in the group,

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

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

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-8C) alkyl, R ¹⁵It is 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 two carbon atoms between any heteroatoms of group at least,

Any other R that exists ⁶Group is selected from that halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) alkenyl, (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)

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

-X ⁸-R ²⁰

X wherein ⁸Be direct key, R ²⁰Be alkyl or two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogeno-group-(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 CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃On the group optional carry 1,2 or 3 halogeno-group or (1-8C) alkyl substituent and/or be selected from that hydroxyl, amino, cyano group, (3-8C) alkenyl, (3-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, the substituting group of alkanoylamino of (2-6C) alkanoylamino and N-(1-6C) alkyl-(2-6C);

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

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-8C) alkyl, R ¹⁵Be 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 two carbon atoms between any heteroatoms of group at least,

Any other R that exists ⁶Group is selected from that halogeno-group, 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)

R wherein ⁶Any aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried 1 or 2 substituting group in the group, described substituting group can be identical or different, be selected from that halogeno-group, 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, one R ⁶Group is the following formula group:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or be selected from O, NH and N (Me), R ¹⁵It is hydroxymethyl, 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, dimethylaminomethyl, the 1-dimethyl aminoethyl, the 2-dimethyl aminoethyl, 1-dimethylamino-1-methylethyl, the 3-dimethylaminopropyl, phenyl, phenmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, thienyl oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro thiapyran base, pyrrolinyl, pyrrolidyl, imidazolidyl, pyrazolidyl, 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 imidazolidyl methyl, the pyrazolidyl 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 ⁶When being O, NH or N (Me), at X ⁶With R ¹⁵Have two carbon atoms between any heteroatoms of group at least,

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, dimethyl amine, hydroxymethyl, 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, dimethylaminomethyl, 2-dimethyl aminoethyl and 3-dimethylaminopropyl

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 following formula group:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or O, R ¹⁵It is hydroxymethyl, 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, dimethylaminomethyl, the 1-dimethyl aminoethyl, the 2-dimethyl aminoethyl, the 3-dimethylaminopropyl, phenyl, phenmethyl, 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 ⁶When being O, at X ⁶With R ¹⁵Have two carbon atoms between any heteroatoms of group at least,

R wherein ⁶Any aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are optional in the group carries the substituting group that is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino and dimethylamino, at R ⁶Any this type of aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical in the group chosen wantonly and carried the other substituting group that is selected from hydroxymethyl, cyano methyl, amino methyl, methylamino methyl and dimethylaminomethyl,

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 hydroxymethyl, 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, dimethylaminomethyl, the 1-dimethyl aminoethyl, the 2-dimethyl aminoethyl, phenyl, phenmethyl, 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

R wherein ⁶Any aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical in the group is optional to carry the substituting group that is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino and dimethylamino, at R ⁶Any this type of aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical in the group chosen wantonly and carried the other substituting group that is selected from hydroxymethyl, cyano methyl, amino methyl, methylamino methyl and dimethylaminomethyl,

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; sec-butyl; isobutyl-; the tertiary butyl; cyclopropyl; cyclobutyl; cyclopentyl; methoxyl group; oxyethyl group; methylamino; ethylamino; propyl group amino; sec.-propyl amino; cyclopropyl amino; 2-hydroxyethyl amino; 2-methoxy ethyl amino; dimethylamino; N-cyclopropyl-N-methylamino; ethanoyl; hydroxymethyl; 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-hydroxyethyl amino methyl; dimethylaminomethyl; the diethylamino methyl; N-ethyl-N-methylamino methyl; the cyclopropyl amino methyl; N-cyclopropyl-N-methylamino methyl; the furyl methyl amino methyl; pyrryl methylamino methyl; the pyridylmethyl amino methyl; phenyl; furyl; thienyl; imidazolyl oxazolyl; thiazolyl; pyrrolidyl; morpholinyl; piperidyl; homopiperidinyl; piperazinyl; high piperazinyl; the azetidin ylmethyl; the pyrrolidyl methyl; the morpholinyl methyl; piperidino methyl; the homopiperidinyl methyl; piperazinyl methyl and high piperazinyl methyl

R wherein ⁶The optional substituting group that is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino, dimethylamino, hydroxymethyl, cyano methyl, amino methyl, methylamino methyl and dimethylaminomethyl that carries of any aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical in the group

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, sec-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, the 2-hydroxyethyl, methoxymethyl, the 2-methoxy ethyl, the methylamino methyl, the ethylamino methyl, the sec.-propyl amino methyl, the cyclopropyl amino methyl, dimethylaminomethyl, methoxyl group, oxyethyl group, methylamino, ethylamino, dimethylamino and diethylamino;

(bbb) two R ⁶Group forms together and strides across the upward divalent group of adjacent ring position of ring A, 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 ¹⁹Each hydrogen, (1-8C) alkyl, (2-8C) alkenyl or (2-8C) alkynyl naturally;

(ccc) two R ⁶Group forms together and strides across the upward divalent group of adjacent ring position of ring A, 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 ¹⁹Each is hydrogen, methyl, ethyl or propyl group naturally;

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

(eee) two R ⁶Group forms together and strides across the upward divalent group of adjacent ring position of ring A, 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 halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, carbamyl, (1-6C) alkoxy carbonyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylcarbamoyl group and N, N-two-[(1-6C) alkyl] carbamyl;

With q be 1, R ²Group is positioned at the 2-position (with respect to C (R ³) (R ⁴) group), be selected from halogeno-group, trifluoromethyl, cyano group, carbamyl, hydroxyl, amino, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylcarbamoyl group and N, N-two-[(1-6C) alkyl] carbamyl;

(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, carbamyl, methoxycarbonyl, ethoxy carbonyl, methyl, ethyl, methoxyl group, oxyethyl group, methylamino, dimethylamino, N-methyl carbamyl and N; N-dimethylamino formyl radical

With 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, carbamyl, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino, dimethylamino, N-methyl carbamyl and N, N-dimethylamino formyl radical;

(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, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, and N-dimethylamino formyl radical and q are 1, is positioned at the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is selected from carbamyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical; 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, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, and N-dimethylamino formyl radical and q are 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.

Concrete The compounds of this invention is quinoline or its pharmacy acceptable salt of formula I, wherein :-

X ¹Be O;

P is 2, R ¹Group is positioned at 6-and 7-position, is positioned at the R of 6-position ¹Group is selected from cyano group, hydroxyl, methoxycarbonyl, ethoxy carbonyl, carbamyl, methoxyl group, oxyethyl group, propoxy-, N-methyl carbamyl, N-ethyl carbamyl, N; N-dimethylamino formyl radical, N; N-diethyl amino formyl radical, tetramethyleneimine-1-base carbonyl, morpholino carbonyl, piperidino-(1-position only) carbonyl and piperazine-1-base carbonyl is positioned at the R of 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-

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-2-base in the substituting group, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are by methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; the optional N-of 2-trifluoroethyl or cyano methyl replaces

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

R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃The optional substituting group that carries one or more chloro bases or be selected from hydroxyl, amino, methoxyl group, methyl sulphonyl, methylamino, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino and N-sec.-propyl-N-methylamino on the 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, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino and dimethylamino;

R ³And R ⁴Each is hydrogen naturally;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is phenyl ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring; And

R be 0 or r be 1 or 2, one 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, one R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group), and be the following formula group:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or O, R ¹⁵It is hydroxymethyl, 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, dimethylaminomethyl, the 1-dimethyl aminoethyl, the 2-dimethyl aminoethyl, the 3-dimethylaminopropyl, phenyl, phenmethyl, 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 ⁶When being O, at X ⁶With R ¹⁵Have two carbon atoms between any heteroatoms of group at least,

R wherein ⁶Any aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are optional in the group carries the substituting group that is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino and dimethylamino, at R ⁶Any this type of aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried the other substituting group that is selected from hydroxymethyl, cyano methyl, amino methyl, methylamino methyl and dimethylaminomethyl in the group,

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

The quinoline 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, carbamyl, methoxyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical, 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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen or methyl;

Ring A is phenyl ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring; And

R be 0 or r be 1 or 2, one 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, one R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group), be selected from hydroxymethyl, 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, dimethylaminomethyl, the 1-dimethyl aminoethyl, the 2-dimethyl aminoethyl, the pyrrolidyl methyl, the morpholinyl methyl, piperidino methyl and piperazinyl methyl

R wherein ⁶The optional substituting group that is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino-and dimethylamino that carries of any heterocyclic radical in the group,

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

The quinoline 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 the 2-position (with respect to C (R ³) (R ⁴) group) and R ²Group is fluoro, chloro, methyl or methoxy;

R ³And R ⁴Each is hydrogen naturally;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is a phenyl; And

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, hydroxymethyl, amino methyl, the methylamino methyl, the ethylamino methyl, the sec.-propyl amino methyl, the cyclopropyl amino methyl, dimethylaminomethyl, the diethylamino methyl, N-ethyl-N-methylamino methyl, N-cyclopropyl-N-methylamino methyl, the azetidin ylmethyl, the pyrrolidyl methyl, the morpholinyl methyl, piperidino methyl, the homopiperidinyl methyl, piperazinyl methyl and high piperazinyl methyl

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

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

The quinoline 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 and R ²Group is the fluoro base;

R ³And R ⁴Each is hydrogen naturally;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is a phenyl; And

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, hydroxymethyl, amino methyl, the methylamino methyl, the ethylamino methyl, the propyl group amino methyl, the sec.-propyl amino methyl, the cyclopropyl amino methyl, dimethylaminomethyl, the diethylamino 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

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

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

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

X ¹Be O;

P is 2 and 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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen, methyl or ethyl;

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

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; 2-hydroxyethyl amino; 2-methoxy ethyl amino; dimethylamino; N-cyclopropyl-N-methylamino; ethanoyl; hydroxymethyl; amino methyl; the methylamino methyl; the ethylamino methyl; the propyl group amino methyl; the sec.-propyl amino methyl; the cyclopropyl amino methyl; dimethylaminomethyl; the diethylamino 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

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

The quinoline 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 and R ²Group is fluoro, chloro, methyl or methoxy;

R ³And R ⁴Each is hydrogen naturally;

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; And

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-hydroxyethyl amino, 2-methoxy ethyl amino, 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,

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

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

X ¹Be O;

P is 2 and R ¹Group is positioned at 6-and 7-position, is positioned at the R of 6-position ¹Group is selected from cyano group, hydroxyl, methoxycarbonyl, ethoxy carbonyl, carbamyl, methoxyl group, oxyethyl group, propoxy-, N-methyl carbamyl, N-ethyl carbamyl, N; N dimethylamino formyl radical, N; N-diethyl amino formyl radical, tetramethyleneimine-1-base carbonyl, morpholino carbonyl, piperidino-(1-position only) carbonyl and piperazine-1-base carbonyl is positioned at the R of 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-

R wherein ¹Any heterocyclic radical is chosen wantonly and is carried 1 or 2 substituting group in the last 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-2-base in the substituting group, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are by methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; the optional N-of 2-trifluoroethyl or cyano methyl replaces

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

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

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

R ³And R ⁴Each is hydrogen naturally;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is furan nucleus, pyrrole ring, thiphene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazoles ring, thiazole ring, isothiazole Huan, oxadiazole ring or thiadiazoles ring; And

R be 0 or r be 1 or 2, one 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 diethylamino

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

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or O, R ¹⁵It is hydroxymethyl, 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, dimethylaminomethyl, the 1-dimethyl aminoethyl, the 2-dimethyl aminoethyl, the 3-dimethylaminopropyl, phenyl, phenmethyl, 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 ⁶When being O, at X ⁶With R ¹⁵Have two carbon atoms between any heteroatoms of group at least,

R wherein ⁶Any aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical in the group is optional to carry the substituting group that is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino and dimethylamino, at R ⁶Any this type of aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried the other substituting group that is selected from hydroxymethyl, cyano methyl, amino methyl, methylamino methyl and dimethylaminomethyl in the group,

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

The quinoline 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, carbamyl, methoxyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical, 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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen or methyl;

Ring A Shi oxazole ring, isoxazole ring, imidazole ring, pyrazoles ring, thiazole ring, isothiazole Huan, oxadiazole ring or thiadiazoles ring; And

R be 0 or r be 1 or 2, one 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, sec-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxyl group, oxyethyl group, methylamino, ethylamino, dimethylamino and diethylamino

Perhaps r is 1 or 2, one R ⁶Group is positioned at the 3-position (with respect to CON (R ⁵) group), be selected from hydroxymethyl, 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, dimethylaminomethyl, the 1-dimethyl aminoethyl, the 2-dimethyl aminoethyl, the pyrrolidyl methyl, the morpholinyl methyl, piperidino methyl and piperazinyl methyl

R wherein ⁶The optional substituting group that is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino and dimethylamino that carries of any heterocyclic radical in the group,

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

The quinoline 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, carbamyl, methoxyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical, 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 and 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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen or methyl;

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

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, sec-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, the 2-hydroxyethyl, methoxymethyl, the 2-methoxy ethyl, the methylamino methyl, the ethylamino methyl, the sec.-propyl amino methyl, the cyclopropyl amino methyl, dimethylaminomethyl, methoxyl group, oxyethyl group, methylamino, ethylamino, dimethylamino and diethylamino.

The quinoline 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, carbamyl, methoxyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical, 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 and 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 ⁴Each is hydrogen naturally;

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; And

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

The anti-pdgf receptor of some compound family Tyrosylprotein kinase, the particularly effect of anti-PDGF beta receptor Tyrosylprotein kinase that drop in the following The compounds of this invention definition obviously are better than vegf receptor tyrosine kinase such as KDR.

The concrete new compound of this respect of the present invention is quinoline 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 halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, carbamyl, (1-6C) alkoxy carbonyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylcarbamoyl group and N; N-two-[(1-6C) alkyl] carbamyl, and

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

With each X ¹, R ³, R ⁴, R ⁵, ring A, r and R ⁶Has the implication that above limits.

The concrete novel cpd of another of this aspect of the present invention is quinoline 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, carbamyl, methoxycarbonyl, ethoxy carbonyl, methyl, ethyl, methoxyl group, oxyethyl group, methylamino, dimethylamino, N-methyl carbamyl and N; N-dimethylamino formyl radical 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, carbamyl, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino, dimethylamino, N-methyl carbamyl and N, N-dimethylamino formyl radical;

With each X ¹, R ³, R ⁴, R ⁵, ring A, r and R ⁶Has the implication that above limits.

The concrete novel cpd of another of this aspect of the present invention is quinoline 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, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical 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 carbamyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethyl methyl acyl group;

With each X ¹, R ³, R ⁴, R ⁵, ring A, r and R ⁶Has the implication that above limits.

The concrete novel cpd of another of this aspect of the present invention is quinoline 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, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical 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;

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

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

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group be positioned at 6-and/or 7-position and be selected from that halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, carbamyl, (1-6C) alkoxy carbonyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkene oxygen base, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, N-(1-6C) alkylcarbamoyl group and N; N-two-[(1-6C) alkyl] carbamyl

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

R ³And R ⁴Each is hydrogen naturally;

R ⁵Be hydrogen;

Ring A is the 5-unit monocycle hetero-aromatic ring with the ring hetero atom that is selected from oxygen, nitrogen and sulphur up to 3; With

R is 0,1,2 or 3, each R of existence ⁶Group can be identical or different, is selected from that halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) alkenyl, (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 quinoline 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 and is selected from fluoro, chloro, trifluoromethyl, cyano group, hydroxyl, amino, carbamyl, methoxycarbonyl, ethoxy carbonyl, methyl, ethyl, methoxyl group, oxyethyl group, methylamino, dimethylamino, N-methyl carbamyl and N; N-dimethylamino formyl radical

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, carbamyl, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino, dimethylamino, N-methyl carbamyl and N, N-dimethylamino formyl radical;

R ³And R ⁴Each is hydrogen naturally;

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, sec-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino, ethylamino, dimethylamino and diethylamino.

Another particular compound of this aspect of the present invention is quinoline or the 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 and is selected from fluoro, chloro, cyano group, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical,

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

R ³And R ⁴Each is hydrogen naturally;

R ⁵Be hydrogen;

Ring A is furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring, and it has 1 or 2 R ⁶Group and a 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, sec-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino, ethylamino, dimethylamino and diethylamino.

Another particular compound of this aspect of the present invention is quinoline 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 and is selected from fluoro, cyano group, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical,

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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen;

Ring A is furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring, and it has 1 or 2 R ⁶Group and a 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, sec-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino, ethylamino, dimethylamino and diethylamino.

The quinoline that a kind of particular compound of the present invention is formula I or its pharmacy acceptable salt, 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, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical,

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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen;

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, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxy ethyl, methylamino methyl, ethylamino methyl, sec.-propyl amino methyl, cyclopropyl amino methyl, dimethylaminomethyl, amino, methylamino, ethylamino, dimethylamino and diethylamino.

Another particular compound of this aspect of the present invention is quinoline 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 and is selected from fluoro, cyano group, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical,

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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen;

Ring A is 2-oxazolyl, 3-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 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 and sec.-propyl;

Or its pharmacy acceptable salt.

Another particular compound of this aspect of the present invention is quinoline 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 and is selected from fluoro, cyano group, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical,

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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen;

Ring A is 2-oxazolyl, 3-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 quinoline of disclosed formula I among the embodiment that for example lists hereinafter.

For example, particular compound of the present invention is quinoline or its pharmacy acceptable salt of formula I :-

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

Another particular compound of the present invention is quinoline or its pharmacy acceptable salt that is selected from following formula I:

1.	N-(1-ethyl-1H-pyrazoles-4-yl)-2-[5-(6-cyano group-7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide;
		2.	N-(1-ethyl-1H-pyrazoles-4-yl)-2-{5-[6-(N, N-dimethylamino formyl radical)-7-methoxy quinoline-4-base oxygen base] pyridine-2-yl } ethanamide;
3.	N-[1-(2-methoxy ethyl) pyrazoles-4-yl]-2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base) pyridine-2-yl] ethanamide;
		4.	N-[1-(2-methoxy ethyl) pyrazoles-4-yl]-2-[5-(6-cyano group-7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide;
5.	N-(5-ethyl-1H-pyrazole-3-yl)-2-{5-[6-(N, N-dimethylamino formyl radical)-7-methoxy quinoline-4-base oxygen base] pyridine-2-yl } ethanamide;
		6.	N-(4,5-dimethyl isoxazole-3-yl)-2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base) pyridine-2-yl] ethanamide; With
7.	N-(4,5-dimethyl isoxazole-3-yl)-2-[5-(6-cyano group-7-methoxy quinoline-4-base oxygen base) pyridine-2-yl acetamide.

Another particular compound of the present invention is quinoline or its pharmacy acceptable salt that is selected from following formula I:

1.	N-(1-ethyl-1H-pyrazoles-4-yl)-2-[3-methoxyl group-5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide;
		2.	N-(1,3-dimethyl-1H-pyrazoles-4-yl)-2-[3-methoxyl group-5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide;
3.	N-(1-ethyl-1H-pyrazoles-4-yl)-2-[5-(6-fluorine quinolyl-4 oxygen base)-3-methoxyl group

	Pyridine-2-yl] ethanamide;
		4.	N-(4,5-dimethyl-1H-pyrazole-3-yl)-2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide;
5.	N-(4,5-dimethyl isoxazole-3-yl)-2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide;
		6.	N-(4,5-dimethyl isoxazole-3-yl)-2-[3-methoxyl group-5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide;
7.	N-(5-Yi isoxazole-3-yl)-2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide; With
		8.	N-(4,5-dimethyl isoxazole-3-yl)-2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide.

Can be by known quinoline or its pharmacy acceptable salt that can be used for preparing any method preparation formula I of chemofacies related compounds.When these class methods are used for the quinoline of preparation formula I, be another feature provided by the invention, illustrate by following exemplary process variant, wherein 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.Available organic chemistry standard schedule obtains essential raw material.The preparation of this type of raw material is described in conjunction with following exemplary process variant in attached embodiment.Perhaps, obtain essential raw material with the illustrational similar rules in the technique of organic chemistry personnel common skill scope.

(a) quinoline of formula II

Wherein L is a displaceable group, p and R ¹Have any implication that above limits, but protect any functional group where necessary, with 2-(2-pyridyl) ethanamide of formula III

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

This reaction can be carried out in the presence of suitable acid or in the presence of suitable alkali easily.Suitable acid is for example mineral acid example hydrochloric acid or Hydrogen bromide.Suitable alkali is for example organic amine alkali such as pyridine, 2,6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.4.0] 11-7-alkene, perhaps for example alkali or alkaline earth metal carbonate or oxyhydroxide, as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide, perhaps for example alkali metal amide such as hexamethyldisilazane sodium, perhaps for example alkalimetal hydride such as sodium hydride.

Suitable displaceable group L is for example halogeno-group, alkoxyl group, aryloxy or sulfonyloxy, as chloro, bromo, methoxyl group, phenoxy group, penta fluoro benzene oxygen base, mesyloxy or toluene-4-sulfonyloxy.Reaction is carried out in the presence of suitable inert solvent or thinner easily, as 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) or dipolar aprotic solvent are (as N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)).Reaction is being carried out under the temperature of for example 0-250 ℃ of scope, preferred 0-120 ℃ of scope easily.

Usually, can be under the temperature of for example 0-150 ℃ of scope, preference such as 0-70 ℃ scope, easily in the presence of alkali such as salt of wormwood or hexamethyldisilazane sodium, at aprotic solvent such as N, under the existence of dinethylformamide, the quinoline of formula II and the reaction of formula III compound.

Can obtain the formula I quinoline of free alkali form from this process, perhaps can obtain the formula I quinoline with the salt form of formula H-L acid, wherein L has the implication that above limits.When needs obtain free alkali with salt, available suitable alkaline purification salt, described alkali is organic amine alkali such as pyridine, 2 for example, 6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.4.0] 11-7-alkene, perhaps for example alkali or alkaline earth metal carbonate or oxyhydroxide are as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide.

Blocking group can be selected from document description or the known any group that is applicable to this group of protection of chemical personnel usually, can introduce by ordinary method.Can remove blocking group by document description or the known any ordinary method that removes this blocking group that is applicable to of chemical personnel, select these class methods so that in the inferior limit disturbing molecule, remove blocking group under the situation of other group.

For simplicity, hereinafter specify the specific examples of blocking group, wherein for example " rudimentary " in low alkyl group refered in particular to the group that preferably has 1-4 carbon atom.Should understand these examples does not describe in detail one by one.When hereinafter providing when being used to remove the concrete grammar example of blocking group, these examples equally describe in detail one by one.Certainly, blocking group purposes of specifically not mentioning and deprotection method are within the scope of the invention.

Carboxy protective group can be into ester aliphatic series or aryl fatty alcohol or become the residue of ester silanol (described alcohol or silanol preferably comprise 1-20 carbon atom).The carboxy protective group example 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, propionyloxy methyl, butyryl acyloxy methyl and pivaloyl oxygen ylmethyl); Elementary alkoxy carbonyl oxygen base-low alkyl group (as 1-methoxycarbonyl oxygen base ethyl and 1-ethoxy carbonyl oxygen base ethyl); Aryl lower alkyl (as phenmethyl, 4-mehtoxybenzyl, 2-oil of mirbane methyl, 4-oil of mirbane methyl, 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 comprise as acid-, alkali-, metal-or enzyme-catalytic pyrolysis.

The hydroxy-protective group example 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 benzyloxy carbonyl, 4-anisole methoxycarbonyl, 2-oil of mirbane methoxy base carbonyl and 4-oil of mirbane methoxy base carbonyl); Three (low alkyl group) silyl (as trimethyl silyl and t-butyldimethylsilyl) and aryl lower alkyl (as phenmethyl) group.

Amido protecting group example comprises formyl radical, aryl lower alkyl (as phenmethyl, 4-mehtoxybenzyl, the 2-oil of mirbane methyl and 2 of phenmethyl and replacement, 4-dimethoxy phenmethyl 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 benzyloxy carbonyl, 4-anisole methoxycarbonyl, 2-oil of mirbane methoxy base carbonyl and 4-oil of mirbane methoxy base carbonyl); Trialkylsilkl (as trimethyl silyl and t-butyldimethylsilyl); The inferior phenmethyl of alkylidene group (as methylene radical) and inferior phenmethyl and replacement.

The method that is fit to remove hydroxyl and amido protecting group for example comprises, acid-, alkali-, metal-or the group of group, hydrogenation such as the phenmethyl of enzyme-catalytic hydrolysis such as 2-oil of mirbane methoxy base carbonyl and group of photodissociation such as 2-oil of mirbane methoxy base carbonyl.

The reader is with reference to Advanced Organic Chemistry, and the 4th edition, J.March, JohnWiley ﹠amp; The general guide that Sons 1992 publishes about reaction conditions and reagent, with reference to Protective Groups in Organic Synthesis, the 2nd edition, T.Green etc. also are by John Wiley ﹠amp; The general guide that Son publishes about blocking group.

The quinoline raw material of formula II can obtain by ordinary method, and described method is as being disclosed in International Patent Application WO 98/13350 and WO 02/12226.For example, 1 of formula IV, 4-dihydroquinoline-4-ketone can with halogenating agent such as thionyl chloride, phosphoryl chloride or tetracol phenixin and triphenyl phosphine mixture reaction, remove any blocking group of existence then,

Wherein p and R ¹Have any implication that above limits, but protect any functional group where necessary.

If desired, can in the presence of suitable alkali such as salt of wormwood and at suitable solvent such as N, make the reaction of thus obtained 4-chloroquinoline and Pentafluorophenol under the existence of dinethylformamide, be converted into 4-penta fluoro benzene phenoxyl quinoline.

Can obtain 2-(2-pyridyl) the ethanamide raw material of formula III by ordinary method.For example, the acetate of formula V

Or its response derivative, wherein X ¹, q, R ², R ³And R ⁴Have any implication that above limits, but protect any functional group where necessary,

Can react with the amine of formula VI,

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

The suitable reactions derivative of formula V acetate is that for example acyl halide reacts the chloride of acid that forms as acid and inorganic chloride of acid, as thionyl chloride; Mixed acid anhydride is as the acid anhydride of acid with chloro-formic ester such as isobutyl chlorocarbonate reaction formation; Active ester, as acid and phenol (as Pentafluorophenol), with ester (as trifluoroacetic acid pentafluorophenyl group ester) or the ester that forms with alcohol (as methyl alcohol, ethanol, Virahol, butanols or N-hydroxybenzotriazole) reaction; Acyl azide is as the trinitride of acid with trinitride such as diphenyl phosphoryl azide reaction formation; Acyl cyanide is as the prussiate of acid with prussiate such as diethyl phosphinylidyne cyanogen reaction formation; Perhaps acid and carbodiimide such as dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide or with uronium compound such as 2-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate (V) or 2-(benzotriazole-1-yl)-1,1,3, the reaction product of 3-tetramethyl-urea a tetrafluoro borate.

Reaction is carried out under the existence of suitable inert solvent or thinner such as 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) easily.Easily, reaction is carried out under the existence of dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO) easily at dipolar aprotic solvent such as N.Reaction is easily in 0-120 ℃ of scope for example, preferably carry out in envrionment temperature or under near the temperature of envrionment temperature.

The amine of the acetogenin of formula V and formula VI can be by those ordinary methods of listed embodiment obtain as being disclosed in hereinafter.

(b) in the presence of suitable alkali, the quinoline of formula VII

Or its response derivative that limits as mentioned, wherein p, R ¹, X ¹, q, R ², R ³And R ⁴Have any implication that above limits, but protect any functional group where necessary,

With the amine coupling easily of formula VI,

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

Suitable alkali is organic amine alkali for example, pyridine, 2 for example, 6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.4.0] 11-7-alkene, perhaps for example alkali or alkaline earth metal carbonate or oxyhydroxide, as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide, perhaps alkali metal amide for example is as hexamethyldisilazane sodium, perhaps alkalimetal hydride for example is as sodium hydride.

Reaction is carried out under the existence of suitable inert solvent or thinner such as 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) easily.Easily, reaction is carried out under the existence of dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO) easily at dipolar aprotic solvent such as N.Reaction is carried out in 0-120 ℃ of scope for example, preferred ambient temperature or under near the temperature of envrionment temperature easily.

The amine of the quinoline of formula VII and formula VI can the ordinary method of listed embodiment obtains with for example being disclosed in hereinafter.

(c) at least one R wherein ¹Group is the following formula group

Q ¹-X ²-

Q wherein ¹Be 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 optional alkyl and the X that replaces ²Be the preparation of those formulas I compound of Sauerstoffatom, in the presence of suitable dewatering agent, any functional group is wherein protected in the quinoline of formula VIII and the coupling easily of suitable alcohol where necessary, removes any blocking group of existence then

Wherein p, R ¹, X ¹, q, R ², R ³, R ⁴, R ⁵, ring A, r and R ⁶Have any implication that above limits, but protect any functional group where necessary.

Suitable dewatering agent for example is, the mixture of carbodiimide reagent such as dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide or azo-compound (as diethyl or di-t-butyl azo-dicarboxylic ester) and phosphine (as triphenyl phosphine).Reaction is easily in the presence of suitable inert solvent or thinner (as halogenated solvent such as methylene dichloride, chloroform or tetracol phenixin), in 10-150 ℃ of scope for example, preferably carry out in envrionment temperature or under near the temperature of envrionment temperature.

Can obtain the quinoline of formula VIII by ordinary method.

(d) for R wherein ⁶Group is formula-X ⁶-R ¹⁵Group, wherein X ⁶Have any implication that above limits, and R ¹⁵Be the preparation of those formulas I compound of (1-6C) alkyl (as dimethylaminomethyl, 2-dimethyl aminoethyl or 4-methylpiperazine-1-ylmethyl) of amino-replacement, formula I compound (R wherein ⁶Group is formula-X ⁶-R ¹⁵Group, wherein R ¹⁵Be (1-6C) alkyl of halogeno-group-replacement) in the presence of the appropriate base that limits as mentioned, carry out easily with suitable amine or with the reaction of nitrogen heterocyclic ring based compound.

Reaction is easily in the presence of suitable inert solvents that limits as mentioned or thinner, in 10-180 ℃ of scope for example, easily 20-120 ℃ of scope, carry out in envrionment temperature or under near the temperature of envrionment temperature more easily.

Can obtain formula I compound, wherein R by above-described any exemplary process variant (a) and (b) or (c) ⁶Group is formula-X ⁶-R ¹⁵Group, wherein R ¹⁵It is (1-6C) alkyl of halogeno-group-replacement.

(e) for R wherein ⁶Group is formula-X ⁶-R ¹⁵Group, wherein X ⁶Have any implication and the R that above limit ¹⁵Be the preparation of those formulas I compound of (1-6C) alkyl (as methylamino methyl, 2-methylamino ethyl or 2-hydroxyethyl amino methyl) of amino-replacement, make formula I compound reductive amination, wherein R ⁶Group is formula-X ⁶-R ¹⁵Group, wherein R ¹⁵Be formyl radical or (2-6C) alkyloyl.

The suitable reductive agent of reductive amination reaction for example is, hydride reducer such as composite alkali aluminum hydride such as lithium aluminum hydride, perhaps preferred as alkali hydroborate such as sodium borohydride, sodium cyanoborohydride, triethyl-boron sodium hydride, trimethoxy sodium borohydride and sodium triacetoxy borohydride.Reaction is carried out in suitable inert solvent or thinner easily, for example tetrahydrofuran (THF) and ether are used for than strong reductant such as lithium aluminum hydride, and for example methylene dichloride or protonic solvent such as methyl alcohol and ethanol are used for than weak reductant such as sodium triacetoxy borohydride and sodium cyanoborohydride.For example be reflected at 10-80 ℃ of scope, carry out in envrionment temperature or under easily near the temperature of envrionment temperature.

Change above-described any exemplary process variant (a) and (b) or (c) can obtain formula I compound, wherein R by routine ⁶Group is formula-X ⁶-R ¹⁵Group, wherein R ¹⁵Be formyl radical or (2-6C) alkyloyl.

(f) for R wherein ⁵Be the preparation of those formulas I compound of (1-8C) alkyl, in the presence of the appropriate base that limits as mentioned, make wherein R with suitable alkylating agent ⁵It is the formula I compound alkanisation easily of hydrogen.

Reaction is easily in the presence of suitable inert solvents that limits as mentioned or thinner, in ℃ of-180 ℃ scopes for example-10, easily 0-100 ℃ of scope, carry out in envrionment temperature or under near the temperature of envrionment temperature more easily.

Suitable alkylating agent for example is, wherein (1-8C) alkyl and suitable leavings group such as chloro, bromo, iodo, methoxyl group, phenoxy group, penta fluoro benzene oxygen base, methoxyl group sulfonyloxy, mesyloxy or compound that toluene-the 4-sulfonyloxy is connected.

(g) for R wherein ¹Be the preparation of those formulas I compound of carboxyl, in the presence of the appropriate base that limits as mentioned, cracking R wherein easily ¹It is the formula I compound of (1-6C) alkoxy carbonyl.

The method that is applicable to cracking (1-6C) alkoxy carbonyl comprise for example acid-, alkali-, metal-or enzyme-catalytic hydrolysis.Reaction is easily in the presence of suitable inert solvents that limits as mentioned or thinner, in ℃ of-100 ℃ scopes for example-10, carry out in envrionment temperature or under near the temperature of envrionment temperature easily.For example, can finish alkali-catalytic cracking with alkali metal hydroxide such as lithium hydroxide at alcohol in as methyl alcohol at ambient temperature.

When quinoline pharmacy acceptable salt that needs formula I such as acid salt, can make for example described quinoline and suitable acid-respons acquisition.

When needing the pharmaceutically acceptable prodrug of quinoline of formula I, available ordinary method obtains.For example, the ester of the interior cleavable of body that can obtain formula I quinoline by the formula I compound and the pharmaceutically acceptable carboxylic acid reaction of for example carboxylic formula I compound and pharmaceutically acceptable alcohol reaction or hydroxyl.For example, can or contain the acid amides of cleavable in the body of amino formula I compound and pharmaceutically acceptable carboxylic acid reaction acquisition formula I quinoline by the reaction of for example carboxylic formula I compound and pharmaceutically acceptable amine.

Many intermediates that this paper limits all are new, and these intermediates are another features provided by the invention.For example, many formula IIIs, VI and VII compound are new compounds.

Biology is measured

Following mensuration can be used for measuring The compounds of this invention as PDGFR α, the inhibitor of PDGFR β and KDR Tyrosylprotein kinase, vitro inhibition agent as the PDGFR phosphorylation that is expressed in the MG63 osteosarcoma cell, vitro inhibition agent as the KDR phosphorylation that is expressed in Human umbilical vein endothelial cells (HUVECs), vitro inhibition agent as MG63 osteosarcoma cell propagation, the effect of inhibitor in the body of in the nude mouse body, growing as the vitro inhibition agent of HUVECs propagation with as mankind tumor tissue heterograft such as CaLu-6 and Colo205.

(a) Vitro enzyme is measured

Make the ability of the peptide substrate phosphorylation that contains tyrosine with conventional ELISA mensuration assessment testing compound inhibition Tyrosylprotein kinase PDGFR α, PDGFR β and KDR.

By full gene synthetic ( International Biotechnology Lab., 1987, 5(3), 19-25) or clone can obtain the to encode DNA in PDGFR α, PDGFR β or KDR recipient cytoplasm territory.Dna fragmentation is expressed in the appropriate expression system, to obtain to have the polypeptide of tyrosine kinase activity.For example, can show to have the endogenous tyrosine kinase activity by PDGFR α, PDGFR β and the KDR recipient cytoplasm territory that obtains at the expressed in insect cells recombinant protein.Under the situation of vegf receptor KDR (Genbank Accession No.L04947), can be with the most of cytoplasm domain of coding (from methionine(Met) 806, comprise terminator codon) dna fragmentation be cloned into the baculovirus replacement vector and [(consult TheBaculovirus Expression System:A Laboratory Guide as pAcYM1, L.A.King and R.D.Possee, Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available from Invitrogen Corporation)] in.This reorganization member and viral DNA (as Pharmingen BaculoGold) cotransfection can be gone in the insect cell [as Spodoptera frugiperda21 (Sf21) or Spodoptera frugiperda 9 (Sf9)], with the preparation recombinant baculovirus.The details of the assemble method of recombinant DNA molecules and the preparation of recombinant baculovirus and use can be consulted normative document, as Sambrook etc., 1989, Molecular cloning-A LaboratoryManual, 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).

When expressing, with the pure KDR recombinant virus infection Sf9 cell of spot, collecting cell after 48 hours.The cell of collecting is washed with ice-cold phosphate buffered salt solution (PBS), this buffered soln comprises 10mM sodium phosphate pH7.4 damping fluid, 138mM sodium-chlor and 2.7mM Repone K, the 1ml cell dilution agent of per 1,000 ten thousand cells, with the cell resuspending in ice-cold cell diluent, this diluent comprises 20mM Hepes pH7.5 damping fluid, 150mM sodium-chlor, 10% v/v glycerine, 1% v/v Triton X100,1.5mM magnesium chloride, 1mM ethylene glycol-two (β amino-ethyl ether) N, N, N ', N '-tetraacethyl (EGTA) and 1mM PMSF (phenyl methyl sulfonic acid fluoride) [the 100mM methanol solution by prepared fresh before facing use adds PMSF].With suspension 4 ℃ with 13, centrifugal 10 minutes of 000rpm.Take out supernatant liquor (enzyme solution of stocking), equal portions are stored in-70 ℃.

[the 2 μ g/ml polyamino acid of 100 μ l gather (Glu, Ala, Tyr) 6:3:1 (Sigma-Aldrich Company Ltd., Poole, Dorset with substrate solution; Catalog number (Cat.No.) P3899) solution in phosphate buffered saline (PBS) (PBS)] a plurality of Nunc 96-hole MaxiSorp immunity of adding plate (Nunc, Roskilde, Denmark; Catalog number (Cat.No.) 439454) in each hole,, stored 16 hours at 4 ℃ with the plate sealing.Discard excessive substrate solution, with each hole successively with containing 0.05% v/v Tween, 20 (PBST; 300 μ l/ holes) PBS washing is with Hepes pH7.4 damping fluid (50mM, 300 μ l/ holes) washing 2 times, trace drying then.

Various testing compounds are dissolved among the DMSO, and the distilled water solution dilution with 10% DMSO obtains a series of diluents (from 40 μ M-0.0012 μ M).The various testing compound diluents of equal portions (25 μ l) are transferred in the hole of assay plate of washing.DMSO with dilution in " maximum " control wells replaces compound.To comprise adenosine-5 '-equal portions (the 25 μ l) magnesium chloride brine (40mM) of triphosphoric acid (ATP) adds in all test holes, except " blank " control wells that no ATP magnesium chloride is housed.For PDGFR α enzyme, with the ATP concentration of 14 μ M; For PDGFR β enzyme, with the ATP concentration of 2.8 μ M, for the KDR enzyme, with the ATP concentration of 8 μ M.

By Upstate Biotechnology Inc., Milton Keynes, UK obtain to be expressed in the active people PDGFR α and the PDGFR β recombinase (the corresponding PDGFR α of product 14-467, the corresponding PDGFR β of product 14-463) of Sf9 insect cell.Active people KDR recombinase is expressed in the Sf9 insect cell described above.

Immediately dilute various kinases with the enzyme thinner that contains 100mM Hepes pH7.4 damping fluid, 0.1mM sodium orthovanadate, 0.1% Triton X-100 and 0.2mM dithiothreitol (DTT) before use.The enzyme of the fresh dilution of equal portions (50 μ l) is added in each hole, plate is shaken 20 minutes at ambient temperature.Discard solution in each hole, wash each hole 2 times with PBST.With the anti-phosphotyrosine antibody of mouse IgG (Upstate Biotechnology Inc.; Product 05-321; 100 μ l) coefficient with 1:3667 dilutes with the PBST that comprises 0.5% w/v bovine serum albumin (BSA), and equal portions are added in each hole.Plate is shaken 1.5 hours at ambient temperature.Abandoning supernatant is washed each hole (* 2) with PBST.Sheep anti mouse Ig antibody (Amersham Pharmacia Biotech, Chalfont St Giles, Buckinghamshire, UK that horseradish peroxidase (HRP) is chain; Catalog number (Cat.No.) NXA 931; 100 μ l) coefficient with 1:550 dilutes with the PBST that comprises 0.5% w/v BSA, adds in each hole.Plate is shaken 1.5 hours at ambient temperature.Abandoning supernatant is washed each hole (* 2) with PBST.Make sodium perborate (PCSB) capsule (Sigma-AldrichCompany Ltd., Poole, Dorset, UK; Catalog number (Cat.No.) P4922) is dissolved in the distilled water (100ml), obtains comprising the phosphoric acid salt-citrate pH5 damping fluid (50mM) of 0.03% sodium perborate.Make this damping fluid of equal portions (50ml) and 2,2 '-the 50mg tablet (ABTS of azino two (3-ethyl benzo thiazole phenanthrolines-6-sulfonic acid); Roche Diagnostics Ltd., Lewes, East Sussex, UK; Catalog number (Cat.No.) 1,204 521) mixes.Equal portions (100 μ l) gained solution is added in each hole.At ambient temperature plate was shaken about 20 minutes, until with read plate spectrophotometer measurement " maximum " control wells in the optical density value of 405nm near 1.0." blank " (no ATP) and " maximum " (no compound) control value are used for definite dilution range that produces the testing compound of 50% enzymic activity inhibition.

(b) External phosphoric acid-Tyr751 PDGFR β ELISA measures

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

MG63 osteosarcoma cell line [American-type culture collection (ATCC) CCL 1427] routine is maintained 37 ℃ and 7.5% CO ₂Under Dulbecco ' s improvement Eagle ' s growth medium (DMEM; Sigma-Aldrich; Catalog number (Cat.No.) D6546) in, this substratum comprises 10% foetal calf serum (FCS; Sigma-Aldrich; Catalog number (Cat.No.) F7524) and 2mM L-glutaminate (InvitrogenLtd., Paisley, UK; Catalog number (Cat.No.) 25030-024).

During mensuration, with trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA) mixture (Invitrogen Ltd.; Catalog number (Cat.No.) 15400-054) cell of separation and Culture bottle, resuspending are in test media, and described substratum comprises no phenol red DMEM (Sigma-Aldrich; Catalog number (Cat.No.) D5921), comprise foetal calf serum (the FCS) (Sigma-Aldrich that 1% carbon removes (charcoal stripped); Catalog number (Cat.No.) F7524, by at 55 ℃ of gacs with dextran coating incubation 30 minutes under continuously stirring, centrifugal then gac and the filtration sterilization removed removes) and 2mM L-glutaminate (Invitrogen Ltd., catalog number (Cat.No.) 25030-024), obtain 6 * 10 ⁴Individual cell/ml.Sample aliquot (100 μ l) is planted transparent 96 hole tissue culturing plates (Corning Life Sciences, Koolhovenlaan, The Netherlands; Catalog number (Cat.No.) 3595) in each hole of 2-12 row (except that the 1st row) and B-G capable (except that A and H are capable), obtains the density of about 6000 cells in every hole.Equal portions (100 μ l) substratum is placed in the outer hole and makes fringing effect reduce to minimum.With cell 37 ℃ with 7.5% CO ₂Following overnight incubation allows the cell adhesion hole.

Testing compound is prepared into 10mM DMSO stock solution, uses the DMSO serial dilution as required, obtain certain concentration range.The sample aliquot (3 μ l) of all cpds concentration is added in the test media (300 μ l) to obtain second dilution range.The sample aliquot (16 μ l) of various gained compound concentrations is added in the cell in each hole." maximum " control cells accepts only to add the DMSO diluent of test media." minimum " control cells is accepted with reference to PDGFR inhibitor (16 μ l).With cell 37 ℃ with 7.5% CO ₂Under cultivated 90 minutes.

With following method PDGF _BBStimulate the gained cell.Make PDGF _BBLyophilisate (Sigma-Aldrich; Catalog number (Cat.No.) P4306) mixes with sterilized water, obtain 10 μ g/ml PDGF _BBStock solution.This stock solution is diluted in the test media, obtain 182ng/ml PDGF _BBSolution.Its sample aliquot (44 μ l) is added in the cell and " maximum " control cells of compound treatment." minimum " control cells is only accepted substratum.Make cell at 37 ℃ and 7.5% CO ₂Under cultivated 5 minutes.Remove each hole solution, add 120 μ l/ hole RIPA damping fluid dissolved cells, described damping fluid comprises 60mM three (methylol) aminomethane hydrochloride (Tris-HCl), 150mM sodium-chlor, 1mM EDTA, 1% v/v Igepal CA-630,0.25% Sodium desoxycholate, 1% v/v inhibitors of phosphatases mixture, 1 P2850,1% inhibitors of phosphatases mixture, 2 P5726 and 0.5% v/v proteinase inhibitor mixture P8340 (all chemical reagent and inhibitor mixture are all available from Sigma-Aldrich Company Ltd.).Made gained tissue culturing plate concussion at ambient temperature 5 minutes, and dissolved fully guaranteeing, freezing standby at-20 ℃ then.

With PDGF β antibody (R﹠amp; D Systems, Abingdon, Oxfordshire, UK; Catalog number (Cat.No.) AF385, comprising and forming final concentration with 100 μ l PBS is the lyophilized antibodies of 100 μ l/ml) coating MaxiSorp elisa plate (Nunc; Catalog number (Cat.No.) 439454).Antibody is diluted in carbonate-bicarbonate buffer (Sigma-Aldrich with 1:40; Catalog number (Cat.No.) C3041; Make a capsule dissolves in 100ml distilled water) in, 2.5 μ g/ml solution obtained.(50 μ l) adds each hole with sample aliquot, at 4 ℃ plate placed 16 hours.5 times (at every turn soaking 1 minute) washed with 300 μ l PBST/ holes in each hole.At ambient temperature each hole was handled 1 hour with 50 μ l, 3% BSA/PBST, then with 300 μ l PBST/ holes washing 2 times.

Allow tissue culturing plate be warmed to 0 ℃ with frozen cell solute.Equal portions (50 μ l) MG63 cytolysis thing is added in the elisa plate.On independent plate, duplicate various samples.Elisa plate was shaken 2 hours.Each hole is washed 2 times with 300 μ l PBST/ holes.With phosphoric acid PDGFR β antibody (Cell Signaling Technology, Beverley, MA, USA; Catalog number (Cat.No.) 3161) is diluted among 1% BSA/PBST with 1:1000.Equal portions (50 μ l) antibody-solutions is added in each hole.At ambient temperature each plate was shaken 1 hour.Plate is washed 2 times with 300 μ lPBST/ holes.Two anti-(the Cell SignalingTechnology that anti-rabbit horseradish peroxidase yoke is closed; Catalog number (Cat.No.) 7074) is diluted among 1% BSA/PBST with 1:2000.(50 μ l) adds in each hole with gained diluent sample aliquot, plate shaken 1 hour at ambient temperature.Each plate is washed 5 times with 300 μ l PBST/ holes.According to working instructions (PierceBiotechnology Inc., Rockford IL, USA; Catalog number (Cat.No.) 34080) preparation chemical luminous substrate.(50 μ l) adds in each hole with chemical luminous substrate solution sample aliquot, and Jiang Geban shook 2 minutes, and (Berkshire UK) reads luminous intensity for Tecan UK Ltd., Reading to read the plate instrument with SpectraFluor Plus.By measuring the ratio of every kind of testing sample " phosphoric acid antibody " plate reading and " total antibody " plate reading, finish analysis to every kind of compound, these ratios are drawn to determine the IC of every kind of testing compound ₅₀Value.

(c) External phosphoric acid-KDR ELISA measures

This mensuration determines that with conventional ELISA method testing compound suppresses the ability of tyrosine phosphorylation among the KDR (VEGFR2).

With Human umbilical vein endothelial cells (HUVECs; PromoCell) the conventional cultivation at 37 ℃ and 7.5% CO ₂Under growth medium in, this substratum comprises MCDB 131 (Gibco catalog number (Cat.No.) 10372-019; 500ml), comprise L-glutaminate (Sigma catalog number (Cat.No.) G3126; 0.848g), 1% penicillin streptomycin (Gibco catalog number (Cat.No.) 15140-122) and foetal calf serum (PAALaboratories catalog number (Cat.No.) A15-043; 50ml).

During mensuration, with trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA) mixture (InvitrogenLtd.; Catalog number (Cat.No.) 15400-054) cell of separation and Culture bottle, resuspending are in " test media ", and this substratum comprises MCDB 131 (500ml), comprise L-glutaminate (0.848g), 1% penicillin streptomycin and foetal calf serum (10ml).Sample aliquot (1ml) is planted (the Corning Life Sciences of 24 hole tissue culturing plates; Catalog number (Cat.No.) 3527) in each hole, obtains near 3.5 * 10 ⁴The density of individual cells/well.With cell 37 ℃ with 7.5% CO ₂Following overnight incubation allows it stick to the surface in hole.Morning next day, decant was measured substratum, and equal portions (0.5ml) " serum free medium " are added in each hole, and this substratum comprises MCDB 131 (500ml), comprises L-glutaminate (0.848g) and 1% penicillin streptomycin.Each plate was cultivated 2.5 hours at 37 ℃.

Testing compound is prepared into 10mM DMSO stock solution, uses the DMSO serial dilution as required.The sample aliquot (3 μ l) of various concentration testing compounds is diluted with " serum free medium " (300 μ l).The sample aliquot (50 μ l) of every kind of gained compound concentration is added in the cell in each hole." maximum " control cells is only accepted the DMSO diluent, and " minimum " contrast is accepted with reference to the KDR inhibitor to obtain the final concentration of 1 μ M.With cell 37 ℃ with 7.5% CO ₂Under cultivated 90 minutes.

Stimulate the gained cell with following method with VEGF.Make VEGF lyophilisate (Sigma-Aldrich; Catalog number (Cat.No.) V7259) mixes with the PBS that comprises 0.1% filtration sterilization BSA (0.1% BSA/PBS) to obtain 10 μ g/ml VEGF stock solutions.This stock solution is diluted in " serum free medium " to obtain 1000ng/ml VEGF solution.With its sample aliquot (50 μ l) add institute porose in.Make cell at 37 ℃ and 7.5% CO ₂Under cultivated 5 minutes.Remove the solution in each hole, add 100 μ l/ hole RIPA damping fluid dissolved cells, this damping fluid comprises 60mMTris-HCl, 150mM sodium-chlor, 1mM EDTA, 1% v/v Igepal CA-630,0.25% Sodium desoxycholate, 1% v/v inhibitors of phosphatases mixture, 1 P2850,1% inhibitors of phosphatases mixture, 2 P5726 and 0.5% v/v proteinase inhibitor mixture P8340.Made gained tissue culturing plate concussion at ambient temperature 5 minutes, and guaranteed to dissolve fully, freezing on dry ice then, be stored in-20 ℃ standby.

With phosphoric acid-VEGFR2 capture antibody (R﹠amp; D Systems, Abingdon, Oxfordshire, UK; Human Phospho-VEGFR2 ELISA, catalog number (Cat.No.) DYC 1766) coating MaxiSorp elisa plate (Nunc; Catalog number (Cat.No.) 439454).Antibody is diluted to 8 μ g/ml concentration in PBS, (100 μ l) adds in each hole with sample aliquot, at ambient temperature each plate stored 16 hours.Each plate is washed 3 times (at every turn soaking 1 minute) with 300 μ l PBST/ holes.PBS (1% BSA/PBS that contains 1% filtration sterilization BSA is used in each hole at ambient temperature; 200 μ l) handled 1 hour, then with 300 μ l PBST/ holes washing 3 times.

Allow tissue culturing plate be warmed to 0 ℃ with frozen cell solute.Add HUVEC cytolysis thing sample aliquot (100 μ l), elisa plate is shaken 3 hours at ambient temperature.Each hole is washed 3 times with 300 μ l PBST/ holes.To resist-phosphoric acid-tyrosine-HRP detection antibody (R﹠amp; D Systems; Human Phospho-VEGFR2 ELISA, catalog number (Cat.No.) DYC 1766) dilute with the 0.1% BSA/Tris-buffered saline solution that comprises 0.05%v/v Tween 20 (TBST), obtain the working concentration of 600ng/ml.(100 μ l) adds each hole with gained diluent sample aliquot, at ambient temperature each plate shaken 2 hours.Each plate is washed 4 times with 300 μ lPBST/ holes.According to working instructions (Pierce Biotechnology Inc., Rockford IL, USA; Catalog number (Cat.No.) 34080) preparation chemical luminous substrate.(50 μ l) adds in each hole with chemical luminous substrate solution sample aliquot, and each plate was shaken 2 minutes, reads plate instrument (Tecan UKLtd.) with SpectraFluor Plus and reads luminous intensity.Analyze the gained data, determine the IC of various testing compounds ₅₀Value,

(d) External MG63 osteosarcoma proliferation assay

This mensuration determines that testing compound suppresses the ability of MG63 osteosarcoma cell (ATCC CCL 1427) propagation.

With the MG63 cell with 1.5 * 10 ³Individual cells/well kind is gone into 96 hole hyaline tissues and is cultivated processing assay plate (Corning Life Sciences; Catalog number (Cat.No.) 3595) in, this plate has added 60 μ l and has measured substratum/hole, and this substratum comprises FCS and the 2mM glutamine that no phenol red DMEM, 1% gac remove, with cell at 37 ℃ and 7.5% CO ₂Following overnight incubation.

Testing compound is dissolved in obtains the 10mM stock solution among the DMSO.The equal portions stock solution is diluted with above-mentioned test media, in the various diluents adding appropriate wells with 20 μ l equal portions.Serial dilution is to obtain the test concentrations of certain limit.Each plate all comprises the control wells that only adds DMSO solution.Each plate is duplicated.Make PDGF _BBLyophilisate mixes with the 4mM hydrochloric acid soln that comprises 0.1% filtration sterilization BSA, obtains 10 μ g/ml PDGF _BBStock solution.This stock solution is diluted in obtains 250ng/ml PDGF in the test media _BBSolution.Its sample aliquot (20 μ l) is added in one group of control wells, obtain " maximum " contrast.Its sample aliquot (20 μ l) is added in one group of compound treatment plate that duplicates, these plates are called ＂ PDGF _BBStimulate the ＂ plate.Second group is duplicated the compound treatment plate and only accepts substratum, and these plates are called " substantially " plate.Substratum is only accepted in " minimum " contrast.With each plate 37 ℃ with 7.5% CO ₂Under cultivated 72 hours.

With BrdU labelled reagent (Roche Diagnostics Ltd., Lewes, East Sussex, UK; Catalog number (Cat.No.) 647229) be diluted in the 1:100 coefficient and contain in the DMEM substratum that 1% gac removes FCS, (10 μ l) adds in each hole with sample aliquot, and obtaining final concentration is 10 μ M.Each plate was cultivated 2 hours at 37 ℃.The decant substratum.With denaturing soln (FixDenat solution, Roche Diagnostics Ltd.; Catalog number (Cat.No.) 647 229; 200 μ l) add in each hole, plate is shaken 30 minutes at ambient temperature.Pour out supernatant liquor, each hole is washed with PBS (200 μ l/ hole).To resist-BrdU-superoxide enzyme solution (Roche Diagnostics Ltd.; Catalog number (Cat.No.) 647229) is diluted in the antibody dilution agent (Roche Diagnostics Ltd., catalog number (Cat.No.) 647229) with the 1:100 coefficient, 100 μ l gained solution are added in each hole.At ambient temperature each plate was shaken 90 minutes.With each hole PBS (* 3; 300 μ l) washing is to guarantee to remove unconjugated antibody conjugates.With each plate trace drying, with tetramethyl benzidine substrate solution (Roche Diagnostics Ltd.; Catalog number (Cat.No.) 647229; 100 μ l) add in each hole.On the rocker instrument, shake each plate lightly, in 10-20 minute, show color simultaneously.With sulphuric acid soln (1M; 50 μ l) the adding appropriate well is interior to stop any further reaction, measures the 450nm absorbancy in each hole.Determine that various testing compounds suppress the degree of cell proliferation in concentration range, derivation antiproliferative IC ₅₀Value.

(e) External HUVEC proliferation assay

The ability of the propagation of the factors stimulated growth of the definite testing compound inhibition Human umbilical vein endothelial cells of this mensuration (HUVECs).

In MCDB 131 (Gibco BRL) and 7.5% v/v foetal calf serum (FCS), separate HUVECs, place in the mixture of 96 orifice plates (passage 2-8) MCDB131,2% v/v FCS, 3 μ g/ml heparin and 1 μ g/ml hydrocortisone with the concentration of 1000 cells/well.After minimum 4 hours, give suitable somatomedin of cell (as VEGF) and testing compound.With culture at 37 ℃ and 7.5% CO ₂Under cultivated 4 days.At the 4th day, cell culture with 1 μ Ci/ hole tritiated thymidine (Amersham product TRA 61) burst process, was cultivated 4 hours.With 96 orifice plate collector (Tomtek) collecting cells, measure the tritium that mixes with Beta plate count device.Mix intracellular radioactivity, be expressed as counting/minute (cpm), be used to measure of the inhibition of every kind of testing compound the cell proliferation of factors stimulated growth.

(f) Solid tumor disease model in the body

This thermometrically compound suppresses the ability of solid tumor growth.

By 1 * 10 in subcutaneous injection 100 μ l 50% (v/v) the Matrigel/ serum-free culture based sols ⁶Individual CaLu-6 cell/mouse is based upon the CaLu-6 tumor xenogeneic graft veutro of female athymia Switzerland nu/nu mouse.After the Transplanted cells 10 days, with mice group, every group had 8-10 animal, has commeasurable group of equal gross tumor volume.Use the vernier caliper measurement tumour, use following formula

(1×w)×√(1×w)×(π/6)

Volume calculated, wherein 1 is longest diameter, w is perpendicular to the diameter of longest diameter.Orally give testing compound once a day, minimum 21 days, control animal was only accepted diluted chemical compound liquid.Measure tumour 2 times weekly.With Student ' s T check and/or Mann-Whitney rank test, the mean tumour volume by compare group and treatment group calculates growth inhibiting level.

Though according to expectation, the pharmacological properties of formula I compound changes along with structural modification, but usually, can above-mentioned test (a) and (b), (c), (d), (e) and (f) one or multinomial in, the activity that has with following concentration or dosage confirmation formula I compound :-

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

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

Test (b) :-to forming the IC of phosphoric acid-Tyr751 among the PDGFR β ₅₀In for example 0.1nM-1 μ M scope;

Test (c) :-to forming the IC of phosphoric acid-tyrosine among the KDR ₅₀In for example 0.1nM-5 μ M scope;

Optionally suppress active those compounds and pdgf receptor family Tyrosylprotein kinase had to have more, to forming the IC of phosphoric acid-tyrosine among the KDR ₅₀At 100nM for example to greater than 5 μ M scopes;

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

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

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

For example, the quinoline compound that is disclosed in embodiment 1 has activity in test (b), for the IC that forms phosphoric acid-Tyr751 in PDGFR β ₅₀Near 2nM; Has activity in test (c), for the IC that in KDR, forms phosphoric acid-tyrosine ₅₀Near 0.76 μ M.

For example, as the quinoline compound of first kind of compound in embodiment 2 Table I, listing be, for the IC that in PDGFR β, forms phosphoric acid-Tyr751 in the activity that test (b) has ₅₀Near 1nM.

For example, disclosed quinoline mixture has activity in test (b) among the embodiment 3, for the IC of the phosphoric acid-Tyr751 that forms in PDGFR β ₅₀Near 30nM.

For example, in test (b), has activity as the quinoline compound of the 5th kind of compound of in embodiment 2 Table I, listing, for the IC that in PDGFR β, forms phosphoric acid-Tyr751 ₅₀Near 2nM; In test (c), has activity, for the IC that in KDR, forms phosphoric acid-tyrosine ₅₀Greater than 2 μ M.

For example, in test (b), has activity as the quinoline compound of the 12nd kind of compound of listing in embodiment 2 Table I, for the IC that in PDGFR β, forms phosphoric acid-Tyr751 ₅₀Near 5nM; In test (c), have activity, in KDR, form the IC of phosphoric acid-tyrosine ₅₀Greater than 2 μ M.

For example, in test (b), has activity as the quinoline compound of the 14th kind of compound of listing in embodiment 2 Table I, for the IC that in PDGFR β, forms phosphoric acid-Tyr751 ₅₀Near 5nM; In test (c), has activity, for the IC that in KDR, forms phosphoric acid-tyrosine ₅₀Greater than 2 μ M.

For example, in test (b), has activity as the quinoline compound of the 15th kind of compound of listing in embodiment 2 Table I, for the IC that in PDGFR β, forms phosphoric acid-Tyr751 ₅₀Near 5nM; In test (c), has activity, for the IC that in KDR, forms phosphoric acid-tyrosine ₅₀Greater than 2 μ M.

For example, in test (b), has activity as the quinoline compound of the 18th kind of compound of listing in embodiment 2 Table I, for the IC that in PDGFR β, forms phosphoric acid-Tyr751 ₅₀Near 5nM; Have activity in test (c), in KDR, form the IC of phosphoric acid-tyrosine ₅₀Greater than 2 μ M.

When the formula I compound that gives the hereinafter above qualification of limiting dose scope or its pharmacy acceptable salt, disadvantageous toxicology reaction does not appear in expection.

According to another aspect of the invention, provide to comprise and the formula I quinoline that above limits of pharmaceutically acceptable diluent or carrier combination or the medicinal compositions of its pharmacy acceptable salt.

Composition of the present invention can adopt the form that is fit to orally use (as tablet, lozenge, hard or soft capsule, water or oil-based suspension, emulsion, dispersible powder or granula, syrup or elixir), the local form of using is (as creme, ointment, gelifying agent or water or oily solution or suspension), the form of inhalation (as meticulous pulvis that separates or liquid aerosol), be blown into the form (as the meticulous pulvis that separates) of administration or the form of parenteral admin and (be used for intravenously as conduct, subcutaneous, the sterile aqueous of intraperitoneal or intramuscular administration or oily solution or as the suppository of rectal administration).

Available conventional pharmaceutical excipient well known in the art obtains composition of the present invention by ordinary method.Therefore, the composition that is intended to orally use can comprise for example one or more tinting materials, sweeting agent, seasonings and/or sanitas.

With one or more excipient composition will be with the active principle for preparing single formulation according to being carried out necessary change by treatment target and concrete route of administration.For example, the preparation that is intended to the orally give people will comprise for example 1mg-1g promoting agent (being more suitable for being 1-250mg, as 1-100mg) usually, the mixed with excipients of promoting agent and suitable and convenient amount, and its amount can change between total about 5-of compound weight about 98%.

According to well-known medical principle, be used for the treatment of or prevent the size nature of the formula I compound dosage of purpose to change according to disease character and severity, animal or patient's age and sex and route of administration.

When formula I compound was used for the treatment of or prevents purpose, the per daily dose of its administration will be usually at for example 1mg/kg-100mg/kg weight range, if desired then gradation administration.Usually, when using the parenteral approach, will give than low dosage.Therefore, for example for intravenous administration, for example dosage of 1mg/kg-25mg/kg weight range will be used usually.Similarly, for inhalation, for example dosage of 1mg/kg-25mg/kg weight range will be used usually.But preferred oral administration, particularly tablet form.When giving more effective compound, make per daily dose at for example 1mg/kg-25mg/kg weight range.When giving compounds effective, make per daily dose at for example 1mg/kg-15mg/kg weight range.Usually, unit dosage will comprise the The compounds of this invention of about 10mg-0.5g.

As mentioned above, antagonism pdgf receptor kinase activity particularly suppresses PDGF α and/or PDGF beta receptor Tyrosylprotein kinase, and expection helps treating various kinds of cell proliferative disease such as cancer, particularly suppresses tumor growth and transfer, suppresses the leukemia progress.

We have found that now new quinoline described herein has the effective active of inhibition of cell proliferation disease.We think that this compound can be used for treating cell proliferation disorders, as providing antitumor action by the effect that suppresses the pdgf receptor Tyrosylprotein kinase.In addition, as mentioned above, PDGF relates to vasculogenesis, and this is the process to the very crucial formation neovascularity of tumour continued growth.Therefore believe that the The compounds of this invention expection helps treating multiple and vasculogenesis and/or vascular permeability increase diseases associated such as cancer, particularly suppresses tumor development.

According to another aspect of the invention, provide the formula I quinoline or its pharmacy acceptable salt that are defined as above, be used for warm-blooded animal such as people as medicine.

According to another aspect of the invention, provide the formula I quinoline or its pharmacy acceptable salt that are defined as above, 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, the formula I quinoline or the purposes of its pharmacy acceptable salt in the preparation medicine that are defined as above are provided, and described medicine is used for the treatment of (or prevention) cell proliferation disorders or treatment (or prevention) and vasculogenesis and/or vascular permeability diseases associated.

This respect according to the present invention, be provided at (or prevention) cell proliferation disorders of treatment in the warm-blooded animal that needs treatment like this (or prevention) or treat the method for treatment (or prevention) and vasculogenesis and/or vascular permeability diseases associated in the warm-blooded animal of (or prevention) at needs like this, comprise the formula I quinoline or its pharmacy acceptable salt that above limit that give described animal effective dose.

Suitable cell proliferation disorders comprises neoplastic disease, for example, lung cancer (nonsmall-cell lung cancer, 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 vulva and skin carcinoma (as dermatofibrosarcoma) and leukemia and lymphoma such as chronic granulocytic leukemia (CML), chronic myeloid monocyte leukemia (CMML), acute lymphoblastic leukemia (ALL), chronic neutrophilic leukemia (CNL), acute myelocytic leukemia (AML) and multiple myeloma.

This respect according to the present invention also is provided at the method for the treatment of cell proliferation disorders (as solid tumor disease) in the warm-blooded animal that needs treatment like this, comprises the formula I quinoline or its pharmacy acceptable salt that above limit that give described animal effective dose.

Other suitable cell proliferation disorders comprises nonmalignant disease such as vascular disease (as atherosclerosis and restenosis, as being secondary to the restenosis process of sacculus angioplasty and heart arter bypass), 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, skin hypersensitivity, atopic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.

The suitable disease relevant with vasculogenesis and/or vascular permeability comprises, for example is found in diabetic retinopathy, psoriatic, cancer, rheumatoid arthritis, sebaceous cyst, Kaposi ' s sarcoma and angiomatous bad or pathologic vessels generation.

According to another aspect of the invention, be provided for the formula I quinoline that is defined as above or its pharmacy acceptable salt 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 quinoline or its pharmacy acceptable salt that are defined as above be used for the treatment of (or prevention) those tumours in preparation the medicine is provided, 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 quinoline that is defined as above or its pharmacy acceptable salt that gives described animal effective dose.

According to another aspect of the invention, be provided for providing the formula I quinoline that is defined as above or its pharmacy acceptable salt of 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 provides the formula I quinoline that is defined as above or its pharmacy acceptable salt to be used for providing the purposes of the medicine of pdgf receptor enzyme inhibition (as PDGF α and/or PDGF beta receptor tyrosine kinase inhibitory activity) in preparation.

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), comprise the formula I quinoline that is defined as above or its pharmacy acceptable salt that give significant quantity.

The anticancer therapy that above limits monotherapy be can be used as, perhaps except quinoline of the present invention, routine operation or radiotherapy or chemotherapy be comprised.This based chemotherapy can comprise the antitumor drug of one or more following kinds :-

(i) be used for other the antiproliferative/antitumour drug and the combination thereof of medical science oncology, as alkylating agent (as cis-platinum, oxaliplatin, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan, Temozolomide and nitrourea); Metabolic antagonist (as antifol such as fluorine pyrimidine such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); Antitumor antibiotics (as anthracycline antibiotics such as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, Mitomycin-C, gengshengmeisu and Plicamycin); Antimitotic agent (as vinca alkaloids such as vincristine(VCR), vinealeucoblastine(VLB), vindesine, vinorelbine, Taxan such as taxol and Docetaxel and polo kinase inhibitor); And topoisomerase enzyme inhibitor (as podophyllin such as Etoposide and teniposide, amsacrine, Hycamtin and camptothecine);

(ii) cytostatic agent such as antiestrogen are (as tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogen is (as bicalutamide, Drogenil, Nilutamide and cyproterone acetate), lhrh antagonist or LHRH agonist are (as goserelin, Leuprolide and buserelin), progestogens (as Magace), aromatase inhibitor is (as Anastrozole, letrozole, vorozole and Exemestane) and 5 inhibitor such as finasteride;

(iii) anti-invasion agent [as c-Src kinases man's group inhibitor such as 4-(6-chloro-2,3-methylenedioxyphenyl amino)-7-[2-(4-methylpiperazine-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base quinazoline (AZD0530; International Patent Application WO 01/94341) and the inhibitor of bosutinib (SKI-606) and inhibitors of metalloproteinase such as Marimastat and upar function];

The (iv) inhibitor of somatomedin function: for example this type of inhibitor comprises growth factor antibodies and growth factor receptor antibody [as anti--erbB2 antibody trastuzumab and anti--erbB1 antibody Cetuximab (C225) and handkerchief Buddhist nun monoclonal antibody]; This type of inhibitor for example also comprises, tyrosine kinase inhibitor is [as the epidermal growth factor family inhibitor (as EGFR family tyrosine kinase inhibitor such as Gefitinib (ZD1839), erlotinib (OSI-774) and CI 1033 and erbB2 tyrosine kinase inhibitor such as lapatinibditosylate), pHGF man group inhibitor, the insulin-like growth factor acceptor inhibitor, kinase whose other inhibitor of Thr6 PDGF BB family and/or bcr/abl such as imatinib, Dasatinib (BMS-354825) and nilotinib (AMN107), pass through MEK, AKT, PI3, c-kit, Flt3, the kinase whose cell signal inhibitor of CSF-IR and/or aurora]; This type of inhibitor comprises that also cell cycle protein dependent kinase inhibitor comprises CDK2 and CDK4 inhibitor; This type of inhibitor for example comprises also that the inhibitor of serine/threonine kinase is (as agent of Ras/Raf signal suppressing such as farnesyl transferase inhibitor, as Xarelto (BAY 43-9006), for than cutting down Buddhist nun (R115777) and lonafarnib (SCH66336);

(v) anti-angiogenic agent is as suppressing the anti-angiogenic agent of vascular endothelial growth factor effect, [as anti-vascular endothelial cell growth factor antibody such as rhuMAb-VEGF (Avastin ^TM), perhaps for example his Buddhist nun (PTK787) of vegf receptor tyrosine kinase inhibitor such as ZD6474 (ZD6474), vara, Sutent (SU11248), A Xi for Buddhist nun (AG-013736), pazopanib (GW786034) 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 WO 00/47212), the perhaps compound (as the inhibitor and the angiostatin of linomide, integrin alpha v beta 3 function) by another kind of machining function for example];

(the vi) compound of vascular lesion agent such as Combretastatin A4 and the International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO02/04434 and the WO 02/08213 that are disclosed in;

(vii) antisense therapy is as pointing to above those antisense therapies of listed target, as ISIS2503, anti--the ras antisense therapy;

(viii) gene therapy approach comprises that displacement distortion gene for example such as distored p53 or distored BRCA1 or BRCA2, GDEPT (gene pacemaker enzyme prodrug therapy) approach are as with the approach of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase with increase approach such as the multidrug resistance gene therapy of patient to chemotherapy or radiotherapy tolerance; With

(ix) immunotherapy approach, comprise and for example increase exsomatizing and the interior approach of body of patient tumors cell immunogenicity, as using cytokine such as interleukin-22, interleukin 4 or granulocyte-macrophage colony stimutaing factor transfection, reduce the approach of T cell anergy, approach with the dendritic cell of the immunocyte of transfection such as cytokine transfection, with the tumor cell line approach of cytokine transfection with the approach of antiidiotypic antibody.

By simultaneously, give the individualized treatment composition in order or separately and can finish this type of combination therapy.This type of combination product is used other forms of pharmacologically active agents in the The compounds of this invention in the above-mentioned dosage range and the dosage range that goes through.

This respect according to the present invention provides the combination that is suitable for treating cell proliferation disorders (as solid tumor disease), comprises formula I quinoline that is defined as above and other antineoplastic agent that is defined as above.

This respect according to the present invention is provided for the medicine of the formula I quinoline that is defined as above comprising of combination therapy cancer and other antineoplastic agent that is defined as above.

Specifically, above the anticancer therapy of Xian Dinging can comprise and the quinoline of the present invention of anti-angiogenic agent combination, and described anti-angiogenic agent is anti-vascular endothelial cell growth factor antibody such as bevacizumab and/or vegf receptor tyrosine kinase inhibitor such as ZD6474, Wa Talani, Sutent or AZD2171 for example.

This respect according to the present invention provides the combination that is suitable for treating cell proliferation disorders (as solid tumor disease), comprises formula I quinoline that is defined as above and the anti-angiogenic agent that is defined as above.

This respect according to the present invention also is provided for the medicine of the formula I quinoline that is defined as above comprising of combination therapy cancer and the anti-angiogenic agent that is defined as above.

Above the anticancer therapy of Xian Dinging also can comprise and the quinoline of the present invention of anti-invasion agent combination, and described anti-invasion agent is c-Src kinases man's group inhibitor such as AZD0530 or bosutinib for example.

This respect according to the present invention provides the combination that is suitable for treating cell proliferation disorders (as solid tumor disease), comprises formula I quinoline that is defined as above and the anti-invasion agent that is defined as above.

This respect according to the present invention also is provided for the medicine of the formula I quinoline that is defined as above comprising of combination therapy cancer and the anti-invasion agent that is defined as above.

Above the anticancer therapy of Xian Dinging also can comprise the quinoline of the present invention that makes up with anti-angiogenic agent, described anti-angiogenic agent is for example c-Src kinases man's group inhibitor such as AZD0530 or bosutinib of anti-vascular endothelial cell growth factor antibody such as bevacizumab and/or vegf receptor tyrosine kinase inhibitor such as ZD6474, Wa Talani, Sutent or AZD2171 and anti-invasion agent for example.

This respect according to the present invention provides the combination that is suitable for treating cell proliferation disorders (as solid tumor disease), the anti-invasion agent that comprises the formula I quinoline that is defined as above, the anti-angiogenic agent that is defined as above and be defined as above.

This respect according to the present invention also is provided for the medicine of combination therapy cancer, the anti-invasion agent that described medicine comprises the formula I quinoline that is defined as above, the anti-angiogenic agent that is defined as above and is defined as above.

In any conjoint therapy of above-described cancer, also can choose wantonly and have bisphosphonate.Bisphosphonate is the bisphosphonic acid derivatives of metallic cation (particularly calcium) process that can regulate warm-blooded animal such as people.Therefore, diphosphonate can be used for prevention or treatment disease, as osteoporosis and molten bone osteopathy, as occurring in the osteolytic lesion of metastatic carcinoma such as kidney, thyroid carcinoma and lung cancer, particularly mammary cancer and prostate cancer.Suitable diphosphonate comprises tiludronic acid, Ibandronic acid, ineadronic acid, risedronic acid, Zoledronic acid, clodronic acid, neridronic acid, pamidronic acid and clinic effect of alendronate.

Be used for the warm-blooded animal therapeutical agent of (comprising the people) though the chief value of formula I compound is conduct, whenever suppress the effect of pdgf receptor Tyrosylprotein kinase at needs, they are also all useful.Therefore, they can be used as the pharmacology standard substance and are used to develop new biology test and study new medicine.

Now will be in the present invention of following examples illustrated, wherein in general:

(i) except as otherwise noted, otherwise to operate in envrionment temperature be to carry out under 17-25 ℃ of scope and rare gas element such as nitrogen or the argon gas atmosphere;

(ii) the reaction of under microwave irradiation, carrying out with instrument such as standard or high be provided with ' SmithSynthesiser ' (300KWatts) carries out, this instrument is regulated microwave power output automatically with temperature sensor, and is temperature required to keep; Perhaps available Emrys Optimizer ' microwave instrument;

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

(iv) when needs, use anhydrous magnesium sulfate drying organic solution, after removing by filter residual solids, carry out aftertreatment, evaporate by rotation vacuum-evaporation;

(v) when having yield, not necessarily obtainable maximum value; Where necessary, greater amount reaction product, then reaction repeated if desired;

(vi) common, with the structure of nucleus magnetic resonance (NMR) and/or mass-spectrometric technique confirmation formula I end product; For example obtain positive and negative ion data and obtain the electrospray ionization mass spectrum data, only report the ion relevant usually with parent structure with Waters ZMD or Waters ZQ LC/ mass spectrograph; With the δ scale measure proton N MR ( ¹H NMR) chemical displacement value for example uses the Bruker Spectrospin DPX300 spectrograph of field intensity as 300MHz; Use following abbreviation: s, unimodal; D, bimodal; T, three peaks; Q, four peaks; M, multimodal; Br, broad peak;

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

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

(ix) column chromatography (fast operation) and medium pressure liquid chromatography (MPLC) carry out on silica gel, as usefulness Merck Kieselgel silica gel (Art.9385) or with Armen Instrument (56890-SaintAve, post France);

(x) preparation HPLC is at the C18 reverse phase silica gel, as preparing reversed-phase column (5 microns silica gel at Waters ' Xterra ', the 19mm diameter, 100mm is long) or on Novasep SAS ' ProchromDAC ' preparation reversed-phase column, carry out, the solvent mixture that reduces with polarity is as eluent, 1% acetic acid aqueous solution that reduces as polarity or the mixture of 1% ammonium hydroxide (d=0.88) aqueous solution and acetonitrile;

(xi) when some compound that obtains was acid salt such as mono-hydrochloric salts or dihydrochloride, the stoichiometry of salt was based on the number and the character of compound neutral and alkali group; Usually, do not obtain the ultimate analysis data to determine the precise chemical structure metering of salt;

(xii) use following abbreviation :-

DMF N, dinethylformamide

The DMA N,N-dimethylacetamide

The DMSO methyl-sulphoxide

The THF tetrahydrofuran (THF)

NMP N-methylpyrrolidin-2-ketone

Mass Spectrum mass spectrum

Embodiment 1

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

Toward the 2-[5-(6 that stirs, 7-dimethoxy-quinoline-4-base oxygen base) pyridine-2-yl] add diisopropyl ethyl amine (0.154ml), 4-amino-1-ethyl-1H-pyrazoles (0.098g) and phosphofluoric acid 2-(7-azepine benzo triazol-1-yl)-1 successively in the mixture of acetate (0.25g) and DMF (3ml), 1,3,3-tetramethyl-urea (V) (0.335g) and at ambient temperature stirs the mixture that obtains 16 hours.Reaction mixture is through preparation HPLC purifying, and the water (containing 0.2% volatile salt) that use Waters ' β Basic Hypersil ' reversed-phase column (5 microns silica gel, 30mm diameter, 250mm length) and polarity reduce gradually and the mixture of acetonitrile are as elutriant.Products therefrom grinds with ether and the alcoholic acid mixture of 19:1.With the solid vacuum-drying that obtains.Obtain title compound (0.076g) thus;

¹ H NMR：(DMSOd ₆)1.3(t，3H)，3.85(s，2H)，3.9(s，3H)，3.95(s，3H)，4.1(q，2H)，6.5(d，1H)，7.4(m，2H)，7.5(m，2H)，7.75(m，1H)，7.9(s，1H)，8.5(m，2H)； Mass Spectrum：M+H ⁺434.

As the 2-[5-of raw material (6,7-dimethoxy-quinoline-4-base oxygen base) pyridine-2-yl] acetate is prepared as follows:

The mixture of 5-hydroxy-2-methyl pyridine (100g), benzyl chloride (116ml), salt of wormwood (177.2g) and DMA (1.5 liters) is stirred and is heated to 90 ℃ of maintenances 5 hours.With this mixture filtration and with filtrate vacuum-evaporation.Resistates is through purification by silica gel column chromatography, and the sherwood oil that use polarity increases gradually and the gradient solvent mixture of ethyl acetate (95:5 to 1:1) are as elutriant.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).

At ambient temperature, the mixture with the product, 3-chloroperoxybenzoic acid (184.3g) and the methylene dichloride (2 liters) that obtain thus stirred 1 hour.This mixture is used 5% aqueous sodium carbonate and water washing 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).

Add the product that obtains thus in the diacetyl oxide (296ml) that stirs and be heated to 135 ℃ (bathing temperature) in batches and under this temperature, the mixture that obtains is continued to stir 30 minutes.With in this mixture impouring mixture of ice and water and stirred 1.5 hours.Add sodium-chlor and make water saturated, subsequently this mixture ethyl acetate extraction.Organic phase is through dried over mgso and evaporation.Crude product is through purification by silica gel column chromatography, and the methylene dichloride that use polarity increases gradually and the solvent mixture of ether (100:0 to 11:9) are as elutriant.Obtain 2-acetoxy-methyl-5-benzyloxy pyridine (119g) thus; Mass spectrum: M+H ⁺258.

In the solution of potassium hydroxide (32.9g) in methyl alcohol (330ml) that stirs, add the product that obtains thus in batches.With the mixture heating up that obtains to refluxing and keeping 1 hour.Remove a large amount of solvents and resistates is distributed between ether and water by evaporation.Organic phase is through dried over mgso and evaporation.Obtain 5-benzyloxy-2-hydroxy-methyl pyridine (93.7g) thus; Mass spectrum: M+H ⁺216.

The product that obtains thus is dissolved in the methylene dichloride (700ml) and this solution is cooled to 0 ℃.In thionyl chloride (34.8ml), this mixture is cooled to 0 ℃.Allow the mixture that obtains rise to envrionment temperature also with this mixture stirring 1 hour.With solvent evaporation, residual solid is ground with ether.The solid filtering that obtains is separated.Obtain 5-benzyloxy-2-chloromethyl pyridine hydrochloride (115.6g) thus; Mass spectrum: M+H ⁺234.

The product that obtains thus is suspended in the ethanol (450ml) and adds potassiumiodide (1.5g), water (150ml) and potassium cyanide (55.6g) successively.Reaction mixture is stirred and is heated to the maintenance 4 hours that refluxes.The mixture that obtains is cooled to envrionment temperature.Add saturated sodium bicarbonate aqueous solution, subsequently this mixture dichloromethane extraction.Organic phase water and salt water washing are through dried over mgso and evaporation.The gained solid grinds with ether.Collect the solid that obtains by filtering, obtain 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).

The product that obtains thus is dissolved in the methyl alcohol.Adding 25% aqueous sodium hydroxide solution (170ml) also keeps this mixture heating up 18 hours to refluxing.This mixture is cooled to envrionment temperature and with solvent evaporation.Be dissolved in the water resistates and filtration.Filtrate is cooled to 0 ℃ and by adding the 6N aqueous hydrochloric acid filtrate is acidified to pH4.7.Precipitate and separate with obtaining washes with water, grinds with ether subsequently.With the solid vacuum-drying that obtains.Obtain 2-(5-benzyloxy pyridine-2-yl) acetate (84.1g) thus; Mass spectrum: M+H ⁺244.

In the suspension of 2-(5-benzyloxy pyridine-2-yl) acetate (84.1g) in methylene dichloride (1.4 liters) that stirs, add the 2-tertiary butyl-1,3-di-isopropyl isourea [629g; By under envrionment temperature, argon gas, DIC (496ml), the trimethyl carbinol (303ml) and cuprous chloride (4.71g) reaction 48 hours and the liquid that this mixture filtration is obtained] and at ambient temperature this mixture was stirred 48 hours.By removing by filter the precipitation that obtains, subsequently with the filtrate vacuum concentration.Resistates is through purification by silica gel column chromatography, and the methylene dichloride that use polarity increases gradually and the solvent mixture of ethyl acetate (100:0 to 19:1) are as elutriant.Obtain buttery 2-(5-benzyloxy pyridine-2-yl) tert.-butyl acetate (63.7g) thus, it is left standstill crystallization;

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).

In the mixture of 2-(the 5-benzyloxy pyridine-2-yl) tert.-butyl acetate (58.7g), 1 (200ml) and the ethanol (1 liter) that stir, add hydroxide palladium/carbon catalyst (10g; About 20% palladium and about 50% water).With the mixture heating up that obtains to refluxing and keeping 2 hours.This mixture is cooled to envrionment temperature, subsequently by removing by filter catalyzer.Filtrate is evaporated.Resistates grinds with ether.With the solids constituent that obtains from.Obtain 2-(5-pyridone-2-yl) tert.-butyl acetate (39.6g) of white solid 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).

With 4-chloro-6,7-dimethoxy-quinoline (3g; The embodiment 2 of International Patent Application WO 98/13350), the mixture of (5-pyridone-2-yl) tert.-butyl acetate (3.22g), 4-dimethylaminopyridine (4.9g) and chlorobenzene (30ml) stirs and is heated to 130 ℃ of maintenances 8 hours.The mixture that obtains is cooled to envrionment temperature and dilutes with ether.This mixture is filtered, and filtrate water washs and extracts (60ml, twice) with the 1N aqueous hydrochloric acid.Acidic solution carefully alkalizes with the ether washing and by adding solid sodium bicarbonate.The mixture aqueous solution ethyl acetate extraction that obtains.Organic phase water and salt water washing are through dried over mgso and evaporation.Obtain buttery 2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base) pyridine-2-yl thus] tert.-butyl acetate (4.38g), it need not to be further purified use; Mass spectrum: M+H ⁺397.

Be cooled to 0 ℃ 2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base) pyridine-2-yl toward what stir] add trifluoroacetic acid (20ml) in the mixture of tert.-butyl acetate (4.38g) and methylene dichloride (60ml).At ambient temperature the mixture that obtains was stirred 16 hours.With solvent evaporation.Add toluene, subsequently a spot of trifluoroacetic acid is removed in this mixture evaporation.Resistates grinds with the mixture of ether and ethyl acetate.With the solid suspension that obtains in methylene dichloride and add methyl alcohol until dissolving.Adding diisopropyl ethyl amine (5ml) also stirs this mixture 30 minutes at ambient temperature.With the mixture evaporation that obtains, remaining oily matter grinds with the mixture of ether and ethyl acetate.With the solids constituent that obtains from and vacuum-drying.Obtain 2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base) pyridine-2-yl thus] acetate (2.43g); Mass spectrum: M+H ⁺341.

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

The 4-nitropyrazole is available from N.D.Zelinsky Institute, Organic Chemistry, Leninsky prospect 47,117913 Moscow B-334, Russia.This compound also can be prepared as follows:

In the solution of pyrazoles (13.6g) in Glacial acetic acid (51ml) that stirs and be cooled to-10 ℃ (using ice-salt bath), drip nitrosonitric acid (9.5ml).Form loose precipitation.Dripping diacetyl oxide (27ml) also stirs the mixture that obtains 2.5 hours at ambient temperature.This mixture is poured on ice and the acidity of this mixture reduced to pH5 by adding salt of wormwood.By filtering with precipitate and separate.The solid that obtains is dissolved in the water aqueous solution extracted with diethyl ether.Organic solution is through dried over mgso and filtration.The filtrate evaporation concentration is become the 50ml volume, add in the filtrate sherwood oil (b.p.60-80 ℃, 50ml).Form precipitation, this precipitation is passed through filtering separation.This solid is considered to 1-nitropyrazole (20.6g); ¹ HNMR: (DMSOd ₆) 6.71 (s, 1H), 7.88 (s, 1H), 8.81 (s, 1H).This compound explosibility and care should be used to are handled.

Toward stirring and in ice bath, drip in the refrigerative 1-nitropyrazole sample (20.3g) vitriol oil (80ml).The mixture that obtains was stirred 16 hours and allow it rise to envrionment temperature.This mixture was poured on ice and stirs 20 minutes.With the solids constituent that obtains from and wash with water.By adding salt of wormwood with the filtrate neutralization and use extracted with diethyl ether.Add the solid that reclaims in diethyl ether solution, the solution that obtains washs with saturated sodium-chloride water solution, through dried over mgso and filtration.By evaporation filtrate is concentrated into about the 50ml volume, in filtrate, add sherwood oil (b.p.60-80 ℃).Form precipitation, this precipitation is passed through filtering separation.Obtain 4-nitropyrazole (16g) thus;

¹ H NMR：(DMSOd ₆+CF ₃CO ₂H)8.57(s，2H).

Slowly drip ethyl sulfate (5.23ml) in 30 ℃ the solution of 4-nitropyrazole (2.26g) in 1N aqueous sodium hydroxide solution (22ml) and under this temperature, the mixture that obtains was stirred 48 hours toward stirring and being warming up to.This mixture is cooled to envrionment temperature and with precipitate and separate, with cold water washing and 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).

Under 3 atmospheric hydrogen, the mixture of a part of product (0.8g), platinum oxide (0.1g), ethyl acetate (10ml) and the ethanol (30ml) that obtain was thus stirred 2 hours.By removing by filter catalyzer and filtrate being evaporated.Obtain desired raw material (productive rate is 89%) 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).

Embodiment 2

Adopt and similar method described in the embodiment 1,, obtain the described compound of Table I suitable 2-pyridine-2-guanidine-acetic acid and suitable amine reaction.Except as otherwise noted, otherwise each amine is commercially available material.

Table I

Numbering and note	(R 1) p	(R 2) q	R
				[1]	6, the 7-dimethoxy	H	5-ethyl pyrazole-3-yl
[2]	6, the 7-dimethoxy	H	5-Yi isoxazole-3-base
				[3]	6, the 7-dimethoxy	H	4-methylthiazol-2-base
[4]	6, the 7-dimethoxy	H	5-methylthiazol-2-base
				[5]	The 7-methoxyl group	The 3-methoxyl group	1-ethyl pyrazoles-4-base
[6]	The 7-methoxyl group	The 3-methoxyl group	1,3-dimethyl pyrazole-4-base
				[7]	The 7-methoxyl group	The 3-methoxyl group	1,5-dimethyl pyrazole-4-base
[8]	The 6-fluorine	The 3-methoxyl group	1-ethyl pyrazoles-4-base

[9]	7-(N-methylamino formyl radical)-6-methoxyl group	The 3-methoxyl group	1-ethyl pyrazoles-4-base
				[10]	The 7-methoxyl group	The 3-methoxyl group	5-ethyl pyrazole-3-yl
[11]	The 6-fluorine	The 3-methoxyl group	5-ethyl pyrazole-3-yl
				[12]	6, the 7-dimethoxy	The 3-methoxyl group	4,5-dimethyl pyrazole-3-base
[13]	The 7-methoxyl group	The 3-methoxyl group	5-Yi isoxazole-3-base
				[14]	The 7-methoxyl group	The 3-methoxyl group	4,5-dimethyl isoxazole-3-base
[15]	The 6-fluorine	The 3-methoxyl group	5-Yi isoxazole-3-base
				[16]	The 6-fluorine	The 3-methoxyl group	4,5-dimethyl isoxazole-3-base
[17]	7-(N-methylamino formyl radical)-6-methoxyl group	The 3-methoxyl group	4,5-dimethyl isoxazole-3-base
				[18]	6, the 7-dimethoxy	The 3-methoxyl group	4,5-dimethyl isoxazole-3-base
[19]	The 7-methoxyl group	The 3-methoxyl group	4-methylthiazol-2-base
				[20]	The 7-methoxyl group	The 3-methoxyl group	3-dimethylaminomethyl-5-aminomethyl phenyl
[21]	The 6-fluorine	The 3-methoxyl group	3-dimethylaminomethyl-5-aminomethyl phenyl
				[22]	7-(N-methylamino formyl radical)-6-methoxyl group	The 3-methoxyl group	3-dimethylaminomethyl-5-aminomethyl phenyl
[23]	5, the 7-dimethoxy	The 3-methoxyl group	1-ethyl pyrazoles-4-base
				[24]	5, the 7-dimethoxy	The 3-methoxyl group	1,3-dimethyl pyrazole-4-base
[25]	The 6-fluorine	The 3-methoxyl group	1-sec.-propyl pyrazoles-4-base
				[26]	6, the 7-dimethoxy	The 3-methoxyl group	The 1-methyl-pyrazol-4-yl
[27]	6, the 7-dimethoxy	The 3-methoxyl group	1,3-dimethyl pyrazole-4-base
				[28]	6, the 7-dimethoxy	The 3-methoxyl group	1-ethyl-3-methyl-pyrazol-4-yl
[29]	The 6-methoxyl group	The 3-methoxyl group	1-ethyl pyrazoles-4-base
				[30]	The 6-methoxyl group	The 3-methoxyl group	1-sec.-propyl pyrazoles-4-base

[31]	The 6-methoxyl group	The 3-methoxyl group	1,3-dimethyl pyrazole-4-base
				[32]	7-oxyethyl group-6-methoxyl group	The 3-methoxyl group	1-ethyl pyrazoles-4-base
[33]	7-oxyethyl group-6-methoxyl group	The 3-methoxyl group	1,3-dimethyl pyrazole-4-base
				[34]	7-oxyethyl group-6-methoxyl group	The 3-methoxyl group	1-ethyl-3-methyl-pyrazol-4-yl
[35]	6, the 7-dimethoxy	The 3-methoxyl group	1,3-dimethyl pyrazole-5-base
				[36]	6, the 7-dimethoxy	The 3-methoxyl group	4-methyl-isoxazole-3-base
[37]	The 6-methoxyl group	The 3-methoxyl group	3-dimethylaminomethyl-5-aminomethyl phenyl

NoteFollowing table is understood the characteristic of each product.

[1] add the phosphofluoric acid 2-(7-azepine benzo triazol-1-yl)-1,1,3 of part in addition, the 3-tetramethyl-urea also is heated to 50 ℃ with reaction mixture and kept 16 hours.The characteristic of product is as follows:

- ¹ H NMR：(DMSOd ₆)1.2(t，3H)，2.55(q，2H)，3.9(s，2H)，3.95(s，3H)，4.0(s，3H)，6.3(brs，1H)，6.55(d，1H)，7.4(s，1H)，7.5(m，2H)，7.75(m，1H)，8.55(m，2H)； Mass Spectrum：M+H ⁺ 434.

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

(1.6M in hexane, 14.06ml) drips acetonitrile (1.17ml) and under this temperature this mixture being stirred 1 hour in the solution toward the n-Butyl Lithium that stirs and be cooled to-78 ℃.Drip ethyl propionate (1.5ml), reaction medium is warming up to-45 ℃ and under this temperature, stirred 2 hours.By adding the 2N aqueous hydrochloric acid mixture that obtains is acidified to pH2 and passes through evaporation concentration.The resistates dichloromethane extraction, organic extract is through dried over mgso and evaporation.Obtain 3-oxo valeronitrile (productive rate is 80%) thus;

¹ H NMR：(CDCl ₃)1.14(t，3H)，2.66(q，2H)，3.46(s，2H).

Under 70 ℃, with the mixture heating up of a part of product (0.6g), hydrazine hydrate (0.28ml) and the ethanol (45ml) that obtain thus 12 hours.With solvent evaporation, resistates is through purification by silica gel column chromatography, and the mixture of the 19:1 of use methylene dichloride and methyl alcohol is as elutriant.Obtain desired raw material (productive rate is 51%) thus;

¹ H NMR：(DMSOd ₆)1.04(t，3H)，2.41(q，2H)，4.4(brs，2H).[2] ¹ H NMR：(DMSOd ₆)1.2(t，3H)，2.75(q，2H)，3.9(s，2H)，3.95(s，3H)，4.0(s，3H)，6.5(d，1H)，6.65(s，1H)，7.45(s，1H)，7.55(m，2H)，7.75(m，1H)，8.55(m，2H)； Mass Spectrum：M+H ⁺ 435.

3-amino-5-Yi isoxazole as raw material is stated in International Patent Application WO 2005/026113 (the 33rd and 34 page).

[3] ¹ H NMR：(DMSOd ₆)2.25(s，3H)，3.9(s，3H)，3.95(s，3H)，4.05(s，2H)，6.55(d，1H)，6.75(s，1H)，7.4(s，1H)，7.5(s，1H)，7.55(d，1H)，7.75(m，1H)，8.5(m，2H)； Mass Spectrum：M+H ⁺ 437.

[4] after 4 hours, add the phosphofluoric acid 2-(7-azepine benzo triazol-1-yl)-1,1,3 of part in addition, the 3-tetramethyl-urea also continues reaction mixture to stir 16 hours.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)2.35(s，3H)，3.9(s，3H)，3.95(s，3H)，4.0(s，2H)，6.55(d，1H)，7.15(s，1H)，7.4(s，1H)，7.5(s，1H)，7.55(d，1H)，7.75(m，1H)，8.55(m，2H)； Mass Spectrum：M+H ⁺ 437.

[5] ¹ H NMR：(DMSOd ₆)1.32(t，3H)，3.79(s，2H)，3.81(s，3H)，3.94(s，3H)，4.07(q，2H)，6.55(d，1H)，7.32(m，1H)，7.41(s，1H)，7.43(d，1H)，7.51(d，1H)，7.87(s，1H)，8.09(d，1H)，8.22(d，1H)，8.65(d，1H)，10.09(s，1H)； Mass Spectrum：M+H ⁺ 434.

As the 2-[3-methoxyl group-5-of raw material (7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] acetate is prepared as follows:

Under argon gas atmosphere, toward the 5-bromo-2-chloro-3-Methoxy Pyridine (embodiment 10 of International Patent Application WO 01/81347 that stirs and be cooled to 18 ℃; 8g), drip the solution of 1M hexamethyl dimethyl silanyl Lithamide in THF (80ml) in the solution of acetonitrile (4.1ml) and THF (80ml).Add acetonitrile (4.1ml) and 1M hexamethyl dimethyl silanyl Lithamide solution (80ml) successively again.In the water (300ml) that allows reaction mixture rise to envrionment temperature and its impouring is stirred and the mixture of ether (300ml).The water extracted with diethyl ether.Merge organic phase, through dried over mgso and evaporation.Resistates is through purification by silica gel column chromatography, and the gradient solvent that uses sherwood oil and ether (4:1 to 1:1) is as elutriant.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.

In the mixture of 2-(5-bromo-3-Methoxy Pyridine-2-yl) acetonitrile (6.6g) that stirs and methyl alcohol (70ml), add trimethylsilyl chloride (21.55ml).With the mixture heating up to 50 that obtains ℃ and kept 12 hours.By evaporation this mixture is concentrated, resistates is dissolved in the ether.Add saturated sodium bicarbonate aqueous solution until stopping to produce gas.With the aqueous phase separation that obtains and use extracted with diethyl ether.With the aqueous phase separation that obtains and use extracted with diethyl ether.Merge organic phase, through dried over mgso and evaporation.Resistates is through silica gel (70g) purifying, and the mixture of the 1:1 of use 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 gas atmosphere, toward stirring 2-(5-bromo-3-Methoxy Pyridine-2-yl) methyl acetate (7.02g) and 1, the mixture and the salt of wormwood (8.21g) that add the 1:1 of hypoboric acid two pinacol esters (8.23g), methylene dichloride (0.661g) and [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) in the mixture of 4-diox (300ml) successively.The mixture that obtains is stirred and be heated to 90 ℃ to be kept 6 hours.This mixture is cooled to envrionment temperature and concentrated by evaporation section.Resistates dilutes with methylene dichloride, this mixture water and salt water washing successively subsequently.Reclaim organic phase, through dried over mgso and evaporation.Obtain dark buttery 2-[3-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) pyridine-2-yl thus] 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.

The product that obtains thus is dissolved in the methylene dichloride (300ml).Add aqueous hydrogen peroxide solution (30%, 15ml) and at ambient temperature with the mixture vigorous stirring that obtains 2 hours.Be separated two.The water dichloromethane extraction.Merge organic phase, use the salt water washing, through dried over mgso and evaporation.Resistates is through purification by silica gel column chromatography, and the polarity ether that use increases gradually and the mixture of ethyl acetate are as elutriant.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 Spectrum；M+H ⁺ 198.

Under argon gas atmosphere, with 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate (0.749g), 4-chloro-7-methoxy quinoline ( J.Med.Chem., 1998, 41, 4918-4926; 0.772g), the mixture of 4-dimethylaminopyridine (1.49g) and chlorobenzene (10ml) stirs and is heated to reflux and kept 5 hours.The mixture that obtains is cooled to envrionment temperature and between water and ethyl acetate, distributes.Organic phase is washed with diluted hydrochloric acid aqueous solution, through dried over mgso and evaporation.Resistates stirs with ether.With the solids constituent that obtains from.Obtain 2-[3-methoxyl group-5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-yl thus] methyl acetate (0.99g);

¹ H NMR：(DMSOd ₆)3.64(s，3H)，3.82(s，3H)，3.83(s，2H)，3.95(s，3H)，6.57(d，1H)，7.31(m，1H)，7.43(d，1H)，7.54(d，1H)，8.09(s，1H)，8.21(d，1H)，8.65(d，1H)； Mass Spectrum：M+H ⁺ 355.

The mixture of a part of product (0.18g) that will obtain thus at ambient temperature, 2N aqueous sodium hydroxide solution (0.765ml) and methyl alcohol (2ml) stirred 2 hours.Add 2N aqueous hydrochloric acid (0.765ml).With the solids constituent that obtains from, wash with water and 50 ℃ of following vacuum-dryings.Obtain 2-[3-methoxyl group-5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-yl thus] acetate (0.15g);

¹ H NMR：(DMSOd ₆)3.74(s，2H)，3.82(s，3H)，3.95(s，3H)，6.57(d，1H)，7.33(m，1H)，7.44(d，1H)，7.52(d，1H)，8.08(s，1H)，8.23(d，1H)，8.66(d，1H)； Mass Spectrum：M+H ⁺ 341.

[6] ¹ H NMR：(DMSOd ₆)2.14(s，3H)，3.71(s，3H)，3.84(s，3H)，3.87(s，2H)，3.96(s，3H)，6.57(d，1H)，7.33(m，1H)，7.45(d，1H)，7.52(d，1H)，7.82(s，1H)，8.1(d，1H)，8.24(d，1H)，8.67(d，1H)，9.53(s，1H)； Mass Spectrum：M+H ⁺ 434.

As the 4-amino-1 of raw material, 3-dimethyl-1H-pyrazoles can be available from Sigma-Aldrich, Gillingham, SP84XT, UK.This compound also can be according to Chemical Abstracts the 94th volume, summary numbering 103228 ( Zhurnal Obshchei Khimii, 1980, 50, 2106-9) middle disclosed method preparation.

[7] ¹ H NMR：(DMSOd ₆)2.18(s，3H)，3.69(s，3H)，3.82(brs，5H)，3.95(s，3H)，6.56(d，1H)，7.32(m，1H)，7.43(d，1H)，7.45(s，1H)，7.5(d，1H)，8.09(d，1H)，8.23(d，1H)，8.65(d，1H)，9.4(s，1H)； Mass Spectrum：M+H ⁺ 434.

As the 4-amino-1 of raw material, 5-dimethyl-1H-pyrazoles is prepared as follows:

Under argon gas atmosphere; toward stirring 1; 5-dimethyl-1H-pyrazoles-4-formic acid (1.4g), the trimethyl carbinol (4ml) and 1 add diisopropyl ethyl amine (3.49ml) and diphenyl phosphoryl azide (2.37ml) successively and also at ambient temperature reaction mixture were stirred 10 minutes in the mixture of 4-diox (40ml).With the mixture heating up to 110 that obtains ℃ and kept 3 hours.With solvent evaporation, reaction product uses ethyl acetate as elutriant through purification by silica gel column chromatography.Obtain 4-(tert-butoxycarbonyl amino)-1 thus, 5-dimethyl-1H-pyrazoles (0.225g);

¹ H NMR：(DMSOd ₆)1.4(s，9H)，2.2(s，3H)，3.55(s，1H)，6.0(br s，1H)，9.3(brs，1H).

At ambient temperature, 1, the mixture of the hydrochloric acid soln in 4-diox (0.96ml) and the methylene dichloride (5ml) stirred 3 days with the product that obtains thus, 4M.Collect the solid that obtains by filtering, with ether washing and vacuum-drying.Obtain the 4-amino-1 of hydrochloride form thus, 5-dimethyl-1H-pyrazoles (0.078g),

¹ H NMR：(DMSOd ₆)2.25(s，3H)，3.65(s，3H)，5.85(s，1H).

As 1 of raw material, 5-dimethyl-1H-pyrazoles-4-formic acid is that commerce is buied.This compound also can according to Australian Journal of Chemistry, 1983, 36, disclosed method preparation among the 135-147.

[8] ¹ H NMR：(DMSOd ₆)1.33(t，3H)，3.8(s，2H)，3.82(s，3H)，4.07(q，2H)，6.76(d，1H)，7.61(s，1H)，7.54(d，1H)，7.74-7.82(m，1H)，7.87(s，1H)，8.01(m，1H)，8.10-8.18(m，2H)，8.73(d，1H)，10.1(s，1H)； Mass Spectrum：M+H ⁺ 422.

As 2-[5-(the 6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl of raw material] acetate is prepared as follows:

Under argon gas atmosphere, with the 4-chloro-6-fluorine quinoline (embodiment 12 in No. the 4th, 560,692, the US patent; 0.7g), the mixture of 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate (0.759g), 4-dimethylaminopyridine (1.42g) and chlorobenzene (9ml) stirs and is heated to 135 ℃ and kept 12 hours.The mixture that obtains is cooled to envrionment temperature.Adding ethyl acetate also filters this mixture.With the filtrate evaporation, resistates is through purification by silica gel column chromatography, and the gradient solvent that uses methylene dichloride and ethyl acetate (3:2 to 0:10) is as elutriant.Obtain 2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl thus] methyl acetate (1.03g);

¹ H NMR：(DMSOd ₆)3.64(s，3H)，3.83(s，2H)，3.84(s，3H)，6.78(d，1H)，7.57(d，1H)，7.77(m，1H)，8.01(m，1H)，8.13(m，2H)，8.72(d，1H)； Mass Spectrum：M+H ⁺ 343.

At ambient temperature, the mixture with the product, methyl alcohol (5ml) and the solution of sodium hydroxide (0.241g) in water (4ml) that obtain thus stirred 4 hours.With methyl alcohol evaporation, water ethyl acetate extraction.Making aqueous phase as acidified by dropping 2N aqueous hydrochloric acid is pH4.5.With the precipitate and separate that obtains, washing of water and ether and vacuum-drying successively.Obtain desired raw material (0.815g) thus;

¹ H NMR：(DMSOd ₆)3.74(s，2H)，3.83(s，3H)，6.76(d，1H)，7.54(d，1H)，7.77(m，1H)，8.0(m，1H)，8.13(m，2H)，8.72(d，1H)； Mass Spectrum：M+H ⁺ 329.

[9] ¹ H NMR：(DMSOd ₆)1.31(t，3H)，2.85(d，3H)，3.8(s，2H)，3.82(s，3H)，4.01(s，3H)，4.07(q，2H)，6.72(d，1H)，7.41(s，1H)，7.53(d，1H)，7.67(s，1H)，7.97(s，1H)，8.12(d，1H)，8.23(s，1H)，8.4(q，1H)，8.63(s，1H)，10.1(s，1H)； Mass Spectrum：M+H ⁺ 491.

As 2-{3-methoxyl group-5-[6-methoxyl group-7-(N-methylamino formyl radical) quinolyl-4 oxygen base of raw material] pyridine-2-yl } acetate is prepared as follows:

Under 1.4 atmospheric hydrogen, the mixture of 2-methoxyl group-5-nitrobenzoic acid methyl esters (20.3g), 5% platinum/C catalyst (1.5g) and ethyl acetate (300ml) was stirred 5 hours.By removing by filter catalyzer and filtrate being evaporated.Obtain 5-amino-O-Anisic Acid methyl esters (17g) thus;

¹ HNMR：(CDCl ₃)3.84(s，3H)，3.89(s，3H)，6.86(m，2H)，7.19(m，1H)； Mass Spectrum：M+H ⁺ 182.

At ambient temperature, with 5-amino-O-Anisic Acid methyl esters (17g; Also referring to Canadian Journal of Chemistry, 1973, 51, 162-170), 5-methoxyl group methylene radical-2,2-dimethyl-1,3-diox-4, the mixture of 6-diketone (17.5g) and Virahol (200ml) stirred 10 minutes.Form yellow mercury oxide, by filtering, successively with Virahol and ether washing and vacuum-drying with its separation.Obtain 5-(4-methoxyl group-3-methoxycarbonyl anilino methylene radical)-2 thus, 2-dimethyl-1,3-diox-4,6-diketone (28.9g);

¹ H NMR：(CDCl ₃)1.76(s，6H)，3.93(s，3H)，3.95(s，3H)，7.05(d，1H)，7.35(m，1H)，7.74(d，1H)，8.56(d，1H)； Mass Spectrum：M+H ⁺ 336.

Add 5-(4-methoxyl group-3-methoxycarbonyl anilino methylene radical)-2,2-dimethyl-1,3-diox-4,6-diketone (28.9g) toward being warming up to 260 ℃ biphenyl and phenyl ether mixture (' DowthermA ') in (200ml) in batches.Under this temperature with this solution stirring 5 minutes.The mixture that obtains is cooled to envrionment temperature and it is added in the mixture of sherwood oil (250ml) and ether (250ml).By filtering collecting precipitation and using petroleum ether.The product that obtains thus is through purification by silica gel column chromatography, and the methylene dichloride that use polarity increases gradually and the solvent mixture of methyl alcohol (10:0 to 17:3) are as elutriant.Obtain 6-methoxyl group-7-methoxycarbonyl-1 thus, 4-dihydroquinoline-4-ketone and 6-methoxyl group-5-methoxycarbonyl-1, the mixture (11.7g) of the 7:3 of 4-dihydroquinoline-4-ketone;

¹ H NMR：(DMSOd ₆)3.85(s，3H)，3.88(s，3H)，6.05(d，1H)，7.61(s，1H)，7.87(s，1H)，7.94(d，1H)and3.75(s，3H)，3.82(s，3H)，5.92(d，1H)，7.55(d，1H)，7.63(d，1H)，7.88(m，1H)； Mass Spectrum：M+H ⁺ 234.

The part (9.41g) of gained quinoline-4-alcohol/ketone mixtures is dissolved in the methyl alcohol (100ml).Adding lithium hydroxide (5.04g) also stirs this mixture 16 hours at ambient temperature.Solvent evaporation is also added entry (100ml) in this resistates.By adding the 6N aqueous hydrochloric acid this mixture is neutralized to pH7.The aqueous solution methylene dichloride and ethyl acetate extraction.By add the 6N aqueous hydrochloric acid with acidified aqueous solution to pH2.With the precipitate and separate that obtains, water and ether washing and vacuum-drying.Obtain 7-carboxyl-6-methoxyl group-1 thus, 4-dihydroquinoline-4-ketone (6.1g);

¹ H NMR：(DMSOd ₆)3.88(s，3H)，6.04(d，1H)，7.59(s，1H)，7.83(s，1H)，7.93(d，1H)，11.85(br s，1H)，13.16(brs，1H)； Mass Spectrum：M+H ⁺ 220.

The mixture heating up to 105 of a part of product (2g) that obtains thus and phosphoryl chloride (4.17ml) ℃ was kept 1 hour.The mixture that obtains is cooled to envrionment temperature and uses methylene dichloride (50ml) dilution.With the slow impouring of gained solution in ice bath in the solution of refrigerative 2M methylamine in THF (100ml).This mixture is stirred and allow it rise to envrionment temperature.This reaction mixture is used saturated sodium bicarbonate aqueous solution and salt water washing successively, through dried over mgso and evaporation.Resistates grinds with ether.With the solids constituent that obtains from, with ether washing and vacuum-drying.Obtain 4-chloro-6-methoxyl group-7-(N-methylamino formyl radical) quinoline (1.54g) thus;

¹ H NMR: (DMSOd ₆) 2.84 (d, 3H), 4.03 (s, 3H), 7.51 (s, 1H), 7.78 (d, 1H), 8.23 (s, 1H), 8.4 (brd, 1H), 8.74 (d, 1H); Mass Spectrum: M+H ⁺252 and 254.

Under argon gas atmosphere, the mixture of 4-chloro-6-methoxyl group-7-(N-methylamino formyl radical) quinoline (1.19g), 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate (1.12g), cesium carbonate (1.85g) and DMF (10ml) is stirred and be heated to 120 ℃ kept 6 hours.This mixture is cooled to envrionment temperature, and dilute with water is also used ethyl acetate extraction.With the organic phase evaporation, resistates is through purification by silica gel column chromatography, and the gradient solvent that uses methylene dichloride, ethyl acetate and methyl alcohol (1:1:0 to 9:9:1) is as elutriant.Obtain 2-{3-methoxyl group-5-[6-methoxyl group-7-(N-methylamino formyl radical) quinolyl-4 oxygen base thus] pyridine-2-yl } methyl acetate (1.05g);

¹ H NMR：(CDCl ₃)3.09(d，3H)，3.76(s，3H)，3.85(s，3H)，3.94(s，2H)，4.12(s，3H)，6.64(d，1H)，7.04(d，1H)，7.67(s，1H)，7.81(br d，1H)，8.13(d，1H)，8.66(d，1H)，8.97(s，1H)； Mass Spectrum：M+H ⁺ 412.

At ambient temperature, the mixture with the product, methyl alcohol (15ml) and the 2N aqueous sodium hydroxide solution (3.65ml) that obtain thus stirred 1 hour.By adding the 1N aqueous hydrochloric acid this mixture is acidified to pH3.With the precipitate and separate that obtains, water, ethyl acetate and ether washing and vacuum-drying successively.Obtain 2-{3-methoxyl group-5-[6-methoxyl group-7-(N-methylamino formyl radical) quinolyl-4 oxygen base thus] pyridine-2-yl } acetate (0.78g);

¹ H NMR：(DMSOd ₆)2.84(d，3H)，3.74(s，2H)，3.83(s，3H)，4.01(s，3H)，6.73(d，1H)，7.53(d，1H)，7.66(s，1H)，8.11(d，1H)，8.23(s，1H)，8.39(brd，1H)，8.63(d，1H)； Mass Spectrum：M+H ⁺ 398.

[10] reaction mixture is heated to 60 ℃ and kept 24 hours.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)1.16(s，3H)，2.56(q，2H)，3.81(s，3H)，3.83(s，2H)，3.95(s，3H)，6.27(s，1H)，6.47(d，1H)，7.32(m，1H)，7.43(d，1H)，7.5(d，1H)，8.08(d，1H)，8.23(d，1H)，8.65(d，1H)，10.4(s，1H)，11.98(s，1H)； Mass Spectrum：M+H ⁺ 434.

[11] reaction mixture is heated to 70 ℃ and kept 12 hours.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)1.16(t，3H)，2.56(q，2H)，3.81(s，3H)3.84(s，2H)，6.26(s，1H)，6.76(d，1H)，7.53(d，1H)，7.74-7.82(m，1H)，8.11(d，1H)，8.14(m，1H)，8.73(d，1H)，10.41(s，1H)，11.98(brs，1H)； Mass Spectrum：M+H ⁺ 422.

[12] ¹ H NMR：(DMSOd ₆)1.77(s，3H)，2.1(s，3H)，3.82(s，2H)，3.83(s，3H)，3.94(s，3H)，3.96(s，3H)，6.59(d，1H)，7.42(s，1H)，7.48(d，1H)，7.53(s，1H)，8.08(d，1H)，8.52(d，1H)，9.63(br s，1H)，12.0(brs，1H)； Mass Spectrum：M+H ⁺ 464.

As the 2-[5-of raw material (6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate is prepared as follows:

Adopt described in last two sections with the preamble note [5] that relates to feedstock production similarly method, with 4-chloro-6, the reaction of 7-dimethoxy-quinoline and 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate, obtain 2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-and 3-Methoxy Pyridine-2-yl] methyl acetate, this compound obtains desired raw material with the hydrolysis of 2N aqueous sodium hydroxide solution.

As the 3-amino-4 of raw material, 5-dimethyl-1H-pyrazoles is stated in UK patent specification the 788th, No. 140 (embodiment 1).

[13] ¹ H NMR：(DMSOd ₆)1.2(t，3H)，2.72(q，2H)，3.81(s，3H)，3.89(s，2H)，3.95(s，3H)，6.55(d，1H)，6.62(s，1H)，7.32(m，1H)，7.43(d，1H)，7.52(d，1H)，8.09(d，1H)，8.22(d，1H)，8.65(d，1H)，11.12(s，1H)； Mass Spectrum：M+H ⁺ 435.

[14] ¹ H NMR：(DMSOd ₆)1.82(s，3H)，2.3(s，3H)，3.83(s，3H)，3.89(s，2H)，3.95(s，3H)，6.58(d，1H)，7.32(m，1H)，7.43(d，1H)，7.52(d，1H)，8.09(d，1H)，8.22(d，1H)，8.65(d，1H)，10.4(br s，1H)； Mass Spectrum：M+H ⁺ 435.

As the 3-amino-4 of raw material, the 5-dimethyl isoxazole exists Tetrahedron Letters, 1996, 37, state among the 3339-3342.

[15] ¹ H NMR：(DMSOd ₆)1.2(t，3H)，2.73(q，2H)，3.82(s，3H)，3.9(s，2H)，6.62(s，1H)，6.76(d，1H)，7.55(d，1H)，7.75-7.81(m，1H)，8.01(m，1H)，8.12(d，1H)，8.14(m，1H)，8.73(d，1H)，11.12(s，1H)； Mass Spectrum：M+H ⁺ 423.

[16] reclaim product by filtering by reaction mixture.Be suspended in the product that obtains thus in the dilute aqueous solution of sodium bicarbonate and stirred 30 minutes.By filter with this solids constituent from, wash with water and vacuum-drying.The characteristic of products therefrom is as follows:

- ¹ H NMR：(DMSOd ₆)1.82(s，3H)，2.3(s，3H)，3.84(s，3H)，3.9(s，2H)，6.78(s，1H)，7.55(d，1H)，7.73-7.82(m，1H)，8.01(m，1H)，8.1-8.18(m，2H)，8.73(d，1H)，10.35(brs，1H)； Mass Spectrum：M+H ⁺ 423.

[17] ¹ H NMR：(DMSOd ₆)1.81(s，3H)，2.3(s，3H)，2.85(d，3H)，3.84(s，3H)，3.9(s。2H)，4.01(s，3H)，6.75(d，1H)，7.54(d，1H)，7.67(s，1H)，8.12(d，1H)，8.33(s，1H)，8.4(q，1H)，8.64(s，1H)，10.35(s，1H)； Mass Spectrum：M+H ⁺ 492.

[18] use DMA to replace DMF as reaction solvent.At ambient temperature, reaction mixture was stirred 14 hours, postheating to 70 ℃ also kept 2 hours.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)1.82(s，3H)，2.3(s，3H)，3.83(s，3H)，3.89(s，2H)，3.94(s，3H)，3.96(s，3H)，6.58(d，1H)，7.42(s，1H)，7.5(d，1H)，7.52(s，1H)，8.09(d，1H)，8.52(d，1H)，10.34(br s，1H)； Mass Spectrum：M+H ⁺ 465.

[19] reclaim product by filtering, successively with DMF, ethyl acetate and ether washing and vacuum-drying by reaction mixture.The characteristic of products therefrom is as follows:

- ¹ H NMR：(DMSOd ₆)2.27(d，3H)，3.82(s，3H)，3.94(s，3H)，3.95(s，2H)，6.57(d，1H)，6.74(q，1H)，7.32(m，1H)，7.43(d，1H)，7.53(d，1H)，8.09(d，1H)，8.22(d，1H)，8.65(s，1H)，12.20(br s，1H)； Mass Spectrum：M+H ⁺ 437.

[20] ¹ H NMR：(DMSOd ₆)2.13(s，6H)，2.25(s，3H)，3.29(s，2H)，3.82(s，3H)，3.85(s，2H)，3.95(s，3H)，6.55(d，1H)，6.78(s，1H)，7.32(m，1H)，7.34(s，1H)，7.37(s，1H)，7.44(d，1H)，7.52(d，1H)，8.09(d，1H)，8.23(d，1H)，8.65(d，1H)，10.05(s，1H)； Mass Spectrum：M+H ⁺ 487.

3-dimethylaminomethyl-5-monomethylaniline as raw material is prepared as follows:

With 1, the mixture of 3-dimethyl-5-oil of mirbane (15.15g), N-bromosuccinimide (2g), benzoyl peroxide (0.484g) and tetracol phenixin (250ml) stirs and is heated to backflow.In the reaction mixture of heating, added the N-bromosuccinimide (21g altogether) of another part through 4 hours in batches.This mixture is cooled to envrionment temperature.Add sherwood oil (b.p.60-80 ℃).With this mixture filtration and with the filtrate evaporation, obtain oily matter (25g), it is the mixture of 3-methyl-5-nitro bromotoluene (76%), unreacted raw material (～19%) and 3-brooethyl-5-nitrobenzyl bromine (～15%) through the NMR analysis revealed.This mixture is used for next step.

Be dissolved in the part (2.3g) of the oily matter that obtains thus in the ethanol (5ml) and add dimethyl amine (6 equivalent) in batches to prevent remarkable heat release.At ambient temperature the reaction mixture that obtains was stirred 12 hours.With this mixture evaporation, resistates is through purification by silica gel column chromatography, and the methylene dichloride that use polarity increases gradually and the mixture of ether are as elutriant.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.

Under 18 atmospheric hydrogen, with N, the mixture of N-dimethyl-N-(3-methyl-5-nitro benzyl) amine (2.2g), platinum oxide (0.11g) and ethyl acetate (40ml) stirred 30 minutes.By removing by filter catalyzer, subsequently filtrate is evaporated.The product vacuum-drying that will obtain thus at ambient temperature 2 hours.Obtain the 3-dimethylaminomethyl-5-monomethylaniline (1.7g) of solid state 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).

[21] ¹ H NMR：(DMSOd ₆)2.13(s，6H)，2.26(s，3H)，3.29(s，2H)，3.83(s，3H)，3.86(s，2H)，6.76(d，1H)，6.78(s，1H)，7.35(s，1H)，7.37(s，1H)，7.55(d，1H)，7.75-7.80(m，1H)，8.02(m，1H)，8.13(d，1H)，8.14(m，1H)，8.73(d，1H)，10.05(s，1H)； Mass Spectrum：M+H ⁺ 475.

[22] ¹ H NMR：(DMSOd ₆)2，13(s，6H)，2.26(s，3H)，2.85(d，3H)，3.22(s，2H)，3.83(s，3H)，3.86(s，2H)，4.01(s，3H)，6.71(d，1H)，6.78(s，1H)，7.35(s，1H)，7.37(s，1H)，7.54(d，1H)，7.67(s，1H)，8.13(s，1H)，8.23(s，1H)，8.4(q，1H)，8.64(s，1H)，10.06(s，1H)； Mass Spectrum：M+H ⁺ 544.

[23] reaction mixture is heated to 45 ℃ and kept 4 hours.Product is through purification by silica gel column chromatography, use methylene dichloride to the gradient solvent mixture of 23:2 methylene dichloride and methyl alcohol as elutriant.The characteristic of this compound is as follows:

¹ H NMR：(DMSOd ₆)1.32(t，3H)，3.75(s，2H)，3.79(s，3H)，3.83(s，3H)，3.91(s，3H)，4.06(q，2H)，6.58(d，1H)，6.67(d，1H)，7.02(d，1H)，7.32(d，1H)，7.4(s，1H)，7.85(s，1H)，7.86(d，1H)，8.58(d，1H)，10.05(s，1H)； Mass Spectrum：M+H ⁺ 464.

As the 2-[5-of raw material (5,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate is prepared as follows:

Toward stirring 5,7-dimethoxy-1,4-dihydroquinoline-4-ketone ( Med.Chem.Letters, 1997,789-792 and Arch.Pharm.Res., 1998,445-451; 2.05g) and the mixture of chlorobenzene (25ml) in add diisopropyl ethyl amine (2.63ml).Under nitrogen atmosphere, this mixture is cooled to 15 ℃ and drip the solution of phosphoryl chloride (1.29ml) in chlorobenzene (5ml).With the solution stirring that obtains and be heated to 65 ℃ and kept 3 hours.This mixture cooled off in ice bath and add sodium bicarbonate aqueous solution (5g).The mixture extracted with diethyl ether that obtains.Organic phase salt water washing is through dried over mgso and evaporation.Obtain 4-chloro-5 thus, 7-dimethoxy-quinoline (2.15g);

¹ H NMR：(DMSOd ₆)3.91(s，3H)，3.92(s，3H)，6.76(d，1H)，7.05(d，1H)，7.39(d，1H)，8.61(d，1H)； Mass Spectrum：M+H ⁺ 224.

With 4-chloro-5, the mixture of 7-dimethoxy-quinoline (1.2g), 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate (1.1g), pyridine (2.16ml) and chlorobenzene (35ml) stirs and is heated to reflux and kept 2 hours.With this mixture cooling and evaporation concentration.In resistates, add entry, add sodium bicarbonate subsequently until stopping to produce gas.This mixture also evaporates through dried over mgso with the mixture extraction of the 1:1 of ether and ethyl acetate, organic phase.Resistates is through purification by silica gel column chromatography, use methylene dichloride to the methylene dichloride of 24:1 and methyl alcohol as gradient eluent.Obtain 2-[5-(5,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl thus] methyl acetate (1.8g);

¹ H NMR：(DMSOd ₆)3.62(s，3H)，3.79(s，3H)，3.8(s，2H)，3.81(s，3H)，3.91(s，3H)，6.62(d，1H)，6.67(d，1H)，7.03(d，1H)，7.33(d，1H)，7.85(d，1H)，8.59(d，1H)； Mass Spectrum：M+H ⁺ 385.

At ambient temperature, the mixture with the product, lithium hydroxide monohydrate (0.287g), water (17.5ml) and the THF (17.5ml) that obtain thus stirred 1 hour.By adding aqueous citric acid solution this solution is acidified to pH5.With precipitate and separate, water, ethanol and ether washing and vacuum-drying successively.Obtain 2-[5-(5,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl thus] acetate (1.63g);

¹ H NMR：(DMSOd ₆)3.69(s，2H)，3.8(s，3H)，3.82(s，3H)，3.91(s，3H)，6.6(d，1H)，6.67(s，1H)，7.03(s，1H)，7.32(s，1H)，7.85(s，1H)，8.59(d，1H)； Mass Spectrum：M+H ⁺ 371.

[24] reaction mixture is heated to 45 ℃ and kept 4 hours.Product is through purification by silica gel column chromatography, use methylene dichloride to the gradient solvent mixture of the methylene dichloride of 23:2 and methyl alcohol as elutriant.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)2.12(s，3H)，3.69(s，3H)，3.79(s，3H)，3.81(s，2H)，3.83(s，3H)，3.91(s，3H)，6.58(d，1H)，6.67(d，1H)，7.02(d，1H)，7.31(d，1H)，7.79(s，1H)，7.86(d，1H)，8.58(d，1H)，9.48(brs，1H)； Mass Spectrum：M+H ⁺ 464.

[25] use DMA to replace DMF as reaction solvent.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)1.37(d，6H)，3.8(s，2H)，3.82(s，3H)，4.44(m，1H)，6.75(d，1H)，7.41(s，1H)，7.54(s，1H)，7.76(m，1H)，7.87(s，1H)，8.02(m，1H)，8.13(m，2H)，8.72(d，1H)，10.1(s，1H)； Mass Spectrum：M+H ⁺ 436.

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

The mixture of 4-nitropyrazole (1.13g), isopropyl iodide (1ml), salt of wormwood (1.38g) and DMF (30ml) is stirred and is heated to 70 ℃ of maintenances 2 hours.With in the mixture impouring water that obtains and, wash with water and vacuum-drying precipitate and separate.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).

Under 3 atmospheric hydrogen, the mixture of a part of product (0.8g), platinum oxide (0.1g), ethyl acetate (10ml) and the ethanol (30ml) that obtain was thus stirred 2 hours.By removing by filter catalyzer and filtrate being evaporated.Obtain the desired raw material (0.607g) of colorless oil thus;

¹ H NMR：(DMSOd ₆)1.31(d，6H)，3.76(brs，2H)，4.27(m，1H)，6.88(s，1H)，7.03(s，1H).

[26] use DMA to replace DMF as reaction solvent.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)3.78(s，3H)，3.79(s，2H)，3.81(s，3H)，3.94(s，3H)，3.96(s，3H)，6.56(d，1H)，7.4(s，1H)，7.42(s，1H)，7.49(d，1H)，7.53(s，1H)，7.83(s，1H)，8.08(d，1H)，8.52(d，1H)，10.09(s，1H)，12.0(br s，1H)； Mass Spectrum：M+H ⁺ 450.

4-amino-1-methyl isophthalic acid H-pyrazoles as raw material is prepared as follows:

Slowly add methyl-sulfate (5ml) in 30 ℃ the solution of 4-nitropyrazole (2g) in 1N aqueous sodium hydroxide solution (20ml) and under this temperature, the mixture that obtains was stirred 48 hours toward stirring and being warming up to.This mixture is cooled to envrionment temperature and with precipitate and separate, with cold water washing 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).

Under 3 atmospheric hydrogen, the mixture of a part of product (0.7g), platinum oxide (0.05g), ethyl acetate (5ml) and the ethanol (15ml) that obtain was thus stirred 2 hours.By removing by filter catalyzer and filtrate being evaporated.Obtain desired raw material (0.6g) thus;

¹ H NMR：(DMSOd ₆)3.64(s，3H)，6.86(s，1H)，6.97(s，1H).

[27] product is through purification by silica gel column chromatography, and methylene dichloride that use polarity increases gradually and methanol mixture are as elutriant.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)2.13(s，3H)，3.69(s，3H)，3.82(s，3H)，3.85(s，2H)，3.94(s，3H)，3.96(s，3H)，6.56(d，1H)，7.42(s，1H)，7.48(d，1H)，7.53(s，1H)，7.81(s，1H)，8.08(d，1H)，8.52(d，1H)，9.51(s，1H)； Mass Spectrum：M+H ⁺ 464.

[28] use DMA to replace DMF as reaction solvent.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)1.09(t，3H)，2.14(s，3H)，3.82(s，3H)，3.85(s，2H)，3.94(s，3H)，3.96(s，3H)，3.99(q，2H)，6.54(d，1H)，7.42(s，1H)，7.48(d，1H)，7.52(s，1H)，7.84(s，1H)，8.08(d，1H)，8.51(d，1H)，9.51(s，1H)； Mass Spectrum：M+H ⁺ 478.

[29] use DMA to replace DMF as reaction solvent.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)1.33(t，3H)，3.8(s，2H)，3.82(s，3H)，3.94(s，3H)，4.07(q，2H)，6.67(d，1H)，7.41(s，1H)，7.48(m，1H)，7.51(s，1H)，7.87(s，1H)，7.97(d，1H)，8.1(d，1H)，8.58(d，1H)，10.09(s，1H)； Mass Spectrum：M+H ⁺ 434.

As the 2-[3-methoxyl group-5-of raw material (6-methoxy quinoline-4-base oxygen base) pyridine-2-yl] acetate is prepared as follows:

Under argon gas atmosphere, with the 4-chloro-6-methoxy quinoline (embodiment 48 in the International Patent Application WO 2006/021448; 0.5g), the mixture of 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate (0.509g), 4-dimethylaminopyridine (0.947g) and chlorobenzene (5ml) stirs and is heated to 140 ℃ and kept 16 hours.This mixture is cooled to envrionment temperature and evaporation concentration.Resistates uses ethyl acetate as elutriant through purification by silica gel column chromatography.Obtain 2-[3-methoxyl group-5-(6-methoxy quinoline-4-base oxygen base) pyridine-2-yl thus] methyl acetate (0.47g);

¹ H NMR：(DMSOd ₆)3.75(s，3H)，3.84(s，3H)，3.93(s，2H)，3.97(s，3H)，6.62(d，1H)，7.03(d，1H)，7.43(m，1H)，7.55(d，1H)，8.03(d，1H)，8.12(d，1H)，8.58(d，1H)； Mass Spectrum：M+H ⁺ 355.

At ambient temperature, the mixture with the product, sodium hydroxide (0.159g), water (3ml), THF (5ml) and the methyl alcohol (8ml) that obtain thus stirred 14 hours.With the mixture evaporation concentration that obtains and between water and ethyl acetate, distribute.By add the 6N aqueous hydrochloric acid with aqueous phase as acidified to pH5.With precipitate and separate and the vacuum-drying that obtains.Obtain 2-[3-methoxyl group-5-(6-methoxy quinoline-4-base oxygen base) pyridine-2-yl thus] acetate (0.363g);

¹ H NMR：(DMSOd ₆)3.74(s，2H)，3.83(s，3H)，3.94(s，3H)，6.68(d，1H)，7.48(m，1H)，7.58(d，1H)，7.97(d，1H)，8.09(d，1H)，8.58(d，1H)； Mass Spectrum：M+H ⁺ 341.

[30] ¹ H NMR：(DMSOd ₆)1.37(d，6H)，3.8(s，2H)，3.82(s，3H)，3.94(s，3H)，4.43(m，1H)，6.67(d，1H)，7.41(s，1H)，7.48(m，1H)，7.51(d，1H)，7.58(d，1H)，7.87(s，1H)，7.97(d，1H)，8.1(d，1H)，8.58(d，1H)，10.09(s，1H)； Mass Spectrum：M+H ⁺ 448.

[31] use DMA to replace DMF as reaction solvent.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)2.13(s，3H)，3.7(s，3H)，3.82(s，3H)，3.85(s，2H)，3.94(s，3H)，6.67(d，1H)，7.47(m，1H)，7.51(s，1H)，7.59(s，1H)，7.81(d，1H)，7.97(d，1H)，8.1(s，1H)，8.58(d，1H)，9.51(brs，1H)； Mass Spectrum：M+H ⁺ 434.

[32] use DMA to replace DMF as reaction solvent.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)1.33(t，3H)，1.43(t，3H)，3.79(s，2H)，3.82(s，3H)，3.94(s，3H)，4.07(q，2H)，4.21(q，2H)，6.54(d，1H)，7.4(d，1H)，7.48(d，1H)，7.52(s，1H)，7.87(s，1H)，8.08(d，1H)，8.51(d，1H)，10.09(s，1H)； Mass Spectrum：M+H ⁺ 478.

As the 2-[5-of raw material (7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate is prepared as follows:

Toward the 4-chloro-7-hydroxyl-6-methoxy quinoline (embodiment 3 in the International Patent Application WO 98/13350 that stirs; 1.6g), add 1,1 '-(azo dicarbapentaborane) two piperidines (2.24g) in the suspension of ethanol (0.868ml), tributylphosphine (2.9ml) and methylene dichloride (50ml) in batches and at ambient temperature the mixture that obtains stirred 16 hours.With this mixture filtration and with the filtrate evaporation concentration.Resistates is through purification by silica gel column chromatography, use methylene dichloride to the gradient solvent mixture of 1:1 methylene dichloride and ethyl acetate as elutriant.Obtain 4-chloro-7-oxyethyl group-6-methoxy quinoline (1.2g) thus;

¹ H NMR：(CDCl ₃)1.57(t，3H)，4.06(s，3H)，4.28(q，2H)，7.35(d，1H)，7.41(d，1H)，8.57(d，1H)； Mass Spectrum：M+H ⁺ 238.

Under argon gas atmosphere, the mixture of 4-chloro-7-oxyethyl group-6-methoxy quinoline (0.5g), 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate (0.456g), 4-dimethylaminopyridine (0.771g) and chlorobenzene (8ml) is stirred and be heated to 145 ℃ kept 16 hours.This mixture is cooled to envrionment temperature and evaporation concentration.Resistates is through purification by silica gel column chromatography, use ethyl acetate to the gradient solvent mixture of 19:1 ethyl acetate and methyl alcohol as elutriant.Obtain 2-[5-(7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl thus] methyl acetate (0.626g);

¹ H NMR：(DMSOd ₆)1.43(t，3H)，3.64(s，3H)，3.82(s，3H)，3.83(s，2H)，3.94(s，3H)，4.21(q，2H)，6.56(d，1H)，7.3(d，1H)，7.52(m，2H)，8.08(s，1H)，8.5(d，1H)； Mass Spectrum：M+H ⁺ 399.

At ambient temperature, the mixture with the product, sodium hydroxide (0.249g), water (3ml), THF (2ml) and the methyl alcohol (8ml) that obtain thus stirred 14 hours.With the mixture evaporation concentration that obtains and between water and ethyl acetate, distribute.By add the 2N aqueous hydrochloric acid with aqueous phase as acidified to pH4.5.With precipitate and separate and the vacuum-drying that obtains.Obtain 2-[5-(7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl thus] acetate (0.528g);

¹ H NMR：(DMSOd ₆)1.43(t，3H)3.73(s，2H)，3.82(s，3H)，3.94(s，3H)，4.21(q，2H)，6.54(d，1H)，7.4(s，1H)，7.49(d，1H)，7.52(s，1H)，8.07(d，1H)，8.5(d，1H)； Mass Spectrum：M+H ⁺ 385.

[33] use DMA to replace DMF as reaction solvent.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)1.43(t，3H)，2.13(s，3H)，3.7(s，3H)，3.82(s，3H)，3.85(s，2H)，3.94(s，3H)，4.21(q，2H)，6.54(d，1H)，7.4(d，1H)，7.48(d，1H)，7.52(s，1H)，7.81(s，1H)，8.08(d，1H)，8.51(d，1H)，9.51(s，1H)； Mass Spectrum：M+H ⁺ 478.[34] ¹ H NMR：(DMSOd ₆)1.3(t，3H)，1.43(t，3H)，2.14(s，3H)，3.82(s，3H)，3.85(s，2H)，3.94(s，3H)，3.97(q，2H)，4.21(q，2H)，6.53(d，1H)，7.4(s，1H)，7.48(d，1H)，7.52(s，1H)，7.84(s，1H)，8.08(d，1H)，8.5(d，1H)，9.51(s，1H)； Mass Spectrum：M+H ⁺ 492.

[35] use DMA to replace DMF as reaction solvent.At ambient temperature reaction mixture was stirred 14 hours postheating to 55 ℃ maintenance 25 hours.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)2.08(s，3H)，3.6(s，3H)，3.84(s，3H)，3.88(s，2H)，3.94(s，3H)，3.96(s，3H)，5.97(s，1H)6.57(d，1H)，7.42(s，1H)，7.5(d，1H)，7.52(s，1H)，8.09(d，1H)，8.52(d，1H)，10.04(s，1H)； Mass Spectrum：M+H ⁺ 464.

[36] use DMA to replace DMF as reaction solvent.At ambient temperature reaction mixture was stirred 14 hours postheating to 70 ℃ maintenance 2 hours.The characteristic of this compound is as follows:

- ¹ H NMR：(DMSOd ₆)1.9(d，3H)，3.83(s，3H)，3.85(s，2H)，3.91(s，3H)，3.96(s，3H)，6.58(d，1H)，7.42(s，1H)，7.5(d，1H)，7.52(s，1H)，8.09(d，1H)，8.52(d，1H)，8.6(q，1H)，10.44(br s，1H)； Mass Spectrum：M+H ⁺ 451.

3-amino-4-methyl-isoxazole as raw material is prepared as follows:

Add bromine (1.9ml) toward being cooled in 0 ℃ the solution of methacrylonitrile (3.65ml) in methyl alcohol (6ml).The mixture that obtains is stirred and be heated to 35 ℃ to be kept 2 hours.This mixture is cooled to 0 ℃.Add hydroxyurea (4.3g), the solution of dropping sodium (4.72g) in water (5ml) subsequently.The mixture heating up that obtains was kept 2.5 hours to refluxing.This mixture is cooled to envrionment temperature and between ethyl acetate and water, distributes.Organic solution is through dried over mgso and evaporation.Resistates is through purification by silica gel column chromatography, and the gradient solvent that uses 1:1 to 0:100 methylene dichloride and ethyl acetate is as elutriant.Obtain desired raw material (1.11g) thus;

¹ H NMR：(DMSOd ₆)1.81(d,3H)，5.43(br s，2H)，8.09(d，1H)； Mass Spectrum：M+H ⁺ 99.

[37] ¹ H NMR：(DMSOd ₆)2.13(s，6H)，2.26(s，3H)，3.29(s，2H)，3.83(s，3H)，3.86(s，2H)，3.94(s，3H)，6.67(d，1H)，6.78(s，1H)，7.36(d，1H)，7.49(m，1H)，7.52(d，1H)，7.59(d，1H)，7.97(d，1H)，8.11(d，1H)，8.59(d，1H)，10.05(s，1H)； Mass Spectrum：M+H ⁺ 487.

Embodiment 3

N-(5-ethyl pyrazole-3-yl)-2-[5-(6-cyano group-7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide

At ambient temperature, toward stirring 2-[5-(6-cyano group-7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.395g) in the mixture of acetate (0.25g), 5-amino-3-ethyl-1H-pyrazoles (0.13g), diisopropyl ethyl amine (0.36ml) and DMF (4ml).At ambient temperature, the mixture that obtains was stirred 16 hours.Reaction mixture is through preparation HPLC purifying, and the water (containing 0.2% volatile salt) that use Waters ' β Basic Hypersil ' reversed-phase column (5 microns silica gel, 30mm diameter, 250mm length) and polarity reduce gradually and the mixture of acetonitrile are as elutriant.Obtain title compound (0.17g) thus;

¹ H NMR：(DMSOd ₆)1.15(t，3H)，2.6(q，2H)，3.9(s，2H)，4.1(s，3H)，6.3(brs，1H)，6.6(d，1H)，7.55(d，1H)，7.65(s，1H)，7.8(m，1H)，8.55(s，1H)，8.75(d，1H)，8.8(s，1H).

As the 2-[5-of raw material (6-cyano group-7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] acetate is prepared as follows:

With 4-chloro-6-cyano group-7-methoxy quinoline (1.5g; Embodiment 1 in the International Patent Application WO 02/12226, its relate to International Patent Application WO 98/13350 in embodiment 1 described in be used for the similar method of feedstock production, difference is to use methyl alcohol to replace 2-methyl cellosolve), the mixture of (5-pyridone-2-yl) tert.-butyl acetate (1.58g), cesium carbonate (3.36g) and DMA (40ml) stirs and is heated to 85 ℃ of maintenances 2 hours.The mixture that obtains is filtered and filtrate is distributed between ethyl acetate and water.Organic solution salt water washing is through dried over mgso and evaporation.Resistates is through purification by silica gel column chromatography, and the methylene dichloride that use polarity increases gradually and the solvent mixture of methyl alcohol (100:0 to 1:4) are as elutriant.Obtain 2-[5-(6-cyano group-7-methoxy quinoline-4-base oxygen base) pyridine-2-yl of solid state thus] tert.-butyl acetate (1.22g);

¹ H NMR：(DMSOd ₆)1.4(s，9H)，3.85(s，2H)，4.1(s，3H)，6.6(d，1H)，7.5(d，1H)，7.65(s，1H)，7.8(dd，1H)，8.55(d，1H)，8.8(d，1H)，8.85(s，1H).

The solution of product in methylene dichloride (20ml) that obtains thus is cooled to 0 ℃.Adding entry (0.5ml) and trifluoroacetic acid (15ml) also stirs reaction mixture 4 hours at ambient temperature.With the mixture evaporation that obtains, by removing remaining trifluoroacetic acid with toluene vacuum component distillation.Resistates is dissolved in the methylene dichloride, adds diisopropyl ethyl amine (2ml) and also at ambient temperature this mixture was stirred 30 minutes.Collect the precipitation that obtains by filtering, with ether washing and vacuum-drying.Obtain 2-[5-(6-cyano group-7-methoxy quinoline-4-base oxygen base) pyridine-2-yl thus] acetate (0.83g);

¹ H NMR：(DMSOd ₆)4.1(s，3H)，6.6(d，1H)，7.55(d，1H)，7.65(s，1H)，7.8(m，1H)，8.55(d，1H)，8.75(d，1H)，8.8(s，1H). Mass Spectrum：M+H ⁺ 336.

Embodiment 4

N-(the 1-tertiary butyl-3,4-dimethyl pyrazole-5-yl)-2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide

Adopt and similar method described in the embodiment 1, difference is to use DMA (3ml) to replace DMF as reaction solvent, at phosphofluoric acid 2-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea (1.1g) and diisopropyl ethyl amine (1ml) exist down with 2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.7g) and 5-amino-1-tertiary butyl-3,4-dimethyl pyrazole (0.4g) reaction.The mixture that obtains is distributed between ethyl acetate and water.Organic phase is through dried over mgso and evaporation.Product is through purification by silica gel column chromatography, and the mixture of the 19:1 of use methylene dichloride and methyl alcohol is as elutriant.Obtain the title compound (0.711g) of solid state thus;

¹ H NMR：(DMSOd ₆)1.49(s，9H)，1.71(s，3H)，2.04(s，3H)，3.82(s，3H)，3.86(s，2H)，3.94(s，3H)，3.95(s，3H)，6.57(d，1H)，7.42(s，1H)，7.49(d，1H)，7.52(s，1H)，8.09(s，1H)，8.51(d，1H)，9.47(s，1H)； Mass Spectrum：M+H ⁺ 520.

As the 5-amino-1-tertiary butyl-3 of raw material, the 4-dimethyl pyrazole is prepared as follows:

Add 1-tertiary butyl hydrazonium salt hydrochlorate (1.55g) in the 2-methyl-solution of 3-oxo butyronitrile (1g) in ethanol (10ml) that stirs and the mixture heating up to 85 that obtains ℃ was kept 5 hours.With this mixture evaporation concentration, resistates is through purification by silica gel column chromatography, use methylene dichloride to the gradient solvent mixture of 7:3 methylene dichloride and ethyl acetate as elutriant.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.

Embodiment 5

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

With N-(the 1-tertiary butyl-3,4-dimethyl pyrazole-5-yl)-and 2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] mixture of ethanamide (0.684g), phenylmethylether (0.429ml) and trifluoroacetic acid (8ml) stirs and is heated to 90 ℃ of maintenances 4 days.Reaction mixture is cooled to envrionment temperature, by adding saturated sodium bicarbonate aqueous solution neutralization and using ethyl acetate extraction.Organic phase is through dried over mgso and evaporation.Resistates is through purification by silica gel column chromatography, and the methylene dichloride of use 19:1 to 4:1 and the gradient solvent of methyl alcohol are as elutriant.Obtain the title compound (0.361g) of solid state thus;

¹ H NMR：(DMSOd ₆)1.77(s，3H)，2.1(s，3H)，3.82(s，2H)，3.83(s，3H)，3.94(s，3H)，3.96(s，3H)，6.59(d，1H)，7.42(s，1H)，7.48(d，1H)，7.53(s，1H)，8.08(d，1H)，8.52(d，1H)，9.63(brs，1H)，12.0(br s，1H)； Mass Spectrum：M+H ⁺ 464.

Embodiment 6

Adopt and similar method described in the embodiment 4 and 5, the amino-pyrazol of suitable 2-pyridine-2-guanidine-acetic acid with the suitable tertiary butyl-protection reacted, obtain the described compound of Table II.

Table II

Numbering	(R 1) p	(R 2) q	R
				[1]	6, the 7-dimethoxy	The 3-methoxyl group	4-ethyl-5-methylpyrazole-3-base
[2]	6, the 7-dimethoxy	The 3-methoxyl group	5-ethyl-4-methylpyrazole-3-base
				[3]	5, the 7-dimethoxy	The 3-methoxyl group	4,5-dimethyl pyrazole-3-base
[4]	7-oxyethyl group-6-methoxyl group	The 3-methoxyl group	4-ethyl pyrazole-3-yl

[5]	7-oxyethyl group-6-methoxyl group	The 3-methoxyl group	4,5-dimethyl pyrazole-3-base
				[6]	7-oxyethyl group-6-methoxyl group	The 3-methoxyl group	4-ethyl-5-methylpyrazole-3-base
[7]	7-oxyethyl group-6-methoxyl group	The 3-methoxyl group	5-ethyl-4-methylpyrazole-3-base
				[8]	The 6-methoxyl group	The 3-methoxyl group	4,5-dimethyl pyrazole-3-base
[9]	The 6-methoxyl group	The 3-methoxyl group	4-ethyl-5-methylpyrazole-3-base
				[10]	The 6-methoxyl group	The 3-methoxyl group	5-ethyl-4-methylpyrazole-3-base
[11]	The 7-methoxyl group	The 3-methoxyl group	4,5-dimethyl pyrazole-3-base
				[12]	The 7-methoxyl group	The 3-methoxyl group	4-ethyl-5-methylpyrazole-3-base
[13]	The 7-methoxyl group	The 3-methoxyl group	5-ethyl-4-methylpyrazole-3-base
				[14]	The 6-fluorine	The 3-methoxyl group	4-ethyl-5-methylpyrazole-3-base
[15]	The 6-fluorine	The 3-methoxyl group	5-ethyl-4-methylpyrazole-3-base
				[16]	6, the 7-dimethoxy	The 3-methoxyl group	4,5-trimethylene pyrazole-3-yl
[17]	7-oxyethyl group-6-methoxyl group	The 3-methoxyl group	4,5-trimethylene pyrazole-3-yl
				[18]	The 6-methoxyl group	The 3-methoxyl group	4,5-trimethylene pyrazole-3-yl
[19]	The 7-methoxyl group	The 3-methoxyl group	4,5-trimethylene pyrazole-3-yl
				[20]	The 6-fluorine	The 3-methoxyl group	4,5-trimethylene pyrazole-3-yl

NoteThe characteristic of each product is as follows:

[1] ¹ H NMR：(DMSOd ₆)0.99(t，3H)，2.12(s，3H)，2.26(q，2H)，3.82(m，5H)，3.94(s，3H)，3.95(s，3H)，6.58(d，1H)，7.42(s，1H)，7.48(s，1H)，7.53(s，1H)，8.07(d，1H)，8.51(d，1H)，9.52(br s，1H)； Mass Spectrum：M+H ⁺ 478.

As N-(the 1-tertiary butyl-4-ethyl-3-methylpyrazole-5-yl)-2-[5-of raw material (6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Under argon gas atmosphere, toward stirring the solution of mixture in THF (40ml) that drips butyronitrile (20ml) and methyl acetate (23.54ml) in the suspension of potassium tert.-butoxide (56.67g) in THF that also has been cooled to 15 ℃.At ambient temperature, the mixture that obtains was stirred 16 hours.With solvent evaporation, resistates grinds with ether.With this solids constituent from.Add entry (200ml) and this mixture is acidified to pH4 by adding the 12N aqueous hydrochloric acid.The aqueous solution dichloromethane extraction of mixture, organic extract liquid 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).

Add 1-tertiary butyl hydrazonium salt hydrochlorate (5.11g) in the 2-ethyl-solution of 3-oxo butyronitrile (3.4g) in ethanol (35ml) that stirs and the mixture heating up that obtains was kept 12 hours to refluxing.With this mixture evaporation.In resistates, add saturated sodium bicarbonate aqueous solution and this mixture is acidified to pH9 by adding the 2N aqueous sodium hydroxide solution.This mixture ethyl acetate extraction.Organic phase salt water washing is through dried over mgso and evaporation.Resistates is through purification by silica gel column chromatography, use methylene dichloride to the gradient solvent mixture of the methylene dichloride of 3:2 and ethyl acetate as elutriant.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(brs，2H).

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-4-ethyl-3-methylpyrazole (0.1g) and 2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-and 3-Methoxy Pyridine-2-yl] acetate (0.2g) reaction, obtain desired raw material (0.143g);

¹ H NMR：(DMSOd ₆)0.98(t，3H)，1.49(s，9H)，2.06(s，3H)，2.17(q，2H)，3.82(s，3H)，3.85(s，2H)，3.94(s，3H)，3.96(s，3H)，6.57(d，1H)，7.42(s，1H)，7.49(d，1H)，7.52(s，1H)，8.07(d，1H)，8.51(d，1H)，9.47(s，1H)； Mass Spectrum：M+H ⁺ 534.

[2] ¹ H NMR：(DMSOd ₆)1.13(t，3H)，1.77(s，3H)，2.5(q，2H)，3.83(s，3H)，3.94(s，2H)，3.95(s，3H)，6.57(d，1H)，7.42(s，1H)，7.48(s，1H)，7.53(s，1H)，8.07(d，1H)，8.51(d，1H)，9.59(br s，1H)； Mass Spectrum：M+H ⁺ 478.

As N-(the 1-tertiary butyl-3-ethyl-4-methylpyrazole-5-the yl)-2-[5-of raw material (6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Under argon gas atmosphere, slowly add n-Butyl Lithium in-78 ℃ the solution of diisopropylamine (17.52ml) in THF (100ml) (2.5M is in hexane, 50ml) toward stirring and being cooled to.The solution that obtains is remained on-78 ℃ and the slow propionitrile (8.92ml) that adds.Under-78 ℃, this mixture was stirred 30 minutes.Dropping methyl propionate (6ml) also stirs this mixture 2 hours under-78 ℃.Allow reaction mixture be warming up to 0 ℃ and adding ice.The solution evaporation that obtains is concentrated and between ether and water, distribute.By add the 6N aqueous hydrochloric acid with acidified aqueous solution to pH2 and use extracted with diethyl ether.The 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).

Adopt and similar method described in the note of related feedstock production [1] part just, 1-tertiary butyl hydrazonium salt hydrochlorate and 2-methyl-3-oxo valeronitrile (5.8g) are reacted.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.

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3-ethyl-4-methylpyrazole (0.11g) and 2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-and 3-Methoxy Pyridine-2-yl] acetate (0.22g) reaction, obtain desired raw material (0.178g);

¹ H NMR：(DMSOd ₆)1.11(t，3H)，1.49(s，9H)，1.73(s，3H)，2.44(q，2H)，3.82(s，3H)，3.86(s，2H)，3.94(s，3H)，3.95(s，3H)，6.56(d，1H)，7.42(s，1H)，7.49(d，1H)，7.52(s，1H)，8.08(d，1H)，8.51(d，1H)，9.44(br s，1H)； Mass Spectrum：M+H ⁺ 534.

[3] ¹ H NMR：(DMSOd ₆)1.75(s，3H)，2.1(s，3H)，3.77(s，2H)，3.8(s，3H)，3.83(s，3H)，3.91(s，3H)，6.6(d，1H)，6.67(d，1H)，7.02(d，1H)，7.31(d，1H)，7.86(d，1H)，8.58(d，1H)，9.58(br s，1H)； Mass Spectrum：M+H ⁺ 464.

As N-(the 1-tertiary butyl-3,4-dimethyl pyrazole-5-the yl)-2-[5-of raw material (5,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3,4-dimethyl pyrazole (0.1g) and 2-[5-(5,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.185g) reaction, obtain desired raw material (0.185g);

¹ H NMR：(DMSOd ₆)1.48(s，9H)，1.7(s，3H)，2.03(s，3H)，3.8(s，2H)，3.82(s，3H)，3.91(s，3H)，6.6(d，1H)，6.67(d，1H)，7.03(d，1H)，7.32(d，1H)，7.85(d，1H)，8.59(d，1H)，9.45(s，1H)； Mass Spectrum：M+H ⁺ 520.

[4] ¹ H NMR：(DMSOd ₆)1.01(t，3H)，1.36(t，3H)，2.23(q，2H)，3.76(2s，5H)，3.87(s，3H)，4.14(q，2H)，6.49(d，1H)，7.33(s，1H)，7.35(m，1H)，7.41(d，1H)，7.45(s，1H)，8.01(d，1H)，8.43(d，1H)，9.58(br s，1H)； Mass Spectrum：M+H ⁺ 478.

As N-(the 1-tertiary butyl-4-ethyl pyrazoles-5-yl)-2-[5-of raw material (7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Under argon gas atmosphere, drip the solution of mixture in THF (4ml) of butyronitrile (2.18ml) and ethyl formate (2.11ml) in the suspension of potassium tert.-butoxide (6.18g) in THF (40ml) that stirs and at ambient temperature with the mixture stirring that obtains 16 hours.With solvent evaporation and with the resistates solid suspension in ether, wash by filtering separation and with ether.This solid is dissolved in the water, by adding the 2N aqueous hydrochloric acid this solution is acidified to pH4 and uses dichloromethane extraction subsequently.Organic extract liquid is through dried over mgso.Obtain 2-formyl radical butyronitrile (1g) thus, it need not to be further purified use.

Add 1-tertiary butyl hydrazine hydrate (1.72g) and acetate (0.59ml) in the solution of 2-formyl radical butyronitrile (1g) in ethanol (10ml) successively and the mixture heating up that obtains was kept 5 hours to refluxing.With the evaporation of this mixture and add saturated sodium bicarbonate aqueous solution.Alkalize this mixture to pH9 and use dichloromethane extraction with the 2N aqueous sodium hydroxide solution.Organic extract liquid is through dried over mgso and evaporation.Resistates is through purification by silica gel column chromatography, use methylene dichloride to the gradient solvent mixture of 1:1 methylene dichloride and ethyl acetate as elutriant.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.

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-4-ethyl pyrazoles (0.104g) and 2-[5-(7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.17g) reaction, obtain desired raw material (0.215g);

¹ H NMR：(DMSOd ₆)1.07(t，3H)，1.43(t，3H)，1.52(s，9H)，2.2(q，2H)，3.86(s，3H)，3.94(s，2H)，4.02(s，3H)，4.21(q，2H)，6.55(d，1H)，7.23(s，1H)，7.4(s，1H)，7.49(d，1H)，7.52(s，1H)，8.08(d，1H)，8.5(d，1H)，9.49(br s，1H)； Mass Spectrum：M+H ⁺ 534.

[5] ¹ H NMR：(DMSOd ₆)1.43(t，3H)，1.76(s，3H)，2.1(s，3H)，3.83(2s，5H)，3.86(s，2H)，3.94(s，3H)，4.21(q，2H)，6.57(d，1H)，7.39(s，1H)，7.48(d，1H)，7.52(s，1H)，8.08(d，1H)，8.5(d，1H)，9.61(br s，1H)； Mass Spectrum：M+H ⁺ 478.

As N-(the 1-tertiary butyl-3,4-dimethyl pyrazole-5-the yl)-2-[5-of raw material (7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3,4-dimethyl pyrazole (0.096g) and 2-[5-(7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.17g) reaction, obtain desired raw material (0.231g);

¹ H NMR：(DMSOd ₆)1.43(t，3H)，1.49(s，9H)，1.71(s，3H)，2.04(s，3H)，3.82(s，3H)，3.86(s，3H)，3.94(s，3H)，4.21(q，2H)，6.56(d，1H)，7.4(s，1H)，7.49(d，1H)，7.52(s，1H)，8.08(d，1H)，8.5(d，1H)，9.47(s，1H)； Mass Spectrum：M+H ⁺ 534.

[6] ¹ H NMR：(DMSOd ₆)1.0(t，3H)，1.44(t，3H)，2.13(s，3H)，2.27(q，2H)，3.83(2s，5H)，4.22(q，2H)，6.58(d，1H)，7.41(s，1H)，7.49(d，1H)，7.53(s，1H)，8.08(d，1H)，8.51(d，1H)，9.57(br s，1H)； Mass Spectrum：M+H ⁺ 492.

As N-(the 1-tertiary butyl-4-ethyl-3-methylpyrazole-5-yl)-2-[5-of raw material (7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-4-ethyl-3-methylpyrazole (0.112g) and 2-[5-(7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.17g) reaction, obtain desired raw material (0.209g);

¹ H NMR：(DMSOd ₆)0.99(t，3H)，1.44(t，3H)，1.5(s，9H)，2.07(s，3H)，2.18(q，2H)，3.83(s，3H)，3.86(s，2H)，3.95(s，3H)，4.22(q，2H)，6.57(d，1H)，7.41(s，1H)，7.5(d，1H)，7.53(s，1H)，8.08(d，1H)，8.51(d，1H)，9.47(s，1H)； Mass Spectrum：M+H ⁺ 548.

[7] ¹ H NMR：(DMSOd ₆)1.14(t，3H)，1.45(t，3H)，1.79(s，3H)，2.51(q，2H)，3.52(2s，5H)，3.84(s，3H)，4.22(q，2H)，6.6(d，1H)，7.41(s，1H)，7.5(d，1H)，7.55(s，1H)，8.1(d，1H)，8.53(d，1H)，9.63(br s，1H)； Mass Spectrum：M+H ⁺ 492.

As N-(the 1-tertiary butyl-3-ethyl-4-methylpyrazole-5-the yl)-2-[5-of raw material (7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3-ethyl-4-methylpyrazole (0.112g) and 2-[5-(7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.17g) reaction, obtain desired raw material (0.226g);

¹ H NMR：(DMSOd ₆)1.11(t，3H)，1.43(t，3H)，1.49(s，9H)，1.73(s，3H)，2.44(q，2H)，3.82(s，3H)，3.86(s，2H)，3.94(s，3H)，4.21(q，2H)，6.54(d，1H)，7.4(s，1H)，7.49(d，1H)，7.52(s，1H)，8.08(d，1H)，8.5(d，1H)，9.43(s，1H)； Mass Spectrum：M+H ⁺ 548.

[8] ¹ H NMR：(DMSOd ₆)1.77(s，3H)，2.1(s，3H)，3.83(2s，5H)，3.94(s，3H)，6.7(d，1H)，7.49(m，2H)，7.59(d，1H)，7.97(d，1H)，8.1(d，1H)，8.58(d，1H)，9.67(br s，1H)； Mass Spectrum：M+H ⁺ 434.

As N-(the 1-tertiary butyl-3,4-dimethyl pyrazole-5-the yl)-2-[5-of raw material (6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3,4-dimethyl pyrazole (0.14g) and 2-[5-(6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.22g) reaction, obtain desired raw material (0.258g);

¹ H NMR：(DMSOd ₆)1.49(s，9H)，1.72(s，3H)，2.04(s，3H)，3.83(s，3H)，3.87(s，2H)，3.93(s，3H)，6.69(d，1H)，7.48(m，1H)，7.52(d，1H)，7.58(d，1H)，7.97(d，1H)，8.1(d，1H)，8.58(d，1H)，9.48(s，1H)； Mass Spectrum：M+H ⁺ 490.

[9] ¹ H NMR：(DMSOd ₆)1.0(t，3H)，2.13(s，3H)，2.27(q，2H)，3.84(2s，5H)，3.95(s，3H)，6.71(d，1H)，7.48(m，1H)，7.51(d，1H)，7.59(d，1H)，7.98(d，1H)，8.11(d，1H)，8.58(d，1H)，9.55(br s，1H)，12.02(br s，1H)； Mass Spectrum：M+H ⁺ 448.

As N-(the 1-tertiary butyl-4-ethyl-3-methylpyrazole-5-yl)-2-[5-of raw material (6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-4-ethyl-3-methylpyrazole (0.152g) and 2-[5-(6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.22g) reaction, obtain desired raw material (0.282g);

¹ H NMR：(DMSOd ₆)0.98(t，3H)，1.49(s，9H)，2.06(s，3H)，2.17(q，2H)，3.83(s，3H)，3.86(s，2H)，3.93(s，3H)，6.69(d，1H)，7.49(m，1H)，7.51(d，1H)，7.58(d，1H)，7.97(d，1H)，8.1(d，1H)，8.58(d，1H)，9.47(s，1H)； Mass Spectrum：M+H ⁺ 504.

[10] ¹ H NMR：(DMSOd ₆)1.13(t，3H)，1.78(s，3H)，2.5(q，2H)，3.83(2s，5H)，3.94(s，3H)，6.7(d，1H)，7.49(m，2H)，7.59(d，1H)，7.96(d，1H)，8.1(d，1H)，8.57(d，1H)，9.6(br s，1H)； Mass Spectrum：M+H ⁺ 448.

As N-(the 1-tertiary butyl-3-ethyl-4-methylpyrazole-5-the yl)-2-[5-of raw material (6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3-ethyl-4-methylpyrazole (0.152g) and 2-[5-(6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.22g) reaction, obtain desired raw material (0.297g);

¹ H NMR：(DMSOd ₆)1.11(t，3H)，1.49(s，9H)，1.74(s，3H)，2.44(q，2H)，3.83(s，3H)，3.87(s，2H)，3.93(s，3H)，6.69(d，1H)，7.48(m，1H)，7.52(d，1H)，7.58(d，1H)，7.96(d，1H)，8.1(d，1H)，8.57(d，1H)，9.44(s，1H)； Mass Spectrum：M+H ⁺ 548.

[11] ¹ H NMR：(DMSOd ₆)1.78(s，3H)，2.09(s，3H)，3.83(s，2H)，3.95(s，3H)，6.59(d，1H)，7.3(m，1H)，7.43(m，2H)，8.06(s，1H)，8.21(d，1H)，8.64(d，1H)，9.43(br s，1H)，11.88(br s，1H)； Mass Spectrum：M+H ⁺ 434.

As N-(the 1-tertiary butyl-3,4-dimethyl pyrazole-5-the yl)-2-[5-of raw material (7-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Under argon gas atmosphere, in the mixture of 2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) methyl acetate (0.813g), salt of wormwood (1.28g) and the DMF (9ml) that stir, add bromotoluene (0.387ml).The mixture heating up to 60 that obtains ℃ was kept 16 hours.This mixture is cooled to envrionment temperature, and dilute with water is also used ethyl acetate extraction.Organic phase washes with water, through dried over mgso and evaporation.Resistates is through purification by silica gel column chromatography, use methylene dichloride to the gradient solvent mixture of 17:3 methylene dichloride and ethyl acetate as elutriant.Obtain 2-(5-benzyloxy-3-Methoxy Pyridine-2-yl) methyl acetate (0.754g) thus;

¹ H NMR：(DMSOd ₆)3.59(s，3H)，3.68(s，2H)，3.79(s，3H)，5.2(s，2H)，7.14(d，1H)，7.35(m，1H)，7.41(m，2H)，7.47(d，2H)，7.86(d，1H)； Mass Spectrum：M+H ⁺ 288.

At ambient temperature, the mixture with the product, sodium hydroxide (0.314g), water (1.5ml) and the methyl alcohol (8ml) that obtain thus stirred 2 days.With the methyl alcohol evaporation and by adding the 2N aqueous hydrochloric acid mixture aqueous solution is acidified to pH4.8.Separate the precipitation that obtains, successively washing of water and ether and vacuum-drying.Obtain 2-(5-benzyloxy-3-Methoxy Pyridine-2-yl) acetate (0.624g) thus;

¹ H NMR：(DMSOd ₆)3.59(s，2H)，3.79(s，3H)，5.19(s，2H)，7.12(d，1H)，7.35(m，1H)，7.41(m，2H)，7.47(m，2H)，7.85(d，1H)； Mass Spectrum：M+H ⁺ 274.

In the mixture of 2-(5-benzyloxy-3-Methoxy Pyridine-2-yl) acetate (0.62g) that stirs and DMA (6ml), add diisopropyl ethyl amine (1.19ml), the 5-amino-1-tertiary butyl-3 successively, 4-dimethyl pyrazole (0.455g) and phosphofluoric acid 2-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea (1.12g).At ambient temperature, the mixture that obtains was stirred 16 hours.Add saturated sodium bicarbonate aqueous solution, this mixture ethyl acetate extraction.Organic phase washes with water, through dried over mgso and evaporation.Resistates is through purification by silica gel column chromatography, use methylene dichloride to the gradient solvent mixture of 7:3 methylene dichloride and ethyl acetate as elutriant.Obtain N-(the 1-tertiary butyl-3,4-dimethyl pyrazole-5-yl)-2-(5-benzyloxy-3-Methoxy Pyridine-2-yl) ethanamide (0.883g) thus;

¹ H NMR：(DMSOd ₆)1.46(s，9H)，1.68(s，3H)，2.02(s，3H)，3.71(s，2H)，3.8(s，3H)，5.2(s，2H)，7.12(d，1H)，7.35(m，1H)，7.41(m，2H)，7.48(m，2H)，7.86(d，1H)，9.4(s，1H)； Mass Spectrum：M+H ⁺ 423.

The mixture of the product, ammonium formiate (1.22g), 10% palladium/carbon catalyst (0.15g) and the DMF (10ml) that obtain is thus stirred and be heated to 50 ℃ to be kept 16 hours.The mixture that obtains is cooled to envrionment temperature and filtration.Filtrate is distributed between water and ethyl acetate.Organic phase washes with water, through dried over mgso and evaporation.Resistates is through purification by silica gel column chromatography, and the methylene dichloride of use 19:1 and methanol mixture are as elutriant.Obtain N-(the 1-tertiary butyl-3,4-dimethyl pyrazole-5-yl)-2-(5-hydroxyl-3-Methoxy Pyridine-2-yl) ethanamide (0.485g) thus;

¹ H NMR：(DMSOd ₆)1.46(s，9H)，1.68(s，3H)，2.02(s，3H)，3.66(s，2H)，3.74(s，3H)，6.8(d，1H)，7.64(d，1H)，9.35(s，1H)，9.8(br s，1H)； Mass Spectrum：M+H ⁺ 333.

The mixture of a part of product (0.189g), 4-chloro-7-methoxy quinoline (0.11g), 4-dimethylaminopyridine (0.208g) and the chlorobenzene (1.5ml) that obtain is thus stirred and be heated to 130 ℃ to be kept 16 hours.This mixture is cooled to envrionment temperature and adds ethyl acetate.With this mixture filtration and with the filtrate evaporation concentration.Resistates is through purification by silica gel column chromatography, and the gradient solvent mixture that uses 97:3 to 93:7 methylene dichloride and methyl alcohol is as elutriant.Obtain N-(the 1-tertiary butyl-3,4-dimethyl pyrazole-5-yl)-2-[5-(7-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl thus] ethanamide (0.173g);

¹ H NMR：(DMSOd ₆)1.49(s，9H)，1.71(s，3H)，2.04(s，3H)，3.82(s，3H)，3.86(s，2H)，3.95(s，3H)，6.56(d，1H)，7.31(m，1H)，7.43(d，1H)，7.51(d，1H)，8.08(d，1H)，8.22(d，1H)，8.64(d，1H)，9.48(s，1H)； Mass Spectrum：M+H ⁺ 490.

[12] ¹ H NMR：(DMSOd ₆+CF ₃CO ₂D)1.08(t，3H)，2.3(s，3H)，2.52(q，2H)，3.87(s，3H)，4.0(s，2H)，4.06(s，3H)，7.02(d，1H)，7.64(s，1H)，7.66(s，1H)，7.77(s，1H)，8.29(d，1H)，8.53(d，1H)，9.07(d，1H)； Mass Spectrum：M+H ⁺ 448.

As N-(the 1-tertiary butyl-4-ethyl-3-methylpyrazole-5-yl)-2-[5-of raw material (7-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-4-ethyl-3-methylpyrazole (0.127g) and 2-[5-(7-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.17g) reaction, obtain desired raw material (0.238g);

¹ H NMR：(DMSOd ₆)0.98(t，3H)，1.49(s，9H)，2.06(s，3H)，2.17(q，1H)，3.82(s，3H)，3.85(s，2H)，3.95(s，3H)，6.56(d，1H)，7.31(m，1H)，7.43(d，1H)，7.51(d，1H)，8.08(d，1H)，8.22(d，1H)，8.64(d，1H)，9.47(s，1H)； Mass Spectrum：M+H ⁺ 504.

[13] ¹ H NMR：(DMSOd ₆)1.13(t，3H)，1.78(s，3H)，2.5(q，2H)，3.83(m，5H)，3.94(s，3H)，6.57(d，1H)，7.31(d，1H)，7.43(d，1H)，7.5(s，1H)，8.08(d，1H)，8.22(d，1H)，8.64(d，1H)，9.59(br s，1H)； Mass Spectrum：M+H ⁺ 448.

As N-(the 1-tertiary butyl-3-ethyl-4-methylpyrazole-5-the yl)-2-[5-of raw material (7-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3-ethyl-4-methylpyrazole (0.11g) and 2-[5-(7-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.16g) reaction, obtain desired raw material (0.196g);

¹ H NMR：(DMSOd ₆)1.11(t，3H)，1.49(s，9H)，1.74(s，3H)，2.43(q，2H)，3.82(s，3H)，3.86(s，2H)，3.95(s，3H)，6.56(d，1H)，7.31(m，1H)，7.43(d，1H)，7.51(d，1H)，8.08(d，1H)，8.22(d，1H)；8.64(d，1H)；9.44(s，1H)； Mass Spectrum：M+H ⁺ 504.

[14] ¹ H NMR：(DMSOd ₆+CF ₃CO ₂D)1.01(t，3H)，2.23(s，3H)，2.45(q，2H)，3.81(s，3H)，4.03(s，2H)，7.17(d，1H)，7.7(s，1H)，8.1(m，1H)，8.23(s，1H)，8.33(m，2H)，9.13(d，1H)； Mass Spectrum：M+H ⁺ 436.

As N-(the 1-tertiary butyl-4-ethyl-3-methylpyrazole-5-yl)-2-[5-(the 6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl of raw material] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-4-ethyl-3-methylpyrazole (0.125g) and 2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.175g) reaction, obtain desired raw material (0.164g);

¹ H NMR：(DMSOd ₆)0.99(t，3H)，1.5(s，9H)，2.07(s，3H)，2.18(q，2H)，3.83(s，3H)，3.87(s，2H)，6.78(d，1H)，7.55(d，1H)，7.79(m，1H)，8.02(m，1H)，8.12(m，2H)，8.73(d，1H)，9.48(s，1H)； Mass Spectrum：M+H ⁺ 492.

[15] ¹ H NMR：(DMSOd ₆+CF ₃CO ₂D)1.17(t，3H)，2.02(s，3H)，2.67(q，2H)，3.86(s，3H)，4.08(s，2H)，7.21(d，1H)，7.73(s，1H)，8.14(m，1H)，8.29(s，1H)，8.35(m，1H)，8.4(m，1H)，9.2(d，1H)； Mass Spectrum：M+H ⁺ 436.

As N-(the 1-tertiary butyl-3-ethyl-4-methylpyrazole-5-yl)-2-[5-(the 6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl of raw material] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3-ethyl-4-methylpyrazole (0.107g) and 2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.15g) reaction, obtain desired raw material (0.16g);

¹ H NMR：(DMSOd ₆)1.11(t，3H)，1.49(s，9H)，1.74(s，3H)，2.44(q，2H)，3.83(s，3H)，3.87(s，2H)，6.77(d，1H)，7.55(d，1H)，7.77(m，1H)，8.0(m，1H)，8.13(m，2H)，8.72(d，1H)，9.44(s，1H)； Mass Spectrum：M+H ⁺ 492.

[16] ¹ H NMR：(DMSOd ₆+CF ₃CO ₂D)2.48(m，2H)，2.67(m，2H)，2.82(m，2H)，3.87(s，3H)，4.01(s，2H)，4.06(s，3H)，4.08(s，3H)，7.03(d，1H)，7.65(s，1H)，7.75(d，1H)，7.79(s，1H)，8.29(d，1H)，8.93(d，1H)； Mass Spectrum：M+H ⁺ 476.

As N-(the 1-tertiary butyl-3,4-trimethylene pyrazoles-5-the yl)-2-[5-of raw material (6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Under nitrogen atmosphere, add 1-tertiary butyl hydrazonium salt hydrochlorate (1.5g) in the 2-oxo-cyclopentane-solution of 1-formonitrile HCN (1.09g) in ethanol (20ml) that stirs and the mixture heating up that obtains was kept 2 hours to refluxing.With this mixture evaporation concentration.In resistates, add entry, add enough sodium bicarbonate aqueous solutions subsequently until stopping to produce gas.The mixture extracted with diethyl ether that obtains is 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(brs，2H)； Mass Spectrum：M+H ⁺ 180.

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3,4-trimethylene pyrazoles (0.107g) and 2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.17g) reaction, obtain desired raw material (0.158g);

¹ H NMR：(DMSOd ₆)1.52(s，9H)，2.25(m，2H)，2.39(m，2H)，2.5(m，2H)，3.82(s，3H)，3.83(s，2H)，3.94(s，3H)，3.95(s，3H)，6.56(d，1H)，7.42(s，1H)，7.49(d，1H)，7.52(s，1H)，8.08(d，1H)，8.51(d，1H)，9.48(br s，1H)； Mass Spectrum：M+H ⁺ 532.

[17] ¹ H NMR：(DMSOd ₆)1.43(t，3H)，2.33(m，2H)，2.58(m，4H)，3.81(2s，5H)，3.94(s，3H)，4.21(q，2H)，6.56(d，1H)，7.4(s，1H)，7.47(d，1H)，7.52(s，1H)，8.07(d，1H)，8.5(d，1H)，10.18(br s，1H)，11.83(brs，1H)； Mass Spectrum：M+H ⁺ 490.

As N-(the 1-tertiary butyl-3,4-trimethylene pyrazoles-5-the yl)-2-[5-of raw material (7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3,4-trimethylene pyrazoles (0.11g) and 2-[5-(7-oxyethyl group-6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.182g) reaction, obtain desired raw material (0.195g);

¹ H NMR：(DMSOd ₆)1.43(t，3H)，1.52(s，9H)，2.25(m，2H)，2.39(m，2H)，2.53(m，2H)，3.82(s，3H)，3.83(s，2H)，3.94(s，3H)，4.21(q，2H)，6.55(d，1H)，7.4(s，1H)，7.49(d，1H)，7.52(s，1H)，8.07(d，1H)，8.5(d，1H)，9.48(s，1H)； Mass Spectrum：M+H ⁺ 546.

[18] ¹ H NMR：(DMSOd ₆)2.34(m，2H)，2.58(m，4H)，3.82(2s，5H)，3.94(s，3H)，6.7(d，1H)，7.49(m，2H)，7.58(d，1H)，7.97(d，1H)，8.09(d，1H)，8.57(d，1H)； Mass Spectrum：M+H ⁺ 446.

As N-(the 1-tertiary butyl-3,4-trimethylene pyrazoles-5-the yl)-2-[5-of raw material (6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3,4-trimethylene pyrazoles (0.136g) and 2-[5-(6-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.2g) reaction, obtain desired raw material (0.284g);

¹ H NMR：(DMSOd ₆)1.53(s，9H)，2.26(m，2H)，2.42(m，2H)，2.54(m，2H)，3.81(s，3H)，3.85(s，2H)，3.94(s，3H)，6.69(d，1H)，7.48(m，1H)，7.52(d，1H)，7.59(d，1H)，7.98(d，1H)，8.11(d，1H)，8.58(d，1H)，9.5(s，1H)； Mass Spectrum：M+H ⁺ 502.

[19] ¹ H NMR：(DMSOd ₆+CF ₃CO ₂D)2.47(m，2H)，2.67(m，2H)，2.81(m，2H)，3.87(s，3H)，4.0(s，2H)，4.06(s，3H)，7.02(d，1H)，7.64(s，1H)，7.66(s，1H)，7.77(s，1H)，8.29(s，1H)，8.53(s，1H)，9.06(s，1H)； Mass Spectrum：M+H ⁺ 446.

As N-(the 1-tertiary butyl-3,4-trimethylene pyrazoles-5-the yl)-2-[5-of raw material (7-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3,4-trimethylene pyrazoles (0.125g) and 2-[5-(7-methoxy quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.17g) reaction, obtain desired raw material (0.232g);

¹ H NMR：(DMSOd ₆)1.52(s，9H)，2.25(m，2H)，2.4(m，2H)，2.54(m，2H)，3.82(s，3H)，3.83(s，2H)，3.94(s，3H)，6.56(d，1H)，7.32(m，1H)，7.43(s，1H)，7.51(s，1H)，8.08(s，1H)，8.21(d，1H)，8.64(d，1H)，9.49(brs，1H)； Mass Spectrum：M+H ⁺ 502.

[20] ¹ H NMR：(DMSOd ₆)2.36(m，2H)，2.57(m，4H)，3.82(2s，5H)，6.77(d，1H)，7.53(d，1H)，7.77(m，1H)，8.0(m，1H)，8.13(m，2H)，8.72(m，1H)，10.18(br s，1H)； Mass Spectrum：M+H ⁺ 434.

As N-(the 1-tertiary butyl-3,4-trimethylene pyrazoles-5-yl)-2-[5-(the 6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl of raw material] ethanamide is prepared as follows:

Adopt and similar method described in the embodiment 4, with 5-amino-1-tertiary butyl-3,4-trimethylene pyrazoles (0.11g) and 2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] acetate (0.155g) reaction, obtain desired raw material (0.175g);

¹ H NMR：(DMSOd ₆)1.52(s，9H)，2.25(m，2H)，2.39(m，2H)，2.53(m，2H)，3.82(s，3H)，3.84(s，2H)，6.77(d，1H)，7.54(d，1H)，7.78(m，1H)，8.0(m，1H)，8.12(d，1H)，8.14(m，1H)，8.72(m，1H)，9.49(br s，1H)； Mass Spectrum：M+H ⁺ 490.

Embodiment 7

N-(5-sec.-propyl pyrazole-3-yl)-2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide

Toward 2-[5-(the 6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl that stirs] add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.437g) and 2 hydroxy pyrimidine N-oxide compound (0.253g) successively in the mixture of acetate (0.25g), 3-amino-5-sec.-propyl pyrazoles (0.162g), diisopropyl ethyl amine (0.4ml) and NMP (1.7ml).At ambient temperature the mixture that obtains was stirred 7 hours postheating to 80 ℃ maintenance 6 hours.With this mixture evaporation, resistates is through preparation HPLC purifying, and the water (containing 0.2% volatile salt) that use Waters ' Xterra ' reversed-phase column (5 microns silica gel, 30mm diameter, 150mm length) and polarity reduce gradually and the mixture of acetonitrile are as elutriant.Obtain title compound (0.047g) thus;

¹ H NMR：(DMSOd ₆)1.19(d，6H)，3.81(s，3H)，3.84(s，2H)，6.27(s，1H)，6.75(d，1H)，7.53(d，1H)，7.77(m，1H)，8.01(m，1H)，8.13(m，2H)，8.72(d，1H)，10.42(br s，1H)，12.0(br s，1H)； Mass Spectrum：M+H ⁺ 436.

3-amino-5-sec.-propyl pyrazoles as raw material is prepared as follows:

(1.6M in hexane, drips acetonitrile (1.17ml) in 14.06ml) and under this temperature this mixture was stirred 1 hour toward the n-butyllithium solution that stirs and be cooled to-78 ℃.Drip ethyl isobutyrate (1.5ml), allow reaction medium be warming up to-45 ℃ and under this temperature, stirred 2 hours.By adding the 2N aqueous hydrochloric acid mixture that obtains is acidified to pH2 and evaporation concentration.The resistates dichloromethane extraction, organic extract is 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 of a part of product (0.6g), hydrazine hydrate (0.288ml) and the ethanol (45ml) that will obtain thus under 70 ℃ also kept 12 hours.With solvent evaporation, resistates is through purification by silica gel column chromatography, and the mixture of the 19:1 of use methylene dichloride and methyl alcohol is as elutriant.Obtain desired raw material (0.574g) thus;

¹ H NMR：(DMSOd ₆)1.13(d，6H)，2.76(m，1H)，4.31(brs，2H)，5.17(brs，1H)，11.05(br s，1H)； Mass Spectrum：M+H ⁺ 126.

Embodiment 8

N-(5-cyclopropyl pyrazole-3-yl)-2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide

Adopt and similar method described in the embodiment 7, with 2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] acetate and 3-amino-5-cyclopropyl pyrazoles reaction.Obtain title compound (productive rate is 18%) thus;

¹ H NMR：(DMSOd ₆)0.64(m，2H)，0.9(m，2H)，1.85(m，1H)，3.81(s，3H)，3.83(s，2H)，6.13(brs，1H)，6.75(d，1H)，7.52(d，1H)，7.77(m，1H)，8.01(m，1H)，8.03(s，1H)，8.13(m，1H)，8.72(d，1H)，10.41(brs，1H)； Mass Spectrum：M+H ⁺ 434.

3-amino-5-cyclopropyl pyrazoles as raw material is prepared as follows:

Adopt preamble to relate to described in embodiment 7 parts of feedstock production similarly method,, obtain cyclopropyl cyanogen methyl ketone, itself and hydrazine hydrate are reacted, obtain desired raw material cyclopropane-1-ethyl formate and acetonitrile reaction.

Embodiment 9

N-(5-sec.-propyl pyrazole-3-yl)-2-[3-methoxyl group-5-(6-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide

Adopt and similar method described in the embodiment 7, difference is reaction mixture is heated to 70 ℃ and kept 3 hours, with 2-[3-methoxyl group-5-(6-methoxy quinoline-4-base oxygen base) pyridine-2-yl] acetate reacts with 3-amino-5-sec.-propyl pyrazoles.Obtain title compound (productive rate is 26%) thus;

¹ H NMR：(DMSOd ₆)1.19(d，6H)，2.89(m，1H)，3.82(s，3H)，3.83(s，2H)，3.94(s，3H)，6.27(brs，1H)，6.66(d，1H)，7.48(m，1H)，7.5(d，1H)，7.59(d，1H)，7.97(d，1H)，8.1(d，1H)，8.57(d，1H)，10.41(brs，1H)； Mass Spectrum：M+H ⁺ 448.

Embodiment 10

N-(5-cyclopropyl pyrazole-3-yl)-2-[3-methoxyl group-5-(6-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide

Adopt and similar method described in the embodiment 7, difference is reaction mixture is heated to 70 ℃ and kept 3 hours, with 2-[3-methoxyl group-5-(6-methoxy quinoline-4-base oxygen base) pyridine-2-yl] acetate reacts with 3-amino-5-cyclopropyl pyrazoles.Obtain title compound (productive rate is 31%) thus;

¹ H NMR：(DMSOd ₆)0.64(m，2H)，0.89(m，2H)，1.85(m，1H)，3.81(s，3H)，3.82(s，3H)，3.94(s，3H)，6.14(brs，1H)，6.66(d，1H)，7.48(m，1H)，7.5(d，1H)，7.58(d，1H)，7.97(d，1H)，8.09(d，1H)，8.57(d，1H)，10.39(br s，1H)； Mass Spectrum：M+H ⁺ 446.

Embodiment 11

N-methyl-N-(5-methylthiazol-2-yl)-2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide

Adopt and similar method described in the embodiment 1, difference is to use DMA to replace DMF to be heated to 50 ℃ of maintenances 5 hours as reaction solvent and with reaction mixture, with 2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] acetate and 5-methyl-2-methylamino thiazole reaction.Reaction product is through purification by silica gel column chromatography, and 19: 1 the mixture that uses methylene dichloride and methyl alcohol is as elutriant.Obtain title compound (productive rate is 46%) thus;

¹ H NMR：(DMSOd ₆)3.24(d，3H)，3.65(s，3H)，3.83(s，3H)，3.94(s，3H)，3.96(s，3H)，4.22(s，2H)，6.6(d，1H)，7.21(q，1H)，7.41(s，1H)，7.53(s，1H)，7.54(d，1H)，8.09(d，1H)，8.53(d，1H)； Mass Spectrum：M+H ⁺ 481.

5-methyl-2-methylamino thiazole as raw material is prepared as follows:

In the 2-amino-suspension of 5-methylthiazol (0.5g) in diacetyl oxide (0.944ml) that stirs, add pyridine (0.107ml).In microwave oven, the mixture heating up to 100 that obtains ℃ was kept 10 minutes.This mixture is cooled to envrionment temperature and adds ether.With precipitate and separate and dry.Obtain 2-acetylaminohydroxyphenylarsonic acid 5-methylthiazol (0.634g) thus;

¹ H NMR：(CDCl ₃)2.3(s，3H)，2.41(s，3H)，7.06(br s，1H)； Mass Spectrum：M+H ⁺ 157.

Under argon gas atmosphere, drip the solution of 1M hexamethyl dimethyl silanyl Lithamide in THF (4.24ml) toward stirring in the solution of 2-acetylaminohydroxyphenylarsonic acid 5-methylthiazol (0.63g) in THF (30ml) that also has been cooled to 0 ℃.After 10 minutes, this mixture is cooled to-30 ℃ and add the solution of methyl-sulfate (0.4ml) in THF (4ml).Under-30 ℃, the mixture that obtains was stirred 1 hour and stirred at ambient temperature 4 hours.With this mixture evaporation, resistates is through purification by silica gel column chromatography, and the methylene dichloride of use 9:1 to 3:7 and the gradient solvent of ethyl acetate are as elutriant.Obtain 2-(N-methyl kharophen)-5-methylthiazol (0.35g) thus;

¹ H NMR：(CDCl ₃)2.38(2s，6H)，3.67(s，3H)，7.13(s，1H)； Mass Spectrum：M+H ⁺ 171.

At ambient temperature, the mixture with 2-(N-methyl kharophen)-5-methylthiazol (0.35g), sodium hydroxide (0.15g) and methyl alcohol (10ml) stirred 16 hours.With this mixture evaporation.Add entry (5ml) and methylene dichloride (5ml) and reduce this mixture alkalescence by adding 2N aqueous hydrochloric acid (2ml).Adding saturated sodium bicarbonate aqueous solution, to make pH be 8.The water dichloromethane extraction that obtains.Organic extract liquid is through dried over mgso and evaporation.Obtain 5-methyl-2-methylamino thiazole (0.26g) thus;

¹ H NMR：(DMSOd ₆)2.19(s，3H)，2.75(s，3H)，6.67(s，1H)，7.22(s，1H)； Mass Spectrum：M+H ⁺ 129.

Claims (19)

1. the quinoline 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 halogeno-group; trifluoromethyl; cyano group; hydroxyl; sulfydryl; amino; carboxyl; (1-6C) alkoxy carbonyl; carbamyl; (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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; 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) perhaps is selected from the following formula group:

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 ¹It is 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)

R wherein 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 halogeno-group; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; carbamyl; 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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; (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 alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the group of following formula:

-X ³-R ⁹

X wherein ³Be direct key or be selected from O and N (R ¹⁰), R wherein ¹⁰Be hydrogen or (1-8C) alkyl, R ⁹It is the alkyl of halogeno-group-(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) perhaps is selected from the following formula group:

-X ⁴-Q ²

X wherein ⁴Be direct key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen or (1-8C) alkyl, Q ²It is 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 halogeno-group, hydroxyl, (1-8C) alkyl and (1-6C) alkoxyl group

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

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

R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halogeno-groups or (1-8C) alkyl substituent and/or be selected from hydroxyl of carrying on the group; sulfydryl; amino; cyano group; carboxyl; carbamyl; 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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; (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) substituting group of alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C)

R wherein ¹Adjacent carbons in the substituting group in any (2-6C) alkylidene chain is inserted into intrachain and is selected from 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 optional separation of group, R wherein ¹²Be hydrogen or (1-8C) alkyl, perhaps when the group that inserts be N (R ¹²) time, R ¹²It can also be (2-6C) alkyloyl;

Q is 0,1 or 2;

R that respectively can be identical or different ²Group is selected from halogeno-group, trifluoromethyl, cyano group, carboxyl, amino, carbamyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylcarbamoyl group, N, N-two-[(1-6C) alkyl] carbamyl, 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 carbamyl-(1-6C), the alkyl of N-(1-6C) alkylcarbamoyl group-(1-6C), N, the alkyl of N-two-[(1-6C) alkyl] carbamyl-(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 halogeno-group-(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 carbamyl-(1-6C), the alkyl of N-(1-6C) alkylcarbamoyl group-(1-6C), N, the alkyl of N-two-[(1-6C) alkyl] carbamyl-(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);

Perhaps 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) alkynyl or following formula group:

-X ⁵-R ¹³

X wherein ⁵Be direct key or be selected from O and N (R ¹⁴), R wherein ¹⁴Be hydrogen or (1-8C) alkyl, R ¹³It is the alkyl of alkyl of the alkyl of the alkyl of halogeno-group-(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 dicyclo aromatic ring or 5-or 6-unit's monocycle or 9-or 10-unit dicyclo hetero-aromatic ring, has 3 ring hetero atoms that are selected from oxygen, nitrogen and sulphur at the most;

R is 0,1,2 or 3; And

Each R ⁶Group can be identical or different; be selected from halogeno-group; trifluoromethyl; cyano group; hydroxyl; sulfydryl; amino; carboxyl; carbamyl; 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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; (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 alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the following formula group:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-8C) alkyl, R ¹⁵It is the alkyl of halogeno-group-(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 carbamyl-(1-6C); the alkyl of N-(1-6C) alkylcarbamoyl group-(1-6C); N; the alkyl of N-two-[(1-6C) alkyl] carbamyl-(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 alkane sulfuryl amino of alkyl of alkane sulfuryl amino-(1-6C) or N-(1-6C) alkyl-(1-6C)-(1-6C) perhaps is selected from the following formula group:

-X ⁷-Q ³

X wherein ⁷Be 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 ³It is 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 together crosses over the upward divalent group of adjacent ring position of ring A, 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, wherein R ¹⁹Be hydrogen, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl or (2-6C) alkyloyl,

R wherein 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 halogeno-group; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; carbamyl; 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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; (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 alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) perhaps is selected from the following formula group:

-X ⁸-R ²⁰

X wherein ⁸Be direct key or be selected from O and N (R ²¹), R wherein ²¹Be hydrogen or (1-8C) alkyl, R ²⁰It is the alkyl of halogeno-group-(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) perhaps is selected from the following formula group:

-X ⁹-Q ⁴

X wherein ⁹Be direct key or be selected from O, CO and N (R ²²), R wherein ²²Be hydrogen or (1-8C) alkyl, Q ⁴It is the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), it is optional carry 1 or 2 can be identical or different substituting group, be selected from halogeno-group, hydroxyl, (1-8C) alkyl and (1-6C) alkoxyl group

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

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

R wherein ⁶Any CH, CH in the group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃Optional one or more halogeno-groups or (1-8C) alkyl substituent and/or be selected from hydroxyl of carrying on the group; sulfydryl; amino; cyano group; carboxyl; carbamyl; 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) alkylcarbamoyl group; N; N-two-[(1-6C) alkyl] carbamyl; (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) substituting group of alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C)

R wherein ⁶Adjacent carbons is inserted into intrachain and is selected from O, S, SO, SO in interior any (2-6C) alkylidene chain of group 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), optional separation of group of CH=CH and C ≡ C, wherein R ²³Be hydrogen or (1-8C) alkyl, perhaps when the group that inserts be N (R ²³) time, R ²³It can also be (2-6C) alkyloyl.

2. the quinoline of the formula I of claim 1 or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2, R ¹Group is positioned at 6-and 7-position and is positioned at the R of 6-position ¹Group is selected from cyano group, hydroxyl, methoxycarbonyl, ethoxy carbonyl, carbamyl, methoxyl group, oxyethyl group, propoxy-, N-methyl carbamyl, N-ethyl carbamyl, N; N-dimethylamino formyl radical, N; N-diethyl amino formyl radical, tetramethyleneimine-1-base carbonyl, morpholino carbonyl, piperidino-(1-position only) carbonyl and piperazine-1-base carbonyl is positioned at the R of 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-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-

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-2-base in the substituting group, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are by methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; the optional N-of 2-trifluoroethyl or cyano methyl replaces

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

R wherein ¹Any CH, CH in the substituting group ₂Or CH ₃Group is at each described CH, CH ₂Or CH ₃The optional substituting group that carries one or more chloro bases or be selected from hydroxyl, amino, methoxyl group, methyl sulphonyl, methylamino, dimethylamino, diisopropylaminoethyl, N-ethyl-N-methylamino and N-sec.-propyl-N-methylamino on the 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, trifluoromethyl, cyano group, hydroxyl, amino, methyl, methoxyl group, methylamino and dimethylamino;

R ³And R ⁴Each is hydrogen naturally;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is phenyl ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring; And

R be 0 or r be 1 or 2, one 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, one R ⁶Group is positioned at 3-or 4-position (with respect to CON (R ⁵) group), and be the following formula group:

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or O, R ¹⁵It is hydroxymethyl, 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, dimethylaminomethyl, the 1-dimethyl aminoethyl, the 2-dimethyl aminoethyl, the 3-dimethylaminopropyl, phenyl, phenmethyl, 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 ⁶When being O, at X ⁶With R ¹⁵Have two carbon atoms between any heteroatoms of group at least,

R wherein ⁶Any aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are optional in the group carries the substituting group that is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino and dimethylamino, at R ⁶Any this type of aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried the other substituting group that is selected from hydroxymethyl, cyano methyl, amino methyl, methylamino methyl and dimethylaminomethyl in the group,

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

3. the quinoline of the formula I of claim 1 or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2 and 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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen, methyl or ethyl;

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

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; 2-hydroxyethyl amino; 2-methoxy ethyl amino; dimethylamino; N-cyclopropyl-N-methylamino; ethanoyl; hydroxymethyl; amino methyl; the methylamino methyl; the ethylamino methyl; the propyl group amino methyl; the sec.-propyl amino methyl; the cyclopropyl amino methyl; dimethylaminomethyl; the diethylamino 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

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

4. the quinoline of the formula I of claim 1 or its pharmacy acceptable salt, wherein:

Ring A is for containing 3 heteroatomic 5 yuan of bicyclic heteroaryls that are selected from O, N and S at most; And

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

5. the quinoline of the formula I of claim 1 or its pharmacy acceptable salt, wherein:

X ¹Be O;

P is 2 and R ¹Group is positioned at 6-and 7-position, is positioned at the R of 6-position ¹Group is selected from cyano group, hydroxyl, methoxycarbonyl, ethoxy carbonyl, carbamyl, methoxyl group, oxyethyl group, propoxy-, N-methyl carbamyl, N-ethyl carbamyl, N; N dimethylamino formyl radical, N; N-diethyl amino formyl radical, tetramethyleneimine-1-base carbonyl, morpholino carbonyl, piperidino-(1-position only) carbonyl and piperazine-1-base carbonyl is positioned at the R of 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-

R wherein ¹Any heterocyclic radical is chosen wantonly and is carried 1 or 2 substituting group in the last 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-2-base in the substituting group, tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base or high piperazine-1-base are by methyl, ethyl, propyl group, allyl group, 2-propynyl, methyl sulphonyl, ethanoyl, propionyl, isobutyryl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; the optional N-of 2-trifluoroethyl or cyano methyl replaces

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

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

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

R ³And R ⁴Each is hydrogen naturally;

R ⁵Be hydrogen, methyl or ethyl;

Ring A is furan nucleus, pyrrole ring, thiphene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazoles ring, thiazole ring, isothiazole Huan, oxadiazole ring or thiadiazoles ring; And

R be 0 or r be 1 or 2, one R ⁶Group is positioned at the 3-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, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino, ethylamino, dimethylamino and diethylamino;

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

-X ⁶-R ¹⁵

X wherein ⁶Be direct key or O, R ¹⁵It is hydroxymethyl, 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, dimethylaminomethyl, the 1-dimethyl aminoethyl, the 2-dimethyl aminoethyl, the 3-dimethylaminopropyl, phenyl, phenmethyl, 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 ⁶When being O, at X ⁶With R ¹⁵Have two carbon atoms between any heteroatoms of group at least,

R wherein ⁶Any aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical in the group is optional to carry the substituting group that is selected from fluoro, chloro, trifluoromethyl, hydroxyl, amino, methyl, methoxyl group, methylamino and dimethylamino, at R ⁶Any this type of aryl, (3-8C) cycloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are carried the other substituting group that is selected from hydroxymethyl, cyano methyl, amino methyl, methylamino methyl and dimethylaminomethyl in the group,

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

6. the quinoline of the formula I of claim 1 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, carbamyl, methoxyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical, 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 and 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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen or methyl;

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

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, sec-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, the 2-hydroxyethyl, methoxymethyl, the 2-methoxy ethyl, the methylamino methyl, the ethylamino methyl, the sec.-propyl amino methyl, the cyclopropyl amino methyl, dimethylaminomethyl, methoxyl group, oxyethyl group, methylamino, ethylamino, dimethylamino and diethylamino.

7. the quinoline of the formula I of claim 1 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, carbamyl, methoxyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical, 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 and 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 ⁴Each is hydrogen naturally;

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; And

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

8. the quinoline of 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 halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, carbamyl, (1-6C) alkoxy carbonyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylcarbamoyl group and N; N-two-[(1-6C) alkyl] carbamyl, and

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

With each X ¹, R ³, R ⁴, R ⁵, ring A, r and R ⁶Implication with claim 1 definition.

9. the quinoline of 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 and is selected from fluoro, chloro, cyano group, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical 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 carbamyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethyl methyl acyl group;

With each X ¹, R ³, R ⁴, R ⁵, ring A, r and R ⁶Implication with claim 1 definition.

10. the quinoline of the formula I of claim 1 or its pharmacy acceptable salt, wherein:

X ¹Be O;

P be 0 or p be 1 or 2, R ¹Group be positioned at 6-and/or 7-position and be selected from that halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, carbamyl, (1-6C) alkoxy carbonyl, (1-8C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkene oxygen base, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, N-(1-6C) alkylcarbamoyl group and N; N-two-[(1-6C) alkyl] carbamyl

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

R ³And R ⁴Each is hydrogen naturally;

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 halogeno-group, trifluoromethyl, cyano group, hydroxyl, amino, (1-8C) alkyl, (2-8C) alkenyl, (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.

11. the quinoline of the formula I of claim 1 or its pharmacy acceptable salt, 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, chloro, trifluoromethyl, cyano group, hydroxyl, amino, carbamyl, methoxycarbonyl, ethoxy carbonyl, methyl, ethyl, methoxyl group, oxyethyl group, methylamino, dimethylamino, N-methyl carbamyl and N; N-dimethylamino formyl radical

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, carbamyl, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino, dimethylamino, N-methyl carbamyl and N, N-dimethylamino formyl radical;

R ³And R ⁴Each is hydrogen naturally;

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 that can be identical or different ⁶Group 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 diethylamino.

12. the quinoline of the formula I of claim 1 or its pharmacy acceptable salt, 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, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical,

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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen;

Ring A is furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base or thiadiazoles basic ring, and it has 1 or 2 R ⁶Group and a 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, sec-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, methylamino, ethylamino, dimethylamino and diethylamino.

13. the quinoline of the formula I of claim 1 or its pharmacy acceptable salt, 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, carbamyl, methoxycarbonyl, methoxyl group, oxyethyl group, N-methyl carbamyl and N, N-dimethylamino formyl radical,

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 ⁴Each is hydrogen naturally;

R ⁵Be hydrogen;

Ring A is 2-oxazolyl, 3-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.

14. the quinoline of the formula I of claim 1 or its pharmacy acceptable salt, described quinoline or its pharmacy acceptable salt are selected from:

1. N-(1-ethyl-1H-pyrazoles-4-yl)-2-[3-methoxyl group-5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide; 2. N-(1,3-dimethyl-1H-pyrazoles-4-yl)-2-[3-methoxyl group-5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide; 3. N-(1-ethyl-1H-pyrazoles-4-yl)-2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide; 4. N-(4,5-dimethyl-1H-pyrazole-3-yl)-2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide; 5. N-(4,5-dimethyl isoxazole-3-yl)-2-[5-(6,7-dimethoxy-quinoline-4-base oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide; 6. N-(4,5-dimethyl isoxazole-3-yl)-2-[3-methoxyl group-5-(7-methoxy quinoline-4-base oxygen base) pyridine-2-yl] ethanamide; 7. N-(5-Yi isoxazole-3-yl)-2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide; With 8. N-(4,5-dimethyl isoxazole-3-yl)-2-[5-(6-fluorine quinolyl-4 oxygen base)-3-Methoxy Pyridine-2-yl] ethanamide.

15. the quinoline of a formula I who is used to prepare claim 1 or the method for its pharmacy acceptable salt, described method comprises:

(a) quinoline of formula II

Wherein L is a displaceable group, p and R ¹Have any implication that claim 1 limits, but protect 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 claim 1 limits, but protect any functional group where necessary, remove any blocking group of existence then;

(b) quinoline of formula VII or its response derivative,

Wherein p, R ¹, X ¹, q, R ², R ³And R ⁴Have any implication that claim 1 limits, but protect any functional group where necessary,

With the amine coupling of formula VI,

R wherein ⁵, ring A, r and R ⁶Have any implication that claim 1 limits, but protect any functional group where necessary, remove any blocking group of existence then;

(c) be used for wherein at least one R of preparation ¹When group is those formulas I compound of following formula group,

Q ¹-X ²-

Q wherein ¹Be alkyl of the alkyl of the alkyl of the alkyl of aryl-(C1-6), (C3-7) cycloalkyl-(C1-6), (C3-7) cycloalkenyl group-(C1-6), heteroaryl-(C1-6) or heterocyclic radical-(C1-6) alkyl or the optional alkyl that replaces, X ²Be Sauerstoffatom,

Make the quinoline of formula VIII and suitable pure coupling, wherein protect any functional group where necessary, remove any blocking group of existence then

Wherein p, R ¹, X ¹, q, R ², R ³, R ⁴, R ⁵, ring A, r and R ⁶Have any implication that claim 1 limits, but protect any functional group where necessary;

(d) be used to prepare wherein R ⁶Group is formula-X ⁶-R ¹⁵During those formulas I compound of group, X wherein ⁶Has any implication that claim 1 limits, R ¹⁵Be (C1-6) alkyl of amino-replacement, make wherein R ⁶Group is formula-X ⁶-R ¹⁵The formula I compound of group and suitable amine or with nitrogen heterocyclic ring based compound reaction, wherein R ¹⁵It is (C1-6) alkyl of halogeno-group-replacement;

(e) be used to prepare wherein R ⁶Group is formula-X ⁶-R ¹⁵During those formulas I compound of group, X wherein ⁶Has any implication that claim 1 limits, R ¹⁵Be (C1-6) alkyl of amino-replacement, make wherein R ⁶Group is formula-X ⁶-R ¹⁵The formula I compound reductive amination of group, wherein R ¹⁵Be formyl radical or (C2-6) alkyloyl;

(f) be used to prepare wherein R ⁵When being those formulas I compound of (C1-8) alkyl, make wherein R with suitable alkylating agent ⁵It is the formula I alkylation of hydrogen; Perhaps

(g) be used to prepare wherein R ¹When being those formulas I compound of carboxyl, make wherein R ¹It is the formula I compound cracking of (C1-6) alkoxy carbonyl;

When the pharmacy acceptable salt of the quinoline that needs formula I, can obtain by making described quinoline and suitable acid-respons.

16. a medicinal compositions, described medicinal compositions comprise formula I quinoline or its pharmacy acceptable salt and the pharmaceutically acceptable diluent or carrier of claim 1.

17. the formula I quinoline of claim 1 or its pharmacy acceptable salt preparation be used for the treatment of cell breeding disease or treatment and blood vessel takes place and/or the medicine of blood vessel infiltration diseases associated symptom in purposes.

18. a composition that is suitable for treating cell breeding disease, described composition comprise formula I quinoline or its pharmacy acceptable salt and other antitumour drugs of claim 1.

19. a composition that is suitable for treating cell breeding disease, described composition comprise formula I quinoline or its pharmacy acceptable salt and other angiogenesis inhibitor medicines of claim 1.