CN102558147A

CN102558147A - Compound, and preparation method and application thereof

Info

Publication number: CN102558147A
Application number: CN2010106047501A
Authority: CN
Inventors: 丛欣; 黄伟; 王鹏; 刘兆刚; 明志会; 施敏锋; 马玉恒; 沈超; 唐锋
Original assignee: Jiangsu Simcere Pharmaceutical R&D Co Ltd
Current assignee: Hainan Simcere Pharmaceutical Co ltd
Priority date: 2010-12-23
Filing date: 2010-12-23
Publication date: 2012-07-11
Anticipated expiration: 2030-12-23
Also published as: CN102558147B

Abstract

The invention provides a compound with the structure shown in a formula I, a preparation method of the compound, and an application of the compound as a tyrosine kinase and/or serine-threonine kinase inhibitor. The compound has a good inhibitory action on the activity of multiple kinases, and has an obvious inhibitory effect on tyrosine kinase and/or serine-threonine kinase in biochemical level and cell level in vitro (P is less than 0.05), and the half inhibitory concentration (IC50) for c-Met kinase is commonly below 10<-6>mol/L; and the compound also has an obvious inhibitory effect on proliferation of multiple tumor cells (P is less than 0.05), and the IC50 is respectively below 10<-5>mol/L. The compound with the structure shown in the formula I can be applied to preparing medicines for treating diseases related to protein kinase in organisms. The formula I is shown in the specification.

Description

Compound, preparation method and application

Technical field

The present invention relates to biomedicine field, particularly a compounds and preparation method, and the application of this compound in preparation tyrosine kinase inhibitor or serine-threonine kinase suppressor factor.

Background technology

Have similar molecular mechanism between the mammalian cell, in the whole cell cycle, regulate propagation, differentiation and the death of cell.Wherein, protein phosphorylation is the main mechanism of striding film or intracellular signal transduction, have regulating cell round-robin function, and phosphorylation receives the control of protein kinase (PKs) and phosphoprotein phosphatase.Protein kinase (protein kinases) is claimed protein phosphorylation enzyme (protein phosphakinase) again; It is the enzyme of one type of catalytic proteins phosphorylation reaction; Be present known maximum protein family, all kinases all have a very conservative catalytic core and various regulation and control model.The effect of protein kinase is that the γ-phosphate with ATP is transferred to specified amino acid residues on their substrates.According to the specificity of these amino-acid residues, these kinases are divided into 4 types, wherein main two types is albumen serine/threonine kinase (STKs) and protein tyrosine kinase (PTKs).In the eukaryote; The separation and the distance that have physics between the acceptor of cell surface and the endonuclear re-reading system; The extracellular signal influences the effect of some protein kinase cascade through acceptor; Through the proteinic phosphorylation of multistep, change the activity of transcription factor at last, genetic transcription is activated or retardance.Wherein, Protein tyrosine kinase and albumen serine/threonine kinase have vital role in Normocellular signal transduction mechanism; Their unconventionality expression will cause the generation of numerous disease; Like tumour, arteriosclerosis, psoriasis and inflammatory reaction etc., thereby regulate and control these kinase whose activity, recover physiological equilibrium and can be used as a kind of new treatment means.

Family tyrosine kinase with transmembrane receptor (receptor tyrosine kinase, RTKs) or the kytoplasm form (nonreceptor tyrosine kinase CTKs) is participated in cell signalling widely.In the human genome, the protein kinase group comprises 30 kinds of family tyrosine kinases, contains 90 kinds of different protein tyrosine kinases altogether, and wherein 58 kinds is receptor tyrosine kinase.Structure according to them is different, and receptor type tyrosine kinase can be divided into 9 types, and wherein more common has 4 types:

EGF-R ELISA (EGFR) family: the EGF-R family member comprises EGF-R (molecular weight is 170kDa, and wide expression is in multiple histocyte), erbB2/neu and erbB-3 gene expression product.Its family member's characteristics are that two zones of being rich in halfcystine are arranged outside after birth, and endochylema contains a zone that the Tyrosylprotein kinase reactivity is arranged.

Insulin Receptor Family: its family member comprises insulin receptor (insulin receptor; IR), IGF-1R (insulin-like growth factor-1 receptor; IGF-1R) and the Regular Insulin associated receptor (insulin related receptor, IRR).The Insulin Receptor Family member is by two alpha subunits and two allos tetramers that β subunit forms through interchain disulfide bond.Wherein alpha subunit is a ligand binding site; Part contains the tyrosine kinase activity zone in the endochylema of β subunit.

The PDGF/MCSF/SCF receptor family: its family member comprises platelet-derived growth factor ' alpha ' acceptor (PDGF-α R), PDGF-β R, macrophage colony-stimulating factor receptor (M-CSFR) and stem cell factor acceptor (SCFR).Above member's characteristics are that after birth contains 5 immunoglobulin like domain outward, and endochylema contains two butyric acid kinase function districts that are cascaded structure.

Fibroblast growth factor acceptor (FGFR) family: the FGFR family member has FGFR1, FGFR2, FGFR3 and FGF4.Their characteristics are outside after birth, to contain 3 immune globulin spline structure territories, wherein between the 1st and the 2nd structural domain, have one to contain 8 successive acidic amino acid structures, claim acid box structure domain (acid box domain) again; Endochylema contains two cruel propylhomoserin kinase function districts that are cascaded structure.

Receptor tyrosine kinase is one type of transmembrane protein with kytoplasm zone, and extracellular region is the ligand structure territory, and part is solubility or membrane-bound polypeptide or protein hormone, comprises Regular Insulin and multiple growth factor.Born of the same parents' inner segment is the catalytic site of protein tyrosine kinase, and has the autophosphorylation site, and its inherent catalytic activity is activated when combining with part.This receptoroid mainly contains c-Met (pHGF), EGFR (EGF-R ELISA), VEGFR (vascular endothelial growth factor receptor), PDGFR (platelet derived growth factor receptor), FGFR (fibroblast growth factor acceptor) etc.Most important downstream signal cascade reaction is by the receptor tyrosine kinase activation, comprising the ERK/MAPK signal path, and PI-3 kinases-AKT signal path and JAK/STAT signal path.Receptor tyrosine kinase is kept mutual signal and communication in all these different transduction pathway, final regulation and control gene transcription.In addition, other cascade reaction also can be used.The regulation mechanism of nonreceptor tyrosine kinase differs greatly, they through with the effect of transmembrane receptor generation physical property, and then participate in the extracellular signal response (Grosios k, et al, Drugs Fut, 2003,28:679).In many intracellular signal proteins (like Shc, Grb2, Src, Cbl, Phospholipase C g and 3 '-phosphoinositide kinases [PI-3 kinase] etc.), these are present in the calmodulin binding domain CaM of Tyrosine O-phosphate as the butt joint site by the tyrosine residues of phosphorylation.The mixture that these are activated in cytolemma impels initial signal cascade reaction, and this has crucial effect to downstream signal and biological effect.If the receptor deficiency catalytic activity, can with nonreceptor tyrosine kinase coupling mutually, the kytoplasm zone through a non-covalent associating and a receptor subunit forms " binary acceptor ".Most important downstream signal cascade is by the receptor tyrosine kinase activation, comprising the ERK/MAPK signal path, and PI-3 kinases-AKT signal path and JAK/STAT signal path.Receptor tyrosine kinase is kept mutual signal and communication in all these different transduction pathway, final regulation and control gene transcription.In addition, other cascade reaction also can be used, and for example insulin receptor (InsR) utilizes the adenylyl cyclase signal transduction system, the special protein kinase of serine-threonine that activation cAMP relies on.

In normal cell, the rapid internalization of activated receptors Tyrosylprotein kinase is also left cell surface, thereby the modification inhibitory enzyme activity takes place, and this activation of guaranteeing the signal cascade reaction is of short duration, and cell can in time return to non-stimulation state.But the change of many structures replaces and the big amino acid whose disappearance of section or inhibition signal and the machine-processed imbalance of self-acting control like single amino acids, can cause kinases and catalysis region thereof to continue to be in active state.Receptor tyrosine kinase sustained activation that numerous disease and this sudden change cause and PTKs false demonstration or over-expresses are relevant.In the characterization of molecules process of malignant tumour, find nearly half the known PTKs, for example c-Met, EGFR, ErbB2, Ret, Kit, Src, Abl, PDGFR, VEGF1/2/3, FGFR1/2/3 etc. exist and suddenly change or the situation of over-expresses.Simultaneously, the over-expresses of clinical studies show Tyrosylprotein kinase or imbalance to prediction tumour patient and symptom have important references be worth (Madhusudan S, et al, Clin Biochem, 2004,37:618).From the above mentioned, Tyrosylprotein kinase is regulated very important from body to physiology, and transgenation/rearrangement can make the unusual or over-expresses of PTKs, thereby causes the generation of disease, therefore can use the agonist of these enzymes or antagonist to treat.

Be that the potential gene alteration or the existence of abnormal receptor all can have disease phenotype (for example cancer) separately, and with cell cycle and born of the same parents in extracellular signal transmit relevantly, for example paracrine transmits with autonomous secretion.The over-expresses of growth factor (for example c-Met, EGF, VEGF, PDGF) acceptor and growth factor often causes propagation and the tumor-blood-vessel growth and the transfer of tumour cell.

Met is an important member in the family tyrosine kinase, belongs to receptor tyrosine kinase (RTK), and Met is considered to tumorigenesis fusion rotein (TPR-MET) at first, proves pHGF (Hepatocyte growth factor, HGF now; Claim the discrete factor again: Scatter Factor, SF) unique high-affinity receptor.HGF changes protein tyrosine kinase (PTK) structural domain in activated receptor intracellular region territory with after the Met specificity combines through inducing Met albumen occurred conformation.The activation of Met can cause the tyrosine phosphorylation of multiple substrate protein; Through the compact cascade type phosphorylation reaction, signal is amplified step by step again, finally change nucleus over to; Cause a series of biological effects, can produce " invasive growth (invasive growth) " program of a kind of uniqueness especially.In vivo, this " invasive growth " program is relevant with biological effects such as cell proliferation survival, cell migration, inducing cell polarization, vascularization, injury repairing, tissue reconstructions.

In tumour took place and develops, especially to the tumour with invasion and attack and metastatic potential, the HGF-Met signal path had played crucial effects.Tumour cell can stimulate contiguous fibroblasts to secrete HGF through discharging cytokines such as IL-1, FGF-2 and PDGF.Some tumour cell can be crossed expression Met and HGF simultaneously through the autocrine approach.The expression of crossing of Met is found in people's cancer of the stomach, liver cancer, cholangiocarcinoma, carcinoma of the pancreas, lung cancer, thyroid carcinoma, pleura mesenchymoma etc.In the tumour that shifts took place, the HGF/Met signal path possibly influence: sticking between (1) tumour cell, promote the migration of tumour cell; (2) promote extracellular matrix degradation, thereby promote the transfer of tumour; (3) induction of vascular generates; (4) promoting mitosis promotes cell proliferation through a plurality of signal paths.Therefore; With the HGF/Met signal path is target; Realization that can be relatively easy is disturbed to many paths the time; In case the HGF-Met signal path of abnormal activation and over-expresses in tumour cell is blocked, cellular form will take place and change in tumour cell, causes that increment slows down, becomes a series of variations of degradation under the reduction of knurl property, the invasive ability.

The discussion more detailed to Tyrosylprotein kinase is referring to Manning G, Science, 2002,298:1912.

Nonreceptor tyrosine kinase (CTKs): with the src gene product is representative, also has Yes, Fyn, Lck, Fgr, Lyn, Fps/Fes and Ab1 etc. in addition.Xu back is outside both, and all the other non-receptor type protein tyrosine kinase Src family molecules reasons are about the protein of 60kDa, form the difference except 80 amino acid of N-terminal between them, and other parts are all closely similar.The regulation mechanism of nonreceptor tyrosine kinase (CTKs) differs greatly, and they are through with transmembrane receptor (like hormone, cytokine and growth factor receptors) the physical property effect taking place, and then participates in the extracellular signal response.In the specified phase of cell cycle,, these acceptors are activated when combining with extracellular part or cell adhesion composition.

Crosstalking of the sudden change of protein kinase, signal protein is the pathology reason that causes tumour, equally also can cause the generation of other disease.In some immunodeficiency symptoms, can observe the mutagenicity inactivation of non-receptor tyrosine, for example the inactivation of JAK3 causes serious severe combined immunodeficiency (Leonard WJ, Nat Rev Immunol, 2001,1:200; Leonard WJ, Int J Hematol, 2001,73:271).Bruton protein tyrosine kinase (BTK or BPK, ATK) belongs to Src family; It is the ripe necessary a kind of Tyrosylprotein kinase of B cell development; And Btk transgenation meeting causes congenital no Immunoglobulinemia (Cheng G, et al, Proc Natl Acad Sci USA; 1994,91:8152; Maas A, et al, J Immunol, 1999,162:6526).

LCK also has the important physical effect in cns; Its not normal generation that also can cause corresponding disease; For example at alzheimer's disease (Alzheimer disease, AD) immunoreactivity relevant (Ferguson SS, the Trends Neurosci of neurone spot and neuregulin-1 (neuregulin-1) and ErbB4 in patient's body; 2003,26:119; Chaudhury AR, et al, J Neuropathol Exp Neurol, 2003,62:42).RhIGF-1 (IGFs) and adjusting albumen thereof are that these factor dysregulations can cause the incidence and development of coronary atherosclerosis and restenosis by the cardiovascular systems secretion, and the effect of IGFs is to be mediated by the specific membranes acceptor; Wherein the IGF receptor type I has tyrosine kinase activity, comes across the smooth muscle cell of atherosclerotic lesions, inflammatory cell and arterial endothelial cell (Bayes-genis A; Et al; Circ Res, 2000,86:125; Bayes-genis A, et al, Artherio Thromb and Vascu Biol, 2001,21:335; Che WY, et al, Circ Res, 2002,90:1222).VEGF and acceptor thereof are expressed in the various kinds of cell of rheumatoid arthritis, and be in the rational angiogenic process of rheumatoid arthritis key factor (De Bandt M, et al, J Immunol, 2003,1712:4853).Jak2 is the endochylema nonreceptor tyrosine kinase, and the JAK2 transgenation causes three kinds of diseases (Spivak JL, Blood, 2002,100:4272 at least; Thiele J, et al, Acta Haematol, 2004,111:155)--polycythemia vera (PV), idiopathic myelofibrosis (IMF), primary thrombocytosis (ET) and some other myeloproliferative diseases that is not true to type (MPD).The trans-regional sudden change of fibroblast growth factor acceptor can cause the most common heredity nanism--and osteochondrodysplasia (Shiang R, et al, Cell, 1994,78:335).In addition, numerous disease with lack tyrosine signal correction, for example NIDDM and peripheral neuropathy, and the transmission through the wild phase induction signal can improve effectively symptom (Hunter T, Cell, 2000,100:111).With blood vessel relevant disease takes place to some other, for example some cardiovascular disorder stimulates vasculogenesis than suppressing more effective.

Serine-threonine kinase (STKs) is the kinases family of one big type of specificity catalytic protein Serine and threonine residues phosphorylation, numbering: EC 2.7.1.37.The same with nonreceptor tyrosine kinase, serine-threonine kinase is dominate in cell, although only have several kinds of serine-threonine receptor kinases.Serine-threonine kinase is modal cytosol kinases; Be kinases in the tenuigenin part rather than in cytoplasmic organoid and cytoskeleton, bring into play their function; And then influence the inside biological chemistry of cell, often as descending reaction to the Tyrosylprotein kinase incident.Serine-threonine kinase can be participated in the signalling process simultaneously, and the latter causes DNA and synthesizes and the mitotic division that causes cell proliferation subsequently.Serine-threonine kinase has related to polytype cancer in addition, like mammary cancer (Cance et al, Int.J.Cancer, 1993,55,571) etc.

To sum up, Tyrosylprotein kinase and serine-threonine kinase all comprise related to cancer with host's pathological condition.Other pathological condition relevant with protein kinase also comprises psoriasis, liver cirrhosis, mellitus, blood vessel generation, restenosis, ophthalmic diseases, rheumatoid arthritis and other inflammatory disease, Immunological diseases, cardiovascular disorder such as arteriosclerosis and multiple ephrosis.

Along with molecular biological research is goed deep into, to cell signalling, the function of regulating growth factor is the effective way of inhibition cell proliferation and treatment tumour with regulation and control oncogene on molecular level.This approach can weaken the effect of improper signalling channel, stops growth of tumor, also can impel death of neoplastic cells simultaneously.Finding so far has half proto-oncogene on encoding histone, all to have the tyrosine structure; They participate in cell signalling through phosphorylation and dephosphorylation; Simultaneously in the tumour generating process; The Tyrosylprotein kinase of variation or over-expresses can change normal cell into cancer cells, promotes the growth and the mitotic division of tumour cell simultaneously.Because Tyrosylprotein kinase and serine-threonine kinase have important effect in the carinogenicity conversion process of cell; And have directly or indirectly with the generation of tumour and development and to get in touch, it is particularly suitable therefore tyrosine kinase inhibitor or serine-threonine kinase suppressor factor to be applied to tumor treatment.

Kinases inhibitor is the compound of one type of arrestin kinase activity.Kinases inhibitor is divided into serine/threonine protein kitase suppressor factor and tyrosine protein kinase inhibitor according to the kinase whose kind of arrestin; The former again can be according to site of action; Be divided into three groups; One group acts on catalytic domain, and one group acts on regulatory region, and another group all has effect to regulatory region and catalytic domain.

Pyridione derivatives has wide biological activity, has important use in fields such as medicine, agricultural chemicals.In recent years; Many pyridinone micromolecular compounds have been used as kinases inhibitor; Be widely used in the relevant disease of treatment multiple and aberrant kinase activity, like tumour, psoriasis, liver cirrhosis, mellitus, blood vessel generation, ophthalmic diseases, rheumatoid arthritis and other inflammatory disease, Immunological diseases, cardiovascular disorder such as arteriosclerosis and multiple ephrosis.Wherein, 3-alkynyl pyridine compounds (PCTWO2008008493), 5-aromatic yl pyridine ketone compound (PCT WO2008008493, WO2008103277, WO2005097750), 3-aromatic yl pyridine ketone compound (PCT WO2004060890), EL-970 ketone compounds (PCT WO 2007044084, WO2007129040, WO2007035428), 6-EL-970 ketone compounds (PCT WO 2007044084, WO2007035428) and other pyridine compounds (PCT WO2008058229, WO2009149188, WO2008005457, WO2007006591) etc. all are used for Tyrosylprotein kinase and/or serine-threonine kinase suppressor factor.But the 2-pyridine compounds is used to treat Tyrosylprotein kinase and/or the serine-threonine kinase suppressor factor does not also appear in the newspapers.

2-pyridone, 2 (1H)-pyridone and 2-oxo pyridine, molecular formula are C ₅H ₅NO, molecular weight is 95.10, to photaesthesia, is dissolved in ethanol, chloroform, water and benzene, is slightly soluble in ether and petroleum naphtha, 106～107 ℃ of fusing points, 280～281 ℃ of boiling points have pungency, have following chemical structure.

The 2-pyridone is not only the Multiple Pesticides of exploitation in recent years, the important intermediate and the raw material of medicine; Also be by methyl alcohol synthesizing alcohol and acetaldehyde simultaneously, prepare polyimide and protect the important catalyst of introducing N-carbobenzoxy or N-4-nitrobenzyl ester group in the amino acid whose novel method.The technology of tradition Synthetic 2-pyridone is to be raw material with pyridine and sodium amide, through Chichibabin reaction, diazotization reaction and nucleophilic substitution reaction completion.Therefore, a kind of 2-pyridine compounds and preparation method thereof is provided, and this compound is significant as the purposes of Tyrosylprotein kinase and/or serine-threonine kinase suppressor factor.

Summary of the invention

The present invention provides compounds and preparation method thereof, and this compound is as the purposes of Tyrosylprotein kinase and/or serine-threonine kinase suppressor factor.This compound on average has remarkable inhibition effect (P＜0.05) to Tyrosylprotein kinase and/or serine-threonine kinase in external biochemical level and cellular water, and significantly anticancer is bred (P＜0.05).

In order to realize the foregoing invention purpose, the present invention provides following technical scheme:

The invention provides structure compound shown by formula I or its pharmacy acceptable salt,

Formula I

Wherein, W and X independently are selected from C or N; If W, X are C, then n is 0-4; If W or X are N, then n is 0-3; If W, X are N, then n is 0-2;

M is 0-3; B is O, NR ⁴, NR ⁴CH ₂, S, SO, SO ₂, CR ⁵R ⁶

R ¹And R ²Independently be selected from hydrogen, halogen, cyanic acid, NO ₂, OR ⁷, NR ⁸R ⁹, alkyl, substituted alkyl, naphthenic base, substituted naphthenic base, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl, substituted Heterocyclylalkyl;

R ⁴, R ⁸And R ⁹Independently be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, naphthenic base, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical or substituted heterocyclic radical;

R ⁵And R ⁶Independently be selected from hydrogen, halogen, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, Heterocyclylalkyl or substituted Heterocyclylalkyl;

R ⁷Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, allyl group, substituted allyl, naphthenic base, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical or substituted heterocyclic radical;

R ³Be selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, alkoxyl group (OR ¹⁰), aryloxy, heteroaryloxy, benzyloxy, halogenated alkoxy ,-NR ¹⁰R ¹¹,-N (CH ₂) _p(R ¹²) (CH ₂) _pR ¹³,-NR ¹⁴C (O) R ¹⁵, aryl, heteroaryl; P is 0-3;

R ¹⁰And R ¹¹Independently be selected from hydrogen, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl, substituted Heterocyclylalkyl or R ¹⁰And R ¹¹The heterocyclic radical that forms;

R ¹², R ¹³, R ¹⁴And R ¹⁵Independently be selected from hydrogen, cyanic acid, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl;

A is selected from following group:

R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²¹, R ²², R ²³, R ²⁴, R ²⁵, R ²⁶, R ²⁷, R ²⁸, R ²⁹, R ³⁰, R ³¹, R ³², R ³³, R ³⁴, R ³⁵, R ³⁶, R ³⁷, R ³⁸, R ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³, R ⁴⁴, R ⁴⁵, R ⁴⁶, R ⁴⁷, R ⁴⁸, R ⁴⁹, R ⁵⁰, R ⁵¹, R ⁵², R ⁵³, R ⁵⁴, R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸, R ⁵⁹, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶And R ⁶⁷Independently be selected from is hydrogen, halogen, haloalkyl, nitro, cyanic acid, OR ⁶⁸, NR ⁶⁹R ⁷⁰, CO ₂R ⁷¹,-C (O) NR ⁷²R ⁷³, SO ₂R ⁷⁴, S (O) ₂NR ⁷⁵R ⁷⁶, NR ⁷⁷S (O) ₂R ⁷⁸, NR ⁷⁹C (O) R ⁸⁰, NR ⁸¹CO ₂R ⁸²,-CO (CH) ₂) _rR ⁸³,-CONH (CH ₂) _rR ⁸⁴, SR ⁸⁵, SOR ⁸⁶, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl; R is 0-4;

R ⁶⁸, R ⁶⁹, R ⁷⁰, R ⁷¹, R ⁷², R ⁷³, R ⁷⁴, R ⁷⁵, R ⁷⁶, R ⁷⁷, R ⁷⁸, R ⁷⁹, R ⁸⁰, R ⁸¹, R ⁸², R ⁸³, R ⁸⁴, R ⁸⁵And R ⁸⁶Independently be selected from hydrogen, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl;

G is O, S or NR ⁸⁷D is CR ⁸⁸Or N; Z is N or CR ⁸⁹

R ⁸⁷, R ⁸⁸And R ⁸⁹Independently be selected from hydrogen, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, alkylsulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl.

Alkyl is represented the saturated aliphatic radical of 1-20 carbon atom, comprises straight chain and branched group, and the alkyl that contains 1-4 carbon atom is called low alkyl group.When low alkyl group does not have substituting group, be called unsubstituted low alkyl group.More preferably, alkyl is the medium sized alkyl that 1-10 carbon atom arranged, like methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.Most preferably, alkyl is the low alkyl group that 1-4 carbon atom arranged, like methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be substituted or unsubstituted; When being substituted alkyl; This substituting group preferably one or more; More preferably 1-3,1 or 2 substituting group most preferably, said substituting group is independently preferably from following group: halogen, hydroxyl, lower alkoxy, aryl, aryloxy, heteroaryl, heterolipid cyclic group ,-C (O) R ⁷,-NR ⁸R ⁹With-C (O) NR ¹¹R ¹², R wherein ⁷, R ⁸, R ⁹, R ¹¹And R ¹²Define the same.

Naphthenic base representes all to be the monocycle or the condensed ring of carbon; Said fused rings refers to each ring and shares a pair of carbon atom that adjoins with other ring in the system; Wherein one or more rings do not have the πDian Zi system that connects fully, and naphthenic base comprises Trimetylene, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, diamantane, cyclohexadiene, suberane and cycloheptatriene.Naphthenic base can be substituted and unsubstituted; When being substituted; Substituting group is preferably one or more following groups that are independently selected from: alkyl, aryl, heteroaryl, heterolipid cyclic group, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkane sulfydryl, aromatic thiohydroxy, cyanic acid, halogen, carbonyl, thiocarbonyl, C-carboxyl, O-carboxyl, O-formamyl, N-formamyl, C-amido, N-amido, nitro, amino and-NR ⁸R ⁹, R wherein ⁸And R ⁹Define the same.

Aryl is represented the full carbon monocycle or the fused polycycle group of 1 to 12 carbon atom, has the πDian Zi system of total conjugated.Aryl comprises phenyl, naphthyl and anthryl; Can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more; More preferably one, two or three, so more preferably one or two, be independently selected from by low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyanic acid, acyl group, sulfo-acyl group, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R ⁸S (O)-, R ⁸S (O) ₂-,-C (O) OR ⁸, R ⁸C (O) O-and-NR ⁸R ⁹The group of forming, R ⁸And R ⁹Define the same.Preferably, aryl is replaced by one or two substituting group alternatively, and substituting group is independently selected from halogen, low alkyl group, three alkylhalide groups, hydroxyl, sulfydryl, cyanic acid, N-amido, list or dialkyl amino, carboxyl or N-sulfonamido.

Heteroaryl is represented the monocycle or the fused rings group of 5 to 12 annular atomses, contains one, two, three or four ring hetero atoms that are selected from N, O or S, and all the other annular atomses are C, have the πDian Zi system of total conjugated in addition.Unsubstituted heteroaryl ground limiting examples has pyrroles, furans, thiophene, imidazoles 、 oxazole, thiazole, pyrazoles, pyrimidine, pyridine, quinoline, isoquinoline 99.9, quinazoline, thienopyridine, Thienopyrimidine, pyrrolopyridine, purine, tetrazolium, triazine and carbazole.Heteroaryl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more; More be preferably one, two or three; And then more preferred one or two, independently be selected from following group: low alkyl group, three alkylhalide groups, halogen, hydroxyl, alkoxyl group, sulfydryl, (low alkyl group) sulfenyl, alkynyl, cyanic acid, acyl group, sulfo-acyl group, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R ⁸S (O)-, R ⁸S (O) ₂-,-C (O) OR ⁸, R ⁸C (O) O-and-NR ⁸R ⁹, R wherein ⁸And R ⁹Define the same.Preferred heteroaryl is replaced by one or two substituting group alternatively, and substituting group is independently selected from halogen, alkoxyl group, alkynyl, amino, benzyloxy, aryl.

The heterolipid cyclic group is represented monocycle or fused rings group, in ring, has 5 to 9 annular atomses, and one of them or two annular atomses are to be selected from N, O or S (O) _mThe heteroatoms of (wherein m is 0 to 2 integer), all the other annular atomses are C.These rings can have one or more pair of key, but these rings do not have the πDian Zi system of total conjugated.Unsubstituted heterolipid cyclic group comprises pyrrolidyl, piperidino-(1-position only), Piperazino, morpholino base, thiomorpholine Dai Ji etc.The heterolipid cyclic group can be substituted or unsubstituted; When being substituted; That substituting group is preferably is one or more, more preferably one, two or three; And then more preferably one or two, be independently selected from following group: low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyanic acid, acyl group, sulfo-acyl group, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R ⁸S (O)-, R ⁸S (O) ₂-,-C (O) OR ⁸, R ⁸C (O) O-and-NR ⁸R ⁹, R wherein ⁸And R ⁹Define the same.Preferably, the heterolipid cyclic group is replaced by one or two substituting group alternatively, and substituting group is independently selected from halogen, low alkyl group, three alkylhalide groups, hydroxyl, sulfydryl, cyanic acid, N-amido, list or dialkyl amino, carboxyl or N-sulfonamido.

Heterocyclic radical is represented the saturated cyclic group of 3 to 8 annular atomses, and one of them or two annular atomses are to be selected from N, O or S (O) _mThe heteroatoms of (wherein m is 0 to 2 integer), all the other annular atomses are C, one of them or two C atoms can be replaced by carbonyl alternatively.The ring of heterocyclic radical can be alternatively independently by one, two or three substituting groups replacements; Substituting group be selected from low alkyl group (replaced by one or two substituting group alternatively, substituting group is independently selected from carboxyl or ester group), haloalkyl, halogen, nitro, cyanic acid, hydroxyl, alkoxyl group, amino, monoalkyl amido, dialkyl amino, aralkyl, heteroaralkyl ,-C (O) R (wherein R is an alkyl) and-(CH ₂) nY, wherein Y is heterolipid cyclic group and R ¹⁰, wherein n is 0 to 2 integer, R ¹⁰Define the same.More specifically; Heterocyclic radical comprises THP trtrahydropyranyl, 2; 2-dimethyl--1; 3-dioxolane, piperidino-(1-position only), N-methyl piperidine-3-base, Piperazino, N-methylpyrrolidin-3-base, pyrrolidyl, morpholino base, thiomorpholine are for base, thiomorpholine generation-1-oxide compound, thiomorpholine generation-1,1-dioxide, 4-ethoxycarbonyl Piperazino, 3-oxo Piperazino, 2-imidazolone, 2-Pyrrolidone, tetrahydropyrimidine-2-ketone and verivate thereof.Preferably; Heterocyclic group is replaced by one or two substituting group alternatively; Substituting group is independently selected from halogen, low alkyl group, by the substituted low alkyl group of hydroxyl, carboxyl or ester group, by the substituted low alkyl group of heterolipid cyclic group, hydroxyl, list or dialkyl amino and heterolipid cyclic group, wherein the heterolipid cyclic group comprises pyrrolidyl, piperidino-(1-position only), Piperazino etc.

Hydroxyl is represented-the OH group; Alkoxyl group representes-O-(unsubstituted alkyl) and-O-(unsubstituted naphthenic base), comprise methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Aryloxy representes-O-aryl and-O-heteroaryl, comprise phenoxy, pyridyloxy, furans oxygen base, thiophene oxy, 2-pyrimidinyl oxy, pyrazine oxygen base etc. and verivate thereof.Benzyloxy is represented-the O-benzyl.Comprise no substituted benzyl, substituted benzyl etc. and verivate thereof; Sulfydryl is represented-the SH group.

Acyl group is represented-C (O)-R ' group; Wherein R ' is selected from: hydrogen, unsubstituted low alkyl group, trihalogenmethyl, unsubstituted naphthenic base, alternatively by one or more, preferably by 1,2 or 3 be selected from unsubstituted low alkyl group, trihalogenmethyl, unsubstituted lower alkoxy, halogen and-NR ⁸R ⁹The substituted aryl of the substituting group of group, wherein R ⁸And R ⁹Define the same, alternatively by one or more, preferably by 1,2 or 3 be selected from unsubstituted low alkyl group, trihalogenmethyl, unsubstituted lower alkoxy, halogen and-NR ⁸R ⁹The substituted heteroaryl of the substituting group of group (through the ring carbon atom bonding), and alternatively by one or more, preferably by 1,2 or 3 be selected from unsubstituted low alkyl group, trihalogenmethyl, unsubstituted lower alkoxy, halogen and-NR ⁸R ⁹The substituted heterolipid cyclic group of the substituting group of group (through the ring carbon atom bonding), representational acyl group comprises ethanoyl, trifluoroacetyl group, benzoyl-etc.The sulfo-acyl group representes-C (S)-R ' group that wherein R ' definition is the same.Ester group representes-C (O) O-R ' group that wherein R ' definition is the same, but R ' can not be a hydrogen.Ethanoyl is represented-C (O) CH ₃Group.

Halogen is represented fluorine, chlorine, bromine or iodine.Trihalogenmethyl is represented-CX ₃Group.Cyanic acid is represented-the CN group.The S-sulfonamido is represented-S (O) ₂NR ⁸R ⁹Group, wherein R ⁸And R ⁹Define the same.The N-sulfonamido is represented-NR ⁸S (O) ₂R ⁹Group, wherein R ⁸And R ⁹Define the same.O-carbamyl basis representation-OC (O) NR ¹¹R ¹²Group, wherein R ¹¹And R ¹²Define the same.N-carbamyl basis representation R ⁸OC (O) NR ⁹-group, wherein R ⁸And R ⁹Define the same.The O-thiocarbamoyl is represented-OC (S) NR ¹¹R ¹²Group, wherein R ¹¹And R ¹²Define the same.The N-thiocarbamoyl is represented R ⁸OC (S) NR ⁹-group, wherein R ⁸And R ⁹Define the same.Amino expression-NH ₂Group.The C-amido is represented-C (O) NR ⁸R ⁹Group, wherein R ⁸And R ⁹Define the same.The N-amido is represented R ⁸C (O) NR ⁹-group, wherein R ⁸And R ⁹Define the same.Nitro is represented-NO ₂Group.Haloalkyl representes that the preferred as above defined low alkyl group of alkyl is replaced by one or more identical or different halogen atoms, for example-and CH ₂Cl ,-CF ₃,-CCl ₃,-CH ₂CF ₃,-CH ₂CCl ₃Deng.Haloalkoxy basis representation alkoxyl group, preferably as above defined-the O-alkyl, wherein alkyl is replaced by one or more identical or different halogen atoms, preferred three halogen methoxyl groups, as-OCF ₃Aralkyl is represented alkyl, preferably as above defined low alkyl group, and the as above defined aryl of its quilt replaces, for example-CH ₂Phenyl ,-(CH ₂) ₂Phenyl ,-(CH ₂) ₃Phenyl, CH ₃CH (CH ₃) CH ₂Phenyl and verivate thereof.Heteroaralkyl is represented alkyl, preferably as above defined low alkyl group, and it is replaced by heteroaryl, for example-CH ₂Pyridyl ,-(CH ₂) ₂Pyrimidyl ,-(CH ₂) ₃Imidazolyl etc. and verivate thereof.Monoalkylamine basis representation group-NHR, wherein R is as above defined alkyl or unsubstituted naphthenic base, for example methylamino, (1-methylethyl) amido, cyclohexylamino etc.Dialkylamine basis representation group-NRR, wherein each R is as above defined alkyl or unsubstituted naphthenic base independently, for example dimethyl amido, diethylammonium amido, N-methylcyclohexyl amido etc.

Piperazino refers to the group with following chemical structure.

The morpholino base refers to the group with following chemical structure.

Piperidino-(1-position only) refers to the group with following chemical structure.

Pyrrolidyl refers to the group with following chemical structure.

As preferably, in the structure compound shown by formula I provided by the invention, B is selected from O, S or NHR ⁴

As preferably, in the structure compound shown by formula I provided by the invention, X is selected from C, R ¹Be hydrogen or halogen;

As preferably, in the structure compound shown by formula I provided by the invention, X is N;

As preferably, in the structure compound shown by formula I provided by the invention, A is selected from substituted pyridine or quinoline, quinazoline, thienopyridine, Thienopyrimidine, Pyrazolopyridine;

As preferably, in the structure compound shown by formula I provided by the invention, A is an EL-970;

Structure compound shown by formula I provided by the invention or its pharmacy acceptable salt, as preferably, structure can be suc as formula shown in the II:

Formula II

Wherein, X is selected from C or N; B is selected from O, S or NH; R ¹Be selected from hydrogen or halogen; R ²Be selected from hydrogen or OR ⁷R ⁷Be selected from hydrogen, alkyl, substituted alkyl, allyl group or substituted allyl;

R ³Be selected from hydroxyl, alkoxyl group ,-NR ¹⁰R ¹¹Or-N (CH ₂) _p(R ¹²) (CH ₂) _pR ¹³P is 0-2;

R ¹⁰And R ¹¹Independently be selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical or R ¹⁰And R ¹¹The heterocyclic radical that forms;

R ¹²And R ¹³Independently be selected from hydrogen, cyanic acid, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical or substituted heterocyclic radical;

A is selected from following group:

R ¹⁶, R ¹⁷, R ¹⁸, R ²⁶, R ²⁷, R ²⁹, R ³⁰, R ³¹And R ³²Independently be selected from hydrogen, halogen, haloalkyl, nitro, cyanic acid, OR ⁶⁸, NR ⁶⁹R ⁷⁰, CO ₂R ⁷¹,-C (O) NR ⁷²R ⁷³, SO ₂R ⁷⁴, S (O) ₂NR ⁷⁵R ⁷⁶, NR ⁷⁷S (O) ₂R ⁷⁸, NR ⁷⁹C (O) R ⁸⁰, NR ⁸¹CO ₂R ⁸²,-CO (CH ₂) _rR ⁸³,-CONH (CH ₂) _rR ⁸⁴, SR ⁸⁵, SOR ⁸⁶, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl; R is 0-4;

Z is selected from N or CR ⁸⁹R ⁸⁹Be selected from hydrogen, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, alkylsulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl.

As preferably; The present invention also provides structure suc as formula the compound shown in the III or its pharmacy acceptable salt,

Formula III

Wherein, X is selected from C or N; If X is C, then n is 0-4; If X is N, then n is 0-3;

M is 0-3; B is O, NR ⁴, NR ⁴CH ₂, S, SO, SO ₂, CR ⁵R ⁶

A is selected from following group:

R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²¹, R ²², R ²³, R ²⁴, R ²⁵, R ²⁶, R ²⁷, R ²⁸, R ²⁹, R ³⁰, R ³¹, R ³², R ³³, R ³⁴, R ³⁵, R ³⁶, R ³⁷, R ³⁸, R ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³, R ⁴⁴, R ⁴⁵, R ⁴⁶, R ⁴⁷, R ⁴⁸, R ⁴⁹, R ⁵⁰, R ⁵¹, R ⁵², R ⁵³, R ⁵⁴, R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸, R ⁵⁹, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶And R ⁶⁷Independently be selected from hydrogen, halogen, haloalkyl, nitro, cyanic acid, OR ⁶⁸, NR ⁶⁹R ⁷⁰, CO ₂R ⁷¹,-C (O) NR ⁷²R ⁷³, SO ₂R ⁷⁴, S (O) ₂NR ⁷⁵R ⁷⁶, NR ⁷⁷S (O) ₂R ⁷⁸, NR ⁷⁹C (O) R ⁸⁰, NR ⁸¹CO ₂R ⁸²,-CO (CH ₂) _rR ⁸³,-CONH (CH ₂) _rR ⁸⁴, SR ⁸⁵, SOR ⁸⁶, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl; R is 0-4;

G is O, S or NR ⁸⁷D is CR ⁸⁸Or N; Z is N or CR ⁸⁹R ⁸⁷, R ⁸⁸And R ⁸⁹Independently be selected from hydrogen, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, alkylsulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl.

The present invention also provides the preparation method of structure suc as formula compound shown in the III, and substrate is a structure suc as formula compound shown in the IIIA and structure suc as formula compound shown in the IIIB,

Formula III A formula III B

Step 1: said substrate is at 4-N, and generating structure makes structure suc as formula the compound shown in the V suc as formula the compound shown in the IIIC through basic hydrolysis under the catalysis of N-dimethyl aminopyridine;

Formula III C formula V

Step 2: structure is reacted suc as formula replacing amine shown in the IIID suc as formula compound shown in the V and structure, makes the compound of said structure shown in formula III.

Formula III D

As preferably, the present invention also provides a kind of structure suc as formula the compound shown in the IV or its pharmacy acceptable salt,

Formula IV

M is 0-3;

R ⁸And R ⁹Independently be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, naphthenic base, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical or substituted heterocyclic radical;

A is selected from following group:

Wherein, R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²¹, R ²², R ²³, R ²⁴, R ²⁵, R ¹⁶, R ²⁷, R ²⁸, R ²⁹, R ³⁰, R ³¹, R ³², R ³³, R ³⁴, R ³⁵, R ³⁶, R ³⁷, R ³⁸, R ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³, R ⁴⁴, R ⁴⁵, R ⁴⁶, R ⁴⁷, R ⁴⁸, R ⁴⁹, R ⁵⁰, R ⁵¹, R ⁵², R ⁵³, R ⁵⁴, R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸, R ⁵⁹, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶And R ⁶⁷Independently be selected from hydrogen, halogen, haloalkyl, nitro, cyanic acid, OR ⁶⁸, NR ⁶⁹R ⁷⁰, CO ₂R ⁷¹,-C (O) NR ⁷²R ⁷³, SO ₂R ⁷⁴, S (O) ₂NR ⁷⁵R ⁷⁶, NR ⁷⁷S (O) ₂R ⁷⁸, NR ⁷⁹C (O) R ⁸⁰, NR ⁸¹CO ₂R ⁸²,-CO (CH ₂) _rR ⁸³,-CONH (CH ₂) _rR ⁸⁴, SR ⁸⁵, SOR ⁸⁶, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl; R is 0-4;

G is selected from O, S or NR ⁸⁷D is selected from CR ⁸⁸Or N; Z is selected from N or CR ⁸⁹

The present invention also provides the preparation method of a kind of structure suc as formula compound shown in the IV, substrate be structure suc as formula compound shown in the IVA,

Formula IVA

Step 1: said substrate and N, dinethylformamide dimethylacetal are at N, and the reaction generating structure is suc as formula compound shown in the IVB in the dinethylformamide;

Formula IVB

Step 2: said structure suc as formula compound shown in compound shown in the IVB and the formula IVC in reflux in ethanol,

Formula IVC

Wherein, Bn is a benzyl, and nucleophilic substitution takes place in the presence of acid binding agent for compound that makes and halogenating agent, and hydrolysis obtains structure suc as formula the compound shown in the XI in aqueous sodium hydroxide solution again;

Formula XI

Step 3: structure suc as formula the substituted heterocycle generation substitution reaction shown in the IVD, makes structure suc as formula compound shown in the IV suc as formula the compound shown in the XI and structure.

Formula IVD

As preferably, structure compound shown by formula I provided by the invention is specially:

Compound 1:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 2:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(3-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 3:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 4:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-chloro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides (I-4)

Compound 5:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 6:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 7:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(3-chloro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 8:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-cyanic acid-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 9:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-benzyl-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 10:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(3-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 11:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 12:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 13:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 14:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 15:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-methyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 16:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-chloro-3-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 17:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-phenyl)-N-(4-fluoro-benzyl-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 18:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluoro-phenyl)-N-isobutyl--6-oxo-1,6-dihydropyridine-3-acid amides

Compound 19:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluoro-the phenyl)-N-tertiary butyl-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 20:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluoro-phenyl)-N-sec.-propyl-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 21:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluoro-phenyl)-N-(2-cyano ethyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 22:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluoro-phenyl)-N-(2-cyano methyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 23:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-cyano methyl)-N-(4-luorobenzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 24:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-5-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) pyridine-2 (1H) ketone

Compound 25:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(furans-2-ylmethyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 26:1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 27:1-(4-((2-amino-3-alkynyl pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 28:1-(4-((2-amino-3-(3-hydroxyl third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 29:1-(4-((2-amino-3-(3-dimethylamino third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 30:1-(4-((1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 31:1-(4-((2-methylol-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 32:1-(4-((dimethylamino methyl-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 33:1-(4-((2-(morpholinyl-methyl)-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 34:1-(4-((2-(piperidines-1-base-methyl)-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 35:1-(3-fluoro-4-(thiophene [3,2-d] pyrimidine-4-yl) oxo-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 36:1-(3-fluoro-4-(thiophene [3,2-b] pyridine-7-yl) oxo-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 37:1-(4-(6,7-dimethoxyquinazoline-4-yl) oxo 3-fluoro-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 38:1-(4-(6-benzyloxy-7-methoxyl group quinazoline-4-yl) oxo 3-fluoro-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 39:1-(3-fluoro-4-(7-methoxyl group-6-(morpholinyl-propoxy--quinazoline-4-yl) oxo-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 40:5 '-((2-amino-3-chloropyridine-4-yl) oxo-N-(4-fluoro-benzyl)-2-oxo-2H [1, the 2-dipyridyl]-5-acid amides

Compound 41:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 42:1-(4-((2-amino-3-chloropyridine-4-yl) oxo phenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 43:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-oxyethyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 44:4-allyloxy-1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-oxyethyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 45:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-(2-methoxyethoxy)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 46:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-4-(2,3-dihydroxyl propoxy-)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 47:1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 48:1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-(2-methoxyethoxy)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 49:1-(4-((2-amino-3-(3-hydroxyl third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4 methoxyl groups-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 50:1-(4-((2-amino-3-(3-dimethylamino third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 51:1-(4-((2-amino-3-(4-fluorophenyl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 52:1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-phenyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 53:1-(3-fluoro-4-(7-methoxyl group-6-(morpholinyl-propoxy--quinazoline-4-yl) oxo-phenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 54:1-(3-fluoro-4-(thiophene [3,2-b] pyridine-7-yl) oxo-phenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 55:1-(3-fluoro-4-(6-methoxyl group-7-(morpholinyl-propoxy--quinolyl-4) oxo-phenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 56:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-acid amides

Compound 57:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-acid amides

Compound 58:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-phenyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 59:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-acid amides

Compound 60:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-2-oxo-1,2-dihydropyridine-3-acid amides

Compound 61:1-(3-fluoro-4-(thiophene [3,2-b] pyridine-7-yl) amino-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 62:1-(3-fluoro-4-(thiophene [3,2-d] pyrimidine-4-yl) amino-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 63:1-(the amino 3-fluoro-phenyl of 4-(6,7-dimethoxyquinazoline-4-yl))-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 64:1-(the amino 3-fluoro-phenyl of 4-(6-benzyloxy-7-methoxyl group quinazoline-4-yl))-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 65:1-(3-fluoro-4-(7-methoxyl group-6-(morpholinyl-propoxy--quinazoline-4-yl) amino-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 66:1-(3-fluoro-((7-methoxy quinoline-4-yl) amino-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

As preferably, the present invention also provides a kind of structure suc as formula the compound shown in the V or its pharmacy acceptable salt,

Formula V

A is selected from following group:

As preferably, structure provided by the invention is specially suc as formula compound shown in the V:

Compound 67:1-(4-((2-carboxamido-group-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid

Compound 68:1-(4-((2-carboxamido-group-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-carboxylic acid

The present invention also provides the preparation method of a kind of structure suc as formula compound shown in the V, and substrate is a structure suc as formula compound shown in the VA and structure suc as formula compound shown in the VB,

Formula VA formula VB

Said substrate is at 4-N, and generating structure makes structure provided by the invention suc as formula compound shown in the V suc as formula the compound shown in the VC through basic hydrolysis under the catalysis of N-dimethyl aminopyridine.

Formula VC

The present invention also provides structure suc as formula the compound shown in the VI or its pharmacy acceptable salt:

Formula VI

Wherein: X is selected from C or N; R ¹Be selected from hydrogen or halogen;

R ²Be selected from hydrogen or OR ⁷R ⁷Be selected from hydrogen, alkyl, substituted alkyl, allyl group or substituted allyl; R ³Be selected from hydroxyl, alkoxyl group ,-NR ¹⁰R ¹¹Or-N (CH ₂) _p(R ¹²) (CH ₂) _pR ¹³P is 0-2;

R ¹⁰And R ¹¹Be independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical or R ¹⁰And R ¹¹Form a heterocyclic radical altogether;

R ¹²And R ¹³Independently be selected from hydrogen, cyanic acid, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical or substituted heterocyclic radical.

As preferably, structure is specially suc as formula the compound shown in the VI:

Compound 69:1-(3-fluoro-4-hydroxy phenyl)-N-4-fluoro-benzyl-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 70:1-(3-fluoro-4-hydroxy phenyl)-N-4-fluoro-benzyl-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

The present invention also provides the preparation method of structure suc as formula compound shown in the VI, substrate be structure suc as formula compound shown in the XI,

Formula XI

Said substrate under the condition that condensing agent exists with structure suc as formula the replacement amine generation substitution reaction shown in the VIA; Generating structure is suc as formula the compound shown in the VIB; Under the catalysis of palladium-carbon, hydrogenating reduction makes structure provided by the invention suc as formula the compound shown in the VI then.

Formula VIA formula VIB

The present invention also provides structure suc as formula the compound shown in the VII or its pharmacy acceptable salt,

Formula VII

Wherein, Y ¹Be selected from hydrogen, aryl, heteroaryl or-(CH ₂) _nY ⁵Y ²Be selected from hydrogen, halogen; Y ³Be selected from hydrogen, hydroxyl, OY ⁴Y ⁴Be selected from hydrogen, alkyl, alkoxyl group, allyl group; Y ⁵Be selected from aryl, heteroaryl; N is 1; B is selected from O, NH.

The present invention also provides the preparation method of structure suc as formula compound shown in the VII, and substrate is a structure suc as formula compound shown in the VIIA and structure suc as formula compound shown in the VIIB,

Formula VIIA formula VIIB

Said substrate is at 4-N, and generating structure makes structure suc as formula the compound shown in the VII through basic hydrolysis again suc as formula the compound shown in the VIIC under the catalysis of N-dimethyl aminopyridine.

Formula VIIC

As preferably; The present invention also provides structure suc as formula the compound shown in the VIII or its pharmacy acceptable salt,

Formula VIII

Wherein, Y ¹Be selected from hydrogen, aryl, heteroaryl or-(CH ₂) _nY ⁵Y ²Be selected from hydrogen, halogen; Y ⁴Be selected from hydrogen, alkyl, alkoxyl group, allyl group; Y ⁵Be selected from aryl, heteroaryl; N is 1; B is selected from O, NH.

The present invention also provides the preparation method of structure suc as formula compound shown in the VIII, and substrate is a structure suc as formula compound shown in the VIIA and structure suc as formula compound shown in the VIIIA,

Formula VIIA formula VIIIA

Said substrate is at 4-N, and generating structure makes structure suc as formula the compound shown in the VIII suc as formula the compound shown in the VIIIB through basic hydrolysis under the catalysis of N-dimethyl aminopyridine.

Formula VIIIB

The present invention also provides the preparation method of a kind of structure suc as formula compound shown in the VIII; Substrate be structure suc as formula compound shown in the IVA,

Formula IVA

Formula IVB

Step 2: said structure obtains structure suc as formula compound shown in the VIIIC suc as formula compound shown in compound shown in the IVB and the formula VIIC in reflux in ethanol;

Formula VIIC formula VIIIC

Step 3: nucleophilic substitution takes place suc as formula compound shown in the VIIIC and halogenating agent in said structure in the presence of acid binding agent, make structure suc as formula compound shown in the VIIID;

Formula VIIID

Step 4: said structure obtains structure suc as formula the compound shown in the VIII suc as formula the hydrolysis in aqueous sodium hydroxide solution of compound shown in the VIIID.

The present invention also provides a kind of structure suc as formula the compound shown in the IX,

Formula IX

Wherein, Y ⁶Be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyanic acid ,-NY ⁹Y ¹⁰, aryl, heteroaryl; Y ⁷Be selected from hydrogen, hydroxyl, OY ¹¹Or-NY ⁹Y ¹⁰Y ⁹And Y ¹⁰Independently be selected from hydrogen, alkyl, alkoxyl group, naphthenic base, aryl, heteroaryl, heterolipid cyclic group, perhaps Y ⁹And Y ¹⁰Form a heterocyclic radical altogether; Y ¹¹Be selected from hydrogen, alkyl, naphthenic base, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Bn is a benzyl.

The present invention also provides the preparation method of structure suc as formula compound shown in the IX, and substrate is a structure suc as formula compound shown in the IXA and structure suc as formula compound shown in the IXB,

Formula IXA formula IXB

Said substrate is at 4-N, and generating structure makes structure suc as formula compound shown in the IX suc as formula the compound shown in the IXC through basic hydrolysis under the catalysis of N-dimethyl aminopyridine.

Formula IXC

As preferably; The present invention also provides structure suc as formula the compound shown in the X or its pharmacy acceptable salt,

Formula X

Wherein, Y ⁶Be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyanic acid ,-NY ⁹Y ¹⁰, aryl, heteroaryl; Y ⁹And Y ¹⁰Independently be selected from hydrogen, alkyl, alkoxyl group, naphthenic base, aryl, heteroaryl, heterolipid cyclic group, perhaps Y ⁹And Y ¹⁰Form a heterocyclic radical altogether; Y ¹¹Be selected from hydrogen, alkyl, naphthenic base, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Bn is a benzyl.

The present invention also provides the preparation method of structure suc as formula compound shown in the X, and substrate is a structure suc as formula compound shown in the XA and structure suc as formula compound shown in the XB,

Formula IXA formula XB

Said substrate is at 4-N, and generating structure makes structure suc as formula the compound shown in the X suc as formula the compound shown in the XC through basic hydrolysis under the catalysis of N-dimethyl aminopyridine.

Formula XC

The present invention also provides the preparation method of structure suc as formula compound shown in the X, substrate be structure suc as formula compound shown in the IVA,

Formula IVA

Formula IVB

Step 2: said structure obtains structure suc as formula compound shown in the XD suc as formula compound shown in compound shown in the IVB and the formula IXA in reflux in ethanol;

Formula IXA formula XD

Step 3: nucleophilic substitution takes place suc as formula compound shown in the XD and structure suc as formula the halogenating agent shown in the XE in said structure in the presence of acid binding agent, make structure suc as formula compound shown in the XF;

Formula XE formula XF

Step 4: said structure obtains structure suc as formula the compound shown in the X suc as formula the hydrolysis in aqueous sodium hydroxide solution of compound shown in the XF.

The present invention also provides structure suc as formula the compound shown in the XI or its pharmacy acceptable salt,

Formula XI

M is 0-3; Bn is a benzyl.

The present invention also provides the preparation method of structure suc as formula compound shown in the XI, substrate be structure suc as formula compound shown in the IVA,

Formula IVA

Formula IVB

Step 2: said structure suc as formula compound shown in compound shown in the IVB and the formula XIA in reflux in ethanol,

Formula XIA

Wherein, Bn is a benzyl, and nucleophilic substitution takes place in the presence of acid binding agent for compound that makes and halogenating agent, the compound that makes again in aqueous sodium hydroxide solution hydrolysis obtain structure suc as formula the compound shown in the XI.

The present invention also provides structure suc as formula the compound shown in the XII or its pharmacy acceptable salt,

Formula XII

Wherein, Y ¹Be selected from hydrogen, aryl, heteroaryl or-(CH ₂) _nY ⁵Y ²Be selected from hydrogen, halogen; Y ³Be selected from hydrogen, hydroxyl, OY ⁴Y ⁴Be selected from hydrogen, alkyl, alkoxyl group, allyl group; Y ⁵Be selected from aryl, heteroaryl; N is 1; B is selected from O, NH;

R ¹⁰And R ¹¹Independently be selected from hydrogen, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl, substituted Heterocyclylalkyl or R ¹⁰And R ¹¹The heterocyclic radical that forms.

The present invention also provides the preparation method of structure suc as formula compound shown in the XII, and substrate is that structure provided by the invention is reacted suc as formula replacing amine shown in the IIID suc as formula compound shown in the VII and structure, makes structure suc as formula the compound shown in the XII.

Formula VII formula III D

As preferably; The present invention also provides structure suc as formula the compound shown in the XIII or its pharmacy acceptable salt,

Formula XIII

Wherein, Y ¹Be selected from hydrogen, aryl, heteroaryl or-(CH ₂) _nY ⁵Y ²Be selected from hydrogen, halogen; Y ⁴Be selected from hydrogen, alkyl, alkoxyl group, allyl group; Y ⁵Be selected from aryl, heteroaryl; N is 1; B is selected from O, NH;

The present invention also provides the preparation method of structure suc as formula compound shown in the XIII, and substrate structure reacts suc as formula replacing amine shown in the IIID suc as formula compound shown in the VIII and structure, makes said compound.

Formula VIII formula III D

The present invention also provides structure suc as formula the compound shown in the XIV or its pharmacy acceptable salt,

Formula XIV

Wherein, Y ⁶Be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyanic acid ,-NY ⁹Y ¹⁰, aryl, heteroaryl; Y ⁷Be selected from hydrogen, hydroxyl, OY ¹¹Or-NY ⁹Y ¹⁰Y ⁹And Y ¹⁰Independently be selected from hydrogen, alkyl, alkoxyl group, naphthenic base, aryl, heteroaryl, heterolipid cyclic group, perhaps Y ⁹And Y ¹⁰Form a heterocyclic radical altogether; Y ¹¹Be selected from hydrogen, alkyl, naphthenic base, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Bn is a benzyl;

The present invention also provides the preparation method of structure suc as formula compound shown in the XIV, and substrate structure reacts suc as formula replacing amine shown in the IIID suc as formula compound shown in the IX and structure, makes said compound.

Formula IX formula III D

The present invention also provides structure suc as formula the compound shown in the XV or its pharmacy acceptable salt,

Formula XV

Wherein, Y ⁶Be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyanic acid ,-NY ⁹Y ¹⁰, aryl, heteroaryl; Y ⁹And Y ¹⁰Independently be selected from hydrogen, alkyl, alkoxyl group, naphthenic base, aryl, heteroaryl, heterolipid cyclic group, perhaps Y ⁹And Y ¹⁰Form a heterocyclic radical altogether; Y ¹¹Be selected from hydrogen, alkyl, naphthenic base, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Bn is a benzyl;

The present invention also provides the preparation method of structure suc as formula compound shown in the X V, and substrate structure reacts suc as formula replacing amine shown in the IIID suc as formula compound shown in the X and structure, makes said compound.

Formula X formula III D

The present invention also provides structure suc as formula the compound shown in the XVI or its pharmacy acceptable salt,

Formula XVI

Wherein, Y ⁶Be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyanic acid ,-NY ⁹Y ¹⁰, aryl, heteroaryl; Y ⁷Be selected from hydrogen, hydroxyl, OY ¹¹Or-NY ⁹Y ¹⁰Y ⁸Be selected from hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy, heteroaryloxy, benzyloxy ,-NY ⁹Y ¹⁰,--N (CH ₂) _m(Y ¹²) (CH ₂) _mY ¹³Y ⁹And Y ¹⁰Independently be selected from hydrogen, alkyl, alkoxyl group, naphthenic base, aryl, heteroaryl, heterolipid cyclic group, perhaps Y ⁹And Y ¹⁰Form a heterocyclic radical altogether; Y ¹¹Be selected from hydrogen, alkyl, naphthenic base, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Y ¹²And R ¹³Independently be selected from hydrogen, cyanic acid, alkyl, aryl, heteroaryl; M is selected from 0,1,2 or 3.

The present invention also provides the preparation method of structure suc as formula compound shown in the X VI; Substrate be structure suc as formula compound shown in the IX,

Formula IX

Said substrate under the condition that condensing agent exists with structure suc as formula the replacement amine generation substitution reaction shown in the XVIB, generating structure is suc as formula the compound shown in the XVIC, under the catalysis of palladium-carbon, hydrogenating reduction makes said compound then.

Formula XVIB formula XVIC

As preferably, the present invention also provides structure suc as formula the compound shown in the XVII or its pharmacy acceptable salt,

Formula XVII

Wherein, Y ⁶Be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyanic acid ,-NY ⁹Y ¹⁰, aryl, heteroaryl; Y ⁸Be selected from hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy, heteroaryloxy, benzyloxy ,-NY ⁹Y ¹⁰,--N (CH ₂) _m(Y ¹²) (CH ₂) _mY ¹³Y ⁹And Y ¹⁰Independently be selected from hydrogen, alkyl, alkoxyl group, naphthenic base, aryl, heteroaryl, heterolipid cyclic group, perhaps Y ⁹And Y ¹⁰Form a heterocyclic radical altogether; Y ¹¹Be selected from hydrogen, alkyl, naphthenic base, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Y ¹²And R ¹³Independently be selected from hydrogen, cyanic acid, alkyl, aryl, heteroaryl; M is selected from 0,1,2 or 3.

The present invention also provides the preparation method of structure suc as formula compound shown in the XVII; Substrate be structure suc as formula compound shown in the X,

Formula X

Said substrate under the condition that condensing agent exists with structure suc as formula the replacement amine generation substitution reaction shown in the XVIIB, generating structure is suc as formula the compound shown in the XVIIC, under the catalysis of palladium-carbon, hydrogenating reduction makes said compound then.

Formula XVIB formula XVIIC

The present invention also provides structure suc as formula the compound shown in the XVIII or its pharmacy acceptable salt,

Formula XVIII

A is selected from following group:

Wherein, R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²¹, R ²², R ²³, R ²⁴, R ²⁵, R ²⁶, R ²⁷, R ²⁸, R ²⁹, R ³⁰, R ³¹, R ³², R ³³, R ³⁴, R ³⁵, R ³⁶, R ³⁷, R ³⁸, R ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³, R ⁴⁴, R ⁴⁵, R ⁴⁶, R ⁴⁷, R ⁴⁸, R ⁴⁹, R ⁵⁰, R ⁵¹, R ⁵², R ⁵³, R ⁵⁴, R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸, R ⁵⁹, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶And R ⁶⁷Independently be selected from is hydrogen, halogen, haloalkyl, nitro, cyanic acid, OR ⁶⁸, NR ⁶⁹R ⁷⁰, CO ₂R ⁷¹,-C (O) NR ⁷²R ⁷³, SO ₂R ⁷⁴, S (O) ₂NR ⁷⁵R ⁷⁶, NR ⁷⁷S (O) ₂R ⁷⁸, NR ⁷⁹C (O) R ⁸⁰, NR ⁸¹CO ₂R ⁸²,-CO (CH ₂) _rR ⁸³,-CONH (CH ₂) _rR ⁸⁴, SR ⁸⁵, SOR ⁸⁶, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, aralkyl, substituted aralkyl, Heterocyclylalkyl or substituted Heterocyclylalkyl; R is 0-4;

The present invention also provides the preparation method of structure suc as formula compound shown in the XVIII, and substrate structure suc as formula the substituted heterocycle generation substitution reaction shown in the formula IVD, makes said compound suc as formula the compound shown in the XVI and structure.

Formula XVI formula IVD

The present invention also provides structure suc as formula the compound shown in the XIX or its pharmacy acceptable salt,

Formula XIX

A is selected from following group:

The present invention also provides the preparation method of structure suc as formula compound shown in the XIX, and substrate structure suc as formula the substituted heterocycle generation substitution reaction shown in the IVD, makes said compound suc as formula the compound shown in the X and structure.

Formula X formula IVD

As preferably, said condensing agent comprises N, N '-NSC 57182, N; N '-DIC, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 2-chloro-4,6-dimethoxy-1,3; 5-triazine, 2; 4-two chloro-6-methoxyl group-1.3.5-triazines, 1,1 '-carbonyl dimidazoles and I-hydroxybenzotriazole, be preferably EDCI and HOBt.

As preferably, said acid binding agent comprises salt of wormwood, yellow soda ash, sodium hydrogencarbonate, sodium hydroxide, Pottasium Hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium ethylate, triethylamine, diethylammonium Isopropylamine, is preferably potassium tert.-butoxide.

In reaction, the structure of acid binding agent itself is more stable, can not cause detrimentally affect to reactant and reaction solution, adds the acid that acid binding agent produces in can complex reaction, reduces the destruction of acid to product, and reaction forward is carried out, and improves yield.

As preferably, said temperature of reaction is 30-80 ℃, is preferably 25-50 ℃.

As preferably, the said reaction times is 5-16h, is preferably 8-12h.

Structure forms the combinatorial libraries with formula IV structural compounds suc as formula the phenol fragment and the reaction of various substituted heterocycle of compound shown in the VI.

Combinatorial libraries refers to all compounds that in the compound of multidimensional array, formed by the compound reaction in each compound of unidimensional and other each dimension.In context of the present invention, said array is two dimension and pyridonecarboxylic acid classes that one-dimensional representation the present invention is all or pyridone phenol fragment and all amine or the halogenated heterocyclics of second dimension expression the present invention.Each pyridonecarboxylic acid class or pyridone phenol fragment can be reacted to form suc as formula the pyridinone compounds shown in the I with each amine or halogenated heterocyclic.All pyridinone compounds that form with this method are in the scope of the invention.

Wherein, X is selected from C or N; B is selected from O, S or NH; R ¹Be selected from hydrogen or halogen; R ²Be selected from hydrogen or OR ⁷N is 0-2; M is 0-2;

R ⁷Be selected from hydrogen, alkyl, substituted alkyl, allyl group or substituted allyl; R ³Be selected from hydroxyl, alkoxyl group ,-NR ¹⁰R ¹¹Or-N (CH ₂) _p(R ¹²) (CH ₂) _pR ¹³P is 0-2;

R ¹⁰And R ¹¹Independently be selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical or R ¹⁰And R ¹¹Form a heterocyclic radical altogether;

A is selected from following figure:

R ¹⁶, R ¹⁷, R ¹⁸, R ²⁶, R ²⁷, R ²⁹, R ³⁰, R ³¹And R ³²Independently be selected from hydrogen, halogen, nitro, cyanic acid, OR ⁶⁸, NR ⁶⁹R ⁷⁰, CO ₂R ⁷¹,-C (O) NR ⁷²R ⁷³, NR ⁷⁹C (O) R ⁸⁰, NR ⁸¹CO ₂R ⁸²,-CO (CH ₂) _rR ⁸³,-CONH (CH ₂) _rR ⁸⁴, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical;

R ⁶⁸, R ⁶⁹, R ⁷⁰, R ⁷¹, R ⁷², R ⁷³, R ⁷⁹, R ⁸⁰, R ⁸¹, R ⁸², R ⁸³, R ⁸⁴, R ⁸⁵And R ⁸⁶Independently be selected from hydrogen, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical;

R is 0-4; Z is N or CR ⁸⁹

R ⁸⁹Independently be selected from hydrogen, alkyl, substituted alkyl, naphthenic base, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical.

The present invention also provides the isomer of above-mentioned each compound, pharmaceutically acceptable Equivalent or pharmacy acceptable salt.

The present invention also provides above-mentioned each compound in the application as Tyrosylprotein kinase and/or serine-threonine kinase suppressor factor.

The present invention also provides above-mentioned each compound to be used for treating the purposes of the medicine of Mammals or human protein kinase relative disease in preparation.

As preferably, said protein kinase related disorder is selected from the relevant disease of receptor tyrosine kinase, disease or the relevant disease of serine-threonine kinase that nonreceptor tyrosine kinase is relevant.

As preferably, said protein kinase related disorder is selected from pHGF, the disease that vascular endothelial growth factor receptor is relevant, the disease that EGF-R ELISA is relevant, relevant disease or the relevant disease of tire liver kinases of disease, IGF-1 that platelet derived growth factor receptor is relevant.

As preferably, said protein kinase related disorder is selected from squamous cell carcinoma, stellate cell cancer, Kaposi, spongioblast cancer, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, mammary cancer, neurospongioma, colorectal carcinoma, liver cancer, kidney, genitourinary cancer, carcinoma of the pancreas or gastrointestinal cancer.

As preferably, said protein kinase related disorder is selected from mellitus, excess proliferative disease, blood vessel generation, inflammatory diseases, immunological disease or cardiovascular disorder.

The present invention also provides a kind of medicinal compsns that is used for treating the organism protein kinase related disorder, comprises above-mentioned each compound provided by the invention and pharmaceutically acceptable carrier or vehicle.

Pharmacy acceptable salt representes to keep those salt of the biological effectiveness and the character of parent compound.This type salt comprises: (1) and sour salify; Free alkali through parent compound and mineral acid or organic acid reaction get; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., and organic acid comprises acetate, propionic acid, vinylformic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, Hydrocerol A, lactic acid, racemic melic acid, succsinic acid or propanedioic acid etc.(2) salt that is present in that acid proton in the parent compound is replaced by metals ion or is generated with the organic bases ligand compound; The metal example is alkalimetal ion, alkaline earth metal ion or aluminum ion for example, and organic bases is thanomin, diethylolamine, trolamine, Trometamol, N-NMG etc. for example.

Medicinal compsns refers to one or more compounds or their pharmacy acceptable salt and prodrug and other chemical ingredients, comprises the mixture of pharmaceutically acceptable carrier and vehicle.The purpose of medicinal compsns is to promote the administration of compound to organism.

Pharmaceutically acceptable carrier refers to organism is not caused tangible pungency and do not disturb the carrier or the thinner of the biological activity and the character of the compound that gives.

Vehicle refers to and joins in the medicinal compsns with the further convenient nonreactant that gives compound.Vehicle comprises lime carbonate, calcium phosphate, various saccharides and polytype starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol.

The compounds of this invention comprises in the purposes that preparation is used for treating in the medicine of organism protein kinase related disorder: the disease that the preferred autoreceptor Tyrosylprotein kinase of protein kinase related disorder is relevant, disease or the relevant disease of serine-threonine kinase that nonreceptor tyrosine kinase is relevant; Said protein kinase related disorder or the disease of preferably being correlated with, disease or the relevant disease of tire liver kinases that disease, IGF-1 that platelet derived growth factor receptor is relevant are relevant from the relevant disease of vascular endothelial growth factor receptor, EGF-R ELISA; Said protein kinase related disorder is perhaps preferably from squamous cell carcinoma, stellate cell cancer, Kaposi, spongioblast cancer, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, mammary cancer, neurospongioma, colorectal carcinoma, liver cancer, kidney, genitourinary cancer, carcinoma of the pancreas or gastrointestinal cancer; Said protein kinase related disorder is perhaps preferably from mellitus, excess proliferative disease, blood vessel generation, inflammatory diseases, immunological disease or cardiovascular disorder; Said organism is Mammals or people; And a kind of medicinal compsns that is used for treating the organism protein kinase related disorder, it comprises The compounds of this invention or salt and pharmaceutically acceptable carrier or vehicle.

In order to check the exposure level of compound provided by the invention, adopt biochemical horizontal enzymic activity test, the test of cell levels enzymic activity, inhibition tumor cell proliferation active testing to confirm activity and the exposure level of all cpds of the present invention to one or more PK for protein kinase.Use the method for knowing in the technology, all test like the design class in the same way for any kinases.

In the horizontal enzymic activity test of biochemistry; Utilize the activity of HTRF technology for detection Tyrosylprotein kinase; HTRF is a kind of time resolved fluorescence resonance ability transfer techniques; Can carry out according to known specification sheets or literature method, referring to Kolb etc., " Tyrosine kinase assays adapted to homogenous time-resolved fluorescence " .Drug Discovery Today magazine .3 volume: pp 333-342.HTRF (homogeneous phase time discrimination fluorescence) is a kind of the most frequently used method that is used for detecting determinand in the homogeneous system; This technology has combined FRET (FRET) and TIME RESOLVED TECHNIQUE (TR), has been widely used in the different steps based on the medicament research and development of cell experiment and biochemical test.Measuring principle according to the HTRF method; With pure enzyme Met after biotinylated substrate and ATP incubation reaction; Add the XL-665 of avidin mark and the antibody of the Eu mark of identification substrate phosphorylation; After substrate is by the Met phosphorylation; The antibody of Eu mark promptly can be discerned this phosphorylation product; The FRET of differentiating with the XL665 formation time of avidin mark (FRET), and not by the substrate of phosphorylation because can not times antibody recognition and can't form the FRET signal, measure determinand inhibition activity to Tyrosylprotein kinases such as c-Met, Flt-3, VEGFR-2, PDGFR-β, c-Kit under different concns through the fluorescent signal difference of measuring 665nm and 620nm.Thereby, adopt this method can measure the active function of The compounds of this invention to the biochemical level of above-mentioned Tyrosylprotein kinase, utilize method well known in the art simultaneously, can use similar measuring method to other protein kinase.

In the test of cell levels enzymic activity, enzyme-linked immunosorbent assay (ELISA) can be used for checking and measuring the existence of tyrosine kinase activity.ELISA can carry out in accordance with known methods, Voller etc. for example, 1980; " enzyme-linked immunosorbent assay " (Enzyme-Linkd Immunosorbent Assay); See " (clinical immunology handbook (Manual of Clinical Immunology), the 2nd edition, pp 359-371 that Rose and Friedman write; AAM publishes, the Washington D.C..The phosphorylation reaction of the peptide substrate of tyrosine-kinase enzyme catalysis ATP such as c-Met, Flt-3, VEGFR-2, PDGFR-β, c-Kit and vitamin H mark mark, inhibitory enzyme activity will suppress this reaction.According to ELISA method measuring principle, will resist the Met antibody sandwich on solid phase carrier, grasp the Met total protein in the cell pyrolysis liquid; Then with the part that phosphorylation takes place in the anti-tyrosine phosphorylation antibody labeling Met albumen; Add the antibody of horseradish peroxidase (HRP) mark, make it and anti-tyrosine phosphorylation antibodies; The substrate TMB colour developing that adds HRP at last.Absorbancy through measuring 450nmol/L absorbing wavelength place detects Met acceptor autophosphorylation level in the cell, thereby it is active to measure determinand inhibition to Tyrosylprotein kinases such as c-Met, Flt-3, VEGFR-2, PDGFR-β, c-Kit under different concns.Thereby, adopt this method can measure the active function of The compounds of this invention to above-mentioned Tyrosylprotein kinase cell levels, utilize method well known in the art simultaneously, can use similar measuring method to other protein kinase.

In suppressing the tumor cell proliferation active testing, measure by routine and adopt blue (MTT) method of bromination tetrazole.Succinodehydrogenase in the viable cell plastosome can make exogenous xanchromatic bromination 3-(4; 5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole (MTT) is reduced to the bluish voilet crystallisate Jia Za (Formazan) of insoluble, and is deposited in the cell; And dead cell does not have this function; Purple crystal thing first Za in DMSO 99.8MIN. (DMSO) the ability dissolved cell is measured its absorbance value with enzyme-linked immunosorbent assay instrument in the 570nm wavelength, can reflect viable cell quantity indirectly.Thereby first Za growing amount is directly proportional with viable count under normal conditions, can infer the number that viable cell according to the OD value, understands that medicine suppresses or the ability of killer cell.This measuring method can be used to measure the inhibition ability of different The compounds of this invention to one or more cancer cell multiplications, utilizes method well known in the art, can use similar measuring method to any cancer cells.

The structure compound shown by formula I of the present invention's preparation has the good restraining effect to multiple kinase activity, and it is to c-Met kinases half-inhibition concentration (IC ₅₀) generally 10 ^-6Below the mol/L.Simultaneously, the compound with formula I structure for preparing in the embodiment of the invention is inhibited to the propagation of kinds of tumor cells, and wherein the effect of majority of compounds inhibition tumor cell proliferation is remarkable, its IC ₅₀Below 10-5mol/L.Have this to know by inference, the compound that the present invention has formula I structure can be applicable to prepare the medicine of treating protein kinase related disorder in the organism.

Embodiment

The invention discloses midbody of a kind of compound and preparation method thereof, this compound and preparation method thereof; And this compound is as the application of Tyrosylprotein kinase and/or serine-threonine kinase suppressor factor; Those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as and are included in the present invention.Method of the present invention and application are described through preferred embodiment; The related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use technology of the present invention.

Below in conjunction with embodiment, further set forth the present invention:

Embodiment 1: preparation compound 67

Take by weighing 1.27g and be about the compound S 1 of 10mmol, 1.71g is about the benzyl bromine of 10mmol, and 1.38g is about the salt of wormwood of 10mmol; Place the 250mL reaction flask, add 100mL DMF, stirred overnight at room temperature; Concentrate yellow solid; Carry out wash-out with petroleum ether-ethyl acetate according to the gradient of 0-25%, obtain 1.85g yellow oily compound S 2, productive rate 85%.

Take by weighing 1.09g and be about the compound S 2 of 5mmol, 0.77g is about the compound S 3 of 5mmol, and the DMAP that 0.61g is about 5mmol places the 250mL reaction flask; Add 100mL ethanol; 90 ℃ of stirring reaction 2h, concentrate yellow solid, carry out wash-out with petroleum ether-ethyl acetate according to 0%～45% Russia's gradient; Obtain 1.41g yellow solid compound S 4, productive rate 80%.

Take by weighing 1.41g and be about the compound S 4 of 4mmol, 0.42g is about the Pd-C of 4mmol, in the atmosphere of hydrogen; Stirring at room, reaction is spent the night, concentrate yellow solid; Carry out wash-out with petroleum ether-ethyl acetate according to 0%～50% gradient, obtain 0.95 yellow solid compound S 5, productive rate 90%.

Take by weighing 0.79g and be about the compound S 5 of 3mmol, 0.57g is about 3 of 3mmol, 4-two chloro-2-picolinamides; 0.34g be about the potassium tert.-butoxide of 3mmol, place the 100mL reaction flask, add 40mLDMF; Stirred overnight at room temperature, concentrate yellow solid, with methyl alcohol-methylene dichloride according to 0%～5% gradient elution; Obtain 1.06g yellow solid compound s 6, productive rate 85%.

Take by weighing 0.84g and be about the compound s 6 of 2mmol, 0.08g is about the sodium hydroxide of 2mmol, water 20mL; 90 ℃ of stirring reaction 5h are neutralized to 7 with reacting liquid pH value, suction filtration with the HCl of 3mol/L; The dry 0.72g yellow solid compound that gets, promptly compound 67, productive rate 89%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：12.1(s，1H)，8.43(d，1H)，7.88(m，2H)，7.76(s，1H)，7.68(m，2H)，6.96(d，1H)，6.64(d，1H)。

MS(ESI)：403.8[M+H] ⁺。

Embodiment 2: preparation compound 68

Take by weighing 1.74g and be about the compound S 7 of 10mmol, 1.19g is about the DMF-DMA of 10mmol, places the 250mL reaction flask; Add 100mL DMF; 90 ℃ of stirring reaction 2h, concentrate yellow solid, with the gradient elution of petroleum ether-ethyl acetate according to 0-15%; Obtain 2.06g yellow solid compound S 8, productive rate 90%.

Take by weighing 2.06g and be about the compound S 8 of 9mmol, 1.95g is about the compound S 2 of 9mmol, and 1.10g is about the DMAP of 9mmol; Place the 250mL reaction flask, add 100mL ethanol, 90 ℃ of stirring reaction 2h; Concentrate yellow solid; With the gradient elution of petroleum ether-ethyl acetate, obtain 2.82g yellow solid compound S 9, productive rate 85% according to 0-45%.

Take by weighing 1.84g and be about the compound S 9 of 5mmol, 1.42g is about the methyl iodide of 10mmol, and 0.69g is about the salt of wormwood of 5mmol; Place the 250mL reaction flask, add the 100mL acetonitrile, 80 ℃ of stirring reaction 2h; Concentrate yellow solid; According to 0%～25% gradient elution, obtain 1.65g yellow solid compound S 10, productive rate 86% with petroleum ether-ethyl acetate.

Take by weighing 1.53g and be about the compound S 10 of 4mmol, 0.42g is about the Pd-C of 4mmol, in the atmosphere of hydrogen; Stirring at room, reaction is spent the night, concentrate yellow solid; According to 0%～50% gradient elution, obtain 1.05 yellow solid compound Ss 11, productive rate 89% with petroleum ether-ethyl acetate.

Take by weighing 0.88g and be about the compound S 11 of 3mmol, 0.57g is about 3 of 3mmol, 4-two chloro-2-picolinamides; Place the 100mL reaction flask 0.34g be about the potassium tert.-butoxide of 3mmol, add 40mLDMF, stirred overnight at room temperature; Concentrate yellow solid; According to 0%～5% gradient elution, obtain 1.04g yellow solid compound S 12, productive rate 78% with methyl alcohol-methylene dichloride.

Take by weighing 0.89g and be about the compound S 12 of 2mmol, 0.08g is about the sodium hydroxide of 2mmol, water 20mL, and 90 ℃ of stirring reaction 5h are neutralized to pH=7 with 3mol/L HCl, suction filtration, dry 0.80g yellow solid compound, promptly compound 68, productive rate 92%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：12.5(s，1H)，8.48(d，1H)，8.32(s，1H)，8.07(d，1H)，7.78(s，2H)，7.56(m，1H)，7.45(d，1H)，6.96(s，1H)，1.32(s，1H)。

MS(ESI)：443.8[M+H] ⁺。

Embodiment 3: preparation compound 69

Take by weighing 1.77 be about 5mmol compound S 4,0.2g is about the sodium hydroxide of 5mmol, water 50mL, 90 ℃ of stirring reaction 5h are neutralized to pH=7 with 3mol/L HCl, suction filtration, dry 1.53g yellow solid compound S 13, productive rate 90%.

Take by weighing 1.36 be about 4mmol compound S 13,0.81mg is about the EDCI of 4mmol, 0.55g is about the HOBt of 4mmol; 0.2g be about the DMAP of 1.64mmol, the NSC 158269 that 0.5g is about 4mmol places the 250mL reaction flask, adds 50mL DMF and 50mL methylene dichloride; Stirred overnight at room temperature, concentrate yellow solid, with methyl alcohol-methylene dichloride according to 0%～5% gradient elution; Obtain 1.07g yellow solid compound S 14, productive rate 75%.

Take by weighing 0.89g and be about the compound S 14 of 2mmol, 0.21g is about the Pd-C of 2mmol, in the atmosphere of hydrogen; The stirring at room reaction is spent the night; Concentrate yellow solid, according to 0%～50% gradient elution, obtain 0.64g yellow solid compound with petroleum ether-ethyl acetate; Be compound 69, productive rate 89%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.84(s，1H)，8.34(dd，1H)，7.83(d，1H)，7.75(d，1H)，7.43(m，2H)，7.36(m，3H)，6.57(t，1H)，6.05(d，1H)，5.85(s，1H)，4.34(d，2H)。

MS(ESI)：356.1[M+H] ⁺。

Embodiment 4: preparation compound 70

Take by weighing 1.92 be about 5mmol compound S 10,0.2g is about the sodium hydroxide of 5mmol, water 50mL, 90 ℃ of stirring reaction 5h are neutralized to pH=7 with 3mol/L HCl, suction filtration, dry 1.70g yellow solid compound S 15, productive rate 92%.

Take by weighing 1.48 be about 4mmol compound S 15,0.81mg is about the EDCI of 4mmol, 0.55g is about the HOBt of 4mmol; 0.2g be about the DMAP of 1.64mmol, 0.5g is about the NSC 158269 of 4mmol, places the 250mL reaction flask; Add 50mL DMF and 50mL methylene dichloride, stirred overnight at room temperature, concentrated yellow solid; According to 0%～5% gradient elution, obtain 1.52g yellow solid compound S 16, productive rate 80% with methyl alcohol-methylene dichloride.

Take by weighing 0.95g and be about the compound S 14 of 2mmol, 0.21g is about the Pd-C of 2mmol, in the atmosphere of hydrogen; Stirring at room, reaction is spent the night, concentrate yellow solid; With petroleum ether-ethyl acetate according to 0%～50% Russia's gradient elution; Obtain 0.73 yellow solid compound, promptly compound 70, productive rate 95%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.80(s，1H)，8.34(dd，1H)，7.83(d，1H)，7.72(d，1H)，7.40(m，2H)，7.34(m，3H)，6.52(t，1H)，5.75(s，1H)，4.34(d，2H)，4.24(s，3H)。

MS(ESI)：386.1[M+H] ⁺。

Embodiment 5: preparation compound 1

Take by weighing 450mg and be about the compound 67 of 1.12mmol, 400mg is about the EDCI of 2.09mmol, and 280mg is about the HOBt of 2.09mmol; 100mg is about the DMAP of 0.82mmol, and 130mg is about the NSC 158269 of 1.04mmol, places the 250mL reaction flask; Add 50mL DMF and 50mL methylene dichloride, stirred overnight at room temperature, concentrated yellow solid; According to 0%～5% gradient elution, obtain the 300mg yellow solid, productive rate 57% with methyl alcohol-methylene dichloride.

Yellow solid to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.86(s，1H)，8.42(m，2H)，8.35(m，3H)，7.97(m，2H)，7.84(m，1H)，7.62(m，1H)，7.35(m，3H)，7.18(d，1H，J＝9.0)，6.94(t，1H)，4.43(d，2H)。

MS(ESI)：533[M+Na] ⁺，509[M-H] ^-。

Take by weighing 300mg and be about the above-mentioned yellow solid of 0.59mmol, be dissolved in 50mL ETHYLE ACETATE, 50mL acetonitrile and the 25mL water, be cooled to 0 ℃, add the iodobenzene diacetate that 228mg is about 0.7mmol, be warming up to 25 ℃, reaction 1h.Concentrate, according to 0%～3% gradient elution, obtain the 200mg white-yellowish solid with methyl alcohol-methylene dichloride, promptly compound 1, productive rate 71%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.84(s，1H)，8.34(dd，1H)，7.97(dd，1H)，7.83(d，1H)，7.75(d，1H)，7.43(m，2H)，7.36(m，4H)，6.57(t，1H)，6.48(s，2H)，6.05(d，1H)，4.42(d，2H)。

MS(ESI)：482.7[M+H] ⁺。

Embodiment 6: preparation compound 2

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 144mg yellow solid through two-step reaction, promptly compound 2, productive rate 27%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.85(m，1H)，8.38(s，1H)，8.02(d，1H)，7.82(d，1H)，7.74(d，1H)，7.45(m，2H)，7.36(m，1H)，7.10-7.20(m，3H)，6.57(t，1H)，6.47(s，2H)，6.05(d，1H)，4.46(d，2H)。

MS(ESI)：482.7[M+H] ⁺。

Embodiment 7: preparation compound 3

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 212mg yellow solid through two-step reaction, promptly compound 3, productive rate 36%.

Product to making is tested, and the result is following:

MS(ESI)：532.1[M+H] ⁺。

Embodiment 8: preparation compound 4

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 203mg yellow solid through two-step reaction, promptly compound 4, productive rate 36%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.85(s，1H)，8.34(dd，1H)，7.97(dd，1H)，7.82(d，1H)，7.73(d，1H)，7.40(m，2H)，7.35(m，4H)，6.57(t，1H)，6.46(s，2H)，6.07(d，1H)，4.43(d，2H)。

MS(ESI)：498.1[M+H] ⁺。

Embodiment 9: preparation compound 5

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 182mg yellow solid through two-step reaction, promptly compound 5, productive rate 38%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.79(s，1H)，8.36(dd，1H)，7.97(dd，1H)，7.82(d，1H)，7.73(d，1H)，7.36(m，2H)，7.17(m，4H)，6.57(t，1H)，6.46(s，2H)，6.05(d，1H)，4.47(d，2H)。

MS(ESI)：482.7[M+H] ⁺。

Embodiment 10: preparation compound 6

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 130mg yellow solid through two-step reaction, promptly compound 6, productive rate 24%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.74(s，1H)，8.33(dd，1H)，7.97(dd，1H)，7.82(d，1H)，7.72(d，1H)，7.43(m，2H)，7.23(d，2H)，6.89(m，2H)，6.58(t，1H)，6.46(s，2H)，6.04(d，1H)，4.37(d，2H)，3.72(s，3H)。

MS(ESI)：494.1[M+H] ⁺。

Embodiment 11: preparation compound 7

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 304mg yellow solid through two-step reaction, promptly compound 7, productive rate 55%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.89(s，1H)，8.36(dd，1H)，7.96(dd，1H)，7.82(d，1H)，7.73(m，2H)，7.35(m，6H)，6.89(m，2H)，6.53(t，1H)，6.46(s，2H)，6.05(d，1H)，4.44(d，2H)。

MS(ESI)：498.1[M+H] ⁺。

Embodiment 12: preparation compound 8

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 119mg yellow solid through two-step reaction, promptly compound 8, productive rate 22%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.93(s，1H)，8.36(dd，1H)，7.97(dd，1H)，7.80(m，4H)，7.50(m，4H)，6.58(t，1H)，6.23(s，2H)，5.86(d，1H)，4.51(d，2H)。

MS(ESI)：489.1[M+H] ⁺。

Embodiment 13: preparation compound 9

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 174mg yellow solid through two-step reaction, promptly compound 9, productive rate 35%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.82(s，1H)，8.36(dd，1H)，7.97(dd，1H)，7.82(d，1H)，7.75(d，1H)，7.32(m，2H)，7.26(m，4H)，6.57(t，1H)，6.47(s，2H)，6.04(d，1H)，4.45(d，2H)。

MS(ESI)：446.1[M+H] ⁺。

Embodiment 14: preparation compound 10

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 223mg yellow solid through two-step reaction, promptly compound 10, productive rate 37%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.97(s，1H)，8.36(dd，1H)，7.96(dd，1H)，7.83(d，1H)，7.75(d，1H)，7.59(m，4H)，7.44(m，2H)，6.59(t，1H)，6.48(s，2H)，6.06(d，1H)，4.52(d，2H)。

MS(ESI)：532.1[M+H] ⁺。

Embodiment 15: preparation compound 11

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 199mg yellow solid through two-step reaction, promptly compound 11, productive rate 33%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.92(s，1H)，8.40(dd，1H)，7.97(dd，1H)，7.81(d，1H)，7.76(d，1H)，7.68(m，3H)，7.44(m，3H)，6.58(t，1H)，6.46(s，2H)，6.05(d，1H)，4.62(d，2H)。

MS(ESI)：532.1[M+H] ⁺。

Embodiment 16: preparation compound 12

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 135mg yellow solid through two-step reaction, promptly compound 12, productive rate 25%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.65(s，1H)，8.36(dd，1H)，7.97(dd，1H)，7.82(d，1H)，7.74(d，1H)，7.45(m，2H)，7.25(m，2H)，6.92(m，2H)，6.57(t，1H)，6.46(s，2H)，6.05(d，1H)，4.41(d，2H)，3.81(s，3H)。

MS(ESI)：494.1[M+H] ⁺。

Embodiment 17: preparation compound 13

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 222mg yellow solid through two-step reaction, promptly compound 13, productive rate 42%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.66(s，1H)，8.38(dd，1H)，7.95(dd，1H)，7.82(d，1H)，7.72(d，1H)，7.46(m，2H)，7.25(m，1H)，7.14(m，3H)，6.58(t，1H)，6.45(s，2H)，6.06(d，1H)，4.42(d，2H)，2.30(s，3H)。

MS(ESI)：478.1[M+H] ⁺。

Embodiment 18: preparation compound 14

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 298mg yellow solid through two-step reaction, promptly compound 14, productive rate 54%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.89(s，1H)，8.50(dd，1H)，7.97(dd，1H)，7.70(m，3H)，7.26(m，6H)，6.55(t，1H)，6.43(s，2H)，6.07(d，1H)，4.52(d，2H)。

MS(ESI)：498.1[M+H] ⁺。

Embodiment 19: preparation compound 15

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 217mg yellow solid, i.e. compound 16 productive rates 41% through two-step reaction.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：11.9(s，1H)，8.80(s，1H)，8.38(dd，1H)，7.95(dd，1H)，7.80(d，1H)，7.46(m，4H)，7.14(m，3H)，6.55(t，1H)，6.43(s，2H)，6.05(d，1H)，4.38(d，2H)，2.35(s，3H)。

MS(ESI)：478.1[M+H] ⁺。

Embodiment 20: preparation compound 16

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 223mg yellow solid through two-step reaction, promptly compound 16, productive rate 37%.

Product to making is tested, and the result is following:

MS(ESI)：532.1[M+H] ⁺。

Embodiment 21: preparation compound 17

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 136mg yellow solid through two-step reaction, promptly compound 17, productive rate 23%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.82(s，1H)，8.32(dd，1H)，7.96(dd，1H)，7.85(d，1H)，7.55(m，2H)，7.45(m，2H)，7.24(m，2H)，7.15(m，2H)，6.57(t，1H)，6.45(s，2H)，6.25(d，1H)，6.12(m，2H)，5.85(d，1H)，4.45(d，2H)。

MS(ESI)：464.1[M+H] ⁺。

Embodiment 22: preparation compound 18

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 207mg yellow solid through two-step reaction, promptly compound 18, productive rate 43%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.28(m，1H)，7.95(d，1H)，7.82(d，1H)，7.60(d，1H)，7.45(m，2H)，6.55(m，3H)，6.03(d，1H)，3.02(t，2H)，1.75(m，1H)，0.85(d，6H)。

MS(ESI)：430.1[M+H] ⁺。

Embodiment 23: preparation compound 19

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 140mg yellow solid through two-step reaction, promptly compound 19, productive rate 29%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.32(m，1H)，7.95(d，1H)，7.85(d，1H)，7.75(d，1H)，7.65(d，1H)，7.38(m，2H)，6.52(m，3H)，6.05(d，1H)，4.02(m，1H)，1.35(d，9H)。

MS(ESI)：430.1[M+H] ⁺。

Embodiment 24: preparation compound 20

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 114mg yellow solid through two-step reaction, promptly compound 20, productive rate 24%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：12.45(b，1H)，8.30(m，1H)，7.96(d，1H)，7.82(d，1H)，7.74(d，1H)，7.60(d，1H)，7.45(m，2H)，6.55(m，3H)，6.03(d，1H)，4.02(m，1H)，1.18(d，9H)。

MS(ESI)：416.8[M+H] ⁺。

Embodiment 25: preparation compound 21

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 172mg yellow solid through two-step reaction, promptly compound 21, productive rate 36%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.80(d，1H)，8.35(d，1H)，7.92(d，1H)，7.85(d，1H)，7.74(d，1H)，7.70(d，1H)，7.45(m，2H)，6.60(d，1H)，6.45(s，2H)，6.03(m，1H)，3.50(m，2H)，2.75(t，2H)。

MS(ESI)：427.1[M+H] ⁺。

Embodiment 26: preparation compound 22

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 102mg yellow solid through two-step reaction, promptly compound 22, productive rate 22%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：9.10(d，1H)，8.39(d，1H)，7.91(d，1H)，7.80(m，2H)，7.70(d，1H)，7.49(m，2H)，6.60(d，1H)，6.50(s，2H)，6.30(d，1H)，6.13(m，2H)，5.90(d，1H)，4.35(d，2H)。

MS(ESI)：413.1[M+H] ⁺。

Embodiment 27: preparation compound 23

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 142mg yellow solid through two-step reaction, promptly compound 23, productive rate 24%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：7.96(dd，1H)，7.81(d，1H)，7.65(m，2H)，7.43(m，4H)，7.20(m，2H)，6.62(t，1H)，6.48(s，2H)，6.05(d，1H)，4.75(s，2H)，4.45(s，2H)。

MS(ESI)：521.1[M+H] ⁺。

Embodiment 28: preparation compound 24

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 173mg yellow solid through two-step reaction, promptly compound 24, productive rate 32%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：7.82(m，2H)，7.74(d，1H)，7.58(d，1H)，7.23(m，6H)，6.68(d，2H)，6.15(m，1H)，5.52(s，2H)，3.85(s，2H)，3.00(t，2H)，1.25(t，2H)。

MS(ESI)：490.1[M+H] ⁺。

Embodiment 29: preparation compound 25

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 230mg yellow solid through two-step reaction, promptly compound 25, productive rate 45%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.70(s，1H)，8.39(dd，1H)，7.95(dd，1H)，7.82(d，1H)，7.75(d，1H)，7.55(m，1H)，7.45(m，2H)，6.59(d，1H)，6.50(s，2H)，6.36(d，1H)，6.30(d，1H)，6.05(d，1H)，4.42(d，2H)。

MS(ESI)：454.8[M+H] ⁺。

Embodiment 30: preparation compound 26

Take by weighing 356mg and be about the compound 68 of 1.0mmol, 282mg is about the 4-chloro-3-iodo-2-picolinamide of 1.0mmol, and 112mg is about the potassium tert.-butoxide of 1.0mmol; Place the 100mL reaction flask, add 40mL DMF, stirred overnight at room temperature; Concentrate yellow solid; According to 0%～5% gradient elution, obtain the 373mg yellow solid, productive rate 62% with methyl alcohol-methylene dichloride.

Take by weighing 300mg and be about the above-mentioned yellow solid of 0.50mmol, be dissolved in 50mL ETHYLE ACETATE, 50mL acetonitrile and the 25mL water, be cooled to 0 ℃, add 228mg and be about 0.7mmol and starve iodobenzene diacetate, be warming up to 25 ℃, reaction 1h.Concentrate, according to 0%～3% gradient elution, obtain the 205mg yellow solid with methyl alcohol-methylene dichloride, that is, and compound 26, productive rate 71%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.85(m，1H)，8.35(s，1H)，7.95(d，1H)，7.78(d，1H)，7.75(d，1H)，7.36(m，4H)，7.15(m，2H)，6.55(d，1H)，6.25(s，2H)，5.90(d，1H)，4.42(d，2H)。

MS(ESI)：574.0[M+H] ⁺。

Embodiment 31: preparation compound 27

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 291mg yellow solid through two-step reaction, promptly compound 27, productive rate 55%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.82(t，1H)，8.34(d，1H)，7.97(d，1H)，7.85(d，1H)，7.74(d，1H)，7.36(m，4H)，7.15(t，2H)，6.65(d，1H)，6.35(s，2H)，5.93(d，1H)，4.42(d，2H)。

MS(ESI)：472.1[M+H] ⁺。

Embodiment 32: preparation compound 28

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 264mg yellow solid through two-step reaction, promptly compound 28, productive rate 47%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.83(t，1H)，8.34(d，1H)，7.96(d，1H)，7.83(d，1H)，7.70(d，1H)，7.41(m，4H)，7.15(t，2H)，6.58(d，1H)，6.37(s，2H)，5.91(d，1H)，5.25(t，1H)4.42(d，2H)，4.35(d，2H)。

MS(ESI)：502.1[M+H] ⁺。

Embodiment 33: preparation compound 29

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 249mg yellow solid through two-step reaction, promptly compound 29, productive rate 42%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.86(t，1H)，8.28(d，1H)，7.94(d，1H)，7.83(d，1H)，7.65(d，1H)，7.35(m，4H)，7.10(t，2H)，6.58(d，1H)，6.52(d，1H)，6.05(d，1H)，4.40(d，2H)，3.50(s，2H)，2.20(s，6H)。

MS(ESI)：529.2[M+H] ⁺。

Embodiment 34: preparation compound 30

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 296mg yellow solid through two-step reaction, promptly compound 30, productive rate 56%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：11.85(s，1H)，8.78(t，1H)，8.38(d，1H)，8.15(d，1H)，7.94(d，1H)，7.75(d，1H)，7.35(m，4H)，7.15(t，2H)，6.57(d，1H)，6.45(d，1H)，6.30(d，1H)，4.42(d，2H)。

MS(ESI)：472.1[M+H] ⁺。

Embodiment 35: preparation compound 31

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 349mg yellow solid through two-step reaction, promptly compound 31, productive rate 62%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：11.80(b，1H)，8.90(t，1H)，8.36(d，1H)，8.08(d，1H)，7.95(d，1H)，7.75(d，1H)，7.40(m，4H)，7.15(m，3H)，6.56(d，1H)，6.45(d，1H)，6.15(d，1H)，5.55(b，1H)，4.55(d，2H)，4.42(d，2H)。

MS(ESI)：502.2[M+H] ⁺。

Embodiment 36: preparation compound 32

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 237mg yellow solid through two-step reaction, promptly compound 32, productive rate 40%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：11.82(b，1H)，8.92(t，1H)，8.32(d，1H)，8.05(d，1H)，7.93(d，1H)，7.65(d，1H)，7.40(m，4H)，7.16(t，2H)，6.58(d，1H)，6.42(d，1H)，6.15(d，1H)，4.45(d，2H)，3.55(s，2H)，2.20(s，6H)。

MS(ESI)：529.2[M+H] ⁺。

Embodiment 37: preparation compound 33

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 320mg yellow solid through two-step reaction, promptly compound 33, productive rate 50%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：11.80(b，1H)，8.90(t，1H)，8.35(d，1H)，8.04(d，1H)，7.95(d，1H)，7.75(d，1H)，7.40(m，4H)，7.14(t，2H)，6.58(d，1H)，6.45(d，1H)，6.20(d，1H)，4.40(d，2H)，3.65(t，4H)，2.58(t，4H)。

MS(ESI)：571.2[M+H] ⁺。

Embodiment 38: preparation compound 34

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 331mg yellow solid through two-step reaction, promptly compound 34, productive rate 52%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：11.75(b，1H)，9.20(t，1H)，8.40(d，1H)，8.02(d，1H)，7.99(d，1H)，7.75(d，1H)，7.42(m，4H)，7.12(t，2H)，6.56(d，1H)，6.40(d，1H)，6.16(d，1H)，4.40(d，2H)，3.55(m，2H)，3.35(m，4H)，2.58(m，4H)。

MS(ESI)：569.2[M+H] ⁺。

Embodiment 39: preparation compound 35

Take by weighing 450mg and be about the compound 67 of 1.12mmol,, obtain 357mg yellow solid I-35, productive rate 65% through two-step reaction according to the method for embodiment 5.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：10.30(s，1H)，8.84(m，2H)，8.65(d，1H)，8.45(d，1H)，8.30(d，1H)，7.95(m，2H)，7.75(t，2H)，7.55(d，1H)，7.35(m，4H)，7.15(m，6H)，6.65(d，1H)，6.50(d，2H)，4.50(d，2H)。

MS(ESI)：490.1[M+H] ⁺。

Embodiment 40: preparation compound 36

Take by weighing 450mg and be about the compound 67 of 1.12mmol,, obtain 372mg yellow solid I-36, productive rate 68% through two-step reaction according to the method for embodiment 5.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.85(t，1H)，8.60(d，1H)，8.35(d，1H)，8.22(d，1H)，8.00(d，1H)，7.85(d，1H)，7.68(m，2H)，7.49(m，1H)，7.35(m，2H)，7.15(t，2H)，6.75(d，1H)，6.55(d，2H)，4.40(d，2H)。

MS(ESI)：489.1[M+H] ⁺。

Embodiment 41: preparation compound 37

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 366mg yellow solid through two-step reaction, promptly compound 37, productive rate 60%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.89(t，1H)，8.56(d，1H)，8.38(d，1H)，8.00(d，1H)，7.75(m，3H)，7.60(s，1H)，7.49(m，2H)，7.35(m，2H)，7.15(m，2H)，6.50(d，1H)，4.50(d，2H)，4.00(s，6H)。

MS(ESI)：545.2[M+H] ⁺。

Embodiment 42: preparation compound 38

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 403mg yellow solid through two-step reaction, promptly compound 38, productive rate 58%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.60(d，1H)，8.18(m，1H)，7.72(m，2H)，7.65(s，1H)，7.45(m，10H)，7.08(t，2H)，6.65(d，1H)，6.15(t，1H)，5.30(d，2H)，4.60(d，2H)，4.05(s，3H)。

MS(ESI)：620.2[M+H] ⁺。

Embodiment 43: preparation compound 39

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 515mg yellow solid through two-step reaction, promptly compound 39, productive rate 70%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.86(t，1H)，8.60(d，1H)，8.45(d，1H)，8.00(d，1H)，7.75(m，2H)，7.60(s，1H)，7.50(d，1H)，7.45(s，1H)，7.35(m，2H)，7.16(t，2H)，6.55(d，1H)，4.60(d，2H)，4.25(t，2H)，4.05(s，3H)，3.60(t，4H)，2.52(m，2H)，2.45(m，4H)，2.00(m，2H)。

MS(ESI)：657.2[M+H] ⁺。

Embodiment 44: preparation compound 40

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 339mg yellow solid through two-step reaction, promptly compound 40, productive rate 65%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.80(t，1H)，8.60(s，1H)，8.50(s，1H)，8.00(dd，1H)，7.83(m，2H)，7.75(d，1H)，7.43(m，2H)，7.35(t，2H)，7.15(t，2H)，6.58(t，1H)，6.50(s，2H)，6.15(d，1H)，4.42(d，2H)。

MS(ESI)：465.1[M+H] ⁺。

Embodiment 45: preparation compound 41

Take by weighing 485mg and be about the compound 68 of 1.12mmol, 400mg is about the EDCI of 2.09mmol, and 280mg is about the HOBt of 2.09mmol; 100mg is about the DMAP of 0.82mmol, and 130mg is about the NSC 158269 of 1.04mmol, places the 250mL reaction flask; Add 50mL DMF and 50mL methylene dichloride, stirred overnight at room temperature, concentrated yellow solid; According to 0%～5% gradient elution, obtain the 393mg yellow solid, productive rate 65% with methyl alcohol-methylene dichloride.

Take by weighing 319mg and be about the above-mentioned yellow solid of 0.59mmol, be dissolved in 50mL ETHYLE ACETATE, 50mL acetonitrile and the 25mL water, be cooled to 0 ℃, add the iodobenzene diacetate that 228mg is about 0.7mmol, be warming up to 25 ℃, reaction 1h.Concentrate, according to 0%～3% gradient elution, obtain the 241mg white-yellowish solid with methyl alcohol-methylene dichloride, promptly compound 41, productive rate 80%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.52(t，1H)，8.11(d，1H)，，7.80(d，1H)，7.65(d，1H)，7.35(m，4H)，7.15(t，2H)，6.57(t，1H)，6.45(s，2H)，6.08(s，1H)，6.00(d，1H)，4.48(d，2H)，3.95(s，3H)。

MS(ESI)：512.1[M+H] ⁺。

Embodiment 46: preparation compound 42

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 343mg yellow solid through two-step reaction, promptly compound 42, productive rate 62%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.50(t，1H)，8.05(d，1H)，7.85(d，1H)，7.49(d，2H)，7.35(m，2H)，7.20(m，2H)，7.15(t，2H)，6.57(t，1H)，6.40(s，2H)，6.12(s，1H)，6.00(d，1H)，4.45(d，2H)，3.95(s，3H)。

MS(ESI)：494.1[M+H] ⁺。

Embodiment 47: preparation compound 43

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 343mg yellow solid through two-step reaction, promptly compound 43, productive rate 62%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.39(t，1H)，8.12(d，1H)，7.80(d，1H)，7.65(d，1H)，7.38(m，4H)，7.14(t，2H)，6.57(t，1H)，6.42(s，2H)，6.08(s，1H)，6.00(d，1H)，4.45(d，2H)，4.18(t，2H)，1.45(q，3H)。

MS(ESI)：526.1[M+H] ⁺。

Embodiment 48: preparation compound 44

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 349mg yellow solid through two-step reaction, promptly compound 44, productive rate 58%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.45(t，1H)，8.10(d，1H)，7.85(d，1H)，7.65(d，1H)，7.40(m，4H)，7.14(t，2H)，6.57(t，1H)，6.52(s，2H)，6.08(m，2H)，6.00(d，1H)，5.40(m，2H)，4.76(m，2H)，4.45(m，2H)。

MS(ESI)：538.1[M+H] ⁺。

Embodiment 49: preparation compound 45

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 386mg yellow solid through two-step reaction, promptly compound 45, productive rate 62%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.41(t，1H)，8.02(d，1H)，7.80(d，1H)，7.35(m，4H)，7.08(t，2H)，6.18(d，1H)，5.98(d，1H)，5.50(b，2H)，4.56(d，2H)，4.20(t，2H)，3.70(t，2H)，3.18(d，3H)。

MS(ESI)：556.1[M+H] ⁺。

Embodiment 50: preparation compound 46

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 352mg yellow solid through two-step reaction, promptly compound 46, productive rate 55%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.55(t，1H)，8.16(d，1H)，7.85(d，1H)，7.65(d，1H)，7.35(m，4H)，7.15(m，2H)，7.08(t，2H)，6.45(m，2H)，6.18(d，1H)，5.98(d，1H)，5.25(d，1H)，4.85(t，2H)，4.45(t，2H)，4.18(t，2H)，3.85(m，2H)，3.48(m，2H)。

MS(ESI)：572.1[M+H] ⁺。

Embodiment 51: preparation compound 47

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 352mg yellow solid through two-step reaction, promptly compound 47, productive rate 55%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.52(t，1H)，8.11(d，1H)，7.76(d，1H)，7.65(d，1H)，7.35(m，4H)，7.15(m，2H)，6.25(s，2H)，6.05(s，1H)，5.95(d，1H)，4.45(d，2H)，3.95(s，3H)。

MS(ESI)：604.0[M+H] ⁺。

Embodiment 52: preparation compound 48

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 435mg yellow solid through two-step reaction, promptly compound 48, productive rate 60%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.41(t，1H)，8.02(d，1H)，7.82(d，1H)，7.30(m，4H)，7.06(t，2H)，6.02(d，1H)，5.95(d，1H)，5.50(b，2H)，4.58(d，2H)，4.20(t，2H)，3.66(t，2H)，3.15(d，3H)。

MS(ESI)：648.1[M+H] ⁺。

Embodiment 53: preparation compound 49

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 393mg yellow solid through two-step reaction, promptly compound 49, productive rate 66%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.52(t，1H)，8.12(d，1H)，7.80(d，1H)，7.65(d，1H)，7.36(m，4H)，7.15(t，2H)，6.58(d，1H)，6.35(s，2H)，6.04(d，1H)，5.92(d，1H)，5.25(t，1H)4.42(d，2H)，4.35(d，2H)，3.95(s，3H)。

MS(ESI)：532.1[M+H] ⁺。

Embodiment 54: preparation compound 50

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 344mg yellow solid through two-step reaction, promptly compound 50, productive rate 55%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.56(t，1H)，8.10(d，1H)，7.85(d，1H)，7.65(d，1H)，7.35(m，4H)，7.15(t，2H)，6.25(s，2H)，6.06(d，1H)，6.00(d，1H)，4.45(d，2H)，4.10(t，2H)，3.50(s，3H)，2.20(s，6H)。

MS(ESI)：559.2[M+H] ⁺。

Embodiment 55: preparation compound 51

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 384mg yellow solid through two-step reaction, promptly compound 51, productive rate 60%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.55(t，1H)，8.30(t，1H)，8.15(m，2H)，7.75(d，1H)，7.65(d，1H)，7.35(m，4H)，7.15(m，3H)，6.55(s，2H)，6.08(s，1H)，6.02(d，1H)，4.46(d，2H)，3.95(s，3H)。

MS(ESI)：572.2[M+H] ⁺。

Embodiment 56: preparation compound 52

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 223mg yellow solid through two-step reaction, promptly compound 52, productive rate 40%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：9.92(t，1H)，8.15(d，1H)，7.80(d，1H)，7.70(m，3H)，7.40(m，2H)，7.20(m，2H)，6.45(s，2H)，6.06(d，2H)，5.95(d，1H)，3.95(s，3H)。

MS(ESI)：498.1[M+H] ⁺。

Embodiment 57: preparation compound 53

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 508mg yellow solid through two-step reaction, promptly compound 53, productive rate 66%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.60(d，1H)，8.55(t，1H)，8.15(d，1H)，7.60(m，3H)，7.50(d，1H)，7.45(m，2H)，7.38(m，2H)，7.16(t，2H)，6.05(d，1H)，4.45(d，2H)，4.25(t，2H)，4.05(s，3H)，3.92(s，3H)，3.60(t，4H)，2.42(m，4H)，2.00(m，2H)。

MS(ESI)：687.2[M+H] ⁺。

Embodiment 58: preparation compound 54

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 337mg yellow solid through two-step reaction, promptly compound 54, productive rate 65%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.65(t，1H)，8.55(d，1H)，8.22(d，1H)，8.15(d，1H)，7.75(d，1H)，7.68(m，2H)，7.45(m，1H)，7.38(m，2H)，7.15(t，2H)，6.75(d，1H)，6.05(d，2H)，4.45(d，2H)，3.95(s，3H)。

MS(ESI)：519.1[M+H] ⁺。

Embodiment 59: preparation compound 55

Take by weighing 450mg and be about the compound 68 of 1.12mmol, according to the method for embodiment 45, obtain the 384mg yellow solid through two-step reaction, promptly compound 55, productive rate 50%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.55(t，1H)，8.15(d，1H)，7.65(m，1H)，7.55(m，1H)，7.52(d，1H)，7.45(m，2H)，7.38(m，2H)，7.13(t，2H)，6.58(d，1H)，6.05(d，1H)，4.45(t，2H)，4.21(s，3H)，3.92(s，3H)，3.60(t，4H)，2.40(m，4H)，2.00(m，2H)。

MS(ESI)：686.3[M+H] ⁺。

Embodiment 60: preparation compound 56

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 331mg yellow solid through two-step reaction, promptly compound 56, productive rate 52%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：11.84(s，1H)，8.34(dd，1H)，7.89(dd，1H)，7.77(dd，1H)，7.51(d，1H)，7.22(m，3H)，7.09(t，1H)，6.50(t，1H)，6.17(s，2H)，5.69(d，1H)。

MS(ESI)：468.1[M+H] ⁺。

Embodiment 61: preparation compound 57

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 351mg yellow solid through two-step reaction, promptly compound 57, productive rate 65%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：9.90(s，1H)，8.48(dd，1H)，8.05(dd，1H)，7.83(d，1H)，7.77(dd，1H)，7.42(m，2H)，7.33(m，3H)，6.66(t，1H)，6.46(s，2H)，6.03(d，1H)，4.50(d，2H)。

MS(ESI)：482.1[M+H] ⁺。

Embodiment 62: preparation compound 58

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 288mg yellow solid through two-step reaction, promptly compound 58, productive rate 55%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：10.10(s，1H)，8.53(d，1H)，8.06(d，1H)，7.84(d，1H)，7.72(d，1H)，7.48(m，2H)，7.22(m，3H)，7.16(m，1H)，6.63(d，1H)，6.50(s，2H)，6.06(d，1H)。

MS(ESI)：468.1[M+H] ⁺。

Embodiment 63: preparation compound 59

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 288mg yellow solid through two-step reaction, promptly compound 59, productive rate 55%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：10.50(s，1H)，7.82(m，4H)，7.45(m，2H)，7.22(m，2H)，7.08(d，1H)，6.70(d，1H)，6.46(s，2H)，6.06(d，1H)。

MS(ESI)：468.1[M+H] ⁺。

Embodiment 64: preparation compound 60

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 351mg yellow solid through two-step reaction, promptly compound 60, productive rate 65%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：9.95(t，1H)，7.85(d，1H)，7.77(d，1H)，7.45(m，4H)，7.28(m，2H)，6.90(d，1H)，6.66(t，1H)，6.46(s，2H)，6.20(t，1H)，6.00(d，1H)，5.85(m，1H)，4.50(d，2H)。

MS(ESI)：482.1[M+H] ⁺。

Embodiment 65: preparation compound 61

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 355mg yellow solid through two-step reaction, promptly compound 61, productive rate 65%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：9.02(s，1H)，8.85(t，1H)，8.35(d，1H)，8.05(d，1H)，7.90(d，1H)，7.45(m，6H)，7.15(t，2H)，7.00(d，1H)，6.52(d，1H)，4.40(d，2H).MS(ESI)：488.1[M+H] ⁺.

Embodiment 66: preparation compound 62

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 394mg yellow solid through two-step reaction, promptly compound 62, productive rate 72%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：9.00(s，1H)，8.88(t，1H)，8.65(d，1H)，8.35(d，1H)，8.28(d，1H)，7.98(m，3H)，7.45(m，2H)，7.35(d，2H)，7.15(t，2H)，6.55(d，1H)，4.42(d，2H)。

MS(ESI)：489.1[M+H] ⁺。

Embodiment 67: preparation compound 63

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 425mg yellow solid through two-step reaction, promptly compound 63, productive rate 70%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：8.55(d，1H)，8.35(t，1H)，8.00(m，3H)，7.75(m，3H)，7.55(d，2H)，7.38(m，2H)，7.20(s，2H)，7.08(t，2H)，6.55(d，1H)，4.45(d，2H)，4.00(s，6H)，3.90(s，3H)。

MS(ESI)：543.2[M+H] ⁺。

Embodiment 68: preparation compound 64

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 499mg yellow solid through two-step reaction, promptly compound 64, productive rate 72%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：9.65(b，1H)，8.95(t，1H)，8.55(d，1H)，8.35(d，1H)，8.00(m，3H)，7.50(m，6H)，7.20(s，2H)，7.08(t，2H)，6.50(d，1H)，4.42(d，2H)，3.90(s，3H)。

MS(ESI)：619.2[M+H] ⁺。

Embodiment 69: preparation compound 65

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 558mg yellow solid through two-step reaction, promptly compound 65, productive rate 75%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：9.66(s，1H)，8.86(t，1H)，8.49(d，1H)，8.35(d，1H)，7.95(m，3H)，7.85(d，1H)，7.45(m，2H)，7.35(m，2H)，7.20(d，1H)，7.13(t，2H)，6.55(d，1H)，4.45(d，2H)，4.23(t，2H)，3.92(s，3H)，3.60(t，4H)，2.40(m，4H)，2.05(m，2H)。

MS(ESI)：665.2[M+H] ⁺。

Embodiment 70: preparation compound 66

Take by weighing 450mg and be about the compound 67 of 1.12mmol, according to the method for embodiment 5, obtain the 390mg yellow solid through two-step reaction, promptly compound 66, productive rate 68%.

Product to making is tested, and the result is following:

H-NMR(300MHz，DMSO-d6)：9.15(b，1H)，8.85(t，1H)，8.45(d，1H)，8.35(d，1H)，8.25(d，1H)，7.95(m，1H)，7.49(m，4H)，7.35(m，3H)，7.15(m，3H)，6.92(m，1H)，6.53(d，1H)，4.42(d，2H)，3.90(s，3H)。

MS(ESI)：512.2[M+H] ⁺。

The horizontal arrestin kinases of embodiment 71 external biochemistry (PK) activity experiment

Materials and methods: c-Met, Flt-3, VEGFR-2, PDGFR-β and c-Kit kinases derive from Invitrogen; HTRF KinEASE; TK kit (Cisbio company); 384 orifice plates (Greiner company); ATP (sigma company), MgCl ₂(sigma) company; The multi-functional ELIASA of PHERAstar FS (BMG company); Low speed centrifuge (StaiteXiangyi company); Thermostat container (Binder company).

Compound dissolution and preservation: look solvability and test-compound is configured to the mother liquor of 0.5-10mmol/L ,-20 ℃ of preservations after the packing with DMSO;

The preparation of compound working fluid: the compound with packing before the test takes out from refrigerator, is diluted to 50 * desired concn with pure DMSO; Then with deionized water with diluted chemical compound to 4 * desired concn;

1.33 the preparation of * Enzymatic buffer: 5 * Enzymatic buffer is derived from HTRF kit) with deionized water be diluted to 1.33 *, and add the corresponding composition of 1.33 * final concentration: 1.33mmol/LDTT and 1.33mmol/L MgCl ₂

The preparation of kinases working fluid: Met is diluted to 2 * required final concentration 0.2ng/ μ L with 1.33 * Enzymatic buffer;

The preparation of substrate working fluid: is the mixed solution of 4 * required final concentration with 1.33 * Enzymatic buffer with substrate-biotin (deriving from HTRF kit) and ATP (10mmol/L) dilution;

The preparation of testing liquid: with HTRF detection buffer the Streptavidin-XL665 of 16.67 μ mol/L is diluted to 4 * required final concentration, mixes (all deriving from HTRF kit) then with isopyknic Antibody-Cryptate.

The enzyme reaction step: in each hole of low volume 384 microwell plates, add the kinases working fluid of 4 μ L, the 1.33 * Enzymatic buffer that adds 4 μ L simultaneously is as negative control (Negative); Add the compound working fluid of 2 μ L to the hole, contrast (is a positive control, Positive) as the pulverised compound concentration to add the 8%DMSO aqueous solution of 2 μ L simultaneously; Hatch 5-10min in 25 ℃ (or 30 ℃); Xiang Kongzhong adds 2 μ L substrate working fluids and starts enzyme reaction, in 25 ℃ of (or 30 ℃) oscillatory reaction 15-60min.

HTRF reagent detects step: the testing liquid termination reaction that adds 8 μ L to the hole; 25 ℃ of reaction 1h;

Reading of HTRF signal: adopt PHERAstar FS reading detection signal, the instrument arrange accordingly is following:

Optic?module

Integration?delay(lag?time)50μs

Integration?time?400μs

Number?of?flashes?200

For the raw data that read in every hole, ratio=665nm/620nm;

The calculating of inhibiting rate:

IC ₅₀The calculating of value: the logarithm with compound concentration is an X-coordinate; Inhibiting rate is an ordinate zou; In GraphPad Prism 5, match nonlinear curve: log (inhibitor) vs.response--Variable slope, obtaining the enzyme inhibiting rate of living is that 50% o'clock testing compound concentration is IC ₅₀

Experimental result: c-Met kinase activity half-inhibition concentration (IC ₅₀Nmol/L)

The present invention provides structure suc as formula the half-inhibition concentration (IC of compound shown in the I to the c-Met kinase activity ₅₀) see table 1:

Table 1 compound is to the half-inhibition concentration (IC of c-Met kinase activity ₅₀)

Compound

?1

?2

3

?4

5

?6

7

8

9

10

Activity intensity

?+++

+++

?+++

+++

?+++

++

+++

Compound

?11

?12

13

?14

15

?16

17

18

19

20

Activity intensity

?++

++

?++

+

?++

++

+

Compound

?21

?22

23

?24

25

?26

27

28

29

30

Activity intensity

?+

+

?++

++

?+++

+++

++

Compound

?31

?32

33

?34

35

?36

37

38

39

40

Activity intensity

?+

+

?+

++

?+++

+++

+

Compound

?41

?42

43

?44

45

?46

47

48

49

50

Activity intensity

?+++

+++

?++

++

?++

+++

Compound

?51

?52

53

?54

55

?56

57

58

59

60

Activity intensity

?+++

?++

+++

?++

+++

?+

++

+

++

Compound

?61

?62

63

?64

65

?66

Activity intensity

?+

+

?+

+

?+

IC ₅₀＜500nmol/L+++；500-5000nmol/L++；＞5000nmol/L+。

The horizontal arrestin kinases of embodiment 72 cell in vitro (PK) activity experiment

Materials and methods: people's adenocarcinoma of stomach cell strain MKN-45 etc. all derives from Chinese Academy of Sciences's Shanghai cell bank; 1640 substratum (GIBCO company); Foetal calf serum (GIBCO company); 24 porocyte culture plates (Costar company); 96 hole water white transparency high-affinity enzyme plates (Costar company); HGF (R&D System company); Cell pyrolysis liquid (green the skies company); C-Met capture antibody (R&D System company); Anti-phosphotyrosine antibody, clone 4G10 (Upstate company); HRP labeled goat-anti-mouse antibody (middle China fir Golden Bridge company); TMB (Pierce company); Enzyme mark detector (Tecan company, Infinite M200); The multi-functional plate machine (Bio-Rad company) of washing

Compound configuration: positive drug and each test-compound are configured to the mother liquor of 10mmol/L ,-20 ℃ of preservations with DMSO.

The Met antibody sandwich: to 2 μ g/mL, in the amount adding enzyme plate with every hole 100 μ L, 4 ℃ encapsulate spend the night (16-18h) with the c-Met antibody dilution.PBST (PBS/0.05%Tween20, pH 7.4) washing 3 times; Every hole adds confining liquid (5%BSA/PBS) 200 μ L, 37 ℃ of sealing 2h; PBST washing 3 times; Grasp c-Met albumen: the MKN-45 cell of inoculation 80-90% degrees of fusion in the 24 porocyte culture plates, behind the 8-10h cell attachment, change serum-free 1640 substratum, hunger is spent the night; Compound with serum-free 1640 substratum gradient dilutions; Substratum in 24 orifice plates is removed in suction, adds 180 μ L/ hole compound concentration gradient dilution liquid fast, and the cell of compound effects is hatched 1h at incubator; With serum-free 1640 substratum HGF is configured to the solution of 800ng/mL, every hole adds 20 μ L in 24 orifice plates, stimulates 5-8min at 37 ℃ behind the slight mixing; Inhaling fast goes supernatant of culture medium in 24 orifice plates, every hole to add 240 μ LRIPA lysates; Every hole adds 100 μ l cell pyrolysis liquids in the enzyme plate after sealing, 37 ℃ of 100rpm jolting 2h; PBST washing 3 times;

The detection of Phosphotyrosine: anti-hatching, every hole adds 100 μ L mouse source Anti-phosphotyrosine antibody, Clone 4G10 (0.5%BSA/PBS (W/V) dilution in 1: 2000), 37 ℃ of 100rpm jolting 1-1.5h; PBST washing 3 times; Two anti-hatching: every hole adds 100 μ LHRP goat anti mouse IgG (1: 3000 times of dilution of 0.5%BSA/PBS (W/V)), 37 ℃ of 100rpm jolting 1h; PBST washing 6 times; The tmb substrate colour developing: every hole adds 100 μ L TMB substrate, room temperature darkroom reflection 2-10min; After treating that substrate arrives suitable color, every hole adds 50mL 2mol/LH ₂SO ₄ELIASA 450nm absorbing wavelength place measures light absorption value.

Two control groups, negative control group are established in experiment: add the SCR-1 of 10-5mol/L high density, not adding HGF stimulates; Positive controls: do not add any medicine, only adding HGF stimulates;

Calculate the MV of all administration groups and control group, calculate inhibiting rate by following formula:

IC ₅₀The calculating of value: the logarithm with compound concentration is an X-coordinate; Inhibiting rate is an ordinate zou; In GraphPad Prism 5, match nonlinear curve: log (inhibitor) vs.response--Variableslope, obtaining the enzyme inhibiting rate of living is that 50% o'clock testing compound concentration is IC ₅₀

Experimental result: part of compounds of the present invention is to the active half-inhibition concentration scope of c-Met kinases cell levels (IC ₅₀) see table 2:

Table 2 compound is to the active half-inhibition concentration scope of c-Met kinases cell levels (IC ₅₀)

Compound

1

2

?3

4

?5

6

?7

?8

?9

10

Activity intensity

++

?++

++

?++

++

?+

?++

++

Compound

11

12

?13

14

?15

16

?17

?18

?19

20

Activity intensity

+

?+

++

?+

++

?++

?+

+

Compound

21

22

?23

24

?25

26

?27

?28

?29

30

Activity intensity

+

?+

+

?++

++

?++

?+++

+

Compound

31

32

?33

34

?35

36

?37

?38

?39

40

Activity intensity

+

?+

+

?++

++

?++

?+++

+

Compound

41

42

?43

44

?45

46

?47

?48

?49

50

Activity intensity

++

?++

+

?++

++

?+++

?++

++

Compound

51

52

?53

54

?55

56

?57

?58

?59

60

Activity intensity

++

+

?+++

++

?+++

+

?+

+

Compound

61

62

?63

64

?65

66

Activity intensity

+

?+

+

?+

+

IC ₅₀＜1μmol/L+++；1-10μmol/L++；＞10μmol/L+。

Embodiment 73 compounds provided by the invention suppress the measuring method (mtt assay) of tumor cell proliferation

Reagent and instrument:

RPMI 1640 substratum (RPMI 1640+12% calf serum+HEPES 3.5g/L+NaHCO ₃2.2g/L+ penicillium mould 0.13g/L+ Streptomycin sulphate 0.15g/L);

RPMI 1640 substratum (RPMI 1640+12% foetal calf serum+HEPES 3.5g/L+NaHCO ₃2.2g/L+ penicillium mould 0.13g/L+ Streptomycin sulphate 0.15g/L);

High sugared DMEM substratum (DMEM+10% calf serum+HEPES 3.5g/L+NaHCO ₃2.2g/L+ penicillium mould 0.13g/L+ Streptomycin sulphate 0.15g/L);

High sugared DMEM substratum (DMEM+12% foetal calf serum+HEPES 3.5g/L+NaHCO ₃2.2g/L+ penicillium mould 0.13g/L+ Streptomycin sulphate 0.15g/L);

MC COYS 5-A substratum (DMEM+12% foetal calf serum+HEPES 3.5g/L+NaHCO ₃2.2g/L+ penicillium mould 0.13g/L+ Streptomycin sulphate 0.15g/L);

Trypsinase; MTT (U.S. Amresco Company products); ELIASA (TECAN infiniteM200)

People's adenocarcinoma of stomach cell strain (BGC); People's nonsmall-cell lung cancer (A549); Human leukemia cell line (K562); Human pancreas cancer cell strain (PANC-1); Human small cell lung carcinoma (NCI-H446); Listed JEG-3 is used RPMI 1640 substratum that contain 12% calf serum, in 37 ℃, and 5%CO ₂Incubator in cultivate;

Human pancreas cancer cell strain (BXPC-3); Human bladder cancer cell's strain (T24); Listed JEG-3 is with RPMI 1640 substratum of 12% foetal calf serum, in 37 ℃, and 5%CO ₂Incubator in cultivate;

Human hepatoma cell strain (HEPG2); Human breast cancer cell strain (MCF-7); Listed JEG-3 is with the high sugared DMEM substratum of 12% calf serum, in 37 ℃, and 5%CO ₂Incubator in cultivate;

Human colon adenocarcinoma cell's strain (CACO-2), with the high sugared DMEM substratum of 12% foetal calf serum, in 37 ℃, 5%CO ₂Incubator in cultivate;

Human colon cancer cell strain (HT29); Human colon cancer cell strain (HCT116); Human oophoroma cell line (SK-OV-3); Listed JEG-3 is with the MC COYS 5-A substratum of 12% foetal calf serum, in 37 ℃, and 5%CO ₂Incubator in cultivate.

Inoculation: get and be in exponential phase of growth, one bottle in cell in good condition adds an amount of tryptic digestive juice; Digestion comes off attached cell; RPMI1640 (or DMEM or 5A) nutrient solution with containing 12% calf serum is made into cell suspension, counts, and the cell density adjustment is diluted to 1.67 * 10 ⁴/ mL obtained cell suspension is inoculated on 96 orifice plates, 180 μ L/ holes (containing tumour cell 3000/ hole).

Cultivate: change culture plate over to constant temperature CO ₂In the incubator, at 37 ℃, 5%CO ₂And cultivated 24 hours under the saturated humidity condition.

Primary dcreening operation: testing compound is mixed with 0.1mol/L concentration with DMSO earlier, remakes 3 extent of dilution, is used for primary dcreening operation, and concentration is followed successively by 10 ^-5Mol/L, 10 ^-6Mol/L and 10 ^-7Mol/L.Add testing compound, cultivated 72 hours in 20 μ L/ holes.Establish 3 parallel holes for every group, and repeat 3 times, measure the every hole of 96 orifice plates light absorption value, the record result calculates inhibitory rate of cell growth, gets MV three times.

Dyeing: MTT is added in 96 orifice plates (attached cell), and 20 μ L/ holes place incubator to hatch 4 hours, inhale and abandon supernatant in the hole, add DMSO 100 μ L/ holes, and concussion is 5 minutes on the horizontalization plate shaking table.MTT is added (suspension cell) in 96 orifice plates, and 20 μ L/ holes place incubator to hatch 4 hours, add 20%SDS 50 μ L/ holes again, place incubator to spend the night.

Measure: it is 570nm that ELIASA is set wavelength, and reference wavelength is 630nm, measures the every hole of 96 orifice plates light absorption value, and the record result also calculates inhibitory rate of cell growth, receives the anti-tumor activity of reagent thing with judgement.

Multiple sieve: in primary dcreening operation concentration is 10 ^-5During mol/L, the compound of 3 cell inhibitory rate>=50% is used for multiple sieve, and 0.1mol/L is remake 10 extent of dilution, and concentration is followed successively by 10 ^-5Mol/L, 0.5 * 10 ^-5Mol/L, 10 ^-6Mol/L, 0.8 * 10 ^-6Mol/L, 0.6 * 10 ^-6Mol/L, 0.4 * 10 ^-6Mol/L, 0.2 * 10 ^-6Mol/L, 10 ^-7Mol/L, 0.8 * 10 ^-7Mol/L and 0.4 * 10 ^-7Mol/L.Add test-compound, cultivated 48 hours in 20 μ L/ holes.Establish 3 parallel holes for same every group, and repeat 3 times, and according to prescreening method, measure the every hole of 96 orifice plates light absorption value, the record result also calculates inhibitory rate of cell growth.

Inhibitory rate of cell growth and IC ₅₀Calculating:

Simultaneously according to the growth inhibition ratio of each concentration, adopt logarithm with compound concentration with the Logit linear regression, obtain that to suppress growth rate be that 50% o'clock testing compound concentration is IC ₅₀, get MV three times.

Test-results: the compound with formula I structure of preparation is inhibited to the propagation of kinds of tumor cells in the embodiment of the invention 5 to 70, and through statistical study, effect is (P＜0.05) significantly, its IC ₅₀All 10 ^-5Below the mol/L.

The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.

Claims

1. structure compound shown by formula I, its pharmaceutically acceptable Equivalent or salt,

Formula I

M is 0-3; B is selected from O, NR ⁴, NR ⁴CH ₂, S, SO, SO ₂, CR ⁵R ⁶

A is selected from following group:

2. a structure is suc as formula the compound shown in the II, its pharmaceutically acceptable Equivalent or salt,

Formula II

Wherein, X is selected from C or N; B is selected from O, S or NH; R ¹Be selected from hydrogen or halogen; R ²Be selected from hydrogen or OR ⁷R ⁷Be selected from hydrogen, alkyl, substituted alkyl, allyl group or substituted allyl; R ³Be selected from hydroxyl, alkoxyl group ,-NR ¹⁰R ¹¹Or-N (CH ₂) _p(R ¹²) (CH ₂) _pR ¹³P is 0-2;

A is selected from following group:

3. structure compound, its pharmaceutically acceptable Equivalent or salt shown in formula III,

Formula III

M is 0-3; B is O, NR ⁴, NR ⁴CH ₂, S, SO, SO ₂, CR ⁵R ⁶

A is selected from following group:

4. a structure is suc as formula the compound shown in the IV, its pharmaceutically acceptable Equivalent or salt,

Formula IV

M is 0-3;

A is selected from following group:

5. like each described compound of claim 1 to 4, be specially:

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(3-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-chloro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides (I-4)

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(3-chloro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-cyanic acid-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-benzyl-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(3-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-methyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-chloro-3-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-phenyl)-N-(4-fluoro-benzyl-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluoro-phenyl)-N-isobutyl--6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluoro-the phenyl)-N-tertiary butyl-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluoro-phenyl)-N-sec.-propyl-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluoro-phenyl)-N-(2-cyano ethyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluoro-phenyl)-N-(2-cyano methyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-cyano methyl)-N-(4-luorobenzyl)-6-oxo-1,6--dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-5-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) pyridine-2 (1H) ketone

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(furans-2-ylmethyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-alkynyl pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-(3-hydroxyl third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-(3-dimethylamino third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-methylol-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((dimethylamino methyl-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-(morpholinyl-methyl)-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-(piperidines-1-base-methyl)-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-4-(thiophene [3,2-d] pyrimidine-4-yl) oxo-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-4-(thiophene [3,2-b] pyridine-7-yl) oxo-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-(6,7-dimethoxyquinazoline-4-yl) oxo 3-fluoro-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-(6-benzyloxy-7-methoxyl group quinazoline-4-yl) oxo 3-fluoro-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-4-(7-methoxyl group-6-(morpholinyl-propoxy--quinazoline-4-yl) oxo-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

5 '-((2-amino-3-chloropyridine-4-yl) oxo-N-(4-fluoro-benzyl)-2-oxo-2H [1, the 2-dipyridyl]-5-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo phenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-oxyethyl group-6-oxo-1,6-dihydropyridine-3-acid amides

4-allyloxy-1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-oxyethyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-(2-methoxyethoxy)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-4-(2,3-dihydroxyl propoxy-)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-(2-methoxyethoxy)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-(3-hydroxyl third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4 methoxyl groups-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-(3-dimethylamino third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-(4-fluorophenyl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-phenyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-4-(7-methoxyl group-6-(morpholinyl-propoxy--quinazoline-4-yl) oxo-phenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-4-(thiophene [3,2-b] pyridine-7-yl) oxo-phenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-4-(6-methoxyl group-7-(morpholinyl-propoxy--quinolyl-4) oxo-phenyl)-N-(4-fluoro-benzyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-phenyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-fluoro-benzyl)-2-oxo-1,2-dihydropyridine-3-acid amides

1-(3-fluoro-4-(thiophene [3,2-b] pyridine-7-yl) amino-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-4-(thiophene [3,2-d] pyrimidine-4-yl) amino-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(the amino 3-fluoro-phenyl of 4-(6,7-dimethoxyquinazoline-4-yl))-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(the amino 3-fluoro-phenyl of 4-(6-benzyloxy-7-methoxyl group quinazoline-4-yl))-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-4-(7-methoxyl group-6-(morpholinyl-propoxy--quinazoline-4-yl) amino-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-((7-methoxy quinoline-4-yl) amino-phenyl)-N-(4-fluoro-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides.

6. a structure is suc as formula the compound shown in the V, its pharmaceutically acceptable Equivalent or salt,

Formula V

A is selected from following group:

7. compound as claimed in claim 6 is specially:

1-(4-((2-carboxamido-group-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid;

1-(4-((2-carboxamido-group-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-carboxylic acid.

8. a structure is suc as formula the compound shown in the VI, its pharmaceutically acceptable Equivalent or salt,

Formula VI

It is characterized in that X is selected from C or N; R ¹Be selected from hydrogen or halogen;

9. compound as claimed in claim 8 is specially:

1-(3-fluoro-4-hydroxy phenyl)-N-4-fluoro-benzyl-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-4-hydroxy phenyl)-N-4-fluoro-benzyl-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides.

10. be used for treating the purposes in the medicine of Mammals or human body protein kinase related disorder like each described compound of claim 1 to 9 in preparation, said protein kinase related disorder is selected from squamous cell carcinoma, stellate cell cancer, Kaposi, spongioblast cancer, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, mammary cancer, neurospongioma, colorectal carcinoma, liver cancer, kidney, genitourinary cancer, carcinoma of the pancreas or gastrointestinal cancer, mellitus, excess proliferative disease, blood vessel generation, inflammatory diseases, immunological disease or cardiovascular disorder.