CN101027305A

CN101027305A - Fused heterocyclic kinase inhibitors

Info

Publication number: CN101027305A
Application number: CN200580027173.1A
Authority: CN
Inventors: 罗伯特·M·博齐尔利; 陈中; 特拉姆·N·海恩; 韦恩·瓦卡罗; 陈小涛; 金敬淳; 蔡真伟
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2004-06-28
Filing date: 2005-06-28
Publication date: 2007-08-29
Anticipated expiration: 2025-06-28
Also published as: CN101005843A; ZA200610780B; CN100577663C; CN1993130B; CN1993130A

Abstract

In general, the instant invention comprises compounds of Formulas (I) and (II) including pharmaceutically acceptable salts thereof. The compounds of the invention are useful as protein kinase inhibitors and therefore are useful for treating cancer and other protein kinase mediated diseases.

Description

Fused heterocyclic kinase inhibitors

The application requires the right of priority of U.S. Provisional Patent Application 60/583,459 (submission on June 28th, 2004) and 60/612,563 (submission on September 23rd, 2004) according to united states patent law 35 § 119 (e), and the content of these two applications is incorporated the application into as a reference.

Invention field

Thereby the present invention relates to suppress growth factor receptors for example the protein hydroxyphenylaminopropionic acid kinase activity of c-Met make the compound of its useful asticancer agents.Except cancer, the pharmaceutical composition that contains above-claimed cpd also can be used for treatment with by somatomedin and angiogenesis inhibitor acceptor (anti-angiogenesis) the c-Met relevant disease of signal transduction pathway of working for example.

Background technology

PHGF (HGF) (being called dispersion factor (SF) again) is owing to can disturb external bacterium colony to form, therefore be a kind of known can in normal and neoplastic cell, induce multiple, pleiotropy respond (multiple pleiotropic response) between matter derivatize cytokine (Sonnenberg et al., J.Cell Bio, 123:223-235,1993; Matsumato et al., Crit.Rev.Oncog.3:27-54,1992; And Stoker et al., Nature 327:239-242,1987).These respond known including: the propagation of epithelial cell and endotheliocyte, the epithelial cell colony is separated into individual cells, stimulate epithelial reactivity [(motogenesis) takes place in motion], cell survival, bring out cellular form (morphogenesis) (Montesano et al. takes place, Cell 67:901-908,1991), and promotion morbidity (Stella, et al., Int.J.Biochem.Cell Biol., 12:1357-62,1999 and Stuart, et al., Int.J. Exp.Path, 81:17-30,2000), all constitute the critical process that shifts the basis.Also existing report points out that HGF can promote blood vessel that (Bussolino et al., J.Cell Biol.119:629-641,1992) take place.In addition, HGF has played the part of the key player in regeneration, wound healing and the fetal tissues process (these are the reactivity and the propagation of dependent cells all simultaneously) of tissue.

HGF is by (the Met protein tyrosine kinase acceptor of related acceptor with it, a kind of verified proto-oncogene) high-affinity combination, cause these physiological processs (Park et al., Proc.Natl.Acad.Sci.USA 84:6379-83,1987 and Bottaro et al., Science 251:802-4,1991).The Met of mature form is made up of outside α-subunit and β-subunit, transmembrane bundle fragment (transmembrane segment) and the tenuigenin Tyrosylprotein kinase zone of the high glycosylation with big extracellular domain.Part engages and brings out Met formation dimer, and causes producing the autophosphorylation activated receptor.The activation of Met promotes signal transduction cascade (cascades), as being responsible for replenishing the commentaries on classics phosphorylation determined (Furge et al., Oncogene 19:5582-9,2000) of the proteic key tenuigenin tyrosine residues of manifold effect.These have comprised the kinase whose p85 subunit of PI3-, Phospholipase C γ (Gaul et al., Oncogene 19:1509-18,2000), Grb2 and Shc adapter protein (adaptor proteins), protein Phospholipid hydrolase SHP2 and Gab1.Back one adaptin occurs with main downstream butt joint (docking) molecule, and it becomes tyrosine phosphorylation (Schaeper et al., J.Cell Biol.149:1419-32,2000 after part occupies; Bardelli et al., Oncogene 18:1139-42,1999 and Sachs et al., J.Cell.Biol.150:1375-84,2000).According to reports, through the HGF stimulated cells (refer to especially Ras, map kinase, STATs, ERK-1 ,-2 and FAK) in have activation (Tanimura et al., Oncogene 17:57-65,1998 of other signaling molecule; Lai et al., J.Biol.Chem.275:7474-80,2000 and Furge et al., Oncogene19:5582-9,2000).Effect in many these signaling molecules is fully confirmed in cell proliferation.

Met (also being called hepatocyte growth factor receptor (HGFR)) mainly expresses in epithelial cell, but confirms also to be expressed in endotheliocyte, myogenous cells, hematopoietic cell and the motor neuron.Think that the promotion of the morbidity of activation and many different tumor types of the overexpression (overexpression) of HGF and Met and progress and metastatic disease is relevant.The Prima Facie Evidence that Met and cancer are linked together has determined to obtain support by kinases zone missense mutation (missense mutaions), this sudden change makes individuality be easy to suffer from corpora mammillaria kidney (PRC) and hepatocellular carcinoma (HCC) (Lubensky et al., Amer.J.Pathology, 155:517-26,1999).The Met of mutant form is in ovarian cancer, child stage HCC, cancer of the stomach, head and neck squamous cell cancer, nonsmall-cell lung cancer, colorectum metastasis of cancer (Christensenet al., Cancer Res.63:7345-55,2003; Lee et al., Oncogene 19:4947-53,2000 and Direnzo et al., Clin.Cancer Res.1:147-54,1995) in obtain to confirm.In addition, support further evidence that Met acts in cancer based on the HGF in the various tumours (comprising Tiroidina, ovary and carcinoma of the pancreas) and the overexpression of Met acceptor.(Rong et al., Cancer Res.55:1963-1970,1995 have also been confirmed in the hepatic metastases of colorectal carcinoma, to be exaggerated; Rong et al., Cancer Res.53:5355-5360,1993; Kenworthy et al., Br.J.Cancer 66:243-247,1992 and Scarpino et al., J.Pathology 189:570-575,1999).In human cancer of the stomach, described and confirmed TPR-Met (being similar to the BCR/Ab1 activated form among the CML) (PNAS 88:4892-6,1991).In the patient and nearest research that suffer from morbidity property mammary cancer to the nonsmall-cell lung cancer patient, the expression of acceptor or part all is the omen that survival rate reduces, the thereby further progress with Met and tumour links together (Camp et al., Cancer 86:2259-65,1999 and Masuya et al., Br.J.Cancer90:1555-62,2004).Generally speaking, the most human tumor and the tumour cell in a matter source are all expressed HGFR and/or HGF inadequately.

A large amount of experimental datas support that HGF and Met invade in tumour, growth, survival and and the final development process that causes shifting in role.Clinically, the transgene expression of HGF can cause the Met that shifts phenotype (Takayama et al., PNAS 94:701-6,1997) and extension/overexpression to be out of shape NIH-3T3 cell (Cooper et al., EMBO J.5:2623-8,1986) naturally.

With HGF or Met is the biotechnological formulation of target, and for example, RNA constitutes enzyme (ribozyme), antibody and sense-rna and shown that can suppress tumour generates (Stabile et al., Gene Therapy, 11:325-35,2004; Jiang et al., Clin.Cancer Res.9:4274-81,2003; And Genentech US 6,214,344,2001).Therefore, be that the selectivity small molecules kinase modulator expection of target has treatment treatment for cancer potentiality with Met, in these cancers, the activation of Met acceptor has been played the part of critical role in development that primary tumor and Secondary cases shift with in worsening.The also known may command blood vessel of HGF takes place, and this is the significant process in tumor growth and the diffusion.Therefore, this class conditioning agent potential impact depends on the disease that blood vessel takes place, comprising ret diab, macular degeneration, obesity and inflammatory diseases, for example, rheumatoid arthritis.

Summary of the invention

The present invention relates to have the compound of following formula I and II:

Comprise their pharmacy acceptable salts, enantiomer, diastereomer and solvate, wherein:

R ¹Be H, alkyl, the alkyl that is substituted, cycloalkyl, the cycloalkyl that is substituted, aralkyl, the aralkyl that is substituted, aryl, the aryl that is substituted, alkenyl, the alkenyl that is substituted, alkynyl group, the alkynyl group that is substituted, heteroaryl, the heteroaryl that is substituted, heterocyclic radical, the heterocyclic radical that is substituted, heteroaralkyl, the heteroaralkyl that is substituted, Heterocyclylalkyl or the Heterocyclylalkyl that is substituted;

Each R ²Independent is H, halogen, cyano group, NO ², OR ⁵, NR ⁶R ⁷, alkyl, the alkyl that is substituted, cycloalkyl, the cycloalkyl that is substituted, aryl, the aryl that is substituted, heteroaryl, the heteroaryl that is substituted, heterocyclic radical, the heterocyclic radical that is substituted, aralkyl, the aralkyl that is substituted, Heterocyclylalkyl or the Heterocyclylalkyl that is substituted;

B is O, NR ⁸, S, SO, SO ², CR ⁹R ¹⁰

V is NR ¹¹Or-(CR ⁴⁷R ⁴⁸) _p-;

W or X independently are C or N;

Y is O, S or NR ¹²

Z is-CR ¹³R ¹⁴-,-(CR ¹³R ¹⁴) _mNR ¹⁵-;

L is 0 to 4;

M is 0 to 2;

N is 0 to 4;

P is 0 to 4, and preceding topic condition is: as if p is 0, then R ¹It is not phenyl;

A is:

Q is CR ¹⁹

D is CR ²⁰Or N;

G is S, O or NR ²¹, preceding topic condition is: if A is

And G is S, then R ⁴It is not the phenyl that is substituted;

R ³, R ⁵, R ⁶, R ⁷, R ⁸, R ¹¹And R ¹⁵Independently separately be H, alkyl, the alkyl that is substituted, cycloalkyl, the cycloalkyl that is substituted, aryl, the aryl that is substituted, heteroaryl, the heteroaryl that is substituted, Heterocyclylalkyl or the Heterocyclylalkyl that is substituted;

R ⁴Be aryl, the aryl that is substituted, heteroaryl, the heteroaryl that is substituted, Heterocyclylalkyl or the Heterocyclylalkyl that is substituted;

R ⁹And R ¹⁰Independent separately is H, halogen, alkyl, the alkyl that is substituted, cycloalkyl, the cycloalkyl that is substituted, aryl, the aryl that is substituted, heteroaryl, the heteroaryl that is substituted, Heterocyclylalkyl or the Heterocyclylalkyl that is substituted;

R ¹²Be H, alkyl, the alkyl that is substituted, CN, NO ₂Or SO ₂NH ₂

R ¹³, R ¹⁴, R ¹⁵, R ⁴⁷And R ⁴⁸Independence is H, halogen, alkyl, the alkyl that is substituted, cycloalkyl, the cycloalkyl that is substituted, aryl, the aryl that is substituted, heteroaryl, the heteroaryl that is substituted, heterocyclic radical, the heterocyclic radical that is substituted or forms carbocyclic ring or the heterocycle with 3 to 8 atoms together separately;

R ¹⁶, R ¹⁷, R ¹⁸, R ²⁰, R ²², R ²³, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶, R ⁶⁷, R ⁶⁸, R ⁶⁹, R ⁷⁰, R ⁷⁵, R ⁷⁶, R ⁷⁸, and R ⁷⁹Independent separately is H, halogen, NO ₂, cyano group, OR ²⁶, NR ²⁷R ²⁸, CO ₂R ²⁹, C (O) NR ³⁰R ³¹, SO ₂R ³², SO ₂NR ³³R ³⁴, NR ³⁵SO ₂R ³⁶, NR ³⁷C (O) R ³⁸, NR ³⁹CO ₂R ⁴⁰,-CO (CH ₂) ₁R ⁴¹,-CONH (CH ₂) ₁R ⁴², alkyl amino alkyl, alkylamino alkynyl group, C ₁-C ₆Alkyl, the C that is substituted ₁-C ₆Alkyl, C ₃-C ₇Cycloalkyl, the C that is substituted ₃-C ₇Cycloalkyl, alkenyl, the alkenyl that is substituted, alkynyl group, the alkynyl group that is substituted, hydroxyalkyl, aryl, the aryl that is substituted, heteroaryl, the heteroaryl that is substituted, aralkyl, the aralkyl that is substituted, Heterocyclylalkyl or the Heterocyclylalkyl that is substituted;

R ¹⁹Be H or cyano group;

R ²¹And R ²⁴Independent separately is H, C ₁-C ₆Alkyl or the C that is substituted ₁-C ₆Alkyl;

R ²⁵, R ⁷⁴And R ⁷⁷Independently separately be H, alkyl, the alkyl that is substituted, cycloalkyl, the cycloalkyl that is substituted, aryl, the aryl that is substituted, aralkyl, the aralkyl that is substituted, heteroaryl, the heteroaryl that is substituted, Heterocyclylalkyl or the Heterocyclylalkyl that is substituted;

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, and R ⁴²Independent is H, alkyl, the alkyl that is substituted, cycloalkyl, the cycloalkyl that is substituted, aryl, the aryl that is substituted, aralkyl, the aralkyl that is substituted, heteroaryl, the heteroaryl that is substituted, Heterocyclylalkyl or the Heterocyclylalkyl that is substituted.

In some embodiments of the present invention, R ¹Be the optional C that is substituted ₁-C ₆Alkyl, alkenyl, alkynyl group, the optional C that is substituted ₃-C ₇Cycloalkyl, C ₃-C ₇Heterocyclylalkyl, the optional phenyl that is substituted, optional xenyl or the C that is substituted ₅-C ₁₁Optional monocycle or the bicyclic heteroaryl that is substituted.Preferably, R ¹Be phenyl, it is optional through Cl, F, OCH ₃, C _1-4Alkyl, alkenyl, alkynyl group, CN, hydroxyl, amide group, phenoxy group, CH ₂CN, benzyl, NHCO ₂CH ₃In at least one replace; Xenyl; Pyridyl; Nitrogen heterocyclic heptyl (azepanyl); Pyrazolyl; Thiazolyl; Indyl; Indazolyl; Indenyl; Cyclopropyl; Sec.-propyl; Styroyl; Aminoalkyl group; Benzyl; Amido alkyl; Morpholinyl; And furyl methyl.

In some embodiments of the present invention, R ²Be H, alkoxyl group, halogen, methyl, alkylhalide group or CN.

In some embodiments of the present invention, R ⁴Be the optional phenyl that is substituted, the optional pyridyl that is substituted, the optional pyrrolidyl that is substituted, the optional pyridyl-N-oxygen base that is substituted or the optional pyridone (pyridinone) that is substituted, wherein said substituting group is selected from, for example: hydroxyl, halogen, C ₁-C ₄Alkyl, C ₃-C ₇Cycloalkyl, CN, alkylthio, alkoxyl group, phenyl, amino, Heterocyclylalkyl, amino alkylamino and alkylamino alkoxyl group.In some embodiments of the present invention, substituting group is F, Br, Cl, methyl, amyl group, methoxyl group, phenyl, morpholinyl, NH ₂Or NHCHNH ₂

According to embodiments more of the present invention, A is one of following:

According to an embodiment of the present invention, R ¹⁹Be H or CN, and R ¹⁶, R ¹⁷And R ¹⁸Independent is H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or-C (O) ₂R ²⁹, wherein, R ²⁹Be C ₁-C ₄Alkyl.

According to an embodiment of the present invention, R ²²And R ⁶¹Be H.

According to another embodiment of the present invention, R ⁶⁸, R ⁶⁹And R ⁷⁰Be H; R ²⁰Be C ₁-C ₄Alkyl; Alkenyl; Alkynyl group; C ₅-C ₆Heterocyclic aryl;-CO (CH ₂) ₁R ⁴¹, wherein, R ⁴¹Be C ₁-C ₄Alkyl; Alkylhalide group; Amino; Alkylamino; C ₅-C ₇Heterocyclylalkyl; C ₅-C ₇Heteroaryl; Perhaps C (O) ₂R ²⁹, wherein, R ²⁹Be ethyl; CN; Alkoxyl group; Phenmethyl; The alkylamino alkynyl group; Alkyl amino alkyl; Hydroxyalkyl; Or methoxyl group alkyl.

According to an embodiment of the present invention, Y is O or S.

According to an embodiment of the present invention, B is O.

In some embodiments of the present invention, Z is-CR ¹³R ¹⁴Or NR ¹⁵, wherein, R ¹³, R ¹⁴And R ¹⁵H or R respectively do for oneself ¹³And R ¹⁴Form cyclopropyl with the carbon that they connected.

The present invention also relates to medical composition, and it comprises the formula I that treats significant quantity or compound or their salt or the solvate of II, together with pharmaceutically acceptable carrier.

The present invention also provides the treatment method for cancer, its comprise with the compound of the formula I of significant quantity pharmaceutically or II or their salt or solvate be administered to the needs treatment the patient, be administered to this patient with at least a other carcinostatic agent also optional comprising.

Detailed description of the invention

The invention provides defined formula I of preamble and II compound, adopt this compound medical composition, prepare the method for this compound and use the method for this compound.

Hereinafter listed definition for the various terms that are used for describing The compounds of this invention.Unless other restriction is arranged, the term that these definition are applicable in whole specification sheets separately or use as the part than macoradical under specific situation.

All refer to contain the group of 1 to 12 carbon atom separately or as the term " alkyl " of another group part in this article, except as otherwise noted by unit price alkane (hydrocarbon) institute deutero-.Preferred alkyl is for having 1 to 6 carbon atom.Alkyl is optional straight chain, side chain or the cyclic saturated hydrocarbyl that is substituted.Alkyl can be substituted on any feasible attachment point.Also be referred to as " branched-chain alkyl " through the alkyl that another alkyl replaced.Exemplary alkyl comprises: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl or the like.Exemplary substituting group is including, but not limited to one or more following groups: alkyl, aryl, halogen (for example, F, Cl, Br, I), alkylhalide group (for example, CCl ₃Or CF ₃), alkoxyl group, alkylthio, hydroxyl, carboxyl (COOH), carbalkoxy (C (O) R), alkane carbonyl oxygen base (OCOR), amino (NH ₂), formamyl (NHCOOR-or-OCONHR-), urea groups (NHCONHR-) or sulfydryl (SH).In some preferred embodiment of the present invention, alkyl is through for example, and amino, Heterocyclylalkyl (for example, morpholinyl, piperazine, piperidines, azetidine), hydroxyl, methoxyl group or heteroaryl (for example, tetramethyleneimine) replace.

In this article separately or refer to contain straight chain, side chain or the cyclic alkyl of 2 to 12 carbon atoms and at least one carbon-to-carbon double bond as the term " alkenyl " of another group part.This alkenyl also can be substituted on any feasible attachment point.The exemplary substituting group of this alkenyl comprises that the front at the cited substituting group of alkyl, especially comprises C ₃-C ₇Cycloalkyl, for example, cyclopropyl, cyclopentyl and cyclohexyl, its can be further by for example, amino, ketone group, hydroxyl or the like replace.

In this article separately or refer to contain straight chain, side chain or the cyclic alkyl of 2 to 12 carbon atoms and at least one carbon-to-carbon triple bond as the term " alkynyl group " of another group part.This alkynyl group also can be substituted on any feasible attachment point.The exemplary substituting group of this alkynyl group comprises the front at the cited substituting group of alkyl, for example, and amino, alkylamino or the like.

Represent the carbonatoms that special groups can contain in symbol " C " index number afterwards.For example, " C _1-6Alkyl " refer to have the saturated carbon chains of the straight or branched of 1 to 6 carbon atom; The example comprises: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, isopentyl and n-hexyl.Based on context, " C _1-6Alkyl " also refer to the C of two groups of bridge joint _1-6Alkylidene group; The example comprises: propane-1,3-two bases, butane-1,4-two bases, 2-methyl-butane-1,4-two bases or the like." C _2-6Alkenyl " refer to have the carbochain of the straight or branched of at least one carbon-to-carbon double bond and 2 to 6 carbon atoms; The example comprises: vinyl, propenyl, pseudoallyl, butenyl, isobutenyl, pentenyl and hexenyl.Based on context, " C _2-6Alkenyl " also can refer to the C of two groups of bridge joint _2-6Olefin 2 base; The example comprises: ethene-1,2-two bases (vinylidene), 2-methyl-2-butene-1,4-two bases, 2-hexene-1,6-two bases or the like." C _2-6Alkynyl group " refer to have the carbochain of the straight or branched of at least one carbon-to-carbon triple bond and 2 to 6 carbon atoms; The example comprises: ethynyl, proyl, butynyl and hexin base.

In this article separately or as the term " alkoxyl group " of another group part or " alkylthio " refer to respectively through peroxide connect (O-) or sulphur connect (S-) continuous previously described alkyl.

Refer to alkoxyl group separately or as the term " carbalkoxy " of another group part in this article by the carbonyl bond.Alkoxycarbonyl group represents that with formula-C (O) OR wherein the R group refers to the C of straight or branched _1-6Alkyl, cycloalkyl, aryl or heteroaryl.

In this article separately or as the term " alkyl carbonyl " of another group part refer to the alkyl that links to each other by carbonyl or-C (O) R.

Refer to connect the alkyl carbonyl that links to each other separately or as the term " alkane carbonyl oxygen base " of another group part in this article by oxygen.

Refer to the aromatic nucleus (for example, benzyl) that connects by alkyl as previously described in this article separately or as the term " aralkyl " of another group part.

Refer to monocycle or bicyclic aromatic nucleus separately or as the term " aryl " of another group part in this article, for example, phenyl, phenyl of being substituted or the like also have the condensed group, for example, and naphthyl, phenanthryl or the like.Therefore, aryl can contain at least one ring with at least 6 atoms, has 5 such rings to have (containing 22 atoms at the most) at the most, and between adjacent carbons or the suitable heteroatoms alternately two keys of (resonance) is arranged.Aryl can be chosen wantonly through one or more group and replace; these groups including, but not limited to: halogen is (for example; Br, F or Cl), alkyl (for example; methyl, ethyl or propyl group), alkoxyl group (for example, methoxy or ethoxy), hydroxyl, carboxyl, formamyl, carbalkoxy, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano group, alkyl-S (O) _m(m=0,1,2) or sulfydryl.

Refer to-NH separately or as the term " amino " of another group part in this article ₂-.The substituting group that this amino can be chosen or inequality identical through one or two wantonly replaces, for example, alkyl, aryl, aralkyl, alkenyl, alkynyl group, heteroaryl, heteroaralkyl, the assorted alkyl of ring, the assorted alkyl-alkyl of ring, cycloalkyl, cycloalkylalkyl, alkylhalide group, hydroxyalkyl, alkoxyalkyl, sulfane base, carbonyl or carboxyl.These substituting groups can further be replaced by carboxylic acid, the listed any alkyl or aryl substituting group of this paper.In some embodiments, this amino is replaced by carboxyl or carbonyl, and forms N-acyl group or N-carbamoyl derivatives.

In this article separately or refer to contain the undersaturated hydrocarbon ring of complete saturated and part of 3 to 9 (preferred 3 to 7) carbon atoms as the term " cycloalkyl " of another group part.In addition, this cycloalkyl can be substituted.The cycloalkyl that is substituted refers to have 1,2 or 3 and is selected from following substituent this ring: halogen, alkyl, the alkyl that is substituted, alkenyl, alkynyl group, nitro, cyano group, oxo (=O), hydroxyl, alkoxyl group, sulfane base ,-CO ₂H ,-C (=O) H, CO ₂-alkyl ,-C (=O) alkyl, ketone group ,=N-OH ,=N-O-alkyl, aryl, heteroaryl, heterocyclic radical, 5 or 6 yuan of ketals (that is, 1,3-dioxolane or 1,3-diox) ,-NR ' R " ,-C (=O) NR ' R " ,-CO ₂NR ' R " ,-C (=O) NR ' R " ,-NR ' CO ₂R " ,-NR ' C (=O) R " ,-SO ₂NR ' R " and-NR ' SO ₂R ", wherein, each R ' and R " independently be selected from: hydrogen, alkyl, the alkyl that is substituted and cycloalkyl, or R ' and R " form heterocyclic radical or heteroaryl ring together.

Refer at least one ring, contain 5 or 6 yuan of monocycle bases that are substituted and are unsubstituted of at least one heteroatoms (O, S or N), 9 or 10 yuan of two cyclic group and 11 to 14 yuan of three cyclic groups separately or as the term " heteroaryl " of another group part in this article.Contain each ring of heteroatomic heteroaryl and can contain one or two oxygen or sulphur atom and/or 1 to 4 nitrogen-atoms, preceding topic condition is: each intra-annular heteroatoms adds up to below 4 or 4 and each ring contains at least one carbon atom.The fused rings that constitutes two rings and three cyclic groups can only contain carbon atom and can be saturated, fractional saturation or undersaturated.Nitrogen and sulphur atom can be chosen wantonly oxidized and this nitrogen-atoms can be chosen wantonly by quaternized.Two rings or trinucleated heteroaryl must comprise at least one aromatic nucleus completely, but another (many) individual fused rings then can be aromaticity or nonaromatic.This heteroaryl can connect (attached) at any feasible nitrogen of any ring or the position of carbon atom.This hetero-aromatic ring system can contain 0,1,2 or 3 and be selected from following substituting group: halogen, alkyl, the alkyl that is substituted, alkenyl, alkynyl group, aryl, nitro, cyano group, hydroxyl, alkoxyl group, sulfane base ,-CO ₂H ,-C (=O) H ,-CO ₂-alkyl ,-C (=O) alkyl, phenyl, benzyl, styroyl, phenoxy group, thiophenyl, cycloalkyl, the cycloalkyl that is substituted, heterocyclic radical, heteroaryl ,-NR ' R " ,-C (=O) NR ' R " ,-CO ₂NR ' R " ,-C (=O) NR ' R " ,-NR ' CO ₂R " ,-NR ' C (=O) R " ,-SO ₂NR ' R " and-NR ' SO ₂R ", wherein each R ' and R " independently be selected from hydrogen, alkyl, the alkyl that is substituted and cycloalkyl, or R ' and R " form heterocycle or hetero-aromatic ring together.

Exemplary bicyclic heteroaryl comprises: pyrryl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, di azoly, isoxazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl, oxadiazole base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl or the like.

Exemplary bicyclic heteroaryl includes: indyl, benzothiazolyl, benzo dioxolyl (benzodioxolyl) benzoxazolyl, benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, the indolizine base, benzofuryl, chromone base (chromonyl), tonka bean camphor base (coumarinyl), benzopyranyl, cinnolines base (cinnolinyl), quinoxalinyl, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydro-iso indolyl, tetrahydric quinoline group or the like.

Exemplary tricyclic heteroaryl comprises: carbazyl, benzindole base (benzidolyl), phenanthroline base, acridyl, phenanthridinyl, xanthenyl (xanthenyl) or the like.

Replace and 3 other carbon atoms are wherein arranged at the most separately or as the heteroatoms that one of carbon atom on term " Heterocyclylalkyl " finger ring of another group part is selected from O, S or N in this article by cycloalkyl (nonaromatic) that this heteroatoms replaced.In this article separately or as the term " Heterocyclylalkyl " of another group part refer to stablize, the saturated or undersaturated single-loop system of part, it contains 5 to 7 ring memberses that comprise carbon atom and be selected from other atom of nitrogen, sulphur and/or oxygen.Heterocycle can be 5,6 or 7-unit monocycle and contain 1,2 or 3 heteroatoms that is selected from nitrogen, oxygen and/or sulphur.This heterocycle can be chosen wantonly and be substituted, and means this heterocycle and can be on one or more commutable ring positions independently is selected from following group and replaces by one or more: alkyl (preferred low alkyl group), Heterocyclylalkyl, heteroaryl, alkoxyl group (preferred lower alkoxy), nitro, single alkylamino (preferred lower alkyl amino), dialkyl amido (preferred two [rudimentary] alkylamino), cyano group, halogen, alkylhalide group (preferred trifluoromethyl), alkyloyl, aminocarboxyl, single alkyl amino-carbonyl, the dialkylamino carbonyl, alkyl amido (preferred low alkyl group amido), alkoxyalkyl (preferred lower alkoxy [rudimentary] alkyl), carbalkoxy (preferred lower alkoxycarbonyl), alkyl carbonyl oxygen base (preferred lower alkylcarbonyl oxygen base), and aryl (preferred phenyl); This aryl is optional to be replaced through halogen, low alkyl group and lower alkoxy.The example of this Heterocyclylalkyl comprises: piperazine, piperidines, morpholine, high morpholine (homomorpholine), thiomorpholine (thiomorpholine), tetramethyleneimine and azetidine.

This heteroaryl or Heterocyclylalkyl also can be two rings of 8-11 unit, and it comprises carbon atom and contains 1,2 or 3 heteroatoms that is selected from nitrogen, oxygen and/or sulphur.Some preferred two ring comprises: benzo dioxole (benzodioxole), quinoxaline, indyl, and quinolyl.In this article; when term " is chosen wantonly and be substituted " when being used for " heteroaryl " or " Heterocyclylalkyl "; refer to that this heterocyclic radical can be on one or more commutable ring positions; independently be selected from following group and replace through one or more: alkyl (preferred low alkyl group); alkoxyl group (preferred lower alkoxy); nitro; single alkylamino (preferred lower alkyl amino); dialkyl amido (preferred two [rudimentary] alkylamino); cyano group; halogen; alkylhalide group (preferred trifluoromethyl); alkyloyl; aminocarboxyl; single alkyl amino-carbonyl; the dialkylamino carbonyl; alkyl amido (preferred low alkyl group amido); alkoxyalkyl (preferred lower alkoxy [rudimentary] alkyl); carbalkoxy (preferred lower alkoxycarbonyl); alkyl carbonyl oxy (preferred low alkyl group carbonyl oxygen base) and aryl (preferred phenyl), this aryl is optional through halogen; low alkyl group and lower alkoxy replace.

Term " heteroatoms " refers to O, S or N, and these atoms are independent selections.What must notice is, suppose to have less than any heteroatoms of valence have hydrogen atom and fill up its valence.

Term " halogen " or " halogen " etc. refer to chlorine, bromine, fluorine or iodine, all are independent selections.

Term " carcinostatic agent " comprises any known pharmaceutical agents that is used for the treatment of cancer, it comprises: 17 α-Ethinylestradiol, diethylstilbestrol, testosterone, prednisone (Prednisone), FL (Fluoxymesterone), Drostanolone propionic salt (Dromostanolone propionate), testolactone, Magace (Megestrolacetate), methylprednisolone (Methylprednisolone), methyltestosterone, prednisolone (Prednisolone), triamcinolone (Triamcinolone), Chlortrianisoestrol (chlorotrianisene), hydroxyprogesterone (Hydroxyprogesterone), aminoglutethimide (Aminoglutethimide), estramustine (Estramustine), medroxyprogesterone acetate (Medroxyprogesteroneacetate), leuprorelin acetate (Leuprolide), flutamide (Flutamide), toremifene (Toremifene), goserelin (Zoladex), matrix metallo-proteinase inhibitor, the VEGF inhibitor (comprises as VEGF antibody, for example, A Fansiting (Avastin)), also comprise small molecules, for example, ZD6474 and SU6668, Fan Talani (vatalanib), BAY-43-9006, SU11248, CP-547632 and CEP-7055.Also can use the anti-Her2 antibody (for example, Trastuzumab (Herceptin)) of Genentech.Suitable EGFR inhibitor comprises: Gefitinib (gefitinib), erlotinib (erlotinib) and Cetuximab body (cetuximab).Pan Her inhibitor comprises: replace Buddhist nun (canertinib), EKB-569 and GW-572-016 in the card.What also included has: and Src inhibitor, Dasatinib (dasatinib, BMS-354825), also have Casodex ^(bicalutamide (bicalutamide), Astra Zeneca), tamoxifen (Tamoxifen), MEK-1 kinase inhibitor, mapk kinase inhibitor, PI3 inhibitor and PDGF inhibitor (for example, she replaces Buddhist nun (imatinib) by wheat).Also comprise anti-angiogenic agent and anti-vascular agent (antivascular agent), they are by interrupting flowing to the blood of solid tumor, by depriving the nutrient of cancer cells, make the cancer cells dormancy.Also can utilize castrating art (castration), it also can make the androgenic cancer knurl of dependence breed.Also include IGF1R inhibitor, non-acceptor and receptor tyrosine kinase inhibitors, and whole connection signal (integrin signaling) inhibitor.Other carcinostatic agent includes: microtubule stabilizer, for example, taxol (is also referred to as Taxol ^), Docetaxel (is also referred to as Taxotere ^); 7-O-methyl thiomethyl taxol (is disclosed in United States Patent (USP) 5; 646; 176); 4-deacetylate-4-methyl carbonic taxol (4-desacetyl-4-methylcarbonatepaclitaxel); 3 '-tertiary butyl-3 '-N-tertbutyloxycarbonyl-4-deacetylate-3 '-go phenyl-3 '-N-to go benzoyl-4-O-methoxycarbonyl-taxol (to be disclosed in USSN 09/712; application on November 14th, 352,2000); C-4 methyl carbonic taxol (C-4 methyl carbonate paclitaxel); Epothilones A (epothilone A); epothilone B; Epothilone C; epothilone d; deoxy Epothilones A (desoxyepothilone A); the deoxy epothilone B; [1S-[1R ^*, 3R ^*(E), 7R ^*, 10S ^*, 11R ^*, 12R ^*, 16S ^*]]-7-11-dihydroxyl-8,8,10,12,16-pentamethyl--3-[1-methyl-2-(2-methyl-4-thiazolyl) vinyl]-4-azepine-17-oxabicyclo [14.1.0] heptadecane-5,9-diketone (being disclosed in WO 99/02514), [1S-[1R ^*, 3R ^*(E), 7R ^*, 10S ^*, 11R ^*, 12R ^*, 16S ^*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-the 1-methyl ethylene]-7,11-dihydroxyl-8,8,10,12,16-pentamethyl--4,17-two oxabicyclos [14.1.0] heptadecane-5,9-diketone (being disclosed in United States Patent (USP) 6,262,094) and these derivative; And microtubule disrupting agent (microtubule-disruptoragent).What also be fit to has: the CDK inhibitor; The antiproliferative cell cycle inhibitor; Epidophylltoxin (epidophyllotoxin); The enzyme of antitumor formation; Topology isomerase (topoisomerase) inhibitor; Procarbazine; Mitoxantrone (mitoxantrone); Platinum coordination complex (for example, cis-platinum and carboplatin); Biological response modifiers (biological response modifier); Growth inhibitor; The hormone antagonist therapeutical agent; Calciumlevofolinate (leucovorin); Tegafur (tegafur); And hemopoieticgrowth factor.

Other cytotoxic agent comprises: melphalan (melphalan), hexamethyl trimeric cyanamide (hexamethyl melamine), plug is for sending (thiotepa), cytosine arabinoside (cytarabin), Yi Da petrin (idatrexate), trimetrexate (trimetrexate), Dacarbazine (dacarbazine), L-Asnase, camptothecine (camptothecin), Hycamtin (topotecan), bicalutamide (bicalutamide), flutamide (flutamide), leuprorelin acetate (leuprolide), pyrido benzindole derivative, Interferon, rabbit, and interleukin (interleukins).

Pyridine ring on the N atom that pyridine-N-oxygen base refers to have Sauerstoffatom to be substituted in pyridine ring.

When the functional group is called " being protected by (warp) ", be meant that this group is modified form, on protected position, to get rid of undesirable side reaction.For The compounds of this invention; suitable blocking group can be according to the present invention and is considered those skilled in the art's level; while reference standard textbook is Greene for example; T.W. wait the people; Protective Groups in Organic Synthesis; Wiley, N.Y. (1991) is confirmed.

All mammal species contained in used in this article " patient " speech.

Be used for " pharmacy acceptable salt " speech herein, except as otherwise noted, comprise come across formula I or II compound in acidity or the salt of basic group.Person's character is the formula I of alkalescence and the compound of II can form kind salt widely with various inorganic and organic acids.The acid that can be used for the pharmaceutically-acceptable acid addition of these basic cpds shown in preparation formula I and the II is those acid that can form non-toxic acid addition salt, this non-toxic acid addition salt, that is contain on the pharmacology and can accept anionic salt, for example, the hydrogen chlorate, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, Yi Yansuan salt, acetate, lactic acid salt, salicylate, Citrate trianion, the acid Citrate trianion, tartrate, pantothenate, bitartrate, ascorbate salt, succinate, maleic acid salt, gentisate, fumarate, gluconate, acetyl gluconate (glucaronate), saccharate, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, tosilate and pamoate (pamoate) (that is, 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)).

Compound of the present invention has the structure of following formula I or II:

Comprise their pharmacy acceptable salts, wherein:

Each R ²Independent is H, halogen, cyano group, NO ₂, OR ⁵, NR ⁶R ⁷, alkyl, the alkyl that is substituted, cycloalkyl, the cycloalkyl that is substituted, aryl, the aryl that is substituted, heteroaryl, the heteroaryl that is substituted, heterocyclic radical, the heterocyclic radical that is substituted, aralkyl, the aralkyl that is substituted, Heterocyclylalkyl or the Heterocyclylalkyl that is substituted;

B is O, NR ⁸, S, SO, SO ₂, CR ⁹R ¹⁰

V is NR ¹¹Or-(CR ⁴⁷R ⁴⁸) _p-;

W or X independently are C or N;

Y is O, S or NR ¹²

Z is-CR ¹³R ¹⁴-,-(CR ¹³R ¹⁴) _mNR ¹⁵-;

L is 0 to 4;

M is 0 to 2;

N is 0 to 4;

A is:

Q is CR ¹⁹

D is CR ²⁰Or N;

G is S, O or NR ²¹, preceding topic condition is: if A is

And G is S, then R ⁴It is not the phenyl that is substituted;

R ¹²Be H, alkyl, the alkyl that is substituted, CN, NO ₂Or SO ₂NH ₂

R ¹⁹Be H or cyano group;

The present invention also provides a kind of treatment proliferative disease, and () method for example, cancer, it is by carrying out to the patient who needs this treatment as the compound administration of defined formula I of preamble or II significant quantity.

In another embodiment, the invention provides a kind of method for the treatment of proliferative disease via the kinase whose mediation of Met, it is to be administered to the patient who needs this treatment by the compound as defined formula I of preamble or II with significant quantity together with (while or priority successive administration) at least a other carcinostatic agent, carries out.In preferred embodiments, this proliferative disease is a cancer.

The present invention also provides medical composition, and it comprises together with the formula I of pharmaceutically acceptable carrier or the compound shown in the II.

Particularly, the compound of formula I and formula II can be used for treating various cancers, includes but is not limited to following cancer:

(a) cancer comprises that bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer comprise that small cell lung cancer, the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma comprise squamous cell carcinoma;

(b) the hematopoiesis tumour of lymphatic system comprises: aleukemic leukemia (leukemia), acute lymphoblastic leukemia, acute lymphoblastic leukemia (acute lymphoblastic leukemia), B cell lymphoma, t cell lymphoma, hodgkin's lymphomas (Hodgkin ' s lymphoma), non-Hodgkin formula lymphoma, galley proof cell lymphoma and Bo Kete lymphomas (Burkett ' s lymphoma);

(c) the hematopoiesis tumour of myeloid lineage comprises: acute and chronic granulocytic leukemia (myelogenous leukemias), myelodysplastic syndrome (myelodysplastic syndrome) and promyelocytic leukemia;

(d) matter source tumour comprises: fibrosarcoma and rhabdosarcoma between;

(e) tumour of maincenter and peripheral nervous system comprises astrocytoma, neuroblastoma, neurospongioma and schwannoma; And

(f) other tumour comprises: melanoma, spermocytoma, teratoma, osteosarcoma, pigment xeroderma (xenoderoma pigmentosum), molluscum pseudocarcinomatosum (keratoctanthoma), Tiroidina folliculus cancer and Kaposi sarcoma (Kaposi ' s sarcoma).

Because the keying action that protein kinase is risen in general cell proliferation, therefore, its inhibitor can be used as the reversible cytostatics, and be used for the treatment of any is the lysis of feature with the abnormal cell proliferation, for example, benign prostate propagation, familial adenomatous polyposis disease (familial adenomatosis), polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, sacroiliitis, psoriasis, glomerulonephritis, restenosis after angioplasty or the vascular operation, the formation of hypertrophic cicatrix, inflammatory bowel, transplant rejection, endotoxin shock, and fungal infection.

Can be used for treating cancer as the compound of the formula I of apoptotic conditioning agent and II (comprises, but be not limited to, the cancer kind that preamble is listed), virus infection (comprises, but be not limited to: simplexvirus (herpevirus), poxvirus, Epstein-Barr virus (Epstein-Barr virus), new this virus of Derby (Sindbisvirus) and adenovirus), the intravital AIDS development of the patient of HIV of having protected from infection, autoimmune disorder (comprises, but be not limited to: systemic lupus erythematosus (systemic lupus), systemic lupus erythematosus (erythematosus), the glomerulonephritis that autoimmunization is regulated, rheumatoid arthritis, psoriasis, inflammatory bowel, and the diabetes of autoimmunity), neurodegenerative disorders (comprises, but be not limited to: the A Erzi Alzheimer disease (Alzheimer ' s disease), with AIDS dependency dementia, Ba Jinshengshi disease (Parkinson ' s disease), amyotrophic lateral sclerosis, retinitis pigmentosa (retinitispigmentosa), Duchenne-Arandisease and cerebellar degeneration), osteomyelodysplasia syndromes (myelodysplastic syndromes), aplastic anemia, with myocardial infarction, the ischemia injury that apoplexy and reperfusion injury are relevant, Arrhythmias, atherosclerosis, that toxin brings out or relevant hepatopathy with alcohol, hematologic disease (comprises, but be not limited to: chronic anaemia and aplastic anemia), the degenerative disease of musculoskeletal system (including, but are not limited to: osteoporosis and sacroiliitis), for acetylsalicylic acid sinusitis paranasal sinusitis hypersensitive (rhinosinusitis), cystic fibrosis (cystic fibrosis), multiple sclerosis, kidney disease and cancer pain.

RNA and DNA synthetic level in the adjustable ganglion cell of the compound of formula I and II.Therefore, these medicaments can be used for treating virus infection (including, but are not limited to: HIV, human papillomavirus, simplexvirus, poxvirus, Epstein-Barr virus, new this virus of Derby and adenovirus).

The compound of formula I and II can be used for the chemoprophylaxis of cancer.So-called chemoprophylaxis is defined as: by the beginning of blocking gene catastrophic event or by blocking the recurrence of cancerate precellular development or the inhibition tumour damaged, suppress the development of morbidity property cancer.

The compound of formula I and II also can be used for suppressing the vasculogenesis and the transfer of tumour.

Through finding that some compound of the present invention can suppress the protein kinase beyond the Met, for example, belongs to those of Trk protein kinase family.

The compounds of this invention can also be united (together or successively administration) known anticancer therapy, radiotherapy or use the cell growth-inhibiting or cytotoxic agent for example, for example (but being not limited to): the DNA agent, for example, cis-platinum or Dx (doxorubicin); Topology isomerase II inhibitor, for example, Etoposide (etoposide); Topology isomerase I inhibitor, for example, CPT-11 or Hycamtin (topotecan); The tubulin agent, for example, the epothilones of taxol, Docetaxel or natural or synthesized form (for example, Yi Shabeipilong (ixabepilone)); The hormone medicament, for example, tamoxifen (tamoxifen); Thymidylic acid (thymidilate) synthetase inhibitors, for example, 5 FU 5 fluorouracil (5-fluorouracil); And anti-metabolic thing (anti-metabolites), for example, methotrexate (methotrexate); Also have other tyrosine kinase inhibitor, for example, Ai Ruisha (Iressa) and OSI-774; Angiogenesis inhibitor; The EGF inhibitor; The VEGF inhibitor; The CDK inhibitor; Src inhibitor; The c-Kit inhibitor; Her 1/2 inhibitor and the directed monoclonal antibody that suppresses growth factor receptors, for example, erbium (erbitux) (EGF) and Trastuzumab (herceptin) (Her2).

The medical composition that contains activeconstituents can be the oral form that is applicable to, for example, and tablet, lozenge, lozenge, water-based or oily suspensions, dispersible pulvis or granula, emulsion, hard or soft capsule or syrup or elixir.Being intended for use oral composition can get according to prior art known any preparation for the method for making medical composition, and said composition can contain one or more and be selected from following medicament: sweeting agent, seasonings, tinting material and sanitas, so that pharmaceutically attractive in appearance and good to eat preparation is provided.Tablet contains activeconstituents together with blended nontoxicity with it, the pharmaceutically acceptable vehicle of making tablet that is applicable to.These vehicle can be, for example, and inert diluent (for example, lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate); Granulation agent and disintegrating agent (for example, Microcrystalline Cellulose, cross-linked cellulose sodium (sodium crosscarmellose), W-Gum or Lalgine); Tackiness agent (for example, starch, gelatin, Polyvinylpyrolidone (PVP) or gum arabic); And lubricant (for example, Magnesium Stearate, stearic acid or talcum).Tablet can be a dressing not, also can be by covering the unhappy smell of medicine or postpone its disintegration in gi tract and the currently known methods of absorption carries out dressing, thereby in the longer time acquisition continuous action.For example, can adopt water-soluble taste masking material, for example, Vltra tears or hydroxypropylcellulose; Or the time-delay material, for example, ethyl cellulose, cellulose acetate butyrate.

Be used for the form that oral preparation also can be hard capsule, wherein, activeconstituents and inert solid diluent (for example, lime carbonate, calcium phosphate or kaolin) mix; Or be the form of soft capsule, wherein, activeconstituents and water-soluble carrier (for example, polyoxyethylene glycol) or oil medium (for example, peanut oil, whiteruss or sweet oil) mix.

The vehicle that is applicable to the manufacturing waterborne suspension that waterborne suspension contains active substance and mixes with it.This vehicle is a suspending agent, for example, and Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, Polyvinylpyrolidone (PVP), tragakanta and gum arabic; Dispersion agent or wetting agent can be natural phosphatide, for example, Yelkin TTS, or the condensation product such as the polyoxyethylene stearic acid ester of alkene oxide (alkyleneoxide) and lipid acid, or the condensation product of ethylene oxide and long chain aliphatic alcohol (for example, 17 (ethene) oxygen base hexadecanol (heptadecaethylene-oxycetanol)), or ethylene oxide and (for example derived from the condensation product of the partial ester of lipid acid and hexitol, the polyoxyethylene sorbitol monoleate), or ethylene oxide and derived from the condensation product (for example, polyoxyethylene dehydration sorbitanic monoleate (polyethylene sorbitanmonooleate)) of the partial ester of lipid acid and hexitan.This waterborne suspension also (for example can contain one or more sanitass, ethyl p-hydroxybenzoate or propyl ester), one or more tinting materials, one or more seasoningss and one or more sweeting agents (for example, sucrose, asccharin or aspartame (aspartame)).

Oily suspensions can be by being suspended in activeconstituents preparation in vegetables oil (for example, peanut oil, sweet oil, Viscotrol C or Oleum Cocois), the mineral oil (for example, whiteruss).This oily suspensions can contain thickening material, for example, and beeswax, paraffinum durum or hexadecanol.Can add sweeting agent as previously described, and seasonings, so that good to eat oral preparations is provided.These compositions can come anticorrosion by adding antioxidant (for example, butylated hydroxyanisol or alpha-tocopherol).

But be applicable to by add water prepare the dispersion powder of waterborne suspension and granula contain activeconstituents and with its blended dispersion agent or wetting agent, suspending agent and one or more sanitass.Suitable dispersion agent or wetting agent and suspending agent such as preamble illustrative those.Also can have other vehicle, for example, sweeting agent, seasonings and tinting material.These compositions can come anticorrosion by adding antioxidant (for example, xitix).

Medical composition of the present invention also can be oil-in-water emulsion form.This oil phase can be vegetables oil, for example, and sweet oil or peanut oil; Mineral oil, for example, whiteruss; Or their mixture.Suitable emulsifying agent can be natural phosphatide, for example, and soybean lecithin; And derived from the ester or the partial ester (for example, dehydrated sorbitol mono-fatty acid ester) of lipid acid and hexitan; And the condensation product of aforementioned partial ester and oxyethane (for example, polyoxyethylene sorbitan monoleate).These emulsions also can contain sweeting agent, seasonings, sanitas and antioxidant.

Syrup and elixir can be formulated together with sweeting agent (for example, glycerine, propylene glycol, Sorbitol Powder or sucrose).These preparations also can contain negative catalyst, sanitas, seasonings, tinting material and antioxidant.

Medical composition of the present invention can be aseptic aqueous solution for injection form.Adoptable carrier and the solvent accepted is water, Ringer's solution (Ringer ' s solution) and isotonic sodium chlorrde solution.

Aseptic injection preparation also can be aseptic water for injection bag oil microemulsion, and wherein, activeconstituents is dissolved in the oil phase.For example, activeconstituents can be dissolved in earlier in the mixture of soybean oil and Yelkin TTS.Then, this oily solution is imported the mixture of water and glycerine, and processed and form micro emulsion.

Injection solution or micro emulsion can import in patient's the blood flow by local bolus injection method.Perhaps, using this solution or micro emulsion so that the circulation composition of The compounds of this invention is kept the constant mode, also is favourable.In order to keep this constant density, can utilize to continue the vein delivery apparatus.The example of this device is the venous pump of Deltec CADD-PLUS.TM. model 5400.

Pharmaceutical composition can be sterile injectable water or the oiliness suspensoid form that is used for intramuscular or subcutaneous administration.This suspension can utilize previously described those suitable dispersion agents or wetting agent and suspending agent to prepare according to currently known methods.This aseptic injection preparation also can be at nontoxicity, non-aseptic injection solution or form of suspension in enteral administration acceptable diluent or solvent, for example, and the solution form in 1,3 butylene glycol.In addition, on convention, use aseptic, nonvolatile oils as solvent or suspension matrix.For reaching this purpose, can adopt any non-irritating non-volatile oils, comprising: the synthetic list-or two glyceryl ester.In addition, lipid acid, for example, oleic acid can be used for preparing injection preparation.

The compound of formula I and II can also suppository form come administration, for the usefulness of the per rectum administration of medicine.These compositions can make by medicine is mixed with suitable nonirritant excipient, and this vehicle is solid-state at normal temperatures, but is liquid under rectal temperature, thereby, can melt and disengage medicine at internal rectum.This material comprises: the mixture of cocoa butter, glycerine gelatin, hydrogenant vegetables oil, various molecular weight polyethylene glycol and the fatty acid ester of polyoxyethylene glycol.

With regard to topical application, can adopt creme, ointment, gel, solution or suspension of comprising formula I compound or the like.(purpose that should use, topical application should comprise mouth wass and gargle).

Compound of the present invention can use carrier and delivery apparatus in the suitable nose via the part, or via through the skin approach, the transdermal patch form that adopts those of ordinary skills to know is come nose administration.For the form with transdermal delivery system is come administration, at whole dosage range, the dosage usage is necessary for successive certainly, but not intermittently.Compound of the present invention can also suppository form send, this suppository adopts for example following matrix: the mixture of cocoa butter, glycerine gelatin, hydrogenant vegetables oil, various molecular weight polyethylene glycol and the fatty acid ester of polyoxyethylene glycol.

When compound administration of the present invention during in human patient, every day, dosage was decided by the doctor who prescribes usually, and this dosage also has the severity of patient's symptom usually along with each patient's age, body weight, sex and reaction, and different.

When if this compound artifact is formulated as fixed dosage, it adopts in the compound of the present invention of aforementioned dosage range and other forms of pharmacologically active agents or treatment in its permissible dose scope.When the preparation that makes up was improper, the compound of formula I and II also can be docile and obedient preface successively, with known carcinostatic agent or cytotoxic agent administration in succession.The present invention is also unrestricted on the order of administration, and the compound of formula I and II can come administration before or after using (one or more) known anticancer agents or cytotoxic agent.

Some compound shown in formula I and the II can prepare according to schema 1-16 hereinafter usually.These compounds use synthetic method well known by persons skilled in the art preparation and.The compounds tautomeric of the compound of formula I and II and solvate (for example, hydrate) also belong to scope of the present invention.The method of solvation is generally known in the art.Therefore, compound of the present invention can be the form of free or hydrate, and can get by the illustrated method preparation of following schema.

Generally speaking, desired condensed heterocyclic compouds can get by the preparation of the route of synthesis shown in the schema 1-3.The leaving group (Lg) of heterocycle (A, the position of wherein having vacant position can be chosen wantonly and be substituted) 1, for example, the phenol 2 that halogen (or trifluoromethanesulfonic acid root (triflate)) can be substituted replaces, and obtains ether 3 (schema 1).Group A-Lg can basis, for example, and the universal program preparation that following document is listed and getting: Hunt, J.T.et al.WO 00/071129; Hunt, J.T.et al.J.Med.Chem.2004,47,4054-4059; Leftheris, K.et al.WO 02/040486; Mastalerz, H.et al.WO 03/042172; Dyckman, A.et al.WO 03/091229; Vite, G.D.et al.WO 04/054514; Salvati, M.E.et al.WO 03/082208; Thibault, C.et al.Org.Lett.2003,5,5023-5025; Zhang, Z.et al.J.Org.Chem.2002,67,2345-2347; Itoh, T.et al.J.HeterocyclicChem.1982,19,513-517; Tedder, M.E.et al.Bioorg.Med.Chem.Lett.2004,14,3165-3168; Dorn, H.et al.J.Prakt.Chem.1982,324,557; Sanghvi, Y.S.et al.J.Med. Chem.1989,32,945-951; Temple, C.Jr.et al.J.Org.Chem.1972,37,3601-3604; Hurst, J.et al.EP119774; Hurst, J.et al.EP151962; Ward, R.W.etal.EP152910; Luzzio, M.J.et al.WO 01/094353; Marx, M.A.et al.WO03/000194; Boschelli, D.H.et al.WO 04/048386; He, M.et al.WO 05/021554; Barker, J.M.et al.J.Chem.Res., Synoses, 1986,4,122-123; The disclosure of these documents is incorporated this paper into as a reference.Utilize, for example, zinc powder and ammonium chloride or Adams'catalyst (Adam ' s catalyst) (platinum oxide (IV)), under the catalytic hydrogenation conditions,, obtain aniline 4 with the nitroreduction of intermediate 3.With isocyanic ester 5 (X=O) or lsothiocyanates 5 (X=S), handle aniline 4, can obtain desired acylurea or acylthioureas 6 respectively.

Schema 1

The Lg=leaving group, for example, halogen

X=O or S

G is O, S or NR ²¹

D is CR ²⁰Or N

V=such as preamble define

Perhaps, with isocyanic ester 5 (X=O) or lsothiocyanates 5 (X=S), handle aniline 7, and obtain phenol 8 (schema 2) through suitable replacement.Intermediate 8 and heterocycle (A-Lg) 1 reaction can provide desired compound 6.

Schema 2

The Lg=leaving group, for example, halogen

X=O or S

G is O, S or NR ²¹

D is CR ²⁰Or N

V=such as preamble define

Generally speaking, amide derivatives of the present invention can pass through schema 3 described chemical processes, the preparation and get.For example, available compound 10 with aniline 9 (deriving from schema 1) acidylate, and obtains acid amides 11.For example using, sodium hydroxide obtains carboxylic acid 12 with ester 11 hydrolysis.Then,, adopt known amido linkage formation condition, obtain desired compound 13 by intermediate 12.Perhaps, adopt carboxylic acid 14 and coupler, for example, benzotriazole-1-base oxygen base three (trimethylammonium amino) phosphine  hexafluorophosphate, 1-(dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride or bromo tripyrrole alkane phosphine  hexafluorophosphate are converted into compound 13 with aniline 9.With acyl chlorides 15 (X=Cl) or carboxylic acid 15 (X=OH) and coupler, handle aniline 9, obtain the acid amides of Class1 6.

Schema 3

G is O, S or NR ²¹

D is CR ²⁰Or N

V=such as preamble define.

The Hete rocyclic derivatives that is substituted, for example, Pyrrolotriazine compounds 26a/b (schema 5) can get by the preparation of the route of synthesis shown in the schema 4 and 5.Carboxylicesters (wherein, R (for example can be alkyl or aryl, phenyl)) 17 can contact, and produce the tertiary alcohol 18 (schema 4) with being no less than 2 normal alkyl or aryl organometallic reagents (for example, Grignard reagent (Grignard reagent), organolithium, organic zinc or the like).This reaction is carried out in ether solvents (for example, tetrahydrofuran (THF), butyl ether or ether) or the reactive solvent of other any not tool (for example, benzene, toluene or hexane) usually.Can exist down at hydrogen peroxide or organo-peroxide (for example, tertbutyl peroxide, isopropyl benzene hydroperoxide) by mixture, handle this tertiary alcohol 18, be hydroxyl pyrrolotriazine 19 and reset with acid.Almost any acid all can be used as the catalyzer of this oxidisability rearrangement reaction, and organic acid, mineral acid and Lewis acid are all through confirming can be used for this reaction.The acid that once was used to this type of reaction comprises: tosic acid, methylsulfonic acid, formic acid, sulfuric acid, nitric acid, BF ₃-OEt ₂, trifluoroacetic acid, acid zeolite and acidic ion exchange resin.The concentration of acid can change, the kinetics that the concentration of acid and intensity are used for controlling reaction.The concentration of superoxide can change between 30-50%.But the reductive agent of any reaction decomposes hydrogen peroxide all can be used for this reaction of cancellation, and described reductive agent is including, but not limited to pyrosulphite hydrogen sodium, sodium bisulfite, Sulfothiorine, V-Brite B (sodium hydrosulfite).Various bases can be used to the cancellation reaction and control pH simultaneously.Hydroxyl pyrrolotriazine 19 can with various acylation reactions, and provide 20 (wherein, for example, P can be pivalate).Compound 20 can with suitable halogenating agent (for example, phosphoryl chloride, POCl ₃) contact, and produce 21 (L=Cl).POCl ₃Other reagent of finishing this conversion reaction in addition comprises: PCl ₅, PCl ₅/ POCl ₃Mixture, PhP (O) Cl ₂, SOCl ₂Usually can use amine (to comprise: triethylamine, PhNMe ₂, DABCO or the like) come this reaction of catalysis.In addition, benzamide type (for example, N, dinethylformamide) and alkylamide (for example, N-Methyl pyrrolidone) also can be used for this reaction of catalysis.This reaction can be carried out in be any solvent of inert (comprising: benzene, toluene, THF or the like) for halogenating agent.

Schema 4

The available optional phenol 2 that is substituted is handled the group with imine moiety 21 (schema 5) through due care, and obtains intermediate 22.Via carrying out three letter reactions (Mitsunobu reaction), can protect (when the P=pivalate, adopting sodium hydroxide) resulting phenol 23 to be converted into ether 24 with going by compound 22 with alcohol.Use and aforementioned schema 1 described identical condition, the nitro substituent reduction with 24 obtains aniline 25.Adopt aforementioned schema 1 and 3 described chemical processes, can finish the reaction that aniline 25 is converted into desired acylurea, acylthioureas or acid amides 26a/b.

Schema 5

Use schema 6 described chemical processes, can make amine compound 30.Ester 27 with, for example, the reaction of diisobutyl aluminium hydride (DIBAL-H) can provide alcohol 28.Compound 28 with, for example, Dai Si-Martin crosses iodine alkanoic acid (periodinane) (1,1,1-three (acetoxyl group)-1,1-dihydro-1,2-benzo iodine heterocyclic pentene-3-(1H)-ketone) (1,1,1-tris (acetyloxy)-1,1-dihydro-1, the oxidizing reaction of 2-benziodoxol-3-(1H)-one) can provide aldehyde 29.Aldehyde 29 and the amine that suitably is substituted carry out the reductive amination reaction under reductive agent (for example, sodium triacetoxy borohydride) exists, desired amine 30 can be provided.

Schema 6

Use flow process chemical process shown in Figure 7, can be with various substituting groups, for example, the optional groups such as aryl, heteroaryl or vinyl that are substituted import on the 5-position of pyrrolo-[2,1-f] [1,2,4] triazine ring.Amino-pyrroles derivative 31 can carry out cyclisation in the presence of methane amide, and produces 5-chlorine pyrrolo-[2,1-f] [1,2,4] triazine-4 (3H)-ketone (32).In the presence of alkali (for example, conspicuous Ning Shi alkali (Hunig ' s base)), at high temperature, use POCl ₃Handle intermediate 32, obtain 4,5-dichloro pyrrolo-[2,1-f] [1,2,4] triazines (33).There is the coupled reaction of being carried out down with compound 33 in phenol 2 through suitably replacing at alkali (for example, salt of wormwood), and intermediate 34 can be provided.Use zinc powder and ammonium chloride, can be with 34 nitroreduction, and produce aniline 35.The coupled reaction of the platinum mediation of being carried out with various boric acid can provide intermediate 36, uses aforesaid chemical process, this intermediate 36 can be converted into desired compound 37 or 38.

Schema 7

By phenol 7 couplings that triethyl ammonium salt 39 and warp are suitably replaced, and then under alkali (for example, conspicuous Ning Shi alkali) exists, handled with amine (HNR ' R "), also can finish the substitution reaction on the 5-position of pyrrolo-[2,1-f] [1; 2,4] triazine ring, and aniline 40 (schema 8) is provided.As mentioned before, can be further processed aniline 40, and produce desired compound 41 or 42.

Schema 8

Perhaps, under the tetracol phenixin medium and high temperature, with for example N-bromosuccinimide (NBS) and 2, the two isopropyl cyanides (AIBN) of 2 '-nitrine are with 5-methyl-4-(methylthio group) pyrrolo-[2,1-f] [1,2,4] triazines (43) bromination (schema 9).In the presence of alkali (for example, conspicuous Ning Shi alkali), handle this bromide intermediate with amine (HNR ' R "), can produce intermediate 44.The oxidation of 44 thiomethyl can be passed through usefulness, and for example, 3-chlorine peroxybenzoic acid (m-CPBA) is finished.Use the phenates (phenoxide) and two (trimethyl silyl) amination sodium (NaHMDS) that are produced by compound 7 to handle the sulfone intermediate, aniline intermediate 45 can be provided.

Schema 9

Use flow process chemical process shown in Figure 10, can make pyrrolo-[2,3-b] pyridine intermediate 50.The use Thibault C. and the described synthetic order of working together thereof (Org.Lett.2003,5,5023-5025) (be illustrated in flow process Figure 10), by commercially available 1H-pyrrolo-[2,3-b] pyridines (46), obtain 4-chloro-1H-pyrrolo-[2,3-b] pyridines (49).At high temperature, handle intermediate 49, obtain crucial intermediate 50,, can be translated into desired compound by schema 1 and 3 described chemical processes with phenol 2.

Flow process Figure 10

Use flow process Figure 11 and 12 described chemical processes, various substituting groups can be imported on the 3-position of pyrrolo-[2,3-b] pyridine ring.For example, in the presence of aluminum chloride, with intermediate 50 acidylates, obtain compound 51 (flow process Figure 11) with the 2-bromoacetyl chloride.Handle intermediate 51 with amine (R " R ' NH) or thiocarbamide, then carry out follow-up reduction reaction, can obtain aniline 52 and 54 respectively with zinc powder and ammonium chloride.

Flow process Figure 11

Perhaps, existing down at alkali (for example, sodium hydride), with for example (2-chlorine methoxyl group) ethyl) trimethyl silane protects compound 50, then gives bromination with NBS, obtains intermediate 55 (flow process Figure 12).Then,, in the presence of palladium and/or copper catalyst, handle bromide 55, can obtain intermediate 59-61 respectively with the alkynes 56, boric acid aryl ester/aryl boric acid 57 or the vinyl stannane 58 that are substituted.With tetrabutylammonium (TBAF), the protecting group of 59-61 is removed, then carry out the reduction of nitro, obtain corresponding aniline intermediate, use schema 1 and 3 described chemical processes, can be with this aniline intermediate acidylate.

Flow process Figure 12

Use the chemical process shown in flow process Figure 13 and 14, various substituting groups can be imported on the 2-position of pyrrolo-[2,3-b] pyridine nucleus.At low temperatures, successively handle 7-azaindole derivatives 62 (derived from compound 49, flow process Figure 10) (flow process Figure 13) through protection with n-Butyl Lithium and triisopropyl borate ester.Then, can be with intermediate hydrolysis that should necessity, and produce boric acid 63.Use palladium catalyst, can finish the coupling of this boric acid 63 and various aryl or heteroaryl halogenide 64, and obtain intermediate 65.Use TBAF, the protecting group with 65 is removed, and obtains compound 66, at high temperature, is handled with phenol 2, obtains intermediate 67.Use and aforementioned similar chemical process, compound 67 further can be modified, and be obtained desired compound.

Flow process Figure 13

Perhaps, use the described chemical process of flow process Figure 14, compound 62 is converted into iodide 68.This intermediate 68 in the presence of transition metal [that is, Pd (OAc) ₂, with reference to Chi, S.M.et al.Tetrahedron Lett.2000,919-922],, and obtain 69 with all ingredients (for example, boric acid, organic tin compound (organo-stannes) or the alkene that is substituted) coupling.Use previously described chemical process, intermediate 69 can be converted into desired analogue.

Flow process Figure 14

By being two step procedure of raw material, obtain pyridone intermediate 74 (flow process Figure 15) with commercially available (E)-dimethyl 2-(3-methoxyl group propenylidene) malonic ester (70).Therefore, at room temperature, handle this compound 70, obtain intermediate 72, then, under alkali (for example, sodium hydride) exists, in methyl-sulphoxide,, and produce 73 these intermediate 72 cyclisation with amine or aniline 71.Under alkaline condition, with intermediate 73 hydrolysis, obtain desired pyridone intermediate 74, schema is described as described above for it, with various aniline category matter couplings.

Flow process Figure 15

By following two step methods: with commercially available 6-bromine 2-pyridine carboxylic acid (75) in the presence of palladium (0) catalyzer and yellow soda ash, with boric acid or (borinate) 76 couplings of hexamethylene borate (ester), then, at high temperature, with intermediate 77 oxidations of necessity, obtain pyridyl N-oxide compound intermediate 78 (flow process Figure 16).Schema is described as described above, intermediate 78 can with various aniline couplings.

Flow process Figure 16

Embodiment hereinafter and preparation example are described manufacturing and are used mode of the present invention and method, and are illustrative and nonrestrictive.It should be understood that to exist and fall into spirit of the present invention and other interior embodiment of scope that appended claims limits.

Analyze

The pharmacological properties of The compounds of this invention can be confirmed by a large amount of pharmacology analysis.Compound of the present invention and/or their pharmacy acceptable salts have carried out the pharmacology analysis that example is hereinafter described used.

The Met kinases is analyzed

Reagent The ultimate density of substrate (substrate) mixture

Stock solution

Tris-HCl(1M，pH7.4) 20mM

MnCl ₂(1M) 1mM

DTT(1M) 1mM

BSA(100mg/ml) 0.1mg/ml

polyGlu ₄/tyr(10mg/ml) 0.1mg/ml

ATP(1mM) 1μM

γ-ATP(10μCi/μl) 0.2μCi/ml

Buffer reagent Enzyme mixture

20 μ l 1M DTT, 4 μ l GST/Met enzyme (3.2mg/ml)=10ng/rxn

200 μ l 1M Tris-HCl, an amount of 12ml buffer reagent of pH7.4

20μl?100mg/ml?BSA

An amount of 20ml H ₂O

The culturing mixt that is used for the analysis of Met kinases contain synthetic substrate polyGlu: Tyr (4: 1), ATP, ATP-γ- ³³P and contain Mn ⁺⁺And/or Mg ⁺⁺Buffer reagent, DTT, BSA and Tris buffer reagent.Reactant was cultivated 60 minutes down in 27 ℃, and passed through to add cold trichoroacetic acid(TCA) (TCA) and termination reaction, and ultimate density is 4%.Use Filtermate Universal Harvester (Packard InstrumentCo., Meriden, CT), with the TCA throw out be collected into GF/C micro-filtration dish (unifilter plate) (PackardInstrument Co., Meriden, CT), and with liquid scintillometer (the PackardInstrument Co. in TopCount 96 holes, Meriden CT), carries out quantitative assay to filter.Make dose response curve, to determine to suppress the required concentration (IC of 50% kinase activity ₅₀).Under 10mM, compound dissolution in dimethyl sulfoxide (DMSO) (DMSO), and to be assessed under six kinds of concentration, each repeats four times.In analysis, the ultimate density of DMSO is 1%.Utilize non-linear regression analysis, obtain IC ₅₀Value, and variation (variance) coefficient (SD/ mean value, n=6)=16%.

The compounds of this invention suppresses the IC of Met kinases ferment ₅₀Value is between 0.01 to 100 μ M.The IC of preferred compound ₅₀Value is less than 1.0 μ M, and is more preferably less than about 0.5 μ M.

Embodiment

All reactions all under the atmosphere of drying nitrogen or argon gas, are carried out under the condition of continuous magnetic agitation.All evaporations and concentration operation all descend, are carried out in rotatory evaporator in decompression.Commercially available reagent directly uses, and is not further purified.Solvent is industrial anhydrous grade, and directly uses, not further drying or purifying.(EMerck Kieselgel 60 carries out on 0.040-0.060mm) flash chromatography at silica gel.

Use Phenomenex Luna C18 S5 4.6mm * 50mm post or YMC S5 ODS 4.6 * 50mm post to carry out analytical anti-phase (RP) HPLC.Under each situation, adopt 4 minutes linear gradients (100%A:0%B to 0%A:100%B), and following moving phase system: A=90% water/methyl alcohol+0.2%H ₃PO ₄B=90% methanol+0.2%H ₃PO ₄, flow velocity=4mL/ minute, and detect at 220nm.

Preparation anti-phase (RP) HPLC (uses through 0.1% trifluoroacetic acid buffered H with linear gradient elution ₂The O/ carbinol mixture comes wash-out), and detect at 220nm, and on one of following chromatography column, carry out: Shimadzu S5 ODS-VP 20 * 100mm (flow velocity=9mL/ minute), or YMC S10 ODS 50 * 500mm (flow velocity=50mL/ minute), or YMC S10 ODS 30 * 500mm (flow velocity=20mL/ minute).

All final products all with ¹HNMR, RP HPLC, electrospray ionization (ESI MS) or atmospheric pressure ionization (API MS) mass spectrometry characterize. ¹H NMR spectrum is obtained on 500MHz JEOL or 400MHz Bruker instrument. ¹³C NMR spectrum 100 or 125MHz under write down.Intensity of field with respect to the δ unit representation at solvent absorbing peak (one of 1,000,000 parts, ppm), and being expressed as follows of the tuple of absorption peak: s, unimodal; D, bimodal; Dd, double doublet; Dm, two multiplets; T, triplet; Q, quartet; Br s, wide unimodal; M, multiplet.

The reagent that following abbreviation is used to use always: Boc or BOC: t-butyl carbamate; Fmoc:9H-fluorenyl methyl carbamate; The NMM:N-methylmorpholine; Ms: methylsulfonyl; DIEA or DIPEA: diisopropylethylamine or conspicuous Nissl alkali (Hunig ' s base); The NMP:N-methyl-2-pyrrolidone; Bop reagent: benzotriazole-1-base oxygen base three (three methylamino-s) Phosphonium hexafluorophosphate; DCC:1, the 3-dicyclohexyl carbodiimide; EDCI:1-(dimethylamino-propyl)-3-ethyl carbodiimide hydrogen chlorate; RT: room temperature; t _R: the residence time; H: hour; Min: minute; PyBrOP: bromo tripyrrole Wan Ji Phosphonium hexafluorophosphate; TBTU:O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (O-(1H-benzotriazol-1-yl)-N, N, N ', N '-tetramethyluroniumtetrafluoroborate); DMAP:4-N, the N-Dimethylamino pyridine; HOBt: hydroxybenzotriazole; HATU:O-(7-nitrine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate; DIBAL-H: diisobutyl aluminium hydride; Na (OAc) ₃BH: sodium triacetoxy borohydride; HOAc: acetate; TFA: trifluoroacetic acid; LiHMDS: two (trimethyl silyl) amination lithium; M-CPBA a: chloro-or 3-chlorine peroxybenzoic acid; AIBN:2, the two isopropyl cyanides of 2 '-nitrine; DMSO: dimethyl sulfoxide (DMSO); MeCN: acetonitrile; MeOH: methyl alcohol; EtOAc: ethyl acetate; DMF: dimethyl formamide; THF: tetrahydrofuran (THF); DCE:1, the 2-ethylene dichloride; Et ₂O: ether.

Embodiment 1

1-(3-fluoro-4-(6-methoxyl group-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-3-(2-phenylacetyl) thiocarbamide

A) 6-(1-hydroxyl-1-methyl-ethyl)-5-methyl-3H-pyrrolo-[2,1-f] [1,2,4] triazine-4-ketone

In inert atmosphere, 5-methyl-4-ketone group-3 of preparation 1.9kg, 4-dihydro-pyrrolo-[2,1-f] [1,2,4] mixture of triazine-6-carboxylic acid, ethyl ester (making) and 17.9kgTHF according to U.S. Patent application 09/573829 described program, and be cooled to-10 ℃.So that temperature of reaction keeps＜35 ℃ speed, the methylmagnesium-chloride (for the 3M solution of THF) of 14.2kg is added in this mixture.This reaction mixture is maintained 25-45 ℃, till reaction is finished, then, be cooled to 0 ℃.Preparation is by ammonium chloride formed solution in 36.7kg water of 9.9kg, and is cooled to 5 ℃.Internal temperature is maintained＜15 ℃ speed, this organic reaction mixture is added in this ammonium chloride solution.Make each phase sedimentation and discharge the water of lower floor, extract again with the THF of other 9.5kg.The 8.6kg ethyl acetate is added in the organic phase of merging, and cleans this mixture with the saturated sodium chloride aqueous solution of 7.6kg.This reaction mixture is filtered, and then, (temperature＜40 ℃) are in a vacuum removed and are desolvated, and become till original about 1/3 to volume.At lasting distillatory simultaneously, add other ethyl acetate, till amount＜7% of THF.The soup compound of gained is cooled to 0-5 ℃, then, utilizes filtration method to collect solid.Clean wet cake with cold (10 ℃) ethyl acetate, then, give drying under vacuum, 40 ℃, obtain 6-(1-hydroxyl-1-methyl-ethyl)-5-methyl-3H-pyrrolo-[2,1-f] [1,2,4] triazine-4-ketone of 1.5kg, purity is 96-99%.

B) 6-hydroxy-5-methyl base-3H-pyrrolo-[2,1-f] [1,2,4] triazine-4-ketone

In being equipped with 1 liter, three mouthfuls round-bottomed flasks of mechanical stirrer and ice/acetone cooling bath, 6-(1-hydroxyl-1-methyl-ethyl)-5-methyl-3H-pyrrolo-[2 of filling 20g, 1-f] [1,2,4] triazine-4-ketone, the THF of 235mL and 50% aqueous hydrogen peroxide solution of 47mL.Can be observed-7 ℃ to 7.3 ℃ heat release, and this mixture becomes solution.During 40 minutes, the solution of chilled 28.5mL water and 63mL methylsulfonic acid in advance is added in this reaction soln, and with temperature maintenance between-5 ℃ to-0.7 ℃.Under-2 ℃, with this solution stirring 95 minutes, till HPLC shows that reaction has been finished; By during 40 minutes, under the 15-25 ℃, with this reaction mixture by part be added into 28.5mL water, 89g NaHSO ₃And in the formed chilled solution of 128mL 28% ammonium hydroxide aqueous solution, the cancellation reaction simultaneously, maintains-2 ℃ with this reaction mixture.At room temperature, this mixture was stirred 20 minutes; Its pH be 6.80 and the superoxide test-results be negative.Each layer separated and with 100mL THF aqueous layer extracted.Two organic layers are merged and concentrated, to remove the 280mL solvent.250mL water is added in the resulting thick soup compound, and continues to concentrate, till the 88mL removal of solvents falls.This soup compound is filtered and, then, clean with the 25mL acetonitrile with 25mL water cleaning filter cake secondary.Be dried to constant weight by suction filtration on strainer, and obtain 6-hydroxy-5-methyl base-3H-pyrrolo-[2,1-f] [1,2,4] triazine-4-ketone of 12.51g, productive rate 75.9%, purity 96.5%.

C) 2,2-dimethyl-propionic acid 5-methyl-4-ketone group-3,4-dihydro-pyrrolo-[2,1-f] [1,2,4] triazine-6-base ester

6-hydroxy-5-methyl base-3H-pyrrolo-[2,1-f] [1,2 with 2.9kg, 4] mixture of the THF of the diisopropylethylamine of triazine-4-ketone, 4.6kg and 17.0kg is cooled to 0-10 ℃, then, with speed, handled with the pivalyl chloride of 2.6kg with temperature maintenance＜20 ℃.Till stirring this mixture and showing that to HPLC reaction has been finished, then, successively add 15% potassium dihydrogen phosphate aqueous solution of 17.8kg toluene and 20.6kg.To respectively be separated, and with 10.2kg water cleaning organic matter.Organic phase is filtered, then,, distill in a vacuum with the highest 65 ℃ temperature.Add other toluene and continue distillation, till the cumulative volume of concentration＜8% of THF and reactor content is reduced to 31L.The soup compound of gained is cooled to 20-25 ℃, and during 1.5 hours, is handled with the 20.3kg heptane.This soup compound is cooled to 0-5 ℃, and kept 1 hour, then, utilize to filter and collect solid and give drying, obtain 2 of 4.0kg, 2-dimethyl-propionic acid 5-methyl-4-ketone group-3,4-dihydro-pyrrolo-[2,1-f] [1,2,4] triazine-6-base ester, purity 95-99%.

D) 4-chloro-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-base pivalate also

Toluene (10mL) is added into 5-methyl-4-ketone group-3, the 4-pyrrolin also [2,1-f] [1,2,4] triazine-6-base pivalate (300mg, 1.20mmol), phosphoryl chloride (2.0mL, 21.4mmol) and DIEA (0.5mL is in mixture 2.80mmol).Under 110 ℃,, then, be cooled to room temperature with this reactant heating 4 hours.Dilute this mixture with ethyl acetate (10mL) and water (5mL).Isolate organic layer, and give drying, concentrate and utilize flash chromatography on silica gel method (with 1-25% ethyl acetate/dichloromethane wash-out) to carry out purifying, the solid title compound that obtains being white in color (250mg, 78%) in a vacuum with sodium sulfate.

E) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-base pivalate also

With DMF (5mL) be added into 4-chloro-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-base pivalate (250mg, 0.94mmol), 2-fluoro-4-nitrophenols (176mg, 1.12mmol, Aldrich) and K ₂CO ₃(154mg is 1.12mmol) in the formed mixture.At room temperature, this reactant was stirred 24 hours.Water (5mL) and methylene dichloride (10mL) should react cancellation.Isolate organic layer, give drying, concentrate in a vacuum, and carry out purifying, the solid title compound that obtains being white in color (160mg, 44%) with flash chromatography on silica gel method (with 1-25% ethyl acetate/dichloromethane wash-out) with sodium sulfate.

F) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-alcohol also

With sodium hydroxide in methanol formed solution (0.2mL, 1M) be added into 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-base pivalate (80mg is 0.2mmol) in the formed solution of THF (1mL).This solution can redden immediately.After 5 minutes, should react cancellation with ethyl acetate (5mL) and water (5mL).Isolate organic layer, give drying and concentrated in a vacuum, obtain being the title compound (52mg, 85%) of yellow solid with sodium sulfate.

G) 4-(2-fluoro-4-nitrophenoxy)-6-methoxyl group-5-methylpyrrole [2,1-f] [1,2,4] triazine also

With Cs ₂CO ₃(65mg, 0.2mmol) be added into 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-alcohol (52mg 0.17mmol) in the formed solution of DMF (2mL), and at room temperature, stirs this mixture 10 minutes.(0.2mL, 0.2mmol 1M), and at room temperature, stir this reaction soln 2 hours the DMF solution of interpolation methyl iodide.Should react cancellation with ethyl acetate (5mL) and water (5mL).Isolate organic layer, give drying and concentrated in a vacuum, obtain being the title compound (35mg, 65%) of yellow solid with sodium sulfate.

H) 3-fluoro-4-(6-methoxyl group-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) aniline

Successively with methyl alcohol (1.0mL), (100mg is 1.5mmol) with ammonium chloride (43mg to reach zinc, 0.80mmol) be added into also [2,1-f] [1,2 of 4-(2-fluoro-4-nitrophenoxy)-6-methoxyl group-5-methylpyrrole, 4] (35mg is 0.11mmol) in the formed solution of THF (1.0mL) for triazine.Under 60 ℃, with this reactant heating 3 hours.This solution is passed through Celite ^Pad filters, and concentrates in a vacuum.Utilize SCX filter cylinder (cartridge) (with ammoniated methyl alcohol (2M) wash-out), with this product mixtures purifying, the solid title compound that obtains being white in color (15mg, 50%).

I) 2-phenyl-1-thiocyano ethyl ketone

((49mg is 0.60mmol) in the formed solution of ethyl acetate (2mL), so that the 0.25M solution of 2-phenyl-1-thiocyano ethyl ketone to be provided Aldrich) to be added into NaSCN for 0.066mL, 0.50mmol with the phenyl Acetyl Chloride 98Min..After 10 minutes, with reaction mixture wait separatory to form corresponding thiocyanate-to determine whether reaction is finished with 4-(phenoxy group) aniline reaction, the latter passes through LCMS (ESI ⁺) m/z363 (M+H) ⁺Detect.Directly use this 2-phenyl-1-thiocyano ethyl ketone, need not to separate or be further purified.

J) 1-(3-fluoro-4-(6-methoxyl group-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-3-(2-phenyl acetyl) thiocarbamide

Solution (0.133mL with 2-phenyl-1-thiocyano ethyl ketone, 0.033mmol, 0.25M, in ethyl acetate) be added into 3-fluoro-4-(6-methoxyl group-5-methylpyrrole also [2,1-f] [1,2,4] triazine-4-base oxygen base) (7.5mg is 0.026mmol) in the formed solution of methylene dichloride (1mL) for aniline.At room temperature, this reactant was stirred 20 minutes, concentrate in a vacuum and utilize flash chromatography on silica gel method (with 1-25% ethyl acetate/dichloromethane wash-out) to carry out purifying, obtain being the title compound (6.1mg, 50%) of faint yellow solid. ¹H?NMR(CDCl ₃)δ8.51(s，1H)，7.87(m，1H)，7.83(s，1H)，7.47(m，5H)，7.31(m，4H)，3.89(s，3H)，3.74(d，2H，J＝10.5Hz)，2.44(s，3H)；MS(ESI ⁺)m/z?466(M+H) ⁺。

Embodiment 2

1-(3-fluoro-4-(6-methoxyl group-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

A) 2-(4-fluorophenyl)-1-thiocyano ethyl ketone

((49mg is 0.60mmol) in the formed solution of ethyl acetate (2mL) Aldrich) to be added into NaSCN for 0.066mL, 0.50mmol with 4-fluorophenyl Acetyl Chloride 98Min..At room temperature, this reactant was stirred 1 hour, obtain 2-(4-the fluorophenyl)-0.25M solution of 1-thiocyano ethyl ketone in ethyl acetate, it can directly use, and need not to be further purified.

B) 1-(3-fluoro-4-(6-methoxyl group-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

According to the similar mode described in the preparation of the compound H of embodiment 1 and J, by 3-fluoro-4-(6-methoxyl group-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) aniline and 2-(4-fluorophenyl)-1-thiocyano ethyl ketone, make title compound. ¹H?NMR(CDCl ₃)δ8.49(s，1H)，7.88(m，1H)，7.83(s，1H)，7.45(s，1H)，7.28(m，5H)，7.12(m，2H)，3.89(s，3H)，3.71(s，2H)，2.44(s，3H)；MS(ESI ⁺)m/z?484(M+H) ⁺。

Embodiment 3

1-(4-(6-chloro-1-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

A) 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

With 2-(4-fluorophenyl)-1-thiocyano ethyl ketone (employing makes with the synthetic similar program of the compd A of embodiment 2) formed 0.25M solution (1.6mL in ethyl acetate, 0.4mmol) be added into 4-amino-2-fluorophenol (50mg, 0.3mmol, Indofine Chemical Co.) and in the formed solution of methylene dichloride (5mL).At room temperature, this reactant was stirred 20 minutes, concentrate in a vacuum and utilize flash chromatography on silica gel method (with 1-25% ethyl acetate/dichloromethane wash-out) to carry out purifying, the solid title compound that obtains being white in color (100mg, 95%).

B) 1-(4-(6-chloro-1-methyl isophthalic acid H-pyrazolo [3,4-d] pyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

DMF (2mL) is added into 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide (24mg; 0.075mmol), 4; 6-two chloro-1-methyl isophthalic acid H-pyrazolos [3; 4-d] pyrimidine (15.3mg; 0.075mmol, preparation: J.Org.Chem.1958,23; 852, its content is incorporated this paper into as a reference) and K ₂CO ₃(10mg is in mixture 0.075mmol).At room temperature, this reactant was stirred 24 hours.Water (2mL) and methylene dichloride (5mL) cancellation should reactions.Isolate organic layer, give drying, concentrate in a vacuum and utilize anti-phase to prepare HPLC and carry out purifying, the solid title compound that obtains being white in color (22.9mg, 60%) with sodium sulfate.MS(ESI ⁺)m/z?457(M+H) ⁺。

Embodiment 4

4-(2-fluoro-4-(3-(2-(4-fluorophenyl) ethanoyl) urea groups) phenoxy group)-5-methylpyrrole also [2; 1-f] [1; 2; 4] triazine-6-base ethyl carbamate (4-(2-Fluoro-4-(3-(2-(4-fluorophenyl) acetyl) ureido) phenoxy)-5-methylpyrrolo[2; 1-f] [1; 2,4] triazin-6-yl ethylcarbamate)

A) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-base ethyl carbamate also

With ethyl isocyanate (0.078mL, 0.1mmol) be added into 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-alcohol (25mg, 0.082mmol, the compound F 17-hydroxy-corticosterone of embodiment 1), DIEA (0.017mL, 0.1mmol) in the formed mixture of methylene dichloride (5mL), and at room temperature stirred 2 hours.Water (5mL) should react cancellation.Isolate organic layer, give drying and concentrated in a vacuum.Utilize flash chromatography method (1-5% ethanol/methylene), with this purifying mixture, the solid title compound that obtains being white in color (12.5mg, 32%).

B) 4-(4-amino-2-fluorophenoxy)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-base ethyl carbamate also

With zinc (20mg, 0.3mmol) and ammonium chloride (20mg 0.37mmol) is added into 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-(12.5mg is 0.033mmol) in the formed solution of ethanol (2mL) for 6-base ethyl carbamate.At room temperature, this reactant was stirred 1 hour, it is passed through Celite ^Filter, and concentrate the solid title compound that obtains being white in color (8mg, 70%) in a vacuum.

C) 2-(4-fluorophenyl) ethanoyl isocyanic ester

(0.175mL 2.00mmol) is added into 4-fluorophenyl ethanamide (77mg, 0.50mmol with oxalyl chloride, referring to J.Med.Chem.2003,46,4333-4341, its disclosure is incorporated this paper into as a reference) in ethylene dichloride (2mL) in the formed solution/suspension.Under 80 ℃,, then, heated two days down at 70 ℃ with this reactant heating 24 hours.At this moment, most solid has dissolved and reactant is yellow all.LC/MS analyzes and to demonstrate molecular weight is 211 peak, and it is corresponding to by 2-(4-fluorophenyl) the acetylamino methyl-formiate that uses methyl alcohol quencher isocyanic ester to obtain.In a vacuum, this reactant is concentrated, obtain yellow soup compound.This soup compound is dissolved in ethylene dichloride (2mL) again, and concentrates in a vacuum once more.Resulting residue is dissolved in the ethylene dichloride (2mL) once more, obtains 2-(4-fluorophenyl) ethanoyl isocyanic ester formed 0.25M solution in ethylene dichloride, it can be directly used in follow-up reaction.

D) 4-(2-fluoro-4-(3-(2-(4-fluorophenyl) ethanoyl) urea groups) phenoxy group)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-base ethyl carbamate also

Solution (2mL with 2-(4-fluorophenyl) ethanoyl isocyanic ester; 0.25M; in ethylene dichloride) be added into 4-(4-amino-2-fluorophenoxy)-5-methylpyrrole also [2; 1-f] [1; 2; 4] triazine-(10mg is 0.029mmol) in the formed solution of methylene dichloride (1mL) for 6-base ethyl carbamate.At room temperature, this reactant was stirred 1 hour, at this moment, LC/MS analyzes and shows that initial carbamate is consumed.In a vacuum, this mixture is concentrated, and resulting residue is suspended in the methyl alcohol, and filtered, and obtain title compound.Utilize the flash chromatography method with the filtrate purifying, more be the title compound (ultimate production is 5.9mg, 40%) of faint yellow solid. ¹HNMR(CDCl ₃)δ10.63(s，1H)，8.42(s，1H)，7.88(s，1H)，7.82(s，1H)，7.67(dd，1H，J＝12.1，2.2Hz)，7.28(m，4H)，7.10(m，2H)，3.73(s，3H)，3.36(m，2H)，2.48(s，3H)，1.26(m，3H)；MS(ESI ⁺)m/z?525(M+H) ⁺。

Embodiment 5

4-(2-fluoro-4-(3-(2-(4-fluorophenyl) ethanoyl) thioureido) phenoxy group)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-base ethyl carbamate also

Solution (0.120mL with 2-(4-fluorophenyl)-1-thiocyano ethyl ketone, 0.025mmol, 0.25M, in ethyl acetate, the compd A of embodiment 2) is added into also [2,1-f] [1 of 4-(4-amino-2-fluorophenoxy)-5-methylpyrrole, 2,4] triazine-6-base ethyl carbamate (8mg, 0.023mmol, the preparation compd B of embodiment 4) is in the formed solution of methylene dichloride (1mL).At room temperature, this reactant was stirred 1 hour, concentrate in a vacuum, and utilize flash chromatography on silica gel method (with 1-25% ethyl acetate/dichloromethane wash-out) to carry out purifying, obtain being the title compound (5.4mg, 43%) of faint yellow solid. ¹H?NMR(CDCl ₃)δ12.41(s，1H)，8.58(s，1H)，7.88(m，3H)，7.28(m，5H)，7.12(m，2H)，3.72(s，2H)，3.37(m，2H)，2.46(m，3H)，1.26(m，3H)；MS(ESI ⁺)m/z?541(M+H) ⁺。

Embodiment 6

4-(2-fluoro-4-(3-(2-(4-fluorophenyl) ethanoyl) thioureido) phenoxy group)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester also

A) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester also

DMF (0.5mL) is added into 4-chloro-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester (24mg, 0.10mmol, preparation: referring to United States Patent (USP) 6,670,357, especially embodiment 61, its content is incorporated this paper into as a reference), 2-fluoro-4-nitrophenols (20mg, 0.125mmol) and K ₂CO ₃(28mg is in mixture 0.20mmol).Under 70 ℃, with this reactant heating 20 minutes, then, be cooled to room temperature, and added 2mL water.This mixture is filtered, and water cleans solid, and with this solid drying, and obtains being the title compound (36mg, 100%) of light yellow solid.

B) 4-(4-amino-2-fluorophenoxy)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester also

Methyl alcohol (0.7mL) is added into also [2,1-f] [1,2 of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole, 4] (36mg is 0.1mmol) in the formed solution of THF (1.0mL), then for triazine-6-carboxylic acid, ethyl ester, add zinc (130mg, 2.0mmol) and ammonium chloride (53mg, 1.0mmol).Under 70 ℃, this reactant is heated a whole night.LC/MS analyzes and shows that major part is a raw material.With this solution vigorous stirring, then, be heated to 75 ℃.After 4 hours, LC/MS analyzes and demonstrates desired product and other many peaks.This reactant is filtered by strainer, and filtrate is concentrated, and obtain the brown residue of 55mg.This residue is suspended among the THF, and it is passed through the HPLC filter, the result obtains clarifying filtrate.In a vacuum this filtrate is concentrated, and obtain the title compound that is crude mixture of 54mg, it is directly used in next procedure, need not to be further purified.

C) 4-(2-fluoro-4-(3-(2-(4-fluorophenyl) ethanoyl) thioureido) phenoxy group)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester also

Solution (0.5mL with 2-(4-fluorophenyl)-1-thiocyano ethyl ketone, 0.12mmol, 0.25M, in ethyl acetate, the compd A of embodiment 2) is added into 4-(4-amino-2-fluorophenoxy)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester (54mg) is in the formed suspension of methylene dichloride (0.6mL).At room temperature, this reactant was stirred 15 minutes, LC/MS analyzes and shows that major part is a raw material.This reactant is warmed to 45 ℃, and after 30 minutes, most suspension all dissolves, and obtains muddy solution.LC/MS analyzes and shows that major part is desired product.At room temperature,, be evaporated to driedly, and carried out purifying, the solid title compound that obtains being white in color (9mg, the overall yield of three steps is 17%) by column chromatography (with 1-7% ethyl acetate/dichloromethane wash-out) with this reactant restir 2 hours. ¹H?NMR(CDCl ₃)δ12.45(s，1H)，8.66(s，1H)，8.18(s，1H)，7.92(dd，1H，J＝11.4，2.4Hz)，7.90(s，1H)，7.41(m，1H)，7.29(m，3H)，7.12(m，2H)，4.38(q，2H，J＝7.1Hz)，3.73(s，2H)，2.82(s，3H)，1.40(t，3H，J＝7.1Hz)；MS(ESI ⁺)m/z526(M+H) ⁺。

Embodiment 7

4-(4-(3-(2-(4-fluorophenyl) ethanoyl) thioureido) phenoxy group)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester also

A) 1-(2-(4-fluorophenyl) ethanoyl)-3-(4-hydroxyphenyl) thiocarbamide

Solution (0.5mL, 0.125mmol, 0.25M with 2-(4-fluorophenyl)-1-thiocyano ethyl ketone, in ethyl acetate, the compd A of embodiment 2) (11mg, 0.1mmol is Aldrich) in the formed solution of methylene dichloride (0.55mL) to be added into 4-amino-phenol.At room temperature, this reactant was stirred 10 minutes, LC/MS analyzes demonstration and has formed title compound.This crude reaction mixture is directly used in next reaction.

B) 4-(4-(3-(2-(4-fluorophenyl) ethanoyl) thioureido) phenoxy group)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester also

With 1-(2-(4-fluorophenyl) ethanoyl)-3-(4-hydroxyphenyl) thiocarbamide (0.5mL; 0.05mmol) be added into 4-chloro-5-methylpyrrole also [2; 1-f] [1; 2,4] triazine-6-carboxylic acid, ethyl ester (7.2mg, 0.03mmol) (preparation can be referring to United States Patent (USP) 6; 670; 357, the content of this patent is incorporated herein as a reference) and DABCO (7mg is 0.06mmol) in the formed solution at room temperature of acetonitrile (0.5mL).At room temperature, stir this reactant.After 30 minutes, LC/MS analyzes and shows that major part is a product.At room temperature, this reactant is stirred a whole night.Be evaporated to this mixture dried.Utilize silica gel chromatography (with 1% ethanol/methylene wash-out) to carry out purifying, obtain by the product of wanting of contaminating impurity.Utilize silica gel chromatography (1-6% ethyl acetate/dichloromethane) once more, carry out the purifying second time, but fail to remove all impurity.With the resulting solid mixture of washed with methanol, and give drying, obtain being the title compound (6mg, 39%) of yellow solid. ¹H?NMR(CDCl ₃)δ12.32(s，1H)，8.62(s，1H)，8.16(s，1H)，7.91(s，1H)，7.76(m，2H)，7.29(m，4H)，7.12(m，2H)，4.38(q，2H，J＝7.1Hz)，3.72(s，2H)，2.82(s，3H)，1.40(t，3H，J＝7.1Hz)；MS(ESI ⁺)m/z508(M+H) ⁺。

Embodiment 8

4-(2-fluoro-4-(3-(2-(4-fluorophenyl) ethanoyl) thioureido) phenoxy group)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-base pivalate also

MeCN (5mL) is added into 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide (60mg; 0.19mmol; the compd A of embodiment 3), 4-chloro-5-methylpyrrole [2,1-f] [1,2 also; 4] triazine-6-base pivalate (50mg; 0.19mmol, the Compound D of embodiment 1) and with 1,4-diazabicyclo [2.2.2] octane (DABCO; 21.3mg, in mixture 0.19mmol).At room temperature, this reactant was stirred 1 hour, and concentrate in a vacuum.Utilize flash chromatography method (using the 1-15% ethanol/methylene) with the residue purifying, the solid title compound that obtains being white in color (91mg, 86%). ¹HNMR(CDCl ₃)δ12.40(s，1H)，8.54(s，1H)，7.87(m，3H)，7.29(m，4H)，7.12(m，2H)，3.71(s，2H)，2.43(s，3H)，1.39(s，9H)；MS(ESI ⁺)m/z554(M+H) ⁺。

Embodiment 9

4-(2-fluoro-4-(3-(2-phenyl acetyl) thioureido) phenoxy group)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-base pivalate also

A) 1-(3-fluoro-4-hydroxyphenyl)-3-(2-phenyl acetyl) thiocarbamide

(50mg is 0.3mmol) in the formed solution of methylene dichloride (2mL) to be added into 4-amino-3-fluorophenol with the solution of 2-phenyl-1-thiocyano ethyl ketone (2mL, 0.4mmol, 0.2M, in ethyl acetate, the Compound I of embodiment 1).At room temperature, this reactant was stirred 20 minutes, LC/MS analyzes demonstration and has formed title compound.This mixture is concentrated, obtain residue, it directly uses and need not to be further purified.

B) 4-(2-fluoro-4-(3-(2-phenyl acetyl) thioureido) phenoxy group)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-base pivalate also

With 4-chloro-5-methylpyrrole also [2; 1-f] [1; 2; 4] triazine-6-base pivalate (13.3mg; 0.19mmol, the Compound D of embodiment 1), 1-(3-fluoro-4-hydroxyphenyl)-3-(2-phenyl acetyl) thiocarbamide (16mg, 0.05mmol), cesium carbonate (spoon looking somebody up and down (spatula tip)) and DMF (2mL) be filled in the bottle; and be warmed to 100 ℃, lasted 26 hours.In a vacuum this mixture is concentrated.Utilize the flash chromatography method, with the residue purifying, the solid title compound that obtains being white in color (6.2mg, 25%).

¹H?NMR(CDCl ₃)δ12.46(s，1H)，8.50(s，1H)，7.88(m，3H)，7.40(m，4H)，7.31(m，2H)，3.75(s，3H)，2.44(s，3H)，1.40(s，9H)；MS(ESI ⁺)m/z?536(M+H) ₊。

Embodiment 10

1-(4-(4a, 7a-dihydro-thiophene be [2,3-d] pyrimidine-4-base oxygen base also)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

MeCN (2mL) is added into 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide (24mg; 0.075mmol; the compd A of embodiment 3), 4-chloro-5-thieno-[2; 3-d] pyrimidine (12.8mg; 0.075mmol, commercially available) and with 1,4-diazabicyclo [2.2.2] octane (DABCO; 8.4mg, in mixture 0.075mmol).At room temperature, reactant was stirred 4 hours, and concentrate in a vacuum.Utilize anti-phase to prepare HPLC, with resulting residue purifying, the solid title compound that obtains being white in color (13.8mg, 40%). ¹H?NMR(CDCl ₃)δ12.41(s，1H)，8.62(s，1H)，8.53(s，1H)，7.93(dd，1H，J＝13.8，2.2Hz)，7.56(m，2H)，7.46(m，1H)，7.29(m，3H)，7.12(m，2H)，3.73(s，2H)；MS(ESI ⁺)m/z?457(M+H) ⁺。

Embodiment 11

1-(3-fluoro-4-(5-methyl-4a, 7a-dihydro-thiophene be [2,3-d] pyrimidine-4-base oxygen base also) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

According to the described similar mode of the preparation of embodiment 10; by commercially available 4-chloro-5-thiotolene also [2,3-d] pyrimidine and 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide (24mg, 0.075mmol; the compd A of embodiment 3), make title compound. ¹H?NMR(CDCl ₃)δ12.42(s，1H)，8.67(s，1H)，8.53(s，1H)，7.88(dd，1H，J＝13.8，2.2Hz)，7.43(s，1H)，7.32(m，3H)，7.09(m，3H)，3.72(s，2H)，2.67(s，3H)；MS(ESI ⁺)m/z471(M+H) ⁺。

Embodiment 12

1-(3-fluoro-4-(7-methyl-4a, 7a-dihydro-thiophene be [3,2-d] pyrimidine-4-base oxygen base also) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

MeCN (2mL) is added into 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide (24mg; 0.075mmol; the compd A of embodiment 3), 4-chloro-7-thiotolene also [3; 2-d] pyrimidine (13.8mg; 0.075mmol, commercially available) and with 1,4-diazabicyclo [2.2.2] octane (DABCO; 8.4mg, in mixture 0.075mmol).At room temperature, this reactant was stirred 4 hours, and concentrate in a vacuum.Utilize anti-phase to prepare HPLC, with resulting residue purifying, the solid title compound that obtains being white in color (11.2mg, 31%). ¹H?NMR(CDCl ₃)δ12.45(s，1H)，8.79(s，1H)，8.61(s，1H)，7.93(dd，1H，J＝13.8，2.2Hz)，7.46(s，1H)，7.43(m，1H)，7.28(m，3H)，7.12(m，2H)，3.72(s，2H)，2.51(s，3H)；MS(ESI ⁺)m/z?471(M+H) ⁺。

Embodiment 13

1-(4-(7,7a-dihydro-4aH-pyrrolo-[2,3-d] pyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

MeCN (2mL) is added into 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide (24mg; 0.075mmol; the compd A of embodiment 3), 4-chloro-7H-pyrrolo-[2; 3-d] pyrimidine (11mg; 0.075mmol, commercially available) and with 1,4-diazabicyclo [2.2.2] octane (DABCO; 8.4mg, in mixture 0.075mmol).At room temperature, this reactant was stirred 4 hours, and concentrate in a vacuum.Utilize anti-phase to prepare HPLC, with resulting residue purifying, the solid title compound that obtains being white in color (5.3mg, 16%). ¹H?NMR(CDCl ₃)δ12.46(s，1H)，8.48(s，1H)，8.44(s，1H)，7.95(dd，1H，J＝11.6，2.8Hz)，7.43(m，1H)，7.34(m，1H)，7.29(m，4H)，7.13(app.T，2H，J＝8.6Hz)，6.80(s，1H)，3.72(s，2H)；MS(ESI ⁺)：m/z?440(M+H) ⁺。

Embodiment 14

N-(4-(3-(cyano group-6-methoxyl group-5-methyl H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl)-3-ketone group-4-phenyl butane thioamides

A) 3-cyano group-4-(2-fluoro-4-nitrophenoxy)-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester

DMF (5mL) is added into 4-chloro-3-cyano group-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester (500mg, 1.90mmol, referring to U.S. Patent application 2004/063712, especially embodiment 1, the disclosure of this application case is all incorporated this paper into as a reference), 2-fluoro-4-nitrophenols (361mg, 2.3mmol) and K ₂CO ₃(315mg is in mixture 2.3mmol).At room temperature, this reactant was stirred 2 hours.Water (5mL) cancellation should reaction.This mixture is filtered, and water cleans resulting solid, give drying, obtain being the title compound (630mg, 86%) of light yellow solid.

B) 4-(4-amino-2-fluorophenoxy)-3-cyano group-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester

Methyl alcohol (5mL) is added into 3-cyano group-4-(2-fluoro-4-nitrophenoxy)-5-methyl H-pyrrolo-[1,2-b] (630mg 1.64mmol) in the formed solution of THF (5mL), then adds zinc (200mg to pyridazine-6-carboxylic acid, ethyl ester, 3.0mmol) and ammonium chloride (200mg, 3.7mmol).Under 60 ℃,, filtered and concentrated in a vacuum this reactant heating 2 hours.Utilize SCX filter cylinder (being used in the 2M ammonia wash-out in the methyl alcohol), with resulting filtrate purifying, the solid title compound that obtains being white in color (420mg, 72%).

C) 4-(4-(carbobenzoxy-(Cbz))-2-fluorophenoxy)-3-cyano group-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester

With salt of wormwood (200mg, 1.43mmol) and chloroformic acid benzene methyl (0.261mL, 1.43mmol) be added into 4-(4-amino-2-fluorophenoxy)-3-cyano group-5-methyl H-pyrrolo-[1,2-b] (420mg is 1.19mmol) in the formed solution of methylene dichloride (10mL) for pyridazine-6-carboxylic acid, ethyl ester.At room temperature, with this solution stirring 24 hours.This solution is filtered and concentrates in a vacuum, and in ethyl acetate/dichloromethane, carry out recrystallize, the solid title compound that obtains being white in color (490mg, 84%).

D) 4-(3-cyano group-6-(2-hydroxy propane-2-yl)-5-methyl H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl carboxylamine benzyl ester

(123mg 0.25mmol) is cooled to 0 ℃ in the formed solution of THF (5mL) with 4-(4-(carbobenzoxy-(Cbz))-2-fluorophenoxy)-3-cyano group-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester.Add the solution (3M is in THF for 0.336mL, 1.00mmol) of methylmagnesium-bromide, and at room temperature, with resulting solution stirring 30 minutes.Add more methylmagnesium-bromide (3M is in THF for 0.336mL, 1.00mmol), and resulting solution is heated to 60 ℃, last 30 minutes.Add ethyl acetate (10ml) and water (5mL), and clean organic layer, it is separated, give drying and concentrated in a vacuum.Utilize flash chromatography method (ethyl acetate of 20-50% in methylene dichloride), with this purifying mixture, the solid title compound that obtains being white in color (97mg, 81%).

E) 4-(3-cyano group-6-hydroxy-5-methyl base H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl carboxylamine benzyl ester

To close hydrogen peroxide (0.033mL) formed-5 ℃ solution being pre-mixed of two etherates (dietherate) in (0.570mL) at water and boron trifluoride, be added into 4-(3-cyano group-6-(2-hydroxyl third-2-yl)-5-methyl H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-(97mg is 0.2mmol) in the formed solution of methylene dichloride (2mL) for 3-fluorophenyl carboxylamine benzyl ester.After 10 minutes, use sodium sulfite solution, should react cancellation, give concentrating in drying, the vacuum, and resulting residue is carried out recrystallize, the solid title compound that obtains being white in color (70mg, 80%) with ethyl acetate and hexane.

F) 4-(3-cyano group-6-methoxyl group-5-methyl H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl carboxylamine benzyl ester

With cesium carbonate (39mg, 0.12mmol) and methyl iodide (0.05mL, 0.072mmol) (3-cyano group-6-hydroxy-5-methyl base H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-(25mg is 0.06mmol) in the formed solution of DMF (1mL) for 3-fluorophenyl carboxylamine benzyl ester to be added into 4-.At room temperature, with this solution stirring 2 hours.Add water (1mL) and with ethyl acetate (2 * 5mL) extraction products, carry out drying reach concentrated, the solid title compound that obtains being white in color (20mg, 74%).

G) 4-(4-amino-2-fluorophenoxy)-6-methoxyl group-5-methyl H-pyrrolo-[1,2-b] pyridazine-3-formonitrile HCN

10% palladium (20mg) that is stated from the carbon is added into 4-(3-cyano group-6-methoxyl group-5-methyl H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl carboxylamine benzyl ester (20mg, 0.045mmol) in the formed solution of ethanol (3mL), and under nitrogen atmosphere, this mixture was stirred 2 hours.This solution is passed through Celite ^Pad filters, and concentrates in a vacuum, obtains title compound (12mg, 85%).

H) N-(4-(3-cyano group-6-methoxyl group-5-methyl H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl)-3-ketone group-4-phenyl butane thioamides

Solution (0.1mL with 2-phenyl-1-thiocyano ethyl ketone, 0.025mmol, 0.25M, in ethyl acetate, the compound F 17-hydroxy-corticosterone of embodiment 1) is added into 4-(4-amino-2-fluorophenoxy)-6-methoxyl group-5-methyl H-pyrrolo-[1,2-b] (6mg is 0.02mmol) in the formed solution of methylene dichloride (1mL) for pyridazine-3-formonitrile HCN.At room temperature, this reactant was stirred 20 minutes, then, concentrate in a vacuum and carry out purifying, obtain being the title compound (3.90mg, 40%) of faint yellow solid with flash chromatography on silica gel method (with 1-25% ethyl acetate/dichloromethane wash-out). ¹HNMR(CD ₃OD)δ8.01(d，1H，J＝12.7Hz)，7.86(s，1H)，7.72(s，1H)，7.19(m，5H)，6.75(m，2H)，3.79(s，3H)，3.20(m，2H)，2.18(s，3H)；MS(ESI ⁺)m/z?490(M+H) ⁺。

Embodiment 15

N-(4-(3-cyano group-6-methoxyl group-5-methyl H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl)-4-(4-fluorophenyl)-3-ketone group butane thioamides

By the program described in the compound H preparation of embodiment 14, by 4-(4-amino-2-fluorophenoxy)-6-methoxyl group-5-methyl H-pyrrolo-[1,2-b] pyridazine-3-formonitrile HCN (the compound G of embodiment 14) and 2-(4-fluorophenyl)-1-thiocyano ethyl ketone (compd A of embodiment 2), make title compound. ¹HNMR(CD ₃OD)δ8.08(dd，1H，J＝12.7，1.7Hz)，7.95(s，1H)，7.80(s，1H)，7.34(m，3H)，7.19(m，1H)，7.04(s，2H)，6.87(m，2H)，3.89(s，3H)，3.30(m，2H)，2.27(s，3H)；MS(ESI ⁺)m/z?508(M+H) ⁺。

Embodiment 16

3-cyano group-4-(2-fluoro-4-(3-(2-phenyl acetyl) urea groups) phenoxy group)-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester

A) 2-phenyl acetyl isocyanic ester

(0.175mL, (68mg is 0.5mmol) in the formed suspension of ethylene dichloride (2mL) 2.0mmol) to be added into the 2-phenyl-acetamides with oxalyl chloride.This suspension dissolves fast, and forms new suspension.After 5 minutes, the LC/MS that reaction mixture is done analyzes the formation as yet of the desired product of demonstration.This mixture is warmed to 80 ℃, and after 30 minutes, LC/MS shows a spot of product and forms.Under 70 ℃, with this reactant heating two days, its major part became clarifying.LC/MS shows that major part is a product.Under 80 ℃, this mixture is stirred and heated other 4 hours.Yellow solid on reactor wall almost dissolves all.Under vacuum, this mixture is concentrated.Resulting residue is dissolved in ethylene dichloride (1.5mL), is concentrated, and it is dissolved in the ethylene dichloride (2mL) again.Resulting 0.25M solution need not to be further purified, and can use.

B) 3-cyano group-4-(2-fluoro-4-(3-(2-phenyl acetyl) urea groups) phenoxy group)-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester

Solution (0.04mmol with 2-phenyl acetyl isocyanic ester; 0.25M; in ethylene dichloride) be added into 4-(4-amino-2-fluorophenoxy)-3-cyano group-5-methyl H-pyrrolo-[1; 2-b] pyridazine-6-carboxylic acid, ethyl ester (7mg; 0.02mmol, the compd B of embodiment 14) and in the formed solution of methylene dichloride (0.3mL).At room temperature, stir this reactant, and give detection with LC/MS.After 2 hours, all raw materials consume all.This mixture is concentrated, and utilize silica gel chromatography (1-10% ethyl acetate/dichloromethane),, obtain being the title compound (8mg, 78%) of yellow solid resulting residue purifying. ¹H?NMR(CDCl ₃)δ10.77(s，1H)，8.51(s，1H)，8.21(s，1H)，7.86(s，1H)，7.73(dd，1H，J＝12.2，2.2Hz)，7.43-7.21(m，7H)，4.37(q，2H，J＝7.1Hz)，3.76(s，2H)，2.80(s，3H)，1.40(t，3H，J＝7.1Hz)；MS(ESI ⁺)m/z?516(M+H) ⁺。

Embodiment 17

3-cyano group-4-(2-fluoro-4-(3-(2-(4-fluorophenyl) ethanoyl) thioureido) phenoxy group)-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester

Solution (0.04mmol with 2-(4-fluorophenyl)-1-thiocyano ethyl ketone, 0.25M, in ethyl acetate, the compd A of embodiment 2) is added into 4-(4-amino-2-fluorophenoxy)-3-cyano group-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester (10.6mg, 0.03mmol, the compd B of embodiment 14) and in the formed solution of methylene dichloride (0.5mL).It is muddy that this reactant becomes immediately.At room temperature, this reactant was stirred 2 hours, then, stirred 1 hour down at 40 ℃.LC/MS analyzes the demonstration reaction and finishes.This reactant is concentrated, and utilize silica gel chromatography (1-6% ethyl acetate/dichloromethane),, obtain being yellow film shape thing/solid title compound (16mg, 97%) resulting residue purifying. ¹H?NMR(CDCl ₃)δ12.52(s，1H)，8.63(s，1H)，8.24(s，1H)，8.01(dd，1H，J＝11.9，2.4Hz)，7.88(s，1H)，7.41(m，1H)，7.29(m，3H)，7.11(m，2H)，4.37(q，2H，J＝7.1Hz)，3.71(s，2H)，2.78(s，3H)，1.40(t，3H，J＝7.1Hz)；MS(ESI ⁺)m/z550(M+H) ⁺。

Embodiment 18

3-cyano group-4-(2-fluoro-4-(3-(2-phenyl acetyl) thioureido) phenoxy group)-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester

By embodiment 17 described methods, by 4-(4-amino-2-fluorophenoxy)-3-cyano group-5-methyl H-pyrrolo-[1,2-b] pyridazine-6-carboxylic acid, ethyl ester (compd B of embodiment 14) and 2-phenyl-1-thiocyano ethyl ketone (0.1mL, 0.025mmol, 0.25M, in ethyl acetate, the Compound I of embodiment 1), make title compound. ¹H?NMR(CDCl ₃)δ12.55(s，1H)，8.58(s，1H)，8.23(s，1H)，8.01(dd，1H，J＝11.9，2.4Hz)，7.88(s，1H)，7.42(m，4H)，7.30(m，3H)，4.37(q，2H，J＝7.1Hz)，3.74(s，2H)，2.78(s，3H)，1.40(t，3H，J＝7.1Hz)；MS(ESI ⁺)m/z532(M+H) ⁺。

Embodiment 19

1-(4-(H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

A) 4-ketone group-1,4-pyrrolin be [1,2-b] pyridazine-3-carboxylic acid, ethyl ester also

Under 125 ℃, with N-amino-pyrroles (575mg, 7.0mmol, commercially available) and ethoxy methylene diethyl malonate (1.82g, 8.4mmol) mixture heating up 2 hours, obtain rough 2-((1H-pyrroles-1-base is amino) methylene radical) diethyl malonate.(2mL) is added in this intermediate with phenyl ether.This reactant is placed nitrogen atmosphere and under 220 ℃, heated 2 hours, formed ethanol in the reactant is steamed remove simultaneously.This reactant is cooled to room temperature, and utilizes flash chromatography on silica gel method (with 100% methylene dichloride wash-out) to carry out purifying, obtain being the title compound (1.03g, 71%) of yellow solid.

B) pyrrolo-[1,2-b] pyridazine-4 (1H)-ketone

Under 150 ℃, with 4-ketone group-1, the 4-pyrrolin also [1,2-b] pyridazine-3-carboxylic acid, ethyl ester (206mg, 1.0mmol), NaCl (64mg, 1.1mmol), water (0.054mL, 3.0mmol) and the mixture heating up of DMSO (2mL) 3 hours.After reaction finishes, DMSO steamed remove and utilize flash chromatography on silica gel method (with 1-10% ethyl acetate/dichloromethane wash-out), to obtain being the title compound (90mg, 67%) of light yellow solid resulting residue purifying.

C) 4-(2-fluoro-4-nitrophenoxy) H-pyrrolo-[1,2-b] pyridazine

With MeCN (0.7mL) be added into pyrrolo-[1,2-b] pyridazine-4 (1H)-ketone (13.4mg, 0.10mmol), 3, the 4-difluoro nitrobenzene (24mg, 0.15mmol) with 1,4-diazabicyclo [2.2.2] octane (DABCO, 22mg is 0.20mmol) in the formed mixture.Under 70 ℃,, and concentrated in a vacuum this reactant heating 72 hours.Utilize flash chromatography on silica gel method (with 100% methylene dichloride wash-out) with resulting residue purifying, obtain being the title compound (20mg, 73%) of yellow solid.

D) 4-(H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluoroaniline

With methyl alcohol (0.8mL) be added into 4-(2-fluoro-4-nitrophenoxy) H-pyrrolo-[1,2-b] pyridazine (17mg, 0.062mmol) in the formed solution of THF (1.2mL), then add zinc (100mg, 1.5mmol) and ammonium chloride (43mg, 0.80mmol).Under 70 ℃,, and concentrated in a vacuum this reactant heating 90 minutes.With methylene dichloride (2mL) and several Et ₃N is added in the resulting residue.Be partly dissolved solid and thus formed mixture is filtered.In a vacuum filtrate is concentrated and utilize flash chromatography on silica gel method (with 1-6% ethyl acetate/dichloromethane wash-out) to carry out purifying, the solid title compound that obtains being white in color (15mg, 99%).

E) 1-(4-(H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

Isocyanate solution (0.16mL, 0.04mmol, 0.25M with 0.25M, in ethyl acetate, the compd A of embodiment 2) (H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-(7mg is 0.03mmol) in the formed solution of methylene dichloride (0.3mL) for the 3-fluoroaniline to be added into 4-.At room temperature, this reactant was stirred 20 minutes, concentrate and utilize flash chromatography on silica gel method (with 1-5% ethyl acetate/dichloromethane wash-out) to carry out purifying in a vacuum, obtain being the title compound (12mg, 95%) of faint yellow solid. ¹H?NMR(CDCl ₃)δ12.46(s，1H)，8.67(s，1H)，7.92(dd，1H，J＝11.5，2.4Hz)，7.85(d，1H，J＝5.3Hz)，7.77(dd，1H，J＝2.6，1.5Hz)，7.39(m，1H)，7.28(m，3H)，7.13(m，2H)，6.83(dd，1H，J＝4.3，2.6Hz)，6.74(dd，1H，J＝4.3，1.5Hz)，5.70(d，1H，J＝5.3Hz)，3.73(s，2H)；MS(ESI ⁺)m/z439(M+H) ⁺。

Embodiment 20

1-(4-(H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

Solution (0.16mL with 2-(4-fluorophenyl) ethanoyl isocyanic ester; 0.04mmol; 0.25M; in methylene dichloride; the Compound C of embodiment 4) is added into 4-(H-pyrrolo-[1; 2-b] pyridazine-4-base oxygen base)-3-fluoroaniline (5mg, 0.02mmol, the Compound D of embodiment 19) is in the formed solution of methylene dichloride (0.3mL).At room temperature, this reactant was stirred 2 hours, concentrate in a vacuum and utilize flash chromatography on silica gel method (with 1-15% ethyl acetate/dichloromethane wash-out) to carry out purifying, obtain being the title compound (5.5mg, 63%) of faint yellow solid. ¹H?NMR(CDCl ₃)δ10.68(s，1H)，8.69(s，1H)，7.83(d，1H，J＝5.3Hz)，7.77(dd，1H，J＝2.6，1.5Hz)，7.68(dd，1H，J＝11.5，2.4Hz)，7.33-7.17(m，4H)，7.09(m，2H)，6.82(dd，1H，J＝4.3，2.6Hz)，6.74(dd，1H，J＝4.3，1.5Hz)，5.69(d，1H，J＝5.3Hz)，3.76(s，2H)；MS(ESI ⁺)m/z423(M+H) ⁺。

Embodiment 21

1-(4-(9-(bicyclic methyl propyl)-8-ethyl-9H-purine-6-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

MeCN (2mL) is added into 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide (24mg; 0.075mmol; the compd A of embodiment 3), 6-chloro-9-(bicyclic methyl propyl)-8-ethyl-9H-purine (20.7mg; 0.075mmol; PCT applies for WO 99/01454; United States Patent (USP) 6; 143; 743; embodiment 831, and its disclosure is incorporated this paper into as a reference) with 1,4-diazabicyclo [2.2.2] octane (DABCO; 8.4mg, 0.075mmol) in the formed mixture.At room temperature, this reactant was stirred 4 hours, and concentrate in a vacuum.Utilize anti-phase to prepare HPLC, with resulting residue purifying, the solid title compound that obtains being white in color (15.3mg, 36%). ¹HNMR(CDCl ₃)δ12.43(m，1H)，8.48(m，1H)，8.40(m，1H)，7.92(m，1H)，7.28(m，4H)，7.13(m，2H)，3.72(s，2H)，3.34(m，3H)，1.53(m，3H)，0.81(m，2H)，0.46(m，4H)，0.23(m，2H)；MS(ESI ⁺)m/z?489(M+H) ⁺。

Embodiment 22

1-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) guanidine

A) 4-chlorine pyrrolo-[2,1-f] [1,2,4] triazine

Successively with the diisopropyl ethyl amine of 4.77mL (27.4mmol) and the phosphoryl chloride of 7.70mL (82.6mmol), be added into pyrrolo-[2,1-f] [1,2,4] triazine-4-alcohol (3.70g, 27.4mmol, generally can apply for WO 2000/071129 referring to PCT, its disclosure is all incorporated this paper into as a reference) in the formed solution at room temperature of 40mL toluene.Under 100 ℃, with this reaction mixture heating 18 hours.After this reactant is cooled to room temperature, add 5% sodium bicarbonate aqueous solution (100mL, 0 ℃) lentamente.After interpolation is finished, at room temperature, this biphasic mixture was stirred 30 minutes.(3 * 100mL) aqueous layer extracted and clean the organic extract liquid compile with salt solution (100mL) through anhydrous magnesium sulfate drying, and concentrate it in a vacuum, obtain being the crude product (4.10g, 97%) of yellow solid with ethyl acetate.

¹H?NMR(CDCl ₃)δ8.14(s，1H)，7.80(dd，1H，J＝2.4，1.5Hz)，6.91(m，2H)。

B) 4-(2-fluoro-4-nitrophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine

Under 60 ℃, will 4-chlorine pyrrolo-[2,1-f] [1,2, the 4] triazine in the 100mL dimethyl formamide (4.1g, 27mmol), 2-fluoro-4-nitrophenols (5.0g, 32mmol) and salt of wormwood (7.4g 53mmol) stirs 15 hours.After this reaction mixture is cooled to room temperature, it is filtered by the silica gel charges with ethyl acetate.In a vacuum, this filtrate is concentrated, and utilize flash chromatography on silica gel method (SiO ₂, ethyl acetate/hexane 1: 4), with resulting crude product purifying, the solid title compound that obtains being white in color (4.25g, 58%). ¹H?NMR(CDCl ₃)δ8.09(m，2H)，7.88(s，1H)，7.77(dd，1H，J＝2.6，1.2Hz)，7.46(t，1H，J＝7.6Hz)，6.98(dd，1H，J＝4.6，1.4Hz)，6.84(dd，1H，J＝4.5，2.6Hz)； ¹³C?NMR(CDCl ₃)δ160.6，154.3(J＝254Hz)，146.5，145.8，144.8(J＝12.9Hz)，125.0，121.7，120.7，114.5，113.9，113.6(J＝23.2Hz)，103.6。

C) 3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline (4)

Successively with zinc powder (3.04g, 46.5mmol,＜10 μ m) and ammonium chloride (2.49g, 46.5mmol) be added into 4-(2-fluoro-4-nitrophenoxy) pyrrolo-[2,1-f] [1,2,4] (4.25g is 15.5mmol) in 40mL tetrahydrofuran (THF) and 60mL methyl alcohol in the formed solution under 0 ℃ for triazine.At room temperature, this mixture is stirred a whole night.Add other zinc powder (6.08g, 93mmol) and ammonium chloride (5.0g 93mmol), and at room temperature, stirs this reactant 4 hours.This uneven mixture is passed through thin Celite with methyl alcohol ^Pad filters, and in a vacuum filtrate is concentrated.Utilize flash chromatography on silica gel method (SiO ₂, ethyl acetate/hexane 1: 1) and carry out purifying, obtain being the title compound (3.5g, 92%) of yellow foam. ¹H?NMR(CDCl ₃)δ7.92(s，1H)，7.70(dd，1H，J＝2.5，1.6Hz)，6.98(t，1H，J＝8.5Hz)，6.92(dd，1H，J＝4.4，1.4Hz)，6.77(m，1H)，6.42(m，2H)，3.71(br?s，2H)；MS(ESI ⁺)m/z?245.2(M+H) ⁺。

D) 1-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) guanidine

Successively with 0.3mL toluene and diisopropylethylamine (15 μ L; 0.086mmol) be added into and contain 3-fluoro-4-(pyrrolo-[2; 1-f] [1; 2; 4] aniline (20mg triazine-4-base oxygen base); 0.082mmol) and 1-(2-(4-fluorophenyl) ethanoyl)-(20mg is in test tube 0.086mmol) for the 2-methyl-isothiourea.Under 110 ℃, this reactant was stirred 6 hours.Add extra umber 1-(2-(4-fluorophenyl)-ethanoyl)-2-methyl-isothiourea (20mg, 0.086mmol) and diisopropylethylamine (15 μ L, 0.086mmol).Under 110 ℃, this reactant stirred a whole night after, this reactant is cooled to room temperature, and utilizes flash chromatography on silica gel method (SiO ₂, ethyl acetate/hexane 1: 1) directly carry out purifying, the solid title compound obtains being white in color.Be used in the 4N HCl (Yu diox under 0 ℃) handled this solid 30 minutes.In a vacuum with this solution concentration, hydrogen chlorate's (15mg, 40%) of the title compound of the powder that obtains being white in color. ¹HNMR(CDCl ₃)δ13.8(br?s，1H)，11.5(br?s，1H)，9.48(br?s，1H)，7.85(s，1H)，7.78(dd，1H，J＝2.5，1.4Hz)，7.30(m，5H)，7.01(m，3H)，6.85(m，1H)；MS(ESI ⁺)m/z423.1(M+H) ⁺。

Embodiment 23

N ¹-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-phenyl Malonamide

A) 3-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenylamino)-3-ethyl ketopropionate

96 μ L (0.55mmol) diisopropylethylamine and 61 μ L (0.48mmol) 3-chloro-3-ethyl ketopropionates are added into 3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] aniline (112mg triazine-4-base oxygen base), 0.459mmol, the Compound C of embodiment 22) and in the solution of methylene dichloride (4mL).Under 0 ℃, this reactant was stirred 1 hour, then, with the saturated sodium hydrogen carbonate solution cancellation reaction of 10mL.With chloroform (3 * 15mL) aqueous layer extracted.The organic extract liquid that merges through anhydrous sodium sulfate drying, and is concentrated in a vacuum, obtain being the crude product of yellow oil, it can solidify (180mg) after leaving standstill. ¹HNMR(CDCl ₃)δ9.45(br?s，1H)，7.89(s，1H)，7.71(dd，1H，J＝2.5，1.5Hz)，7.68(dd，1H，J＝11.8，2.2Hz)，7.18(m，2H)，6.93(dd，1H，J＝4.4，1.4Hz)，6.78(dd，1H，J＝4.4，2.6Hz)，4.19(q，2H，J＝7.2Hz)，3.41(s，2H)，1.25(t，3H，J＝7.2Hz)；MS(ESI ⁺)m/z359.1(M+H) ⁺。

B) 3-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenylamino)-3-ketopropionic acid

1N aqueous sodium hydroxide solution (10mL) is added into aforementioned rough 3-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenylamino)-3-ethyl ketopropionate (180mg) in the formed solution under 0 ℃ of ethanol (10mL).Under 0 ℃, this reactant stirring after 3 hours, is cleaned with the 20mL ethyl acetate.1N aqueous sodium hydroxide solution reextraction ethyl acetate layer with 20mL.With the 1N spirit of salt aqueous solution, with the acidified aqueous solution that merges to pH5.With ethyl acetate (3 * 30mL) aqueous layer extracted.The organic extract liquid that merges through the anhydrous slufuric acid inner drying, and is concentrated in a vacuum, obtain rough acid (150mg), it need not to be further purified and can use.MS(ESI ⁺)m/z331.1(M ⁺+H) ⁺。

C) N ¹-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-phenyl Malonamide

At room temperature, with 3-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] phenylamino triazine-4-base oxygen base))-the 3-ketopropionic acid (17mg, 0.052mmol), bop reagent (34mg, 0.077mmol), 4-methylmorpholine (28 μ L, 0.26mmol) and aniline (4.7 μ L are 0.052mmol) in the formed solution stirring of dimethyl formamide (0.5mL) 16 hours.(4mL) dilutes this reactant with ethyl acetate, and water, the 10% lithium chloride aqueous solution and salt solution (respectively 1 * 3mL) are cleaned.Organic solution through anhydrous sodium sulfate drying, then, is concentrated in a vacuum.Utilize flash chromatography method (SiO ₂, ethyl acetate/hexane 7: 3) and carry out purifying, the solid that obtains being white in color is wanted compound.Use acetonitrile/water, with this product lyophilize, the title compound (12mg, 57%) of the powder that obtains being white in color. ¹H?NMR(CDCl ₃)δ9.23(brs，1H)，8.22(brs，1H)，7.90(s，1H)，7.72(m，1H)，7.46(d，1H，J＝8.2Hz)，7.20(m，7H)，6.95(m，1H)，6.78(m，1H)，3.47(s，2H)；MS(ESI ⁺)m/z?406.1(M+H) ⁺。

Embodiment 24

N ¹-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide

At room temperature, with 3-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] phenylamino triazine-4-base oxygen base))-3-ketopropionic acid (18mg, 0.55mmol, the compd B of embodiment 23), bop reagent (36mg, 0.082mmol), the 4-methylmorpholine (30 μ L, 0.27mmol) and the 4-fluoroaniline (5.2 μ L are 0.055mmol) in the formed solution stirring of dimethyl formamide (0.5mL) 16 hours.(4mL) dilutes this reactant with ethyl acetate, and (each 1 * 3mL) cleaning of water, the 10% lithium chloride aqueous solution and salt solution.Organic solution through anhydrous sodium sulfate drying, is concentrated then in a vacuum.Utilize flash chromatography method (SiO ₂, ethyl acetate/hexane 7: 3) and carry out purifying, the solid that obtains being white in color is wanted compound.Use acetonitrile/water, with this product lyophilize, the title compound (14mg, 61%) of the powder that obtains being white in color. ¹HNMR(CDCl ₃)δ9.28(br?s，1H)，8.64(br?s，1H)，7.89(s，1H)，7.73(dd，1H，J＝2.5，1.5Hz)，7.69(dd，1H，J＝11.6，1.9Hz)，7.42(m，3H)，7.21(m，1H)，6.97(m，3H)，6.80(dd，1H，J＝4.5，2.6Hz)，3.49(s，2H)；MS(ESI ⁺)m/z?424.1(M+H) ⁺。

Embodiment 25

N ¹-(3-fluoro-4-(thieno-[3,2-d] pyrimidine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide

A) 3-(4-fluorophenyl amino)-3-ketopropionic acid

Successively with diisopropylethylamine (8.4mL, 48mmol) and the 4-fluoroaniline ((5.0mL, 40mmol is Aldrich) in the formed solution under 0 ℃ of methylene dichloride (100mL) Aldrich) to be added into 3-chloro-3-ethyl ketopropionate for 3.6mL, 38mmol.At room temperature, this reactant is stirred a whole night, then, with the saturated sodium hydrogen carbonate solution cancellation reaction of 100mL.With chloroform (3 * 100mL) aqueous layer extracted.The organic extract liquid that merges through anhydrous sodium sulfate drying, and is concentrated in a vacuum, obtain being the crude product of yellow oil, it can solidify (10g) after leaving standstill. ¹H?NMR(CDCl ₃)δ9.30(brs，1H)，7.55(m，2H)，7.05(t，2H，J＝8.8Hz)，4.28(q，2H，J＝7.2Hz)，3.49(s，2H)，1.35(t，3H，J＝7.1Hz)；MS(ESI ⁺)m/z226.1(M+H) ⁺。

Aforementioned ester cpds is dissolved in the 100mL ethanol, and is cooled to 0 ℃.Add 1N aqueous sodium hydroxide solution (100mL), and under 0 ℃, this reactant was stirred 1 hour.This reactant is concentrated, to remove ethanol.(50mL) extracts this aqueous solution with ethyl acetate, then, with the 1N spirit of salt aqueous solution, makes it be acid.(5 * 100mL) extract this aqueous solution with ethyl acetate.The organic extract liquid that merges through anhydrous sodium sulfate drying, and is concentrated in a vacuum, obtain being the crude product (6.31g, 84%) of yellow solid, it need not to be further purified, and can use. ¹HNMR(DMSO-d ₆)δ12.9(br?s，1H)，10.3(br?s，1H)，7.59(m，2H)，7.16(t，2H，J＝8.9Hz)，3.34(s，2H)；MS(ESI ⁺)m/z?198.4(M+H) ⁺。

B) N ¹-(3-fluoro-4-hydroxyphenyl)-N ³-(4-fluorophenyl) Malonamide

Successively (1.70g, (1.00g is 6.37mmol) in 4mL tetrahydrofuran (THF) and 6mL methyl alcohol in the formed 0 ℃ solution 31.8mmol) to be added into 2-fluoro-4-nitrophenols with zinc powder (2.08g, 31.8mmol,＜10 μ m) and ammonium chloride.At room temperature, this mixture is stirred a whole night.This uneven mixture is passed through thin Celite with methyl alcohol ^Pad filters, and in a vacuum, resulting filtrate is concentrated, and obtains brown solid (656mg, 81%), and it need not to be further purified and can use.

With 3-(4-fluorophenyl amino)-(197mg 1.00mmol) is dissolved in the 4mL dimethyl formamide 3-ketopropionic acid.(140 μ L 1.00mmol), and are cooled to 0 ℃ with this solution to add triethylamine.Successively add 4-amino-2-fluorophenol (127mg, 1.00mmol, Aldrich) and bop reagent (442mg, 1.00mmol).This reactant is warmed to room temperature, then, at room temperature, was stirred 3 hours.This reaction mixture is concentrated,, and add water, so that the product precipitation is separated out with the removal methylene dichloride.Filter and grind, the solid title compound that obtains being white in color (211mg, 69%) with water.

¹H?NMR(CD ₃OD)δ7.61(m，2H)，7.51(dd，1H，J＝13，2.5Hz)，7.08(m，3H)，6.88(t，1H，J＝9.4Hz)，3.51(s，2H)；MS(ESI ⁺)m/z?307.4(M+H) ⁺。

C) N ¹-(3-fluoro-4-(thieno-[3,2-d] pyrimidine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide

With N ¹-(3-fluoro-4-hydroxyphenyl)-N ³-(4-fluorophenyl) Malonamide (46mg, 0.15mmol), the 4-chlorothiophene also [3,2-d] pyrimidine (17mg, 0.10mmol), cesium carbonate (49mg, 0.15mmol) and cupric chloride (I) (10mg 0.10mmol) places test tube.With this test tube sealing, washed with nitrogen, successively be packed into 1-Methyl-2-Pyrrolidone (0.3mL) and 2,2,6,6-tetramethyl--3, the 5-heptadione (4.0 μ L, 0.02mmol).Under 120 ℃, this reactant was stirred 2 hours.Utilize preparation HPLC, with this reaction mixture purifying.Suitable level part is concentrated,, and, make the resulting aqueous solution become alkalescence with saturated sodium hydrogen carbonate solution (5mL) with removal methyl alcohol.With ethyl acetate (3 * 10mL) extract this aqueous solution, and with the organic extract liquid that merges through anhydrous sodium sulfate drying, and concentrate in a vacuum, obtain being the desired product of colorless oil.After carrying out lyophilize with methanol, the solid title compound that obtains being white in color (23mg, 52%). ¹H?NMR(CD ₃OD)δ8.54(s，1H)，8.21(d，1H，J＝5.5Hz)，7.69(dd，1H，J＝12.4，2.0Hz)，7.49(m，3H)，7.27(m，2H)，6.96(t，2H，J＝8.9Hz)，3.47(s，2H)；MS(ESI ⁺)m/z?441.1(M+H) ⁺。

Embodiment 26

N ¹-(3-fluoro-4-(thieno-[2,3-d] pyrimidine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide

With N ¹-(3-fluoro-4-hydroxyphenyl)-N ³-(4-fluorophenyl) Malonamide (46mg, 0.15mmol, the compd B of embodiment 25), 4-chlorothiophene also [2,3-d] pyrimidine (17mg, 0.10mmol), cesium carbonate (49mg, 0.15mmol) and cupric chloride (I) (10mg 0.10mmol) places test tube.With this test tube sealing, washed with nitrogen, successively be packed into 1-Methyl-2-Pyrrolidone (0.3mL) and 2,2,6,6-tetramethyl--3, the 5-heptadione (4.0 μ L, 0.02mmol).Under 120 ℃, this reactant was stirred 1 hour.Utilize preparation HPLC, with this reaction mixture purifying.Suitable level part is concentrated,, and, make the resulting aqueous solution become alkalescence with saturated sodium hydrogen carbonate solution (5mL) with removal methyl alcohol.With ethyl acetate (3 * 10mL) extract this aqueous solution, and with the organic extract liquid that merges through anhydrous sodium sulfate drying, and concentrated in a vacuum, obtain being the desired product of colorless oil.After carrying out lyophilize with methanol, the solid title compound that obtains being white in color (27mg, 61%). ¹HNMR(DMSO-d ₆)δ10.7(s，1H)，10.4(s，1H)，8.77(s，1H)，8.15(d，1H，J＝5.9Hz)，7.95(dd，1H，J＝12.8，2.0Hz)，7.85(d，1H，J＝5.9Hz)，7.77(m，2H)，7.54(m，2H)，7.30(t，2H，J＝8.8Hz)，3.48(s，2H)；MS(ESI ⁺)m/z?441.1(M+H) ⁺。

Embodiment 27

1-(3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

At room temperature, in the nitrogen atmosphere, (28 μ L, (21mg is 0.26mmol) in ethyl acetate (1mL) in the formed homogeneous solution 0.20mmol) to be added into Sodium Thiocyanate 99 with 4-fluorophenyl-Acetyl Chloride 98Min..This mixture was stirred 30 minutes, then, under nitrogen atmosphere, it is added directly to 3-fluoro-4-(pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline (37mg, 0.15mmol, the Compound C of embodiment 22) is in anhydrous methylene chloride (3mL) in the formed homogeneous solution.At ambient temperature, this mixture was stirred 4 hours, then, in a vacuum, concentrate.Utilize silica gel (Merck KGaA, 230-400 order granularity) flash chromatography method (using the chloroform wash-out) to carry out purifying, obtain title compound (55mg, 83%).

¹H NMR (CDCl ₃) δ 12.41 (s, 1H), 8.50 (s, 1H), 7.97 (s, 1H), 7.92 (m, 1H), 7.81 (m, 1H), 7.42 (m, 1H), 7.35-7.25 (m, 3H), 7.17-7.10 (m, 2H), 7.05-7.02 (m, 1H), 6.85-6.90 (m, 1H), 3.72 (s, 2H); HRMS (ESI), theoretical value: 440.0993 (M+H) ⁺, measured value: 440.0988 (M+H) ⁺

Embodiment 28

1-(3-fluoro-4-(the 5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

A) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole [2,1-f] [1,2,4] triazine also

Under nitrogen atmosphere, with 4-chloro-5-methylpyrrole [2,1-f] [1 also, 2,4] triazine (3.37g, 20.11mmol, PCT patent application WO 2000/071129, U.S. Patent application 2003/0186982, its disclosure is incorporated this paper into as a reference) and 2-fluoro-4-nitrophenols (3.48g, 22.12mmo1) formed mixture stirred 5 minutes in dry DMF (100mL), then, the interpolation Anhydrous potassium carbonate (6.11g, 44.24mmol).Under 60 ℃, with this mixture heating up 15 hours, then, (1.00g 6.37mmol), and under 60 ℃, continued to stir 4.5 hours to add 2-fluoro-4-nitrophenols.This mixture is cooled to room temperature, is diluted with methylene dichloride, the water and the 10% lithium chloride aqueous solution clean successively, through anhydrous magnesium sulfate drying and after concentrating in a vacuum, obtain filemot solid again.Utilize silica gel (Merck KGaA, 230-400 order granularity) flash chromatography method (using the chloroform wash-out) to carry out purifying, obtain being the title compound (4.19g, 72%) of faint yellow solid. ¹H NMR (CDCl ₃) δ 8.20-8.13 (m, 2H), 7.83 (s, 1H), 7.73 (d, 1H, J=2.6Hz), 7.58-7.53 (m, 1H), 6.69 (d, 1H, J=2.4Hz), 2.62 (s, 3H); HRMS (ESI), theoretical value: 289.0737, measured value: 289.0733 (M+H) ⁺

B) 3-fluoro-4-(the 5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) aniline

At ambient temperature, in the nitrogen atmosphere, with zinc powder (6.90g, 105mmol) and ammonium chloride (5.64g, 105mmol) be added into 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole also [2,1-f] [1,2,4] (3.04g is 10.55mmol) in anhydrous methanol (60mL) and anhydrous tetrahydro furan (40mL) in the formed heterogeneous mixture for triazine.This mixture was stirred 7 hours, and then, filtration catalizer and in a vacuum that resulting filtrate is concentrated obtains flaxen solid, and it is distributed between chloroform and water.Then, with chloroform extraction water layer secondary.Water cleans the chloroform layer that merges, and it through anhydrous magnesium sulfate drying and concentrated in a vacuum, is obtained being solid title compound (2.51g, 92%). ¹HNMR (CDCl ₃) δ 7.86 (s, 1H), 7.64 (d, 1H, J=2.6Hz), 7.08-7.03 (m, 1H), 6.61 (d, 1H, J=2.4Hz), 6.55-6.45 (m, 2H), 3.78 (s, 2H), 2.60 (s, 3H); HRMS (ESI), theoretical value: 259.0995 (M+H) ⁺, measured value: 259.0997 (M+H) ⁺

C) 1-(3-fluoro-4-(the 5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

Comply with and the similar mode of the preparation of embodiment 27, (39mg 0.15mmol) is converted into title compound (42mg, 62%) to aniline with 3-fluoro-4-(the 5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also). ¹HNMR (CDCl ₃) δ 12.41 (s, 1H), 8.48 (s, 1H), 7.92-7.82 (m, 2H), 7.68 (d, 1H, J=2.5Hz), 7.39-7.27 (m, 4H), 7.15-7.10 (m, 2H), 6.64 (d, 1H, J=2.3Hz), 3.72 (s, 2H), 2.60 (s, 3H); HRMS (ESI), theoretical value: 454.1149 (M+H) ⁺, measured value: 454.1154 (M+H) ⁺

Embodiment 29

N ¹-(3-fluoro-4-(the 5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-N ³-(4-fluorophenyl) Malonamide

At room temperature, in the nitrogen atmosphere, with diisopropylethylamine (52 μ L, (the 5-methylpyrrole is [2,1-f] [1 also 0.30mmol) to be added into 3-fluoro-4-, 2,4] triazine-4-base oxygen base) aniline (52mg, 0.20mmol, the compd B of embodiment 28) and 3-(4-fluorophenyl amino)-3-ketopropionic acid (39mg, 0.20mmol, the compd A of embodiment 25) and in the formed homogeneous solution of dry DMF (2mL).This mixture was stirred 5 minutes, then, once add O-benzotriazole-1-base-N of one whole part, N, N ', N '-tetramethyl-urea a tetrafluoro borate (o-benzotriazol-1-yl-N, N, N ', N '-tetramethyluronium tetrafluoroborate) (96mg, 0.30mmol).This mixture was stirred 17.5 hours, then, in a vacuum, this reactant is concentrated, to remove volatile matter.Dilute resultant residue with ethyl acetate, and clean secondary, then, in a vacuum, concentrate with the 10% lithium chloride aqueous solution.Utilize silica gel (Merck KGaA, 230-400 order granularity) flash chromatography method (with the methyl alcohol in 1% the chloroform) to carry out purifying, obtain linen solid, in the presence of anhydrous diethyl ether (3mL), with this solid abrasive and with supersound process.By filtration method, the separable solid title compound that goes out to be white in color (66mg, 75%). ¹H NMR (CDCl ₃) δ 9.28 (s, 1H), 8.67 (s, 1H), 7.83 (s, 1H), 7.80-7.73 (m, 1H), 7.67 (d, 1H, J=2.5Hz), 7.54-7.49 (m, 2H), 7.28-7.26 (m, 2H), 7.10-7.02 (m, 2H), 6.64 (d, 1H, J=2.3Hz), 3.56 (s, 2H), 2.60 (s, 3H); HRMS (ESI), theoretical value: 436.1221 (M+H) ⁺, measured value: 436.1230 (M+H) ⁺

Embodiment 30

N ¹-(4-(H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malonamide

With 3-(4-fluorophenyl amino)-3-ketopropionic acid (41mg, 0.21mmol, the compd A of embodiment 25), DIPEA (42 μ L, 0.25mmol) and TBTU (81mg, 0.25mmol), handle 4-(H-pyrrolo-[1,2-b] pyridazine-4-base oxygen base)-3-fluoroaniline (51mg, 0.21mmol, the Compound D of embodiment 19) is in the formed solution of DMF (1mL), and at room temperature, this mixture was stirred 16 hours.In a vacuum, this mixture is concentrated, removing DMF, and the residue of gained is distributed between ethyl acetate (2mL) and saturated sodium bicarbonate solution (2mL).Clean the ethyl acetate phase with the 10% lithium chloride aqueous solution (2mL), salt solution (2ml), it through dried over mgso, and is concentrated in a vacuum.Grind resulting crude product secondary with ethyl acetate, and ground secondary, obtain being the title compound (17mg, 19%) of pale solid with methyl alcohol. ¹H?NMR(DMSO-d ₆)δ10.56(s，1H)，10.28(s，1H)，8.01(d，1H，J＝5.4Hz)，7.92-7.91(m，1H)，7.65-7.62(m，2H)，7.48-7.44(m，2H)，7.22-7.15(m，3H)，6.86(dd，1H，J＝4.2，2.7Hz)，6.72(dd，1H，J＝4.4，1.4Hz)，5.8?1(d，1H，J＝5.4Hz)，3.51(s，2H)；MS(ESI ⁺)m/z423.3(M+H) ⁺。

Embodiment 31

1-(3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide, two hydrogen chlorates

A) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-base pivalate also

At room temperature, in the nitrogen atmosphere, with DABCO (462mg, 4.12mmol) be added into also [2,1-f] [1,2 of 4-chloro-5-methylpyrrole, 4] triazine-6-base pivalate (1.00g, 3.74mmol, the Compound D of embodiment 1) and 2-fluoro-4-nitrophenols (588mg is 3.74mmol) in the formed homogeneous solution of anhydrous acetonitrile (25mL).Then, under 50 ℃, with this mixture heating up 3 hours.This mixture is cooled to room temperature, then, it is distributed between chloroform and saturated aqueous ammonium chloride.With chloroform extraction water layer secondary.With saturated aqueous ammonium chloride and saturated sodium-chloride water solution, the organic layer that merges is respectively cleaned once respectively, through anhydrous magnesium sulfate drying and after concentrating in a vacuum, obtain a flaxen solid, it need not to be further purified, and promptly can be used for next procedure.MS(ESI ⁺)m/z389.1(M+H) ⁺。

B) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-alcohol also

At room temperature, in the nitrogen atmosphere, the 1N aqueous sodium hydroxide solution is added into also [2,1-f] [1,2 of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole, 4] triazine-(1.45g is 3.74mmol) in the formed heterogeneous mixture of dehydrated alcohol (19mL) for 6-base pivalate.At ambient temperature, this reaction mixture thing was stirred 1.5 hours, then, it is neutralized to pH7 with 1N hydrochloric acid.This reaction mixture is concentrated,, then, it is distributed between ethyl acetate and water to remove ethanol.With ethyl acetate extraction water layer secondary.The organic extract liquid secondary that water clean to merge is cleaned once with saturated sodium-chloride water solution again, with it through anhydrous magnesium sulfate drying and concentrated in a vacuum.Utilize silica gel (MerckKGaA, 230-400 order granularity) flash chromatography method (with 2: 1 hexane/ethyl acetate wash-outs) to carry out purifying, obtain being the title compound (602mg, the productive rate 53% of steps A-B) of yellow solid. ¹HNMR(CDCl ₃)δ8.20-8.12(m，2H)，7.84(s，1H)，7.58-7.53(m，1H)，7.53(s，1H)，4.76(s，1H)，2.48(s，3H)；MS(ESI ⁺)m/z305.2(M+H) ⁺。

C) 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine

In nitrogen atmosphere, with 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-alcohol (100mg, 0.33mmol) and triphenylphosphine (129mg, 0.49mmol) formed uniform mixture is cooled to 0 ℃ in 1: 1 anhydrous methylene chloride/anhydrous tetrahydro furan of 4mL, dropwise add 2-(4-methylpiperazine-1-yl) ethanol (71mg then, 0.49mmol) and diisopropyl azo-2-carboxylic acid (0.10 μ L, 0.49mmol) formed mixture in 1: 1 anhydrous methylene chloride/anhydrous tetrahydro furan of 2mL.Be warmed to room temperature with this mixture stirring and with it.This reactant was stirred 12 hours, then, in a vacuum, concentrated.Utilize preparation HPLC (YMC S10 ODS, 30 * 500mm, 30 minutes gradients of 50% to 90% methanol aqueous solution (containing 0.1%TFA)), with resulting residue purifying.With part merging of suitable level, neutralized with saturated sodium bicarbonate aqueous solution, then, concentrate in a vacuum, to remove methyl alcohol.(3 * 10mL) extract this mixture with chloroform.The organic layer that each cleaning of water and salt solution merges once through anhydrous magnesium sulfate drying and after concentrating in a vacuum, obtains being the title compound (34mg, 24%) of yellow solid. ¹H?NMR(CDCl ₃)δ8.20-8.10(m，2H)，7.82(s，1H)，7.58-7.52(m，1H)，7.49(s，1H)，4.16(t，2H，J＝5.7Hz)，2.87(t，2H，J＝5.7Hz)，2.80-2.40(m，8H)，2.45(s，3H)，2.31(s，3H)；MS(ESI ⁺)m/z43?1.3(M+H) ⁺。

D) 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline

According to the similar mode of preparation of the compd B of embodiment 28, with 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-g] [1,2,4] (20mg 0.05mmol) is converted into title compound (16mg, 87%) to triazine. ¹H?NMR(CDCl ₃)δ7.86-7.83(m，1H)，7.50-7.38(m，2H)，7.09-7.00(m，1H)，6.56-6.45(m，1H)，4.14(t，2H，J＝5.5Hz)，2.99-2.38(m，18H)；MS(ESI ⁺)m/z?401.4(M+H) ⁺。

E) 1-(3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide, two hydrogen chlorates

According to the similar mode of the preparation of embodiment 27, with 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) (18mg 0.05mmol) is converted into title compound (7mg, 26%) to aniline.(0.05mL 0.05mmol) handles, and carries out lyophilize then, and the result obtains being the title compound (5mg, 64%) of faint yellow solid with 1N hydrochloric acid earlier.

¹H NMR (CD ₃OD) δ 8.06-7.99 (m, 2H), 7.83 (s, 1H), 7.79 (s, 1H), 7.48-7.30 (m, 4H), 7.13-7.02 (m, 2H), 4.56-4.45 (m, 2H), 3.87-3.59 (m, 4H), 3.09-2.44 (m, 15H); HRMS (ESI), theoretical value: 596.2255 (M+H) ⁺, measured value: 596.2261 (M+H) ⁺

Embodiment 32

1-(4-(6-(3-dimethylamino) propoxy-)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also)-3-fluorophenyl)-and 3-(2-(4-fluorophenyl) ethanoyl) urea, the hydrogen chlorate

A) 3-(4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-base oxygen base also)-N, N-dimethylpropane-1-amine

Under 0 ℃, in the nitrogen atmosphere, via syringe, with diethylazodicarboxylate (138 μ L, 0.87mmol) dropwise be added into the triphenylphosphine [3mmol (triphenylphosphine)/1g (resin) that combines with polymkeric substance, 583mg, 1.75mmol] in the formed mixture of anhydrous tetrahydro furan (5mL).This mixture was stirred 15 minutes, then, interpolation 3-dimethylamino propyl alcohol (103 μ L, 0.87mmol).After 30 minutes, under 0 ℃, add also [2,1-f] [1,2,4] triazine-6-alcohol (133mg, 0.44mmol, the compd B of embodiment 31) of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole, and allow this mixture be warmed to room temperature lentamente.14.5 after hour, utilize filtration method, resin is removed, and cleaned with 1: 1 methyl alcohol/tetrahydrofuran (THF).In a vacuum the filtrate that merges is concentrated, obtain a yellow residue, it need not to be further purified, and promptly can be used for next procedure.MS(ESI ⁺)m/z?390.2(M+H) ⁺。

B) 4-(6-(3-(dimethylamino) propoxy-)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also)-3-fluoroaniline

According to the similar mode of preparation of the compd B of embodiment 28, (4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole is [2,1-f] [1 also with 3-, 2,4] triazine-6-base oxygen base)-and N, (170mg 0.44mmol) is converted into title compound to N-dimethylpropane-1-amine.The yellow solid of gained need not to be further purified, and promptly can be used for next procedure.MS(ESI ⁺)m/z360.3(M+H) ⁺。

C) 1-(4-(6-(3-dimethylamino) propoxy-)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also)-3-fluorophenyl)-and 3-(2-(4-fluorophenyl) ethanoyl) urea, the hydrogen chlorate

According to the similar mode of preparation of the compd E of embodiment 31; but; replace the benzenesulfonyl isocyanic ester with 2-(4-fluorophenyl) ethanoyl isocyanic ester (0.10mL, 0.04mmol, the Compound C of embodiment 4); and with 4-(6-(3-(dimethylamino) phenoxy group)-5-methylpyrrole also [2; 1-f] [1,2,4] triazine-4-base oxygen base)-3-fluoroaniline (12mg; 0.03mmol) be converted into title compound (2.5mg, 13%). ¹H NMR (CD ₃OD) δ 10.77 (s, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.40-7.23 (m, 5H), 7.11-7.02 (m, 3H), 4.15-4.12 (m, 2H), 3.71 (s, 2H), 3.41-3.36 (m, 2H), 2.97 (s, 6H), 2.44 (s, 3H), 2.31-2.22 (m, 2H); HRMS (ESI), theoretical value: 539.2218 (M+H) ⁺, measured value: 539.2218 (M+H) ⁺

Embodiment 33

1-(4-(6-(2-(dimethylamino) oxyethyl group)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, the hydrogen chlorate

A) 2-(4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-base oxygen base also)-N, the N-dimethyl amine

According to the similar mode of preparation of the compd A of embodiment 32, but, use N, N-dimethylethanolamine (75 μ L, 0.75mmol) replace 3-dimethylamino propyl alcohol and with diisopropyl azo-2-carboxylic acid (148 μ L, 0.75mmol) replace the diethylazodicarboxylate, and with 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole [2,1-f] [1 also, 2,4] triazine-6-alcohol (91mg, 0.30mmol, the compd B of embodiment 31) is converted into title compound.Utilize preparation HPLC (YMC S10 ODS, 30 * 500mm, 30 minutes gradients of 70% to 90% methanol aqueous solution (containing 0.1%TFA)), with resulting residue purifying.With part merging of suitable level, neutralized with saturated sodium bicarbonate aqueous solution, then, concentrate in a vacuum, to remove methyl alcohol.(3 * 10mL) extract this mixture with chloroform.Respectively water and salt solution clean the organic layer that merges once, and it through anhydrous magnesium sulfate drying, and is concentrated in a vacuum, can produce to be solid title compound (22mg, 19%).MS(ESI ⁺)m/z?376.2(M+H) ⁺。

B) 4-(6-(2-dimethylamino) oxyethyl group)-5-methylpyrrole [2,1-f] [1,2,4] triazine-4-base oxygen base also)-the 3-fluoroaniline

According to the similar mode of preparation of the compd B of embodiment 28, (4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole is [2,1-f] [1 also with 2-, 2,4] triazine-6-base oxygen base)-and N, N-dimethyl amine (22mg, 0.06mmol) be converted into title compound (20mg, 100%).Resulting yellow glass shape thing need not to be further purified, and promptly can be used for next procedure.MS(ESI ⁺)m/z?346.3(M+H) ⁺。

C) 1-(4-(6-(2-(dimethylamino) oxyethyl group)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, the hydrogen chlorate

According to the similar mode of preparation of the Compound C of embodiment 32, with 4-(6-(2-dimethylamino) oxyethyl group)-5-methylpyrrole [2,1-f] [1 also, 2,4] triazine-4-base oxygen base)-(20mg 0.06mmol) is converted into title compound (6.5mg, 19%) to the 3-fluoroaniline. ¹H NMR (CD ₃OD) δ 10.79 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.40-7.21 (m, 5H), 7.10-6.97 (m, 3H), 4.43-4.39 (m, 2H), 3.71 (s, 2H), 3.68-3.62 (m, 2H), 3.03 (s, 6H), 2.48 (s, 3H); HRMS (ESI), theoretical value: 525.2062 (M+H) ⁺, measured value: 525.2079 (M+H) ⁺

Embodiment 34

N ¹-(4-(6-(2-dimethylamino) oxyethyl group)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malonamide, the hydrogen chlorate

According to the similar mode of the preparation of embodiment 29, still, with PyBroP (52mg, 0.11mmol) replacement O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate, (6-(2-(dimethylamino) oxyethyl group)-5-methylpyrrole is [2,1-f] [1,2 also and with 4-, 4] triazine-4-base oxygen base)-3-fluoroaniline (35mg, 0.10mmol, the compd B of embodiment 33) and be converted into title compound (4.2mg, 8%).(1mL 1mmol) handles, and carries out lyophilize again, and the result produces the title compound (1.7mg, 38%) that is faint yellow solid with 1N hydrochloric acid earlier. ¹H NMR (CD ₃OD) δ 7.83 (s, 1H), 7.77 (s, 1H), 7.62-7.58 (m, 2H), 7.40-7.27 (m, 5H), 7.09-7.04 (m, 2H), 4.43-4.41 (m, 2H), 3.70-3.54 (m, 4H), 3.04 (s, 6H), 2.50 (s, 3H); HRMS (ESI), theoretical value: 525.2062 (M+H) ⁺, measured value: 525.2059 (M+H) ⁺

Embodiment 35

N ¹-(4-(6-(3-dimethylamino) propoxy-)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malonamide, the hydrogen chlorate

According to the similar mode of the preparation of embodiment 34, with 4-(6-(3-dimethylamino) propoxy-)-5-methylpyrrole [2,1-f] [1 also, 2,4] triazine-4-base oxygen base)-3-fluoroaniline (54mg, 0.15mmol, the compd B of embodiment 32) is converted into title compound (13mg, 15%). ¹HNMR (CD ₃OD) δ 7.83-7.75 (m, 2H), 7.67 (s, 1H), 7.63-7.57 (m, 2H), 7.39-7.27 (m, 2H), 7.09-7.02 (m, 2H), 4.18-4.13 (m, 2H), 3.58 (s, 2H), 3.42-3.36 (m, 2H), 2.96 (s, 6H), 2.48-2.42 (m, 4H), 2.32-2.25 (m, 2H); HRMS (ESI), theoretical value: 537.2062 (M-H) ^-, measured value: 537.2073 (M-H) ^-

Embodiment 36

N ¹-(3-fluoro-4-(5-methyl-6-(2-morpholino oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, the hydrogen chlorate

A) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole [2,1-f] [1,2,4] triazine-6-alcohol also

At room temperature, with 1N sodium hydroxide (12mL, 12mmol) dropwise be added into 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-base pivalate (2.40g, 6.19mmol, the compd E of embodiment 1) is in 20mL THF and 30mL alcoholic acid mixture in the formed solution.With the solution stirring of gained 45 minutes, at this moment, HPLC analyzed and shows that reaction is complete.Therefore, should reaction with the 1N HCl cancellation of 13mL.After decompression is removed organic solvent down, filtration method is separated out and utilized to the product precipitation, collected.Resulting product is also [2,1-f] [1,2,4] triazine-6-alcohol (1.65g, 88%) of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole.MS(ESI ⁺)m/z305.1(M+H) ⁺。

B) 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-morpholino oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine

With DIAD (72mg, 0.36mmol) be added into 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-alcohol (55mg, 0.18mmol), 2-morpholino ethanol (47mg, 0.36mmol) and the PPh3 (3.0mmol/g that combines with polymkeric substance, 167mg is 0.50mmol) in the formed solution at room temperature of the THF of 1mL.This mixture was stirred 1 hour, and at this moment, HPLC analyzes and shows that most raw material disappears all.Pass through Celite ^The filtering polymkeric substance concentrates and utilizes preparation HPLC to carry out purifying filtrate, obtains title compound (50mg, 67%).MS(ESI ⁺)m/z418.2(M+H) ⁺。

C) 3-fluoro-4-(5-methyl-6-(2-morpholino oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline

With ammonium chloride (70mg, 1.3mmol) and zinc powder (85mg, 1.3mmol) be added into 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-morpholino oxyethyl group) pyrrolo-[2,1-f] [1,2,4] (54mg is 0.13mmol) in 0.8mL THF and 1.2mL methanol mixture in the formed solution for triazine.At room temperature, this suspension was stirred 2 hours.HPLC analyzes and the LC-MS analysis shows that all reaction is complete, therefore, and with the solid filtering.After filtrate is concentrated, residue is dissolved in the methylene dichloride that contains 10% methyl alcohol.Then, once more this solution is filtered, incorporate in the vacuum, filtrate is concentrated, obtain title compound (50mg, 92%).MS(ESI ⁺)m/z?388.4(M+H) ⁺。

D) N ¹-(3-fluoro-4-(5-methyl-6-(2-morpholino oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, the hydrogen chlorate

At room temperature, with DIEA (0.04mL) and PyBrOP (32mg, 0.06mmol) be added into 3-fluoro-4-(5-methyl-6-(2-morpholino oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline (16mg, 0.041mmol), 3-(4-fluorophenyl amino)-3-ketopropionic acid (12mg, 0.06mmol, the compd A of embodiment 25) and in 1mL THF in the formed solution.This reactant is stirred a whole weekend, and LC-MS analyzes and shows product formation, but also is left to have some raw materials.Directly this solution is prepared the HPLC purifying, the HPLC level part that will contain desired product is by Water Oasis ^MCX 20cc 500mg LP extracts filter cylinder, and uses washed with methanol, to remove TFA.Then, use 7N NH ₃This filter cylinder of (in methyl alcohol) wash-out, and in decompression down, be concentrated into this ammonia solution dried.Then, resulting residue is suspended in the mixture of methyl alcohol and water and adds several 1N HCl.This suspension can become settled solution, and utilizes dry ice-propanone to bathe, and gives freezing.Then, with this refrigerated solution lyophilize, and obtain title compound (20mg, 80%). ¹H?NMR(CD ₃OD)δ7.71(m，2H)，7.60(s，1H)，7.53(m，2H)，7.28(m，2H)，7.00(m，2H)，4.13(s，2H)，3.67(s，4H)，2.80(s，2H)，2.58(s，4H)，2.37(s，3H)；MS(ESI ⁺)m/z?567.2(M+H) ⁺。

Embodiment 37

1-(3-fluoro-4-(5-methyl-6-(2-morpholino oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide, the hydrogen chlorate

With 2-(4-fluorophenyl) ethanoyl lsothiocyanates (19mg; 0.1mmol; the compd A of embodiment 2) is added into 3-fluoro-4-(5-methyl-6-(2-morpholino oxyethyl group) pyrrolo-[2; 1-f] [1; 2; 4] triazine-4-base oxygen base) aniline (30mg, 0.072mmol, the Compound C of embodiment 36) is in 1mL THF in the formed solution.At room temperature, with this solution stirring 2 hours, at this moment, HPLC analyzed and shows that reaction is complete.Then, use NH ₃(in propyl alcohol) should react cancellation, and resulting solution is filled in preparation HPLC to carry out purifying.According to the similar handling procedure that carries out with the Compound D of embodiment 36, obtain being hydrogen chlorate's title compound (13mg, 30%). ¹HNMR(DMSO-d ₆)δ12.45(s，1H)，11.85(s，1H)，11.50(br?s，1H)，8.15(s，1H)，8.10(s，1H)，7.90(d，1H)，7.50(m，2H)，7.40(m，2H)，7.20(m，2H)，4.50(br?s，2H)，4.00(m，2H)，3.85(s，2H)，3.25-3.70(m，8H)，2.40(s，3H)；MS(ESI ⁺)m/z?583.2(M+H) ⁺。

Embodiment 38

2-fluoro-N-(3-fluoro-4-(5-methyl-6-(2-morpholino oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-5-methyl benzamide, the hydrogen chlorate

According to the synthetic similar program of the Compound D of embodiment 36, with 3-fluoro-4-(5-methyl-6-(2-morpholino oxyethyl group) pyrrolo-[2,1-f] [1,2,4] aniline (16mg triazine-4-base oxygen base), 0.042mmol, the Compound C of embodiment 36) and be converted into the title compound (5.6mg, 23%) that is hydrogen chlorate's form. ¹H?NMR(CD ₃OD)δ7.85(d，1H)，7.80(s，1H)，7.69(s，1H)，7.55(m，1H)，7.50(m，1H)，7.35(m，2H)，7.13(m，1H)，4.22(m，2H)，3.73(m，4H)，2.88(m，2H)，2.66(m，4H)，2.44(s，3H)，2.38(s，3H)；MS(ESI ⁺)m/z?262.3(M+H) ⁺。

Embodiment 39

1-(3-fluoro-4-(5-methyl-6-(3-morpholino propoxy-) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide, the hydrogen chlorate

A) 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(3-morpholino propoxy-) pyrrolo-[2,1-f] [1,2,4] triazine

According to the synthetic similar program of the compd B of embodiment 36, with 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole [2,1-f] [1 also, 2,4] triazine-6-alcohol (50mg, 0.16mmol, the compd A of embodiment 36) is converted into title compound (32mg, 46%).MS(ESI ⁺)m/z?432.2(M+H) ⁺。

B) 3-fluoro-4-(5-methyl-6-(3-morpholino propoxy-) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline

According to the synthetic similar program of the Compound C of embodiment 36, with 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(3-morpholino propoxy-) pyrrolo-[2,1-f] [1,2,4] (31mg 0.072mmol) is converted into title compound (28mg, 95%) to triazine.MS(ESI ⁺)m/z?402.3(M+H) ⁺。

C) 1-(3-fluoro-4-(5-methyl-6-(3-morpholino propoxy-) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide, the hydrogen chlorate

According to the synthetic similar program of the Compound D of embodiment 36, with 3-fluoro-4-(5-methyl-6-(3-morpholino propoxy-) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) (28mg 0.07mmol) is converted into the title compound (30mg, 68%) that is hydrogen chlorate's form to aniline. ¹HNMR(DMSO-d ₆)δ12.45(s，1H)，11.80(s，1H)，11.65(br?s，1H)，8.00(s，2H)，7.90(d，1H)，7.50(m，2H)，7.40(m，2H)，7.25(m，2H)，3.10-4.10(m，16H)，2.40(s，3H)；MS(ESI ⁺)m/z?597.2(M+H) ⁺。

Embodiment 40

4-(2-fluoro-4-(3-(4-fluorophenyl amino)-3-ketone group propionamido-) phenoxy group)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester also

According to the synthetic similar program of the Compound D of embodiment 36, with 4-(4-amino-2-fluorophenoxy)-5-methylpyrrole [2,1-f] [1 also, 2,4] triazine-6-carboxylic acid, ethyl ester (70mg, 0.21mmol, the compd B of embodiment 6) is converted into title compound (50mg, 47%). ¹H?NMR(DMSO-d ₆)δ10.50(s，1H)，10.30(s，1H)，8.45(s，1H)，8.16(s，1H)，7.90(d，1H)，7.67(m，2H)，7.51(t，1H)，7.40(t，1H)，7.20(m，2H)，4.33(q，2H)，3.52(s，2H)，2.77(s，3H)，1.35(t，3H)；MS(ESI ⁺)m/z?510.1(M+H) ⁺。

Embodiment 41

N ¹-(3-fluoro-4-(6-(methylol)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-N ³-(4-fluorophenyl) Malonamide

With DIBAL-H (1M, 1.65mL) be added into 4-(2-fluoro-4-(3-(4-fluorophenyl amino)-3-ketone group propionamido-) phenoxy group)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester (66mg, 0.13mmol embodiment 40) in the formed solution under-78 ℃ of 20mL THF.Under-78 ℃, this reaction mixture was stirred 1 hour, then, at room temperature, stirred 2 hours.At this moment, HPLC analyzes and shows that reaction is complete.Should react with the cancellation of 4mL methyl alcohol, then add 4mL water.This mixture was stirred 0.5 hour, then, add sodium sulfate (Na ₂SO ₄).Continue to stir 1 hour.Filter and concentrate, obtain title compound (50mg, 82%). ¹H?NMR(CD ₃OD)δ7.70(m，3H)，7.50(m，2H)，7.25(m，2H)，7.00(m，2H)，4.60(s，2H)，3.45(s，2H)，2.50(s，3H)；MS(ESI ⁺)m/z?468.2(M+H) ⁺。

Embodiment 42

N ¹-(3-fluoro-4-(6-formyl radical-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-N ³-(4-fluorophenyl) Malonamide

At room temperature, (48mg, 0.11mmol Aldrich) are added into N Dai Si-Martin to be crossed iodine alkanoic acid (Dess-Martin peirodinane) ¹-(3-fluoro-4-(6-(methylol)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-N ³-(4-fluorophenyl) Malonamide (embodiment 41 for 12mg, 0.026mmol) is in the formed solution of 1mL THF.This mixture was stirred 2 hours, and HPLC analyzes and shows that raw material all consumes.This mixture is passed through SiO ₂Charges filter, and are cleaned with ethyl acetate.Then, under reduced pressure, remove organic solvent, and utilize preparation HPLC, and obtain title compound (10mg, 83%) resulting residue purifying.MS(ESI ⁺)m/z?466.2(M+H) ⁺。

Embodiment 43

N ¹-(3-fluoro-4-(5-methyl-6-((2-morpholino ethylamino) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, two-trifluoroacetate

With 2-morpholino ethamine (21mg, 0.16mmol), DIEA (0.04mL) and NaBH (OAc) ₃(52mg 0.2mmol) is added into N ¹-(3-fluoro-4-(6-formyl radical-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-N ³-(4-fluorophenyl) Malonamide (embodiment 42 for 15mg, 0.032mmol) is in the formed solution of 1mLDMF.At room temperature, this mixture was stirred 4 days.At this moment, HPLC analysis and LC-MS analyze and show that product forms.Then, this solution is dissolved in the methyl alcohol, and utilizes preparation HPLC, carry out purifying, obtain being the title compound (4mg, 21%) of 2TFA salt form.

¹H?NMR(CD ₃OD)δ7.92(s，1H)，7.82(s，1H)，7.70(d，1H)，7.50(m，2H)，7.28(m，2H)，6.98(m，2H)，4.31(s，2H)，3.68(s，4H)，3.20(m，4H)，2.82(m，2H)，2.65(s，4H)，2.56(s，3H)；MS(ESI ⁺)m/z?580.2(M+H) ⁺。

Embodiment 44

N ¹-(3-fluoro-4-(5-methyl-6-((4-methylpiperazine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, two-trifluoroacetate

According to the synthetic similar program of embodiment 43, with N ¹-(3-fluoro-4-(6-formyl radical-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-N ³-(4-fluorophenyl) Malonamide (embodiment 42 for 15mg, 0.032mmol) is converted into the title compound (4mg, 23%) that is the 2TFA salt form.MS(ESI ⁺)m/z?550.2(M+H) ⁺。

Embodiment 45

N ¹-(3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, two hydrogen chlorates

A) 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine

According to the synthetic similar program of the compd B of embodiment 36, with 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-6-alcohol (55mg, 0.18mmol, the compd A of embodiment 36), 2-morpholino ethanol (304mg, 1.0mmol) be converted into title compound (352mg, 82%).MS(ESI ⁺)m/z?431.2(M+H) ⁺。

B) 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline

According to the synthetic similar program of the Compound C of embodiment 36, with 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] (2.90g 6.74mmol) is converted into title compound (1.38g, 51%) to triazine.MS(ESI ⁺)m/z?401.3(M+H) ⁺。

C) N ¹-(3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, two-hydrogen chlorate

According to the synthetic similar step of the Compound D of embodiment 36, with 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] aniline (60mg triazine-4-base oxygen base), 0.15mmol) be converted into the title compound (30mg, 46%) that is the 2HCl salt form. ¹HNMR(DMSO-d ₆)δ10.63(s，1H)，10.37(s，1H)，8.04(s，1H)，7.99(s，1H)，7.80(d，1H)，7.61(m，2H)，7.40(m，2H)，7.16(m，2H)，4.42(br?s，2H)，3.38-3.60(m，10H)，2.81(s，3H)，2.40(s，3H)；MS(ESI ⁺)m/z?580.3(M+H) ⁺。

Embodiment 46

1-(3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, two-hydrogen chlorate

Toluene solution (0.36M with 2-(4-fluorophenyl) ethanoyl isocyanic ester; 0.18mL; the Compound C of embodiment 4) is added into 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2; 1-f] [1; 2,4] triazine-4-base oxygen base) aniline (20mg, 0.05mmol; the compd B of embodiment 45) in the formed solution of 1mL THF, and with this solution stirring a whole night.HPLC analyzes and the LC-MS analysis shows that reaction is complete, therefore, in decompression down, organic solvent is removed.On preparation HPLC, resulting residue is carried out purifying.After described similar program is handled according to the Compound D of embodiment 36, obtain being the title compound (15mg, 46%) of 2HCl salt form at last. ¹H?NMR(DMSO-d ₆)δ11.02(s，1H)，10.58(s，1H)，8.04(s，1H)，7.99(s，1H)，7.70(d，1H)，7.35(m，4H)，7.16(m，2H)，4.44(brs，2H)，3.40-3.70(m，12H)，2.81(s，3H)，2.39(s，3H)；MS(ESI ⁺)m/z?580.1(M+H) ⁺。

Embodiment 47

3-ethanoyl-N-(3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl) aniline, two-hydrogen chlorate

According to the synthetic similar program of the Compound D of embodiment 36, with 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] aniline (20mg triazine-4-base oxygen base), 0.05mmol, the compd B of embodiment 45) and be converted into the title compound (11mg, 35%) that is the 2HCl salt form. ¹H?NMR(CD ₃OD)δ8.20(m，1H)，7.90(m，2H)，7.84(s，1H)，7.80(s，1H)，7.70(m，1H)，7.50(m，2H)，7.32(m，1H)，4.54(m，2H)，3.60-4.10(m，10H)，3.08(s，3H)，2.50(s，3H)；MS(ESI ⁺)m/z?547.2(M+H) ⁺。

Embodiment 48

N-(3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl) niacinamide, three-hydrogen chlorate

According to the synthetic similar program of the Compound D of embodiment 36, with 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] aniline (20mg triazine-4-base oxygen base), 0.05mmol, the compd B of embodiment 45) and be converted into the title compound (10mg, 32%) that is the 3HCl salt form. ¹H?NMR(CD ₃OD)δ9.46(s，1H)，9.20(d，1H)，9.08(d，1H)，8.29(m，1H)，7.92(d，1H)，7.81(s，1H)，7.82(s，1H)，7.61(m，1H)，7.42(m，1H)，4.54(m，2H)，3.82-4.05(m，10H)，3.05(s，3H)，2.51(s，3H)；MS(ESI ⁺)m/z506.2(M+H) ⁺。

Embodiment 49

2-fluoro-N-(3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-5-methyl benzamide, two-hydrogen chlorate

According to the synthetic similar mode of the Compound D of embodiment 36, with 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] aniline (20mg triazine-4-base oxygen base), 0.05mmol, the compd B of embodiment 45) and be converted into the title compound (8mg, productive rate 26%) that is the 2HCl salt form. ¹H?NMR(CD ₃OD)δ7.85(d，1H)，7.85(s，1H)，7.80(s，1H)，7.55(m，1H)，7.50(m，1H)，7.33(m，2H)，7.13(t，1H)，4.54(m，2H)，3.70-4.10(m，10H)，3.04(s，3H)，2.50(s，3H)，2.37(s，3H)；MS(ESI ⁺)m/z?537.2(M+H) ⁺。

Embodiment 50

4-(2-fluoro-4-(2-fluoro-5-toluyl amino) phenoxy group)-5-methyl-N-(2-morpholino ethyl) pyrrolo-[2,1-f] [1,2,4] triazine-6-methane amide, the hydrogen chlorate

A) 4-hydroxy-5-methyl base pyrrolo-[2,1-f] [1,2,4] triazine-6-formic acid

Solution (1N with sodium hydroxide, 6.0mL) be added into 4-hydroxy-5-methyl base pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester (442mg, 2.0mmol) (referring to the embodiment 6 of U.S. Patent application 2003/0186982, its disclosure is incorporated this paper into as a reference) in the formed solution of 10mL THF.Under 60 ℃, with this mixture heating up a whole night, HPLC analyzes and shows that reaction finishes.After this solution cooling, neutralized with 6.0mL 1N HCl.Then, remove organic solvent, and after filtration, collect solid, and obtain title compound (350mg, 91%).MS(ESI ⁺)m/z194.2(M+H) ⁺。

B) 4-(2-fluoro-4-nitrophenoxy)-5-methyl-N-(2-morpholino ethyl) pyrrolo-[2,1-f] [1,2,4] triazine-6-methane amide

Under 110 ℃, (100mg is 0.52mmol) in 2mL POCl with 4-hydroxy-5-methyl base pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid ₃Formed suspension heating 4 hours.This suspension becomes settled solution, and removes excessive POCl with toluene ₃Then, resulting residue is dissolved in 0 ℃ the acetonitrile.With triethylamine (0.72mL, 5.2mmol) and 2-morpholino ethamine (0.13mL 1.04mmol) is added in this solution.Mixture was stirred 0.5 hour, and HPLC analyzes and shows that product forms.Then, dilute this solution, and water and salt solution are cleaned with ethyl acetate.With organic layer through dried over mgso.After filtering and concentrating, resulting crude material is used for next reaction.

This crude material is dissolved in the 2mL acetonitrile, and add 2-fluoro-4-nitrophenols (94mg, 0.60mmol) and DABCO (78mg, 0.70mmol).Should react and stir 1 hour, HPLC analyzes the demonstration reaction and finishes.After concentrating, on preparation HPLC,, obtain title compound (75mg, 33%) with resulting residue purifying.MS(ESI ⁺)m/z445.2(M+H) ⁺。

C) 4-(4-amino-2-fluorophenoxy)-5-methyl-N-(2-morpholino ethyl) pyrrolo-[2,1-f] [1,2,4] triazine-6-methane amide

According to the synthetic similar program of the Compound C of embodiment 36, with 4-(2-fluoro-4-nitrophenoxy)-5-methyl-N-(2-morpholino ethyl) pyrrolo-[2,1-f] [1,2,4] (75mg 0.17mmol) is converted into title compound (65mg, 92%) to triazine-6-methane amide.LCMS(ESI ⁺)m/z?415.3(M+H) ⁺。

D) 4-(2-fluoro-4-(2-fluoro-5-toluyl amino) phenoxy group)-5-methyl-N-(2-morpholino ethyl) pyrrolo-[2,1-f] [1,2,4] triazine-6-methane amide, the hydrogen chlorate

At room temperature, with triethylamine (0.2mL) and 2-fluoro-5-methyl benzoyl chloride (20mg, 0.11mmol) in the formed solution of 1mL THF, be added into 4-(4-amino-2-fluorophenoxy)-5-methyl-N-(2-morpholino ethyl) pyrrolo-[2,1-f] [1,2,4] (25mg is 0.06mmol) in the formed solution of 1mL THF for triazine-6-methane amide.This mixture was stirred 1 hour, and HPLC analyzes and shows that raw material consumes.Should reaction with the methyl alcohol cancellation.Then, in a vacuum,, and utilize preparation HPLC,, obtain being the title compound (8.0mg, 23%) of hydrogen chlorate's form resulting residue purifying with this solution concentration.

¹H?NMR(CD ₃OD)δ8.48(d，1H)，7.83(m，3H)，7.28(m，3H)，7.00(m，1H)，2.90-4.00(m，12H)，2.76(s，3H)，2.33(s，3H)；MS(ESI ⁺)m/z551.2(M+H) ⁺。

Embodiment 51

4-(2-fluoro-4-(nicotinoyl amino) phenoxy group)-5-methyl-N-(2-morpholino ethyl) pyrrolo-[2,1-f] [1,2,4] triazine-6-methane amide, two-hydrogen chlorate

According to the synthetic similar program of the Compound D of embodiment 50, with 4-(4-amino-2-fluorophenoxy)-5-methyl-N-(2-morpholino ethyl) pyrrolo-[2,1-f] [1,2,4] triazine-6-methane amide (30mg, 0.07mmol, the Compound C of embodiment 50) and be converted into the title compound (16mg, 39%) that is the 2HCl salt form. ¹H?NMR(CD ₃OD)δ9.08(s，1H)，8.70(s，1H)，8.44(s，1H)，8.17(s，1H)，7.87(m，2H)，7.38(m，2H)，7.22(m，2H)，3.82(s，4H)，3.61(m，2H)，2.75(m，9H)；MS(ESI ⁺)m/z520.2(M+H) ⁺。

Embodiment 52

N-(4-(6-(3-dimethylamino) propoxy-)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also)-3-fluorophenyl) niacinamide, nicotinium dihydrochloride

According to the similar mode of preparation of the Compound D of embodiment 36, with 4-(6-(3-(dimethylamino) propoxy-)-5-methylpyrrole also [2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluoroaniline (54mg, 0.15mmol, the compd B of embodiment 32) and be converted into title compound (8.7mg, 11%). ¹HNMR (CD ₃OD) δ 9.47 (s, 1H), 9.20-9.19 (m, 1H), 9.08-9.07 (m, 1H), and 8.30-8.27 (m, 1H), 7.97-7.93 (m, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.64-7.61 (m, 1H), and 7.43-7.39 (m, 1H), 4.26-4.11 (m, 2H), 3.43-3.39 (m, 2H), 2.98 (s, 6H), 2.46 (s, 3H), 2.34-2.30 (m, 2H); HRMS (ESI), theoretical value: 463.1894 (M-H) ^-, measured value: 463.1905 (M-H) ^-

Embodiment 53

1-(3-fluoro-4-(5-sec.-propyl-3,4-pyrrolin be [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

A) 5-sec.-propyl pyrrolo-[2,1-f] [1,2,4] triazines-4 (3H)-ketone

With 5-sec.-propyl-4-ketone group-3,4-pyrrolin also [2,1-f] [1,2,4] triazine-6-formic acid (0.025g, 1.13mmol, 1.0 equivalent makes according to patent application US 2004/063708 described similar fashion, the full content of this application case is incorporated this paper into as a reference) be added into polyphosphoric acid (5.0g), and this reaction mixture is heated to 160 ℃, lasts 1 hour.This reactant is cooled to room temperature, and water (50mL) cancellation reaction.(3 * 50mL) extract this solution, and (1 * 100mL) cleans the organic part that merges, dry (Na with saturated sodium bicarbonate with ethyl acetate ₂SO ₄), filtered and in a vacuum, concentrated.Utilize silica gel (Merck KGaA, 230-400 order granularity) flash chromatography method (with 3/1 ethyl acetate/hexane wash-out) to carry out purifying, obtain title compound (0.060g, 30%).MS (ESI ^-) m/z176 (M-H) ^-HRMS (ESI), theoretical value: 176.0824 (M-H) ^-, measured value: 176.0818 (M-H) ^-

B) 4-chloro-5-sec.-propyl pyrrolo-[2,1-f] [1,2,4] triazine

In nitrogen atmosphere, 5-sec.-propyl pyrrolo-[2,1-f] [1,2,4] triazines-4 (3H)-ketone (0.035g, 0.198mmol, 1.0 equivalents) is added in the phosphoryl chloride (2.0mL, 21.5mmol, 109 equivalents).This reaction mixture is heated to backflow 1.5 hours.This mixture is cooled to room temperature, then, concentrates in a vacuum.Resulting residue is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.With ethyl acetate extraction water layer secondary.Organic washing lotion of merging through anhydrous magnesium sulfate drying, and is concentrated in a vacuum, obtain the tawny solid, it need not to be further purified, and promptly can be used for next procedure.MS(ESI ⁺)m/z?196(M+H) ⁺。

C) 4-(2-fluoro-4-nitrophenoxy)-5-sec.-propyl-3, the 4-pyrrolin is [2,1-f] [1,2,4] triazine also

Under nitrogen atmosphere, with 4-chloro-5-sec.-propyl pyrrolo-[2,1-f] [1,2,4] triazine (0.038g, 0.194mmol, 1.0 equivalents) and 2-fluoro-4-nitrophenols (0.062g, 0.388mmol, 2.0 equivalents) in anhydrous CH ₃The mixture of CN (2mL) stirred 5 minutes, then, added DABCO (0.044g, 0.388mmol, 2.0 equivalents), and under 50 ℃, with this reaction mixture heating 2 hours.This mixture is cooled to room temperature, and reacts with 1N HCl cancellation.With methylene dichloride (3 * 30mL) extract this solution, and with the organic extract liquid that merges through anhydrous magnesium sulfate drying, filtered and carried out drying in a vacuum.Utilize silica gel (Merck KGaA, 230-400 order granularity) flash chromatography method (with 2/1 hexane/ethyl acetate wash-out) with resulting residue purifying, obtain title compound (0.048g, 79%). ¹HNMR (CDCl ₃) δ 8.07-8.13 (m, 2H), 7.77 (s, 1H), 7.68-7.69 (m, 1H), 7.46-7.50 (m, 1H), 6.71-6.72 (m, 1H), 3.53-3.56 (m, 1H), 1.29-1.31 (m, 6H); HRMS (ESI), theoretical value: 317.1050 (M+H) ⁺, measured value: 317.1039.

D) 3-fluoro-4-(5-sec.-propyl-3,4-pyrrolin be [2,1-f] [1,2,4] triazine-4-base oxygen base also) aniline

In envrionment temperature, nitrogen atmosphere, with zinc powder (0.090g, 0.139mmol, 1.0 equivalents) and ammonium chloride (0.075g, 1.39mmol, 1.0 equivalent) be added into 4-(2-fluoro-4-nitrophenoxy)-5-sec.-propyl-3, the 4-pyrrolin is [2,1-f] [1 also, 2,4] triazine (0.044g, 1.39mmol, 1.0 equivalents) is in the formed heterogeneous mixture of 1/1 anhydrous methanol/tetrahydrofuran (THF) (2mL).This mixture was stirred 4 hours, then, filtration catalizer and in a vacuum that filtrate is concentrated, and obtain being solid title compound (0.040g, 100%), it need not to be further purified, and can use.HRMS (ESI), theoretical value: 287.1308 (M+H) ⁺, measured value: 287.1300 (M+H) ⁺

E) 1-(3-fluoro-4-(5-sec.-propyl-3,4-pyrrolin be [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) thiocarbamide

Under room temperature, nitrogen atmosphere, 4-fluorophenyl Acetyl Chloride 98Min. (0.048mL, 0.35mmol, 2.5 equivalents) is added into Sodium Thiocyanate 99 (0.037g, 0.46mmol, 3.3 equivalents) in the formed homogeneous solution of ethyl acetate (1mL).This mixture was stirred 2 hours, then, under nitrogen atmosphere, it is added directly to 3-fluoro-4-, and (5-sec.-propyl-3,4-pyrrolin be [2,1-f] [1 also, 2,4] triazine-4-base oxygen base) aniline (0.040g, 0.139mmol, 1.0 equivalents) is in the formed homogeneous solution of anhydrous 1/1/THF/-methylene dichloride (3mL).At ambient temperature, this reaction mixture was stirred 16 hours, then, with 1N HCl cancellation reaction.(3 * 50mL) extract this solution, clean the organic moiety that merges with 1N sodium hydroxide (50mL), and it through dried over sodium sulfate, is filtered and concentrate in a vacuum with methylene dichloride.Utilize silica gel (Merck KGaA, 230-400 order granularity) flash chromatography method (with 4/1 hexane/ethyl acetate wash-out) to carry out purifying, obtain title compound (0.050g, 75%). ¹HNMR (CDCl ₃) δ 12.34 (s, 1H), 8.47 (m, 1H), 7.65-7.78 (m, 2H), 7.63-7.64 (m, 1H), and 7.19-7.32 (m, 4H), 7.03-7.08 (m, 2H), 6.66-6.67 (m, 1H), 3.65 (s, 2H), 3.40-3.50 (m, 1H), 1.28-1.30 (m, 6H); HRMS (ESI), theoretical value: 482.1462 (M+H) ⁺, measured value: 482.1461 (M+H) ⁺Ultimate analysis: C ₂₄H ₂₁N ₅O ₂SF ₂0.23H ₂O-theoretical value: C, 59.35; H, 4.45; N, 14.42; Measured value: C, 59.36; H, 4.44; N, 14.03.

Embodiment 54-85

Embodiment 54 to 85 shown in the table 1 is by adopting 1 normal corresponding carboxylic acid (1 equivalent), PyBrOP (1 equivalent), the DIEA (1 equivalent) in DMF, by 3-fluoro-4-(5-methylpyrrole also [2,1-f] [1,2,4] triazine-4-base oxygen base) aniline (compd B of embodiment 28) is synthetic.Reaction mixture is heated to 70 ℃, and uses preparation HPLC (H ₂O/ alcohol/0.1%TFA, 35-90% methyl alcohol gradient is lasted 10 minutes, 20 * 100mm, 5 μ m YMC ODS-A posts), and utilize the directed fractionating process (mass-directedfraction) of quality, with resulting crude product purifying.With purified sample at 1: 1/ methyl alcohol: reconstruct among the DEC (reconstitute), be transferred in 2.5mL taring (tared) the plastics microtubule, through centrifugal method of evaporation drying, weigh and utilize LCMS (H ₂O/ methyl alcohol/0.1%TFA), analyze.

Table 1

Embodiment 86 to 130

The embodiment 86 to 130 of table 2 example is made by 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline (compd B of embodiment 45).At 48-position (position) MiniBlock ^In each hole of XT reactor, add 375 μ L by chloride of acid in 1, the formed 0.2M solution of 2-ethylene dichloride (DCE) (0.075mmol, 2.5 equivalents); 50 μ L pyridines (0.62mmol, 20 equivalents); And the amine of 150 μ L is in the formed 0.2M solution of DCE (0.03mmol, 1 equivalent).By the rail mounted agitator, this reactor was stirred 14 hours.With methyl alcohol crude product (in DCE) is diluted to the volume of 1mL, then, by standard fabrication HPLC (H ₂O/ methyl alcohol/0.1%TFA, gradient: 35-90% methyl alcohol, last 10 minutes, 20 * 100mm, 5 μ m YMC ODS-A posts), and utilize the directed fractionating process of quality to carry out purifying.With purified sample at 1: 1/ methyl alcohol: reconstruct among the DEC, be transferred in 2.5mL taring (tared) the plastics microtubule, through centrifugal method of evaporation drying, weigh and utilize LCMS (H ₂O/ methyl alcohol/0.1%TFA), analyze.

Table 2

Embodiment 131

1-(3-fluoro-4-(6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, trifluoroacetate

A) 6-(pyridin-3-yl) pyrrolo-[2,1--f] [1,2,4] triazine-4-alcohol

With 6-bromine pyrrolo-[2,1-f] [1,2,4] triazine-4-alcohol (100mg, 0.47mmol, make by 4-bromo-1H-pyrroles-2-carboxylate methyl ester: referring to Kitamura, C.and Yamashita, Y.J.Chem.Soc.Perkin Trans.1,1997,1443, its disclosure is all incorporated this paper into as a reference, adopts the 00/71129 described similar program with PCT application WO) and pyridin-3-yl boric acid (172mg is 1.40mmol) in the 2mL DMF and the formed solution degassing of 2mL unsaturated carbonate aqueous solutions of potassium, then, add Pd (PPh ₃) ₄(57mg, 0.05mmol).Then, with this mixture heating up to 120 ℃, last 3 hours.LC-MS analyzes and shows that raw material has disappeared.With this mixture cooling, and filtering solution.Utilize preparation HPLC with the filtrate purifying, obtain being the title compound (100mg, 65%) of tfa salt form.MS(ESI ⁺)m/z?213.2(M+H) ⁺。

B) 4-chloro-6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine

With POCl ₃(0.18mL, 1.88mmol) and DIEA (0.09mL, (100mg is 0.30mmol) in the formed suspension of 10mL toluene 0.5mmol) to be added into 6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-alcohol.Under 100 ℃, with this suspension heating 7 hours.After cooling, in decompression down, remove excessive POCl ₃Resulting residue is suspended in the ethyl acetate, then, with saturated NaHCO ₃Neutralized.Then, clean organic layer with salt solution and with it through dried over mgso.After filtering and concentrating, utilize the rapid column chromatography method, with resulting residue purifying, obtain title compound (23mg, 33%).MS(ESI ⁺)m/z?231.2/233.2(M+H) ⁺。

C) 4-(2-fluoro-4-nitrophenoxy)-6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine

According to the synthetic similar program of the compd B of embodiment 2, (23mg 0.1mmol) is converted into title compound (35mg, 95%) with 4-chloro-6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine.MS(ESI ⁺)m/z?352.3(M+H) ⁺。

D) 3-fluoro-4-(6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline

According to the synthetic similar program of the Compound C of embodiment 36, (35mg 0.10mmol) is converted into title compound (15mg, 46%) with 4-(2-fluoro-4-nitrophenoxy)-6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine.MS(ESI ⁺)m/z?322.3(M+H) ⁺。

E) 1-(3-fluoro-4-(6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, trifluoroacetate

According to the synthetic similar program of embodiment 46, with 3-fluoro-4-(6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) (15mg 0.046mmol) is converted into title compound to aniline, can make the title compound (5.0mg, 18%) that is the tfa salt form. ¹H?NMR(DMSO-d ₆)δ10.99(s，1H)，10.53(s，1H)，9.12(s，1H)，8.75(s，1H)，8.50(m，1H)，8.30(m，1H)，8.12(s，1H)，7.67(m，2H)，7.30-7.50(m，5H)，7.12(m，2H)，3.69(s，2H)；MS(ESI ⁺)m/z501.2(M+H) ⁺。

Embodiment 132

1-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, the hydrogen chlorate

A) 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridine

Under microwave irradiation, 200 ℃, with 4-chloro-1H-pyrrolo-[2,3-b] and pyridine (457mg, 3.0mmol is according to Thibault, C.et al.Org.Lett.2003,5,5023 make) and 2-fluoro-4-nitrophenols (706mg, 4.5mmol), N, (580mg is 4.5mmol) in (3mL) formed mixture heating up 1.0 hours of 1-Methyl-2-Pyrrolidone (NMP) for the N-diisopropylethylamine.(150mL) dilutes this mixture with ethyl acetate, with saturated KH ₂PO ₄The aqueous solution and Na ₂CO ₃(aqueous solution 1M) is cleaned, and with it through dried over sodium sulfate.Utilize rapid column chromatography method (silica gel is with methylene dichloride to 30% ethyl acetate/dichloromethane wash-out),, obtain brown solid (350mg, 43%) resulting product purification.MS(ESI ⁺)m/z274(M+H) ⁺。

B) 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline

With zinc powder (350mg, 5.5mmol) and ammonium chloride (294mg, (300mg is 1.1mmol) in tetrahydrofuran (THF) (5mL) and the formed suspension of methyl alcohol (10mL) 5.5mmol) to be added into 4-(2-fluorine 4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridine.At room temperature, this mixture is stirred a whole night.This mixture is passed through Celite ^Pad filters, and is cleaned with methyl alcohol.Resulting filtrate is concentrated.Utilize rapid column chromatography method (silica gel, 1-5% methyl alcohol (in methylene dichloride)),, obtain being the desired product (205mg, 77%) of pale solid product purification.MS(ESI ⁺)m/z?244(M+H) ⁺。

C) 1-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, the hydrogen chlorate

At room temperature; with 4-(1H-pyrrolo-[2; 3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (30mg; 0.12mmol) and 2-(4-fluorophenyl) ethanoyl isocyanic ester (Compound C of embodiment 4; 0.25M; in toluene, 0.18mmol) stirred 1 hour in the formed mixture of THF (0.5mL).In a vacuum this mixture is concentrated, utilize preparation HPLC to carry out purifying.With desired level part lyophilize, obtain the tfa salt of white, it is dissolved in the methanol (0.2mL) of a spot of 1N of containing HCl.Then, with this solution lyophilize, the solid title compound that obtains being white in color (15mg, 27%). ¹HNMR(CDCl ₃)δ11.74(s，1H)，8.12(d，1H，J＝6.4Hz)，7.73(dd，1H，J＝2.4，13.0Hz)，7.39(d，1H，J＝3.6Hz)，6.90-7.3(m，6H)，6.65(d，1H，J＝6.4Hz)，6.50(d，1H，J＝3.2Hz)，3.68(s，2H)；MS(ESI ⁺)m/z?423(M+H) ⁺。

Embodiment 133

N ¹-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malonamide, trifluoroacetate

Successively with TBTU (48mg, 0.15mmol) and DIPEA (0.1mL) be added into 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-the 3-fluoroaniline (compd B of embodiment 132,25mg, 0.10mmol) and 3-(4-fluorophenyl amino)-3-ketopropionic acid (compd A of embodiment 25,25mg is 1.27mmol) in the formed solution of DMF (0.5mL).At room temperature, the mixture with gained stirred 2 hours.Utilize preparation HPLC with product purification, the solid title compound that obtains being white in color (tfa salt, 26mg, 62%). ¹H?NMR(CDCl ₃)δ7.94(d，1H，J＝6.4Hz)，7.66(dd，1H，J＝2.4，13.0Hz)，7.54(m，2H)，6.90-7.25(m，5H)，6.31(d，2H，J＝2.8Hz)，3.37(s，2H)；MS(ESI ⁺)m/z?423(M+H) ⁺。

Embodiment 134

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2, the 6-difluorobenzamide

Successively with 2, the 6-difluoro benzoyl chloride (20mg, 0.11mmol) and DIPEA (0.1mL) be added into 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (compd B of embodiment 132,20mg is 0.08mmol) in the formed solution of DMF (0.5mL).At room temperature, this mixture was stirred 2 hours, and utilize preparation HPLC, with product purification.With desired level part lyophilize, and obtain white tfa salt,, neutralized with saturated sodium bicarbonate aqueous solution.(3 * 5mL) extract this mixture with ethyl acetate., and concentrated the solid title compound that obtains being white in color (14mg, 37%) in a vacuum with the organic layer drying. ¹H?NMR(CD ₃OD)δ8.15(d，1H，J＝6.4Hz)，7.87(d，1H，J＝2.4，12.8Hz)，7.40(m，4H)，7.04(m，2H)，6.69(d，2H，J＝7.6Hz)，6.52(m，1H)；MS(ESI ⁺)m/z?384(M+H) ⁺。

Embodiment 135

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl) niacinamide

According to the similar mode described in the preparation of embodiment 134, use commercially available nicotine acyl chlorides and 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (compd B of embodiment 132), prepare title compound, the separable title compound that goes out to be the tfa salt form.Productive rate: 55%. ¹HNMR(CD ₃OD)δ9.09(s，1H)，8.73(d，1H，J＝4.4Hz)，8.44(d，1H，J＝8.0Hz)，8.22(d，1H，J＝6.8Hz)，8.22(dd，1H，J＝2.4，12.4Hz)，7.40-7.80(m，4H)，6.79(d，1H，J＝6.8Hz)，6.59(d，1H，J＝3.6Hz)；MS(ESI ⁺)m/z349(M+H) ⁺。

Embodiment 136

N ¹-(3-fluoro-4-(6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, trifluoroacetate

In room temperature, nitrogen atmosphere, with diisopropylethylamine (26 μ L, 0.15mmol) be added into 3-fluoro-4-(6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline (32mg, 0.10mmol, the Compound D of embodiment 131) with 3-(4-fluorophenyl amino)-3-ketopropionic acid (20mg, 0.10mmol, the compd A of embodiment 25) in the formed homogeneous solution of dry DMF (3mL).This mixture was stirred 5 minutes, then, once add O-benzotriazole-1-base-N of one whole part, N, N ', N '-tetramethyl-urea a tetrafluoro borate (48mg, 0.15mmol).This mixture was stirred 63 hours, then, it is distributed between chloroform and salt solution.With chloroform extraction water layer three times, and with the organic layer that merges through anhydrous magnesium sulfate drying, filter and concentrate in a vacuum, to remove volatile matter.Utilize preparation HPLC (YMC S10 ODS, 30 * 500mm is by 30 minutes gradients of 58% to 90% methanol aqueous solution (containing 0.1%TFA)) with resulting residue purifying.Suitable level part is merged and give lyophilize, obtain being the title compound (18mg, 30%) of pale solid. ¹H NMR (CDCl ₃) δ 10.35 (brs, 1H), 9.49 (s, 1H), 9.18 (s, 1H), 8.80-8.65 (m, 2H), 8.36-8.29 (m, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.83-7.68 (m, 2H), 7.55-7.49 (m, 2H), 7.35-7.23 (m, 2H), 7.10-7.00 (m, 2H), 3.58 (s, 2H); HRMS (ESI): theoretical value, 501.1487 (M+H) ⁺Measured value, 501.1491 (M+H) ⁺

Embodiment 137

2,6-two fluoro-N-(3-fluoro-4-(6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl) benzamide, trifluoroacetate

Under room temperature, nitrogen atmosphere, with diisopropylethylamine (49 μ L, 0.28mmol) be added into 3-fluoro-4-(6-(pyridin-3-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline (64mg, 0.20mmol, the Compound D of embodiment 131) is in the formed homogeneous solution of anhydrous chloroform (5mL).This mixture was stirred 5 minutes, then, add 2, and the 6-difluoro benzoyl chloride (33 μ L, 0.26mmol, Aldrich).This mixture was stirred 87 hours, then, it is distributed between chloroform and saturated sodium bicarbonate aqueous solution.Clean organic layer with saturated sodium bicarbonate aqueous solution and once and with salt solution clean once,, filtered and in vacuum-drying, with the removal volatile matter then with the organic layer anhydrous magnesium sulfate drying that merges.Utilize preparation HPLC (YMC S10 ODS, 30 * 500mm, 30 minutes gradients of 58% to 90% methanol aqueous solution (containing 0.1%TFA)), with resulting residue purifying.Suitable level part is merged and carry out lyophilize, the solid title compound that obtains being white in color (24mg, 21%). ¹HNMR (CD ₃OD) δ 9.20 (s, 1H), 8.85-8.78 (m, 1H), 8.65-8.60 (m, 1H), 8.51 (d, 1H, J=1.6Hz), 8.00 (s, 1H), 7.98-7.90 (m, 1H), 7.81-7.74 (m, 1H), 7.58 (d, 1H, J=1.8Hz), 7.51-7.27 (m, 3H), 7.00-7.10 (m, 2H); HRMS (ESI): theoretical value, 462.1178 (M+H) ⁺Measured value, 462.1168 (M+H) ⁺

Embodiment 138

1-(4-(5-(3-acetamido phenyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 5-chlorine pyrrolo-[2,1-f] [1,2,4] triazines-4 (3H)-ketone

Under 170 ℃, 1-amino-3-chloro-1H-pyrroles-2-carboxylate methyl ester (WO 03/099286 for 10.0g, 57.3mmol, the compd A of embodiment 9) in the formed solution heating of methane amide (40ml) 1 hour, then, under 190 ℃, was heated 1 hour.After being cooled to room temperature, this mixture can solidify.By separating out from the ethyl acetate recrystallize, with this product purification, and the solid title compound that obtains being white in color (6.53g, 67%). ¹H?NMR(CDCl ₃)δ10.24(brs，1H)，7.48(d，1H，J＝3.6Hz)，7.29(d，1H，J＝2.8Hz)，6.47(d，1H，J＝2.8Hz)；MS(ESI ⁺)m/z170.1(M+H) ⁺。

B) 4,5-dichloro pyrrolo-[2,1-f] [1,2,4] triazine

Under room temperature, nitrogen atmosphere, successively with diisopropylethylamine (5.14mL, 29.5mmol) and phosphorus (III) acyl chlorides (8.25mL, 88.5mmol) be added into 5-chlorine pyrrolo-[2,1-f] [1,2,4] (5.00g is 29.5mmol) in the formed solution of toluene (100mL) for triazine-4 (3H)-ketone.Under 100 ℃,, then, be cooled to room temperature with this mixture heating up 20 hours.This reactant is added into saturated sodium bicarbonate aqueous solution (500mL) under 0 ℃ lentamente.After interpolation is finished, at room temperature, this mixture was stirred 30 minutes.(3 * 500mL) aqueous phase extracted through anhydrous magnesium sulfate drying and after concentrating in a vacuum, obtain being the crude product (3.73g, 67%) of yellow solid, and it need not to be further purified, and can use with ethyl acetate. ¹H?NMR(CDCl ₃)δ8.03(s，1H)，7.70(d，1H，J＝2.8Hz)，6.84(d，1H，J＝2.8Hz)；MS(ESI ⁺)m/z?188.1(M+H) ⁺。

C) 5-chloro-4-(2-fluoro-4-nitrophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine

Under 60 ℃, with 4,5-dichloro pyrrolo-[2,1-f] [1,2,4] triazine (3.73g, 19.8mmol), 2-fluoro-4-nitrophenols (3.43g, 21.8mmol) and salt of wormwood (5.47g 39.6mmol) stirred 1 hour in the formed mixture of DMF (100mL).After being cooled to room temperature, this reactant is filtered by segment silica gel charges with ethyl acetate, then, concentrate in a vacuum.By separating out from ethyl acetate/hexane (1: 1) recrystallize, with resulting crude product purifying, the solid title compound that obtains being white in color (4.37g, 71%). ¹H?NMR(CDCl ₃)δ8.22-8.17(m，2H)，7.92(s，1H)，7.77(d，1H，J＝2.8Hz)，7.58(t，1H，J＝7.2Hz)，6.87(d，1H，J＝3.2Hz)；MS(ESI ⁺)m/z309.3(M+H) ⁺。

D) 4-(5-chlorine pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluoroaniline

Successively with zinc powder (2.12g, 32.4mmol) and ammonium chloride (1.73g 32.4mmol) is added into 5-chloro-4-(2-fluoro-4-nitrophenoxy) pyrrolo-[2,1-f] [1,2,4] (2.00g is 6.48mmol) in THF (50mL)/formed solution of methyl alcohol (80mL) for triazine.After at room temperature stirring 8 hours, this reaction mixture is passed through Celite with methyl alcohol ^Pad filters, and then, concentrates in a vacuum.Resulting residue is dissolved in ethyl acetate (200mL), and successively water (2 * 100mL) and salt solution (1 * 100mL) is cleaned.With organic phase through anhydrous sodium sulfate drying and concentrate in a vacuum.Utilize flash chromatography on silica gel method (50% ethyl acetate/hexane),, obtain being the title compound (1.51g, 84%) of faint yellow solid resulting crude product purifying. ¹H?NMR(CDCl ₃)δ7.95(s，1H)，7.69(d，1H，J＝2.8Hz)，7.09(t，1H，J＝8.4Hz)，6.79(d，1H，J＝2.8Hz)，6.58(dd，1H，J＝11.6，2.6Hz)，6.51(d，1H，J＝8.7Hz)，3.92(br?s，2H)；MS(ESI ⁺)m/z?279.2(M+H) ⁺。

E) N-(3-(4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) phenyl) ethanamide

In regular turn with acid chloride (4.5mg, 0.02mmol), X-Phos part (24mg, 0.05mmol, Strem), 4-(5-chlorine pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-and the 3-fluoroaniline (56mg, 0.20mmol), 3-kharophen phenylo boric acid (72mg, 0.40mmol, Lancaster) and potassiumphosphate (127mg 0.60mmol) is added in the flask.Wash this flask with nitrogen, then, add tertiary butyl alcohol (0.40mL).Under 80 ℃, with this mixture heating up 8 hours.Add again many parts of acid chlorides (4.5mg, 0.02mmol), the X-Phos part (24mg, 0.05mmol), and 3-kharophen phenylo boric acid (72mg 0.40mmol), and under 80 ℃, stirred 9 hours this reactant more.After being cooled to room temperature, this reactant is filtered (use methyl alcohol), to remove potassiumphosphate, then, concentrate in a vacuum.Utilize anti-phase HPLC,, and in a vacuum, suitable level part is concentrated, to remove methyl alcohol with resulting crude product purifying.With saturated sodium hydrogen carbonate solution, make resulting water layer become alkalescence, and extracted with ethyl acetate.With the organic extract liquid that merges through anhydrous sodium sulfate drying and concentrate the solid title compound that obtains being white in color (20mg, 26%) in a vacuum. ¹H?NMR(CD ₃OD)δ7.84-7.94(m，2H)，7.44-7.41(m，1H)，7.34-7.19(m，3H)，6.92(t，1H，J＝8.8Hz)，6.87(d，1H，J＝2.8Hz)，6.50(dd，1H，J＝12.4，2.4Hz)，6.46-6.43(m，1H)，2.04(s，3H)；MS(ESI ⁺)m/z?378.3(M+H) ⁺。

F) 1-(4-(5-(3-acetylamino phenyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

Under room temperature, nitrogen atmosphere; with 2-(4-fluorophenyl) ethanoyl isocyanic ester (250 μ L; 0.064mmol; 0.25M, in toluene, the Compound C of embodiment 4) and be added into N-(3-(4-(4-amino-2-fluorophenoxy) pyrrolo-[2; 1-f] [1; 2,4] phenyl triazine-5-yl)) (20mg 0.053mmol) forms in the solution in methylene dichloride (0.5mL) ethanamide.At room temperature, this reactant was stirred 1 hour, then, concentrate in a vacuum.Be suspended in resulting residue in the methyl alcohol and filtered, can collect the solid title compound that is white in color (14mg, 47%). ¹H?NMR(DMSO-d ₆)δ11.09(s，1H)，10.63(s，1H)，10.04(s，1H)，8.25-8.21(m，2H)，8.05(s，1H)，7.78(d，1H，J＝13.2Hz)，7.51-7.38(m，7H)，7.23(t，2H，J＝8.4Hz)，7.13(s，1H)，3.81(s，2H)，2.10(s，3H)；MS(ESI ⁺)m/z557.4(M+H) ⁺。

Embodiment 139-144 is to make with embodiment 138 similar modes.

Embodiment 139

1-(3-fluoro-4-(the 5-phenylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

¹H?NMR(DMSO-d ₆)δ10.56(s，1H)，8.55(s，1H)，7.89(s，1H)，7.77(d，1H，J＝2.8Hz)，7.62-7.57(m，3H)，7.33(t，2H，J＝7.7Hz)，7.26-7.1?9(m，4H)，7.10(m，1H)，7.02(t，2H，J＝8.6Hz)，6.88(d，1H，J＝2.7Hz)，3.65(s，2H)；MS(ESI ⁺)m/z500.3(M+H) ⁺。

Embodiment 140

1-(3-fluoro-4-(5-(thiene-3-yl-) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl-3-(2-(4-fluorophenyl) ethanoyl) urea

¹H?NMR(DMSO-d ₆)δ11.05(s，1H)，10.59(s，1H)，8.1?6(d，1H，J＝2.8Hz)，8.12(s，1H)，7.81(d，1H，J＝1.6Hz)，7.75(dd，1H，J＝12.4，2Hz)，7.62-7.49(m，3H)，7.39-7.36(m，3H)，7.21-7.16(m，3H)，3.76(s，2H)；MS(ESI ⁺)m/z506.3(M+H) ⁺。

Embodiment 141

1-(3-fluoro-4-(5-pyrimidine-5-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

¹H?NMR(DMSO-d ₆)δ11.10(s，1H)，10.65(s，1H)，9.21(s，2H)，9.18(s，1H)，8.37(d，1H，J＝2.4Hz)，8.31(s，1H)，7.80(dd，1H，J＝12.4，2Hz)，7.58(t，1H，J＝8.8Hz)，7.44-7.40(m，4H)，7.23(t，2H，J＝8.4Hz)，3.80(s，2H)；MS(ESI ⁺)m/z502.3(M+H) ⁺。

Embodiment 142

1-(4-(5-(3,5-dimethyl isoxazole-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

¹H?NMR(DMSO-d ₆)δ11.04(s，1H)，10.58(s，1H)，8.24(d，1H，J＝2.4Hz)，8.17(s，1H)，7.42(dd，1H，J＝13.2，2Hz)，7.38-7.35(m，4H)，7.18(t，2H，J＝7.6Hz)，7.06(d，1H，J＝2.8Hz)，3.75(s，2H)，2.37(s，3H)，2.20(s，3H)；MS(ESI ⁺)m/z519.3(M+H) ⁺。

Embodiment 143

1-(3-fluoro-4-(5-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

¹H?NMR(DMSO-d ₆)δ11.04(s，1H)，10.59(s，1H)，8.11(d，1H，J＝2.8Hz)，8.05(d，2H，J＝2.4Hz)，7.85(s，1H)，7.76(dd，1H，J＝12.4，2Hz)，7.52(t，1H，J＝8.4Hz)，7.39-7.36(m，3H)，7.18(t，2H，J＝8.8Hz)，7.12(d，1H，J＝2.8Hz)，3.86(s，3H)，3.76(s，2H)；MS(ESI ⁺)m/z504.3(M+H) ⁺。

Embodiment 144

1-(3-fluoro-4-(5-(3-nitrophenyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

¹H?NMR(DMSO-d ₆)δ11.03(s，1H)，10.57(s，1H)，8.62(s，1H)，8.27(d，1H，J＝2.4Hz)，8.23(s，1H)，8.20-8.16(m，2H)，7.76-7.72(m，2H)，7.49(t，1H，J＝8.8Hz)，7.39-7.34(m，4H)，7.18(t，2H，J＝9.2Hz)，3.75(s，2H)；MS(ESI ⁺)m/z545.2(M+H) ⁺。

Embodiment 145

1-(4-(5-(4-aminophenyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 4-(4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) the phenylcarbamic acid tert-butyl ester

According to being prepared, obtain being the title compound (46%) of yellow oil with the similar mode of the step e of embodiment 138. ¹H?NMR(CDCl ₃)δ7.88(s，1H)，7.73(d，1H，J＝4Hz)，7.54(d，2H，J＝8Hz)，7.33-7.30(m，2H)，6.93(t，1H，J＝7.6Hz)，6.82(d，1H，J＝4Hz)，6.60-6.47(m，2H)，1.44(s，9H)；MS(ESI ⁺)m/z436.4(M+H) ⁺。

B) 1-(4-(5-(4-aminophenyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared, obtain material (51%) through the Boc protection with the similar mode of the step F of embodiment 138.This material through the Boc protection is suspended in the ether (2mL), is cooled to 0 ℃, and add TFA (0.5mL).At room temperature, stir after 1 hour, in a vacuum this reactant is concentrated.Resulting residue is suspended in (10mL) in the ethyl acetate, cleans with saturated sodium bicarbonate aqueous solution (5mL), and with it through anhydrous sodium sulfate drying, and concentrated.Utilize flash chromatography on silica gel (60% ethyl acetate/hexane), with resulting crude product purifying.After acetonitrile (1mL)/water (3mL) lyophilize, obtain being light brown solid title compound (38%). ¹H?NMR(DMSO-d ₆)δ10.95(s，1H)，10.50(s，1H)，8.02(d，1H，J＝2.8Hz)，7.98(s，1H)，7.67(dd，1H，J＝12.4，2Hz)，7.36(t，1H，J＝8.8Hz)，7.31-7.28(m，5H)，7.10(t，2H，J＝8.8Hz)，6.89(d，1H，J＝2.8Hz)，6.51(d，2H，J＝8.8Hz)，5.08(s，2H)，3.68(s，2H)；MS(ESI ⁺)m/z515.3(M+H) ⁺。

Embodiment 146

1-(4-(5-((the amino cyclohexylidene of 4-) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-(fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 4-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methylene radical) pimelinketone

According to the similar mode of the step e of embodiment 138, use 4-((4,4,5,5-tetramethyl--1,3,2-dioxy ring pentaborane-2-yl) methylene radical) pimelinketone (according to Morrill, C.and Grubbs, R.H.J.Org.Chem.2003,68, the step of 6031-6034 makes) be prepared, obtain being the title compound (11%) of yellow oil. ¹H?NMR(CD ₃OD)δ7.76(s，1H)，7.73(d，1H，J＝2.8Hz)，7.54-7.51(m，1H)，7.33(d，1H，J＝2.8Hz)，6.92(t，1H，J＝7.6Hz)，6.84(d，1H，J＝2.8Hz)，6.46-6.41(m，1H)，2.83(t，2H，J＝6.8Hz)，2.65(t，2H，J＝6.8Hz)，2.45-2.38(m，4H)；MS(ESI ⁺)m/z353.2(M+H) ⁺。

According to being prepared, obtain being the title compound (38%) of yellow solid with the similar mode of the step F of embodiment 138. ¹H NMR (acetone-d ₆) δ 10.62 (s, 1H), 9.87 (s, 1H), 7.80 (s, 1H), 7.79 (d, 1H, J=2.8Hz), 7.70 (dd, 1H, J=12.8,2.4Hz), 7.33-7.19 (m, 4H), 6.96-6.93 (m, 3H), 6.16 (m, 1H), 3.75 (s, 2H), 2.82 (t, 2H, J=6.8Hz), 2.62 (t, 2H, J=6.8Hz), 2.37 (t, 2H, J=6.8Hz), 2.30 (t, 2H, J=6.8Hz); MS (ESI ⁺) m/z532.2 (M+H) ⁺

C) 1-(4-(5-((the amino cyclohexylidene of 4-) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

Successively with ammonium acetate (30mg; 0.40mmol) and sodium cyanoborohydride (2.5mg; 0.040mmol) be added into 1-(4-(5-(4-aminophenyl) pyrrolo-[2; 1-f] [1; 2; 4] triazine-4-base oxygen base)-the 3-fluorophenyl)-(21mg is 0.040mmol) in methyl alcohol (0.5mL) and the formed solution under 0 ℃ of THF (0.5mL) for 3-(2-(4-fluorophenyl) ethanoyl) urea.After stirring 1 hour under 0 ℃, in a vacuum this reactant is concentrated.Utilize anti-phase to prepare HPLC,, and in a vacuum suitable level part is concentrated resulting crude product purifying.Interpolation toluene (2 * 5mL), and concentrated, to remove excessive TFA.After acetonitrile (1mL)/water (3mL) lyophilize, the tfa salt (19%) of the solid title compound that obtains being white in color. ¹H?NMR(CD ₃OD)δ7.77(s，1H)，7.76(d，1H，J＝2.8Hz)，7.63(dd，1H，J＝12.8，2.4Hz)，7.29-7.14(m，4H)，7.03-6.93(m，2H)，6.91(d，1H，J＝2.8Hz)，6.67(s，1H)，3.62(s，2H)，3.15-3.08(m，1H)，2.50-2.30(m，2H)，2.21-2.05(m，2H)，1.46-1.30(m，4H)；MS(ESI ⁺)m/z533.2(M+H) ⁺。

Embodiment 147

N-(4-(5-chlorine pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl) niacinamide

Successively with nicotinic acid (53mg, 0.431mmol, Aldrich), DIPEA (300 μ L, 1.80mmol) and TBTU (173mg, 0.539mmol, Fluka) be added into 4-(5-fluorine pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluoroaniline (100mg, 0.359mmol, the Compound D of embodiment 138) and in the formed solution of DMF (2mL).At room temperature, this reactant is stirred a whole night, then, is diluted with the 20mL ethyl acetate, successively use the 10% lithium chloride aqueous solution (2 * 10mL) and salt solution (1 * 10mL) cleans, and it is through anhydrous sodium sulfate drying, and concentrated in a vacuum.Utilize flash chromatography on silica gel method (10% methanol/ethyl acetate), with resulting crude product purifying, the solid title compound that obtains being white in color (125mg, 91%). ¹H?NMR(DMSO-d ₆)δ10.75(s，1H)，9.14(d，1H，J＝2Hz)，8.80(dd，1H，J＝4.8，1.2Hz)，8.34-8.31(m，1H)，8.18(d，1H，J＝2.8Hz)，8.17(s，1H)，7.96(dd，1H，J＝12.8，2Hz)，7.66-7.60(m，2H)，7.54(t，1H，J＝8.8Hz)，7.10(d，1H，J＝2.8Hz)；MS(ESI ⁺)m/z383.9(M+H) ⁺。

Embodiment 148

N-(4-(5-((the amino cyclohexylidene of 4-) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl) niacinamide

A) N-(3-fluoro-4-(5-((4-ketone group cyclohexylidene) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl) niacinamide

According to being prepared, obtain being the title compound (66%) of yellow solid with the similar mode of the step e of embodiment 138. ¹H?NMR(DMSO-d ₆)δ10.75(s，1H)，9.14(d，1H，J＝2Hz)，8.82(dd，1H，J＝4.8，1.2Hz)，8.36-8.33(m，1H)，8.13(d，1H，J＝2.8Hz)，8.10(s，1H)，7.99-7.93(m，1H)，7.68-7.63(m，1H)，7.54(t，1H，J＝8.8Hz)，7.07(d，1H，J＝2.8Hz)，6.92(s，1H)，2.90(t，2H，J＝6.8Hz)，2.74(t，2H，J＝6.8Hz)，2.51(t，2H，J＝6.8Hz)，2.42(t，2H，J＝6.8Hz)；MS(ESI ⁺)m/z?458.2(M+H) ⁺。

B) N-(4-(5-((the amino cyclohexylidene of 4-) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl) niacinamide

According to being prepared, obtain being the tfa salt (6%) of the title compound of faint yellow solid with the similar mode of the step C of embodiment 146. ¹H?NMR(CD ₃OD)δ9.15(s，1H)，8.80(s，1H)，8.59(d，1H，J＝8Hz)，7.84-7.76(m，4H)，7.48(d，1H，J＝8Hz)，7.29(t，1H，J＝8Hz)，6.80(d，1H，J＝4Hz)，6.67(s，1H)，3.62(s，2H)，3.10-3.08(m，1H)，2.48-2.05(m，4H)，1.47-1.20(m，4H)；MS(ESI ⁺)m/z?459.2(M+H) ⁺。

Embodiment 149

N ¹-(3-fluoro-4-(5-((4-ketone group cyclohexylidene) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide

According to the similar mode of the step e of embodiment 138, carry out the Suzuki linked reaction, then shown in the steps A of embodiment 133, carry out Malonamide and form reaction, obtain being the title compound (39%) of yellow solid. ¹H?NMR(DMSO-d ₆)δ10.55(s，1H)，10.31(s，1H)，8.15(d，1H，J＝2.4Hz)，8.11(s，1H)，7.86(dd，1H，J＝12.4，2.8Hz)，7.52(t，1H，J＝8.8Hz)，7.44-7.42(m，1H)，7.25-7.19(m，2H)，7.09(d，1H，J＝2.8Hz)，6.93(s，1H)，3.54(s，2H)，2.91(t，2H，J＝6.8Hz)，2.73(t，2H，J＝6.4Hz)，2.53(t，2H，J＝6.8Hz)，2.45(t，2H，J＝6.8Hz)；MS(ESI ⁺)m/z?532.3(M+H) ⁺。

Embodiment 150

N ¹-(3-fluoro-4-(5-((4-hydroxyl cyclohexylidene) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide

The sodium borohydride of the most advanced and sophisticated amount of medicine spoon is added into N ¹-(3-fluoro-4-(5-((4-ketone group cyclohexylidene) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide (embodiment 149 for 80mg, 0.15mmol) is in the formed solution under 0 ℃ of methyl alcohol (2mL).Under 0 ℃, this reactant was stirred 30 minutes, then,, and under 0 ℃, stirred 5 minutes with saturated aqueous ammonium chloride solution (10mL) cancellation reaction.With ethyl acetate (3 * 10mL) extract this mixture, and with the organic extract liquid that merges through anhydrous sodium sulfate drying, and concentrate in a vacuum.Utilize flash chromatography on silica gel method (10% methanol/ethyl acetate),, obtain being the title compound (30mg, 37%) of pale solid resulting crude product purifying. ¹H?NMR(DMSO-d ₆)δ10.57(s，1H)，10.34(s，1H)，8.11(d，1H，J＝2.8Hz)，8.10(s，1H)，7.86(dd，1H，J＝12.8，2.4Hz)，7.71-7.68(m，2H)，7.53(t，1H，J＝8.4Hz)，7.46-7.43(m，1H)，7.25-7.21(m，2H)，6.99(d，1H，J＝2.8Hz)，6.64(s，1H)，4.65(br?s，1H)，3.76-3.75(m，1H)，3.56(s，2H)，2.90-2.85(m，1H)，2.51-2.45(m，1H)，2.27-2.24(m，2H)，1.92-1.85(m，2H)，1.46-1.41(m，2H)；MS(ESI ⁺)m/z?534.3(M+H) ⁺。

Embodiment 151

N ¹-(4-(5-((the amino cyclohexylidene of 4-) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malonamide

According to being prepared with the similar mode of the step C of embodiment 146, the tfa salt (12%) of the solid title compound that obtains being white in color. ¹H?NMR(DMSO-d ₆)δ10.51(s，1H)，10.26(s，1H)，8.02(d，1H，J＝2.4Hz)，7.99(s，1H)，7.74(dd，1H，J＝12.8，2Hz)，7.59-7.55(m，2H)，7.38(t，1H，J＝8.4Hz)，7.32-7.35(m，1H)，7.13-7.08(m，2H)，6.90(d，1H，J＝2.8Hz)，6.59(s，1H)，3.44(s，2H)，2.95-3.00(m，1H)，2.20-2.41(m，2H)，1.96-2.11(m，2H)，1.32-1.39(m，2H)，1.17-1.13(m，2H)；MS(ESI ⁺)m/z533.3(M+H) ⁺。

Embodiment 152

N ¹-(3-fluoro-4-(5-((4-methylamino-) cyclohexylidene) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, trifluoroacetate

Successively with methylamine (2M is in THF for 23 μ L, 0.045mmol), acetate (2.6 μ L, 0.045mmol) and sodium triacetoxy borohydride (13mg 0.056mmol) is added into N in ethylene dichloride (1mL) ¹-(3-fluoro-4-(5-((4-ketone group cyclohexylidene) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide (embodiment 149 for 20mg, 0.038mmol).After at room temperature this reactant being stirred 2 hours, then, react with 5% sodium bicarbonate aqueous solution (1mL) cancellation.Isolate each layer, and clean organic layer, it through anhydrous sodium sulfate drying, and is concentrated in a vacuum with salt solution.Utilize anti-phase to prepare HPLC,, and in a vacuum, suitable level part is concentrated resulting crude product purifying.Add toluene (2 * 4mL) and concentrate, to remove excessive TFA.After acetonitrile (1mL)/water (3mL) lyophilize, the tfa salt (44%) of the solid title compound that obtains being white in color. ¹H?NMR(DMSO-d ₆)δ10.51(s，1H)，10.26(s，1H)，8.02(d，1H，J＝2.8Hz)，8.00(s，1H)，7.74(dd，1H，J＝12.8，2Hz)，7.59-7.55(m，2H)，7.40(t，1H，J＝8.4Hz)，7.35-7.32(m，1H)，7.13-7.06(m，2H)，6.90(d，1H，J＝2.8Hz)，6.60(s，1H)，3.44(s，2H)，3.10-3.13(m，1H)，3.02-2.98(m，1H)，2.52-2.39(m，4H)，2.23-2.21(m，1H)，2.08-2.02(m，3H)，1.36-1.31(m，2H)；MS(ESI ⁺)m/z547.1(M+H) ⁺。

Embodiment 153

N ¹-(3-fluoro-4-(5-((4-hydroxy-4-methyl cyclohexylidene) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, trifluoroacetate

(1M is in THF for 76 μ L, 0.076mmol) is added into the N in THF (1mL) under 0 ℃ with lithium methide ¹-(3-fluoro-4-(5-((4-ketone group cyclohexylidene) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide (embodiment 149 for 10mg, 0.019mmol).At room temperature, this reactant stirred a whole night after, with salt solution (1mL) cancellation reaction.Each layer separated and with organic layer through anhydrous sodium sulfate drying, and concentrate in a vacuum.Utilize anti-phase to prepare HPLC,, and in a vacuum suitable level part is concentrated resulting crude product purifying.Interpolation toluene (2 * 2mL), and concentrated, to remove excessive TFA.After acetonitrile (1mL)/water (3mL) lyophilize, obtain being the tfa salt (3mg, 21%) of the title compound of faint yellow solid. ¹H?NMR(DMSO-d ₆)δ10.45(s，1H)，10.21(s，1H)，7.98(d，1H，J＝2.8Hz)，7.96(s，1H)，7.74(dd，1H，J＝12.8，2Hz)，7.58-7.55(m，2H)，7.40(t，1H，J＝8Hz)，7.33-7.31(m，1H)，7.13-7.08(m，2H)，6.87(d，1H，J＝2.8Hz)，6.51(s，1H)，4.20(br?s，1H)，3.43(s，2H)，2.60-2.45(m，3H)，2.09-2.06(m，1H)，1.56-1.52(m，2H)，1.41-1.36(m，2H)，1.07(s，3H)；MS(ESI ⁺)m/z?548.3(M+H) ⁺。

Embodiment 154

N ¹-(4-(5-((4-amino piperidine-4-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malonamide, trifluoroacetate

A) 5-brooethyl-4-chlorine pyrrolo-[2,1-f] [1,2,4] triazine

In nitrogen atmosphere, with 4-chloro-5-methylpyrrole [2,1-f] [1,2 also, 4] triazine (2.0g, 11.93mmol WO 03/042172) and AIBN (195mg is 1.19mmol) in the formed mixture heating up to 100 of tetracol phenixin (80mL) ℃, last 5 minutes, then, and interpolation NBS (2.55g, 14.3mmol).This reaction mixture was stirred 10 minutes, then, be cooled to room temperature and filtration.Sodium bicarbonate aqueous solution with dilution cleans carbon tetrachloride layer, gives drying (sal epsom), filters and concentrates, and obtains desired product (2.70g, 92%).

B) bromination (4-chlorine pyrrolo-[2,1-f] [1,2,4] triazine-5-ylmethyl)-triethyl ammonium

At room temperature, with 5-brooethyl-4-chlorine pyrrolo-[2,1-f] [1,2,4] triazine (2.7g, 11mmol), (5mL 36mmol) stirred 12 hours in the formed mixture of THF (20mL) triethylamine.Filter out solid, and cleaned, carry out drying, obtain desired product (3.38g, 89%) with THF and ether.Analysis HPLC retention time=0.776 minute (Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA) lasts 4 minutes, the 4mL/ clock detects in 220nm).MS(ESI ⁺)m/z?267(M+H) ⁺。

C) 1-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl) the piperidines 4-aminocarbamic acid tert-butyl ester

In-78 ℃, nitrogen atmosphere, with NaHMDS (1M is in hexane for 650 μ L, 0.650mmol) be added into 4-amino-2-fluorophenol in THF (5mL) (82mg, 0.646mmol).-78 ℃ down stir 20 minutes after, flask is transferred in 0 ℃ the bath, and add immediately solid bromination N-((4-chlorine pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl)-triethyl ammonium (200mg, 0.807mmol).This reactant is warmed to room temperature, and was stirred 2 hours.Add DIPEA (280 μ L, 1.6mmol), the piperidin-4-yl t-butyl carbamate (129mg, 0.646mmol, Aldrich) and DMF (2mL).This reactant is heated to 120 ℃, lasts 4 hours.After this reactant is cooled to room temperature, concentrated in a vacuum and utilize anti-phase to prepare HPLC, with resulting crude product purifying.In a vacuum suitable level part is concentrated.Add toluene (2 * 2mL) and concentrated, obtain being the tfa salt (100mg, 27%) of the title compound of yellow solid. ¹H?NMR(CD ₃OD)δ8.09(s，1H)，8.03(d，1H，J＝2.4Hz)，7.23-7.13(m，2H)，6.83-6.61(m，2H)，4.73(s，2H)，3.67-3.64(m，1H)，3.30-3.19(m，2H)，2.31-2.24(m，2H)，1.76-1.63(m，2H)，1.49-1.45(m，2H)，1.45(s，9H)；MS(ESI ⁺)m/z?457.5(M+H) ⁺。

D) N ¹-(4-(5-((4-amino piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malonamide, trifluoroacetate

According to being prepared with the similar mode of the steps A of embodiment 133.With resulting substance dissolves through Boc protection in 0 ℃ ether (1mL) and add 4N HCl (in the 3mL diox).Under 0 ℃, this reactant was stirred 3 hours, then, concentrated in a vacuum.Utilize anti-phase HPLC,, and in a vacuum suitable level part is concentrated resulting crude product purifying.Add toluene (2 * 2mL) and concentrated, the tfa salt (4mg, 12%) of the solid title compound that obtains being white in color. ¹H?NMR(DMSO-d ₆)δ10.49(s，1H)，10.22(s，1H)，8.18(s，1H)，7.90(d，1H，J＝2.8Hz)，7.76(dd，1H，J＝12.8，2.4Hz)，7.57-7.56(m，2H)，7.43-7.36(m，2H)，7.13-7.09(m，3H)，4.57(s，2H)，3.51-3.48(m，1H)，3.44(s，2H)，3.09-3.06(m，2H)，2.53-2.50(m，2H)，2.00-1.97(m，2H)，1.72-1.67(m，2H)；MS(ESI ⁺)m/z536.5(M+H) ⁺。

Embodiment 155

1-(4-(5-((4-amino piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, trifluoroacetate

With 2-(4-fluorophenyl) ethanoyl isocyanic ester (290 μ L; 0.088mmol; 0.3M; in toluene, the Compound C of embodiment 4) is added into 1-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1 in 0 ℃ of methylene dichloride (1mL); 2; 4] methyl triazine-5-yl)) in the piperidin-4-yl t-butyl carbamate (50mg, 0.088mmol, the Compound C of embodiment 154).Under 0 ℃, this reactant was stirred 0.5 hour, and utilize flash chromatography on silica gel method (10% methanol/ethyl acetate), give direct purification, obtain being the material (33mg, 59%) through the Boc protection of colorless oil.This material through the Boc protection is suspended in 0 ℃ of ether (2mL), and adds in the 4N HCl (Yu diox, 5mL).Under 0 ℃, this reactant was stirred 1.5 hours, then, in a vacuum, concentrated.Utilize anti-phase to prepare HPLC,, and in a vacuum, suitable level part is concentrated resulting crude product purifying.Add toluene (2 * 2mL), and concentrate, the tfa salt (3mg, 8%) of the solid title compound that obtains being white in color.

¹H?NMR(DMSO-d ₆)δ11.01(s，1H)，10.57(s，1H)，8.21-8.18(m，2H)，7.73(dd，1H，J＝12.8，2.4Hz)，7.48-7.33(m，4H)，7.18-7.11(m，3H)，4.57(m，1H)，3.69(s，2H)，3.44(s，2H)，3.59-3.48(m，2H)，3.13-3.06(m，2H)，2.05-1.98(m，2H)，1.71-1.55(m，2H)；MS(ESI ⁺)m/z?535.3(M+H) ⁺。

Embodiment 156

1-(3-fluoro-4-(5-((4-methylpiperazine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 1-(3-fluoro-4-(5-((4-methylpiperazine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared, obtain being the tfa salt (9%) of the title compound of brown solid with the similar mode of the step C of embodiment 154. ¹H?NMR(CD ₃OD)δ7.90(s，1H)，7.85(d，1H，J＝2.8Hz)，7.17(t，1H，J＝8.8Hz)，6.94(d，1H，J＝2.8Hz)，6.75(dd，1H，J＝11.6，2.4Hz)，6.72-6.69(m，1H)，4.39(s，2H)，3.40-3.31(m，8H)，2.79(s，3H)；MS(ESI ⁺)m/z?357.3(M+H) ⁺。

B) 10 (3-fluoro-4-(5-((4-methylpiperazine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) ureas

According to being prepared with embodiment 155 similar modes, solid title compound (83%) obtains being white in color. ¹H?NMR(CD ₃OD)δ7.80(s，1H)，7.77(d，1H，J＝2Hz)，7.62(dd，1H，J＝12.4，2.4Hz)，7.27-7.17(m，4H)，6.99-6.95(m，2H)，6.84(d，1H，J＝2.4Hz)，3.94(s，2H)，3.62(s，2H)，2.70-2.45(m，8H)，2.26(s，3H)；MS(ESI ⁺)m/z536.2(M+H) ⁺。

Embodiment 157

1-(3-fluoro-4-(5-(morpholino methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 3-fluoro-4-(5-(morpholino methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline

According to being prepared, obtain being the tfa salt (10%) of light brown solid title compound with the similar mode of the step C of embodiment 154. ¹H?NMR(CD ₃OD)δ7.98(s，1H)，7.91(d，1H，J＝2.8Hz)，7.11(t，1H，J＝8.4Hz)，7.02(d，1H，J＝2.8Hz)，6.62(dd，1H，J＝12.4，2.8Hz)，6.60-6.57(m，1H)，4.67(s，2H)，4.00-3.94(m，2H)，3.68-3.61(m，2H)，3.43-3.40(m，2H)，3.22-3.20(m，2H)；MS(ESI ⁺)m/z?344.3(M+H) ⁺。

B) 1-(3-fluoro-4-(5-(morpholino methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared with embodiment 155 similar modes, solid title compound (83%) obtains being white in color. ¹H?NMR(CD ₃OD)δ7.89(s，1H)，7.85(d，1H，J＝2.8Hz)，7.67(dd，1H，J＝12.4，2.4Hz)，7.30-7.19(m，4H)，7.01-6.94(m，3H)，4.28(s，2H)，3.70-3.76(m，4H)，3.62(s，2H)，2.88-2.80(m，2H)；MS(ESI ⁺)m/z?523.2(M+H) ⁺。

Embodiment 158

1-(4-(5-((4-amino piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base is amino) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 1-((4-(4-amino phenyl amino) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl) piperidin-4-yl t-butyl carbamate

Be prepared according to the similar mode of the step C of embodiment 154, obtain being the tfa salt (38%) of the title compound of yellow oil. ¹H?NMR(CD ₃OD)δ7.57(s，1H)，7.33(d，1H，J＝2.4Hz)，7.24-7.21(m，2H)，6.71-6.68(m，2H)，6.45(d，1H，J＝2.8Hz)，3.67(s，2H)，3.34-3.28(m?1H)，2.95-2.90(m，2H)，1.80-1.77(m，2H)，1.41-1.33(m，2H)，1.32(s，9H)；MS(ESI ⁺)m/z?438.3(M+H) ⁺。

B) 1-(4-(5-((4-amino piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base is amino) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared, obtain being the title compound (47%) of pale solid with embodiment 155 similar modes. ¹H?NMR(DMSO-d ₆)δ11.01(s，1H)，10.53(s，1H)，8.00-7.89(m，2H)，7.61-7.59(m，3H)，7.45-7.41(m，2H)，7.26-7.22(m，4H)，3.77(s，2H)，3.63(s，2H)，3.35-3.32(m，1H)，3.20-3.14(m，2H)，2.19-1.90(m，6H)；MS(ESI ⁺)m/z517.3(M+H) ⁺。

Embodiment 159

N-(4-(5-((4-amino piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-2, the 6-difluorobenzamide

According to being prepared with embodiment 147 similar modes, the tfa salt (5%) of the solid title compound that obtains being white in color. ¹H?NMR(DMSO-d ₆)δ11.10(s，1H)，8.19-8.17(m，2H)，7.82(dd，1H，J＝12.8，2.4Hz)，7.49(t，1H，J＝8.8Hz)，7049-7.47(m，2H)，7.25-7.21(m，2H)，7.14-7.09(m，1H)，4.59(s，2H)，3.54-3.48(m，3H)，3.15-3.08(m，2H)，2.08-2.00(m，2H)，1.74-1.66(m，2H)；MS(ESI ⁺)m/z?497.2(M+H) ⁺。

Embodiment 160

1-(3-fluoro-4-(5-(piperazine-1-ylmethyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 3-fluoro-4-(5-(piperazine-1-ylmethyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline

According to being prepared, obtain being the title compound of yellow oil with the similar mode of the step C of embodiment 154.MS(ESI ⁺)m/z?443.3(M+H) ⁺。

B) 1-(3-fluoro-4-(5-(piperazine-1-ylmethyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared with embodiment 155 similar modes, solid title compound (6%) obtains being white in color. ¹H?NMR(DMSO-d ₆)δ11.00(s，1H)，10.55(s，1H)，8.12(s，1H)，8.11(d，1H，J＝2.8Hz)，7.71(dd，1H，J＝12.8，2.4Hz)，7.42(t，1H，J＝8.8Hz)，7.35-7.28(m，3H)，7.11(t，2H，J＝9.2Hz)，7.03(m，1H)，4.58(s，2H)，3.69(s，2H)，3.66-3.59(m，4H)，3.32-3.05(m，4H)；MS(ESI ⁺)m/z?522.3(M+H) ⁺。

Embodiment 161

1-(3-fluoro-4-(5-((methyl (piperidin-4-yl) amino) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) N-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl)-N-methyl piperidine-4-amine

According to being prepared, obtain being the title compound (38%) of yellow oil with the similar mode of the step C of embodiment 154.MS(ESI ⁺)m/z?471.3(M+H) ⁺。

B) 1-(3-fluoro-4-(5-((methyl (piperidin-4-yl) amino) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared with embodiment 155 similar modes, solid title compound (32%) obtains being white in color. ¹H?NMR(DMSO-d ₆δ11.00(s，1H)，10.55(s，1H)，8.19(s，1H)，8.16(d，1H，J＝2.4Hz)，7.71(dd，1H，J＝12.4，2Hz)，7.42-7.34(m，2H)，7.32-7.28(m，2H)，7.16-7.06(m，3H)，4.44(s，2H)，3.69(s，2H)，3.64-3.59(m，4H)，2.87-2.84(m，1H)，2.72(s，3H)，2.19-2.15(m，2H)，1.87-1.82(m，2H)；MS(ESI ⁺)m/z?550.3(M+H) ⁺。

Embodiment 162

1-(4-(5-((4-aminomethyl) piperidines-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) (1-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl) piperidin-4-yl) methyl carbamic acid tert-butyl ester

According to being prepared, obtain being the title compound (29%) of yellow oil with the similar mode of the step C of embodiment 154.MS(ESI ⁺)m/z471.3(M+H) ⁺。

B) 1-(4-(5-((4-aminomethyl) piperidines-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared with embodiment 155 similar modes, solid title compound (26%) obtains being white in color. ¹H?NMR(DMSO-d ₆)δ11.01(s，1H)，10.53(s，1H)，7.99(s，1H)，7.97(d，1H，J＝2.4Hz)，7.66(dd，1H，J＝13.2，2.4Hz)，7.36-7.28(m，4H)，7.09(t，2H，J＝8.8Hz)，6.82(d，1H，J＝2.4Hz)，3.77(s，2H)，3.68(s，2H)，3.84-3.82(m，2H)，2.38-2.36(m，1H)，1.88(t，2H，J＝10Hz)，1.58-1.55(m，2H)，1.20-1.01(m，4H)；MS(ESI ⁺)m/z?550.2(M+H) ⁺。

Embodiment 163

(R)-1-(4-(5-((3-amino-pyrrolidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-1-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 1-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl) tetramethyleneimine-3-aminocarbamic acid (R)-tert-butyl ester

According to being prepared, obtain being the title compound (30%) of yellow oil with the similar mode of the step C of embodiment 154.MS(ESI ⁺)m/z?443.3(M+H) ⁺。

B) (R)-1-(4-(5-((3-amino-pyrrolidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared with embodiment 155 similar modes, solid title compound (11%) obtains being white in color. ¹H?NMR(DMSO-d ₆)δ10.54(s，1H)，10.21(s，1H)，7.99(s，1H)，7.98(d，1H，J＝2.4Hz)，7.67(dd，1H，J＝12.4，2Hz)，7.40-7.26(m，3H)，7.13-7.07(m，3H)，6.84(d，1H，J＝2.8Hz)，3.90(s，2H)，3.68(s，2H)，2.67-2.41(m，3H)，2.20-2.16(m，2H)，1.96-1.91(m，1H)，1.32-1.29(m，1H)；MS(ESI ⁺)m/z?522.2(M+H) ⁺。

Embodiment 164

(S)-1-(4-(5-((3-amino-pyrrolidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 1-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl) tetramethyleneimine-3-aminocarbamic acid (S)-tert-butyl ester

B) (S)-1-(4-(5-((3-amino-pyrrolidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared with embodiment 155 similar modes, solid title compound (7%) obtains being white in color. ¹H?NMR(DMSO-d ₆)δ10.54(s，1H)，10.21(s，1H)，7.99(s，1H)，7.98(d，1H，J＝2.4Hz)，7.67(dd，1H，J＝12.4，2Hz)，7.40-7.26(m，3H)，7.13-7.07(m，3H)，6.84(d，1H，J＝2.8Hz)，3.90(s，2H)，3.68(s，2H)，2.67-2.41(m，3H)，2.20-2.16(m，2H)，1.96-1.91(m，1H)，1.32-1.29(m，1H)；MS(ESI ⁺)m/z?522.2(M+H) ⁺。

Embodiment 165

(S)-1-(4-(5-((3-amino piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 1-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl) piperidines-3.. aminocarbamic acid (S)-tert-butyl ester

According to being prepared, obtain being the title compound (40%) of yellow oil with the similar mode of the step C of embodiment 154.MS(ESI ⁺)m/z?457.3(M+H) ⁺。

B) (S)-1-(4-(5-((3-amino piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared with embodiment 155 similar modes, the tfa salt (29%) of the solid title compound that obtains being white in color. ¹H?NMR(DMSO-d ₆)δ11.00(s，1H)，10.55(s，1H)，8.15(m，2H)，7.71(dd，1H，J＝12.4，2Hz)，7.41(t，1H，J＝8.4Hz)，7.35-7.28(m，3H)，7.11(t，2H，J＝8.8Hz)，7.05(d，1H，J＝2.8Hz)，4.58(s，2H)，3.69(s，2H)，3.66-3.30(m，5H)，1.95-1.83(m，2H)，1.67-1.53(m，1H)，1.40-1.32(m，1H)；MS(ESI ⁺)m/z536.2(M+H) ⁺。

Embodiment 166

1-(3-fluoro-4-(5-((4-hydroxy piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, trifluoroacetate

A) 5-methyl-4-first sulfydryl-pyrrolo-[2,1-f] [1,2,4] triazine (5-Methyl-4-methylsulfanyl-pyrrolo[2,1-f] [1,2,4] triazine)

Under 0 ℃, to add in the formed solution of anhydrous THF (200mL) with 4-chloro-5-methyl-pyrrolo-[2,1-f] [1,2,4] triazine (WO 03/042172 for 4.02g, 24.0mmol) of nitrogen bubble NaSMe (1.85g, 26.3mmol).Continued bubbling 5 minutes.Then, at room temperature, this reaction mixture is stirred a whole night, be concentrated into the volume of about 50mL in a vacuum, water (280mL) dilutes and stirs under 0 ℃.Filter out solid, cleaned, after drying, obtain desired product (3.91g, 91%) with cold water.Analyze HPLC retention time=3.38 minutes (YMC S5 ODS post 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.2% phosphoric acid) lasts 4 minutes, 4mL/ minute, detects at 220nm); MS (ESI ⁺) m/z 180 (M+H) ⁺

B) 1-((4-(methylthio group) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl) piperidines-4-alcohol

Under 80 ℃, with 5-methyl-4-first sulfydryl-pyrrolo-[2,1-f] [1,2,4] triazine (200mg, 1.12mmol), NBS (218mg, 1.23mmol) and AIBN (spoon looking somebody up and down (spatula tip)) in the formed solution heating of tetracol phenixin (4mL) 1 hour.After this solution is cooled to room temperature, filtered, to remove succinimide.With the 4-hydroxy piperidine (126mg, 1.34mmol, Aldrich) and DIPEA (214 μ L 1.23mmol) are added in the resultant filtrate.At room temperature, this reactant is stirred a whole night, then, concentrate in a vacuum.Be suspended in resulting residue in the methyl alcohol and filtered.Filtrate is concentrated, and utilize flash chromatography on silica gel method (20% methanol/ethyl acetate),, obtain being the title compound (229mg, 74%) of colorless solid resulting crude product purifying. ¹HNMR(DMSO-d ₆)δ8.25(s，1H)，7.88(d，1H，J＝2Hz)，6.81(d，1H，J＝2Hz)，4.54(brs，1H)，3.76(s，2H)，3.48-3.44(m，1H)，2.75-2.71(m，2H)，2.62(s，3H)，2.10-2.08(m，2H)，1.70-1.68(m，2H)，1.38-1.36(m，2H)；MS(ESI ⁺)m/z279.3(M+H) ⁺。

C) 1-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl) piperidines-4-alcohol

Successively with TFA (78 μ L, 1.01mmol) and m-CPBA (166mg, 0.675mmol,～70% purity) be added into 1-((4-(methylthio group) pyrrolo-[2,1-f] [1,2 in 0 ℃ of methylene dichloride (7mL), 4] methyl triazine-5-yl)) piperidines-4-alcohol (188mg, 0.675mmol) in.Under 0 ℃, this mixture was stirred 1 hour, then, in a vacuum, concentrated.Add ether (20mL), then, carry out decant, to remove phenylformic acid.Under high vacuum, with resulting rough sulfoxide drying.(343mg 2.7mmol) is dissolved among the THF (10mL), is cooled to-78 ℃ with 4-amino-2-fluorophenol, and add NaHMDS (2.7mL, 2.7mmol, 1M, in THF), after being stirred 5 minutes under 0 ℃, add the rough sulfoxide among the THF (3mL).Under 0 ℃, reactant was stirred 30 minutes, then, concentrate in a vacuum.Resulting residue is suspended in the ethyl acetate (20mL), and water (10mL) is cleaned, and it through anhydrous sodium sulfate drying, and is concentrated in a vacuum.Utilize anti-phase to prepare HPLC,, and in a vacuum, suitable level part is concentrated, to remove methyl alcohol with resulting crude product purifying.Use 5% sodium bicarbonate aqueous solution, make the resulting aqueous solution become alkalescence, and (3 * 10mL) extract with ethyl acetate.The extraction liquid that merges through anhydrous sodium sulfate drying, and is concentrated the solid title compound that obtains being white in color (36mg, 15%) in a vacuum. ¹HNMR(DMSO-d ₆)δ8.04(s，1H)，8.00(d，1H，J＝2.8Hz)，7.02(t，1H，J＝8.8Hz)，6.88(d，1H，J＝2.8Hz)，6.51(dd，1H，J＝12.8，2.8Hz)，6.46-6.42(m，1H)，5.45(brs，2H)，3.83(s，2H)，3.18(m，1H)，2.76-2.71(m，2H)，2.12-2.06(m，2H)，1.72-1.67(m，2H)，1.41-1.38(m，2H)；MS(ESI ⁺)m/z?358.4(M+H) ⁺。

D) 1-(3-fluoro-4-(5-((4-hydroxy piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, trifluoroacetate

According to being prepared with embodiment 155 similar modes, the tfa salt (12%) of the solid title compound that obtains being white in color. ¹H?NMR(DMSO-d ₆)δ11.00(s，1H)，10.55(s，1H)，8.18(s，1H)，8.16-8.14(m，1H)，7.71(d，1H，J＝12.4Hz)，7.41-7.28(m，4H)，7.11-7.08(m，3H)，4.59-4.54(m，2H)，3.68(s，2H)，3.60-3.00(m，5H)，1.92-1.87(m，1H)，1.81-1.68(m，2H)，1.53-1.48(m，1H)；MS(ESI ⁺)m/z?537.2(M+H) ⁺。

Embodiment 167

1-(3-fluoro-4-(5-piperidin-4-yl amino) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 4-((4-(methylthio group) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methylamino-) piperidines-1-carboxylic acid tert-butyl ester

According to being prepared, obtain being the title compound (50%) of colorless oil with the similar mode of the steps A of embodiment 166. ¹H?NMR(CD ₃OD)δ8.14(s，1H)，7.73(d，1H，J＝2.8Hz)，6.91(d，1H，J＝2.8Hz)，4.21(s，2H)，4.10-4.07(m，2H)，2.83-2.77(m，3H)，2.71(s，3H)，1.99-1.97(m，2H)，1.48(s，9H)，1.34-1.31(m，2H)；MS(ESI ⁺)m/z378.3(M+H) ⁺。

B) 4-[tertbutyloxycarbonyl-(4-first sulfydryl-pyrrolo-[2,1-f] [1,2,4] triazine-5-ylmethyl)-amino]-piperidines-1-carboxylic acid tert-butyl ester

With 4-((4-(methylthio group) pyrrolo-[2,1-f] [1,2,4] piperidines-1-carboxylic acid tert-butyl ester (210mg methylamino-triazine-5-yl)), 0.556mmol) be dissolved in methylene dichloride (5mL) and triethylamine (120 μ L, 0.834mol) in, then add tert-Butyl dicarbonate (134mg, 0.612mmol).At room temperature, this reactant stirred 8 hours after, (20mL) dilutes this reactant with methylene dichloride, (10mL) cleaned with saturated aqueous ammonium chloride solution, and it is through anhydrous sodium sulfate drying, and concentrated in a vacuum.Utilize flash chromatography on silica gel method (20% ethyl acetate/hexane),, obtain being the title compound (207mg, 78%) of colorless oil resultant crude product purifying. ¹H?NMR(CDCl ₃)δ8.01(s，1H)，7.51(d，1H，J＝2.8Hz)，6.57(d，1H，J＝2.8Hz)，4.71(s，2H)，4.06-4.04(m，3H)，2.68-2.61(m，2H)，2.61(s，3H)，1.60-1.57(m，2H)，1.46-1.36(m，2H)，1.35(s，18H)；MS(ESI ⁺)m/z?478.2(M+H) ⁺。

C) 4-{[4-(4-amino-2-fluoro-phenoxy group)-pyrrolo-[2,1-f] [1,2,4] triazine-5-ylmethyl]-tertbutyloxycarbonyl-amino }-piperidines-1-carboxylic acid tert-butyl ester

According to being prepared, obtain being the title compound (43%) of colorless oil with the similar mode of the step C of embodiment 166. ¹H?NMR(CDCl ₃)δ7.84(s，1H)，7.62(d，1H，J＝2.8Hz)，6.98(t，1H，J＝8.8Hz)，6.70(d，1H，J＝2.8Hz)，6.47-6.41(m，2H)，4.72(s，2H)，4.10-4.04(m，2H)，3.77-3.75(m，1H)，2.62-2.60(m，2H)，1.71-1.38(m，4H)，1.35(s，18H)；MS(ESI ⁺)m/z?557.2(M+H) ⁺。

D) 1-(3-fluoro-4-(5-((piperidin-4-yl amino) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared with embodiment 155 similar modes, solid title compound (34%) obtains being white in color. ¹H?NMR(DMSO-d ₆)δ11.01(s，1H)，10.55(s，1H)，8.16(s，1H)，8.12(d，1H，J＝2.4Hz)，7.71(dd，1H，J＝12.4，2Hz)，7.42-7.28(m，4H)，7.18-7.08(m，3H)，4.51(s，2H)，3.69(s，2H)，3.50-3.29(m，3H)，2.88-2.85(m，2H)，2.23-2.18(m，2H)，1.72-1.64(m，2H)；MS(ESI ⁺)m/z?536.2(M+H) ⁺。

Embodiment 168

1-(4-(5-(amino third amino of 3-) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 3-((4-(methylthio group) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methylamino-) the propyl carbamic acid tert-butyl ester

According to being prepared, obtain being the title compound (51%) of yellow solid with mode like the step category-B of embodiment 166. ¹H?NMR(CD ₃OD)δ8.16(s，1H)，7.75(d，1H，J＝2.4Hz)，6.94(d，1H，J＝2.8Hz)，4.30(s，2H)，3.14(t，2H，J＝6.4Hz)，2.83(t，2H，J＝7.2Hz)，2.72(s，3H)，1.82-1.75(m，2H)，1.40(s，9H)；MS(ESI ⁺)m/z?352.3(M+H) ⁺。

B) 3-[tertbutyloxycarbonyl-(4-first sulfydryl-pyrrolo-[2,1-f] [1,2,4] triazine-5-ylmethyl)-amino]-propyl group }-t-butyl carbamate

According to being prepared, obtain being the title compound (77%) of faint yellow oily thing with mode like the step category-B of embodiment 167. ¹H?NMR(CDCl ₃)δ8.14(s，1H)，7.73(d，1H，J＝2.4Hz)，6.75(d，1H，J＝2Hz)，4.88(s，2H)，3.29-3.25(m，2H)，3.04-3.02(m，2H)，2.71(s，3H)，1.72-1.68(m，2H)，1.54(s，9H)，1.42(s，9H)；MS(ESI ⁺)m/z?452.2(M+H) ⁺。

C) (3-{[4-(4-amino-2-fluoro-phenoxy group)-pyrrolo-[2,1-f] [1,2,4] triazine-5-ylmethyl]-tertbutyloxycarbonyl-amino }-propyl group)-t-butyl carbamate

According to being prepared, obtain being the title compound (29%) of colorless oil with the similar mode of the step C of embodiment 166. ¹H?NMR(CDCl ₃)δ7.85(s，1H)，7.64(d，1H，J＝2.8Hz)，7.00(t，1H，J＝8.8Hz)，6.82-6.78(m，1H)，6.62(dd，1H，J＝12.8，2.4Hz)，6.54-6.51?(m，1H)，4.72(m，2H)，3.28-3.23(m，2H)，3.02-3.00(m，2H)，1.58-1.55(m，2H)，1.43(s，9H)，1.35(s，9H)；MS(ESI ⁺)m/z?531.2(M+H) ⁺。

D) 1-(4-(5-((amino third amino of 3-) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared with embodiment 155 similar modes, solid title compound (17%) obtains being white in color. ¹H?NMR(DMSO-d ₆)δ11.01(s，1H)，10.52(s，1H)，8.00(s，1H)，7.98(d，1H，J＝2.8Hz)，7.68(dd，1H，J＝12.8，2.4Hz)，7.34-7.28(m，4H)，7.13(t，2H，J＝9.2Hz)，6.84(d，1H，J＝2.4Hz)，3.68(s，2H)，3.52(s，2H)，2.90-2.85(m，2H)，2.28-2.20(m，2H)，1.35-1.30(m，2H)；MS(ESI ⁺)m/z?510.2(M+H) ⁺。

Embodiment 169

1-(4-(5-((3-aminomethyl) azetidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) (1-((4-(methylthio group) pyrrolo-[2,1-f] [1,2,4] triazine-5-ylmethyl) azetidine-3-yl) the methyl carbamic acid tert-butyl ester

According to being prepared with mode like the step category-B of embodiment 166, solid title compound (31%) obtains being white in color. ¹H?NMR(CD ₃OD)δ8.12(s，1H)，7.72(d，1H，J＝2.4Hz)，6.81(d，1H，J＝2.8Hz)，4.07(s，2H)，3.46(t，2H，J＝8Hz)，3.34-3.33(m，1H)，3.20-3.18(m，2H)，3.08(t，2H，J＝7.6Hz)，2.65(s，3H)，1.44(s，9H)；MS(ESI ⁺)m/z364.3(M+H) ⁺。

B) (1-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl) azetidine-3-yl) methyl carbamic acid tert-butyl ester

According to being prepared, obtain being the title compound (33%) of brown solid with the similar mode of the step C of embodiment 166.MS(ESI ⁺)m/z?443.2(M+H) ⁺。

C) 1-(4-(5-((3-aminomethyl) azetidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to being prepared with embodiment 155 similar modes, solid title compound (4%) obtains being white in color. ¹H?NMR(DMSO-d ₆)δ11.02(s，1H)，10.56(s，1H)，8.18-8.15(m，2H)，7.68(dd，1H，J＝12.8，2.4Hz)，7.45-7.28(m，4H)，7.18-7.08(m，3H)，4.67(s，2H)，4.44-4.41(m，2H)，4.05-3.98(m，2H)，3.69(s，2H)，3.10-2.97(m，3H)；MS(ESI ⁺)m/z?522.3(M+H) ⁺。

Embodiment 170

1-(4-(5-(((3R, 4R)-4-amino-3-hydroxy piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-the 3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) (3R, 4R)-4-azido--1-((4-(methylthio group) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl) piperidines-3-alcohol

According to being prepared, obtain being the title compound (65%) of yellow foam with mode like the step category-B of embodiment 166. ¹H?NMR(CD ₃OD)δ8.36(s，1H)，7.99(d，1H，J＝2.4Hz)，6.93(d，1H，J＝2.8Hz)，3.92-3.88(m，2H)，3.35-3.30(m，1H)，3.08-2.90(m，2H)，2.72(s，3H)，2.14-2.10(m，2H)，2.00-1.91(m，2H)，1.47-1.44(m，1H)；MS(ESI ⁺)m/z?320.2(M+H) ⁺。

B) (3R, 4R)-1-((4-(4-amino-2-fluorophenoxy) pyrrolo-[2,1-f] [1,2,4] triazine-5-yl) methyl)-4-azido-piperidines-3-alcohol

According to being prepared, obtain being the title compound (24%) of brown solid with the similar mode of the step C of embodiment 166.MS(ESI ⁺)m/z?399.2(M+H) ⁺。

C) 1-(4-(5-(((3R, 4R)-4-amino-3-hydroxy piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to embodiment 155 similar modes, the preparation acylurea, obtain corresponding trinitride (48%).MS(ESI ⁺)m/z?578.16(M+H) ⁺。Then, with this trinitride (35mg 0.06mmol) is dissolved in 0 ℃ ethyl acetate (1mL), and successively add trimethyl-phosphine (0.11mL, 0.11mmol) and water (1).Under room temperature, this reactant stirring after 3 hours, is concentrated in a vacuum, and utilizes anti-phase to prepare HPLC, carry out purifying.In a vacuum suitable level part is concentrated, and add toluene (2 * 2mL), then, concentrated the tfa salt (8mg, 17%) of the solid title compound that obtains being white in color. ¹H?NMR(DMSO-d ₆)δ11.00(s，1H)，10.55(s，1H)，8.18-8.16(m，2H)，7.72(dd，1H，J＝12.8，2.4Hz)，7.36-7.28(m，4H)，7.14-7.09(m，3H)，4.62(s，2H)，3.69(s，2H)，3.22-2.85(m，6H)，2.03-1.98(m，1H)，1.68-1.65(m，1H)；MS(ESI ⁺)m/z?510.2(M+H) ⁺。

Embodiment 171

1-(4-(5-(((3R, 4R)-4-amino-3-hydroxy piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base amino) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 1-(2-(4-fluorophenyl) ethanoyl)-3-(4-nitrophenyl) urea

(200mg is 1.45mmol) in the solution of the formed stirring of the tetrahydrofuran (THF) under room temperature (1mL) to be added into p-Nitroaniline with 2-(4-fluorophenyl) ethanoyl isocyanic ester (2mL, 0.32M, in toluene, the Compound C of embodiment 4).After 18 hours, in a vacuum this mixture is concentrated, and resulting residue is dissolved in (5mL) in the ethyl acetate.On rotatory evaporator, under the condition of not heating, this solution is concentrated lentamente.When throw out begins to form, shift out flask in this rotatory evaporator certainly, and it was left standstill 2 hours.Filter out formed solid, and cleaned with a spot of ethyl acetate, and dry in a vacuum, obtain pale yellow crystals shape compound (200mg, 44%).MS(ESI ⁺)m/z?318.3(M+H) ⁺。

B) 1-(4-aminophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

Being stated from palladium (15mg) on the carbon with 10% is added into 1-(2-(4-fluorophenyl) ethanoyl)-3-(4-nitrophenyl) urea (200mg 0.63mmol) in the formed solution of ethyl acetate (10mL), and fills hydrogen with balloon with this flask.This mixture was stirred 18 hours, then, filter, and use the ethyl acetate cleaning catalyst.In a vacuum, filtrate is concentrated, obtain solid, grind this solid, and drying in a vacuum, obtain the desired compound (180mg) of faint yellow solid with a spot of ether.MS(ESI ⁺)m/z?287.4(M+H) ⁺。

C) N; N-diethyl-N-((4-(4-(3-(2-(4-fluorophenyl) ethanoyl) urea groups) phenylamino) pyrrolo-[2; 1-f] [1; 2; 4] methyl triazine-5-yl)) the ethane brometo de amonio (N, N-diethyl-N-((4-(4-(3-(2-(4-fluorophenyl) acetyl) ureido) phenylamino) pyrrolo[2,1-f] [1; 2,4] ethanaminium bromide methyl triazin-5-yl)))

With 1-(4-aminophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea (50mg; 0.17mmol) be added into bromination (4-chloro-pyrrolo-[2; 1-f] [1; 2; 4]-three second ammonium (75mg triazine-5-ylmethyl); 0.22mmol, the compd B of embodiment 154) and in the formed solution of chloroform (1.5mL), and with this mixture heating up backflow 6 hours.Mixture is cooled to room temperature, concentrates in a vacuum and grind resulting residue with acetonitrile.Resulting solid need not to be further purified, and promptly can be used for next procedure.

D) 1-(4-(5-(((3R, 4R)-4-azido--3-hydroxy piperidine-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base is amino) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

(3R; 4R)-4-azido-piperidines-3-alcohol (0.28mg; 0.2mmol; WO 04/058144) and triethylamine (0.2mL) be added into rough N; N-diethyl-N-((4-(4-(3-(2-(4-fluorophenyl) ethanoyl) urea groups) phenylamino) pyrrolo-[2; 1-f] [1,2,4] triazine-5-yl) methyl) the ethane brometo de amonio is in the formed solution of chloroform (3mL).Under 60 ℃, this reaction mixture was stirred 2 hours, then, be cooled to room temperature, then, water is cleaned.With chloroform (3 * 8mL) aqueous layer extracted.In a vacuum, the organic extract liquid that merges is concentrated, obtain being the crude product of yellow solid.

Aforementioned rough solid is dissolved in the tetrahydrofuran (THF) (3mL), adds triphenylphosphine (80mg) and water (0.02mL), and with the reaction mixture reflux of gained 2 hours.This reaction mixture is cooled to room temperature, concentrates and utilize preparation anti-phase HPLC in a vacuum, resulting crude product purifying.Collect suitable level part, concentrated and handled with 1N HCl (2mL).True in this solution concentration, resulting residue is water-soluble and give lyophilize, the solid title compound that obtains being white in color (48mg, the overall yield 47% of three steps). ¹H?NMR(CD ₃OD)δ7.87(s，1H)，7.77(s，1H)，7.65(d，2H，J＝8.4Hz)，7.46(d，2H，J＝8.3Hz)，7.28(dd，2H，J＝5.4，8.4Hz)，7.06(s，1H)，6.98(t，2H，J＝8.7Hz)，4.7(brs，2H)，3.9(br?s，2H)，3.63(s，2H)，3.56(br?s，2H)，3.20-3.10(br?s，2H)，2.99-2.87(br?s，1H)，2.96(br?d，1H，J＝10.8Hz)，1.91(br?t，J＝10.8Hz)；MS(ESI ⁺)m/z?533.4(M+H) ⁺。

Embodiment 172

1-(4-(5-((4-kharophen piperidines-1-yl) methyl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

Successively with pyridine (6 μ L; 0.067mmol) and Acetyl Chloride 98Min. (5 μ L; 0.067mmol) be added into 1-(4-(5-((4-amino piperidine-1-yl) methyl) pyrrolo-[2 in methylene dichloride (1mL); 1-f] [1; 2; 4] triazine 4-base oxygen base)-the 3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea (embodiment 155 for 30mg, 0.056mmol).Add DMF (0.5mL), with reactants dissolved.After stirring 2 hours under the room temperature, add second part pyridine (6 μ L) and Acetyl Chloride 98Min. (5 μ L).After stirring 1 hour under the room temperature, (10ml) dilutes this reactant with ethyl acetate, and (each 1 * 5mL) cleans, and it is through anhydrous sodium sulfate drying, and concentrated in a vacuum successively to use the 10% lithium chloride aqueous solution and salt solution.Utilize anti-phase to prepare HPLC, with rough product purification.In a vacuum suitable level part is concentrated, and add toluene (2 * 2mL), concentrated the tfa salt (15mg, 39%) of the solid title compound that obtains being white in color then. ¹HNMR(DMSO-d ₆)δ11.00(s，1H)，10.55(s，1H)，8.19(s，1H)，8.14(d，1H，J＝2.8Hz)，7.89(d，1H，J＝7.2Hz)，7.71(dd，1H，J＝12.4，2.4Hz)，7.43-7.28(m，4H)，7.14-7.07(m，3H)，4.54(s，2H)，3.68(s，2H)，3.45-2.42(m，3H)，3.12-3.10(m，2H)，1.88-1.85(m，2H)，1.73(s，3H)，1.52-1.50(m，2H)；MS(ESI ⁺)m/z?578.2(M+H) ⁺。

Embodiment 173

N ¹-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-N ³-(3-methoxyphenyl) Malonamide, trifluoroacetate

A) 3-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-3-ketopropionic acid

Successively with 3-chloro-3-ethyl ketopropionate (555mg, 3.7mmol, Aldrich) and pyridine (1mL) be added into 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (900mg, 3.7mmol, the compd B of embodiment 132) and in the formed solution of-40 ℃ of methylene dichloride (30mL).Under-40 ℃, resulting mixture was stirred 1 hour.Dilute this mixture with methylene dichloride, with saturated KH ₂PO ₄Cleaned, and with it through dried over mgso.This mixture is filtered by the segment silica gel filler,, obtain brown oil (1.1g) with 2% methanol/ethyl acetate wash-out.With this ester in 0 ℃ ethanol (15mL) and sodium hydroxide (1N, Yu Shuizhong, 15mL) in saponification 1 hour, be neutralized to pH4 with 1N HCl.In decompression down, this reaction mixture is removed ethanol certainly, and filters and collect the solid that is produced.Then, water clean this solid and with it through dried over mgso, obtain being beige solid title compound (670mg, 55%).LC/MS(ESI ⁺)m/z?330(M+H) ⁺。

B) N ¹-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-N ³-(3-methoxyphenyl) Malonamide, trifluoroacetate

Successively with HATU (38mg, 0.1mmol) and 3-anisidine (18mg, 0.15mmol) and DMAP (3mg), be added into 3-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-5-fluorophenyl amino)-(16.5mg is 0.05mmol) in the formed solution that had stirred of DMF (0.4mL) for the 3-ketopropionic acid.Under 45 ℃, this mixture was stirred 4 hours.Utilize preparation HPLC, with desired product purification, the solid title compound that obtains being white in color (17mg, 62%). ¹HNMR(CD ₃OD)δ8.15(d，1H，J＝6.6Hz)，7.80(dd，1H，J＝11.8，2.2Hz)，7.41(d，1H，J＝3.9Hz)，7.29-7.38(m，2H)，7.23(m，1H)，7.12(t，1H，J＝8.3Hz)，7.00(dd，1H，J＝8.3，1.1Hz)，6.69(d，1H，J＝6.6Hz)，6.60(dd，1H，J＝8.3，2.2Hz)，6.51(d，1H，J＝3.3Hz)，3.90(s，3H)；LCMS(ESI ⁺)m/z?435(M+H) ⁺。

Embodiment 174-236

HATU, the DIPEA of embodiment 174-236 shown in the table 3 in DMF, and DMAP in the presence of, by 3-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-3-ketopropionic acid (compd A of embodiment 173) and the preparation of corresponding amine and get.Utilize preparation HPLC (water/methyl alcohol/0.1%TFA, gradient 35-90% methyl alcohol last 10 minutes, 20 * 100mm, 5 μ m YMC ODS-A posts), with rough product purification.With part centrifugal evaporation of desired level, weigh and utilize LCMS (water/methyl alcohol/0.1%TFA), analyze.

Embodiment 237

2,6-two fluoro-N-(3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl) benzamide, hydrogen chlorate

A) 4-chloro-1-((2-trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine

In-40 ℃, nitrogen atmosphere, with sodium hydride (60%, in mineral oil, 880mg, 22mmol) be added into 4-chloro-1H-pyrrolo-[2,3-b] pyridine (3.05g, 20mmol is according to Thibault, C.et al.Org.Lett.2003,5,5023 make) in the formed solution of DMF (50mL).At room temperature, this mixture was stirred 15 minutes, be cooled to-40 ℃ then.(3.67g 22mmol) is added in this solution with (2-(chlorine methoxyl group) ethyl) trimethyl silane.The gained mixture at room temperature stirs a whole night.Dilute this mixture with ethyl acetate, clean secondary with 10% lithium chloride, and with it through dried over mgso.Utilize rapid column chromatography method (silica gel is successively with hexane and ether wash-out),, obtain being the desired product (5.6g, quantitative yield) of oily matter resulting title compound purifying.LC/MS(ESI ⁺)m/z283(M+H) ⁺。

B) 4-chloro-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine-2-ylboronic acid

In-40 ℃, nitrogen atmosphere, (2.0M is in hexanaphthene with n-Butyl Lithium, Aldrich, 2.4mmol) be added into that 4-chloro-1-((2-(trimethyl silyl) oxyethyl group) methyl)-(565mg is 2mmol) in the formed solution of THF (5mL) for 1H-pyrrolo-[2,3-b] pyridine.Under-40 ℃, this reaction mixture was stirred 1 hour, then, (489mg 2.6mmol) is handled with triisopropyl borate ester.This mixture is warmed to room temperature lentamente and stirs a whole night.With the 1N HCl of 20ml (in H ₂Among the O) be added in this solution, then, this mixture was stirred 20 minutes, with saturated K ₂HPO ₄The aqueous solution is neutralized, and uses extracted with diethyl ether.With organic layer through dried over sodium sulfate.After concentrating under filtration and the decompression, obtain being light beige solid title compound (640mg, quantitative yield).LC/MS(ESI ⁺)m/z327(M+H) ⁺。

C) 4-chloro-2-(pyridin-3-yl)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine

With argon gas feed 4-chloro-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine-2-ylboronic acid (5.55g, 17mmol), the 3-iodine pyridine (6.97g, 34mmol), Pd (OAc) ₂, 2-dicyclohexyl phosphino--2 ', 4 ', 6 '-triisopropyl-1,1 '-xenyl (405mg, 0.85mmol), and K ₃PO ₄(2M, Yu Shuizhong 34mmol) in the formed mixture of DME (50mL), last 10 minutes, then, give reflux a whole night.Dilute this reaction mixture with ethyl acetate, and with saturated K ₂HPO ₄The aqueous solution is cleaned.Utilize rapid column chromatography method (silica gel, 20% ethyl acetate/dichloromethane),, obtain being the desired product (3.2g, productive rate 52%) of oily matter resulting title compound purifying.LC/MS(ESI ⁺)m/z?361(M+H) ⁺。

D) 3-fluoro-4-(2-(pyridin-3-yl)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) aniline

In the pipe of sealing, under 185 ℃, with 4-chloro-2-(pyridin-3-yl)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine (3.2g, 8.9mmol), 2-fluoro-4-nitrophenols (2.79g, 17.8mmol), and DIPEA (3.5mL is 20mmol) in the formed mixture heating up of NMP (15mL) three days.Dilute this mixture with ethyl acetate, and with its Celite by weak point ^Pad filters (ethyl acetate).Clean resulting filtrate with 5% aqueous sodium carbonate, and with it through dried over mgso.Utilize rapid column chromatography method (silica gel, 100% methylene dichloride to 50% ethyl acetate/dichloromethane),, obtain being the light brown solid and want product (295mg, 7.4%) resulting title compound purifying.LC/MS(ESI ⁺)m/z?451(M+H) ⁺。

E) 3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) aniline

Under 65 ℃, with 3-fluoro-4-(2-(pyridin-3-yl)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) aniline (275mg, 0.61mmol), tetrabutyl ammonium fluoride (1M, in THF, 4mL) and 1 (0.2mL) formed mixture heating up 24 hours in THF (4mL).In a vacuum, remove solvent.Utilize rapid column chromatography method (silica gel, 5% methanol/ethyl acetate),, obtain being the product of wanting (180mg, 92%) of yellow solid resulting residue purifying.LC/MS(ESI ⁺)m/z?321(M+H) ⁺。

F) 2,6-two fluoro-N-(3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl) benzamide, hydrogen chlorate

With 2, the 6-difluoro benzoyl chloride (10mg, 0.056mmol) be added into 3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) aniline (15mg, 0.047mmol) and pyridine (0.1mmol) in the formed solution of 0 ℃ THF.Under 0 ℃, this reaction mixture was stirred 1 hour, concentrate in a vacuum, and utilize preparation HPLC, with resulting residue purifying.With desired level part lyophilize, obtain the tfa salt of white, it is dissolved in a spot of methanol (the 1N HCl that contains 0.2mL).Then, with this solution lyophilize, obtain being the title compound (HCl salt, 12mg, 48%) of yellow solid. ¹H?NMR(CD ₃OD)δ9.29(s，1H)，8.85(d，1H，J＝9.6Hz)，8.74(d，1H，J＝5.2Hz)，8.26(d，1H，J＝6.8Hz)，8.01(dd，1H，J＝8.4，5.6Hz)，7.88(dd，1H，J＝12.4，2.4Hz)，7.50-7.35(m，4H)，7.10-7.00(m，2H)，6.73(d，1H，J＝6.4Hz)；LC/MS(ESI ⁺)m/z?461(M+H) ⁺。

Embodiment 238

N-(3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl) niacinamide

With with embodiment 237 similar modes, the preparation and get. ¹H?NMR(CD ₃OD)δ9.36(s，1H)，9.33(s，1H)，9.00-8.90(m，3H)，8.79(d，1H，J＝5.2Hz)，8.31(d，1H，J＝6.8Hz)，8.12-8.05(m，2H)，7.99(dd，1H，J＝12.8，2.4Hz)，7.63(d，1H，J＝8.8Hz)，7.52(s，1H)，7.48-7.40(m，2H)，6.78(d，1H，J＝6.4Hz)；LCMS(ESI ⁺)m/z?461(M+H) ⁺。

Embodiment 239

N ¹-(3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, the hydrogen chlorate

DIPEA (0.1mL) is added into 3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) aniline (16mg, 0.05mmol, the compd E of embodiment 237), 3-(4-fluorophenyl amino)-3-ketopropionic acid (19.7mg, 0.1mmol, the compd A of embodiment 25), (38mg is 0.1mmol) in the formed solution that had stirred of DMF (0.5mL) to reach HATU.At room temperature, this mixture was stirred 2 hours, concentrate in a vacuum, and utilize preparation HPLC, with resulting residue purifying.With desired level part lyophilize, obtain the tfa salt of white, it is dissolved in small amount of methanol/water (containing 0.2mL 1N HCl), and carries out lyophilize, obtain being the title compound (HCl salt, 12mg, 42%) of yellow solid. ¹H?NMR(CD ₃OD)δ9.25(s，1H)，8.81(d，1H，J＝8.7Hz)，8.72(d，1H，J＝5.4Hz)，8.25(d，1H，J＝6.7Hz)，8.00(dd，1H，J＝8.1，6.1Hz)，7.82(dd，1H，J＝12.1，1.3Hz)，7.53-7.48(m，2H)，7.40-7.32(m，3H)，7.00-6.95(m，2H)，6.71(d，1H，J＝6.72Hz)，3.48(s，2H)；LC/S(ESI ⁺)m/z?500(M+H) ⁺。

Embodiment 240

6-(4-fluoro-phenyl)-1-oxygen base-pyridine-2-carboxylic acids [3-fluoro-4-(2-pyridin-3-yl-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides, trifluoroacetate

A) 6-(4-fluorophenyl) 2-pyridine carboxylic acid

(Aldrich) formed solution in the DME that contains 4mL 10% aqueous sodium carbonate then, is successively used Pd (PPh for 2.02g, 10mmol to clean 2-bromo-2-pyridine carboxylic acid with argon gas ₃) ₄, 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxy hexamethylene borine (2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane) (2.40g, 11.5mmol, Aldrich) and ethanol (20mL) handled.Then, also clean this mixture with argon gas.In the sealing test tube, under 100 ℃, with this reaction mixture heating 2.5 hours.Add other 2-bromo-2-pyridine carboxylic acid (900mg) and Pd (PPh ₃) ₄, and after cleaning through argon gas, under 100 ℃, heated 4.5 hours.Trifluoroacetic acid (20mL) is added into this reactant and in a vacuum, the mixture of gained is concentrated.(150mL) is added in the resulting residue with methyl alcohol, and the filtering insolubles.In a vacuum, filtrate is concentrated, and utilize silica gel rapid column chromatography method (successively using ethyl acetate/methanol (9: 1) and ethyl acetate/methanol/acetate (HOAc) (14: 30: 1) wash-out), with resulting residue purifying, the desired product of thing solid (1.0g, 40% (based on hexamethylene borine raw material)) obtains being white in color. ¹H?NMR(CD ₃OD)δ8.01(d，1H，J＝7.7Hz)，7.94-7.87(m，3H)，7.73(d，1H，J＝7.7Hz)，7.13(t，2H，J＝8.8Hz)；MS(ESI ⁺)m/z234(M+H) ⁺。

B) 6-(4-fluorophenyl) 2-pyridine carboxylic acid-N-oxide compound

At room temperature, with aforesaid 2-picolinic acid derivatives (1.0g, 4.6mmol), Na ₂HPO ₄(1.2g) and m-CPBA (1.1g ,～70%, Aldrich) stirred 2 hours in the formed mixture of ethylene dichloride (30mL).With other Na ₂HPO ₄(0.8g) and m-CPBA (1.0g) be added in this reaction mixture, and at room temperature, stirred 3 hours.Once more with Na ₂HPO ₄(0.5g) and m-CPBA (0.5g) be added in this reaction mixture, and at room temperature stirred a whole night.With CHCl ₃(160mL) and the 2N HCl aqueous solution (50mL) be added in this mixture, and isolate organic layer, with it and in a vacuum, concentrated through dried over mgso.Utilize silica gel rapid column chromatography method (with ethyl acetate/methanol/acetate (70: 24: 6) wash-out),, obtain being doped with the product of wanting of m-CPBA resulting residue purifying.HPLC will this impure material purifying with preparation, and the solid that obtains being white in color is wanted product (175mg, 16%). ¹H?NMR(DMF-d ₇)δ8.45(dd，1H，J＝8.3，2.2Hz)，8.15(d，1H，J＝2.2Hz)，8.13-8.00(m，4H)，7.45(t，2H，J＝8.7Hz)。

C) 6-(4-fluoro-phenyl)-1-oxygen base-pyridine-2-carboxylic acids [3-fluoro-4-(2-pyridin-3-yl-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides, trifluoroacetate

At room temperature, with 3-fluoro-4-(2-pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) aniline (40mg, 0.12mmol, the compd E of embodiment 237) is added into 6-(4-fluorophenyl) 2-pyridine carboxylic acid N-oxide compound (30mg, 0.13mmol), (50mg is 0.26mmol) in the formed solution of DMF (4mL) for HOBT (16mg) and EDCIHCl.At room temperature, this reaction mixture is stirred a whole night, and under decompression, concentrate.Utilize preparation HPLC,, obtain being the beige solid and want product (20mg, 24%) resulting residue purifying. ¹H?NMR(DMF-d ₇)δ14.07(brs，1H)，12.64(br?s，1H)，9.35(s，1H)，8.65(d，1H，J＝4.4Hz)，8.53(d，1H，J＝7.7Hz)，8.49(dd，1H，J＝8.2，2.2Hz)，8.23(d，1H，J＝5.5Hz)，8.19(dd，1H，J＝13.2，2.8Hz)，8.02-7.62(m，6H)，7.55(t，1H，J＝8.8Hz)，7.43(t，2H，J＝8.8Hz)，7.22(s，1H)，6.55(d，1H，J＝5.5Hz)；MS(ESI ⁺)m/z?459.1(M+H) ⁺。

Embodiment 241

6-(4-fluoro-phenyl)-1-oxygen base-pyridine-2-carboxylic acids [3-fluoro-4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides, trifluoroacetate

At room temperature, with 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (50mg, 0.20mmol, the compd B of embodiment 132) is added into 6-(4-fluorophenyl) 2-pyridine carboxylic acid N-oxide compound (47mg, 0.20mmol, the compd B of embodiment 240), (60mg is 0.31mmol) in the formed solution of DMF (4mL) for HOBT (20mg) and EDCIHCl.At room temperature, this mixture is stirred a whole night, and concentrate down in decompression.Utilize preparation HPLC, with resulting residue purifying, the solid that obtains being white in color is wanted product (68mg, 12%). ¹H?NMR(DMF-d ₇)δ14.07(br?s，1H)，12.14(br?s，1H)，8.49(dd，1H，J＝7.7，1.7Hz)，8.26(d，1H，J＝6.1Hz)，8.18(dd，1H，J＝12.7，1.7Hz)，8.02-7.96(m，3H)，7.84(t，1H，J＝8.3Hz)，7.67(d，1H，J＝8.8Hz)，7.57-7.52(m，2H)，7.43(d，2H，J＝8.8Hz)，6.62(d，1H，J＝6.0Hz)，6.46(d，1H，J＝2.8Hz)；MS(ESI ⁺)m/z?536.1(M+H) ⁺。

Embodiment 242

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, trifluoroacetate

A) 1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate

At room temperature, (1.67g, (2.31g, 15mmol Aldrich) in THF (40mL) and the formed solution of DMF (10mL), and stir this reaction mixture 2.5 hours 15mmol) to be added into 2-ketone group-2H-pyrans-3-methyl-formiate with the 4-fluoroaniline.At room temperature, with EDCIHCl (3.85g, 20mmol) and DMAP (120mg) but be added into this via in the formed 4-fluoroaniline intermediate of wheat addition reaction (Michael addition).At room temperature, this reaction mixture is stirred a whole night.The 1NHCl aqueous solution (50mL) and ethyl acetate (150mL) are added in this reaction mixture.Isolate ethyl acetate layer, and clean water layer with ethyl acetate (150mL).The ethyl acetate layer that merges through dried over mgso, and is concentrated in a vacuum, obtain semi-solid material (～4.4g).The product that this is rough is dissolved in ether (100mL) and the methyl alcohol (15mL), and will stir the formed solid filtering in back.In a vacuum, filtrate is concentrated, obtain being the semi-solid product of wanting (2.95g, 80%), its purity is enough to be directly used in next procedure, need not to be further purified. ¹H?NMR(DMSO-d ₆)δ8.23(dd，1H，J＝7.2，2.2Hz)，7.57(dd，1H，J＝6.6，1.7Hz)，7.32-7.34(m，2H)，7.17(t，2H，J＝8.8Hz)，6.32(t，1H，J＝7.1Hz)，3.89(s，3H)；MS(ESI ⁺)m/z?248.2(M+H) ⁺。

B) 1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-formic acid

At room temperature, with 1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate (rough 2.45g, 12mmol) and 6N aqueous sodium hydroxide solution (2.5mL) formed mixture in methyl alcohol (60mL) stirred 4 hours.At room temperature, while stirring concentrated hydrochloric acid (1mL) is added in this reaction mixture lentamente.Filter out formed throw out, cleaned and give drying, obtain being the desired acid product (2.1g) of yellow solid with a spot of water.In a vacuum, filtrate is concentrated.Resulting residue is mixed with water (50mL) and (2 * 130mL) are cleaned with ethyl acetate.Ethyl acetate layer through dried over mgso, and is concentrated in a vacuum.Grind the residue of gained with a spot of ether, and obtain second batch of product (195mg, 2.30g altogether, 82%). ¹H?NMR(DMSO-d ₆)δ8.47(dd，1H，J＝7.2，2.2Hz)，8.19(dd，1H，J＝6.6，1.7Hz)，7.62-7.60(m，2H)，7.42(t，2H，J＝8.8Hz)，6.78(t，1H，J＝7.1Hz)；MS(ESI ⁺)m/z?234.2(M+H) ⁺。

C) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2--dihydropyridine-3-methane amide, trifluoroacetate

At room temperature, with 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base-3-fluoroaniline (70mg, 0.29mmol, the compd B of embodiment 132) is added into 1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-formic acid (70mg, 0.30mmol), (200mg is 1.04mmol) in the formed solution of DMF (8mL) for HOBT (30mg) and EDCIHCl.At room temperature, this mixture is stirred a whole night, and concentrate in a vacuum.Utilize preparation HPLC,, obtain being the beige solid and want product (71mg, 43%) resulting residue purifying. ¹H?NMR(DMSO-d ₆)δ12.04(br?s，1H)，11.96(br?s，1H)，8.52(dd，1H，J＝7.2，2.2Hz)，8.08(t，2H，J＝5.5Hz)，7.96(dd，1H，J＝12.7，2.2Hz)，7.55-7.53(m，2H)，7.84(t，1H，J＝8.3Hz)，7.43(dd，1H，J＝8.8，1.7Hz)，7.38-7.32(m，3H)，6.67(t，1H，J＝7.2Hz)，6.43(d，1H，J＝6.1Hz)，6.46(dd，1H，J＝3.3，1.4Hz)；MS(ESI ⁺)m/z?459.1(M+H) ⁺。

Embodiment 243

1-oxygen base-6-phenyl-pyridine-2-carboxylic acids [3-fluoro-4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides, trifluoroacetate

A) 6-phenyl 2-pyridine carboxylic acid

With argon gas clean 6-bromine 2-pyridine carboxylic acid (2.02g, 10mmol), phenyl-boron dihydroxide (1.22g, 10mmol), cesium carbonate (5.00g) and PdCl ₂[(t-Bu) ₂P (OH)] ₂(Inc.Princeton is NJ) in DMF (20mL) and the formed mixture of water (3mL), and under 110 ℃, with this mixture heating up 24 hours for 70mg, CombiPhos Catalysts.This reaction is carried out not exclusively and is no longer further carried out.The ethyl acetate (200mL) and the 1N HCl aqueous solution (40mL) are added in this reaction mixture.Isolate ethyl acetate layer and clean water layer with ethyl acetate (150mL).The ethyl acetate layer that merges through dried over sodium sulfate, and is concentrated in a vacuum.Utilize preparation HPLC, with resulting residue purifying, the desired product of solid (350mg, 18%) obtains being white in color. ¹H?NMR(CDCl ₃)δ10.45(s，1H)，8.18-7.96(m，5H)，7.51-7.53(m，3H)。

B) 6-phenyl 2-pyridine carboxylic acid N-oxide compound

Under 60 ℃, with 6-phenyl 2-pyridine carboxylic acid (150mg, 0.75mmol), K ₂HPO ₄(600mg), m-CPBA (300mg, maximum 70%, Aldrich) formed mixture heating up 1.5 hours in ethylene dichloride (8.0mL).Add other m-CPBA (2 * 300mg), and under 60 ℃, mixture was heated 40 minutes.Utilize preparation HPLC, with this reaction mixture purifying, the solid that obtains being white in color is wanted product (110mg, 68%). ¹H?NMR(DMF-d ₇)δ8.57(s，1H)，8.43(d，1H，J＝2.2Hz)，8.10-7.88(m，5H)，7.59-7.57(m，3H)。

C) 1-oxygen base-6-phenyl-pyridine-2-carboxylic acids [3-fluoro-4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides, trifluoroacetate

At room temperature, with 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (40mg, 0.16mmol, the compd B of embodiment 132) is added into 6-phenyl 2-pyridine carboxylic acid N-oxide compound (25mg, 0.12mmol), (120mg is 1.14mmol) in the formed solution of DMF (3.5mL) for HOBT (20mg) and EDCIHCl.At room temperature, this reaction mixture is stirred a whole night, and concentrate in a vacuum.Utilize preparation HPLC, with resulting residue purifying, the solid that obtains being white in color is wanted product (36mg, 54%). ¹H?NMR(DMF-d ₇)δ14.12(br?s，1H)，12.10(br?s，1H)，8.48(dd，1H，J＝7.9，1.6Hz)，8.24(d，1H，J＝5.5Hz)，8.18(dd，1H，J＝14.8，2.2Hz)，7.95-7.89(m，3H)，7.83(t，1H，J＝7.7Hz)，7.67(dd，1H，J＝8.6，1.2Hz)，7.61-7.51(m，5H)，6.60(d，1H，J＝5.5Hz)，6.44(d，1H，J＝3.3Hz)；MS(ESI ⁺)m/z?441.1(M+H) ⁺。

Embodiment 244

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-6-phenylpyridine acid amides, trifluoroacetate

At room temperature, with 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (65mg, 0.26mmol, the compd B of embodiment 132) is added into 6-phenyl 2-pyridine carboxylic acid (48mg, 0.24mmol, the compd A of embodiment 243), (155mg is 0.81mmol) in the formed solution of DMF (3.5mL) for HOBT (25mg) and EDCIHCl.At room temperature, this mixture is stirred a whole night, and concentrate in a vacuum.Utilize preparation HPLC,, obtain being the light brown solid and want product (25mg, 19%) resulting residue purifying. ¹H?NMR(DMF-d ₇)δ11.93(br?s，1H)，11.01(br?s，1H)，8.36(dd，2H，J＝7.2，1.6Hz)，8.31-8.17(m，5H)，7.59-7.50(m，6H)，6.53(d，1H，J＝5.5Hz)，6.41(d，1H，J＝2.8Hz)；MS(ESI ⁺)m/z?425.1(M+H) ⁺。

Embodiment 245

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-ketone group-1-phenyl-1,2-dihydropyridine-3-methane amide, trifluoroacetate

At room temperature, with 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (31mg, 0.13mmol, the compd B of embodiment 132) is added into 2-ketone group-1-phenyl-1,2-dihydropyridine-3-formic acid (30mg, 0.14mmol, according to making with mode like the steps A of embodiment 242 and the category-B), (80mg is 0.42mmol) in the formed solution of DMF (3.5mL) for HOBT (20mg) and EDCIHCl.At room temperature, this reaction mixture is stirred a whole night, and concentrate in a vacuum.Utilize preparation HPLC,, obtain being the desired product of beige solid (10mg, 14%) resulting residue purifying. ¹H NMR (acetone-d ₆) δ 13.40 (br s, 1H), 12.32 (br s, 1H), 8.66 (dd, 1H, J=7.1,1.6Hz), 8.43 (d, 1H, J=6.6Hz), 8.18 (dd, 1H, J=13.2,2.2Hz), 8.03 (dd, 1H, J=6.6,2.2Hz), 7.67-7.49 (m, 8H), 6.89 (d, 1H, J=6.6Hz), 6.75 (t, 1H, J=6.3Hz), 6.58 (d, 1H, J=3.3Hz); MS (ESI ⁺) m/z 441.1 (M+H) ⁺

Embodiment 246

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-ketone group-5-phenyl-1,2-dihydropyridine-3-methane amide, trifluoroacetate

A) 2-ketone group-5-phenyl-1,2-dihydropyridine-3-formic acid

Clean 5-bromo-2-hydroxy niacin (436mg, 2.00mmol, Syn.Comm., 19 (3﹠amp with argon gas; 4), 553-559 (1989)), phenyl-boron dihydroxide (248mg, 2.03mmol), Cs ₂CO ₃(1.20g) and PdCl ₂[(t-Bu) ₂P (OH)] ₂(Inc.Princeton NJ) in DMF (10mL) and the formed mixture of water (1.0mL), and under 110 ℃, was heated 6 hours for 170mg, CombiPhos Catalysts.Add other phenyl-boron dihydroxide (75mg), and under 110 ℃, with this mixture heating up 5 hours.TFA (3mL) is added in this reactant, and in a vacuum, this mixture is concentrated into～volume of 12mL.Utilize preparation HPLC,, obtain desired product (78mg, 18%) this purifying mixture. ¹H?NMR(DMF-d ₇)δ14.8(br?s，1H)，13.8(br?s，1H)，8.73(s，1H)，8.46(s，1H)，7.74(d，1H，J＝7.2Hz)，7.53-7.42(m，3H)，5.81(s，1H)。

B) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-ketone group-5-phenyl-1,2-dihydropyridine-3-methane amide

At room temperature, with 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (30mg, 0.12mmol, the compd B of embodiment 132) is added into 2-ketone group-5-phenyl-1,2-dihydropyridine-3-formic acid (35mg, 0.16mmol), (80mg is 0.42mmol) in the formed solution of DMF (3.0mL) for HOBT (25mg) and EDCIHCl.At room temperature, this mixture is stirred a whole night, and concentrate in a vacuum.Utilize preparation HPLC,, obtain being the light brown solid and want product (12mg, 13%) resulting residue purifying. ¹H?NMR(CD ₃OD)δ8.81(d，1H，J＝2.8Hz)，8.17(d，1H，J＝6.6Hz)，8.00(dd，1H，J＝12.6，2.2Hz)，7.94(d，1H，J＝3.3Hz)，7.52-7.27(m，7H)，6.80(d，1H，J＝9.3Hz)，6.72(d，1H，J＝6.6Hz)，6.54(d，1H，J＝3.8Hz)；MS(ESI ⁺)m/z?441.1(M+H) ⁺。

Embodiment 247

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-5-benzyl-4-ketone group-1,4-dihydropyridine-3-methane amide, trifluoroacetate

At room temperature, successively with EDCIHCl (80mg, 0.42mmol) and 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (35mg, 0.16mmol, the compd B of embodiment 132) be added into 5-benzyl-4-ketone group-1,4-dihydropyridine-3-formic acid (35mg, 0.15mmol) and HOBt (30mg) in the formed solution of DMF (2.5mL).At room temperature, this reaction mixture was stirred 40 hours, and concentrate in a vacuum.Utilize preparation HPLC, with resulting residue purifying, the solid that obtains being white in color is wanted product (38mg, 45%). ¹H?NMR(DMSO-d ₆)δ13.21(br?s，1H)，12.38(s，1H)，12.08(br?s，1H)，8.59(d，1H，J＝4.4Hz)，8.17(d，1H，J＝5.5Hz)，8.03(dd，1H，J＝13.2，2.2Hz)，7.80(d，1H，J＝3.9Hz)，7.48-7.19(m，8H)，6.52(d，1H，J＝5.5Hz)，6.34(d，1H，J＝1.6Hz)，3.81(s，2H)；MS(ESI ⁺)m/z?455.1(M+H) ⁺。

Embodiment 248

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-ketone group-1-(pyridin-3-yl)-1,2-dihydropyridine-3-methane amide, trifluoroacetate

A) 2-ketone group-1-(pyridin-3-yl)-1,2-dihydropyridine-3-methyl-formiate

At room temperature, (282mg, (462mg, 3mmol is Aldrich) in the formed solution of DMF (6mL) 3mmol) to be added into 2-ketone group-2H-pyrans-3-methyl-formiate with the 3-aminopyridine.At room temperature, this reaction mixture is stirred a whole night, with EDCIHCl (650mg, 3.4mmol) and DMAP (200mg) handled, continue to stir 24 hours, and concentrate in a vacuum.Utilize preparation HPLC with resultant residue purifying, obtain being the beige solid and want product (980mg, 95%). ¹H?NMR(CDCl ₃)δ13.00(br?s，1H)，8.83(br?s，1H)，8.74(br?s，1H)，8.29(dd，1H，J＝7.2，1.7Hz)，8.18(d，1H，J＝8.3Hz)，7.73(dd，1H，J＝7.7，5.0Hz)，7.66(dd，1H，J＝6.6，1.6Hz)，6.42(t，1H，J＝7.1Hz)，3.87(s，3H)。

B) 2-ketone group-1-(pyridin-3-yl)-1,2-dihydropyridine-3-formic acid

At room temperature, with 2-ketone group-1-(pyridin-3-yl)-1,2-dihydropyridine-3-methyl-formiate (980mg, 2.85mmol) and the formed mixture of 6N sodium hydroxide (1mL) and methyl alcohol (20mL) stir a whole night.The 1N HCl aqueous solution (6mL) is added in this reaction mixture, and concentrates in a vacuum, obtain being the acid that contains small amount of sodium chloride (1.0g, 100%) of light yellow solid.This material can be directly used in next procedure, need not to be further purified. ¹H?NMR(CD ₃OD)δ8.85(d，1H，J＝1.7Hz)，8.77(d，1H，J＝4.9Hz)，8.59(dd，1H，J＝7.1，1.7Hz)， 8.21(d，1H，J＝8.2Hz)，8.10(dd，1H，J＝6.6，2.2Hz)，7.79(dd，1H，J＝8.2，5.0Hz)，6.80(t，1H，J＝6.6Hz)；MS(ESI ⁺)m/z?217.2(M+H) ⁺。

C) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-ketone group-1-(pyridin-3-yl)-1,2-dihydropyridine-3-methane amide, trifluoroacetate

At room temperature, successively with EDCIHCl (24.5mg, 0.13mmol) and 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (24mg, 0.10mmol, the compd B of embodiment 132) be added into 2-ketone group-1-(pyridin-3-yl)-1,2-dihydropyridine-3-formic acid (22mg, 0.10mmol) and HOBt (5mg) in the formed solution of DMF (3mL).At room temperature, this reaction mixture is stirred a whole night, and concentrate in a vacuum.Utilize preparation HPLC,, obtain being the beige solid and want product (25mg, 45%) resulting residue purifying. ¹H?NMR(DMF-d ₇)δ12.26(br?s，1H)，12.18(s，1H)，8.90(d，1H，J＝2.2Hz)，8.78(d，1H，J＝3.9Hz)，8.71(dd，1H，J＝7.1，2.2Hz)，8.28-8.15(m，4H)，7.72-7.48(m，4H)，6.87(t，1H，J＝7.2Hz)，6.64(d，1H，J＝5.5Hz)，6.47(br?s，1H)；MS(ESI ⁺)m/z?442.2(M+H) ⁺。

Embodiment 249

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-ketone group-1-(pyridine-2-yl)-1,2-dihydropyridine-3-methane amide, trifluoroacetate

A) 2-ketone group-1-(pyridine-2-yl)-1,2-dihydropyridine-3-methyl-formiate

At room temperature, (282mg, (462mg, 3mmol is Aldrich) in the formed solution of DMF (6mL) 3mmol) to be added into 2-ketone group-2H-pyrans-3-methyl-formiate with the 3-aminopyridine.At room temperature, this reaction mixture was stirred 12 hours, and with EDCIHCl (650mg, 3.4mmol) and DMAP (200mg) handled.At room temperature, this reaction mixture was stirred 2.5 days, and in a vacuum, remove most DMF.Utilize preparation HPLC,, obtain being the desired product (500mg, 72%) of glassy mass resulting residue purifying. ¹H?NMR(CDCl ₃)δ8.53(d，1H，J＝5.0Hz)，8.20(dd，1H，J＝9.2，2.2Hz)，8.06(dd，1H，J＝6.0，1.1Hz)，7.89-7.82(m，2H)，7.32(dd，1H，J＝6.6，5.0Hz)，6.36(t，1H，J＝6.6Hz)，3.86(s，3H)；MS(ESI ⁺)m/z?231.2(M+H) ⁺。

B) 2-ketone group-1-(pyridine-2-yl)-1,2-dihydropyridine-3-formic acid

At room temperature, with 2-ketone group-1-(pyridine-2-yl)-1,2-dihydropyridine-3-methyl-formiate (500mg, 2.17mmol) and the formed mixture of 3N sodium hydroxide (1ml) and methyl alcohol (10mL) stir a whole night.Be added into TFA (0.5mL) in this reactant and concentrated in a vacuum.In resulting residue water-soluble (3mL) and Virahol (10mL).Filter out formed solid, cleaned, and give drying, the solid acid that obtains being white in color (260mg, 55%) with a spot of water and Virahol. ¹HNMR(DMF-d ₇)δ14.14(brs，1H)，8.72(d，1H，J＝4.9Hz)，8.62(dd，1H，J＝7.7，2.2Hz)，8.47(dd，1H，J＝6.6，2.2Hz)，8.18-7.98(m，2H)，7.67(dd，1H，J＝7.2，5.3Hz)，6.97(t，1H，J＝6.6Hz)；MS(ESI ⁺)m/z?217.2(M+H) ⁺。

C) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-ketone group-1-(pyridine-2-yl)-1,2-dihydropyridine-3-methane amide, trifluoroacetate

At room temperature, successively with EDCIHCl (250mg, 1.30mmol) and 4-(the 1H-pyrrolo-[2 in DMF (4mL), 3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (226mg, 0.93mmol, the compd B of embodiment 132) be added into 2-ketone group-1-(pyridine-2-yl)-1,2-dihydropyridine-3-formic acid (200mg, 0.93mmol) and HOBt (100mg) in the formed solution of DMF (5mL).At room temperature, this reaction mixture is stirred a whole night, and concentrate in a vacuum.Utilize preparation HPLC with resulting residue purifying, the solid that obtains being white in color is wanted product (290mg, 56%). ¹HNMR(DMF-d ₇)δ12.16(br?s，1H)，12.15(brs，1H)，11.99(br?s，1H)，8.77-8.55(m，2H)，8.39-8.35(m，1H)，8.22-8.15(m，4H)，7.72-7.47(m，3H)，6.87(t，1H，J＝7.2Hz)，6.55(t，1H，J＝5.5Hz)，6.42(d，1H，J＝2.3Hz)；MS(ESI ⁺)m/z442.1(M+H) ⁺。

Embodiment 250

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-luorobenzyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, hydrogen chlorate

A) 1-(4-luorobenzyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate

At room temperature, with 2-ketone group-2H-pyrans-3-methyl-formiate (2.0g, 13mmol, 1.0 equivalents, Aldrich) and 4-flunamine (1.5mL, 13mmol, 1.0 equivalents) stirred 3 hours in the formed heterogeneous mixture of DMF (10mL).At room temperature, handle this reaction mixture with EDCI (3.4g, 18mmol, 1.4 equivalents) and DMAP (0.11g, 9.91mmol, 0.07 equivalent), and with the solution stirring of gained 12 hours.Make this reaction mixture cancellation reaction with the 1N HCl aqueous solution, and (4 * 50mL) extract this solution with ethyl acetate.(3 * 70mL) clean the organic extract liquid that merges, and are filtered and in a vacuum filtrate are concentrated, and obtain being solid product (2.5g, 73%), and it need not to be further purified, and can use with the 10% lithium chloride aqueous solution. ¹H NMR (DMSO-d ₆) δ 8.17-8.20 (m, 1H), 8.03-8.05 (m, 1H), 7.38-7.46 (m, 2H), 7.16-7.22 (m, 2H), 6.37 (dd, 1H, J=6.94Hz), 5.13 (s, 2H), 3.73 (s, 3H); HRMS (ESI): theoretical value, 262.0879; Measured value, 262.0885.

B) 1-(4-luorobenzyl)-2-ketone group-1,2-dihydropyridine-3-formic acid

At room temperature, with 5N aqueous sodium hydroxide solution (4.6mL, 24mmol, 2.6 equivalent) handle 1-(4-luorobenzyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate (2.4g, 9.2mmol, 1.0 formed solution in methyl alcohol (25mL) equivalent), and with this reaction mixture stirring 15 hours.In a vacuum this reaction mixture is concentrated, water is diluted, and with this solution of ethyl acetate extraction (organic moiety is abandoned).To contain water section and be cooled to 0 ℃, and give acidifying with concentrated hydrochloric acid.Filter out resulting solid, water is cleaned and in a vacuum with this solid drying, is obtained desired product (1.6g, 70%), and its purity is enough to be directly used in next procedure, need not to be further purified. ¹HNMR (DMSO-d ₆) δ 8.44-8.39 (m, 2H), 7.46-7.42 (m, 2H), 7.24-7.18 (m, 2H), 6.78 (d, 1H, J=6.98Hz), 5.31 (s, 2H); HRMS (ESI): theoretical value, 248.0723; Measured value, 248.0718.

C) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-luorobenzyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, hydrogen chlorate

At room temperature, with DIPEA (0.11mL, 0.62mmol, 3.0 equivalent) handle 1-(4-luorobenzyl)-2-ketone group-1,2-dihydropyridine-3-formic acid (0.051g, 0.21mmol, 1.0 equivalents), 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (0.50g, 0.21mmol, 1.0 equivalents, the compd B of embodiment 132) and TBTU (0.086g, 0.23mmol, 1.1 equivalents) and in the formed homogeneous solution of DMF (1mL).This reaction mixture was stirred 12 hours, and react with the 10% lithium chloride aqueous solution (15mL) cancellation.With the ethyl acetate (solution of 4 * 40mL) extraction gained.(4 * 50mL) clean the organic extract liquid that merges, and it through dried over sodium sulfate, is filtered and in a vacuum filtrate is concentrated with the 10% lithium chloride aqueous solution.Utilize flash chromatography method (SiO ₂, with 0-2.5% methyl alcohol/chloroform wash-out), with resulting residue purifying, and isolate suitable level part, concentrated in a vacuum.This free alkali is dissolved among the THF, is cooled to 0 ℃, and with in the anhydrous 4N HCl (Yu diox) handle this homogeneous solution.This reaction mixture is warmed to room temperature, concentrates in a vacuum and grind resulting residue with ether.In a vacuum, with this solid drying, obtain being the title compound (0.062g, 59%) of hydrogen chlorate's form. ¹H NMR (DMSO-d ₆) δ 12.43 (s, 1H), 12.27 (s, 1H), 8.50-8.52 (m, 1H), and 8.35-8.37 (m, 1H), 8.25-8.27 (m, 1H), 8.05-8.08 (m, 1H), 7.43-7.55 (m, 5H), 7.20-7.24 (m, 2H), 6.71 (t, 1H, J=6.89Hz), 6.65 (d, 1H, J=6.03Hz), 6.43 (s, 1H), 5.32 (s, 2H); HRMS (ESI ⁺): theoretical value-473.1425; Measured value-473.1427.

Embodiment 251

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-N-(4-luorobenzyl) cyclopropane-1,1-diformamide, trifluoroacetate

A) 1-((4-luorobenzyl) formamyl) cyclopropane-carboxylic acid

(0.418mL 3.0mmol) is added into 1, and (390mg, 3.0mmol is Aldrich) in the formed solution of 0 ℃ of THF (5mL) for the 1-cyclopropane-carboxylic acid with triethylamine.Under 0 ℃, this mixture was stirred 30 minutes, and (0.219mL, 3.0mmol Aldrich) are handled with thionyl chloride.Then, under 0 ℃, with this reaction mixture restir 30 minutes, and (375mg, 3.0mmol was Aldrich) in the formed solution of 2mL THF to add the 4-flunamine.Under 0 ℃, this reaction mixture was stirred 2 hours, diluted with the 100mL ethyl acetate, and extracted with 1N sodium hydroxide (10mL).Use 1N HCl, with aqueous phase as acidified to pH1-2.Utilize filtration method to collect formed solid (343mg, 48%).MS(ESI ⁺)m/z?238.2(M+H) ⁺。

B) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-N-(4-luorobenzyl) cyclopropane-1,1-diformamide, trifluoroacetate

At room temperature; with HATU (57mg; 0.15mmol; Perseptive Biosystem) and DIEA (0.05mL, 0.3mmol Aldrich) are added into 4-(1H-pyrrolo-[2; 3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (45mg; 0.1mmol, the compd B of embodiment 132) and 1-((4-luorobenzyl) formamyl) cyclopropane-carboxylic acid (24mg is 0.1mmol) in the formed solution of DMF (0.5mL).At room temperature, this reaction mixture was stirred 2 hours, then, by adding 2mL methyl alcohol, the cancellation reaction.Utilize preparation HPLC, with this reaction mixture purifying.With part merging of desired level, concentrate and give lyophilize down to dried in decompression, the desired product of solid that obtains being white in color (39mg, 67%). ¹H?NMR(DMSO-d ₆)δ11.99(brs，1H)，10.81(s，1H)，8.46(t，1H，J＝5.8Hz)，8.13(d，1H，J＝6.1Hz)，7.86(dd，1H，J＝13.2，2.2Hz)，7.41-7.46(m，2H)，7.37(t，1H，J＝9.1Hz)，7.28-7.32(m，2H)，7.13(t，3H，J＝9.1Hz)，6.44(d，1H，J＝6.1Hz)，6.30(s，1H)，4.30(d，2H，J＝5.5Hz)，1.39(d，4H，J＝2.2Hz)；MS(ESI ⁺)m/z?463.1(M+H) ⁺。

Embodiment 252

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1, the 1-diformamide

A) 1-((4-fluorophenyl) formamyl) cyclopropane-carboxylic acid

Under 0 ℃, (0.418mL 3.0mmol) is added into 1, and (390mg, 3.0mmol is Aldrich) in the formed solution of THF (5mL) for the 1-cyclopropane-carboxylic acid with triethylamine.Under 0 ℃, this reaction mixture was stirred 30 minutes, and (0.219mL, 3.0mmol Aldrich) are handled with thionyl chloride.Under 0 ℃, this reaction mixture was stirred 30 minutes again, and (333mg, 3.0mmol Aldrich) are handled in the formed solution of 2mL THF with the 4-fluoroaniline.Under 0 ℃, this reaction mixture was stirred 2 hours, then, diluted and extracted with 1N sodium hydroxide (10mL) with the 100mL ethyl acetate.Use 1N HCl, with aqueous phase as acidified to pH1-2.Utilize filtration method, collect formed solid (508mg, 76%).MS(ESI ⁺)m/z?224.2(M+H) ⁺。

B) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1, the 1-diformamide

According to mode like the step category-B of embodiment 251, preparation and get (41mg, 73%). ¹HNMR(DMSO-d ₆)δ11.97(br?s，1H)，10.35(s，1H)，9.99(s，1H)，8.12(d，1H，J＝5.5Hz)，7.85(d，1H，J＝13.2Hz)，7.62(m，2H)，7.43(m，2H)，7.36(t，1H，J＝9.4Hz)，7.14(t，2H，J＝9.1Hz)，6.43(d，1H，J＝5.5Hz)，6.29(s，1H)，1.46(d，4H，J＝2.8Hz)；MS(ESI ⁺)m/z?449.1(M+H) ⁺。

Embodiment 253

N-(4-(3-(thiazolamine-4-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

A) 2-bromo-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethyl ketone

At room temperature, aluminum chloride (2.43g, 18.3mmol, Alfa Aesar) is added into 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridine (1.00g, 3.66mmol, the compd A of embodiment 132) in the formed solution of DCE (100mL).At room temperature, this reaction mixture was stirred 1 hour, then, (7.32mmol Aldrich) is handled with the bromo Acetyl Chloride 98Min..Then, at room temperature, this reaction mixture was stirred 2 hours, and by adding 100mL ethyl acetate, 30mL methyl alcohol and the saturated K of 30mL ₂HPO ₄The aqueous solution, the cancellation reaction.This mixture is passed through Celite ^Pad filters.Clean organic layer with salt solution, give drying (sal epsom), and in a vacuum, concentrated.Utilize flash chromatography method (SiO ₂, with 2-5% methyl alcohol (in methylene dichloride) wash-out), with resulting residue purifying, obtain being the product of wanting (1.12g, 78%) of light yellow solid.MS(ESI ⁺)m/z393.9(M+H) ⁺。

B) 4-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) thiazole-2-amine

((392mg is 1.0mmol) in the formed solution of acetate (10mL) Aldrich) to be added into 2-bromo-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethyl ketone for 228mg, 3.0mmol with thiocarbamide.At room temperature, this reaction mixture was stirred 3 hours, then, diluted with the 50mL ethyl acetate.Clean this reaction mixture with saturated sodium bicarbonate aqueous solution and salt solution.Organic layer through dried over mgso and concentrate in a vacuum, is obtained light yellow solid.This solid is dissolved in mixed solvent (20mL THF and 40mL methyl alcohol).Then, with ammonium chloride (267mg, 5.0mmol, EMD) and zinc powder (327mg, 5.0mmol Aldrich) are added in the solution of gained.At room temperature, this reaction mixture is stirred a whole night, diluted with the 100mL ethyl acetate, and it is passed through Celite ^Pad filters.In a vacuum, filtrate is concentrated, and with preparing HPLC with resulting residue purifying.With part merging of desired level, neutralized with saturated sodium bicarbonate aqueous solution, and concentrated down in decompression.Utilize filtration method, collect the solid generated (194mg, two steps totally 57%).MS(ESI ⁺)m/z?342.2(M+H) ⁺。

C) N-(4-(3-(thiazolamine-4-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step C of embodiment 242, preparation and get (5.6mg, 12%). ¹HNMR(CD ₃OD)δ8.60(dd，1H，J＝5.5，1.7Hz)，8.08(d，1H，J＝5.5Hz)，7.90-7.88(m，2H)，7.67(s，1H)，7.45-7.42(m，2H)，7.29(d，1H，J＝5.5Hz)，7.25-7.18(m，4H)，6.65(t，1H，J＝7.4Hz)，6.43(d，1H，J＝6.1Hz)；MS(ESI ⁺)m/z?557.1(M+H) ⁺。

Embodiment 254

N-(4-(3-(thiazolamine-4-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2,6-difluorobenzamide, trifluoroacetate

Under-20 ℃, with 2,6-difluoro benzoyl chloride (10.6mg, 0.06mmol, Aldrich) be added into 4-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2 in the formed solution of 0.3mL methylene dichloride, 3-b] pyridin-3-yl) thiazole-2-amine (20mg, 0.06mmol, the compd B of embodiment 253) is in the formed solution of 0.5mL pyridine.Under-20 ℃, this reaction mixture was stirred 30 minutes, then, by adding methyl alcohol (0.5mL) cancellation reaction.In a vacuum, this reaction mixture is concentrated and utilizes preparation HPLC, with resulting residue purifying.With part merging of desired level, concentrate down in decompression, and give lyophilize, the desired product of solid that obtains being white in color (tfa salt, 9.2mg, 22%). ¹HNMR(CD ₃OD)δ8.10(d，1H，J＝6.1Hz)，7.68(s，1H)，7.48-7.37(m，2H)，7.24(t，1H，J＝8.3Hz)，7.05-7.01(m，3H)，6.86(s，1H)，6.46(d，1H，J＝5.5Hz)；MS(ESI ⁺)m/z482.1(M+H) ⁺。

Embodiment 255

1-(4-(3-(2-(dimethylamino) ethanoyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 2-(dimethylamino)-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethyl ketone

Under 0 ℃, with the dimethylamine (solution in THF of 1.0M, 0.72mL, 0.72mmol) be added into 2-bromo-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethyl ketone (96mg, 0.24mmol, the compd A of embodiment 253) and in the formed solution of THF (5mL).Under 0 ℃, this reaction mixture was stirred 1 hour, and in decompression down, concentrated, obtain being the desired product (80mg, 93%) of light yellow solid, cleaned and given air-dry with cold water.MS(ESI ⁺)?m/z?359.2(M+H) ⁺。

B) 1-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl)-2-(dimethylamino) ethyl ketone

With ammonium chloride (64.2g, 1.2mmol, EMD) and zinc powder (78.4mg, 1.2mmol, Aldrich) be added into 2-(dimethylamino)-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) (80mg is 0.22mmol) in the formed solution of mixed solvent (5mL THF and 5mL methyl alcohol) for ethyl ketone.At room temperature, this reaction mixture is stirred a whole night, diluted with the 30mL ethyl acetate, and it is passed through Celite ^Pad filters.In a vacuum filtrate is concentrated, and utilize preparation HPLC, with resulting residue purifying.With part merging of desired level, neutralized with saturated sodium bicarbonate aqueous solution, and concentrated in a vacuum.Utilize filtration method, collect formed solid (51mg, 71%).MS(ESI ⁺)m/z?328.1(M+H) ⁺。

C) 1-(4-(3-(2-(dimethylamino) ethanoyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to the similar mode of the step C of embodiment 132, preparation and get (5.7mg, 11%). ¹HNMR(CD ₃OD)δ10.67(s，1H)，8.27(s，1H)，8.08(d，1H，J＝6.1Hz)，7.65(d，1H，J＝12.6Hz)，7.24-7.16(m，4H)，6.96(t，2H，J＝8.8Hz)，6.45(d，1H，J＝5.5Hz)，4.74(s，2H)，3.60(s，2H)，2.86(s，6H)；MS(ESI ⁺)m/z?508.2(M+H) ⁺。

Embodiment 256

2,6-two fluoro-N-(3-fluoro-4-(3-(2-(3-hydroxyl pyrrolidine-1-yl) ethanoyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl) benzamide

According to embodiment 254 similar modes, the preparation and get. ¹H?NMR(CD ₃OD)δ8.29(d，1H，J＝6.6Hz)，8.13(d，1H，J＝5.5Hz)，7.80(dd，1H，J＝12.7，2.2Hz)，7.46-7.38(m，2H)，7.23(t，1H，J＝9.1Hz)，7.03(t，2H，J＝8.3Hz)，6.53(d，1H，J＝5.5Hz)，5.01-4.86(m，2H)，4.49-4.46(m，1H)，3.77-3.64(m，2H)，3.35-3.06(m，2H)，2.25-1.98(m，2H)；MS(ESI ⁺)m/z511.2(M+H) ⁺。

Embodiment 257

2,6-two fluoro-N-(3-fluoro-4-(3-(2-(4-methylpiperazine-1-yl) ethanoyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl) benzamide

According to embodiment 254 similar modes, the preparation and get. ¹H?NMR(CD ₃OD)δ8.23(s，1H)，8.11(d，1H，J＝5.5Hz)，7.79(dd，1H，J＝12.1，2.2Hz)，7.46-7.34(m，2H)，7.16(t，1H，J＝8.8Hz)，7.03(t，2H，J＝8.3Hz)，6.53(d，1H，J＝6.1Hz)，4.11(s，2H)，3.21-2.92(m，8H)，2.76(s，3H)；MS(ESI ⁺)m/z?524.3(M+H) ⁺。

Embodiment 258

N-(3-fluoro-4-(3-(2-(4-methylpiperazine-1-yl) ethanoyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to embodiment 253 similar modes, the preparation and get. ¹H?NMR(CD ₃OD)δ8.59(dd，1H，J＝7.2，2.2Hz)，8.53(s，1H)，8.08(d，1H，J＝5.5Hz)，7.89-7.85(m，2H)，7.44-7.41(m，2H)，7.28-7.18(m，3H)，7.15(t，1H，J＝8.8Hz)，6.65(t，1H，J＝6.7Hz)，6.48(d，1H，J＝5.5Hz)，4.13(s，2H)，3.21-2.89(bm，8)，2.76(s，3H)；MS(ESI ⁺)m/z599.2(M+H) ⁺。

Embodiment 259

1-(3-fluoro-4-(3-(2-(4-methylpiperazine-1-yl) ethanoyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to embodiment 255 similar modes, the preparation and get. ¹H?NMR(CD ₃OD)δ8.28(s，1H)，8.12(d，1H，J＝6.1Hz)，7.66(dd，1H，J＝10.1，2.8Hz)，7.28-7.16(m，4H)，6.97-6.92(m，3H)，6.51(d，1H，J＝6.1Hz)，4.43(s，2H)，3.88(s，2H)，3.49(s，2H)，3.37-3.20(m，4H)，2.82(s，3H)；MS(ESI ⁺)m/z563.2(M+H) ⁺。

Embodiment 260

1-(3-fluoro-4-(3-(2-(3-hydroxyl pyrrolidine-1-yl) ethanoyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to embodiment 255 similar modes, the preparation and get. ¹H?NMR(CD ₃OD)δ10.69(s，1H)，8.27(d，1H，J＝8.8Hz)，8.09(d，1H，J＝5.5Hz)，7.66(d，1H，J＝12.7Hz)，7.27-7.16(m，4H)，6.98(t，2H，J＝8.8Hz)，6.47(d，1H，J＝5.5Hz)，4.99(m，1H)，4.49-4.44(m，2H)，3.90-3.68(m，2H)，3.62(s，2H)，3.37-3.09(m，2H)，2.15-1.92(m，2H)；MS(ESI ⁺)m/z?550.1(M+H) ⁺。

Embodiment 261

2-fluoro-N-(3-fluoro-4-(3-(pyridin-4-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-6-methoxy benzamide

A) 4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine

With sodium hydride (271mg, 6.77mmol, 60%, in mineral oil, Aldrich) be added into 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridine (1.68g, 6.15mmol, the compd A of embodiment 132) and in formed-40 ℃ solution of 20mL DMF.Under 0 ℃, this reaction mixture was stirred 30 minutes, be cooled to-40 ℃, and (1.20mL, 6.77mmol are handled Aldrich) with 2-(trimethyl silyl) ethoxyl methyl chlorine.At room temperature, reaction mixture was stirred 1 hour, react by adding cold water (40mL) cancellation, and (3 * 100mL) extract with ethyl acetate.The organic extract liquid that merges through dried over mgso, and is concentrated in a vacuum, obtain being the desired product (2.40g, 97%) of brown solid.MS(ESI ⁺)m/z?404.2(M+H) ⁺。

B) 3-bromo-4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine

With NBS (1.01g, 5.69mmol, Aldrich) be added into 4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2 in the formed solution of 10mL acetonitrile, 3-b] (2.40g is 5.96mmol) in the formed 0 ℃ of solution of 20mL acetonitrile for pyridine.Under 0 ℃, this reaction mixture was stirred 30 minutes, react by adding cold water (50mL) cancellation, and (3 * 120mL) extract with ethyl acetate.The organic extract liquid that merges through dried over mgso, and is concentrated in a vacuum.Utilize flash chromatography method (SiO ₂, use the methylene dichloride wash-out), with resulting residue purifying, and obtain being the desired product (2.70g, 94%) of light yellow oil.MS(ESI ⁺)m/z482.9(M+H) ⁺。

C) 4-(2-fluoro-4-nitrophenoxy)-3-(pyridin-4-yl)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine

With 3-bromo-4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine (480mg, 1.0mmol) solution, pyridine 4-ylboronic acid (246mg in toluene (5mL), 2.0mmol, Lancaster), 0.5mL ethanol and potassiumphosphate (1.0mL, 2M solution, 2.0mmol) pack into the sealing test tube in.Argon gas was fed this mixture 15 minutes, and (58mg, 0.05mmol are handled Strem) with four (triphenylphosphine) Pd (0).With the sealing of this test tube, and in 95 ℃ of following heated mixt 18 hours and stir intensely simultaneously.Then, this reaction mixture is cooled to room temperature, and is diluted with ethyl acetate.Clean this mixture with saturated sodium bicarbonate aqueous solution and salt solution, give drying (sal epsom), and concentrate in a vacuum.Utilize flash chromatography method (SiO ₂, with 2% methyl alcohol (in methylene dichloride) wash-out), with resulting residue purifying, obtain being the desired product (237mg, 49%) of brown dense thick oily matter.MS(ESI ⁺)m/z?481.1(M+H) ⁺。

D) 3-fluoro-4-(3-(pyridin-4-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) aniline

With ammonium chloride (131mg, 2.49mmol, EMC) and zinc powder (163mg, 2.49mmol, Aldrich) be added into 4-(2-fluoro-4-nitrophenoxy)-3-(pyridin-4-yl)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] (237mg is 0.49mmol) in the formed solution of mixed solvent (8mL methyl alcohol and 4mL THF) for pyridine.At room temperature, this reaction mixture was stirred 3 hours, (40mL) diluted with ethyl acetate, and it is passed through Celite ^Pad filters.In a vacuum filtrate is concentrated, obtain solid.MS(ESI ⁺)m/z?451.3(M+H) ⁺。This solid is dissolved in 15mL THF, and (in THF, Aldrich) and ethane-1, (0.4mL is handled Aldrich) the 2-diamines for 4mL, 1.0M solution with TBAF.With this reaction mixture refluxed 16 hours, then, it is cooled to room temperature, with the ethyl acetate dilution, clean with salt solution, dry and concentrate in a vacuum through sulfuric acid.Utilize flash chromatography method (SiO2, with 2-5% methyl alcohol (in methylene dichloride) wash-out),, obtain desired product (127mg, two steps totally 81%) resulting residue purifying.MS(ESI ⁺)m/z?321.2(M+H) ⁺。

E) 2-fluoro-N-(3-fluoro-4-(3-(pyridin-4-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-6-methoxy benzamide

According to embodiment 254 similar modes, preparation and get (3.2mg, 7%). ¹HNMR(DMSO-d ₆)δ12.92(s，1H)，10.80(s，1H)，8.72(d，2H，J＝7.2Hz)，8.44(s，1H)，8.31(d，2H，J＝7.2Hz)，8.16(d，2H，J＝5.5Hz)，7.94-7.86(m，1H)，7.55-7.41(m，2H)，6.97-6.91(m，1H)，6.88(t，1H，J＝8.8Hz)，6.45(d，1H，J＝5.5Hz)，3.78(s，3H)；MS(ESI ⁺)m/z?473.1(M+H) ⁺。

Embodiment 262

2-fluoro-N-(3-fluoro-4-(3-(pyridin-4-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl) benzamide

According to embodiment 261 similar modes, the preparation and get. ¹H?NMR(DMSO-d ₆)δ12.97(s，1H)，10.76(s，1H)，8.78(d，2H，J＝8.8Hz)，8.50(s，1H)，8.36(d，2H，J＝6.1Hz)，8.23(d，1H，J＝5.5Hz)，7.96(d，1H，J＝8.8Hz)，7.70-7.54(m，4H)，7.39-7.35(m，2H)，6.50(d，1H，J＝5.5Hz)；MS(ESI ⁺)m/z?443.1(M+H) ⁺。

Embodiment 263

2,6-two fluoro-N-(3-fluoro-4-(3-(pyridin-4-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl) benzamide

According to embodiment 261 similar modes, the preparation and get. ¹H?NMR(DMSO-d ₆)δ12.89(s，1H)，11.10(s，1H)，8.70(d，2H，J＝6.6Hz)，8.42(s，1H)，8.27(d，2H，J＝6.6Hz)，8.16(d，1H，J＝5.5Hz)，7.86(d，1H，J＝11.6Hz)，7.58-7.48(m，3H)，7.23(t，2H，J＝8.3Hz)，6.45(d，1H，J＝5.5Hz)；MS(ESI ⁺)m/z461.1(M+H) ⁺。

Embodiment 264

1-(4-(3-(thiazolamine-4-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, trifluoroacetate

At room temperature; with 2-(4-fluorophenyl) ethanoyl isocyanic ester in the formed solution (0.4M of toluene; 0.25mL; 0.1mmol; the Compound C of embodiment 4) is added into 4-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2; 3-b] pyridin-3-yl) thiazole-2-amine (34mg, 0.1mmol, the compd B of embodiment 253) is in the formed solution of mixed solvent (0.5mL DMF and 0.5mL THF).At room temperature, this reaction mixture was stirred 1 hour, concentrate and utilize preparation HPLC in a vacuum, the residue purifying of gained.With part merging of desired level, concentrate down in decompression, and give lyophilize, the desired product of solid that obtains being white in color (tfa salt, 21.2mg, 28%). ¹HNMR(CD ₃OD)δ10.69(s，1H)，8.08(d，1H，J＝5.5Hz)，7.68(s，1H)，7.66(d，1H，J＝12.1Hz)，7.26-7.18(m，4H)，6.98(t，2H，J＝8.8Hz)，6.84(s，1H)，6.42(d，1H，J＝6.1Hz)，3.62(s，2H)；MS(ESI ⁺)m/z?521.1(M+H) ⁺。

Embodiment 265

1-(3-fluoro-4-(3-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to embodiment 264 similar modes, the preparation and get. ¹H?NMR(DMSO-d _6-)δ12.71(s，1H)，11.04(s，1H)，10.61(s，1H)，9.18(s，1H)，8.84(d，1H，J＝8.3Hz)，8.74(d，1H，J＝5.5Hz)，8.20(d，1H，J＝5.5Hz)，8.12(s，1H)，8.06(dd，1H，J＝8.3，2.8Hz)，7.78(dd，1H，J＝12.7，2.2Hz)，7.47(t，1H，J＝8.8Hz)，7.40-7.34(m，3H)，7.16(t，2H，J＝8.8Hz)，6.41(d，1H，J＝5.5Hz)，3.75(s，2H)；MS(ESI ⁺)m/z?500.1(M+H) ⁺。

Embodiment 266

6-(4-fluoro-phenyl)-1-oxygen base-pyridine-2-carboxylic acids [3-fluoro-4-(3-pyridin-3-yl-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides

According to embodiment 24 1 similar modes, the preparation and get. ¹H?NMR(DMSO-d ₆)δ13.58(s，1H)，12.50(s，1H)，9.10(s，1H)，8.66(d，1H，J＝5.5Hz)，8.32(dd，1H，J＝8.2，2.2Hz)，8.19(d，1H，J＝5.5Hz)，8.05-8.02(m，2H)，7.89-7.85(m，5H)，7.73(t，1H，J＝7.7Hz)，7.60(d，1H，J＝8.8Hz)，7.50(t，1H，J＝8.8Hz)，7.38(t，2H，J＝8.8Hz)，6.41(d，1H，J＝6.5Hz)；MS(ESI ⁺)m/z?536.2(M+H) ⁺。

Embodiment 267

N-(3-fluoro-4-(3-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-2-ketone group-1-phenyl-1,2-dihydropyridine-3-methane amide

According to embodiment 245 similar modes, the preparation and get. ¹H?NMR(DMSO-d ₆)δ12.48(s，1H)，12.15(s，1H)，9.09(s，1H)，8.65-8.59(m，3H)，8.18(d，1H，J＝5.5Hz)，8.15(dd，1H，J＝6.6，2.2Hz)，8.04-7.99(m，2H)，7.88(m，1H)，7.59-7.46(m，7H)，6.74(t，1H，J＝7.2Hz)，6.40(d，1H，J＝5.5Hz)；MS(ESI ⁺)m/z518.1(M+H) ⁺。

Embodiment 268

N-(3-fluoro-4-(3-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl) niacinamide

According to embodiment 254 similar modes, the preparation and get. ¹H?NMR(DMSO-d ₆)δ12.65(s，1H)，10.96(s，1H)，9.22(s，1H)，9.18(s，1H)，8.84(t，2H，J＝5.0Hz)，8.74(d，1H，J＝5.5Hz)，8.49(d，1H，J＝8.3Hz)，8.21(d，1H，J＝5.5Hz)，8.11(d，1H，J＝1.7Hz)，8.08-8.01(m，2H)，7.73-7.69(m，2H)，7.54(t，1H，J＝8.8Hz)，6.43(d，1H，J＝5.5Hz)；MS(ESI ⁺)m/z?426.2(M+H) ⁺。

Embodiment 269

2,6-two fluoro-N-(3-fluoro-4-(3-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl) benzamide

According to embodiment 254 similar modes, the preparation and get. ¹H?NMR(DMSO-d ₆)δ11.23(s，1H)，9.20(d，1H，J＝1.7Hz)，8.87(d，1H，J＝8.3Hz)，8.77(d，1H，J＝5.5Hz)，8.23(d，1H，J＝5.5Hz)，8.55(s，1H)，8.08(dd，1H，J＝8.2，2.2Hz)，7.90(d，1H，J＝13.7Hz)，7.62-7.55(m，3H)，7.27(t，2H，J＝8.3Hz)，6.50(d，1H，J＝5.5Hz)；MS(ESI ⁺)m/z461.1(M+H) ⁺。

Embodiment 270

1-(3-fluoro-4-(3-(2,2,2-tribromo-acetyl base)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 1-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl)-2,2,2-trichlorine ethyl ketone

At room temperature, (1.33g, 10mmol AlfaAesar) are added into 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridine (546mg, 2.0mmol, the compd A of embodiment 132) in the formed solution of 100mL ethylene dichloride with aluminum chloride.At room temperature, this reaction mixture was stirred 30 minutes, (0.34mL 3.0mmol) is handled, and then, under 45 ℃, is stirred 5 hours with trichoroacetic chloride.After this mixture is cooled to 0 ℃, adds cold water (30mL), and use K ₂HPO ₄The aqueous solution is 7-8 with its pH regulator.Then, this mixture is passed through Celite ^Pad filters.Organic layer through dried over mgso, is concentrated in a vacuum, and with flash chromatography method (SiO ₂, with 2-7% methyl alcohol (in methylene dichloride) wash-out) and with resulting residue purifying, obtain 2,2,2-three chloro-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethyl ketone (498mg, 60%).MS(ESI ⁺)m/z?417.9(M+H) ⁺。

With ammonium chloride (53.5mg, 1.0mmol, EMC) and zinc powder ((83mg is 0.2mmol) in the formed solution of mixed solvent (3mL methyl alcohol and 2mL THF) Aldrich) to be added into aforementioned intermediate for 65.4mg, 1.0mmol.At room temperature, this reaction mixture was stirred 3 hours, (10mL) diluted with ethyl acetate, and it is filtered Celite ^Pad passes through.In a vacuum filtrate is concentrated, and obtain being the desired product of solid (78mg, 100%).MS(ESI ⁺)m/z?390.1，392.1(M+H) ⁺。

B) 1-(3-fluoro-4-(3-(2,2,2-tribromo-acetyl base)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to embodiment 264 similar modes, preparation and get (33mg, 37%). ¹HNMR(DMSO-d ₆)δ13.18(s，1H)，11.02(s，1H)，10.57(s，1H)，8.62(s，1H)，8.25(d，1H，J＝5.5Hz)，7.78(dd，1H，J＝10.5，2.2Hz)，7.38-7.35(m，3H)，7.28(t，1H，J＝9.4Hz)，7.18(t，2H，J＝8.8Hz)，6.52(d，1H，J＝5.5Hz)，3.75(s，2H)；MS(ESI ⁺)m/z567.05(M+H) ⁺。

Embodiment 271

1-(4-(3-((pyridin-3-yl methyl) formamyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

With 3-(aminomethyl) pyridine (10mg; 0.092mmol; Aldrich) ((3-(2 for 3-fluoro-4-to be added into 1-; 2; 2-tribromo-acetyl base)-1H-pyrrolo-[2; 3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea (embodiment 270 for 7.0mg, 0.012mmol) is in the formed solution of 0.5mL DMF.At room temperature, this reaction mixture was stirred 1 hour, and by adding 1mL cold water, the cancellation reaction.Utilize filtration method, collect formed throw out, cleaned with cold water (1mL) and cold acetonitrile (1mL), and dry in a vacuum, and the solid that obtains being white in color is wanted product (4.3mg, 64%). ¹H?NMR(DMSO-d ₆)δ12.38(s，1H)，11.03(s，1H)，10.57(s，1H)，8.48(s，1H)，8.40(t，1H，J＝5.5Hz)，8.34(d，1H，J＝3.3Hz)，8.11(d，1H，J＝5.5Hz)，8.00(s，1H)，7.73(d，1H，J＝13.2Hz)，7.65(d，1H，J＝7.7Hz)，7.37-7.29(m，4H)，7.16(t，3H，J＝8.8Hz)，6.34(d，1H，J＝5.5Hz)，4.48(d，2H，J＝5.5Hz)，3.74(s，2H)；MS(ESF ⁺)m/z?567.1(M+H) ⁺。

Embodiment 272

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-Ketopyrroles alkane-3-methane amide

A) 1-(4-fluorophenyl)-2-Ketopyrroles alkane-3-formic acid

With the 4-fluoroaniline (666mg, 6.0mmol Aldrich) are added into 6,6-dimethyl-5,7-dioxo spiro [2,5]-octane-4, (1.02g, 6.0mmol is Aldrich) in the formed solution of 3mL DMF for the 8-diketone.At room temperature, this reaction mixture is stirred a whole night.This reaction mixture is poured in the cold water (10mL).Utilize filtration method to collect formed precipitation, water is cleaned and in a vacuum, is given drying, obtains being the desired product of tawny solid (980mg, 73%).MS(ESI ⁺)m/z224.3(M+H) ⁺。

B) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-Ketopyrroles alkane-3-methane amide

According to mode like the step category-B of embodiment 251, preparation and get (98mg, 49%). ¹HNMR(DMSO-d ₆)δ11.76(s，1H)，10.63(s，1H)，8.06(d，1H，J＝5.5Hz)，7.86(dd，1H，J＝13.2，2.2Hz)，7.71-7.68(m，2H)，7.45-7.36(m，3H)，7.25(t，2H，J＝8.8Hz)，6.38(d，1H，J＝6.5Hz)，6.22(dd，1H，J＝3.3，2.2Hz)，3.94-3.89(m，2H)，3.77(t，1H，J＝8.5Hz)，2.49-2.33(m，2H)；MS(ESI ⁺)m/z?449.2(M+H) ⁺。

Embodiment 273

N-(3-fluoro-4-(3-(piperidines-1-ylmethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-1-(4-fluorophenyl)-2-Ketopyrroles alkane-3-methane amide, trifluoroacetate

With piperidines (8.5mg, 0.1mmol) be added into N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-the 3-fluorophenyl)-1-(4-fluorophenyl)-2-Ketopyrroles alkane-3-methane amide (22.4mg, 0.05mmol, the compd B of embodiment 272) and Paraformaldehyde 96 (2.4mg is 0.08mmol) in the formed solution of mixed solvent (1mL Virahol and 0.2mL DMF).Under 85 ℃, with this reaction mixture heating 7 hours, concentrate in a vacuum, and utilize preparation HPLC, resulting residue purifying.With desired level part lyophilize, and the solid that obtains being white in color is wanted product (tfa salt, 3.4mg, 13%). ¹H?NMR(CD ₃OD)δ8.15(d，1H，J＝5.5Hz)，7.91(dd，1H，J＝11.0，2.2Hz)，7.67-7.63(m，3H)，7.48-7.38(m，2H)，7.15(t，2H，J＝8.8Hz)，6.45(d，1H，J＝5.5Hz)，4.64(s，2H)，3.99-3.95(m，2H)，3.81(t，1H，J＝8.8Hz)，3.61-3.59(m，2H)，3.10-3.06(m，2H)，2.61-2.47(m，2H)，1.97-1.93(m，2H)，1.81-1.71(m，4H)；MS(ESI ⁺)m/z?546.2(M+H) ⁺。

Embodiment 274

N-(3-fluoro-4-(3-tetramethyleneimine-1-ylmethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-1-(4-fluorophenyl)-2-Ketopyrroles alkane-3-methane amide

According to embodiment 273 similar modes, the preparation and get. ¹H?NMR(DMSO-d ₆)δ12.13(s，1H)，10.62(s，1H)，8.04(d，1H，J＝5.5Hz)，7.84(dd，1H，J＝13.2，2.2Hz)，7.65-7.62(m，3H)，7.43-7.39(m，2H)，7.19(t，2H，J＝8.8Hz)，6.25(d，1H，J＝6.5Hz)，4.54(d，2H，J＝3.3Hz)，3.91-3.85(m，2H)，3.72(t，1H，J＝8.5Hz)，3.38-3.37(m，2H)，3.20-3.77(m，2H)，2.38-2.31(m，2H)，1.95-1.91(m，2H)，1.81-1.76(m，2H)；MS(ESI ⁺)m/z?532.2(M+H) ⁺。

Embodiment 275

N-(3-fluoro-4-(3-((4-hydroxy piperidine-1-yl) methyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-1-(4-fluorophenyl)-2-Ketopyrroles alkane-3-methane amide

According to embodiment 273 similar modes, the preparation and get. ¹H?NMR(DMSO-d ₆)δ11.71(s，1H)，10.88(s，1H)，8.00(d，1H，J＝5.5Hz)，7.79(dd，1H，J＝12.7，2.2Hz)，7.67-7.64(m，2H)，7.30-7.35(m，3H)，7.20(t，2H，J＝8.8Hz)，6.30(d，1H，J＝6.5Hz)，6.16(s，1H)，4.51(d，1H，J＝4.4Hz)，3.83-3.79(m，2H)，3.38(m，1H)，3.70-2.69(m，5H)，2.28-2.19(m，3H)，1.65-1.62(m，2H)，1.37-1.26(m，2H)；MS(ESI ⁺)m/z?562.2(M+H) ⁺。

Embodiment 276

1-(4-(3-(3-luorobenzyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 4-(3-(3-luorobenzyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline

With sodium hydroxide (40mg, 1.0mmol, EMD) and 3-fluorobenzaldehyde (62mg, 0.5mmol, Aldrich) be added into 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (49mg, 0.2mmol, the compd B of embodiment 132) and in the formed solution of 2mL methyl alcohol.At room temperature, this reaction mixture was stirred 16 hours, then, be poured in the cold water (5mL), and (3 * 30mL) are extracted with ethyl acetate.With organic extract liquid through dried over mgso and concentrate in a vacuum.Resulting residue is dissolved in the 2mL methylene dichloride, and is handled with 1mL TFA and 0.2mL triethyl silicane (Aldrich).This reaction mixture was stirred 1 hour, and concentrate down in decompression.Utilize preparation HPLC,, and, concentrated in a vacuum, neutralized with saturated sodium bicarbonate aqueous solution, and use dichloromethane extraction part merging of desired level with resulting residue purifying.Organic extract liquid through dried over mgso, and is concentrated in a vacuum, obtain desired compound (12.1mg, two steps totally 35%).MS(ESI ⁺)m/z?351.4(M+H) ⁺。

B) 1-(4-(3-(3-luorobenzyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to embodiment 264 similar modes, preparation and get (3.4mg, 11%). ¹HNMR(DMSO-d ₆)δ11.58(s，1H)，10.96(s，1H)，10.49(s，1H)，7.95(d，1H，J＝5.5Hz)，7.67(dd，1H，J＝11.6，2.1Hz)，7.31-6.67(m，12H)，6.10(d，1H，J＝5.5Hz)，4.09(s，2H)，3.68(s，2H)；MS(ESI ⁺)m/z?531.2(M+H) ⁺。

Embodiment 277

N-(4-(3-(3-luorobenzyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-Ketopyrroles alkane-3-methane amide

According to embodiment 273 similar modes, the preparation and get. ¹H?NMR(DMSO-d ₆)δ11.74(s，1H)，10.62(s，1H)，8.03(d，1H，J＝5.5Hz)，7.84(dd，1H，J＝12.7，2.2Hz)，7.71-7.68(m，2H)，7.41(d，1H，J＝8.8Hz)，7.30(d，1H，J＝1.7Hz)，7.26-7.22(m，3H)，7.16(t，1H，J＝8.5Hz)，7.08(d，1H，J＝7.7Hz)，7.01(d，1H，J＝10.4Hz)，6.94(t，1H，J＝8.8Hz)，6.22(d，1H，J＝5.5Hz)，4.17(s，2H)，3.94-3.90(m，2H)，3.76(t，1H，J＝8.5Hz)，2.49-2.35(m，2H)；MS(ESI ⁺)m/z?557.2(M+H) ⁺。

Embodiment 278

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-fluoro-6-methoxy benzamide

According to embodiment 261 similar modes, preparation and get (12.1mg, 31%). ¹HNMR(DMSO-d ₆)δ11.97(s，1H)，10.86(s，1H)，8.14(d，1H，J＝5.5Hz)，7.92(dd，1H，J＝13?.2，2.2Hz)，7.54-7.42(m，4H)，7.03(d，1H，J＝8.2Hz)，6.95(t，1H，J＝8.8Hz)，6.48(d，1H，J＝6.1Hz)，6.35(d，1H，J＝1.4Hz)；MS(ESI ⁺)m/z?396.2(M+H) ⁺。

Embodiment 279

1-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-cyclopropyl ethanoyl) urea

A) 2-cyclopropyl ethanoyl isocyanic ester

((435mg, 3.0mmol is Aldrich) in the formed suspension of 10mL toluene Aldrich) to be added into silver cyanate for 313mg, 3.0mmol with the cyclopropyl Acetyl Chloride 98Min..With this reaction mixture refluxed 2 hours, be cooled to room temperature, and filtered.Resulting filtrate is used for next reaction with the form of 0.3M solution.

B) 1-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-cyclopropyl ethanoyl) urea

According to embodiment 264 similar modes, preparation and get (13.5mg, 59%). ¹HNMR(CD ₃OD)δ8.03(d，1H，J＝5.5Hz)，7.80-7.76(m，1H)，7.27-7.24(m，3H)，6.41(d，1H，J＝5.5Hz)，6.38(d，1H，J＝3.9Hz)，2.25(d，1H，J＝7.2Hz)，0.64-0.59(m，2H)，0.28-0.23(m，2H)；MS(ESI ⁺)m/z?369.2(M+H) ⁺。

Embodiment 280

1-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(cyclopropane carbonyl) urea

A) cyclopropanecarbonyl-based isocyanate

According to preparing with the similar mode of the steps A of embodiment 279 and getting.

B) 1-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(cyclopropane carbonyl) urea

According to mode like the step category-B of embodiment 279, preparation and get (17.2mg, 60%). ¹HNMR(CD ₃OD)δ7.93(d，1H，J＝5.5Hz)，7.57(d，1H，J＝13.8Hz)，7.12-7.08(m，3H)，6.31(m，2H)，1.02(m，2H)，0.90(m，2H)；MS(ESI ⁺)m/z?355.19(M+H) ⁺。

Embodiment 281

1-(2-cyclopropyl ethanoyl)-3-(3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl) urea

According to embodiment 264 similar modes, get with the compd A preparation of the compd B of embodiment 45 and embodiment 279 (21.0mg, 81%). ¹H?NMR(CD ₃OD)δ7.81(s，1H)，7.74(d，1H，J＝5.5Hz)，7.25(m，3H)，4.18(t，2H，J＝5.5Hz)，3.35(t，2H，J＝1.7Hz)，2.90(t，2H，J＝5.5Hz)，2.74-2.54(m，4H)，2.45(s，3H)，2.33(t，4H，J＝2.8Hz)，1.12(m，1H)，0.67-0.64(m，2H)，0.29-0.25(m，2H)；MS(ESI ⁺)m/z?529.3(M+H) ⁺。

Embodiment 282

1-cyclopropane carbonyl-3-(3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazine-1-yl) oxyethyl group) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl) urea

According to embodiment 264 similar modes, get with the compd A preparation of the compd B of embodiment 45 and embodiment 280 (20.3mg, 64%). ¹H?NMR(CD ₃OD)δ10.85(s，1H)，7.70(s，1H)，7.76-7.72(m，2H)，7.22-7.14(m，2H)，4.14(t，2H，J＝5.5Hz)，2.94(t，2H，J＝5.5Hz)，2.89-2.60(m，4H)，2.78(s，3H)，2.34(s，4H)，1.70-1.67(m，1H)，0.99-0.95(m，2H)，0.91-0.86(m，2H)；MS(ESI ⁺)m/z?512.3(M+H) ⁺。

Embodiment 283

N-(4-(3-(3-(dimethylamino) third-1-alkynyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, trifluoroacetate

A) 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo-[2,3-b] pyridine

At room temperature, with 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridine (550mg, 2mmol, the compd A of embodiment 132) and N-iodosuccinimide (450mg 2mmol) stirred 1 hour in the formed mixture of methylene dichloride (50mL).Clean this mixture with salt solution, it through dried over mgso, and is filtered it by the segment silica gel filler, use eluent ethyl acetate.In a vacuum, filtrate is concentrated, obtain being the product of wanting (quantitative yield) of yellow solid.LC/MS(ESI ⁺)m/z?400(M+H) ⁺。

B) 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester

In-40 ℃, nitrogen, (60%, in mineral oil, (400mg is 1mmol) in the formed solution of DMF (10mL) 1.2mmol) to be added into 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo-[2,3-b] pyridine with sodium hydride.Under 0 ℃, this mixture was stirred 20 minutes, and be cooled to-40 ℃.With Boc ₂(330mg 1.5mmol) is added in this mixture O.Under-40 ℃, this mixture was stirred 1 hour, diluted with 5% sodium citrate aqueous solution, use ethyl acetate extraction.Organic layer through dried over mgso, and is concentrated in a vacuum.Utilize rapid column chromatography method (silica gel, 20% ethyl acetate/dichloromethane),, obtain being the compound of wanting (460mg, 92%) of yellow solid resulting crude compound purifying.LC/MS(ESI ⁺)m/z?500(M+H) ⁺。

C) 3-(3-(dimethylamino) third-1-alkynyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester

With argon gas stream feed 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester (200mg, 0.4mmol), N, N-dimethyl propylene-2-alkynes-1-amine (66mg, 0.8mmol), Pd (dppf) ₂Cl ₂: CH ₂Cl ₂(33mg, 0.04mmol) and cupric iodide (20mg) in triethylamine (0.4mL) and the formed mixture of THF (3mL), last 5 minutes.In the sealing test tube, under 70 ℃,, and remove solvent in a vacuum with this reaction mixture heating 2 hours.Utilize rapid column chromatography method (silica gel, 5% methanol/ethyl acetate),, and obtain being the product of wanting (170mg, 95%) of yellow oil resulting crude compound purifying.LC/MS(ESI ⁺)m/z?455(M+H) ⁺。

D) 4-(3-(3-dimethylamino) third-1-alkynyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-the 3-fluoroaniline

With zinc powder (＜10 μ m, 500mg) and ammonium chloride (500mg) be added into 3-(3-(dimethylamino) third-1-alkynyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] (170mg is 0.374mmol) in THF (10mL) and the formed mixture of methyl alcohol (10mL) for pyridine-1-carboxylic acid tert-butyl ester.At room temperature, this reaction mixture was stirred 2 hours, diluted with ethyl acetate, and it is passed through Celite ^Pad filters.With saturated KH ₂PO ₄Aqueous solution wash filtrate through dried over mgso, is filtered it and concentrated in a vacuum, and obtains being the desired product (110mg, 90%) of yellow solid.LC/MS(ESI ⁺)m/z?325(M+H) ⁺。

E) N-(4-(3-(3-(dimethylamino) third-1-alkynyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, trifluoroacetate

DIPEA (0.1mL) is added into 4-(3-(3-(dimethylamino) third-1-alkynyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (33mg, 0.1mmol), 1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-formic acid (46mg, 0.2mmol, the compd B of embodiment 242) and HATU (PerseptiveBiosystems, 76mg is 0.2mmol) in the formed mixture of DMF (1mL).At room temperature, this reaction mixture is stirred a whole night, and concentrate in a vacuum.Utilize preparation HPLC, with resulting crude compound purifying, and level part lyophilize that will be suitable, and obtain being the title compound (15mg, tfa salt, 23%) of yellow solid. ¹H?NMR(CD ₃OD)δ8.73(dd，1H，J＝7.6，2.4Hz)，8.14(d，1H，J＝5.6Hz)，8.00-8.16(m，2H)，7.74(s，1H)，7.54-7.60(m，2H)，7.30-7.47(m，4H)，6.78(dd，1H，J＝6.8，6.8Hz)，6.47(d，1H，5.6Hz)，4.30(s，2H)，2.99(s，6H)；LC/MS(ESI ⁺)m/z?540(M+H) ⁺。

Embodiment 284

N-(4-(3-(3-(dimethylamino) propyl group)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, trifluoroacetate

Under 1 normal atmosphere, with N-(4-(3-(3-(dimethylamino) third-1-alkynyl)-1-(1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-carbonyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-the 3-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide (32mg, tfa salt, 0.037mmol, obtain with the by-product form of the step e of embodiment 283) and Pd/C (10%, 100mg) in the formed mixture hydrogenation of methyl alcohol (5mL) 1 hour.Nitrogen gas stream is fed this mixture, last 5 minutes, then it is passed through Celite ^Pad filters.Utilize preparation HPLC, with resulting filtrate purifying, the solid title compound that obtains being white in color (10mg, tfa salt, productive rate 39%). ¹H?NMR(CD ₃OD)δ8.62(dd，1H，J＝7.2，2.0Hz)，8.04(d，1H，J＝6.4Hz)，7.95(dd，1H，J＝12.8，1.2Hz)，7.90(dd，1H，J＝6.8，2.4Hz)，7.20-7.50(m，6H)，6.66(t，1H，J＝7.20Hz)，6.43(d，1H，J＝6.4Hz)，3.11(t，2H，J＝8.0Hz)，2.96(t，2H，J＝7.2Hz)，2.77(s，6H)，2.11(m，2H)；LC/MS(ESI ⁺)m/z?544(M+H) ⁺。

Embodiment 285

1-(4-(3-(3-(dimethylamino) third-1-alkynyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, trifluoroacetate

At room temperature; with 2-(4-fluorophenyl) ethanoyl isocyanic ester (0.05mmol; the Compound C of embodiment 4) is added into 4-(3-(3-(dimethylamino) third-1-alkynyl)-1H-pyrrolo-[2; 3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (15mg; 0.046mmol, the Compound D of embodiment 283) and in the formed solution of THF (1.5mL).This mixture was stirred 1 hour, and concentrate in a vacuum.Utilize preparation HPLC, with resulting crude compound purifying, and the desired product of solid that obtains being white in color (tfa salt, 12mg, productive rate 42%). ¹H?NMR(DMSO-d ₆)δ12.30(s，1H)，10.98(s，1H)，10.52(s，1H)，10.00(s，1H)，8.07(d，1H，J＝5.6Hz)，7.74(d，1H，J＝2.4Hz)，7.73(dd，1H，J＝12.4，2.4Hz)，7.25-7.40(m，4H)，7.10(m，2H)，6.26(d，1H，J＝5.2Hz)，4.21(s，2H)，3.68(s，2H)，2.43(s，6H)；LC/MS(ESI ⁺)m/z?504(M+H) ⁺。

Embodiment 286

N-(4-(3-(3-(dimethylamino) third-1-alkynyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2,6-difluorobenzamide, trifluoroacetate

With 2,6-difluoro benzoyl chloride (9mg, 0.05mmol) be added into 4-(3-(3-(dimethylamino) third-1-alkynyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (15mg, 0.046mmol, the Compound D of embodiment 283) and pyridine (0.05mL) in the formed 0 ℃ of solution of methylene dichloride (1.0mL).Under 0 ℃, this mixture was stirred 30 minutes, concentrate in a vacuum then.Utilize preparation HPLC, with resulting crude compound purifying, and the desired product of solid that obtains being white in color (tfa salt, 11mg, 41%). ¹H?NMR(CD ₃OD)δ8.05(d，1H，J＝5.6Hz)，7.82(dd，1H，J＝12.4，2.4Hz)，7.63(s，1H)，7.3?5-7.50(m，2H)，7.25(t，1H，J＝8.8Hz)，7.00-7.06(m，2H)，6.38(d，1H，J＝5.6Hz)，4.19(s，2H)，2.87(s，6H)；LC/MS(ESI ⁺)m/z?465(M+H) ⁺。

Embodiment 287

N-(4-(3-cyano group-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-fluoro-6-methoxy benzamide, the hydrogen chlorate

A) 4-(3-bromo-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline

At room temperature, with 3-bromo-4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine (626mg, 1.3mmol, the compd B of embodiment 261), zinc powder (1.0g) and ammonium chloride (1.0g) stirs a whole night in THF (25mL) and the formed mixture of MeOH (25mL).Dilute this mixture with methylene dichloride, and with its Celite by weak point ^Pad filters.Then, under reduced pressure, with the solution concentration of gained, and utilize rapid column chromatography method (silica gel is with 30% ethyl acetate/dichloromethane wash-out), and obtain being the desired product (420mg, 71%) of clarifying oily matter resulting residue purifying.LC/MS(ESI ⁺)m/z?453(M+H) ⁺。

B) N-(4-(3-bromo-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-fluoro-6-methoxy benzamide

Successively with DIPEA (387mg, 3mmol) and DMAP (50mg) be added into 4-(3-bromo-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (400mg, 0.85mmol), 2-fluoro-6-methoxybenzoic acid (226mg, 1.33mmol) and HATU (641mg is 1.33mmol) in the formed solution that had stirred of DMF (6mL).At room temperature, resulting mixture is stirred a whole night, diluted with ethyl acetate, and with saturated K ₂HPO ₄The aqueous solution and salt solution clean.With organic layer through dried over mgso and concentrate in a vacuum.Utilize rapid column chromatography method (silica gel is with 30% ethyl acetate/dichloromethane wash-out), with resulting residue purifying, and the desired product of solid that obtains being white in color (370mg, 72%).LC/MS(ESI ⁺)m/z605(M+H) ⁺。

C) N-(4-(3-cyano group-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-fluoro-6-methoxy benzamide, the hydrogen chlorate

Under 120 ℃, in the test tube of sealing, with N-(4-(3-bromo-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-fluoro-6-methoxy benzamide (30mg, 0.05mmol), Zn (CN) ₂(17mg, 0.15mmol), Pd (dppf) ₂Cl ₂: CH ₂Cl ₂(5mg, Aldrich), Zn (OAc) ₂(1mg) and zinc powder (1mg) in the formed mixture heating up of DMF (0.6mL) 15 hours.Dilute this mixture with methylene dichloride, it is passed through Celite ^Pad filters (methylene dichloride).Use the salt solution wash filtrate, it through dried over mgso, is filtered and concentrate down in decompression.(1M in THF, 1.0mmol) and ethane-1, handles resulting residue in the 2-diamines (30 μ L) (in THF (3mL)) with TBAF.This mixture was refluxed 15 hours, and concentrate in a vacuum.Utilize preparation HPLC, with resulting residue purifying.With desired level part lyophilize, and obtain white tfa salt, it is dissolved in the small amount of methanol/water that contains 1N HCl (0.1mL).Then, with this solution lyophilize, and obtain the title compound (HCl salt, 12mg, 53%) of white solid. ¹HNMR(DMSO-d ₆)δ10.80(s，1H)，8.36(d，1H，J＝2.8Hz)，8.14(d，1H，J＝5.6Hz)，7.87(dd，1H，J＝12.8，2.0Hz)，7.37(m，3H)，6.95(d，1H，J＝8.4Hz)，6.88(t，1H，J＝8.8Hz)，6.41(d，1H，J＝5.2Hz)，3.79(s，3H)；LC/MS(ESI ⁺)m/z?421(M+H) ⁺。

Embodiment 288

N-(4-(3-(6-aminopyridine-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-fluoro-6-methoxy benzamide

Use argon gas, with N-(4-(3-bromo-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-the 3-fluorophenyl)-2-fluoro-6-methoxy benzamide (50mg, 0.08mmol, the compd B of embodiment 287), 5-(4,4,5,5-tetramethyl--1,3-dioxolane-2-yl) pyridine-2-amine (36mg, 0.16mmol, Oakwood), Pd (PPh ₃) ₄(10mg) and K ₃PO ₄(2M, Yu Shuizhong 0.32mmol) cleaned 10 minutes in the formed mixture of toluene (1mL), ethanol (0.2mL) and DME (0.4mL).Under 95 ℃,, diluted with ethyl acetate, and cleaned with salt solution with this reaction mixture heating 2 hours.Organic layer through dried over mgso, is filtered and concentrates in a vacuum, and obtain a residue, and (1M, in THF, 1mL) and ethane-1,2-diamines (50 μ L) (in 3mL THF) is handled, and refluxes 24 hours with TBAF.Dilute this mixture with ethyl acetate, cleaned, it through dried over mgso, and is concentrated in a vacuum with salt solution.Utilize rapid column chromatography method (silica gel, 5%2M NH ₃(in ethanol/methylene) wash-out) with resulting residue purifying, and obtains desired product, utilize, this product is converted into hydrogen chlorate's (white solid, 10mg, productive rate 26%) with 1N HCl (Yu Shuizhong) lyophilize. ¹H?NMR(CD ₃OD)δ8.32(dd，1H，J＝9.2，2.0Hz)，8.21(d，1H，J＝6.1Hz)，8.15(d，1H，J＝2.0Hz)，7.94(dd，1H，J＝12.7，2.5Hz)，7.70(s，1H)，7.44-7.50(m，2H)，7.36(t，1H，J＝8.7Hz)，7.08(d，1H，J＝9.2Hz)，6.98(d，1H，J＝8.7Hz)，6.85(t，1H，J＝8.7Hz)，6.56(d，1H，J＝5.6Hz)，3.92(s，3H)；LC/MS(ESI ⁺)m/z?488(M+H) ⁺。

Embodiment 289

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-isopentyl-2-ketone group-1,2-dihydropyridine-3-methane amide, trifluoroacetate

A) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

DIPEA (0.1mL) and DMAP (5mg) are added into 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3 fluoroaniline (24mg, 0.1mmol, the compd B of embodiment 132), 2-hydroxy niacin (27mg, 0.2mmol) and HATU (76mg is 0.2mmol) in the formed solution that had stirred of DMF (1mL).At room temperature, should stir 2 hours by resulting mixture, and concentrate in a vacuum.Utilize preparation HPLC, with resulting residue purifying, the solid that obtains being white in color is wanted product (8mg, 22%).LC/MS(ESI ⁺)m/z?365(M+H) ⁺。

B) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base-3-fluorophenyl)-1-isopentyl-2-ketone group-1,2-dihydropyridine-3-methane amide, trifluoroacetate

At room temperature, with N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide (8mg, 0.02mmol), Na ₂CO ₃(50mg) and 1-iodo-3-methylbutane (50mg) stir a whole night in the formed mixture of DMF (1mL).In a vacuum, this reaction mixture is concentrated, and utilize preparation HPLC, with resulting residue purifying, and the desired product of solid that obtains being white in color (tfa salt, 5mg, 42%). ¹H?NMR(CD ₃OD)δ12.50(s，1H)，8.46(dd，1H，J＝7.1，2.0Hz)，8.16(d，1H，J＝6.1Hz)，7.90-8.00(m，2H)，7.38-7.44(m，2H)，7.33(t，1H，J＝8.7Hz)，6.70(d，1H，J＝6.6Hz)，6.51-6.57(m，2H)，4.08(t，2H，J＝7.6Hz)，1.51-1.53(m，3H)，0.92(d，6H，J＝6.1Hz)；LC/MS(ESI ⁺)m/z?435(M+H) ⁺。

Embodiment 290

N-(3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-2-ketone group-1-phenyl-1,2-dihydropyridine-3-methane amide

According to embodiment 239 similar modes, use 3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) aniline (compd E of embodiment 237) and 2-ketone group-1-phenyl-1,2-dihydropyridine-3-formic acid, preparation and getting. ¹H?NMR(DMSO-d ₆)δ12.87(s，1H)，12.18(s，1H)，9.39(s，1H)，8.70-8.85(m，2H)，8.60(d，1H，J＝7.1Hz)，8.00-8.25(m，3H)，7.94(s，1H)，7.30-7.75(m，8H)，6.77(t，1H，J＝6.6Hz)，6.45(d，1H，J＝4.6Hz)，4.21(s，2H)，3.68(s，2H)，2.43(s，6H)；LC/MS(ESI ⁺)m/z?518(M+H) ⁺。

Embodiment 291

1-(3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, the hydrogen chlorate

At room temperature; with 3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo-[2; 3-b] pyridin-4-yl oxygen base) aniline (25mg; 0.078mmol; the compd E of embodiment 237) and 2-(4-fluorophenyl) ethanoyl isocyanic ester (0.09mmol; in toluene, the Compound C of embodiment 4) stirred 1 hour in the formed mixture of THF.Remove solvent in a vacuum, and utilize preparation HPLC,, obtain being the desired product (HCl salt, 18mg, 40%) of yellow solid resulting residue purifying. ¹HNMR(CD ₃OD)δ10.76(s，1H)，9.19(s，1H)，8.70(d，1H，J＝8.0Hz)，8.66(d，1H，J＝5.2Hz)，8.18(d，1H，J＝6.4Hz)，8.00(dd，1H，J＝8.4，5.6Hz)，7.75(dd，1H，J＝13.2，2.4Hz)，7.10-7.35(m，4H)，6.90-7.03-7.40(m，3H)，6.63(d，1H，J＝6.4Hz)；LC/MS(ESI ⁺)m/z?500(M+H) ⁺。

Embodiment 292

N-(3-fluoro-4-(2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

A) 4-chloro-1-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine

At room temperature, while stirring with 4-chloro-1H-pyrrolo-[2,3-b] pyridine (305mg, 2mmol, according to Thibault, C.et al, Org.Lett.2003,5,5023) be added into sodium hydride (88mg, 60%, in mineral oil, 2.2mmol) in the formed suspension of DMF (1mL).This mixture was stirred 5 minutes, and interpolation trimethyl silyl ethyl chloride methyl ether (350mg, 2.1mmol, Aldrich).At room temperature, this mixture was stirred 1 hour, pour in the ice, and (3 * 10mL) are extracted with ethyl acetate.Clean the extraction liquid that merges with salt solution, give drying (sal epsom) and concentrated down, and obtain crude product in decompression; Utilize flash chromatography method (5% ethyl acetate/hexane) with this crude product purifying, and the title compound that obtains being in a liquid state (300mg, 1.06mmol, 53%). ¹H NMR (CDCl ₃) δ 8.28 (d, 1H, J=5.5Hz), 7.45 (d, 1H, J=3.6Hz), 7.18 (d, 1H, J=5.5Hz), 6.69 (d, 1H, J=3.6Hz), 5.74 (s, 2H), 3.60 (t, 2H, J=6.8Hz), 0.96 (t, 2H, J=6.8Hz), 0.07 (s, 9H); MS (ESI ⁺) m/z 283 and 285 (M+H, 1 Cl) ⁺

B) 4-chloro-2-methyl isophthalic acid-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine

In argon atmospher, under-78 ℃, with butyllithium (0.4mL, 1.6M, in hexane, 6.4mmol) be added into dropwise that 4-chloro-1-((2-(trimethyl silyl) oxyethyl group) methyl)-(150mg is 0.53mmol) in the formed solution of THF (1mL) for 1H-pyrrolo-[2,3-b] pyridine.Under identical temperature, this mixture was stirred 5 minutes, and handled with methyl iodide (0.1mL).This mixture is warmed to room temperature, react by adding saturated ammonium chloride solution cancellation, and (3 * 10mL) extracts with ethyl acetate.The extraction liquid that clean to merge with salt solution through dried over mgso and concentrate in a vacuum, and obtains crude product (150mg, 95%) with it, and it is directly used in next reaction. ¹HNMR (CDCl ₃) δ 8.19 (d, 1H, J=5.5Hz), 7.14 (d, 1H, J=5.5Hz), 6.42 (s, 1H), 5.74 (s, 2H), 3.60 (t, 2H, J=6.8Hz), 2.61 (s, 3H), 0.96 (t, 2H, J=6.8Hz), 0.07 (s, 9H); MS (ESI ⁺) m/z 297 and 299 (M+H, 1Cl) ⁺

C) 4-chloro-2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine

With 4-chloro-2-methyl isophthalic acid-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-pyrrolo-[2,3-b] pyridine (296.5mg, 1mmol) and TBAF (in THF, Aldrich) mixture refluxes a whole night for 5mL, 1M.Under reduced pressure, THF is removed, and water (5mL) dilutes resulting residue.Collect formed throw out, water cleaned and with it through dried over mgso, and obtain title compound (101mg, 60%). ¹H NMR (CD ₃OD) δ 7.99 (d, 1H, J=5.5Hz), 7.06 (d, 1H, J=5.5Hz), 6.23 (s, 1H), 2.46 (s, 3H); MS (ESI ⁺) m/z 167 and 169 (M+H, 1Cl) ⁺

D) 2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-4-alcohol

Under 200 ℃, with 4-chloro-2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine (120mg, 0.72mmol) and sodium acetate (150mg is 1.83mmol) in the formed mixture microwave heating of acetate (1.5mL) 40 minutes.Utilize preparation HPLC, with this purifying mixture, and in a vacuum suitable level part is concentrated, and give lyophilize, and obtain title compound (90mg, 47%). ¹HNMR(CD ₃OD)δ8.09(d，1H，J＝5.5Hz)，6.80(d，1H，J＝5.5Hz)，6.49(s，1H)，2.46(s，3H)；MS(ESI ⁺)m/z?149(M+H) ⁺。

E) 4-(2-fluoro-4-nitrophenoxy)-2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine

Under 50 ℃, (0.34mmol), 3, (100mg 0.72mmol) stirred 2 hours in the formed mixture of DMF (1mL) for 4-difluoro nitrobenzene (0.05mL) and salt of wormwood for 90mg, tfa salt with 2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-4-alcohol.This mixture of dilute with water and with ethyl acetate (3 * 5mL) extraction.The extraction liquid that water clean to merge through dried over mgso and concentrate in a vacuum, and obtains crude product with it, utilizes preparation HPLC, with this product purification, obtains title compound (45mg, 46%). ¹H?NMR(CD ₃OD)δ8.25(dd，2H，J＝10.4，2.6Hz)，8.12(m，1H)，8.04(d，1H，J＝5.5Hz)，7.30(t，1H，J＝8.3Hz)，6.67(d，1H，J＝5.5Hz)，5.95(s，1H)，2.41(s，3H)；MS(ESI ⁺)m/z?288(M+H) ⁺。

F) 3-fluoro-4-(2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) aniline

At room temperature, with 4-(2-fluoro-4-nitrophenoxy)-2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine (43mg, 0.15mmol), zinc powder (50mg, 0.75mmol) and ammonium chloride (50mg) in THF/ alcohol (1/2,0.6mL) formed mixture stirred 1 hour, filtered and concentrated in a vacuum, and obtained desired product (35mg, 90%), this degree of purity of production is enough pure, and can be directly used in ensuing reaction. ¹H?NMR(DMSO-d ₆)δ11.71(s，1H)，8.04(d，1H，J＝5.5Hz)，7.10(t，1H，J＝8.4Hz)，6.64(dd，1H，J＝10.4，2.6Hz)，6.51(m，1H)，6.35(d，1H，J＝5.5Hz)，5.95(s，1H)，5.50(s，2H)，2.41(s，3H)；MS(ESI ⁺)m/z?258(M+H) ⁺。

G) N-(3-fluoro-4-(2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

Under 50 ℃, with 3-fluoro-4-(2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) aniline (17mg, 0.066mg), 1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-formic acid (20mg, 0.086mmol) in the formed mixture of DMF (0.5mL) and bop reagent (50mg, 0.11mmol) and triethylamine (0.01mL) stirred together 1 hour.This reaction mixture is cooled to room temperature, and dilute with water.Collect the throw out that is produced, and water is cleaned.Utilize preparation HPLC,, and collect suitable level part, neutralized and concentrate in a vacuum, obtain being solid title compound (7.85mg, 25%) resulting crude product purifying. ¹H?NMR(DMSO-d ₆)δ12.07(s，1H)，11.56(s，1H)，8.49(d，1H，J＝6.2Hz)，8.12(d，1H，J＝6.2Hz)，7.98(dd，1H，J＝10.4，2.6Hz)，7.95(d，1H，J＝5.5Hz)，7.61(m，2H)，7.43(m，3H)，7.29(t，1H，J＝8.40Hz)，6.72(t，1H，J＝6.2Hz)，6.36(d，1H，J＝5.5Hz)，5.88(s，1H)，2.32(s，3H)；MS(ESI ⁺)m/z?473(M+H) ⁺。

Embodiment 293

N ¹-(3-fluoro-4-(2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-N3-(4-fluorophenyl) Malonamide, the hydrogen chlorate

DIPEA (0.1mL) is added into 3-fluoro-4-(2-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-4-base oxygen base) aniline (20mg, 0.078mmol, the compd E of embodiment 292), 3-(4-fluorophenyl amino)-3-ketopropionic acid (20mg, 1mmol, the compd A of embodiment 25) and HATU (44mg is 0.12mmol) in the formed mixture of DMF (0.5mL).At room temperature, this reaction mixture was stirred 2 hours, and concentrated in a vacuum.Utilize preparation HPLC, with resulting residue purifying, the desired product of solid (HCl salt, 12.5mg, 34%) obtains being white in color. ¹HNMR(CD ₃OD)δ8.05(d，1H，J＝7.2Hz)，7.79(dd，1H，J＝12.7，2.8Hz)，7.50-7.53(m，2H)，7.27-7.36(m，2H)，6.97(m，2H)，6.70(d，1H，J＝6.6Hz)，6.20(s，2H)，3.47(s，2H)，2.40(s，3H)；LC/MS(ESI ⁺)m/z?437(M+H) ⁺。

Embodiment 294

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-5-amino-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, hydrogen chlorate

A) 5-nitro-2-ketone group-1,2-dihydropyridine-3-methyl-formiate

Thionyl chloride (1mL) dropwise is added into 2-hydroxyl-5-nitro nicotinic acid, and (0.80g, 4.35mmol is Combi-Blocks) in the formed solution under 0 ℃ of methyl alcohol (10mL).Mixture was stirred 1 hour down at 0 ℃, stirred 2 hours down at 60 ℃ then.Remove excessive methyl alcohol, and resulting residue is neutralized with sodium bicarbonate aqueous solution in decompression down.Collect solid, water is cleaned and is given drying, and obtains title compound (0.85g, 99%). ¹H?NMR(DMSO-d ₆)δ8.44(s，1H)，8.34(s，1H)，3.67(s，3H)；MS(ESI ⁺)m/z?199(M+H) ⁺。

B) 1-(4-fluorophenyl)-5-nitro-2-ketone group-1,2-dihydropyridine-3-methyl-formiate

Under 80 ℃, with 5-nitro-2-ketone group-1,2-dihydropyridine-3-methyl-formiate (850mg, 4.29mmol), 4-fluorophenyl boric acid (1.40g, 10mmol, Combi-Blocks) and venus crystals (200mg, 1.1mmol) in pyridine (1mL) He the mixture that diox (20mL) forms stirred 4 hours.This reaction mixture is cooled to room temperature and is diluted with ammonia solution.Collect solid, water cleans and gives drying, and obtains title compound (656mg, 52%). ¹H?NMR(DMSO-d ₆)δ8.95(d，1H，J＝3.2Hz)，8.80(d，1H，J＝3.2Hz)，7.40(m，2H)，7.25(m，2H)，3.95(s，3H)；MS(ESI ⁺)m/z?293(M+H) ⁺。

C) 1-(4-fluorophenyl)-5-nitro-2-ketone group-1,2-dihydropyridine-3-formic acid

Under 80 ℃, with 1-(4-fluorophenyl)-5-nitro-2-ketone group-1,2-dihydropyridine-3-methyl-formiate (75mg, 0.245mmol) and the mixture of 2N sodium hydroxide solution (1mL) stirred 2 hours.This reaction mixture is cooled to room temperature, and gives acidifying with 1N HCl solution.Collect formed solid, water cleans and gives drying, and obtains title compound (45mg, 66%), and it is directly used in next reaction. ¹H?NMR(DMSO-d ₆)δ13.41(s，1H)，9.28(d，1H，J＝3.2Hz)，8.70(d，1H，J＝3.2Hz)，7.60(m，2H)，7.41(m，2H)；MS(ESI ⁺)m/z?279(M+H) ⁺。

D) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-5-nitro-2-ketone group-1,2-dihydropyridine-3-methane amide

Under 50 ℃, with 1-(4-fluorophenyl)-5-nitro-2-ketone group-1,2-dihydropyridine-3-formic acid (40mg, 0.14mmol) and 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (35mg, 0.14mmol, the compd B of embodiment 132) in the formed mixture of DMF (1mL) and bop reagent (100mg, 0.23mmol) and triethylamine (0.1mL) stirred together 1 hour.This reaction mixture is cooled to room temperature, and water is diluted.Collect formed solid, cleaned with sodium bicarbonate aqueous solution, 1N HCl solution and water, and obtain title compound (54mg, 76%). ¹HNMR(DMSO-d ₆)δ12.19(s，1H)，11.04(s，1H)，9.37(d，1H，J＝2.6Hz)，9.03(d，1H，J＝2.6Hz)，8.18(d，1H，J＝5.5Hz)，8.01(dd，1H，J＝10.2，2.6Hz)，7.71(m，2H)，7.61(m，1H)，7.46(m，4H)，6.55(d，1H，J＝5.5Hz)，6.36(s，1Hz)；MS(ESI ⁺)m/z504(M+H) ⁺。

E) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-5-amino-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, hydrogen chlorate

Under nitrogen atmosphere, room temperature, at Pd/C (10%, 10mg) exist down, with N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-the 3-fluorophenyl)-1-(4-fluorophenyl)-5-nitro-2-ketone group-1, (51mg is 0.1mmol) in DMF (1mL) and the formed solution hydrogenation of ethanol (5mL) 4 hours for 2-dihydropyridine-3-methane amide.This reaction mixture is filtered and concentrate in vacuum.Utilize preparation HPLC, with resulting residue purifying, collection contains the level part of wanting compound to some extent, and concentrates in a vacuum.By adding 1N HCl solution, this product is converted into HCl salt, and gives lyophilize, and obtain being the title compound (7.6mg, 15%) of light yellow solid. ¹H?NMR(CD ₃OD)δ8.56(d，1H，J＝3.2Hz)，8.31(d，1H，J＝5.5Hz)，8.08(dd，1H，J＝10.4，2.6Hz)，7.78(m，1H)，7.56(m，5H)，7.48(m，2H)，7.35(t，1H，J＝8.7Hz)，6.90(d，1H，J＝5.5Hz)，6.69(s，1H)；MS(ESI ⁺)m/z?474(M+H) ⁺。

Embodiment 295

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-5-(dimethylamino)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

A) 5-amino-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate

At room temperature, with 1-(4-fluorophenyl)-5-nitro-2-ketone group-1,2-dihydropyridine-3-methyl-formiate (1.46g, 5mmol, the compd B of embodiment 294), zinc powder (1.63g, 25mmol) and ammonium chloride (1.5g, 28mmol) (1: 1,20mL) formed mixture stirred 2 hours in methyl alcohol/TFH.This reaction mixture is filtered and concentrated in a vacuum, obtain desired product (1.30g, 99%), it is directly used in next reaction, need not to be further purified. ¹H?NMR(CD ₃OD)δ8.08(s，1H)，7.41?(m，2H)，7.29(m，3H)，3.84(s，3H)；MS(ESI ⁺)m/z?263(M+H) ⁺。

B) 5-(dimethylamino)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate

With sodium triacetoxy borohydride (50mg, 0.23mmol) be added into 5-amino-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate (30mg, 0.11mmol) and formalin (37%, 0.1mL) in the formed solution of acetate (1mL).At room temperature, this reaction mixture was stirred 1 hour, and utilize preparation HPLC, carry out purifying.Collection contains the level part of desired product, is neutralized and concentrates in a vacuum, and obtain solid.This solid collection is got up, and water is cleaned and is given drying, obtains title compound (25mg, 77%). ¹H?NMR(CD ₃OD)δ8.31(d，1H，J＝2.6Hz)，7.41(m，2H)，7.26(m，3H)，3.89(s，3H)，2.79(s，6H)；MS(ESI ⁺)m/z?291(M+H) ⁺。

C) 5-(dimethylamino)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-formic acid

Utilize the described program of step C of embodiment 294, by 5-(dimethylamino)-1-(4-fluorophenyl)-2-ketone group-1, (25mg 0.086mmol), makes title compound (20mg, 84%) to 2-dihydropyridine-3-methyl-formiate. ¹H?NMR(CD ₃OD)δ8.31(d，1H，J＝2.6Hz)，7.41(m，2H)，7.26(m，3H)，2.70(s，6H)；MS(ESI ⁺)m/z?277(M+H) ⁺

D) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-5-(dimethylamino)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

Utilize the described program of step D of embodiment 294, by 5-(dimethylamino)-1-(4-fluorophenyl)-2-ketone group-1, (20mg 0.072mmol), makes title compound (13.5mg, 37%) to 2-dihydropyridine-3-formic acid. ¹H?NMR(DMSO-d ₆)δ12.54(s，1H)，11.79(s，1H)，8.45(d，1H，J＝3.2Hz)，8.10(d，1H，J＝5.5Hz)，8.01(dd，1H，J＝10.4，2.6Hz)，7.62(m，1H)，7.44(m，6H)，6.40(d，1H，J＝5.5Hz)，6.24(s，1Hz)，2.82(s，6H)；MS(ESI ⁺)m/z?502(M+H) ⁺。

Embodiment 296

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-5-bromo-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

A) 5-bromo-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate

Utilize steps A and the described program of B of embodiment 294,, make title compound (productive rate 69%) by 5-bromo-2-hydroxy niacin (Combi-Blocks). ¹H NMR (DMSO-d ₆) δ 8.29 (d, 1H, J=3.2Hz), 8.14 (d, 1H, J=3.2Hz), 7.50 (m, 2H), 7.37 (m, 2H), 3.75 (s, 3H); MS (ESI ⁺) m/z 326 and 328 (M+H, 1Br) ⁺

B) 5-bromo-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-formic acid

Utilize the described program of step C of embodiment 294, by 5-bromo-1-(4-fluorophenyl)-2-ketone group-1, (65mg 0.2mmol), makes title compound (55mg, 88%) to 2-dihydropyridine-3-methyl-formiate. ¹HNMR (DMSO-d ₆) δ 8.58 (d, 1H, J=2.6Hz), 8.44 (d, 1H, J=2.6Hz), 7.69 (m, 2H), 7.43 (t, 2H, J=8.8Hz); MS (ESI ⁺) m/z 312 and 314 (M+H, 1Br) ⁺

C) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-5-bromo-1-(4-fluorophenyl 1-2-ketone group-1,2-dihydropyridine-3-methane amide

Utilize the described program of step D of embodiment 294, by 5-bromo-1-(4-fluorophenyl)-2-ketone group-1, (31.2g 0.1mmol), makes title compound (28mg, 52%) to 2-dihydropyridine-3-formic acid. ¹HNMR (DMSO-d ₆) δ 11.93 (s, 1H), 11.80 (s, 1H), 8.53 (m, 2H), 8.01 (dd, 1H, J=10.4,2.6Hz), 7.64 (m, 2H), 7.41 (m, 6H), 6.41 (br s, 1H), 6.27 (s, 1H); MS (ESI ⁺) m/z537 and 539 (M+H, 1Br) ⁺

Embodiment 297

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-5-morpholino-2-ketone group-1,2-dihydropyridine-3-methane amide

Under 160 ℃, with N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-the 3-fluorophenyl)-5-bromo-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide (40mg, 0.074mmol embodiment 296) and morpholine (0.1mL) in the formed mixture microwave heating of N,N-DIMETHYLACETAMIDE (1mL) 30 minutes.This reaction mixture is cooled to room temperature, and utilizes preparation HPLC to give purifying.Collection contains the level part of desired compound, is neutralized and concentrates in a vacuum, and obtain solid.Collect this solid, water is cleaned and is given drying, obtains title compound (7.5mg, 18%). ¹HNMR(DMSO--d ₆)δ12.38(s，1H)，11.75(s，1H)，8.50(d，1H，J＝2.6Hz)，8.06(d，1H，J＝5.5Hz)，8.01(dd，1H，J＝10.4，2.6Hz)，7.60(m，2H)，7.41(m，6H)，6.41(d，1H，J＝5.5Hz)，6.21(s，1H)，3.72(m，4H)，3.00(m，4H)；MS(ESI ⁺)m/z?544(M+H) ⁺。

Embodiment 298

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-5-(the amino ethylamino of 2-)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

A) 5-(2-tertbutyloxycarbonyl) ethylamino)-and 1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate

With sodium triacetoxy borohydride (212mg, 1mmol) be added into 5-bromo-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate (131mg, 0.5mmol, the compd A of embodiment 296) and the 2-ketone group ethyl carbamic acid tert-butyl ester (159mg, 1mmol is Aldrich) in the formed solution of acetate (1mL).At room temperature, this reaction mixture was stirred 1 hour, by adding the shrend reaction of going out, and (3 * 10mL) extract with ethyl acetate.Clean the organic extract liquid that merges, and give drying with salt solution, sodium bicarbonate aqueous solution.In a vacuum, with this solution concentration, and with rapid column chromatography method (SiO ₂, 10% ethyl acetate (in hexane)), with resulting residue purifying, and obtain being the title compound (60mg, 30%) of jelly. ¹H?NMR(CDCl ₃)δ7.90(d，1H，J＝2.6Hz)，7.37(m，2H)，7.13(m，2H)，6.81(d，1H，J＝2.6Hz)，3.88(s，3H)，3.30(m，2H)，3.10(m，2H)，1.46(s，9H)；MS(ESI ⁺)m/z?406(M+H) ⁺。

B) 5-(2-(tertbutyloxycarbonyl) ethylamino)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-formic acid

Utilize the described program of step C of embodiment 294, by 5-(2-(tertbutyloxycarbonyl) ethylamino)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methyl-formiate (60mg, 0.15mmol), make title compound (50mg, 85%), it is directly used in next reaction, need not to be further purified. ¹HNMR(CDCl ₃)δ8.26(d，1H，J＝2.6Hz)，7.50(m，2H)，7.25(m，2H)，6.91(d，1H，J＝2.6Hz)，3.30(m，2H)，3.10(m，2H)，1.46(s，9H)；MS(ESI ⁺)m/z?392(M+H) ⁺。

C) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-5-(the amino ethylamino of 2-)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

Under 50 ℃, with 5-(2-(tertbutyloxycarbonyl) ethylamino)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-formic acid (50mg, 0.13mmol) and 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (40mg, 0.16mmol, the compd B of embodiment 132), (100mg 0.23mmol) stirred 1 hour with triethylamine (0.1mL) in the formed mixture of DMF (1mL) bop reagent.This reaction mixture is cooled to room temperature, and water is diluted and with dichloromethane extraction (3 * 10mL).Water cleans the organic extract liquid that merges, and gives drying and concentrated in a vacuum.At room temperature, residue was stirred 30 minutes with TFA (1mL).Remove TFA and utilize preparation HPLC, with resulting residue purifying.Collection contains level part of desired product, and concentrates in a vacuum.By adding 1N HCl solution, resulting residue is converted into HCl salt, and gives lyophilize, and obtain title compound (20mg, 27%). ¹H?NMR(CD ₃OD)δ8.35(d，1H，J＝2.6Hz)，8.26(d，1H，J＝5.5Hz)，8.01(dd，1H，J＝10.4，2.6Hz)，7.48(m，2H)，7.41(m，6H)，6.81(d，1H，J＝5.5Hz)，6.60(s，1H)，3.26(t，2H，J＝6.1Hz)，3.07(t，2H，J＝6.1Hz)；MS(ESI ⁺)m/z?517(M+H) ⁺。

Embodiment 299

N ¹-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-fluorophenyl)-N ³-(4-fluorophenyl) Malonamide, trifluoroacetate

A) 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-fluoroaniline

With 4-amino-3-fluorophenol (51mg, 0.40mmol) and DIEA (0.1mL, 0.57mmol) be added into 4-chloro-1H-pyrrolo-[2,3-b] pyridine (50mg, 0.33mmol, according to Thibault, C.et al.Org.Lett.2003,5,5023 the preparation and) in the formed solution of NMP (0.5mL).In 250 ℃ of microwave ovens,, then, it is cooled to room temperature with this mixture heating up 1 hour.(10mg 0.4mmol) was added in this mixture, and once more under 250 ℃, with this mixture heating up 3 hours with sodium hydride.After the cooling of this mixture, water is diluted and is used ethyl acetate extraction.Water, salt solution clean organic layer and with it through dried over mgso.Filter and vacuum in concentrate after, with resulting residue through rapid column chromatography method (ISCO RediSep ^The silica gel filter cylinder) purifying, and obtain title compound (15mg, 19%).MS(ESI ⁺)m/z?244.1(M+H) ⁺。

B) N ¹-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-fluorophenyl)-N ³-(4-fluorophenyl) Malonamide, trifluoroacetic acid

With DIEA (0.04mL, 0.23mmol) and TBTU (22mg, 0.07mmol) be added into 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-fluoroaniline (14mg, 0.058mmol) and 3-(4-fluorophenyl amino)-3-ketopropionic acid (12mg, 0.06mmol, the compd A of embodiment 25) and in the formed solution of DMF (1mL).At room temperature, this reaction mixture was stirred 2 days, and concentrate in a vacuum.Utilize preparation HPLC,, obtain title compound (18mg, 74%) resulting residue purifying. ¹H?NMR(CD ₃OD)δ8.25(d，1H，J＝7.5Hz)，8.19(t，1H，J＝7.5Hz)，7.55(m，2H)，7.49(d，1H，J＝3.5Hz)，7.25(d，1H，J＝8.0Hz)，7.13(d，1H，J＝7.0Hz)，7.01(m，2H)，6.84(d，1H，J＝7.0Hz)，6.60(d，1H，J＝3.5Hz)，3.60(s，2H)；MS(ESI ⁺)m/z423.1(M+H) ⁺。

Embodiment 300

N ¹-(3-fluoro-4-(6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide

A) 6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-alcohol

With saturated wet chemical (2.0mL) and Pd (PPh ₃) ₄(60mg, 0.05mmol) be added into 6-bromine pyrrolo-[2,1-f] [1,2,4] triazine-4-alcohol (100mg, 0.47mmol, make by 4-bromo-1H-pyrroles-2-methyl-formiate: referring to Kitamura, C.and Yamashita, Y.J.Chem.Soc.Perkin Trans.1,1997,1433 (its disclosure is incorporated this paper into as a reference), adopt described similar program with PCT application WO00/71129) and 4-(4-(4,4,5,5-tetramethyl--1,3,2-dioxy ring pentaborane-2-yl) pyridine-2-yl) (290mg is 1.0mmol) in the formed solution of DMF (2mL) for morpholine.Use N ₂Cleaned this reaction mixture 10 minutes, and then, under 80 ℃, heated 5 hours, under 100 ℃, heated 12 hours in addition.After this mixture cooling, water is diluted and is filtered, and obtains crude product, is ground with DCM, obtains title compound (114mg, productive rate 82%).MS(ESI) ⁺m/z?298.2(M+H) ⁺。

B) 4-chloro-6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine

With a DMF and POCl ₃(110mg is 0.37mmol) in the formed suspension of toluene (100ml) (30mL) to be added into 6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-alcohol.Heated three days down with the flask sealing and in 100 ℃.This reaction mixture is cooled to room temperature and concentrates in a vacuum.Then, resulting residue is dissolved among the DCM, is neutralized and isolate organic layer with saturated sodium bicarbonate aqueous solution.With DCM (2 * 50mL) aqueous layer extracted.The organic layer that merges through dried over mgso, is filtered and concentrated in a vacuum, obtain desired product, it is directly used in next procedure.MS(ESI ⁺)m/z?316.2/318.2(M+H) ⁺。

C) 4-(2-fluoro-4-nitrophenoxy)-6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine

With 2-fluoro-4-nitrophenols (59mg, 0.37mmol) and DABCO (45mg 0.4mmol) is added into rough 4-chloro-6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine in the formed suspension of MeCN (5mL).At room temperature, this reaction mixture was stirred 2 hours.In a vacuum, except that desolvating and utilizing rapid column chromatography method (ISCO RediSep ^The silica gel filter cylinder), with resulting residue purifying, and obtain desired compound (54mg, the productive rate of two steps are 33%).MS(ESI ⁺)m/z437.2(M+H) ⁺。

D) 3-fluoro-4-(6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline

With ammonium chloride (127mg, 2.4mmol) and zinc powder (78mg, 1.2mmol) be added into 4-(2-fluoro-4-nitrophenoxy)-6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] (54mg is 0.12mmol) in the formed solution of mixture of THF (2.0mL) and methyl alcohol (2.0mL) for triazine.At room temperature, this reaction mixture was stirred 3 hours, filtered and concentrated in a vacuum.Utilize preparation HPLC,, and obtain desired product (40mg, productive rate 82%) resulting residue purifying.

MS(ESI ⁺)m/z?407.19(M+H) ⁺。

E) N ¹-(3-fluoro-4-(6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide

With DIEA (0.1mL, 0.57mmol) and TBTU (13mg, 0.04mmol) be added into 3-fluoro-4-(6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline (15mg, 0.037mmol) and 3-(4-fluorophenyl amino)-3-ketopropionic acid (8mg, 0.04mmol, the compd A of embodiment 25) and in the formed solution of DMF (1mL).At room temperature, this reaction mixture is stirred a whole night, then, HPLC gives purifying with preparation.Collection contains level part of desired product, and is concentrated in a vacuum.With 1N ammonium hydroxide resulting residue is neutralized, and concentrate once more.Filter out formed solid, cleaned, it is dissolved in the methanol with 1N ammonium hydroxide, and lyophilize, title compound (8mg, 37%) obtained. ¹HNMR(DMSO-d ₆)δ10.49(s，1H)，10.23(s，1H)，8.63(s，1H)，8.55(s，1H)，8.06(s，1H)，8.00(d，1H，J＝7.5Hz)，7.70(m，1H)，7.50(m，2H)，7.30-7.45(m，3H)，7.04-7.17(m，3H)，6.85-6.92(m，2H)，3.36(s，4H)，3.44(s，6H)；MS(ESI ⁺)m/z586.2(M+H) ⁺。

Embodiment 301

1-(3-fluoro-4-(6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

With DIEA (0.1mL; 0.57mmol) and 2-(4-fluorophenyl) ethanoyl isocyanic ester (0.347M; 0.21mL; 0.074mmol, the Compound C of embodiment 4) and be added into 3-fluoro-4-(6-(2-morpholino pyridin-4-yl) pyrrolo-[2,1-f] [1; 2; 4] triazine-4-base oxygen base) aniline (15mg, 0.037mmol, the Compound D of embodiment 300) is in the formed solution of THF (1mL).At room temperature, this reaction mixture was stirred 1 hour, and on B the collecting precipitation thing, cleaned with toluene, and obtained title compound (10mg, 46%). ¹H?NMR(DMSO-d ₆)δ11.05(s，1H)，10.60(s，1H)，8.71(s，1H)，8.62(s，1H)，8.13(s，1H)，8.09(d，1H，J＝7.5Hz)，7.80(d，1H，J＝8.0Hz)，7.35-7.54(m，5H)，7.18(t，2H，J＝7.5Hz)，6.91(d，1H，J＝8.0Hz)，3.71-3.76(m，6H)，3.48-3.51(m，4H)；MS(ESI ⁺)m/z?586.2(M+H) ⁺。

Embodiment 302

N ¹-(3-fluoro-4-(6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, trifluoroacetate

A) 6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-alcohol

According to the described similar program of the steps A of embodiment 300, with 6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] (100mg is 0.47mmol) with pyridin-4-yl boric acid (172mg for triazine-4-alcohol, 1.40mmol) coupling, and obtain title compound (72mg, 72%).MS(ESI ⁺)m/z?213.2(M+H) ⁺。

B) 4-chloro-6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine

According to the described similar program of the step B of embodiment 300, (62mg 0.29mmol) is converted into title compound (30mg, 45%) with 6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-alcohol.MS(ESI ⁺)m/z?231.1/233.1(M+H) ⁺。

C) 4-(2-fluoro-4-nitrophenoxy)-6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine

According to the described similar mode of the step C of embodiment 300, (37mg 0.16mmol) is converted into desired compound (50mg, 89%) with 4-chloro-6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine.MS(ESI ⁺)m/z?352.2(M+H) ⁺。

D) 3-fluoro-4-(6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline

According to the described similar program of the step D of embodiment 300, (50mg 0.14mmol) is converted into desired compound (50mg, quantitative yield) with 4-(2-fluoro-4-nitrophenoxy)-6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine.MS(ESI ⁺)m/z?322.3(M+H) ⁺。

E) N ¹-(3-fluoro-4-(6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide, trifluoroacetate

According to the described similar program of the step e of embodiment 300, (20mg 0.06mmol) is converted into title compound (8.5mg, 28%) to aniline with 3-fluoro-4-(6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base). ¹H?NMR(DMSO-d ₆)δ10.53(s，1H)，10.27(s，1H)，9.06(s，1H)，8.80(d，2H，J＝7.0Hz)，8.30(d，2H，J＝6.0Hz)，8.24(s，1H)，7.98(s，1H)，7.80(d，1H，J＝8-0Hz)，7-60(m，2H)，7-35-7-45(m，2H)，7-16(t，2H，J＝8-0Hz)，3-49(s，2H)；MS(ESI ⁺)m/z?501-2(M+H) ⁺。

Embodiment 303

2,6-two fluoro-N-(3-fluoro-4-(6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl) benzamide, trifluoroacetate

At room temperature, with DIEA (0-1mL, 0-57mmoL) and 2, the 6-difluoro benzoyl chloride is in the formed solution of DCM (0-5M, 0-14mL, 0-07mmol) be added into 3-fluoro-4-(6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline (20mg, 0.06mmol, the Compound D of embodiment 302) and in the formed solution of DCM (1mL).This reaction mixture was stirred 0.5 hour, and react with the cancellation of 1N ammonium hydroxide.Then, in a vacuum,, and utilize preparation HPLC,, and obtain title compound (15mg, 54%) resulting residue purifying with this solution concentration. ¹HNMR(DMSO-d ₆)δ11.09(s，1H)，8.96(s，1H)，8.70(m，2H)，8.18(s，1H)，8.10(brs，2H)，7.90(s，1H)，7.80(d，1H，J＝8.0Hz)，7.45-7.55(m，3H)，7.23(t，2H，J＝8.0Hz)；MS(ESI ⁺)m/z?462.2(M+H) ⁺。

Embodiment 304

1-(3-fluoro-4-(6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea, trifluoroacetate

According to embodiment 301 described similar programs, 3-fluoro-4-(6-(pyridin-4-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline (16mg, 0.05mmol, the Compound D of embodiment 302) is converted into title compound (6.5mg, 26%). ¹H?NMR(DMSO-d ₆)δ10.99(s，1H)，10.55(s，1H)，9.04(s，1H)，8.78(d，2H，J＝6.4Hz)，8.31(d，2H，J＝6.4Hz)，8.20(s，2H)，7.96(s，1H)，7.72(m，1H)，7.09-7.44(m，6H)，3.69(s，2H)；MS(ESI ⁺)m/z501.2(M+H) ⁺。

Embodiment 305

N-(4-(6-(3-dimethylamino) propoxy-)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also)-3-fluorophenyl)-2,6-difluorobenzamide, hydrogen chlorate

According to embodiment 134 described similar programs, (6-(3-(dimethylamino) propoxy-)-5-methylpyrrole is [2,1-f] [1 also with 4-, 2,4] triazine-4-base oxygen base)-3-fluoroaniline (36mg, 0.1mmol, the compd B of embodiment 32) is converted into title compound (20mg, 40%). ¹H?NMR(DMSO-d ₆)δ11.17(s，1H)，10.40(s，1H)，8.00(d，2H，J＝4.0Hz)，7.86(d，1H，J＝12.0Hz)，7.65(m，1H)，7.5?1(d，2H，J＝5.0Hz)，7.29(t，2H，J＝8.0Hz)，4.15(m，2H)，3.24(m，2H)，2.80(s，6H)，2.40(s，3H)，2.18(m，2H)；MS(ESI ⁺)m/z?500.3(M+H) ⁺。

Embodiment 306

2,5-two chloro-N-(4-(6-(3-dimethylamino) propoxy-)-5-methylpyrrole is [2,1-f] [1,2,4] triazine-4-base oxygen base also)-3-fluorophenyl) niacinamide, the hydrogen chlorate

According to embodiment 1 34 described similar programs, ((3-(dimethylamino) propoxy--5-methylpyrrole is [2,1-f] [1 also for 6-with 4-, 2,4] triazine-4-base oxygen base)-3-fluoroaniline (36mg, 0.1mmol, the compd B of embodiment 32) is converted into title compound (10mg, 18%). ¹H?NMR(DMSO-d ₆)δ11.12(s，1H)，10.50(s，1H)，8.69(s，1H)，8.42(s，1H)，8.00(s，1H)，7.86(d，1H，J＝12Hz)，7.52(s，1H)，7.38(s，1H)，7.25(s，1H)，7.12(s，1H)，4.12(m，2H)，3.26(m，2H)，2.78(s，6H)，2.41(s，3H)，2.20(m，2H)；MS(ESI ⁺)m/z?533.2(M+H) ⁺。

Embodiment 307

1-(3-fluoro-4-(5-methyl-6-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 4-hydroxy-5-methyl base pyrrolo-[2,1-f] [1,2,4] triazine-6-acyl cyanide (4-Hydroxy-5-methylpyrrolo[2,1-f] [1,2,4] triazine-6-carbohydrazide)

4-hydroxy-5-methyl base pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid, ethyl ester (467mg, 2.11mmol, preparation: referring to United States Patent (USP) 6,670,357) is dissolved in N ₂H ₄H ₂O/ ethanol (4: 1,5mL).Under 88 ℃, with this solution heating 4 hours, it is cooled to room temperature, and concentrates in a vacuum, obtain title compound (450mg,＞95%).MS(ESI ⁺)m/z?208.1(M+H) ⁺。

B) 4-chloro-5-methyl-6-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyrrolo-[2,1-f] [1,2,4] triazine

(50mg 0.83mmol) is added into that 4-hydroxy-5-methyl base pyrrolo-[2,1-f] [1,2,4] triazine-(100mg is 0.48mmol) in POCl for the 6-acyl cyanide with acetate ₃(5mL) in the formed suspension.Under 80 ℃,, it is cooled to room temperature, and concentrates in a vacuum this reaction mixture heating 3 days.Resulting residue be dissolved in ethyl acetate and handled with saturated sodium bicarbonate aqueous solution, salt solution, and with it through dried over mgso.After successively filtering and concentrating, obtain title compound, it is directly used in next reaction.MS(ESI ⁺)m/z?250.1/252.1(M+H) ⁺。

C) 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyrrolo-[2,1-f] [1,2,4] triazine

According to the described similar program of the step C of embodiment 300,4-chloro-5-methyl-6-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyrrolo-[2,1-f] [1,2,4] triazine is converted into title compound (50mg, two steps totally 28%).MS(ESI ⁺)m/z?371.2(M+H) ⁺。

D) 3-fluoro-4-(5-methyl-6-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) aniline

According to the described similar program of the step D of embodiment 300, with 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyrrolo-[2,1-f] [1,2,4] (50mg 0.13mmol) is converted into title compound (45mg,＞95%) to triazine.MS(ESI ⁺)m/z?341.2(M+H) ⁺。

E) 1-(3-fluoro-4-(5-methyl-6-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

According to embodiment 301 described similar programs, with 3-fluoro-4-(5-methyl-6-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) (20mg 0.06mmol) is converted into title compound (11mg, 35%) to aniline. ¹H?NMR(CDCl ₃)δ10.80(s，1H)，8.69(s，1H)，8.18(s，1H)，7.96(s，1H)，7.70(m，1H)，7.10-7.30(m，6H)，3.75(s，2H)，2.92(s，3H)，2.64(s，3H)；MS(ESI ⁺)m/z?520.2(M+H) ⁺。

Embodiment 308

N ¹-(3-fluoro-4-(5-methyl-6-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) phenyl)-N ³-(4-fluorophenyl) Malonamide

According to the described similar program of the step e of embodiment 300, with 3-fluoro-4-(5-methyl-6-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyrrolo-[2,1-f] [1,2,4] triazine-4-base oxygen base) (20mg 0.06mmol) is converted into title compound (8mg, 26%) to aniline. ¹H?NMR(CDCl ₃)δ9.26(s，1H)，8.47(s，1H)，8.21(s，1H)，7.96(s，1H)，7.80(m，1H)，7.50(m，2H)，7.10-7.30(m，4H)，3.60(s，2H)，2.93(s，3H)，2.69(s，3H)；MS(ESI ⁺)m/z?520.1(M+H) ⁺。

Embodiment 309

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-6-methyl-2-ketone group-1,2-dihydropyridine-3-methane amide

A) 1-(4-fluorophenyl)-6-methyl-2-ketone group-1,2-dihydropyridine-3-formic acid

According to step B and the similar mode of C of embodiment 294, standing and get by 2-hydroxyl-6-methylnicotinic acid (Aldrich). ¹H?NMR(DMSO-d ₆)δ8.41(d，1H，J＝6.5Hz)，8.08(s，1H)，7.51-7.48(m，4H)，6.81(d，1H，J＝6.5Hz)，2.10(s，3H)；MS(ESI ⁺)m/z?248(M+H) ⁺。

B) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-6-methyl-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step D of embodiment 294, preparation and get (productive rate 21%). ¹HNMR(DMSO-d ₆)δ12.11(s，1H)，11.83(s，1H)，8.56(d，1H，J＝6.5Hz)，8.13(d，1H，J＝5.5Hz)，8.01(dd，1H，J＝10.4，2.6Hz)，7.56-7.50(m，7H)，6.78(d，1H，J＝6.5Hz)，6.44(d，1H，J＝5.5Hz)，6.30(s，1H)，2.14(s，3H)；MS(ESI ⁺)m/z?473(M+H) ⁺。

Embodiment 310

4-(2-fluoro-4-(3-(2-(4-fluorophenyl) ethanoyl) urea groups) phenoxy group)-1H-pyrrolo-[2,3-b] Nicotinicum Acidum methyl esters

A) 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] Nicotinicum Acidum methyl esters

With 1N sodium hydroxide (10mL, 10mmol) be added into 2,2,2-three chloro-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethyl ketone (490mg, 1.17mmol, referring to: the steps A of embodiment 270) in the formed solution of mixed solvent (10mL methyl alcohol and 10mL THF).To temperature, this reaction mixture was stirred 3 hours, and diluted with ethyl acetate (30mL).Clean organic layer with saturated sodium bicarbonate aqueous solution, give drying and concentrated in a vacuum, obtain being the desired product of light brown solid (235mg, 61%).MS(ESI ⁺)m/z?332.2(M+H) ⁺。

B) 4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] Nicotinicum Acidum methyl esters

With ammonium chloride (185mg, 3.45mmol) and zinc powder (226mg, 3.45mmol) (230mg is 0.69mmol) in the formed solution of mixed solvent (10mL methyl alcohol and 10mL THF) to be added into 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] Nicotinicum Acidum methyl esters.At room temperature, this reaction mixture is stirred a whole night, (50mL) diluted with ethyl acetate, and it is passed through Celite ^Pad filters.In a vacuum, resulting filtrate is concentrated, and obtain being the desired product (207mg, 100%) of yellow solid.MS(ESI ⁺)m/z?302.2(M+H) ⁺。

C) 4-(2-fluoro-4-(3-(2-(4-fluorophenyl) ethanoyl) urea groups) phenoxy group)-1H-pyrrolo-[2,3-b] Nicotinicum Acidum methyl esters

According to the similar mode of the step C of embodiment 132, preparation and get (61mg, 36%). ¹HNMR(DMSO-d ₆)δ11.01(s，1H)，10.54(s，1H)，8.15(s，1H)，8.14(d，1H，J＝5.5Hz)，7.74(dd，1H，J＝12.5，2.2Hz)，7.31-7.36(m，3H)，7.14-7.19(m，3H)，6.45(d，1H，J＝5.5Hz)，3.73(s，2H)，3.69(s，3H)。MS(ESI ⁺)m/z?481.1(M+H) ⁺。

Embodiment 311

1-(3-fluoro-4-(3-(methylol)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

Embodiment 312

1-(3-fluoro-4-(3-(methoxymethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

With DIBAL-H (1.5M; solution in toluene; 133 μ L; 0.2mmol; Aldrich) be added into 4-(2-fluoro-4-(3-(2-(4-fluorophenyl) ethanoyl) urea groups) phenoxy group)-1H-pyrrolo-[2; 3-b] pyridine-3-carboxylic acid methyl esters (19.2mg, 0.04mmol, the Compound C of embodiment 310) is in the formed solution under 0 ℃ of THF (1mL).Under 0 ℃, this reaction mixture was stirred 2 hours, and by adding 2mL methyl alcohol cancellation reaction.In a vacuum, this reaction mixture is concentrated, and, carry out purifying by preparation HPLC.With part merging of desired level, concentrate and give lyophilize in a vacuum, obtain white solid.LC/MS shows that this solid contains two kinds of compounds.By rapid column chromatography method (ISCO RediSep ^The silica gel filter cylinder is with 1-10% ethanol/methylene wash-out), with this solid purifying once more, obtain the compound of embodiment 311 and 312.1-(3-fluoro-4-(3-(methylol)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea (embodiment 311,7.47mg, 42%): ¹H NMR (DMSO-d ₆) δ 11.47 (s, 1H), 10.94 (s, 1H), 10.49 (s, 1H), 7.92 (d, 1H, J=5.5Hz), 7.68 (dd, 1H, J=13.2,2.2Hz), 7.31-7.19 (m, 5H), 7.09 (t, 2H, J=8.8Hz), 6.10 (d, 1H, J=5.5Hz), 4.68 (q, 1H, J=5.5Hz), 4.65 (d, 1H, J=5.5Hz), 3.67 (s, 2H); MS (ESI ⁺) m/z 453.3 (M+H) ⁺1-(3-fluoro-4-(3-(methoxymethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea (embodiment 312): ¹HNMR (DMSO-d ₆) δ 11.67 (s, 1H), 10.97 (s, 1H), 10.64 (s, 1H), 7.96 (d, 1H, J=5.5Hz), 7.68 (d, 1H, J=12.5Hz), 7.34-7.28 (m, 5H), 7.23 (t, 1H, J=8.8Hz), 7.01 (t, 2H, J=8.8Hz), 6.16 (d, 1H, J=5.5Hz), 4.54 (s, 2H), 3.70 (s, 2H), 3.18 (s, 3H); MS (ESI ⁺) m/z 467.2 (M+H) ⁺

Embodiment 313

N-(6-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-5-chloropyridine-3-yl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, trifluoroacetate

A) 4-(3-chloro-5-nitropyridine-2-base oxygen base)-1H-pyrrolo-[2,3-b] pyridine

(240mg 1.74mmol) is added into 1H-pyrrolo-[2,3-b] pyridine-4-alcohol (210mg, 1.56mmol is referring to Thibault, C.et al.Org.Lett.2003,5,5023) in the formed solution of 3mL MeCN with salt of wormwood.This suspension was stirred 10 minutes, and with 2,3-two chloro-5-nitropyridines (270mg, 1.40mmol, referring to: Koch, V.and Schnatterer, S.Synthesis, 1990,499), handled.Reaction mixture was stirred 12 hours, again with the 20mL shrend reaction of going out.With this solution of ethyl acetate extraction, and clean organic layer with salt solution, and with it through dried over mgso.Behind filtration and vacuum concentration, utilize rapid column chromatography method (ISCO RediSep ^The silica gel filter cylinder), with resulting residue purifying, obtain title compound (220mg, 54%).MS(ESI ⁺)m/z?291.1(M+H) ⁺。

B) 6-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-5-chloropyridine-3-amine

According to the described similar program of the step B of embodiment 132, (3-chloro-5-nitropyridine-2-base oxygen base)-(140mg 0.48mmol) is reduced to title compound (90mg, 72%) to 1H-pyrrolo-[2,3-b] pyridine with 4-.MS(ESI ⁺)m/z?261.1(M+H) ⁺。

C) N-(6-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-5-chloropyridine-3-yl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, trifluoroacetate

According to the described similar program of the step C of embodiment 242, with 6-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-5-chloropyridine-3-amine, (14mg 0.042mmol) is converted into title compound (5.0mg, 20%) to nicotinium dihydrochloride. ¹H?NMR(DMSO-d ₆)δ12.08(s，1H)，11.86(s，1H)，8.67(d，1H，J＝2.0Hz)，8.57(dd，1H，J＝7.0，2.0Hz)，8.41(d，1H，J＝2.0Hz)，8.18(d，1H，J＝5.5Hz)，8.14(dd，1H，J＝6.5，2.0Hz)，7.60(dd，2H，J＝9.0，5.0Hz)，7.38-7.43(m，3H)，6.76(d，1H，J＝5.5Hz)，6.73(t，1H，J＝7.0Hz)，6.08(m，1H)；MS(ESI ⁺)m/z476.2(M+H) ⁺。

Embodiment 314

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, trifluoroacetate

A) 4-(2,5-two fluoro-4-nitrophenoxys)-1H-pyrrolo-[2,3-b] pyridine

According to the described similar program of the steps A of embodiment 313, and use 1,2,4-three fluoro-5-oil of mirbane, (268mg 2.0mmol) is converted into title compound (230mg, 40%) with 1H-pyrrolo-[2,3-b] pyridine-4-alcohol.MS(ESI ⁺)m/z?292.2(M+H) ⁺。

B) 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2, the 5-difluoroaniline

According to the described similar program of the step B of embodiment 132, (230mg 0.79mmol) is converted into title compound (34mg, 17%) with 4-(2,5-two fluoro-4-nitrophenoxys)-1H-pyrrolo-[2,3-b] pyridine.MS(ESI ⁺)m/z?262.2(M+H) ⁺。

C) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, trifluoroacetic acid

According to the described similar program of the step C of embodiment 242, with 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2, the 5-difluoroaniline, (14mg 0.042mmol) is converted into title compound (4.5mg, 18%) to nicotinium dihydrochloride. ¹H?NMR(DMSO-d ₆)δ12.42(s，1H)，11.86(s，1H)，8.61(dd，1H，J＝7.0，2.0Hz)，8.55(dd，1H，J＝12.5，7.0Hz)，8.15(dd，1H，J＝6.5，2.0Hz)，8.10(d，1H，J＝6.5Hz)，7.57-7.62(m，3H)，7.40-7.44(m，3H)，6.75(t，1H，J＝7.0Hz)，6.47(d，1H，J＝5.5Hz)，6.29(m，1H)；MS(ESI ⁺)m/z?477.2(M+H) ⁺。

Embodiment 315

1-(3-fluoro-4-(3-(2-hydroxyethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

A) 2-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl)-2-ketone group ethyl ester

With sodium formiate (52mg, 0.75mmol, Aldrich) be added into 2-bromo-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethyl ketone (100mg, 0.25mmol, the compd A of embodiment 253) and in the formed solution of 1mL DMF.At room temperature, this reaction mixture was stirred 4 hours, and with saturated K ₂HPO ₄The aqueous solution (2mL) is diluted.Utilize filtration method, collect formed throw out, cleaned with cold water (2mL) and ether (5mL), and dry in a vacuum, and obtain being the desired product of light brown solid (81mg, 90%).MS(ESI ⁺)m/z360.16(M+H) ⁺。

B) 1-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethane-1,2-glycol and 2-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethanol

(1M solution, in THF, 1.0mL 1.0mmol) is added into anhydrous aluminum hydride (266mg, 2.0mmol, Alfa Aesar) in 5mL 1, in the formed suspension under 0 ℃ of 2-glycol dimethyl ether with lithium aluminum hydride.Dropwise add 2-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl)-2-ketone group ethyl ester (72mg, 0.2mmol) in 5mL 1, the formed solution of 2-glycol dimethyl ether.At room temperature, this reaction mixture was stirred 2 hours, and by adding 5mL cold water, the cancellation reaction.With ethyl acetate (3 * 30mL) extract this mixture, and with the organic extract liquid that merges through dried over mgso, concentrated and utilized rapid column chromatography method (ISCO RediSep in a vacuum ^The silica gel filter cylinder is with 2-10% methyl alcohol (in methylene dichloride) wash-out) carry out purifying, and obtain 1-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethane-1,2-glycol (27mg, 45%): MS (ESI ⁺) m/z 304.3 (M+H) ⁺) and 2-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethanol (10mg, 18%): MS (ESI ⁺) m/z 288.3 (M+H) ⁺

C) 1-(3-fluoro-4-(3-(2-hydroxyethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

Adopt and embodiment 264 described similar programs, get by 2-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethanol preparation (4.5mg, 28%). ¹HNMR(CD ₃OD)δ10.74(s，1H)，8.06(d，1H，J＝5.5Hz)，7.74(d，1H，J＝12.1Hz)，7.29-7.25(m，4H)，7.00-6.96(m，3H)，6.51(d，1H，J＝5.5Hz)，3.80(t，2H，J＝6.6Hz)，3.62(s，2H)，3.06(t，2H，J＝6.6Hz)；MS(ESI ⁺)m/z?467.3(M+H) ⁺。

Embodiment 316

1-(4-(3-(1, the 2-dihydroxy ethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

Embodiment 317

1-(3-fluoro-4-(3-(2-hydroxyl-1-methoxy ethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea

Embodiment 316 and 317 compound by with embodiment 264 described similar programs, by 1-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) ethane-1, the 2-glycol (referring to: the step B of embodiment 315) preparation and.In a vacuum, reaction mixture is concentrated and utilize preparation HPLC, carry out purifying.With part merging of desired level, concentrate and give lyophilize in a vacuum, and obtain white solid.LC/MS shows and contains 1-by this solid ((3-(1 for 4-; the 2-dihydroxy ethyl)-1H-pyrrolo-[2; 3-b] pyridin-4-yl oxygen base)-the 3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea and 1-(3-fluoro-4-(3-(2-hydroxyl-1-methoxy ethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea.Utilize rapid column chromatography method (ISCO RediSep ^The silica gel filter cylinder is with 1-10% ethanol/methylene wash-out), with this solid purifying once more, ((3-(1 for 4-to obtain two kinds of product: 1-, the 2-dihydroxy ethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-the 3-fluorophenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea (6.3mg, 17%); ¹H NMR (DMSO-d ₆) δ 11.57 (s, 1H), 11.03 (s, 1H), 10.59 (s, 1H), 7.99 (d, 1H, J=5.5Hz), 7.77 (dd, 1H, J=12.6,2.2Hz), 7.41-7.32 (m, 4H), 7.28 (d, 1H, J=2.2Hz), 7.18 (t, 1H, J=8.8Hz), 7.01 (t, 2H, J=8.8Hz), 6.15 (d, 1H, J=5.5Hz), 5.05 (m, 1H), 4.91 (d, 1H, J=4.4Hz), 4.60 (t, 1H, J=5.8Hz), 3.79-3.75 (m, 1H), 3.75 (s, 2H), 3.47-3.44 (m, 1H); MS (ESI ⁺) m/z483.3 (M+H) ⁺1-(3-fluoro-4-(3-(2-hydroxyl-1-methoxy ethyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) ethanoyl) urea (3.2mg, 8%): ¹HNMR (CD ₃OD) δ 8.05 (d, 1H, J=5.5Hz), 7.71 (d, 1H, J=12.1Hz), 7.37 (s, 1H), 7.28-6.25 (m, 4H), 6.98 (t, 1H, J=8.2Hz), 6.45 (d, 1H, J=5.5Hz), 3.81 (m, 1H), 3.73-3.71 (m, 2H), 3.63 (s, 2H), 3.34 (s, 3H); MS (ESI ⁺) m/z 497.2 (M+H) ⁺

Embodiment 318

6-(4-fluorophenyl)-1-oxygen base-pyridine-2-carboxylic acids [2-fluoro-4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl] acid amides

According to embodiment 241 similar modes, the preparation and get.HPLCt _R(YMC S5ODS 4.6 * 50mm, the 10-90% methanol aqueous solution (contained 0.2%H in=3.328 minutes ₃PO ₄), 4 minutes gradients detect at 220nm); MS (ESI ⁺) m/z 459.2 (M+H) ⁺

Embodiment 319

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(2-(3-(dimethylamino) propoxy-) phenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, hydrogen chlorate

A) 1-(2-(3-(dimethylamino) propoxy-) phenyl)-2-ketone group-1,2-dihydropyridine-3-formic acid

According to mode like the steps A of embodiment 242 and the category-B, preparation and getting. ¹HNMR (DMSO-d ₆) δ 10.53 (br m, 1H), 8.51-8.53 (m, 1H), 8.18-8.20 (m, 1H), 7.48-7.51 (m, 2H), 7.30 (d, 1H, J=7.96Hz), 7.13-7.17 (m, 1H), 6.82 (t, 1H, J=6.95Hz), 4.11-4.18 (m, 2H), 2.66-2.68 (m, 2H), 2.67 (s, 6H), 1.98-2.05 (m, 2H); HRMS (ESI ⁺), theoretical value: 317.1501; Measured value: 317.1490.

B) N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(2-(3-(dimethylamino) propoxy-) phenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide, hydrogen chlorate

According to the similar mode of the step C of embodiment 242, the preparation and get. ¹HNMR (CD ₃OD) δ 8.62-8.65 (m, 1H), 8.23 (d, 1H, J=6.90Hz), 7.98-8.01 (m, 1H), and 7.83-7.85 (m, 1H), 7.39-7.50 (m, 2H), 7.31-7.49 (m, 3H), 7.20 (d, 1H, J=7.93), 7.10-7.13 (m, 1H), 6.80 (d, 1H, J=6.72Hz), 6.69 (t, 1H, J=6.75Hz), 6.59-6.60 (m, 1H), 4.12 (t, 2H, J=5.61Hz), 3.02-3.06 (m, 2H), 2.70 (s, 6H), 2.03-2.04 (m, 2H); HRMS (ESI ⁺), theoretical value: 542.2204; Measured value: 542.2194.

Embodiment 320

6-(4-fluoro-phenyl)-1-oxygen base-pyridine-2-carboxylic acids [2-chloro-5-fluoro-4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides

According to embodiment 241 similar modes, the preparation and get.HPLCt _R=3.293 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 493 (M+H) ⁺

Embodiment 321

6-(4-fluoro-phenyl)-1-oxygen base-pyridine-2-carboxylic acids [2-bromo-5-fluoro-4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides

According to embodiment 241 similar modes, the preparation and get.HPLCt _R=3.371 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 537 (M+H) ⁺

Embodiment 322

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-chloro-5-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step C of embodiment 242, the preparation and get.HPLCt _R=3.070 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 493 (M+H) ⁺

Embodiment 323

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-bromo-5-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step C of embodiment 242, the preparation and get.HPLCt _R=3.115 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 538 (M+H) ⁺

Embodiment 324

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-chloro-phenyl-)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step C of embodiment 242, the preparation and get.HPLCt _R=2.946 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 475 (M+H) ⁺

Embodiment 325

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-methoxyphenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step C of embodiment 242, the preparation and get.HPLCt _R=2.795 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 471 (M+H) ⁺

Embodiment 326

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-cyano-phenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step C of embodiment 242, the preparation and get.HPLCt _R=2.618 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 466 (M+H) ⁺

Embodiment 327

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-chloro-6-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step C of embodiment 242, the preparation and get.HPLCt _R=2.805 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 493 (M+H) ⁺

Embodiment 328

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2,6-difluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step C of embodiment 242, the preparation and get.HPLCt _R=2.653 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 477 (M+H) ⁺

Embodiment 329

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-methyl-4-fluorophenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step C of embodiment 242, the preparation and get.HPLCt _R=3.010 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 473 (M+H) ⁺

Embodiment 330

N-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-2-trifluoromethyl-phenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

According to the similar mode of the step C of embodiment 242, the preparation and get.HPLCt _R=2.943 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 509 (M+H) ⁺

Embodiment 331

6-(4-fluoro-phenyl)-1-oxygen base-pyridine-2-carboxylic acids [2-trifluoromethyl-4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides

According to embodiment 241 similar modes, the preparation and get.HPLCt _R=3.205 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 509 (M+H) ⁺

Embodiment 332

6-(4-fluoro-phenyl)-1-oxygen base-pyridine-2-carboxylic acids [2-fluoro-4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides

According to embodiment 241 similar modes, the preparation and get.HPLCt _R(YMC S5ODS 4.6 * 50mm, the 10-90% methanol aqueous solution (contained 0.1%H in=1.103 minutes ₃PO ₄), 4 minutes gradients detect at 220 nm); MS (ESI ⁺) m/z 459 (M+H) ⁺

Embodiment 333

6-(4-fluoro-phenyl)-1-oxygen base-pyridine-2-carboxylic acids [2-methyl-4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides

According to embodiment 241 similar modes, the preparation and get.HPLCt _R=3.120 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 455 (M+H) ⁺

Embodiment 334

6-(4-fluoro-phenyl)-1-oxygen base-pyridine-2-carboxylic acids [5-chloro-4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-phenyl]-acid amides

According to embodiment 241 similar modes, the preparation and get.HPLCt _R=3.200 minutes (4 minutes gradients detect at 220nm for Chromolith SpeedROD 4.6 * 50mm, 10-90% methanol aqueous solution (containing 0.1%TFA)); MS (ESI ⁺) m/z 475 (M+H) ⁺

Embodiment 335

N-(3-fluoro-4-(3-(3-hydroxypropyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-methane amide

A) 4-(2-fluoro-4-nitrophenoxy)-3-(3-hydroxyl third-1-alkynyl)-1H-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester

With argon gas stream feed 4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester (400mg, 0.8mmol, the compd B of embodiment 283), propargyl alcohol (90mg, 1.6mmol), Pd (dppf) ₂Cl ₂: CH ₂Cl ₂(66mg, 0.08mmol) and CuI (40mg) in triethylamine (0.8mL) and the formed mixture of THF (6mL), last 5 minutes.This reaction mixture is sealed in the test tube, and under 75 ℃, heated 1 hour.Dilute this mixture with methylene dichloride, and cleaned with salt solution.Organic layer through dried over mgso, and is concentrated in a vacuum.Utilize rapid column chromatography method (silica gel, 30% ethyl acetate/dichloromethane),, and obtain being the desired product (220mg, productive rate 64%) of yellow solid resulting rough residue purifying.LC/MS(ESI ⁺)m/z428(M+H) ⁺。

B) 3-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) propane-1-alcohol

Under 1 normal atmosphere, with 4-(2-fluoro-4-nitrophenoxy)-3-(3-hydroxyl third-1-alkynyl)-1H-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester (50mg, 0.15mmol) and 10%Pd/C (contain 50% water, 120mg) in THF (10mL) and the formed mixture hydrogenation of methyl alcohol (2mL) 5 hours.Dilute this mixture with methyl alcohol, and it is passed through Celite ^Pad filters.Utilize preparation HPLC, should resulting crude mixture purifying, and the desired product of solid that obtains being white in color (6mg, productive rate 13%).LC/MS(ESI ⁺)m/z?302(M+H) ⁺。

C) N-(3-fluoro-4-(3-(3-hydroxypropyl)-1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base) phenyl)-1-(4-fluorophenyl-2-ketone group-1,2-dihydropyridine-3-methane amide

DIPEA (0.1mL) is added into 3-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo-[2,3-b] pyridin-3-yl) propane-1-alcohol (5mg, 0.0166mmol), 1-(4-fluorophenyl)-2-ketone group-1,2-dihydropyridine-3-formic acid (5.8mg, 0.025mmol, the compd B of embodiment 242), (PerseptiveBiosystems, 10mg is 0.025mmol) in the formed mixture that had stirred of DMF (0.5mL) to reach HATU.At room temperature, this reaction mixture was stirred 2 hours, and concentrate in a vacuum.Utilize preparation HPLC, with resulting residue purifying, and the solid title compound that obtains being white in color (6mg, HCl salt, productive rate 66%). ¹H?NMR(CD ₃OD)δ8.71(dd，1H，J＝7.2，2.0Hz)，8.22(d，1H，J＝6.8Hz)，8.10(dd，1H，J＝12.4，2.0Hz)，8.00(dd，1H，J＝6.4，2.0Hz)，7.25-7.60(m，7H)，7.70-7.80(m，2H)，3.64(t，2H，J＝6.4Hz)，3.05(t，2H，J＝7.2Hz)，2.00(m，2H)；LC/MS(ESI ⁺)m/z?517(M+H) ⁺。

Claims

1. compound with formula I or II,

Comprise their pharmacy acceptable salts,

Wherein:

B is O, NR ⁸, S, SO, SO ₂, CR ⁹R ¹⁰

V is NR ¹¹Or-(CR ⁴⁷R ⁴⁸) _p-;

W or X independently are C or N;

Y is O, S or NR ¹²

Z is-CR ¹³R ¹⁴-,-(CR ¹³R ¹⁴) _mNR ¹⁵-;

L is 0 to 4;

M is 0 to 2;

N is 0 to 4;

A is:

Q is CR ¹⁹

D is CR ²⁰Or N;

G is S, O or NR ²¹, preceding topic condition is: if A is

And G is S, then R ⁴It is not the phenyl that is substituted;

R ¹²Be H, alkyl, the alkyl that is substituted, CN, NO ₂Or SO ₂NH ₂

R ¹⁶, R ¹⁷, R ¹⁸, R ²⁰, R ²², R ²³, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶, R ⁶⁷, R ⁶⁸, R ⁶⁹, R ⁷⁰, R ⁷⁵, R ⁷⁶, R ⁷⁸, and R ⁷⁹Independent separately is H, halogen, NO ₂, cyano group, OR ²⁶, NR ²⁷R ²⁸, CO ₂R ²⁹, C (O) NR ³⁰R ³¹, SO ₂R ³², SO ₂NR ³³R ³⁴, NR ³⁵SO ₂R ³⁶, NR ³⁷C (O) R ³⁸, NR ³⁹CO ₂R ⁴⁰,

-CO (CH ₂) ₁R ⁴¹,-CONH (CH ₂) ₁R ⁴², alkyl amino alkyl, alkylamino alkynyl group, C ₁-C ₆Alkyl, the C that is substituted ₁-C ₆Alkyl, C ₃-C ₇Cycloalkyl, the C that is substituted ₃-C ₇Cycloalkyl, alkenyl, the alkenyl that is substituted, alkynyl group, the alkynyl group that is substituted, hydroxyalkyl, aryl, the aryl that is substituted, heteroaryl, the heteroaryl that is substituted, aralkyl, the aralkyl that is substituted, Heterocyclylalkyl or the Heterocyclylalkyl that is substituted;

R ¹⁹Be H or cyano group;

2. compound as claimed in claim 1, wherein R ¹Be the optional C that is substituted ₁-C ₆Alkyl, alkenyl, alkynyl group, the optional C that is substituted ₃-C ₇Cycloalkyl, C ₃-C ₇Heterocyclylalkyl, the optional phenyl that is substituted, optional xenyl or the C that is substituted ₅-C ₁₁Optional monocycle or the bicyclic heteroaryl that is substituted.

3. compound as claimed in claim 2, wherein R ¹Be selected from optional through Cl, F, OCH ₃, alkyl, alkenyl, alkynyl group, hydroxyl, cyano group, amide group, phenoxy group, CH ₂CN, benzyl, NHCO ₂CH ₃The phenyl that is replaced; Xenyl, pyridyl, nitrogen heterocyclic heptyl, pyrazolyl, thiazolyl, indyl, indazolyl, indenyl, cyclopropyl, sec.-propyl, styroyl, aminoalkyl group, benzyl, amido alkyl, morpholinyl or furyl methyl.

4. compound as claimed in claim 1, wherein R ²Be H, methyl, alkoxyl group, halogen, alkylhalide group or cyano group.

5. compound as claimed in claim 1, wherein R ⁴Be the optional phenyl that is substituted, the optional pyridyl that is substituted, the optional pyrrolidyl that is substituted, the optional pyridyl-N-oxygen base that is substituted or the optional pyridone that is substituted.

6. compound as claimed in claim 5, wherein this phenyl, pyridyl, pyridone or N-oxygen yl pyridines base are through hydroxyl, halogen, C ₁-C ₄Alkyl, C ₃-C ₇Cycloalkyl ,-COCH ₃, alkoxyl group, amino, Heterocyclylalkyl, amino alkylamino, cyano group, alkylthio, phenyl or alkylamino alkoxyl group replace.

7. compound as claimed in claim 6, wherein this substituting group is F, Br, Cl, methyl, amyl group, methoxyl group, phenyl, morpholinyl, NH ₂, or NHCHNH ₂

8. compound as claimed in claim 1, wherein A is

9. compound as claimed in claim 8, wherein R ¹⁹Be H or CN; R ¹⁶And R ¹⁷Independent is H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or-C (O) ₂R ₂₉, R wherein ²⁹Be C ₁-C ₄Alkyl, and R ¹⁸Be H.

10. compound as claimed in claim 8, wherein R ²²And R ⁶¹Be H.

11. compound as claimed in claim 8, wherein R ⁶⁸, R ⁶⁹And R ⁷⁰Be H; R ²⁰Be C ₁-C ₄Alkyl; Alkenyl; Alkynyl group; C ₅-C ₆Heterocyclic aryl; CO (CH ₂) ₁R ⁴¹, R ⁴¹Be C ₁-C ₄Alkyl, alkylhalide group, amino, alkylamino, C ₅-C ₇Heterocyclylalkyl or C ₅-C ₇Heteroaryl; C (O) ₂R ²⁹, R wherein ²⁹Be ethyl; CN; Alkoxyl group; Phenmethyl; The alkylamino alkynyl group; Alkyl amino alkyl; Hydroxyalkyl; Or methoxyl group alkyl.

12. compound as claimed in claim 8, wherein A is

13. compound as claimed in claim 1, wherein Y is O or S.

14. compound as claimed in claim 1, wherein B is O.

15. compound as claimed in claim 1, wherein Z is-CR ¹³R ¹⁴Or NR ¹⁵, wherein, R ¹³, R ¹⁴, and R ¹⁵Respectively be H, or R ¹³And R ¹⁴Form cyclopropyl with the carbon that they connected.

16. compound as claimed in claim 1, wherein R ⁴Be phenyl.

17. compound as claimed in claim 1, wherein R ⁴Be pyridyl.

18. compound as claimed in claim 1, wherein R ⁴Be pyrrolidyl.

19. compound as claimed in claim 1, wherein R ⁴Be pyridyl-N-oxygen base.

2O. compound as claimed in claim 1, wherein R ⁴Be pyridone.

21. as the compound of claim 12, wherein R ²⁰For-COCH ₂-R, wherein R is amino, tetramethyleneimine or piperazine.

22. as the compound of claim 12, wherein R ²⁰Be pyridine or thiazole.

23. as the compound of claim 12, wherein R ²⁰For-COC (Cl) ₃Or CONHCH ₂Pyridine.

24. as the compound of claim 12, wherein R ²⁰Be CH ₂Piperidines, CH ₂Phenyl ,-C ≡ C-amino, cyano group ,-CO ₂CH ₃-,-CH ₂OH-, CH ₂OMe, hydroxyethyl ,-CHOH (CH ₂) ₂OH or CH (OCH ₃) CH ₃

25. compound as claimed in claim 1, its IC ₅₀Value is less than about 5 μ M.

26. compound as claimed in claim 1, its IC ₅₀Value is less than about 1 μ M.

27. a treatment method for cancer, it comprises the compound with formula I or II to the claim 1 of patient's drug treatment significant quantity of needs treatment.

28. a medical composition, it comprises the compound and the pharmaceutically acceptable carrier of the claim 1 for the treatment of significant quantity.

29. the method for claim 18, it also comprises at least a other carcinostatic agent of described patient's administration.