CN101321751A

CN101321751A - Met kinase inhibitors

Info

Publication number: CN101321751A
Application number: CNA2006800451122A
Authority: CN
Inventors: 罗伯特·M·博齐勒里; 陈小涛; 戴维·K·威廉斯; 约翰·S·托卡斯基; 罗伯特·F·卡腾巴克
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2005-09-30
Filing date: 2006-09-29
Publication date: 2008-12-10

Abstract

The present invention is directed to compounds having the formula I or II: including salts thereof, and methods for using them for the treatment of cancer.

Description

The Met kinase inhibitor

Related application

The application requires the U.S. Provisional Application No.60/722 that submitted on September 30th, 2005 according to Title 35 § 119 (e), and 089 right of priority is incorporated herein by reference its content at this.

Technical field

The present invention relates to suppress the compound of the protein hydroxyphenylaminopropionic acid kinase activity of growth factor receptors (such as c-Met), make these compound useful as anti-cancer agents thus.The pharmaceutical composition that comprises these compounds also can be used for treating the disease except that cancer, and described disease is relevant with the signal transduction pathway that plays a role by somatomedin and angiogenesis inhibitor acceptor (anti-angiogenesis receptor) (such as c-Met).

Background technology

PHGF (HGF), because it can form at external destruction colony and be also referred to as dispersion factor (scatter factor, SF), HGF is a mesenchyme deutero-cytokine, it is known induces multiple multiple-effect to reply (pleiotropic response) (Sonnenberg et al. in normal cell and tumour cell, J.CellBiol.123:223-235,1993, Matsumato et al., Crit.Rev.Oncog.3:27-54,1992 and Stoker et al., Nature 327:239-242,1987).Known these are replied the propagation that comprises epithelial cell and endotheliocyte, epithelium colony (epithelial colony) is dissociated into one cell, stimulate epithelial cell mobility (motogenesis), cell survival, (Montesano et al. takes place in the inducing cell form, Cell67:901-908,1991) and promote to invade (invasion) (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 these critical process all are the bases of shifting.Reported also that HGF promoted vasculogenesis (Bussolino et al., J.Cell Biol.119:629-641,1992).In addition, HGF brings into play keying action in tissue regeneration, wound healing and normal embryo development (embryonic process), and all these processes all depend on cell mobility and propagation.

HGF is owing to the high-affinity of related acceptor with it (cognate receptor) causes these physiological processs, described related acceptor is a Met protein tyrosine kinase acceptor, a kind of definite proto-oncogene (Park et al., Proc.Natl.Acad.Sci.USA 84:6379-83,1987 and Bottaro et al., Science 251:802-4,1991).The mature form of Met is made up of together with big extracellular domain, transmembrane segment and tenuigenin tyrosine kinase domain the outside alpha subunit and the β subunit of high glycosylation.Aglucon zygotic induction Met dimerization, this generates the activated receptor of autophosphorylation.The activation of Met promotes following signal transduction cascade (signal transduction cascade), described signal transduction cascade is by the commentaries on classics phosphorylation of raising the key cells matter tyrosine residues that multiple effect protein (effector protein) works is limited (Furge et al., Oncogene 19:5582-9,2000).These signal transduction cascades comprise the kinase whose p85 of PI3 subunit, Phospholipase C γ (Gaul et al., Oncogene 19:1509-18,2000), Grb2 and Shc adaptin, protein phosphatase SHP2 and Gab1.Just now the described adaptin in back (adapter) occurred as main downstream anchored molecule (docking molecule), described downstream anchored molecule becomes in response to aglucon captures by the tyrosine of phosphorylation (Schaeper et al., J.Cell Biol.149:1419-32,2000, Bardelli, et al., Oncogene 18:1139-46,1999 and Sachs et al., J.Cell Biol.150:1375-84,2000).Reported the activation of other signal transduction molecule in the HGF stimulated cells, it should be noted that most Ras, map kinase, STATs, ERK-1, ERK-2 and FAK (Tanimura et al., Oncogene 17:57-65,1998, Lai et al., J.Biol.Chem.275:7474-80 2000 and Furge et al., Oncogene 19:5582-9,2000).Determined the effect of multiple these signal transduction molecules in cell proliferation well.

Met (being also referred to as hepatocyte growth factor receptor (HGFR)) is expressed in the epithelial cell to dominance, but is also determined in endotheliocyte, sarcoplast, hematopoietic cell and motor neuron.Crossing of HGF expressed and the activation of Met and the generation and the progress and related of multiple different tumor types the promotion of metastatic disease (metastatic disease).The initial evidence that Met is related with cancer has obtained the support of the following fact: determined to make individuality to be easy to suffer from corpora mammillaria kidney (papillary renal carcinomas, PRC) and the kinases of hepatocellular carcinoma (HCC) zone missense mutation (Lubensky et al., Amer.J.Pathology, 155:517-26,1999).The mutant form of Met is also determined in following cancer: ovarian cancer, the Childhood HCC (childhood HCC), cancer of the stomach, head and neck squamous cell cancer, nonsmall-cell lung cancer and colorectum metastasis of cancer (colorectal metastasis) (Christensen et al., CancerRes., 63:7345-55,2003, Lee et al., Oncogene, 19:4947-53,2000 and Direnzo et al., Clin.Cancer Res., 1:147-54,1995).In addition, support that other evidence of the effect of Met in cancer is that HGF and Met acceptor crossing in kinds of tumors (comprising thyroid carcinoma, ovarian cancer and carcinoma of the pancreas) are expressed.Also certifiedly be, Met is (the Rong et al.Cancer Res.55:1963-1970 of amplification in the hepatic metastases of colorectal carcinoma, 1995, Rong et al., Cancer Res.53:5355-5360,1993, Kenworthy et al., Br.J.Cancer 66:243-247,1992 and Scarpino et al.J.Pathology189:570-575,1999).TPR-Met (a kind of activatory form is similar to the BCR/Abl among the CML) has described in human cancer of the stomach and definite (PNAS 88:4892-6,1991).In the patient who suffers from infiltrative breast carcinoma (invasive breast carcinoma), and in the research to the small cell lung cancer patient in the recent period, the expression of above-mentioned acceptor or aglucon is the index that the prediction survival rate reduces, this is further with related (the Camp et al. with tumour progression of Met, Cancer 86:2259-65 1999 and Masuya et al., Br.J.Cancer 90:1555-62,2004).Usually, the tumor cell line of most of human tumors and mesenchyme origin is expressed HGFR and/or HGF inadequately.

Many experimental datas are supported HGF and the Met effect (finally causing shifting) in tumour intrusion, growth, survival and progress.In preclinical study, the transgene expression of HGF causes transitivity phenotype (metastatic phenotype) (Takayama et al., PNAS, 94:701-6,1997), and amplification/Met that cross to express spontaneously transforms NIH-3T3 cell (Cooper et al., EMBO J., 5:2623-8,1986).

What shown is, the biological substance of target HGF or Met (such as ribozyme, antibody and the sense-rna of target in HGF or Met) can suppress tumour and generate (tumorogenesis) (Stabile et al., GeneTherapy, 11:325-35,2004, Jiang et al., Clin.Cancer Res, 9:4274-81,2003 and Genentech US 6,214,344,2001).Thereby the selectivity small molecules kinase modulator of target Met is supposed to treat in pairs the Met receptor activation and has the treatment potentiality in the cancer that primary tumor and Secondary cases shift performance keying action in the development of (secondarymetastasis) and the progress.Be known that also HGF regulates vasculogenesis, promptly to tumor growth and the crucial process of diffusion.Therefore, the potentiality of this class conditioning agent also can influence the disease of other angiogenesis-dependent except that cancer, comprise diabetic retinopathy, macular degeneration, obesity and inflammatory diseases (such as rheumatoid arthritis).

Summary of the invention

The present invention relates to can be used for the compound that therefore target Met can be used for treating cancer.Particularly, the present invention relates to have compound with following formula I or II:

Wherein

R ¹H, halogen, haloalkyl, cyano group, NO respectively do for oneself ₂, OR ⁶, NR ⁷R ⁸, alkyl, replacement heteroaryl, arylalkyl (arylalkyl), the Heterocyclylalkyl of the arylalkyl, Heterocyclylalkyl or the replacement that replace of aryl, heteroaryl, replacement of cycloalkyl, aryl, replacement of alkyl, cycloalkyl, replacement;

B is O, NR ⁹, S, SO, SO ₂Or CR ¹⁰R ¹¹

W and X independently are C or N separately;

V is CO;

N is 1 to 4;

M is 1 to 4;

P is 0 to 2;

L is 1 to 2;

R ²Cycloalkyl for alkyl, cycloalkyl or the replacement of H, alkyl, replacement;

R ³And R ⁴Independent is the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl or replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkynyl, cycloalkyl, the replacement of thiazolinyl, alkynyl, the replacement of alkyl, thiazolinyl, the replacement of H, halogen, alkyl, replacement, or R ³And R ⁴Form the carbocyclic ring or the heterocycle of 3 to 8 atoms together;

R ⁵For-NR ¹²R ¹³,-OR ¹⁴, alkyl, replacement the Heterocyclylalkyl of arylalkyl, Heterocyclylalkyl or replacement of heteroaryl, arylalkyl, replacement of aryl, heteroaryl, replacement of cycloalkyl, aryl, replacement of alkyl, haloalkyl, cycloalkyl, replacement;

R ⁶, R ⁷, R ⁸And R ⁹Independent separately is the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl or replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkynyl, cycloalkyl, the replacement of thiazolinyl, alkynyl, the replacement of alkyl, thiazolinyl, the replacement of H, alkyl, replacement;

R ¹⁰And R ¹¹Independent separately is the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl or replacement of aryl, benzyl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of H, halogen, alkyl, replacement, or R ¹⁰And R ¹¹Form the carbocyclic ring or the heterocycle of 3 to 8 atoms together;

R ¹²And R ¹³Independent separately is the Heterocyclylalkyl of heteroarylalkyl, Heterocyclylalkyl or replacement of heteroaryl, heteroarylalkyl, the replacement of aryl, heteroaryl, the replacement of arylalkyl, aryl, the replacement of cycloalkyl, arylalkyl, the replacement of alkyl, cycloalkyl, the replacement of H, alkyl, replacement, or R ¹²And R ¹³Form the heterocycle of 3 to 8 atoms together;

For

With

For

A is

Wherein

G is O, S or NR ¹⁰⁶

D is CR ¹⁰⁷Or N;

Z is N or CR ¹⁰⁸

Q is optional carbocyclic ring that comprises 4-8 atom or the heterocycle that replaces;

R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²¹, R ²², R ²³, R ²⁴, R ²⁵, R ²⁶, R ²⁷, R ²⁸, R ²⁹, R ³⁰, R ³¹, R ³⁴, R ³⁵, R ³⁶, R ³⁷, R ³⁸, R ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³, R ⁴⁴, R ⁴⁵, R ⁴⁶, R ⁴⁷, R ⁴⁸, R ⁴⁹, R ⁵⁰, R ⁵¹, R ⁵², R ⁵³, R ⁵⁴, R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸, R ⁵⁹, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶, R ⁶⁷, R ⁶⁸, R ⁶⁹, R ⁷⁰, R ⁷¹, R ⁷², R ⁷³, R ⁷⁴, R ⁷⁵, R ⁷⁶, R ⁷⁷, R ⁷⁸, R ⁷⁹, R ⁸⁰, R ⁸¹, R ⁸², R ⁸⁴, R ⁸⁶, R ⁸⁷, R ⁸⁸, R ⁸⁹, R ⁹⁰, R ⁹¹, R ⁹², R ⁹³, R ⁹⁴, R ⁹⁵, R ⁹⁶, R ⁹⁷, R ⁹⁸, R ⁹⁹, R ¹⁰², R ¹⁰³, R ¹⁰⁴, R ¹⁰⁵, R ¹⁰⁷And R ¹⁰⁸Independent separately is H, halogen, haloalkyl, NO ₂, cyano group, OR ¹⁰⁹, NR ¹¹⁰R ¹¹¹, CO ₂R ¹¹², C (O) NR ¹¹³R ¹¹⁴, SO ₂R ¹¹⁵, SO ₂NR ¹¹⁶R ¹¹⁷, NR ¹¹⁸SO ₂R ¹¹⁹, NR ¹²⁰C (O) R ¹²¹, NR ¹²²CO ₂R ¹²³,-CO (CH ₂) _mR ¹²⁴,-CONH (CH ₂) _mR ¹²⁵, SR ¹²⁶, SOR ¹²⁷, aminoalkyl group, alkylamino alkyl, alkylamino alkylamino, dialkyl aminoalkyl amino, alkylamino alkynyl, C ₁To C ₆The C of alkyl, replacement ₁To C ₆Alkyl, C ₃To C ₇The C of cycloalkyl, replacement ₃To C ₇The Heterocyclylalkyl of arylalkyl, Heterocyclylalkyl or the replacement of the heteroaryl of the aryl of the alkynyl of the thiazolinyl alkyl of the thiazolinyl of cycloalkyl, thiazolinyl, replacement, thiazolinyl alkyl, replacement, alkynyl, replacement, hydroxyalkyl, aryl, replacement, heteroaryl, replacement, arylalkyl, replacement; Or

R ⁴⁰With R ³⁹, or R ⁴⁰With R ⁴¹Form the unsaturated or saturated heterocycle of carbocyclic ring of 3 to 8 atoms together;

R ³², R ³³, R ⁸³And R ⁸⁵Independent separately be H, haloalkyl ,-CO ₂R ¹²⁸,-SO ₂R ¹²⁹,-CO (CH ₂) _mR ¹³⁰, alkylamino alkyl, alkylamino alkynyl, C ₁To C ₆The C of alkyl, replacement ₁To C ₆Alkyl, C ₃To C ₇The C of cycloalkyl, replacement ₃To C ₇The arylalkyl of the heteroaryl of the aryl of cycloalkyl, hydroxyalkyl, aryl, replacement, heteroaryl, replacement, arylalkyl, replacement or Heterocyclylalkyl;

R ¹⁰⁰And R ¹⁰¹Independently be selected from the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl or replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of H, halogen, alkyl, replacement, or R ¹⁰⁰And R ¹⁰¹Form the carbocyclic ring or the heterocycle of 3 to 8 atoms together;

R ¹⁴, R ¹⁰⁶, R ¹⁰⁹, R ¹¹⁰, R ¹¹¹, R ¹¹², R ¹¹³, R ¹¹⁴, R ¹¹⁵, R ¹¹⁶, R ¹¹⁷, R ¹¹⁸, R ¹¹⁹, R ¹²⁰, R ¹²¹, R ¹²², R ¹²³, R ¹²⁴, R ¹²⁵, R ¹²⁶, R ¹²⁷, R ¹²⁸, R ¹²⁹And R ¹³⁰Independent separately is the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl or replacement of arylalkyl, heteroaryl, the replacement of aryl, arylalkyl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of H, alkyl, replacement.

One embodiment of the invention are provided for treating cancer, and especially those comprise the patient that defined formula I of the application or II compound with the treatment significant quantity in pharmaceutically acceptable carrier need this treatment with the method for cancer that patient HGF level or Met expression level improve.

The present invention also relates to comprise the pharmaceutical composition of the defined formula I of the application who treats significant quantity or II compound and pharmaceutically acceptable carrier.

Embodiment

The invention provides formula I defined above or II compound, use these compounds pharmaceutical composition, prepare the method for these compounds and use the method for these compounds.

Below listed be definition to the various terms that are used to describe The compounds of this invention.These definition are applied to the employed everywhere term of specification sheets (unless they have qualification in addition under specific situation), and no matter these terms use the more part of macoradical of still conduct separately.

Unless otherwise defined, the employed term of the application " alkyl " (use separately or as the part of another group) refers to that alkane (hydrocarbon) deutero-comprises the univalent perssad of 1 to 12 carbon atom.Preferred alkyl has 1 to 6 carbon atom.Alkyl is optional straight chain, side chain or the cyclic saturated hydrocarbon base that replaces.Alkyl can be substituted at any available tie point.The alkyl that is substituted with another alkyl is called " branched-chain alkyl ".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 etc.Alkyl can be substituted with and be selected from following substituting group: alkyl, aryl, aryloxy, halogen (such as F, Cl, Br, I), haloalkyl are (such as CCl ₃Or CF ₃), alkoxyl group, alkylthio, hydroxyl ,-CN, nitro, carboxyl (COOH), alkoxy carbonyl (C (O) _nR), the alkyl-carbonyl oxygen base (OCOR), amino (NR ' R "), carbamyl (NHCOOR-or-OCONHR-), urea (NHCONHR-) or sulfydryl (SH).

The employed term of the application " thiazolinyl " (use separately or as the part of another group) refers to comprise straight chain, side chain or the cyclic hydrocarbon group of 2 to 12 carbon atoms and at least one carbon-to-carbon double bond.Thiazolinyl also can be substituted at any available tie point.The exemplary substituting group that is used for thiazolinyl comprises above with regard to those listed substituting groups of alkyl, especially comprises C ₃To C ₇Cycloalkyl, such as cyclopropyl, cyclopentyl and cyclohexyl, these cycloalkyl can further be substituted with for example amino, oxo, hydroxyl etc.

The employed term of the application " alkynyl " (use separately or as the part of another group) refers to comprise straight chain, side chain or the cyclic hydrocarbon group of 2 to 12 carbon atoms and at least one carbon-to-carbon three key.Alkynyl also can be substituted at any available tie point.The exemplary substituting group that is used for alkynyl comprises above with regard to those listed substituting groups of alkyl, such as amino, alkylamino etc.

Index number behind the symbol " C " has defined the number of the carbon atom that concrete group can comprise." C for example ₁To C ₆Alkyl " refer to have a straight or branched saturated carbon chains to six carbon atom; 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 ₁To C ₆Alkyl " also can refer to connect the C of two groups ₁To C ₆Alkylidene group; Example comprises propane-1,3-two bases, butane-1,4-two bases, 2-methyl-butane-1,4-two bases etc." C ₂To C ₆Thiazolinyl " refer to have at least one carbon-to-carbon double bond and have two straight or branched carbochains to six carbon atom; Example comprises vinyl, propenyl, pseudoallyl, butenyl, isobutenyl, pentenyl and hexenyl.Based on context, " C ₂To C ₆Thiazolinyl " also can refer to connect the C of two groups ₂To C ₆Alkenylene (C ₂To C ₆Alkenediyl); Example comprises ethene-1,2-two bases (vinylidene), 2-methyl-2-butene-1,4-two bases, 2-hexene-1,6-two bases etc." C ₂To C ₆Alkynyl " refer to have at least one carbon-to-carbon three key and two straight or branched carbochains to six carbon atom; Example comprises ethynyl, proyl, butynyl and hexin base.

The employed term of the application " acyl group " (use separately or as the part of another group) refer to the alkyl that connects by carbonyl or-C (O) R.

The employed term of the application " alkoxyl group " (use separately or as the part of another group) refers to the alkyl that preferably has 1 to 6 carbon atom that connects by Sauerstoffatom, such as-OR, wherein R is described alkyl.

The employed term of the application " alkoxy carbonyl " (use separately or as the part of another group) refers to-C (O) OR, and wherein R is an alkyl.

The employed term of the application " arylalkyl " or " aralkyl " (use separately or as the part of another group) refer to the aromatic ring (such as benzyl) that connects by alkyl described above.

The employed term of the application " haloalkyl " (use separately or as the part of another group) refers to the halogen atom that connects by alkyl, such as-CF ₃

The amino that the employed term of the application " aminoalkyl group " (use separately or as the part of another group) refers to connect by alkyl (NR ' R ").

The employed term of the application " alkylamino alkylamino " (use separately or as the part of another group) refers to such as-NR-alkyl-NR-CH ₃Such group.

The employed term of the application " aryl-alkyl amino " (use separately or as the part of another group) refers to the aryl that connects by alkyl, and described alkyl connects by amino.

The employed term of the application " aryl " (use separately or as the part of another group) refers to monocyclic aromatic ring or bicyclic aromatic ring, for example for example naphthyl, phenanthryl etc. of the phenyl of phenyl, replacement etc. and condensed group.Thereby aryl comprises at least one ring with at least 6 atoms, comprises five such rings (wherein comprising 22 atoms at the most) at the most, and has the two keys of alternative (conjugated) between adjacent carbon atom or the suitable heteroatoms.Preferred aryl groups comprises 6 to 14 carbon atoms in ring.Aryl can be chosen wantonly and be substituted with one or more group, and described group includes but not limited to halogen (such as Br, F or Cl), alkyl (such as methyl, ethyl, propyl group), alkoxyl group (such as methoxy or ethoxy), hydroxyl, carboxyl, carbamyl, alkoxy carbonyl, nitro, thiazolinyl oxygen base, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano group, alkyl S (O) _m(m=0,1,2) or sulfydryl.

The employed term of the application " amino " (use separately or as the part of another group) refers to-NH ₂" amino " can be chosen wantonly and be substituted with one or two substituting group (NR ' R "); wherein R ' and R " can be identical or different, such as alkyl, aryl, arylalkyl, thiazolinyl, alkynyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl, alkyl, Heterocyclylalkyl alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio (thioalkyl), carbonyl or carboxyl.These substituting groups can further be substituted with any one in the listed alkyl or aryl substituting group of carboxylic acid or the application.In some embodiments, amino is substituted with carboxyl or carbonyl, forms N-acyl group or N-carbamyl deriveding group.

The employed term of the application " cycloalkyl " (use separately or as the part of another group) refers to that 3 to 9 carbon atoms are preferably the hydrocarbon ring of the complete saturated and fractional saturation of 3 to 7 carbon atoms.In addition, cycloalkyl can replace.The cycloalkyl that replaces refer to have once, two or three be selected from following substituent ring: the alkyl of halogen, alkyl, replacement (wherein substituting group such as above alkyl substituent define), thiazolinyl, alkynyl, nitro, cyano group, oxo (=O), hydroxyl, alkoxyl group, alkylthio ,-CO ₂H ,-C (=O) H, CO ₂-alkyl ,-C (=O) alkyl, ketone group ,=N-OH ,=N-O-alkyl, aryl, heteroaryl, five or hexa-atomic ketal (promptly 1,3-dioxane 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 R ' and R " in the alkyl and the cycloalkyl that independently are selected from hydrogen, alkyl, replacement separately, or R ' and R " form Heterocyclylalkyl or heteroaryl ring together.

The employed term of the application " heteroaryl " or " heteroaromatic group " (use separately or as the part of another group) refer to replace and unsubstituted aromatics 5 or 6 yuan of monocyclic groups, 9 or 10 yuan of bicyclic radicals and 11 to 14 yuan of three cyclic groups, and these groups have at least one heteroatoms (O, S or N) at least one encircles.Each ring that comprises heteroatomic heteroaryl all can comprise one or two Sauerstoffatom or sulphur atom and/or one to four nitrogen-atoms, and condition is four or still less for heteroatomic sum in each ring, and each encircles and all has at least one carbon atom.The condensed ring that forms above-mentioned bicyclic radicals and three cyclic groups can only comprise carbon atom, and can be saturated or fractional saturation.Nitrogen-atoms and sulphur atom can be oxidations, and nitrogen-atoms can be quaternised.Dicyclo or trinucleated heteroaryl must comprise the ring of at least one Wholly aromatic, but other condensed ring or a plurality of ring can be aromatics or non-aromatics.Heteroaryl can be in any available nitrogen-atoms or the connection of carbon atom place of ring arbitrarily.The heteroaryl ring system can comprise zero, one, two or three be selected from following substituting group: the alkyl of halogen, alkyl, replacement, thiazolinyl, alkynyl, aryl, nitro, cyano group, hydroxyl, alkoxyl group, alkylthio ,-CO ₂H ,-C (=O) H ,-CO ₂-alkyl ,-C (=O) alkyl, phenyl, benzyl, phenylethyl, phenyl oxygen base, thiophenyl, cycloalkyl, replacement cycloalkyl, Heterocyclylalkyl, 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 R ' and R " in the alkyl and the cycloalkyl that independently are selected from hydrogen, alkyl, replacement separately, or R ' and R " form Heterocyclylalkyl or heteroaryl ring together.

The example of bicyclic heteroaryl comprises pyrryl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, di azoly, isoxazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl, oxadiazole base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl etc.

The example of bicyclic heteroaryl comprises indyl, benzothiazolyl, benzodioxole base, benzoxazolyl (benzoxaxolyl), benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, indolizine base, benzofuryl, chromone base, tonka bean camphor base, benzofuryl, cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridyl, dihydro-iso indolyl, tetrahydric quinoline group etc.

The example of tricyclic heteroaryl comprises carbazyl, benzindole base (benzidolyl), phenanthroline base, acridyl, phenanthridinyl, xanthenyl etc.

The heteroatoms that a carbon atom in the employed term of the application " Heterocyclylalkyl " (use separately or as the part of another group) finger ring is selected from O, S or N replaces and 3 extra carbon atoms can be by the displaced cycloalkyl of described heteroatoms (non-aromatics) at the most.The employed term of the application " Heterocyclylalkyl " (use separately or as the part of another group) refers to comprise the undersaturated monocycle ring system of stable saturated or part of 5 to 7 annular atomses (carbon atom and be selected from other atom of nitrogen, sulphur and/or oxygen).Heterocycle can be 5,6 or 7 yuan of monocycles, and comprises one, two or three heteroatoms that is selected from nitrogen, oxygen and/or sulphur.Heterocycle can be optional the replacement; this means that heterocycle can be substituted with one or more at one or more commutable ring position and independently be selected from following group: alkyl (being preferably low alkyl group); Heterocyclylalkyl; heteroaryl; alkoxyl group (being preferably lower alkoxy); nitro; alkyl monosubstituted amino (being preferably low-grade alkyl amino); dialkyl amido (being preferably two [rudimentary] alkylamino); cyano group; halogen; haloalkyl (being preferably trifluoromethyl); alkyloyl; aminocarboxyl; the alkyl monosubstituted amino carbonyl; dialkyl amino carbonyl; alkyl amido (being preferably the low alkyl group amido); alkoxyalkyl (being preferably lower alkoxy [rudimentary] alkyl); alkoxy carbonyl (being preferably elementary alkoxy carbonyl); alkyl-carbonyl oxygen base (being preferably lower alkylcarbonyl oxygen base) and aryl (being preferably phenyl), the optional halogen that is substituted with of described aryl; low alkyl group and lower alkoxy.The example of these Heterocyclylalkyls comprises: piperazine, piperidines, morpholine, high morpholine (homomorpholine), parathiazan (thiomorpholine), tetramethyleneimine and azetidine.

Term " heteroatoms " refers to independent O, S or the N that selects.It should be noted that the ungratified any heteroatom of valency all is considered to be connected with hydrogen atom, thereby satisfies valency.

Term " halogen " or " halogen " refer to independent chlorine, bromine, fluorine or the iodine of selecting.

The employed phrase of the application " gene amplification " refers to that the selectivity of dna fragmentation is synthetic, the synthetic multiple copied that causes the chromosome segment of Met gene or coding Met of this selectivity.

The employed phrase of the application " activatory Met sudden change " refers to the selectively changing of the dna sequence dna of Met, and this selectively changing causes the Met protein of constitutive character (promptly permanent) phosphorylation.

The employed phrase of the application " HGF stimulation " refers to HGF in conjunction with its related acceptor (Met) and activate the ability of described acceptor in this way, and this activation causes phenotype to reply (phenotypicresponse).Under the situation of Met, it can be cell proliferation, cell mobility, cytodifferentiation and/or cell survival that this phenotype is replied.

Term " anticarcinogen " comprises any known drug that can be used for treating cancer, comprises the female alcohol of 17 alpha-acetylenes, stilboestrol, testosterone, prednisone, Fluoxymesterone, dromostanolone propionate, testolactone, Magace (megestrolacetate), methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, Chlortrianisoestrol, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, Leuprolide, flutamide, toremifene, Zoladex (Zoladex); Matrix metallo-proteinase inhibitor; The VEGF inhibitor is such as VEGF antibody (Avastin (Avastin)) and small molecules such as ZD6474, AZD-2171 and SU6668; Wa Talani (Vatalanib), BAY-43-9006, SU11248, CP-547632 and CEP-7055; Her1 and Her2 inhibitor comprise anti-Her2 antibody (Trastuzumab (Herceptin)); The EGFR inhibitor comprises Gefitinib (gefitinib), erlotinib (erlotinib), ABX-EGF, EMD72000,11F8 and Cetuximab; The Eg5 inhibitor is such as SB-715992, SB-743921 and MKI-833; Pan Her inhibitor replaces Buddhist nun (canertinib), EKB-569, CI-1033, AEE-788, XL-647, mAb 2C4 and GW-572016 such as the card knob; The Src inhibitor, BMS-354825, AZD-0530, SKI-606 and AP-23464; Casodex

, Bcr-Abl inhibitor (Ge Liweike (GLEEVAC)) (bicalutamide, Astra Zeneca), tamoxifen; MEK-1 kinase inhibitor, mapk kinase inhibitor, PI3 kinase inhibitor; Met inhibitor, aurora kinase (aurora kinase) inhibitor, PDGF inhibitor (such as imatinib); Angiogenesis inhibitor and anti-vascular medicine no longer make cancer cells dormancy (quiescent) to their keepings thereby these medicines flow to solid tumor by occlude blood; Make and depend on the no longer outgrowth medicine (castration) that goes of androgenic cancer; IGF1R inhibitor (such as at disclosed in the US2004/44203A1 those), the inhibitor of non-acceptor and the inhibitor of receptor tyrosine kinase; The inhibitor of integrin signal conduction; Act on the medicine of tubulin, such as vinealeucoblastine(VLB); vincristine(VCR); vinorelbine; Vinflunine; taxol; Docetaxel; 7-O-methylthiomethyl taxol; 4-deacetylate-4-methyl taxol carbonic ether (4-desacetyl-4-methylcarbonatepaclitaxel); 3 '-tertiary butyl-3 '-N-tertiary butyl oxygen base carbonyl-4-deacetylate-3 '-go phenyl-3 '-N-to remove benzoyl-4-O-methoxycarbonyl-taxol; C-4-methyl taxol carbonic ether (C-4 methyl carbonate paclitaxel); Epothilones A; epothilone B; Epothilone C; epothilone d; Epothilone C A; Epothilone C B; ipsapirone (ixabepilone); [1S-[1R ^*, 3R ^*(E), 7R ^*, 10S ^*, 11R ^*, 12R ^*, 16S ^*]]-3-[2-[2-(amino methyl)-4-thiazolyl]-the 1-methyl ethylene]-7,11-dihydroxyl-8,8,10,12,16-pentamethyl--4-17-two oxa-dicyclo [14.1.0]-heptadecanes-5,9-diketone and derivative thereof; CDK inhibitor, anti proliferative cell cycle inhibitor, epidophylltoxin (epidophyllotoxin), Etoposide, VM-26; Antineoplastic enzyme inhibitors, for example topoisomerase I inhibitor, camptothecine, Hycamtin (topotecan), SN-38; Procarbazine; Mitoxantrone; Platinum coordination complex is such as cis-platinum, carboplatin and oxaliplatin; Biological response modifier; Growth inhibitor; The hormone antagonist therapeutical agent; Folinic acid; Tegafur; Antimetabolite is such as purine antagonist (for example 6-thioguanine and Ismipur); Glutamine antagonist, for example DON (AT-125; D-oxo-nor-leucine); The ribonucleotide reductase inhibitor; The mTOR inhibitor; And hemopoieticgrowth factor (haematopoietic growth factor).

Other cytotoxic drug comprises that endoxan, Dx, daunorubicin, mitoxantrone (mitoxanthrone), melphalan, hexamethyl trimeric cyanamide (hexamethyl melamine), plug are for group, cytosine arabinoside, ethyl denitrification ammonia pteridine (idatrexate), trimetrexate, Dacarbazine, L-Asparaginase, bicalutamide, Leuprolide, pyrido benzindole derivative, Interferon, rabbit and interleukin-.

When functional group being called " shielded " functional group, its meaning is that described group is the form of being modified, thereby stops the side reaction of not expecting in shielded site.Consider those skilled in the art's level, and the textbook of reference standard (such as Greene, T.W.et al.; Protective Groupsin Organic Synthesis; Wiley, N.Y. (1991)), can recognize the suitable protecting group that is used for The compounds of this invention from the application.

All mammalian species contained in the employed term of the application " patient ", comprises people, ox, horse, dog and cat.

Phrase " treatment effectively " is intended to quantitative every kind of medicine can realize improving the amount that the purpose of disease severity and sickness rate is avoided relevant with replacement therapy (alternative therapy) usually harmful side effect simultaneously when treating with it separately.For example, effectively anticarcinogen improves patient's survival possibility, suppresses the cell of the fast breeding relevant with tumour and grows, or influence the degeneration (regression) of tumour.

Unless point out in addition, the employed phrase of the application " pharmacologically acceptable salt (multiple pharmacologically acceptable salt) " or " salt " comprise by being present in the salt that acidic-group in formula I and the II compound or basic group form.The formula I and the II compound that are essentially alkalescence can form a variety of salt with multiple mineral acid and organic acid.Therefore, the compound with formula I and II comprises free alkali and salt form.The acid of pharmaceutically acceptable acid additive salt that can be used for preparing these alkaline formula I and II compound is for forming those acid that nontoxic acid salt promptly comprises pharmaceutically acceptable anionic salt, described nontoxic acid salt promptly comprises pharmaceutically acceptable anionic salt such as being hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, Yi Yansuan salt, acetate, lactic acid salt, salicylate, citrate, the acid citrate, tartrate, pantothenate, bitartrate, ascorbate salt, succinate, maleate, gentisate, fumarate, gluconate, glucuronate (glucaronate), mesylate (mesylate), saccharate (saccharate), formate, benzoate, glutaminate, mesylate (methanesulfonate), esilate, benzene sulfonate, tosilate and pamoate [promptly 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)].

Therefore compound of the present invention can comprise one or more extra asymmetric carbon atoms, has two or multiple stereoisomeric forms in any ratio.The present invention includes various steric isomers and the various tautomeric form (under suitable situation) and their mixture of formula I and II compound.

The separation of diastereomer can be finished by routine techniques, for example carries out fractional crystallization, chromatogram or H.P.L.C. by the three-dimensional heterogeneous mixture to formula I and/or II compound or its suitable salt or derivative.The independent enantiomer of formula I or II compound also can prepare from the simple intermediate of corresponding optics, or by preparing: utilize suitable chirality padding (support) that corresponding racemoid is carried out H.P.L.C. and split, or corresponding racemoid and suitable optically active acid or alkali are reacted formed diastereoisomeric salt carry out fractional crystallization under suitable situation such as following such way.

The present invention relates to have compound (comprising its salt) with following formula I or II:

Wherein

R ¹H, halogen, haloalkyl, cyano group, NO respectively do for oneself ₂, OR ⁶, NR ⁷R ⁸, alkyl, replacement the Heterocyclylalkyl of arylalkyl, Heterocyclylalkyl or replacement of heteroaryl, arylalkyl, replacement of aryl, heteroaryl, replacement of cycloalkyl, aryl, replacement of alkyl, cycloalkyl, replacement;

B is O, NR ⁹, S, SO, SO ₂Or CR ¹⁰R ¹¹, be preferably O;

W and X independently are C or N separately;

V is CO;

N is 1 to 4;

M is 1 to 4;

P is 0 to 2;

L is 1 to 2;

R ⁶, R ⁷, R ⁸And R ⁹Independent separately is aryl, the heteroaryl of Heterocyclylalkyl, aryl, the replacement of cycloalkyl, Heterocyclylalkyl, the replacement of alkynyl, cycloalkyl, the replacement of thiazolinyl, alkynyl, the replacement of alkyl, thiazolinyl, the replacement of H, alkyl, replacement, the heteroaryl of replacement;

For

With

For

A is

Wherein

G is O, S or NR ¹⁰⁶

D is CR ¹⁰⁷Or N;

Z is N or CR ¹⁰⁸

R ⁴⁰With R ³⁹, R ⁴⁰With or R ⁴¹Form the unsaturated or saturated heterocycle of carbocyclic ring of 3 to 8 atoms together;

According to one embodiment of the invention, A is

According to embodiment preferred, D is-CH, and G is-NH, Z be N or-CH, and R ⁵⁰, R ⁵¹, R ⁵², R ⁵⁸And R ⁵⁹Independent separately is the low alkyl group of H, amino or replacement.

According to one embodiment of the invention,

For

And be preferably

Each R wherein ²², R ²⁴And R ¹⁶All as defined above, and be preferably H, hydroxyl, alkoxyl group (such as methoxyl group), halogen (being preferably Cl or Br), low alkyl group (being preferably methyl, ethyl or propyl group), (SCH ₃), haloalkyl (is preferably-CF ₃) ,-NR ¹⁰R ¹¹,-SR ¹²⁶,-CN, amino, aminoalkyl group, alkylamino, dialkyl aminoalkyl amino, aryl-alkyl amino or Heterocyclylalkyl.In preferred embodiments, each R ²², R ²⁴And R ¹⁶All independent be H ,-OH ,-OCH ₃, Br, Cl ,-CH ₃,-SCH ₃,-CF ₃,-CN ,-CH ₂NH ₂, morpholinyl, piperazinyl ,-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Independent is H, low alkyl group, benzyl or dialkyl aminoalkyl.

According to one embodiment of the invention, W and X are C, and each R ¹All independent is H or F.It should be noted, be under the situation of carbon at W and X, W and X is expressed as-CH, unless the monovalence in its valency is by the R that is not H ₁Occupy.

According to one embodiment of the invention, compound has formula I or II, wherein R ⁵Be the optional phenyl that replaces, and preferably be substituted with halogen, low alkyl group, hydroxyalkyl, Heterocyclylalkyl, amino or alkylamino.

One embodiment of the invention provide following method: formula I as defined above by will treating significant quantity or II compound and at least a other anticarcinogen combination give the patient that (simultaneously or successively) needs this treatment, treat proliferative disease (such as cancer) via regulating the Met kinases.In preferred embodiments, proliferative disease is a cancer.

Particularly, formula I and II compound can be used for treating multiple cancer, are specially most and depend on those cancers of Met activatory.The Met activation can stimulate by gene amplification, sudden change (various mutations) and/or HGF to be regulated, and wherein HGF is provided by tumour (autocrine) or host's (paracrine) tissue.Thereby, the present invention also relates to treat such as following such method for cancer: bladder cancer, mammary cancer, colorectal carcinoma, cancer of the stomach, head and neck cancer, kidney, liver cancer, lung cancer, ovarian cancer, carcinoma of the pancreas/carcinoma of gallbladder, prostate cancer, thyroid carcinoma, osteosarcoma, rhabdosarcoma, MFH/ fibrosarcoma, glioblastoma (glioblastoma)/astrocytoma, melanoma and mesothelioma (mesothelioma).

Usually, compound of the present invention can be used for the treatment of following cancer:

A) cancer comprises bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising 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 (comprising squamous cell carcinoma);

B) the hematopoiesis tumour of lymph pedigree (hematopoietic tumors of lymphoid lineage) comprises leukemia, acute lymphoblastic leukemia (acute lymphocytic leukemia), acute lymphoblast leukemia (acute lymphoblastic leukemia), B cell lymphoma, t cell lymphoma, Hodgkin lymphoma (Hodgkins lymphoma), non-Hodgkin lymphoma (non-Hodgkinslymphoma), hair cell lymphoma (hairy cell lymphoma) and Burkitt lymphoma (Burkett ' slymphoma);

C) the hematopoiesis tumour of marrow pedigree (hematopoietic tumors of myeloid lineage) comprises acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia;

D) tumour (tumors of mesenchymal origin) of mesenchyme origin comprises fibrosarcoma and rhabdosarcoma;

E) tumour of maincenter and peripheral nervous system comprises astrocytoma, neuroblastoma, neurospongioma and schwannoma; With

F) other tumour comprises melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xeroderma pitmentosum, keratoacanthoma, follicular carcinoma of thyroid (thyroid follicular cancer) and Kaposi sarcoma.

Because protein kinase is brought into play keying action usually in regulating cell proliferation, so inhibitor can be as the reversibility cytostatics that can be used for treating any lysis that is characterized as abnormal cellular proliferation, these lysises for example are benign prostatic hyperplasia, familial adenomatous polyposis disease (familialadenomatosis polyposis), neurofibromatosis, atherosclerosis, pulmonary fibrosis, sacroiliitis, psoriasis, glomerulonephritis, the restenosis that occurs after angioplasty or the vascular surgery, hypertrophic cicatrix forms (hypertrophic scar formation), inflammatory bowel, graft-rejection (transplantation rejection), endotoxin shock and fungi infestation.

Formula I and II compound are as apoptotic conditioning agent, can be used for treating cancer (including but not limited to those mentioned hereinbefore types), virus infection (includes but not limited to simplexvirus, poxvirus, Epstein-Barr virus (Epstein-Barr virus), sindbis alphavirus (Sindbis virus) and adenovirus), the prevention of the AIDS development of HIV infected individuals, autoimmune disorder (include but not limited to systemic lupus hung classes (systemic lupus, erythematosus), the glomerulonephritis of autoimmunization mediation, rheumatoid arthritis, psoriasis, inflammatory bowel and autoimmune diabetes (autoimmune diabetes mellitus)), neurodegenerative disease (includes but not limited to alzheimer's disease (Alzheimer ' s disease), AIDS is relevant dull-witted, Parkinson's disease (Parkinson ' s disease), amyotrophic lateral sclerosis, retinitis pigmentosa (retinitis pigmentosa), Duchenne-Arandisease and cerebellar degeneration), myelodysplastic syndrome, aplastic anemia, with myocardial infarction, the ischemic injuries that apoplexy is relevant with reperfusion injury, irregular pulse, atherosclerosis, toxin brings out or the relevant hepatopathy of ethanol, hematologic disease (including but not limited to chronic anaemia and aplastic anemia), the degenerative disease of musculoskeletal system (including but not limited to osteoporosis and sacroiliitis), aspirin sensitive sinusitis paranasal sinusitis (aspirin-sensitive rhinosinusitis), cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

Adjustable ganglion cell RNA of formula I and II compound and DNA synthetic level.Therefore, these materials can be used for the treatment of virus infection (including but not limited to HIV, human papillomavirus, simplexvirus, poxvirus, Epstein-Barr virus, sindbis alphavirus and adenovirus).

Formula I and II compound can be used for the chemoprophylaxis of cancer.Chemoprophylaxis is defined as by blocking initial mutagenesis incident or suppressing the development of invasive cancer or suppress tumor recurrence by the precellular progress that cancerates that blocking-up has been damaged.

Formula I and II compound can be used for suppressing tumor-blood-vessel growth and transfer.

Compound of the present invention also can be used in combination (give or successively give) with known anticarcinogen or anticancer therapy (such as radiotherapy), or be used in combination (give or successively give) with cytostatic or cytotoxicity medicine, described cytostatic or cytotoxicity medicine for example are (but being not limited to) DNA interaction medicine, such as cis-platinum or Dx; The topoisomerase II inhibitor is such as Etoposide; The topoisomerase I inhibitor is such as CPT-11 or Hycamtin; Natural existence or synthetic tubulin interaction medicine are such as taxol, Docetaxel or epothilones (for example ipsapirone); Hormone drug is such as tamoxifen; Thymidylate synthetase (thymidilate synthase) inhibitor is such as 5 FU 5 fluorouracil; Antimetabolite is such as methotrexate; Other tyrosine kinase inhibitor is such as Iressa (Iressa) and OSI-774; Angiogenesis inhibitor; The EGF inhibitor; The VEGF inhibitor; The CDK inhibitor; Src inhibitor; The c-Kit inhibitor; The Her1/2 inhibitor; With the monoclonal antibody relevant, (EGF) and Trastuzumab (Her2) such as Erbitux (erbitux) with growth factor receptors.

The pharmaceutical composition that comprises activeconstituents can be the form that is suitable for orally using, and for example is tablet, lozenge (troche), lozenge (lozenge), water-based or oiliness suspensoid, dispersible pulvis or granule, emulsion, hard or soft capsule or syrup or elixir.The composition that is intended to orally use can prepare according to any means that is used for pharmaceutical compositions known in the art, and these compositions can comprise one or more material that is selected from sweeting agent, seasonings, tinting material and sanitas, so that pharmaceutically exquisite and agreeable to the taste preparation are provided.Tablet comprises activeconstituents, and is mixed with nontoxic pharmaceutically acceptable vehicle or the carrier that is suitable for preparing tablet.These vehicle or carrier can for example be inert diluent, such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent (granulating agent) and disintegrating agent, for example Celluloasun Microcrystallisatum, cross-linked carboxymethyl cellulose sodium (sodium crosscarmellose), W-Gum or alginic acid; Tackiness agent, for example starch, gelatin, polyvinylpyrrolidone or gum arabic; And lubricant, for example Magnesium Stearate, stearic acid or talcum.Tablet can be a dressing not, maybe can come dressing by known technology, thereby cover the medicine taste that makes us unhappy, or postpone disintegration and absorption in gi tract, provides lasting effect thus in the long period.For example, can use water miscible taste to cover material (such as hydroxypropyl-methylcellulose gum or hydroxypropyl-Mierocrystalline cellulose) or time lag material (such as ethyl cellulose, cellulose acetate butyrate (cellulose acetate buryrate)).

Also the formulation preparation that is used to orally use can be become hard-gelatin capsules, wherein for example lime carbonate, calcium phosphate or kaolin mix with inert solid diluent with activeconstituents, or also the formulation preparation that is used to orally use can be become Gelseal, wherein activeconstituents is mixed with water-soluble carrier (such as polyoxyethylene glycol) or oily medium (for example peanut oil, whiteruss or sweet oil).

Aqueous suspension comprises active substance, and is mixed with the vehicle that is suitable for preparing aqueous suspension.These vehicle are suspending agent, for example sodium carboxy methyl cellulose, methylcellulose gum, hydroxypropylmethyl-Mierocrystalline cellulose, sodiun alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; Dispersant or wetting agent can be the condensation product (for example polyoxyethylene 8 stearate ester) of naturally occurring phosphatide (for example lecithin) or oxidation alkene and aliphatic acid or the condensation product of oxidation ethene and long-chain fatty alcohol (for example 17 oxygen ethene spermaceti alcohol (heptadecaethylene-oxycetanol)) or oxidation ethene and the condensation product (such as polyoxyethylene 80 sorbitan monooleate) of the inclined to one side ester of deriving from aliphatic acid and hexitol or the oxidation ethene condensation product (for example polyethylene dehydrated sorbitol mono-fatty acid ester) with the inclined to one side ester of deriving from aliphatic acid and hexitan mixture. Aqueous suspension also can comprise one or more sanitas (for example ethyl p-hydroxybenzoate or n-propyl), one or more tinting material, one or more seasonings and one or more sweeting agent (such as sucrose, asccharin or aspartame).

The oiliness suspensoid can be prepared by activeconstituents being suspended in vegetables oil (for example peanut oil, sweet oil, sesame oil or cocounut oil) or the mineral oil (such as whiteruss).The oiliness suspensoid can comprise thickening material, for example beeswax, paraffinum durum or hexadecanol.Can add sweeting agent (such as above listed those) and seasonings, thereby agreeable to the taste oral preparations is provided.These compositions can come anticorrosion by adding antioxidant (such as Butylated Hydroxyanisole (butylated hydroxyanisol) or alpha-tocopherol).

Be suitable for comprising activeconstituents, and be mixed with dispersion agent or wetting agent, suspending agent and one or more sanitas by adding dispersible pulvis and the granule that water prepares aqueous suspension.The example of suitable dispersion agent or wetting agent and suspending agent is above those that mentioned.Also can comprise other vehicle, for example sweeting agent, seasonings and tinting material.These compositions can come anticorrosion by adding antioxidant (such as xitix).

Pharmaceutical composition of the present invention also can be the form of oil-in-water-type (oil-in-water) emulsion.Oil phase can be vegetables oil (for example sweet oil or peanut oil) or mineral oil (for example whiteruss) or their mixture.Suitable emulsifying agent can be naturally occurring phosphatide (for example soybean lecithin), from the condensation product (for example polyoxyethylene sorbitan monoleate) of lipid acid and hexitan mixture deutero-ester or partial ester (for example dehydrated sorbitol mono-fatty acid ester) and described partial ester and ethylene oxide.Emulsion also can comprise sweeting agent, seasonings, sanitas and antioxidant.

Syrup and elixir can be prepared with sweeting agent (for example glycerine, propylene glycol, sorbyl alcohol or sucrose).These preparations also can comprise negative catalyst (demulcent), sanitas, seasonings, tinting material and antioxidant.

Pharmaceutical composition can be the form of the sterile injectable aqueous solution.Spendable carrier and the solvent accepted has water, Ringer's solution (Ringer ' s solution) and isoosmotic sodium chloride solution.

Sterile injectable preparation can be the sterile injectable water oil-packaging type micro-emulsion also, wherein activeconstituents is dissolved in the oil phase.For example, at first activeconstituents is dissolved in the mixture of soybean oil and Yelkin TTS.Then, resulting oil solution is imported in the mixture of water and glycerine and handle, thereby form micro emulsion.

Injectable solution or micro emulsion can be injected in the blood flow that imports to the patient by the part.Replacedly, maybe advantageously, give described solution or micro emulsion in some way, thereby keep the circulation composition of constant The compounds of this invention.In order to keep this constant concentration, can use continuous intravenous administration device.The example of this device is a Deltec CADD-PLUS.TM.5400 type infusion pump (intravenouspump).

Pharmaceutical composition can be to be used for the sterile injectable water-based of intramuscular or subcutaneous administration or the form of oil-based suspension.Those suitable dispersion agents that this suspension has been mentioned more than can using according to known technology or wetting agent and suspending agent dispose.Sterile injectable preparation also can be the sterile injectable solution or the suspension of nontoxic pharmaceutically acceptable diluent or solvent, for example solution of 1,3 butylene glycol.In addition, aseptic fixed oil (fixed oil) can be used as solvent or suspension medium easily.For this purpose, gentle arbitrarily fixed oil all can use, and comprises synthetic direactive glyceride or two glyceryl ester.In addition, lipid acid (such as oleic acid) can use in the preparation injection.

Formula I and II compound also can give by the form of the suppository that is used for rectal administration.These compositions can prepare by hybrid medicine and suitable nonirritant excipient, and described vehicle is solid at normal temperature but is liquid in rectal temperature, therefore melts in rectum, thereby discharge medicine.These materials comprise the mixture of theobroma oil, glycogelatin, hydrogenated vegetable oil, different molecular weight polyethylene glycol and the fatty acid ester of polyoxyethylene glycol.

With regard to use the part, can use ointment, ointment, jelly, solution or the suspensoid etc. that comprise formula I compound.(with regard to the application, topical application should comprise mouth wass and mouth wash shua.)

Compound of the present invention can use that carrier and doser give with form in the nose in the suitable nose by the part, or use those skilled in the art well-known form through the skin skin patch by giving through the skin approach.With regard to come administration with the form of transdermal delivery system with regard to, it should be successive certainly that medicine gives in whole dosage regimen, rather than intermittently.Compound of the present invention also can be by using the form such as the suppository of following such matrix to give: the mixture of theobroma oil, glycogelatin, hydrogenated vegetable oil, different molecular weight polyethylene glycol and the fatty acid ester of polyoxyethylene glycol.

When being administered to compound of the present invention in the human subject body, every day, dosage was generally determined by the doctor of prescription, and described dosage changes with the severity of patient's age, body weight, sex and reaction and patient's symptom usually.

If be mixed with fixed dosage (fixed dose), these combined prods use The compounds of this invention in dosage range described above and other medical active agent or the treatment in the dosage range of its approval so.When combination preparation was improper, formula I and II compound also can successively give with known anticarcinogen or cytotoxicity medicine.The present invention is not subjected to the restriction of order of administration; Formula I and II compound can give before or after known anticarcinogen (multiple anticarcinogen) or the cytotoxicity medicine (various kinds of cell toxicity medicine) giving.

Some formula I and II compound can prepare according to following scheme 1-12 usually.The tautomer of formula I and II compound and solvate (for example hydrate) are also within the scope of the invention.The method of solvation is normally known in the art.Therefore, compound of the present invention can be free form or hydrate forms, and can obtain by the method for following scheme institute example.

Usually, formula I compound can utilize the chemical reaction described in scheme 1 to prepare, and wherein B is O, NH or S, and LV is leavings group (for example halogen, trifluoromethanesulfonic acid ester group (triflate) or other sulfonate group).Compd A-LV (1) can buy, or utilizes the known synthetic method of those skilled in the art easily to prepare.For example, compd A-LV (1) can prepare according to the general method of being summarized in following document: 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, Hennequin, L.F.et al.J.Med.Chem.1999,42,4369-5389, Hagmann, W.K.et al.Bioorg.Med.Chem.Lett.2000,10,1975-1978, Spitzner, D.Science of Synthesis 2005,15,11-284, Bhagwat, S.S.etal.WO 01/057040, Soloducho, J.et al.Arch.de Pharmazie 1990,323,513-515, Phuan, P.-W.and Kozlowski, M.C.Science of Synthesis 2005,15,947-985, Nishikawa, S.Et al.J.Ag.and Food Chem.1995,43,1034-1038, Johns, A.et al.WO 99/58533, Rewcastle, G.W.et al.J.Med.Chem.1996,39,1823-1835, 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 and Barker, J.M.et al.J Chem.Res., Synnopses 1986,4,122-123 is incorporated herein by reference in this content that these documents are disclosed.Compd A-LV also can prepare according to the method for institute's general description in following U.S. Patent application: the U.S. Patent application 11/167 that on June 24th, 2005 submitted to, 049, the U.S. Patent application of submitting on April 21st, 2,005 11/111,144, the U.S. Patent application of submitting on April 24th, 2,005 11/113, the U.S. Patent application 11 that on June 24th, 838 and 2005 submitted to, 167,043.

Compound 1 is handled with suitable functionalized compound 2 (phenol of replacement, aniline or thiophene) in the presence of alkali (such as potassium tert.-butoxide), and next resulting nitro intermediate obtains compound 3 (scheme 1) with for example zinc powder and ammonium chloride reduction.Replacedly, intermediate 3 can mix in the presence of alkali (for example cesium carbonate, salt of wormwood, potassium tert.-butoxide) by making compound 4 and 5, reduces subsequently and obtains.When 6 Y ring comprised at least one heteroatoms, compound 3 and 6 coupling can be finished (Galeeva, R.N.et al.Khim.Farm.Zh.1998,32,31 under acidic conditions; Kermack, W.O.et.al.J.Chem.Soc.1942,726; Promptly encircling Y is pyridine ring), thus formula I compound obtained.Replacedly, formula I compound can obtain by the following method: utilize the catalysis of metal (such as palladium or copper), make compound 3 and 6 that coupling (Wolfe take place, J.P.et.al.Tetrahedron Lett.1997,38,6359 and Lowe, J.A.et.al.J.Med.Chem.1991,34,624).

Scheme 1

According to scheme 2, (wherein LV is leavings group (such as halogen, trifluoromethanesulfonic acid ester group or other sulfonate group), and p, Y, R for acid amides or ester derivative 6 ³, R ⁴, R ⁵, R ¹²And R ¹³Can obtain as defined above) from carboxylic acid III.Ketone derivatives 6 can utilize suitable organometallic reagent (M=metal) (such as organolithium or Grignard reagent (Grignard reagent)) to prepare from corresponding Weinreb acid amides IV.For example work as

During for following group, compound III can utilize the known method of those skilled in the art to prepare, or replacedly, compound III can be commercially available:

Following starting raw material III also is commercially available:

Other starting raw material carboxylic acid III (or ester intermediate) (such as following listed those) can be incorporated herein by reference in this content that these reference are disclosed in full according to preparing below with reference to document.

Starting raw material III with following structure can be according at Ichimoto, I.et al., Agricultural﹠amp; Biol.Chem.1967,31, the method described in the 979-989 prepares:

Ester with following formula can be according at Battesti, P.et al., and Bull.Soc.Chim.Fr.1975,2185-2188 and Gelin, S.J.Org.Chem.1979,44, the general method of being summarized among the 3053-3057 prepares:

Starting raw material III with following structure can be according at Radwan, S.M.et al., and Pharmazie1997,52,483-485 and Yanai, M.et.al.Chem.Pharm.Bull.1977,25, the general method of being summarized among the 1856-1861 prepares:

Starting raw material III with following structure can be according at Zhang, H.et al., and J.Med.Chem.2005,48, the method for being summarized among the 5215-5223 prepares:

Starting raw material III with following structure can be according at Tehrani, K.A.et al., and Tetrahedron1999,55, the method for being summarized among the 4133-4152 prepares:

Starting raw material III with following structure can be according at Tsuge, O.et al., and Tetrahedron 1973,29, and the general method of being summarized among the 1983-1990 prepares:

Starting raw material III with following structure can be according at Roques, B.et al., and Bull.Soc.Chim.Fr.1971, the method for being summarized among the 242-245 prepares:

Starting raw material III with following structure can be according at Pinna, G.A.et al., and Farmaco 1999,54, and the general method of being summarized among the 542-550 prepares:

Starting raw material III with following structure can be according at Grifantini, M.et al., Annal.diChim. (Rome, Italy) 1965,55, the general method of being summarized among the 576-582 prepares:

Starting raw material III with following structure can be according at Nesi, R.et al., and J.Chem.Soc.Perkin Trans 1 1985, the method for being summarized among the 1871-1874 prepares:

Starting raw material III with following structure can be according at Adembri, G.et al., and BollettinoScientifico della Facolta di Chimica Industria di Bologna 1965,23, the general method of being summarized among the 203-222 prepares:

Starting raw material III with following structure can be according at Howe, R.K., and J.Org.Chem.1977,42, the general method of being summarized among the 3230-3233 prepares:

Starting raw material III with following structure can be according at Wakefield, B.J., and ScienceofSynthesis 2002,11, and the general method of being summarized among the 229-288 prepares:

Starting raw material III with following structure can be according at Bowden, K., and J.Chem.Soc.SectionC.1968, the general method of being summarized among the 172-85 prepares:

Starting raw material III with following structure can be according to Rojahn, C.A.et.al.Ann.1923, and 434,252-264 prepares:

Starting raw material III with following structure usually can be according at Sedov, A.L.et al., and KhimiyaGeterotsiklicheskikh Soedinenii 1994, the method for being summarized among the 1369-1374 prepares:

Starting raw material III with following structure usually can be according at Tilly, D.et.al.Chem.Lett.2005, and 34, the general method of being summarized among the 446-447 prepares:

Starting raw material III with following structure usually can be according at Evans, R.et al., and the method for being summarized among the WO04/106305 prepares:

Starting raw material III with following structure usually can be according at Cairns, B.et al., and J.Chem.Soc.1950, the method for being summarized among the 1322-1327 prepares:

Starting raw material III with following structure usually can be according at Bartmann, W., and Heterocycles1989,29, the method for being summarized among the 707-718 prepares:

Starting raw material III with following structure usually can be according at Raveglia, L.F.et al., and J.Heterocyclic Chem.1997,34, the method for being summarized among the 557-559 prepares:

Starting raw material III with following structure usually can be according to Barber, C.G.et al., and the method that US05/020611 summarized prepares:

Starting raw material III with following structure usually can be according at Hansen, D.W., and Jr.et al., the method for being summarized among the WO91/08211 (US 5,360,796) prepares:

Be incorporated herein by reference in this content that above document is disclosed.

Scheme 2

B=CR in formula I ¹⁰R ¹¹The time, the synthetic of these formulas I compound can utilize chemical reaction illustrated in scheme 3 to finish.Thereby compound 1 can form (Grignardformation) or lithium-halogen exchange by Grignard, and compound 1 is changed into corresponding organometallic reagent 7.Handle compound 7 with suitable functionalized aldehyde 8, next resulting intermediate with nitroreduction (for example using zinc and ammonium chloride), obtains intermediate 9 subsequently with for example triethyl silicane, trifluoroacetic acid deoxidation.Utilize above condition described in scheme 1, make intermediate 9 and compound 6 couplings, obtain desired formula I analogue.

Scheme 3

Formula I

The LV=leavings group

The M=metal is such as Mg or Li

A, W, X, Y, n, p, R ¹, R ³-R ⁵As defined above

Scheme 4 has illustrated the preparation of the specific embodiment of formula I.Thereby, from commercially available 4-chloropyridine formic acid (TCI America) deutero-4-chloropyridine acid amides (10) can (11, Aldrich) processing obtains affixture 12 with 3-fluoro-4-hydroxyanilines under alkaline condition.Then, intermediate 12 can (13, Maybridge) processing obtains intermediate 14 (Galeeva, R.N.et al.Khim.Farm.Zh.1998,32,31 with commercially available N-(4-chloro-phenyl-)-2-chloro-nicotinamide in microwave under acidic conditions; Kermack, W.O.et.al.J.Chem.Soc.1942,726 (being hereby incorporated by)).14 can handle with two (trifluoroacetyl oxygen base) iodobenzene (Yu, C.et.al.Tetrahedron Lett.2001,42,1449 (being hereby incorporated by)) and pyridine, obtain compound 15.

Scheme 4

Pyrrolo-[2,3-b] pyridine analogs 21 can prepare by the mode that is similar to described in the scheme 5.Thereby, 4-hydroxyl pyrrolopyridine (16, Thibault, C.et al.Org.Lett.2003,5,5023) can be with commercially available 3 under alkaline condition, 4-difluoro nitrobenzene (17) is handled, obtain compound 18, described compound 18 can easily reduce with zinc and ammonium chloride in methyl alcohol, obtains aniline 19.Then, intermediate 19 can with commercially available nicotinamide derivates 20 (Maybridge) under situation, coupling taking place in the presence of TsOH and the NMP with microwave oven heating, obtain desired compound 21 (Galeeva, R.N.et al.Khim.Farm.Zh.1998,32,31; Kermack, W.O.et.al.J.Chem.Soc.1942,726 (being incorporated herein by reference) in this content that these documents are disclosed).

Scheme 5

Usually, formula II compound can prepare according to scheme 6.There are nitrogenous 5 yuan of heterocycles 22 of leavings group under alkaline condition, to react at the α bit strip, obtain intermediate 24 with compound 23 (such as acyl chlorides or isocyanic ester).Then, desired formula II compound can obtain by the following method: utilize the known method of those skilled in the art, intermediate 24 is combined with the anils 3 (preparing according to scheme 1) of suitable replacement.

Scheme 6

The LV=halogen, methylthio group etc.

V '=acyl chlorides, isocyanic ester etc.

B＝O，NH，S，OR ¹⁰R ¹¹

A, W, X, Y ', n, p, R ¹, R ³-R ⁵, R ¹⁰, R ¹¹As defined above

Scheme 7 and 8 has been described the preparation of the specific embodiment of formula II.Thereby, the 2-thiamazole (25, according to Nicolaou, K.C.et.al.J.Am.Chem.Soc.2004,126,5192 (being hereby incorporated by) prepare) can under alkaline condition, handle with commercially available 4-fluorophenyl Acetyl Chloride 98Min. (26), obtain intermediate 27.Can make intermediate 27 under acidic conditions, combine (Zhong, Z.et.al.Angew.Chem.Int.Ed.2003,42,3005 (being hereby incorporated by)) with anils 19 (deriving from scheme 5), obtain desired product 28 (scheme 7).

Scheme 7

Replacedly, the available commercially available isocyanic ester 29 of 2-thiamazole (25) (scheme 8) is handled, and obtains intermediate 30.Then, compound 30 can be changed into desired product 31 (Zhong, Z.et.al.Angew.Chem.Int.Ed.2003,42,2005) under acidic conditions.

Scheme 8

Pyridine derivate 39 can prepare according to the synthetic route of being summarized in scheme 9.Thereby; 4-chloro-3-iodine pyridine-2-amine (is derived: by the following method to (4-chloro-pyridine-2-yl)-t-butyl carbamate (CB Research and Development; Inc) carry out ortho lithiation (ortho lithiation); subsequently N-Boc is carried out deprotection) available phenol 33 processing, obtain compound 34.Sonagashira coupling (Sonagashiracoupling) can take place with the trimethyl silicane ethyl-acetylene in intermediate 34 in the presence of palladium catalyst, next with nitroreduction, obtain acetylene-derivative 35.35 can obtain intermediate 37 under the mediation at palladium coupling taking place in the presence of the alkali (for example salt of wormwood, Hunig alkali (Hunig ' s base) or triethylamine) with commercially available 2-chlorine apellagrin ethyl ester (36).37 ester group can issue unboiled water and separate in the catalysis of alkali, next make necessary carboxylic acid intermediate and commercially available 2,4 difluorobenzene amine (38) under the peptide coupling condition of standard coupling take place, and obtains desired compound 39.

Scheme 9

Scheme 10 has been described compound 42 (X=CH ₂Synthesizing or NH).Pyrroles's borine 40 (Takigi, J.et.al.Tetrahedron Lett.2002,43,5649-5651 (being hereby incorporated by)) available compound 26 (scheme 7) acidylate obtains intermediate 41.Intermediate 41 can with aniline 19 (scheme 5) coupling, obtain desired product 42a (X=CH ₂) (Chan, D.M.T.et.al.Tetrahedron Lett.2003,44,3863-3865).Replacedly, 2-bromine pyrroles (43, Chen, W.et.al.Org.Synth.1992,70,151-156) can react, obtain intermediate 44 with isocyanic acid 4-fluorobenzene ester (29, scheme 8), described intermediate 44 can changed into 45 (Ishiyama under the catalytic coupling condition of the Pd (0) of standard in the presence of connection boric acid pinacol ester (bis (pinacolato) diboron) then, T.et.al.J.Org.Chem.1995,60,7508-7510).Compound 45 can change into 42b (X=NH) under condition described above.

Scheme 10

Scheme 11 has illustrated the preparation of compound 50.Thereby the pyrimidine 46 (AlphaAesar) that methylthio group replaces can be handled with aniline 12 (deriving from scheme 4) under acidic conditions, obtains intermediate 47.47 available bases (such as sodium hydroxide) saponification obtains carboxylate salt 48, described carboxylate salt 48 can with the coupling of commercially available 2,4 difluorobenzene amine, obtain intermediate 49.49 can handle with two (trifluoroacetyl oxygen base) iodobenzene (described in scheme 4), obtain compound 50.

Scheme 11

Scheme 12 has illustrated the preparation of another specific embodiment of formula I.Thereby the pyrimidine 49 (scheme 11) that methylthio group replaces can obtain sulfone 51 with for example metachloroperbenzoic acid oxidation in DMF.Then, next the available nucleophilic reagent of sulfone part (such as morpholine) displacement uses two (trifluoroacetyl oxygen base) iodobenzene (described in scheme 4) to handle, and obtains compound 52.

Scheme 12

Measure

The pharmacological properties of The compounds of this invention can be measured to determine by multiple pharmacology.Carried out the pharmacology mensuration of example shown below with compound of the present invention and/or their pharmacologically acceptable salt.

The Met kinase assays

Reagent substrate mixture final concentration

Stock solution

Tris-HCl，(1M，pH?7.4) 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

The damping fluid enzyme mixture

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

200 μ l 1M Tris-HCL, pH 7.4 12ml damping fluids, an amount of

20μl?100mg/ml?BSA

20ml H ₂O, an amount of

The mixtures incubated that is used for the Met kinase assays comprise synthetic substrate polyGlu: Tyr (4: 1), ATP, ATP-γ- ³³P and damping fluid (comprise Mn ⁺⁺And/or Mg ⁺⁺, DTT, BSA and Tris damping fluid).Reaction mixture was hatched 60 minutes at 27 ℃, and reaction is 4% to stop by cold trichoroacetic acid(TCA) (TCA) to the final concentration of interpolation then.Utilize Filtermate common collector (universalharvester) (Packard Instrument Co., Meriden, CT), the TCA precipitation is collected single filter plate (unifilter plate) (the Packard Instrument Co. of GF/C, Meriden, CT) on, utilize TopCount 96-hole liquid scintillation counter (Packard Instrument Co. then, Meriden CT) carries out quantitative analysis to strainer.Obtain dose response curve, thereby determine to suppress 50% the needed concentration (IC of kinase activity ₅₀).The concentration of compound with 10mM is dissolved in the dimethyl sulfoxide (DMSO) (DMSO), estimates with 6 kinds of concentration then, every kind of concentration repeats four times.The final concentration of DMSO is 1% in the mensuration.IC ₅₀Value obtains by nonlinear regression analysis, and (SD/ mean value is 16% n=6) to its variation coefficient (coefficient of variance).

Preferred compound of the present invention is with the IC of 0.01 to 100 μ M ₅₀Value suppresses the Met kinases.Preferred compound has the IC less than 1.0 μ M ₅₀Value is most preferably less than the IC of about 0.5 μ M ₅₀Value.

Following examples and preparation method have described preparation and have used mode of the present invention and method, and are illustratives and nonrestrictive.It should be understood that other embodiment also may drop in the defined the spirit and scope of the invention of appended claims.

Embodiment

To respond all be to utilize continuous magnetic agitation to carry out in the atmosphere of drying nitrogen or argon gas.All evapn and concentration operation all reduce pressure and carry out on rotatory evaporator down.Commercially available reagent in statu quo uses, and does not have further purifying.Solvent is commercially available anhydrous rank, and does not have further drying or purifying just to use.Flash chromatography utilizes silica gel, and (EMerck Kieselgel 60 0.040-0.060mm) carries out.

Analytical anti-phase (RP) HPLC utilizes Phenomenex Luna C18 S5 4.6mm * 50mm chromatographic column or YMC S5 ODS 4.6 * 50mm chromatographic column to carry out.(100%A: 0%B to 0%A: 100%B), wherein the moving phase system is A=90%H all to use the 4min linear gradient in each case ₂O/MeOH+0.2%H ₃PO ₄And B=90%MeOH/H ₂O+0.2%H ₃PO ₄, flow velocity is 4mL/min, and detects at 220nm.

Preparation property anti-phase (RP) HPLC carries out under the following conditions: utilize 10% methyl alcohol, 90% water, 0.1%TFA (solvent orange 2 A) and 90% methyl alcohol, 10% water, 0.1%TFA (solvent B) wash-out, detect at 220nm, on one of following chromatographic column, carry out: A-Shimadzu S5 ODS-VP 20 * 100mm chromatographic column (flow velocity is 20mL/min), B-YMC S5 ODS 30 * 100mm chromatographic column (flow velocity is 20mL/min), C-Phenomonex 30 * 250mm chromatographic column (flow velocity is 10mL/min), D-YMCS5 ODS 20 * 250mm chromatographic column (flow velocity is 10mL/min), E-YMC S10 ODS 50 * 500mm chromatographic column (flow velocity is 50mL/min) or F-YMC S10 ODS 30 * 500mm chromatographic column (flow velocity is 20mL/min).

All end products all pass through ¹H NMR, RP HPLC, electrospray ionization (ESI MS) or air pressure stream ionization (API MS) mass spectrum characterize. ¹H NMR spectrum obtains on 500MHz JEOL or 400MHzBruker instrument.The unit representation of field intensity be δ (1,000,000/, ppm), with respect to solvent peak; And peak multiplicity such as following showing: s are unimodal, and d is bimodal, and dd is a double doublet, and dm is two multiplets, and t is a triplet, and q is a quartet, and br s is wide unimodal, and m is a multiplet.

The abbreviation of common reagent is as follows: Boc or BOC are t-butyl carbamate; Fmoc is a carboxylamine 9H-fluorenyl methyl esters; TEA is a triethylamine; NMM is a N-methylmorpholine; Ms is a methylsulfonyl; DIEA or DIPEA are diisopropyl ethyl amine or Hunig alkali; NMP is a N-Methyl pyrrolidone; bop reagent is benzotriazole-1-base oxygen base three (the amino) Phosphonium of trimethylammonium hexafluorophosphates; DCC is 1, the 3-dicyclohexylcarbodiimide, and EDCI is 1-(dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; RT or rt are room temperature, t _RBe retention time, h is hour, and min is minute, and PyBroP is a bromine tripyrrole alkane Ji Phosphonium hexafluorophosphate, and TBTU is O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-

A tetrafluoro borate, DMAP are 4-N, and N-dimethyl aminopyridine, HOBt or HOBT are hydroxybenzotriazole, Na (OAc) ₃BH is a sodium triacetoxy borohydride, and HOAc is an acetate, and TFA is a trifluoroacetic acid, LiHMDS is two (TMS) Lithamide (lithium bis (trimethylsilyl) amide), DMSO is a dimethyl sulfoxide (DMSO), and MeCN is an acetonitrile, and MeOH is a methyl alcohol, EtOAc is an ethyl acetate, DMF is a dimethyl formamide, and THF is a tetrahydrofuran (THF), and DCE is 1, the 2-ethylene dichloride, Et ₂O is an ether, and DCM is a methylene dichloride, and m-CPBA is the 3-chloroperoxybenzoic acid.

Embodiment 1

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

A) 4-chloro-N-(2,4 difluorobenzene base) niacinamide

With bromo-three-pyrrolidino-Phosphonium hexafluorophosphate (PyBroP

Novabiochem, 1.4g, 3.0mmol) add to 4-chlorine apellagrin (Lancaster Synthesis, 0.31g, 2.0mmol) and 2,4-difluoroaniline (Aldrich, 0.20mL, 2.0mmol) mixture in anhydrous methylene chloride (5mL), next add diisopropyl ethyl amine (1.1mL, 6.4mmol).(2mL) adds in the mixture with dry DMF, and reaction mixture is stirred in envrionment temperature.After 255 hours, reaction mixture is distributed between chloroform and 10%LiCl (aqueous solution).Organic layer is used anhydrous MgSO with 10%LiCl (aqueous solution) washing three times ₄Drying, vacuum concentration then.Resistates is by flash column chromatography (SiO ₂, with 1: 1 hexane/EtOAc wash-out) and come purifying, obtain desired compound (0.23g, 42%). ¹H?NMR(DMSO-d ₆)δ10.58(s，1H)，8.78(s，1H)，8.66(d，1H，J＝5.4Hz)，7.82-7.88(m，1H)，7.71(d，1H，J＝5.4Hz)，7.37-7.43(m，1H)，7.14-7.19(m，1H)；MS(ESI ⁺)m/z?269(M+H) ⁺。

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

With 4-chloro-1H-pyrrolo-[2,3-b] pyridine (457mg, 3.0mmol, usually according to Thibault, C.et al.Org.Lett.2003,5,5023 prepare), 2-fluoro-4-nitrophenols (706mg, 4.5mmol) and N, the N-diisopropyl ethyl amine (580mg, 4.5mmol) the mixture of 1-Methyl-2-Pyrrolidone (NMP) in (3mL) under microwave irradiation at 200 ℃ of heating 1h.Mixture is with ethyl acetate (150mL) dilution, with saturated KH ₂PO ₄The aqueous solution and Na ₂CO ₃Na is used in (aqueous solution of 1M) washing then ₂SO ₄Dry.(silica gel is used CH to product by flash column chromatography ₂Cl ₂To 30%EtOAc/CH ₂Cl ₂Wash-out) comes purifying, obtain desired compound (350mg, 43%), be brown solid.MS(ESI ⁺)m/z274(M+H) ⁺。

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

With zinc powder (350mg, 5.5mmol) and ammonium chloride (294mg 5.5mmol) adds to 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo-[2,3-b] pyridine (300mg, 1.1mmol) suspension in tetrahydrofuran (THF) (5mL) and methyl alcohol (10mL).With mixture in stirred overnight at room temperature.Mixture is filtered through Celite

Pad is used washed with methanol.Filtrate is carried out vacuum concentration, and resulting then resistates is by flash column chromatography (silica gel, the CH of 1-5%MeOH ₂Cl ₂Solution) come purifying, obtain desired product (205mg, 77%), be pale solid.MS(ESI ⁺)m/z?244(M+H) ⁺。

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

4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoro-aniline (0.039g, 0.16mmol), 4-chloro-N-(2, the 4-difluorophenyl) niacinamide (0.043g, 0.16mmol) and tosic acid monohydrate (Aldrich, 0.024g 0.13mmol) homogenizing mixture in anhydrous NMP (1mL) is used microwave treatment in CEMExplorer PLS microwave system (300W).Temperature is measured with the IR temperature sensor, and maintains 160 ℃.After 1 hour, reaction mixture is distributed between chloroform and salt solution.Water layer chloroform extraction twice, the organic layer that is combined then carries out vacuum concentration.Resulting resistates comes purifying by preparation property HPLC (YMC S10 ODS, 30 * 500mm, 30 minutes gradients, 34% to 90% methanol aqueous solution (containing 0.1%TFA)).Suitable cut is merged, and freeze-drying then obtains pale solid, and described pale solid is dissolved among the anhydrous THF (1mL), is cooled to 0 ℃, and (4N De dioxane solution, 1.0mL 4.0mmol) handle to use HCl then.Reaction mixture was stirred 10 minutes, and freeze-drying afterwards obtains title compound (0.015g, 18%), is pale solid. ¹H NMR (DMSO-d ₆) δ 12.29 (s, 1H), 10.96 (s, 1H), 10.80 (s, 1H), 9.01 (s, 1H), 8.33 (d, 1H, J=7.2Hz), 8.17 (d, 1H, J=5.9Hz), 7.11-7.67 (m, 8H), 6.59 (d, 1H, J=5.8Hz), 6.38-6.39 (m, 1H); HRMS (ESI ⁺), 476.1334 (M+H) ⁺(calculated value), 476.1342 (M+H) ⁺(measured value).

Embodiment 2

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

To be similar to preparation 4-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2, the 4-difluorophenyl) mode of niacinamide hydrochloride (Compound D of embodiment 1), with 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (0.073g, 0.30mmol, the Compound C of embodiment 1) changes into title compound (0.032g, 21%), different is to use 2-chloro-N-(2, the 4-difluorophenyl) niacinamide (Maybridge, 0.081g, 0.30mmol) replace 4-chloro-N-(2,4 difluorobenzene base) niacinamide. ¹H NMR (DMSO-d ₆) δ 12.83 (s, 1H), 10.75 (s, 1H), 10.52 (s, 1H), 8.28-8.41 (m, 3H), 8.15 (dd, 1H, J=13.6,2.2Hz), 7.32-7.56 (m, 5H), 7.09-7.13 (m, 1H), 6.98-7.01 (m, 1H), 6.72 (d, 1H, J=6.5Hz), 6.48-6.49 (m, 1H); HRMS (ESI ⁺), 476.1334 (M+H) ⁺(calculated value), 476.1350 (M+H) ⁺(measured value).

Embodiment 3

2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) niacinamide hydrochloride

A) 4-chloropyridine acid amides

The heterogeneous body mixture of 4-chloropyridine formic acid (TCI America, 5.4g, 34.2mmol, 1.0 equivalents) and thionyl chloride (30mL) is heated 2h at 80 ℃.Reaction mixture is cooled to room temperature, then vacuum concentration.(7N 45mL) handles the MeOH solution of resistates usefulness ammonia in ice bath, and reaction mixture was stirred 15 minutes.Then, ice bath is removed, reaction mixture is warmed to room temperature, stir 3h then.Reaction mixture is carried out vacuum concentration, and resistates comes purifying by recrystallization in EtOAc then, obtains desired product (5.14g, 96%), is solid. ¹HNMR(DMSO-d ₆)δ8.61-8.63(m，1H)，8.21(m，1H)，8.03-8.04(m，1H)，7.76-7.83(m，2H)；MS(ESI ⁺)m/z157(M+H) ⁺。

B) 2-fluoro-4-amino-phenol

Mixture in MeOH (100mL) is at the H of room temperature at 50psi with platinum oxide (0.010g) and 2-fluoro-4-nitrophenols (Aldrich, 1.24g, 7.78mmol, 1.0 equivalents) ₂Stir under the atmosphere.Reaction mixture is filtered through Celite , then filtrate is carried out vacuum concentration, obtain desired compound (1.00g, 100%), be solid, it just is not further purified and uses. ¹H?NMR(DMSO-d ₆)δ8.57(s，1H)，6.46-6.47(m，1H)，6.33-6.46(m，1H)，6.19-6.21(m，1H)，4.79(s，2H)；MS(ESI ⁺)m/z?128(M ⁺H) ⁺。

C) 4-(4-amino-2-fluorophenoxy) picolinamide

DMF (6.5mL) solution of 4-amino-2-fluorophenol (0.81g, 6.4mmol, 1.0 equivalents) is handled with potassium tert.-butoxide (0.79g, 7.1mmol, 1.1 equivalents) in room temperature, and reaction mixture is stirred 1h.Add 4-chloropyridine acid amides (1.0g, 6.4mmol, 1.0 equivalents), reaction mixture is heated to 110 ℃ then, keep 8h.Reaction mixture is cooled to room temperature, then the cancellation of reaction mixture water.Resulting heterogeneous solution is filtered, then solid matter water used wash.Solid is ground with a spot of MeOH, next with Et ₂O grinds together.With solid filtering, vacuum-drying then obtains desired product (1.3g, 82%), is solid. ¹H?NMR(DMSO-d ₆)δ8.49-8.50(m，1H)，8.12(brs，1H)，7.71(br?s，1H)，7.35-7.36(m，1H)，7.14-7.16(m，1H)，7.01-7.06(m，1H)，6.44-6.47(m，2H)，5.53(s，2H)；MS(ESI ⁺)m/z?248(M+H) ⁺。

D) 2-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) niacinamide

To be similar to preparation 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2, the 4-difluorophenyl)-mode of niacinamide (embodiment 2), with 4-(4-amino-2-fluorophenoxy) picolinamide (0.12g, 0.50mmol) change into desired compound (0.088g, 37%).HRMS (ESI ⁺), 480.1283 (M+H) ⁺(calculated value), 480.1281 (M+H) ⁺(measured value).

E) 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4-two fluoro-phenyl) niacinamide hydrochloride

In room temperature; with two (trifluoroacetyl oxygen base) iodobenzene (0.10g; 0.23mmol) add to 2-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2; 4-two fluoro-phenyl) niacinamide (0.080g; 0.17mmol), water (0.006g; 0.33mmol) and pyridine (0.27mL, dry DMF 3.33mmol) (5mL) solution.Reaction mixture was stirred 69 hours, add the 6N HCl aqueous solution (2mL) afterwards, with reaction mixture restir 15 minutes.Mixture Et ₂The O extracting twice is abandoned the organic layer that merges then.Water layer 1M NaHCO ₃(aqueous solution) neutralization extracts with EtOAc then.With the anhydrous MgSO of organic layer that merges ₄Drying, vacuum concentration then.Resulting resistates comes purifying by preparation property HPLC (YMCS10 ODS, 30 * 500mm, 30 minutes gradients, 34% to 90% methanol aqueous solution (containing 0.1%TFA)).Suitable cut is merged, be lyophilized into pale solid then, described pale solid is dissolved among the anhydrous THF (2mL), be cooled to 0 ℃, (4N De dioxane solution, 1.0mL 4.0mmol) handle to use HCl then.Reaction mixture was stirred 10 minutes, and freeze-drying afterwards obtains title compound (0.029g, 35%), is pale solid. ¹H NMR (DMSO-d ₆) δ 10.72 (s, 1H), 10.49 (s, 1H), 8.32-8.40 (m, 2H), 8.13 (dd, 1H, J=13.7,2.4Hz), 7.82-7.92 (m, 3H), 7.29-7.53 (m, 4H), 7.05-7.15 (m, 1H), 6.97-7.01 (m, 1H), 6.64-6.66 (m, 1H), 6.12 (d, 1H, J=2.4Hz); HRMS (ESI ⁺), 452.1334 (M+H) ⁺(calculated value), 452.1341 (M+H) ⁺(measured value).

Embodiment 4

2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(4-chloro-phenyl-) niacinamide dihydrochloride

A) 2-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(4-chloro-phenyl-) niacinamide

To be similar to preparation 2-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl)-mode of niacinamide (the step D of embodiment 3); with 4-(4-amino-2-fluorophenoxy) picolinamide (0.12g; 0.50mmol; the Compound C of embodiment 3) changes into desired compound (0.090g; 47%); different is; use 2-chloro-N-(4-chloro-phenyl-) niacinamide (Maybridge; 0.11g; 0.40mmol) replacement 2-chloro-N-(2,4 difluorobenzene base) niacinamide.HRMS (ESI ⁺), 478.1082 (M+H) ⁺(calculated value), 478.1059 (M+H) ⁺(measured value).

B) 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(4-chloro-phenyl-)-niacinamide hydrochloride

To be similar to preparation 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl) mode of niacinamide (step e of embodiment 3); with 2-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(4-chloro-phenyl) niacinamide (0.088g; 0.18mmol) change into title compound (0.022g, 25%). ¹H NMR (DMSO-d ₆) δ 10.65 (s, 1H), 10.40 (s, 1H), 8.36 (dd, 1H, J=4.9,1.6Hz), 8.25-8.28 (m, 1H), 8.11 (dd, 1H, J=13.6,2.4Hz), 7.71-7.92 (m, 5H), and 7.29-7.45 (m, 4H), 6.98 (dd, 1H, J=7.7,4.9Hz), 6.65 (dd, 1H, J=7.3,2.5Hz), 6.13 (d, 1H, J=2.4Hz); HRMS (ESI ⁺), 450.1148 (M+H) ⁺(calculated value), 450.1133 (M+H) ⁺(measured value).

Embodiment 5

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) niacinamide dihydrochloride

A) 4-(4-(3-(2,4 difluorobenzene base carbamyl) pyridin-4-yl amino)-2-fluorophenoxy) picolinamide

To be similar to preparation 4-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4-two-fluorophenyl) mode of niacinamide (the step D of embodiment 1), with 4-(4-amino-2-fluorophenoxy) picolinamide (0.12g, 0.50mmol, the Compound C of embodiment 3) changes into desired compound (0.030g, 12%).HRMS (ESI ⁺), 480.1284 (M+H) ⁺(calculated value), 480.1273 (M+H) ⁺(measured value).

B) 4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) niacinamide dihydrochloride

To be similar to preparation 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl) mode of niacinamide (step e of embodiment 3); ((3-(2 for 4-with 4-; 4-difluorophenyl carbamyl) pyridin-4-yl amino)-and 2-fluoro-phenoxy group) picolinamide (0.030g; 0.062mmol) change into title compound (0.010g, 34%). ¹H NMR (DMSO-d ₆) δ 10.93 (s, 1H), 10.73 (s, 1H), 9.01 (s, 1H), 8.33 (d, 1H, J=6.6Hz), 7.90-8.05 (m, 3H), 7.07-7.70 (m, 7H), 6.66 (dd, 1H, J=7.2,2.3Hz), 6.28 (s, 1H); HRMS (ESI ⁺), 452.1334 (M+H) ⁺(calculated value), 452.1332 (M+H) ⁺(measured value).

Embodiment 6

2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-benzyl niacinamide dihydrochloride

A) ((3-(2 for 4-to be similar to preparation 4-for picolinamide for 4-(4-(3-(benzyl carbamyl) pyridine-2-base is amino)-2-fluoro-phenoxy group); 4-difluorophenyl carbamyl) pyridin-4-yl amino)-and the 2-fluorophenoxy) mode of picolinamide (the step D of embodiment 1); with 4-(4-amino-2-fluorophenoxy) picolinamide (0.099g; 0.40mmol; the Compound C of embodiment 3) changes into desired compound (0.080g; 44%); different is; use N-benzyl-2-chloro-nicotinamide (Maybridge; 0.099g; 0.40mmol) replacement 4-chloro-N-(2,4 difluorobenzene base) niacinamide.MS(ESI ⁺)m/z?458(M+H) ⁺。

B) 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-benzyl niacinamide dihydrochloride

To be similar to preparation 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl) mode of niacinamide (step e of embodiment 3); with 4-(4-(3-(benzyl carbamyl) pyridine-2-base is amino)-2-fluorophenoxy) picolinamide (0.068g; 0.15mmol) change into title compound (0.051g, 69%). ¹HNMR (DMSO-d ₆) δ 11.17 (s, 1H), 9.44 (t, 1H, J=5.7Hz), 8.10-8.35 (m, 3H), 7.91 (d, 1H, J=7.2Hz), 7.82 (br s, 2H), 7.15-7.42 (m, 7H), 6.90-6.94 (m, 1H), 6.65 (dd, 1H, J=7.2,2.5Hz), 6.12 (d, 1H, J=2.5Hz), 4.45 (d, 2H, J=5.8Hz); HRMS (ESI ⁺), 430.1679 (M+H) ⁺(calculated value), 430.1683 (M+H) ⁺(measured value).

Embodiment 7

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

To be similar to preparation 4-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2, the 4-difluorophenyl) mode of niacinamide hydrochloride (Compound D of embodiment 1), with 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (0.043g, 0.18mmol, the Compound C of embodiment 1) changes into title compound (0.015g, 17%), different is to use N-benzyl-2-chloro-nicotinamide (Maybridge, 0.043g, 0.18mmol) replacement 4-chloro-N-(2,4 difluorobenzene base) niacinamide. ¹HNMR (DMSO-d ₆) δ 12.55 (s, 1H), 11.18 (s, 1H), 9.37-9.45 (m, 1H), 8.10-8.36 (m, 4H), 7.18-7.54 (m, 8H), 6.90-6.97 (m, 1H), 6.64 (d, 1H, J=6.3Hz), 6.40-6.44 (m, 1H), 4.46 (d, 2H, J=5.8Hz); HRMS (ESI ⁺), 454.1679 (M+H) ⁺(calculated value), 454.1684 (M+H) ⁺(measured value).

Embodiment 8

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

A) 2-fluoro-N-o-tolyl niacinamide

(3.2mmol) (0.56mL 6.4mmol) handles the homogenizing mixture in anhydrous THF (12mL) the 2-fluorine nicotinic acid, next uses dry DMF (2) to handle with oxalyl chloride for Aldrich, 0.45g.Behind the reflux 1.5 hours, reaction mixture is carried out vacuum concentration, obtain 2-fluorine nicotinoyl chlorine, be resistates, it just is not further purified and uses.With resistates be dissolved in anhydrous THF (8mL), anhydrous DCM (2mL), pyridine (1mL) and DMF (to cumulative volume be 16mL) in.Then, the 2-fluorine nicotinoyl chlorine mixture (2mL) of this homogeneous is added to fast Ortho Toluidine (Aldrich, 0.17mL, 1.6mmol) mixture in anhydrous THF (2mL) of stirring.After 15 hours, the cancellation of reaction water, the chloroformic solution with 10% Virahol extracts then.Organic layer is with saturated NaHCO ₃Solution washing once with saturated NaCl solution washing once, is used anhydrous Na ₂SO ₄Drying, vacuum concentration obtains desired product (0.084g, 91%) then, is greenish orange look solid, and it just is not further purified and uses.MS(ESI ⁺)m/z231(M+H) ⁺。

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

With HCl (1 of 4N, the 4-dioxane solution, 0.18mL, 0.72mmol) add to 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (0.042g, 0.17mmol, the Compound C of embodiment 1) and 2-fluoro-N-o-tolyl niacinamide (0.040g, 0.17mmol) anhydrous 1, the homogenizing mixture among 4-diox (0.22mL) and the anhydrous NMP (0.40mL).Reaction mixture was heated 65 hours at 140 ℃ in the pipe of sealing, between chloroform and 10%LiCl (aqueous solution), distribute afterwards.The water layer chloroform extraction, the organic layer that is combined then carries out vacuum concentration.Resulting resistates comes purifying by preparation property (RP) HPLC (YMC S10 ODS, 30 * 500mm, 30 minutes gradients, 34% to 90% methanol aqueous solution (containing 0.1%TFA)).Suitable cut is merged, and vacuum concentration obtains the tawny solid then, and described tawny solid is dissolved among the anhydrous THF (1mL), is cooled to 0 ℃, and (0.5mL 2.0mmol) handles for 1 of 4N, 4-dioxane solution to use HCl then.Reaction mixture was stirred 10 minutes, and freeze-drying afterwards obtains title compound (0.025g, 29%), is the tawny solid. ¹H NMR (DMSO-d ₆) δ 12.74 (s, 1H), 10.89 (s, 1H), 10.26 (s, 1H), 8.10-8.50 (m, 4H), 7.10-7.70 (m, 7H), 6.95-7.05 (m, 1H), 6.65-6.75 (m, 1H), 6.45-6.53 (m, 1H), 2.19 (s, 3H); HRMS (ESI ⁺), 454.1674 (M+H) ⁺(calculated value), 454.1680 (M+H) ⁺(measured value).

Embodiment 9

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

A) 2-fluoro-N-(4-fluoro-2-aminomethyl phenyl) niacinamide

To be similar to the mode of preparation 2-fluoro-N-o-tolyl niacinamide (steps A of embodiment 8), (Aldrich, 0.18mL 1.6mmol) change into desired compound (0.098g, 99%) with 4-fluoro-2-aminotoluene.MS(ESI ⁺)m/z?249(M+H) ⁺。

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

To be similar to preparation 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-mode of N-o-tolyl niacinamide (the step B of embodiment 8), with 2-fluoro-N-(4-fluoro-2-aminomethyl phenyl) niacinamide (0.050g, 0.20mmol) change into title compound (0.043g, 42%). ¹HNMR (DMSO-d ₆) δ 12.85 (s, 1H), 10.87 (s, 1H), 10.28 (s, 1H), 8.10-8.40 (m, 4H), 6.96-7.60 (m, 7H), 6.72 (d, 1H, J=6.5Hz), 6.45-6.53 (m, 1H), 2.20 (s, 3H); HRMS (ESI ⁺), 472.1580 (M+H) ⁺(calculated value), 472.1590 (M+H) ⁺(measured value).

Embodiment 10

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

A) N-(2-chloro-phenyl-)-2-fluorine niacinamide

To be similar to the mode of preparation 2-fluoro-N-o-tolyl niacinamide (steps A of embodiment 8), (Aldrich, 0.17mL 1.6mmol) change into desired compound (0.084g, 84%) with the 2-chloroaniline.MS(ESI ⁺)m/z?251(M+H) ⁺。

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

To be similar to preparation 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-mode of N-o-tolyl niacinamide (the step B of embodiment 8), with N-(2-chloro-phenyl-)-2-fluorine niacinamide (0.050g, 0.20mmol) change into title compound (0.037g, 36%). ¹H NMR (DMSO-d ₆) δ 12.75 (s, 1H), 10.80 (s, 1H), 10.49 (s, 1H), 8.10-8.44 (m, 4H), 7.24-7.60 (m, 7H), 6.96-7.10 (m, 1H), 6.70 (m, 1H), 6.45-6.50 (m, 1H); HRMS (ESI ⁺), 474.1133 (M+H) ⁺(calculated value), 474.1129 (M+H) ⁺(measured value).

Embodiment 11

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

A) 2-fluoro-N-(4-luorobenzyl) niacinamide

To be similar to the mode of preparation 2-fluoro-N-o-tolyl niacinamide (steps A of embodiment 8), (Aldrich, 0.18mL 1.6mmol) change into desired compound (0.099g, 100%) with 4-luorobenzyl amine.MS(ESI ⁺)m/z?249(M+H) ⁺。

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

To be similar to preparation 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-mode of N-o-tolyl niacinamide (the step B of embodiment 8), with 2-fluoro-N-(4-luorobenzyl) niacinamide (0.050g, 0.20mmol) change into title compound (0.035g, 35%). ¹H NMR (DMSO-d ₆) δ 12.63 (s, 1H), 11.17 (s, 1H), 9.44 (t, 1H, J=5.8Hz), 8.10-8.40 (m, 4H), 7.50-7.60 (m, 1H), 7.30-7.45 (m, 4H), 7.08-7.10 (m, 2H), 6.90-6.95 (m, 1H), 6.66 (d, 1H, J=6.3Hz), 6.43-6.46 (m, 1H), 4.44 (d, 2H, J=5.7Hz); HRMS (ESI ⁺), 472.1585 (M+H) ⁺(calculated value), 472.1587 (M+H) ⁺(measured value).

Embodiment 12

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

A) 2-fluoro-N-(2-morpholino base-1-phenylethyl) niacinamide

To be similar to the mode of preparation 2-fluoro-N-o-tolyl niacinamide (steps A of embodiment 8), (0.33g 1.6mmol) changes into desired compound (0.12g, 87%) for Array Biopharma, Inc. with 2-morpholino base-1-phenyl ethyl amine.HRMS (ESI ⁺), 330.1618 (M+H) ⁺(calculated value), 330.1620 (M+H) ⁺(measured value).

B) 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2-morpholino base-1-phenylethyl) niacinamide tri hydrochloride

To be similar to preparation 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-mode of N-o-tolyl niacinamide (the step B of embodiment 8), with 2-fluoro-N-(2-morpholino base-1-phenylethyl) niacinamide (0.096g, 0.29mmol) change into title compound (0.022g, 13%). ¹HNMR (DMSO-d ₆) δ 12.53 (s, 1H), 10.93-11.05 (m, 2H), 9.73 (d, 1H, J=7.8Hz), 8.59 (dd, 1H, J=7.9,1.3Hz), 8.35 (dd, 1H, J=4.7,1.4Hz), 8.20 (d, 1H, J=6.2Hz), 8.06-8.15 (m, 1H), 7.45-7.55 (m, 3H), 7.23-7.40 (m, 4H), 6.90-6.99 (m, 1H), 6.60 (d, 1H, J=6.2Hz), 6.38-6.45 (m, 1H), and 5.53-5.64 (m, 1H), 3.10-4.00 (m, 10H); HRMS (ESI ⁺), 553.2363 (M+H) ⁺(calculated value), 553.2368 (M+H) ⁺(measured value).

Embodiment 13

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2-(2-hydroxyethyl) phenyl) niacinamide two (trifluoroacetic acid) salt

A) 2-(2-(tert-butyl diphenyl siloxy-) ethyl) aniline

At 0 ℃, (Aldrich, 0.87mL 6.6mmol) add to sodium hydride (60% mineral oil dispersion liquid, 0.29g, anhydrous THF (30mL) suspension 7.3mmol) with 2-amino-benzene ethanol.After 17 hours (during this period reaction mixture slowly being warmed to room temperature), mixture is inclined in saturated sodium chloride aqueous solution, extract with EtOAc then.The anhydrous MgSO of organic layer that merges ₄Drying, vacuum concentration becomes resistates then, and described resistates obtains desired compound (2.5g, 100%) by flash chromatography on silica gel (with 3: 1 hexane/EtOAc wash-outs) purifying, is oily matter.MS(ESI ⁺)m/z?376(M+H) ⁺。

B) N-(2-(2-(tert-butyl diphenyl siloxy-) ethyl) phenyl)-2-fluorine niacinamide

(2.9mmol) mixture in thionyl chloride (15mL) refluxed 2 hours for Aldrich, 0.42g, and vacuum concentration becomes resistates afterwards, and it just is not further purified and uses with the 2-fluorine nicotinic acid.Resistates is dissolved among the anhydrous DCM (5mL), then it is dropwise added to 0 ℃ 2-(2-(tert-butyl diphenyl siloxy-) ethyl) aniline (1.10g, 2.9mmol) and TEA (0.43mL, anhydrous DCM (15mL) solution 3.1mmol).Then, reaction mixture was stirred 16 hours in envrionment temperature, water cancellation afterwards, and then stirred 30 minutes.Each layer separated, and water layer extracts with DCM then.The organic layer that merges is water, saturated NaHCO successively ₃Anhydrous MgSO is used in the aqueous solution and salt water washing afterwards ₄Drying, vacuum concentration then.Resulting resistates obtains desired compound (1.1g, 72%) by flash chromatography on silica gel (with 4: 1 hexane/EtOAc wash-outs) purifying, is white solid. ¹HNMR (DMSO-d ₆) δ 9.93 (s, 1H), 8.41 (d, 1H, J=4.4Hz), 8.22 (t, 1H, J=7.6Hz), 7.27-7.60 (m, 15H), 3.84 (t, 2H, J=6.7Hz), 2.98 (t, 2H, J=6.7Hz), 0.92 (s, 9H); HRMS (ESI ⁺), 499.2217 (M+H) ⁺(calculated value), 499.2230 (M+H) ⁺(measured value).

C) 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2-(2-hydroxyethyl) phenyl) niacinamide two (trifluoroacetic acid) salt

With HCl (1 of 4N, 4-dioxane solution, 0.30mL, 1.2mmol) add to 0 ℃ 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-homogenizing mixture of 3-fluoroaniline (0.040g, 0.16mmol, the Compound C of embodiment 1) in anhydrous MeOH (3mL).Then, with reaction mixture at stirring at room 10 minutes, vacuum concentration afterwards.Resulting solid is with the toluene azeotropic, vacuum concentration becomes pale solid then, described pale solid dry DMF (2mL) and N-(2-(2-(tert-butyl diphenyl siloxy-) ethyl) phenyl)-2-fluorine niacinamide (0.90g, 0.18mmol) handle, then 110 ℃ of heating 121 hours.The reaction mixture vacuum concentration is become resistates, and described resistates comes purifying by preparation property (RP) HPLC (YMC S10 ODS, 30 * 500mm, 30 minutes gradients, 58% to 90% methanol aqueous solution (containing 0.1%TFA)).Suitable cut is merged, and vacuum concentration obtains title compound (0.014g, 15%) then, is the tawny solid. ¹H NMR (DMSO-d ₆) δ 11.89 (s, 1H), 10.86 (s, 1H), 10.43 (s, 1H), and 8.35-8.45 (m, 1H), 8.24 (d, 1H, J=7.8Hz), and 8.05-8.14 (m, 2H), 7.13-7.48 (m, 7H), 6.95-6.99 (m, 1H), 6.35-6.41 (m, 1H), 6.24-6.29 (m, 1H), 3.59 (t, 2H, J=6.5Hz), 2.74 (t, 2H, J=6.5Hz); HRMS (ESI ⁺), 484.1785 (M+H) ⁺(calculated value), 484.1788 (M+H) ⁺(measured value).

Embodiment 14

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(5-fluorine pyridine-2-yl) niacinamide two (trifluoroacetic acid) salt

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

With HCl (1 of 4N, the 4-dioxane solution, 0.42mL, 1.7mmol) add to 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (0.10g, 0.42mmol, the Compound C of embodiment 1) and 2-fluorine nicotinic acid (Aldrich, 0.084g, the 0.59mmol) homogenizing mixture in anhydrous NMP (0.50mL).Mixture is used microwave treatment in CEM Explorer PLS microwave system (300W).Temperature is measured with the IR temperature sensor, and keeps 2 hours at 120 ℃, next keeps 6 hours at 140 ℃.Reaction mixture is distributed between water and EtOAc.Water layer EtOAc extracting twice, the organic layer that is combined then carries out vacuum concentration.Resulting resistates comes purifying by preparation property (RP) HPLC (YMC S10 ODS, 30 * 500mm, 30 minutes gradients, 50% to 90% methanol aqueous solution (containing 0.1%TFA)).Suitable cut is merged, and vacuum concentration obtains desired compound (0.13g, 82%) then, is pale solid. ¹H NMR (DMSO-d ₆) δ 13.75 (br s, 1H), 12.11 (s, 1H), 10.60 (s, 1H), 8.40 (dd, 1H, J=4.7,1.9Hz), 8.24 (dd, 1H, J=7.7,1.9Hz), 8.10-8.20 (m, 2H), and 7.30-7.49 (m, 3H), 6.90 (dd, 1H, J=7.7,4.8Hz), 6.48 (d, 1H, J=5.8Hz), 6.31-6.40 (m, 1H); HRMS (ESI ⁺), 365.1050 (M+H) ⁺(calculated value), 365.1038 (M+H) ⁺(measured value).

B) 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(5-fluorine pyridine-2-yl) niacinamide two (trifluoroacetic acid) salt

With the inferior phosphonyl chloride (0.025g of two (2-oxos-3-oxazolidinyl), 0.010mmol) add to 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino) nicotinic acid (0.036g, 0.10mmol), 2-amino-5-fluorine pyridine (Aldrich, 0.22g, 2.0mmol) and TEA (0.020g, 0.20mmol) homogenizing mixture in anhydrous DCM (2mL) (being cooled to 0 ℃).After 15 hours (during this period reaction mixture slowly being warmed to room temperature), mixture is distributed between chloroform and water.The water layer chloroform extraction merges organic layer afterwards, uses the salt water washing, uses anhydrous MgSO ₄Drying, vacuum concentration then.Resulting resistates comes purifying by preparation property (RP) HPLC (YMC S10 ODS, 30 * 500mm, 30 minutes gradients, 58% to 90% methanol aqueous solution (containing 0.1%TFA)).Suitable cut is merged, and vacuum concentration obtains desired compound (8.0mg, 14%) then, is faint yellow solid. ¹HNMR (DMSO-d ₆) δ 11.12 (s, 1H), 10.29 (s, 1H), 10.20 (s, 1H), 8.02-8.49 (m, 6H), 7.75-7.83 (m, 1H), 7.25-7.48 (m, 3H), 6.92 (dd, 1H, J=7.7,4.8Hz), 6.37-6.40 (m, 1H), 6.26 (dd, 1H, J=3.1,1.7Hz); HRMS (ESI ⁺), 459.1376 (M+H) ⁺(calculated value), 459.1367 (M+H) ⁺(measured value).

Embodiment 15

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-4-methoxyl group niacinamide two (trifluoroacetic acid) salt

With

Embodiment 16

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-4-hydroxy nicotinoyl amine two (trifluoroacetic acid) salt

A) 2-chloro-N-(2,4 difluorobenzene base)-4-iodine niacinamide

Successively with PyBroP (Novabiochem, 1.4g, 3.1mmol) and DIPEA (1.1mL 6.6mmol) adds to 2-chloro-4-iodine nicotinic acid (CB Research﹠amp; Development, Inc., 0.58g is 2.0mmol) with 2,4 difluorobenzene amine (Aldrich, 0.21mL, 2.0mmol) homogenizing mixture in dry DMF (7mL).Mixture was stirred 63 hours, between chloroform and 10%LiCl (aqueous solution), distribute then.The water layer chloroform extraction, latter incorporated organic layer with 10%LiCl (aqueous solution) washed twice, use anhydrous MgSO ₄Drying, vacuum concentration then.Resistates is by flash column chromatography (SiO ₂, with 1: 1 hexane/EtOAc wash-out) and come purifying, obtain desired compound (0.43g, 53%).MS(ESI ⁺)m/z395(M+H) ⁺。

B) 2-chloro-N-(2,4 difluorobenzene base)-4-methoxyl group niacinamide

(0.17g 0.43mmol) adds to sodium methylate (0.023g, anhydrous methanol 0.43mmol) (3mL) solution with 2-chloro-N-(2,4 difluorobenzene base)-4-iodine niacinamide.Mixture 60 ℃ of heating 12 hours, is cooled to envrionment temperature then.Reaction mixture is concentrated, obtain resistates, described resistates is ground with the first alcohol and water.Separate by vacuum filtration, obtain desired compound (0.035g), be pale solid.The filtrate vacuum concentration is become resistates, and described resistates is by flash column chromatography (SiO ₂, with 25-100%EtOAc/ hexane wash-out) come purifying, obtain additional quantity desired compound (with initially-separate to material be consistent on spectrum) (0.049g, overall yield is 65%). ¹HNMR(DMSO-d ₆)δ10.48(s，1H)，8.38(d，1H，J＝5.8Hz)，7.85-7.96(m，1H)，7.33-7.40(m，1H)，7.27(d，1H，J＝5.8Hz)，7.05-7.20(m，1H)，3.92(s，3H)；MS(ESI ⁺)m/z?299(M+H) ⁺。

C) 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2, the 4-difluorophenyl)-4-methoxyl group niacinamide two (trifluoroacetic acid) salt (embodiment 15) and 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-4-hydroxy nicotinoyl amine two (trifluoroacetic acid) salt (embodiment 16)

With HCl (1 of 4N, the 4-dioxane solution, 0.15mL, 0.60mmol) add to 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (0.037g, 0.15mmol, the Compound C of embodiment 1) and 2-chloro-N-(2, the 4-difluorophenyl)-4-methoxyl group niacinamide (0.045g, 0.15mmol) homogenizing mixture in anhydrous NMP (0.50mL).Mixture is used microwave treatment in CEM Explorer PLS microwave system (300W), temperature is measured with the IR temperature sensor, and keeps 6 hours at 140 ℃.Reaction mixture is distributed between water and EtOAc.Water layer EtOAc extracting twice, the organic layer that is combined then carries out vacuum concentration.Resulting resistates comes purifying by preparation property (RP) HPLC (YMC S10 ODS, 30 * 500mm, 30 minutes gradients, 50% to 90% methanol aqueous solution (containing 0.1%TFA)).Suitable cut is merged, vacuum concentration then, obtain 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2, the 4-difluorophenyl)-4-methoxyl group niacinamide (embodiment 15) (0.006g) (being pale solid) and 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-4-hydroxy nicotinoyl amine (embodiment 16) (0.042g) (being white solid).

Embodiment 15:

¹H NMR (DMSO-d ₆) δ 13.42 (s, 1H), 12.10 (s, 1H), 11.12 (s, 1H), 8.54 (d, 1H, J=7.1Hz), 8.23-8.35 (m, 1H), 7.80 (d, 1H, J=3.3Hz), 7.55-7.75 (m, 2H), and 7.25-7.41 (m, 3H), 6.89-7.10 (m, 2H), 6.77 (d, 1H, J=3.3Hz), 6.00-6.09 (m, 1H), 4.23 (s, 3H); HRMS (ESI+), 506.1440 (M+H) ⁺(calculated value), 506.1438 (M+H) ⁺(measured value).

Embodiment 16:

¹H NMR (DMSO-d ₆) δ 12.04 (s, 1H), 11.93 (s, 1H), 11.03 (s, 1H), 8.25-8.40 (m, 1H), 8.11 (d, 1H, J=5.6Hz), 7.59 (dd, 1H, J=11.6,1.9Hz), 7.20-7.50 (m, 5H), and 6.99-7.10 (m, 1H), 6.48 (d, 1H, J=5.6Hz), 6.35 (dd, 1H, J=3.3,1.9Hz), 6.02 (d, 1H, J=7.4Hz), 4.85 (br s, 1H); HRMS (ESI ⁺), 492.1283 (M+H) ⁺(calculated value), 492.1282 (M+H) ⁺(measured value).

Embodiment 17

2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-5-bromo-N-(2,4 difluorobenzene base) niacinamide two (trifluoroacetic acid) salt

A) 5-bromo-2-chloro-N-(2,4 difluorobenzene base) niacinamide

The DMF of 1mL is slowly added to 5-bromo-2-hydroxy niacin (2.20g, 10mmolSynthesis, 2002,10mL SOCl 528-532) in room temperature ₂In the suspension, then resulting solution is heated 2h at 80 ℃.Excessive SOCl is removed in decompression ₂Resistates is dissolved in the methylene dichloride (DCM) of 50mL.Successively with 2, (1.29g 10mmol) adds to mixture with the 4mL triethylamine to 4-two-fluoroaniline.Reaction mixture at stirring at room 1h, is used the H of 20mL then ₂The O dilution.With two separate, water layer extracts with EtOAc then.MgSO is used in the organic layer salt water washing that merges then ₄Dry.Filter, concentrate then, afterwards resistates is ground with DCM, filter then,, obtain desired compound (1.40g, productive rate are 40%) with the DCM washing.MS(ESI ⁺)m/z?347.13，349.12，351.09(M+H) ⁺。

B) 4-(4-(5-bromo-3-(2,4 difluorobenzene base carbamyl) pyridine-2-base is amino)-2-fluorophenoxy) picolinamide

With toluenesulphonic acids monohydrate (71mg, 0.37mmol) add to 5-bromo-2-chloro-N-(2,4 difluorobenzene base) niacinamide (126mg, 0.51mmol) and 4-(4-amino-2-fluorophenoxy) picolinamide (172mg, 0.49mmol, the Compound C of embodiment 3) the 3mL nmp solution in.Mixture is stirred 2h at 120 ℃, stir 15h at 160 ℃ then.Solution is cooled to room temperature, on preparation property (RP) HPLC, comes purifying then.The fraction that will comprise desired product merges, then vacuum concentration.Then, resistates is distributed between 1N NaOH and EtOAc, then with two separate.MgSO is used in organic layer salt water washing then ₄Dry.Filter, concentrate then, obtain desired product (30mg, productive rate are 11%) afterwards.MS(ESI ⁺)m/z?558.22，560.22(M+H) ⁺。

C) 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-5-bromo-N-(2,4 difluorobenzene base) niacinamide two (trifluoroacetic acid) salt

With H ₂O (50mg, 2.7mmol), pyridine (100mg, 1.2mmol) and PhI (OCOCF ₃) ₂(26mg 0.06mmol) adds to 4-(4-(5-bromo-3-(2,4 difluorobenzene base carbamyl) pyridine-2-base is amino)-2-fluorophenoxy) picolinamide (28mg, 1mL DMF solution 0.05mmol).Mixture is stirred 30min, add another normal PhI (OCOCF then ₃) ₂(26mg, 0.06mmol).Continue to stir 1h, reaction mixture comes purifying on preparation property (RP) HPLC then.The fraction that will comprise desired product merges, and vacuum concentration obtains title compound (5mg, productive rate are 13%) then, is two (trifluoroacetic acid) salt. ¹H?NMR(DMSO-d ₆)δ10.59(s，1H)，10.52(s，1H)，8.49(s，2H)，8.02(d，1H，J＝13.4Hz)，7.89(d，1H，J＝7.1Hz)，7.31-7.56(m，4H)，7.12(m，1H)，6.64(d，1H，J＝7.1Hz)，6.09(s，1H)；MS(ESI ⁺)m/z?530.17，532.17(M+H) ⁺。

Embodiment 18

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-5-bromo-N-(2,4 difluorobenzene base) niacinamide dihydrochloride

A) 5-bromo-2-chlorine apellagrin methyl esters

The DMF of 1mL is slowly added to 5-bromo-2-hydroxy niacin (4.34g, 20mL SOCl 20mmol) in room temperature ₂In the suspension.Then, solution is heated 2h at 80 ℃.Removal of solvent under reduced pressure is dissolved in resistates among the DCM of 50mL then.The MeOH of 10mL is added to mixture, continue to stir 1h.Solution is carried out vacuum concentration, resistates is dissolved among the EtOAc of 200mL then.Then, MgSO is used in mixture salt water washing ₄Dry.Filter, vacuum concentration obtains desired product (5.0g, productive rate＞95%) afterwards then.MS(ESI)m/z?250.04，252.05，254.05(M+H) ⁺。

B) 5-bromo-2-fluorine nicotinic acid methyl esters

(152mg 1.0mmol) adds to 5-bromo-2-chlorine apellagrin methyl esters (170mg, 3mL DMSO solution 0.68mmol) with CsF.With solution stirring at room 2 days, then at 60 ℃ of heating 4h.After the cooling, the mixture H of 30mL ₂The O dilution.The aqueous solution extracts with EtOAc, and MgSO is used in the organic layer of He Binging salt water washing then ₄Dry.Filter, vacuum concentration then, resistates comes purifying by flash chromatography on silica gel afterwards, obtains desired product (90mg, productive rate are 57%).MS(ESI ⁺)m/z234.06，236.09(M+H) ⁺。

C) 5-bromo-N-(2,4 difluorobenzene base)-2-fluorine niacinamide

(1.0mL 1.0mmol) adds to 5-bromo-2-fluorine nicotinic acid methyl esters (90mg, 2mL THF solution 0.38mmol) in room temperature with 1N NaOH.At stirring at room 2h, the 1N HCl with 1.0mL neutralizes afterwards with reaction mixture.Then, solution is carried out concentrating under reduced pressure, resistates comes purifying on preparation property (RP) HPLC then, obtains 5-bromo-2-fluorine nicotinic acid (55mg).

With (COCl) ₂(0.13mL 1.5mmol) adds to 5-bromo-2-fluorine nicotinic acid (55mg, 0.25mmol) solution in the mixture of 2.0mL THF and 5.0mL DCM.Mixture at stirring at room 1h, is spent the night 40 ℃ of stirrings then.After the cooling, removal of solvent under reduced pressure.Resistates is dissolved among the DCM of 2.0mL, then to its add 2,4 difluorobenzene amine (0.05mL, 0.5mmol) and the TEA of 0.1mL.Mixture at stirring at room 2h, is used H then ₂The O dilution.Organic layer is separated, and water layer extracts with EtOAc then.MgSO is used in the organic layer salt water washing that merges then ₄Dry.Filter, vacuum concentration then, resistates comes purifying on preparation property (RP) HPLC afterwards, obtains desired product (60mg, productive rate are 73%).MS(ESI ⁺)m/z?331.18，333.18(M+H) ⁺。

D) 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-5-bromo-N-(2,4 difluorobenzene base) niacinamide dihydrochloride

With 1 of 4N HCl, 4-dioxane solution (0.05mL, 0.20mmol) add to 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (17mg, 0.07mmol, the Compound C of embodiment 1) and 5-bromo-N-(2,4 difluorobenzene base)-2-fluorine niacinamide (26mg, 1mL nmp solution 0.08mmol).Mixture was stirred 4 days at 110 ℃.After the cooling, mixture comes purifying on preparation property (RP) HPLC, obtain comprising the fraction of desired product.Above-mentioned fraction is merged, vacuum concentration then, resistates is handled with the 1N HCl of 10mL, and then it is concentrated, and obtains title compound (8.0mg, productive rate are 18%). ¹H?NMR(DMSO-d ₆)δ10.66(s，1H)，10.62(s，1H)，8.55(d，2H，J＝7.5Hz)，8.06(d，1H，J＝13.4Hz)，7.35-7.62(m，5H)，7.16(m，1H)，6.62(d，1H，J＝6.0Hz)，6.43(s，1H)；MS(ESI ⁺)m/z?554.15，556.14(M+H) ⁺。

Embodiment 19

2-(4-(2-amino-3-(hydroxymethyl) pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) niacinamide dihydrochloride

A) N-(2,4 difluorobenzene base)-2-(3-fluoro-4-(2-oxo-2,4-dihydro-1H-pyrrolo-[2,3-d] [1,3] oxazine-5-base oxygen base) phenyl amino) niacinamide trifluoroacetate

With 1 of 4N HCl, 4-dioxane solution (0.025mL, 0.1mmol) add to N-(2, the 4-difluorophenyl)-2-fluorine niacinamide (25mg, 0.1mmol, the Compound C of embodiment 1) and the 1mL nmp solution of 4-(4-amino-2-fluorophenoxy)-3-((t-butyldimethylsilyloxy base) methyl) pyridine-2-aminocarbamic acid tert-butyl ester (46mg, 0.1mmol, the compd B of embodiment 129 among the US 2005/0245530).Reaction mixture is spent the night 110 ℃ of stirrings, stirred 3 days at 120 ℃ then.Then, (0.05mL 0.2mmol) adds to mixture, 140 ℃ of heated overnight with 4NHCl.After the cooling, mixture comes purifying on preparation property (RP) HPLC, obtain desired product (10mg, productive rate are 16%).MS(ESI ⁺)m/z?508.12(M+H) ⁺。

B) 2-(4-(2-amino-3-(hydroxymethyl) pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) niacinamide dihydrochloride

(0.5mL 0.5mmol) adds to N-(2,4 difluorobenzene base)-2-(3-fluoro-4-(2-oxo-2 with 1N NaOH, 4-dihydro-1H-pyrrolo-[2,3-d] [1,3] oxazine-5-base oxygen base) phenyl amino) niacinamide trifluoroacetate (10mg, 1mL THF solution 0.016mmol).Mixture at stirring at room 1h, is spent the night 50 ℃ of stirrings then.After the cooling, mixture comes purifying by preparation property (RP) HPLC, obtains comprising the fraction of desired product.Above-mentioned fraction is merged, vacuum concentration then, resistates is handled with excessive 1N HCl, and then concentrated, obtains title compound (7mg, productive rate are 79%). ¹H?NMR(DMSO-d ₆)δ10.77(s，1H)，10.56(s，1H)，8.44(d，1H，J＝6.3Hz)，8.39(d，1H，J＝7.5Hz)，8.16(d，1H，J＝13.0Hz)，7.89-7.92(m，3H)，7.28-7.58(m，4H)，7.15(m，1H)，7.03(m，1H)，6.24(d，1H，J＝7.0Hz)，4.64(s，2H)；MS(ESI ⁺)m/z?482.16(M+H) ⁺。

Embodiment 20

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

A) 2-fluoro-N-(4-fluorophenyl)-N-methylnicotinamide

In room temperature, with 2 DMF add to the 2-fluorine nicotinic acid (820mg, 5.83mmol) and oxalyl chloride (1.27g, CH 10mmol) ₂Cl ₂(10mL) suspension.Resulting mixture is stirred 3h.Solvent removed in vacuo obtains 2-fluorine nicotinoyl chlorine (920mg).

In room temperature, with 2-fluorine nicotinoyl chlorine (80mg, CH 0.5mmol) ₂Cl ₂(2mL) solution add to 4-fluoro-methylphenylamine (75mg, 0.6mmol) and DIPEA (90mg, THF 0.7mmol) (2mL) solution.The mixture stirring is spent the night.Mixture CH ₂Cl ₂Dilution is with 5% aqueous solution of citric acid and saturated K ₂HPO ₄Solution washing is used MgSO then ₄Dry.(silica gel is used CH to product by flash column chromatography ₂Cl ₂The gradient elution of/EtOAc) comes purifying, obtain desired product (120mg, productive rate are 97%), be faint yellow solid.MS(ESI ⁺)m/z?249(M+H) ⁺。

B) 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(4-fluorophenyl)-N-methylnicotinamide dihydrochloride

With 2-fluoro-N-(4-fluorophenyl)-N-methylnicotinamide (50mg, 0.2mmol) and 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-mixture of 3-fluoroaniline (122mg, 0.5mmol, the Compound C of embodiment 1) in DMA (0.8mL) in microwave 160 ℃ the heating 20min.Product comes purifying by preparation property (RP) HPLC, obtains title compound (11mg, productive rate are 11%) (dihydrochloride), is beige solid. ¹H?NMR(CD ₃OD)δ8.56(d，1H，J＝3.5Hz)，8.23(dd，1H，J＝7.6，1.0Hz)，8.19(d，1H，J＝7.1Hz)，7.58(m，3H)，7.32(dd，1H，J＝11.2，2.5Hz)，7.22(d，1H，J＝8.6Hz)，7.04(d，1H，J＝4.1Hz)，6.96(d，1H，J＝7.9Hz)，6.47(m，4H)，3.27(s.3H)。MS(ESI ⁺)m/z?472(M+H) ⁺。

Embodiment 21

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-6-methylnicotinamide dihydrochloride

A) 2-chloro-N-(2,4 difluorobenzene base)-6-methylnicotinamide

(500mg 2.9mmol) is suspended in CH with 2-chloro-6-methylnicotinic acid ₂Cl ₂(14.6mL).(0.3mL 3.5mmol) with 3 DMF, stirs 2h with reaction mixture at 23 ℃ successively to add oxalyl chloride.Rotary evaporation removes and desolvates, and then resistates is carried out vacuum-drying.Thick acyl chlorides is dissolved in CH ₃Among the CN (14mL), add then 2,4 difluorobenzene amine (0.33mL, 3.2mmol), next add triethylamine (0.41mL, 2.9mmol).Reaction mixture is stirred 16h, vacuum concentration then at 23 ℃.With resistates at EtOAc (30mL) and saturated NaHCO ₃Distribute between the aqueous solution (30mL).Add a spot of water, thereby help to decompose some remaining salt.(3 * 30mL) extract water layer with EtOAc.The organic layer MgSO that merges ₄Drying, vacuum concentration then.5%EtOAc-hexane with heat grinds, and obtains desired product (559mg, 68%), is khaki powder. ¹H?NMR(400MHz，CDCl ₃)δ2.60(s，3H)，6.82-7.09(m，2H)，7.22-7.32(d，1H，J＝7.63Hz)，8.18(d，1H，J＝8.14Hz)，8.28-8.50(m，1H)，8.57(s，1H)。

B) 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-6-methylnicotinamide dihydrochloride

4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (40mg, 164 μ mol, the Compound C of embodiment 1) and 2-chloro-N-(2,4 difluorobenzene base)-6-methylnicotinamide (51mg, 181 μ mol) are suspended in 1,4 diox (1mL).(0.16mL, 0.333mmol), (CEM Personal Microwave 300W), keeps 60min to 1,4 dioxane solution of interpolation 4N HCl then reaction mixture to be exposed to 160 ℃.Reaction mixture is cooled to envrionment temperature, adds NMP (1mL) then.Reaction mixture is heated to 160 ℃ once more, and (microwave irradiation 300W), kept 2 hours.Rotary evaporation removes 1, the 4-diox, then with resistates at 10%NaHCO ₃Distribute between the aqueous solution (10mL) and the EtOAc (10mL).Organic layer is separated, and (2 * 10mL) extract water layer with EtOAc then.The organic layer that merges washs with 10%LiCl (20mL), dry (Na ₂SO ₄), vacuum concentration then.Crude product comes purifying by preparation property (RP) HPLC chromatogram (YMC S5 ODS, 20 * 100mm, 10 minutes gradients, 33% to 90% methanol aqueous solution (containing 0.1%TFA)).The fraction that will comprise desired product merges, and concentrates then.In MeOH (1mL), with 1 of 4N HCl, 4-dioxane solution (0.10mL) acidifying concentrates then with the substance dissolves of purifying.EtOAc with heat grinds with resulting salt, collects by filtering then, obtains brown solid (4.4mg, HPLC purity＞97%). ¹H?NMR(DMSO-d ₆)δ3.15(s，3H)，6.48(s，1H)，6.69(d，1H，J＝6.10Hz)，6.91(d，1H，J＝7.63Hz)，7.06-7.21(m，1H)，7.31-7.44(m，2H)，7.46-7.64(m，3H)，8.12-8.42(m，3H)，10.41(s，1H)，10.96(s，1H)，12.58(s，1H)；MS(ESI ⁺)m/z?490.2(M+H) ⁺。

Embodiment 22

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino) pyridin-3-yl) (5-fluorine indoline-1-yl) ketone dihydrochloride

A) (2-chloropyridine-3-yl)-(5-fluorine indoline-1-yl) ketone

(200mg 1.14mmol) is dissolved in CH with the 2-chloronicotinoyl chloride ₃Among the CN (5.6mL).(171mg, 1.25mmol), (0.24mL 1.71mmol), stirs 16h with reaction mixture at 23 ℃ next to add triethylamine to add 5-fluorine indoline.Solvent by the evaporation remove, then with resistates at CH ₂Cl ₂(10mL) with saturated NaHCO ₃Distribute between the aqueous solution (10mL).Organic phase is removed, then water CH ₂Cl ₂(2 * 10mL) extractions.The organic phase Na that merges ₂SO ₄Drying, vacuum concentration then.By flash column chromatography (40g SiO ₂, 2%CH ₃OH-CH ₂Cl ₂) obtain desired product (247.8mg, 79%), be pale solid. ¹H?NMR(DMSO-d ₆)δ3.14(t，2H，J＝8.39Hz)，3.82(t，2H，J＝8.39Hz)，7.09(dt，1H，J＝9.03，2.80Hz，)，7.20(dd，1H，J＝8.39，2.80Hz)，7.60(dd，1H，J＝7.38，4.83Hz)，8.10(dd，1H，J＝7.63，2.03Hz)，8.15(dd，1H，J＝8.90，4.83Hz)，8.55(dd，1H，J＝4.83，1.78Hz)。

B) (5-fluorine indoline-1-yl) ketone dihydrochloride 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino) pyridin-3-yl)

With 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (40mg, 0.16mmol, the Compound C of embodiment 1) and (2-chloropyridine-3-yl) (5-fluorine indoline-1-yl) ketone (46mg 0.16mmol) is suspended in the Virahol (1.6mL).Add 1 of 4N HCl, (0.16mL 0.64mmol), is heated to reaction mixture 80 ℃ to the 4-dioxane solution then, keeps 72h.Add NMP (1mL), reaction mixture is heated to 100 ℃ then, until the conversion of not observing to product.Rotary evaporation is removed Virahol, then resulting resistates is distributed between the 10%LiCl aqueous solution (10mL) and EtOAc (10mL).Organic layer is separated, and (2 * 10mL) extract water layer with EtOAc then.The organic layer that merges washs with 10%LiCl (20mL), dry (Na ₂SO ₄), concentrate then.Crude product by preparation property (RP) HPLC chromatogram (YMC S5 ODS, 30 * 75mm, 10 minutes gradients, 33% to 90% methanol aqueous solution (containing 0.1%TFA) 40mL/min) comes purifying.The fraction that will comprise desired product merges, and concentrates then.The substance dissolves of purifying in MeOH (1mL), is used 4N HCl-1,4-diox (0.10mL) acidifying then.With the EtOAc-Et of resulting salt with heat ₂O grinds together, collects by filtering then, obtains tawny powder (2.7mg, HPLC purity＞95%). ¹H?NMR(DMSO-d ₆)δ3.10(t，2H，J＝8.11Hz)，3.42-3.53(m，1H)，3.61-3.75(m，1H)，6.38(d，1H，J＝1.37Hz)，6.53(d，1H，J＝5.77Hz)，6.99(dd，1H，J＝7.42，4.95Hz)，7.04(s，1H)，7.17(dd，1H，J＝8.25，2.47Hz)，7.32(t，1H，J＝9.21Hz)，7.44(d，1H，J＝9.90Hz)，7.46-7.51(m，1H)，7.85(d，1H，J＝6.60Hz)，7.90(d，1H，J＝12.92Hz)，8.19(d，1H，J＝6.05Hz)，8.34(dd，1H，J＝4.95，1.65Hz)，8.92(s，1H)，12.23(s，1H)；MS(ESI ⁺)m/z?484.3(M+H) ⁺。

Embodiment 23

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino) niacinamide two (trifluoroacetic acid) salt

(26mg 0.16mmol) is suspended in the Virahol (1.6mL) with 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (40mg, 0.16mmol, the Compound C of embodiment 1) and 2-chloro-nicotinamide.Add 1 of 4N HCl, (0.16mL 0.33mmol), is heated to reaction mixture 80 ℃ to the 4-dioxane solution then, keeps 72h.Add NMP (1mL), reaction mixture is heated to 100 ℃ then, keep 48h.Rotary evaporation is removed Virahol, then with resulting resistates at 5%NaHCO ₃Distribute between the aqueous solution (10mL) and the EtOAc (10mL).Organic layer is separated, and (2 * 10mL) extract water layer with EtOAc then.The organic layer that merges washs with 10%LiCl (20mL), dry (MgSO ₄), concentrate then.Crude product by preparation property (RP) HPLC chromatogram (YMC S5 ODS, 30 * 75mm, 10 minutes gradients, 33% to 90% methanol aqueous solution (containing 0.1%TFA) 40mL/min) comes purifying.The fraction that will comprise desired product merges, and concentrates then.Material and 10 with purifying: 1Et ₂O-MeOH (3mL) grinds together, obtains desired product (21.0mg, HPLC purity＞99%), is cream-colored solid. ¹HNMR(DMSO-d ₆)δ6.32(dd，1H，J＝3.05，1.53Hz)，6.46(d，1H，J＝5.60Hz)，6.92(dd，1H，J＝7.88，4.83Hz)，7.30-7.40(m，2H)，7.42(t，1H)，7.79(s，1H)，8.12(d，1H，J＝5.59Hz)，8.17(dd，1H，J＝23.65，1.78Hz)，8.16-8.19(m，1H，J＝1.53Hz)，8.32-8.39(m，2H)，11.45(s，1H)，11.96(s，1H)；MS(ESI ⁺)m/z364.3(M+H) ⁺。

Embodiment 24

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

A) 2-chloro-N-methylnicotinamide

With methylamine (0.425mL, 3.41mmol) and triethylamine (0.792mL 5.68mmol) is dissolved in CH at 23 ℃ ₃Among the CN (14.2mL).(500mg 2.84mmol), stirs 16h with reaction mixture at 23 ℃ to add the 2-chloronicotinoyl chloride.Rotary evaporation removes and to desolvate, then with resistates at EtOAc (20mL) and saturated NaHCO ₃Distribute between the aqueous solution (20mL).(3 * 20mL) extract water with EtOAc.The organic phase MgSO that merges ₄Drying concentrates then.Resulting solid is ground with the 5%EtOAc-hexane, obtain desired product (153.2mg, 31%), be white powder. ¹HNMR(CD ₃OD)δ8.43(dd，1H，J＝5.09，2.03Hz)，7.88(dd，1H，J＝7.63，2.03Hz)，7.45(dd，1H，J＝7.38，4.83Hz)，2.91(s，3H)；MS(ESI ⁺)m/z?171.1(M+H) ⁺。

B) 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-methylnicotinamide dihydrochloride

With 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (75mg, 0.31mmol) and 2-chloro-N-methylnicotinamide (53mg 0.31mmol) is suspended in 3: 1 Virahol-NMP (3.0mL).Add 1 of 4N HCl, (0.23mL 0.93mmol), is heated to reaction mixture 100 ℃ to the 4-dioxane solution then, keeps 24h.Rotary evaporation is removed Virahol, then with resulting resistates at 5%NaHCO ₃Distribute between the aqueous solution (10mL) and the EtOAc (10mL).Organic layer is separated, and (3 * 10mL) extract water layer with EtOAc then.The organic layer that merges washs with 10%LiCl (20mL), dry (MgSO ₄), concentrate then.Crude product by preparation property (RP) HPLC chromatogram (YMC S5 ODS, 30 * 75mm, 10 minutes gradients, 33% to 90% methanol aqueous solution (containing 0.1%TFA) 40mL/min) comes purifying.The fraction that will comprise desired product merges, and concentrates then.The product resistates is dissolved among the MeOH (2mL), uses 1 of 4N HCl then, 4-dioxane solution (0.10mL) acidifying.After concentrating, product is ground with 5%EtOAc-hexane (3mL), obtain desired product (16.4mg, HPLC purity＞99%), be the tawny solid. ¹H?NMR(CD ₃OD)δ8.44(d，1H，J＝6.10Hz)，8.37(d，1H，J＝7.12Hz)，8.13(d，1H，J＝6.10Hz)，7.78(dd，1H，J＝11.70，2.03Hz)，7.58-7.69(m，2H)，7.48(d，1H，J＝8.14Hz)，7.09-7.21(m，1H)，7.05(d，1H，J＝7.12Hz)，6.83(d，1H，J＝3.56Hz)，3.34(s，1H)，2.97(s，1H)；MS(ESI ⁺)m/z378.3(M+H) ⁺。

Embodiment 25

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-5-chloro-N-methylnicotinamide dihydrochloride

A) 2,5-two chloro-N-methylnicotinamides

With methylamine (0.355mL, 2.85mmol) and triethylamine (0.662mL 4.75mmol) is dissolved in CH at 23 ℃ ₃Among the CN (14.2mL).Add 2, (500mg 2.376mmol), stirs 16h with reaction mixture to 5-two chloronicotinoyl chlorides then.Rotary evaporation removes and to desolvate, then with resistates at EtOAc (20mL) and 5%NaHCO ₃Distribute between the aqueous solution (20mL).(3 * 20mL) extract water with EtOAc.MgSO is used in the organic phase salt water washing that merges ₄Drying concentrates then.Resulting solid is ground in the 5%EtOAc-hexane, and desired product (456.7mg, 94%) is cream-colored powder. ¹HNMR(CD ₃OD)δ8.46(d，1H，J＝2.54Hz)，7.96(d，1H，J＝2.54Hz)，2.90(s，3H)；MS(ESI ⁺)m/z?205.1(M+H) ⁺。

B) 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-5-chloro-N-methylnicotinamide dihydrochloride

With 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (70mg, 0.29mmol, the Compound C of embodiment 1) and 2, (59mg 0.29mmol) is suspended in 3: 1 Virahol-NMP (2.9mL) 5-two chloro-N-methylnicotinamides.Add 1 of 4N HCl, (0.22mL 0.86mmol), is heated to reaction mixture 100 ℃ to the 4-dioxane solution then, keeps 168h.The reaction mixture H of 30mL ₂Saturated NaHCO is used in the O dilution then ₃The aqueous solution (5mL) alkalization.(3 * 10mL) extract water layer with EtOAc.The organic layer that merges washs with 10%LiCl (15mL), dry (MgSO ₄), concentrate then.Crude product by preparation property (RP) HPLC chromatogram (YMC S5 ODS, 30 * 75mm, 10 minutes gradients, 33% to 90% methanol aqueous solution (containing 0.1%TFA) 40mL/min) comes purifying.The fraction that will comprise desired product merges, and concentrates then.The product resistates is dissolved among the MeOH (2mL), uses 1 of 4N HCl then, 4-dioxane solution (0.10mL) acidifying.Concentrate and obtain desired product (3.3mg, HPLC purity＞99%), be brown solid. ¹H?NMR(CD ₃OD)δ8.33(d，1H，J＝2.54Hz)，8.31(d，1H，J＝7.12Hz)，8.17(dd，1H，J＝13.48，2.29Hz)，8.09(d，1H，J＝2.03Hz)，7.56(d，1H，J＝3.56Hz)，7.33-7.43(m，2H)，6.91(d，1H，J＝6.61Hz)，6.68(d，1H，J＝3.56Hz)，2.93(s，3H)；MS(ESI ⁺)m/z?412.2(M+H) ⁺。

Embodiment 26

A) 5-bromo-2-chloro-nicotinamide

(229mg 0.798mmol) is suspended in CH with 5-bromo-2-chlorine apellagrin sodium ₂Cl ₂(7.9mL).(0.084ml, 0.957mmol), (0.002mL 0.080mmol), stirs 1h with reaction mixture at 23 ℃ next to add DMF to add oxalyl chloride.Solvent is removed by evaporation, then the intermediate resistates is carried out vacuum-drying 90 minutes.Thick acyl chlorides is suspended in CH ₃Among the CN (7.9mL), add NH then ₃(the MeOH solution of 7M, 0.125mL 0.877mmol), stirs 16h with reaction mixture in envrionment temperature.Solvent by the evaporation remove, then with resistates at EtOAc (20mL) and H ₂Distribute between the O (20mL).The EtOAc layer is removed, and (3 * 25mL) extract water layer with EtOAc then.MgSO is used in the organic phase salt water washing that merges ₄Drying concentrates then.With resulting solid and cold CH ₂Cl ₂Grind together, obtain desired product (80.5mg, 43%), be the tawny powder. ¹H?NMR(CDCl ₃)δ6.08(s，1H)，6.66(s，1H)，8.36(d，1H，J＝2.54Hz)，8.54(d，1H，J＝2.54Hz)。

B) 2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino) niacinamide two (trifluoroacetic acid) salt

With 4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluoroaniline (51.7mg, 0.21mmol) and 5-bromo-2-chloro-nicotinamide (50mg 0.21mmol) is suspended in 3: 1 Virahol-NMP (2.1mL).Add 1 of 4N HCl, (0.21mL 0.84mmol), is heated to reaction mixture 100 ℃ to the 4-dioxane solution then, keeps 240h.Rotary evaporation is removed Virahol, then with resulting resistates at 5%NaHCO ₃Distribute between the aqueous solution (10mL) and the EtOAc (10mL).Organic layer is separated, and (2 * 10mL) extract water layer with EtOAc then.The organic layer that merges washs with 10%LiCl (20mL), dry (MgSO ₄), concentrate then.Crude product by preparation property (RP) HPLC chromatogram (YMC S5 ODS, 30 * 75mm, 10 minutes gradients, 33% to 90% methanol aqueous solution (containing 0.1%TFA) 40mL/min) comes purifying.The fraction that will comprise desired product merges, and concentrates then, obtains desired product (10.1mg, HPLC purity＞98%), is the tawny powder. ¹H?NMR(DMSO-d ₆)δ12.00(s，1H)，11.38(s，1H)，8.44(s，1H)，8.44(dd，1H，J＝23.91，2.03Hz)，8.13(d，1H，J＝5.59Hz)，8.06(d，1H，J＝13.23Hz)，7.92(s，1H)，7.42(s，1H)，7.29-7.38(m，2H)，6.46(d，1H，J＝5.59Hz)，6.32(s，1H)；MS(ESI ⁺)m/z?442.1(M+H) ⁺。

Embodiment 27

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methylthio group) pyrimidine-5-methane amide two (trifluoroacetic acid) salt

A) 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-2-(methylthio group) pyrimidine-5-carboxylic acid carbethoxy hydrochloride

With 1 of 4N HCl, 4-dioxane solution (4mL, 16mmol) add to 4-chloro-2-(methylthio group) pyrimidine-5-carboxylic acid ethyl ester (Alpha Aesar, 2.08g, 8.93mmol) and 4-(4-amino-2-fluorophenoxy) picolinamide (2.0g, 8.09mmol, the Compound C of embodiment 3) and mixture in NMP (10mL).After stirring is spent the night, reaction mixture water (200mL) dilution, with resulting solid filtering, vacuum-drying then obtains desired product (3.6g, 93%), is white solid.MS(ESI ⁺)m/z?444(M+H) ⁺。

B) 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-2-(methylthio group) pyrimidine-5-carboxylic acid sodium

1: 1 methanol/water solution (5mL with 4N sodium hydroxide; 20mmol) add to 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-2-(methylthio group) pyrimidine-5-carboxylic acid carbethoxy hydrochloride (3.88g, 8.08mmol) suspension in methyl alcohol (20mL) and water (20mL).After stirring was spent the night, reaction mixture used extra sodium hydroxide solution (4mL) to handle with methyl alcohol (100mL) and water (100mL) dilution then.After stirring 5h, mixture is carried out the part concentrating under reduced pressure, then resulting suspension is filtered.Resulting solid is ground with ebullient ethanol, filter, vacuum-drying then obtains carboxylate salt (2.94g, 83%), is white solid.MS(ESI ⁺)m/z?416(M+H) ⁺。

C) 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methylthio group) pyrimidine-5-carboxamide hydrochloride

(4.9mL, (4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-(2-(methylthio group) pyrimidine-5-carboxylic acid sodium refluxes solution 3h then for 2.94g, benzene 6.72mmol) (75mL) suspension 62mmol) to add to 4-with thionyl chloride.Reaction mixture is cooled to room temperature, then vacuum concentration.Resistates is handled with benzene, and then vacuum concentration, thereby removes remaining thionyl chloride.Resulting solid is absorbed among the THF (75mL), and (2.6g 20.2mmol) handles to use 2,4 difluorobenzene amine then.After stirring was spent the night, mixture diluted with rare HCl acidified aqueous solution, water (400mL), filtered then.Resulting solid obtains acid amides (1.69g, 45%) by grinding purifying with methyl alcohol or ethyl acetate repeatedly, is solid.MS(ESI ⁺)m/z?527(M+H) ⁺。

D) 4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methylthio group) pyrimidine-5-methane amide two (trifluoroacetic acid) salt

To be similar to preparation 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl) mode of niacinamide (step e of embodiment 3); with 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl)-2-(methylthio group) pyrimidine-5-carboxamide hydrochloride (169mg; 0.30mmol) change into title compound (99mg, 53%). ¹H?NMR(DMSO-d ₆)δ11.06(s，1H)，10.51(s，1H)，8.94(s，1H)，8.12(dd，1H，J＝13.0，2.3Hz)，7.98(d，1H，J＝7.2Hz)，7.90(br?s，2H)，7.61-7.40(m，4H)，7.18(m，1H)，6.74(dd，1H，J＝7.3，2.5Hz)，6.18(d，1H，J＝2.4Hz)，2.57(s，3H)；MS(ESI ⁺)m/z?499(M+H) ⁺。

Embodiment 28

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(trifluoromethyl) pyrimidine-5-methane amide dihydrochloride

The mode of the method for being summarized to the D with the steps A that is similar to embodiment 27 changes into title compound with 4-chloro-2-(trifluoromethyl) pyrimidine-5-carboxylic acid's ethyl ester (Maybridge). ¹H?NMR(CD ₃OD)δ9.3(s，1H)，8.14(dd，1H，J＝12.8，2.5Hz)，7.86(d，1H，J＝7.3Hz)，7.75(m，1H)，7.56(m，1H)，7.41(m，1H)，7.20-7.03(m，2H)，6.71(dd，1H，J＝7.2，2.4Hz)，6.27(d，1H，J＝2.1Hz)；MS(ESI ⁺)m/z?521(M+H) ⁺。

Embodiment 29

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-2-cyano group-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide dihydrochloride

A) 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methyl sulphonyl) pyrimidine-5-methane amide

With m-CPBA (about 90%; 1.33g; 6.9mmol) add to 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methylthio group) pyrimidine-5-carboxamide hydrochloride (1.67g, DMF 2.95mmol) (25mL) solution by part.After (16h) finished in reaction, solvent is carried out the part concentrating under reduced pressure.Resulting suspension with resulting solid filtering, washes with water, then vacuum-drying then with excessive 10% sodium sulfite aqueous solution dilution.Solid obtains sulfone (1.34g, 81%) by grinding purifying with ethyl acetate/hexane repeatedly, is white solid.MS(ESI ⁺)m/z559(M+H) ⁺。

B) 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-2-cyano group-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide

With potassium cyanide (94mg; 1.44mmol) add to 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl)-(200mg, DMF 0.36mmol) (4mL) solution is then with mixture heating up to 80 ℃ for 2-(methyl sulphonyl) pyrimidine-5-methane amide.Behind the 5h, mixture is cooled to room temperature, then solvent removed in vacuo.Resistates dilutes with salt solution, extracts with EtOAc then.Anhydrous MgSO is used in the organic layer salt water washing that merges ₄Drying, vacuum concentration obtains nitrile (171mg, 94%) then, is solid.MS(ESI ⁺)m/z?506(M+H) ⁺。

C) 4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-2-cyano group-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide dihydrochloride

To be similar to preparation 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl) mode of niacinamide (step e of embodiment 3); with 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-2-cyano group-N-(2; the 4-difluorophenyl) pyrimidine-5-methane amide (171mg; 0.33mmol) change into title compound (90mg, 53%). ¹H?NMR(DMSO-d ₆)δ10.85(s，1H)，10.83(s，1H)，9.11(s，1H)，7.99(m，2H)，7.83(br?s，2H)，7.68-7.40(m，4H)，7.20(m，1H)，6.75(dd，1H，J＝7.3，2.4Hz)，6.20(d，1H，J＝2.4Hz)；MS(ESI ⁺)m/z478(M+H) ⁺。

Embodiment 30

2-(amino methyl)-4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide tri hydrochloride

Ether (30 μ L with 1N HCl, 0.03mmol) solution and 20% palladium hydroxide/carbon (48mg) adds to 4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-2-cyano group-N-(2, the 4-difluorophenyl) pyrimidine-5-methane amide dihydrochloride (48mg, methyl alcohol 0.092mmol) (1mL) solution.Suspension is with the hydrogen purge and stir 2h.Add extra palladium hydroxide (38mg) and methyl alcohol (1mL), then with mixture restir 4h.Mixture is filtered through Celite , then filtrate is carried out vacuum concentration.Resulting resistates comes purifying by preparation property (RP) HPLC (gradient is 34% to 90% methanol aqueous solution (containing 0.1%TFA)).Suitable fraction is merged, use Amberlyst A-21 ion exchange resin treatment then, filter, vacuum concentration obtains free alkali then.Resistates is dissolved among the anhydrous THF (2mL), uses the diethyl ether solution acidifying of 1N HCl then.Reaction mixture is stirred 10min, and solvent removed in vacuo is ground solid then in ether, obtains amine (20mg, 39%), is pale solid. ¹HNMR(DMSO-d ₆)δ10.99(s，1H)，10.78(s，1H)，9.16(s，1H)，8.48(br?s，2H)，8.17(dd，1H，J＝12.9，2.4Hz)，7.99(d，1H，J＝7.2Hz)，7.87(br?s，2H)，7.62(m，2H)，7.43(m，2H)，7.20(m，1H)，6.70(dd，1H，J＝7.2，2.4Hz)，6.21(d，1H，J＝2.3Hz)，4.21(m，2H)；MS(ESI ⁺)m/z?482(M+H) ⁺。

Embodiment 31

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-morpholino yl pyrimidines-5-methane amide tri hydrochloride

A) 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-morpholino yl pyrimidines-5-methane amide

With morpholine (100mg; 1.1mmol) add to 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl)-(75mg, THF 0.13mmol) (4mL) suspension stirs 15min with reaction mixture to 2-(methyl sulphonyl) pyrimidine-5-methane amide.Solvent removed in vacuo is ground resulting solid then in methanol, obtain desired product (55mg, 75%), is white solid.MS(ESI ⁺)m/z?566(M+H) ⁺。

B) 4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-morpholino yl pyrimidines-5-methane amide tri hydrochloride

To be similar to preparation 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl) mode of niacinamide (step e of embodiment 3); with 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl)-2-morpholino yl pyrimidines-5-methane amide (55mg; 0.01mmol) change into title compound (16mg, 26%). ¹H?NMR(DMSO-d ₆)δ11.24(s，1H)，10.20(s，1H)，8.85(s，1H)，7.92(m，2H)，7.82(br?s，2H)，7.48-7.35(m，4H)，7.08(m，1H)，6.65(dd，1H，J＝7.3，2.5Hz)，6.12(d，1H，J＝2.4Hz)，3.74(m，4H)3.63(m，4H)；MS(ESI ⁺)m/z?538(M+H) ⁺。

(method of being summarized in the steps A-B) prepares following compound by suitable amine to be similar to embodiment 31.

Embodiment 32

2-amino-4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide tri hydrochloride

To be similar to the embodiment 31 (mode of the method for being summarized in the steps A-B); use the methanol solution of ammonia that 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methyl sulphonyl) pyrimidine-5-methane amide (compd A of embodiment 29) is changed into title compound.MS(ESI ⁺)m/z?468(M+H) ⁺。

Embodiment 33

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methylamino) pyrimidine-5-methane amide tri hydrochloride

To be similar to the embodiment 31 (mode of the method for being summarized in the steps A-B); use the ethanolic soln of methylamine that 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methyl sulphonyl) pyrimidine-5-methane amide (compd A of embodiment 29) is changed into title compound.MS(ESI ⁺)m/z?482(M+H) ⁺。

Embodiment 34

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(dimethylamino) pyrimidine-5-methane amide tri hydrochloride

To be similar to the embodiment 31 (mode of the method for being summarized in the steps A-B); use the THF solution of dimethyl amine that 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methyl sulphonyl) pyrimidine-5-methane amide (compd A of embodiment 29) is changed into title compound.MS(ESI ⁺)m/z?496(M+H) ⁺。

Embodiment 35

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(2-(dimethylamino) ethylamino) pyrimidine-5-methane amide tri hydrochloride

With similar in the embodiment 31 (mode of the method for being summarized in the steps A-B); use N; the N-dimethyl-ethylenediamine changes into title compound with 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methyl sulphonyl) pyrimidine-5-methane amide (compd A of embodiment 29).MS(ESI ⁺)m/z?539(M+H) ⁺。

Embodiment 36

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(piperidines-1-yl) pyrimidine-5-methane amide tri hydrochloride

To be similar to the embodiment 31 (mode of the method for being summarized in the steps A-B); use piperidines that 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methyl sulphonyl) pyrimidine-5-methane amide (compd A of embodiment 29) is changed into title compound.MS(ESI ⁺)m/z536(M+H) ⁺。

Embodiment 37

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-2-(benzylamino)-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide tri hydrochloride

To be similar to the embodiment 31 (mode of the method for being summarized in the steps A-B); use benzyl amine that 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methyl sulphonyl) pyrimidine-5-methane amide (compd A of embodiment 29) is changed into title compound.MS(ESI ⁺)m/z558(M+H) ⁺。

Embodiment 38

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide two (trifluoroacetic acid) salt

A) 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino) pyrimidine-5-carboxylic acid's ethyl ester

With Raney nickel/water (Raney

2400, about 3g) adds to 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-2-(methylthio group) pyrimidine-5-carboxylic acid ethyl ester (260mg, ethanol 0.58mmol) (5mL) solution.With mixture heating up to 70 ℃ and stir and spend the night.Mixture is filtered through Celite

, then filtrate is carried out vacuum concentration, obtain desired product (91mg, 39%), be solid.MS(ESI ⁺)m/z398(M+H) ⁺。

B) 4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide two (trifluoroacetic acid) salt

To be similar to the mode of the method that embodiment 27 (step B-D) summarized, 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino) pyrimidine-5-carboxylic acid's ethyl ester is changed into title compound. ¹HNMR(CD ₃OD)δ9.04(s，1H)，8.83(s，1H)，8.15(dd，1H，J＝13.0，2.3Hz)，7.86(d，1H，J＝7.4Hz)，7.72(m，1H)，7.53(m，1H)，7.38(m，1H)，7.18-7.03(m，2H)，6.71(dd，1H，J＝7.2，2.4Hz)，6.26(d，1H，J＝2.3Hz)；MS(ESI ⁺)m/z?453(M+H) ⁺。

Embodiment 39

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-methoxy pyrimidine-5-methane amide dihydrochloride

With

Embodiment 40

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-hydroxy pyrimidine-5-methane amide dihydrochloride

With sodium methylate (60mg; 1.1mmol) add to 4-(4-(2-carbamyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2; the 4-difluorophenyl)-(100mg, methyl alcohol 0.18mmol) (5mL) solution is then with mixture heating up to 64 ℃ for 2-(methyl sulphonyl) pyrimidine-5-methane amide.After stirring 4.5h, reaction mixture is cooled to room temperature, stirring is spent the night.Mixture hcl acidifying, solvent removed in vacuo then.Resulting solid is heated in ethyl acetate, filter then.Filtrate is carried out vacuum concentration, resulting solid is ground with water, filter then, obtain the pyrimidine of methoxyl group replacement and the mixture (66mg) of the pyrimidine that hydroxyl replaces, be solid.To be similar to preparation 2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2, the 4-difluorophenyl) mode of niacinamide (step e of embodiment 3), mixture is changed into title compound, then product separates through preparation property (RP) HPLC (gradient is 44 to 90%), obtains title compound.

Embodiment 39:

¹H?NMR(CD ₃OD)δ8.89(s，1H)，7.86(m，1H)，7.77(d，1H，J＝7.3Hz)，7.61(m，1H)，7.52(m，1H)，7.38(m，1H)，7.03(m，1H)，6.95(m，1H)，6.58(dd，1H，J＝7.3，2.5Hz)，6.19(d，1H，J＝2.4Hz)，4.12(s，3H)；MS(ESI ⁺)m/z?483(M+H) ⁺。

Embodiment 40:

¹H?NMR(CD ₃OD)δ8.74(s，1H)，7.90(m，2H)，7.72(m，1H)，7.48(m，2H)，7.13(m，1H)，7.05(m，1H)，6.72(dd，1H，J＝7.2，2.4Hz)，6.37(d，1H，J＝2.3Hz)；MS(ESI ⁺)m/z?469(M+H) ⁺。

Embodiment 41

3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrazine-2-methane amide two (trifluoroacetic acid) salt

A) 3-chloro-N-(2,4 difluorobenzene base) pyrazine-2-methane amide

(593mg 4.7mmol) adds to 3-chloropyrazine-2-carboxylic acid (Tyger Scientific, 500mg, 3.15mmol) mixture in methylene dichloride (30mL) and DMF (0.1mL) with oxalyl chloride.After stirring 30min, reaction mixture is carried out vacuum concentration.Resistates is absorbed in the acetonitrile (12mL), and (920mg, 9.1mmol) (430mg 3.3mmol) handles and stirs 30min with 2,4 difluorobenzene amine to use triethylamine then.Reaction mixture is distributed between ethyl acetate and salt solution.Anhydrous MgSO is used in organic layer salt water washing ₄Drying, vacuum concentration then.With resulting solid recrystallization (ethyl acetate/hexane), obtain acid amides (455mg, 53%), be solid.MS(ESI ⁺)m/z?270(M+H) ⁺。

B) 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrazine-2-methane amide two (trifluoroacetic acid) salt

The mode of the method for being summarized in the step e with the step D that is similar to embodiment 1 and embodiment 3 changes into title compound with 3-chloro-N-(2,4 difluorobenzene base) pyrazine-2-methane amide and 4-(4-amino-2-fluorophenoxy) picolinamide. ¹H?NMR(CD ₃OD)δ11.24(s，1H)，8.50(d，1H，J＝2.4Hz)，8.19(m，3H)，7.86(d，1H，J＝7.2Hz)，7.52(m，1H)，7.33(m，1H)，7.18(m，1H)，7.08(m，1H)，6.70(dd，1H，J＝7.3，2.5Hz)，6.25(d，1H，J＝2.2Hz)；MS(ESI ⁺)m/z453(M+H) ⁺。

Embodiment 42

3-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrazine-2-methane amide two (trifluoroacetic acid) salt

Mode with the method summarized among the step D that is similar to embodiment 1 changes into title compound with 3-chloro-N-(2,4 difluorobenzene base) pyrazine-2-methane amide. ¹H?NMR(CD ₃OD)δ8.44(d，1H，J＝2.4Hz)，8.27-8.11(m，4H)，7.49(m，2H)，7.38(m，1H)，7.13(m，1H)，7.01(m，1H)，6.83(dd，1H，J＝7.3，2.4Hz)，6.62(d，1H，J＝2.3Hz)；MS(ESI ⁺)m/z477(M+H) ⁺。

Claims

1. have compound or its salt with following formula I or II:

Wherein

B is O, NR ⁹, S, SO, SO ₂Or CR ¹⁰R ¹¹

W and X independently are C or N separately;

V is CO;

N is 1 to 4;

M is 1 to 4;

P is 0 to 2;

L is 1 to 2;

For

With

For

Wherein

G is O, S or NR ¹⁰⁶

D is CR ¹⁰⁷Or N;

Z is N or CR ¹⁰⁸

2. the compound of claim 1, wherein A is

3. 2 compounds of claim, wherein D is-CH, G is-NH, Z be N or-CH, and R ⁵⁰, R ⁵¹, R ⁵², R ⁵⁸And R ⁵⁹Independent separately is the low alkyl group of H, amino or replacement.

4. the compound of claim 1, wherein B is O.

5. the compound of claim 1, wherein

For

6. the compound of claim 5, wherein

For

7. the compound of claim 6, wherein each R ²², R ²⁴And R ¹⁶All independent be H, hydroxyl, alkoxyl group, halogen, low alkyl group, haloalkyl ,-NR ¹⁰R ¹¹,-SR ¹²⁶,-CN, amino, aminoalkyl group, alkylamino, dialkyl aminoalkyl amino, aryl-alkyl amino or Heterocyclylalkyl.

8. the compound of claim 7, wherein each R ²², R ²⁴And R ¹⁶All independently be-OH ,-OCH ₃, Br, Cl ,-CH ₃,-SCH ₃,-CF ₃,-CN ,-CH ₂NH ₂, morpholinyl, piperazinyl ,-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Independent is H, low alkyl group, benzyl or dialkyl aminoalkyl.

9. the compound of claim 1, wherein W and X are C, and each R ¹All independent is H or F.

10. the compound of claim 1, wherein R ⁵For the optional phenyl that replaces, the optional indolinyl that replaces ,-NR ¹⁰R ¹¹Or alkylamino.

11. the compound of claim 10, wherein said phenyl is substituted with halogen, low alkyl group, hydroxyalkyl, heteroaryl, Heterocyclylalkyl, amino or alkylamino.

12. have compound or its salt with following formula I:

Wherein

B is O, NR ⁹, S, SO, SO ₂Or CR ¹⁰R ¹¹

W and X independently are C or N separately;

V is CO;

N is 1 to 4;

M is 1 to 4;

P is 0 to 2;

L is 1 to 2;

R ¹⁰And R ¹¹Independent separately is the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl or replacement of aryl, heteroaryl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of H, halogen, alkyl, replacement, or R ¹⁰And R ¹¹Form the carbocyclic ring or the heterocycle of 3 to 8 atoms together;

For

A is

Wherein

R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²², R ²⁴, R ⁵⁰, R ⁵¹, R ⁵², R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸And R ⁵⁹Independent separately is H, halogen, haloalkyl, NO ₂, cyano group, OR ¹⁰⁹, NR ¹¹⁰R ¹¹¹, CO ₂R ¹¹², C (O) NR ¹¹³R ¹¹⁴, SO ₂R ¹¹⁵, SO ₂NR ¹¹⁶R ¹¹⁷, NR ¹¹⁸SO ₂R ¹¹⁹, NR ¹²⁰C (O) R ¹²¹, NR ¹²²CO ₂R ¹²³,-CO (CH ₂) _mR ¹²⁴,-CONH (CH ₂) _mR ¹²⁵, SR ¹²⁶, SOR ¹²⁷, alkylamino alkyl, alkylamino alkynyl, C ₁To C ₆The C of alkyl, replacement ₁To C ₆Alkyl, C ₃To C ₇The C of cycloalkyl, replacement ₃To C ₇The Heterocyclylalkyl of arylalkyl, Heterocyclylalkyl or the replacement of the heteroaryl of the aryl of the alkynyl of the thiazolinyl alkyl of the thiazolinyl of cycloalkyl, thiazolinyl, replacement, thiazolinyl alkyl, replacement, alkynyl, replacement, hydroxyalkyl, aryl, replacement, heteroaryl, replacement, arylalkyl, replacement; With

R ¹⁴, R ¹⁰⁶, R ¹⁰⁹, R ¹¹⁰, R ¹¹¹, R ¹¹², R ¹¹³, R ¹¹⁴, R ¹¹⁵, R ¹¹⁶, R ¹¹⁷, R ¹¹⁸, R ¹¹⁹, R ¹²⁰, R ¹²¹, R ¹²², R ¹²³, R ¹²⁴, R ¹²⁵, R ¹²⁶And R ¹²⁷Independent separately is the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl or replacement of arylalkyl, heteroaryl, the replacement of aryl, arylalkyl, the replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of H, alkyl, replacement.

13. the compound of claim 12, wherein each R ²², R ²⁴And R ¹⁶All independent be H, hydroxyl, alkoxyl group, halogen, low alkyl group, alkylthio, haloalkyl ,-NR ¹⁰R ¹¹,-SR ¹²⁶,-CN, amino, aminoalkyl group, alkylamino, dialkyl aminoalkyl amino, aryl-alkyl amino or Heterocyclylalkyl.

14. the compound of claim 12, wherein W and X are C, and each R ¹All independent is H or F.

15. the compound of claim 12, wherein R ⁵For the optional phenyl that replaces, the optional indolinyl that replaces ,-NR ¹⁰R ¹¹Or alkylamino.

16. the compound of claim 12, wherein said phenyl is substituted with halogen, low alkyl group, hydroxyalkyl, heteroaryl, Heterocyclylalkyl, amino or alkylamino.

17. a compound is selected from following:

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

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

2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) niacinamide hydrochloride;

2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(4-chloro-phenyl-) niacinamide dihydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) niacinamide dihydrochloride;

2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-benzyl niacinamide dihydrochloride;

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

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

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

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

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

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2-morpholino base-1-phenylethyl) niacinamide tri hydrochloride;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2-(2-hydroxyethyl) phenyl) niacinamide two (trifluoroacetic acid) salt;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(5-fluorine pyridine-2-yl) niacinamide two (trifluoroacetic acid) salt;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-4-methoxyl group niacinamide two (trifluoroacetic acid) salt;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-4-hydroxy nicotinoyl amine two (trifluoroacetic acid) salt;

2-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-5-bromo-N-(2,4 difluorobenzene base) niacinamide two (trifluoroacetic acid) salt;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-5-bromo-N-(2,4 difluorobenzene base) niacinamide dihydrochloride;

2-(4-(2-amino-3-(hydroxymethyl) pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) niacinamide dihydrochloride;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(4-fluorophenyl)-N-methylnicotinamide dihydrochloride;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-6-methylnicotinamide dihydrochloride;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino) pyridin-3-yl) (5-fluorine indoline-1-yl) ketone dihydrochloride;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino) niacinamide two (trifluoroacetic acid) salt;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-methylnicotinamide dihydrochloride;

2-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-5-chloro-N-methylnicotinamide dihydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methylthio group) pyrimidine-5-methane amide two (trifluoroacetic acid) salt;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(trifluoromethyl) pyrimidine-5-methane amide dihydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-2-cyano group-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide dihydrochloride;

2-(amino methyl)-4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide tri hydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-morpholino yl pyrimidines-5-methane amide tri hydrochloride;

2-amino-4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide tri hydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(methylamino) pyrimidine-5-methane amide tri hydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(dimethylamino) pyrimidine-5-methane amide tri hydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(2-(dimethylamino) ethylamino) pyrimidine-5-methane amide tri hydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-(piperidines-1-yl) pyrimidine-5-methane amide tri hydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-2-(benzylamino)-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide tri hydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrimidine-5-methane amide two (trifluoroacetic acid) salt;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-methoxy pyrimidine-5-methane amide dihydrochloride;

4-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base)-2-hydroxy pyrimidine-5-methane amide dihydrochloride;

3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrazine-2-methane amide two (trifluoroacetic acid) salt; With

3-(4-(1H-pyrrolo-[2,3-b] pyridin-4-yl oxygen base)-3-fluorophenyl amino)-N-(2,4 difluorobenzene base) pyrazine-2-methane amide two (trifluoroacetic acid) salt.

18. treatment patient's method for cancer, wherein said cancer depends on the Met activation, wherein said Met activation stimulates by gene amplification, activatory Met sudden change and/or HGF to be regulated, and described method comprises that the compound with the claim 1 of the treatment significant quantity in pharmaceutically acceptable carrier gives described patient.

19. 18 methods of claim also comprise giving described patient with at least a extra anticarcinogen.

20. 18 methods of claim, wherein said cancer are selected from bladder cancer, mammary cancer, colorectal carcinoma, cancer of the stomach, head and neck cancer, kidney, liver cancer, lung cancer, ovarian cancer, carcinoma of the pancreas/carcinoma of gallbladder, prostate cancer, thyroid carcinoma, osteosarcoma, rhabdosarcoma, MFH/ fibrosarcoma, glioblastoma/astrocytoma, melanoma and mesothelioma.