CN101128199A

CN101128199A - Monocyclic heterocycles as kinase inhibitors

Info

Publication number: CN101128199A
Application number: CN200580020112.2A
Authority: CN
Inventors: R·M·博尔齐莱里; L·A·M·科恩利乌斯; R·J·施米德特; G·M·施勒德尔; K·S·金
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2004-04-23
Filing date: 2005-04-22
Publication date: 2008-02-20
Anticipated expiration: 2025-04-22
Also published as: CN101128199B; ES2359836T3; ZA200608775B; UA85087C2

Abstract

The present invention is directed to compounds having the formula [I + II] and methods for using them for the treatment of cancer.

Description

Monocyclic heterocycles as inhibitors of kinases

Related application

[0001] the present invention is according to clause 35 § 119 (e), 60/639,178 the priority that requires that number 60/564,842 and 2004 year December of the U.S. Provisional Patent Application submitted on April 23rd, 2004 submitted on the 23rd, and its content is attached to herein by reference.

Invention field

[0002] the present invention relates to for example tyrosine kinase activity of c-Met of Profilin growth factor receptors, thereby make them be used as the chemical compound of cancer therapy drug.The Pharmaceutical composition that contains these chemical compounds also can be used for treating with by somatomedin and the angiogenesis inhibitor receptor relevant non-Cancerous disease of signal transduction path that works of c-Met for example.

Summary of the invention

[0003] the present invention relates to the following chemical compound that can be used for treating cancer with formula I and II

Or its enantiomer, diastereomer, hydrate, solvate or pharmaceutically acceptable salt, wherein:

R ¹It is the Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl or replacement of heterocyclic radical, heteroaryl alkyl, the replacement of heteroaryl, heterocyclic radical, the replacement of alkynyl, heteroaryl, the replacement of thiazolinyl, alkynyl, the replacement of aryl, thiazolinyl, the replacement of aryl alkyl, aryl, the replacement of cycloalkyl, aryl alkyl, the replacement of alkyl, cycloalkyl, the replacement of H, alkyl, replacement;

Each R ²Independently be H, halogen, cyano group, NO ₂, OR ⁵, NR ⁶R ⁷, alkyl, replacement the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or replacement of heterocyclic radical, aralkyl, replacement of heteroaryl, heterocyclic radical, replacement of aryl, heteroaryl, replacement of cycloalkyl, aryl, replacement of alkyl, cycloalkyl, replacement;

B is O, NR ⁸, NR ⁸CH ₂, S, SO, SO ₂Or CR ⁹R ¹⁰

V is NR ¹¹Or-(CR ³⁷R ³⁸) _p-, prerequisite is to work as VR ¹¹During for N, R ¹Be alkyl or cycloalkyl;

W and X independently are C or N separately;

Y is selected from O, S and NR ¹²

Z is-CR ¹³R ¹⁴-or-(CR ¹³R ¹⁴) ₁NR ¹⁵-;

1 is 0-2;

When if W and X are C, n is 0-4; If when among X or the W one was N, n was 0-3, and if X and W are N, then n is 0-2;

P is 1-4;

R ³, R ⁵, R ⁶, R ⁷, R ⁸, R ¹¹And R ¹⁵Independently be selected from heteroaryl, the heterocyclic radical 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, the heterocyclic radical of replacement;

R ⁴Be selected from the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl and replacement of aryl, heteroaryl, the replacement of aryl, replacement, prerequisite is

(a) if R ⁴It is phenyl

(i) R ⁴Do not replaced by hydroxyl and acylamino-; With

(ii) R ⁴Not by-NRSO ₂R-replaces, and wherein R is an alkyl or aryl;

(b) if R ⁴Be pyridine radicals, R ⁴Do not replaced by hydroxyl and methoxyl group; With

(c) if R ⁴Be pyrimidine radicals, it is not replaced by=O;

R ⁹And R ¹⁰Independently 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;

R ¹²Be selected from alkyl, thiazolinyl, the thiazolinyl of replacement, alkynyl, the alkynyl of replacement, CN, the NO of H, alkyl, replacement ₂Or SO ₂NH ₂

R ¹³And R ¹⁴Independently be selected from heteroaryl, the Heterocyclylalkyl 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, the Heterocyclylalkyl of replacement, or connect together and form the carbocyclic ring or the heterocycle of 3-8 atom;

It is one of following that A is selected from:

Wherein

D is S or O;

M is 0-6;

R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²¹, R ²², R ²³, R ²⁴, R ²⁵, R ²⁶And R ²⁷Independently be selected from H, halogen, NR ³⁰R ³¹, OR ³², CO ₂R ³³, CONR ³⁴R ³⁵, SO ₂R ³⁶, alkyl, replacement alkyl, cycloalkyl, replacement cycloalkyl, thiazolinyl, replacement thiazolinyl, alkynyl, replacement alkynyl ,-Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl or the replacement of the aryl of CN, aryl, replacement, heteroaryl, replacement;

R ²⁸And R ²⁹Independently be selected from cycloalkyl, the aryl of alkyl, cycloalkyl, the replacement of H, alkyl, replacement, the aryl of replacement, or connect together and form the carbocyclic ring or the heterocycle of 3-8 atom;

R ³⁰, R ³¹, R ³², R ³³, R ³⁴, R ³⁵And R ³⁶Independently be selected from the Heterocyclylalkyl of heterocyclic radical, Heterocyclylalkyl or replacement of heteroaryl, heterocyclic radical, the replacement of aryl, heteroaryl, the replacement of cycloalkyl, alkoxy carbonyl, aryl, the replacement of alkynyl, cycloalkyl, the replacement of thiazolinyl, alkynyl, the replacement of alkyl, thiazolinyl, the replacement of H, alkyl, replacement; With

R ³⁷And R ³⁸Independently be H, halogen or alkyl separately.

Invention is set forth

[0004] the invention provides above definition formula I and II chemical compound, contain the Pharmaceutical composition of this compounds and use this compounds for treating method for cancer.

[0005] except that other has definition, is meant by the deutero-unit price alkane of the group that contains 1-12 carbon atom (hydrocarbon) separately or as a part of term " alkyl " that uses of another group herein.Preferred alkyl is the low alkyl group with 1-6 carbon atom.Alkyl is optional straight chain, side chain or the cyclic saturated hydrocarbon that replaces.Alkyl can be substituted on any spendable junction point.The alkyl that is replaced by other alkyl is called " branched alkyl " again.Exemplary alkyl comprises methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, isohesyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc.Exemplary substituent group includes but not limited to one or more following groups: alkyl, cycloalkyl, Heterocyclylalkyl ,-CN, aryl, heteroaryl, halogen (for example F, Cl, Br, I), haloalkyl (CCl for example ₃Or CF ₃), hydroxyl, alkoxyl, alkylthio group, alkyl amino ,-COOH ,-COOR ,-C (O) R ,-OCOR, amino, carbamoyl (NHCOOR-or-OCONHR-), urea (NHCONHR-) or mercaptan (SH).

[0006] is meant straight chain, side chain or the cyclic hydrocarbon that contains 2-12 carbon atom and at least one carbon-to-carbon double bond separately or as a part of term " thiazolinyl " that uses of another group herein.Thiazolinyl also can be substituted on any available junction point.The exemplary substituent group of thiazolinyl comprises above to enumerating in the alkyl those.

[0007] is meant straight chain, side chain or the cyclic hydrocarbon that contains 2-12 carbon atom and at least one carbon-to-carbon triple bond separately or as a part of term " alkynyl " that uses of another group herein.Alkynyl also can be substituted on any available junction point.The exemplary substituent group of alkynyl comprises above to enumerating in the alkyl those.

[0008] carbon number that the concrete group of target numeral definition can contain under symbol " C " back." C for example _1-6Alkyl " expression has the straight or branched saturated carbon chains of 1-6 carbon atom; Example comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, sec-amyl, isopentyl and n-hexyl.Based on context, " C _1-6Alkyl " also can refer to the C of two groups of bridge joint _1-6Alkylidene; Example comprises propane-1,3-two bases, butane-1,4-two bases, 2-methyl-butane-1,4-two bases etc." C _2-6Thiazolinyl " expression has a straight or branched carbochain of at least one carbon-to-carbon double bond and 2-6 carbon atom; Example comprises vinyl, acrylic, isopropenyl, cyclobutenyl, isobutenyl, pentenyl and hexenyl.Based on context, " C _2-6Thiazolinyl " also can refer to the C of two groups of bridge joint _2-6Alkenylene; Example comprises ethylene-1,2-two bases (vinylene), 2-methyl-2-butene-1,4-two bases, 2-hexene-1,6-two bases etc." C _2-6Alkynyl " expression has a straight or branched carbochain of at least one carbon-to-carbon triple bond and 2-6 carbon atom; Example comprises acetenyl, propinyl, butynyl and hexin base.

[0009] term " cycloalkyl " independent herein or that use as another group part is the alkyl kind that contains 3-15 carbon atom, and conversion or resonance do not take place the two keys between the carbon atom.It can contain 1-4 ring.Exemplary group comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, adamantyl etc.Cycloalkyl can be substituted at any available junction point.Exemplary substituent group comprises one or more following groups: halogen, for example F, Br or Cl; Hydroxyl, alkyl, alkoxyl, amino, nitro, cyano group, mercaptan, alkylthio group and in any substituent group described in the above alkyl.

[0010] herein separately or the term " alkoxyl " that uses as another group part or the logical respectively peroxide bridge of " alkylthio group " expression (O-) or sulfide linkage (S-) bonded abovementioned alkyl.

[0011] passes through the bonded alkoxyl of carbonyl separately or as term " alkoxy carbonyl " expression that another group part is used herein.Alkoxy carbonyl is by formula :-C (O) OR representative, and wherein the R group is straight or branched C _1-6Alkyl, cycloalkyl, aryl or heteroaryl.

[0012] is meant by the bonded alkyl of carbonyl separately or as a part of term " alkyl-carbonyl " that uses of another group herein.

[0013] passes through the bonded alkyl-carbonyl of oxygen key separately or as term " alkyl-carbonyl oxygen base " expression that another group part is used herein.

[0014] herein separately or the term " aryl " that uses as another group part be meant monocycle or dicyclo aromatic ring, phenyl for example, phenyl of replacement etc. and condensed group, naphthyl for example, phenanthryl etc.Therefore aryl contains the ring that at least one has at least 6 atoms, exists to contain to be up to 5 these type of rings, wherein contains and is up to 22 atoms, the two key generation conversion (resonance) between adjacent carbon atom or the suitable hetero atom.Aryl can be chosen wantonly by one and the replacement of a plurality of group, and they include but not limited to halogen, alkyl, alkoxyl, hydroxyl, carboxyl, carbamoyl, alkoxy carbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano group, alkyl S (O) _m(m=0,1,2) or mercaptan.

[0015] passes through the bonded above-mentioned aryl of abovementioned alkyl separately or as term " aryl alkyl " or " aralkyl " expression that another group part is used herein.The example of aralkyl is a benzyl.

[0016] is meant-NH separately or as a part of term " amino " that uses of another group herein ₂" amino " can choose wantonly by following one or two can be identical or different substituent group replace: alkyl, aryl, aryl alkyl, thiazolinyl, alkynyl, heteroaryl, heteroaryl alkyl, the assorted alkyl of ring, the assorted alkyl-alkyl of ring, cycloalkyl, cycloalkyl-alkyl, haloalkyl, hydroxy alkyl, alkoxyalkyl, alkylthio group, carbonyl or carboxyl.Any carboxylic acid that these substituent groups can further be listed by this paper, alkyl or aryl substituent group replace.In certain embodiments, amino can be formed N-acyl group or N-carbamoyl derivatives by carboxyl or carbonyl substituted.

[0017] be meant the replacement that at least one ring, has at least one hetero atom (O, S or N) herein separately or as the term " heteroaryl " that another group part is used with unsubstituted 5 yuan or 6 yuan of monocycles, 9 yuan or 10 yuan of dicyclos and 11 yuan of-14 yuan of three cyclophane bases.Each contains heteroatomic hetero-aromatic ring can contain one or two oxygen or sulphur atom and/or 1-4 nitrogen-atoms, and prerequisite is that the hetero atom sum in each ring is equal to or less than 4, and each ring has at least one carbon atom.Constitute dicyclo and trinucleated fused rings and can only contain carbon atom, and can saturated, fractional saturation or unsaturated.Nitrogen and sulphur atom can be chosen oxidation wantonly, and nitrogen-atoms can be chosen seasonization wantonly.Dicyclo or tricyclic antidepressants heteroaryl must comprise at least one aromatic ring completely, but other condensed ring or ring can be aromatic ring or non-aromatic ring.Heteroaryl can connect on any available nitrogen of any ring or carbon atom.Heteroaromatic ring system can contain and is selected from 0,1,2 or 3 following substituent group: the alkyl of halogen, alkyl, replacement, thiazolinyl, alkynyl, aryl, nitro, cyano group, hydroxyl, alkoxyl, alkylthio group ,=O ,-CO ₂H ,-C (=O) H ,-CO ₂-alkyl ,-C (=O) alkyl, phenyl, benzyl, phenethyl, phenoxy group, thiophenyl, bad alkyl, replacement cycloalkyl, heterocyclic radical, heteroaryl ,-NR ' R " ,-C (=O) NR ' R " ,-CO ₂NR ' R " ,-C (=O) NR ' R " ,-NR ' CO ₂R " ,-NR ' C (=O) R " ,-SO ₂NR ' R " and-NR ' SO ₂R ", wherein R ' and R " independently is selected from the alkyl and the cycloalkyl of hydrogen, alkyl, replacement separately, or R ' and R " form heterocycle or hetero-aromatic ring together.

[0018] exemplary bicyclic heteroaryl comprises pyrrole radicals, pyrazolyl, pyrazolinyl, imidazole radicals,  azoles base, di azoly, different  azoles base, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl,  di azoly, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, triazine radical etc.

[0019] exemplary bicyclic heteroaryl comprises indyl, benzothiazolyl, benzo dioxolyl, benzoxaxolyl, benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizine base, benzofuranyl, chromone base, coumarin base, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridine radicals, dihydro-iso indolyl, tetrahydric quinoline group etc.

[0020] exemplary tricyclic heteroaryl comprises carbazyl, benzidolyl, phenanthroline base (phenanthrollinyl), acridinyl, phenanthridinyl, xanthyl etc.

[0021] is meant that containing 5-7 ring carbon atom is selected from the stable undersaturated single loop system of saturated or part of the atom of nitrogen, sulfur and/or oxygen with other separately or as " heterocyclic ring " that another group part is used herein.Preferably, heterocycle is 5 yuan or 6 yuan of monocycles, and contains 1,2 or 3 hetero atom that is selected from nitrogen, oxygen and/or sulfur.Heterocycle can be chosen wantonly and be substituted, and the expression heterocycle can be on one or more commutable ring positions independently be selected from following group and replaces by one or more: alkyl (preferred low alkyl group); alkoxyl (preferred lower alkoxy); nitro; alkyl monosubstituted amino (preferred low-grade alkyl amino); dialkyl amido (preferred two [rudimentary] alkyl amino); cyano group; halogen; haloalkyl (preferred trifluoromethyl); alkanoyl; amino carbonyl; the alkyl monosubstituted amino carbonyl; dialkyl amino carbonyl; alkyl amido (preferred low alkyl group acylamino-); alkoxyalkyl (preferred lower alkoxy [rudimentary] alkyl); alkoxy carbonyl (preferred elementary alkoxy carbonyl); alkyl-carbonyl oxygen base (preferred lower alkylcarbonyl oxygen base) and aryl (preferred phenyl); described aryl is optional to be replaced by following group: halogen; low alkyl group and lower alkoxy.This type of heterocyclic example is different  azoles base, imidazolinyl, thiazolinyl, imidazolidinyl, pyrrole radicals, pyrrolinyl, pyranose, pyrazinyl, piperidyl, morpholinyl and triazolyl.Heterocycle can be by forming stable structure heterocyclic radical carbon atom or be connected with precursor structure by any hetero atom.

[0022] independent O, S or the N that selects of term " hetero atom " expression.It should be noted that inferring any hetero atom with unsaturated linkage has the hydrogen atom of filling these keys.

[0023] term " halogen " or " halo " are meant independent chlorine, bromine, fluorine or the iodine of selecting.

[0024] when functional group is called as " protection ", represents the modified forms of this group, so that get rid of unwanted side reaction at the protection position.According to the art technology level, and reference standard textbook Greene for example, T.W. etc., Protective Groups in OrganicSynthesis, Wiley, N.Y. (1991) can recognize the suitable blocking group of The compounds of this invention from the application.

[0025] term used herein " patient " comprises all mammal.

[0026] the suitable example of salt with The compounds of this invention of inorganic or organic acid is hydrochlorate, hydrobromate, sulfate, mesylate, maleate, fumarate and phosphate.Also comprise and be not suitable for medicinal but can be used for the salt of the free formula I of isolated or purified for example or II chemical compound, its pharmaceutically acceptable salt.

[0027] generally speaking, the present invention includes chemical compound with formula I or II:

Each R ²Independently be H, halogen, cyano group, NO ₂, OR ⁵, NR ⁶R ⁷, alkyl, replacement the Heterocyclylalkyl of aryl alkyl, Heterocyclylalkyl or replacement of heterocyclic radical, aryl alkyl, replacement of heteroaryl, heterocyclic radical, replacement of aryl, heteroaryl, replacement of cycloalkyl, aryl, replacement of alkyl, cycloalkyl, replacement;

B is O, NR ⁸, NR ⁸CH ₂, S, SO, SO ₂Or CR ⁹R ¹⁰

V is NR ¹¹Or-(CR ³⁷R ³⁸) _p-, prerequisite is when V is N, R ¹It is alkyl or cycloalkyl;

W and X independently are C or N separately;

Y is selected from O, S and NR ¹²

Z is-CR ¹³R ¹⁴-or-(CR ¹³R ¹⁴) ₁NR ¹⁵-;

1 is 0-2;

When if W and X are C, n is 0-4; If one among X or the W is N, n is 0-3, if X and W are N, n is 0-2;

P is 1-4;

(a) if R ⁴It is phenyl

(i) R ⁴Do not replaced by hydroxyl and acylamino-; With

(ii) R ⁴Not by-NRSO ₂R-replaces, and wherein R is an alkyl or aryl;

(c) if R ⁴Be pyrimidine radicals, it is not replaced by=O;

R ¹³And R ¹⁴Independently be selected from heteroaryl, the Heterocyclylalkyl 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, the Heterocyclylalkyl of replacement, or be combined together to form the carbocyclic ring or the heterocycle of 3-8 atom;

It is one of following that A is selected from:

Wherein

D is S or O;

M is 0-6;

R ²⁸And R ²⁹Independently be selected from cycloalkyl, the aryl of alkyl, cycloalkyl, the replacement of H, alkyl, replacement, the aryl of replacement, or be combined together to form the carbocyclic ring or the heterocycle of 3-8 atom;

R ³⁷And R ³⁸Independently be H, halogen or alkyl separately.

[0028] in certain embodiments of the invention, R ¹Be that replace or unsubstituted phenyl, for example fluorophenyl, replacement or unsubstituted C ₁-C ₄Alkyl is methyl for example; Or that replace or unsubstituted C ₃-C ₈Cycloalkyl, for example cyclohexyl or cyclopenta.

[0029] in certain embodiments of the invention, R ²Be C ₁-C ₄Alkyl, halogen or haloalkyl.

[0030] in certain embodiments of the invention, R ⁴Be the optional phenyl that replaces, or 5 yuan or 6 membered nitrogen-containing heteroaryl bases, for example pyridine radicals, pyridone (pyridinone), pyrazolyl or pyrrolidinyl.

[0031] according to one embodiment of the invention, B is O, NHCH ₂, CH ₂Or CH (OH); Y is O or S, and Z is-CR ¹³R ¹⁴Or-NR ¹⁵, R wherein ¹³, R ¹⁴And R ¹⁵Each is H naturally.

[0032] in certain embodiments of the invention, A is optional pyridine or the pyrimidine that replaces, wherein substituent group be alkyl, thiazolinyl, alkynyl, halogen, cycloalkyl, Heterocyclylalkyl ,-NR ³⁹COR ⁴⁰,-NR ³⁹C (O) ₂R ⁴⁰,-NR ⁴¹R ⁴²Or-C (O) NR ⁴³R ⁴⁴, R wherein ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³And R ⁴⁴Independently be aryl, the heteroaryl of cycloalkenyl group, aryl, the replacement of Heterocyclylalkyl, cycloalkenyl group, the replacement of cycloalkyl, Heterocyclylalkyl, the replacement of low alkyl group, hydroxy alkyl, aminoalkyl, cycloalkyl, the replacement of H, low alkyl group, replacement, the heteroaryl of replacement, or-NR ⁴³R ⁴⁴Form Heterocyclylalkyl.

[0033] in certain embodiments of the invention, the pyridine that replaced by following group of A :-NR ⁴¹R ⁴²,-NR ³⁹COR ⁴⁰,-C (O) NR ⁴³R ⁴⁴, halogen, the optional C that is replaced by hydroxyl, hydroxy alkyl amino, alkyl amino, aminoalkyl amino or heteroaryl alkyl ₁-C ₄Alkyl; Or-C=C-R ⁴⁵,-C ≡ C-R ⁴⁶, R wherein ⁴⁵And R ⁴⁶Be alkyl, hydroxy alkyl, aminoalkyl, cycloalkyl, Heterocyclylalkyl ,-C (O) R ⁴⁷,-NR ³⁹COR ⁴⁰, aryl or heteroaryl; Or by the aryl pyridine that replaces of phenyl for example, described aryl can further be replaced by following group: CONH ₂, methyl, amino-ethyl, ethoxy ,-CONHCH ₂CH ₂NHCH ₃Or CH ₂CONH ₂But described pyridine is pyridyl or piperidyl replacement also.

[0034] in certain embodiments of the invention, A is the optional pyrimidine that replaces.Preferred substituted comprises-NR ⁴¹R ⁴²Or-NR ³⁹CO ₂R ⁴⁰, wherein preferred R ⁴¹And R ⁴²Be H or methyl, preferred R ³⁹And R ⁴⁰Be H or alkyl.

In one embodiment of the invention, chemical compound has Formula Il I:

Wherein

R ¹Be optional phenyl or the alkyl that replaces; Z is NH or NCH ₃R ²Be F, Cl, CH ₃Or CF ₃, R ³Be H; Y is O or S.In certain embodiments, R ¹Be C ₃-C ₇Phenyl cycloalkyl, replacement or unsubstituted or-(CH ₂) _n-R ⁵⁰, wherein n is 1-3, R ⁵⁰Be H, replacement or unsubstituted phenyl, amino, acylamino-, CN ,-C (O) ₂H or-C (O) ₂CH ₃

In certain embodiments of the invention, chemical compound has following formula I V:

R wherein ²Be halogen or H; R ³Be H; R ⁴Be the optional phenyl that replaces, the optional pyrazoles that replaces or optional pyridine radicals, pyridone or the pyridine-N-oxides that replaces.

In one embodiment of the invention, chemical compound has following formula V:

R wherein ¹It is the alkyl or cycloalkyl of choosing wantonly; A is optional pyrimidine or the pyridine that replaces; R ²Be halogen or H; R ¹³And R ¹⁴Perhaps H, perhaps the carbon that connects with their forms cycloalkyl, for example cyclopropyl.

[0035] also the formula I or the II chemical compound of the above definition of the mammal effective dose by needing this treatment of the present invention provides for example method for cancer of treatment proliferative disease.In another embodiment, the present invention needs formula I or II chemical compound and at least a other cancer therapy drug of above definition of the mammal effective dose of this treatment simultaneously by associating (or sequential), provide by regulating the Met kinases and treat the method for proliferative disease.In preferred embodiments, proliferative disease is a cancer.

[0036], can prepare some formula I and II chemical compound usually according to following flow process 1-14.Easily synthetic these chemical compounds of available synthetic method well known by persons skilled in the art.The solvate of formula I and II chemical compound (for example hydrate) also within the scope of the present invention.Common in the art known solvent method.Therefore, The compounds of this invention can be free or hydrate forms, can obtain by the illustrational method of following flow process.

[0037] in flow process 1, sets forth the total path that obtains pyridine described in the present invention and pyrimidine analogue.Can for example in the presence of sodium hydride, sodium hydroxide or the potassium carbonate, handle pyridine or the pyrimidine 1 that suitably replaces at alkali, obtain required ether 3,5 and 9 respectively with functionalized phenol 2,4 and 8.In methanol, remove the acetamide blocking group of chemical compound 3 with the HCl aqueous solution, obtain key intermediate 5.Perhaps,, use or zinc powder and ammonium chloride or Adams ' catalyst (platinum oxide (IV)) reduction nitro, can obtain aniline 5 by chemical compound 9 by under hydrogenation conditions.Then can by with for example isocyanates, acyl chlorides with aniline 5 acidylates; or with carboxylic acid and coupling agent; for example: benzothiazole-1-base oxygen base three (trimethyl amino) phosphorus  hexafluorophosphates (bop reagent), bromine tripyrrole alkyl phosphorus  hexafluorophosphate (PyBroP), O-(1H-benzotriazole-1-yl)-N; N; N ', N '-tetramethylurea  tetrafluoroborate (TBTU) is handled can prepare analog 6 and 7.Can pass through to use the isothiocyanate that suitably replaces to handle aniline 5, and realization formation acylthioureas 6 (Y=S, Z=NH).

Flow process 1

T=CR ¹⁹Or N

L=leaving group, for example halogen or NO ₂

[0038] generalized two kinds of similar things 14 of different regional isomer aminopyrimidines of route of synthesis preparation and 19 in the available flow process 2 and 3.Generalized identical chemical method in the available flow process 1 will be by commercially available 2, and (10, Aldrich) aminopyrimidine 11 of deutero-PMB-protection is converted into ether 13 through aniline 12 to the 4-dichloro pyrimidine.Available trifluoroacetic acid and methoxybenzene are realized removing 13 PMB group, obtain chemical compound 14.

Flow process 2

[0039] same, after PMB deprotection steps (flow process 3), can be with by commercially available 4, the aminopyrimidine 16 of the deutero-PMB protection of 6-dichloro pyrimidine (15, TCI America) is converted into ether 17.Handle the amine 17 that two-Boc (tert-butoxycarbonyl) protects with excessive Bis(tert-butoxycarbonyl)oxide, use the hydrogenation of Adams ' catalyst then, obtain aniline 18.Form step and after removing the Boc blocking group under the acid condition, can obtain amine 19 in acidylate or thiourea by chemical compound 18.

Flow process 3

[0040] generalized route of synthesis prepares amino pyridazine derivant 26 in the available flow process 4, flow process 4 is based on below with reference to the similar chemistry of quoting in the document: Chung, H.-A. wait J.Heterocyclic Chem.1999,36, J. HeterocyclicChem.1995 such as 905-910 and Bryant R. D., 32,1473-1476, its content is attached to herein by reference.Available for example Pentamethylene oxide. (THP) radical protection 4; 5-dichloro-pyridazine-3 (2H)-ketone (20, Aldrich), obtain phenol and alkali (for example sodium hydride) processing chemical compound 21 that intermediate 21 usefulness suitably replace; reduction contains the intermediate of nitro under the catalytic hydrogenation condition subsequently, can obtain aniline 22.The protection of 22 aniline groups for carbamic acid dibenzyl ester (Cbz), is removed the THP group subsequently under acid condition, can obtain chemical compound 23.Alkali for example triethylamine or diisopropylethylamine in the presence of, handle chemical compound 23 with trifluoroacetic anhydride (TFAA), phosphoryl chloride phosphorus oxychloride or phosphoryl bromide (phosphorous oxybromide), can introduce essential leaving groups 3 of chemical compound 24.Leaving group X with the amine of suitable replacement displacement chemical compound 24 can remove the Cbz group subsequently, obtains intermediate 25.Aforementioned chemistry among the available flow process 1-3 is converted into aniline 25 the 3-amino pyridazine analog 26 that needs.

Flow process 4

[0041] generalized synthetic route prepares the 2-aminopyrazole derivatives in the available flow process 5 and 6.When in benzylamine, heating, can intermediate 28 (flow process 5) will be converted into by aniline 27 chemically derived described in the flow process 1 with Cu powder and potassium carbonate.Under palladium on carbon catalytic hydrogenation condition, remove the benzyl protection group of chemical compound 28, obtain aminopyridine 29.Can in the presence of coupling reagent, handle intermediate 28 or 29 with isothiocyanate 30, isothiocyanate 32 and carboxylic acid 34 respectively, obtain acylthioureas 31, acylureas 33 and amide 35.

Flow process 5

[0042] in method, in chloroform, 2-chloropyridine intermediate 36 (obtaining with chemistry described in the flow process 1) is converted into N-oxide 37 (referring to WO2004/002410) (flow process 6) with 3-chloroperoxybenzoic acid (m-CPBA).Amine with suitable replacement is handled chemical compound 37, can obtain intermediate 38.Under acid condition, with for example N-oxide of triphenyl phasphine reducing compound 38, remove the acetamide blocking group subsequently, can obtain aniline 39.Aforementioned chemistry is finished aniline 39 is converted into the analog 40 that needs among the available flow process 1-5.

Flow process 6

[0043] in the alternative approach of the chemical compound relevant, can prepare 2-aminopyrazole derivatives 47 and 48 according to the synthetic order of setting forth in the flow process 7 with 40.At last, with the two-step method that relates to thionyl chloride, use the methanol solution of ammonia 4-chloropyridine formic acid (41, TCI America) can be converted into 4-chloropyridine amide (42) subsequently.Alkali for example potassium tert-butoxide in the presence of, make intermediate 42 and 43 couplings of 4-aminophenol derivates with fungicidal property, can obtain picolinamide derivatives 44.Make intermediate 44 acidylates or form acylureas, can obtain intermediate for example 45 and 46.With two-(trifluoroacetyl oxygen base)-iodobenzene, pyridine and DMF in water or bromine, potassium hydroxide in water, handle picolinamide derivatives 45 and 46, impel Hofmann to reset, obtain the 2-aminopyrazole derivatives 47 and 48 that needs.

Flow process 7

[0044] preparation of synthetic route described in the available flow process 8-10 contains the chemical compound 53,57 and 62 of thiazole.With the leaving group of aniline/phenol 50 displacement 49 (flow processs 8) or 54 (flow processs 9), can obtain intermediate 51 and 55 respectively.Be used in zinc powder among the THF-MeOH and ammonium chloride and reduce 51 and 55 nitro substituent respectively, should obtain aniline 52 and 56.Can finish the chemical compound 53 and 57 that aniline 52 and 56 is converted into needs with aforementioned chemistry (the same).

Flow process 8

Flow process 9

[0045] method described in the available WO 2004/001059 (being attached to this paper by reference in full) with aldehyde 58 reductive aminations, can obtain nitro intermediate 60 (flow process 10) with the aniline 59 that suitably replaces.The available then chemistry that is similar to described in flow process 8 and 9 obtains the aminothiazole derivs 62 that needs.

Flow process 10

[0046] generalized chemistry is implemented in 3 of pyridine nucleus and introduces various substituent groups in the available flow process 11.At last, can alkali for example diisopropylethylamine (Hunig ' s alkali) in the presence of, make 4-chloro-3-iodo pyridine (63, Tabanella, Org.Biomol.Chem.2003 such as S., 1,4254-4261) with 8 couplings of 4-nitrophenol derivative, obtain the iodide intermediate 64 that needs.Available iodine compound derivative 64 is implemented the coupling reaction of multiple organic metal mediation then, and their example is set forth in flow process 11.In the presence of palladium or copper catalyst; can use amine (R " R ' NH), the alkynes 66, aryl boride 67, vinyl stannane (stannanes) and the α that replace; beta-unsaturated esters is handled iodide 64; obtaining intermediate 65,68-71 can be with for example zinc powder in THF-MeOH and the mixture reducing compound 65 of ammonium chloride and the nitro part of 68-71, and aforementioned chemistry makes the aniline intermediate acidylate that obtains among the available flow process 1-5 respectively.

[0047] then intermediate 71 is converted into α, beta-unsaturated acyl amine 73 (flow process 12).Can coupling reagent such as but not limited to EDCI, TBTU, DCC in the presence of, make that (" R ' NH) coupling obtains the amide intermediate 73 that needs to R with various amine in acid-catalyzed hydrolysis derived compounds 72 by ester 71.The nitro part of aforementioned electronation 73 among the available flow process 1-5 makes the aniline intermediate acidylate that needs subsequently.

Flow process 11

[0048] also intermediate 74 further can be modified, with preparation propargylamine 76 (flow process 13).Can alkali for example diisopropylethylamine (Hunig ' s alkali) in the presence of, make propargyl alcohol 74 methylsulfonylizations with mesyl chloride, obtain methanesulfonates 75.With the various amine (R " displacement of R ' NH) chemical combination

Flow process 12

The methanesulfonates group of thing 75 obtains propargylamine 76.Aforementioned electronation 76 nitro parts among the available flow process 1-5 make the aniline intermediate acidylate that needs subsequently.

Flow process 13

[0049] can prepare 3-aminopyrazole derivatives 79 and 80 by synthetic route described in the flow process 14.At last, can alkali for example sodium hydride in the presence of, in DMF, make 4-chloro-3-nitropyridine (77, Lancaster Synthesis Ltd.) and the coupling of 4-amino-phenol, obtain nitro intermediate 78.Available aforementioned chemistry is converted into intermediate 78 chemical compound 79 and 80 that needs.Also can further modify 79 and 80 amino substituent group for example by alkylation, acidylate, arylation or sulfonylation.

Flow process 14

[0050] available iodide intermediate 83 and 86 adds substituent group (flow process 15 and 16) respectively 5 or 3 of 2-aminopyridine ring.Aforementioned Hofmann resets scheme in the available flow process 7, and 2-carboxamides derivatives 81 is converted into 2-aminopyrazole derivatives 82.Available N-iodosuccinimide makes 5 iodate of chemical compound 82 in the mixture of acetonitrile-isopropyl alcohol.Obtain the iodide intermediate 83 of needs.Perhaps, can be at low temperatures, the two-step method of the THF solution by relating to n-BuLi is with 4-chloropyridine-2-aminocarbamic acid tert-butyl ester (84, CBResearch and Development Inc.) is converted into 4-chloro-3-iodo pyridine-2-aminocarbamic acid tert-butyl ester (85), adds iodine subsequently.By refluxing with aqueous solution of hydrogen bromide; remove 85 N-Boc (t-butyl carbamate) blocking group; at high temperature subsequently; in the presence of diisopropylamine (Hunig ' s alkali); in N-Methyl pyrrolidone (NMP); make chloride intermediate and 8 couplings of 4-nitrophenol derivative, can obtain iodide intermediate 86.Aforementioned similar chemistry is further handled iodide intermediate 83 and 86 in available and the flow process 11.

Flow process 15

Flow process 16

[0051] can prepare methene key according to generalized synthetic order in the flow process 17 and meet (B=CH ₂) analog 93 and 94.Can be at low temperatures; use the different cigarette aldehyde of methyl-magnesium-bromide, tert-butyl lithium and 2-chlorine (isonicotinaldehyde) (Frey successively; Tetrahedron Lett.2001 such as L F.; 42; 6815-6818) handle 4-bromine-aniline derivatives 87 derived compounds of protecting by N-Boc 88, obtain intermediate 90.With the pyridine ring of 3-chloroperoxybenzoic acid (m-CPBA) oxidation 90, use subsequently amine (R ' NH ₂) the replace chlorine substituent group, available then zinc and ammonium formate reduce the N-oxide intermediate in methanol, obtain intermediate 91.When allylamine as nucleophilic amine (R ' NH ₂) time, available rhodium catalyst is removed the pi-allyl of 91 amine in the mixed liquor of alcohol-water.Can remove 91 hydroxyl by two kinds of diverse ways.For example, hydrogenolysis chemical compound 91 in the presence of palladium catalyst, subsequently under acid condition (methanol solution of HCl), carry out on the aniline the N-Boc group go protection, can obtain chemical compound 92.Perhaps, can be by making 91 pure acidylate, subsequently in the presence of palladium catalyst,, remove the N-Boc blocking group at acid condition (dichloromethane solution of trifluoroacetic acid) hydrogenolysis intermediate down, obtain chemical compound 92.Aforementioned chemistry makes intermediate 92 acidylates among the available then flow process 1-5, obtains the chemical compound 93 and 94 that needs.

Flow process 17

R '=H, the 3-dimethylaminopropyl

[0052] can prepare heterocyclic amide derivative 100 and 105 according to synthetic route described in flow process 18 and 19.At last, can be by two-step method, so that commercially available 2-(3-methoxyl group allylidene (allylidene)) malonic acid (E)-dimethyl esters (95) (flow process 18) is a raw material, obtains 2-oxo-1-phenyl-1,2-dihydropyridine-3-methyl formate (97).Therefore at room temperature, handle chemical compound 95, can obtain intermediate 96 with aniline, then alkali for example sodium hydride in the presence of, in dimethyl sulfoxine, can make its cyclization, obtain 97.Hydrolysis intermediate 97 under alkali condition can obtain 2-oxo-1-phenyl-1,2-dihydropyridine-3-formic acid (98).Then, can coupling reagent for example 1-(dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) and hydroxybenzotriazole (HOBt) in the presence of, in DMF, make formic acid 98 and anil 99 couplings, obtain the chemical compound 100 that needs.

Flow process 18

[0053] can obtain pyridine radicals N-oxide intermediate 104 (flow process 19) by two-step method, wherein under palladium (0) catalyst and sodium carbonates' presence, make commercially available 6-bromopyridine formic acid (101) and phenyl-1,3,2-two oxa-bora cyclohexane extraction (dioxaborinane) 102 (Aldrich) couplings, at high temperature subsequently, with intermediate 103 oxidations of needs.Make intermediate 104 and anil 99 couplings, can obtain the chemical compound 105 that needs.

Flow process 19

[0054] formula I and II chemical compound can be used for treating multiple cancer, and they include but not limited to following:

(a) cancer: they comprise bladder cancer, breast carcinoma, colon cancer, renal carcinoma, hepatocarcinoma, the pulmonary carcinoma that comprises small cell lung cancer, esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, gastric cancer, cervical cancer, thyroid carcinoma, carcinoma of prostate and comprise the skin carcinoma of squamous cell carcinoma;

(b) lymphatic system hemopoietic tumor: comprise leukemia, acute lymphoblastic leukemia, acute lymphoblast leukemia, B-chronic myeloid leukemia, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell lymphoma and Burkett ' s lymphoma;

(c) myeloid lineage hemopoietic tumor: they comprise acute and chronic lymphocytic leukemia, myelodysplastic syndrome and promyelocyte leukemia;

(d) be derived from mesochymal tumor: comprise fibrosarcoma and rhabdomyosarcoma;

(e) maincenter and peripheral nervous system tumor: comprise astrocytoma, neuroblastoma, glioma and schwannoma; With

(f) other tumor: comprise melanoma, spermocytoma, lopsided tumor (teratocarcinoma), osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid carcinoma follicular carcinoma and Kaposi.

[0055] generally speaking, because the pivotal role of protein kinase in regulating cell proliferation, inhibitor can be used as the reversibility cytostatics, they can be used for treating any lysis that is characterized as abnormal cell proliferation, for example restenosis, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, endotoxin shock and the fungal infection after benign prostatic hyperplasia, familial adenomatous polyposis disease, neurofibromatosis, atherosclerosis, pnemnofibrosis, arthritis, psoriasis, glomerulonephritis, angioplasty or the vascular surgery.

[0056] can be used for treating cancer (include but not limited to above introduce those) as the formula I of apoptosis regulator and II chemical compound, viral infection (includes but not limited to herpes virus, poxvirus, Epstein-Barr virus, Xin Peisi virus (Sindbis virus) and adenovirus), the protect from infection AIDS development of individuality of HIV, autoimmune disease (includes but not limited to the general lupus, erythema (erythematosus), the glomerulonephritis of autoimmune mediation, rheumatic arthritis, psoriasis, inflammatory bowel disease and Autoimmune Diabetes), neurodegenerative disease (includes but not limited to presenile dementia, the dementia relevant with AIDS, parkinson, amyotrophic lateral sclerosis, retinitis pigmentosa, ridge amyotrophy and cerebellum degeneration), myelodysplastic syndrome, aplastic anemia, the ischemic injury relevant with myocardial infarction, apoplexy and reperfusion injury, arrhythmia, atherosclerosis, that toxin causes or relevant hepatopathy with ethanol, hematopathy (including but not limited to chronic anaemia and aplastic anemia), the degenerative disease of flesh and skeletal system (including but not limited to osteoporosis and arthritis) aspirin allergic sinusitis, cystic fibrosis, multiple sclerosis, renal carcinoma and cancer pain.

[0057] level of synthetic RNA of formula I and II chemical compound scalable cell and DNA.Therefore, these medicines can be used for treating viral infection (including but not limited to HIV, human papillomavirus, herpes virus, poxvirus, Epstein-Barr virus, Xin Peisi virus and adenovirus).

[0058] formula I and II chemical compound can be used for the chemoprophylaxis cancer.Chemoprophylaxis is defined as by retardance mutation incident and starts or develop or the inhibition tumor recurrence by cell progression inhibiting invasive carcinoma precancer that retardance has suffered damage.

[0059] formula I and II chemical compound also can be used for suppressing the tumor vessel generation and shift.

[0060] term " anticancer " medicated bag is drawn together any known drug that can be used for treating cancer, comprises bent his androsterone of the female alcohol of 17 alpha-acetylenes, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, propanoic acid, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuproside, flutamide, toremifene, Zoladex, matrix metalloprotease inhibitors of kinases; The VEGF inhibitor comprises for example for example ZD6474 and SU6668, vatalanib, BAY-43-9006, SUI 1248, CP-547632 and CEP-7055 of Avastin and micromolecule of VEGF antibody.Also can use the anti-Her2 antibody (for example trastuzumab) of Genentech.Suitable EGFR inhibitor comprises gefitinib, erlotinib and Cetuximab.Pan Her inhibitor comprises canertinib, EKB-569 and GW-572016.Also comprise Src inhibitor and Casodex ^(bicalutamide, Astra Zeneca), tamoxifen, MEK-1 inhibitors of kinases, mapk kinase inhibitor, PI3 inhibitor and PDGF inhibitor be imatinib for example.Also comprise by middle Herba Clinopodii to entity tumor, cause immobilized angiogenesis inhibitor of cancerous cell and anti-angiogenic medicine by depriving its nutrition.Also can use and also can cause relying on the castrating that androgenic cancer is not bred.Also comprise IGF1R inhibitor, non-tyrosine kinase receptor and tyrosine kinase receptor inhibitor and the agent of integrin signal suppressing.Other cancer therapy drug comprises that microtubule stablizes medicine, and for example paclitaxel (be called not only Taxol ), many Xi Tasai (but also are called Taxotere ^), 7-O-methylthiomethyl paclitaxel (is disclosed in United States Patent (USP) 5; 646; 176), 4-deacetylate-4-methyl carbonic acid paclitaxel, 3 '-tert-butyl group-3 '-N-tert-butoxycarbonyl-4-deacetylate-3 '-Tuo phenyl-3 '-N-takes off benzoyl-4-O-methoxycarbonyl-paclitaxel (be disclosed on November 14th, 2000 submitted to USSN 09/712,352), C-4 methyl carbonic acid paclitaxel, macrolide A (epothiloneA), macrolide B, macrolide C, macrolide D, deoxidation macrolide A, deoxidation macrolide B, [1S-[1R ^*, 3R ^*(E), 7R ^*, 10S ^*, 11R ^*, 12R ^*, 16S ^*]]-7-11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl) vinyl]-4-azepine-17 oxabicyclo [14.1.0] heptadecane-5,9-diketone (being disclosed in WO 99/02514), [1S-[1R ^*, 3R ^*(E), 7R ^*, 10S ^*, 11R ^*, 12R ^*, 16S ^*]]-3-[2-[2-(amino methyl)-4-thiazolyl]-the 1-methyl ethylene]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-two oxa-dicyclo [14.1.0] heptadecanes-5,9-diketone (being disclosed in USP 6,262,094) and derivant thereof; With the microtubule medicine that breaks.CDK inhibitor, antiproliferative cell cycle inhibitor, epidophyllotoxin; The antitumor enzyme; Topoisomerase enzyme inhibitor; Procarbazine; Mitoxantrone; Platinum coordination complex, for example cisplatin and carboplatin; Biological respinse modifier; Growth inhibitor; The hormone antagonist medicine; Folinic acid; Ftorafur; Also suitable with hemopoietic growth factor.

[0061] other cell toxicity medicament comprises melphalan, altretamine, Tespamin, cytarabin, idatrexate, trimetrexate, dacarbazine, altheine enzyme, camptothecine, hycamtin, bicalutamide, flutamide (flutamide), leuproside, pyrido benzindole derivant, interferon and interleukin.

[0062] Pharmaceutical composition that contains active component can be to be applicable to oral form, but for example tablet, dragee, lozenge, water or oil suspension dispersed powders or granule, emulsion, hard or soft capsule, or syrup or elixir.Can prepare composition for oral administration according to any known method for preparing Pharmaceutical composition in this area, this based composition can contain one or more and be selected from following composition: sweeting agent, correctives, coloring agent and antiseptic, and so that pleasing and good to eat pharmaceutical formulation to be provided.Tablet contains active component and is used for the nontoxic pharmaceutically acceptable excipient of blended suitable preparation tablet.These excipient can be for example inert diluent, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, corn starch or alginic acid; Binding agent, for example starch, gelatin, polyvinylpyrrolidone or arabic gum and lubricant, for example magnesium stearate, stearic acid or Pulvis Talci.These tablets unpleasant taste that coating maybe can be by not covering medicine or in gastrointestinal tract, postpone disintegrate and absorption, thereby the known technology that slow releasing function is provided in a long time is with they coatings.For example, can use water solublity taste masked material for example hydroxypropyl emthylcellulose or hydroxypropyl cellulose, or time expand material for example ethyl cellulose, acetylbutyrylcellulose.

[0063] also available wherein active component and the inert solid diluent blended hard gelatin capsule of calcium carbonate, calcium phosphate or Kaolin for example, or wherein active component and water-solubility carrier for example Polyethylene Glycol or oily solvent for example the Perle of Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil oral formulations is provided.

[0064] aqueous suspension contains active substance and the excipient that is used for blended suitable preparation aqueous suspension.This type of excipient is a suspending agent, for example sodium carboxy methyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, Tragacanth and arabic gum; Dispersant or wetting agent can be the phospholipid lecithin for example of natural generation, or the condensation product of alkylene oxide and fatty acid Myrj 45 for example, or the condensation product of oxirane and long-chain fatty alcohol, 17 carbon ethyleneoxy group spermols (heptadecaethyleneoxy) for example, or oxirane and by the condensation product of fatty acid and the deutero-part ester of hexitol, poly(ethylene oxide) sorbitol monooleate for example, or oxirane and by the condensation product of fatty acid and the deutero-partial ester of hexitan, for example poly(ethylene oxide) Arlacel-80.Aqueous suspension also can contain one or more antiseptic for example ethyl hydroxybenzoate or nipalgin n-propyl, one or more coloring agent, one or more correctivess and one or more sweeting agents, for example sucrose, glucide or aspartame.

[0065] can be suspended in vegetable oil for example Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois by making active component, or the mineral oil suspension that for example makes up oil in the liquid paraffin.Oil suspension can contain thickening agent, for example peak wax, hard paraffin or spermol.Can add sweeting agent for example above-mentioned those and correctives, so that good to eat preparation to be provided.Can for example butylated hydroxyanisole or alpha-tocopherol be preserved these compositionss by adding antioxidant.

[0066] by adding entry, is applicable to that the dispersed powders and the granule that prepare aqueous suspension provide active component and be used for blended dispersant or wetting agent, suspending agent and one or more antiseptic but can make.Suitable dispersant or wetting agent and suspending agent can provide above-mentioned those to illustrate.Also can add other excipient for example sweeting agent, correctives and coloring agent.By add antioxidant for example ascorbic acid preserve these compositionss.

[0067] Pharmaceutical composition of the present invention also can be the form of oil in water emulsion.Oil phase can be for example olive oil or an Oleum Arachidis hypogaeae semen of vegetable oil, or mineral oil for example liquid paraffin or these mixture.Examples of suitable emulsifiers can be the phospholipid of natural generation, soybean lecithin and for example by fatty acid and the deutero-ester of hexitan or the partial ester condensation product poly(ethylene oxide) Arlacel-80 for example of the smooth monoleate of Pyrusussuriensis and described partial ester and oxirane for example.Emulsion also can contain sweeting agent, correctives, antiseptic and antioxidant.

[0068] for example glycerol, propylene glycol, sorbitol or sucrose syrup blend and elixir of available sweeting agent.This type of preparation also can contain demulcent, antiseptic, coloring agent and antioxidant.

[0069] Pharmaceutical composition can be an aseptic injection aqueous solution form.In spendable acceptable solvent and solvent, water, ringer's solution and isotonic sodium chlorrde solution are arranged.

[0070] aseptic injection preparation also can be that wherein active component is dissolved in the aseptic injection water bag oil microemulsion of oil phase.For example, can active component be dissolved in the mixture of soybean oil and lecithin earlier.Then oil solution is added in the mixture of entry and glycerol, handle, form microemulsion.

[0071] can pass through local large bolus injection, injection or microemulsion are injected patient's blood flow.Perhaps, preferably give solution or microemulsion by the mode that can keep The compounds of this invention constant circulation concentration.For keeping this constant density, can use continuous intravenous drug delivery systems.The example of this device is a Deltec CADD-PLUS.TM.5400 type intravenous injection pump.

[0072] Pharmaceutical composition can be the form that is used for the aseptic injection water or the oil suspension of intramuscular and subcutaneous administration.Can be by known technology, prepare this suspension with above-mentioned those suitable dispersants or wetting agent and suspending agent.Aseptic injection preparation also can be aseptic injectable solution or the suspension for preparing in nontoxic parenteral acceptable diluent or solvent, the solution that for example prepares in 1,3 butylene glycol.In addition, can be easily with aseptic fixedly oil as solvent or suspension media.For this purpose, can use the fixing oil of any mediation that comprises synthetic glycerine list or diester.In addition, fatty acid for example oleic acid also can be used for preparing injection.

[0073] can be by suppository form giving construction I that is used for rectally and II chemical compound.Can by with medicine with under ordinary temp, be solid but under rectal temperature, be liquid, thereby can fusing in rectum and the suitable nonirritant excipient that discharges medicine mixes, prepare these compositionss.This type of material comprises the mixture of the fatty acid ester of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, various molecular weight polyethylene glycol and Polyethylene Glycol.

[0074] uses for the part, use cream, ointment, gel, solution or the suspensoid etc. that contain formula I chemical compound.(in this purposes, local use should comprise mouthwash and collutory).

[0075] can use suitable intranasal solvent and drug delivery systems or with those forms of transdermal patch well known to those skilled in the art, give the The compounds of this invention of intranasal form by transdermal route by local.For pressing the form administration of transdermal delivery system, in whole dosage regimen, give dosage and want naturally continuously but not interruption.Also can by adopt substrate for example the suppository of the mixture of the fatty acid ester of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, various molecular weight polyethylene glycol and Polyethylene Glycol send The compounds of this invention.

[0076] when giving patient's The compounds of this invention, by doctor's determination date dosage of signature prescription, dosage is decided according to age, body weight, sex and the reaction of individual patient and the seriousness of patient's symptom usually usually.

[0077] if be mixed with fixed dosage, this type of combination product is used The compounds of this invention and other medicines active component or the treatment in its approved dosage range in the above-mentioned dosage range.When combination preparation is improper, also can sequential giving construction I and II chemical compound and known anticancer or cell toxicity medicament.The invention is not restricted to this order of administration; Can be before or after giving known anticancer or cell toxicity medicament giving construction I and II chemical compound.

Measure

[0078] can measure the pharmacological properties of verifying The compounds of this invention by multiple pharmacology.Carrying out following illustrational pharmacology with The compounds of this invention and salt thereof measures.

The Met kinase assays

Reagent	The substrate mixture final concentration
Reagent	The substrate mixture final concentration	Storing solution
Tris-HCl，(1M，pH 7.4)	20mM	Storing solution
Tris-HCl，(1M，pH 7.4)	20mM	MnCl ₂(1M)	1mM
DTT(1M)	1mM	MnCl ₂(1M)	1mM
DTT(1M)	1mM	BSA(100mg/ml)	0.1mg/ml
Poly-Glu ₄/tyr(10mg/ml)	0.1mg/ml	BSA(100mg/ml)	0.1mg/ml
Poly-Glu ₄/tyr(10mg/ml)	0.1mg/ml	ATP(1mM)	1μM
γ-ATP(10μCi/μl)	0.2μCi/μl	ATP(1mM)	1μM

Buffer	Enzymatic mixture
Buffer	Enzymatic mixture	20μl1M DTT	4 μ lGST/Met enzyme (3.2mg/ml)=10ng/rxn
200μl1M Tris-HCl，pH7.4	Qs 12ml buffer	20μl1M DTT	4 μ lGST/Met enzyme (3.2mg/ml)=10ng/rxn
200μl1M Tris-HCl，pH7.4	Qs 12ml buffer	20μl100mg/mlBSA
Add H ₂O to 20ml		20μl100mg/mlBSA

[0079] the incubation mixture that is used for the Met kinase assays contains the poly-Glu:Tyr of synthetic substrate, and (4: 1), ATP, ATP-γ- ³³P and contain Mn ⁺⁺And/or Mg ⁺⁺, DTT, the buffer of BSA and Tris buffer.With reactant 27 ℃ of following incubations 60 minutes, by adding cold trifluoroacetic acid (TCA) to final concentration 4% cessation reaction.With the general harvesting device of Filtermate (Packard InstrumentCo., Meriden, CT), at GF/Cunifilter plate (Packard Instrument Co., Meriden CT) goes up collection TCA precipitation, with TopCount 96 hole liquid scintillation counter (PackardInstrument Co., Meriden, CT) quantitative filter.The preparation dose-effect curve is measured and is suppressed 50% kinase activity desired concn (IC ₅₀).Chemical compound is dissolved in dimethyl sulfoxine (DMSO) with 10mM, estimates under 6 kinds of concentration, every kind of concentration is by quadruplicate operation.The DMSO final concentration of measuring is 1%.By nonlinear regression analysis derivation IC ₅₀Value, (SD/ is average, n=6)=16% for the coefficient of variation.

[0080] preferred The compounds of this invention suppresses the kinase whose IC of Met ₅₀Value is 0.01-100 μ M.The IC of most preferred ₅₀Value is less than 0.5 μ M.

[0081] another subject content of the present invention also comprises the medicine with such use, these purposes comprise control cancer, inflammation and arthritis, and these medicines contain acceptable acid-addition salts at least a above formula I that defines and II chemical compound or its at least a pharmacology; And have the active medicine of anti-aforementioned proliferative disease that comprises anticancer, antiinflammatory and/or arthritis with the formula I of above definition and II compound.

[0082] following examples and preparation are set forth preparation and are used mode of the present invention and method, are illustrative rather than definitive thereof the present invention.Should be understood that other embodiment in the spirit and scope of the invention that may exist in the definition of this paper claims.

Embodiment

[0083] now further set forth the present invention by following work embodiment, they are preferred embodiment of the present invention.Institute responds all under successive magnetic stirs, and carries out under drying nitrogen or argon gas atmosphere.All evapn and concentrated all the decompression on Rotary Evaporators are carried out.The commercial reagent that receives is without being further purified direct use.Solvent is commercially available anhydrous level, without further drying or purification directly use.(EMerck Kieselgel 60 0.040-0.060mm) carries out flash chromatography with silica gel.

[0084] carries out analytical type anti-phase (RP) HPLC with Phenomenex Luna C18S54.6mm * 50mm post or YMCS5ODS4.6 * 50mm post.Under each situation, use 4min linear gradient (from 100%A:%0B to 0%A:100%B), use following flow phase system: A=90%H ₂O/MeOH+0.2%H ₃PO ₄B=90%MeOH/H ₂O+0.2%H ₃PO ₄, flow velocity=4mL/min detects wavelength 220nm.

[0085] is prepared type anti-phase (RP) HPLC with linear gradient elution liquid, use 10% methanol, 90% water, 0.1%TFA (solvent orange 2 A) and 90% methanol, 10% water, 0.1%TFA (solvent B) eluting detects wavelength 220nm, use one of colonnade down: A-Shimadzu S5ODS-VP 20 * 100mm post, flow velocity 20mL/min; B-YMC S5ODS 30 * 100mm post, flow velocity 20mL/min; C-Phenomonex 30 * 250mm post, flow velocity 10mL/min; D-YMC S5ODS 20 * 250mm post, flow velocity 10mL/min; E-YMC S10ODS50 * 500mm post, flow velocity 50mL/min; Or F-YMC S10ODS 30 * 500mm post, flow velocity 20mL/min.

[0086] all end-products all pass through ¹HNMR, RPHPLC, electro-spray ionization (ESIMS) or atmospheric pressure ionization (APIMS) mass spectral characteristi.On 500MHzJEOL or 400MHzBruker instrument, obtain ¹The HNMR spectrum.100 or 125MHz under record ¹³The CNMR spectrum.Field intensity with respect to the δ unit of solvent peak (per hundred is several very much, ppm) expression, multiplicity regulation in peak is as follows: s, unimodal; D, bimodal; Dd, doublet of doublet; Dm, multiple bimodal; T, triplet; Q, quartet; Br s, wide unimodal; M, multiplet.

[0087] following abbreviation is used to represent common agents: Boc or BOC: t-butyl carbamate; Fmoc:9H-fluorenyl methyl carbamate; TEA: triethylamine; The NMM:N-methyl morpholine; Ms: mesyl; DIEA or DIPEA: diisopropylethylamine or Hunig ' s alkali; The NMP:N-methyl pyrrolidone; Bop reagent: benzotriazole-1-base oxygen base three (trimethyl amino) phosphorus  hexafluorophosphate; DCC:1, the 3-dicyclohexylcarbodiimide; EDCI:1-(dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; RT or rt: room temperature; t _R: retention time; H: hour; Min: minute; PyBroP: bromine tripyrrole alkyl phosphorus  hexafluorophosphate; TBTU:O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethylurea  tetrafluoroborate; DMAP:4-N, the N-dimethyl aminopyridine; HOBt or HOBT: hydroxybenzotriazole; Na (OAc) ₃BH: triacetic acid base sodium borohydride; HOAc: acetic acid; TFA: trifluoroacetic acid; LiHMDS: two (trimethyl silyl) lithium amide; DMSO: dimethyl sulfoxine; MeCN: acetonitrile; MeOH: methanol; EtOAc: ethyl acetate; DMF: dimethyl formamide; THF: oxolane; DCE:1, the 2-dichloroethanes; Et ₂O: ether; DCM: dichloromethane; The m-CPBA:4-chloroperoxybenzoic acid.

Embodiment 1

N-(4-fluorophenyl)-N-(4-(pyridin-4-yl oxygen base) phenyl) Malondiamide

A) 4-(4-amino-benzene oxygen) pyridine

[0088] (20.0mmol) (2.0g, (dimethyl sulfoxine 20.0mmol) (40mL) solution heats 18h with mixture down at 100 ℃ for Aldrich, 3.0g 50.0mmol) to handle 4-chloropyridine hydrochlorate with the sodium hydride pearl for Aldrich, 2.1g with the 4-amino-phenol.Mixture is cooled to room temperature, in impouring ice-water (300g) mixture, uses Et ₂O (3 * 150mL) extractions.With the extract that the salt water washing merges, dry (MgSO ₄), concentrate, obtain 4-(4-amino-benzene oxygen) aniline, be light yellow solid (3.5g, 94%).

¹HNMR(DMS0-d ₆)δ8.38(dd，2H，J＝5.5，1.5Hz)，6.83-6.79(m，4H)，6.63-6.59(m，2H)，5.13(br s，2H)；MS(ESI ⁺)m/z 187.2(M+H) ⁺.

B) 3-(4-fluorophenyl amino)-3-oxo propanoic acid

[0089] under 0 ℃, to 3-chloro-3-oxo ethyl propionate (Aldrich, 5.0mL, add in dichloromethane 40mmol) (100mL) solution diisopropylethylamine (8.4mL, 48mmol), add subsequently the 4-fluoroaniline (Aldrich, 3.6mL, 38mmol).Reactant mixture at room temperature stirred spend the night, use the saturated NaHCO of 100mL then ₃The solution quencher.With chloroform (3 * 100mL) aqueous layer extracted.The organic extract liquid that merges is through anhydrous Na ₂SO ₄Drying, vacuum concentration obtains crude product, is yellow oil, leaves standstill after fixing (10g).

¹H NMR(CDCl ₃)δ9.30(br s，1H，7.55(m，2H)，7.05(t，2H，J＝8.8Hz) 4.28(q，2H，J＝7.2Hz)，3.49(s，2H)，1.35(t，3H，J＝7.1Hz)；MS(ESI ⁺)m/z226.11(M+H) ⁺.

[0090] above ester is dissolved in 100mL ethanol, is cooled to 0 ℃.Add 1N NaOH aqueous solution (100mL), reactant is stirred 1h down at 0 ℃.With the reactant vacuum concentration, remove ethanol.With EtOAc (50mL) extraction water solution, make acidity with 1N HCl aqueous solution then.With EtOAc (5 * 100mL) extraction water solution.The organic extract liquid that merges is through anhydrous Na ₂SO ₄Drying, vacuum concentration obtains crude product, is yellow solid (6.31g, 84%), need not repurity during use.

¹H NMR(DMS0-d ₆)δ12.9(brs，1H)，10.3(brs，1H)，7.59(m，2H)，7.16(t，2H，J＝8.9Hz)，3.34(s，2H)；MS(ESI ⁺)m/z 198.43(M+H) ⁺.

C) N-(4-fluorophenyl)-N-(4-(pyridin-4-yl oxygen base) phenyl) Malondiamide

[0091] with 3-(4-fluorophenyl amino)-3-oxo propanoic acid (99mg, 0.50mmol), DIPEA (113 μ L, 0.65mmol) and TBTU (209mg 0.65mmol) handles 4-(4-amino-benzene oxygen) pyridine (93mg, 0.50mmol) DMF solution, mixture is at room temperature stirred 2h.Enriched mixture is removed DMF, and residue is distributed between EtOAc and saturated sodium bicarbonate solution.EtOAc is used saturated sodium bicarbonate solution, salt water washing mutually, dry (MgSO ₄), concentrate, obtain title compound, be canescence foam (140mg, 76%).

¹H NMR(DMSO-d ₆)δ10.30(s，1H)，10.24(s，1H)，8.43(dd，2H，J＝5.5，1.5Hz)，7.70(d，2H，J＝9.1Hz)，7.63-7.60(m，2H)，7.17-7.14(m，4H)，6.89(dd，2H，J＝5.5，1.5Hz)，3.46(s，2H)；MS(ESI ⁺)m/z365.9(M+H) ⁺.

Embodiment 2

1-(4-(6-chloropyrimide-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) thiourea

A) 4-chloro-6-(2-fluoro-4-nitrophenoxy) pyrimidine

[0092] with potassium carbonate (0.72g 5.2mmol) handles 4, the 6-dichloro pyrimidine (Aldrich, 0.74g, 5.0mmol), (Aldrich, 0.79g 5.0mmol) and the mixture of DMF (10ml), heat 3h down at 80 ℃ to 2-fluoro-4-nitrophenol.With the mixture cooling, dilute with water is used ethyl acetate extraction.With salt water washing acetic acid ethyl acetate extract, dry (MgSO ₄), concentrate, obtain crude product, be yellow solid.Grind crude product with isopropyl ether, obtain 4-chloro-6-(2-fluoro-4-nitrophenoxy) pyrimidine, be yellow solid (1.3g, 94%).

¹H NMR(DMSO-d ₆)δ8.80(s，1H)，8.51(dd，1H，J＝8.6，2.5Hz)，8.31(d，1H，J＝9.1Hz)，7.87(d，1H，J＝9.1Hz)，7.84(s，1H).

B) 4-chloro-6-(2-amino-2-fluorophenoxy) pyrimidine

[0093] with Raney nickel (1.5g, water slurry) handle 4-chloro-6-(2-fluoro-4-nitrophenoxy) pyrimidine (1.3g, methanol 4.8mmol) (120mL) solution, under hydrogen (being provided by latex balloon) covers, at room temperature, stirred reaction mixture 3h.The elimination catalyst, concentrated filtrate makes residue at CH ₂Cl ₂And distribute between the water.The separate dichloromethane phase, dry (MgSO ₄), concentrate.Crude product is used 1-2%MeOH/CH through the flash chromatography on silica gel purification ₂Cl ₂Make eluent, obtain 4-chloro-6-(2-amino-2-fluorophenoxy) pyrimidine, be white solid (600mg, 52%).

¹HNMR(DMSO-d ₆)δ8.64(s，1H)，7.39(s，1H)，6.97(dd，1H，J＝8.8，8.8Hz)，6.46(dd，1H，J＝13.1，2.5Hz)，6.33(dd，1H，J＝8.6，2.5Hz)，5.44(br s，2H)；MS(ESI ⁺)m/z240.04(M+H) ⁺.

C) 1-(4-(6-chloropyrimide-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) thiourea

[0094] ((0.27g 3.3mmol) and in the mixture of EtOAc (12mL), at room temperature stirs 30min with the mixture that obtains 3.0mmol) to add NaSCN for Lancaster, 0.52g with 4-fluorophenyl chloroacetic chloride.1: 1 the EtOAc/CH that this mixture is added 4-chloro-6-(2-amino-2-fluorophenoxy) pyrimidine ₂Cl ₂(5ml) in the solution, the mixture that obtains at room temperature stirred spend the night.Enriched mixture, with residue at EtOAc/H ₂Distribute between the O.Separate the EtOAc phase, use the salt water washing, dry (MgSO ₄) and concentrate.Product is made eluent through the flash chromatography purification with the 10-35%EtOAc/ hexane, obtains title compound, is yellow crystal solid (0.85g, 65%).

¹H NMR(DMSO-d ₆)δ12.40(s，1H)，11.81(s，1H)，8.67(s，1H)，7.90(dd，1H，J＝12.1，2.0Hz)，7.62(s，1H)，7.47-7.41(m，2H)，7.38-7.35(m，2H)，7.17(t，2H，J＝8.8Hz)，3.81(s，2H)；MS(ESI ⁺)m/z434.98(M+H) ⁺.

Embodiment 3

1-(2-(4-fluorophenyl) acetyl group)-3-(4-(pyridin-4-yl oxygen base) phenyl) thiourea

[0095] prepares title compound with 4-(4-amino-benzene oxygen) pyridine (compd A of embodiment 1) with Compound C similar methods described in the preparation embodiment 2.Yield: 10%.

¹H NMR(CDCI ₃)δ12.3(s，1H)，8.63(s，1H)，8.49，(d，2H，J＝6.2Hz)，7.71(d，2H，J＝8.9Hz)，7.31-7.27(m，2H)，7.14-7.09(m，4H)，6.90(dd，2H，J＝4.8，1.4Hz)，3.73(s，2H)；MS(ESI ⁺)m/z 382.2(M+H) ⁺.

Embodiment 4

N ¹-(4-(6-chloropyrimide-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

[0096] with DIPEA (24 μ l, 0.14mmol) and TBTU (46mg, 0.14mmol) processing 4-chloro-6-(2-amino-2-fluorophenoxy) pyrimidine (29mg, 0.12mmol, the compd B of embodiment 2), 3-(4-fluorophenyl amino)-3-oxo propanoic acid (26mg, 0.13mmol, the compd B of embodiment 1) DMF (1.5mL) solution.Reactant mixture at room temperature stirred spend the night, with EtOAc (25mL) dilution, with saline (3 * 20mL) washing organic faciess, dry (MgSO ₄), concentrate.Product is used 1-3%MeOH/CH through the flash chromatography purification ₂Cl ₂Make eluent, obtain title compound, be white solid (35mg, 78%).

¹H NMR(DMSO-d ₆)δ10.49(s，1H)，10.25(s，1H)，8.65(s,1H)，7.78(d，1H，J＝12.1Hz)，7.63-7.57(m，3H)，7.40-7.34(m，2H)，7.16(t，2H，J＝8.8Hz)，3.48(s，2H)；MS(ESI ⁺)m/z419.21(M+H) ⁺.

Embodiment 5

N ¹-(3-fluoro-4-(6-(methylamino) pyrimidine-4-base oxygen base) phenyl)-N ³(4-fluorophenyl) Malondiamide

[0097] handles N with 2M methylamine/THF (0.2mL) ¹-(4-(6-chloropyrimide-4-base oxygen base)-3-fluorophenyl)-N ³N-BuOH (3mL) solution of-(4-fluorophenyl) Malondiamide (embodiment 4 for 100mg, 0.42mmol) with bottle cap screwing, heats 12h down at 80 ℃.Mixture is concentrated, and residue uses the MeOH-H that contains 0.1%TFA through the preparation HPLC purification ₂O gradient liquid.To contain the flow point lyophilizing of product, obtain title compound, be light yellow solid (60mg, 34%).

¹H NMR(DMSO-d ₆)δ10.58(s，1H)，10.36(br s，2H)，8.19(br s，1H)，7.76(d，1H，J＝12.1Hz)，7.64-7.62(m，2H)，7.36-7.27(m，2H)，7.15(dd，2H，J＝8.8，8.8Hz)，5.95(br s，1H)，3.49(s，2H)，2.80(s，3H)；MS(ESI ⁺)m/z414.16(M+H) ⁺.

Embodiment 6

6-(2-fluoro-4-(3-(4-fluorophenyl the amino)-3-oxo propionamido) phenoxy group) pyrimidine-4-aminocarbamic acid tert-butyl ester

A) N-(2,4,6-trimethoxy benzyl)-6-chloropyrimide-4-amine

[0098] under 100 ℃, with 4, the 6-dichloro pyrimidine (Aldrich, 1.48g, 10.0mmol), 2,4,6-trimethoxy benzylamine hydrochloride (2.33g, 10.0mmol), DIPEA (4.8mL, 27.7mmol) and the mixture heated 2h of n-BuOH (50mL).With the mixture cooling, water (200mL) dilution, vacuum filtration on buchner funnel, collecting precipitation product.Product washs with cold water, ether, and vacuum drying obtains pale solid (2.8g, 90%).

¹H NMR(DMSO-d ₆)δ8.28(s，1H)，7.38(s，1H)，6.49(s，1H)，6.25(s，2H)，4.34(s，2H)，3.77(s，9H).

B) 6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-amine

[0099] (1.1g, 7.0mmol) mixture with 2-methoxy ethyl ether (50mL) heats 60h down at 160 ℃ with N-(2,4,6-trimethoxy benzyl)-6-chloropyrimide-4-amine (2.2g7.11mmol), 2-fluoro-4-nitrophenol.Reactant mixture is cooled to room temperature, impouring H ₂Among the O (200mL).Collect solid, use 2M Na ₂CO ₃Aqueous solution and H ₂O washing, vacuum drying on buchner funnel then.Two  alkane (40mL) solution-treated crude products with TFA (20mL) at room temperature stir 4h.Concentrated reaction mixture makes residue at EtOAc and saturated NaHCO ₃Distribute between the solution.Separate the EtOAc phase, dry (MgSO ₄), concentrating, crude product is used 1-2%MeOH/CH through the flash chromatography purification ₂Cl ₂Make eluent, obtain 6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-amine (440mg, 31%).

¹H NMR(DMSO-d ₆)δ8.31(dd，1H，J＝10.4，2.5Hz)，8.14(dd，1H，J＝9.8，2.0Hz)，8.04(s，1H)，7.61(dd，1H，J＝8.3，8.3Hz)，7.07(s，2H)，6.02(s，1H)；MS(ESI ⁺)m/z251.15(M+H) ⁺.

C) 6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-aminocarbamic acid tert-butyl ester

[00100] with 6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-amine (439mg, 1.2mmol), BOC ₂(261mg, 1.2mmol), the mixture of DMAP (10mg) and THF (10mL) at room temperature stirs 1h, vacuum concentration obtains crude product to O then.Product is used 1-2%MeOH/CH through the flash chromatography purification ₂Cl ₂Make eluent, obtain 6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-aminocarbamic acid tert-butyl ester, be white solid (110mg, 26%).

¹H NMR(DMSO-d ₆)δ10.59(s，1H)，8.39(dd，1H，J＝8.8，1.1Hz)，8.32(dd，1H，J＝10.3，2.4Hz)，8.15(ddd，1H，J＝9.1，2.5，1.0Hz，7.67(dd，1H，J＝8.8，8.8Hz)，7.45(s，1H)，1.44(s，9H)；MS(ESR-)m/z349.08(M-H).

D) 6-(4-amino-2-fluorophenoxy) pyrimidine-4-aminocarbamic acid tert-butyl ester

[00101] uses PtO ₂(11mg, MeOH 0.031mmol) (2mL) solution under hydrogen (being provided by latex balloon) covers, stir 2h with reactant mixture to handle 6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-aminocarbamic acid tert-butyl ester.The elimination catalyst, concentrated filtrate obtains 6-(4-amino-2-fluorophenoxy) pyrimidine-4-aminocarbamic acid tert-butyl ester (8mg, 81%).

¹H NMR(DMSO-d ₆)δ10.62(s，1H)，8.43(d，1H，J＝2.5Hz)，8.36(dd，1H，J＝9.8，2.5Hz)，8.36(dd，1H，J＝9.8，2.5Hz)，8.20-8.17(m，1H)，7.71(dd，1H，J＝8.8，8.8Hz)，7.49(s，1H)，1.48(s，9H).

E) 6-(2-fluoro-4-(3-(4-fluorophenyl the amino)-3-oxo propionamido) phenoxy group) pyrimidine-4-aminocarbamic acid tert-butyl ester

[00102] uses and the Compound C of preparation described in the embodiment 1 similar methods, by 6-(4-amino-2-fluorophenoxy) pyrimidine-4-aminocarbamic acid tert-butyl ester (8mg, 0.025mmol) and (4-fluorophenyl amino)-3-oxo propanoic acid (6mg, 0.031mmol, compd B among the embodiment 1), TBTU (11mg, 0.034mmol) and DIPEA (6 μ L, 0.030mmol) preparation title compound.Use 1-1.5%MeOH/CH ₂Cl ₂Make eluent, carry out flash chromatography, obtain title compound, be white solid (10mg, 80%).

¹H NMR(DMSO-d ₆)δ10.48(s，1H)，10.46(s，1H)，10.25(s，1H)，8.39(s，1H)，7.74-7.77(m，1H)， 7.62(d，1H，J＝5.5Hz)，7.61(d，1H，J＝4.9Hz)，7.36-7.30(m，2H)，7.1％7.13(m，2H)，3.48(s，2H)，1.46(s，9H)；MS(ESI ⁺)m/z500.12(M+H) ⁺.

Embodiment 7

6-(2-fluoro-4-(3-(4-fluorophenyl amino)-3-oxo propionamido) phenoxy group) pyrimidine-4-base (methyl) t-butyl carbamate

A) 6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-base (methyl) t-butyl carbamate

[00103] with 6-(the 2-fluoro-4-nitrophenoxy) pyrimidine-4-aminocarbamic acid tert-butyl ester (Compound C among the embodiment 6,44mg, dry DMF 0.13mmol) (1mL) solution cools off in ice bath, with 60%NaH (44mg, 0.16mmol) handle, under uniform temp, stirred 30 minutes.(10 μ L, 0.15mmol) reaction mixture stir 10min down at 0-5 ℃ with methyl iodide.Allow reactant mixture be warming up to room temperature, stir 30min.Use H ₂O (10mL) diluted mixture thing is with EtOAc (2 * 10mL) extractions.With the extract drying (MgSO that merges ₄), vacuum concentration obtains product (35mg, 74%), is light yellow solid.

¹H NMR(DMSO-d ₆)δ8.57(d，1H，J＝1.1Hz)，8.37(dd，1H，J＝9.8，3.0Hz)，8.19(ddd，1H，J＝9.1，2.5，1.0Hz)，7.71(dd，1H，J＝8.8，8.8Hz)，7.66(s，1H)，3.38(s，3H)，1.51(s，9H).

B) 6-(4-amino-2-fluorophenoxy) pyrimidine-4-base (methyl) t-butyl carbamate

[00104] uses PtO ₂(10mg) handle the mixture of the EtOH/MeOH (2mL) of 6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-base (methyl) t-butyl carbamate and 1: 1, at H ₂(being provided by latex balloon) covers down, and reactant mixture is stirred 2h.Filter reaction mixture concentrates, and obtains the product (30mg, 75%) of needs, is the light brown solid.MS(ESI ⁺)m/z 365.13(M+H) ⁺。

C) 6-(2-fluoro-4-(3-(4-fluorophenyl amino)-3-oxo propionamido) phenoxy group) pyrimidine-4-base (methyl) t-butyl carbamate

[00105] uses and similarity method described in the Compound C for preparing embodiment 2, by 6-(4-amino-2-fluorophenoxy) pyrimidine-4-base (methyl) t-butyl carbamate (30mg, 0.068mmol), 4-fluorophenyl chloroacetic chloride (Lancaster, 15mg, 0.088mmol) and NaSCN (9mg, EtOAc/CH 0.11mmol) ₂Cl ₂The formulations prepared from solutions title compound.Make eluent with the 1-40%EtOAc/ hexane, carry out SiO ₂Flash chromatography obtains title compound (30mg, 83%), is white solid.

¹HNMR(DMSO-d ₆)δ12.40(s，1H)，11.79(s，1H)，8.55(s，1H)，7.86(dd，1H，J＝12.1，2.5Hz)，7.54(d，1H，J＝1.1Hz)，7.45-7.35(m，4H)，7.20-7.14(ddd，2H，J＝8.8，8.8，2.1Hz)，3.81(s，2H)，3.36(s，3H)，1.49(s，9H)；MS(ESI ⁺)m/z 530.09(M+H) ⁺.

Embodiment 8

1-(3-fluoro-4-(6-(methylamino) pyrimidine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) thiourea

[00106] with 1 of 4M HCl, 4-two  alkane (3mL) solution-treated 6-(2-fluoro-4-(3-(4-fluorophenyl amino)-3-oxo propionamido) phenoxy group) pyrimidine-4-base (methyl) t-butyl carbamate (embodiment 7,25mg, 0.047mmol), at room temperature stir 4h, vacuum concentration.With residue at saturated NaHCO ₃Distribute between aqueous solution and the EtOAc.Separate the EtOAc phase, dry (MgSO ₄), vacuum concentration.Use 1%MeOH/CH ₂Cl ₂Make eluent, carry out SiO ₂Flash chromatography obtains title compound (10mg, 50%), is white solid.

¹H NMR(DMSO-d ₆)δ12.37(s，1H)，11.77(s，1H)，8.09(s，1H)，7.82(d，1H，J＝11.6Hz)，7.41-7.35(m，5H)，7.32-7.28(m，1H)，7.19-7.14(m，2H)，3.81(s，2H)，2.78(s，3H)；MS(ESI ⁺)m/z430.07(M+H) ⁺.

Embodiment 9

1-(4-(6-aminopyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) thiourea

A) 6-(N, N-two tert-butoxycarbonyls) amino-4-(2-fluoro-4-nitrophenoxy) pyrimidine

[00107] with 6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-amine (compd B among the embodiment 6,150mg, 0.60mmol), BOC ₂O (275mg, 1.26mmol), the mixture of DMAP (5mg) and THF (20mL) at room temperature stirs 2.5h.The vacuum concentration reactant mixture obtains crude product.Make eluent with the 5-15%EtOAc/ hexane, at SiO ₂On carry out flash chromatography, obtain title compound (180mg, 67%), be white solid.

¹H NMR(DMSO-d ₆)δ8.62(d，1H，J＝1.0Hz)，8.42-8.39(m，1H)，8.21(ddd，1H，J＝9.1，2.5，1.0Hz)，7.77(dd，1H，J＝8.8，8.8Hz)，7.49(d，1H，J＝1.1Hz)，1.49(s，18H)；MS(ESI ⁺)m/z 451.12(M+H) ⁺.

B) 6-(N, N-two tert-butoxycarbonyls) amino-4-(4-amino-2-fluorophenoxy) pyrimidine

[00108] uses PtO ₂(175mg, the 0.38mmol) mixture in toluene (5mL) and MeOH (3mL) is at H (35mg) to handle 6-(N, N-two tert-butoxycarbonyls) amino-4-(2-fluoro-4-nitrophenoxy) pyrimidine ₂(being provided by latex balloon) covers down, and reactant mixture is stirred 15h.Filtration catalizer, vacuum concentrated filtrate makes residue at SiO ₂Go up through the flash chromatography purification, use 1-10%MeOH/CH ₂Cl ₂Make eluent, obtain product (110mg, 68%), be white solid.

¹H NMR(DMSO-d ₆)δ8.56(s，1H)，7.17(s，1H)，6.97(dd，1H，J＝8.8，8.8Hz)，6.46(dd，1H，J＝12.6，2.5Hz)，6.38(dd，1H，J＝8.8，2.5Hz)，5.40(s，2H)，1.89(s，18H).

C) 1-(4-(N, N-two tert-butoxycarbonyl 6-aminopyrimidines-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) thiourea

[00109] uses and similarity method described in the Compound C for preparing embodiment 2, by 6-(N, N-two tert-butoxycarbonyls) amino-4-(4-amino-2-fluorophenoxy) pyrimidine (20mg, 0.048mmol), 4-fluorophenyl chloroacetic chloride (Lancaster, 10mg, 0.062mmol) and NaSCN (95mg, EtOAc/CH 0.062mmol) ₂Cl ₂The formulations prepared from solutions title compound.Carry out SiO ₂Flash chromatography is made eluent with the 10-20%EtOAc/ hexane, obtains title compound (23mg, 77%), is white solid.

¹H NMR(DMSO-d ₆)δ12.40(s，1H)，11.79(s，1H)，8.59(s，1H)7.88(dd，1H，J＝12.5，1.8Hz)，7.46-7.41(m，2H)，7.38-7.35(m，3H)，7.17(dd，2H，J＝8.8，8.8Hz)，3.81(s，2H)，1.47(s，18H)；MS(ESI ⁺)m/z 616.12(M+H) ⁺.

D) 1-(4-(6-aminopyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) thiourea

[00110] with 1-(4-N; N-di-t-butyl carbonyl 6-aminopyrimidine-4-base oxygen base)-the 3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) thiourea (18mg; 0029mmol) at room temperature stir 18h, concentrate then, obtain crude product with the mixture of 4M HCl in two  alkane (1.5mL).With crude product at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.Separate the EtOAc phase, dry (MgSO ₄), vacuum concentration makes residue at SiO ₂Go up through the flash chromatography purification, use 1-2%MeOH/CH ₂Cl ₂Eluting obtains title compound (12mg, 99%), is white solid.

¹H NMR(DMSO-d ₆)δ12.38(s，1H)，11.77(s，1H)，8.05(s，1H)，7.83(dd，1H，J＝12.3，1.8Hz)，7.41-7.35(m，3H)，7.31(dd，2H，J＝8.8，8.8Hz)，7.17(t，1H，J＝8.8Hz)7.02(s，2H)，5.89(s，1H)，3.81(s，2H)；MS(ESI ⁺)m/z 416.06(M+H) ⁺.

Embodiment 10

N ¹-1-(4-(6-aminopyrimidine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

A) N ¹-(4-(N, N-di-t-butyl carbonyl 6-aminopyrimidine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

[00111] with the method described in the Compound C that is similar to preparation embodiment 1, by 6-(N, N-two tert-butoxycarbonyls) amino-4-(4-amino-2-fluorophenoxy) pyrimidine (compd B among the embodiment 9,20mg, 0.048mmol), 3-(4-fluorophenyl the amino)-3-oxo propanoic acid (compd B among the embodiment 1,14mg, 0.072mmol), (12 μ L, 0.069mmol) mixture in DMF prepares title compound to DIPEA.Carry out SiO ₂Flash chromatography is made eluent with the 15-50%EtOAc/ hexane, obtains title compound (23mg, 80%), is white solid.

¹H NMR(DMSO-d ₆)δ10.47(s，1H)，10.24(s，1H)，8.58(d，1H，J＝1Hz)，7.77(dd，1H，J＝12.9，1.8Hz)，7.63-7.60(m，2H)，7.37-7.36(m，2H)，7.32(s，1H)，7.15(t，2H，J＝8.8Hz)，1.47(s，18H)；MS(ESI ⁺)m/z 600.17(M+H) ⁺.

B) N ¹-(4-(6-aminopyrimidine-4-base oxygen base)-3-fluorophenyl) N ³-(4-fluorophenyl) Malondiamide

[00112] with the method described in the Compound D that is similar to preparation embodiment 9, by N-1-(4-(N, N-di-t-butyl carbonyl 6-aminopyrimidine-4-base oxygen base)-the 3-fluorophenyl)-N-3-(4-fluorophenyl) Malondiamide (20mg, 0.032mmol) the preparation title compound, obtain title compound (13mg, 98%), is white solid.

¹H NMR(DMSO-d ₆)δ10.42(s，1H)，10.24(s，1H)，8.03(s，1H)，7.73(d，1H，J＝11.0Hz)，7.61(dd，2H，J＝9.2，4.9Hz)，7.33-7.30(m，1H)，7.28-7.23(m，1H)，7.18-7.13(m，2H)，6.89(s，2H)，5.80(s，1H)，3.47(s，2H)；MS(ESI ⁺)m/z 400.09(M+H) ⁺.

Embodiment 11

1-(4-(6-(4-methoxy-benzyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) N-(4-methoxy-benzyl)-6-chloropyrimide-4-amine

[00113] with 4, the 6-dichloro pyrimidine (Aldrich, 3.6g, 24.2mmol), the 4-methoxybenzylamine (2.7g, 19.7mmol), DIPEA (5ml, 28.8mmol) and the mixture reflux 3h of n-BuOH.Enriched mixture is used H ₂O (150mL) and EtOAc (175mL) handle residue.Separate the EtOAc phase, use saturated NaHCO ₃Aqueous solution and salt water washing, dry (MgSO ₄), concentrate, obtain title compound (4.5g), need not be further purified during use.

¹H NMR(DMSO-d ₆)δ8.29(s，1H)，8.13(brs，1H)，7.25(d，2H，J＝8.2Hz)，6.90(d，2H，J＝8.2Hz)，6.56(s，1H)，4.48(s，2H)，3.75(s，3H).

B) N-(4-methoxy-benzyl)-6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-amine

[00114] in the sealing load bottle, with N-(4-methoxy-benzyl)-6-chloropyrimide-4-amine (2.3g, 9.2mmol), 2-fluoro-4-nitrophenol (1.45g, 9.2mmol), the mixture of DIPEA (15mL) and 2-methoxy ethyl ether (75mL) is at 160 ℃ of heating 50h down.With the mixture cooling, in the impouring trash ice (200g), handle with EtOAc (200mL).Behind the vigorous stirring 10min, the filtering insoluble substance.EtOAc uses saturated Na mutually ₂CO ₃Aqueous solution (100mL), saline (3 * 100mL) washings, dry (MgSO ₄), vacuum concentration.Grind the viscous solid that obtains with diisopropyl ether, obtain title compound (1.75g, 76%), be brown solid.

¹H NMR(DMSO-d ₆)δ8.32(dd，1H，J＝10.2，2.0Hz)，8.15(d，2H，J＝9.2Hz)，8.05(brs，1H)，7.61(dd，1H，J＝8.4，8.4Hz)，7.26(d，2H，J＝8.5Hz)，6.91(d，2H，J＝8.5Hz)，6.14(brs，1H) 4.48(brs，2H)，3.74(s，3H).

C) N-(4-methoxy-benzyl)-6-(4-amino-2-fluorophenoxy) pyrimidine-4-amine

[00115] with ammonium chloride (0.22g, 4.1mmol) and (＜20 microns of zinc powders, 0.27g, 4.2mmol) handle N-(4-methoxy-benzyl)-6-(2-fluoro-4-nitrophenoxy) pyrimidine-4-amine (150mg, 1: 1 MeOH/THF (20mL) solution 0.41mmol).Reactant mixture is at room temperature stirred 1h.Another part zinc powder (150mg) is added mixture, reactant mixture is at room temperature stirred 1h, heat 20min down at 70 ℃.Filtering mixt is removed inoganic solids, and vacuum concentration distributes residue between EtOAc and saline.Separate the EtOAc phase, use the salt water washing, dry (MgSO ₄), vacuum concentration obtains title compound (145mg, 99%).

¹H NMR(DMSO-d ₆)δ8.10(brs，1H)，7.76(br s，1H)，7.21(d，2H，J＝8.6Hz)，6.88(d，3H，J＝8.6Hz)，6.44(dd，1H，J＝-12.7，2.0Hz)，6.36(dd，1H，J＝8.3，2.3Hz)，5.79(s，1H)，4.41(brs，2H)，3.73(s，3H)；MS(ESI ⁺)m/z 341.18(M+H) ⁺.

D) 2-(4-fluorophenyl) acetyl group isocyanates

[00116] at room temperature, silver cyanate (0.912g, 6.08mmol, 1.05 equivalents) is added in toluene (16ml) solution of 4-fluorophenyl chloroacetic chloride (Lancaster, 0.794ml, 5.79mmol, 1.0 equivalents).Make the reactant mixture lucifuge, be heated to backflow.After 60 minutes, mixture is cooled to room temperature, filters (Acrodisc, PTFE 0.2 μ M), obtain the toluene solution of 0.36M 2-(4-fluorophenyl) acetyl group isocyanates, need not be further purified during use.

E) 1-(4-(6-(4-methoxybenzyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00117] toluene (0.72mL of usefulness 0.36M 2-(4-fluorophenyl) acetyl group isocyanates; 0.26mmol) solution-treated N-(4-methoxy-benzyl)-6-(4-amino-2-fluorophenoxy) pyrimidine-4-amine (88mg; 0.26mmol) THF (2mL) solution, reactant mixture is at room temperature stirred 1h.Vacuum concentrated mixture grinds the solid that obtains with diisopropyl ether, obtains title compound (125mg, 93%), is pale solid.

¹HNMR(DMSO-d ₆)δ11.00(s，1H)，10.50(s，1H)，8.09(s，1H)，7.85(brs，0.5H)，7.66(d，1H，J＝12.6Hz)，7.36-7.15(m，9.5H)，6.88(d，1H，J＝8.1Hz)，5.91(s，1H)，4.42(br s，2H)，3.72(s，2H)，3.71(s，3H)；MS(ESI ⁺)m/z 520.14(M+H) ⁺.

Embodiment 12

N ¹-(4-(6-(4-methoxy-benzyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

[00118] with the method described in the Compound C that is similar to preparation embodiment 1, by N-(4-methoxy-benzyl)-6-(4-amino-2-fluorophenoxy) pyrimidine-4-amine (Compound C among the embodiment 11,200mg, 0.59mmol), 3-(4-fluorophenyl the amino)-3-oxo propanoic acid (compd B among the embodiment 1,128mg, 0.65mmol), TBTU (228mg, 0.71mmol) and DIPEA (123 μ L, DMF formulations prepared from solutions title compound 0.71mmol).By grinding the purification crude product with diisopropyl ether, obtain title compound (250mg, 82%), be pale solid.

¹H NMR(DMSO-d ₆)δ10.43(s，1H)，10.25(s，1H)，8.09(s，1H)，7.85(s，1H)，7.72(dd，1H，J＝9.1，5.0Hz)，7.62(dd，2H，J＝8.8，5.0Hz)，7.31-7.21(m，4H)7.15(dd，2H，J＝8.8，8.8Hz)，6.88(m，2H)，5.90(s，1H)，4.42(brs，2H)，3.71(s，3H)，3.46(s，2H)；MS(ESI ⁺)m/z 520.14(M+H) ⁺.

Embodiment 13

1-(4-(6-aminopyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) N-(3-fluoro-4-hydroxy phenyl) acetamide

[00119] according to Burckhalter, the method for J.H. etc. (J.Am.Chem.Soc.1948,70,1363) prepares title compound by commercially available 2-fluoro-4-nitrophenol.With nitrophenol (5.73g, 36.5mmol) and acetic anhydride (3.72g 36.5mmol) is dissolved in acetic acid (20mL), adds PtO then ₂(150mg).At H ₂Under the atmosphere (50psi), at room temperature, with reactant mixture jolting 24h.Collect the precipitation that forms by vacuum filtration, with acetic acid (25mL) washing filter paper.Filtrate and cleaning mixture that vacuum concentration merges obtain title compound (2.0g).Handle the solid that remains on the filter paper with MeOH, with product dissolving, filtering Pt ₂O.Vacuum concentrated filtrate grinds the solid that obtains with 1: 1 EtOAc/ hexane (200mL), obtains second batch of title compound (1.8g, 62% adds up to).

¹H NMR(DMSO-d ₆)δ9.83(s，.1H)，9.51(s，1H)，7.50(dd，1H，J＝13.6，2.5Hz)，7.03(d，1H，J＝8.5Hz)，6.84(dd，1H，J＝9.3，9.3Hz)，1.98(s，3H)；MS(ESI ⁺)m/z 170.23(M+H) ⁺.

B) N-(4-(6-chloropyrimide-4-base oxygen base)-3-fluorophenyl) acetamide

[00120] under 70 ℃, with 4, the 6-dichloro pyrimidine (1.50g, 10.0mmol), N-(3-fluoro-4-hydroxy phenyl) acetamide (1.70g, 10.0mmol), K ₂CO ₃(1.8g, 13.0mmol) and the mixture heated 1.5h of DMF (15mL).Mixture is concentrated into half of its initial volume, in ice bath, cools off.Use H ₂O (100mL) treatment mixture makes the product precipitation, by the vacuum filtration collecting precipitation.Use H ₂The O washed product, vacuum drying spends the night on funnel, obtains title compound (2.0g, 71%), is gray solid.

¹H NMR(DMSO-d ₆)δ10.26(s，1H)，8.67(s，1H)，7.78(dd，1H，J＝12.6，2.0Hz)，7.56(s，1H) 7.37-7.30(m，2H)，2.08(s，3H)；MS(ESI ⁺)m/z 282.10(M+H) ⁺.

C) N-(4-(6-aminopyrimidine-4-base oxygen base)-3-fluorophenyl) acetamide

[00121] in the sealing load bottle, (1.0g is 3.5mmol) with about 7M NH for acetamide with N-(4-(6-aminopyrimidine-4-base oxygen base)-3-fluorophenyl) ₃Mixture in MeOH (5mL) is at 100 ℃ of heating 2h.Vacuum concentrated mixture makes residue at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.Separate the EtOAc phase, use the salt water washing, dry (MgSO ₄), concentrate. at SiO ₂On carry out flash chromatography, earlier use the 50%EtOAc/ hexane, use 5%MeOH/CH then ₂Cl ₂Make eluent, obtain title compound (175mg, 20%), be brown solid.

¹H NMR(DMSO-d ₆)δ10.17(s，1H)，8.02(s，1H)，7.70(dd，1H，J＝13.2，2.2Hz)，7.26(dd，1H，J＝8.8，2.2Hz)，7.22(dd，1H，J＝8.8，8.8Hz)，6.89(br s，2H)，2.05(s，3H)；MS(ESI ⁺)m/z 263.15(M+H) ⁺.

D) 6-(4-amino-2-fluorophenoxy) pyrimidine-4-amine

[00122] with N-(4-(6-aminopyrimidine-4-base oxygen base)-3-fluorophenyl) acetamide (175mg, 0.67mmol), the mixture reflux 3h of 1M HC1 (6mL) and MeOH (2mL).Reaction mixture is used Na ₂CO ₃Aqueous solution is made alkalescence (pH8), with EtOAc (2 * 25mL) extractions.With the extract drying (MgSO that merges ₄), vacuum concentration obtains title compound (140mg, 96%), is brown solid.

¹HNMR(DMSO-d ₆)δ8.02(s，1H)，6.89(dd，1H，J＝9.0，9.0Hz)，6.80(brs，2H)，6.43(dd，1H，J＝12.7，2.8Hz)，6.35(dd，1H，J＝8.8，2.2Hz)，5.67(s，1H)，5.34(br s，2H).

E) 1-(4-(6-aminopyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00123] by 6-(4-amino-2-fluorophenoxy) pyrimidine-4-amine (92mg; 0.42mmol) and the foregoing description 11 in the toluene (Compound D among the embodiment 11 of 0.36M 2-(4-fluorophenyl) acetyl group isocyanates; 1.3mL, 0.45mmol) in THF, prepare title compound.By using 1: 1 EtOH/H successively ₂O, anhydrous EtOH grind, the purification crude product.The vacuum drying product obtains title compound (100mg, 60%).Filtrate by extraction merges with the EtOAc washing, obtains second batch of not really pure product (45mg, 27%)

¹H NMR (DMSO-d ₆)δ10.99(s，1H) 10.50(s，1H)，8.01(s，1H)，7.65(dd，1H，J＝12.6，2.1Hz)，7.33(dd，2H，J＝8.1，6.0Hz)，7.28(dd，1H，J＝8.6，2.0Hz)，7.22(dd，1H，J＝8.8，8.8Hz)，7.17-7.12(m，2H) 6.89(br s，2H) 5.80(s，1H)，3.71(s，2H)；MS(ESI ⁺)m/z 400.09(M+H) ⁺.

Embodiment 14

N ¹-(4-(2-(4-methoxy-benzyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

A) 2-chloro-4-(2-fluoro-4-nitrophenoxy) pyrimidine

[00124] under 100 ℃, with 2, the 4-dichloro pyrimidine (Aldrich, 0.74g, 5.0mmol), 2-fluoro-4-nitrophenol (Avacado, 0.79g, 5.0mmol), K ₂CO ₃(0.76g, 5.5mmol) and the mixture heated 2h of DMF (50mL).Cooling mixture is used saturated NaHCO ₃Solution (100mL) dilution extracts with EtOAc.With salt water washing EtOAc extract, dry (MgSO ₄), vacuum concentration obtains 2-phenoxy group-and the mixture of 4-phenoxy pyrimidine regional isomer, is yellow solid.Separate these regional isomers by flash chromatography, make eluent, obtain title compound (0.71g53%), be white solid with the 10-40%EtOAc/ hexane.

¹HNMR(DMSO-d ₆)δ8.76(dd，，1H，J＝6.0，1.6Hz)8.43(dt，1H，J＝9.8，2.2Hz)，8.23(dd，1H，J＝8.8，1.6Hz)，7.80(dt，1H，J＝9.8，2.2Hz)，7.48(dd，1H，J＝6.0，2.2Hz).

B) N-(4-methoxy-benzyl)-4-(2-fluoro-4-nitrophenoxy) pyrimidine-2-amine

[00125] under 100 ℃, with 2-chloro-4-(2-fluoro-4-nitrophenoxy) pyrimidine (0.66g, 2.44mmol), the 4-methoxybenzylamine (0.34g, 3.45mmol), K ₂CO ₃(0.37g, 2.66mmol) and the mixture heated 1h of DMF (15mL).Cooling mixture is used H ₂O (100mL) dilution is with EtOAc (100mL) extraction.The saturated NaHCO of organic facies ₃Each washed twice of solution and saline.With Organic substance drying (MgSO ₄), concentrate, obtain crude product.At SiO ₂On carry out flash chromatography, use 1-3%MeOH/CH ₂Cl ₂Make eluent, obtain title compound (275mg, 29%), be light yellow solid.

¹H NMR(DMSO-d ₆)δ8.40-8.21(m，2H)，8.16(dd，1H，J＝8.8，1.7Hz)7.98(brs，0.5H)，7.73-7.55(m，1.5H)，7.16(brs，1H)，6.85-6.71(m，3H)，6.37(s，1H)，4.43(br s，1H)，3.95(brs，1H)，3.69(s，3H).

C) N-(4-methoxy-benzyl)-4-(4-amino-2-fluorophenoxy) pyrimidine-2-amine

[00126] with the method described in the Compound C that is similar to preparation embodiment 11, by with zinc powder (475mg, 7.3mmol) and NH ₄(387mg, (270mg 0.73mmol), obtains title compound to 1: 1 THF/MeOH (20mL) solution reduction N-(4-methoxy-benzyl)-4-(2-fluoro-4-nitrophenoxy) pyrimidine-2-amine 7.3mmol) to Cl.Carry out SiO ₂Flash chromatography is used 1-3%MeOH/CH ₂Cl ₂Make eluent, obtain title compound (235mg, 95%), be brown tympan.

¹H NMR(DMSO-d ₆)δ8.01(s，1H)，7.65(brs，0.5H)，7.49(brs，0.5H)，7.08(brs，1H)，6.83(brs，2H)，6.81(m，1H)，6.69(brs，2H)，6.39(brs，0.5H)，6.31(brs，0.5H)，6.01(m，1H)，5.26(brs，2H)，4.24(brs，1H)，3.95(br s，1H)，3.61(s，3H)；MS(ESI ⁺)m/z 341.16(M+H) ⁺.

D) N ¹-(4-(2-(4-methoxy-benzyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

[00127] with the method described in the Compound C that is similar to preparation embodiment 1, by N-(4-methoxy-benzyl)-4-(4-amino-2-fluorophenoxy) pyrimidine-2-amine (34mg, 0.10mmol), 3-(4-fluorophenyl the amino)-3-oxo propanoic acid (compd B among the embodiment 1,22mg, 0.11mmol), TBTU (39mg, 0.12mmol) and DIPEA (23mL 0.17mmol) obtains title compound.Grind crude product with 3: 1 diisopropyl ethers/EtOAc, obtain title compound (35mg, 61%), be pale solid.

¹H NMR(DMSO-d ₆)δ10.47(brs，1H)，10.26(s，1H)，8.15(s，1H)，7.77(m，3H)，7.61(m，2H)，7.35-7.25(M，2H)，7.15(dd，2H，J＝8.8，8.8Hz)，6.81-6.73(m，2H)，6.24(s，1H)，4.32(brs，1H)，3.96(br s，1H)，3.68(s，1H)，3.48(s，2H)；MS(ESI ⁺)m/z 520.14(M+H) ⁺.

Embodiment 15

1-(4-(2-(4-methoxy-benzyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00128] toluene solution (Compound D among the embodiment 11 of usefulness 0.36M 2-(4-fluorophenyl) acetyl group isocyanates; 0.31mL; 0.11mmol) processing N-(4-methoxy-benzyl)-4-(4-amino-2-fluorophenoxy) pyrimidine-2-amine (Compound C among the embodiment 14; 34mg; 0.10mmol) THF (1ml) solution; at room temperature, the 1h that stirs the mixture.Vacuum concentrated mixture is used 3: 1 diisopropyl ether/EtOAc, CH successively ₂Cl ₂The solid that grinding obtains obtains title compound (32mg, 62%), is pale solid.

¹H NMR(DMSO-d ₆)δ10.47(s，1H)，10.26(s，1H)，8.15(s，1H)，7.76(d，1H，J＝12.6Hz)，7.61(dd，3H，J＝9.1，5.0Hz)，7.29(s，2H)，7.31-7.21(m，3H)，6.81(s，3H)，6.24(s，1H)，4.32(s，1H)，3.96(s，1H)，3.68(s，3H)，3.48(s，2H)；MS(ESI ⁺)m/z 520.14(M+H) ⁺.

Embodiment 16

N ¹-(4-(2-aminopyrimidine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide [00129] is under 85 ℃, with N ¹-(4-(2-(4-methoxybenzyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide (embodiment 14,25mg, 0.048mmol), methoxybenzene (52mg, 0.48mmol) the mixture heated 6h in TFA (1mL).Remove TFA under the vacuum, with residue at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With salt water washing EtOAc phase, dry (MgSO ₄), vacuum concentration.Carry out SiO ₂Flash chromatography is used EtOAc, 1-2%MeOH/CH successively ₂Cl ₂Make eluent, obtain title compound (12mg, 63%), be pale solid.

¹H NMR(DMSO-d ₆)δ11.00(s，1H)，10.51(s，1H)，8.02(s，1H)，7.66(dd，1H，J＝12.6，2.0Hz)，7.42-7.31(m，2H)，7.32-7.27(m，1H)，7.23(t，2H，J＝8.6Hz)，7.16(t，2H，J＝9.1Hz)，6.91(s，2H)，3.73(s，2H)；MS(ESI ⁺)m/z 400.11(M+H) ⁺.

Embodiment 17

1-(4-(2-aminopyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00130] with being similar to method described in the embodiment 16, (4-(2-(4-methoxy-benzyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-(embodiment 15,20mg, 0.039mmol) preparation title compound for 3-(2-(4-fluorophenyl) acetyl group) urea by 1-.At SiO ₂On carry out flash chromatography, use EtOAc, 1-2%MeOH/CH successively ₂Cl ₂Eluting obtains title compound (10mg, 62%), is pale solid.

¹H NMR (DMSO-d ₆)δ11.01(s，1H)，10.52(s，1H)，8.20(d，1H，J＝6.0Hz)，7.70(dd，1H，J＝12.1，2.0Hz)，7.36-7.30(m，6H)，7.16(dd，2H，J＝8.8，8.8Hz)，6.45(d，1H，J＝6.1Hz)，3.73(s，2H)；MS(ESI ⁺)m/z 400.09(M+H) ⁺.

Embodiment 18

N ¹-(3-fluoro-4-(2-(2-morpholino ethylamino) pyridin-4-yl oxygen base) phenyl)-N ³-(4-fluorophenyl) Malondiamide, hydrochlorate

A) N-(4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl) acetamide

[00131] under 100 ℃, with N-(3-fluoro-4-hydroxy phenyl) acetamide (compd A among the embodiment 13,1.33g, 7.87mmol), 2-chloro-4-nitropyridine (Aldrich, 1.24g, 7.87mmol), K ₂CO ₃(1.6g, 11.8mmol) and the mixture heated 9h of DMF (25mL).The vacuum concentration reactant mixture makes residue at EtOAc and saturated NaHCO ₃Distribute between the solution.With salt water washing EtOAc phase, dry (MgSO ₄), concentrate.Carry out flash chromatography, make eluent, obtain title compound (1.6g, 73%), be light yellow solid with the 30-80%EtOAc/ hexane.

¹HNMR(DMSO-d ₆)δ10.24(s，1H)，8.65(s，1H)，7.89-7.64(m，1H)，7.56(s，1H)，7.46-7.19(m，2H)，2.06(s，3H)；MS(ESI ⁺)m/z 281.16(M+H) ⁺.

B) N-(4-(2-chloropyridine-4-base Oxy-1-oxide)-3-fluorophenyl) acetamide

[00132] with N-(4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl) acetamide (0.98g, 3.5mmol) ,-(＞90%, 1.3g is 7.6mmol) at CHCl for chloroperoxybenzoic acid ₃Mixture (50mL) at room temperature stirs 60h.Enriched mixture is used Et ₂(2 * 100mL) grind residue to O, obtain title compound (0.89g, 87%), are light yellow solid.

¹H NMR(DMSO-d ₆)δ10.25（s，1H)，8.34(d，1H，J＝7.1Hz)，7.80(d，1H，J＝13.2Hz)，7.49(d，1H，J＝3.3Hz)，7.33(d，2H，J＝4.9Hz)，7.02(dd，1H，J＝7.1，3.3Hz)，2.06(s，3H)；MS(ESI)m/z 295.04(M-H).

C) N-(3-fluoro-4-(2-(2-morpholino ethylamino) pyridin-4-yl Oxy-1-oxide) phenyl) acetamide

[00133] with N-(4-(2-chloropyridine-4-base Oxy-1-oxide)-3-fluorophenyl) acetamide (205mg, 0.62mmol), 4-(2-amino-ethyl) morpholine (Aldrich, 169mg, 1.30mmol) and the mixture reflux 16h of anhydrous EtOH.The vacuum concentration reactant mixture is used H ₂O (3mL) handles residue, is loaded on the 10g Varoan C-18 post.Use H successively ₂O, 30%MeOH/H ₂This post of O eluting.Merge the flow point of the product that contains needs, be concentrated into the 5mL volume, with EtOAc extraction 3 times.With the extract that the salt water washing merges, dry (MgSO ₄), concentrate, obtain title compound (100mg, 40%).

¹H NMR(DMSO-d ₆)δ10.22(s，1H)，7.84(d，1H，J＝6.1Hz)，7.77(dd，1H，J＝13.2，2.2Hz)，7.31(dd，1H，J＝8.8，2.2Hz)，7.24(t，1H，J＝8.8Hz)，6.41(m，1H)，6.13(dd，1H，J＝5.5，2.2Hz)，5.81(d，1H，J＝2.2Hz)，3.60-3.52(m，4H)，3.31-3.28(m，2H)，2.38(t，2H，J＝7.1Hz)，2.34(m，4H)，2.06(s，3H)；MS(ESI ⁺)m/z 405.22(M+H) ⁺.

D) N-(3-fluoro-4-(2-(2-morpholino ethylamino) pyridin-4-yl oxygen base) phenyl) acetamide, trifluoroacetate

[00134] under 135 ℃, with N-(3-fluoro-4-(2-(2-morpholino ethylamino) pyridin-4-yl Oxy-1-oxide) phenyl) acetamide (100mg, 0.26mmol) and the mixture of triphenyl phasphine (1.4-2.0mmol/g) on poly styrene polymer (500mg) carrier and DMF (2mL) stir 15h.Filtering mixt is removed resin, with DMF and EtOAc washing resin.Merging filtrate and cleaning mixture concentrate.(Shimadzu S5VP-ODS 20 * 100mm) purification obtain title compound (45mg, 46%) to crude product, are white solid through preparation HPLC.

¹H NMR(DMSO-d ₆)δ10.33(s，1H)，8.02.(d，1H，J＝6.6Hz)7.84(dd，1H，J＝13.2，2.0Hz)，7.39-7.31(m，2H)，6.52(s，1H)，6.10(s，1H)，3.83(brs，4H)，3.64(m，2H)，3.28(m，6H)，2.08(s，3H)；MS(ESI ⁺)m/z375.12(m+H) ⁺.

E) 4-(4-amino-2-fluorophenoxy)-N-(2-morpholino ethyl) pyridine-2-amine, hydrochlorate

[00135] with the mixture reflux 3h of N-(3-fluoro-4-(2-(2-morpholino ethylamino) pyridin-4-yl oxygen base) phenyl) acetamide trifluoroacetate (40mg), MeOH (1mL) and 6M HCl (0.2mL).Concentrated reaction mixture on Rotary Evaporators, the lyophilizing residue obtains title compound (30mg, 76%), is white solid.

¹H NMR(DMSO-d ₆)δ11.12(brs，1h)，8.85(br s，1H)，7.95(d，1H，J＝7.2Hz)，7.08(dd，1H，J＝8.8，8.8Hz)，6.65-6.63(m，2H)，6.54(d，1H，J＝8.3Hz)，6.31(brs，1H)，3.85(m，6H)，3.33(m，6H)；MS(ESI ^-)m/z 373.14(M，-H).

F) N ¹-(3-fluoro-4-(2-(2-morpholino ethylamino) pyridin-4-yl oxygen base) phenyl)-N ³-(4-fluorophenyl) Malondiamide

[00136] with the method described in the Compound C that is similar to preparation embodiment 1, by 4-(4-amino-2-fluorophenoxy)-N-(2-morpholino ethyl) pyridine-2-amine, hydrochlorate (15mg, 0.043mmol), 3-(4-fluorophenyl the amino)-3-oxo propanoic acid (compd B among the embodiment 1,10mg, 0.052mmol), TBTU (17mg, 0.052mmol), DIPEA (30 μ L) and the mixture of DMF (1mL) prepare title compound.By preparation HPLC (Shimadzu S5VP-ODS 20 * 100mm) purification crude products.Handle the product that obtains by the HPLC purification with 1M HCl, obtain title compound (10mg, 40%), be white solid.

¹H NMR(DMSO-d ₆)δ10.37(s，1H)，10，05(s，1H)，9.90(brs，1H)，7.90(d，1H，J＝6.1Hz)，7.75(d，1H，J＝13.2Hz)，7.58-7.55(m，2H)，7.53-7.50(M，1H)，7.40(d，1H，J＝8.8Hz)，7.24(t，1H，J＝8.8Hz)，7.08-7.03(m，3H)，6.39(d，1H，J＝6.1Hz)，6.11(s，1H)，3.80-3.81(m，4H)，3.67-3.65(m，2H)，3.47(brs，2H)，3.20(brs，4H)；MS(ESI ⁺)m/z 512.12(M+H) ⁺.

Embodiment 19

N ¹-(3-fluoro-4-(pyridin-4-yl oxygen base) phenyl)-N ³-(4-fluorophenyl) Malondiamide

A) N ¹-(3-fluoro-4-hydroxy phenyl)-N ³-(4-fluorophenyl) Malondiamide

[00137] under 0 ℃, to 2-fluoro-4-nitrophenol (Avacado, 1.00g add zinc powder (2.08g, 31.8mmol,＜10 microns) in 4mL oxolane 6.37mmol) and the 6mL methanol solution, add subsequently ammonium chloride (1.70g, 31.8mmol).Mixture at room temperature stirred spend the night.Make non-homogeneous mixture by containing the Celite of methanol ^The thin pad of kieselguhr filters, and vacuum concentrated filtrate obtains 4-amino-2-fluorophenol, is brown solid, need not be further purified (656mg, 81%) during use.

[00138] (the compound B-11 97mg among the embodiment 1 1.00mmol) is dissolved in dimethyl formamide (4mL) with 3-(4-fluorophenyl amino)-3-oxo propanoic acid.Add triethylamine (140 μ L, 1.00mmol), cooling solution to 0 ℃.Add 4-amino-2-fluorophenol (steps A among the embodiment 19,127mg, 1.00mmol), add subsequently benzotriazole-1-base oxygen base three (dimethylamino) phosphorus  hexafluorophosphate (bop reagent, 442mg, 1.00mmol).Allow reactant be warming up to room temperature, at room temperature stir 3h then.Concentrated reaction mixture is removed dichloromethane, adds entry and makes the product precipitation.Filter, water grinds, and obtains title compound (211mg, 69%), is white solid.

¹H NMR(CD ₃OD)δ7.61-7.57(m，2H)，7.51(dd，1H，J＝13，2.5Hz)，7.08-6.99(m，3H)，6.88(t，1H，J＝9.4Hz)，3.51(s，2H)；MS(ESI ⁺)m/z 307.44(M+H) ⁺.

B) N ¹-(3-fluoro-4-(pyridin-4-yl oxygen base) phenyl)-N ³-(4-fluorophenyl) Malondiamide

[00139] with N ¹-(3-fluoro-4-hydroxy phenyl)-N ³-(4-fluorophenyl) Malondiamide (31mg, 0.10mmol), copper acetate (II) (27mg, 0.15mmol), pyridin-4-yl boric acid (25mg, 0.20mmol) and pyridine (16 μ L 0.20mmol) put into manometer tube successively.In this pipe, add dichloromethane (0.5mL), sealing.Reactant is stirred 5h down at 120 ℃.Make reactant mixture pass through filtered through silica gel, with 5% methanol/ethyl acetate eluting.After concentrating, by preparation HPLC purification crude product.Concentrate suitable flow point, remove methanol, use saturated NaHCO ₃Solution (5mL) is made alkalescence with the aqueous solution that obtains.(3 * 10mL) extraction water solution, the organic extract liquid of merging is through anhydrous Na with EtOAc ₂SO ₄Drying, vacuum concentration.With the two  alkane solution-treated products of 4N HCl, concentrate.Lyophilizing removes and anhydrates, and obtains title compound (8mg, 21%), is yellow solid.

¹HNMR(CD ₃OD)δ8.31(d，2H，J＝6.1Hz)，7.72(dd，1H，J＝12.7，2.4Hz)，7.4-7.46(m，2H)，7.27-7.25(m，1H)，7.15(t，1H，J＝8.8Hz)，6.97(t，2H，J＝8.7Hz)，6.85(dd，2H，J＝5.1，1.2Hz)，3.46(s，2H)；MS(ESI ⁺)m/z 384.21(M+H) ⁺.

Embodiment 20

N ¹-(4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

A) 2-fluoro-4-amino-phenol

[00140] at 50psi H ₂Under the atmosphere, the mixture in MeOH (100ml) at room temperature stirs with platinum oxide (0.010g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24g, 7.78mmol, 1.0 equivalents).By the diatomite filtration reactant mixture, vacuum concentrated filtrate obtains title compound (1.00g, 100%), is solid, need not be further purified during use.

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) ⁺.

B) 4-(2-chloropyridine-4-base oxygen base)-3-fluoroaniline (benzenamine)

[00141] at room temperature, sodium hydride (60%, 0.104g, 2.60mmol, 1.1 equivalents) is added in DMF (6.5mL) solution of 2-fluoro-4-amino-phenol (0.30g, 2.36mmol, 1.0 equivalents) stirred reaction mixture 30 minutes.Add 2-chloro-4-nitropyridine (Aldrich, 0.374g2.36mmol, 1.0 equivalents), reactant mixture is heated to 90 ℃, keep 12h.Reactant mixture is cooled to room temperature, with the quencher of saturated NaCl aqueous solution, with ethyl acetate (3 * 70mL) extractions.(3 * 70mL) washings are through Na with the 10%LiCl aqueous solution for the organic extract liquid that merges ₂SO ₄Drying is filtered, and vacuum concentrated filtrate obtains title compound (0.430g, 76%), need not be further purified during use.

¹H NMR(DMSO-d ₆)δ8.27(d，1H，J＝5.7Hz)，6.90-7.04(m，3H)，6.42-6.54(m，2H)，5.54(s，2H)；MS(ESI ⁺)m/z 239(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 239.0387, measured value: 239.0391.

C) N ¹-(4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl Malondiamide

[00142] under 0 ℃, with diisopropylethylamine (0.091mL, 0.525mmol, 2.5 equivalents) and adding 4-(2-chloropyridine-4-base oxygen base)-3-fluoroaniline (0.050g, 0.21mmol, 1.0 3-(4-fluorophenyl amino)-3-oxo propanoic acid (compd B among the embodiment 1 equivalent),, 0.041g, 0.21mmol, 1.0 equivalents) and PyBroP (0.117g, 0.252mmol, 1.2 equivalents) CH ₂Cl ₂(1.0mL) in the solution.Make reactant mixture be warming up to room temperature, stir 12h.With saturated NaCl aqueous solution quencher reactant mixture, use CH ₂Cl ₂(3 * 20mL) extraction mixture.The organic extract that merges is through Na ₂SO ₄Drying is filtered vacuum concentrated filtrate.Residue obtains title compound (0.056g, 64%) through flash chromatography on silica gel (the 230-240 order is with 3/1 ethyl acetate/hexane eluting for Merck, 40-63 μ M) purification, is solid.

¹H NMR(DMSO-d ₆)δ10.61(s，1H)，10.34(s，1H)，8.36-8.38(m，1H)，7.91-7.93(m，1H)，7.67-7.71(m，2H)，7.46-7.48(m，2H)，7.04-7.26(m，4H)，3.56(s，2H)；MS(ESI ⁺)m/z 418(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 418.0770, measured value: 418.0767.

Embodiment 21

1-(4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) thiourea

[00143] at room temperature; with 4-fluorophenyl chloroacetic chloride (Aldrich; 0.072mL; 0.525mmol; 2.5 equivalent) add in ethyl acetate (2.0mL) solution of sodium rhodanate (0.056g, 0.695mmol, 3.3 equivalents); stirred reaction mixture 1.5h obtains 2-(4-fluorophenyl) acetyl group isothiocyanate (0.263M) solution.CH with 4-(2-chloropyridine-4-base oxygen base)-3-fluoroaniline (0.050g, 0.21mmol, 1.0 equivalents) ₂Cl ₂(1.0mL) drips of solution is added in 2-(4-fluorophenyl) the acetyl group isothiocyanic acid ester solution, and reactant mixture is at room temperature stirred 12h.The vacuum concentration reactant mixture, the residue that obtains obtains title compound (0.058g, 64%) through flash chromatography on silica gel (the 230-240 order is used 3/1 hexane/ethyl acetate for Merck, 40-63 μ M) purification, is solid.

¹HNMR(DMSO-d ₆)δ12.46(s，1H)，11.84(s，1H)，8.35-8.33(m，1H)，8.02-8.33(m，1H)，6.99-7.52(m，8H)，3.84(s，2H)；MS(ESI ⁺)m/z 434(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 434.0542, measured value: 434.0547.

Embodiment 22

N ¹-(4-(2-(benzylamino) pyridin-4-yl oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

A) 4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl t-butyl carbamate

[00144] with Bis(tert-butoxycarbonyl)oxide (0.920g, 4.22mmol, 4.5 equivalent) add 4-(2-chloropyridine-4-base oxygen base)-3-fluoroaniline (compd B among the embodiment 20,0.224g, 0.939mmol, 1.0 equivalents) and triethylamine (0.391mL, 3.00mmol, 3.0 in THF equivalent) (10mL) solution, reactant mixture is heated 14h down at 55 ℃.Reactant mixture is cooled to room temperature, with 1N HCl quencher.Use CH ₂Cl ₂(3 * 70mL) extract this solution, and the organic extract of merging washs with 1N NaOH (100mL), dry (Na ₂SO ₄), filter vacuum concentration.Residue obtains title compound (0.270g, 85%) through flash chromatography on silica gel (the 230-240 order was with 4: 1 hexane/ethyl acetate eluting for Merck, 40-63 μ M) purification.

¹H NMR(DMSO-d ₆)δ8.35-8.36(m，1H) 7.55-7.57(m，1H)，7.45-7.46(m，1H)，7.21-7.24(m，1H)，6.96-6.97(m，2H)，1.40(s，9H)；MS(ESI ⁺)m/z 339(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 339.0912, measured value: 339.0915.

B) 4-(2-(benzylamino) pyridin-4-yl oxygen base)-3-fluorophenyl t-butyl carbamate

[00145] at room temperature, 4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl t-butyl carbamate (0.100g, 0.295mmol, 1.0 equivalents) is added the dppf.PdCl of the degassing ₂In the toluene solution of (MatrixScientific, 0.011g, 0.0148mmol, 0.05 equivalent), dppf (0.012g, 0.022mmol, 0.075 equivalent) and NaOt-Bu (0.040g, 0.414mmol, 1.4 equivalents).Benzylamine (0.045mL, 0.414mmol, 1.4 equivalents) is added reactant mixture, the solution that obtains is stirred 4h down at 80 ℃.Reactant mixture is cooled to room temperature,, uses CHCl with 1N HCl quencher ₃(3 * 50mL) extraction solutions.With the organic extract liquid that 1N NaOH (70mL) washing merges, dry (Na ₂SO ₄), filter vacuum concentration.Residue obtains title compound (0.020g, 17%) through flash chromatography on silica gel (Merck, 40-63 μ M, 230-240 order, 2: 1 hexane/ethyl acetate eluting) purification.

¹H NMR.(CDCl ₃)δ7.80-7.90(m，1H)，7.35-7.45(m，1H)，7.19-7.24(m，3H)，6.91-6.93(m，2H)，6.59(brm，1H)，6.10-6.20(m，1H)，5.75(brm，1H)，5.30-5.40(m，1H)，4.34(s，2H)，1.46(s，9H)；MS(ESI ⁺)m/z 410(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 410.1880, measured value: 410.1884.

C) 4-(4-amino-2-fluorophenoxy)-N-benzyl pyridine-2-amine, hydrochlorate

[00146] with two  alkane (4N, 2.00mL, the 8.00mmol of anhydrous HCl, 165 equivalents) solution adds 4-(2-(benzylamino) pyridin-4-yl oxygen base)-3-fluorophenyl t-butyl carbamate (0.020g, 0.0489mmol, 1.0 equivalents), reactant mixture is at room temperature stirred 12h.The vacuum concentration reactant mixture obtains title compound solid (0.017g, 100%), need not be further purified during use.MS (ESI ⁺) m/z 310 (M+H) ⁺HRMS (ESI ⁺) theoretical value: 310.1356, measured value: 310.1364.

D) N ¹-(4-(2-(benzylamino) pyridin-4-yl oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

[00147] at 0 ℃, diisopropylethylamine (0.014mL, 0.081mmol, 3.5 equivalents) is added 4-(4-amino-2-fluorophenoxy)-N-benzyl pyridine-2-amine, hydrochlorate (0.008g, 0.023mmol, 1.0 equivalents), 3-(4-fluorophenyl amino)-3-oxo propanoic acid (compd B among the embodiment 1,0.005g, 0.023mmol, 1.0 equivalent) and the CH of PyBroP (0.013g, 0.028mmol, 1.2 equivalents) ₂Cl ₂(1.0mL) in the solution.Make reactant mixture be warming up to room temperature, stir 16h.The vacuum concentration reactant mixture, residue is through reversed-phase HPLC chromatography (YMC-ODS-A, C-18, S10,30 * 500mm, usefulness 20-90%MeOH/0.1%TFA aqueous solution gradient elution 30min) purification.The flow point that vacuum concentration is suitable is used saturated NaHCO ₃CHCl is used in the solution neutralization ₃(3 * 10mL) extraction mixture.With the organic extract liquid drying (Na that merges ₂SO ₄), filtering, vacuum concentration obtains title compound (0.0025g, 45%), is solid.MS (ESI ⁺) m/z 489 (M+H) ⁺HRMS (ESI ⁺) theoretical value: 489.1738, measured value: 489.1743.

Embodiment 23

1-(3-fluoro-4-(pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) 3-fluoro-4-(pyridin-4-yl oxygen base) aniline

[00148] under room temperature, with hydrofining (30%, 0.520g, 3.90mmol, 3.0 equivalents) and adding 2-fluoro-4-amino-phenol (compd A among the embodiment 20,0.254g, 2.00mmol, 1.5 equivalents) DMF (5.0mL) solution in, reactant mixture was stirred 15 minutes.Add 4-chloro-pyridine (Aldrich, 0.200g, 1.30mmol, 1.0 equivalents), reactant mixture is heated 2h down at 150 ℃.Reactant mixture is cooled to room temperature, and with 1N NaOH quencher, (3 * 50mL) extract this solution with ethyl acetate.The organic extract liquid that merges use successively 1N NaOH aqueous solution (2 * 30mL), (3 * 50mL) washings of 10%LiCl aqueous solution.With the organic extract liquid drying (Na that merges ₂SO ₄), filtering, vacuum concentration obtains title compound, is solid.

¹H NMR(DMSO-d ₆)δ8.44-8.46(m，2H)，6.89-7.03(m，1H)，6.87-6.88(m，2H)，6.44-6.56(m，2H)，5.51(s，2H)；MS(ESI ⁺)m/z205(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 205.0777, measured value: 205.0775.

B) 1-(3-fluoro-4-(pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00149] at room temperature, lucifuge adds silver cyanate (0.912g, 6.08mmol, 1.05 equivalents) in toluene (16mL) solution of 4-fluorophenyl chloroacetic chloride (Aldrich, 0.794mL, 5.79mmol, 1.0 equivalents).With reaction mixture refluxed heating 60 minutes, be cooled to room temperature then.At room temperature; filter (Acrodisc; PTFE 0.2 μ M) reactant mixture; with 2-(4-fluorophenyl) acetyl group isocyanate solution (0.36M that obtains; 0.75mL, 0.27mmol, 1.1 equivalents) and adding 3-fluoro-4-(pyridin-4-yl oxygen base) aniline (0.050g; 0.245mmol, 1.0 equivalents) CH ₂Cl ₂(2.0mL) in the solution.Reactant mixture is at room temperature stirred 1h,, use CH with the quencher of saturated NaCl aqueous solution ₂Cl ₂(3 * 30mL) extraction mixture.With the organic extract liquid drying (Na that merges ₂SO ₄), filter vacuum concentration.(the 230-240 order is used 0-5%MeOH/CHCl to residue for Merck, 40-63 μ M through flash chromatography on silica gel ₃Eluting) purification obtains title compound (0.043g, 46%), is solid.

¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.60(s，1H)，8.47(s，2H)，7.77-7.80(M，1H)，6.92-7.48(m，8H)，3.75(s，2H)；MS(ESI ⁺)m/z384(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 384.1160, measured value: 384.1147.

Embodiment 24

1-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) 4-(4-amino-2-fluorophenoxy)-N-benzyl pyridine-2-amine

[00150] benzylamine (9.1mL, 83.8mmol, 20 equivalents) is added in 4-in the sealed tube (2-chloropyridine-4-base oxygen base)-3-fluoroaniline (compd B among the embodiment 20,1.0g, 4.19mmol, 1.0 equivalents), copper powder (0.266g, 4.19mmol, 1.0 equivalents) and K ₂CO ₃In (0.578g, 4.19mmol, 1.0 equivalents), reacting by heating mixture to 160 ℃ keeps 12h.Reactant mixture is cooled to room temperature, with the quencher of saturated NaCl aqueous solution.(3 * 100mL) extract this solution, dry (Na with ethyl acetate ₂SO ₄) organic extract liquid that merges, filter vacuum concentration.Residue is through preparation type reversed-phase HPLC (YMC C-18ODS-A S1050 * 500mm uses 10-90%MeOH/0.1%TFA aqueous solution gradient elution 30 minutes) purification, the flow point that vacuum concentration is suitable.Use saturated NaHCO ₃In the aqueous solution and concentrate, use CH ₂Cl ₂(3 * 100mL) extractions.Dry (Na ₂SO ₄) organic extract liquid that merges, filtering, vacuum concentration obtains title compound (0.675g, 52%), is solid.

¹HNMR(CD ₃OD)δ7.78-7.80(m，1H)，7.28-7.30(M，5H)，6.80-6.90(m，1H)，6.52-6.55(m，2H)，6.18-6.20(m，1H)，5.87-5.88(m，1H)，4.40(s，2H)；MS(ESI ⁺)m/z310(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 310.1356, measured value: 310.1360.

B) 4-(4-amino-2-fluorophenoxy) pyridine-2-amine

[00151] cover down at hydrogen (providing) by balloon, at room temperature, with drape over one's shoulders palladium dydroxide carbon (10%, the 0.050g) 5%HCO of adding 4-(4-amino-2-fluorophenoxy)-N-benzyl pyridine-2-amine (0.245g, 0.790mmol, 1.0 equivalents) ₂In H-MeOH (10mL) solution.Reactant mixture is at room temperature stirred 12h, pass through Celite ^Diatomite filtration, vacuum concentrated filtrate.Residue is through anti-phase preparation HPLC (YMC ODS-A S1030 * 500mm., 10-90%MeOH/0.1%TFA aqueous solution gradient elution 30 minutes) purification, the flow point that vacuum concentration is suitable.Use saturated NaHCO ₃In the aqueous solution and concentrate, use CH ₂Cl ₂(3 * 35mL) extract this mixture.Dry (Na ₂SO ₄) organic extract liquid that merges, filtering, vacuum concentration obtains title compound (0.045g, 26%), is solid.

¹H NMR(CD ₃OD)δ7.62-7.63(m，1H)，6.77-6.82(M，1H)，6.38-6.47(m，2H)，6.09-6.11(m，1H)，5.83-5.84(m，1H)；MS(ESI ⁺)m/z220(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 220.0886, measured value: 220.0877.

C) 1-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00152] at room temperature, with 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11,0.362M; 0.351mL, 0.127mmol, 1.3 equivalents) and adding 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (0.022g; 0.100mmol, 1.0 equivalents) CH ₂Cl ₂(2.0mL) in the solution.Reactant mixture is at room temperature stirred 13h, vacuum concentration then.Residue obtains title compound (0.025g, 64%) through flash chromatography on silica gel (Merck gel 40-63 μ M, 230-240 order, 1: 1 ethyl acetate/hexane) purification, is solid.

¹H NMR(CD ₃OD)δ7.62-7.67(m，2H)，7.23-7.29(m，2H)，7.07-7.12(m，2H)，6.95-6.99(m，2H)，6.12-6.14(m，1H)，5.86-5.87(m，1H)，3.61(s，2H)；MS(ESI ⁺)m/z 399(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 399.1269, measured value: 399.1269.

[00153] or, prepare embodiment 24 in the following manner:

A ') 4-chloropyridine amide

[00154] non-homogeneous mixture with 4-chloropyridine formic acid (TCI America, 5.4g, 34.2mmol, 1.0 equivalents) and thionyl chloride (30mL) heats 2h down at 80 ℃.Reactant mixture is cooled to room temperature, vacuum concentration.In ice bath, (7N 45mL) handles residue to the MeOH solution of usefulness ammonia, and reactant mixture was stirred 15 minutes.Remove ice bath then, make reactant be warming up to room temperature, stir 3h then.The vacuum concentration reactant mixture by making residue at the EtOAc recrystallization purifying, obtains product (5.14g, 96%), is solid.

¹H NMR(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/z 157(M+H) ⁺.

B ') 4-(4-amino-2-fluorophenoxy) picolinamide

[00155] under room temperature, with DMF (6.5mL) solution of potassium tert-butoxide (0.79g, 7.1mmol, 1.1 equivalents) processing 4-amino-2-fluorophenol (compd A among the embodiment 20,0.81g, 6.4mmol, 1.0 equivalents), stirred reaction mixture 1h.Add 4-chloropyridine amide (1.0g, 6.4mmol, 1.0 equivalents), reactant mixture is heated to 110 ℃, keep 8h.Reactant is cooled to room temperature, water quencher reactant mixture.The heterogeneous solution that filtration obtains washes solid matter with water.Use a small amount of MeOH, Et successively ₂The O abrasive solid.Cross filter solid, vacuum drying obtains product (1.3g, 82%), is solid.

¹H NMR(DMSO-d ₆)δ8.49-8.50(m，1H)，8.12(brs，1H)，7.71(brs，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) ⁺.

C ') 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00156] at room temperature; with 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.29M toluene solution; 54.9mL; 15.9mmol, 2.1 equivalents) and solution adding 4-(4-amino-2-fluorophenoxy) picolinamide (1.86g, 7.53mmol; 1.0 in 10/3DCM/DMF equivalent) (65mL) solution, stirred reaction mixture 17h.The vacuum concentration reactant mixture is dissolved in CHCl with residue ₃With saturated NaCl solution washing organic layer, separate organic moiety, dry (Na ₂SO ₄), filter vacuum concentration.Residue (with 1/3 hexane/EtOAc eluting, is used 5%MeOH/CHCl then through silica gel column chromatography ₃Eluted product) purification, the flow point that vacuum concentration is suitable obtains product (2.2g, 69%), is solid.

¹H NMR(DMSO-d ₆)δ11.07(s，1H)，10.62(s，1H)，8.54(d，1H，J＝5.60Hz)，8.16-8.19(m，1H)，7.76-7.84(m，2H)，7.35-7.49(m，5H)，7.16-7.23(m，3H)，3.76(s，2H)；MS(ESI ⁺)m/z 427(m+H) ⁺.

HRMS (ESI ⁺) theoretical value: 427.1218, measured value: 427.1214.

D ') 1-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00157] at room temperature; with two (trifluoroacetic acid base)-iodobenzene (Aldrich, 3.09g, 7.20mmol; 1.4 equivalent) add 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (2.19g; 5.14mmol, 1.0 equivalents), water (0.241mL, 13.4mmol; 2.6 equivalent) and pyridine (1.62mL; 20mmol, 3.9 equivalents) in DMF (20mL) solution, reactant mixture is stirred 5h.With 1N HCl quencher reactant mixture, use Et ₂O extraction water solution discards organic layer.Water layer extracts with EtOAc with 1N NaOH neutralization.With the organic layer that the 10%LiCl solution washing merges, dry (Na ₂SO ₄), filter vacuum concentration.Residue (is used 0-5%MeOH/CHCl through silica gel column chromatography ₃Eluting) purification, the flow point that vacuum concentration is suitable.Residue is dissolved in the THF (50mL) that is cooled to 0 ℃, handles with anhydrous HCl (4N, 10mL, 40mmol, 7.8 equivalents).Allow reactant mixture be warming up to room temperature, stir 2h, obtain heterogeneous solution.Filtering solution is used Et ₂O washs solid, and vacuum drying obtains title compound (1.38g, 63%), is solid.

¹H NMR(DMSO-d ₆)δ11.09(s，1H)，10.65(s，1H)，7.97-8.00(m，1H)，7.83-7.90(m，3H)，7.35-7.48(m，4H)，7.15-7.21(m，2H)，6.70-6.72(m，1H)，6.16-6.17(m，1H)，3.77(s，2H)；MS(ESI ⁺)m/z399(M+H) ⁺.

HRMS (ESI ⁺) theoretical value: 399.1269; Measured value: 399.1258.Elementary analysis C ₂₀H ₁₆N ₄O ₃F ₂1.0HCl.0.22H ₂O theoretical value: C; 54.75, H; 4.01, N; 12.77, Cl; 8.08.Measured value: C; 54.75, H; 4.35, N; 4.35, Cl; 8.06.

Embodiment 25

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-2-fluoro-5-methyl benzamide

[00158] at room temperature, with diisopropylethylamine (0.035mL, 0.200mmol, 2.0 equivalent) add 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,0.022g, 0.100mmol, 1.0 2-fluoro-5-ar-Toluic acid (Aldrich equivalent),, 0.015g, 0.100mmol, 1.0 equivalents), EDCI (0.021g, 0.11mmol, 1.1 equivalent) and in DMF (0.700mL) solution of HOBT (0.014g, 0.100mmol, 1.0 equivalents).Reactant mixture is at room temperature stirred 8h, use saturated NaHCO ₃CHCl is used in the aqueous solution quencher ₃(3 * 10mL) extractions.Dry (Na ₂SO ₄) organic extract liquid that merges, filter vacuum concentration.Residue is through anti-phase preparation HPLC (YMC ODS-A S1030 * 500mm, 30-90%MeOH/0.1%TFA aqueous solution gradient elution 30 minutes) purification, the flow point that vacuum concentration is suitable.Use saturated NaHCO ₃In the aqueous solution and concentrate, use CHCl ₃(3 * 30mL) extraction mixture.Dry (Na ₂SO ₄) organic liquor that merges, filtering, vacuum concentration obtains title compound (0.014g, 40%), is solid.

¹H NMR(CD ₃OD)δ7.67-7.80(m，2H)，7.36-7.45(m，3H)，7.03-7.14(m，2H)，6.14-6.16(m，1H) 5.89-5.90(m，1H），2.29(s，3H)；MS(ESI ⁺)m/z356(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 356.1211, measured value: 356.1203.

Embodiment 26

N ¹-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl Malondiamide

[00159] under 0 ℃, diisopropylethylamine (0.105mL, 0.604mmol, 3.3 equivalents) is added 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,0.040g, 0.183mmol, 1.0 equivalents), 3-(4-fluorophenyl amino)-3-oxo propanoic acid (compd B among the embodiment 1,0.054g, 0.274mmol, 1.5 equivalent) and the CH of PyBroP (0.139g, 0.298mmol, 1.6 equivalents) ₂Cl ₂(2.0mL) solution.Make reactant mixture be warming up to room temperature, stir 18h.Use saturated NaHCO ₃Aqueous solution quencher reactant mixture is used CHCl ₃(3 * 10mL) extract this solution.With the organic extract liquid drying (Na that merges ₂SO ₄), filter vacuum concentration.(Merck 40-63 μ M, the 230-240 order is used 0-6%MeOH/CHCl to residue through flash chromatography on silica gel ₃The eluting purification obtains title compound (0.056g, 77%), is solid.

¹H NMR(CD ₃OD)δ7.6-7.68(m，2H)，7.48-7.52(m，2H)，7.13-7.25(m，1H)，7.10-7.12(m，1H)，6.94-6.99(m，2H)，6.16-6.17(m，1H)，5.88-5.89(m，1H)，3.30(s，2H)；MS(ESI)m/z 399(M-H ⁺)；

HRMS (ESI ⁺) theoretical value: 399.1269, measured value: 399.1261.

Embodiment 27

1-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) thiourea

[00160] at room temperature; with 4-fluorophenyl chloroacetic chloride (Aldrich; 0.017mL; 0.126mmol; 2.5 equivalent) add in ethyl acetate (1.0mL) solution of sodium isocyanate (0.014g, 0.176mmol, 3.5 equivalents); reactant mixture is stirred 1.5h, obtain 2-(4-fluorophenyl) acetyl group isocyanate solution (0.126M).4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,0.011g, 0.050mmol, 1.0 equivalents) is dissolved in CH ₂Cl ₂(1.0mL), add 2-(4-fluorophenyl) acetyl group isocyanates (0.126M, 0.50mL, 0.063mmol, 1.3 equivalents), reactant mixture is at room temperature stirred 20h.The vacuum concentration reactant mixture, (the 230-240 order is used 0-6%MeOH/CHCl to the residue that obtains for Merck, 40-63 μ M through flash chromatography on silica gel ₃Eluting) purification obtains title compound (0.008g, 38%), is solid.

¹H NMR(CD ₃OD)δ7.85-7.95(m，1H)，7.67-7.69(m，1H)，7.13-7.28(m,4H)，6.95-7.00(m，2H)，6.05-6.15(m，1H)，5.90-5.91(m，1H)，3.65(s，2H)；MS(ESI ⁺)m/z 415(M+H) ⁺；

HRMS (ESI ⁺) theoretical value: 415.1040, measured value: 415.1041.

Embodiment 28

1-(3-fluoro-4-(2-(4-fluorophenyl amino) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) N-(3-fluoro-4-(2-(4-fluorophenyl amino) pyridin-4-yl Oxy-1-oxide) phenyl) acetamide

[00161] under 140 ℃, heating N-(4-(2-chloropyridine-4-base Oxy-1-oxide)-3-fluorophenyl) acetamide (compd B among the embodiment 18,62mg, 0.21mmol), 4-fluoroaniline (47mg, 0.42mmol) and the mixture of 2-methoxy ethyl ether (91mL), keep 15min.Mixture is cooled to room temperature,, uses saturated NaHCO with EtOAc (20mL) dilution ₃Solution and saline (several times) washing, dry (MgSO ₄), vacuum concentration obtains 4: 1 the title compound and the mixture of parent pyridine, is light brown oily thing (45mg, 58%).When being used for subsequent step, product need not be further purified.MS(ESI ⁺)m/z 372.1(M+H) ⁺。

B) N-(3-fluoro-4-(2-(4-fluorophenyl amino) pyridin-4-yl oxygen base) phenyl) acetamide

[00162] under 135 ℃, with N-(3-fluoro-4-(2-(4-fluorophenyl amino) pyridin-4-yl Oxy-1-oxide) phenyl) acetamide (45mg), poly styrene polymer carrier (200mg, Fluka) triphenyl phasphine on (～3mmol/g) and the mixture heated 48h of DMF (3mL).The filtering resin is with DMF and EtOAc washing.Merging filtrate and cleaning mixture, vacuum concentration.Crude product is made eluent through the flash chromatography purification with the 30-80%EtOAc/ hexane, obtains title compound (22mg, 51%), is pink solid.

¹H NMR(DMSO-d ₆)δ10.24(s，1H)，8.99(s，1H)，8.03(d，1H，J＝6.3Hz)，7.80(dd，1H，J＝13.0，2.1Hz)，7.63-7.60(M，2H)，7.36-7.29(m，2H)，7.05(dd，1H，J＝9.1，8.6Hz)，6.44(dd，1H，J＝5.5，2.2Hz)，6.09(d，1H，J＝2Hz)，2.07(s，3H)；MS(ESI ⁺)m/z356.7(M+H) ⁺.

C) 4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl) pyridine-2-amine

[00163] with N-(3-fluoro-4-(2-(4-fluorophenyl amino) pyridin-4-yl oxygen base) phenyl) acetamide (18mg, 0.051mmol), 6M HCl (0.1mL, 0.60mmol) and the mixture reflux 2h of MeOH (1.5mL).Vacuum concentrated mixture is used saturated NaHCO ₃Aqueous solution makes residue be alkalescence, extracts with EtOAc then.With extract drying (MgSO ₄), vacuum concentration obtains title compound (14mg, 88%), is red colloid.

¹H NMR(DMSO-d ₆)δ8.97(s，1H)，7.98(d，1H，J＝5.8Hz)，7.64-7.60(m，2H)，7.05(dd，2H，J＝9.1，8.8Hz)，6.97(dd，1H，J＝9.4，8.8Hz)，6.51(dd，1H，J＝13.3，2.6Hz)，6.40(ddd，2H，J＝9.0，6.2，2.1Hz)，6.08(d，1H，J＝2.0Hz)，5.44(brs，2H)；MS(ESI ⁺)m/z 314.17(M+H) ⁺.

D) 1-(3-fluoro-4-(2-(4-fluorophenyl amino) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00164] in ice bath; cooling 4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl) pyridine-2-amine (11mg; 0.035mmol) THF (1mL) solution; with 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 250 μ L; 0.070mmol) toluene solution handle, at room temperature stir 2h.Vacuum concentrated mixture grinds residue with diisopropyl ether, obtains title compound (11mg, 65%), is white solid.

¹H NMR(DMSO-d ₆)δ11.04(s，1H)，10.56(s，1H)，9.01(s，1H)，8.03(d，1H，J＝5.6Hz)，7.77(dd，1H，J＝13.3，2.0Hz)，7.63-7.60(m，2H)，7.41-7.31(m，5H)，7.19-7.14(m，2H)，7.05(dd，1H，J＝9.1，8.5Hz)，6.43(dd，1H，J＝6.2，2.1Hz)，6.10(d，1H，J＝2.1Hz)，3.74(s，2H)；MS(ESI ⁺)m/z493.2(M+H) ⁺.

Embodiment 29

N ¹-(4-(6-(4-(benzyloxy) phenylamino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

A) N-(4-(6-(4-(benzyloxy) phenyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl) acetamide

[00165] under 160 ℃, with N-(4-(6-chloropyrimide-4-base oxygen base)-3-fluorophenyl) acetamide (compd B among the embodiment 13,281mg, 1.00mmol), 4-benzyloxy-aniline (Aldrich, 398mg, 2.00mmol) and the mixture heated 45min of 2-methoxy ethyl ether (2mL).Use H ₂O (50mL) handles chilled mixture, with EtOAc (100mL) extraction.With saline (3 * 25mL) washing EtOAc extracts, dry (MgSO ₄), vacuum concentration obtains title compound (200mg, 22%), is the purple solid.

¹HNMR(400MHz，DMSO-d ₆)δ10.19(s，1H)，9.43(s，1H)，8.23(s，1H)，7.72(dd，1H，J＝12.5，2.0Hz)，7.44-7.42(m，4H)，7.38(dd，2H，J＝8.0，6.9Hz)，7.33-7.23(m，3H)，6.98(d，2H，J＝9.0Hz)，6.07(s，1H)，5.07(s，2H)，2.05(s，3H)；MS(ESI ⁺)m/z445.13(M+H) ⁺.

B) 6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy) phenyl) pyrimidine-4-amine

[00166] with N-(4-(6-(4-(benzyloxy) phenyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl) acetamide (150mg, 0.34mmol), the mixture reflux 2h of 6M HCl (0.5mL) and MeOH (3mL).Enriched mixture is removed MeOH, uses saturated NaHCO ₃Solution grinds residue, extracts with EtOAc.With organic facies drying (MgSO ₄), vacuum concentration obtains title compound (123mg, 90%), is pink solid.

¹H NMR(DMSO-d ₆)：δ9.37(s，1H)，8.24(s，1H)，7.46-7.31(m，7H)，6.99-6.92(m，3H)，6.48(dd，1H，J＝12.5，2.7Hz)，6.39(dd，1H，J＝8.6，2.7Hz)5.97(s，1H)，5.39(brs，2H)，5.08(s，2H)；MS(ESI ⁺)m/z403.09(M+H) ⁺.

C) N ¹-(4-(6-(4-(benzyloxy) phenyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-N ³-(4-fluorophenyl) Malondiamide

[00167] with the method described in the Compound C that is similar to preparation embodiment 1, by 6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy) phenyl) pyrimidine-4-amine (45mg, 0.11mmol), 3-(4-fluorophenyl the amino)-3-oxo propanoic acid (compd B among the embodiment 1,24mg, 0.12mmol), TBTU (48mg, 0.15mmol), DIPEA (0.26mL, 0.15mmol) and the mixture of DMF (1mL) prepare title compound.Grind crude product with diisopropyl ether, obtain title compound (56mg, 88%), be pink solid.

¹H NMR(DMSO-d ₆)δ10.47(s，1H)，10.27(s，1H)，9.45(s，1H)，8.25(s，1H)，7.77(dd，1H，J＝12.7，2.0Hz)，7.65-7.62(m，2H)，7.46(d，4H，J＝7.3Hz)，7.40(dd，2H，J＝7.6，7.3Hz)，7.37-7.29(m，3H)，7.17(dd，2H，J＝9.0，8.3Hz)，7.00(d，2H，J＝9.0Hz)6.09(s，1H)，5.09(s，2H)3.49(s，2H)；MS(ESI ⁺)m/z582.3(M+H) ⁺.

Embodiment 30

1-(4-(6-(4-(benzyloxy) phenyl amino) pyrimidine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00168] with the described method of compd E that is similar among the preparation embodiment 11; by 6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy) phenyl) pyrimidine-4-amine (compd B among the embodiment 29; 45mg; 0.11mmol) and 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11, THF formulations prepared from solutions title compound 0.13mmol).Grind crude product with diisopropyl ether, obtain title compound (58mg, 90%), be pink solid.

¹H NMR(DMSO-d ₆)δ11.02(s，1H)，10.54(s，1H)，9.46(s，1H)，8.24(s，1H)，7.70(dd，1H，J＝12.7，2.4Hz)，7.46-7.26(m，9H)7.18(dd，2H，J＝9.6，8.3Hz)，7.00(d，2H，J＝9.6Hz)，6.11(s，1H)，5.09(s，2H)，3.75(s，2H)；MS(ESI ⁺)m/z 582.3(M+H) ⁺.

Embodiment 31

1-(3-fluoro-4-(2-(4-fluorophenyl amino) pyrimidine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) N-(4-(2-chloropyrimide-4-base oxygen base)-3-fluorophenyl) acetamide

[00169] with 2, the 4-dichloro pyrimidine (Aldrich, 1.5g, 10.0mmol), N-(3-fluoro-4-hydroxy phenyl) acetamide (0.85g, 5.0mmol), K ₂CO ₃(0.76g, 5.5mmol) and CH ₃The mixture reflux 2h of CN (100mL).Enriched mixture makes residue at EtOAc and saturated NaHCO ₃Distribute between the solution.EtOAc is used saturated NaHCO mutually ₃Solution, salt water washing, dry (MgSO ₄), vacuum concentration.Crude product with 30%EtOAc/ hexane-100%EtOAc gradient, obtains title compound (1.1g, 78%) through the flash chromatography purification, is white solid.

¹H NMR(DMSO-d ₆)δ10.22(s，1H)，8.63(d，1H，J＝5.6Hz)，7.74(dd，1H，J＝12.6，2.4Hz)，7.34-7.26(m，3H)，2.01(s，3H).

B) N-(3-fluoro-4-(2-(4-fluorophenyl amino) pyrimidine-4-base oxygen base) phenyl) acetamide

[00170] with N-(4-(2-chloropyrimide-4-base oxygen base)-3-fluorophenyl) acetamide (100mg, 0.36mmol), the 4-fluoroaniline (Aldrich, 40mg, 0.36mmol) and 1, the mixture reflux 2h of 4-two  alkane (3mL).Vacuum concentrated mixture grinds residue with ether, obtains gray solid.Product is dissolved in MeOH, handles with silica gel (150mg), enriched mixture is to doing.Chemical compound is concentrated on the silica gel, is carried on the silicagel column, use EtOAc, 100: 1 MeOH/NH successively ₄OH/CH ₂Cl ₂Eluting obtains title compound (40mg, 31%), is white solid.

¹H NMR(DMSO-d ₆)δ10.19(s，1H)，9.61(s，1H)，8.33(d，1H，J＝5.6Hz)，7.71(d，1H，J＝12.7Hz)，7.40(s，2H)，7.30-7.26(m，2H)，6.86(dd，2H，J＝8.3，8.3Hz)，6.50(d，1H，J＝5.4Hz)，2.05(s，3H)；MS(ESI ⁺)m/z 357.13(M+H) ⁺.

C) 4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl) pyrimidine-2-amine

[00171] with N-(3-fluoro-4-(2-(4-fluorophenyl amino) pyrimidine-4-base oxygen base) phenyl) acetamide (32mg, 0.09mmol), the mixture reflux 2h of 6M HCl (0.2mL) and MeOH (2mL).Cooling mixture with EtOAc (20mL) dilution, is used saturated NaHCO ₃Solution and salt water washing, dry (MgSO ₄), vacuum concentration.At SiO ₂Carry out flash chromatography, the 30-40%EtOAc/ that is used in the hexane contains 1%Et ₃The N eluting obtains title compound (15mg, 46%), is white solid.

¹H NMR(DMSO-d ₆)δ9.55(s，1H)，8.25(d，1H，J＝5.5Hz)，7.43(brs，2H)，6.92-6.85(m，3H)，6.45(dd，1H，J＝13.5，2.1Hz)，6.38-6.35(m，2H)，5.35(brs，2H).MS(ESI ⁺)m/z 315.17(M+H) ⁺.

D) 1-(3-fluoro-4-(2-(4-fluorophenyl amino) pyrimidine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00172] with 4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl) pyrimidine-2-amine (10mg; 0.032mmol) THF (1mL) solution in ice bath, cool off; with 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 228 μ L; 0.064mmol) toluene solution handle, at room temperature stir 2h.The vacuum concentration reactant mixture grinds residue with diisopropyl ether, obtains title compound (15mg, 93%), is white solid.

¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.56(s，1H) 9.68(s，1H)，8.39(d，1H，J＝5.7Hz)，7.76(dd，1H，J＝13.5，2.1Hz)，7.43(brs，2H)，7.46-7.35(m，6H)，7.18(dd，2H，J＝8.8，8.8Hz)，6.57(d，1H，J＝5.4Hz)，3.76(s，2H)；MS(ESI ⁺)m/z 492.0(M+H) ⁺.

Embodiment 32

1-(2-(4-fluorophenyl) acetyl group)-3-(4-((2-(pyridine-2-base is amino) thiazole-5-yl) methylamino) phenyl) thiourea

A) N ¹-((2-(pyridine-2-base is amino) thiazole-5-yl) methyl) benzene-1, the 4-diamidogen

[00173] at ambient temperature, stir 2-(pyridine-2-base is amino)-thiazole-5-formaldehyde (0.10g, 0.49mmol, WO2004/001059), benzene-1, the 4-diamidogen (0.105g, 0.97mmol) and triethyl silicane (0.19mL, CH 1.2mmol) ₂Cl ₂-TFA (3: 1,4mL) solution 4h.The vacuum concentration reactant mixture makes residue at CH ₂Cl ₂With saturated NaHCO ₃Distribute between the aqueous solution.With the saturated NaHCO of organic facies ₃Aqueous solution, salt water washing, dry (MgSO ₄), vacuum concentration.To contain title compound and raw material aldehyde and benzene-1, the crude product of 4-diamidogen is directly brought next step into.

B) 1-(2-(4-fluorophenyl) acetyl group)-3-(4-((2-(pyridine-2-base is amino) thiazole-5-yl) methylamino) phenyl) thiourea

[00174] (7.4 μ L, (4.5mg in EtOAc 0.055mmol) (0.5mL) suspension, at room temperature stirs 30min with the mixture that obtains 0.053mmol) to add NaSCN with 4-fluorophenyl chloroacetic chloride.The CH that then this mixture is added the mixture (14.5mg) that obtains among the above A ₂Cl ₂(0.5ml) in the solution, the mixture that obtains is stirred 2h at ambient temperature.The vacuum concentration reactant mixture, residue is through SiO ₂The flash chromatography purification is used 2-5%MeOH-CHCl ₃Gradient eluent obtains title compound (2mg), is orange tympan.MS(ESI ⁺)m/z 493.2(M+H) ⁺。

Embodiment 33

1-(4-(3-ethylpyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine

[00175] under 150 ℃, with 4-chloro-3-iodo pyridine (1.50g, 6.30mmol, according to Tabanella, S. wait Org.Biomol.Chem.2003,1,4254-4261 preparation), 2-fluoro-nitrophenol (Lancaster, 2.0g, 12.7mmol), the mixture heated of DIPEA (5mL) and NMP (10mL).Behind the 12h, (0.50g 3.18mmol) adds in the reactant mixture, continues heating 4h with 2-fluoro-nitrophenol again.Under 75 ℃, remove most of volatile ingredients, use saturated NaHCO ₃Aqueous solution (150mL) is handled residue, with EtOAc (2 * 100mL) extractions.With the extract that the salt water washing merges, dry (MgSO ₄), vacuum concentration obtains crude product.Through the flash chromatography on silica gel purification, use 0-100%CH successively ₂Cl ₂/ hexane, 2%MeOH/CH ₂Cl ₂Eluting obtains title compound (1.0g, 43%), is yellow solid.

¹H NMR(DMSO-d ₆)δ8.96(s，1H)，8.47(d，2H，J＝5.5Hz)，8.44(dd，1H，J＝2.7，9.2Hz)，7.49(dd，1H，J＝8.8，8.2Hz)，7.07(d，1H，J＝5.5Hz)；MS(ESI ⁺)：m/z 361.05(M+H) ⁺.

B) 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridine

[00176] use successively CsF (169mg, 1.12mmol), (Ph ₃P) ₄Pd (36mg, 0.031mmol) and CuI (10mg 0.056mmol) handles 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine (200mg, 0.56mmol), tributylvinyl tin (212mg, 0.67mmol) DMF (1mL) solution, under 45 ℃, heating blends 1h.Cooling mixture is used CH ₂Cl ₂(15mL) and H ₂O (10mL) dilution, Celite is passed through in violent jolting then ^Filter.CH with 1: 1 ₂Cl ₂/ EtOAc washing leaching cake merges cleaning mixture and filtrate.Use the saline wash solution, dry (MgSO ₄), vacuum concentration obtains brown oil.Crude product is through SiO ₂The flash chromatography purification is used 0-2%MeOH/CH ₂Cl ₂Eluting obtains half pure products.Use 2M HCl/Et ₂O (10mL) handles product, filters and collects hydrochlorate derivant precipitation, uses Et ₂O and EtOAc wash to yellow solid (145mg, 87%).

¹H NMR(DMSO-d ₆)δ9.11(s，1H)，8.64(s，1H)，8.51-8.48(m，1H)，8.24(d，1H，J＝7.7Hz)，7.83-7.79(m，1H)，7.28(d，1H，J＝6.0Hz)，7.02-6.95(m，1H)，6.24(d，1H，J＝17.6Hz)，5.68(d，1H，11.5Hz)；MS(ESI ⁺)：m/z 261.18(M+H) ⁺.

[00177] with the following free alkali that is converted into of above hydrochlorate: with pyridine hydrochloride (230mg) and NaHCO ₃(25mL) and EtOAc (20mL) stir together until homogeneous phase, separate the EtOAc phase, use the salt water washing, drying (MgSO ₄), concentrate.Obtain title compound (190mg), be yellow oil.

C) 4-(3-ethylpyridine-4-base oxygen base)-3-fluoroaniline

[00178] (80mg, 1: 1 EtOAc/MeOH (2mL) solution 0.30mmol) is used the H that is provided by latex balloon through 10% palladium-carbon (30mg) to make 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridine ₂Hydrogenation 1h.With Pt ₂O (10mg) adds in the mixture, continues reaction 1h.Pass through Celite ^Filtering mixt, vacuum concentration obtains title compound (50mg, 63%), is yellow oil.

¹HNMR(DMSO-d ₆)δ8.33(s，1H)，8.22(d，1H，J＝5.6Hz)，6.96(dd，1H，J＝8.7，9.1Hz)，6.50(dd，1H，J＝2.0，13.7Hz)，6.56(d，1H，J＝5.6Hz)，6.41(dd，1H，J＝2.5，6.1Hz)，2.69(q，2H，J＝7.6Hz)，1.21(t，3H，J＝7.6Hz).

D) 1-(4-(3-ethylpyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00179] (Compound D among the embodiment 11,0.33mL, toluene solution 0.11mmol) handle 4-(3-ethylpyridine-4-base oxygen base)-3-fluoroaniline (23mg, CH 0.10mmol) with 0.3M 2-(4-fluorophenyl) acetyl group isocyanates ₂Cl ₂(1mL) solution at room temperature stirs 2.5h with mixture.Enriched mixture under the vacuum grinds residue with 1: 1 diisopropyl ether/EtOAc, obtains yellow solid.With anhydrous MeOH (1mL) and 2M HCl/Et ₂O (1mL) handles product, at room temperature stirs 5min, concentrates under the vacuum, obtains title compound (15mg, 36%), is light yellow solid.

¹HNMR(DMSO-d ₆)δ11.04(s，1H)，10.57(s，1H)，8.41(s，1H)，8.26(d，1H，J＝5.6Hz)，7.76(dd，1H，J＝2.0，12.7Hz)，7.40-7.28(m，4H)，7.19-7.14(m，3H)，6.54(d，1H，J＝5.6Hz)，3.73(s，2H)，2.72(q，2H，J＝7.6Hz)，1.23(t，3H，J＝7.6Hz)；MS(ESI ⁺)：m/z 412.20(M+H) ⁺.

Embodiment 34

1-(4-(2-amino-3-ethylpyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

A) (4-chloro-3-iodo pyridine-2-yl)-t-butyl carbamate

[00180] with (4-chloro-pyridine-2-yl)-t-butyl carbamate (CB Research andDevelopment Inc., 5.0g, 22.0mmol), anhydrous THF (100mL) solution of TMEDA (8mL) places under the blanket of nitrogen, be cooled to-70 ℃, in 30min, drip hexane (22.0mL 54.8mmol) solution-treated of 2.5M n-BuLi.Mixture is stirred 1h down at-70 ℃, under-70 ℃, drip I then ₂(14g, anhydrous THF (16mL) solution-treated 110mmol).After adding end, under-70 ℃, reaction stirred 30min is cooled to room temperature then.H with sodium sulfite (16g) ₂O (100mL) solution-treated mixture stirs 30min, extracts with EtOAc then.With salt water washing extract, dry (MgSO ₄), vacuum concentration.Product is through SiO ₂The flash chromatography purification is used 0-5%MeOH/CH ₂Cl ₂Eluting obtains title compound (5.8g, 78%), is white solid.

¹H NMR(DMSO-d ₆)δ9.46(s，1H)，8.29(d，1H，J＝5.6Hz)，7.46(d，1H，J＝5.0Hz)，1.44(s，9H)；MS(ESI ^-)：m/z 352.99(M-H) ^-.

B) 4-chloro-3-iodo pyridine-2-amine

[00181] under 100 ℃, (4-chloro-3-iodo-pyridine-2-yl)-(5.6g, 15.8mmol) the suspension 10min in 48% hydrobromic acid obtains settled solution to t-butyl carbamate in heating.Cooling mixture is handled with trash ice, makes it alkalize with 6M NaOH.By vacuum filtration collecting precipitation product, use H ₂The O washing, part is drained funnel, obtains white solid.Product is dissolved in THF, and solution is through MgSO ₄Drying, vacuum concentration obtains title compound (3.7g, 93%), is white solid.

¹H NMR(DMSO-d ₆)δ7.84(d，1H，J＝5.1Hz)，6.73(d，1H，J＝5.6Hz)，6.51(brs，2H)；MS(ESI ⁺)：m/z254.97(M+H) ⁺.

C) 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine-2-amine

[00182] (3.6g is 14.2mmol) with 2-fluoro-4-nitrophenol (Lancaster, 4.5g with 4-chloro-3-iodo pyridine-2-amine, 28.4mmol), DIPEA (3.6mL, 20.7mmol) and the mixture of NMP (8mL) place the glass pressure container, quickly heat up to 170 ℃, continue heating 18h.Decompression filtering volatile component is in adhesive residue impouring ice-water (150mL).With mixture supersonic vibration 15min, gummy solid is broken, use saturated NaHCO ₃Aqueous solution transfers to 7.5 with mixture pH.Collect solid by vacuum filtration, use H ₂The O washing is drained on funnel top.In toluene (150mL), vacuum concentrated mixture repeats this process 3 times, obtains brown solid with the exsiccant solid suspension of part.Product is dissolved in MeOH (150mL), uses 4M HCl/1,4-two  alkane (8mL) are handled, and at room temperature stir 5min, then vacuum concentrated mixture.With EtOAc washing with grind the hydrochlorate that obtains thus, with it at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.Separate the EtOAc phase, use the salt water washing, dry then (MgSO ₄).With activated carbon treatment EtOAc solution, at room temperature stir 10min, filtering carbon.Vacuum concentrated solution obtains title compound (3.9g, 74%), is yellow solid.

¹H NMR(DMSO-d ₆)δ8.39(dd，1H，J＝2.5，10.7Hz)，8.12(dd，1H，J＝1.5，9.2Hz)，7.86(d，1H，J＝5.6Hz)，7.32(dd，1H，J＝8.6，8.6Hz)，6.40(br s，2H)，6.18(d，1H，J＝5.6Hz).

D) 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridine-2-amine

[00183] presses the described mode of step B among the embodiment 33,, prepare title compound by the Stille coupling reaction by 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine-2-amine and tributylvinyl tin.

¹H NMR(DMSO-d ₆))δ8.35(dd，1H，J＝10.7，3.1Hz)，8.09(d，1H，J＝9.2Hz)，7.85(d，1H，J＝5.6Hz)，7.31-7.15(m，1H)，6.54(dd，1H，J＝17.8，11.7Hz)，6.24(br s，2H)，6.20(d，1H，J＝5.6Hz)，5.71(d，1H，J＝17.8Hz)，5.46(d，1H，J＝11.7Hz)；MS(ESI ⁺)：m/z276.17(M+H) ⁺.

E) 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridine-2-aminocarbamic acid tert-butyl ester

[00184] under 65 ℃, uses Boc ₂O (140mg, 0.64mmol) handle 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridine-2-amine (60mg, 0.22mmol) 1,4-two  alkane (0.5mL) and the tert-butyl alcohol (1.5mL) solution 5h.Cooling mixture makes it at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.Separate the EtOAc phase, use the salt water washing, dry (MgSO ₄), vacuum concentration.Crude product is through SiO ₂The flash chromatography purification obtains title compound (50mg, 60%), is yellow solid.

¹H NMR(DMSO-d ₆)δ9.37(s，1H)，8.41(dd，1H，J＝10.7，2.5Hz)，8.22(d，1H，J＝5.6Hz)，8.15(d，1H，J＝8.6Hz)，7.42(t，1H，J＝8.6Hz)，6.86(d，1H，J＝5.6Hz)，6.58(dd，1H，J＝17.8，11.7Hz)，5.82(d，1H，J＝16.3Hz)，5.52(d，1H，J＝11.7Hz)，1.42(s，9H)；MS(ESI ⁺)：m/z 376.18(M+H) ⁺.

F) 4-(4-amino-2-fluorophenoxy)-3-ethylpyridine-2-aminocarbamic acid tert-butyl ester

[00185] (48mg, 0.13mmol) solution is through 10% palladium-carbon (10mg) and Pt will to make 4-(2-fluoro-4-nitrophenoxy)-3-vinylpyridine-2-aminocarbamic acid tert-butyl ester ₂O (5mg) uses by the H from rubber balloon ₂Hydrogenation 1.5h.Pass through Celite ^Filtering mixt, vacuum concentrated filtrate obtains title compound (40mg, 89%), is light yellow solid.

¹H NMR(DMSO-d ₆)δ9.04(s，1H)，8.03(d，1H，J＝5.6Hz)，6.95(dd，1H，J＝8.6，8.6Hz)，6.50(dd，1H，J＝2.5，13.2Hz)，6.41(dd，1H，J＝2.5，9.4Hz)，6.36(d，1H，J＝5.6Hz)，5.44(s，2H)，2.67-2.62(m，2H)，1.43(s，9H)，1.11(t，3H，J＝7.1Hz)；MS(ESI ⁺)：m/z348.22(M+H) ⁺.

G) 3-ethyl-4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridine-2-aminocarbamic acid tert-butyl ester

[00186] presses the same way as of the step D of embodiment 33; by 4-(4-amino-2-fluorophenoxy)-3-ethylpyridine-2-aminocarbamic acid tert-butyl ester (20mg; 0.058mmol) and 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (232 μ L 0.070mmol) prepare title compound in toluene and THF.MS(ESI ⁺)：m/z 527.31(M+H) ⁺。

H) 1-(4-(2-amino-3-ethylpyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

[00187] with 3-ethyl-4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridine-2-aminocarbamic acid tert-butyl ester (16mg; 0.03mmol) solution is dissolved in anhydrous THF (0.5mL); use 4M HCl/1,4-two  alkane (1.5mL) are handled, and at room temperature stir 3h.Vacuum concentrated mixture, product obtain title compound (5mg, 36%) through preparation HPLC method A purification, are white solid.

¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.6(s，1H)，7.80-7.79(m，4H)，7.43-7.33(m，4H)，7.16(dd，2H，J＝8.9，8.9Hz)，6.19(d，1H，J＝7.1Hz)，3.73(s，2H)，2.71-2.66(m，2H)，1.10(t，3H，J＝7.1Hz)；MS(ESI ⁺)：m/z 427.18(M+H) ⁺.

Embodiment 35

1-(4-(3-(2-(the amino hexamethylene of 4--1-thiazolinyl) acetenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) 4-(tert-butoxycarbonyl) hexamethylene-1-thiazolinyl triflate

[00188] (THF 1.0mmol) (7mL) solution is cooled to-70 ℃ for Astatech Inc., 213mg, with toluene (2.4ml, 1.2mmol) solution-treated of 0.5M KHMDS with the amino Ketohexamethylene of N-Boc-4-.Mixture is stirred 20min down at-70 ℃, and (392mg, THF 1.1mmol) (4mL) solution-treated stir 25min down at-70 ℃ to drip phenyl trifluoromethanesulfonate methylsulfonyl imines.With saturated NH4Cl aqueous solution quencher mixture,, use 10%Na with the EtOAc dilution ₂CO ₃With the salt water washing, dry (MgSO ₄), vacuum concentration.Crude product is through SiO ₂The flash chromatography purification with 10-25%EtOAc/ hexane eluting, obtains title compound (180mg, 52%), is white solid.

¹H NMR(DMSO-d ₆)δ5.68(s，1H)，4.50(s，1H)，3.82(s，1H)，2.68-2.25(m，3H)，2.22-1.89(m，2H)，1.87-1.63(m，1H)，1.43(s，9H)，

B) 4-(2-(trimethyl silyl) acetenyl) hexamethylene-3-alkenyl amino t-butyl formate

[00189] to the 4-in reaction bulb (tert-butoxycarbonyl) hexamethylene-1-thiazolinyl triflate (170mg, 0.49mmol), trimethyl silyl acetylene (138 μ L, 0.98mmol), Et ₃Charge into argon in the mixture of N (0.68mL) and THF (8mL), (14mg is 0.072mmol) with (Ph to use CuI successively ₃P) ₄(27mg 0.024mmol) handles Pd.Reactant mixture is at room temperature stirred 25min, use EtOAc (50mL) dilution then, use saturated NaHCO ₃Aqueous solution and salt water washing, dry (MgSO ₄), vacuum concentration.Crude product is through SiO ₂The flash chromatography purification with 0-25%EtOAc/ hexane eluting, obtains title compound (116mg, 81%), is yellow solid.

¹H NMR(DMSO-d ₆)δ6.06(s，1H)，4.50(s，1H)，3.76(s，1H)，2.46(d，1H，J＝18.8Hz)，2.36-2.14(m，2H)，2.00-1.78(m，2H)，1.66-1.50(m，1H)，1.43(s，9H)，0.27-0.05(m，9H).

C) 4-acetenyl hexamethylene-3-alkenyl amino t-butyl formate

[00190] with 4-(2-(trimethyl silyl) acetenyl) hexamethylene-3-alkenyl amino t-butyl formate (112mg, 0.38mmol) THF solution be cooled to-15 ℃, THF (Aldrich with the 1.0M tetrabutylammonium fluoride, 440 μ L, 0.44mmol) solution-treated, under-15 ℃, 40min stirs the mixture.Use 5%Na ₂CO ₃(25mL) treatment mixture is used extracted with diethyl ether.Use 5%Na ₂CO ₃With salt water washing ether extraction liquid, dry (MgSO ₄), vacuum concentration obtains title compound (83mg, 99%), is brown oil.

¹H NMR(DMSO-d ₆)δ6.09(s，1H)，4.51(s，1H)，3.77(s，1H)，2.82(s，1H)，2.47(d，1H，J＝18.3Hz)，2.35-2.16(m，2H)，2.04-1.79(m，2H)，1.72-1.51(m，1H)，1.43(s，9H).

D) 4-(2-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acetenyl) hexamethylene-3-alkenyl amino t-butyl formate

[00191] uses Et ₃N (2mL) handles 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine (compd A among the embodiment 33,130mg, 0.36mmol) and N-Boc-4-acetenyl hexamethylene-3-enamine (80mg, anhydrous THF (2mL) solution 0.36mmol) is by the degassing of vacuum/argon purge.With four (triphenyl phasphines) close palladium (20mg, 0.0018mmol) and CuI (10mg, 0.054mmol) Treatment Solution, reflux 2h then.Cooling mixture makes it at saturated NaHCO ₃Distribute between aqueous solution and the EtOAc.Separate the EtOAc phase, use the salt water washing, dry (MgSO ₄), vacuum concentration.Crude product with 0-40%EtOAc/ hexane eluting, obtains title compound (124mg, 76%) through the flash chromatography on silica gel purification, is yellow solid.

¹H NMR(DMSO-d ₆)δ8.68(s，1H)，8.51(d，1H，J＝5.6Hz)，8.43(dd，1H，J＝2.5，10.7Hz)，8.15(d，1H，J＝9.2Hz)，7.49(dd，1H，J＝8.6，8.6Hz)，7.14(d，1H，J＝5.6Hz)，6.85(d，1H，J＝7.1Hz)，6.04-6.00(m，1H)，3.48-3.35(m，1H)，2.36-2.25(m，1H)，2.17-2.04(m，2H)，2.03-1.89(m，1H)，1.78-1.69(m，1H)，1.46-1.35(m，1H)，1.36(s，9H)；MS(ESI ⁺)：m/z 454.27(M+H) ⁺.

E) 4-(2-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) acetenyl) hexamethylene-3-alkenyl amino t-butyl formate

Under [00192] 100 ℃, with 4-(2-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acetenyl) hexamethylene-3-alkenyl amino t-butyl formate (110mg, 0.24mmol) ,～325 purpose iron powders (150mg, 2.7mmol), NH ₄Cl (280mg, 5.3mmol), DMF (1mL), H ₂The mixture heated of O (1mL) and EtOH (1mL) 30 minutes.Pass through Celite ^The pad filtering mixt is used the DMF washing leaching cake, uses saturated NaHCO ₃Aqueous solution makes alkalize (pH8) with filtrate.With EtOAc extraction mixture twice, dry (MgSO ₄), vacuum concentration obtains title compound (105mg), need not anyly be further purified during use.MS(ESI ⁺)：m/z424.27(M+H) ⁺。

F) 4-(2-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) acetenyl) hexamethylene-3-alkenyl amino t-butyl formate

[00193] with 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.8mL; 0.24mmol) toluene solution handle 4-(2-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) acetenyl) hexamethylene-3-alkenyl amino t-butyl formate (50mg, anhydrous CH 0.12mmol) ₂Cl ₂(2mL) solution at room temperature stirs 1h with mixture.Evaporating solvent under the vacuum, residue with 10-60%EtOAc/ hexane eluting, obtain title compound (50mg, 69%) through the flash chromatography on silica gel purification, are white solid.

¹H NMR(DMSO-d ₆)δ11.03(s，1H)，10.57(s，1H)，8.57(s，1H)，8.36(d，1H，J＝5.7Hz)，7.78(dd，1H，J＝1.8，13.1Hz)，7.41-7.29(m，3H)，7.16(dd，3H，J＝8.6，8.6Hz)，6.85(d，1H，J＝8.3Hz)，6.70(d，1H，J＝5.7Hz)，6.13-6.08(m，1H)，3.73(s，2H)，3.51-3.41(m，1H)，2.38-2.27(m，1H)，2.27-2.20(m，2H)，1.82-1.72(m，1H)，1.54-1.28(m，2H)，1.37(s，9H)；ESIMS)：m/z 603.24(M+H) ⁺.

G) 1-(4-(3-(2-(the amino hexamethylene of 4--1-thiazolinyl) acetenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00194] with 4-(2-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) acetenyl) hexamethylene-3-alkenyl amino t-butyl formate (40mg; 0.066mol) anhydrous 1; 4-two  alkane (2mL) solution are cooled to-10 ℃; use 4M HCl/1,4-two  alkane (4mL) are handled.The 2.5h that stirs the mixture under-5 ℃ at room temperature stirs 1h then.Enriched mixture under the vacuum need not anyly heat, and obtains title compound (32mg, 84%), is yellow solid.

¹H NMR(DMSO-d ₆)δ11.05(s，1H)，10.61(s，1H)，8.69(s，1H)，8.44(d，1H，J＝6.1Hz)，8.06(d，1H，J＝2.0Hz)，7.80(dd，1H，J＝12.7，2.0Hz)，7.46-7.38(m，1H)，7.35(dd，1H，J＝8.6，5.6Hz)，7.19-7.13(m，1H)，6.82(d，1H，J＝5.6Hz)，6.17(s，1H)，3.74(s，2H)，3.73-3.62(m，2H)，3.62-3.54(m，1H)，3.34-3.22(m，1H)，2.31(s，1H)，1.99-1.96(m，1H)，1.71-1.66(m，1H)；MS(ESI ⁺)：m/z503.12(M+H) ⁺.

Embodiment 36

1-(4-(3-(3-(3-(amino methyl) azetidine-1-yl) third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, tri hydrochloride

A) 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol

[00195] by vacuum/argon purge, make 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine (compd A among the embodiment 33,300mg, propargyl alcohol 0.83mmol) (Aldrich, 145 μ L, 2.50mmol), Et ₃The N (2mL) and the degassing of anhydrous THF (2mL) solution are with Pd (PH ₃P) ₄(31mg, 0.027mmol) and CuI (10mg 0.054mmol) handles.Under argon atmospher, with mixture reflux 10min, be cooled to room temperature, with EtOAc (25mL) and H ₂O (20mL) dilution.With EtOAc phase water and salt water washing, dry (MgSO ₄), vacuum concentration.Thick residue is used 0-3%MeOH/CH through the flash chromatography on silica gel purification ₂Cl ₂Eluting obtains the product (185mg, 77%) that needs, is light yellow solid.

¹H NMR(DMSO-d ₆)δ8.69(s，1H)，8.49(d，1H，J＝5.6Hz)，8.43(dd，1H，J＝10.7，2.5Hz)，8.17(d，1H，J＝9.2Hz)，7.57(t，1H，J＝8.6Hz)，7.04(d，1H，J＝5.6Hz)，5.40(t，1H，J＝6.1)4.28(d，2H，J＝6.1Hz)；MS(ESI ⁺)：m/z 289.13(M+H) ⁺.

B) (1-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl) azetidine-3-yl) methyl carbamic acid tert-butyl ester

[00196] with 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol (43mg, 0.15mmol) and DIPEA (45 μ L, 0.26mmol) anhydrous THF (1.5mL) solution be cooled to 0 ℃, with mesyl chloride (15mg, 0.11mmol) batch processing.After stirring 1h under 0 ℃, the concentrating under reduced pressure mixture.With DMF (1.0mL), DIPEA (45 μ L, 0.26mmol) and azetidine-3-ylmethyl-t-butyl carbamate (Beta Pharma Inc., 145mg 0.78mmol) handle residue, at room temperature stir 2h.Make reactant mixture at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution, separate the EtOAc phase, use the salt water washing, dry (MgSO ₄), vacuum concentration.Residue is through SiO ₂The flash chromatography purification is used 1-5%MeOH/CH ₂Cl ₂Eluting obtains title compound (33mg, 48%), is colorless oil.

¹H NMR(DMSO-d ₆)δ8.74(s，1H)，8.51(d，1H，J＝5.6Hz)，8.41(dd，1H，J＝10.7，2.5Hz)，8.15(d，1H，J＝9.2Hz)，7.53(t，1H，J＝8.6Hz)，7.09(d，1H，J＝6.1Hz)，6.86(t，1H，J＝5.6Hz)，3.39(s，2H)，3.24-3.14(M，2H)，3.07-2.98(M，2H)，2.94-2.87(m，2H)，2.37-2.26(m，1H)，1.33(s，9H)；MS(ESI ⁺)：m/z 401.20(100)，[(M-C ₄H ₉)] ⁺；m/z457.20(25)，(M+H) ⁺.

C) (1-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl) azetidine-3-yl) methyl carbamic acid tert-butyl ester

[00197] by with embodiment 35 in the identical mode of step e, by with the Fe powder (50mg, 0.091mmol) and NH ₄(96mg, 1.82mmol) (30mg 0.66mmol), prepares title compound to reduction (1-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl) azetidine-3-yl) methyl carbamic acid tert-butyl ester to Cl.Need not any purification when product is used for subsequent reactions.

MS(ESI ⁺)：m/z371.24(100)，[(M-C ₄H ₉)] ⁺；m/z 427.27(25)，M+H) ⁺.

D) (1-(3-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) Propargyl) azetidine-3-yl) methyl carbamic acid tert-butyl ester

[00198] by with embodiment 33 in the identical mode of step D; by (1-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl) azetidine-3-yl) the methyl carbamic acid tert-butyl ester (25mg; 0.059mmol) and 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.37mL; 0.11mmol) toluene solution prepare title compound; obtain title compound, be white solid (20mg, 57%).

¹H NMR(DMSO-d ₆)δ11.04(s，1H)，10.58(s，1H)，8.63(s，1H)，8.37(d，1H，J＝5.5Hz)，7.78(d，1H，J＝12.6Hz)，7.40-7.33(m，4H)，7.16(dd，2H，J＝8.8，8.9Hz)，6.89-6.87(m，1H)，6.68(d，1H，J＝5.5Hz)，3.73(s，2H)，3.45(s，2H)，3.26-3.24(m，2H)，3.07-3.04(m，2H)，2.98-2.96(m，2H)，2.38-2.35(m，2H)，1.32(s，9H)；MS(ESI ⁺)：m/z606.26(M+H) ⁺.

E) 1-(4-(3-(3-(3-(amino methyl) azetidine-1-yl) third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, tri hydrochloride

[00199] (20mg 0.033mmol) is dissolved in CH with (1-(3-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) Propargyl) azetidine-3-yl) methyl carbamic acid tert-butyl ester ₂Cl ₂(2mL), handle with TFA (0.5mL), 1.5h at room temperature stirs the mixture.Vacuum concentrated mixture by preparation HPLC (post A) purification, obtains tfa salt.Tfa salt is dissolved in anhydrous MeOH, handles with 1.0M HCl/ ether, stir 5min, vacuum concentration obtains title compound (9mg, 45%), is white solid.

¹H NMR(DMSO-d ₆)δ11.07(s，1H)，10.06(s，1H)，8.96(m，1H)，8.61-8.52(m，1H)，8.36-8.25(s，2H)，7.82(d，1H，J＝12.2Hz)，7.45-7.42(m，2H)，7.37-7.33(m，2H)，7.18-7.14(m，2H)，6.92(d，1H，J＝6.1Hz)，4.48(s，2H)，4.27-3.98(m，2H)，3.76(s，2H)，3.30-3.20(m，1H)，3.16-3.00(m，2H)；MS(ESI ⁺)：m/z 506.18(M+H) ⁺.

[00200] by preparing embodiment 37-40 to mode similar described in the embodiment 36.

Embodiment 37

1-(4-(3-(3-(the amino azetidine of 3--1-yl) third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, tri hydrochloride

[00201]MS(ESI ⁺)：m/z 492.17(M+H) ⁺

Embodiment 38

1-(3-fluoro-4-(3-(3-(piperazine-1-yl) third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, tri hydrochloride

[00202] ¹H NMR(DMSO-d ₆)δ11.07(s，1H)，10.63(s，1H)，9.44(s，1H)，8.91(s，1H)，8.50(d，1H，J＝6.2Hz)，7.84-7.78(m，1H)，7.45-7.39(m，2H)，7.38-7.32(m，2H)，7.16(t，2H，J＝8.8Hz)，6.85(d，1H，J＝6.2Hz)，4.26(s，2H)，3.75(s，2H)，3.34(brs，4H)，2.49(brs，4H)；MS(ESI ⁺)：m/z 506.23(M+H) ⁺.

Embodiment 39

1-(4-(3-(3-(4-amino piperidine-1-yl) third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, tri hydrochloride

[00203] ¹H NMR(DMSO-d ₆)δ11.07(s，1H)，10.62(s，1H)，8.81(s，1H)，8.48(d，1H，J＝6.1Hz)，8.31(s，2H)，7.80(dd，1H，J＝2.2，12.7Hz)，7.44-7.33(m，4H)，7.19-7.13(m，2H)，6.78(d，1H，J＝5.7Hz)，4.40(s，2H)，3.74(s，2H)，3.64-3.60(m，2H)，3.34-3.22(m,1H)，3.19-3.13(M，2H)，2.16-2.13(m，2H)，1.99-1.88(m，2H)；MS(ESI ⁺)：m/z506.23(M+H) ⁺.

Embodiment 40

(±)-1-(4-(3-(3-(3-amino-pyrrolidine-1-yl) third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, tri hydrochloride

[00204] ¹H NMR(DMSO-d ₆)δ11.08(s，1H)，10.65(s，1H)，8.96(s，1H)，8.54(d，1H，J＝6.1Hz)，7.83(d，1H，J＝12.7Hz)，7.43(s，2H)，7.37-7.33(m，2H)，7.16-7.14(m，2H)，6.90(d，1H，J＝5.6Hz)，4.62(s，2H)，4.06-3.87(m，1H)，3.75(s，2H)，3.70-3.55(m，3H)，3.49-3.44(m，2H)，2.25-2.08(m，1H)；MS(ESI ⁺)：m/z506.22(M+H) ⁺.

Embodiment 41

1-(3-fluoro-4-(3-(3-((3R, 4R)-3-hydroxyl-4-(pyrrolidine-1-yl) pyrrolidine-1-yl) third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, tri hydrochloride

A) (3R, 4R)-1-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl)-4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol

[00205] with 3-(4-(the 2-fluoro-4-nitrophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol (compd A among the embodiment 36,43mg, 0.15mmol) and DIPEA (45 μ L, 0.26mmol) anhydrous THF (1.5mL) solution be cooled to 0 ℃, with mesyl chloride (15mg, 0.11mmol) batch processing, after stirring 1h under 0 ℃, the concentrating under reduced pressure mixture.With DMF (1.0mL), DIPEA (45 μ L, 0.26mmol) and (3R, 4R)-(Lexicon Pharmaceutical Corp., 94mg 0.6mmol) handle residue to 4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol, at room temperature stir 2h.Make reactant mixture at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution, separate the EtOAc phase, use the salt water washing, dry (MgSO ₄), vacuum concentration.Crude product is through SiO ₂The flash chromatography purification is used 0-1.5%MeOH/CH ₂Cl ₂Eluting obtains title compound (38mg, 59%), is brown oil.

¹H NMR(DMSO-d ₆)δ8.72(s，1H)，8.54(d，1H，J＝5.6Hz)，8.40(dd，1H，J＝10.7，2.5Hz)，8.14(d，1H，J＝9.2Hz)，7.43(t，1H，J＝8.6Hz)，7.15(d，1H，J＝5.6Hz)，4.99-4.81(m，1H)，4.11-4.10(m，0.5H)，3.92-3.84(m，1H)，3.54(s，2H)，3.59-3.50(m，0.5H)，3.16-3.15(m，1H)，2.79-2.75(m，1H)，2.60-2.32(m，4H)，1.70-1.59(m，4H)；MS(ESI ⁺)：m/z427.24(M+H) ⁺.

B) (3R, 4R)-1-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl)-4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol

[00206] with Fe powder (67mg, 1.2mmol, 2.4mmol) handle (3R, 4R)-1-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl)-4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol (35mg, 0.082mmol), DMF (1mL), EtOH (1mL) and H ₂The mixture of O (1mL) heats 45min down at 100 ℃.Pass through Celite ^Filtering mixt is used NaHCO ₃Make it alkalize, vacuum concentration.Make residue at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With the dry mutually (MgSO of EtOAc ₄), vacuum concentration obtains crude benzol amine (16mg, 50%), need not be further purified and be directly used in next step.MS(ESI ⁺)：m/z397.28(M+H) ⁺。

C) 1-(3-fluoro-4-(3-(3-((3R, 4R)-3-hydroxyl-4-(pyrrolidine-1-yl) pyrrolidine-1-yl) third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, tri hydrochloride

[00207] by with embodiment 33 in the identical mode of step D; by (3R; 4R)-1-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl)-4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol (16mg; 0.04mmol) and 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.13mL toluene solution 0.04mmol) prepares title compound.By with embodiment 36 in the identical mode of step e, product through preparation HPLC (post A) purification, is converted into hydrochlorate, obtain title compound (9mg, 33%), be white solid.

¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.62(s，1H)，8.86(s，1H)，8.45(d，1H，J＝6.1Hz)，7.81(d，1H，J＝12.2Hz)，7.45-7.40(m，4H)，7.33-7.28(m，4H)，7.16(dd，2H，J＝9.2，8.6Hz)，6.80(d，1H，J＝6.1Hz)，4.64(s，1H)，4.34(s，2H)，3.84-3.70(m，4H)，2.70-3.55(m，2H)，3.55-2.98(m，3H)，2.08-1.92(m，2H)，1.92-1.75(m，2H)；MS(ESI ⁺)：m/z 576.25(M+H) ⁺.

Embodiment 42

1-(3-fluoro-4-(3-(3-(2-(pyrrolidine-1-yl) acetylamino) third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

A) N-Boc-propargylamine

[00208] (21.8mg 100.0mmol) is dissolved in THF (25mL), and solution is cooled to 0 ℃, and (90.0mmol) solution-treated keeps temperature to be lower than 15 ℃ for Aldrich, 5.0g to drip propargylamine with Bis(tert-butoxycarbonyl)oxide.Mixture is at room temperature stirred 1.5h, concentrate under the vacuum then.Residue is dissolved in hexane, filters, use 0-100%CH by silicagel column ₂Cl ₂/ hexane eluted product.Vacuum concentration contains the eluent of product, obtains colorless oil, and it is dissolved in hexane (150mL), is cooled to 0 ℃, obtains white crystals.Filter and collect crystallization, dry under the vacuum, obtain title compound (10.5g, 75%). ¹H NMR(CDCl ₃)δ4.75(s，1H)，3.95(s，2H)，2.25-2.24(m，1H)，1.48(s，9H)。

B) 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl t-butyl carbamate

[00209] by the crosslinked coupling reaction of Sonagashira, presses the step C among the embodiment 35, with Pd (Ph ₃P) ₄(9mg, 0.008mmol) and CuI (1.5mg, 1: 1 Et 0.008mmol) ₃N/THF (3mL) solution, by the N-Boc-propargylamine (98mg, 0.63mmol) and 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine (compd A among the embodiment 33,150mg, 0.42mmol) preparation title compound.Obtain title compound (124mg, 76%), be red oil.

¹H NMR(DMSO-d ₆)δ8.66(s，1H)，8.50(d，1H，J＝5.6Hz)，8.40(dd，1H，J＝2.5，10.7Hz)，8.15(d，1H，J＝9.2Hz)，7.52(dd，1H，J＝8.1，8.6Hz)，7.33-7.30(m，1H)，7.07(d，1H，J＝5.6Hz)，3.95(d，2H，J＝5.6Hz)，1.35(s，9H)；MS(ESI ⁺)：m/z388.21(M+H) ⁺.

C) 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) third-2-alkynes-1-amine

[00210] handles 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl t-butyl carbamate (300mg, CH 0.78mmol) with TFA (2mL) ₂Cl ₂(10mL) solution at room temperature stirs 45min.Enriched mixture under the vacuum makes residue at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.Separate the EtOAc phase, use the salt water washing, dry (MgSO ₄), vacuum concentration obtains title compound (180mg, 80%), is red oil.

¹H NMR(DMSO-d ₆)δ8.65(S，1H)，8.47(d，1H，J＝5.6Hz)，8.43(dd，1H，J＝10.7，2.5Hz)，8.17(d，1H，J＝8.6Hz)，7.54(t，1H，J＝8.6Hz)，7.04(d，1H，J＝5.6Hz)，3.49(s，2H)；MS(ESI ⁺)：m/z288.17(M+H) ⁺.

D) N-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl)-2-(pyrrolidinyl-1-yl) acetamide

[00211] with 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) third-2-alkynes-1-amine (80mg, anhydrous CH 0.26mmol) ₂Cl ₂(2.5mL) solution is cooled to 0 ℃, and (40mg 0.37mmol) handles, and 1h at room temperature stirs the mixture with chloracetyl chloride.Enriched mixture under the vacuum removes and desolvates and excess reagent, and residue is dissolved in CH ₃CN (1.5mL), (55mg 0.78mmol) handles, and at room temperature stirs 4h with ketopyrrolidine.Make mixture at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution, separate organic facies, use the salt water washing, dry (MgSO ₄), concentrate, obtain crude product.Residue is used 0-10%MeOH/CH through the flash chromatography on silica gel purification ₂Cl ₂Eluting obtains title compound (40mg, 39%), is brown oil.

¹H NMR(DMSO-d ₆)δ8.66(s，1H)，8.50(d，1H，J＝6.1Hz)，8.41(dd，1H，J＝2.8，10.4Hz)，8.18-8.15(m，2H)，7.51(dd，1H，J＝8.3，8.8Hz)，7.06(d，1H，J＝5.5Hz)4.10(d，2H，J＝5.5Hz)，3.01(s，2H)，2.47-2.43(m，4H)，1.67-1.63(m，4H)；MS(ESI ⁺)：m/z 399.27(M+H) ⁺.

E) N-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl)-2-(pyrrolidine-1-yl) acetamide

[00212] by the mode that is similar to step e among the embodiment 35, with the Fe powder (67mg, 1.21mmol) and NH ₄(128mg, 2.42mmol) (35mg 0.088mmol), prepares title compound to reduction N-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl)-2-(pyrrolidine-1-yl) acetamide to Cl.Need not purification when product is used for subsequent reactions.Yellow oil (30mg, 93%).MS(ESI ⁺)：m/z 319.24(M+H) ⁺。

F) 1-(3-fluoro-4-(3-(3-(2-(pyrrolidine-1-yl) acetylamino) third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00213] by the mode that is similar to step D among the embodiment 33; with THF (0.5ml); by N-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl)-2-(pyrrolidine-1-yl) acetamide (32mg; 0.088mmol) and 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.40ml toluene solution 0.12mmol) prepares title compound.Product is through preparation HPLC (post B) purification.Contain the flow point of product with the acid treatment of excessive 1M salt, vacuum concentration, lyophilizing obtains title compound (30mg, 63%), is light yellow solid.

¹H NMR(DMSO-d ₆)δ11.07(s，1H)，10.62(s，1H)，10.09(s，1H)，9.17-9.14(m，1H)，8.65(s，1H)，8.43(d，1H，J＝5.6Hz)，7.81(dd，1H，J＝2.5，12.7Hz)，7.44-7.33(m，4H)，7.19-7.12(m，2H)，4.31(d，2H，J＝5.6Hz)，4.05(d，2H，J＝5.6Hz)，3.74(s，2H)，3.56-3.51(m，2H)，3.05-2.99(m，2H)，1.96-1.90(m，2H)，1.88-1.79(m，2H)；MS(ESI ⁺)：m/z 548.26(M+H) ⁺.

Embodiment 43

1-(3-fluoro-4-(3-(3-(2-(4-hydroxy piperidine-1-yl) acetylamino) third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

A) N-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl)-2-(4-hydroxy piperidine-1-yl) acetamide

[00214] by with embodiment 42 in the identical mode of step D, by 3-(4-(the 2-fluoro-4-nitrophenoxy) pyridin-3-yl) third-2-alkynes-1-amine (compd A among the embodiment 36,80mg, 0.26mmol), 4-hydroxy piperidine (79mmol, 0.78mmol) and chloracetyl chloride (40mg, 0.36mmol) preparation title compound.Residue is used 1-3%MeOH/CH through the flash chromatography on silica gel purification ₂Cl ₂Eluting obtains white foam shape thing (40mg, 36%).

¹H NMR(DMSO-d ₆)δ8.65(s，1H)，8.49(d，1H，J＝5.5Hz)，8.41(dd，1H，J＝10.4，2.7Hz)，8.18-8.12(m，2H)，7.55-7.50(m，1H)，7.05(d，1H，J＝6.0Hz)，4.54(d，1H，J＝3.8Hz)，4.11(d，2H，J＝6.0Hz)，3.43-3.36(m，1H)，2.86(s，2H)，2.64-2.58(m，2H)，2.12-2.05(m，2H)，1.67-1.61(m，2H)，1.44-1.36(m，2H)；MS(ESI ⁺)：m/z 429.18(M+H) ⁺.

B) N-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl)-2-(4-hydroxy piperidine-1-yl) acetamide

[00215] by the mode that is similar to step e among the embodiment 35, with Fe (powder, 67mg, 1.21mmol), NH ₄(128mg, 2.42mmol) (33mg 0.077mmol), prepares title compound to reduction N-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl)-2-(4-hydroxy piperidine-1-yl) acetamide to Cl.Obtain product (30mg, 100%), be yellow oil, be directly used in subsequent step.MS(ESI ⁺)：m/z 399.27(M+H) ⁺。

C) 1-(3-fluoro-4-(3-(3-(2-(4-hydroxy piperidine-1-yl) acetylamino) third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00216] by the mode that is similar to step D among the embodiment 33; with THF (0.5ml); by N-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl)-2-(4-hydroxy piperidine-1-yl) acetamide (25mg; 0.063mmol) and 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.40mL toluene solution 0.12mmol) prepares title compound.Product is through preparation HPLC (post B) purification.Contain the flow point of product with the acid treatment of excessive 1N salt, concentrate, lyophilizing obtains title compound (10mg, 30%), is light yellow solid.

¹H NMR(DMSO-d ₆)δ11.08(s，1H)，10.64(s，1H)，9.83-9.72(m，1H)，9.25-9.20(m，1H)，8.66(s，1H)，8.45(d，1H，J＝6.1Hz)，7.83(dd，1H，J＝2.0，13.2Hz)，7.46-7.35(m，3H)，7.21-7.11(m，2H)，6.77(d，1H，J＝6.1Hz)，4.33-4.31(m，2H)，3.99-3.94(m，2H)，3.92-3.89(m，1H)，3.76(s，2H)，3.46-3.40(m，2H)，3.29-3.21(m，2H)，3.10-3.00(m，1H)，1.98-1.87(m，2H)，1.72-1.62(m，2H)；MS(ESI ⁺)：m/z 528.25(M+H) ⁺.

Embodiment 44

(S)-and 1-(3-fluoro-4-(3-(3-(2-(pyrrolidine-1-ylmethyl) pyrrolidine-1-formamido group) third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

A) (S)-N-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl)-2-(pyrrolidine-1-ylmethyl) pyrrolidine-1-Methanamide

[00217] (compd A among the embodiment 36,55mg 0.19mmol) are dissolved in CH to third-2-alkynes-1-amine with 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) ₂Cl ₂(5mL), with the 4-chloroformate nitrophenyl ester (0.38mg, 0.19mmol) and pyridine (15 μ L, 0.19mmol) processing.Stirred reaction mixture at room temperature.Behind the 1h, use Et ₃N (30mL, 0.20mmol) and (S)-(+)-(0.21mmol) treatment mixture at room temperature stirs 15h to 1-(2-pyrrolidinyl methyl) ketopyrrolidine for Aldrich, 32mg.Use CH then ₂Cl ₂(50mL) diluted mixture thing, with 1MNaOH and salt water washing, dry (MgSO ₄), vacuum concentration obtains crude product.Residue is used 0-10%MeOH/CH through the flash chromatography on silica gel purification ₂Cl ₂Eluting obtains title compound (53mg, 60%), is yellow oil.

¹H NMR(DMSO-d ₆)δ8.65(s，1H)，8.49(d，1H，J＝6.1Hz)，8.41(dd，1H，J＝2.8Hz，10.5Hz)，8.16(d，1H，J＝7.7Hz)，7.52(dd，1H，J＝8.3，8.8Hz)，7.05(d，1H，J＝6.1Hz)，4.11-4.06(m，2H)，3.99-3.95(m，2H)，3.76(s，2H)，3.16-3.11(m，2H)，2.57-2.48(m，2H)，2.43-2.41(m，2H)，3.36-2.34(m，2H)，1.90-1.86(m，2H)，1.76-1.62(m，3H)；MS(ESI ⁺)：m/z 468.27(M+H) ⁺.

B) (S)-N-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl)-2-(pyrrolidine-1-ylmethyl) pyrrolidine-1-Methanamide

[00218] by the mode that is similar to step e among the embodiment 35, with Fe (powder, 67mg, 1.21mmol), NH ₄(128mg, 2.42mmol) (50mg 0.11mmol), prepares title compound to reduction (S)-N-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl)-2-(pyrrolidine-1-ylmethyl) pyrrolidine-1-Methanamide to Cl.Obtain product (36mg, 75%), be yellow oil, can be directly used in subsequent step.MS(ESI ⁺)：m/z438.30(M+H) ⁺。

C) (S)-and 1-(3-fluoro-4-(3-(3-(2-(pyrrolidine-1-ylmethyl) pyrrolidine-1-formamido group) third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00219] by with embodiment 33 in the identical mode of step D; by (S)-N-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl)-2-(pyrrolidine-1-ylmethyl) pyrrolidine-1-Methanamide (36mg; 0.057mmol) and 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.37mL toluene solution 0.11mmol) prepares title compound.Product is pressed step C among the embodiment 43 through preparation HPLC (post B) purification, is translated into hydrochlorate, obtains title compound (10mg, 25%), is amber oily thing.

¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.60(s，1H)，9.56(s，1H)，8.58(s，1H)，8.38(d，1H，J＝5.6Hz)，7.80(dd，1H，J＝2.6，12.7Hz)，7.42(dm，1H，J＝10.6Hz)，7.38-7.31(m，2H)，7.30-7.25(m，1H)，7.20-7.10(m，2H)，6.69(d，1H，J＝6.1Hz)，4.26-.4.12(m，2H)，3.79-3.69(m,3H)，3.56(s，2H)，3.31-3.18(m，2H)，3.17-2.93(m，2H)，2.14-2.02(m，4H)，2.03-1.76(m，5H)，1.71-1.61(m，1H)；MS(ESI ⁺)：m/z 617.20(M+H) ⁺.

Embodiment 45

(E)-and 1-(4-(3-(3-(4-amino piperidine-1-yl)-3-oxo third-1-thiazolinyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, two trifluoroacetates

A) 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acrylic acid (E)-tertiary butyl ester

[00220] by vacuum/argon purge, make 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine (compd A among the embodiment 33,150mg, 0.42mmol), tert-butyl acrylate base (Aldrich, 107mg, 0.84mmol), tri-n-butylamine (0.21mL, 0.92mmol) and the mixture of DMF (2mL) degassing, with Pd (OAc) ₂(17mg 0.078mmol) handles.Under argon, under 100-130 ℃, heating blends 45min is cooled to room temperature with mixture then, makes it at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.Separate each phase, use saturated NaHCO ₃Aqueous solution and salt water washing EtOAc extract, dry (MgSO ₄), vacuum concentration.Crude product is through SiO ₂The flash chromatography purification is used 0-20%EtOAc/CH ₂Cl ₂Eluting obtains title compound (118mg, 78%), is light yellow oil, and it at room temperature solidifies.

¹H NMR(DMSO-d ₆)δ9.02(s，1H)，8.49(d，1H，J＝5.5Hz)，8.46(dd，1H，J＝2.5，11.7Hz)，8.21(dm，1H，J＝9.2Hz)，7.74(d，1H，J＝16.3Hz)，7.65(dd，1H，J＝8.1，8.6Hz)，6.95(d，1H，J＝6.1Hz)，6.77(d，1H，J＝16.3Hz)，1.47(s，9H)；MS(ESI ⁺)：m/z 361.15(M+H) ⁺.

B) (E)-3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acrylic acid

[00221] with 1: 1 TFA/CH ₂Cl ₂(115mg 0.32mmol), at room temperature stirs 1.5h to acrylic acid (E)-tertiary butyl ester (6mL) to handle 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl).Enriched mixture under the vacuum is with MeOH (5mL) and 2M HCl/Et ₂O (15mL) handles residue, concentrates under the vacuum.With MeOH (5mL) and 2M HCl/Et ₂O (15mL) handles for the second time, and reconcentration obtains title compound (120mg).

¹H NMR(DMSO-d ₆)δ9.17(s，1H)，8.62(d，1H，J＝6.6Hz)，8.50(dd，1H，J＝2.6，10.1Hz)，8.25(d，1H，J＝9.1Hz)，7.78(d，1H，J＝16.3Hz)，7.74(dd，1H，J＝8.1，8.6Hz)，7.17(d，1H，J＝6.1Hz)，6.87(d，1H，J＝16.3Hz)；MS(ESI ⁺)：m/z 305.11(M+H) ⁺.

C) 1-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acryloyl group) piperidin-4-yl carbamic acid (E)-tertiary butyl ester

[00222] with DIPEA (160 μ L, 0.92mmol) and TBTU (160mg, 0.50mmol) processing (E)-3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acrylic acid (143mg, 0.42mmol), 4-N-Boc-amino piperidine (Aldrich, 84mg, 0.42mmol) DMF (1.5mL) solution, 2h at room temperature stirs the mixture.With EtOAc diluted mixture thing, use saturated NaHCO ₃Aqueous solution and salt water washing, dry (MgSO ₄), vacuum concentration.Crude product is used 30-100%EtOAc/ hexane, 5%MeOH/CH successively through the flash chromatography on silica gel purification ₂Cl ₂Eluting obtains title compound (110mg, 54%), is the light brown solid.

¹H NMR(DMSO-d ₆)δ9.15(s，1H)，8.48(d，1H，J＝5.6Hz)，8.44(dd，1H，J＝2.5，10.5Hz)，8.18(d，1H，J＝9.2Hz)，7.69(d，1H，J＝15.3Hz)，7.58(dd，1H，J＝8.6，8.6Hz)，7.50(d，1H，J＝15.7Hz)，6.97(d，1H，J＝5.6Hz)，6.89(d，1H，J＝7.6Hz)，4.31-4.16(m，2H)，3.55-3.46(m，1H)，3.20-3.14(m，1H)，2.83-2.81(m，1H)，1.82-1.71(m，2H)，1.34-1.18(m，2H)，1.37(s，9H)；MS(ESI ⁺)：m/z431.04(100)[(M-C ₄H ₉) ⁺H] ⁺；m/z487.10(90)(M+H) ⁺.

D) 1-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) acryloyl group) piperidin-4-yl carbamic acid (E)-tertiary butyl ester

[00223] by the mode that is similar to step e among the embodiment 35, with the Fe powder (55mg, 2.7mmol), NH ₄(280mg, 5.3mmol) (100mg 0.21mmol), prepares title compound to reduction 1-(3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acryloyl group) piperidin-4-yl carbamic acid (E)-tertiary butyl ester to Cl.Obtain product (90mg, 95%), be the light brown solid, it can be directly used in subsequent step.MS(ES1 ⁺)：m/z 457.18(M+H) ⁺。

E) 1-(3-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) acryloyl group) piperidin-4-yl carbamic acid (E)-tertiary butyl ester

[00224] by the mode that is similar to step D among the embodiment 33; by 1-(3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) acryloyl group) piperidin-4-yl carbamic acid (E)-tertiary butyl ester (42mg; 0.092mmol) and 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.50mL toluene solution 0.15mmol) prepares title compound.Crude product is adsorbed on the silica gel,, uses the 0-5%MeOH/EtOAc eluting, obtain product (20mg, 33%), be white solid through the flash chromatography purification.

¹H NMR(DMSO-d ₆)δ11.05(s，1H)，10.59(s，1H)，9.03(s，1H)，8.37(d，1H，J＝5.6Hz)，7.82-7.74(m，2H)，7.47(d，1H，J＝15.8Hz)，7.42-7.33(m，4H)，7.20-7.13(m，2H)，6.89(d，1H，J＝8.1Hz)，6.63(d，1H，J＝5.6Hz)，4.31(d，1H，J＝13.7Hz)，4.19(d，1H，J＝12.7Hz)，3.74(s，2H)，3.56-3.47(m，1H)，3.22-3.13(m，1H)，2.84-2.76(m，1H)，1.76(s，2H)，1.37(s，9H)，1.32-1.20(m，2H)；MS(ESI ⁺)：m/z 636.23(M+H) ⁺.

F) (E)-and 1-(4-(3-(3-(4-amino piperidine-1-yl)-3-oxo third-1-thiazolinyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, two trifluoroacetates

[00225] with 1-(3-(4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) acryloyl group) piperidin-4-yl carbamic acid (E)-tertiary butyl ester (15mg; 0.024mmol) be dissolved in anhydrous MeOH (0.5mL); use 4M HCl/1; 4-two  alkane (1.5mL) are handled, and at room temperature stir 1h.Enriched mixture under the vacuum obtains crude product, through preparation HPLC (post A) purification.Contain the flow point of product with the acid treatment of excessive 1M salt, concentrate, lyophilizing obtains title compound (8mg, 44%), is light yellow solid.

¹H NMR(DMSO-d ₆)δ11.07(s，1H)，10.61(s，1H)，9.10(s，1H)，8.44(s，1H)，7.91(m，3H)，7.86-7.69(m，2H)，7.55-7.28(m，5H)，7.23-7.08(m，2H)，6.80-6.72(m，1H)，5.61-5.33(m，1H)，4.45-4.20(m，2H)，3.74(s，2H)，3.39-3.07(m，2H)，2.82-2.68(m，1H)，1.91-1.51(m，2H)，1.50-1.15(m，1H)；MS(ESI ⁺)：m/z536.16(M+H) ⁺.

Embodiment 46

1-(3-fluoro-4-(3-(2-(pyridine-2-yl) acetenyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

A) 2-(2-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acetenyl) pyridine

[00226] by vacuum/argon purge, make 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine (compd A among the embodiment 33,50mg, 0.14mmol) and the 2-ethynyl pyridine (Aldrich, 57mg, 0.54mmol), THF (1mL) and Et ₃The mixture degassing of N (1mL), (3mg is 0.016mmol) with (Ph to use CuI successively ₃P) ₄(10mg 0.009mmol) handles Pd.Under 60 ℃, heating blends 45 minutes, cooling makes it dry between EtOAc and saturated sodium bicarbonate, dry (MgSO ₄) the EtOAc phase, vacuum concentration obtains crude product.Residue is through SiO ₂The rapid column chromatography purification is used 0-1.5%MeOH/CH ₂Cl ₂Eluting obtains title compound (42mg, 89%), is brown solid.

¹H NMR(DMSO-d ₆)δ8.91(s，1H)，8.60(d，1H，J＝4.5Hz)，8.45(dd，1H，J＝2.6，10.7Hz)，8.19(d，1H，J＝9.1Hz)，7.86-7.83(m，1H)，7.66(dd，1H，J＝8.7，8.7Hz)，7.57(d，1H，J＝7.6Hz)，7.45-7.42(m，2H)，7.14(d，1H，J＝4.5Hz)；MS(ESI ⁺)：m/z 336.20(M+H) ⁺.

B) 3-fluoro-4-(3-(2-(pyridine-2-yl) acetenyl) pyridin-4-yl oxygen base) aniline

[00227] by the mode that is similar to step e among the embodiment 35, (30mg, 0.090mmol) the preparation title compound obtains title compound (20mg), is brown solid by 2-(2-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acetenyl) pyridine.MS(ESI ⁺)：m/z 306.20(M+H) ⁺。

C) 1-(3-fluoro-4-(3-(2-(pyridine-2-yl) acetenyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00228] by the mode that is similar to step D among the embodiment 33; by 3-fluoro-4-(3-(2-(pyridine-2-yl) acetenyl) pyridin-4-yl oxygen base) aniline (19mg; 0.062mmol) and 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.50mL toluene solution 0.15mmol) prepares title compound.Reactant mixture is through SiO ₂The flash chromatography purification is used 0-100%EtOAc/CH ₂Cl ₂Eluting obtains white solid, and the mode by being similar to step D among the embodiment 33 is translated into hydrochlorate, obtains title compound (19mg, 60%), is white solid.

¹H NMR(DMSO-d ₆)δ11.07(s，1H)，10.61(s，1H)，8.79(s，1H)，8.63(d，1H，J＝5.6Hz)，8.47(d，1H，J＝5.6Hz)，7.89-7.86(m，1H)，7.83(dd，1H，J＝1.5，12.7Hz)7.67(d，1H，J＝7.6Hz)，7.47-7.43(m，2H)，7.39～7.35(m，1H)，7.30-7.27(m，1H)，7.20-7.16(m，2H)，7.14-7.10(m，1H)，6.77(d，1H，J＝5.6Hz)，3.75(s，2H)；MS(ESI ⁺)：m/z485.17(M+H) ⁺.

Embodiment 47

1-(3-fluoro-4-(3-(2-(pyridin-3-yl) acetenyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

A) 3-(2-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acetenyl) pyridine

[00229] by vacuum/argon purge, make 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine (compd A among the embodiment 33,50mg, 0.14mmol) and the 3-ethynyl pyridine (57mg, 0.54mmol), THF (1mL) and Et ₃The mixture degassing of N (1mL), (3mg is 0.016mmol) with (Ph to use CuI successively ₃P) ₄(10mg 0.009mmol) handles Pd.Under 60 ℃, heating blends 45 minutes, cooling distributes it between EtOAc and saturated sodium bicarbonate, dry (MgSO ₄) the EtOAc phase, vacuum concentration.Residue is through SiO ₂The flash chromatography purification is used 0-1.5%MeOH/CH ₂Cl ₂Eluting obtains title compound (33mg, 77%), is brown solid.

¹H NMR(DMSO-d ₆)δ8.86(s，1H)，8.65(s，1H)，8.61-8.57(m，2H)，8.45(dd，1H，J＝2.6，10.7Hz)，8.18(d，1H，J＝9.2Hz)，7.90(d，1H，J＝9.2Hz)，7.62(dd，1H，J＝8.7，8.7Hz)，7.46(dd，1H，J＝4.6，8.1Hz)，7.17(d，1H，J＝5.6Hz)；MS(ESI ⁺)：m/z 336.19(M+H) ⁺.

B) 3-fluoro-4-(3-(2-(pyridin-3-yl) acetenyl) pyridin-4-yl oxygen base) aniline

[00230] by the mode that is similar to step e among the embodiment 35, (30mg 0.090mmol) prepares title compound, obtains title compound by 3-(2-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acetenyl) pyridine, be brown solid (25mg, 93%).MS(ESI ⁺)：m/z 306.20(M+H) ⁺。

C) 1-(3-fluoro-4-(3-(2-(pyridin-3-yl) acetenyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00231] by the mode that is similar to step D among the embodiment 33; by 3-fluoro-4-(3-(2-(pyridin-3-yl) acetenyl) pyridin-4-yl oxygen base) aniline (22mg; 0.072mmol) and 0.3M2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.50mL toluene solution 0.15mmol) prepares title compound.Reactant mixture is through SiO ₂The rapid column chromatography purification is used 0-100%EtOAc/CH ₂Cl ₂Eluting obtains white solid, by by the mode that is similar to step D among the embodiment 33, is translated into hydrochlorate, obtains title compound (15mg, 38%), is white solid.

¹H NMR(DMSO-d ₆)δ11.04(s，1H)，10.59(s，1H)，8.76(s，1H)，8.74(d，1H，J＝1.1Hz)，8.60(dd，1H，J＝5.6，1.1Hz)，8.45(d，1H，J＝6.1Hz)，7.98(d，1H，J＝7.7Hz)，7.80(d，1H，J＝12.1Hz)，7.47-7.45(m，1H)，7.41(s，2H)，7.36-7.34(m，2H)，7.16(dd，2H，J＝8.8，8.9Hz)，6.78(d，1H，J＝5.5Hz)，3，74(s，2H)；MS(ESI ⁺)：485.13m/z.

Embodiment 48

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-2-bromine Pyrazinamide, trifluoroacetate

A) the different nicotinoyl chlorine of 2-bromo-(isonicotinicacyl chloride)

[00232] (thionyl chloride 0.34mmol) (1.2mL) solution is heated to reflux temperature for Lancaster, 70mg, keeps 1.5h with 2-bromo-.gamma.-pyridinecarboxylic acid.Enriched mixture, the crude product of the different nicotinoyl chlorine of 2-bromine need not be further purified, and is directly used in next step.

B) N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-2-bromine Pyrazinamide

[00233] at room temperature, in above residue, add 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,70mg, CH 0.32mmol) ₂Cl ₂(3mL) solution, reaction stirred 1h.Concentrated reaction mixture, residue obtain title compound (75mg, 45%) through the preparation HPLC purification, are yellow solid (tfa salt).

¹H NMR(DMSO-d ₆)δ11.03(s，1H)，8.62(d，1H，J＝5.0Hz)，8.17(s，1H)，7.89-8.04(m，4H)，7.71(d，1H，J＝8.8Hz)，7.51(t，1H，J＝9.3Hz)，6.72(dd，1H，J＝7.1，2.2Hz)，6.18(d，1H，J＝2.2Hz)；MS(ESI ⁺)m/z403，405(M+H) ⁺.

Embodiment 49

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-2-(4-fluorophenyl amino) Pyrazinamide, two trifluoroacetates

A) 2-(4-fluorophenyl amino) .gamma.-pyridinecarboxylic acid

[00234] at room temperature, to 2-fluoro-.gamma.-pyridinecarboxylic acid (Aldrich, 423mg, 3.0mmol) and the 4-fluoroaniline (555mg 5.0mmol) adds NaH (500mg, 60% in oil) in the mixture in DMF (18mL), under 85 ℃, heating blends 75min.Acetic acid (0.7mL) is added in the reactant mixture vacuum concentration.Add EtOAc (100mL) and water (20mL) in residue, stir 20min, filter solid with EtOAc washing, drying, obtains the product (600mg, 50%) of needs excessively, is the sepia solid.

¹H NMR(DMSO-d ₆))δ8.98(s，1H)，8.43(s，1H)，8.04(d，1H，J＝4.9Hz)，7.69(dd，2H，J＝8.8，4.9Hz)，7.24(s，1H)，7.05(dd，2H，J＝8.2，6.0Hz)；MS(ESI ⁺)m/z 233.3(M+H) ⁺.

B) the different nicotinoyl chlorine of 2-(4-fluorophenyl amino)

[00235] with 2-(4-fluorophenyl amino) .gamma.-pyridinecarboxylic acid (464mg, 2.0mmol) and the mixture reflux 2h of thionyl chloride (10mL).The vacuum concentration reactant, crude product is directly used in next step.

C) N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-2-(4-fluorophenyl amino) Pyrazinamide

[00236] under the ice bath temperature, stirs down, 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,450mg, 2.1mmol) 1,1 of the acyl chlorides that 2-dichloroethanes (10mL) solution obtains more than slowly adding is in 2-dichloroethanes (10mL) solution.At room temperature, standing and reacting mixture overnight.In reactant mixture, add EtOAc (150mL) and saturated NaHCO ₃Aqueous solution (50mL).Separate the EtOAc layer, through MgSO ₄Drying, vacuum concentration.Residue obtains title compound (69mg, 6.3%) through the preparation HPLC purification, is yellow solid (two tfa salts).

¹H NMR(DMSO-d ₆)δ10.90(s，1H)，9.32(s，1H)，8.27(d，1H，J＝5.5Hz)，7.92-7.07(m，11H)，6.68(dd，1H，J＝7.1，2.2Hz)，6.10(d，1H，J＝2.2Hz)；MS(ESI ⁺)m/z 217.9(M+H) ⁺.

Embodiment 50

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-6-oxo-1,6-dihydropyridine-2-Methanamide, trifluoroacetate

[00237] at room temperature, to 6-hydroxy-picolinic acid (Aldrich, 28mg, 0.20mmol) and HOBt (28mg, 0.21mmol) DMF (2mL) solution in add successively EDCI.HCl (50mg, 0.26mmol), 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,42mg, 0.19mmol), stirred reaction mixture at room temperature.Reactant mixture obtains the product (24mg, 25%) of needs through the preparation HPLC purification, is light brown solid (tfa salt).

¹H NMR(CD ₃OD)δ8.03(dd，1H，J＝12.6，2.2Hz)，7.79-7.36(m，5H)，6.85(d，1H，J＝8.8Hz)，6.67(dd，1H，J＝7.2，4.4Hz)，6.22(d，1H，J＝2.2Hz)；MS(ESI ⁺)m/z 341.3(M+H) ⁺.

Embodiment 51

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, trifluoroacetate

[00238] at room temperature, to 2-hydroxy niacin (Aldrich, 42mg, 0.30mmol) and DMF (2mL) solution of HOBt (18mg) in add EDCI.HCl (80mg successively, 0.42mmol), 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,65mg, 0.30mmol), stirred reaction mixture 20h at room temperature.Reactant mixture obtains the product (70mg, 49%) of needs through the preparation HPLC purification, is beige solid (tfa salt).

¹H NMR(CD ₃OD)δ8.59(dd，1H，J＝7.1，2.2Hz)，8.03(dd，1H，J＝12.6，2.2Hz)，7.83(d，1H，J＝7.7Hz)，7.75(dd，1H，J＝6.6，2.2Hz)，7.44(d，1H，J＝8.8Hz)，7.32(t，1H，J＝8.8Hz)，6.67(m，2H)，6.21(d，1H，J＝2.2Hz)；MS(ESI ⁺)m/z 341.2(M+H) ⁺.

Embodiment 52

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-Methanamide, trifluoroacetate

[00239] at room temperature, to 2-hydroxyl-6-methylnicotinic acid (Lancaster, 72mg, 0.47mmol) and DMF (5mL) solution of HOBt (50mg) in add EDCI.HCl (130mg successively, 0.68mmol), 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,110mg, 0.50mmol), stirred reaction mixture 72h at room temperature.Reactant mixture obtains the product (125mg, 55%) of needs through the preparation HPLC purification, is beige solid (tfa salt).

¹H NMR(CD ₃OD)δ8.46(d，1H，J＝7.9Hz)，8.03(dd，1H，J＝12.7，2.8Hz)，7.83(d，1H，J＝7.1Hz)，7.44(dd，1H，J＝8.8，2.2Hz)，7.33(t，1H，J＝8.8Hz)，6.67(dd，1H，J＝7.7，2.7Hz)，6.45(d，1H，J＝7.7Hz)，6.21(d，1H，J＝2.8Hz)，2.40(s，3H)；MS(ESI ⁺)m/z 355.2(M+H) ⁺.

Embodiment 53

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-5-chloro-2-oxo-1,2-dihydropyridine-3-Methanamide, trifluoroacetate

[00240] at room temperature, to 2-hydroxyl-5-chlorine apellagrin (Avocado, 87mg, 0.50mmol) and DMF (4mL) solution of HOBt (40mg) in add EDCI.HCl (130mg successively, 0.68mmol), 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,110mg, 0.50mmol), stirred reaction mixture 72h.Reactant mixture obtains the product (115mg, 45%) of needs through the preparation HPLC purification, is beige solid (tfa salt).

¹H NMR(CD ₃OD)δ8.50(d，1H，J＝3.3Hz)，8.03(dd，1H，J＝12.6，2.1Hz)，7.84(m，2H)，7.46(d，1H，J＝8.8Hz)，7.34(t，1H，J＝8.8Hz)，6.67(dd，1H，J＝7.2，2.2Hz)，6.21(d，1H，J＝2.2Hz)；MS(ESI ⁺)m/z 375.1，377.1(M+H) ⁺.

Embodiment 54

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-5-bromo-2-oxo-1,2-dihydropyridine-3-Methanamide, trifluoroacetate

[00241] to 2-hydroxyl-5-bromo-nicotinic acid (147mg, 0.67mmol, Syn.Comm., 1989,19,553-559) and in DMF (4mL) solution of HOBt (30mg) add EDCI.HCl (160mg successively, 0.83mmol), 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,147mg 0.67mmol), at room temperature stirs the mixture and spends the night.Reactant mixture obtains title compound (120mg, 33%) through the preparation HPLC purification, is beige solid (tfa salt).

¹HNMR(DMSO-d ₆)δ13.22(s，1H)，12.23(s，1H)，8.40(d，1H，J＝2.8Hz)，8.14(d，1H，J＝2.8Hz)，8.12-7.46(m，5H)，6.68(dd，1H，J＝7.2，2.2Hz)，6.14(d，1H，J＝2.2Hz)；MS(ESI ⁺)m/z419/421(M+H) ⁺.

Embodiment 55

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-6-methyl-4-oxo-1,4-dihydropyridine-3-Methanamide, trifluoroacetate

[00242] at room temperature, to 4-hydroxyl-6-methyl-nicotinic acid (Wako, 77mg, 0.50mmol) and DMF (5mL) solution of HOBt (50mg) in add EDCI.HCl (130mg successively, 0.68mmol), 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,110mg, 0.50mmol), at room temperature stirred reaction mixture spends the night, and heats 1.5h down at 75 ℃ then.After reactant mixture is cooled to room temperature,, obtain title compound (70mg, 29%), be white solid (tfa salt) by the preparation HPLC purification.

¹H NMR(DMSO-d ₆)δ13.22(brs，1H)，12.53(s，1H)，8.47(d，1H，J＝5.5Hz)，8.04(d，1H，J＝2.2Hz)，7.95(d，1H，J＝8.2Hz)，7.82(s，2H)，7.46-7.42(m，2H)，6.70(dd，1H，J＝7.7，2.7Hz)，6.39(s，1H)，6.14(d，1H，J＝2.2Hz)；MS(ESI ⁺)m/z 355.3(M+H) ⁺.

Embodiment 56

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-5-benzyl-4-oxo-1,4-dihydropyridine-3-Methanamide, trifluoroacetate

A) 3-bromo-5-(hydroxyl (phenyl) methyl) pyridine-4-phenol

[00243] under-78 ℃, under Ar atmosphere, to 3,5-two bromo-4-pyridone (2.53g, 10mmol, press Synthesis, 2001,14, method among 2175-2179 preparation) non-homogeneous mixture in anhydrous THF (20mL) adds phenyl-magnesium-bromide solution (11mL, the THF solution of 1M, 11mmol).After stirring 15min, add n-BuLi solution (5.5mL, the cyclohexane solution of 2M), under-78 ℃, under Ar atmosphere, stirred reaction mixture 15min.In this mixture, add benzaldehyde (2.15mL), under-78 ℃, under Ar atmosphere, stirred reaction mixture 2h.By adding HOAc (3mL) and TFA (3mL) quencher reactant mixture, vacuum concentration, residue are used hexane/EtOAc/MeOH//750: 250: 50, hexane/EtOAc/MeOH/Et successively through silica gel rapid column chromatography purification ₃N//460: 460: 50: 10 eluting, obtain the product (2.85g, 91%) that needs, be white solid.

¹H NMR(CD ₃OD)δ8.13(s，1H)，8.04(s，1H)，7.41-7.20(m，5H)，5.94(s，1H)；MS(ESI ⁺)m/z 280，282(M+H) ⁺.

B) 3-benzyl-5-bromopyridine-4-phenol

[00244] with 3-bromo-5-(hydroxyl (phenyl) methyl) pyridine-4-phenol (2.55g, 91mmol), TFA (16mL) and Et ₃SiH is at CH ₂Cl ₂Mixture (30ml) at room temperature stirs 10h.Vacuum concentration reactant mixture, residue are used hexane/EtOAc/MeOH//600: 300: 50, hexane/EtOAc/MeOH//400: 400: 50 successively through silica gel rapid column chromatography purification: 10 eluting, obtain impure product, with it with a small amount of MeOH and Et ₂O grinds, and obtains the product (255mg, 10%) of needs, is white solid.

¹H NMR(DMSO-d ₆)δ11.75(br s，1H)，8.13(s，1H)，7.54(s，1H)，7.26-7.14(m，5H)，2.49(s，2H).

C) 5-benzyl-4-hydroxy niacin

[00245] under-78 ℃, under Ar atmosphere, to 3-benzyl-5-bromopyridine-4-phenol (220mg, add in anhydrous THF (8mL) solution 0.83mmol) MeLi solution (0.61mL, the THF solution of 1.5M, 0.92mmol).After stirring 5min, (1.0mmol), under-78 ℃, under Ar atmosphere, 15min stirs the mixture for 0.5mL, the cyclohexane solution of 2M to add n-BuLi solution.Under-78 ℃, make carbon dioxide pass through reactant mixture bubbling 20min.Add HOAc (2mL) quencher reactant mixture then, vacuum concentration, residue obtain the product (100mg, 35%) of needs through the preparation HPLC purification, are white solid (tfa salt).

¹HNMR(DMF-d ₇)δ12.99(brs，1H)，8.69(s，1H)，8.28(s，1H)，7.35-7.19(m，5H)，3.90(s，2H)；MS(ESI ⁺)m/z 230.1(M+H) ⁺.

D) N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-5-benzyl-4-oxo-1,4-dihydropyridine-3-Methanamide, trifluoroacetate

[00246] at room temperature, to 4-hydroxyl-5-benzyl nicotinic acid (35mg, 0.15mmol) and DMF (2.5mL) solution of HOBt (30mg) in add EDCI.HCl (80mg successively, 0.42mmol), 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,35mg, 0.16mmol), at room temperature, stirred reaction mixture 40h.Reactant mixture obtains the product (35mg, 43%) of needs through the preparation HPLC purification, is white TFA solid salt.

¹H NMR(DMSO-d ₆)δ13.25(brs，1H)，12.44(s，1H)，8.59(d，1H，J＝4.9Hz)，8.08(dd，1H，J＝13.2，2.2Hz)，7.97(d，1H，J＝7.1Hz)，7.81(d，1H，J＝9.4Hz)，7.52-7.19(m，7H)，6.72(dd，1H，J＝7.2，2.2Hz)，6.15(d，1H，J＝2.5Hz)，3.81(s，2H)，3.51(brs，2H)；MS(ESI ⁺)m/z 431.2(M+H) ⁺.

Embodiment 57

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide, trifluoroacetate

A) 2-(3-(phenyl amino) allylidene) malonic acid (E)-dimethyl esters

[00247] at room temperature, to 2-(3-methoxyl group allylidene (allylidene)) dimethyl malenate (Acros Organics, 200mg, 1.0mmol) THF (2mL) solution in add aniline (300mg, 3.2mmol), under 60 ℃, reacting by heating mixture 8.5h.Reactant mixture obtains the product (150mg, 57%) of needs through the preparation HPLC purification, is yellow solid.

¹H NMR(DMSO-d ₆)δ10.16(d，1H，J＝12.7Hz)，8.06(t，1H，J＝12.7Hz)，7.74(d，1H，J＝12.7Hz)，7.30(t，2H，J＝8.7Hz)，7.16(d，2H，J＝7.7Hz)，6.98(t，1H，J＝7.7Hz)，6.35(t，1H，J＝12.1Hz)，3.69(s，3H)，3.65(s，3H).

B) 2-oxo-1-phenyl-1,2-dihydropyridine-3-methyl formate

[00248] at room temperature, (130mg, (50mg, 60%NaH are in oil, and 1.2mmol), 3h at room temperature stirs the mixture to add NaH in methanol 0.50mmol) (8mL) solution to the above aniline addition product that obtains.Acetic acid (0.3mL) is added mixture, be concentrated into～the 4mL volume, reactant mixture obtains the product (105mg, 92%) of needs through the preparation HPLC purification, is yellow solid.

¹HNMR(CD ₃OD)δ8.30(dd，1H，J＝7.2，2.2Hz)，7.87(dd，1H，J＝6.6，1.7Hz)，7.57-7.38(m，5H)，6.53(t，1H，J＝7.0Hz)，3.84(s，3H)；MS(ESI ⁺)m/z230.3(M+H) ⁺.

C) 2-oxo-1-phenyl-1,2-dihydropyridine-3-formic acid

[00249] at room temperature, stir 2-oxo-1-phenyl-1, and 2-dihydropyridine-3-methyl formate (70mg, 0.31mmol) and the mixture overnight of LiOH (40mg) in methanol (6mL) and water (1mL).In reactant mixture, add EtOAc (50mL) and 1N HCl aqueous solution (15mL), separate the EtOAc layer, through MgSO ₄Drying, vacuum concentration obtains product (55mg, 83%), is light yellow solid.

¹H NMR(DMF-d ₇)δ11.77(brs，1H)，8.57(dd，1H，J＝7.4，2.0Hz)，8.26(dd，1H，J＝6.6，1.6Hz)，7.64-7.55(m，5H)，6.88(t，1H，J＝7.0Hz)；MS(ESI ⁺)m/z 216.2(M+H) ⁺.

D) N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide

[00250] to 2-oxo-1-phenyl-1,2-dihydropyridine-3-formic acid (36mg, 0.17mmol) and DMF (3mL) solution of HOBt (18mg) in add EDCI.HCl (45mg successively, 0.23mmol), 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,36mg, 0.17mmol), at room temperature stirred reaction mixture spends the night.Reactant mixture obtains title compound (32mg, 36%) through the preparation HPLC purification, is beige solid (tfa salt).

¹HNMR(DMSO-d ₆)δ13.35(brs，1H)，12.11(s，1H)，8.52(dd，1H，J＝7.3，2.1Hz)，8.08(dd，1H，J＝6.6，2.1Hz)，8.03(d，1H，J＝2.3Hz)，7.89(d，1H，J＝7.2Hz)，7.81(s，1H)，7.54-7.36(m，6H)，6.69-6.63(m，2H)，6.08(d，1H，J＝2.4Hz)，3.55(brs，1H)；MS(ESI ⁺)m/z 417.2(M+H) ⁺.

Embodiment 58

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-6-(4-fluorophenyl) pyridine radicals-N-oxide-amide, trifluoroacetate

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

[00251] to 2-bromo-pyridine carboxylic acid (Aldrich, 2.02g, 10mmol) contain 4mL10%Na ₂CO ₃Charge into Ar gas in the DME solution of aqueous solution.In this mixture, add Pd (PPh successively ₃) ₄, 2-(4-fluorophenyl)-5,5-dimethyl-1,3, (Aldrich, 2.40g 11.5mmol) and EtOH (20mL), charge into Ar gas to ring in 2-dioxo bora ninth of the ten Heavenly Stems (dioxaborinane) in mixture.In sealed tube, under 100 ℃, reacting by heating mixture 2.5h.Add 2-bromo-pyridine carboxylic acid (900mg) and Pd (PPh again ₃) ₄, charge into Ar gas after, at 100 ℃ of following heating 4.5h.Trifluoroacetic acid (20mL) is added in the reactant vacuum concentrated mixture.MeOH (150mL) is added residue, filter insoluble substance, vacuum concentrated filtrate.Residue is used EtOAc/MeOH//900: 100, EtOAc/MeOH/HOAc//700: 1500: 50 eluting successively through the rapid column chromatography purification, obtains the product (1.0g is by bora ring in the ninth of the ten Heavenly Stems (borinane) raw material 40%) of needs, is white solid.

¹H NMR(CD ₃OD)δ8.01(d，1H，J＝7.7Hz)，7.94-7.87(m，3H)，7.73(d，1H，J＝7.7Hz)，7.13(t，2H，J＝8.8Hz)；MS(ESI ⁺)m/z 234(M+H) ⁺.

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

[00252] at room temperature, stir picolinic acid derivatives (1.0g, 4.6mmol), Na ₂HPO ₄(1.2) and m-CPBA (1.1g ,～70%Aldrich produce) at CH ₂ClCH ₂Mixture 2h among the Cl (30mL).With Na ₂HPO ₄(0.8g) and m-CPBA (1.0g) add again in the reactant mixture, at room temperature stir 3h.Again with Na ₂HPO ₄(0.5g) and m-CPBA (0.5g) add in the reactant mixture, at room temperature stir and spend the night.With CHCl ₃(160mL) add in the reactant mixture, separate organic layer, through MgSO with 2NHCl aqueous solution (50mL) ₄Drying, vacuum concentration.Residue with EtOAc/MeOH/HOAc//700: 240: 60 eluting, obtains the product of needs through silica gel rapid column chromatography purification, wherein is mixed with m-CPBA.This foreign body obtains the product (175mg, 16%) of needs through the preparation HPLC purification, is white solid.

¹H NMR(DMF-d ₇)8.45(dd，1H，J＝8.3，2.2Hz)，8.15(d，1H，J＝2.2Hz)，8.13-8.00(m，4H)，7.45(t，2H，J＝8.7Hz).

C) N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-6-(4-fluorophenyl) pyridine radicals-N-oxide-amide, trifluoroacetate

[00253] at room temperature, to 6-(4-fluorophenyl) pyridine carboxylic acid-N-oxide (23mg, 0.1mmol) and DMF (2mL) solution of HOBt (10mg) in add EDCI.HCl (30mg successively, 0.16mmol), 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,22mg, 0.1mmol), at room temperature stirred reaction mixture spends the night.Reactant mixture obtains title compound (25mg, 46%) through the preparation HPLC purification, is white solid (tfa salt).

¹H NMR(DMF-d ₇)δ14.00(S，1H)，8.43(dd，1H，J＝8.0，2.2Hz)，8.15(dd，1H，J＝12.8，2.4Hz)，8.08(d，1H，J＝7.1Hz)，7.99-7.37(m，9H)，6.72(dd，1H，J＝7.0，2.4Hz)，6.32(d，1H，J＝2.3Hz)，3.7(brs，2H)；MS(ESI ⁺)m/z 417.2(M+H) ⁺.

Embodiment 59

1-(4-(3-(4-(2-amino-2-oxoethyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 2-(4-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetic acid

[00254] in the 25mL round-bottomed flask, add 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine (compd A among the embodiment 33,120mg, 0.33mmol), (4-(4 for 2-, 4,5,5-tetramethyl-1,3,2-two oxa-bora penta ring (dioxaborolan)-2-yl) acetic acid (FrontierScientific phenyl), 131mg, 0.50mmol), four (triphenyl phasphines) close palladium (0) (Strem Chemicals, 38mg, 0.033mmol) and sodium carbonate (245mg, 2.3mmol).In this flask, charge into nitrogen, add two  alkane and water (each 1mL) then.After stirring 10h under 80 ℃, mixture is cooled to room temperature, then vacuum concentration.Crude product obtains title compound (120mg, 99%) through silica gel rapid column chromatography (30%MeOH/EtOAc) purification, is white solid.

¹H NMR(CD ₃OD)δ8.61(s，1H)，8.48(d，1H，J＝5.6Hz)，8.22(dd，1H，J＝10.4，2.8Hz)8.14-8.11(m，1H)，7.54(d，2H，J＝8.1Hz)，7.41(d，2H，J＝8.0Hz)，7.40(m，1H)，7.05(d，1H，J＝5.7Hz)，3.56(s，2H)；MS(ESI ⁺)m/z369.16(M+H) ⁺.

B) 2-(4-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetamide

[00255] in the 25mL round-bottomed flask, add 2-(4-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetic acid (50mg, 0.136mmol), HOBT (46mg, 0.34mmol) and EDCI (65mg, 0.34mmol).In this flask, charge into nitrogen, add DMF (1mL) then.After at room temperature stirring 1h, solution is cooled to 0 ℃, adds ammonium hydroxide (0.5mL) then.Under 0 ℃, reaction stirred 1h uses saline (5mL) dilution then, with ethyl acetate (3 * 5mL) dilutions.The organic extract liquid that merges is through anhydrous Na ₂SO ₄Drying, vacuum concentration.Crude product obtains title compound (33mg, 66%) through silica gel rapid column chromatography (20%MeOH/EtOAc) purification, is colorless oil.

¹H NMR(CD ₃OD)δ8.49(s，1H），8.38(d，1H，J＝5.6Hz)，8.10(dd，1H，J＝10.4，2.4Hz)，7.99(m，1H)，7.45(d，2H，J＝8.2Hz)，7.30(d，2H，J＝8.2Hz)，7.28(m，1H)，6.93(d，1H，J＝5.6Hz)，3.44(s，2H)；MS(ESI ⁺)m/z368.18(M+H) ⁺.

C) 1-(4-(3-(4-(2-amino-2-oxoethyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00256] use successively the Zn powder (59mg, 0.9mmol), (48mg 0.9mmol) handles 2-(4-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetamide (33mg, THF 0.09mmol) (0.8mL) and methanol (1.2mL) solution to ammonium chloride.At room temperature, the 4h that stirs the mixture is then by containing the Celite of methanol ^Thin pad filters.Concentrated filtrate distributes residue between EtOAc and saturated sodium bicarbonate aqueous solution.EtOAc is through anhydrous Na ₂SO ₄Drying, vacuum concentration obtains crude product (25mg, 82%), is yellow oil, and it is enough pure, need not be further purified to be directly used in next step.

¹H NMR(CD ₃OD)δ8.33(s，1H)，8.19(d，1H，J＝5.6Hz)，7.49(d，2H，J＝8.1Hz)，7.32(d，2H，J＝8.2Hz)，6.82(t，1H，J＝8.8Hz)，6.61(d，1H，J＝5.6Hz)，6.44(qd，1H，J＝12.8，2.8Hz)，3.48(s，2H)；MS(ESI ⁺)m/z338.25(M+H) ⁺.

[00257] above amine is dissolved in THF (1mL), adds 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11,250 μ L, 0.074mmol, the toluene solution of 0.3M) then.After at room temperature stirring 1h, reactant obtains title compound through flash chromatography on silica gel (10%MeOH/EtOAc) direct purification, is white solid.Solid is dissolved in two  alkane (2mL), is cooled to 0 ℃.Add anhydrous HCl (2mL, the diethyl ether solution of 1N).After stirring 5min under 0 ℃, vacuum concentrated solution.The HCl salt lyophilizing that will obtain in acetonitrile/water obtains title compound (23mg, 57%), is white solid.

¹HNMR(DMSO-d ₆)δ11.02(s，1H)，10.59(s，1H)，8.83(s，1H)，8.58(d，1H，J＝6.4Hz)，7.79(dd，1H，J＝12.8，2.4Hz)，7.60(d，2H，J＝8.4Hz)，7.46-7.34(m，4H)，7.31-7.28(m，2H)，7.11(t，2H，J＝8.7Hz)，6.88(d，1H，J＝5.6Hz)，3.70(s，2H)，3.40(s，2H)；MS(ESI ⁺)m/z 517.19(M+H) ⁺.

Embodiment 60

1-(4-(3-(4-(amino methyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

A) 4-(4-(2-fluorine 4-nitrophenoxy) pyridin-3-yl) benzaldehyde

[00258] prepares by the mode that is similar to steps A among the embodiment 59, obtain title compound (86%), be colorless oil.

¹H NMR(CD ₃OD)δ9.92(s，1H)，8.56(s，1Ｈ)，8.41(d，1H，J＝6Hz)，8.12(dd，1H，J＝10.3，2.6Hz)，8.05-8.01(m，1H)，7.90(d，2H，J＝8.3Hz)，7.73(d，2H，J＝8.2Hz)7.35(t，1H，J＝8.4Hz)，6.95(d，1H，J＝6Hz)；MS(ESI ⁺)m/z 339.19(M+H) ⁺.

B) 4-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) benzylamino t-butyl formate

[00259] to 4-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) benzaldehyde (81mg, add successively in methanol 0.24mmol) (2mL) solution ammonium acetate (185mg, 2.4mmol), sodium cyanoborohydride (16mg, 0.24mmol).At room temperature reaction stirred 4h, vacuum concentration then.With residue water-soluble (5mL), with EtOAc (2 * 5mL) extractions.With the organic extract liquid of saturated sodium bicarbonate aqueous solution washing merging, through anhydrous Na ₂SO ₄Drying, vacuum concentration.Crude product is dissolved in dichloromethane (2mL), add successively then triethylamine (50 μ L, 0.36mmol), DMAP (cochleariform process point) and Bis(tert-butoxycarbonyl)oxide (Aldrich, 57mg, 0.26mmol).At room temperature reaction stirred 2h then through silica gel rapid column chromatography (EtOAc) direct purification, obtains title compound (13mg, 12%), is colorless oil.

¹H NMR(CD ₃OD)δ8.50(s，1H)，8.37(d，1H，J＝5.6Hz)，8.09(dd，1H，J＝6.1，2.6Hz)，8.01-7.99(m，1H)，7.45(d，2H，J＝8Hz)，7.26(d，2H，J＝8.2Hz)，7.25(m，1H)，6.95(d，1H，J＝5.6Hz)，4.16(s，2H)，1.35(s，9H)；MS(ESI ⁺)m/z440.19(M+H) ⁺.

C) 1-(4-(3-(4-(amino methyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00260] prepares by the mode that is similar to step C among the embodiment 59.After acylureas forms, add two  alkane (5mL) solution of 4N HCl.At room temperature stir 5min, the vacuum concentration reactant.Residue is suspended in EtOAc, with the saturated sodium bicarbonate aqueous solution washing, through anhydrous Na ₂SO ₄Drying, vacuum concentration.Thick material is through the preparation HPLC purification.The flow point that vacuum concentration is suitable is removed methanol.Add toluene, concentrate (2 * 5mL) then.The solid lyophilizing that will obtain in acetonitrile/water obtains the tfa salt (6mg, 25%) of title compound, is white solid.

¹H NMR(DMSO-d ₆)δ11.00(s，1H)，10.53(s，1H)，8.55(s，1H)，8.40(d，1H，J＝4Hz)，7.73(dd，1H，J＝12，4Hz)，7.67(d，2Ｈ,J＝8Hz)，7.51(d，2H，J＝8Hz)，7.34-7.27(m，4H)，7.13-7.09(m，2H)，6.73(d，1H，J＝4Hz)，4.03(s，2H)，3.68(s，2H)；MS(ESI ⁺)m/z 489.18(M+H) ⁺.

Embodiment 61

1-(3-fluoro-4-(3-(6-(piperazine-1-yl) pyridin-3-yl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 4-(5-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) pyridine-2-yl) piperazine-1-t-butyl formate

[00261] prepares by the mode that is similar to steps A among the embodiment 59, obtain title compound (87%), be colorless oil.

¹H NMR(CD ₃OD)δ8.62(s，1H)，8.46(d，1H，J＝6Hz)，8.36(d，1H，J＝2.4Hz)，8.24(dd，1H，J＝10.4，2.8Hz)，8.15-8.11(m，1H)，7.84(dd，1H，J＝8.8，2.4Hz)，7.41(t，1H，J＝8.4Hz)，7.04(d，1H，J＝5.6Hz)，6.92(d，1H，J＝8.8Hz)，3.61-3.59(m，4H)，3.56-3.54(m，4H)，1.50(s，9H)；MS(ESI ⁺)m/z496.23(M+H) ⁺.

B) 4-(5-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) pyridine-2-yl) piperazine-1-t-butyl formate

[00262] prepares by the mode that is similar to step C among the embodiment 59, obtain title compound (96%), be colorless oil.

¹H NMR(CD ₃OD)δ8.34(s，1H)，8.29(d，1H，J＝2Hz)，8.18(d，1H，J＝6Hz)，7.78(dd，1H，J＝9.2，2.8Hz)，6.87-6.83(m，2H)，6.61(d，1H，J＝5.6Hz)，6.48(dd，1H，J＝12.8，2.8Hz)，6.44-6.41(m，1H)，3.50-3.46(m，8H)，1.38(s，9H)；MS(ESI ⁺)m/z 466.25(M+H) ⁺.

C) 1-(3-fluoro-4-(3-(6-(piperazine-1-yl) pyridin-3-yl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00263] prepares by the mode that is similar to step C among the embodiment 59, obtain title compound (28%), be HCl salt.

¹H NMR(DMSO-d ₆)δ11.33(s，1H)，10.76(s，1H)，9.09(s，1H)，8.74(d，1H，J＝6.8Hz)，8.57(d，1H，J＝2.4Hz)，8.16(dd，1H，J＝8.8，2Hz)，7.91(dd，1H，J＝12.8，2Hz)，7.61(t，1H，J＝8.8Hz)，7.55-7.50(m，1H)，7.42-7.38(m，2H)，7.28(d，1H，J＝6.5Hz)，7.27-7.18(m，3H)，3.98(m，4H)，3.82(s，2H)，3.23(m，4H)；MS(ESI ⁺)m/z 545.19(M+H) ⁺.

Embodiment 62

N-(3-fluoro-4-(3-(6-(piperazine-1-yl) pyridin-3-yl) pyridin-4-yl oxygen base) phenyl)-2-oxo-1-base-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00264] to 4-(5-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) pyridine-2-yl) piperazine-1-t-butyl formate (compd B among the embodiment 61,32mg, 0.069mmol) THF/DMF (each 1mL) solution in add 2-oxo-1-phenyl-1,2-dihydropyridine-3-formic acid (Compound C among the embodiment 57,15mg, 0.069mmol), DIPEA (60 μ L, 0.35mmol), add then TBTU (Fluka, 33mg, 0.10mmol).After at room temperature stirring 18h, with EtOAc (5mL) diluting reaction thing, use successively 10% lithium chloride aqueous solution (2 * 5mL), (1 * 5mL) washing is through anhydrous Na for saturated sodium bicarbonate solution ₂SO ₄Drying, vacuum concentration.Residue is suspended in the ether, is cooled to 0 ℃, with two  alkane (5mL) solution-treated of 4N HCl.Allow solution be warming up to room temperature, at room temperature stir 2h then.Vacuum concentrated solution, the crude product that obtains is through the preparation HPLC purification.Concentrate suitable flow point, remove methanol, make alkalize with saturated sodium bicarbonate aqueous solution then.(2 * 10mL) extraction water solution, the organic extract liquid of merging is through anhydrous Na with EtOAc ₂SO ₄Drying, vacuum concentration then.Residue is dissolved in THF (2mL), is cooled to 0 ℃, with ether (0.5mL) solution-treated of 1N HCl.Stir 5min, enriched mixture down at 0 ℃.In acetonitrile/water, with the white solid lyophilizing that obtains, obtain the HCl salt (26mg, 56%) of title compound, be light yellow solid.

¹H NMR(DMSO-d ₆)δ12.16(s，1H)，8.92(s，1H)，8.59(d，1H，J＝6.4Hz)，8.53(dd，1H，J＝7.2，2Hz)，8.47(d，1H，J＝2.4Hz)，8.10(dd，1H，J＝6.4，2Hz)，8.04(d，1H，J＝12Hz)，7.99(dd，1H，J＝8.8，2.4Hz)，7.54-7.46(m，7H)，7.20(d，1H，J＝6.4Hz)，7.97(d，1H，J＝9.2Hz)，6.68(t，1H，J＝6.8Hz)，3.82-3.80(m，4H)，3.12(m，4H)；MS(ESI ⁺)m/z 545.19(M+H) ⁺.

Embodiment 63

N ¹-((R)-2-amino-2-oxo-1-phenethyl)-N ³-(3-fluoro-4-(3-(6-(piperazine-1-yl) pyridin-3-yl) pyridin-4-yl oxygen base) phenyl) Malondiamide, hydrochlorate

[00265] to 4-(5-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) pyridine-2-yl) piperazine-1-t-butyl formate (compd B among the embodiment 61,32mg, 0.069mmol) THF (1mL) solution in add DIPEA (60 μ L successively, 0.35mmol), 3-chloro-3-oxo ethyl propionate (Aldrich, 10 μ L, 0.076mmol).After at room temperature stirring 2h, with EtOAc (5mL) diluting reaction thing, (1 * 5mL) washing is through anhydrous Na with saturated sodium bicarbonate aqueous solution ₂SO ₄Drying, vacuum concentration.The yellow oil (65mg) that obtains is dissolved in THF (2mL), adds 1N sodium hydrate aqueous solution (2mL) then.At room temperature, agitating solution 6h.Concentrated solution is removed THF, uses 1N HCl acidified aqueous solution to pH4-5 then.Collect solid by vacuum filtration, wash with water, obtain corresponding acid, be white solid (30mg, 78%2 steps added up to).MS(ESI ⁺)m/z 552.21(M+H) ⁺。

[00266] uses above-mentioned TBTU, make above acid and D (-)-phenylglycinamide (Bachem) coupling, obtain the HCl salt (32%) of title compound, be white solid.

¹H NMR(DMSO-d ₆)δ10.64(s，1H)，8.89(s，1H)，8.74(d，1H，J＝8Hz)，8.56(d，1H，J＝5.6Hz)，8.46(d，1H，J＝2.4Hz)，7.96(d，1H，J＝8.8Hz)，7.84(d，1H，J＝12Hz)，7.74(s，1H)，7.46-7.37(m，4Ｈ），7.31-7.22(m，5H)，7.06(d，1H，J＝9.2Hz)，5.34(d，1H，J＝8Hz)，3.81-3.78(m，4H)，3.40(s，2H)，3.12(m，4H)；MS(ESI ⁺)m/z584.25(M+H) ⁺.

Embodiment 64

1-(3-fluoro-4-(3-(pyridin-3-yl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) pyridine

[00267] prepares by the mode that is similar to steps A among the embodiment 59, obtain title compound, be colorless oil.

¹H NMR(CD ₃OD)δ8.83(d，1H，J＝1.6Hz)，8.69(s，1H)，8.61(d，1H，J＝5Hz)，8.56(d，1H，J＝5.8Hz)，8.27(dd，1H，J＝10.4，2.8Hz)，8.20-814(m，2H)，7.72-7.55(m，1H)，7.53(t，1H，J＝8.6Hz)，7.08(d，1H，J＝6Hz)；MS(ESI ⁺)m/z 312.15(M+H) ⁺.

B) 3-fluoro-4-(3-(pyridin-3-yl) pyridin-4-yl oxygen base) aniline

[00268] prepares by the mode that is similar to step C among the embodiment 59, obtain title compound, be colorless oil.MS(ESI ⁺)m/z 282.12(M+H) ⁺。

C) 1-(3-fluoro-4-(3-(pyridin-3-yl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00269] prepares by the mode that is similar to step C among the embodiment 59, obtain the HCl salt (the total yield 47% of step B and C) of title compound, be yellow solid.

¹H NMR(DMSO-d ₆)δ11.14(s，1H)，10.73(s，1H)，9.16(d，1H，J＝1.6Hz)，9.08(s，1H)，8.90(dd，1H，J＝5.2，1.2Hz)，8.78(d，1H，J＝6.4Hz)，8.56(d，1H，J＝8Hz)，7.95-7.90(m，2H)，7.60(t，1H，J＝8.8Hz)，7.55-7.52(m，1H)，7.44-7.41(m，2H)，7.26-7.21(m，3H)，3.82(s，2H)；MS(ESI ⁺)m/z 461.16(M+H) ⁺.

Embodiment 65

1-(3-fluoro-4-(3-(4-(piperazine-1-yl) phenyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, tri hydrochloride

A) 4-(4-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) piperazine-1-t-butyl formate

[00270] prepares by the mode that is similar to steps A among the embodiment 59, obtain title compound, be colorless oil.

¹H NMR(CD ₃OD)δ8.48(s，1H)，8.32(d，1H，J＝5.6Hz)，8.08(dd，1H，J＝l2，4Hz)，7.97(d，1H，J＝8Hz)，7.38(d，2H，J＝8.8Hz)，7.21-7.18(m，1H)，6.95-6.92(m，3H)，3.46(m，4H)，3.09-3.06(m，4H)，1.10(s，9H)；MS(ESI ⁺)m/z495.23(M+H) ⁺.

B) 4-(4-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) phenyl) piperazine-1-t-butyl formate

[00271] prepares by the mode that is similar to step C among the embodiment 59, obtain title compound (the total yield 94% of steps A and B), be colorless oil.

¹H NMR(CD ₃OD)δ8.30(s，1H)，8.14(d，1H，J＝5.6Hz)，7.45(d，2H，J＝8.8Hz)，6.98(d，2H，J＝8.8Hz)，6.83(t，1H，J＝8.8Hz)，6.58(d，1H，J＝5.6Hz)，6.48(dd，1H，J＝12.8，2.4Hz)，6.43-6.41(m，1H)，3.49(m，4H)，3.11-3.09(m，4H)，1.16(s，9H)；MS(ESI ⁺)m/z 465.24(M+H) ⁺.

C) 1-(3-fluoro-4-(3-(4-(piperazine-1-yl) phenyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00272] prepares by the mode that is similar to step C among the embodiment 59, obtain the HCl salt (37%) of title compound, be light yellow solid.

¹H NMR(DMSO-d ₆)δ11.01(s，1H)，10.60(s，1H)，8.77(s，1H)，8.51(d，1H，J＝6.4Hz)，7.78(d，1H，J＝12Hz)，7.59(d，2H，J＝8.4Hz)，7.44-7.40(m，2H)，7.31-7.28(m，2H)，7.13-7.08(m，4H)，7.03(d，1H，J＝6.4Hz)，3.70(s，2H)，3.42(m，4H)，3.15(m，4H)；MS(ESI ⁺)m/z544.26(M+H) ⁺.

Embodiment 66

N-(3-fluoro-4-(3-(4-(piperazine-1-yl) phenyl) pyridin-4-yl oxygen base) phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide, tri hydrochloride

[00273] prepares by the mode that is similar to embodiment 62, obtain the HCl salt (43%) of title compound, be light yellow solid.

¹H NMR(DMSO-d ₆)δ12.15(s，1H)，8.83(s，1H)8.56-8.52(m，2H)，8.10(dd，1H，J＝6.8，2.4Hz)，8.04(dd，1H，J＝11.6，2Hz)，7.61(d，2H，J＝8.8Hz)，7.55-7.45(m，7H)，7.15(d，1H，J＝6.8Hz)，7.09(d，2H，J＝8.8Hz)，6.61(t，1H，J＝6.8Hz)，3.44(m，4H)，3.15(m，4H)；MS(ESI ⁺)m/z 562.36(M+H) ⁺.

Embodiment 67

N-(3-fluoro-4-(3-(4-(2-hydroxyethyl) phenyl) pyridin-4-yl oxygen base) phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide

A) 3-(4-(2-(t-butyldimethylsilyloxy base) ethyl) phenyl)-4-(2-fluoro-4-nitrophenoxy) pyridine

[00274] prepares by the mode that is similar to steps A among the embodiment 59, obtain title compound (77%), be colorless oil.

¹H NMR(CD ₃OD)δ8.67(s，1H)，8.56(d，1H，J＝8Hz)，8.27(dd，1H，J＝12，4Hz)，8.16(d，1H，J＝8Hz)，7.58(d，2H，J＝8Hz)，7.39(d，2H，J＝8Hz)，7.36(m，1H)，7.15(d，1H，J＝4Hz)，3.91(t，2H，J＝8Hz)，2.90(t，2H，J＝8Hz)，0.90(s，9H)，0.00(s，6H)；MS(ESI ⁺)m/z 469.25(M+H) ⁺.

B) 3-(4-(2-(t-butyldimethylsilyloxy base) ethyl) phenyl)-4-(2-fluoro-4-nitrophenoxy) pyridine

[00275] prepares by the mode that is similar to step C among the embodiment 59, obtain title compound (76%), be light yellow oil.

¹H NMR(CD ₃OD)δ8.44(s，1H)，8.32(d，1H，J＝4Hz)，7.57(d，2H，J＝8Hz)，7.36(d，2H，J＝8.4Hz)，6.95(t，1H，J＝8Hz)，6.75(d，1H，J＝4Hz)，6.61(d，1H，J＝8Hz)，6.55(d，1H，J＝4Hz)，3.90(t，2H，J＝6.8Hz)，2.89(t，2H，J＝6.4Hz)，0.87(s，9H)，0.00(s，6H)；MS(ESI ⁺)m/z 439.26(M+H) ⁺.

C) N-(3-fluoro-4-(3-(4-(2-hydroxyethyl) phenyl) pyridin-4-yl oxygen base) phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide

[00276] prepares by the mode that is similar to step C among the embodiment 62.After amide forms, the yellow oil that obtains is dissolved in THF (2mL), then at room temperature, handles 1h with TBAF (Aldrich, 180 μ L, the THF solution of 1M).With EtOAc (10mL) diluting reaction thing, water and saline (each 5mL) washing successively is through anhydrous Na ₂SO ₄Drying, vacuum concentration.(purification of 10% methanol/EtOAc) obtains title compound (72%) to crude product, is light yellow solid through flash chromatography on silica gel.

¹H NMR(CD ₃OD)δ8.59(dd，1H，J＝7.6，2.0Hz)，8.41(s，1H)，8.26(d,1H，J＝5.6Hz)，7.91-7.85(m，2H)，7.55-7.46(m，5H)，7.41(d，2H，J＝6.7Hz)，7.29(d，2H，J＝8.1Hz)，7.26(m，1H)，7.13(t，1H，J＝8.7Hz)，6.69(d，1H，J＝6Hz)，6.64(t，1H，J＝7.2Hz)，3.73(t，2H，J＝7.2Hz)，2.82(t，2H，J＝6.8Hz)；MS(ESI ⁺)m/z 522.27(M+H) ⁺.

Embodiment 68

N-(4-(3-(4-(2-amino-ethyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide, dihydric salt hydrochlorate

[00277] to N-(3-fluoro-4-(3-(4-(2-hydroxyethyl) phenyl) pyridin-4-yl oxygen base) phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide (the Compound C among the embodiment 67,40mg, 0.077mmol) THF (1mL) solution in add DIPEA (27 μ L successively, 0.154mmol), mesyl chloride (Aldrich, 7 μ L, 0.092mmol).After at room temperature stirring 30min, the vacuum concentration reactant.Residue is dissolved in 3mL ethanol, is transferred in the manometer tube.Add ammonium hydroxide (7mL),, heat 8h down at 50 ℃ with the seal of tube.After being cooled to room temperature, with EtOAc (10mL) diluting reaction thing, successively water (2 * 10mL), (1 * 10mL) washing is through anhydrous Na for saline ₂SO ₄Drying, vacuum concentration.Crude product is through the preparation HPLC purification.Concentrate suitable flow point, remove methanol, alkalize with saturated sodium bicarbonate solution.(2 * 20mL) aqueous layer extracted, (1 * 10mL) washing is through anhydrous Na with saline for the organic extract liquid of merging with EtOAc ₂SO ₄Drying concentrates.Residue is dissolved in two  alkane (2mL), adds ether (1mL) solution of 1N HCl.Concentrated solution in acetonitrile/water, with the solid lyophilizing that obtains, obtains the HCl salt (24mg, 53%) of title compound, is white solid.

¹HNMR(DMSO-d ₆)δ12.13(s，1H)，8.74(s，1H)，8.55-8.51(m，2H)，8.09(dd，1H，J＝6.4，2Hz)，8.03(m，1H)，7.64(d，2H，J＝6Hz)，7.63(m，1H)，7.54-7.41(m，6H)，7.38(d，2H，J＝8.4Hz)，7.04(d，1H，J＝6Hz)，6.68(t,1H，J＝6.8Hz)，3.02(m，2H)，2.89(m，2H)；MS(ESI ⁺)m/z 521.27(M+H) ⁺.

Embodiment 69

N-(4-(3-(4-((2-(methylamino) ethyl) carbamoyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, dihydrochloride

A) 4-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) essence of Niobe

[00278] prepares by the mode that is similar to steps A among the embodiment 59, obtain title compound (77%), be colorless oil.

¹H NMR(CD ₃OD)δ8.66(s，1H)，8.52(d，1H，J＝6Hz)，8.22(dd，1H，J＝10.4，2.8Hz)，8.16-8.13(m，1H)，8.10(d，2H，J＝8.4Hz)，7.97(d，2H，J＝8Hz)，7.44(t，1H，J＝8.5Hz)，7.06(d，1H，J＝6Hz)，3.93(s，3H)；MS(ESI ⁺)m/z369.22(M+H) ⁺.

B) 4-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) essence of Niobe

[00279] prepares by the mode that is similar to step C among the embodiment 59, obtain title compound (99%), be yellow oil.

¹H NMR(CD ₃OD)δ8.38(s，1H)，8.24(d，1H，J＝6Hz)，8.01(d，2H，J＝8.4Hz)，7.66(d，2H，J＝8.4Hz)，6.85(t，1H，J＝9.2Hz)，6.65(d，1H，J＝6Hz)，6.48(dd，1H，J＝12.8，2.4Hz)，6.43(d，1H，J＝2.8Hz)，3.82(s，3H)；MS(ESI ⁺)m/z339.28(M+H) ⁺.

C) 4-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formamido group) phenoxy group) pyridin-3-yl) essence of Niobe

[00280] prepares by the mode that is similar to step C among the embodiment 62, obtain title compound (81%), be yellow oil.

¹H NMR(CD ₃OD)δ8.66(dd，1H，J＝7.2，2Hz)，8.56(s，1H)，8.40(d，1H，J＝6Hz)，8.13(d，2H，J＝8.4Hz)，7.97-7.95(m，2H)，7.78(d，2H，J＝8.4Hz)，7.55-7.52(m，2H)，7.38-7.31(m，3H)，7.26(t，1H，J＝7.2Hz)，6.82(d，1H，J＝5.6Hz)，6.72(t，1H，J＝6.7Hz)，3.94(s，3H)；MS(ESI ⁺)m/z 554.21(M+H) ⁺.

D) N-(4-(3-(4-((2-(methylamino) ethyl) carbamoyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide

[00281] (159mg adds 1N NaOH aqueous solution (5mL) in THF 0.29mmol) (5mL) solution to above ester.After at room temperature stirring 20h, the concentration response thing is removed THF.With 1N HCl aqueous solution with acidified aqueous solution to pH4.Collect acid by filtering, wash with water, obtain the product (144mg, 92%) of needs, be the sepia solid.MS(ESI ⁺)m/z 540.21(M+H) ⁺。

[00282] by above-mentioned, prepares amide, obtain the HCl salt (62%) of title compound, be white solid with TBTU.

¹H NMR(DMSO-d ₆)δ12.21(s，1H)，8.93-8.90(m，2H)，8.68-8.64(m，2H)，8.21(dd，1H，J＝6.4，2Hz)，8.16(m，1H)，8.11(d，2H，J＝8Hz)，7.90(d，2H，J＝8.4Hz)，7.69-7.65(m，2H)，7.60-7.47(m，4H)，7.16(d，1H，J＝5.6Hz)，6.80(t，1H，J＝7Hz)，3.64(t，2H，J＝5.2Hz)，3.17(t，2H，J＝5.2Hz)，2.65(s，3H)；MS(ESI ⁺)m/z 596.37(M+H) ⁺.

Embodiment 70

N-(4-(3-(4-((2-amino-ethyl) carbamoyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, dihydrochloride

[00283] prepares by the mode that is similar to embodiment 69, obtain the HCl salt of title compound, be pale solid.

¹H NMR(DMSO-d ₆)δ12.17(s，1H)，8.87-8.85(m，2H)，8.64(d，1H，J＝6.4Hz)，8.59(dd，1H，J＝7.6，2.4Hz)，8.16(dd，1H，J＝6.8，2.4Hz)8.10(m，1H)，8.06(d，2H，J＝8.4Hz)，8.00(br s，2H)，7.85(d，2H，J＝8.4Hz)，7.64-7.60(m，2H)，7.55-7.42(m，4H)，7.13(d，1H，J＝6Hz)，6.75(t，1H，J＝7.2Hz)，3.56-3.53(m，2H)，3.04-2.99(m，2H)；MS(ESI ⁺)m/z 582.32(M+H) ⁺.

Embodiment 71

N-(4-(3-(4-((2-(dimethylamino) ethyl) carbamoyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, dihydrochloride

[00284] prepares by the mode that is similar to embodiment 69, obtain the HCl salt (56%) of title compound, be pale solid.

¹H NMR(DMSO-d ₆)δ12.08(s，1H)，8.87(brs，1H)，8.75(s，1H)，8.54-8.51(m，2H)，8.08(dd，1H，J＝6.8，2.4Hz)，8.02(m，1H)，7.99(d，2H，J＝8.4Hz)，7.77(d，2H，J＝8.4Hz)，7.56-7.53(m，2H)，7.47-7.34(m，4H)，6.99(d，1H，J＝5.6Hz)，6.67(t，1H，J＝6.8Hz)，3.61-3.57(m，2H)，3.23-3.21(m，2H)，2.77(s，3H)，2.76(s，3H)；MS(ESI ⁺)m/z 610.30(M+H) ⁺.

Embodiment 72

1-(4-(3-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) 3-fluoro-4-(3-nitropyridine-4-base oxygen base) aniline

[00285] at room temperature, under nitrogen, (DMF 1.0mmol) (5mL) solution adds sodium hydride (80mg, 2mmol, 60%) for steps A in referring to embodiment 19,127mg to 4-amino-2-fluorophenol.After at room temperature stirring 10min, and adding 4-chloro-3-nitropyridine hydrochlorate (Lancaster, 195mg, 1.0mmol).At room temperature, the 1h that stirs the mixture uses EtOAc (50mL) dilution then, successively water, 10% lithium chloride aqueous solution, saline (1 * each 30mL) washing.Organic layer is through anhydrous Na ₂SO ₄Drying, vacuum concentration.Crude product silica gel rapid column chromatography purification is used the EtOAc eluting, obtains title compound (150mg, 60%), is yellow-orange solids.

¹H NMR(DMSO-d ₆)δ9.13(s，1H)，8.63(d，1H，J＝6Hz)，7.09(t，1H，J＝9.2Hz)，6.92(d，1H，J＝6Hz)，6.55(dd，1H，J＝13.2，2.4Hz)，6.45(dd，1H，J＝9.2，2.4Hz)，5.61(s，2H)；MS(ESI ⁺)m/z250.18(M ⁺H) ⁺.

B) 1-(3-fluoro-4-(3-nitropyridine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00286] with 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 1.3mmol) toluene solution handle 3-fluoro-4-(3-nitropyridine-4-base oxygen base) aniline (158mg; 0.63mmol) THF (3mL) solution; at room temperature stir 2h, stir 5min down at 50 ℃ then.Enriched mixture is with DMF (15mL) and SiO ₂(150mg) handle residue, enriched mixture is carried in SiO to doing under the vacuum ₂On the post.With 20-60%EtOAc/ hexane eluting post, obtain product, by grinding, it is further purified with diisopropyl ether, obtain light yellow solid (120mg, 25%).

¹H NMR(DMSO-d ₆)δ11.07(s，1H)，10.63(s，1H)，9.19(s，1H)，8.67(d，1H，J＝5.6Hz)，7.85(d，1H，J＝11.7Hz)，7.46-7.45(m，2H)，7.39-7.35(m，2H)，7.18(dd，2H，J＝8.6，8.6Hz)，7.01(d，1H，J＝6.1Hz)，3.76(s，2H).

C) 1-(4-(3-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00287] (3-fluoro-4-(3-nitropyridine-4-base oxygen base) phenyl)-(125mg, 3: 1 MeOH/THF (20mL) suspension 0.29mmol) is through Pt for 3-(2-(4-fluorophenyl) acetyl group) urea to make 1- ₂O (50mg), the H that provides with latex balloon ₂Hydrogenation 6h is by Celite ^Filtration catalizer, concentrated filtrate obtains title compound (85mg, 74%), is white solid.

¹H NMR(DMSO-d ₆)δ11.03(s，1H)，10.55(s，1H)，8.03(s，1H)，7.75(dd，1H，J＝2.5，13.2Hz)，7.65(d，1H，J＝5.1Hz)，7.38-7.35(m，3H)，7.23-7.16(m，3H)，6.42(d，1H，J＝5.1Hz)，5.26(s，2H)，3.75(s，2H)；MS(ESI ⁺)：m/z 399.35(M+H) ⁺.

Embodiment 73

1-(4-(3-((1S, 4S)-4-aminocyclohexane formamido group) pyridin-4-yl oxygen base)-the 3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

A) (1S, 4S)-4 ((4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) carbamoyl) cyclohexyl t-butyl carbamate

[00288] with N-Boc-cis-1, (THF 0.10mmol) (1mL) solution is cooled to 0 ℃ to 4-diamino-cyclohexane formic acid, uses Et successively for Chem-ImprexInternational, 24mg ₃N and isobutyl chlorocarbonate are handled.Behind the 5min; with 1-(4-(3-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (Compound C among the embodiment 72; 27mg; 0.068mmol) THF (0.5mL) solution-treated mixture; under 0 ℃; continue to stir 10min, at room temperature stir 2h then.Make mixture at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution, separate the EtOAc phase, dry (MgSO ₄), vacuum concentration obtains crude product.Residue is through SiO ₂The rapid column chromatography purification with 50-100%EtOAc/ hexane eluting, obtains title compound (13mg, 21%), is white solid.MS(ESI ⁺)：m/z 624.25(M+H) ⁺。

B) 1-(4-(3-((1S, 4S)-4-aminocyclohexane formamido group) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

[00289] with (1S; 4S)-4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) carbamoyl) cyclohexyl t-butyl carbamate (10mg; 0.016mmol) anhydrous MeOH (0.5mL) solution be cooled to 0 ℃; use 4M HCl/1,4-two  alkane (2mL) are handled.Under 0 ℃, the 1.5h that stirs the mixture at room temperature stirs 20min then, and last vacuum concentration obtains crude product.Residue obtains title compound (4mg, 33%) through preparation HPLC (post A) purification, is yellow solid.

¹H NMR(DMSO-d ₆)δ11.07(s，1H)，10.64(s，1H)，9.28(s，1H)，8.40-8.37(m，1H)，7.94(s，1H)，7.83(dd，1H，J＝2.1，12.7Hz)，7.47-7.33(m，5H)，7.19-7.14(m，3H)，7.07-7.02(m，1H)，3.75(s，2H)，3.25-3.15(m，1H)，2.85-2.76(m，1H)，1.97-1.84(m，2H)，1.85-1.61(m，5H)；MS(ESI ⁺)：m/z 524.26(M+H) ⁺.

Embodiment 74

1-(4-(3-((1R, 4R)-4-aminocyclohexane formamido group) pyridin-4-yl oxygen base)-the 3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, two trifluoroacetates

A) (1R, 4R)-4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) carbamoyl) cyclohexyl t-butyl carbamate

[00290] by being similar to the described mode of the steps A of embodiment 73; by 1-(4-(3-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (Compound C among the embodiment 72; 57mg; 0.14mmol) and N-Boc-trans-4-aminocyclohexane-1-formic acid (Anaspec Inc.; 51mg, 0.21mmol) the preparation title compound obtains title compound (32mg; 66%), is white solid.MS(ESI ⁺)：m/z 624.41(M+H) ⁺。

B) 1-(4-(3-((1R, 4R)-4-aminocyclohexane formamido group) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, two trifluoroacetates

[00291] by being similar to mode described in the embodiment 73; by (1S, 4S)-4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) carbamoyl) cyclohexyl t-butyl carbamate (25mg) preparation title compound.Reactant mixture obtains title compound (7mg, 23%) through preparation HPLC (post A) purification, is white solid.

¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.61(s，1H)，9.94(s，1H)，9.19(s，1H)，8.28(d，1H，J＝5.6Hz)，7.82(dd，1H，J＝2.0，13.2Hz)，7.79-7.76(m，3H)，7.43(dd，1H，J＝2.0，8.6Hz)，7.38-7.33(m，2H)，7.17(dd，2H，J＝9.2，6.6Hz)，6.86(d，1H，J＝5.6Hz)，3.74(s，2H)，3.08-2.95(m，1H)，2.67-2.43(m，1H)，2.01-1.88(m，4H)，1.53-1.43(m，2H)，1.37-1.27(m，2H)；MS(ESI ⁺)：m/z524.35(M+H) ⁺.

Embodiment 75

1-(4-(3-((1R, 4R)-4-(amino methyl) cyclohexane extraction formamido group) pyridin-4-yl oxygen base)-the 3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) ((1R, 4R)-4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) carbamoyl) cyclohexyl) methyl carbamic acid benzyl ester

[00292] presses steps A among the embodiment 73; by 1-(4-(3-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (Compound C among the embodiment 72,50mg, 0.13mmol) and trans-4-((benzyloxycarbonyl) methyl) naphthenic acid (40mg; 0.14mmol; press Schaus, J.Med.Chem.1998 such as J.M., 41; the preparation of synthetic route described in the 1943-1955) preparation title compound; obtain title compound (30mg, 34%), be white solid.MS(ESI ⁺)：m/z 672.34(M+H) ⁺。

B) 1-(4-(3-((1R, 4R)-4-(amino methyl) cyclohexane extraction formamido group) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00293] makes ((1R; 4R)-and 4-((4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) carbamoyl) cyclohexyl) MeOH (1.5mL) solution of methyl carbamic acid benzyl ester (25mg 0.037mmol) is through 10% palladium-carbon (15mg), and the H that is provided by latex balloon is provided ₂Hydrogenation 4h.Filtration catalizer, vacuum concentrated filtrate obtains title compound (18mg, 90%), is yellow solid.

¹H NMR(DMSO-d ₆)δ10.62(s，1H)，9.64(s，1H)，9.01(s，1H)，8.17(d，1H，J＝5.6Hz)，7.79(dd，1H，J＝2.5，12.7Hz)，7.42-7.35(m，4H)，7.30(dd，1H，J＝8.6，9.2Hz)，7.18(m，2H)，6.66(d，1H，J＝5.6Hz)，3.75(s，2H)，2.39(d，2H，J＝6.6Hz)，1.87-1.81(m，4H)，1.46-1.35(m，1H)，1.33-1.10(m，1H)，0.95-0.77(m，4H)；MS(ESI ⁺)：m/z 538.28(M+H) ⁺.

Embodiment 76

1-(4-(3-(cyclohexane extraction formamido group) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00294] uses Et ₃N (10 μ L; 0.074mmol) and cyclohexane extraction phosgene (Aldrich, 11mg, 0.074mmol) processing 1-(4-(3-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (Compound C among the embodiment 72; 25mg, CH 0.062mmol) ₂Cl ₂(2mL) solution at room temperature stirs 2h.(11mg 0.074mmol) adds in the mixture, and 18h is proceeded in reaction with another part cyclohexane extraction phosgene.Use CH ₂Cl ₂The diluted mixture thing is used saturated NaHCO ₃Solution washing, dry (MgSO ₄), vacuum concentration.Residue is through SiO ₂The rapid column chromatography purification with 50-100%EtOAc/ hexane eluting, obtains title compound (19mg, 61%), is white solid.

¹HNMR(DMSO-d ₆)δ11.03(s，1H)，10.57(m，1H)，9.60(m，1H)，8.99(s，1H)，8.15(d，1H，J＝5.6Hz)，7.76(dd，1H，J＝2.0，13.2Hz)，7.39-7.33(m，3H)，7.28(dd，1H，J＝8.6，9.2Hz)，7.18-7.14(m，2H)，6.65(d，1H，J＝5.1Hz)，3.73(s，2H)，1.81-1.71(m，5H)，1.64-1.61(m，1H)，1.43-1.34(m，2H)，1.29-1.14(m，3H)；MS(ESI+)：m/z509.27(M+H) ⁺.

Embodiment 77

1-(4-(3-(4-amino piperidine-1-formamido group) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, two trifluoroacetates

A) 1-(3-fluoro-4-(3-(4-(2-phenoxy group acetylamino) piperidines-1-formamido group) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00295] with triphosgene (50mg, CH 0.17mmol) ₂Cl ₂(0.4mL) solution is cooled to-10 ℃, with 1-(4-(3-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (Compound C among the embodiment 72,67mg, 0.17mmol) and DIPEA (65 μ L, CH 0.37mmol) ₂Cl ₂(0.4mL) solution-treated.Under-10 ℃, the 10min that stirs the mixture uses 4 ((carbobenzoxy group) acylamino-) piperidines (40mg, 0.17mmol use Schaus, J. Med Chem.1998 such as J.M., 41, the preparation of method described in the 1943-1955) and DIPEA (65 μ l, CH 0.37mmol) then ₂Cl ₂(0.4mL) solution-treated.After 2 minutes, mixture is warming up to room temperature, is heated to 40 ℃ then and keeps 10min.With EtOAc diluted mixture thing, use saturated NaHCO ₃Aqueous solution and salt water washing, dry (MgSO ₄), vacuum concentration.Product is through SiO ₂The rapid column chromatography purification is used 0-5%MeOH/CH ₂Cl ₂Eluting obtains title compound (50mg, 45%), is yellow solid.MS(ESI ⁺)m/z 659.29(M+H) ⁺。

B) 1-(4-(3-(4-amino piperidine-1-formamido group) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, two trifluoroacetates

[00296] makes 1-(3-fluoro-4-(3-(4-(2-phenoxy group acetylamino) piperidines-1-formamido group) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (45mg; 0.068mmol) anhydrous MeOH (2.5mL) solution through 10% palladium-carbon (15mg), use by H from rubber balloon ₂Hydrogenation 2.5h.Filtering catalyst, vacuum concentrated filtrate, residue obtains title compound through preparation HPLC (post A) purification.

¹H NMR(DMSO-d ₆)δ10.57(s，1H)，8.55(s，1H)，8.27(m，1H)，8.14(d，1H，J＝5.6Hz)，7.75(dd，1H，J＝2.0，12.7Hz)，7.37-7.33(m，3H)，7.23-7.14(m，3H)，6.65(d，1H，J＝5.1Hz)，4.05-3.98(m，2H)，3.73(s，2H)，3.05-2.91(m，1H)，2.88-2.83(m，2H)，1.83-1.74(m，2H)，1.34-1.20(m，2H)；MS(ESI+)m/z 525.35(M+H) ⁺.

Embodiment 78

1-(4-(2-amino-3-(4-(2-amino-2-oxoethyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

A) 2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetic acid

[00297] by vacuum/argon purge, make 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine-2-amine (Compound C among the embodiment 34,88mg, 0.23mmol), 4-(dihydroxy borine) phenylacetic acid 2-pinacol ester (Frontier Scientific Inc., 92mg, 0.35mmol), Na ₂CO ₃(170mg, 1.61mmol), 1,4-two  alkane (2mL) and H ₂The mixture degassing of O (2mL), (27mg 0.023mmol) handles to close palladium with four (triphenyl phasphines).Behind heating 3h under 100 ℃, mixture pH is transferred to pH6 with 1N hydrochloric acid.Vacuum concentrated mixture distributes residue between EtOAc and phosphate buffer pH7.Use the EtOAc aqueous phase extracted, with the extract drying (MgSO that merges ₄), vacuum concentration obtains crude product.With 2: 1 EtOAc/MeOH grinding product, obtain the product (70mg, 80%) of needs, be orange-brown solid.

¹H NMR(DMSO-d ₆)δ12.34(s，1H)，8.23(dd，1H，J＝3.1，10.5Hz)，8.05(d，1H，J＝10.2Hz)，7.94(d，1H，J＝6.1Hz)，7.32-7.25(m，5H)，6.26(d，1H，J＝6.1Hz)，5.62(s，2H)，3.57(s，2H)；MS(ESI ⁺)：m/z 384.16(M+H) ⁺.

B) 2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetamide

[00298] use successively PyBOP (125mg, 0.24mmol) and HOBt (32mg, 0.24mmol), DIPEA (60 μ L, 0.35mmol) and NH ₄(19mg 0.35mmol) handles 2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetic acid (65mg, dry DMF 0.17mmol) (1.2mL) solution to Cl.After at room temperature stirring 20min, vacuum concentrated mixture makes residue at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With salt water washing EtOAc phase, dry (MgSO ₄), vacuum concentration.Product is through SiO ₂The rapid column chromatography purification is used 0-8%MeOH/CH ₂Cl ₂Eluting obtains title compound (40mg, 62%), is amber oily thing.

¹H NMR(DMSO-d ₆)δ8.23(dd，1H，J＝10.7，2.5Hz)，8.05(d，1H，J＝9.2Hz)，7.93(d，1H，J＝6.1Hz)，7.42-7.32(m，2H)，7.33-7.25(m，4H)，6.92(s，1H)，6.25(d，1H，J＝5.6Hz)，5.64(s，2H)，3.36(s，2H)；MS(ESI ⁺)：m/z 383.17(M+H) ⁺.

C) 2-(4-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl) phenyl) acetamide

[00299] with the Fe powder (67mg, 1.2mmol) and NH ₄Cl (128mg, 2.4mmol) handle 2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) phenyl) acetamide (32mg, 0.086mmol), DMF (1mL), EtOH (1mL) and H ₂The mixture of O (1mL) is at 100 ℃ of following heating blends 20min.Pass through Celite ^Filtering mixt transfers to pH7 with phosphate buffer with the pH of filtrate, extracts mixture with EtOAc then.With organic extract liquid drying (MgSO ₄), concentrate, obtain the product (20mg, 67%) of needs, yellow-brown solid.MS(ESI ⁺)：m/z 353.32(M+H) ⁺。

D) 1-(4-(2-amino-3-(4-(2-amino-2-oxoethyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea trifluoroacetate

[00300] by being similar to described mode to the step D of embodiment 33; by 2-(4-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl) phenyl) acetamide (19mg; 0.054mmol) and 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.27mL toluene solution 0.081mmol) prepares title compound.Reactant mixture obtains title compound (9mg, 26%) through preparation HPLC (post A) purification, is white solid.

¹H NMR(DMSO-d ₆)：δ11.03(s，1H)，10.57(s，1H)，7.93(d，1H，J＝7.1Hz)，7.76(dd，1H，J＝2.0，13.2Hz)，7.44-7.42(m，3H)，7.37-7.29(m，6H)，7.16(dd，2H，J＝8.6，8.8Hz)，6.94(s，1H)，6.31(d，1H，J＝7.1Hz)，3.72(s，2H)，3.43(s，2H)；MS(ESI ⁺)：m/z 532.24(M+H) ⁺.

Embodiment 79

1-(4-(2-amino-3-(2-(pyridine-2-yl) acetenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

A) 4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridine-2-yl) acetenyl) pyridine-2-amine

[00301] by vacuum/argon purge, make 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine-2-amine (Compound C among the embodiment 34,100mg, 0.27mmol) and the 2-ethynyl pyridine (Aldrich, 57mg, 0.54mmol), THF (2mL) and Et ₃The mixture degassing of N (2mL), (6mg is 0.032mmol) with (Ph with CuI ₃P) ₄(20mg 0.017mmol) handles Pd.

Under 60 ℃, heating blends 45 minutes, cooling distributes it between EtOAc and saturated sodium bicarbonate aqueous solution.With organic facies drying (MgSO ₄), vacuum concentration obtains crude product.Residue is through SiO ₂The rapid column chromatography purification is used 0-1.5%MeOH/CH ₂Cl ₂Eluting obtains title compound (55mg, 58%), is brown solid.

¹H NMR(DMSO-d ₆)δ8.53(d，1H，J＝5.1Hz)，8.39(dd，1H，J＝2.5，10.7Hz)，8.15(dm，1H，J＝8.1Hz)，7.97(d，1H，J＝5.6Hz)，7.81(d，1H，J＝8.1Hz)，7.71(d，1H，J＝7.6Hz)，7.52(dd，1H，J＝8.6，8.6Hz)，7.38-7.34(m，1H)，6.71(s，2H)，6.21(d，1H，J＝5.6Hz)；MS(ESI ⁺)：m/z 351.25(M+H) ⁺.

B) 4-(4-amino-2-fluorophenoxy)-3-(2-(pyridine-2-yl) acetenyl) pyridine-2-amine

[00302] with zinc powder (65mg, 1.0mmol) and NH ₄(53mg, (35mg 0.1mmol), the mixture of THF (1.5mL) and MeOH (1.5ml), heats 45min down at 60 ℃ to Cl 1.0mmol) to handle 4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridine-2-yl) acetenyl) pyridine-2-amine.Reaction mixture is filtered vacuum concentration.Make residue at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.Separate organic facies, use the salt water washing, dry (MgSO ₄), concentrate, obtain title compound (25mg, 78%), be brown solid.MS(ESI ⁺)：m/z 321.2(M+H) ⁺。

C) 1-(4-(2-amino-3-(2-(pyridine-2-yl) acetenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00303] with 4-(4-amino-2-fluorophenoxy)-3-(2-(pyridine-2-yl) acetenyl) pyridine-2-amine (25mg; 0.078mmol) THF (2mL) solution be cooled to 0 ℃; with 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.26mL toluene solution 0.078mmol) is handled.Behind the 1h, make mixture be warming up to room temperature, stir 15min.Vacuum concentrated mixture, residue obtain the tfa salt of title compound through preparation HPLC (post A) purification.This tfa salt is dissolved in anhydrous MeOH, under 0 ℃, uses 1M HCl/Et ₂O handles, and stirs 5min.Vacuum concentrated mixture obtains title compound (18mg, 41%) then, is brown solid.

¹HNMR(DMSO-d ₆)δ11.06(s，1H)，10.63(s，1H)，8.62(d，1H，J＝4.5Hz)，8.22(s，2H)，7.99(d，1H，J＝7.1Hz)，7.94-7.81(m，3H)，7.48-7.44(m，3H)，7.37-7.33(m，2H)，7.16(dd，2H，J＝6.2，9.2Hz)，6.30(d，1H，J＝7.1Hz)，3.74(s，2H)；MS(ESI ⁺)：m/z 500.21(M+H) ⁺.

Embodiment 80

1-(4-(2-acetylamino pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl t-butyl carbamate

[00304] under 65 ℃, and heating 4-(4-amino-2-fluorophenoxy) picolinamide (compd B among the embodiment 24 ', 190mg, 0.76mmol), the tert-butyl alcohol (2mL), 1,4-two  alkane (1mL), DMF (1mL) and Boc ₂O (167mg, mixture 16h 0.76mmol).Behind 16h and the 32h, add other Boc respectively again ₂O (85mg and 60mg), heating blends adds up to 40h.Vacuum concentrated mixture makes residue at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With the dry mutually (MgSO of EtOAc ₄), vacuum concentration obtains crude product.Residue is through SiO ₂The rapid column chromatography purification with 30-60%EtOAc/ hexane eluting, obtains title compound (180mg, 68%), is brown solid.

¹H NMR(DMSO-d ₆)δ9.74(s，1H)，8.52(d，1H，J＝5.6Hz)，8.13(s，1H)，7.72(s，1H)，7.62(d，1H，J＝13.7Hz)，7.35-7.31(m，3H)，7.18(dd，1H，J＝5.6，2.5Hz)，1.39(s，9H)；MS(ESI ⁺)：m/z 348.22(M+H) ⁺.

B) 4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl t-butyl carbamate

[00305] with KOH (280mg, H 5.0mmol) ₂O (2mL) solution is cooled to 0-5 ℃, and (162mg 1.0mmol) handles dripping bromine, and 5min stirs the mixture.(347mg 1.0mmol) in the disposable adding mixture, adds 1 then, and 4-two  alkane (3mL) are with dissolved solid with 4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl t-butyl carbamate solid.At room temperature, stirred reaction mixture 30min stirs 45min down at 55 ℃ then.Then mixture is cooled to room temperature, handles, stir and disappear until foam with HOAc (0.5mL).With mixture reheat to 55 ℃ maintenance 20min, be cooled to room temperature, handle with KOH (350mg), use CH ₂Cl ₂Extraction.With organic extract drying (MgSO ₄), vacuum concentration.Residue is through SiO ₂The rapid column chromatography purification with 30-70%EtOAc/ hexane eluting, obtains title compound (265mg, 83%).

¹H NMR(DMSO-d ₆)δ9.67(s，1H)，7.77(d，1H，J＝6.1Hz)，7.56(d，1H，J＝11.7Hz)，7.26-7.18(m，2H)，6.12(dd，1H，J＝2.0，6.1Hz)，5.93(s，2H)，5.74(d，1H，J＝2.5Hz)，1.47(s，9H)；MS(ESI ⁺)：m/z320.23(M+H) ⁺.

C) 4-(2-acetylamino pyridin-4-yl oxygen base)-3-fluorophenyl t-butyl carbamate

[00306] with 4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl t-butyl carbamate (150mg, anhydrous pyridine 0.47mmol) (0.5mL) solution is cooled to 10 ℃, (33 μ L 0.47mmol) handle, and 45min stirs the mixture with chloroacetic chloride.(16 μ L 0.24mmol) add in the reactant, continue to stir 25min with another part chloroacetic chloride.With EtOAc (20mL) diluted mixture thing, use the salt water washing, dry (MgSO ₄), vacuum concentration obtains title compound (115mg, 68%).

¹H NMR(DMSO-d ₆)δ10.55(s，1H)，9.71(s，1H)，8.16(d，1H，J＝5.5Hz)，7.63-7.55(m，2H)，7.29-7.23(m，2H)，6.68-6.63(m，1H)，2.02(s，3H)，1.48(s，9H)；MS(ESI ⁺)：m/z 362.22(M+H) ⁺.

D) N-(4-(4-amino-2-fluorophenoxy) pyridine-2-yl) acetamide

[00307] under 0 ℃, (4-two  alkane (1.5mL) solution 20min at room temperature stir 25min then for 110mg, 4M HCl/1 0.30mmol) to stir 4-(2-acetylamino pyridin-4-yl oxygen base)-3-fluorophenyl t-butyl carbamate.With EtOAc (25mL) and saturated NaHCO ₃Aqueous solution (20mL) diluted mixture thing, vigorous stirring 5min.With salt water washing EtOAc phase, dry (MgSO ₄), vacuum concentration obtains title compound (69mg, 87%), is yellow solid.

¹HNMR(DMSO-d ₆)δ10.49(s，1H)，8.13(d，1H，J＝5.6Hz)，7.60(m，1H)，6.95(dd，1H，J＝8.6，9.2Hz)，6.60(dd，1H，J＝2.5，5.6Hz)，6.48(dd，1H，J＝2.5，13.2Hz)，6.40(dd，1H，J＝2.0，8.6Hz)，5.44(s，2H)，2.02(s，3H).

E) 1-(4-(2-acetylamino pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00308] with 0.3M 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.26mL; 0.77mmol) toluene solution handle N-(4-(4-amino-2-fluorophenoxy) pyridine-2-yl) acetamide (20mg; 0.077mmol) THF (1mL) solution, 1h at room temperature stirs the mixture.Vacuum concentrated mixture, residue obtain the tfa salt of title compound through preparation HPLC (post A) purification.This tfa salt is dissolved in anhydrous MeOH, under 0 ℃, uses 1M HCl/Et ₂O handles, and stirs 5min.Vacuum concentrated mixture obtains title compound (12mg, 33%) then, is white solid.

¹H NMR(DMSO-d ₆)：δ11.04(s，1H)，10.65(s，1H) 10.58(s，1H)，8.18(d，1H，J＝6.1Hz)，7.77(dd，1H，J＝2.0，12.7Hz)，7.56(m，1H)，7.40-7.30(m，5H)，7.18-7.14(m，2H)，6.71(dd，1H，J＝2.5，6.1Hz)，3.74(s，2H)，2.03(s，3H)；MS(ESI ⁺)：m/z 441.18(M+H) ⁺.

Embodiment 81

N-(4-(2-acetylamino pyridin-4-yl oxygen base)-3-fluorophenyl)-2,6-difluorobenzamide, hydrochlorate

[00309] with DIPEA (15 μ L, 0.086mmol) and 2-6-difluoro benzoyl chloride (10mg, 0.057mmol) processing N-(4-(4-amino-2-fluorophenoxy) pyridine-2-yl) acetamide (compd B among the embodiment 24 ', 15mg, 0.057mmol) THF (0.5mL) solution, 1.5h at room temperature stirs the mixture.Vacuum concentrated mixture, residue obtain the tfa salt of title compound through preparation HPLC (post A) purification.This tfa salt is dissolved in anhydrous MeOH, under 0 ℃, uses 1M HCl/Et ₂O handles, and stirs 5min.Vacuum concentrated mixture obtains title compound (15mg, 60%) then, is pale solid.

¹H NMR(DMSO-d ₆)δ11.17(s，1H)，10.79(s，1H)，8.21(d，1H，J＝6.1Hz)，7.89(dd，1H，J＝2.0，12.7Hz)，7.66-7.59(m，1H)，7.53-7.50(m，2H)，7.42(dd，1H，J＝8.6，9.2Hz)，7.28(dd，2H，J＝8.1，8.1Hz)，6.80(dd，1H，J＝2.0，6.1Hz)，2.06(s，3H)；MS(ESI ⁺)：m/z 402.13(M+H) ⁺.

Embodiment 82

1-(3-fluoro-4-(2-(2-morpholino ethylamino) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

A) N-(4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl) acetamide

[00310] with N-(3-fluoro-4-hydroxy phenyl) acetamide (compd A of embodiment 13,1.33g, 7.87mmol), 2-chloro-4-nitropyridine (Aldrich, 1.24g, 7.87mmol), K ₂CO ₃(1.6g, 11.8mmol) and the mixture of DMF (25mL) at 100 ℃ of following heating 9h.Vacuum concentrated mixture makes residue at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With salt water washing EtOAc phase, dry (MgSO ₄), vacuum concentration.Residue is through SiO ₂The rapid column chromatography purification with 30-80%EtOAc/ hexane eluting, obtains title compound (1.6g, 73%), is light yellow solid.

¹H NMR(DMSO-d ₆)δ10.25(s，1H)，8.35(d，1H，J＝7Hz)，7.80(d，1H，J＝14Hz)，7.50(d，1H，J＝3Hz)，7.33(m，2H)，7.02(m，1H)，2.06(s，3H)；MS(ESI ⁺)：m/z 281.16(M+H) ⁺.

B) N-(4-(2-chloropyridine-4-base Oxy-1-oxide)-3-fluorophenyl) acetamide

[00311] at room temperature, stir N-(4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl) acetamide (0.98g, 3.5mmol),＞90% ,-chloroperoxybenzoic acid (1.3g, 7.6mmol) and CHCl ₃Mixture 60h (50mL).Vacuum concentrated mixture is used Et ₂(2 * 100mL) grind residue to O, obtain title compound (0.89g, 86%), are light yellow solid.

¹H NMR(DMSO-d ₆)δ10.25(s，1H)，8.35(d，1H，J＝7.3Hz)，7.80(d，1H，J＝13Hz)，7.33-7.32(m，3H)，7.02(dd，1H，J＝3.5，7.5Hz)，2.06(s，3H)；MS(ESI ^-)：m/z 295.04(M+H) ⁺.

[00312] with N-(4-(2-chloropyridine-4-base Oxy-1-oxide)-3-fluorophenyl) acetamide hydrochloride (205mg, 0.62mmol), 4-(2-amino-ethyl) morpholine (Aldrich, 169mg, 1.30mmol) and the mixture reflux 16h of anhydrous EtOH.The vacuum concentration reactant mixture is used H ₂O (3mL) handles residue, is loaded on the 10g Varian C-18 post.This post is used H successively ₂O, 30%MeOH/H ₂The O eluting.Merge the eluent of the product that contains needs, be concentrated into the 5mL volume, with EtOAc extraction 3 times.With the extract that the salt water washing merges, dry (MgSO ₄), vacuum concentration obtains title compound (100mg, 40%).

¹H NMR(DMSO-d ₆)δ10.22(s，1H)，7.84(d，1H，J＝6Hz)，7.77(dd，1H，J＝2，12Hz)，7.31(dd，1H，J＝2，9Hz)，7.24(dd，1H，J＝9，9Hz)，6.41(m，1H)，6.13(dd，1H，J＝2，6Hz)，5.81(d，1H，J＝2.5Hz)，3.56-3.48(m，2H)，3.31-3.19(m，4H)，2.38(t，2H，J＝7Hz)，2.40-2.28(m，4H)，2.06(s，3H)；MS(ESI ⁺)：m/z405.22(m+H) ⁺.

[00313] under 135 ℃, with N-(3-fluoro-4-(2-(2-morpholino ethylamino) pyridin-4-yl Oxy-1-oxide) phenyl) acetamide (100mg, 0.26mmol) and triphenyl phasphine (1.4-2.0mmol/g) on the poly styrene polymer carrier (500mg) and the mixture of DMF (2mL) stirring 15h.Filtering mixt is removed resin, with DMF and EtOAc washing resin.Merging filtrate and cleaning mixture concentrate.Crude product obtains title compound (45mg, 24%) through preparation HPLC (post A) purification, is white solid.

¹H NMR(DMSO-d ₆)δ10.33(s，1H)，8.02(d，1H，J＝7Hz)7.84(dd，1H，J＝2，13Hz)，7.39-7.31(m，2H)，6.52(s，1H)，6.10(s，1H)，3.83(s，4H)， 3.60-3.48(m，2H)，3.32-3.18(m，6H)，2.08(s，3H)；MS(ESI ⁺)：m/z375.12(M+H) ⁺.

[00314] with the mixture reflux 3h of N-(3-fluoro-4-(2-(2-morpholino ethylamino) pyridin-4-yl oxygen base) phenyl) acetamide trifluoroacetate (40mg), MeOH (1mL) and 6M HCl (0.2mL).Enriched mixture on Rotary Evaporators, the lyophilizing residue obtains title compound (30mg), is white solid.

¹H NMR(DMSO-d ₆)δ11.12(s，1H)，8.85(s，1H)，7.95(d，1H，J＝7Hz)，7.08(dd，1H，J＝9，9Hz)，6.65-6.63(m，2H)，6.54(d，1H，J＝8Hz)，6.31(s，1H)，3.90-3.75(m 6H)，3.37-3.21(m，6H)；MS(ESI ^-)：m/z 373.14(M+H) ⁺.

F) 1-(3-fluoro-4-(2-(2-morpholino ethylamino) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00315] uses Et ₃4-(4-amino-2-fluorophenoxy)-(N-(2-morpholino ethyl) pyridine-2-amine hydrochlorate at room temperature stirs the mixture 5min for 15mg, MeOH 0.045mmol) (5mL) solution in N (2mL) processing.Vacuum concentrated mixture is removed MeOH, and residue is suspended among the THF (1mL), and (toluene solution 0.054mmol) is handled for the Compound D among the embodiment 11,180mL with 0.3M 2-(4-fluorophenyl) acetyl group isocyanates.After the stirring, vacuum concentrated mixture makes residue at EtOAc and saturated NaHCO ₃Between distribute.Separate the EtOAc phase, use the salt water washing, dry (MgSO ₄), concentrate.Enriched mixture under the vacuum, residue obtain the tfa salt of title compound through preparation HPLC (post A) purification.This tfa salt is dissolved in anhydrous MeOH, under 0 ℃, uses 1N HCl/Et ₂O handles, and stirs 5min.Vacuum concentrated mixture obtains title compound (10mg, 43%) then, is white solid.

¹H NMR(DMSO-d ₆)δ11.05(s，1H)，10.61(s，1H)，7.98(d，1H，J＝7.1Hz)，7.86-7.73(m，1H)，7.48-7.38(m，1H)，7.37-7.30(m，3H)，7.24-7.04(m，2H)，6.60(s，1H)，6.26(s，1H)，3.98-3.60(m，8H)，3.74(s，2H)，3.39-3.19(m，4H)；MS(ESI ⁺)：m/z 512.2(M+H) ⁺.

[00316] mode prepares embodiment 83-85 described in the embodiment 82 by being similar to.

Embodiment 83

1-(3-fluoro-4-(2-(3-morpholino propyl group amino) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00317] ¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.62(s，1H)，7.93(d，1H，J＝7.1Hz)，7.83(d，1H，J＝12.7Hz)，7.45-7.33(m，4H)，7.16(dd，2H，J＝8.6，9.2Hz)，6.64(s，1H)，6.23(s，1H)，335-3.76(m，4H)，3.74(s，2H)，3.70-3.48(m，4H)，3.48-3.35(m，2H)，3.20-3.-04(m，2H)，2.02-1.93(m，2H).

Embodiment 84

1-(4-(2-(3-(dimethylamino) propyl group amino) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00318] ¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.62(s，1H)，10.37(s，1H)，7.93(d，1H，J＝7.1Hz)，7.82(dd，1H，J＝2.0，12.7Hz)，7.45(dd，1H，J＝2.6，8.6Hz)，7.40(d，1H，J＝8.6Hz)，7.37-7.33(m，2H)，7.16(dd，2H，J＝8.7，9.1Hz)，6.65(s，1H)，6.24(s，1H)，3.75(s，2H)，3.45-3.36(m，2H)，3.13-3.03(m，2H)，2.73(s，3H)，2.72(s，3H)，1.94-1.90(m，2H).

Embodiment 85

1-(4-(2-(4-(dimethylamino) butyl amino) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00319]MS(ESI ⁺)：m/z 498.2(M+H) ⁺。

Embodiment 86

1-(4-(2,6-diamino-pyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 4-chloropyridine-2, the 6-diformamide

[00320] with chelidonamic acid (3.19g, 17.0mmol), PCl ₅(2.1g) and CCl ₄Mixture backflow 6h (30mL) is cooled to 65 ℃ then, under gentle the backflow, handles with MeOH (5mL).With mixture reflux 5h, vacuum concentration then.Handle residue with ice-water (50mL), filter, the solid of collecting precipitation is drained on funnel, obtains white needles 2,6-diformazan ester group-4-chloropyridine (2.4g).With～7M NH ₃/ MeOH handles product, at room temperature stirs 1h.Filtering mixt is collected title compound, is white solid (1.8g, 53%).

¹H NMR(DMSO-d ₆)δ8.91(s，2H)，8.15(s，2H)，7.87(s，2H).

B) 4-(2,6-diaminourea formoxyl pyridin-4-yl oxygen base)-3-fluorophenyl t-butyl carbamate

[00321] (124mg, amino-(the 2-fluorophenol at room temperature stirs the mixture 2h for 228mg, DMF 1.0mmol) (2mL) solution 1.1mmol) to handle N-Boc-4-with t-BuOK.With 4-chloropyridine-2, and the 6-diformamide (200mg, 1.0mmol) and K ₂CO ₃(35mg, 0.5mmol) treatment mixture heat 1.5h down at 80 ℃.Vacuum concentrated mixture is with EtOAc (10mL) and H ₂O (10mL) handles, and filters, and removes insoluble matter.With salt water washing EtOAc phase, dry (MgSO ₄), vacuum concentration.Residue is through SiO ₂The rapid column chromatography purification with 30-100%EtOAc/ hexane eluting, obtains title compound (170mg, 44%), for containing the white solid of 10% chloropyridine raw material.

¹H NMR(DMSO-d ₆)δ9.77(s，1H)，8.86(s，2H)，7.87(s，1H)，7.63(d，1H，J＝12.1Hz)，7.55(s，2H)，7.38-7.31(m，2H)，1.48(s，9H).

C) 4-(2,6-diamino-pyridine-4-base oxygen base)-3-fluorophenyl t-butyl carbamate

[00322] with being similar to described mode, by 4-(2,6-diaminourea formoxyl pyridin-4-yl oxygen base)-3-fluorophenyl t-butyl carbamate (110mg, 0.28mmol) preparation title compound to the step B of embodiment 80.At SiO ₂On carry out flash chromatography, use the 0-2%MeOH/EtOAc eluting, obtain title compound (60mg, 63%), be white solid.

¹H NMR(DMSO-d ₆)δ9.60(s，1H)，7.50(dd，1H，J＝1.8，13.6Hz)，7.21(dd，1H，J＝2.2，8.7Hz)，7.13(dd，1H，J＝8.7，9.2Hz)，5.40(s，4H)，5.13(s，2H)，1.47(s，9H)；MS(ESI ⁺)：m/z335.23(M+H) ⁺.

D) 4-(4-amino-2-fluorophenoxy) pyridine-2, the 6-diamidogen

[00323] with the mode that is similar to the step D among the described embodiment 80, (2,6-diamino-pyridine-4-base oxygen base)-(30mg, 0.089mmol) the preparation title compound obtains clarifying grease (20mg, 100%) to 3-fluorophenyl t-butyl carbamate by 4-.MS(ESI ⁺)：m/z235.22(M+H) ⁺。

E) 1-(4-(2,6-diamino-pyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00324] with the described mode of step D that is similar to embodiment 33; by 4-(4-amino-2-fluorophenoxy) pyridine-2; 6-diamidogen (19mg; 0.081mmol) and 2-(4-fluorophenyl) acetyl group isocyanates (0.3M; Compound D among the embodiment 11; 0.27mL toluene solution 0.081mmol) prepares title compound.Reactant mixture obtains the tfa salt of title compound through preparation HPLC (post A) purification.Under 0 ℃, this tfa salt is dissolved in anhydrous MeOH, use 1M HCl/Et ₂O handles, and stirs 5min.Vacuum concentrated mixture obtains title compound (8mg, 24%) then, is light yellow solid.

¹H NMR(DMSO-d ₆)δ11.01(s，1H)，10.51(s，1H) 7.68(dd，1H，J＝2.6，12.7Hz)，7.36-7.30(m，3H)，7.22-7.14(m，3H)，5.52(s，4H)，5.15(s，2H)，3.73(s，2H)；MS(ESI ⁺)：m/z 414.09(M+H) ⁺.

Embodiment 87

1-(4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

A) 4-bromo-3-fluorophenyl t-butyl carbamate

[00325] at room temperature, (Lancaster, 7.05g add in anhydrous tetrahydro furan 37.1mmol) (40mL) solution (Boc) to 4-bromo-3-fluoroaniline ₂O (8.10g, 37.1mmol) and triethylamine (5.17mL, 37.1mmol).With the reaction mixture refluxed heated overnight.After the cooling, the concentrating under reduced pressure reactant mixture.Residue is through SiO ₂The rapid column chromatography purification is used 20% dichloromethane/hexane, 20% ethyl acetate/hexane eluting successively, obtains 4-bromo-3-fluorophenyl t-butyl carbamate (5.30g, 49% yield).MS(ESI ⁺)：m/z290.2(M+H) ⁺。

B) 4 ((2-chloropyridine-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamates

[00326] under-78 ℃, (2.60g adds the MeMgBr (Et of 3.0M in anhydrous THF (30mL) solution 9.0mmol) to 4-bromo-3-fluorophenyl t-butyl carbamate by syringe ₂O solution, 3.1mL, 9.3mmol).Under this temperature, agitating solution 10min is warming up to 0 ℃ then, keeps 0.5h.Again solution is cooled to-78 ℃, in 4min, adding t-BuLi solution (hexane solution of 1.7M, 10.6mL, 18.1mmol).The solution 5min that stirring obtains in 3min, adds the 2-different cigarette aldehyde of chlorine (isonicotinaldehyde) (1.41g then, 10mmol) (preparation method, referring to Frey, Tetrahedron Lett.2001 such as L.F., 42,6815) anhydrous THF (25mL) solution.Under-78 ℃, stirred reaction mixture 20min adds 2.0mL MeOH.Decompression concentrated solution is dissolved in 200mLEtOAc with residue then.Use H subsequently ₂O (2 * 50mL), saline (2 * 50mL) washing, through MgSO ₄Dry.Filter, after concentrating, residue is through SiO ₂The flash chromatography purification with 0%-50%EtOAc/ hexane eluting, obtains 4-((2-chloropyridine-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (1.30g, 41% yield).MS(ESI ⁺)：m/z 353.28/355.24(M+H) ⁺。

C) 4-((2-chloropyridine-N-oxide-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate

[00327] to 4-((2-chloropyridine-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (1.20g, 3.40mmol) descend in the solution in dichloromethane (100mL) and ethyl acetate (10mL) mixture to add m-CPBA (70%, 2.34g, 9.48mmol).At room temperature stirred reaction mixture 2h, reflux 5h then.Removal of solvent under reduced pressure, residue is through SiO ₂The flash chromatography purification is used 50%EtOAc/ hexane, 100%EtOAc, 10%MeOH/EtOAc eluting successively, obtains 4-((2-chloropyridine-N-oxide-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (840mg, 67% yield).MS(ESI ⁺)：m/z 369.13/371.13(M+H) ⁺。

D) 4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate

[00328] ((2-chloropyridine-N-oxide-4-yl) (hydroxyl) methyl)-(80mg adds N in EtOH 0.22mmol) (2.0mL) solution to 3-fluorophenyl t-butyl carbamate to 4- ¹, N ¹-dimethylpropane-1, and the 3-diamidogen (225mg, 2.2mmol).Under 80 ℃, reacting by heating mixture 12h removes and desolvates, and obtains thick 4-((2-(3-(dimethylamino) propyl group amino) pyridine-N-oxides-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate, and it can be directly used in next step.MS(ESI ⁺)：m/z 435.37(M+H) ⁺。

[00329] to 4-((2-(3-(dimethylamino) propyl group amino) pyridine-N-oxides-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (add in～0.22mmol) MeOH (2.0mL) solution zinc (114mg, 1.75mmol) and NH ₄CO ₂H (139mg, 2.20mmol).Suspension returning is spent the night.Add zinc (114mg) and NH again ₄CO ₂H (139mg), suspension 2h again refluxes.After the cooling, filtering solution, concentrating under reduced pressure filtrate.Residue is through SiO then ₂The flash chromatography purification is used the 10-30%MeOH/DCM eluting, obtains 4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (80mg, 87% yield).MS(ESI ⁺)：m/z 419.34(M+H) ⁺。

E) 4-(4-amino-2-luorobenzyl)-N-(3-(dimethylamino) propyl group) pyridine-2-amine

[00330] to 4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (80mg, add in MeOH 0.19mmol) (5.0mL) solution dense HCl of 2mL and palladium on carbon (10%, 200mg).Under 75 ℃, at H ₂Under the atmosphere, add hot suspension 24h.After the mixture cooling, filter vacuum concentration.Residue is dissolved in the dense NH of 1mL ₄OH is with DCM (5 * 5mL) extractions.The organic layer that merges is through Na ₂SO ₄Dry.After the filtration, vacuum concentration obtains 4-(4-amino-2-luorobenzyl)-N-(3-(dimethylamino) propyl group) pyridine-2-amine (31mg, 40% yield).MS(ESI ⁺)：m/z 303.31(M+H) ⁺。

F) 1-(4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00331] to 4-(4-amino-2-luorobenzyl)-N-(3-(dimethylamino) propyl group) pyridine-2-amine (30mg; 0.1mmol) DCM (2mL) solution in add 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.347M toluene solution, 0.25mL) solution.At room temperature, the 0.5h that stirs the mixture uses the MeOH quencher then.Vacuum concentrated solution, residue is through the preparation HPLC purification.Collect the flow point that needs, vacuum concentration.Residue is dissolved in MeOH, adds the diethylenetriamines (50mg) that combines with polymer, remove trifluoroacetic acid.Filter, after concentrating, add 1N HCl (0.5mL); residue is converted into hydrochlorate; lyophilizing obtains 1-(4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea hydrochlorate (8.0mg, 14% yield).MS(ESI ⁺)：m/z 482.24(M+H) ⁺。

Embodiment 88

1-(4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) (hydroxyl) methyl) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) 4-((2-chloropyridine-4-yl) (hydroxyl) methyl) the phenylcarbamic acid tert-butyl ester

[00332] prepares by the described mode of the step B that is similar to embodiment 87.(141mg 1.0mmol) is converted into 4-((2-chloropyridine-4-yl) (hydroxyl) methyl) the phenylcarbamic acid tert-butyl ester (190mg, 57% yield) with the different cigarette aldehyde of 2-chlorine.MS(ESI ⁺)：m/z 335.27/337.27(M+H) ⁺。

B) 4 ((2-chloropyridine-N-oxide-4-yl) (hydroxyl) methyl) phenylcarbamic acid tertiary butyl ester

[00333] prepares by the described mode of the step C that is similar to embodiment 87.(78mg 0.23mmol) is converted into 4-((2-chloropyridine-N-oxide-4-yl) (hydroxyl) methyl) the phenylcarbamic acid tert-butyl ester (36mg, 44% yield) with 4-((2-chloropyridine-4-yl) (hydroxyl) methyl) the phenylcarbamic acid tert-butyl ester.MS(ESI ⁺)：m/z 351.28/353.27(M+H) ⁺。

C) 4 ((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) (hydroxyl) methyl) phenylcarbamic acid tert-butyl ester

[00334] prepares by the described mode of the step D that is similar to embodiment 87.With 4-((2-chloropyridine-N-oxide-4-yl) (hydroxyl) methyl) the phenylcarbamic acid tert-butyl ester (36mg, 0.1mmol) be converted into 4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) (hydroxyl) methyl) the phenylcarbamic acid tert-butyl ester (16mg, 40% yield).MS(ESI ⁺)：m/z 401.38(M+H) ⁺。

D) (4-aminophenyl) (2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) methanol

[00335] (16mg adds Et in 1mL DCM solution 0.04mmol) to the phenylcarbamic acid tert-butyl ester to 4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) (hydroxyl) methyl) ₃The DCM of SiH (0.1mL)/TFA (10%, 0.2mL) solution.The 1/2h that stirs the mixture, this moment, LC-MS should detect less than reactant.Add 0.1mL Et again ₃The DCM of SiH and 0.8mL TFA (10%) solution, 2h stirs the mixture.Remove and desolvate, through solid phase extraction (WatersOasis ^The MCX extraction column) purification obtains (4-aminophenyl) (2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) methanol (6.0mg, 50% yield).MS(ESI ⁺)：m/z 301.40(M+H) ⁺。

E) 1-(4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) (hydroxyl) methyl) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00336] prepares by the described mode of the step F that is similar to embodiment 87.With 4-aminophenyl-(2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) methanol (6.0mg; 0.02mmol) be converted into 1-(4-((2-(3-(dimethylamino) propyl group amino) pyridin-4-yl) (hydroxyl) methyl) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea; two-trifluoroacetic acid (6.1mg, 43% yield).

¹H NMR(CD ₃OD)δ7.82(d，1H，J＝6.4Hz)，7.50(m，2H)，7.36(m，4H) 7.07(m，3H)，6.75(m，1H)，5.68(s，1H)，3.71(s，2H) 3.21-3.49(m，4H)， 2.90(s，6H)，2.08(m，2H)；MS(ESI ⁺)；m/z 480.31(M+H) ⁺.

Embodiment 89

1-(4-((2-aminopyridine-4-yl) methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

A) 4-((2-(allyl amino) pyridine-N-oxides-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate

[00337] to 4-((2-chloropyridine-N-oxide-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (the step C among the embodiment 87,500mg, add in EtOH 1.36mmol) (14mL) solution allylamine (1.0mL, 13.6mmol).Under 80 ℃, mixture heated is spent the night.After the cooling, remove and desolvate, residue is through SiO ₂The flash chromatography purification is used the 0%-15%MeOH/DCM eluting, obtains 4-((2-(allyl amino) pyridine-N-oxides-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (440mg, 83% yield).MS(ESI ⁺)：m/z390.19(M+H) ⁺。

B) 4-((2-(allyl amino) pyridin-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate

[00338] prepares by the described mode of the step D that is similar to embodiment 87.With 4-((2-(allyl amino) pyridine-N-oxides-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (440mg, 1.13mmol) be converted into 4-((2-(allyl amino) pyridin-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (400mg, 95% yield).MS(ESI ⁺)：m/z374.33(M+H) ⁺。

C) acetic acid (2-(allyl amino) pyridin-4-yl) (4-(tert-butoxycarbonyl)-2-fluorophenyl) methyl ester

[00339] to 4-((2-(allyl amino) pyridin-4-yl) (hydroxyl) methyl)-3-fluorophenyl t-butyl carbamate (400mg, 1.1mmol) THF (10mL) solution in add diisopropylethylamine (DIEA) (0.2mL, 1.1mmol), 4-dimethylaminopyridine (DMAP) (360mg, 3.0mmol) and Ac ₂O (0.29mL, 3.0mmol).The mixture stirring is spent the night, then reflux 1h.After the cooling, removal of solvent under reduced pressure, residue is through SiO ₂The flash chromatography purification with 0%-100%EtOAc/ hexane eluting, obtains (2-(allyl amino) pyridin-4-yl) (4-(tert-butoxycarbonyl)-2-fluorophenyl) methyl acetic acid ester (390mg, 85% yield).MS(ESI ⁺)：m/z416.33(M+H) ⁺。

D) acetic acid (2-aminopyridine-4-yl) (4-(tert-butoxycarbonyl)-2-fluorophenyl) methyl ester

[00340] by feed N2 bubbling 1h in solution, (380mg is 0.91mmol) at EtOH/H to make acetic acid (2-(allyl amino) pyridin-4-yl) (4-(tert-butoxycarbonyl)-2-fluorophenyl) methyl ester ₂The O mixture (10: 1,40mL) the solution degassing in.In mixture, add Rh (PPh ₃) ₃Cl (80mg, 0.09mmol).Reflux solution is removed and is desolvated, and residue is through SiO ₂The flash chromatography purification by the preparation HPLC purification, obtains acetic acid (2-aminopyridine-4-yl) (4-(tert-butoxycarbonyl)-2-fluorophenyl) methyl ester, trifluoroacetate (185mg, 42% yield) then.MS(ESI ⁺)：m/z 376.26(M+H) ⁺。

E) 4-((2-aminopyridine-4-yl) methyl)-3-fluorophenyl t-butyl carbamate

[00341] (180mg adds 10%Pd/C (90mg) in MeOH 0.37mmol) (10mL) solution to (2-aminopyridine-4-yl) (4-(tert-butoxycarbonyl)-2-fluorophenyl) methyl acetic acid ester tfa salt.At H ₂Under the atmosphere, stirred suspension 1h.Remove catalyst, vacuum concentrated filtrate.Residue is through SiO then ₂The flash chromatography purification is used the 3%MeOH/DCM eluting, obtains the tfa salt (73mg, 46% yield) of 4-((2-aminopyridine-4-yl) methyl)-3-fluorophenyl t-butyl carbamate.MS(ESI ⁺)：m/z 318.24(M+H) ⁺。

F) 4-(4-amino-2-luorobenzyl) pyridine-2-amine

[00342] to 4-((2-aminopyridine-4-yl) methyl)-(73mg adds TFA (1.0mL) in DCM 0.17mmol) (4.0mL) solution to 3-fluorophenyl t-butyl carbamate tfa salt.At room temperature, agitating solution 2h, solvent removed in vacuo obtains 4-(4-amino-2-luorobenzyl) pyridine-2-amine, two trifluoroacetates (70mg, 93% yield).MS(ESI ⁺)：m/z218.12(M+H) ⁺。

G) 1-(4-((2-aminopyridine-4-yl) methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

[00343] prepares by the described mode of the step F that is similar to embodiment 87.(19mg 0.042mmol) is converted into 1-(4-((2-aminopyridine-4-yl) methyl)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate (19mg, 88% yield) with 4-(4-amino-2-luorobenzyl) pyridine-2-amine 2TFA salt.

¹H NMR(DMSO-d ₆)δ10.94(s，1H)，10.47(s，1H)，7.76(m，3H)，7.50(d，1H，J＝11.5Hz)，7.10-7.26(m，4H)，7.10(m，2H)，6.65(d，1H，J＝6.5Hz)，6.55(s，1H)，3.89(s，2H)，3.65(s，2H)；MS(ESI ⁺)：m/z 397.26(M+H) ⁺.

Embodiment 90

1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-chlorphenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) 4-(4-amino-2-chlorophenoxy) picolinamide

[00344] at room temperature, to 4-amino-2-chlorophenol (Aldrich, 430mg, add in DMF 3.0mmol) (2.0mL) solution KOt-Bu (352mg, 3.2mmol).At room temperature, the 1h that stirs the mixture.In solution, add then 4-chloropyridine amide (468mg, 3.0mmol) and K ₂CO ₃(221mg, 1.6mmol).With the suspension that obtains 90 ℃ of following heated overnight.After the cooling, with 100mL EtOAc and 50mL H ₂The O diluted suspension.Separate organic layer, (2 * 25mL) washings are through MgSO with saline ₄Dry.Filter, after concentrating, with 50mL DCM abrasive solid.Collect solid then, with DCM (2 * 20mL), EtOAc (5.0mL) washing, drying obtains 4-(4-amino-2-chlorophenoxy) picolinamide (320mg, 40% yield).MS(ESI ⁺)：m/z 264.12/266.07(M+H) ⁺。

B) 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-chlorphenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00345] prepares by the mode that is similar to the step F among the described embodiment 87.With 4-(4-amino-2-chlorophenoxy) picolinamide (79mg; 0.30mmol) DMF (1.0mL) solution be converted into 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-chlorphenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (65mg, 49% yield).

¹H NMR(DMSO-d ₆)δ11.05(s，1H)，10.58(s，1H)，8.52(d，1H，J＝4.5Hz)，8.15(s，1H)，7.98(s，1H)，7.70(s，1H)，7.55(m，1H)，7.39(m，3H)，7.27(m，1H)，7.16(m，3H)，3.73(s，2H)；MS(ESI ⁺)：m/z443.17(M+H) ⁺.

Embodiment 91

1-(4-(2-aminopyridine-4-base oxygen base)-3-chlorphenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00346] at room temperature, to 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-chlorphenyl)-(embodiment 90, and 27mg adds H in DMF 0.06mmol) (1.0mL) solution for 3-(2-(4-fluorophenyl) acetyl group) urea ₂O (2.2mg, 0.12mmol), pyridine (0.04mL) and two (trifluoroacetic acid base) iodobenzene (Aldrich, 39mg, 0.09mmol).Solution stirring is spent the night; then through the preparation HPLC purification; obtain the product of needs; by adding 1N HCl solution (0.5mL); it further is converted into 1-(4-(2-aminopyridine-4-base oxygen base)-3-chlorphenyl)-3-(2-(4-fluorophenyl) acetyl group) urea hydrochlorate (19mg, 70% yield).

¹H NMR(DMSO-d ₆)δ13.50(s，1H)，11.02(s，1H)，10.57(s，1H)，7.80-7.95(m，4H)，7.55(m，1H)，7.37(m，1H)，7.30(m，2H)，7.11(m，2H)，6.60(m，1H)，6.00(s，1H)，3.70(s，2H)；MS(ESI ⁺)：m/z 415.16(M+H) ⁺.

Embodiment 92

1-(4-(2-aminopyridine-4-base oxygen base)-2-chlorphenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2-aminophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00347] prepares by the mode described in the steps A that is similar to embodiment 90.Behind the preparation HPLC purification; with 4-(4-amino-3-chlorophenoxy) picolinamide (39mg; 0.19mmol) in DMF (1.0mL), be converted into 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2-chlorphenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (18mg, 41% yield).MS(ESI ⁺)：m/z443.13/445.14(M+H) ⁺。

B) 1-(4-(2-aminopyridine-4-base oxygen base)-2-chlorphenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00348] mode prepares described in the embodiment 91 by being similar to.With 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2-chlorphenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (18mg; 0.04mmol) in DMF (1.0mL), be converted into 1-(4-(2-aminopyridine-4-base oxygen base)-2-chlorphenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (10mg, 55% yield).

¹HNMR(DMSO-d ₆)δ13.47(s，1H)，11.26(s，1H)，11.08(s，1H)，8.37(d，1H，J＝8.5Hz)，7.95(d，1H，J＝7.5Hz)，7.88(s，2H)，7.62(s，1H)，7.35(m，3H)，7.17(m，2H)，6.64(d，1H，J＝7.5Hz)，6.13(s，1H)，3.76(s，2H)；MS(ESI ⁺)：m/z 415.18/417.17(M+H) ⁺.

Embodiment 93

1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-aminomethyl phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

A) 4-(4-amino-2-methyl phenoxy group) picolinamide

[00349] prepares by the mode described in the steps A that is similar to embodiment 90.(246mg 2.0mmol) is converted into 4-(4-amino-2-methyl phenoxy group) picolinamide (230mg, 47% yield) with 4-amino-2-methyl phenol.MS(ESI ⁺)：m/z 244.15(M+H) ⁺。

B) 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-aminomethyl phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00350] prepares by the described mode of the step F that is similar to embodiment 87.With 4-(4-amino-2-methyl phenoxy group) picolinamide (48mg; 0.2mmol) in DMF (1.0mL), be converted into 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-aminomethyl phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (35mg, 41% yield.

¹H NMR(DMSO-d ₆)δ10.92(s，1H)，10.44(s，1H)，8.44(d，1H，J＝5.5Hz)，8.06(s，1H)，7.63(s，1H)，7.50(s，1H)，7.42(m，1H)，7.31(m，2H)，7.24(d，1H，J＝2.0Hz)，7.06-7.12(m，4H)，3.69(s，2H)，2.02(s，3H)；).MS(ESI ⁺)：m/z 423.17(M+H) ⁺.

Embodiment 94

1-(4-(2-aminopyridine-4-base oxygen base)-3-aminomethyl phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00351] prepares by the mode described in the steps A that is similar to embodiment 91.Behind the HPLC purification; with 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-aminomethyl phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (27mg; 0.06mmol) in DMF (1.0mL), be converted into 1-(4-(2-aminopyridine-4-base oxygen base)-3-aminomethyl phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea; hydrochlorate (24mg, 88% yield).

¹H NMR(DMSO-d ₆)δ13.18(s，1H)，10.93(s，1H)，10.45(s，1H)，7.88(d，1H，J＝7.0Hz)，7.73(s，2H)，7.50(m，2H)，7.29(m，2H)，7.10(m，3H)，6.56(d，1H，J＝7.0Hz)，5.91(d，1H，J＝2.5Hz)，3.68(s，2H)，2.02(s，3H)；MS(ESI ⁺)：m/z 395.20(M+H) ⁺.

Embodiment 95

1-(4-(2-aminopyridine-4-base oxygen base)-2-(trifluoromethyl) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 4-amino-3-(trifluoromethyl) phenol

[00352] (Aldrich, 414mg add 10%Pd/C (100mg) in 10mL MeOH solution 2.0mmol) to 4-nitro-3-(trifluoromethyl) phenol.At H ₂Under the atmosphere, stirred suspension 12h filters then, and vacuum concentration obtains 4-amino-3-(trifluoromethyl) phenol (350mg, 95% yield), and it is enough pure, can be used for next step.MS(ESI ⁺)：m/z 178.02(M+H) ⁺。

B) 4-(4-amino-3-(trifluoromethyl) phenoxy group) picolinamide

[00353] prepares by the mode described in the steps A that is similar to embodiment 90.(177mg 1.0mmol) is converted into 4-(4-amino-3-(trifluoromethyl) phenoxy group) picolinamide (180mg, 61% yield) in DMF (2.0mL) with 4-amino-3-(trifluoromethyl) phenol.MS(ESI ⁺)：m/z298.20(M+H) ⁺。

C) 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2-(trifluoromethyl) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00354] prepares by the described mode of the step F that is similar to embodiment 87.With 4-(4-amino-3-(trifluoromethyl) phenoxy group) picolinamide (30mg; 0.1mmol) in DMF (1.0mL), be converted into 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2-(trifluoromethyl) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (30mg, 63% yield).MS(ESI ⁺)：m/z 477.12(M+H) ⁺。

D) 1-(4-(2-aminopyridine-4-base oxygen base)-2-(trifluoromethyl) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00355] prepares by the mode described in the steps A that is similar to embodiment 91.Behind the preparation HPLC purification; with 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2-(trifluoromethyl) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea (26mg; 0.055mmol) in DMF (1.0mL), be converted into 1-(4-(2-aminopyridine-4-base oxygen base)-2-(trifluoromethyl) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea hydrochlorate (15mg; 56% yield)

¹H NMR(DMSO-d ₆)δ13.40(s，1H)，11.28(s，1H)，10.95(s，1H)，8.25(d，1H，J＝8.5Hz)，7.97(d，1H，J＝7.0Hz)，7.88(s，2H)，7.72(d，1H，J＝2.5Hz)，7.65(m，1H)，7.35(m，2H)，7.19(m，2H)，6.66(d，1H，J＝2.5Hz)，3.75(s，2H)；MS(ESI ⁺)：m/z449.14(M+H) ⁺.

Embodiment 96

1-(4-(2-aminopyridine-4-base oxygen base)-2-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

A) 4-(3-fluoro-4-pivaloyl amino-benzene oxygen) picolinamide

[00356] to 4-amino-3-fluorophenol (Oakwood Products Inc., 252mg, add in NMP 2.0mmol) (4.0mL) solution 4-chloropyridine amide (312mg, 2.0mmol) and DIEA (0.3mL).In microwave box, under 250 ℃, heated solution.After the cooling, use H ₂The O dilute solution is with EtOAc (3 * 40mL) extraction solutions.With the organic layer of salt water washing merging, through MgSO ₄Dry.Filter, after concentrating, residue is through SiO ₂The flash chromatography purification is used the 0-30%MeOH/DCM eluting, obtains containing the flow point (50% is pure, and HPLC-UV detects) of 4-(4-amino-3-fluorophenoxy) picolinamide.MS(ESI ⁺)：m/z 248.12(M+H) ⁺。

[00357] at room temperature, in the THF (3.0mL) of the 4-that obtains by back (4-amino-3-fluorophenoxy) picolinamide and DCM (10.0mL) solution, add 1N NaOH (5.0mL) and trimethyl-aceyl chloride (0.25mL, 2mmol).Agitating solution 2h extracts with EtOAc then.With salt water washing organic layer, through MgSO ₄Dry.Filter, after concentrating, residue is through SiO ₂The flash chromatography purification with 0%-100%EtOAc/ hexane eluting, obtains 4-(3-fluoro-4-pivaloyl amino-benzene oxygen) picolinamide (110mg, two step yields 17%).MS(ESI ⁺)：m/z332.18(M+H) ⁺。

B) N-(4-(2-aminopyridine-4-base oxygen base)-2-fluorophenyl) pivaloyl amine

[00358] prepares by the mode described in the steps A that is similar to embodiment 91.(110mg 0.33mmol) is converted into N-(4-(2-aminopyridine-4-base oxygen base)-2-fluorophenyl) pivaloyl amine (70mg, 70% yield) in acetonitrile (4mL) with 4-(3-fluoro-4-pivaloyl amino-benzene oxygen) picolinamide.MS(ESI ⁺)：m/z 304.21(M+H) ⁺。

C) 4-(4-amino-3-fluorophenoxy) pyridine-2-amine

[00359] (70mg adds 2mL 6N HCl to pivaloyl amine in 3mL MeOH solution 0.23mmol) to N-(4-(2-aminopyridine-4-base oxygen base)-2-fluorophenyl).Then with mixture reflux 48h.After the cooling, removal of solvent under reduced pressure is by solid phase extraction (WatersOasis ^The MCX extraction column) purification residue obtains 4-(4-amino-3-fluorophenoxy) pyridine-2-amine (27mg, 54% yield).MS(ESI ⁺)：m/z 220.21(M+H) ⁺。

D) 1-(4-(2-aminopyridine-4-base oxygen base)-2-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

[00360] prepares by the described mode of the step F that is similar to embodiment 87.Behind the preparation HPLC purification; with 4-(4-amino-3-fluorophenoxy) pyridine-2-amine (28mg; 0.095mmol) THF (2.0mL) be converted into 1-(4-(2-aminopyridine-4-base oxygen base)-2-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea trifluoroacetic acid (23mg, 47% yield).

¹H NMR(DMSO-d ₆)δ11.20(s，1H)，10.77(s，1H) 8.23(m，1H)，7.94(d，1H，J＝6.5Hz)，7.70(s，2H)，7.45(m，1H)，7.35(m，2H)，7.16(m，3H)，6.64(d，1H，J＝2.5Hz)，6.11(s，1H)，3.75(s，2H)；MS(ESI ⁺)：m/z 399.12(M+H) ⁺.

Embodiment 97

1-(4-(2-aminopyridine-4-base oxygen base)-2,3-difluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

A) 4-amino-2, the 3-difluorophenol

[00361] to 1,2, (Aldrich, 15.0g add K in DMF 84.7mmol) (25.0mL) solution to 3-three fluoro-4-Nitrobenzol ₂CO ₃(17.6g, 127.8mmol) and benzyl alcohol (8.8mL, 85.0mmol).The suspension stirring is spent the night.In reactant mixture, add H then ₂O (100mL) spends the night solution preservation under 4 ℃.Collecting precipitation is used H then ₂The O washing obtains two kinds of mixture of isomers (22.4g) [1: 1 1-of ratio (benzyloxy)-2,3-two fluoro-4-Nitrobenzol and 2-(benzyloxy)-3,4-two fluoro-1-Nitrobenzol].

[00362] (22.4g adds 10%Pd/C (1.0g) in EtOAc 84.5mmol) (20.0mL) and MeOH (100.0mL) solution to [1-(benzyloxy)-2,3-two fluoro-4-Nitrobenzol and 2-(benzyloxy)-3,4-two fluoro-1-Nitrobenzol].Under H2 atmosphere, stirred suspension 12h.Filtering suspension liquid then, vacuum concentration obtains two kinds of mixture of isomers (12.6g) [1: 1 4-amino-2 of ratio, 3-difluorophenol and 6-amino-2,3-difluorophenol].MS(ESI ⁺)：m/z 146.00(M+H) ⁺。

B) N-(4-(2-aminopyridine-4-base oxygen base)-2,3-difluorophenyl) pivaloyl amine

[00363] prepares by the mode described in the steps A that is similar to embodiment 90.With 4-amino-2,3-difluorophenol and 6-amino-2, and the 3-difluorophenol (580mg, 4.0mmol) mixture in DMF (3.0mL) is converted into 4-(4-amino-2,3-two fluorophenoxies) mixture (300mg) of picolinamide and 4-(6-amino-2,3-two fluorophenoxies) picolinamide.MS(ESI ⁺)：m/z266.13(M+H) ⁺。

[00364] prepares by the mode described in the steps A that is similar to embodiment 96.With 4-(4-amino-2,3-two fluorophenoxies) picolinamide and 4-(6-amino-2,3-two fluorophenoxies) picolinamide (300mg, 1.13mmol) mixture be converted into 4-(2,3-two fluoro-4-pivaloyl amino-benzene oxygens) mixture (406mg) of picolinamide and 4-(2,3-two fluoro-6-pivaloyl amino-benzene oxygens) picolinamide.MS(ESI ⁺)：m/z 350.20(M+H) ⁺。

[00365] prepares by the mode described in the steps A that is similar to embodiment 91.Behind the preparation HPLC purification, make 4-(2,3-two fluoro-4-pivaloyl amino-benzene oxygens) picolinamide and 4-(2,3-two fluoro-6-pivaloyl amino-benzene oxygens) mixture (400mg) and two (trifluoroacetic acid base) iodobenzene of picolinamide reaction, obtain N-(4-(2-aminopyridine-4-base oxygen base)-2, the 3-difluorophenyl) pivaloyl amine, trifluoroacetate (120mg, 24% yield).MS(ESI ⁺)：m/z322.23(M+H) ⁺。

C) 4-(4-amino-2,3-two fluorophenoxies) pyridine-2-amine

[00366] prepares by the described mode of the step C that is similar to embodiment 96.With N-(4-(2-aminopyridine-4-base oxygen base)-2,3-difluorophenyl) pivaloyl amine, (120mg 0.27mmol) is converted into 4-(4-amino-2,3-two fluorophenoxies) pyridines-2-amine (52mg, 81% yield) to trifluoroacetate.MS(ESI ⁺)：m/z 238.11(M+H) ⁺。

D) 1-(4-(2-aminopyridine-4-base oxygen base)-2,3-difluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

[00367] prepares by the described mode of the step F that is similar to embodiment 87.With 4-(4-amino-2; 3-two fluorophenoxies) (24mg 0.10mmol) transforms 1-(4-(2-aminopyridine-4-base oxygen base)-2,3-difluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea to pyridine-2-amine in THF (3.0mL); trifluoroacetic acid (21mg, 40% yield).

¹H NMR(DMSO-d ₆)δ11.27(s，1H)，10.84(s，1H)，8.02(m，1H)，7.96(d，1H，J＝8.5Hz)，773(s，2H)，7.34(m，3H)，7.17(m，2H)；6.70(m，1H)，6.20(d，1H，J＝2.0Hz)，3.75(s，2H)；MS(ESI ⁺)：m/z 417.10(M+H) ⁺.

Embodiment 98

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-benzyl-5-methyl isophthalic acid H-pyrazole-3-formamide, hydrochlorate

A) 1-benzyl-5-methyl isophthalic acid H-pyrazoles-3-formic acid

[00368] to 1-benzyl hydrazine dihydrochloride (Aldrich, 0.98g add DIEA (2.0mL) and 2 in EtOH 5.0mmol) (30mL) solution, 4-dioxo ethyl valerate (0.70mL, 5.0mmol).At room temperature, the 12h that stirs the mixture, vacuum concentration.Residue is dissolved in 1NNaOH (10mL).Under 60 ℃, heated solution 1h.After the cooling, with DCM (3 * 50mL) extraction solutions.Water layer is neutralized to pH2.0, extracts with EtOAc then.With salt water washing organic layer, through MgSO ₄Dry.Filter, concentrate, obtain 1-benzyl-5-methyl isophthalic acid H-pyrazoles-3-formic acid (1.0g, 92% yield).MS(ESI ⁺)：m/z 217.12(M+H) ⁺。

B) N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-benzyl-5-methyl isophthalic acid H-pyrazole-3-formamide, hydrochlorate

[00369] by the described mode of the step C that is similar to embodiment 1, make 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,25mg, 0.11mmol) and 1-benzyl-5-methyl isophthalic acid H-pyrazoles-3-formic acid (25mg, 0.11mmol) coupling, behind the preparation HPLC purification, obtain N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-benzyl-5-methyl isophthalic acid H-pyrazole-3-formamide hydrochlorate (10mg, 20% yield).

¹H NMR(DMSO-d ₆)δ10.64(s，1H)，7.8-7.98(m，3H)，7.00-7.65(m，9H)，6.71(m，1H)，6.15(s，1H)，5.65(s，2H)，2.24(s，3H)；MS(ESI ⁺)：m/z418.21(M+H) ⁺.

Embodiment 99

2-(4-luorobenzyl sulfinyl)-N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) acetamide, hydrochlorate

A) 2-(4-fluorine benzylthio) ethyl acetate

[00370] (Aldrich, 1.0mL add K in acetonitrile 9.1mmol) (10.0mL) solution to the 2-ethyl thioglycolate ₂CO ₃(2.76g, 20.0mmol) and 1-(bromomethyl)-4-fluorobenzene (2.27g, 12.0mmol).At room temperature, the 12h that stirs the mixture.Filter, after concentrating, residue is through SiO ₂The rapid column chromatography purification obtains 2-(4-fluorine benzylthio) ethyl acetate (1.89g, 91% yield).MS(ESI ⁺)：m/z 251.08(M+H) ⁺。

B) 2-(4-luorobenzyl sulfinyl) ethyl acetate

[00371] under-40 ℃, to 2-(4-fluorine benzylthio) ethyl acetate (1.89g, drip in DCM 8.29mmol) (20.0mL) solution m-CPBA (77%, 1.86g, DCM 8.29mmol) (20.0mL) solution.-40 ℃ to room temperature, solution stirring is spent the night.Use the diethylenetriamines quencher solution that combines with polymer then.After filtering and concentrating, residue is through SiO ₂The flash chromatography purification obtains 2-(4-luorobenzyl sulfinyl) ethyl acetate (2.0g, 98% yield).MS(ESI ⁺)：m/z267.09(M+H) ⁺。

C) 2-(4-luorobenzyl sulfinyl) acetic acid

[00372] (1.60g adds 1N NaOH (20.0mmol) in THF 6.55mmol) (10.0mL) and MeOH (20.0mL) solution to 2-(4-luorobenzyl sulfinyl) ethyl acetate.At room temperature, the 2h that stirs the mixture.After organic solvent is removed in decompression, use among the 1N HCl (25.0mL) and remaining aqueous solution.(3 * 100mL) extractions, the organic layer of merging is through MgSO with EtOAc ₄Dry.Filtering solution then, vacuum concentration obtains 2-(4-luorobenzyl sulfinyl) acetic acid (1.25g, 88% yield).MS(ESI ⁺)：m/z 217.05(M+H) ⁺。

D) 2-(4-luorobenzyl sulfinyl)-N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) acetamide, hydrochlorate

[00373] by the described mode of the step C that is similar to embodiment 1; make 4-(4-amino-2-fluorophenoxy) pyridine-2-amine dihydrochloride (compd B among the embodiment 24; 29mg; 0.10mmol) and 2-(4-luorobenzyl sulfinyl) acetic acid (22mg; 0.1mmol) coupling; obtain 2-(4-luorobenzyl sulfinyl)-N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) acetamide, hydrochlorate (17mg, 37% yield).

¹H NMR(DMSO-d ₆)δ10.94(s，1H)，7.97(d，1H，J＝7.5Hz)，7.85(m，3H)，7.39-7.45(m，4H)，7.23(t，2H，J＝7.5Hz)，6.70(m，1H)，6.13(d，1H，J＝2.5Hz)，4.32(d，1H，J＝11.0Hz)，4.11(d，1H，J＝11.0Hz)，3.98(d，1H，J＝13.0Hz)，3.65(d，1H，J＝13.0Hz)；MS(ESI ⁺)：m/z418.26(M+H) ⁺.

Embodiment 100

2-(4-luorobenzyl sulfonyl)-N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) acetamide, hydrochlorate

A) 2-(4-luorobenzyl sulfonyl) ethyl acetate

[00374] 2-(4-luorobenzyl sulfinyl) ethyl acetate (370mg, add in DCM 1.52mmol) (5.0mL) solution m-CPBA (77%, 450mg, 2.0mmol).At room temperature, the 2h that stirs the mixture uses ethylidene triamine (1.5g) quencher that combines with polymer then.Filter reaction mixture, vacuum concentration obtains 2-(4-luorobenzyl sulfonyl) ethyl acetate (360mg, 91% yield).MS(ESI ⁺)：m/z 283.10(M+H) ⁺。

B) 2-(4-luorobenzyl sulfonyl) acetic acid

[00375] prepares by the described mode of the step C that is similar to embodiment 99.(340mg 1.31mmol) is converted into 2-(4-luorobenzyl sulfonyl) acetic acid (270mg, 81% yield) with 2-(4-luorobenzyl sulfonyl) ethyl acetate.MS(ESI ⁺)：m/z 255.05(M+H) ⁺。

C) 2-(4-luorobenzyl sulfonyl)-N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) acetamide, hydrochlorate

[00376] by the described mode of the step C that is similar to embodiment 1; make 4-(4-amino-2-fluorophenoxy) pyridine-2-amine dihydrochloride (50mg; 0.17mmol) and 2-(4-luorobenzyl sulfonyl) acetic acid (33mg; 0.14mmol) coupling; obtain 2-(4-fluorophenyl sulfonyl)-N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) acetamide; hydrochlorate (30mg, 45% yield).

¹H NMR(DMSO-d ₆)δ13.40(s，1H)，11.15(s，1H)，7.97(d，1H，J＝7.0Hz)，7.80-7.90(m，3H)， 7.47(m，4H)，7.26(t，2H，J＝8.5Hz)，6.72(d，1H，J＝7.0Hz)，6.14(d，1H，J＝2.0Hz)，4.69(s，2H)，4.27(s，2H)；MS(ESI ⁺)：m/z434.15(M+H) ⁺.

Embodiment 101

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

A) 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-methyl formate

[00377] at room temperature, to 2-oxo-2H-pyrans-3-methyl formate (Aldrich, 2.31g, add in THF 15mmol) (40mL) and DMF (10mL) solution 4-fluoroaniline (1.67g, 15mmol), stirred reaction mixture 2.5h.Solid precipitation appears.At room temperature, in the 4-fluorobenzene amine adduct intermediate that the Michael addition product that obtains by original position forms, add EDCI.HCl (3.85g, 20mmol) and DMAP (120mg).At room temperature, the reactant mixture stirring is spent the night.Add 1N HCl aqueous solution (50mL) and EtOAc (150mL) in reactant mixture, separate the EtOAc layer, with EtOAc (150mL) washing water layer, the EtOAc layer of merging is through MgSO ₄Drying, vacuum concentration, obtain semi-solid material (～4.4g).In this crude product, add ether (100mL) and methanol (15mL), stir, cross filter solid, obtain unwanted solid product (870mg).Concentrated filtrate obtains required semi-solid crude product (2.95g, crude product 80%), and it is enough pure, need not be further purified to can be used for next step.

¹HNMR(DMSO-d ₆)δ8.23(dd，1H，J＝7.2，2.2Hz)，7.57(dd，1H，J＝6.6，1.7Hz)，7.32-7.34(m，2H)，7.17(t，2H，J＝8.8Hz)，6.32(t，1H， J＝7.1Hz)，3.89(s，3H)；MS(ESI ⁺)m/z248.2(M+H) ⁺.

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

[00378] at room temperature, stir 1-(4-fluorophenyl)-2-oxo-1, (crude product 2.45g is 12mmol) with the mixture 4h of 6N NaOH (2.5mL) aqueous solution in methanol (60mL) for 2-dihydropyridine-3-methyl formate.At room temperature, stir down, in reactant mixture, slowly add dense HCl (1mL), filter solid precipitation,, obtain the acid product (2.1g) that needs, be yellow solid with low amounts of water washing, drying.Vacuum concentrated filtrate.Residue is mixed with water (50mL), with EtOAc (2 * 130mL) washings.The EtOAc layer is through MgSO ₄Drying, vacuum concentration.Grind residue with a small amount of ether, obtain the 2nd batch of product (195mg adds up to 2.30g, 82%).

¹H NMR(DMSO-d ₆)δ8.47(dd，1H，J＝7.2，2.2Hz)，8.19(dd，1H，J＝6.6，1.7Hz)，7.62-7.60(m，2H)，7.42(t，2H，J＝8.8Hz)，6.78(t，1H，J＝7.1Hz；MS(ESI ⁺)m/z234.2(M+H) ⁺.

C) N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00379] by the described mode of the step C that is similar to embodiment 1.Make 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,58mg, 0.20mmol) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formic acid (47mg, 0.20mmol) coupling, obtain N (4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate (22mg, 23% yield).

¹H NMR(DMSO-d ₆)δ13.40(s，1H)，12.13(s，1H)，8.58(d，1H，J＝5.0Hz)，8.13(d，1H，J＝5.0Hz)，8.07(d，1H，J＝10.0Hz)，7.98(d，IH，J＝7.5Hz)，7.89(s，2H)，7.40-7.60(m，6H) ,6.72(m，2H)，6.17(d，1H，J＝2.5Hz)；MS(ESI ⁺)m/z435.18(M+H) ⁺.

Embodiment 102

(S)-N ¹-(2-amino-2-oxo-1-phenethyl)-N ³-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) Malondiamide, hydrochlorate

A) 3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-3-oxo ethyl propionate

[00380] to 4-(4-amino-2-fluorophenoxy) picolinamide (compd B among the embodiment 24 ', 1.0g, 4.0mmol) DMF (10.0mL) solution in add DIEA (2.0mL) and 3-chloro-3-oxo ethyl propionate (Aldrich, 0.75mL, 6.0mmol).At room temperature, the 12h that stirs the mixture, add again 3-chloro-3-oxo ethyl propionate (0.20mL, 1.6mmol).The 2h that stirs the mixture uses EtOAc (200mL) dilution then.Use H ₂O, salt water washing are then through MgSO ₄Dry.Filter, after concentrating, grind residue, filter, obtain 3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-3-oxo ethyl propionate (900mg, 62% yield) with DCM.MS(ESI ⁺)m/z 362.28(M+H) ⁺。

B) 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo ethyl propionate

[00381] prepares by the mode described in the steps A that is similar to embodiment 91.With 3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl amino)-3-oxo ethyl propionate (900mg; 2.5mmol) in DMF (10.0mL), be converted into 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo ethyl propionate (710mg, 86% yield).MS(ESI ⁺)m/z334.26(M+H) ⁺。

C) 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propanoic acid

[00382] prepares by the described mode of the step C that is similar to embodiment 99.(700mg 2.10mmol) is converted into 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propanoic acid (630mg, 98% yield) with 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo ethyl propionate.MS(ESI ⁺)m/z 306.20(M+H) ⁺。

D) (S)-N ¹-(2-amino-2-oxo-1-phenylethyl)-N ³-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) Malondiamide, hydrochlorate

[00383] by the described mode of the step C that is similar to embodiment 1, make 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propanoic acid (30mg, 0.10mmol) and (S)-2-amino-2-phenyl-acetamides hydrochlorate (Acros, 28mg, 0.15mmol) coupling, obtain (S)-N ¹-(2-amino-2-oxo-1-phenethyl)-N ³-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) Malondiamide, hydrochlorate (25mg, 53% yield).

¹H NMR(DMSO-d ₆)δ10.68(s，1H)，8.80(d，1H，J＝8.0Hz)，7.96(d，1H，J＝7.5Hz)7.77-7.90(m，4H)，7.20-7.45(m，8H)，6.70(m，1H)，6.12(s，1H)，5.39(d，1H，J＝7.5Hz)，3.48(d，1H，J＝15.0Hz)，3.41(d，1H，J＝15.0Hz)；MS(ESI ⁺)m/z 438.26(M+H) ⁺.

Embodiment 103

(R)-N ¹-(2-amino-2-oxo-1-phenethyl)-N ³-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) Malondiamide, hydrochlorate

[00384] by the described mode of the step C that is similar to embodiment 1, make 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propanoic acid (Compound C among the embodiment 102,30mg, 0.10mmol) and (R)-2-amino-2-phenyl-acetamides hydrochlorate (Bachem, 28mg, 0.15mmol) coupling, obtain (R)-N ¹-(2-amino-2-oxo-1-phenethyl)-N ³-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) Malondiamide, hydrochlorate (14mg, 30% yield).

¹H NMR(DMSO-d ₆)δ10.65(s，1H) 8.76(d，1H，J＝8.0Hz)，7.92(d，1H，J＝7.0Hz)，7.75-7.88(m，4H)，7.20-7.43(m，8H)，6.66(m，1H)，6.09(s，1H)，5.35(d，1H，J＝8.0Hz)，3.45(d，1H，J＝15.0Hz)，3.37(d，1H，J＝15.0Hz)；MS(ESI ⁺)m/z438.23(M+H) ⁺.

Embodiment 104

2-(3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propionamido)-2-phenylacetic acid (S)-methyl ester, hydrochlorate

[00385] by the described mode of the step C that is similar to embodiment 1, make 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propanoic acid (Compound C among the embodiment 102,30mg, 0.10mmol) and 2-amino-2-phenylacetic acid (S)-methyl ester hydrochlorate (Aldrich, 30mg, 0.10mmol) coupling, obtain 2-(3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propionamido)-2-phenylacetic acid (S)-methyl ester, hydrochlorate (21mg, 43% yield).

¹H NMR(DMSO-d ₆)δ10.58(s，1H)，9.04(d，1H，J＝7.0Hz)，7.97(d，1H，J＝7.0Hz)，7.75-7.88(m，3H)，7.42(m，7H)，6.72(d，1H，J＝7.0Hz)，6.12(s，1H)，5.45(d，1H，J＝7.0Hz)，3.63(s，3H)，3.43-3.38(m，2H)；MS(ESI ⁺)m/z453.26(M+H) ⁺.

Embodiment 105

2-(3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propionamido)-2-phenylacetic acid (R)-methyl ester, hydrochlorate

[00386] by the described mode of the step C that is similar to embodiment 1, make 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propanoic acid (Compound C among the embodiment 102,30mg, 0.10mmol) and 2-amino-2-phenylacetic acid (R)-methyl ester, hydrochlorate (Aldrich, 30mg, 0.10mmol) coupling, obtain 2-(3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propionamido)-2-phenylacetic acid (R)-methyl ester, hydrochlorate (25mg, 51% yield).

¹H NMR(DMSO-d ₆)δ10.58(s，1H)，9.03(d，1H，J＝7.0Hz)，7.96(d，1H，J＝7.0Hz)，7.77-7.88(m，3H)，7.42(m，7H)，6.71(d，1H，J＝7.5Hz)，6.12(s，1H)，5.44(d，1H，J＝7.0Hz)3.63(s，3H)，3.44-3.38(m，2H)；MS(ESI ⁺)m/z453.29(M+H) ⁺.

Embodiment 106

N ¹-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-N ³-cyclopenta Malondiamide, hydrochlorate

[00387], makes 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propanoic acid (Compound C among the embodiment 102,30mg by the described mode of the step C that is similar to embodiment 1,0.10mmol) and Aminocyclopentane (Aldrich, 17mg, 0.2mmol) coupling obtains N ¹-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-N ³-cyclopenta Malondiamide, hydrochlorate (18mg, 44% yield).

¹HNMR(DMSO-d ₆)δ13.34(s，1H)，10.66(s，1H) 8.15(d，1H，J＝7.0Hz)，7.96(d，1H，J＝7.0Hz)，7.77-7.88(m，3H)，7.42(m ,2H)，6.70(d，1H，J＝7.5Hz)，6.12(s，1H)，3.98(m ,1H)，3.69(s，2H)，1.78(m，2H)，1.63(m，2H)，1.49(m，2H) 1.37(m，2H)；MS(ESI ⁺)m/z373.30(M+H) ⁺.

Embodiment 107

N ¹-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-N ³-cyclohexyl Malondiamide, hydrochlorate

[00388], makes 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propanoic acid (Compound C among the embodiment 102,30mg by the described mode of the step C that is similar to embodiment 1,0.10mmol) and cyclohexylamine (Aldrich, 20mg, 0.2mmol) coupling obtains N ¹-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-N ³-cyclohexyl Malondiamide, hydrochlorate (22mg, 52% yield).

¹HNMR(DMSO-d ₆)δ14.00(s，1H)，10.72(s，1H)，8.10(d，1H，J＝7.0Hz)，7.97(d，1H，J＝7.0Hz)，7.88(m，3H)，7.44(m，2H)，6.70(m，1H)，6.14(d，1H，J＝2.0Hz)，3.54(m，1H)，3.27(s，2H)，1.66-1.75(m,4H)，1.52(m，1H)，1.15-1.25(m，5H)；MS(ESI ⁺)m/z387.32(M+H) ⁺.

Embodiment 108

N ¹-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-N ³-neopentyl Malondiamide, hydrochlorate

[00389] by the described mode of the step C that is similar to embodiment 1, make 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propanoic acid (Compound C among the embodiment 102,30mg, 0.10mmol) with 2,2-dimethyl propylene-1-amine (Aldrich, 12mg, 0.2mmol) coupling obtains N ¹-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-N ³-neopentyl Malondiamide, hydrochlorate (13mg, 32% yield).

¹HNMR(DMSO-d ₆)δ13.34(s，1H)，10.69(s，1H)，8.08(m，1H)，7.96(d，1H，J＝7.0Hz)，7.87(m，3H)，7.44(m，2H)，6.70(m，1H)，6.13(d，1H，J＝2.0Hz)，3.34(s，2H)，2.91(d，2H，J＝6.5Hz)，0.84(s，9H)；MS(ESI ⁺)m/z 375.32(M+H) ⁺.

Embodiment 109

(S)-and 2-(3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propionamido)-2-phenylacetic acid, hydrochlorate

[00390] by the described mode of the step C that is similar to embodiment 99, with 2-(3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propionamido)-2-phenylacetic acid (S)-methyl ester hydrochlorate (Compound D among the embodiment 102,14mg, 0.028mmol) hydrolysis, obtain (S)-2-(3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl amino)-3-oxo propionamido)-2-phenylacetic acid, hydrochlorate (13mg, 97% yield).

¹H NMR(DMSO-d ₆)δ13.20(s，1H)，10.57(s，1H)，8.92(d，1H，J＝7.0Hz)，7.95(d，1H，J＝7.0Hz)，7.87(d，1H，J＝11.0Hz)，7.70(s，2H)，7.41(m，8H)，6.69(d，1H，J＝7.5Hz)，6.12(d，1H，J＝2.0Hz)，5.35(d，1H，J＝7.5Hz)，3.42(s，2H)；MS(ESI ⁺)m/z 439.27(M+H) ⁺.

Embodiment 110

N-(4-(2-(3-(dimethylamino) propyl group amino) pyridin-4-yl oxygen base)-3-fluorophenyl)-2,6-difluorobenzamide, hydrochlorate

A) N-(4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl)-2, the 6-difluorobenzamide

[00391] with 2, (Aldrich, 33 μ L 0.27mmol) drip processing 4-(2-chloropyridine-4-base oxygen base)-3-fluoroaniline (compd B among the embodiment 20,64mg, THF 0.27mmol) (1ml), Et to the 6-difluoro benzoyl chloride ₃N (100 μ L) solution, at room temperature, 30min stirs the mixture.Make mixture at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution, separate the EtOAc phase, dry (MgSO ₄), vacuum concentration obtains title compound (102mg, 100%), is white solid.MS(ESI ⁺)：m/z 418.18(M+H) ⁺。

B) N-(4-(2-(3-(dimethylamino) propyl group amino) pyridin-4-yl oxygen base)-3-fluorophenyl)-2,6-difluorobenzamide, hydrochlorate

[00392] to the N-in the spiral cover bottle (4-(2-chloropyridine-4-base oxygen base)-3-fluorophenyl)-2, the 6-difluorobenzamide (70mg, 0.19mmol), 3-(dimethylamino) propylamine (44mL, 0.35mmol), Cs ₂CO ₃(85mg, 0.26mmol) and CuCl (17mg charges into N in mixture 0.17mmol) ₂With NMP and 2,2,6,6-tetramethyl-3, (31mg 0.17mmol) adds in the mixture 5-heptadione, heats 4h down at 120 ℃ then.Cooling mixture makes it at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution, separate the EtOAc phase, dry (MgSO ₄), vacuum concentration obtains crude product.Residue by the described mode of the step D that is similar to embodiment 33, is converted into hydrochlorate through preparation HPLC (post C) purification, obtains title compound (7mg, 7%), is pale solid.MS(ESI ⁺)：m/z 517.37(M+H) ⁺。

Embodiment 111

N-(4-(2-amino-3-(4-(2-amino-2-oxoethyl) phenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00393] with 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formic acid (the compd B among the embodiment 101,11mg, 0.05mmol), DIPEA (10 μ L, 0.06mmol) and TBTU (19mg, 0.06mmol) processing 2-(4-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl) phenyl) acetamide (Compound C among the embodiment 78,18mg, DMF 0.05mmol) (1.5mL) solution.At room temperature, the 40h that stirs the mixture.Vacuum concentrated mixture, residue obtain the tfa salt of title compound through preparation HPLC (post A) purification.This tfa salt is dissolved in anhydrous MeOH, under 0 ℃, uses 1M HCl/Et ₂O handles, and stirs 5min.Vacuum concentrated mixture obtains title compound (15mg, 47%) then, is yellow solid.

¹H NMR(DMSO-d ₆)δ12.11(s，1H)，8.56(dd，1H，J＝2.2，7.1Hz)，8.13(dd，1H，J＝2.2，6.7Hz)，8.00(dd，1H，J＝2.2，12.6Hz)，7.96(d，1H，J＝7.7Hz)，7.60-7.57(m，2H)，7.48-7.33(m，10H)，6.94(s，1H)，6.72(dd，1H，J＝7.2，7.2Hz)，6.38(d，1H，J＝7.2Hz)，3.95(s，2H)；MS(ESI ⁺)：m/z568.23(M+H) ⁺.

Embodiment 112

1-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl group) urea, hydrochlorate

A) 1-((2,5-two fluoro-4-nitrophenoxys) methyl) benzene

[00394] at ambient temperature, stir 2,4, the 5-trifluoronitrobenzene (5.4g, 30.8mmol), benzyl alcohol (3.2mL, 30.8mmol) and potassium carbonate (6.4g, 46.1mmol) the mixture 72h in DMF (20mL).Add entry (60mL), under 4 ℃, cooling mixture 24h.The precipitation that filtration obtains, the water flushing, vacuum drying obtains product (7.5g, 92%), is light yellow solid. ¹H NMR(CDCl ₃)δ7.90-7.94(m，1H)，7.38-7.44(m，5H)，6.85-6.90(m，1H)，5.22(s，2H)。

B) 4-amino-2, the 5-difluorophenol

[00395] (4.1g, 15.6mmol), evacuation is used nitrogen wash three times subsequently, adds 10% palladium on carbon (0.40g) to add 1-((2,5-two fluoro-4-nitrophenoxys) methyl) benzene in flask.Under blanket of nitrogen, in solid, add absolute methanol (100mL).Under nitrogen atmosphere, 16h stirs the mixture then.Feed nitrogen in reactant mixture, bubbling 30 minutes passes through Celite then ^The pad filtering mixt is used washed with methanol then.Vacuum concentrated filtrate with methylbenzene azeotropic, obtains title compound then, is dark brown solid (2.2g, 99%). ¹H NMR(DMSO-d ₆)δ9.05(brs，1H)，6.53-6.65(m，2H)，4.68(s，2H)。MS(ESI ⁺)：m/z 146(M+H) ⁺。

C) 4-(4-amino-2,5-two fluorophenoxies) picolinamide

[00396] (30-35% is scattered in the mineral oil, and 1.9g 13.9mmol) adds 4-amino-2,5-difluorophenol (1.7g, DMF 11.6mmol) (5mL) solution in the mixture of DMF (30mL) to hydrofining.At ambient temperature, stir after 1 hour, (1.8g, 11.6mmol), reacting by heating mixture to 100 ℃ keeps 135h to add 4-chloropyridine amide.Cooling mixture is to room temperature, with 10% lithium chloride aqueous solution quencher, then with EtOAc extraction three times.With the organic layer drying (MgSO that merges ₄), filter vacuum concentration.The solid that obtains is distributed between chloroform and water.With salt water washing organic layer, dry (MgSO ₄), filtering, vacuum concentration obtains solid (3.0g, 98%).

¹H NMR(DMSO-d ₆)δ8.51-8.57(m，1H)，8.14(brs，1H)，7.74(brs，1H)，7.37-7.38(m，1H)，7.17-7.30(m，2H)，6.74-6.80(m，1H)，5.62(s，2H)；MS(ESI ⁺)m/z 266(M+H) ⁺.

D) 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00397] to 4-(4-amino-2,5-two fluorophenoxies) picolinamide (0.15g, 0.57mmol) add in the homogeneous mixture in THF (5mL) diisopropylethylamine (0.10mL, 0.57mmol).At ambient temperature, stirred the mixture 2 minutes, add then 2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11, the toluene solution of 0.36M, 2.0mL, 0.72mmol).3.5 after hour, (toluene solution of 0.36M, 2.0mL 0.72mmol) add in the reactant mixture with 2-(4-fluorophenyl) acetyl group isocyanates.After 2 hours, (toluene solution of 0.36M, 2.0mL 0.72mmol) add in the reactant mixture, stir the mixture then 16 hours, then vacuum concentration with 2-(4-fluorophenyl) acetyl group isocyanates.Use Et ₂O and supersound process residue remove by filter the white solid of generation.Use Et ₂O handles solid, and ultrasonic again 2 times, vacuum filtration obtains white solid (0.23g, 91%) then.

¹H NMR(DMSO-d ₆)δ11.29(s，1H)，10.92(s，1H)，8.56(d，1H，J＝5.6Hz)，8.21-8.26(m，1H)，8.16(brs，1H)，7.76(brs，1H)，7.66-7.71(m，1H)，7.12-7.44(m，6H)，3.77(s，2H)；MS(ESI ⁺)m/z445(M+H) ⁺.

E) 1-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl group) urea, hydrochlorate

[00398] at room temperature; with two (trifluoroacetic acid base) iodobenzene (Aldrich; 0.18g; 0.42mmol) adding 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2; the 5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl group) urea (0.13g; 0.30mmol), water (0.01mL, 0.60mmol) and pyridine (0.05mL is in DMF 0.66mmol) (2mL) solution.After 10 minutes, add DMF (2mL) again.Stirred reaction mixture is 16 hours then, and vacuum concentration is to half of its initial volume.Make the mixture that obtains at 6N HCl and Et ₂Distribute between the O, use Et ₂O extraction water solution discards the organic layer of merging.Water layer NaHCO ₃(aqueous solution) neutralization extracts with EtOAc.With the organic layer drying (Na that merges ₂SO ₄), filter vacuum concentration.Residue (is used 0-5%MeOH/CHCl through silica gel column chromatography ₃Eluting) purification, the flow point that vacuum concentration is suitable.Residue is dissolved in THF (1mL), is cooled to 0 ℃, (the two  alkane solution of 4N, 0.5mL 2.0mmol) handle with HCl.Allow reactant mixture be warming up to room temperature, stirred 1 hour, lyophilizing then obtains title compound (73mg, 53%), is white solid.

¹H NMR(DMSO-d ₆)δ13.54(br s，1H)，11.35(s，1H)，10.95(s，1H)，8.24-8.28(m，1H)，7.95-8.01(m，3H)，7.73-7.77(m，1H)，7.35-7.39(m，2H)，7.16-7.20(m，2H)，6.72-6.74(m，1H)，6.25(s，1H)，3.78(s，2H)；

HRMS (ESI ⁺): theoretical value 417.1175 (M+H) ⁺, measured value 417.1187 (M+H) ⁺

Embodiment 113

1-(4-(2-aminopyridine-4-base oxygen base)-3,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl group) urea, trifluoroacetate

A) 2,6-two fluoro-4-nitrophenols

[00399] by being similar to Kirk etc. at J.Heterocyclic Chem.1976, the condition described in 13,1253, with 2, (10.0g 76.9mmol) is converted into title compound (12.7g, 94%) to the 6-difluorophenol. ¹HNMR(CDCl ₃)δ12.15(br s，1H)，8.01-8.10(m，2H)。

B) 4-amino-2, the 6-difluorophenol

[00400] by being similar to Demopoulos etc. at J. Med.Chem.2004, mode described in 47,2706, with 2, (2.1g 12.1mmol) is converted into title compound (1.7g, 99%) to 6-two fluoro-4-nitrophenols.MS(ESI ⁺)m/z 146(M+H) ⁺。

C) 4-(4-amino-2,6-two fluorophenoxies) picolinamide

[00401] remove the amino-2 with 4-, (0.44g 3.0mmol) replaces 4-amino-2 to the 6-difluorophenol, outside the 5-difluorophenol, press and the similar manner for preparing the Compound C among the embodiment 112,4-chloropyridine amide (0.47g, 3.0mmol) be converted into title compound (0.23g, 29%).

¹H NMR(DMSO-d ₆)δ8.60(d，1H，J＝5.6Hz)，8.22(brs，1H)，7.83(brs，1H)，7.45-7.46(m，1H)，7.30-7.32(m，1H)，6.43-6.49(m，2H)，5.94(s，2H)；MS(ESI ⁺)m/z 266(M+H) ⁺.

D) 1-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3,5-difluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00402] press and the similar mode of Compound D for preparing embodiment 112, (104mg 0.39mmol) is converted into title compound (91mg, 52%) with 4-(4-amino-2,6-two fluorophenoxies) picolinamide.

¹H MR(DMSO-d ₆)δ11.07(s，1H)，10.62(s，1H)，8.50(d，1H，J＝5.6Hz)，8.11(brs，1H)，7.72(brs，1H)，7.61(m，2H)，7.36-7.37(d，1H，J＝2.3Hz)，7.23-7.31(m ,3H)，7.11(m，2H)，3.69(s，2H)；

HRMS (ESI ⁺), theoretical value 445.1124 (M+H) ⁺, measured value 445.1117 (M+H) ⁺

E) 1-(4-(2-aminopyridine-4-base oxygen base)-3,5-difluorophenyl)-3-(2-(4-fluorophenyl)-acetyl group) urea, trifluoroacetate

[00403] removes crude product through preparation HPLC (YMC S10 ODS; 30 * 500mm; from 58% to 90% methanol-water/0.1%TFA gradient; 30 minutes) outside the purification; press the similar mode of compd E to preparation embodiment 112; (4-(2-carbamoyl pyridin-4-yl oxygen base)-3,5-difluorophenyl)-(87mg 0.20mmol) is converted into title compound to urea to 3-(2-(4-fluorophenyl) acetyl group) with 1-.Merge suitable flow point, lyophilizing obtains title compound (23mg, 22%), is white solid.

¹H NMR(DMSO-d ₆)δ11.09(s，1H)，10.63(s，1H)，7.92(d，1H，J＝7.2Hz)，7.62-7.72(m，4H)，7.27-7.31(m，2H)，7.09-7.14(m，2H)，6.68-6.70(m，1H)，6.17-6.18(m,1H)，3.69(s，2H)；MS(ESI ⁺)m/z 417(M+H) ⁺.

Embodiment 114

N-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide, hydrochlorate

A) 4-(2,5-two fluoro-4-(2-oxo-1-phenyl-1,2-dihydropyridine-3-formamido group)-phenoxy group) picolinamide

[00404] to 2-oxo-1-phenyl-1,2-dihydropyridine-3-formic acid (Compound C among the embodiment 57,43mg, 0.20mmol) add in the homogeneous mixture in DMF (4mL) 1-hydroxyl-benzotriazole hydrate (22mg, 0.16mmol).Stirring the mixture forms until homogeneous phase, add then 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (102mg, 0.53mmol).After 2 minutes, and adding 4-(4-amino-2,5-two fluorophenoxies) picolinamide (Compound C among the embodiment 112,53g, 0.20mmol), and at room temperature, stirred reaction mixture 17h.Make reactant mixture be warming up to 40 ℃, restir 143h then.After being cooled to ambient temperature, mixture is distributed between EtOAc and 10%LiCl (aqueous solution).Organic layer 10%LiCl (aqueous solution) washed twice, vacuum concentration then.Residue is through silica gel column chromatography (with 1: 3 hexane/EtOAc eluting) purification, and the flow point that vacuum concentration is suitable obtains title compound (45mg, 49%).MS(ESI ⁺)m/z 463(M+H) ⁺。

B) N-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00405] presses and the similar mode of compd E for preparing embodiment 112, with 4-(2,5-two fluoro-4-(2-oxo-1-phenyl-1,2-dihydropyridine-3-formamido group)-phenoxy group) picolinamide (45mg, 0.10mmol) be converted into title compound (19mg, 40%).

¹HNMR(DMSO-d ₆)δ13.40(brs，1H)，12.47(s，1H)，8.53-8.57(m，2H)，8.12-8.13(m，1H)，7.92-7.93(m，1H)，7.83(s，2H)，7.66-7.71(m，1H)，7.46-7.53(m，5H)，6.66-6.72(m，2H)，6.19(s，1H)；

HRMS (ESI ⁺), theoretical value 435.1269 (M+H) ⁺, measured value 435.1258 (M+H) ⁺

Embodiment 115

N-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

A) 4-(2,5-two fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formamido group) phenoxy group) picolinamide

[00406] to 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formic acid (the compd B among the embodiment 101,50mg, 0.21mmol) and 4-(4-amino-2, the 5-two fluorophenoxies) picolinamide (Compound C among the embodiment 112,69mg, 0.26mmol) add in the homogeneous mixture in DMF (3mL) DIPEA (0.05mL, 0.26mmol) and O-benzotriazole-1-base-N, N, N ' N '-two (tetramethylene)-urea  hexafluorophosphate (TBTU) (83mg, 0.26mmol).With the solution stirring that obtains 18 hours, use 10%LiCl (aqueous solution) quencher then.Mixture is distributed between EtOAc and 10%LiCl (aqueous solution), separate water layer, use the EtOAc aqueous layer extracted.The organic layer that merges 10%LiCl (aqueous solution) washed twice, vacuum concentration then.Residue is through silica gel column chromatography (with 1: 3 hexane/EtOAc eluting) purification, and the flow point that vacuum concentration is suitable obtains title compound (22mg, 22%).MS(ESI ⁺)m/z 481(M+H) ⁺。

B) N-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00407] by to the compd E similar mode of preparation among the embodiment 112, with 4-(2,5-two fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formamido group) phenoxy group) picolinamide (22mg, 0.04mmol) be converted into title compound (21mg, 95%).

¹H NMR(DMSO-d ₆)δ13.71(brs，1H)，12.43(s，1H)， 8.48-8.57(m，2H)，8.10-8.13(m，1H)，7.93-7.95(m，3H)，7.61-7.70(m，1H)，7.53-7.56(m，2H)，7.29-7.39(m，2H)，6.64-6.72(m，2H)，6.10(s，1H)；

HRMS (ESI ⁺), theoretical value 453.1175 (M+H) ⁺, measured value 453.1168 (M+H) ⁺

Embodiment 116

(±)-N ¹-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-N ³-(1-phenylethyl) Malondiamide, hydrochlorate

A) 3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2,5-difluorophenyl amino)-3-oxo ethyl propionate

[00408] press and the similar mode of compd A for preparing embodiment 102, (Compound C among the embodiment 112,1.0g 3.9mmol) are converted into title compound (320mg, 22%) with 4-(4-amino-2,5-two fluorophenoxies) picolinamide.

¹H NMR(DMSO-d ₆)δ10.32(s，1H)，8.54(d，1H，J＝5.5Hz)，8.14-8.17(m，2H)，7.75(brs，1H)，7.61-7.65(m，1H)，7.42-7.43(m，1H)，7.24-7.25(m，1H)，4.12(q，2H，J＝7.2Hz)，3.60(s，2H)，1.20(t ,3H，J＝7.2Hz)；MS(ESI ⁺)m/z380(M+H) ⁺.

B) 3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2,5-difluorophenyl amino)-3-oxo propanoic acid

[00409] to 3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2; 5-difluorophenyl amino)-3-oxo ethyl propionate (305mg; 0.80mmol) add in the non-homogeneous mixture in MeOH (8mL) 1M NaOH aqueous solution (1.70mL, 1.70mmol).Stir after 1 hour, with 1N HCl (5mL) acidified aqueous solution mixture.With EtOAc extractive reaction thing, then with the organic layer drying (MgSO that merges ₄), filtering, vacuum concentration obtains title compound (317mg), need not be further purified during use.HRMS (ESI ⁺), theoretical value 352.0745 (M+H) ⁺, measured value 352.0752 (M+H) ⁺

C) (±)-4-(2,5-two fluoro-4-(3-oxo-3-(1-phenethyl amino) propionamido)-phenoxy group) picolinamide

[00410] to 3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2; 5-difluorophenyl amino)-3-oxo propanoic acid (89mg; 0.25mmol) and (±)-1-phenyl-ethamine (Aldrich; 0.05mL (0.07mL is 0.38mmol) with O-benzotriazole-1-base-N 0.38mmol) to add DIPEA in the homogeneous mixture in DMF (3mL); N; N ', and N '-two (tetramethylene) urea  hexafluorophosphate (TBTU) (121mg, 0.38mmol).With the solution stirring that obtains 15 hours, use 10%LiCl (aqueous solution) quencher then.Mixture is distributed between EtOAc and 10%LiCl (aqueous solution), separate each layer, use the EtOAc aqueous layer extracted.With the organic layer twice of 10%LiCl (aqueous solution) washing merging, vacuum concentration then.Residue is through silica gel column chromatography (with 1: 3 hexane/EtOAc eluting) purification, and the flow point that vacuum concentration is suitable obtains title compound (42mg, 37%.HRMS (ESI ⁺), theoretical value 455.1532 (M+H) ⁺, measured value 455.1528 (M+H) ⁺

D) (±)-N ¹-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-N ³-(1-phenyl-ethyl) Malondiamide, hydrochlorate

[00411] presses and the similar mode of compd E for preparing embodiment 112, with (±)-4-(2,5-two fluoro-4-(3-oxo-3-(1-phenethyl amino) propionamido) phenoxy group)-(41mg 0.09mmol) is converted into title compound (26mg, 62%) to picolinamide.

¹H NMR(DMSO-d ₆)δ10.46(s，1H)，8.70(d，1H，J＝7.8Hz)，8.21-8.26(m，1H)，8.00(d，1H，J＝7.2Hz)，7.89(s，2H)，7.67-7.72(m，1H)，7.22-7.36(m，5H)，6.73-6.76(m，1H)，6.21-6.22(m，1H)，4.93-4.96(m，1H)，3.57(s，2H)，1.35(d，3H，J＝7.0Hz)；

HRMS (ESI ⁺), theoretical value 427.1582 (M+H) ⁺, measured value 427.1574 (M+H) ⁺

Embodiment 117

(±)-N ¹-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-N ³-(cyano group (phenyl)-methyl) Malondiamide, trichloroacetate

A) (±)-4-(4-(3-(cyano group (phenyl) methylamino)-3-oxo propionamido)-2,5-two fluorophenoxies) picolinamide

[00412] removes with (±)-2-amino-2-phenylacetonitrile hydrochlorate (Aldrich; 47mg; 0.28mmol) replace outside (+)-1-phenylethylamine; press the similar mode of Compound C to preparation embodiment 116; with 3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2,5-difluorophenyl amino)-3-oxo propanoic acid (compd B among the embodiment 116,70mg; 0.20mmol) be converted into title compound (67mg, 72%).MS(ESI ⁺)m/z 466(M+H) ⁺。

B) ()-and N1-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-N3-(cyano group-(phenyl) methyl) Malondiamide, trifluoroacetate

[00413] removes crude product through preparation HPLC (YMC S10 ODS, 30 * 500mm, from 34% to 90% methanol aqueous solution/0.1%TFA gradient 30 minutes) outside the purification, press the similar mode of compd E to preparation embodiment 112, with (±)-4-(4-(3-(cyano group (phenyl) methylamino)-3-oxo propionamido)-2,5-two fluoro-phenoxy groups) (65g 0.14mmol) is converted into title compound to picolinamide.Merge suitable flow point, lyophilizing obtains title compound (38mg, 49%), is white solid.

¹H NMR(DMSO-d ₆)δ10.40(s，1H)，9.47(d，1H，J＝7.63Hz)，8.21-8.26(m，1H)，7.99(d，1H，J＝7.2Hz)，7.86(brs，2H)，7.68-7.73(m，1H)，7.43-7.54(m，5H)，6.74-6.77(m，1H)，6.20-6.22 (m，2H)，3.55(m，2H)；

HRMS (ESI ⁺), theoretical value 438.1378 (M+H) ⁺, measured value 438.1374 (M+H) ⁺

Embodiment 118

(±)-N ¹-(2-amino-1-phenethyl)-N ³-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl) Malondiamide, two trifluoroacetates

[00414] by being similar to (Tetrahedron 2002,58,3689) described conditions such as Campiani, with (±)-N ¹-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl)-N ³-(cyano group (phenyl)-methyl) Malondiamide, (compd B among the embodiment 117,21mg 0.04mmol) are converted into title compound to trifluoroacetate.The boronation cobalt is available from Alfa Aesar.Crude product through preparation HPLC (YMC S5 ODS, 10 * 250mm, from 10% to 90% methanol aqueous solution/0.1%TFA gradient, 30 minutes) purification.Merge suitable flow point, lyophilizing obtains title compound (5mg, 21%), is white solid.

¹H NMR(DMSO-d ₆)δ10.39(s，1H)，8.72(d，1H，J＝8.5Hz)，8.12-8.17(m，1H)，7.90-7.94(m，3H)，7.59-7.63(m，2H)，7.27-7.34(m，4H)，6.60-6.62(m，1H)，6.09-6.10(m,1H)，5.09-5.10(m，1H)，3.10-3-50(m，6H)；

HRMS (ESI ⁺), theoretical value 442.1691 (M+H) ⁺, measured value 442.1678 (M+H) ⁺

Embodiment 119

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-pyrrolidine-3-Methanamide

A) 1-(4-fluorophenyl)-2-oxo-pyrrolidine-3-formic acid

[00415] at room temperature, to 6,6-dimethyl-5,7-dioxo spiro [25]-octane-4, the 8-diketone (Aldrich, 51mg, adding 4-fluoroaniline in DMF 0.3mmol) (0.5mL) solution (Aldrich, 33mg, 0.3mmol).Under 90 ℃, reacting by heating mixture 2h, cooling ester room temperature is directly used in next step.

B) N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-pyrrolidine-3-Methanamide

[00416] to 1-(4-fluorophenyl)-2-oxo-pyrrolidine-3-formic acid (0.3mol), 4-(4-amino-2-fluorophenoxy) pyridine-2-amine (compd B among the embodiment 24,21.9mg, 0.1mmol) add HATU (76mg successively in the mixture in DMF (0.5ml), 0.2mmol) and diisopropylethylamine (0.1mL, 0.57mmol).At room temperature, the reactant mixture stirring is spent the night, use the quencher of 2mL methanol then.Reactant mixture is through the preparation HPLC purification.Merge the flow point that needs, use saturated NaHCO ₃The aqueous solution neutralization, vacuum concentration obtains title compound (18mg, 43%), is white solid,

¹H NMR(DMSO-d ₆)δ10.76(brs，1H)，7.95(d，1H，J＝7.2Hz)，7.91(m，1H)，7.68(m，2h)，7.50(m，1H)，7.44(t，1H，J＝10.0Hz)，7.24(m，2H)，6.70(m，1H)，6.11(d，1H，J＝2.8Hz)，3.91(m，2H)，3.78(t，1H，J＝5.0Hz)，2.41(m，2H)；MS(ESI ⁺)m/z425.15(M+H) ⁺.

Embodiment 120

N-(4-(3-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide

A) N-(3-fluoro-4-(3-nitropyridine-4-base oxygen base) phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide

[00417] by the mode that is similar to embodiment 62, by 3-fluoro-4-(3-nitropyridine-4-base oxygen base) aniline (compd A among the embodiment 72) preparation, obtain title compound (89%), be the sepia solid.

¹H NMR(CD ₃OD)δ9.13(s，1H)，8.72(dd，1H，J＝8，4Hz)，8.60(d，1H，J＝6Hz)，8.07(d，1H，J＝12Hz)，8.01-7.99(m，1H)，7.58-7.55(m，2H)，7.45(t，1H，J＝8Hz)，7.40-7.32(m，3H)，6.99(d，1H，J＝4Hz)，6.76(t，1H，J＝8Hz)；MS(ESI ⁺)m/z 465.18(M+H) ⁺.

B) N-(4-(3-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide

[00418] prepares by the mode similar to the step C among the embodiment 59.Crude product obtains the HCl salt (58%) of title compound through flash chromatography on silica gel (10%MeOH/EtOAc) purification, is pale solid.

¹H NMR(DMSO-d ₆)δ12.07(s，1H)，8.59(dd，1H，J＝7.6，2.4Hz)，8.14(dd，1H，J＝6.4，2Hz)，8.04(s，1H)，7.99(dd，1H，J＝13.2，2.4Hz)，7.66(d，1H，J＝5.2Hz)，7.63-7.60(m，2H)，7.46-7.41(m，3H)，7.22(t，1H，J＝9.2Hz)，6.74(t，1H，J＝7.2Hz)，6.46(d，1H，J＝5.2Hz)，5.26(br s，2H)；MS(ESI ⁺)：m/z 435.26(M+H) ⁺.

Embodiment 121

N-(3-fluoro-4-(3-(pyrrolidine-3-ylmethyl amino) pyridin-4-yl oxygen base) phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00419] to N-(4-(3-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1; (embodiment 120 for 2-dihydropyridine-3-Methanamide; 30mg; 0.07mmol) DCE (1mL) solution in add 3-formoxyl-pyrrolidine-1-t-butyl formate (CB Researchand Development Inc. successively; 28mg; 0.14mmol), acetic acid (5 μ L, 0.084mmol), triacetic acid base sodium borohydride (23mg, 0.104mmol).At room temperature, behind the stirring 6h, add second part of (23mg) triacetic acid base sodium borohydride.At room temperature, behind the stirring 2h, in reactant mixture, add two  alkane (5mL) solution of 4N HCl, more at room temperature, stir 1h.With 10%MeOH/EtOAc (10mL) diluting reaction thing, with saturated sodium bicarbonate solution (10mL) washing.Water is stripped with 10mL 10%MeOH/EtOAc, and the organic layer of merging is through anhydrous Na ₂SO ₄Drying, vacuum concentration then.The crude product that obtains is through the preparation HPLC purification.Concentrate suitable flow point, remove methanol, make alkalize with saturated sodium bicarbonate aqueous solution then.(3 * 20mL) extraction water solution, the organic extract liquid of merging is through anhydrous Na with 10%MeOH/EtOAc ₂SO ₄Drying, vacuum concentration then.To obtain the HCl salt (25mg, 60%) of title compound in the residue lyophilizing in acetonitrile (1mL)/water (3mL)/1N HCl aqueous solution (0.2mL), be white solid.

¹H NMR(DMSO-d ₆)δ12.17(s，1H)，8.59(dd，1H，J＝7.6，2Hz)，8.30(s，1H)，8.16(dd，1H，J＝6.4，2Hz)，8.10(dd，1H，J＝12.8，2Hz)，8.00(d，1H，J＝6.4Hz)，7.64-7.58(m，3H)，7.52(t，1H ,J＝9.2Hz)，7.46-7.42(m，2H)7.00(d，1H，J＝6Hz)，6.75(t，1H，J＝7.2Hz)，3.72-3.64(m，3H)，3.37-3.26(m，1H)，3.17-3.10(m,1H)，2.97-2.92(m，1H)，2.74-2.66(m，1H)，2.10-2.03(m，1H)，1.75-1.68(m，1H)；MS(ESI ⁺)m/z 518.29(M+H) ⁺.

Embodiment 122

N-(4-(3-(2-aminoethylamino) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00420] prepares by the mode that is similar to embodiment 121, obtain the HCl salt (52%) of title compound, be white solid.

¹H NMR(DMSO-d ₆)δ12.10(s，1H)，8.52(dd，1H，J＝7.6，2.4Hz)，8.25(s，1H)，8.09(dd，1H，J＝6.8，2.4Hz)，8.06-8.02(m，1H)，7.96(d，1H，J＝6.4Hz)，7.56-7.52(m，3H)，7.42-7.34(m，3H)，6.92(d，1H，J＝6Hz)，6.68(t，1H，J＝6.8Hz)，3.50-3.48(m，2H)，3.00-2.99(m，2H)；MS(ESI ⁺)m/z478.29(M+H) ⁺.

Embodiment 123

N-(3-fluoro-4-(3-(piperidines-2-base methylamino) pyridin-4-yl oxygen base) phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00421] prepares by the mode that is similar to embodiment 121, obtain the HCl salt (71%) of title compound, be yellow solid.

¹H NMR(DMSO-d ₆)δ12.17(s，1H)，8.59(dd，1H，J＝7.2，2Hz)，8.51(s，1H)，8.16(dd，1H，J＝6.8，2Hz)，8.11(dd，1H，J＝13.2，2.4Hz)，8.02(d，1H，J＝6.4Hz)，7.63-7.58(m，3H)，7.51(t，1H，J＝8.8Hz)，7.46-7.41(m，2H)，7.01(d，1H ,J＝6Hz)，6.75(t，1H，J＝6.8Hz)，3.70-3.63(m，1H)，3.52-3.45(m，1H)，3.30-3.27(m，2H)，2.86-2.84(m，1H)，1.95-1.93(m，1H)，1.80-1.62(m，3H)，1.58-1.44(m，2H)；MS(ESI ⁺)m/z 532.31(M+H) ⁺.

Embodiment 124

N-(4-(3-(3-(dimethylamino)-2,2-dimethyl propyl amino) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00422] prepares by the mode that is similar to embodiment 121, obtain the HCl salt (58%) of title compound, be white solid.

¹H NMR(DMSO-d ₆)δ12.10(s，1H)，8.57(s，1H)，8.52(dd，1H，J＝7.6，2Hz)，8.09(dd，1H，J＝6.8，2.4Hz)，8.03(dd，1H，J＝13.2，2.4Hz)，7.90(d，1H，J＝6.4Hz)，7.56-7.51(m，3H)，7.44(t，1H，J＝8.8Hz)，7.39-7.35(m，2H)，6.92(d，1H，J＝6.4Hz)，6.68(t，1H，J＝7.2Hz)，3.33(s，2H)，3.10(s，2H)，2.77(s，3H)，2.76(s，3H)，1.07(s，6H)；MS(ESI ⁺)m/z 548.34(M+H) ⁺.

Embodiment 125

N-(4-(3-(2-amino-3-hydroxypropyl amino) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00423] prepares by the mode that is similar to embodiment 121, obtain the HCl salt (65%) of title compound, be white solid.

¹H NMR(OMSO-d ₆)δ12.10(s，1H)， 8.52(dd，1H，J＝7.2，2Hz)，8.30(s，1H)，8.09(dd，1H，J＝6.8，2.4Hz)，8.03(dd，1H，J＝12.8，2Hz)，7.96(d，1H，J＝6.4Hz)7.56-7.52(m，3H)，7.43-7.35(m，3H)，6.93(d，1H，J＝6Hz)，6.68(t，1H，J＝7.2Hz)，3.65-3.56(m，2H)，3.48-3.45(m，3H)；MS(ESI ⁺).m/z 508.27(M+H) ⁺.

Embodiment 126

1-(4-(2-amino-3-(hydroxymethyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 4-chloro-3-formoxyl pyridine-2-aminocarbamic acid tert-butyl ester

[00424] under nitrogen, under-78 ℃, to (4-chloro-pyridine-2-yl)-t-butyl carbamate (CB Research and Development Inc., 2.0g, 8.75mmol) THF (18mL) solution in drip n-BuLi (13.7mL, 21.9mmol, the hexane solution of 1.6M).After stirring 45min under-78 ℃, drip THF (2mL) solution of DMF (1.93mL).Under-78 ℃, reaction stirred 30min slowly is warming up to room temperature then.With 1N HCl aqueous solution quencher reactant, use saturated sodium bicarbonate aqueous solution (50mL) alkalization then, with ethyl acetate (3 * 50mL) extractions.The organic extract liquid that merges is through anhydrous Na ₂SO ₄Drying, vacuum concentration.Crude product obtains title compound (0.95g, 42%) through silica gel rapid column chromatography (EtOAc) purification, is white solid.

¹H NMR(DMSO-d ₆)δ10.44(s，1H)，10.13(s，1H)，8.47(d，1H，J＝5.2Hz)，7.40(d，1H，J＝5.6Hz)，1.48(s，9H).

B) 4-(2-fluoro-4-nitrophenoxy)-3-formoxyl pyridine-2-aminocarbamic acid tert-butyl ester

[00425] to 2-fluoro-nitrophenol (Aldrich, 700mg, add in DMF 4.44mmol) (5mL) solution sodium hydride (60%, 180mg, 4.44mmol).After at room temperature stirring 5min, (0.95g, DMF 5mL solution 3.7mmol) adds in the mixture with 4-chloro-3-formoxyl pyridine-2-aminocarbamic acid tert-butyl ester.Under 60 ℃, stirred reaction mixture 20h.After being cooled to room temperature, with EtOAc (50mL) diluting reaction thing, use successively 10% lithium chloride aqueous solution (2 * 40mL), saturated sodium bicarbonate aqueous solution (40mL) washing, through anhydrous Na ₂SO ₄Drying, vacuum concentration.Crude product obtains title compound (1.0g, 72%) through flash chromatography on silica gel (50%EtOAc/ hexane) purification, is yellow oil.

¹H NMR(CD ₃OD)δ10.59(s，1H)，8.37-8.25(m，2H)，7.67(t，1H，J＝7.6Hz)，6.60(d，1H，J＝6Hz)，1.59(s，9H).

C) 4-(2-fluoro-4-nitrophenoxy)-3-(hydroxymethyl) pyridine-2-aminocarbamic acid tert-butyl ester

[00426] under 0 ℃, to 4-(2-fluoro-4-nitrophenoxy)-3-formoxyl pyridine-2-aminocarbamic acid tert-butyl ester (75mg, add in methanol 0.2mmol) (1mL) solution sodium borohydride (7.6mg, 0.20mmol).After stirring 30min under 0 ℃, with saturated aqueous ammonium chloride (1mL) quencher reaction.With EtOAc (5mL) diluting reaction thing, separate each layer.Organic layer is through anhydrous Na ₂SO ₄Drying, vacuum concentration obtains title compound (65mg, 86%), is white solid, need not be further purified during use.

¹H NMR(CD ₃OD)δ8.28(dd，1H，J＝10.4，2.8Hz)，8.22-8.18(m，2H)，7.45(t，1H，J＝8.4Hz)，6.68(d，1H，J＝6Hz)，4.81(s，2H)，1.57(s，9H)；MS(ESI ⁺)m/z 380.27(M+H) ⁺.

D) 4-(4-amino-2-fluorophenoxy)-3-(hydroxymethyl) pyridine-2-aminocarbamic acid tert-butyl ester

[00427] prepares by the mode similar, obtain title compound, be white solid to the step C among the embodiment 59.

¹H NMR(CD ₃OD)δ8.14(d，1H，J＝6Hz)，6.97(t，1H，J＝8.8Hz)，6.62-6.54(m，2H)，6.46(d，1H，J＝6.4Hz)，4.64(s，2H)，1.55(s，9H)；MS(ESI ⁺)m/z 350.11(M+H) ⁺.

E) 1-(4-(2-amino-3-(hydroxymethyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00428] prepares by the mode similar, obtain the HCl salt of title compound, be white solid to the step C among the embodiment 59.

¹H NMR(DMSO-d ₆)δ10.99(s，1H)，10.56(s，1H)，7.82(d，1H，J＝7.2Hz)，7.74(dd，1H，J＝13.6，2.8Hz)，7.31-26(m，3H)，7.19-7.02(m，3H)，6.16(d，1H，J＝7.2Hz)，4.57(s，2H)，3.69(s，2H)；MS(ESI ⁺)m/z429.16(M+H) ⁺.

Embodiment 127

1-(4-(2-amino-3-((methylamino) methyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) (2-two-BOC-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) methyl (methyl) t-butyl carbamate

[00429] under 0 ℃; to 4-(2-fluoro-the 4-nitrophenoxy)-3-formoxyl pyridine-2-aminocarbamic acid tert-butyl ester (compd B among the embodiment 126; 75mg; 0.2mmol) dichloroethanes (1rnL) solution in add methylamine (240 μ L successively; 0.24mmol; the THF solution of 2M), acetic acid (14 μ L, 0.24mmol), triacetic acid base sodium borohydride (400mg, 1.89mmol).At room temperature, behind the stirring 16h, with EtOAc (5mL) diluted reaction mixture, with saturated sodium bicarbonate aqueous solution (5mL) washing, through anhydrous Na ₂SO ₄Drying, vacuum concentration.Crude product obtains 4-(2-fluoro-4-nitrophenoxy)-3-((methylamino) methyl) pyridine-2-aminocarbamic acid tert-butyl ester (37mg, 47%) through silica gel rapid column chromatography (20%MeOH/EtOAc) purification, is yellow oil.

[00430] to 4-(2-fluoro-4-nitrophenoxy)-3-((methylamino) methyl) pyridine-2-aminocarbamic acid tert-butyl ester (48mg, 0.122mmol) and DMAP (16mg, 0.134mmol) dichloromethane (1mL) solution in add Bis(tert-butoxycarbonyl)oxide (Aldrich, 32mg, 0.15mmol).After at room temperature stirring 30min, the mixture of two-BOC and three-BOC material (2: 1) appears.Add a DMAP and Bis(tert-butoxycarbonyl)oxide again.After at room temperature stirring 30min, reactant obtains title compound (44mg, 61%) through silica gel rapid column chromatography (EtOAc) direct purification, is yellow oil.

¹H NMR(CD ₃OD)δ8.50(d，1H，J＝5.2Hz)，8.15-7.97(m，2H)，7.43(d，1H，J＝5.6Hz)，7.07(t，1H，J＝8.4Hz)，4.64(s，2H)，2.83(s，3H)，1.44(s，27H)；MS(ESI ⁺)m/z 593.34(M+H) ⁺.

B) 1-(4-(2-amino-3-((methylamino) methyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00431] prepares by the mode similar, obtain the HCl salt (60%) of title compound, be white solid to the step C among the embodiment 59.

¹H NMR(DMSO-d ₆)δ10.88(s，1H)，10.35(s，1H)，7.45-7.42(m，1H)，7.30(m，3H)，7.11-7.07(m，4H)，6.52(d，1H，J＝7.2Hz)，4.02(s，2H)，3.66(s，2H)，2.54(s，3H)；MS(ESI ⁺)m/z442.30(M+H) ⁺.

Embodiment 128

1-(4-(2-amino-3-((2-hydroxyethyl amino) methyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

A) (2-BOC-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) methyl (2-hydroxyethyl) t-butyl carbamate

[00432] prepares by the mode similar, obtain title compound (14%), be yellow oil to the steps A among the embodiment 127.

¹H NMR(CD ₃OD)δ8.30(dd，1H，J＝10.4，2.8Hz)，8.23-8.20(m，2H)，7.52(t，1H，J＝8.4Hz)，6.64(d，1H，J＝7.2Hz)，4.71(s，2H)，3.65(t，2H，J＝6Hz)，3.40(m，2H)，1.57(s，18H)；MS(ESI ⁺)m/z523.32(M+H) ⁺.

B) 1-(4-(2-amino-3-((2-hydroxyethyl amino) methyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, trifluoroacetate

[00433] prepares by the mode similar, obtain the tfa salt (45%) of title compound, be white solid to the step C among the embodiment 59.

¹H NMR(DMSO-d ₆)δ11.12(s，1H)，10.69(s，1H)，8.01(d，1H，J＝6.8Hz)，7.87(dd，1H，J＝12.8，2.4Hz)，7.53-7.40(m，4H)，7.26-7.20(m，2H)，6.68(d，1H，J＝7.2Hz)，4.34(s，2H)，3.81(s，2H)，3.75(t，2H，J＝7.2Hz)，3.18(m，2H)；MS(ESI ⁺)m/z472.24(M+H) ⁺.

Embodiment 129

N-(4-(2-amino-3-((2-aminoethylamino) methyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, trifluoroacetate

A) (2-BOC-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) methyl (2-BOC-amino-ethyl) t-butyl carbamate

[00434] prepares by the mode similar, obtain title compound (19%), be yellow oil to the steps A among the embodiment 127.

¹H NMR(CD ₃OD)δ8.30(dd，1H，J＝10，2.4Hz)，8.23-8.20(m，2H)，7.52(t，1H，J＝8.4Hz)，6.61(d，1H，J＝7.2Hz)，4.65(s，2H)，3.39(m，2H)，3.25(m，2H)，1.61(s，27H)；MS(ESI ⁺)m/z 622.47(M+H) ⁺.

B) N-(4-(2-amino-3-((2-aminoethylamino) picoline-4-base oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, trifluoroacetate

[00435] reduces nitro by the step C mode among the embodiment 59 of being similar to, form amide by the mode that is similar to embodiment 62 then, obtain the tfa salt (28%) of title compound, be white solid.

¹H NMR(DMSO-d ₆)δ12.09(s，1H)，8.52(dd，1H，J＝7.2，2Hz)，8.09(dd，1H，J＝6.4，2Hz)，7.99(dd，1H，J＝12.8，2.4Hz)，7.89(d，1H，J＝6.4Hz)，7.56-7.52(m，2H)，7.49-7.47(m，1H)，7.39-7.33(m，3H)，6.68(t，1H，J＝7.2Hz)，6.07(d，1H，J＝7.2Hz)，4.25(s，2H)，3.20(m，2H)，3.08(m，2H)；MS(ESI ⁺)m/z 507.23(M+H) ⁺.

Embodiment 130

N-(4-(2-amino-3-(hydroxymethyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, trifluoroacetate

A) 3-((t-butyldimethylsilyloxy base) methyl)-4-(2-fluoro-4-nitrophenoxy) pyridine-2-aminocarbamic acid tert-butyl ester

[00436] to 4-(2-fluoro-4-nitrophenoxy)-3-(hydroxymethyl) pyridine-2-aminocarbamic acid tert-butyl ester (Compound C among the embodiment 126,100mg, 0.26mmol) dichloromethane (3mL) solution in add imidazoles (21mg successively, 0.31mmol), tert-butyldimethylsilyl chloride (40mg, 0.26mmol).At room temperature, stir 1h after, add second part of equivalent tert-butyldimethylsilyl chloride (40mg, 0.26mmol).At room temperature, reaction stirred 3h uses dichloromethane (10mL) dilution then, and water (10mL) washing is through Na ₂SO ₄Drying, vacuum concentration.Crude product obtains title compound (102mg, 79%) through silica gel rapid column chromatography (50%EtOAc/ hexane) purification, is white solid.

¹H NMR(CD ₃OD)δ8.16(dd，1H，J＝10.4，2.8Hz)，8.09-8.05(m，2H)，7.29(t，1H，J＝8.4Hz)，6.53(d，1H，J＝5.6Hz)，4.84(s，2H)，1.43(s，9H)，0.84(s，9H)，0.00(s，6H)；MS(ESI ⁺) m/z 494.29(M+H) ⁺.

B) 4-(4-amino-2-fluorophenoxy)-3-((t-butyldimethylsilyloxy base)-methyl) pyridine-2-aminocarbamic acid tert-butyl ester

[00437] prepares by the mode that is similar to step C among the embodiment 59, obtain title compound (95mg, 98%), be yellow oil.

¹H NMR(CD ₃OD)δ7.90(d，1H，J＝6Hz)，6.76(t，1H，J＝8.8Hz)，6.43(dd，1H，J＝12.8，2.8Hz)，6.39-6.37(m，1H)，6.21(d，1H，J＝5.6Hz)，4.85(s，2H)，1.39(s，9H)，0.81(s，9H)，0.01(s，6H)；MS(ESI ⁺)m/z464.34(M+H) ⁺.

C) 3-((t-butyldimethylsilyloxy base) methyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1, the 2-dihydropyridine-3-formamido group) phenoxy group) pyridine-2-aminocarbamic acid tert-butyl ester

[00438] prepares by being similar to embodiment 62 modes, obtain title compound (86%), be colorless oil.

¹H NMR(CD ₃OD)δ8.51(dd，1H，J＝7.6，2.4Hz)，7.93(d，1H，J＝6Hz)，7.84-7.80(m，2H)，7.40-7.37(m，2H)，7.21-7.15(m，3H)，7.06(t，1H，J＝8.8Hz)，6.57(t，1H，J＝6.8Hz)，6.26(d，1H，J＝5.6Hz)，4.86(s，2H)，1.40(s，9H)，0.82(s，9H)0.00(s，6H)；MS(ESI ⁺)m/z679.34(M+H) ⁺.

D) 4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formamido group) phenoxy group)-3-(hydroxymethyl) pyridine-2-aminocarbamic acid tert-butyl ester

[00439] at room temperature, to 3-((t-butyldimethylsilyloxy base) methyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formamido group) pyridine-2-aminocarbamic acid tert-butyl ester (119mg phenoxy group), 0.176mmol) THF (2mL) solution in add tetrabutylammonium fluoride (260 μ L, 0.264mmol, the THF solution of 1M.At room temperature, behind the stirring 30min, with ethyl acetate (20mL) diluting reaction thing, water, saline (each 10mL) washing successively.Through anhydrous MgSO ₄Drying, vacuum concentration.Crude product obtains title compound (66mg, 66%) through silica gel rapid column chromatography (5%MeOH/EtOAc) purification, is yellow oil.

¹HNMR(CD ₃OD)δ8.62(dd，1H，J＝7.2，2Hz)，8.04(d，1H，J＝6Hz)，7.94-7.90(m，2H)，7.50-7.46(m，2H)，7.33-7.25(m，3H)，7.20(t，1H，J＝8.8Hz)，6.67(t，1H，J＝6.8Hz)，6.40(d，1H，J＝5.2Hz)，4.78(s，2H)，1.49(s，9H)；MS(ESI ⁺)m/z 565.17(M+H) ⁺.

E) N-(4-(2-amino-3-(hydroxymethyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, trifluoroacetate

[00440] at room temperature, to 4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formamido group) phenoxy group)-3-(hydroxymethyl) pyridine-2-aminocarbamic acid tert-butyl ester (33mg, two  alkane (10mL) solution of adding 4N HCl in THF 0.058mmol) (2mL) solution.

At room temperature, behind the stirring 8h, the vacuum concentration reactant.The crude product that obtains is through the preparation HPLC purification.Concentrate suitable flow point, and adding toluene (2 * 3mL), concentrate the mixture that obtains once more.With the residue lyophilizing in acetonitrile (1mL)/water (3mL), obtain the tfa salt (14mg, 42%) of title compound, be white solid.

¹H NMR(DMSO-d ₆)δ12.08(s，1H)，8.52(dd，1H，J＝7.2，2Hz)，8.09(dd，1H，J＝6.8，2Hz)，7.99(dd，1H，J＝12.8，2.4Hz)，7.81(d，1H，J＝7.2Hz)，7.56-7.52(m，2H)，7.48-7.46(m，1H)，7.39-7.34(m，2H)，7.30(t，1H，J＝9.2Hz)，6.67(t，1H，J＝7.2Hz)，6.21(d，1H，J＝7.2Hz)，4.58(s，2H)；MS(ESI ⁺)m/z465.17(M+H) ⁺.

Embodiment 131

A) 4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridine-2-yl) acetenyl) pyridine-2-amine

[00441] by vacuum/argon purge, make 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine-2-amine (Compound C among the embodiment 34,100mg, 2-ethynyl pyridine 0.27mmol) (Aldrich, 56 μ L, 0.54mmol), Et ₃The N (2mL) and the degassing of THF (2mL) solution, (6mg is 0.032mmol) with (Ph to use CuI then ₃P) ₄(20mg 0.017mmol) handles Pd.Under 60 ℃, reacting by heating mixture 45min is cooled to room temperature, dilutes with EtOAc.Use saturated NaHCO ₃Aqueous solution, saline purging compound, dry (MgSO ₄), vacuum concentration.Crude product is through SiO ₂The flash chromatography purification is used 0-1.5%MeOH/CH ₂Cl ₂Eluting obtains title compound (55mg, 57%), is the olive green solid.

¹H NMR(DMSO-d ₆)δ8.53(d，1H，J＝5.1Hz)，8.42-8.37(m，1H)，8.19-8.12(m，1H)，7.96(d，1H，J＝5.6Hz)，7.85-7.78(m，1H)，7.71(d，1H，J＝7.6Hz)，7.52(t,1H，J＝8.6Hz)，7.36(ddd，1H，J＝7.6，5.1，1.0Hz)6.71(s，2H)，6.21(d，1H，J＝5.6Hz)；MS(ESI ⁺)：m/z 351.25(M+H) ⁺.

B) 4-(4-amino-2-fluorophenoxy)-3-(2-(pyridine-2-yl) acetenyl) pyridine-2-amine

[00442] by the mode that is similar to step C among the embodiment 11, with zinc powder (65mg, 1.0mmol) and NH ₄(53mg, 1.0mmol) (35mg 0.10mmol), prepares title compound to reduction 4-(2-fluoro-4-nitrophenoxy)-3-(2-(pyridine-2-yl) acetenyl) pyridine-2-amine to Cl.Obtain title compound (25mg, 78%) thus, be brown oil.MS(ESI ⁺)：m/z 321.25(M+H) ⁺。

[00443] by the mode that is similar to step e among the embodiment 11; by 4-(4-amino-2-fluorophenoxy)-3-(2-(pyridine-2-yl) acetenyl) pyridine-2-amine (25mg; 0.078mmol) and 0.3M2-(4-fluorophenyl) acetyl group isocyanates (Compound D among the embodiment 11; 0.26mL toluene solution 0.078mmol) prepares title compound.Crude product is through preparation HPLC (post B) purification.Mode by being similar to step e among the embodiment 36 is converted into hydrochlorate with tfa salt, obtains title compound (18mg, 40%), is brown solid.

¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.63(s，1H)，8.62(d，1H，J＝4.6Hz)，8.23(s，1H)，7.99(d，1H，J＝7.1Hz)，7.94-7.84(m，3H)，7.87-7.76(m，1H)，7.51-7.42(m，3H），7.39-7.32(m，2H)，7.21-7.13(m，2H)，6.30(d，1H，J＝7.1Hz)，3.74(s，2H)MS(ESI ⁺)：m/z 498.11(M+H) ⁺.

Embodiment 132

[00444] presses the mode of embodiment 62, by 2-(4-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl) phenyl) acetamide (Compound C among the embodiment 78,18mg, 0.05mmol) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formic acid (the compd B among the embodiment 101,11mg, 0.05mmol) preparation title compound.Crude product is converted into tfa salt hydrochlorate (15mg, 50%) subsequently through preparation HPLC (post B) purification.

¹H NMR(DMSO-d ₆)δ12.11(s，1H)，8.58-8.54(m，1H)，8.13(dd，1H，J＝6.6，2.2Hz)，8.00(dd，1H，J＝12.6，2.2Hz)，7.96(d，1H，J＝7.7Hz)，7.59(dd，2H，J＝8.8，4.9Hz)，7.47-7.41(m，6H)，7.40-7.35(m，3H)，6.94(s，1H)，6.72(t，1H，J＝7.1Hz)，6.38(d，1H，J＝7.1Hz)，3.44(s，2H)；MS(ESI ⁺)：m/z568.23(M+H) ⁺.

Embodiment 133

1-(4-(2-amino-3-(2-(5-aminopyridine-2-yl) acetenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

A) 6-(2-(trimethyl silyl) acetenyl) pyridine-3-amine

[00445] (60mg is 0.32mmol) with (Ph with CuI ₃P) ₄Pd (114mg, 0.10mmol) handle 3-amino-6-bromopyridine (Alfa Aesar, 1.0g, 5.8mmol), the acetenyl trimethyl silane (1.7mL, 17.3mmol), CH ₃CN (3mL), DMF (2mL) and Et ₃The mixture of N (2mL), under 45 ℃, 1.5h stirs the mixture.(1.7mL 17.3mmol) adds in the reactant, and 2h stirs the mixture with the acetenyl trimethyl silane again.Vacuum concentrated mixture makes residue at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With salt water washing EtOAc phase, dry (MgSO ₄), vacuum concentration.Crude product is through SiO ₂The flash chromatography purification with 0-6%EtOAc/ hexane eluting, obtains title compound (0.75g, 68%), is brown solid.

¹H NMR(DMSO-d ₆)δ7.85(s，1H)，7.15(d，1H，J＝8.1Hz)，6.81(d，1H，J＝8.1Hz)，5.76(s，2H)，0.19(s，9H)；MS(ESI ⁺)：m/z 191.20(M+H) ⁺.

B) 6-(2-(trimethyl silyl) acetenyl) pyridin-3-yl t-butyl carbamate

[00446] (0.5g, THF solution 2.6mmol) are cooled to-50 ℃, drip THF (5.3mL, 5.5mmol) solution-treated of 1.0M NaHMDS with 6-(2-(trimethyl silyl) acetenyl) pyridine-3-amine.Make mixture be warming up to-20 ℃,, in 25min, be warming up to room temperature with the disposable processing of BOC acid anhydride.Make mixture at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution, separate the EtOAc phase, use the salt water washing.With EtOAc solution drying (MgSO ₄), vacuum concentration.Crude product is through SiO ₂The flash chromatography purification with 0-25%EtOAc/ hexane eluting, obtains product (0.5g, 67%), is white solid.

¹H NMR(DMSO-d ₆)δ9.80(s，1H)，8.58(d，1H，J＝2.0Hz)，7.86(dd，J＝8.6，2.5Hz，1H)，7.44(d，1H，J＝8.6Hz)，1.47(s，9H)，0.22(s，9H)；MS(ESI ⁺)：m/z 291.34(M+H) ⁺.

C) 6-ethynyl pyridine-3-aminocarbamic acid tert-butyl ester

[00447] (62mg, THF 0.21mmol) (5mL) solution is cooled to-15 ℃, with 1.0M tetrabutylammonium fluoride (Aldrich, 0.25mL, 0.25mmol) processing 40min with 6-(2-(trimethyl silyl) acetenyl) pyridin-3-yl t-butyl carbamate.Vacuum concentrated mixture makes it at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.With salt water washing EtOAc phase, dry (MgSO ₄), vacuum concentration obtains title compound (45mg, 100%), is pale solid.

¹H NMR(DMSO-d ₆)δ9.78(s，1H)，8.58(d，1H，J＝2.5Hz)，7.92-7.84(m，1H)，7.46(d，1H，J＝8.6Hz)，4.17(s，1H)，1.47(s，9H)；MS(ESI ⁺)：m/z 219.20(M+H) ⁺.

D) 6-(2-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acetenyl) pyridin-3-yl t-butyl carbamate

[00448] by with embodiment 46 in the identical mode of steps A, by 6-ethynyl pyridine-3-aminocarbamic acid tert-butyl ester and 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine-2-amine (Compound C among the embodiment 34) preparation title compound, yield 44%.

¹H NMR(DMSO-d ₆)δ9.77(s，1H)，8.56(s，1H)，8.40-8.36(m，1H)，8.14(d，1H，J＝8.8Hz)，7.94(d，1H，J＝5.5Hz)，7.89(d，1H，J＝8.2Hz)7.59(d，1H，J＝8.8Hz)，7.53-7.47(m，1H)，6.63(brs，2H)，6.21(d，1H，J＝6.0Hz)，1.47(s，9H)；MS(ESI ⁺)：m/z 466.22(M+H) ⁺.

E) 6-(2-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl) acetenyl) pyridin-3-yl t-butyl carbamate

[00449] by with embodiment 11 in the identical mode of step C, prepare title compound, quantitative yield by 6-(2-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acetenyl) pyridin-3-yl t-butyl carbamate.MS(ESI ⁺)：m/z436.29(M+H) ⁺。

F) 6-(2-(2-amino-4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) acetenyl) pyridin-3-yl t-butyl carbamate

[00450] by with embodiment 11 in the identical mode of step e, prepare title compound, 80% yield by 6-(2-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) acetenyl) pyridin-3-yl t-butyl carbamate.

¹H NMR(DMSO-d ₆)δ11.02(s，1H)，10.56(s，1H)，9.78(s，1H)，8.59(d，1H，J＝2.5Hz)，7.91(dd，1H，J＝8.6，2.5Hz)，7.81(d，1H，J＝5.6Hz)，7.75(dd，1H，J＝12.7，2.5Hz)，7.68(d，1H，J＝8.6Hz，)，7.44-7.27(M，5H)，7.19-7.13(m，2H)，6.47(s，2H)，5.86-5.81(m，1H)，1.48(s，9H)；MS(ESI ⁺)：m/z 615.34(M+H) ⁺.

G) 1-(4-(2-amino-3-(2-(5-aminopyridine-2-yl) acetenyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00451] handles 6-(2-(2-amino-4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) acetenyl) pyridin-3-yl t-butyl carbamate (23mg, CH 0.037mmol) with TFA (0.5mL) ₂Cl ₂(2mL) solution at room temperature, stirs 1h.Vacuum concentrated mixture, crude product be through preparation HPLC (post B) purification, by with embodiment 36 in the identical mode of step e, be translated into hydrochlorate (11mg, 52%).

¹H NMR(DMSO-d ₆)δ11.05(s，1H)，10.62(s，1H)，8.05(s，1H)，7.97(d，1H，J＝2.7Hz)，7.94(d，1H，J＝7.1Hz)，7.82(d，1H，J＝12.1Hz)，7.66(d，1H，J＝8.8Hz)，7.45-7.45(m，2H)，7.35(dd，2H，J＝8.2，5.5Hz)，7.20(d，1H，J＝6.6Hz)，7.16(t，2H，J＝8.8Hz)， 6.24(d，1H，J＝6.6Hz)，3.74(s，2H)；MS(ESI ⁺)：m/z 515.19(M+H) ⁺.

Embodiment 134

N-(4-(2-amino-3-(3-((3R, 4R)-3-hydroxyl-4-(pyrrolidine-1-yl) pyrrolidine-1-yl)-3-methyl fourth-1-alkynyl) pyridin-4-yl oxygen base)-the 3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, tri hydrochloride

A) (3R, 4R)-1-(2-methyl fourth-3-alkynes-2-yl)-4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol

[00452] with CuI (77mg, 0.78mmol) handle (3R, 4R)-4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol (Lexicon Pharma, 1.56g, 10.0mmol) with 3-chloro-3-methyl isophthalic acid-butine (GFS Chmeical, Inc., 1.36g, 13.2mmol), THF (15mL) and Et ₃The mixture of N (13.3mmol).Exothermic reaction guarantees to form simultaneously precipitation.At room temperature, behind the stirring 15h, vacuum concentrated mixture makes it at EtOAc and saturated NaHCO ₃Distribute between the aqueous solution.Use the EtOAc aqueous phase extracted, with the dry mutually (MgSO of EtOAc that merges ₄), concentrate, obtain light brown solid (1.0g, 45%).

¹H NMR(CDCl ₃)δ4.20(br s，1H)，3.13-3.04(m，1H)，2.95(dd，1H，J＝10.1，6.6Hz)，2.77(dd，1H，J＝10.1，2.6Hz)，2.64(m，3H)，2.61(m，2H)，2.55-2.46(m，1H)，2.26(s，1H)，1.85-1.74(m，4H)，1.38(s，3H)，1.36(s，3H)；MS(ESI ⁺)：m/z 223.29(M+H) ⁺.

B) (3R, 4R)-1-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl)-2-methyl fourth-3-alkynes-2-yl)-4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol

[00453] by with embodiment 35 in the identical mode of step D, by (3R, 4R)-and 1-(2-methyl fourth-3-alkynes-2-yl)-4-(pyrrolidine-1-yl) pure and mild 4-of pyrrolidine-3-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine-2-amine (Compound C among the embodiment 34) preparation title compound, 57% yield.

¹H NMR(CDCl ₃)δ8.10(dd，1H，J＝10.2，2.5Hz)，8.03(d，1H，J＝9.2Hz)，7.99(d，1H，J＝5.6Hz)，7.13-7.06(m，1H)，6.26(d，1H，J＝6.1Hz)，5.18(brs，2H)，4.21(m，1H)，3.10-2.99(m，1H)，2.96(s，1H)，2.70(dd，2H，J＝9.7，3.1Hz)，2.66-1.15(m，2H)，1.87-1.76(m，5H)，133-1.32(m，2H)，1.32(m，3H)；1.34(m，3H)；MS(ESI ⁺)：m/z470.20(M+H) ⁺，

C) (3R, 4R)-1-(4-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl)-2-methyl fourth-3-alkynes-2-yl)-4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol

[00454] by with embodiment 11 in the identical mode of step C, by (3R, 4R)-and 1-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl)-2-methyl fourth-3-alkynes-2-yl)-4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol preparation title compound, 95% yield.MS(ESI ⁺)：m/z 440.37(M+H) ⁺。

D) N-(4-(2-amino-3-(3-((3R, 4R)-3-hydroxyl-4-(pyrrolidine-1-yl) pyrrolidine-1-yl)-3-methyl fourth-1-alkynyl) pyridin-4-yl oxygen base)-the 3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, tri hydrochloride

[00455] by the mode identical with embodiment 62, by (3R, 4R)-1-(4-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl)-2-methyl fourth-3-alkynes-2-yl)-4-(pyrrolidine-1-yl) the pure and mild 1-of pyrrolidine-3-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formic acid (compd B among the embodiment 101) preparation title compound, 50% yield.

¹H NMR(DMSO-d ₆)δ12.14(s，1H)，8.62-8.54(m，1H)，8.14(dd，3H，J＝6.6，2.0Hz)，8.05(d，1H，J＝13.2Hz)，7.99(d，1H，J＝7.1Hz)，7.62-7.51(m，5H)，7.42(t，2H，J＝8.6Hz)，6.78-6.70(m，1H)，6.32(d，1H，J＝7.1Hz)， 4.65(brs，1H)，3.94-3.84(m，1H)，3.71(d，2H，J＝16.8Hz)，3.60(m，2H)，3.52(m，1H)，3.22-3.08(m，2H)，2.00-1.91(m，2H)，1.88-1.78(m，2H)，1.70(s，6H)；MS(ESI ⁺)：m/z 655.40(M+H) ⁺.

Embodiment 135

1-(4-(2-amino-3-(3-((3R, 4R)-3-hydroxyl-4-(pyrrolidine-1-yl) pyrrolidine-1-yl)-3-methyl fourth-1-alkynyl) pyridin-4-yl oxygen base)-the 3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, tri hydrochloride

[00456] by with embodiment 11 in the identical mode of step e, by (3R, 4R)-and 1-(4-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl)-2-methyl fourth-3-alkynes-2-yl)-4-(pyrrolidine-1-yl) pyrrolidine-3-alcohol preparation title compound, 40% yield.

¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.62(s，1H)，7.97(d，2H，J＝6.6Hz)，7.80(d，1H，J＝11.7Hz)，7.51-7.40(m，2H)，7.38-7.32(m，2H)，7.16(t，2H，J＝8.6Hz)，6.25(d，1H，J＝6.6Hz)，4.63-4.53(m，1H)，3.79-3.68(m，1H)，3.74(s，2H)，3.68-3.56(m，2H)，3.51-3.43(m，2H)，3.08-2.99(m，4H)，1.98-1.92(m，2H)，1.89-1.77(m，2H)，1.64(s，6H)；MS(ESI ⁺)：m/z 619.41(M+H) ⁺.

Embodiment 136

1-(3-fluoro-4-(3-(3-hydroxyl third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol

[00457] by with embodiment 36 in the identical mode of steps A, prepare title compound, 77% yield by 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine (compd A of embodiment 33) and propargyl alcohol (Aldrich).

¹H NMR(DMSO-d ₆)δ8.69(s，1H)，8.49(d，1H，J＝5.6Hz)，8.43(dd，1H，J＝10.7，2.5Hz)，8.17(d，1H，J＝9.2Hz)，7.57(t，1H，J＝8.6Hz)，7.04(d，1H，J＝5.6Hz)，5.40(t，1H，J＝6.1Hz)，4.28(d，2H，J＝6.1Hz)；MS(ESI ⁺)；m/z 289.15(M+H) ⁺.

B) 3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol

[00458] by with embodiment 11 in the identical mode of step C, by 3-(4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol preparation title compound, 95% yield.MS(ESI ⁺)：m/z 259.21(M+H) ⁺。

C) 1-(3-fluoro-4-(3-(3-hydroxyl third-1-alkynyl) pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00459] by with embodiment 11 in the identical mode of step e, by 3-(4-(4-amino-2-fluorophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol preparation title compound, 36% yield.

¹H NMR(DMSO-d ₆)δ11.06(s，1H)，10.63(s，1H)，8.79(s，1H)，8.49(d，1H，J＝6.1Hz)，7.82(d，1H，J＝12.2Hz)，7.45-7.40(m，2H)，7.38-7.33(m，2H)，7.23-7.13(m，2H)，6.89(d，1H，J＝6.1Hz)，4.37(s，2H)，3.74(s，2H)；MS(ESI ⁺)：m/z 438.23(M+H) ⁺.

Embodiment 137

N-(4-(2-amino-3-(3-amino third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, dihydrochloride

A) 3-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl t-butyl carbamate

[00460] by identical with steps A among the embodiment 42 mode, by N-Boc propargylamine (compd A among the embodiment 42) and 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine-2-amine (Compound C among the embodiment 34) preparation title compound, 59% yield.

¹H NMR(DMSO-d ₆)δ8.35(dd，1H，J＝10.7，2.5Hz)，8.12(d，1H，J＝9.2Hz)，7.88(d，1H，J＝5.6Hz)，7.39(t,1H，J＝8.6Hz)，7.31(t，1H，J＝5.1Hz)，6.53(s，2H)，6.15(d，1H，J＝5.6Hz)，3.92(d，2H，J＝5.6Hz)，1.36(s，9H)；MS(ESI ⁺)：m/z403.34(M+H) ⁺.

B) 3-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl t-butyl carbamate

[00461] by with embodiment 11 in the identical mode of step C, prepare title compound, quantitative yield by 3-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) Propargyl t-butyl carbamate.MS(ESI ⁺)：m/z 373.35(M+H) ⁺。

C) 3-(2-amino-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formamido group) phenoxy group) pyridin-3-yl) the Propargyl carbamic acid tert-butyl group

[00462] by the mode identical with embodiment 62, by 3-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl t-butyl carbamate and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formic acid (compd B of embodiment 101) preparation title compound, 48% yield.

¹H NMR(DMSO-d ₆)δ12.07(s，1H)，8.57(dd，1H，J＝7.1，2.0Hz)，8.12(dd，1H，J＝6.6，2.0Hz)，8.00-7.93(m，1H)，7.75(d，1H，J＝6.1Hz)，7.61(d，2H，J＝5.1Hz)，7.59(d，1H，J＝4.6Hz)，7.48-7.37(m，4H)，7.30-7.25(m，1H)，6.72(t，1H，J＝7.1Hz)，6.37(brs，1H)，5.80(d，1H，J＝6.1Hz)，4.00(d，2H，J＝5.1Hz)，1.38(s，9H)；MS(ESI ⁺)：m/z 588.26(M+H) ⁺.

D) N-(4-(2-amino-3-(3-amino third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, dihydrochloride

[00463] by with embodiment 36 in the identical mode of step e, by 3-(2-amino-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formamido group) pyridin-3-yl phenoxy group)) the Propargyl t-butyl carbamate prepares title compound, 80% yield.

¹H NMR(DMSO-d ₆)δ12.13(s，1H)，8.57(dd，1H，J＝7.1，2.0Hz)，8.51(s，2H)，8.14(dd，1H，J＝6.6，2.0Hz)，8.11-8.02(m，1H)，7.98-7.90(m，1H)，7.60(dd，2H，J＝9.2，5.1Hz)，7.53(d，1H，J＝9.2Hz)，7.46-7.37(m，3H)，6.76-6.71(m，1H)，6.20(d，1H，J＝6.6Hz)，4.11-4.04(m，2H)；MS(ESI ⁺)：m/z 488.16(M+H) ⁺.

Embodiment 138

1-(4-(2-amino-3-(3-amino third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

A) 3-(2-amino-4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) Propargyl t-butyl carbamate

[00464] by with embodiment 11 in the identical mode of step e, prepare title compound, 38% yield by 3-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl) Propargyl t-butyl carbamate.

¹H NMR(DMSO-d ₆)δ11.02(s，1H)，10.55(s，1H)，7.80-7.73-7.69(m，2H)，7.38-7.29(m，3H)，7.33(d，1H，J＝5.1Hz)，7.30-7.21(m，1H)，7.21-7.13(m，2H)，6.37(brs，1H)，5.76(d，1H，J＝6.1Hz)，4.00(s，2H)，3.73(s，2H)，1.38(s，9H)；MS(ESI ⁺)：m/z 552.24(M+H) ⁺.

B) 1-(4-(2-amino-3-(3-amino third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00465] by with embodiment 11 in the identical mode of step e, prepare title compound, 65% yield by 3-(2-amino-4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl group) urea groups) phenoxy group) pyridin-3-yl) Propargyl t-butyl carbamate.

¹H NMR(DMSO-d ₆)δ11.05(s，1H)，10.61(s，1H)，8.48(brs，3H)，27.90(d，1H，J＝6.6Hz)，7.84-7.76(m，2H)，7.45-7.39(m，1H)，7.39-7.32(m，3H)，7.20-7.13(m，2H)，6.11(d，1H，J＝6.1Hz)，4.09-4.03(m，2H)，3.74(s，2H)；MS(ESI ⁺)：m/z452.12(M+H) ⁺.

Embodiment 139

1-(4-(2-amino-3-(3-hydroxyl third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 3-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol

[00466] by with embodiment 36 in the identical mode of steps A, prepare title compound, 46% yield by propargyl alcohol (Aldrich) and 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine-2-amine (Compound C among the embodiment 34).

¹H NMR(DMSO-d ₆)δ8.40-8.34(m，1H)，8.13(d，1H，J＝8.6Hz)，7.88(d，1H，J＝5.6Hz)，7.42(t，1H，J＝8.6Hz)，6.49(s，2H)，6.14(d，1H，J＝6.1Hz)，5.26-5.20(m，1H)，4.26(d，2H，J＝6.1Hz)；MS(ESI ⁺)：m/z 304.23(M+H) ⁺.

B) 3-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol

[00467] by 3-(2-amino-4-(2-fluoro-4-nitrophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol preparation title compound, 65% yield.MS(ESI ⁺)：m/z 274.21(M+H) ⁺。

C) 1-(4-(2-amino-3-(3-hydroxyl third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00468] by 3-(2-amino-4-(4-amino-2-fluorophenoxy) pyridin-3-yl) third-2-alkynes-1-alcohol preparation title compound.48% yield.

¹H NMR(DMSO-d ₆)δ11.05(s，1H)，10.60(s，1H)，7.86(d，1H，J＝7.1Hz)，7.83-7.77(m，1H)，7.44-7.37(m，2H)，7.37-7.32(m，3H)，7.20-7.13(m，2H)，6.14(d，J＝6.6Hz，1H)，4.37(s，2H)，3.74(s，2H)；MS(ESI ⁺)：m/z 453.28(M+H) ⁺.

Embodiment 140

N-(4-(2-amino-3-(3-(dimethylamino) third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, dihydrochloride

A) 3-(3-(dimethylamino) third-1-alkynyl)-4-(2-fluoro-4-nitrophenoxy) pyridine-2-amine

[00469] by with embodiment 42 in the identical mode of steps A, prepare title compound, 64% yield by 1-dimethyl amine-2-propine (Aldrich) and 4-(2-fluoro-4-nitrophenoxy)-3-iodo pyridine-2-amine (Compound C among the embodiment 34).

¹H NMR(DMSO-d ₆)δ8.36(dd，1H)，J＝10.7，2.5Hz)，8.11(d，1H)，J＝8.6Hz)，7.93(d，1H，J＝5.6Hz)，7.30(t，1H，J＝8.6Hz)，6.43(brs，2H)，6.28(d，1H，J＝6.1Hz)，3.41(s，2H)，2.05(s，6H)；MS(ESI ⁺)：m/z 331.28(M+H) ⁺.

B) 4-(4-amino-2-fluorophenoxy)-3-(3-(dimethylamino) third-1-alkynyl) pyridine-2-amine

[00470] by with embodiment 11 in the identical mode of step C, prepare title compound, 77% yield by 3-(3-(dimethylamino) third-1-alkynyl)-4-(2-fluoro-4-nitrophenoxy) pyridine-2-amine.MS(ESI ⁺)：m/z 301.30(M+H) ⁺。

C) N-(4-(2-amino-3-(3-(dimethylamino) third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-Methanamide, dihydrochloride

[00471] by the mode identical with embodiment 62, by 4-(4-amino-2-fluorophenoxy)-3-(3-(dimethylamino) third-1-alkynyl) pyridine-2-amine and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formic acid (compd B among the embodiment 101) preparation title compound, 71% yield.

¹H NMR(DMSO-d ₆)δ12.14(s，1H)，11.39(s，1H)，8.60-8.53(m，1H)，8.33(s，1H)，8.14(dd，1H，J＝6.6，2.2Hz)，8.05(dd，1H，J＝12.7，2.2Hz)，7.98(d，1H，J＝7.0Hz)，7.61(d，1H，J＝5.3Hz)，7.58(d，1H，J＝4.8Hz)，7.56-7.50(m，1H) 7.37-7.47(m，3H)，6.76-6.69(m，1H)，6.30(d，1H，J＝7.0Hz)，4.39(s，2H)，2.84(s，6H)；MS(ESI ⁺)：m/z480.28(M+H) ⁺.

Embodiment 141

1-(4-(2-amino-3-(3-(dimethylamino) third-1-alkynyl) pyridin-4-yl oxygen base)-3-fluorophenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, dihydrochloride

[00472] by with embodiment 11 in the identical mode of step e, prepare title compound, 70% yield by 4-(4-amino-2-fluorophenoxy)-3-(3-(dimethylamino) third-1-alkynyl) pyridine-2-amine.

¹H NMR(DMSO-d ₆)δ11.46(brs，1H)，11.07(s，1H)，10.64(s，1H)，8.37br(s，1H)，7.98(t，1H，J＝7.5Hz)，7.81(d，1H，J＝13.6Hz)，7.43-7.32(m，4H)，7.20-7.09(m，2H)，6.27(d，1H，J＝7.0Hz)，4.38(s，2H)，3.75(s，2H)，2.84(s，6H)；MS(ESI ⁺)：m/z 516.31(M+H) ⁺.

Embodiment 142

1-(4-(2-aminopyridine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

A) 4-(4-amino-benzene oxygen) picolinamide

[00473] by the mode that is similar to step B ' among the embodiment 24, be raw material with the 4-amino-phenol, the preparation title compound.Yield: 85%.MS(ESI ⁺)m/z 230(M+H) ⁺。

B) 1-(4-(2-carbamoyl pyridin-4-yl oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea

[00474] by the mode that is similar to step C ' among the embodiment 24, the preparation title compound.Yield: 95%.MS(ESI ⁺)m/z 409(M+H) ⁺。

C) 1-(4-(2-aminopyridine-4-base oxygen base) phenyl)-3-(2-(4-fluorophenyl) acetyl group) urea, hydrochlorate

[00475] by the mode that is similar to step D ' among the embodiment 24, the preparation title compound.Yield: 58%.

¹H NMR(DMSO-d ₆)δ12.86(s，1H)，10.97(s，1H)，10.51(s，1H)，7.91(d，1H，J＝6.0Hz)，7.67(d，3H，J＝9.0Hz)，7.34(dd，2H，J＝9.0，5.0Hz)，7.21(d，2H，J＝9.0Hz)，7.16(t，2H，J＝9.0Hz)，6.63(dd，1H，J＝9.5，2.0Hz)，6.05(d，1H，J＝2.0Hz)，3.73(s，2H)；MS(ESI ⁺)m/z381(M+H) ⁺.

Embodiment 143

1-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(3-hydroxy phenyl) acetyl group) urea

A) 2-(3-(benzyloxy) phenyl) acetic acid

[00476] at room temperature, (Acros, 3.04g add K in DMF 20mL solution 20mmol) to the 3-hydroxyphenyl acetic acid ₂CO ₃(6.90g, 50mmol) and benzyl bromide a-bromotoluene (4.75mL, 40mmol).Stirred reaction mixture 24h.Filtering suspension liquid washs with ether.Use the saline wash filtrate then, through MgSO ₄Dry.Filter, concentrate subsequently, obtain crude product 2-(3-(benzyloxy) phenyl) benzyl acetate, it is used for next step.MS(ESI ⁺)m/z 355(M+Na) ⁺。

[00477] crude product 2-(3-(benzyloxy) phenyl) benzyl acetate is dissolved in the mixture of MeOH (20mL) and THF (50mL).In this solution, add 40mL 1N NaOH (40mmol).At room temperature, stirred reaction mixture 2h.Vacuum is removed organic solvent.With ether (2 * 50mL) extraction residual water solution.Use 1N HCl (50mL) acidified aqueous solution then, produce the title compound precipitation.Filter, collect solid (4.35g, 90% liang of step adds up to).MS(ESI ⁺)m/z 265(M+Na) ⁺。

B) 2-(3-(benzyloxy) phenyl) acetyl group isocyanates

[00478] at room temperature, to 2-(3-(benzyloxy) phenyl) acetic acid (484mg, add in DCM 2.0mmol) (10mL) solution 1 DMF and thionyl chloride (0.30mL, 4mmol).At room temperature, stirred reaction mixture 1h stirs 0.5h down at 50 ℃ then.Cooling mixture, solvent removed in vacuo.Residue is dissolved in 5mL toluene, and adding AgOCN (600mg, 4.0mmol).Stirred suspension 0.5h with its filtration, obtains toluene (0.40M) solution of 2-(3-(benzyloxy) phenyl) acetyl group isocyanates.

C) 1-(2-(3-(benzyloxy) phenyl) acetyl group)-3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl) urea

[00479] by being similar to the mode described in the embodiment 24 step C ', with the formulations prepared from solutions title compound of this embodiment step B.Yield: 63%.MS(ESI ⁺)m/z 515(M+H) ⁺。

D) 1-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(3-(benzyloxy) phenyl) acetyl group) urea

[00480] by being similar to the mode described in the embodiment 24 step D ', the preparation title compound.Yield: 61%.MS(ESI ⁺)m/z 487(M+H) ⁺。

E) 1-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-3-(2-(3-hydroxy phenyl) acetyl group) urea

[00481] (4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-(150mg 0.31mmol) adds 10%Pd/C (200mg) in the solution in the mixture of 5mL EtOAc and 3mL MeOH to urea to 3-(2-(3-(benzyloxy) phenyl) acetyl group) to 1-.At H ₂Under the atmosphere, stirred suspension 1h.Filter, concentrate subsequently, obtain title compound (77mg, 63%).

¹H NMR(DMSO-d ₆)δ10.95(s，1H)，10.54(s，1H)，9.35(s，1H)，7.74(d，1H，J＝6.0Hz)，7.68(dd，1H，J＝13.0，2.0Hz)，7.30(dd，1H，J＝9.0，1.1Hz)，7.23(t，1H，J＝9.0Hz)，7.07(t，1H，J＝8.0Hz)，6.69(s，1H)，6.68(d，1H，J＝7.0Hz)，6.62(dd，1H，J＝7.0，2.0Hz)，6.10(dd，1H，J＝6.0，2.0Hz)，5.90(s，2H)，5.73(d，1H，J＝2.0Hz)，3.27(s，2H)；MS(ESI ⁺)m/z 397(M+H) ⁺.

Embodiment 144

3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-(2-(4-fluorophenyl) acetyl group)-1-methyl urea, hydrochlorate

A) 2-(4-fluorophenyl)-N-methylacetamide

[00482] under-78 ℃, to the THF of methylamine (2.0M, 5mL, 10mmol) add in the solution 4-fluorophenyl chloroacetic chloride (518mg, 3.0mmol).-78 ℃ to room temperature, stirred reaction mixture 1h.Use H ₂The O dilute solution extracts with EtOAc.With salt water washing organic layer, through MgSO ₄Dry.Filter, concentrate subsequently, obtain title compound (490mg, 98%).MS(ESI ⁺)m/z 168(M+H) ⁺。

B) 3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl)-1-(2-(4-fluorophenyl) acetyl group)-1-methyl urea

[00483] under-78 ℃, to 2-(4-fluorophenyl)-N-methylacetamide (89mg, the Et of adding MeLi in 2mL THF solution 0.53mmol) ₂O (1.6M, 0.34mL, 0.55mmol) solution.Under-78 ℃, agitating solution 5min adds toluene (1.9M, 0.29mL, 0.55mmol) solution of 20% triphosgene then fast.Behind the 2min, and adding 4-(4-amino-2-fluorophenoxy) picolinamide (compd B among the embodiment 24 ', 100mg 0.40mmol), adds DMF (2mL) and DIEA (0.4mL) subsequently.At room temperature, stirred reaction mixture 1h uses H ₂The O quencher.Use the EtOAc extraction solution then, with salt water washing organic layer, through MgSO ₄Dry.Filter, after concentrating, residue obtains title compound (77mg, 33%) through the silica gel column chromatography purification.MS(ESI ⁺)m/z 441(M+H) ⁺。

C) 3-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-(2-(4-fluorophenyl) acetyl group)-1-methyl urea, hydrochlorate

[00484] prepares title compound by being similar to the mode described in the embodiment 24 step D '.Yield: 24%.

¹H NMR(DMSO-d ₆)δ13.20(s，1H)，11.17(s，1H)，7.90(d，1H，J＝7.0Hz)，7.78-7.74(m，3H)，7.39-7.34(m，2H)，7.23-7.21(m，2H)，7.10-7.05(m，2H)，6.63(dd，1H，J＝7.0，2.0Hz)，6.08(d，1H，J＝2.0Hz)，4.00(s，2H)，3.24(s，3H)；MS(ESI ⁺)m/z413(M+H) ⁺.

Embodiment 145

(R)-N ¹-(2-amino-2-oxo-1-phenylethyl)-N ³-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl) Malondiamide, trifluoroacetate

A) 3-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl amino)-3-oxo ethyl propionate

[00485] by the mode that is similar to compd E among the preparation embodiment 112; with 3-(4-(2-carbamoyl pyridin-4-yl oxygen base)-2; 5-difluorophenyl amino)-the 3-oxo ethyl propionate (compd A among the embodiment 116; 0.73g; 1.9mmol) be converted into title compound (0.24g, 35%).MS(ESI ⁺)m/z 352(M+H) ⁺。

B) 3-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl amino)-3-oxo propanoic acid

[00486] by the mode that is similar to compd B among the preparation embodiment 116, (4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl amino)-(0.24g 0.68mmol) is converted into title compound (0.039mg, 18%) to 3-oxo ethyl propionate with 3-.HRMS (ESI ⁺), theoretical value: 324.0796 (M+H) ⁺, measured value: 324.0795 (M+H) ⁺

C) (R)-N ¹-(2-amino-2-oxo-1-phenethyl)-N ³-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl) Malondiamide trifluoroacetate

[00487] by the mode that is similar to preparation embodiment 103, make 3-(4-(2-aminopyridine-4-base oxygen base)-2,5-difluorophenyl amino)-3-oxo propanoic acid (0.039g, 0.12mmol) and (R)-2-amino-2-phenyl-acetamides hydrochlorate (Bachem, 0.023g, 0.12mmol) coupling, obtain title compound (0.0048g, 7%).

¹H NMR(DMSO-d ₆)δ10.33(s，1H)，8.77(d，1H，J＝7.8Hz)，8.10-8.19(m，1H)，7.90(d，1H，J＝7.2Hz)，7.60-7.75(m，4H)，7.11-7.39(m，6H)，6.66-6.69(m，1H)，6.11(s，1H) 5.35(d，1H，J＝7.8Hz)；

HRMS (ESI ⁺), theoretical value: 456.1483 (M+H) ⁺, measured value: 456.1487 (M+H) ⁺

Embodiment 146

N-(4-(2-aminopyridine-4-base oxygen base) phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide, hydrochlorate

A) 4-(4-(2-oxo-1-phenyl-1,2-dihydropyridine-3-formamido group) phenoxy group) picolinamide

[00488] by the mode that is similar to compd A among the preparation embodiment 115, make 4-(4-amino-benzene oxygen) picolinamide (compd A among the embodiment 142,0.030g, 0.13mmol) with embodiment 57 in Compound C (0.028g, 0.13mmol) coupling, obtain title compound (0.057g, 100%), need not be further purified during use.MS(ESI ⁺)m/z 427(M+H) ⁺。

B) N-(4-(2-aminopyridine-4-base oxygen base) phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00489] by being similar to the mode of compd E among the preparation embodiment 112, with 4-(4-(2-oxo-1-phenyl-1,2-dihydropyridine-3-formamido group) phenoxy group) picolinamide (0.055,0.13mmol) be converted into title compound (0.0093g, 16%).

¹HNMR(CD ₃OD)δ12.10(s，1H)，8.59-8.61(m，1H)，7.88-7.90(m，1H)，7.69-7.76(m，3H)，7.39-7.53(m，5H)，7.10-7.13(m，2H)，6.66(t，1H，J＝6.9Hz)，6.53-6.55(m，1H)，6.07-6.08(m，1H)，4.75(brs，2H)；

HRMS (ESI ⁺), theoretical value: 399.1457 (M+H) ⁺, measured value: 399.1453 (M+H) ⁺

Embodiment 147

N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-benzyl-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

A) 1-benzyl-2-oxo-1,2-dihydropyridine-3-methyl formate

[00490] at room temperature, stir 2-oxo-2H-pyrans-3-methyl formate (Aldrich, 2.0g, 13mmol, 1.0 equivalents) and the non-homogeneous mixture 3h of 4-flunamine (1.5mL, 13mmol, 1.0 equivalents) in DMF (10ml).At room temperature, with EDCI (3.4g, 18mmol, 1.4 equivalents) and DMAP (0.11g, 9.91mmol, 0.07 equivalent) reaction mixture, stir the solution 12h that obtains.With 1N HCl aqueous solution quencher reactant mixture, with ethyl acetate (4 * 50mL) extraction solutions.With 10%LiCl aqueous solution (organic extract liquid that 3 * 70mL) washings merge, dry (Na ₂SO ₄), filtering, vacuum concentrated filtrate obtains product (2.5g, 73%), is solid, need not be further purified during use.

¹H NMR(DMSO-d ₆)δ8.17-8.20(m，1H)，8.03-8.05(m，1H)，7.38-7.46(m，2H)，7.16-7.22(m，2H)，6.37(dd，1H，J＝6.94Hz)，5.13(s，2H)，3.73(s，3H)；

HRMS (ESI ⁺), theoretical value: 262.0879, measured value: 262.0885.

B) 1-benzyl-2-oxo-1,2-dihydropyridine-3-formic acid

[00491] at room temperature, handle 1-benzyl-2-oxo-1, MeOH (25mL) solution of 2-dihydropyridine-3-methyl formate (2.4g, 9.2mmol, 1.0 equivalents), stirred reaction mixture 15h with 5N sodium hydrate aqueous solution (4.6mL, 24mmol, 2.6 equivalents).With the reactant mixture vacuum concentration, dilute with water is used ethyl acetate extraction solution, discards organic component then.Water component is cooled to 0 ℃, with dense HCl acidify.The solid that filtration obtains washes with water, and the vacuum drying solid obtains product (1.6g, 70%), need not be further purified during use.

¹H NMR(DMSO-d ₆)δ8.39-8.44(m，2H)，7.42-7.46(m，2H)，7.18-7.24(m，2H)，6.78(dd，1H，J＝6.98Hz)，5.31(s，2H)；

HRMS (ESI ⁺), theoretical value: 248.0723, measured value: 248.0718.

C) 4-(4-(1-benzyl-2-oxo-1,2-dihydropyridine-3-formamido group)-2-fluorophenoxy) picolinamide

[00492] at room temperature, handle 1-benzyl-2-oxo-1 with DIPEA (0.18mL, 1.0mmol, 2.5 equivalents), 2-dihydropyridine-3-formic acid (0.10g, 0.41mmol, 1.0 equivalents), 4-(4-amino-2-fluorophenoxy) picolinamide (0.10g, 0.41mmol, 1.0 equivalent) and TBTU (0.17g, 0.45mmol, 1.1 equivalents) DMF (2mL) homogeneous phase solution, stirred reaction mixture 12h.With 10%LiCl aqueous solution (15mL) quencher reactant mixture, with the ethyl acetate (solution that 4 * 40mL) extractions obtain.With 10%LiCl aqueous solution (organic extract liquid that 4 * 50mL) washings merge, dry (Na ₂SO ₄), filter vacuum concentrated filtrate.Residue is through rapid column chromatography (SiO ₂, use eluent ethyl acetate) and purification, obtain product (0.13g, 67%), be solid.

¹HNMR(DMSO-d ₆)δ12.26(s，1H)，8.49-8.56(m，2H)，8.33-8.36(m，1H)，8.15(brm，1H)，8.03-8.07(m，1H)，7.74-7.75(m，1H)，7.51-7.54(m，1H)，7.41-7.46(m，4H)，7.20-7.24(m，3H)，6.71(dd，1H，J＝6.89Hz)，5.32(s，2H)

HRMS (ESI ⁺), theoretical value: 477.1374, measured value: 477.1378.

D) N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl)-1-benzyl-2-oxo-1,2-dihydropyridine-3-Methanamide, hydrochlorate

[00493] at room temperature, with two (trifluoroacetic acid base) iodobenzene (0.12g, 0.28mmol, 1.1 equivalent) add 4-(4-(1-benzyl-2-oxo-1,2-dihydropyridine-3-formamido group)-and the 2-fluorophenoxy) picolinamide (0.12g, 0.26mmol, 1.0 equivalents) and water (0.01mL, 0.51mmol, 20 equivalents) DMF (1mL) solution in.Pyridine (0.065mL, 0.77mmol, 3.0 equivalents) is added in this homogeneous mixture, at room temperature, stirred reaction mixture 12h.With 1N HCl aqueous solution (1mL) quencher reactant mixture, (solution that 3 * 5mL) extractions obtain discards organic layer with ether.With in the 1N NaOH aqueous solution and water component, the solution that obtains is with 9/1 CHCl ₃/ MeOH (4 * 10mL) extractions.With the extract drying (Na that merges ₂SO ₄), filter vacuum concentrated filtrate.Residue is through flash chromatography (SiO ₂, use 0-3%MeOH/CHCl ₃Eluting) purification, the component that vacuum concentration is suitable.Free alkali is dissolved in THF, is cooled to 0 ℃, with two these homogeneous phase solutions of  alkane solution-treated of anhydrous 4N HCl.Make reactant mixture be warming up to room temperature, vacuum concentration grinds residue with ether, discards filtrate.The vacuum drying solid obtains title compound (0.082g, 66%), is HCl salt.

¹H NMR(DMSO-d ₆)δ13.66(brs，1H)，8.49-8.51(m，1H)，8.39-8.49(m，1H)，8.37-8.39(m，1H)，8.00-8.09(m，3H)，7.54-7.56(m，1H)，7.43-7.48(m，3H)，7.19-7.24(m，2H)，6.69-6.72(m，2H)，6.21-6.22(m，1H)，5.32(s，2H)；

HRMS (ESI ⁺), theoretical value: 449.1425, measured value: 449.1406.

Embodiment 148

N-(4-luorobenzyl)-N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) cyclopropane-1, the 1-diformamide

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

[00494] under 0 ℃, to 1, the 1-cyclopropane-carboxylic acid (Aldrich, 390mg, add in THF 3.0mmol) (5mL) solution triethylamine (0.42mL, 3.0mmol).Under 0 ℃, behind the stirring 30min, (0.219mL 3.0mmol) adds in the reactant mixture with thionyl chloride.Under 0 ℃, again mixture is stirred 30min, add 4-flunamine (Aldrich, 375mg, THF 3.0mmol) (2mL) solution.Under 0 ℃, stirred reaction mixture 2h is with ethyl acetate (100mL) dilution, with 1N NaOH (10mL) extraction.With 1N HCl with aqueous phase as acidified to pH1-2.Filter and collect the solid (343mg, 48%) that forms.MS(ESI ⁺)m/z 238.24(M+H) ⁺。

B) N-(4-luorobenzyl)-N-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl) cyclopropane-1, the 1-diformamide

[00495] at room temperature; to 4-(4-amino-2-fluorophenoxy) picolinamide (compd B among the embodiment 24 '; 49mg; 0.2mmol) DMF (2mL) solution in add 1-((4-luorobenzyl) carbamoyl) cyclopropane-carboxylic acid (47mg; 0.2mmol), HATU (PerseptiveBiosystem; 114mg, 0.3mmol) and DIEA (0.2mL, 1.1mmol).At room temperature, stirred reaction mixture 2h adds the quencher of 4mL methanol then.Reactant mixture is through the preparation HPLC purification.Merge the component that needs, use K ₂HPO ₄The aqueous solution neutralization, vacuum concentration.Filter and collect the solid (29mg, 31%) that forms.

¹H NMR(DMSO-d ₆)δ10.78(br s，1H)，8.53(d，1H，J＝5.5Hz)，8.47(t，1H，J＝5.5Hz)，8.11(s，1H)，7.88(dd，1H，J＝13.2，2.3Hz)，7.70(s，1H)，7.47(d，1H，J＝9.2Hz)，7.38(t，1H，J＝9.2Hz)，7.34-7.29(m，3H)，7.22(dd，1H，J＝5.5，2.8Hz)，7.13(t，2H，J＝8.8Hz)，4.30(d，2H，J＝5.5Hz)，1.37(d，4H，J＝10.6Hz)；MS(ESI ⁺)m/z 467.12(M+H) ⁺.

C) N-(4-luorobenzyl)-N-(4-(2-aminopyridine-4-base oxygen base)-3-fluorophenyl) cyclopropane-1, the 1-diformamide

[00496] at room temperature; to N-(4-luorobenzyl)-N-(4-(2-carbamoyl pyridin-4-yl oxygen base)-3-fluorophenyl) cyclopropane-1; 1-diformamide (25mg; 0.05mmol) DMF (1mL) solution in add pyridine (0.2mL), water (0.1mL) and [two (trifluoroacetic acid base)-iodine] benzene (Aldrich; 34mg, 0.08mmol).At room temperature, stirred reaction mixture 2h adds the quencher of 2mL methanol then.Reactant mixture is through the preparation HPLC purification.Merge the component that needs, use K ₂HPO ₄The aqueous solution neutralization concentrates, and uses ethyl acetate extraction.Organic extract liquid is through MgSO ₄Drying, vacuum concentration.Residue is dissolved in a small amount of CH ₃CN/H ₂O, lyophilizing obtains title compound (21mg, 90%), is white solid.

¹H NMR(DMSO-d ₆)δ10.87(brs，1H)，8.44(t，1H，J＝6.0Hz)，7.91(d，1H，J＝6.6Hz)，7.88(d，1H，J＝13.2Hz)，7.37-7.29(m，6H)，7.13(t，2H，J＝8.8Hz)，4.29(d，2H，J＝6.1Hz)，1.38(d，4H，J＝2.2Hz)；MS(ESI ⁺)m/z439.14(M+H) ⁺.

Claims

1. the chemical compound that has formula I or II:

R ¹It is the Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl or replacement of heterocyclic radical, heteroaryl alkyl, the replacement of heteroaryl, heterocyclic radical, the replacement of alkynyl, heteroaryl, the replacement of thiazolinyl, alkynyl, the replacement of aryl, thiazolinyl, the replacement of aralkyl, aryl, the replacement of cycloalkyl, aralkyl, the replacement of alkyl, cycloalkyl, the replacement of H, alkyl, replacement;

B is O, NR ⁸, NR ⁸CH ₂, S, SO, SO ₂Or CR ⁹R ¹⁰

W and X independently are C or N separately;

Y is selected from O, S and NR ¹²

Z is-CR ¹³R ¹⁴-or-(CR ¹³R ¹⁴) _lNR ¹⁵-;

L is 0-2;

If W and X are C, n is 0-4; If one among X or the W is N, n is 0-3, if X and W are N, n is 0-2;

P is 1-4;

(a) if R ⁴It is phenyl

(i) R ⁴Do not replaced by hydroxyl and acylamino-; With

(ii) R ⁴Not by-NRSO ₂R-replaces, and wherein R is an alkyl or aryl;

(c) if R ⁴Be pyrimidine radicals, it is not replaced by=O;

A is selected from one of following group:

Wherein

D is S or O;

M is 0-6;

R ³⁷And R ³⁸Independently be H, halogen or alkyl separately.

2. the chemical compound of claim 1, wherein R ¹Be replace or unsubstituted phenyl, replacement or unsubstituted C ₁-C ₄Alkyl, or that replace or unsubstituted C ₃-C ₈Cycloalkyl.

3. the chemical compound of claim 2, wherein R ¹Be methyl, cyclohexyl or the cyclopenta of fluorophenyl, replacement.

4. the chemical compound of claim 1, wherein R ²Be C ₁-C ₄Alkyl, halogen or haloalkyl.

5. the chemical compound of claim 1, wherein R ⁴Be optional phenyl, pyridone, pyridine radicals, pyridine radicals-N-oxide, pyrazolyl or the pyrrolidinyl that replaces.

6. the chemical compound of claim 5, wherein R ⁴By oxygen, phenyl, C ₁-C ₄Alkyl or halogen replace.

7. the chemical compound of claim 1, wherein B is O, NHCH ₂, CH ₂Or CH (OH); Y is that O or S and Z are-CR ¹³R ¹⁴Or-NR ¹⁵, R wherein ¹³, R ¹⁴And R ¹⁵Each is H naturally.

8. the chemical compound of claim 1, wherein A is optional pyridine or the pyrimidine that replaces.

9. the chemical compound of claim 8, wherein said substituent group be alkyl, thiazolinyl, alkynyl, halogen, cycloalkyl, Heterocyclylalkyl ,-NR ³⁹COR ⁴⁰,-NR ³⁹C (O) ₂R ⁴⁰,-NR ⁴¹R ⁴²Or-C (O) NR ⁴³R ⁴⁴, R wherein ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³And R ⁴⁴Independently be aryl, the heteroaryl of cycloalkenyl group, aryl, the replacement of Heterocyclylalkyl, cycloalkenyl group, the replacement of cycloalkyl, Heterocyclylalkyl, the replacement of low alkyl group, hydroxy alkyl, aminoalkyl, cycloalkyl, the replacement of H, low alkyl group, replacement, the heteroaryl of replacement, or-NR ⁴³R ⁴⁴Form Heterocyclylalkyl.

10. the chemical compound of claim 7, the wherein pyridine that replaced by following group of A :-NR ⁴¹R ⁴²,-NR ³⁹COR ⁴⁰,-C (O) NR ⁴³R ⁴⁴, halogen, C ₁-C ₄Alkyl ,-C=C-R ⁴⁵,-C ≡ C-R ⁴⁶, aryl or heteroaryl, wherein R ⁴⁵And R ⁴⁶Be alkyl, hydroxy alkyl, aminoalkyl, cycloalkyl, Heterocyclylalkyl ,-C (O) R ⁴⁷,-NR ³⁹COR ⁴⁰, aryl or heteroaryl.

11. the chemical compound of claim 10, wherein said C ₁-C ₄Alkyl is replaced by following group: hydroxyl, hydroxy alkyl amino, alkyl amino, aminoalkyl amino or heteroaryl alkyl.

12. the chemical compound of claim 8, wherein R ⁴¹And R ⁴²Independently be H, methyl, ethyl, propyl group, butyl, phenyl or benzyl separately, and R ³⁹Be H and R ⁴⁰Be methyl, cycloalkyl or Heterocyclylalkyl.

13. the chemical compound of claim 8, wherein R ⁴³And R ⁴⁴Be H, and R ⁴⁵And R ⁴⁶Each is cyclohexene, azetidine, piperazine, piperidines, pyrrolidine or pyridine naturally, chooses wantonly to be replaced by following group: C ₁-C ₄Alkyl ,-CH ₂NH ₂,-NH ₂Or pyrrolidine.

14. the chemical compound of claim 8, wherein said pyridine is replaced by phenyl, pyridine or piperazine, and described phenyl is optional to be replaced by following group: CONH ₂, methyl, amino-ethyl, ethoxy ,-CONHCH ₂CH ₂NHCH ₃Or CH ₂CONH ₂

15. the chemical compound of claim 8, wherein A is by-NR ⁴¹R ⁴²Or-NR ³⁹CO ₂R ⁴⁰The pyrimidine that replaces.

16. the chemical compound of claim 15, wherein R ⁴¹And R ⁴²Be H or methyl, and R ³⁹And R ⁴⁰Independently be H or alkyl.

17. the chemical compound of claim 1, described chemical compound has formula III:

Wherein

R ¹Be optional phenyl or the alkyl that replaces; Z is NH or NCH ₃R ²Be F, Cl, CH ₃Or CF ₃R ³Be H; Y is O or S.

18. the chemical compound of claim 17, wherein R ¹Be C ₃-C ₇Phenyl cycloalkyl, replacement or unsubstituted or-(CH ₂) _n-R ⁵⁰, wherein n is 1-3, R ⁵⁰Be H, replacement or unsubstituted phenyl, amino, acylamino-, CN ,-C (O) ₂H or-C (O) ₂CH ₃

19. the chemical compound of claim 1, described chemical compound has formula IV:

R wherein ²Be halogen or H; R ³Be H; R ⁴Be the optional phenyl that replaces, the optional pyrazoles that replaces or the optional pyridine radicals that replaces; And A is the optional pyridine radicals that replaces.

20. the chemical compound of claim 19, wherein R ⁴Be optional pyridone or the pyridine-N-oxides that replaces.

21. the chemical compound of claim 1, described chemical compound has formula V:

R wherein ¹Optional is alkyl or cycloalkyl; A is optional pyrimidine or the pyridine that replaces; And R ²Be halogen or H; And R ¹³And R ¹⁴Or H, perhaps the carbon that connects with them forms cyclopropyl.

22. the chemical compound of claim 1, the IC of described chemical compound ₅₀Value is less than about 1.0 μ M.

23. treat method for cancer for one kind in the patient who needs is arranged, described method comprises the chemical compound of the claim 1 that gives described patient treatment effective dose.

24. a Pharmaceutical composition, described compositions comprise the chemical compound and the pharmaceutically acceptable carrier of the claim 1 for the treatment of effective dose.