CN102458580A

CN102458580A - Heterocyclic compounds as MEK inhibitors

Info

Publication number: CN102458580A
Application number: CN2009801598607A
Authority: CN
Inventors: D·奇卡娜; C·麦卡蒂; H·莫彼茨; C·潘迪特; R·斯特拉; H·萨布瑞曼娅
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2009-04-21
Filing date: 2009-04-21
Publication date: 2012-05-16
Also published as: CA2761108A1; EA201101533A1; KR20120028882A; AU2009344690A1; EP2421612A1; BRPI0925050A2; WO2010121646A1; MX2011011083A; JP2012524114A

Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts. These compounds can act as potential MEK inhibitors in the treatment of hyperproliferative diseases, like cancer and inflammation. The present invention also reveals methods of preparation thereof.

Description

Heterocyclic compound as mek inhibitor

The present invention relates to chemical compound for the specific inhibitor of MEK kinase activity.The invention still further relates to said chemical compound, their prodrug or the pharmaceutically acceptable compositions that comprises said chemical compound or their prodrug and disposing excess proliferative disease (hyperproliferative disease) like the purposes in cancer and the inflammation.

Excess proliferative disease such as cancer and inflammation are attracting the scientist that the treatment benefit is provided.In this regard, make great efforts to identify always with targeting in making the specific mechanisms that plays a role in the disease hypertrophy.

The overactivity of known MAP (MAP) kinase cascade plays an important role in cell proliferation and differentiation.When somatomedin combined with its receptor tyrosine kinase, this path can be activated.This interaction promotes RAS and RAF to associate and starts via the phosphorylation cascade of MEK (map kinase kinases) to ERK.It is known that in excess proliferative disease, to suppress this path be useful.Because the unique known substrate of MEK phosphorylation is map kinase-ERK1 and ERK2, so MEK is attractive treatment target.In pancreas, colon, lung, kidney and ovary primary tumor sample, had been found that the composition activation of MEK/ERK.

The phosphorylation of MEK as if increase its to the affinity of ERK and catalytic activity with and to the affinity of ATP.The invention describes through regulating ATP combination, MEK and ERK association (through competitiveness and/or allostery and/or noncompetitive mechanism) and suppress the active chemical compound of MEK.

In the numerous disease model, proved the activation of MEK, thereby the inhibition that shows MEK possibly have potential treatment benefit in numerous disease, said disease as

Pain: the effect in pain model prove (Evidence of Efficacy in Pain Models) ( J.Neurosci.22:478,2002; Acta Pharmacol Sin.26:789 2005; Expert Opin Ther Targets.9:699,2005; Mol.Pain.2:2,2006)

Apoplexy: the effect in apoplexy model proves: through suppress MEK to local ischemic brain injury have significant neuroprotective (Evidence of Efficacy in Stroke Models Significant Neuroprotection against Ischemic Brain Injury by Inhibition of the MEK) ( J.Pharmacol.Exp.Ther.304:172,2003; Brain Res.996:55,2004)

Diabetes: the proof in diabetic complication (Evidence In Diabetic Complications) (Am.J.Physiol.Renal.286, F120 2004)

Inflammation: the effect in inflammatory model prove (Evidence of Efficacy in Inflammation Models) ( Biochem Biophy.Res.Com.268:647,2000)

Arthritis: the effect in experimental osteoarthritis prove (Evidence of efficacy in experimental osteoarthritis) ( Arthritis & (J.Clin.Invest.116:163.2006)

The inhibition that in multiple research, has shown MEK has potential treatment benefit.

Therefore, as first embodiment, the invention provides the chemical compound of formula I

With its pharmaceutically acceptable salt, wherein

X representes C _1-3-Alkylidene ,-N (R ⁶)-,-O-or-S (O) _p-;

R ¹Expression aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl, wherein said each ring is optional to be replaced by one or more groups that are independently selected from tabulation 1;

R ²Expression H, cyanic acid or group-Y-R ⁷

R ³And R ⁴Represent H, C independently _1-6-Alkyl, C _1-6-Haloalkyl, C _1-6-Hydroxy alkyl, hydroxyl, C _1-6-Alkoxyl, amino, C _1-6-Alkyl amino, two C _1-6-Alkyl amino, perhaps R ³Also represent monocyclic cycloalkyl or monocyclic Heterocyclylalkyl, wherein said each ring is optional to be replaced by one or more groups that are independently selected from tabulation 1;

R ⁵Expression H, halogen, C _1-3-Alkyl, C _1-3Alkoxyl ,-SC _1-3Alkyl or C _1-3-Haloalkyl;

Y representes to be selected from-D-,-E-,-D-E-or-group of E-D-;

D representes to be selected from-N (R ⁸)-,-CO-,-CO ₂-,-SO-,-SO ₂-, CON (R ⁹) O-,-CON (R ¹⁰)-,-N (R ¹¹) SO ₂-,-N (R ²⁴) SO ₂NR ²⁵-,-SO ₂N (R ¹²)-,-N (R ¹³) CO-,-N (R ¹⁴) CON (R ¹⁵)-,-N (R ¹⁶) CO-or-C (=NH) N (R ¹⁷)-group;

E representes monocyclic arlydene, inferior heteroaryl, cycloalkylidene or inferior Heterocyclylalkyl, and wherein said each ring is optional to be replaced by one or more groups that are independently selected from tabulation 1;

R ⁷Expression H, C _1-6-Alkyl, C _2-6-Alkenyl, C _2-6-Alkynyl, cycloalkyl, aryl, Heterocyclylalkyl or heteroaryl, wherein when being not H, R ⁷Choose wantonly and be independently selected from halogen, cyanic acid, hydroxyl, C by 1 to 3 _1-6-Alkoxyl, C ₂-C ₆-alkenyl oxy, C ₂-C ₆-alkynyloxy base, C _1-6-Alkylthio group (C _1-6-Thioalkyl), C _1-6Haloalkyl, amino, C _1-6Alkyl amino, two-C _1-6Alkyl amino, C _1-6Acyl amino, C _1-6Acyl group C _1-6The group of alkyl amino, monocyclic cycloalkyl or monocyclic Heterocyclylalkyl replaces, and wherein said each ring can be chosen wantonly by 1 or 2 and be independently selected from halogen, cyanic acid, hydroxyl, C _1-6-Alkoxyl, C ₂-C ₆-alkenyl oxy, C ₂-C ₆-alkynyloxy base, C _1-6-Alkylthio group, C _1-6-Haloalkyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino, C _1-6-Acyl amino and C _1-6-Acyl group C _1-6-The group of alkyl amino replaces;

Z is O or N (R ¹⁸);

Tabulation 1 is selected from hydroxyl, cyanic acid, nitro, C _1-6-Alkyl, C _2-6-Alkenyl, C _2-6-Alkynyl, C _1-6-alkoxyl, C _2-6-Alkenyl oxy, C _2-6-Alkynyloxy base, halogen, C _1-6-Alkyl-carbonyl, carboxyl, C _1-6-Alkoxy carbonyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino, C _1-6-Alkyl amino-carbonyl, two-C _1-6-Alkyl amino-carbonyl, C _1-6-Alkyl-carbonyl-amino, C _1-6-Alkyl-carbonyl (C _1-6-Alkyl) amino, C _1-6-Alkyl sulfonyl-amino, C _1-6-Alkyl sulphonyl (C _1-6-Alkyl) amino, C _1-6-Alkylthio group, C _1-6-Alkyl sulphinyl, C _1-6-Alkyl sulfenyl (C _1-6-Alkylsulfanyl), C _1-6-Alkyl sulphonyl, amino-sulfonyl, C _1-6-Alkyl amino sulfonyl and two-C _1-6-Alkyl amino sulfonyl, wherein above-mentioned hydrocarbyl group can be chosen wantonly by one or more halogens, hydroxyl, C separately _1-6-Alkoxyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino or cyanic acid replace;

R ²⁶Expression H, C _1-6-Alkyl, C _1-6-Haloalkyl, C _1-6-Hydroxy alkyl, hydroxyl, C _1-6-Alkoxyl, amino, C _1-6-Alkyl amino or two C _1-6-Alkyl amino;

R ⁶, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸, R ²⁴And R ²⁵Be H or C independently _1-6-Alkyl;

M and n are 0,1,2 or 3 independently; And m+n=2 or 3;

P is 0,1 or 2; And wherein

Alkyl or alkylidene are meant straight chain, side chain and/or the cyclic hydrocarbon of 1 to 20 carbon atom.Alkyl with 1 to 5 carbon is called as " low alkyl group ", instance include but not limited to methyl, ethyl, propyl group, isopropyl, just-butyl, tert-butyl and isobutyl group.

Cycloalkyl or cycloalkylidene are represented the monocycle or the bicyclic carbocyclic ring of 3-14 unit; A wherein said monocycle or a said bicyclic ring be saturated or part undersaturated; And can choose wantonly further and comprise-C (O)-ring members; Another ring can be aromatics, saturated or part undersaturated, and can comprise 1 to 3 and be selected from-C (=O) ,-N (R ²⁰) q-,-ring members of O-and S (O) r, wherein R ²⁰Be H or C _1-6-Alkyl, q are that 0-1 and r are 0-2;

Aryl or arlydene are represented the monocycle or the bicyclic carbocyclic ring of 6-14 unit, and a wherein said monocycle or a said bicyclic ring are aromatics, another ring can be aromatics, saturated or part undersaturated, and can comprise 1 to 3 and be selected from-C (O) ,-N (R ¹⁹) q-,-ring members of O-and S (O) r, wherein R ¹⁹Be H or C _1-6-Alkyl, q are that 0-1 and r are 0-2;

Heteroaryl or inferior heteroaryl are represented the monocycle or the bicyclo-of 5-14 unit; A wherein said monocycle or a said bicyclic ring are to comprise the perhaps aromatic group of (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms of (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom; Another ring can be aromatics, saturated or part undersaturated, and can comprise 1 to 3 and be selected from-C (O) ,-N (R ²¹) q-,-ring members of O-and S (O) r, wherein R ²¹Be H or C _1-6-Alkyl, q are that 0-1 and r are 0-2; And

Heterocyclylalkyl or inferior Heterocyclylalkyl are represented the monocycle or the bicyclo-of 3-14 unit, and a wherein said monocycle or a said bicyclic ring are to comprise 1 or 2 to be selected from-N (R ²²)-,-O-and-S (O) _r-ring members and can choosing wantonly further comprise-the saturated or undersaturated group of part of C (O)-ring members, another ring can be aromatics, saturated or part undersaturated, and can comprise 1 to 3 and be selected from-C (=O) ,-N (R ²³) q-,-ring members of O-and S (O) r, wherein R ²²Or R ²³Be H or C _1-6-Alkyl, q are that 0-1 and r are 0-2.

Can the following specific embodiments of formula of the present invention (I) be integrated with in the definition of formula (I) and can be with the suitable method combination of any number.

In one embodiment, X represent-N (H)-.

In another embodiment, R ¹The optional substituted phenyl of expression.

In another embodiment, R ¹On optional substituent group represent that 1 to 3 is independently selected from halogen for example fluorine, bromine or iodine, C _1-6-Alkyl is ethyl, C for example _2-6-Alkynyl is acetenyl, C for example _1-6-Haloalkyl is trifluoromethyl and C for example _1-6-Alkylthio group is the group of methyl mercapto (thiomethyl) for example.

In another embodiment, R ¹Be illustrated in 2,4 and optional 6-position, suitably at 2 and 4 substituted phenyl.In a further embodiment, R ¹Expression 2-fluorine and the substituted phenyl of 4-bromine, or 4-iodo-2-fluorophenyl, or the 2-of iodine, trifluoromethyl, methyl mercapto, acetenyl or ethyl and the substituted combination in any of 4-.

In one embodiment ,-and D-representes to be selected from-C (O)-,-CO ₂-, C (O) N (H) O-,-C (O) N (C _1-6-Alkyl) O-,-C (O) N (H)-with-C (O) N (C _1-6-Alkyl)-group.

In one embodiment ,-E-representes the inferior Heterocyclylalkyl of 5-unit inferior heteroaryl or 5-unit.In a further embodiment, E representes to be selected from following ring:

In another embodiment, represent at Y-situation of D-E-under ,-D-can represent-C (O) N (H)-,-E-can represent for example cyclopenta or optional substituted heteroaryl thiazole for example of optional substituted cycloalkyl.

In another embodiment; Represent at Y-situation of E-D-under;-E-can represent for example

diazole of optional substituted heteroaryl ,-D-can represent-and C (O) N (H)-.

In another embodiment, Y represent group-D-or-E-.

In another embodiment, R ⁷Expression H, C _1-6-Alkyl is methyl or ethyl, substituted C for example ₁- _6-Alkyl is for example by 1 to 3 group, replaced by one or two group in another embodiment, and said group is selected from hydroxyl (comprising two-hydroxyl), C _1-6-Alkoxyl is methoxyl group, C for example ₂-C ₆-alkenyl oxy is vinyl oxygen base, two-C for example _1-6-Alkyl amino is dimethylamino, C for example _1-6-Acyl amino is acetyl-amino and optional substituted monocyclic cycloalkyl cyclopropyl for example for example.

In another embodiment, R ⁷Expression H, methyl, ethyl, cyclopropyl methyl, 2-hydroxyethyl, 2-vinyl oxygen base ethyl, 3-hydroxypropyl, 2-methoxy ethyl, acetyl-amino methyl, 2-dimethyl aminoethyl or 2, the 3-dihydroxypropyl.

In another embodiment, R ²Expression-CO ₂H, COH ,-CO ₂Et, C (O) N (H or CH ₃) OR ^7a, R wherein ^7aExpression methyl, ethyl, cyclopropyl methyl, 2-vinyl oxygen base ethyl, 2-hydroxyethyl and 2, the 3-dihydroxypropyl ,-C (O) N (H or CH ₃) R ^7b, R wherein ^7bExpression H, methyl, ethyl, cyclopropyl methyl, 2-methoxy ethyl, 2-hydroxyethyl, 3-hydroxypropyl, acetyl-amino methyl, 2-dimethyl aminoethyl, cyclopenta or 2-thiazolyl, perhaps R ²Expression

Di azoly is amino.

In another embodiment, the present invention includes wherein R ²Expression CONHOR ^7aFormula I chemical compound, R wherein ^7aRepresentative ring propyl group methyl or 2-hydroxyethyl.

In another embodiment, m and n all are 1, and perhaps among m and the n is 1, and another is 2.

In another embodiment, R ³And R ⁴Expression H.

In another embodiment, R ⁵Expression H, halogen be fluorine or chlorine, C for example _1-3Alkoxyl for example methoxy or ethoxy ,-SC _1-3Alkyl is SCH for example ₃Or C _1-3Alkyl is methyl or ethyl for example.In a further embodiment, R ⁵It is fluorine.In a further embodiment, R ⁵It is methyl.

In another embodiment, Z representes O.

In another embodiment, aryl or arlydene are represented optional substituted phenyl or phenylene respectively.

In another embodiment, cycloalkyl or cycloalkylidene are represented the first saturated monocyclic carbocyclic ring of optional substituted 3-7, for example cyclopropyl or cyclopenta.

In another embodiment; Heteroaryl or inferior heteroaryl are represented the first monocyclic aromatic group of optional substituted 5-6; It comprises (a) 1 to 4 nitrogen-atoms, (b) 1 oxygen atom or 1 sulphur atom perhaps (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen-atoms, for example tetrazole radical, thiazolyl or

di azoly.

In another embodiment, Heterocyclylalkyl or inferior Heterocyclylalkyl are represented to comprise 1 or 2 and are selected from-N (R ²²)-,-O-and-S (O) _r-the saturated monocycle of optional substituted 5-6 unit of ring members.

In another one embodiment of the present invention, said compound formation is selected from the pharmaceutically acceptable salt of acid-addition salts and base addition salts.

In another embodiment, the present invention includes the chemical compound that comprises formula I or Id and the pharmaceutical composition of pharmaceutically acceptable carrier or excipient.In another embodiment, the present invention includes the pharmaceutical composition of the chemical compound that comprises formula I or Id and second kind of activating agent and pharmaceutically acceptable carrier or excipient.

In another embodiment, the present invention includes the chemical compound of formula Id:

And salt, wherein

Rd ¹Expression H, halogen, C _1-3-Alkyl or C _1-3-Haloalkyl;

Rd ²Expression H, cyanic acid or group-Y-Rd ⁵

Rd ³And Rd ⁴Represent hydroxyl, cyanic acid, nitro, C independently _1-6-Alkyl, C _2-6-Alkenyl, C _2-6-Alkynyl, C _1-6-alkoxyl, C _2-6-Alkenyl oxy, C _2-6-Alkynyloxy base, halogen, C _1-6-Alkyl-carbonyl, carboxyl, C _1-6-Alkoxy carbonyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino, C _1-6-Alkyl amino-carbonyl, two-C _1-6-Alkyl amino-carbonyl, C _1-6-Alkyl-carbonyl-amino, C _1-6-Alkyl-carbonyl (C _1-6-Alkyl) amino, C _1-6-Alkyl sulfonyl-amino, C _1-6-Alkyl sulphonyl (C _1-6-Alkyl) amino, C _1-6-Alkylthio group, C _1-6-Alkyl sulphinyl, C _1-6-Alkyl sulfenyl, C _1-6-Alkyl sulphonyl, amino-sulfonyl, C _1-6-Alkyl amino sulfonyl and two-C _1-6-Alkyl amino sulfonyl, wherein above-mentioned hydrocarbyl group can be chosen wantonly by one or more halogens, hydroxyl, C separately _1-6-Alkoxyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino or cyanic acid replace;

Y representes to be selected from-D-,-E-,-D-E-or-group of E-D-;

D representes to be selected from-N (Rd ⁸)-,-CO-,-CO ₂-,-SO-,-SO ₂-, CON (Rd ⁹) O-,-CON (Rd ¹⁰)-,-N (Rd ¹¹) SO ₂-,-N (Rd ¹²) So ₂NRd ¹³-,-SO ₂N (Rd ¹⁴)-,-N (Rd ¹⁵) CO-,-N (Rd ¹⁶) CON (Rd ¹⁷)-,-N (Rd ¹⁸) CO-or-C (=NH) N (Rd ¹⁹)-group;

E representes monocyclic arlydene, inferior heteroaryl, cycloalkylidene or inferior Heterocyclylalkyl, and wherein said each ring is optional to be replaced by one or more groups that are independently selected from tabulation defined herein 1;

Rd ⁵Expression H, C _1-6-Alkyl, C _2-6-Alkenyl, C _2-6-Alkynyl, cycloalkyl, aryl, Heterocyclylalkyl or heteroaryl, wherein when being not H, Rd ⁵Choose wantonly and be independently selected from halogen, cyanic acid, hydroxyl, C by 1 to 3 _1-6-Alkoxyl, C ₂-C ₆-alkenyl oxy, C ₂-C ₆-alkynyloxy base, C _1-6-Alkylthio group, C _1-6Haloalkyl, amino, C _1-6Alkyl amino, two-C _1-6Alkyl amino, C _1-6Acyl amino, C _1-6Acyl group C _1-6The group of alkyl amino, monocyclic cycloalkyl or monocyclic Heterocyclylalkyl replaces, and wherein said each ring can be chosen wantonly by 1 or 2 and be independently selected from halogen, cyanic acid, hydroxyl, C _1-6-Alkoxyl, C ₂-C ₆-alkenyl oxy, C ₂-C ₆-alkynyloxy base, C _1-6-Alkylthio group, C _1-6-Haloalkyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino, C _1-6-Acyl amino and C _1-6-Acyl group C _1-6-The group of alkyl amino replaces;

Rd ⁶And Rd ⁷Represent hydroxyl, cyanic acid, nitro, C independently _1-6-Alkyl, C _2-6-Alkenyl, C _2-6-Alkynyl, C _1-6-Alkoxyl, C _2-6-Alkenyl oxy, C _2-6-Alkynyloxy base, halogen, C _1-6-Alkyl-carbonyl, carboxyl, C _1-6-Alkoxy carbonyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino, C _1-6-Alkyl amino-carbonyl, two-C _1-6-Alkyl amino-carbonyl, C _1-6-Alkyl-carbonyl-amino, C _1-6-Alkyl-carbonyl (C _1-6-Alkyl) amino, C _1-6-Alkyl sulfonyl-amino, C _1-6-Alkyl sulphonyl (C _1-6-Alkyl) amino, C _1-6-Alkylthio group, C _1-6-Alkyl sulphinyl, C _1-6-Alkyl sulfenyl, C _1-6-Alkyl sulphonyl, amino-sulfonyl, C _1-6-Alkyl amino sulfonyl and two-C _1-6-Alkyl amino sulfonyl, wherein above-mentioned hydrocarbyl group can be chosen wantonly by one or more halogens, hydroxyl, C separately _1-6-Alkoxyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino or cyanic acid replace;

J and g represent 0,1,2 or 3 independently; And

Rd ⁸, Rd ⁹, Rd ¹⁰, Rd ¹¹, Rd ¹², Rd ¹³, Rd ¹⁴, Rd ¹⁵, Rd ¹⁶, Rd ¹⁷, Rd ¹⁸And Rd ¹⁹Be H or C independently _1-6-Alkyl.

In one embodiment, j and g are 0,1,2 or 3 independently, and j+g=2,3 or 4.In another embodiment, j is 0,1 or 2, and g is 1,2 or 3.In another embodiment, j is 0, and g is 0,1 or 2.

Relating to formula (I) and (Id) time, alkyl, alkenyl, alkynyl and the alkoxyl that contains required carbon number can be unbranched or side chain.The instance of alkyl comprise methyl, ethyl, just-propyl group, different-propyl group, just-butyl, different-butyl, the second month in a season-butyl and tert-butyl.The instance of alkoxyl comprise methoxyl group, ethyoxyl, just-propoxyl group, different-propoxyl group, just-butoxy, different-butoxy, the second month in a season-butoxy and uncle-butoxy.

" halogen " or " halo " can be fluorine, chlorine, bromine or iodine.

C ₁- _6-Haloalkyl is meant by the substituted alkyl of fluorin radical for example of 7 halogen groups at the most.For example, be under the situation of fluorine in substituent group, common haloalkyl has trifluoroalkyl, 2,2,2-trifluoroethyl or 2,2,2,1,1-pentafluoroethyl group.

Term " alkenyl " is meant the monoradical derived from the hydrocarbon with at least one carbon-to-carbon double bond.Term " C ₂-C ₆-alkenyl " be meant derived from having 2 to 6 carbon atoms and comprising the monoradical of the hydrocarbon of at least one carbon-to-carbon double bond.

Term " alkynyl " is meant derived from having the monoradical of the hydrocarbon of carbon-to-carbon triple bond at least.Term " C ₂-C ₆-alkynyl " be meant derived from having 2 to 6 carbon atoms and comprising the monoradical of the hydrocarbon of at least one carbon-to-carbon triple bond.

Term " alkoxyl " is meant the group that alkyl wherein links to each other with oxygen, wherein alkyl like the front definition.

Should be understood that term C (O) is meant-the C=O group, no matter it is ketone, aldehyde or acid, or acid derivative.Similarly, S (O) is meant-the S=O group.

The instance of defined cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl or ring octyl group in the formula (I).

The instance of defined aryl comprises phenyl, naphthyl, anthryl and phenanthryl in the formula (I).

The instance of defined Heterocyclylalkyl comprises [1 among the formula I; 3] dioxolanes, [1,4] two

alkane, Oxyranyle, '-aziridino, oxetanyl, azetidinyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl, morpholino, thio-morpholinyl, piperazinyl, azepine base, oxa-

base (oxapinyl), oxa-azepine

base (oxazepinyl) and diaza

base.

The instance of defined bicyclic heteroaryl comprises pyridine radicals in the formula (I); Thienyl; Furyl; Pyrrole radicals; Pyrazolyl; Imidazole radicals;

azoles base; Different

azoles base; Thiazolyl; Isothiazolyl; Triazolyl;

di azoly; Thiadiazolyl group and tetrazole radical.The instance of bicyclic heteroaryl comprises indyl, benzofuranyl, quinolyl, isoquinolyl, indazolyl, indolinyl, isoindolyl, indolizine base, benzimidazolyl and quinolyl.

In this description and claims subsequently; Only if context has different needs; Otherwise wording " comprises " or its modification " comprises " group that should be understood that to represent to comprise described integer or step or integer or step, but does not get rid of the group of any other integer or step or integer or step.

In another one embodiment of the present invention, said chemical compound is stereoisomer or tautomer.

Suitable single chemical compound of the present invention is selected from:

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclopropyl-methoxyl group-amide;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid dimethylformamide;

7-(4-bromine 2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene indolizine 8-formic acid methoxyamide;

7-(4-bromine 2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene indolizine 8-Methanamide;

7-(4-bromine 2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene indolizine 8-formic acid ethyoxyl amide;

7-(4-bromine 2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene indolizine 8-formic acid (2-hydroxyethyl) amide;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine 8-formic acid methyl nitrosourea;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-ethyl-amide;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formaldehyde;

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-vinyl oxygen base-ethyoxyl)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide;

2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6,7,8,9-tetrahydrochysene-4H-quinolizine-1-Ethyl formate;

2-(4-bromo-2-fluoro-phenyl-amino)-4-oxo-6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid;

2-(4-bromo-2-fluoro-phenyl-amino)-4-oxo-6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid-cyclopropyl-methoxyamide;

2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6,7,8,9-tetrahydrochysene-4H-quinolizine-1-Methanamide;

2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid-(2-vinyl oxygen base-ethyoxyl)-amide;

2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid methoxyamide;

2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid ethyoxyl amide;

7-(4-bromo-2-fluorophenyl is amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-oxethyl) amide;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (3-hydroxyl-propyl group)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-methoxyl group-ethyl)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-acetyl-amino-ethyl)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-dimethylamino-ethyl)-amide;

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclopentyl amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid buserelin;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (3-methoxyl group-propyl group)-amide;

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid;

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide;

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate;

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide;

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide;

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid;

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide;

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide;

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid;

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide;

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide;

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide;

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid thiazol-2-yl amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (3-hydroxyl-propyl group)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid dimethylformamide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-methoxyl group-ethyl)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-acetyl-amino-ethyl)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (pyridine-2-ylmethyl)-amide;

6-fluoro-7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid;

6-fluoro-7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

6-fluoro-7-(2-fluoro-4-methyl sulfenyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-[5-(2-hydroxyl-ethylamino)-[1; 3; 4]

diazole-2-yl]-2,3-dihydro-1H-indolizine-5-ketone;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide;

7-(4-bromo-2-methyl-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid;

7-(4-bromo-2-methyl-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

7-(4-bromo-2-methyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid;

7-(4-bromo-2-methyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-8-(3-hydroxyl-3-piperidines-2-base-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-keto hydrochloride;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(3-hydroxyl-3-piperidines-2-base-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-ketone;

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-8-(3-hydroxyl-3-piperidines-2-base-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-ketone;

Cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide;

N-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-N, N-dimethyl-amino-sulfonamide;

2,3-dihydroxy-propane-amino-sulfonic acid-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide;

1-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-base sulfamoyl]-pyrrolidine-2-formic acid;

2-hydroxymethyl-pyrrolidine-1-sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(1-hydroxyl-Ding-3-thiazolinyl)-2,3-dihydro-1H-indolizine-5-ketone;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(1-hydroxyl-pi-allyl)-2,3-dihydro-1H-indolizine-5-ketone;

7-(4-bromo-2-fluoro-phenyl amino)-8-(2,3-dihydroxy-propiono)-6-fluoro-2,3-dihydro-1H-indolizine-5-ketone;

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(2-hydroxyl-acetyl group)-2,3-dihydro-1H-indolizine-5-ketone;

7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate;

7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid;

7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

7-(2-fluoro-4-methoxyl group-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formaldoxime;

7-(4-bromo-2-fluoro-phenyl amino)-8-(3-hydroxyl-3-pyridine-2-base-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-ketone;

7-(4-bromo-2-fluoro-phenyl amino)-8-(3-hydroxyl-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-ketone;

3-(4-bromo-2-fluoro-phenyl)-1-mesyl-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene (as-indacene)-2,5-diketone;

Cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide;

N-[7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-4-fluoro-benzsulfamide;

[7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-carbamic acid tert-butyl ester;

Cyclohexane extraction sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide;

N-[7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-4-trifluoromethyl-benzsulfamide;

N-[7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-N, N-dimethylamino sulfonamide;

5-(4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid;

7-(4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate;

7-(4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide;

7-(4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide;

7-(4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclobutyl methoxy base-amide;

7-(4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (3-hydroxy-2-methyl-propoxyl group)-amide;

1-(2,3-dihydroxy-propyl group)-cyclopropane sulfonic acid [6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide;

1-(2,3-dihydroxy-propyl group)-cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide;

1-(2,3-dihydroxy-propyl group)-cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide;

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide;

7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy amide;

7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide;

7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclobutyl methoxy base-amide;

1-(2,3-dihydroxy-propyl group)-cyclopropane sulfonic acid [7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide; With

Cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide, or its pharmaceutically acceptable salt.

The represented chemical compound lot of formula I and Id can form acid-addition salts, particularly pharmaceutically-acceptable acid addition.The pharmaceutically-acceptable acid addition of formula I chemical compound comprises the salt of mineral acid, and said mineral acid is halogen acids example hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid for example; With organic acid salt, said organic acid for example mono carboxylic acid of aliphatic series such as formic acid, acetic acid, propanoic acid and butanoic acid, aliphatic hydroxide radical acid like lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acid such as benzoic acid, right-chlorobenzoic acid, diphenyl acetic acid or triphenylacetic acid, aromatic hydroxy acid such as neighbour-hydroxy benzoic acid, right-hydroxy benzoic acid, 1-hydroxyl naphthalene-2-formic acid or 3-hydroxyl naphthalene-2-formic acid and sulfonic acid such as methanesulfonic acid or benzenesulfonic acid.These salt can prepare through the chemical compound of known salify operation by formula I and Id.

Contain acidic-group for example the chemical compound of formula I and the Id of carboxyl also can form salt with alkali, particularly pharmaceutically acceptable alkali such as those alkali well known in the art; Such suitable salt comprises slaine, particularly alkali metal or alkali salt such as sodium, potassium, magnesium or calcium salt, or the salt that forms with ammonia or pharmaceutically acceptable organic amine or heterocyclic bases such as ethanolamine, benzylamine or pyridine.These salt can prepare through the chemical compound of known salify operation by formula I and Id.

In these chemical compounds, exist under the situation of asymmetric carbon atom, chemical compound exists with each optical activity isomeric form or its mixture, for example racemic mixture or non-enantiomer mixture form.The present invention includes each optically active R and S isomer with and composition thereof, for example racemic mixture or non-enantiomer mixture.

The present invention includes that wherein one or more atoms are had the same atoms number but all pharmaceutically acceptable isotope-labeled formula (I) and chemical compounds (Id) with atom replacement of atomic mass different or mass number with atomic mass of usually finding at occurring in nature or mass number.

Be suitable for being included in the isotope that isotopic instance in the chemical compound of the present invention comprises hydrogen, as ²H with ³H; The isotope of carbon, as ¹¹C, ¹³C with ¹⁴C; The isotope of chlorine, as ³⁶Cl; The isotope of fluorine, as ¹⁸F; The isotope of iodine, as ¹²³I with ¹²⁵I; The isotope of nitrogen, as ¹³N with ¹⁵N; The isotope of oxygen, as ¹⁵O, ¹⁷O with ¹⁸O; The isotope of phosphorus, as ³²P; With the isotope of sulfur, as ³⁵S.

Replace with heavier isotope such as deuterium, promptly ²H can provide some treatment advantage, and this is because metabolic stability is higher, and for example the half-life increases or the dose requirements reduction in the body, possibly be preferred in some situation therefore.

Isotope-labeled formula (I) and chemical compound (Id) usually can known by one of skill in the art routine techniquess or are prepared through used cold reagent before replacing with suitable isotope-labeled reagent with the similar method of the described method of preparation part with appended embodiment.

On the other hand, the invention provides and prepare the formula (I) and (Id) method of chemical compound.The flow process of describing in detail has below provided the flow process of passing through of synthesis type (I) and chemical compound (Id).Should be realized that the pairing chemical compound of the Roman number in these flow processs does not also correspond to the Roman number of claimed compounds.

Flow process 1.

The chemical compound of formula II can be used J.Org.Chem., and 1995,60,2912 and Tetrahedron, 2002,58, the disclosed method described in 2821 prepares.

The chemical compound of formula II can be through being converted to the chemical compound of formula III with the reaction under the temperature in room temperature to 140 ℃ under the situation that does not add other material or in suitable solvent such as toluene of halogenating agent such as phosphorus oxybromide (phosphorus oxybromide).

Perhaps; Can make chemical compound and the nine fluorine butane sulfuryl fluorides of formula II have alkali such as diisopropyl ethyl amine and catalyst such as N; Reaction at room temperature in solvent such as dichloromethane under the situation of N-dimethyl-4-aminopyridine; Perhaps with N-phenyl trifluoromethanesulfonate Methanesulfomide under the situation that has alkali such as diisopropyl ethyl amine at suitable solvent as 1, under the temperature of the reflux temperature of room temperature to solvent, react in the 2-dimethoxy-ethane.In addition, can the chemical compound of formula II handled to the temperature of ambient temperature at-20 ℃ in solvent such as dichloromethane under the situation that has alkali such as pyridine with trifluoromethanesulfanhydride anhydride.

The chemical compound of formula IV can be obtained by the chemical compound of formula III through using Buchwald-Hartwig C-N/S/O coupling condition and the aniline that suits or phenol or phenylmercaptan. reaction.Said Buchwald-Hartwig reaction can exist catalyst like three (dibenzalacetones), two palladiums (0) or acid chloride, alkali such as potassium phosphate, uncle-sodium butoxide, 1.8-diazabicylo [5.4.1] 11 carbon-7-alkene (1.8-Diazobicyclo [5.4.1] undec-7-ene) or cesium carbonate, part as 9; 9 '-dimethyl-4; Two (the diphenylphosphino)-xanthenes, 2 of 5-; 2 '-two (diphenylphosphino)-1-1 '-dinaphthalene, 2-dicyclohexyl phosphino--2 '-(N; The N-dimethylamino) biphenyl, 2-dicyclohexyl phosphino--2 '; Under the situation of 6 '-(dimethoxy) biphenyl or tributylphosphine at suitable solvent such as toluene, 1, in 2-dimethoxy-ethane, oxolane or two alkane under the temperature of the reflux temperature of room temperature to solvent or under 70 ℃ to 150 ℃ temperature, carrying out under the microwave radiation.

The chemical compound of formula V can be obtained through under the temperature of the reflux temperature of room temperature to solvent, reacting in proton solvent such as ethanol or methanol with alkali such as sodium hydroxide by the chemical compound of formula IV.

Can be with the chemical compound of formula V with functionalized azanol or amine and suitable coupling agents such as hexafluorophosphoric acid O-(7-azepine benzo-triazol-1-yl)-N; N; N '; N '-four-methyl urea hydrochloric acid N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide or N; The N-dicyclohexylcarbodiimide under the situation that has N-hydroxybenzotriazole and suitable alkali such as diisopropyl ethyl amine or triethylamine at proton solvent such as oxolane, N; Handle to the temperature of room temperature at 0 ℃ in dinethylformamide or the dichloromethane, obtain the chemical compound of formula VI.Perhaps, the chemical compound of formula VI can be directly by the chemical compound of formula IV through obtaining in solvent such as dichloromethane, reacting under the temperature at the reflux temperature of room temperature to solvent under the situation that has lewis acid such as trimethyl aluminium with amine or azanol.

Flow process 2

Flow process 2.

The chemical compound that can be through using reagent in suitable solvent such as acetonitrile, under the temperature of room temperature to 70 ℃, to carry out close electric halogenation the chemical compound of formula III be transformed accepted way of doing sth VII like [1-(chloromethyl)-4-fluoro-1,4-phenodiazine

is bicyclo-[2.2.2] octane-two (tetrafluoroborates) (diazonia)].

Can use the chemical compound that the chemical compound of formula VII is transformed accepted way of doing sth VIII like the preparation described condition of formula IV chemical compound (flow process 1).Can use the chemical compound that the chemical compound of formula VIII is transformed accepted way of doing sth IX like the preparation described condition of formula V chemical compound (flow process 1).Can use the chemical compound that the chemical compound of formula IX is transformed accepted way of doing sth X like the preparation described condition of formula VI chemical compound (flow process 1).

Perhaps, the chemical compound of formula X can be directly by the chemical compound of formula VIII through with as the preparation described condition of formula VI chemical compound (flow process 1) obtain with amine or azanol reaction.

Flow process 3.

The chemical compound of formula XI can be through reacting the chemical compound of formula II and alkali such as NaH and alkylating agent such as iodomethane or halogenating agent such as deoxyfluor, NCS, NBS, NIS to the compound by formula II under the temperature of room temperature to 100 ℃ in suitable solvent such as THF or DMF.Can use the condition (flow process 1) identical the chemical compound of formula XI to be transformed the chemical compound of accepted way of doing sth VII with preparing the described condition of formula II chemical compound.

Flow process 4.

The chemical compound of formula XII can be obtained through under the temperature of the reflux temperature of room temperature to solvent, reacting in proton solvent such as ethanol or methanol with alkali such as sodium hydroxide or Lithium hydrate by the chemical compound of formula VII.

Then, can use S _NThe AR reaction transforms the chemical compound of formula XII the chemical compound of accepted way of doing sth IX.Said S _NAR be reflected among suitable solvent such as the THF with amide alkali such as LDA, LiHMDS, NaHMDS or KHMDS in suitable temperature, typically be-78 ℃ and to the temperature of room temperature, carry out.

Can use the condition (flow process 1) identical the chemical compound of formula IX to be transformed the chemical compound of accepted way of doing sth X with preparing the described condition of formula VI chemical compound.

Flow process 5.

Can in appropriate organic solvent such as DMF, THF or dichloromethane, carry out the chemical compound that standard coupling operation transforms the chemical compound of formula IX with hydrazine accepted way of doing sth XIII under the situation of HOBt existing through using reagent such as EDCI or PyBOP.

Then, can use carbonyl dimidazoles, phosgene or phosgene equivalent in appropriate organic solvent such as DMF, toluene or dichloromethane, the chemical compound of formula XIII to be transformed the chemical compound of accepted way of doing sth XIV.

The chemical compound of formula XV can by the chemical compound of formula XIV through add suitable amine, then with triphenylphosphine, triethylamine and CCl4 in dichloromethane with the intermediate hydrazides again cyclisation obtain.

Flow process 6.

The aldehyde of formula XVI and ketone can be prepared with standard method by the acid of formula IX, as acid being changed into corresponding Weinreb amide, handle with suitable organometallic reagent then.

diazole of formula XVII can be through with each amidoxim acidylate, cyclodehydration prepares then.

The acyl azide of formula XVIII can be prepared with standard conditions via carboxylic acid halides, for example acyl chlorides by the chemical compound of general formula I X.Can reset the chemical compound that the chemical compound of formula XVIII is changed into general formula X IX via Ku Ertisi then.According to standard method, the acid of formula IX is changed into corresponding amide, then with dehydration of amide, obtain the nitrile of corresponding formula XX.Can be with TMSA or NaN ₃At suitable aprotic solvent such as N, under the temperature of room temperature to 100 ℃, handle the chemical compound of formula XX in the dinethylformamide, obtain the chemical compound of formula XXI.

Can prove the inhibition activity of the chemical compound of formula I and Id with following test operation:

Measure with the BRAF-MEK-ERK cascade and to estimate the effect of these chemical compounds as the map kinase pathway inhibitor.Using recombined human activated b RAF (V599E) kinases (catalog number (Cat.No.) 14-557), people's total length non-activity MEK1 kinases (catalog number (Cat.No.) 14-706) and the people's total length non-activity map kinase 2/ERK2 (catalog number (Cat.No.) 14-536) that are obtained by Upstate to set up the enzyme cascade measures.Carry out reading with TR-FRET (transfer of time-resolved fluorescence resonance energy) detection technique.Measure buffer and in 384 hole forms, contain the MEK1 of 50mM Tris pH 7.5,10mM MgCl2,1mM DTT, 0.01% polysorbas20, the activatory BRAF of 0.1nM, 2nM non-activity, ERK2,100 μ M ATP and the 500nM long-chain biotin-peptide substrates (LCB-FFKNIVTPRTPPP) of 10nM non-activity.(phosphoric acid of 2nM Eu-labelling-serine/threonine antibody (catalog number (Cat.No.) AD0176-Perkin Elmer) stops kinase reaction, adds 20nM SA-APC (catalog number (Cat.No.) CR130-100-Perkin Elmer) to detect mixture with 10mM EDTA and Lance after 90 minutes.Reading TR-FRET signal (under 340nm, exciting emission under 615nm and 665nm) time delay with 50 μ s in the Victor3V exometer.Read-around ratio with under 665nm and the 615nm is calculated data.The final concentration of DMSO is 2.5% in this mensuration.Existing under the situation of test compound, under 10 μ M concentration, chemical compound is screened enzyme preincubate 45 minutes.

Use is used for the nonlinear regression curve fitting of S shape dose response (variable slope) and uses (San Diego, California, the IC50 of each chemical compound of dose response curve mensuration of 10 points that USA) produce by GraphPad Prism software Version 4.

Using the activatory map kinase 2/ERK2 (catalog number (Cat.No.) 14-550) that is obtained by Upstate to set up external map kinase measures.Carry out reading with the TR-FRET detection technique.

Measure buffer and in 384 hole forms, contain 50mM Tris pH 7.5,10mM MgCl2,1mM DTT, 0.01% polysorbas20, the activatory ERK2 of 1nM, 100 μ M ATP and 500nM long-chain biotin-peptide substrates (LCB-FFKNIVTPRTPPP).After 90 minutes; (phosphoric acid of 2nM Eu-labelling-serine/threonine antibody (catalog number (Cat.No.) AD0176-Perkin Elmer) stops kinase reaction, adds 20nM SA-APC (catalog number (Cat.No.) CR130-100-Perkin Elmer) to detect mixture with 10mM EDTA and Lance.Reading TR-FRET signal (under 340nm, exciting emission under 615nm and 665nm) time delay with 50 μ s in the Victor3V exometer.Read-around ratio with under 665nm and the 615nm is calculated data.The final concentration of DMSO is 2.5% in this mensuration.Existing under the situation of test compound, under 10 μ M concentration, chemical compound is screened enzyme preincubate 45 minutes.

Use recombined human activated b RAF (V599E) kinases (catalog number (Cat.No.) 14-557) and the dead MEK1 of kinases (K97R) (catalog number (Cat.No.) 14-737) that obtain by Upstate that the radioactivity filter is combined bioassay standardization.With 50mM Tris pH 7.5; 10mM MgCl2,1mM DTT, 100mM sucrose; The former sodium vanadate of 100 μ M, the final mensuration buffer conditions of 5 μ M ATP and 2 μ Ci [γ 32P] ATP and the dead substrate of 500mg MEK1 kinases is measured P32 the mixing in MEK1 (K97R) of BRAF (V599E).After 120 minutes, stop enzyme reaction with 8N HCl (hydrochloric acid) and 1mM ATP.The solution point sample to P81 filter paper, with 0.75% orthophosphoric acid washing 4 times, is used washing with acetone at last.In Micro-beta Trilux scintillation counter, exsiccant P81 filter paper is carried out reading.The final concentration of DMSO is 1% in this mensuration.Existing under the situation of test compound, under 10 μ M concentration, chemical compound is screened enzyme preincubate 45 minutes.

At Han; People such as Shulin, among Bioorganic MediCinal Chemistry Letters (2005) 15, the 5467-5473 with people such as Yeh; Clin Cancer Res (2007) 13 (5) has carried out sufficient detailed description to above-mentioned these mensuration among the 1576-1583.

The cell survival of in 96 orifice plate forms, setting up the A375 cell with XTT is measured.

XTT is a kind of xanchromatic tetrazolium

salt; Its mitochondrion by the metabolic activity cell is cracked into this operation of a kind of orange first

and makes and can in microtitration plate, measure rapidly, provides the result of reproducible sensitivity.

The A375 cell is grown in the DMEM culture medium that contains 10% FBS and 1mM Sodium Pyruvate.Cell is used trypsin treatment, inoculate with 1000 cells/well.After cell adhesion was spent the night, Xiang Kongzhong added chemical compound with following final concentration: 10,3,1,0.3,0.1,0.03,0.01,0.001 and 0.0001 μ M.For each concentration, measure in triplicate.DMSO concentration is maintained at 0.5%/hole.After adding chemical compound three days, carry out XTT and measure.With the hole once with the PBS washing.In each hole, add the DMEM culture medium that 100 μ L do not have phenol red or FBS.Prepare the XTT working solution (storing solution concentration is 0.383mg/ml) that every 5ml contains 1mg/ml XTT and 100 μ L PMS.In each hole, add this XTT working solution of 50 μ L.Under 465nm, read the absorbance of plate with Spectramax190 (Molecular Devices).To there be the absorbance of the hole acquisition of cell to deduct this blank by only having culture medium and XTT as blank and from the foraminous reading of institute.

Only deriving from the deducting under the situation of barren value as 100% existence of the hole of handling, calculate viability percentage ratio with DMSO.Calculate the GI50 value with Graphpad Prism, the nonlinear regression curve fitting that is used for S shape dose response (variable slope).

People such as Scudiero, Cancer Research (1988) 48,4827-4833; People such as Weislow, J.Natl.Cancer Institute is among (1989) 81, the 577-586; With people such as Roehm, the pair cell viability is measured among J.Immunol.Methods [1991] 142:257-265 has further description.

Disease or disease that chemical compound of the present invention can be used for prevention and treatment and MEK hyperkinesia (hyperactivity) diseases associated or disease and regulated by the Raf/Ras/Mek path.

Therefore; As another aspect; The present invention relates to treat the disease of regulating with MEK hyperkinesia diseases associated or disease or by the MEK cascade or the method for disease, it comprises formula (I) or chemical compound (Id) or its pharmaceutically acceptable salt of using effective therapeutic dose.

As another aspect, the present invention relates to treat proliferative disease such as method for cancer, it comprises formula (I) or chemical compound (Id) or its pharmaceutically acceptable salt of using effective dose.

The instance of cancer includes but not limited to: angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma; Bronchogenic carcinoma; Squamous cell carcinoma; Undifferentiated small cell carcinoma (undifferentiated small cell carcinoma); Do not break up large cell carcinoma (undifferentiated large cell carcinoma); Bronchioloalveolar carcinoma (bronchiolar carcinoma); Bronchial adenoma; Lymphoma; Chondroma property hamartoma (chondromatous hanlartoma); Mesothelioma (inesothelioma); Esophageal squamous cell carcinoma; Leiomyosarcoma; Leiomyosarcoma; Duct adenocarcinoma (ductal adenocarcinoma); Insulinoma; Glucagonoma; Gastrinoma; Vasoactive intestinal peptide tumor; Harmonization of the stomach enteric carcinoid tumor; Adenocarcinoma; Kaposi sarcoma; Leiomyoma; Hemangioma; Lipoma; Neurofibroma; Fibroma; Canalicular adenoma; Villous adenoma (villous adenoma); Hamartoma; Wilms' tumor [nephroblastoma; Leukemia; Bladder and urethra squamous cell carcinoma; Transitional cell carcinoma; Adenocarcinoma; Spermocytoma; Teratoma; Embryonal carcinoma; Teratocareinoma; Choriocarcinoma; The Interstitial cell cancer; Fibroadenoma; Adenomatoid tumor; Hepatoma (hepatocarcinoma); Cancer of biliary duct; Hepatoblastoma; Adenoma; Hemangioma; Osteogenic sarcoma (osteosarcoma); Malignant fibrohistiocytoma; Chondrosarcoma; Ewing sarcoma; Malignant lymphoma (reticulosarcoma); Multiple myeloma; Pernicious giant cell tumor chordoma; Osteochondroma (osteochronfroma) (osteocartilaginous exostosis); Optimum chondroma; Chondroblastoma; Chondromyxoid fibroma (chondromyxofibroma); Osteoid osteoma and giant cell tumor; Osteoma; Granuloma; Xanthoma; Osteitis deformans; Meningioma; Meningiosarcoma; Neurogliosis; Astrocytoma; Medulloblastoma; Glioma; Ependymoma; Germinoma [pinealoma]; Glioblastoma multiforme; Mesoglioma; Schwannoma; Retinoblastoma; Congenital tumor (congenital tumor); The spinal nerves fibroma; Meningioma; Glioma; Carcinoma of endometrium; Cervical cancer; Cervical atypical hyperplasia (pre-tumor cervical dysplasia) before the tumor; Ovarian cancer; The serosity adenocarcinoma cystic; The mucus adenocarcinoma cystic; Granulosa cell tumor; Sai-Lai glucagonoma; Dysgerminoma; Malignant teratoma; Intraepithelial carcinoma; Adenocarcinoma; Melanoma); Vaginal clear cell carcinoma; Fructus Vitis viniferae bunch shape sarcoma (embryonal rhabdomyosarcoma); Carcinoma of fallopian tube (fallopian tube carcinoma); Acute and chronic myelogenous leukemia; Acute lymphoblastic leukemia (acute lymphoblastic leukemia); Chronic lymphocytic leukemia (chronic lymphocytic leukemia); Myeloproliferative disease; Multiple myeloma; Myelodysplastic syndrome; Hodgkin; Non-Hodgkin lymphoma; Malignant lymphoma; Malignant melanoma; Basal cell carcinoma; Nevus; Dysplastic nevus; Hemangioma; Dermatofibroma; Keloid; Psoriasis and neuroblastoma.

Chemical compound of the present invention also can be used for treating other disease or the disease relevant with the MEK hyperkinesia.Therefore, as another aspect, the present invention relates to treat the method that is selected from following disease: xenograft (cellos), skin, extremity, organ or bone marrow graft) repel; Osteoarthritis; Rheumatoid arthritis; Cystic fibrosis; Diabetic complication (comprising diabetic retinopathy and diabetic nephropathy); Hepatomegaly; Megalocardia; Apoplexy (like acute focus Ischemic Stroke (acute focal ischemic stroke) and GBI); Heart failure; Septic shock; Asthma; Chronic obstructive pulmonary disease; Alzheimer; With chronic or neuropathic pain.

With regard to the object of the invention, term " chronic pain " includes but not limited to the special property sent out pain (idiopathic pain) and the pain relevant with chronic alcoholism, vitamin deficiency, uremia or hypothyroidism.Chronic pain is relevant with multiple situation, and said situation includes but not limited to inflammation and postoperative pain.

Term used herein " neuropathic pain " is relevant with multiple situation, and said situation includes but not limited to that pain (postherpetic pain) after inflammation, postoperative pain, phantom pain, calcination pain, gout, trigeminal neuralgia, acute herpetic pain and the herpes, causalgia, diabetic neuropathy, clump tear the nerve injury between (plexus avulsion), neuroma, vasculitis, viral infection, crush injury, repressive damage, tissue injury, amputation and peripheral nervous system and the central nervous system.

Chemical compound of the present invention also can be used as antiviral agent be used to treat viral infection such as HIV, hepatitis B virus (HBV), human papillomavirus (HPV), cytomegalovirus (CMV] and epstein-barr virus (EBV).

Chemical compound of the present invention also can be used for treating restenosis, psoriasis, contact dermatitis, autoimmune disease, atherosclerosis and inflammatory bowel for example crohn and ulcerative colitis.

Mek inhibitor of the present invention can be with another kind of pharmacologically active chemical compounds or with two kinds or more kinds of other pharmacologically active chemical compounds, use especially for the chemical compound combination of treatment cancer.For example; The chemical compound of the defined formula of preceding text (I) or its pharmaceutically acceptable salt can be selected from following combinations of substances with one or more and be used for simultaneously, use in succession or respectively: chemotherapeutics; For example mitotic inhibitor such as taxane, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine; With other anticarcinogen, for example cisplatin, 5-fluorouracil or 5-fluoro-2-4 (1H, 3H)-hybar X (5FU), flutamide or gemcitabine.

Said combination can provide significant advantage in treatment, comprise synergistic activity.

Formula (I) or chemical compound (Id) also can advantageously use with other anti-proliferative compounds combination.Said anti-proliferative compounds includes but not limited to aromatase inhibitor; Antiestrogen; The topoisomerase I inhibitor; The topoisomerase II inhibitor; The microtubule reactive compound; Alkylated compound; Histone deacetylase inhibitor is like LBH589; The chemical compound of inducing cell atomization; Cyclooxygenase-2 inhibitor; The MMP inhibitor; The mTOR inhibitor is like RAD001; The antineoplastic antimetabolite; Platinum compounds; Targeting in/reduce the chemical compound of albumen or the active chemical compound of lipid kinase and other angiogenesis inhibitor; Targeting is in the chemical compound of, reduction or CKIs or lipid phosphatase activity; Gonadorelin agonist (gonadorelin agonist); Antiandrogen; The methionine aminopeptidase inhibitor; Diphosphate; Biological respinse modifier; Antiproliferation antibodies; Heparanase (heparanase) inhibitor; The inhibitor of the carcinogenic isoform of Ras; Telomerase inhibitor; Proteasome inhibitor; Be used to treat the chemical compound of hematology's malignant disease; Targeting in, reduce or suppress the active chemical compound of Flt-3, like PKC412; Hsp90 inhibitor such as 17-AAG (17-allyl amino-geldanamycin; NSC330507), 17-DMAG (17-dimethyl aminoethyl amino-17-demethoxylation-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (deriving from Conforma Therapeutics) and AUY922; Temozolomide (TEMODAL); Kinesin spindle protein inhibitor, as derive from the SB715992 of GlaxoSmithKline or pentamidine/chlorpromazine that SB743921 perhaps derives from CombinatoRx; The PI3K inhibitor is like BEZ235; The RAF inhibitor is like RAF265; EDG bonding agent, leukemia chemical compound, ribonucleotide reductase inhibitor, S adenosylmethionine decarboxylase inhibitor, antiproliferation antibodies or other chemotherapy compound.In addition; As alternative ground perhaps additionally; They can use with other tumor therapeuticing method combination, and said Therapeutic Method comprises that operation, ionizing radiation, photodynamic therapy, implant for example contain the implant of corticosteroid, hormone, and perhaps they can be used as radiosensitizer.In addition, in antiinflammatory and/or antiproliferative treatment, also comprise combination with anti-inflammatory agent.Can also make up with antihistamine drug, bronchodilator, NSAID or chemokine receptor anagonists.

Term used herein " aromatase inhibitor " relates to and suppresses estrogen and generate, be the chemical compound that substrate androstenedione and testosterone transform to estrone and estradiol respectively.This term includes but not limited to steroid; Especially atamestane, exemestane and Formestane; Particularly on-steroidal, especially aminoglutethimide, Rogletimide, (.+-.)-Pyridoglutethimide, trilostane, testolactone, ketoconazole, R 83842, Arensm, Anastrozole and letrozole.Exemestane can be for example with its commercial form, for example with the commercially available administered of trade mark AROMASIN.Formestane can be for example with its commercial form, for example with the commercially available administered of trade mark LENTARON.Arensm can be for example with its commercial form, for example with the commercially available administered of trade mark AFEMA.Anastrozole can be for example with its commercial form, for example with the commercially available administered of trade mark ARIMIDEX.Letrozole can be for example with its commercial form, for example with trade mark FEMARA or the commercially available administered of FEMAR.Aminoglutethimide can be for example with its commercial form, for example with the commercially available administered of trade mark ORIMETEN.The combination of the present invention that is included as the chemotherapeutics of aromatase inhibitor is particularly useful for treating hormone receptor positive tumor, for example mammary neoplasms.

Term used herein " antiestrogen " relates to the chemical compound of antagonism estrogen action on the estrogen receptor level.This term includes but not limited to tamoxifen, fulvestrant, raloxifene and RALOXIFENE HCL.Tamoxifen can be for example with its commercial form, for example with the commercially available administered of trade mark NOLVADEX.RALOXIFENE HCL can be for example with its commercial form, for example with the commercially available administered of trade mark EVISTA.Fulvestrant can be like US 4,659, in 516 disclosed that kind prepare or its can be for example with its commercial form, for example with the commercially available administered of trade mark FASLODEX.The combination of the present invention that is included as the chemotherapeutics of antiestrogen is particularly useful for treating estrogen receptor positive tumors, for example mammary neoplasms.

Term used herein " antiandrogen " relates to any material that can suppress the androgen biological agent, includes but not limited to bicalutamide (CASODEX), and it can be for example like US 4,636, and disclosed that kind is prepared in 505.

Term used herein " gonadorelin agonist " includes but not limited to 1: PN: WO02056903 PAGE: 25 claimed protein, goserelin and acetic acid goserelin.Goserelin is disclosed in US 4,100, in 274, can be for example with its commercial form, for example with the commercially available administered of trade mark ZOLADEX.1: PN: WO02056903 PAGE: 25 claimed protein can be for example like US 5,843, and disclosed that kind is prepared in 901.

Term used herein " topological isomer I inhibitor " includes but not limited to TPT, gefitinib, irinotecan, camptothecine and analog thereof, 9-nitrocamptothecin and macromole camptothecine conjugate PNU-166148 (compd A 1 among the WO 99/17804).Irinotecan can be for example with its commercial form, for example with the commercially available administered of trade mark CAMPTOSAR.TPT can be for example with its commercial form, for example with the commercially available administered of trade mark HYCAMTIN.

Term used herein " topoisomerase II inhibitor " includes but not limited to the anthracene nucleus class; (comprise Liposomal formulation like doxorubicin; CAELYX for example), daunorubicin, epirubicin, idarubicin and Nemorubicin; The mitoxantrone of anthraquinone class and losoxantrone, and the etoposide of podophillotoxines and teniposide.Etoposide can be for example with its commercial form, for example with the commercially available administered of trade mark ETOPOPHOS.Teniposide can be for example with its commercial form, for example with the commercially available administered of trade mark VM 26-BRISTOL.Doxorubicin can be for example with its commercial form, for example with trade mark ADRIBLASTIN or the commercially available administered of ADRIAMYCIN.Epirubicin can be for example with its commercial form, for example with the commercially available administered of trade mark FARMORUBICIN.Idarubicin can be for example with its commercial form, for example with the commercially available administered of trade mark ZAVEDOS.Mitoxantrone can be for example with its commercial form, for example with the commercially available administered of trade mark NOVANTRON.

Term " microtubule reactive compound " relates to microtubule stable compound, microtubule stabilization removal compound and tubulin polymerization inhibitor, includes but not limited to taxanes, for example paclitaxel and docetaxel; Vinca alkaloids, for example vinblastine, especially vinblastine sulfate, vincristine, especially vincristine sulfate and vinorelbine; Wash rice suberite lactone; Colchicine; With Epothilones and derivant thereof, for example epothilone B or D or derivatives thereof.Paclitaxel can be for example with its commercial form, for example with the commercially available administered of TAXOL.Docetaxel can be for example with its commercial form, for example with the commercially available administered of trade mark TAXOTERE.Vinblastine sulfate can be for example with its commercial form, for example with the commercially available administered of trade mark VINBLASTIN R.P..Vincristine sulfate can be for example with its commercial form, for example with the commercially available administered of trade mark FARMISTIN.Wash rice suberite lactone can be for example like US 5,010, and disclosed that kind obtains in 099.Also comprise WO 98/10121, US6,194,181, disclosed epothilone derivate among WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and the WO 00/31247.Especially preferred is Epothilones A and/or B.

Term used herein " alkylated compound " includes but not limited to cyclophosphamide, ifosfamide, melphalan or nitroso ureas (BCNU or Gliadel).Cyclophosphamide can be for example with its commercial form, for example with the commercially available administered of trade mark CYCLOSTIN.Ifosfamide can be for example with its commercial form, for example with the commercially available administered of trade mark HOLOXAN.

Term " histone deacetylase inhibitor " or " hdac inhibitor " relate to the inhibition of histone deacetylase and have the chemical compound of antiproliferative activity.This comprises disclosed LDH589 among chemical compound such as sodium butyrate, the WO 02/22577; Especially N-hydroxyl-3-[4-[[(2-hydroxyethyl) [2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylamide, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl)-ethyl]-amino] methyl] phenyl]-2E-2-acrylamide and pharmaceutically acceptable salt thereof, especially lactate.It also especially comprises Vorinostat (SAHA), MS275, FK228 (FR901228 in the past), Trichostatin A and US 6; 552; Disclosed chemical compound in 065; Particularly N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl)-ethyl]-amino]-methyl] phenyl]-2E-2-acrylamide, or its pharmaceutically acceptable salt.

Term " antineoplastic antimetabolite " includes but not limited to 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylation chemical compound such as 5-azacytidine and decitabine, methotrexate and edatrexate and antifol such as pemetrexed.Capecitabine can be for example with its commercial form, for example with the commercially available administered of trade mark XELODA.Gemcitabine can be for example with its commercial form, for example with the commercially available administered of trade mark GEMZAR.

Term used herein " platinum compounds " includes but not limited to carboplatin, cisplatin, cisplatin and oxaliplatin.Carboplatin can be for example with its commercial form, for example with the commercially available administered of trade mark CARBOPLAT.Oxaliplatin can be for example with its commercial form, for example with the commercially available administered of trade mark ELOXATIN.

Term used herein " targeting in/reduce albumen or the active chemical compound of lipid kinase "; Perhaps " targeting in/reduce the chemical compound of albumen or lipid phosphatase activity "; Perhaps " chemical compound of other angiogenesis inhibitor " includes but not limited to protein tyrosine kinase and/or serine and/or threonine kinase enzyme inhibitor or lipid kinase inhibitors, for example:

A) targeting in, reduce or suppress the active chemical compound of platelet derived growth factor receptor (PDGFR); As targeting in, reduce or suppress the active chemical compound of PDGFR; Especially the chemical compound that suppresses pdgf receptor; For example N-phenyl-2-pyrimidine-amine derivatives, for example imatinib, SU101, SU6668 and GFB-111;

B) targeting in, reduce or be suppressed to the active chemical compound of bfgf receptor (FGFR);

C) targeting in, reduce or suppress the active chemical compound of IGF-1 I (IGF-IR); As targeting in, reduce or suppress the active chemical compound of IGF-IR; Especially the chemical compound that suppresses the kinase activity of IGF-I receptor is like disclosed those chemical compounds among the WO 02/092599; Perhaps targeting is in the antibody of the extracellular domain of IGF-I receptor or its somatomedin;

D) targeting in, reduce or suppress the chemical compound of Trk receptor tyrosine kinase family active; Or liver is joined albumen (ephrin) B4 inhibitor;

E) targeting in, reduce or suppress the chemical compound of Axl receptor tyrosine kinase family active;

F) targeting in, reduce or suppress the chemical compound of Ret receptor tyrosine kinase activity;

G) targeting in, reduce or suppress the Kit/SCFR receptor tyrosine kinase, be C-kit receptor tyrosine kinase-(part of PDGFR family) active chemical compound; As targeting in, reduce or suppress the chemical compound of c-Kit receptor tyrosine kinase family active; Especially the chemical compound that suppresses the c-Kit receptor, for example imatinib;

H) targeting in, reduce or suppress c-Abl family member, their gene-fusion product (for example BCR-Abl kinases) and the active chemical compound of mutant; As targeting in, reduce or suppress the active chemical compound of c-Abl family member and their gene-fusion product; N-phenyl-2-pyrimidine-amine derivatives for example, for example imatinib or Buddhist nun Lip river are for Buddhist nun (AMN107); PD180970; AG957; NSC 680410; Derive from the PD173955 of ParkeDavis; Or Dasatinib (BMS-354825);

I) targeting is in, reduction or CKIs kinase c (PKC) member and serine/threonine kinase Raf family member, MEK, SRC, JAK, FAK, PDK1, PKB/Akt and Ras/MAPK family member and/or the member's of cell cycle protein dependent kinase family (CDK) active chemical compound; Especially US 5; 093; Disclosed those staurosporine derivatives, for example midostaurin in 330; Other examples for compounds comprises for example UCN-01, Safingol, BAY 43-9006, bryostatin 1, perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis3521; LY333531/LY379196; Isoquinoline compound, as among the WO 00/09495 disclosed those; FTI; BEZ235 (a kind of P13K inhibitor) or AT7519 (CDK inhibitor);

J) targeting is in, reduction or the active chemical compound of CKIs tyrosine kinase inhibitor, comprises imatinib mesylate (GLEEVEC) or tyrphostin like targeting in, reduction or the active chemical compound of CKIs tyrosine kinase inhibitor.Tyrphostin is low-molecular-weight (mw＜1500) chemical compound preferably; Or its pharmaceutically acceptable salt; Especially be selected from the chemical compound of benzal Cyanoacetyl-Cyacetazid class or S-aryl phenylpropyl alcohol dintrile or Double bottom thing quinolines, more particularly be selected from following any compound: Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{ [(2, the 5-dihydroxy phenyl) methyl] amino }-the benzoic acid adamantane esters; NSC680410, adaphostin);

K) targeting in, reduce or suppress epidermal growth factor family (EGFR, ErbB2, ErbB3, the ErbB4 of receptor tyrosine kinase; For all-or the form of assorted-dimer) or their the active chemical compound of mutant; As targeting in, reduce or suppress the active chemical compound of Epidermal Growth Factor Receptor Family especially suppress EGF receptor tyrosine kinase family member for example EGF receptor, ErbB2, ErbB3 and ErbB4 or with EGF or the bonded chemical compound of EGF dependency part, protein or antibody; Those disclosed chemical compound, protein or monoclonal antibody: WO 97/02266 in following document prevailingly and particularly particularly; The chemical compound of embodiment 39 for example; Perhaps EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5; 747; 498, WO 98/10767, WO 97/30034, WO97/49688, WO 97/38983, and especially WO 96/30347 (chemical compound that for example is called as CP358774), WO 96/33980 (for example chemical compound ZD 1839) and WO 95/03283 (for example chemical compound ZM105180); Disclosed 7H-pyrrolo-[2,3-d] pyrimidine derivatives among trastuzumab (Herceptin), Cetuximab (Erbitux), Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and the WO 03/013541 for example; With

L) targeting in, reduce or suppress the chemical compound of c-Met receptor active; As targeting in, reduce or suppress the active chemical compound of c-Met; Especially the chemical compound that suppresses the kinase activity of c-Met receptor, perhaps targeting in the extracellular domain of c-Met or with the bonded antibody of HGF.

The chemical compound of other angiogenesis inhibitor comprise have other activity mechanism, for example with the chemical compound of the irrelevant mechanism of albumen or lipid kinase inhibitory action, for example Thalidomide (THALOMID) and TNP-470.

Targeting has the for example inhibitor of phosphatase 1, phosphatase 2A or CDC25, for example okadaic acid or derivatives thereof in the chemical compound of, reduction or CKIs or lipid phosphatase activity.

The chemical compound of inducing cell atomization has for example tretinoin or tocopherol or tocotrienol.

Term used herein " cyclooxygenase-2 inhibitor " includes but not limited to for example Cox-2 inhibitor, 5-alkyl substituted 2-arylamino phenylacetic acid and derivant thereof, like celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or 5-alkyl-2-arylamino phenylacetic acid 5-methyl-2-(2 '-chloro-6 '-fluoroanilino) phenylacetic acid, Lu Mikao former times for example.

Term used herein " diphosphate " includes but not limited to etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic Acid, ibandronic acid, risedronic acid and zoledronic acid." etidronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark DIDRONEL." clodronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark BONEFOS." tiludronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark SKELID." pamidronic acid " can be for example with its commercial form, for example with trade mark AREDIA ^TMCommercially available administered." alendronic Acid " can be for example with its commercial form, for example with the commercially available administered of trade mark FOSAMAX." ibandronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark BONDRANAT." risedronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark ACTONEL." zoledronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark ZOMETA.

Term " mTOR inhibitor " relates to mammal target (mTOR) that suppresses rapamycin and the chemical compound with antiproliferative activity, like sirolimus (Rapamune), everolimus

CCI-779 and ABT578.

Term used herein " heparanase inhibitors " be meant targeting in, reduce or suppress the chemical compound of heparin sulfate degraded.This term includes but not limited to PI-88.

Term used herein " biological respinse modifier " is meant lymphokine or interferon, for example interferon.

Term used herein " the carcinogenic isoform inhibitor of Ras " (for example H-Ras, K-Ras or N-Ras) be meant targeting in, reduce or suppress the chemical compound of the carcinogenic activity of Ras; For example " farnesyl transferase inhibitor ", for example L-744832, DK8G557 or R115777 (Zarnestra).

Term used herein " telomerase inhibitor " be meant targeting in, reduce or suppress the chemical compound of telomerase activation.Targeting in, reduce or the chemical compound that suppresses telomerase activation especially suppresses the chemical compound of telomerase receptor, for example telomere chalone.

Term used herein " methionine aminopeptidase inhibitor " be meant targeting in, reduce or suppress the active chemical compound of methionine aminopeptidase.Targeting in, reduce or suppress the active chemical compound of methionine aminopeptidase and have for example than Ge Maide (bengamide) or derivatives thereof.

Term used herein " proteasome inhibitor " is meant that targeting is in, reduction or the active chemical compound of CKIs enzyme body.Targeting comprises for example bortezomib (Velcade) and MLN 341 in, reduction or the active chemical compound of CKIs enzyme body.

Term used herein " NMPI " or (" MMP inhibitor ") include but not limited to that collagen intends peptide and non-plan inhibitor peptides, tetracycline derivant, but for example hydroxamic acid is intended analog Marimastat (BB-2516), prinomastat (AG3340), Mei Tasita (metastat) (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or the AAJ996 of inhibitor peptides batimastat and its oral biological utilisation.

Term used herein " is used to treat the chemical compound of hematology's malignant disease " and includes but not limited to FMS-appearance tyrosine kinase inhibitor, for example targeting in, reduce or suppress the active chemical compound of FMS-appearance tyrosine kinase receptor (Flt-3R); Interferon, 1-b-D-arabinofuranosyl base cytosine (ara-c) and bisulfan; With the ALK inhibitor, for example targeting in, reduce or suppress the chemical compound of anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase.

Targeting in, reduce or suppress chemical compound, protein or the antibody that the active chemical compound of FMS-appearance tyrosine kinase receptor (Flt-3R) especially suppresses Flt-3R receptor kinase family member, for example PKC412, TKI258, midostaurin, staurosporine derivatives, SU11248 and MLN518.

Term used herein " HSP90 inhibitor " include but not limited to targeting in, reduce or suppress the chemical compound of the endogenous atpase activity of HSP90; Via ubiquitin proteasome pathway degraded, targeting in, reduce or suppress the chemical compound of HSP90 client's albumen (client protein).Targeting in, reduce or the chemical compound that suppresses the endogenous atpase activity of HSP90 especially suppresses chemical compound, protein or the antibody of the atpase activity of HSP90; 17-allyl amino for example, 17-de-methoxy geldanamycin (17AAG)-geldanamycin derivant; The chemical compound that other is relevant with geldanamycin, and radicicol.

Term used herein " anti proliferative antibody " includes but not limited to that trastuzumab (Herceptin), trastuzumab-DM1, Erbitux, shellfish cut down pearl monoclonal antibody (Avastin), Rituximab (Rituxanr), PRO64553 (anti-CD 40) and 2C4 antibody.Multi-specificity antibody and antibody fragment that " antibody " means for example complete monoclonal antibody, polyclonal antibody, formed by at least 2 complete antibodies are as long as they show required BA.

For the treatment of acute myeloid leukaemia (AML), formula (I) chemical compound can use with the combination of standard white disorders of blood therapy, especially with the therapy combination use that is used to treat AML.Especially; Formula (I) chemical compound can be used with the drug regimen that for example farnesyl transferase inhibitor and/or other can be used for treating AML, for example daunorubicin, amycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC412.

Term " antileukemie chemical compound " comprises for example Ara-C-pyrimidine analogue, and it is 2-Alpha-hydroxy ribose (galactoside) derivant of deoxycytidine.Also comprise hypoxanthic purine analogue, Ismipur (6-MP) and fludarabine phosphate.

The somatostatin receptor antagonist used herein be meant targeting in, reduce or suppress chemical compound such as the octreotide and the SOM230 (SOM230) of the somatostatin receptor.

The method of infringement tumor cell for example is meant methods such as ionizing radiation.The term of being mentioned in the context " ionizing radiation " means the ionizing radiation that occurs with electromagnetic radiation (like X-ray and gamma-rays) or particle (like α and beta-particle) form.Ionizing radiation provides in X-ray therapy, but is not limited thereto, and is known in the art.Referring to Hellman, Principles of Radiation Therapy, Cancer, Principles and Practice of Oncology, people such as Devita edit, and the 4th edition, the 1st volume, 248-275 page or leaf (1993).

Term used herein " EDG bonding agent " is meant one type of immunosuppressant of regulating the lymphocyte recirculation, like FTY720.

Term " ribonucleotide reductase inhibitor " is meant pyrimidine or purine nucleoside analogs, includes but not limited to fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, Ismipur (especially being used to resist ALL with the ara-C combination) and/or pentostatin.Ribonucleotide reductase inhibitor is hydroxyurea or 2-hydroxyl-1H-iso-indoles-1 especially, and the 3-derovatives is like people such as Nandy; Acta Oncologica; The 33rd volume, the 8th phase, the PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or the PL-8 that mention in the 953-961 page or leaf (1994).

Term used herein " S adenosylmethionine decarboxylase inhibitor " includes but not limited to US5, disclosed chemical compound in 461,076.

The monoclonal antibody that also comprises disclosed those chemical compounds, protein or VEGF among the WO98/35958 particularly; 1-(4-chloroanilino)-4-(4-pyridylmethyl) phthalazines or its pharmaceutically acceptable salt for example; For example succinate, perhaps those disclosed among WO00/09495, WO00/27820, WO00/59509, WO98/11223, WO00/27819 and the EP0 769 947; Described in the following document those: people such as Prewett, Cancer Res, the 59th volume, 5209-5218 page or leaf (1999); People such as Yuan, Proc Natl Acad Sci U S A, the 93rd volume, 14765-14770 page or leaf (1996); People such as Zhu, Cancer Res, the 58th volume, 3209-3214 page or leaf (1998); With people such as Mordenti, Toxicol Pathol, the 27th volume, the 1st phase, 14-21 page or leaf (1999); WO00/37502 and WO94/10202; People such as O ' Reilly, Cell, the 79th volume, the ANGIOSTATIN described in the 315-328 page or leaf (1994); People such as O ' Reilly, Cell, the 88th volume, the ENDOSTATIN described in the 277-285 page or leaf (1997); The ortho-aminobenzoic acid amide; ZD4190; ZD6474; SU5416; SU6668; Shellfish is cut down the pearl monoclonal antibody; Or anti-VEGF antibodies or anti-VEGF receptor antibody, for example rhuMAb and RHUFab, VEGF is fit Macugon for example; FLT-4 inhibitor, FLT-3 inhibitor, VEGFR-2 IgG1 antibody, Angiozyme (RPI 4610) and shellfish are cut down pearl monoclonal antibody (Avastin).

" photodynamic therapy " used herein is meant that the chemical substance that adopts some to be called as light-sensitive compound is treated or the therapy of prophylaxis of cancer.The instance of photodynamic therapy comprises the treatment of carrying out with for example chemical compound such as VISUDYNE and porfimer sodium.

The steroid of inhibition blood vessel used herein is meant blocking-up or suppresses the chemical compound of angiogenesis, for example anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, deoxidation cortisone, 17 α-hydroxyprogesterone, corticosterone, desoxycortone, testosterone, estrone and dexamethasone.

The implant that contains corticosteroid is meant for example chemical compound such as fluocinolone acetonide, dexamethasone.

" other chemotherapy compound " includes but not limited to plant alkaloid, hormonal compounds and antagonist; Biological respinse modifier, preferred lymphokine or interferon; Antisense oligonucleotide or oligonucleotide derivative; ShRNA or siRNA; Or mixed compounds (miscellaneous compounds) or have other mechanism of action or chemical compound that the mechanism of action is unknown.

The structure of the reactive compound that is identified through Code Number, common name or trade name can for example obtain the Patents International (for example IMS World Publications) from the current edition of standard directories " Merck index (The Merck Index) " or from the data base.

In the disclosure thing quoting of list of references all should not be construed as and admit that the list of references of being quoted is with the prior art that patentability of the present invention is had negative influence.

Chemical compound of the present invention can also be used for while, difference or sequential application with one or more other suitable activity agent combinations, and said other suitable activity agent is selected from: anti-IL-1 material, for example: Antril (Synergen); The material of antibacterial agent and antibacterial agent receptor, for example anti-IL-6 R Ab, anti-IL-15Ab, anti-IL-17Ab, anti-IL-12Ab; B-cell and T-cell are regulated medicine, for example anti-CD20Ab; CTL4-Ig, the rheumatism (DMARD) that palliates a disease, for example methotrexate, leflunomide (leflunamide), sulfasalazine; Gold salt, penicillamine, oxychloroquine and chloroquine, azathioprine, glucocorticoid and NSAID (NSAID); For example cyclooxygenase-2 inhibitor, selective COX-2-inhibitor 2, regulate the material of immunocyte migration; For example chemokine receptor anagonists, adhesion molecule regulator, the for example inhibitor of LFA-1, VLA-4.

The invention still further relates to the chemical compound that comprises formula I or Id or the pharmaceutical composition of its prodrug and pharmaceutically acceptable excipient.

In another one embodiment of the present invention, said prodrug is selected from the group that comprises ester and hydrate.

Term " prodrug " also comprises any covalently bound carrier that when said prodrug is applied to mammalian subject, discharges reactive compound of the present invention in vivo.Can be through modifying the prodrug for preparing chemical compound of the present invention to the functional group that exists in the chemical compound of the present invention with conventional treatment cracking or the mode that is cracked into parent compound of the present invention in vivo with the modification carried out.

In another one embodiment of the present invention, said excipient is selected from the group that comprises binding agent, antiplastering aid, disintegrating agent, filler, diluent, correctives, coloring agent, fluidizer, lubricant, antiseptic, adsorbent and sweeting agent or its combination.

In another one embodiment of the present invention, compositions is formulated into the various dosage forms that are selected from the group that comprises following dosage form: tablet, dragee (troches), lozenge (lozenges), aqueous or oiliness suspensoid, ointment, patch, gel, lotion, dentifrice (dentifrice), capsule, Emulsion, ointment, spray, drop, dispersible powder or granule, be arranged in Emulsion, syrup and the elixir of hard or Perle.

The dosage of used activating agent of the present invention will change according to the concrete disease of for example being treated, required effect and method of application certainly during embodiment of the present invention.Generally speaking, be used for Orally administered suitable daily dose in 0.1 to 10mg/kg rank.

Non-limiting example through following further specifies the present invention, has wherein used following abbreviation:

TEA: triethylamine

DPPA: azido diphenyl phosphate

LDA: lithium diisopropylamine

EDCI:1-ethyl-3-(3 '-dimethylaminopropyl) carbodiimide

The DMAP:4-dimethyl aminopyridine

The HOBt:1-hydroxybenzotriazole

Selectfluor:1-chloromethyl-4-fluoro-1,4-phenodiazine

bicyclo-[2.2.2] octane two (tetrafluoroborate)

Dai Si-Martin crosses iodine alkane (Dess-martin periodinane): 1,1, and 1-triacetyl Oxy-1,1-dihydro-1,2-benzo ioda oxole (benziodoxol)-3 (1H)-ketone

DCM: dichloromethane

THF: oxolane

DMF: dimethyl formamide

DIBAL-H: diisobutylaluminium hydride

EtOH: ethanol

EtOAc: ethyl acetate

Trifluoromethanesulfanhydride anhydride: Trifluoromethanesulfonic anhydride;

DCM: dichloromethane;

Pd (OAc) 2: acid chloride;

Cs ₂CO ₃: cesium carbonate;

BINAP:2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene;

LiOH: Lithium hydrate;

EDCI:1-ethyl-3-(3 '-dimethylaminopropyl) carbodiimide;

RT: room temperature;

TLC: thin layer chromatography,

The NCS:N-chloro-succinimide,

NBS:N-bromine succinamide,

NIS:N-iodine butanimide,

LiHMDS: (TMS) Lithamide.,

LDA: lithium diisopropylamine,

NaHMDS: two (TMS) Sodamide.,

KHMDS: two (TMS) potassamide,

ByBOP: hexafluorophosphoric acid BTA-1-base-oxygen base tripyrrole alkane subbase

TMS: TMS,

MgCl ₂: magnesium chloride,

TBTU: fluoboric acid O-(BTA-1-yl)-N; N; N ', N '-tetramethylurea

NMR: nuclear magnetic resonance, NMR,

DMSO-d6: the deuterate dimethyl sulfoxide,

CDCl ₃: the deuterate chloroform,

LC-MS: liquid chromatography-mass spectrography,

HPLC: HPLC or HPLC.

The embodiment that is provided in this description only is that present invention is described, therefore should they be construed to limitation of the scope of the invention.

Embodiment 1.

Step 1.

The chemical compound of step I & II can be used J.Org.Chem., the preparation of describing in 1995,60,2912 and Tetrahedron, 2002,58,2821 of disclosed method.

5-methoxyl group-3,4-dihydro-2 h-pyrrole synthetic

Under nitrogen atmosphere, (85g 1mol) goes through and was added drop-wise to the DMS that is stirring in 2 hours (126g is 1mol) in the solution with pyrrolidin-2-one.Reactant mixture was stirred 16 hours down at 60 ℃.With reactant mixture be poured into ice with the unsaturated carbonate potassium solution on, with extracted with diethyl ether (2 * 500ml), use brine wash, the drying (anhydrous sodium sulfate).Organic extract is removed in decompression under 20 ℃, obtains 73g 5-methoxyl group-3, and 4-dihydro-2 h-pyrrole bullion is weak yellow liquid.This chemical compound promptly is used for next step without being further purified.The NMR spectrum of title compound conforms to theory.

¹H?NMR(CDCl ₃，300MHZ)：δ3.80(s，3H)，3.66(t，2H)，2.48(t，2H)，2.08-1.95(m，2H)。

Step 2.

7-hydroxyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

At room temperature, triethylamine is joined 5-methoxyl group-3, (73g, 0.73mmol) (200g is in mixture 0.99mmol) with 3-ketoglutaric acid diethylester for the 4-dihydro-2 h-pyrrole.With gained solution stirring 5 days, afterwards reactant mixture is filtered, obtain 39g (yield 24%) 7-hydroxyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate is white solid.The NMR spectrum of title compound conforms to theory.

¹H?NMR(CDCl ₃，300MHZ)：δ11.4(s，1H)，5.80(s，1H)，4.40(q，2H)，4.15(t，2H)，3.50(t，2H)，2.3-2.15(m，2H)，1.40(t，3H)。

Step 3.

5-oxo-7-trifyl Oxy-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

With the 7-hydroxyl-5-oxo-1,2,3 that is stirring, 5-tetrahydrochysene-indolizine-8-Ethyl formate (60mg, 0.2mmol) and triethylamine (30mg, 0.4mmol) solution in the 5ml dichloromethane is cooled to-78 ℃.Then, (91mg 0.32mmol), stirs the gained reactant mixture 12 hours down in TLC monitoring (100%EtOAc) at ambient temperature to go through 20 minutes dropping trifluoromethanesulfanhydride anhydrides.Reactant mixture is washed with sodium bicarbonate aqueous solution (4ml) and water (4ml).Organic layer is used anhydrous Na ₂SO ₄Drying concentrates, and products therefrom with silica gel column chromatography (60-120 order) purification, as eluant, is obtained 40mg (yield 48%) title compound with the hexane solution of 15% ethyl acetate.

LC-MS purity: 95%, m/z 356 (M+1).

¹H?NMR(CDCl ₃，300MHZ)：δ6.15(s，1H)，4.40(q，2H)，4.20(t，2H)，3.58(t，2H)，2.32-2.2(m，2H)，1.40(t，3H)。

Step 4.

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

With the 5-oxo that is stirring-7-trifyl Oxy-1,2,3; 5-tetrahydrochysene-indolizine-8-Ethyl formate (2.3g, 6.4mmol), 2-fluoro-4-bromo-aniline (1.25g, 6.5mmol), cesium carbonate (3.17g; 9.7mmol), BINAP (0.6g, 0.97mmol) and Pd (OAc) ₂(0.15g, 0.64mmol) suspension in toluene (100ml) heated 16 hours down at 80 ℃.With TLC (9: 1 CHCl ₃-MeOH v/v) monitoring reaction.Reactant mixture with ethyl acetate (60ml) dilution, is filtered.With filtrate water (100ml) washing, water layer is stripped with ethyl acetate (30ml).With the dry (anhydrous Na of the organic extract that merges ₂SO ₄), concentrate, bullion with silica gel column chromatography (60-120 order) purification, with the chloroformic solution eluting of 0.1-0.5% MeOH, is obtained the title compound of 336mg (yield 13%).

LC-MS purity: 98%, m/z 395,397 (M+, Br pattern).

¹H?NMR(DMSO-D ₆，300MHZ)：δ9.48(s，1H)，7.70(d，1H)，7.49-7.39(m，2H)，5.32(s，1H)，4.30(q，2H)，3.95(t，2H)，3.48(t，2H)，2.14-2.0(m，2H)，1.30(t，3H)。

Embodiment 2.

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

To 7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3, (280mg, 0.71mmol) at THF: (4: 1, v/v added 1N LiOH aqueous solution (2ml) to MeOH to 5-tetrahydrochysene-indolizine-8-Ethyl formate in the solution in 6ml).At TLC monitoring (CHCl ₃-MeOH, 8: 2) under, the gained mixture was at room temperature stirred 3 hours.With the 10%HCl aqueous solution pH of reactant mixture is transferred to 1, the gained deposition is leached, water (20ml) washs with ethyl acetate (10ml), obtains the title compound of 240mg (yield 92%).

LC-MS purity: 96%, m/z 367,369 (M+, Br pattern).

¹H?NMR(DMSO-D ₆，300MHZ)：δ13.40(s，1H)，9.90(s，1H)7.70(d，1H)，7.45(s，2H)，5.35(s，1H)，3.95(t，2H)，3.49(t，2H)，2.15-2.0(m，2H)。

Embodiment 3.

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclopropyl-methoxyl group-amide synthetic

To the 7-that is stirring (4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (140mg, 0.38mmol) add in the solution in the dry DMF of 10ml EDCI (220mg, 1.14mmol) and HOBt (160mg, 1.14mmol).Reactant mixture was stirred 30 minutes, and (141mg is 1.14mmol) with TEA (232mg, 1.14mmol) processing to use O-cyclopropyl methyl hydroxylamine then.At TLC monitoring (MeOH-CHCl ₃2: 8, v/v) under, the gained reactant mixture was stirred 16 hours.Reactant mixture with ethyl acetate (20ml) dilution, is used saturated NH ₄Cl aqueous solution (25ml), saturated NaHCO ₃Aqueous solution (25ml) and saline (25ml) washing.With the dry (anhydrous Na of the organic extract that merges ₂SO ₄), concentrate.With residue with the silica gel column chromatography (CHCl of 1%MeOH ₃Solution) purification, the yield with 36% obtains title compound.

LC-MS purity: 97%, m/z 436,438 (M+, Br pattern).

¹H?NMR(DMSO-D ₆，300MHZ)：δ11.20(s，1H)，8.25(s，1H)，7.65(d，1H)，7.45-7.3(m，2H)，5.38(s，1H)，3.91(t，2H)，3.72(d，2H)，3.25(t，2H)，2.15-2.0(m，2H)，1.18-1.02(m，1H)，0.6-0.5(m，2H)，0.31-0.25(m，2H)。

Embodiment 4.

7-(4-bromine 2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene indolizine 8-formic acid methoxyamide synthetic

Use the condition identical with embodiment 3, make 7-(4-bromine 2-fluoro-phenyl amino)-5-oxo-1,2,3, (0.2g, 0.544mmol) (136mg 1.63mmol) reacts 5-tetrahydrochysene indolizine 8-formic acid, obtains the bullion product with methoxy-amine hydrochloride.With the silica gel column chromatography (CHCl of 4% methanol ₃Solution), then use the preparation HPLC purified product, the yield with 16% obtains title compound.

LC-MS purity: 99.27%, m/z=396,398.9, (M ⁺The Br pattern).

H ¹?NMR：(DMSO-D ₆300MHZ)：11.4(s，1H)，8.4(s，1H)，7.7-7.6(m，1H)，7.5-7.3(m，2H)，7.223(t，1H)，5.3(s，1H)，3.9(t，2H)，3.3-3.1(m，4H)，3.0(s，3H)，2.1(t，2H)。

Embodiment 5.

7-(4-bromine 2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene indolizine 8-Methanamide synthetic

Use the condition identical with embodiment 3, with 7-(4-bromine 2-fluoro-phenyl amino)-5-oxo-1,2,3, (0.2g 0.544mmol) changes into title compound to 5-tetrahydrochysene indolizine 8-formic acid with ammonium chloride and triethylamine.With the silica gel column chromatography (CHCl of 5% methanol ₃Solution) behind the purification, the yield with 30% obtains this test compound, is white solid.

LC-MS purity: 98.74%, m/z=366,368, (M ⁺The Br pattern)

H ¹?NMR：(DMSO-D ₆300MHZ)：9.0(s，1H)，7.7-7.6(m，2H)，7.4(t，2H)，5.3(s，1H)，3.9(t，2H)，3.2-3.1(m，2H)，3.0(s，3H)，2.1(t，2H)

Embodiment 6.

7-(4-bromine 2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene indolizine 8-formic acid ethyoxyl amide synthetic

Use the condition identical with embodiment 3, with 7-(4-bromine 2-fluoro-phenyl amino)-5-oxo-1,2,3, (0.2g 0.54mmol) changes into title compound to 5-tetrahydrochysene indolizine 8-formic acid with the hydrochloric acid amine ethoxylate.With the silica gel column chromatography (CHCl of 5% methanol ₃Solution), then use the preparation HPLC purified product, the yield with 28% obtains test compound, is white solid.

LC-MS purity: 99.27%, m/z=410,412, (M ⁺The Br pattern).

H ¹?NMR：(DMSO-D ₆300MHZ)：11.4(s，1H)，8.3(s，1H)，7.7-7.5(m，1H)，7.5-7.3(m，2H)，5.3(s，1H)，4.0-3.8(m，4H)，3.4-3.2(m，2H)，2.1(t，2H)，1.2(t，3H)。

Embodiment 7.

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formaldehyde synthetic

Under-78 ℃; Go through 7-(4-bromo-2-fluoro-the phenyl amino)-5-oxo-1 of 5 fens clockwise under nitrogen; 2; 3, (0.1g 0.25mmol) drips 0.76ml (0.76mmol) DIBAH-H (diethyl ether solution of 1.0M) to 5-tetrahydrochysene-indolizine-8-formic acid methoxy amide in the solution in the 5ml dry THF.Reactant mixture was stirred 4 hours down at 78 ℃, with saturated aqueous ammonium chloride (10ml) cancellation.Reactant mixture is used ethyl acetate extraction, and with the organic extract water and the brine wash that merge, dry (anhydrous sodium sulfate) then concentrates.With the silica gel column chromatography (CH of 2% methanol ₂Cl ₂Solution) behind the purification, the yield with 41% obtains title compound.

LC-MS purity: 90%, m/z=350, (M+2Br pattern)

HPLC：92％

H ¹?NMR：(DMSO-D ₆，300MHZ)：δ10.0(s，1H)，9.56(s，1H)，7.54(d，1H)，7.50(s，2H)，5.35(s，1H)，4.0(t，2H)，3.55(t，2H)，2.4-2.2(m，2H)。

Embodiment 8.

Step 1.

7-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

To 7-hydroxyl-5-oxo-1,2,3, (500mg is 2.2mmol) at POCl for 5-tetrahydrochysene-indolizine-8-Ethyl formate ₃(2g, (0.226g 2.2mmol), stirs reactant mixture 14 hours to add TEA in the suspension in 13.4mmol).Reactant is poured in the frozen water and uses K ₂CO ₃Aqueous solution transfers to 7 with the pH of mixture.Reactant mixture is extracted with EtOAc, with the dry (anhydrous Na of the organic extract that merges ₂SO ₄), concentrate.In that (1: 1 EtOAc-hexane, v/v) behind the purification, the yield with 74% obtains title compound with silica gel column chromatography.

LC-MS purity: 100%, m/z=242, (M+)

¹H?NMR(CDCl ₃，300MHZ)：6.60(s，1H)，4.40(q，2H)，4.12(t，2H)，3.50(t，2H)，2.32-2.19(m，2H)，1.40(t，3H)。

Step 2.

7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

With 7-chloro-5-oxo-1,2,3, and 5-tetrahydrochysene-indolizine-8-Ethyl formate (14.5g, 0.06mol) and 1-(chloromethyl)-4-fluoro-1, the 4-phenodiazine

(44.7g is 0.13mol) at 700ml CH for bicyclo-[2.2.2] octane-two (tetrafluoroborates) ₃Mixture among the CN under agitation heated 5-10 minute down at 80 ℃; Remove thermal source then.Volatile component is removed in decompression, and residue is dissolved in the water, and extracts with EtOAc.With the dry (anhydrous Na of the organic extract that merges ₂SO ₄), concentrate, obtain 14g bullion product.After with silica gel column chromatography (hexane solution of 40%EtOAc) purification, the yield with 33% obtains title compound, and it promptly is used for next step without being further purified.

LC-MS purity: 87%, m/z=260, (M+).

Step 3.

7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

To containing 5.2g 7-chloro-6-fluoro-5-oxo-1,2,3, (4: 1, adding 30ml 1N LiOH aqueous solution stirred its integral body 3 hours the 120ml THF of 5-tetrahydrochysene-indolizine-8-Ethyl formate (0.02mol): MeOH at ambient temperature in solution v/v).The pH of reactant mixture is transferred to 1 and extract with EtOAc.With the dry (anhydrous Na of the organic extract that merges ₂SO ₄), concentrate, obtain the bullion product.Grind with EtOAc, the yield with 78% obtains title compound, is gray solid.

LC-MS purity: 95%, m/z=232, (M+)

¹H?NMR(DMSO-D ₆，300MHZ)：13.4(s，1H)，s?4.08(t，2H)，3.30(t，2H)，2.18-2.06(m，2H)。

Step 4.

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

Under-78 ℃, under nitrogen, (6.4g, 0.027mol) (4g 0.037mol) handles the solution in 60ml THF with LDA with the 2-fluoro-4-iodo-phenyl amine that is stirring.After 20 minutes, add and contain 7-chloro-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2.5g, the solution of THF 0.011mol) (330ml).-78 ℃ of following restir 30 minutes, make it be warmed to ambient temperature then reactant mixture.Volatile component is removed in reactant mixture stirring 3 days and decompression.Residue is distributed between 50ml 3N HCl solution and 50ml ether.Stir after 15 minutes, collect the gained solid, the yield with 72% obtains title compound, is the light brown solid.

LC-MS purity: 96%, m/z=433, (M+)

¹H?NMR(DMSO-D ₆，300MHZ)：δ13.8-13.6(br?s，1H)，9.42(s，1H)，7.62(d，1H)，7.48(d，1H)，6.9-6.8(m，1H)，4.04(t，2H)，3.46(t，2H)，2.18-2.04(m，2H)。

Embodiment 9.

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

Use the condition identical, with 6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2 with embodiment 3; 3, and 5-tetrahydrochysene-indolizine-8-formic acid (100mg, 0.23mmol), EDCI (133mg; 0.69mmol) and HOBt (93mg, 0.69mmol) mixture in the dry DMF of 6ml stirred 30 minutes, with O-cyclopropyl methyl-azanol (86mg; 0.69mmol) and TEA (70mg 0.69mmol) merges, with the silica gel column chromatography (CHCl of 0-2%MeOH ₃Solution) behind the purification, the yield with 34% obtains title compound, is gray solid.

LC-MS purity: 91%, m/z 500, (M-)

¹H?NMR(DMSO-D ₆，300MHZ)：δ11.40(s，1H)，8.08(s，1H)，7.58(d，1H)，7.42(d，1H)，6.86-6.76(m，1H)，4.00(t，2H)，3.52(d，2H)，3.18(t，2H)，2.2-2.0(m，2H)，1.08-0.98(m，1H)，0.57-0.47(m，2H)，0.27-0.19(m，2H)。

Embodiment 10.

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide synthetic

Use like embodiment 5 described same reaction conditions and reagent, with 6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3, (300mg 0.69mmol) changes into 200mg title compound bullion to 5-tetrahydrochysene-indolizine-8-formic acid.Grind with EtOAc and ether, the yield with 40% obtains this test compound, is light yellow solid.

LC-MS purity: 96%, m/z 432, (M+)

¹H?NMR(DMSO-D ₆，300MHZ)：δ8.58(s，1H)，7.75(d，2H)，7.60(d，1H)，7.45(d，1H)6.82-6.7(m，1H)，4.02(t，2H)，3.3(t，2H)，2.2-2.08(m，2H)。

Embodiment 11.

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

Use and embodiment 8, reaction condition and reagent that those reaction conditions described in the step 4 are identical with reagent are with 4-bromo-2-fluoro-phenyl amine (925mg; 4.8mmol) and 7-chloro-6-fluoro-5-oxo-1,2,3; 5-tetrahydrochysene-indolizine-8-formic acid (450mg; 1.94mol) merge, the yield with 60% obtains title compound, is the light brown solid.

LC-MS purity: 94%, m/z=385,387 (M+, Br patterns)

¹H?NMR(DMSO-D ₆，300MHZ)：δ13.9-13.80(br?s，1H)，9.44(s，1H)，7.56(d，1H)，7.34(d，1H)，7.18-6.9(m，1H)，4.04(t，2H)，3.48(t，2H)，2.18-2.05(m，2H)。

Embodiment 12.

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

Use and embodiment 9 described those reaction conditions reaction condition and reagent identical with reagent; With 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1; 2,3,5-tetrahydrochysene-indolizine-8-formic acid (100mg; 0.25mmol) change into title compound, with the silica gel chromatography (CHCl of 0-2%MeOH ₃Solution) after the processing, the yield with 32% obtains title compound, is white solid.

LC-MS purity: 98%, m/z=454,456 (M+, Br patterns).

¹H?NMR(DMSO-D ₆，300MHZ)：δ11.40(s，1H)，8.06(s，1H)，7.54(d，1H)，7.28(d，1H)，7.04-6.94(m，1H)，4.00(t，2H)，3.52(d，2H)，3.20(t，2H)，2.18-2.04(m，2H)，1.08-0.98(m，1H)，0.55-0.45(m，2H)，0.28-0.19(m，2H)。

Embodiment 13.

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide synthetic

Use like embodiment 5 described same reaction conditions and reagent, with 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (250mg, 0.64mmol)) changes into 140mg title compound bullion.Grind with EtOAc and ether, the yield with 25% obtains this test compound, is faint yellow solid.

LC-MS purity: 99%, m/z 384,386 (M+, Br pattern).

¹H?NMR(DMSO-D ₆，300MHZ)：δ8.58(s，1H)，7.74(d，2H)，7.54(d，1H)，7.29(d，1H)7.0-6.9(m，1H)，4.00(t，2H)，3.3(t，2H)，2.19-2.08(m，2H)。

Embodiment 14.

Step 1.

7-hydroxyl-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic:

Under 0 ℃, in the suspension of the sodium hydride that under inert atmosphere, is stirring in THF, drip 7-hydroxyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate (7.5g, 33.6mmol) solution in THF.Make reactant mixture be warmed to ambient temperature, handle with iodomethane then.The gained reactant mixture is stirred 2 days, and (the TLC monitoring 100%EtOAc), is used the ice cancellation then.Volatile matter is removed in decompression, and remaining water is used ethyl acetate extraction.The organic extract that merges is used brine wash, concentrate.The bullion product is handled with silica gel column chromatography (hexane solution of 70% ethyl acetate), and the yield with 38% obtains title compound.

¹H?NMR(DMSO-D ₆)：δ11.5(s，1H)，4.3(q，2H)，4.0(t，2H)，3.48(t，2H)，2.1(q，2H)，1.8，(s，3H)，1.3(t，3H)。

Step-2

6-methyl-5-oxo-7-trifyl Oxy-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

Use and embodiment 1, the identical reaction condition of those reaction conditions of step 3, stir 12 hours at ambient temperature after; With trifluoromethanesulfanhydride anhydride (1.06g; 3.79mmol) with 7-hydroxyl-6-methyl-5-oxo-1,2,3; (0.75g 3.16mmol) changes into title compound to 5-tetrahydrochysene-indolizine-8-Ethyl formate.After handling with silica gel column chromatography (hexane solution of 25% ethyl acetate), the yield with 40% obtains this test compound.

¹H?NMR(DMSO-D ₆)：4.40(q，2H)，4.20(t，2H)，3.5(t，2H)，2.3-2.2(m，2H)，2.05(s，3H)，1.35(t，3H)。

Step 3.

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

Contain 6-methyl 5-oxo-7-trifyl Oxy-1,2,3 with what stirring; 5-tetrahydrochysene-indolizine-8-Ethyl formate (0.47g, 1.26mmol), 2-fluoro-4-bromo-aniline (0.287g, 1.26mmol), cesium carbonate (0.617g; 1.89mmol), BINAP (0.6g, 0.19mmol) and Pd (OAc) ₂(0.028g, the solution of toluene 0.126mmol) (100ml) heated 4 hours down at 90 ℃.Reactant mixture is filtered and will filtrate concentrated.Residue is absorbed in the ethyl acetate, with brine wash twice, dry then (anhydrous Na ₂SO ₄), concentrate.The bullion product is handled with silica gel column chromatography (hexane solution of 75% ethyl acetate), and the yield with 19% obtains title compound.

LC-MS purity: 96.24%, m/z 409, (M+, Br pattern).

¹H?NMR(DMSO-D ₆)：δ8.5(s，1H)，7.50(d，1H)，7.25(d，1H)，6.6(t，1H)，4.2-4.0(m，4H)，3.45(d，2H)，2.2-2.1(m，2H)，1.70(t，3H)，1.3(t，3H)。

Embodiment 15.

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

With the NaOH aqueous solution (1ml 1N) joins and is positioned at THF: MeOH (3: 1, the v/v) 7-in the solvent mixture (4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate (40mg, 0.10mmol) in.The gained reactant mixture was at room temperature stirred 3 hours, with 1N HCl aqueous solution the pH of reactant mixture is transferred to 1.5, the gained deposition is leached, water (20ml) washs with ethyl acetate (10ml), and the yield with 53% obtains title compound.

LC-MS purity: 99.2%, m/z 381 (M+, Br pattern).

¹H?NMR(DMSO-D ₆)：δ13.30(s，1H)，9.10(s，1H)7.5(d，1H)7.20(d，1H)，6.5(s，1H)，4.05(t，2H)，3.5(t，2H)，2.10(t，2H)，1.6(s，3H)。

Embodiment 16.

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

Use reaction condition and the reagent identical with embodiment 9, with O-cyclopropyl methyl hydroxylamine with 7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2; 3; (300mg 0.787mmol) changes into title compound to 5-tetrahydrochysene-indolizine-8-formic acid, with the silica gel column chromatography (CHCl of 1%MeOH ₃Solution) behind the purification, yield is 8%.

LC-MS purity: 92.7%, m/z 450 (M+, Br pattern).

¹H?NMR(DMSO-D ₆)：δ11.20(s，1H)，7.7(s，1H)，7.5(d，1H)，7.2(d，1H)，6.56(t，1H)，4.0(t，2H)，3.5(d，2H)，3.2(t，2H)，2.18(q，2H)，1.78(s，3H)，1.0(s，1H)，0.5(d，2H)，0.2(d，2H)。

Embodiment 17.

Step 1

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-vinyl oxygen base-ethyoxyl)-amide synthetic

Under 0 ℃; To the 7-that is stirring (4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3; 5-tetrahydrochysene-indolizine-8-formic acid (300mg; 0.787mmol) add in the solution in dry DMF of 6ml and 2ml dichloromethane EDCI (165mg, 0.865mmol) and HOBt (116mg, 0.865mmol).The gained reactant mixture was stirred 2 hours down at 0 ℃, and (71mg is 0.787mmol) with TEA (158mg, 1.57mmol) processing to use O-(2-vinyl oxygen base-ethyl)-azanol then in succession.After 12 hours, reactant mixture is diluted with ethyl acetate, use saturated NaHCO ₃Solution washing.With the dry (anhydrous Na of organic facies ₂SO ₄), concentrating under reduced pressure.Residue is handled the (CHCl of 1%MeOH in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel ₃Solution), obtain the title compound of 180mg low-purity.

LC MS:31.7%, m/z=466, (M+Br pattern)

Step 2

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide synthetic

With 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3, (180mg 0.386mmol) is dissolved in the ethanol that contains 1ml 1N HCl and at room temperature stirred 16 hours 5-tetrahydrochysene-indolizine-8-formic acid (2-vinyl oxygen base-ethyoxyl)-amide bullion.Reactant mixture is concentrated, residue is dissolved in the ethyl acetate.Organic facies is used brine wash, concentrate, residue is handled the (CHCl of 2%MeOH with silica gel column chromatography ₃Solution), obtain title compound with 30% yield.

LC MS:96.5%, m/z=440, (M+Br pattern)

HPLC：94.05％

¹H?NMR(DMSO-D ₆)：δ11.20(s，1H)，7.65(s，1H)，7.48(d，1H)，7.18(d，1H)，6.5(t，1H)，4.0(t，2H)，3.7(t，2H)，3.5(s，3H)，3.2(t，2H)，2.14(quin，2H)，1.72(s，3H)。

Embodiment 18.

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide synthetic

Under 0 ℃, to 7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2; 3; (200mg, 0.524mmol) adding contains TBTU (292mg 0.787mmol) and TEA (79mg, THF solution 0.787mmol) to 5-tetrahydrochysene-indolizine-8-formic acid in the solution in 6ml THF.Make reactant mixture slowly be warmed to room temperature, stirred then 1 hour.Add ammonium chloride, with reactant mixture restir 12 hours at ambient temperature.Reactant mixture is concentrated, residue is dissolved in the ethyl acetate.Organic facies is used NaHCO ₃Solution washing concentrates.With the neutral aluminum oxide column chromatography (CHCl of 2%MeOH ₃Solution) after the processing, the yield with 25% obtains title compound.

LC MS:93.7%, m/z=380, (M+Br pattern).

HPLC：98.7％

¹H?NMR(DMSO-D ₆)：δ7.7(s，1H)，7.5(dd，1H)，7.2(d，1H)，6.5(t，1H)，4.0(t，2H)，3.3(s，2H)，2.1(quin，2H)，1.78(s，3H)。

Embodiment 19.

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide synthetic

Use reaction condition and the reagent identical with embodiment 4, (45mg is 0.55mmol) with 7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1 with methoxy-amine hydrochloride; 2; 3, (200mg 0.525mmol) changes into title compound to 5-tetrahydrochysene-indolizine-8-formic acid.Through the silica gel column chromatography (CHCl of 1%MeOH ₃Solution) after the processing, the yield with 19% obtains this test compound.

LC-MS purity: 96.42%, m/z=410, (M+Br pattern).

HPLC：97.8％

¹H?NMR(DMSO-D ₆)：δ11.20(s，1H)，7.7(s，1H)，7.5-7.4(dd，1H)，7.2(d，1H)，6.5(t，1H)，4.0(t，2H)，3.5(s，3H)，3.2(t，2H)，2.1(quin，2H)，1.78(s，3H)。

Embodiment 20.

7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide synthetic

Use the reaction condition identical with embodiment 3, make 7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3, (200mg, 0.523mmol) (53mg 0.55mmol) reacts 5-tetrahydrochysene-indolizine-8-formic acid, obtains title compound with the hydrochloric acid amine ethoxylate.At the silica gel column chromatography (CHCl of 1%MeOH ₃Solution) after the processing, the yield with 23% obtains this test specimen.

LC-MS purity: 95.58%, m/z=424, (M+Br pattern)

HPLC：98.61％

¹H?NMR(DMSO-D ₆)：δ11.20(s，1H)，7.7(s，1H)，7.5-7.4(dd，1H)，7.2(d，1H)6.5(t，1H)，4.0(t，2H)，3.7(q，2H)，3.2(t，2H)，2.1(quin，2H)，1.78(s，3H)，1.1(t，3H)。

Embodiment 21.

2-(4-bromo-2-fluoro-phenyl-amino)-4-oxo--6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid-cyclopropyl-methoxyamide synthetic

According to embodiment 3 described operations, with 150mg 2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid (0.39mmol) changes into title compound with O-cyclopropyl methyl hydroxylamine.With the silica gel column chromatography (CHCl of 3% methanol ₃Solution) after the processing, the yield with 29% obtains title compound.

LC-MS purity: 99.3%, m/z=451, (M+Br pattern)

¹H?NMR(DMSO-D ₆)：δ11.8(s，1H)，7.64(d，1H)，7.54(s，1H)，7.4(d，1H)，7.3(t，1H)，5.2(s，1H)，3.8(t，2H)，3.7(d，2H)，2.7(t，2H)，1.85-1.65(m，4H)，1.1-1.0(m，1H)，0.55-0.45(m，2H)，0.3-0.2(m，2H)。

Embodiment 22.

Step 1

2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid-(2-vinyl oxygen base-ethyoxyl)-amide synthetic

Use and embodiment 17; The identical reaction condition of described those reaction conditions of step 1, (64mg 0.62mmol) will be arranged in 2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6 of 5ml DMF with O-(2-vinyl oxygen base-ethyl)-azanol; 7; 8, (200mg 0.52mmol) changes into title compound to 9-tetrahydrochysene-4H-quinolizine-1-formic acid.(methanol: chloroform) after the processing, the yield with 62% obtains the product of purification with silica gel column chromatography.

Step 2

2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid-(2-hydroxyl-ethyoxyl)-amide synthetic

Use and embodiment 17, the identical reaction condition of described those reaction conditions of step 2 is with 2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6; 7; 8,9-tetrahydrochysene-4H-quinolizine-1-formic acid-(2-vinyl oxygen base-ethyoxyl)-(150mg 0.032mmol) changes into title compound to amide; After handling with preparation HPLC, the yield with 12% obtains title compound.

LC-MS purity: 98.7%, m/z=441, (M+Br pattern).

¹H?NMR(DMSO-D ₆)：δ11.6(s，1H)，7.68-7.58(dd，2H)，7.46-7.42(dd，1H)，7.3(t，1H)，5.2(s，1H)，4.85(t，1H)，4.0(t，2H)，3.8(t，2H)，3.6(q，2H)，2.7(t，2H)，1.85-1.65(m，4H)。

Embodiment 23.

2-(4-bromo-2-fluoro-phenyl amino)-4-oxo--6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid methoxyl group-amide synthetic

Use reaction condition and the reagent identical with embodiment 5, (131mg, 1.52mmol) with 2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6,7,8, (200mg 0.52mmol) changes into title compound to 9-tetrahydrochysene-4H-quinolizine-1-formic acid with methoxy-amine hydrochloride.With the silica gel column chromatography (CHCl of 3.5%MeOH ₃Solution), with preparation HPLC product is carried out purification then, obtain this test compound of 25mg.

LC-MS purity: 96.4%, m/z=409.9, (M+Br pattern).

¹H?NMR(DMSO-D ₆)：δ11.65(s，1H)，7.64(d，1H)，7.59(s，1H)，7.4(d，1H)，7.3(t，1H)，5.2(s，1H)，3.8(t，2H)，3.7(s，3H)，2.7(t，2H)，1.85-1.65(m，4H)。

Embodiment 24.

2-(4-bromo-2-fluoro-phenyl amino)-4-oxo--6,7,8,9-tetrahydrochysene-4H-quinolizine-1-formic acid ethyoxyl-amide synthetic

Use reaction condition and the reagent identical, make 2-(4-bromo-2-fluoro-phenyl amino)-4-oxo-6,7 with embodiment 3; 8; (200mg is 0.52mmol) with hydrochloric acid amine ethoxylate (153mg, 1.5mmol) reaction for 9-tetrahydrochysene-4H-quinolizine-1-formic acid; After preparation HPLC is handled, obtain 55mg (yield 25%) title compound.

LC-MS purity: 97.9%, m/z=425.8, (M+Br pattern).

¹H?NMR(DMSO-D ₆)：δ11.6(s，1H)，7.64(d，1H)，7.52(s，1H)，7.4(d，1H)，7.3(t，1H)，5.2(s，1H)，4.0(q，2H)，3.8(t，2H)，2.7(t，2H)，1.85-1.65(m，4H)，1.3-1.15(m，3H)。

Embodiment 25

Step 1 to 4 usefulness are carried out with the similar mode of embodiment 1 described mode, and step 5 is used with the similar mode of embodiment 2 described modes and carried out.

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (3-hydroxyl-propyl group)-amide synthetic

Under 0 ℃, with EDCI (390mg, 0.002mol) and HOBt (162mg 0.002mol) joins 7-(4-bromo-2-fluoro-the phenyl amino)-5-oxo-1,2,3 that is stirring, and (250mg is 0.001mol) in the solution in DMF (6ml) for 5-tetrahydrochysene indolizine-8-formic acid.Reactant mixture was stirred 1 hour down at 0 ℃.To wherein add the 3-amino-propanol (0.156ml, 0.002mol), add then TEA (1mL, 0.012mol).With reactant mixture stirred overnight under RT.Reactant mixture is distributed between ethyl acetate and cold water (20ml).Organic layer is used NaHCO ₃Solution washing concentrates.Use the preparation HPLC purification, obtain 41mg (yield 14.13%) 7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (3-hydroxyl-propyl group)-amide.

LC-MS purity: 97.2%, m/z=426,428 (M+Br patterns)

H ¹?NMR(DMSO-D ₆，300MHZ)δ8.68(s，1H)，8.28(t，1H)，7.7-7.6(m，1H)，7.5-7.3(m，2H)，5.49(s，1H)，3.9(t，2H)，3.5(t，2H)，3.4-3.1(m，4H)，2.1(quin，2H)，1.7-1.5(q，2H)

Embodiment 26

Step 1 to 4 usefulness are carried out with the similar mode of embodiment 8 described modes.

Step 5

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-vinyl oxygen base-ethyoxyl)-amide synthetic

Under 0 ℃, with EDCI (530mg, 0.003mol) and HOBt (364mg; 0.003mol) join 6-fluoro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1,2 that is stirring, 3; (200mg is 0.46mmol) in the solution in DMF (20mL) and DCM (10mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 2 hours down at 0 ℃.(280mg, 0.003mol), (272mg continues 0.003mol) and under RT to stir 20 hours to add TEA then in reaction flask, to add O-(2-vinyl oxygen base-ethyl)-azanol.Reactant mixture is distributed between water and ethyl acetate (20mL), organic layer is used saturated NaHCO ₃(20mL), NH ₄Na is used in Cl (20mL) and saline solution (20mL) washing ₂SO ₄Drying concentrates.The bullion product (450mg) of remnants promptly is used for next step without being further purified.

LCMS purity: 25%, m/z=518, (M+)

Step 6

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide synthetic

1N HCl (3ml) is joined 6-fluoro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1 that is stirring; 2; 3, in 5-tetrahydrochysene-indolizine-8-formic acid (2-vinyl oxygen base-ethyoxyl)-solution of amide (450mg 0.22mmol) in 1: 1 chemical compound (12ml) of THF and EtOH.Reactant mixture was stirred 90 minutes.By distilling solvent in the reactant mixture, reactant mixture is dissolved in the water (3mL), with 2N NaOH solution pH is transferred to 6, distribute with EtOAc.Organic layer is used Na ₂SO ₄Drying concentrates.Use the preparation HPLC purification, obtain 61mg (yield 26%) 6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide is white solid.

LCMS purity: 95%, m/z=491.9, (M+)

HPLC：96.6％

H ¹?NMR(DMSO-D ₆，300MHz)11.5-11.4(br?s，1H)，8.2-8.0(br?s，1H)，7.6(d，1H)，7.4(d，1H)，6.82-6.72(m，1H)，4.0(t，2H)，3.8(t，2H)，3.6(t，2H)，3.2(t，2H)，2.2-2.0(m，2H)

Flow process 7

Embodiment 27

Step 1

7-chloro-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

(58.27mmol 8.4mL) joins the 7-hydroxyl-5-oxo-1,2,3 that is stirring, and (13g is 58.27mmol) at distillatory POCl for 5-tetrahydrochysene-indolizine-8-Ethyl formate with TEA ₃(32ml is in the solution in 349mmol).Reactant mixture was being stirred 16 hours under nitrogen atmosphere under the RT.By distilling POCl in the reactant mixture ₃, residue is poured in the icy water, use saturated K ₂CO ₃Solution alkalization (pH=8.5).Reactant mixture is extracted with EtOAc.Organic layer is used anhydrous Na ₂SO ₄Drying concentrates, and concentrate with column chromatography (use silica gel, with the hexane solution of 75% ethyl acetate as eluant) purification, is obtained 7.5mg (yield 53.5%) 7-chloro-1,2,3, and 5-tetrahydrochysene-indolizine-8-Ethyl formate is yellow solid.

¹H?NMR(DMSO_D ₆，300MHz)：δ6.6-6.5(br?s，1H)，4.4-4.3(m，2H)，4.2-4.1(m，2H)，3.5-3.3(t，2H)，2.3-2.2(m，2H)，1.4-1.3(t，2H)

Step 2

7-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

1N LiOH (40ml) is joined the 7-hydroxyl-5-oxo-1,2,3 that is stirring, and (7.5g is 31.1mmol) in the solution in (4: 1) THF: MeOH (75ml) for 5-tetrahydrochysene-indoline-8-Ethyl formate.Reactant mixture was at room temperature stirred 15 hours.Reactant mixture is concentrated, with 1N HCl acidify, collect formed deposition, obtain 5.2g (yield 78.7%) 7-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid is white solid.

LC-MS purity: 99%, m/z=212, (M-1)

H ¹?NMR(DMSO-D ₆，300MHz)：δ13.25-13.15(br?s，1H)，6.4(s，1H)，4.0(t，3H)，2.15-2.05(m，3H)。

Step 3

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

Under-78 ℃, under nitrogen atmosphere, (16.5ml, (5.6g is 23.47mmol) in the solution in dry THF (40mL) 32.8mmol) to join the 2-fluoro-4-Iodoaniline that is stirring with lithium diisopropylamine.Add the 7-chloro-5-oxo-1,2,3 that is arranged in dry THF (150mL) then, (2g 9.38mmol), at first stirs the gained mixture 30 minutes down at-78 ℃ 5-tetrahydrochysene-indolizine-8-formic acid, under RT, stirs 5 days then.Reactant mixture is concentrated, use 1N HCl to be acidified to pH and be about 2.Collect formed deposition and with the ether washing, obtain 2.5g (yield 65.7%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid is white solid.

LC-MS purity: 92.8%, m/z=414.8, (M+1)

H ¹?NMR(DMSO-D ₆，300MHz)δ13.45-13.35(br?s，1H)，10.05-9.95(br?s，1H)，7.8(dd，1H)，7.6(d，1H)，7.4-7.2(t，1H)，5.4-5.3(s，1H)，4.0(t，2H)，3.5-3.4(t，2H)，2.1-2.0(m，2H)

Embodiment 28

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 27 described modes.

Step 4

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide synthetic

Under 0 ℃, with EDCI (0.415mg, 2.17mmol) and HOBt (0.293mg; 1.7mmol) join 7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1,2 that is stirring, 3; (0.300mg is 0.72mmol) in the solution in DMF (5mL) and TEA (0.05mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was being stirred 30 minutes under nitrogen atmosphere under 0 ℃.Add NH then ₄(0.115mg, 2.17mmol), (0.3ml 2.17mmol), stirs reactant mixture 6 hours under RT Cl to add TEA then.With the reactant mixture dilute with water, extract with EtOAc.With organic layer water and saline solution washing.Collect formed deposition, obtain 0.040mg (yield 13%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide is white solid.

LC-MS purity: 98.7%, m/z=412, (M-1)

H ¹?NMR(DMSO-D ₆，300MHz)δ9.0(br?s，2H)，7.7(dd，1H)，7.7-7.6(d，1H)，7.3-7.2(t，1H)，5.5(s，1H)，3.9(t，2H)，2.1-2.0(m，2H)

Embodiment 29

Step 4

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

Under RT, with EDCI (0.101mg, 0.53mmol) and HOBt (0.072mg; 0.53mmol) join 7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1 that is stirring; 2,3,5-tetrahydrochysene-indolizine-8-formic acid (0.200mg; 0.48mmol) (0.1ml is in the solution in 1.44mmol) at DMF (4mL) and TEA.Reactant mixture was being stirred 30 minutes under nitrogen atmosphere under the RT.Add then hydrochloric acid O-cyclopropyl methyl-azanol (0.072mg, 0.57mol), (0.4ml 1.44mmol), stirs reactant mixture 18 hours under RT TEA.With the reactant mixture dilute with water, extract with EtOAc.With organic layer water, NaHCO ₃With the saline solution washing, use anhydrous Na ₂SO ₄Drying concentrates.Residue with DCM (5mL) and methanol (1mL) recrystallization, is obtained 0.059mg (yield 25%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3, and 5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide is brown solid.

LC-MS purity: 97%, m/z=481.9, (M-1)

H ¹?NMR(DMSO-D ₆，300MHz)δ11.4-11.3(br?s，1H)，8.3-8.2(br?s，1H)7.7(dd，1H)7.6-7.5，(d，1H)，7.2(t，1H)，5.4(s，1H)，3.9(t，2H)，3.7-3.6(d，2H)，3.2-3.1(m，2H)，2.1-2.0(m，2H)，1.1-1.0(m，1H)，0.5-0.4(m，2H)，0.3-0.2(m，2H)

Embodiment 30

Step 4

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

With dense H ₂SO ₄(0.6mL) join 7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1 among the EtOH (5ml) that is dissolved in that is stirring; 2,3,5-tetrahydrochysene-indolizine-8-formic acid (0.300mg; 0.72mol) solution in, reactant mixture was being stirred under nitrogen atmosphere 3 days under 85 ℃.Reactant mixture is concentrated and between EtOAc and water, distributes.Organic layer is used NaHCO ₃, saline solution washing, concentrate, wash with ether.With column chromatography (use silica gel, with the chloroformic solution of 1.5% methanol as eluant) purification, obtain 0.095mg, (yield 29.6%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate is white solid.

LC-MS purity: 96%, m/z=443, (M+1)

H ¹?NMR(DMSO-D ₆，300MHz)δ9.5-9.4(br?s，1H)，7.8(dd，1H)7.6(d，1H)7.3-7.2(m，1H)，5.4-5.3(br?s，1H)，4.4-4.2(m，2H)，3.9(t，2H)，3.5(t，2H)，2.1-2.0(m，2H)，1.4-1.2(m，3H)

Embodiment 31

Step 4

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-vinyl oxygen base-ethyoxyl)-amide synthetic

Under RT, with EDCI (0.138mg, 0.72mmol) and HOBt (0.097mg; 0.72mmol) join 7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1 that is stirring; 2,3,5-tetrahydrochysene-indolizine-8-formic acid (0.200mg; 0.48mmol) (0.13ml is in the solution in 0.96mmol) at DMF (5ml) and TEA.Add then O-(2-vinyl oxygen base-ethyl)-azanol (0.99mg, 0.96mmol), (0.13ml 0.96mmol), was stirring reaction flask 5 hours under the RT TEA under nitrogen atmosphere.With the reactant mixture dilute with water, distribute with EtOAc.Organic layer is used NH ₄Cl, NaHCO ₃, saline solution washing, use anhydrous Na ₂SO ₄Drying concentrates.Use the preparation HPLC purification, obtain 135mg (yield 56%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-vinyl oxygen base-ethyoxyl)-amide is brown gumminess solid.

Step 5

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide synthetic

1N HCl (1.5ml) and EtOH (3ml) are joined 7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1 that is stirring; 2,3,5-tetrahydrochysene-indolizine-8-formic acid-(2-vinyl oxygen base-ethyoxyl)-amide (0.135mg; 0.27mmol) solution in, reactant mixture was stirred 3 hours under RT.With 2N NaOH solution pH is transferred to 5-7.Reactant mixture is extracted with EtOAc.With organic layer water, saline solution washing, use anhydrous Na ₂SO ₄Drying concentrates.Use the preparation HPLC purification, obtain 12mg (yield 10%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide is white solid.

LC-MS purity: 98.9%, m/z=473.9, (M+1)

H ¹?NMR(DMSO-D ₆，300MHz)11.4-11.3(br?s，1H)，8.3-8.2(br?s，1H)，7.8-7.7(dd，1H)7.6-7.5(d，1H)7.2-7.1(m，1H)，5.4-5.3(br?s，1H)，4.0-3.8(m，4H)，3.6(t，2H)，3.2(t，2H)，2.1-2.0(m，2H)

Embodiment 32

Step 4

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide

Under 0 ℃; With EDCI (0.280mg, 0.001mol) and HOBt (0.197mg 0.001mmol) joins 7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1 that is stirring; 2; 3, (0.200mg is 0.0005mol) in the solution in DMF (5ml), TEA (0.005ml) and chloroform (2mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was being stirred 1.30 hours under 0 ℃, under nitrogen atmosphere.(0.121mg, 0.001mol), (0.2ml 0.001mol), stirs reactant mixture 18 hours under RT to add TEA then to add hydrochloric acid O-methoxyl group-azanol then.With the reactant mixture dilute with water, extract with EtOAc.With organic layer water, NaHCO ₃Wash with saline solution.Reactant mixture is used anhydrous Na ₂SO ₄Drying concentrates.Concentrate is used the preparation HPLC purification, obtain 6mg (yield 2.8%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide is white solid.

LC-MS purity: 98%, m/z=443.8, (M+1)

H ¹?NMR(DMSO-D ₆，300MHz)δ11.4-11.3(br?s，1H)，8.3-8.2(br?s，1H)7.7(dd，1H)7.5，(d，1H)，7.2-7.1(t，1H)，5.3(s，1H)，3.9(t，2H)，3.8-3.6(br?s，2H)，3.3-3.2(m，2H)，2.1-2.0(m，2H)

Embodiment 33

Step 4

7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide synthetic

Under 0 ℃; With EDCI (0.277mg, 0.001mol) and HOBt (0.200mg 0.001mmol) joins 7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1 that is stirring; 2; 3, (0.200mg is 0.0005mol) in the solution in DMF (5mL), TEA (0.1mL) and DCM (2mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was being stirred 1.30 hours under 0 ℃, under nitrogen atmosphere.(0.141mg, 0.001mol), (0.2ml 0.001mol), stirs reactant mixture 18 hours under RT to add TEA then to add hydrochloric acid O-ethyoxyl-azanol then.With the reactant mixture dilute with water, extract with EtOAc.With organic layer water, NaHCO ₃Wash with saline solution.Reactant mixture is used anhydrous Na ₂SO ₄Drying concentrates.Use the preparation HPLC purification, obtain 13mg (yield 6%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide is white solid.

LC-MS purity: 98%, m/z=457.8, (M+1)

H ¹?NMR(DMSO-D ₆，300MHz)δ11.4-11.3(br?s，1H)，8.3-8.25(br?s，1H)7.8-7.7(d，1H)7.6-7.5，(d，1H)，7.3-7.1(t，1H)，5.4(s，1H)，4.0-3.8(m，4H)，3.3-3.0(m，2H)，2.1-2.0(t，2H)，1.3-1.1(t，3H)

Embodiment 34

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-amide synthetic

Under 0 ℃, with EDCI (155mg, 0.816mmol) and HOBt (110mg; 0.816mmol) join 7-(4-bromo-2-fluoro-the phenyl amino)-5-oxo-1,2 that is stirring, 3; (0.2g is 0.544mmol) in the solution in DMF (6mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1 hour down at 0 ℃.Add then O-(4,4-dimethyl-[1,3] dioxolanes-2-ylmethyl)-azanol (180mg, 0.653mmol), TEA (0.45ml, 3.264mmol).With reactant mixture stirred overnight under RT.Reactant mixture is distributed between ethyl acetate (50mL) and cold water (50mL).Organic layer is used saturated NaHCO ₃Solution washing is used Na ₂SO ₄Drying concentrates.(use silica gel with column chromatography; With the chloroformic solution of 5% methanol as eluant) purification, obtain the required product 7-of 50mg (yield 19.13%) (4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2; 3; 5-tetrahydrochysene-indolizine-8-formic acid (2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-amide.

Step 7

7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide synthetic

With 1N HCl (1mL) join stirring be dissolved in 7-(4-bromo-2-fluoro-the phenyl amino)-5-oxo-1,2 in the ethanol (2mL), 3; 5-tetrahydrochysene-indolizine-8-formic acid (2; 2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-(50mg is in solution 0.010mmol) for amide.Reactant mixture was stirred 3 hours under RT.Distill ethanol, reactant mixture is distributed between water and ethyl acetate (20mL).Organic layer is used Na ₂SO ₄Drying concentrates and comes concentrate is carried out purification through carry out recrystallization with DCM, obtains the required product 7-of 25mg (yield 17.35%) (4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide.

LC-MS：95.8％；m/z＝456(M+1)，458(M+2)

HPLC：97.3％

H ¹?NMR(DMSO-D ₆，300MHz)：δ11.2(br?s，1H)，8.3-8.2(br?s，1H)，7.6-7.5(d，1H)，7.5-7.3(m，2H)，5.3(s，1H)，4.9(d，1H)，4.6-4.4(t，1H)，4.0-3.8(m，3H)，3.8-3.5(m，2H)，3.4(m，2H)，3.3-3.2(m，2H)，2.1-2.0(m，2H)

Flow process 8:

Embodiment 35

Step 1

7-chloro-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

(58.27mmol 8.4mL) joins the 7-hydroxyl-5-oxo-1,2,3 that is stirring, and (13g is 58.27mmol) at distillatory POCl for 5-tetrahydrochysene-indolizine-8-Ethyl formate with TEA ₃(32ml is in the solution in 349mmol), with reactant mixture at room temperature, under nitrogen atmosphere, stirred 16 hours.Distill POCl ₃, reactant mixture is poured in the icy water, use saturated K ₂CO ₃Solution alkalizes to pH about 8.5.Reactant mixture is extracted with EtOAc.Organic layer is used anhydrous Na ₂SO ₄Drying concentrates.Concentrate with column chromatography (use silica gel, with the hexane solution of 75% ethyl acetate as eluant) purification, is obtained 7.5mg (yield 53.5%) 7-chloro-1,2,3, and 5-tetrahydrochysene-indolizine-8-Ethyl formate is yellow solid.

¹H?NMR(DMSO-D ₆，300MHz)：δ6.6-6.5(br?s，1H)，4.4-4.3(m，2H)，4.2-4.1(m，2H)，3.5-3.3(t，2H)，2.3-2.2(m，2H)，1.4-1.3(t，2H)

Step 2

6,7-two chloro-5-oxos-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

(304mg 0.002282mol) joins the 7-chloro-1,2,3 that is dissolved among the DMF, and (500mg in solution 0.00201mol), under the RT, under nitrogen atmosphere is stirring reactant mixture 18 hours 5-tetrahydrochysene-indolizine-8-Ethyl formate with NCS.Reactant mixture is used ethyl acetate extraction, water and saline solution washing.Organic layer is used anhydrous Na ₂SO ₄Drying concentrates, and obtains the required product 6 of 400mg (yield 70%), 7-two chloro-5-oxos-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate.

¹H?NMR(DMSO-D ₆，300MHz)：δ4.3-4.2(m，2H)，4.1-4.0(t，2H)，3.3(t，2H)，2.2-2.1(m，2H)，1.3(t，3H)

LCMS：78％；m/z＝278，M+2

HPLC：89％

Step 3

6,7-two chloro-5-oxos-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

With 1N LiOH (10mL) join stirring 6,7-two chloro-5-oxos-1,2,3, (400mg 0.001mol) in the solution in (4: 1) THF: MeOH (10mL), stirs reactant mixture 3 hours under RT 5-tetrahydrochysene-indolizine-8-Ethyl formate.Reactant mixture is concentrated, be acidified to pH about 2 with 1N HCl.Under reduced pressure collecting precipitation obtains the required product 6 of 375mg (yield 100%), 7-two chloro-5-oxos-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid.

H ¹?NMR(DMSO-D ₆，300MHZ)：δ13.2(s，1H)，4.1-4.0(t，2H)，3.3(t，2H)，2.2-2.1(m，2H)

LCMS：92％；m/z＝248，M+1；249.7，M+2

HPLC：90.8％

Step 4

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

Under-78 ℃; Go through 5 minutes will be just-butyl lithium (2ml; 0.003mol) (0.65ml 0.005mol) in the solution in dry THF (40mL), stirs reactant mixture 30 minutes to be added drop-wise to the diisopropylamine that is stirring; Then-78 ℃ add down the 4-bromo-2-fluoro-phenyl amine that are dissolved in the dry THF (5mL) (462mg, 0.002mol).With reactant mixture restir 30 minutes, then under-78 ℃, under agitation go through to add in 30 minutes and be dissolved in 6 in the dry THF (10mL), 7-two chloro-5-oxos-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (200mg, 0.001mol).Under RT, continue again to stir 16 hours.Distill THF,, under agitation add ether then and reach 10 minutes through adding 1N HCl with the residue acidify.Collect formed deposition, with the ether washing, drying obtains the required product 7-of 232mg (yield 72%) (4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid.

H ¹?NMR(DMSO-D ₆，300MHz)δ13.3(s，1H)，9.6-9.5(br?s，1H)，7.6-7.5(dd，1H)，7.3(d，1H)，6.9(t，1H)，4.1-4.0(t，2H)，3.5-3.4(t，2H)，2.2-2.1(m，2H)

LCMS：96％；m/z＝400.9，M+1

HPLC＝95.5％

Embodiment 36

Step 5

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

Operation:

Under 0 ℃, with EDCI (143mg, 0.001mol) and HOBt (102mg; 0.001mol) join 7-(4-bromo-2-fluoro-the phenyl amino)-6-chloro-5-oxo-1,2 that is stirring, 3; (100mg is 0.0002mol) in the solution in DMF (3mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1.5 hours down at 0 ℃. then 0 ℃ add down hydrochloric acid O-cyclopropyl methyl-azanol (92mg, 0.001mol), TEA (0.1ml, 0.001mol).Reactant mixture was stirred 18 hours under RT.Reactant mixture is distributed between ethyl acetate and water.Organic layer is used saturated NH ₄Cl solution, NaHCO ₃Anhydrous Na is used in solution and saline solution washing ₂SO ₄Drying concentrates.Use the preparation HPLC purification, obtain the required product 7-of 42mg (yield 36%) (4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide.

H ¹?NMR(DMSO-D ₆，300MHz)δ11.4-11.2(br?s，1H)，8.04-7.96(br?s，1H)，7.5(d，1H)，7.3(d，1H)，6.9(t，1H)，4.1-4.0(t，2H)，3.2(d，2H)，3.1(t，2H)，2.2-2.1(m，2H)，1.0-0.9(m，1H)，0.5(d，2H)，0.3(s，2H)

LCMS：100％；m/z＝471.7，M+1

HPLC＝99％

Embodiment 37

Step 1 to 4 usefulness are carried out with the similar mode of embodiment 1 described mode.

Step 5

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide synthetic

Under 0 ℃, with EDCI (286mg, 0.001mol) and HOBt (202mg; 0.001mol) join 7-(4-bromo-2-fluoro-the phenyl amino)-6-chloro-5-oxo-1,2 that is stirring, 3; (200mg is 0.0005mol) in the solution in dry DMF (5mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1.30 hours down at 0 ℃.Then 0 ℃ add down hydrochloric acid O-methoxyl group-azanol (125mg, 0.001mol), TEA (0.21ml, 0.001mol).Reactant mixture was being stirred 16 hours under the RT, under nitrogen atmosphere.Reactant mixture is distributed between EtOAc and water.With organic layer water, saturated NaHCO ₃Anhydrous Na is used in solution and saline solution washing ₂SO ₄Drying concentrates, and the bullion product is used methanol wash, obtains 0.020g (yield 9.3%) 7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3, and 5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide is white solid.

H ¹?NMR(DMSO-D ₆，300MHz)δ11.4-11.2(br?s，1H)，8.0(br?s，1H)，7.5(dd，1H)，7.3(d，1H)，6.9(t，1H)，4.0(t，2H)，3.4(s，3H)，3.1(t，2H)，2.1-2.0(m，2H)

LCMS：90％；m/z＝431.9，M+1

HPLC：99％

Embodiment 38

Step 5

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide synthetic

Under 0 ℃, with EDCI (286mg, 0.001mol) and HOBt (202mg; 0.0.001mol) join 7-(4-bromo-2-fluoro-the phenyl amino)-6-chloro-5-oxo-1,2 that is stirring, 3; (200mg is 0.005mol) in the solution in dry DMF (5mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1.30 hours down at 0 ℃.Add NH down at 0 ℃ then ₄Cl (80mg, 0.001mol), add then TEA (0.2ml, 0.001mol).Reactant mixture was stirred 16 hours under RT.Reactant mixture is distributed between EtOAc and water.With organic layer water, saturated NaHCO ₃Anhydrous Na is used in solution and saline solution washing ₂SO ₄Drying concentrates, and obtains the required product 7-of 0.020g (yield 9.3%) (4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide.

H ¹?NMR(DMSO-D ₆，300MHz)δ8.44-8.4(br?s，1H)，7.64-7.58(br?s，2H)，7.5(dd，1H)，7.2(d，1H)，6.9-6.8(t，1H)，4.0(t，2H)，3.3-3.2(t，2H)，2.1-2.0(m，2H)

LCMS：94.2％；m/z＝401.9，M+1

HPLC：94.5％

Embodiment 39

Step 5

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide synthetic

Under 0 ℃, with EDCI (286mg, 0.001mol) and HOBt (202mg; 0.001mol) join 7-(4-bromo-2-fluoro-the phenyl amino)-6-chloro-5-oxo-1,2 that is stirring, 3; (200mg is 0.0005mol) in the solution in dry DMF (5mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1.30 hours down at 0 ℃.Then 0 ℃ add down hydrochloric acid O-ethyoxyl-azanol (145mg, 0.001mol), add then TEA (0.2ml, 0.001mol).Reactant mixture was being stirred 18 hours under the RT, under nitrogen atmosphere.Reactant mixture is distributed between EtOAc and water.With organic layer water, saturated NaHCO ₃Anhydrous Na is used in solution and saline solution washing ₂SO ₄Drying concentrates, and the bullion product is used recrystallizing methanol, obtains the required product 7-of 52g (yield 23.6%) (4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide.

H ¹?NMR(DMSO-D ₆，300MHz)δ11.4-11.2(br?s，1H)，8.1-7.9(br?s，1H)，7.5(dd，1H)，7.3(d，1H)，6.9(t，1H)，4.0(t，2H)，3.6-3.5(m，2H)，3.1(t，2H)，2.2-2.0(m，2H)，1.1(t，3H)

LCMS：100％；m/z＝445.7，M+1；443.8，M-1

HPLC：96％

Embodiment 40

Step 5

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-amide synthetic

Under 0 ℃, with EDCI (572mg, 0.003mol) and HOBt (191.7mg; 0.003mol) join 7-(4-bromo-2-fluoro-the phenyl amino)-6-chloro-5-oxo-1,2 that is stirring, 3; (400mg is 0.0016mol) in the solution in dry DMF (10mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1.30 hours down at 0 ℃.Then 0 ℃ add down O-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethyl)-azanol (440mg, 0.003mol), (0.4ml 0.003mol), continues stirring 16 hours to TEA under RT.Reactant mixture is distributed between EtOAc and water.With organic layer water, saturated NaHCO ₃Anhydrous Na is used in solution and saline solution washing ₂SO ₄Drying concentrates.(use silica gel with column chromatography; With 2% methanol and chloroform as eluant) purification, obtain the required product 7-of 0.3g (yield 56.8%) (4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2; 3; 5-tetrahydrochysene-indolizine-8-formic acid (2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-amide.

H ¹?NMR(DMSO-D ₆，300MHz)δ11.4(br?s，1H)，7.94-8.06(br?s，1H)，7.5(dd，1H)，7.3-7.24(d，1H)，6.9(t，1H)，4.2-4.1(m，1H)，4.1-4.0(m，3H)，3.6-3.5(m，3H)，3.1(t，2H)，2.1-2.0(m，2H)，0.8-0.7(s，6H)

LCMS：65％；m/z＝529.9M+1

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide synthetic

With 1N HCl (0.6mL) join stirring be dissolved in 7-(4-bromo-2-fluoro-the phenyl amino)-6-chloro-5-oxo-1,2 among the EtOH (12mL), 3; 5-tetrahydrochysene-indolizine-8-formic acid (2; 2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-(300mg is in solution 0.001mol) for amide.Reactant mixture was at room temperature stirred 2 hours.Distill ethanol, residue is extracted with EtOAc.With organic layer water, saturated NaHCO ₃Anhydrous Na is used in solution, saline solution washing ₂SO ₄Drying concentrates.Use recrystallizing methanol, obtain 50mg (yield 18.5%) 7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide is white solid.

H ¹?NMR(DMSO-D ₆，300MHz)δ11.4(br?s，1H)，8.0(br?s，1H)，7.5-7.4(dd，1H)，7.3-7.2(d，1H)，6.9(t，1H)，4.8(d，1H)，4.6-4.5(t，1H)，4.0(t，2H)，3.7-3.5(m，2H)，3.5-3.4(m，1H)，3.2-3.1(t，2H)，2.1-2.0(m，2H)。

LCMS：85％；m/z＝491.7，M+1

HPLC＝96％

Embodiment 41

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 1 described mode.

Step 4

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

Under-78 ℃, will be just-(20ml 0.032mol) goes through and was added drop-wise to the diisopropylamine that stirring in 5 minutes (4.5ml 0.032mol) in the solution in dry THF (5mL), stirs reactant mixture 30 minutes butyl lithium.Then-78 ℃ add down the 2-fluoro-4-iodo-phenyl amine that are dissolved in the dry THF (10mL) (5.75g, 0.002mol).With reactant mixture restir 30 minutes, then under-78 ℃, under agitation go through to add in 30 minutes and be dissolved in 6 in the dry THF (130mL), 7-two chloro-5-oxos-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2g, 0.008mol).Under RT, under nitrogen atmosphere, continue again to stir 2 days.Distill THF, through adding the remaining reactant mixture of 1N HCl acidify.Add ether, stirred 10 minutes, produce deposition, collect and be somebody's turn to do deposition, with the ether washing, drying obtains the required product 6-chloro-of 2.3g (yield 63.8%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid.

H ¹?NMR(DMSO-D ₆，300MHz)δ13.6(s，1H)，9.5(br?s，1H)，7.6(dd，1H)，7.4(d，1H)，6.7(t，1H)，4.1-4.0(t，2H)，3.5-3.4(t，2H)，2.2-2.1(m，2H)

LCMS：92％；m/z＝448.7

HPLC：98％

Embodiment 42

Step 5

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

Under 0 ℃, with EDCI (256mg, 0.001mol) and HOBt (181mg; 0.001mol) join 6-chloro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1,2 that is stirring, 3; (200mg is 0.0004mol) in the solution in dry DMF (5mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1.30 hours down at 0 ℃.Then 0 ℃ add down hydrochloric acid O-cyclopropyl methyl-azanol (165mg, 0.001mol), TEA (0.2ml, 0.001mol).Reactant mixture was being stirred 16 hours under the RT, under nitrogen atmosphere.Reactant mixture is distributed between EtOAc and water.With organic layer water, saturated NH ₄Cl, saturated NaHCO ₃Anhydrous Na is used in solution and saline solution washing ₂SO ₄Drying concentrates, and concentrate is used methanol wash, obtains the required product 6-chloro-of 55mg (yield 24%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide.

H ¹?NMR(DMSO-D ₆，300MHz)δ11.25-11.2(br?s，1H)，8.0-7.94(br?s，1H)，7.6-7.5(dd，1H)，7.4(d，1H)，6.8-6.7(t，1H)，4.0(t，2H)，3.2(d，2H)，3.1(t，2H)，2.1(t，2H)，1.0-0.9(m，1H)，0.5(d，2H)，0.3(s，2H)

LCMS：94.5％；m/z＝517.6

HPLC：94.79％

Embodiment 43

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 1 described mode, and step 4 is used with the similar mode of embodiment 6 described modes and carried out.

Step 5

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide synthetic

Under 0 ℃, with EDCI (256mg, 0.001mol) and HOBt (181mg; 0.001mol) join 6-chloro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1,2 that is stirring, 3; (200mg is 0.0004mol) in the solution in dry DMF (10mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1.30 hours down at 0 ℃.Then 0 ℃ add down hydrochloric acid O-methyl-azanol (111mg, 0.001mol), add then TEA (0.2ml, 0.001mol).Reactant mixture was being stirred 16 hours under the RT, under nitrogen atmosphere.Reactant mixture is distributed between EtOAc and water.With organic layer water, saturated NaHCO ₃Anhydrous Na is used in solution and saline solution washing ₂SO ₄Drying concentrates, and concentrate is used methanol wash, obtains the required product 6-chloro-of 105mg (yield 48%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide.

H ¹?NMR(DMSO-D ₆，300MHz)δ11.4-11.2(br?s，1H)，8.02-7.96(br?s，1H)，7.6-7.5(dd，1H)，7.4(d，1H)，6.8-6.7(t，1H)，4.0(t，2H)，3.4(s，3H)，3.1(t，2H)，2.1-2.0(m，2H)

LCMS：90％；m/z＝477.9

HPLC：96.6％

Embodiment 44

Step 5

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide synthetic

Under 0 ℃, with EDCI (256mg, 0.001mol) and HOBt (181mg; 0.001mol) join 6-chloro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1,2 that is stirring, 3; (200mg is 0.0004mol) in the solution in dry DMF (5mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was being stirred 1.30 hours under 0 ℃, under nitrogen atmosphere.Add NH down at 0 ℃ then ₄Cl (0.071g, 0.001mol), add then TEA (0.2ml, 0.001mol).Reactant mixture was stirred 16 hours under RT.Reactant mixture is distributed between EtOAc and water.With organic layer water, saturated NaHCO ₃Anhydrous Na is used in solution and saline solution washing ₂SO ₄Drying concentrates, and concentrate is used methanol wash, obtains the required product 6-chloro-of 60mg (yield 30%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Methanamide.

H ¹?NMR(DMSO-D ₆，300MHz)δ8.46-8.4(br?s，1H)，7.68-7.52(m，3H)，7.4(d，1H)，6.7(t，1H)，4.0(t，2H)，3.3-3.2(t，2H)，2.1-2.0(m，2H)

LCMS：98.68％；m/z＝447.8

HPLC：97.5％

Embodiment 45

Step 5

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide synthetic

Under 0 ℃, with EDCI (256mg, 0.001mol) and HOBt (181mg; 0.001mol) join 6-chloro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1,2 that is stirring, 3; (200mg is 0.000446mol) in the solution in dry DMF (5mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was being stirred 1.30 hours under 0 ℃, under nitrogen atmosphere.Then 0 ℃ add down hydrochloric acid O-ethyl-azanol (130mg, 0.001mol), TEA (0.2ml, 0.001mol).Reactant mixture was stirred 18 hours under RT.Reactant mixture is distributed between EtOAc and water.With organic layer water, saturated NaHCO ₃Anhydrous Na is used in solution and saline solution washing ₂SO ₄Drying concentrates, and concentrate is used methanol wash, obtains the required product 6-chloro-of 105mg (yield 48%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide.

H ¹?NMR(DMSO-D ₆，300MHz)δ11.25-11.2(br?s，1H)，8.02-7.94(br?s，1H)，7.6-7.5(d，1H)，7.4(d，1H)，6.8-6.7(t，1H)，4.0(t，2H)，3.6-3.5(m，2H)，3.1(t，2H)，2.1-2.0(m，2H)，1.1(t，3H)

LCMS：99％；m/z＝491.6

HPLC：96％

Embodiment 46

Step 5

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-amide synthetic

Under 0 ℃, with EDCI (256mg, 0.001mol) and HOBt (180mg; 0.001mol) join 6-chloro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1,2 that is stirring, 3; (200mg is 0.0004mol) in the solution in dry DMF (5mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was being stirred 1.30 hours under 0 ℃, under nitrogen atmosphere.Then 0 ℃ add down O-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethyl)-azanol (196mg, 0.001mol), TEA (0.2ml, 0.001mol).Reactant mixture was stirred 18 hours under RT.Reactant mixture is distributed between EtOAc and water.With organic layer water, saturated NaHCO ₃Anhydrous Na is used in solution and saline solution washing ₂SO ₄Drying concentrates, and obtains the required product 6-chloro-of 170mg (yield 66%) 7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-amide.

LCMS：61％；m/z＝577.8，M+1

Step 6

6-chloro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide synthetic

With 1N HCl (0.6mL) join stirring be dissolved in 6-chloro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1,2 among the EtOH (6mL), 3; 5-tetrahydrochysene-indolizine-8-formic acid (2; 2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-(170mg is in solution 0.0003mol) for amide.Reactant mixture was at room temperature stirred 2 hours.Distill ethanol, through with recrystallizing methanol with the bullion product purification, obtain 25mg (yield 17.35%) 7-(4-bromo-2-fluoro-phenyl amino)-6-chloro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide is white solid.

H ¹?NMR(DMSO-D ₆，300MHz)δ11.4-11.35(br?s，1H)，8.0-7.96(br?s，1H)，7.6-7.5(dd，1H)，7.4(dd，1H)，7.4(d，1H)，6.8(t，1H)，4.8(d，1H)，4.6(t，1H)，4.0(t，2H)，3.7-3.4(m，1H)，3.1(t，2H)，2.1-2.0(m，2H)

LCMS：85％；m/z＝491.7，M+1

HPLC：96％

Embodiment 47

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 8 described modes.

Step 4

6-fluoro-7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

Under-78 ℃, (416mg, (484mg 0.003mol) in the solution in THF (10mL), stirs the gained mixture 1 hour down at-78 ℃ 0.004mol) to join 2-fluoro-4-trifluoromethyl-phenyl amine with LDA.Add the 7-chloro-6-fluoro-5-oxo-1,2,3 that is arranged in THF (30mL) down at-78 ℃ then, (250mg 0.001mol), continues to stir 18 hours under RT 5-tetrahydrochysene-indolizine-8-formic acid again.By distilling THF in the reactant mixture, add 1N HCl (5mL) and ether (10mL) then.Reactant mixture was stirred 15 minutes and collecting precipitation, obtain the required product 6-fluoro-of 150mg (yield 37%) 7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid.

LC-MS purity: 100%, m/z=375, (M+)

HPLC：91.4％

¹H?NMR(DMSO-D ₆，300MHz)：δ13.8-13.6(br?s，1H)，9.6(s，1H)，7.7(d，1H)，7.52(d，1H)，7.15(q，1H)，4.1(t，2H)，3.5(t，2H)，2.2-2.1(m，2H)。

Embodiment 48

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 8 described modes, and step 4 is used with the similar mode of embodiment 47 described modes and carried out.

Step 5

6-fluoro-7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

With EDCI (138mg; 0.001mol) and HOBt (98mg 0.001mol) joins 6-fluoro-7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2 that is stirring; 3; (90mg 0.0002mol) in the solution in DMF (6mL), stirs reactant mixture 30 minutes under RT 5-tetrahydrochysene-indolizine-8-formic acid.Add then hydrochloric acid O-cyclopropyl methyl-azanol (90mg, 0.001mol) and TEA (73mg, 0.001mol).Reactant mixture was stirred 20 hours under RT.Reactant mixture is distributed between water and ethyl acetate (20mL).Organic layer is used saturated NaHCO ₃(20mL), NH ₄Na is used in Cl (20mL) and saline solution (20mL) washing ₂SO ₄Drying concentrates, and concentrate is dissolved in methanol (0.5mL) and the ether (10mL).Collect formed deposition, obtain the required product 6-fluoro-of 35mg (yield 33%) 7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide.

LCMS purity: 100%, m/z=443, (M+)

HPLC：94.3％

¹H?NMR(DMSO-D ₆，300MHz)：δ11.40(s，1H)，8.4(s，1H)，7.65(d，1H)，7.43(d，1H)，7.12-7.02(m，1H)，4.1(t，2H)，3.5(d，2H)，3.2(t，2H)，2.2-2.1(m，2H)，1.05-0.95(m，1H)，0.52-0.42(m，2H)，0.25-0.15(m，2H)。

Embodiment 49

Step 3a

Synthesizing of 2-fluoro-4-thiocyano (thiocyanato)-phenyl amine

With 2-fluoro-phenyl amine (2g, 0.018mol) join selectfluor reagent (5.9g, 0.017mol) and KSCN (1.81g 0.019mol) in the solution in acetonitrile, stirs the gained reactant 70 hours under RT.Distill solvent, reactants dissolved in water (300mL), with DCM (75mL) extracted twice, is washed organic layer water (100mL) and saline solution (100mL).Reactant mixture is used Na ₂SO ₄Drying concentrates, and concentrate with column chromatography (use silica gel, with the hexane solution of 5-10% ethyl acetate as eluant) purification, is obtained 740mg (yield 25%) 2-fluoro-4-thiocyano-phenyl amine, is light yellow liquid.

¹H?NMR(DMSO-D ₆，300MHz)：δ7.3-7.15(m，2H)，6.8(t，1H)，4.15-4.0(br?s，2H)

Step 3b

Synthesizing of 2-fluoro-4-methyl sulfenyl-phenyl amine

To be arranged in the Na of water (2.2mL) ₂(1.04g, (730mg 0.004mol) in the solution in ethanol (12mL), stirs reactant mixture 2 hours down at 50 ℃ S 0.011mol) to join 2-fluoro-4-thiocyano-phenyl amine.Add the CH that is arranged in ethanol (2mL) then ₃(683mg 0.0047mol), continues to stir 3 hours I again.Reactant is diluted with ethyl acetate, add entry (50mL) then, use ethyl acetate extraction.With organic layer water (20mL), saline solution (20mL) washing, concentrate, obtain the required product 2-fluoro-of 610mg (yield 89%) 4-methyl sulfenyl-phenyl amine.

¹H?NMR(DMSO-D ₆，300MHz)：δ7.2-6.92(m，2H)，6.72(t，1H)，3.8-3.6(br?s，2H)，2.4(s，3H)

Step 4

6-fluoro-7-(2-fluoro-4-methyl sulfenyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

Under-78 ℃, (316mg, (322mg 0.002mol) in the solution in THF (10mL), stirs the gained mixture 1.30 hours down at-78 ℃ 0.00296mol) to join 2-fluoro-4-methyl sulfenyl-phenyl amine with LDA.Add the 7-chloro-6-fluoro-5-oxo-1,2,3 that is arranged in THF (30mL) down at-78 ℃ then, (190mg 0.001mol), continues to stir 24 hours under RT 5-tetrahydrochysene-indolizine-8-formic acid again.By distilling THF in the reactant mixture, add 1N HCl (12mL) and ether (10mL) then.Reactant mixture was stirred 15 minutes and collecting precipitation, obtain 128mg 6-fluoro-7-(2-fluoro-4-methyl sulfenyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid and raw material promptly is used for next step with it without being further purified.

LC-MS purity: 50%, m/z=353, (M+)

Step 5

6-fluoro-7-(2-fluoro-4-methyl sulfenyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

With EDCI (227mg; 0.001mol) and HOBt (160mg 0.001mol) joins 6-fluoro-7-(2-fluoro-4-methyl sulfenyl-phenyl amino)-5-oxo-1,2 that is stirring; 3; (120mg 0.0003mol) in the solution in DMF (5mL), stirs reactant mixture 1 hour under RT 5-tetrahydrochysene-indolizine-8-formic acid.Add then hydrochloric acid O-cyclopropyl methyl-azanol (147mg, 0.001mol) and TEA (120mg, 0.001mol).Reactant mixture was stirred 16 hours under RT.Reactant mixture is distributed between ethyl acetate and water.Organic layer is used saturated NaHCO ₃, NH ₄Na is used in Cl, saline solution washing ₂SO ₄Drying concentrates.Concentrate is dissolved in methanol (0.5mL) and the ether (10mL).Collecting precipitation obtains the required product 6-fluoro-of 7mg (yield 9.8%) 7-(2-fluoro-4-methyl sulfenyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide.

LCMS purity: 89.5%, m/z=422, (M+)

HPLC：91％

¹H?NMR(DMSO-D ₆，300MHz)：δ11.4(s，1H)，8.0(s，1H)，7.2(d，1H)，7.0(s，2H)，4.0(t，2H)，3.5(d，2H)，3.2(t，2H)，2.5(s，3H)，2.14-2.04(m，2H)，1.05-0.95(m，1H)，0.55-0.45(m，2H)，0.25-0.15(m，2H)。

Embodiment 50

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 8 described modes, and step 4 is used with the similar mode of embodiment 11 described modes and carried out.

Flow process 9

Step 5

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid pentafluorophenyl group ester synthetic

With 2,3,4; 5, and 6-five fluoro-benzoic acid methyl ester trifluoroacetates (136mg, 0.0005mol) and pyridine (38mg; 0.0005mol) join 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3; (170mg 0.0004mol) in the solution in DMF (3ml), stirs reactant mixture 4 hours under RT 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture is distributed between ethyl acetate and water.Organic layer is used NaHCO ₃Washing is with 1M HCl solution and saline solution washed twice.Organic layer is used Na ₂SO ₄Drying concentrates, and obtains 256mg 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3, and 5-tetrahydrochysene-indolizine-8-formic acid pentafluorophenyl group ester bullion product promptly is used for next step with it without being further purified.

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formylhydrazine synthetic

(98mg, (35mg 0.001mol) in the solution in DCM (5ml), stirs reactant mixture 1 hour 0.001mol) to join the hydrazine hydrochloride that is stirring with TEA.Add 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3 then, (251mg 0.0005mol), continues to stir 8 hours 5-tetrahydrochysene-indolizine-8-formic acid pentafluorophenyl group ester again.Reactant mixture is distributed between ethyl acetate and water.With organic layer water washed twice, use saturated NaHCO ₃The saline solution washed twice is used in washing.Organic layer is used Na ₂SO ₄Drying concentrates, and obtains the required product 7-of 138mg (yield 55%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formylhydrazine.

LCMS purity: 78%, m/z=399,401, (M+)

Step 6a

Synthesizing of 2-(tert-butyl-dimethyl-silanyloxy base)-ethylamine

(23.4g, (20g 0.327mol) in the solution in DMF (400mL), is cooled to 0 ℃ with reactant mixture 0.344mol) to join 2-amino-ethanol with imidazoles.(51.8g 0.344mol), stirs reactant mixture 3 hours under RT to add tert-butyl-chloro-dimethyl-silane then.With residue water (1L) dilution, with ethyl acetate (300mL) extracted twice.With ethyl acetate layer water, 0.1N HCl (100mL) and saline solution (100mL) washing.Organic layer is used Na ₂SO ₄Drying concentrates, and the bullion product with column chromatography (use silica gel, with the hexane solution of 30-40% ethyl acetate as elution system) purification, is obtained the required product 2-of 18.1g (yield 31%) (tert-butyl-dimethyl-silanyloxy base)-ethylamine.

LCMS purity: 92%, m/z=176, (M+)

Step 6b

Synthesizing of imidazoles-1-formic acid [2-(tert-butyl-dimethyl-silanyloxy base)-ethyl]-amide

Under RT, (7.3g, (10.11g 0.062mol) in the solution in THF (60mL), down stirs reactant mixture 8 hours at 50 ℃ 0.042mol) to join CDI will to be arranged in 2-(tert-butyl-dimethyl-silanyloxy base)-ethylamine of DCM (150mL).From reactant mixture, distill solvent; The bullion product of remnants (is used silica gel with column chromatography; With the hexane solution of 20-40% ethyl acetate as elution system) purification, obtain the required product imidazoles of 2.1g (yield 19%)-1-formic acid [2-(tert-butyl-dimethyl-silanyloxy base)-ethyl]-amide.

LCMS purity: 94.5%, m/z=270, (M+)

Step 7

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid N '-2-(tert-butyl-dimethyl-silanyloxy base)-ethyl-amino-carbonyl-hydrazides synthetic

With acetic acid (63mg; 0.0003mol) and 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3; 5-tetrahydrochysene-indolizine-8-formylhydrazine (135mg; 0.0003mol) join that imidazoles-1-formic acid [2-(tert-butyl-dimethyl-silanyloxy base)-ethyl]-(91mg 0.0003mol) in the solution in THF (10mL), stirs reactant mixture 14 hours amide under RT.From reactant mixture, distill solvent; Obtain 213mg 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1; 2; 3,5-tetrahydrochysene-indolizine-8-formic acid N '-2-(tert-butyl-dimethyl-silanyloxy base)-ethyl-amino-carbonyl-hydrazides bullion product promptly is used for next step with it without being further purified.

LCMS purity: 49%, m/z=600, (M+)

Step 8

7-(4-bromo-2-fluoro-phenyl amino)-8-{5-[2-(tert-butyl-dimethyl-silanyloxy base)-ethylamino]-[1; 3; 4]

diazole-2-yl }-6-fluoro-2,3-dihydro-1H-indolizine-5-ketone synthetic

With toluene sulfochloride (63mg; 0.0003mol) and TEA (84mg 0.0008mol) joins 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-5-oxo-1,2 that is stirring; 3; (200mg 0.0003mol) in the solution in DCM (8mL), stirs reactant mixture 12 hours under RT 5-tetrahydrochysene-indolizine-8-formic acid N '-2-(tert-butyl-dimethyl-silanyloxy base)-ethyl-amino-carbonyl-hydrazides.From reactant mixture, distill DCM,, use ethyl acetate extraction the mixture dilute with water of remnants.Organic layer is used Na ₂SO ₄Drying concentrates, and obtains 18.1g (yield 31%) 7-(4-bromo-2-fluoro-phenyl amino)-8-{5-[2-(tert-butyl-dimethyl-silanyloxy base)-ethylamino]-[1,3,4] two

Azoles-2-yl }-6-fluoro-2,3-dihydro-1H-indolizine-5-ketone bullion product promptly is used for next step with it without being further purified.

Step 9

diazole-2-yl]-2,3-dihydro-1H-indolizine-5-ketone synthetic

Under 0 ℃; With acetic acid (25mg; 0.0004mol) and tetrabutylammonium (168mg 0.0006mol) joins 7-(4-bromo-2-fluoro-phenyl amino)-8-{5-[2-(tert-butyl-dimethyl-silanyloxy base)-ethylamino]-[1,3; 4]

diazole-2-yl }-6-fluoro-2; (250mg 0.0004mol) in the solution in THF (6mL), stirs reactant mixture 3 hours under RT 3-dihydro-1H-indolizine-5-ketone.Reactant mixture is diluted with ethyl acetate and water.Organic layer is used NaHCO ₃Na is used in solution, 1M HCl and saline solution washing ₂SO ₄Drying concentrates.The bullion product is dissolved among the DCM (2mL); Add ether then; Collect formed deposition; Drying obtains the required product 7-of 27.5mg (yield 14%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-[5-(2-hydroxyl-ethylamino)-[1,3; 4]

diazole-2-yl]-2,3-dihydro-1H-indolizine-5-ketone.

LCMS purity: 92.2%, m/z=468,470 (M+)

HPLC：95％

¹H?NMR(DMSO-D ₆，300MHz)：δ9.1(s，1H)，7.82(t，1H)，7.55(d，1H)，7.32(s，1H)，7.12(m，1H)，4.8(t，1H)，4.1(t，2H)，3.6-3.5(q，12H)，3.4-3.2(m，4H)，2.3-2.1(m，2H)。

Embodiment 51

Step 5

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide synthetic

With EDCI (296mg; 0.0015mol) and HOBt (209mg 0.0015mol) joins 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-5-oxo-1,2 that is stirring; 3; (200mg 0.0005mol) in the solution in DMF (5mL), stirs reactant mixture 1 hour under RT 5-tetrahydrochysene-indolizine-8-formic acid.Add then O-methyl-azanol (130mg, 0.002mol) and TEA (156mg, 0.002mol).Reactant mixture was stirred 19 hours under RT.Reactant mixture is distributed between water and ethyl acetate.Organic layer is used saturated NaHCO ₃, saturated NH ₄Na is used in Cl and saline solution washing ₂SO ₄Drying concentrates.Concentrate is dissolved among the IPA (2mL), adds ether (15mL) then.Collect formed deposition, obtain the required product 7-of 57mg (yield 27%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-amide.

LCMS purity: 97%, m/z 413,415 (M+, Br pattern)

HPLC：99％

¹H?NMR(DMSO-D ₆，300MHz)：δ11.42(s，1H)，8.1(s，1H)，7.5(d，1H)，7.3(d，1H)，6.98(m，1H)，4.00(t，2H)，3.6(s，3H)，3.3(t，2H)，2.10(m，2H)

Embodiment 52

Step 5

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide synthetic

With EDCI (296mg; 0.002mol) and HOBt (209mg 0.002mol) joins 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-5-oxo-1,2 that is stirring; 3; (200mg 0.0005mol) in the solution in DMF (5mL), stirs reactant mixture 1 hour under RT 5-tetrahydrochysene-indolizine-8-formic acid.Add then O-ethyl-azanol (152mg, 0.002mol) and TEA (156mg, 0.002mol).Reactant mixture was stirred 18 hours under RT.Reactant mixture is distributed between water and ethyl acetate.Organic layer is used saturated NaHCO ₃, saturated NH ₄Na is used in Cl and saline solution washing ₂SO ₄Drying concentrates.Concentrate is dissolved in the methanol (1mL),, collects formed deposition to wherein adding ether (10mL); Obtain the required product 7-of 97mg (yield 44%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1; 2,3,5-tetrahydrochysene-indolizine-8-formic acid ethyoxyl-amide.

LCMS purity: 97%, m/z 428,430 (M+, Br pattern)

HPLC：97.6％

¹H?NMR(DMSO-D ₆，300MHz)：δ11.4(s，1H)，8.08(s，1H)，7.52(d，1H)，7.28(d，1H)，6.98(m，1H)，4.00(t，2H)，3.8(q，2H)，3.2(t，2H)，2.10(m，2H)，1.12(t，3H)

Embodiment 53

Step 5

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-vinyl oxygen base-ethyoxyl)-amide synthetic

With EDCI (148mg; 0.001mol) and HOBt (104mg 0.001mol) joins 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-5-oxo-1,2 that is stirring; 3; (100mg 0.0003mol) in the solution in DMF (3mL), stirs reactant mixture 1.30 hours under RT 5-tetrahydrochysene-indolizine-8-formic acid.Add then O-(2-vinyl oxygen base-ethyl)-azanol (80mg, 0.001mol) and TEA (78mg, 0.001mol).Reactant mixture was stirred 19 hours under RT.Reactant mixture is distributed between water and ethyl acetate.Organic layer is used saturated NaHCO ₃, saturated NH ₄Na is used in Cl and saline solution washing ₂SO ₄Drying concentrates, and obtains 110mg bullion product, and it promptly is used for next step without being further purified.

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide synthetic

1N HCl (1.6mL) is joined 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-5-oxo-1 that is stirring; 2; 3, (110mg is 0.0002mol) in 1: 1 THF and the solution in the EtOH mixture (2mL) for 5-tetrahydrochysene-indolizine-8-formic acid (2-vinyl oxygen base-ethyoxyl)-amide.Reactant mixture was stirred 1 hour.Reactant mixture is diluted with ethyl acetate; With 2N NaOH pH is transferred to 5, extract with EtOAc.

Organic layer is used Na ₂SO ₄Drying concentrates.Concentrate is dissolved among the 2mL IPA; To wherein adding the 10mL ether and collecting formed deposition, obtain the required product 7-of 8mg (yield 7%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2; 3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide.

LCMS purity: 91.8%, m/z=443.9,445.9 (M+, Br patterns)

HPLC：98.2％

¹H?NMR(DMSO-D ₆，300MHz)：δ11.42(s，1H)，8.1(s，1H)，7.5(d，1H)，7.3(d，1H)，6.98(m，1H)，4.8(t，1H)，4.00(t，2H)，3.8(t，2H)3.55(t，2H)，3.2(t，2H)，2.12(m，2H)

Embodiment 54

Step 4

7-(4-bromo-2-methyl-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

Under-78 ℃, (2.33g, (1.4mg 0.008mol) in the solution in THF (10mL), stirs the gained mixture 1 hour down at-78 ℃ 0.011mol) to join 4-bromo-2-methyl-phenyl amine with LDA.Add the 7-chloro-6-fluoro-5-oxo-1,2,3 that is arranged in THF (50mL) down at-78 ℃ then, (700mg 0.003mol), continues to stir 20 hours under RT 5-tetrahydrochysene-indolizine-8-formic acid again.Distill THF, add 1N HCl (20mL), water (25mL) and ether (10mL) then.Collect formed deposition, obtain 281mg (yield 24%) 7-(4-bromo-2-methyl-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid.

LCMS purity: 96%, m/z 380,382 (M+, Br pattern)

HPLC：95.89％

¹H?NMR(DMSO-D ₆，300MHz)：δ13.70(s，1H)，9.4(s，1H)，7.4(s，1H)，7.3(d，1H)，6.8(m，1H)，4.04(t，2H)，3.48(t，2H)，2.25(s，3H)，2.10(m，2H)。

Embodiment 55

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 8 described modes, and step 4 is used with the similar mode of embodiment 54 described modes and carried out.

Step 5

7-(4-bromo-2-methyl-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

With EDCI (346mg; 0.002mol) and HOBt (244mg 0.002mol) joins 7-(4-bromo-2-methyl-phenyl amino)-6-fluoro-5-oxo-1,2 that is stirring; 3; (230mg 0.001mol) in the solution in DMF (3mL), stirs reactant mixture 1 hour under RT 5-tetrahydrochysene-indolizine-8-formic acid.Add then O-cyclopropyl methyl-azanol (224mg, 0.002mol) and TEA (183mg, 0.002mol).Reactant mixture was stirred 24 hours under RT.Reactant mixture is distributed between water and ethyl acetate.Organic layer is used saturated NaHCO ₃, saturated NH ₄Na is used in Cl and saline solution washing ₂SO ₄Drying concentrates.Concentrate is dissolved in the 5mL methanol; To wherein adding the 25mL ether and collecting formed deposition, obtain the required product 7-of 40mg (yield 14.7%) (4-bromo-2-methyl-phenyl amino)-6-fluoro-5-oxo-1,2; 3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide.

LCMS purity: 95%, m/z 450,452 (M+, Br pattern)

HPLC：96.1％

¹H?NMR(DMSO-D ₆，300MHz)：δ11.30(s，1H)，7.78(s，1H)，7.4(s，1H)，7.22(d，1H)，6.88(m，1H)，4.00(t，2H)，3.4(d，2H)，3.20(t，2H)，2.2(s，3H)2.10(m，2H)，1.00(m，1H)，0.50(m，2H)，0.20(m，2H)

Embodiment 56

Step 4

7-(4-bromo-2-methyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

Under-78 ℃, (2.7g, (3.28mg 0.018mol) in the solution in THF (30mL), stirs the gained mixture 45 minutes down at-78 ℃ 0.0253mol) to join 4-bromo-2-methyl-phenyl amine with LDA.Add down the 7-chloro-5-oxos-1,2,3 that are arranged in THF (90mL) at-78 ℃ then, and 5-tetrahydrochysene-indolizine-8-formic acid (1.5g, 0.01mol) and under RT, continue again to stir 21 hours.Distill THF, add 60mL 1N HCl (pH=1), water (115mL) and ether (115mL) then.Collect formed deposition, obtain 610mg (yield 36%) 7-(4-bromo-2-methyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid.

LCMS purity: 93%, m/z 363,365 (M+, Br pattern)

HPLC：95.3％

¹H?NMR(DMSO-D ₆，300MHz)：δ13.30(s，1H)，9.8(s，1H)，7.6(s，1H)，7.42(d，1H)，7.2(m，1H)，5.08(s，1H)，3.8(t，2H)，3.48(t，2H)，2.35(s，3H)，2.15(m，2H)。

Embodiment 57

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 8 described modes, and step 4 is used with the similar mode of embodiment 56 described modes and carried out.

Step 5

7-(4-bromo-2-methyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

With EDCI (473mg; 0.002mol) and HOBt (334mg 0.002mol) joins 7-(4-bromo-2-methyl-phenyl amino)-5-oxo-1,2 that is stirring; 3; (300mg 0.001mol) in the solution in DMF (3mL), stirs reactant mixture 1 hour under RT 5-tetrahydrochysene-indolizine-8-formic acid.Add then O-cyclopropyl methyl-azanol (306mg, 0.002mol) and TEA (250mg, 0.002mol).Reactant mixture was stirred 26 hours under RT.Reactant mixture is distributed between EtOAc and water.Organic layer is used saturated NH ₄Cl, saturated NaHCO ₃Na is used in solution and saline solution washing ₂SO ₄Drying concentrates.Concentrate is dissolved in the 2.5mL methanol; To wherein adding the 10mL ether and collecting formed deposition, obtain the required product 7-of 47mg (yield 13%) (4-bromo-2-methyl-phenyl amino)-5-oxo-1,2; 3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide.

LCMS purity: 96%, m/z 432,434 (M+, Br pattern)

HPLC：92.1％

¹H?NMR(DMSO-D ₆，300MHz)：δ11.36(s，1H)，8.02(s，1H)，7.58(s，1H)，7.4(d，1H)，7.15(m，1H)，5.02(s，1H)3.8(t，2H)，3.7(d，2H)，3.20(t，2H)，2.2(s，3H)2.16(m，2H)，1.10(m，1H)，0.52(m，2H)，0.30(m，2H)

Embodiment 58

Step 5

2-{1-[6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-carbonyl]-3-hydroxyl-azetidine-3-yl }-piperidines-1-formic acid tert-butyl ester synthetic

With EDCI (154mg; 0.001mol) and HOBt (100mg 0.001mol) joins 6-fluoro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1,2 that is stirring; 3; (140mg 0.0003mol) in the solution in DMF (4mL), stirs reactant mixture 1 hour under RT 5-tetrahydrochysene-indolizine-8-formic acid.Add then 2-(3-hydroxyl-azetidine-3-yl)-piperidines-1-formic acid tert-butyl ester (S-isomer) (166mg, 0.001mol) and TEA (98mg, 0.001mol).Reactant mixture was stirred 16 hours under RT.Reactant mixture is distributed between EtOAc and water.Organic layer is used saturated NH ₄Cl, saturated NaHCO ₃Na is used in solution and saline solution washing ₂SO ₄Drying concentrates.Concentrate (is used silica gel with column chromatography; With the DCM solution of 2-3% methanol as eluant) purification; Obtain the required product 2-{1-of 180mg (yield 82.9%) [6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1; 2,3,5-tetrahydrochysene-indolizine-8-carbonyl]-3-hydroxyl-azetidine-3-yl }-piperidines-1-formic acid tert-butyl ester (S-isomer).

Step 6

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-8-(3-hydroxyl-3-piperidines-2-base-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-keto hydrochloride synthetic

With 4N be arranged in two

of HClalkane (2.5mL) joins 2-{1-[6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1; 2; 3; 5-tetrahydrochysene-indolizine-8-carbonyl]-3-hydroxyl-azetidine-3-yl }-piperidines-1-formic acid tert-butyl ester (S-isomer) (50mg; 0.0001mol) in the solution in methanol (2mL), the gained mixture was stirred 1 hour under RT.From reactant mixture, distill solvent; Residue is ground with ether; Obtain the required product 6-fluoro-of 34mg (yield 75%) 7-(2-fluoro-4-iodo-phenyl amino)-8-(3-hydroxyl-3-piperidines-2-base-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-keto hydrochloride (S-isomer).

LCMS purity: 95.5%, m/z=570.9 (M+)

HPLC：91.6％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.4-8.2(br?s，1H)，8.1(s，1H)，7.6(d，1H)，7.4(d，1H)，7.02-6.92(m，1H)，4.2-4.1(m，1H)，4.10-3.95(m，3H)，3.9-3.8(m，1H)，3.75-3.65(m，1H)，3.5-3.45(m，1H)，3.2-3.1(m，2H)，3.08(t，2H)，2.9-2.8(m，1H)，2.2-2.08(m，2H)，1.75-1.65(m，4H)，1.5-1.35(m，2H)

Embodiment 59

Step 5

2-{1-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-carbonyl]-3-hydroxyl-azetidine-3-yl }-piperidines-1-formic acid tert-butyl ester synthetic

With EDCI (185mg; 0.001mol) and HOBt (131mg 0.001mol) joins 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-5-oxo-1,2 that is stirring; 3; (250mg 0.001mol) in the solution in DMF (5mL), stirs reactant mixture 1 hour under RT 5-tetrahydrochysene-indolizine-8-formic acid.Add then 2-(3-hydroxyl-azetidine-3-yl)-piperidines-1-formic acid tert-butyl ester (racemic mixture) (199mg, 0.001mol) and TEA (196mg, 0.002mol).Reactant mixture was stirred 16 hours under RT.Reactant mixture is distributed between EtOAc and water.Organic layer is used saturated NH ₄Cl (10mL), saturated NaHCO ₃Na is used in solution (10mL) and saline solution (10mL) washing ₂SO ₄Drying concentrates.Concentrate is dissolved in the 3mL ethyl acetate; Obtain deposition; It is collected, obtain the required product 2-{1-of 200mg (yield 49.6%) [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2; 3,5-tetrahydrochysene-indolizine-8-carbonyl]-3-hydroxyl-azetidine-3-yl }-piperidines-1-formic acid tert-butyl ester (racemic mixture).

HPLC：98.4％

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(3-hydroxyl-3-piperidines-2-base-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-ketone synthetic

With 4N be arranged in two

of HClalkane (4mL) joins 2-{1-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1; 2; 3; 5-tetrahydrochysene-indolizine-8-carbonyl]-3-hydroxyl-azetidine-3-yl }-piperidines-1-formic acid tert-butyl ester (racemic mixture) (75mg; 0.0001mol) in the solution in methanol (1mL), the gained mixture was stirred 1 hour under RT.From reactant mixture, distill solvent.Grind with the 5mL ether; Obtain deposition; It is collected, obtain the required product 7-of 48mg (yield 71.6%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(3-hydroxyl-3-piperidines-2-base-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-ketone (racemic mixture).

LC-MS purity: 97%, m/z 523,525 (M+, Br pattern)

¹H?NMR(DMSO-D ₆)：δ8.3-8.2(br?s，1H)，8.12(s，1H)，7.52(d，1H)，7.3(d，1H)，7.16-7.02(m，1H)，4.2-4.1(m，1H)，4.10-3.90(m，4H)，3.75-3.65(m，1H)，3.5-3.45(m，1H)，3.2-3.1(m，2H)，3.08(t，2H)，2.9-2.8(m，1H)，2.2-2.08(m，2H)，1.8-1.5(m，4H)，1.45-1.3(m，2H)

Embodiment 60

Step 5

With EDCI (165mg; 0.001mol) and HOBt (178mg 0.001mol) joins 6-fluoro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1,2 that is stirring; 3; (250mg 0.001mol) in the solution in DMF (5mL), stirs reactant mixture 1 hour under RT 5-tetrahydrochysene-indolizine-8-formic acid.Add then 2-(3-hydroxyl-azetidine-3-yl)-piperidines-1-formic acid tert-butyl ester (racemic mixture) (180mg, 0.001mol) and TEA (175mg, 0.002mol).Reactant mixture was stirred 16 hours under RT.Reactant mixture is distributed between EtOAc and water.Organic layer is used saturated NH ₄Cl (10mL), saturated NaHCO ₃Na is used in solution (10mL) and saline solution (10mL) washing ₂SO ₄Drying concentrates.Concentrate (100mg) promptly is used for next step without being further purified.

Step 6

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-8-(3-hydroxyl-3-piperidines-2-base-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-ketone synthetic

With 4N be arranged in two

of HClalkane (5mL) joins 2-{1-[6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1; 2; 3; 5-tetrahydrochysene-indolizine-8-carbonyl]-3-hydroxyl-azetidine-3-yl }-piperidines-1-formic acid tert-butyl ester (racemic mixture) (100mg; 0.0001mol) in the solution in methanol (1mL), the gained mixture was stirred 1 hour under RT.From reactant mixture, distill solvent; Obtain deposition; It is used the preparation HPLC purification; Obtain the required product 6-fluoro-of 15mg (yield 16.6%) 7-(2-fluoro-4-iodo-phenyl amino)-8-(3-hydroxyl-3-piperidines-2-base-azetidine-1-carbonyl)-2,3-dihydro-1H-indolizine-5-ketone (racemic mixture).

LC-MS purity: 95%, m/z 571 (M+)

¹H?NMR(DMSO-D ₆)：δ8.6-8.4(br?s，1H)，8.2(s，1H)，7.6(d，1H)，7.44(d，1H)，6.98-6.9(m，1H)，4.2-4.1(m，1H)，4.10-3.95(m，3H)，3.9-3.8(m，1H)，3.75-3.65(m，1H)，3.5-3.45(m，1H)，3.2-3.1(m，2H)，3.08(t，2H)，2.9-2.8(m，1H)，2.2-2.08(m，2H)，1.75-1.65(m，4H)，1.5-1.35(m，2H)

Embodiment 61

Flow process: 10 ^*

^*In step 8, B must be 2.

Step 5

3-(4-bromo-2-fluoro-phenyl)-4-fluoro-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

With TEA (0.12mL; 0.001mol) and DPPA (0.18mL 0.001mol) joins 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2; 3; (300mg 0.001mol) in the solution in DMF (5mL), under the RT, under nitrogen atmosphere is stirring reactant mixture 4 hours 5-tetrahydrochysene-indolizine-8-formic acid.Add toluene (5mL) then, reactant mixture is heated to 90 ℃ reaches 2 hours.With the reactant mixture concentrating under reduced pressure, add entry, obtain deposition, it is collected and drying; Obtain the required product 3-of 250mg (yield 84%) (4-bromo-2-fluoro-phenyl)-4-fluoro-1,6,7,8-tetrahydrochysene-3H-1; 3,5a-three azepines-asymmetric-indacene-2,5-diketone.

Step 6

3-(4-bromo-2-fluoro-phenyl)-1-cyclopropane sulfonyl-4-fluoro-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Under 0-5 ℃, under nitrogen atmosphere, with 60%NaH (30mg; 0.001mol) join 3-(4-bromo-2-fluoro-the phenyl)-4-fluoro-1,6,7 that is stirring; 8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2; (0.2g 0.001mol) in the solution in dry DMF (4mL), stirs the gained mixture 1 hour under RT the 5-diketone.Under 0 ℃, go through then and dripped the cyclopropane sulfonic acid chloride be arranged in dry THF in 10 minutes (110mg 0.001mol), next continues stirring 16 hours under RT.The bullion product promptly is used for next step without being further purified.

Step 7

Synthesizing of cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

1N NaOH aqueous solution (6mL) is joined 3-(4-bromo-2-fluoro-phenyl)-1-cyclopropane sulfonyl-4-fluoro-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2 in the 5-diketone, ℃ reach gained mixture heated to 65 at 4 hours.In reactant mixture, add icy water, it is about 4 to be neutralized to pH with 5% ice-cold HCl, and reactant mixture is distributed between ethyl acetate and water.Organic layer is used Na ₂SO ₄Drying, concentrating under reduced pressure (uses silica gel with concentrate with column chromatography; With the DCM solution of 2% methanol as eluant) purification, obtain the required product cyclopropane sulfonic acid of 21mg (yield 8.5%) [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2; 3,5-tetrahydrochysene-indolizine-8-yl]-amide.

LCMS purity: 98.89%, m/z=461.9 (M+)

HPLC：93.6％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.9(s，1H)，7.65-7.25(m，3H)，4.1(t，2H)，3.2(t，2H)，2.8-2.7(m，1H)，2.2-2.1(m，2H)，0.95-0.85(m，4H)

Embodiment 62

Step 1 to 4 usefulness are carried out with the similar mode of embodiment 8 described modes, and step 5 is used with the similar mode of embodiment 61 described modes and carried out.

Step 6

3-(4-bromo-2-fluoro-phenyl)-4-fluoro-2,5-dioxo-2,3,5,6,7,8-six hydrogen-1,3,5a-three azepines-asymmetric-indacene-1-formic acid tert-butyl ester synthetic

Under RT, under nitrogen atmosphere, (0.4g 0.01mol) joins 3-(4-bromo-2-fluoro-the phenyl)-4-fluoro-1 that is stirring with 60%NaH; 6,7,8-tetrahydrochysene-3H-1,3; 5a-three azepines-asymmetric-indacene-2, (2.5g is 0.007mol) in the solution in dry DMF (20mL) for the 5-diketone.The gained mixture was stirred 30 minutes.Under 0 ℃, go through then and dripped the BOC anhydride be arranged in dry THF in 5 minutes (1.9g 0.009mol), stirs reactant mixture 4 hours under RT.The bullion product promptly is used for next step without being further purified.

Step 7

Synthesizing of [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-carbamic acid tert-butyl ester

Under 0 ℃, 1N NaOH aqueous solution (15mL) is joined 3-(4-bromo-2-fluoro-phenyl)-4-fluoro-2,5-dioxo-2,3; 5,6,7,8-six hydrogen-1; 3, in 5a-three azepines-asymmetric-indacene-1-formic acid tert-butyl ester, the gained mixture was stirred 6 hours under RT.Reactant is used ethyl acetate extraction.Organic layer is used water washing, use Na ₂SO ₄Drying, concentrating under reduced pressure obtains the required product of 1.15g (yield 28%) [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-carbamic acid tert-butyl ester.

¹HNMR(CDCl ₃，300MHz)：δ7.45-6.7(m，3H)，6.1(s，1H)，5.65(s，1H)，4.25(t，2H)，3.15(t，2H)，2.25-2.0(m，2H)，1.45(s，9H)。

Step 8

8-amino-7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-2,3-dihydro-1H-indolizine-5-ketone synthetic

The dense HCl of 1N (4mL) is joined [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1 that is stirring; 2,3,5-tetrahydrochysene-indolizine-8-yl]-carbamic acid tert-butyl ester (0.9g; 0.002mol) in the solution in THF (10mL), reactant mixture was stirred 4 hours under RT.With the reactant mixture concentrating under reduced pressure, add saturated NaHCO ₃Solution is used ethyl acetate extraction.Organic layer is used anhydrous Na ₂SO ₄Drying, concentrating under reduced pressure obtains the required product 8-amino-7-of 360mg (yield 72%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-2,3-dihydro-1H-indolizine-5-ketone.

¹HNMR(DMSO，300MHz)：δ7.85-6.85(m，3H)，4.2(s，2H)，4.12(t，2H)，3.1(t，2H)，2.25-2.0(m，2H)

Step 9

N-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-N, N-dimethyl-amino-sulfonamide synthetic

Pyridine (2mL) is joined 8-amino-7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-2, and (200mg in solution 0.001mol), stirs reactant mixture 5 minutes under nitrogen atmosphere 3-dihydro-1H-indolizine-5-ketone.(5mg 0.0004mol), is cooled to 0 ℃ with reactant, adds N, and (85mg 0.001mol), next continues under RT, to stir 16 hours N-dimethyl-sulfonic acid chloride to add DMAP then.With TLC (100% ethyl acetate) monitoring reaction, it shows and has raw material.Reactant mixture is heated to 50 ℃ reaches 2 hours.With reactant mixture ethyl acetate (3 * 50mL) and water between distribute.Organic layer is used saturated NH ₄The Cl solution washing is used Na ₂SO ₄Drying, concentrating under reduced pressure (uses neutral alumina with concentrate with column chromatography; With ethyl acetate as eluant) purification; Obtain the required product N-of 22mg (yield 8%) [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3; 5-tetrahydrochysene-indolizine-8-yl]-N, N-dimethyl-amino-sulfonamide.

LCMS purity: 96.189%, m/z=463 (M+)

HPLC：98％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.7(s，1H)，7.6-6.85(m，3H)，4.15(t，2H)，3.29(t，2H)，2.7(s，6H)，2.2-2.1(m，2H)

Embodiment 63

Step 1 to 4 usefulness are carried out with the similar mode of embodiment 8 described modes, and step 5 is used with the similar mode of embodiment 61 described modes and carried out, and step 6 to 8 usefulness are carried out with the similar mode of embodiment 62 described modes.

Step 8a

Synthesizing of N-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethyl)-chloro-sulfonamide

Under-78 ℃, will be arranged in dry DCM C-(2,2-dimethyl-[1; 3] dioxolanes-4-yl)-methyl amine (300mg, 0.00229mol) and DMAP (295mg 0.0024mol) joins the chlorosulfuric acid (320mg that is stirring; 0.0023mol) in the solution in DCM; The gained mixture was stirred 1 hour down at 78 ℃, stirred 2 hours down, under RT, stirred 2 hours at-50 ℃.Formed product is used for next step.

Step 9

Synthesizing of N-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-C-(2,2-dimethyl-[1,3] dioxolanes-4-yl)-methyl amine-sulfonamide

Under 0 ℃; Go through and N-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethyl)-chloro-sulfonamide (0.001mol) was added drop-wise in 10 minutes 8-amino-7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-2 that is stirring; 3-dihydro-1H-indolizine-5-ketone (200mg; 0.001mol) (50mg in the solution in 0.0004mol), is heated to 40 ℃ with reactant mixture and reaches 16 hours at dry pyridine (3mL) and DMAP.With the reactant mixture concentrating under reduced pressure, concentrate is distributed between ethyl acetate and water.With organic layer concentrate and with concentrate with column chromatography (use neutral alumina; With DCM as eluant) purification, obtain the required product N-of 26mg (yield 5%) [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2; 3; 5-tetrahydrochysene-indolizine-8-yl]-C-(2,2-dimethyl-[1,3] dioxolanes-4-yl)-methyl amine-sulfonamide.

¹H?NMR(DMSO，300MHz)：δ8.7(s，1H)，7.6-6.7(m，3H)，4.1-3.8(m，4H)，3.65-3.5(m，1H)，3.3-3.2(m，1H)，3.2(t，2H)，3.1-2.9(m，1H)，2.9-2.6(m，1H)，2.1(t，2H)，1.2(d，6H)

Step 10

2,3-dihydroxy-propane-amino-sulfonic acid-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide synthetic

Under 20 ℃, dense HCl (1mL) is joined the N-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2 that is stirring; 3; 5-tetrahydrochysene-indolizine-8-yl]-C-(2,2-dimethyl-[1,3] dioxolanes-4-yl)-methyl amine-sulfonamide (26mg; 0.00005mol) in the solution in ethanol (4mL), reactant mixture was stirred 4 hours under RT.With the reactant mixture concentrating under reduced pressure, add ether, decantation; Drying under reduced pressure obtains the required product 2 of 16mg (yield 70%), 3-dihydroxy-propane-amino-sulfonic acid-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1; 2,3,5-tetrahydrochysene-indolizine-8-yl]-amide.

LCMS purity: 97.1%, m/z=509 (M+)

HPLC：96.8％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.7(s，1H)，7.6-6.85(m，3H)，4.15(t，2H)，3.4(t，2H)，3.25-3.15(m，2H)，3.1-3.0(m，2H)，2.85-2.75(m，1H)

Embodiment 64

Flow process 11

Step 8a

Synthesizing of pyrrolidine-2-carboxylic acid benzyl ester hydrochloride

Under-10 ℃, under nitrogen atmosphere, (3g 0.026mol) joins in the benzylalcohol (20mL), and reactant mixture was stirred 16 hours under RT with thionyl chloride (8mL) and pyrrolidine-2-formic acid.Reactant is diluted with dry ether, under RT, stirred 2 hours, obtain deposition, with excessive ether washing precipitation, decantation and drying under reduced pressure obtain the required product pyrrolidine of 4g (yield 66%)-2-carboxylic acid benzyl ester hydrochloride.

¹H?NMR(CDCl ₃，300MHz)：δ10.9(s，1H)，9.2(s，1H)，7.2-7.6(s，5H)，5.2(t，2H)，4.9(s，1H)，4.5(s，1H)，3.5(t，2H)，2.4-2.3(m，1H)，2.2-2.1(m，2H)

Step 8b

Synthesizing of 1-chlorosulfonyl-pyrrolidine-2-benzyl formate

Under RT, with DMAP (0.5g, 0.004mol) and TEA (1.6mg, (3g 0.015mol) in the solution in dry toluene (40mL), stirs the gained mixture 20 minutes 0.016mol) to join pyrrolidine-2-carboxylic acid benzyl ester hydrochloride of stirring.Reactant mixture is cooled to-10 ℃, go through then dripped in 15 minutes chlorosulfuric acid (2g, 0.015mol) and under RT, continue stirring 3 hours.Reactant is used saturated NH ₄The cancellation of Cl solution with the DCM extraction, is used Na with organic layer ₂SO ₄Drying concentrates, and obtains 1.2g 1-chlorosulfonyl-pyrrolidine-2-benzyl formate bullion product.

¹H?NMR(DMSO-D ₆，300MHz)：δ10.9(s，1H)，9.2(s，1H)，7.6-7.2(br?s，5H)，5.2(t，2H)，4.9(s，1H)，4.5(s，1H)，3.5(t，2H)，2.4(m，1H)，2.2(m，2H)

Step 9

Synthesizing of 1-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-base sulfamoyl]-pyrrolidine-2-benzyl formate

Under nitrogen atmosphere, with pyridine (3mL) and DMAP (20mg 0.0002mol) joins 8-amino-7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-2,3-dihydro-1H-indolizine-5-ketone (110mg, 0.0003mol) in, reactant mixture is cooled to 0 ℃.Go through then and dripped the 1-chlorosulfonyl-pyrrolidine-2-benzyl formate be arranged in DCM in 15 minutes (300mg, 0.001mol), stirring is 1 hour under RT, is heated to 60 ℃ and reaches 16 hours.With the reactant concentrating under reduced pressure, concentrate is distributed between ethyl acetate and water.Organic layer is used Na ₂SO ₄Drying is with column chromatography (use silica gel, 100% ethyl acetate is as eluant) purification; Obtain the required product 1-of 65mg (yield 33%) [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1; 2,3,5-tetrahydrochysene-indolizine-8-base sulfamoyl]-pyrrolidine-2-benzyl formate.

¹H?NMR(DMSO-D ₆，300MHz)：δ7.4-7.15(m，8H)，6.85-6.75(m，1H)，6.7-6.6(s，1H)，5.2(q，3H)，4.65-4.55(m，1H)，4.25-4.2(m，3H)，3.65-3.55(m，3H)，3.4(t，2H)，3.3(t，2H)，3.25-3.15(m，1H)，2.4(t，2H)，2.2(t，2H)，2.15-2.05(m，8H)

Step 10

Synthesizing of 1-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-base sulfamoyl]-pyrrolidine-2-formic acid

With LiOH solution (20mg; 0.0004mol) join the 1-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1 that is stirring; 2,3,5-tetrahydrochysene-indolizine-8-base sulfamoyl]-pyrrolidine-2-benzyl formate (65mg; 0.0001mol) in the solution in methanol: THF (2: 3), the gained mixture was stirred 3 hours under RT.With the reactant concentrating under reduced pressure, dilute with water is neutralized to pH about 2 with 10%HCl; Collect formed deposition; Drying obtains the required product 1-of 20mg (yield 36%) [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2; 3,5-tetrahydrochysene-indolizine-8-base sulfamoyl]-pyrrolidine-2-formic acid.

HPLC：91.17％

¹H?NMR(DMSO-D ₆，300MHz)：12.85(s，1H)，8.9(s，1H)，7.6-7.2(m，3H)，4.3-4.2(m，1H)，4.1(t，2H)，3.1(t，2H)，2.15-2.05(m，2H)，1.75-1.65(m，2H)

Embodiment 65

Step 8

Synthesizing of 1-chlorosulfonyl-pyrrolidine-2-methyl formate

Under RT, with DMAP (0.5g, 0.00409mol) and TEA (2.54g, (4g 0.024mol) in the solution in dry toluene (50mL), stirs the gained mixture 10 minutes 0.0251mol) to join pyrrolidine-2-methyl formate hydrochlorate of stirring.Reactant mixture is cooled to-20 ℃, (3.3g 0.024mol) and at-10 ℃ continues down to stir 1 hour, under RT, continues stirring 2 hours again to go through 30 minutes dropping chlorosulfuric acids then.Reactant is diluted with DCM, use NH ₄The Cl solution washing.Organic layer is used Na ₂SO ₄Drying concentrates, and obtains the required product 1-chlorosulfonyl-pyrrolidine of 1.2g (yield 24%)-2-methyl formate.

Step 9

Synthesizing of 1-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-base sulfamoyl]-pyrrolidine-2-methyl formate

With DMAP (50mg; 0.0004mol) join 8-amino-7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-2 that is stirring; (300mg 0.001mol) in the solution in dry pyridine (5mL), is cooled to 0 ℃ with reactant mixture to 3-dihydro-1H-indolizine-5-ketone under nitrogen atmosphere.Go through then and dripped the 11-chlorosulfonyl-pyrrolidine-2-methyl formate be arranged in DCM in 10 minutes (1g 0.004mol), stirs the gained mixture 4 hours under RT.Reactant mixture is heated to 65 ℃ reaches 16 hours.Distribute between ethyl acetate and water with the reactant concentrating under reduced pressure and with concentrate.Organic layer is washed with saline solution; Concentrating under reduced pressure also (uses silica gel with concentrate with column chromatography; With the hexane solution of 70% ethyl acetate as eluant) purification, obtain the required product 1-of 110mg (yield 24%) [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2; 3,5-tetrahydrochysene-indolizine-8-base sulfamoyl]-pyrrolidine-2-methyl formate.

Step 10

Synthesizing of 2-hydroxymethyl-pyrrolidine-1-sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

Under nitrogen atmosphere, with NaBH ₄(25mg; 0.00065mol) join the 1-[7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1 that is stirring; 2,3,5-tetrahydrochysene-indolizine-8-base sulfamoyl]-pyrrolidine-2-methyl formate (110mg; 0.0002mol) in the solution in dry THF (3mL), with the gained mixture 60 ℃ of heating down.Go through dripping methanol (2mL) in 5 minutes then, simultaneously temperature maintenance is reached 1 hour at 60 ℃.With the reactant concentrating under reduced pressure, add icy water, with 5% rare HCl neutralization, use ethyl acetate extraction, organic layer is used Na ₂SO ₄Drying concentrates.The bullion product is dissolved in 1: 9 methanol: among the DCM; Add ether and collect formed deposition, obtain the required product 2-hydroxymethyl-pyrrolidine of 75g (yield 70%)-1-sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2; 3,5-tetrahydrochysene-indolizine-8-yl]-amide.

LCMS purity: 99.66%, m/z=521 (M+2)

HPLC：95.4％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.7(s，1H)，7.6-7.25(m，3H)，4.15(t，2H)，3.65(m，1H)，3.1-3.2(m，4H)，2.15-2.05(m，2H)，1.85-1.75(m，4H)

Embodiment 66

Flow process 12

Step 5

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-methyl-amide synthetic

With EDCI (0.99g; 0.005mol) and HOBt (0.702g 0.005mol) joins 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-5-oxo-1,2 that is stirring; 3; (1g 0.003mol) in the solution in DMF (50mL), stirs reactant mixture 1.30 hours under RT 5-tetrahydrochysene-indolizine-8-formic acid.Under nitrogen atmosphere, add hydrochloric acid O then, N-dimethyl-azanol (0.506g, 0.005mol) and TEA (2.16mL, 0.016mol).Reactant mixture was stirred 16 hours under RT.Reactant mixture is distributed between ethyl acetate and water.Organic layer is used saturated NH ₄Anhydrous Na is used in Cl, saline solution washing ₂SO ₄Drying concentrates, and obtains the required product 7-of 0.800mg (yield 72.7%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-methyl-amide.

LCMS purity: 96.9%, m/z=428 (M+1)

¹H?NMR(DMSO-D ₆，300MHz)：δ8.0-7.95(br?s，1H)，7.5-7.4(dd，1H)，7.3-7.2(dd，1H)，7.0(t，1H)，4.1-3.9(m，2H)，3.6(s，3H)，3.4(s，3H)，3.0-2.9(m，2H)，2.15-2.05(m，2H)

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formaldehyde synthetic

Under-78 ℃; (5.7mL 5.7mmol) joins 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2 with DIBAL-H (toluene solution of 1.0M); 3; (0.7g 1.635mmol) in the solution in dry THF (20mL), stirs reactant mixture 2 hours down at-78 ℃ 5-tetrahydrochysene-indolizine-8-formic acid methoxyl group-methyl-amide.Reactant is used saturated NH ₄Ethyl acetate extraction is used in the Cl cancellation.Water layer is used ethyl acetate extraction,, use anhydrous Na organic layer water, saline (10mL) washing ₂SO ₄Drying concentrates.Concentrate with column chromatography (use silica gel, with the DCM solution of 2% methanol as eluant) purification, is obtained the required product 7-of 0.2g (yield 33.16%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formaldehyde.

¹H?NMR(DMSO-D ₆，300MHz)：δ9.83-9.8(d，1H)，9.6(d，1H)，7.6(dd，1H)，7.4-7.3(d，1H)，7.2-7.15(m，1H)，4.1-4.0(t，2H)，3.5(t，2H)，2.2(t，2H)

Step 7

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(1-hydroxyl-Ding-3-thiazolinyl)-2,3-dihydro-1H-indolizine-5-ketone synthetic

Under-78 ℃, under nitrogen atmosphere, with pi-allyl bromination magnesium (11.65mL; 0.011653mol) join 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3; (0.430g is 0.001mol) in the solution in dry THF (10mL) for 5-tetrahydrochysene-indolizine-8-formaldehyde.Reactant mixture was stirred 2 hours under RT.Reactant mixture is used saturated NH ₄Ethyl acetate extraction is used in the cancellation of Cl solution.With organic layer water, saline solution washing, use anhydrous Na ₂SO ₄Drying concentrates.Concentrate (is used silica gel with column chromatography; With the DCM solution of 1-1.5% methanol as eluant) purification; Obtain the required product 7-of 0.250mg (yield 52.4%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(1-hydroxyl-Ding-3-thiazolinyl)-2,3-dihydro-1H-indolizine-5-ketone.

LCMS：84.4％，m/z＝411(M+)

HPLC：90％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.2-8.1(br?s，1H)，7.6-7.5(dd，1H)，7.3(d，1H)，6.8-6.7(m，1H)，6.4(d，1H)，5.7(m，1H)，5.0-4.8(m，2H)，4.7-4.6(d，1H)，4.0-3.9(m，2H)，3.1-2.9(m，2H)，3.0-2.9(m，1H)，2-5-2.4(m?1H)，2.3-2.2(m，1H)，2.1(t，2H)。

Embodiment 67

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 8 described modes, and step 4 is used with the similar mode of embodiment 111 described modes and carried out, and step 5 to 6 usefulness are carried out with the similar mode of embodiment 66 described modes.

Step 7

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(1-hydroxyl-pi-allyl)-2,3-dihydro-1H-indolizine-5-ketone synthetic

Under-78 ℃; Under nitrogen atmosphere, (1.62mL 0.002mol) joins 7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1 with vinyl bromination magnesium (solution in THF of 1M); 2; 3, (0.1g is 0.0003mol) in the solution in dry THF (10mL) for 5-tetrahydrochysene-indolizine-8-formaldehyde.Reactant mixture was stirred 2 hours under RT.Reactant mixture is used saturated NH down at-78 ℃ ₄The cancellation of Cl solution is used ethyl acetate extraction under RT.With organic layer water, saline solution washing, use anhydrous Na ₂SO ₄Drying concentrates.Concentrate is used the preparation HPLC purification, obtain the required product 7-of 10mg (yield 9%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(1-hydroxyl-pi-allyl)-2,3-dihydro-1H-indolizine-5-ketone.

LCMS：96.4％，m/z＝399(M+2)，398(M+1)

HPLC：98％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.0-7.8(br?s，1H)，7.6-7.4(d，1H)，7.6-7.3(d，1H)，6.6(t，1H)，6.6-6.5(br?s，1H)，5.8-6.0(m，1H)，5.2(d，2H)，5.0(d，1H)，4.0(t，2H)，3.1(m，2H)，2.1(t，2H)。

Embodiment 68

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 8 described modes; Step 4 is used with the similar mode of embodiment 11 described modes and is carried out; Step 5 to 6 usefulness are carried out with the similar mode of embodiment 66 described modes, and step 7 is used with the similar mode of embodiment 67 described modes and carried out.

Step 8

8-acryloyl group-7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-2,3-dihydro-1H-indolizine-5-ketone synthetic

Dai Si-Martin is crossed iodine alkane (0.582g; 0.001mol) join 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-8-(1-hydroxyl-pi-allyl)-2 that is stirring; 3-dihydro-1H-indolizine-5-ketone (0.440g; 0.001mol) in the solution in DCM (10mL), reactant mixture was stirred 12 hours under RT.Add 0.8g then and be dissolved in the NaHCO in the 10mL water ₃Be dissolved in the sodium thiosulfate 5H in the 10mL water with 2.48g ₂Next O continues to stir 5 minutes.Reactant mixture is extracted with DCM, organic layer is used saturated NaHCO ₃Solution, brine wash are used anhydrous Na ₂SO ₄Drying concentrates, and obtains 0.400g8-acryloyl group-7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-2, and 3-dihydro-1H-indolizine-5-ketone bullion product promptly is used for next step with it without being further purified.

Step 9

7-(4-bromo-2-fluoro-phenyl amino)-8-(2,3-dihydroxy-propiono)-6-fluoro-2,3-dihydro-1H-indolizine-5-ketone synthetic

Under nitrogen atmosphere; With 4-methyl-morpholine-N-oxide (0.118g; 0.001012mol) and Osmic acid. (0.025g 0.0001mol) joins 8-acryloyl group-7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-2 that is stirring, 3-dihydro-1H-indolizine-5-ketone (0.4g; 0.001mol) in the solution in THF (10mL), the gained mixture was stirred 2 hours under RT.Reactant mixture is distributed between ethyl acetate and water.Organic layer is used anhydrous Na ₂SO ₄Drying concentrates, and concentrate (is used silica gel with column chromatography; With the DCM solution of 1.5% methanol as eluant) purification; Obtain yellow solid, it is further purified with preparation HPLC, obtain the required product 7-of 10mg (yield 2.3%) (4-bromo-2-fluoro-phenyl amino)-8-(2; 3-dihydroxy-propiono)-and 6-fluoro-2,3-dihydro-1H-indolizine-5-ketone.

LCMS：m/z＝431(M+2)

HPLC：90％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.6-8.5(br?s，1H)，7.5-7.4(dd，1H)，7.3-7.2(dd，1H)，6.9-6.8(m，1H)，5.3(d，1H)，5.0(t，1H)，4.5-4.4(m，1H)，4.1-4.0(m，2H)，3.5(t，2H)，3.3-3.2(m，1H)，3.1-3.0(m，1H)，2.1(t，2H)

Embodiment 69

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 8 described modes, and step 4 is used with the similar mode of embodiment 11 described modes and carried out, and step 5 to 6 usefulness are carried out with the similar mode of embodiment 66 described modes.

Step 7

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(1-hydroxyl-2-methoxymethoxy-ethyl)-2,3-dihydro-1H-indolizine-5-ketone synthetic

Under-78 ℃; Go through 5 minutes will be just-butyl lithium (hexane solution of 2.5M) (6.6mL; 6.775mmol) (3.72g 10.17mmol) in the solution in dry THF, stirs the gained mixture 5 minutes to be added drop-wise to the tributyl-methoxymethoxy methyl-stannane that is stirring.Add down 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-5-oxos-1,2,3 that are arranged in THF at-78 ℃ then, and 5-tetrahydrochysene-indolizine-8-formaldehyde (250mg, 0.678mmol) and under-78 ℃, continue again to stir 40 minutes.Under-78 ℃, reactant mixture is used saturated NH ₄The cancellation of Cl solution is warmed to RT, dilutes with ethyl acetate.Organic layer is washed with saline solution, use anhydrous Na ₂SO ₄Drying concentrates.Concentrate promptly is used for next step without being further purified.

Step 8

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(2-methoxymethoxy-acetyl group)-2,3-dihydro-1H-indolizine-5-ketone synthetic

Dai Si-Martin is crossed iodine (0.180g; 0.0004mol) join 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-8-(1-hydroxyl-2-methoxymethoxy-ethyl)-2 that is stirring; 3-dihydro-1H-indolizine-5-ketone (0.160g; 0.0004mol) in the solution in DCM (10mL), reactant mixture was stirred 1.30 hours under RT.Add 10mL then and contain 300mg sodium thiosulfate 5H ₂The saturated NaHCO of O ₃Next solution continue to stir 10 minutes.The mixture of remnants is used ethyl acetate extraction, organic layer is used saturated NaHCO ₃Solution, brine wash are used anhydrous Na ₂SO ₄Drying concentrates.Concentrate (is used silica gel with column chromatography; With the hexane solution of 60-65% ethyl acetate as eluant) purification; Obtain the required product 7-of 100mg (yield 62.8%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(2-methoxymethoxy-acetyl group)-2,3-dihydro-1H-indolizine-5-ketone.

LCMS purity: 76.1%, m/z=444 (M+1), 445 (M+2)

HPLC：80％

Step 9

7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(2-hydroxyl-acetyl group)-2,3-dihydro-1H-indolizine-5-ketone synthetic

10%HCl aqueous solution (4mL) and water (3mL) are joined 7-(4-bromo-2-fluoro-the phenyl amino)-6-fluoro-8-(2-methoxymethoxy-acetyl group)-2 that is stirring; 3-dihydro-1H-indolizine-5-ketone (100mg; 0.0002mol) in the solution in methanol (3mL), the gained mixture was stirred 18 hours under RT.Reactant mixture is used saturated NaHCO ₃The solution neutralization is used brine wash with the ethyl acetate dilution and with organic layer, uses anhydrous Na ₂SO ₄Drying concentrates.Concentrate is used the preparation HPLC purification, obtain the required product 7-of 14mg (yield 15.7%) (4-bromo-2-fluoro-phenyl amino)-6-fluoro-8-(2-hydroxyl-acetyl group)-2,3-dihydro-1H-indolizine-5-ketone.

LCMS：98.4％，m/z＝401(M+2)

HPLC：98.7％

¹H?NMR(DMSO-D ₆，300MHz)：δ9.0-8.8(br?s，1H)，7.5(dd，1H)，7.3(d，1H)，6.9-6.8(m，1H)，5.2(t，1H)，4.3-4.0(m，2H)，4.0(t，2H)，3.3-3.2(m，2H)，2.1(t，2H)

Flow process 13

Embodiment 70

Step 1

(5.082g 0.0502242mol) joins the 7-hydroxyl-6-methyl-5-oxo-1,2,3 that is dissolved among the DCM (70mL), and (7.0g in solution 0.031mol), is cooled to reactant mixture-78 ℃ to 5-tetrahydrochysene-indolizine-8-Ethyl formate with TEA.(11.51g 0.041mol), stirred reactant mixture 16 hours at ambient temperature in reactant mixture, to add trifluoromethanesulfanhydride anhydride.Reactant mixture is with sodium bicarbonate solution (20mL) washing, dry with organic layer, concentrate.Concentrate (is used silica gel, with the CHCl of 5%MeOH with column chromatography ₃Solution is as eluant) purification, obtain the required product 5-oxo of 7.78g (yield 73.0%)-7-trifyl Oxy-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate.

¹H?NMR(CDCl ₃，300MHz)：6.3(s，1H)，4.4(q，2H)，4.2(t，2H)，3.5(t，2H)，2.35(q，3H)，1.4(t，3H)。

Step 2

7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

With acid chloride (0.063g, 0.003mol), BINAP (0.263g, 0.0003mol), cesium carbonate (1.37g 0.004mol) is dissolved in the toluene, with the gained mixture with nitrogen bubble 30 minutes.Add 5-oxo-7-trifyl Oxy-1 then, 2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate (1g, 0.003mol) with 2-fluoro-4-5-trifluoromethylaniline (0.549g, 0.003mol), with reaction flask bubbling 15 minutes again.Reactant mixture was heated 1.30 hours down at 110 ℃.Also will filtrate concentrated with diatomite filtration reactant mixture.Concentrate (is used 60-120 purpose silica gel, with the CHCl of 70%MeOH with column chromatography ₃Solution is as eluant) purification, obtain the required product 7-of 0.4g (yield 37%) (2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate.

¹H?NMR(DMSO-D ₆)：7.6(t，1H)，7.4(t，2H)，6.0(s，1H)，4.4(q，2H)，4.2(t，2H)，3.5(t，2H)，2.2(q，3H)，1.4(t，3H)

Embodiment 71

Step 1 is carried out with the similar mode of embodiment 70 described modes with 2 usefulness.

Step 3

7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

(0.07g 0.002mol) joins 7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2 among the MeOH that is dissolved in that is stirring: the THF (6mL) with LiOH; 3; (0.30g in solution 0.0008mol), stirs reactant mixture 4 hours under RT 5-tetrahydrochysene-indolizine-8-Ethyl formate.Reactant mixture is concentrated and concentrate use the 10%HCl acidify, obtain deposition, it is collected and drying; Obtain the required product 7-of 0.270g (yield 95.74%) (2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1; 2,3,5-tetrahydrochysene-indolizine-8-formic acid.

¹H?NMR(DMSO-D ₆，300MHz)：13.4(s，1H)，10.4(s，1H)，7.85-7.75(m，2H)，7.6(d，1H)，5.7(s，1H)，4.0(t，2H)，3.5(t，2H)，2.1(t，2H)

Embodiment 72.

Step 1 to 2 usefulness are carried out with the similar mode of embodiment 70 described modes, and step 3 is used with the similar mode of embodiment 71 described modes and carried out.

Step 4

7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy amide synthetic

With EDCI (0.322g, 0.002mol), HOBt (0.23g, 0.002mol) and 7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1; 2,3,5-tetrahydrochysene-indolizine-8-formic acid (0.2g; 0.001mol) under inert atmosphere, be dissolved among the DMF, reactant mixture was stirred 30 minutes under RT.Add then hydrochloric acid cyclopropyl methyl hydroxylamine (0.21g, 0.002mol) and TEA (0.17g 0.002mol), stirs reactant mixture 16 hours under RT.In reactant mixture, add entry and reactant mixture is used saturated NH ₄Ethyl acetate extraction is used in the Cl cancellation.Organic layer with saturated bicarbonate solution, saline solution washing, is used Na ₂SO ₄Drying obtains deposition, and it is ground with ether, obtains 0.1g (yield 41.8%) 7-(2-fluoro-4-trifluoromethyl-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy amide pure products.

¹H?NMR(DMSO-D ₆，300MHz)：11.4(s，1H)，8.7(s，1H)，7.8(d，1H)，7.65-7.55(m，2H)，5.8(s，1H)，3.8(t，2H)，3.6(d，2H)，3.2(t，2H)，2.2(t，2H)，1.25-1.15(m，1H)，0.65-0.55(m，2H)，0.45-0.35(m，2H)。

Flow process 14

Embodiment 73

Step 1 is used with the similar mode of embodiment 70 described modes and is carried out.

Step 2:7-(2-fluoro-4-methoxyl group-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

With acid chloride (0.06g, 0.003mol), BINAP (0.26g, 0.0002mol), cesium carbonate (1.37g 0.004mol) is dissolved in the toluene, with the gained mixture with nitrogen bubble 30 minutes.Add 5-oxo-7-trifyl Oxy-1 then, 2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate (1g, 0.003mol) with 2-fluoro-4-aminoanisole (0.54g, 0.003mol), with reaction flask bubbling 15 minutes again.Reactant mixture was heated 1.30 hours down at 110 ℃.Also will filtrate concentrated with diatomite filtration reactant mixture.Concentrate (is used silica gel, with the CHCl of 70%MeOH with column chromatography ₃Solution is as eluant) purification, obtain the required product 7-of 0.230g (yield 23.6%) (2-fluoro-4-methoxyl group-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate.

¹H?NMR(DMSO-D ₆，300MHz)：9.2(s，1H)，7.2(t，1H)，6.85-6.75(m，2H)，5.5(s，1H)，4.4(q，2H)，4.2(t，2H)，3.8(s，3H)，3.5(t，2H)，2.2(q，2H)，1.4(t，3H)。

Step 3

7-(2-fluoro-4-methoxyl group-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

(0.05g 0.001mol) joins 7-(2-fluoro-4-methoxyl group-phenyl amino)-5-oxo-1,2 among the MeOH that is dissolved in that is stirring: the THF (6mL) with LiOH; 3; (0.19g 0.001mol) in the solution, stirs the gained mixture 4 hours under RT 5-tetrahydrochysene-indolizine-8-Ethyl formate.Distill solvent, the bullion product is used the 10%HCl acidify, obtain deposition, it is collected and drying, obtain 0.130g (yield 76.023%) 7-(2-fluoro-4-methoxyl group-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid.

¹H?NMR(DMSO-D ₆，300MHz)：13.45-13.35(br?s，1H)，9.6(s，1H)，7.3(t，1H)，7.0(d，1H)，6.8(d，1H)，5.0(s，1H)，4.0(t，2H)，3.8(s，3H)，3.5(t，2H)，2.15-2.05(m，2H)。

Step 4

7-(2-fluoro-4-methoxyl group-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy amide synthetic

Under inert atmosphere, with EDCI (0.22g, 0.001mol), HOBt (0.15g; 0.001mol) and 7-(2-fluoro-4-methoxyl group-phenyl amino)-5-oxo-1,2,3; (0.12g 0.0004mol) is dissolved among the DMF 5-tetrahydrochysene-indolizine-8-formic acid, and reactant mixture was stirred 30 minutes under RT.Add then hydrochloric acid cyclopropyl methyl hydroxylamine (0.140g, 0.001mol) and TEA (0.114g, 0.001mol), with reactant mixture stirred overnight under RT.In reactant mixture, add entry, add saturated NH then ₄Cl also uses ethyl acetate extraction.Organic layer with saturated bicarbonate solution, saline solution washing, is used Na ₂SO ₄Drying obtains deposition, and it is ground with ether, obtains the required product 7-of 0.09g (yield 61.6%) (2-fluoro-4-methoxyl group-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy amide.

¹H?NMR(DMSO-D ₆，300MHz)：11.4(s，1H)，7.9(s，1H)，7.2(t，1H)，6.9(d，1H)，6.8(d，1H)，5.0(s，1H)，3.9(t，2H)，3.8(s，3H)，3.7(d，2H)，3.2(t，2H)，2.05-2.0(m，2H)，1.05-1.0(m，1H)，0.65(d，2H)，0.2(d，2H)。

Embodiment 74

Flow process 15

Step 1 to 2 usefulness are carried out with the similar mode of embodiment 27 described modes.

Step 3

Under-78 ℃, LDA (50mL) is joined 2-fluoro-4-bromo-phenyl amine, and (7g 0.037mol) in the solution in THF (550mL), stirs the gained mixture 1 hour.Add the 7-chloro-5-oxo-1,2,3 that is arranged in dry THF (200mL) down at-78 ℃ then, (5.5g 0.025mol), at room temperature stirred reactant 16 hours 5-tetrahydrochysene-indolizine-8-formic acid.With the reactant mixture concentrating under reduced pressure, with rare HCl neutralization.Add ether, stirred 1 hour, obtain deposition, collect and to precipitate, obtain the required product 7-of 5.2g (yield 56%) (4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid.

Step 4

3-(4-bromo-2-fluoro-phenyl)-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Under nitrogen atmosphere, (1.52mg 0.015mol) joins 7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3, and (5g 0.014mol) in the solution in dry DMF (8mL), stirs reactant mixture 30 minutes 5-tetrahydrochysene-indolizine-8-formic acid with TEA.Then under 10 ℃, stirring go through under the condition dripped in 15 minutes DPPA (4.14g, 0.015mol).Under RT, continue again to stir 5 hours.Add toluene (80mL) then, reaction mass heated to 90 ℃ is reached 4 hours.With the reactant concentrating under reduced pressure, add refrigerated water then.Collect formed deposition, drying obtains the required product 3-of 3.4g (yield 70%) (4-bromo-2-fluoro-phenyl)-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone.

Step 5

3-(4-bromo-2-fluoro-phenyl)-1-mesyl-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Under 0-5 ℃, under nitrogen atmosphere, with 60%NaH (70mg; 0.003mol) join the 3-(4-bromo-2-fluoro-phenyl)-1,6,7 that is stirring; 8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2; (300mg 0.001mol) in the solution in dry DMF (10mL), stirs the gained mixture 1 hour under RT the 5-diketone.Under 0 ℃, go through then dripped in 5 minutes the mesyl chloride be arranged in dry THF (150mg, 0.001mol), next stirring 16 hours under RT.Under agitation in reaction flask, add icy water and reach 5 minutes, pH is transferred to 5.Use ethyl acetate extraction, use Na then ₂SO ₄Drying, concentrating under reduced pressure obtains the required product 3-of 160mg (yield 47%) (4-bromo-2-fluoro-phenyl)-1-mesyl-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone.

HPLC：93.7％

¹H?NMR(DMSO-D ₆，300MHz)：δ，7.9-7.45(m，3H)，5.45(s，1H)，3.9(t，2H)，3.65(s，3H)，3.3(t，2H)，2.15-2.05(m，2H)

Embodiment 75

Step 1 to 2 usefulness are carried out with the similar mode of embodiment 27 described modes, and step 3 to 4 usefulness are carried out with the similar mode of embodiment 74 described modes.

Step 5

3-(4-bromo-2-fluoro-phenyl)-1-cyclopropane sulfonyl-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Under 0-5 ℃, under nitrogen atmosphere, 60%NaH (20mg) is joined the 3-(4-bromo-2-fluoro-phenyl)-1 that is stirring; 6,7,8-tetrahydrochysene-3H-1; 3,5a-three azepines-asymmetric-indacene-2,5-diketone (200mg; 0.001mol) in the solution in dry DMF (5mL), the gained mixture was stirred 1 hour under RT.Under 0 ℃, go through then and dripped the cyclopropane sulfonic acid chloride be arranged in dry THF in 10 minutes (150mg 0.002mol), next continues stirring 16 hours under RT.In 0 ℃ of downhill reaction mixture, add NaH (20mg), stirred 15 minutes, (150mg 0.002mol), continues to stir 5 hours under RT again to add the cyclopropane sulfonic acid chloride that is arranged in dry DMF then.The bullion product promptly is used for next step without being further purified.

Step 6

Synthesizing of cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

1N NaOH aqueous solution (7mL) is joined 3-(4-bromo-2-fluoro-phenyl)-1-cyclopropane sulfonyl-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2 in the 5-diketone, ℃ reach gained mixture heated to 75 at 4 hours.In reactant mixture, add icy water, it is about 3 to be neutralized to pH with 5% ice-cold HCl, between ethyl acetate and water, distributes then.Organic layer is used Na ₂SO ₄Drying concentrates, and with column chromatography (use silica gel, with the DCM solution of 3% methanol as eluant) purification, obtains the required product cyclopropane sulfonic acid of 17mg (yield 7%) [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide.

LC-MS purity: 98.5%

HPLC：97％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.75(s，1H)，7.65-7.25(m，3H)，5.25(s，1H)，3.9(t，2H)，3.2(t，2H)，2.9-2.8(m，1H)，2.2-2.1(m，2H)，0.95-0.85(m，4H)

Embodiment 76

Step 5

3-(4-bromo-2-fluoro-phenyl)-1-(4-fluoro-benzenesulfonyl)-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Under 0-5 ℃, under nitrogen atmosphere, with 60%NaH (50mg; 0.001mol) join the 3-(4-bromo-2-fluoro-phenyl)-1,6,7 that is stirring; 8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2; (300mg 0.001mol) in the solution in dry DMF (6mL), stirs the gained mixture 1 hour under RT the 5-diketone.Go through then and dripped the 4-fluoro-benzene sulfonyl chloride be arranged in dry THF in 10 minutes (200mg 0.001mol), next continues stirring 16 hours under RT.The bullion product promptly is used for next step without being further purified.

Step 6

Synthesizing of N-[7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-4-fluoro-benzsulfamide

1N NaOH solution (6mL) is joined 3-(4-bromo-2-fluoro-phenyl)-1-(4-fluoro-benzenesulfonyl)-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2 in the 5-diketone, ℃ reach gained mixture heated to 60 at 1 hour.In reactant mixture, add icy water, it is about 4 to be neutralized to pH with 5%HCl, between ethyl acetate and water, distributes then.Organic layer is used NaHCO ₃Na is used in washing ₂SO ₄Drying concentrates, and with column chromatography (use silica gel, with the DCM solution of 2% methanol as eluant) purification, obtains the required product N-of 20mg (yield 6%) [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-4-fluoro-benzsulfamide.

LC-MS purity: 97.5%

HPLC：96.274％

¹H?NMR(DMSO-D ₆，300MHz)：δ9.25(s，1H)，7.0-7.85(m，7H)，5.25(s，1H)，3.9(t，2H)，2.75(t，2H)，1.95-1.8(m，1H)

Embodiment 77

Step 5

3-(4-bromo-2-fluoro-phenyl)-2,5-dioxo-2,3,5,6,7,8-six hydrogen-1,3,5a-three azepines-asymmetric-indacene-1-formic acid tert-butyl ester synthetic

Under 0 ℃, under nitrogen atmosphere, (67mg 0.003mol) joins 3-(4-bromo-2-fluoro-the phenyl)-4-fluoro-1 that is stirring with 60%NaH; 6,7,8-tetrahydrochysene-3H-1,3; 5a-three azepines-asymmetric-indacene-2, (2.5mg is 0.001mol) in the solution in dry DMF (10mL) for the 5-diketone.Under 0 ℃, go through then and dripped the BOC anhydride be arranged in dry THF in 5 minutes (260mg 0.001mol), stirs the gained mixture 4 hours under RT.The bullion product promptly is used for next step without being further purified.

Step 6

Synthesizing of [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-carbamic acid tert-butyl ester

1N NaOH aqueous solution (6mL) is joined 3-(4-bromo-2-fluoro-phenyl)-2,5-dioxo-2,3,5,6,7,8-six hydrogen-1,3 in 5a-three azepines-asymmetric-indacene-1-formic acid tert-butyl ester, ℃ reach gained mixture heated to 65 at 3 hours.In reactant mixture, add icy water, it is about 7 to be neutralized to pH with 5%HCl, and reactant mixture is distributed between ethyl acetate and water.Organic layer is used Na ₂SO ₄Dry; Concentrating under reduced pressure, with concentrate with column chromatography (use neutral alumina, with the DCM solution of 3% methanol as eluant) purification; Obtain the required product of 165mg (yield 43.8%) [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1; 2,3,5-tetrahydrochysene-indolizine-8-yl]-carbamic acid tert-butyl ester.

HPLC：94.2％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.15(s，1H)，7.9-7.45(m，3H)，5.15(s，1H)，3.9(t，2H)，2.9(t，2H)，2.2-2.1(m，2H)，1.45(s，9H)

Embodiment 78

Step 1 to 2 usefulness are carried out with the similar mode of embodiment 27 described modes, and step 3 to 4 usefulness are carried out with the similar mode of embodiment 74 described modes, and step 5 to 6 usefulness are carried out with the similar mode of embodiment 77 described modes.

Step 7

8-amino-7-(4-bromo-2-fluoro-phenyl amino)-2,3-dihydro-1H-indolizine-5-ketone synthetic

Under-10 ℃; Go through and TFA (1mL) was added drop-wise in 5 minutes the [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1 that is stirring; 2,3,5-tetrahydrochysene-indolizine-8-yl]-carbamic acid tert-butyl ester (200mg; 0.0005mol) in the solution in dry DCM (5mL), the gained mixture was stirred 4 hours under RT.With the reactant concentrating under reduced pressure.Add entry, use NaHCO ₃Ethyl acetate extraction is used in the solution neutralization, uses Na ₂SO ₄Drying obtains the required product 8-amino-7-of 120mg (yield 79%) (4-bromo-2-fluoro-phenyl amino)-2,3-dihydro-1H-indolizine-5-ketone.

LCMS purity: 88.3%

Step 8

Synthesizing of cyclohexane extraction sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

The pyridine (4mL) that will be arranged in DCM joins 8-amino-7-(4-bromo-2-fluoro-phenyl amino)-2, and (110mg in solution 0.0003mol), stirs reactant mixture 10 minutes under nitrogen atmosphere 3-dihydro-1H-indolizine-5-ketone.(5mg 0.0004mol), is cooled to 0-5 ℃ with reactant, goes through to drip the cyclohexyl sulfonic acid chloride be arranged in DCM in 10 minutes (80mg 0.0004mol), next continues stirring 16 hours under RT to add DMAP then.Reactant mixture is distributed between ethyl acetate and water, with organic layer water and the rare HCl washing of 1N.Organic layer is used Na ₂SO ₄Drying, concentrate and with concentrate with column chromatography (use silica gel, with the DCM solution of 2% methanol as eluant) purification; Obtain the required product cyclohexane extraction sulfonic acid of 10mg (yield 8.5%) [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1; 2,3,5-tetrahydrochysene-indolizine-8-yl]-amide.

LC-MS purity: 96.8%, m/z=484, (M+1)

HPLC：93.4％

¹H?NMR(DMSO-D ₆，300MHz)：δ7.8(s，1H)，7.65-7.25(m，3H)，5.95(s，1H)，4.1(t，2H)，3.2(t，2H)，3.15-3.05(m，1H)，2.25-2.15(m，1H)，2.2-2.1(m，2H)，1.85-1.75(m，2H)，1.65-1.6(m，4H)，1.3-1.25(m，2H)

Embodiment 79

Step 5

3-(4-bromo-2-fluoro-phenyl)-1-(4-trifluoromethyl-benzenesulfonyl)-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Under 0 ℃, (31mg 0.001mol) joins the 3-(4-bromo-2-fluoro-phenyl)-1 that is stirring with 60%NaH; 6,7,8-tetrahydrochysene-3H-1; 3,5a-three azepines-asymmetric-indacene-2,5-diketone (200mg; 0.001mol) in the solution in dry DMF (4mL), the gained mixture was stirred 1 hour under RT.Under 0 ℃, go through then dripped in 10 minutes the 4-trifluoromethyl-benzene sulfonyl chloride be arranged in dry THF (180mg, 0.001mol).Next under RT, continue to stir 2 days, obtain the bullion product, it promptly is used for next step without being further purified.

Step 6

Synthesizing of N-[7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-4-trifluoromethyl-benzsulfamide

1N NaOH aqueous solution (15mL) is joined 3-(4-bromo-2-fluoro-phenyl)-1-(4-trifluoromethyl-benzenesulfonyl)-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2 in the 5-diketone, ℃ reach gained mixture heated to 65 at 2 hours.Under RT, in reactant, add rare HCl (pH=4), use Na then ₂CO ₃Aqueous solution transfers to 7 with pH, uses the ethyl acetate extraction reactant.Organic layer is used brine wash, use Na ₂SO ₄Drying, concentrating under reduced pressure with column chromatography (using silica gel, the DCM solution of 1.5% methanol) purification, obtains the required product of 102mg (yield 33%) with concentrate.

LC-MS purity: 98.9%, m/z=548, (M+2)

HPLC：99.6％

¹H?NMR(DMSO-D ₆，300MHz)：δ9.4(s，1H)，7.85-6.85(m，7H)，5.25(s，1H)，3.9(t，2H)，2.85(t，2H)，2.0-1.9(m，1H)

Embodiment 80

Step 1 to 2 usefulness are carried out with the similar mode of embodiment 27 described modes; Step 3 to 4 usefulness are carried out with the similar mode of embodiment 74 described modes; Step 5 to 6 usefulness are carried out with the similar mode of embodiment 77 described modes, and step 7 is used with the similar mode of embodiment 78 described modes and carried out.

Step 8

N-[7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-N, N-dimethylamino sulfonamide synthetic

Under-35 ℃; With N, (40mg 0.0003mol) joins 8-amino-7-(4-bromo-2-fluoro-phenyl amino)-2 to N-dimethyl methyl acyl chlorides; 3-dihydro-1H-indolizine-5-ketone (80mg; 0.0002mol) (30mg in the solution in 0.0002mol), stirs reactant mixture 2 hours under RT at dry THF and DMAP.Add dry pyridine (1.5mL) then, reactant mixture is heated to 40 ℃ reaches 4 hours.With the reactant concentrating under reduced pressure, concentrate is used the preparation HPLC purification, obtain the required product N-of 6mg (yield 9%) [7-(4-bromo-2-fluoro-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-N, N-dimethylamino sulfonamide.

HPLC：91.4％

¹H?NMR(DMSO-D ₆，300MHz)：δ7.15(s，1H)，7.85-7.25(m，3H)，5.9(s，1H)，4.2(t，2H)，3.29(t，2H)，2.9(s，6H)，2.25-2.15(m，2H)

Flow process 16

Embodiment 81

Step 1

5-hydroxyl-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-Ethyl formate synthetic

Go through 30 minutes with malonyl chloride (8.10g, 0.057mol) be added drop-wise to (2,2-dimethyl-tetrahydrochysene-[1; 3] dioxole [4,5-c] pyrroles-4-subunit also)-ethyl acetate (J.Chem.Soc., Perkins Transactions 1:Organic and Bio-organic Chemistry; The 2371-2376 page or leaf; (1987)) (10.2g 0.048mol) in the solution in DCM (300mL), stirs reactant mixture 3 hours under RT.With reactant with 5mL TEA cancellation and concentrated solvent.Concentrate (is used silica gel with column chromatography; With the hexane solution of 30-45% ethyl acetate as eluant) purification, obtain the required product 5-hydroxyl-2 of 9.25g (yield 69%), 2-dimethyl-7-oxo-3a; 7; 8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-Ethyl formate.

¹H?NMR(CDCl ₃，300MHz)：11.25-11.15(br?s，1H)，6.0(s，1H)，6.0-5.95(m，1H)，5.05-4.95(m，1H)，4.45-4.35(m，3H)，4.15-4.05(m，1H)，1.45-1.35(m，6H)，1.3(s，3H)。

Step 2

2,2-dimethyl-7-oxo-5-trifyl oxygen base-3a, 7,8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-Ethyl formate synthetic

Under-70 ℃, (4.9g 0.049mol) joins 5-hydroxyl-2 with TEA; 2-dimethyl-7-oxo-3a, 7,8; 8a-tetrahydrochysene-1, (9.25g is 0.033mol) in the solution in DCM (200mL) for 3-dioxa-7a-azepine-cyclopenta [a] indenes-4-Ethyl formate.Go through then and dripped the trifluoromethanesulfanhydride anhydride be arranged in DCM (500mL) in 1 hour (12.06g 0.0427mol), stirs reactant mixture 1 hour under RT.Reactant is distributed between ethyl acetate and water.Organic layer is washed with saline solution, concentrate.Concentrate with column chromatography (using silica gel, as eluant) purification, is obtained the required product 2 of 9g (yield 64.3%); 2-dimethyl-7-oxo-5-trifyl oxygen base-3a, 7,8; 8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-Ethyl formate.

¹H?NMR(CDCl ₃，300MHz)：6.4(s，1H)，6.0(d，1H)，5.0(t，1H)，4.45-4.35(m，3H)，4.15-4.05(m，1H)，1.45-1.35(m，6H)，1.3(s，3H)。

Step 3

5-(4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-Ethyl formate synthetic

With acid chloride (0.47g, 0.002mol), BINAP (1.96g, 0.003mol), cesium carbonate (10.26g 0.032mol) is dissolved in the toluene (200mL), with the gained mixture with nitrogen bubble 30 minutes.Add 2 then, 2-dimethyl-7-oxo-5-trifyl oxygen base-3a, 7; 8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-Ethyl formate (9g; 0.021mol) and 2-fluoro-4-bromaniline (4.4g 0.023mol), simultaneously continued bubbling 15 minutes again.Reactant mixture is heated to 90 ℃ reaches 1.30 hours.With the reactant mixture cooling, with the dilution of 200mL ethyl acetate, Na is used in water, saline solution washing ₂SO ₄Drying concentrates.Concentrate (is used silica gel with column chromatography; With the hexane solution of 10-70% ethyl acetate as eluant) purification, obtain the required product 5-of 5g (yield 51.5%) (4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a; 7; 8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-Ethyl formate.

LCMS：m/z＝467(M+H)

¹H?NMR(CDCl ₃，300MHz)：9.3(s，1H)，7.45-7.35(m，1H)，7.35-7.25(m，2H)，6.0(d，1H)，5.8(s，1H)，5.0(t，1H)，4.45-4.35(m，2H)，4.15-4.05(m，1H)，1.45-1.35(m，6H)，1.3(s，3H)。

Step 4

5-(4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid synthetic

(0.22g 0.005mol) joins 5-(4-bromo-2-fluoro-phenyl amino)-2 among the MeOH that is dissolved in that is stirring: the THF (1: 4), 2-dimethyl-7-oxo-3a with the LiOH that is in water; 7; 8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-Ethyl formate (1g; 0.002mol) solution in, the gained mixture was stirred 2 hours under RT.Reactant mixture is concentrated, residue is distributed between ethyl acetate and water, with water layer with 10% citric acid solution acidify (pH 2.5).Collect formed deposition and drying under reduced pressure, obtain the bullion product, it is used the preparation HPLC purification; Obtain the required product 5-of 50mg (yield 58.5%) (4-bromo-2-fluoro-phenyl amino)-2; 2-dimethyl-7-oxo-3a, 7,8; 8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid.

LCMS purity: 99.5%, m/z=439.0 (M-H)

H is at PLC:99.3%

¹H?NMR(DMSO-D ₆，300MHz)：13.65-13.55(br?s，1H)，9.55-9.45(br?s，1H)，7.7(dd，1H)，7.55-7.45(m，2H)，6.0(d，1H)，5.4(s，1H)，4.9(t，1H)，4.05-3.95(m，2H)，1.4(s，3H)，1.2(s，3H)。

Embodiment 82

Step 1 to 12 usefulness are carried out with the similar mode of embodiment 81 described modes.

Step 5

5-(4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid cyclo propyl methoxy-amide synthetic

With EDCI (262.4mg, 1.369mmol), HOBt (184.61mg, 1.369mmol) and DIPEA (387mg; 2.736mmol) join the 5-(4-bromo-2-fluoro-phenyl amino)-2 that is stirring, 2-dimethyl-7-oxo-3a, 7; 8; 8a-tetrahydrochysene-1, (200mg is 0.456mmol) in the solution in DMF (5mL) and DCM (5mL) for 3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid.(168.38mg 1.369mmol), stirs reactant mixture 16 hours under RT to add O-cyclopropyl methyl-azanol then.Reactant mixture is distributed between water and ethyl acetate.Organic layer is used saturated NaHCO ₃, saline solution washing, use Na ₂SO ₄Drying concentrates, and obtains the required product 5-of 120mg (yield 51.7%) (4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid cyclo propyl methoxy-amide.

LCMS purity: 82.9%, m/z=508.1 (M+H).

HPLC：79.5％

¹H?NMR(DMSO-D ₆，300MHz)：10.5(s，1H)，9.3(s，1H)，7.2-7.4(m，3H)，5.9(s，1H)，5.6(d，1H)，5.0(t，1H)，4.45-4.35(m，1H)，4.15-4.05(m，1H)，3.95-3.85(m，1H)，3.85-3.75(m，1H)，1.6(s，3H)，1.5(s，3H)，0.85-0.75(m，1H)，0.65-0.55(m，2H)，0.45-0.35(m，2H)。

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide synthetic

Dense HCl (3mL) is joined the 5-(4-bromo-2-fluoro-phenyl amino)-2 that is dissolved in the methanol (3mL); 2-dimethyl-7-oxo-3a; 7,8,8a-tetrahydrochysene-1; In the solution of 3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid cyclo propyl methoxy-amide (120mg), the gained mixture was stirred 3 hours under RT.Reactant mixture is concentrated, concentrate is ground twice (2 * 0.5mL) with ethyl acetate.Exsiccant residue provides the required product 7-of 20mg (yield 18.2%) (4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy-amide.

LCMS purity: 95.3%, m/z=470 (M+H).

HPLC：94.1％

¹H?NMR(DMSO-D ₆，300MHz)：11.4(s，1H)，8.1(s，1H)，7.6(dd，1H)，7.45-7.35(m，2H)，5.4(s，1H)，5.1(d，1H)，4.35-4.25(m，1H)，3.95-3.85(m，1H)，3.8-3.7(m，3H)，1.25-1.15(m，1H)，0.6(d，2H)，0.4(d，2H)

Embodiment 83

Step 5

5-(4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid (2-hydroxyl-ethyoxyl)-amide synthetic

With EDCI (262.4mg, 1.369mmol), HOBt (186.6mg, 1.369mmol), TEA (279mg; 2.736mmol) and O-(uncle 2--butoxy-ethyl)-azanol (182mg 1.369mmol) joins the 5-(4-bromo-2-fluoro-phenyl amino)-2 that is stirring, 2-dimethyl-7-oxo-3a; 7,8,8a-tetrahydrochysene-1; (200mg is 0.456mmol) in the solution in DMF (5mL) and DCM (5mL) for 3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid.Reactant mixture was stirred 16 hours under RT.Reactant mixture is distributed between water and ethyl acetate.Organic layer is used saturated NaHCO ₃, saline solution washing, use Na ₂SO ₄Drying concentrates.Concentrate (is used silica gel with column chromatography; With the DCM solution of 2% methanol as eluant) purification, obtain the required product 5-of 100mg (yield 39.5%) (4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a; 7; 8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid (2-hydroxyl-ethyoxyl)-amide.

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide synthetic

Dense HCl (3mL) is joined 5-(4-bromo-2-fluoro-phenyl amino)-2; 2-dimethyl-7-oxo-3a, 7,8; 8a-tetrahydrochysene-1; (100mg 0.18mmol) in the solution in methanol (3mL), stirs reactant mixture 3 hours under RT 3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid (2-hydroxyl-ethyoxyl)-amide.Reactant mixture is concentrated, concentrate is ground with ethyl acetate.Collected deposition is used the preparation HPLC purification, obtain the required product 7-of 50mg (yield 61.3%) (4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide.

LCMS purity: 98.9%, m/z=458.0 (M+H).

HPLC：98.7％

¹H?NMR(DMSO-D ₆，300MHz)：11.4(s，1H)，8.2(s，1H)，7.7(d，1H)，7.45-7.35(m，2H)，5.8(s，1H)，5.4(d，1H)，5.3(s，1H)，5.1(t，1H)，4.8(t，1H)，4.3(t，1H)，4.0(t，2H)，3.7-3.9(m，2H)，3.65-3.55(m，2H)。

Embodiment 84

Step 5

5-(4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid cyclobutyl methoxy base-amide synthetic

With EDCI (262.4mg, 1.369mmol), HOBt (61mg, 0.456mmol), TEA (279mg; 2.736mmol) and O-cyclobutylmethyl-azanol (138mg 1.369mmol) joins the 5-(4-bromo-2-fluoro-phenyl amino)-2 that is stirring, 2-dimethyl-7-oxo-3a; 7,8,8a-tetrahydrochysene-1; (200mg is 0.456mmol) in the solution in DMF (5mL) and DCM (5mL) for 3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid.Reactant mixture was stirred 16 hours under RT.Reactant mixture (is distributed between 2 * 25mL) at water and ethyl acetate.Organic layer is used saturated NaHCO ₃, saline solution washing, use Na ₂SO ₄Drying concentrates.Concentrate (is used silica gel with column chromatography; With the DCM solution of 2% methanol as eluant) purification, obtain the required product 5-of 140mg (yield 61.4%) (4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a; 7; 8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid cyclobutyl methoxy base-amide.

LCMS：m/z＝522.1(M+H)。

¹H?NMR(DMSO-D ₆，300MHz)：10.4(s，1H)，9.2(s，1H)，7.2-7.4(m，3H)，5.8(s，1H)，5.6(d，1H)，5.1(t，1H)，4.4(d，1H)，3.95-4.05(m，3H)，2.85-2.75(m，1H)，2.15-2.05(m，2H)，1.95-1.85(m，4H)，1.5(s，6H)

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclobutyl methoxy base-amide synthetic

Dense HCl (3mL) is joined the 5-(4-bromo-2-fluoro-phenyl amino)-2 that is dissolved in the methanol (3mL); 2-dimethyl-7-oxo-3a, 7,8; 8a-tetrahydrochysene-1; 3-dioxa-7a-azepine-cyclopenta [a] indenes-(130mg in solution 0.249mmol), stirs the gained mixture 3 hours under RT 4-formic acid cyclobutyl methoxy base-amide.Reactant mixture is concentrated and concentrate is ground with ethyl acetate.Collect formed deposition, use the preparation HPLC purification, obtain the required product 7-of 35mg (yield 29.1%) (4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclobutyl methoxy base-amide.

¹H?NMR(DMSO-D ₆，300MHz)：11.4(s，1H)，8.1(s，1H)，7.7(d，1H)，7.45-7.35(m，2H)，5.3(s，1H)，5.1(s，1H)，4.35-4.25(m，1H)，3.85-3.75(m，6H)，3.8-3.7(m，3H)，2.65-2.55(m，1H)，2.05-1.95(m，2H)，1.85-1.75(m，4H)。

Embodiment 85

Step 5

5-(4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a, 7,8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid (uncle 3--butoxy-2-methyl-propoxyl group)-amide synthetic

With EDCI (262.4mg, 1.369mmol), HOBt (186.6mg, 1.369mmol), TEA (279mg; 2.736mmol) and O-(uncle 3--butoxy-2-methyl-propyl group)-azanol (220mg 1.369mmol) joins the 5-(4-bromo-2-fluoro-phenyl amino)-2 that is stirring, 2-dimethyl-7-oxo-3a; 7,8,8a-tetrahydrochysene-1; (200mg is 0.456mmol) in the solution in DMF (5mL) and DCM (5mL) for 3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid.Reactant mixture was stirred 16 hours under RT.Reactant mixture is distributed between water and ethyl acetate.Organic layer is used saturated NaHCO ₃, saline solution washing, use anhydrous Na ₂SO ₄Drying concentrates.Concentrate (is used silica gel with column chromatography; With the DCM solution of 0-2% methanol as eluant) purification, obtain the required product 5-of 100mg (yield 37.8%) (4-bromo-2-fluoro-phenyl amino)-2,2-dimethyl-7-oxo-3a; 7; 8,8a-tetrahydrochysene-1,3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid (uncle 3--butoxy-2-methyl-propoxyl group)-amide.

LCMS purity: 76.9%, m/z=568.1 (M+H)

HPLC：52.3％

Step 6

7-(4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (3-hydroxy-2-methyl-propoxyl group)-amide synthetic

Dense HCl (3mL) is joined the 5-(4-bromo-2-fluoro-phenyl amino)-2 that is dissolved in the methanol (3mL); 2-dimethyl-7-oxo-3a, 7,8; 8a-tetrahydrochysene-1; (120mg in solution 0.21mmol), stirs the gained mixture 2 hours under RT 3-dioxa-7a-azepine-cyclopenta [a] indenes-4-formic acid (uncle 3--butoxy-2-methyl-propoxyl group)-amide.Reactant mixture is concentrated and concentrate is ground with ethyl acetate, obtain deposition.Use the preparation HPLC purification, obtain the required product 7-of 50mg (yield 48.5%) (4-bromo-2-fluoro-phenyl amino)-1,2-dihydroxy-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (3-hydroxy-2-methyl-propoxyl group)-amide.

¹H?NMR(DMSO-D ₆，300MHz)：11.4(s，1H)，8.1(d，1H)，7.7(dd，1H)，7.45-7.35(m，2H)，5.85-5.75(m，1H)，5.4(t，1H)，5.3(s，1H)，5.15-5.05(m，1H)，4.7(dt，1H)，4.35-4.25(m，1H)，4.15-4.05(m，1H)，3.8(dd，1H)，3.7(dd，1H)，3.55-3.45(m，2H)，1.2(d，3H)。

Flow process 17

Step 1-4 is identical with embodiment 8.

Embodiment 86

Step 5

4-fluoro-3-(2-fluoro-4-iodo-phenyl)-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Under 0 ℃, with TEA (1.30mL, 9.259mmol) and DPPA (2.0mL; 9.259mmol) join 6-fluoro-7-(2-fluoro-4-iodo-the phenyl amino)-5-oxo-1 that is stirring; 2,3,5-tetrahydrochysene-indolizine-8-formic acid (4.0g; 9.259mmol) in the solution in DMF (30mL), reactant mixture was being stirred 4 hours under the RT, under nitrogen atmosphere.Reactant mixture is heated to 65 ℃ to spend the night.With TLC (the DCM solution of 15%MeOH) monitoring reaction.With the cooling of gained reactant mixture, add entry and impel the formation deposition, collect and be somebody's turn to do also drying under reduced pressure of deposition, obtain 3.65g product (yield 91%).

LCMS purity: 98.96%, m/z=429.9 (M+1)

HPLC：84.6％

¹H?NMR(DMSO-D ₆，300MHz)：δ11.3(s，1H)，7.9-7.25(m，3H)，4.0(t，2H)，3.1(t，2H)，2.3-2.2(m，2H)

Step 6

1-(1-pi-allyl-cyclopropane sulfonyl)-4-fluoro-3-(2-fluoro-4-iodo-phenyl)-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Under 0 ℃, under nitrogen atmosphere, with 60%NaH (0.37g; 9.324mol) join the 4-fluoro-3-(2-fluoro-4-iodo-phenyl)-1,6,7 that is stirring; 8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2; (2.0g 4.662mmol) in the solution in dry DMF (20mL), stirs the gained mixture 20 minutes down at 0 ℃ the 5-diketone.(1.26g 6.993mol), next continues to stir 18 hours under RT to add 1-pi-allyl-cyclopropane sulfonic acid chloride down at 0 ℃ then.With TLC (the DCM solution of 10%MeOH) monitoring reaction.Reactant mixture is distributed between water and ethyl acetate.Organic layer is used water washing, use Na ₂SO ₄Drying concentrates.With silica gel column chromatography (hexane solution of 60% ethyl acetate) purification, obtain 1.22g product (yield 46%).

LCMS purity: 77.1%, m/z=573.9 (M+1)

¹H?NMR(CDCl ₃，300MHz)：δ7.62(d，2H)，7.15(t，1H)，5.7-5.6(m，1H)，5.1(d，2H)，4.4(t，2H)，3.5(t，2H)，2.7-2.6(m，2H)，2.3-2.2(m，2H)，1.9-1.8(m，1H)，1.8-1.7(m，1H)，1.2-1.1(m，2H)

Step 7

Synthesizing of 1-pi-allyl-cyclopropane sulfonic acid [6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

(0.23g 1.776mmol) joins 1-(1-pi-allyl-cyclopropane sulfonyl)-4-fluoro-3-(2-fluoro-4-iodo-phenyl)-1,6 with trimethyl silicane potassium alcoholate (potassium trimethyl silanoate); 7; 8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2; (0.50g is 0.888mmol) in the solution in THF (10mL) for the 5-diketone.With reactant mixture 65 ℃ of refluxed 30 minutes.With TLC (the DCM solution of 10%MeOH) monitoring reaction.Reactant mixture is distributed between water and ethyl acetate.Organic layer is used Na ₂SO ₄Drying concentrates.Concentrate is washed with ether, obtain 405mg product (yield 83%).

LCMS purity: 92.%, m/z=548 (M+1)

HPLC：95.8％

¹H?NMR(CDCl ₃，300MHz)：δ7.4-7.3(m，2H)，6.7(s，1H)，6.6-6.5(m，1H)，5.8-56(m，1H)，5.2-5.1(m，2H)，4.2(t，2H)，3.3(t，2H)，2.7(d，2H)，2.3-2.1(m，2H)，1.3(t，2H)，0.8(t，2H)

Step 8

Synthesizing of 1-(2,3-dihydroxy-propyl group)-cyclopropane sulfonic acid [6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

With N-methyl-morpholine-N-oxide (0.078g, 0.676mmol) and OsO ₄(0.02g; 0.067mmol) join 1-pi-allyl-cyclopropane sulfonic acid [the 6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1 that is stirring; 2,3,5-tetrahydrochysene-indolizine-8-yl]-amide (0.37g; 0.676mmol) in the solution in THF (10mL), with gained mixture stirred overnight under RT.With TLC (the DCM solution of 10%MeOH) monitoring reaction.Reactant mixture is distributed between water and ethyl acetate.With organic layer water, saline solution washing, use Na ₂SO ₄Drying concentrates.With silica gel column chromatography (chloroformic solution of 5% methanol) purification, obtain 86mg product (yield 22%).

LCMS purity: 96.2%, m/z=582.1 (M+1)

HPLC：98.7％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.95-8.85(br?s，1H)，7.9-7.8(br?s，1H)，7.6(d，1H)，7.45(d，1H)，6.9-6.7(m，1H)，4.8-4.6(m，2H)，4.2-4.0(m，2H)，3.8-3.7(m，1H)，3.4-3.2(m，3H)，2.3(d，1H)，2.1(t，2H)，1.6-1.4(m，1H)，1.1-0.8(m，3H)

Embodiment 87

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 14 described modes, and step 4 is used with the similar mode of embodiment 15 described modes and carried out.

Step-5

3-(4-bromo-2-fluoro-phenyl)-4-methyl isophthalic acid, 6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Use the reaction condition identical, make 7-(4-bromo-2-fluoro-the phenyl amino)-6-methyl-5-oxo-1,2 in DMF (20mL) with the step 5 of embodiment 86; 3; 5-tetrahydrochysene-indolizine-8-formic acid (2.75g, 7.21784mmol) with TEA (1.0mL, 7.218mmol) and DPPA (1.55mL; 7.218mmol) reaction, obtain 2.2g product (yield 80%).

¹H?NMR(DMSO-D ₆，300MHz)：δ11.0(s，1H)，7.8(dd，1H)，7.6(m，2H)，4.0(t，2H)，3.0(t，2H)，2.2(t，2H)，1.5(s，3H)

Step-6

1-(1-pi-allyl-cyclopropane sulfonyl)-3-(4-bromo-2-fluoro-phenyl)-4-methyl isophthalic acid, 6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Under 0 ℃, (0.15mL 1.06mmol) joins 3-(4-bromo-2-fluoro-the phenyl)-4-methyl isophthalic acid that is stirring, 6 with TEA; 7,8-tetrahydrochysene-3H-1,3; 5a-three azepines-asymmetric-indacene-2, (0.20g is 0.531mmol) in the solution in DCM (8mL) for the 5-diketone.Then 0 ℃ add down 1-pi-allyl-cyclopropane sulfonic acid chloride (0.196g, 1.06mmol) and DMAP (0.013g, 0.106mmol), with gained mixture stirred overnight under RT.With TLC (the DCM solution of 10%MeOH) monitoring reaction.Reactant mixture is distributed between water and DCM.With organic layer water, saline solution washing, use Na ₂SO ₄Drying concentrates.With silica gel column chromatography (hexane solution of 70% ethyl acetate) purification, obtain 70mg product (yield 25%).

¹H?NMR(DMSO-D ₆，300MHz)：δ7.5-7.3(m，3H)，5.9-5.6(m，1H)，5.1-4.9(m，3H)，4.2(t，2H)，3.5(t，2H)，2.7(t，2H)，2.3-2.1(m，2H)，2.1-2.0(m，2H)，1.9-1.8(m，1H)，1.8-1.7(m，2H)，1.2-1.1(m，4H)

Step-7

Synthesizing of 1-pi-allyl-cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

Use the reaction condition identical, make 1-(1-pi-allyl-cyclopropane sulfonyl)-3-(4-bromo-2-fluoro-the phenyl)-4-methyl isophthalic acid in THF (4.0mL), 6 with the step 7 of embodiment 86; 7,8-tetrahydrochysene-3H-1,3; 5a-three azepines-asymmetric-indacene-2, (0.065g is 0.124mmol) with trimethyl silicane potassium alcoholate (0.032g for the 5-diketone; 0.249mmol) reaction, obtain 40mg product (yield 59%).

LCMS purity: 87.3%, m/z=497.9 (M+)

¹H?NMR(DMSO-D ₆，300MHz)：δ8.9-8.8(br?s，1H)，7.5(d，1H)，7.35(s，1H)，7.2(d，1H)，6.4(t，1H)，5.7-5.5(m，1H)，5.1-4.9(m，2H)，4.1(t，2H)，3.2(t，2H)，2.6(d，2H)，2.2-2.1(m，2H)，1.7(s，3H)，1.05(t，2H)，0.75(t，2H)

Step-8

Synthesizing of 1-(2,3-dihydroxy-propyl group)-cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

Use the reaction condition identical with the step 8 of embodiment 86; Make the 1-pi-allyl-cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1 in THF (4.0mL); 2,3,5-tetrahydrochysene-indolizine-8-yl]-amide (0.025g; 0.050mmol) with N-methyl-morpholine-N-oxide (0.006g, 0.050mmol), OsO ₄(0.001g, 0.005mmol) reaction obtains the bullion product.With silica gel column chromatography (the DCM solution of 5% methanol) purification, use the preparation HPLC purification then, obtain 8mg product (yield 26%).

LCMS purity: 96.32%, m/z=530 (M+)

HPLC：93.5％

¹H?NMR(CDCl ₃-D ₆，300MHz)：δ7.45-7.4(br?s，1H)，7.21(d，1H)，7.15(d，1H)，7.1-7.0(br?s，1H)，6.45(t，1H)，4.25(t，2H)，4.1-3.9(m，1H)，3.7-3.6(m，1H)，3.5-3.4(m，1H)，3.3(t，2H)，2.4-2.1(m，3H)，1.8-1.6(m，4H)，1.6-1.3(m，2H)，0.9(t，2H)

Embodiment 88

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 8 described modes, and step 4 is used with the similar mode of embodiment 11 described modes and carried out, and step 5 is used with the similar mode of embodiment 61 described modes and carried out.

Step-6

1-(1-pi-allyl-cyclopropane sulfonyl)-3-(4-bromo-2-fluoro-phenyl)-4-fluoro-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Use the reaction condition identical, make 3-(4-bromo-2-fluoro-the phenyl)-4-fluoro-1,6 in DMF (12mL) with the step 6 of embodiment 86; 7,8-tetrahydrochysene-3H-1,3; 5a-three azepines-asymmetric-indacene-2, (1.0g is 2.624mmol) with NaH (0.21g for the 5-diketone; 5.249mmol) and 1-pi-allyl-cyclopropane sulfonic acid chloride (0.71g, 3.937mmol) reaction, obtain the bullion product.With silica gel column chromatography (the DCM solution of 5% methanol) purification, obtain 300mg product (yield 21%).

LCMS purity: 97.3%, m/z=526 (M+)

HPLC：95.2％

¹H?NMR(CDCl ₃，300MHz)：δ7.5-7.4(m，2H)，7.35(d，1H)，5.8-5.6(m，1H)，5.1(d，2H)，4.25(t，2H)，3.45(t，2H)，2.8-2.6(m，2H)，2.3-2.1(m，2H)，2.0-1.7(m，2H)，1.3-1.1(m，2H)

Step-7

Synthesizing of 1-pi-allyl-cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

Use the reaction condition identical, make 1-(1-pi-allyl-cyclopropane sulfonyl)-3-(4-bromo-2-fluoro-the phenyl)-4-fluoro-1,6 in THF (8mL) with the step 7 of embodiment 86; 7,8-tetrahydrochysene-3H-1,3; 5a-three azepines-asymmetric-indacene-2, (0.26g is 0.494mmol) with trimethyl silicane potassium alcoholate (0.12g for the 5-diketone; 0.989mmol) reaction, obtain 195mg product (yield 79.2%).

LCMS purity: 96.4%, m/z=500.0 (M+)

HPLC：98.5％

¹H?NMR(CDCl ₃，300MHz)：δ7.25-7.1(m，2H)，6.8-6.1(m，1H)，6.65(s，1H)，6.4(s，1H)，5.8-5.6(m，1H)，5.2-5.1(m，2H)，4.2(t，2H)，3.3(t，2H)，2.7(d，2H)，2.3-2.1(quin，2H)，1.3(t，2H)，0.85(t，2H)

Step-8

Synthesizing of 1-(2,3-dihydroxy-propyl group)-cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

Use the reaction condition identical with the step 8 of embodiment 86; Make the 1-pi-allyl-cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-fluoro-5-oxo-1 in THF (4.0mL); 2,3,5-tetrahydrochysene-indolizine-8-yl]-amide (0.19g; 0.38mmol) with N-methyl-morpholine-N-oxide (0.045g, 0.380mmol), OsO ₄(0.01g, 0.038mmol) reaction obtains the bullion product.With silica gel column chromatography (chloroformic solution of 7% methanol) purification, obtain 68mg product (yield 34%).

LCMS purity: 96.8%, m/z=534.0 (M+)

HPLC：99.7％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.95-8.85(br?s，1H)，7.9-7.8(br?s，1H)，7.55(d，1H)，7.3(d，1H)，7.1-6.9(m，1H)，4.8-4.6(m，2H)，4.1(t，2H)，3.8-3.7(br?s，1H)，3.3-3.1(m，4H)，2.3(d，1H)，2.1(m，2H)，1.6-1.5(m，1H)，1.2-0.8(m，4H)

Embodiment 89

Step-5

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-amide synthetic

With EDCI (1.45mg, 0.008mol) and HOBt (1.03g 0.008mol) joins 6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3, and (1.1g is 0.003mol) in the solution in DMF (20mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1 hour under RT.Add then O-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethyl)-azanol (1.12g, 0.008mol) and TEA (0.77g, 0.008mol).The gained mixture was stirred 18 hours under RT.Reactant mixture is distributed between ethyl acetate (100mL) and water (150mL).Organic layer is used saturated NaHCO ₃Solution (50mL), NH ₄Na is used in Cl, saline solution washing ₂SO ₄Drying, concentrating under reduced pressure obtains 780mg bullion chemical compound, and it promptly is used for next step without being further purified.

Step-6

6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide synthetic

2N HCl (5ml) is joined 6-fluoro-7-(2-fluoro-4-iodo-phenyl amino)-5-oxo-1,2,3, and (780mg is 0.001mol) in the solution in methanol (20mL) for 5-tetrahydrochysene-indolizine-8-formic acid (2,3-dihydroxy-propoxyl group)-amide.Reactant mixture was stirred 1 hour under RT.With the reactant mixture concentrating under reduced pressure, adding 1N NaOH then is about 8 until pH, with ethyl acetate extraction (2 * 100ml).Organic layer is used Na ₂SO ₄Drying, concentrating under reduced pressure obtains 250mg bullion product.Use the preparation HPLC purification, obtain 18mg product (yield 2.4%).

LC-MS purity: 96%, m/z=521.9, (M+)

¹H?NMR(DMSO-D ₆，300MHz)：δ11.5(s，1H)，8.06(s，1H)，7.58(d，1H)，7.42(d，1H)，6.80(t，1H)，4.9-4.4(m，2H)，4.00(t，2H)，3.9-3.8(m，1H)，3.7-3.6(m，3H)，3.14-3.12(m，3H)2.18-2.04(m，2H)

Embodiment 90

Flow process 18

Step 1 is used with the similar mode of embodiment 18 described modes and is carried out.

Step-2

7-chloro-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-Ethyl formate synthetic

Under RT, (5.8g 0.038mol) joins 7-hydroxyl-6-methyl-5-oxo-1,2,3, and (2g is 0.008mol) in the solution in toluene (75mL) for 5-tetrahydrochysene-indolizine-8-Ethyl formate with phosphoryl chloride phosphorus oxychloride (phosphorusoxy chloride).Reactant mixture was stirred 2 hours down at 110 ℃.With TLC (hexane solution of 60% ethyl acetate) monitoring reaction.With the reactant mixture concentrating under reduced pressure, add frozen water (50mL) and saturated K then ₂CO ₃Solution (75mL) (pH=10).With the gained reactant mixture with ethyl acetate extraction (3 * 50mL).The organic layer that merges is used Na ₂SO ₄Drying, concentrating under reduced pressure obtains 1.6g bullion chemical compound.Through carrying out purification, obtain 1.54g product (yield %) with the hexane recrystallization.

Step-3

7-chloro-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

1N LiOH solution (25mL) is joined 7-chloro-6-methyl-5-oxo-1,2,3, and (1.5g is 0.006mol) in the solution in 75ml THF: MeOH (4: 1) for 5-tetrahydrochysene-indolizine-8-Ethyl formate.Reactant mixture was stirred 18 hours under RT.With TLC (the DCM solution of 20% methanol) monitoring reaction.With the reactant mixture concentrating under reduced pressure, adding 1N HCl (100mL) then is about 1 until pH.Collecting precipitation and drying under reduced pressure obtain 1.12g product (yield 84%).

LC-MS purity: 98%, m/z=226 (M-)

¹H?NMR(DMSO-D ₆，300MHz)：δ13.2(s，1H)，4.00(t，2H)，3.28(t，2H)，2.2-2.02(m，5H)

Step-4

7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid synthetic

Under-78 ℃, (1.86g, (2.9g is 0.012mol) in the solution in dry THF (20mL) 0.017mol) to join 2-fluoro-4-iodo-phenyl amine with LDA.Reactant mixture was stirred 45 minutes down at-78 ℃.Add down the 7-chloro-6-methyl-5-oxos-1,2,3 that are arranged in THF (90mL) at-78 ℃ then, and 5-tetrahydrochysene-indolizine-8-formic acid (1.1g, 0.005mol) and under RT, continue again to stir 20 hours.With TLC (the DCM solution of 20% methanol) monitoring reaction.With the reactant mixture concentrating under reduced pressure, add 2N HCl solution (50mL) and ether (50mL) then.Reactant mixture was stirred 15 minutes.Collecting precipitation, with ether washing (2 * 20mL) and drying under reduced pressure, obtain 820mg product (yield 41%).

LC-MS purity: 94%, m/z=429 (M+)

¹H?NMR(DMSO-D ₆，300MHz)：δ13.30(s，1H)，9.36(s，1H)，7.60(d，1H)，7.38(s，1H)，6.40(t，1H)，4.04(t，2H)，3.48(t，2H)，2.18-2.02(m，2H)，1.64(s，3H)

Step-5

7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclo propyl methoxy amide synthetic

With EDCI (334mg, 0.002mol) and HOBt (236mg 0.002mol) joins 7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3, and (250mg is 0.001mol) in the solution in DMF (10mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1 hour under RT.Add then hydrochloric acid O-cyclopropyl methyl-azanol (216mg, 0.002mol) and TEA (176mg, 0.002mol).The gained mixture was stirred 2 hours under RT.With TLC (the DCM solution of 10% methanol) monitoring reaction.Reactant mixture is distributed between ethyl acetate (75mL) and water (125mL).Organic layer is used saturated NH ₄Cl (50mL), NaHCO ₃, saline solution washing, use Na ₂SO ₄Drying, concentrating under reduced pressure obtains 210mg bullion chemical compound.Through carrying out purification, obtain 140mg product (yield 48.2%) with methanol (2mL) and ether (20mL) recrystallization.

LC-MS purity: 97%, m/z=498, (M+)

¹H?NMR(DMSO-D ₆，300MHz)：δ11.22(s，1H)，7.7(s，1H)，7.56(d，1H)，7.32(d，1H)，6.40(t，1H)，4.02(t，2H)，3.48(d，2H)，3.2(t，2H)，2.18-2.04(m，2H)，1.68(s，3H)，1.04-.094(m，1H)，0.58-0.46(m，2H)，0.26-0.18(m，2H)。

Embodiment 91

Step 1 is used with the similar mode of embodiment 14 described modes and is carried out, and step 2 to 4 usefulness are carried out with the similar mode of embodiment 90 described modes.

Step-5

7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (uncle 2--butoxy-ethyoxyl)-amide synthetic

With EDCI (334mg, 0.002mol) and HOBt (236mg 0.002mol) joins 7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3, and (250mg is 0.001mol) in the solution in DMF (10mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 30 minutes under RT.Add then O-(uncle 2--butoxy-ethyl)-azanol (233mg, 0.002mol) and TEA (176mg, 0.002mol).The gained mixture was stirred 16 hours under RT.With TLC (the DCM solution of 10% methanol) monitoring reaction.Reactant mixture is distributed between ethyl acetate (100mL) and water (100mL).Organic layer is used saturated NH ₄Cl (50mL), NaHCO ₃, saline solution washing, use Na ₂SO ₄Drying, concentrating under reduced pressure obtains 300mg bullion chemical compound.With silica gel column chromatography (the DCM solution of 2% methanol) purification, obtain 228mg product (yield 71%).

LC-MS purity: 96%, m/z=544, (M+)

Step-6

7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid (2-hydroxyl-ethyoxyl)-amide synthetic

Under 0 ℃, trifluoroacetic acid (2.5mL) is joined 7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3, (220mg is 0.0004mol) in the solution in DCM (2.5mL) for 5-tetrahydrochysene-indolizine-8-formic acid (uncle 2--butoxy-ethyoxyl)-amide.Reactant mixture was stirred 2 hours.With TLC (the DCM solution of 10% methanol) monitoring reaction.With the reactant mixture concentrating under reduced pressure, add NaHCO then ₃Until pH is about 8, uses ethyl acetate extraction.The organic layer that merges is used 5%NaHCO ₃Solution washing is used Na ₂SO ₄Drying, concentrating under reduced pressure.Concentrate with ether and ethyl acetate washing, is obtained 89mg product (yield 45%).

LC-MS purity: 93%, m/z=488, (M+)

¹H?NMR(DMSO-D ₆，300MHz)：δ11.24(s，1H)，7.68(s，1H)，7.54(d，1H)，7.32(d，1H)，6.40(t，1H)，4.7(s，1H)，4.00(t，2H)，3.7(t，2H)，3.55-3.42(m，2H)，3.18(t，2H)，2.18-2.04(m，2H)，1.72(s，3H)

Embodiment 92

Step-5

7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-formic acid cyclobutyl methoxy base-amide synthetic

With EDCI (167mg, 0.001mol) and HOBt (118mg 0.001mol) joins 7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3, and (125mg is 0.0003mol) in the solution in DMF (8mL) for 5-tetrahydrochysene-indolizine-8-formic acid.Reactant mixture was stirred 1 hour under RT.Add then O-cyclobutylmethyl-azanol (88mg, 0.001mol) and TEA (88mg, 0.001mol).The gained mixture was stirred 2 hours under RT.With TLC (the DCM solution of 10% methanol) monitoring reaction.Reactant mixture is distributed between ethyl acetate (50mL) and water (75mL).Organic layer is used saturated NH ₄Cl (50mL), NaHCO ₃, saline solution washing, use Na ₂SO ₄Drying, concentrating under reduced pressure obtains 150mg bullion chemical compound.Through carrying out purification, obtain 85mg product (yield 57%) with ethyl acetate (10mL) and ether (50mL) recrystallization.

LC-MS purity: 94%, m/z=512, (M+)

¹H?NMR(DMSO-D ₆，300MHz)：δ11.2(s，1H)，7.68(s，1H)，7.58(d，1H)，7.34(d，1H)，6.40(t，1H)，4.00(t，2H)，3.56(d，2H)，3.18(t，2H)，2.18-2.04(m，2H)，2.02-1.92(m，3H)，1.9-1.62(m，7H)。

Embodiment 93

Step and 3 usefulness are carried out with the similar mode of embodiment 14 described modes, and step 4 is used with the similar mode of embodiment 15 described modes and carried out.

Step-5

3-(2-fluoro-4-iodo-phenyl)-4-methyl isophthalic acid, 6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Use the reaction condition identical, make 7-(2-fluoro-4-iodo-the phenyl amino)-6-methyl-5-oxo-1,2 in DMF (30mL) with the step 5 of embodiment 86; 3; 5-tetrahydrochysene-indolizine-8-formic acid (3.14g, 7.34mmol) with TEA (1.03mL, 7.34mmol) and DPPA (1.59mL; 7.34mmol) reaction, obtain 1.85g product (yield 59%).

LCMS purity: 97.0%, m/z=426.0 (M+)

¹H?NMR(DMSO-D ₆，300MHz)：δ11.1(s，1H)，7.9(d，1H)，7.7(d，1H)，7.4-7.1(m，2H)，3.9(t，2H)，3.1(t，2H)，2.4-2.2(m，2H)，1.45(s，3H)

Step-6

1-(1-pi-allyl-cyclopropane sulfonyl)-3-(2-fluoro-4-iodo-phenyl)-4-methyl isophthalic acid, 6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Use the identical reaction condition of step 6 (current embodiment group) with embodiment 109, make 3-(2-fluoro-4-iodo-the phenyl)-4-methyl isophthalic acid in DMF (20mL), 6; 7,8-tetrahydrochysene-3H-1,3; 5a-three azepines-asymmetric-indacene-2, (1.80g is 4.24mmol) with NaH (0.34g for the 5-diketone; 8.47mmol) and 1-pi-allyl-cyclopropane sulfonic acid chloride (1.14g, 6.35mmol) reaction, obtain the bullion product.With silica gel column chromatography (hexane solution of 50% ethyl acetate) purification, obtain 490mg product (yield 20%).

LCMS purity: 83.9%, m/z=569.9 (M+)

¹H?NMR(CDCl ₃，300MHz)：δ7.7-7.6(m，2H)，7.15(t，1H)，5.7-5.6(m，1H)，5.1-4.9(m，2H)，4.2(t，2H)，3.5(t，2H)，2.7(t，2H)，2.3-2.1(m，3H)，1.9-1.8(m，1H)，1.8-1.6(m，1H)，1.3-1.11(m，2H)

Step-7

1-pi-allyl-cyclopropane sulfonic acid [7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

Use the identical reaction condition of step 7 (current embodiment group) with embodiment 109, make 1-(1-pi-allyl-cyclopropane sulfonyl)-3-(2-fluoro-4-iodo-the phenyl)-4-methyl isophthalic acid in THF (12mL), 6; 7,8-tetrahydrochysene-3H-1,3; 5a-three azepines-asymmetric-indacene-2, (0.48g is 0.84mmol) with trimethyl silicane potassium alcoholate (0.21g for the 5-diketone; 1.69mmol) reaction, obtain 310mg product (yield 63%).

LCMS purity: 85.2%, m/z=544.0 (M+)

HPLC：86.7％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.8(s，1H)，7.6(d，1H)，7.35(d，2H)，6.3(t，1H)，5.7-5.5(m，1H)，5.1(d，2H)，4.1(t，2H)，3.25(t，2H)，2.6(d，2H)，2.1(quin，2H)，1.7(s，3H)，1.1(t，2H)，0.75(t，2H)

Step-8

Synthesizing of 1-(2,3-dihydroxy-propyl group)-cyclopropane sulfonic acid [7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

Use the identical reaction condition of step 8 (current embodiment group) with embodiment 109; Make the 1-pi-allyl-cyclopropane sulfonic acid [7-(2-fluoro-4-iodo-phenyl amino)-6-methyl-5-oxo-1 in THF (10mL); 2,3,5-tetrahydrochysene-indolizine-8-yl]-amide (0.25g; 0.46mmol) with N-methyl-morpholine-N-oxide (0.054g, 0.46mmol), OsO ₄(0.01g, 0.046mmol) reaction obtains the bullion product.With the silica gel column chromatography (CHCl of 5% methanol ₃Solution) purification is used the preparation HPLC purification then, obtains 95mg product (yield 36%).

LCMS purity: 96.7%, m/z=577.8 (M+)

HPLC：97.2％

¹H?NMR(DMSO-D ₆，300MHz)：δ8.75(s，1H)，7.6-7.3(m，3H)，6.3(t，1H)，4.6(t，2H)，4.1(t，2H)，3.6-3.5(m，1H)，3.3-3.2(m，4H)，2.1-2.0(m，3H)，1.75-1.6(m，5H)，1.3-1.0(m，4H)

Flow process 19

Embodiment 94

Step 1 to 3 usefulness are carried out with the similar mode of embodiment 14 described modes, and step 4 is used with the similar mode of embodiment 15 described modes and carried out, and step 5 is used with the similar mode of embodiment 87 described modes and carried out.

Step-6

3-(4-bromo-2-fluoro-phenyl)-1-cyclopropane sulfonyl-4-methyl isophthalic acid, 6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone synthetic

Under 0 ℃, (0.04gm 0.001mol) joins 3-(4-bromo-2-fluoro-phenyl)-4-methyl isophthalic acid, 6 with sodium hydride; 7,8-tetrahydrochysene-3H-1,3; 5a-three azepines-asymmetric-indacene-2, (0.2gm is 0.0005mol) in the solution in dry DMF (3mL) for the 5-diketone.Then 0 ℃ add down the cyclopropane sulphonyl (0.11gm, 0.0008mol), with reactant mixture stirred overnight under RT.With the TLC (CHCl of 5%MeOH ₃Solution) monitoring reaction.Add ice,, use ethyl acetate extraction, concentrate then, obtain 0.25g bullion product, it promptly is used for next step without being further purified with rare HCl neutralization.

Step-7

Synthesizing of cyclopropane sulfonic acid [7-(4-bromo-2-fluoro-phenyl amino)-6-methyl-5-oxo-1,2,3,5-tetrahydrochysene-indolizine-8-yl]-amide

6ml 1N NaOH solution is added 3-(4-bromo-2-fluoro-the phenyl)-1-cyclopropane sulfonyl-4-methyl isophthalic acid that is arranged in DMF, 6,7; 8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2; In the 5-diketone (0.25g), mixture heated to 65 ℃ is reached 1.30 hours.Add ice,, use ethyl acetate extraction, concentrate then, with the silica gel column chromatography (CHCl of 2% methanol with rare HCl neutralization ₃Solution) purification obtains 0.090g product (yield 37.34%).

¹H?NMR(DMSO-D ₆，300MHz)：δ8.9(s，1H)，7.5(d，1H)，7.4(s，1H)，7.2(d，1H)，6.5(t，1H)，4.0(t，2H)，3.3(t，2H)，2.5(m，1H)，2.1(q，2H)，1.7(s，3H)，0.9(m，4H)

In BRAF-MEK-ERK enzyme cascade mensuration and cell viability are measured, the chemical compound of embodiment above as the map kinase pathway inhibitor is assessed, in table 1, concentrated to have provided its result.Be clear that those skilled in the art can prepare other chemical compound as herein described with its known method and/or method as herein described.

Table 1.

The embodiment that is provided in this description only is used to describe the present invention, so it should not be understood that limitation of the scope of the invention.

Claims

1. the chemical compound of formula I:

With its pharmaceutically acceptable salt, wherein

X representes C _1-3-Alkylidene ,-N (R ⁶)-,-O-or-S (O) _p-;

R ²Expression H, cyanic acid or group-Y-R ⁷

R ⁵Expression H, halogen, C _1-3-Alkyl or C _1-3-Haloalkyl;

Y representes to be selected from-D-,-E-,-D-E-or-group of E-D-;

R ⁷Expression H, C _1-6-Alkyl, C _2-6-Alkenyl, C _2-6-Alkynyl, cycloalkyl, aryl, Heterocyclylalkyl or heteroaryl, wherein when being not H, R ⁷Choose wantonly and be independently selected from halogen, cyanic acid, hydroxyl, C by 1 to 3 _1-6-Alkoxyl, C ₂-C ₆-alkenyl oxy, C ₂-C ₆-alkynyloxy base, C _1-6-Alkylthio group, C _1-6Haloalkyl, amino, C _1-6Alkyl amino, two-C _1-6Alkyl amino, C _1-6Acyl amino, C _1-6Acyl group C _1-6The group of alkyl amino, monocyclic cycloalkyl or monocyclic Heterocyclylalkyl replaces, and wherein said each ring can be chosen wantonly by 1 or 2 and be independently selected from halogen, cyanic acid, hydroxyl, C _1-6-Alkoxyl, C ₂-C ₆-alkenyl oxy, C ₂-C ₆-alkynyloxy base, C _1-6-Alkylthio group, C _1-6-Haloalkyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino, C _1-6-Acyl amino and C _1-6-Acyl group C _1-6-The group of alkyl amino replaces;

Z is O or N (R ¹⁸);

Tabulation 1 is selected from hydroxyl, cyanic acid, nitro, C _1-6-Alkyl, C _2-6-Alkenyl, C _2-6-Alkynyl, C _1-6-Alkoxyl, C _2-6-Alkenyl oxy, C _2-6-Alkynyloxy base, halogen, C _1-6-Alkyl-carbonyl, carboxyl, C _1-6-Alkoxy carbonyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino, C _1-6-Alkyl amino-carbonyl, two-C _1-6-Alkyl amino-carbonyl, C _1-6-Alkyl-carbonyl-amino, C _1-6-Alkyl-carbonyl (C _1-6-Alkyl) amino, C _1-6-Alkyl sulfonyl-amino, C _1-6-Alkyl sulphonyl (C _1-6-Alkyl) amino, C _1-6-Alkylthio group, C _1-6-Alkyl sulphinyl, C _1-6-Alkyl sulfenyl, C _1-6-Alkyl sulphonyl, amino-sulfonyl, C _1-6-Alkyl amino sulfonyl and two-C _1-6-Alkyl amino sulfonyl, wherein above-mentioned hydrocarbyl group can be chosen wantonly by one or more halogens, hydroxyl, C separately _1-6-Alkoxyl, amino, C _1-6-Alkyl amino, two-C _1-6-Alkyl amino or cyanic acid replace;

M and n are 0,1,2 or 3 independently; And m+n=2 or 3;

P is 0,1 or 2; And wherein

Heterocyclylalkyl or inferior Heterocyclylalkyl are represented the monocycle or the bicyclo-of 3-14 unit, and a wherein said monocycle or a said bicyclic ring are to comprise 1 or 2 to be selected from-N (R ²²)-,-O-and-ring members of S (O) r-and can choosing wantonly further comprises-the saturated or undersaturated group of part of C (O)-ring members; Another ring can be aromatics, saturated or part undersaturated, and can comprise 1 to 3 and be selected from-C (=O) ,-N (R ²³) q-,-ring members of O-and S (O) r, wherein R ²²Or R ²³Be H or C _1-6-Alkyl, q are that 0-1 and r are 0-2.

2. the chemical compound of claim 1, wherein X represent-N (H)-.

3. the chemical compound of claim 1 or claim 2, wherein R ¹Be illustrated in 2 and 4 substituted phenyl.

4. any one chemical compound, wherein R among the claim 1-3 ¹Expression 4-bromo-2-fluorophenyl or 4-iodo-2-fluorophenyl.

5. any one chemical compound among the claim 1-4, wherein Y representes D, D representes to be selected from-C (O)-,-CO ₂-, C (O) N (H) O-,-C (O) N (C _1-6-Alkyl) O-,-C (O) N (H)-or-C (O) N (C _1-6-Alkyl)-group.

6. any one chemical compound, wherein R among the claim 1-4 ²Expression-COH-,-CO ₂H ,-CO ₂Et, CON (H or CH ₃) OR ^7a, R wherein ^7aExpression methyl, ethyl, cyclopropyl methyl, 2-vinyl oxygen base ethyl, 2-hydroxyethyl or 2, the 3-dihydroxypropyl ,-CON (H or CH ₃)-R ^7b, R wherein ^7bExpression H, methyl, ethyl, cyclopropyl methyl, 2-methoxy ethyl, 2-hydroxyethyl, 3-hydroxypropyl, acetyl-amino methyl, 2-dimethyl aminoethyl, cyclopenta or 2-thiazolyl, perhaps R ²Expression

Di azoly is amino.

7. any one chemical compound, wherein R among the claim 1-4 or 6 ²Expression CONHOR ^7a, R wherein ^7aRepresentative ring propyl group methyl or 2-hydroxyethyl.

8. any one chemical compound among the claim 1-4, wherein-E-representative ring alkyl, the inferior Heterocyclylalkyl of 5-unit's inferior heteroaryl or 5-unit, it can be substituted or unsubstituted.

9. any one chemical compound among the claim 1-4 or 8; Wherein E representative ring amyl group, thiazole or

diazole, it can be substituted or unsubstituted.

10. any one chemical compound, wherein R among the claim 1-9 ³And R ⁴Expression H.

11. any one chemical compound among the claim 1-10, wherein R ⁵Be H, methyl, ethyl, chlorine or fluorine.

12. any one chemical compound among the claim 1-8, wherein R ⁵It is methyl.

13. any one chemical compound among the claim 1-12, wherein Z is O.

14. any one chemical compound among the claim 1-13, wherein m and n all are 1, perhaps among m and the n one be 1 and another be 2.

15. the chemical compound of formula Id:

With its salt, wherein

Rd ¹Expression H, halogen, C _1-3-Alkyl or C _1-3-Haloalkyl;

Rd ²Expression H, cyanic acid or group-Y-Rd ⁵

Y representes to be selected from-D-,-E-,-D-E-or-group of E-D-;

J and g represent 0,1,2 or 3 independently;

Rd ⁸, Rd ⁹, Rd ¹⁰, Rd ¹¹, Rd ¹², Rd ¹³, Rd ¹⁴, Rd ¹⁵, Rd ¹⁶, Rd ¹⁷, Rd ¹⁸And Rd ¹⁹Be H or C independently _1-6-Alkyl;

Alkyl or alkylidene are meant straight chain, side chain and/or the cyclic hydrocarbon of 1 to 20 carbon atom.Alkyl with 1 to 5 carbon is called as " low alkyl group ", instance include but not limited to methyl, ethyl, propyl group, isopropyl, just-butyl, tert-butyl and isobutyl group;

16. any one chemical compound among the claim 1-15, it is used in the treatment.

Use chemical compound any among the claim 1-15 or its prodrug or comprise formula I chemical compound or the pharmaceutical composition of its prodrug and pharmaceutically acceptable excipient 17. disease, obstacle or syndromic method that treatment is relevant with MEK inhibition, said method comprise to its individuality of needs.

18. the described Therapeutic Method of claim 17, wherein said disease, obstacle or syndrome are excess proliferative in individuality, wherein said individuality is an animal, comprises the people, and said disease, obstacle or syndrome are selected from cancer and inflammation.

19. suppress relevant disease, obstacle or syndromic method with embodiment formula I chemical compound as described herein basically, treatment and MEK together.

20. pharmaceutical composition, it comprises formula I chemical compound any among the claim 1-15 and pharmaceutically acceptable carrier or excipient.

21. pharmaceutical composition, it comprises formula I chemical compound any among the claim 1-15 and second kind of activating agent and pharmaceutically acceptable carrier or excipient.

22. a chemical compound, it is selected from

diazole-2-yl]-2,3-dihydro-1H-indolizine-5-ketone;

3-(4-bromo-2-fluoro-phenyl)-1-mesyl-1,6,7,8-tetrahydrochysene-3H-1,3,5a-three azepines-asymmetric-indacene-2,5-diketone;