TW201229047A - Pyridone amide derivatives, preparation process and pharmaceutical use thereof - Google Patents

Abstract

The present disclosure relates to pyridone amide derivatives, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel pyridone amide derivatives presented by formula (I) or pharmaceutically acceptable salts thereof, the uses for treatment especially for c-Met protein kinase inhibitors, in which each substitute group of general formula (I) is as defined in the specification.

Description

201229047 VI. Description of the Invention: [Technical Field] The present invention relates to a novel pyridone amide derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as c-Met Use of protein kinase inhibitors. [Prior Art] Signal transduction, as a basic regulatory mechanism of cells, transmits various extracellular signals to the interior of cells, allowing cells to respond and achieve processes such as proliferation, differentiation, and apoptosis. Protein kinases (PKs) play an important role in this process. PKs can be divided into tyrosine kinases (PTKs) and serine/threonine kinases (STKs). PTKs phosphorylate tyrosine residues on proteins, and sTKs phosphorylate serine and threonine residues. Tyrosine kinases can be further divided into receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases.

The RTKs family can be further divided into many subfamilies, including (i) ErbB (Her) scorpions 'including EGFR (Her_l), Her-2, Her_3, Her-4; (2) insulin receptor family, including insulin receptors Ir, insulin-like growth factor I receptor (IGF1R), etc.; (3) family 111, including platelet-derived growth factor receptor PDGFR, stem cell factor SCFR (c-Kit) and the like. In addition, hepatocyte growth factor receptor (HGFR, also known as "c-Met"), and vascular endothelial growth factor receptor VEGFR belong to the RTKs family. They act as signal transmitters in regulating cell proliferation and differentiation and dying (Schlessinger and Ullrich, (6) (10) 1992, 9, 383). 4 95165 201229047 Hepatocyte growth fat (HGF), also known as Scatter factor (SF), is a multi-effect growth factor that induces cell mitosis and tissue life activities, and enhances cancer growth. Moreover, HGF can also promote metastasis by stimulating cell motility and infiltration by various signaling pathways. In order to produce these cellular effects, it must act by binding its receptors, see Maggi ora et al., 6W, 173: 183-186, 1997. Hepatocyte growth factor receptor (HGFR, also known as "c-Met") is a receptor-type tyrosine kinase, and the glycosylated mature receptor has a molecular weight of 19〇kD. Is a heterodimer linked by a disulfide bond of a 50 kD extracellular alpha subunit to a 145 kD transmembrane cold subunit (M Park et al, Proc. Natl. Acad. Sci. USA, 84: 6379-6383, 1987). It has been reported that C-Met is overexpressed in various tumors such as pancreatic cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, lung cancer, kidney cancer, brain tumor, ovarian cancer, and esophageal cancer (see Christine TT). Etc., Oncology Reports, 5: 1013-1024, 1998). It is generally believed that the high expression of c-Met in the above tumor cells is closely related to various features of malignant tumors (including abnormal proliferation, infiltration, or hyperfunction of metastasis). Under the mediated action of HGF, tyrosine residues in the c-Met intracellular region are autophosphorylated, triggering a related signaling pathway that regulates cell proliferation and promotes cancer cell growth. In addition, it has been reported that C-Met is also expressed in vascular endothelial cells. c-Met regulates the process of tumor blood formation by promoting the proliferation and migration of vascular endothelial cells (Advance in Cancer Research, 5 95165 201229047 67 :257-279, 1995). The compound that is used by Tanjung to evaluate the c-Met-staining effect is an antitumor agent, an angiogenesis inhibitor or a cancer cell metastasis inhibitor. Another important member of RTKs is vascular endothelial growth factor (10) FR) 〇 VEGFR is directly related to angiogenesis, it can promote the migration of skin cells, promote capillary formation, and form a super-osmotic immature vascular network. Growth provides nutrition. In addition to pro-angiogenic activity, VEGFR and VEGF promote tumor growth directly in tumor cells by the pro-survi va 1 mechanism. By research, it is found that vegfr is overexpressed in various malignant solid tumors, such as lung cancer, breast cancer m_cancer and melanoma. Therefore, inhibition of tumor growth by inhibiting VEGFR activity has great application value for tumor therapy. . It has been reported in the literature that biological agents that are lightly directed to HGF or c-Met, such as ribozymes, antibodies and antisense RNA, can inhibit tumorigenesis (see stabile et al, Gene Therapy, 11:325, 35, 2004 and Genentech U.S). Pat.

No. 6,214,344,2001) The HGF antagonist peptide NK4 inhibits tumor cell invasion by blocking HGF-HGFR interaction and inhibits tumor angiogenesis (汾ί / Μ of 84:864-873, 2001 and Gnce/* 5W. , 94:321-327, 2003), but due to the large molecular weight and poor bioavailability of peptides, it is difficult to develop drugs. It is urgent to develop a new class of small molecules c-Met with high activity and low toxicity. Inhibitor. To date, a number of patents have been publicly reported for the use of small molecule c-Met inhibitors, including bulky hydrophobic group-substituted derivatives (see patents W02006116713 and W02005117867, etc.). 6 95165 201229047 At present, no small molecule c-Met protein kinase inhibitor is marketed, and it is an object of the present invention to provide a medicament having c_Met inhibitory activity and which can be used for the treatment or alleviation of cancer or the like. SUMMARY OF THE INVENTION In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide novel derivatives of the formula (I), and their tautomers, enantiomers, diastereomers , racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs,

Wherein: A is selected from -CRa or N; D is selected from -CRb or N; X is selected from -Cf- or N; R is selected from a aryl or heteroaryl group, wherein the aryl or heteroaryl group is further protected by one Or a plurality selected from the group consisting of alkyl, alkoxy, nitro, -C(0)OR9, -OC(0)R9, -〇(CH2)mC-〇C(0)NRlflRn^-S(0)nR9 &gt ; -〇〇〇oP9 ^ _cr , halogen, hydroxy, cyano, -〇(CH2)mC(0)〇R9,

, alkoxy, alkoxy or aryl: 〇2R9 ' -S〇2NR10Rn > -NHC(0)R9 〆 are each independently selected from a hydrogen atom, an alkyl group or a dentate; 95165 7 201229047 R is selected from a hydrogen atom or a stimuli group 'wherein the s-alkyl group needs to be further substituted by a substituent of a dentate or an alkoxy group; R8 is selected from a bicycloalkyl group, a biheterocyclic group, a bridged cycloalkyl group, a bridged heterocyclic group, a spirocycloalkyl group or a spiro a cycloalkyl group, wherein the bicycloalkyl group, the bicycloheterocyclyl group, the bridged cycloalkyl group, the bridged heterocyclyl group, the spiroalkyl group or the spiroheterocyclic group is further selected from the group consisting of Base, dentate, hydroxyl, cyano, moth, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl, _C(〇)〇R9, -OUO, 9,0(CH2)raC( 0) Substituted by a substituent of 0R9, -OCCOMRl11, -S(〇)nR9, -OS〇2R9, -SOAI^R11, -NHC(0)R9 or _NRlflRn; or 'R7 and R8 together with its associated N atom Forming a bi-heterocyclic group, a bridged heterocyclic group or a spiroheterocyclic group of 5 to 4 members, wherein the diheterocyclic group, the bridged heterocyclic group or the spiroheterocyclic group is further optionally selected from one or more selected from the group consisting of Alkoxy, _, hydroxy, cyano, nitro, carbonyl Base, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(0)0R9, -0C(0)R9, -0(CH2)mC(0)0R9, -〇C(O)NR, 0Rn ^ -S(〇)nR9 ' -OSOzR9 > -S〇2NR10Rn > -NHC(0)R9 or -NR1%11 substituted; R9 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or a aryl group a group wherein the alkyl group, the cycloalkyl group or the aryl group is further substituted with one or more amine groups as needed; R1Q or R11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group. Or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro , cycloalkyl, heterocyclic, -C(0)〇R9, -0C(0)R9,-0(CH2)mC(0)0R9, -0C(0)NR12R13, -S(0)nR9, _os Substituting a substituent of 〇2R9, ~S〇2NR12R13, _nhc(o)r9 or -nr12r13; 8 95165 201229047 Alternatively, R1() and R11 together with the nitrogen atom to which they are attached form a heterocyclic group of 3 to 8 members, wherein The 3 to 8 member heterocyclic ring further contains one or more N, 0 or S(0) n atoms, and the 3 to 8 member heterocyclic ring is further subjected to one or more Selected from alkyl, alkoxy, halogen, hydroxy, cyano, nitro, carbonyl, cycloalkyl, heterocyclic, aryl, heteroaryl, _c(〇)〇R9, _〇c(〇) Substituted by a substituent of R9, -0(CH2)mC(0)0R9, -〇C(〇)NR12R13, _s(〇)nR9, -OSO2R9, -S〇2NR12R13, -NHC(0)R9 or -NR12R13; R12 and R13 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group; m is 0, 1 or 2; and η is 〇, 1 or 2. A preferred embodiment of the invention is a compound of the formula (11) or a pharmaceutically acceptable salt thereof,

Wherein: R is selected from a aryl or heteroaryl group, wherein the aryl or heteroaryl group is progressively selected by one or more selected from the group consisting of an alkyl group, an alkoxy group, a halogen group, a thiol group, a gas group, and a -NHC group. )r9 nitro, -C(0)〇R9, -〇(X〇)R9, -〇(CH2)mC(0)OR9, -〇C(0)NR,0Rn > -S(0)nR9 &gt ; -OSO2R9 ^ -S〇2NR10Rn or a substituent of -NI^R11; "selected from a hydrogen atom or an alkoxy group; 9 95165 201229047 RRR or R are each independently selected from a hydrogen atom, an alkyl group or a halogen; a hydrogen atom or an alkyl group; R is selected from the group consisting of a bicycloalkyl group, a bicyclohetero group, a bridged cycloalkyl group, a bridged heterocyclic group, a monospiroalkyl group, a monospiroheterocyclic group, and a double-heterocyclic, diheterocyclic group. , bridged cycloalkyl, heterobridged cycloalkyl, monospirocycloalkyl or monospiroheterocyclyl optionally further selected from one or more selected from the group consisting of alkyl, alkoxy, _, hydroxy, cyano, nitro , cycloalkyl, heterocyclic, aryl, heteroaryl, _c(〇)〇R9, -0C(0)R9, -〇(CH2)mC(0)〇R9, -OCCOMI^R11, carbonyl, _s Substituting (n) a substituent of nR9, or -NR1%11; or 'R and R8 together with the nitrogen atom to which they are attached form a 5 to 14 member a hetero-hetero group, a bridged heterocyclic group or a monospiroheterocyclic group, wherein the bi-heterocyclic group, the bridged heterocyclic group or the monospiroheterocyclic group is further further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, and i. , hydroxy, cyano, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(〇)〇r9, -〇c(〇)R9, _〇(CH2)mC(0) OR9, a 0C(0)NRl°RU, a carbonyl group, a -S(0)nR9, -OS〇2R9, -SOARl11, -ΝΙΚ:(〇)ί{9 or a substituent of -NR1%11; From a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the alkyl group, cycloalkyl or aryl group is further substituted with one or more amine groups as needed;

R1° or R11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is regarded as Further required to be further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclic, _C(〇)〇R9, -〇C(〇)R9, - 0(CH2)mC(0)0R9 > -0C(0)NR12R13 ' -S(0)nR9 'substituted by _OS〇2R9, -S〇2NR12R13, -NHC(0)R9 or -nr12r13; 95165 201229047 Alternatively, R and R11 together with the nitrogen atom to which they are attached form a 3 to 8 membered heterocyclic group wherein the 3 to 8 membered heterocyclic group contains one or more N, hydrazine or s(0)n atoms, And the 3 to 8 membered heterocyclic group is further selected from one or more selected from the group consisting of an alkoxy group, an alkoxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen group, a hydroxyl group, a cyano group, a carbonyl group, and a -C (0). Substituting 〇r9, _〇c(〇)r9, -CKCIWnCXCOOR9, -〇c(〇)NR12R13, _s(〇)nR9, -OSO2R9, -S〇2NR12R13, _NHC(0)R9 or -NR12R13 ; R12 and R13 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group; m is 0 1 or 2; and η is 0, 1 or 2. A preferred embodiment of the invention, a compound of the formula (π), or a pharmaceutically acceptable salt thereof, wherein R1 is an aryl group, wherein the aryl group is further selected from one or more selected from the group consisting of an alkyl group and an alkoxy group, if necessary Base, element, hydroxyl, cyano, nitro, -C(0)0R9 > -0C(0)R9 > -0(CH2)mC(0)0R9 > -OC(O)NR10Rn > - Substituted by a substituent of S(0)nR9, -〇S〇2R9, -SOzNRl11, -NHC(0)R9 or -NRl11; preferably an aryl group further substituted with one or more alkyl or halogen. A preferred embodiment of the invention, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, wherein R7 is selected from alkyl and R8 is selected from the group consisting of a bicycloalkyl or a biheterocyclyl The yl or bicyclic heterocyclic group may further be selected from one or more selected from the group consisting of alkyl, alkoxy, _, hydroxy, cyano, nitro, carbonyl, -C(0)0Rg, -〇C(〇)R9 as needed. , -〇(CH2)mC(0)OR9, -OCCOMI^R11, -S(〇)nR9, -〇s〇2R9, -soaW1, -NHC(0)R9 or -NRl" taken 11 95165 201229047 Substituted; m, η, R9 to R11 are as defined in the general formula (I). A preferred embodiment of the invention, wherein the compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R7 is selected from the group consisting of leucoyl R8 is selected from the group consisting of bicyclooctyl or azabicyclononyl, wherein the bicyclooctane The base or azabicyclooctyl group is further required to be further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, a dentate group, a thiol group, a cyano group, a nitro group, a carbonyl group, a —C(〇)or9, and a _0C(0) R9, -OC(O)NR10Rn ' -S(0)nK9 '~〇S〇2R9 ' -S〇2NR10Rn '-NHCC〇) substituted with a substituent of R9 or -NRll*Rn; the r8 is preferably To be further substituted by one or more alkyl or merid groups, m, η, R9 to R11 are as defined in the general formula (1). A preferred embodiment of the invention, wherein the compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R7 and R8 together with the nitrogen atom to which they are bonded form a bicycloalkyl or biheterocyclic group of 5 to 14 members ' wherein the bicycloalkyl or biheterocyclic group is further further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, a heterocyclic group, a halogen, a thiol group, a cyano group, a nitro group, a aryl group, and a -C(0). ) 0R9, -〇C(0)R9, -0(CH2)mC(〇)〇R9 > -〇c(0)NR1〇Ru ' -S(0)„R9 > -OSO2R9 ' -sowiTr11,- Substituted by a substituent of nhc(o)r9 or -NR1R1; m, η, R9 to Ru are as defined in the general formula (I). A preferred embodiment of the invention, a general formula (I) Or a pharmaceutically acceptable salt thereof, wherein R7 and R8 together with the nitrogen atom to which they are attached form a bicyclooctane or azabicyclooctane, wherein the bicyclooctyl or azabicyclooctyl group is further required to be further Or plural selected from the group consisting of alkyl, alkoxy, heterocyclic, halogen, thiol, cyano, schishyl, number base, -C(0)0R9, -0C(0)R9, 12 95165 201229047 -0 (CH2 )eC(0)0R9, -OC(〇)NirRll, _s(〇)nR9, _〇s〇2R9 _s〇2NRl°R11, -NHC(〇)R9 or a substituent substituted by 2; m, n, R to R are as defined in the general formula (i). A preferred embodiment of the invention, a general formula (1) The compound or the pharmaceutically acceptable salt of the bean wherein m is bonded to the nitrogen material thereof to form an anthracycline or an azabicyclooctane, and the residue is subjected to one or more selected from the group consisting of Substituted by a substituent of a hydroxyl group, -0C(0)R9 or -ΝΡγι; m, n, R9 to R11 are as defined in the formula (1). The compound of the formula (I) may contain an asymmetric carbon atom, thus It may be present as an optically pure diastereomer, a diastereomeric compound, a diastereomeric racemate, a mixture of diastereomeric racemes or as a mesogenic compound. The invention includes all These forms. Mixtures of diastereomers, diastereomeric racemates or diastereomeric racemates can be separated by conventional methods, for example by column chromatography, thin layer chromatography and HpLC. Typical compounds of the invention include, but are not limited to:

Structure and chemical name

ο ο

Η ΗΟ_ (3a5; 6a^)-N-{4-(2, 5-difluoro-4-(1-(4-fluorophenyl)-2-oxooxy-1,2-dihydropyridine-3 Monomethylamino)phenoxy)° 0-but-2-yl}-5 /5-hydroxyhexahydrocyclopenta[c]pyrrole-2 (1^-formamide 95165 13 201229047

2 Η 4/χ9χχ 来Ά F Η 1 Η (2,5_二气_4_{2_[3-曱基_3_((3a_^, 6a5*)-2-methyl-octahydro-cyclopenta[ c]pyrrol-5 α -yl)-yl group]_° ratio _4-yloxy}-phenyl)-1-(4-f-phenyl)-2- oxo-1,2 -Dihydro-α ratio 0 -3--3-amine 3 Η 叉 fork iV -JV^NNNH [(3a·^,6aiS〇-4-(2,5_difluoro-phenyl)_2-side oxygen Base-1,2-dihydro-0 to 0 -3- arylamino]-amino}-phenoxy)_D than bite 2-yl]-5-(4-mercapto-l-azine- 1-yl)-hexahydro-cyclopenta[c]D is a specific ratio of 2-nonylamine 4H; xA?"Clf, Ψ..λ4 Η 1 Η (3_it_4_{2-[3_曱基-3-((3a^,6a_2-fluorenyl-octahydro-cyclopenta[c]n is Β-5-5-yl)-glycosyl]-oxaridin-4-yloxy}-phenyl)- 1-(4-Fluoro-phenyl)-2-oxooxy-1,2-dihydropyridin-3-ylamine 5 Xr"/?XXF r〇KN 14 95165 201229047 (3a^,6a5") -[4-(2-it-4-{[ 1 -(4-Gas-phenyl)-2-yloxy-1,2-dihydro-D ratio bit-3-carbamido]-amine } _ phenoxy) _D ratio π ̄-2-yl]-5-(4-methyl-Bound-1-yl)-hexahydro-cyclopenta- each 2-carbamoylamine 6 AHr9uF v. NI iS r<ybn (3a_^,6a5")-[4-(3-Dun -4-{[ 1-(4-Gas-phenyl)-2-oxooxy-1,2-dihydro-pyridin-3-indenyl]-amino}_phenoxy)_π ratio -2-yl]-5-(4-methyl-branches-heptan-1-yl)-hexahydro-cyclopenta[(^吼17)-2-carbamamine 7 (3a^,6^ 51)-[4-(3-1-4-{[ 1 -(4-Gas-phenyl)-2-o-oxy-1,2-dichloro-indole-Bite-3-Alanine] -amino}-phenoxy)-pyridin-2-yl]-5/3-hydroxyhexahydro-cyclopentanyl-2-indenylamine 8 η AnHi?Olf Η 1 Η (2-fluoro- 4-{2-[3-indolyl-3-((3a especially 6a«-2-mercapto-octahydro-cyclopenta[(^吼17-5-5-yl)-glycosyl]-acridine) 4--4-yloxy}-phenyl)-1-(4-fluoro-phenyl)-2-isoxyl-1,2-dihydro-ytidine-3 - anthraquinone 9 9J0r"l ?NUF H | Η 15 95165 201229047 N-(2, 5-difluoro-4-(2-(3-((3a especially 6aS)-f^ hydroxy octadecylcyclopentadiene-2 syl-))- 3-mercaptoureido)α-p--4-yloxy)phenyl)-1-(4-fluorophenyl)-2-yloxy-1,2-dihydroρ ratio p--3- Invitrogen: x/r9xx ίο

(3 a疋,~Θε^-Ν-(4-(2-1^-4-(1-(4-^3⁄4^'))))-oxyl-1,2-di-based 吼Ding-3-carboamino)phenoxy)-5y3-transhexahydrocyclopentarene|>]pyrrole-2(1^)-nonylamine 11 12 13 Ν-(2-fluoro-4 -(2-(3-((3a brother 6aS)-5 octahydrocyclopentadien-2-yl)-3-methylureido).pyridin-4-yloxy)phenyl)- 1-(4-fluorophenyl)-2-oxooxy-1,2-dihydropyridine-3-carboxamide

;xxBr?NCLF (^aS,6ai?)-N-(4-(2-Ga-4-(1-(4-fluorophenyl)j-o-oxy-1,2-dihydropyridine-3-indole)醯 ))) 氧基 氧基 -2- -2- 基 基 基 基 基 基 基 基 基 基 基 基 c c c c c c c c c c c c c c c c

;^rNANUF Λ Ν Ν 16 95165 201229047

(3a brother 6 & 5 ·)-Ν-(4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-yloxy-1,2-dihydro. 3-mercapto)-2-denyloxyl ratio α-di-2-yl-pyridylhexahydrocyclopenta[c]0 is more than each -2 (1 milk-formamide 14 々i?〇 LF Η〇^ Η (3a5; 6a^〇-N-(4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-yloxy-1,2-dihydropyridine) -3-carbamimidino)-2,5-difluorophenoxy)acridin-2-yl)-5-hydroxyhexahydrocyclopenta[c]0 is more than p-2 (1 Z〇- Indoleamine 15 η fork iV A Η (3a5; 6aA〇-N-(4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-yloxy-1,2- Dihydroacridin-3-ylamino)_2,5-difluorophenoxy)π ratio σ定-2_yl)_5α _transylhexahydrocyclopenta[c]pyrrole-2-(1 milk - guanamine 16 X)rB?9NOLF AH (3a)?,6&5·)-Ν-(4-(4-(4-ethoxy-1-(4-fluorophenyl)-2)-side Oxy-1,2-dihydrogen 0 is determined to be -3 - arylamino)-2-fluorophenoxy) ° bite-2-yl)-5 〇: _-based hexahydrocyclopenta[ c]^^-2(l/〇-曱醯amine 17 H IlSF Yn人N入〆AH 17 95165 201229047 (3&19,6&/?)-Bu {4-(2,5-two says-4 -(1-(4-fluoro-based)_2-sideoxy-1,2-di 0 咬-3-carbamidoamino)phenoxy)° 唆-2-yl}-5〇:-yl hexahydrocyclopenta[c]pyrrolecarbamide 18 (3a^,6a5*) -N-(4-(4-(4-ethoxy-1-(4-phenyl)-2-oxoyl-1,2-dihydropyridine-3-carboxamido)-3- Defensyloxy)pyridinyl-2-yl)-5/5-ylaminohexahydrocyclopenta[c]pyrrole-2 (1 phantom-indoleamine 19 Η XX) (3a^,68^)- 2-((4-(2-fluoro-4-((1-(4-phenylphenyl)-2-oxo-acridine-3-carboxamido)phenoxy)-2-° ratio Alkyl)amino-hydrocarbyl)-hexahydrocyclopenta[c] 0 to 11 groups 5-point-yl-2-(1^0-aminoacetic acid hydrazine 20:; 〇rV?NXX η, Λ-CV η (3a especially 6a«-2-((4-(2-fluoro-4-((1-(4-fluorophenyl)-2- oxo-o) Amino)phenoxy)-2-pyridyl)aminocarboxamido)-hexahydrocyclopenta[c]pyrrolyl)-5α-yl-2-(1^-aminoacetate 21 ; ^ϊίΝΧΧ XX XX) Λ〆18 95165 201229047 (3a7?,685^-2-((4-(4-Fluoro-4-((1-(4-fluorophenyl)-2-yloxy-pyridine-) 3-nonylamino)phenyloxy)-2-pyridyl)aminoindenyl)-hexahydrocyclopenta[c]pyrrolyl)-5α-yl-acetate

(3ai?,6avS)-2-((4-(2-fluoro-4-((1-(4-fluorophenyl)-2-yloxy)pyridin-3-ylamino)phenoxy -2- oxalyl)aminomercapto)-hexahydrocyclopenta[e]pyrrolyl)-5 α-yl-(250-aminopropionate 22 or a pharmaceutically acceptable salt thereof) The present invention relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which process comprises:

Under the conditions of the test, the compound of the formula (ΙΑ) is reacted with a chloroformate and then reacted with an amine of the formula NHR7R8 to obtain a compound of the formula; wherein A, D, X, R to R8 are as defined in the formula (I) Said in the middle. One aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier thereof; Use of a pharmaceutical composition for the preparation of a medicament for treating a protein kinase-related disease, wherein the protein kinase described in 95165 19 201229047 is selected from the group consisting of c-Met and VEGFR receptor tyrosine kinase; the present invention also provides the medicament The use of the composition for the preparation of a medicament for the treatment of cancer is preferably for the preparation of a medicament for the treatment of lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. Another aspect of the invention provides a method of modulating catalytic activity of a protein kinase, comprising contacting said protein kinase with a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, The protein kinase is selected from the group consisting of Ciet and the VEGFR receptor glycosyl kinase. Another aspect of the present invention provides a pharmaceutical composition of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, the compound or a pharmaceutically acceptable salt thereof, for use in the preparation of a protein kinase inhibitor, wherein The protein kinase is selected from the group consisting of c-Met and the VEGFR receptor tyrosine kinase. Another aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with a protein kinase selected from the group consisting of c-Met and VEGFR receptor cheese Amino acid kinase. Another aspect of the present invention provides a pharmaceutical composition of the compound of the formula (I), or a pharmaceutically acceptable salt thereof, containing the compound or a pharmaceutically acceptable salt thereof, for use as a medicament for treating a protein kinase-related disease, Wherein the protein kinase is selected from the group consisting of c-Met and VEGFR receptors. Another aspect of the present invention provides a pharmaceutical composition of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, containing the compound or a pharmaceutically acceptable salt thereof, for use as a medicament for treating cancer, preferably for use as a treatment A drug for lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. 20 95165 201229047 Another aspect of the present invention provides a use of a compound of the formula (1) or a pharmaceutically acceptable hydrazine thereof for the treatment of cancer, preferably for the treatment of cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer Use of the drug. This month is monthly. Can be used to treat neoplasia, including cancer and metastasis including but not limited to: cancer such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (non-small cell lung cancer), skin cancer; lymphoid hematopoietic tumors (including Leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, etc.) 'Bone Zhao system for umbilical tumors (including acute and chronic myelogenous leukemia and dysplasia and pre-Zhao cell leukemia); mesenchymal origin of tumors ( Includes fibrosarcoma and rhabdomyosarcoma and other sarcomas such as soft tissue sarcoma and osteosarcoma; tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and nerve endings); and v, his tumor (including malignant melanoma, seminoma, teratoma, thyroid follicular carcinoma and Kaposi's sarcoma, etc.). Preferred compounds of the invention are useful in the treatment of lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. The active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges', aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups. Or tincture. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, and preservatives to provide a pleasing appearance. And delicious pharmaceutical preparations. The tablet contains the active ingredient and a non-toxic pharmaceutically acceptable excipient which is suitable for the preparation of tablets for use in admixture. These excipients may be inert excipients such as calcium carbonate, 95165 21 201229047 sodium carbonate, lactose, acid-filled or sodium sulphate; granulating and disintegrating agents, microcrystalline cellulose, cross-linked carboxymethyl Cellulose sodium, corn powder or curtain acid. Drying agents, such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a door slip, such as magnesium stearate, stearic acid or talc. These tablets can be coated or masked by the taste of the drug or delayed in the gastrointestinal tract. It is coated and thus coated with a known technique that provides sustained release over a longer period of time. For example, a water-soluble taste masking substance such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or a prolonged material such as ethylcellulose or cellulose acetate butyrate may be used. It is also possible to use a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid sarcophagus or olive oil. Soft gelatin capsules provide oral preparations. The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending agents, for example, resole methylcellulose, thioglycolic acid, propylmethylcellulose, sodium sulphate, polyethylene t-codone and gum arabic; dispersing or wetting agents It may be a naturally occurring fat-filling such as a phospholipid or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate or a condensation product of ethylene oxide with a long-chain fatty alcohol, such as a seventeenth gorge ethylene group. Heptadecaethylene〇Xy cetanol' or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexanol, such as polyethylene oxide sorbitan monooleate, or epoxy A condensation product of a partial ester of a fatty acid and a hexitol anhydride, such as polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain a 22 95165 201229047 or various preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners, such as sucrose , saccharin or aspartame. The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent such as bee sting, hard scorpion or worm. The above sweeteners and humectants can be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as diced anesthesia or alpha-probiotic. The dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid. The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy egg fat and vinegar derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation of the partial esters and ethylene bromide. A product such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant. 23 95165 201229047 The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. It can be used in the acceptable materials and dissolved in water, forest money to hide the gas solution. The sterile injectable preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and fat, and the oil solution is added to a mixture of water and glycerin to form a microparticle. The solution and microemulsion may be administered by injection into the patient's <RTIgt;</RTI>> or by a large amount of injection, preferably in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous (iv) drug can be used. An example of such a device is the De 1 tec CADD-PLUS. TM. 5400 intravenous pump. The drug conjugate can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The slits can be prepared according to known techniques using those suitable dispersing agents or suspending agents and suspending agents as described above. The domain injection preparation is also a sterile parenteral suspension prepared in a parenterally acceptable diluent or solvent, for example, a solution of (tetra) in -butanediol. Further, it is convenient to use a sterile fixed oil as a solvent or suspension :: any synthetic oil including synthetic glycerol mono- or di- vinegar. In addition, fatty acids such as oleic acid can also be prepared as an injection. These pharmaceutical combinations can be prepared by administering the compound for rectal administration, and being solid at ordinary temperature but liquid in the rectum: and thus releasing the drug in the rectal towel to release the drug. Things. Such materials include cocoa months: = plant: oil, a mixture of polyethylene glycols of various molecular weights and heart-staining Sa. 95165 201229047: As is well known to those skilled in the art, the dosage of the drug depends on a number of factors, including but not limited to the following factors: (4) the activity of the compound, the age of the patient, the weight of the patient, the health of the patient, the patient The sputum, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the amount of hydrazine of the formula (1) or the pharmaceutically acceptable salt The type can be verified according to traditional treatment options. DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the procedures used in the specification and claims have the following meanings. "Alkyl" means a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups of up to 2 carbon atoms, preferably having a fluorene group of from 1 to 10 (for example, methyl or ethyl). Base, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl, etc. More preferred are lower grades containing from 1 to 4 carbon atoms, methyl, ethyl, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group or a t-butyl group, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups. Independently selected from alkoxy, _, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)0R9, _〇c(〇)R9, _ 〇(CH2)raC(0)〇R9,-0(:(0)^111, carbonyl, -S(0)nR9, -〇S〇2R9, ίο·1%11, -NHC(0)R9 or - NR% 11. The cycloalkyl group refers to a 3 to 8 membered all carbon monocyclic group in which 3 to 8 members of the all carbon monocyclic ring may contain one or more double bonds, but none of the rings have a fully conjugated 7 Å electron system. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexane, cycloheptyl, ring Trienyl 95165 25 201229047, etc. The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkoxy, halogen, Hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(0)0R9, -0C(0)R9, ~〇(ch2)„c(〇)〇R9, -OCCOMRl11, Prison base, -S(0)nR9, -OSO2R, -SOzNRWr", -NHC(0)R9 or -NR1QRU. Lean base refers to a composition consisting of at least two carbon atoms and at least one carbon-carbon double bond. The alkyl group defined above, for example, a vinyl group, a fluorene-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group, etc., may be substituted or unsubstituted, and when substituted, substituted The group is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, dentate, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - C(〇)〇R9, -〇C(〇)R9, -0(CH2)mC(0)0R9, -OCCCONITR11, several groups, _s(〇)nR9, -〇s〇2R9, -SOzNlTR11, -NHC( 0) R9 or -NR1QRU. "Alkynyl" means at least two carbon atoms and at least one carbon-carbon An alkyl group as defined above, such as ethynyl, 丨-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. alkynyl groups may be substituted or unsubstituted, When substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, dentate, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl , heteroaryl, -C(〇)〇r9, —〇c(〇)R9, -0(CH2)〇«C(0)OR9,-0(:(0)^13⁄411, Yiji, —s( 〇) nR9, -〇S〇2R9, -SCMI^V1, -NHC(0)R9 or -NR%11. "Heterocyclyl" means a 3 to 8 membered monocyclic group wherein one or more ring atoms are selected from nitrogen, oxygen or S(0)n (wherein η is an integer from 0 to 2) heteroatoms, the remaining ring atoms are carbon. These rings can also have one or more double bonds, but 26 95165 201229047 does not have a ring with a fully shared 7-inch electronic system. For example, ° ratio ρ each burning base, brigade 11 fixed base, pie ° Qinji, 淋 基 、, thio 琳 琳 基, high brig. Heterocyclic groups may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkoxy, _, thio, nitro, cyano, cycloalkyl, heterocyclyl, aryl Base, heteroaryl, -C(0)0R9, -0C(0)R9, -0(CH〇mC(0)0R9, -OCCCDNW1, carbonyl, -S(0)nR9, -OS〇2R9, -SOARWR11 , -NHC(0)R9 or -NfR11. "Bicycloalkyl" means a 5 to 14 membered all-carbon fused ring ("fused" ring system means that each ring in the system is adjacent to the other rings in the system. a pair of carbon atoms) groups in which one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated 7-inch electronic system.

It is preferably 5 members/5 members or 5 members/6 members bicycloalkyl groups, more preferably 5 members/5 members. Bicycloalkyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, Heteroaryl, -C(0)0R9, -0C(0)R9, -0(CH2)mC(0)0R9, -OCCO)·1%11, carbonyl, -S(0)nR9, -OS〇2R9 , -SOzNlTR11, -NHC(0)R9 or -NR1%11. "Bicyclic heterocyclyl" refers to a 5 to 14 membered fused ring ("fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system), one or more of which The ring atoms are selected from nitrogen, oxygen or S(0)n (the η of which is η is an integer 0 to 2 in 27 95165 201229047), and the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have fully conjugated 7-inch electrical subsystems. It is preferably 7 to 10 members. E.g

Further preferably, it is 5 members/5 or 5 members/6 members of the heterocyclic group, and more preferably 5 members/5 members. The bicyclic heterocyclic group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl. , -C(0)0R9, -0C(0)R9, -0(CH2)X(0)0R9, -0C(0)NR1QRn, carbonyl, -S(0)nR9, -〇S〇2R9, -SOaWR11 , -NHC(0)R9 or -NR1GRn. "Bridge cycloalkyl" refers to 5 to 14 members, any two rings sharing two interatomic all-carbon polycyclic groups that are not directly attached, these may contain one or more double bonds, but none of the rings have a total The yoke's 7-inch electronic system. It is preferably 7 to 10 members. E.g:

28 95165 201229047 Depending on the number of constituent rings, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. The bridged cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, nitro, cyanide. Base, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(0)0R9, -0C(0)R9, -0(CH2)mC(0)OR9, -0C(0)NRlflRu, carbonyl , -S(0)nR9, -OS〇2R9, -SOzNlTR11, -NHC(0)R9 or -NR1QRn. "Bridge heterocyclyl" refers to a 5 to 14 member, any two rings sharing a polycyclic group of an atom that is not directly attached to the atom, these may contain one or more double bonds, but none of the rings have a fully conjugated 7Γ An electronic system wherein one or more ring atoms are selected from the group consisting of nitrogen, oxygen or a hetero atom of S(0)n (where n is an integer from 0 to 2) and the remaining ring atoms are carbon. It is preferably 7 to 10 members. For example: ο Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring. The bridged heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, nitro, cyano , cycloalkyl, heterocyclic, aryl, heteroaryl, -C(0)0R9, -0C(0)R9, -0(CH2)mC(0)0R9, -OCCOHi^R11, carbonyl, -S (0) nR9, -OS〇2R9, -SOzNRWR11, -NHC(0)R9 or -NCR11. "Spirocycloalkyl" refers to a polycyclic group of 5 to 14 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. 7Γ electronic system. Preferably 7 to 29 95165 201229047 10 members. E.g

The spirocycloalkyl group is classified into a monospiroalkyl group, a double spiro ring base group or a multi-spiro ring base group according to the number of common spiro atoms between the ring and the ring, preferably a monospiroalkyl group and a double spiro ring group. base. More preferably 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of the monospirocycloalkyl group. The spirocycloalkyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, dentate, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, Aryl, heteroaryl, -c(〇)〇R9, _〇c(〇)r9, -〇(CH〇nC(9)(10), -_)nry, county, _s(9), ·2R9, -SOWITr11, -nhc(o) R9 or -NiTR11. Refers to 5 to 14 members, a single atom sharing a single atom (referred to as 'where one or two ring atoms are selected from nitrogen, oxygen or spiroheterocyclic group) refers to a polycyclic hydrocarbon of 5 to 14 members, a spiro atom), wherein One or but none of the rings have a total of a total of t number 0 to 2). The remaining ring atoms are carbon. § or multiple double bonds, but the rule is - add: a θ. Preferably 7 to 1 ο .E.g

Heteroatoms of s(〇)n (where n is an integer 〇 to 2) These may contain one or more double bonds, but none; a light π-electron system. Preferably, the spirocycloalkyl group is divided into a single spiro ring according to the number of the common spiro atom between the ring and the ring 95165 30 201229047 alkyl, a spirocycloalkyl or a polyspiro, preferably Single spiro alkyl group and .double f ring alkyl group, more preferably 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members single-spiral heterocyclic rings base. The spiroheterocyclyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkoxy group, a dentate element, a thiol group, and a Schiffki group. Cyano, ring-based, heterocyclic, aryl, heteroaryl, _c(8)〇r9, rhyme)r9, -〇谏(9)0Rl0c(0)NRl〇Rll, silk, _s(8),·9, -SOzNW1, -NHC (0) R9 or -NW1. / member / Q member of the bicyclic alkyl, biheterocyclyl, monospiroalkyl or monospiro, the base 'refers to the double ring, double miscellaneous, single spiro or single spiro heterocyclic ring of two rings The number of atoms is P and Q, respectively, and is selected from an integer of 3 to 8, preferably an integer of 4 to 7. 3 to 8 membered heterocyclic group means that the number of ring atoms constituting the ring atom is 3 to 8 members, and the atom of the ring contains - or more n, q or .n hetero atoms, and the ring is 'ί 1 to 2 double bonds ' is a monocyclic or bicyclic non-family ring double bond. When the atom contains a nitrogen atom, it can extend from the nitrogen atom to the junction - U to a 6-membered heterocyclic group, more preferably 5 to 6 members. a pyridyl group, a (tetra) group or a yl group, etc. The 3 to 8 membered heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more = groups independently selected from the group , silk group, (four), recorded, confirmed, cyclohexyl, heterocyclic, aryl, heteroaryl - SQ NRi (9) 〇Κ 9, 1 (〇) ΝΚ, ν, several groups, - (10), Μ, S (MR R, -nhC(〇)R9 or (10)lflRU. Square group & 6 to 14 members of the all-carbon monocyclic or fused polycyclic ring (that is, a total of 95165 31 201229047 with a ring adjacent to a carbon atom) group The group of the π-electron system of the yoke (i.e., the ring having an adjacent pair of carbon atoms) is preferably 6 to 1 Å. For example, phenyl, naphthyl and anthracenyl. The aryl group may be substituted. Or unsubstituted, when substituted, the substituent is preferably one One or more of the following groups, independently selected from the group consisting of alkyl, alkoxy, dentate, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0) 0r9,_0C(0)R9, ^ '〇S〇2R9 -0(CH2)dC(0)0R9, -OCCOHW1, carbonyl, _s(〇W, -SOAR%11, -NHC(0)R9 or -NRlflR" "Heteroaryl" means a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms. The hetero atom of the towel includes oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 or 6 members. Aryl. For example, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, =azolyl, etc. Heteroaryl may be substituted or unsubstituted, When substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, haro, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl , Heteroaryl, -C(0)0R9, -0C(0)R9, -0(CH2;)mC(〇)〇R9, _0C(0)NRl°Rl1, carbonyl, _s(0)nR9, -OS 〇2R9, -SChNW1, -NHC(0)R9 or -NR1DRU. "Aryloxy" means -O-aryl and heteroaryl, and aryl and heteroaryl are as defined above. Such as phenoxy, pyridyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyridazinyloxy and the like and derivatives thereof. Alkoxy" means -0-(alkyl) and -〇-(unsubstituted Cycloalkyl), such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. alkoxy can be substituted Or not taken 32 95165 201229047

Heterocyclic group. "Hydroxy" refers to the -OH group. "Halogen" means fluorine, chlorine, bromine or broken. "Amine" refers to -NH2. "Cyano" means _CN. "Nitro" means -n〇2.

"Azabicyclooctyl" means %. "As needed or as needed" means that what is described subsequently or the environment may, but need not, occur where the event or environment occurs where it does not occur. For example, "heterocyclic groups that are optionally substituted with alkyl groups" , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically and/or pharmaceutically acceptable salt or prodrug thereof, and other chemical components, to the s* agent. The purpose of the absorption of other components such as physiological/pharmaceutically acceptable carriers and derivatized deltas is to promote the administration of the organism, thereby facilitating the activity and thereby exerting biological activity. 33 95165 201229047 m, η and R9 to R11 The invention is defined as described in the compound of the formula (I). The synthesis method of the compound of the invention In order to accomplish the object of the invention, the invention adopts the following technical scheme: The preparation method of the compound of the invention of the formula (I) or a pharmaceutically acceptable salt thereof , including the following steps:

The compound of the formula (IA) is reacted with a gas phthalate ester under an alkaline condition with an amine of the formula NHR7R8 to give a compound of the formula (I). In a preferred embodiment of the present invention, the compound of the formula (IA) is dissolved in tetrahydrofuran and reacted with a chlorodecanoate under the action of a basic condition such as triethylamine, preferably phenyl phthalate. The product is isolated and purified, dissolved in hydrazine, hydrazine-dimethylformamide, and further reacted with an amine of the formula NHR7R8 under triethylamine to give a compound of the formula (I). Wherein A, D, X, R1 to R8 are as defined in the formula (I). The following examples are provided to further describe the present invention, but these examples are not intended to limit the scope of the invention. EXAMPLES The structure of the compounds was determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm).匪R was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was determined to be 34 95165 201229047 deuterated dimethyl sulfoxide (DMSO-cW, deuterated gas (CDC13) internal standard was tetradecyl decane (TMS). The measurement was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX). The HPLC was determined using an Agilent 2D DAD high pressure liquid chromatograph (Sunfire C18 150 x 4. 6 mm chromatography column). Waters 2695-2996 Pressure Liquid Chromatograph (Gimini C18 150><4.6111111 Chromatography Column). The average inhibition rate of S# and IC5 were measured using a NovoStar plate reader (BMG, Germany). The tantalum sheet is made of Yantai Huanghai HSGF254 or Qingdao GF254 tantalum sheet 'TLC is 〇15mm to 0.2 mm, and the thin layer color is used to separate and purify the product. The specification is 〇. 4 mm to 0. 5 min. Column chromatography Yantai Huanghai silicone 200-300 mesh silicone is generally used as a carrier. The starting materials in the examples of the present invention are known and commercially available, or can be synthesized or synthesized according to methods known in the art. all of Unless otherwise specified, the reaction is carried out under continuous magnetic stirring, under a dry nitrogen or nitrogen atmosphere. The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon of about 1 L volume. The hydrogen atmosphere refers to the reaction bottle connection. A hydrogen balloon having a volume of about 1 L. Unless otherwise specified in the examples, the solution means an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Room temperature is an optimum reaction temperature of 20 ° C to 3 ( TC. 95165 35 201229047 The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The catalysts used in the reaction were: methylene chloride and decyl alcohol systems, n-hexane and ethyl acetate systems. The volume ratio of petroleum ether and ethyl acetate system, acetone and solvent is adjusted according to the polarity of the compound. The system of eluent for column chromatography includes: A: dioxane and decyl alcohol system, B: n-hexane And ethyl acetate system, c: dichlorodecane and ethyl acetate system, D: ethyl acetate and methanol, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of ammonia water and vinegar may also be added. The adjustment was carried out, etc. Example 1 (3a5; 6a«-N-{4-(2, 5-difluoro-4-(1-(4-fluorophenyl)-2- oxo-1,2-di Hydrogen ratio. D--3-indolyl)phenoxy hexahydrocyclopenta[c*]pyrrole-2 (1^-formamide

The first step (3avS·,6aA)-tert-butyl-5/3-pyridylhexahydrocyclopenta[c]nbilo_2 (丨奶_ carboxylic acid 酉 将 (3a6; 6a and)-5- The pendant oxy-hexahydrocyclopenta[c] „pyrrolidine-2 (1. 01 g, 17.80 mm〇i, prepared by the well-known method 36 95165 201229047 “patent W02008089636”) Dissolved in 60 mL of methanol, sodium borohydride (〇. 74 g, 19.60 mmol), and reacted for 1 hour. Concentrated under reduced pressure, 15 mL water was added and extracted with ethyl acetate (20 mL×3) The organic phase was dried <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> tert-Butyl ester lb (4.22 g, reddish-brown liquid), yield: 99.5%. The second step (3aA, GavS1)-octahydro-cyclopenta[c]0 is p-5 points - Alcohol (3a5; 6aiP)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1)7)-tert-butyl phthalate lb (4.02 g, 17.8 mmol) was dissolved in 50 mL of methane. 'Ice was cooled to 〇C' and added trifluoroacetic acid (40 mL, 0.53 mol), and reacted for 1 hour at 〇 ° C. Concentrated under reduced pressure, added with ammonia to adjust P H value to 7~8, concentration under reduced pressure 'purified residue obtained by eluent column chromatography with eluent column chromatography' to give the title product (3a^6aS)-octahydro-cyclopenta[c]α ratio d - 50,000-ol lc (2.33 g, yellow solid) MS m/z (ESI): 128.1 [M+l] W NMR (400 MHz, CD3〇D): (5 4.27 (m,1H), 3.33-3.28 (m, 4H), 3.01 (m, 2H), 2.00 (m, 2H), 1.73-1.69 (m, 2H) The third step (3a5; 6a^-N-{4-(2, 5- Difluoro-4-(1-(4-fluorophenyl)-2-oxooxy-1,2-dihydropyridin-3-indenyl)phenoxy)pyridin-2-ylindole-5 -transylhexahydrocyclopentazone|&gt;]pyrrole-2 (1-blade-formamide) Ν-[4-(2-aminopyridin-4-yloxy)-2, 5-difluorobenzene -1-(4-fluorophenyl)-2-oxooxy-1,2-dihydrogen octa-3-amine AId 37 95165 201229047 (95 mg ' 0.21 mmol, using a known method "patent US2〇〇5G24553G” was prepared by dissolving in 5′tetrahydrofuran, followed by 〇3. 3 mL of triethylamine and phlegnic acid (42&quot;L,. 33 with (4), react 20 knives under 〇 C. The reaction solution was poured into a mixed solution of 46 ethyl acetate and a saturated gasification solution (V/V = 1.8:1), and the organic phase was washed with a saturated sodium carbonate solution (2 mL). Drying with anhydrous sodium sulfate, filtration, concentration under reduced pressure, and 3 rL of N,N-didecylamine and hydrazine. 29 mL·triethylamine was added for 1 hour, and the crude product was added (3a especially 6a51). _ octahydro-cyclopenta[c]pyrrole-5-ol lc (112 mg, 0.88 mmol), 4 (TC reaction for 16 hours. The reaction solution was poured into 70 mL of ethyl acetate and saturated sodium chloride solution (v /v=4:3) In a mixed solution, the organic phase was washed with 1M sodium hydroxide solution (3 mL) and saturated sodium carbonate solution (40 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. Concentrated filtrate 'The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford the title product (SaS,6a^〇-N-{4-(2,5-difluoro-4-(1-(4) -It phenyl)-2- oxo-1,2-dihydrogen thioglycanyl) oxy)D is more than -2-yl}-50,000-pyridyl hexahydrocyclopenta[c ]n pirox-2 (1 milk-melamine 1 (20 mg, pale yellow solid)' yield: 15. 〇%. MS m/z (ESI): 606.3 [M +l] NMR (400 MHz, dlSO-de): δ 12.44 (Sj 1H), 8.74 (s, 1H), 8.63 (m, 1H), 8.60 (m, 1H), 8.17 (m, 2H), 7.61 ( m, 3H), 7.51 (ra, 1H), 7. 44 (m, 2H), 6. 77 (m, 1H), 6.45 (m, 1H), 4. 62 (m, 1H), 4. 07 ( m, 1H), 3. 55 (m, 2H), 3.45 (m, 2H), 2.01 (m, 2H), 1.31 (m, 4H) Example 2 95165 38 201229047 (2, 5-difluoro-4- {2-[3-methyl-3-((3aiP,685)-2-mercapto-octahydro-cyclodecano[^&gt; than "» each _5α-yl)-ureido]-acridine_ 4_yloxyindole-phenyl)-1-(4-a-phenyl)-2-yloxy 2_dihydropyridinyl-3-indoleamine

The first step (3a^?,6a«-50,000-sulfonyloxyl-hexahydro-cyclopenta[c]n-pyr/2-carboxylic acid tert-butyl ester (3aiP,6aS)-5/3 - Hydroxyhexahydro-cyclopenta[c]pyrrole-2-butyrate tert-butyl ester lb (9. 00 g, 40 mmol) was dissolved in 150 inL of dichloromethane, and sulfonium chloride (4.70) was added at 0 °C. mL, 60 mmol) and triethylamine (11.20 mL, 80 mmol), react at room temperature for 2 hours. Add 2 mL of saturated sodium bicarbonate solution to the reaction solution, and separate the organic phase with saturated sodium chloride solution (200) (mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Butyl 2a (12.00 g, yellow liquid), yield: 39 95165 201229047 98. 4% 〇 second step (3a_A*,6a5&quot;)_5 α _ nitrogen-hexahydro-cyclopenta[c]β ratio Ha_2_曱酸叔丁丁g will be (3aiP, 6a5&quot;)-5々-methanesulfonyloxy-hexahydro-cyclopenta[c]pyrrole-2-furic acid tert-butyl ester 2a (12. 00 g, 40 mmol) dissolved in 150 mL of N,N-dimercaptoamine, sodium azide (6.50 g, loo mm〇i), reaction at 7 to 80 C The reaction mixture was added with 2 mL of water, EtOAc (EtOAc)EtOAc. The resulting residue was purified by eluent column chromatography using eluent column chromatography to afford the title product (3a s. 6a.sup.5-5:-azido-hexahydro-cyclopenta[c]pyrrole_2-decanoate tert-butyl] 2b (8. 00 g, yellow liquid), yield: 79.4%. The third step (3a left, 6aS)-5λ base-hexa-cyclopenta[c]nj^p each_2_formic acid叔丁酉 will (3ai?,6a5〇-5a-azido-hexahydro-cyclopenta[c]pyrrole-2-tert-butyl tert-butyl ester 2b (3.80 g, 15 mmol) dissolved in 50 mL曱Palladium/carbon (4.0 g, 10%) was added to the alcohol for 16 hours. Filtration, the filter cake was washed with 2 mL of decyl alcohol, and the filtrate was concentrated under reduced pressure to give the title product (3ayp, 6a51) _5a_amine- Hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 2C (2.65 g, yellow liquid), yield: 77.7% MS m/z (LC-MS): 227 [M+l] The fourth step (3a;?,635·)-5α-acetamido-hexahydro-cyclopenta[C]D-Bilo-2-butyric acid tert-butyl ester 95165 40 201229047 (3a and, amino-hexahydro-cyclopenta[c]pyrene, p-butyl-2-butyric acid tert-butyl ester 2c (2.65 g, 11. 7 mmol) dissolved in 45 mL of E, added three Ethylamine (3·26 mL, 23.40 mmol) was dissolved in 5 mL of ethyl chloroformate (1. 12 mL, 11.70 mmol) at 0 ° C, and the above reaction solution was added dropwise. In the reaction, 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc EtOAc (EtOAc m. The obtained residue was purified with eluent system B to give the titled product (3a^6850-5 (2-ethylamino-hexahydro-cyclopenta[c][rho]. (2.35 g, yellow liquid), Yield: 67.3% MS ra/z (ESI): 597 [2M+1] Step 5 (3ae, 6850-(2 - mercapto-octahydro-cyclopenta) [c]nbilo-5α-yl)-nonylamine The tetrahydromylon chain (1.20 g, 31.50 mmol) was dissolved in 70 mL of tetrahydrofuran, and the acetamido-hexahydro-cyclopenta[ c]e is slightly soluble in tert-butyl phthalate 2d (2. 35 g, 7.88 mmol) dissolved in 40 mL of tetra-gas pentane, added dropwise to the above reaction solution, and reacted at 40 ° C. The reaction solution was added with 10 mL of water, filtered, and the filter cake was washed with 20 mL of methanol, and the filtrate was concentrated to give the title product (3a7?,6a&gt;S)-(2-mercapto-octahydro-cyclopenta[ c] 0 piro-5 α-yl)-methylamine 2e (700 mg, yellow liquid) 'yield: 57.4%. MS m/z (LC-MS): 155.2 [M+l] (2,5-Difluoro-4-{2-[3-mercapto-3-((3&amp; especially 6351)-2-mercapto-octahydro-cyclopenta[ehbiolo_5 α-yl)) -ureido]-4-yloxyphenyl) 41 95165 201229047 -1-(4-fluoro-phenyl)-2-oxo-1,2~dihydro-π-pyridin-3-yl Indoleamine [4-(2-Amino-pyridin-4-yloxy)_2, 5-difluoro-phenyl]-1-(4-fluoro-phenyl)-2-oxooxy-1 , 2-Dihydro-pyridine_3_decylamine η (120 mg, 0.227 mmol) was dissolved in 3 mL of tetrahydrofuran, followed by the addition of 〇. 29 mL of triethylamine and phenyl chloroformate (125 mg, 0.80) _〇1), react at room temperature for 1 ' '45 ° C reaction for 50 minutes. Pour the reaction solution into a mixed solution of ethyl acetate and saturated sodium chloride solution (V / V = 2: 1), dispense The organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated, and evaporated. Amine, reaction for 1 hour, add (3aA, 6aS)-(2-mercapto-octahydro-cyclopenta[c]0 to slightly-5-alpha-yl)-decylamine 2e (163 mg, 1. 06 mmol) , the reaction was carried out for 64 hours. The reaction solution was poured into 60 mL of ethyl acetate and saturated sodium chloride solution (V/V = 2:1). In the solution, the organic phase was washed with 30 mL of 1M sodium hydroxide solution and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by de-branching system B to give the title product (2, 5-difluoro-4-{2-[3-indolyl-3-((3aiP,6a«-2-methyl-octahydro-cyclopentane) And [c]° 咯-5-5-yl)-ureido] butyl-4-yloxyphenyl)-1-(4-f-phenyl)-2-oxo-1,2 9%。 Dihydro-pyridine-3-indole 2 (60 mg, pale yellow solid), yield: 35.9%. MS m/z (ESI): 633 [M+l] NMR (400 MHz, DMSO-^): ^ 12.44 (s, 1H), 8.83 (s, 1H), 8.64 (m, 1H), 8.59 (m) , 1H), 8.20 (m, 2H), 7.64 (m, 3H), 7.45 (m, 3H), 6.78 (m, 1H), 6. 66 (m, 1H), 4.70 42 95165 201229047 (m, 1H) , 2.77 (m, 3H), 2.50 (m, 3H), 2.22 (in, 4H), 2.00 (m, 2H), 1. 77 (m, 2H), 1. 46 (m, 2H) Example 3 [ (3a^P, 685^-4-(2, 5-difluoro-4-{[1-(H-phenyl)-2-yloxy-1,2-dihydro-pyridine-3-indole) Amino]-amino}-phenoxy)-pyridin-2-yl]-5-(4-mercapto-piperazin-1-yl)-hexahydro-cyclopenta[c]pyrrole-2-indole Guanamine

The first step (3aA, 6aiS)-5-(4-indolyl-β-bottom Qin_1_yl)_hexahydro-cyclopenta[c]D ratio σ each 2-tert-butyl tert-butyl ester will be 5 - alkoxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester la (10·00 g, 44.44 mmol) dissolved in 400 mL of dioxane, added 8. 〇〇g The dried molecular sieve and 1-methyl-piperazine (7.80 mL, 66.67 mmol) were reacted for 30 minutes, and sodium cyanoside sodium hydride (5. 58 g, 17.78 mmol) and 60 mL of methanol were added to continue the reaction. hour. The reaction solution was concentrated under reduced pressure to give the title product: (3 &amp;)?, 685·)-5-(4-methyl-piperazin-1-yl)-hexahydro-cyclopenta[〇&gt; 2-tert-Butyl phthalate 3a (20.00 g, brown oil), 43 95165 201229047 was used in the next step without isolation. MS m/z (ESI): 310 [M+l] The second step (3a7?, 685)-5-(4-indolyl-[beta]-indol-1-yl)-octahydro-cyclopentane [pounds 嚷The hydrochloride salt will be crude (3 &amp; skin, 6a5 &quot;)-5-(4-methyl-〇底uqin-1 -yl)_hexahydro-cyclopenta[匸]pyridol-2-carboxylic acid tert-butyl From the purpose of 3a (13.73 g, 44.44 mmol) dissolved in 250 mL of methanol, '200 mL of 4.3 hydrazine hydrogenated decyl alcohol solution was added and reacted for 2 hours. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2%。 The hydrochloride salt 3b (9. 〇9 g white solid), yield: 64. 2%. MS m/z (ESI): 210 [M+l] Step 3 [(3^6&amp;5·)-4-(2, 5-difluoro-4-{[l-(4-fluoro-phenyl) _2_Sideoxy-1,2-dihydro-pyridine-3-carbamimidyl]-aminophenphenoxy)-pyridine-2-yl]-5-(4-methyl-piperazine-1 a group of hexahydro-cyclopenta[c]pyrrole-2-amines [4-(2-amino-acridin-4-yloxy)_2,5-difluoro-phenyl] ( 4_Any-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide Id (1 〇〇 mg, 0.22 mmol) was dissolved in 4 THF, and 0.3 was added in this order. 5小时。 Ethylamine and chloroformic acid ester (83 eL, 0.66 mmol), reaction 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was combined with a mixture of ethyl acetate and saturated sodium carbonate (V/V = 2:1), and the organic phase was washed with saturated sodium chloride solution (20 mL) Dry over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. 44 95165 201229047 The residue was added to 4 mL of N,N-didecylguanamine and 1 乩 triethylamine and (3ai?,6a5〇-5-(4-indolyl-piperazine _;[_yl)_8 Hydrogen_cyclopenta[c]pyrrole hydrochloride 3b (280 mg, 〇. 88 mmol), reaction for 16 hours. The reaction solution was poured into 60 mL of ethyl acetate and 2 mL of saturated sodium chloride solution (v/v = In the mixed solution of 2:l), the organic phase was separated by 1M sodium hydroxide solution (2〇 and saturated sodium carbonate solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography Chromatography of the residue obtained by eluent system B gave the title product [(3aiip, 6a phantom_4_(2 5_difluoro 4-{[1-(4-fluoro-phenyl)-2-) Oxy-1,2-dihydrogen ratio 3-methylaminoamino]-amino}-styloxy)-π ratio bite_2_yl]_5-(4-methyl-Brigade-i_ ))) hexahydro-cyclopenta[c]pyrrole-2-indoleamine 3 (45 mg, pale yellow solid), Yield: 29.8%. MS m/z (ESI): 688 [M+l ] 4 Xinjiang R (400 MHz, DMSO-heart): 5 12.45 (s, 1H), 8. 81 (s, 1H), 8.63 (m, 2H), 8.16 (m, 2H), 7.62 (m, 6H) , 6.76 (m, 2H), 4. 04(m, 1H), 3.45 (m, 7H), 2. 51 (m, 4H), 2.11 (m, 4H), 1.40 (m, 6H) Example 4 (3-fluoro-4-{2-[3-methyl-3-((3a^6a«-2-methyl-octahydro-cyclopentane) And [c]吼嘻-5α-yl)-ureido]-σ-pyridyl-4-yloxybuphenylbubufluoro-phenyl)-2-oxo-1,2-dihydro -σ-pyridin-3-carboxamide

45 95165 201229047

4a 4b 2· 4 First step [4-(2-fluoro-4-{[1-(4-fluoro-phenyl)-2-o-oxy-1,2-dihydro-n-pyridin-3- Carbonyl]-aminoindole-phenoxy)-pyridin-2-yl]-aminodicarboxylic acid diphenyl ester [4-(2-amino-acridin-4-yloxy)-3-fluoro -Phenyl]-1-(4-fluoro-phenyl)-2-oxooxy-1,2-dihydro-pyridine-3-carboxamide 4a (217 mg, 0.50 〇1, using a known method "1^20050245530" was prepared by dissolving in 4 mL of tetrahydrofuran, adding triethylamine (152 mg, 1.50 mmol) and phenyl chloroantimonate (235 mg, 1. 50 mmol) for 10 minutes. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with 1 M sodium hydroxide solution (1 mL), water (10 mL) and saturated sodium carbonate solution (i 〇 mL), dried over anhydrous magnesium sulfate The filtrate was concentrated to give the title product [4-(2-fluoro-4-{[1-(4-fluoro-phenyl)-2-yloxy-1,2-dihydro-»» ratio -3- The hydrazide was used to give the next reaction without isolation. 4b (387 mg, pale yellow solid). The second step (3-fluoro-4-{2-[3_mercapto-3-((3a疋685^-2-methyl-octahydro-cyclopenta[c]n) is more than B___alpha ))-ureido]-β ratio -4-yloxy}-phenyl)-1-(4-fluoro-phenyl)-2-oxooxy-1,2-dihydro-pyridine-3- Methionine will be crude [4-(2-fluoro-4-{[1-(4-fluoro-phenyl)-2-yloxy-1,2-dihydro-11-pyridine-3-carbonyl]- Amino}_phenoxy)-°-diphenyl-2-yl]-aminodicarboxylate 4b (387 mg, 0.57 mmol) dissolved in 4 mL hydrazine, Ν-46 95165 201229047 To the amine, triethylamine (303 mg, 3 mmol) and (3ai?, decyl-octahydro-cyclopenta[c]pyrrole-5-yl)-methylamine 2e (308 rag, 2 mmol), The reaction was carried out for 16 hours. 30 mL of a mixed solvent of ethyl acetate and water (V/V = 2:1) was added, and the organic phase was successively treated with 1 M sodium hydroxide solution (10 mL), water (10 mL) and saturated gas. The sodium salt solution was washed (1 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified to the titled product (3-fluoro-4-{ 2-[3-methyl-3-((3ae,6aiS)-2-mercapto-octahydro-cyclopenta[e]pyr-5-yl)-ureido]-acridin-4-yl 4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide 4 (140 mg, white solid), yield: 45 6% MS m/z (ESI): 670 [M+l] 4 R (400 MHz, CDC13): 5 11.95 (s, 1H), 8.75 (m, 1H), 8.04 (d, 1H), 7.98 (d, 1H), 7.68 (dd, 1H), 7.62 (m, 1H), 7.42-7.09 (m, 7H), 6.61 (t, 1H), 6.48 (dd, 1H), 4.80 (m, 1H) , 2.89-2.69 (m, 5H), 2.42 (m, 2H), 2. 29 (s, 3H), 2. 11 (m, 2H), 1. 72 (m, 2H), 1. 61 (m, 2H) Example 5 (3a and 685^-1^4-(2-fluoro-4-{[1-(4-fluoro-phenyl)-2-yloxy_i,2-dihydro-pyridine- 3-carbamido]-aminophenphenoxy)-pyridine-2-yl]-5-(4-indolyl-piperazin-1-yl)-hexahydro-cyclopenta[c]pyrrole_ 2_ guanamine 95165 47 201229047

[4-(2-Fluoro-4-{[1-(4-fluoro-phenyl)-2-yloxy-1,2-dihydropyridin-3-carbonyl]-amino}-phenoxy] Diphenyl- 4-(anthracene-2-yl)-aminodicarboxylate 4b (312 mg, 0.446 mmol) was dissolved in 4 mL of N,N-dimethylamine and triethylamine (280) Mg, 2.76 mmol) and (33^&gt;,6&amp;5')-5-(4-mercapto-indenyl-1-yl)-octahydro-cyclopenta[(^]«1 Acid salt 3b (586 mg, 1.84 mmol), react for 16 hours. Add 30 mL of a mixed solvent of ethyl acetate and water (V/V = 2:1), separate the liquid, and then use the organic phase with 1M sodium hydroxide solution. (1 〇mL), water (10 mL) and saturated sodium chloride solution (10 mL) dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent system B. The residue gave the title product (3a#,6a5*)-[4-(2-fluoro-4-{[1-(4-fluoro-phenyl)-2- oxo-1,2-dihydrol.咬-3-Mercaptoamine]-amino}-phenoxy)-rhodopyridine_2_yl]-5-(4-mercapto-infrared-1-yl)-hexahydro-cyclopentyl And [(:]°° &lt;» each -2- decylamine 5 (74 mg, white solid), yield: 24.0°/. MS m/z (ESI): 670 [M+l] !HNMR ( 400 MHz, CDCh): 5 11.94(s, 1H), 8. 73 (m, 1H), 95165 48 201229047 8.01 (d, 1H), 7.91 (dd, 1H), 7.70 (s, 1H), 7.62 (m , 1H), 7.42 (m, 1H), 7.33-7.25 (m, 4H), 7. H (t, 2H), 6. 91 (t, 1H), 6. 50 (m, 1H), 3. 60 (m, 2H), 3. 39 (m, 2H), 2.69-2.57 (in, 10H), 2.28 (s, 3H), 2.17 (m, 2H), 1.41 (m, 2H) Example 6 Fluorine-4 -{[l-(4-fluoro-phenyl)-2-oxooxy-1,2-dihydro-pyridinium-3-carboxamido]-amino}_phenoxy)-pyridine- 2_基]_5_(4-曱 base 嗓-1-yl)-hexahydro-cyclopenta[c]n ratio 0 _2 曱醯 曱醯

The first step of 4-amino-3-fluoro-benzoquinone is to dissolve 3-fluoro-4-nitro-phenol 6a (15.7 lg, 〇. 1〇m〇i) and palladium/carbon (1.57 g, 10«). The reaction was carried out for 16 hours in a hydrogen atmosphere of 120 mL of methanol. The reaction mixture was filtered, and the mixture was washed with 1 mL of methanol. The filtrate was concentrated under reduced pressure 95165 49 201229047 to give the title product 4-amino-3-fluoro-phenol 6b (11. 80 g, brown solid), Yield: 92.8%. MS m/z (ESI): 128 [M+l] Step 2 4-(4-Amino-3-fluoro-phenoxy ))-pyridine-2-decylamine 4-amino-3-fluoro-benzoin 6b (l 1. 80 g, 93 mmol) was dissolved in 70 mL of diterpene sulphur, and a t-butoxy clock was added. 16.72 g, 149 mmol), reacted at 〇 ° C for 1.5 hours, and 4- gas-pyridin-2-decylamine 6c (9. 71 g, 62 mmol ' was prepared by the known method "Patent US20050245530". The reaction was carried out at 80 to 85 ° C for 3 hours, cooled to room temperature, and 140 mL of 1 M sodium hydroxide solution was added dropwise for 16 hours. Filtration, the filter cake was washed with water (14 〇 mL x 3), and then washed (50 mL×2). ' Vacuum drying to give the title product 4-(4-amino-3-fluoro-phenoxy)-pyridin-2-decylamine 6d (8. 10 g, purple Yield: 52.9% MS m/z (ESI): 248 [M+l] Step 3 4-(3-fluoro-4-{[1-(4-fluoro-phenyl)- 2-Phenoxy-1,2-dihydro-n-butoxy-3-ylideneamino]-amino}-phenoxy)-indole-But-2-indole amine 1_(4-fluoro-benzene Bis-2-oxo-1,2-dihydroindol-3-indole 6e (1.40 g, 6 mmol) dissolved in 30 mL of dichloromethane -3- ° ° sit 烧 base) 醯 醯 ( (1.53 g, 6 mmol), reaction for 15 minutes, add 4- (4-amino-3-fluoro-phenoxy)-bite bit-2- The amine (0.74 g, 3 mmol) and diisopropylethylamine (2.33 g, 18 mmol) were reacted for 64 hr. filtered, washed with dichloromethane (30 mL×3). The residue was added to a mixed solution of 75 mL of ethyl acetate and saturated sodium bicarbonate solution (V/V = 2:0), and the aqueous phase was extracted with ethyl acetate (25 mL×3), and the organic phase was combined. The organic phase was washed with saturated sodium carbonate solution (50 mL×2) and saturated sodium sulfate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography Residual , Recrystallized from ethyl acetate. The title product 4-(3-fluoro-4-{[1-(4-carbo-phenyl)-2-yloxy-1,2-dihydro-π ratio β-1,3-SS·amino group] was obtained. -aminophen- phenoxypyridin-2-indoleamine 6f (250 mg, yellow solid), yield: 10.0%. MS m/z (ESI): 463 [M+l] ^^RUOOMHz , CDCIO: 6 12.07 (s, 1H), 8.75~8.42 (m, 3H), 7.88~7.49 (m, 3H), 7.41 (m, 2H), 7.27~6.58 (ra, 8H), 5.56 (s, 1H )

I fourth step [4-(2-Amino-n-pyridin-4-yloxy)-2-fluoro-phenyl]-1-(4-fluoro-phenyl)-2-sideoxy-1 ,2-dihydro-π ratio π定-3 _ 曱 胺 amine 4-(3-乱-4-{[1-(4-)-phenyl)-2- oxo-1,2-di Hydrogen-pyridin-3-indenyl]-amino-p-phenoxy)-pyridin-2-indoleamine 6f (250 mg, 0. 54 mmol) dissolved in 10 mL of N,N-dimercaptopurine To the amine, water (0.024 mL, 1.35 mmol), bis(trifluoroethyloxy) benzene (465 mg, 1 - 08 mmol) and σ ratio bite (128 mg, 1.62 mmol) were reacted at room temperature for 16 hours. 5小时。 Reaction at 60 ° C 0. 5 hours. 25 mL of 0.5 Μ sodium hydroxide solution was added to the reaction solution, filtered, and the cake was washed with 50 mL of water and dried in vacuo to give the title product [4-(2-Amino-acridin-4-yloxy) Base)-2- 51 95165 201229047 Fluoro-phenyl]-1-(4-fluoro-phenyl)-2-oxo-oxyl-1,2-dihydro-° ratio 0-methylamine 6 g (207 mg, 1%。 Yellow solid), yield: 88.1%. MS m/z (ESI): 435 [M+l] 'HNMR (400 MHz, CDCh): δ 12.01 (s, 1H), 8. 74 (m, 1H), 8.73 (m, 1H), 7.95 (d , 1H), 7. 60~5. 97 (in, 12H), 4.42 (s, 2H) Step 5 [4-(3-Fluoro-4-{[1-(4-fluoro-phenyl)-2) - a side oxy-1,2-dihydro-D to 唆_3-mono)-amino}-phenoxy)-n ratio. [4-(2-aminopyridin-4-yloxy)-2-fluoro-phenyl]-1-(4-fluoro-benzene) The base 2-yloxy-1,2-dihydrol-6-ylamine 6g (207 mg, 0.48 mmol) was dissolved in 20 mL of tetrahydrofuran in hydrazine. Triethylamine (144 mg, 1.43 mmol) and phenyl chloroformate (224 mg, 1.43 mmol) were added under reduced pressure for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) The organic phase was washed with water (4 mL) and a saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, and the filtrate was evaporated to give the title product [4-(3-fluoro-4-{[ L-(4-Fluoro-phenyl)-2-oxooxy-1,2-dihydro-pyridine-3-carbonyl]-aminophenylphenoxy 0 to 0-but-2-yl]-amino group Diphenyl phthalate (282 mg, yellow solid) was used in the next step without isolation. MS m/z (ESI): 675 [M+l] Step 6 [4-(3-fluoro-) 4-{[ 1-(4-fluoro-phenyl)-2-oxo-oxime, 2-dihydro-0 ratio 95165 52 201229047 °-3--3-yl]-amino}-phenoxy ]-Aminodicarboxylic acid dip vinegar 6h (310 mg, 〇. 46 mmol) dissolved in 8 mL of N,N-didecyl guanamine 'Add (3a foot 6a5&quot;)-5-(4-fluorenyl - π 辰 _; [1 yl) _ octahydro _ cyclopentamidine hydrochloride 3b (586 mg, 1. 84 mmol) and triethylamine (745 mg, 7. 36 mmol) 'reaction for 16 hours. Add 20 mL of saturated sodium bicarbonate solution, The mixture was separated and the aqueous phase was extracted with ethyl acetate (20 mL×4), and the organic phase was combined and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to give the title product (3 &amp; , 2-dihydro-indole ratio β 1,4- 曱醯 曱醯 ] ] ] ] 苯 苯 苯 苯 苯 -2- 咬 咬 基 基 基 基 嗓 嗓 嗓 嗓 嗓 嗓 嗓) _ _ _ _ _ -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 +l] NMR (400 MHz, DMS0-i/〇: δ 12.24 (d, 1H), 8.75 (s, 1H), 8.62-8.52 (in, 2H), 8.15 (m, 2H), 7.63-7.07 (m , 7H), 6.75 (t, 1H), 6.61 (d, 1H), 3.62 (m, 2H), 3.43 (d, 2H), 2.56 (ra, 2H), 2.49 (m, 1H), 2. 34 ( m, 6H), 2.12 (s, 3H), 2.08 (m, 2H), 1.23 (m, 2H) Example 7 (3 &amp; Foot 6 &amp; 5')-[4-(3-Fluoro-4-{[ 1-(4-Fluoro-phenyl)-2-oxooxy-1,2-dihydro-pyridinium-3-indenyl]-amino}-phenoxy)-pyridin-2-yl ] -5 stone-hydroxy hexahydro-cyclopenta[c]pyrrole-2-indole Amine 5,395,165,201,229,047

[4-(3-Fluoro-4-{[1-(4-fluoro-phenyl)-2-yloxy-1,2-dihydro-° ratio -3-yl]-amino] - phenoxy)-n ratio. Di-2-(diphenyl)-diaminodicarboxylate 6h (280 mg, 0.42 mmol) was dissolved in 5 mL of N,N-didecylguanamine. 'Add (3a^?,6akS)-octahydro- Cyclopenta[c]pyrene was reacted for 16 hours than p-5-ol 1 c (211 mg, 1.66 mmol) and triethylamine (168 mg, 1.66 mmol). The reaction mixture was added with 20 mL of aq. EtOAc. EtOAc (EtOAc (EtOAc) The residue obtained was purified by eluent column chromatography to afford the title product (3a.sup.6a5M4-(3-fluoro-4-{[l-(4-fluoro-phenyl)-2-yloxy)- 1,2-di-pyridyl-pyridin-3-carboxamido]-amino-p-phenoxy)-pyridin-2-yl]-5 cold-peryl hexahydro-cyclopenta[c]D ratio σ -2-decylamine 7 (70 mg, yellow solid), yield: 28.8%. MS m/z (ESI): 588 [M+l] 4 R (400 MHz, DMSO-form): 5 12.25 (s, 1H), 8.71 (s, 1H), 8.62 (t, 1H), 8.54 (t, 1H), 8.14 (m, 2H), 7.63 (m, 2H), 7.52 (d, 1H), 7.43 (m, 2H), 7. 29 (t, 1H), 7.06 54 95165 201229047 (d, 1H), 6. 76 (t, 1H), 6. 61 (d, 1H), 4. 63 (d, 1H), 4. 07 (m, 2H), 3.53(t, 2H), 3. 33 (m, 2H), 2. 02 (m, 2H), 1.33 (m, 2H) Example 8 (2-Fluorine -4-{2-[3-mercapto-3-((3ai?,6a«-2_mercapto-octahydro-cyclopentyl)_5 α-yl)-yl]-° ratio bite-4 -yloxyindole-phenyl)-indole-(4_fluoro- Yl) -2-oxo-1,2-dihydro than bite -3- Yue Amides

[4-(3-Fluoro-4-{[1-(4-fluoro-phenyl)-2-yloxy-1,2-dihydro-pyridine-3-carbonyl]-amino}-phenoxy] 6-(pyridin-2-yl)-aminodicarboxylate diphenyl ester 6h (270 mg, 0.40 mmol) dissolved in 6 mL hydrazine, hydrazine-dimethyl decylamine, added (3a especially 6a«-(2 - mercapto-octahydro-cyclopenta[c]pyrrole-5-yl)-nonylamine 2e (247 mg, 1.60 mmol) and triethylamine (162 mg, 1.60 mmol), react for 16 hours. Add 20 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford the title product (2-fluoro-4-{2-[3-methyl-3-55 95165 201229047 (3a and 6350-2 -mercapto-octahydro-cyclopenta[c]B than aromo-5α-yl)-ureido]-indole butyl-4-yloxy}-phenyl)-1-(4-fluoro-benzene ) -2- -2- -1 -1 -1 -1 -1 -1 -1 曱醯 曱醯 曱醯 曱醯 曱醯 曱醯 曱醯 曱醯 曱醯 ( ( ( ( ( ( ( ( ( ( MS MS MS MS MS MS MS MS MS 615.0 [M+l] 'H NMR (400 MHz, DMSO-^) : δ 12.24 (s, 1H), 8.79 (s , 1H), 8.62 (t, 1H), 8.55 (t, 1H), 8.14 (d, 2H), 7.62 (m, 2H), 7.44 (m, 3H), 7. 28 (m, 1H), 7. 04 (d, 1H), 6.74 (t, 1H), 6.62(t, 1H), 4. 76(m, 1H), 2. 80 (s, 3H), 2.54 (m, 4H), 2.16 (s, 3H), 1.69 (m, 2H), 1.45 (m, 2H) Example 9 N-(2,5-difluoro-4-(2-(3-((3aiP, 6aS)-5y5-hydroxy octahydro) Cyclopentadiene-2 /3-yl)-3-methylureido) π ratio bit-4-yloxy)phenyl)-bu (4-fluorophenyl)-2- oxo-1,2 -Dihydroanthracene

56 95165 201229047 First step (lR, 5S)-33_Amidino-7,7-(ethylidene-acid)bicyclo[3 3 〇] Xinyuan will (IS, 5R)-7, 7-( Ethylene acetal) bicyclo[3 &amp; 〇] octyl _3_ ketone 9a (3. 30 g, 18.10 mmol, prepared by the metric method "W020071 12669") dissolved in 3 〇 mL of gas The appropriate amount of 3A molecular sieve and guanamine hydrochloride (3. 67 g, 54. 40 mmol), reaction 3.5 hours, adding 10 mL of sterol and sodium cyanoborohydride (3. 43 g, 54. 40 mmol ), continue to react for 1 hour. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure to give the title product (1R, 5S)-3/3-decylamino-7, 7-(ethyl acetal) bicyclo [3. 3. 0] octane 9b ( 3. 56 g, colorless oil), used directly in the next reaction without isolation. MS m/z (ESI): 198 [M+l] The second step (3ae, 6a5 &quot;)-5 cold-nonylamino-hexahydro-cyclopentadiene_2__ crude product (1R, 3S, 5S)-3-Aminoamino-7,7-(ethylene acetal)bicyclo[3·3]octane 9b (3.66 g, 18.1 mmol) dissolved in 50 mL of tetrahydrofuran and water 5小时。 The mixture was stirred for 1.5 hours. The reaction solution was added with sodium hydroxide to adjust the pH to 7, filtered, and the filtrate was concentrated under reduced pressure to give the titled product (3,?, &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&& 9c (2.77 g, light yellow oil) was used in the next step without isolation. The third step (3a 疋 6 &amp; Λ-5 曱-decylamine-octahydro-cyclopenta[c]pyrrole- 2-Alcohol The crude product (3af, 6350-5 o-ammonium-hexahydro-cyclopenta[c]pyrrole 57 95165 201229047 -2-one 9c (2. 77 g, 18.10 mmol) was dissolved in 50 methanol. The mixture was cooled to 〇C in an ice bath, and sodium hydride (757 mg was added in portions, and reacted for 1 hour at 〇C. i〇mL 1M hydrochloric acid was added, and the pH of the reaction solution was adjusted to 10 with 1 NaOH solution of 1 M. Concentration under reduced pressure, and the residue obtained was purified by eluent column chromatography eluting with eluent system B to give the title product (3a) P, 6850-5 s- s- s- s- s s s s s s 2 - alcohol (10) (2. 70 g, colorless oil), yield: 96.4%. MS m/z (ESI): 156 [M+l] Step 4 N-(2, 5- Difluoro-4-(2-(3-((3a)?,6aS)-5/3-hydroxyoctahydrocyclopentadien-2-yl)-3-indenylureido;) acridine-4 Monooxy) stupid base (4-(phenyl)-2-oxo-1,2-dihydro"pyridin-3-ylamine [4-(2-amino-pyridin-4-yloxy)-2, 5-difluoro-phenylbubu(4-fluoro-phenyl)-2-oxooxy-1,2-dihydromonopyridine-3-carboxamide ld (18〇mg, 0·40 mmol) Into 20 mL of tetrahydrofuran, add 1 triethylamine and phenyl chloroantimonate (151//L, 1.20 mmol), and react for 0.5 hour. Concentrate the reaction solution under reduced pressure, add 60 mL of ethyl acetate and saturated chlorine. A mixed solution of sodium solution (V/V = 2:1) was separated, and the organic phase was washed with saturated sodium sulfate solution (20 mL) dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. N,N-dimercaptocarhamamine and 1 mL of triethylamine, added (3aA, 6aiS)_5 β-nonylamino-octahydro-cyclopenta[吼洛_2-ol (10) (248 mg, 1.6 mraol The reaction was carried out for 16 hours. The reaction solution was poured into a mixed solution of 6 〇乩 ethyl acetate and a saturated sodium chloride solution (V/v = 2:1), and the organic phase was successively treated with 1 M sodium hydroxide solution ( 2〇mL) and saturated sodium carbonate 58 95165 201229047 solution washing (30 mLx2), dry anhydrous sodium sulfate, filtered, concentrated filtrate under reduced pressure, with silicone The resulting residue was purified by column chromatography eluting to afford titled product (2,5-difluoro-4-{2-[3-((3 &amp; billion 635')-5-hydroxy-octahydro-ring Pentero[c]D-pyrrol-2-yl)-3-indolyl-ureido]-n ratio -4--4-oxyphenyl)-1-(4-fluoro-phenyl)-2- 4%。 The side oxy-1,2-dihydroindole than biting octadecylamine 9 (120 mg, yellow solid), yield: 47.4%. MS m/z (ESI): 634 [M+l] NMR (400 MHz, MSO-de): δ 12.45 (s, 1H), 8.83 (s, 1H), 8.63 (m, 1H), 8.52 (m) , 1H), 8.18 (m, 2H), 7.64 (m, 3H), 7.45 (m, 3H), 6. 78 (m, 1H), 6. 65 (m, 1H), 4.51 (m, 1H), 4.44(m, 1H), 4. 13 (m, 1H), 2. 78 (s, 3H), 2.33 (m, 2H), 1.85 (in, 4H), 1.60 (m, 2H), 1.43 (m, 2H) Example 10 (3&amp;No, 635') 4-(4-(2-Fluoro-4-(1-(4-fluorophenyl)-2-yloxy-l, di-pyryl) D--3-indenyl)phenoxy)α-pyridyl-2-yl)-5-yl-pyrohydrocyclopenta[c]pyrrole-2(1 pi)-decylamine

[4-(2-Fluoro-4-{[1-(4-fluoro-phenyl)-2-oxooxy-1, 2-di 59 95165 201229047 Hydrogen-° ratio pyridine-3-carbonyl]-amine Dibuphenyloxy)-n-dipyridin-2-yl]-aminodicarboxylate 4b (339 mg, 0.50 mmol) dissolved in 4 mL of N,N-didecylguanamine Amine (304 mg, 3 mmol) and (3ai?, 6a5·)-octahydro-cyclopenta[[&gt;bibromo-5-ol lc (294 mg, 2 mmol) were reacted for 16 hours. The reaction solution was added with a mixed solvent of 30 mL of ethyl acetate and water (v/V = 2:1), and the organic phase was successively treated with 1 M sodium hydroxide solution (1 mL), water (10 mL) and saturated gasification. The title solution (3ay?, 685·)-Ν was obtained by washing with EtOAc (3 mL). -(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-yloxy-1,2-dihydroxypyridin-3-ylamino)phenoxy)β-biting- 2-基)-5β-Pyrylhexahydrocyclopenta[c]a ratio π each-2 (1 milk-formamide 10 (40 mg, white solid), yield: 13.6%. MS m /z (ESI): 588 [M+l] !Η NMR (400 MHz, CDCh): δ 11.99 (s, 1H), 8.78 (m, 1H), 8.05 (d, 1H), 7.96 (dd, 1H) , 7.76 (s, 1H), 7.66 (m, 1H), 7.45 (m, 2H), 7. 37~7. 29(m, 4H), 7. 16(t, 1H), 6. 65 ( t, 1H), 6. 56 (m, 1H), 4. 41 (m, 1H), 3. 70 (m, 2H), 3.55 (m, 2H), 2.77 (m, 2H), 2.25 (m, 2H), 1.82 (br.s, 1H), 1.62 (ra, 2H) Example 11 N-(2-Fluoro-4-(2-(3-((3a) 6aS)-5/S-hydroxy octahydro And cyclopentadienyl-2-yl)-3-mercaptoureido)n ratio 4-yloxy) phenyl) _ BU (4-fluorophenyl) -2-oxo-1,2-dihydropyridine-3-Amides 6,095,165,201,229,047

[4-(3-Fluoro-4-{[1-(4-fluoro-phenyl)-2-oxooxy-1,2-dihydro-p--3-yl]-amino}-benzene Oxy)-&lt;» than di-2-yl]-aminodicarboxylate diphenyl ester 6h (372 mg, 0.55 mmol) dissolved in 5 mL hydrazine, hydrazine-dihydrazinamide, added (3a 6850-5-decylamino-octahydro-cyclopenta[c]pyrrole-2-ol 9d (342 mg, 2.21 mmol) and triethylamine (223 mg, 2.21 〇1) were reacted for 16 hours. Add 80 The mixture solution of ethyl acetate and saturated sodium carbonate solution (V/V=3:1) was separated, and the organic phase was washed with saturated sodium carbonate solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue obtained was purified by eluent column chromatography using eluent column chromatography to give the title product 1^-(2-^-4-(2-(3-((3))))) Hydrode-cyclopentadien-2-nonyl--3-mercapto-glycosyl)n-yt-4-yloxy)phenyl)-1,4-(4-fluorophenyl)-2-oxooxy-1 , 2-dihydropyridin-3-indoleamine ll (i 〇〇 mg, white solid), Yield: 29. 5% MS m/z (ESI): 616 [M+l] 丽 R (400 MHz , DMSO-A): d 12.25 (s, 1H), 8.79 (s, 1H), 8.62 (in, 2H), 8.15 (t, 2H), 7.62 (m, 2H), 7.45 (m, 2H), 7.29 ((1, 1H), 7. 06 (d, 1H), 6. 76 (t, 1H), 6.61 61 95165 201229047 (d, 1H), 4. 43 ( m, 2H), 4. 17 (m, 1H), 2. 78 (s, 3H), 2. 33 (t, 2H), 1.83 (in, 4H), 1.57 (m, 2H), 1.42 (m, 2H), 1.24 (s, 1H) Example 12 (3a6; 6a friend)-N-(4-(2-fluoro-4-(1-(4-fluorophenyl))-2-oxo-1,2 -Dihydrogen ratio biting 3-carbamidoamine)phenoxy)D than biting 2 -yl)-5 α -ylhexahydrocyclopenta[c]pyrrole-2(1^-decylamine

(3af, 6a5&quot;)-2-{4-(2-Fluoro-4-(1-(4-fluorophenyl)-2-oxooxy-1,2-dihydropyridine-3-carboxamido) Phenoxy)pyridin-2-yl-aminocarbamimidyl}decahydrocyclopenta[c]pyrrole-5α-yl-4-nitrobenzyl ester (3a·^,6a5〇-[4 -(2-Fluoro-4-{[1-(4-fluoro-phenyl)-2-oxooxy-1, dihydro-D ratio nibble-3-amine amino]-amino}-phenoxy Base)-n-biti-2-yl]-5-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-indoleamine 1 〇 (588 mg, 1 mmol) dissolved in 25 mL of tetrahydrofuran, added sequentially 4-Nitrobenzoic acid (672 rag, 4. 02 mmol) and triphenylphosphine (1.05 g, 3.99 mmol), diethyl azodicarboxylate (70 〇 mg, dropwise at 0 ° C, 4. 〇 2mmol), 62 95165 201229047 10 °C reaction for 12 hours 'reaction at 40 C for 3 hours. Add 75 mL of ethyl acetate in the reaction solution with a saturated carbonated solution (4 〇 mL x 2), water phase Stretching ethyl acetate (40 mL) 'The organic phase was combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous magnesium sulfate, filtered, and filtrated under reduced pressure. The resulting residue was purified to give the title product (38). 6&amp;5|)-2-{4-(2-Fluoro-4-(1-(4-fluorophenyl)-2-oxoyl-1,2-dihydro- 0-bito-3-carboxamide Benzyloxyl ratio. Benz-2-yl-aminocarbamimidyl}decahydrocyclopentaylpyrrol-5-yl-4-nitrobenzyl ester 12a (274 mg, white solid). Yield: 37 2%. ^ NMR (400 MHz, CDCh): &lt;5 11.98 (s, 1H), 8.76-8.74 (m, lH), 8.30~8.27 (m, 2H), 8.19~8.17 (m, 2H), 8.01~ 7. 95 (m, 2H), 7. 77 (d, 1H), 7. 42-7. 40 (m, 2H), 7. 30~ 7.25 (m, 3H), 7.14-7.10 (m, (H, 2H), 5.59-5.57 (m, 1H) 3.01 (m, 2H), 2.23-2.21 (m, 2H), 2.05-2.01 (m, 2H) The second step (3avS*, 6a friend)-N-(4-(2-fluoro-4-(1-) (4-fluorophenyl)-2-oxooxy-1,2-monohydrogen ratio -3-aminoguanido)phenoxy). Ding-2-yl)-5 α-ylaminohexahydrocyclopenta[c]pyrrole-2 (1/〇-decylamine will (3&foot 6&amp;5&lt;)-2-{4-(2- Fluoro-4-(1-(4-fluorophenyl)-2-oxo-oxime, 2-dihydro- 0-bito-3-carboxamido)phenoxy) "Bitter-2-yl- Aminomethyl hydrazinium decahydrocyclopenta[c]pyrrole-5 α-yl-4-nitroindole I2a (274 m§, 0.37 mmol) dissolved in 40 mL of methanol and chloroform (V/V =l: 1) Mixed solution 63 95165 201229047 Ingredients 'Add potassium hydroxide (21 mg, 0 37 mmol), react for 1 hour. Concentrate the reaction solution under reduced pressure, and purify with eluent system B by gel column chromatography. Residue 'obtained the title product (3a5; 6a _n_(4-(2-fluoro-4-(1-(4-fluorophenyl))-2-oxo-1,2-dihydro. -Amidino)phenoxy)pyridin-2-yl)-5?-hydroxyhexahydrocyclopenta[c]pyrrole-2(1^)-decylamine 12 (162 mg, white solid). Yield: 74.7% MS m/z (ESI): 588 [M+l] &lt;RTI ID=0.0&gt;&gt; 7.95~7.90(m,2H), 7.69~7.61(m,2H), 7.43~ 7.40 (m, 2H), 7.33-7.24 (m, 3H), 7.13-7.09 (in, 2H), 6.63-6.51 (m , 2H), 4.51-4.49 (m, 1H), 3.66-3.61 (m, 2H), 3· 29~3.25 (m, 2H), 2. 98~2.93 (m, 2H), 1.97~1.92 (m, 2H), 1.76-1.70 ( m, 2H) Example 13 (3a^6850^-(4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-yloxy-1,2-dihydro- 0 ratio) Bite _3-methylamino)-2- phenoxy) ** 〇 _2 _2 2 - 2) - 5 / 5 - hydroxy hexahydrocyclopenta[c]pyrrole-2 (1 ^ - formazan) amine

F,

95165 201229047 First Step 4-(4-{[4-Ethoxy-1-(4-fluoro-phenyl)_2_sideoxy-1,2-dihydroindolepyridin-3-carbonyl]-amine Keb 2_fluoro-phenoxy)-pyridinecarboxylic acid 4-ethoxy-1-(4-fluorophenyl)-2-oxoxy-indole, dihydro D-pyridyl-3-acid 13b (2. 89 g, 1〇·1〇mm〇i, prepared by the well-known method "W02009094427") dissolved in 44 mL of toluene, added with thionyl chloride (5. 56 mL, 78.38 mmol), Reaction for 3 hours. Concentrate under reduced pressure, add 50 mL of hydrazine to dissolve, and concentrate under reduced pressure to give a solid. 4-(4-Amino-2-fluorophenoxy)-pyridinium i3a (192 g, 7.76 mmol, prepared by the known method "CN200680021939") dissolved in 70 mL of tetrahydrofuran and n, N - Slowly add diisopropylethylamine (1.20 g, 9.31 mmol) in a mixed solvent of dimethyl decylamine (V/V = 4:3)

The reaction was carried out for 12 hours with the above-mentioned alternate solid. Add 1 〇〇inL water to the reaction solution and extract with ethyl acetate (150 mL). The organic phase was washed with saturated sodium bicarbonate (100 raL) and saturated sodium carbonate solution (1 〇〇mL×2). Drying <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTIgt; 2-Phenoxy-1,2-dihydropyridine-3-carbonyl]-amino}-2-fluoro-phenoxy)-pyridin-2-ylamine 13c (3. 10 g, yellow solid ), Yield: 78.9%. MS m/z (ESI): 507 [M+l] D. R (400 MHz, CDC13): 5 11.59 (s, 1H), 8.40 (d, 1H), ^.95-7.91 (dd, 1H), 7.84 (d, 1H), 7.70 (d, 1H), 7.51 (d, 1H), 7.38-7.35 (m, 2H), 7.27-7.21 (m, 3H), 65 95165 201229047 7.09~7.07(m,lH), 6.97~6.95(m,lH),6.36(d,lH), 5.76 (m, 1H), 4.36 (q, 2H), 1.57 (t, 3H) Step 2 4-Ethoxy-1-(4- Fluoro-phenyl)-2-oxooxy-1,2-dihydro D-pyridyl-3~marnic acid [4-(2-aminopurin-4-yloxy)-3-fluoro-phenyl ]-amine 4-(4-{[4-ethoxy-1-(4-carb-phenyl)-2-oxooxy-1,2, dihydroacridin-3-yloxy]- Amino}-2-fluoro-phenoxy)pyridin-2-methylamine 13c (3·10 g, 6.12 mmol) is dissolved in 40 mL of hydrazine, hydrazine-dimethyl oxamine Water (276 mg, 15.3 mmol) and 0-bit (1.45 g, 18.36 mmol) were added bis(trifluoroethyloxy)iodobenzene (5.26 g, 12.24 mmol) in portions and allowed to react for 12 hours. The reaction solution was diluted with 1 mL of acetic acid acetic acid (washed sequentially with water (80 mL×2) and saturated sodium carbonate solution (8 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. B, 50 mL) gave the title product 4-ethoxy-1-(4-fluoro, phenyl)-2-oxooxy-1,2-dihydropyridine-3-carboxylic acid [4-(2) -Aminopyridin-3-dioxy)-3-fluoro-phenyl]-amine 13d (1·16 g, pink solid). Yield: 40. 0%. MS m/z (ESI): 495 [M+l] NMR (400 MHz, DMSO-i/,): &lt;5 10.64 (s, 1H), 7. 97~7. 93 (m, 2H), 7.86 (d, 2H), 7.69 (br.s, 2H), 7.49-7.34 (m 6H), 6.72-6.69 (dd, 1H), 6.52 (d, 1H), 6.12 (d, 1H)! 4.26 (q, 2H), 1.29 (t, 3H) The third step (3ai?' 6a5*)-N-(4-(4-(4-ethoxy-1-(4-fluorophenyl)_2-sideoxy 95165) 66 201229047 -1,2-dihydropyridine-3-nonylamino)_2-fluoroaldooxy)pyridine_2_yl)-5/3-hydroxyhexahydrocyclopenta[c]pyrrole-2 (1 blade) -Procarbazine will 4-ethoxy-i-(4-fluoro-phenyl)_2-sideoxy_1&gt;2_dihydro-indole ratio bite-3-decanoic acid group [4-(2-amine) Base-t-1,4-yloxy)_3_fluoro-phenyl]-amine 13d (479 mg, lmm〇i) is soluble in 4 mL of tetrahydroanhydride and ν,ν-dimethylformamide The mixture was sprayed with triethylamine (3 〇 4 mg, 3 mmol) and phenyl chloroantimonate (47 〇 mg, 3 〇 1), and reacted for 2 hrs. The reaction solution was added with 1 mL of ethyl acetate. Washed with water (5 mL mL), 1M sodium hydroxide solution (50 mL) and saturated sodium chloride solution (5 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. , In N-dimethyl decylamine, triethylamine (608 mg, 6 mmol) and (3ay?, 6a5*)-octahydro-cyclopenta[c]pyrrole-50,000-ol 1 (; 588 mg were added. , 4 匪〇 1) 'Reaction for 12 hours. Add 0.7 mL of ethyl acetate to the reaction solution, and wash with water (50 mL×2), 1M sodium hydroxide solution (5G mL) and saturated sodium carbonate solution (50 mL). The magnesium was dried, filtered, and the filtrate was evaporatedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4_(4__ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydroacridin-3-carboxamido)-2-fluorophenoxy)n-pyridinium -2-yl)-5/3-hydroxyhexahydrocyclopenta[〇]&gt; pyrrole-2 (1^-decylamine 13 (〇. 18 g, white solid). Yield: 28.0%. MS m/z (ESI): 632 [M+1] &lt;RTI ID=0.0&gt;&gt; d, 1H), 7.50 (d, 1H), 7.39-7.35 (m, 2H), 7.27-7.22 (m, 4H), 7.07 (t, 1H), 67 95165 201229047 6.51-6.48 (m, 1H), 6.35 (d, 1H), 4.38-4.33 (m, 3H), 3·68~3.64 (m, 2H), 3. 53~3.49 9 (m, 2H)' 2. 75~2.71 (m, 2H), 2.24-2.17 (m, 2H), 1.61-1.55 (m, 5H) Example 14 (3a5&quot;, 6aA〇-N-(4- (4-(4-Ethoxy-1-(4-fluorophenyl)-2-oxooxy-1,2-dinitrogen 0 to sigma _3-曱 胺 ))-2,5 - Gas-based oxy)n ratio bite - 2~ yl)-5/3 - thiol hexahydrocyclopenta[c] 0 piroxicam-2 (1 counter)- ergic amine

The first step is 4-(4-{[4-ethoxy-1-(4-fluorophenyl)-2-oxooxy-1,2-dihydro. 唆3-3-yl]-amino }-2, 5-Difluorophenoxy)-indole bite 2-carbalamine 4-ethoxy-1-(4-phenylphenyl)-2-yloxy-1,2-di Hydrogen 11 ratio. Ding-3-Resin 13b (2. 77 g, 0.01 mol, prepared by the well-known method "W02009094427") dissolved in 40 mL of terpene, adding two gases 95165 68 201229047 sulfoxide (2.2 mL' 0.03 M〇i) 'In i2〇~13 (reflux under rc to a water-free state, stand-by. 4-(4-Amino-2-fluorophenoxy)pyridinecarboxylic acid 14a (2. 65 g, 0.01111〇1) , using the well-known method "(^2〇〇68〇〇21939, prepared) dissolved in 50 mL of tetrahydrofuran, adding the above-mentioned standby solution and diisopropylethylamine (5. 20 mL, 0.03 m〇 i), the reaction was carried out for 12 hours, filtered, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure and dissolved in ethyl acetate (200 mL). The mixture was washed with a saturated aqueous solution of sodium sulfate (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated. -(4-fluorophenyl)-2-oxooxydihydropyridinium-3-ylcarbonyl]-amino}-2,5-difluorophenoxy)-indenylpyridin-2-amine 141) (2.07 bogey, 39. 5%) MS m/z (ESI): 525 [M+l] second 4-ethoxy-1-(4-fluorophenyl)-2-oxo-i,2-dihydropyridine-3-carboxylic acid [4-(2-aminopurin-4-yloxy) -2,5-difluorophenyl]-amine 4-(4-{[4-ethoxy-1-(4-fluorophenyl)-2-yloxy_ι, 2-dihydropyridine 3-carbonyl]-amino}-,5-difluorophenoxy)-pyridine-2-carbamide 14b (2.07 g, 3.95 mmol) dissolved in 30 niL N,N-dimethyl In the first month of the month, we added water (180 mg, 9.88 mmol) and hydrazine (〇. 96 inL, 11.86 mmol) in 0 C, and added bis(trifluoroacetic acid) iodine stupid in batches (3.4). 〇g, 7. 91 mmol), react for 12 hours. Distill off N,N_: mercaptoamide under reduced pressure to cool to room temperature, and add 25 mL of water and 15 mL of 1M oxyhydrogen 95165 69 201229047 sodium solution The aqueous phase was extracted with acetic acid ethyl acetate (30 mL χ 3). The organic phase was combined, washed sequentially with water (30 mL×2), saturated sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The filtrate was recrystallized (in a suitable ratio of system B, 60 mL) to give the title product 4-ethoxy-1-(4-fluorophenyl)-2- oxo-1,2-dihydropyridine-3- Carboxylic acid [4-(2-aminopyridin-4-yloxy) ) -2, 5-difluorophenyl] - amine 14c (1.94 g, pink solid). Yield: 98.8%. MS m/z (ESI): 495 [M+l] WNMRUOOMHz, DMSO-&amp;)······································ ), 7.60-7.43 (m, 2H), 7.42-7.32 (m, 2H), 6.56 (d, 3H), 6.41-6.25 (in, 1H), 5.99-5.86 (m, 1H), 4.29 (q, 2H) ), 4.03 (d, 1H), 1.99 (s, 1H), 1. 34 (t, 3H), 1. 17 (t, 1H) Step 3 4-Ethoxy-1-(4-fluorophenyl) )-2-oxo-oxy-1,2-dihydro D ratio e--3-resorbed acid [4-(2-aminopyridinium π-dec-4-yloxy)-2,5-difluorobenzene 4-ethoxy-1-(4- phenyl)-2-oxo-l,2-dihydroindole quinone-3-indole [4] -(2-Amino-pyrano-butoxy-4-yloxy)-2,5-diphenylene]-amine 14c (1.49 g, 3.91 mmol) was dissolved in 50 mL of tetrahydrofuran Triethylamine (1.63 mL, 11.72 mmol) and phenyl chloroformic acid (1.47 mL, 11.72 mmo 1 ) were sequentially added at 0 ° C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to ethyl acetate (200 mL), filtered, and the mixture was washed with water (60 mL×2) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, and dried. 95165 201229047 The filtrate was concentrated under reduced pressure to give the title product 4- ethoxy-i-(4-fluorophenyl)-2-oxooxy-1,2-dihydropyridine-3-carboxylic acid [4-(2- Aminopyridin-4-yloxy)-2,5-difluorophenyl]-aminodidecanoic acid diphenyl ester 14 (m (3.30 g, yellow solid). MS s/z (ESI): 617 [ M+l] The fourth step (3a5; 6aiP)-N-(4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-yloxy-1,2-diindole) Acridine-3-carboxamido)-2,5-difluorophenoxy)pyridine-2-yl)-5/3-hydroxyhexahydrocyclopenta[c]° ratior-2 (1^7) -Metformamide 4-ethoxy-1-(4-phenylphenyl)-2- oxo-1,2-dihydro"• 比〇定-3-塔酸酸[4-(2- Amino π butyl-4-yloxy)-2,5-difluorophenyl]-aminodicarboxylic acid diphenyl ester 14d (3. 30 g, 3.91 mmol) dissolved in 25 mL Ν, Ν - In the dimercaptoamine, (38^6851)-octahydro-cyclopenta[c]π is added in sequence to each of the -5/3-alcohols lc (994 mg, 7.81 mmol) and triethylamine (4. 13 mL 31. 91 mmo 1) 'Reaction for 24 hours. Add 120 mL of saturated sodium carbonate solution, extract with ethyl acetate (50 mL×4), combine the organic phases, and wash with water (1 mL) and saturated sodium chloride solution ( 100 mL), dried over anhydrous sodium sulfate, dried over EtOAc, EtOAc EtOAc EtOAc. (4-(4-Ethoxy-1-(4-fluorophenyl)-2-oxooxy-1,2-dihydrogen ° °~3~ 曱 胺)) 2, 5- Fluorophenoxy&gt; butyl-2-yl)-5 /3 - hexahydrocycloindole-2-(1^)-nonylamine 14 (0.54 g, white solid). Yield: 2i. 3% MS m/z (ESI): 651 [M+l] 4 NMR (400 MHz, DMSO-cW: (5 11.21 (s, 1H), 8.74 (s, 95165 71 201229047 1 Η), 8.33 (dd, 1Η) 819 (a 1 8.12 (d, 1 H), 7.93 (d, 1H), 7. 58~7. 46 Cm, 3H) 7 44 7 〇c / on;, 44-7. 25 ( m, 2 H), 6.63 (dd, 1H), 6.56 (d, 1H), 4 61 (ή 1u, a 01 1H), 4.30 (q, 2H), 4.16-3.94 (m,1H), 3.66 ~3. 44 Cm 9H, *3 /1 , .w, m, 2H), 3.44~3.33 (m, 2H), 2.54 (br. s. , 1H), 2. 08-1 qq rm 〇u \ 丄.W Cm,2H), 1.40~1.32 (m,3H), 1.32*Ί·27 (m,1H), 1.26~1.14 (m,1H) Example 15 (3仏6 济卜(4~( 4-(4-Ethoxy-bu (4-fluorophenyl)_2_sideoxy_1'2_m3-carbamido)-2, 5-di-phenoxy) guan-2-yl) -5α-radio-hexahydrocyclopenta[raha_2_(1 milk_甲甲胺

Oh,,,

UF 15 First step (3a5; 6a left)-2-((4-(4-Ethoxy-1-(4-fluorophenyl))_2-oxy-1,2-dihydropyridine-3- Amidino) 2,5-difluorophenoxy)pyridinyl)aminomethylmercapto)-decahydrocyclopenta[c]pyrrole-5 α-yl-4-nitrobenzoate ( 3a5;6a«-N-(4-(4-(4-ethoxy)-1-(4-fluorophenyl)-2, oxime-oxy-1,2-dihydron-bipyridyl_3_曱Amidino) 2,5~difluorophenoxy)pyr 95165 72 201229047 pyridine-2-yl)-5 million-hydroxyhexahydrocyclopentapyrrole_2 (1 milk _, decylamine 14 (0.46 g' 〇 · 71 mmol) dissolved in 2 mL of tetrahydrofuran, followed by 4-nitrobenzoic acid (473 mg, 2.83 mm 〇1) and triphenylphosphine (743 Å, 2. 83 mmol) ' at 〇 ° C Diethyl azodicarboxylate (493?, 2. 83 mraol) was slowly added dropwise, and reacted at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The filtrate was filtered, and the filtrate was washed with EtOAc (EtOAc) (EtOAc) mL two The methane was dissolved, and washed with 5 M sodium hydroxide solution (25 mL×2) and saturated sodium sulfate solution (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by eluent EtOAc (EtOAc: EtOAc (EtOAc) 2-Dihydroacridin-3-carboxamido)-2,5-difluorophenoxy)0-pyridine-2-yl)aminomethylmercapto)-decahydrocyclopenta[c]pyrrole_ _5α-yl-4_nitrobenzoate 15a (410 mg, yellow solid), Yield: 76.2 〇/〇 MS m/z (ESI): 797 [Ml] H R (400 MHz, DMS0-〇^): (5 1ΐ·23 (g iH) 8 81 (s 1H), 8.42-8. 30 (m, 3H), 8.25-8.16 (m, 2H), 8.14 (d, 1H), 7.93 (d, 1H), 7.63 (s, 1H), 7.54-7.47 (m, 3H), 7.43-7.29 (m, 2 H), 6.65 (dd, 1H), 6. 57 (d, 1H), 5.76 ( s' 1H)' 5.47 (dt, /=5.3Hz, 1H), 4.30 (q, 2H), 4-03 (q, lH), 3.66-3.50 (m, 2H), 3.40~3.32 (m, 2H) , 2.94~ 2.83 (m, 2H), 2. 14~2.04 (m' 2H), ι·99 (s, 1H), 1.94~ 95165 73 201229047 1.84 (m, 2H), 1· 36 (t, 3H), 1.18 (t, 1H) The second step (3&amp;5;63 phantom'-(4-(4-(4-ethoxy-bu(4-fluorophenyl)-2- oxo-l-1) ,2-dihydropyridin-3-ylamino)_2,5-difluorophenoxy)pyridine_2_yl)-5α-pyridylhexahydrocyclopenta[c]pyrrole_2_(1 milk_曱Indoleamine (3a5; 6a/?)-2-((4-(4-ethoxy-1-(4-fluorophenyl)-2-yloxy-1,2-dihydron-pyridyl) 3_Mercaptoamine)_2,5-difluorophenoxy)pyridin-2-yl)aminoindenyl)-decahydrocyclopenta[c]pyrrole_5_yl_4_nitro alum The ester 15a (410 mg, 〇·51 mmol) was dissolved in 4 mL of a mixed solvent of decyl alcohol and di-methane (V/V = 5:3), and then added with 32 mg of potassium hydroxide' for 7 hours. The reaction mixture was concentrated under reduced pressure, and then purified and purified eluted eluted elute -1,2-dihydro. Specific bite_3_carbamido)-2,5-difluorophenoxy)pyridin-2-yl)-5α-hydroxyhexahydrocyclopenta[c]pyrrole-2 - (1 blade - guanamine i5 (110 mg, white solid), yield: 33. 〇%. !H NMR (400 MHz, DMSO-^): 5 11. 37^ 1. 24 (m, 1H), 8 74 (s' 1 H), 8.36 (dd, 1H), 8. 12 (d, iH), 7. 98 (Mountain 1H), 7.57~7.45 (m, 4H), 7.42~7.35 (m, 2H) , 6.64 (dd, lH), 6. 60 (d, 1H), 4. 47 (d, 1H), 4. 21 (d, 1H), 4. 〇 3 (q, 1H), 3. 98 (s , 2H), 3.51 (dd, 2H), 3.25-3. 19 (m, 1H), 2. 79~ 2.69 (m, 2H), 1.99 (s, 1H), 1.91 (s, 1H), 177~166 (m, 2H), 1.59-1. 49 (m, 2H), 1.24 (s, in), 1.18 (t, 2H) Example 16 (SavP'eae-NU"-ethoxy-b (4_gas Phenyl)_2_sideoxy 95165 74 201229047 -1,2-dihydropyridin-3-indenyl)-2-fluorophenoxy)pyridin-2-yl)-5 α-peryl hexahydrocyclo Pentacene [匚]°Biha-2 (1/〇-valeramine

The first step (3aiP, 6a5〇-5 α-(4-nitrophenoxy)hexahydrocyclopenta[c] D is more than 2-(1 milk-tert-butyl citrate (3a5; 6a〇) -5/5-hydroxyhexahydrocyclopenta[c]pyrrole-2 (l-milt-tert-butyl decanoate lb (5·00 g, 22 mmol) was dissolved in 250 mL of tetranitrofuran, followed by 4-nitrobenzene Citrate (14. 70 g, 88 mmol) and triphenylphosphine (23. 08 g, 88 mmol) ' Slowly add diethyl azobisphosphate (15.32 g, 88 mmol) at 〇 °C The reaction was carried out at room temperature for 12 hours, and the reaction was continued at 50 ° for 3 hours. The reaction solution was added to 230 mL of ethyl acetate, washed with saturated sodium bicarbonate solution (160 mL×2), and the aqueous phase was extracted with ethyl acetate (160 mL) 'The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was added to 30 mL of methyl tert-butyl ether. The mixture was allowed to stand for 2 hours, 95165 75 201229047, and 30 mL of ethyl acetate was added. Filtration, the filter cake was washed with tridecyl-tert-butyl ether, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B to give the title product (3 a 疋 6 a _ 5 α _ (4 _Nitrophenylhydrazineoxy) hexahydrocyclopenta [c]pyrrole-2 (1 milk-tert-butyl formate 16a (3.8 g, white solid), yield: 47.2%. Second step (3a5; 6a^〇-5o:-hydroxyhexahydro) Cyclopenta[c]pyrrole_2 (1-blade-tert-butyl phthalate) (33^6β6·)-5-(4-nitrophenoxy)hexahydrocyclopenta[c]吼-2 (1 still - tert-butyl formate 16a (3.80 g, 1 〇 · 38 mmol) dissolved in 1200 mL of a mixed solvent of ethyl acetate and decyl alcohol (v / v = 1:1), added 71 〇 mg 虱 oxidation clock The reaction was allowed to stand for 1 hour. The reaction mixture was concentrated under reduced pressure. c]v»tt~-2(1疋)-tert-butyl phthalate 16b (1.88 g, white solid), yield: 84. 30 / 〇. Step 3 (3a and, 6351) - gossip -cyclopenta[c]° ratio ～5 α-alcohol hydrochloride salt (3a5; 6a/?)-5a-hydroxyhexahydrocyclopenta[c]pyrrole_2 (y-milk-tert-butyl ester 16b) (l. 98 g, 17. 8 mmol) dissolved in 13 mL of ethyl acetate. Add 8 mL of 5. mM hydrogen chloride in 1,4-dioxane solution for 3 hours. Concentrate the reaction mixture under reduced pressure. With 60 mL of ethyl acetate and ethanol Solvent of (V / V-1: 1) was dissolved, was added 1 mL of triethylamine square, square grant stirred for 3 minutes. Concentration under reduced pressure, the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc Acid salt 16c (480 mg, off-white solid), yield: 43. 6%. MS m/z (ESI): 128 [M+l] Step 4 (3a7?, 635.)-Ν-(4-( 4-(4-Ethoxy-l-(4-fluorophenyl)_2_sideoxy-1,2-dihydroπ ratio -3--3-mercaptoamino)-2-fluorophenyloxy)0 Ratio _2_ yl)-5 α -transylhexahydrocyclopenta[c]n ratio °-2(1)7)-formamide 4-ethoxy-1-(4-fluoro- Phenyl)-2-oxooxy-1,2-dihydrogen ratio bit-3-reetic acid [4-(2-amino-inden-4-yloxy)-3_fluoro-phenyl]- Amine 13d (377 mg, 〇·79 mmol) was dissolved in 10 mL of tetrahydrofuran in hydrazine. 0.45 mL of triethylamine and chloroformic acid ester (37 〇mg, 2.4 〇1) were added successively, and the reaction was carried out at 0 ° C for 30 minutes, concentrated under reduced pressure, and the residue was dissolved in 40 mL of ethyl acetate. The mixture was washed with a saturated aqueous solution of sodium bicarbonate (4 mL) and brine (2 mL). The residue was dissolved in 4 mL of N,N-didecylguanamine, and 1 mL of triethylamine and (SayP'GaS)-octahydro-cyclopenta[c]pyrrole-5α-ol 16c (4〇〇) were added. , .16 mmol) 'Reaction at room temperature for 12 hours, 45 ° C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was evaporated, evaporated, evaporated, evaporated, evaporated. Using a column chromatography with an eluent for the eluent - B: deuteration: the residue is obtained to give the title product (3) (4) -N-(4- 酼 a a 氧基 氧基 4 4 4 4 4 4 4 1,2-Dihydrogen ratio bite_3_ "Ί基)~2~Fluorophenoxy)Endo)_5α_secret hexahydrocyclopentayl 2 (1 milk monomethylamine 16 (10) yellow solid). Yield: 95165 77 201229047 16. 10/〇 MS m/z (ESI): 632[M+1] !HNMR (400 MHz, DMSO-de): (5 10.55 (s, 1H), 8.69 (s, 1H), 8.10 (d, /= 5.8 Hz, 1H), 7.92 - 7.82 (m, 2H), 7. 51 - 7. 42 (m, 3H), 7. 42 - 7. 26 (in, 3H), 6. 60 (m, 1H), 6.51 (d, /= 8.0 Hz, 1H), 4.46 (d, / = 3. 8 Hz, 1H), 4.26 (d, /= 7.0 Hz, 3H), 3.53 - 3.46 (m, 2H), 3.25 -3. 17 (in, 2H), 2. 77 - 2. 68 (m, 2H), 1. 69 (m, 2H), 1. 53 (m, 2H), 1.30 ( m, 3H) Example 17 (3a5; 6aiW-N-{4-(2,5-difluoro-4-(1-(4-fluorophenyl)-2-yloxy-1,2-dihydrol) Pyridin-3-nonylamino Phenoxy)pyridin-2-yl}-5〇;-hydroxy hexahydrocyclopenta[c]pyrrole-2 (1 milk-formamide)

(3a5; 6ai?)-N-{4-(2,5-difluoro-4-(1-(4-fluorophenyl)-2-oxooxy-1,2-dihydro-ratio-3 -曱醯amino)phenoxy)pyridin-2-yl}aminocarboxamido)-hexahydrocyclopenta[c]pyrrole-5 α-yl-4-nitrobenzoate (3aS,6aR)-N-{4-(2, 5-di-n--4-(1-(4-fluorophenyl)- 2-95165 78 201229047 pendant oxy-1,2-dihydrogen ° Ding-3-carboxamido)phenoxy) 吼_2_基卜5call-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-nonylamine 1 (6〇0 mg, 0. 99 mmol) was dissolved in 60 mL of tetrahydrofuran, followed by the addition of 4-nitromethane (672 mg, 4. 1 mmol) and triphenylphosphine (936 mg, 4 mmol). 693 693 mg of diethyl azodicarboxylate was slowly added dropwise and allowed to react at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified eluting with EtOAc (150 mL) The mixture was filtered, and the residue was evaporated to dryness eluted elution elution elution elution elution elution Difluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-3-indenyl)phenoxy)pyridin-2-yl}aminopurine Sulfhydryl)-hexahydrocyclopenta[(:]°°°-5-5-yl-4-; ε succinyl citrate 17a (600 mg, yellow solid), yield: 80%. Step (3851,6&amp;Friend)-1^-{4-(2,5-Difluoro-4-(1-(4-fluorophenyl)-2-oxoyl-1,2-dihydropyridine- 3-nonylamino)phenoxy)pyridine-2-yl}-5〇:-hydroxyhexahydrocyclopenta[c&gt;bibromo-2 (l/〇-decylamine will (3a^?,5 -difluoro-4-(1-(4-fluorophenyl)-2-oxooxy-1,2-dihydropyridin-3-indenyl)phenoxy)pyridin-2-yl}amino Sulfhydryl)-hexahydrocyclopenta[C]D is more soluble than pyrrol-5α-yl-4-nitrobenzoate 17a (600 mg, 〇·8 mmol) In a mixed solvent of 30 mL of decyl alcohol and methylene chloride (m=l/2), 44 mg of potassium hydroxide was added and reacted for 1 hour. The reaction solution was directly purified by eluent column chromatography using eluent column chromatography. Title product (3a5·,6ae)-N-{4-(2,5-difluoro-4-(1-(4-fluorophenyl))

S 79 95165 201229047 -2-Sideoxy-1,2-dihydropyridin-3-indenyl)phenoxy)pyridin-2-yl}-5〇;-hydroxyhexahydrocyclopentane|&gt; Pyrrole-2 (1^0-carboxamide 17 (420 mg, white solid), yield: 87%. MS m/z (ESI): 606.3 [M+l] !H NMR (400 MHz, CDCLa) δ 12.17 (in, 1H), 8.77 (dd, /=2.3, 7. 3 Hz, 1H), 8.64 (dd, /=7.3, 12. 3 Hz, 1H), 8.07 (d, /=6. 0 Hz , 1H), 7.85 (m, 1H), 7.73 (m, 1H), 7.51 (m, 2H), 7.30 (m, 3H), 7.02 (dd, /= 7.0, 10.3

Hz, 1H), 6. 70 (m, 2H), 4. 59 (m, 1H), 3. 71 (m, 2H), 3. 38 (m, 2H), 3.07 (m, 2H), 2.04 ( m, 2H), 1.83 (m, 2H) Example 18 (3ay?, 63504-(4-(4-(4-ethoxy-1-(4-fluorophenyl))) ,2-dihydropyridin-3-indenyl)-3-fluorophenoxy)pyridin-2-yl)-5/3-hydroxyhexahydrocyclopenta[c]n ratior-2 (1 still -Procarbamide

80 95165 201229047 First step 4-(4-{[4-Ethoxy-1-(4-fluoro-indenyl)-2-yloxy-1,2-dihydropyridine-3-carbonyl]-amine Kib 3-fluoro-phenoxy)-pyridine-2-cartoamine 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydro. It is dissolved in 30 mL of tetrahydrobite and is diluted with 2 drops of N, N-II. Catalyzed reaction of mercaptocarbamide, adding thionyl chloride (1751^, 24 mmol) 'reaction for 2 hours, concentrated under reduced pressure, adding 25 mL of tetrahydrofuran dissolved, 0 C added 4-(4-amino-3 -fluorophenoxy). The reaction was carried out for 12 hours by reacting guanamine gd (1.98 liter, 8 匪〇1, using a known method gas like 00680021939, prepared) and diisopropylethylamine (4.2 mL, 24 mmol). The reaction solution was concentrated under reduced pressure. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Washed with saturated sodium chloride solution (6 mL), dried over anhydrous sodium sulfate and concentrated under vacuo to give the title product 4-(4-{[4-ethoxy-1-(4-fluoro-phenyl)-2- 7%。 The oxy-1,2-dihydrol. butyl-3-ylamino-amino}_3_fluoro-phenoxy aryl amine I8a (4.0 g, gray solid), yield: 98.7%. MS m/z (ESI): 507 [M+l] Step 2 4-Ethoxy-1-(4-fluoro-phenyl)-2-yloxy-1,2-dihydro-n-bit 3-carboxylic acid [4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl]-amine 4-(4-{[4-ethoxy-1-(4~fluoro) -Phenyl)-2-oxooxy-1,2-dihydrogen ratio °-3-lateral oxy]-aminoindole-3-fluoro-phenoxy)-bite-2-曱醯81 95165 201229047 Amine 18a (4.0 g, 7.9 mmol) was dissolved in 15 mL of N,N-didecylcarbamide and water (0. 36 g, 19.7 mmol) was added sequentially at 0 °C. 0 (1. 87 g, 23.7 mmol), bis(trifluoroethyloxy)iodobenzene (6.8 g, 15.8 匪〇1) was added in portions and reacted for 12 hours. The solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc)EtOAc. The solution was washed (60 mL×2), dried over anhydrous sodium sulfate Hydrogenidine-3-carboxylic acid [4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl]-amine 18b (3. 68 g, brown solid). : 97. 3% MS m/z (ESI): 479 [M+l] Step 3 4-Ethoxy-1-(4-fluorophenyl)-2-oxooxy-1,2-di Hydrogen ratio n -3 - decanoic acid [4-(2-amino. butyl-4-yloxy)-2-1 phenyl]-aminodicarboxylic acid di- bromo ester 4-ethoxy- 1-(4-Fluorophenyl)-2-oxooxy-1,2-dihydrotonate-3-carboxylic acid [4-(2-Aminopyridin-4-yloxy)-2- Fluorophenyl]-amine (〇· 98 g, 2. 05 mmol) was dissolved in 45 mL of tetrahydrotetramine, hydrazine. 〇 · 欠 into diethylamine (0.85 mL, 6.14 mmol) and phenyl phthalate (ο.??乱六. 14匪〇1), reaction for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The resulting residue was purified by column chromatography using eluent A: to give the title product 4- ethoxy-1-(4-fluorophenyl) 2 _ s oxy~~~~~~~~~~~ [4-(2-Amino. butyl-4-yloxy)-2-fluorophenyl]~month: 95165 82 201229047 Diphenyl biscarboxylate 18c (500 mg, white solid) 'yield: 34 . 4%. MS m/z (ESI): 719 [M+l] Step 4 (3a^ 68504-(4-(4-(4-ethoxy-1-(4-fluorophenyl))) -1,2-dihydro. 0-but-3-amino-amino)-3-It phenoxy). Ratio π _2 _ base) -50,000-hydroxyhexahydrocyclopenta[c]pyrrole - 2 (1 phantom-nonylamine 4-ethoxy-1-(4-fluorophenyl)-2- oxo-1,2-dihydrogen ratio bite-3-carboxylic acid [4-(2 -Aminopyridin-4-yloxy)-2-fluorophenyl]-aminodiphthalic acid diphenyl ester 18c (500 mg, 0.69 mmol) dissolved in 30 mL of N,N-dimethyl decylamine In the middle, (3ai?, 6a5·)-octahydrocyclopenta[c]pyrrole-5/3-alcohol lc (178 mg, 1.39 mmol) and triethylamine (0.3 mL, 2.09 mmo 1) were added. </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> The filtrate was concentrated by pressure, and the residue obtained was purified by eluent from EtOAc (EtOAc) eluting to afford the title product (3aA*,6aiS〇-N-(4-(4-(4-ethoxy-1-)- 4- Fluorophenyl)-2-oxooxy-1,2-dihydron-pyridin-3-carboxyindolyl)-3-fluorophenoxy) Ratio 定-2-yl)-5-ylaminohexahydrocyclopenta- each-2(li7)-amine II (30 mg, white solid), yield: 7%. !H NMR (400 MHz, DMSO-de) 5 10.72 - 10.69 (m, 1H), 8. 78(s, 1H), 8. 18(t, 1H), 8. 12 (d, 1H), 7. 89 (d, 1H), ^•52 - 7.46 (m, 3H), 7.42 - 7.33 (in, 2H), 7.20 (dd, &gt;11.4 Hz, 1H), 7.03 - 6.98 (m, 1H), 6.61 (dd, /=5.8 Hz, 1H), 6.53 (d, 1H), 5.09 - 5.01 (m, 1H), 4.28 (q, 83 95165 201229047 2H), 4.03 (q, 2H), 3.61 - 3.53 (m, 2H), 3.43 - 3.35 (in , 2H), 2.70 - 2.62 (m, 2H), 2. 33 - 2. 24 (m, 2H), 1.99 (s, 3H), 1.73 - 1.65 (m, 2H), 1.35 (t, 4H), 1.18 (t, 3H) Example 19 (3ae, 6ai9)-2-((4-(2-Fluoro-4-((1-(4-fluorophenyl))-2-oxyl) Amidino)phenoxy)-2-D ratio 11 aryl)aminoglycolyl)-hexahydrocyclopenta[c]n than succinyl-5-amino-aminoacetate

(3a^*,6851)-octahydro-cyclopenta[c]D than 嘻-5 /3 - alkoxide hydrochloride compound (3a5; 6aA〇-5-hydroxyhexahydrocyclopenta[c]pyrrol first step

-2 (1 Ζ〇-tert-butyl phthalate lb (50 g, 0.22 mmol) was dissolved in 250 mL of ethyl acetate, and a hydrogen chloride in 1,4-dioxane solution (11 〇mL, 0. 88 mmol) was added. , the reaction was carried out for 12 hours, and filtered to give the title compound (3a,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, % 95 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' )-2-oxooxy-1,2-dihydroindolizine-3-carboxamido]-aminophenphenoxydipin-byl]_5yg-radiohexahydro-cyclopenta[c ] 〇 ρ 曱醯 曱醯 曱醯 将 将 4- [4-(2-fluoro-4-{[ 1-(4-fluorophenyl)-2- oxo-1,2-dihydro-D ratio bite -3-yl]-amino}-phenoxy)-. than bite_2_yl]-aminodicarboxylic acid

Diphenyl ester 4b (200 mg, 0. 29 mmol) and (3ae, 6aS)-octahydro-cyclopenta[c] 0 piroxicam-5/3-ol hydrochloride 19a (194 mg, 1·18 mmol Dissolved in 5 mL of N,N-didecylguanamine, and then added with 6 mL of triethylamine for 12 hours. Add 50 mL of di-gas methane and 2 mL of water, then add 1 M 30 mL of sodium hydroxide solution, layer, and separate the organic phase with 1M sodium hydroxide solution (3〇mLx2) and saturated sodium chloride solution (3〇mLx2). After washing, it is dried over anhydrous sodium sulfate, and filtered, and the filtrate is evaporated to dryness, and the residue is purified to the titled compound (3a^6i9) _[4_(2_ fluoro-4-{ [1-(4-Fluorophenyl)-2-yloxy-1,2-dihydrooxazolidine-3-indenyl]-amino}-phenoxypyridin-2-yl]-5 々-Hydroxyhexahydro-cyclopenta[c]pyrrole-2-decylamine 19b (50 mg, yellow solid), yield 29.4%. MS m/z (ESI): 588 [M+l] Three steps (35疋6a«-2-((4-(4-fluoro-4((1-(4-fluorophenyl)-2-yloxy-barridin-3-ylamino)phenoxy) ~)~2-pyridyl)aminoindenyl)-hexahydrocyclopenta[c]pyrrolyl)-5/3-yl-2-(1-(tert-butoxycarbonylamino)acetate (3a7?,6&amp;5Ή4-(2-Fluoro-4-{[l-(4-fluorophenyl)-2-oxooxo 85 95165 201229047-based-1,2-dihydropyridine_3_decylamine ] _ _ 苯 苯 苯 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 c c c c c c c c c c c c c c c I9b (57 ,, 0.97 mmol) 'tert-butoxycarbonylaminoacetic acid (34 〇, 194 ca 〇 1), 1-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride ( 372 mg, 1.94 mmol) and 4-dimethylaminopyridinium (12 mg, 〇〇97 mmol) were dissolved in 20 mL of dioxane, reacted for 12 hours, and 50 mL of water and 50 mL of dichloromethane were added. The liquid phase was extracted with two gas methane (30 mL×2), and the combined organic phases were washed sequentially with saturated sodium bicarbonate solution (3 mL), 1M hydrochloric acid (30 mL) and saturated sodium carbonate solution (3 mL). Drying with anhydrous sodium sulfate, filtration <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Fluorine-4((1-(4-fluorophenyl)-2-oxo-p-(3-carbamoylamino)phenoxy)-2-pyridinyl)aminomethane)-hexahydro 1%% Cyclopenta[c]n than aryl) _5 一 基 -2- (1 milk-(tert-butoxymethylamino) acetic acid vinegar iQc (5 〇〇 mg, yellow solid), yield 69. 1% MS m/z (ESI): 745 [M+l] The fourth step (3a7?,6a5〇-2-((4-(2-fluoro-4-((1-(4-fluorophenyl)))) 2-sided oxygen ratio 3--3-carboxamido)phenoxy)-2-n-pyridyl)aminoindenyl)-hexahydrocyclopentazone|»pyryl)-5/3-yl-2-(1^ )-Aminoacetate will (33疋6a«-2-((4-(2-fluoro-4)(1-(4-fluorophenyl)-2-yloxy)-α ratio -3-甲 胺 ) 本 本 本 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Butyroxycarbonylamino)acetate 19c (500 mg, 0.67 mmol) was dissolved in 10 mL of dioxane, 86 95165 201229047 〇 ° C, trifluoroacetic acid (1 mL, 13.4 mmol), 〇 Stir at °c for 10 minutes and react at room temperature for 12 hours. Dissolve the carbonic acid clock (560 mmg, 4 mmol) in a small amount of water and add to the system for 10 minutes. 15 mL of water and 1 〇mL of dioxane were added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (10 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue obtained was purified by eluent column chromatography using eluent to afford the title compound (3a. 2-sided oxy-° ratio 曱醢-3-hydrazinyl)phenoxy)-2-n ratio π-decyl) amino fluorenyl)-hexahydrocyclopenta[(^&gt; ratio ° basis -5/3 -yl-2-(1-milyl-aminoacetate 19 (210 mg, pale yellow solid), yield 48. 5%. 19 (120 mg, white solid), yield: 23.0% MS m/z (ESI): 645 [M+l] 4 NMR (400 MHz, CDCI3): (5 11.95 (s, 1H), 8. 75 (dd, 1H), 8.03 (d, 1H), 7.94 (d, 1H), 7.70 (s, 1H), 7.63 (dd, 1H), 7.37-7.48 (m, 2H), 7.23-7.37 (m, 3H), 7.13 (t, 1H), 6.62 (t, 1H), 6.54 (dd, 1H), 5.25 (br. s., 1H), 4.13 (d, 1H), 3.58-3.75 (in, 2H), 3.44-3.52 (m, 2H), 3.39 (s, 2H), 2.77 (br. s., 2H), 2.24-2.43 (m, 2H), 1.71 (d, 2H), 1. 22-1.31 (m, 2H) Example 20 (3aiP, 68^-2-((4-(4-fluoro-4-((1-(4-fluorophenyl)-2-yloxy)-. Pyridin-3-indenyl)phenoxy)-2-pyridyl)aminocarboxamido)-hexahydrocyclopenta[(:]° 洛洛基)-5〇:-yl-2-( 1/〇-Aminoacetate 95165 87 201229047

First step (3^?, 655^2-((4-(2-fluoro-4((1-(4-fluorophenyl)-2-yloxy-acridin-3-ylamino)) Phenoxy)-2-pyridyl)aminocarboxamyl)-hexahydrocyclopenta[c]pyrrolidin-5 α-yl)~4-nitrobenzoate (3a especially 6a5*)- [4-(2-Fluoro-4-{ [1-(4-fluorophenyl)-2-yloxy-1,2_·---------------------------------------------------------- Oxyl]-5/5-hydroxyhexahydro-cyclopenta[e]pyrrole-2-carboxamide I9b (10 g, 17 mmol) '4-nitrobenzoic acid (11.36 g, 68 mmol) and three Phenylphosphine (17. 84 g, 68 mmol) was dissolved in 500 mL of tetrahydrofuran, cooled to 〇〇c, and diethyl azodicarboxylate (11.85 g, 68 mmol) was added dropwise, and the temperature was controlled below 10 °. C, room temperature reaction for 12 hours. Add 25 mL of ethyl acetate to the reaction solution, wash with saturated sodium bicarbonate solution (250 mL×2), combine the aqueous layer, and extract the aqueous layer with ethyl acetate (250 inL) Drying with anhydrous sulphuric acid ore, filtering, concentrating the filtrate under reduced pressure, and purifying the residue obtained by eluent column chromatography using eluent column chromatography to give the title compound 88 95165 201229047 (3 Xiu 6 (350-2-((4) -(2-fluoro-4((1-(4-fluoro) Phenyl)-2-oxo-n-pyridin-3-ylamino)phenoxy)-2-pyridyl)aminoindenyl)-hexahydrocyclopenta[c]pyrrolyl-5α - yl) 4-nitrobenzoate 20a (7.02 g, off-white solid), yield 56.0. MS m/z (ESI): 737 [M+l] Step 2 (3a&gt;? ,6&5〇-Ν-[4-(2-Fluoro-4-{[1-(4-fluorophenyl)-2-yloxy-1,2-dihydropyridin-3-ylamino) ]-Amino}-phenoxy)-pyridin-2-yl]-5 α-hydroxyhexahydrocyclopenta[c]pyrrole-2-(1^-carboxamide) (3a7?, 63^9) -2-((4-(2-fluoro-4)(2-(4-fluorophenyl)-2-yloxy)pyridin-3-ylamino)phenoxy)-2-0-pyridinium Aminomethylmercapto)-hexahydrocyclopenta[c]pyrrolyl)-5α-yl-4-nitrobenzoic acid 20a (7.22 g, 9.53 mmol) dissolved in 200 mL of tri-methane and hydrazine In a mixed solvent of alcohol (ν/ν=ι:ι), 'potassium hydroxide (533 mg, 9.53 mmol) was added and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, using a gel column chromatography to eluent system A. The obtained residue was purified to give the title compound (3a, 6 6 6 -1: 4-(2-carbo[1-(4-phenylphenyl)-2-oxo-l-l, 2-dihydroindole ratio bite- 3-mercaptoamino]-amino group Phenoxy)-n ratio keto-2-yl]-5 α -transylhexahydrocyclopenta[c]n piroxi-2-(1 pi)-cartoamine 2〇b (3. 60 g, White solid), yield 64.3%. MS m/z (ESI): 588 [M+l] Step 3 (3aV?, 6^9)-2-((4-(2-fluoro-4((1-(4-fluorophenyl))) 2-sided oxy-acridine-3-carboxamido)phenoxy)_2-° ratio dimethylamino)-hexahydrocyclopenta[c]pyrrolyl-5 α-yl uncle Butoxycarbonylamino)acetate 95165 89 201229047 _(3a)i&gt;' 6a5&lt;)-N-[4-(2-Fluoro-4-{[l-(4-fluorophenyl)-2- --Alkoxy-1,2-dihydroacridine~3_Mercaptosylamine phenoxypyridin-2-yl]-5 α-hydroxyhexahydrocyclopenta[c]pyrrole_2_ (丨奶_Metamine 2〇b (630 mg, 1. 10 _〇1), tert-butoxycarbonylamino acetic acid (376?, 2.2 〇-mmol), 1-(3-dimethylamino) Propyl)_3_ethylcarbodiimide hydrochloride (411 mg' 2. 20 mmol) and 4-dimethylaminopyridine (13, 〇. 10 leg 〇1) dissolved in 20 mL of dichlorinated broth 'Reaction 12 hours. Add 30 mL of dichloromethane to dilute'. Wash with saturated sodium bicarbonate solution (3〇raL), 1M hydrochloric acid (3〇mL) and saturated sodium chloride solution (3〇mL). Drying with anhydrous sodium sulfate 'filtered' filtrate concentrated under reduced pressure> Purified residue obtained by eluent system column chromatography using eluent column chromatography The title compound was obtained (3aA&gt; 6a5()_2_((4-(2-fluoro-4((1-(4-fluorophenyl)_2)-oxyl-pyridyl_3-methylamino)phenoxy Alkyl fluorenyl) hexahydrocyclopenta[c]pyrrolidin-5α-yl)-2-(1Ζ〇-(tert-butoxycarbonylamino)acetate 2〇c (56〇, yellow solid), yield 70.0% MS m/z (ESI): 745 [M+l] Step 4 (3ai?,6av9)-2-((4-(2- Fluoro-4-((1-(4-fluorophenyl)-2_sideoxy-° ratio D-1,3-ethylamino)phenoxy)_2_ηpyridyl)aminoindenyl)_ Hexahydrocyclopenta[c]pyrrolidinyl)-5〇j-ylaminoacetate (3a)?,6a«-2-((4-(2-fluoro-4((1-(4-) Fluorophenyl)-2-oxooxyl butyl-3-hydrazinyl)phenoxy)_2_npyridyl)aminoindenyl)-hexahydrocyclopenta[〇>pyryl)- 5α-yl(tert-butoxycarbonylamino)acetic acid vinegar 20c (530 mg, 〇. 70 〇1〇1) is dissolved in 1 〇mL of dichloro decane, 90 95165 201229047 〇C, added trifluoroacetic acid (〇 6 mL, 8. 50 mmol), react for 10 minutes, react at room temperature for 12 hours, dissolve solid potassium carbonate (590 mg, 4.30 mmol) in 1 mL of water and add to the reaction. In the solution, react for 10 minutes, add 20 mL of water and 10 mL of dioxane, separate the liquid, and extract the aqueous phase with dioxane (1 〇mLx2), combine the organic phase, dry with anhydrous sodium sulfate, filter, filtrate Concentration by pressure, the residue obtained by purifying the column system A with eluent column chromatography to obtain the title compound (3a_/?,6a5〇-2-((4-(2-fluoro-4-((1- (4-cyclophenyl)-2-oxo-n-pyridin-3-ylamino)phenoxy)-2-acridinyl)aminocarboxamido)-hexahydrocyclopentyl -5 α-yl-2-(1Λ〇-aminoacetate 20 (320 mg, white solid), yield 69.7%. MS m/z (ESI): 645 [M+l] NMR (400 MHz, MSO-de): δ 12.09 (s, 1H), 8.75 (s, 1H), 8.59 (dd, 1H), 8.19-7.96 ( m, 5H), 7.66-7.56 (m, 2H), 7.52-7.39 (m, 4H), 7.33 (t, 1H), 6.81-6.68 (m, 1H), 6.61 (dd, 1H), 5.34-5.24 ( In, 1H), 3.77 (s, 2H), 3.60-3.45 (m, 2H), 2.95-2.69 (in, 2H), 2.30 (s, 3H), 2.00-1.88 (m, 2H), 1.85-1.71 ( m, 2H), 1.32-1.19 (m, 2H) Example 21 (3af, 6350-2-((4-(2-fluoro-4-)(1-(4-fluorophenyl)-2-oxoxy) 〇-〇 咬 -3- 醯 醯 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) c c c c c c c c -acetate 95165 91 201229047

2a

The first step (Sa&amp;GayiO-Sa-acetoxy-hexahydro-cyclopenta[c]npirin-2-butyrate tert-butyl ester (3a7?, 6β5·)-5々-methanesulfonate The baseoxy-hexahydro-cyclopenta-tert-but-2-butyric acid tert-butyl ester 2a (2 g, 6.55 mmol) was dissolved in 60 mL of N,N-dimethylformamide and potassium acetate was added ( 1.90 g, 19.65 mmol), react at 80 ° C for 12 hours. Add 100 mL of ethyl acetate and wash with saturated sodium bicarbonate solution (100 mL×2) and saturated sodium carbonate solution (1〇〇mLx2), organic The residue was dried over anhydrous sodium sulfate (MgSO4), filtered,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj - Cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 21a (1.1 g, yellow liquid), yield 62. 5% MS m/z (ESI): 214 [M-55] (3a5&quot;,63 and)-octahydro-cyclopenta[c]D than 嘻-5 α-acetic acid vinegar hydrochloride (36s_/??)-5 (2 _ ethoxylate-hexazacyclopenta [c]*·Bilo-2-carboxylic acid tert-butyl ester 21 a (lg, 3.70 mmol) dissolved in 20 mL·ethyl acetate 95165 92 201229047, 1,4-dioxacyclohexane with hydrogen chloride added The alkane solution (3 mL, 14.9 mmol) was reacted for 1 hour, and the reaction mixture was concentrated under reduced pressure to give the title compound (3a5; 6a#)- octahydro-cyclopenta[c]pyrrole-5-acetate Acid salt 2ib (540 mg, yellow solid), yield 71% 。% MS m/z (ESI): 170 [M+l] The third step (3a and, 68^9)-2-((4- (2-Fluoro-4-((1-(4-fluorophenyl)-2~~ pendant oxy-indolepyridin-3-carboxamido) phenoxy)-2-pyridyl)aminopurine Sulfhydryl>hexahydrocyclopenta[c]pyrrolyl)-5α-yl-acetate The compound [4-(2-amino-pyridin-4-yloxy)-3-fluoro-phenyl] 1-(4-Fluoro-phenyl)-2-oxooxy-1,2-dihydro-indolepyridin-3-ylamine 4a (1. 15 g, 2.65 mmol) dissolved in 40 mL In tetrahydrofuran, phenoxymethyl chloride (1.25 g, 7.95 mmol) was added, and the reaction was carried out for 20 minutes. Triethylamine (0. 80 g, 7.95 mmol) was added and the reaction was carried out for 30 minutes. 50 mL of ethyl acetate was added, and the organic phase was washed with saturated sodium chloride solution (25 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mercaptoamine was dissolved, and triethylamine (1.61 g, 15.90 mmol) and chloranil were added. Acid benzene g (417 mg, 2. 66 mmol), react for 5 minutes, add (3a5; 6ai?)-octahydro-cyclopenta[c]pyrrole-5 α-acetate 21b

(897 mg, 5.30 mmol), reacted at 45 ° C for 3 hours. It was diluted with 50 mL of ethyl acetate and washed with saturated sodium sulphate solution (25 mL×2), dried over anhydrous magnesium sulfate, filtered, filtered, and concentrated under reduced pressure, and purified by eluent column chromatography with eluent system B to obtain the residue. The title compound (3a&gt;?,6a«-2-((4-(2-fluoro-4-((1-(4-fluorophenyl))-2-oxyl ratio 93 95165 201229047 ° _3-曱Acrylamino)phenoxy)-2-° ratio 定 ) ) 胺 ) ) ) 六 六 六 六 六 六 六 554 554 554 554 554 554 554 554 554 554 554 554 554 554 554 554 554 554 554 554 The yield is 33.2%. MS m/z (ESI): 630 [M+l] NMR (400 MHz, DMS0-i«: 5 11.95 (s, 1H), 8.75-8. 73 (m, 1H ), 8. 03-8. 02 (m, 1H), 7. 94-7. 91 (m, 1H), 7. 7〇-7.67 (m, 1H), 7.64-7.62 (m, 1H), 7.43 -7.40 (ra, 2H), 7.34-7.25 (m, 2H), 7.14-7.10 (m, 2H), 6.63-6.52 (m, 2H), 5.30-5.28 (m, 1H), 3.68-3.64 (m, 2H), 3.31-3.28 (ra, 2H), 2.92-2.90 (m, 2H), 2.05-2.02 (m, 5H), 1.86-1.80 (m, 2H) Example 22 (3a)?, 6a«-2 -((4-(2-fluoro-4-((1-(4-fluorophenyl)-2-yloxy)pyridin-3-carbinyl)phenoxy)-2-pyridyl)amine Carbenyl)-hexahydrocyclopenta[ c]° 略 基)-5 α-ylaminopropionate

Nh2

94 95165 201229047 (3ai?,6a5V2-((4-(2-fluoro-4-((1-(4-fluorophenyl)_2)-oxyl-. (2-pyridyl)aminocarbinyl)-hexahydrocyclopenta[c]pyrrolyl)-5 α-yl-(260-2-benzyloxycarbonylaminopropionate (3a^) 6850^44-(2-Fluoro-4-{[1-(4-fluorophenyl)-2-oxooxy-1,2-dihydroacridin-3-ylamino]-aminophenylbenzene Oxy)) bispyridin-2-yl]-5 α-hydroxyhexahydrocyclopenta[c]pyrrole_2-(1Λτ)-nonylamine 2〇b (587 mg, 1 mmol), (250- 2-phenoxycarbonylaminopropionic acid (446 mmg, 2 mmol) and 1-(3-diamidinopropyl)-3-ethylcarbodiimide hydrochloride (383 mg, 2 mmol) In 30 mL of dioxane, 4-diaminoamine 0-pyridine (24 mg, 0.2 mmol) was added to react for 12 hours. Add 2 mL of turmeric, followed by saturated sodium bicarbonate ( 2 〇mL) and EtOAc (20 mL), EtOAc (EtOAc m. ((1-(4-Fluorophenyl)2-saltyl-**-bend-3-ylamino)phenoxy)_2-d ratio dimethyl)amino fluorenyl - hexa-argon% penta[^]11 to '1 each group)-5 〇;-yl-(2151)-2'~ ethoxylated aminopropionate 22a (lg, pale yellow solid), The product was directly subjected to the next reaction without purification. MS m/z (ESI): 793 [M+l] The second step (3ae, 6350-2-((4-(2-fluoro-4-((1-) 4-fluorophenyl)_2_sideoxy-(J-pyridine-3-carboxamido)phenoxy)-2-oxaridinylaminocarbazino)-hexahydrocyclopenta[c] Pyrrolyl)-5 α-yl-(251)-aminopropionate crude product (3a especially 6a5*)-2-((4-(2-fluoro-4-((1-(4-fluoro-4-)) -2-Sideoxy-acridin-3-carbamoylamino)phenoxy)_2_indolinyl)aminomethyl 95165 95 201229047 fluorenyl)-hexahydrocyclopenta[c]D ratio ))-5 α-yl-(2^)-2-benzyloxycarbonylaminopropionate 22a (lg, 1 mmol) dissolved in 15 mL of methanol, added to the epoch/carbon (200 mg, 10%) The hydrogen was replaced three times and reacted for 3 hours. The reaction liquid was filtered with silica gel (200 to 300 mesh), and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent (D. The title compound (3aW, 68^-2-((4-(4-fluoro-4-)-2-yloxy-η) Amino-3-mercaptoamino)phenoxy)_2-π ratio dimethylamino)-hexahydrocyclopenta[c]pyrrolyl-5-yl-(251)-aminopropyl 2%。 Acidate 22 (324 mg, white solid), yield 49.2%. MS m/z (ESI): 659 [M+l]]H NMR (400 MHz, MSO-de): δ 12.09 (s, 1H), 8.74 (s, 1H), 8.59-8.57 (m, 1H), 8.14-8.11 (m, 2H), 8.01-7.98 (m, lH), 7.63~7.60 (m, 2H), 7.49~7.40 (m, 4H), 7.35~ 7.30 (t, 1H), 6.74-6.71 (m , (1,1H) -1.73 (m, 6H), 1.14-1.12 (d, 3H) Test Example: i. Physical Evaluation Example 1. c-Met Cell Proliferation Inhibition Test The following in vitro test can be used to determine the compound of the present invention for high expression of c-Met. Proliferation inhibitory activity of human gastric cancer cell line SNU-5. The in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound against tumor cell SNU-5, and its activity can be expressed by the iC5D value in Table 96 95165 201229047. The general protocol for such an experiment is as follows: First select human tumor cell SNU-5 (purchased in Institute of biochemistry and cell biology) with high expression of c-Met, and inoculate 96 at a suitable cell concentration (eg 5000 cells/mL medium). On the well culture plate, a series of gradient concentration (generally 6 to 7 concentrations) of the test compound solution diluted with the medium was added to each well, and culture was continued for 72 hours. After 72 hours, the activity of the compound to inhibit cell proliferation was measured by the cel 1 counting kit-8 (CCK-8, described in DojinDo) method. The IC5Q value can be calculated from the inhibition of cell proliferation by a test compound at a range of different concentrations. Activity of the compound of the present invention The biochemical activity of the compound of the present invention was measured by the above test, and the measured ICso value is shown in the following table. Example No. IC5〇(SNU-5)(^M) 1 0. 024 2 0. 03 3 0. 05 10 0. 02 12 0. 06 15 0. 027 16 0. 041 17 0. 03 Conclusion: The present invention The compounds of the examples all showed significant proliferation inhibitory activity against SNU-5 cells. Example 2. Determination of c-Met kinase activity The activity of c-Met kinase in vitro was determined by the following method. 97 95165 201229047 The method described below can be used to determine the inhibition of the activity of the enzyme. Half of the compound inhibits a certain concentration of enzyme activity to the desired compound of the 5_ temple

It is calculated by combining a certain amount of kinase with a specific substrate and a different concentration of the ?-? The C Met transcript used in this experiment (purchased from Cel 1 Signal ing technology) is a human recombinant protein. The enzyme contains 60 mM HEPES (pH 7.5), 5 mM MgCh, 5 mM.

MnCl2 '3eMNa3V〇4, 1.25MDTT (1000x) buffer solution and 3〇μΜ ATP reaction system were reacted with the polypeptide matrix and different concentrations of the test compound (25 ° C, 45 min), followed by anti-phosphate cheese The substrate was labeled with an amino acid antibody and a guanidine-labeled antibody, and the c-Met kinase activity was quantitatively determined by time-resolved fluorimetry. Activity of the compound of the present invention The biochemical activity of the compound of the present invention was measured by the above test, and the measured ICso value is shown in the following table. 98 95165 201229047 Example number ICs〇(c-Met/BI0)(^M) 1 0. 016 4 0. 013 6 0. 027 7 0. 028 8 0. 016 10 0. 021 12 0. 017 13 0. 017 14 0.007 15 0. 004 16 0. 008 17 0. 031 Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on c-Met kinase activity. Example 3. VEGFR cell proliferation inhibition test The following in vitro test can be used to determine the proliferation inhibitory activity of the compound of the present invention against human VEGFR-expressing human umbilical vein endothelial cells HUVEC. The in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound against a specific HUVEC cell which highly expresses VEGFR, and its activity can be expressed by an IC5° value. The general protocol for this type of trial is as follows: First, select high-surface human venous endothelial cells HUVEC (purchased in the American Standard Biological Collection Center, biologically, and, in., with the cell biology ATCC biochemistry and cell biology\ medium) In a suitable cell concentration (eXP 5000 cells / ml incubator on a 6-well culture plate, then (4) in carbon dioxide 惶. Lips, when they grow to 85% confluence, change the medium to 95165 99 201229047 plus one Serial concentration (generally 6 to 7 concentrations) of the test compound solution medium's put the culture plate back into the incubator for 72 hours and 72 hours after continuous culture, the compound can be tested for inhibition of cell proliferation by sulforhodamine B (SRB) method. The activity. ICs. The value can be calculated by a series of different concentrations of the test compound's inhibition value for the cell. The activity of the compound of the invention The biochemical activity of the compound of the invention is determined by the above test 'Measured IC5 The value is shown in the table below. --Example number IC5〇(HUVEC)( ^M) ----_l〇0. 07 _____12 0. 05 Circle_______J7 0. 18 Conclusion: The compounds of the present invention have significant proliferation inhibitory activity against HUVEC cells.Example 4. Measurement of VEGFR kinase activity VEGFR kinase activity was measured by the following method under in vitro conditions.

The method described below can be used to determine the ability of the compound of the present invention to inhibit the activity of the kinase, and is expressed by the ICsq value. The half-inhibitory concentration of the compound is ICs. (Required for inhibiting a certain concentration of enzyme activity to 5 (10). The concentration of the compound is determined by mixing a certain amount of the kinase with a specific matrix and different concentrations of the test compound. The GFR spur used in this experiment (purchased from cei 1 Signaiing technology) is a human recombination. Protein, the enzyme contains 6 mM HEPES (pH 7.5), 5 mM MgCh, 5 mM 100 95165 201229047

MnCl2, 3#M Na3V〇4, 1.25M DTT (ΙΟΟΟχ) buffer solution and 30μΜ ATP reaction system were reacted with the polypeptide matrix and different concentrations of the test compound (25 ° C, 45 min), followed by anti-phosphoric acid The tyrosine antibody and the europium-labeled antibody pair were labeled, and finally the VEGFR kinase activity was quantitatively determined by time-resolved fluorescence. Activity of the Compound of the Invention The biochemical activity of the compound of the present invention was determined by the above test, and the measured IC5 enthalpy value is shown in the following table. Example No. IC5(VEGF/BI0)(^M) 12 0. 023 Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on VEGFR kinase activity. Pharmacokinetics Evaluation Example 5, Pharmacokinetic Test of the Compound of the Invention 1. Abstract Rats were used as test animals, and the compound of Example 10 was administered orally by LC/MS/MS method. The concentration of the drug in the blood at various times after the compound of Example 12. The pharmacokinetic behavior of the compounds of the invention in rats was studied&apos; to evaluate their pharmacokinetic profile. 2. Test protocol 2.1 Test drug Example 10 compound and example 丨2 compound 2. 2 test animal 101 95165 201229047 Healthy adult SD rat 8 'male and female, average 2 divided into 4 each group' purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. became a production license number: SCXK (Shanghai) 2008-0016. Animals 2. 3 Drug preparation Weigh a certain amount of the drug, add 1. 〇 mL 曱 曱 亚 ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε ε Mouth 2.4 Administration SD rats were intragastrically administered overnight after fasting, and the doses were all 〇. Q mg/kg, the administration volume was no this / kg. 3. The rats of Example 10 were administered intragastrically with the compound of Example 10 and the compound of Example 12, before and after administration, 〇·5, L 〇, 2. 〇, 3. 0, 4. 0, 6. 〇, 8. 0, 12· 0 ' 24. 〇, 36. 0 hours by eyelid blood collection 0. 2 Ml, placed in heparinized tester '4 it, 10,000 rpm / centrifugation 1 minute to separate plasma, at _2 〇 C save 'feed 2 hours after administration. Determination of test compounds in rat plasma after intragastric administration of different concentrations of drug: take 50//L of rat plasma at each time after administration, add internal standard solution to dissolve L 'methanol 1 〇〇", vortex mixing After 3 minutes, centrifuge for 1 〇 minutes (13500 rpm), and take the supernatant lOyL for LC/MS/MS analysis. 4' K kinetic parameter results The pharmacokinetic parameters of the compounds of the present invention are as follows: 102 95165 201229047 Generational kinetics experiment (10 rag/kg) such as drug concentration curve area half-life retention time clearance rate apparent volume of distribution Cmax (μg/mL) AUC (β g /mL*h) tl/2(h) MRT(h) CL /F (L/h/kg) Vz/F (L/kg) Example 10 0.9110.31 4.72±1.98 1.74±0.22 4.12±0.36 2. 37±0.81 5. 89±1.93 Example 12 5. 55 ±0. 65 21.28±3.41 2. 75±0. 22 3. 70±0. 54 0. 45±0. 08 1.89±0.16 Conclusion: The compound of the present invention has good pharmacopoietin absorption and has obvious pharmacokinetic advantages. [Simple description of the diagram] No [Main component symbol description] None 103 95165

Claims (1)

201229047, the scope of patent application: a compound of the formula (I) or a pharmaceutically acceptable salt thereof, 七· Α is selected from -CRa or Ν; D is selected from -CRb or Ν; X is selected from -CRe or Ν; R1 is selected from aryl or hybrid, wherein "the base or heteroaryl is further broken as needed or A plurality of selected from the group consisting of alkyl, alkoxy, -, hydroxy, cyano, decyl, -C(〇)()r9, -〇C(W, -〇(CH2)raC(〇)〇R9, - OCCONR-R-1 &gt; -S(〇)nR^ -OS〇2R9^S〇2NR10R-, -NHC(0)R9 or _NRlt&gt; is substituted with a substituent of Rl1; R, Re or R2 is independently selected from hydrogen An atom, an alkyl group, an alkoxy group or an aryl group; each of V, R4, R5 or R6 is independently selected from a hydrogen atom, an alkyl group or a dentate; R7 is selected from a hydrogen atom or an alkyl group wherein the alkyl group is further protected by a halogen Or substituted with an alkoxy substituent; R8 is selected from a bicycloalkyl group, a biheterocyclyl group, a bridged cycloalkyl group, a bridged heterocyclic group, a spirocycloalkyl group or a spiroheterocyclic group, wherein the bicycloalkyl group, the bicyclohetero ring Further, one or more selected from the group consisting of alkyl, alkoxy, _, hydroxy, cyano, 1 95165 201229047 Base, cycloalkyl, heterocyclic, aryl, heteroaryl, carbonyl, —c(〇)(9)9, -0C(0)R9, -〇(CH2)mc(〇)〇R9,-0C(0)NR,i,~s(〇) r9, -OS〇2R9, -SOzNRl11, -NHC(0)R9 or Substitution of -NR1QR" with a substitution; & R7 and R8 together with the N atom to which they are attached form a 5- to 14-membered bicyclic heterocyclic group, a bridged heterocyclic group or a spiroheterocyclic group, wherein the diheterocyclic group, bridge The heterocyclic group or spiroheterocyclyl is further optionally substituted by a plurality of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, carbonyl, cycloalkyl, heterocyclic, aryl, heteroaryl, _C (〇)〇R9, _〇C(;〇)R9, earth-0(CH2)mC(0)0R9, -〇C(0)NRi.!^, _S(〇)nR9,,〇s〇2R9, a substituent of -SO·%11, -NHC(〇)R9 or _NW is substituted 2; R9 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the alkyl group, the succinyl group or the aryl group is regarded as Further required to be substituted by one or more amine groups. R1() or R11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, naphthenic group a base, a heterocyclic group, a aryl group or a heterocyclic group, further optionally selected from one or more selected from the group consisting of an alkyl group, an oxo group, a halogen group, a hydroxyl group, Base, nitro, cycloalkyl, heterocyclic group, -C(0)0R9 &gt; -0C(0)R9 &gt; -〇(CH2)mC(0)OR9' -〇C(〇)nr12r*3 n Substituted by a substituent of -S(0)nR9, -〇S〇2R9, -S〇2NR12R13, -NHC(0)R9 or -NR12R13; or 'R1() and R11 together with the nitrogen atom to which they are attached form 3 to 8 a heterocyclic group, wherein the 3 to 8 membered heterocyclic ring further contains a plurality of N, 0 or S(0) n atoms, and the 3 to 8 membered heterocyclic ring is further selected from one or more as needed Alkyl, alkoxy, halogen, hydroxy, 2 95165 201229047 cyano, nitro, carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)0R9, -0C(0)R9 Substituted by a substituent of -(CH2)mC(0)〇R9, -〇C(〇)NR12R13, -S(0)nR9, -OSO2R9, -S〇2NR12R13, -NHC(0)R9 or -NR12R13 R12 and R13 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group; m is 0, 1, or 2; and η is 0, 1, or 2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising a compound of the formula (II) or a pharmaceutically acceptable salt thereof, Wherein: R1 is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, -C (optionally). 0) 0R9, -〇C(0)R9, -〇(CH2)nC(0)〇R9, ~〇C(〇)NR10Rn' -S(0)nR9' -OSO2R9' -S〇2NR10Rn' -NHC( 0) Substituted by a substituent of R9 or -NR1DRn; 1^ is selected from a hydrogen atom or an alkoxy group; R3, R4, R5 or R6 are each independently selected from a hydrogen atom, an alkyl group or a halogen; and R7 is selected from a hydrogen atom or an alkyl group. ; R 8 is selected from the group consisting of a bicycloalkyl group, a bicyclohetero group, a bridged cycloalkyl group, a bridged heterocyclic group, 95165 3 201229047 a monospirocycloalkyl group, a monospiroheterocyclic group, wherein the bicycloalkyl group, a biheterocyclic group, a bridge The cycloalkyl, heterobridged cycloalkyl, monospirocycloalkyl or monospiroheterocyclyl is further further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, cycloalkane. Base, heterocyclic group, aryl group, heteroaryl group, _C(〇)〇R9, -〇C(0)R9,-0(CH2)mC(0)0R9,-0(χ0)ΝΚιγι, carbonyl, -S (0) Substituted by nR9, -〇S〇2R9, -SOWR, 11, -NHC(0)R9 or -NlTR11; or, R7 R8 together with its attached nitrogen atom form a 5 to 14 membered diheterocyclyl, bridged heterocyclyl or monospiroheterocyclyl, wherein the biheterocyclyl, bridged heterocyclyl or monospiroheterocyclyl is further desired One or more selected from the group consisting of an alkyl group, an alkoxy group, a ketone group, a thiol group, a cyano group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(〇)〇R9,- 〇C(〇)R9, -0(CH2)mC(0)0R9, -OCCOMR1. ?11, substituted by a substituent of a carbonyl group, -S(0)nR9, -〇S〇2R9, -S〇2NR1QRu, -NHC(0)R9 or -NR1QRn; R9 is selected from a hydrogen atom, an alkyl group, a cycloalkane Or an aryl group, wherein the alkyl group, the cycloalkyl group or the aryl group is further substituted with one or more amine groups as needed; R1() or R11 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, or a heterocyclic group. a cycloalkyl, aryl or heteroaryl group, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, Cyano, nitro, cycloalkyl, heterocyclic, -C(0)〇R9, -〇C(0)R9, -〇(CH2)mC(0)OR9, -0C(0)NR12R13, -S (0) Substituted by nR9, -〇S〇2R9, -S〇2NR12R13, -NHC(0)R9 or -NR12R13; 4 95165 201229047 Alternatively, R111 and R11 together with the nitrogen atom to which they are attached form 3 to 8 members Heterocyclyl, wherein the 3 to 8 membered heterocyclic group contains one or more N, 0 or S(0) n atoms, and the 3 to 8 membered heterocyclic group is further selected by one or more From alkyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy Cyano, carbonyl, a c(〇)〇R9, a 〇c(〇)R9, -0(CH2)mC(0)0R9, -0C(0)NR12R13, -S(0)nRg, _os〇2R9, Substituting -SO2NR R, -NHC(0)R9 or -NR12R13; R12 and R13 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group; m is 0, 1 or 2; It is 0, 1, or 2. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from aryl, wherein the aryl group is further selected from one or more selected from the group consisting of alkyl, alkoxy, and halogen. , hydroxy, cyano, nitro, -C(0)〇R, -〇C(0)R9, -〇(CH2)mC(0)〇R9' -〇C(O)NR10Rn ' -S(〇) Substituted by a substituent of nR9, -〇S〇2R9, -SiMRl11, -NHC(〇)R9 or -NR1%11; πι,η,R9 to R11 are as defined in claim j. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 is an aryl group further substituted with one or more alkyl or halogen as needed. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group, and R is selected from a bicyclic or diheterocyclic group, wherein the bicycloalkyl or biheterocyclic group is Need to be further selected by one or more selected from 95165 5 201229047, ~c(〇)OR9, Anthracenyl, oximeoxy, arginyl, thiol, aryl, nitro, carbonyl, -0C(0)R1 &gt; -0(CH2)mC(0)0R1 ^ -〇C(〇: -〇S 〇2R1, -S〇2NRl〇Ru, _mc(〇)r94_ are substituted; m, n, R1 to r2 are as defined in the scope of claim 2, as described in claim 1 A pharmaceutically acceptable oxime, wherein R3 is selected from the group consisting of a ruthenium group, and R4 is selected from the group consisting of a bicyclooctyl or azabicyclooctyl group, wherein the bicyclooctyl or azabicyclooctyl group is required to be one or more Selected from alkyl, alkoxy, dentate, hydroxy, cyano, nitro, carbonyl, -C(0)0R1, _oc(〇)R1, -〇(CH2)mC(0)OR1, -〇C (O)NR5Rn . -S(0)nR1' -〇s〇2R1' -S〇2NR5Rn' -Substitution of NHC(0)R1 or -NCR2; m,η,R1 to R2 are as defined in the patent application Wherein the cyclic alkyl or biheterocyclyl group of the formula 6 wherein the bicycloalkyl or biheterocyclic group is further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, a heterocyclic group, and a halogen , 2 -o(ch2)x(o)or1, -〇C(〇)NRl°Rl1, _S(0)nR9, -〇s〇2R9, 3 as in the scope of claim 6 The compound or a pharmaceutically acceptable salt thereof, wherein the bicyclooctyl or azabicyclooctyl group is further substituted by one or more alkyl or hydroxyl groups as needed. 4 as described in claim 1 a compound or a pharmaceutically acceptable salt thereof, wherein R3 and R4 together with the nitrogen atom to which they are attached form a 5- to 5-membered bis 5-hydroxy, cyano, nitro, carbonyl, _C(0)0R9, _oc(〇)r9, 201229047 -SChNRl11, substituted with a substituent of -NHC(0)R9 or -NR1QRn; m, η, R9 to R11 are as defined in claim 1 of the patent application. 9. As described in claim 1 Or a pharmaceutically acceptable salt thereof, wherein R7 and R8 together with the nitrogen atom to which they are attached form a bicyclooctane or azabicyclooctane, wherein the bicyclooctyl or azabicyclooctyl group is further required to be further A plurality of selected from the group consisting of alkyl, alkoxy, heterocyclic, halogen, hydroxy, cyano, nitro, carbonyl, -C(0)0R9, -0C(0)R9, -0(CH2)mC(0) 0R9 ' -〇C(O)NR10Rn ' -S(0)nR9 ' -OSO2R9 '-S〇2NR1QRn, substituted with a substituent of -NHC(0)R9 or -NR1QRn; m,η,R9 to R11 are as defined The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the bicyclooctyl or azabicyclooctyl group is further required to be further one or A plurality of substituents selected from the group consisting of a hydroxyl group, -0C(0)R9 or -NfR11 are substituted. 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 7 95165 201229047 12. A method of preparing a compound according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: (IA) (I) 8 95165 201229047 Under basic conditions, a compound of the formula (ΙΑ) is reacted with a gas phthalate and then reacted with an amine of the formula NHR7R8 to give a compound of the formula (I); wherein A, D, X The definitions of R1 to R8 are as described in item 1 of the patent application. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier or excipient thereof. A method for modulating catalytic activity of a protein kinase, which comprises contacting the protein kinase with the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 13 The protein kinase is selected from the group consisting of c-Met and the VEGFR receptor tyrosine kinase. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a protein kinase-related disease, wherein the protein kinase is selected from the group consisting of c-Met and VEGFR receptors. · Aminic acid kinase. 16. The use of a pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a protein kinase-related disease, wherein the protein kinase is selected from the group consisting of c-Met and VEGFR receptor tyrosine Kinase. A pharmaceutical composition for treating a disease associated with a protein kinase, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, wherein the protein The kinase is selected from the group consisting of c-Met and the VEGFR receptor tyrosine kinase. 18. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of cancer 9 95165 201229047. 19. Use of the medicament described in claim 13 for the treatment of cancer. ...in the case of I. Claims 18 or 19 of the patent application are lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. The compound described in the above item (4), or a pharmaceutically acceptable salt thereof, is a medicament for treating cancer. 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. 3. The pharmaceutical composition according to claim 13, which is a medicament for treating cancer. The pharmaceutical composition according to claim 23, wherein the cancer is lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. 95165 10 201229047 ' IV. Designated representative map: There is no schema in this case (1) The representative representative figure of this case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 3 95165