WO2011095045A1 - Pyridinone amide derivatives, preparation methods and medical uses thereof - Google Patents

Abstract

Provided are pyridinone amide derivatives, preparation methods and medical uses thereof. Particularly, novel pyridinone amide derivatives of formula (I) and pharmaceutical acceptable salts thereof, and uses thereof as therapeutic agents (especially as c-Met protein kinase inhibitors) are provided, wherein the substituents of formula (I) are defined as same as the description.

Description

 Pyridone amide derivative, preparation method thereof and application thereof in medicine

 The present invention relates to a novel pyridone amide derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same and its use as a therapeutic agent, particularly as a c-Met protein kinase inhibitor. Background technique

 As a basic regulatory mechanism of cells, signal transduction 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 poorly acidify 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 (1) the ErbB (Her) family, including EGFR (Her-1), Her-2, Her-3, Her-4; (2) the insulin receptor family, including Insulin receptor IR, insulin-like growth factor I receptor (IGF1 R), etc.; (3) 111 family, including platelet-derived growth factor receptor PDGFR, stem cell factor SCFR (c-Kit) and the like. In addition, the hepatocyte growth factor receptor (HGFR, also known as "c-Met"), and the vascular endothelial growth factor receptor VEGFR belong to the RTKs family. They act as signal transmitters and play a key role in regulating cell proliferation and differentiation. (Schlessinger and Ullrich, Neuron 1992, 9, 383).

 Hepatocyte growth fator (hereinafter referred to as "HGF'), also known as Scatter factor (SF), is a pleiotropic growth factor that induces cell mitosis and tissue life activities, and can enhance cancer growth. HGF can also promote metastasis by stimulating cell motility and infiltration by various signaling pathways. To produce these cellular effects, it must act by binding its receptors, see Maggiora et al., J. Cell. Physiol. 173: 183-186, 1997.

Hepatocyte growth factor receptor (HGFR), also known as "c-Met", is a receptor-type tyrosine kinase. The molecular weight of the glycosylated mature receptor is 190kD. A heterodimer linked by a 50 kD extracellular alpha subunit to a 145 kD transmembrane beta subunit by a disulfide bond (Μ Park et al, Pro 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 et al., Oncology Reports, 5: 1013-1024, 1998). It is generally believed that among the above tumor cells, high expression of c-Met is closely related to various features of malignant tumors (including abnormal proliferation, infiltration, or hyperfunction of metastasis:). Under the mediated by HGF, the tyrosine residue in the c-Met cell region is autophosphorylated, and activates a signaling pathway regulating cell proliferation to promote cancer cell growth. In addition, it has been reported that c-Met is also expressed in vascular endothelial cells, and C-Met regulates tumor angiogenesis by promoting proliferation and migration of vascular endothelial cells (Advance in Cancer Research, 67:257- 279, 1 995).

 Therefore, a compound having an action of inhibiting c-Met kinase activity is expected to be an antitumor agent, an angiogenesis inhibitor or a cancer cell metastasis inhibitor.

 Another important member of RTKs is the vascular endothelial growth factor receptor (VEGFR). VEGFR is directly involved in the process of angiogenesis, which induces proliferation and migration of endothelial cells, promotes capillary formation, and forms a network of super-osmotic immature blood vessels that provide nutrients for tumor growth. In addition to pro-angiogenic activity, VEGFR and VEGF promote tumor growth directly in tumor cells via pro-survival mechanisms. Through research, it has been found that VEGFR is overexpressed in various malignant solid tumors, such as lung cancer, breast cancer, ovarian cancer, pancreatic cancer and melanoma. Therefore, inhibition of tumor growth by inhibiting VEGFR activity is very important for tumor treatment. Value.

 It has been reported in the literature that biological agents targeting 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 US Pat). No. 6,214,344, 2001). HGF antagonist peptide NK4 inhibits cancer cell infiltration by blocking HGF-HGFR interaction, inhibiting tumor angiogenesis ΟδπΥ Journal of Cancer, 84:864-873, 200] and Owcer & . , 94:321 -327, 2003), However, due to the large molecular weight and poor bioavailability of peptides, it is difficult to develop a drug. It is urgent to develop a new class of small molecule c-Met inhibitors with high activity and low toxicity. To date, 巳 has publicly reported the use of a series of patents for small molecule c-Met inhibitors, including bulky hydrophobic group-substituted derivatives (see patents WO2006116713 and WO2005117867, etc.). ― .

 At present, no small molecule c-Met protein kinase inhibitor is marketed, and it is an object of the present invention to provide a drug having c-Met inhibitory activity and which can be used for the treatment or mitigation 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), as well as their tautomers, enantiomers, diastereomers, Racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or

 among them:

A is selected from -CR ^a or N;

D is selected from -CR ^b or N; X is selected from -CR ^e - or N;

R ^{1 is} selected from aryl or heteroaryl, wherein the aryl or heteroaryl is optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, halogen, hydroxy, cyano, nitro, -C (0)OR ⁹ , -0C(0)R ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ , -OC^NR^R ^{1 1} , -S(0) _N R ⁹ , -OS0 ₂ R _{^{9, -SO 2 NR 10 R "}} , -NHC (0) R 9 or -NR '^ R ^{1 1} group is substituted with a substituent;

R ^a , R ^b , or R ^{2 is} selected from independently selected from a hydrogen atom, an alkyl group, an alkoxy group or an aryl group;

R ³ , R ⁴ , R ⁵ or R ⁶ are each independently selected from a hydrogen atom, a fluorenyl group or a halogen;

R ^{7 is} selected from a hydrogen atom or a fluorenyl group, wherein the fluorenyl group is optionally substituted with a substituent of a halogen or an alkoxy group;

R ^{8 is} selected from the group consisting of a bicycloindenyl group, a bicyclic heterocyclic group, a bridged cycloalkyl group, a bridged heterocyclic group, a spirocyclic fluorenyl group or a spiroheterocyclic group, wherein the bicyclononyl group, the diheterocyclic group, the bridged fluorenyl group, The bridged heterocyclyl, spirocyclinyl or spiroheterocyclyl is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, cyclodecyl, heterocyclyl, aryl Base, heteroaryl, carbonyl, -C(0)OR ⁹ , -OC(0) ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ -OC(O)NR ¹⁰ R , -S(0) Substituted by a substituent of _N R ⁹ , —OS0 ₂ R ⁹ , —SO ₂ NR ¹⁰ R ^N —NHC(0)R ⁹ or —NR ^R ^{1 1} ;

Alternatively, R ⁷ and R ⁸ together with the N atom to which they are bonded form a 5 to 14 membered bicyclic heterocyclic group, a bridged heterocyclic group or a spiroheterocyclic group, wherein said biheterocyclic group, bridged heterocyclic group or spirohetero The cyclic group is optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, halogen, hydroxy, cyano, nitro, carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0 )OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ , -OC(O)NR ^{10 N} , -S(0),,R ⁹ , - OS0 ₂ R ⁹ Substituted with -SO ₂ NR ¹⁰ R ^N . -NHC(0)R ⁹ or -NRWR ¹¹ ;

R ^{9 is} selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group or an aryl group, wherein the alkyl group, cyclodecyl group or aryl group is optionally further substituted with one or more amino groups;

R ^{1 ()} or R′ ¹ are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the cycloalkyl group, the heterocyclic group, the aryl group aryl or heteroaryl group is optionally further substituted by one or more groups selected from the embankment, embankment alkoxy, halogen, hydroxy, cyano, nitro, alkyl with cycloalkyl, ^{heterocyclyl, -C (0) 0R 9,} -OC ( 0) R ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ , -OC(0)NR ¹² R ^{L 3} , -S(0) _N R ⁹ , -OS0 ₂ R ⁹ , - S0 ₂ NR ¹² Substituted by a substituent of R ¹³ , —NHC(0)R ⁹ or —NR ¹² R ¹³ ;

Alternatively, R ¹⁽⁾ and R ^{1 1} together with the nitrogen atom to which they are bonded form a 3 to 8 membered heterocyclic group, wherein the 3 to 8 membered heterocyclic ring further contains one or more N, 0 or S(0) „Atom, and the 3 to 8 membered heterocyclic ring is optionally further selected from one or more selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, carbonyl, cyclodecyl, heterocyclyl, aryl Base, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , - 0(CH ₂ ) _M C(0)OR ⁹ , -OC(0)NR ¹² R ¹³ , -S(0 _{^{) N R 9, -OS0 2 R}} 9, -S0 2 NR 12 R 13, -NHC (0) R 9 or -NR ¹² R ^13, substituted with a substituent;

R ¹² and R ¹³ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group;

 m is 0, 1 or 2;

n is 0, 1, or 2. A preferred embodiment of the invention is a compound of the formula (II) or a pharmaceutically acceptable salt thereof,

 (") among them:

R' is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further selected from one or more selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, -C (0)OR ⁹ , -OC(0)R ⁹ , - 0(CH ₂ ) _m C(0)OR ⁹ , -OC(O)NR ^{l 0} R ⁿ , -S(0) _n R ⁹ , -OS0 Substituting a substituent of ₂ R ⁹ , -SChNR' OR ^{1 1} , -NHC(0)R ⁹ or -NR^R ¹¹ ;

R ^{a is} selected from a hydrogen atom or an alkoxy group;

RR ⁴ , R ⁵ or R ⁶ are each independently selected from a hydrogen atom, a fluorenyl group or a halogen;

R ^{7 is} selected from a hydrogen atom or an alkyl group;

R ^{8 is} selected from the group consisting of a bicyclic fluorenyl group, a bicyclic heterocyclic group, a bridged fluorenyl group, a bridged heterocyclic group, a monospirocyclic fluorenyl group, a monospiroheterocyclic group, wherein the bicyclic fluorenyl group, the heterocyclic group, the bridge Cyclodecyl, heterobridged cycloalkyl, monospiroindolyl or monospiroheterocyclyl optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, fluorene , heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _m C(0)OR ⁹ , -OC(O)NR ¹⁰ R ⁿ , a carbonyl group, -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ¹⁰ R ¹¹ , a substituent substituted with -NHC(0)R ⁹ or -NR' OR ^{1 1} ;

Alternatively, R ⁷ and R ⁸ together with the nitrogen atom to which they are bonded form a 5- to 14-membered bicyclic heterocyclic group, a bridged heterocyclic group or a monospiroheterocyclic group, wherein said biheterocyclic group, bridged heterocyclic group or The monospiroheterocyclyl optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, cyclodecyl, heterocyclo: aryl, heteroaryl, -C (0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _m C(0)OR ⁹ , -OC C NR' OR^carbonyl, -S(0) _n R ⁹ , -OS0 ₂ R _{^{9, -SO 2 NR 10 R 11}} , -NHC (0) R 9 or -NR ^{1 Q} R ^1] the substituents;

R ^{9 is} selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group or an aryl group, wherein the alkyl group, cycloalkyl group or aryl group is optionally substituted with one or more amino groups;

R ^1Q or R ¹¹ are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group Further optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, cyclodecyl, heterocyclyl, -C(0)OR ⁹ , -OC(0)R ⁹ , - 0(CH ₂ ) _m C(0)OR ⁹ , - OC(0)NR ¹² R ¹³ , -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -S0 ₂ NR ¹² R ¹³ , - Substituted by a substituent of NHC(0)R ⁹ or -NR ¹² R ¹³ ;

Alternatively, R ^IQ and R ¹¹ 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, 0 or S(0) _n atoms, And the 3 to 8 membered heterocyclic group is optionally further selected from one or more selected from the group consisting of a decyl group, an alkoxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen, a hydroxyl group, and a cyanogen group. Base, carbonyl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(C3⁄4) _M C(0)OR ⁹ , -OC(0)N ¹² R ¹³ , -S(0) _N R _{^{9, -OS0 2 R 9, -S0}} 2 NR P - R 13, -NHC (0) R 9 or -NR ¹² R ^13, substituted with a substituent;

R ¹² and R ¹³ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group;

 m is 0, 1 or 2;

n is 0, 1, or 2. A preferred embodiment of the invention, a compound of the formula (II), wherein R ¹ is an aryl group, or a pharmaceutically acceptable salt thereof, wherein the aryl group is further further selected from one or more selected from the group consisting of thiol groups, Alkoxy, halogen, hydroxy, cyano, nitro, -C(0)OR ⁹ , -OC(0)R ⁹ , - 0(CH ₂ ) _M C(0)OR ⁹ , -OC(O)NR ¹⁰ R - S(0) _N R ⁹ ,

Substituted with a substituent of -OSO ₂ R ⁹ , -SO ₂ NR ^{, 0} R" , -NHC(O)R ⁹ or -NR ^R ¹¹ ; preferably a further substituted by one or more mercapto or halogen A preferred embodiment of the present invention, which is a compound of the formula (I), wherein R ^{7 is} selected from an alkyl group, and R ^{8 is} selected from a bicyclic indenyl group or a diheterocyclic group, wherein bicyclic alkyl or bis-described heterocyclyl optionally further substituted by one or more groups selected from the embankment, embankment group, a halogen, a hydroxyl group, a cyano group, a nitro group, a carbonyl ^{group, -C (C oR 9, -OC} (0 R ⁹ , -0(C3⁄4) _M C(0)OR ⁹ , -OC(O)NR ^{, 0} R ^N , - S(0) _N R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ¹⁰ R' Substituting a substituent of NHC(0)R ⁹ or -NR ^R ^{1 1} ;

m, n, ⁹ to !^ ¹ 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 R ^{7 is} selected from the group consisting of fluorenyl, and R ^{8 is} selected from the group consisting of bicyclooctyl or azabicyclooctyl, wherein the bicyclic ring oct-azabicyclo oct-alkyl with or alkyl with optionally further substituted with one or more substituents selected from alkyl, embankment group, a halogen, a hydroxyl group, a cyano group, a nitro group, a carbonyl ^{group, -C (0) oR 9,} - OC (0) R 9 , -0(CH ₂ ) _M C(0)OR ⁹ . -OC(O)NR ^L0 R' ¹ , -S(0) _N R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ^{, 0} R ^U , Substituting a substituent of -NHC(0)R ⁹ or -NRWR ¹¹ ; said R ⁸ is preferably further substituted with one or more mercapto or hydroxy groups;

m, n, ! The definition of the ruler ¹¹ is as described in the general formula (I). A preferred embodiment of the invention, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ together with the nitrogen atom to which they are bonded form a 5 to 14 membered bicycloalkyl group or a double hetero a cycloalkyl group, wherein said bicycloalkyl or biheterocyclyl group is further further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclyl, halogen, hydroxy, cyano, nitro, carbonyl, -C (0)OR ⁹ , -OC(0)R ⁹ , -0(C3⁄4) _M C(0)OR ⁹ , -OC(O)NR ¹⁰ R ^{] 1} , -S(0)„R ⁹ , -OS0 ₂ Substituting a substituent of R ⁹ , —SO ₂ NR ¹⁰ R ^{1 1} , —NHC(0)R ⁹ or —NR^R ^{1 1} ;

m, n, ! The definition of ^~ ¹¹ is as described in the general formula (I). A preferred embodiment of the invention, a compound of the formula (I), or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a bicyclooctyl or azabicyclooctane, wherein The bicyclooctyl or azabicyclooctyl group is optionally further further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclyl, halogen, Hydroxy, cyano, nitro, carbonyl, -C(0)OR ⁹ -OC(0)R ⁹ -0(CH ₂ ) _m C(0)OR ⁹ -OC(O)NR ¹⁰ R' -S(0 _n R ⁹ -OS0 ₂ R ⁹ -SO ₂ NR ¹⁰ R' \ -NHC(0)R ⁹ or -NR^R ^{1 1} substituted by a substituent; mn R'j R ^{1 1} is as defined in the formula ( Said in I). A preferred embodiment of the invention, a compound of the formula (II), or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a bicyclooctane or azabicyclooctane, Further selected by one or more substituents selected from the group consisting of hydroxy, -OC(0)R ⁹ or -NR ^{1 Q} R";

The definition of mn, R ⁹ !^ is as described in the general formula (I). The compound of the formula (I) may contain an asymmetric carbon atom and may therefore exist in the form of an optically pure diastereomer, a mixture of diastereomers, a diastereomeric racemate, a mixture of diastereomeric racemates. Or exist as a meso compound. The invention includes all of these forms. Mixtures of diastereomeric mixtures, 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:

环戊 M吡咯 -2-甲酰胺

Cyclopentyl Mpyrrole-2-carboxamide

,

 ^^ Entering people ■

 (3-Fluoro-4-{2-[3-methyl-3-((3a 6aS)-2-methyl-octahydro-cyclopenta[c]pyrrole-5α-yl)-ureido]-pyridine- 4-yloxy}-phenyl)-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine

 -3-carboxamide

^H

 (3a ?,6aS)-[4-(2-Fluoro-4-{[l-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide] -amino}-phenoxy)-pyridin-2-yl]-5-(4-methyl-piperazin-1-yl)-hexahydro-cyclopentane

 [c]pyrrole-2-carboxamide

. . . Χί ^Ν χ

(3a/?,6a5 [4-(3-Fluoro-4-{[l-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamido] - Amino}-phenoxy)-pyridin-2-yl]-5-(4-methyl-piperazin-1-yl)-hexahydro-cyclopentyl

 |c]pyrrole-2-carboxamide

丄

(3ai?,6a5)-[4-(3-Fluoro-4-{[1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-bipyridine-3-carboxamide ]-amino}-phenoxy)-pyridin-2-yl]-5β-hydroxyhexahydro-cyclopenta[c]pyrrole-2-carboxamide

(2-Fluoro-4-{2-[3-methyl-3-((3ai?,6aS 2-methyl-octahydro-cyclopenta[c]pyrrole-5a-yl)-ureido]-pyridine- 4-yloxy}-phenyl)-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridinium

-3-carboxamide

 N-(2,5-Difluoro-4-(2-(3-((3a 6aS)-5p-hydroxy octahydrocyclopentadienyl-2β-yl)-3-methylureido)pyridine-4 -yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-hydropyridine

 -3-carboxamide

(3aR, 6a5)-N-(4-(2-anally 4-(l-(4-fluorophenyl)-2-oxo-1,2-dihydroxypyridine-3-carboxamido)phenoxy Pyridin-2-yl)-5β-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

 Ν-(2-Fluoro-4-(2-(3-((3a7?,6aS)-5P-hydroxy octahydrocyclopentadienyl-2β-yl)-3-methylureido)pyridine-4- Benzyl)phenyl)-1 -(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

, c~ ^H

 (3a5, 6ai?)- N-(4-(2-Fluoro-4-(1 -(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide)phenoxy Pyridin-2-yl)-5α-hydroxyhexahydrocyclopenta[c|pyrrole-2(1H)-carboxamide

(3ai?,6aS)-N-(4-(4-(4-ethoxy-l-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide) -2-fluorophenoxy)pyridin-2-yl)-5β-hydroxyhexahydrocyclopenta[c]pyrrole

 -2(1H)-carboxamide

(3ΕΙ5, 6&7?)-Ν-(4-(4-(4-ethoxysuccinyl(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide) - 2 5-difluorophenoxy)pyridin-2-yl)-5β-hydroxyhexahydrocyclopenta[c]pyrrole -2(]H)-carboxamide

^H

(3a5,6a/?)-N-(4-(4-(4-ethoxy-l-(4-fluorophenyl)-2-oxo- 1 ,2-dihydropyridine-3-carboxamide -2,5-difluorophenoxy)pyridine-2-yl)-5α-hydroxyhexahydrocyclopenta[ _C ]pyrrole

 - 2-(1)-carboxamide

(3ai?, 6aS)-N-(4-(4-(4-ethoxysuccinyl(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide)- 2-fluorophenoxy) P-pyridin-2-yl)-5α-hydroxyhexahydrocyclopentamolazole

 -2(1H)-carboxamide

. ?

^H

 (3aS, 6ai?)-N-{4-(2,5-Difluoro-4-0(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide) Phenoxy)pyridin-2-yl}-501-light hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

 ,. cross '

(3a 6aS N-(4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbamido)-3- Fluorophenoxy) P-pyridin-2-yl)-5β-hydroxyhexahydrocyclopenta[c]pyrrole

 -2 1H)-carboxamide

(3ai?,6aS 2-((4-(2-fluoro-4-((l-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)- 2- Pyridyl)carbamoyl)-hexahydrocyclopenta[c]pyrrolyl-5β-yl-2-(lH)-aminoacetate 20

 (3a ?,6aS)-2-((4-(2-fluoro-4-((1-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)) 2-pyridyl)carbamoyl)-hexahydrocyclopenta[c]pyrrolyl)-5α-yl-2-(1H)-aminoacetate

twenty one

 η

(3a 6a5 2-((4-(2-fluoro-4-(2-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2-pyridyl) Carbamoyl:)-hexahydrocyclopenta[ _C ]pyrrolyl)-5(x-yl-acetate

 3⁄4. =

. Λ^ ο Λ _Ρ

 People

 twenty two .

 (3^,63^-2-((4-(2-fluoro-4-((1-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)) 2-pyridyl)carbamoyl)-hexahydrocyclopenta[c]pyrrolyl-5-yl-(25)-aminopropionate

Or a pharmaceutically acceptable salt thereof. Further, the present invention relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

在碱性条件下， 通式 (ΙΑ)化合物与氯甲酸酯反应， 再与式 NHR⁷R⁸的胺反应， 得到通式（I )化合物；

Under basic conditions, a compound of the formula (ΙΑ) is reacted with a chloroformate and then reacted with an amine of the formula NHR ⁷ R ⁸ to give a compound of the formula (I);

Wherein A, D, X, R' R ⁸ are as defined in the formula (I). One aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier thereof; Use of the pharmaceutical composition 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 receptor tyrosine kinases; the present invention also provides the pharmaceutical composition Preparation The use in the medicament for treating cancer is preferably the use in the preparation of a medicament for treating lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. Another aspect of the present invention provides a method for modulating catalytic activity of a protein kinase, which comprises contacting the protein kinase with a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, The protein kinase is selected from the group consisting of c-met and VEGFR receptor tyrosine kinases. 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 VEGFR receptor tyrosine kinases. 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 Another aspect of the invention provides a pharmaceutical composition of the compound of formula (I), or a pharmaceutically acceptable salt thereof, containing the compound or a pharmaceutically acceptable salt thereof, for use in the treatment of protein kinases A medicament for a disease, wherein the protein kinase is selected from the group consisting of c-Met and a VEGFR receptor tyrosine kinase. Another aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, containing the compound or A pharmaceutical composition of a pharmaceutically acceptable salt thereof for use as a medicament for treating cancer, preferably as a medicament for treating lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. Another aspect of the present invention is to provide a compound of the formula (I) or Use of a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer, preferably for the preparation of a medicament for treating lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. The compound of the present invention can be used for treating tumor shape , 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 marrow system hematopoietic tumors (including acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia); mesenchymal-derived tumors (including fibrosarcoma and rhabdomyosarcoma and other sarcomas) For example, soft tissue sarcoma and osteosarcoma; central and peripheral sacral system tumors (including astrocytoma, neuroblastoma, glioma, and nerve endings); and other tumors (including malignant melanoma, spermatogonium) Cell tumors, teratocarcinoma, thyroid follicular carcinoma and Kaposi's sarcoma, etc.).

 Preferably, the compounds of the invention are used to treat lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, lozenges, ingots A suspension of the agent, water or oil, a dispersible powder or granule, an emulsion, a hard or soft capsule, or a syrup or elixir. Oral compositions can be prepared according to any method known in the art for preparing a pharmaceutical composition, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.

 It is also possible to use hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium 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 paraffin 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, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents can be naturally occurring a phospholipid such as egg pity, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of an epoxy oxime with a long chain fatty alcohol, such as heptadecyl ethyleneoxy cetyl wax An alcohol (heptadecaethyleneoxy cetanol), or a condensation product of epoxy oxime with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitan monooleate, or oxirane with a fatty acid and a hexitol anhydride A condensation product of a derivatized partial ester, such as a poly(ethylene oxide sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavoring agents 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 suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.

 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 sweeteners, flavoring agents, and coloring agents can 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 lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, 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.

 The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable 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 lecithin. The oil solution is then added to a mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the patient's bloodstream by local injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous pump.

 The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution prepared in 1,3-butanediol. In addition, sterile fixed oils can be conveniently employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be prepared as an injection.

 The compounds of the invention may be administered in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug. Such materials include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

 As is well known to those skilled in the art, the dosage of the drug depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; alternatively, the preferred mode of treatment such as the mode of treatment, the daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt It can be verified according to traditional treatment options. Detailed description of the invention

 Terms used in the specification and claims have the following meanings unless stated to the contrary.

- NHC(0)R⁹或 ¹⁰!^ ¹。 "Mercapto" refers to a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. A mercapto group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group, a t-butyl group or a pentyl group or the like is preferable. More preferred are lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The fluorenyl 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 a decyloxy group, a halogen group, a hydroxyl group, a nitro group, a cyano group, a cycloalkyl group, Heterocyclic group, aryl group, heteroaryl group, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ , -OC(O)NR ¹⁰ R' Carbonyl, -S(0) _N R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ^{, 0} R ^N , -NHC(0)R ⁹ or -NR R^ "Cycloalkyl" refers to a 3 to 8 membered all carbon monocyclic group wherein the 3 to 8 membered all carbon monocyclic ring may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cycloheptatriene, and the like. The cycloalkyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, decyloxy, halo, hydroxy, nitro, cyano, cyclodecyl, heterocyclyl, aryl, hetero Aryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _m C(0)OR ⁹ , -OC(O)NR ¹⁰ R ^{, J} , carbonyl, -S(0 )„R ⁹ , -OS0 ₂ R ⁹ ,

- NHC(0)R ⁹ or ¹⁰ !^ ¹ .

- NHC(0)R⁹或 -NR¹⁰R'】。 "Alkenyl" refers to a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. The alkenyl 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 indenyl group, an alkoxy group, a halogen group, a hydroxyl group, a nitro group, a cyano group, and a ring. Alkyl, heterocyclic, aryl, heteroaryl, -CD)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _m C(0)OR ⁹ , -OC^NR^ ¹¹ , carbonyl , -S(0) _n R ⁹ , -OS0 ₂ R ⁹ ,

- NHC(0)R ⁹ or -NR ¹⁰ R'].

"Alkynyl" means a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. The alkynyl 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 a fluorenyl group, an alkoxy group, a halogen group, a hydroxyl group, a nitro group, a cyano group, and a ring. Alkyl, heterocyclic, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _m C(0)OR ⁹ , -OC(0)NR '°R'], carbonyl, -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ^I0 R" , -NHC(0)R ⁹ or -NR^R ¹

"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 n is an integer from 0 to 2) heteroatoms, the remaining ring atoms are carbon. These rings may also have one or more double bonds, but none of the rings have a fully conjugated pi-electron system. For example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like, the heterocyclic 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, halogen, hydroxy, nitro, cyano, cyclodecyl, heterocyclyl, aryl, hetero Aryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _m C(0)OR ⁹ , -OC^NR'V . carbonyl, -S(0) _n R ⁹ - OS0 ₂ R ⁹ , -SO ₂ NR ¹⁰ R ^{1 !} , -NHC(0)R ⁹ or -NR^R ¹ ^

 "Bicyclic fluorenyl" means a 5 to 14 membered all-carbon 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 of which Multiple rings may contain one or more double bonds and one ring has a fully conjugated pi-electron system. E.g

-NHC(0)R⁹或 -NR'OR' It is preferably 5 yuan/5 yuan or 5 yuan / 6 yuan bicyclononyl group, more preferably 5 yuan/5 yuan. 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 fluorenyl groups, Alkoxy, halogen, hydroxy, nitro, cyano, cyclodecyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH _{2 M} C(0)OR ⁹ , -OC(O)NR ¹⁰ R ^1J , carbonyl, -S(0) _N R ⁹ , -OS0 ₂ R ⁹ ,

-NHC(0)R ⁹ or -NR'OR'

 "Biheterocyclyl" means a 5 to 14 membered fused ring ("fused" ring system means 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 a hetero atom of S(0)n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the π electronic systems. It is preferably 7 to 0 yuan. E.g

Further, it is preferably a 5-member/5-member or a 5-membered/6-membered bicyclic heterocyclic group, and more preferably 5 member/5 member. 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 fluorenyl, alkoxy, halogen, hydroxy, nitro, cyano, cyclodecyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ , -OC(O)NR ¹⁰ R ^N > carbonyl, - S(0) _N R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ^{, 0} R ^N , -NHC(0)R ⁹ or - NR ¹⁰ !^

 "Bridge ring thiol" means 5 to 14 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The π electronic system of the yoke.

根据组成环的数目可以分为双环、 三环、 四环或多环桥环垸基， 优选为双环、 三 环或四环， 更有选为双环或三环。 桥环烷基可以是取代的或未取代的， 当被取代 时， 取代基优选为一个或多个以下基团， 独立地选自烷基、 垸氧基、 卤素、 羟基、 硝基、 氰基、 环垸基、 杂环基、 芳基、 杂芳基、 -C(0)OR⁹、 -OC(0)R⁹、 -0(CH₂)_MC(0)OR⁹、 -OC^NR^R¹¹ , 羰基、 -S(0)_NR⁹、 - OS0₂R⁹、 -SO₂NR¹⁰R^N . (0 或 -NR'

Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged fluorenyl 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, decyloxy, halogen, hydroxy, nitro, cyano , cyclodecyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ , -OC^NR ^R ¹¹ , carbonyl, -S(0) _N R ⁹ , - OS0 ₂ R ⁹ , -SO ₂ NR ¹⁰ R ^N . (0 or -NR'

"Bridge heterocyclyl" means 5 to 14 members, any two rings sharing two polycyclic groups of atoms which are not directly bonded, these may contain one or more double bonds, but none of the rings have a fully conjugated _π An electronic system wherein one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(0)n (where n is an integer from 0 to 2), and the remaining ring atoms are

Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged fluorenyl 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 fluorenyl, decyloxy, halogen, hydroxy, nitro, cyano, Cyclodecyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ), _N C(0)OR ⁹ , -OC(0 NR ^{1 G} R ^U , carbonyl, -S(0) _N R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ¹⁰ R ^N , -NHC(0)R ⁹ or -NR'.

 "Spirocycloalkyl" means 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. π electronic system. It is preferably 7 to 0 yuan. E.g

The spirocyclic fluorenyl group is classified into a monospirocycloalkyl group, a bispirocyclic fluorenyl group or a polyspirocyclic fluorenyl group, preferably a monospirocycloalkyl group and a bisspirocycloalkyl group, depending on the number of common snail atoms between the ring and the ring. . More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group. The spirocycloalkyl 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, heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ , -OC(O NR ¹⁰ R", carbonyl, -S(0) _N R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ¹⁰ R ^N , -NHC(0)R ⁹ or -NR ^{1 G} R ^U .

 "spiroheterocyclyl" means a polycyclic hydrocarbon of 5 to 14 members sharing a single atom (called a spiro atom) between monocyclic rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (where n It is a hetero atom of the integer 0 to 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 7 to 10 yuan.

根据环与环之间共用螺原子的数目将螺环垸基分为单螺环烷基、 双螺环垸基基或 多螺环垸基， 优选为单螺环垸基和双螺环烷基， 更优选为 4元 /4元、 4元 /5元、 4 元 /6元、 5元 /5元或 5元 /6元单螺杂环基。 螺杂环基可以是取代的或未取代的， 当 被取代时， 取代基优选为一个或多个以下基团， 独立地选自垸基、 烷氧基、 卤素、 羟基、 硝基、 氰基、 环垸基、 杂环基、 芳基、 杂芳基、 -C(0)OR⁹、 - OC(0)R⁹、 -0(C¾)_mC(0)OR⁹、 -OC(O)NR¹⁰R'\ 羰基、 -S(0)„R⁹、 -OS0₂R⁹、 -SO₂NR¹⁰R' -NHC(0)R⁹或 -NR^iaR"。

The spirocyclic fluorenyl group is classified into a monospirocycloalkyl group, a bispirocyclic fluorenyl group or a polyspirocyclic fluorenyl group, preferably a monospirocyclic fluorenyl group and a bisspirocycloalkyl group, depending on the number of common snail atoms between the ring and the ring. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiroheterocyclic group. 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 indenyl group, an alkoxy group, a halogen group, a hydroxyl group, a nitro group, and a cyano group. , cyclodecyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , - OC(0)R ⁹ , -0(C3⁄4) _m C(0)OR ⁹ , -OC(O) NR ¹⁰ R'\ carbonyl, -S(0) „ R ⁹ , —OS0 ₂ R ⁹ , —SO ₂ NR ¹⁰ R′ —NHC(0)R ⁹ or —NR ^ia R”.

 a p-membered/q-membered bicyclic fluorenyl group, a bicyclic heterocyclic group, a monospirocyclic fluorenyl group or a monospiroheterocyclic group, which means two of a bicyclic fluorenyl group, a diheterocyclic group, a monospirocyclic fluorenyl group or a monospiroheterocyclic group. The number of ring atoms of each ring is p and q, respectively, and p or q 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 is 3 to 8 yuan, and the atoms constituting the ring contain one or more N, 0 or S(0) n hetero atoms, and the ring may contain ~ 2 The double bond is a monocyclic or bicyclic non-aromatic ring group, and when a nitrogen atom is contained in the atom constituting the ring, a bond bond may be extended from the nitrogen atom. It is preferably a 4- to 6-membered heterocyclic group, more preferably 5 to 6 members, such as a pyrrolidinyl group, a piperidinyl group or a piperazinyl group. The 3 to 8 membered 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 an indenyl group, a decyloxy group, a halogen group, a hydroxyl group, and a nitro group. , cyano, cyclodecyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , - 0(CH ₂ ) _ni C(0)OR ⁹ , OC(0)NR ¹⁽⁾ R ^{] 1} , carbonyl, -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -SO眞¹⁰ R , -NHC(0)R ⁹ or -NR' c

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated π-electron system (ie, having adjacent pairs) The ring group of a carbon atom is preferably 6 to 10 members such as a phenyl group, a naphthyl group and an anthracenyl group. The aryl 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 indenyl group, a decyloxy group, a halogen group, a hydroxyl group, a nitro group, a cyano group, and a ring. Indenyl, heterocyclic, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , - 0(CH ₂ ) _m C(0)OR ⁹ , -OC(O)NR ¹⁰ R ^{] l} , carbonyl, -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ¹⁰ R' -NHC(0)R ⁹ or -NI^R ¹¹ .

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5- or 6-membered heteroaryl group. For example, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl 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, Cyclodecyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _m C(0)OR ⁹ , -OC(O) NR ^{10 H} , carbonyl, -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -SO2NR ¹⁰ R ⁿ , -NHC(0)R ⁹ or -NR'OR'

 "Aryloxy" means -o-aryl and -o-heteroaryl, and aryl and heteroaryl are as defined above. For example, phenoxy, pyridyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy and the like and derivatives thereof.

"Alkoxy" means -0-(fluorenyl) and -0-(unsubstituted cycloalkyl). For example, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. The methoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from halogen, decyloxy, Hydroxy, amino, cyano, nitro, cycloalkyl or heterocyclic.

 "Light base" means an -OH group.

 "Halogen" means fluoro, chloro, bromo or iodo.

"Amino" means -NH ₂ .

 "Cyano" means -CN.

"" refers to -N0 ₂ .

 "Optional" or "optionally" means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by a thiol group" means that a fluorenyl group may be, but is not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by a thiol group. .

 "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby the biological activity.

m, and n are as defined compound ⁹ ~! ^ ¹ of the general formula (I) in the. Methods of Synthesizing the Compounds of the Invention In order to accomplish the objectives of the present invention, the present invention employs the following technical solutions:

 The preparation method of the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof comprises the following steps:

 (IA)

The compound of the formula (I) is reacted with a chloroformate under basic conditions with an amine of the formula NHR ⁷ R ⁸ 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 chloroformate under basic conditions, such as triethylamine, preferably phenyl chloroformate, and the obtained product is isolated and purified. Thereafter, it is dissolved in hydrazine, hydrazine-dimethylformamide, and further reacted with an amine of the formula NHR ⁷ R ⁸ under triethylamine to give a compound of the formula (I).

Wherein A, D, X, R^R ⁸ are as defined in the formula (1). detailed description

 The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention. Example

 The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm). The NMR was determined by using a Bmker AVANCE-400 nuclear magnetic apparatus. The solvent was deuterated dimethyl sulfoxide (DMSO-t3⁄4, deuterated chloroform (CDCb), internal standard was tetramethylsilane.

The MS was assayed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

 The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The average inhibition rate of the kinase and the IC _5Q value were determined using a NovoStar plate reader (BMG, Germany).

 The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of TLC is 0.15mn! ~ 0.2 mm, thin layer chromatography separation and purification products are available in sizes from 0.4 mm to 0.5 mm.

 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as a carrier.

 The starting materials in the examples of the invention are known and commercially available, or may be synthesized or synthesized according to methods known in the art.

 All reactions of the present invention were carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere without any particular explanation.

 An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

 The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

 There is no particular description in the examples, and the solution means an aqueous solution.

 There is no particular description in the examples, and the reaction temperature is room temperature.

 The optimum temperature for the reaction at room temperature is from 20 ° C to 30 ° C.

 The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The systems used for the reaction were: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, petroleum ether and ethyl acetate systems, The volume ratio of acetone to solvent is adjusted depending on the polarity of the compound.

Column chromatography eluent systems include: A: chloroform and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and ethyl acetate systems, D: ethyl acetate and methanol, The volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water, acetic acid or the like. Example

 (3 6a7?)-NM-(2,5-Difluoro-4-(l-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide)phenoxy Base)

 First step

(3aS, 6ai?)-tert-butyl-5β-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid oxime I (3a^6a-5-oxo-hexahydrocyclopenta[c]pyrrole - 2 (1H) tert-butyl formate l (4.01 g, 17.80 mmol, prepared by the known method "WO2008089636") dissolved in 60 mL of methanol, sodium borohydride (0.74 g 19.60 mmol), reaction 1 The title product (3a5, 6^-5β-) was obtained. The title product was obtained. Hydroxy hexahydrocyclopenta[ _C ]pyrrole-2(1H)-carboxylic acid tert-butyl ester lb (4.02 g, reddish brown liquid), Yield: 99.5%

 First less

 (3ai?,6a5 octahydro-cyclopenta[c]pyrrole-5β-ol

 (3a5,6aW)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2 (1H>tert-butyl formate lb (4.02 g, 17.8 mmol) was dissolved in 50 mL of dichloromethane and cooled to 0. Trifluoroacetic acid (40 mL, 0.53 mol) was added at ° C, and the reaction was carried out at 0 ° C for 1 hour. The mixture was concentrated under reduced pressure. The resulting residue was purified to give the title compound (3a 6aS)- s.

MS m/z (ESI): 128.1 [M+l]

NMR NMR (400 MHz, CD ₃ OD): δ 4.27 (m, 1H), 3.33-3.28 (m, 4H), 3.01 (m, 2H), 2.00 (m, 2H), 1.73-1.69 (m, 2H)

 third step

(3a5, 6ai?)-N-{4-(2,5-Difluoro-4-(l-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide Phenyloxy)pyridin-2-yl}-53-hydroxyhexahydrocyclopenta[ _C ]pyrrole-2(1H)-carboxamide

N-[4-(2-Aminopyridin-4-yloxy)-2,5-difluorophenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydro -pyridine-3-carboxamide Id (95 mg, 0.21 mmol, prepared by the known method "Patent US20050245530") dissolved in 5 mL of tetrahydrofuran, followed by 0.3 mL of triethylamine and phenyl chloroformate (42 0.33 mmol) ), react at 0 ° C for 20 minutes. Pour the reaction solution into 46 mL of ethyl acetate and saturated sodium chloride solution. (V/V=1.8: l) in a mixed solution, the organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. N, N-dimethylformamide and 0.29 mL of triethylamine were reacted for 1 hour, and the crude product was added (3ai?,6a,S octahydro-cyclopenta[c|pyrrole-5-ol lc (112 mg, 0.88 mmol)) The reaction was carried out for 16 hours at 40 ° C. The reaction solution was poured into a mixed solution of 70 mL of ethyl acetate and a saturated sodium chloride solution (V/V = 4:3), and the organic phase was sequentially treated with 1 M sodium hydroxide solution. (30 mL) and a saturated sodium chloride solution (40 mL), EtOAcjjjjjjjjjj 6ai?)-N-{4-(2,5-Difluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)benzene Oxy)pyridin-2-yl}-5^-dia-hexahydrocyclopenta[ _C ]pyrrole-2(1H)-carboxamide 1 (20 nig, pale yellow solid), Yield: 15.0%.

MS m/z (ESI): 606.3 [M+l]

H NMR (400 MHz, OMSO-d ₆ ): 6 12.44 (s, 1H), 8.74 (s, IH), 8.63 (m, 1H), 8.60 (m, 1H), 8.1 7 (m, 2H), 7.61 (m, 3H), 7.51 (m, 1H), 7.44 (m, 2H), 6.77 (m, 1H), 6.45 (ra, 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

(2,5-Difluoro-4-indole-"3-methyl-3-(T3ai?, 6 ₁ ?)-2-methyl-octahydro-cyclopenta"c|pyrrole-5?-yl)-urea Base 1-pyridine- 4-

 First step

(3ai?,6a)-5p-methanesulfonyloxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (3ai?,6aS)-5p-hydroxyhexahydro-cyclopenta[c] Pyrrole-2-carboxylic acid tert-butyl ester lb (9.00 g, 40 mmol) was dissolved in 150 mL of dichloromethane, and methanesulfonyl chloride (4.70 mL, 60 mmol;) and triethylamine (1 1.20 mL) were added at 0 °C. , 80 mmol), react at room temperature for 2 hours. The reaction mixture was poured into a solution of 200 mL of aq. NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Title product (3a7?, 6aS)-5p-methanesulfonyloxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 2a (12.00 g, yellow liquid), yield: 98.4%.

 Second step

 (3a 6a5 5a-azido-hexahydro-cyclopenta [c]pyrrole-2-carboxylic acid tert-butyl ester

(3a 635 5β-methanesulfonyloxy-hexahydro-cyclopenta[ _C ]pyrrole-2-carboxylic acid tert-butyl ester 2a (12.00 g, 40 mmol) was dissolved in 150 mL of hydrazine, hydrazine-dimethylformamide Add sodium azide (6.50 g, 100 mmol), and react at 70-80 ° C for 4 hours. Add 20 mL of water to the reaction solution, extract with ethyl acetate (20 mL><3), combine the organic phase, and saturate The sodium chloride solution was washed (200 mL), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjj _a -Azido-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 2b (8.00 g, yellow liquid), Yield: 79.4%.

 third step

(3ai?,6aS)-5a-amino-hexahydro-cyclopenta[ _C ]pyrrole-2-carboxylic acid tert-butyl ester (3aW,6aS)-5a-azido-hexahydro-cyclopenta[c]pyrrole- 2-tert-Butyl 2-butyrate 2b (3.80 g, 15 mmol) was dissolved in 50 mL of methanol, and palladium/carbon (4.00 g, 10%) was added and reacted for 16 hours. Filtration, the filter cake was washed with 20 mL of methanol, and the filtrate was evaporated to give the title product (3a/?, 6aS 5oi-amino-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

(3aT?, 6aS 5a-acetamido-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester. (3aW, 6aS 5-amino-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-Butyl ester 2c (2.65 g, 1 .7 mmol) was dissolved in 45 mL diethyl ether. Triethylamine (3.26 mL, 23.40 mmol) was added and ethyl chloroformate (1.12 mL, 11.70 mmol) was dissolved at 0 °C. The reaction mixture was added dropwise to 5 ml of diethyl ether and reacted for 1 hour. The reaction mixture was concentrated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with dichloromethane ( 00 mL×3), and the organic phase was combined. dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product _{-5 a (3a, 6a5?)} - acetamido - hexahydro - ring Butyl [ _C ]pyrrole-2-carboxylic acid tert-butyl ester 2d (2.35 g, yellow liquid), Yield: 67.3%.

MS m/z (ESI): 597 [2M+1]

 the fifth step

 (3a^6a5K2-methyl-octahydro-cyclopenta-M-pyrrole-5a-yl)-Methylamine Lithium tetrahydrogenate (1.20 g, 31.50 mmol) was dissolved in 70 mL of tetrahydrofuran, (3a?,6a5 5- Acetylamino-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 2d (2.35 g, 7.88 mmol) was dissolved in 40 mL of tetrahydrofuran, added dropwise to the above reaction solution, and reacted at 40 ° C for 24 hours. 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 under reduced pressure to give the title product (33 635)-(2-methyl-octahydro-cyclopenta[c]pyrrole-5?-yl -Methylamine 2e (700 mg, yellow liquid), Yield: 57.4%.

MS m/z (LC-MS): 155.2 [M+l]

Step 6 (2,5-Difluoro-4-{2-[3-methyl-3-((3aW, 6aS 2-methyl-octahydro-cyclopenta] c]pyrrole-5α-yl)-ureido] - Pyridin-4-yloxy}-phenyl)-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyrazole-3-carboxamide [4-(2- Amino-pyridin-4-yloxy)-2,5-difluoro-phenyl]-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-methyl The amide Id (120 mg, 0.27 mmol) was dissolved in 3 mL of tetrahydrofuran, and 0.29 mL of triethylamine and phenyl chloroformate (125 mg, 0.80 mmol) were added in sequence, and reacted at room temperature for 10 minutes and at 45 ° C for 50 minutes. The liquid was poured into a mixed solution of 60 mL of ethyl acetate and a saturated sodium chloride solution (V/V = 2:), and the organic phase was washed with a saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure. The residue was added 3 mL of hydrazine, hydrazine-dimethylformamide and 0.29 mL of triethylamine for 1 hour, and (3aW, 6aS)-(2-methyl-octahydro- Cyclopentyl [c]pyrrole-5α-yl)-methylamine 2e (163 mg, 1.06 mmol), reacted for 64 hours. The reaction solution was poured into 60 mL of ethyl acetate and saturated sodium chloride solution (V/V = In the mixed solution of 2:l), the liquid phase is separated, and the organic phase is sequentially dissolved in 30 mL of 1 M sodium hydroxide. It was washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated. Difluoro-4-{2-[3-methyl-3-((3aW,6aS 2-methyl-octahydro-cyclopenta[c]pyrrole-5α-yl)-ureido]-pyridin-4-yl Oxyphenyl)-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro41pyridin-3-yl 2 (60 mg, pale yellow solid), Yield: 35.9 %.

MS m/z (ESI): 633 [M+l]

'Η NMR (400 MHz, DMSO- ₆ ): δ 12.44 (s, 1H), 8.83 (s, 1H), 8.64 (m, 1H), 8.59 (m, 1 H), 8.20 (m, 2H), 7.64 (m, 3H), 7.45 (m, 3H), 6.78 (m, 1H), 6.66 (m, 1H), 4.70 (m, 1 H), 2.77 (m, 3H), 2.50 (m, 3H), 2.22 (m, 4H), 2.00 (m, 2H), 1.77 (m, 2H), 1.46 (m, 2H)

Example 3

Ri3ai?,6aSV4-(2,5-difluoro-4-m-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamido-amino

 First step

(3&/?,635 5-(4-Methyl-piperazin-1-yl)-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butylindole I 5-oxo-hexahydro-cyclopenta[ c] pyrrole-2-carboxylic acid tert-butyl ester la (10.00 g, 44.44 mmol) dissolved in 400 mL of dichloromethane, 8.00 g of dried molecular sieve and 1-methyl-piperazine (7.80 mL, 66.67 mmol) , After reacting for 30 minutes, sodium cyanoborohydride (5.58 g, 17.78 mmol) and 60 mL of methanol were added and the reaction was continued for 16 hours. The reaction mixture was concentrated under reduced pressure to give the title product: (3a^,6a^- 5-(4-methyl-piperazine-]-yl)-hexahydro-cyclopentane|c]pyrrole-2-carboxylic acid tert-butyl ester 3a (20.00 g, brown oil), used in the next step without isolation. MS m/z (ESI): 310 [M+1]

 Second

(3a/?,6aS)-5-(4-Methyl-piperazin-1-yl)-octahydro-cyclopenta[ _C ]pyrrole hydrochloride will be crude (3ai?,6a3⁄4-5-(4-A) Tert-butyl-piperazine- 1 -yl)-hexahydro-cyclopenta[c]pyrrole-2-carboxylate 3a (13.73 g, 44.44 mmol) was dissolved in 250 mL of methanol, and 200 mL of a solution of 4.3 M hydrogen chloride in methanol was added. The reaction was concentrated for 2 hr. EtOAc was evaporated.jjjjjjjjjjj - octahydro-cyclopenta[ _C ]pyrrole hydrochloride 3b (9.09 g, white solid;), Yield: 64.2%.

MS m/z (ESI): 210 [M+1]

 Second step

[(3ai?,6a<S 4-(2,5-Difluoro-4-{[1 -(4-fluoro-phenyl)-2-oxo-],2-dihydro-pyridine-3-) Amido]-aminophenoxy)-pyridin-2-yl]- 5-(4-methyl-piperazin-1-yl)-hexahydro-cyclopenta[ _C ]pyrrole-2-carboxamide [4 -(2-amino-pyridin-4-yloxy)-2,5-difluoro-phenyl]-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P The pyridine carboxamide Id (100 mg, 0.22 mmol) was dissolved in 4 mL of tetrahydrofuran, and 0.3 mL of triethylamine and phenyl chloroformate (83 L, 0.66 mmol) were added in sequence, and the reaction was carried out for 3.5 hours. The mixture was added to a mixed solution of 60 mL of ethyl acetate and a saturated sodium chloride solution (V/V = 2:1), and the organic phase was washed with saturated sodium chloride solution (20 mL), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure. 4 mL EtOAc, dimethyl-dimethylformamide and 1 mL of triethylamine and (3a^,6aS)-5-(4-methyl-piperazines) - octahydro-cyclopenta[c]pyrrole hydrochloride 3b (280 mg, 0.88 mmol), reaction for 16 hours. Pour the reaction solution into 60 mL of ethyl acetate and 20 mL of saturated sodium chloride solution (V/V = 2 :1) In a mixed solution, the liquid phase is separated, and the organic phase is sequentially saturated with 1 M sodium hydroxide solution (20 mL). The sodium chloride solution was washed (10 mL×2), dried over anhydrous sodium sulfate, filtered, filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjj 4-(2,5-difluoro-4-{[1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridyl-3-carboxamido]-amino Phenoxy;)-pyridin-2-yl]-5-(4-methyl-piperazin-1-yl)-hexahydro-cyclopenta[c]pyrrole-2-carboxamide 3 (45 mg, light yellow Solid), Yield: 29.8%.

 S m/z (ESI): 688 [M+1]

NMR NMR (400 MHz, DMSO-J ₆ ): 812.45 (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-ί2-"3-methyl-3-((3ai?,6a V2-methyl-octahydro-cyclopenta"c!pyrrole-5α-yl)-ureido 1-pyridine-4 -yloxyphenyl)-1-(4-fluoro-phenyl)-2-oxo-U-dihydro-pyridine-3-carboxyamide

 First step

 [4-(2-Fluoro-4-{[l-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridin-3-carbonyl]-aminophenoxy)- Pyridin-2-yl]-aminodicarboxylate

 [4-(2-Amino-pyridin-4-yloxy)-3-fluoro-phenyl]-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine -3-carboxamide 4a (217 mg, 0.50 mmol, prepared by the known method "US20050245530") dissolved in 4 mL of tetrahydrofuran, added with triethylamine (152 mg, 1.50 mmo) and phenyl chloroformate (235) Nig, 1.50 mmol), react for 10 minutes. Add 20 mL of ethyl acetate to the reaction solution, and wash with 1 M sodium hydroxide solution (10 mL), water (10 mL) and saturated sodium chloride solution (10 mL), dry over anhydrous magnesium sulfate, The filtrate was concentrated to give the title product [4-(2-fluoro-4-{[1 -(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridin-3-carbonyl] -Amino}-phenoxy)-pyridin-2-yl]-aminodicarboxylic acid diphenyl ester 4b (387 mg, pale yellow solid) was used in the next step without isolation.

 Second step

 (3-Fluoro-4-{2-[3-methyl-3-((3a 6a5 2-methyl-octahydro-cyclopenta[c]pyrrole-5ct-yl)-ureido]-pyridine-4- Benzyl}-phenyl)-]-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide crude [4-(2-fluoro-4- {[1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridyl-3-carbonyl]-aminophenoxy)-pyridin-2-yl]-aminodicarboxylic acid Diphenyl ester 4b (387 mg, 0.57 mmol) was dissolved in 4 mL of N,N-dimethylformamide, triethylamine (303 mg, 3 mmol) and (3ai?,6a5)-(2-methyl - octahydro-cyclopenta[c]pyrrole-5-yl)-methylamine 2e (308 mg, 2 mmol), reaction for 16 hours. Add 30 mL of a mixed solvent of ethyl acetate and water (V/V = 2:1 The organic phase was washed with 1 M sodium hydroxide solution (10 mL), water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue obtained was purified by column chromatography eluting to afford the title product (3-fluoro-4-{2-[3-methyl-3-((3ai?,6aS)-2-methyl-octahydro) -cyclopenta[c]pyrrole-5(x-yl)-ureido]-pyridin-4-yloxy}-phenyl)-1-(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+1]

1H NMR (400 MHz, CDC1 ₃ ): δ 11.95 (s, 1 Η), 8.75 (m, 1H), 8.04 (d, 1H), 7.98 (d, 1H), 7.68 (dd, 1H), 7.62 (m, (H, 5H) (s, 3H), 2.11 (m, 2H), 1.72 (m, 2H), 1.61 (m, 2H) Example 5

Aj?,6a>$ ^f )-"4-(2-Fluoro-4-m-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-"I-pyridine-3- Amido-1-amino}-phenoxy)-(4-methyl-piperazine small group)-hexahydro-cyclopenta"c!pyrrole-2-carboxamide

将 [4- (2-氟 -4- {[1-(4-氟-苯基) -2-氧代 -1,2-二氢 -P比啶- 3-羰基] -氨基 } -苯氧基) -吡 啶 -2-基] -氨基二甲酸二苯酯 4b (312 mg, 0.46 mmol )溶于 4 mL Ν,Ν-二甲基甲酰胺 中， 加入三乙胺 (280 mg, 2.76 mmol)和 (3& 60^-5-(4-甲基-哌嗪 -1-基)-八氢-环戊 [c] 吡咯盐酸盐 3b (586 mg,】 .84 mmol), 反应 16小时。加入 30 mL乙酸乙酯和水的混 合溶剂 (V/V=2: l)， 分液， 有机相依次用 1M氢氧化钠溶液 (10 mL)、 水 （10 mL)和 饱和氯化钠溶液洗漆 (10 mL)， 无水硫酸镁干燥， 过滤， 减压浓缩滤液， 用硅胶柱 色谱法以洗脱剂体系 B纯化所得残余物，得到标题产物 (3& 63^-[4-(2-氟 -4-{[1- (4- 氟-苯基) -2-氧代 -1,2-二氢 -P比啶 -3-甲酰胺基] -氨基 } -苯氧基) -吡啶 -2-基] -5-(4-甲基- 哌嗪 -1-基) -六氢 -环戊 M吡咯 -2-甲酰胺 5 (74 mg, 白色固体 )， 产率： 24.0%。

[4-(2-Fluoro-4-{[1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridyl-3-carbonyl]-amino}-phenoxy Diphenyl-pyridin-2-yl]-diaminodicarboxylate 4b (312 mg, 0.46 mmol) was dissolved in 4 mL of hydrazine, dimethyl-dimethylformamide and triethylamine (280 mg, 2.76 mmol) And (3& 60^-5-(4-methyl-piperazin-1-yl)-octahydro-cyclopenta[c]pyrrole hydrochloride 3b (586 mg, ] .84 mmol), reaction for 16 hours. 30 mL of a mixed solvent of ethyl acetate and water (V/V = 2: l), liquid separation, organic phase washed with 1M sodium hydroxide solution (10 mL), water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 4-{[1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-Pbipyridine-3-carboxamido]-amino}-phenoxy)-pyridine-2- -5-(4-Methyl-piperazin-1-yl)-hexahydro-cyclopentamethylpyrrole-2-carboxamide 5 (74 mg, white solid), yield: 24.0%.

MS m/z (ESl): 670 [M+1]

'H MR (400 MHz, CDC1 ₃ ): δ 11.94 (s, 1Η), 8.73 (m, 1H), 8.01 (d,)H), 7.91 (dd, 1 H), 7.70 (s, 1H), 7.62 (m, 1H), 7.42 (m, 1H), 7.33-7.25 (m, 4H), 7.1 1 (t, 2H), 6.91 (t, 1H), 6.50 (m, 1H), 3.60 (m, 2H) , 3.39 (m, 2H), 2.69-2.57 (m, 10H), 2.28 (s, 3H), 2.17 (m, 2H), 1.41 (m, 2H) Example 6

(3a7?,6ay>-"4-(-Fluoro-4-m-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamidoaminophenoxy -pyridin-2-yl1-5-(4-penta-fc|pyrrole-2-carboxamide

第一步

first step

 4-amino-3-fluoro-phenol

 3-Fluoro-4-nitro-phenol 6a (15.71 g, 0.10 mol) and palladium/carbon (1.57 g, 10%) were dissolved in 120 raL of methanol and reacted under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered with EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj z (ESI): 128 [M+l]

 Second step

 4-(4-Amino-3-fluoro-phenoxy)-pyridine-2-carboxamide

 4-Amino-3-fluoro-phenol 6b (11.80 g, 93 mmol) was dissolved in 70 mL of dimethyl sulfoxide, and potassium t-butoxide (16.72 g, 149 mmol) was added and reacted at 0 ° C for 1.5 hours. 4-Chloro-pyridine-2-carboxamide 6c (9.71 g, 62 mmol, prepared by the known method "US20050245530"), reacted at 80~85 °C for 3 hours, cooled to room temperature, and added 140 mL lM sodium hydroxide solution, reaction for 16 hours. Filtration, the filter cake was washed with water (1.40 mL×3) EtOAc (EtOAc) 6d (8.10 g, purple solid), Yield: 52.9%.

MS m/z (ESI): 248 [M+l]

 third step

 4-(3-Fluoro-4-{[1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridin-3-amido]-amino}-phenoxy )-pyridine-2-formamide

1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridyl-3-carboxylic acid 6e (1.40 g, 6 mmol) was dissolved in dichloromethane (30 mL) (2-oxo-3-oxazolidinyl)phosphoryl chloride (1.53 g, 6 mmol), reacted for 15 min, added 4-(4-amino-3-fluoro-phenoxy)-pyridine-2-methyl The amide 6d (0.74 g, 3 mmol) and diisopropylethylamine (2.33 g, 18 mmol) were reacted for 64 hours. Filtration, the filter cake was washed with dichloromethane (30 mL×3), and the filtrate was concentrated under reduced pressure. The residue was added to a mixture of 75 mL of ethyl acetate and saturated sodium hydrogen carbonate (V/V=2:0). The aqueous phase was extracted with ethyl acetate (25 mL×3). The organic phase was combined and washed with saturated sodium carbonate solution (50 mL×2) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated The filtrate was concentrated, and the obtained residue was purified eluting elut elut The title product 4-(3-fluoro-4-{[1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridin-3-amido]-amino}- Phenoxy)-pyridine-2-carboxamide 6f (250 mg, yellow solid), Yield: 18.0%. MS m/z (ESI): 463 [M+l]

'HNMR (400 MHz, CDC1 ₃ ): S12.07 (s, ] H), 8.75-8.42 (m, 3H), 7.88-7.49 (m, 3H), 7.41 (m, 2H), 7.27~6.58 (m , 8H), 5.56 (s, 1H)

 Fourth

 [4-(2-Amino-pyridin-4-yloxy)-2-fluoro-phenyl]-1 -(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P ratio Pyridine-3-carboxamide

4-(3-Fluoro-4-{[1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamido]-amino}-phenoxy -pyridine-2-carboxamide 6f (250 mg, 0.54 mmol) dissolved in 10 niL of N,N-dimethylformamide, water (0.024 mL, 1.35 mmol), bis(trifluoroacetoxy) iodine Benzene (465 mg, 1.08 mmol) and pyridine (128 mg, 1.62 mmol) were reacted at room temperature for 16 hours and at 60 ° C for 0.5 hour. 25 mL of O.5 M sodium hydroxide solution was added to the reaction mixture, which was filtered, and the filter cake was washed with 50 ml of water and dried in vacuo to give the title product [4-(2-amino-pyridin-4-yloxy)-2 -Fluoro-phenyl]- 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide 6 _g (207 mg, yellow solid), Yield: 88.1 %.

MS nVz (ESI): 435 [M+l ]

'HNMR (400 MHz, CDC1 ₃ ): δ 12.01 (s, 1 H), 8.74 (m, 1H), 8.73 (m, 1 H), 7.95 (d, 1 H), 7.60-5.97 (m, 12H) , 4.42 (s, 2H)

 the fifth step

 [4-(3-Fluoro-4-{[l-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridin-3-carbonyl]-amino}-phenoxy )-pyridin-2-yl]-aminodicarboxylate

 [4-(2-Amino-pyridin-4-yloxy)-2-fluoro-phenyl]-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine 6-formamide 6g (207 mg, 0.48 mmol) was dissolved in 20 mL of tetrahydrofuran, and triethylamine (144 mg, 1.43 mmol) and phenyl chloroformate (224 mg 1.43 mmol) were added at 0 ° C. hour. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.) The organic phase was washed with water (40 mL) EtOAc (EtOAc) (4-fluoro-phenyl)-2-oxo-1,2-dihydro-Ppyridin-3-carbonyl]-amino}-phenoxy)-pyridin-2-yl]-aminodicarboxylic acid diphenyl Ester 6h (282 mg, yellow solid) was used in the next step without isolation.

MS m/z (ESI): 675 [M+l]

 t.

 Eight young

[4-(3-Fluoro-4-{[1 -(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-phenoxy) -Pyridine-2-yl]-diaminodicarboxylate 6h (310 mg, 0.46 mmol) dissolved in 8 mL hydrazine, hydrazine-dimethylformamide, (3ai?,6a5)-5-(4- Methyl-piperazin-1-yl)-octahydro-cyclopenta[c]pyrrole hydrochloride 3b (586 mg, 1.84 mmol) and triethylamine (745 rag, 7.36 mmol) were reacted for 16 hours. After adding 20 mL of a saturated aqueous solution of sodium hydrogencarbonate, the mixture was separated, and the aqueous layer was combined with ethyl acetate (20 mL EtOAc). The residue obtained was purified by eluent system B. The crude material was purified by HPLC to give the title product (3a?, 6a5)-[4-(3-fluoro-4-{[1-(4-fluoro-phenyl) -2-oxo-1,2-dihydro-pyridine-3-carboxamido]-aminophenoxy)-pyridin-2-yl]-5-(4-methyl-piperazine small group) Hexahydro-cyclopenta[c]pyrrole-2-carboxamide 6 (102 mg, white solid), yield: 33.

MS m/z (ESl): 670 [M+1 ]

 Ί-I NMR (400 MHz, DMSO-^): δ 12.24 (d, IH), 8.75 (s, IH), 8.62-8.52 (m, 2H), 8.1 5 (m, 2H), 7.63-7.07 (m , 7H), 6.75 (t, IH), 6.61 (d, IH), 3.62 (m, 2H), 3.43 (d, 2H), 2.56 (m, 2H), 2.49 (m, IH), 2.34 (m, 6H), 2.12 (s, 3H), 2.08 (m, 2H), 1.23 (m, 2H) Example 7

 (3a 6aS>r4-(3-fluoro-4-{ Π-(4-fluoro-phenyl)-2-oxo-U-dihydro-pyridine-3-carboxamide 1-aminophenoxy

[4-(3-Fluoro-4-{[1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridin-3-carbonyl]-amino}-phenoxy] (2-pyridin-2-yl)-diaminodicarboxylate 6h (280 mg, 0.42 mmol) dissolved in 5 mL of N,N-dimethylformamide, added (3ai?,6a5 octahydro-cyclopentane [c] Pyrrol-5-ol lc (21 1 mg, 1.66 mmol) and triethylamine (168 mg, 1.66 mmol), reaction for 16 hours. The reaction solution was added to 20 mL of saturated sodium carbonate solution and extracted with ethyl acetate (20) </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; Title product (3a/?,6a5 [4-(3-fluoro-4-phenyl][2-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-P-pyridin-3-yl) Amido]-amino}-phenoxy)-pyridin-2-yl]-5β-hydroxyhexahydro-cyclopenta[ _C ]pyrrole-2-carboxamide 7 (70 mg, yellow solid), Yield: 28.8% .

 MS m/z (ESI): 588 [M+1]

1H NMR (400 MHz, OMSO-d ₆ ): δ 12.25 (s, IH), 8.71 (s, 1H), 8.62 (t, IH), 8.54 (t, IH), 8.14 (m, 2H), 7.63 ( m, 2H), 7.52 (d, IH), 7.43 (m, 2H), 7.29 (t, IH), 7.06 (d, IH), 6.76 (t, IH), 6.61 (d, IH), 4.63 (d , IH), 4.07 (m, 2H), 3.53 (t, 2H), 3.33 (m, 2H), 2.02 (m, 2H), 1.33 (m, 2H) Example 8

 (2-Fluoro-4-{2-"3-methyl-3-(T3ai?,6a^-2-methyl-octahydro-cyclopenta-c-pyrrole-5α-yl)-ureidopyridinium- 4-based oxygen

Phenyl) 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide

将 [4-(3-氟- 4-{[l-(4-氟-苯基) -2-氧代- 1 ,2-二氢 -I批啶- 3-羰基] -氨基 } -苯氧基) -吡 啶 -2-基] -氨基二甲酸二苯酯 6h (270 mg, 0.40 mmol )溶于 6 mL N，N-二甲基甲酰胺 中， 加入 (3a/?,6aSK2-甲基-八氢 -环戊 [c]吡咯 -5-基;) -甲胺 2e (247 mg, 1.60 mmol)和 三乙胺 (162 mg, 1.60 mmol) , 反应 16小时。 加入 20 mL饱和碳酸钠溶液， 分液， 水相用乙酸乙酯萃取 (20 mLx4) , 合并有机相， 有机相用饱和氯化钠溶液洗涤 (30 Lx2), 无水硫酸钠干燥， 过滤， 减压浓缩滤液， 用硅胶柱色谱法以洗脱剂体系 B 纯化所得残余物，得到标题产物 (2-氟 -4-{2-[3-甲基 -3-((3ai?,6aS)-2-甲基 -八氢 -环戊 [C] 吡咯 -5(x-基)-脲基] -吡啶 -4-基氧基 苯基 )-1-(4-氟-苯基) -2-氧代- 1,2-二氢 -P比啶 -3-甲 酰胺 8 (90 mg, 黄色固体)， 产率： 36.7%。

[4-(3-Fluoro-4-{[l-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-I-acridin-3-carbonyl]-amino}-phenoxy (2-pyridin-2-yl)-diaminodicarboxylate 6h (270 mg, 0.40 mmol) dissolved in 6 mL of N,N-dimethylformamide, (3a/?,6aSK2-methyl- Octahydro-cyclopenta[c]pyrrole-5-yl;)-methylamine 2e (247 mg, 1.60 mmol) and triethylamine (162 mg, 1.60 mmol) were reacted for 16 hours. Add 20 mL of saturated sodium carbonate solution, separate the liquid, extract the aqueous phase with ethyl acetate (20 mL×4), combine the organic phase, wash the organic phase with saturated sodium chloride solution (30 Lx2), dry over anhydrous sodium sulfate, filter, reduce The filtrate was concentrated, and the obtained residue was purified to silica gel elute -methyl-octahydro-cyclopenta[C]pyrrole-5(x-yl)-ureido]-pyridin-4-yloxyphenyl)-1-(4-fluoro-phenyl)-2-oxo Generation - 1,2-dihydro-P-pyridin-3-carboxamide 8 (90 mg, yellow solid), Yield: 36.7%.

MS m/z (ESI): 615.0 [M+l]

1H NMR (400 MHz, DMSO- ₆ ): δ 12.24 (s, 1 H), 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-((3ai?,6aS)-5P-hydroxyoctahydrocyclopentadienyl-2β-yl)-3-methylureido)pyridine -4-yloxy)phenyl)-1 pyridine-3-carboxamide

第一步

first step

 (1R,5S)-3P-methylamino-7,7-(ethylene acetal)bicyclo[3.3.0]octane (IS, 5R)-7,7-(ethylene acetal) Cyclo[3.3.0]octane-3-one 9a (3.30 g, 18.10 mmol, prepared by metric method "WO2007112669") was dissolved in 30 mL of dichloromethane, and an appropriate amount of 3A molecular sieve and methylamine hydrochloride were added. The salt (3.67 g, 54.40 mmol) was reacted for 3.5 hours, then 10 mL methanol and sodium cyanoborohydride (3.43 g, 54.40 mmol) were added and the reaction was continued for 1 hour. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure to give the title product (1R,5S)-3P-methylamino-7,7-(ethyl acetal)bicyclo[3.3.0] octone 9b (3.56 g, none Color oil), used directly in the next reaction without isolation.

MS m/z (ESI): 198 [M+1]

 Second step

 (3a/?, 6£uS 5p-methylamino-hexahydro-cyclopentadien-2-one will be crude (1 R, 3S, 5S)-3-methylamino-7,7- (ethylene condensate) Aldehyde)bicyclo[3.3.0]octyl 9b (3.56 g, 18.1 mmol) was dissolved in a mixed solvent of 50 mL of tetrahydrofuran and water (V/V = 4:), and 2.5 mL of concentrated hydrochloric acid was added to react for 1.5 hours. The reaction mixture was adjusted to pH 7 with sodium hydroxide, filtered, and the filtrate was evaporated to vacuo to give the title product (3A?, 6aS 5p-methylamino-hexahydro-cyclopenta[c]pyrrol-2-one 9c (2.77 g, Light yellow oil), used directly in the next reaction without isolation.

 third step

 (3ai?,6a5 5P-methylamino-octahydro-cyclopenta[c]pyrrole-2-ol will be crude (3ai?,6a5-5p-methylamino-hexahydro-cyclopenta[c]pyrrole-2-one 9c (2.77 g, 18.10 mmol) was dissolved in 50 mL of methanol, cooled to 0 ° C in an ice-bath, and sodium borohydride (757 mg, 19.90 mmol) was added portionwise and reacted at 0 ° C for 1 hour. Add 10 mL of 1 M hydrochloric acid The reaction mixture was adjusted to pH 10 with 10 mL of 1M sodium hydroxide solution, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to eluent system B to give the title product (3a?, 6aS)-5? Amino-octahydro-cyclopenta[c]pyrrole-2-ol 9d (2.70 g, colorless oil;), yield: 96.4%.

 MS m/z (ESI): 156 [M+1]

 the fourth step

N-(2,5-Difluoro-4-(2-(3-((3ai?,6aS)-5p-hydroxy octahydrocyclopentadienyl-2β-yl)-3-methylureido)pyridine - 4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide [4-(2-Amino-pyridin-4-yloxy)-2,5-difluoro-phenyl]-l-(4-fluoro-phenyl)-2-oxo-1,2-di Hydrogen-pyridine-3-carboxamide Id (1 80 rag, 0.40 mmol) was dissolved in 20 mL of tetrahydrofuran, and then added to mL mL of triethylamine and phenyl chloroformate (151 μί, .20 nimoj) for 0.5 hour. The reaction solution was concentrated under reduced pressure, and a mixture solution of 60 mL of ethyl acetate and saturated sodium chloride (V/V=2:1) was added, and the organic phase was washed with saturated sodium chloride solution (20 mL), anhydrous Dry over sodium sulfate, filter, and concentrate. The residue was added to 3 mL of hydrazine, hydrazine-dimethylformamide and 1 mL of triethylamine, and (3ai?,6aS 5p-methylamino-octahydro-cyclopenta[ _C ]pyrrole-2-ol 9d (248 mg, 1.6 mmol), the reaction was carried out for 16 hours. The reaction solution was poured into a mixed solution of 60 mL of ethyl acetate and a saturated sodium chloride solution (V/V = 2:1), and the organic phase was sequentially treated with M sodium hydroxide. The solution (20 mL) and a saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated. 2,5-Difluoro-4-{2-[3-((3aW,6aS)-5-hydroxy-octahydro-cyclopentamethylpyrrol-2-yl)-3-methyl-ureido]-pyridine- 4-yloxy}-phenyl)-1 -(4-fluoro-phenyl)-2-oxo-],2-dihydropyridine-3-carboxamide 9 (120 nig, yellow solid), yield : 47.4%.

MS m/z (ESI): 634 [M+l ]

 H NM (400 MHz, DMSO-^): δ 12.45 (s, 1 H), 8.83 (s, 1 H), 8.63 (m, 1H), 8.52 (m, 1H), 8.1 8 (m, 2H) , 7.64 (m, 3H), 7.45 (m, 3H), 6.78 (m, 1H), 6.65 (m, 1 H), 4.51 (m, 1 H), 4.44 (m, 1H), 4.13 (m, 1H) ), 2.78 (s, 3H), 2.33 (ra, 2H), 1.85 (m, 4H), 1.60 (ηι, 2H), 1.43 (m, 2H) Example 10

 (3a7?, 6aSVN-(4-(2-fluoro-4-indolyl-(4-fluorophenyl)-2-oxo-1,2-dihydroxypyridin-3-amido)phenoxy) P ratio

将 [4-(2-氟 -4-{ [1 -(4-氟-苯基) -2-氧代 -1 ,2-二氢 -吡啶 - 3-羰基] -氨基 } -苯氧基) -吡 啶 -2-基] -氨基二甲酸二苯酯 4b (339 mg, 0.50 mmol)溶于 4 mL Ν,Ν-二甲基甲酰胺 中， 加入三乙胺 (304 mg, 3 mmol)和 (3ai?,6aS 八氢 -环戊 [c]吡咯- 5-醇 lc (294 mg, 2 mmol), 反应 16小时。 反应液加入 30 mL乙酸乙酯和水 (V/V=2: l)的混合溶剂， 分 液，有机相依次用 1M氢氧化钠溶液 (10 mL) , 水 (10 mL)和饱和氯化钠溶液洗涤 (10 mL) , 无水硫酸镁干燥， 过滤， 减压浓缩滤液， 有固体析出， 用适量乙酸乙酯洗涤， 用甲醇重结晶，得到标题产物 (3ai?， 6a5)-N- (4-(2-就 -4-(1- (4-氟苯基 )-2-氧代 -1 ,2-二羟

[4-(2-Fluoro-4-{[1 -(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-phenoxy) -Pyridine-2-yl]-diaminodicarboxylate 4b (339 mg, 0.50 mmol) was dissolved in 4 mL of hydrazine, dimethyl-dimethylformamide, triethylamine (304 mg, 3 mmol) and 3ai?, 6aS octahydro-cyclopenta[c]pyrrole-5-ol lc (294 mg, 2 mmol), reaction for 16 hours. Add 30 mL of ethyl acetate and water (V/V=2:1). The solvent was mixed and the organic layer was washed with EtOAc (EtOAc) (EtOAc) A solid precipitated, which was washed with EtOAc (EtOAc) EtOAc (EtOAc) -oxo-1,2-dihydroxy

[] 99 (S3⁄4ΐΜΐI+:

 P)999 3⁄4 90(Ηΐ) 6ζΔHZ)VH τ9Ηζ(HI 19Lm/. iL L日-.. "-.

(r) inch Γ XZ) HΙHs day

 First step

(3a 6a 2-{4-(2-Fluoro-4-(l-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy) P Bis-2-yl-carbamoyl} decahydrocyclopenta[ _C ]pyrrole-5α-yl-4-nitrobenzyl ester (3£^,63)-[4-(2-fluoro-4- { [1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamido]-amino}-phenoxy)-indenyl-2-yl] -5β-hydroxyhexahydro-cyclopenta[c]pyrrole-2-carboxamide 10 (588 mg, 1 mmol) was dissolved in 25 mL of tetrahydrofuran, followed by 4-nitrobenzoic acid (672 mg, 4.02 mmol) and Phenylphosphine (1.05 g, 3.99 mmol), diethyl azodicarboxylate (700 mg, 4.02 mmol) was added dropwise at 0 ° C, and reacted at 10 ° C for 12 hours and at 40 ° C for 3 hours. The reaction mixture was washed with ethyl acetate (75 mL), EtOAc (EtOAc) The title compound (3ai?, 6a5)-2-{4-(2-fluoro-4) was purified by silica gel column chromatography eluting with EtOAc. -(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide .) Phenoxy) pyridin-2-yl - carbamoyl} decahydrocyclopenta [C | -5α- pyrrol-4-nitrophenyl ester 12a (274mg, white solid) Yield: 37.2%.

NMR NMR (400 MHz, CDC1 ₃ ): δ 1 1.98 (s, 1H), 8.76-8.74 (m, 1H), 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), 7.14-7.1 0 (m, 1H), 6.65-6.57 (m, 2H), 5.59 -5.57 (m, 1H), 4.06-4.03 (m, 1H), 3.74-3.73 (m, 2H), 3.42-3.39 (m, 2H), 3.03-3.01 (m, 2H), 2.23-2.21 (m, 2H), 2.05-2.01 (m, 2H)

 Second step

(3aS, 6ai?)-N-(4-(2-Fluoro-4-(l-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide)phenoxy Base) pyridin-2-yl)-5ct-hydroxyhexahydrocyclopenta[C]pyrrole-2 (1H>formamide will (3ai?,6aS 2-{4-(2-fluoro-4-(1 -(4) -fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-yl-carbamoyl}decahydrocyclopenta[ _C ]pyrrole-5α- Base 4-nitrobenzyl ester 12a (274 mg, 0.37 mmol) was dissolved in 40 mL of a mixture of methanol and chloroform (V/V = 1:1), and potassium hydroxide (21 mg, 0.37 mmol) was added. After 1 hour, the reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjj -(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-yl)-5α-hydroxyhexahydrocyclopenta[ _C ]pyrrole- 2(1H)-carboxamide 12 (162 mg, white solid). Yield: 74.7%. MS m/z (ESI): 588 [M+l ]

Ή NM (400 MHz, CDC) ₃ ): δ 11 .96 (s, 1H), 8.75-8.72 (m, 1H), 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 (m, 2H), 6.63-6.51 (m, 2H), 4.51 -4.49 (m, IH), 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 6aSVN-(4-(4-(4-ethoxy small (4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide)-2-fluorobenzene

 First step

 4-(4-{[4-Ethoxy-1 -(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl]-amino}-2-fluoro-benzene Oxy)pyridine-carboxylic acid

 4-Ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 13b (2.89 g, 1 0.10 mmol, using a known method "WO2009094427" Prepared) dissolved in 44 mL of toluene, added with thionyl chloride (5.56 mL, 78.38 mmol) for 3 hours. Concentrate under reduced pressure, add 50 mL of toluene to dissolve, and concentrate under reduced pressure to give a solid.

4-(4-Amino-2-fluorophenoxy)pyridinecarboxamide 13a (1.92 g, 7.76 mmol, prepared by the known method "CN200680021939") was dissolved in 70 mL of tetrahydrofuran and hydrazine, hydrazine-dimethyl In a mixed solvent of formamide CV/V = 4 _: 3), diisopropylethylamine (1.20 g, 9.31 mmol) and the above-mentioned alternate solid were slowly added and reacted for 12 hours. Add 100 mL of water to the reaction solution, and extract with ethyl acetate (150 mL). The organic phase is washed with saturated sodium bicarbonate (100 mL) and saturated sodium chloride solution (100 mL×2), dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography elut elut elut elut elut -1,2-Dihydropyridine-3-carbonyl]-amino}-2-fluoro-phenoxy)-pyridine-2-carboxamide 13c (3.10 g, yellow solid), Yield: 78.9%.

MS m/z (ESI): 507 [M+l]

1H NMR (400 MHz, CDC1 ₃ ): 511 .59 (s, IH), 8.40 (d, IH), 7.95-7.91 (dd, IH), 7.84 (d, IH), 7.70 (d, IH), 7.51 (d, IH), 7.38-7.35 (m, 2H), 7.27-7.21 (m, 3H), 7.09-7.07 (m, IH), 6.97-6.95 (m, IH), 6.36 (d, IH), 5.76 (m, IH), 4.36 (q, 2H), 1.57 (t, 3H)

Second step

Is08w%ζ- . PP SΗί) 06£6/.( 3⁄408H) ί3sλΔHi 0一ςπ3GDl 00 lz Hs :-..··..

 QΗΐ 8 inch 9ϊ9 ΧΗΐ 3⁄4 L3Zz(ςLΗ inch TLiLHi 0(ΗΔΐ-----.. ,·

(Ης gnl9 (H^r inch XrztKs--. inch) (3a & 6aW)-N-(~4-(4-ethoxy small (4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide)-2, 5-Difluorophenoxy)pyridin-2-yl)-5β-hydroxyhexahydrocyclopentanium klpyrrole-20 H)-carboxamide

 First step

 4-(4-{[4-ethoxysuccinyl(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl]-amino}-2,5-difluorophenoxy Base) - Pyridine-2-carboxamide

 4-Ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 13b (2.77 g, 0.01 mol, prepared by a known method "WO2009094427" It is dissolved in 40 mL of toluene, added with thionyl chloride (2.2 mL, 0.03 mol), and refluxed at 120-130 ° C to a water-free state.

 4-(4-Amino-2-fluorophenoxy)picolinic acid 14a (2.65 g, 0.01 mol, prepared by the known method "CN200680021939") was dissolved in 50 mL of tetrahydrofuran, and the above-mentioned standby solution was added. Diisopropylethylamine (5.20 mL, 0.03 mol) was reacted for 12 hours. Filtration, the filter cake was washed with ethyl acetate (100 mL;), and the filtrate was concentrated under reduced pressure, ethyl acetate (200 mL) was added, and then washed with 0.5 M sodium hydroxide solution (50 mL) and saturated sodium chloride solution ( 50 mL), dried over anhydrous sodium sulfate, EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Phenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl]-amino}- 2,5-difluorophenoxy)-pyridine-2-carboxamide 14b (2.07 g, 39.5%) .

MS m/z (ESI): 525 [M+l ]

 Second step

 4-ethoxy-l-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [4-(2-aminopyridin-4-yloxy)-2 ,5-difluorophenyl]-amine

4-(4-{[4-Ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl]-amino}-, 5-difluoro Phenoxy)-pyridine-2-carboxamide 14b (2.07 g, 3.95 mmol) dissolved in 30 mL of N,N-dimethylformamide, Water (180 mg, 9.88 mmol) and pyridine (0.96 mL, 11.86 mmol) were added in vacuo, and bis(trifluoroacetic acid) iodobenzene (3.40 g, 7.91 mmol) was added portionwise for 12 hours. Ν, Ν-dimethylformamide, cooled to room temperature, the residue was added to 25 mL of water and 15 mL of 1M sodium hydroxide solution, and the aqueous phase was extracted with ethyl acetate (30mL×3), and the organic phase was combined with water (30mL×2) The mixture was washed with a saturated aqueous solution of sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. (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): 497 [M+1]

'HN R (400 MHZ, DMSO- ₆ ): δ 11.14 (s, 1H), 8.32 (dd, 1H), 7.93 (d, 1H), 7.86 (d, 1H), 7.60-7.43 (m, 2H), 7.42-7.32 (m, 2H), 6.56 (d, 3H), 6.41-6.25 (m, 1H), 5.99-5.86 (m, 1H), 4.29 (q, 2H), 4.03 (d, 1H), 1.99 ( s, IH), 1.34 (t, 3H), 1.17 (t, 1H)

 third step

 4-ethoxy-l-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [4-(2-aminopyridine-4-yloxy 2,5) - difluorophenyl]-diaminodicarboxylate

 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, 3.91 mmol) was dissolved in 50 mL of tetrahydrofuran, and triethylamine (].63 mL, ??? 1.72 mmo) and chloroformic acid were sequentially added at 0 °C. Phenyl ester (1.47 mL, 11.72 mmol) was reacted for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title product 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [4-(2-aminopyridin-4-yloxy) was obtained. - 2,5-Difluorophenyl]-diaminodicarboxylate 14d (3.30 g, yellow solid).

MSm/z (ESI): 617 [M+1]

 the fourth step

(3aS,6aT?)-N-(4-(4-(4-Ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide) -2,5-Difluorophenoxy)pyridin-2-yl)-5β-hydroxyhexahydrocyclopenta[ _C ]pyrrole-2(1H)-carboxamide 4-Ethoxy-1-(4- Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [4-(2-aminopyridin-4-yloxy)-2,5-difluorophenyl]-amino Diphenyl formate 14d (3.30 g, 3.91 mmol) was dissolved in 25 mL of N,N-dimethylformamide, and (3ai?,6a5)-octahydro-cyclopenta[c]pyrrole-5?-ol lc ( 994 mg, 7.81 mmol) and triethylamine (4.13 mL, 31.91 mmol) were reacted for 24 hours. After adding 120 mL of saturated sodium carbonate solution, the mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) The filtrate was purified by silica gel column chromatography elutd elut elut elut elut elut elut elut elut 2-oxo-1,2-dihydropyridine-3-carboxamido)-2,5-difluorophenoxy)P-pyridin-2-yl)-5β-hydroxyhexahydrocyclopentane _C ]pyrrole-2(1H)-carboxamide 14 (0.54 g, white solid). Yield: 21.3%.

MSm/z (ESI): 651 [M+1]

'Η NMR (400 MHz, DMSO-J ₆ ): δ 11.21 (s, 1H), 8.74 (s, 1 H), 8.33 (dd, 1H), 8.12 (d, 1 H), 7.93 (d, 1H) , 7.58-7.46 (m, 3H), 7.44-7.25 (m, 2 H), 6.63 (dd, 1H), 6.56 (d, 1H), 4.61 (d, 1 H), 4.30 (q, 2H), 4.16-3.94 (m, 1H), 3.66-3.44 (m, 2H), 3.44-3.33 (m, 2H), 2.54 (br. s" 1H) , 2.08-1.93 (m, 2H), 1.40-1.32 (m, 3H), 1.32-1 .27 (m, 1H), 1.26-1.14 (nx 1H) Example 15

 (3£uS,6a?)-N-(4-(4-(4-ethoxyl small(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide) ) -2,5-two

 -2-yl) -5α-hydroxyhexahydrocyclopentane "c|pyrrole-2-(lH>-carboxamide)

 First step

(3aS, 6ai?)-2-((4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide)- 2,5-Difluorophenoxy)pyridin-2-yl)carbamoyl)-decahydrocyclopenta[ _C ]pyrrole-5ot-yl-4-nitrobenzoate (3a,6ai?)- N-(4-(4-(4-ethoxy- 1 -(4-fluorophenyl)-2-oxo-1 ,2-dihydropyridine-3-carboxamide) -2,5-di Fluorophenoxy)pyridin-2-yl)-5β-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide 14 (0.46 g, 0.71 mmol) was dissolved in 20 mL of THF. Nitrobenzoic acid (473 mg, 2.83 mmol) and triphenylphosphine (743 mg, 2.83 mmol), slowly add diethyl azodicarboxylate (493 mg, 2.83 mmol) at 0 °C, react at room temperature 12 hour. The reaction mixture was concentrated under reduced pressure. EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filter cake was dissolved in 50 mL of dichloromethane and washed sequentially with 0.5 M sodium hydroxide solution (25 mL×2) and saturated sodium chloride solution (25 mL) The title compound (3aS, 6ai?)-2- ((4-()) was obtained. 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2,5-difluorophenoxy)pyridine-2- Carbamoyl)-decahydrocyclopenta[ _C ]pyrrole-5α-yl-4-nitrobenzoate 15a (4) O mg, yellow solid), Yield: 72.6%.

MS m/z (ESI): 797 [M-l]

NMR NMR (400 MHz, DMSO-i3⁄4: δ 1 1.23 (s, 1H), 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, J=5.3Hz, 1H), 4.30 (q, 2H), 4.03 (q, 1 H), 3.66-3.50 (m, 2H), 3.40-3.32 (m, 2H), 2.94-2.83 (m, 2H), 2.14-2.04 (m, 2H), 1.99 (s, 1H), 1.94-1.84 (m, 2H), 1.36 (t, 3H), 1.18 (t, 1H) ( I ^omui ZZ '§ OO'S) tU ^{厘 3⁄4丄] 邈} i- («Ί)ζ, W3⁄43⁄4 3⁄43⁄4-i)S-(^39's^)琳

(HZ 3⁄4 8ΪΊ '(HI 's) [ HZ 6V\ - 6S't HZ 't") 99" 1 - LL'\ '(Hi 's) Ϊ6Ί '(H[ 's) 66' 1 %BZ ' ∞) 69 - 6 Z '(HI '^)

6V£ - ςζτ '(ΗΖ 'ΡΡ) ις Xuz 's) 86 '(Η[ εο '(Η【 'Ρ) Ο '(ΗΙ 'Ρ) LVV '(HI 'Ρ)

09·9 '(Η[ 'ΡΡ) 179·9 XUZ 9£'L - ZVL '(Ht^ ξΥί - IS' L '(HI 'Ρ) 86·B'(HI 'Ρ) ZY '(HI 'ΡΡ ) 9 8 '(Η ΐ 's) '(ΗΙ '^) t/Γΐ -LW 9 'ζΗΝ 001/) 3⁄41ΑίΜ Η【

°%ο·εε '(tm^ ' ^u ou)siSi3⁄4 i±r(/ [)-3-

3⁄4ι 3⁄4d [ ] 3⁄4j ^ 3⁄4 3⁄4 S 3⁄4 fla (sound 3⁄4 3⁄4 2 3⁄4 3⁄4ί m ώ -£- 3⁄4 3⁄4d 3⁄4 = -ζ'ΐ-3⁄4|3⁄4 (sound*)10 3⁄43⁄42 ) )-1)- (^9 '5^)铋^迩3⁄4陋

^ ΒΙ °^、「/ ¾¾ί '赫 w¾ ¾u

^ ΒΙ °^, "/ 3⁄43⁄4ί 'He w3⁄4 3⁄4u

ΥΙ-Η Λ/Λ)ψ 谬 ^ ^ ^ ι ι3⁄4:3⁄43⁄4ώΊ«ι 0 -im(l ^omm ISO ^Oll/) «SX Wei 出 ^爱-声- ^ ! ^^^^+ 耷纲声惊^-B-^! Sound ^! !二^^爱3⁄4纲ώ -ε- ι 3⁄4d 3⁄4二-ζ'ΐ-3⁄4- 3⁄4 - B-( 3⁄4 ) 十3⁄4 3⁄4

劲顿ώ-ωι)-ε- ι3⁄4 1⁄2 焉3⁄43⁄4-^-(3⁄4-ζ- ι (3⁄43⁄4* :

810000/110ZN3/X3d Sl70S60/llOZ OAV After 12 hours of reaction, the reaction was continued at 50 ° C for 3 hours. The reaction mixture was added with aq. EtOAc (EtOAc) (EtOAc (EtOAc. The filtrate was poured into 30 mL of methyl tert-butyl ether. The mixture was stirred at -18 ° C for 20 hr, then 30 mL ethyl acetate was added and filtered, and the filter cake was washed with 30 mL of methyl tert-butyl ether. purified by silica gel column chromatography with eluent systems B resulting residue to give the title product (3a ^, 6a5 -5α- (4- nitrophenyl acyloxy) hexahydrocyclopenta _[C] pyrrol -2 (1H) - tert-butyl formate 16a (3.80 g, white solid), yield: 47.2%.

 Second step

 (3aS,6ai?)-5a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

(3a 6a5) 5-(4-nitrobenzoyloxy)hexahydrocyclopenta[ _C ]pyrrole-2(1 H)-carboxylic acid tert-butyl ester 16a (3.80 g, 10.38 mmol) was dissolved in 1200 mL of acetic acid In a mixed solvent of ethyl ester and methanol (V/V = 1 : 1), 710 mg of potassium hydroxide was added and reacted for 1 hour. The reaction mixture was concentrated under reduced pressure and purified tolulujjjjjjjjjjjjjjjjjjjjj - tert-butyl formate 16b (1.98 g, white solid), Yield: 84.3%.

 Two younger brothers

 Oi?,6aS octahydro-cyclopenta [c]pyrrole-5a-alcohol hydrochloride

(3a&6ai?)-5ct-hydroxyhexahydrocyclopenta[c|pyrrole-2(1H)-carboxylic acid tert-butyl ester 16b (1.98 g, 17.8 mmol;) was dissolved in 13 mL of ethyl acetate, and 8 mL of 5.05M was added. A solution of hydrogen chloride in 1, 4-dioxane was reacted for 3 hours. The reaction mixture was concentrated under reduced pressure. and the residue was dissolved in 60 ml of ethyl acetate and ethyl alcohol (V/V = l: l), and 10 mL of triethylamine was added and stirred for 30 minutes. Concentrated under reduced pressure, purified by silica gel column chromatography with eluent systems B resulting residue to give the title product (3ai, 6aS?) - octahydro - cyclopentyl _[C] pyrrol-ol hydrochloride -5ot- 16c (480 Mg, off-white solid), Yield: 43.6%.

MS m/z (ESI):]28 [M+1]

 the fourth step

(3^,6Β5)-Ν-(4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide) )-2-fluorophenoxy:)pyridin-2-yl)-5α-hydroxyhexahydrocyclopenta[ _C ]pyrrole-2GH)-carboxamide 4-ethoxy-1 -(4-fluoro-phenyl -2-oxo-1,2-dihydro-P-pyridyl-3-carboxylic acid [4-(2-amino-pyridin-4-yloxy)-3-fluoro-phenyl]-amine 13d ( 377 mg, 0.79 mmol) was dissolved in 10 mL of tetrahydrofuran, and 0.45 mL of triethylamine and phenyl chloroformate (370 mg, 2.4 mmol) were added at 0 ° C, and reacted at 0 ° C for 30 min. The residue was dissolved in EtOAc (EtOAc)EtOAc. The residue was dissolved in 4 mL of N,N-dimethylformamide, and 1 mL of triethylamine and (3a 6aS octahydro-cyclopenta[c]pyrrole-5α-ol 16c (400 mg, 3.16 mmol) at room temperature The reaction was carried out for 12 hours, and the reaction was carried out for 2 hours. The reaction mixture was concentrated under reduced pressure. and the residue was dissolved in ethyl acetate (75 mL), and then washed with 1M sodium hydroxide solution (30 mL) and saturated sodium chloride solution (30 mL), The residue was dried over anhydrous sodium sulfate (MgSO4). -fluorophenyl)-2-oxo-1,2-dihydropyridine-3-formyl Amino)-2-fluorophenoxy)pyridin-2-yl)-5α-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide 16 (80 mg, yellow solid). Yield: ] 6.1%.

MS m/z (ESI): 632 [M+1]

'HN R (400 MHz, DMSO-d ₆ ): δ 10.55 (s, 1H), 8.69 (s, 1H), 8.10 (d, J = 5.8 Hz, 1H), 7.92 - 7.82 (m, 2H), 7.51 - 7.42 (m, 3H), 7.42 - 7.26 (m, 3H), 6.60 (m, 1H), 6.51 (d, J = 8.0 Hz, 1H), 4.46 (d, J= 3.8 Hz, IH), 4.26 (d, J = 7.0 Hz, 3H), 3.53 - 3.46 (m, 2H), 3.25 - 3.17 (m, 2H), 2.77 - 2.68 (m, 2H), 1.69 (ra, 2H), 1.53 (m, 2H) ), 1.30 (m, 3H) Example 17

 (3aS, 6aW)-N-M-(2,5-Difluoro-4-indole-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)benzene Oxyl)

 -2-yl}-5α-hydroxyhexahydrocyclopentane "c!pyrrole-2aHV formamide

 First step

(3aS, 6ai?)-N-{4-(2,5-Difluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide Phenyloxy)pyridin-2-yl}carbamoyl)-hexahydrocyclopenta[ _C ]pyrrole-5ot-yl-4-nitrobenzoate (3aS,6aR)-N-{4- (2,5-Difluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-yl} -53-Hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide 1 (600 mg, 0.99 mmol) dissolved in 60 niL of tetrahydrofuran, followed by 4-nitrobenzoic acid (672 mg, 4.1 mmol) With triphenylphosphine (936 mg, 4 mmol), 693 mg of diethyl azodicarboxylate was slowly added dropwise at 0 ° C and allowed to react at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The filtrate was concentrated under reduced pressure, and the residue obtained was purified to silica gel column chromatography eluting to elute to afford the title product (3 6 - - - - - - - - - - - - - - 4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-yl}carbamoyl)-hexahydrocyclopenta[c]pyrrole- 5α-yl-4-nitrobenzoate 17a (600 mg, yellow solid), Yield: 80%.

 Second step

(3aS, 6 R)- N-{4-(2,5-Difluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide Phenoxy)pyridin-2-yl}-501-hydroxyhexahydrocyclopenta[ _C ]pyrrole-2(1H)-carboxamide

(3a?,6aS N-{4-(2,5-Difluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide) ) Phenoxy)pyridine-2-yl}carbamoyl)-hexahydrocyclopentyl lc]pyrrole-5α-yl-4-nitrobenzoate 17a (600 mg, 0.8 raraol) dissolved in 30 mL of methanol and In a mixed solvent of methyl chloride (V/V = 1 / 2), 44 mg of potassium hydroxide was added, and the reaction was carried out for an hour. The reaction solution was directly purified by silica gel column chromatography eluting to afford the title product (3a5,6ai?)-N-{4-(2,5-difluoro-4-(1 -(4-fluorophenyl) )-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)P-pyridin-2-yl}-501-hydroxyhexahydrocyclopenta[c|pyrrole-2(1H) _carboxamide 17 (420 mg, white solid), Yield: 87%.

 MS m/z (ESI): 606.3 [M+1]

^{] H NMR (400 MHz, CDCL} 3) δ 12.17 (m, 1H), 8.77 (dd, J = 2.3, 7.3 Hz, 1H), 8.64 (dd, J = 7.3, 12.3 Hz, 1 H), 8.07 (d , J- 6.0 Hz, 1 H), 7.85 (m, 1H), 7.73 (m, 1 H), 7.51 (m, 2H), 7.30 (m, 3H), 7.02 (dd, J= 7.0, 10.3 Hz, 1H), 6.70 (m, 2H), 4.59 (m,)H), 3.71 (m, 2H), 3.38 (m, 2H), 3.07 (m, 2H), 2.04 (m, 2H), 1.83 ( m, 2H) Example 18

 (3aW,6ay>-N-(4-(4-(4-ethoxy) 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide 3 -fluorobenzene

 First step

 4-(4-{[4-Ethoxy-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl]-amino}-3-fluoro-benzene Oxy)pyridine-carboxamide

4-Ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 13b (2.44 g, 8.8 mmol, prepared by a known method "WO2009094427" It is dissolved in 30 mL of tetrahydrofuran, and 2 drops of hydrazine is added dropwise. The reaction is catalyzed by hydrazine-dimethylformamide. Thionyl chloride (1.75 mL, 24 mmol) is added, the reaction is carried out for 2 hours, concentrated under reduced pressure, and 25 mL is added. Tetrahydrofuran was dissolved, and 4-(4-amino-3-fluorophenoxy)P was added to the carboxamide 6d (1.98 g, 8 mmol, prepared by the known method "CN200680021939") and diisopropyl. Ethylamine (4.2 mL, 24 mmo 1) was reacted for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc)EtOAc. Washed with a saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate -Oxo-1,2-dihydropyridine-3-carbonyl]-amino}-3-fluoro-phenoxy)-pyridine-2-carboxamide 18a (4.0 g, m.p.).

MS m/z (ESI): 507 [M+1]

 Second

 4-Ethoxy-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [4-(2-aminopyridine-4-yloxy)- 3-fluoro-phenyl]-amine

 4-(4-{[4-Ethoxy-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridin-3-oxo]-amino}-3-fluoro - phenoxy)-pyridine-2-carboxamide 18a (4.0 g, 7.9 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and ice (0.36 g, 19.7 mmol) was added sequentially at 0 °C. And pyridine (1.87 g, 23.7 mmol), bis(trifluoroacetoxy)iodobenzene (6.8 g, 15.8 mmol) was added portionwise and reacted for 12 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc). The sodium salt solution was washed (60 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give the title product 4-ethoxy-1-(4-fluoro-phenyl)-2-oxo-1, 2 -Dihydropyridine-3-carboxylic acid [4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl]-amine 18b (3.68 g, brown solid). Yield: 97.3%

 MS m/z (ESI): 479 [M+1]

 third step

 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [4-(2-aminopyridin-4-yloxy)-2 -fluorophenyl]-diphenyl dicarboxylate

 4-Ethoxy-]-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [4-(2-aminopyridin-4-yloxy)- 2-Fluorophenyl]-amine 18b (0.98 g, 2.05 mmol) was dissolved in 45 mL of THF, and then triethylamine (0.85 mL, 6.14 mmol) and phenyl chloroformate (0.77 mL, 6.14 , reaction for 12 hours. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The obtained residue was purified to silica gel column chromatography eluting elut elut [4-(2-Aminopyridin-4-yloxy)-2-fluorophenyl]-aminodicarboxylic acid diphenyl ester 18c (500 mg, white solid), yield: 34.4%.

MS m/z (ESI): 719 [M+1]

 the fourth step

(3a ?,6a3⁄4-N-(4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide) 3-fluorophenoxy)pyridin-2-yl)-5β-hydroxyhexahydrocyclopenta[ _C ]pyrrole-2(1H)-carboxamide 4-ethoxy-1 -(4-fluorophenyl) 2-oxo-1,2-dihydropyridine-3-carboxylic acid [4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]-aminodicarboxylic acid diphenyl ester 18c (500 Mg, 0.69 mmol) was dissolved in 30 mL of N,N-dimethylformamide, followed by (3ai?,6a5)-octahydrocyclopenta[c]pyrrole-5?-ol lc (178 mg, 1.39 mmol) and Triethylamine (0.3 mL, 2.09 mmol), react for 24 hours. Add 10 mL of saturated sodium carbonate solution to the reaction solution. Ethyl acetate (30 mL×4), EtOAc (EtOAc) (EtOAc) The obtained residue was purified to give the title product (3a 6a5 N-(4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydro). Pyridine-3-carboxamido)-3-fluorophenoxy)pyridin-2-yl)-5β-light hexahydrocyclopenta[c|pyrrole-2(]H)-carboxamide 18 (30 nig, white Solid), Yield: 7%.

'HNl R(400 MHZ , DMSO-d ₆ ) δΐ 0.72 - 10.69 (m, 1H), 8.78 (s, ]H), 8.18 (t, 1H), 8.12 (d, 1H), 7.89 (d, 1H) , 7.52 - 7.46 (m, 3H), 7.42 - 7.33 (m, 2H), 7.20 (dd, J=11.4 Hz, 1H) _; 7.03 - 6.98 (m, 1H), 6.61 (dd, J=5.8 Hz, 1H ), 6.53 (d, 1H), 5.09 - 5.0] (m, 1H), 4.28 (q, 2H), 4.03 (q, 2H), 3.61 - 3.53 (m, 2H), 3.43 - 3.35 (m, 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, 31- I) Example 19

 (3a 6 ^ -2-((4-(2-fluoro-4-(0-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2-pyridine Base)

 -hexahydrocyclopenta"c|pyrrolyl-5β-yl-2-indole-aminoacetate

 First step

 (3a 6aS octahydro-cyclopenta [c]pyrrole -5β-alcohol hydrochloride

 The compound (3a5,6ai?)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester lb (50 g, 0.22 mmol) was dissolved in 250 mL of ethyl acetate. A 1,4-dioxane solution of hydrogen chloride (110 mL, 0.88 mmol), mpjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs g, white solid), yield 83.0%.

MSm/z (ESI): 128 [M+1]

 Second step

(3ai?,6aS [4-(2-Fluoro-4-{[1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido]-amino} - Phenoxy)-pyridin-2-yl]-5β-hydroxyhexahydro-cyclopenta[ _C ]pyrrole-2-carboxamide

[4-(2-Fluoro-4-{[1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-phenoxy)- Pyridin-2-yl]-aminodicarboxylic acid diphenyl ester 4b (200 mg, 0.29 mmol) and (3a/?, 6aS)-octahydro-cyclopenta[c]pyrrole-5β- The alkanoic acid hydrochloride 19a (194 mg, U 8 mmoj) was dissolved in 5 mL of N,N-dimethylformamide, and then 0.6 mL of triethylamine was added for 2 hours. Add 50 mL of dichloromethane and 20 mL of water, then add] M 30 niL sodium hydroxide solution, layer, and organic phase with 1 M sodium hydroxide solution (30 mLx2), saturated sodium chloride solution (30 mLx2). The title compound (3a7?,6a5)-[4-(2-fluoride) was purified by silica gel column chromatography. -4-{[1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido]-aminophenoxy)-pyridin-2-yl]- 5β- Hydroxy hexahydro-cyclopenta[ _C ]pyrrole-2-carboxamide 19b (50 mg, yellow solid), yield 29.4%.

MS m/z (ESI): 588 [M+1]

 third step

(3α??,6" -2-((4-(2-fluoro- 4((1-(4-fluorophenyl)-2-oxo-P-pyridyl-3-carboxamido)phenoxy) )-2-pyridyl)carbamoyl)-hexahydrocyclopentyl Mpyryl)-5β-yl-2-(lH)-(tert-butoxycarbonylamino)acetate (3 _a /?, 6aS [ 4-(2-Fluoro-4-{[1 -(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido]-aminophenoxy)-pyridine-2 -5β-hydroxyhexahydro-cyclopenta[c]pyrrole-2-carboxamide 19b (570 mg, 0.97 ramol), tert-butoxycarbonyl glycine (340 mg, 1.94 mmol),] -(3- Methylaminopropyl)-3-ethylcarbodiimide hydrochloride (372 mg, 1.94 mmol) and 4-dimethylaminopyridine (12 mg, 0.097 mmol) were dissolved in 20 mL of dichloromethane. The reaction was carried out for 12 hours, 50 mL of water and 50 mL of dichloromethane were added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (30 mL×2:), and the organic phases were combined, and then saturated sodium bicarbonate (30 mL; The residue was purified by EtOAc (EtOAc) eluting 3 ?,6aS 2-((4-(2-fluoro-4-)((1 -(4-fluorophenyl))-2) -oxo-pyridine-3-carboxamido)phenoxy)-2-pyridyl)carbamoyl)-hexahydrocyclopentamethylpyryl)-5β-yl-2-(lH)-(tert-butoxy Carbonylamino)acetate 19c (500 mg, yellow solid), yield 69.1%.

 MS m/z (ESI): 745 [M+1]

 the fourth step

(3a 6aS 2-((4-(2-Fluoro-4-(1-(4-fluorophenyl)-2-oxo-P-pyridyl-3-carboxamido)phenoxy)-2- Pyridyl)carbamoyl)-hexahydrocyclopenta[clpyrrolyl)-5β-yl-2-(l H)-aminoacetate (3fli?, 6 5 2- ((4-(2-fluoro) -4((1 -(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2-pyridyl)carbamoyl)-hexahydrocyclopentamethylpyrrolyl) -5β-yl-2-(lHH-tert-butoxycarbonylamino)acetate 19c (500 mg, 0.67 mmol) was dissolved in 10 mL dichloromethane. EtOAc (1 mL, 13.4 Stirring at 0 ° C for 10 minutes, reacting at room temperature for 12 hours, dissolving potassium carbonate (560 mmg, 4 mmol) in a small amount of water, adding to the system, and reacting for 10 minutes. Add 15 mL of water and 10 mL of the reaction solution. Chloroformamide, liquid separation, aqueous phase extraction with methylene chloride (10 mL×2), combined organic phase, dried over anhydrous sodium sulfate, filtered, filtered, evaporated. The residue was obtained to give the title compound (3a?, 6aS)-2-((4-(2-fluoro-4-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamide) yl) phenoxy) -2-pyridyl) carbamoyl) - hexahydro-cyclopenta _[c] Pyrrolyl) 5 beta yl -2- (lH) -. Aminoacetate 19 (210 mg, pale yellow solid), 48.5% yield and further purified by preparative HPLC chromatography the resulting product, the title product 19 (120 Mg, white solid), ■ Yield 23.0%.

MS m/z (ESI): 645 [M+1]

NMR NMR (400 MHz, CDC1 ₃ ): δ 11.95 (s, IH), 8.75 (dd, ll-I), 8.03 (d, IH), 7,94 (d, IH), 7.70 (s, IH), 7.63 (dd, IH), 7.37-7.48 (m, 2H), 7.23-7.37 (m, 3H), 7.13 (t, 1-1), 6.62 (t, IH), 6.54 (dd, IH), 5.25 (br. s" IH), 4.13 (d, IH), 3.58-3.75 (m, 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

(3 _a i?,6a V2-((4-(4-fluoro-4-((1-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)- 2-pyridyl)

 -hexahydrocyclopentyl W pyrrolyl)-5(fluorenyl-yl-2-nH)-aminoacetate

 First step

(3a/,6oS 2-((4-(4-fluorophenyl)-2-oxo-P-pyridyl-3-carboxamido)phenoxy)-2 -pyridyl)carbamoyl)-hexahydrocyclopenta-M pyrrolyl-5ot-yl)- 4-nitrobenzoate (3a/?,6aS [4-(2-fluoro-4-{[1 -(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido]-amino}-phenoxy)-pyridin-2-yl]-5β-hydroxyhexahydro- Cyclopenta[c]pyrrole-2-carboxamide 19b (10 g, 17 mmol), 4-nitrobenzoic acid (11.36 g, 68 mmol) and triphenylphosphine (17.84 g, 68 mmol) dissolved in 500 mL of tetrahydrofuran Cool to 0 ° C, add diethyl azodicarboxylate (11.85 g, 68 mmol), control the temperature to less than 10 ° C, and react at room temperature for 12 hours. Add 250 mL of ethyl acetate to the reaction solution with saturated hydrogen carbonate. The sodium solution was washed (250 mL×2), and the aqueous layer was evaporated, evaporated, evaporated, evaporated, evaporated The obtained residue was purified to give the title compound (3????, 6??)-2-((4-(4-fluorophenyl)-2-oxo-P-pyridine. -3-carboxamido)phenoxy)-2-pyridyl)carbamoyl) - Hydrogen cyclopentyl _[C] pyrrolyl -5ot--yl) -4-nitrobenzoate 20a (7.02 g, white solid), yield 56.0%.

MS m/z (ESI): 737 [M+1]

Second step (3a 6 _a 5 N-[4-(2-Fluoro-4-{ [l-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido]-amino }-Phenoxy)-pyridin-2-yl]-5α-hydroxyhexahydrocyclopenta[ _C ]pyrrole-2-(1H)-carboxamide (3^? 5 2- ((4-(2-fluoro) -4((1 -(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2-pyridyl)carbamoyl)-hexahydrocyclopentamethylpyrrolyl) -5α-yl-4-nitrobenzoic acid 20a (7.02 g, 9.53 mmol) was dissolved in 200 mL of a mixture of trichloromethane and methanol (V/V = 1 : ] ), and potassium hydroxide (533 mg, 9.53 mmol), the reaction was carried out for 1 hr. The reaction mixture was evaporated.jjjjjjjjjjjjjjjjj {[1 -(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido]-amino}-phenoxy)-pyridin-2-yl]-5ct-hydroxyl Hexahydrocyclopenta[ _C ]pyrrole-2-(lH)-formylurea 20b (3.60 g, white solid), yield 64.3%.

MS m/z (ESI): 588 [M+1]

 third step

(3ai?,6aS)-2-((4-(2-fluoro-4((1-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2 -pyridyl)carbamoyl)-hexahydrocyclopentamethylpyrrolyl-5α-yl)-2-(1HH-tert-butoxycarbonylamino)acetate (3a?,6a5)-N-[4-(2 -Fluoro-4-{[1 -(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido]-aminophenoxy)-pyridin-2-yl]- 5ct-hydroxyhexahydrocyclopenta[ _C ]pyrrole-2-(lH)-carboxamide 20b (630 rag, 1.10 mmol), tert-butoxycarbonyl glycine (376 mg, 2.20 mmol), 1 - (3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41 mg, 2.20 mmol) and 4-dimethylaminopyridine (13 mg, 0.10 mmol) dissolved in 20 mL of dichloromethane. Reaction for 12 hours. Add 30 mL of dichloromethane, dilute with saturated sodium bicarbonate (30 mL), 1M hydrochloric acid (30 mL) and saturated sodium chloride (30 mL). The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjjj Phenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2-pyridyl)carbamoyl)-hexahydrocyclopenta[c]pyrrolyl-5(x-yl)-2 - (lHH tert-butoxycarbonylamino) acetate 20c (560 mg, yellow solid), yield 70.0%.

MS m/z (ESI): 745 [M+1]

 the fourth step

(3a ?,6aS)-2-((4-(2-fluoro-4-((1 - (4-fluorophenyl)-2-oxo-P-pyridyl-3-carboxamido)phenoxy) )-2-pyridyl)carbamoyl)-hexahydrocyclopenta[c]pyrrolyl)-5α-yl-2-(lH)-aminoacetate (3Ω 6α5)-2- ((4- 2-fluoro-4((1-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2-pyridyl)carbamoyl)-hexahydrocyclopenta[ c]pyrrolyl)-5α-yl-2-(lHH-tert-butoxycarbonylamino)acetate 20c (530 mg, 0.70 mmol) dissolved in 10 mL of dichloromethane, at 0 ° C, trifluoroacetic acid (0.6 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 solution for 10 minutes, add 20 mL of water and 10 mL of Chloroformamide, liquid separation, aqueous phase extraction with methylene chloride (10 mL×2), combined organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using silica gel column chromatography to eluent system A. The obtained residue was purified to give the title compound (3 <RTI ID=0.0>#</RTI></RTI><RTIgt;</RTI><RTIgt; Formamide)phenoxy)-2-pyridyl)carbamoyl)-hexahydrocyclopentanyl pyridyl Yl)-5a-yl -2- (lH) - amino acid ester 20 (320 mg, white solid), (^^^^-(^^^(声纲!^- -^^耷塞)^》-!/-^)-!))-^^?^^)

 ^i?二

Ii+n] o :(isa)z/∞sw °%o' Pull: ^ ' ^ιη ο ς)

^丄) 邈由 ^^- ^-愛 綱？-^-^^^^)琳

'dourai 06 1 ' £) ^ ^ '[ Υ 'φ^Ι^ϋ'Ζ, 0Ζ ±

^丄) 邈 by ^^- ^- Ai Gang? -^-^^^^) Lin

°%ς·ζ9 Umbrella ^ '( M^- ' ^s on) nz ^丄邈

ooi) ³mm wM ^ iz^ ooOmw ' m^ ooi yn^ z\ ^ 丄〇。08 '(1。画 S9"61 '§

' Ψ Μώ ¾i ， 09 G。画 SS'9 '3 Z) ¾IL 邈 ϋ¾ϋ Φ]¾ί¾- -¾¾聲綱齄 Ek- S-CS^' E) ' m mm '粱'ti

Ooi) ³ mm wM ^ iz^ ooOmw ' m^ ooi yn^ z\ ^ 丄〇. 08 '(1. Painting S9"61 '§

' Ψ Μώ 3⁄4i , 09 G. Draw SS'9 '3 Z) 3⁄4IL 邈ϋ3⁄4ϋ Φ]3⁄4ί3⁄4- -3⁄43⁄4 声 E齄-E-S-CS^' E)

(Sound | (3⁄43⁄43⁄4 (Sound 3⁄4 ώ-ε- Φ-»»-B-(Sound *笃)-[))卞笃 -ζ)-ΐ7 (^9

(UZ '^)61"[-2£'1 ΚΖ 'at) 'l-S8'l XUZ '^) 88'1"00 (H£ 's) 0£- _z Xm 'ui) RZ 09·£ XUZ > LLi '(HI '∞) Z^-^5 '(HI

PP) [9·9 '(HI '冚) 89'9-18'9 '(H[ 3⁄4 i ^c LX '«ι) 6 ' L- L hiZ '∞) 9ζ' L~99. L lli 'ω 96·/τ6Γ8 '(HI 'ΡΡ) 658 '(HI 's) ς 8 '(Hi 's) 60ΧΪ 9 -( ⁹ P-OS Q 'zffl/ OOt ^I NiM H _r

,HUT0000/ll0ZN3/X3d Sl70S60/llOZ OAV Carbamoyl)-hexahydrocyclopenta-M pyrrolyl)-5cx-yl-acetate

The compound [4-(2-amino-P-pyridin-4-yloxy)-3-fluoro-phenyl]-1-(4-fluoro-phenyl)-2-oxo-1,2-di Hydrogen-pyridine-3-carboxamide 4a (1.15 g, 2.65 mmol) was dissolved in 40 mL of tetrahydrofuran, then phenoxy acid chloride (1.25 g, 7.95 mmol) was added and reacted for 20 minutes, and triethylamine (0.80 g, 7.95 mmo]), reaction for 30 minutes. After adding 50 mL of ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride (25 mL?). The residue obtained was dissolved in 20 mL of N,N-dimethylformamide, triethylamine (1. 6 g, 15.90 mmol) and phenyl chloroformate (417 mg, 2.66 mmol). 3o&6)-octahydro-cyclopenta[c]pyrrole-5α-acetate 21b (897 mg, 5.30 mmol), and reacted at 45 ° C for 3 hours. It was diluted with 50 mL of ethyl acetate and washed with a saturated sodium chloride solution (25 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Title Compound (3a 6aS 2-((4-(2-Fluoro-4-((1-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2- Pyridyl)carbamoyl)-hexahydrocyclopenta[ _C ]pyrrolyl)-5α-yl-acetate 21 (554 mg, white solid), yield 33.2%.

MS m/z (ESI): 630 [M+l ]

 'H NMR (400 MHz, DMSO-i3⁄4): δ 1 1.95 (s, 1 H), 8.75-8.73 (m, 1H), 8.03-8.02 (m, 1H), 7.94-7.91 (m, 1H), 7.70 -7.67 (m, 1 H), 7.64-7.62 (m, ] H), 7.43-7.40 (m, 2H), 7.34-7.25 (m, 2H), 7.14-7.10 (m, 2H), 6.63-6.52 ( m, 2H), 5.30-5.28 (m, 1 H), 3.68-3.64 (m, 2H), 3.31-3.28 (m, 2H), 2.92-2.90 (m, 2H), 2.05-2.02 (m, 5H) , 1.86-1 .80 (m, 2H) Example 22

 (3ai?,6aS)-2-((4-(2-fluoro-4-(indolyl-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2 -pyridyl)

 First step

(3ai?,6aS 2-((4-(2-fluoro-4-((1-(4-fluorophenyl)-2-oxo-P-pyridyl-3-carboxamido)phenoxy)- 2-pyridyl)carbamoyl)-hexahydrocyclopenta[c]pyrrolyl)-5α-yl-(25)-2-benzyloxycarbonylaminopropionate (3a/?,6aS)-N- [4-(2-Fluoro-4-{{1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido]-aminophenoxy)-pyridine- 2-yl]- 5α-hydroxyhexahydrocyclopenta[c]pyrrole-2-(lH)-carboxamide 20b (587 mg, 】 mmol), phenoxycarbonylaminopropionic acid (446 mmg, 2 mmol) and 1 -(3-dimethylaminopropyl)-3-B The carbodiimide hydrochloride (383 mg, 2 nmiol) was dissolved in 30 mL of dichloromethane, and 4-dimethylaminopyridine (24 mg, 0.2 mmol) was added for 12 hours. After adding 20 mL of dichloromethane, it was washed with EtOAc (EtOAc) (EtOAc) ,6aS)-2-((4-(2-Fluoro-4-(()-(4-fluorophenyl)) 2-oxo-pyridine-3-carboxamido)phenoxy)-2-pyridine Carbamoyl)-hexahydrocyclopenta[ |pyrrolyl)-5α-yl-(25)-2-benzyloxycarbonylaminopropionate 22a (1 g, pale yellow solid), product Carry out the next reaction.

MS m/z (ESl): 793 [M+l]

 Second

(3a 6aS 2-((4-(4-Fluoro-4-)-2-oxo-Ipyridine-3-carboxamido)phenoxy)-2-pyridine Carbamoyl)-hexahydrocyclopenta[c]pyrrolyl)-5α-ylaminopropionate crude product (3 ai?,6a, )-2-((4-(2-fluoro-4-() (1-(4-Fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2-pyridyl)carbamoyl)-hexahydrocyclopenta[ _C ]pyrrolyl)- 5α-yl-(2,-2-benzyloxycarbonylaminopropionate 22a (1 g, 1 mmol) dissolved in 15 mL of methanol, palladium/carbon (200 mg, 10%), three times of hydrogen, reaction The reaction mixture was filtered with EtOAc (EtOAc) (EtOAc) 2-((4-(2-Fluoro-4-(().-(4-fluorophenyl)-2-oxo-pyridine-3-carboxamido)phenoxy)-2-pyridyl)amino Formyl)-hexahydrocyclopenta[c]pyrrolyl)-5α-yl-(25 aminopropionate 22 (324 mg, white solid), yield 49.2%.

MS m/z (ESI): 659 [M+l ]

 NMR NMR (400 MHz, DMSO- δ 12.09 (s, IH), 8.74 (s, IH), 8.59-8.57 (m, IH), 8.14-8.11 (m, 2H), 8.01-7.98 (m, IH), 7.63-7.60 (m, 2H), 7.49-7.40 (m, 4H), 7.35-7.30 (t, IH), 6.74-6.71 (m, IH), 6.62-6.60 (m, IH), 5.16-5.15 (m , IH), 3.53-3.48 (m, 2H), 3.35-3.26 (m, 3H), 2.76-2.75 (m, 2H), 1.87-1.73 (m, 6H), 1.14-1.12 (d, 3H) Test case:

 Biological evaluation Example 1. c-Met cell proliferation inhibition test

 The following in vitro assays can be used to determine the proliferation inhibitory activity of the compounds of the invention against human gastric cancer cell SNU-5, which highly expresses c-Met.

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 IC _5Q value. The general protocol for such an assay 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 test solutions (generally 6 to 浓度 concentration) of the test compound solution diluted with the medium were added to each well, and culture was continued for 72 hours. After 72 hours, the activity of the compound to inhibit cell proliferation can be measured by the method of cell counting kit-8 (CCK-8, available from DojinDo). The IC _5G value can be calculated from the inhibition of cell proliferation by a test compound at a range of different concentrations. Activity of the compounds of the invention

The biochemical activity of the compound of the present invention was measured by the above test, and the measured value of 1C _{5 () is} shown in the following table.

 Conclusion: The compounds of the examples of the present invention have significant proliferation inhibitory activity against SNU-5 cells. Example 2. Determination of c-Met kinase activity

 The c-Met kinase activity was measured by the following method under in vitro conditions.

The methods described below can be used to determine the ability of the compounds of the invention to inhibit C-Met kinase activity and are expressed by IC _5Q values. 'The half-inhibitory concentration of the compound IC _5Q (the concentration of the compound required to inhibit a certain concentration of enzyme activity to 50%) is calculated by mixing a certain amount of kinase with a specific substrate and different concentrations of the test compound. of. The c-Met kinase (purchased from Cell Signaling technology) used in this experiment is a human recombinant protein containing 60 mM HEPES (pH 7.5), 5 mM MgCl ₂ , 5 mM MnCl ₂ , ₃ μΜ Na ₃ V0 ₄ , 1.25 M DTT ( 1000x) buffer solution and 30μΜ ATP reaction system were reacted with peptide substrate and different concentrations of test compound (25 ° C, 45 min), followed by labeling antibody against substrate with anti-phosphotyrosine antibody and guanidine element Labeling was performed and finally the C-Met kinase activity was quantified by time-resolved fluorescence.

 Activity of the compounds of the invention

The biochemical activity of the compound of the present invention was measured by the above test, and the measured IC _5Q value is shown in the following table.

14 0.007

14 0.007

 15 0.004

 16 0.008

 17 0.03〗

 Conclusion: The compounds of the examples of the present invention have significant inhibitory effects on c-Met kinase activity. Example 3, VEGFR cell proliferation inhibition test

 The following in vitro assays can be used to determine the proliferation inhibitory activity of the compounds of the invention against human umbilical vein endothelial cells HUVECs that express VEGFR. '

The following in vitro cell assay may be determined for a particular high expression of VEGFR HUVEC cells proliferation inhibitory activity of the test compound, the activity available IC _5. The value is expressed. The general protocol for such an experiment is as follows: First, select human VEGFR-expressing human umbilical vein endothelial cells HUVEC (purchased in ATCC biochemistry and cell biology) at a suitable cell concentration (exp 5000 Cells/ml medium were seeded in 96-well culture plates, and then the cells were cultured in a carbon dioxide incubator. When they grew to 85% confluence, the medium was changed to a series of concentration (generally 6 to 7 concentrations). The culture medium of the test compound solution was returned to the incubator for 72 hours. After 72 hours, the compound can be tested for its activity in inhibiting cell proliferation using the sulfoi'hodamine B (SRB) method. The IC _5Q value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.

 Activity of the compounds of the invention

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC ₅ o values are shown in the following table.

 Conclusion: The compounds of the examples of the present invention have significant proliferation inhibitory activity on HUVEC cells. Example 4, VEGFR kinase activity assay

 VEGFR kinase activity was measured by the following method under in vitro conditions.

The methods described below can be used to determine the ability of a compound of the invention to inhibit VEGFR kinase activity and are expressed by IC _5Q values. The half-inhibitory concentration of the compound IC _5Q (the concentration of the compound required to inhibit a certain concentration of the enzyme activity to 50%) is determined by mixing a certain amount of the kinase with a specific substrate and a different concentration of the test compound. of. The VEGFR kinase (purchased from Cell Signaling technology) used in this experiment is a human recombinant protein containing 60 mM HEPES (pH 7.5), 5 niM MgCl ₂ , 5 mM MnCl ₂ , ₃ μΜ Na ₃ V0 ₄ , 1.25 M DTT (1000×). The buffer solution and the 30 μΜ ATP reaction system are reacted with the polypeptide substrate and different concentrations of the test compound (25 ° C, 45 min), followed by the anti-phosphotyrosine antibody The substrate was labeled with a ruthenium-labeled antibody, and finally the VEGFR kinase activity was quantitatively determined by time-resolved fluorescence.

Activity of the compounds of the invention

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC ₅ o values are shown in the following table.

Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on VEGFR kinase activity. Pharmacokinetic evaluation

Example 5. Pharmacokinetic testing of the compounds of the invention

 1, abstract

 Rats were used as test animals, and the concentration of the drug in plasma at different times after administration of the compound of Example 10 or the compound of Example 12 by intragastric administration was determined by LC/MS/MS. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

 2. Test plan

2.1 Test drugs

 Example 10 Compound and Example 12 Compound

2.2 Test animals

 Healthy adult SD rats, 8 males and females, divided into 2 groups, 4 in each group, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

2.3 Drug preparation

 Weigh a certain amount of drug, force n i .O mL dimethyl sulfoxide to dissolve, add normal saline to make 1.0 mg / mL solution, DMSO content is 5%.

2.4 Administration

 SD rats were intragastrically administered overnight after fasting, and the dose was 10.0 mg/kg, and the dose was 10.0.

3, operation

 The compound of Example 10 and the compound of Example 12 were administered orally by the rats, and 0.2 niL was collected from the eyelids before and after the administration of 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0 hours. The cells were placed in heparinized tubes, and the plasma was separated by centrifugation at 10,000 rpm for 10 minutes at 4 C, stored at -20 ° C, and fed 2 hours after administration.

 To determine the test compound in rat plasma after different concentrations of the drug: 100 μί of rat plasma at each time after administration, add 50 μL of internal standard solution, 100 L of methanol, vortex for 3 minutes, centrifuge 10 minutes (13500 rpm), 10 μL of the supernatant was taken for LC/MS/MS analysis.

 4, pharmacokinetic parameters results

The pharmacokinetic parameters of the compounds of the invention are as follows: Pharmacokinetic experiment (10 mg/kg)

 Apparent distribution blood drug skin curve area half-life retention time clearance rate number volume

 Cmax AUC CL/F Vz/F tl/2 (h) MRT(h)

 (^ig /mL*h) (L/h/kg) (L/kg) Example 10 0.91 ± 0.31 4.72 ± ] 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 ] .89±0.16 Conclusion: The compound of the present invention has good pharmacological absorption and has obvious pharmacokinetic advantages.

Claims

The claims: a compound of the formula (the compound or a pharmaceutically acceptable salt thereof,

 among them:  Selected from or  Selected from or X is selected from ^t ^ N;  Or an aryl or heteroaryl group, wherein the aryl or heteroaryl group is further optionally selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, , Substituted by a substituent of O, , V ⁹ or ^-11 ;  Or , selected independently from a hydrogen atom, a decyl group, an alkoxy group or an aryl group;  , or each independently selected from a hydrogen atom, a sulfhydryl group or a halogen;  Selected from a hydrogen atom or a fluorenyl group, wherein the alkyl group is optionally further substituted with a substituent of a halogen or a decyloxy group;  Or a heterocyclic fluorenyl group, a bicyclic heterocyclic group, a bridged fluorenyl group, a bridged heterocyclic group, a spirocyclic fluorenyl group or a spiroheterocyclic group, wherein the bicyclic fluorenyl group, the heterocyclic group, the bridged cycloalkyl group, and the bridged The cyclo, spirocyclic or spiroheterocyclic group is further optionally further selected from one or more selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, cyclodecyl, heterocyclyl, aryl, Heteroaryl, carbonyl, ,,  Substituted by a substituent of , , , , or -;  Or, together with the atom to which it is attached, a di-heterocyclic group, a bridged heterocyclic group or a spiroheterocyclic group, wherein the diheterocyclic group, the bridged heterocyclic group or the spiroheterocyclic group is optionally further Or a plurality of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, , , , , , , -^^^((^!^ or ^!^;^ ¹ substituted by a substituent;  Or a hydrogen atom, a fluorenyl group, a cycloalkyl group or an aryl group, wherein the fluorenyl group, cyclodecyl group or aryl group is optionally further substituted with one or more amino groups; Or each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group is optionally further One or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, cyclodecyl, heterocyclyl, (C OR ⁹ , , -0(CH ₂ ) _M C(0)OR person - OC(0)NR"R", -S(0) _N R ^Y , -OS0 ₂ R\ -S0 ₂ NR' ² R", -NHC(0 Substituting a substituent of R ^Y or -NR ¹² R ^B ; Alternatively, R' ^Q and R ^N 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 ring contains one or more N, 0 or S(0) _N groups. An atom, and the 3 to 8 membered heterocyclic ring is optionally further further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, carbonyl, cyclodecyl, heterocyclyl, aryl , heteroaryl, -C(0)OR ⁹ , -0C(0)R ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ , - 0C(0)NR'3⁄4 ^{L 3} , - S(0 _{^{) N R 9, -OS0 2 R}} 9, -S0 2 NR 12 R L 3, - NHC (0) R 9 or -NR ¹² R ^13, substituted with a substituent; R ¹² and R ¹³ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group;  m is 0, 1 or 2;  n is 0, 1, or 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (A) or a pharmaceutically acceptable salt thereof,

R' is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further selected from one or more selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, -C (0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ , -OC(O)NR ¹⁰ R ^N , -S(0) _N R ⁹ , -OS0 ₂ Substituted by a substituent of R ⁹ , —SOzNR′ ¹ ^ —NHC(0)R ⁹ or —NR′OR ¹¹ ; R ^{A is} selected from a hydrogen atom or a decyloxy group; R ³ , R ⁴ , R ⁵ or R ⁶ are each independently selected from a hydrogen atom, a fluorenyl group or a halogen; R ^{7 is} selected from a hydrogen atom or an alkyl group; R ^{8 is} selected from the group consisting of a bicyclic fluorenyl group, a bicyclic heterocyclic group, a bridged fluorenyl group, a bridged heterocyclic group, a monospirocyclic fluorenyl group, a monospiroheterocyclic group, wherein the bicyclic fluorenyl group, the heterocyclic group, the bridged ring The alkyl, hetero bridged fluorenyl, monospiroindole or monospiroheterocyclyl is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, cycloalkyl , heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(C3⁄4) _M C(0)OR ⁹ , -OC(0)NR'°R Substituent of a substituent of ^U , carbonyl, -S(0) _N R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ¹⁰ R ^{1 1} , -NHC(0)R ⁹ or -NR ¹⁰ R ; Alternatively, R ⁷ and R ⁸ together with the nitrogen atom to which they are bonded form a 5- to 14-membered bicyclic heterocyclic group, a bridged heterocyclic group or a monospirocyclic group, wherein the diheterocyclic group and the bridged heterocyclic group are described. Or a single spiro heterocyclic group optionally further Or a plurality selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, cyclodecyl, heterocyclyl, aryl, heteroaryl, -C(0)OR ⁹ , -OC(0) R ⁹ , -0(CH ₂ ) _m C(0)OR ⁹ , -OC(O)NR ¹⁰ R ⁿ , carbonyl, -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -SO2NR ^{, 0} R ^{, ],} -NHC (0) R ⁹ or -NR ^{1 G} R "a substituents; R ^{9 is} selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group or an aryl group, wherein the fluorenyl group, cyclodecyl group or aryl group is optionally further substituted with one or more amino groups; R ^{1 ( )} or R" are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl is optionally further substituted by one or more groups selected from the embankment, embankment alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, ^{heterocyclyl, - C (0) oR 9} , -OC (0 R ⁹ , -0(CH ₂ ) _m C(0)OR ⁹ , -OC(0)NR ¹² R ¹³ , -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -S0 ₂ NR] ² R ^13, -NHC (0) R ⁹ or -NR ¹² R ^13, substituted with a substituent; Or alternatively, R ^IQ and R ^{1 1} 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, O or S(0) „ An atom, and the 3 to 8 membered heterocyclic group is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, carbonyl, C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _m C(0)OR ⁹ , -OC(0)NR ¹² R ¹³ , -S(0) _n R ⁹ , -OS0 Substituted by a substituent of ₂ R ⁹ , -S0 ₂ NR ⁱ² R ¹³ , -NHC(0)R ⁹ or -NR ¹² R ¹³ ; And R' ³ 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  n is 0, or 2. 3, or a pharmaceutically acceptable salt of a compound according to claim 1, in which R ¹ is selected from aryl, wherein the aryl group is optionally further substituted by one or more substituents selected from alkyl, embankment, halogen, Hydroxy, cyano, nitro, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CI- I ₂ ) _m C(0)OR ⁹ , -OC(O)NR ^{, 0} R' -S(0) _n R ⁹ ^ -OS0 ₂ R ⁹ , -SOzNR'V, -NHC(0)R ⁹ or -NR ^IQ substituted with a substituent of R ^M ; The definition of m, n, R ^{9 to} R" is as set forth in claim 1. 4. The compound of Claim or a pharmaceutically acceptable salt thereof according to claim 3, in which R ¹ is further substituted with one or more halogen or alkyl with the aryl group is optionally substituted. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a fluorenyl group, and R ^{8 is} selected from a bicyclic fluorenyl group or a bicyclic heterocyclic group, wherein the bicyclic fluorenyl group or the biheterocyclic group is optionally further substituted with one or more substituents selected from alkyl, embankment group, a halogen, a hydroxyl group, a cyano group, a nitro group, a carbonyl ^{group, -C (0) oR 9,} -OC (0) R 9, -0 (C) _m C(0)OR ⁹ , -OCCC NR' OR ¹ ^ -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ¹⁰ R' -NHC(0)R ⁹ or -NRWR ¹¹ Substituted by The definition of m, n, R ^{9 to} R" is as set forth in claim 1. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^{7 is} selected from the group consisting of fluorenyl, and R ^{8 is} selected from the group consisting of bicyclooctyl or azabicyclooctyl, wherein the bicyclooctyl or azabicyclooctyl Optional Further substituted by one or more substituents selected from alkyl, alkoxy, halo, hydroxy, cyano, nitro, ^{carbonyl, -C (0) 0R 9,} -0C (0) R 9, -0 (C¾) M C (0)0R ⁹ ,

Substituted by a substituent of -NHC(0)R ⁹ or -NR R ¹¹ ; m, n, R ⁹ to R ⁿ are as defined in claim 1. 7. A compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein said bicyclooctyl or azabicyclooctyl is optionally substituted with one or more thiol or hydroxy groups. . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ together with the nitrogen atom to which they are bonded form a 5- to 14-membered bicyclic indenyl or bicyclic heterocyclic group, wherein said bicyclic ring alkyl with or bis heterocyclyl is further optionally substituted with one or more groups selected from the embankment, embankment group, a heterocyclic group, a halogen, a hydroxyl group, a cyano group, a nitro group, a carbonyl ^{group, -C (0) oR 9,} - OC (0) R ⁹ , -0(CH ₂ ),,, C(0)OR ⁹ , -OC(O)NR ^{, 0} R ^U , -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -S0 ₂ NR ^{1 Q} R", - NHC(0)R ⁹ or -NR ^{I (} substituted by a substituent of R"; The definition of m, n, R ^{9 to} R" is as set forth in claim 1. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a bicyclooctyl or azabicyclooctane wherein said bicyclooctyl or aza The bicyclooctyl group is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclyl, halogen, hydroxy, cyano, nitro, carbonyl, -C(0)OR ⁹ , -OC(0)R ⁹ , -0(CH ₂ ) _M C(0)OR ⁹ , -OC^NR^R ^{1 1} , -S(0) _n R ⁹ , -OS0 ₂ R ⁹ , -SO ₂ NR ^{! 0} R ^N , -NHC Substituting (0) a substituent of R ⁹ or -NR ^R"; m , n, R ^{9 to} R" are as defined in claim 1. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein the bicyclooctyl or azabicyclooctyl group is further further selected from one or more selected from the group consisting of hydroxyl groups, -OC(0)R ⁹ Or substituted with a substituent of -NRWR ^{1 1} .

A method of preparing a compound according to claim 1 or a pharmaceutically acceptable salt thereof, the method

The compound of the formula (IA) is reacted with a chloroformate under basic conditions, and then reacted with an amine of the formula NHR ⁷ R ⁸ to give a compound of the formula (I); Wherein A, D, X, and RR ⁸ are as defined in claim 1. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier or excipient thereof. A method for modulating the catalytic activity of a protein kinase, which comprises contacting the protein kinase with a compound according to the claims or a pharmaceutically acceptable salt thereof, according to the pharmaceutical composition according to claim 13, The protein kinase is selected from the group consisting of c-Met and VEGFR receptor tyrosine kinases. The use of a pharmaceutical composition according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 for the manufacture of a medicament for treating a protein kinase-related disease, wherein said protein kinase is selected from the group consisting of c-Met and VEGFR receptor tyrosine kinases. A pharmaceutical composition according to claim B, wherein the protein kinase is selected from the group consisting of c-Met, or a pharmaceutically acceptable salt thereof, according to claim B. And VEGFR receptor tyrosine kinase. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 for the manufacture of a medicament for the treatment of cancer. The use according to claim 17, wherein the cancer is lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer A compound according to claim 1 or a pharmaceutically acceptable salt thereof, as a medicament for treating cancer. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer. A pharmaceutical composition according to claim 13 as a medicament for treating cancer. The pharmaceutical composition according to claim 21, wherein the cancer is lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer.