CN103183674B - One class fused heterocyclic derivative and its application - Google Patents

One class fused heterocyclic derivative and its application Download PDF

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CN103183674B
CN103183674B CN201110460766.4A CN201110460766A CN103183674B CN 103183674 B CN103183674 B CN 103183674B CN 201110460766 A CN201110460766 A CN 201110460766A CN 103183674 B CN103183674 B CN 103183674B
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heteroaryl
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CN103183674A (en
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黄伟
丛欣
叶军
赵兴俄
王佳
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Hainan Simcere Pharmaceutical Co ltd
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Jiangsu Simcere Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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Abstract

The present invention relates to a class fused heterocyclic derivative and its application, it has formula (I) structure.Compound of the structure as shown in formula (I) of the present invention has good inhibiting effect to a variety of kinase activities, and its half-inhibition concentration to kinases such as c Met, KDR, c kit is universal 10‑7mol.L‑1Below.Meanwhile, the compound with formula (I) structure prepared in the embodiment of the present invention is inhibited to the propagation of kinds of tumor cells.In addition, the invention further relates to the preparation method of the intermediate of such compound and intermediate.

Description

Fused heterocyclic derivative and application thereof
Technical Field
The invention relates to the field of biological medicines, in particular to fused heterocyclic derivatives with a structure shown in a formula (I) and application thereof in preparing a tyrosine kinase inhibitor or a serine-threonine kinase inhibitor. The invention also relates to intermediates of the compounds and a preparation method of the intermediates.
Background
Signal transduction, an integrated regulatory mechanism of cells, transmits various extracellular signals into the interior of cells, and allows the cells to respond to processes such as proliferation, differentiation, apoptosis, and the like. Protein Kinases (PKs) play an important role in this process. PKs can be divided into tyrosine kinases (PTKs) which phosphorylate tyrosine residues on proteins and serine/threonine kinases (STKs) which phosphorylate serine/threonine residues on proteins, and they play an important role in the signal transduction mechanisms of normal cells.
With the intensive research of molecular biology, the regulation of the function of growth factors and the regulation of oncogenes for cell signal transduction at the molecular level is an effective way to inhibit cell proliferation and treat tumors. This pathway can attenuate the effects of abnormal signaling pathways, prevent tumor growth, and also promote tumor cell death. It has been discovered to date that half of proto-oncogenes have tyrosine structures in their protein codes and are involved in cell signal transduction through phosphorylation and dephosphorylation, while mutated or overexpressed tyrosine kinases can convert normal cells into cancer cells during tumorigenesis while promoting tumor cell growth and mitosis. Tyrosine kinase and serine-threonine kinase play important roles in the oncogenic transformation process of cells and are directly or indirectly connected with the generation and development of tumors, so that the application of a tyrosine kinase inhibitor or a serine-threonine kinase inhibitor to the treatment of tumors is particularly suitable.
The naphthyridine derivatives have wide biological activity and important application in the field of medicine. In recent years, many naphthyridine small molecule compounds have been used as protein kinase inhibitors and are widely used for treating various diseases associated with abnormal kinase activity, such as tumors, psoriasis, liver cirrhosis, diabetes, angiogenesis, ophthalmic diseases, rheumatoid arthritis and other inflammatory diseases, immune diseases, cardiovascular diseases such as arteriosclerosis and various renal diseases. Among them, 2, 7-naphthyridine compounds (WO0192256 and WO0242264), 1, 5-naphthyridine compounds (WO2006106046), 1, 6-naphthyridine compounds (WO2007060028, WO2010037249 and WO2010088177), 2, 6-naphthyridine compounds (WO2008122614), heterocyclic fused naphthyridine compounds (WO2009148887 and WO2009148916), 2, 7-naphthyridine ketone compounds (WO2008109613 and WO2009097287) and 1, 8-naphthyridine ketone compounds (WO2010002779) are all used for tyrosine kinase and/or serine-threonine kinase inhibitors. However, the fused heterocyclic naphthyridine derivatives are not reported to be used for treating tyrosine kinase and/or serine-threonine kinase inhibitors.
Disclosure of Invention
The invention aims to provide a fused heterocyclic derivative shown in a general formula (I) or a pharmaceutically acceptable salt thereof:
wherein,
a is selected from C5-C10Heteroaryl or C6-C10Aryl, wherein said heteroaryl, aryl may optionally be further substituted by one or more groups selected from hydrogen, C1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C5-C10Heteroaryl group, C6-C10Aryl radical C1-C10Alkyl radical, C5-C10Heteroaryl C1-C10Alkyl, halogen, halogeno C1-C10Alkyl, 5-to 8-membered heteroalicyclic, hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, cyano, nitro, -NR7R8、-NR7C(＝O)R8、-C(＝O)R9、-C(＝O)OR9、-C(＝O)NR7R8、-S(O)R10、-S(O)2R10、-S(O)2NR7R8、-O(CH2)nR11or-OC (═ O) R9Substituted with the substituent(s);
b is selected from-O-, -NR7-、-S-、-SO-、-SO2-or-CR12R13-；
X and W are independently selected from C or N;
m is 0, 1, 2, 3 or 4;
R1selected from hydrogen, halogen, C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, hydroxy, C1-C10Alkoxy, -OC (═ O) R9、-C(＝O)R9、-C(＝O)OR9、-C(＝O)NR7R8、-NR7R8or-NR7C(＝O)R8In which C is1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl group, C1-C10The alkoxy group may optionally be further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy or halogen;
R2and R3Independently selected from hydrogen, halogen, C1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C5-C10Heteroaryl, halo C1-C10Alkyl, hydroxy, C1-C10Alkoxy, halo C1-C10Alkoxy radical, C6-C10Aryloxy, cyano, nitro, -OC (═ O) R9、-NR7R8、-NR7C(＝O)R8、-C(＝O)R9、-C(＝O)OR9、-C(＝O)NR7R8、-S(O)R10、-S(O)2R10or-S (O)2NR7R8In which C is1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C5-C10Heteroaryl, halo C1-C10Alkyl radical, C1-C10Alkoxy, halo C1-C10Alkoxy radical, C6-C10The aryloxy group may optionally be further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy or halogen;
R4selected from hydrogen, hydroxy, C1-C10Alkyl radical, C6-C10Aryl radicals、C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic, -C (═ O) R9or-S (O)2R10In which C is1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic optionally further substituted with one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, -O (CH)2)nR11、-OC(＝O)R10、-NR7R8or-NR7C(＝O)R8Substituted with the substituent(s);
R5selected from hydrogen, C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, hydroxy, cyano, or a carboxylic acid;
R6selected from hydrogen, C6-C10Aryl radical, C5-C10Heteroaryl group, C1-C10Alkyl radical, C6-C10Aryl radical C1-C10Alkyl or C5-C10Heteroaromatic C1-C10Alkyl radical, wherein C6-C10Aryl radical, C5-C10Heteroaryl group, C1-C10Alkyl radical, C6-C10Aryl radical C1-C10Alkyl radical, C5-C10Heteroaromatic C1-C10The alkyl group may optionally be further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, cyano or carboxylic acid;
R7and R8Independently selected from hydrogen, C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, C6-C10Aryl radical, C5-C10Heteroaryl, wherein said C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl, hydroxy, amino, cyano, C1-C10Alkoxy or a carboxylic acid;
while R is7And R8Together with the nitrogen atom to which they are attached form a 5-to 8-membered heterocyclic group containing one or more N, O, S heteroatoms within the 5-to 8-membered heterocyclic ring, and the 5-to 8-membered heterocyclic ring may optionally be further substituted with one or more substituents selected from C1-C10Alkyl, halogen, C6-C10Aryl radical, C5-C10Heteroaryl, halo C1-C10Alkyl, hydroxy, cyano, C1-C10Alkoxy, amino C1-C10Alkyl or carboxylic acid;
R9is selected from C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R10is selected from C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R11selected from hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl or-NR7R8In which C is1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R12and R13Independently selected from hydrogen, C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
n is 1, 2, 3 or 4.
Further, in the compound with the structure shown in the formula (I) or the pharmaceutically acceptable salt thereof provided by the invention,
a in the present invention may be selected from C5-C10Heteroaryl or C6-C10Aryl, wherein said heteroaryl, aryl may optionally be further substitutedOne or more selected from hydrogen and C1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C5-C10Heteroaryl group, C6-C10Aryl radical C1-C10Alkyl radical, C5-C10Heteroaryl C1-C10Alkyl, halogen, halogeno C1-C10Alkyl, 5-to 8-membered heteroalicyclic, hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, cyano, nitro, -NR7R8、-NR7C(＝O)R8、-C(＝O)R9、-C(＝O)OR9、-C(＝O)NR7R8、-S(O)R10、-S(O)2R10、-S(O)2NR7R8、-O(CH2)nR11or-OC (═ O) R9Substituted with the substituent(s);
a is further selected from C5-C10Heteroaryl or C6-C10Aryl, wherein said heteroaryl, aryl may optionally be further substituted with one or more substituents selected from hydrogen, halogen, -C (═ O) NH2、-C(＝O)NHR8、-C(＝O)R9、-C(＝O)OR9Cyano, amino, -NHC (═ O) R8、C1-C10Alkoxy radical, C6-C10Aryloxy radical, C1-C10Alkyl, hydroxy, -O (CH)2)nR11or-OC (═ O) R9Substituted with the substituent(s);
a is further selected from six-membered heteroaryl, five-membered and six-membered heteroaryl, six-membered aromatic ring or six-membered and six-membered aromatic ring group, wherein six-membered heteroaryl, five-membered and six-membered heteroaryl, six-membered aromatic ring or six-membered and six-membered aromatic ring group is further selected from one or more groups selected from hydrogen, halogen, -C (═ O) NH2、-C(＝O)NHR8、-C(＝O)R9、-C(＝O)OR9Cyano, amino, -NHC (═ O) R8、C1-C10Alkoxy radical, C6-C10Aryloxy radical, C1-C10Alkyl, hydroxy, -O (CH)2)nR11or-OC (═ O) R9Substituted with the substituent(s);
a is further selected from six-membered heteroaryl, five-membered and six-membered heteroaryl, six-membered aromatic ring or six-membered and six-membered aromatic ring group, wherein six-membered heteroaryl, five-membered and six-membered heteroaryl, six-membered aromatic ring or six-membered and six-membered aromatic ring group is further selected from one or more of hydrogen, halogen, amino, -CONH2Cyano, C1-C4Alkoxy or-O (CH)2)nR11Substituted with the substituent(s);
a may further be selected from pyridyl, thienopyrimidinyl, quinazolinyl, quinolinyl, naphthyl, or phenyl, wherein said pyridyl, thienopyrimidinyl, quinazolinyl, quinolinyl, naphthyl, or phenyl may be further optionally substituted with one or more substituents selected from hydrogen, halogen, -C (═ O) NH2、-C(＝O)NHR8、-C(＝O)R9、-C(＝O)OR9Cyano, amino, -NHC (═ O) R8、C1-C10Alkoxy radical, C6-C10Aryloxy radical, C1-C10Alkyl, hydroxy, -O (CH)2)nR11or-OC (═ O) R9Substituted with the substituent(s);
a may further be selected from pyridyl, thienopyrimidinyl, quinazolinyl, quinolinyl, naphthyl, or phenyl, wherein said pyridyl, thienopyrimidinyl, quinazolinyl, quinolinyl, naphthyl, or phenyl may be further substituted with one or more groups selected from hydrogen, halogen, amino, -CONH2Cyano, C1-C4Alkoxy or-O (CH)2)nR11Substituted with the substituent(s);
more preferably a is selected from the following groups:
wherein R isaAnd RbIndependently selected from hydrogen, halogen, -C (═ O) NH2、-C(＝O)NHR8、-C(＝O)R9、-C(＝O)OR9Cyano, amino, -NHC (═ O) R8、C1-C10Alkoxy radical, C6-C10Aryloxy radical, C1-C10Alkyl, hydroxy, -O (CH)2)nR11or-OC (═ O) R9Substituted with the substituent(s);
a is most preferably selected from the following groups:
wherein R isaAnd RbIndependently selected from hydrogen, halogen, amino, -CONH2Cyano, C1-C4Alkoxy or-O (CH)2)nR11。
In the present invention B is further selected from-O-, -S-, -NH-or-CH2-; b is most preferably-O-.
W in the present invention is further selected from C.
In the present invention, X is further selected from C or N.
M in the present invention is further 0 or 1.
R in the invention1、R2And R3Further independently selected from hydrogen or halogen. When R is1Most preferred for halogen is at the 3-position of the phenyl ring (based on the 1-position of the phenyl ring site attached to the-NH-group).
R in the invention4Further selected from hydrogen, hydroxy, C1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic, -C (═ O) R9or-S (O)2R10In which C is1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered monocyclic cycloalkylThe heteroalicyclic group may be further optionally substituted with one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, -O (CH)2)nR11、-OC(＝O)R10、-NR7R8or-NR7C(＝O)R8Substituted with the substituent(s);
R4still further selected from hydrogen, C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl, wherein C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Substituted with the substituent(s);
R4more preferably, hydrogen or C1-C4Alkyl, allyl, benzyl or-CH2COOEt。
R in the invention5And may further be selected from hydrogen.
R in the invention6Further selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl may optionally be further substituted with one or more substituents selected from halogen, trihalomethyl or C1-C10Substituted by a substituent of alkoxy;
R6still further selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein, C1-C10Alkyl, phenyl,Benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl optionally further substituted with one or more substituents selected from halogen, trihalomethyl or C1-C10Substituted by a substituent of alkoxy;
R6further may be hydrogen, phenyl or 2-thienyl, wherein phenyl may be optionally further substituted with one or more halogens, trihalomethyl or C1-C4Alkoxy substitution;
R6most preferred are H, phenyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-methoxyphenyl, p-trifluoromethylphenyl.
R in the invention7And R8Further independently selected from hydrogen, C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein said C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl optionally further substituted with one or more substituents selected from C1-C10Alkyl, hydroxy, amino, cyano, C1-C10Alkoxy or a carboxylic acid; while R is7And R8Together with the nitrogen atom to which they are attached form a 5-to 8-membered heterocyclic group containing one or more N, O, S heteroatoms within the 5-to 8-membered heterocyclic ring, and the 5-to 8-membered heterocyclic ring may optionally be further substituted with one or more substituents selected from C1-C10Alkyl, halogen, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, halo C1-C10Alkyl, hydroxy, cyano, C1-C10Alkoxy, amino C1-C10Alkyl or carboxylic acid;
R7and R8Yet further independently selected from hydrogen, C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyranylPyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein said C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl optionally further substituted with one or more substituents selected from C1-C10Alkyl, hydroxy, amino, cyano, C1-C10Alkoxy or a carboxylic acid; while R is7And R8Together with the nitrogen atom to which they are attached form a 5-to 8-membered heterocyclic group containing one or more N, O, S heteroatoms within the 5-to 8-membered heterocyclic ring, and the 5-to 8-membered heterocyclic ring may optionally be further substituted with one or more substituents selected from C1-C10Alkyl, halogen, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, halo C1-C10Alkyl, hydroxy, cyano, C1-C10Alkoxy, amino C1-C10Alkyl or carboxylic acid.
R in the invention9Further selected from C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R9and may be further selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl or imidazolyl.
R in the invention10Further selected from C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid.
R in the invention11Further selected from hydroxyl, C1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl or-NR7R8In which C is1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R11and may be further selected from C1-C10Alkoxy radical, C6-C10Aryloxy, hydroxy or-NR7R8；
R11Further may preferably be C1-C4Alkoxy, N-methylpiperazino, morpholino, piperidino, pyrrolidinyl or-N (C)2H5)2。
N in the present invention may further be 1, 2, 3 or 4.
n is preferably 2 or 3.
The more preferable combination of the compound with the structure shown in the formula (I) or the pharmaceutically acceptable salt thereof provided by the invention is as follows:
a is selected from the following groups:
wherein R isaAnd RbIndependently selected from hydrogen, halogen, amino, -CONH2Cyano, C1-C4Alkoxy or-O (CH)2)nR11。
B is selected from-O-;
w is selected from C;
x is selected from C or N;
m is 0 or 1;
R1、R2and R3Independently selected from hydrogen or halogen;
R4selected from hydrogen, C1-C4Alkyl, allyl, benzyl or-CH2COOEt；
R5Selected from hydrogen;
R6selected from hydrogen, phenyl or 2-thienyl, wherein the phenyl group may be further substituted by one or more halogens, trihalomethyl or C1-C4Alkoxy substitution;
R11is selected from C1-C4Alkoxy, N-methylpiperazino, morpholino, piperidino, pyrrolidinyl or-N (C)2H5)2；
n is 2 or 3.
The wavy line in the radicals of the invention denotes the point of attachment to other radicals, such as B.
The term "optionally further substituted with a.
Preferred compounds of formula (I) of the present invention include, but are not limited to:
or a pharmaceutically acceptable salt thereof.
Further, the present invention includes compounds of formula (II) which are intermediates in the synthesis of compounds of formula (I):
wherein,
R2and R3Independently selected from hydrogen, halogen, C1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C5-C10Heteroaryl, halo C1-C10Alkyl, hydroxy, C1-C10Alkoxy, halo C1-C10Alkoxy radical, C6-C10Aryloxy, cyano, nitro, -OC (═ O) R9、-NR7R8、-NR7C(＝O)R8、-C(＝O)R9、-C(＝O)OR9、-C(＝O)NR7R8、-S(O)R10、-S(O)2R10or-S (O)2NR7R8In which C is1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C5-C10Heteroaryl, halo C1-C10Alkyl radical, C1-C10Alkoxy, halo C1-C10Alkoxy radical, C6-C10The aryloxy group may optionally be further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy or halogen;
R4selected from hydrogen, hydroxy, C1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic, -C (═ O) R9or-S (O)2R10In which C is1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic optionally further substituted with one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, -O (CH)2)nR11、-OC(＝O)R10、-NR7R8or-NR7C(＝O)R8Substituted with the substituent(s);
R5selected from hydrogen, C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, hydroxy,Cyano or carboxylic acid;
R6selected from hydrogen, C6-C10Aryl radical, C5-C10Heteroaryl group, C1-C10Alkyl radical, C6-C10Aryl radical C1-C10Alkyl or C5-C10Heteroaromatic C1-C10Alkyl radical, wherein C6-C10Aryl radical, C5-C10Heteroaryl group, C1-C10Alkyl radical, C6-C10Aryl radical C1-C10Alkyl radical, C5-C10Heteroaromatic C1-C10The alkyl group may optionally be further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, cyano or carboxylic acid;
R7and R8Independently selected from hydrogen, C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, C6-C10Aryl radical, C5-C10Heteroaryl, wherein said C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl, hydroxy, amino, cyano, C1-C10Alkoxy or a carboxylic acid;
while R is7And R8Together with the nitrogen atom to which they are attached form a 5-to 8-membered heterocyclic group containing one or more N, O, S heteroatoms within the 5-to 8-membered heterocyclic ring, and the 5-to 8-membered heterocyclic ring may optionally be further substituted with one or more substituents selected from C1-C10Alkyl, halogen, C6-C10Aryl radical, C5-C10Heteroaryl, halo C1-C10Alkyl, hydroxy, cyano, C1-C10Alkoxy, amino C1-C10Alkyl or carboxylic acid;
R9is selected from C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R10is selected from C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R11selected from hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl or-NR7R8In which C is1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
n is 1, 2, 3 or 4.
Further, in the compound with the structure shown in the formula (II), wherein,
R2and R3Independently selected from hydrogen or halogen;
R4selected from hydrogen, hydroxy, C1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic, -C (═ O) R9or-S (O)2R10In which C is1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic optionally further substituted with one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, -O (CH)2)nR11、-OC(＝O)R10、-NR7R8or-NR7C(＝O)R8Substituted with the substituent(s);
R5selected from hydrogen;
R6selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl may optionally be further substituted with one or more substituents selected from halogen, trihalomethyl or C1-C10Substituted by a substituent of alkoxy;
R7and R8Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein said C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl optionally further substituted with one or more substituents selected from C1-C10Alkyl, hydroxy, amino, cyano, C1-C10Alkoxy or a carboxylic acid;
while R is7And R8Together with the nitrogen atom to which they are attached form a 5-to 8-membered heterocyclic group containing one or more N, O, S heteroatoms within the 5-to 8-membered heterocyclic ring, and the 5-to 8-membered heterocyclic ring may optionally be further substituted with one or more substituents selected from C1-C10Alkyl, halogen, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, halo C1-C10Alkyl, hydroxy, cyano, C1-C10Alkoxy, amino C1-C10Alkyl or carboxylic acid;
R9is selected from C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R10is selected from C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R11selected from hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl or-NR7R8In which C is1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
n is 1, 2, 3 or 4.
As a preference, among others,
R4selected from hydrogen, C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl, wherein C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Substituted with the substituent(s);
R6selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein, C1-C10The alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl may optionally be further substituted with one or more substituents selected from halogen, trihalomethyl or C1-C10Substituted by a substituent of alkoxy;
R9is selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl or imidazolyl.
Furthermore, in the compound with the structure shown in the formula (II),
R2and R3Preference is given toIs hydrogen or halogen;
R4preferably hydrogen, C1-C4Alkyl, allyl, benzyl or-CH2COOEt；
R5Preferably hydrogen;
R6preferably hydrogen, phenyl or 2-thienyl, wherein phenyl may optionally be further substituted by one or more halogen, trihalomethyl or methoxy groups.
Preferred compounds of the compounds of formula (II) of the present invention include, but are not limited to:
in another aspect the present invention relates to a process for the preparation of a compound represented by intermediate (II), characterized in that it comprises the following steps:
(1) reacting the compound a with the compound b under the action of alkali to obtain a compound c;
(2) reacting the compound c with an aminopyridine compound d in a protic solvent under the catalysis of acid to obtain a compound e;
(3) reacting the compound e under the action of diphenyl ether to obtain a compound (II) with a general formula;
wherein R is2、R3、R4、R5And R6Is as defined for formula (I).
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
(1) and (3) reacting the ethyl acetate compound a with the compound b under the action of alkali at the temperature of between 15 ℃ below zero and 50 ℃ for 2 to 48 hours to obtain a compound (c).
The reaction is carried out in the presence of an inorganic base, wherein the base comprises sodium hydroxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, in a preferred embodiment of the invention, the base is preferably sodium hydride.
The reaction temperature is generally from-15 ℃ to 50 ℃, preferably from 0 ℃ to 30 ℃.
The reaction time of the reaction is 2 to 48 hours, and preferably 5 to 24 hours.
(2) And (3) reacting the compound c with an aminopyridine compound d in a protic solvent under the catalysis of acid at the reaction temperature of 60-100 ℃ for 2-20 hours to obtain a compound e.
The reaction is carried out in a protic solvent, including isopropanol, ethanol, methanol, in a preferred embodiment of the invention, the solvent is preferably ethanol.
The reaction is carried out under acid catalysis, wherein the acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or acetic acid, and in a preferred embodiment of the invention, the acid is preferably concentrated hydrochloric acid.
The reaction temperature is generally 60 ℃ to 100 ℃, preferably 60 ℃ to 85 ℃.
The reaction time of the reaction is 2 to 20 hours, and preferably 5 to 10 hours.
(3) And reacting the compound e in diphenyl ether at the reaction temperature of 90-258 ℃ for 30 minutes-10 hours to obtain the compound (II).
The reaction temperature is generally from 90 ℃ to 258 ℃, preferably from 160 ℃ to 258 ℃,
the reaction time of the reaction is 30 minutes to 10 hours, and preferably 30 minutes to 5 hours.
Further, the compound (III) of the present invention can be prepared according to the literature report existing in the art. Such as CN 201110027560; borzilleri, Robert M.et al, Journal of Medicinal Chemistry, 2009, 52: 1251; WO 2008058229; mannion, m.et al, Bioorganic & Medicinal chemistry letters, 2009, 19: 6552; WO 2009127417; US 20080004273; WO 2007146824; zhao, Ailing et al, Bioorganic & Medicinal Chemistry, 2011, 19: 3906 and the related documents in which they are cited. The compound (II) related to the present invention can be prepared by referring to methods reported in similar documents in the field, such as WO2010083444 and related documents cited in the same.
The invention also relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of formula (I) in free form or in pharmaceutically acceptable salt form; one or more pharmaceutically acceptable carrier substances and/or diluents. The compound of the general formula (I) provided by the invention and a pharmaceutically acceptable carrier, excipient or diluent can also be included.
The invention also relates to a combined pharmaceutical composition comprising an effective amount of a compound of formula (I) in free form or in pharmaceutically acceptable salt form; one or more pharmaceutically acceptable carrier substances and/or diluents.
The fused heterocyclic derivative and the pharmaceutical composition shown in the general formula (I) can be applied to the preparation of drugs for treating protein kinase mediated diseases. Characterized in that the protein kinase comprises c-Met, KDR or c-kit.
Preferably, the protein kinase related disease is selected from a receptor tyrosine kinase related disease, a non-receptor tyrosine kinase related disease or a serine-threonine kinase related disease.
Preferably, the protein kinase related disease is selected from hepatocyte growth factor, vascular endothelial growth factor receptor related diseases, stem cell factor receptor related diseases, epidermal growth factor receptor related diseases, platelet derived growth factor receptor related diseases, insulin-like growth factor receptor related diseases or fetal liver kinase related diseases.
Preferably, the protein kinase related disease is selected from diabetes, a hyperproliferative disease, angiogenesis, an inflammatory disease, an immunological disease or a cardiovascular disease.
Preferably, the protein kinase associated disease (or proliferative disease) is selected from colorectal cancer, bladder cancer, breast cancer, liver cancer, lung cancer, pancreatic cancer, gastrointestinal cancer, leukemia, ovarian cancer, head and neck cancer, prostate cancer, kidney cancer, nasopharyngeal cancer, glioblastoma, squamous cell carcinoma, astrocytic cancer, kaposi's sarcoma, melanoma, glioma, genitourinary tract cancer or a myeloproliferative disorder.
To examine the level of action of the compounds provided herein on protein kinases, biochemical level enzyme activity assays, cellular level enzyme activity assays, and assays for inhibiting tumor cell proliferation activity were used to determine the activity and level of action of various compounds of the invention on one or more PKs. Similar experiments can be designed in the same way for any kinase using methods well known in the art.
In biochemical level enzyme activity assays, Tyrosine kinase activity is measured using the HTRF technique, a time-resolved fluorescence resonance energy transfer technique, which can be performed according to known instructions or literature methods, as described by Kolb et al, "Tyrosine kinase assays adapted to homologous time-resolved fluorescence Spectroscopy". Drug Discovery Today, Vol.3: pp 333-. HTRF (homogeneous time-resolved fluorescence) is one of the most commonly used methods for detecting analytes in homogeneous systems, combining Fluorescence Resonance Energy Transfer (FRET) and time-resolved Techniques (TR), and has been widely used in various stages of drug development based on cell and biochemical experiments. According to the determination principle of an HTRF method, after incubation reaction of pure enzyme Met, biotinylated substrate and ATP, avidin labeled XL-665 and Eu labeled antibody for recognizing phosphorylation of the substrate are added, after the substrate is phosphorylated by the Met, the Eu labeled antibody can recognize the phosphorylation product and form time-resolved Fluorescence Resonance Energy Transfer (FRET) with the avidin labeled XL665, but the non-phosphorylated substrate cannot form FRET signal due to the fact that the substrate cannot be recognized by the antibody, and the inhibition activity of the object to be detected on tyrosine kinases such as c-Met, Flt-3, VEGFR-2, PDGFR-beta, c-Kit and the like under different concentrations is determined by determining the difference value of the fluorescence signals of 665nm and 620 nm. Thus, the effect of the compounds of the invention on the biochemical level of the tyrosine kinases described above can be determined using this method, while similar assays can be used for other protein kinases using methods well known in the art.
In cellular level enzyme activity assays, enzyme-linked immunosorbent assays (ELISAs) can be used to test for and determine the presence of tyrosine kinase activity. ELISA can be performed according to known methods, for example, by Voller et al, 1980, "Enzyme-linked Immunosorbent Assay" (Enzyme-linked Immunosorbent Assay), see handbook of Clinical Immunology (Manual of Clinical Immunology), 2 nd edition, pp 359 & 371, published by the American society for microbiology, Washington D.C.. Tyrosine kinases such as c-Met, Flt-3, VEGFR-2, PDGFR-beta, c-Kit and the like catalyze the phosphorylation reaction of ATP and biotin labeled substrate peptide, and the inhibition of enzyme activity inhibits the reaction. According to the determination principle of an ELISA method, an anti-Met antibody is coated on a solid phase carrier to grab the total Met protein in a cell lysate; then, labeling a phosphorylated part in the Met protein by using an anti-tyrosine phosphorylation antibody; adding horseradish peroxidase (HRP) labeled antibody, and combining the HRP labeled antibody with the anti-tyrosine phosphorylation antibody; and finally, adding a substrate TMB of HRP for color development. The autophosphorylation level of Met receptor in cells is detected by measuring the absorbance at the absorption wavelength of 450nM, so that the inhibition activity of the substance to be detected on tyrosine kinases such as c-Met, Flt-3, VEGFR-2, PDGFR-beta, c-Kit and the like under different concentrations is determined. Thus, the effect of the compounds of the invention on the activity at the cellular level of the tyrosine kinases described above can be determined using this method, while similar assays can be used for other protein kinases using methods well known in the art.
In the activity test for inhibiting the proliferation of tumor cells, the tetrazolium bromide (MTT) method is adopted conventionally. Succinate dehydrogenase in the mitochondria of living cells can reduce exogenous yellow 3- (4, 5-dimethylthiazol-2) -2, 5-diphenyltetrazolium bromide (MTT) to the poorly soluble bluish-violet crystal Formazan (Formazan) and deposit in the cells, while dead cells do not have this function, and dimethyl sulfoxide (DMSO) can solubilize the purple crystal Formazan in the cells and its light absorption value is measured at 570nm wavelength with an enzyme linked immunosorbent detector, which indirectly reflects the viable cell number. Thus formazan production is typically proportional to the number of viable cells, and the number of viable cells can be inferred from the OD values, knowing the ability of the drug to inhibit or kill the cells. This assay can be used to determine the ability of different compounds of the invention to inhibit the proliferation of one or more cancer cells, and similar assays can be used for any cancer cell using methods well known in the art.
The compound prepared by the invention and having the structure shown in the formula (I) has good inhibition effect on the activity of various kinases, and half Inhibition Concentration (IC) of the compound on kinases such as c-Met, KDR, c-kit and the like50) Is commonly used at 10-7mol/L is less than. Meanwhile, the compound with the structure shown in the formula I prepared in the embodiment of the invention has an inhibition effect on the proliferation of various tumor cells, wherein most of the compounds have an obvious effect on inhibiting the proliferation of the tumor cells, and the IC of the compounds is50At 10-5mol/L is less than. It is presumed that the compounds of the present invention having the structure of formula (I) can be used for the preparation of a medicament for treating a protein kinase-associated disease in an organism.
Detailed description of the invention
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
Alkyl "refers to a saturated aliphatic hydrocarbon group. Including straight or branched chain groups of 1to 20 carbon atoms. Medium-sized alkyl groups containing 1to 10 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. More preferred is a lower alkyl group having 1to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, or the like. Alkyl groups may be substituted or unsubstituted, and when substituted, preferred groups are: halogen, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, halo C1-C10Alkyl, 5-to 8-membered heteroalicyclic, hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy radical, -NR7R8、-NR7C(＝O)R8、-C(＝O)OR9or-OC (═ O) R9。
"cycloalkyl" refers to a 3 to 8 membered all carbon monocyclic, all carbon 5/6 or 6/6 membered fused ring or multiple fused ring (by "fused" ring is meant that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system) group wherein one or more rings have a □ electron system attached completely, examples of cycloalkyl are (without limitation) cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene. Cycloalkyl groups are substitutable and are substituted. When substituted, the substituents are preferably one or more groups each selected from the group consisting of: c1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, halogen, 5-to 8-membered heteroalicyclic, hydroxy, mercapto, C1-C10Alkoxy radical, C6-C10Aryloxy radical, C1-C10Alkanemercapto group, C6-C10Aromatic mercapto, cyano, nitro, -NR7R8、-NR7C(＝O)R8、-C(＝O)NR7R8、-C(＝O)R9、-C(＝O)OR9、-S(O)R10、-S(O)2R10、-S(O)2NR7R8or-OC (═ O) R9。
"aryl" means an all-carbon monocyclic or fused polycyclic group of 6 to 14 carbon atoms having a completely conjugated pi-electron system. "aryl" includes:
six-membered carbon aromatic rings, such as benzene;
bicyclic rings in which at least one of the rings is a carbon aromatic ring, such as naphthalene, indene and 1, 2, 3, 4-tetrahydroquinoline; and
tricyclic rings in which at least one ring is a carbocyclic aromatic ring, e.g., fluorene.
For example, an aryl group includes a six-membered carbocyclic aromatic ring and a six-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, provided that the point of attachment is on the carbocyclic aromatic ring. However, aryl does not include, nor overlap in any way with, the heterocyclic aryl groups respectively defined below. Thus, as defined herein, if one or more carbocyclic aromatic rings are fused to a heteroaromatic ring, the resulting ring system is heteroaryl, not aryl. Non-limiting examples of aryl groups are phenyl, naphthyl. The aryl group may be substituted or unsubstituted. When substituted, preferred groups are: hydrogen, C1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C5-C10Heteroaryl group, C6-C10Aryl radical C1-C10Alkyl radical, C5-C10Heteroaryl C1-C10Alkyl, halogen, halogeno C1-C10Alkyl, 5-to 8-membered heteroalicyclic, hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, cyano, nitro, -NR7R8、-NR7C(＝O)R8、-C(＝O)R9、-C(＝O)OR9、-C(＝O)NR7R8、-S(O)R10、-S(O)2R10、-S(O)2NR7R8、-O(CH2)nR11or-OC (═ O) R9。
"heteroaryl" denotes a monocyclic or fused ring group of 5 to 14 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and additionally having a completely conjugated pi-electron system. Heteroaryl refers to:
5-8 membered monocyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as 1-4 heteroatoms, and in some embodiments 1-3 heteroatoms, with the other atoms in the ring being carbon atoms;
8-12 membered bicyclic arenes containing one or more heteroatoms selected from N, O and S, such as 1-4 heteroatoms, and in some embodiments 1-3 heteroatoms, with the other atoms in the ring being carbon atoms; wherein at least one ring is aromatic; and
11-14 membered tricyclic aromatic hydrocarbons containing one or more heteroatoms selected from N, O and S, such as 1-4 heteroatoms, and in some embodiments 1-3 heteroatoms, with the other atoms in the ring being carbon atoms; wherein at least one ring is aromatic.
For example, heteroaryl includes a 5-6 membered heteroaromatic ring and a 5-6 membered cycloalkyl. For such bicyclic fused heteroaryl groups, only one ring contains one or more heteroatoms and the attachment site is on the heteroaromatic ring.
When the total number of sulfur and oxygen atoms on the heteroaryl group exceeds 1, these heteroatoms are not adjacent one to another. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group is no more than 2. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group is no more than 1.
Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, pyridine, pyridone, imidazoie, pyrazine, pyridazine, indole, azaindole, benzimidazole, indoline, indolinone, quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, and the like. Preferred examples of such groups are thiophene, pyridine, quinoline, quinazoline, thienopyrimidine. One or all of the hydrogen atoms in the heteroaryl group may be substituted by: c1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C5-C10Heteroaryl group, C6-C10Aryl radical C1-C10Alkyl radical, C5-C10Heteroaryl C1-C10Alkyl, halogen, halogeno C1-C10Alkyl, 5-to 8-membered heteroalicyclic, hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, cyano, nitro, -NR7R8、-NR7C(＝O)R8、-C(＝O)R9、-C(＝O)OR9、-C(＝O)NR7R8、-S(O)R10、-S(O)2R10、-S(O)2NR7R8、-O(CH2)nR11or-OC (═ O) R9。
"Heterocyclyl" means a monocyclic or fused ring group having 5 to 9 ring atoms in the ring, wherein one or two ring atoms are selected from N, O or S (O)p(wherein p is an integer from 0 to 2) and the remaining ring atoms are C. These rings may have one or more double bonds, but these rings do not have a completely conjugated pi-electron system. Non-limiting examples of unsubstituted heteroalicyclic groups are pyrrolidinyl, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino, and the like. The heteroalicyclic group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, even more preferably one or two, independently selected from the group comprising: hydrogen, hydroxy, C1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic, -C (═ O) R9or-S (O)2R10In which C is1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic further substituted with one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, -O (CH)2)nR11、-OC(＝O)R10、-NR7R8or-NR7C(＝O)R8Substituted with the substituent(s).
Piperazino refers to a group having the following chemical structure.
Morpholino refers to a group having the following chemical structure.
Piperidino refers to a group having the following chemical structure.
Pyrrolidinyl refers to a group having the following chemical structure.
"alkenyl" means a straight or branched chain hydrocarbon group having 1 or more double bonds. Is typically C2-C6Alkenyl groups, such as vinyl, allyl, butenyl, butadienyl, pentenyl or hexenyl.
"alkynyl" means a straight or branched chain hydrocarbon group having 1 or more triple bonds. Is typically C2-C6Alkynyl groups, such as ethynyl, propynyl, butynyl.
"alkoxy" means-O- (unsubstituted alkyl) and-O (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"aryloxy" means-O-aryl and-O-heteroaryl. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furyloxy, thiophenyloxy, pyrimidyloxy, pyrazinyloxy, and the like, and derivatives thereof.
"aralkyl" denotes alkyl, preferably lower alkyl as defined above, substituted by aryl as defined above, e.g. -CH2Phenyl, - (CH)2)2Phenyl, - (CH)2)3Phenyl radical, CH3CH(CH3)CH2Phenyl and its derivatives.
"Heteroaralkyl" denotes alkyl, preferably lower alkyl as defined above, substituted by heteroaryl as defined above, e.g. -CH2Pyridyl, - (CH)2)2Pyrimidinyl, - (CH)2)3Imidazolyl and the like and derivatives thereof.
"hydroxy" means an-OH group.
"mercapto" means an-SH group.
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"haloalkyl" denotes alkyl, preferably lower alkyl as defined above, substituted by one or more identical or different halogen atoms, e.g. -CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3And the like.
"Trihalomethyl" means-CX3A radical in which X is halogen as defined above.
"cyano" means a-CN group.
"amino" means-NH2A group.
"nitro" means-NO2A group.
By "optionally," it is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where it does or does not occur.
In some embodiments, "substituted with one or more groups" means that the same or different groups selected from the group in which the indicated atom or group has one, two, three, or four hydrogen atoms in the group, respectively, indicated for the range are replaced.
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) salts with acids are obtained by reaction of the free base of the parent compound with inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like, or with organic acids including acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, malonic acid, and the like.
(2) The acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or is complexed with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.
"pharmaceutical composition" refers to the combination of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration process to an animal.
By "pharmaceutically acceptable carrier" is meant an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to: calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic or methacrylic polymers, gelatin, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or hydrogenated or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.
The aforementioned pharmaceutical compositions may contain, in addition to pharmaceutically acceptable carriers, adjuvants commonly used in pharmacology, such as: antibacterial agents, antifungal agents, antimicrobial agents, shelf-stable agents, hueing agents, solubilizing agents, thickening agents, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, flavors or combinations thereof, and the like.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Example 1: preparation of Compound 1
Preparation of (Z) -ethyl-3-hydroxy-2-phenylacrylate
28g of ethyl phenylacetate and 230mL of ethyl formate were placed in a 1L three-necked flask and ice-cooled. 20g of NaH was weighed, slowly added to the three-necked flask, and a large amount of gas was bubbled out for about 30 minutes. After the addition, stirring at normal temperature for 5h, stopping the reaction, adding the reaction solution into a proper amount of water, adjusting the pH value to be acidic, extracting an organic layer by using a proper amount of ethyl acetate, combining, drying, and removing the organic solvent by spinning to obtain 32g of an oily product.
Preparation of (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2-benzeneacrylate
Ethyl-3-hydroxy-2-phenylacrylate (19g, 1eq), 2-chloro-4-aminopyridine (12.7g, 1eq), ethanol (300mL), concentrated hydrochloric acid (0.5mL) were added to a reaction flask, mixed well and heated to 85 ℃ to react for 5 hours, the reaction was stopped, ethanol was removed under reduced pressure, and the residue was separated by column chromatography to give ethyl-3- ((2-chloropyridin-4-yl) amino) -2-phenylacrylate (19.3 g).
Preparation of 5-chloro-3-phenyl-1, 6-naphthyridin-4 (1H) -one
Adding ethyl-3- ((2-chloropyridin-4-yl) amino) -2-phenylacrylate (10g, 1eq) and diphenyl ether (80mL) into a reaction bottle, uniformly mixing, heating to 258 ℃ for half an hour, stopping the reaction, cooling to 50-60 ℃, pouring into 500mL petroleum ether, filtering the precipitated solid, and separating by a solid chromatographic column to obtain 5-chloro-3-phenyl-1, 6-naphthyridin-4 (1H) -one (2.0 g).
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-3-phenyl-1, 6-naphthyridin-4 (1H) -one
5-chloro-3-phenyl-1, 6-naphthyridin-4 (1H) -one (50mg, 1eq), 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline (61.5mg, 1eq), concentrated hydrochloric acid (1 drop) and isopropanol (65mL) are added into a reaction flask, mixed, stirred electromagnetically, heated to 50 ℃ for reaction for 3 hours, insoluble substances are filtered out, and a filter cake is washed by the isopropanol and dried in vacuum to obtain the 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-3-phenyl-1, 6-naphthyridin-4 (1H) -one (38 mg).
1H-NMR(400M，DMSO-d6)13.59(s，1H)，12.88(s，1H)，8.57(s，1H)，8.32-8.35(m，1H)，8.15(s，1H)，8.07-8.08(d，1H)，7.68-7.70(d，2H)，7.58(s，1H)，7.44-7.46(m，1H)，7.35-7.41(m，1H)，7.28-7.30(m，1H)，3.99(s，6H)ppm。
Example 2: preparation of Compound 2
Preparation of 3-chloro-4- (2-fluoro-4- ((4-oxo-3-phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine
Adding 5-chloro-3-phenyl-1, 6-naphthyridin-4 (1H) -ketone (150mg, 1eq), 4- (4-amino-2-fluorophenoxy) -3-chloro-2-amidopyridine (162mg, 1eq), concentrated hydrochloric acid (3 drops) and isopropanol (130mL) into a reaction bottle, mixing, electromagnetically stirring, heating to 50 ℃ for reacting for 3 hours, filtering out insoluble substances, washing a filter cake with isopropanol, and drying in vacuum to obtain 3-chloro-4- (2-fluoro-4- ((4-oxo-3-phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine (68 mg). Preparation of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3-phenyl-1, 6-naphthyridin-4 (1H) -one
Adding iodobenzene trifluoroacetate (98mg, 2eq) into a solution of 3-chloro-4- (2-fluoro-4- ((4-oxo-3-phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine (65mg, 1eq), acetonitrile (35mL), ethyl acetate (35mL) and water (7mL), pumping nitrogen, reacting for 2 hours under the protection of nitrogen, completely performing plate reaction, stopping the reaction, adding water (20mL), saturated sodium bicarbonate (15mL), extracting ethyl acetate (20mL) 5, combining organic phases, drying by anhydrous sodium sulfate, performing suction filtration, concentrating, and performing crude silica gel column chromatography to obtain 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3 -phenyl-1, 6-naphthyridin-4 (1H) -one (31 mg). MS: [ M-H ]]+＝472.4.
1H-NMR(400M，DMSO-d6)13.61(s，1H)，12.55(s，1H)，8.34-8.37(d，1H)，8.16(d，1H)，8.08(d，1H)，7.74-7.75(d，1H)，7.68-7.69(d，2H)，7.38-7.44(m，2H)，7.23-7.30(m，2H)，6.34(s，2H)，5.94-6.03(m，3H)ppm。
Example 3: preparation of Compound 3
Preparation of 4- (4-amino-2-fluorophenoxy) -3-iodo-2-pyridineamide
3-iodo-4-chloro-2-picolinamide (281mg, 1.0eq), 2-fluoro-4-aminophenol (127mg, 1.0eq), potassium tert-butoxide (145.6mg, 1.3eq), anhydrous DMF (25mL) were added to a reaction flask, heated to 90 ℃ for 4 hours, spotted on a plate for completion of reaction, the reaction was stopped, the solvent was recovered under reduced pressure, and the residue was subjected to silica gel column chromatography to give 4- (4-amino-2-fluorobenzene) -3-iodo-2-picolinamide (300 mg).
Preparation of 4- (2-fluoro-4- ((4-oxo-3-phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -3-iodo-2-amidopyridine
To a 100mL round bottom flask were added 4- (4-amino-2-fluorophenoxy) -3-iodo-2-picolinamide (580mg, 1.0eq), 5-chloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (426mg, 1eq), 100mL of isopropanol, and 0.1mL of concentrated hydrochloric acid, and the mixture was heated to 50 ℃ to react for 6 hours, the reaction was stopped, the solid was filtered off, washed with 30mL of isopropanol and dried under vacuum to weigh 200mg of 4- (2-fluoro-4- ((4-oxo-3-phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -3-iodo-2-amidopyridine.
Preparation of 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy) -3-fluorophenyl) amino) -3-phenyl-1, 6-naphthyridin-4 (1H) one
Adding 4- (2-fluoro-4- ((4-oxo-3-phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -3-iodo-2-amidopyridine (100mg, 1eq), acetonitrile (18mL), ethyl acetate (18mL) and water (9mL) into a 100mL round-bottom flask at room temperature, stirring for 5min, adding iodobenzene acetate (125mg, 2eq) into the reaction, pumping nitrogen, reacting for 1 hour under the protection of nitrogen, and (3) completely carrying out plate reaction, stopping reaction, adding water (20mL), extracting with ethyl acetate (20mL × 5), combining organic phases, drying with anhydrous sodium sulfate, carrying out suction filtration, concentrating, and carrying out silica gel column chromatography on a crude product to obtain the 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy) -3.-fluorophenyl) amino) -3-phenyl-1, 6-naphthyridin-4 (1H) one (61.5 mg). MS: [ M + H ]]+＝566.1.
1H-NMR(400M，DMSO-d6)13.2(s，1H)，12.4(s，1H)，8.34-8.25(d，1H)，8.20-8.10(m，2H)，7.70-7.60(m，2H)，7.40-7.50(m，4H)，7.30-7.41(t，1H)，7.20-7.29(t，1H)，6.80-6.91(d，2H)，6.15-6.20(s，2H)，5.74-5.85(d，H)ppm。
Example 4: preparation of Compound 4
Preparation of (Z) -ethyl-2- (4-fluorophenyl) -3-hydroxyacrylate
Ethyl 2- (4-fluorophenyl) acetate (17.2g, 1eq) and ethyl formate (84mL, 15eq) were added to a reaction flask, sodium hydride (22.6g, 6eq) was slowly added under ice bath conditions, the reaction was carried out for 16 hours, the reaction was stopped after the completion of the spotting reaction, an appropriate amount of water was added to adjust the pH to acidity, extraction was carried out with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain an oily (Z) -ethyl-2- (4-fluorophenyl) -3-hydroxyacrylate (10.0 g).
Preparation of (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (4-fluorophenyl) acrylate
(Z) -ethyl-2- (4-fluorophenyl) -3-hydroxyacrylate (10.0g, 1eq), 2-chloro-4-aminopyridine (7.3g, 1.2eq), ethanol (100mL) and concentrated hydrochloric acid (0.3mL) were added to a reaction flask, mixed uniformly, heated to 60 ℃ for 10 hours, stopped, and subjected to reduced pressure to remove ethanol, and the residue was subjected to column chromatography to obtain (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (4-fluorophenyl) acrylate (5.9 g).
Preparation of 5-chloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (4-fluorophenyl) acrylate (5.9g, 1eq) and diphenyl ether (40mL) into a reaction bottle, uniformly mixing, heating to 160 ℃, reacting for 5 hours, stopping the reaction, cooling to 50-60 ℃, pouring into 400mL petroleum ether, filtering to separate out a solid, and separating by using a solid chromatographic column to obtain 5-chloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (700 mg).
Preparation of 3-chloro-4- (2-fluoro-4- ((3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine
The procedure was as for the synthesis of 3-chloro-4- (2-fluoro-4- ((4-oxo-3-phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine in example 2, except that 5-chloro-3-phenyl-1, 6-naphthyridin-4 (1H) -one was changed to 5-chloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one and the reaction time was 5 hours.
Preparation of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3-phenyl-1, 6-naphthyridin-4 (1H) -one in example 2, except that 3-chloro-4- (2-fluoro-4- ((4-oxy-3-phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine was changed to 3-chloro-4- (2-fluoro-4- ((3- (4-fluorophenyl) -4-oxy-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine, reaction time 2 hours. MS: [ M + H ]]+＝493.1.
1H-NMR(400M，DMSO-d6)13.14(s，1H)，12.41(s，1H)，8.31-8.35(d，1H)，8.17-8.18(d，2H)，7.70-7.76(m，3H)，7.45-7.47(m，1H)，723-7.29(m，3H)，6.85-6.87(d，1H)，6.35(s，2H)，5.94-5.95(d，1H)ppm。
Example 5: preparation of Compound 5
Preparation of 4- (2-fluoro-4- ((3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -3-iodo-2-amidopyridine
To a 100mL round bottom flask were added 4- (4-amino-2-fluorophenoxy) -3-iodo-2-picolinamide (373mg, 1.0eq), 5-chloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (275mg, 1eq), isopropyl alcohol 65mL, and concentrated hydrochloric acid 0.1mL, heated to 50 ℃ for 7 hours, the reaction was stopped, the solid was filtered off, washed with 30mL of isopropanol and dried under vacuum to weigh 213mg of 4- (2-fluoro-4- ((3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -3-iodo-2-carboxamide pyridine.
Preparation of 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding 4- (2-fluoro-4- ((3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -3-iodo-2-amidopyridine (100mg, 1eq), acetonitrile (18mL), ethyl acetate (18mL) and water (9mL) into a 100mL round bottom flask at room temperature, stirring for 5min, adding iodobenzene acetate (128mg, 2eq) into the reaction, pumping nitrogen, reacting for 1 hour under the protection of nitrogen, stopping the reaction by spotting, adding water (20mL), extracting ethyl acetate (20mL 5), combining organic phases, drying anhydrous sodium sulfate, carrying out suction filtration, concentrating, and carrying out silica gel column chromatography to obtain 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy) -3-fluorobenzene crude product Yl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (57.1 mg). MS: [ M + H ]]+＝583.03.
1H-NMR(400M，DMSO-d6)13.15(s，1H)，12.42(s，1H)，8.32-8.34(m，1H)，8.20-8.10(m，2H)，7.70-7.60(m，3H)，7.40-7.50(m，1H)，7.22-7.27(m，3H)，6.80-6.91(d，1H)，6.15-6.20(s，2H)，5.74-5.85(d，1H)ppm。
Example 6: preparation of Compound 6
Preparation of 3-chloro-4- (4- ((1-ethyl-3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -2-amidopyridine
Adding 3-chloro-4- (2-fluoro-4- ((3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amide pyridine (50mg, 1eq), bromoethane (15mg, 1.5eq), potassium carbonate (19mg, 1.5eq) and DMF (30mL) into a reaction bottle, mixing, electromagnetically stirring, heating to 90 ℃ for reaction for 3 hours, the 3-chloro-4- (4- ((1-ethyl 3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -2-amidopyridine (45mg) was obtained by column chromatography.
Preparation of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -1-ethyl-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3-phenyl-1, 6-naphthyridin-4 (1H) -one in example 2, except that 3-chloro-4- (2-fluoro-4- ((4-oxy-3-phenyl-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine was changed to 3-chloro-4- (4- ((1-ethyl 3- (4-fluorophenyl) -4-oxy-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -2-amidopyridine, for 2 hours. MS: [ M + H ]]+＝520.1.
1H-NMR(400M，DMSO-d6)13.49(s，1H)，8.34-8.37(d，2H)，8.29-8.30(d，1H)，7.73-7.77(m，3H)，7.62-7.64(d，2H)，7.46-7.48(d，1H)，7.26-7.32(m，3H)，7.06-7.08(d，1H)，6.43(s，2H)，5.94-5.96(d，1H)ppm。
Example 7: preparation of Compound 7
Preparation of 5- ((3-fluoro-4- ((7-methoxyquinolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
5-chloro-4-fluorophenyl-1, 6-naphthyridin-4 (1H) -one (50mg, 1eq), 4- ((7-methoxyquinolin-4-yl) oxy) -3-fluoroaniline (52mg, 1eq), concentrated hydrochloric acid (1 drop) and isopropanol (25mL) were added to a reaction flask, mixed and stirred magnetically, warmed to 40 ℃ for 4 hours to react, insoluble matter was filtered off, the filter cake was washed with isopropanol and dried under vacuum to give 5- ((3-fluoro-4- ((7-methoxyquinolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (18 mg).
1H-NMR(400M，DMSO-d6)13.30(s，1H)，13.06(s，1H)，9.02-9.04(d，1H)，8.53-8.55(d，1H)，8.32.-8.36(d，1H)，8.27-8.29(d，1H)，8.11-8.13(d，1H)，7.71-7.76(m，3H)，7.59-7.67(m，3H)，7.27-7.32(m，2H)，7.20-7.26(d，1H)，7.02-7.04(d，1H)，4.05(s，3H)ppm。
Example 8: preparation of Compound 8
Preparation of 3-chloro-4- (2-fluoro-4- ((3- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine
The procedure was as for the synthesis of 3-chloro-4- (4- ((1-ethyl 3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -2-amidopyridine in example 6, except that ethyl bromide was changed to methyl iodide and the reaction time was 2 hours.
Preparation of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -one
Preparation was carried out as described for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -1-ethyl-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 6, except that 3-chloro-4- (4- ((1-ethyl 3- (4-fluorophenyl) -4-oxy-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -2-amidopyridine was changed to 3-chloro-4- (2-fluoro-4- ((3- (4-fluorophenyl) -1-methyl-4-oxy-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine with a reaction time of 2 hours. MS: [ M + H ]]+＝506.0.
1H-NMR(400M，DMSO-d6)13.27(s，1H)，8.21-8.25(m，2H)，7.67(s，1H)，7.54(s，1H)，7.45-7.46(m，2H)，7.35-7.37(d，1H)，7.04-7.11(m，3H)，6.54-6.56(d，1H)，6.09-6.11(d，1H)，5.74(s，2H)，5.27-5.29(d，2H)ppm。
Example 9: preparation of Compound 9
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-3-phenyl-1, 6-naphthyridin-4 (1H) -one in example 1, except that 5-chloro-3-phenyl-1, 6-naphthyridin-4 (1H) -one was changed to 5-chloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one MS: [ M + H ] -M]+＝554.1.
1H-NMR(400M，DMSO-d6)13.37(s，1H)，13.07(s，1H)，8.64(s，1H)，8.29-8.31(d，1H)，8.10-8.13(d，1H)，8.04-8.06(d，1H)，7.73-7.76(m，2H)，7.61(s，1H)，7.49-7.58(m，2H)，7.45(s，1H)，7.27-7.31(m，2H)，7.00-7.01(m，2H)，4.01(s，6H)ppm。
Example 10: preparation of Compound 10
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-1-ethyl-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 3-chloro-4- (4- ((1-ethyl 3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -2-amidopyridine in example 6, except that 3-chloro-4- (2-fluoro-4- ((3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine was changed to 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one. MS: [ M + H ]]+＝582.1.
1H-NMR(400M，DMSO-d6)13.47(s，1H)，8.58(s，1H)，8.37(s，1H)，8.29-8.35(m，3H)，7.74-7.78(m，1H)，7.59(s，1H)，7.48-7.51(d，1H)，7.39-7.44(m，2H)，7.27-7.31(m，2H)，7.06-7.07(d，1H)，4.35(m，2H)，4.00(s，6H)，1.38-1.41(d，3H)ppm。
Example 11: preparation of Compound 11
Preparation of 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy) -3-fluorophenyl) amino) -1-ethyl-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
To a 50mL round bottom flask at room temperature was added 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (58mg, 1eq), N, N-dimethylFormamide (15mL), bromoethane (214mg, 2eq), potassium carbonate (414mg, 3eqL), stirring for 5min, heating to 90 ℃ for reaction for 2 hours under the protection of nitrogen, spotting the reaction on a plate to complete the reaction, stopping the reaction, removing DMF under reduced pressure, adding water (20mL), stirring to separate out a solid, performing suction filtration, drying, and performing silica gel column chromatography on a crude product to obtain 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy) -3-fluorophenyl) amino) -1-ethyl-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (51 mg). MS: [ M + H ]]+＝512.0.
1H-NMR(400M，DMSO-d6)13.1(s，1H)，12.4(s，1H)，8.34(d，1H)，8.20-8.10(m，2H)，7.70-7.60(m，2H)，7.40-7.50(m，4H)，7.30-7.41(t，1H)，7.22-7.27(t，2H)，6.80-6.91(d，2H)，6.15-6.20(ds，2H)，5.74-5.85(d，H)ppm，4.31-4.37(dd，2H)，1.31-1.47(t，2H)。
Example 12: preparation of Compound 12
Preparation of 1-ethyl-5- ((3-fluoro-4- ((7-methoxyquinolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding 5- ((3-fluoro-4- ((7-methoxyquinolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (52.2mg, 1eq), N, N-dimethylformamide (25mL), bromoethane (214mg, 2eq), potassium carbonate (414mg, 3eqL) into a 50mL round-bottomed flask at room temperature, stirring for 5min, heating to 90 ℃ for 2 hours under the protection of nitrogen, carrying out plate reaction, stopping the reaction, removing DMF under reduced pressure, adding water (20mL), stirring to separate out a solid, carrying out suction filtration, drying, and carrying out crude silica gel column chromatography to obtain 1-ethyl-5- ((3-fluoro-4- ((7-methoxyquinolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (43 mg). MS: [ M + H ] + -550.1.
1H-NMR(400M，DMSO-d6)13.5(s，1H)，，8.62-8.64(d，1H)，8.31-8.44(m，2H)，8.30-8.32(d，1H)，8.25-8.27(d，1H)，7.74-7.78(m，2H)，7.55-7.56(d，1H)，7.42-7.46(m，2H)，7.27-7.33(m 3H)，7.08-7.09(d，1H)，6.51-6.52(d，1H)，4.31-4.37(dd，2H)，1.31-1.47(t，2H)。
Example 13: preparation of Compound 13
Preparation of 1-allyl-5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy-3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxygen) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -ketone (582mg, 1eq), N, N-dimethylformamide (25mL), allyl bromide (238mg, 2eq) and potassium carbonate (414mg, 3eqL) into a 50mLl round-bottom flask at room temperature, stirring for 5min, heating to 90 ℃ for reaction for 2 hours under the protection of nitrogen, carrying out plate-spotting reaction completely, stopping reaction, removing DMF under reduced pressure, adding water (20mL), stirring to separate out a solid, carrying out suction filtration, drying, and carrying out crude silica gel column chromatography to obtain 1-allyl-5- ((4- ((2-amino-3-iodopyridin-4-yl) oxygen-3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (57.0 mg). MS: [ M + H ]]+＝623.0.
1H-NMR(400M，DMSO-d6)13.42(s，1H)，8.32-8.36(m，2H)，7.71-7.74(m，3H)，7.45-7.48(d，1H)，7.25-7.31(m，3H)，6.95-6.97(d，2H)，6.24(s，2H)，6.00-6.11(m，1H)，5.80-5.82(d，2H)，5.17-5.32(m，2H)，4.95-4.97(d，2H)。
Example 14: preparation of Compound 14
Preparation of 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy) -3-fluorophenyl) amino) -1-benzyl-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxygen) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -ketone (58.2mg, 1eq), N, N-dimethylformamide (25mL), benzyl bromide (338mg, 2eq) and potassium carbonate (414mg, 3eq) into a 50mL round bottom flask at room temperature, stirring for 5min, heating to 90 ℃ for 2 hours under the protection of nitrogen, carrying out plate addition reaction completely, stopping the reaction, removing DMF under reduced pressure, adding water (20mL), stirring to separate out a solid, carrying out suction filtration, drying, and carrying out silica gel column chromatography to obtain 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxygen) -3-fluorophenyl) amino) -1-benzyl-3-, ( 4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (78.3 mg). MS: [ M + H ]]+＝673.0.
1H-NMR(400M，DMSO-d6)13.42(s，1H)，8.61(s，1H)，8.30-8.34(d，1H)，8.18-8.20(d，1H)，7.76-7.79(m，3H)，7.74-7.79(d，1H)，7.27-7.49(m，8H)，6.89-6.90(d，1H)，6.38(s，2H)，5.91-5.92(d，1H)，5.59(s，2H)，4.95-4.97(d，2H)。
Example 15: preparation of Compound 15
Preparation of ethyl-2- (5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -4-oxy-1, 6-naphthyridin-1 (4H) -yl) acetate
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-iodopyridin-4-yl) oxy) -3-fluorophenyl) amino) -1-ethyl-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 11, except that ethyl bromide was changed to ethyl chloroacetate and the reaction time was 3 hours. MS: [ M + H ]]+＝669.0.
1H-NMR(400M，DMSO-d6)13.10(s，1H)，8.22-8.28(m，2H)，7.78-7.80(d，1H)，7.55-7.99(m，3H)，7.40-7.42(d，1H)，7.11-7.19(m，3H)，6.38-6.40(d，1H)，5.95-5.97(d，1H)，5.22(s，2H)，4.77(s，2H)，4.31-4.36(dd，2H)，3.47-3.53(m，1H)，1.33-1.36(t，3H)。
Example 16: preparation of Compound 16
Preparation of 4- (4- ((1-benzyl-3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -3-chloro-2-amidopyridine
The procedure was as for the synthesis of 3-chloro-4- (4- ((1-ethyl 3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -2-amidopyridine in example 6, except that ethyl bromide was changed to benzyl chloride and the reaction time was 2 hours.
5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -1-benzyl-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -1-ethyl-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 6, except that 3-chloro-4- (4- ((1-ethyl 3- (4-fluorophenyl) -4-oxy-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -2-amidopyridine was changed to 4- (4- ((1-benzyl-3- (4-fluorophenyl) -4-oxy-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -3-chloro-2-amidopyridine, for a reaction time of 2 hours. MS: [ M + H ]]+＝583.1.
1H-NMR(400M，DMSO-d6)13.42(s，1H)，8.61(s，1H)，8.30-8.34(d，1H)，8.18-8.20(d，1H)，7.76-7.79(m，3H)，7.74-7.79(d，1H)，7.27-7.49(m，8H)，6.89-6.90(d，1H)，6.38(s，2H)，5.91-5.92(d，1H)，5.59(s，2H)，4.95-4.97(d，2H)ppm。
Example 17: preparation of Compound 17
Preparation of ethyl-2- (5- ((4- ((2-formyl-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -4-oxy-1, 6-naphthyridin-1 (4H) -yl) acetate
The procedure was as for the synthesis of 3-chloro-4- (4- ((1-ethyl 3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -2-amidopyridine in example 6, except that ethyl bromide was changed to ethyl chloroacetate and the reaction time was 2 hours.
Preparation of ethyl-2- (5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -4-oxy-1, 6-naphthyridin-1 (4H) -yl) acetate
Preparation was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -1-ethyl-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 6, except that 3-chloro-4- (4- ((1-ethyl 3- (4-fluorophenyl) -4-oxy-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) -2-fluorophenoxy) -2-amidopyridine was changed to ethyl-2- (5- ((4- ((2-formyl-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) Ethyl) -3- (4-fluorophenyl) -4-oxo-1, 6-naphthyridin-1 (4H) -yl) acetate, reaction time 2 hours. MS: [ M + H ]]+＝578.0.
1H-NMR(400M，DMSO-d6)13.32(s，1H)，8.36(s，1H)，8.32-8.36(d，1H)，8.26-8.27(d，1H)，7.70-7.76(m，3H)，7.47-7.50(d，1H)，7.28-7.33(m，3H)，6.84-6.86(d，1H)，6.44(s，2H)，5.94-5.96(d，1H)，5.27(s，2H)，4.19-4.24(m，2H)，1.23-1.26(m，6H)ppm。
Example 18: preparation of Compound 18
Preparation of 5- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
To a 100mL round bottom flask were added 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline (314mg, 1.0eq), 5-chloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (274mg, 1eq), 100mL isopropanol, and 0.1mL concentrated hydrochloric acid, heated to 70 ℃ for 4 hours, the reaction was stopped, the solid filtered off, washed with 30mL of isopropanol and dried under vacuum to weigh 300mg of 5- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one. MS: [ M + H ]]+＝552.1.
1H-NMR(400M，DMSO-d6)13.51(s，1H)，12.89(s，1H)，8.26-8.27(d，1H)，8.20-8.21(d，1H)，7.60-7.76(m，4H)，7.68-7.70(d，1H)，7.26-7.31(t，2H)，7.02-7.03(d，1H)，6.76-6.77(d，1H)，6.56(s，2H)，3.94(s，3H)，3.73(s，3H)。
Example 19: preparation of Compound 19
Preparation of 7- (benzyloxy) -4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinoline
After 7-benzyloxy-6-methoxyquinolin-4-ol (0.84g, 1eq), cesium carbonate (6.5g, 10eq), DMF (50mL) and acetonitrile (50mL) were added to a reaction flask and reacted at room temperature for 1 hour, 1, 2-difluoro-4-nitrobenzene (0.48g, 1.5eq) was added to the system and heated to 40 ℃ for 6 hours to stop the reaction, the solvent was removed under reduced pressure, and the mixture was passed through a column by a dry method to obtain 0.75g of 7- (benzyloxy) -4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinoline.
Preparation of 4- (4-amino-2-fluorophenoxy) -6-methoxyquinolin-7-ol
To a reaction flask were added 7- (benzyloxy) -4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinoline (0.75g, 1eq), methanol (50mL), and Pd-C (0.1g), and the mixture was reacted under hydrogen at room temperature for 2 hours, whereupon the reaction was terminated, insoluble materials were removed by filtration, and the reaction mixture was concentrated to give 0.5g of 4- (4-amino-2-fluorophenoxy) -6-methoxyquinolin-7-ol.
Preparation of 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) aniline
4- (4-amino-2-fluorophenoxy) -6-methoxyquinolin-7-ol (500mg, 1eq), 4- (3-chloropropyl) morpholine (817mg, 3eq), potassium carbonate (690mg, 3eq), and DMF (75mL) were added to a reaction flask, heated to 80 ℃ for 2 hours, stopped, filtered, and concentrated to give 213.5mg of crude 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) aniline.
Preparation of 5- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
To a 100mL round bottom flask was added 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) aniline (213.5mg, 1.0eq), 5-chloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (137mg, 1eq), isopropanol 50mL, concentrated HCl 0.05mL, heated to 90 ℃ for 3 hours, stopped, the solid filtered, washed with 15mL isopropanol and dried under vacuum to weigh 5- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one 189 mg. MS: [ M + H ]]+＝665.2.
1H-NMR(400M，CDCl3)13.33(s，1H)，12.18(s，1H)，8.50-8.54(d，1H)，8.21-8.22(d，1H)，7.84-7.85(d，1H)，7.82(s，1H)，7.57-7.63(m，4H)，7.31-7.35(t，1H)，7.14-7.18(t，2H)，6.90-6.92(d，1H)，6.39-6.44(t，2H)，3.94-3.97(m，6H)，3.71(s，3H)，2.50-2.56(m，6H)，2.02-2.05(m，2H)。
Example 20: preparation of Compound 20
Preparation of 3-chloro-4- (2-fluoro-4- ((3- (4-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine
The procedure was as for the synthesis of 5- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 19, except that 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) aniline was changed to 4- (4-amino-2-fluorophenoxy) -3-chloro-2-amidopyridine, and the reaction time was 3.5 hours. MS: [ M + H ]]+＝519.0.
1H-NMR(400M，DMSO-d6)13.22(s，1H)，12.47(s，1H)，8.40-8.44(dd，1H)，8.34-8.35(d，1H)，8.19-8.20(d，2H)，8.07(s，2H)，7.71-7.76(m，3H)，7.52-7.54(d，1H)，7.36-7.40(t，1H)，7.25-7.29(t，2H)，36.85-6.89(dd，2H)。
Example 21: preparation of Compound 21
Preparation of (4- (7-benzyloxy-6-methoxyquinazolin-4-yl) oxy) -3-fluoroaniline
Adding 7-benzyloxy-4-chloro-6-methoxyquinazoline (11.5g, 1eq), 4-amino-2-fluorophenol (5.3g, 1.1eq), potassium tert-butoxide (5.1g, 1.2eq) and DMF (250mL) into a reaction flask, heating to 80 ℃ for reaction for 2 hours, stopping the reaction, removing the solvent under reduced pressure, and performing dry column chromatography to obtain 8.1g of (4- (7-benzyloxy-6-methoxyquinazolin-4-yl) oxy) -3-fluoroaniline.
Preparation of 4- (4-amino-2-fluorophenoxy) -6-methoxyquinazolin-7-ol
To a reaction flask were added (4- (7- (benzyloxy) -6-methoxyquinazolin-4-yl) oxy) -3-fluoroaniline (3.91g, 1eq), methanol (240mL), Pd-C (0.4g), and the mixture was reacted at 0 ℃ for 6 hours under hydrogen, the reaction was stopped, insoluble materials were removed by filtration, and 2.3g of 4- (4-amino-2-fluorophenoxy) -6-methoxyquinazolin-7-ol was obtained by column chromatography after concentration.
Preparation of 3-fluoro-4- ((6-methoxy-7- (3- (pyrrol-1-yl) propoxy) quinazolin-4-yl) oxy) aniline
Adding 4- (4-amino-2-fluorophenoxy) -6-methoxyquinazolin-7-ol (50mg, 1eq), 1- (3-chloropropyl) pyrrolidine (73.5mg, 3eq), potassium carbonate (68mg, 3eq) and DMF (10mL) into a reaction flask, heating to 80 ℃ for reaction for 2 hours, stopping the reaction, filtering and concentrating to obtain 38mg of crude 3-fluoro-4- ((6-methoxy-7- (3- (pyrrol-1-yl) propoxy) quinazolin-4-yl) oxy) aniline.
Preparation of 5- ((3-fluoro-4- ((6-methoxy-7- (3- (pyrrol-1-yl) propoxy) quinazolin-4-yl) oxy) benzene) amine) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Preparation was carried out as described for the synthesis of 5- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 19, except that 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yl) oxy) aniline was changed to 3-fluoro-4- ((6-methoxy-7- (3- (pyrrol-1-yl) propoxy) quinazolin-4-yl) oxy) aniline, and the reaction time was 5 hours. MS: [ M + H ]]+＝650.3.
1H-NMR(400M，DMSO-d6)13.30(s，1H)，8.39-8.42(d，1H)，8.28(s，1H)，8.20-8.23(t，2H)，7.72-7.75(t，2H)，7.54-7.55(t，3H)，7.25-7.29(t，3H)，6.96-6.97(d，1H)，4.26-4.29(t，2H)，3.92(s，3H)，3.17-3.22(t，6H)，2.21-2.25(t，2H)，1.93(s，4H)。
Example 22: preparation of Compound 22
Preparation of (4- (6-benzyloxy-7-methoxyquinazolin-4-yl) oxy) -3-fluoroaniline
6-benzyloxy-4-chloro-7-methoxyquinazoline (10.0g, 1eq), 4-amino-2-fluorophenol (4.65g, 11eq), potassium tert-butoxide (4.5g, 1.2eq) and DMF (500mL) were added to a reaction flask, and the mixture was heated to 55 ℃ to react for 3 hours, and the reaction was stopped, and after removing the solvent under reduced pressure, the mixture was passed through a column by a dry method to obtain 7g of (4- (6-benzyloxy-7-methoxyquinazolin-4-yl) oxy) -3-fluoroaniline.
Preparation of 4- (4-amino-2-fluorophenoxy) -7-methoxyquinazolin-6-ol
(4- (6-benzyloxy-7-methoxyquinazolin-4-yl) oxy) -3-fluoroaniline (3.0g, 1eq), methanol (150mL), Pd-C (0.6g) was added to a reaction flask, and the mixture was reacted at 0 ℃ for 6 hours under the action of hydrogen gas, the reaction was stopped, insoluble materials were removed by filtration, and 1.6g of 4- (4-amino-2-fluorophenoxy) -7-methoxyquinazolin-6-ol was obtained by column chromatography after concentration.
Preparation of 3-fluoro-4- ((7-methoxy-6- (3- (pyrrol-1-yl) propoxy) quinazolin-4-yl) oxy) aniline
Adding 4- (4-amino-2-fluorophenoxy) -7-methoxyquinazolin-6-ol (200mg, 1eq), 1- (3-chloropropyl) pyrrolidine (294mg, 3eq), potassium carbonate (275mg, 3eq) and DMF (30mL) into a reaction flask, heating to 80 ℃ for reaction for 2 hours, stopping the reaction, filtering, and concentrating to obtain 123mg of crude 3-fluoro-4- ((7-methoxy-6- (3- (pyrrol-1-yl) propoxy) quinazolin-4-yl) oxy) aniline.
Preparation of 5- ((3-fluoro-4- ((7-methoxy-6- (2-methoxyethoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((7-methoxy-6- (2-methoxyethoxy) quinazolin-4-yl) oxy) aniline for 6 hours (1753-23-15). MS: [ M-H ]]+＝596.1.
1H-NMR(400M，DMSO-d6)13.43(s，1H)，13.26(s，1H)，8.69(s，1H)，8.31-8.32(d，1H)，8.01-8.07(m，2H)，7.74-7.77(m，2H)，7.65(s，1H)，7.56-7.60(m，2H)，7.48-7.52(m，2H)，7.28-7.32(t，2H)，7.05-7.07(m，1H)，4.34-4.37(m，2H)，4.03-4.05(m，5H)，3.35(s，3H)ppm。
Example 23: preparation of Compound 23
Preparation of 5- ((3-fluoro-4- ((7-methoxy-6- (3- (pyrrolidin-1-yl) propoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((7-methoxy-6- (3- (pyrrolidin-1-yl) propoxy) quinazolin-4-yl) oxy) aniline for a reaction time of 5 hours. MS: [ M + H ]]+＝651.2，[M-H]+＝649.2.
1H-NMR(400M，DMSO-d6)13.36(s，1H)，13.16(s，1H)，10.79(s，1H)，8.66(s，1H)，8.27-8.29(m，1H)，8.11-8.14(m，1H)，8.06-8.08(d，1H)，7.73-7.77(m，2H)，7.64(s，1H)，7.48-7.53(m，2H)，7.27-7.31(t，2H)，7.03-7.04(d，1H)，4.32-4.35(m，2H)，4.03(s，3H)，3.01-3.30(m，6H)，1.89-2.27(m，6H)ppm。
Example 24: preparation of Compound 24
Preparation of 4- ((6- (3-diethylamino) propoxy) -7-methoxyquinazolin-4-yl) oxy) -3-fluoroaniline
4- (4-amino-2-fluorophenoxy) -7-methoxyquinazolin-6-ol (200mg, 1eq), 3-chloro-N, N-diethylpropyl-1-amine (298mg, 3eq), potassium carbonate (275mg, 3eq), and DMF (30mL) were added to a reaction flask, heated to 80 ℃ for 2 hours, stopped, filtered, and concentrated to give 128mg of crude 4- ((6- (3-diethylamino) propoxy) -7-methoxyquinazolin-4-yl) oxy) -3-fluoroaniline.
Preparation of 5- ((4- ((6- (3-diethylamino) propoxy) -7-methoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 4- ((6- (3-diethylamino) propoxy) -7-methoxyquinazolin-4-yl) oxy) -3-fluoroaniline for 6 hours. MS: [ M + H ]]+＝653.3，[M-H]+＝651.3.
1H-NMR(400M，DMSO-d6)13.31(s，1H)，12.94(s，1H)，10.21(s，1H)，8.64(s，1H)，8.26-8.27(m，1H)，8.18-8.21(d，1H)，8.10-8.12(d，1H)，7.73-7.77(m，2H)，7.65(s，1H)，7.47-7.53(m，2H)，7.27-7.33(m，2H)，6.98-6.99(d，1H)，4.34-4.35(m，2H)，3.82(s，3H)，3.15-3.27(m，6H)，2.23-2.27(m，2H)，1.26-1.27(m，6H)ppm。
Example 25: preparation of Compound 25
Preparation of 3-fluoro-4- ((7-methoxy-6- (3- (piperidin-1 yl) propoxy) quinazolin-4-yl) oxy) aniline 4- (4-amino-2-fluorophenoxy) -7-methoxyquinazolin-6-ol (200mg, 1eq), 1- (3-chloropropyl) piperidine (322mg, 3eq), potassium carbonate (275mg, 3eq), DMF (30mL) were added to a reaction flask, heated to 80 ℃ for 2 hours, stopped, filtered, and concentrated to give 220mg of crude 3-fluoro-4- ((7-methoxy-6- (3- (piperidin-1 yl) propoxy) quinazolin-4-yl) oxy) aniline.
Preparation of 5- ((3-fluoro-4- ((7-methoxy-6- (3- (piperidin-1 yl) propoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((7-methoxy-6- (3- (piperidin-1-yl) propoxy) quinazolin-4-yl) oxy) aniline for a reaction time of 5 hours. MS: [ M + H ]]+＝665.3，[M-H]+＝663.2.
1H-NMR(400M，DMSO-d6)13.18(s，1H)，12.84(s，1H)，10.86(s，1H)，8.59(s，1H)，8.32-8.36(m，1H)，8.18-8.20(d，1H)，7.72-7.76(m，2H)，7.62(s，1H)，7.49-7.52(m，1H)，7.38-7.43(m，2H)，7.25-7.29(t，2H)，6.95-6.97(d，1H)，4.27-4.30(m，2H)，4.02(s，3H)，2.82-2.97(m，6H)，2.21-2.24(m，2H)，1.71-1.73(m，4H)，1.49-1.51(m，2H)ppm。
Example 26: preparation of Compound 26
Preparation of 3-fluoro-4- ((7-methoxy-6- (3- (4-methylpiperazin-1 yl) propoxy) quinazolin-4-yl) oxy) aniline
4- (4-amino-2-fluorophenoxy) -7-methoxyquinazolin-6-ol (200mg, 1eq), 1- (3-chloropropyl) -4-methylpiperazine (352mg, 3eq), potassium carbonate (275mg, 3eq), and DMF (30mL) were added to a reaction flask, heated to 80 ℃ for 2 hours, stopped, filtered, and concentrated to give 140mg of crude 3-fluoro-4- ((7-methoxy-6- (3- (4-methylpiperazin-1 yl) propoxy) quinazolin-4-yl) oxy) aniline.
Preparation of 5- ((3-fluoro-4- ((7-methoxy-6- (3- (4-methylpiperazin-1-yl) propoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((7-methoxy-6- (3- (4-methylpiperazin-1-yl) propoxy) quinazolin-4-yl) oxy) aniline, and the reaction time was 2 hours. MS: [ M + H ]]+＝680.3，[M-H]+＝678.3.
1H-NMR(400M，DMSO-d6)13.29(s，1H)，12.98(s，1H)，12.00(s，1H)，8.63(s，1H)，8.24-8.25(m，2H)，8.11-8.12(d，1H)，7.73-7.76(m，2H)，7.64(s，1H)，7.47-7.50(m，2H)，7.27-7.31(m，2H)，6.99-7.00(d，1H)，4.33-4.36(m，2H)，4.04(s，3H)，3.36-3.48(m，10H)，2.85(s，3H)，2.09-2.11(m，2H)ppm。
Example 27: preparation of Compound 27
Preparation of 3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline
Adding 4- (4-amino-2-fluorophenoxy) -7-methoxyquinazolin-6-ol (200mg, 1eq), 4- (3-chloropropyl) morpholine (326mg, 3eq), potassium carbonate (275mg, 3eq) and DMF (30mL) into a reaction flask, heating to 80 ℃ for reaction for 2 hours, stopping the reaction, filtering, and concentrating to obtain crude 3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline 136 mg.
Preparation of 5- ((3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline for 2 hours. MS: [ M + H ]]+＝667.3.
1H-NMR(400M，DMSO-d6)13.31(s，1H)，12.93(s，1H)，10.86(s，1H)，8.64(s，1H)，8.26-8.27(d，1H)，8.18-8.21(d，1H)，8.10-8.12(d，1H)，7.73-7.77(m，2H)，7.65(s，1H)，7.48-7.51(m，2H)，7.27-7.31(t，2H)，6.98-7.00(d，1H)，4.34-4.35(m，2H)，4.21(s，3H)，3.79-3.85(m，2H)，3.50-3.53(m，2H)，3.14-3.16(m，2H)，3.09-3.11(m，2H)，2.31-2.34(m，2H)，1.04-1.06(m，2H)ppm。
Example 28: preparation of Compound 28
Preparation of 5- ((3-fluoro-4- ((6-methoxy-7- (3- (pyrrolidin-1-yl) propoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((6-methoxy-7- (3- (pyrrolidin-1-yl) propoxy) quinazolin-4-yl) oxy) aniline for 5 hours (1753-28-13). MS: [ M-H ]]+＝649.2.
1H-NMR(400M，DMSO-d6)13.30(s，1H)，13.16(s，1H)，10.79(s，1H)，8.63(s，1H)，8.19-8.26(m，2H)，8.11-8.12(d，1H)，7.73-7.77(m，2H)，7.63(s，1H)，7.47-7.51(m，2H)，7.27-7.31(t，2H)，7.00-7.01(d，1H)，4.34-4.37(m，2H)，4.02-4.05(m，2H)，3.84(s，3H)，3.59-3.61(m，2H)，3.31-3.33(m，2H)，2.28-2.32(m，2H)，1.90-1.93(m，4H)ppm。
Example 29: preparation of Compound 29
Preparation of 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline
Adding 4- (4-amino-2-fluorophenoxy) -6-methoxyquinazolin-7-ol (200mg, 1eq), 4- (3-chloropropyl) morpholine (326mg, 3eq), potassium carbonate (275mg, 3eq) and DMF (30mL) into a reaction flask, heating to 80 ℃ for reaction for 2 hours, stopping the reaction, filtering, and concentrating to obtain 125mg of crude 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline.
Preparation of 5- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline for 6 hours. MS: [ M-H ]]+＝665.2.
1H-NMR(400M，DMSO-d6)13.30(s，1H)，12.91(s，1H)，10.90(s，1H)，8.63(s，1H)，8.25-8.27(d，1H)，8.18-8.22(d，1H)，8.10-8.12(d，1H)，7.73-7.77(m，2H)，7.63(s，1H)，7.48-7.53(m，2H)，7.27-7.31(m，2H)，6.97-7.00(d，1H)，4.34-4.37(m，2H)，3.98-4.02(m，7H)，3.11-3.33(m，6H)，2.30-2.32(m，2H)ppm。
Example 30: preparation of Compound 30
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) aniline for 4 hours. MS: [ M + H ]]+＝536.2，[M-H]+＝534.1.
1H-NMR(400M，DMSO-d6)13.22(s，1H)，12.58(s，1H)，8.27(s，1H)，8.15-8.18(m，2H)，8.03-8.05(d，2H)，7.73-7.76(m，2H)，7.53(s，1H)，7.45-7.47(d，2H)，7.23-7.29(m，3H)，6.88-6.90(d，1H)，3.93(s，6H)ppm。
Example 31: preparation of Compound 31
Preparation of 3-fluoro-4- ((6-methoxy-7- (2-methoxyethoxy) quinazolin-4-yl) oxy) aniline
Adding 4- (4-amino-2-fluorophenoxy) -6-methoxyquinazolin-7-ol (200mg, 1eq), 1-chloro-2-methoxyethane (188mg, 3eq), potassium carbonate (183mg, 3eq) and DMF (30mL) into a reaction flask, heating to 80 ℃ for reaction for 2 hours, stopping the reaction, filtering, and concentrating to obtain 134mg of crude 3-fluoro-4- ((6-methoxy-7- (2-methoxyethoxy) quinazolin-4-yl) oxy) aniline.
Preparation of 5- ((3-fluoro-4- ((6-methoxy-7- (2-methoxyethoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((6-methoxy-7- (2-methoxyethoxy) quinazolin-4-yl) oxy) aniline, and the reaction time was 4.5 hours. MS: [ M + H ]]+＝598.2.
1H-NMR(400M，DMSO-d6)13.17(s，1H)，12.57(s，1H)，8.58(s，1H)，8.32-8.36(dd，1H)，8.19-8.20(m，2H)，7.72-7.76(m，2H)，7.60(s，1H)，7.49-7.51(m，1H)，7.39-7.44(m，2H)，7.25-7.30(m，2H)，6.89-6.91(d，1H)，4.34-4.36(m，2H)，4.11(s，3H)，4.01-4.02(m，2H)，3.18(s，3H)ppm。
Example 32: preparation of Compound 32
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) amino) -3-phenyl-1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino) -3-phenyl-1, 6-naphthyridin-4 (1H) -one in example 1, except that 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline was changed to 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) aniline, and the reaction time was 4 hours. MS: [ M + H ]]+＝518.2.
1H-NMR(400M，DMSO-d6)13.51(s，2H)，8.73(s，1H)，8.33-8.35(d，1H)，7.89-7.90(d，1H)，7.70-7.75(m，4H)，7.62(s，1H)，7.45-7.52(m，5H)，7.40-7.42(m，1H)，7.06-7.08(d，1H)，4.02(s，6H)ppm。
Example 33: preparation of Compound 33
Preparation of 4- ((6, 7-di (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-fluoroaniline
To a solution of 4-amino-2-fluorophenol (200mg, 2eq) in DMF (10mL) was added 60% sodium hydride (94.5mg, 3eq), stirred at room temperature for 10 minutes, a solution of 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline (492mg, 1eq) in DMF (15mL) was slowly added to the system, and after completion of the dropwise addition, the reaction was stopped at room temperature for 2 hours, followed by concentration and column chromatography to obtain 200mg of 4- ((6, 7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-fluoroaniline.
Preparation of 5- ((4- ((6, 7-di (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 4- ((6, 7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) -3-fluoroaniline, and the reaction time was 5 hours. MS: [ M + H ]]+＝642.3.
1H-NMR(400M，DMSO-d6)13.40(s，1H)，13.16(s，1H)，8.67(s，1H)，8.30-8.31(d，1H)，8.03-8.10(m，2H)，7.74-7.77(m，2H)，7.66(s，1H)，7.49-7.52(m，3H)，7.28-7.32(t，2H)，7.03-7.04(d，1H)，4.37(s，6H)，3.77-3.80(m，8H)ppm。
Example 34: preparation of Compound 34
Preparation of 4- ((6-benzyloxy-7-methoxyquinazolin-4-yl) oxy) aniline
6-benzyloxy-4-chloro-7-methoxyquinazoline (5g, 1eq), 4-aminophenol (2.0g, 1.1eq), potassium tert-butoxide (2.2g, 1.2eq) and DMF (250mL) were added to a reaction flask, heated to 55 ℃ for reaction for 3 hours, the reaction was stopped, the solvent was removed under reduced pressure, and the mixture was dried over a column to give 3.7g of 4- ((6-benzyloxy-7-methoxyquinazolin-4-yl) oxy) aniline.
Preparation of 4- (4-aminophenoxy) -7-methoxyquinazolin-6-ol
4- ((6-benzyloxy-7-methoxyquinazolin-4-yl) oxy) aniline (3.0g, 1eq), methanol (160mL) and Pd-C (0.7g) are added into a reaction flask, and the mixture reacts at 0 ℃ for 6 hours under the action of hydrogen, stops reacting, is filtered to remove insoluble substances, and is concentrated to obtain 1.5g of 4- (4-aminophenoxy) -7-methoxyquinazolin-6-ol after passing through a column.
Preparation of 4- ((7-methoxy-6- (2-methoxyethoxy) quinazolin-4-yl) oxy) aniline
Adding 4- (4-aminophenoxy) -7-methoxyquinazolin-6-ol (200mg, 1eq), 1-chloro-2-methoxyethane (200mg, 3eq), potassium carbonate (293mg, 3eq) and DMF (30mL) into a reaction flask, heating to 80 ℃ for 2 hours, stopping the reaction, filtering, and concentrating to obtain 120mg of crude product 4- ((7-methoxy-6- (2-methoxyethoxy) quinazolin-4-yl) oxy) aniline.
Preparation of 3- (4-fluorophenyl) -5- ((4- ((7-methoxy-6- (methoxyethoxy) quinazolin-4-yl) oxy) phenyl) amino) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 4- ((7-methoxy-6- (2-methoxyethoxy) quinazolin-4-yl) oxy) aniline for a reaction time of 5.5 hours. MS: [ M-H ]]+＝577.9.
1H-NMR(400M，DMSO-d6)13.56(s，1H)，13.46(s，1H)，8.74(s，1H)，8.34-8.35(d，1H)，7.90-7.91(d，1H)，7.73-7.77(m，4H)，7.66(s，1H)，7.49-7.52(m，3H)，7.28-7.33(m，2H)，7.09-7.10(d，1H)，4.34-4.36(m，2H)，3.76-3.79(m，8H)ppm。
Example 35: preparation of Compound 35
Preparation of 5- ((3-fluoro-4- (thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- (thiophene [3, 2-d) -one]Pyrimidin-4-yloxy) aniline, for a reaction time of 4 hours. MS: [ M-H ]]+＝497.8.
1H-NMR(400M，DMSO-d6)13.32(s，1H)，12.88(s，1H)，8.76(s，1H)，8.54-8.55(d，1H)，8.27-8.28(d，1H)，8.18-8.21(d，1H)，8.09-8.10(d，1H)，7.73-7.77(m，3H)，7.49-7.58(m，2H)，7.27-7.32(t，2H)，6.97-6.98(d，1H)ppm。
Example 36: preparation of Compound 36
Preparation of (Z) -ethyl-3-hydroxy-2- (4-methoxy) acrylate
Adding ethyl 2- (4-methoxyphenyl) acetate (28.3g, 1eq) and ethyl formate (129.9mL, 15eq) into a reaction bottle, slowly adding sodium hydride (34.9g, 6eq) under ice bath conditions, reacting for 8 hours, finishing the reaction of the reaction, stopping the reaction, adding proper amount of water, adjusting the pH to be acidic, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and distilling under reduced pressure to obtain oily (Z) -ethyl-3-hydroxy-2- (4-methoxy) acrylate (29.5 g).
Preparation of (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (4-methoxy) acrylate
(Z) -ethyl-3-hydroxy-2- (4-methoxy) acrylate (29.5g, 1eq), 2-chloro-4-aminopyridine (11g, 1eq), ethanol (260mL), concentrated hydrochloric acid (0.4mL) were added to a reaction flask, mixed well and heated to 70 ℃ for 5 hours, the reaction was stopped, ethanol was removed under reduced pressure, and the residue was subjected to column chromatography to give (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (4-methoxy) acrylate (19.3 g).
Preparation of 5-chloro-3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one
Adding (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (4-methoxy) acrylate (10g, 1eq) and diphenyl ether (80mL) into a reaction bottle, uniformly mixing, heating to 200 ℃ for half an hour, stopping the reaction, cooling to 50-60 ℃, pouring into 500mL petroleum ether, filtering the precipitated solid, and separating by using a solid chromatographic column to obtain 5-chloro-3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one (1.0 g).
Preparation of 3-chloro-4- (2-fluoro-4- ((3- (4-methoxyphenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine
Adding 5-chloro-3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -ketone (50mg, 1eq), 4- (4-amino-2-fluorophenoxy) -3-chloro-2-amidopyridine (78mg, 1eq), concentrated hydrochloric acid (1 drop) and isopropanol (65mL) into a reaction bottle, mixing, electromagnetically stirring, heating to 60 ℃ for reaction for 3 hours, insoluble matter was filtered off, and the filter cake was washed with isopropanol and dried under vacuum to give 3-chloro-4- (2-fluoro-4- ((3- (4-methoxyphenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine (76 mg).
Preparation of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one
Adding iodobenzene trifluoroacetate (137mg, 2eq) into a solution of 3-chloro-4- (2-fluoro-4- ((3- (4-methoxyphenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine (85mg, 1eq), acetonitrile (35mL), ethyl acetate (35mL) and water (7mL) at room temperature, pumping nitrogen, reacting for 2 hours under the protection of nitrogen, stopping the reaction by spotting, adding water (20mL), saturated sodium bicarbonate (15mL), extracting ethyl acetate (20mL 5), combining organic phases, drying anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography to obtain 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) Amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one (31 mg). MS: [ M-H ]]+＝502.1.
1H-NMR(400M，DMSO-d6)13.25(s，1H)，12.38(s，1H)，8.35-8.39(dd，1H)，8.17-8.18(d，1H)，8.13(s，1H)，7..76-7.77(d，1H)，7.62-7.64(d，2H)，7.46-7.48(d，1H)，7.27-7.32(dd，1H)，7.00-7.02(d，2H)，6.86-6.88(d，1H)，6.40(s，2H)，5.95-5.97(d，1H)，3.81(s，3H)ppm。
Example 37: preparation of Compound 37
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one in example 36, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline and the reaction time was 4 hours. MS: [ M + H ]]+＝566.3.
1H-NMR(400M，DMSO-d6)13.21(s，1H)，12.58(s，1H)，8.66-8.68(d，1H)，8.26-8.27(d，1H)，7.98-8.00(m，2H)，7.65-7.67(d，2H)，7.60-7.62(m，2H)，7.50-7.52(d，1H)，7.46-7.47(m，2H)，7.02-7.06(m，2H)，4.01(s，6H)，3.82(s，3H)ppm。
Example 38: preparation of Compound 38
Preparation of 5- ((3-fluoro-4- (thiophene [3, 2-d ] pyrimidin-4-yloxy) phenyl) amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one in example 36, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- (thiophene [3, 2-d)]Pyrimidin-4-yloxy) aniline, for a reaction time of 4 hours. MS: [ M-2H ]]+＝511.0.
1H-NMR(400M，DMSO-d6)13.47(s，1H)，12.96(s，1H)，8.77(s，1H)，8.54-8.56(d，1H)，8.22-8.24(d，1H)，8.11-8.12(d，1H)，8.02-8.04(d，1H)，7.73-7.75(d，1H)，7.64-7.67(d，2H)，7.51-7.53(m，1H)，7.49-7.50(m，1H)，6.99-7.04(m，3H)，3.82(s，3H)ppm。
Example 39: preparation of Compound 39
Preparation of 5- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one in example 36, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline, and the reaction time was 4 hours. MS: [ M-H ]]+＝563.2.
1H-NMR(400M，DMSO-d6)13.61(s，1H)，12.82(s，1H)，8.46-8.49(d，1H)，8.38-8.40(d，1H)，8.17-8.22(dd，2H)，7.64-7.75(m，5H)，7.01-7.03(m，3H)，6.78-6.80(d，1H)，6.59(s，1H)，3.95(s，3H)，3.82(s，3H)，3.75(s，3H)ppm。
Example 40: preparation of Compound 40
Preparation of (Z) -ethyl-2- (3-fluorophenyl) -3-hydroxyacrylate
Ethyl 2- (3-fluorophenyl) acetate (14.3g, 1eq) and ethyl formate (70mL, 15eq) were added to a reaction flask, sodium hydride (18.8g, 6eq) was slowly added under ice bath conditions, the reaction was carried out for 16 hours, the reaction was stopped after the completion of the spotting reaction, an appropriate amount of water was added to adjust the pH to acidity, extraction was carried out with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain an oily (Z) -ethyl-2- (3-fluorophenyl) -3-hydroxyacrylate (10.0 g).
Preparation of (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (3-fluorophenyl) acrylate
(Z) -ethyl-2- (3-fluorophenyl) -3-hydroxyacrylate (10.0g, 1eq), 2-chloro-4-aminopyridine (7.3g, 1.2eq), ethanol (100mL) and concentrated hydrochloric acid (0.3mL) were added to a reaction flask, mixed uniformly, heated to 60 ℃ for 10 hours, stopped, and subjected to reduced pressure to remove ethanol, and the residue was subjected to column chromatography to obtain (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (3-fluorophenyl) acrylate (7.1 g).
Preparation of 5-chloro-3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (3-fluorophenyl) acrylate (7.1g, 1eq) and diphenyl ether (50mL) into a reaction bottle, uniformly mixing, heating to 160 ℃, reacting for 5 hours, stopping the reaction, cooling to 50-60 ℃, pouring into 500mL petroleum ether, filtering to separate out a solid, and separating by using a solid chromatographic column to obtain 5-chloro-3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (900 mg).
Preparation of 3-chloro-4- (2-fluoro-4- ((3- (3-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine
Adding 5-chloro-3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -ketone (74mg, 1eq), 4- (4-amino-2-fluorophenoxy) -3-chloro-2-amide pyridine (72mg, 1eq), concentrated hydrochloric acid (1 drop) and isopropanol (30mL) into a reaction bottle, mixing, electromagnetically stirring, heating to 65 ℃ for reaction for 4 hours, insoluble substances are filtered off, and the filter cake is washed with isopropanol and dried under vacuum to give 3-chloro-4- (2-fluoro-4- ((3- (3-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine (50 mg).
Preparation of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding iodobenzene trifluoroacetate (75mg, 2eq) into a solution of 3-chloro-4- (2-fluoro-4- ((3- (3-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine (50mg, 1eq), acetonitrile (5mL), ethyl acetate (5mL) and water (1.25mL) at room temperature, pumping nitrogen, reacting for 2 hours under the protection of nitrogen, stopping the reaction by spotting, adding water (20mL), saturated sodium bicarbonate (15mL), extracting ethyl acetate (20mL and 5), combining organic phases, drying anhydrous sodium sulfate, carrying out suction filtration, concentrating, and carrying out silica gel column chromatography to obtain 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxo) -3-fluorophenyl) ammonia Yl) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (40 mg). MS: [ M + H ]]+＝492.1，[M-H]+＝490.1.
1H-NMR(400M，DMSO-d6)13.11(s，1H)，12.17(s，1H)，8.29-8.36(m，3H)，8.04-8.06(m，2H)，7.76(s，1H)，7.49-7.57(m，5H)，7.37-7.42(t，1H)，7.21-7.23(m，1H)，6.85-6.86(d，1H)ppm。
Example 41: preparation of Compound 41
Preparation of (Z) -ethyl-3-hydroxy-2- (2-fluorophenyl) acrylate
Ethyl 2- (2-fluorophenyl) acetate (20.0g, 1eq) and ethyl formate (140mL, 15eq) were added to a reaction flask, sodium hydride (16.0g, 6eq) was slowly added under ice bath conditions, the reaction was carried out for 8 hours, the reaction was stopped after the on-plate reaction was completed, an appropriate amount of water was added, the pH was adjusted to acidity, extraction was carried out with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and distillation under reduced pressure was carried out to obtain an oily (Z) -ethyl-3-hydroxy-2- (2-fluorophenyl) acrylate (10.0 g).
Preparation of (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (2-fluorophenyl) acrylate
Adding (Z) -ethyl-3-hydroxy-2- (2-fluorophenyl) acrylate (10.0g, 1eq), 2-chloro-4-aminopyridine (7.3g, 1.2eq), ethanol (100mL) and concentrated hydrochloric acid (0.3mL) into a reaction bottle, uniformly mixing, heating to 70 ℃ for reaction for 10 hours, stopping the reaction, removing the ethanol under reduced pressure, and carrying out column chromatography on residues to obtain (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (2-fluorophenyl) acrylate (7.1 g).
Preparation of 5-chloro-3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (2-fluorophenyl) acrylate (7.1g, 1eq) and diphenyl ether (50mL) into a reaction bottle, uniformly mixing, heating to 200 ℃ for reacting for 1 hour, stopping the reaction, cooling to 50-60 ℃, pouring into 500mL petroleum ether, filtering to separate out a solid, and separating by using a solid chromatographic column to obtain 5-chloro-3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (900 mg).
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) 3-fluorophenyl) amino) -3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding 5-chloro-3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -ketone (30mg, 1eq), 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline (35mg, 1eq), concentrated hydrochloric acid (1 drop) and isopropanol (20mL) into a reaction bottle, mixing, electromagnetically stirring, heating to 60 ℃ for reacting for 4 hours, and separating outThe pale yellow solid was filtered and the filter cake washed with isopropanol and dried under vacuum to give 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) 3-fluorophenyl) amino) -3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (25 mg). MS: [ M + H ]]+＝554.2.
1H-NMR(400M，DMSO-d6)13.13(s，1H)，12.69(s，1H)，8.60(s，1H)，8.19-8.21(m，2H)，8.13-8.15(m，1H)，7.59(s，1H)，7.42-7.49(m，5H)，7.26-7.31(m，2H)，6.92-6.93(d，1H)，4.01(s，6H)ppm。
Example 42: preparation of Compound 42
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) 3-fluorophenyl) amino) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 40, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline and the reaction time was 5 hours. MS: [ M + H ]]+＝554.2，[M-H]+＝552.1.
1H-NMR(400M，DMSO-d6)13.29(s，1H)，13.01(s，1H)，8.45(s，1H)，8.35-8.36(m，1H)，8.09-8.14(m，2H)，7.60-7.63(m，2H)，7.56(s，1H)，7.51-7.52(m，3H)，7.45(s，1H)，7.19-7.24(m，1H)，7.00-7.01(d，1H)，4.01(s，6H)ppm。
Example 43: preparation of Compound 43
Preparation of 5- ((3-fluoro-4- (thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) amino) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Preparation was carried out as described for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino-3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 40, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- (thiophene [3, 2-d ] -amino]Pyrimidin-4-yloxy) aniline. MS: [ M + H ]]+＝500.2，[M-H]+＝498.1.
1H-NMR(400M，DMSO-d6)13.30(s，1H)，13.07(s，1H)，8.76(s，1H)，8.53-8.54(d，1H)，8.34-8.35(d，1H)，8.13-8.16(d，1H)，8.07-8.08(m，1H)，7.72-7.74(d，1H)，7.46-7.61(m，5H)，7.19-7.23(m，1H)，7.00-7.02(d，1H)ppm。
Example 44: preparation of Compound 44
Preparation of 3-fluoro-4- ((7-methoxy-6- (2-morpholinoethoxy) quinazolin-4-yl) oxy) aniline
Adding 4- (4-amino-2-fluorophenoxy) -7-methoxyquinazolin-6-ol (200mg, 1eq), 4- (2-chloroethyl) morpholine (298mg, 3eq), potassium carbonate (275mg, 3eq) and DMF (30mL) into a reaction flask, heating to 80 ℃ for reaction for 2 hours, stopping the reaction, filtering, and concentrating to obtain crude 3-fluoro-4- ((7-methoxy-6- (2-morpholinoethoxy) quinazolin-4-yl) oxy) aniline 136 mg.
Preparation of 5- ((3-fluoro-4- ((7-methoxy-6- (2-morpholinoethoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The preparation method is the same asExample 4 Synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((7-methoxy-6- (2-morpholinoethoxy) quinazolin-4-yl) oxy) aniline, reaction time was 6 hours. MS: [ M-H ]]+＝650.8.
1H-NMR(400M，DMSO-d6)13.35(s，1H)，13.08(s，1H)，11.56(s，1H)，8.67(s，1H)，8.27-8.29(d，1H)，8.14-8.17(d，1H)，8.08-8.09(d，1H)，7.74-7.77(m，3H)，7.50-7.53(m，2H)，7.27-7.32(t，2H)，7.01-7.03(d，1H)，4.71-4.73(m，2H)，4.39(s，3H)，3.89-3.99(m，4H)，3.26-3.31(m，6H)ppm。
Example 45: preparation of Compound 45
Preparation of 3-chloro-4- (2-fluoro-4- ((3- (2-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine
The procedure was as for the synthesis of 3-chloro-4- (2-fluoro-4- ((3-phenyl-4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine in example 2, except that 5-chloro-3-phenyl-1, 6-naphthyridin-4 (1H) -one was changed to 5-chloro-3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one and the reaction time was 3 hours.
Preparation of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -8-chloro-3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3-phenyl-1, 6-naphthyridin-4 (1H) -one in example 2, except that 3-chloro-4- (2-fluoro-4- ((3-phenyl-4-oxy-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine was modifiedIs 3-chloro-4- (2-fluoro-4- ((3- (2-fluorophenyl) -4-oxo-1, 4-dihydro-1, 6-naphthyridin-5-yl) amino) phenoxy) -2-amidopyridine, and the reaction time is 2 hours. MS: [ M + H ]]+＝526.1.
1H-NMR(400M，DMSO-d6)13.02(s，1H)，12.18(s，1H)，8.37(s，1H)，8.23-8.27(dd，1H)，8.01(s，1H)，7.75-7.76(d，1H)，7.45-7.53(m，3H)，7.27-7.32(m，3H)，6.39(s，2H)，5.94-5.95(d，1H)ppm。
Example 46: preparation of Compound 46
Preparation of 5- ((2-chloropyridin-4-yl) amino) methyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione
2-chloro-4-aminopyridine (5.0g, 1eq), 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (5.6g, 1eq) and triethyl orthoformate (50mL) were added to a reaction flask and stirred electromagnetically, the mixture was heated to 150 ℃ to react for 3 hours after mixing, the reaction liquid was dark red, the solid was filtered out after cooling to room temperature, the solid was washed with petroleum ether and dried in vacuum to obtain 5- ((2-chloropyridin-4-yl) amino) methyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (6.7 g).
Preparation of 5-chloro-1, 6-naphthyridin-4 (1H) -one
Adding 5- ((2-chloropyridin-4-yl) amino) methyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (5.0g, 1eq) and diphenyl ether (40mL) into a reaction bottle, electromagnetically stirring, mixing, heating to 220 ℃ for reaction for 30 minutes, cooling the reaction liquid to room temperature, pouring into 300mL petroleum ether, stirring to separate out a solid, filtering the solid, and carrying out silica gel column chromatography on the solid to obtain 5-chloro-1, 6-naphthyridine-4 (1H) -ketone (0.4 g).
Preparation of 5- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino-1, 6-naphthyridin-4 (1H) -one
Adding 5-chloro-1, 6-naphthyridin-4 (1H) -ketone (50mg, 1eq), 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline (44mg, 1eq), concentrated hydrochloric acid (1 drop) and isopropanol (35mL) into a reaction bottle, mixing, electromagnetically stirring, heating to 50 ℃ for reacting for 4 hours, filtering out insoluble substances, washing a filter cake with isopropanol, and drying in vacuum to obtain 5- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino-1, 6-naphthyridin-4 (1H) -ketone (15 mg). MS: [ M + H ], []+＝459.1，[M-H]+＝457.0.
1H-NMR(400M，DMSO-d6)13.43(s，1H)，12.78(s，1H)，8.50-8.52(d，1H)，8.41-8.44(d，1H)，8.14-8.16(d，1H)，8.03-8.06(m，1H)，7.76-7.81(t，1H)，7.64-7.67(d，2H)，6.97-7.03(m，2H)，6.65(s，1H)，6.34-6.36(d，1H)，3.96(s，3H)，3.78(s，3H)ppm。
Example 47: preparation of Compound 47
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-1, 6-naphthyridin-4 (1H) -one
The procedure is as for the synthesis of 5- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino-1, 6-naphthyridin-4 (1H) -one in example 46, except that 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline is replaced with 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline MS: [ M-H ] O]+＝458.1.
1H-NMR(400M，DMSO-d6)13.21(s，1H)，12.58-12.59(m，1H)，8.61-8.63(d，1H)，8.15-8.17(d，1H)，8.04-8.08(m，2H)，7.61(s，1H)，7.45-7.52(m，3H)，6.91-6.93(d，1H)，6.35-6.36(d，1H)，4.01(s，6H)ppm。
Example 48: preparation of Compound 48
Preparation of 3-fluoro-4- ((6-methoxy-7- (2-morpholinoethoxy) quinazolin-4-yl) oxy) aniline
Adding 4- (4-amino-2-fluorophenoxy) -6-methoxyquinazolin-7-ol (200mg, 1eq), 4- (2-chloroethyl) morpholine (298mg, 3eq), potassium carbonate (275mg, 3eq) and DMF (30mL) into a reaction flask, heating to 80 ℃ for reaction for 2 hours, stopping the reaction, filtering, and concentrating to obtain 120mg of crude 3-fluoro-4- ((6-methoxy-7- (2-morpholinoethoxy) quinazolin-4-yl) oxy) aniline.
Preparation of 5- ((3-fluoro-4- ((6-methoxy-7- (2-morpholinoethoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((6-methoxy-7- (2-morpholinoethoxy) quinazolin-4-yl) oxy) aniline for 7 hours. MS: [ M + H ]]+＝653.3，[M-H]+＝650.8.
1H-NMR(400M，DMSO-d6)13.35(s，1H)，13.09(s，1H)，11.56(s，1H)，8.66(s，1H)，8.27-8.28(d，1H)，8.18-8.22(d，1H)，8.07-8.09(d，1H)，7.73-7.77(m，2H)，7.66(s，1H)，7.52-7.56(m，2H)，7.27-7.31(t，2H)，7.02-7.03(d，1H)，4.73-4.76(m，2H)，4.00(m，5H)，3.59-3.71(m，6H)，3.27-3.30(m，2H)ppm。
Example 49: preparation of Compound 49
Preparation of 5- ((3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one in example 36, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline. MS: [ M + H ]]+＝679.3.
1H-NMR(400M，DMSO-d6)13.38(s，1H)，12.79(s，1H)，10.66(s，1H)，8.62(s，1H)，8.18-8.19(d，2H)，8.07-8.08(d，1H)，7.63-7.65(m，3H)，7.46-7.50(m，2H)，7.00-7.02(d，2H)，6.94-6.96(d，1H)，4.34(s，2H)，4.31-4.33(s，6H)，3.49-3.52(m，3H)，3.28-3.33(m，3H)，3.10-3.15(m，2H)，2.29-2.32(m，2H)，1.03-1.05(m，2H)ppm。
Example 50: preparation of Compound 50
Preparation of 5- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one
Preparation was carried out as described for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-methoxyphenyl) -1, 6-naphthyridin-4 (1H) -one in example 36, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinazolin-4-yl)Oxy) aniline. MS: [ M +2H ]]+＝680.4
1H-NMR(400M，DMSO-d6)13.38(s，1H)，12.79(s，1H)，8.57(s，1H)，8.31-8.35(m，1H)，8.16-8.17(d，1H)，8.11(s，1H)，7.62-7.64(d，2H)，7.59(s，1H)，7.48-7.50(d，1H)，7.38-7.42(m，2H)，6.99-7.01(d，2H)，6.89-6.90(d，1H)，4.26-4.27(m，2H)，3.99-4.00(m，3H)，3.80-3.81(m，3H)，3.60-3.61(m，4H)，2.50(s，6H)，1.08-1.23(m，2H)ppm。
Example 51: preparation of Compound 51
Preparation of 5- ((3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) phenyl) amino) -1, 6-naphthyridin-4 (1H) -one
To a 100mL round bottom flask was added 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline (427mg, 1.0eq), 5-chloro-1, 6-naphthyridin-4 (1H) -one (186mg, 1eq), 100mL isopropanol, 0.1mL concentrated HCl, heated to 60 ℃ for 6 hours, the reaction was stopped, the solid was filtered off, washed with 30mL of isopropanol and dried under vacuum to weigh 318mg of 5- ((3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) phenyl) amino) -1, 6-naphthyridin-4 (1H) -one. MS: [ M + H ]]+＝572.2.
1H-NMR(400M，DMSO-d6)13.17(s，1H)，12.60(s，1H)，10.82(s，1H)，8.62(s，1H)，8.16-8.19(d，1H)，8.08(s，1H)，8.01-8.03(d，1H)，7.46-7.48(d，1H)，6.89-6.91(d，1H)，6.31-6.33(s，1H)，4.30-4.34(t，2H)，4.02(s，3H)，3.97-4.01(m，3H)，3.75-3.78(t，2H)，3.20-3.33(m，3H)，3.09-3.02(m，2H)，2.28-2.32(m，2H)。
Example 52: preparation of Compound 52
Preparation of 5-chloro-3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -one
Adding 5-chloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -ketone (274mg, 1eq), N, N-dimethylformamide (25mL), iodomethane (284mg, 2eq) and potassium carbonate (414mg, 3eq) into a 50mL round-bottomed flask at room temperature, stirring for 5min, heating to 70 ℃ for 2 hours under the protection of nitrogen, stopping reaction, removing DMF under reduced pressure, adding water (20mL), stirring to precipitate a solid, performing suction filtration, drying, and performing silica gel column chromatography to obtain 5-chloro-3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -ketone (178.3 mg).
Preparation of 5- ((5- ((6, 7-dimethoxyquinazolin-4-yl) oxy) pyridin-2-yl) amino) -3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -one
Adding 5-chloro-3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -one (144mg, 1.0eq), 5- ((6, 7-dimethoxyquinazolin-4-yl) oxy) pyridin-2-amine (150mg, 1.0eq), tris (dibenzylideneacetone) dipalladium (57.9mg, 0.2eq), 1, 2-bis (diphenylphosphino) propane (91.5mg, 0.2eq), sodium tert-butoxide (12.74mg, 1.3eq) and 1, 4-dioxane (100mL) to a reaction flask, pumping three times with nitrogen, reacting at 90 ℃ for 8 hours, completing the reaction at a point plate, cooling to room temperature, suction filtering, concentrating, and subjecting the crude silica gel (PE/EA 6/1to column chromatography to 3.5/1) to obtain 5- ((5- ((6), 7-Dimethoxyquinazolin-4-yl) oxy) pyridin-2-yl) amino) -3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -one (84 mg). MS: [ M + H ]]+＝550.1.
1H-NMR(400M，DMSO-d6)13.62(s，1H)，8.79-8.81(d，1H)，8.57(s，1H)，8.33-8.35(m，3H)，7.83-7.86(dd，1H)，7.73-7.76(t，2H)，7.60(s，1H)，7.40(s，1H)，7.25-7.30(t，2H)，7.02-7.03(d，1H)。
Example 53: preparation of Compound 53
Preparation of 5- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) 3-fluorophenyl) amino) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 40, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline, and the reaction time was 4 hours. MS: [ M + H ]]+＝553.2.
1H-NMR(400M，DMSO-d6)13.47(s，1H)，12.98(s，1H)，8.46-8.50(m，2H)，8.33-8.35(d，1H)，8.20-8.22(d，1H)，7.71-7.77(m，2H)，7.69(s，1H)，7.63-7.66(m，1H)，7.55-7.57(m，1H)，7.46-7.52(m，1H)，7.17-7.22(m，1H)，7.04-7.05(d，1H)，6.89-6.91(d，1H)，6.60(s，1H)，3.75(s，6H)ppm。
Example 54: preparation of Compound 54
Preparation of 5- ((3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 40, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridine-The 2-amino group is changed into 3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline, and the reaction time is 7 hours. MS: [ M + H ]]+＝667.2.
1H-NMR(400M，DMSO-d6)13.29(s，1H)，13.05(s，1H)，10.91(s，1H)，8.67(s，1H)，8.35-8.36(d，1H)，8.18-8.22(d，1H)，8.12-8.14(d，1H)，7.63-7.67(m，6H)，7.22-7.24(m，1H)，7.02-7.03(m，1H)，4.36-4.38(m，2H)，4.00-4.05(m，6H)，3.52-3.55(m，2H)，3.32(s，3H)，3.12-3.15(m，2H)，2.34-2.36(m，2H)ppm。
Example 55: preparation of Compound 55
Preparation of 5- ((3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (3-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 40, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 3-fluoro-4- ((6-methoxy-7- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline for 7 hours. MS: [ M + H ]]+＝667.2.
1H-NMR(400M，DMSO-d6)13.27(s，1H)，13.07(s，1H)，11.04(s，1H)，8.64(s，1H)，8.33-8.34(d，1H)，8.14-8.18(d，1H)，8.09-8.10(d，1H)，7.46-7.63(m，6H)，7.18-7.23(m，1H)，7.00-7.02(d，1H)，4.35-4.36(m，2H)，3.98-4.02(m，6H)，3.81(s，3H)，3.28-3.32(m，2H)，3.08-3.16(m，2H)，2.34-2.38(m，2H)ppm。
Example 56: preparation of Compound 56
Preparation of 5- ((5- ((6, 7-dimethoxyquinazolin-4-yl) oxy) pyridin-2-yl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 4, except that 4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-amino was changed to 5- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -2-aminopyridine for 4 hours. MS: [ M + H ]]+＝537.2.
1H-NMR(400M，DMSO-d6)13.37(s，1H)，12.91(s，1H)，8..80-8.01(d，1H)，8.58(s，1H)，8.32-8.33(m，1H)，8.21-8.23(d，1H)，8.18-8.19(m，1H)，7.83-7.85(m，1H)，7.73-7.77(m，2H)，7.61(s，1H)，7.41(s，1H)，7.24-7.28(m，2H)，7.02-7.04(d，1H)，3.99(s，6H)ppm。
Example 57: preparation of Compound 57
(E) Preparation of (E) -ethyl-3-hydroxy-2-thiopheneacrylate
The preparation method is the same as the synthesis of (Z) -ethyl-3-hydroxy-2-phenylacrylate in example 1, except that ethyl phenylacetate is changed into thiophene ethyl acetate, and the reaction time is 16 hours.
(E) Preparation of (E) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2-thiopheneacrylate
The preparation method is the same as the synthesis of (Z) -ethyl-3-hydroxy-2-acrylate in example 1, except that ethyl phenylacetate is changed into thiophene ethyl acetate, and the reaction time is 9 hours.
Preparation of 5-chloro-3- (thien-2-yl) -1, 6-naphthyridin-4 (1H) -one
The preparation method is the same as the synthesis of (Z) -ethyl-3-hydroxy-2-acrylate in example 1, except that ethyl phenylacetate is changed into thiophene ethyl acetate, the reaction temperature is 180 ℃, and the reaction time is 2 hours.
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-3- (thien-2-yl) -1, 6-naphthyridin-4 (1H) -one
The preparation method was the same as the synthesis of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-3-phenyl-1, 6-naphthyridin-4 (1H) -one in example 1, except that 5-chloro-3-phenyl-1, 6-naphthyridin-4 (1H) -one was changed to 5-chloro-3- (thien-2-yl) -1, 6-naphthyridin-4 (1H) -one for 4 hours]+＝542.9.
1H-NMR(400M，DMSO-d6)13.28(s，1H)，13.10(s，1H)，8.81-8.82(d，1H)，8.67(s，1H)，8.11-8.14(d，1H)，8.04-8.05(d，1H)，7.79-7.80(m，1H)，7.62(s，1H)，7.52-7.60(m，3H)，7.45(s，1H)，7.16-7.18(m，1H)，7.05-7.06(d，1H)，4.02(s，6H)ppm。
Example 58: preparation of Compound 58
Preparation of 5- ((3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) phenyl) amino) -3- (thien-2-yl) -1, 6-naphthyridin-4 (1H) -one
The preparation method is the same as that of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-3- (thien-2-yl) -1, 6-naphthyridine-Synthesis of 4(1H) -one, except that 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline was changed to 3-fluoro-4- ((7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-yl) oxy) aniline, reaction time was 3 hours. MS: [ M + H ]]+＝667.3.
1H-NMR(400M，DMSO-d6)13.26(s，1H)，13.14(s，1H)，10.83(s，1H)，8.80(s，1H)，8.79(s，1H)，8.17-8.20(d，1H)，8.07-8.09(d，1H)，7.78-7.79(d，1H)，7.54-7.57(m，3H)，7.48(s，1H)，7.16-7.17(t，1H)，7.05-7.06(d，1H)，4.34(m，2H)，4.03(s，3H)，3.98(m，2H)，3.79-3.85(m，2H)，3.14-3.16(m，2H)，2.12-2.14(m，2H)，3.09-3.11(m，2H)，2.33(m，2H)ppm。
Example 59: preparation of Compound 59
Preparation of 5- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) 3-fluorophenyl) amino) -3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 41, except that 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline was changed to 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline, and the reaction time was 5 hours. MS: [ M + H ]]+＝553.2.
1H-NMR(400M，DMSO-d6)13.31(s，1H)，12.54(s，1H)，8.46-8.50(dd，1H)，8.25-8.27(d，1H)，8.19(s，1H)，7.86-7.88(d，1H)，7.58-7.63(m，3H)，7.47-7.49(m，2H)，7.26-7.31(m，2H)，6.94-6.95(d，1H)，6.33(s，1H)，6.11-6.12(d，1H)，3.86(s，3H)，3.63(s，3H)ppm。
Example 60: preparation of Compound 60
Preparation of 5- ((3-fluoro-4- (thieno [3, 2-d ] pyrimidin-4-yloxy) phenyl) amino) -3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) 3-fluorophenyl) amino) -3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 41, except that 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline was changed to 3-fluoro-4- (thiophene [3, 2-d)]Pyrimidin-4-yloxy) aniline, reaction time 45 minutes. MS: [ M + H ]]+＝500.1.
1H-NMR(400M，DMSO-d6)13.13(s，1H)，12.68(s，1H)，8.74(s，1H)，8.52-8.53(d，1H)，8.19-8.25(m，2H)，8.14-8.16(d，1H)，7.71-7.72(d，1H)，7.44-7.51(m，4H)，7.27-7.31(m，2H)，6.92-6.93(d，1H)ppm。
Example 61: preparation of Compound 61
Preparation of (Z) -ethyl-3-hydroxy-2- (4-trifluoromethylphenyl) acrylate
Adding 2- (4-trifluoromethylphenyl) ethyl acetate (10.0g, 1eq) and ethyl formate (35mL, 10eq) into a reaction flask, slowly adding sodium hydride (12.8g, 10eq) under ice bath conditions, reacting for 18 hours, finishing the reaction of the reaction, stopping the reaction, adding proper amount of water, adjusting the pH to be acidic, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and distilling under reduced pressure to obtain oily (Z) -ethyl-3-hydroxy-2- (4-trifluoromethylphenyl) acrylate (11.0 g).
Preparation of (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (4-trifluoromethylphenyl) acrylate
To a reaction flask were added (Z) -ethyl-3-hydroxy-2- (4-trifluoromethylphenyl) acrylate (11.0g, 1eq), 2-chloro-4-aminopyridine (5.5g, 1eq), ethanol (200mL), concentrated hydrochloric acid (0.3mL), mixed well and warmed to 70 ℃ for 5 hours, the reaction was stopped, the ethanol was removed under reduced pressure, and the residue was separated by column chromatography to give (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (4-trifluoromethylphenyl) acrylate (6.5 g).
Preparation of 5-chloro-3- (4-trifluoromethylphenyl) -1, 6-naphthyridin-4 (1H) -one
Adding (Z) -ethyl-3- ((2-chloropyridin-4-yl) amino) -2- (4-trifluoromethylphenyl) acrylate (6.5g, 1eq) and diphenyl ether (50mL) into a reaction bottle, uniformly mixing, heating to 220 ℃, reacting for half an hour, stopping the reaction, cooling to 50-60 ℃, pouring into 500mL petroleum ether, filtering to separate out a solid, and separating by using a solid chromatographic column to obtain 5-chloro-3- (4-trifluoromethylphenyl) -1, 6-naphthyridin-4 (1H) -one (1.0 g).
Preparation of 5- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-trifluoromethylphenyl) -1, 6-naphthyridin-4 (1H) -one
Adding 5-chloro-3- (4-trifluoromethylphenyl) -1, 6-naphthyridin-4 (1H) -ketone (68mg, 1eq), 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline (40mg, 1eq), concentrated hydrochloric acid (1 drop) and isopropanol (20mL) into a reaction bottle, mixing, electromagnetically stirring, heating to 60 ℃ for reaction for 3 hours, a pale yellow solid precipitated, which was filtered, and the filter cake was washed with isopropanol and dried under vacuum to give 5- ((4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-trifluoromethylphenyl) -1, 6-naphthyridin-4 (1H) -one (25 mg). MS: [ M-H ]]+＝603.3.
1H-NMR(400M，DMSO-d6)13.37(s，1H)，12.73-12.75(d，1H)，8.50-8.53(d，1H)，8.35-8.36(d，1H)，8.25-8.27(d，1H)，8.11-8.13(d，1H)，7.93--7.95(dd，2H)，7.79-7.81(dd，2H)，7.65-7.66(m，2H)，7.61(s，1H)，6.98-6.99(s，1H)，6.40-6.43(m，2H)，3.90(s，3H)，3.68(s，3H)ppm。
Example 62: preparation of Compound 62
Preparation of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluorophenyl) amino-3- (4-trifluoromethylphenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) 3-fluorophenyl) amino) -3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 61, except that 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline was changed to 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline, and the reaction time was 4 hours. MS: [ M + H ]]+＝604.2.
1H-NMR(400M，DMSO-d6)13.18(s，1H)，12.84(s，1H)，8.18(s，1H)，8.35-8.37(d，1H)，8.21-8.24(d，1H)，8.14-8.16(d，1H)，7.94-7.96(dd，2H)，7.80-7.82(dd，2H)，7.60(s，1H)，7.45-7.51(m，2H)，7.429(s，1H)，6.94-6.96(s，1H)，3.99(s，3H)，4.01(s，3H)ppm。
Example 63: preparation of Compound 63
Preparation of 5- ((3-fluoro-4- (thiophene [2, 3-d ] pyrimidin-4-yloxy) phenyl) amino) -3- (4-trifluoromethylphenyl) -1, 6-naphthyridin-4 (1H) -one
The preparation method is the same as that of 5- ((4- ((6, 7-bis) in example 61Synthesis of methoxyquinolin-4-yl) oxy) -3-fluorophenyl) amino) -3- (4-trifluoromethylphenyl) -1, 6-naphthyridin-4 (1H) -one, except that 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) -3-fluoroaniline was changed to 3-fluoro-4- (thiophene [3, 2-d ] -e]Pyrimidin-4-yloxy) aniline, reaction time 45 minutes. MS: [ M + H ]]+＝550.1.
1H-NMR(400M，DMSO-d6)13.16(s，1H)，12.71(s，1H)，8.76(s，1H)，8.53-8.54(d，1H)，8.35-8.36(d，1H)，8.28-8.31(m，2H)，8.19-8.20(d，1H)，7.95-7.97(dd，2H)，7.80-7.82(dd，2H)，7.50-7.51(m，2H)，6.93-6.94(d，1H)ppm。
Example 64: preparation of Compound 64
Preparation of 5- ((3-fluoro-4- (thiophene [3, 2-d ] pyrimidine-4-oxy) phenyl) amino) -1, 6-naphthyridin-4 (1H) -one
To a 100mL round bottom flask was added 3-fluoro-4- (thiophene [3, 2-d ]]Pyrimidine-4-yloxy) aniline (261mg, 1.0eq), 5-chloro-1, 6-naphthyridin-4 (1H) -one (186mg, 1eq), isopropanol 100mL, concentrated hydrochloric acid 0.1mL, heating to 60 ℃ for 4 hours, stopping reaction, filtering out solid, washing the solid with 30mL isopropanol, drying in vacuum and weighing to obtain 5- ((3-fluoro-4- (thiophene [3, 2-d ])]Pyrimidin-4-oxy) phenyl) amino) -1, 6-naphthyridin-4 (1H) -one 221 mg. MS: [ M + H ]]+＝406.1.
1H-NMR(400M，DMSO-d6)13.27(s，1H)，12.76(s，1H)，8.76(s，1H)，8.54-8.55(d，1H)，8.02-8.12(m，3H)，7.73-7.74(d，1H)，7.57-7.61(t，1H)，7.45-7.48(dd，1H)，6.95-6.96(d，1H)，6.37-6.39(d，1H)ppm。
Example 65: preparation of Compound 65
Preparation of 5- ((3-fluoro-4- ((7-methoxyquinolin-4-yl) oxy) phenyl) amino-3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding 5-chloro-2-fluorophenyl-1, 6-naphthyridin-4 (1H) -ketone (36.2mg, 1eq), 4- ((7-methoxyquinolin-4-yl) oxy) -3-fluoroaniline (37.5mg, 1eq), concentrated hydrochloric acid (1 drop) and isopropanol (20mL) into a reaction bottle, mixing, electromagnetically stirring, heating to 60 ℃ for reacting for 3 hours, filtering off insoluble substances, washing a filter cake with isopropanol, and performing vacuum drying to obtain 5- ((3-fluoro-4- ((7-methoxyquinolin-4-yl) oxy) phenyl) amino-3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -ketone (21mg)]+＝523.2.
1H-NMR(400M，DMSO-d6)13.21(s，1H)，12.73(s，1H)，8.98-9.00(d，1H)，8.52-8.55(d，1H)，8.42-8.46(d，1H)，8.19-8.21(d，1H)，7.58-7.64(m，4H)，7.47-7.49(m，2H)，7.27-7.31(m，2H)，7.06-7.08(d，1H)，6.96-6.97(d，1H)，7.02-7.04(d，1H)，4.04(s，3H)ppm。
Example 66: preparation of Compound 66
Preparation of 5- ((4- ((6, 7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy) 3-fluorophenyl) amino) -3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
The procedure was as for the synthesis of 5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) 3-fluorophenyl) amino) -3- (2-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one in example 41, except that 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline was changed to 4- ((6, 7-bis (2-methoxyethoxy) quinazolin-4-yl) oxy)Lin-4-yl) oxy) -3-fluoroaniline, for 7 hours. MS: [ M + H ]]+＝642.3.
1H-NMR(400M，DMSO-d6)1311(s，1H)，12.65(s，1H)，8.59(s，1H)，8.19-8.20(m，2H)，8.15-8.16(m，1H)，7.63(d，1H)，7.45-7.49(m，5H)，7.26-7.30(m，2H)，6.91-6.93(d，1H)，4.32-4.38(m，4H)，3.76-3.77(m，4H)，3.23(s，6H)ppm。
Example 67: preparation of Compound 67
Preparation of (Z) -ethyl-3- ((2, 6-dichloropyridin-4-yl) amino) -2- (4-fluorophenyl) acrylate
Adding (Z) -ethyl-2- (4-fluorophenyl) -3-hydroxyacrylate (15g, 1eq), 2, 6-dichloro-4-aminopyridine (11.6g, 1eq), ethanol (250mL) and concentrated hydrochloric acid (0.5mL) into a reaction bottle, uniformly mixing, heating to 80 ℃ for reaction for 5 hours, stopping the reaction, removing the ethanol under reduced pressure, and carrying out column chromatography on residues to obtain (Z) -ethyl-3- ((2, 6-dichloropyridin-4-yl) amino) -2- (4-fluorophenyl) acrylate (22.8 g).
Preparation of 5, 7-dichloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one
Adding (Z) -ethyl-3- ((2, 6-dichloropyridin-4-yl) amino) -2- (4-fluorophenyl) acrylate (10g, 1eq) and diphenyl ether (80mL) into a reaction bottle, uniformly mixing, heating to 250 ℃, reacting for half an hour, stopping the reaction, cooling to 50-60 ℃, pouring into 500mL petroleum ether, filtering to separate out a solid, and separating by using a solid chromatographic column to obtain 5, 7-dichloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -one (2.35 g).
Preparation of 5, 7-dichloro-3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -one
Adding 5, 7-dichloro-3- (4-fluorophenyl) -1, 6-naphthyridin-4 (1H) -ketone (307mg, 1eq), N, N-dimethylformamide (25mL), iodomethane (284mg, 2eq), potassium carbonate (414mg, 3eqL) into a 50mL round-bottom flask at room temperature, stirring for 5min, heating to 70 ℃ for 2 hours under the protection of nitrogen, carrying out plate spotting reaction to complete reaction, removing DMF under reduced pressure, adding water (20mL), stirring to precipitate a solid, carrying out suction filtration, drying, and carrying out silica gel column chromatography to obtain 5, 7-dichloro-3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -ketone (330 mg).
7-chloro-5- ((4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline) -3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -one
Adding 5, 7-dichloro-3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -one (322mg, 1.0eq), 4- ((6, 7-dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline (315mg, 1.0eq), tris (dibenzylideneacetone) dipalladium (57.9mg, 0.2eq), 1, 2-bis (diphenylphosphino) propane (91.5mg, 0.2eq), sodium tert-butoxide (12.74mg, 1.3eq) and 1, 4-dioxane (100mL) to a reaction flask, pumping nitrogen three times, reacting at 80 ℃ for 8 hours, completing the reaction on a dot plate column, cooling to room temperature, performing column chromatography by suction, concentrating, and obtaining a crude silica gel (PE/EA 6/1to 3.5/1) to obtain 7-chloro-5- ((4- ((6), 7-Dimethoxyquinazolin-4-yl) oxy) -3-fluoroaniline) -3- (4-fluorophenyl) -1-methyl-1, 6-naphthyridin-4 (1H) -one 221 mg. MS: [ M + H ]]+＝602.2.
1H-NMR(400M，DMSO-d6)13.54(s，1H)，8.59(s，1H)，8.33(s，1H)，8.14-8.17(d，1H)，7.72-7.75(m，2H)，7.60(s，1H)，7.42-7.52(m，3H)，7.27-7.31(t，2H)，7.06(s，6H)，3.87(s，3H)ppm。
Example 68: in vitro biochemical level inhibition Protein Kinase (PK) activity experiment
Materials and methods c-Met, Flt-3, VEGFR-2, PDGFR- β and c-Kit kinase from Invitrogen, HTRF KinEASE, TKkit (Cisbio), 384 well plates (Greiner), ATP (sigma), MgCl2(sigma) corporation; PHERAstar FS multifunctional microplate reader (BMG company); low speedCentrifuge (StaiteXiangyi Co.); incubator (Binder Co.). The selected positive drug is BMS777607, and the structure is as follows:
compound dissolution and preservation: preparing a test compound into a mother solution of 0.5-10mmol/L by DMSO according to solubility, subpackaging and storing at-20 ℃;
preparing a compound working solution: before testing, the dispensed compound was removed from the freezer and diluted to 50 × the desired concentration with pure DMSO; then the compound was diluted to 4 x the desired concentration with deionized water;
1.33 × preparation of enzyme buffer: 5 × enzymic buffer from HTRF kit) was diluted 1.33 × with deionized water and 1.33 × final concentration of the corresponding ingredients were added: 1.33mmol/LDTT and 1.33mmol/LMgCl 2;
preparation of a kinase working solution: met was diluted to 2X desired final concentration of 0.2 ng/. mu.L with 1.33X Enzymatic buffer;
preparing a substrate working solution: substrate-biotin (from HTRF kit) and ATP (10mM) were diluted with 1.33 × Enzymatic buffer to 4 × the desired final concentration of the mixture;
preparation of detection working solution: 16.67. mu. mol/L of Streptavidin-XL665 were diluted to 4 Xthe desired final concentration with HTRF detection buffer and then mixed with an equal volume of Antibody-Cryptate (both from HTRFkit).
An enzyme reaction step: mu.l of kinase working solution was added to each well of a low volume 384 microwell plate, together with 4. mu.l of 1.33 × Enzymatic buffer as Negative control (Negative); add 2. mu.l of compound working solution to the wells, while adding 2. mu.l of 8% DMSO aqueous solution as a zero compound concentration control (i.e., Positive control); incubating at 25 deg.C (or 30 deg.C) for 5-10 min; add 2. mu.L of substrate working solution to the wells to start the enzymatic reaction, shake the reaction at 25 deg.C (or 30 deg.C) for 15-60 min.
HTRF reagent detection step: adding 8 mu L of detection working solution into the hole to terminate the reaction; reacting for 1h at 25 ℃;
reading of HTRF signal: the PHERAStar FS reading is adopted to detect signals, and the corresponding settings of the instrument are as follows:
Optic module
Integration delay(lag time)50μs
Integration time 400μs
Number of flashes 200
for the raw data read out per well, the ratio is 665nm/620 nm;
calculation of inhibition ratio:
IC50calculation of the value: taking the logarithm of the compound concentration as abscissa and the inhibition as ordinate, in GraphPadPrism 5, a non-linear curve was fitted: log (inhibitor) vs. response-Variable slope, and determining the concentration of the compound to be tested, namely IC when the enzyme activity inhibition rate is 50 percent50。
The experimental results are as follows: half Inhibitory Concentration (IC) of c-Met kinase Activity50nM)
The invention provides half Inhibitory Concentration (IC) of a compound with a structure shown as a formula I on the activity of c-Met kinase50) See table 1:
TABLE 1 half Inhibitory Concentration (IC) of the compounds on c-Met kinase activity50)
Compound (I) 1 2 3 4 5 6 7 8 9 10
Strength of activity +++ +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound (I) 11 12 13 14 15 16 17 18 19 20
Strength of activity +++ +++ +++ +++ +++ +++ +++ +++ + +++
Compound (I) 21 22 23 24 25 26 27 28 29 30
Strength of activity +++ +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound (I) 31 32 33 34 35 36 37 38 39 40
Strength of activity +++ +++ +++ +++ +++ ++ ++ + + +
Compound (I) 41 42 43 44 45 46 47 48 49 50
Strength of activity +++ +++ +++ +++ +++ ++ + +++ +++ +++
Compound (I) 51 52 53 54 55 56 57 58 59 60
Strength of activity ++ + + +++ ++ +++ ++ +++ +++ +++
Compound (I) 61 62 63 64 65 66 67 BMS777607
Strength of activity + +++ +++ + +++ +++ +++
+ + + + + denotes IC50< 500 nM; + denotes IC50The range is 500-; + denotes IC50In the range of 5000nM to 50. mu.M; means no test
TABLE 2 half Inhibitory Concentration (IC) of the Compounds on KDR kinase Activity50)
Compound (I) 1 2 3 4 5 6 7 8 9 10
Strength of activity +++ +++ +++ +++ +++ ++ +++ - +++ ++
Compound (I) 11 12 13 14 15 16 17 18 19 20
Strength of activity - - - - - - ++ - - -
Compound (I) 21 22 23 24 25 26 27 28 29 30
Strength of activity - +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound (I) 31 32 33 34 35 36 37 38 39 40
Strength of activity +++ +++ +++ +++ +++ +++ +++ + +++
Compound (I) 41 42 43 44 45 46 47 48 49 50
Strength of activity +++ +++ +++ +++ +++ +++ + +++ +++ +++
Compound (I) 51 52 53 54 55 56 57 58 59 60
Strength of activity +++ ++ + +++ + +++ +++ +++ +++ +++
Compound (I) 61 62 63 64 65 66 67 BMS777607
Strength of activity + +++ +++ ++ +++ ++ - +++
+ + + + + denotes IC50< 500 nM; + denotes IC50The range is 500-; + denotes IC50In the range of 5000nM to 50. mu.M; means no test
TABLE 3 half Inhibitory Concentration (IC) of the compounds on c-Kit kinase activity50)
Compound (I) 1 2 3 4 5 6 7 8 9 10
Strength of activity +++ +++ +++ +++ +++ ++ +++ - +++ -
Compound (I) 11 12 13 14 15 16 17 18 19 20
Strength of activity - - - - - - - - - -
Compound (I) 21 22 23 24 25 26 27 28 29 30
Strength of activity - +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound (I) 31 32 33 34 35 36 37 38 39 40
Strength of activity +++ +++ +++ +++ +++ +++ +++ ++ +++
Compound (I) 41 42 43 44 45 46 47 48 49 50
Strength of activity +++ +++ +++ +++ +++ +++ + +++ +++ +++
Compound (I) 51 52 53 54 55 56 57 58 59 60
Strength of activity ++ +++ + +++ + +++ +++ +++ +++ +++
Compound (I) 61 62 63 64 65 66 67 BMS777607
Strength of activity + +++ +++ ++ +++ +++ - +++
+ + + + + denotes IC50< 500 nM; + denotes IC50The range is 500-; + denotes IC50In the range of 5000nM to 50. mu.M; means no test
The experimental results are as follows: the inhibition activity of the partial compound of the invention on the biochemical level of c-Met kinase is equivalent to that of positive drug BMS777607, and the inhibition activity on the biochemical level of VEGR-2 kinase and c-kit kinase is obviously better than that of the positive drug BMS 777607.
Example (b): 69: in vitro cell level inhibition of Protein Kinase (PK) activity assay
The material and the method are as follows: human gastric adenocarcinoma cell strains MKN-45 and the like are all from Shanghai cell banks of Chinese academy of sciences; 1640 medium (GIBCO); fetal bovine serum (GIBCO); 24-well cell culture plates (Costar corporation); a 96-well colorless transparent high-affinity microplate (Costar corporation); HGF (R & D systems); cell lysate (pecan corporation); c-Met capturentibody (R & D System Co.); anti-phosphotyrosine antibody, clone 4G10 (Upstate); HRP (horse radish-anti-mouse antibody) (China fir bridge); TMB (Pierce corporation); enzyme-labeled detector (Tecan corporation, Infinite M200); multifunctional plate washing machine (Bio-Rad company)
Compound preparation: the positive drug and each test compound were prepared in DMSO as a 10mM stock solution and stored at-20 ℃.
Met antibody coating: the c-Met antibody was diluted to 2. mu.g/mL, added to the microplate at 100. mu.L per well, and coated overnight at 4 ℃ (16-18 h). PBST (PBS/0.05% Tween20, pH 7.4) 3 washes; adding blocking solution (5% BSA/PBS)200 μ l per well, and blocking at 37 deg.C for 2 hr; PBST wash 3 times; grabbing c-Met protein: inoculating MKN-45 cells with the fusion degree of 80-90% in a 24-hole cell culture plate, replacing a serum-free 1640 culture medium after the cells adhere to the wall for 8-10h, and starving for overnight; compounds diluted with a gradient of serum-free 1640 medium; absorbing the culture medium in the 24-well plate, quickly adding 180 mu L/well compound concentration gradient diluent, and incubating the cells acted by the compound in an incubator for 1 h; preparing HGF into 800ng/mL solution with serum-free 1640 medium, adding 20 μ l of HGF into each well of 24-well plate, slightly mixing, and stimulating at 37 deg.C for 5-8 min; quickly absorbing the culture medium supernatant in the 24-well plate, and adding 240 mu l of RIPA lysate in each well; adding 100 mul of cell lysate into each hole of the closed ELISA plate, and shaking at 37 ℃ and 100rpm for 2 h; PBST wash 3 times;
detection of Phosphotyrosine: primary antibody incubation: adding 100 μ of Anti-phosphotyrosineantabodies of murine origin, Clone 4G10 (0.5% BSA/PBS (W/V) 1: 2000 diluted), shaking at 37 deg.C at 100rpm for 1-1.5 h; PBST wash 3 times; and (3) secondary antibody incubation: add 100. mu.l HRP coat anti mouse IgG (0.5% BSA/PBS (W/V) 1: 3000 fold dilution) to each well and shake at 37 ℃ for 1h at 100 rpm; PBST wash 6 times; TMB substrate color development: adding 10% L TMB substrate to each well, and reflecting in dark room at room temperature for 2-10 min; after the substrate is in placeAfter color of (2), 50. mu.L of 2M H was added per well2SO4(ii) a And measuring the light absorption value at the absorption wavelength of 450nm by using a microplate reader.
Two control groups, negative control group: adding 10-5mol/L high-concentration SCR-1 without HGF stimulation; positive control group: no medicine is added, and only HGF is added for stimulation;
the average value of all the administration groups and the control group was calculated, and the inhibition ratio was calculated according to the following formula:
IC50calculation of the value: taking the logarithm of the compound concentration as abscissa and the inhibition as ordinate, in GraphPadPrism 5, a non-linear curve was fitted: log (inhibitor) vs. response-Variable slope, and determining the concentration of the compound to be tested, namely IC when the enzyme activity inhibition rate is 50 percent50。
The experimental results are as follows: the activity of partial compounds of the invention on the c-Met kinase cell level is equivalent to that of positive drug BMS777607, and the half inhibitory concentration range (IC) of partial compounds50) As shown in the table 2, see,
TABLE 2 half inhibitory concentration Range (IC) of the activity of the Compounds on the cellular level of c-Met kinase50)
Compound (I) 1 2 3 4 5 6 7 8 9 10
Strength of activity +++ +++ +++ +++ +++ +++ ++ +++ +++ -
Compound (I) 11 12 13 14 15 16 17 18 19 20
Strength of activity - - - - - - - +++ + ++
Compound (I) 21 22 23 24 25 26 27 28 29 30
Strength of activity + +++ +++ +++ +++ +++ +++ +++ +++ +++
Compound (I) 31 32 33 34 35 36 37 38 39 40
Strength of activity +++ +++ +++ +++ - - - - - -
Compound (I) 41 42 43 44 45 46 47 48 49 50
Strength of activity - - - - - - - - - -
Compound (I) 51 52 53 54 55 56 57 58 59 60
Strength of activity - - - - - - - - - -
Compound (I) 61 62 63 64 65 66 67 BMS777607
Strength of activity - - - - - - - +++
+ + + + + denotes IC50< 1. mu.M; + denotes IC50The range is 1-10 μ M; + denotes IC50The range is 10 mu M-100 mu M; means no test
Example 70: method for measuring inhibition of tumor cell proliferation (MTT method) by using compound provided by the invention
Reagents and instrumentation:
RPMI1640 medium (RPMI 1640+ 12% calf serum + HERES 3.5g/L + NaHCO)32.2g/L + penicillin 0.13g/L + streptomycin 0.15 g/L);
RPMI1640 medium (RPMI 1640+ 12% fetal bovine serum + HERES 3.5g/L + NaHCO α)32.2g/L + penicillin 0.13g/L + streptomycin 0.15 g/L);
high-sugar DMEM medium (DMEM + 10% calf serum + HEPES 3.5g/L + NaHCO)32.2g/L + penicillin 0.13g/L + streptomycin 0.15 g/L);
high-glucose DMEM medium (DMEM + 12% fetal bovine serum + HERES 3.5g/L + NaHCO)32.2g/L + penicillin 0.13g/L + streptomycin 0.15 g/L);
MC COYS 5-A medium (DMEM + 12% fetal bovine serum + HERES 3.5g/L + NaHCO)32.2g/L + penicillin 0.13g/L + streptomycin 0.15 g/L);
(ii) trypsin; MTT (product of Amresco, USA); enzyme mark instrument (TECAN infinite M200)
Human gastric adenocarcinoma cell line (BGC); human non-small cell lung cancer (a 549); human leukemia cell line (K562); human pancreatic cancer cell line (PANC-1); human small cell lung cancer (NCI-H446); the cancer cell lines are cultured in RPMI1640 medium containing 12% calf serum at 37 deg.C and 5% CO2Culturing in an incubator;
a human pancreatic cancer cell line (BXPC-3); human bladder cancer cell line (T24); the cancer cell lines are cultured in 12% fetal bovine serum RPMI1640 medium at 37 deg.C and 5% CO2Culturing in an incubator;
a human hepatoma cell line (HEPG 2); human breast cancer cell line (MCF-7); the cancer cell lines are cultured in high-glucose DMEM medium containing 12% calf serum at 37 deg.C and 5% CO2Culturing in an incubator;
human colon adenocarcinoma cell line (CACO-2) was cultured in 12% fetal bovine serum-containing high-glucose DMEM medium at 37 deg.C and 5% CO2Culturing in an incubator;
human colon cancer cell line (HT 29); human colon cancer cell line (HCT 116); human ovarian cancer cell line (SK-OV-3); the cancer cell lines are cultured in MC COYS 5-A culture medium containing 12% fetal calf serum at 37 deg.C and 5% CO2Cultured in an incubator.
Inoculating, adding appropriate amount of trypsin digestion solution into one bottle of cells in exponential growth phase, digesting to make adherent cells shed, preparing cell suspension with RPMI1640 (or DMEM or 5A) culture solution containing 12% calf serum, counting, and adjusting and diluting cell density to 1.67 × 104Cell suspension was taken out at/mL and seeded in 96-well plate at 180. mu.L/well (containing 3000 tumor cells/well).
Culturing: transfer the plates to constant temperature CO2In an incubator at 37 ℃ with 5% CO2And culturing under saturated humidity condition for 24 hours.
Primary screening: the test compound is first prepared with DMSO to 0.1M concentration and then diluted 3 times for preliminary screening, with the concentration of 10-5mol/L、10-6mol/L and 10-7mol/L. Test compound was added at 20. mu.L/well and incubated for 72 hours. Each group is provided with 3 parallel holes and repeated for 3 times, the light absorption value of each hole of a 96-hole plate is measured, the result is recorded, the cell growth inhibition rate is calculated, and the average value of three times is taken.
Dyeing: MTT was added to a 96-well plate (adherent cells) at 20. mu.L/well, incubated in an incubator for 4 hours, the supernatant in the well was aspirated, DMSO at 100. mu.L/well was added, and the plate was shaken on a flat plate shaker for 5 minutes. MTT was added to a 96-well plate (cell suspension), 20. mu.L/well, incubated in an incubator for 4 hours, followed by addition of 50. mu.L/well of 20% SDS, and placed in the incubator overnight.
And (3) determination: setting the wavelength of the microplate reader to 570nm and the reference wavelength to 630nm, measuring the light absorption value of each hole of a 96-hole plate, recording the result and calculating the cell growth inhibition rate so as to judge the anti-tumor activity of the tested medicine.
Re-screening: at a preliminary screening concentration of 10-5When mol/L, the compound with the cell inhibition rate more than or equal to 50 percent for 3 times is used for re-screening, 0.1mol/L is diluted by 10 times, and the concentration is 10 in sequence-5mol/L、0.5×10-5mol/L、10-6mol/L、0.8×10- 6mol/L、0.6×10-6mol/L、0.4×10-6mol/L、0.2×10-6mol/L、10-7mol/L、0.8×10-7mol/L and 0.4 × 10-7mol/L. Test compounds were added at 20. mu.L/well and incubated for 48 hours. Likewise, 3 parallel wells per group were set and repeated 3 times, and the absorbance of each well of the 96-well plate was measured according to the primary screening method, and the results were recorded and the cell growth inhibition rate was calculated.
Cell growth inhibition rate and IC50The calculation of (2):
meanwhile, according to the growth inhibition rate of each concentration, the logarithm of the compound concentration is linearly regressed with the Logit to calculate the concentration of the compound to be measured, namely the IC when the inhibition growth rate is 50 percent50And taking the average value of three times.
And (3) test results: the compounds with the structure shown in the formula I prepared in the embodiments 1to 67 of the invention have inhibition effect on the proliferation of various tumor cells, and the statistical analysis shows that the effect is obvious (P is less than 0.05), and the IC is50Are all at 10-5mol/L is less than.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (21)

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:
wherein,
a is selected from C5-C10Heteroaryl or C6-C10Aryl, wherein said heteroaryl, aryl may optionally be further substituted by one or more groups selected from hydrogen, C1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C5-C10Heteroaryl group, C6-C10Aryl radical C1-C10Alkyl radical, C5-C10Heteroaryl C1-C10Alkyl, halogen, halogeno C1-C10Alkyl, 5-to 8-membered heteroalicyclic, hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, cyano, nitro, -NR7R8、-NR7C(＝O)R8、-C(＝O)R9、-C(＝O)OR9、-C(＝O)NR7R8、-S(O)R10、-S(O)2R10、-S(O)2NR7R8、-O(CH2)nR11or-OC (═ O) R9Substituted with the substituent(s);
b is selected from-O-, -S-, -NH-or-CH2-；
W is selected from C;
x is selected from C or N;
m is 0 or 1;
R1、R2and R3Independently selected from hydrogen or halogen;
R4selected from hydrogen, hydroxy, C1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic, -C (═ O) R9or-S (O)2R10In which C is1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic optionally further substituted with one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, -O (CH)2)nR11、-OC(＝O)R10、-NR7R8or-NR7C(＝O)R8Substituted with the substituent(s);
R5selected from hydrogen;
R6selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl may optionally be further substituted with one or more substituents selected from halogen, trihalomethyl or C1-C10Substituted by a substituent of alkoxy;
R7and R8Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein said C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl optionally further substituted with one or more substituents selected from C1-C10Alkyl, hydroxy, amino, cyano, C1-C10Alkoxy or a carboxylic acid;
or R7And R8Together with the nitrogen atom to which they are attached form a 5-to 8-membered heterocyclic group containing one or more N, O, S heteroatoms within the 5-to 8-membered heterocyclic ring, and the 5-to 8-membered heterocyclic ring may optionally be further substituted with one or more substituents selected from C1-C10Alkyl, halogen, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, halo C1-C10Alkyl, hydroxy, cyano, C1-C10Alkoxy, amino C1-C10Alkyl or carboxylic acid;
R9is selected from C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy radicalRadical, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R10is selected from C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R11selected from hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl or-NR7R8In which C is1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
n is 1, 2, 3 or 4.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein,
a is selected from C5-C10Heteroaryl or C6-C10Aryl, wherein said heteroaryl, aryl may optionally be further substituted with one or more substituents selected from hydrogen, halogen, -C (═ O) NH2、-C(＝O)NHR8、-C(＝O)R9、-C(＝O)OR9Cyano, amino, -NHC (═ O) R8、C1-C10Alkoxy radical, C6-C10Aryloxy radical, C1-C10Alkyl, hydroxy, -O (CH)2)nR11or-OC (═ O) R9Substituted with the substituent(s);
b is selected from-O-, -S-, -NH-or-CH2-；
W is selected from C;
x is selected from C or N;
m is 0 or 1;
R1、R2and R3Independently selected from hydrogen or halogen;
R4selected from hydrogen, C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl, wherein C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Substituted with the substituent(s);
R5selected from hydrogen;
R6selected from hydrogen, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein, C1-C10The alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl may optionally be further substituted with one or more substituents selected from halogen, trihalomethyl or C1-C10Substituted by a substituent of alkoxy;
R9is selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, or imidazolyl;
R11is selected from C1-C10Alkoxy radical, C6-C10Aryloxy, hydroxy or-NR7R8；
R7And R8Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein said C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl optionally further substituted with one or more substituents selected from C1-C10Alkyl, hydroxy, amino, cyano, C1-C10Alkoxy or a carboxylic acid;
or R7And R8Together with the nitrogen atom to which they are attached form a 5-to 8-membered heterocyclic group containing one or more N, O, S heteroatoms within the 5-to 8-membered heterocyclic ring, and the 5-to 8-membered heterocyclic ring may optionally be further substituted with one or more substituents selected from C1-C10Alkyl, halogen, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, halo C1-C10Alkyl, hydroxy, cyano, C1-C10Alkoxy, amino C1-C10Alkyl or carboxylic acid;
n is 1, 2, 3 or 4.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein:
a is selected from six-membered heteroaryl, five-membered and six-membered heteroaryl, six-membered aromatic ring or six-membered and six-membered aromatic ring group, wherein six-membered heteroaryl, five-membered and six-membered heteroaryl, six-membered aromatic ring or six-membered and six-membered aromatic ring group can be further selected from one or more of hydrogen, halogen, -C (═ O) NH2、-C(＝O)NHR8、-C(＝O)R9、-C(＝O)OR9Cyano, amino, -NHC (═ O) R8、C1-C10Alkoxy radical, C6-C10Aryloxy radical, C1-C10Alkyl, hydroxy, -O (CH)2)nR11or-OC (═ O) R9Substituted with the substituent(s);
b is selected from-O-.
4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein:
a is selected from pyridyl, thienopyrimidinyl, quinazolinyl, quinolinyl, naphthyl, or phenyl, wherein said pyridyl, thienopyrimidinyl, quinazolinyl, quinolinyl, naphthyl, or phenyl may optionally be further substituted with one or more groups selected from hydrogen, halogen, -C (═ O) NH2、-C(＝O)NHR8、-C(＝O)R9、-C(＝O)OR9Cyano, amino, -NHC (═ O) R8、C1-C10Alkoxy radical, C6-C10Aryloxy radical, C1-C10Alkyl, hydroxy, -O (CH)2)nR11or-OC (═ O) R9Substituted with the substituent(s);
b is selected from-O-.
5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein:
a is selected from the following groups:
wherein R isaAnd RbIndependently selected from hydrogen, halogen, -C (═ O) NH2、-C(＝O)NHR8、-C(＝O)R9、-C(＝O)OR9Cyano, amino, -NHC (═ O) R8、C1-C10Alkoxy radical, C6-C10Aryloxy radical, C1-C10Alkyl, hydroxy, -O (CH)2)nR11or-OC (═ O) R9A substituent group;
b is selected from-O-.
6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein,
a is selected from six-membered heteroaryl, five-membered and six-membered heteroaryl, six-membered aromatic ring or six-membered and six-membered aromatic ring group, wherein six-membered heteroaryl, five-membered and six-membered heteroaryl, six-membered aromatic ring or six-membered and six-membered aromatic ring groupOptionally further substituted with one or more groups selected from hydrogen, halogen, amino, -CONH2Cyano, C1-C4Alkoxy or-O (CH)2)nR11Substituted with the substituent(s);
b is selected from-O-;
w is selected from C;
x is selected from C or N;
m is 0 or 1;
R1、R2and R3Independently selected from hydrogen or halogen;
R4selected from hydrogen, C1-C4Alkyl, allyl, benzyl or-CH2COOEt；
R5Selected from hydrogen;
R6selected from hydrogen, phenyl or 2-thienyl, wherein the phenyl group may be further substituted by one or more halogens, trihalomethyl or C1-C4Alkoxy substitution;
R11is selected from C1-C4Alkoxy, N-methylpiperazino, morpholino, piperidino, pyrrolidinyl or-N (C)2H5)2；
n is 2 or 3.
7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein:
a is selected from pyridyl, thienopyrimidinyl, quinazolinyl, quinolinyl, naphthyl, or phenyl, wherein said pyridyl, thienopyrimidinyl, quinazolinyl, quinolinyl, naphthyl, or phenyl may optionally be further substituted with one or more groups selected from hydrogen, halogen, amino, -C (═ O) NH2Cyano, C1-C4Alkoxy or-O (CH)2)nR11Substituted with the substituent(s).
8. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein:
a is selected from the following groups:
wherein R isaAnd RbIndependently selected from hydrogen, halogen, amino, -CONH2Cyano, C1-C4Alkoxy or-O (CH)2)nR11。
9. A compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
10. a compound of formula (II) which is an intermediate in the synthesis of a compound of formula (I) as claimed in claim 1:
wherein R is2、R3、R4And R5Is as defined in claim 1;
R6is selected from C6-C10Aryl radical, C5-C10Heteroaryl group, C1-C10Alkyl radical, C6-C10Aryl radical C1-C10Alkyl or C5-C10Heteroaromatic C1-C10Alkyl radical, wherein C6-C10Aryl radical, C5-C10Heteroaryl group, C1-C10Alkyl radical, C6-C10Aryl radical C1-C10Alkyl radical, C5-C10Heteroaromatic C1-C10The alkyl group may optionally be further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, cyano or carboxylic acid.
11. The compound of claim 10, wherein,
R2and R3Independently selected from hydrogen or halogen;
R4selected from hydrogen, hydroxy, C1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic, -C (═ O) R9or-S (O)2R10In which C is1-C10Alkyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, 3-to 8-membered all-carbon monocyclic cycloalkyl, 5-to 8-membered heteroalicyclic optionally further substituted with one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy, -O (CH)2)nR11、-OC(＝O)R10、-NR7R8or-NR7C(＝O)R8Substituted with the substituent(s);
R5selected from hydrogen;
R6is selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl,Pyrimidinyl, pyrazinyl, imidazolyl, wherein phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl are optionally substituted with one or more substituents selected from halogen, trihalomethyl or C1-C10Substituted by a substituent of alkoxy;
R7and R8Independently selected from hydrogen, C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein said C1-C10Alkyl, 3-to 8-membered all-carbon monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl optionally further substituted with one or more substituents selected from C1-C10Alkyl, hydroxy, amino, cyano, C1-C10Alkoxy or a carboxylic acid;
or R7And R8Together with the nitrogen atom to which they are attached form a 5-to 8-membered heterocyclic group containing one or more N, O, S heteroatoms within the 5-to 8-membered heterocyclic ring, and the 5-to 8-membered heterocyclic ring may optionally be further substituted with one or more substituents selected from C1-C10Alkyl, halogen, phenyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, halo C1-C10Alkyl, hydroxy, cyano, C1-C10Alkoxy, amino C1-C10Alkyl or carboxylic acid;
R9is selected from C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R10is selected from C1-C10Alkyl, halo C1-C10Alkyl radical、C6-C10Aryl or C5-C10Heteroaryl group, wherein C1-C10Alkyl, halo C1-C10Alkyl radical, C6-C10Aryl or C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
R11selected from hydroxy, C1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl or-NR7R8In which C is1-C10Alkoxy radical, C6-C10Aryloxy radical, C6-C10Aryl radical, C5-C10Heteroaryl is optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C1-C10Alkoxy, halogen, halogeno C1-C10Alkyl, hydroxy, amino, cyano, or carboxylic acid;
n is 1, 2, 3 or 4.
12. The compound of claim 11, wherein:
R4selected from hydrogen, C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl, wherein C1-C10Alkyl, 3 to 8 membered all carbon monocyclic cycloalkyl optionally further substituted by one or more groups selected from C1-C10Alkyl radical, C2-C6Alkenyl radical, C6-C10Aryl radical, C5-C10Heteroaryl, -C (═ O) R9、-C(＝O)OR9Substituted with the substituent(s);
R6is selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, wherein, C1-C10Alkyl, phenyl, benzyl, thienyl, furyl,Pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl optionally substituted with one or more substituents selected from halogen, trihalomethyl or C1-C10Substituted by a substituent of alkoxy;
R9is selected from C1-C10Alkyl, phenyl, benzyl, thienyl, furyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl or imidazolyl.
13. The compound of claim 10, wherein,
R2and R3Independently selected from hydrogen or halogen;
R4selected from hydrogen, C1-C4Alkyl, allyl, benzyl or-CH2COOEt；
R5Selected from hydrogen;
R6selected from phenyl or 2-thienyl, wherein phenyl is optionally substituted with one or more halogen, trihalomethyl or methoxy.
14. The compound of claim 10, wherein said compound is selected from the group consisting of:
15. process for the preparation of a compound of formula (II) according to claim 10, characterized in that it comprises the following steps:
(1) reacting the compound a with the compound b under the action of alkali to obtain a compound c;
(2) reacting the compound c with an aminopyridine compound d in a protic solvent under the catalysis of acid to obtain a compound e;
(3) reacting the compound e under the action of diphenyl ether to obtain a compound (II) with a general formula;
wherein R is2、R3、R4、R5And R6Is as defined in claim 1.
16. The synthetic method according to claim 15, wherein,
the alkali in the step (1) is inorganic alkali selected from sodium hydroxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide, the reaction temperature is-15 ℃ to 50 ℃, and the reaction time is 2 hours to 48 hours;
in the step (2), the protic solvent is isopropanol, ethanol or methanol, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or acetic acid, the reaction temperature is 60-100 ℃, and the reaction time is 2-20 hours;
in the step (3), the reaction solvent is diphenyl ether, and the reaction temperature is 90-258 ℃; the reaction time is 30 minutes to 10 hours.
17. The synthetic method according to claim 16, wherein,
the alkali in the step (1) is sodium hydride, the reaction temperature is 0-30 ℃, and the reaction time is 5-24 hours;
in the step (2), the solvent is ethanol, the acid is concentrated hydrochloric acid, the reaction temperature is 60-85 ℃, and the reaction time is 5-10 hours;
in the step (3), the reaction solvent is diphenyl ether, and the reaction temperature is 160 ℃ to 258 ℃; the reaction time is 30 minutes to 5 hours.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of claims 1to 9 in free form or in pharmaceutically acceptable salt form; one or more pharmaceutically acceptable carrier substances and/or diluents.
19. The use of a compound for the manufacture of a medicament for the treatment of a protein kinase mediated disease by administering to a patient a therapeutically effective amount of a compound according to any one of claims 1to 9.
20. Use according to claim 19, characterized in that the protein kinase related diseases are selected from the group of diseases related to c-Met, KDR or c-kit.
21. Use according to claim 20, characterized in that the disease is selected from colorectal cancer, bladder cancer, breast cancer, liver cancer, lung cancer, pancreatic cancer, gastrointestinal cancer, leukemia, ovarian cancer, head and neck cancer, prostate cancer, kidney cancer, nasopharyngeal cancer, glioblastoma, squamous cell carcinoma, astrocytic cancer, kaposi's sarcoma, melanoma, glioma, genitourinary tract cancer or a myeloproliferative disorder.
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