CN103382206A - Quinoline or quinazoline derivative, its preparation method and application in medicines - Google Patents

Quinoline or quinazoline derivative, its preparation method and application in medicines Download PDF

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CN103382206A
CN103382206A CN2013101429132A CN201310142913A CN103382206A CN 103382206 A CN103382206 A CN 103382206A CN 2013101429132 A CN2013101429132 A CN 2013101429132A CN 201310142913 A CN201310142913 A CN 201310142913A CN 103382206 A CN103382206 A CN 103382206A
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aryl
cycloalkyl
alkyl
tautomer
diastereomer
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CN103382206B (en
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吕贺军
陈一千
王胜蓝
胡齐悦
郑苏欣
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Abstract

The invention relates to a quinoline or quinazoline derivative, its preparation method and an application in medicines, specifically to new quinoline or quinazoline derivative as shown in a general formula (I) and its medicinal salt or a pharmaceutical composition containing the derivative and a preparation method thereof. The invention further relates to an application of the quinoline or quinazoline derivative and its medicinal salt or the pharmaceutical composition containing the derivative in the preparation of a therapeutic agent, especially a protein kinase inhibitor. Each substituent group in the general formula (I) has the same definition as in the specification.

Description

Quinoline or quinazoline derivative, its preparation method and in pharmaceutically application
Technical field
The present invention relates to a kind of new quinoline or quinazoline derivative and pharmaceutically useful salt thereof or contain its pharmaceutical composition, and preparation method thereof.The invention further relates to described quinoline or quinazoline derivant and pharmaceutically useful salt thereof or contain its pharmaceutical composition in the purposes of preparation therapeutical agent, particularly kinases inhibitor.
Background technology
The signal conduction of cell is a kind of mechanism of action of basis, in the signal conductive process, is passed to cell interior from extracellular stimulation, and then regulates the process of different cells.These signals can be regulated multiple physiological responses, comprise that cell proliferation, differentiation, accent are died and motion etc., and they exist with different sorts dissolution factor form, comprise take paracrine factor, autocrine factor and endocrine factor as main somatomedin.By being combined with specific transmembrane receptor, the somatomedin part is delivered to signal pathway in cell with extracellular signal, thereby causes that individual cells is to the reaction of extracellular signal.A lot of signal transduction process are reversing processes of utilizing protein phosphorylation, relate to specific protein kinases and phosphorylated enzyme.
Protein kinase (Protein kinases, PKs) has very important effect in the signal conductive process.It can be transferred to γ-phosphate of ATP on the particular amino acid residue of functional protein, causes a series of biological respinses.According in the phosphorylation process as the amino acid classification of substrate, protein kinase can be divided into serine-threonine kinase (STKs) and Tyrosylprotein kinase (PTKs).
Tyrosylprotein kinase can simply be divided into receptor type and non-receptor type.Receptor type tyrosine kinase be a class across the relatively large kinases of cytolemma, it has the ectodomain, membrane spaning domain of ligand binding and plays zymogenesis-at the specific tyrosine residues of phosphorylation and affect thus born of the same parents' intracellular domain of cell proliferation.Kinase whose unconventionality expression as described in (as mammary cancer, gastrointestinal cancer, leukemia, ovarian cancer, segmental bronchus cancer or lung cancer) has been found in general human cancer.Therefore this class kinases has become important treatment target spot.
Vascular endothelial growth factor receptor (Vascular Endothelial Growth Factor Receptor, VEGFR) is the transmembrane receptor tyrosine kinase.It is characterized in that with tyrosine kinase domain in 7 immunoglobulin like domain and born of the same parents.Oneself identifies three kinds of VEGFR:VEGFR-1 (Flt-1), VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4).The formation of tumour neovascularity and infiltration are mainly regulated, are played a role by two kinds of different acceptors at least: VEGFR-1 and VEGFR-2 by (tumour derives) vascular endothelial growth factor (VEGF).VEGF is in various malignant entity tumors, have than high expression level as lung cancer, mammary cancer, non-Hodgkin′s malignant lymphoma, ovarian cancer, carcinoma of the pancreas, malignant pleural mesothelioma and melanoma, and relevant to the canceration process, expression is also arranged in leukocytosis and lymphoma.
Important somatomedin is Thr6 PDGF BB (the Platelet Derivation Growth Factor that comprises peptide growth factor family in tumor development, PDGF), it is by cell surface tyrosine kinase receptor (PDGFR) transmission signal and irritate various cell functions, comprises growth, hyperplasia and differentiation.The member of PDGFR also comprises colony-stimulating factor 1 acceptor (Colony Stimulating Factor-1 Receptor, CSF-1R), stem cell factor acceptor c-kit etc. except PDGFR-α and PDGFR-β.The PDGFR activation is also relevant to some malignant tumours.Just depend on the PDGFR activation such as the eosinophil leucocyte increase disease.In another illness dermatofibrosarcoma protuberans (perviousness skin tumour), the mutual transposition that relates to the gene of coding PDGF-beta ligands causes the composing type chimeric part of secretion and receptor activation.In addition, combining is activated then when c-Kit and part STEM CELL FACTOR (Stem Cell Factor, SCF).In sarcoma, the gi tract glioma, in spermocytoma and carcinoid tumor, c-Kit has overexpression.
Fibroblast growth factor acceptor (Fibroblast Growth Factor Receptor, FGFR) belongs to the new receptor type tyrosine kinase of a class, by four kinds of hypotype FGFR-1～4 and some isomery molecular compositions.These acceptors by with fibroblast growth factor (FGF) and Suleparoid protein-polysaccharide (Heparan-SulfateProteoglycans, HSPGs) form ternary complex, and then cause a series of signal conduction, participate in regulating the physiological process in organism.
FGFRs is the glycoprotein molecule of strand, also is comprised of extracellular region, cross-film district and intracellular region.At first, extracellular ligand binding region comprises signal peptide and the cysteine residues (Cysteine of a N-terminal, Cys) 2～3 immunoglobulin like domain (Immunoglobin (Ig)-like domains, Ig) I～III that forms.Between Ig I and Ig II structural domain, an acidic amino acid box (Acidicbox, AB) is arranged.The intracellular region territory comprises a relatively long membrane-proximal region (Juxtamembrane, JM), tyrosine kinase activity district and C-terminal.The tyrosine kinase activity district is divided into two complete kinase domains (Kinase domain I and II) by one section 14 amino acid whose insertion sequence again.C-terminal comprises 7 tyrosine residuess, with ligand binding after may be by phosphatide.
FGFs belongs to heparin binding growth factor family (Heparin binding growth factor, HBGF), and they are combined with the extracellular region of FGFR under HSPGs is collaborative, acceptor generation dimerization.In the acceptor of dimerization, acceptor molecule can another acceptor molecule of phosphorylation, thereby realizes the autophosphorylation of acceptor, and FGFR is activated.It receives this molecule, the PLC_ γ of activation to be hydrolyzed its substrate 4,5 bisphosphate phosphatidylinositols (Ptdlns (4,5) P by the combination of the SH2 structural domain on continuous and lecithinase C _ γ (PhospolipaseC_ γ, PLC_ γ) molecule fast subsequently 2) 2 second signals of formation: DG and Isosorbide-5-Nitrae, 5 InsP3s (Ins (Isosorbide-5-Nitrae, 5) P3).Ins (Isosorbide-5-Nitrae, 5) P3 is by the storage of the calcium in irritation cell discharges Ca with cell internal specific receptors bind 2+Ca 2+Thereby be combined with calmodulin and activate a class and be called Ca 2+/ calmodulin-dependent protein kinase.In addition, Ca 2+With DG can activated protein kinase C (Protein kinase C, PKC) member in family.The second signal that is produced by Ptdlns (4,5) P2 hydrolysis has also stimulated the reaction in various kinds of cell except phosphorylation and activating transcription factor.
FGFR has physiological and pathological roles widely in vivo.As: fetal development, wound healing and vasculogenesis.FGFR expresses the generation that meeting out of control causes numerous disease, wherein most typical is exactly that the generation of tumour and the growth FGFR of metastatic tumor can promote endothelial cell migration, propagation and differentiation, and play an important role in the regulation and control of vascularization and vasculogenesis, vasculogenesis out of control can be led the growth of oncogenic generation and metastatic tumor.In addition, FGFR may have direct hormesis to tumour cell, in the patient with breast cancer, we are increased in a large number at find the to encode gene of FGFR1 and FGFR2, in astrocytoma, and the sialisterium sarcoma, in the patient of ovarian cancer and prostate cancer, also found a large amount of FGFR.A large amount of skeletal diseases is all relevant with the transgenation of FGFR, as: fetal rickets is all relevant with the transgenation of FGFR-3 with thanatophoric dwarfism.The sudden change in the zone, extracellular of FGFR also can cause some diseases, as: cranium face syndromes etc.
Have been found that now compound as described below is to have favourable pharmacological characteristics and suppress the active class new compound of Tyrosylprotein kinase (as VEGFR, PDGFR, FGFR, c-kit etc.).
The patent application of a series of FGFR inhibitor is disclosed at present, comprising WO2005070891, WO200780047672, WO2005021553 or WO200780051605 etc.
So far some drugmakers still suppress the new compound of FGFR, VEGFR and the many target spots of PDGFR in research, find safer and more effective newtype drug compound with expectation, and treat Cancerous disease by single drug or with the other drug coupling.The compound that the present invention design has the structure shown in general formula (I), and find that the compound with this class formation shows excellent effect and effect, especially as FGFR, VEGFR and many target spots of PDGFR inhibitor in pharmaceutically application.
Summary of the invention
The object of the present invention is to provide the compound shown in a kind of general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
Wherein:
G is selected from C-R ' or N;
Y is selected from a key, C (R 4R 5), O, S or N-R 4
Ring Q is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl;
Ring A is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl;
R 1Be selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl;
R 2Or R 3Be selected from independently of one another hydrogen atom, halogen, cyano group, nitro, alkyl, cycloalkyl, aryl, heteroaryl ,-NR 6R 7,-CONR 6R 7,-O (CH 2) rR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8, wherein said alkyl, cycloalkyl, aryl or heteroaryl independently of one another optional further by one or more be selected from hydroxyl, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8Substituting group replace;
R 4Or R 5Be selected from independently of one another hydrogen atom, alkyl, cycloalkyl, aryl, heteroaryl ,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8, wherein said alkyl, cycloalkyl, aryl or heteroaryl independently of one another optional further by one or more be selected from hydroxyl, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8Substituting group replace;
R 6Or R 7Be selected from independently of one another hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another optional further by one or more be selected from alkyl, halogen, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 11,-OC (O) R 11,-C (O) R 11,-C (O) NR 9R 10,-NR 9C (O) R 10,-NR 9R 10,-OC (O) NR 9R 10,-NHC (O) NR 9R 10,-S (O) mR 11,-NHC (O) is R (O) 11Or-NHS (O) mR 11Or-C (O) OR 11Substituting group replace;
Perhaps, R 6And R 7Form heterocyclic radical together with the N atom that is connected, wherein said heterocyclic radical contains one or more N of being selected from, O or S (O) mHeteroatoms, and described heterocyclic radical optional further by one or more be selected from alkyl, halogen, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 11,-OC (O) R 11,-C (O) R 11,-C (O) NR 9R 10,-NR 9C (O) R 10,-NR 9R 10,-OC (O) NR 9R 10,-NHC (O) NR 9R 10,-S (O) mR 11,-NHC (O) OR 11Or-NHS (O) mR 11Or-C (O) OR 11Substituting group replace;
R 8Be selected from hydrogen atom, alkyl, hydroxyl ,-NR 9R 10, cycloalkyl, heterocyclic radical, cyano group, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another optional further by one or more be selected from alkyl, halogen, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 11,-OC (O) R 11,-C (O) R 11,-C (O) NR 9R 10,-NR 9C (O) R 10,-NR 9R 10,-OC (O) NR 9R 10,-NHC (O) NR 9R 10,-S (O) mR 11,-NHC (O) OR 11Or-NHS (O) mR 11Or-C (O) OR 11Substituting group replace;
R 9, R 10Or R 11Be selected from independently of one another hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl;
R 12Be selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl;
R is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl;
Z is selected from O, S, N-R ' or CH-R ';
R ' is selected from hydrogen atom, cyano group, amino, alkyl, haloalkyl, alkoxyl group or halogenated alkoxy;
M is 0,1 or 2; And
R is 0,1,2,3 or 4.
In one embodiment of the invention, compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein said ring Q is aryl, is preferably naphthyl or phenyl.
In one embodiment of the invention, compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein said ring A is heterocyclic radical, be preferably 5 yuan or 6 yuan of heterocyclic radicals, more preferably tetrahydrofuran bases.
In one embodiment of the invention, the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein said R 1Or R 12Be hydrogen atom.
In another embodiment of the invention, compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, for the compound shown in general formula (II) or its tautomer, mesomeride and racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
Figure BDA00003089852000051
Wherein: Z, G, ring A, R 1～R 3, R 12With described in the definition such as general formula (I) of R.
In another embodiment of the invention, compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, for the compound shown in general formula (III) or its tautomer, mesomeride and racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
Figure BDA00003089852000052
Wherein: Z, G, R 2, R 3, R 12With described in the definition such as general formula (I) of R; And n is 1 or 2.
In another embodiment of the invention, compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, for the compound shown in general formula (IV) or its tautomer, mesomeride and racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
Wherein: Z, G, R 2, R 3, R 12With described in the definition such as general formula (I) of R.
In another embodiment of the invention, compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, for the compound shown in logical formula V or its tautomer, mesomeride and racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
Figure BDA00003089852000062
Wherein: Z, G, Y, ring A, R 1～R 3With described in the definition such as general formula (I) of R.
In another embodiment of the invention, compound shown in logical formula V or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, its be the compound shown in general formula (VI) or its tautomer, mesomeride and racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
Figure BDA00003089852000063
Wherein: Z, G, Y, R 2, R 3With described in the definition such as general formula (I) of R.
In one embodiment of the invention, the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein said Y is CH 2Or NH.
In one embodiment of the invention, the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein said R 3Be hydrogen atom.
In one embodiment of the invention, the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein said R 2For-O (CH 2) rR 8
R 8Be selected from hydrogen atom, alkyl, hydroxyl ,-NR 9R 10, cycloalkyl, heterocyclic radical, cyano group, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another optional further by one or more be selected from alkyl, halogen, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 11Or-NR 9R 10Substituting group replace; And
R 9, R 10Or R 11Be selected from independently of one another hydrogen atom or alkyl.
In one embodiment of the invention, the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein said G is CH.
In one embodiment of the invention, the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein Z is O.
Typical compound of the present invention includes, but are not limited to:
Figure BDA00003089852000071
Figure BDA00003089852000081
Figure BDA00003089852000091
Figure BDA00003089852000101
Figure BDA00003089852000111
Figure BDA00003089852000121
Figure BDA00003089852000131
Figure BDA00003089852000151
Figure BDA00003089852000161
Or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof.
The invention further relates to a kind of prepare the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof the method for form and pharmaceutically useful salt thereof, the method comprises the following steps:
Figure BDA00003089852000162
General formula (I-A) compound and general formula (I-B) compound are in solvent, and the lower heating of alkaline condition (being preferably cesium carbonate or salt of wormwood) is reacted, and obtains general formula (I) compound;
Wherein: LG is leavings group, is preferably halogen or sulfonyloxy, more preferably aryl-sulfonyl oxygen; And
Z, G, Y, ring A, ring Q, R 1～R 3, R 8, R 12, r and R definition such as general formula (I) described in.
In another aspect of the present invention, a kind of pharmaceutical composition is provided, described pharmaceutical composition contain the compound shown in the described general formula (I) for the treatment of significant quantity or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt and pharmaceutically acceptable carrier.
In another aspect of the present invention, also relate to the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, or the pharmaceutical composition that comprises it is preferably the purposes in FGFR, PDGFR, VEGFR-2, EGFR, HER-2, HER-3, HER-4, c-Kit, c-Met or Flt3 inhibitor at the preparation kinases inhibitor.
In another aspect of the present invention, also relate to a kind of method of regulating the protein kinase catalytic activity, comprising with the compound shown in described protein kinase and general formula (I) or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, or its pharmacy acceptable salt, or comprise its pharmaceutical composition contact.Preferably, described protein kinase is selected from receptor tyrosine kinase, nonreceptor tyrosine kinase or serine-threonine kinase.
In another aspect of the present invention, also relate to the compound shown in general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, or comprise its pharmaceutical composition, it is preferably FGFR, PDGFR, VEGFR-2, EGFR, HER-2, HER-3, HER-4, c-Kit, c-Met or Flt3 inhibitor as kinases inhibitor.
In another aspect of the present invention, also relate to the compound shown in general formula (I) or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, or comprise its purposes of pharmaceutical composition in the medicine of the preparation treatment disease relevant with protein kinase.Preferably, the described disease relevant with protein kinase is selected from the disease relevant with FGFR, PDGFR, VEGFR-2, EGFR, HER-2, HER-3, HER-4, c-Kit, c-Met or Flt3.Another preferred, the described disease relevant with protein kinase is selected from leukemia, diabetes, sick from immunological disease, hyperplasia disease, psoriasis, osteoarthritis, rheumatoid arthritis, vasculogenesis, cardiovascular diseases, Von-Heppel-LindauShi disease, inflammation or fibrosis.Another preferred, the described disease relevant with protein kinase is cancer, be preferably squamous cell carcinoma, prostate cancer, renal cell carcinoma, Ka Boxi (Kaposi) sarcoma, nonsmall-cell lung cancer, small cell lung cancer, lymphatic cancer, thyroid carcinoma, mammary cancer, head and neck cancer, uterus carcinoma, esophagus cancer, melanotic cancer, bladder cancer, Genito-urinary cancer, gastrointestinal cancer, neuroglia cancer, colorectal carcinoma or ovarian cancer, preferred mammary cancer or colorectal carcinoma.
In another aspect of the present invention, the method that also relates to a kind for the treatment of or the prevention Mammals disease relevant with protein kinase, comprise to the compound shown in the general formula of the present invention (I) of this administration treatment effective dose or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, or comprise its pharmaceutical composition.The described disease relevant with protein kinase is selected from the relevant disease of FGFR, VEGFR-2, PDGFR, EGFR, HER-2, HER-3, HER-4, c-Kit, c-Met or Flt3.The described disease relevant with protein kinase can also be leukemia, diabetes, sick from immunological disease, hyperplasia disease, psoriasis, osteoarthritis, rheumatoid arthritis, vasculogenesis, cardiovascular diseases, Von-Heppel-LindauShi disease, inflammation, fibrosis.The described disease relevant with protein kinase can also be squamous cell carcinoma, prostate cancer, renal cell carcinoma, Kaposi sarcoma, nonsmall-cell lung cancer, small cell lung cancer, lymphatic cancer, thyroid carcinoma, mammary cancer, head and neck cancer, uterus carcinoma, esophagus cancer, melanotic cancer, bladder cancer, Genito-urinary cancer, gastrointestinal cancer, neuroglia cancer, colorectal carcinoma and ovarian cancer, preferred mammary cancer or colorectal carcinoma.Preferably, described Mammals is the people.
Another aspect of the present invention relate to the compound shown in general formula (I) or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, or comprising its pharmaceutical composition, it is as the medicine of the treatment disease relevant with protein kinase.The wherein said disease relevant with protein kinase is selected from the disease relevant with FGFR, VEGFR-2, PDGFR, EGFR, HER-2, HER-3, HER-4, c-Kit, c-Met or Flt3; Perhaps, the wherein said disease relevant with protein kinase is selected from leukemia, diabetes, sick from immunological disease, hyperplasia disease, psoriasis, osteoarthritis, rheumatoid arthritis, vasculogenesis, cardiovascular diseases, Von-Heppel-LindauShi disease, inflammation or fibrosis; Perhaps the described disease relevant with protein kinase is cancer, be preferably squamous cell carcinoma, prostate cancer, renal cell carcinoma, Kaposi sarcoma, nonsmall-cell lung cancer, small cell lung cancer, lymphatic cancer, thyroid carcinoma, mammary cancer, head and neck cancer, uterus carcinoma, esophagus cancer, melanotic cancer, bladder cancer, Genito-urinary cancer, gastrointestinal cancer, neuroglia cancer, colorectal carcinoma and ovarian cancer, preferred mammary cancer or colorectal carcinoma.
The present invention relates to differentiate the compound of protein kinase catalytic activity, the cell of expressing this protein kinase is contacted with the compounds of this invention or salt, then detect the effect to cell.
The invention still further relates to the compound of differentiating the protein kinase catalytic activity, the synthetic kinase protein of artificial recombination is contacted with the compounds of this invention or salt, then with the impact of Elisa method detection on kinase activity.
Detailed description of the invention
Unless the phase counter-statement is arranged, otherwise the following term that is used in specification sheets and claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 10 carbon atom more preferably contains the alkyl of 1 to 6 carbon atom.non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, the 1-ethyl propyl, the 2-methyl butyl, the 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-trimethylammonium propyl group, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, the 2-ethyl-butyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl hexyl, 3-methyl hexyl, 4-methyl hexyl, 5-methyl hexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, the 2-ethyl pentyl group, the 3-ethyl pentyl group, n-octyl, 2,3-dimethyl hexyl, 2,4-dimethyl hexyl, 2,5-dimethyl hexyl, 2,2-dimethyl hexyl, 3,3-dimethyl hexyl, 4,4-dimethyl hexyl, the 2-ethylhexyl, the 3-ethylhexyl, the 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethyl amyl group, positive decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers etc.the low alkyl group that more preferably contains 1 to 6 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1, the 1-dimethyl propyl, 1, the 2-dimethyl propyl, 2, the 2-dimethyl propyl, the 1-ethyl propyl, the 2-methyl butyl, the 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1, 1, 2-trimethylammonium propyl group, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, the 2-ethyl-butyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 2, 3-dimethylbutyl etc.Alkyl can be that replace or unsubstituted, when being substituted, substituting group can be substituted on any spendable tie point, be preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8
" thiazolinyl " refers to the alkyl as defined above that is comprised of at least two carbon atoms and at least one carbon-to-carbon double bond.For example vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.Thiazolinyl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8
" alkynyl " refers to the alkyl as defined above that at least two carbon atoms and at least one carbon-to-carbon triple bond form.For example ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.Alkynyl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8
" cycloalkyl " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, and it comprises 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.The polycyclic naphthene base comprises the cycloalkyl of volution, condensed ring and bridged ring.
" spiro cycloalkyl group " refers to 5 to 20 yuan, shares many cyclic groups of a carbon atom (title spiro atom) between monocycle, and these can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to the number that shares spiro atom between ring and ring, spiro cycloalkyl group is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
Figure BDA00003089852000191
" condensed ring alkyl " refers to 5 to 20 yuan, each ring in system and other rings in system are shared the many cyclic groups of full carbon of a pair of carbon atom that adjoins, wherein one or more rings can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl according to the number of makeup ring, be preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.The non-limiting example of condensed ring alkyl comprises
" bridge ring alkyl " refers to 5 to 20 yuan, and any two rings share two not many cyclic groups of full carbon of direct-connected carbon atom, and these can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more according to the number of makeup ring, being preferably dicyclo, three ring or Fourth Rings, more electing dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises
Figure BDA00003089852000202
The cycloalkyl ring of above-mentioned " cycloalkyl ", " spiro cycloalkyl group ", " condensed ring alkyl " or " bridge ring alkyl " can condense on aryl, heteroaryl or heterocycloalkyl ring, the ring that wherein links together with precursor structure is cycloalkyl, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.Cycloalkyl can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8
" heterocyclic radical " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, and it comprises 3 to 20 annular atomses, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) mThe heteroatoms of (wherein m is integer 0 to 2), preferred nitrogen or oxygen heteroatom; But do not comprise-O-O-,-O-S-or-loop section of S-S-, all the other annular atomses are carbon.Preferably include 3 to 12 annular atomses, wherein 1～4 is heteroatoms; More preferably heterocyclic ring comprises 3 to 10 annular atomses, and wherein 1～3 is heteroatoms; Most preferably heterocyclic ring comprises 5 to 6 annular atomses, and wherein 1～2 is heteroatoms.The non-limiting example of monocyclic heterocycles base comprises dihydrofuran base, tetrahydrofuran base, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc.
Many ring heterocyclic radicals comprise the heterocyclic radical of volution, condensed ring and bridged ring." spiro heterocyclic radical " refers to 5 to 20 yuan, shares many rings heterocyclic group of an atom (title spiro atom) between monocycle, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) mThe heteroatoms of (wherein m is integer 0 to 2), all the other annular atomses are carbon.These can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to the number that shares spiro atom between ring and ring, spiro cycloalkyl group is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals, is preferably single spiro heterocyclic radical and two spiro heterocyclic radical.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro heterocyclic radical comprises
Figure BDA00003089852000211
" fused heterocycle base " refers to 5 to 20 yuan, each ring in system and other rings in system are shared many rings heterocyclic group of a pair of atom that adjoins, one or more rings can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) mThe heteroatoms of (wherein m is integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Can be divided into dicyclo, three rings, Fourth Ring or encircle the fused heterocycle alkyl more according to the number of makeup ring, being preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of fused heterocycle base comprises
Figure BDA00003089852000212
" bridge heterocyclic radical " refers to 5 to 14 yuan, any two rings share two not many rings heterocyclic groups of direct-connected atom, these can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) mThe heteroatoms of (wherein m is integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.7 to 10 yuan.Can be divided into dicyclo, three rings, Fourth Ring or encircle the bridge heterocyclic radical more according to the number of makeup ring, being preferably dicyclo, three ring or Fourth Rings, more electing dicyclo or three rings as.The non-limiting example of bridge heterocyclic radical comprises:
Figure BDA00003089852000213
Described heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring that wherein links together with precursor structure is heterocyclic radical, and non-limiting example comprises:
Figure BDA00003089852000214
Deng.Heterocyclic radical can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, is independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8
" aryl " refers to have 6 to 14 yuan of full carbon monocycles or fused polycycle (namely share and adjoin the right ring of the carbon atom) group of the π-electron system of conjugation, is preferably 6 to 10 yuan, more preferably phenyl and naphthyl, most preferably phenyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring that wherein links together with precursor structure is aryl rings, and non-limiting example comprises:
Figure BDA00003089852000221
Aryl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8
" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 5 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl is preferably, such as furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring that wherein links together with precursor structure is heteroaryl ring, and non-limiting example comprises:
Figure BDA00003089852000222
Heteroaryl can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio,--NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8
" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl is described as defined above.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from into alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8
One " key " refers to a covalent linkage with "-" expression.
" hydroxyl " refers to-the OH group.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" cyano group " refers to-CN.
" nitro " refers to-NO 2
" choose wantonly " or " randomly " mean describe subsequently ground event or environment can but needn't occur, this explanation comprises that this event or environment occur or spot occasion not.For example, " the optional heterocyclic group that is replaced by alkyl " mean alkyl can but must not exist, this explanation comprises the situation that situation that heterocyclic group is replaced by alkyl and heterocyclic group are not replaced by alkyl.
" replacement " refers to the one or more hydrogen atoms in group, is preferably maximum 5, and more preferably 1～3 hydrogen atom is replaced by the substituting group of respective number independently of one another.Self-evident, substituting group only is in their possible chemical position, those skilled in the art can in the situation that do not pay too much effort determine (by experiment or theoretical) may or impossible replacement.For example, the amino or the hydroxyl that have a free hydrogen may be unsettled when the carbon atom with unsaturated (as olefinic) key is combined.
" pharmaceutical composition " expression contains on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components physiology/pharmaceutically useful carrier and vehicle for example.The purpose of pharmaceutical composition is the administration that promotes organism, is beneficial to absorption and then the performance biological activity of activeconstituents.
The synthetic method of the compounds of this invention
In order to complete purpose of the present invention, the present invention adopts following technical scheme:
The preparation method of the described compound of general formula of the present invention (I) or its pharmaceutically useful salt comprises the following steps:
Figure BDA00003089852000241
General formula (I-A) compound and general formula (I-B) compound are in solvent, and under alkaline condition, heating is reacted, and obtains general formula (I) compound; Described solvent is preferably N,N-DIMETHYLACETAMIDE;
Wherein: LG is leavings group, is preferably halogen or sulfonyloxy, more preferably aryl-sulfonyl oxygen; When LG was halogen, described alkaline condition was preferably and adds salt of wormwood to react; When LG was sulfonyloxy, described alkaline condition was preferably and adds cesium carbonate to react;
Z, G, Y, ring A, ring Q, R 1～R 3, R 8, R 12, r and R definition such as general formula (I) described in.
The preparation method of the described compound of general formula of the present invention (II) or its pharmaceutically useful salt comprises the following steps:
Figure BDA00003089852000242
General formula (I-A) compound and general formula (II-B) compound are in solvent, and under alkaline condition, heating is reacted, and obtains general formula (II) compound; Described solvent is preferably N,N-DIMETHYLACETAMIDE;
Wherein: LG is leavings group, is preferably halogen or sulfonyloxy, more preferably aryl-sulfonyl oxygen; When LG was halogen, described alkaline condition was preferably and adds salt of wormwood to react; When LG was sulfonyloxy, described alkaline condition was preferably and adds cesium carbonate to react;
Z, G, ring A, R 1～R 3, R 12With described in the definition such as general formula (II) of R, and R 8, r definition such as general formula (I) described in.
Compound shown in general formula of the present invention (III) or the preparation method of its pharmaceutically useful salt comprise the following steps:
Figure BDA00003089852000243
General formula (I-A) compound and general formula (III-B) compound are in solvent, and under alkaline condition, heating is reacted, and obtains general formula (III) compound; Described solvent is preferably N,N-DIMETHYLACETAMIDE;
Wherein: LG is leavings group, is preferably halogen or sulfonyloxy, more preferably aryl-sulfonyl oxygen; When LG was halogen, described alkaline condition was preferably and adds salt of wormwood to react; When LG was sulfonyloxy, described alkaline condition was preferably and adds cesium carbonate to react;
Z, G, R 2, R 3, R 12With described in the definition such as general formula (III) of R, and R 8, r definition such as general formula (I) described in.
Compound shown in general formula of the present invention (IV) or the preparation method of its pharmaceutically useful salt comprise the following steps:
Figure BDA00003089852000251
General formula (I-A) compound and general formula (IV-B) compound are in solvent, and under alkaline condition, heating is reacted, and obtains general formula (IV) compound; Described solvent is preferably N,N-DIMETHYLACETAMIDE;
Wherein: LG is leavings group, is preferably halogen or sulfonyloxy, more preferably aryl-sulfonyl oxygen; When LG was halogen, described alkaline condition was preferably and adds salt of wormwood to react; When LG was sulfonyloxy, described alkaline condition was preferably and adds cesium carbonate to react;
Z, G, R 2, R 3, R 12With described in the definition such as general formula (IV) of R, and R 8, r definition such as general formula (I) described in.
Compound shown in the logical formula V of the present invention or the preparation method of its pharmaceutically useful salt comprise the following steps:
Figure BDA00003089852000252
General formula (I-A) compound and general formula (V-B) compound are in solvent, and under alkaline condition, heating is reacted, and obtain logical formula V compound; Described solvent is preferably N,N-DIMETHYLACETAMIDE;
Wherein: LG is leavings group, is preferably halogen or sulfonyloxy, more preferably aryl-sulfonyl oxygen; When LG was halogen, described alkaline condition was preferably and adds salt of wormwood to react; When LG was sulfonyloxy, described alkaline condition was preferably and adds cesium carbonate to react;
Z, G, Y, ring A, R 1～R 3With the definition of R described in logical formula V, and R 8, r definition such as general formula (I) described in.
Compound shown in general formula of the present invention (VI) or the preparation method of its pharmaceutically useful salt comprise the following steps:
General formula (I-A) compound and general formula (VI-B) compound are in solvent, and under alkaline condition, heating is reacted, and obtains general formula (VI) compound; Described solvent is preferably N,N-DIMETHYLACETAMIDE;
Wherein: LG is leavings group, is preferably halogen or sulfonyloxy, more preferably aryl-sulfonyl oxygen; When LG was halogen, described alkaline condition was preferably and adds salt of wormwood to react; When LG was sulfonyloxy, described alkaline condition was preferably and adds cesium carbonate to react;
Z, G, Y, R 2～R 3With described in the definition such as general formula (VI) of R, and R 8, r definition such as general formula (I) described in.
Above-mentioned reaction provides the condition of alkalescence to comprise organic bases and inorganic base, described organic bases includes but not limited to triethylamine, N, N-diisopropylethylamine, N, dinethylformamide, n-Butyl Lithium, potassium tert.-butoxide, Tetrabutyl amonium bromide, be preferably triethylamine or DIPEA; Described inorganic base includes but not limited to sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus or cesium carbonate, is preferably cesium carbonate.
Solvent for use includes but not limited to: acetic acid, methyl alcohol, ethanol, acetonitrile, tetrahydrofuran (THF), methylene dichloride, dimethyl sulfoxide (DMSO), Isosorbide-5-Nitrae-dioxane, water, N,N-DIMETHYLACETAMIDE or DMF.
Embodiment
Further describe explanation the present invention below in conjunction with specific embodiment, but these embodiment are in no way meant to be limiting for the scope of the invention.
The experimental technique of unreceipted actual conditions in the embodiment of the present invention, usually according to normal condition, or the condition of advising according to raw material or commodity manufacturers.The reagent in unreceipted concrete source is the conventional reagent of market purchase.
Embodiment
The structure of compound by nucleus magnetic resonance (NMR) or/and mass spectrum (MS) come to determine.NMR displacement (δ) is with 10 -6(ppm) unit provides.The mensuration of NMR is that measuring solvent is deuterated dimethyl sulfoxide (DMSO-d with Bruker AVANCE-400 nuclear magnetic resonance spectrometer 6), deuterochloroform (CDCl 3), deuterated methanol (CD 3OD), be designated as tetramethylsilane (TMS) in.
The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
The mensuration of HPLC is used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 * 4.6mm chromatographic column) and Waters2695-2996 high pressure liquid chromatograph (Gimini C18150 * 4.6mm chromatographic column).
The average inhibiting rate of kinases and IC 50The mensuration of value is with NovoStar microplate reader (German BMG company).
The tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) is used adopts is 0.15mm～0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm～0.5mm.
Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.
Known starting raw material of the present invention can adopt or synthesize according to methods known in the art, maybe can buy the GmbH﹠amp from ABCR; Co.KG, Acros Organics, Aldrich Chemical Company, reaches the company such as auspicious chemical at splendid chemistry science and technology far away (Accela ChemBio Inc).
In embodiment, without specified otherwise, reaction can all be carried out under argon atmospher or nitrogen atmosphere.
Argon atmospher or nitrogen atmosphere refer to that reaction flask connects approximately argon gas or the nitrogen balloon of 1L volume.
Nitrogen atmosphere refers to that reaction flask connects an approximately hydrogen balloon of 1L volume.
Parr3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument are used in the pressure hydration reaction.
Hydrogenation vacuumizes usually, is filled with hydrogen, repeatable operation 3 times.
Microwave reaction uses CEM Discover-S908860 type microwave reactor.
In embodiment, without specified otherwise, solution refers to the aqueous solution.
In embodiment, without specified otherwise, the temperature of reaction is room temperature, is 20 ℃～30 ℃.
Tlc (TLC) is adopted in the monitoring of the reaction process in embodiment, the system of the developping agent that reaction is used has: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: normal hexane, ethyl acetate and methylene dichloride, D: the acetone system, the volume ratio of solvent is according to different adjusting of polarity of compound.The system of the eluent of the column chromatography that purifying compounds adopts and the developping agent system of tlc comprise: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: normal hexane, ethyl acetate and methylene dichloride system, D: acetone system, E: methylene dichloride, methyl alcohol and ammoniacal liquor system, the volume ratio of solvent is different according to the polarity of compound regulates, and also can add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent to regulate.
Embodiment 1
6-(4-((the amino cyclopropyl of 1-) methoxyl group)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthalene first Acid amides
Figure BDA00003089852000271
Figure BDA00003089852000281
The first step
N-methoxyl group-N-methyl-2,3-Dihydrobenzofuranes-7-ammonium formiate
With 2,3-Dihydrobenzofuranes-7-formic acid 1a (according to Bioorganic﹠amp; Medicinal Chemistry Letters, 15 (24), 5567-5573; 2005 are prepared from) (10.8g, 66mmol) be dissolved in the 30mL thionyl chloride, back flow reaction 1 hour, concentrating under reduced pressure reaction solution, vacuum-drying 1 hour.Add the 50mL methylene dichloride in resistates, add N, O-dimethyl hydroxylamine hydrochloride (7.7g, 79mmol) and 10mL DIPEA, under room temperature, reaction is 1 hour.The concentrating under reduced pressure reaction solution adds 50mL water, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with eluent system A purifying gained resistates, obtain title product N-methoxyl group-N-methyl-2 with silica gel column chromatography, 3-Dihydrobenzofuranes-7-ammonium formiate 1b (10.9g, yellow solid), productive rate: 80.1%.
MS?m/z(ESI):208.6[M+1]
Second step
1-(2,3-Dihydrobenzofuranes-7-yl) ethyl ketone
With N-methoxyl group-N-methyl-2,3-Dihydrobenzofuranes-7-ammonium formiate 1b (10.9g, 52.65mmol) is dissolved in the 150mL tetrahydrofuran (THF), and argon replaces three times drips methyl-magnesium-bromide (35mL, 105mmol), finishes reaction 1 hour.The concentrating under reduced pressure reaction solution, the hydrochloric acid soln adjust pH that drips 1M in the resistates is 3-4, with ethyl acetate extraction (30mL * 4), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with eluent system B purifying gained resistates, obtain title product 1-(2,3-Dihydrobenzofuranes-7-yl) ethyl ketone 1c (6.21g with silica gel column chromatography, faint yellow solid), productive rate: 73.1%.
MS?m/z(ESI):163.1[M+1]
The 3rd step
1-(5-nitro-2,3-Dihydrobenzofuranes-7-yl) ethyl ketone
1-(2,3-Dihydrobenzofuranes-7-yl) ethyl ketone 1c (3.8g, 23.4mmol) is dissolved in 15mL sulfuric acid, adds saltpetre (3.96g, 39mmol) under ice bath in batches, finish temperature control 0-5 ℃ of reaction 2 hours.Reaction solution is poured in the 100mL frozen water, with ethyl acetate extraction (40mL * 3), merged organic phase, successively with saturated sodium bicarbonate solution washing (30mL), saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying filters, concentrating under reduced pressure filtrate, with eluent system C purifying gained resistates, obtain title product 1-(5-nitro-2,3-Dihydrobenzofuranes-7-yl) ethyl ketone 1d (3.3g with silica gel column chromatography, faint yellow solid), productive rate: 70.5%.
MS?m/z(ESI):208.2[M+1]
The 4th step
5-nitro-2,3-Dihydrobenzofuranes-7-alcohol
With trifluoroacetic anhydride (15.75g, 75mmol) put into reaction flask, cryosel is bathed lower 30% the hydrogen peroxide (2.65g that drips, 23.4mmol), under temperature control-10 ℃, reaction is 10 minutes, drips 15mL1-(5-nitro-2,3-Dihydrobenzofuranes-7-yl) ethyl ketone 1d (1.56g, 7.5mmol) dichloromethane solution, finish under room temperature reaction 30 minutes.Add 20mL water in reaction solution, with dichloromethane extraction (10mL * 2), merge organic phase, anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, the sodium hydroxide solution that adds 20mL tetrahydrofuran (THF) and 7.5mL3M in the resistates, under room temperature, reaction is 1 hour.The concentrating under reduced pressure reaction solution, hydrochloric acid soln to the pH value that drips 1M in the resistates be 3-4, use ethyl acetate extraction (20mL * 3), merging organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, obtain title product 5-nitro-2,3-Dihydrobenzofuranes-7-alcohol 1e (1.0g, yellow solid), productive rate: 74.1%.
MS?m/z(ESI):182.0[M+1]
The 5th step
7-(benzyloxy)-5-nitro-2, the 3-Dihydrobenzofuranes
With 5-nitro-2,3-Dihydrobenzofuranes-7-alcohol 1e (2.2g, 12mmol) is dissolved in the 25mL DMF, adds bromobenzyl (2.5g, 14.6mmol) and salt of wormwood (2.5g, 182mmol), and reaction is 4 hours under 80 ℃.Reaction solution is chilled to room temperature, adds 100mL water, with ethyl acetate extraction (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with eluent system C purifying gained resistates, obtain title product 7-(benzyloxy)-5-nitro-2,3-Dihydrobenzofuranes 1f (2.6g with silica gel column chromatography, yellow solid), productive rate: 79.0%.
The 6th step
7-(benzyloxy)-2,3-Dihydrobenzofuranes-5-amine
With 7-(benzyloxy)-5-nitro-2,3-Dihydrobenzofuranes 1f (2.6g, 9.6mmol) be dissolved in the mixing solutions of 60mL second alcohol and water (V/V=4/1), add ammonium chloride (4.1g, 76.8mmol), add iron powder (2.15g, 38.4mmol) under 80 ℃, 80 ℃ of reactions of temperature control 30 minutes in batches.Reaction solution is chilled to room temperature, filters concentrating under reduced pressure filtrate, add 20mL water in resistates, with ethyl acetate extraction (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, obtain title product 7-(benzyloxy)-2,3-Dihydrobenzofuranes-5-amine 1g (1.82g, gray solid), productive rate: 79.1%.
MS?m/z(ESI):242.2[M+1]
The 7th step
5-((7-(benzyloxy)-2,3-Dihydrobenzofuranes-5-base is amino) methylene radical)-2,2-dimethyl-1,3-diox-4,6-two
Ketone
With 7-(benzyloxy)-2,3-Dihydrobenzofuranes-5-amine 1g (1.7g, 7.05mmol) be dissolved in the 15mL Virahol, add 5-(oxyethyl group methylene radical)-2,2-dimethyl-1,3-diox-4,6-diketone 1h (method disclosed according to WO2006117552 is prepared from) (1.4g, 7.05mmol), reaction is 30 minutes under 80 ℃.Reaction solution is chilled to room temperature, filtering reacting liquid, filter cake is collected filter cake with washed with isopropyl alcohol (2mL * 3), oven dry, obtain title product 5-((7-(benzyloxy)-2,3-Dihydrobenzofuranes-5-base is amino) methylene radical)-2,2-dimethyl-1,3-diox-4,6-diketone 1i (1.5g, yellow solid), productive rate: 54.0%.
MS?m/z(ESI):396.8[M+1]
The 8th step
4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-alcohol also
With 5-((7-(benzyloxy)-2,3-Dihydrobenzofuranes-5-base is amino) methylene radical)-2,2-dimethyl-1,3-diox-4,6-diketone 1i (1.5g, 3.79mmol) is dissolved in the 15mL phenyl ether, and reaction is 15 minutes under 220 ℃.Reaction solution is chilled to 40 ℃, pour in the 75mL ether, stirred 20 minutes, filter, filter cake washs (10mL * 3) with ether, collect filter cake, oven dry obtains title product 4-(benzyloxy)-1,2-dihydrofuran also [3,2-f] quinoline-9-alcohol 1j (800mg, gray solid), productive rate: 72.1%.
MS?m/z(ESI):294.1[M+1]
The 9th step
4-(benzyloxy)-9-chloro-1,2-dihydrofuran be [3,2-f] quinoline also
With 4-(benzyloxy)-1,2-dihydrofuran also [3,2-f] quinoline-9-alcohol 1j (300mg, 1.02mmol) is dissolved in the 3mL phosphorus oxychloride, argon replaces three times, back flow reaction 1 hour.The concentrating under reduced pressure reaction solution, add the 20mL ether, vigorous stirring 30 minutes is filtered, filter cake washs (5mL * 3) with ether, collect filter cake, oven dry obtains title product 4-(benzyloxy)-9-chloro-1,2-dihydrofuran also [3,2-f] quinoline 1k (283mg, gray solid), productive rate: 89.0%.
MS?m/z(ESI):312.1[M+1]
The tenth step
6-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide
With 4-(benzyloxy)-9-chloro-1,2-dihydrofuran also [3,2-f] quinoline 1k (283mg, 0.9mmol), 6-hydroxy-n-methyl isophthalic acid-naphthoamide 1m (method disclosed according to WO2008112408 is prepared from) (548mg, 2.7mmol) and DMAP (165mg, 1.35mmol) be dissolved in 10mL2, in the 6-lutidine, argon replaces three times, reaction is 4 hours under 140 ℃.The concentrating under reduced pressure reaction solution, the mixing solutions that adds 20mL methyl alcohol and methylene dichloride (V/V=1/1) in the resistates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 6-(4-(benzyloxy)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1n (70mg, gray solid), productive rate; 16.4%.
MS?m/z(ESI):477.1[M+1]
The 11 step
6-(4-hydroxyl-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide
6-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide 1n (70mg, 0.15mmol) is dissolved in the 5mL trifluoroacetic acid, and reaction is 1 hour under 80 ℃.The concentrating under reduced pressure reaction solution, vacuum-drying obtains title product 6-(4-hydroxyl-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide 1p (40mg, brown oil), productive rate: 71.4%.
MS?m/z(ESI):387.2[M+1]
The 12 step
1-((9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1, the 2-dihydrofuran is [3,2-f] quinolyl-4 oxygen base also) methyl) cyclopropylamino t-butyl formate
With 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (40mg, 0.1mmol), (1-(tert-butoxycarbonyl is amino) cyclopropyl) methyl mesylate 1q (method disclosed according to WO2010118207 is prepared from) (40mg, 0.15mmol) and cesium carbonate (98mg, 0.3mmol) be dissolved in the 3mL N,N-DIMETHYLACETAMIDE, under 100 ℃ the reaction 4 hours.The concentrating under reduced pressure reaction solution; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product 1-((9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) methyl) cyclopropylamino t-butyl formate 1r (20mg; white solid), productive rate: 36.4%.
MS?m/z(ESI):556.4[M+1]
The 13 step
6-(4-((the amino cyclopropyl of 1-) methoxyl group)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide
With 1-((9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) methyl) cyclopropylamino t-butyl formate 1r (20mg; 0.036mmol) be dissolved in the dioxane solution of 1mL3.9M hydrogenchloride, reacted 2 hours.Filtering reacting liquid, filter cake washs (1mL * 2) with ether, collect filter cake, vacuum-drying, obtain title product 6-(4-((the amino cyclopropyl of 1-) methoxyl group)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide 1 (11mg, white solid), productive rate: 68.7%.
MS?m/z(ESI):456.2[M+1]
1H?NMR(400MHz,DMSO-d 6):δ8.65(d,1H),8.60-8.59(m,1H),8.50(d,1H),8.08(d,1H),7.97(s,1H),7.75-7.53(m,4H),6.93(d,1H),5.02-4.94(m,2H),4.53(s,2H),4.13-4.05(m,2H),3.03(s,3H),1.34-1.22(m,4H)
Embodiment 2
N-methyl-6-(4-(3-morpholino propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide
Figure BDA00003089852000321
The first step
3-morpholino propane-1-alcohol
Morpholine 2a (3.1g, 36mmol) and 3-bromo-1-propyl alcohol (2.5g, 18mmol) are dissolved in 20mL toluene, and reaction is 4 hours under 80 ℃.Reaction solution is chilled to room temperature, filtering reacting liquid, filter cake washs (2mL * 2) with ethyl acetate, and concentrating under reduced pressure filtrate obtains title product 3-morpholino propane-1-alcohol 2b (2.3g, yellow oil), productive rate: 88.5%.
MS?m/z(ESI):146.2[M+1]
Second step
3-4-toluene sulfonic acide morpholino propyl ester
With 3-morpholino propane-1-alcohol 2b (1.45g, 10mmol) be dissolved in the 20mL methylene dichloride, add triethylamine (2.01g, 20mmol) and DMAP (122mg, 1mmol), reacted 10 minutes, add Tosyl chloride (2.86g, 15mmol), reaction is 16 hours.The concentrating under reduced pressure reaction solution, add a small amount of ethyl acetate in resistates, stirred 10 minutes, filter, concentrating under reduced pressure filtrate with eluent system A purifying gained resistates, obtains title product 3-4-toluene sulfonic acide morpholino propyl ester 2c (1.3g with silica gel column chromatography, yellow oil), productive rate: 43.5%.
MS?m/z(ESI):300.2[M+1]
The 3rd step
N-methyl-6-(4-(3-morpholino propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide
With 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (30mg, 0.078), 3-4-toluene sulfonic acide morpholino propyl ester 2c (35mg, 0.12mmol) and cesium carbonate (76mg, 0.23mmol) be dissolved in the 2mL N,N-DIMETHYLACETAMIDE, under 60 ℃ the reaction 16 hours.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product N-methyl-6-(4-(3-morpholino propoxy-)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-1-naphthoamide 2 (18mg, white solid), productive rate: 46.2%.
MS?m/z(ESI):514.4[M+1]
1H?NMR(400MHz,DMSO-d 6):δ8.52-8.46(m,2H),8.36(d,1H),7.99(d,1H),7.72(s,1H),7.59-7.48(m,3H),7.36(s,1H),6.62(d,1H),4.75-4.70(m,2H),4.25-4.21(m,2H),3.75-3.70(m,2H),3.61-3.59(m,4H),2.87-2.86(m,3H),2.49-2.45(m,2H),2.43-2.38(m,4H),1.98-1.97(m,2H)
Embodiment 3
6-(4-(3-hydroxy-3-methyl butoxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoyl Amine
Figure BDA00003089852000331
The first step
3-hydroxy-3-methyl-4-toluene sulfonic acide butyl ester
With 3-methylbutane-1,3-glycol 3a (1.0mL, 9.60mmol) be dissolved in the 40mL methylene dichloride, add triethylamine (2.7mL, 19.20mmol), DMAP (117mg, 0.96mmol) and Tosyl chloride (1.83g, 9.60mmol), reacted 17 hours.Reaction solution washes (50mL * 3) successively with water, saturated sodium bicarbonate solution washing (50mL * 3), saturated nacl aqueous solution washing (50mL * 3), merge organic phase, anhydrous magnesium sulfate drying filters, concentrating under reduced pressure filtrate, obtain title product 3-hydroxy-3-methyl-4-toluene sulfonic acide butyl ester 3b (1.80g, yellow oil), productive rate: 72.7%.
MS?m/z(ESI):276.2[M+18]
Second step
6-(4-(3-hydroxy-3-methyl butoxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide
With 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (70mg, 0.18mmol), 3-hydroxy-3-methyl-4-toluene sulfonic acide butyl ester 3b (94mg, 0.36mmol) and cesium carbonate (176mg, 0.54mmol) be dissolved in the 5mL N,N-DIMETHYLACETAMIDE, under 60 ℃ the reaction 21 hours.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product 6-(4-(3-hydroxy-3-methyl butoxy)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 3 (40mg, yellow solid), productive rate: 46.5%.
MS?m/z(ESI):473.3[M+1]
1H?NMR(400MHz,DMSO-d 6):δ8.53-8.46(m,2H),8.34(d,1H),7.98(d,1H),7.71(d,1H),7.60-7.48(m,3H),7.37(s,1H),6.62-6.60(m,1H),4.71(t,2H),4.46(s,1H),4.36-4.27(m,2H),3.72(t,2H),3.51(q,2H),2.86-2.85(m,3H),1.20(s,3H),1.07(s,3H)
Embodiment 4
6-(4-(2-hydroxy-2-methyl propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoyl Amine
Figure BDA00003089852000341
The first step
2-methylpropane-1, the 2-glycol
2-hydroxy-2-methyl methyl propionate 4a (2.0mL, 17mmol) is dissolved in the 80mL tetrahydrofuran (THF), adds Lithium Aluminium Hydride (964mg, 25mmol) under 0 ℃, finish under room temperature and reacted 1 hour.Add 20mL water and 200mL ethyl acetate in reaction solution, filtering reacting liquid, filtrate is used anhydrous magnesium sulfate drying, filters, and concentrating under reduced pressure filtrate obtains title product 2-methylpropane-1,2-glycol 4b (1.26g, yellow oil), productive rate: 82.6%.
Second step
2-hydroxy-2-methyl-4-toluene sulfonic acide propyl ester
With 2-methylpropane-1,2-glycol 4b (1.26g, 14mmol) is dissolved in the 50mL methylene dichloride, add triethylamine (3.9mL, 28mmol), DMAP (171mg, 1.40mmol) and Tosyl chloride (2.67g, 14mmol), reacted 16 hours.Reaction solution is successively with saturated sodium bicarbonate solution washing (30mL * 3), saturated nacl aqueous solution washing (30mL * 3), merge organic phase, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate obtains title product 2-hydroxy-2-methyl-4-toluene sulfonic acide propyl ester 4c (2.32 g, brown oil), productive rate: 67.9%.
MSm/z(ESI):262.2[M+18]
The 3rd step
6-(4-(2-hydroxy-2-methyl propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide
With 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (20mg, 0.052mmol), 2-hydroxy-2-methyl-4-toluene sulfonic acide propyl ester 4c (25 mg, 0.104 mmol), cesium carbonate (50mg, 0.155mmol) and the 2mL N,N-DIMETHYLACETAMIDE put into the microwave reaction pipe, tube sealing was in 100 ℃ of lower microwave reactions 2.5 hours.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product 6-(4-(2-hydroxy-2-methyl propoxy-)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 4 (4mg, yellow solid), productive rate: 16.7%.
MS?m/z(ESI):459.2[M+1]
1HNMR(400MHz,DMSO-d 6):δ8.53-8.45(m,2H),8.33(d,1H),7.96(d,1H),7.69(d,1H),7.59-7.35(m,4H),6.62-6.61(m,1H),4.65(t,2H),4.30(s,1H),4.02(s,2H),3.69(t,2H),2.85-2.84(m,3H),1.18(s,3H),1.03(s,3H)
Embodiment 5
N-methyl-6-(4-((1-methyl piperidine-4-yl) methoxyl group)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthalene Methane amide
Figure BDA00003089852000351
The first step
4-(toluenesulphonic acids methyl esters) piperidines-1-t-butyl formate
With 4-(methylol) piperidines-1-t-butyl formate 5a (2.15g, 10mmol) (splendid chemistry far away, article No.: SY005902), triethylamine (2.77mL, 20mmol), DMAP (122mg, 1mmol) be dissolved in the 30mL methylene dichloride, add Tosyl chloride (2.86g, 15mmol), reacted 16 hours.Add 50mL water in reaction solution, separatory, water merges organic phase with dichloromethane extraction (10mL * 3), with saturated nacl aqueous solution washing (20mL), anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography with eluent system C purifying gained resistates, obtain title product 4-(toluenesulphonic acids methyl esters) piperidines-1-t-butyl formate 5b (2.6g, faint yellow solid), productive rate: 70.5%.
Second step
4-((9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1, the 2-dihydrofuran is [3,2-f] quinolyl-4 oxygen base also) methyl) piperidines-1-t-butyl formate
With 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (100mg, 0.26mmol), 4-(toluenesulphonic acids methyl esters) piperidines-1-t-butyl formate 5b (143mg, 0.39mmol) and cesium carbonate (253mg, 0.78mmol) be dissolved in the 5mL N,N-DIMETHYLACETAMIDE, under 60 ℃ the reaction 16 hours.The concentrating under reduced pressure reaction solution; with tlc with developping agent system A purifying gained resistates; obtain title product 4-((9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) methyl) piperidines-1-t-butyl formate 5c (106mg; faint yellow solid), productive rate: 70.2%.
The 3rd step
N-methyl-6-(4-(piperidin-4-yl methoxyl group)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide
With 4-((9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) methyl) piperidines-1-t-butyl formate 5c (100mg; 0.17mmol) be dissolved in the dioxane solution of 10mL2M hydrogenchloride, reacted 2 hours.The concentrating under reduced pressure reaction solution, add the 5mL ether in resistates, stirred 10 minutes, filter, collect filter cake, with ether drip washing (2mL * 3), oven dry obtains title product N-methyl-6-(4-(piperidin-4-yl methoxyl group)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-1-naphthoamide 5d (68mg, white solid), productive rate: 82.9%.
The 4th step
N-methyl-6-(4-((1-methyl piperidine-4-yl) methoxyl group)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide
With N-methyl-6-(4-(piperidin-4-yl methoxyl group)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-1-naphthoamide 5d (68mg, 0.14mmol) be dissolved in 4mL methyl alcohol, add the formaldehyde solution of 1.6mL37% and the sodium cyanoborohydride solution of 1.2mL0.3M zinc chloride, reacted 20 minutes.Add the 20mL saturated sodium bicarbonate solution, with dichloromethane extraction (5mL * 6), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate obtains title product N-methyl-6-(4-((1-methyl piperidine-4-yl) methoxyl group)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-1-naphthoamide 5 (51mg, white solid), productive rate: 73.9%.
MS?m/z(ESI):498.3[M+1]
1H?NMR(400MHz,DMSO-d 6):δ9.57(s,1H),8.46(d,1H),8.34(s,1H),7.98(d,1H),7.71(s,1H),7.58-7.47(m,3H),7.34(s,1H),6.61(d,1H),4.82-4.79(m,2H),4.75-4.66(m,4H),4.05-4.03(m,2H),3.74-3.70(m,2H),2.87-2.86(m,3H),2.82-2.75(m,2H),2.17(s,3H),1.92-1.86(m,2H),1.79-1.76(m,1H)
Embodiment 6
1-methyl-3-(4-(4-(3-morpholino propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) phenyl) urea
Figure BDA00003089852000361
Figure BDA00003089852000371
The first step
4-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) aniline
With 4-(benzyloxy)-9-chloro-1,2-dihydrofuran also [3,2-f] quinoline 1k (500mg, 1.61mmol), PAP 6a (526mg, 4.82mmol) and potassium tert.-butoxide (810mg, 7.22mmol) are dissolved in 20mL N, in dinethylformamide, reaction is 17 hours under 70 ℃.Reaction solution is poured in the mixing solutions of 400mL ethyl acetate and saturated nacl aqueous solution (V/V=1/1), separatory, water ethyl acetate extraction (100mL * 2), merge organic phase, with saturated nacl aqueous solution washing (200mL * 2), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, obtain title product 4-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) aniline 6b (600mg, the brownish black solid), productive rate: 97.2%.
Second step
1-(4-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) phenyl)-3-MU
With triphosgene (171mg, 0.58mmol) be dissolved in the 15mL methylene dichloride, (4-(benzyloxy)-1,2-dihydrofuran also [3 to add 4-under 0 ℃, 2-f] quinoline-9-base oxygen base) aniline 6b (600mg, 1.56mmol) and 10mLN, the dichloromethane solution of N-diisopropylethylamine (816 μ L, 4.68mmol), under room temperature, reaction is 40 minutes, add methylamine (2.3mL, 4.68mmol), under room temperature, reaction is 16 hours.Add 50mL water in reaction solution, with ethyl acetate extraction (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with tlc with developping agent system A purifying gained resistates, obtain title product 1-(4-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) phenyl)-3-MU 6c (250mg, the brown color solid), productive rate: 36.3%.
MS?m/z(ESI):442.3[M+1]
The 3rd step
1-(4-(4-hydroxyl-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also) phenyl)-3-MU
With 1-(4-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) phenyl)-3-MU 6c (250mg, 0.57mmol) be dissolved in 20mL methyl alcohol, add 25mg palladium/carbon, hydrogen exchange 6 times, reaction is 16 hours under nitrogen atmosphere.Filtering reacting liquid, concentrating under reduced pressure filtrate obtains title product 1-(4-(4-hydroxyl-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also) phenyl)-3-MU 6d (110mg, brown color solid), productive rate: 55.6%.
The 4th step
1-methyl-3-(4-(4-(3-morpholino propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) phenyl) urea
With 1-(4-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base) phenyl)-3-MU 6d (50mg, 0.11mmol), 3-4-toluene sulfonic acide morpholino propyl ester 2c (68mg, 0.23mmol) and cesium carbonate (110mg, 0.34mmol) be dissolved in the 5mL N,N-DIMETHYLACETAMIDE, under 90 ℃ the reaction 3 hours.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product 1-methyl-3-(4-(4-(3-morpholino propoxy-)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base) phenyl) urea 6 (5mg, yellow solid), productive rate: 9.3%.
MS?m/z(ESI):479.3[M+1]
1H?NMR(400MHz,DMSO-d 6):δ8.63(s,1H),8.38(d,1H),7.50(d,2H),7.29(s,1H),7.11-7.08(m,2H),6.40-6.39(m,1H),6.06-6.02(m,1H),4.71(t,2H),4.20(t,2H),3.73(t,2H),3.60-3.57(m,4H),2.65-2.64(m,3H),2.45(t,2H),2.39-2.37(m,4H),1.98-1.91(m,2H)
Embodiment 7
N-methyl-6-(4-(3-(4-methylpiperazine-1-yl) propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1- Naphthoamide
Figure BDA00003089852000381
The first step
4-(3-(9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1, the 2-dihydrofuran is [3,2-f] quinolyl-4 oxygen base also) propyl group) piperazine-1-t-butyl formate
With 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (100mg, 0.26mmol), 4-(3-(tosyloxy) propyl group) piperazine-1-t-butyl formate 7a (being prepared from according to EP388309) (155mg, 0.39mmol) and cesium carbonate (253mg, 0.78mmol) be dissolved in the 5mL N,N-DIMETHYLACETAMIDE, under 60 ℃ the reaction 16 hours.The concentrating under reduced pressure reaction solution; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product 4-(3-(9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) propyl group) piperazine-1-t-butyl formate 7b (68mg; gray solid), productive rate: 42.8%.
Second step
N-methyl-6-(4-(3-(piperazine-1-yl) propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide
With 4-(3-(9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) propyl group) piperazine-1-t-butyl formate 7b (60mg, 0.1mmol) is dissolved in the methanol solution of 4mL2M hydrogenchloride, reacted 2 hours.The concentrating under reduced pressure reaction solution obtains title product N-methyl-6-(4-(3-(piperazine-1-yl) propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide 7c (48mg, yellow solid), productive rate: 94.1%.
MS?m/z(ESI):513.4[M+1]
The 3rd step
N-methyl-6-(4-(3-(4-methylpiperazine-1-yl) propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide
With N-methyl-6-(4-(3-(piperazine-1-yl) propoxy-)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-1-naphthoamide 7c (98mg, 0.94mmol) be dissolved in 4mL methyl alcohol, add the sodium cyanoborohydride solution of 1.2mL0.3M zinc chloride and the formaldehyde solution of 1.6mL37%, reacted 20 minutes.Add the 20mL saturated sodium bicarbonate solution, filter, filter cake is used water wash (1mL * 3) successively, and filter cake is collected in ethyl acetate drip washing (1mL * 2), oven dry, obtain title product N-methyl-6-(4-(3-(4-methylpiperazine-1-yl) propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide 7 (36mg, gray solid), productive rate: 73.5%.
MS?m/z(ESI):527.4[M+1]
1H?NMR(400MHz,DMSO-d 6):δ9.55(s,1H),8.92-8.89(d,1H),8.15-8.07(m,2H),7.63-7.40(m,3H),7.26-7.10(m,2H),6.68(d,1H),4.25-4.23(m,2H),4.08-4.04(m,2H),2.97-2.90(m,2H),2.82-2.80(m,3H),2.46-2.35(m,10H),2.26(s,3H),1.86-1.81(m,2H)
Embodiment 8
N-methyl-6-(4-(2-morpholino oxyethyl group)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide
Figure BDA00003089852000391
With 2-4-toluene sulfonic acide morpholino ethyl ester 8a (method disclosed according to WO2008045834 is prepared from) (126mg, 0.47mmol), 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (90mg, 0.23mmol) and cesium carbonate (227mg, 0.70mmol) be dissolved in the 3mL N,N-DIMETHYLACETAMIDE, under 100 ℃ the reaction 2 hours.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product N-methyl-6-(4-(2-morpholino oxyethyl group)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-1-naphthoamide 8 (21mg, white solid), productive rate: 18.1%.
MS?m/z(ESI):500.3[M+1]
1H?NMR(400MHz,DMSO-d 6):δ8.52-8.50(m,1H),8.48-8.47(d,1H),8.37-8.35(d,1H),8.00-7.98(m,1H),7.72-7.71(m,1H),7.60-7.55(m,2H),7.51-7.48(m,1H),7.39(s,1H),6.63-6.62(d,1H),4.75-4.70(m,2H),4.32-4.29(m,2H),3.75-3.73(m,2H),3.62-3.59(m,4H),2.86(d,3H),2.80-2.77(m,2H),2.53-2.49(m,4H)
Embodiment 9
N-methyl-2-(4-(4-(3-morpholino propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) phenyl) ethanamide
Figure BDA00003089852000401
The first step
2-(4-hydroxy phenyl)-N-methylacetamide
With 2-(4-hydroxy phenyl) acetic acid 9a (5g, 33mmol) be dissolved in the 150mL methylene dichloride, add 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (14.74g, 39mmol), methylamine (19.7mL, 39mmol) and triethylamine (13.7mL, 98mmol), reaction is 6 hours.Reaction solution is successively with saturated sodium bicarbonate solution washing (200mL * 3), saturated nacl aqueous solution washing (200mL * 3), merge organic phase, anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-(4-hydroxy phenyl)-N-methylacetamide 9b (2.77g, yellow oil), productive rate: 51.0%.
MS?m/z(ESI):164.2[M-1]
Second step
2-(4-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) phenyl)-N-methylacetamide
With 4-(benzyloxy)-9-chloro-1,2-dihydrofuran also [3,2-f] quinoline 1k (530mg, 1.70mmol), 2-(4-hydroxy phenyl)-N-methylacetamide 9b (843mg, 5.10mmol) and DMAP (311mg, 2.55mmol) be dissolved in 20mL2, in the 6-lutidine, argon replaces 3 times, back flow reaction 24 hours.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product 2-(4-(4-(benzyloxy)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base) phenyl)-N-methylacetamide 9c (94mg, yellow solid), productive rate: 12.6%.
MS?m/z(ESI):441.3[M+1]
The 3rd step
2-(4-(4-hydroxyl-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also) phenyl)-N-methylacetamide
With 2-(4-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) phenyl)-N-methylacetamide 9c (90mg, 0.20mmol) be dissolved in 15mL methyl alcohol, add 10mg palladium/carbon, hydrogen exchange seven times reacted 3.5 hours.Filtering reacting liquid, concentrating under reduced pressure filtrate obtains title product 2-(4-(4-hydroxyl-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also) phenyl)-N-methylacetamide 9d (37mg, yellow solid), productive rate: 51.4%.MS?m/z(ESI):351.1[M+1]
The 4th step
N-methyl-2-(4-(4-(3-morpholino propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also) phenyl) ethanamide
With 2-(4-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base) phenyl)-N-methylacetamide 9d (35mg, 0.1mmol), 3-4-toluene sulfonic acide morpholino propyl ester 2c (75mg, 0.25mmol) and cesium carbonate (97mg, 0.3mmol) be dissolved in the 2mL N,N-DIMETHYLACETAMIDE, under 90 ℃ the reaction 16 hours.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product N-methyl-2-(4-(4-(3-morpholino propoxy-)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base) phenyl) ethanamide 9 (20mg, yellow solid), productive rate: 41.7%.
MS?m/z(ESI):478.3[M+1]
1H?NMR(400MHz,DMSO-d 6):δ8.64(s,1H),8.37-8.38(m,1H),7.52(d,2H),7.27(s,1H),7.13-7.11(m,2H),6.45-6.42(m,1H),4.67(t,2H),4.35(s,2H),4.14(t,2H),3.72(t,2H),3.58-3.54(m,4H),2.71-2.69(m,3H),2.51(t,2H),2.41-2.38(m,4H),2.02-1.98(m,2H)
Embodiment 10
(S)-6-(4-(the amino propoxy-of 2-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide
Figure BDA00003089852000421
The first step
(S)-1-(9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1, the 2-dihydrofuran is [3,2-f] quinolyl-4 oxygen base also) propyl group-2-aminocarbamic acid tert-butyl ester
With 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (100mg, 0.27mmol), (S)-2-(tert-butoxycarbonyl is amino) methylsulfonic acid propyl ester 10a (203mg, 0.80mmol) and cesium carbonate (347mg, 1.07mmol) be dissolved in the 15mL N,N-DIMETHYLACETAMIDE, under 100 ℃ the reaction 3 hours.The concentrating under reduced pressure reaction solution; with tlc with developping agent system A purifying gained resistates; obtain title product (S)-1-(9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) propyl group-2-aminocarbamic acid tert-butyl ester 10b (62mg; yellow solid), productive rate: 42.8%.
Second step
(S)-6-(4-(the amino propoxy-of 2-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide
With (S)-1-(9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) propyl group-2-aminocarbamic acid tert-butyl ester 10b (60mg; 0.11mmol) be dissolved in the dioxane solution of 1mL2M hydrogenchloride; add 0.15mL methyl alcohol, reacted 1 hour.Add 2mL acetone in reaction solution, filtering reacting liquid dissolves filter cake with the 10mL methylene dichloride, with saturated sodium bicarbonate solution washing (5mL * 2), merge organic phase, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, vacuum-drying obtains title product (S)-6-(4-(the amino propoxy-of 2-)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 10 (50mg, yellow solid), productive rate: 94.3%.
MS?m/z(ESI):444.3[M+1]
1H?NMR(400MHz,DMSO-d 6):δ8.76-8.75(m,1H),8.49-8.46(m,2H),8.09-8.05(m,2H),7.84(s,1H),7.71-7.69(m,1H),7.67-7.61(m,2H),6.90-6.88(m,1H),4.90(t,2H),4.42-4.41(m,2H),3.98-3.93(m,4H),3.75-3.72(m,1H),2.87(d,3H),1.39(d,3H)
Embodiment 11
N-methyl-6-(4-(2-(4-methylpiperazine-1-yl) oxyethyl group)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1- Naphthoamide
Figure BDA00003089852000422
Figure BDA00003089852000431
The first step
4-(2-hydroxyethyl) piperazine-1-t-butyl formate
With piperazine-1-t-butyl formate 11a (3.72g, 20mmol), ethylene bromohyrin (3.0g, 24mmol) and salt of wormwood (4.14g, 30mmol) are dissolved in the 100mL acetonitrile, back flow reaction 16 hours.Be chilled to room temperature, filtering reacting liquid, concentrating under reduced pressure filtrate, add the 50mL ethyl acetate in resistates, filter concentrating under reduced pressure filtrate, obtain title product 4-(2-hydroxyethyl) piperazine-1-t-butyl formate 11b (3.8g, yellow oil), productive rate: 82.6%.
Second step
4-(2-(tosyloxy) ethyl) piperazine-1-t-butyl formate
With 4-(2-hydroxyethyl) piperazine-1-t-butyl formate 11b (2.3g, 10mmol) be dissolved in the 50mL methylene dichloride, add triethylamine (3.03g, 30mmol), DMAP (122mg, 1.0mmol) and Tosyl chloride (2.86g, 15mmol), reacted 16 hours.Add the 40mL saturated sodium bicarbonate solution, separatory, water merges organic phase with dichloromethane extraction (10mL * 2), with saturated nacl aqueous solution washing (10mL * 2), anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 4-(2-(tosyloxy) ethyl) piperazine-1-t-butyl formate 11c (2.6g, white solid), productive rate: 74.5%.
The 3rd step
4-(2-(9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1, the 2-dihydrofuran is [3,2-f] quinolyl-4 oxygen base also) ethyl) piperazine-1-t-butyl formate
With 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (100mg, 0.26mmol), 4-(2-(tosyloxy) ethyl) piperazine-1-t-butyl formate 11c (150mg, 0.39mmol) and cesium carbonate (253mg, 0.78mmol) be dissolved in the 3mL N,N-DIMETHYLACETAMIDE, under 100 ℃ the reaction 3 hours.The concentrating under reduced pressure reaction solution; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product 4-(2-(9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) ethyl) piperazine-1-t-butyl formate 11d (62mg; white solid), productive rate: 40.0%.
The 4th step
N-methyl-6-(4-(2-(piperazine-1-yl) oxyethyl group)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide
With 4-(2-(9-(5-(methylcarbamoyl) naphthalene-2-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) ethyl) piperazine-1-t-butyl formate 11d (62mg, 0.1mmol) is dissolved in the methanol solution of 5mL2M hydrogenchloride, reacted 2 hours.The concentrating under reduced pressure reaction solution, add the 10mL ether in resistates, stirred 30 minutes, and filtered, collect filter cake, vacuum-drying, obtain title product N-methyl-6-(4-(2-(piperazine-1-yl) oxyethyl group)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide 11e (50mg, white solid), productive rate: 90.9%.
The 5th step
N-methyl-6-(4-(2-(4-methylpiperazine-1-yl) oxyethyl group)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide
With N-methyl-6-(4-(2-(piperazine-1-yl) oxyethyl group)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-1-naphthoamide 11e (50mg, 0.1mmol) be dissolved in 1.6mL methyl alcohol, add the formaldehyde solution of 1.6mL37% and the sodium cyanoborohydride solution of 1.2mL0.3M zinc chloride, reacted 20 minutes.Add 10mL water, with dichloromethane extraction (5mL * 5), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate obtains title product N-methyl-6-(4-(2-(4-methylpiperazine-1-yl) oxyethyl group)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-1-naphthoamide 11 (32mg, gray solid), productive rate: 66.7%.
MS?m/z(ESI):513.3[M+1]
1H?NMR(400MHz,DMSO-d 6):δ8.74-8.73(m,1H),8.63-8.61(m,1H),8.47-8.45(m,1H),8.08-8.05(m,2H),7.77(s,1H),7.70-7.62(m,3H),6.87-6.85(m,1H),4.90-4.85(m,2H),4.39-4.36(m,2H),3.95-3.92(m,2H),3.45(s,3H),3.41-3.36(m,4H),3.17-3.15(m,2H),2.88-2.85(m,3H),2.38-2.34(m,2H),1.89-1.84(m,2H)
Embodiment 12
(R)-6-((4-((tetrahydrofuran (THF)-3-yl) oxygen base)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-yl also) oxygen base)-N-methyl isophthalic acid-naphthalene Methane amide
Figure BDA00003089852000441
Under argon shield; with 6-(4-hydroxyl-1; 2-dihydrofuran also [3; 2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (50mg, 0.13mmol), (S)-tetrahydrofuran (THF)-3-base p-toluenesulfonic esters 12a (method disclosed according to WO2007007040 is prepared from) (63mg; 0.26mmol); cesium carbonate (127mg, 0.39mmol) and 2mL N,N-DIMETHYLACETAMIDE are put into reaction flask, and reaction is 2 hours under 60 ℃.Cooling, add 2mL water and 10mL ethyl acetate to mix, ethyl acetate extraction (4mL * 2), merge organic phase, organic phase is washed with saturated nacl aqueous solution, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate with developping agent system A purifying products therefrom, obtains title product (R)-6-((4-((tetrahydrofuran (THF)-3-yl) oxygen base)-1 with tlc, 2-dihydrofuran also [3,2-f] quinoline-9-yl) the oxygen base)-N-methyl isophthalic acid-naphthoamide 12 (40mg, light yellow solid), productive rate: 68.0%.
MS?m/z(ESI):457.2[M+1]
1H?NMR(400MHz,CDCl 3):δ8.45-8.47(m,2H),7.83(d,1H),7.59(d,1H),7.47-7.50(m,2H),7.38(d,1H),7.29(s,1H),6.54(d,1H),6.10(d,1H),5.16(s,1H),4.80(t,2H),4.07-4.15(m,2H),4.06(t,1H),3.96(t,1H),3.83(t,2H),3.12(d,3H),2.31-2.37(m,2H)
Embodiment 13
(S)-6-((4-((tetrahydrofuran (THF)-3-yl) oxygen base)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-yl also) oxygen base)-N-methyl isophthalic acid-naphthalene Methane amide
Figure BDA00003089852000451
Under argon shield; with 6-(4-hydroxyl-1; 2-dihydrofuran also [3; 2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (20mg, 0.052mmol), (R)-tetrahydrofuran (THF)-3-base p-toluenesulfonic esters 13a (method disclosed according to WO2007007886 is prepared from) (63mg; 0.26mmol); cesium carbonate (127mg, 0.39mmol) and 2mL N,N-DIMETHYLACETAMIDE are put into reaction flask, and reaction is 30 minutes under 60 ℃.Cooling, add 2mL water and 5mL ethyl acetate, separatory, water ethyl acetate extraction (3mL * 2), merge organic phase, wash with saturated nacl aqueous solution, anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, with tlc with developping agent system A purifying products therefrom, obtain title product (S)-6-((4-((tetrahydrofuran (THF)-3-yl) oxygen base)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-yl also) oxygen base)-N-methyl isophthalic acid-naphthoamide 13 (40mg, light yellow solid), productive rate: 67.0%.
MS?m/z(ESI):457.2[M+1]
1H?NMR(400MHz,CDCl 3):δ8.45-8.47(m,2H),7.84(d,1H),7.60(d,1H),7.48-7.51(m,2H),7.39(d,1H),7.32(s,1H),6.54(d,1H),6.10(d,1H),5.17(s,1H),4.81(t,2H),4.07-4.15(m,2H),4.06(t,1H),3.96(t,1H),3.83(t,2H),3.12(d,3H),2.32-2.37(m,2H)
Embodiment 14
6-((4-(2-(dimethylamino) oxyethyl group)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-yl also) oxygen base)-N-methyl isophthalic acid-naphthalene first Acid amides
Figure BDA00003089852000461
The first step
6-((4-(2-bromine oxethyl)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-yl also) oxygen base)-N-methyl isophthalic acid-naphthoamide
With 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (50mg, 0.13mmol), glycol dibromide (73mg, 0.39mmol) and salt of wormwood (53mg, 0.39mmol) be suspended in the 2mL dimethylacetamide solution, reaction is 4 hours under 90 ℃.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain crude product title product 6-((4-(2-bromine oxethyl)-1,2-dihydrofuran also [3,2-f] quinoline-9-yl) the oxygen base)-N-methyl isophthalic acid-naphthoamide 14a (50mg, yellow solid), productive rate: 78.0%.
MS?m/z(ESI):493.1[M+1]
Second step
6-((4-(2-(dimethylamino) oxyethyl group)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-yl also) oxygen base)-N-methyl isophthalic acid-naphthoamide
With 6-((4-(2-bromine oxethyl)-1,2-dihydrofuran also [3,2-f] quinoline-9-yl) the oxygen base)-N-methyl isophthalic acid-naphthoamide 14a (50mg, 0.10mmol), 0.2mL2M tetrahydrofuran solution and the salt of wormwood (27mg, 0.20mmol) of dimethylamine be suspended in the 0.5mL dimethylacetamide solution, put into the microwave reaction pipe, tube sealing was in 80 ℃ of lower microwave reactions 30 minutes.Filter, concentrating under reduced pressure filtrate, with tlc with developping agent system A purifying gained resistates, obtain title product 6-((4-(2-(dimethylamino) oxyethyl group)-1,2-dihydrofuran also [3,2-f] quinoline-9-yl) the oxygen base)-N-methyl isophthalic acid-naphthoamide 14 (15mg, light yellow solid), productive rate: 32.0%.
MS?m/z(ESI):458.5[M+1]
1H?NMR(400MHz,CD 3OD):δ8.38-8.43(m,2H),7.98(d,1H),7.72(s,1H),7.66(d,1H),7.59(t,1H),7.46(d,1H),7.38(s,1H),6.63(d,1H),4.81(t,2H),4.53(s,2H),3.88(t,2H),3.46(s,2H),3.03(s,3H),2.85(s,6H)
Embodiment 15
6-((4-(3-(dimethylamino) propoxy-)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-yl also) oxygen base)-N-methyl isophthalic acid-naphthalene first Acid amides
Figure BDA00003089852000471
The first step
6-((4-(3-bromine propoxy-)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-yl also) oxygen base)-N-methyl isophthalic acid-naphthoamide
With 6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 1p (60mg, 0.44mmol), 1,3-dibromopropane (94mg, 0.46mmol) and salt of wormwood (64mg, 0.46mmol) be suspended in 0.5mL N,N-DIMETHYLACETAMIDE and 1mL alcohol mixed solution, reaction is 16 hours under 70 ℃.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product 6-((4-(3-bromine propoxy-)-1,2-dihydrofuran also [3,2-f] quinoline-9-yl) the oxygen base)-N-methyl isophthalic acid-naphthoamide 15a (40mg, yellow solid), productive rate: 51.0%.
MS?m/z(ESI):507.1[M+1]
Second step
6-((4-(3-(dimethylamino) propoxy-)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-yl also) oxygen base)-N-methyl isophthalic acid-naphthoamide
With 6-((4-(3-bromine propoxy-)-1,2-dihydrofuran also [3,2-f] quinoline-9-yl) the oxygen base)-N-methyl isophthalic acid-naphthoamide 15a (40mg, 0.08mmol), 0.2mL2M tetrahydrofuran solution and the salt of wormwood (33mg, 0.236mmol) of dimethylamine be suspended in 0.5mL N,N-DIMETHYLACETAMIDE and 1mL alcohol mixed solution, put into the microwave reaction pipe, tube sealing was in 80 ℃ of lower microwave reactions 30 minutes.Filter, with tlc with developping agent system A purifying gained resistates, obtain title product 6-((4-(3-(dimethylamino) propoxy-)-1,2-dihydrofuran also [3,2-f] quinoline-9-yl) the oxygen base)-N-methyl isophthalic acid-naphthoamide 15 (25mg, yellow solid), productive rate: 67.0%.
MS?m/z(ESI):472.5[M+1]
1H?NMR(400MHz,CD 3OD):δ8.37-8.39(m,2H),7.95(s,1H),7.69(s,1H),7.63(s,1H),7.56(s,1H),7.43(d,1H),7.29(s,1H),6.58(s,1H),4.79(s,2H),4.32(s,2H),3.82(t,2H),3.31(s,2H),3.01(s,3H),2.92(s,6H),2.32(s,2H)
Embodiment 16
(S)-6-((4-(2-(dimethylamino) propoxy-)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-yl also) oxygen base)-N-methyl isophthalic acid- Naphthoamide
Figure BDA00003089852000481
With (S)-6-((4-(the amino propoxy-of 2-)-1,2-dihydrofuran also [3,2-f] quinoline-9-yl) the oxygen base)-N-methyl isophthalic acid-naphthoamide 10 (20mg, 0.042mmol) join in the single port bottle of 25mL, add 3mL methyl alcohol, the formalin of 3mL37%, 3mL0.3M sodium cyanoborohydride solution reacted 1 hour.add 2mL ammonia soln and the 20mL shrend reaction of going out in the reaction solution, separatory, water dichloromethane extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with tlc with developping agent system A purifying products therefrom, obtain title product (S)-6-((4-(2-(dimethylamino) propoxy-)-1,2-dihydrofuran also [3,2-f] quinoline-9-yl) the oxygen base)-N-methyl isophthalic acid-naphthoamide 16 (18mg, white solid), productive rate: 90.0%.
MS?m/z(ESI):472.3[M+1]
1H?NMR(400MHz,DMSO-d 6):δ8.52-8.49(m,1H),8.47-8.46(m,1H),8.36-8.34(m,1H),7.99-7.97(m,1H),7.72-7.71(m,1H),7.59-7.54(m,2H),7.50-7.47(m,1H),7.38(s,1H),6.62-6.61(m,1H),4.75-4.70(m,2H),4.42-4.37(m,1H),4.25-4.21(m,1H),4.06-4.02(m,1H),3.74-3.70(m,2H),2.86-2.85(m,3H),2.27(s,6H),1.09-1.07(m,3H)
Embodiment 17
7-(4-((the amino cyclopropyl of 1-) methoxyl group)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide
Figure BDA00003089852000482
Figure BDA00003089852000491
The first step
7-nitro-3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine
2-Amino-5-nitrophenol 17a (15.4g, 100mmol) is dissolved in the 200mL DMF, adds glycol dibromide (75g, 400mmol) and salt of wormwood (55g, 400mmol), reaction is 16 hours under 120 ℃.Be cooled to room temperature, filter concentrating under reduced pressure filtrate, add 100mL ethyl acetate and 100mL water in resistates, separatory, water ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate obtains title product 7-nitro-3,4-dihydro-2H-benzo [b] [1,4] oxazine 17b (15g, yellow solid), productive rate: 83.3%.
Second step
N-methyl-7-nitro-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide
With triphosgene (10.8g, 36.6mmol) be dissolved in the 200mL tetrahydrofuran (THF), cooling under ice bath, slowly add 7-nitro-3,4-dihydro-2H-benzo [b] [1,4] oxazine 17b (10g, 55mmol) and DIPEA (21.4g, 166mmol), react the tetrahydrofuran solution that drips the 83mL2M methylamine after 1 hour, rose to room temperature reaction 16 hours.Filtering reacting liquid, concentrating under reduced pressure filtrate uses silica gel column chromatography with eluent system A purifying gained resistates, obtain title product N-methyl-7-nitro-2H-benzo [b] [1,4] oxazine-4 (3H)-methane amide 17c (7.0g, yellow solid), productive rate: 53.8%.
The 3rd step
7-amino-N-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide
[Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide 17c (7.0g, 29.5mmol) is dissolved in 100mL methyl alcohol, adds palladium/carbon of 700mg10%, and under nitrogen atmosphere, reaction is 16 hours with N-methyl-7-nitro-2H-benzo [b].Filtering reacting liquid, concentrating under reduced pressure filtrate obtains crude product title product 7-amino-N-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide 17d (6.5g, brown oil), not purifiedly is directly used in next step reaction.
The 4th step
7-hydroxy-n-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide
With crude product 7-amino-N-methyl-2H-benzo [b] [1,4] oxazine-4 (3H)-methane amide 17d (2.07g, 10mmol) be dissolved in 20mL water, drip the 2.4mL vitriol oil under ice bath, react and drip 4mL Sodium Nitrite (828mg after 10 minutes, aqueous solution 12mmol) reacted 30 minutes.The reaction solution that obtains is added drop-wise in 100mL copper sulfate (7g) aqueous solution, drips the complete room temperature that naturally cools to.With ethyl acetate extraction reaction solution (40mL * 3), merge organic phase, with saturated nacl aqueous solution washing (40mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with developping agent system A purifying gained resistates, obtain title product 7-hydroxy-n-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide 17e (900mg with tlc, yellow solid), productive rate: 45.0%
The 5th step
7-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-N-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide
With 7-hydroxy-n-methyl-2H-benzo [b] [1,4] oxazine-4 (3H)-methane amide 17e (850mg, 4mmol) and 4-(benzyloxy)-9-chloro-1,2-dihydrofuran also [3,2-f] quinoline 1k (1.65g, 5.3mmol) is dissolved in 8mL2, in the 6-lutidine, add DMAP (232mg, 6mmol), reaction is 7 hours under 140 ℃.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product 7-(4-(benzyloxy)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl-2H-benzo [b] [1,4] oxazine-4 (3H)-methane amide 17f (130mg, yellow solid), productive rate: 6.7%.
MS?m/z(ESI):484.2[M+1]
The 6th step
7-(4-hydroxyl-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide
With 7-(4-(benzyloxy)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide 17f (110mg, 0.23mmol) be dissolved in the 2mL trifluoroacetic acid, reaction is 2 hours under 90 ℃.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product 7-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl-2H-benzo [b] [1,4] oxazine-4 (3H)-methane amide 17g (70mg, yellow solid), productive rate: 78.7%.
The 7th step
1-((9-(4-(methylcarbamoyl)-3, and 4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-7-base oxygen base)-1, the 2-dihydrofuran is [3,2-f] quinolyl-4 oxygen base also) methyl) the cyclopropylamino t-butyl formate
With 7-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl-2H-benzo [b] [1,4] oxazine-4 (3H)-methane amide 17g (30mg, 0.076mmol) and (1-(tert-butoxycarbonyl amino) cyclopropyl) methyl mesylate 1q (30mg, 0.11mmol) is dissolved in the 2mL N,N-DIMETHYLACETAMIDE, adds cesium carbonate (37mg, 0.11mmol), reaction is 2 hours under 60 ℃.add 4mL water and 8mL ethyl acetate in reaction solution, separatory, water ethyl acetate extraction (4mL * 2), merge organic phase, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with tlc with developping agent system A purifying gained resistates, obtain title product 1-((9-(4-(methylcarbamoyl)-3, 4-dihydro-2H-benzo [b] [1, 4] oxazines-7-base oxygen base)-1, 2-dihydrofuran also [3, 2-f] quinolyl-4 oxygen base) methyl) cyclopropylamino t-butyl formate 17h (20mg, yellow solid), productive rate: 46.8%.
MS?m/z(ESI):563.3[M+1]
The 8th step
7-(4-((the amino cyclopropyl of 1-) methoxyl group)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide
With 1-((9-(4-(methylcarbamoyl)-3; 4-dihydro-2H-benzo [b] [1; 4] oxazines-7-base oxygen base)-1; 2-dihydrofuran also [3; 2-f] quinolyl-4 oxygen base) methyl) cyclopropylamino t-butyl formate 17h (20mg; 0.036mmol) be dissolved in the methanol solution of 2mL2M hydrogenchloride, under room temperature, reaction is 8 hours.The concentrating under reduced pressure reaction solution, add a small amount of dissolve with methanol in resistates, add 50mg sodium carbonate, stirred 30 minutes, filtering reacting liquid, concentrating under reduced pressure filtrate, with tlc with developping agent system A purifying gained resistates, obtain title product 7-(4-((the amino cyclopropyl of 1-) methoxyl group)-1, the 2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl-2H-benzo [b] [Isosorbide-5-Nitrae] oxazine-4 (3H)-methane amide 17 (10mg, white solid), productive rate: 62.5%.
MS?m/z(ESI):463[M+1]
1H?NMR(400MHz,DMSO-d 6)δ8.45(d,1H),7.68(d,1H),7.33(s,1H),6.97(d,1H),6.74-6.69(m,2H),6.56(d,1H),4.75(t,2H),4.26(s,2H),4.22(t,3H),3.75-3.70(m,4H),2.67(d,3H),1.04(t,2H),0.88(t,2H)
Embodiment 18
7-chloro-5-fluoro-N-methyl-6-(4-(morpholinyl propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthalene Methane amide
Figure BDA00003089852000511
The first step
5,5-, two fluoro-N-methyl-6-carbonyl-5,6-dihydronaphthalene-1-methane amide
With 4-(benzyloxy)-9-chloro-1,2-dihydrofuran also [3,2-f] quinoline 1k (283mg, 0.9mmol), 6-hydroxy-n-methyl isophthalic acid-naphthoamide 1m (1.25g, 6.2mmol) is scattered in the 75mL acetonitrile, add 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt (4.46g, 12.6mmol) reacted 3 hours.Add 50mL ethyl acetate and 50mL water in reaction solution, separatory, water ethyl acetate extraction (30mL * 2), merge organic phase, anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 5,5-two fluoro-N-methyl-6-carbonyl-5,6-dihydronaphthalene-1-methane amide 18a (906mg, faint yellow solid), productive rate: 61.7%.
Second step
5-fluoro-N-methyl-6-carbonyl-5,6-dihydronaphthalene-1-methane amide
With 5,5-, two fluoro-N-methyl-6-carbonyl-5,6-dihydronaphthalene-1-methane amide 18a (630mg, 2.65mmol) is dissolved in 20mL acetic acid, adds zinc (224mg, 3.45mmol), reacts 2 hours.Filtering reacting liquid, concentrating under reduced pressure filtrate with eluent system A purifying gained resistates, obtains title product 5-fluoro-N-methyl-6-carbonyl-5,6-dihydronaphthalene-1-methane amide 18b (500mg, white solid), productive rate: 86.2% with silica gel column chromatography.
The 3rd step
7-chloro-5-fluoro-N-methyl-6-carbonyl-5,6-dihydronaphthalene-1-methane amide
With 5-fluoro-N-methyl-6-carbonyl-5,6-dihydronaphthalene-1-methane amide 18b (500mg, 2.27mmol) is scattered in 10mL toluene, add the 0.06mL Isopropylamine, drip SULPHURYL CHLORIDE (0.36mL, 4.45mmol), drip to finish and to add the 0.12mL Isopropylamine, reaction is 1 hour under 60 ℃.Reaction solution is chilled to room temperature, adds 10mL ethyl acetate and 10mL saturated nacl aqueous solution, separatory, water ethyl acetate extraction (5mL), merge organic phase, with saturated nacl aqueous solution washing (5mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains title product 7-chloro-5-fluoro-N-methyl-6-carbonyl-5,6-dihydronaphthalene-1-methane amide 18c (570mg, tawny oily matter), productive rate: 99.1%.
The 4th step
7-chloro-5-fluoro-6-hydroxy-n-methyl isophthalic acid-naphthoamide
With 7-chloro-5-fluoro-N-methyl-6-carbonyl-5,6-dihydronaphthalene-1-methane amide 18c (570mg, 2.28mmol) is dissolved in 10mL acetic acid, adds sodium bisulfite (1.3g, 12.5mmol), reacts 16 hours.Reaction solution is poured in 10mL water, filter, filter cake is collected filter cake with washed with dichloromethane (5mL * 3), with the mixing solutions dissolving of 20mL methylene dichloride and methyl alcohol (V/V=3/1), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains title product 7-chloro-5-fluoro-6-hydroxy-n-methyl isophthalic acid-naphthoamide 18d (270mg, white solid), productive rate: 47.0%.
The 5th step
6-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-7-chloro-5-fluoro-N-methyl isophthalic acid-naphthoamide
With 4-(benzyloxy)-9-chloro-1,2-dihydrofuran also [3,2-f] quinoline 1k (680mg, 2.18mmol) and 7-chloro-5-fluoro-6-hydroxy-n-methyl isophthalic acid-naphthoamide 18d (220mg, 0.87mmol) be dissolved in the 10mL lutidine, add DMAP (266mg, 2.13mmol), reaction is 5 hours under 155 ℃.The concentrating under reduced pressure reaction solution, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 6-(4-(benzyloxy)-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-7-chloro-5-fluoro-N-methyl isophthalic acid-naphthoamide 18e (300mg, brown oil), productive rate: 65.1%.
The 6th step
7-chloro-5-fluoro-6-(4-hydroxyl-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N-methyl isophthalic acid-naphthoamide
6-(4-(benzyloxy)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-7-chloro-5-fluoro-N-methyl isophthalic acid-naphthoamide 18e (300mg, 0.57mmol) is dissolved in the 5mL trifluoroacetic acid, in 80 ℃ of lower back flow reaction 2.5 hours.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product 7-chloro-5-fluoro-6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 18f (65mg, the tawny solid), productive rate: 26.2%.
MS?m/z(ESI):439.1[M+1]
The 7th step
7-chloro-5-fluoro-N-methyl-6-(4-(morpholinyl propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide
With 7-chloro-5-fluoro-6-(4-hydroxyl-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N-methyl isophthalic acid-naphthoamide 18f (65mg, 0.15mmol) and 3-4-toluene sulfonic acide morpholino propyl ester 2c (58mg, 0.19mmol) be dissolved in the 5mL N,N-DIMETHYLACETAMIDE, add cesium carbonate (145mg, 0.45mmol), reaction is 2 hours under 70 ℃.The concentrating under reduced pressure reaction solution, resistates prepares title product 7-chloro-5-fluoro-N-methyl-6-(4-(morpholinyl propoxy-)-1,2-dihydrofuran be [3,2-f] quinoline-9-base oxygen base also)-1-naphthoamide 18 (12mg through HPLC, white solid), productive rate: 14.3%.
MSm/z(ESI):566.3[M+1]
1H?NMR(400MHz,CDCl 3)δ8.45(d,1H),8.41(d,1H),8.19(d,1H),7.73(dd,1H),7.61(dd,1H),7.39(s,1H),6.25(dd,1H),6.08(s,1H),4.88(t,2H),4.32(t,2H),3.98-4.04(m,2H),3.76-3.80(m,4H),3.14(d,3H),2.59(t,2H),2.50(s,4H),2.15-2.18(m,2H)
Embodiment 19
5-(4-oxyethyl group-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N, 1-dimethyl-1H-indoles-3-methane amide
Figure BDA00003089852000531
Figure BDA00003089852000541
The first step
9-chloro-1,2-dihydrofuran be [3,2-f] quinoline-4-alcohol also
With 4-(benzyloxy)-9-chloro-1,2-dihydrofuran also [3,2-f] quinoline 1k (5g, 16mmol) is dissolved in the 100mL trifluoroacetic acid, back flow reaction 2 hours.The concentrating under reduced pressure reaction solution, add the 100mL ethyl acetate in resistates, stirred 30 minutes, filter, filter cake washs (20mL * 3) with ethyl acetate, collect filter cake, vacuum-drying obtains title product 9-chloro-1,2-dihydrofuran also [3,2-f] quinoline-4-alcohol 19a (3.4g, brown color solid), productive rate: 95.6%.
MS?m/z(ESI):222.1[M+1]
Second step
9-chloro-4-oxyethyl group-1, the 2-dihydrofuran is [3,2-f] quinoline also
With 9-chloro-1, the 2-dihydrofuran is [3,2-f] quinoline-4-alcohol 19a (3.4g also, 15.3mmol) be dissolved in 100mLN, in dinethylformamide, add salt of wormwood (6.36g, 46.0mmol) and iodoethane (2.5mL, 30.7mmol), reaction is 4 hours under 50 ℃.Filtering reacting liquid adds 200mL water in filtrate, with ethyl acetate extraction (150mL * 4), merge organic phase, with saturated nacl aqueous solution washing (300mL * 2), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate with eluent system B purifying gained resistates, obtains title product 9-chloro-4-oxyethyl group-1 with silica gel column chromatography, 2-dihydrofuran also [3,2-f] quinoline 19b (2g, yellow solid), productive rate: 52.2%.
MS?m/z(ESI):250.1[M+1]
The 3rd step
1-Methyl-1H-indole-3-methyl-formiate
60% sodium hydride (3.28g, 82mmol) is scattered in 50mLN, in dinethylformamide, adds 1H-indole-3-carboxylic acid 19c (6g, 37.2mmol) in batches, under room temperature, reaction is one hour.Add methyl iodide (13.2g, 92.9mmol), under room temperature, reaction is 16 hours.Add the 50mL ethyl acetate, with saturated nacl aqueous solution washing (10mL * 4), merge organic phase, anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-Methyl-1H-indole-3-methyl-formiate 19d (5.4g, pale pink solid), productive rate: 77.1%.
The 4th step
5-(2-chloracetyl)-1-Methyl-1H-indole-3-methyl-formiate
1-Methyl-1H-indole-3-methyl-formiate 19d (1g, 5.29mmol) is dissolved in the 25mL methylene dichloride, adds chloroacetyl chloride (3mL.37.7mmol) and aluminum chloride (2.1g, 15.7mmol), under room temperature, reaction is 3 hours.Reaction solution is put into ice cooling; separatory, water merges organic phase with dichloromethane extraction (10mL * 3); with saturated sodium bicarbonate solution washing (10mL * 3); anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 5-(2-chloracetyl)-1-Methyl-1H-indole-3-methyl-formiate 19e (320mg, white solid), productive rate: 22.9%.
MS?m/z(ESI):266.1[M+1]
The 5th step
5-(2-chloroethene acyloxy)-1-Methyl-1H-indole-3-methyl-formiate
With 5-(2-chloracetyl)-1-Methyl-1H-indole-3-methyl-formiate 19e (320mg; 1.2mmol) be dissolved in the 10mL methylene dichloride; add Sodium phosphate dibasic (17mg; 0.12mmol) and 70% metachloroperbenzoic acid (446mg; 1.81mmol), under room temperature, reaction is 3 hours.Add 10mL saturated sodium bicarbonate solution and a small amount of sodium bisulfite solid in reaction solution, stirred 15 minutes under room temperature, separatory, water merges organic phase with dichloromethane extraction (5mL * 2), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains crude product title product 5-(2-chloroethene acyloxy)-1-Methyl-1H-indole-3-methyl-formiate 19f (350mg, faint yellow solid), not purifiedly be directly used in next step reaction.
MS?m/z(ESI):282.1[M+1]
The 6th step
5-hydroxyl-1-Methyl-1H-indole-3-methyl-formiate
With crude product 5-(2-chloroethene acyloxy)-1-Methyl-1H-indole-3-methyl-formiate 19f (320mg, 1.14mmol) be scattered in the mixing solutions of 11.25mL first alcohol and water (V/V=8/1), add sodium hydroxide (50mg, 1.2mmol), under room temperature, reaction is 2 hours.The concentrating under reduced pressure reaction solution, add 10mL water and 10mL methylene dichloride in resistates, separatory, water merges organic phase with dichloromethane extraction (5mL * 2), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains title product 5-hydroxyl-1-Methyl-1H-indole-3-methyl-formiate 19g (202mg, brown solid), productive rate: 86.7%.
MS?m/z(ESI):206.1[M+1]
The 7th step
5-hydroxyl-1-Methyl-1H-indole-3-formic acid
With 5-hydroxyl-1-Methyl-1H-indole-3-methyl-formiate 19g (100mg, 0.49mmol) be dissolved in the mixing solutions of 8mL first alcohol and water (V/V=3/1), add a hydronium(ion) oxidation lithium (62mg, 1.48mmol), reaction is 2 hours under 50 ℃, add 70mg sodium hydroxide and 2mL tetrahydrofuran (THF), reaction is 2 hours under 55 ℃.The concentrating under reduced pressure reaction solution adds 2mL dioxane and 4mL water in resistates, reaction is 3 hours under 80 ℃.The concentrating under reduced pressure reaction solution, adding in the resistates after 5mL water the careful 1M of dropping hydrochloric acid soln to transfer reacting liquid pH value is 1, mixing solutions extraction (5mL * 3) with methylene dichloride and methyl alcohol (V/V=10/1), merge organic phase, anhydrous sodium sulfate drying filters, concentrating under reduced pressure filtrate, obtain title product 5-hydroxyl-1-Methyl-1H-indole-3-formic acid 19h (76mg, brown solid), productive rate: 81.7%.
The 8th step
The 5-hydroxy-n, 1-dimethyl-1H-indoles-3-methane amide
With 5-hydroxyl-1-Methyl-1H-indole-3-formic acid 19h (76mg, 0.39mmol) be dissolved in the mixing solutions of 15mL methylene dichloride and tetrahydrofuran (THF) (V/V=2/1), add oxalyl chloride (100mg, 0.79mmol) and the N of catalytic amount, dinethylformamide, under room temperature, reaction directly adds the tetrahydrofuran solution of 2mL2M methylamine after 30 minutes, and under room temperature, reaction is 30 minutes.The concentrating under reduced pressure reaction solution with developping agent system A purifying gained resistates, obtains title product 5-hydroxy-n, 1-dimethyl-1H-indoles-3-methane amide 19i (10mg, brown oil), productive rate: 12.3% with tlc.
The 9th step
5-(4-oxyethyl group-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N, 1-dimethyl-1H-indoles-3-methane amide
With the 5-hydroxy-n, 1-dimethyl-1H-indoles-3-methane amide 19i (10mg, 0.049mmol) be dissolved in the 3mL lutidine, add 9-chloro-4-oxyethyl group-1, the 2-dihydrofuran is [3,2-f] quinoline 19b (27mg also, 0.1mmol) and DMAP (10mg, 0.082mmol), argon replaces three times, reaction is 4 hours under 160 ℃.The concentrating under reduced pressure reaction solution, resistates prepares title product 5-(4-oxyethyl group-1,2-dihydrofuran also [3 through HPLC, 2-f] quinoline-9-base oxygen base)-N, 1-dimethyl-1H-indoles-3-methane amide 19 (7mg, pale solid), productive rate: 35.0%.
MS?m/z(ESI):418.3[M+1]
1H?NMR(400MHz,DMSO-d 6)δ8.38(d,1H),8.01(s,1H),7.92(d,1H),7.82-7.89(m,1H),7.63(d,1H),7.30(s,1H),7.12(dd,1H),6.35(d,1H),4.73(t,2H),4.22(q,2H),3.88(s,3H),3.80(t,2H),2.74(d,3H),1.42(t,3H)
Embodiment 20
6-(4-oxyethyl group-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N, 1-dimethyl-1H-indoles-3-methane amide
Figure BDA00003089852000561
The first step
6-hydroxyl-1-Methyl-1H-indole-3-methyl-formiate
With 6-(2-chloroethene acyloxy)-1-Methyl-1H-indole-3-methyl-formiate 20a (according to Heterocycles, 26 (6), 1471-4; 1987 are prepared from) (440mg, 1.56mmol) be dissolved in 10mL methyl alcohol, adds 1.75mL water and sodium hydroxide (69mg, 1.73mmol), reacted 1 hour.The concentrating under reduced pressure reaction solution, the hydrochloric acid soln adjust pH that drips 1M in the resistates is 2, mixing solutions extraction (11mL * 3) with methylene dichloride and methyl alcohol (V/V=10/1), merge organic phase, anhydrous sodium sulfate drying filters, concentrating under reduced pressure filtrate, obtain title product 6-hydroxyl-1-Methyl-1H-indole-3-methyl-formiate 20b (310mg, brown solid), productive rate: 96.9%.
Second step
6-hydroxyl-1-Methyl-1H-indole-3-formic acid
With 6-hydroxyl-1-Methyl-1H-indole-3-methyl-formiate 20b (310mg, 1.51mmol) be dissolved in 8mL1, in the mixing solutions of 4-dioxane and water (V/V=1/1), add sodium hydroxide (302mg, 7.55mmol), reaction is 3 hours under 80 ℃.The concentrating under reduced pressure reaction solution, the hydrochloric acid soln adjust pH that drips 1M in the resistates is 1, mixing solutions extraction (11mL * 3) with methylene dichloride and methyl alcohol (V/V=10/1), merge organic phase, anhydrous sodium sulfate drying filters, concentrating under reduced pressure filtrate, obtain title product 6-hydroxyl-1-Methyl-1H-indole-3-formic acid 20c (200mg, brown solid), productive rate: 69.2%.
MS?m/z(ESI):192.2[M+1]
The 3rd step
The 6-hydroxy-n, 1-dimethyl-1H-indoles-3-methane amide
6-hydroxyl-1-Methyl-1H-indole-3-formic acid 20c (200mg, 1.05mmol) is dissolved in tetrahydrofuran (THF), adds catalytic amount DMF and oxalyl chloride (0.15mL, 1.76mmol), reacted 30 minutes.The concentrating under reduced pressure reaction solution adds a small amount of tetrahydrofuran (THF) to make its dissolving in resistates, is added dropwise in the tetrahydrofuran solution of 20mL2M methylamine, drips Bi Fanying 16 hours.The concentrating under reduced pressure reaction solution with developping agent system A purifying gained resistates, obtains title product 6-hydroxy-n, 1-dimethyl-1H-indoles-3-methane amide 20d (150mg, brown solid), productive rate: 70.1% with tlc.
MS?m/z(ESI):205.2[M+1]
The 4th step
6-(4-oxyethyl group-1,2-dihydrofuran is [3,2-f] quinoline-9-base oxygen base also)-N, 1-dimethyl-1H-indoles-3-methane amide
With the 6-hydroxy-n, 1-dimethyl-1H-indoles-3-methane amide 20d (62mg, 0.3mmol), 9-chloro-4-oxyethyl group-1, the 2-dihydrofuran is [3,2-f] quinoline 19b (152mg, 0.61mmol) and DMAP (56mg also, 0.46mmol) be dissolved in the 3mL lutidine, reaction is 4.5 hours under 160 ℃.The concentrating under reduced pressure reaction solution, with tlc with developping agent system A purifying gained resistates, obtain title product 6-(4-oxyethyl group-1,2-dihydrofuran also [3,2-f] quinoline-9-base oxygen base)-N, 1-dimethyl-1H-indoles-3-methane amide 20 (28mg, brown solid), productive rate: 22.0%.
MS?m/z(ESI):418.3[M+1]
1H?NMR(400MHz,DMSO-d 6)δ8.38(d,1H),8.22(d,1H),7.95(s,1H),7.89(d,1H),7.44(d,1H),7.29(s,1H),7.03(dd,1H),6.41(d,1H),4.73(t,2H),4.22(q,2H),3.74-3.83(m,5H),2.78(d,3H),1.42(t,3H)
Adopt synthetic route one, with reference to the operation steps of embodiment 1 to embodiment 20, utilize the compound of suitable reactant synthetic example 21-52.
Figure BDA00003089852000581
Figure BDA00003089852000591
Figure BDA00003089852000601
Figure BDA00003089852000611
Figure BDA00003089852000621
Figure BDA00003089852000641
Figure BDA00003089852000651
Test case:
Biological assessment
Further describe explanation the present invention below in conjunction with test case, but these embodiment are in no way meant to be limiting for the scope of the invention.
The experimental technique of unreceipted actual conditions in test case of the present invention, usually according to normal condition, or the condition of advising according to commodity manufacturers.The reagent in unreceipted concrete source is the conventional reagent of market purchase.
Test case 1, the compounds of this invention are to the kinase whose active mensuration that suppresses of FGFR-1
It is active to the inhibition of FGFR-1 kinases (Invitrogen, PV3146) that the vitro kinase experiment of the following stated can be measured test-compound.With Invitrogen company test kit
Figure BDA00003089852000662
Kinase Assay Kit-Tyrosine 4Peptide(Invitrogen, PV3193) the FGFR-1 inhibitor is carried out the external activity detection.Press the test kit operation instruction, enzyme buffer liquid (50mM HEPES PH7.5,0.01%BRIJ-35, the 10mM MgCl of configuration respective concentration 2, 4mM MnCl 2, 1mM EGTA, 2mMDTT), enzyme/peptide substrate section solution, ATP solution and complete phosphorylated substrate peptide section mix gently; Testing compound solution with distilled water preparation 4 * concentration mixes.
With the enzyme that configures/peptide substrate section solution and fully phosphorylated substrate peptide section 5 μ L add 384 orifice plates, then add 2.5uL ATP solution and 2.5uL compound solution in experimental group, add 2.5uL enzyme buffer liquid and 2.5uL respective concentration DMSO solution in suppressing control group fully, add 2.5uL ATP solution and 2.5uL respective concentration DMSO solution in the unrestraint control group, adding 2.5uL enzyme buffer liquid and 2.5uL respective concentration DMSO solution in the phosphorylated substrate control group fully; Post shrouding and be attached on vibrator vibration and each solution mixed in 30 seconds, incubated at room 1 hour.
By operation instruction, developing solution press corresponding proportion preparation development reagent, add each 5uL of reacting hole after mixing, post shrouding and be attached to vibrate on vibrator and each solution mixed in 30 seconds, incubated at room 1 hour.Every hole adds the 5uL stop buffer, after mixing, excites at 445nm and 520nm place with 400nm and reads fluorescence.
The biochemical activity of the compounds of this invention is measured by above test, the IC that records 50Value sees the following form 1.
Table 1 the compounds of this invention is to the kinase whose active IC that suppresses of FGFR-1 50
The embodiment numbering IC 50(FGFR-1/Bio)(nM)
1 92
2 25
3 363
5 88
6 69
7 239
8 50
10 116
11 82
12 329
13 141
14 163
15 64
16 149
18 66
21 198
22 93
23 66
25 152
26 207
28 277
29 355
30 66
31 280
32 25
33 161
34 149
35 90
38 224
39 47
41 41
44 145
45 172
46 26
49 148
51 95
Conclusion: embodiment of the present invention compound has restraining effect significantly to the FGFR-1 kinases.
Test case 2, the compounds of this invention are to the kinase whose active mensuration that suppresses of VEGFR-2
It is active to the inhibition of VEGFR-2 kinases (Invitrogen, PV3660) that the vitro kinase experiment of the following stated can be measured test-compound.With Invitrogen company test kit
Figure BDA00003089852000681
Kinase Assay Kit-Tyrosine 1Peptide (Invitrogen, PV3190) carries out external activity to the VEGFR-2 inhibitor and detects.Press the test kit operation instruction, enzyme buffer liquid (50mM HEPES PH7.5,0.01%BRIJ-35, the 10mM MgCl of configuration respective concentration 2, 4mM MnCl 2, 1mM EGTA, 2mMDTT), enzyme/peptide substrate section solution, ATP solution and complete phosphorylated substrate peptide section mix gently; Testing compound solution with distilled water preparation 4 * concentration mixes.
With the enzyme that configures/peptide substrate section solution and fully phosphorylated substrate peptide section 5uL add 384 orifice plates, then add 2.5uL ATP solution and 2.5uL compound solution in experimental group, add 2.5uL enzyme buffer liquid and 2.5uL respective concentration DMSO solution in suppressing control group fully, add 2.5uL ATP solution and 2.5uL respective concentration DMSO solution in the unrestraint control group, adding 2.5uL enzyme buffer liquid and 2.5uL respective concentration DMSO solution in the phosphorylated substrate control group fully; Post shrouding and be attached on vibrator vibration and each solution mixed in 30 seconds, incubated at room 1 hour.
By operation instruction, developing solution press corresponding proportion preparation development reagent, add each 5uL of reacting hole after mixing, post shrouding and be attached to vibrate on vibrator and each solution mixed in 30 seconds, incubated at room 1 hour.Every hole adds the 5uL stop buffer, after mixing, excites at 445nm and 520nm place with 400nm and reads fluorescence.
The biochemical activity of the compounds of this invention is measured by above test, the IC that records 50Value sees the following form 2.
Table 2 the compounds of this invention is to the kinase whose active IC that suppresses of VEGFR-2 50
The embodiment numbering IC 50(VEGFR-2/Bio)(nM)
1 12
2 19
3 54
5 36
6 36
8 18
10 41
11 44
12 31
13 14
14 41
15 22
16 76
18 24
21 82
22 18
23 26
25 51
26 38
27 119
28 29
29 77
30 57
31 106
32 21
34 78
35 93
38 87
39 30
41 18
44 59
45 41
46 10
48 50
49 35
51 12
Conclusion: embodiment of the present invention compound has restraining effect significantly to the VEGFR-2 kinases.
Test case 3, the compounds of this invention suppress to measure to the propagation of Human umbilical vein endothelial cells (HUVEC cell)
HUVEC cell (ATCC, CRL-1730) cultivate (Hyclone in the IMDM substratum, SH30228.01B) (contain 20%FBS, 100units/ml P/S, 5ng/ml VEGF), when cell covers 80～90%, plant in 96 orifice plates after dispelling with 0.25% pancreatin (EDTA) digestion, every hole 2000 cells (100 μ l IMDM (2%FBS, P/S) substratum) are positioned over 37 ℃, 5%CO 2Cultivated 24 hours in incubator.Medicine is configured to the storage liquid of 20mM, becomes 200 * concentration gradient with the 100%DMSO gradient dilution, then use 20 times (guaranteeing that with this in each culture system, DMSO concentration is 0.5%) of IMDM (2%FBS, 100units/ml P/S) dilution.Remove substratum after 24 hours, every hole adds 90 μ l (IMDM, 10%FBS, 100units/ml P/S, 5ng/ml VEGF) and 10 μ l medicines, the mixing that vibrates gently, control group and blank group only contain 100 μ l (IMDM, 10%FBS, P/S, 5ng/ml VEGF), place 37 ℃, 5%CO 2Cultivate in incubator, after 72 hours, every hole adds 10 μ l CCK-8, then puts into 37 ℃, 5%CO 2Hatched in incubator 4 hours, 450nm surveys absorption value.
The compounds of this invention biological activity is measured by above test, the IC that records 50Be worth as following table 3:
The IC of table 3 the compounds of this invention to the propagation inhibition of HUVEC cell 50
The embodiment numbering IC 50(HUVEC)/μM
1 0.14
2 0.15
6 0.21
7 0.14
8 0.21
10 0.14
11 0.18
12 0.2
13 0.22
14 0.15
15 0.07
16 0.16
21 0.41
22 0.098
23 0.15
25 0.22
26 0.19
28 0.15
32 0.24
34 0.33
39 0.14
41 0.06
46 0.01
Conclusion: embodiment of the present invention compound all has restraining effect significantly to HUVEC cell proliferation.
Test case 4, the compounds of this invention suppress to measure to the propagation of human colon carcinoma HT-29 Nude Mice
HT-29 cell (typical case's culture collection council of Chinese Academy of Sciences cell bank, Catalog No.TCHu103) cultivate (Hyclone in the IMDM substratum, SH30228.01B) (contain 20%FBS, 100units/ml P/S, 5ng/ml VEGF), when cell covers 80～90%, plant in 96 orifice plates after dispelling with 0.25% pancreatin (EDTA) digestion, every hole 2000 cells (100 μ l IMDM (2%FBS, P/S) substratum) are positioned over 37 ℃, 5%CO 2Cultivated 24 hours in incubator.Medicine is configured to the storage liquid of 20mM, becomes 200 * concentration gradient with the 100%DMSO gradient dilution, then use 20 times (guaranteeing that with this in each culture system, DMSO concentration is 0.5%) of IMDM (2%FBS, 100units/ml P/S) dilution.Remove substratum after 24 hours, every hole adds 90 μ l (IMDM, 10%FBS, 100units/ml P/S, 5ng/ml VEGF) and 10 μ l medicines, the mixing that vibrates gently, control group and blank group only contain 100 μ l (IMDM, 10%FBS, P/S, 5ng/ml VEGF), place 37 ℃, 5%CO 2Cultivate in incubator, after 72 hours, every hole adds 10 μ l CCK-8, then puts into 37 ℃, 5%CO 2Hatched in incubator 4 hours, 450nm surveys absorption value.
The compounds of this invention biological activity is measured by above test, the IC that records 50Be worth as following table 4:
The IC of table 4 the compounds of this invention to the propagation inhibition of HT-29 cell 50
The embodiment numbering IC 50(HT-29)/μM
1 3
2 1.6
8 1.1
13 0.95
14 0.27
16 0.30
23 2.72
32 1.18
34 1.27
39 0.38
Conclusion: embodiment of the present invention compound all has restraining effect significantly to HT-29 cell proliferation.
Pharmacokinetic Evaluation
The pharmacokinetics test of test case 5, the compounds of this invention
1, summary
Take rat as animal subject, use the LC/MS/MS method and measured rat oral gavage and give after embodiment 1 compound, embodiment 2 compounds, embodiment 8 compounds, embodiment 13 compounds, embodiment 41 compounds and embodiment 46 compounds not drug level in blood plasma in the same time.Study the pharmacokinetics behavior of FGFR compound of the present invention in the rat body, estimate its characteristics of pharmacokinetics.
2, testing program
2.1 test drug
Embodiment 1 compound, embodiment 2 compounds, embodiment 8 compounds, embodiment 13 compounds, embodiment 41 compounds and embodiment 46 compounds.
2.2 experimental animal
24 of healthy adult SD rats, male and female half and half are divided into 6 groups, and 4 every group, available from Shanghai west pul-Bi Kai laboratory animal company limited, animal production licence number: SCXK (Shanghai) 2008-0016.
2.3 medicine preparation
Take appropriate sample, add 0.5%CMC-Na, the ultrasonic 0.5mg/ml suspension of making.
2.4 administration
24 of SD rats, male and female half and half are divided into 4 groups, and fasting is distinguished gastric infusion after one night, and dosage is 5.0mg/kg, administration volume 10ml/kg.
3, operation
Rat oral gavage administration embodiment 1 compound, embodiment 2 compounds, embodiment 8 compounds, embodiment 13 compounds, embodiment 41 compounds and embodiment 46 compounds, before administration and administration after 0.5,1.0,2.0,3.0,4.0,6.0,8.0,11.0 24.0 hours blood sampling 0.1ml are placed in the heparinization test tube, the centrifugal 5min separated plasma of 3500rpm is preserved in-20 ° of C.Feed in 2 hours after administration.
With the testing compound content in rat plasma after the medicine gastric infusion of LC/MS/MS method mensuration different concns.The linearity range of method is 1.00～2000ng/ml; Plasma sample is analyzed after methanol extraction albumen is processed.
4, pharmacokinetic parameter result
The pharmacokinetic parameter of the compounds of this invention is as follows:
Figure BDA00003089852000721
Conclusion: the medicine of the compounds of this invention is good for absorbing, and has obvious pharmacokinetics advantage.

Claims (21)

  1. Compound shown in a general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
    Figure FDA00003089851900011
    Wherein:
    G is selected from C-R ' or N;
    Y is selected from a key, C (R 4R 5), O, S or N-R 4
    Ring Q is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl;
    Ring A is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl;
    R 1Be selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl;
    R 2Or R 3Be selected from independently of one another hydrogen atom, halogen, cyano group, nitro, alkyl, cycloalkyl, aryl, heteroaryl ,-NR 6R 7,-CONR 6R 7,-O (CH 2) rR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8, wherein said alkyl, cycloalkyl, aryl or heteroaryl independently of one another optional further by one or more be selected from hydroxyl, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8Substituting group replace;
    R 4Or R 5Be selected from independently of one another hydrogen atom, alkyl, cycloalkyl, aryl, heteroaryl ,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8, wherein said alkyl, cycloalkyl, aryl or heteroaryl independently of one another optional further by one or more be selected from hydroxyl, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR 6R 7,-CONR 6R 7,-OR 8,-C (O) R 8,-NR 6C (O) R 7,-OC (O) R 8Or-C (O) OR 8Substituting group replace;
    R 6Or R 7Be selected from independently of one another hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another optional further by one or more be selected from alkyl, halogen, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 11,-OC (O) R 11,-C (O) R 11,-C (O) NR 9R 10,-NR 9C (O) R 10,-NR 9R 10,-OC (O) NR 9R 10,-NHC (O) NR 9R 10,-S (O) mR 11,-NHC (O) OR 11Or-NHS (O) mR 11Or-C (O) OR 11Substituting group replace;
    Perhaps, R 6And R 7Form heterocyclic radical together with the N atom that is connected, wherein said heterocyclic radical contains one or more N of being selected from, O or S (O) mHeteroatoms, and described heterocyclic radical optional further by one or more be selected from alkyl, halogen, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 11,-OC (O) R 11,-C (O) R 11,-C (O) NR 9R 10,-NR 9C (O) R 10,-NR 9R 10,-OC (O) NR 9R 10,-NHC (O) NR 9R 10,-S (O) mR 11,-NHC (O) is R (O) 11Or-NHS (O) mR 11Or-C (O) OR 11Substituting group replace;
    R 8Be selected from hydrogen atom, alkyl, hydroxyl ,-NR 9R 10, cycloalkyl, heterocyclic radical, cyano group, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another optional further by one or more be selected from alkyl, halogen, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 11,-OC (O) R 11,-C (O) R 11,-C (O) NR 9R 10,-NR 9C (O) R 10,-NR 9R 10,-OC (O) NR 9R 10,-NHC (O) NR 9R 10,-S (O) mR 11,-NHC (O) OR 11Or-NHS (O) mR 11Or-C (O) OR 11Substituting group replace;
    R 9, R 10Or R 11Be selected from independently of one another hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl;
    R 12Be selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, aryl or heteroaryl;
    R is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl;
    Z is selected from O, S, N-R ' or CH-R ';
    R ' is selected from hydrogen atom, cyano group, amino, alkyl, haloalkyl, alkoxyl group or halogenated alkoxy;
    M is 0,1 or 2, and
    R is 0,1,2,3 or 4.
  2. Compound shown in general formula according to claim 1 (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein encircling Q is aryl.
  3. Compound shown in general formula according to claim 1 and 2 (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein encircling A is heterocyclic radical, is preferably 5 yuan or 6 yuan of heterocyclic radicals.
  4. Compound shown according to claim 1～3 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, its be the compound shown in general formula (II) or its tautomer, mesomeride and racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
    Figure FDA00003089851900021
    Wherein: Z, G, ring A, R 1～R 3, R 12With described in the definition such as claim 1 of R.
  5. Compound shown according to claim 1～4 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, its be the compound shown in general formula (III) or its tautomer, mesomeride and racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
    Figure FDA00003089851900031
    Wherein: Z, G, R 2, R 3, R 12With described in the definition such as claim 1 of R; And
    N is 1 or 2.
  6. Compound shown according to claim 1～5 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, its be the compound shown in general formula (IV) or its tautomer, mesomeride and racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
    Figure FDA00003089851900032
    Wherein: Z, G, R 2, R 3, R 12With described in the definition such as claim 1 of R.
  7. Compound shown according to claim 1～3 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, its for the compound shown in logical formula V or its tautomer, mesomeride and racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
    Figure FDA00003089851900033
    Wherein: Z, G, Y, ring A, R 1～R 3With described in the definition such as claim 1 of R.
  8. Compound shown in logical formula V according to claim 7 or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, its be the compound shown in general formula (VI) or its tautomer, mesomeride and racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof:
    Figure FDA00003089851900041
    Wherein: Z, G, Y, R 2, R 3With described in the definition such as claim 1 of R.
  9. Compound shown in general formula according to claim 8 (VI) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein Y is CH 2Or NH.
  10. Compound shown according to claim 1～9 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt, wherein R 3Be hydrogen atom.
  11. 11. the compound shown according to claim 1～10 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein
    R 2For-O (CH 2) rR 8
    R 8Be selected from hydrogen atom, alkyl, hydroxyl ,-NR 9R 10, cycloalkyl, heterocyclic radical, cyano group, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another optional further by one or more be selected from alkyl, halogen, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 11Or-NR 9R 10Substituting group replace; And
    R 9, R 10Or R 11Be selected from independently of one another hydrogen atom or alkyl.
  12. 12. the compound shown according to claim 1～11 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein G is CH.
  13. 13. the compound shown according to claim 1～12 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein Z is O.
  14. 14. the compound shown according to claim 1～13 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, wherein this compound is:
    Figure FDA00003089851900061
    Figure FDA00003089851900062
    Or
    Figure FDA00003089851900063
  15. 15. one kind prepare the compound shown in general formula according to claim 1 (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof the method for form and pharmaceutically useful salt thereof, the method comprises the following steps:
    Figure FDA00003089851900064
    General formula (I-A) compound and general formula (I-B) compound are in solvent, and under alkaline condition, heating is reacted, and obtains general formula (I) compound;
    Wherein: LG is leavings group, is preferably halogen or sulfonyloxy, more preferably aryl-sulfonyl oxygen;
    And Z, G, Y, ring A, ring Q, R 1～R 3, R 8, R 12, r and R definition such as claim 1 described in.
  16. 16. a pharmaceutical composition, described pharmaceutical composition contain the compound shown according to claim 1～14 described general formulas of any one (I) for the treatment of significant quantity or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt and pharmaceutically acceptable carrier.
  17. 17. the compound shown according to claim 1～14 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, or pharmaceutical composition according to claim 16 is preferably the purposes in FGFR, PDGFR, VEGFR-2, EGFR, HER-2, HER-3, HER-4, c-Kit, c-Met or Flt3 inhibitor at the preparation kinases inhibitor.
  18. 18. the compound shown according to claim 1～14 described general formulas of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, and composition thereof form and pharmaceutically useful salt thereof, or the purposes of pharmaceutical composition according to claim 16 in the medicine of the preparation treatment disease relevant with protein kinase.
  19. 19. purposes according to claim 18, the wherein said disease relevant with protein kinase are selected from the disease relevant with FGFR, PDGFR, VEGFR-2, EGFR, HER-2, HER-3, HER-4, c-Kit, c-Met or Flt3.
  20. 20. purposes according to claim 18, the wherein said disease relevant with protein kinase are selected from leukemia, diabetes, sick from immunological disease, hyperplasia disease, psoriasis, osteoarthritis, rheumatoid arthritis, vasculogenesis, cardiovascular diseases, Von-Hippel-LindauShi disease, inflammation or fibrosis.
  21. 21. purposes according to claim 18, the wherein said disease relevant with protein kinase is cancer, is preferably squamous cell carcinoma, prostate cancer, renal cell carcinoma, Kaposi sarcoma, nonsmall-cell lung cancer, small cell lung cancer, lymphatic cancer, thyroid carcinoma, mammary cancer, head and neck cancer, uterus carcinoma, esophagus cancer, melanotic cancer, bladder cancer, Genito-urinary cancer, gastrointestinal cancer, neuroglia cancer, colorectal carcinoma or ovarian cancer.
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CN106045942A (en) * 2016-06-30 2016-10-26 山东诚汇双达药业有限公司 Preparation method of pramoxine hydrochloride
WO2016173400A1 (en) * 2015-04-27 2016-11-03 江苏恒瑞医药股份有限公司 Use of protein kinase inhibitor in preparing drug for treating fibrotic disease
RU2686692C1 (en) * 2018-06-29 2019-04-30 Федеральное Государственное Бюджетное Учреждение Науки Институт Биохимической Физики Им. Н.М. Эмануэля Российской Академии Наук (Ибхф Ран) Use of n-(6,8,8-trimethyl-8,9-dihydrofuro[3,2-h]quinolin-5-yl)acetamide as an agent for phototherapy of psoriasis and psoriatic arthritis
CN109748902A (en) * 2017-11-02 2019-05-14 杭州科巢生物科技有限公司 A kind of hydrochloric acid peace sieve replaces the preparation method of Buddhist nun
CN110483392A (en) * 2018-05-14 2019-11-22 上海海和药物研究开发有限公司 Synthesize the method and synthetic intermediate of the quinoline -7- base oxygroup methylcyclopropyl groups amine derivative of N-protected
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CN110577546A (en) * 2018-06-08 2019-12-17 江苏威凯尔医药科技有限公司 VEGFR inhibitor and preparation method and application thereof
CN110862398A (en) * 2018-08-27 2020-03-06 北京赛特明强医药科技有限公司 Urea substituted aromatic ring-linked dioxane quinazoline or quinoline compound, composition and application thereof
CN110862397A (en) * 2018-08-27 2020-03-06 北京赛特明强医药科技有限公司 Dioxane quinazoline and dioxane quinoline compounds, and preparation method and application thereof
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CN105017227A (en) * 2014-07-08 2015-11-04 四川百利药业有限责任公司 N-(1H-pyrazol-5-yl)quinazoline-4-amine compounds
CN106535896B (en) * 2015-04-27 2019-06-21 江苏恒瑞医药股份有限公司 Purposes of the kinases inhibitor in the drug of preparation treatment fibrotic disease
WO2016173400A1 (en) * 2015-04-27 2016-11-03 江苏恒瑞医药股份有限公司 Use of protein kinase inhibitor in preparing drug for treating fibrotic disease
CN106535896A (en) * 2015-04-27 2017-03-22 江苏恒瑞医药股份有限公司 Use of protein kinase inhibitor in preparing drug for treating fibrotic disease
TWI715570B (en) * 2015-04-27 2021-01-11 大陸商江蘇恆瑞醫藥股份有限公司 Use of protein kinase inhibitors in the preparation of a medicament for the treatment of fibrotic diseases
CN106045942A (en) * 2016-06-30 2016-10-26 山东诚汇双达药业有限公司 Preparation method of pramoxine hydrochloride
CN109748902A (en) * 2017-11-02 2019-05-14 杭州科巢生物科技有限公司 A kind of hydrochloric acid peace sieve replaces the preparation method of Buddhist nun
JP7018224B2 (en) 2018-02-11 2022-02-10 北京賽特明強医薬科技有限公司 Urea-substituted aromatic ring-bonded dioxynoquinoline compounds, their preparation methods and uses
JP2021512936A (en) * 2018-02-11 2021-05-20 北京賽特明強医薬科技有限公司 Urea-substituted aromatic ring-bonded dioxynoquinoline compounds, their preparation methods and uses
CN110483392A (en) * 2018-05-14 2019-11-22 上海海和药物研究开发有限公司 Synthesize the method and synthetic intermediate of the quinoline -7- base oxygroup methylcyclopropyl groups amine derivative of N-protected
WO2019233458A1 (en) * 2018-06-08 2019-12-12 江苏威凯尔医药科技有限公司 Vegfr inhibitor, preparation method therefor and use thereof
CN110577546A (en) * 2018-06-08 2019-12-17 江苏威凯尔医药科技有限公司 VEGFR inhibitor and preparation method and application thereof
CN110577546B (en) * 2018-06-08 2021-09-07 江苏威凯尔医药科技有限公司 VEGFR inhibitor and preparation method and application thereof
RU2686692C1 (en) * 2018-06-29 2019-04-30 Федеральное Государственное Бюджетное Учреждение Науки Институт Биохимической Физики Им. Н.М. Эмануэля Российской Академии Наук (Ибхф Ран) Use of n-(6,8,8-trimethyl-8,9-dihydrofuro[3,2-h]quinolin-5-yl)acetamide as an agent for phototherapy of psoriasis and psoriatic arthritis
CN110862397A (en) * 2018-08-27 2020-03-06 北京赛特明强医药科技有限公司 Dioxane quinazoline and dioxane quinoline compounds, and preparation method and application thereof
CN110862398A (en) * 2018-08-27 2020-03-06 北京赛特明强医药科技有限公司 Urea substituted aromatic ring-linked dioxane quinazoline or quinoline compound, composition and application thereof
CN112010864A (en) * 2019-05-31 2020-12-01 江苏威凯尔医药科技有限公司 Vascular endothelial growth factor receptor inhibitor and preparation method and application thereof

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