CN117343046A - Novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compound and application thereof - Google Patents
Novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compound and application thereof Download PDFInfo
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- CN117343046A CN117343046A CN202311237658.XA CN202311237658A CN117343046A CN 117343046 A CN117343046 A CN 117343046A CN 202311237658 A CN202311237658 A CN 202311237658A CN 117343046 A CN117343046 A CN 117343046A
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- dihydropyrazine
- oxo
- compound
- carboxamide
- phenyl
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- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 19
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims abstract description 10
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims abstract description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 9
- 201000005202 lung cancer Diseases 0.000 claims abstract description 9
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 9
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 8
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 7
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 7
- 201000007270 liver cancer Diseases 0.000 claims abstract description 7
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 7
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 7
- 208000032839 leukemia Diseases 0.000 claims abstract description 4
- -1 nitro, amino Chemical group 0.000 claims description 107
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims description 56
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
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- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 5
- 229940127007 Compound 39 Drugs 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 3
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- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 claims description 3
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- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 claims description 3
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 claims description 3
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 claims description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 3
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 3
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- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 claims description 3
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- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 claims description 3
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 claims description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
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- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compound and application thereof, and particularly relates to a compound shown in a general formula (I). The invention also relates to a compound with strong c-Met kinase inhibition effect in the general formula (I), and also relates to application of the compound and pharmaceutically acceptable salts thereof in preparing medicines for treating and/or preventing diseases caused by abnormal high expression of c-Met kinaseIn particular to the application in preparing a medicament for treating and/or preventing cancers. The compound is particularly suitable for preparing medicaments for treating and/or preventing lung cancer, gastric cancer, liver cancer, leukemia, gastrointestinal stromal tumor and colon cancer.
Description
Technical Field
The invention relates to novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-formyl-containing 4-phenoxyquinoline compounds, 4-phenoxypyridine compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compounds. The invention also relates to application of the compounds and pharmaceutically acceptable salts thereof in preparing medicines for treating diseases caused by abnormal high expression of c-Met kinase, in particular to application in preparing medicines for treating and/or preventing cancers.
Background
Cancer is a major disease that threatens human life and health. The development of antitumor drugs has been a very challenging and significant field in life sciences and pharmaceutical sciences. Abnormalities in tumor cell signaling pathways are the leading cause of early tumor development and late invasive metastasis. Protein kinase signaling plays an important role in the tumorigenesis and progression. Along with the rapid development of life science in recent years, the pathogenesis of tumors is gradually clarified, and the focus of development of antitumor drugs is developed from traditional low-selectivity cytotoxic antitumor drugs to high-selectivity low-toxicity antitumor drugs targeting protein kinases.
In 1984 Cooper, when studying human osteosarcoma Hos cell line, cloned a fragment with transforming activity, designated as c-Met. After the specific combination of the c-Met and the HGF, the c-Met protein is induced to change in conformation, and then important signal molecules such as PLC gamma, PI3K, ERK1/2 and the like and corresponding signal channels are activated through a series of phosphorylation reactions, and finally, transcriptional mechanisms in nuclei are influenced through cascade reactions, so that proliferation, migration, invasion capacity and the like of tumor cells are regulated. The abnormal activity of HGF/c-Met is closely related to the occurrence, division, angiogenesis, invasiveness, metastasis, drug resistance and the like of tumors, and the c-Met kinase presents abnormal high expression in various tumor tissues such as lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer and the like. In addition, high expression of c-Met and HGF is also associated with poor prognosis and metastatic process of tumor, and c-Met gene amplification is closely related to 20% EGFR-TKIs acquired drug resistance. The c-Met kinase is used as a key node protein in a tumor cell signal transduction pathway, can interact with other kinases and receptors, is highly expressed and abnormally activated in most tumor tissues, and plays a key role in various links such as tumorigenesis, development, invasion metastasis, chemotherapy and the like. Therefore, c-Met has become an important target for the development of antitumor drugs.
The 4-phenoxyquinoline compound and the 4-phenoxypyridine compound with the basic parent nucleus structure of the 4-phenoxypyridine are representative class-II compounds in a Type II small molecule c-Met kinase inhibitor. 4-phenoxyquinolines, cabozantinib (Cabozantinib), was approved by the U.S. FDA for marketing in month 11 of 2012, which is currently the only Type II small molecule c-Met kinase inhibitor on the market. For the treatment of non-resectable malignant locally advanced or metastatic Medullary Thyroid Cancer (MTC). Cabatinib was approved by the FDA for use in the treatment of advanced renal cancer in month 4 of 2016. The FDA approved cabatinib tablet at 12 2017 for use in the treatment of advanced Renal Cell Carcinoma (RCC) enlargement indications. In addition, the study of this drug for lung cancer and glioblastoma is in phase II clinical study. The other 4-phenoxyquinoline compound Foretinib (XL 880) is an analogue of cabatinib, and has a strong inhibition effect on various tyrosine kinases and tumor cells. Foretinib is also used for research of thyroid medullary cancer (MTC), non-small cell lung cancer, breast cancer and other cancers, and enters different clinical research stages. Small molecule c-Met kinase inhibitors of Type II 4-phenoxypyridines have also been of interest to scientists, as represented by compounds Golvatinib, altiratinib and BMS-777607, which both have better c-Met kinase inhibition activity, have entered different clinical stages of research, but have not yet been approved for market. On the other hand, compounds containing pyrazine structural units have been the focus of attention of pharmaceutical chemists, and often have a wide range of biological activities such as antitumor, antiviral and antibacterial activities, and thus have attracted great attention from chemists and pharmaceutical professionals. In the application of antitumor drugs, pyrazine structural units are often introduced into anticancer drugs as antitumor pharmacophores. The pyrazine structural unit-containing compound can be used as STAT3 inhibitor, SHP2 inhibitor and the like. Currently, the following problems are mainly present in c-Met inhibitor studies: has larger toxic and side effects in clinical application, unsatisfactory clinical treatment effect and pharmacokinetic parameters, low oral bioavailability and the like. Therefore, the development of novel, safe and effective c-Met kinase inhibitors is still an important field for research of antitumor drugs at home and abroad.
Disclosure of Invention
The inventor designs and synthesizes a series of novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-formamide compounds on the basis of reference documents. In vitro activity screening shows that the compounds have anti-tumor activity. The invention relates to a novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compound serving as a c-Met inhibitor, which is not reported in the literature.
The technical scheme adopted by the invention is as follows: novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compounds and pharmaceutically acceptable salts thereof, and the structural formula is shown as the general formula (I):
wherein:
x is selected from 1 to 4 identical or different substituents: hydrogen, halogen, C 1 -C 10 Alkyl, or C 1 -C 4 Alkoxy radicalA base;
ar is selected from 6-10 membered aryl or 5-10 membered heteroaryl; wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S and Ar is optionally substituted with 1 to 3R' S, which may be the same or different 1 Substituted;
R 1 is hydrogen, hydroxy, halogen, nitro, amino, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, optionally C by hydroxy or amino or halogen 1 -C 6 Alkyl, optionally hydroxy or amino or halogenated C 1 -C 6 Alkoxy, singly or di-C 1 -C 6 Alkyl-substituted amino, C 1 -C 6 Alkylamido, free or salified or esterified or amidated carboxyl groups, C 1 -C 6 Alkylsulfinyl, sulfonyl, C 1 -C 6 Alkanoyl, carbamoyl, mono-or di-C 1 -C 6 An alkyl-substituted carbamoyl group.
A is selected from
R 2 And R is 3 The same or different are each independently selected from hydrogen, C 1 -C 10 Alkyl or C 3 -C 7 Cycloalkyl;
or R is 2 And R is 3 Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclic group, said heterocyclic group being other than R 2 And R is 3 Optionally containing 1 to 4 hetero atoms selected from N, O and S, optionally including 1 or 2 carbon-carbon double or triple bonds, optionally substituted with 1 to 3 identical or different R' S, in addition to the attached nitrogen atom 6 Substitution;
R 6 selected from C 1 -C 6 Alkyl or C 1 -C 4 An alkoxy group;
R 4 selected from C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl radicalsOr C 1 -C 6 Alkyl substituted C 1 -C 6 An alkyl group;
R 5 selected from hydrogen, C 1 -C 10 Alkyl, C 3 -C 7 Cycloalkyl, or halogenated C 1 -C 10 An alkyl group.
The novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compounds and pharmaceutically acceptable salts thereof,
x is selected from 1 to 4 identical or different substituents: hydrogen or halogen;
ar is selected from C 6 -C 10 Meta-aryl, C 6 -C 10 Aralkyl radicals, C 5 -C 10 A membered heteroaryl group; the heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 1 to 5R' S, which may be the same or different 1 Substituted;
said R is 1 Selected from hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl or C 1 -C 6 An alkoxy group.
A is selected from
R 2 And R is 3 The same or different, each independently selecting C 1 -C 10 An alkyl group;
or R is 2 And R is 3 Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclic group, said heterocyclic group being other than R 2 And R is 3 Optionally containing 1 to 4 hetero atoms selected from N, O and S, optionally including 1 or 2 carbon-carbon double or triple bonds, optionally substituted with 1 to 3 identical or different R' S, in addition to the attached nitrogen atom 6 Substitution;
R 6 selected from C 1 -C 6 An alkyl group;
R 4 selected from C 1 -C 6 Alkyl, C 1 -C 6 Alkyl substitutedC 1 -C 6 An alkyl group;
R 5 selected from C 1 -C 10 An alkyl group.
The novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compounds and pharmaceutically acceptable salts thereof,
x is selected from 1-2 identical or different substituents: hydrogen or fluorine;
ar is selected from phenyl, pyridyl, thiophene, furan, naphthyl, quinolinyl and indolyl, and Ar is optionally substituted with 1-5R's, which may be the same or different 1 Substituted;
said R is 1 Selected from hydrogen, halogen, trifluoromethyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group;
a is selected from
R 2 And R is 3 Forms, together with the nitrogen atom to which they are attached, 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl or 1-pyrrolidinyl;
R 4 Selected from methyl, ethyl, n-propyl, methoxypropyl or ethoxypropyl;
R 5 selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compounds and pharmaceutically acceptable salts thereof, wherein the compound of the general formula (I) is selected from the following compounds:
compound 1: n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 2: n- (3-fluoro-4- { 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
the compound 3:N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 4 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 5 n- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 6:N- {4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 7 n- (4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 8, n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 9 n- (3-fluoro-4- { 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 10, n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 11, n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 12, n- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 13, n- {4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
Compound 14, n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 15 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -4- (4-fluorophenyl) -3-oxo-3, 4-dihydropyrazine-2-carboxamide;
compound 16 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 17 n- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 18:n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 19 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 20 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 21, n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 22, n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 23 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 24 n- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 25:n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-trifluoromethylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 26 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-trifluoromethylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 27 n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 28 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 29 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 30:n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 31 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 32, n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 33, n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (3-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 34 n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 35 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 36, n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (3, 4-dichlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 37 n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (3, 4-difluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 38, n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3, 4-difluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 39 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 40 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 41 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 42 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 43 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 44 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 45 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 46, n- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 47, n- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 48 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 49 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 50:n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 51, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 52, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-trifluoromethylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 53 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 54, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 55, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 56 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (3-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 57 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 58 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (3, 4-difluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 59 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (3, 4-dichlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 60:n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 61, n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 62, n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 65 n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 66, n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 67: n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 68, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 69 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 70: n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 71 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 72, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 73, n- {4- [2- (acetamido) pyridin-4-oxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 74, n- {4- [2- (acetamido) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 75 n- {4- [2- (acetamido) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 76N- {4- [2- (acetamido) pyridin-4-yloxy ] phenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide.
The following synthetic schemes describe the preparation of novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamides of formula (I) according to the invention, all starting materials being prepared or commercially available by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry. All final derivatives of the invention are prepared by the methods described in the following schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variable factors applied in these equations are as defined below or as defined in the claims.
The novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamides of the general formula (I) according to the invention can be prepared from the corresponding intermediates M and the corresponding Q by condensation according to the method of scheme 1;
route 1
According to the invention compounds of general formula (I), intermediate Q is prepared by the process as shown in scheme 2, the other substituents being as defined in the claims.
Route 2
According to the invention compounds of general formula (I), intermediate M may be prepared by the process as shown in scheme 3, the other substituents being as defined in the claims, wherein M-1 represents a subset of intermediate M.
Route 3
According to the invention compounds of general formula (I), intermediate M may also be prepared by the process as shown in scheme 4, the other substituents being as defined in the claims, wherein M-2 represents a subset of intermediate M.
Route 4
According to the invention compounds of general formula (I), intermediate M may also be prepared by the process as shown in scheme 5, the other substituents being as defined in the claims, wherein M-3 represents a subset of intermediate M.
Route 5
Substituents A, R of all intermediates in the above five routes 1 、R 2 、R 3 、R 4 、R 5 X, ar are as defined in the claims.
A pharmaceutical composition comprising the novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compound and pharmaceutically acceptable salts thereof as active ingredients and pharmaceutically acceptable excipients.
The application of any novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compound and pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicaments for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase.
The application of any one of the novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compounds and pharmaceutically acceptable salts thereof or the pharmaceutical composition in preparing medicaments for treating and/or preventing proliferative diseases.
The application of any one of the novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compounds and pharmaceutically acceptable salts thereof or the pharmaceutical composition in preparing medicaments for treating and/or preventing cancers.
The application of any novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compound and pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicaments for treating and/or preventing lung cancer, gastric cancer, liver cancer, leukemia, gastrointestinal stromal tumor and colon cancer.
Furthermore, the novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamides of formula (I) of the present invention may form pharmaceutically acceptable salts with acids according to some of the usual methods in the art to which the present invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acid addition salts being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In the present invention, "halogen" means fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight or branched chain alkyl group; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "aryl" refers to a monocyclic or polycyclic aromatic ring system of carbon atoms, such as phenyl, naphthyl, and the like; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being aromatic, such as imidazolyl, pyridyl, pyrazolyl, (1, 2, 3) -and (1, 2, 4) -triazolyl, furyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and the like; "heterocyclyl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, and the like.
Through in vitro activity tests of inhibiting human lung adenocarcinoma A549, human gastric cancer cell strain MKN45, human lung cancer cell H460, human liver cancer cell HepG2, human chronic myelogenous leukemia cell K562, human gastrointestinal stromal tumor cell GIST882, imatinib resistant human gastrointestinal stromal tumor cell GIST1210 and human colon cancer cell HCT116, the compound has remarkable inhibition effect on the tumor cells, and is particularly used for preparing medicaments for treating and/or preventing lung cancer, gastric cancer, liver cancer, leukemia, gastrointestinal stromal tumor and colon cancer.
Through the c-Met enzyme activity test, the compound has obvious c-Met kinase inhibition activity, and is particularly used for preparing medicaments for treating and/or preventing diseases caused by the abnormal high expression of the c-Met kinase, and particularly for preparing medicaments for treating and/or preventing cancers.
Detailed Description
The examples and preparations provided below further illustrate and exemplify the compounds of the invention and methods of preparing the same. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way. The examples are intended to illustrate, but not limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by Bruker ARX-400 or ARX-600, and the mass spectrum is measured by Agilent 6460 QQ; the reagents used are analytically pure or chemically pure.
EXAMPLE 1 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 1)
Compound 1
Step 1: synthesis of 3-oxo-3, 4-dihydropyrazine-2-carboxylic acid
A reaction flask was taken, 110mL of sulfuric acid was added, the temperature was lowered to below 0deg.C, and 10.00g (144.92 mmol) of sodium nitrite was added in portions. The method comprises The reaction solution was slowly added to a solution of 20.00g (143.84 mmol) of 2-amino-3-carboxylic acid pyrazine dissolved in 90mL of concentrated sulfuric acid, and the reaction temperature was kept at not higher than 0℃for 2 hours. Slowly adding the reaction solution into a large amount of ice water, precipitating a large amount of dark yellow solid, carrying out suction filtration, vacuum drying and recrystallizing with anhydrous methanol to obtain 15.17g of dark yellow solid 3-oxo-3, 4-dihydropyrazine-2-carboxylic acid. MS (ESI) m/z 139.0[ M-H ]] - 。
Step 2: synthesis of methyl 3-oxo-3, 4-dihydropyrazine-2-carboxylate
15.00g (107.11 mmol) of 3-oxo-3, 4-dihydropyrazine-2-carboxylic acid and 300mL of absolute methanol were placed in a reaction flask, followed by stirring in an ice bath, and 15.29g (128, 53 mmol) of thionyl chloride was slowly added to react at 40℃for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained solid was recrystallized from absolute ethanol to obtain a crude product, which was purified by silica gel column chromatography to obtain 12.24g of methyl 3-oxo-3, 4-dihydropyrazine-2-carboxylate as pale yellow solid. MS (ESI) m/z 155.0[ M+H ]] + ,177.0[M+Na] + 。
Step 3: synthesis of methyl 4- (4-fluorophenyl) -3-oxo-3, 4-dihydropyrazine-2-carboxylate
To the reaction flask were added 6.00g (38.94 mmol) of methyl 3-oxo-3, 4-dihydropyrazine-2-carboxylate, 6.54g (46.74 mmol) of 4-fluorobenzeneboronic acid, 11.67g (58.45 mmol) of copper acetate, 9.06g (89.56 mmol) of triethylamine, 3.00g of activated 4A molecular sieve and 100mL of dichloromethane, and the mixture was reacted at room temperature for 4 hours. The reaction solution was filtered, the filter cake was washed with methylene chloride, the organic phases were combined, washed with water for 2 times, saturated sodium chloride solution was washed with 2 times, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.12g of methyl 4- (4-fluorophenyl) -3-oxo-3, 4-dihydropyrazine-2-carboxylate as a pale yellow solid. 1 H NMR(300MHz,CDCl 3 )δ7.51(d,J＝4.1Hz,1H),7.44-7.37(m,3H),7.22(t,J＝8.3Hz,2H),3.99(s,3H)。
Step 5: synthesis of 4- (4-fluorophenyl) -3-oxo-3, 4-dihydropyrazine-2-carboxylic acid
To the reaction flask was added 3.00g (12.09 mmol) of methyl 4- (4-fluorophenyl) -3-oxo-3, 4-dihydropyrazine-2-carboxylate, 30mL of anhydrous methanol, 15mL of water, 0.73g (18.25 mmol) of sodium hydroxide, and the mixture was reacted at 50℃for 2 hours. The anhydrous methanol is removed by decompression concentration, 100mL of water is added, the ethyl acetate is used for extraction, the water phase is taken, the pH value of the water phase is adjusted to 5 by 3M hydrochloric acid, a large amount of solid is separated out, suction filtration is carried out, the filter cake is washed to be neutral by water, and the filter cake is dried in vacuum at low temperature, thus obtaining 1.5g of deep yellow solid 4- (4-fluorophenyl) -3-oxo-3, 4-dihydropyrazine-2-formic acid. MS (ESI) m/z 233.0[ M-H ]] - ； 1 H NMR(600MHz,DMSO-d 6 )δ13.70(d,J＝39.1Hz,1H),7.97-7.86(m,1H),7.65-7.51(m,3H),7.48-7.37(m,2H)。
Step 6 4 Synthesis of- (3-Chloropropoxy) -3-methoxyacetophenone
3-methoxy-4-hydroxyacetophenone (319 g,1.5 mol) and anhydrous potassium carbonate (579.6 g,2.1 mol) were added to 1250mL of acetone, 1-bromo-3-chloropropane (661.3 g,4.2 mol)/acetone (1200 mL) was slowly added dropwise at a temperature below 25℃and the mixture was stirred overnight at room temperature. After the reaction is finished, leaching a filter cake by using 100mL of acetone, merging the filter cake, slowly pouring the filtrate into 15L of ice water, stirring vigorously at the same time, precipitating a large amount of white solid, leaching, and vacuum drying the filter cake at 40 ℃ for 48 hours to obtain 695.5g of white powder 4- (3-chloropropoxy) -3-methoxyacetophenone and ESI-MS [ M+H ] ] + (m/z):242.7。
Step 7 4 Synthesis of- (3-Chloropropoxy) -3-methoxy-2-nitroacetophenone
4- (3-Chloropropoxy) -3-methoxyacetophenone (200 g,0.82 mol) was added to CH 2 Cl 2 (5 v/w,1000 mL), fully stirring to fully dissolve 4- (3-chloropropoxy) -3-methoxyacetophenone, cooling the reaction liquid to-20 ℃, slowly dropwise adding fuming nitric acid (130 g,2.06 mol), controlling the dropwise adding speed to keep the temperature of the reaction liquid below-10 ℃, and reacting for 2 hours at-10 to-20 ℃ after the dropwise adding is finished. After the reaction was completed, the reaction solution was poured into ice water, and the organic layer was collected, washed with saturated brine until the aqueous layer was neutral, and dried over anhydrous sodium sulfate. Evaporating the solvent to dryness to obtain yellow solid 4- (3-chloropropoxy) -3-methoxy-2-nitroacetophenone 210g, ESI-MS [ M+H ]] + (m/z):287.7。
Step 8 1 Synthesis of- [4- (3-Chloropropoxy) -5-methoxy-2-nitrophenyl ] -3- (dimethylamino) propyl-2-en-1-one
4- (3-Chloropropoxy) -3-methoxy-2-nitroacetophenone (200 g,0.695 mL) was added to toluene (5 v/w,1000 mL), heated to 110℃to dissolve 4- (3-Chloropropoxy) -3-methoxy-2-nitroacetophenone completely, and N, N-dimethylformamide dimethyl acetal (DMF-DMA) (414.2 g, 3.470 mol) was added thereto and the mixture was heated under reflux for 16h. After the reaction is finished, cooling the reaction liquid to room temperature, then placing the reaction liquid into a cold trap for stirring, separating out solid, carrying out suction filtration, and drying a filter cake to obtain yellow solid 1- [4- (3-chloropropoxy) -5-methoxy-2-nitrophenyl ]-3- (dimethylamino) propyl-2-en-1-one 180g, ESI-MS [ M+H ]] + (m/z):342.8。
Step 9 7 Synthesis of- (3-Chloropropoxy) -6-methoxy-4 (1H) -quinolinone
1- [4- (3-Chloropropoxy) -5-methoxy-2-nitrophenyl]-3- (dimethylamino) propyl-2-en-1-one (150 g,0.44 mol) was added to glacial acetic acid (8 v/w1200 mL) was heated to 40℃until 1- [4- (3-chloropropoxy) -5-methoxy-2-nitrophenyl]After complete dissolution of 3- (dimethylamino) propyl-2-en-1-one, iron powder (123.1 g,2.20 mol) was added slowly in portions and the reaction was stirred mechanically for 2h at 80 ℃. After the reaction is finished, the reaction solution is filtered while the reaction solution is hot, the filtrate is collected, a large amount of solids are separated out after the filtrate is cooled, and the earthy yellow solid is obtained through filtering. Dissolving the filter cake in glacial acetic acid, stirring at 80deg.C for about 30min, vacuum filtering again, collecting filtrate, cooling, separating out solid, vacuum filtering, washing the filter cake with water to neutrality, and drying to obtain solid 7- (3-chloropropoxy) -6-methoxy-4 (1H) -quinolinone 79g, ESI-MS [ M+H ]] + (m/z):267.7。
Step 10 Synthesis of 6-methoxy-7- [4- (3-morpholinopropoxy) ] -4 (1H) -quinolinone
7- (3-Chloropropoxy) -6-methoxy-4 (1H) -quinolinone (62 g,0.232 mol), morpholine (120.6 g,1.38 mol) was added to acetonitrile (620 mL) and heated under reflux for 8H. After the reaction is finished, most of the solvent is evaporated, the residual liquid is placed in a cold trap, solid is separated out, suction filtration and ethyl acetate washing are carried out, and the solid 6-methoxy-7- [4- (3-morpholinopropoxy) is obtained ]-4 (1H) -quinolinone 69.5g, ESI-MS [ M+H ]] + (m/z):319.3。
Step 11 Synthesis of 4-chloro-6-methoxy-7- [4- (3-morpholinopropoxy) ] quinoline
6-methoxy-7- [4- (3-morpholinopropoxy) radical]-4 (1H) -quinolinone (60.5 g,0.19 mol), phosphorus oxychloride (5 v/w,315 mL) was added to acetonitrile (5 v/w,315 mL), and the mixture was heated to 85℃and reacted under reflux for 6H. After the reaction, the mixture was evaporated to dryness under reduced pressure to give a gray viscous solid, which was added to a large amount of ice water mixture, and the pH was adjusted to 10 with 10% potassium hydroxide solution. By CH 2 Cl 2 Extraction (200 ml. Times.3), collection of organic layer, drying over anhydrous sodium sulfate, evaporation of solventCooling to obtain off-white solid 4-chloro-6-methoxy-7- [4- (3-morpholinopropoxy)]Quinoline 59.2g, ESI-MS [ M ]] + (m/z):336.2,338.2。
Step 12 Synthesis of 4- (2-fluoro-4-nitrophenoxy) -6-methoxy-7- [4- (3-morpholinopropoxy) ] quinoline
2-fluoro-4-nitrophenol (36.73 g,0.234 mol) was added to dry chlorobenzene (5 v/w,250 mL), heated to 145℃and 4-chloro-6-methoxy-7- [4- (3-morpholinopropoxy) was added to the reaction mixture]Quinoline (67.4 g,0.2 mol) was reacted at this temperature for 30h. After the reaction, evaporating the solvent to dryness to obtain a grey solid, dissolving the solid in dichloromethane, washing with a saturated potassium carbonate solution, collecting an organic layer, drying, evaporating the solvent to dryness, and recrystallizing with ethanol to obtain a solid product of 4- (2-fluoro-4-nitrophenoxy) -6-methoxy-7- [4- (3-morpholinopropoxy) ]Quinoline 59.4g, ESI-MS [ M ]] + (m/z):457.2。
Step 13 Synthesis of 3-fluoro-4- { 6-methoxy-7- [4- (3-morpholinopropoxy) ] quinolin-4-yloxy } aniline
Iron powder (61.42 g,1.1 mol), 6mL of concentrated hydrochloric acid were added to 90% ethanol (25 v/w,1210.5 mL), the temperature was raised to 80℃and stirred for 15min, then 4- (2-fluoro-4-nitrophenoxy) -6-methoxy-7- [4- (3-morpholinopropoxy) ] quinoline (51.3 g,0.11 mol) was added to the reaction mixture in portions, and the mixture was reacted under reflux for 3h. After the reaction, the mixture was filtered while it was still hot, the filtrate was collected and the solvent was evaporated to dryness to give 46g of 3-fluoro-4- { 6-methoxy-7- [4- (3-morpholinopropoxy) ] quinolin-4-yloxy } aniline, ESI-MS [ M+H ] (M/z): 428.2 as a yellow solid.
Step 14 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 1)
4- (4-fluorophenyl) -3-oxo-3, 4-dihydropyrazine-2-carboxylic acid (1.20 mmol), 3-fluoro-4- { 6-methoxy-7- [4- (3-morpholinopropoxy) was added to the reaction flask]Quinoline-4-oxy } aniline (1.00 mmol), HATU (1.20 mmol), triethylamine (1.20 mmol), 10ml DMF, stirred at room temperature for 10 h. The reaction solution was poured into 100mL of 20% aqueous potassium carbonate solution, extracted three times with 50mL of dichloromethane, the organic phases were combined, the organic phase was washed three times with 20% aqueous potassium carbonate solution, the organic layer was washed twice with saturated brine, and the separated organic layer was dried over anhydrous sodium sulfate. Filtering, evaporating dichloromethane under reduced pressure, and separating by column chromatography to obtain the product. 1 H NMR(600MHz,CDCl 3 )δ11.81(s,1H),8.49(d,J＝5.3Hz,1H),8.00(dd,J＝12.0,2.4Hz,1H),7.94(d,J＝4.0Hz,1H),7.57(s,1H),7.51(d,J＝4.0Hz,1H),7.49-7.39(m,4H),7.32(t,J＝8.4Hz,2H),7.23(t,J＝8.6Hz,1H),6.43(dd,J＝5.3,1.0Hz,1H),4.28(t,J＝6.7Hz,2H),4.04(s,3H),3.73(t,J＝4.6Hz,4H),2.58(t,J＝7.1Hz,2H),2.49(s,4H),2.19-2.09(m,2H)；MS(ESI)m/z:644.1[M+H] + ,666.1[M+Na] + 。
Examples 2-38 (compounds 2-38) were finally prepared according to the preparation protocol of example 1, substituting the appropriate starting materials and reagents.
EXAMPLE 2 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 2)
1 H NMR(600MHz,CDCl 3 )δ11.81(s,1H),8.49(d,J＝5.2Hz,1H),8.00(dd,J＝12.0,2.1Hz,1H),7.94(d,J＝4.0Hz,1H),7.57(s,1H),7.51(d,J＝4.0Hz,1H),7.49-7.37(m,4H),7.32(t,J＝8.4Hz,2H),7.23(t,J＝8.6Hz,1H),6.44(d,J＝5.2Hz,1H),4.26(t,J＝6.2Hz,2H),4.03(s,3H),3.69-2.45(m,6H),2.40-2.19(m,2H),2.02-1.67(m,4H),1.65-1.39(m,2H)；MS(ESI)m/z(％):642.3[M+H] + ,664.3[M+Na] + 。
Example 3:N Synthesis of- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 3)
1 H NMR(600MHz,CDCl 3 )δ11.81(s,1H),8.48(d,J＝5.2Hz,1H),8.05-7.97(m,1H),7.93(d,J＝3.9Hz,1H),7.56(s,1H),7.51(d,J＝3.9Hz,1H),7.49-7.39(m,4H),7.31(t,J＝8.3Hz,2H),7.23(t,J＝8.6Hz,1H),6.43(d,J＝5.1Hz,1H),4.25(t,J＝6.6Hz,2H),4.03(s,3H),2.94(d,J＝9.4Hz,2H),2.57(br,2H),2.19-2.11(m,2H),1.98(br,2H),1.63(d,J＝12.2Hz,2H),1.27(d,J＝14.5Hz,3H),0.93(d,J＝6.3Hz,3H)；MS(ESI)m/z:656.3[M+H] + ,678.3[M+Na] + 。
EXAMPLE 4 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 4)
1 H NMR(600MHz,CDCl 3 )δ11.82(s,1H),8.48(d,J＝5.2Hz,1H),8.00(d,J＝10.3Hz,1H),7.93(d,J＝3.9Hz,1H),7.57(s,1H),7.52(d,J＝3.9Hz,1H),7.49-7.39(m,4H),7.31(t,J＝8.3Hz,2H),7.24(t,J＝8.6Hz,1H),6.43(d,J＝5.1Hz,1H),4.26(s,2H),4.04(s,3H),2.86-2.38(m,10H),2.30(s,3H),2.20-2.07(m,3H)；MS(ESI)m/z:657.2[M+H] + ,679.2[M+Na] + 。
EXAMPLE 5 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 5)
1 H NMR(600MHz,CDCl 3 )δ11.83(s,1H),8.50(d,J＝5.0Hz,1H),8.01(d,J＝11.0Hz,1H),7.94(d,J＝3.8Hz,1H),7.59(s,1H),7.52(d,J＝3.9Hz,1H),7.50-7.39(m,4H),7.32(t,J＝8.3Hz,2H),7.26-7.18(m,1H),6.47(d,J＝5.1Hz,1H),4.28(t,J＝5.3Hz,2H),4.03(s,3H),3.52-3.25(m,2H),2.70-2.50(m,2H),2.38-2.06(m,4H),1.98-1.65(m,4H)；MS(ESI)m/z:628.3[M+H] + ,650.3[M+Na] + 。
Example 6:N Synthesis of- {4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 6)
1 H NMR(600MHz,CDCl 3 )δ11.73(s,1H),8.49(d,J＝5.3Hz,1H),7.92(d,J＝4.0Hz,1H),7.87(d,J＝8.9Hz,2H),7.55(s,1H),7.52-7.41(m,4H),7.31(t,J＝8.4Hz,2H),7.19(d,J＝8.9Hz,2H),6.50(d,J＝5.3Hz,1H),4.28(t,J＝6.6Hz,2H),4.03(s,3H),3.74(t,J＝4.4Hz,4H),2.79-2.34(m,6H),2.25-2.05(m,2H).
EXAMPLE 7 Synthesis of N- (4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 7)
MS(ESI)m/z:638.3[M+H] + ,660.3[M+Na] + 。
EXAMPLE 8 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 8)
1 H NMR(600MHz,CDCl 3 )δ11.90(s,1H),8.49(d,J＝5.1Hz,1H),8.14-7.86(m,2H),7.82-7.51(m,5H),7.44(d,J＝4.1Hz,4H),7.25-7.08(m,1H),6.43(s,1H),4.27(t,J＝6.4Hz,2H),4.03(s,3H),3.88-3.48(m,4H),2.73-2.31(m,6H),2.13(d,J＝6.1Hz,2H)；MS(ESI)m/z:626.3[M+H] + ,648.3[M+Na] + 。
EXAMPLE 9 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 9)
1 H NMR(600MHz,CDCl 3 )δ11.89(s,1H),8.48(d,J＝5.0Hz,1H),8.00(d,J＝11.8Hz,1H),7.93(d,J＝3.6Hz,1H),7.69-7.51(m,5H),7.51-7.36(m,4H),7.23(t,J＝8.5Hz,1H),6.43(d,J＝4.9Hz,1H),4.25(t,J＝6.4Hz,2H),4.03(s,3H),2.64-2.35(m,6H),2.18-2.10(m,2H),1.67-1.55(m,4H),1.50-1.39(m,2H)；MS(ESI)m/z(％):624.3[M+H] + ,646.3[M+Na] + 。
EXAMPLE 10 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 10)
1 H NMR(600MHz,CDCl 3 )δ11.89(s,1H),8.49(d,J＝4.6Hz,1H),8.00(d,J＝11.6Hz,1H),7.94(d,J＝2.8Hz,1H),7.74-7.52(m,5H),7.51-7.35(m,4H),7.23(t,J＝8.2Hz,1H),6.43(d,J＝4.2Hz,1H),4.25(s,2H),4.03(s,3H),2.97(br,2H),2.61(br,2H),2.17(br,2H),2.02(br,2H),1.69-1.58(m,2H),1.31-1.09(m,3H),0.93(d,J＝5.3Hz,3H)。
EXAMPLE 11 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 11)
1 H NMR(600MHz,CDCl 3 )δ11.90(s,1H),8.48(d,J＝4.3Hz,1H),8.17-7.84(m,2H),7.80-7.52(m,5H),7.51-7.35(m,4H),7.23(t,J＝8.1Hz,1H),6.44(d,J＝4.0Hz,1H),4.27(t,J＝6.2Hz,2H),4.04(s,3H),3.15-2.63(m,10H),2.54(s,3H),2.15(s,2H)；MS(ESI)m/z:639.2[M+H] + ,661.2[M+Na] + 。
EXAMPLE 12 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 12)
1 H NMR(600MHz,CDCl 3 )δ11.89(s,1H),8.49(d,J＝5.1Hz,1H),8.00(d,J＝11.9Hz,1H),7.94(d,J＝3.8Hz,1H),7.73-7.51(m,5H),7.51-7.33(m,4H),7.23(t,J＝8.6Hz,1H),6.43(d,J＝5.1Hz,1H),4.27(t,J＝6.4Hz,2H),4.04(s,3H),2.90-2.73(m,2H),2.72-2.46(m,4H),2.28-2.14(m,2H),1.96-1.71(m,4H)
EXAMPLE 13 Synthesis of N- {4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 13)
MS(ESI)m/z:638.3[M+H] + ,660.3[M+Na] + 。
EXAMPLE 14 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 14)
1 H NMR(600MHz,CDCl 3 )δ11.94(s,1H),8.49(s,1H),8.00(d,J＝11.2Hz,1H),7.92(s,1H),7.55(d,J＝25.1Hz,2H),7.48-7.38(m,4H),7.33(d,J＝6.5Hz,2H),7.23(t,J＝7.5Hz,1H),6.43(s,1H),4.28(br,2H),4.04(s,3H),3.84-3.65(m,4H),2.64-2.55(m,2H),2.54-2.39(m,7H),2.14(br,2H)。
EXAMPLE 15 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 15)
MS(ESI)m/z:652.3[M+H] + ,674.3[M+Na] + 。
EXAMPLE 16 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 16)
MS(ESI)m/z:652.2[M+H] + ,674.2[M+Na] + 。
EXAMPLE 17 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 17)
MS(ESI)m/z:624.3[M+H] + ,646.3[M+Na] + 。
EXAMPLE 18 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 18)
1 H NMR(600MHz,CDCl 3 )δ11.79(s,1H),8.49(d,J＝5.1Hz,1H),8.00(d,J＝11.8Hz,1H),7.93(d,J＝3.8Hz,1H),7.70-7.55(m,3H),7.50(d,J＝3.8Hz,1H),7.48-7.36(m,4H),7.24(t,J＝8.6Hz,1H),6.43(d,J＝5.0Hz,1H),4.28(t,J＝6.5Hz,2H),4.04(s,3H),3.82-3.67(m,4H),2.59(t,J＝6.9Hz,2H),2.55-2.40(m,4H),2.23-2.07(m,2H)。
EXAMPLE 19 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 19)
MS(ESI)m/z:672.3[M+H] + ,694.3[M+Na] + 。
EXAMPLE 20 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 20)
MS(ESI)m/z:673.2[M+H] + ,695.2[M+Na] + 。
EXAMPLE 21 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 21)
1 H NMR(600MHz,CDCl 3 )δ11.95(s,1H),8.49(d,J＝5.0Hz,1H),8.01(d,J＝11.7Hz,1H),7.92(d,J＝3.4Hz,1H),7.58(s,1H),7.54(d,J＝3.4Hz,1H),7.48-7.41(m,2H),7.37(d,J＝8.5Hz,2H),7.23(t,J＝8.5Hz,1H),7.10(d,J＝8.5Hz,2H),6.44(d,J＝4.8Hz,1H),4.28(t,J＝6.3Hz,2H),4.04(s,3H),3.89(s,3H),3.81-3.68(m,4H),2.67-2.58(m,2H),2.57-2.43(m,4H),2.21-2.11(m,2H)。
EXAMPLE 22 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 22)
MS(ESI)m/z:656.3[M+H] + ,676.3[M+Na] + 。
EXAMPLE 23 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 23)
MS(ESI)m/z:669.2[M+H] + ,691.2[M+Na] + 。
EXAMPLE 24 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 24)
MS(ESI)m/z:640.3[M+H] + ,662.3[M+Na] + 。
EXAMPLE 25 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-trifluoromethylphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 25)
1 H NMR(600MHz,CDCl 3 )δ11.71(s,1H),8.48(dd,J＝13.8,5.2Hz,1H),8.15-7.95(m,2H),7.91(d,J＝8.0Hz,2H),7.63(d,J＝7.9Hz,2H),7.57(s,1H),7.52(d,J＝3.4Hz,1H),7.44(br,2H),7.24(t,J＝8.6Hz,1H),6.43(d,J＝4.6Hz,1H),4.28(t,J＝6.0Hz,2H),4.04(s,3H),3.81-3.67(m,4H),2.58(t,J＝6.7Hz,2H),2.54-2.38(m,4H),2.19-2.08(m,2H)。
EXAMPLE 26 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-trifluoromethylphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 26)
MS(ESI)m/z:706.3[M+H] + ,728.3[M+Na] + 。
EXAMPLE 27 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 27)
MS(ESI)m/z:703.1[M+H] + ,725.2[M+Na] + 。
EXAMPLE 28 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 28)
MS(ESI)m/z:716.2[M+H] + ,738.2[M+Na] + 。
EXAMPLE 29 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 29)
MS(ESI)m/z:717.2[M+H] + ,739.2[M+Na] + 。
EXAMPLE 30 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 30)
MS(ESI)m/z:644.1[M+H] + ,666.2[M+Na] + 。
EXAMPLE 31 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 31)
MS(ESI)m/z:656.3[M+H] + ,678.3[M+Na] + 。
EXAMPLE 32 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 32)
MS(ESI)m/z:657.2[M+H] + ,679.2[M+Na] + 。
EXAMPLE 33 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (3-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 33)
MS(ESI)m/z:660.2[M+H] + ,682.2[M+Na] + 。
EXAMPLE 34 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 34)
1 H NMR(600MHz,CDCl 3 )δ11.94(s,1H),8.49(d,J＝4.3Hz,1H),8.13-7.83(m,2H),7.56(d,J＝13.1Hz,2H),7.50-7.35(m,2H),7.23(t,J＝8.2Hz,1H),7.16-6.80(m,3H),6.43(d,J＝4.1Hz,1H),4.28(br,2H),4.04(s,3H),3.97(s,3H),3.94(s,3H),3.84-3.50(m,4H),2.79-2.37(m,6H),2.14(d,J＝6.0Hz,2H)；MS(ESI)m/z:686.3[M+H] + ,708.3[M+Na] + 。
EXAMPLE 35 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 35)
MS(ESI)m/z:699.3[M+H] + ,721.3[M+Na] + 。
EXAMPLE 36 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (3, 4-dichlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 36)
MS(ESI)m/z:694.2[M+H] + ,716.2[M+Na] + 。
EXAMPLE 37 Synthesis of N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (3, 4-difluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 37)
MS(ESI)m/z:662.2[M+H] + ,684.2[M+Na] + 。
EXAMPLE 38 Synthesis of N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3, 4-difluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 38)
MS(ESI)m/z:674.2[M+H] + ,696.2[M+Na] + 。
EXAMPLE 39 Synthesis of N- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 39)
Step 1 Synthesis of 4, 5-dimethoxy-2-nitroacetophenone
3, 4-Dimethoxyacetophenone (120.0 g,0.67 mol) was added to 600mL of methylene chloride, stirred until it was completely dissolved, cooled to-10℃and fuming nitric acid (157.4 g,2.50 mol) was slowly added dropwise thereto, and the mixture was reacted at-5℃for 1 hour. The reaction solution was poured into 500mL of ice water, followed by extraction with 300mL of methylene chloride, and the organic phase was collectedThe organic layer was washed with water until the water layer became colorless, then with saturated brine for 3 times, dried over anhydrous sodium sulfate, suction filtered, the filtrate was distilled off under reduced pressure to remove dichloromethane, and dried to give 139.0g of 4, 5-dimethoxy-2-nitronitroacetophenone as a pale yellow solid. MS (ESI), m/z (%) 226.0[ M+H ]] + ,248.0[M+Na] + 。
Step 2 1 Synthesis of- (4, 5-dimethoxy-2-nitro) phenyl-3-dimethylamino-2-en-1-one
4, 5-dimethoxy-2-nitroacetophenone (113.0 g,0.50 mol) was added to 280mL of toluene, DMF-DMA (179.4 g,1.50 mol) was added, and the reaction was refluxed for 15h. The reaction solution was cooled to 25℃with stirring for crystallization for 4 hours, a large amount of solids were precipitated, and the resulting mixture was suction-filtered and dried to give 113.5g of 1- (4, 5-dimethoxy-2-nitro) phenyl-3-dimethylamino-2-en-1-one as a yellow solid, MS (ESI), m/z (%) was 281.0[ M+H ]] + ,302.9[M+Na] + 。
Step 3 Synthesis of 6, 7-dimethoxy-4 (1H) -quinolinone
1- (4, 5-dimethoxy-2-nitro) phenyl-3-dimethylamino-2-en-1-one (108 g,0.39 mol) was added to 650mL glacial acetic acid, dissolved by stirring, and iron powder (64.7 g,1.16 mol) was slowly added thereto, and the temperature was raised to 90℃for reaction for 1 hour. Cooling the reaction solution to 15 ℃ for crystallization for 3 hours, filtering to obtain a brownish red solid, then adding the brownish red solid into 300mL of absolute methanol, heating to 65 ℃ for refluxing for 1 hour, filtering while the reaction solution is hot, and evaporating the filtrate under reduced pressure to obtain 60.4g of brownish red solid 6, 7-dimethoxy-4 (1H) -quinolinone. MS (ESI), m/z (%) 206.0[ M+H ] ] + 。
Step 44 Synthesis of chloro-6, 7-dimethoxyquinoline
6, 7-dimethoxy-4 (1H) -quinolinone (96.5 g,0.47 mol) was added to 700mL of acetonitrile, and thionyl chloride (383 mL,4 v/w) and DIPEA (121.6 g,0.94 mol) were slowly added in this order with stirring, and the reaction was refluxed for 3 hours. The reaction solution was evaporated to dryness under reduced pressure to give a brown oil, the residue was added to 1.5L of ice water, stirred vigorously, the pH was adjusted to 12-13 with 10% aqueous potassium hydroxide solution at a temperature of not higher than 25℃and a large amount of solid was precipitated, extracted with methylene chloride (200 mL. Times.2), the organic layer was collected, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was evaporated to dryness under reduced pressure to give 90.8g of 4-chloro-6, 7-dimethoxyquinoline as a tan solid. MS (ESI), m/z (%) 224.0[ M+H ]] + 。
Step 5 Synthesis of 6, 7-dimethoxy-4- [ (4-nitrophenyl) oxy ] quinoline
4-chloro-6, 7-dimethoxyquinoline (98.6 g,0.44 mol) was added to chlorobenzene (986 mL,10 v/w), p-nitrophenol (153.3 g,1.1 mol) and DIPEA (113.9 g,0.88 mol) were added sequentially with stirring, and after the addition, the reaction was refluxed for 14h. After the reaction is finished, the reaction solution is cooled to 10 ℃ under stirring, stirred and crystallized for 4 hours, suction filtration is carried out to obtain a yellowish green solid, the solid is dissolved in 600mL of dichloromethane, 10 percent aqueous solution of sodium hydroxide is used for washing until a water layer is colorless, an organic layer is collected, anhydrous sodium sulfate is dried, suction filtration is carried out, the filtrate is decompressed and distilled to remove the dichloromethane to obtain a beige solid 6, 7-dimethoxy-4- [ (4-nitrophenyl) oxy group ]Quinoline 122.9g. MS (ESI), m/z (%) 327.0[ M+H ]] + 。
Step 64 Synthesis of- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline
Reduced iron powder (87.8 g,1.57 mol) and 17mL of concentrated hydrochloric acid were added sequentially to 1300mL of 90% ethanol, the temperature was raised to reflux, and 6, 7-dimethoxy-4- [ (4-nitrophenyl) oxy group was slowly added]Quinoline (85.3 g,0.26 mol) was added and reacted at reflux for 2h. Filtering while hotEvaporating the filtrate under reduced pressure to remove most of the solvent, adding into 10% potassium carbonate aqueous solution (1L), stirring for 5 hr, vacuum filtering, and drying to obtain yellow-white solid 4- [ (6, 7-dimethoxy-4-quinolyl) oxy]Aniline 64.6g. 1 H-NMR(400MHz,DMSO-d 6 ):δ8.42(d,J＝4.1Hz,1H),7.50(s,1H),7.36(s,1H,),6.92(d,J＝7.3Hz,2H),6.66(d,J＝7.3Hz,1H),6.36(d,J＝4.1Hz,1H),5.16(s,2H),3.93(s,6H)；MS(ESI),m/z(％):296.6[M+H] + 。
Step 7 Synthesis of N- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 39)
4- (4-fluorophenyl) -3-oxo-3, 4-dihydropyrazine-2-carboxylic acid (1.20 mmol), 4- [ (6, 7-dimethoxy-4-quinolyl) oxy group, was added to the reaction flask]Aniline (1.00 mmol), HATU (1.20 mmol), triethylamine (1.20 mmol), 10ml DMF and stirring at room temperature for 10 h. The reaction solution was poured into 100mL of 20% aqueous potassium carbonate solution, extracted three times with 50mL of dichloromethane, the organic phases were combined, the organic phase was washed three times with 20% aqueous potassium carbonate solution, the organic layer was washed twice with saturated brine, and the separated organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, the methylene chloride was distilled off under reduced pressure, and the product was isolated by column chromatography, compound 39. 1 H NMR(600MHz,DMSO-d 6 )δ11.19(s,1H),8.48(d,J＝5.2Hz,1H),7.98(d,J＝4.2Hz,1H),7.86(d,J＝8.7Hz,2H),7.73-7.58(m,3H),7.52(s,1H),7.45(t,J＝8.6Hz,2H),7.40(s,1H),7.29(d,J＝8.7Hz,2H),6.49(d,J＝5.2Hz,1H),3.95(s,3H),3.94(s,3H)；MS(ESI),m/z:513.1[M+H] + ,535.1[M+Na] + 。
Examples 40-47 (compounds 40-47) were finally prepared according to the preparation protocol of example 39, substituting the appropriate starting materials and reagents.
EXAMPLE 40 Synthesis of N- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 40)
1 H NMR(600MHz,DMSO-d 6 )δ11.20(s,1H),8.48(d,J＝5.2Hz,1H),7.98(d,J＝4.1Hz,1H),7.86(d,J＝8.9Hz,2H),7.65(d,J＝4.2Hz,1H),7.63-7.53(m,5H),7.52(s,1H),7.40(s,1H),7.30(d,J＝8.9Hz,2H),6.49(d,J＝5.2Hz,1H),3.95(s,3H),3.94(s,3H)；MS(ESI),m/z:495.0[M+H] + ,517.0[M+Na] + 。
EXAMPLE 41 Synthesis of N- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 41)
MS(ESI),m/z:509.1[M+H] + ,531.1[M+Na] + 。
EXAMPLE 42 Synthesis of N- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 42)
MS(ESI),m/z:529.1[M+H] + ,551.1[M+Na] + 。
EXAMPLE 43 Synthesis of N- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 43)
1 H NMR(600MHz,CDCl 3 )δ11.82(s,1H),8.50(d,J＝3.9Hz,1H),8.23-7.77(m,2H),7.59(s,1H),7.55-7.39(m,5H),7.39-7.28(m,2H),7.23(d,J＝8.3Hz,1H),6.45(d,J＝3.7Hz,1H),4.07(s,3H),4.06(s,3H)；MS(ESI),m/z:531.2[M+H] + ,553.2[M+Na] + 。
EXAMPLE 44 Synthesis of N- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 44)
1 H NMR(600MHz,DMSO-d 6 )δ11.34(s,1H),8.49(d,J＝5.2Hz,1H),8.19-7.89(m,2H),7.66(d,J＝4.2Hz,1H),7.63-7.52(m,7H),7.49(t,J＝8.9Hz,1H),7.42(s,1H),6.51(d,J＝5.1Hz,1H),3.96(s,6H)；MS(ESI),m/z:513.2[M+H] + ,535.2[M+Na] + 。
EXAMPLE 45 Synthesis of N- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 45)
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MS(ESI),m/z:527.2[M+H] + ,549.2[M+Na] + 。
EXAMPLE 46 Synthesis of N- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 46)
1 H NMR(600MHz,DMSO-d 6 )δ11.78(d,J＝2.1Hz,1H),8.76-8.37(m,2H),8.07(d,J＝4.1Hz,1H),7.79(d,J＝4.0Hz,1H),7.72-7.56(m,2H),7.56-7.32(m,5H),7.19(dd,J＝9.1,2.7Hz,1H),6.61(d,J＝5.2Hz,1H),3.95(s,3H),3.93(s,3H)；MS(ESI),m/z:531.1[M+H] + ,553.1[M+Na] + 。
EXAMPLE 47 Synthesis of N- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 47)
1 H NMR(600MHz,DMSO-d 6 )δ11.81(s,1H),8.50(dd,J＝6.8,5.1Hz,2H),8.08(d,J＝3.9Hz,1H),7.80(d,J＝3.9Hz,1H),7.65-7.53(m,5H),7.49(s,1H),7.45-7.36(m,2H),7.19(d,J＝6.8Hz,1H),6.61(d,J＝5.1Hz,1H),3.95(s,3H),3.93(s,3H)；MS(ESI),m/z:513.0[M+H] + ,535.0[M+Na] + 。
EXAMPLE 48 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 48)
Compound 48
Step 1 Synthesis of N- (4-chloropyridin-2-yl) cyclopropylcarboxamide
8.80g of 2-amino-4-chloropyridine and 20.80g of triethylamine are dissolved in 80mL of methylene chloride, 30mL of a methylene chloride solution containing 9.30g of cyclopropylcarboxychloride is added dropwise to the solution under ice-bath conditions, and the solution is warmed to room temperature after the addition. Stirring for 12h, and after the reaction, using 20% K 2 CO 3 The solution and saturated saline water are respectively washed for 3 times, an organic phase is separated, dried by anhydrous sodium sulfate, filtered and evaporated to dryness to obtain a crude product, and the crude product is separated by column chromatography to obtain white solid N- (4-chloropyridine-2-yl) cyclopropylcarboxamide. MS (ESI) m/z (%) 197.1[ M+H ]] + 。
Step 2 Synthesis of N- [4- (2-fluoro-4-nitrophenoxy) -2-pyridinyl ] cyclopropylcarboxamide
8.00g of N- (4-chloropyridin-2-yl) cyclopropylcarboxamide and 15.98g of 2-fluoro-4-nitrophenol were added to 100mL of chlorobenzene and reacted at 140℃for 40h. Cooled to room temperature, concentrated under reduced pressure, and the residue is dissolved in an appropriate amount of dichloromethane to K 2 CO 3 Washing the solution and saturated saline solution for 3 times respectively, separating out organic phase, drying with anhydrous sodium sulfate, filtering, evaporating solvent to obtain brown solid, and column chromatography to obtain light yellow solid product N- [4- (2-fluoro-4-nitrophenoxy) -2-pyridyl]Cyclopropyl carboxamides. 1 H NMR(600MHz,DMSO-d 6 )δ11.00(s,1H),8.43(m,1H),8.30(d,J＝5.7Hz,1H),8.19(m,1H),7.76(d,J＝2.2Hz,1H),7.61(t,J＝8.5Hz,1H),6.86(m,1H),2.04-1.95(m,1H),0.78(t,J＝6.3Hz,4H)。
Step 3 Synthesis of N- [4- (4-amino-2-fluorophenoxy) -2-pyridinyl ] cyclopropylcarboxamide
N- [4- (2-fluoro-4-nitrophenoxy) -2-pyridinyl]6.00g of cyclopropyl formamide, 5.28g of iron powder and 11.36g of acetic acid are added into 100mL of ethyl acetate, then 20mL of water is added, heating reflux is carried out for 2h, the reaction is completed, the hot filtration is carried out, the organic phase is separated, anhydrous sodium sulfate is dried, the filtration is carried out, the solvent is evaporated under reduced pressure to obtain white solid N- [4- (4-amino-2-fluorophenoxy) -2-pyridyl]Cyclopropyl carboxamides. 1 H NMR(600MHz,DMSO-d 6 )δ10.79(s,1H),8.15(d,J＝5.7Hz,1H),7.59(s,1H),6.95(t,J＝9.0Hz,1H),6.67-6.61(m,1H),6.49(dd,J＝13.1,2.2Hz,1H),6.40(d,J＝8.7Hz,1H),5.44(s,2H),2.03-1.88(m,1H),0.76(br,4H)。
Step 4 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 48)
Into the reaction flask was charged 4- (4-fluorophenyl) -3-oxo-3, 4-dihydropyrazine-2-carboxylic acid (1.20 mmol), N- [4 ](4-amino-2-fluorophenoxy) -2-pyridinyl]Cyclopropylcarboxamide (1.00 mmol), HATU (1.20 mmol), triethylamine (1.20 mmol), 10ml DMF and stirring at room temperature for 10 h. The reaction solution was poured into 100mL of 20% aqueous potassium carbonate solution, extracted three times with 50mL of dichloromethane, the organic phases were combined, the organic phase was washed three times with 20% aqueous potassium carbonate solution, the organic layer was washed twice with saturated brine, and the separated organic layer was dried over anhydrous sodium sulfate. Filtering, evaporating dichloromethane under reduced pressure, and separating by column chromatography to obtain the product. 1 H NMR(600MHz,CDCl 3 )δ11.76(s,1H),8.30(s,1H),8.11(d,J＝5.7Hz,1H),8.02-7.86(m,2H),7.78(s,1H),7.50(d,J＝4.0Hz,1H),7.48-7.42(m,2H),7.38(d,J＝8.7Hz,1H),7.31(t,J＝8.4Hz,2H),7.14(t,J＝8.6Hz,1H),6.60(dd,J＝5.9,2.4Hz,1H),1.51(m,1H),1.13-0.99(m,2H),0.94-0.76(m,2H).
Examples 49-76 (compounds 49-76) were finally prepared according to the preparation protocol of example 48, substituting the appropriate starting materials and reagents.
EXAMPLE 49 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 49)
1 H NMR(600MHz,CDCl 3 )δ11.84(s,1H),8.19(s,1H),8.10(d,J＝5.7Hz,1H),8.02-7.87(m,2H),7.79(s,1H),7.61(dq,J＝14.7,7.3Hz,3H),7.52(d,J＝4.0Hz,1H),7.45(d,J＝7.2Hz,2H),7.39(d,J＝8.3Hz,1H),7.14(t,J＝8.7Hz,1H),6.59(dd,J＝5.7,2.1Hz,1H),1.53-1.47(m,1H),1.10-1.03(m,2H),0.90-0.83(m,2H)。
EXAMPLE 50 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 50)
1 H NMR(600MHz,DMSO-d 6 )δ11.34(s,1H),10.87(s,1H),8.20(d,J＝5.7Hz,1H),8.07-7.88(m,2H),7.79-7.59(m,2H),7.54(d,J＝8.7Hz,1H),7.49(d,J＝8.9Hz,2H),7.38(t,J＝8.9Hz,1H),7.12(d,J＝8.9Hz,2H),6.87-6.59(m,1H),3.84(s,3H),2.06-1.76(m,1H),0.91-0.63(m,4H)；MS(ESI)m/z:516.1[M+H] + ,538.0[M+Na] + 。
EXAMPLE 51 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 51)
1 H NMR(600MHz,DMSO-d 6 )δ11.28(s,1H),10.87(s,1H),8.20(d,J＝4.5Hz,1H),7.99(d,J＝2.2Hz,1H),7.94(d,J＝12.6Hz,1H),7.88-7.58(m,6H),7.54(d,J＝8.6Hz,1H),7.38(t,J＝8.2Hz,1H),6.98-6.51(m,1H),2.22-1.72(m,1H),1.11-0.30(m,4H)；MS(ESI)m/z:520.0[M+H] + ,542.0[M+Na] + 。
EXAMPLE 52 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-trifluoromethylphenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 52)
1 H NMR(600MHz,DMSO-d 6 )δ11.26(s,1H),10.87(s,1H),8.21(d,J＝5.7Hz,1H),8.04(d,J＝4.1Hz,1H),8.00(d,J＝8.3Hz,2H),7.95(d,J＝10.9Hz,1H),7.84(d,J＝8.2Hz,2H),7.76-7.61(m,2H),7.54(d,J＝8.7Hz,1H),7.39(t,J＝8.9Hz,1H),6.73(dd,J＝5.5,1.9Hz,1H),2.14-1.82(m,1H),0.93-0.66(m,4H)；MS(ESI)m/z:554.2[M+H] + ,576.2[M+Na] + 。
EXAMPLE 53 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 53)
1 H NMR(600MHz,DMSO-d 6 )δ11.27(s,1H),10.87(s,1H),8.21(d,J＝5.7Hz,1H),8.02(d,J＝4.1Hz,1H),7.95(dd,J＝12.7,1.8Hz,1H),7.78-7.61(m,3H),7.56(t,J＝9.2Hz,2H),7.50-7.29(m,3H),6.73(dd,J＝5.6,2.1Hz,1H),2.11-1.85(m,1H),0.90-0.67(m,4H)；MS(ESI)m/z:504.2[M+H] + ,526.2[M+Na] + 。
EXAMPLE 54 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 54)
1 H NMR(600MHz,DMSO-d 6 )δ11.27(s,1H),10.87(s,1H),8.20(d,J＝5.7Hz,1H),7.99(d,J＝4.2Hz,1H),7.94(dd,J＝12.8,2.1Hz,1H),7.81(d,J＝8.6Hz,2H),7.65(d,J＝4.1Hz,2H),7.58-7.48(m,3H),7.38(t,J＝8.9Hz,1H),6.73(dd,J＝5.7,2.3Hz,1H),2.08-1.86(m,1H),0.76(dd,J＝15.5,6.4Hz,4H)。
EXAMPLE 55 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 55)
1 H NMR(600MHz,DMSO-d 6 )11.32(s,1H),10.87(s,1H),8.20(d,J＝5.7Hz,1H),8.05-7.86(m,2H),7.65(dd,J＝7.5,3.0Hz,2H),7.53(d,J＝8.7Hz,1H),7.44(d,J＝8.2Hz,2H),7.41-7.21(m,3H),6.73(dd,J＝5.6,2.2Hz,1H),2.40(s,3H),2.07-1.87(m,1H),0.88-0.67(m,4H)；MS(ESI)m/z:500.2[M+H] + ,522.2[M+Na] + 。
EXAMPLE 56 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (3-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 56)
1 H NMR(600MHz,DMSO-d 6 )δ11.27(s,1H),10.87(s,1H),8.20(d,J＝5.6Hz,1H),8.02(d,J＝4.1Hz,1H),7.95(d,J＝12.5Hz,1H),7.76(s,1H),7.73-7.59(m,4H),7.55(d,J＝9.4Hz,2H),7.38(t,J＝8.9Hz,1H),6.95-6.52(m,1H),2.10-1.78(m,1H),0.90-0.57(m,4H)；MS(ESI)m/z:520.2[M+H] + ,542.2[M+Na] + 。
EXAMPLE 57 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 57)
1 H NMR(600MHz,DMSO-d 6 )δ11.35(s,1H),10.87(s,1H),8.21(d,J＝5.7Hz,1H),8.04-7.90(m,2H),7.75-7.60(m,2H),7.54(d,J＝8.2Hz,1H),7.38(t,J＝8.9Hz,1H),7.19(d,J＝2.1Hz,1H),7.13(d,J＝8.6Hz,1H),7.08(dd,J＝8.5,2.2Hz,1H),6.74(dd,J＝5.7,2.3Hz,1H),3.83(s,3H),3.79(s,3H),2.07-1.87(m,1H),0.86-0.66(m,4H)；MS(ESI)m/z:546.1[M+H] + ,568.1[M+Na] + 。
EXAMPLE 58 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (3, 4-difluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 58)
1 H NMR(600MHz,DMSO-d 6 )δ11.26(s,1H),10.87(s,1H),8.21(d,J＝5.7Hz,1H),8.00(d,J＝4.1Hz,1H),7.95(dd,J＝12.7,2.0Hz,1H),7.89-7.79(m,1H),7.77-7.61(m,3H),7.55(d,J＝8.7Hz,1H),7.50(d,J＝8.7Hz,1H),7.39(t,J＝8.9Hz,1H),6.73(dd,J＝5.6,2.2Hz,1H),2.05-1.83(m,1H),0.97-0.50(m,4H)；MS(ESI)m/z:522.0[M+H] + ,544.0[M+Na] + 。
EXAMPLE 59 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (3, 4-dichlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 59)
1 H NMR(600MHz,DMSO-d 6 )δ11.24(s,1H),10.87(s,1H),8.21(d,J＝5.7Hz,1H),8.10-7.98(m,2H),7.97-7.92(m,1H),7.90(d,J＝8.6Hz,1H),7.76-7.59(m,3H),7.55(d,J＝8.7Hz,1H),7.38(t,J＝8.9Hz,1H),6.73(dd,J＝5.5,2.0Hz,1H),2.06-1.87(m,1H),0.77(t,J＝6.4Hz,4H)。
EXAMPLE 60 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 60)
1 H NMR(600MHz,CDCl 3 )δ11.85(s,1H),8.10(d,J＝5.8Hz,1H),8.02(s,1H),7.96(dd,J＝12.2,2.3Hz,1H),7.92(d,J＝4.0Hz,1H),7.87-7.75(m,1H),7.69-7.56(m,3H),7.52(d,J＝4.0Hz,1H),7.45(d,J＝7.1Hz,2H),7.40(d,J＝8.7Hz,1H),7.15(t,J＝8.7Hz,1H),6.58(dd,J＝5.7,2.2Hz,1H),2.16(s,3H)；MS(ESI)m/z:460.0[M+H] + ,482.0[M+Na] + 。
EXAMPLE 61 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 61)
1 H NMR(600MHz,DMSO-d 6 )δ11.31(s,1H),10.57(s,1H),8.19(d,J＝5.7Hz,1H),8.00(d,J＝4.2Hz,1H),7.95(dd,J＝12.8,2.2Hz,1H),7.76-7.60(m,4H),7.59-7.51(m,1H),7.45(t,J＝8.8Hz,2H),7.39(t,J＝9.0Hz,1H),6.70(dd,J＝5.7,2.3Hz,1H),2.04(s,3H)；MS(ESI)m/z:478.0[M+H] + ,500.0[M+Na] + 。
EXAMPLE 62 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 62)
1 H NMR(600MHz,DMSO-d 6 )δ11.35(s,1H),10.57(s,1H),8.19(d,J＝5.7Hz,1H),8.04-7.89(m,2H),7.78-7.60(m,2H),7.54(d,J＝8.1Hz,1H),7.49(d,J＝8.8Hz,2H),7.39(t,J＝8.9Hz,1H),7.12(d,J＝8.9Hz,2H),6.70(dd,J＝5.6,2.2Hz,1H),3.84(s,3H),2.04(s,3H)；MS(ESI)m/z:490.0[M+H] + ,512.0[M+Na] + 。
EXAMPLE 63 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 63)
1 H NMR(600MHz,DMSO-d 6 )δ11.28(s,1H),10.57(s,1H),8.19(d,J＝5.7Hz,1H),7.99(d,J＝4.1Hz,1H),7.95(d,J＝12.7Hz,1H),7.82-7.59(m,6H),7.54(d,J＝8.5Hz,1H),7.39(t,J＝8.9Hz,1H),6.70(dd,J＝5.5,2.0Hz,1H),2.04(s,3H)；MS(ESI)m/z:494.0[M+H] + ,516.0[M+Na] + 。
EXAMPLE 64 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 64)
1 H NMR(600MHz,DMSO-d 6 )δ11.27(s,1H),10.57(s,1H),8.19(d,J＝5.6Hz,1H),7.97(dd,J＝25.1,8.1Hz,2H),7.81(d,J＝8.3Hz,2H),7.73-7.61(m,2H),7.55(t,J＝7.7Hz,3H),7.39(t,J＝8.8Hz,1H),6.70(d,J＝4.2Hz,1H),2.04(s,3H)。
EXAMPLE 65 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 65)
1 H NMR(600MHz,DMSO-d 6 )δ11.32(s,1H),10.57(s,1H),8.19(d,J＝5.5Hz,1H),8.03-7.89(m,2H),7.76-7.61(m,2H),7.54(d,J＝8.5Hz,1H),7.42(dd,J＝28.8,6.9Hz,5H),6.70(d,J＝3.3Hz,1H),2.40(s,3H),2.04(s,3H)；MS(ESI)m/z:474.0[M+H] + ,496.0[M+Na] + 。
EXAMPLE 66 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 66)
1 H NMR(600MHz,DMSO-d 6 )δ11.35(s,1H),10.57(s,1H),8.19(d,J＝5.7Hz,1H),8.05-7.89(m,2H),7.73-7.60(m,2H),7.54(d,J＝8.4Hz,1H),7.39(t,J＝8.9Hz,1H),7.19(d,J＝1.9Hz,1H),7.16-7.00(m,2H),6.70(dd,J＝5.6,2.1Hz,1H),3.83(s,3H),3.79(s,3H),2.04(s,3H)。
EXAMPLE 67 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 67)
1 H NMR(600MHz,DMSO-d 6 )δ11.18(s,1H),10.82(s,1H),8.18(d,J＝5.7Hz,1H),7.98(d,J＝4.2Hz,1H),7.81(d,J＝8.9Hz,2H),7.65(d,J＝4.2Hz,2H),7.62-7.50(m,5H),7.18(d,J＝8.9Hz,2H),6.68(dd,J＝5.7,2.3Hz,1H),2.09-1.85(m,1H),0.92-0.64(m,4H)；MS(ESI)m/z(％):468.1[M+H] + ,490.0[M+Na] + 。
EXAMPLE 68 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 68)
1 H NMR(600MHz,DMSO-d 6 )δ11.17(s,1H),10.82(s,1H),8.18(d,J＝5.7Hz,1H),7.97(d,J＝4.2Hz,1H),7.80(d,J＝8.9Hz,2H),7.71-7.58(m,4H),7.45(t,J＝8.8Hz,2H),7.18(d,J＝8.9Hz,2H),6.68(dd,J＝5.7,2.3Hz,1H),2.10-1.83(m,1H),0.85-0.68(m,4H)；MS(ESI)m/z(％):486.1[M+H] + ,508.0[M+Na] + 。
EXAMPLE 69 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] phenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 69)
1 H NMR(600MHz,DMSO-d 6 )δ11.20(s,1H),10.82(s,1H),8.18(d,J＝5.7Hz,1H),7.94(d,J＝4.2Hz,1H),7.80(d,J＝9.0Hz,2H),7.70-7.58(m,2H),7.49(d,J＝8.9Hz,2H),7.18(d,J＝8.9Hz,2H),7.12(d,J＝9.0Hz,2H),6.68(dd,J＝5.7,2.4Hz,1H),3.83(s,3H),2.03-1.85(m,1H),0.88-0.64(m,4H)；MS(ESI)m/z(％):498.1[M+H] + ,520.0[M+Na] + 。
EXAMPLE 70 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] phenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 70)
1 H NMR(600MHz,DMSO-d 6 )δ11.14(s,1H),10.82(s,1H),8.18(d,J＝5.4Hz,1H),7.97(d,J＝3.9Hz,1H),7.80(d,J＝8.5Hz,2H),7.74-7.39(m,6H),7.18(d,J＝8.5Hz,2H),6.68(d,J＝3.5Hz,1H),2.15-1.75(m,1H),1.04-0.50(m,4H)；MS(ESI)m/z(％):502.0[M+H] + ,524.0[M+Na] + 。
EXAMPLE 71 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] phenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 71)
1 H NMR(600MHz,DMSO-d 6 )δ11.18(s,1H),10.82(s,1H),8.18(d,J＝5.7Hz,1H),7.94(d,J＝4.1Hz,1H),7.80(d,J＝8.7Hz,2H),7.64(dd,J＝10.3,2.9Hz,2H),7.44(d,J＝8.1Hz,2H),7.39(d,J＝8.1Hz,2H),7.18(d,J＝8.7Hz,2H),6.68(dd,J＝5.5,1.9Hz,1H),2.40(s,3H),2.04-1.88(m,1H),0.89-0.66(m,4H)；MS(ESI)m/z(％):482.2[M+H] + ,504.2[M+Na] + 。
EXAMPLE 72 Synthesis of N- {4- [2- (cyclopropanecarboxamide) pyridin-4-yloxy ] phenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 72)
1 H NMR(600MHz,DMSO-d 6 )δ11.22(s,1H),10.82(s,1H),8.18(d,J＝5.7Hz,1H),7.94(d,J＝4.1Hz,1H),7.81(d,J＝8.9Hz,2H),7.72-7.54(m,2H),7.18(dd,J＝5.6,3.1Hz,3H),7.13(d,J＝8.6Hz,1H),7.08(dd,J＝8.6,2.2Hz,1H),6.68(dd,J＝5.7,2.3Hz,1H),3.83(s,3H),3.79(s,3H),2.10-1.83(m,1H),0.87-0.66(m,4H)；MS(ESI)m/z(％):528.1[M+H] + ,550.1[M+Na] + 。
EXAMPLE 73 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide (Compound 73)
1 H NMR(600MHz,DMSO-d 6 )δ11.18(s,1H),10.52(s,1H),8.17(d,J＝5.7Hz,1H),7.98(d,J＝4.2Hz,1H),7.81(d,J＝8.9Hz,2H),7.74-7.63(m,2H),7.63-7.44(m,5H),7.19(d,J＝8.9Hz,2H),6.65(dd,J＝5.7,2.4Hz,1H),2.04(s,3H)；MS(ESI)m/z:442.0[M+H] + ,464.0[M+Na] + 。
EXAMPLE 74 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide (compound 74)
1 H NMR(600MHz,DMSO-d 6 )δ11.17(s,1H),10.52(s,1H),8.17(d,J＝5.7Hz,1H),7.97(d,J＝4.2Hz,1H),7.81(d,J＝8.9Hz,2H),7.73-7.54(m,4H),7.44(t,J＝8.8Hz,2H),7.19(d,J＝8.9Hz,2H),6.65(dd,J＝5.7,2.3Hz,1H),2.04(s,3H)；MS(ESI)m/z:460.1[M+H] + ,482.1[M+Na] + 。
EXAMPLE 75 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] phenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 75)
1 H NMR(600MHz,DMSO-d 6 )δ11.21(s,1H),10.52(s,1H),8.17(d,J＝5.7Hz,1H),7.94(d,J＝4.1Hz,1H),7.81(d,J＝8.8Hz,2H),7.66(s,1H),7.63(d,J＝4.1Hz,1H),7.49(d,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,2H),7.12(d,J＝8.9Hz,2H),6.65(dd,J＝5.6,2.2Hz,1H),3.83(s,3H),2.04(s,3H)；MS(ESI)m/z:472.0[M+H] + ,494.0[M+Na] + 。
EXAMPLE 76 Synthesis of N- {4- [2- (acetamido) pyridin-4-yloxy ] phenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide (Compound 76)
1 H NMR(600MHz,DMSO-d 6 )δ11.22(s,1H),10.52(s,1H),8.17(d,J＝5.2Hz,1H),7.94(d,J＝3.3Hz,1H),7.81(d,J＝8.2Hz,2H),7.73-7.44(m,2H),7.38-6.79(m,5H),6.65(d,J＝3.2Hz,1H),3.83(s,3H),3.79(s,3H),2.04(s,3H)；MS(ESI)m/z:502.1[M+H] + ,424.1[M+Na] + 。
Example 47 in vitro anti-tumor cell Activity
The novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compounds with the general formula (I) are subjected to in vitro activity screening for inhibiting human lung adenocarcinoma A549, human gastric cancer cell strain MKN45, human lung cancer cell H460, human liver cancer cell HepG2, human chronic myelogenous leukemia cell K562, human gastrointestinal stromal tumor cell GIST882, imatinib-resistant human gastrointestinal stromal tumor cell GIST1210 and human colon cancer cell HCT 116.
(1) After resuscitating and passaging 2-3 times for stabilization, the cells were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digests into a centrifuge tube, the culture broth is then added to terminate digestion. Centrifuging the centrifuge tube at 800r/min for 10min, removing supernatant, adding 5mL of culture solution, blowing and mixing uniformly, sucking 10 μL of cell suspension, adding into a cell counting plate, counting, and adjusting cell concentration to 10 4 And/or holes. Except that the A1 well was blank, no cells were added, and 100. Mu.L of the cell suspension was added to the 96-well plate. The 96-well plate was placed in an incubator for cultivation for 24 hours.
(2) The test sample was dissolved with 50. Mu.L of dimethyl sulfoxide, then an appropriate amount of culture solution was added to dissolve the sample into 2mg/mL of a liquid medicine, and then the sample was diluted to 20,4,0.8,0.16,0.032. Mu.g/mL in a 24-well plate.
3 wells were added at each concentration, wherein the surrounding two rows and columns of cells grew significantly under environmental impact and were used only as blank cells. The 96-well plate was placed in an incubator for culturing for 72 hours.
(3) The medicated culture solution in the 96-well plate was discarded, the cells were washed twice with Phosphate Buffered Saline (PBS), 100. Mu.L of MTT (tetrazolium) (0.5 mg/mL) was added to each well, and after 4 hours in the incubator, the MTT solution was discarded, and 100. Mu.L of dimethyl sulfoxide was added. And (3) oscillating on a magnetic oscillator to enable the living cells and MTT reaction product formazan to be fully dissolved, and putting the dissolved cells and MTT reaction product formazan into an enzyme-labeled instrument to measure the result. Drug IC can be determined by the Bliss method 50 Values. The results of the compounds for inhibiting the activities of human lung adenocarcinoma A549, human gastric cancer cell strain MKN45, human lung cancer cell H460, human liver cancer cell HepG2, human chronic myelogenous leukemia cell K562, human gastrointestinal stromal tumor cell GIST882, imatinib-resistant human gastrointestinal stromal tumor cell GIST1210 and human colon cancer cell HCT116 are shown in the table one, and the IC in the table one 50 Less than or equal to 1.0 mu M, expressed as A, 1.0 mu M < IC 50 Less than or equal to 10.0 mu M, expressed as B, 10.0 mu M < IC 50 And C is equal to or less than 100.0 μm.
List one
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EXAMPLE 48c-Met enzymatic Activity assay
The assay for measuring c-Met kinase activity is based on an enzyme-linked immunosorbent assay (ELISA). The specific operation is as follows: the compound of example, 50pM c-Met (His-tagged recombinant human Met (amino acid 974-terminal), expressed by baculovirus) and 5. Mu.M ATP were assayed on 0.25mg/mLPGT coated plates at room temperatureIn the flushing liquid (25mM MOPS,PH 7.4,5mM MgCl) 2 ,0.5raM MnCl 2 100. Mu.M sodium orthovanadate, 0.01% Triton X-100,1mM DTT, and finally 1% (v/v) DMSO concentration were incubated for 20 minutes. The reaction mixture was removed by washing and the phosphorylated polymer substrate was detected with 0.2 μg/mL of phosphotyrosine specific monoclonal antibody (PY 20) conjugated with horseradish peroxidase (HRP). After the addition of 1M phosphoric acid to terminate the coloration, the color of the substrate (TMB) developed was quantified spectrophotometrically at 450 nm.
The results of the inhibition of c-Met kinase activity by the compounds are shown in Table II, IC in Table 1 50 And +.10.0 nM, expressed as A, 10.0nM < IC 50 And +.100.0 nM, expressed as B, 100.0nM < IC 50 And C is +.1000.0 nM.
And (II) table:
from the above test results, it is clear that the novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compounds of the general formula (I) to be protected in the present invention have good in vitro antitumor activity. The compound has good development and application prospects of anti-tumor medicaments.
While the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the specific details of the above embodiments, and various equivalent modifications can be made to the technical solutions of the present invention within the scope of the technical concept of the present invention, and various possible combinations will not be described further in order to avoid unnecessary repetition. Any modification, equivalent replacement or improvement made within the technical concept of the present invention is included in the protection scope of the present invention.
Claims (9)
1. Novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compounds and pharmaceutically acceptable salts thereof, wherein the structural formula is shown in the general formula (I):
Wherein:
x is selected from 1 to 4 identical or different substituents: hydrogen, halogen, C 1 -C 10 Alkyl, or C 1 -C 4 An alkoxy group;
ar is selected from 6-10 membered aryl or 5-10 membered heteroaryl; wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S and Ar is optionally substituted with 1 to 3R' S, which may be the same or different 1 Substituted;
R 1 is hydrogen, hydroxy, halogen, nitro, amino, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, optionally C by hydroxy or amino or halogen 1 -C 6 Alkyl, optionally hydroxy or amino or halogenated C 1 -C 6 Alkoxy, singly or di-C 1 -C 6 Alkyl-substituted amino, C 1 -C 6 Alkylamido, free or salified or esterified or amidated carboxyl groups, C 1 -C 6 Alkylsulfinyl, sulfonyl, C 1 -C 6 Alkanoyl, carbamoyl, mono-or di-C 1 -C 6 An alkyl-substituted carbamoyl group;
a is selected from
R 2 And R is 3 The same or different are each independently selected from hydrogen, C 1 -C 10 Alkyl or C 3 -C 7 Cycloalkyl;
or R is 2 And R is 3 Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclic group, said heterocyclic group being other than R 2 And R is 3 Optionally containing 1-4 heteroatoms selected from N, O and S, optionally including 1 or 2 carbon-carbon double bonds, in addition to the attached nitrogen atomOr triple bonds, optionally interrupted by 1 to 3 identical or different R 6 Substitution;
R 6 selected from C 1 -C 6 Alkyl or C 1 -C 4 An alkoxy group;
R 4 selected from C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 1 -C 6 Alkyl substituted C 1 -C 6 An alkyl group;
R 5 selected from hydrogen, C 1 -C 10 Alkyl, C 3 -C 7 Cycloalkyl, or halogenated C 1 -C 10 An alkyl group.
2. The novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compounds and pharmaceutically acceptable salts thereof as claimed in claim 1,
x is selected from 1 to 4 identical or different substituents: hydrogen or halogen;
ar is selected from C 6 -C 10 Meta-aryl, C 6 -C 10 Aralkyl radicals or C 5 -C 10 A membered heteroaryl group; the heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 1 to 5R' S, which may be the same or different 1 Substituted;
said R is 1 Selected from hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl or C 1 -C 6 An alkoxy group;
a is selected from
R 2 And R is 3 The same or different, each independently selecting C 1 -C 10 An alkyl group;
or R is 2 And R is 3 Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclic group, said heterocyclic group being other than R 2 And R is 3 Optionally containing 1 to 4 hetero atoms selected from N, O and S, optionally including 1 or 2 carbon-carbon double or triple bonds, optionally substituted with 1 to 3 identical or different R' S, in addition to the attached nitrogen atom 6 Substitution;
R 6 selected from C 1 -C 6 An alkyl group;
R 4 selected from C 1 -C 6 Alkyl or C 1 -C 6 Alkyl substituted C 1 -C 6 An alkyl group;
R 5 selected from C 1 -C 10 An alkyl group.
3. A novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compound and pharmaceutically acceptable salts thereof as claimed in claim 2,
x is selected from 1-2 identical or different substituents: hydrogen or fluorine;
ar is selected from phenyl, pyridyl, thiophene, furan, naphthyl, quinolinyl or indolyl, and Ar is optionally substituted with 1-5R's, which may be the same or different 1 Substituted;
said R is 1 Selected from hydrogen, halogen, trifluoromethyl, C 1 -C 6 Alkyl or C 1 -C 6 An alkoxy group;
a is selected from
R 2 And R is 3 Forms, together with the nitrogen atom to which they are attached, 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl or 1-pyrrolidinyl;
R 4 selected from methyl, ethyl, n-propyl, methoxypropyl or ethoxypropyl;
R 5 selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
4. A novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein the compound of formula (I) is selected from the group consisting of:
Compound 1: n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 2: n- (3-fluoro-4- { 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
the compound 3:N- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 4 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 5 n- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 6:N- {4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide; compound 7 n- (4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 8, n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide; compound 9 n- (3-fluoro-4- { 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
Compound 10, n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 11, n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 12, n- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 13, n- {4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 14, n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 15 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -4- (4-fluorophenyl) -3-oxo-3, 4-dihydropyrazine-2-carboxamide;
compound 16 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 17 n- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 18:n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 19 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 20 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 21, n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 22, n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 23 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 24 n- (3-fluoro-4- { 6-methoxy-7- [3- (1-tetrahydropyrrolidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 25:n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-trifluoromethylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 26 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-trifluoromethylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 27 n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 28 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 29 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 30:n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 31 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 32, n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 33, n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (3-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 34 n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 35 n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 36, n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl } -3-oxo-4- (3, 4-dichlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 37 n- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl } -3-oxo-4- (3, 4-difluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 38, n- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-yloxy } phenyl) -3-oxo-4- (3, 4-difluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 39 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 40 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 41 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 42 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 43 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 44 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 45 n- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 46, n- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 47, n- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
Compound 48 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide; compound 49 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 50:n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 51, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide; compound 52, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-trifluoromethylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 53 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (3-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide; compound 54, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide; compound 55, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-methylphenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 56 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (3-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide; compound 57 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 58 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (3, 4-difluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 59 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (3, 4-dichlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 60:n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 61, n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 62, n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-bromophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 65 n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 66, n- {4- [2- (acetamido) pyridin-4-oxy ] -3-fluorophenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 67: n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide;
compound 68, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 69 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 70: n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 71 n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-chlorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 72, n- {4- [2- (cyclopropanecarboxamide) pyridin-4-oxy ] phenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 73, n- {4- [2- (acetamido) pyridin-4-oxy ] phenyl } -3-oxo-4-phenyl-3, 4-dihydropyrazine-2-carboxamide; compound 74, n- {4- [2- (acetamido) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-fluorophenyl) -3, 4-dihydropyrazine-2-carboxamide;
Compound 75 n- {4- [2- (acetamido) pyridin-4-oxy ] phenyl } -3-oxo-4- (4-methoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide;
compound 76N- {4- [2- (acetamido) pyridin-4-yloxy ] phenyl } -3-oxo-4- (3, 4-dimethoxyphenyl) -3, 4-dihydropyrazine-2-carboxamide.
5. A pharmaceutical composition comprising a novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamide compound as defined in any one of claims 1 to 4 and pharmaceutically acceptable salts thereof as active ingredient together with pharmaceutically acceptable excipients.
6. Use of a novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamides compound as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 5 for the preparation of a medicament for the treatment and/or prophylaxis of diseases caused by abnormally high expression of c-Met kinase.
7. Use of a novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamides compound as defined in any of claims 1 to 4, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 5 for the preparation of a medicament for the treatment and/or prophylaxis of proliferative diseases.
8. Use of a novel 3-oxo-4-substituted aryl-3, 4-dihydropyrazine-2-carboxamides compound as defined in any of claims 1 to 4, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 5 for the preparation of a medicament for the treatment and/or prophylaxis of cancer.
9. The use according to claim 8, wherein the cancer comprises lung cancer, stomach cancer, liver cancer, leukemia, gastrointestinal stromal tumor and colon cancer.
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