CN105461687B - Dihydropyridazinone-containing quinoline compound and application thereof - Google Patents
Dihydropyridazinone-containing quinoline compound and application thereof Download PDFInfo
- Publication number
- CN105461687B CN105461687B CN201410425226.6A CN201410425226A CN105461687B CN 105461687 B CN105461687 B CN 105461687B CN 201410425226 A CN201410425226 A CN 201410425226A CN 105461687 B CN105461687 B CN 105461687B
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- China
- Prior art keywords
- phenyl
- methyl
- dihydropyridazinone
- oxo
- propoxy
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- -1 quinoline compound Chemical class 0.000 title claims description 79
- SSDAKJLEKSSAMH-UHFFFAOYSA-N 2,4-dihydro-1h-pyridazin-3-one Chemical compound O=C1CC=CNN1 SSDAKJLEKSSAMH-UHFFFAOYSA-N 0.000 title abstract description 11
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 22
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- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 230000014509 gene expression Effects 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 58
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 43
- 238000006467 substitution reaction Methods 0.000 claims description 32
- 150000003254 radicals Chemical class 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 14
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims description 12
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- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 9
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 7
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
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- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 abstract description 2
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to dihydropyridazinone-containing quinoline derivatives shown as a general formula I, and pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein substituents Ar and R are1、R2、R3X, Y, n have the meaning given in the description. The invention also relates to a compound of the general formula I, which has a strong effect of inhibiting c-Met kinase, and also relates to application of the compound and pharmaceutically acceptable salts, solvates or prodrugs thereof in preparing medicines for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase, in particular to application in preparing medicines for treating and/or preventing cancers.
Description
Technical Field
The invention relates to a preparation method of a novel dihydropyridazinone-containing quinoline compound, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, a pharmaceutical composition containing the compound, and application of the compound in preparing a medicament for treating and/or preventing c-Met high-expression cancers.
Technical Field
Protein kinases represent a class of proteins that play an important role in the maintenance of control over cellular function and the regulation of various cellular pathologies. By regulating signal response pathways, protein kinases govern cell metabolism, cell division cycle progression, cell proliferation and apoptosis, differentiation and survival. There are currently 500 human kinase groups, of which up to 150 are associated with various human diseases, such as inflammatory diseases, cardiovascular diseases, metabolic diseases, neurodegenerative diseases and cancer.
Malignant tumors are a frequently encountered disease and a common disease that seriously endanger human health. In China, due to rapid development of economy, accompanying industrial pollution is more and more serious, and the life health of people is greatly threatened. Data show that 200 ten thousand new cancer cases and 140 ten thousand deaths due to cancer exist in China every year; in some cities in continental china, malignant tumors have surpassed cardiovascular and cerebrovascular diseases and become the first cause of death. The causes of cancer are various, and the number of "cancer villages" caused by environmental pollution is increasing year by year in continental china. The data show that the number of cancer villages in China exceeds 247, and 27 provinces in continental China are covered.
c-Met is a heterodimeric transmembrane receptor encoded by proto-oncogene Met, is one of tyrosine kinase receptor family members, is widely expressed in various normal tissues of human body, but exhibits abnormally high expression, mutation or activity change in many tumor tissues. The continuous activation of c-Met will destroy the adhesion between tumor cells, promote cell movement and the generation of tumor new blood vessels, make the tumor cells easy to enter blood circulation and obtain the ability of invasion and metastasis. Because c-M et is the cross point of a plurality of pathways causing tumor formation and metastasis, simultaneous interference on the plurality of pathways can be relatively easily realized by taking c-Met as a target, and once the HGF/c-Met signal pathway which is abnormally activated in tumor cells is blocked, the tumor cells have a series of changes such as cell morphology change, slow proliferation, reduced tumorigenicity, reduced invasive capacity and the like. Thus c-Met has become a promising new target for anti-tumor metastasis therapy.
The c-Met kinase is widely present in epithelial tissues and plays an important role in embryonic development and wound healing, and the c-Met kinase has become an important target for research of antitumor drugs. LIU L, et a1.j.med.chem.2008, 51 (13): 3688-; DANGELOND, et a1.j.med.chem.2008, 51 (18): 5766-; KUNG P, eta1.eur.j.med.chem.2008, 43 (6): 1321-1329 and other documents report the synthesis and pharmacological activity research of some quinoline compounds, and the widely existing human malignant tumors have persistent c-Met stimulation, overexpression or variation, including breast cancer, liver cancer, lung cancer, ovarian cancer, kidney cancer, thyroid cancer, colon cancer, glioblastoma, prostate cancer and the like. The c-Met is also involved in atherosclerosis and pulmonary fibrosis, the invasive growth rate of the cancer cells is thoroughly improved through the interaction of tumor mesenchyme, including HGF/c-Met pathway, and researches show that the quinoline structure-containing c-Met kinase inhibitor has obvious inhibition effect on proliferative diseases, and especially plays a good role in the treatment of non-small cell lung cancer and small cell lung cancer with high c-Met expression.
The Foretinib (Fig.1) reported in the literature belongs to quinoline compounds, is an oral c-Met and VEGFR/KDR kinase inhibitor, and has the name of N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] N]Oxygen gas]Quinolin-4-yl]Oxygen gas]Phenyl radical]-N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, IC for c-Met kinase and KDR kinase50Values of 0.4 and 0.8nM, respectively, are currently in phase III clinical study. Clinical research shows that the Foretinib has obvious proliferation inhibiting effect on various human tumor cell strains (human lung cancer cells, human gastric cancer cells and the like).
The inventor conducts extensive research on quinoline compounds, and synthesizes a series of quinoline derivatives with novel structures by modifying and reconstructing a plurality of structural sites. The compounds have c-Met kinase inhibition effect and anti-tumor activity through in vitro anti-human tumor cell strain activity and c-Met kinase activity screening tests.
Disclosure of Invention
The invention relates to a dihydropyridazinone-containing quinoline compound shown in a general formula I and pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
x is O, S;
y is H or halogen;
n is an integer between 2 and 6;
R1and R2The same or different, are respectively and independently selected from hydrogen and C1-C6Alkyl radical, C3-C6Cycloalkyl which may optionally be substituted by 1 to 3 identical or different R4Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-to 10-membered heterocyclic group, except for R1And R2Optionally containing, in addition to the nitrogen atom to which it is attached, from 1 to 4 heteroatoms selected from N, O and S, optionally including 1 or 2 carbon-carbon double or triple bonds, optionally interrupted by 1 to 3 identical or different R4Substitution;
R4is C1-C6An alkyl group;
R3is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, optionally halogenated C1-C6An alkyl group;
ar is C6-C10Aryl or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally 1-3R, the same or different5Substitution;
R5is hydroxy, halogen, nitro, amino, cyano, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Alkylthio, C optionally substituted by hydroxy, amino or halogen1-C6Alkyl or C1-C6Alkoxy, mono-or di-C1-C6Alkyl-substituted amino, C1-C6Alkylamido, free, salified, esterified and amidated carboxyl, C1-C6Alkylsulfinyl, sulfonyl, C1-C6Alkanoyl, carbamoyl, mono-or di-C1-C6Alkyl-substituted carbamoyl, C1-C3An alkylenedioxy group.
The invention preferably relates to dihydropyridazinone-containing quinoline compounds shown in the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
x is O;
y is H, F;
n is an integer between 2 and 4;
R1and R2The same or different, are respectively and independently selected from hydrogen and C1-C6Alkyl radical, C3-C4Cycloalkyl which may optionally be substituted by 1 to 3 identical or different R4Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group, except for R1And R2Optionally containing, in addition to the nitrogen atom to which it is attached, from 1 to 4 heteroatoms selected from N, O and S, optionally including 1 or 2 carbon-carbon double or triple bonds, optionally interrupted by 1 to 3 identical or different R4Substitution;
R4is C1-C6An alkyl group;
R3is H, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Alkoxy, trifluoromethyl, difluoromethyl;
ar is C6-C10Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar optionally 1-3R, which may be the same or different5Substitution;
R5is hydroxy, halogen, nitro, amino, cyano, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Alkylthio, C optionally substituted by hydroxy, amino or halogen1-C6Alkyl or C1-C6Alkoxy, mono-or di-C1-C6Alkyl-substituted amino, C1-C6Alkylamido, free, salified, esterified and amidated carboxyl, C1-C6Alkylsulfinyl, sulfonyl, C1-C6Alkanoyl, carbamoyl, mono-or di-C1-C6Alkyl-substituted carbamoyl, C1-C3An alkylenedioxy group.
The invention also preferably relates to dihydropyridazinone-containing quinoline compounds shown in the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
x is O;
y is F, and the substitution position of the F is the ortho position of the carbon atom connected with the X on the benzene ring;
n is an integer between 2 and 4;
R1and R2The same or different, are respectively and independently selected from hydrogen and C1-C4Alkyl radical, C3-C4Cycloalkyl which may optionally be substituted by 1 to 3 identical or different R4Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group, except for R1And R2Optionally containing, in addition to the nitrogen atom to which it is attached, from 1 to 4 heteroatoms selected from N, O and S, optionally including 1 or 2 carbon-carbon double or triple bonds, optionally interrupted by 1 to 3 identical or different R4Substitution;
R4is C1-C6An alkyl group;
R3is H, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Alkoxy, trifluoromethyl, difluoromethyl;
ar is phenyl, naphthyl, quinolyl, 5-6 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar optionally 1-3R, the same or different5And (4) substitution.
R5Is hydroxy, halogen, nitro, amino, cyano, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Alkylthio, C optionally substituted by hydroxy, amino or halogen1-C6Alkyl or C1-C6Alkoxy, mono-or di-C1-C6Alkyl-substituted amino, C1-C6Alkylamido, free, salified, esterified and amidated carboxyl, C1-C6Alkylsulfinyl, sulfonyl, C1-C6Alkanoyl, carbamoyl, mono-or di-C1-C6Alkyl-substituted carbamoyl, C1-C3An alkylenedioxy group.
The invention particularly preferably relates to dihydropyridazinone-containing quinoline compounds shown in the general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
x is O;
y is F, and the substitution position of the F is the ortho position of the carbon atom connected with the X on the benzene ring;
n is an integer between 2 and 4;
R1and R2Together with the nitrogen atom to which they are attached form a 5-6 membered saturated heterocyclic group, except that R1And R2Optionally containing, in addition to the nitrogen atom to which it is attached, from 1 to 4 heteroatoms selected from N, O and S, optionally including 1 or 2 carbon-carbon double or triple bonds, optionally interrupted by 1 to 3 identical or different R4Substitution;
R3is H, C1-C4Alkyl radical, C3-C6Cycloalkyl, trifluoromethyl;
R4is C1-C4An alkyl group;
ar is phenyl, naphthyl, quinolyl, pyridyl, furyl, thienyl, pyrrolyl, and Ar is optionally 1-3 same or different R5Substitution;
R5is halogen, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Alkylthio, optionally halogenated C1-C4Alkyl or C1-C4Alkoxy, mono-or di-C1-C4Alkyl-substituted amino, C1-C6Alkanoyl, carbamoyl, mono-or di-C1-C6Alkyl-substituted carbamoyl, mono-or di-C1-C6Alkyl-substituted sulfonyl, C1-C3An alkylenedioxy group.
The invention also particularly preferably relates to dihydropyridazinone-containing quinoline compounds shown in the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
x is O;
y is F, and the substitution position of the F is the ortho position of the carbon atom connected with the X on the benzene ring;
n is an integer between 2 and 4;
R1and R2Together with the nitrogen atom to which they are attached form 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 1-pyrrolidinyl;
R3is methyl, ethyl, cyclopropyl, trifluoromethyl;
ar is phenyl, and Ar optionally 1 to 3 identical or different R5Substitution;
R5is halogen, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Alkylthio, optionally halogenated C1-C4Alkyl or C1-C4Alkoxy, mono-or di-C1-C4Alkyl-substituted amino, C1-C6Alkanoyl, carbamoyl, mono-orDouble C1-C6Alkyl-substituted carbamoyl, mono-or di-C1-C6Alkyl-substituted sulfonyl, C1-C3An alkylenedioxy group.
More particularly, the invention relates to dihydropyridazinone-containing quinoline compounds shown in the general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein,
x is O;
y is F, and the substitution position of the F is the ortho position of the carbon atom connected with the X on the benzene ring;
n is 3;
R3is methyl;
R1and R2Together with the nitrogen atom to which they are attached form 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 1-pyrrolidinyl;
ar is phenyl and optionally 1 to 3 identical or different R5Substitution;
R5is fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, trifluoromethoxy, N-methylcarboxamido, N-methylsulfonamido, methoxymethylene, methylthio, N-dimethylamino and C1-C3And (3) methylenedioxy.
The compounds of formula I according to the invention and their pharmaceutically acceptable salts, solvates or prodrugs are preferably the following compounds, but these compounds are not meant to limit the invention in any way:
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-methylphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-methylphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-methylphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-trifluoromethylphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-trifluoromethoxyphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-fluorophenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-chlorophenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3-chloro-4-fluorophenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (4-bromophenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3H-pyrrol-3-yl) -5-ethyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3- (N' -methylmethanesulfonamido) phenyl) -5-ethyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-furanyl) -5-trifluoromethyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-thienyl) -5-trifluoromethyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3-pyridinyl) -5-cyclopropyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3-methylsulfanylphenyl) -5-cyclopropyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
1- ((3-methoxymethylene) phenyl) -5-cyclopropyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide is N- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- ((3-methoxymethylene) phenyl;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3- (N' -methylcarboxamido) phenyl) -5-cyclopropyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3- (N, N-dimethylamino) phenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3- (1, 3-benzodioxole) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [4- ((7- (3- (dimethylamino) propoxy) -6-methoxyquinolin-4-yl) -oxy) -3-fluorophenyl ] -1- (4-methoxyphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [4- ((7- (3- (diethylamino) propoxy) -6-methoxyquinolin-4-yl) -oxy) -3-fluorophenyl ] -1- (4-methoxyphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1-phenyl-5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1-phenyl-5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide.
Furthermore, the quinoline derivatives of formula I of the present invention can be combined with an acid to form a pharmaceutically acceptable salt thereof according to conventional methods in the art. The acid may include inorganic or organic acids, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, and the like.
In addition, the present invention also includes prodrugs of the compounds of the present invention. Prodrugs, according to the present invention, are derivatives of compounds of formula I which may themselves have poor or even no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The term "halo" as used herein, unless otherwise indicated, refers to fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "alkenyl" means straight or branched chain alkenyl; "alkynyl" refers to straight or branched chain alkynyl groups; "aryl" refers to an organic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, such as phenyl, naphthyl; 5-to 10-membered heteroaryl includes those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic, the ring system is aromatic, and contains a total of 5 to 10 atoms, and examples thereof include imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, (1, 2, 3) -and (1, 2, 4) -triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, quinolyl and the like; 5-10 membered heterocyclic groups include those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic but is non-aromatic, the ring system containing a total of 5 to 10 atoms and may optionally include 1 or 2 carbon-carbon double or triple bonds, and there may be mentioned, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like.
The invention also relates to a compound of the general formula I, which has strong effect of inhibiting c-Met kinase, and also relates to application of the compound and pharmaceutically acceptable salts and solvates 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.
The following schemes 1-3 describe the preparation of compounds of formula I of the present invention, all starting materials prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or commercially available. All of the final compounds of the present invention are prepared by the methods described in these 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 diagrams are as defined below or in the claims.
The compounds of formula I according to the invention can be prepared in a manner according to scheme 1 from the corresponding intermediates A and the corresponding intermediates B by substitution reactions.
The compounds of formula I, intermediates a, according to the invention are prepared as in scheme 2, the other substituents being as defined in the claims.
The compounds of general formula I, intermediates B, according to the invention are prepared as shown in scheme 3, and the other substituents are as defined in the claims.
When R is3In the case of methyl, intermediate B can be prepared by substitution, cyclization, and hydrolysis of substituted arylamine and propionyl ethyl acetate in scheme 3.
When R is3In the case of ethyl, compound B can be prepared by ring-opening substitution of substituted arylamine and butyrylacetic acid ethyl ester in scheme 3And carrying out synthesis and hydrolysis reaction.
When R is3In the case of cyclopropyl, compound B can be prepared from substituted arylamine and 4-cyclopropyl-3-oxo-butyric acid ethyl ester in scheme 3 by substitution, cyclization, and hydrolysis reactions.
When R is3When trifluoromethyl, compound B can be prepared from substituted arylamine and 5, 5, 5-trifluoro-3-oxo-pentanoic acid ethyl ester in scheme 3 by substitution, cyclization, and hydrolysis.
Substituents R of all intermediates in the above three routes1、R2、R3、R4Ar is as defined in the claims.
Detailed Description
The examples are intended to illustrate, but not to limit, the scope of the invention. NMR of the compounds was measured using BrukeraRx-400 and Mass Spectroscopy was measured using Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
General method for preparation
Step A1- (4- (3-chloropropyloxy) -3-methoxy) acetophenone (II)
3-methoxy-4-hydroxyacetophenone (249g, 1.5mol) and anhydrous potassium carbonate (579.6g, 2.1mol) were added to 1250mL of acetone, and 1-bromo-3-chloropropane (661.3g, 4.2 mol)/acetone (1200mL) was slowly added dropwise while controlling the temperature below 25 ℃ and stirred overnight at room temperature after completion of the addition. After the reaction is finished, performing suction filtration, leaching a filter cake by using 100mL of acetone, combining the filter cakes, slowly pouring the filtrate into 15L of ice water, stirring vigorously at the same time to separate out a large amount of white solid, performing suction filtration, and performing vacuum drying on the filter cake at 40 ℃ for 48 hours to obtain 695.5g of white powder, wherein the yield is 92.5%, and ESI-MS (M + H) (M/z): 242.70.
step B1- (4- (3-chloropropoxy) -5-methoxy-2-nitro) acetophenone (III)
Intermediate II (200g, 0.82mol) was added to CH2Cl2(5v/w, 1000mL), fully stirring to completely dissolve the intermediate II, cooling the reaction solution to-20 ℃, slowly dropwise adding fuming nitric acid (130g, 2.06mol), controlling the dropwise adding speed to keep the temperature of the reaction solution to be lower than-10 ℃, and reacting for 2 hours at-10 to-20 ℃ after the dropwise adding is finished. After the reaction is finished, pouring the reaction liquid into ice water, and collectingThe organic layer was washed with saturated brine until the aqueous layer was neutral, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to give 210g of a yellow solid, 89% yield, ESI-MS [ M + H ]](m/z)：287.70。
Step C (E) -1- (4- (3-chloropropoxy) -5-methoxy-2-nitrophenyl) -3- (dimethylamino) propyl-2-en-1-one (IV)
Intermediate III (200g, 0.695moL) was added to toluene (5v/w, 1000mL), heated to 110 ℃ to completely dissolve intermediate III, N-dimethylformamide dimethyl acetal (414.2g, 3.476moL) was added, and the mixture was heated under reflux for 16 h. After the reaction is finished, cooling the reaction liquid to room temperature, then putting the reaction liquid into a cold trap for stirring, separating out a solid, performing suction filtration, and drying a filter cake to obtain 180g of yellow solid, wherein the yield is 75.8%, and ESI-MS [ M + H ] (M/z): 342.77.
step D7- (3-Chloropropoxy) -6-methoxy-4 (1H) -quinolinone (V)
Adding the intermediate IV (150g, 0.44mol) into glacial acetic acid (8v/w, 1200mL), heating to 40 ℃, after the intermediate IV is completely dissolved, slowly adding iron powder (123.1g, 2.20mol) in batches, heating to 80 ℃, and mechanically stirring for reaction for 2 hours. And after the reaction is finished, carrying out suction filtration on the reaction solution while the reaction solution is hot, collecting filtrate, cooling the filtrate to separate out a large amount of solid, and carrying out suction filtration to obtain a khaki solid. Dissolving the filter cake in glacial acetic acid, stirring at 80 ℃ for about 30min, performing suction filtration while the solution is hot, collecting filtrate, cooling the filtrate to separate out a solid, performing suction filtration, washing the filter cake to be neutral, and drying to obtain 79g of a solid, wherein the yield is 65%, and ESI-MS [ M + H ] (M/z): 267.71.
step E6- (methoxy) -7- (3- (1-pyrrolidinyl) propoxy) -4(1H) -quinolinone (VI)
Intermediate V (62g, 0.232mol), tetrahydropyrrole (98.6g, 1.38mol) were added to acetonitrile (620mL) and heated at reflux for 8 h. After the reaction is finished, most of solvent is evaporated, the residual liquid is placed in a cold trap, solid is separated out, the filtration and the washing with ethyl acetate are carried out, 68.5g of solid is obtained, the yield is 95.5%, and ESI-MS [ M + H ] (M/z): 302.37.
step F4-chloro-6-methoxy-7- (3- (1-pyrrolidinyl) propoxy) quinoline (VII)
Intermediate VI (64g, 0.19mol), phosphorus oxychloride (5v/w, 315mL) was added to the solutionIn nitrile (5v/w, 315mL), the reaction was refluxed at 85 ℃ for 6 h. After the reaction, the reaction mixture was evaporated to dryness under reduced pressure to obtain a gray viscous solid, which was added to a large amount of ice-water mixed solution and adjusted to pH 10 with 10% potassium hydroxide solution. By CH2Cl2Extracting (200mL x 3), collecting organic layer, drying with anhydrous sodium sulfate, evaporating solvent, cooling to obtain off-white solid 58g, yield 87%, ESI-MS [ M + H ]](m/z)：320.81。
Step G4- (2-fluoro-4-nitrophenoxy) -6-methoxy-7- (3- (1-pyrrolidinyl) propoxy) quinoline (VIII)
2-fluoro-4-nitrophenol (36.73g, 0.234mol) was added to dry chlorobenzene (5v/w, 250mL), heated to 145 deg.C, intermediate VII (62.5g, 0.2mol) was added to the reaction and reacted at this temperature for 20 h. After the reaction, the solvent was evaporated to dryness to obtain a gray solid, which was dissolved in dichloromethane, washed with saturated potassium carbonate solution, the organic layer was collected, dried, the solvent was evaporated to dryness, and recrystallized with ethanol to obtain 50.15g of a solid, yield 70.9%, ESI-MS [ M + H ] (M/z): 441.45.
step H3-fluoro-4- (6-methoxy-7- (3- (1-pyrrolidinyl) propoxy) quinolin-4-yloxy) aniline (A)
Iron powder (61.42g, 1.1mol) and 6mL of concentrated hydrochloric acid were added to 90% ethanol (25v/w, 1210.5mL), the temperature was raised to 80 ℃ and stirred for 15min, then intermediate VIII (49.5g, 0.11mol) was added to the reaction mixture in portions, and after the addition, the reaction was refluxed for 2 h. After the reaction, the reaction mixture was filtered while hot, the filtrate was collected, and the solvent was evaporated to dryness to obtain 44g of a yellow solid with a yield of 95%, ESI-MS [ M + H ] (M/z): 411.47.
step I Ethyl 3-oxo-2- (2- (2-methylphenyl) hydrazono) pentanoate (a)
Adding o-toluidine (6.42g, 0.06mol) into 50mL of 20% hydrochloric acid solution, cooling to 0 ℃ in an ice water bath, dropwise adding 50mL of sodium nitrite (5g, 0.072mol) aqueous solution into the reaction solution, and controlling the dropwise adding speed to enable the reaction temperature to be between 0 and 5 ℃. After dripping, reacting for 30min at 0-5 ℃ for later use. Adding propionyl ethyl acetate (9.08g, 0.063mol) and anhydrous sodium acetate (14.76g, 0.18mol) into a mixed solvent of 50mL of water and 200mL of ethanol, cooling to 0 ℃ in an ice water bath, and slowly dropping the prepared diazonium salt solution, wherein the reaction temperature is kept between 0 and 5 ℃. After the dripping is finished, the reaction is carried out for 1h at the temperature of 0-5 ℃. After the reaction is finished, filtering, washing a filter cake by water, and drying to obtain 13g of light yellow solid, wherein the yield is 95%, and ESI-MS [ M + H ] (M/z): 262.30.
step J5-methyl-4-oxo-1- (2-methylphenyl) -1, 4-dihydropyridazinone-3-carboxylic acid ethyl ester (b)
Intermediate a (20g, 0.076mol) and DMF-DMA (18.1g, 0.152mol) were added to a 500mL round bottom flask, added to 200mL toluene, and heated to reflux for 4 h. Cooling the reaction solution to room temperature, evaporating the solvent to dryness to obtain a light yellow viscous substance, adding diethyl ether into the viscous substance to solidify to obtain 15g of off-white solid, wherein the yield is 76%, and ESI-MS [ M + H ] (M/z): 272.30.
step K5-methyl-4-oxo-1- (2-methylphenyl) -1, 4-dihydropyridazinone-3-carboxylic acid (B)
Intermediate b (12g, 0.04mol) was added to 160mL of a mixed solution of ethanol and tetrahydrofuran (1)∶1) Then, 50mL of a 10% aqueous solution of sodium hydroxide was added dropwise to the reaction mixture, and the mixture was reacted at 50 ℃ for 3 hours. After the reaction, the reaction solution was concentrated, the residue was poured into water, the pH was adjusted to 2 with 15% hydrochloric acid solution, and a solid was precipitated, filtered, and dried to obtain 10g of a white solid with a yield of 91.5%, ESI-MS [ M-H ]](m/z)：243.03。
Step L N- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-methylphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide (example 1)
Adding the intermediate B (0.386g, 2mmol), EDCI (0.38g, 2mmol), HOBt (0.27g, 2mmol) and triethylamine (0.04mL, 2mmol) into 40mL DMF at room temperature, stirring the reaction solution for 30min, adding the intermediate A (0.5g, 1mmol), and heating the reaction solution to 30 ℃ for reaction for 4 h. After the reaction, the reaction mixture was poured into 100mL of a 20% aqueous potassium carbonate solution, stirred for half an hour, transferred to a 250mL separatory funnel, 100mL of dichloromethane was added, the organic layer was washed three times with a 20% aqueous potassium carbonate solution, the organic layer was washed twice with a saturated saline solution, and the separated organic layer was dried over anhydrous sodium sulfate. After filtration and evaporation of dichloromethane under reduced pressure, the residue was solidified by addition of diethyl ether to give an off-white solid (0.58 g) in 75.5% yield.
ESI-MS[M+H](m/z)：637.70；1H NMR(400MHz，CDCl3)δ12.87(s，1H)，8.50(d，J＝5.3Hz，1H)，8.10(s，1H)，8.05(dd，J＝12.2，2.3Hz，1H)，7.59(s，1H)，7.51(d，J＝9.0Hz，1H)，7.45(d，J＝4.5Hz，2H)，7.41-7.34(m，3H)，7.25(d，J＝8.7Hz，1H)，6.45(d，J＝5.2Hz，1H)，4.29(t，J＝6.7Hz，2H)，4.06(s，3H)，2.70(t，J＝7.4Hz，2H)，2.57(s，4H)，2.31(s，3H)，2.28(s，3H)，2.23-2.13(m，2H)，1.81(t，J＝3.1Hz，4H).
The compounds of examples 1-56 were prepared according to the general procedure (see Table I), respectively.
Table one:
in vitro antitumor cell Activity
Dihydropyridazinone containing quinoline derivatives of the above formula I according to the invention are screened for inhibiting the activities of colon cancer cells HT-29, lung cancer cells H460, human gastric cancer cells MKN-45, lung adenocarcinoma cells A549 and bladder cancer cells U87MG in vitro.
(1) After cells were thawed and passaged for 2-3 stabilities, they were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digest into the centrifuge tube, the culture medium is added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
(2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture solution was added to dissolve the sample to 2mg/mL of the liquid, 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 for each concentration, two columns of cells surrounding each, which were greatly affected by the environment, and only used as blank wells. The 96-well plate was placed in an incubator for 72 h.
(3) The drug-containing culture solution in the 96-well plate is discarded, the cells are washed twice by using Phosphate Buffer Solution (PBS), 100 mu L of MTT (tetrazole) (0.5mg/mL) is added into each well and put into an incubator for 4h, the MTT solution is discarded, and 100 mu L of dimethyl sulfoxide is added. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. Determination of drug IC by Bliss method50The value is obtained.
The results of the compounds for inhibiting the activities of colon cancer cells HT-29, lung cancer cells H460, human gastric cancer cells MKN-45, lung adenocarcinoma cells A549 and bladder cancer cells U87MG take foretinib as a positive control (see Table II).
Watch two
c-Met enzyme Activity assay
The assay used to measure c-Met kinase activity is based on an enzyme-linked immunosorbent assay (ELISA). The specific operation is as follows:
the example compound, 50pM c-Met (His-tagged recombinant human Met (amino acid 974-terminus), expressed by baculovirus) and 5. mu.M ATP in assay buffer (25mM MOPS, pH 7.4, 5mM MgCl) were added to 0.25mg/mL PGT-coated plates at room temperature2，0.5raM MnCl2100 μ M sodium orthovanadate, 0.01% Triton X-100, 1mM DTT, and finally DMSO concentration 1% (v/v)) for 20 minutes. The reaction mixture was removed by washing and the phosphorylated polymer substrate was detected with 0.2. mu.g/mL of a phosphotyrosine-specific monoclonal antibody (PY20) conjugated to horseradish peroxidase (HR). After the color development was stopped by adding 1M phosphoric acid, the color was determined by spectrophotometry at 450nmThe color of the chromogenic substrate (TMB). The compounds of the examples and the positive control (foretinib) showed data on the inhibition of c-Met kinase (see table three).
Table three:
from the above test results, it is clear that the compound of formula I to be protected according to the present invention has good in vitro anti-tumor activity, comparable to or superior to the control drug, foretinib.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (11)
1. A compound of formula I or a pharmaceutically acceptable salt thereof
Wherein,
x is O, S;
y is H or halogen;
n is an integer between 2 and 6;
R1and R2The same or different, are respectively and independently selected from hydrogen and C1-C6Alkyl radical, C3-C6Cycloalkyl optionally substituted by 1 to 3R which may be the same or different4Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-to 10-membered heterocyclic group, except for R1And R2Optionally containing, in addition to the nitrogen atom to which it is attached, from 1 to 4 heteroatoms selected from N, O and S, optionally including 1 or 2 carbon-carbon double or triple bonds, optionally interrupted by 1 to 3 identical or different R4Substitution;
R4is C1-C6An alkyl group;
R3is hydrogen, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6Alkoxy, optionally halogenated C1-C6An alkyl group;
ar is C6-C10Aryl or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally 1-3R, the same or different5Substitution;
R5is halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylthio, optionally halogenated C1-C6Alkyl or C1-C6Alkoxy, mono-or di-C1-C6Alkyl-substituted amino, C1-C6Alkanoyl, carbamoyl, mono-or di-C1-C6Alkyl-substituted carbamoyl, mono-or di-C1-C6Alkyl-substituted sulfonyl, C1-C3And (3) methylenedioxy.
2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof
Wherein,
x is O;
y is H, F;
n is an integer between 2 and 4;
R1and R2The same or different, are respectively and independently selected from hydrogen and C1-C4Alkyl radical, C3-C4Cycloalkyl optionally substituted by 1 to 3R which may be the same or different4Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group, except for R1And R2Optionally containing, in addition to the nitrogen atom to which it is attached, from 1 to 4 heteroatoms selected from N, O and S, optionally including 1 or 2 carbon-carbon double or triple bonds, optionally interrupted by 1 to 3 identical or different R4Substitution;
R3is hydrogen, C1-C4Alkyl radical, C3-C4Cycloalkyl radical, C1-C4Alkoxy radicalTrifluoromethyl, difluoromethyl;
ar is phenyl, naphthyl, quinolyl, 5-6 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 1-3R, the same or different5And (4) substitution.
3. A compound of formula I according to claim 2 or a pharmaceutically acceptable salt thereof,
wherein,
y is F, and the substitution position of the F is the ortho position of the carbon atom connected with the X on the benzene ring;
n is 3;
R1and R2Together with the nitrogen atom to which they are attached form a 5-6 membered saturated heterocyclic group, except that R1And R2Optionally containing, in addition to the nitrogen atom to which it is attached, 1 to 3 heteroatoms selected from N, O and S, optionally substituted by 1 to 3R which may be the same or different4Substitution;
R4is C1-C4An alkyl group;
R3is hydrogen, C1-C4Alkyl radical, C3-C4Cycloalkyl, trifluoromethyl;
ar is phenyl, naphthyl, quinolyl, pyridyl, furyl, thienyl, pyrrolyl, and Ar is optionally substituted with 1-3R, which may be the same or different5And (4) substitution.
4. A compound of formula I according to claim 3,
wherein,
R1and R2Together with the nitrogen atom to which they are attached form 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 1-pyrrolidinyl;
R3is methyl, ethyl, cyclopropyl, trifluoromethyl.
5. A compound of formula I according to claim 4 or a pharmaceutically acceptable salt thereof,
wherein,
R3is methyl;
ar is phenyl and optionally substituted by 1 to 3 identical or different R5And (4) substitution.
6. A compound or a pharmaceutically acceptable salt thereof:
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-methylphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-methylphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-methylphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-trifluoromethylphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-trifluoromethoxyphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-fluorophenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-chlorophenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3-chloro-4-fluorophenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (4-bromophenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3H-pyrrol-3-yl) -5-ethyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3- (N' -methylmethanesulfonamido) phenyl) -5-ethyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-furanyl) -5-trifluoromethyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (2-thienyl) -5-trifluoromethyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3-pyridinyl) -5-cyclopropyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3-methylsulfanylphenyl) -5-cyclopropyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
1- ((3-methoxymethylene) phenyl) -5-cyclopropyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide is N- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- ((3-methoxymethylene) phenyl;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3- (N' -methylcarboxamido) phenyl) -5-cyclopropyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3- (N, N-dimethylamino) phenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1- (3- (1, 3-benzodioxole) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [4- ((7- (3- (dimethylamino) propoxy) -6-methoxyquinolin-4-yl) -oxy) -3-fluorophenyl ] -1- (4-methoxyphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [4- ((7- (3- (diethylamino) propoxy) -6-methoxyquinolin-4-yl) -oxy) -3-fluorophenyl ] -1- (4-methoxyphenyl) -5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1-phenyl-5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide;
n- [ 3-fluoro-4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy ] quinolin-4-oxy ] phenyl ] -1-phenyl-5-methyl-4-oxo-1, 4-dihydropyridazinone-3-carboxamide.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and pharmaceutically acceptable salts thereof as an active ingredient together with pharmaceutically acceptable excipients.
8. The use of a compound as claimed in any one of claims 1 to 6, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prevention of proliferative diseases with high c-Met expression.
9. The use of claim 8, wherein the proliferative disease is metastatic cancer, colon cancer, bladder cancer, breast cancer, gastric adenocarcinoma, pancreatic cancer, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
10. The use of a compound of any one of claims 1 to 6, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prevention of non-small cell lung cancer and small cell lung cancer which are highly expressed in c-Met.
11. The use of a compound according to any one of claims 1 to 6, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of lung cancer, liver cancer, stomach cancer, colon cancer, breast cancer.
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| CN102643268A (en) * | 2011-12-30 | 2012-08-22 | 沈阳药科大学 | Quinoline and cinnoline compound and application thereof |
| CN102675282A (en) * | 2011-03-15 | 2012-09-19 | 广东东阳光药业有限公司 | Substitutive quinoline compound and application method and uses thereof |
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| CN102675282A (en) * | 2011-03-15 | 2012-09-19 | 广东东阳光药业有限公司 | Substitutive quinoline compound and application method and uses thereof |
| CN102643268A (en) * | 2011-12-30 | 2012-08-22 | 沈阳药科大学 | Quinoline and cinnoline compound and application thereof |
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| "Discovery and optimization of novel 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazones as c-Met kinase inhibitors";Baohui Qi et al.;《Bioorganic & Medicinal Chemistry》;20130619;第21卷;第5246-5260页 * |
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