CN108314682A - The preparation and application of the miscellaneous quinolines of the disubstituted -4- virtues of 6,7- - Google Patents
The preparation and application of the miscellaneous quinolines of the disubstituted -4- virtues of 6,7- Download PDFInfo
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- CN108314682A CN108314682A CN201810097257.1A CN201810097257A CN108314682A CN 108314682 A CN108314682 A CN 108314682A CN 201810097257 A CN201810097257 A CN 201810097257A CN 108314682 A CN108314682 A CN 108314682A
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- Prior art keywords
- phenyl
- methoxy
- fluoro
- oxy
- naphthyridine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000003248 quinolines Chemical class 0.000 title description 2
- 229940111121 antirheumatic drug quinolines Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 229940002612 prodrug Drugs 0.000 claims abstract description 14
- 239000000651 prodrug Substances 0.000 claims abstract description 14
- 239000012453 solvate Substances 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 238000011282 treatment Methods 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- -1 3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl Chemical group 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 150000004677 hydrates Chemical class 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 5
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- YETZVIRAFFXQHK-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-(4-fluorophenyl)-2-oxo-1,8-naphthyridine-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCCCC1)NC(=O)C=1C(N(C2=NC=CC=C2C=1)C1=CC=C(C=C1)F)=O YETZVIRAFFXQHK-UHFFFAOYSA-N 0.000 claims description 4
- COKXWNOQZZDYDW-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridine-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCCCC1)NC(=O)C=1C(N(C2=NC=CC=C2C=1)C1=CC=C(C=C1)OC)=O COKXWNOQZZDYDW-UHFFFAOYSA-N 0.000 claims description 4
- LODWOBAYUQRWKD-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(4-fluorophenyl)-2-oxo-1,8-naphthyridine-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C=1C(N(C2=NC=CC=C2C=1)C1=CC=C(C=C1)F)=O LODWOBAYUQRWKD-UHFFFAOYSA-N 0.000 claims description 4
- CHBYTVJJYHIOOD-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridine-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C=1C(N(C2=NC=CC=C2C=1)C1=CC=C(C=C1)OC)=O CHBYTVJJYHIOOD-UHFFFAOYSA-N 0.000 claims description 4
- ZBWJMTPYNUJUEH-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridine-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCC(CC1)C)NC(=O)C=1C(N(C2=NC=CC=C2C=1)C1=CC=C(C=C1)OC)=O ZBWJMTPYNUJUEH-UHFFFAOYSA-N 0.000 claims description 4
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- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- NEURYOYRKPFLKH-UHFFFAOYSA-N 2-chloro-1-isocyanato-4-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC=C(N=C=O)C(Cl)=C1 NEURYOYRKPFLKH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
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- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- ZEBJQMMWHJUJCH-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-2-oxo-1-phenyl-1,8-naphthyridine-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCCCC1)NC(=O)C=1C(N(C2=NC=CC=C2C=1)C1=CC=CC=C1)=O ZEBJQMMWHJUJCH-UHFFFAOYSA-N 0.000 claims description 3
- QPWCVXSHMUHRKE-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(4-fluorophenyl)-2-oxo-1,8-naphthyridine-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCC(CC1)C)NC(=O)C=1C(N(C2=NC=CC=C2C=1)C1=CC=C(C=C1)F)=O QPWCVXSHMUHRKE-UHFFFAOYSA-N 0.000 claims description 3
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- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
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- 125000001544 thienyl group Chemical group 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Abstract
The present invention relates to 6 shown in general formula I, the miscellaneous quinoline derivatives of 7 disubstituted 4 virtues and its pharmaceutically acceptable salt, hydrate, solvate and prodrug, wherein substituent R1, X, Y there is the meaning that provides in the description.Has the function of strong inhibition c Met kinases the invention further relates to the compound of general formula I, and it further relates to such compound and its pharmaceutically acceptable salt, hydrate, solvate or prodrug to treat due to the purposes in the drug of c Met kinases overexpression diseases caused in preparation, the purposes especially in preparing the drug for the treatment of and/or pre- anti-cancer.
Description
Technical Field
The invention relates to a 6, 7-disubstituted-4-arylheteroquinoline compound, a geometric isomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application thereof in preparing a medicament for treating and/or preventing cancers.
Background
Malignant tumors are a disease that seriously jeopardizes human health and life. The receptor tyrosine kinase c-Met is an important target for anti-tumor therapy. c-Met is not only aberrantly expressed in a variety of malignancies, regulating the processes of tumor cell growth, invasion, metastasis and apoptosis, but also interacts with a variety of membrane receptors. Research shows that the interaction between c-Met and membrane receptor influences the action of signal molecules, further influences the invasion and metastasis of tumor and the generation process of new blood vessels, and thus leads to the emergence of tumor drug resistance. A large number of studies prove that the c-Me signal pathway is related to tumor drug resistance, which provides a foundation for the development of multi-target kinase inhibitors. The receptor tyrosine kinase c-Met plays an important role in cell proliferation and metabolism, tumor generation, metastasis and angiogenesis, and becomes an important target for antitumor therapy. The interaction of the HGF/c-Met signal channel and other channels such as VEGFR influences the action effect of the antitumor drug and generates drug resistance, so that the multi-kinase target combined administration becomes a new antitumor treatment means.
the extracellular domain comprises 3 functionally distinct domains, namely an N-terminal ligand binding domain (SEMA domain) covering the whole alpha chain and part of the β chain, a cystine-rich domain with 4 conserved disulfide bonds, and an immunoglobulin-like domain.the intracellular domain also comprises 3 regulatory regions, a membrane-proximal domain with a Tyr phosphorylation site, a tyrosine kinase catalytic domain with Tyr1234 and Tyr1235 phosphorylation sites, and a C-terminal multifunctional binding domain with Tyr1349 and RAS 1356 binding tyrosine, after binding of HGF to the extracellular domain, phosphorylation of C-Met is induced, multiple cell factors such as GAB survival factors (GAB 35), growth factors such as GAB binding protein, MAPK binding protein, and the like, which are highly binding to the receptor tyrosine kinase, and inhibit the proliferation of tumor cells, such as tumor metastasis of breast cancer cells, tumor metastasis of tumor cells, tumor metastasis of breast cancer cells, tumor metastasis of tumor cells, tumor metastasis of breast cancer cells, tumor metastasis of breast cancer metastasis of tumor cells, tumor metastasis of tumor cells, tumor metastasis of tumor cells, tumor metastasis of tumor cells, tumor.
At present, two anti-tumor therapeutic drugs aiming at the c-Met pathway are provided, one is a monoclonal antibody against HGF or c-Met; one is a small molecule inhibitor against c-Met. Based on the chemical structure of the inhibitor and the crystal combination mode with c-Met, the c-Met small-molecule inhibitor is divided into two classes, i.e. the class I c-Met inhibitor is combined with the c-Met in a kinase pocket to form a U-shaped conformation, surrounds Met1121 and is combined with a hinge region, and the class I inhibitor has high selectivity on the c-Met; class II C-Met inhibitors are more structurally extended, with the binding region extending from the ATP site to Ile1145 near the C-C helix. Most of the II inhibitors are nonspecific inhibitors, have inhibition effect on multiple kinase targets, and have better action effect than the I inhibitors.
In order to develop a novel high-efficiency anti-tumor drug, the inventor conducts extensive research on the 6, 7-disubstituted-4-arylheteroquinoline compound, modifies and reforms a plurality of structural sites, and synthesizes a series of 6, 7-disubstituted-4-arylheteroquinoline derivatives with novel structures. In vitro antitumor activity screening tests show that the compounds have antitumor activity.
Disclosure of Invention
The invention relates to a 6, 7-disubstituted-4-arylheteroquinoline compound shown in a general formula I and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
Wherein
R1Morpholine, 4-methylpiperazine, piperidine, 4-methylpiperidine, tetrahydropyrrole and tetrahydrothiophene;
n＝3；
x is H, F;
y is-Ar1-Ar2；
Ar1Is (C)6-C10) Heteroaryl, the heteroaryl containing 2 heteroatoms of N, Ar1And Ar2And, in addition, optionally substituted by 1 to 2 identical or different R2Substitution; ar (Ar)2Is (C)6-C10) Heteroaryl group, Ar2Removing Ar1And in addition, is also represented by R3Substituted aryl substitution;
R2、R3is 1-2 selected from hydrogen, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl, sulfonyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) A substituent of an alkylenedioxy group.
The present invention preferably also relates to compounds of the general formula I as defined below, or racemates or optical isomers thereof, or pharmaceutically acceptable salts and/or hydrates thereof,
R1morpholine, 4-methylpiperazine, piperidine, 4-methylpiperidine and tetrahydropyrrole;
n＝3；
x is H, F;
y is-Ar1-Ar2；
Ar1Is an 8-membered heteroaryl group containing 2 heteroatoms of N, Ar1And Ar2And, in addition, optionally substituted by 1 to 2 identical or different R2Substitution; ar (Ar)2Is 6-membered aryl, Ar2Removing Ar1And in addition, is also represented by R3Substituted aryl substitution;
R2、R3is 1-2 selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, optionally halogenated (C)1-C4) Alkyl or (C)1-C4) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C4) Alkoxy group, (C)1-C4) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or bis (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) Alkylene oxide(iii) a dioxy group.
The present invention preferably also relates to compounds of the general formula I as defined below, or racemates or optical isomers thereof, or pharmaceutically acceptable salts and/or hydrates thereof,
R1morpholine, 4-methylpiperazine, piperidine, 4-methylpiperidine and tetrahydropyrrole;
n＝3；
x is F;
y is
R2Is H;
R3fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.
Very particular preference is given according to the invention to the following derivatives of the general formula I, including racemates or optical isomers thereof, and pharmaceutically acceptable salts and/or hydrates thereof, without these compounds being intended as any restriction to the invention:
(1) n- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(2) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(3) N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(4) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(5)1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(6)1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(7)1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(8)1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(9)1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(10)1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(11)1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(12)1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(13) N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(14) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(15) N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(16) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(17) N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(18) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl 1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(19) N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(20) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl 1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(21)1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(22)1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(23)1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(24)1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(25)1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(26)1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(27)1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(28)1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(29)1- (2-chloro-4- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(30)1- (2-chloro-4- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(31) N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1, -1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(32) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl 1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
The 6, 7-disubstituted-4-arylheteroquinoline derivatives of the general formula I of the present invention can be used with acids to form pharmaceutically acceptable salts thereof according to conventional methods in the art to which the present invention pertains. 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 there may be mentioned, for example, imidazolyl, pyridyl, pyrimidyl, 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 with a 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 and hydrates 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 the compounds of general formula I according to the invention, all starting materials being prepared by the methods described in schemes 1-3, by methods well known to those skilled 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 synthetic schemes 1-3 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 synthetic routes 1-3 are as defined below or as defined in the claims.
According to the invention, compounds of the formula I in which Y isR2、R3As defined in the summary of the invention, can be prepared in the manner of scheme 1 from intermediate a and intermediate B by substitution.
The compounds of formula I according to the invention, intermediates A, are prepared as in scheme 2, and the other substituents are as defined in the claims.
According to the invention, compounds of the formula I in which Y isIntermediate B is prepared as in scheme 3, with the other substituents as defined in the claims.
Substituents R of all intermediates in the above three routes1、R2、R3As defined in the previous claims.
The specific implementation mode is as follows:
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 Agilent1100 LC/MSD; all reagents used were analytically or chemically pure.
The compounds of examples 1-32 were prepared according to general procedure 1 (see Table I), respectively.
Table one:
example 1N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:693.71；1H NMR(400MHz,DMSO-d6)δ11.95(s,1H),9.17(s, 1H),8.63(s,1H),8.61(d,J＝2.3Hz,1H),8.58(d,J＝5.5Hz,1H),8.11(dd,J＝12.9, 2.1Hz,1H),7.67(d,J＝8.9Hz,1H),7.62(s,1H),7.51(dd,J＝8.8,3.7Hz,2H), 7.50–7.47(m,2H),7.46–7.42(m,2H),6.63(d,J＝5.2Hz,1H),4.28(d,J＝5.7Hz, 2H),3.98(s,3H),3.51(d,J＝11.8Hz,2H),2.99–2.87(m,2H),2.32(s,2H),1.80(d, J＝13.4Hz,2H),1.55–1.42(m,2H),0.93(d,J＝6.3Hz,2H).
Step I preparation of 1- (4- (3-chloropropoxy) -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 at room temperature overnight after completion of the addition. After the reaction is finished, performing suction filtration, leaching a filter cake with 100mL of acetone, combining filtrates, slowly pouring the filtrate into 15L of ice water, stirring vigorously at the same time, separating 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 as follows: 92.5 percent; m.p. 64-65 ℃; MS (ESI) M/z 243.4[ M + H ]]+。
Step two preparation of 1- (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 (130 g, 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, the reaction mixture 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. Drying by distillationSolvent to obtain 210g of yellow solid with yield of 89%; m.p. 60-61 ℃; MS (ESI) M/z 288.6[ M + H ]]+,310.2[M+Na]+。
Step preparation of tris 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 reaction was heated under reflux for 16 hours. After the reaction is finished, cooling the reaction liquid to room temperature, then putting the reaction liquid into a cold trap, stirring, separating out a solid, performing suction filtration, and drying a filter cake to obtain 180g of yellow solid with the yield of 75.8%; 117-119 ℃ in M.p.; MS (ESI) M/z 343.5[ M + H ]]+。
Step four preparation of 7- (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, adding iron powder (123.1g, 2.20mol) in batches slowly, 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 for about 30min at 80 ℃, performing suction filtration while the solution is hot, collecting filtrate, cooling the filtrate to separate out solids, performing suction filtration, washing the filter cake to be neutral, and drying to obtain 79g of solids with the yield of 65%; m.p. 232-234 ℃; MS (ESI) M/z 268.9[ M + H ]]+。
Step four preparation of 6-methoxy-7- (3-morpholino) quinolin-4 (1H) -one (VI)
Intermediate V (62g, 0.232mol), morpholine (1.16mol) were added to acetonitrile (620mL) and heated at reflux for 8 h. After the reaction is finished, evaporating most of the solvent, putting the residual solution into a cold trap, separating out solid, performing suction filtration, washing with ethyl acetate, taking a filter cake, and drying to obtain the product with the yield of 93.7%; m.p. 207-208 ℃; MS (ESI) M/z 319.1[ M + H ]]+,659.3[2M+Na]+。
Step five 4- (3- ((4-chloro-6-methoxyquinolin-7-yl) oxy) propyl) morpholine (VII)
Intermediate VI, phosphorus oxychloride (5v/w, 300mL) was added to acetonitrile (5v/w, 300mL) and the temperature was raised to 85 ℃ for reflux reaction 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 mixture and adjusted to pH 10 with 10% potassium hydroxide solution. By CH2Cl2Extraction (200mL x 3), collection of organic layer, anhydrous sodium sulfate drying, evaporation of solvent, cooling to obtain off-white solid, intermediate VII.
Step preparation of hexa-4- (3- ((4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinolin-7-yl) oxy) propyl) morpholine (VIII)
2-fluoro-4-nitrophenol (36.73g, 0.234mol) was added to dry chlorobenzene (5v/w, 250mL), heated to 145 ℃ and intermediate VII (0.2mol) was added to the reaction and reacted at this temperature for 20 h. After the reaction is finished, the solvent is evaporated to dryness to obtain a gray solid, the solid is dissolved in dichloromethane and washed by saturated potassium carbonate solution, an organic layer is collected, dried and evaporated to dryness, and the solvent is recrystallized by ethanol to obtain an intermediate VIII.
Step hepta 3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) aniline (A)
Adding the intermediate VIII (0.1mol) into absolute ethyl alcohol (457mL), heating to 80 ℃, fully stirring to completely dissolve the raw materials, adding saturated ammonium chloride aqueous solution (450mL), adding 65g (1.0 mol) of iron powder in batches, and reacting at 80 ℃ for 5 hours. After the reaction is finished, carrying out suction filtration while the reaction is hot, and collecting filtrate; and adding the filter cake into 250mL of absolute ethyl alcohol, performing reflux reaction for 30min, performing suction filtration while the filter cake is hot, combining the filtrates, cooling to separate out a solid, and performing suction filtration to obtain an intermediate A.
Step eight 2-phenylamino-nicotinic acid (d)
2-Chloronicotinic acid (5.001g,1.575mol) and aniline (5.899g,0.932mol) were added to a 100mL round bottom flask in sequence, and glacial acetic acid (50mL) was added and the reaction was allowed to dissolve completely with sonication for 5 min. The temperature is increased to 100 ℃ and the reflux is carried out for about 4 hours. Cooling the reaction solution, adding 100mL of distilled water, stirring, measuring pH to 6, slowly adding 50% KOH solution dropwise until pH is 12, precipitating a large amount of light yellow solid, performing suction filtration, taking filtrate, slowly adding 37% HCl solution dropwise until pH is 3, precipitating a large amount of white solid, performing suction filtration, and drying filter cakes to obtain 3.582 g of white powder with the yield of 83.6%
Step nine (2-phenylamino-pyridin-3-yl) -methanol (e)
Adding 40mL of tetrahydrofuran into a 100mL round-bottom flask, exhausting the air in the container by using a nitrogen balloon, adding lithium aluminum hydride (1.534g,0.4795mol) under an ice bath condition, stirring for 10min, ultrasonically dissolving an intermediate d by using 40mL of tetrahydrofuran, slowly and dropwisely adding the intermediate d into the reaction solution by using a burette, stirring for 3.5h, adding the reaction solution into 200mL of ethyl acetate, dropwisely adding a KOH solution until the pH value is 12, precipitating a large amount of white solid, performing suction filtration, performing rotary evaporation on the filtrate, adding 60mL of petroleum ether, precipitating a large amount of white solid, performing suction filtration, drying a filter cake to obtain 2.873g of white powder, wherein the yield is 69.5%.
Step ten 2-phenylamino-pyridine-3-carbaldehyde (f)
Adding the intermediate e and pyridinium dichromate (3.153g,0.215mol) into a 100mL round-bottom flask, adding 75mL dichloromethane for ultrasonic dissolution, adding 5.000g silica gel, stirring at room temperature for 6h, performing suction filtration, performing rotary evaporation on filtrate, adding 50mL distilled water to separate out a large amount of light yellow solid, performing suction filtration, and drying a filter cake to obtain 2.073g of light yellow powder with the yield of 58.5%.
Step eleven 2-oxo-1-phenyl-1, 2-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester (g)
And sequentially adding the intermediate f, diethyl malonate (1.853g,0.102mol) and piperidine (0.342g,0.085mol) into a 100mL round-bottom flask, adding 75mL of ethanol, ultrasonically dissolving, heating to 100 ℃, refluxing for 34h, spin-drying, adding 70mL of distilled water to precipitate a large amount of light yellow solid, performing suction filtration, and drying a filter cake to obtain 1.764g of light yellow powder, wherein the yield is 48.6%.
Step dodeca 2-oxo-1-phenyl-1, 2-dihydro- [1,8] naphthyridine-3-carboxylic acid (B)
Adding the intermediate g and potassium carbonate (1.354g, 0.135mol) into a 100mL round-bottom flask in sequence, adding 40mL of distilled water and 40mL of 1.4-dioxane, ultrasonically dissolving, heating to 80 ℃, refluxing for 4.5h, pouring the reaction solution into 100mL of distilled water under ice bath, dropwise adding 37% HCl until the pH value is 6, precipitating a large amount of light yellow solid, performing suction filtration, and drying a filter cake to obtain 1.304g of light yellow powder, wherein the yield is 85.6%.
Step thirteen N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
Intermediate A (0.065g, 0.00032mol) and N, N-diisopropylethylamine (0.6mL, 0.004mol) were added to 10mL of dichloromethane, intermediate B (0.2g, 0.00073mol) was dissolved in 5mL of dichloromethane, and the solution was added dropwise to the dichloromethane solution at 0 ℃ and slowly warmed to room temperature after completion of the addition, and the reaction was carried out for 1-2 hours. After completion of the reaction, 5mL of an 5% aqueous solution of sodium hydroxide was added, stirred for half an hour, transferred to a 250mL separatory funnel, and 25mL of dichloromethane was added, washed three times with a saturated aqueous solution of sodium carbonate (50 mL. times.3), washed once with saturated brine, and dichloromethane was distilled off under reduced pressure to obtain 0.05g of a pale yellow solid powder with a yield of 56.14%.
The compounds of examples 2 to 34 were each prepared according to the method of example 1.
Example 2
N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:706.27.
Example 3
N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:693.27.
Example 4
N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:705.28；1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.56(s, 1H),9.16(s,1H),8.78(d,J＝5.9Hz,1H),8.62(s,2H),8.16(d,J＝12.7Hz,1H), 7.75(d,J＝7.7Hz,2H),7.70(d,J＝9.0Hz,1H),7.60(t,J＝9.0Hz,1H),7.47–7.42 (m,3H),6.93(d,J＝5.9Hz,1H),4.33(s,2H),4.03(s,3H),3.22(s,3H),2.93(d,J＝ 10.7Hz,2H),2.37(s,2H),1.78(d,J＝13.3Hz,2H),1.60–1.50(m,2H),1.24(s, 1H),0.93(d,J＝5.3Hz,3H),0.85(s,1H).
Example 5
1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:709.22；1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),11.22(s, 1H),9.34(s,1H),9.16(s,1H),8.67(d,J＝5.6Hz,1H),8.62–8.59(m,2H),8.15– 8.09(m,1H),7.66(s,2H),7.64(s,1H),7.48–7.45(m,2H),7.44(s,1H),6.77(s, 1H),5.75(s,1H),4.30(d,J＝5.7Hz,2H),3.99(s,2H),3.95(s,1H),3.83(t,J＝11.7 Hz,2H),3.60–3.54(m,3H),3.48(d,J＝12.1Hz,3H),3.11(s,1H),3.10(s,1H), 3.09(s,1H),3.08(s,1H),2.34(s,1H).
Example 6
1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:722.25.
Example 7
1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:707.24.
Example 8
1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:721.26；1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),10.08(s, 1H),9.16(s,1H),8.60(d,J＝5.6Hz,2H),8.57(d,J＝5.6Hz,1H),8.10(dd,J＝12.8, 2.0Hz,1H),7.65(d,J＝8.6Hz,3H),7.60(s,1H),7.53–7.50(m,2H),7.46(s,1H), 7.44(s,1H),6.62(d,J＝4.9Hz,1H),5.75(s,1H),4.27(t,J＝5.7Hz,2H),3.97(s, 2H),3.48(d,J＝10.9Hz,3H),3.21(s,2H),2.90(d,J＝9.8Hz,2H),2.30(s,2H), 1.78(s,4H),1.26(dd,J＝12.3,6.6Hz,3H).
Example 9
1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:754.19；1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),9.24(s, 1H),8.68(d,J＝5.7Hz,2H),8.55(d,J＝5.1Hz,1H),8.16(d,J＝12.8Hz,1H),7.87 (d,J＝8.5Hz,1H),7.69(s,1H),7.61(s,1H),7.56(d,J＝8.5Hz,2H),7.49(s,2H), 7.46(s,1H),6.56(d,J＝5.0Hz,1H),4.30(s,3H),4.03(s,2H),3.79(s,2H),3.69– 3.64(m,2H),3.19(d,J＝7.2Hz,2H),2.58(s,2H),2.19(s,2H),1.37(s,1H),1.35(s, 2H),1.34(s,1H).
Example 10
1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:766.20.
Example 11
1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:751.28.
Example 12
1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:765.20；1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),9.25(s, 1H),8.69(d,J＝6.5Hz,2H),8.19(d,J＝12.7Hz,1H),7.87(d,J＝8.5Hz,2H),7.75 –7.68(m,2H),7.62(s,1H),7.57(dd,J＝10.9,6.8Hz,2H),7.47(d,J＝8.5Hz,2H), 6.72(s,1H),4.36(s,2H),4.06(s,3H),3.67(d,J＝4.1Hz,1H),3.59(d,J＝11.5Hz, 2H),3.29(s,2H),3.20(dd,J＝7.3,4.2Hz,2H),3.01(d,J＝11.2Hz,1H),2.41(s, 2H),1.87(d,J＝13.3Hz,2H),1.64–1.53(m,2H),1.01(d,J＝6.1Hz,3H).
Example 13
N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:705.75.
Example 14
N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:718.29；1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),9.64(s, 1H),9.13(s,1H),8.59(dd,J＝17.7,6.5Hz,2H),8.09(d,J＝12.7Hz,1H),7.67– 7.56(m,2H),7.47(dd,J＝13.4,8.5Hz,2H),7.30(d,J＝8.6Hz,1H),7.12(d,J＝ 8.6Hz,1H),6.58(d,J＝4.3Hz,1H),5.76(s,2H),4.29(s,1H),3.96(d,J＝10.0Hz, 3H),3.85(d,J＝4.5Hz,3H),3.11(dd,J＝7.0,4.1Hz,1H),2.35(s,1H),1.31(t,J＝ 5.0Hz,5H),1.29–1.26(m,5H),1.24(s,1H).
Example 15
N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:708.29.
Example 16
N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:717.30；1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),9.89(s, 1H),9.16(s,1H),8.61(t,J＝6.3Hz,2H),8.53(d,J＝5.3Hz,1H),8.10(d,J＝12.8 Hz,1H),7.64(d,J＝8.8Hz,1H),7.59(s,1H),7.49(t,J＝11.7Hz,3H),7.30(d,J＝ 8.7Hz,1H),7.12(d,J＝8.8Hz,1H),6.56(d,J＝5.1Hz,1H),4.28(s,2H),3.98(s, 3H),3.86(s,3H),3.53(d,J＝11.2Hz,2H),2.95(d,J＝10.6Hz,2H),2.31(s,2H), 1.81(d,J＝13.8Hz,2H),1.63(s,1H),1.53–1.43(m,2H),1.28(dd,J＝11.6,6.5Hz, 3H),0.94(d,J＝6.3Hz,2H).
Example 17
N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:671.25；1H NMR(400MHz,DMSO-d6)δ11.94(s,1H),9.16(s, 1H),8.55(d,J＝47.4Hz,3H),8.08(d,J＝11.7Hz,1H),7.68–7.53(m,5H),7.45(d, J＝10.6Hz,3H),7.39(d,J＝5.8Hz,2H),6.50(s,1H),4.26(s,2H),3.96(s,3H), 2.50(s,5H),2.28(s,2H),1.79(d,J＝11.2Hz,2H),1.48(s,2H),1.25(d,J＝12.0Hz, 2H),0.94(s,3H).
Example 18
N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl 1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MSm/z:688.29.
Example 19
N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1, -1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MSm/z:673.28.
Example 20
N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl 1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:687.29；1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),9.15(s, 1H),8.60(d,J＝5.8Hz,2H),8.53(d,J＝5.0Hz,1H),8.08(d,J＝12.6Hz,1H),7.58 (d,J＝5.0Hz,3H),7.49(t,J＝8.8Hz,4H),7.39(d,J＝7.6Hz,2H),6.55(d,J＝4.8 Hz,1H),4.27(s,2H),3.97(s,3H),2.90(d,J＝9.2Hz,2H),2.33(s,1H),1.98(s,1H), 1.80(s,3H),1.28(dd,J＝15.0,6.4Hz,6H),1.17(t,J＝7.1Hz,1H).
Example 21
1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:727.20；1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),9.17(s, 1H),8.62(s,2H),8.47(d,J＝4.4Hz,1H),8.08(d,J＝12.6Hz,1H),7.81(d,J＝5.5 Hz,1H),7.65(dd,J＝17.8,8.8Hz,2H),7.51(d,J＝12.9Hz,3H),7.39(s,1H),6.47 (d,J＝4.4Hz,1H),4.19(s,2H),3.94(s,3H),3.60(s,5H),2.44(s,4H),1.99(s,3H).
Example 22
1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MSm/z:740.24.
Example 23
1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MSm/z:725.22.
Example 24
1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:739.24；1H NMR(400MHz,DMSO-d6)δ11.89(s,1H),10.73(d, J＝38.1Hz,1H),9.14(s,1H),8.81(d,J＝6.3Hz,1H),8.60(d,J＝8.1Hz,2H),8.19 –8.09(m,1H),7.81(s,1H),7.73(d,J＝10.5Hz,1H),7.70–7.62(m,2H),7.48(dd, J＝7.3,4.9Hz,2H),6.96(d,J＝6.2Hz,1H),4.32(s,2H),4.03(s,3H),1.96(s,3H), 1.82–1.71(m,2H),1.62–1.53(m,2H),1.29(d,J＝6.5Hz,2H),1.25(d,J＝6.5Hz, 2H),1.15(s,2H),0.91(d,J＝5.4Hz,3H).
Example 25
1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:771.15；1H NMR(400MHz,DMSO-d6)δ11.93(d,J＝25.8Hz, 1H),9.16(s,1H),8.60(d,J＝5.9Hz,2H),8.52(d,J＝5.1Hz,1H),8.09(d,J＝12.6 Hz,1H),7.78(d,J＝8.5Hz,2H),7.63(d,J＝7.5Hz,1H),7.57(d,J＝5.6Hz,1H), 7.49(s,1H),7.45(d,J＝4.8Hz,1H),7.38(d,J＝8.4Hz,2H),6.56(s,1H),4.22(s, 2H),3.95(s,3H),2.97(d,J＝49.3Hz,5H),2.71(s,5H),2.31(s,1H),2.04(s,3H), 1.30–1.18(m,1H).
Example 26
1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:784.18.
Example 27
1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:769.17.
Example 28
1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:783.19.
Example 29
1- (2-chloro-4- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:777.21；1H NMR(400MHz,DMSO-d6)δ8.45(d,J＝5.2Hz,1H), 7.51(s,1H),7.38(s,1H),7.07(t,J＝9.0Hz,1H),6.56(dd,J＝13.2,2.4Hz,1H), 6.47(dd,J＝8.7,2.3Hz,1H),6.39(d,J＝5.2Hz,1H),5.76(s,4H),5.50(s,2H), 4.19(t,J＝6.4Hz,2H),3.94(s,3H),3.59(t,J＝4.4Hz,4H),2.50–2.49(m,1H), 2.47(t,J＝7.1Hz,2H),2.39(s,4H),1.98(p,J＝6.6Hz,2H).
Example 30
1- (2-chloro-4- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:790.23.
Example 31
1- (2-chloro-4- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:775.22.
Example 32
1- (2-chloro-4- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
ESI-MS m/z:789.24；1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),9.20(s, 1H),8.64(d,J＝8.0Hz,2H),8.48(d,J＝5.2Hz,1H),8.09(d,J＝15.7Hz,2H),8.01 (d,J＝8.5Hz,1H),7.85(d,J＝8.3Hz,1H),7.65(d,J＝8.9Hz,1H),7.55–7.47(m, 3H),7.39(s,1H),6.48(d,J＝5.1Hz,1H),4.19(t,J＝6.3Hz,2H),3.95(s,3H),2.87 (d,J＝10.1Hz,2H),2.47(s,1H),1.96(dd,J＝19.0,12.1Hz,4H),1.59(d,J＝12.1 Hz,2H),1.30(s,1H),1.25(d,J＝11.1Hz,1H),1.21–1.07(m,2H),0.89(d,J＝6.4 Hz,3H).
In vitro antitumor cell Activity
The quinoline derivative containing pyrimidine and pyridine of the formula I is screened for inhibiting the activity of lung cancer cells H460, colon cancer cells HT-29, human gastric cancer cells MKN-45, lung adenocarcinoma cells A549 and bladder cancer cells U-87MG 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 tube at 800r/min for 10min, discarding supernatant, and adding 5mBlowing and beating the mixed cells by using L culture solution, sucking 10 mu L of cell suspension, adding the cell suspension into a cell counting plate for counting, and adjusting the 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 rows and two columns of cells around the perimeter, which were greatly affected by the environment, were used only 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. Oscillating on a magnetic oscillator to ensure that the survival cells react with MTT reaction product AFully dissolving, and placing into an enzyme-linked immunosorbent assay device to determine the result. Determination of drug IC by Bliss method50The value is obtained.
The results of the compounds on inhibiting the activities of lung cancer cells H460, colon cancer cells HT-29, human gastric cancer cells MKN-45, lung adenocarcinoma cells A549 and bladder cancer cells U-87MG (see table II).
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, 50pMc-Met (His-tagged recombinant human Met (amino acid 974-terminus), was expressed by baculovirus and 5. mu. MATP in assay buffer (25mM OPS, pH7.4,5mM MgCl) at room temperature on 0.25mg/mL PGT coated plates2,0.5raMMnCl2100 μ M sodium orthovanadate, 0.01% TritonX-100, 1mM DTT, and finally DMSO-d6 concentration 1% (II) ((III))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 with horseradish peroxidase (HRP). After the color development was stopped by adding 1M phosphoric acid, the color of the developed substrate (TMB) was quantified spectrophotometrically at 450 nm. Data for c-Met kinase inhibition by the compounds of the examples (see table two).
Table two:
from the above test results, it is clear that the compound of formula I to be protected by the present invention has good in vitro anti-tumor activity, which is equivalent to or superior to the anti-tumor drug cisplatin on the market.
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.
Application example 1: drop pills
10g of the compound in the embodiment 3 is mixed with 50g of a substrate such as gelatin and the like, heated, melted and mixed evenly, and then dropped into low-temperature liquid paraffin to prepare 1000 pills.
Application example 2: ointment formulation
Prepared by grinding 10g of the compound of example 22, and then uniformly grinding the ground compound with 500g of oil-based substances such as vaseline.
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.
Application example 3: injection preparation
10g of the compound obtained in example 14 was adsorbed by activated carbon in accordance with a conventional pharmaceutical procedure, filtered through a 0.55 μm microporous membrane, and then filled in nitrogen gas bottles to prepare 2mL of each of water-injection preparations and 100 bottles in total.
Application example 4: film agent
10g of the compound of example 6 was dissolved by heating after swelling with stirring polyvinyl alcohol, medicinal glycerin, water, etc., and filtered with a 80-mesh screen, and the compound of example 18 was dissolved by stirring in the filtrate to prepare 100 films by a film coating machine.
Application example 5: tablet formulation
10g of the compound obtained in example 9 was mixed with 20g of an adjuvant by a usual tableting method in pharmacy, and the mixture was compressed into 100 tablets each weighing 300 mg.
Application example 6: capsule preparation
10g of the compound in example 10 is mixed with 20g of auxiliary materials according to the requirement of a pharmaceutical capsule, and then the mixture is filled into hollow capsules, wherein each capsule weighs 300 mg.
Application example 7: external liniment
10g of the compound obtained in example 19 was mixed with 2.5g of an adjuvant such as an emulsifier and the like and ground by a conventional pharmaceutical method, and then distilled water was added thereto to make 200mL of the mixture.
Application example 8: suppository
10g of the compound of example 19 was ground into fine powder and added with an appropriate amount of glycerin, and after the fine powder was uniformly ground, the molten glycerin gelatin was added, and the mixture was uniformly ground and poured into a mold coated with a lubricant to prepare 40 suppositories.
Application example 9: aerosol formulation
Dissolving 10g of the compound in example 28 in a proper amount of propylene glycol, adding distilled water and other auxiliary materials, and preparing 500mL of clear solution.
Claims (8)
1. A compound of formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, characterized in that: the structural formula is as follows:
wherein
R1Morpholine, 4-methylpiperazine, piperidine, 4-methylpiperidine, tetrahydropyrrole and tetrahydrothiophene;
n＝3；
x is H, F;
y is-Ar1-Ar2；
Ar1Is (C)6-C10) Heteroaryl, the heteroaryl containing 2 heteroatoms of N, Ar1And Ar2And, in addition, optionally substituted by 1 to 2 identical or different R2Substitution; ar (Ar)2Is (C)6-C10) Heteroaryl group, Ar2Removing Ar1And in addition, is also represented by R3Substituted aryl substitution;
R2、R3is 1-2 selected from hydrogen, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl, sulfonyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or di (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) A substituent of an alkylenedioxy group.
2. A compound of formula i as claimed in claim 1, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein:
wherein
R1Morpholine, 4-methylpiperazine, piperidine, 4-methylpiperidine and tetrahydropyrrole;
Ar1is an 8-membered heteroaryl group containing 2 heteroatoms of N, Ar1And Ar2And, in addition, optionally substituted by 1 to 2 identical or different R2Substitution; ar (Ar)2Is 6-membered aryl, Ar2Removing Ar1And in addition, is also represented by R3Substituted aryl substitution;
R2、R3is 1-2 selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, optionally halogenated (C)1-C4) Alkane (I) and its preparation methodRadical or (C)1-C4) Alkoxy, mono-or di (C)1-C6Alkyl) substituted amino, (C)1-C4) Alkoxy group, (C)1-C4) Alkyl, (C)1-C6) Alkanoyl, carbamoyl, mono-or bis (C)1-C6Alkyl) substituted carbamoyl, (C)1-C3) An alkylenedioxy group.
3. A compound of formula i as claimed in claim 1, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein:
wherein,
x is F;
y is
R2Is H;
R3fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.
4. A compound of formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof, characterized in that:
comprises the following substances:
(1) n- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(2) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(3) N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(4) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(5)1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(6)1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(7)1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(8)1- (4-chlorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(9)1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(10)1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(11)1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(12)1- (4-bromophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(13) N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(14) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(15) N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(16) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(17) N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(18) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl 1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(19) N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(20) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl 1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(21)1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(22)1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(23)1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(24)1- (3-chloro-4-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(25)1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(26)1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(27)1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(28)1- (4-bromo-2-fluorophenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(29)1- (2-chloro-4- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3-morpholino) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(30)1- (2-chloro-4- (trifluoromethyl) phenyl) -N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperazin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(31) N- (3-fluoro-4- ((6-methoxy-7- (3- (piperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl-1, -1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
(32) N- (3-fluoro-4- ((6-methoxy-7- (3- (4-methylpiperidin-1-yl) propoxy) quinolin-4-yl) oxy) phenyl) -2-oxo-1-phenyl 1, 2-dihydro-1, 8-naphthyridine-3-carboxamide.
5. A pharmaceutical composition characterized by: comprising as active ingredient a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, in combination with pharmaceutically acceptable excipients.
6. The use of a compound of any one of claims 1 to 4, and pharmaceutically acceptable salts, solvates or prodrugs thereof, or a pharmaceutical composition according to claim 5, for the preparation of a medicament for the treatment and/or prevention of a proliferative disease.
7. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to claim 5, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
8. Use of a compound of any one of claims 1-4 and pharmaceutically acceptable salts, solvates or prodrugs thereof, or a pharmaceutical composition according to claim 5, for the preparation of a medicament for the treatment and/or prophylaxis of lung cancer, liver cancer, stomach cancer, colon cancer, breast cancer.
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| WO2021235811A1 (en) * | 2020-05-18 | 2021-11-25 | 웰마커바이오 주식회사 | Pharmaceutical composition for preventing or treating small-cell lung cancer associated with ron mutants and method using same |
| WO2021235813A1 (en) * | 2020-05-18 | 2021-11-25 | 웰마커바이오 주식회사 | Pharmaceutical composition for preventing or treating pancreatic cancer associated with ron mutation and method using same |
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Application publication date: 20180724 |