HK1071136B - Quinoline derivative and quinazoline derivative and medicinal composition containing the same - Google Patents

Description

Quinoline derivatives and quinazoline derivatives and pharmaceutical compositions containing them

Technical Field

The present invention relates to quinoline derivatives and quinazoline derivatives having an antitumor effect, and more particularly, to quinoline derivatives and quinazoline derivatives having an inhibitory effect on autophosphorylation of hepatocyte growth factor receptor and an inhibitory effect on abnormal cell proliferation or cell motility.

Background

In the proliferation of cells, epithelial Growth Factor, platelet-derived Growth Factor, insulin-like Growth Factor, Hepatocyte Growth Factor (Hepaticyte Growth Factor, et al, in order toHereinafter, abbreviated as "HGF") among them, HGF is known to play an important role as a liver regeneration factor and a kidney regeneration factor and to be involved in the regeneration of injured liver and kidney (Oncogenesis, 3,27(1992))。

however, overexpression of HGF or its receptor (hereinafter, abbreviated as "met") in various tumors such as brain tumor, lung cancer, stomach cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell carcinoma, prostate cancer, etc. has been reported (Oncology Reports,51013(1998)), particularly, the overexpression of met centered on gastric scleroma and the increase of HGF level in serum in gastric cancer are reported (int.j. cancer,55,72, (1993)). HGF is also known to have an angiogenic effect by promoting proliferation and migration of vascular endothelial cells (Circulation,97，381(1998)、ClinicalCancer Res.，53695, (1999)), induce dispersion and invasion of cells (J Biol Chem,27027780(1995)), it is considered that HGF-met signals are involved in the proliferation, invasion, and metastasis of various cancer cells.

The partial peptide of HGF, NK4, which is the HGF receptor antagonist, was reported, and it was reported that NK4 can inhibit met phosphorylation of various cancer cells, inhibit cell motility, cell invasion, and possibly also show an effect of inhibiting tumor growth via angiogenesis inhibition in an in vivo cancer transplantation model (Oncogene,17，3045(1998)、Cancer Res.，60，6737(2000)、British J Cancer，84，864(2001)、Int J Cancer，85，563(2000))。

however, since NK4 is a peptide, further studies have been required to ensure reliability in vivo, a method of administration, and the like when it acts as a therapeutic drug. On the other hand, there is no report on a low molecular weight compound having an inhibitory effect on met autophosphorylation and a low toxic substance having an antitumor effect by oral administration.

Brief description of the invention

The inventors have found that a certain class of quinoline derivatives and quinazoline derivatives have an inhibitory effect on met autophosphorylation and have an antitumor effect.

The present invention aims to provide a compound having a potent antitumor activity.

The compounds of the present invention are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

(in the above formula,

x represents a group of a CH or an N,

z represents O or S, and Z represents O or S,

l represents O or S, and L represents O or S,

m represents

-C(-R¹⁰)(-R¹¹) - (in the formula, R¹⁰And R¹¹May be the same or different and represents a hydrogen atom, C_1-4Alkyl or C_1-4Alkoxy) or

-N(-R¹²) - (in the formula R)¹²Represents a hydrogen atom or C_1-4An alkyl group),

R¹、R²and R³May be the same or different and represent

A hydrogen atom,

A hydroxyl group,

A halogen atom,

Nitro, nitro,

Amino group,

C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

C_2-6An alkenyl group,

C_2-6Alkynyl or

C_1-6An alkoxy group,

1 or 2 hydrogen atoms of the above-mentioned amino group may be replaced by C_1-6Alkyl substitution of the C_1-6The alkyl group may be further substituted by hydroxy or C_1-6The substitution of alkoxy groups is carried out,

c above_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl and C_1-6Alkoxy groups may be substituted by hydroxy groups, halogen atoms, C_1-6Alkoxy radical, C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl, amino (1 or 2 hydrogen atoms on the amino group may be replaced by C)_1-6Alkyl substitution of the C_1-6The alkyl group may be further substituted by hydroxy or C_1-6Alkoxy-substituted) or a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group which may be substituted by C_1-6Alkyl substitution of the C_1-6The alkyl group may be further substituted by hydroxy or C_1-6Alkoxy substituted) with a substituent(s),

R⁴represents a hydrogen atom, and is represented by,

R⁵、R⁶、R⁷and R⁸May be the same or different and represents a hydrogen atom, a halogen atom, C_1-4Alkyl or C_1-4An alkoxy group,

R⁹to represent

C_1-6Alkyl (the C)_1-61 or more hydrogen atoms on the alkyl group may be replaced by-R¹⁴、-T-R¹⁵or-NR¹⁶R¹⁷Substituted, T represents-O-, -S-or-NH-, R¹⁴Represents a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group, R¹⁵、R¹⁶And R¹⁷May be the same or different and represents C_1-6Alkyl or a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group, R¹⁴、R¹⁵、R¹⁶And R¹⁷The 3-to 8-membered carbocyclic or heterocyclic group represented may be substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl or a saturated or unsaturated 5-or 6-membered heterocyclyl, when said 3-8-membered carbocyclyl or heterocyclyl is substituted by 2C_1-6When substituted with alkyl groups, the 2 alkyl groups may together form an alkylene chain, the 3-8 membered carbocyclic or heterocyclic group may also condense with other saturated or unsaturated 3-8 membered carbocyclic or heterocyclic groups to form a bicyclic group)

-N(-R¹⁸)(-R¹⁹) (in the formula, R¹⁸And R¹⁹May be the same or different and represents a hydrogen atom, C_1-6Alkyl (the C)_1-6Alkyl groups may be substituted by C_1-6Alkoxy radical, C_1-6Alkylthio, or a saturated or unsaturated 3-8-membered carbocyclic or heterocyclic group (the 3-8-membered carbocyclic or heterocyclic group may be substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl, or a saturated or unsaturated 5-or 6-membered heterocyclic ring, when the 3-8 membered carbocyclic or heterocyclic group is substituted by 2C_1-6When substituted with alkyl, the 2 alkyl groups may together form an alkylene chain, the 3-8 membered carbocyclic or heterocyclic group may also be substituted with other saturated or unsaturated 3-8 membered carbocyclic or heterocyclic groups which condense to form a bicyclic group), or a saturated or unsaturated 3-8 membered carbocyclic or heterocyclic group (the 3-8 membered carbocyclic or heterocyclic group may be substituted with C)_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl, or a saturated or unsaturated 5-or 6-membered heterocyclic ring, when the 3-8 membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form an alkylene chain, the 3-8 membered carbocyclic or heterocyclic group may also condense with other saturated or unsaturated 3-8 membered carbocyclic or heterocyclic groups to form a bicyclic group)), or

A saturated or unsaturated 3-8 membered carbocyclic or heterocyclic group (the 3-8 membered carbocyclic or heterocyclic group may be substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trisFluoromethyl group, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl, or a saturated or unsaturated 5-or 6-membered heterocyclic ring, when the 3-8 membered carbocyclic or heterocyclic group is substituted by 2C_1-6When substituted with alkyl groups, the 2 alkyl groups may together form an alkylene chain, the 3-8 membered carbocyclic or heterocyclic group may also be condensed with other saturated or unsaturated 3-8 membered carbocyclic or heterocyclic groups to form a bicyclic group),

however, when X represents CH, Z represents O, L represents an oxygen atom, M represents-NH-, R¹、R⁴、R⁵、R⁶、R⁷And R⁸Represents a hydrogen atom, R²And R³When represents a methoxy group, R⁹Do not represent phenyl, ethoxy or pyridin-2-yl. )

The compounds of the invention are useful for the treatment of malignant tumors.

Detailed Description

Compound (I)

In this specification, the terms "alkyl", "alkoxy", "alkenyl" and "alkynyl" as a group or part of a group, and the like, mean that the group is straight or branched chain alkyl, alkoxy, alkenyl and alkynyl.

C_1-6The alkyl group is preferably C_1-4An alkyl group.

C_1-6Alkoxy is preferably C_1-4An alkoxy group.

C_2-6Alkenyl is preferably C_2-4An alkenyl group.

C_2-6Alkynyl is preferably C_2-4Alkynyl.

C_1-6Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.

C_1-6Examples of alkoxy are methoxy, ethoxyAlkyl, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

C_2-6Examples of alkenyl are 2-propenyl, butenyl, pentenyl, hexenyl.

C_2-6Examples of alkynyl are 2-propynyl, butynyl, pentynyl and hexynyl.

The maximum number of substituents depends on the number of hydrogen atoms that can be substituted on the alkyl group, which is well known to those skilled in the art.

The halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The saturated or unsaturated 3-to 8-membered carbocyclic ring may be preferably a saturated or unsaturated 4-to 7-membered carbocyclic ring, more preferably a saturated or unsaturated 5-or 6-membered carbocyclic ring. Examples of saturated or unsaturated 3-to 8-membered carbocyclic rings are phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The saturated or unsaturated 3-to 8-membered heterocyclic ring may preferably contain 1 or 2 heteroatoms, and the remaining ring atoms are carbon atoms.the saturated or unsaturated 3-to 8-membered heterocyclic ring may preferably be a saturated or unsaturated 4-to 7-membered heterocyclic ring, and more preferably a saturated or unsaturated 5-or 6-membered heterocyclic ring. Examples of saturated or unsaturated 3-to 8-membered heterocyclic groups are thienyl, pyridyl, 1, 2, 3-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, piperazinyl, piperazino, piperidinyl, piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl and azepanyl.

Examples of such bicyclic groups are naphthyl, quinolinyl, 1, 2, 3, 4-tetrahydroquinolinyl, 1, 4-benzoxelohexyl, indanyl, indolyl, and 1, 2, 3, 4-tetrahydronaphthyl.

When carbocyclic or heterocyclic radical is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form an alkylene chain, preferably C_1-3Examples of such a carbocyclic or heterocyclic group having a crosslinked structure are bicyclo [2.2.2 ]]Octyl and bicyclo [2.2.1]A heptalkyl group.

R¹Preferably represents a hydrogen atom.

R²And R³Preferably represents a group other than a hydrogen atom, and more preferably R²Represents unsubstituted C_1-6Alkoxy, more preferably represents methoxy, R³Represents optionally substituted C_1-6An alkoxy group.

R³A substituent represented by_1-6The substituent of the alkoxy group may preferably be a halogen atom, a hydroxyl group, or C_1-6Alkyl (the C)_1-6Alkyl may be substituted) 1-or 2-substituted amino, or a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group which may be substituted (more preferably a saturated or unsaturated 5-to 7-membered carbocyclic or heterocyclic group)_1-6Alkyl 1-or 2-substituted amino, phenyl, piperazinyl, piperazino, piperidinyl, piperidino, morpholinyl, morpholino, homopiperazino, thiomorpholinyl, tetrahydropyrrolyl, azepanyl, imidazolyl, diazepanyl, and pyrrolidinyl.

R³The optionally substituted alkoxy group preferably represents-O- (CH)₂)_m-R¹³(m represents an integer of 1 to 6, R¹³Substituents representing alkoxy radicals, i.e. hydroxy, halogen atoms, C_1-6Alkoxy radical, C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl group, amino group which may be substituted, or saturated group which may be substitutedOr an unsaturated 3-8 membered carbocyclic or heterocyclic group).

R⁵、R⁶、R⁷And R⁸Preferably all represent hydrogen atoms, or R⁵、R⁶、R⁷And R⁸Either or both of them represent a group other than a hydrogen atom, and the rest all represent a hydrogen atom.

R⁹、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸And R¹⁹And R described later¹⁰⁹、R¹¹⁴、R¹¹⁵、R¹¹⁶、R¹¹⁷、R¹¹⁸、R¹¹⁹、R²⁰⁹、R²¹⁴、R²¹⁵、R²¹⁶、R²¹⁷、R²¹⁸、R²¹⁹、R³¹⁹、R⁴¹⁹And R⁵²⁰Examples of the carbocyclic group represented by the carbocyclic group and the carbocyclic group on the alkyl group represented by these groups are a phenyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a naphthyl group, an indanyl group and a 1, 2, 3, 4-tetrahydronaphthyl group. Examples of the preferable substituent of such a carbocyclic group are a fluorine atom, a chlorine atom, a methyl group and a methoxy group.

R⁹、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸And R¹⁹And R described later¹⁰⁹、R¹¹⁴、R¹¹⁵、R¹¹⁶、R¹¹⁷、R¹¹⁸、R¹¹⁹、R²⁰⁹、R²¹⁴、R²¹⁵、R²¹⁶、R²¹⁷、R²¹⁸、R²¹⁹、R³¹⁹、R⁴¹⁹And R⁵²⁰Examples of the heterocyclic group represented by the above-mentioned group and the heterocyclic group on the alkyl group represented by these groups are thienyl, pyridyl, tetrahydropyrrolyl, indolyl, 1, 2, 3-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, quinolyl, 1, 2, 3, 4-tetrahydroquinolyl, thiomorpholinyl and 1, 4-benzoxelohexylPreferred examples of such heterocyclic groups are thienyl, pyridyl, isoxazolyl and quinolyl.

R⁹The optionally substituted alkyl group preferably represents- (CH)₂)p-R¹⁴、-(CH₂)p-T-R¹⁵Or- (CH)₂)p-NR¹⁶R¹⁷(p represents an integer of 1 to 6, R¹⁴、R¹⁵、R¹⁶And R¹⁷The same as defined above).

R⁹Represented by-N (-R)¹⁸)(-R¹⁹) Among them, R is preferred¹⁸Represents a hydrogen atom or C_1-6Alkyl radical, R¹⁹Is represented by C_1-6Alkyl (the C)_1-6The alkyl group may be substituted with a saturated or unsaturated 5-or 6-membered carbocyclic or heterocyclic group which may be substituted) or a saturated or unsaturated 5-or 6-membered carbocyclic or heterocyclic group (the 5-or 6-membered carbocyclic or heterocyclic group may be substituted).

R⁹Preferred examples of (a) are benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, anilino, fluoroanilino, difluoroanilino, chloroanilino, methylanilino, methoxyanilino, naphthyl, thien-2-yl-methyl and thien-3-yl-methyl.

R¹⁰And R¹¹Preferably, both represent a hydrogen atom or an alkyl group, or one represents an alkoxy group and the other represents a hydrogen atom.

R¹²Preferably represents a hydrogen atom.

Preferred examples of compounds of the invention are:

x represents CH or N, Z represents O, L represents O, and M represents-N (-R)¹²) A compound of formula (I) or (II),

X represents CH or N, Z represents O, L represents O, and M represents-C (-R)¹⁰)(-R¹¹) A compound of formula (I) or (II),

X represents CH or N, Z represents O, L represents S, and M represents-N (-R)¹²) A compound of formula (I) of (a).

Preferred examples of compounds of the invention are also:

x represents CH or N, Z represents O, L represents O, and M represents-N (-R)¹²)-，R¹And R⁴Represents a hydrogen atom, R²Represents unsubstituted C_1-6Alkoxy radical, R³Represents optionally substituted C_{1- 6}Alkoxy radical, R⁵、R⁶、R⁷And R⁸All represent a hydrogen atom, or R⁵、R⁶、R⁷And R⁸Any one of the compounds of the formula (I) represents a group other than a hydrogen atom and the remaining represents a hydrogen atom,

X represents CH or N, Z represents O, L represents O, and M represents-C (-R)¹⁰)(-R¹¹)-，R¹And R⁴Represents a hydrogen atom, R²Represents unsubstituted C_1-6Alkoxy radical, R³Represents optionally substituted C_1-6Alkoxy radical, R⁵、R⁶、R⁷And R⁸All represent a hydrogen atom, or R⁵、R⁶、R⁷And R⁸Any one of the compounds of the formula (I) represents a group other than a hydrogen atom and the remaining represents a hydrogen atom,

X represents CH or N, Z represents O, L represents S, and M represents-N (-R)¹²)-，R¹And R⁴Represents a hydrogen atom, R²Represents unsubstituted C_1-6Alkoxy radical, R³Represents optionally substituted C_{1- 6}Alkoxy radical, R⁵、R⁶、R⁷And R⁸All represent a hydrogen atom, or R⁵、R⁶、R⁷And R⁸Any one of them represents a group other than a hydrogen atom and the others represent a hydrogen atom.

Preferred examples of the compound of the present invention are compounds of formula (100).

(in the above formula,

R¹⁰³represents a hydroxyl group or C_1-4Alkoxy (the C)_1-4Alkoxy groups may be substituted by halogen atoms, hydroxy groups, amino groups (1 or 2 hydrogen atoms in the amino group may be substituted by C)_1-6Alkyl substitution of the C_1-6The alkyl radical being further substituted by hydroxy or C_1-6Alkoxy-substituted), or a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic group which may be substituted by C_1-6Alkyl substitution of the C_1-6The alkyl radical being further substituted by hydroxy or C_1-6Alkoxy substituted),

R¹⁰⁵、R¹⁰⁶、R¹⁰⁷and R¹⁰⁸May be the same or different and represents a hydrogen atom, a halogen atom, C_1-4Alkyl or C_1-4An alkoxy group,

R¹⁰⁹to represent

C_1-6Alkyl (the C)_1-61 or more hydrogen atoms on the alkyl group may be replaced by-R¹¹⁴、-T-R¹¹⁵or-NR¹¹⁶R¹¹⁷Substituted, T represents-O-, -S-or-NH-, R¹¹⁴Represents a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group, R¹¹⁵Is represented by C_1-6Alkyl or a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group, R¹¹⁶And R¹¹⁷May be the same or different and represents C_1-6Alkyl or a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group, R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷The 3-to 8-membered carbocyclic or heterocyclic group represented may be substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl or a saturated or unsaturated 5-or 6-membered heterocyclyl, when said 3-8-membered carbocyclyl or heterocyclyl is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form an alkylene chain, preferably C_1-3Alkylene chains, said 3-to 8-membered carbocyclic or heterocyclic radicals also being able to react with other saturated radicalsOr an unsaturated 3-to 8-membered carbocyclic or heterocyclic group condensed to form a bicyclic group), or

A saturated or unsaturated 3-8 membered carbocyclic or heterocyclic group (the 3-8 membered carbocyclic or heterocyclic group may be substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl, or a saturated or unsaturated 5-or 6-membered heterocyclic ring, when the 3-8 membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form an alkylene chain, preferably C_1-3An alkylene chain, said 3-8 membered carbocyclic or heterocyclic group may also be condensed with other saturated or unsaturated 3-8 membered carbocyclic or heterocyclic groups to form a bicyclic group). )

R¹⁰⁵、R¹⁰⁶、R¹⁰⁷And R¹⁰⁸Preferably all represent hydrogen atoms, or R¹⁰⁵、R¹⁰⁶、R¹⁰⁷And R¹⁰⁸Any one of them represents a group other than a hydrogen atom, and the rest all represent hydrogen atoms.

In the formula (100), R¹⁰⁹The optionally substituted alkyl group preferably represents- (CH)₂)p-R¹¹⁴、-(CH₂)p-T-R¹¹⁵Or- (CH)₂)p-NR¹¹⁶R¹¹⁷(p represents an integer of 1 to 6, R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷The same as defined above).

R¹⁰⁹Represented by-N (-R)¹¹⁸)(-R¹¹⁹) Among them, R is preferred¹¹⁸Represents a hydrogen atom or C_1-6Alkyl radical, R¹¹⁹Is represented by C_1-6Alkyl (the C)_1-6The alkyl group may be substituted with a saturated or unsaturated 5-or 6-membered carbocyclic or heterocyclic group which may be substituted) or a saturated or unsaturated 5-or 6-membered carbocyclic or heterocyclic group (the 5-or 6-membered carbocyclic or heterocyclic group may be substituted).

R¹⁰⁹Preferred examples of (B) are benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzylMethoxybenzyl, naphthyl and thienyl.

Preferred examples of the compound of the present invention are compounds of formula (200).

(in the above formula,

R²⁰³represents a hydroxyl group or C_1-4Alkoxy (the C)_1-4Alkoxy groups may be substituted by halogen atoms, hydroxy groups, amino groups (1 or 2 hydrogen atoms in the amino group may be substituted by C)_1-6Alkyl substitution of the C_1-6The alkyl radical being further substituted by hydroxy or C_1-6Alkoxy-substituted), or a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic group which may be substituted by C_1-6Alkyl substitution of the C_1-6The alkyl radical being further substituted by hydroxy or C_1-6Alkoxy substituted),

R²⁰⁵、R²⁰⁶、R²⁰⁷and R²⁰⁸May be the same or different and represents a hydrogen atom, a halogen atom, C_1-4Alkyl or C_1-4An alkoxy group,

R²⁰⁹to represent

C_1-6Alkyl (the C)_1-61 or more hydrogen atoms on the alkyl group may be replaced by-R²¹⁴、-T-R²¹⁵or-NR²¹⁶R²¹⁷Substituted, T represents-O-, -S-or-NH-, R²¹⁴Represents a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group, R²¹⁵Is represented by C_1-6Alkyl or a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group, R²¹⁶And R²¹⁷May be the same or different and represents C_1-6Alkyl or a saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic group, R²¹⁴、R²¹⁵、R²¹⁶And R²¹⁷The 3-to 8-membered carbocyclic or heterocyclic group represented may be substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl or a saturated or unsaturated 5-or 6-membered heterocyclic ring, when the 3-8 membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form an alkylene chain, preferably C_1-3An alkylene chain, said 3-to 8-membered carbocyclic or heterocyclic group may also be condensed with other saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic groups to form a bicyclic group), or

A saturated or unsaturated 3-8 membered carbocyclic or heterocyclic group (the 3-8 membered carbocyclic or heterocyclic group may be substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl, or a saturated or unsaturated 5-or 6-membered heterocyclic ring, when the 3-8 membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form an alkylene chain, preferably C_1-3An alkylene chain, said 3-8 membered carbocyclic or heterocyclic group may also be condensed with other saturated or unsaturated 3-8 membered carbocyclic or heterocyclic groups to form a bicyclic group))

R²⁰⁵、R²⁰⁶、R²⁰⁷And R²⁰⁸Preferably all represent hydrogen atoms, or R²⁰⁵、R²⁰⁶、R²⁰⁷And R²⁰⁸Any one of them represents a group other than a hydrogen atom, and the rest all represent hydrogen atoms.

In the formula (200), R²⁰⁹The optionally substituted alkyl group preferably represents- (CH)₂)p-R²¹⁴、-(CH₂)p-T-R²¹⁵Or- (CH)₂)p-NR²¹⁶R²¹⁷(p represents an integer of 1 to 6, R²¹⁴、R²¹⁵、R²¹⁶And R²¹⁷The same as defined above).

R²⁰⁹Represented by-N (-R)²¹⁸)(-R²¹⁹) Among them, R is preferred²¹⁸Represents a hydrogen atom or C_1-6Alkyl radical, R²¹⁹Is represented by C_1-6Alkyl (the C)_1-6The alkyl group may be substituted with a saturated or unsaturated 5-or 6-membered carbocyclic or heterocyclic group which may be substituted) or a saturated or unsaturated 5-or 6-membered carbocyclic or heterocyclic group (the 5-or 6-membered carbocyclic or heterocyclic group may be substituted).

R²⁰⁹Preferred examples of (B) are benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl and methoxybenzyl.

Preferred examples of the compound of the present invention are compounds of formula (300).

(in the above formula,

R³⁰³represents a hydroxyl group or C_1-4Alkoxy (the C)_1-4The alkoxy group may be substituted with a halogen atom or a saturated or unsaturated 6-membered carbocyclic or heterocyclic group (the carbocyclic or heterocyclic group may be substituted with C)_1-6Alkyl substitution of the C_1-6The alkyl radical being further substituted by hydroxy or C_1-6Alkoxy substituted),

R³⁰⁵、R³⁰⁶、R³⁰⁷and R³⁰⁸May be the same or different and represents a hydrogen atom, a halogen atom, C_1-4Alkyl or C_1-4An alkoxy group,

R³¹⁰and R³¹¹Represents a hydrogen atom, C_1-4Alkyl or C_1-4An alkoxy group,

R³¹⁸represents a hydrogen atom or C_1-4An alkyl group, a carboxyl group,

R³¹⁹to represent

C_1-4Alkyl (the C)_1-4The alkyl group may be substituted with a saturated or unsaturated 6-membered carbocyclic group, and the 6-membered carbocyclic group may be substituted with C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano, or a salt thereof,Cyano group C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl or a saturated or unsaturated 5-or 6-membered heterocyclic ring, when the 6-membered carbocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form an alkylene chain, preferably C_1-3An alkylene chain, said 6-membered carbocyclic group also being condensable with other saturated or unsaturated 3-8 membered carbocyclic or heterocyclic groups to form a bicyclic group), or

A saturated or unsaturated 4-7-membered carbocyclic or heterocyclic group (the 4-7-membered carbocyclic or heterocyclic group may be substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_1-6Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl, or a saturated or unsaturated 5-or 6-membered heterocyclic ring, when the 4-7-membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form an alkylene chain, preferably C_1-3An alkylene chain, said 4-7 membered carbocyclic or heterocyclic group may also be condensed with other saturated or unsaturated 3-8 membered carbocyclic or heterocyclic groups to form a bicyclic group). )

R³⁰⁵、R³⁰⁶、R³⁰⁷And R³⁰⁸Preferably all represent hydrogen atoms, or R³⁰⁵、R³⁰⁶、R³⁰⁷And R³⁰⁸Any one of them represents a group other than a hydrogen atom, and the rest all represent hydrogen atoms.

R³¹⁹Preferred examples of (a) are phenyl, fluorophenyl, difluorophenyl, chlorophenyl, methylphenyl and methoxyphenyl.

Preferred examples of the compound of the present invention are compounds of formula (400).

(in the above formula,

R⁴⁰⁵、R⁴⁰⁶、R⁴⁰⁷and R⁴⁰⁸May be the same or different and represents a hydrogen atom, a halogen atom, C_1-4Alkyl or C_1-4An alkoxy group,

R⁴¹⁹represents an unsaturated 5-or 6-membered carbocyclic or heterocyclic group which may be substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, C_{1- 6}Alkoxycarbonyl, cyano C_1-6Alkyl radical, C_1-6Alkylthio, phenoxy, acetyl, or a saturated or unsaturated 5-or 6-membered heterocyclic ring, when the 5-or 6-membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form an alkylene chain, preferably C_1-3An alkylene chain, said 5-or 6-membered carbocyclic or heterocyclic group also being condensable with other saturated or unsaturated 3-to 8-membered carbocyclic or heterocyclic groups to form a bicyclic group.)

R⁴⁰⁵、R⁴⁰⁶、R⁴⁰⁷And R⁴⁰⁸Preferably all represent hydrogen atoms, or R⁴⁰⁵、R⁴⁰⁶、R⁴⁰⁷And R⁴⁰⁸Any one of them represents a group other than a hydrogen atom, and the rest all represent hydrogen atoms.

R⁴¹⁹Preferred examples of (a) are phenyl, fluorophenyl, difluorophenyl, chlorophenyl, methylphenyl, methoxyphenyl, pyridyl, isoxazolyl and quinolinyl.

Preferred examples of the compounds of the present invention are also compounds of formula (500).

(in the above formula,

x represents a group of a CH or an N,

l represents O, M represents-N (-R)¹²) When Q represents CH₂Or a combination of NH and hydrogen, or a combination of NH,

l represents O, M represents-C (-R)¹⁰)(-R¹¹) when-is-Q represents NH,

l represents S, M represents-N (-R)¹²) When Q represents CH₂，

R⁵⁰³Represents a hydroxyl group or C_1-4Alkoxy (the C)_1-4Alkoxy groups may be substituted by halogen atoms, hydroxy groups, amino groups (1 or 2 hydrogen atoms in the amino group may be substituted by C)_1-6Alkyl substitution of the C_1-6The alkyl radical being further substituted by hydroxy or C_1-6Alkoxy-substituted), or a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic group which may be substituted by C_1-6Alkyl substitution of the C_1-6The alkyl radical being further substituted by hydroxy or C_1-6Alkoxy substituted),

R⁵⁰⁵、R⁵⁰⁶、R⁵⁰⁷and R⁵⁰⁸May be the same or different and represents a hydrogen atom, a halogen atom, C_1-4Alkyl or C_1-4An alkoxy group,

R⁵²⁰represents a saturated or unsaturated 5-or 6-membered carbocyclic or heterocyclic group which may be substituted by C_1-6Alkyl radical, C_1-6Alkoxy or halogen substituted.)

R⁵⁰⁵、R⁵⁰⁶、R⁵⁰⁷And R⁵⁰⁸Preferably all represent hydrogen atoms, or R⁵⁰⁵、R⁵⁰⁶、R⁵⁰⁷And R⁵⁰⁸Any one of them represents a group other than a hydrogen atom, and the rest all represent hydrogen atoms.

The following compounds are preferred examples of the compounds of the present invention, and the numbers attached to the compounds indicate the numbers of the examples.

(1) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -N' -phenylacetylthiourea

(2) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -N' - [2- (4-fluorophenyl) acetyl ] thiourea

(3) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -N' - [2- (4-fluorophenyl) acetyl) urea

(4)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetyl urea

(5) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -N' - (4-fluorophenyl) malonamide

(6) N- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -N' - (2, 4-difluorophenyl) malonamide

(7)1- (2-Cyclopentylsulfanylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl) urea

(8)1- (3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2, 3-dihydro-1H-1-indol-1-yl) acetyl ] urea

(9) N-phenyl- ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(10) N- (4-fluorophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(11)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) quinolin-4-yloxy ] phenyl } -3-phenylacetyl urea

(12)1- (3-fluoro-4- { 6-methoxy-7- [4- (4-methyl-piperazin-1-yl) -butoxy ] quinolin-4-yloxy } phenyl-3-phenylacetyl urea

(13)1- { 3-fluoro-4- [ 6-methoxy-7- (2-piperidin-1-yl-ethoxy) quinolin-4-yloxy ] phenyl } -3-phenylacetyl urea

(14)1- {4- [7- (3-chloro-propoxy) -6-methoxyquinolin-4-yloxy ] -3-fluorophenyl } -3-phenylacetyl urea

(15) N- (2, 4-difluorophenyl) -N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -2-methylmalonamide

(16)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3-phenylacetyl urea

(17)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-phenylacetyl urea

(18)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetyl urea

(19)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-thiophen-3-ylacetyl) urea

(20)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-thiophen-3-ylacetyl) urea

(21)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiophen-3-ylacetyl) urea

(22)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (4-fluorophenyl) acetyl ] urea

(23)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (4-fluorophenyl) acetyl ] urea

(24)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (4-fluorophenyl) acetyl ] urea

(25)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-fluorophenyl) acetyl ] urea

(26)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2-fluorophenyl) acetyl ] urea

(27)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2-fluorophenyl) acetyl ] urea

(28)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-fluorophenyl) acetyl ] urea

(29)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiophen-2-ylacetyl) urea

(30)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-thiophen-2-ylacetyl) urea

(31)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-thiophen-2-ylacetyl) urea

(32)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiophen-2-ylacetyl) urea

(33)1- [2- (2, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(34)1- [2- (2, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(35)1- [2- (3, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(36)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (3-fluorophenyl) acetyl ] urea

(37)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (3-fluorophenyl) acetyl ] urea

(38)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenyl ] -3- [2- (4-fluorophenyl) acetyl ] urea

(39)1- [2- (3, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] urea

(40)1- [4- (7-benzyloxy-6-methoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (4-fluorophenyl) acetyl ] urea

(41)1- { 3-fluoro-4- [ 6-methoxy-7- (4-morpholin-4-yl-butoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(42)1- { 3-fluoro-4- [ 6-methoxy-7- (4-piperidin-1-yl-butoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(43)1- (3-fluoro-4- { 6-methoxy-7- [4- (4-methyl-piperazin-1-yl) -butoxy ] quinolin-4-yloxy } phenyl) -3- [2- (4-fluorophenyl) acetyl ] urea

(44)1- { 2-fluoro-4- [ 6-methoxy-7- (4-morpholin-4-yl-butoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(45)1- { 2-fluoro-4- [ 6-methoxy-7- (4-piperidin-1-yl-butoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(46)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(47)1- { 3-fluoro-4- [ 6-methoxy-7- (3-piperidin-1-yl-propoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(48)1- { 3-fluoro-4- [ 6-methoxy-7- (2-piperidin-1-yl-ethoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(49)1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy ] quinolin-4-yloxy } phenyl) -3- [2- (4-fluorophenyl) acetyl ] urea

(50)1- { 2-fluoro-4- [ 6-methoxy-7- (3-piperidin-1-yl-propoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(51)1- (2-fluoro-4- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] quinolin-4-yloxy } phenyl) -3- [2- (4-fluorophenyl) acetyl ] urea

(52)1- { 3-fluoro-4- [ 6-methoxy-7- (3-piperidin-1-yl-propoxy) quinolin-4-yloxy ] phenyl } -3-phenylacetyl urea

(53)1- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] quinolin-4-yloxy } phenyl) -3-phenylacetyl urea

(54)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) quinolin-4-yloxy ] phenyl } -3-phenylacetyl urea

(55)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(56)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (naphthalene-1-carbonyl) thiourea

(57)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (naphthalene-1-carbonyl) thiourea

(58)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3-phenylacetylthiourea

(59)1- [2- (2-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(60)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetylthiourea

(61)1- (2-Cyclohexylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] Thiourea

(62)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (3-ethoxypropionyl) thiourea

(63)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetylthiourea

(64)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (3-o-tolylpropanoyl) thiourea

(65)1- [ 2-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetylthiourea

(66)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiophen-2-ylacetyl) thiourea

(67)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-methylphenyl ] -3-phenylacetylthiourea

(68)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-methoxyphenyl ] -3-phenylacetylthiourea

(69)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenyl ] -3-phenylacetylthiourea

(70)1- [3, 5-dichloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetylthiourea

(71)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (4-fluorophenyl) acetyl ] thiourea

(72)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (4-fluorophenyl) acetyl ] thiourea

(73)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (4-fluorophenyl) acetyl ] thiourea

(74)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (3-fluorophenyl) acetyl ] thiourea

(75)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (3-fluorophenyl) acetyl ] thiourea

(76)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (3-fluorophenyl) acetyl ] thiourea

(77)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-m-tolylacetyl) thiourea

(78)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-m-tolylacetyl) thiourea

(79)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-o-tolylacetyl) thiourea

(80)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2-fluorophenyl) acetyl ] thiourea

(81)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2-fluorophenyl) acetyl ] thiourea

(82)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-p-tolylacetyl) thiourea

(83)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2-methoxyphenyl) acetyl ] thiourea

(84)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-o-tolylacetyl) thiourea

(85)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-thiophen-3-ylacetyl) thiourea

(86)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenyl ] -3- (2-thiophen-3-ylacetyl) thiourea

(87)1- [2- (2-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(88)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(89)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(90)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(91)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(92)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-p-tolylacetyl) thiourea

(93)1- [2- (2, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(94)1- [2- (2, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(95)1- [2- (2, 6-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(96)1- [2- (2, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(97)1- [2- (2, 6-dichlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(98) N- (2, 4-difluorophenyl) -N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] malonamide

(99) N- (2, 4-difluorophenyl) -N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] malonamide

(100) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -N' -phenylmalonamide

(101) N-cycloheptyl-N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] malonamide

(102) N- (2, 4-difluorophenyl) -N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] malonamide

(103) N- (2, 4-difluorophenyl) -N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -2-methoxypropanimidamide

(104) N- (2, 4-difluorophenyl) -N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -2, 2-dimethylmalonamide

(105) N- (4-methyl-2-pyridinyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(106)1- [ 3-fluoro-4- (7-hydroxy-6-methoxyquinolin-4-yloxy) phenyl ] -3-phenylacetyl urea

(107)1- (2-chloro-benzoyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(108)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-methyl-benzoyl) urea

(109)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-valerylurea

(110)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-diethylaminoacetyl) urea

(111)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-pyrrolidine (ピロシジン) -1-ylacetyl) urea

(112)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (isopropylmethylamino) acetyl ] urea

(113)1- (2-Cyclohexylsulfanylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] urea

(114)1- (2-Cyclohexylsulfanylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(115)1- (2-Cyclohexylsulfanylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(116)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-cyclopentylsulfanylacetyl) urea

(117)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-o-tolylaminoacetyl) urea

(118)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiophen-3-ylacetyl) urea

(119)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (6-methyl-3, 4-dihydro-2H-quinolin-1-yl) acetyl ] urea

(120)1- [2- (4-benzyl-piperidin-1-yl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(121)1- [2- (2, 3-dihydro-1H-1-indol-1-yl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(122)1- [2- (2, 3-dihydro-1H-1-indol-1-yl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(123)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2- [1, 2, 3] triazol-1-ylacetyl) urea

(124)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-p-tolylacetyl) urea

(125)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] urea

(126)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(127)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(128)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] urea

(129)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-phenylsulfamoyl acetyl) urea

(130)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (1-methyl-1H-imidazol-2-ylsulfanyl) acetyl ] urea

(131)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiomorpholin-4-ylacetyl) urea

(132)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiomorpholin-4-ylacetyl) urea

(133)1- [2- (2, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(134)1- [2- (2, 6-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(135)1- [2- (2, 6-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(136)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2-trifluoromethylphenyl) acetyl ] urea

(137)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2-trifluoromethylphenyl) acetyl ] urea

(138)1- [2- (2, 3-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl) urea

(139)1- [2- (2, 3-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(140)1- [2- (3, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(141)1- [2- (3, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(142)1- [2- (3, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(143) 1-Cyclopentanecarbonyl-3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(144)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (3-methoxy-benzoyl) thiourea

(145)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (3-trifluoromethyl-benzoyl) thiourea

(146)1- (2-bromobenzoyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(147)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (3-methylsulfanylpropanoyl) thiourea

(148)1- (4-chloro-butyryl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(149)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-o-tolylacetyl) thiourea

(150)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-phenylcyclopropanecarbonyl) thiourea

(151)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-fluorophenyl) acetyl ] thiourea

(152)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-fluorophenyl) acetyl ] thiourea

(153)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-methoxyphenyl) acetyl ] thiourea

(154)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-methoxyphenyl) acetyl ] thiourea

(155)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-nitrophenyl) acetyl ] thiourea

(156)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-nitrophenyl) acetyl ] thiourea

(157)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-phenoxyacetyl) thiourea

(158)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-phenyl-propionyl) thiourea

(159)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (3-ethoxypropionyl) thiourea

(160)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (5-methylthiophene-2-carbonyl) thiourea

(161)1- (3-Cyclopentylpropionyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(162)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-methylphenyl ] -3-phenylacetylthiourea

(163)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2, 5-dimethylphenyl ] -3-phenylacetylthiourea

(164)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (3-fluorophenyl) acetyl ] thiourea

(165)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (3-ethoxypropionyl) thiourea

(166)1- (2-Cyclohexylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] Thiourea

(167)1- (2-butoxyacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(168)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-p-tolylacetyl) thiourea

(169)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2-methoxyphenyl) acetyl ] thiourea

(170)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-o-tolylacetyl) thiourea

(171)1- [2- (3-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(172)1- [2- (3-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(173)1- [2- (3-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(174)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (3-chlorophenyl) acetyl ] thiourea

(175)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-m-tolylacetyl) thiourea

(176)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-m-tolylacetyl) thiourea

(177)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (5-methyl-hexanoyl) thiourea

(178)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (5-methyl-hexanoyl) thiourea

(179)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (5-methyl-hexanoyl) thiourea

(180)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (3-methoxy-propionyl) thiourea

(181)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (3-methoxyphenyl) acetyl ] thiourea

(182)1- [2- (2-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(183)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-chlorophenyl) acetyl ] thiourea

(184)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (3-methoxyphenyl) acetyl ] thiourea

(185)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (3-methoxyphenyl) acetyl ] thiourea

(186)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (3-methoxyphenyl) acetyl ] thiourea

(187)1- [2- (4-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(188)1- [2- (4-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(189)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (4-chlorophenyl) acetyl ] thiourea

(190)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-p-tolylacetyl) thiourea

(191)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (4-methyl-cyclohexyl) acetyl ] thiourea

(192)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (4-methyl-cyclohexyl) acetyl ] thiourea

(193)1- (2-butoxyacetyl) -3- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(194)1- [2- (2, 3-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(195)1- [2- (2, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(196)1- [2- (3, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(197)1- [2- (3, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(198)1- [2- (3, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(199)1- [2- (3, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(200)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2-trifluoromethylphenyl) acetyl ] thiourea

(201)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2-trifluoromethylphenyl) acetyl ] thiourea

(202)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (3-trifluoromethylphenyl) acetyl ] thiourea

(203)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (3-trifluoromethylphenyl) acetyl ] thiourea

(204)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2, 3, 6-trifluorophenyl) acetyl ] thiourea

(205)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2, 3, 6-trifluorophenyl) acetyl ] thiourea

(206)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2, 3, 6-trifluorophenyl) acetyl ] thiourea

(207)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2, 3, 6-trifluorophenyl) acetyl ] thiourea

(208)1- [2- (2, 6-dichlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(209) N-butyl-N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] malonamide

(210) N- (3-chlorophenyl) -N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] malonamide

(211) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -N' - (2-methoxyphenyl) malonamide

(212) N-cyclobutyl-N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] malonamide

(213)3- {2- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenylcarbamoyl ] acetylamino } benzoic acid methyl ester

(214) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -N' - (1-phenylethyl) malonamide

(215) N-benzyl-N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] malonamide

(216) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl-N '-methyl-N' -phenylmalonamide

(217) N-cyclohexyl-N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] malonamide

(218) N-cyclohexylmethyl-N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] malonamide

(219) N- (4-chlorophenyl) -N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] malonamide

(220) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -N' - (3-hydroxyphenyl) malonamide

(221) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -N' - (3, 3-dimethyl-butyl) malonamide

(222) N- [ 2-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -N' - (2, 4-difluorophenyl) malonamide

(223) N- (2, 4-difluorophenyl) -N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-methylphenyl ] malonamide

(224) N- (2, 4-difluorophenyl) -N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) -2, 5-dimethylphenyl ] malonamide

(225) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -2-methyl-N' -phenylmalonamide

(226) N-cyclohexyl-N' - [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -2-methylmalonamide

(227) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -N' -pyridin-3-ylmalonamide

(228) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -2, 2-dimethyl-N' -phenylmalonamide

(229) N- (2, 4-difluorophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(230) N- (3-bromo-5-methyl-2-pyridinyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(231) N- (5-chloro-2-pyridinyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(232) N- (5-methyl-3-isoxazolyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(233) N- (3-methyl-2-pyridinyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(234) N- (6-methyl-2-pyridinyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(235) N- (5-methyl-2-pyridinyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(236) N- (2-pyridinyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(237) N- (1-methyl-1H-5-pyrazolyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(238) N- (2, 3-dihydro-1, 4-benzodioxin-6-yl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(239) N- (3-cyanophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(240) N- [2- (trifluoromethyl) phenyl ] - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(241) N- [4- (cyanomethyl) phenyl ] - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(242) N- (4-chloro-2-methylphenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(243) N- (2, 3-dihydro-1H-5-indenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(244) N- (3-methoxyphenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(245) Methyl 2- ({ ({ [4- (6, 7-Dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) benzoate

(246) N- (2-benzylphenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(247) N- (2-bromophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(248) N- (2-chlorophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(249) N- (4-chlorophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(250) N- (2-chloro-4-fluorophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(251) N- (3-fluorophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(252) N- (2-fluorophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(253) N- [2- (methylthio) phenyl ] - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(254) N- (4-Nitrophenyl) - ({ [4- (6, 7-Dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(255) N- (2-phenoxyphenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(256) N- (3-methylphenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(257) N- (4-methylphenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(258) N- (2, 6-dimethylphenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(259) N- [2- (1H-1-pyrrolyl) phenyl ] - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(260) N- (8-quinolyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(261) N- (3-acetylphenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(262) N- (5-quinolyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(263) N- (2, 6-dichlorophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(264) N- (3, 4-difluorophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(265) N- (2, 6-difluorophenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(266) N- (2-methoxyphenyl) - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(267) N- [2- (2-hydroxyethyl) phenyl ] - ({ [4- (6, 7-dimethoxyquinolin-4-yloxy) anilino ] carbonyl } amino) carboxamide

(268) N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-ylpropoxy) quinolin-4-yloxy ] phenyl } -N' -phenylacetylthiourea

(269) N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-ylpropoxy) quinolin-4-yloxy ] phenyl } -N' - (4-fluorophenyl) malonamide

(270)1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy ] -quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

(271)1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy ] -quinolin-4-yloxy } -phenyl) -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(272)1- {4- [7- (2-diethylamino-ethoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3-phenylacetyl-thiourea

(273)1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl- [1, 4] diazepan-1-yl) -ethoxy ] -quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

(275)1- {4- [7- (2-diethylamino-ethoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(276)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

(277)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(278)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluorophenyl) -acetyl ] -thiourea

(279)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(282)1- (3-fluoro-4- {7- [2- (4-hydroxymethyl-piperidin-1-yl) -ethoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(283)1- (3-fluoro-4- {7- [2- (4-hydroxymethyl-piperidin-1-yl) -ethoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl urea

(284)1- (3-fluoro-4- {7- [2- (4-hydroxymethyl-piperidin-1-yl) -ethoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

(285)1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -thiourea

(286)1- { 2-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -urea

(287)1- { 2-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3-phenyl-acetyl-urea

(288)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(289)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(291)1- {4- [7- (3-diethylamino-propoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3-phenyl-acetyl-urea

(292)1- { 3-fluoro-4- [ 6-methoxy-7- (3-pyrrolidin-1-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3-phenyl-acetyl-urea

(293)1- {4- [7- (3-diethylamino-propoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

(294)1- { 3-fluoro-4- [ 6-methoxy-7- (3-pyrrolidin-1-yl-propoxy) -quinolin-4-yl-oxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

(295)1- { 3-fluoro-4- [ 6-methoxy-7- (3-piperidin-1-yl-propoxy) -quinolin-4-yl-oxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

(296)1- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinolin-4-yloxy } -phenyl) -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

(297)1- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinolin-4-yloxy } -phenyl) -3- (2-m-tolylacetyl (toluyl-acetyl)) -thiourea

(298)1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(299)1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(300)1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

(301)1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-o-tolylacetyl) -thiourea

(302)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-o-tolylacetyl) -thiourea

(303)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-m-tolylacetyl) -thiourea

(304)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-p-tolylacetyl) -thiourea

(305)1- { 3-fluoro-4- [7- (3-imidazol-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3-phenylacetyl urea

(306)1- { 3-fluoro-4- [7- (3-imidazol-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

(307)1- { 3-fluoro-4- [7- (3-imidazol-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

(308)1- (3-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-urea

(309)1- (3-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

(310)1- (3-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(311)1- (2-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-urea

(312)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

(313)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(314)1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(315)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(316)1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(317)1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(318)1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(319)1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(320)1- [2- (3-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(321)1- [2- (3-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(322)1- [2- (3-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(323)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(324)1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(325)1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(326)1- [2- (4-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(327)1- [2- (4-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(328)1- [2- (4-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(329)1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(330)1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(331)1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-phenyl-acetyl) -thiourea

(332)1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-phenyl-acetyl) -thiourea

(333)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-o-tolylacetyl) -thiourea

(334)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-m-tolylacetyl) -thiourea

(335)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-p-tolylacetyl) -thiourea

(336)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -urea

(337)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-phenylacetyl) -urea.

Particularly preferred examples of the compounds of the present invention are 1 to 6, 9 to 13, 16 to 39, 42, 43, 49, 52 to 54, 56 to 102, 105, 106, 266-269, 285, 286, 288, 312, 313, 333 and 334.

The most preferred examples of compounds of the present invention are compounds 1, 2, 3, 11 and 268.

Preferred examples thereof include alkali metal or alkaline earth metal salts such as sodium salt, potassium salt or calcium salt, hydrohalic acid salts such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, and inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate; lower alkylsulfonic acid salts such as methanesulfonic acid salt, trifluoromethanesulfonic acid salt, ethanesulfonic acid salt and the like; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate, acetate, malate, lactate, and ascorbate; and amino acid salts such as glycinate, phenylalanine, glutamate and aspartate.

Such solvates are, for example, hydrates, alcoholates (e.g., methanolates, ethanolates) and etherates (e.g., etherates).

Preparation of the Compounds

The compounds of the present invention may be prepared, for example, according to schemes 1-9. The starting materials necessary for the synthesis of the compounds of the invention are either commercially available or can be readily prepared by conventional methods¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹⁸、R¹⁹And X is as defined above. PG represents a protecting group, R³' O represents an optionally substituted alkoxy group, Hal represents a halogen atom, R⁵¹And R⁵²May be the same or different and represents C which may be substituted_1-6Alkyl, or R⁵¹And R⁵²May form a saturated or unsaturated 3-to 8-membered heterocyclic ring together with the nitrogen atom to which it is attached, and n represents an integer of 1 to 6.

Scheme 1: preparation of 4- (aminophenylamino) quinoline derivatives and corresponding quinazoline derivatives Prepare for

The 4-chloroquinoline derivative can be synthesized, for example, by a method commonly used in the literature such as org. synth. col. vol.3, 272(1955), Acta Chim. Hung., 112, 241(1983) or WO 98/47873, scheme 1 shows a synthesis example of the 4-chloroquinoline derivative, a 2-aminoacetophenone derivative is reacted in a suitable solvent (e.g., tetrahydrofuran) in the presence of a formic acid ester (e.g., ethyl formate) and a base (e.g., sodium methoxide) to obtain a quinoline derivative, and the quinoline derivative is reacted in the presence of a chlorinating agent (e.g., phosphorus oxychloride) to obtain the 4-chloroquinoline derivative.

The 4-chloroquinazoline derivative can be produced, for example, by reacting a 2-aminobenzoate derivative in an appropriate solvent (for example, a mixed solvent of N, N-dimethylformamide and methanol) in the presence of formamide and a base (for example, sodium methoxide) to obtain a quinazolinone derivative, and reacting the quinazolinone derivative in the presence of a chlorinating agent (for example, phosphorus oxychloride) to obtain a 4-chloroquinazoline derivative.

Subsequently, the 4-chloroquinoline derivative or the corresponding quinazoline derivative is allowed to act on a nitrophenol derivative in an appropriate solvent (e.g., chlorobenzene) to synthesize a 4- (nitrophenoxy) quinoline derivative or a corresponding quinazoline derivative, which is then reacted in an appropriate solvent (e.g., N-dimethylformamide) in the presence of a catalyst (e.g., palladium hydroxide-carbon, palladium on carbon) in a hydrogen atmosphere to give a 4- (aminophenoxy) quinoline derivative or a corresponding quinazoline derivative.

Alternatively, 4- (aminophenoxy) quinoline derivatives or corresponding quinazoline derivatives can be obtained by reacting them with aminophenol derivatives in the presence of a base (e.g., sodium hydride) in a suitable solvent (e.g., dimethylsulfoxide). 4- (aminophenoxy) quinazoline derivatives can be prepared by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the resulting solution to a two-phase reaction with a 4-chloroquinazoline derivative dissolved in an appropriate organic solvent (e.g., ethyl methyl ketone) in the presence or absence of a phase transfer catalyst (e.g., tetra-n-butylammonium chloride).

Scheme 2: preparation of Compounds of formula (I)

The 4- (aminophenoxy) quinoline derivative or quinazoline derivative is reacted with a carbonylthioisocyanate derivative in an appropriate solvent (e.g., a toluene-ethanol mixed solvent) to obtain a carbonylthiourea derivative. For example, carbonyl thioisocyanate derivatives can be prepared by reacting potassium thiocyanate with an acyl chloride derivative in a suitable solvent (e.g., acetonitrile).

Carbonyl urea derivatives can be obtained by reacting carbonyl isocyanate derivatives with 4- (aminophenoxy) quinoline derivatives or quinazoline derivatives in an appropriate solvent (e.g., N-dimethylformamide). Carbonyl isocyanate derivatives are commercially available or can also be readily prepared according to conventional methods, e.g., as described in j.304306(1965), by reacting oxalyl chloride with an amide derivative in a suitable solvent (e.g., 1, 2-dichloroethane), a carbonyl isocyanate derivative can be obtained.

The aminocarbonylurea derivatives are obtained by reacting an N- (chlorocarbonyl) isocyanate with a 4- (aminophenoxy) quinoline derivative or a quinazoline derivative in the presence of a base (e.g. diisopropylamine) in a suitable solvent (e.g. dichloromethane) and then reacting the amine derivative.

The carboxylic acid derivative or metal salt thereof is reacted with a 4- (aminophenoxy) quinoline derivative or quinazoline derivative in the presence of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and a carboxylic acid activating agent such as 1-hydroxybenzotriazole monohydrate in a suitable solvent such as chloroform to give an amide derivative.

Scheme 3:4- (aminophenoxy) quinolines substituted in position 7 of the quinoline ring with a specific group Preparation of derivatives

A derivative having a specific substituent at the 7-position of the quinoline ring can be prepared, for example, according to scheme 3, a commercially available 4' -hydroxyacetophenone derivative is protected with an appropriate substituent (e.g., benzyl group) and then a nitro group is introduced by acting it with a nitrating agent (e.g., fuming nitric acid-acetic acid). the same operation as scheme 1 is started. In this chlorination reaction, when phosphoryl chloride is used as a chlorinating agent, a base (e.g., N-diisopropylethylamine) is added to improve the yield. Subsequently, 4- (nitrophenoxy) quinoline derivatives are synthesized by reacting 4-chloroquinoline derivatives with nitrophenol derivatives, and then reacted in a suitable solvent in the presence of a catalyst in a hydrogen atmosphere to obtain 4- (aminophenoxy) quinoline derivatives. The nitro group can be reduced by zinc, iron, etc. The 4- (aminophenoxy) quinoline derivative can also be produced by reacting a 4-chloroquinoline derivative with an aminophenol derivative in the presence of a base.

Scheme 4: 4- (aminophenoxy) quinazines substituted in position 7 of the quinazoline ring with specific groups Preparation of oxazoline derivatives

For example, a derivative having a specific substituent at the 7-position of the quinazoline ring can be prepared according to scheme 4 after the hydroxyl group of a commercially available 4' -hydroxybenzoate derivative is protected with an appropriate substituent (e.g., benzyl group), a nitro group can be introduced by reacting it with a nitrating agent (e.g., fuming nitric acid-acetic acid). That is, 4-chloroquinazoline derivatives can be produced by reducing a nitro group to an amino group, reacting the amino group with formamide in the presence of a base to form a quinazolinone ring, and then reacting a chlorinating agent therewith. Subsequently, the 4-chloroquinazoline derivative is allowed to act on a nitrophenol derivative to synthesize a 4- (nitrophenoxy) quinazoline derivative, and then the 4- (aminophenoxy) quinazoline derivative is allowed to react in a suitable solvent in the presence of a catalyst in a hydrogen atmosphere to obtain a 4- (aminophenoxy) quinazoline derivative, the nitro group can be reduced with zinc, iron or the like, the 4- (aminoaryloxoxy) quinazoline derivative can also be obtained by allowing the 4-chloroquinazoline derivative to act on an aminophenol derivative in the presence of a base, the aminophenol derivative is dissolved in an aqueous sodium hydroxide solution, and the 4-chloroquinazoline derivative dissolved in an organic solvent is allowed to react in two phases with the phase transfer catalyst or without a catalyst, whereby the 4- (aminophenoxy) quinazoline derivative can also be obtained.

Scheme 5: carbonyl sulfide substituted with specific substituent at 7-position of quinoline ring or quinazoline ring Urea derivatives (formula (I) wherein L-S-, M-NR ¹² Compound of (a) to (b) and (b) preparation of

For example, a carbonylthiourea derivative having a specific substituent at the 7-position of a quinoline ring or a quinazoline ring can be prepared according to scheme 5, that is, a 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative can be prepared by removing the protecting group of the hydroxyl group of the 4- (nitrophenoxy) quinoline derivative or quinazoline derivative obtained in scheme 3 or scheme 4 under appropriate conditions (for example, when the protecting group is a benzyl group, for example, by reacting it in N, N-dimethylformamide in the presence of palladium hydroxide-on-carbon or palladium-on-carbon under a hydrogen atmosphere). N-dimethylformamide) in the presence of a catalyst (e.g., palladium hydroxide-carbon, palladium on carbon) in a hydrogen atmosphere to obtain a 4- (aminophenoxy) quinoline derivative or a corresponding quinazoline derivative. The nitro group can be reduced by zinc, iron, etc. The same operation as in scheme 2 is thereby started. That is, a carbonylthiourea derivative can be obtained by reacting a carbonylthioisocyanate derivative with a 4- (aminophenoxy) quinoline derivative or a quinazoline derivative in an appropriate solvent.

Scheme 6: carbonyl urea derivatives substituted in position 7 of quinoline or quinazoline ring by specific groups Biological compounds (formula (I) wherein L-O-, M-NR ¹² Compound of (a) to (b) and (b) preparation of

For example, carbonyl urea derivatives having a specific substituent at the 7-position of the quinoline or quinazoline ring may be prepared according to scheme 6. that is, 4- (aminophenoxy) quinoline derivatives or corresponding quinazoline derivatives, the 7-position of which is alkylated as obtained in scheme 5, are reacted as in scheme 2. That is, a 4- (aminophenoxy) quinoline derivative or a quinazoline derivative is reacted with a carbonyl isocyanate derivative in an appropriate solvent to prepare a carbonyl urea derivative, or a carbonyl urea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be synthesized by other methods. That is, a carbonyl urea derivative can be produced by reacting a 4- (aminophenoxy) quinoline derivative or quinazoline derivative with a carbonyl isocyanate derivative in an appropriate solvent. The hydroxy group of the carbonylurea derivative is deprotected under suitable conditions (for example, when the protecting group is benzyl, it is allowed to react in, for example, N-dimethylformamide in the presence of palladium hydroxide-carbon or palladium on carbon under a hydrogen atmosphere) to give a 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative. subsequently, the alkylation reaction of the 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative under suitable conditions (for example, in a suitable solvent in the presence of a base, with an alkyl halide) gives a carbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring.

Scheme 7: aminocarbonyl substituted in position 7 of quinoline or quinazoline ring by a specific group Urea derivatives (formula (I) wherein L ═ O-, M ═ NR) ¹² -、R ⁹ is-NR ¹⁸ R ¹⁹ Compound of (1) preparation

For example, aminocarbonyl urea derivatives having a specific substituent at the 7-position of the quinoline or quinazoline ring can be prepared according to scheme 7. that is, 4- (aminophenoxy) quinoline derivatives or corresponding quinazoline derivatives, which are alkylated at the 7-position as obtained in scheme 5, are reacted as in scheme 2. That is, an aminocarbonylurea derivative can be produced by reacting a 4- (aminophenoxy) quinoline derivative or quinazoline derivative with an N- (chlorocarbonyl) isocyanate in an appropriate solvent in the presence of a base and then with an amine derivative, or an aminocarbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be synthesized by other methods, first, the 4- (aminophenoxy) quinoline derivative or quinazoline derivative obtained in scheme 3 or scheme 4 is reacted as in scheme 2, that is, a 4- (aminophenoxy) quinoline derivative or quinazoline derivative is reacted with an N- (chlorocarbonyl) isocyanate in an appropriate solvent in the presence of a base and then with an amine derivative, an aminocarbonylurea derivative can be produced, under appropriate conditions (for example, when the protecting group is a benzyl group, it is reacted in, for example, N-dimethylformamide in the presence of palladium hydroxide-carbon or palladium on carbon under a hydrogen atmosphere) to deprotect the hydroxyl group of the aminocarbonylurea derivative, a 7-hydroxyquinoline derivative or the corresponding 7-hydroxyquinazoline derivative can be obtained. Subsequently, alkylation of a 7-hydroxyquinoline derivative or the corresponding 7-hydroxyquinazoline derivative under appropriate conditions (e.g., in an appropriate solvent, in the presence of a base, with an alkyl halide) affords an aminocarbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring.

Scheme 8: amide derivatives substituted in position 7 of quinoline or quinazoline ring with specific groups The compound (formula (I) wherein L ═ O-, M ═ CR ¹⁰ R ¹¹ -、R ⁹ is-NR ¹⁸ R ¹⁹ Compound of (1) preparation

For example, an amide derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be prepared according to scheme 8. that is, a 4- (aminophenoxy) quinoline derivative or a corresponding quinazoline derivative, which is obtained in scheme 5 and is alkylated at the 7-position, is reacted as in scheme 2. that is, an amide derivative can be prepared by reacting a 4- (aminophenoxy) quinoline derivative or a quinazoline derivative with a carboxylic acid derivative or a metal salt thereof in an appropriate solvent in the presence of a condensing agent and a carboxylic acid activator. Alternatively, an amide derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring may be synthesized by other methods. First, the 4- (aminophenoxy) quinoline derivative or quinazoline derivative obtained in scheme 3 or scheme 4 is reacted as in scheme 2, that is, the 4- (aminophenoxy) quinoline derivative or quinazoline derivative is reacted with a carboxylic acid derivative or a metal salt thereof in an appropriate solvent in the presence of a condensing agent and a carboxylic acid activator to prepare an amide derivative. The hydroxy group of the amide derivative is deprotected under suitable conditions (for example, when the protecting group is benzyl, it is reacted in, for example, N-dimethylformamide in the presence of palladium hydroxide-carbon or palladium on carbon under a hydrogen atmosphere) to give a 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative. Subsequently, the 7-hydroxyquinoline derivative or the corresponding 7-hydroxyquinazoline derivative is subjected to an alkylation reaction under appropriate conditions (for example, in an appropriate solvent, in the presence of a base, with an alkyl halide) to give an amide derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring.

Scheme 9: carbonyl urea derivatives with specific substituents in position 7 of quinoline or quinazoline ring Preparation of compounds and carbonylthiourea derivatives

For example, a carbonylurea derivative or carbonylthiourea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be prepared according to scheme 9. namely, a 4-aminophenoxyquinoline derivative or a corresponding quinazoline derivative, the 7-position of which is protected with a benzyl group, is deprotected under acidic conditions to produce a phenol compound, and then reacted with an alkyl halide in an appropriate solvent in the presence of a base to produce a corresponding ether compound, and then reacted with an appropriate amine in an appropriate solvent in the presence of a base to produce a corresponding 7-amino-substituted- (4-aminophenoxy) quinoline derivative, which is then reacted with a carbonyl isocyanate derivative or carbonyl isothiocyanate derivative to produce a carbonylurea derivative or carbonylthiourea derivative. Alternatively, a carbonylthiourea derivative can be obtained by reacting a carbonylisothiocyanate derivative with an ether compound obtained by the action of an alkyl halide, and then reacting the resulting compound with an appropriate amine in the presence of a base in an appropriate solvent to obtain a carbonylthiourea derivative having a specific substituent at the 7-position.

Use of compound/pharmaceutical composition

The compounds of the present invention have the effect of inhibiting tumor growth in vivo (see pharmacological tests 3, 4 and 5).

The compound of the present invention can also inhibit in vitro the HGF-stimulated met autophosphorylation induced by human epithelial cancer cells A431 and HGF-independent and constantly occurring met autophosphorylation of gastric cancer cells MKN45 (see pharmacological test examples 1 and 2).

Met autophosphorylation via HGF stimulation, or depending on HGF from cancer cell to cancer cell, via tyrosine kinase of its intracellular domain, promotes proliferation and motility of various cell species (j. biochem,119，591，(1996)、Jpn.J.Cancer Res.，88，564，(1997)、Int.J.Cancer，78750, (1998)). in particular, an increase in HGF concentration, overexpression of met, expression of HGF-independent met mutant obtained, etc. in various cancers, in blood, are reported, and the signal of met is considered to be involved in proliferation and invasion, metastasis of various cancer cells (int.j. cancer,55，72，(1993)、Oncology Reports，5，1013(1998)、Proc.Natl.Acad.Sci.USA，88，4892，(1991)、Cancer，88,1801, (2000)). HGF has also been reported to have an effect of promoting the proliferation and migration of vascular endothelial cells via met, promoting angiogenesis (Circulation,97，381(1998)，ClinicalCancer Res.，53695, (1999)), presumably associated with angiogenesis in cancer.

Thus, the compounds of the present invention can inhibit the proliferation, invasion, metastasis and angiogenesis of these cancer cells, and thus the compounds of the present invention can be used for the treatment of malignant tumors.

The pharmaceutical composition can be used for treating malignant tumors such as brain tumor, gastric cancer, brain tumor, colon cancer, pancreatic cancer, lung cancer, kidney cancer, ovarian cancer, prostate cancer and the like.

The present invention provides a method for treating malignant tumors, which comprises administering a therapeutically effective amount of a compound of the present invention to a mammal, including a human, together with a pharmaceutically acceptable carrier.

The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a malignant tumour.

The compounds of the present invention can be administered to humans and animals other than humans by any route of administration, both oral and parenteral (e.g., intravenous, intramuscular, subcutaneous, rectal, transdermal). Thus, a pharmaceutical composition containing the compound of the present invention as an active ingredient can be formulated into an appropriate dosage form according to the administration route. Specifically, oral preparations include tablets, capsules, powders, granules, syrups and the like, and parenteral preparations include injections, suppositories, patches, ointments and the like.

The above-mentioned various preparations can be produced by a conventional method using a commonly used excipient, disintegrant, binder, lubricant, colorant, diluent, etc.

Examples of the excipient include lactose, glucose, corn starch, sorbitol, crystalline cellulose, etc., examples of the disintegrant include starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin, etc., examples of the binder include dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc., and examples of the lubricant include talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil, etc.

The injection can be prepared by adding a buffer, a pH adjuster, a stabilizer, an isotonic agent, a preservative, etc., as required.

The content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, and is usually 0.5 to 50% by weight, preferably 1 to 20% by weight, based on the total amount of the composition.

The dose is determined by considering the age, body weight, sex, difference in disease, degree of symptoms, etc. of the patient, and it is preferable to administer 1 to 100mg/kg once a day or several times in parts, depending on the case.

The compound of the present invention may be administered in combination with other drugs, for example, with an anticancer agent, simultaneously or sequentially.

Examples

The present invention is illustrated by the following examples, but the present invention is not limited to these examples.

The starting materials required for the synthesis can be prepared according to the descriptions of WO 97/17329, WO 98/47873, WO00/43366 and Japanese patent application laid-open No. Hei 9-328782.

Scheme 10: preparation of starting materials 1 to 10

Scheme 11: preparation of feedstocks 11 and 12

Preparation example 1 (starting Material 1)

7- (benzyloxy) -4-chloro-6-methoxyquinoline (29g), 3-fluoro-4-nitrophenol (20g), N-diisopropylethylamine (33ml) and chlorobenzene (14ml) were added thereto, and the mixture was heated and stirred at 140 ℃ for 15 hours, and after the completion of the reaction, a 2N aqueous sodium hydroxide solution (30ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 40g of the objective compound in a yield of 50%.

¹H-N MR(CDCl₃，400MHz)：δ8.58(d，J＝5.1Hz，1H)，8.48-8.44(m，1H)，8.21-8.19(m，1H)，7.64-7.35(m，8H)，6.79(d，J＝5.1Hz，1H)，5.33(s，2H)，3.94(s，3H)

Mass spectrum analysis value (m/z): 421[ M + H]⁺

Preparation example 2 (starting Material 2)

7- (benzyloxy) -4- (3-fluoro-4-nitrophenoxy) -6-methoxyquinoline (35g), zinc (74g) and ammonium chloride (14g) were added to ethanol/water (20/1, 525ml), and the mixture was stirred at 120 ℃ for 18 hours. After the reaction was completed, the reaction mixture was filtered through celite, and the filtrate was concentrated and washed with water to obtain 32g of the objective compound with a yield of 94%.

¹H-NMR(CDCl₃，400MHz)：8.58(d，J＝5.1Hz，1H)，8.48-8.44(m，1H)，8.24(m，2H)，7.64-7.38(m，9H)，6.75(d，J＝5.1H z，1H)，5.31(s，2H)，3.94(s，3H)

Mass spectrum analysis value (m/z): 391[ M + H]⁺

Preparation example 3 (starting Material 3)

4-Fluorophenylacetamide (78mg, preparation method refer to example 3) was dissolved in 1, 2-dichloroethane (20ml), oxalyl chloride (56. mu.l) was then added, and the mixture was heated under reflux at 110 ℃ for 15.5 hours after the completion of the reaction, the mixture was concentrated under reduced pressure, and dimethylformamide (10ml) and 4- { [7- (benzyloxy) -6-methoxy-4-quinoline ] oxy } -2-fluoroaniline (50mg) were added to the resulting crude product, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography on silica gel using chloroform/methanol to obtain 49mg of the objective compound in a yield of 67%.

¹H-NMR(DMSO-d₆，400MHz)：11.16(br，1H)，10.75(br，1H)，8.49(d，J＝4.9Hz，1H)，8.24-8.19(m，1H)，7.53-7.35(m，10H)，7.19-7.11(m，3H)，6.56(d，J＝5.4Hz，1H)，5.31(s，2H)，3.94(s，3H)，3.75(s，2H)

Mass spectrum analysis value (m/z): 570[ M + H]⁺

Preparation example 4 (starting Material 4)

N- (4- { [7- (benzyloxy) -6-methoxy-4-quinoline ] oxy } -2-fluorophenyl) -N' - [2- (4-fluorophenyl) acetyl ] urea (1.6g) and palladium hydroxide-carbon (1.3g) were added to dimethylformamide (14ml), and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere, after the completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to obtain 1.3g of the objective compound in 98% yield.

¹H-NMR(CDCl₃，400MHz)：8.39(m，2H)，8.21-8.18(m，1H)，7.45(m，1H)，7.33-7.23(m，8H)，7.01(m，1H)，6.42(m，1H)，6.18(m，2H)，3.92(s，3H)

Mass spectrum analysis value (m/z): 480[ M + H ]]⁺

Preparation example 5 (starting Material 5)

7- (benzyloxy) -4-chloro-6-methoxyquinoline (81g), 2-fluoro-4-nitrophenol (51g), N-diisopropylethylamine (94ml) and chlorobenzene (40ml) were added thereto, and the mixture was heated and stirred at 140 ℃ for 18 hours, and after the completion of the reaction, a 2N aqueous sodium hydroxide solution (40ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 100g of the objective compound in a yield of 92%.

¹H-NMR(CDCl₃，400MHz)：8.45(d，J＝5.4Hz，1H)，7.53-7.34(m，7H)，7.07-7.03(m，1H)，6.89-6.82(m，2H)，6.43(d，J＝5.4Hz，1H)，5.29(s，2H)，3.94(s，3H)

Mass spectrum analysis value (m/z): 421[ M + H]⁺

Preparation example 6 (starting Material 6)

7- (benzyloxy) -4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinoline (36g), zinc (74g) and ammonium chloride (14g) were added to ethanol/water (20/1, 525ml), and the mixture was stirred at 120 ℃ for 19 hours. After the reaction was completed, the reaction mixture was filtered through celite, and the filtrate was concentrated and washed with water to obtain 35g of the objective compound with a yield of 96%.

¹H-NMR(CDCl₃，400MHz)：8.57(d，J＝5.1Hz，1H)，8.44-8.37(m，1H)，8.22(m，2H)，7.65-7.38(m，9H)，6.78(d，J＝5.1H z，1H)，5.33(s，2H)，3.96(s，3H)

Mass spectrum analysis value (m/z): 391[ M + H]⁺

Preparation example 7 (starting material 7)

4-Fluorophenylacetamide (86mg, preparation method refer to example 3) was dissolved in 1, 2-dichloroethane (200ml) at 80 ℃ and oxalyl chloride (150. mu.l) was added thereto, followed by stirring at 80 ℃ for 10 hours after the completion of the reaction, and the mixture was concentrated under reduced pressure, and dimethylformamide (2ml) and 4- { [7- (benzyloxy) -6-methoxy-4-quinoline ] oxy } -2-fluoroaniline (170mg) were added to the resulting crude product, followed by stirring at room temperature for 3 hours after the completion of the reaction, and the mixture was concentrated under reduced pressure to obtain 248mg of the objective compound.

¹H-NMR(CDCl₃，400MHz)：8.46(d，J＝5.1Hz，1H)，7.50-6.85(m，16H)，6.44(d，J＝5.2Hz，1H)，5.31(s，2H)，3.93(s，3H)，3.74(s，2H)

Mass spectrum analysis value (m/z): 570[ M + H]⁺

Preparation example 8 (starting Material 8)

N- (4- { [7- (benzyloxy) -6-methoxy-4-quinoline ] oxy } -3-fluorophenyl) -N' - [2- (4-fluorophenyl) acetyl ] urea (1.5g) and palladium hydroxide-carbon (1.1g) were added to dimethylformamide (20ml), and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere, after the completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to obtain 1.1g of the objective compound with a yield of 88%.

¹H-NMR(CDCl₃，400MHz)：8.51(d，J＝5.2Hz，1H)，7.89-7.70(m，1H)，7.51-7.07(m，11H)，6.31(d，J＝5.1H z，1H)，3.94(s，3H)，3.74(s，2H)

Mass spectrum analysis value (m/z): 480[ M + H ]]⁺

Preparation example 9 (starting material 9)

2-Phenylacetamide (76mg) was dissolved in 1, 2-dichloroethane (200ml) at 80 ℃ and oxalyl chloride (150. mu.l) was added thereto, followed by stirring at 80 ℃ for 10 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, dimethylformamide (2ml) and 4- { [7- (benzyloxy) -6-methoxy-4-quinoline ] oxy } -2-fluoroaniline (170mg) were added to the resulting crude product, and the mixture was stirred at room temperature for 3 hours.

¹H-NMR(CDCl₃，400MHz)：8.43(d，J＝5.3Hz，1H)，7.55-7.19(m，17H)，6.42(d，J＝5.4Hz，1H)，5.31(s，2H)，3.95(s，3H)，3.75(s，2H)

Mass spectrum analysis value (m/z): 552[ M + H ]]⁺

Preparation example 10 (starting Material 10)

N- (4- { [7- (benzyloxy) -6-methoxy-4-quinolino ] oxy } -3-fluorophenyl) -N' - (2-phenylacetyl) urea (1.2g) and palladium hydroxide-carbon (1.0g) were added to dimethylformamide (20ml), and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere, after the completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to obtain 0.85g of the objective compound (yield: 85%).

¹H-NMR(CDCl₃，400MHz)：8.43(d，J＝5.1Hz，1H)，7.82-7.79(m，1H)，7.49-7.08(m，12H)，6.36(d，J＝5.1Hz，1H)，3.95(s，3H)，3.75(s，2H)

Mass spectrum analysis value (m/z): 462[ M + H ]]⁺

Preparation example 11 (starting Material 11)

3-fluoro-4- [ (7-benzyloxy-6-methoxy-4-quinoline) oxy ] nitrobenzene (2.5g) was heated under reflux with trifluoroacetic acid (15ml) and methanesulfonic acid (0.7ml) for 1 hour, the solvent was distilled off, the mixture was made neutral with 10% aqueous sodium hydroxide solution, and the precipitated crystals were suction-filtered to give crude crystals (1.95 g). This was directly dissolved in dimethylformamide (50ml) without purification, potassium carbonate (4.3g) and 1-bromo-3-chloropropane (4.9g) were added, and the mixture was stirred at room temperature for 16 hours, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the resulting crude product was washed with a mixed solution of ethyl acetate/hexane (1/1), whereby 1.76g of the objective compound was obtained in 73% yield.

¹H-NMR(CDCl₃，400MHz)：2.35-2.41(m，2H)，3.80(t，J＝6.3Hz，2H)，3.99(s，3H)，4.34(t，J＝6.3Hz，2H)，6.53(d，J＝5.1Hz，1H)，7.27-7.34(m，1H)，7.42(s，1H)，7.46(s，1H)，8.10-8.18(m，2H)，8.56(d，J＝5.1Hz，1H)

Preparation example 12 (starting Material 12)

3-fluoro-4- { [7- (3-chloropropyl) -6-methoxy-4-quinoline ] oxy } nitrobenzene (500mg) was dissolved in dimethylformamide (20ml), and potassium carbonate (890mg), sodium iodide (290mg) and morpholine (645mg) were added to stir at 70 ℃ for 18 hours. The crude product was dissolved in methanol (30ml) without purification, and ammonium chloride (207mg) and zinc (1.26g) were added to the solution, followed by reflux under heating for 5 hours, the zinc was filtered off, chloroform was added to the filtrate, the filtrate was washed with a saturated aqueous sodium bicarbonate solution, and the solvent was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography using chloroform/methanol to give 440mg of the objective compound in a yield of 80%.

¹H-NMR(CDCl₃，400MHz)：2.02-2.11(m，2H)，2.35-2.47(m，4H)，2.50(t，J＝6.3Hz，2H)，3.61-3.69(m，4H)，3.75(s，2H)，3.96(s，3H)，4.20(t，J＝6.6Hz，2H)，6.33(d，J＝5.4Hz，1H)，6.41-6.51(m，2H)，6.96(t，J＝8.5Hz，1H)，7.35(s，1H)，7.51(s，1H)、8.39(d，J＝5.4Hz，1H)

Example 1

Phenylacetyl chloride [ starting material B ] (1.89g), potassium thiocyanate (2.09g) was dissolved in acetonitrile (15ml), which was then stirred at 80 ℃ for 1 hour, water was added to the reaction solution, extraction was performed with chloroform, chloroform was distilled off under reduced pressure, the resulting crude product was dissolved in toluene/ethanol (1/1), 4- [ (6, 7-dimethoxy-4-quinoline) oxy ] -3-fluoroaniline [ starting material A ] (3.03g) was added, and the mixture was stirred at room temperature overnight. The reaction solvent was distilled off under reduced pressure and purified by chromatography on silica gel using chloroform/acetone to give 0.69g of the title compound in 14.5% yield.

¹H-NMR(CDCl₃，400MHz)：δ3.76(s，2H)，4.05(s，3H)，4.06(s，3H)，6.46(d，J＝4.4Hz，1H)，7.23-7.34(m，3H)，7.38-7.48(m，5H)，7.56(s，1H)，7.93(m，1H)，8.48(br，1H)，8.51(d，J＝5.4Hz，1H)，12.47(br，1H)

Mass spectrum analysis value (m/z): 492[ M + H]⁺

Example 2

To 4-fluorophenylacetic acid [ starting material B ] (123mg) was added thionyl chloride (348. mu.l), and the mixture was stirred with heating at 50 ℃ for 1 hour, after the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting crude product was dissolved in acetonitrile (20 ml). Potassium thiocyanate (155mg) was added thereto, and the mixture was stirred with heating at 50 ℃ for 40 minutes, after which 4- [ (6, 7-dimethoxy-4-quinoline) oxy ] -3-fluoroaniline [ starting material A ] (50mg) was added, and the mixture was stirred with heating for 60 minutes, after the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting crude product was added with a saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the resulting crude product was purified by chromatography on silica gel using chloroform/acetone to give 61mg of the title compound in 75% yield.

¹H-NMR(CDCl₃，400MHz)：δ3.87(s，2H)，4.05(s，3H)，4.06(s，3H)，6.45(d，J＝5.1Hz，1H)，7.12(m，2H)，7.23-7.32(m，3H)，7.40(m，1H)，7.44(s，1H)，7.56(s，1H)，7.93(m，1H)，8.51(d，J＝5.1Hz，1H)，8.70(br，1H)，12.45(br，1H)

Mass spectrum analysis value (m/z): 510[ M + H]⁺

Example 3

4-Fluorophenylacetic acid [ starting Material B ] (15g) was dissolved in thionyl chloride (15ml), heated at 60 ℃ for 1 hour, excess thionyl chloride was distilled off under reduced pressure to give 4-fluorophenylacetyl chloride, the acid chloride was dissolved in acetone (200ml), and ammonium acetate (112g) was added thereto and stirred at room temperature for 17 hours. Saturated aqueous sodium bicarbonate (150ml) was added thereto, the mixture was stirred at room temperature for 1 hour, and then extracted with chloroform, and the solvent of the extract was distilled off, and the obtained crude crystal was washed with a mixed solution of hexane/ethyl acetate (2/1), whereby 10.5g of 4-fluorophenylacetamide was obtained in a yield of 70%.

¹H-NMR(CDCl₃，400MHz)：δ3.53(s，2H)，5.25-5.70(m，2H)，7.00-7.05(m，2H)，7.20-7.26(m，2H)

4-Fluorophenylacetamide (2.05g) was dissolved in 1, 2-dichloroethane (250ml), oxalyl chloride (1.63ml) was then added thereto, the mixture was refluxed for 15.5 hours, the solvent was distilled off under reduced pressure, and then the resulting crude product was dissolved in dimethylformamide (50ml), a solution of 4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline [ starting material A ] (2.10g) previously dissolved in dimethylformamide (30ml) was added thereto at room temperature, the mixture was stirred at the same temperature for 5 hours, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by column chromatography on silica gel using chloroform/methanol. The solvent was distilled off under reduced pressure, and the obtained crude compound was washed with methanol to obtain 2.27g of the title compound in a yield of 69%.

¹H-NMR(CDCl₃，400MHz)：δ3.74(s，2H)，4.04(s，3H)，4.05(s，3H)，6.52(d，J＝5.4Hz，1H)，6.99(m，2H)，7.10(m，2H)，7.30(m，2H)，7.45(s，1H)，7.49(s，1H)，8.17-8.24(m，2H)，8.52(d，J＝5.4Hz，1H)，10.73(br，1H)

Mass spectrum analysis value (m/z): 494[ M + H]⁺

Example 4

2-Benzeneacetamide [ starting Material B ] (91mg) was dissolved in 1, 2-dichloroethane (250ml), oxalyl chloride (73. mu.l) was added thereto, the mixture was refluxed at 110 ℃ for 15.5 hours, after the completion of the reaction, the mixture was concentrated under reduced pressure, dimethylformamide (10ml) and 4- [ (6, 7-dimethoxy-4-quinoline) oxy ] aniline [ starting Material A ] (50mg) were added to the resulting crude product, the mixture was stirred at room temperature for 5 hours, after the completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by chromatography on silica gel developed with chloroform/methanol to give 44mg of the title compound in a yield of 57%.

¹H-NMR(DMSO-d₆，400MHz)：δ10.96(s，1H)，10.52(s，1H)，8.45(d，J＝5.1Hz，1H)，8.30(s，1H)，7.64(d，J＝9.0Hz，2H)，7.49(s，1H)，7.43-6.84(m，7H)，6.44(d，J＝5.4Hz，1H)，3.95(s，3H)，3.86(s，3H)，3.72(s，2H)

Mass spectrum analysis value (m/z): 458[ M + H ]]⁺

Example 5

4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline [ starting material A ] (5.00g) was dissolved in chloroform (100ml), potassium carbonate (4.66g) was added thereto, and the mixture was stirred at 0 ℃ while adding methylmalonyl chloride [ starting material B ] (2.18ml) to the reaction mixture, and the mixture was stirred at room temperature for 60 minutes. Water was added to the reaction solution, extraction was performed with chloroform, the chloroform layer was washed with saturated brine, and the mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was dissolved in ethanol/water (10/1, 165ml), and lithium hydroxide monohydrate (1.42g) was added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was allowed to stand at 0 ℃ overnight and then filtered to obtain 6.45g of crystals (hereinafter referred to simply as "carboxylic acid"). Carboxylic acid (30mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (30mg), 1-hydroxybenzotriazole monohydrate (24mg), and 4-fluoroaniline [ starting material C ] (10mg) were dissolved in chloroform (3ml), and the mixture was stirred at 60 ℃ overnight. the reaction mixture was developed on Celite containing a saturated aqueous sodium hydrogencarbonate solution, extracted with chloroform, the solvent of the extract was distilled off, and the crude product was purified by HPLC using chloroform/methanol to obtain 0.7mg of the title compound in 1.9% yield.

¹H-NMR(CDCl₃/CD₃OD，400MHz)：δ3.49(s，2H)，4.05(s，3H)，4.06(s，3H)，6.46(d，J＝5.1Hz，1H)，7.01-7.08(m，2H)，7.15-7.19(m，2H)，7.41(s，1H)，7.52-7.56(m，3H)，7.66-7.70(m，2H)，8.46(d，J＝5.4Hz，1H)

Mass spectrum analysis value (m/z): 476[ M + H ]]⁺

Example 6

2, 4-difluoroaniline [ starting material C ] (3.0g) was dissolved in chloroform (50ml), potassium carbonate (6.24g) was added thereto, and the mixture was stirred, ethylmalonyl chloride [ starting material B ] (4ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction mixture, which was then extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. After concentration under reduced pressure, 5.12g of crude product were obtained. 2.85g of 5.12g of the crude product was dissolved in ethanol/water (10/1, 33ml), lithium hydroxide monohydrate (0.99g) was added, and the mixture was stirred at room temperature for 4 hours, and after the reaction solution was concentrated under reduced pressure, 3.76g of a crude product (hereinafter referred to simply as "carboxylic acid") was obtained, chloroform (3ml) was added to 3-chloro-4- [ (6, 7-dimethoxy-4-quinolyloxy ] aniline [ starting material A ] (32mg), carboxylic acid (31mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (28mg), 1-hydroxybenzotriazole monohydrate (22mg), and the mixture was stirred at 60 ℃ overnight, the reaction solution was developed on celite containing a saturated aqueous sodium bicarbonate solution, extracted with chloroform, the solvent of the extract was distilled off, and the crude product was purified by HPLC developed with chloroform/methanol, 0.1mg of the title compound was obtained in 2.0% yield.

¹H-NMR(CDCl₃，400MHz)：δ3.59(s，2H)，4.05(s，3H)，4.07(s，3H)，6.33(d，J＝5.1Hz，1H)，6.90-7.33(m，4H)，7.45(s，1H)，7.52(s，1H)，7.58(s，1H)，7.90-7.93(m，1H)，8.48(d，J＝5.4Hz，1H)

Mass spectrum analysis value (m/z): 528[ M + H ]]⁺

Example 7

4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline [ starting material A ] (100mg) was dissolved in chloroform (3ml), and chloroacetylisocyanate [ starting material B ] (40mg) was added thereto, followed by stirring at room temperature for 10 hours. The reaction mixture was purified by silica gel chromatography to give 16mg of N- (2-chloroacetyl) -N' - {4- [ (6, 7-dimethoxy-4-quinoline) oxy ] phenyl } urea in 83% yield. Subsequently, N- (2-chloroacetyl) -N' - {4- [ (6, 7-dimethoxy-4-quinoline) oxy ] phenyl } urea (50mg) and potassium carbonate (26mg) were added to chloroform, and cyclopentylthiol [ starting material C ] (38. mu.l) was added with stirring. After stirring at room temperature for 3 hours, the reaction mixture was filtered through celite, and then concentrated under reduced pressure. The resulting crude product was purified by chromatography on silica gel using chloroform/methanol to give 35mg of the title compound in 60% yield.

¹H-NMR(DMSO-d₆，400MHz)：δ10.84(br，1H)，10.49(br，1H)，8.48(d，J＝5.1Hz，1H)，7.69-7.67(m，4H)，7.51(s，1H)，7.39(s，1H)，7.26-7.24(d，J＝9.0Hz，1H)，3.93(s，6H)，3.41(s，2H)，2.08-1.97(m，2H)，1.67-1.42(m，7H)

Mass spectrum analysis value (m/z): 482[ M + H ]]⁺

Example 8

3-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline [ starting material A ] (100mg) was dissolved in chloroform (3ml), and chloroacetylisocyanate [ starting material B ] (42mg) was added thereto, and the mixture was stirred at room temperature for 10 hours, and the reaction mixture was purified by silica gel chromatography to give 115mg of N- (2-chloroacetyl) -N' - { 3-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] phenyl } urea in 85% yield. Subsequently, N- (2-chloroacetyl) -N' - { 3-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] phenyl } urea (50mg) and potassium carbonate (28mg) were added to chloroform, and indoline [ starting material C ] (36. mu.l) was added with stirring. After stirring at room temperature for 3 hours, the reaction solution was filtered through celite, and concentrated under reduced pressure, and the resulting crude product was purified by chromatography on silica gel using chloroform/methanol to give 33mg of the title compound in 56% yield.

¹H-NMR(DMSO-d₆，400MHz)：δ10.64(br，1H)，8.46(d，J＝5.6Hz，1H)，7.90(d，J＝2.7Hz，1H)，7.63(s，1H)，7.54-7.51(m，2H)，7.34(s，1H)，7.22-7.11(m，3H)，6.86-6.83(m，1H)，6.48(d，J＝7.8Hz，1H)，6.42(d，J＝5.6Hz，1H)，4.08(s，6H)，3.87(s，2H)，3.55-3.51(m，2H)，3.13-3.09(m，2H)

Mass spectrum analysis value (m/z): 533[ M + H ]]⁺

Example 9:

4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline [ starting material A ] (415mg) was dissolved in 10ml of a 1% AcOH/DMF solution, and 10 units of aldianthanated lanthanum (ァルデヒドリンカ - ランタン) (D-series; 28. mu. mol/unit) were added. The reaction mixture was slowly shaken for 19 hours, and then sodium triacetoxyborohydride (475mg) was added thereto, followed by further slow shaking for 24 hours. Lanthanum was removed from the reaction solution, washed with N, N-dimethylformamide and dichloromethane alternately and separately for 3 times, and dried under reduced pressure to obtain lanthanum having 4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline supported thereon. The lanthanum (3 units) was added to 1ml of dichloromethane, a dichloromethane solution (0.2ml) in which N- (chlorocarbonyl) isocyanate [ starting material B ] (55. mu.l) was dissolved was added at 0 ℃, after slowly shaking overnight at room temperature, a mixed solution of aniline [ starting material C ] (68. mu.l), diisopropylamine (0.2ml) and dichloromethane (0.3ml) was added at 0 ℃, after shaking at room temperature for 7 hours, the mixture was washed with N, N-dimethylformamide and dichloromethane alternately for 5 times, dried under reduced pressure, a 50% TFA/dichloromethane solution (1ml) was added, soaked for 50 minutes at room temperature, and the resulting product was cleaved from lanthanum, and purified by thin layer silica gel chromatography to obtain 6.8mg of the title compound.

¹H-NMR(CDCl₃，400MHz)：δ3.98(s，6H)，6.40(d，J＝5.4Hz，1H)，7.09(m，1H)，7.10(d，J＝9Hz，2H)，7.27(t，J＝7.8Hz，2H)，7.33(s，1H)，7.38(d，J＝7.8Hz，2H)，7.47(s，1H)，7.48(d，J＝8.5Hz，2H)，8.37(d，J＝5.4Hz，1H)

Mass spectrum analysis value (m/z): 457[ M-H]⁺

Example 10

4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline [ starting material A ] (500mg) was dissolved in 20ml of methylene chloride, and N- (chlorocarbonyl) isocyanate [ starting material B ] (145. mu.l) was slowly added thereto, and after stirring at room temperature for 2.5 hours, 4-fluoroaniline [ starting material C ] (205mg) and diisopropylamine (0.35ml) were added thereto at 0 ℃ to return the reaction mixture to room temperature, and the mixture was stirred for 2.5 hours. Water was added to the reaction solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, purification by silica gel chromatography gave 380mg of the title compound.

¹H-NMR(CDCl₃，400MHz)：δ4.03(s，3H)，4.04(s，3H)，6.42(d，J＝5.4Hz，1H)，7.00(m，2H)，7.14(d，J＝9Hz，2H)，7.33(br，2H)，7.40(s，1H)，7.45(br，2H)，7.53(s，1H)，8.48(d，J＝5.4Hz，1H)

Mass spectrum analysis value (m/z): 475[ M-H ]]⁺

Example 11

N- { 3-fluoro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' - (2-phenylacetyl) urea [ starting material A ] (100mg), potassium carbonate (150mg), and 1, 3-dibromopropane [ starting material C ] (66. mu.l) were dissolved in dimethylformamide (5ml), and the mixture was stirred at room temperature for 5 hours, followed by addition of morpholine [ starting material B ] (57. mu.l) and stirring at room temperature for 3 hours. After completion of the reaction, filtration through celite, followed by concentration under reduced pressure, and the resulting crude product was purified by thin layer silica gel chromatography using chloroform/methanol to give 23mg of the title compound in 18% yield.

¹H-NMR(CDCl₃，400MHz)：δ2.07(m，2H)，2.44(m，4H)，2.53(t，J＝7.1Hz，2H)，3.66(m，4H)，3.69(s，2H)，3.96(s，3H)，4.20(t，J＝6.6Hz，2H)，6.33(d，J＝5.4Hz，1H)，7.11-7.45(m，8H)，7.49(s，1H)，7.61(m，1H)，8.01(br，1H)，8.41(d，J＝5.4Hz，1H)，10.59(br，1H)

Mass spectrum analysis value (m/z): 589[ M + H]⁺

Example 12

N- { 3-fluoro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' - (2-phenylacetyl) urea [ starting material a ] (100mg), potassium carbonate (150mg), 1, 4-dibromobutane [ starting material C ] (78 μ l) were dissolved in dimethylformamide (5ml), and stirred at room temperature for 5 hours, after which 1-methylpiperazine [ starting material B ] (72 μ l) was added thereto, stirred at room temperature for 3 hours, after the reaction was completed, the reaction was filtered through celite, and then concentrated under reduced pressure, and the resulting crude product was purified by chromatography on thin layer silica gel developed with chloroform/methanol to obtain 24mg of the title compound in 18% yield.

¹H-NMR(DMSO-d₆，400MHz)：δ11.07(br，1H)，10.70(br，1H)，8.76(d，J＝6.3Hz，1H)，7.88(d，J＝11.7Hz，1H)，7.70(s，1H)，7.55(s，1H)，7.53-7.49(m，3H)，7.34-7.27(m，4H)，6.86(br，1H)，4.28-4.26(m，2H)，4.01(s，4H)，3.74(s，3H)，3.65-3.63(m，1H)，3.28-3.16(m，3H)，2.99-2.49(m，3H)，2.31-1.89(m，8H)

Mass spectrum analysis value (m/z): 616[ M + H [ ]]⁺

Example 13

N- { 3-fluoro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' - (2-phenylacetyl) urea [ starting material A ] (100mg), potassium carbonate (150mg), and 1, 2-dibromoethane [ starting material C ] (54. mu.l) were dissolved in dimethylformamide (5ml), and stirred at room temperature for 5 hours, after which piperidine [ starting material B ] (64. mu.l) was added, stirred at room temperature for 3 hours, after completion of the reaction, the reaction was filtered through celite, and then concentrated under reduced pressure, and the resulting crude product was purified by thin layer silica gel chromatography using chloroform/methanol to give 22mg of the title compound in 18% yield.

¹H-NMR(DMSO-d₆，400MHz)：δ11.08(br，1H)，10.71(br，1H)，8.77(d，J＝6.3Hz，1H)，7.88(d，J＝13.6Hz，1H)，7.73(s，1H)，7.59(s，1H)，7.53-7.36(m，2H)，7.34-7.25(m，5H)，6.87(d，J＝6.3Hz，1H)，4.59-4.56(m，2H)，4.04(s，4H)，3.95-3.92(m，2H)，3.74(s，2H)，2.08(s，9H)

Mass spectrum analysis value (m/z): 573[ M + H]⁺

Example 14

N- { 3-fluoro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' - (2-phenylacetyl) urea (100mg), potassium carbonate (145mg) and 1-bromo-3-chloropropane (53. mu.l) were dissolved in dimethylformamide (5ml), and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through celite, concentrated under reduced pressure, and the resulting crude product was purified by thin layer silica gel chromatography using chloroform/methanol to give 90mg of the title compound in 78% yield.

¹H-NMR(DMSO-d₆，400MHz)：δ11.21(br，1H)，10.34(br，1H)，8.43(d，J＝5.4Hz，1H)，7.92(d，J＝10.2Hz，1H)，7.83(d，J＝12.2Hz，1H)，7.50(s，1H)，7.39-7.28(m，7H)，6.41(d，J＝5.1Hz，1H)，3.94(s，3H)，3.63(s，2H)，2.67(m，3H)，2.43(s，1H)，1.93-1.82(m，2H)

Mass spectrum analysis value (m/z): 538[ M + H]⁺

Example 15

Dimethyl methylmalonate [ starting material B ] (1.33ml) was dissolved in ethanol/water (10/1, 6ml), lithium hydroxide monohydrate (0.42g) was added, the reaction mixture was stirred overnight at room temperature, and after concentration under reduced pressure, 1.41g of a crude product was obtained, the crude product (0.71g), 4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline [ starting material A ] (1.00g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.97g), and 1-hydroxybenzotriazole monohydrate (0.78g) were dissolved in chloroform (30ml), and the mixture was refluxed overnight, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, extraction was performed with chloroform, the chloroform layer was washed with a saturated brine, the chloroform layer was dried over anhydrous sodium sulfate, this crude product was dissolved in ethanol/water (10/1, 50ml), lithium hydroxide monohydrate (0.28g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added, the resulting solution was adjusted to weak acidity with hydrochloric acid, extracted with chloroform, the chloroform layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.68g of a crude product (hereinafter referred to as "carboxylic acid"). Carboxylic acid (96mg), 2, 4-difluoroaniline [ starting material C ] (0.037ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (70mg), and 1-hydroxybenzotriazole monohydrate (56mg) were dissolved in chloroform (4ml), and the mixture was refluxed overnight. The reaction solution was developed on celite containing a saturated aqueous solution of sodium hydrogencarbonate, extracted with chloroform, and the solvent of the extract was distilled off to purify the crude product by thin layer silica gel chromatography using chloroform/methanol to obtain 105mg of the title compound.

¹H-NMR(CDCl₃，400MHz)：δ1.74(d，J＝7.3Hz，3H)，3.47(q，J＝7.3Hz，1H)，4.05(s，3H)，4.06(s，3H)，6.47(d，J＝5.4Hz，1H)，6.87-6.95(m，2H)，7.18(d，J＝9.0Hz，2H)，7.48(s，1H)，7.55(s，1H)，7.68(d，J＝8.8Hz，2H)，8.15-8.23(m，1H)，8.45-8.50(m，2H)，8.63(br，1H)

Mass spectrum analysis value (m/z): 508[ M + H ]]⁺

Example 268

Phenylacetyl chloride (86. mu.l) and potassium thiocyanate (80mg) were dissolved in acetonitrile (50ml), and the mixture was stirred at 40 ℃ for 50 minutes, and acetonitrile was distilled off under reduced pressure, to the crude product, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added and stirred at room temperature for 20 minutes, extraction was performed with ethyl acetate, washing was performed with saturated brine, drying was performed with sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained crude product was dissolved in toluene/ethanol (1/1), and 3-fluoro-4- { [7- (3-morpholinopropoxy) -6-methoxy-4-quinolyl ] oxy } aniline (70mg) was added and stirred at room temperature for 3 hours. The reaction solvent was distilled off under reduced pressure and purified by thin layer silica gel chromatography using chloroform/methanol to give 43.6mg of the title compound in 44.0% yield.

¹H-NMR(CDCl₃，400MHz)：δ2.13(m，2H)，2.49(m，4H)，2.58(t，J＝7.2Hz，2H).3.73(m，4H)，3.76(s，2H)，4.03(s，3H)，4.28(t，J＝6.6Hz，2H)，6.44(d，J＝5.1Hz，1H)，7.22-7.48(m，8H)，7.54(s，1H)，7.93(m，1H)，8.46(br，1H)，8.50(d，J＝5.1Hz，1H)，12.47(br，1H)

Mass spectrum analysis value (m/z): 605[ M + H]⁺

Example 269

3-fluoro-4- { [7- (3-morpholinopropoxy) -6-methoxy-4-quinolyl ] oxy } aniline (60mg) was dissolved in chloroform (15ml), and 3- (4-fluoroanilino) -3-oxopropanoic acid (50mg), 1-hydroxybenzotriazole monohydrate (43mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (54mg) were added to the solution to heat and reflux for 3 hours, followed by washing with a saturated aqueous sodium hydrogencarbonate solution, removal of the solvent by evaporation under reduced pressure from the silica gel column, and purification of the resulting crude product by chromatography using chloroform/methanol to give 41mg of the title compound in 48% yield.

¹H-NMR(CDCl₃，400MHz)：2.04-2.10(m，2H)，2.35-2.46(m，4H)，2.51(t，J＝7.1Hz，2H)，3.50(s，2H)，3.63-3.68(m，4H)，3.96(s，3H)，4.18(t，J＝6.6Hz，2H)，6.32(d，J＝5.3Hz，1H)，6.97-7.02(m，2H)，7.13-7.24(m，2H)，7.36(s，1H)，7.43-7.50(m，2H)，7.49(s，1H)，7.70-7.74(m，1H)，8.40(d，J＝5.3Hz，1H)，8.55(s，1H)，9.35(s，1H)

Mass spectrum analysis value (ESI-MS, m/z): 607[ M + H]⁺

The structures of the compounds of examples 1-15, 268 and 269 are shown below.

The compounds of examples 16-267 were synthesized according to the methods of examples 1-15, 268 and 269 the data identifying the chemical structures, starting materials, synthetic methods and materials of the resulting compounds are set forth below.

Example 277: 1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

1) Synthesis of 3-fluoro-4- [ (7- (3-bromoethyl) -6-methoxy-4-quinolyl) oxy ] aniline)

3-fluoro-4- [ (7-benzyloxy-6-methoxy-4-quinolyl) oxy ] aniline (7.8g) was stirred with trifluoroacetic acid (80ml) and methanesulfonic acid (1ml) at 80 ℃ for 2 hours. After the solvent was distilled off, the reaction solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the precipitated crystals were collected by suction filtration to give crude crystals (8.8g) (starting material A). The crude crystals (5g) were dissolved in dimethylformamide (120ml), and potassium carbonate (9.2g) and dibromoethane (12.5g) (starting material C) were added thereto and the mixture was stirred at room temperature for about 90 hours. The residue was purified by silica gel column chromatography [ chloroform: methanol ] to give 1.88g of 3-fluoro-4- [ (7- (3-bromoethyl) -6-methoxy-4-quinolyl) oxy ] aniline in 29% yield.

2) Synthesis of 1- { 3-fluoro-4- [7- (3-bromoethyl) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

4-Fluorophenylacetic acid (2.37g) (starting material D) was dissolved in thionyl chloride (8ml), and the solution was stirred at 40 ℃ for 1 hour, and the solvent was distilled off under reduced pressure. Acetonitrile (300ml) was added to the resultant residue to dissolve it, potassium thiocyanate (1.87g) was added, stirring was carried out at 40 ℃ for 50 minutes, the solvent was distilled off under reduced pressure, ethyl acetate (50ml) and a saturated aqueous solution of sodium hydrogencarbonate (50ml) were added to the resulting residue, after stirring at room temperature for 10 minutes, the mixture was filtered through celite, the filtrate was extracted with ethyl acetate, and then washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, the obtained residue was dissolved in ethanol/toluene (1: 1 ═ 10ml), to this was added 3-fluoro-4- [ (7- (3-bromoethyl) -6-methoxy-4-quinolyl) oxy ] aniline (1.4g) synthesized in 1), after stirring at room temperature for 18 hours, the precipitated crystals were collected by filtration to obtain 1.58g of the title compound in 73% yield.

¹H-NMR(DMSO，400MHz)：δ3.85(s，2H)，3.96(t，J＝5.4Hz，2H)，4.06(s，3H)，4.62(t，J＝5.4Hz，2H)，6.98(d，J＝6.3Hz，1H)，7.15-7.23(m，2H)，7.37-7.43(m，2H)，7.55(s，1H)，7.60-7.68(m，1H)，7.79(s，1H)，8.15-8.18(m，1H)，8.85(d，J＝6.3Hz，1H)，11.86(s，1H)，12.54(s，1H)

3) Synthesis of 1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea (example 277)

To the compound (200mg) obtained in 2) was added dimethylformamide (3ml) to dissolve it, morpholine (29mg) (starting material B) and potassium carbonate (46mg) were added, stirred at room temperature for 18 hours, ethyl acetate: water was added, extraction was performed with ethyl acetate, washing was performed with saturated brine, drying was performed with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative TLC [ chloroform: methanol ] to obtain 92mg of the title compound (example 277) in 46% yield.

¹H NMR(CDCl₃，400MHz)：δ2.89(s，4H)，2.95(s，4H)，3.73(s，2H)，3.73-3.78(m，2H)，4.03(s，3H)，4.34(t，J＝6.1Hz，2H)，6.43(d，J＝5.1Hz，1H)，7.12(t，J＝8.8Hz，1H)，7.23-7.32(m，6H)，7.43(s，1H)，7.94(dd，J＝2.4，11.5Hz，1H)，8.50(d，J＝5.1Hz，1H)，8.66(br，1H)，12.44(s，1H)

ESI-MS：m/z＝607(M-1)

Example 285: 1- [2- (2-chlorophenyl) -acetyl ] -3- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl) -thiourea

2-Chlorophenylacetic acid (96mg) (starting material D) was dissolved in thionyl chloride (0.5ml), and stirred at 40 ℃ for 1 hour. The solvent was distilled off under reduced pressure, acetonitrile (30ml) was added to the resulting residue to dissolve it, potassium thiocyanate (68mg) was added thereto, and stirring was carried out at 40 ℃ for 50 minutes, the solvent was distilled off under reduced pressure, and ethyl acetate (15ml) and a saturated aqueous solution of sodium hydrogencarbonate (15ml) were added to the resulting residue and stirred at room temperature for 20 minutes. After extraction with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, the obtained residue was dissolved in ethanol/toluene (1: 1 ═ 6ml), and then 12(60mg) (starting material a) was added thereto, followed by stirring at room temperature for 18 hours, and the solvent was distilled off under reduced pressure, followed by preparative TLC [ chloroform: methanol ] to obtain 44mg of the title compound in 49% yield.

¹H NMR(CDCl₃，400MHz)：δ2.10-2.18(m，2H)，2.47-2.54(m，4H)，2.59(t，J＝7.2Hz，2H)，3.73(t，J＝4.5Hz，4H)，3.89(s，2H)，4.03(s，3H)，4.28(t，J＝6.7Hz，2H)，6.44(d d，J＝1.0，5.4Hz，1H)，7.31-7.52(m，6H)，7.54(s，1H)，7.95(d d，J＝2.4，11.5Hz，1H)，8.50(d，J＝5.4Hz，1H)，8.64(s，1H)，12.42(s，1H)

ESI-MS：m/z＝639(M+1)，637(M-1)

Example 287: 1- { 2-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-urea

1) Synthesis of 2-fluoro-4- [ (7- (3-chloropropyl) -6-methoxy-4-quinolyl) oxy ] aniline

2-fluoro-4- [ (7-benzyloxy-6-methoxy-4-quinolyl) oxy ] aniline (4.2g) (starting material 2) was heated under reflux with trifluoroacetic acid (20ml) and methanesulfonic acid (1ml) for 1 hour, the solvent was distilled off, then the mixture was made neutral with a 10% aqueous solution of sodium hydroxide, and the precipitated crystal was suction-filtered to obtain a crude crystal (3.8g) (starting material A). The crude crystal (2g) was dissolved in dimethylformamide (80ml), potassium carbonate (4.9g) and 1-bromo-3-chloro-propane (5.6g) (starting material C) were added, and the mixture was stirred at room temperature for 16 hours, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 1.65g of the title compound in 77% yield from the chloroform: methanol (99: 1) eluted fraction.

¹H-NMR(CDCl₃，400MHz)：2.36-2.43(m，2H)，3.75(s，2H)，3.79-3.83(m，2H)，3.96(s，3H)，4.32-4.36(m，2H)，6.44(d，J＝5.3Hz，1H)，6.80-6.92(m，3H)，7.43(s，1H)，7.52(s，1H)，8.48(d，J＝5.3Hz，1H)

2) Synthesis of 2-fluoro-4- [ (6-methoxy-7- (3-morpholinopropyl) -4-quinolyl) oxy ] aniline

Aniline (0.7g) obtained in 1) was dissolved in dimethylformamide (40ml), and potassium carbonate (1.4g), sodium iodide (0.6g) and morpholine (0.85g) (starting material B) were added thereto, followed by stirring at 70 ℃ for 20 hours. After extraction with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography on silica gel to obtain 0.64g of the title compound in a yield of 76% from the fraction eluted with chloroform: methanol (95: 5).

¹H-NMR(CDCl₃，400MHz)：2.01-2.11(m，2H)，2.37-2.50(m，4H)，2.44-2.57(m，2H)，3.64-3.74(m，4H)，3.67(s，2H)，3.95(s，3H)，4.13-4.22(m，2H)，6.36(d，J＝5.4Hz，1H)，6.73-6.84(m，3H)，7.35(s，1H)，7.46(s，1H)，8.40(d，J＝5.4H z，1H)

3) Synthesis of 1- { 2-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3-phenyl-acetyl-urea (example 287)

Phenylacetamide (95mg) (starting material D) was suspended in anhydrous dichloroethane (10ml), oxalyl chloride (0.09ml) was added, the mixture was refluxed for 17 hours, and the solvent was distilled off under reduced pressure to obtain a crude crystal, which was suspended in anhydrous chloroform (10ml), and aniline (100mg) and triethylamine (330mg) obtained in 2) were added at room temperature to a solution of anhydrous chloroform (10ml), and the mixture was stirred at room temperature for 5 hours, a 2% aqueous sodium hydroxide solution was added, the chloroform layer was separated, the chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 115mg of the title compound (example 287) in 84% yield from the chloroform: methanol (97: 3) eluted fraction.

¹H-NMR(CDCl₃，400MHz)：2.07-2.15(m，2H)，2.44-2.51(m，4H)，2.55(t，J＝7.0Hz，2H)，3.69-3.75(m，4H)，3.75(s、2H)，3.98(s，3H)，4.24(t，J＝6.5Hz，2H)，6.48(d，J＝5.1Hz，1H)，6.94-7.00(m，4H)，7.24-7.40(m，5H)，7.36(s，1H)，7.40(s，1H)，8.18(t，J＝8.8Hz，1H)，8.48(d，J＝5.1Hz，1H)，8.49(s，1H)，10.76(s、1H)

Mass spectrum analysis value (ESI-MS, m/z): 589 (M)⁺+1)

Example 313: 1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

1) Synthesis of 1- { [4- (4-aminophenoxy) -6-methoxy-7-quinolinyl ] oxy } -3-morpholino-2-propanol

The starting material 2(10g) was refluxed with trifluoroacetic acid (100ml) and methanesulfonic acid (1ml) for 1 hour, returned to room temperature, the solvent was distilled off, and then adjusted to be weakly basic with a saturated aqueous sodium bicarbonate solution to precipitate a solid. The resulting solid was filtered, washed with water and dried to give crude crystals (9.6g) (starting material a), dimethylformamide (300ml) was added, after dissolution of the crystals, potassium carbonate (23.5g) and epibromohydrin (3.1ml) (starting material C) were added, stirring was carried out overnight at room temperature, potassium carbonate (2.3g) and epibromohydrin (0.3ml) (starting material C) were added, stirring was carried out overnight at room temperature, morpholine (14.8ml) (starting material B) was added, stirring was carried out overnight at 70 ℃, returned to room temperature, water was added, extraction was carried out with ethyl acetate, the organic layer was washed with saturated brine, dried with sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel using chloroform: methanol to give 6.9g of the title compound.

¹H-NMR(CDCl₃，400MHz)：2.48-2.54(m，2H)，2.62-2.64(m，2H)，2.67-2.73(m，2H)，3.52(brs，1H)，3.73-3.76(m，4H)，3.82(brs，2H)，4.16-4.23(m，2H)，4.26-4.32(m，1H)，6.42(d d，J＝1.0，5.4Hz，1H)，6.50(d d d，J＝1.0，2.7，8.5Hz，1H)，6.57(d d，J＝2.7，12.0Hz，1H)，7.04(t，J＝8.5Hz，1H)，7.45(s，1H)，7.58(s，1H)，8.47(d，J＝5.4Hz，1H)

Mass spectrum analysis value (ESI-MS, m/z): 442 (M)⁺-1)

2)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea (example 313)

To 4-fluorophenylacetic acid (4.3g) (starting material D) was added thionyl chloride (10ml), and after stirring at 40 ℃ for 1 hour, the mixture was concentrated, and dried with a vacuum pump, acetonitrile (250ml) was added, potassium isothiocyanate (3.4g) was added, and after stirring at 40 ℃ for 50 minutes, the mixture was concentrated, a saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine, after drying with sodium sulfate, the solvent was distilled off, a mixed solvent of toluene (50ml) and ethanol (50ml) was added, and amine (3.0g) was added. Stir at room temperature overnight. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with chloroform-methanol mixed solvent, the organic layer was washed with saturated brine, dried over sodium sulfate and concentrated, and the obtained residue was purified by silica gel column chromatography using chloroform-methanol to give 1.4g of the title compound in 44% yield.

¹H NMR(CDCl₃，400MHz)：δ2.48-2.55(m，2H)，2.60-2.73(m，4H)，3.72-3.77(m，6H)，4.02(s，3H)，4.16-4.32(m，3H)，6.45(d，J＝4.4Hz，1H)，7.12(t，J＝8.5Hz，2H)，7.23-7.32(m，3H)，7.40(d，J＝8.8Hz，1H)，7.45(s，1H)，7.54(s，1H)，7.93(d d，J＝2.6，11.5Hz，1H)，8.50(d，J＝5.4Hz，1H)，8.65(s，1H)，12.44(s，1H)

ESI-MS：m/z＝639(M+1)

The structures of the compounds of examples 277, 285, 287 and 313 are shown below.

The compounds of examples 270-276, 278-284, 286, 288-312 and 314-337 were synthesized according to the methods of examples 277, 285, 287 and 313.

Example 270: 1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy ] -quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

¹H NMR(DMSO，400MHz)：δ2.20(s，3H)，2.33-2.57(m，8H)，2.79(t，J＝5.6Hz，2H)，3.83(s，2H)，3.94(s，3H)，4.26(t，J＝5.9Hz，2H)，6.48(d，J＝5.1Hz，1H)，7.23-7.57(m，9H)，8.01(d d，J＝2.2，12.2Hz，1H)，8.49(d，J＝5.1Hz，1H)，11.82(br，1H)，12.50(br，1H)

ESI-MS：m/z＝604(M+1)，602(M-1)

Example 271: 1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy ] -quinolin-4-yloxy } -phenyl) -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(DMSO，400MHz)：δ2.16(s，3H)，2.28-2.62(m，8H)，2.78(t，J＝5.9Hz，2H)，3.83(s，2H)，3.94(s，3H)，4.26(t，J＝5.9Hz，2H)，6.48(d d，J＝1.0，5.1Hz，1H)，7.10-7.41(m，6H)，7.44(s，1H)，7.52(s，1H)，8.00(d d，J＝2.2，12.2Hz，1H)，8.49(d，J＝5.1Hz，1H)，11.81(br，1H)，12.47(br，1H)

Example 272: 1- {4- [7- (2-diethylamino-ethoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3-phenylacetyl-thiourea

¹H-NMR(DMSO-d₆，400MHz)：1.01(t，J＝7.1Hz，6H)，2.50-2.70(m，4H)，2.80-3.00(m，2H)，3.81(s，2H)，3.92(s，3H)，4.20(t，J＝5.9Hz，2H)，6.46(d，J＝5.1Hz，1H)，7.07-7.57(m，9H)，7.93-8.10(m，1H)，8.48(d，J＝5.1Hz，1H)，11.80(s，1H)，12.50(s，1H)

Mass spectrometry values: (ESI-MS, m/z): 577(M +1)⁺

Example 273: 1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl- [1, 4] diazepan-1-yl) -ethoxy ] -quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

¹H NMR(CDCl₃∶CD₃OD＝20∶1，400MHz)：δ1.84-1.94(m，2H)，2.42(s，3H)，2.68-2.78(m，4H)，2.88-2.97(m，4H)，3.12(t，J＝6.4Hz，2H)，3.76(s，2H)，4.02(s，3H)，4.29(t，J＝6.4Hz，2H)，6.44(d，J＝5.1Hz，1H)，7.24-7.49(m，8H)，7.54(s，1H)，7.93(d d，J＝2.4，11.7Hz，1H)，8.51(d，J＝5.1Hz，1H)

ESI-MS：m/z＝618(M+1)，616(M-1)

Example 275: 1- {4- [7- (2-diethylamino-ethoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃，400MHz)：δ1.11(t，J＝7.1Hz，6H)，2.66-2.74(m，4H)，3.02-3.08(m，2H)，3.73(s，2H)，4.02(s，3H)，4.29(t，J＝6.5Hz，2H)，6.44(d，J＝5.1Hz，1H)，7.09-7.46(m，7H)，7.53(s，1H)，7.93(d d，J＝2.4，11.5Hz，1H)，8.50(d，J＝5.1Hz，1H)，8.51(br，1H)，12.42(s，1H)

ESI-MS：m/z＝595(M+1)，593(M-1)

Example 276: 1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

¹HNMR(CDCl₃，400MHz)：δ2.62-2.72(m，4H)，2.98(t，J＝5.7Hz，2H)，3.70-3.78(m，6H)，4.02(s，3H)，4.35(t，J＝5.7Hz，2H)，6.46(d，J＝5.4Hz，1H)，7.21-7.45(m，8H)，7.55(s，1H)，7.93(d d，J＝2.4，11.5Hz，1H)，8.52(d，J＝5.4Hz，1H)，9.33(s，1H)，12.57(s，1H)

ESI-MS：m/z＝591(M+1)，589(M-1)

Example 278: 1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.63-2.78(m，4H)，2.98(t，J＝5.8Hz，2H)，3.75-3.82(m，4H)，3.80(s，2H)，4.03(s，3H)，4.37(t，J＝5.8Hz，2H)，6.46(d，J＝5.4Hz，1H)，7.05-7.43(m，6H)，7.47(s，1H)，7.55(s，1H)，7.94(d d，J＝2.4，11.7Hz，1H)，8.50(d，J＝5.4Hz，1H)，8.92(s，1H)，12.45(s，1H)

ESI-MS：m/z＝607(M-1)

Example 279: 1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.66-3.06(m，6H)，3.70-3.85(m，6H)，4.03(s，3H)，4.39(t，J＝5.8Hz，2H)，6.48(d，J＝5.4Hz，1H)，7.04-7.14(m，3H)，7.25-7.45(m，3H)，7.50(s，1H)，7.56(s，1H)，7.94(d d，J＝2.4，11.7Hz，1H)，8.51(d，J＝5.4Hz，1H)，8.74(s，1H)，12.44(s，1H)

ESI-MS：m/z＝607(M-1)

Example 282: 1- (3-fluoro-4- {7- [2- (4-hydroxymethyl-piperidin-1-yl) -ethoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃∶CD₃OD＝20∶1，400MHz)：δ1.58-1.99(m，5H)，2.43-2.62(m，2H)，3.16-3.40(m，4H)，3.50-3.54(m，2H)，3.73(s，2H)，4.03(s，3H)，4.45-4.51(m，2H)，6.47(d，J＝5.4Hz，1H)，7.06-7.15(m，2H)，7.22-7.34(m，4H)，7.42(s，1H)，7.57(s，1H)，7.94(d d，J＝2.4，11.7Hz，1H)，8.47(d，J＝5.4Hz，1H)

ESI-MS：m/z＝637(M+1)，635(M-1)

Example 283: 1- (3-fluoro-4- {7- [2- (4-hydroxymethyl-piperidin-1-yl) -ethoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-urea

¹H-NMR(CDCl₃，400MHz)：1.13-1.76(m，7H)，2.11-2.26(m，2H)，2.87-3.11(m，4H)，3.37-3.48(m，2H)，3.70(s，2H)，3.95(s，3H)，4.26-4.33(m，2H)，6.32(d，J＝5.1Hz，1H)，7.07-7.50(m，7H)，7.35(s，1H)，7.48(s，1H)，7.57-7.65(m，1H)，8.13(s，1H)，8.40(d，J＝5.1Hz，1H)，10.59(s，1H)

Mass spectrometry values: (ESI-MS, m/z): 603 (M)⁺+1)

Example 284: 1- (3-fluoro-4- {7- [2- (4-hydroxymethyl-piperidin-1-yl) -ethoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

¹H NMR(CDCl₃∶CD₃OD＝10∶1，400MHz)：δ1.45-1.88(m，5H)，2.37-2.50(m，2H)，3.08-3.18(m，2H)，3.26-3.34(m，2H)，3.50-3.54(m，2H)，3.76(s，2H)，4.02(s，3H)，4.41-4.47(m，2H)，6.47(d，J＝5.1Hz，1H)，7.22-7.47(m，7H)，7.56(s，1H)，7.94(d d，J＝2.4，11.7Hz，1H)，8.48(d，J＝5.1Hz，1H)

ESI-MS：m/z＝619(M+1)，617(M-1)

Example 286: 1- { 2-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl) -3- [2- (4-fluoro-phenyl) -acetyl ] urea

¹H-NMR(CDCl₃，400MHz)：2.02-2.25(m，2H)，2.40-2.49(m，4H)，2.51(t，J＝7.1Hz，2H)，3.64-3.67(m，4H)，3.67(s，2H)，3.93(s，3H)，4.19(t，J＝6.7Hz，2H)，6.44(d，J＝5.4Hz，1H)，6.89-7.02(m，4H)，7.20-7.25(m，2H)，7.36(s，1H)，7.39(s，1H)，8.13(t，J＝8.5Hz，1H)，8.43(d，J＝5.4Hz，1H)，9.30(s，1H)，10.74(s，1H)

Mass spectrometry values: (ESI-MS, m/z): 607 (M)⁺+1)

Example 288: 1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.12-2.19(m，2H)，2.50-2.66(m，6H)，3.72-3.81(m，6H)，4.03(s，3H)，4.28(t，J＝6.6Hz，2H)，6.45(d，J＝5.4Hz，1H)，7.16-7.42(m，6H)，7.45(s，1H)，7.54(s，1H)，7.94(d d，J＝2.4，11.5Hz，1H)，8.51(d，J＝5.4Hz，1H)，8.61(s，1H)，12.41(s，1H)

ESI-MS：m/z＝623(M+1)，621(M-1)

Example 289: 1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.10-2.18(m，2H)，2.44-2.56(m，4H)，2.59(t，J＝7.2Hz，2H)，3.70-3.76(m，6H)，4.03(s，3H)，4.28(t，J＝6.6Hz，2H)，6.45(d，J＝5.4Hz，1H)，7.01-7.13(m，3H)，7.26-7.44(m，3H)，7.44(s，1H)，7.54(s，1H)，7.93(d d，J＝2.4，11.5Hz，1H)，8.50(d，J＝5.4Hz，1H)，8.55(s，1H)，12.41(s，1H)

ESI-MS：m/z＝623(M+1)，621(M-1)

Example 291: 1- {4- [7- (3-diethylamino-propoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3-phenylacetyl-urea

¹H NMR(CDCl₃，400MHz)：δ1.31(t，J＝7.3Hz，6H)，2.29-2.39(m，2H)，2.93-3.02(m，4H)，3.06-3.17(m，2H)，3.80(s，2H)，4.01(s，3H)，4.26(t，J＝6.0Hz，2H)，6.38(d，J＝5.1Hz，1H)，7.18-7.44(m，8H)，7.56(s，1H)，7.68(dd，J＝2.4，12.2Hz，1H)，8.4-6(d，J＝5.1Hz，1H)，8.85(br，1H)，10.72(s ，1H)

ESI-MS：m/z＝575(M+1)

Example 292: 1- { 3-fluoro-4- [ 6-methoxy-7- (3-pyrrolidin-1-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-urea

¹H NMR(CDCl₃，400MHz)：δ1.94-2.05(m，4H)，2.30-2.40(m，2H)，2.80-3.15(m，6H)，3.78(s，2H)，4.02(s，3H)，4.27(t，J＝6.1Hz，2H)，6.38(d，J＝1.0，5.4Hz，1H)，7.16-7.44(m，8H)，7.56(s，1H)，7.68(d d，J＝2.4，12.7Hz，1H)，8.45(br，1H)，8.47(d，J＝5.4Hz，1H)，10.69(s，1H)

Example 293: 1- {4- [7- (3-diethylamino-propoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

¹H NMR(CDCl₃，400MHz)：δ1.27(t，J＝7.2Hz，6H)，2.25-2.35(m，2H)，2.87-3.10(m，6H)，3.84(s，2H)，4.01(s，3H)，4.26(t，J＝6.1Hz，2H)，6.38(d，J＝5.4Hz，1H)，7.10-7.25(m，4H)，7.29-7.40(m，2H)，7.41(s，1H)，7.56(s，1H)，7.67(d d，J＝2.2，12.7Hz，1H)，8.47(d，J＝5.4Hz，1H)，8.91(br，1H)，10.67(s，1H)

ESI-MS：m/z＝593(M+1)

Example 294: 1- { 3-fluoro-4- [ 6-methoxy-7- (3-pyrrolidin-1-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

¹H NMR(CDCl₃，400MHz)：δ1.93-2.00(m，4H)，2.28-2.36(m，2H)，2.75-3.09(m，6H)，3.83(s，2H)，4.02(s，3H)，4.27(t，J＝6.3Hz，2H)，6.38(d d，J＝1.0，5.1Hz，1H)，7.10-7.28(m，4H)，7.30-7.39(m，2H)，7.41(s，1H)，7.55(s，1H)，7.68(d d，J＝2.2，11.7Hz，1H)，8.46(d，J＝5.1Hz，1H)，8.85(b r，1H)，10.66(s，1H)

ESI-MS：m/z＝593(M+1)

Example 295: 1- { 3-fluoro-4- [ 6-methoxy-7- (3-piperidin-1-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

¹H NMR(CDCl₃，400MHz)：δ1.45-1.55(m，2H)，1.68-1.79(m，4H)，2.09-2.16(m，2H)，2.54-2.82(m，6H)，3.83(s，2H)，4.02(s，3H)，4.25(t，J＝6.6Hz，2H)，6.38(d d，J＝0.7，5.4Hz，1H)，7.10-7.31(m，4H)，7.30-7.39(m，2H)，7.41(s，1H)，7.55(s，1H)，7.68(d d，J＝2.2，12.7Hz，1H)，8.46(d，J＝5.4Hz，1H)，9.00(br，1H)，10.68(s，1H)

ESI-MS：m/z＝605(M+1)

Example 296: 1- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinolin-4-yloxy } -phenyl) -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

¹H NMR(CDCl₃，400MHz)：δ2.08-2.17(m，2H)，2.28-2.70(m，13H)，3.81(s，2H)，4.03(s，3H)，4.23-4.39(m，2H)，6.39(d，J＝5.4Hz，1H)，7.12-7.23(m，4H)，7.17-7.40(m，2H)，7.43(s，1H)，7.55(s，1H)，7.69(d d，J＝2.2，12.1Hz，1H)，8.47(d，J＝5.4Hz，1H)，8.70(br，1H)，10.65(s，1H)

Example 297: 1- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinolin-4-yloxy } -phenyl) -3- (2-m-tolyl-acetyl) -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.08-2.17(m，2H)，2.32-2.44(m，5H)，2.52-2.65(m，8H)，3.71(s，2H)，4.02(s，3H)，4.26(t，J＝6.3Hz，2H)，6.44(d，J＝5.4Hz，1H)，7.01-7.55(m，8H)，7.93(d d，J＝2.7，11.5Hz，1H)，8.48-8.54(m，2H)，12.49(s，1H)

ESI-MS：m/z＝632(M+1)

Example 298: 1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.15-2.22(m，2H)，2.52-2.58(m，4H)，2.63(t，J＝7.1Hz，2H)，3.76(t，J＝4.6Hz，4H)，3.80(s，2H)，4.03(s，3H)，4.28(t，J＝6.6Hz，2H)，6.38(d，J＝5.1Hz，1H)，7.13-7.25(m，3H)，7.29-7.42(m，2H)，7.46(s，1H)，7.55(s，1H)，7.62(d d，J＝2.4，8.8Hz，1H)，8.00(d，J＝2.4Hz，1H)，8.50(d，J＝5.1Hz，1H)8.97(s，1H)，12.39(s，1H)

ESI-MS：m/z＝639(M+1)

Example 299: 1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.15-2.26(m，2H)，2.55-2.75(m，6H)，3.77(s，2H)，3.78-3.83(m，4H)，4.03(s，3H)，4.29(t，J＝6.6Hz，2H)，6.39(d，J＝5.1Hz，1H)，7.02-7.13(m，4H)，7.36-7.44(m，1H)，7.48(s，1H)，7.55(s，1H)，7.62(d d，J＝2.4，8.8Hz，1H)，8.00(d，J＝2.4Hz，1H)，8.50(d，J＝5.1Hz，1H)8.85(s，1H)，12.39(s，1H)

ESI-MS：m/z＝639(M+1)

Example 300: 1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

¹H NMR(CDCl₃，400MHz)：δ2.14-2.24(m，2H)，2.53-2.72(m，6H)，3.76-3.80(m，6H)，4.03(s，3H)，4.28(t，J＝6.6Hz，2H)，6.38(d，J＝5.4Hz，1H)，7.22-7.45(m，7H)，7.55(s，1H)，7.62(d d，J＝2.4，8.8Hz，1H)，8.00(d，J＝2.4Hz，1H)，8.50(d，J＝5.4Hz，1H)8.72(s，1H)，12.44(s，1H)

ESI-MS：m/z＝621(M+1)

Example 301: 1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-o-tolyl-acetyl) -thiourea

¹HNMR(CDCl₃∶CD₃OD＝30∶1，400MHz)：δ2.20-2.32(m，2H)，2.36(s，3H)，2.72-2.90(m，6H)，3.78(s，2H)，3.80-3.85(m，4H)，4.04(s，3H)，4.36(t，J＝6.1Hz，2H)，6.41(d，J＝5.4Hz，1H)，7.21-7.33(m，5H)，7.54-7.61(m，2H)，7.65(d d，J＝2.4，8.6Hz，1H)，8.04(d，J＝2.4Hz，1H)，8.45(br，1H)9.00(br，1H)，12.50(br，1H)

ESI-MS：m/z＝635(M+1)

Example 302: 1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-o-tolyl-acetyl) -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.20-2.33(m，2H)，2.36(s，3H)，2.50-2.59(m，6H)，3.79(s，2H)，3.81-3.90(m，4H)，4.03(s，3H)，4.29(t，J＝6.3Hz，2H)，6.47(d，J＝5.4Hz，1H)，7.22-7.34(m，5H)，7.42(d，J＝8.1Hz，1H)，7.49(s，1H)，7.55(s，1H)，7.96(d d，J＝2.4，11.7Hz，1H)，8.44(br，1H)8.50(d，J＝5.4Hz，1H)，12.52(s，1H)

ESI-MS：m/z＝619(M+1)

Example 303: 1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-m-tolyl-acetyl) -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.10-2.20(m，2H)，2.39(s，3H)，2.55-2.67(m，6H)，3.71(s，2H)，3.75-3.80(m，4H)，4.03(s，3H)，4.28(t，J＝6.6Hz，2H)，6.46(d，J＝4.6Hz，1H)，7.08-7.36(m，5H)，7.41(d，J＝8.8Hz，1H)，7.44(s，1H)，7.55(s，1H)，7.91-8.01(m，1H)，8.48-8.54(m，1H)8.96(br，1H)，12.53(s，1H)

ESI-MS：m/z＝619(M+1)

Example 304: 1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-p-tolyl-acetyl) -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.14-2.24(m，2H)，2.38(s，3H)，2.55-2.72(m，6H)，3.72(s，2H)，3.76-3.82(m，4H)，4.03(s，3H)，4.28(t，J＝6.4Hz，2H)，6.46(d，J＝5.4Hz，1H)，7.16-7.28(m，5H)，7.40(d，J＝8.8Hz，1H)，7.46(s，1H)，7.54(s，1H)，7.93(d d，J＝2.4，11.5Hz，1H)，8.50(d，J＝5.4Hz，1H)，8.64(s，1H)，12.52(s，1H)

ESI-MS：m/z＝619(M+1)

Example 305: 1- { 3-fluoro-4- [7- (3-imidazol-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-urea

¹H-NMR(DMSO-d₆，400MHz)：2.19-2.38(m，2H)，3.74(s，2H)，3.97(s，3H)，4.09(t，J＝6.3Hz，2H)，4.19(t，J＝6.8Hz，2H)，6.44(d，J＝5.4Hz，1H)，6.89(s，1H)，7.15-7.50(m，9H)，7.54(s，1H)，7.64(s，1H)，7.76-7.88(m，1H)，8.47(d，J＝5.4Hz，1H)，10.64(s，1H)，11.05(s，1H)

Mass spectrometry values: (ESI-MS, m/z): 570(M +1)⁺

Example 306: 1- { 3-fluoro-4- [7- (3-imidazol-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

¹H-NMR(DMSO-d₆，400MHz)：2.20-2.40(m，2H)，3.85(s，2H)，3.97(s，3H)，4.05-4.15(m，2H)，4.15-4.26(m，2H)，6.45(d，J＝5.1Hz，1H)，6.90(s，1H)，7.08-7.50(m，8H)，7.54(s，1H)，7.64(s，1H)，7.77-7.90(m，1H)，8.47(d，J＝5.1Hz，1H)，10.57(s，1H)，11.08(s，1H)

Mass spectrometry values: (ESI-MS, m/z): 588(M +1)⁺

Example 307: 1- { 3-fluoro-4- [7- (3-imidazol-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

¹H-NMR(DMSO-d₆，400MHz)：2.21-2.39(m，2H)，3.83(s，2H)，3.97(s，3H)，4.00-4.20(m，2H)，4.15-4.30(m，2H)，6.50(d，J＝5.3Hz，1H)，6.91(s，1H)，7.17-7.60(m，10H)，7.70(s，1H)，7.95-8.07(m，1H)，8.49(d，J＝5.3Hz，1H)，11.80(s，1H)，12.51(s，1H)

Mass spectrometry values: (ESI-MS, m/z): 586(M +1)⁺

Example 308: 1- (3-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-urea

¹H-NMR(CDCl₃，400MHz)：1.22-2.43(m，9H)，2.50-2.65(m，2H)，2.98-3.12(m，2H)，3.39-3.49(m，2H)，3.70(s，2H)，3.95(s，3H)，4.13-4.26(m，2H)，6.31(d，J＝5.4Hz，1H)，7.04-7.41(m，7H)，7.35(s，1H)，7.48(s，1H)，7.57-7.63(m，1H)，8.21(s，1H)，8.40(d，J＝5.4Hz，1H)，10.69(s，1H)

Mass spectrometry values: (ESI-MS, m/z): 617 (M)⁺+1)

Example 309: 1- (3-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

¹H NMR(CDCl₃∶CD₃OD＝10∶1，400MHz)：δ1.75-3.00(m，9H)，3.30-3.72(m，6H)，3.76(s，2H)，4.04(s，3H)，4.34(t，J＝5.4Hz，2H)，6.50(d，J＝5.4Hz，1H)，7.24-7.46(m，8H)，7.58(s，1H)，7.96(d d，J＝2.4，11.7Hz，1H)，8.47(d，J＝5.4Hz，1H)

ESI-MS：m/z＝633(M+1)

Example 310: 1- (3-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃∶CD₃OD＝20∶1，400MHz)：δ1.00-3.20(m，15H)，3.73(s，2H)，4.02(s，3H)，4.27(t，J＝6.1Hz，2H)，6.45(d，J＝5.4Hz，1H)，7.08-7.17(m，2H)，2.22-7.44(m，5H)，7.54(s，1H)，7.94(d d，J＝2.4，11.5Hz，1H)，8.49(d，J＝5.4Hz，1H)

ESI-MS：m/z＝651(M+1)

Example 311: 1- (2-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl) -3-phenylacetyl-urea

¹H-NMR(CDCl₃，400MHz)：1.22-2.19(m，9H)，2.49-2.69(m，2H)，2.87-3.07(m，2H)，3.41-3.50(m，2H)，3.70(s，2H)，3.93(s，3H)，4.17-4.21(m，2H)，6.43(d，J＝5.3Hz，1H)，6.89-6.94(m，2H)，7.19-7.45(m，5H)7.36(s，1H)，7.40(s，1H)，7.65(s，1H)，8.13(t，J＝8.8Hz，1H)，8.43(d，J＝5.3Hz，1H)，10.66(s，1H)

Mass spectrometry values: (ESI-MS, m/z): 617 (M)⁺+1)

Example 312: 1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

¹H-NMR(DMSO-d₆，400MHz)：3.17-3.40(m，6H)，3.50-3.65(m，4H)，3.83(s，2H)，3.94(s，3H)，4.00-4.13(m，2H)，4.13-4.26(m，1H)，4.90-5.00(m，1H)，6.48(d，J＝5.1Hz，1H)，7.17-7.57(m，9H)，7.93-8.10(m，1H)，8.49(d，J＝5.1Hz，1H)，11.81(s，1H)，12.50(s，1H)

Mass spectrometry values: (ESI-MS, m/z): 621(M +1)⁺

Example 314: 1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.48-2.54(m，2H)，2.57-2.73(m，4H)，3.70-3.79(m，4H)，3.90(s，2H)，4.02(s，3H)，4.15-4.32(m，3H)，6.45(d，J＝5.4Hz，1H)，7.32-7.43(m，5H)，7.45(s，1H)，7.47-7.52(m，1H)，7.54(s，1H)，7.95(d d，J＝2.6，11.6Hz，1H)，8.50(d，J＝5.4Hz，1H)，8.69(s，1H)，12.43(s，1H)

ESI-MS：m/z＝655(M+1)

Example 315: 1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.49-2.56(m，2H)，2.61-2.66(m，2H)，2.67-2.74(m，2H)，3.72-3.81(m，6H)，4.02(s，3H)，4.16-4.24(m，2H)，4.26-4.33(m，1H)，6.45(d，J＝5.4Hz，1H)，7.14-7.42(m，6H)，7.46(s，1H)，7.54(s，1H)，7.94(d d，J＝2.4，11.5Hz，1H)，8.50(d，J＝5.4Hz，1H)，8.73(s，1H)，12.42(s，1H)

ESI-MS：m/z＝639(M+1)

Example 316: 1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

¹HNMR(DMSO，400MHz)：δ1.40-1.52(m，2H)，1.55-1.70(m，4H)，2.62-2.93(m，6H)，3.63(s，2H)，3.96(s，3H)，3.98-4.22(m，3H)，6.50(d，J＝5.1Hz，1H)，7.27-7.51(m，6H)，7.54(s，1H)，7.82(d d，J＝2.2，11.9Hz，1H)，8.49(d，J＝5.1Hz，1H)，9.95(s，1H)，11.91(br，1H)，12.45(br，1H)

ESI-MS：m/z＝653(M+1)

Example 317: 1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

¹H NMR(DMSO，400MHz)：δ1.84-1.92(m，4H)，3.01-3.36(m，6H)，3.63(s，2H)，3.97(s，3H)，4.10-4.26(m，3H)，6.51(d，J＝5.1Hz，1H)，7.27-7.51(m，6H)，7.55(s，1H)，7.84(d d，J＝2.4，12.2Hz，1H)，8.51(d，J＝5.1Hz，1H)，9.96(s，1H)，11.91(br，1H)，12.45(br，1H)

ESI-MS：m/z＝639(M+1)

Example 318: 1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(DMSO，400MHz)：δ1.32-1.60(m，6H)，2.50-2.68(m，6H)，3.63(s，2H)，3.95(s，3H)，4.04-4.20(m，3H)，6.49(d，J＝5.1Hz，1H)，7.12-7.24(m，2H)，2.26-7.57(m，6H)，8.02(dd，J＝2.2，12.2Hz，1H)，8.50(d，J＝5.1Hz，1H)，11.87(br，1H)，12.42(br，1H)

ESI-MS：m/z＝637(M+1)

Example 319: 1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

¹HNMR(DMSO，400MHz)：δ1.78-1.85(m，4H)，2.80-3.15(m，4H)，3.32-3.35(m，2H)，3.63(s，2H)，3.96(s，3H)，4.08-4.20(m，3H)，6.50(d，J＝5.4Hz，1H)，7.13-7.46(m，6H)，7.54(s，1H)，7.83(d d，J＝2.7，12.9Hz，1H)，8.49(d，J＝5.4Hz，1H)，9.93(s，1H)，11.88(br，1H)，12.43(br，1H)

ESI-MS：m/z＝623(M+1)

Example 320: 1- [2- (3-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

¹H NMR(DMSO，400MHz)：δ3.34-3,43(m，6H)，3.59-3.64(m，4H)，3.87(s，2H)，3.95(s，3H)，4.06-4.14(m，2H)，4.19(d，J＝6.6Hz，1H)，6.49(d，J＝5.4Hz，1H)，7.26-7.57(m，8H)，8.01(d d，J＝2.6，12.4Hz，1H)，8.50(d，J＝5.4Hz，1H)，11.83(s，1H)，12.43(s，1H)

ESI-MS：m/z＝655(M+1)

Example 321: 1- [2- (3-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

¹H NMR(DMSO，400MHz)：δ1.37-1.61(m，6H)，2.50-2.55(m，6H)，3.62(s，2H)，3.95(s，3H)，4.05-4.21(m，3H)，6.49(d，J＝5.1Hz，1H)，7.21-7.55(m，7H)，7.32(d d，J＝2.4，12.4Hz，1H)，8.49(d，J＝5.1Hz，1H)，9.93(s，1H)，11.79(br，1H)，12.42(br，1H)

ESI-MS：m/z＝655(M+1)

Example 322: 1- [2- (3-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

¹H NMR(DMSO，400MHz)：δ1.82-1.90(m，4H)，2.90-3.50(m，6H)，3.62(s，2H)，3.97(s，3H)，4.09-4.25(m，3H)，6.51(d，J＝5.1Hz，1H)，7.22-7.57(m，7H)，7.82(d d，J＝2.2，12.0Hz，1H)，8.50(d，J＝5.1Hz，1H)，9.94(s，1H)，11.83(br，1H)，12.44(br，1H)

Example 323: 1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl } -thiourea

¹H NMR(DMSO，400MHz)：δ3.33-3.41(m，6H)，3.57-3.63(m，4H)，3.87(s，2H)，3.95(s，3H)，4.04-4.22(m，3H)，6.48(d，J＝5.4Hz，1H)，7.05-7.23(m，3H)，7.36-7.56(m，5H)，8.01(dd，J＝2.1，12.3Hz，1H)，8.50(d，J＝5.4Hz，1H)，11.83(s，1H)，12.45(s，1H)

ESI-MS：m/z＝639(M+1)

Example 324: 1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(DMSO，400MHz)：δ1.38-1.48(m，2H)，1.52-1.64(m，4H)，2.51-2.79(m，6H)，3.61(s，2H)，3.95(s，3H)，4.06-4.21(m，3H)，6.49(d，J＝5.1Hz，1H)，7.06-7.56(m，7H)，8.02(d d，J＝2.4，12.4Hz，1H)，8.50(d，J＝5.1Hz，1H)，9.96(s，1H)，11.83(br，1H)，12.45(br，1H).

ESI-MS：m/z＝637(M+1)

Example 325: 1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(DMSO，400MHz)：δ1.84-1.92(m，4H)，3.00-3.40(m，6H)，3.88(s，2H)，3.96(s，3H)，4.10-4.25(m，3H)，6.50(d，J＝5.1Hz，1H)，7.06-7.58(m，7H)，8.01(d d，J＝2.4，12.2Hz，1H)，8.51(d，J＝5.1Hz，1H)，9.97(s，1H)，11.83(br，1H)，12.45(br，1H)

ESI-MS：m/z＝623(M+1)

Example 326: 1- [2- (4-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

¹H NMR(CDCl₃∶CD₃OD＝20∶1，400MHz)：δ2.53-2.73(m，6H)，3.72(s，2H)，3.73-3.78(m，4H)，4.03(s，3H)，4.14-4.34(m，3H)，6.47(d，J＝5.4Hz，1H)，7.20-7.34(m，4H)，7.37-7.42(m，2H)，7.44(s，1H)，7.56(s，1H)，7.94(d d，J＝2.6，11.6Hz，1H)，8.48(d，J＝5.4Hz，1H)

ESI-MS：m/z＝655(M+1)

Example 327, the following: 1- [2- (4-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

¹H NMR(CDCl₃∶CD₃OD＝20∶1，400MHz)：δ1.39-1.43(m，2H)，1.57-1.66(m，4H)，2.55-2.72(m，6H)，3.61(s，2H)，3.95(s，3H)，4.06-4.09(m，2H)，4.24-4.31(m，1H)，6.39(d，J＝5.4Hz，1H)，7.10-7.30(m，7H)，7.43-7.49(m，1H)，7.48(s，1H)，8.34(d，J＝5.4Hz，1H)

ESI-MS：m/z＝653(M+1)

Example 328: 1- [2- (4-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

¹H NMR(CDCl₃∶CD₃OD＝20∶1，400MHz)：δ2.01-2.08(m，4H)，3.3.30-3.35(m，6H)，3.65(s，2H)，3.95(s，3H)，4.06-4.20(m，2H)，4.35-4.45(m，1H)，6.41(d，J＝5.4Hz，1H)，7.12-7.32(m，7H)，7.49(s，1H)，7.88(d d，J＝2.4，11.7Hz，1H)，8.37(d，J＝5.4Hz，1H)

ESI-MS：m/z＝639(M+1)

Example 329: 1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃∶CD₃OD＝20∶1，400MHz)：δ1.43-1.55(m，2H)，1.62-1.78(m，4H)，2.48-2.90(m，6H)，3.63(s，2H)，3.95(s，3H)，4.05-4.18(m，2H)，4.32-4.43(m，1H)，6.38(d，J＝5.4Hz，1H)，6.83-7.03(m，1H)，7.15-7.30(m，6H)，7.32(s，1H)，8.48(s，1H)，8.37(d，J＝5.4Hz，1H)

ESI-MS：m/z＝637(M+1)

Example 330: 1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

¹H NMR(CDCl₃∶CD₃OD＝20∶1，400MHz)：δ2.09-2.15(m，4H)，3.33-3.43(m，6H)，3.70(s，2H)，4.04(s，3H)，4.14-4.27(m，2H)，4.46-4.53(m，1H)，6.49(d，J＝5.4Hz，1H)，6.96-7.13(m，2H)，7.22-7.40(m，5H)，7.58(s，1H)，7.96(d d，J＝2.4，11.5Hz，1H)，8.44(d，J＝5.4Hz，1H)

ESI-MS：m/z＝623(M+1)

Example 331: 1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-phenyl-acetyl) -thiourea

¹H NMR(CDCl₃∶CD₃OD＝20∶1，400MHz)：δ1.50-1.60(m，2H)，1.76-1.84(m，4H)，2.93-3.07(m，6H)，3.70(s，2H)，3.97(s，3H)，4.08-4.19(m，2H)，4.43-4.51(m，1H)，6.42(d，J＝5.4Hz，1H)，7.18-7.40(m，8H)，7.51(s，1H)，7.90(d d，J＝2.3，11.6Hz，1H)8.40(d，J＝5.4Hz，1H)

ESI-MS：m/z＝619(M+1)

Example 332: 1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-phenyl-acetyl) -thiourea

¹H NMR(CDCl₃∶CD₃OD＝20∶1，400MHz)：δ2.03-2.11(m，4H)，3.20-3.40(m，6H)，3.70(s，2H)，3.98(s，3H)，4.09-4.22(m，2H)，4.43-4.51(m，1H)，6.43(d，J＝5.0Hz，1H)，7.19-7.40(m，8H)，7.52(s，1H)，7.90(d d，J＝2.6，11.7Hz，1H)8.41(d，J＝5.0Hz，1H)

ESI-MS：m/z＝605(M+1)

Example 333: 1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-o-tolyl-acetyl) -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.36(s，3H)，2.70-2.90(m，6H)，3.77-3.87(m，6H)，4.02(s，3H)，4.20-4.24(m，2H)，4.40-4.47(m，1H)，6.49(d，J＝5.4Hz，1H)，7.16-7.32(m，5H)，7.42(d，J＝9.0Hz，1H)，7.55(s，1H)，7.62(s，1H)，7.97(d d，J＝2.4，11.7Hz，1H)，8.50(d，J＝5.4Hz，1H)，8.55(s，1H)，12.54(s，1H)

ESI-MS：m/z＝635(M+1)

Example 334: 1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-m-tolyl-acetyl) -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.39(s，3H)，2.60-2.85(m，6H)，3.72(s，2H)，3.77-3.83(m，4H)，4.02(s，3H)，4.22(d，J＝5.1Hz，2H)，4.34-4.42(m，1H)，6.49(d，J＝5.4Hz，1H)，7.09-7.35(m，5H)，7.41(d，J＝9.0Hz，1H)，7.54(s，1H)，7.55(s，1H)，7.95(d d，J＝2.6，11.6Hz，1H)，8.51(d，J＝5.4Hz，1H)，8.57(s，1H)，12.52(s，1H)

ESI-MS：m/z＝635(M+1)

Example 335: 1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-p-tolyl-acetyl) -thiourea

¹H NMR(CDCl₃，400MHz)：δ2.37(s，3H)，2.55-2.79(m，6H)，3.70-3.80(m，6H)，4.01(s，3H)，4.19-4.23(m，2H)，4.31-4.38(m，1H)，6.46(d，J＝5.4Hz，1H)，7.10-7.28(m，5H)，7.40(d，J＝9.0Hz，1H)，7.51(s，1H)，7.56(s，1H)，7.93(d d，J＝2.4，11.7Hz，1H)，8.51(d，J＝5.4Hz，1H)，8.84(s，1H)，12.54(s，1H)

ESI-MS：m/z＝635(M+1)

Example 336; 1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -urea

¹H-NMR(CDCl₃，400MHz)：2.43-2.65(m，6H)，3.62-3.72(m，4H)，3.67(s，2H)，3.94(s，3H)，4.09-4.25(m，3H)，6.33(d，J＝5.4Hz，1H)，6.91-7.24(m，6H)，7.38(s，1H)，7.48(s，1H)，7.60-7.64(m，1H)，8.41(d，J＝5.4Hz，1H)，8.88(s，1H)，10.62(s，1H)

Mass spectrum analysis value (ESI-MS, m/z): 623 (M)⁺+1)

Example 337: 1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-phenyl-acetyl) -urea

¹H-NMR(CDCl₃，400MHz)：2.44-2.65(m，6H)，3.68-3.76(m，4H)，3.69(s，2H)，3.94(s，3H)，4.08-4.23(m，3H)，6.32(d，J＝5.1Hz，1H)，7.11-7.35(m，7H)，7.39(s，1H)，7.49(s，1H)，7.60-7.63(m，1H)，8.41(m，d，J＝5.1Hz，1H)，8.60(s，1H)，10.64(s，1H)

Mass spectrum analysis value (ESI-MS, m/z): 605(M + +1)

Pharmacological test example 1: measurement of met autophosphorylation inhibitory Activity by ELISA method (1)

Human epithelial carcinoma cells A431 were cultured in RPMI1640 medium (purchased from GIBCO BRL) containing 10% fetal bovine serum in a 5% carbon dioxide incubator until 50-90% confluence, and the harvested cells were plated on 96-well flat-bottom plates at 3X 10 using RPMI medium containing 0.1% fetal bovine serum⁴The cells were inoculated per well and cultured overnight at 37 ℃ the medium was replaced with a new RPMI medium containing 0.1% fetal bovine serum, the test substance dissolved in dimethyl sulfoxide was added to each well, and further cultured at 37 ℃ for 1 hour, human recombinant hepatocyte growth factor (hereinafter abbreviated as HGF) was added to a final concentration of 50ng/ml, and the cells were stimulated at 37 ℃ for 5 minutes. After removing the medium and washing the cells with phosphate buffered saline (pH7.4), 50. mu.l of lysis buffer (20mM HEPES (pH7.4), 150mM NaCl, 0.2% TritonX-100, 10% glycerol, 5mM sodium orthovanadate (sodium orthovanadate), 5mM disodium ethylenediaminetetraacetate, 2mM Na₄P₂O₇) Then, the mixture was shaken at 4 ℃ for 2 hours to prepare an extract solution of the cells.

Mu.l of phosphate buffered saline (pH7.4) containing 5. mu.g/ml of an antiphosphotyrosine antibody (PY 20; available from Transduction Laboratories) was added to a microplate for ELISA (Maxisorp; available from NUNC), and the mixture was allowed to stand overnight at 4 ℃ to solidify the antibody, and after washing the plate, 300. mu.l of a blocking solution was added, and the plate was allowed to stand at room temperature for 2 hours to block the cells, and after washing, the whole cell extract was transferred and allowed to stand overnight at 4 ℃. After washing, it was reacted with an anti-HGF receptor antibody (h-Met (C-12), available from Santa Cruz Biotechnology) for 1 hour at room temperature, washed again, and then reacted with an anti-rabbit Ig antibody labeled with peroxidase (available from Amersham) for 1 hour at room temperature. After washing, a peroxidase chromogenic substrate (available from Sumitomo Bakelite) was added to start a reaction, and after appropriate color development was obtained, a reaction suspension was added to terminate the reaction, and the absorbance at 450nm was measured by a microplate reader, and then the met phosphorylation inhibitory activity of each well was determined using the absorbance without adding a drug and with adding HGF as 0% met phosphorylation inhibitory activity and using the absorbance without adding a drug and with HGF as 100% met phosphorylation inhibitory activity, and the met phosphorylation inhibitory activity in each case was determined by changing the concentration of the test substance by several levels, and the 50% met phosphorylation inhibitory concentration of the test substance was calculated (IC 50). The results are shown in Table 1.

TABLE 1

Example numbering	IC(μM)
		1	0.0087
2	0.0118
		3	0.0197
11	0.0581

Pharmacological test example 2: measurement of met autophosphorylation inhibitory Activity by ELISA method (2)

Human gastric cancer cell line MKN45 was cultured in RPMI1640 medium (purchased from GIBCO BRL) containing 10% fetal bovine serum in a 5% carbon dioxide incubator until 50-90% confluence, and the harvested cells were plated out on 96-well flat bottom plates with RPMI medium containing 0.1% fetal bovine serum at 2X 10⁴The cells were inoculated per well and incubated overnight at 37 ℃. The medium was replaced with a new RPMI medium containing 0.1% fetal bovine serum, and the test substance dissolved in dimethyl sulfoxide was added to each well, followed by culturing at 37 ℃ for 1 hour. After removing the medium and washing the cells with phosphate buffered saline (pH7.4), 50. mu.l of lysis buffer (20mM HEPES (pH7.4), 150mM NaCl, 0.2% Triton X-100, 10% glycerol, 5mM sodium orthovanadate, 5mM disodium ethylenediaminetetraacetate, 2mM Na₄P₂O₇) Then, the mixture was shaken at 4 ℃ for 2 hours to prepare an extract solution of the cells.

To a microplate for ELISA (Maxisorp; from NUNC) was added 50. mu.l of phosphate-buffered saline (pH7.4) containing 5. mu.g/ml of an anti-phosphotyrosine antibody (PY20, from Transduction Laboratories), allowed to stand overnight at 4 ℃ to immobilize, after washing the plate, 300. mu.l of a blocking solution was added, allowed to stand at room temperature for 2 hours to carry out blocking, after washing, the above-mentioned cell extract was completely transferred, allowed to stand overnight at 4 ℃ to wash, after which it was reacted with an anti-HGF receptor antibody (h-Met (C-12), from Santa Cruz Biotechnology, at room temperature for 1 hour, further washed, then reacted with an anti-rabbit Ig antibody labeled with peroxidase (from Amersham) at room temperature for 1 hour, after washing, a peroxidase chromogenic substrate (from Sumitomo Bakelite) was added to start the reaction, after obtaining an appropriate chromogenic stop solution, the reaction was stopped, the absorbance at 450nM was measured by a microplate reader, the met phosphorylation activity in each well was determined by using the absorbance without the addition of the drug as 100% met phosphorylation activity and the absorbance with the addition of a large excess of the positive control (compound 1,1000nM) as 0% met phosphorylation activity, the inhibition rate of met phosphorylation in each case was determined by changing the concentration of the test substance by several levels, and 50% of the test substance was calculatedmet phosphorylation Inhibitory Concentration (IC)₅₀) The results are shown in table 2.

TABLE 2

Example numbering	IC50(μM)	Example numbering	IC50(μM)	Example numbering	IC50(μM)
						1	0.0112	51	0.2035	101	0.0444
2	0.0181	52	0.1706	102	0.0918
						3	0.0304	53	0.0374	103	2.7714
4	0.0750	54	0.0261	104	0.3442
						5	0.0189	55	0.2449	105	0.1037
6	0.0316	56	0.1400	106	0.0427
						7	0.2922	57	0.1320	107	0.3450
8	0.2976	58	0.0270	108	2.0800
						9	0.0364	59	0.1930	109	1.4756
10	0.1459	60	0.0370	110	2.3751
						11	0.0202	61	0.1130	111	1.8118
12	0.1990	62	0.0920	112	1.7334
						13	0.1411	63	0.0244	113	0.6535
14	0.2909	64	0.1405	114	0.4850
						15	0.3017	65	0.0663	115	0.3592
16	0.0328	66	0.0792	116	0.3440
						17	0.0307	67	0.0197	117	1.3037
18	0.1496	68	0.1944	118	0.2114
						19	0.1040	69	0.0044	119	0.4420
20	0.0318	70	0.0153	120	1.5748
						21	0.1876	71	0.0299	121	0.3380
22	0.0246	72	0.0279	122	0.3026
						23	0.0263	73	0.0281	123	2.0088
24	0.0277	74	0.1825	124	0.2643
						25	0.1401	75	0.0336	125	0.2933
26	0.1256	76	0.0517	126	0.3295
						27	0.0800	77	0.1776	127	0.3189
28	0.1624	78	0.0663	128	0.2847
						29	0.0371	79	0.1454	129	1.0060
30	0.0351	80	0.0302	130	2.1555
						31	0.0341	81	0.0277	131	2.3731
32	0.1709	82	0.0743	132	0.2683
						33	0.0618	83	0.0391	133	0.2610
34	0.0463	84	0.0400	134	0.2319
						35	0.0414	85	0.0488	135	0.2260
36	0.1982	86	0.0235	136	0.3417
						37	0.0584	87	0.1983	137	0.2707
38	0.0291	88	0.0492	138	0.2843
						39	0.1145	89	0.0526	139	0.2432
40	0.2421	90	0.0281	140	0.2288
						41	0.2807	91	0.0401	141	0.3361
42	0.1899	92	0.1480	142	0.2847
						43	0.1674	93	0.1215	143	3.5910
44	0.2915	94	0.0307	144	0.6990
						45	0.2071	95	0.0413	145	0.3640
46	0.2290	96	0.1706	146	1.2100
						47	0.2153	97	0.0376	147	1.1660
48	0.2240	98	0.0278	148	2.4790
						49	0.0514	99	0.0256	149	0.2360
50	0.2355	100	0.0308	150	1.2780

Example numbering	IC50(μM)	Example numbering		IC50(μM)	Example numbering	IC50(μM)
							151	0.2561	201		0.2255	251	0.3862
152	0.2475	202		0.6416	252	0.3005
							153	0.2320	203		0.2813	253	1.3400
154	0.8760	204		0.3209	254	0.3655
							155	0.9820	205		0.2651	255	0.2601
156	0.3730	206		0.4436	256	0.2808
							157	0.4820	207		0.2998	257	0.2859
158	0.4650	208		0.2580	258	0.3574
							159	0.5850	209		0.9285	259	0.6143
160	1.6327	210		0.2277	260	2.2325
							161	0.2460	211		0.2521	261	0.3426
162	0.2096	212		0.3787	262	0.2689
							163	0.2018	213		2.4266	263	0.4835
164	0.2417	214		2.5273	264	0.3472
							165	0.4950	215		1.9770	265	0.2589
166	0.3183	216		0.2278	266	0.1806
							167	0.2586	217		0.3331	267	0.1091
168	0.3056	218		0.4793	268	0.0228
							169	0.2759	219		0.7359	269	0.0125
170	0.2736	220		0.2967	270	0.0267
							171	0.2817	221		0.2212	271	0.0391
172	0.4228	222		0.2014	272	0.0336
							173	0.2217	223		0.2680	273	0.0240
174	0.2522	224		0.3160	275	0.0230
							175	0.9552	225		0.2814	276	0.0190
176	0.2211	226		3.2308	277	0.0204
							177	0.2672	227		4.3638	278	0.0251
178	0.2680	228		0.3936	279	0.0204
							179	0.2613	229		0.2730	282	0.0166
180	2.5610	230		0.3403	283	0.0146
							181	0.2431	231		0.3288	284	0.0150
182	0.2559	232		0.2567	285	0.0753
							183	0.2238	233		0.3217	286	0.0293
184	0.2677	234		0.4568	287	0.0225
							185	0.2477	235		0.2146	288	0.0226
186	0.2340	236		0.2351	289	0.0238
							187	0.2575	237		1.4669	291	0.0195
188	0.2525	238		4.0204	292	0.0203
							189	0.2323	239		1.5818	293	0.0211
190	0.2237	240		2.7412	294	0.0230
							191	0.9767	241		3.3169	295	0.0241
192	0.6874	242		0.8512	296	0.0197
							193	0.4442	243		3.0098	297	0.0632
194	0.3188	244		0.3419	298	0.0890
							195	0.2914	245		0.3082	299	0.0435
196	0.3219	246		2.9114	300	0.0224
							197	0.2842	247		0.6502	301	0.0611
198	0.2938	248		0.9569	302	0.0291
							199	0.2415	249		0.5256	303	0.0267
200	0.3052	250		0.4474	304	0.0659

Example numbering	IC50(μM)
		305	0.0214
306	0.0339
		307	0.0574
308	0.0214
		309	0.0201
310	0.0211
		311	0.0185
312	0.0191
		313	0.0211
314	0.0232
		315	0.0210
316	0.1882
		317	0.0422
318	0.0283
		319	0.1267
320	0.0140
		321	0.1248
322	0.0426
		323	＜0.0100
324	0.0234
		325	0.0185
326	0.0131
		327	0.7978
328	0.0432
		329	0.0518
330	0.0206
		331	0.0220
332	0.0142
		333	0.0211
334	0.0227
		335	0.0236
336	0.0328
		337	0.0220

Pharmacological test example 3: tumor growth inhibition of human gastric cancer cells (MKN45)

Human gastric cancer cells (MKN45) were transplanted into nude mice when the tumor volume reached 100-³On the left and right sides, the nude mice were divided into 5 groups, the mean value of the tumor volume of each group was made uniform, and the test substance suspended in 0.5% methylcellulose was orally administered 1 day 2 times for 5 days.

Tumor Growth Inhibition Ratio (TGIR) ═ 1-TX/CX × 100 was determined with tumor volume on the start day of administration as 1, tumor volume on day X of the control group as CX, and tumor volume of the subject compound administration group as TX.

The tumor growth inhibition rates of representative examples of the group of compounds of the present invention are given in table 3.

TABLE 3

Amount administered (mg/kg/dose)% TGIR

Example 11021

30 47

100 54

Example 21031

30 65

Example 31024

30 52

Example 111023

30 52

Example 2683081

Pharmacological test example 4: tumor growth inhibition of human brain tumor cells (U87MG)

Transplanting human brain tumor cells (U87MG) into nude mice when the tumor volume reaches 100-³On the left and right sides, the nude mice were divided into 5 groups, the mean value of the tumor volume of each group was made uniform, and the test substance suspended in 0.5% methylcellulose was orally administered 1 day 2 times for 5 days.

Control group was also given 05% methylcellulose. The Tumor Growth Inhibition Ratio (TGIR) × 100 was determined with the tumor volume on the day of initiation of administration being 1, the tumor volume on day X of the control group being CX, and the tumor volume of the subject compound administration group being TX.

The tumor growth inhibition rates of representative examples of the group of compounds of the present invention are given in table 4.

TABLE 4

Amount administered (mg/kg/dose)% TGIR

Example 13042

100 70

Example 21038

30 61

Example 33051

100 60

Pharmacological test example 5: tumor growth inhibition on various human tumor cells

Human gastric cancer cells (MKN45) (obtained from physical research), human brain tumor cells (U87MG) (obtained from ATCC), human pancreatic cancer (KP4) (obtained from physical research), human pancreatic cancer (SUIT-2) (obtained from national kyushu cancer center), human signet ring cell carcinoma (NUGC-4) (obtained from physical research) or human lung cancer cells (LC6) (obtained from central research of experimental animals) were transplanted into nude mice when the tumor volume reached 100mm³On the left and right sides, nude mice were divided into 4-5 groups, the mean value of tumor volume was made uniform in each group, and the test substance suspended in 0.5% methylcellulose was orally administered 1 day 1 time or 1 day 2 times for 5 days. The control group was administered with 0.5% methylcellulose in the same manner, or the test substance dissolved in a physiological salt solution (1N aqueous hydrochloric acid solution was added) was administered by 1 intravenous injection 1 day for 5 days, and the control group was administered with a physiological salt solution (1N aqueous hydrochloric acid solution was added) in the same manner, so that the tumor volume on the day of administration was 1, the tumor volume on the day 5 of the control group was CX, and the tumor volume in the test compound administration group was TX, and the Tumor Growth Inhibition Ratio (TGIR) ═ was determined(1-TX/CX)×100.

The tumor growth inhibition rates of representative examples of the group of compounds of the present invention are given in table 5.

TABLE 5

Example numbering	Tumor(s)	Method of administration	Number of times of administration (mg/kg) ×	TGIR(％)
					1	LC 6	Through the mouth	30×2	26
2	NUGC-4	Through the mouth	30×2	75
					2	LC 6	Through the mouth	30×2	27
2	KP-4	Through the mouth	30×2	54
					3	NUGC-4	Through the mouth	30×2	71
3	LC 6	Through the mouth	30×2	18
					3	KP-4	Through the mouth	30×2	31
11	MKN 45	Through the mouth	30×2	63
					11	U 87MG	Through the mouth	30×2	62
11	LC 6	Through the mouth	30×2	26
					46	MKN 45	Through the mouth	25×1	38
268	MKN 45	Through the mouth	10×1	52
					268	LC 6	Intravenous injection	30×2	35
268	U 87MG	Through the mouth	30×2	74
					277	MKN 45	Through the mouth	30×2	17
282	MKN 45	Through the mouth	30×2	13
					282	MKN 45	Through the mouth	10×1	31
285	MKN 45	Through the mouth	30×2	66
					285	LC 6	Through the mouth	30×2	48
286	MKN 45	Through the mouth	30×2	64
					286	LC 6	Through the mouth	30×2	37
286	U 87MG	Through the mouth	30×2	66
					288	MKN 45	Through the mouth	30×2	64
299	MKN 45	Through the mouth	25×1	14
					312	MKN 45	Through the mouth	30×2	75

313	MKN 45	Through the mouth	12.5×1	37
					313	MKN 45	Through the mouth	25×1	73
313	MKN 45	Through the mouth	50×1	78
					313	MKN 45	Intravenous injection	10×1	68
313	SUIT-2	Through the mouth	25×1	28
					313	KP-4	Through the mouth	12.5×1	34
313	KP-4	Through the mouth	25×1	45
					313	KP-4	Through the mouth	50×1	48
314	MKN 45	Through the mouth	30×2	38
					315	MKN 45	Through the mouth	30×2	36
320	MKN 45	Through the mouth	30×2	20
					323	MKN 45	Through the mouth	30×2	34
326	MKN 45	Through the mouth	30×2	17
					331	MKN 45	Through the mouth	30×2	40
332	MKN 45	Through the mouth	30×2	14
					333	MKN 45	Through the mouth	30×2	75
334	MKN 45	Through the mouth	30×2	65

Claims (46)

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof,

in the above formula, the first and second carbon atoms are,

x represents a group of a CH or an N,

z represents O or S, and Z represents O or S,

l represents O or S, and L represents O or S,

m represents

-N(-R¹²) -, in which R¹²Represents a hydrogen atom or C_1-4An alkyl group, a carboxyl group,

R¹、R²and R³May be the same or different and represent

A hydrogen atom,

Hydroxy, or

C_1-6An alkoxy group,

c above_1-6Alkoxy being optionally substituted by hydroxy, halogen atoms, C_1-6Alkoxy, amino or a saturated or unsaturated 5-to 7-membered heterocyclyl, wherein 1 or 2 hydrogen atoms of the amino group are optionally substituted by C_1-6Alkyl substitution, said C_1-6Alkyl optionally substituted by hydroxy or C_1-6Alkoxy, said heterocyclyl being optionally substituted by C_1-6Alkyl substitution of the C_1-6Alkyl optionally substituted by hydroxy or C_1-6The substitution of alkoxy groups is carried out,

R⁴represents a hydrogen atom, and is represented by,

R⁵、R⁶、R⁷and R⁸May be the same or different and represents a hydrogen atom, a halogen atom, C_1-4Alkyl or C_1-4An alkoxy group,

R⁹to represent

C_1-6Alkyl radical, C_1-61 or more hydrogen atoms of the alkyl group being represented by-R¹⁴、-T-R¹⁵or-NR¹⁶R¹⁷Substituted, T represents-O-, -S-or-NH-, R¹⁴Represents a saturated or unsaturated 5-6 membered carbocyclic or heterocyclic group, R¹⁵、R¹⁶And R¹⁷May be the same or different and represents C_1-6Alkyl or a saturated or unsaturated 5-6 membered carbocyclic or heterocyclic group, R¹⁴、R¹⁵、R¹⁶And R¹⁷The 5-to 6-membered carbocyclic or heterocyclic group being optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, when the 5-to 6-membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form C_1-3The alkylene chain, said 5-6 membered carbocyclyl or heterocyclyl may also be fused with another saturated or unsaturated 5-6 membered carbocyclyl to form a bicyclic group.

2. The compound of claim 1, wherein R¹And R⁴Represents a hydrogen atom, R²And R³Represents a group other than a hydrogen atom.

3. The compound of claim 1, wherein R⁵、R⁶、R⁷And R⁸All represent a hydrogen atom, or R⁵、R⁶、R⁷And R⁸Either or both of them represent a group other than a hydrogen atom, and the rest all represent a hydrogen atom.

4. The compound of claim 1, wherein R⁹The optionally substituted alkyl group represents- (CH)₂)p-R¹⁴、-(CH₂)p-T-R¹⁵Or- (CH)₂)p-NR¹⁶R¹⁷P represents an integer of 1 to 6, R¹⁴、R¹⁵、R¹⁶、R¹⁷And T is as defined in claim 1.

5. A compound of claim 1, wherein X represents CH or N, Z represents O, L represents O, and M represents-N (-R)¹²)-，R¹And R⁴Represents a hydrogen atom, R²Represents unsubstituted C_1-6Alkoxy radical, R³Represents optionally substituted C_1-6Alkoxy radical, R⁵、R⁶、R⁷And R⁸All represent a hydrogen atom, or R⁵、R⁶、R⁷And R⁸Any one of them represents a group other than a hydrogen atom and the others represent a hydrogen atom.

6. A compound of claim 1, wherein X represents CH or N, Z represents O, L represents S, M represents-N (-R)¹²)-，R¹And R⁴Represents a hydrogen atom, R²Represents unsubstituted C_1-6Alkoxy radical, R³Represents optionally substituted C_1-6Alkoxy radical, R⁵、R⁶、R⁷And R⁸All represent a hydrogen atom, or R⁵、R⁶、R⁷And R⁸Any one of them represents a group other than a hydrogen atom and the others represent a hydrogen atom.

7. The compound of claim 1, having a structure represented by formula (100),

in the above formula, the first and second carbon atoms are,

R¹⁰³represents a hydroxyl group or C_1-4Alkoxy radical, C_1-4Alkoxy is optionally substituted by halogen atom, hydroxyl, amino or saturated or unsaturated 5-7 membered heterocyclic group, wherein 1 or 2 hydrogen atoms on the amino group are optionally substituted by C_1-6Alkyl substitution of the C_1-6Alkyl is optionally further substituted by hydroxy or C_1-6Alkoxy, said heterocyclyl being optionally substituted by C_1-6Alkyl substitution of the C_1-6Alkyl is optionally further substituted by hydroxy or C_1-6The substitution of alkoxy groups is carried out,

R¹⁰⁵、R¹⁰⁶、R¹⁰⁷and R¹⁰⁸May be the same or different and represents a hydrogen atom, a halogen atom, C_1-4Alkyl or C_1-4Alkoxy radical, and

R¹⁰⁹to represent

C_1-6Alkyl radical, C_1-61 or more hydrogen atoms of the alkyl group being represented by-R¹¹⁴、-T-R¹¹⁵or-NR¹¹⁶R¹¹⁷Substituted, T represents-O-, -S-or-NH-, R¹¹⁴Represents a saturated or unsaturated 5-6 membered carbocyclic or heterocyclic group, R¹¹⁵Is represented by C_1-6Alkyl or a saturated or unsaturated 5-6 membered carbocyclic or heterocyclic group, R¹¹⁶And R¹¹⁷May be the same or different and represents C_1-6Alkyl or a saturated or unsaturated 5-6 membered carbocyclic or heterocyclic group, R¹¹⁴、R¹¹⁵、R¹¹⁶And R¹¹⁷The 5-to 6-membered carbocyclic or heterocyclic group being optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, when the 5-to 6-membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form C_1-3The alkylene chain, or the 5-6 membered carbocyclic or heterocyclic group may also be fused with another saturated or unsaturated 5-6 membered carbocyclic group to form a bicyclic group.

8. The compound of claim 7, wherein R¹⁰⁹The optionally substituted alkyl group represents- (CH)₂)p-R¹¹⁴、-(CH₂)p-T-R¹¹⁵Or- (CH)₂)p-NR¹¹⁶R¹¹⁷P represents an integer of 1 to 6, R¹¹⁴、R¹¹⁵、R¹¹⁶、R¹¹⁷And T is as defined in claim 7.

9. The compound of claim 7, wherein R¹⁰³Is represented by C_1-4An alkoxy group.

10. The compound of claim 7, wherein R¹⁰³Represents a methoxy group.

11. The compound of claim 7, wherein R¹⁰⁵、R¹⁰⁶、R¹⁰⁷And R¹⁰⁸May be the same or different and represents a hydrogen atom or C_1-4An alkoxy group.

12. The compound of claim 7, wherein R¹⁰⁵、R¹⁰⁶、R¹⁰⁷And R¹⁰⁸Which may be the same or different, represents a hydrogen atom or a methoxy group.

13. The compound of claim 7, wherein R¹⁰⁵Represents a methoxy group; r¹⁰⁶、R¹⁰⁷And R¹⁰⁸Represents a hydrogen atom.

14. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴Substituted C_1-6An alkyl group; r¹¹⁴Represents an optionally substituted, saturated or unsaturated, 5-6 membered carbocyclic or heterocyclic ring.

15. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴Substituted C_1-6An alkyl group; r¹¹⁴Represents an optionally substituted phenyl group.

16. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴A substituted methyl group; r¹¹⁴Represents an optionally substituted, saturated or unsaturated, 5-6 membered carbocyclic or heterocyclic ring.

17. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴A substituted methyl group; r¹¹⁴Represents an optionally substituted phenyl group.

18. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴Substituted C_1-6An alkyl group; r¹¹⁴Represents a saturated or unsaturated 5-to 6-membered carbocyclic or heterocyclic ring optionally substituted by halogen atoms.

19. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴Substituted C_1-6An alkyl group; r¹¹⁴Represents a phenyl group optionally substituted by a halogen atom.

20. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴A substituted methyl group; r¹¹⁴Represents a saturated or unsaturated 5-to 6-membered carbocyclic or heterocyclic ring optionally substituted by halogen atoms.

21. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴SubstitutionA methyl group of (a); r¹¹⁴Represents a phenyl group optionally substituted by a halogen atom.

22. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴Substituted C_1-6An alkyl group; r¹¹⁴Represents a saturated or unsaturated 5-to 6-membered carbocyclic or heterocyclic ring optionally substituted by fluorine atoms.

23. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴Substituted C_1-6An alkyl group; r¹¹⁴Represents a phenyl group optionally substituted by a fluorine atom.

24. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴A substituted methyl group; r¹¹⁴Represents a saturated or unsaturated 5-to 6-membered carbocyclic or heterocyclic ring optionally substituted by fluorine atoms.

25. The compound of claim 7, wherein R¹⁰⁹Is represented by-R¹¹⁴A substituted methyl group; r¹¹⁴Represents a phenyl group optionally substituted by a fluorine atom.

26. The compound of claim 7, wherein R¹⁰³Represents C substituted by a saturated or unsaturated 5-to 7-membered heterocyclic group_1-4Alkoxy, said heterocyclic group being optionally substituted by C_1-6Alkyl substitution.

27. The compound of claim 7, wherein R¹⁰³Represents C substituted by a saturated 6-membered heterocyclic group₃An alkoxy group.

28. The compound of claim 26 or 27, wherein R¹⁰⁵、R¹⁰⁶、R¹⁰⁷And R¹⁰⁸May be the same or different and represents a hydrogen atom or a halogen atom.

29. The compound of claim 26 or 27, wherein R¹⁰⁵Represents a halogen atom; r¹⁰⁶、R¹⁰⁷And R¹⁰⁸Represents a hydrogen atom.

30. The compound of claim 26 or 27, wherein R¹⁰⁶Represents a halogen atom; r¹⁰⁵、R¹⁰⁷And R¹⁰⁸Represents a hydrogen atom.

31. The compound of claim 26 or 27, wherein R¹⁰⁹Is represented by-R¹¹⁴Substituted C₁An alkyl group; r¹¹⁴Represents a saturated or unsaturated 5-to 6-membered carbocyclic or heterocyclic group optionally substituted by: c_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, when the 5-to 6-membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form C_1-3The alkylene chain, or the 5-6 membered carbocyclic or heterocyclic group may also be fused with another saturated or unsaturated 5-6 membered carbocyclic group to form a bicyclic group.

32. The compound of claim 26 or 27, wherein R¹⁰⁹Is represented by-R¹¹⁴Substituted C₁An alkyl group; r¹¹⁴Represents a phenyl group optionally substituted by a halogen atom.

33. The compound of claim 1, having a structure represented by formula (200):

in the above formula, the first and second carbon atoms are,

R²⁰³represents a hydroxyl group or C_1-4Alkoxy radical, C_1-4Alkoxy is optionally substituted by a halogen atom, a hydroxyl group, an amino group or a saturated or unsaturated 5-to 7-membered heterocyclic group, wherein1 or 2 hydrogen atoms of the amino group being optionally substituted by C_1-6Alkyl substitution of the C_1-6Alkyl is optionally further substituted by hydroxy or C_1-6Alkoxy, said heterocyclyl being optionally substituted by C_1-6Alkyl substitution of the C_1-6Alkyl is optionally further substituted by hydroxy or C_1-6The substitution of alkoxy groups is carried out,

R²⁰⁵、R²⁰⁶、R²⁰⁷and R²⁰⁸May be the same or different and represents a hydrogen atom, a halogen atom, C_1-4Alkyl or C_1-4Alkoxy radical, and

R²⁰⁹to represent

C_1-6Alkyl radical, C_1-61 or more hydrogen atoms of the alkyl group being represented by-R²¹⁴、-T-R²¹⁵or-NR²¹⁶R²¹⁷Substituted, T represents-O-, -S-or-NH-, R²¹⁴Represents a saturated or unsaturated 5-6 membered carbocyclic or heterocyclic group, R²¹⁵Is represented by C_1-6Alkyl or a saturated or unsaturated 5-6 membered carbocyclic or heterocyclic group, R²¹⁶And R²¹⁷May be the same or different and represents C_1-6Alkyl or a saturated or unsaturated 5-6 membered carbocyclic or heterocyclic group, R²¹⁴、R²¹⁵、R²¹⁶And R²¹⁷The 5-to 6-membered carbocyclic or heterocyclic group being optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl, when the 5-to 6-membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form C_1-3The alkylene chain, said 5-6 membered carbocyclyl or heterocyclyl may also be fused with another saturated or unsaturated 5-6 membered carbocyclyl or heterocyclyl to form a bicyclic group.

34. The compound of claim 33, wherein R²⁰⁹The optionally substituted alkyl group represents- (CH)₂)p-R²¹⁴、-(CH₂)p-T-R²¹⁵Or- (CH)₂)p-NR²¹⁶R²¹⁷P represents an integer of 1 to 6, R²¹⁴、R²¹⁵、R²¹⁶、R²¹⁷And T is as defined in claim 33.

35. The compound of claim 33, wherein R²⁰³Represents C optionally substituted by a saturated or unsaturated 5-to 7-membered heterocyclic group_1-4Alkoxy, said heterocyclic group being optionally substituted by C_1-6Alkyl substitution.

36. The compound of claim 33, wherein R²⁰³Is represented by C₁An alkoxy group.

37. The compound of claim 33, 35 or 36, wherein R²⁰⁵、R²⁰⁶、R²⁰⁷And R²⁰⁸May be the same or different and represents a hydrogen atom or a halogen atom.

38. The compound of claim 33, 35 or 36, wherein R²⁰⁵Represents a halogen atom; r²⁰⁶、R²⁰⁷And R²⁰⁸Represents a hydrogen atom.

39. The compound of claim 33, 35 or 36, wherein R²⁰⁶Represents a halogen atom; r²⁰⁵、R²⁰⁷And R²⁰⁸Represents a hydrogen atom.

40. The compound of claim 33, 35 or 36, wherein R²⁰⁹Is represented by-R²¹⁴Substituted C₁An alkyl group; r²¹⁴Represents a saturated or unsaturated 5-to 6-membered carbocyclic or heterocyclic ring optionally substituted with: c_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, trifluoromethyl; when the 5-to 6-membered carbocyclic or heterocyclic group is substituted by 2C_1-6When alkyl is substituted, the 2 alkyl groups may together form C_1-3The alkylene chain, or the 5-6 membered carbocyclic or heterocyclic group may also be fused with another saturated or unsaturated 5-6 membered carbocyclic group to form a bicyclic group.

41. The compound of claim 33, 35 or 36, wherein R²⁰⁹Is represented by-R²¹⁴Substituted C₁An alkyl group; r²¹⁴Represents a phenyl group optionally substituted by a halogen atom.

42. The compound of claim 1, having a structure represented by formula (500):

in the above formula, the first and second carbon atoms are,

x represents a group of a CH or an N,

l represents O, M represents-N (-R)¹²) When Q represents CH₂，

L represents S, M represents-N (-R)¹²) When Q represents CH₂，

R⁵⁰³Represents a hydroxyl group or C_1-4Alkoxy radical, C_1-4Alkoxy is optionally substituted by halogen atom, hydroxyl, amino or saturated or unsaturated 5-7 membered heterocyclic group, wherein 1 or 2 hydrogen atoms on the amino group are optionally substituted by C_1-6Alkyl substitution of the C_1-6Alkyl is optionally further substituted by hydroxy or C_1-6Alkoxy, said heterocyclyl being optionally substituted by C_1-6Alkyl substitution of the C_1-6Alkyl is optionally further substituted by hydroxy or C_1-6The substitution of alkoxy groups is carried out,

R⁵⁰⁵、R⁵⁰⁶、R⁵⁰⁷and R⁵⁰⁸May be the same or different and represents a hydrogen atom, a halogen atom, C_1-4Alkyl or C_1-4Alkoxy radical, and

R⁵²⁰represents a saturated or unsaturated 5-or 6-membered carbocyclic or heterocyclic group, which is optionally substituted by C_1-6Alkyl radical, C_1-6Alkoxy or halogen atom.

43. The compound of claim 1 selected from the group consisting of:

(1) n- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -N' -phenylacetylthiourea

(2) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -N' - [2- (4-fluorophenyl) acetyl ] thiourea

(3) N- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -N' - [2- (4-fluorophenyl) acetyl) urea

(4)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetyl urea

(7)1- (2-Cyclopentylsulfanylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] urea

(8)1- (3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2, 3-dihydro-1H-1-indol-1-yl) acetyl ] urea

(11)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) quinolin-4-yloxy ] phenyl } -3-phenylacetyl urea

(12)1- (3-fluoro-4- { 6-methoxy-7- [4- (4-methyl-piperazin-1-yl) -butoxy ] quinolin-4-yloxy } phenyl) -3-phenylacetyl urea

(13)1- { 3-fluoro-4- [ 6-methoxy-7- (2-piperidin-1-yl-ethoxy) quinolin-4-yloxy ] phenyl } -3-phenylacetyl urea

(14)1- {4- [7- (3-chloro-propoxy) -6-methoxyquinolin-4-yloxy ] -3-fluorophenyl } -3-phenylacetyl urea

(16)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3-phenylacetyl urea

(17)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3-phenylacetyl urea

(18)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetyl urea

(19)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-thiophen-3-ylacetyl) urea

(20)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-thiophen-3-ylacetyl) urea

(21)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiophen-3-ylacetyl) urea

(22)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (4-fluorophenyl) acetyl ] urea

(23)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (4-fluorophenyl) acetyl ] urea

(24)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (4-fluorophenyl) acetyl ] urea

(25)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-fluorophenyl) acetyl ] urea

(26)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2-fluorophenyl) acetyl ] urea

(27)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2-fluorophenyl) acetyl ] urea

(28)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-fluorophenyl) acetyl ] urea

(29)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiophen-2-ylacetyl) urea

(30)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-thiophen-2-ylacetyl) urea

(31)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-thiophen-2-ylacetyl) urea

(32)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiophen-2-ylacetyl) urea

(33)1- [2- (2, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(34)1- [2- (2, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(35)1- [2- (3, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(36)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (3-fluorophenyl) acetyl ] urea

(37)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (3-fluorophenyl) acetyl ] urea

(38)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenyl ] -3- [2- (4-fluorophenyl) acetyl ] urea

(39)1- [2- (3, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] urea

(40)1- (4- (7-benzyloxy-6-methoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (4-fluorophenyl) acetyl ] urea

(41)1- { 3-fluoro-4- [ 6-methoxy-7- (4-morpholin-4-yl-butoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(42)1- { 3-fluoro-4- [ 6-methoxy-7- (4-piperidin-1-yl-butoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(43)1- (3-fluoro-4- { 6-methoxy-7- [4- (4-methyl-piperazin-1-yl) -butoxy ] quinolin-4-yloxy } phenyl) -3- [2- (4-fluorophenyl) acetyl ] urea

(44)1- { 2-fluoro-4- [ 6-methoxy-7- (4-morpholin-4-yl-butoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(45)1- { 2-fluoro-4- [ 6-methoxy-7- (4-piperidin-1-yl-butoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(46)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(47)1- { 3-fluoro-4- [ 6-methoxy-7- (3-piperidin-1-yl-propoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(48)1- { 3-fluoro-4- [ 6-methoxy-7- (2-piperidin-1-yl-ethoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(49)1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy ] quinolin-4-yloxy } phenyl) -3- [2- (4-fluorophenyl) acetyl ] urea

(50)1- { 2-fluoro-4- [ 6-methoxy-7- (3-piperidin-1-yl-propoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(51)1- (2-fluoro-4- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] quinolin-4-yloxy } phenyl) -3- [2- (4-fluorophenyl) acetyl ] urea

(52)1- { 3-fluoro-4- [ 6-methoxy-7- (3-piperidin-1-yl-propoxy) quinolin-4-yloxy ] phenyl } -3-phenylacetyl urea

(53)1- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] quinolin-4-yloxy } phenyl) -3-phenylacetyl urea

(54)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) quinolin-4-yloxy ] phenyl } -3-phenylacetyl urea

(55)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) quinolin-4-yloxy ] phenyl } -3- [2- (4-fluorophenyl) acetyl ] urea

(58)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3-phenylacetylthiourea

(59)1- [2- (2-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(60)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetylthiourea

(61)1- (2-Cyclohexylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] Thiourea

(62)1- [4- (6, 7-Methoxyquinolin-4-yloxy) phenyl ] -3- (3-ethoxypropionyl) thiourea

(63)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetylthiourea

(64)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (3-o-tolylpropanoyl) thiourea

(65)1- [ 2-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetylthiourea

(66)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiophen-2-ylacetyl) thiourea

(67)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-methylphenyl ] -3-phenylacetylthiourea

(68)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-methoxyphenyl ] -3-phenylacetylthiourea

(69)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenyl ] -3-phenylacetylthiourea

(70)1- [3, 5-dichloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3-phenylacetylthiourea

(71)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (4-fluorophenyl) acetyl ] thiourea

(72)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (4-fluorophenyl) acetyl ] thiourea

(73)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (4-fluorophenyl) acetyl ] thiourea

(74)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (3-fluorophenyl) acetyl ] thiourea

(75)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (3-fluorophenyl) acetyl ] thiourea

(76)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (3-fluorophenyl) acetyl ] thiourea

(77)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-m-tolylacetyl) thiourea

(78)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-m-tolylacetyl) thiourea

(79)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-o-tolylacetyl) thiourea

(80)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2-fluorophenyl) acetyl ] thiourea

(81)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2-fluorophenyl) acetyl ] thiourea

(82)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-p-tolylacetyl) thiourea

(83)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2-methoxyphenyl) acetyl ] thiourea

(84)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-o-tolylacetyl) thiourea

(85)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-thiophen-3-ylacetyl) thiourea

(86)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenyl ] -3- (2-thiophen-3-ylacetyl) thiourea

(87)1- [2- (2-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(88)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(89)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(90)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(91)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(92)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-p-tolylacetyl) thiourea

(93)1- [2- (2, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(94)1- [2- (2, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(95)1- [2- (2, 6-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(96)1- [2- (2, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(97)1- [2- (2, 6-dichlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(106)1- [ 3-fluoro-4- (7-hydroxy-6-methoxyquinolin-4-yloxy) phenyl ] -3-phenylacetyl urea

(110)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-diethylaminoacetyl) urea

(111)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-pyrrolidin-1-ylacetyl) urea

(112)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (isopropylmethylamino) acetyl ] urea

(113)1- (2-Cyclohexylsulfanylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] urea

(114)1- (2-Cyclohexylsulfanylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(115)1- (2-Cyclohexylsulfanylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(116)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-cyclopentylsulfanylacetyl) urea

(117)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-o-tolylaminoacetyl) urea

(118)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiophen-3-ylacetyl) urea

(119)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (6-methyl-3, 4-dihydro-2H-quinolin-1-yl) acetyl ] urea

(121)1- [2- (2, 3-dihydro-1H-1-indol-1-yl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(122)1- [2- (2, 3-dihydro-1H-1-indol-1-yl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(123)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2- [1, 2, 3] triazol-1-ylacetyl) urea

(124)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-p-tolylacetyl) urea

(125)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] urea

(126)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(127)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(128)1- (2-bicyclo [2.2.1] heptan-7-ylacetyl) -3- (3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] urea

(129)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-phenylsulfamoyl acetyl) urea

(130)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (1-methyl-1H-imidazol-2-ylsulfanyl) acetyl ] urea

(131)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-thiomorpholin-4-ylacetyl) urea

(132)1- [2- (2, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(133)1- [2- [2, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(134)1- [2- (2, 6-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(135)1- [2- (2, 6-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(136)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2-trifluoromethylphenyl) acetyl ] urea

(137)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2-trifluoromethylphenyl) acetyl ] urea

(138)1- [2- (2, 3-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl) urea

(139)1- [2- (2, 3-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(140)1- [2- (3, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(141)1- [2- (3, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] urea

(142)1- [2- (3, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] urea

(147)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (3-methylsulfanylpropanoyl) thiourea

(149)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-o-tolylacetyl) thiourea

(151)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-fluorophenyl) acetyl ] thiourea

(152)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-fluorophenyl) acetyl ] thiourea

(153)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-methoxyphenyl) acetyl ] thiourea

(154)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-methoxyphenyl) acetyl ] thiourea

(155)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-nitrophenyl) acetyl ] thiourea

(156)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-nitrophenyl) acetyl ] thiourea

(157)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-phenoxyacetyl) thiourea

(158)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-phenyl-propionyl) thiourea

(159)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (3-ethoxypropionyl) thiourea

(161)1- (3-Cyclopentylpropionyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(162)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-methylphenyl ] -3-phenylacetylthiourea

(163)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2, 5-dimethylphenyl ] -3-phenylacetylthiourea

(164)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (3-fluorophenyl) acetyl ] thiourea

(165)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (3-ethoxypropionyl) thiourea

(166)1- (2-Cyclohexylacetyl) -3- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] Thiourea

(167)1- (2-butoxyacetyl) -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(168)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- (2-p-tolylacetyl) thiourea

(169)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2-methoxyphenyl) acetyl ] thiourea

(170)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-o-tolylacetyl) thiourea

(171)1- [2- (3-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(172)1- [2- (3-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(173)1- [2- (3-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(174)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (3-chlorophenyl) acetyl ] thiourea

(175)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- (2-m-tolylacetyl) thiourea

(176)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-m-tolylacetyl) thiourea

(180)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- (3-methoxy-propionyl) thiourea

(181)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (3-methoxyphenyl) acetyl ] thiourea

(182)1- [2- (2-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(183)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2-chlorophenyl) acetyl ] thiourea

(184)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (3-methoxyphenyl) acetyl ] thiourea

(185)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (3-methoxyphenyl) acetyl ] thiourea

(186)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (3-methoxyphenyl) acetyl ] thiourea

(187)1- [2- (4-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(188)1- [2- (4-chlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(189)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (4-chlorophenyl) acetyl ] thiourea

(190)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- (2-p-tolylacetyl) thiourea

(191)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (4-methyl-cyclohexyl) acetyl ] thiourea

(192)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (4-methyl-cyclohexyl) acetyl ] thiourea

(193)1- (2-butoxyacetyl) -3- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] thiourea

(194)1- [2- (2, 3-fluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(195)1- [2- (2, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(196)1- [2- (3, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(197)1- [2- (3, 5-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(198)1- [2- (3, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(199)1- [2- (3, 4-difluorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] thiourea

(200)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2-trifluoromethylphenyl) acetyl ] thiourea

(201)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2-trifluoromethylphenyl) acetyl ] thiourea

(202)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (3-trifluoromethylphenyl) acetyl ] thiourea

(203)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (3-trifluoromethylphenyl) acetyl ] thiourea

(204)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2, 3, 6-trifluorophenyl) acetyl ] thiourea

(205)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] -3- [2- (2, 3, 6-trifluorophenyl) acetyl ] thiourea

(206)1- [4- (6, 7-Dimethoxyquinolin-4-yloxy) -3-fluorophenyl ] -3- [2- (2, 3, 6-trifluorophenyl) acetyl ] thiourea

(207)1- [ 3-chloro-4- (6, 7-dimethoxyquinolin-4-yloxy) phenyl ] -3- [2- (2, 3, 6-trifluorophenyl) acetyl ] thiourea

(208)1- [2- (2, 6-dichlorophenyl) acetyl ] -3- [4- (6, 7-dimethoxyquinolin-4-yloxy) -2-fluorophenyl ] thiourea

(268) N- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-ylpropoxy) quinolin-4-yloxy ] phenyl } -N' -phenylacetylthiourea

(270)1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy ] -quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

(271)1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy ] -quinolin-4-yloxy } -phenyl) -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(272)1- {4- [7- (2-diethylamino-ethoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3-phenylacetyl-thiourea

(273)1- (3-fluoro-4- { 6-methoxy-7- [2- (4-methyl- [1, 4] diazepan-1-yl) -ethoxy ] -quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

(275)1- {4- [7- (2-diethylamino-ethoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(276)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

(277)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(278)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(279)1- { 3-fluoro-4- [ 6-methoxy-7- (2-morpholin-4-yl-ethoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(282)1- (3-fluoro-4- {7- [2- (4-hydroxy-methyl-piperidin-1-yl) -ethoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(283)1- (3-fluoro-4- {7- [2- (4-hydroxy-methyl-piperidin-1-yl) -ethoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenyl-acetyl-urea

(284)1- (3-fluoro-4- {7- [2- (4-hydroxymethyl-piperidin-1-yl) -ethoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

(285)1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -thiourea

(286)1- { 2-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -urea

(287)1- { 2-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3-phenyl-acetyl-urea

(288)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(289)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(291)1- {4- [7- (3-diethylamino-propoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3-phenylacetyl-urea

(292)1- { 3-fluoro-4- [ 6-methoxy-7- (3-pyrrolidin-1-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-urea

(293)1- {4- [7- (3-diethylamino-propoxy) -6-methoxy-quinolin-4-yloxy ] -3-fluoro-phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

(294)1- { 3-fluoro-4- [ 6-methoxy-7- (3-pyrrolidin-1-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

(295)1- { 3-fluoro-4- [ 6-methoxy-7- (3-piperidin-1-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

(296)1- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinolin-4-yloxy } -phenyl) -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

(297)1- (3-fluoro-4- { 6-methoxy-7- [3- (4-methyl-piperazin-1-yl) -propoxy ] -quinolin-4-yloxy } -phenyl) -3- (2-m-tolylacetyl) -thiourea

(298)1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(299)1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(300)1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

(301)1- { 3-chloro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-o-tolylacetyl) -thiourea

(302)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-o-tolylacetyl) -thiourea

(303)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-m-tolylacetyl) -thiourea

(304)1- { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy ] -phenyl } -3- (2-p-tolylacetyl) -thiourea

(305)1- { 3-fluoro-4- [7- (3-imidazol-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-urea

(306)1- { 3-fluoro-4- [7- (3-imidazol-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -urea

(307)1- { 3-fluoro-4- [7- (3-imidazol-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

(308)1- (3-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-urea

(309)1- (3-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-thiourea

(310)1- (3-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(311)1- (2-fluoro-4- {7- [3- (4-hydroxymethyl-piperidin-1-yl) -propoxy ] -6-methoxy-quinolin-4-yloxy } -phenyl) -3-phenylacetyl-urea

(312)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3-phenylacetyl-thiourea

(313)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(314)1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(315)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(316)1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(317)1- [2- (2-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(318)1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(319)1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (2-fluoro-phenyl) -acetyl ] -thiourea

(320)1- [2- (3-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(321)1- [2- (3-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(322)1- [2- (3-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(323)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(324)1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(325)1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (3-fluoro-phenyl) -acetyl ] -thiourea

(326)1- [2- (4-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(327)1- [2- (4-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(328)1- [2- (4-chloro-phenyl) -acetyl ] -3- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -thiourea

(329)1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(330)1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -thiourea

(331)1- { 3-fluoro-4- [7- (2-hydroxy-3-piperidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-phenyl-acetyl) -thiourea

(332)1- { 3-fluoro-4- [7- (2-hydroxy-3-pyrrolidin-1-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-phenyl-acetyl) -thiourea

(333)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-o-tolylacetyl) -thiourea

(334)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-m-tolylacetyl) -thiourea

(335)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-p-tolylacetyl) -thiourea

(336)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- [2- (4-fluoro-phenyl) -acetyl ] -urea

(337)1- { 3-fluoro-4- [7- (2-hydroxy-3-morpholin-4-yl-propoxy) -6-methoxy-quinolin-4-yloxy ] -phenyl } -3- (2-phenyl-acetyl) -urea.

44. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

45. Use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament useful for the treatment of malignant tumors.

46. The use of claim 45, wherein the malignancy is selected from the group consisting of gastric, brain, colon, pancreatic, lung, renal, ovarian and prostate cancer.