QUINOLINE DERIVATIVE AND QUINAZOLINE DERIVATIVE INHIBITING SELF-PHOSPHORYLATION OF HEPATOCYTUS PROLIFERATOR RECEPTOR, AND MEDICINAL COMPOSITION CONTAINING THE SAME

Info

Publication number: 20080312221
Type: Application
Filed: Jul 17, 2008
Publication Date: Dec 18, 2008
Applicant: KIRIN BEER KABUSHIKI KAISHA (Tokyo-To)
Inventors: Yasunari Fujiwara (Tokyo-To), Terufumi Senga (Takasaki-shi), Tsuyoshi Nishitoba (Tokyo-To), Tatsushi Osawa (Takasaki-shi), Atsushi Miwa (Takasaki-shi), Kazuhide Nakamura (Takasaki-shi)
Application Number: 12/175,361

Abstract

An objective of the present invention is to provide compounds having potent antitumor activity. The compounds of the present invention are represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: wherein X=CH or N; Z=O or S; L=O or S; M=CR10R11, wherein R10 and R11=H, alkyl, or alkoxy, NR12 wherein R12=H or alkyl; R1, R2, and R3=H or optionally substituted alkoxy; R4=H; R5-8=H, halogen, alkoxy or the like; and R9=alkyl optionally substituted by —R14, -T-R15, or —NR16R17 wherein T=O, S, or NH; R14=an optionally substituted carbocyclic or heterocyclic ring; and R15-17=alkyl or an optionally substituted carbocyclic or heterocyclic ring, or —NR18R19 wherein R18 and R19=H, optionally substituted alkyl, or an optionally substituted carbocylic or heterocyclic ring, or optionally substituted carbocyclic or heterocyclic ring.

Description

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to quinoline derivatives and quinazoline derivatives which have antitumor activity. More particularly, the present invention relates to quinoline derivatives and quinazoline derivatives which have inhibitory activity against the autophosphorylation of hepatocyte growth factor receptors and have inhibitory activity against abnormal cell proliferation or cell movement.

2. Background Art

Growth factors such as epithelial growth factors, platelet-derived growth factors, insulin-like growth factors, and hepatocyte growth factors (hereinafter abbreviated to “HGF”) play an important role in cell proliferation. Among others, HGF is known to be involved, as a liver regenerating factor and a kidney regenerating factor, in the regeneration of damaged liver and kidney (Oncogenesis, 3, 27 (1992)).

However, the overexpression of HGF and a receptor thereof (hereinafter abbreviated to “met”) is reported to be found in various tumors such as brain tumors, lung cancer, gastric cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cancer, and prostate cancer (Oncology Reports, 5, 1013 (1998)). In particular, in gastric cancer, excessive development of met and an increase in HGF level of serum mainly in scirrhous gastric cancers are reported (Int. J. Cancer, 55, 72, (1993)). Further, it is also known that HGF has angiogenesis activity due to the acceleration of the proliferation and migration of vascular endothelial cells (Circulation, 97, 381 (1998), and Clinical Cancer Res., 5, 3695, (1999)) and induces the dispersion and invasion of cells (J Biol Chem, 270, 27780 (1995)). For this reason, HGF-met signals are considered to be involved in the proliferation, invasion, and metastasis of various cancer cells.

NK4, a partial peptide of HGF, is reported as an HGF receptor antagonist. For example, it is reported that NK4 inhibits met phosphorylation of various cancer cells and, further, suppresses cell movement and cell invasion and has tumor growth inhibitory activity in in-vivo cancer xenograft models probably through angiogenesis inhibitory activity (Oncogene, 17, 3045 (1998), Cancer Res., 60, 6737 (2000), British J Cancer, 84, 864 (2001), and Int J Cancer, 85, 563 (2000)).

Since, however, NK4 is a peptide, the use of NK4 as a therapeutic agent requires a design regarding reliable stability in vivo, administration method and the like. On the other hand, there is no report on low toxic orally active small molecule compounds having met autophosphorylation inhibitory activity.

SUMMARY OF THE INVENTION

The present inventors have found that a certain group of quinoline derivatives and quinazoline derivatives have met autophosphorylation inhibitory activity and, at the same time, have antitumor effects.

An object of the present invention is to provide compounds having potent antitumor activity.

According to the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:

wherein

X represents CH or N;

Z represents O or S;

L represents O or S;

M represents

—C(—R¹⁰)(—R¹¹)— wherein R¹⁰and R¹¹, which may be the same or different, represent a hydrogen atom, C_1-4alkyl, or C_1-4alkoxy, or

—N(—R¹²)— wherein R¹²represents a hydrogen atom or C_1-4alkyl;

R¹, R², and R³, which may be the same or different, represent

a hydrogen atom,

hydroxyl,

a halogen atom,

nitro,

amino,

C_1-6alkyl,

C_2-6alkenyl,

C_2-6alkynyl, or

C_1-6alkoxy,

in which one or two hydrogen atoms on the amino group are optionally substituted by C_1-6alkyl which is optionally substituted by hydroxyl or C_1-6alkoxy, and

in which the C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6alkoxy groups are optionally substituted by hydroxyl; a halogen atom; C_1-6alkoxy; C_1-6alkylcarbonyl; C_1-6alkoxy carbonyl; amino on which one or two hydrogen atoms is optionally substituted by C_1-6alkyl which is optionally substituted by hydroxyl or C_1-6alkoxy; or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl which is optionally substituted by hydroxyl or C_1-6alkoxy;

R⁴represents a hydrogen atom;

R⁵, R⁶, R⁷, and R⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C_1-4alkyl, or C_1-4alkoxy;

R⁹represents

C_1-6alkyl on which one or more hydrogen atoms are optionally substituted by —R¹⁴, -T-R¹⁵, or —NR¹⁶R¹⁷wherein T represents —O—, —S—, or —NH—; R¹⁴represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R¹⁵, R¹⁶, and R¹⁷, which may be the same or different, represent C_1-6alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R¹⁴, R¹⁵, R¹⁶, and R¹⁷is optionally substituted by C_1-6alkyl, C_1-6alkoxy, a halogen atom, nitro, trifluoromethyl, C_1-6alkoxy carbonyl, cyano, cyano C_1-6alkyl, C_1-6alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,

—N(—R¹⁸)(—R¹⁹) wherein R¹⁸and R¹⁹, which may be the same or different, represent a hydrogen atom; C_1-6alkyl which is optionally substituted by C_1-6alkoxy, C_1-6alkylthio, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C_1-6alkyl, C_1-6alkoxy, a halogen atom, nitro, trifluoromethyl, C_1-6alkoxy carbonyl, cyano, cyano C_1-6alkyl, C_1-6alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl, C_1-6alkoxy, a halogen atom, nitro, trifluoromethyl, C_1-6alkoxy carbonyl, cyano, cyano C_1-6alkyl, C_1-6alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl, C_1-6alkoxy, a halogen atom, nitro, trifluoromethyl, C_1-6alkoxy carbonyl, cyano, cyano C_1-6alkyl, C_1-6alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,

provided that, when X represents CH; Z represents O; L represents an oxygen atom; M represents —NH—; R¹, R⁴, R⁵, R⁶, R⁷, and R⁸represent a hydrogen atom; and R²and R³represent methoxy, R⁹does not represent phenyl, ethoxy, or pyridin-2-yl.

The compound according to the present invention can be used for the treatment of malignant tumors.

DETAILED DESCRIPTION OF THE INVENTION Compound

The terms “alkyl,” “alkoxy,” “alkenyl,” and “alkynyl” as used herein as a group or a part of a group respectively mean straight chain or branched chain alkyl, alkoxy, alkenyl, and alkynyl.

C_1-6alkyl is preferably C_1-4alkyl.

C_1-6alkoxy is preferably C_1-4alkoxy.

C_2-6alkenyl is preferably C_2-4alkenyl.

C_2-6alkynyl is preferably C_2-4alkynyl.

Examples of C_1-6alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.

Examples of C_1-6alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.

Examples of C_2-6alkenyl include allyl, butenyl, pentenyl, and hexenyl.

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

The expression “alkyl optionally substituted by” as used herein refers to alkyl, on which one or more hydrogen atoms are substituted by one or more substituents which may be the same or different, and unsubstituted alkyl. It will be understood by those skilled in the art that the maximum number of substituents may be determined depending upon the number of substitutable hydrogen atoms on the alkyl group. This applies to a group having a substituent other than the alkyl group.

The term “halogen atom” means a fluorine, chlorine, bromine, or iodine atom.

The saturated or unsaturated three- to eight-membered carbocyclic ring is preferably a four- to seven-membered, more preferably five- or six-membered, saturated or unsaturated carbocyclic ring. Examples of saturated or unsaturated three- to eight-membered carbocyclic rings include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The saturated or unsaturated three- to eight-membered heterocyclic ring contains at least one hetero-atom selected from oxygen, nitrogen, and sulfur atoms.

The saturated or unsaturated three- to eight-membered heterocyclic ring preferably contains one or two hetero-atoms with the remaining ring-constituting atoms being carbon atoms. The saturated or unsaturated three- to eight-membered heterocyclic ring is preferably a saturated or unsaturated four- to seven-membered heterocyclic ring, more preferably a saturated or unsaturated five- or six-membered heterocyclic ring. Examples of saturated or unsaturated three- to eight-membered heterocyclic groups include thienyl, pyridyl, 1,2,3-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, piperazinyl, piperazino, piperidyl, piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, and azepanyl.

The saturated or unsaturated carboxylic and heterocyclic groups may condense with another saturated or heterocyclic group to form a bicyclic group, preferably a saturated or unsaturated nine- to twelve-membered bicyclic carbocyclic or heterocyclic group.

Bicyclic groups include naphthyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, 1,4-benzoxanyl, indanyl, indolyl, and 1,2,3,4-tetrahydronaphthyl.

When the carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain, preferably a C_1-3alkylene chain. Carbocyclic or heterocyclic groups having this crosslinked structure include bicyclo[2.2.2]octanyl and norbornanyl.

R¹preferably represents a hydrogen atom.

R²and R³preferably represents a group other than a hydrogen atom. More preferably, R²represents unsaturated C_1-6alkoxy, still further preferably methoxy, and R³represents optionally substituted C_1-6alkoxy.

The substituent of substituted C_1-6alkoxy, which may be represented by R³, is preferably a halogen atom, hydroxyl, amino optionally mono- or disubstituted by optionally substituted C_1-6alkyl, or optionally substituted saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, more preferably a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group. Such substituents include amino mono- or disubstituted by C_1-6alkyl, phenyl, piperazinyl, piperazino, piperidyl, piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, azepanyl, imidazolyl, diazepanyl, and pyrrolidyl.

Optionally substituted alkoxy represented by R³preferably represents —O—(CH₂)m-R¹³wherein m is an integer of 1 to 6, R¹³is a substituent of the alkoxy group, that is, hydroxyl, a halogen atom, C_1-6alkoxy, C_1-6alkylcarbonyl, C_1-6alkoxy carbonyl, optionally substituted amino, or an optionally substituted saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

Preferably, all of R⁵, R⁶, R⁷, and R⁸represent a hydrogen atom, or alternatively any one or two of R⁵, R⁶, R⁷, and R⁸represent a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

Carbocylic group represented by R⁹, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸and R¹⁹and R¹⁰⁹, R¹¹⁴, R¹¹⁵, R¹¹⁶, R¹¹⁷, R¹¹⁸, R¹¹⁹, R²⁰⁹R²¹⁴, R²¹⁵, R²¹⁶, R²¹⁷, R²¹⁸, R²¹⁹, R³¹⁹, R⁴¹⁹, and R⁵²⁰, which will be described later, and carbocylic groups on the alkyl group represented by these groups include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthyl. Preferred substituents of the carbocyclic group include a fluorine atom, a chlorine atom, methyl, and methoxy. Examples of preferred carbocyclic groups include phenyl and naphthyl.

Heterocyclic groups represented by R⁹, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹and R¹⁰⁹, R¹¹⁴, R¹¹⁵, R¹¹⁶, R¹¹⁷, R¹¹⁸, R¹¹⁹, R²⁰⁹, R²¹⁴, R²¹⁵, R²¹⁶, R²¹⁷, R²¹⁸, R²¹⁹, R³¹⁹, R⁴¹⁹, and R⁵²⁰, which will be described later, and heterocyclic groups on the alkyl group represented by these groups include thienyl, pyridyl, tetrahydropyrrolyl, indolyl, 1,2,3-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, thiomorpholino, and 1,4-benzoxanyl. Preferred substituents of the heterocyclic group include a chlorine atom, a bromine atom, and methyl. Examples of preferred heterocyclic groups include thienyl, pyridyl, isoxazolyl, and quinolyl.

The optionally substituted alkyl group represented by R⁹preferably represents —(CH₂)p-R¹⁴, —(CH₂)p-T-R¹⁵, or —(CH₂)p-NR¹⁶R¹⁷wherein p is an integer of 1 to 6 and R¹⁴, R¹⁵, R¹⁶, and R¹⁷are as defined above.

In —N(—R¹⁸)(—R¹⁹) represented by R⁹, preferably, R¹⁶represents a hydrogen atom or C_1-6alkyl, and R¹⁹represents C_1-6alkyl which is optionally substituted by an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group; or an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group.

Preferred examples of R⁹include benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, anilino, fluoroanilino, difluoroanilino, chloroanilino, methylanilino, methoxyanilino, naphthyl, thienyl-2-yl-methyl, and thienyl-3-yl-methyl.

Both R¹⁰and R¹¹preferably represent a hydrogen atom or alkyl, or alternatively any one of R¹⁰and R¹¹represents alkoxy with the other group representing a hydrogen atom.

R¹²preferably represents a hydrogen atom.

Examples of preferred compounds according to the present invention include

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents O, and M represents —N(—R¹²)—,

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents O, M represents —C(—R¹⁰)(—R¹¹)—, and

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents S, and M represents —N(—R¹²)—.

Another examples of preferred compounds according to the present invention include

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents O, M represents —N(—R¹²)—, R¹and R⁴represent a hydrogen atom, R²represents unsubstituted C_1-6alkoxy, R³represents optionally substituted C_1-6alkoxy, and all of R⁵, R⁶, R⁷, and R⁸represent a hydrogen atom or alternatively any one of R⁵, R⁶, R⁷, and R⁸represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom,

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents O, M represents —C(—R¹⁰)(—R¹¹)—, R¹and R⁴represent a hydrogen atom, R²represents unsubstituted C_1-6alkoxy, R³represents optionally substituted C_1-6alkoxy, and all of R⁵, R⁶, R⁷, and R⁸represent a hydrogen atom or alternatively any one of R⁵, R⁶, R⁷, and R⁸represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom, and

compounds of formula (I) wherein X represents CH or N, Z represents O, L represents S, M represents —N(—R¹²)—, R¹and R⁴represent a hydrogen atom, R²represents unsubstituted C_1-6alkoxy, R³represents optionally substituted C_1-6alkoxy, all of R⁵, R⁶, R⁷, and R⁸represent a hydrogen atom or alternatively any one of R⁵, R⁶, R⁷, and R⁸represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

Examples of preferred compounds according to the present invention include compounds represented by formula (100):

wherein

R¹⁰³represents hydroxyl or C_1-4alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C_1-6alkyl which is optionally substituted by hydroxyl or C_1-6alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl which is optionally substituted by hydroxyl or C_1-6alkoxy,

R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸, which may be the same or different, represents a hydrogen atom, a halogen atom, C_1-4alkyl, or C_1-4alkoxy, and

R¹⁰⁹represents

C_1-6alkyl on which one or more hydrogen atoms are optionally substituted by —R¹¹⁴, -T-R¹¹⁵, or —NR¹¹⁶R¹¹⁷in which T represents —O—, —S—, or —NH—; R¹¹⁴represents saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R¹¹⁵represents C_1-6alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R¹¹⁶and R¹¹⁷, which may be the same or different, represent C_1-6alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R¹¹⁴, R¹¹⁵, R¹¹⁶, and R¹¹⁷is optionally substituted by C_1-6alkyl, C_1-6alkoxy, a halogen atom, nitro, trifluoromethyl, C_1-6alkoxy carbonyl, cyano, cyano C_1-6alkyl, C_1-6alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group or

a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl, C_1-6alkoxy, a halogen atom, nitro, trifluoromethyl, C_1-6alkoxycarbonyl, cyano, cyano C_1-6alkyl, C_1-6alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-carbocyclic or heterocyclic group.

Preferably, all of R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸represent a hydrogen atom or alternatively any one of R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

In formula (100), the optionally substituted alkyl group represented by R¹⁰⁹preferably represents —(CH₂)p-R¹¹⁴, —(CH₂)p-T-R¹¹⁵, or —(CH₂)p-NR¹¹⁶R¹¹⁷wherein p is an integer of 1 to 6 and R¹¹⁴, R¹¹⁵, R¹¹⁶, and R¹¹⁷are as defined above.

In —N(—R¹¹⁸)(—R¹¹⁹) represented by R¹⁰⁹, preferably, R¹¹⁸represents a hydrogen atom or C_1-6alkyl, and R¹¹⁹represents C_1-6alkyl which is optionally substituted by an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group; or an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group.

Preferred examples of R¹⁰⁹include benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, naphthyl, and thienyl.

Examples of preferred compounds according to the present invention include compounds of formula (200):

wherein

R²⁰³represents hydroxyl or C_1-4alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C_1-6alkyl which is optionally substituted by hydroxyl or C_1-6alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl which is optionally substituted by hydroxyl or C_1-6alkoxy,

R²⁰⁶, R²⁰⁷, and R²⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C_1-4alkyl, or C_1-4alkoxy, and

R²⁰⁹represents

C_1-6alkyl on which one or more hydrogen atoms are optionally substituted by —R²¹⁴, -T-R²¹⁵, or —NR²¹⁶R²¹⁷wherein T represents —O—, —S—, or —NH—; R²¹⁴represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R²¹⁵represents C_1-6alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R²¹⁶and R²¹⁷, which may be the same or different, represent C_1-6alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R²¹⁴, R²¹⁵, R²¹⁶, and R²¹⁷is optionally substituted by C_1-6alkyl, C_1-6alkoxy, a halogen atom, nitro, trifluoromethyl, C_1-6alkoxy carbonyl, cyano, cyano C_1-6alkyl, C_1-6alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or

a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl, C_1-6alkoxy, a halogen atom, nitro, trifluoromethyl, C_1-6alkoxy carbonyl, cyano, cyano C_1-6alkyl, C_1-6alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

Preferably, all of R²⁰⁵, R²⁰⁶, R²⁰⁷and R²⁰⁸represent a hydrogen atom, or alternatively any one of R²⁰⁵, R²⁰⁶, R²⁰⁷, and R²⁰⁸represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

In formula (200), preferably, the optionally substituted alkyl group represented by R²⁰⁹represents —(CH₂)p-R²¹⁴, —(CH₂)p-T-R²¹⁵, or —(CH₂)p-NR²¹⁶R²¹⁷wherein p is an integer of 1 to 6, R²¹⁴, R²¹⁵, R²¹⁶, and R²¹⁷are as defined above.

In —N(—R²¹⁸)(—R²¹⁹) represented by R²⁰⁹, preferably, R²¹⁸represents a hydrogen atom or C_1-6alkyl, and R²¹⁹represents C_1-6alkyl which is optionally substituted by an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group; or an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group.

Preferred examples of R²⁰⁹include benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl, and methoxybenzyl.

Examples of preferred compounds according to the present invention include compounds represented by formula (300):

wherein

R³⁰³represents hydroxyl or C_1-4alkoxy which is optionally substituted by a halogen atom or a saturated or unsaturated six-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl which is optionally substituted by hydroxyl or C_1-6alkoxy,

R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C_1-4alkyl, or C_1-4alkoxy,

R³¹⁰and R³¹¹represent a hydrogen atom, C_1-4alkyl, or C_1-4alkoxy,

R³¹⁸represents a hydrogen atom or C_1-4alkyl,

R³¹⁹represents

C_1-4alkyl which is optionally substituted by a saturated or unsaturated six-membered carbocyclic group which is optionally substituted by C_1-6alkyl; C_1-6alkoxy; a halogen atom; nitro; trifluoromethyl; C_1-6alkoxy carbonyl; cyano; cyano C_1-6alkyl; C_1-6alkylthio; phenoxy; acetyl; or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or

a saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl, C_1-6alkoxy, a halogen atom, nitro, trifluoromethyl, C_1-6alkoxy carbonyl, cyano, cyano C_1-6alkyl, C_1-6alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the four- to seven-membered carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the four- to seven-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

Preferably, all of R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸represent a hydrogen atom, or alternatively any one of R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

Preferred examples of R³¹⁹include phenyl, fluorophenyl, difluorophenyl, chlorophenyl, methylphenyl, and methoxyphenyl.

Examples of preferred compounds according to the present invention include compounds represented by formula (400):

wherein

R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷, and R⁴⁰⁸, which may be the same or different, represent a hydrogen atom, a halogen atom, C_1-4alkyl, or C_1-4alkoxy,

R⁴¹⁹represents an unsaturated five- or six-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl, C_1-6alkoxy, a halogen atom, nitro, trifluoromethyl, C_1-6alkoxy carbonyl, cyano, cyano C_1-6alkyl, C_1-6alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the five- or six-membered carbocyclic or heterocyclic group is substituted by two C_1-6alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the five- or six-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

Preferably, all of R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷and R⁴⁰⁸represent a hydrogen atom, or alternatively any one of R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷, and R⁴⁰⁸represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

Preferred examples of R⁴¹⁹include phenyl, fluorophenyl, difluorophenyl, chlorophenyl, methylphenyl, methoxyphenyl, pyridyl, isoxazolyl, and quinolyl.

Examples of preferred compounds according to the present invention include compounds represented by formula (500):

wherein

X represents CH or N,

when L represents O and M represents —N(—R¹²)—, Q represents CH₂or NH,

when L represents O and M represents —C(—R¹⁰)(—R¹¹)—, Q represents NH,

when L represents S and M represents —N(—R¹²)—, Q represents CH₂,

R⁵⁰³represents hydroxyl or C_1-4alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C_1-6alkyl which is optionally substituted by hydroxyl or C_1-6alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl which is optionally substituted by hydroxyl or C_1-6alkoxy,

R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, and R⁵⁰⁹, which may be the same or different, represent a hydrogen atom, a halogen atom, C_1-4alkyl, or C_1-4alkoxy, and

R⁵²⁰represents a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group which is optionally substituted by C_1-6alkyl, C_1-6alkoxy, or a halogen atom.

Preferably, all of R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, and R⁵⁰⁸represent a hydrogen atom, or alternatively any one of R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷, and R⁵⁰⁸represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

Examples of preferred compounds according to the present invention are as follows. The number attached to the compound represents the number of the corresponding working example described below.

(1) N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-N′-phenylacetylthiourea;
(2) N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-N′-[2-(4-fluorophenyl)acetyl]thiourea;
(3) N-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-N′-[2-(4-fluorophenyl)acetyl]urea;
(4) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenyl-acetylurea;
(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)methanamide;
(10) N-(4-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(11) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea;
(12) 1-(3-fluoro-4-{6-methoxy-7-[4-(4-methyl-piperazin-1-yl)-butoxy]quinolin-4-yloxy}phenyl)-3-phenylacetylurea;
(13) 1-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea;
(14) 1-{4-[7-(3-chloro-propoxy)-6-methoxyquinolin-4-yloxy]-3-fluorophenyl}-3-phenylacetylurea;
(15) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2-methylmalonamide;
(16) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-phenylacetylurea;
(17) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-phenylacetylurea;
(18) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylurea;
(19) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)urea;
(20) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-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-fluoro-phenyl]-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-fluoro-phenyl]-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-fluoro-phenyl]-3-(2-thiophen-2-ylacetyl)urea;
(31) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-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-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]urea;
(37) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-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-piperidine-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-piperidine-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-phenylacetylurea;
(53) 1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]quinolin-4-yloxy}phenyl)-3-phenylacetylurea;
(54) 1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea;
(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-fluoro-phenyl]-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-dimethoxy-quinolin-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-fluoro-phenyl]-3-(3-o-tolylpropionyl)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-methyl-phenyl]-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-fluoro-phenyl]-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-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea;
(75) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-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-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea;
(81) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-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-fluoro-phenyl]-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-fluoro-phenyl]-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]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;
(89) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;
(90) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea;
(91) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea;
(92) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-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-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]malonamide;
(99) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-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-dimethoxy-quinolin-4-yloxy)phenyl]malonamide;
(103) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2-methoxymalonamide;
(104) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2,2-dimethylmalonamide;
(105) N-(4-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(106) 1-[3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl]-3-phenylacetylurea;
(107) 1-(2-chloro-benzoyl)-3-[4-(6,7-dimethoxy-quinolin-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-pentanoylurea;
(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;
(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]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea;
(126) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea;
(127) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea;
(128) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea;
(129) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylsulfanylacetyl)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-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]thiourea;
(144) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-methoxybenzoyl)thiourea;
(145) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-trifluoromethyl-benzoyl)thiourea;
(146) 1-(2-bromobenzoyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea;
(147) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-methylsulfanylpropionyl)thiourea;
(148) 1-(4-chloro-butyryl)-3-[4-(6,7-dimethoxy-quinolin-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-phenylpropionyl)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-methylthiophen-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-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]thiourea;
(167) 1-(2-butoxyacetyl)-3-[4-(6,7-dimethoxy-quinolin-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-dimethoxy-quinolin-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) methyl 3-{2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenylcarbamoyl]acetylamino}benzoate;
(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-dimethoxy-quinolin-4-yloxy)phenyl]malonamide;
(219) N-(4-chlorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-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-dimethoxy-quinolin-4-yloxy)-2-methylphenyl]malonamide;
(224) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-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-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(230) N-(3-bromo-5-methyl-2-pyridyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(231) N-(5-chloro-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(232) N-(5-methyl-3-isoxazolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(233) N-(3-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(234) N-(6-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(235) N-(5-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(236) N-(2-pyridyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(237) N-(1-methyl-1H-5-pyrazolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(238) N-(2,3-dihydro-1,4-benzodioxin-6-yl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(239) N-(3-cyanophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(240) N-[2-(trifluoromethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methan-amide;
(241) N-[4-(cyanomethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(242) N-(4-chloro-2-methylphenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(243) N-(2,3-dihydro-1H-5-indenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(244) N-(3-methoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(245) methyl 2-({({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)carbonyl}amino)benzoate;
(246) N-(2-benzylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(247) N-(2-bromophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(248) N-(2-chlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(249) N-(4-chlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(250) N-(2-chloro-4-fluorophenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(251) N-(3-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(252) N-(2-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(253) N-[2-(methylsulfanyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(254) N-(4-nitrophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(255) N-(2-phenoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(256) N-(3-methylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(257) N-(4-methylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(258) N-(2,6-dimethylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(259) N-[2-(1H-1-pyrrolyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(260) N-(8-quinolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(261) N-(3-acetylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(262) N-(5-quinolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(263) N-(2,6-dichlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(264) N-(3,4-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(265) N-(2,6-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(266) N-(2-methoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide;
(267) N-[2-(2-hydroxyethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide;
(268) N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-N′-phenylacetyl-thiourea;
(269) N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)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-phenylacetylthio-urea;
(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-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-phenylacetylurea;
(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-toluoyl-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-toluoyl-acetyl)-thiourea;
(302) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea;
(303) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea;
(304) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-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-phenylacetyl)-thiourea;
(332) 1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-thiourea;
(333) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea;
(334) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea;
(335) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-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; and
(337) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-urea.

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

Examples of most preferred compounds according to the present invention include compounds 1, 2, 3, 11, and 268.

The compounds according to the present invention may form pharmaceutically acceptable salts thereof. Preferred examples of such salts include: alkali metal or alkaline earth metal salts such as sodium salts, potassium salts or calcium salts; hydrohalogenic acid salts such as hydrofluoride salts, hydrochloride salts, hydrobromide salts, or hydroiodide salts; inorganic acid salts such as nitric acid salts, perchloric acid salts, sulfuric acid salts, or phosphoric acid salts; lower alkylsulfonic acid salts such as methanesulfonic acid salts, trifluoromethanesulfonic acid salts, or ethanesulfonic acid salts; arylsulfonic acid salts such as benzenesulfonic acid salts or p-toluenesulfonic acid salts; organic acid salts such as fumaric acid salts, succinic acid salts, citric acid salts, tartaric acid salts, oxalic acid salts, maleic acid salts, acetic acid salts, malic acid salts, lactic acid salts, or ascorbic acid salts; and amino acid salts such as glycine salts, phenylalanine salts, glutamic acid salts, or aspartic acid salts.

The compounds according to the present invention may form solvates. Such solvates include, for example, hydrates, alcoholates, for example, methanolates and ethanolates, and etherates, for example, diethyl etherate.

Production of Compounds

Compounds according to the present invention may be produced, for example, according to schemes 1 to 9.

Starting compounds necessary for the synthesis of the compounds according to the present invention are commercially available or alternatively can be easily produced by conventional methods. In the schemes, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹⁸, R¹⁹, and X are as defined above; PG represents a protective group; R³′O represents optionally substituted alkoxy; Hal represents a halogen atom; R⁵¹and R⁵², which may be the same or different, represent optionally substituted C_1-6alkyl, or alternatively R⁵¹and R⁵²may combine to form a saturated or unsaturated three- to eight-membered heterocylic ring together with a nitrogen atom attached thereto; and n is an integer of 1 to 6.

For example, a 4-chloroquinoline derivative can be synthesized by a conventional method as described, for example, in Org. Synth. Col. Vol. 3, 272 (1955), Acta Chim. Hung., 112, 241 (1983), or WO 98/47873. Scheme 1 shows an example of the synthesis of the 4-chloroquinoline derivative. A quinolone derivative is produced by reacting a 2-aminoacetophenone derivative with a formic ester, for example, ethyl formate, in a suitable solvent, for example, tetrahydrofuran, in the presence of a base, for example, sodium methoxide. The 4-chloroquinoline derivative is produced by reacting the quinolone derivative in the presence of a chlorinating agent, for example, phosphorus oxychloride.

For example, a 4-chloroquinazoline derivative may be produced as follows. A quinazolone derivative is produced by reacting a 2-aminobenzoic acid derivative with formamide in a suitable solvent, for example, a mixed solvent composed of N,N-dimethylformamide and methanol, in the presence of a base, for example, sodium methoxide. The 4-chloroquinazoline derivative is produced by reacting the quinazolone derivative in the presence of a chlorinating agent, for example, phosphorus oxychloride.

Next, a 4-(aminophenoxy)quinoline derivative or a corresponding quinazoline derivative is produced by reacting a nitrophenol derivative with the 4-chloroquinoline derivative or corresponding quinazoline derivative in a suitable solvent, for example, chlorobenzene, to synthesize a 4-(nitrophenoxy)quinoline derivative or a corresponding quinazoline derivative and then reacting the 4-(nitrophenoxy)quinoline derivative or corresponding quinazoline derivative in a suitable solvent, for example, N,N-dimethyl formamide, in the presence of a catalyst, for example, palladium hydroxide-carbon, palladium-carbon, under a hydrogen atmosphere. The nitro group can also be reduced with zinc, iron or the like.

Alternatively, the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative may be produced by reacting an aminophenol derivative with the 4-chloroquinoline derivative or corresponding quinazoline derivative in a suitable solvent, for example, dimethyl sulfoxide, in the presence of a base, for example, sodium hydride. Alternatively, the 4-(aminophenoxy)quinazoline derivative may also be produced by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the solution to a two-phase reaction with a solution of the 4-chloroquinazoline derivative in a suitable organic solvent, for example, ethyl methyl ketone, in the presence of a phase transfer catalyst, for example, tetra-n-butylammonium chloride, or in the absence of the catalyst.

A carbonylthiourea derivative is produced by reacting a 4-(aminophenoxy)quinoline derivative or a quinazoline derivative with a carbonyl thioisocyanate derivative in a suitable solvent, for example, a mixed solvent composed of toluene and ethanol. The carbonyl thioisocyanate derivative is commercially available or can be easily produced by a conventional method. For example, the carbonyl thioisocyanate derivative is produced by reacting an acid chloride derivative with potassium thiocyanate in a suitable solvent, for example, acetonitrile.

A carbonylurea derivative is produced by reacting a 4-(aminophenoxy)quinoline derivative or a quinazoline derivative with a carbonyl isocyanate derivative in a suitable solvent, for example, N,N-dimethylformamide. The carbonyl isocyanate derivative is commercially available or can be easily produced by a conventional method. For example, as described in J. Org. Chem., 30, 4306 (1965), the carbonyl isocyanate derivative is produced by reacting an amide derivative with oxalyl chloride in a suitable solvent, for example, 1,2-dichloroethane.

An aminocarbonylurea derivative is produced by reacting a 4-(aminophenoxy)quinoline derivative or a quinazoline derivative with N-(chlorocarbonyl) isocyanate in a suitable solvent, for example, dichloromethane, in the presence of a base, for example, diisopropylamine and then reacting the product with an amine derivative.

An amide derivative is produced by reacting a 4-(aminophenoxy)quinoline derivative or a quinazoline derivative with a carboxylic acid derivative or a metal salt thereof in a suitable solvent, for example, in chloroform, in the presence of a condensing agent, for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and a carboxylic acid activating agent, for example, 1-hydroxybenzotriazole monohydrate.

For example, a derivative having a specific substituent at the 7-position of the quinoline ring can be produced according to scheme 3. A nitro group can be introduced by protecting a commercially available 4′-hydroxyacetophenone derivative with a suitable substituent, for example, benzyl, and then reacting the protected 4′-hydroxyacetophenone derivative with a nitrating agent, for example, fuming nitric acid-acetic acid. The later steps are carried out as shown in scheme 1. Specifically, the nitro group is reduced to an amino group which is then reacted with a formic ester in the presence of a base to give a quinolone ring. Next, the quinolone ring is reacted with a chlorinating agent to give a 4-chloroquinoline derivative. In the chlorination reaction, when phosphorus oxychloride is used as the chlorinating agent, the yield can be improved by adding a base, for example, N,N-diisopropylethylamine. Next, a 4-(aminophenoxy)quinoline derivative is produced by reacting the nitrophenol derivative with a 4-chloroquinoline derivative to synthesize a 4-(nitrophenoxy)quinoline derivative which is then reacted in a suitable solvent in a hydrogen atmosphere in the presence of a catalyst. The nitro group can also be reduced with zinc, iron or the like. Alternatively, the 4-(aminophenoxy)quinoline derivative may be produced by reacting an aminophenol derivative with a 4-chloroquinoline derivative in the presence of a base.

For example, a derivative having a specific substituent at the 7-position of the quinazoline ring can be produced according to scheme 4. A nitro group can be introduced by protecting a hydroxyl group in a commercially available 4′-hydroxybezoic acid ester derivative with a suitable substituent, for example, benzyl, and then reacting the product with a nitrating agent, for example, fuming nitric acid-acetic acid. Later steps are carried out as shown in scheme 1. Specifically, a quinazolone ring is formed by reducing the nitro group to an amino group and then reacting the product with formamide in the presence of a base. Next, a 4-chloroquinazoline derivative can be produced by reacting the product with a chlorinating agent. In the chlorination reaction, when phosphorus oxychloride is used as a chlorinating agent, the addition of a base, for example, N,N-diisopropylethylamine can improve the yield. Next, a 4-(aminophenoxy)quinazoline derivative is produced by reacting the nitrophenol derivative with a 4-chloroquinazoline derivative to synthesize a 4-(nitrophenoxy)quinazoline derivative which is then reacted in a suitable solvent in a hydrogen atmosphere in the presence of a catalyst. The nitro group can also be reduced with zinc, iron or the like. The 4-(aminophenoxy)quinazoline derivative may also be produced by reacting an aminophenol derivative with a 4-chloroquinazoline derivative in the presence of a base. Alternatively, the 4-(aminophenoxy)quinazoline derivative may be produced by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the solution to a two-phase reaction with a solution of the 4-chloroquinazoline derivative in an organic solvent in the presence of a phase transfer catalyst or in the absence of the catalyst.

For example, a carbonylthiourea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be produced according to scheme 5. Specifically, a 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative is produced by removing the protective group of the hydroxyl group in the 4-(nitrophenoxy)quinoline derivative or quinazoline derivative produced in scheme 3 or 4 under suitable conditions. For example, when the protective group is benzyl, for example, the deprotection reaction is carried out in N,N-dimethylformamide in a hydrogen atmosphere in the presence of palladium hydroxide-carbon or palladium-carbon. Next, a 4-(aminophenoxy)quinoline derivative or a corresponding quinazoline derivative is produced by alkylating the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative under suitable conditions, for example, by reacting the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative with an alkyl halide in a suitable solvent in the presence of a base and then reacting the alkylation product in a suitable solvent, for example, N,N-dimethylformamide, in a hydrogen atmosphere in the presence of a catalyst, for example, palladium hydroxide-carbon or palladium-carbon. The nitro group can also be reduced with zinc, iron or the like. Later steps are carried out as shown in scheme 2. Specifically, a carbonylthiourea derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with a carbonylthio isocyanate derivative in a suitable solvent.

For example, a carbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be produced according to scheme 6. Specifically, the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative, of which the 7-position has been alkylated in scheme 5, is reacted as shown in scheme 2. More specifically, a carbonylurea derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or quinazoline derivative with a carbonyl isocyanate derivative in a suitable solvent. The carbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can also be synthesized by other methods. At the outset, the 4-(aminophenoxy)quinoline derivative or quinazoline derivative produced in scheme 3 or 4 is reacted as shown in scheme 2. Specifically, a carbonylurea derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with a carbonyl isocyanate derivative in a suitable solvent. A 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative is produced by removing the protective group of the hydroxyl group in the carbonylurea derivative under suitable conditions. For example, when the protective group is benzyl, for example, the deprotection reaction is carried out in a hydrogen atmosphere in N,N-dimethylformamide in the presence of palladium hydroxide-carbon or palladium-carbon. Next, a carbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring is produced by alkylating the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative under suitable conditions, for example, by reacting the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative with an alkyl halide in a suitable solvent in the presence of a base.

For example, an aminocarbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be produced according to scheme 7. Specifically, the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative, of which the 7-position has been alkylated, prepared in scheme 5 is reacted as shown in scheme 2. That is, an aminocarbonylurea derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with N-(chlorocarbonyl)isocyanate in a suitable solvent in the presence of a base and then reacting the product with an amine derivative. The aminocarbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can also be synthesized by other methods. At the outset, the 4-(aminophenoxy)quinoline derivative or quinazoline derivative produced in scheme 3 or 4 is reacted as shown in scheme 2. Specifically, an aminocarbonylurea derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with N-(chlorocarbonyl)isocyanate in a suitable solvent in the presence of a base and then reacting the product with an amine derivative. A 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative is produced by removing the protective group of the hydroxyl group in the aminocarbonylurea derivative under suitable conditions. For example, when the protective group is benzyl, the deprotection reaction is carried out, for example, in N,N-dimethylformamide, in a hydrogen atmosphere in the presence of palladium hydroxide-carbon or palladium-carbon. Next, an aminocarbonylurea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring is produced by alkylating the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative under suitable conditions, for example, with an alkyl halide in a suitable solvent in the presence of a base.

For example, an amide derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be produced according to scheme 8. Specifically, the 4-(aminophenoxy)quinoline derivative or corresponding quinazoline derivative, of which the 7-position has been alkylated, prepared in scheme 5 is reacted as shown in scheme 2. That is, an amide derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with a carboxylic acid derivative or a metal salt thereof in a suitable solvent in the presence of a condensing agent and a carboxylic acid activating agent. The amide derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can also be synthesized by other methods. At the outset, the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative produced in scheme 3 or 4 is reacted as shown in scheme 2. That is, an amide derivative is produced by reacting the 4-(aminophenoxy)quinoline derivative or the quinazoline derivative with a carboxylic acid derivative or a metal salt thereof in a suitable solvent in the presence of a condensing agent and a carboxylic acid activating agent. A 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazoline derivative is produced by removing the protective group of the hydroxyl group in the amide derivative under suitable conditions. For example, when the protective group is benzyl, the deprotection reaction is carried out, for example, in N,N-dimethylformamide, in a hydrogen atmosphere in the presence of palladium hydroxide-carbon or palladium-carbon. Next, an amide derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring is produced by alkylating the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative under suitable conditions, for example, by reacting the 7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazoline derivative with an alkyl halide in a suitable solvent in the presence of a base.

For example, a carbonylurea derivative and carbonylthiourea derivative having a specific substituent at the 7-position of the quinoline or quinazoline ring can be produced according to scheme 9. Specifically, a carbonylurea derivative or a carbonylthiourea derivative can be produced by deprotecting the 4-aminophenoxyquinoline derivative or corresponding quinazoline derivative, of which the 7-position has been protected by benzyl, under acidic conditions to give a phenol compound, then reacting the phenol compound with an alkyl halide in a suitable solvent in the presence of a base to give a corresponding ether compound, and then reacting the product with a suitable amine in a suitable solvent in the presence of a base to give a corresponding 7-amino-substituted (4-aminophenoxy)quinoline derivative and then reacting this derivative with a carbonyl isocyanate derivative or a carbonylisothiocyanate derivative. Alternatively, a corresponding carbonylthiourea derivative having a specific substituent at the 7-position can be produced by reacting the ether compound, provided after the reaction with the alkyl halide, with a carbonylisothiocyanate derivative to give a carbonylthiourea derivative and then reacting the carbonylthiourea derivative with a suitable amine in a suitable solvent in the presence of a base.

Use of Compounds/Pharmaceutical Composition

The compounds according to the present invention have tumor growth inhibitory activity in vivo (see Pharmacological Test Examples 3, 4, and 5).

Further, the compounds according to the present invention inhibit in vitro the met autophosphorylation caused by the stimulation of human epidermal cancer cells A431 with HGF and the met autophosphorylation which constantly occurs in gastric cancer cells MKN45 non-dependently upon HGF (see Pharmacological Test Examples 1 and 2).

Upon HGF stimulation or in a HGF-non-dependent manner for certain cancer cells, met accelerates proliferation and motility in various cell species through the autophosphorylation of intracellular region with tyrosine kinase (J. Biochem., 119, 591, (1996), Jpn. J. Cancer Res., 88, 564, (1997), and Int. J. Cancer, 78, 750, (1998)). In particular, in a plurality of cancers, for example, the increasing of HGF concentration in the blood, excessive development of met, and the development of met mutants which have acquired HGF non-dependency are reported. met signals are considered to be involved in the proliferation and invasion of various cancer cells and metastasis (Int. J. Cancer, 55, 72, (1993), Oncology Reports, 5, 1013 (1998), Proc. Natl. Acad. Sci. USA, 88, 4892, (1991), and Cancer, 88, 1801, (2000)). Further, it is also reported that HGF accelerates through met the proliferation and migration activity of vascular endothelial cells and accelerates angiogenesis (Circulation, 97, 381 (1998) and Clinical Cancer Res., 5, 3695, (1999)), and, consequently, it is estimated that HGF is also related to angiogenesis in cancers.

Accordingly, the compounds according to the present invention can inhibit the growth, invasion, metastasis, and angiogenesis of cancer cells and thus can be used in the treatment of malignant tumors.

According to the present invention, there is provided a pharmaceutical composition comprising the compound according to the present invention. The pharmaceutical composition according to the present invention can be used in the treatment of malignant tumors such as brain tumors, gastric cancer, colon cancer, pancreatic cancer, lung cancer, renal cancer, ovarian cancer, and prostate cancer.

Further, according to the present invention, there is provided a method for treating a malignant tumor, comprising the step of administering a therapeutically effective amount of the compound according to the present invention together with a pharmaceutically acceptable carrier to a mammal including a human.

Furthermore, according to the present invention, there is provided use of the compound according to the present invention, for the manufacture of a medicament for use in the treatment of a malignant tumor.

The compounds according to the present invention can be administered to human and non-human animals orally or parenterally by administration routes, for example, intravenous administration, intramuscular administration, subcutaneous administration, rectal administration, or percutaneous administration. Therefore, the pharmaceutical composition comprising as an active ingredient the compound according to the present invention is formulated into suitable dosage forms according to the administration routes. Specifically, oral preparations include tablets, capsules, powders, granules, and syrups, and parental preparations include injections, suppositories, tapes, and ointments.

These various preparations may be prepared by conventional methods, for example, with commonly used excipients, disintegrants, binders, lubricants, colorants, and diluents.

Excipients include, for example, lactose, glucose, corn starch, sorbit, and crystalline cellulose. Disintegrants include, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, and dextrin. Binders include, for example, dimethylcellulose, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, and polyvinyl pyrrolidone. Lubricants include, for example, talc, magnesium stearate, polyethylene glycol, and hydrogenated vegetable oils.

In preparing the injections, if necessary, for example, buffers, pH adjustors, stabilizers, tonicity agents, and preservatives may be added.

The content of the compound according to the present invention in the pharmaceutical composition according to the present invention may vary depending upon the dosage form. In general, however, the content is 0.5 to 50% by weight, preferably 1 to 20% by weight, based on the whole composition.

The dose may be appropriately determined in consideration of, for example, the age, weight, sex, difference in diseases, and severity of condition of individual patients, preferably in the range of 1 to 100 mg/kg. This dose is administered at a time daily or divided doses of several times daily.

The compound according to the present invention may be administered in combination with other medicament, for example, a carcinostatic agent. In this case, the compound according to the present invention may be administered simultaneously with or after or before the administration of other medicament. The type, administration intervals and the like of the carcinostatic agent may be determined depending upon the type of cancer and the condition of patients.

EXAMPLES

The present invention is further illustrated by Examples that are not intended as a limitation of the invention.

Starting compounds necessary for synthesis were produced as described in WO 97/17329, WO 98/47873, WO 00/43366, and Japanese Patent Laid-Open Publication No. 328782/1997. Starting compounds not described in these publications were produced as described in Production Examples below.

Production Example 1 Starting compound 1

7-(Benzyloxy)-4-chloro-6-methoxyquinoline (29 g), 3-fluoro-4-nitrophenol (20 g), N,N-diisopropylethylamine (33 ml), and chlorobenzene (14 ml) were added, and the mixture was stirred with heating at 140° C. for 15 hr. After the completion of the reaction, a 2 N aqueous sodium hydroxide solution (30 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give the target compound (40 g, yield 50%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.58 (d, J=5.1 Hz, 1H), 8.48-8.44 (m, 1H), 8.21-8.19 (m, 1H), 7.64-7.35 (m, 8H), 6.79 (d, J=5.1 Hz, 1H), 5.33 (s, 2H), 3.94 (s, 3H)

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

Production Example 2 Starting Compound 2

7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline (35 g), zinc (74 g), and ammonium chloride (14 g) were added to ethanol/water (20/1, 525 ml), and the mixture was stirred with heating at 120° C. for 18 hr. After the completion of the reaction, the reaction solution was filtered through Celite. The filtrate was concentrated, and the concentrate was washed with water to give the target compound (32 g, yield 94%).

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

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

Production Example 3 Starting Compound 3

4-Fluorophenylacetamide (78 mg, see Example 3 for the production process thereof) was dissolved in 1,2-dichloroethane (20 ml) to prepare a solution. Oxalyl chloride (56 μl) was then added to the solution, and the mixture was heated under reflux at 110° C. for 15.5 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. Dimethylformamide (10 ml) and 4-{[7-(benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-fluoroaniline (50 mg) were added to the crude, and the mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude which was then purified by chromatography on silica gel using chloroform/methanol for development to give the target compound (49 mg, yield 67%).

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

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

Production Example 4 Starting Compound 4

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-fluorophenyl)-N′-[2-(4-fluorophenyl)acetyl]urea (1.6 g) and palladium hydroxide-carbon (1.3 g) were added to dimethylformamide (14 ml), and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 hr. After the completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated to give the target compound (1.3 g, yield 98%).

¹H-NMR (CDCl₃, 400 MHz): δ 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 spectrometric value (m/z): 480 [M+H]⁺

Production Example 5 Starting Compound 5

7-(Benzyloxy)-4-chloro-6-methoxyquinoline (81 g), 2-fluoro-4-nitrophenol (51 g), N,N-diisopropylethylamine (94 ml), and chlorobenzene (40 ml) were added, and the mixture was stirred with heating at 140° C. for 18 hr. After the completion of the reaction, a 2 N aqueous sodium hydroxide solution (40 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give the target compound (100 g, yield 92%).

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

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

Production Example 6 Starting Compound 6

7-(Benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (36 g), zinc (74 g), and ammonium chloride (14 g) were added to ethanol/water (20/1, 525 ml), and the mixture was stirred with heating at 120° C. for 19 hr. After the completion of the reaction, the reaction solution was filtered through Celite. The filtrate was concentrated, and the concentrate was washed with water to give the target compound (35 g, yield 96%).

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

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

Production Example 7 Starting Compound 7

4-Fluorophenylacetamide (86 mg, see Example 3 for the production process thereof) was dissolved in 1,2-dichloroethane (200 ml) at 80° C. to prepare a solution. Oxalyl chloride (150 μl) was added to the solution, and the mixture was stirred at 80° C. for 10 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. Dimethylformamide (2 ml) and 4-{[7-(benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluoroaniline (170 mg) were added to the crude, and the mixture was stirred at room temperature for 3 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give 248 mg of the target compound.

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

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

Production Example 8 Starting Compound 8

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluorophenyl)-N′-[2-(4-fluorophenyl)acetyl]urea (1.5 g) and palladium hydroxide-carbon (1.1 g) were added to dimethylformamide (20 ml), and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 hr. After the completion of the reaction, the reaction solution was filtered through Celite. The filtrate was concentrated to give the target compound (1.1 g, yield 88%).

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

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

Production Example 9 Starting Compound 9

2-Phenylacetamide (76 mg) was dissolved in 1,2-dichloroethane (200 ml) at 80° C. to prepare a solution. Oxalyl chloride (150 μl) was added to the solution, and the mixture was stirred at 80° C. for 10 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. Dimethylformamide (2 ml) and 4-{[7-(benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluoroaniline (170 mg) were added to the crude which was then stirred at room temperature for 3 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give 228 mg of the target compound.

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

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

Production Example 10 Starting Compound 10

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-3-fluorophenyl)-N′-(2-phenylacetyl)urea (1.2 g) and palladium hydroxide-carbon (1.0 g) were added to dimethylformamide (20 ml), and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 hr. After the completion of the reaction, the reaction solution was filtered through Celite. The filtrate was concentrated to give the target compound (0.85 g, yield 85%).

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

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

Production Example 11 Starting Compound 11

3-Fluoro-4-[(7-benzyloxy-6-methoxy-4-quinolyl)oxy]-nitrobenzene (2.5 g), together with trifluoroacetic acid (15 ml) and methanesulfonic acid (0.7 ml), was heated under reflux for one hr. The solvent was removed by evaporation, and the residue was then neutralized with a 10% aqueous sodium hydroxide solution. The precipitated crystal was collected by suction filtration to give a crude crystal (1.95 g). The crude crystal was dissolved in dimethylformamide (50 ml) without purification. Potassium carbonate (4.3 g) and 1-bromo-3-chloropropane (4.9 g) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was extracted with ethyl acetate, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give a crude which was then washed with an ethyl acetate/hexane (1/1) mixed solution to give the target compound (1.76 g, yield 73%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.35-2.41 (m, 2H), 3.80 (t, J=6.3 Hz, 2H), 3.99 (s, 3H), 4.34 (t, J=6.3 Hz, 2H), 6.53 (d, J=5.1 Hz, 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=5.1 Hz, 1H)

Production Example 12 Starting Compound 12

3-Fluoro-4-{[7-(3-chloropropyl)-6-methoxy-4-quinolyl]oxy}nitrobenzene (500 mg) was dissolved in dimethylformamide (20 ml) to prepare a solution. Potassium carbonate (890 mg), sodium iodide (290 mg), and morpholine (645 mg) were added to the solution, and the mixture was stirred at 70° C. for 18 hr. The mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give a crude. The crude was dissolved in methanol (30 ml) without purification. Ammonium chloride (207 mg) and zinc (1.26 g) were added to the solution, and the mixture was heated under reflux for 5 hr. Zinc was removed by filtration. Chloroform was added to the filtrate, the mixture was washed with a saturated sodium hydrogencarbonate solution, and the solvent was then removed by evaporation under the reduced pressure to give a crude. The crude was purified by column chromatography on silica gel using chloroform/methanol for development to give the target compound (440 mg, yield 80%).

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

Example 1

Phenylacetyl chloride [starting compound B] (1.89 ml) and potassium thiocyanate (2.09 g) were dissolved in acetonitrile (15 ml) to prepare a solution, and the solution was then stirred at 80° C. for one hr. Water was added to the reaction solution, the mixture was extracted with chloroform, and chloroform was then removed by evaporation under the reduced pressure to give a crude. The crude was dissolved in toluene/ethanol (1/1). 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline [starting compound A] (3.03 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solvent was removed by evaporation under the reduced pressure. The residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (0.69 g, yield 14.5%.

¹H-NMR (CDCl₃, 400 MHz): δ 3.76 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.46 (d, J=4.4 Hz, 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=5.4 Hz, 1H), 12.47 (br, 1H)

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

Example 2

Thionyl chloride (348 μl) was added to 4-fluorophenylacetic acid [starting compound B] (123 mg), and the mixture was stirred with heating at 50° C. for one hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. The crude was dissolved in acetonitrile (20 ml). Potassium thiocyanate (155 mg) was added to the solution, and the mixture was stirred with heating at 50° C. for 40 min. Thereafter, 4-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluoroaniline [starting compound A] (50 mg) was added thereto, and the mixture was then further stirred with heating for 60 min. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. An aqueous saturated sodium hydrogencarbonate solution was added to the crude, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and was concentrated under the reduced pressure. The concentrate was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 75%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.87 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.45 (d, J=5.1 Hz, 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=5.1 Hz, 1H), 8.70 (br, 1H), 12.45 (br, 1H)

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

Example 3

4-Fluorophenylacetic acid [starting compound B] (15 g) was dissolved in thionyl chloride (15 ml) to prepare a solution which was then heated at 60° C. for one hr. Excess thionyl chloride was removed by evaporation under the reduced pressure to give 4-fluorophenylacetyl chloride. The acid chloride was dissolved in acetone (200 ml). Ammonium acetate (112 g) was added to the solution, and the mixture was stirred at room temperature for 17 hr. An aqueous saturated sodium hydrogencarbonate solution (150 ml) was added thereto, and the mixture was stirred at room temperature for one hr. The reaction solution was then extracted with chloroform, and the solvent in the extract was removed by evaporation to give a crude crystal. The resultant crude crystal was washed with a hexane/ethyl acetate (2/1) mixed solution to give 4-fluorophenylacetamide (10.5 g, yield 70%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.53 (s, 2H), 5.25-5.70 (m, 2H), 7.00-7.05 (m, 2H), 7.20-7.26 (m, 2H)

4-Fluorophenylacetamide (2.05 g) was dissolved in 1,2-dichloroethane (250 ml) to prepare a solution. Oxalyl chloride (1.63 ml) was then added to the solution, and the mixture was heated for 15.5 hr under reflux. The solvent was removed by evaporation under the reduced pressure to give a crude. The crude was then dissolved in dimethylformamide (50 ml) to prepare a solution which was then added at room temperature to a previously prepared solution of 4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-fluoroaniline [starting compound A] (2.10 g) in dimethylformamide (30 ml). The mixture was stirred at that temperature for 5 hr. The solvent was removed by evaporation under the reduced pressure to give a crude. The crude was purified by column chromatography on silica gel using chloroform/methanol for development. The solvent was removed by evaporation under the reduced pressure to give a crude compound which was then washed with methanol to give the title compound (2.27 g, yield 69%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.74 (s, 2H), 4.04 (s, 3H), 4.05 (s, 3H), 6.52 (d, J=5.4 Hz, 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=5.4 Hz, 1H), 10.73 (br, 1H)

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

Example 4

2-Phenylacetamide [starting compound B] (91 mg) was dissolved in 1,2-dichloroethane (250 ml) to prepare a solution. Oxalyl chloride (73 μl) was added to the solution, and the mixture was heated under reflux at 110° C. for 15.5 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. Dimethylformamide (10 ml) and 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (50 mg) were added to the crude, and the mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure to give a crude. The crude was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (44 mg, yield 57%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 10.96 (s, 1H), 10.52 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.30 (s, 1H), 7.64 (d, J=9.0 Hz, 2H), 7.49 (s, 1H), 7.43-6.84 (m, 7H), 6.44 (d, J=5.4 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.72 (s, 2H)

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

Example 5

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (5.00 g) was dissolved in chloroform (100 ml) to prepare a solution. Potassium carbonate (4.66 g) was added to the solution, and the mixture was stirred at 0° C. Methylmalonyl chloride [starting compound B] (2.18 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 60 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The dried chloroform layer was then concentrated under the reduced pressure to give a crude. The crude was then dissolved in ethanol/water (10/1, 165 ml). Lithium hydroxide monohydrate (1.42 g) was added to the solution, and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated under the reduced pressure. Water was then added to the concentrate, and the solution was made weakly acidic by the addition of hydrochloric acid. The solution was allowed to stand overnight at 0° C., followed by filtration to give 6.45 g of a crystal (hereinafter referred to simply as “carboxylic acid”). The carboxylic acid (30 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (30 mg), 1-hydroxybenzotriazole monohydrate (24 mg), and 4-fluoroaniline [starting compound C] (10 mg) were dissolved in chloroform (3 ml) to prepare a solution which was then stirred at 60° C. overnight. The reaction solution was developed on diatomaceous earth impregnated with an aqueous saturated sodium hydrogencarbonate solution, followed by extraction with chloroform. The solvent in the extract was removed by evaporation to give a crude. The crude was purified by HPLC using chloroform/methanol for development to give the title compound (0.7 mg, yield 1.9%).

¹H-NMR (CDCl₃/CD₃OD, 400 MHz): δ 3.49 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.46 (d, J=5.1 Hz, 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=5.4 Hz, 1H)

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

Example 6

2,4-Difluoroaniline [starting compound C] (3.0 g) was dissolved in chloroform (50 ml) to prepare a solution. Potassium carbonate (6.24 g) was added to the solution, and the mixture was stirred. Ethylmalonyl chloride [starting compound B] (4 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 10 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The dried chloroform layer was concentrated under the reduced pressure to give 5.12 g of a crude. In ethanol/water (10/1, 33 ml) was dissolved 2.85 g out of 5.12 g of the crude. Lithium hydroxide monohydrate (0.99 g) was added to the solution, and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated under the reduced pressure to give 3.76 g of a crude (hereinafter referred to simply as “carboxylic acid”). Chloroform (3 ml) was added to 3-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (32 mg), carboxylic acid (31 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28 mg), and 1-hydroxybenzotriazole monohydrate (22 mg), and the mixture was stirred at 60° C. overnight. The reaction solution was developed on diatomaceous earth impregnated with an aqueous saturated sodium hydrogencarbonate solution, followed by extraction with chloroform. The solvent in the extract was removed by evaporation to give a crude. The crude was purified by HPLC using chloroform/methanol for development to give the title compound (0.1 mg, yield 2.0%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.59 (s, 2H), 4.05 (s, 3H), 4.07 (s, 3H), 6.33 (d, J=5.1 Hz, 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=5.4 Hz, 1H)

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

Example 7

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (100 mg) was dissolved in chloroform (3 ml) to prepare a solution. Chloroacetyl isocyanate [starting compound B] (40 mg) was added to the solution, and the mixture was stirred at room temperature for 10 hr. The reaction solution was purified by chromatography on silica gel to give N-(2-chloroacetyl)-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (116 mg, yield 83%). Next, N-(2-chloroacetyl)-N′-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (50 mg) and potassium carbonate (26 mg) were added to chloroform, and cyclopentanethiol [starting compound C] (38 μl) was added to the mixture with stirring. The mixture was stirred at room temperature for 3 hr, and the reaction solution was filtered through Celite. The filtrate was then concentrated under the reduced pressure to give a crude. The crude was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (35 mg, yield 60%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 10.84 (br, 1H), 10.49 (br, 1H), 8.48 (d, J=5.1 Hz, 1H), 7.69-7.67 (m, 4H), 7.51 (s, 1H), 7.39 (s, 1H), 7.26-7.24 (d, J=9.0 Hz, 1H), 3.93 (s, 6H), 3.41 (s, 2H), 2.08-1.97 (m, 2H), 1.67-1.42 (m, 7H)

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

Example 8

3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (100 mg) was dissolved in chloroform (3 ml) to prepare a solution. Chloroacetyl isocyanate [starting compound B] (42 mg) was added to the solution, and the mixture was stirred at room temperature for 10 hr. The reaction solution was purified by chromatography on silica gel to give N-(2-chloroacetyl)-N′-{3-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (115 mg, yield 85%). Next, N-(2-chloroacetyl)-N′-{3-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (50 mg) and potassium carbonate (28 mg) were added to chloroform, and indoline [starting compound C] (36 μl) was added to the mixture with stirring. The mixture was stirred at room temperature for 3 hr, and the reaction solution was filtered through Celite. The filtrate was then concentrated under the reduced pressure. The concentrate was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (33 mg, yield 56%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 10.64 (br, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.90 (d, J=2.7 Hz, 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=7.8 Hz, 1H), 6.42 (d, J=5.6 Hz, 1H), 4.08 (s, 6H), 3.87 (s, 2H), 3.55-3.51 (m, 2H), 3.13-3.09 (m, 2H)

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

Example 9

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (415 mg) was dissolved in 10 ml of a 1% AcOH/DMF solution to prepare a solution. Further, aldehyde linker lanthanum (D-series; 28 μmol/unit) (10 units) was added to the solution. The reaction mixture was slowly shaken for 19 hr. Sodium boron triacetoxyhydride (475 mg) was added thereto, and the mixture was further slowly shaken for 24 hr. Lanthanum was taken out of the reaction solution and was washed with alternate N,N-dimethylformamide and dichloromethane each three times, followed by drying under the reduced pressure to give lanthanum with 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline supported thereon. This lanthanum (3 units) was added to 1 ml of dichloromethane, and a solution of N-(chlorocarbonyl)isocyanate [starting compound B] (55 μl) in dichloromethane (0.2 ml) was added to the mixture at 0° C. The mixture was slowly shaken overnight at room temperature. Further, a mixed solution composed of aniline [starting compound C] (68 μl), diisopropylamine (0.2 ml), and dichloromethane (0.3 ml) was then added thereto at 0° C. The mixture was shaken at room temperature for 7 hr and was then washed with alternate N,N-dimethylformamide and dichloromethane each five times. Drying under the reduced pressure was carried out, a 50% TFA/dichloromethane solution (1 ml) was added thereto, and the mixture was shaken at room temperature for 50 min to take off the product from lanthanum, followed by purification by thin layer chromatography on silica gel to give 6.8 mg of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 3.98 (s, 6H), 6.40 (d, J=5.4 Hz, 1H), 7.09 (m, 1H), 7.10 (d, J=9 Hz, 2H), 7.27 (t, J=7.8 Hz, 2H), 7.33 (s, 1H), 7.38 (d, J=7.8 Hz, 2H), 7.47 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 8.37 (d, J=5.4 Hz, 1H)

Mass spectrometric value (m/z): 457 [M−H]⁺

Example 10

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (500 mg) was dissolved in 20 ml of dichloromethane to prepare a solution, and N-(chlorocarbonyl)isocyanate [starting compound B] (145 μl) was slowly added to the solution. The mixture was stirred at room temperature for 2.5 hr. 4-Fluoroaniline [starting compound C] (205 mg) and diisopropylamine (0.35 ml) were then added thereto at 0° C. Further, the temperature of the reaction solution was returned to room temperature before stirring for 2.5 hr. Water was added to the reaction solution, and the mixture was then extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The dried chloroform layer was concentrated under the reduced pressure, and the concentrate was then purified by chromatography on silica gel to give 380 mg of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 4.03 (s, 3H), 4.04 (s, 3H), 6.42 (d, J=5.4 Hz, 1H), 7.00 (m, 2H), 7.14 (d, J=9 Hz, 2H), 7.33 (br, 2H), 7.40 (s, 1H), 7.45 (br, 2H), 7.53 (s, 1H), 8.48 (d, J=5.4 Hz, 1H)

Mass spectrometric 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 compound A] (100 mg), potassium carbonate (150 mg), and 1,3-dibromopropane [starting compound C] (66 μl) were dissolved in dimethylformamide (5 ml) to prepare a solution which was then stirred at room temperature for 5 hr. Thereafter, morpholine [starting compound B] (57 μl) was further added thereto, and the mixture was stirred at room temperature for 3 hr. After the completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was then concentrated under the reduced pressure to give a crude. The crude was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give the title compound (23 mg, yield 18%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.07 (m, 2H), 2.44 (m, 4H), 2.53 (t, J=7.1 Hz, 2H), 3.66 (m, 4H), 3.69 (s, 2H), 3.96 (s, 3H), 4.20 (t, J=6.6 Hz, 2H), 6.33 (d, J=5.4 Hz, 1H), 7.11-7.45 (m, 8H), 7.49 (s, 1H), 7.61 (m, 1H), 8.01 (br, 1H), 8.41 (d, J=5.4 Hz, 1H), 10.59 (br, 1H)

Mass spectrometric 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 compound A] (100 mg), potassium carbonate (150 mg), and 1,4-dibromobutane [starting compound C] (78 μl) were dissolved in dimethylformamide (5 ml) to prepare a solution which was then stirred at room temperature for 5 hr. Thereafter, 1-methylpiperazine [starting compound B] (72 μl) was further added thereto, and the mixture was stirred at room temperature for 3 hr. After the completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was then concentrated under the reduced pressure to give a crude. The crude was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give the title compound (24 mg, yield 18%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.07 (br, 1H), 10.70 (br, 1H), 8.76 (d, J=6.3 Hz, 1H), 7.88 (d, J=11.7 Hz, 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 spectrometric 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 compound A] (100 mg), potassium carbonate (150 mg), and 1,2-dibromoethane [starting compound C] (54 μl) were dissolved in dimethylformamide (5 ml) to prepare a solution which was then stirred at room temperature for 5 hr. Thereafter, piperidine [starting compound B] (64 μl) was further added thereto, and the mixture was stirred at room temperature for 3 hr. After the completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was then concentrated under the reduced pressure to give a crude. The crude was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give the title compound (22 mg, yield 18%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.08 (br, 1H), 10.71 (br, 1H), 8.77 (d, J=6.3 Hz, 1H), 7.88 (d, J=13.6 Hz, 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=6.3 Hz, 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 spectrometric value (m/z): 573 [M+H]⁺

Example 14

N-{3-Fluoro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2-phenylacetyl)urea (100 mg), potassium carbonate (145 mg), and 1-bromo-3-chloropropane (53 μl) were dissolved in dimethylformamide (5 ml) to prepare a solution which was then stirred at room temperature for 5 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated under the reduced pressure to give a crude. The crude was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give the title compound (90 mg, yield 78%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 11.21 (br, 1H), 10.34 (br, 1H), 8.43 (d, J=5.4 Hz, 1H), 7.92 (d, J=10.2 Hz, 1H), 7.83 (d, J=12.2 Hz, 1H), 7.50 (s, 1H), 7.39-7.28 (m, 7H), 6.41 (d, J=5.1 Hz, 1H), 3.94 (s, 3H), 3.63 (s, 2H), 2.67 (m, 3H), 2.43 (s, 1H), 1.93-1.82 (m, 2H)

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

Example 15

Dimethyl methyl malonate [starting compound B] (1.33 ml) was dissolved in ethanol/water (10/1, 6 ml) to prepare a solution. Lithium hydroxide monohydrate (0.42 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under the reduced pressure to give 1.41 g of a crude. This crude (0.71 g), 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (1.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.97 g), and 1-hydroxybenzotriazole monohydrate (0.78 g) were dissolved in chloroform (30 ml), and the solution was heated under reflux overnight. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine. The chloroform layer was dried over anhydrous sodium sulfate, and the dried chloroform layer was concentrated under the reduced pressure to give a crude. The crude was dissolved in ethanol/water (10/1, 50 ml). Lithium hydroxide monohydrate (0.28 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under the reduced pressure. Water was added to the concentrate, and the solution was made weakly acidic by the addition of hydrochloric acid, followed by extraction with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the dried chloroform layer was concentrated under the reduced pressure to give 0.68 g of a crude (hereinafter referred to simply as “carboxylic acid”). This carboxylic acid (96 mg), 2,4-difluoroaniline [starting compound C] (0.037 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (70 mg), and 1-hydroxybenzotriazole monohydrate (56 mg) were dissolved in chloroform (4 ml), and the solution was heated under reflux overnight. The reaction solution was developed on diatomaceous earth impregnated with an aqueous saturated sodium hydrogencarbonate solution, followed by extraction with chloroform. The solvent in the extract was removed by evaporation to give a crude. The crude was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give 105 mg of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 1.74 (d, J=7.3 Hz, 3H), 3.47 (q, J=7.3 Hz, 1H), 4.05 (s, 3H), 4.06 (s, 3H), 6.47 (d, J=5.4 Hz, 1H), 6.87-6.95 (m, 2H), 7.18 (d, J=9.0 Hz, 2H), 7.48 (s, 1H), 7.55 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 8.15-8.23 (m, 1H), 8.45-8.50 (m, 2H), 8.63 (br, 1H)

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

Example 268

Phenylacetyl chloride (86 μl) and potassium thiocyanate (80 mg) were dissolved in acetonitrile (50 ml) to prepare a solution which was then stirred at 40° C. for 50 min. Acetonitrile was removed by evaporation under the reduced pressure to give a crude. An aqueous saturated sodium hydrogencarbonate solution and ethyl acetate were added to the crude, and the mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure to give a crude which was then dissolved in toluene/ethanol (1/1). 3-Fluoro-4-{[7-(3-morpholinopropoxy)-6-methoxy-4-quinolyl]oxy}aniline (70 mg) was added to the solution, and the mixture was stirred at room temperature for 3 hr. The reaction solvent was removed by evaporation under the reduced pressure, and the residue was purified by thin layer chromatography on silica gel using chloroform/methanol for development to give the title compound (43.6 mg, yield 44.0%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.13 (m, 2H), 2.49 (m, 4H), 2.58 (t, J=7.2 Hz, 2H), 3.73 (m, 4H), 3.76 (s, 2H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.44 (d, J=5.1 Hz, 1H), 7.22-7.48 (m, 8H), 7.54 (s, 1H), 7.93 (m, 1H), 8.46 (br, 1H), 8.50 (d, J=5.1 Hz, 1H), 12.47 (br, 1H)

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

Example 269

3-Fluoro-4-{[7-(3-morpholinopropoxy)-6-methoxy-4-quinolyl]oxy}aniline (60 mg) was dissolved in chloroform (15 ml) to prepare a solution. 3-(4-Fluoroanilino)-3-oxopropanoic acid (50 mg), 1-hydroxybenzotriazole monohydrate (43 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg) were added to the solution, and the mixture was heated under reflux for 3 hr, followed by washing with an aqueous saturated sodium hydrogencarbonate solution. The solvent was then removed by evaporation under the reduced pressure to give a crude. The crude was purified by column chromatography on silica gel using chloroform/methanol for development to give the title compound (41 mg, yield 48%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.04-2.10 (m, 2H), 2.35-2.46 (m, 4H), 2.51 (t, J=7.1 Hz, 2H), 3.50 (s, 2H), 3.63-3.68 (m, 4H), 3.96 (s, 3H), 4.18 (t, J=6.6 Hz, 2H), 6.32 (d, J=5.3 Hz, 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=5.3 Hz, 1H), 8.55 (s, 1H), 9.35 (s, 1H)

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

Compounds of Examples 1 to 15, 268, and 269 had the following respective structures.

Compounds of Examples 16 to 267 were synthesized as described in Examples 1 to 15, 268, and 269. For these compounds, chemical structural formulae, starting compounds, synthesis methods, and data for identifying the compounds are as follows.

Ex. No. Compound structure 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 Ex. Starting Starting No. compound A compoud B 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 Mass spectro- Ex. Starting metric value Synthesis No. compound C (m/z) H¹-NMR method^a 16 476[M + H]+ (CDCl3, 400 MHz): δ 3.75(s, 2 H), 4.01 Ex. 4 (s, 3 H), 4.02(s, 3 H), 6.49(d, J = 5.3 Hz, 1 H), 6.95-7.00(m, 2 H), 7.28-7.48 (m, 5 H), 7.41(s, 1 H), 7.50(s, 1 H), 8.01(s, 1 H), 8.18(t, J = 9.1 Hz, 1 H), 8.49(d, J = 5.3 Hz, 1 H), 10.74(s, 1 H) 17 476[M + H]+ (CDCl3, 400 MHz): δ 3.75(s, 2 H), 4.03 Ex. 4 (s, 3 H), 4.04(s, 3 H), 6.38(d, J = 5.3 Hz, 1 H), 6.97-7.42(m, 7 H), 7.40(s, 1 H), 7.55(s, 1 H), 7.65-7.68(m, 1 H), 8.09(s, 1 H), 8.46(d, J = 5.3 Hz, 1 H), 10.60(s, 1 H) 18 492[M + H]+ (CDCl3, 400 NHz): δ 375(s, 2 H), 4.03 Ex. 4 (s, 3 H), 4.04(s, 3 H), 6.29(d, J = 5.3 Hz, 1 H), 7.17-7.43(m, 7 H), 7.41(s, 1 H), 7.56(s, 1 H), 7.82(d, J = 2.5 Hz, 1 H), 8.07(br, 1 H), 8.45(d, J = 5.3 Hz, 1 H), 10.62(s, 1 H) 19 482[M + H]+ (DMSO-d6, 400 MHz): δ 11.23(br, 1 H), Ex. 3 10.75(br, 1 H), 8.49(d, J = 5.1 Hz, 1 H), 8.22(m, 1 H), 7.52-7.37(m, 3 H), 7.23(m, 1 H), 7.10-7.02(m, 2 H), 6.87- 6.85(m, 1 H), 6.56(d, J = 5.4 Hz, 1 H), 3.94(s, 6 H), 3.77(s, 2 H) 20 482[M + H]+ (DMSO-d6, 400 MHz): δ 11.00(br, 1 H), Ex. 3 10.63(br, 1 H), 8.48(d, J = 5.1 Hz, 1 H), 7.82(d, J = 14.15 Hz, 1 H), 7.52- 7.38(m, 5 H), 7.23(m, 1 H), 7.02(d, J = 6.1 Hz, 1 H), 6.45(d, J = 5.4 Hz, 1 H), 3.95(s, 6 H), 3.77(s, 2 H) 21 498[M + H]+ (DMSO-d6, 400 MHz): δ 10.63(br, 1 H), Ex. 3 8.47(d, J = 5.1 Hz, 1 H), 8.01(s, 1 H), 7.59-7.38(m, 5 H), 7.23(s, 1 H), 7.09 (d, J = 4.8 Hz, 1 H), 7.02(d, J = 4.8 Hz, 1 H), 6.35(d, J = 5.4 Hz, 1 H), 3.94 (s, 6 H), 3.77(s, 2 H) 22 476[M + H]+ (DMSO-d6, 400 MHz): δ 10.96(br, 1 H), Ex. 3 10.50(br, 1 H), 8.31(d, J = 5.4 Hz, 1 H), 7.65(d, J = 9.0 Hz, 2 H), 7.38- 7.08(m, 8 H), 6.45(d, J = 5.1 Hz, 1 H), 3.94(s, 3 H), 3.93(s, 3 H), 3.74(s, 2 H) 23 494[M + H]+ (DMSO-d6, 400 MHz): δ 11.03(br, 1 H), Ex. 3 10.61(br, 1 H), 8.47(d, J = 5.4 Hz, 1 H), 7.81(d, J = 14.1 Hz, 1 H), 7.52 (s, 1 H), 7.42-7.08(m, 6 H), 6.85(br, 1 H), 6.44(d, J = 4.9 Hz, 1 H), 3.94(s, 6 H), 3.75(s, 2 H) 24 510[M + H]+ (DMSO-d6, 400 MHz): δ 11.08(br, 1 H), Ex. 3 10.62(br, 1 H), 8.46(d, J = 5.1 Hz, 1 H), 7.85(d, J = 2.7 Hz, 1 H), 7.59- 7.57(m, 1 H), 7.52(br, 1 H), 7.42-7.09 (m, 5 H), 6.87(br, 1 H), 6.34(d, J = 5.1 Hz, 1 H), 3.93(s, 6 H), 3.75(s, 2 H) 25 498[M + Na]+ (CDCl3, 400 MHz): δ 3.79(s, 2 H), 4.05 Ex. 3 (s, 3 H), 4.06(s, 3 H), 6.47(d, J = 5.1 Hz, 1 H), 7.13-7.42(m, 6 H), 7.46(s, 1 H), 7.55(s, 1 H), 7.60(d, J = 9.0 Hz, 2 H), 7.73(s, 1 H), 8.48(d, J = 5.4 Hz, 1 H), 10.47(s, 1 H) 26 516[M + Na]+ (CDCl3, 400 MHz): δ 3.80(s, 2 H), 4.04 Ex. 3 (s, 3 H), 4.06(s, 3 H), 6.52(d, J = 5.4 Hz, 1 H), 6.96-7.02(m, 2 H), 7.13-7.42 (m, 4 H), 7.46(s, 1 H), 7.49(s, 1 H), 7.76(s, 1 H), 8.20-8.26(m, 1 H), 8.51 (d, J = 5.4 Hz, 1 H), 10.68(s, 1 H) 27 494[M + H]+ (DMSO-d6, 400 MHz): δ 10.62(br, 1 H), Ex. 3 8.48(d, J = 5.1 Hz, 1 H), 7.82(d, J = 13.9 Hz, 1 H), 7.52-7.11(m, 8 H), 6.93 (br, 1 H), 6.45(d, J = 5.1 Hz, 1 H), 3.85(s, 2 H), 3.44(s, 6 H) 28 532[M + Na]+ (CDCl3, 400 MHz): δ 3.79(s, 2 H), 4.06 Ex. 3 (s, 3 H), 4.07(s, 3 H), 6.34(d, J = 5.4 Hz, 1 H), 7.14-7.54(m, 7 H), 7.59(s, 1 H), 7.70(s, 1 H), 7.84(d, J = 2.7 Hz, 1 H), 8.48(d, J = 5.4 Hz, 1 H), 10.55 (s, 1 H) 29 464[M + H]+ (DMSO-d6, 400 MHz): δ 10.97(br, 1 H), Ex. 3 10.47(br, 1 H), 8.47(d, J = 5.4 Hz, 1 H), 7.67-7.65(m, 2 H), 7.50(s, 1 H), 7.44(d, J = 6.6 Hz, 1 H), 7.39(s, 1 H), &.25-7.23(m, 2 H), 7.01-6.99(m, 2 H), 6.46(d, J = 5.4 Hz, 1 H), 4.00(s, 2 H), 3.98(s, 6 H) 30 482[M + H]+ (DMSO-d6, 400 MHz): δ 11.17(br, 1 H), Ex. 3 10.69(br, 1 H), 8.47(d, J = 5.1 Hz, 1 H), 8.23-8.19(m, 1 H), 7.47-7.33(m, 3 H), 7.14(d, J = 8.8 Hz, 1 H), 7.02- 6.89(m, 3 H), 6.55(d, J = 5.1 Hz, 1 H), 3.98(s, 2 H), 3.92(s, 6 H) 31 482[M + H]+ (DMSO-d6, 400 MHz): δ 8.48(d, J = 5.1 Ex. 3 Hz, 1 H), 7.82(d, J = 13.4 Hz, 1 H), 7.53-7.33(m, 4 H), 7.01-6.89(m, 5 H), 6.45(d, J = 5.1 Hz, 1 H), 3.97(s, 2 H), 3.95(s, 6 H) 32 498[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H), Ex. 3 10.54(br, 1 H), 8.47(d, J = 5.1 Hz, 1 H), 8.00(s, 1 H), 7.61-7.59(m, 1 H), 7.53(s, 1 H), 7.45-7.33(m, 3 H), 7.01- 6.89(m, 2 H), 6.35(d, J = 5.1 Hz, 1 H), 3.99(s, 2 H), 3.94(s, 6 H) 33 512[M + H]+ (CDCl3, 400 MHz): δ 3.74(s, 2 H), 4.01 Ex. 3 (s, 3 H), 4.03(s, 3 H), 6.49(d, J = 5.3 Hz, 1 H), 6.86-6.99(m, 4 H), 7.21-7.32 (m, 1 H), 7.41(s, 1 H), 7.47(s, 1 H), 8.15(br, 1 H), 8.20(t, J = 9.5 Hz, 1 H), 8.49(d, J = 5.3 Hz, 1 H), 10.63 (s, 1 ) 34 512[M + H]+ (CDCl3, 400 MHz): δ 3.74(s, 2 H), 4.02 Ex. 3 (s, 3 H), 4.04(s, 3 H), 6.39(d, J = 5.3 Hz, 1 H), 6.88-7.69(m, 6 H), 7.24(s, 1 H), 7.55(s, 1 H), 8.29(br, 1 H), 8.48 (d, J = 5.3 Hz, 1 H), 10.56(s, 1 H) 35 512[M + H]+ (CDCl3, 400 MHz): δ 3.73(s, 2 H), 4.06 Ex. 3 (s, 6 H), 6.42(d, J = 5.1 Hz, 1 H), 7.03-7.08(m, 1 H), 7.14-7.26(m, 4 H), 7.49(br, 1 H), 7.58(s, 1 H), 7.67-7.72 (m, 1 H), 8.13(br, 1 H), 8.51(d, J = 5.1 Hz, 1 H), 10.56(s, 1 H) 36 494[M + H]+ (CDCl3, 400 MHz): δ 3.74(s, 2 H), 4.01 Ex. 3 (s, 3 H), 4.03(s, 3 H), 6.50(d, J = 5.3 Hz, 1 H), 6.51-7.10(m, 5 H), 7.31-7.35 (m, 1 H), 7.42(s, 1 H), 7.47(s, 1 H), 8.18(t, J = 9.5Hz, 1 H), 8.50(d, J = 5.3 Hz, 1 H), 8.89(s, 1 H), 10.74(s, 1 H) 37 494[M + H]+ (CDCl3, 400 MHz): δ 3.74(s, 2 H), 4.03 Ex. 3 (s, 3 H), 4.04(s, 3 H), 6.39(d, J = 5.3 Hz, 1 H), 7.02-7.68(m, 7 H), 7.41(s, 1 H), 7.55(s, 1 H), 8.26(s, 1 H), 8.47 (d, J = 5.3 Hz, 1 H), 10.60(s, 1 H) 38 506[M + H]+ (DMSO-d6, 400 MHz): δ 10.98(br, 1 H), Ex. 3 10.84(br, 1 H), 8.47(d, J = 5.4 Hz, 1 H), 8.25(d, J = 8.8 Hz, 1 H), 7.51(s, 1 H), 7.38-7.04(m, 6 H), 6.84-6.82(m, 1 H), 6.49(d, J = 5.1 Hz, 1 H), 3.95(s, 3 H), 3.93(s, 3 H), 3.84(s, 3 H), 3.72 (s, 2 H) 39 516[M + Na]+ (CDCl3, 400 MHz): δ 3.72(s, 2 H), 4.04 Ex. 3 (s, 3 H), 4.05(s, 3 H), 6.47(d, J = 5.4 Hz, 1 H), 7.03-7.09(m, 1 H), 7.15-7.23 (m, 4 H), 7.44(s, 1 H), 7.43(s, 1 H), 7.60(d, J = 9.0 Hz, 2 H), 8.49(d, J = 5.4 Hz, 1 H), 8.67(s, 1 H), 10.51(s, 1 H) 40 570[M + H]+ (DMSO-d6, 400 MHz): δ 11.16(br, 1 H), Ex. 3^b 10.75(br, 1 H), 8.49(d, J = 4.9 Hz, 1 H), 8.24-8.19(m, 1 H), 7.53-7.35(m, 10 H), 7.19-7.11(m, 3 H), 6.56(d, J = 5.4 Hz, 1 H), 5.31(s, 2 H), 3.94(s, 3 H), 3.75(s, 2 H) 41 621[M + H]+ (DMSO-d6, 400 MHz): δ 11.03(br, 1 H),10.60(br, 1 H), 8.46(d, J = 5.1 Hz,1 H), 7.80(d, J = 13.6 Hz, 1 H), 7.51-7.07(m, 5 H), 6.85(br, 3 H), 6.43(d, J =5.1 Hz, 1 H), 4.18-4.16(m, 2 H), 3.95(s, 3 H), 3.58-3.56(m, 3 H), 2.89(s,2 H), 2.73(s, 2 H), 2.36(s, 5 H), 1.84(m, 2 H), 1.63(m, 2 H) Ex. 12 42 619[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H),10.62(br, 1 H), 8.46(d, J = 5.4 Hz,1 H), 7.81(d, J = 13.4 Hz, 1 H), 7.53(s, 1 H), 7.41-7.33(m, 5 H), 7.19-7.14(m, 2 H), 6.44(d, J = 5.1 Hz, 1 H), 4.19(m, 2 H), 3.95(s, 2 H), 3.75(s, 2 H),3.29-3.27(m, 3 H), 2.50-2.49(m, 2 H),1.90-1.85(m, 3 H), 1.69(m, 9 H) Ex. 12 43 634[M + H]+ (DMSO-d6, 400 MHz): δ 11.03(br, 1 H),10.61(br, 1 H), 8.45(d, J = 3.9 Hz,1 H), 7.81(d, J = 13.4 Hz, 1 H), 7.50(s, 1 H), 7.41-7.34(m, 5 H), 7.18-7.14(m, 2 H), 6.42(d, J = 8.1 Hz, 1 H),4.18-4.15(m, 2 H), 3.94(s, 3 H), 3.74(s, 2 H), 3.29-3.28(m, 4 H), 2.50-2.49(m, 4 H), 2.36(br, 2 H), 2.18-2.17(m,3 H), 1.83(m, 2 H), 1.61(m, 2 H) Ex. 12 44 621[M + H]+ (DMSO-d6, 400 MHz): δ 11.16(br, 1 H),10.75(br, 1 H), 8.47(d, J = 5.1 Hz,1 H), 8.22(m, 1 H), 7.95(m, 1 H), 7.46-7.08(m, 3 H), 6.86(br, 4 H), 6.55(d, J =5.4 Hz, 1 H), 4.19-4.17(m, 2 H), 3.92(s, 4 H), 3.75(s, 2 H), 3.57(br, 4 H),2.49(br, 5 H), 1.84(m, 2 H), 1.62(m,2 H) Ex. 12 45 619[M + H]+ (DMSO-d6, 400 MHz): δ 11.16(br, 1 H),10.76(br, 1 H), 8.49(d, J = 5.1 Hz,1 H), 8.25-8.20(m, 1 H), 7.48(s, 1 H),7.42-7.34(m, 4 H), 7.19-7.10(m, 3 H),6.56(d, J = 5.4 Hz, 1 H), 4.19(br,2 H), 3.93(s, 3 H), 3.75(s, 2 H), 3.34-3.28(m, 6 H), 2.50-2.49(m, 5 H), 1.91-1.85(m, 5 H) Ex. 12 46 607[M + H]+ (DMSO-d6, 400 MHz): δ 11.21(br, 1 H),10.54(br, 1 H), 8.31(d, J = 5.2 Hz,1 H), 7.81(d, J = 13.5 Hz, 1 H), 7.48-7.06(m, 5 H), 6.51(br, 3 H), 6.31(d, J =5.1 Hz, 1 H), 4.18-4.13(m, 2 H), 3.94(s, 3 H), 3.57-3.50(m, 3 H), 2.89(s,2 H), 2.73(s, 2 H), 2.36(br, 3 H), 1.81(m, 2 H), 1.61(m, 2 H) Ex. 11 47 605[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H),10.62(br, 1 H), 8.48(d, J = 5.4 Hz,1 H), 7.81(d, J = 13.2 Hz, 1 H), 7.55(s, 1 H), 7.45-7.35(m, 5 H), 7.19-7.15(m, 2 H), 6.46(d, J = 5.4 Hz, 1 H), 4.18(br, 2 H), 3.96(s, 3 H), 3.75(s, 2 H),3.51(br, 1 H), 3.29(m, 5 H), 2.50-2.49(m, 4 H), 2.26(m, 2 H), 1.83(m, 1 H),1.70(m, 1 H) Ex. 11 48 591[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H),01.62(br, 1 H), 8.48(d, J = 5.1 Hz,1 H), 7.81(d, J = 14.2 Hz, 1 H), 7.55(s, 1 H), 7.48-7.34(m, 5 H), 7.18-7.14(m, 2 H), 6.45(d, J = 4.9 Hz, 1 H), 3.96(s, 3 H), 3.75(s, 2 H), 2.50-2.49(m,7 H), 1.91-1.23(m, 7 H) Ex. 13 49 606[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H),10.61(br, 1 H), 8.46(d, J = 5.4 Hz,1 H), 7.80(d, J = 13.6 Hz, 1 H), 7.52(s, 1 H), 7.43-7.35(m, 5 H), 7.18-7.14(m, 2 H), 6.43(d, J = 5.1 Hz, 1 H), 4.27(br, 2 H), 3.94(s, 3 H), 3.74(s, 2 H),2.89-2.38(m, 8 H), 1.27-1.39(m, 5 H) Ex. 13 50 605[M + H]+ (DMSO-d6, 400 MHz): δ 11.16(br, 1 H),10.77(br, 1 H), 8.51(d, J = 5.3 Hz,1 H), 8.23(m, 1 H), 7.50-7.17(m, 8 H),6.95(d, J = 5.3 Hz, 1 H), 4.26(br,2 H), 3.93(s, 4 H), 3.75(br, 2 H), 3.50(m, 1 H), 3.29(m 3 H), 2.94(m, 1 H),2.67(s, 1 H), 2.49(m, 3 H), 2.32-2.25(m, 2 H), 1.83(m, 1 H), 1.69(m, 1 H) Ex. 11 51 620[M + H]+ (DMSO-d6, 400 MHz): δ 11.10(br, 1 H),10.76(br, 1 H), 8.50(d, J = 5.1 Hz,1 H), 8.23(m, 1 H), 7.50-7.14(m, 8 H),6.93(d, J = 5.1 Hz, 1 H), 4.22(br,2 H), 3.94(s, 3 H), 3.75(s, 2 H), 3.29(m, 6 H), 2.67(s, 1 H), 2.52-2.49(m,7 H), 2.32(s, 1 H) Ex. 11 52 587[M + H]+ (DMSO-d6, 400 MHz): δ 11.05(br, 1 H),10.63(br, 1 H), 8.46(d, J = 5.1 Hz,1 H), 7.81(d, J = 13.9 Hz, 1 H), 7.53(s, 3 H), 7.43-7.27(m, 8 H), 6.44(d, J =5.1 Hz, 1 H), 4.23(m, 1 H), 3.95(s,1 H), 3.74(s, 2 H), 3.28-3.26(m, 4 H),2.89(s, 1 H), 2.73(s, 1 H), 2.50-2.48(m, 5 H), 1.67-1.23(m, 4 H) Ex. 11 53 602[M + H]+ (DMSO-d6, 400 MHz): δ 11.04(br, 1 H),10.63(br, 1 H), 8.45(d, J = 5.4 Hz,1 H), 7.95(d, J = 11.2 Hz, 1 H), 7.80(d, J = 13.9 Hz, 1 H), 7.50(s, 1 H),7.39-7.28(m, 5 H), 6.41(d, J = 5.1 Hz,1 H), 4.19-4.16(m, 2 H), 3.94(s, 3 H),3.74(s, 2 H), 3.36-3.27(m, 7 H), 2.89(s, 1 H), 2.73(s, 1 H), 2.32-2.19(m,6 H), 1.98-1.95(m, 2 H) Ex. 11 54 575[M + H]+ (DMSO-d6, 400 MHz): δ 11.12(br, 1 H),10.51(br, 1 H), 8.45(d, J = 5.3 Hz,1 H), 7.80(d, J = 13.9 Hz, 1 H), 7.52(s, 1 H), 7.43-7.28(m, 8 H), 6.41(d, J =5.3 Hz, 1 H), 4.29(br, 2 H), 3.94(s,3 H), 3.89(s, 2 H), 3.61-3.56(m, 4 H),2.52-2.49(m, 6 H) Ex. 13 55 593[M + H]+ (DMSO-d6, 400 MHz): δ 11.10(br, 1 H),10.75(br, 1 H), 8.49(d, J = 5.3 Hz,1 H), 8.21(m, 1 H), 7.53-7.09(m, 8 H),6.44(d, J = 5.3 Hz, 1 H), 4.28(br,2 H), 3.94(s, 3 H), 3.88(s, 2 H), 3.60-3.51(m, 4 H), 3.25-3.24(m, 2 H), 2.51-2.48(m, 4 H) Ex. 13 56 510[M + H]+ (DMSO-d6, 400 MHz): δ 12.69(br, 1 H), Ex. 2 12.04(br, 1 H), 8.72(d, J = 5.9 Hz, 1 H), 8.25(d, J = 8.5 Hz, 1 H), 8.17(d, J = 8.3 Hz, 1 H), 8.05(d, J = 8.8 Hz, 1 H), 7.97(d,J = 8.8 Hz, 1 H), 7.84(d, J = 7.1 Hz, 1 H), 7.68-7.61(m, 4 H), 7.48-7.43(m, 4 H), 6.79(d, J = 5.9 Hz, 1 H), 4.00(s, 6 H) 57 528[M + H]+ (DMSO-d6, 400 MHz): δ 12.54(br, 1 H), Ex. 2 12.21(br, 1 H), 8.57(d, J = 5.4 Hz, 1 H), 8.23-8.14(m, 3 H), 8.05(d, J = 7.6 Hz, 1 H), 7.86(d, J = 6.1 Hz, 1 H), 7.69-7.52(m, 3 H), 7.48-7.41(m, 3 H), 7.19(m, 1 H), 6.69(d, J = 5.1 Hz, 1 H), 3.98(s, 3 H), 3.93(s, 3 H) 58 492[M + H]+ (DMSO-d6, 400 MHz): δ 12.26(br, 1 H), Ex. 1 11.89(br, 1 H), 8.55(d, J = 5.1 Hz, 1 H), 8.05(t, J = 8.7 Hz, 1 H), 7.46(s, 1 H), 7.41(s, 1 H), 7.29-7.35(m, 6 H), 7.13(d, J = 9.5 Hz, 1 H), 6.64(d, J = 5.1 Hz, 1 H), 3.95(s, 3 H), 3.92(s, 3 H), 3.83(s, 2 H) 59 508[M + H]+ (DMSO-d6, 400 MHz): δ 3.92(s, 3 H), Ex. 2 3.95(s, 3 H), 4.04(s, 2 H), 6.54(d, J = 5.1 Hz, 1 H), 7.27-7.50(m, 7 H), 7.74- 7.79(m, 2 H), 8.31(s, 1 H), 8.51(d, J = 5.1 Hz, 1 H), 11.80-11.83(br, 1 H) 60 474[M + H]+ (DMSO-d6, 400 MHz): δ 12.47(br, 1 H), Ex. 1 11.81(br, 1 H), 8.14-8.16(m, 1 H), 7.69 (m, 1 H), 7.51(s, 1 H), 7.48(d, J = 8.8 Hz, 1 H), 7.44(s, 1 H), 7.25-7.35(m, 7 H), 6.51(d, J = 6.1 Hz, 1 H), 3.98(s, 3 H), 3.96(s, 3 H), 3.82(s, 2 H) 61 480[M + H]+ (DMSO-d6, 400 MHz): δ 12.41(br, 1 H), Ex. 2 11.48(br, 1 H), 8.63(m, 1 H), 7.81-7.84 (m, 2 H), 7.59(s, 1 H), 7.44(s, 1 H) 7.34-7.36(m, 2 H), 6.67(m, 1 H), 3.95 (s, 6 H), 2.37(d, J = 6.8 Hz, 2 H), 1.69 (m, 3 H), 1.19-1.25(m, 6 H), 0.86-1.00 (m, 2 H) 62 456[M + H]+ (DMSO-d6, 400 MHz): δ 12.48(br, 1 H), Ex. 2 10.09(br, 1 H), 8.54(d, J = 6.3 Hz, 1 H), 8.09(s, 1 H), 7.90(d, J = 8.8 Hz, 1 H), 7.62(s, 1 H), 7.26-7.25(m, 3 H), 6.74(d, J = 6.1 Hz, 1 H), 4.22(s, 3 H), 4.16(s, 3 H), 3.79-3.77(m, 2 H), 3.66- 3.62(m, 2 H), 2.65-2.64(m, 2 H), 1.23- 1.18(m, 3 H) 63 508[M + H]+ (CDCl3, 400 MHz): δ 3.76(s, 2 H), 4.05 Ex. 1 (s, 3 H), 4.06(s, 3 H), 6.39(d, J = 5.1 Hz, 1 H), 7.23-7.47(m, 6 H), 7.51(s, 1 H), 7.57(s, 1 H), 7.61-7.64(m, 1 H), 8.00(d, J = 2.4 Hz, 1 H), 8.53(d, J = 5.4 Hz, 1 H) 64 520[M + H]+ (DMSO-d6, 400 MHz): δ 12.62(br, 1 H), Ex. 2 11.64(br, 1 H), 8.51(d, J = 5.4 Hz, 1 H), 8.64(d, J = 11.5 Hz, 1 H), 7.57- 7.42(m, 4 H), 7.16-7.13(m, 4 H), 6.51 (d,J = 5.4 Hz, 1 H), 3.96(s, 8 H), 2.91-2.88(m, 1 H), 2.79-7.75(m, 1 H), 2.31(s, 3 H) 65 508[M + H]+ (DMSO-d6, 400 MHz): δ 12.37(br, 1 H), Ex. 1 11.89(br, 1 H), 8.54(d, J = 5.1 Hz, 1 H), 8.07(d, J = 8.9 Hz, 1 H), 7.56(d, J = 2.7 Hz, 1 H), 7.46(s, 1 H), 7.41(s, 1 H), 7.37-7.23(m, 6 H), 6.63(d, J = 5.1 Hz, 1 H), 3.94(s, 3 H), 3.91(s, 3 H), 3.84(s, 2 H) 66 480[M + H]+ (DMSO-d6, 400 MHz): δ 12.4 (br, 1 H), Ex. 2 11.69(br, 1 H), 8.53(d, J = 5.1 Hz, 1 H), 8.49-7.00(m, 9 H), 6.56(d, J = 5.1 Hz, 1 H), 3.95(s, 3 H), 3.94(s, 3 H), 3.84(s, 2 H) 67 488[M + H]+ (DMSO-d6, 400 MHz): δ 12.42(br, 1 H), Ex. 1 11.73(br, 1 H), 8.47(d, J = 5.4 Hz, 1 H), 8.30(s, 1 H), 7.66-7.63(m, 2 H), 7.55(s, 1 H), 7.39(s, 1 H), 7.35-7.19 (m, 8 H), 6.34(d, J = 5.4 Hz, 1 H), 3.94 (s, 6 H), 3.82(s, 2 H) 68 504[M + H]+ (DMSO-d6, 400 MHz): δ 11.76(br, 1 H), Ex. 1 10.95(br, 1 H), 8.44(d, J = 5.4 Hz, 1 H), 8.30(s, 1 H), 7.63(s, 2 H), 7.51 (s, 1 H), 7.38-7.22(m, 6 H), 6.31(d, J = 5.4 Hz, 1 H), 3.94(s, 3 H), 3.82(s, 6 H), 3.69(s, 2 H) 69 504[M + H]+ (DMSO-d6, 400 MHz): δ 12.71(br, 1 H), Ex. 1 11.71(br, 1 H), 8.63(d, J = 8.8 Hz, 1 H), 8.49(d, J = 5.1 Hz, 1 H), 7.50(s, 1 H), 7.40(s, 1 H), 7.38-7.11(m, 5 H), 7.03(s, 1 H), 6.87(d, J = 11.5 Hz, 1 H), 6.57(d, J = 5.1 Hz, 1 H), 3.95(s, 9 H), 3.83(s, 2 H) 70 543[M + H]+ (DMSO-d6, 400 MHz): δ 12.43(br, 1 H), Ex. 1 11.89(br, 1 H), 8.48(d, J = 5.1 Hz, 1 H), 8.07(s, 2 H), 7.55(s, 1 H), 7.42 (s, 1 H), 7.35-7.28(m, 5 H), 6.33(d, J = 5.3 Hz, 1 H), 3.95(s, 6 H), 3.83(s, 2 H) 71 492[M + H]+ (DMSO-d6, 400 MHz): δ 12.39(br, 1 H), Ex. 2 11.73(br, 1 H), 8.53(d, J = 5.4 Hz, 1 H), 7.75(d, J = 9.0 Hz, 2 H), 7.51(s, 1 H), 7.41-7.16(m, 7 H), 6.56(d, J = 5.4 Hz, 1 H), 3.95(s, 3 H), 3.93(s, 3 H), 3.83(s, 2 H) 72 510[M + H]+ (DMSO-d6, 400 MHz): δ 12.22(br, 1 H), Ex. 2 11.89(br, 1 H), 8.58(d, J = 5.4 Hz, 1 H), 8.04(t, J = 8.8 Hz, 1 H), 7.85(s, 1 H), 7.43-7.11(m, 7 H), 6.68(d, J = 5.4 Hz, 1 H), 3.96(s, 3 H), 3.93(s, 3 H), 3.57(s, 2 H) 73 527[M + H]+ (DMSO-d6, 400 MHz): δ 12.43(br, 1 H), Ex. 2 11.83(br, 1 H), 8.61(d, J = 5.6 Hz, 1 H), 8.15(s, 1 H), 7.73-7.70(m, 1 H), 7.60(s, 1 H), 7.53-7.10(m, 6 H), 6.55 (d, J = 5.1 Hz, 1 H), 3.97(s, 6 H), 3.84 (s, 2 H) 74 510[M + H]+ (DMSO-d6, 400 MHz): δ 3.88(s, 2 H), 3.91 Ex. 2 (s, 3 H), 3.95(s, 3 H), 6.64(d, J = 5.1 Hz, 1 H), 7.12-7.22(m, 4 H), 7.35-7.47 (m, 4 H), 7.99-8.04(m, 1 H), 8.55(d, J = 5.3 Hz, 1 H), 11.90(s, 1 H), 12.18(s, 1 H) 75 510[M + H]+ (DMSO-d6, 400 MHz): δ 3.87(s, 2 H), Ex. 2 3.94(s, 3 H), 3.95(s, 3 H), 6.49(d, J = 4.9 Hz, 1 H), 7.08-7.23(m, 3 H), 7.34- 7.56(m, 5 H), 8.00-8.05(m, 1 H), 8.50 (d, J = 5.1 Hz, 1 H), 11.82(s, 1 H), 12.44(s, 1 H) 76 526[M + H]+ (DMSO-d6, 400 MHz): δ 3.87(s, 2 H), Ex. 2 3.93(s, 3 H), 3.95(s, 3 H), 6.40(d, J = 5.4 Hz, 1 H), 7.09-7.24(m, 3 H), 7.35- 7.54(m, 4 H), 7.65-7.71(m, 1 H), 8.09- 8.13(m, 1 Hz, 1 H), 8.50(d, J = 5.4 Hz, 1 H), 11.82(s, 1 H), 12.38(s, 1 H) 77 488[M + H]+ (DMSO-d6, 400 MHz): δ 2.31(s, 3 H), Ex. 2 3.78(s, 2 H), 3.93(s, 3 H), 3.95(s, 3 H), 6.39(d, J = 5.1 Hz, 1 H), 7.05- 7.27(m, 5 H), 7.41(s, 1 H), 7.45(d, J = 8.8 Hz, 1 H), 7.51(s, 1 H), 7.67(dd, J = 2.4, 8.5 Hz, 1 H), 8.11(d, J = 2.4 Hz, 1 H), 8.49(d, J = 5.1 Hz, 1 H), 11.79(s, 1 H), 12.44(s, 1 H) 78 522[M + H]+ (DMSO-d6, 400 MHz): δ 2.30(s, 3 H), Ex. 2 3.77(s, 2 H), 3.92(s, 3 H), 3.94(s, 3 H), 6.53(d, J = 5.1 Hz, 1 H), 7.08- 7.31(m, 5 H), 7.40(s, 1 H), 7.48(s, 1 H), 7.74(d, J = 8.7 Hz, 2 H), 8.49(d, J = 5.1 Hz, 1 H), 11.71(s, 1 H), 12.42 (s, 1 H) 79 488[M + H]+ (DMSO-d6, 400 MHz): δ 2.29(s, 3 H), Ex. 2 3.89(s, 2 H), 4.02(s, 3 H), 4.04(s, 3 H), 6.87(d, J = 6.6 Hz, 1 H), 7.12- 7.30(m, 4 H), 7.44(d, J = 9.0 Hz, 2 H), 7.51(s, 1 H), 7.74(s, 1 H), 7.88(d, J = 9.0 Hz, 2 H), 8.12(d, J = 6.4 Hz, 1 H), 11.77(s, 1 H), 12.49(s, 1 H) 80 510[M + H]+ (DMSO-d6, 400 MHz): δ 12.45(br, 1 H), Ex. 2 11.87(br, 1 H), 8.56(d, J = 5.6 Hz, 1 H), 8.05-8.02(m, 1 H), 7.56-7.18(m, 8 H), 6.57(d, J = 5.4 Hz, 1 H), 3.96(s, 8 H) 81 510[M + H]+ (DMSO-d6, 400 MHz): δ 12.19(br, 1 H), Ex. 2 11.95(br, 1 H), 8.62(d, J = 5.6 Hz, 1 H), 8.07-8.05(m, 1 H), 7.51(s, 1 H), 7.43-7.18(m, 7 H), 6.72(d, J = 5.6 Hz, 1 H), 3.97(s, 8 H) 82 522[M + H]+ (DMSO-d6, 400 MHz): δ 2.29(s, 3 H), Ex. 2 3.77(s, 2 H), 3.93(s, 3 H), 3.95(s, 3 H), 6.39(d, J = 5.1 Hz, 1 H), 7.16(d, J = 8.1 Hz, 2 H), 7.23(d, J = 8.1 Hz, 2 H), 7.41(s, 1 H), 7.46(d, J = 8.8 Hz, 1 H), 7.51(s, 1 H), 7.66(dd, J = 2.7, 9.0 Hz, 1 H), 8.11(d, J = 2.4 Hz, 1 H), 8.49(d, J = 5.1 Hz, 1 H), 11.78(s, 1 H), 12.44(s, 1 H) 83 522[M + H]+ (DMSO-d6, 400 MHz): δ 3.79(s, 3 H), Ex. 2 3.81(s, 2 H), 3.94(s, 3 H), 3.95(s, 3 H), 6.49(d, J = 5.1 Hz, 1 H), 6.88- 7.03(m, 2 H), 7.20-7.32(m, 2 H), 7.41 (s, 1 H), 7.44-7.58(m, 3 H), 8.05(d, J = 12.4 Hz, 1 H), 8.51(d, J = 2.1 Hz, 1 H), 11.71(s, 1 H), 12.55(s, 1 H) 84 506[M + H]+ (CDCl3, 400 MHz): δ 2.36(s, 3 H), 3.77 Ex. 2 (s, 2 H), 4.05(s, 6 H), 6.46(d, J = 5.1 Hz, 1 H), 7.22-7.34(m, 5 H), 7.41(d, J = 8.8 Hz, 1 H), 7.46(s, 1 H), 7.55(s, 1 H), 7.95(dd, J = 2.4, 11.7 Hz, 1 H), 8.37(s, 1 H), 8.51(d, J = 5.4 Hz, 1 H), 12.50(s, 1 H) 85 498[M + H]+ (DMSO-d6, 400 MHz): δ 12.50(br, 1 H), Ex. 2 11.78(br, 1 H), 8.56(d, J = 5.1 Hz, 1 H), 7.56-7.28(m, 3 H), 7.11-7.00(m, 5 H), 6.57(m, 1 H), 3.95(s, 6 H), 3.84 (s, 2 H) 86 510[M + H]+ (DMSO-d6, 400 MHz): δ 12.71(br, 1 H), Ex. 2 11.67(br, 1 H), 8.64(d, J = 5.1 Hz, 1 H), 8.52-8.48(m, 1 H), 7.52-7.40(m, 4 H), 7.12-7.04(m, 3 H), 6.59(d, J = 5.1 Hz, 1 H), 3.95(s, 6 H), 3.85(s, 5 H) 87 527[M + H]+ (DMSO-d6, 400 mHz): δ 12.45(br, 1 H), Ex. 2 11.91(br, 1 H), 8.53(d, J = 5.1 Hz, 1 H), 8.05-8.03(m, 1 H), 7.54-7.33(m, 8 H), 6.56-6.54(m, 1 H), 4.04(s, 2 H), 3.95(s, 6 H) 88 492[M + H]+ (DMSO-d6, 400 MHz): δ 12.57(br, 1 H), Ex. 2 11.45(br, 1 H), 8.52(d, J = 5.1 Hz, 1 H), 7.79-7.76(m, 2 H), 7.57(s, 1 H), 7.45(s, 1 H), 7.31-7.28(m, 2 H), 6.54 (d, J = 5.1 Hz, 1 H), 3.97(s, 3 H), 3.95 (s, 3 H), 3.31(s, 2 H), 2.49-2.30(m, 2 H), 1.52-1.08(m, 9 H) 89 510[M + H]+ (DMSO-d6, 400 MHz): δ 12.41(br, 1 H), Ex. 2 11.93(br, 1 H), 8.56(d, J = 5.1 Hz, 1 H), 8.15-8.07(m, 1 H), 7.47(s, 1 H), 7.42(s, 1 H), 7.34(d, J = 13.6 Hz, 1 H), 7.15(d, J = 8.8 Hz, 1 H), 6.65(d, J = 5.1 Hz, 1 H), 3.96(s, 3 H), 3.92(s, 3 H), 3.31(s, 2 H), 2.45-2.31(m, 2 H), 1.51-1.07(m, 9 H) 90 510[M + H]+ (DMSO-d6, 400 MHz): δ 12.66(br, 1 H), Ex. 2 11.54(br, 1 H), 8.54(d, J = 5.1 Hz, 1 H), 8.08(m, 1 H), 7.55-7.43(m, 4 H), 6.54(d, J = 5.6 Hz, 1 H), 3.96(s, 6 H), 3.31(s, 2 H), 2.43-2.30(m, 2 H), 1.48- 1.06(m, 9 H) 91 527[M + H]+ (DMSO-d6, 400 MHz): δ 12.59(br, 1 H), Ex. 2 11.54(br, 1 H), 8.51(d, J = 5.1 Hz, 1 H), 8.17-8.15(m, 1 H), 7.70-7.68(m, 1 H), 7.53(s, 1 H), 7.47(d, J = 8.8 Hz, 1 H), 7.43(s, 1 H), 6.42(d, J = 5.1 Hz, 1 H), 3.94(s, 6 H), 3.31(s, 2 H), 2.42- 2.31(m, 2 H), 1.47-1.05(m, 9 H) 92 506[M + H]+ (DMSO-d6, 400 MHz): δ 12.32(br, 1 H), Ex. 2 11.89(br, 1 H), 8.73(d, J = 5.9 Hz, 1 H), 7.62(s, 1 H), 7.51-7.48(m, 2 H), 7.24-7.12(m, 6 H), 6.84(d, J = 6.1 Hz, 1 H), 4.01(s, 6 H), 3.78(s, 2 H), 2.28 (s, 3 H) 93 ND^c (DMSO-d6, 400 MHz): δ 3.92(s, 5 H), Ex. 2 3.95(s, 3 H), 6.65(d, J = 5.4 Hz, 1 H), 7.06-7.50(m, 7 H), 7.99-8.05(m, 1 H), 8.55(d, J = 5.1 Hz, 1 H), 11.94(s, 1 H), 12.12(s, 1 H) 94 528[M + H]+ (DMSO-d6, 400 MHz): δ 3.92(s, 2 H), Ex. 2 3.95(s, 3 H), 3.96(s, 3 H), 6.51(d, J = 5.1 Hz, 1 H), 7.04-7.12(m, 2 H), 7.20- 7.29(m, 2 H), 7.41-7.57(m, 3 H), 7.99- 8.05(m, 1 H), 8.52(d, J = 5.1 Hz, 1 H), 11.87(s, 1 H), 12.39(s, 1 H) 95 528[M + H]+ (DMSO-d6, 400 MHz): δ 12.32(br, 1 H), Ex. 2 11.94(br, 1 H), 8.51(d, J = 5.1 Hz, 1 H), 8.02-7.99(m, 1 H), 7.54-7.41(m, 4 H), 7.15-7.11(m, 3 H), 6.49(d, J = 5.4 Hz, 1 H), 3.97(s, 2 H), 3.94(s, 6 H) 96 528[M + H]+ (DMSO-d6, 400 MHz): δ 12.38(br, 1 H), Ex. 2 11.88(br, 1 H), 8.51(d, J = 4.9 Hz, 1 H), 8.02-7.99(m, 1 H), 7.53-7.19(m, 7 H), 6.50(d, J = 5.1 Hz, 1 H), 3.94(s, 8 H) 97 561[M + H]+ (DMSO-d6, 400 MHz): δ 12.33(br, 1 H), Ex. 2 11.85(br, 1 H), 8.52(d, J = 4.9 Hz, 1 H), 8.06-7.93(m, 4 H), 7.63-7.43(m, 4 H), 6.48(d, J = 5.1 Hz, 1 H), 3.94(s, 8 H) 98 ND^c (CDCl3, 400 MHz): δ 3.64(s, 2 H), 4.04(s, 3 H), 4.05(s, 3 H), 6.53(d, J = 5.1Hz, 1 H), 6.87-6.94(m, 2 H), 6.98-7.04(m, 2 H), 7.43(s, 1 H), 7.49(s, 1 H),8.16-8.24(m, 1 H), 8.31-8.37(m, 1 H),8.52(d, J = 5.4 Hz, 1 H), 8.81(br,1 H), 9.04(br, 1 H) Ex. 6 99 ND^c (CDCl3, 400 MHz): δ 3.62(s, 2 H), 4.05(s, 3 H), 4.06(s, 3 H), 6.40(d, J =5.1 Hz, 1 H), 6.87-6.96(m, 2 H), 7.20-7.34(m, 2 H), 7.43(s, 1 H), 7.58(s,1 H), 7.76-7.82(m, 1 H), 8.10-8.18(m,1 H), 8.49(d, J = 5.4 Hz, 1 H), 8.72(br, 1 H), 9.38(br, 1 H) Ex. 6 100 458[M + H]+ (DMSO-d6, 400 MHz): δ 3.49(s, 2 H),3.92(s, 3 H), 3.93(s, 3 H), 6.44(d, J =5.4 Hz, 1 H), 7.04-7.08(m, 1 H), 7.24(d, J = 9.0 Hz, 2 H), 7.28-7.34(m, 2 H),7.38(s, 1 H), 7.50(s, 1 H), 7.61(d, J =7.6 Hz, 2 H), 7.74(d, J = 9.0 Hz,2 H), 8.45(d, J = 5.4 Hz, 1 H), 10.19(s, 1 H), 10.34(s, 1 H) Ex. 5 101 478[M + H]+ (CDCl3, 400 MHz): δ 1.24-2.04(m, 12 H),3.30(s, 2 H), 3.90-4.01(m, 1 H), 4.05(s, 6 H), 6.45(d, J = 5.4 Hz, 1 H),7.14-71.7(m, 2 H), 7.42(s, 1 H), 7.55(s, 1 H), 7.65-7.68(m, 2 H), 8.48(d, J =5.1 Hz, 1 H) Ex. 5 102 ND^c (CDCl3, 400 MHz): δ 3.60(s, 2 H), 4.05(s, 3 H), 4.06(s, 3 H), 6.47(d, J = 5.4Hz, 1 H), 6.88-6.94(m, 2 H), 7.18(d, J =9.0 Hz, 2 H), 7.45(s, 1 H), 7.55(s,1 H), 7.68(d, J = 9.0 Hz, 2 H), 8.14-8.20(m, 1 H), 8.49(d, J = 5.4 Hz, 1 H),8.78(br, 1 H), 8.91(br, 1 H) Ex. 5 103 524[M + H]+ (CDCl3, 400 MHz): δ 3.81(s, 3 H), 4.05(s, 3 H), 4.07(s, 3 H), 4.50(s, 1 H),6.48(d, J = 5.6 Hz, 1 H), 6.87-6.94(m,2 H), 7.19(d, J = 9.0 Hz, 2 H), 7.52(s,1 H), 7.55(s, 1 H), 7.70(d, J = 9.0 Hz,2 H), 8.21-8.29(m, 1 H), 8.48(d, J =5.6 Hz, 1 H), 8.79(br, 1 H), 8.93(br,1 H) Ex. 15 104 522[M + H]+ (CDCl3, 400 MHz): δ 1.73(s, 6 H), 4.05(s, 3 H), 4.05(s, 3 H), 6.44(d, J = 5.1Hz, 1 H), 6.87-6.94(m, 2 H), 7.18(d, J =9.0 Hz, 2 H), 7.43(s, 1 H), 7.55(s,1 H), 7.65(d, J = 9.0 Hz, 2 H), 8.14-8.21(m, 1 H), 8.48(d, J = 5.1 Hz, 1 H),8.56(br, 1 H), 8.70(br, 1 H) Ex. 15 105 472[M − H]− (CDCl3, 400 MHz): δ 2.37(s, 3 H), 4.06(s, 6 H), 6.49(d, J = 5.1 Hz, 1 H), 6.88(d, J = 5.1 Hz, 1 H), 7.2(m, 2 H), 7.43(s, 1 H), 7.58(s, 1 H), 7.7(m, 2 H), 8.2(m, 2 H), 8.49(d, J = 5.2 Hz, 1 H) Ex. 10 106 462[M + H]+ (CDCl3, 400 MHz): δ 8.43(d, 1 H, J = Ex. 10^b 5.1 Hz), 7.82-7.79(m, 1 H), 7.49-7.08 (m, 12 H), 6.36(d, 1 H, J = 5.1 Hz), 3.95(s, 3 H), 3.75(s, 2 H) Ex. No. Compound structure Starting compound A 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 Ex. Mass spectrometric No. Starting compound B Starting compound C value (m/z) Synthesis method^a 107 496[M + H]+ Ex. 3 108 476[M + H]+ Ex. 3 109 458[M + H]+ Ex. 3 110 487[M + H]+ Ex. 8 111 485[M + H]+ Ex. 8 112 487[M + H]+ Ex. 8 113 496[M + H]+ Ex. 7 114 514[M + H]+ Ex. 7 115 514[M + H]+ Ex. 7 116 516[M + H]+ Ex. 7 117 488[M + H]+ Ex. 8 118 463[M + H]+ Ex. 3 119 545[M + H]+ Ex. 8 120 573[M + H]+ Ex. 8 121 517[M + H]+ Ex. 8 122 517[M + H]+ Ex. 8 123 483[M + H]+ Ex. 8 124 490[M + H]+ Ex. 3 125 476[M + H]+ Ex. 3 126 494[M + H]+ Ex. 3 127 494[M + H]+ Ex. 3 128 511[M + H]+ Ex. 3 129 490[M + H]+ Ex. 7 130 528[M + H]+ Ex. 7 131 517[M + H]+ Ex. 8 132 512[M + H]+ Ex. 3 133 512[M + H]+ Ex. 3 134 512[M + H]+ Ex. 3 135 512[M + H]+ Ex. 3 136 544[M + H]+ Ex. 3 137 544[M + H]+ Ex. 3 138 512[M + H]+ Ex. 3 139 512[M + H]+ Ex. 3 140 512[M + H]+ Ex. 3 141 512[M + H]+ Ex. 3 142 512[M + H]+ Ex. 3 143 470[M + H]+ Ex. 2 144 508[M + H]+ Ex. 2 145 528[M + H]+ Ex. 2 146 557[M + H]+ Ex. 2 147 476[M + H]+ Ex. 1 148 478[M + H]+ Ex. 1 149 522[M + H]+ Ex. 2 150 500[M + 1]+ Ex. 2 151 492[M + H]+ Ex. 2 152 526[M + H]+ Ex. 2 153 504[M + 1]+ Ex. 2 154 539[M + 1]+ Ex. 2 155 519[M + 1]+ Ex. 2 156 553[M + 1]+ Ex. 2 157 524[M + 1]+ Ex. 2 158 488[M + 1]+ Ex. 2 159 490[M + 1]+ Ex. 2 160 480[M + 1]+ Ex. 2 161 480[M + 1]+ Ex. 1 162 488[M + H]+ Ex. 1 163 502[M + H]+ Ex. 1 164 492[M + H]+ Ex. 2 165 474[M + H]+ Ex. 2 166 498[M + H]+ Ex. 2 167 488[M + H]+ Ex. 2 168 488[M + H]+ Ex. 2 169 522[M + H]+ Ex. 2 170 506[M + H]+ Ex. 2 171 508[M + H]+ Ex. 2 172 526[M + H]+ Ex. 2 173 526[M + H]+ Ex. 2 174 542[M + H]+ Ex. 2 175 506[M + H]+ Ex. 2 176 506[M + H]+ Ex. 2 177 468[M + H]+ Ex. 2 178 486[M + H]+ Ex. 2 179 486[M + H]+ Ex. 2 180 476[M + H]+ Ex. 2 181 522[M + H]+ Ex. 2 182 526[M + H]+ Ex. 2 183 543[M + H]+ Ex. 2 184 504[M + H]+ Ex. 2 185 522[M + H]+ Ex. 2 186 539[M + H]+ Ex. 2 187 508[M + H]+ Ex. 2 188 526[M + H]+ Ex. 2 189 543[M + H]+ Ex. 2 190 506[M + H]+ Ex. 2 191 512[M + H]+ Ex. 2 192 512[M + H]+ Ex. 2 193 505[M + H]+ Ex. 2 194 528[M + H]+ Ex. 2 195 528[M + H]+ Ex. 2 196 528[M + H]+ Ex. 2 197 528[M + H]+ Ex. 2 198 528[M + H]+ Ex. 2 199 528[M + H]+ Ex. 2 200 560[M + H]+ Ex. 2 201 560[M + H]+ Ex. 2 202 560[M + H]+ Ex. 2 203 560[M + H]+ Ex. 2 204 528[M + H]+ Ex. 2 205 546[M + H]+ Ex. 2 206 546[M + H]+ Ex. 2 207 562[M + H]+ Ex. 2 208 561[M + H]+ Ex. 2 209 438[M + H]+ Ex. 5 210 492[M + H]+ Ex. 5 211 488[M + H]+ Ex. 5 212 436[M + H]+ Ex. 5 213 516[M + H]+ Ex. 5 214 486[M + H]+ Ex. 5 215 472[M + H]+ Ex. 5 216 472[M + H]+ Ex. 5 217 464[M + H]+ Ex. 5 218 478[M + H]+ Ex. 5 219 492[M + H]+ Ex. 5 220 474[M + H]+ Ex. 5 221 466[M + H]+ Ex. 5 222 528[M + H]+ Ex. 6 223 508[M + H]+ Ex. 6 224 522[M + H]+ Ex. 6 225 472[M + H]+ Ex. 15 226 478[M + H]+ Ex. 15 227 459[M + H]+ Ex. 5 228 486[M + H]+ Ex. 15 229 493[M − H]− Ex. 9 230 550[M − H]− Ex. 9 231 492[M − H]− Ex. 9 232 462[M − H]− Ex. 9 233 472[M − H]− Ex. 9 234 472[M − H]− Ex. 9 235 472[M − H]− Ex. 9 236 458[M − H]− Ex. 9 237 461[M − H]− Ex. 9 238 515[M − H]− Ex. 9 239 482[M − H]− Ex. 9 240 525[M − H]− Ex. 9 241 496[M − H]− Ex. 9 242 505[M − H]− Ex. 9 243 497[M − H]− Ex. 9 244 487[M − H]− Ex. 9 245 515[M − H]− Ex. 9 246 547[M − H]− Ex. 9 247 535[M − H]− Ex. 9 248 491[M − H]− Ex. 9 249 491[M − H]− Ex. 9 250 509[M − H]− Ex. 9 251 475[M − H]− Ex. 9 252 475[M − H]− Ex. 9 253 503[M − H]− Ex. 9 254 502[M − H]− Ex. 9 255 549[M − H]− Ex. 9 256 471[M − H]− Ex. 9 257 571[M − H]− Ex. 9 258 485[M − H]− Ex. 9 259 522[M − H]− Ex. 9 260 508[M − H]− Ex. 9 261 499[M − H]− Ex. 9 262 508[M − H]− Ex. 9 263 525[M − H]− Ex. 9 264 493[M − H]− Ex. 9 265 493[M − H]− Ex. 9 266 487[M − H]− Ex. 9 267 501[M − H]− Ex. 9 ^aSynthesized as in Examples described below. ^bSynthesized as described in indicated Synthesis Example. ^cNo data

Example 277 1-{3-Fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-[2-(4-fluorophenyl)-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 (7.8 g), together with trifluoroacetic acid (80 ml) and methanesulfonic acid (1 ml), was stirred at 80° C. for 2 hr. After the removal of the solvent by evaporation, the residue was neutralized with an aqueous saturated sodium hydrogencarbonate solution, and the precipitated crystal was collected by suction filtration to give a crude crystal (8.8 g) (starting compound A). This crude crystal (5 g) was dissolved in dimethylformamide (120 ml). Potassium carbonate (9.2 g) and dibromoethane (12.5 g) (starting compound C) were added to the solution, and the mixture was stirred at room temperature for about 90 hr. The reaction solution was filtered through Celite, and the solvent was removed from the filtrate by evaporation under the reduced pressure. The residue was purified by column chromatography on silica gel [chloroform:methanol] to give 3-fluoro-4-[(7-(3-bromoethyl)-6-methoxy-4-quinolyl)oxy]aniline) (1.88 g, yield 29%).

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 (2.37 g) (starting compound D) was dissolved in thionyl chloride (8 ml) to prepare a solution which was then stirred at 40° C. for one hr. The solvent was removed by evaporation under the reduced pressure. Acetonitrile (300 ml) was added to the residue to dissolve the residue. Potassium thiocyanate (1.87 g) was added to the solution, and the mixture was stirred at 40° C. for 50 min. The solvent was removed by evaporation under the reduced pressure. Ethyl acetate (50 ml) and an aqueous saturated sodium hydrogencarbonate solution (50 ml) were added to the residue, and the mixture was stirred at room temperature for 10 min. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was dissolved in ethanol:toluene (1:1=10 ml). 3-Fluoro-4-[(7-(3-bromoethyl)-6-methoxy-4-quinolyl)oxy]aniline (1.4 g) synthesized in step 1) was added to the solution, and the mixture was stirred at room temperature for 18 hr. The precipitated crystal was collected by filtration to give the title compound (1.58 g, yield 73%).

¹H-NMR (DMSO, 400 MHz): δ 3.85 (s, 2H), 3.96 (t, J=5.4 Hz, 2H), 4.06 (s, 3H), 4.62 (t, J=5.4 Hz, 2H), 6.98 (d, J=6.3 Hz, 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=6.3 Hz, 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-fluorophenyl)-acetyl]-thiourea (Example 277)

Dimethylformamide (3 ml) was added to the compound (200 mg) prepared in step 2) to dissolve the compound. Morpholine (29 mg) (starting compound B) and potassium carbonate (46 mg) were added to the solution, and the mixture was stirred at room temperature for 18 hr. Ethyl acetate:water was added thereto, and the mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was purified by TLC preparation [chloroform:methanol] to give the title compound (Example 277) (92 mg, yield 46%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.89 (s, 4H), 2.95 (s, 4H), 3.73 (s, 2H), 3.73-3.78 (m, 2H), 4.03 (s, 3H), 4.34 (t, J=6.1 Hz, 2H), 6.43 (d, J=5.1 Hz, 1H), 7.12 (t, J=8.8 Hz, 1H), 7.23-7.32 (m, 6H), 7.43 (s, 1H), 7.94 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.66 (br, 1H), 12.44 (s, 1H)

ESI-MS: m/z=607 (M−1)

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

2-Chlorophenylacetic acid (96 mg) (starting compound D) was dissolved in thionyl chloride (0.5 ml) to prepare a solution which was then stirred at 40° C. for one hr. The solvent was removed by evaporation under the reduced pressure. Acetonitrile (30 ml) was added to the residue to dissolve the residue. Potassium thiocyanate (68 mg) was added to the solution, and the mixture was stirred at 40° C. for 50 min. The solvent was removed by evaporation under the reduced pressure. Ethyl acetate (15 ml) and an aqueous saturated sodium hydrogencarbonate solution (15 ml) were added to the residue, and the mixture was stirred at room temperature for 20 min. The reaction solution was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was dissolved in ethanol:toluene (1:1=6 ml). Starting compound 12 (60 mg) (starting compound A) was added to the solution, and the mixture was stirred at room temperature for 18 hr. The solvent was removed by evaporation under the reduced pressure, and the residue was purified by TLC preparation [chloroform:methanol] to give the title compound (44 mg, yield 49%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.10-2.18 (m, 2H), 2.47-2.54 (m, 4H), 2.59 (t, J=7.2 Hz, 2H), 3.73 (t, J=4.5 Hz, 4H), 3.89 (s, 2H), 4.03 (s, 3H), 4.28 (t, J=6.7 Hz, 2H), 6.44 (dd, J=1.0, 5.4 Hz, 1H), 7.31-7.52 (m, 6H), 7.54 (s, 1H), 7.95 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 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-phenyl-acetyl-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 (4.2 g) (starting compound 2), together with trifluoroacetic acid (20 ml) and methanesulfonic acid (1 ml), was heated under reflux for one hr. The solvent was removed by evaporation, and the residue was then neutralized with a 10% aqueous sodium hydroxide solution. The precipitated crystal was collected by suction filtration to give a crude crystal (3.8 g) (starting compound A). This crude crystal (2 g) was dissolved in dimethylformamide (80 ml). Potassium carbonate (4.9 g) and 1-bromo-3-chloro-propane (5.6 g) (starting compound C) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography on silica gel, and the title compound (1.65 g, yield 77%) was obtained from the fraction of chloroform:methanol (99:1).

¹H-NMR (CDCl₃, 400 MHz): δ 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=5.3 Hz, 1H), 6.80-6.92 (m, 3H), 7.43 (s, 1H), 7.52 (s, 1H), 8.48 (d, J=5.3 Hz, 1H)

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

The aniline compound (0.7 g) prepared in step 1) was dissolved in dimethylformamide (40 ml) to prepare a solution. Potassium carbonate (1.4 g), sodium iodide (0.6 g) and morpholine (0.85 g) (starting compound B) were added to the solution, and the mixture was stirred at 70° C. for 20 hr. The reaction solution was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography on silica gel, and the title compound (0.64 g, yield 76%) was obtained from the fraction of chloroform:methanol (95:5).

¹H-NMR (CDCl₃, 400 MHz): δ 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=5.4 Hz, 1H), 6.73-6.84 (m, 3H), 7.35 (s, 1H), 7.46 (s, 1H), 8.40 (d, J=5.4 Hz, 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 (95 mg) (starting compound D) was suspended in anhydrous dichloroethane (10 ml). Oxalyl chloride (0.09 ml) was added to the suspension, and the mixture was heated under reflux for 17 hr. The solvent was removed by evaporation under the reduced pressure to give a crude crystal. The crude crystal was suspended in anhydrous chloroform (10 ml). The suspension was added at room temperature to a solution of the aniline compound (100 mg) prepared in step 2) and triethylamine (330 mg) in anhydrous chloroform (10 ml), and the mixture was stirred at room temperature for 5 hr. A 2% aqueous sodium hydroxide solution was added thereto, and the chloroform layer was separated. The separated chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was purified by column chromatography on silica gel, and the title compound (Example 287) (115 mg, yield 84%) was obtained from the fraction of chloroform:methanol (97:3).

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

Mass spectrometric 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-fluorophenyl)-acetyl]-thiourea 1) Synthesis of 1-{[4-(4-aminophenoxy)-6-methoxy-7-quinolyl]oxy}-3-morpholino-2-propanol

Starting compound 2 (10 g), together with trifluoroacetic acid (100 ml) and methanesulfonic acid (1 ml), was heated under reflux for one hr. The temperature of the reaction solution was returned to room temperature, and the solvent was removed by evaporation. The residue was then made weakly alkaline with an aqueous saturated sodium hydrogencarbonate solution to precipitate a solid. The solid was collected by filtration, was washed with water, and was then dried to give a crude crystal (9.6 g) (starting compound A). Dimethylformamide (300 ml) was added to the crude crystal to dissolve the crystal. Potassium carbonate (23.5 g) and epibromohydrin (3.1 ml) (starting compound C) were then added to the solution, and the mixture was stirred at room temperature overnight. Further, potassium carbonate (2.3 g) and epibromohydrin (0.3 ml) (starting compound C) were added thereto, and the mixture was stirred at room temperature overnight. Morpholine (14.8 ml) (starting compound B) was added thereto, and the mixture was stirred at 70° C. overnight. The temperature of the reaction solution was returned to room temperature, and water was added thereto. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over sodium sulfate, and the dried organic layer was then concentrated. The residue was purified by column chromatography on silica gel using chloroform:methanol for development to give 6.9 g of the title compound.

¹H-NMR (CDCl₃, 400 MHz): δ 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 (dd, J=1.0, 5.4 Hz, 1H), (ddd, J=1.0, 2.7, 8.5 Hz, 1H), 6.57 (dd, J=2.7, Hz, 1H), 7.04 (t, J=8.5 Hz, 1H), 7.45 (s, 1H), (s, 1H), 8.47 (d, J=5.4 Hz, 1H)

Mass spectrometric 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)

4-Fluorophenylacetic acid (4.3 g) (starting compound D) was added to thionyl chloride (10 ml). The mixture was stirred at 40° C. for one hr and was then concentrated, and the residue was then dried by means of a vacuum pump. Acetonitrile (250 ml) was added thereto, and potassium isothiocyanate (3.4 g) was added to the mixture. The mixture was stirred at 40° C. for 50 min, followed by concentration. An aqueous saturated sodium hydrogencarbonate solution was added to the concentrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over sodium sulfate, and the solvent was then removed by evaporation. A mixed solvent composed of toluene (50 ml) and ethanol (50 ml) was added to the residue, and amine (3.0 g) was added thereto. The mixture was stirred at room temperature overnight. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with a mixed solvent composed of chloroform and methanol. The organic layer was washed with saturated brine and was dried over sodium sulfate. The dried organic layer was then concentrated, and the residue was purified by column chromatography on silica gel using chloroform:methanol for development to give the title compound (1.4 g, yield 44%).

¹H-NMR (CDCl₃, 400 MHz): δ 2.48-2.55 (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=4.4 Hz, 1H), 7.12 (t, J=8.5 Hz, 2H), 7.23-7.32 (m, 3H), 7.40 (d, J=8.8 Hz, 1H), 7.45 (s, 1H), 7.54 (s, 1H), 7.93 (dd, J=2.6, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.65 (s, 1H), 12.44 (s, 1H)

ESI-MS: m/z=639 (M+1)

Compounds of Examples 277, 285, 287, and 313 had the following respective structures.

Compounds of Examples 270 to 276, 278 to 284, 286, 288 to 312, and 314 to 337 were synthesized as described in Examples 277, 285, 287, and 313. For these compounds, chemical structural formulae, starting compounds, synthesis methods, and data for identifying the compounds are as follows.

Ex. Compound Starting No. structure compound A 270 271 272 273 275 276 277 278 279 282 283 284 286 288 289 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 Ex. Starting Starting Starting Synthesis No. compound B compound C compound D method^a 270 Ex. 277 271 Ex. 277 272 Ex. 277 273 Ex. 277 275 Ex. 277 276 Ex. 277 277 Ex. 277 278 Ex. 277 279 Ex. 277 282 Ex. 277 283 Ex. 287 284 Ex. 277 286 Ex. 287 288 Ex. 285 289 Ex. 285 291 Ex. 287 292 Ex. 287 293 Ex. 287 294 Ex. 287 295 Ex. 287 296 Ex. 287 297 Ex. 277 298 Ex. 277 299 Ex. 277 300 Ex. 277 301 Ex. 277 302 Ex. 285 303 Ex. 285 304 Ex. 285 305 Ex. 287 306 Ex. 287 307 Ex. 277 308 Ex. 287 309 Ex. 277 310 Ex. 277 311 Ex. 287 312 Ex. 313 314 Ex. 313 315 Ex. 313 316 Ex. 313 317 Ex. 313 318 Ex. 313 319 Ex. 313 320 Ex. 313 321 Ex. 313 322 Ex. 313 323 Ex. 313 324 Ex. 313 325 Ex. 313 326 Ex. 313 327 Ex. 313 328 Ex. 313 329 Ex. 313 330 Ex. 285 331 Ex. 285 332 Ex. 285 333 Ex. 285 334 Ex. 285 335 Ex. 285 336 Ex. 287 337 Ex. 287

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, 400 MHz): δ 2.20 (s, 3H), 2.33-2.57 (m, 8H), 2.79 (t, J=5.6 Hz, 2H), 3.83 (s, 2H), 3.94 (s, 3H), 4.26 (t, J=5.9 Hz, 2H), 6.48 (d, J=5.1 Hz, 1H), 7.23-7.57 (m, 9H), 8.01 (dd, J=2.2, 12.2 Hz, 1H), 8.49 (d, J=5.1 Hz, 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, 400 MHz): δ 2.16 (s, 3H), 2.28-2.62 (m, 8H), 2.78 (t, J=5.9 Hz, 2H), 3.83 (s, 2H), 3.94 (s, 3H), 4.26 (t, J=5.9 Hz, 2H), 6.48 (dd, J=1.0, 5.1 Hz, 1H), 7.10-7.41 (m, 6H), 7.44 (s, 1H), 7.52 (s, 1H), 8.00 (dd, J=2.2, 12.2 Hz, 1H), 8.49 (d, J=5.1 Hz, 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, 400 MHz): δ 1.01 (t, J=7.1 Hz, 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=5.9 Hz, 2H), 6.46 (d, J=5.1 Hz, 1H), 7.07-7.57 (m, 9H), 7.93-8.10 (m, 1H), 8.48 (d, J=5.1 Hz, 1H), 11.80 (s, 1H), 12.50 (s, 1H)

Mass spectrometric value (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, 400 MHz): δ 1.84-1.94 (m, 2H), 2.42 (s, 3H), 2.68-2.78 (m, 4H), 2.88-2.97 (m, 4H), 3.12 (t, J=6.4 Hz, 2H), 3.76 (s, 2H), 4.02 (s, 3H), 4.29 (t, J=6.4 Hz, 2H), 6.44 (d, J=5.1 Hz, 1H), 7.24-7.49 (m, 8H), 7.54 (s, 1H), 7.93 (dd, J=2.4, 11.7 Hz, 1H), 8.51 (d, J=5.1 Hz, 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, 400 MHz): δ 1.11 (t, J=7.1 Hz, 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=6.5 Hz, 2H), 6.44 (d, J=5.1 Hz, 1H), 7.09-7.46 (m, 7H), 7.53 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.1 Hz, 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

¹H-NMR (CDCl₃, 400 MHz): δ 2.62-2.72 (m, 4H), 2.98 (t, J=5.7 Hz, 2H), 3.70-3.78 (m, 6H), 4.02 (s, 3H), 4.35 (t, J=5.7 Hz, 2H), 6.46 (d, J=5.4 Hz, 1H), 7.21-7.45 (m, 8H), 7.55 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H), 8.52 (d, J=5.4 Hz, 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, 400 MHz): δ 2.63-2.78 (m, 4H), 2.98 (t, J=5.8 Hz, 2H), 3.75-3.82 (m, 4H), 3.80 (s, 2H), 4.03 (s, 3H), 4.37 (t, J=5.8 Hz, 2H), 6.46 (d, J=5.4 Hz, 1H), 7.05-7.43 (m, 6H), 7.47 (s, 1H), 7.55 (s, 1H), 7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.50 (d, J=5.4 Hz, 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, 400 MHz): δ 2.66-3.06 (m, 6H), 3.70-3.85 (m, 6H), 4.03 (s, 3H), 4.39 (t, J=5.8 Hz, 2H), 6.48 (d, J=5.4 Hz, 1H), 7.04-7.14 (m, 3H), 7.25-7.45 (m, 3H), 7.50 (s, 1H), 7.56 (s, 1H), 7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 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, 400 MHz): δ 1.58-1.99 (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=5.4 Hz, 1H), 7.06-7.15 (m, 2H), 7.22-7.34 (m, 4H), 7.42 (s, 1H), 7.57 (s, 1H), 7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.47 (d, J=5.4 Hz, 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, 400 MHz): δ 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=5.1 Hz, 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=5.1 Hz, 1H), 10.59 (s, 1H)

Mass spectrometric value (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, 400 MHz): δ 1.45-1.88 (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=5.1 Hz, 1H), 7.22-7.47 (m, 7H), 7.56 (s, 1H), 7.94 (dd, J=2.4, 11.7 Hz, 1H), 8.48 (d, J=5.1 Hz, 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, 400 MHz): δ 2.02-2.25 (m, 2H), 2.40-2.49 (m, 4H), 2.51 (t, J=7.1 Hz, 2H), 3.64-3.67 (m, 4H), 3.67 (s, 2H), 3.93 (s, 3H), 4.19 (t, J=6.7 Hz, 2H), 6.44 (d, J=5.4 Hz, 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=8.5 Hz, 1H), 8.43 (d, J=5.4 Hz, 1H), 9.30 (s, 1H), 10.74 (s, 1H)

Mass spectrometric value (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, 400 MHz): δ 2.12-2.19 (m, 2H), 2.50-2.66 (m, 6H), 3.72-3.81 (m, 6H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.45 (d, J=5.4 Hz, 1H), 7.16-7.42 (m, 6H), 7.45 (s, 1H), 7.54 (s, 1H), 7.94 (dd, J=2.4, 11.5 Hz, 1H), 8.51 (d, J=5.4 Hz, 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, 400 MHz): δ 2.10-2.18 (m, 2H), 2.44-2.56 (m, 4H), 2.59 (t, J=7.2 Hz, 2H), 3.70-3.76 (m, 6H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.45 (d, J=5.4 Hz, 1H), 7.01-7.13 (m, 3H), 7.26-7.44 (m, 3H), 7.44 (s, 1H), 7.54 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 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, 400 MHz): δ 1.31 (t, J=7.3 Hz, 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=6.0 Hz, 2H), 6.38 (d, J=5.1 Hz, 1H), 7.18-7.44 (m, 8H), 7.56 (s, 1H), 7.68 (dd, J=2.4, 12.2 Hz, 1H), 8.46 (d, J=5.1 Hz, 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, 400 MHz): δ 1.94-2.05 (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=6.1 Hz, 2H), 6.38 (d, J=1.0, 5.4 Hz, 1H), 7.16-7.44 (m, 8H), 7.56 (s, 1H), 7.68 (dd, J=2.4, 12.7 Hz, 1H), 8.45 (br, 1H), 8.47 (d, J=5.4 Hz, 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, 400 MHz): δ 1.27 (t, J=7.2 Hz, 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=6.1 Hz, 2H), 6.38 (d, J=5.4 Hz, 1H), 7.10-7.25 (m, 4H), 7.29-7.40 (m, 2H), 7.41 (s, 1H), 7.56 (s, 1H), 7.67 (dd, J=2.2, 12.7 Hz, 1H), 8.47 (d, J=5.4 Hz, 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, 400 MHz): δ 1.93-2.00 (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=6.3 Hz, 2H), 6.38 (dd, J=1.0, 5.1 Hz, 1H), 7.10-7.28 (m, 4H), 7.30-7.39 (m, 2H), 7.41 (s, 1H), 7.55 (s, 1H), 7.68 (dd, J=2.2, 11.7 Hz, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.85 (br, 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, 400 MHz): δ 1.45-1.55 (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=6.6 Hz, 2H), 6.38 (dd, J=0.7, 5.4 Hz, 1H), 7.10-7.31 (m, 4H), 7.30-7.39 (m, 2H), 7.41 (s, 1H), 7.55 (s, 1H), 7.68 (dd, J=2.2, 12.7 Hz, 1H), 8.46 (d, J=5.4 Hz, 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, 400 MHz): δ 2.08-2.17 (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=5.4 Hz, 1H), 7.12-7.23 (m, 4H), 7.17-7.40 (m, 2H), 7.43 (s, 1H), 7.55 (s, 1H), 7.69 (dd, J=2.2, 12.1 Hz, 1H), 8.47 (d, J=5.4 Hz, 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-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.08-2.17 (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=6.3 Hz, 2H), 6.44 (d, J=5.4 Hz, 1H), 7.01-7.55 (m, 8H), 7.93 (dd, J=2.7, 11.5 Hz, 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, 400 MHz): δ 2.15-2.22 (m, 2H), 2.52-2.58 (m, 4H), 2.63 (t, J=7.1 Hz, 2H), 3.76 (t, J=4.6 Hz, 4H), 3.80 (s, 2H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.38 (d, J=5.1 Hz, 1H), 7.13-7.25 (m, 3H), 7.29-7.42 (m, 2H), 7.46 (s, 1H), 7.55 (s, 1H), 7.62 (dd, J=2.4, 8.8 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 8.50 (d, J=5.1 Hz, 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, 400 MHz): δ 2.15-2.26 (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=6.6 Hz, 2H), 6.39 (d, J=5.1 Hz, 1H), 7.02-7.13 (m, 4H), 7.36-7.44 (m, 1H), 7.48 (s, 1H), 7.55 (s, 1H), 7.62 (dd, J=2.4, 8.8 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 8.50 (d, J=5.1 Hz, 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, 400 MHz): δ 2.14-2.24 (m, 2H), 2.53-2.72 (m, 6H), 3.76-3.80 (m, 6H), 4.03 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.38 (d, J=5.4 Hz, 1H), 7.22-7.45 (m, 7H), 7.55 (s, 1H), 7.62 (dd, J=2.4, 8.8 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 8.50 (d, J=5.4 Hz, 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-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃:CD₃OD=30:1, 400 MHz): δ 2.20-2.32 (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=6.1 Hz, 2H), 6.41 (d, J=5.4 Hz, 1H), 7.21-7.33 (m, 5H), 7.54-7.61 (m, 2H), 7.65 (dd, J=2.4, 8.6 Hz, 1H), 8.04 (d, J=2.4 Hz, 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-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.20-2.33 (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=6.3 Hz, 2H), 6.47 (d, J=5.4 Hz, 1H), 7.22-7.34 (m, 5H), 7.42 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 7.55 (s, 1H), 7.96 (dd, J=2.4, 11.7 Hz, 1H), 8.44 (br, 1H), 8.50 (d, J=5.4 Hz, 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-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.10-2.20 (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=6.6 Hz, 2H), 6.46 (d, J=4.6 Hz, 1H), 7.08-7.36 (m, 5H), 7.41 (d, J=8.8 Hz, 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-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.14-2.24 (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=6.4 Hz, 2H), 6.46 (d, J=5.4 Hz, 1H), 7.16-7.28 (m, 5H), 7.40 (d, J=8.8 Hz, 1H), 7.46 (s, 1H), 7.54 (s, 1H), 7.93 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 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, 400 MHz): δ 2.19-2.38 (m, 2H), 3.74 (s, 2H), 3.97 (s, 3H), 4.09 (t, J=6.3 Hz, 2H), 4.19 (t, J=6.8 Hz, 2H), 6.44 (d, J=5.4 Hz, 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=5.4 Hz, 1H), 10.64 (s, 1H), 11.05 (s, 1H)

Mass spectrometric value (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, 400 MHz): δ 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=5.1 Hz, 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=5.1 Hz, 1H), 10.57 (s, 1H), 11.08 (s, 1H)

Mass spectrometric value (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, 400 MHz): δ 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=5.3 Hz, 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=5.3 Hz, 1H), 11.80 (s, 1H), 12.51 (s, 1H)

Mass spectrometric value (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, 400 MHz): δ 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=5.4 Hz, 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=5.4 Hz, 1H), 10.69 (s, 1H)

Mass spectrometric value (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, 400 MHz): δ 1.75-3.00 (m, 9H), 3.30-3.72 (m, 6H), 3.76 (s, 2H), 4.04 (s, 3H), 4.34 (t, J=5.4 Hz, 2H), 6.50 (d, J=5.4 Hz, 1H), 7.24-7.46 (m, 8H), 7.58 (s, 1H), 7.96 (dd, J=2.4, 11.7 Hz, 1H), 8.47 (d, J=54 Hz, 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, 400 MHz): δ 1.00-3.20 (m, 15H), 3.73 (s, 2H), 4.02 (s, 3H), 4.27 (t, J=6.1 Hz, 2H), 6.45 (d, J=5.4 Hz, 1H), 7.08-7.17 (m, 2H), 2.22-7.44 (m, 5H), 7.54 (s, 1H), 7.94 (dd, J=2.4, 11.5 Hz, 1H), 8.49 (d, J=5.4 Hz, 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-phenyl-acetyl-urea

¹H-NMR (CDCl₃, 400 MHz): δ 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=5.3 Hz, 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=8.8 Hz, 1H), 8.43 (d, J=5.3 Hz, 1H), 10.66 (s, 1H)

Mass spectrometric value (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, 400 MHz): δ 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=5.1 Hz, 1H), 7.17-7.57 (m, 9H), 7.93-8.10 (m, 1H), 8.49 (d, J=5.1 Hz, 1H), 11.81 (s, 1H), 12.50 (s, 1H)

Mass spectrometric value (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, 400 MHz): δ 2.48-2.54 (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=5.4 Hz, 1H), 7.32-7.43 (m, 5H), 7.45 (s, 1H), 7.47-7.52 (m, 1H), 7.54 (s, 1H), 7.95 (dd, J=2.6, 11.6 Hz, 1H), 8.50 (d, J=5.4 Hz, 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, 400 MHz): δ 2.49-2.56 (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=5.4 Hz, 1H), 7.14-7.42 (m, 6H), 7.46 (s, 1H), 7.54 (s, 1H), 7.94 (dd, J=2.4, 11.5 Hz, 1H), 8.50 (d, J=5.4 Hz, 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

¹H-NMR (DMSO, 400 MHz): δ 1.40-1.52 (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=5.1 Hz, 1H), 7.27-7.51 (m, 6H), 7.54 (s, 1H), 7.82 (dd, J=2.2, 11.9 Hz, 1H), 8.49 (d, J=5.1 Hz, 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, 400 MHz): δ 1.84-1.92 (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=5.1 Hz, 1H), 7.27-7.51 (m, 6H), 7.55 (s, 1H), 7.84 (dd, J=2.4, 12.2 Hz, 1H), 8.51 (d, J=5.1 Hz, 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, 400 MHz): δ 1.32-1.60 (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=5.1 Hz, 1H), 7.12-7.24 (m, 2H), 2.26-7.57 (m, 6H), 8.02 (dd, J=2.2, 12.2 Hz, 1H), 8.50 (d, J=5.1 Hz, 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

¹H-NMR (DMSO, 400 MHz): δ 1.78-1.85 (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=5.4 Hz, 1H), 7.13-7.46 (m, 6H), 7.54 (s, 1H), 7.83 (dd, J=2.7, 12.9 Hz, 1H), 8.49 (d, J=5.4 Hz, 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, 400 MHz): δ 3.34-3, 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=6.6 Hz, 1H), 6.49 (d, J=5.4 Hz, 1H), 7.26-7.57 (m, 8H), 8.01 (dd, J=2.6, 12.4 Hz, 1H), 8.50 (d, J=5.4 Hz, 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, 400 MHz): δ 1.37-1.61 (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=5.1 Hz, 1H), 7.21-7.55 (m, 7H), 7.32 (dd, J=2.4, 12.4 Hz, 1H), 8.49 (d, J=5.1 Hz, 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, 400 MHz): δ 1.82-1.90 (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=5.1 Hz, 1H), 7.22-7.57 (m, 7H), 7.82 (dd, J=2.2, 12.0 Hz, 1H), 8.50 (d, J=5.1 Hz, 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, 400 MHz): δ 3.33-3.41 (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=5.4 Hz, 1H), 7.05-7.23 (m, 3H), 7.36-7.56 (m, 5H), 8.01 (dd, J=2.1, 12.3 Hz, 1H), 8.50 (d, J=5.4 Hz, 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, 400 MHz): δ 1.38-1.48 (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=5.1 Hz, 1H), 7.06-7.56 (m, 7H), 8.02 (dd, J=2.4, 12.4 Hz, 1H), 8.50 (d, J=5.1 Hz, 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, 400 MHz): δ 1.84-1.92 (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=5.1 Hz, 1H), 7.06-7.58 (m, 7H), 8.01 (dd, J=2.4, 12.2 Hz, 1H), 8.51 (d, J=5.1 Hz, 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, 400 MHz): δ 2.53-2.73 (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=5.4 Hz, 1H), 7.20-7.34 (m, 4H), 7.37-7.42 (m, 2H), 7.44 (s, 1H), 7.56 (s, 1H), 7.94 (dd, J=2.6, 11.6 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H)

ESI-MS: m/z=655 (M+1)

Example 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

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.39-1.43 (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=5.4 Hz, 1H), 7.10-7.30 (m, 7H), 7.43-7.49 (m, 1H), 7.48 (s, 1H), 8.34 (d, J=5.4 Hz, 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, 400 MHz): δ 2.01-2.08 (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=5.4 Hz, 1H), 7.12-7.32 (m, 7H), 7.49 (s, 1H), 7.88 (dd, J=2.4, 11.7 Hz, 1H), 8.37 (d, J=5.4 Hz, 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, 400 MHz): δ 1.43-1.55 (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=5.4 Hz, 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=5.4 Hz, 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, 400 MHz): δ 2.09-2.15 (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=5.4 Hz, 1H), 6.96-7.13 (m, 2H), 7.22-7.40 (m, 5H), 7.58 (s, 1H), 7.96 (dd, J=2.4, 11.5 Hz, 1H), 8.44 (d, J=5.4 Hz, 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-phenylacetyl)-thiourea

¹H-NMR (CDCl₃:CD₃OD=20:1, 400 MHz): δ 1.50-1.60 (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=5.4 Hz, 1H), 7.18-7.40 (m, 8H), 7.51 (s, 1H), 7.90 (dd, J=2.3, 11.6 Hz, 1H) 8.40 (d, J=5.4 Hz, 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, 400 MHz): δ 2.03-2.11 (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=5.0 Hz, 1H), 7.19-7.40 (m, 8H), 7.52 (s, 1H), 7.90 (dd, J=2.6, 11.7 Hz, 1H), 8.41 (d, J=5.0 Hz, 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-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.36 (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=5.4 Hz, 1H), 7.16-7.32 (m, 5H), 7.42 (d, J=9.0 Hz, 1H), 7.55 (s, 1H), 7.62 (s, 1H), 7.97 (dd, J=2.4, 11.7 Hz, 1H), 8.50 (d, J=5.4 Hz, 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-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.39 (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=5.1 Hz, 2H), 4.34-4.42 (m, 1H), 6.49 (d, J=5.4 Hz, 1H), 7.09-7.35 (m, 5H), 7.41 (d, J=9.0 Hz, 1H), 7.54 (s, 1H), 7.55 (s, 1H), 7.95 (dd, J=2.6, 11.6 Hz, 1H), 8.51 (d, J=5.4 Hz, 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-toluoyl-acetyl)-thiourea

¹H-NMR (CDCl₃, 400 MHz): δ 2.37 (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=5.4 Hz, 1H), 7.10-7.28 (m, 5H), 7.40 (d, J=9.0 Hz, 1H), 7.51 (s, 1H), 7.56 (s, 1H), 7.93 (dd, J=2.4, 11.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 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, 400 MHz): δ 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=5.4 Hz, 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=5.4 Hz, 1H), 8.88 (s, 1H), 10.62 (s, 1H)

Mass spectrometric 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, 400 MHz): δ 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=5.1 Hz, 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=5.1 Hz, 1H), 8.60 (s, 1H), 10.64 (s, 1H)

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

Pharmacological Test Example 1 Measurement (1) of Inhibitory Activity Against Met-Autophosphorylation Using ELISA Method

Human epidermal cancer cells A431 were cultured in an RPMI 1640 medium containing 10% fetal calf serum (purchased from GIBCO BRL) within a 5% carbon dioxide incubator until 50 to 90% confluent. Cells were cultured with RPMI medium containing 0.1% fetal calf serum in 96-well flat-bottom plate in an amount of 3×10⁴per well, and were incubated at 37° C. overnight. The medium was then replaced by a fresh RPMI medium containing 0.1% fetal calf serum. A solution of the test compound in dimethyl sulfoxide was added to each well, and the cells were incubated at 37° C. for additional one hr. A human recombinant hepatocyte growth factor (hereinafter abbreviated to “HGF”) was added to a final concentration of 50 ng/ml, and the stimulation of cells was carried out at 37° C. for 5 min. The medium was removed, the cells were washed with phosphate buffered saline (pH 7.4), and 50 μl of lysis buffer (20 mM HEPES (pH 7.4), 150 mM NaCl, 0.2% Triton X-100, 10% glycerol, 5 mM sodium orthovanadylate, 5 mM disodium ethylenediaminetetraacetate, and 2 mM Na₄P₂O₇) was then added thereto. The mixture was shaken at 4° C. for 2 hr to prepare a cell extract.

Separately, phosphate buffered saline (50 μl, pH 7.4) containing 5 μg/ml of anti-phospho-tyrosine antibody (PY20; purchased from Transduction Laboratories) was added to a microplate for ELISA (Maxisorp; purchased from NUNC), followed by gentle agitation at 4° C. overnight to coat the surface of the wells with the antibody. After washing of the plate, 300 μl of a blocking solution was added, followed by gentle agitation at room temperature for 2 hr to perform blocking. After washing, the whole quantity of the cell extract was transferred to the wells, and the plate was then allowed to incubate at 4° C. overnight. After washing, an anti-HGF receptor antibody (h-Met (C-12), purchased from Santa Cruz Biotechnology) was allowed to react at room temperature for one hr, and, after washing, a peroxidase-labeled anti-rabbit Ig antibody (purchased from Amersham) was allowed to react at room temperature for one hr. After washing, a chromophoric substrate for peroxidase (purchased from Sumitomo Bakelite Co., Ltd.) was added thereto to initiate a reaction. After a suitable level of color development, a reaction termination solution was added to stop the reaction, and the absorbance at 450 nm was measured with a microplate reader. The met-phosphorylation inhibitory activity for each well was determined by presuming the absorbance with the addition of HGF and the vehicle to compounds to be 0% met-phosphorylation inhibitory activity and the absorbance with the addition of the vehicle to compounds and without HGF to be 100% met phosphorylation inhibitory activity. The concentration of the test compound was varied on several levels, the inhibition (%) of met-phosphorylation was determined for each case, and the concentration of the test compound necessary for inhibiting 50% of met phosphorylation (IC₅₀) was calculated. The results are shown in Table 1.

TABLE 1 Example No. IC₅₀, μM 1 0.0087 2 0.0118 3 0.0197 11 0.0581

Pharmacological Test Example 2 Measurement (2) of Inhibitory Activity Against Met-Autophosphorylation Using ELISA Method

Human gastric cancer cells MKN45 were maintained in RPMI 1640 medium containing 10% fetal calf serum (purchased from GIBCO BRL) in 5% carbon dioxide incubator until 50 to 90% confluent. Cells were cultured with RPMI medium containing 0.1% fetal calf serum in 96-well flat-bottom plate in an amount of 3×10⁴per well, and were incubated at 37° C. overnight. The medium was then replaced by a fresh RPMI medium containing 0.1% fetal calf serum. A solution of the test compound in dimethyl sulfoxide was added to each well, and the incuvation was continued at 37° C. for additional one hr. The medium was removed, the cells were washed with phosphate buffered saline (pH 7.4), and 50 μl of a lysis buffer (20 mM HEPES (pH 7.4), 150 mM NaCl, 0.2% Triton X-100, 10% glycerol, 5 mM sodium orthovanadylate, 5 mM disodium ethylenediaminetetraacetate, and 2 mM Na₄P₂O₇) was then added thereto. The mixture was shaken at 4° C. for 2 hr to prepare a cell extract.

Separately, phosphate buffered saline (50 μl, pH 7.4) containing 5 μg/ml of anti-phospho-tyrosine antibody (PY20; purchased from Transduction Laboratories) was added to a microplate for ELISA (Maxisorp; purchased from NUNC), followed by gentle agitation at 4° C. overnight to coat the surface of the wells with the antibody. After washing of the plate, 300 μl of a blocking solution was added, followed by gentle agitation at room temperature for 2 hr to perform blocking. After washing, the whole quantity of the cell extract was transferred to the wells, and the plate was then allowed to stand at 4° C. overnight. After washing, an anti-HGF receptor antibody (h-Met (C-12), purchased from Santa Cruz Biotechnology) was allowed to react at room temperature for one hr, and, after washing, a peroxidase-labeled anti-rabbit Ig antibody (purchased from Amersham) was allowed to react at room temperature for one hr. After washing, a chromophoric substrate for peroxidase (purchased from Sumitomo Bakelite Co., Ltd.) was added thereto to initiate a reaction. After a suitable level of color development, a reaction termination solution was added to stop the reaction, and the absorbance at 450 nm was measured with a microplate reader. The met phosphorylation activity for each well was determined by presuming the absorbance with the addition of the vehicle to be 100% met phosphorylation activity and the absorbance with the addition of a largely excessive amount of positive control (compound 1, 1000 nM) to be 0% met phosphorylation activity. The concentration of the test compound was varied on several levels, the inhibition (%) of met-phosphorylation was determined for each case, and the concentration of the test compound necessary for inhibiting 50% of met phosphorylation (IC₅₀) was calculated. The results are shown in Table 2.

TABLE 2 Ex. No. IC₅₀, μM 1 0.0112 2 0.0181 3 0.0304 4 0.0750 5 0.0189 6 0.0316 7 0.2922 8 0.2976 9 0.0364 10 0.1459 11 0.0202 12 0.1990 13 0.1411 14 0.2909 15 0.3017 16 0.0328 17 0.0307 18 0.1496 19 0.1040 20 0.0318 21 0.1876 22 0.0246 23 0.0263 24 0.0277 25 0.1401 26 0.1256 27 0.0800 28 0.1624 29 0.0371 30 0.0351 31 0.0341 32 0.1709 33 0.0618 34 0.0463 35 0.0414 36 0.1982 37 0.0584 38 0.0291 39 0.1145 40 0.2421 41 0.2807 42 0.1899 43 0.1674 44 0.2915 45 0.2071 46 0.2290 47 0.2153 48 0.2240 49 0.0514 50 0.2355 51 0.2035 52 0.1706 53 0.0374 54 0.0261 55 0.2449 56 0.1400 57 0.1320 58 0.0270 59 0.1930 60 0.0370 61 0.1130 62 0.0920 63 0.0244 64 0.1405 65 0.0663 66 0.0792 67 0.0197 68 0.1944 69 0.0044 70 0.0153 71 0.0299 72 0.0279 73 0.0281 74 0.1825 75 0.0336 76 0.0517 77 0.1776 78 0.0663 79 0.1454 80 0.0302 81 0.0277 82 0.0743 83 0.0391 84 0.0400 85 0.0488 86 0.0235 87 0.1983 88 0.0492 89 0.0526 90 0.0281 91 0.0401 92 0.1480 93 0.1215 94 0.0307 95 0.0413 96 0.1706 97 0.0376 98 0.0278 99 0.0256 100 0.0308 101 0.0444 102 0.0918 103 2.7714 104 0.3442 105 0.1037 106 0.0427 107 0.3450 108 2.0800 109 1.4756 110 2.3751 111 1.8118 112 1.7334 113 0.6535 114 0.4850 115 0.3592 116 0.3440 117 1.3037 118 0.2114 119 0.4420 120 1.5748 121 0.3380 122 0.3026 123 2.0088 124 0.2643 125 0.2933 126 0.3295 127 0.3189 128 0.2847 129 1.0060 130 2.1555 131 2.3731 132 0.2683 133 0.2610 134 0.2319 135 0.2260 136 0.3417 137 0.2707 138 0.2843 139 0.2432 140 0.2288 141 0.3361 142 0.2847 143 3.5910 144 0.6990 145 0.3640 146 1.2100 147 1.1660 148 2.4790 149 0.2360 150 1.2780 151 0.2561 152 0.2475 153 0.2320 154 0.8760 155 0.9820 156 0.3730 157 0.4820 158 0.4650 159 0.5850 160 1.6327 161 0.2460 162 0.2096 163 0.2018 164 0.2417 165 0.4950 166 0.3183 167 0.2586 168 0.3056 169 0.2759 170 0.2736 171 0.2817 172 0.4228 173 0.2217 174 0.2522 175 0.9552 176 0.2211 177 0.2672 178 0.2680 179 0.2613 180 2.5610 181 0.2431 182 0.2559 183 0.2238 184 0.2677 185 0.2477 186 0.2340 187 0.2575 188 0.2525 189 0.2323 190 0.2237 191 0.9767 192 0.6874 193 0.4442 194 0.3188 195 0.2914 196 0.3219 197 0.2842 198 0.2938 199 0.2415 200 0.3052 201 0.2255 202 0.6416 203 0.2813 204 0.3209 205 0.2651 206 0.4436 207 0.2998 208 0.2580 209 0.9285 210 0.2277 211 0.2521 212 0.3787 213 2.4266 214 2.5273 215 1.9770 216 0.2278 217 0.3331 218 0.4793 219 0.7359 220 0.2967 221 0.2212 222 0.2014 223 0.2680 224 0.3160 225 0.2814 226 3.2308 227 4.3638 228 0.3936 229 0.2730 230 0.3403 231 0.3288 232 0.2557 233 0.3217 234 0.4568 235 0.2146 236 0.2351 237 1.4669 238 4.0204 239 1.5818 240 2.7412 241 3.3169 242 0.8512 243 3.0098 244 0.3419 245 0.3082 246 2.9114 247 0.6502 248 0.9569 249 0.5256 250 0.4474 251 0.3862 252 0.3005 253 1.3400 254 0.3655 255 0.2601 256 0.2808 257 0.2859 258 0.3574 259 0.6143 260 2.2325 261 0.3426 262 0.2689 263 0.4835 264 0.3472 265 0.2589 266 0.1806 267 0.1091 268 0.0228 269 0.0125 270 0.0267 271 0.0391 272 0.0336 273 0.0240 275 0.0230 276 0.0190 277 0.0204 278 0.0251 279 0.0204 282 0.0166 283 0.0146 284 0.0150 285 0.0753 286 0.0293 287 0.0225 288 0.0226 289 0.0238 291 0.0195 292 0.0203 293 0.0211 294 0.0230 295 0.0241 296 0.0197 297 0.0532 298 0.0890 299 0.0435 300 0.0224 301 0.0611 302 0.0231 303 0.0267 304 0.0659 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 Inhibitory Activity Against Human Gastric Cancer Cells (MKN 45)

Human gastric cancer cells (MKN 45) were transplanted into nude mice. When the tumor volume became about 100 to 200 mm³, the mice were grouped so that the groups each consisted of five mice and had an even average tumor volume. The test compound suspended in 0.5% methylcellulose was orally administered twice a day for 5 days.

Only 0.5% methylcellulose was administered to the control group in the manner as in the test groups. The tumor growth inhibition rate (TGIR) was calculated as follows: The tumor growth inhibition rate (TGIR)=(1−TX/CX)×100 wherein CX represents the relative tumor volume at day X for the control group when the tumor volume at the day of the start of the administration was presumed to be 1; and TX represents the relative tumor volume for test compound administration groups.

The tumor growth inhibition rate for representative examples of a group of compounds according to the present invention is shown in Table 3.

TABLE 3 Dose, mg/kg/time TGIR, % Example 1 10 21 30 47 100 54 Example 2 10 31 30 65 Example 3 10 24 30 52 Example 11 10 23 30 52 Example 268 30 81

Pharmacological Test Example 4 Tumor Growth Inhibitory Activity Against Human Brain Tumor Cells (U87MG)

Human brain tumor cells (U87MG) were transplanted into nude mice. When the tumor volume became about 100 to 200 mm³, the mice were grouped so that the groups each consisted of five mice and had an even average tumor volume. The test compound suspended in 0.5% methylcellulose was orally administered twice a day for 5 days.

Only 0.5% methylcellulose was administered to the control group in the manner as in the test groups. The tumor growth inhibition rate (TGIR) was calculated as follows: The tumor growth inhibition rate (TGIR)=(1−TX/CX)×100 wherein CX represents the relative tumor volume at day X for the control group when the tumor volume at the day of the start of the administration was presumed to be 1; and TX represents the relative tumor volume for test compound administration groups.

The tumor growth inhibition rate for representative examples of a group of compounds according to the present invention is shown in Table 4.

TABLE 4 Dose, mg/kg/time TGIR, % Example 1 30 42 100 70 Example 2 10 38 30 61 Example 3 30 51 100 60

Pharmacological Test Example 5 Tumor Growth Inhibitory Activity Against Various Human Tumor Cells

Human gastric cancer cells (MKN 45) (obtained from RIKEN), human brain tumor cells (U87MG) (obtained from ATCC), human pancreatic cancer cells (KP4) (obtained from RIKEN), human pancreatic cancer cells (SUIT-2) (obtained from National Kyushu Cancer Center), and human signet-ring type gastric cancer cells (NUGC-4) (obtained from RIKEN), or human lung cancer cells (LC6) (obtained from Central Laboratories for Experimental Animals) were transplanted into nude mice. When the tumor volume became about 100 mm³, the mice were grouped so that the groups each consisted of four or five mice and had an even average tumor volume. The test compound suspended in 0.5% methylcellulose was orally administered once or twice a day for 5 days. Only 0.5% methylcellulose was administered to the control group in the manner as in the test groups. Alternatively, the test compound dissolved in physiological saline (with a 1 N aqueous hydrochloric acid solution added thereto) was intraveneously injected once a day for 5 days, and only physiological saline (with a 1 N aqueous hydrochloric acid solution added thereto) was administered to the control group in the same manner as in the test groups. The tumor growth inhibition rate (TGIR) was calculated as follows: The tumor growth inhibition rate (TGIR)=(1−TX/CX)×100 wherein CX represents the relative tumor volume at the 5^thday for the control group when the tumor volume at the day of the start of the administration was presumed to be 1; and TX represents the relative tumor volume for test compound administration groups.

The tumor growth inhibition rate for representative examples of a group of compounds according to the present invention is shown in Table 5.

TABLE 5 Ex. Administration Dose, mg/kg × No. Tumor method number of times TGIR, % 1 LC6 Oral 30 × 2 26 2 NUGC-4 Oral 30 × 2 75 2 LC6 Oral 30 × 2 27 2 KP-4 Oral 30 × 2 54 3 NUGC-4 Oral 30 × 2 71 3 LC6 Oral 30 × 2 18 3 KP-4 Oral 30 × 2 31 11 MKN45 Oral 30 × 2 63 11 U87MG Oral 30 × 2 62 11 LC6 Oral 30 × 2 26 46 MKN45 Oral 25 × 1 38 268 MKN45 i.v. injection 10 × 1 52 268 LC6 Oral 30 × 2 35 268 U87MG Oral 30 × 2 74 277 MKN45 Oral 30 × 2 17 282 MKN45 Oral 30 × 2 13 282 MKN45 i.v. injection 10 × 1 31 285 MKN45 Oral 30 × 2 66 285 LC6 Oral 30 × 2 48 286 MKN45 Oral 30 × 2 64 286 LC6 Oral 30 × 2 37 286 U87MG Oral 30 × 2 66 288 MKN45 Oral 30 × 2 64 299 MKN45 Oral 25 × 1 14 312 MKN45 Oral 30 × 2 75 313 MKN45 Oral 12.5 × 1 37 313 MKN45 Oral 25 × 1 73 313 MKN45 Oral 50 × 1 78 313 MKN45 i.v. injection 10 × 1 68 313 SUIT-2 Oral 25 × 1 28 313 KP-4 Oral 12.5 × 1 34 313 KP-4 Oral 25 × 1 45 313 KP-4 Oral 50 × 1 48 314 MKN45 Oral 30 × 2 38 315 MKN45 Oral 30 × 2 36 320 MKN45 Oral 30 × 2 20 323 MKN45 Oral 30 × 2 34 326 MKN45 Oral 30 × 2 17 331 MKN45 Oral 30 × 2 40 332 MKN45 Oral 30 × 2 14 333 MKN45 Oral 30 × 2 75 334 MKN45 Oral 30 × 2 65

Claims

1: A method for treating a malignant tumor, comprising the step of administering a therapeutically effective amount of at least one compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof to a mammal:

wherein

X represents CH or N;

Z represents O or S;

L represents O or S;

M represents

—C(—R10)(—R11)— wherein R10 and R11, which may be the same or different, represent a hydrogen atom, C1-4 alkyl, or C1-4 alkoxy, or

—N(—R12)— wherein R12 represents a hydrogen atom or C1-4 alkyl;

R1, R2, and R3, which may be the same or different, represent

a hydrogen atom,

hydroxyl,

a halogen atom,

nitro,

amino,

C1-6 alkyl,

C2-6 alkenyl,

C2-6 alkynyl, or

C1-6 alkoxy,

in which one or two hydrogen atoms on the amino group are optionally substituted by C1-6 alkyl which is optionally substituted by hydroxyl or C1-6 alkoxy, and

in which the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkoxy groups are optionally substituted by hydroxyl; a halogen atom; C1-6 alkoxy; C1-6 alkylcarbonyl; C1-6 alkoxy carbonyl; amino on which one or two hydrogen atoms is optionally substituted by C1-6 alkyl which is optionally substituted by hydroxyl or C1-6 alkoxy; or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl which is optionally substituted by hydroxyl or C1-6 alkoxy;

R4 represents a hydrogen atom;

R5, R6, R7, and R8, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, or C1-4 alkoxy;

R9 represents

C1-6 alkyl on which one or more hydrogen atoms are optionally substituted by —R14, -T-R15, or —NR16R17 wherein T represents —O—, —S—, or —NH—; R14 represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R15, R16, and R17, which may be the same or different, represent C1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R14, R15, R16, and R17 is optionally substituted by C1-6 alkyl, C1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C1-6 alkoxy carbonyl, cyano, cyano C1-6 alkyl, C1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,

—N(—R18)(—R19) wherein R18 and R19, which may be the same or different, represent a hydrogen atom; C1-6 alkyl which is optionally substituted by C1-6 alkoxy, C1-6 alkylthio, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C1-6 alkyl, C1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C1-6 alkoxy carbonyl, cyano, cyano C1-6 alkyl, C1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl, C1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C1-6 alkoxy carbonyl, cyano, cyano C1-6 alkyl, C1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or

a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl, C1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C1-6 alkoxy carbonyl, cyano, cyano C1-6 alkyl, C1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,

provided that, when X represents CH; Z represents O; L represents an oxygen atom; M represents —NH—; R1, R4, R5, R6, R7, and R8 represent a hydrogen atom; and R2 and R3 represent methoxy, R9 does not represent phenyl, ethoxy, or pyridin-2-yl.

2: The method according to claim 1, wherein R1 and R4 represent a hydrogen atom and R2 and R3 represent a group other than a hydrogen atom.

3: The method according to claim 1 or 2, wherein all of R5, R6, R7, and R8 represent a hydrogen atom, or any one or two of R5, R6, R7, and R8 represent a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

4: The method according to any one of claims 1 to 3, wherein the optionally substituted alkyl group represented by R9 represents —(CH2)p-R14, —(CH2)p-T-R15, or —(CH2)p-NR16R17 wherein p is an integer of 1 to 6 and R14, R15, R16, and R17 are as defined in claim 1.

5: The method according to any one of claims 1 to 3, wherein R18 represents a hydrogen atom or C1-6 alkyl; R19 represents C1-6 alkyl which is optionally substituted by an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group; or an optionally substituted saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group.

6: The method according to any one of claims 1 to 6, wherein X represents CH or N, Z represents O, L represents O, M represents —N(—R12)—, R1 and R4 represent a hydrogen atom, R2 represents unsubstituted C1-6 alkoxy, R3 represents optionally substituted C1-6 alkoxy, and all of R5, R6, R7, and R8 represent a hydrogen atom, or any one of R5, R6, R7, and R8 represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

7: The method according to any one of claims 1 to 6, wherein X represents CH or N, Z represents O, L represents O, M represents —C(—R10)

(—R11)—, R1 and R4 represent a hydrogen atom, R2 represents unsubstituted C1-6 alkoxy group, R3 represents optionally substituted C1-6 alkoxy, and all of R5, R6, R7, and R8 represent a hydrogen atom, or any one of R5, R6, R7, and R8 represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

8: The method according to any one of claims 1 to 6, wherein X represents CH or N, Z represents O, L represents S, M represents —N(—R12)—, R1 and R4 represent a hydrogen atom, R2 represent unsubstituted C1-6 alkoxy, R3 represents optionally substituted C1-6 alkoxy, and all of R5, R6, R7, and R8 represent a hydrogen atom, or any one of R5, R6, R7, and R8 represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.

9: The method according to claim 1, wherein the compound is represented by formula (100):

wherein

R103 represents hydroxyl or C1-4 alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C1-6 alkyl which is optionally substituted by hydroxyl or C1-6 alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl which is optionally substituted by hydroxyl or C1-6 alkoxy,

R105, R106, R107, and R108, which may be the same or different, represents a hydrogen atom, a halogen atom, C1-4 alkyl, or C1-4 alkoxy, and

R109 represents

C1-6 alkyl on which one or more hydrogen atoms are optionally substituted by —R114, -T-R115, or —NR116R117 in which T represents —O—, —S—, or —NH—; R114 represents saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R115 represents C1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R116 and R117, which may be the same or different, represent C1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R114, R115, R116, and R117 is optionally substituted by C1-6 alkyl, C1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C1-6 alkoxy carbonyl, cyano, cyano C1-6 alkyl, C1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group or

a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl, C1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C1-6 alkoxycarbonyl, cyano, cyano C1-6 alkyl, C1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-carbocyclic or heterocyclic group.

10: The method according to claim 9, wherein the optionally substituted alkyl group represented by R109 represents —(CH2)p-R114, —(CH2)p-T-R115, or —(CH2)p-NR116R117 in which p is an integer of 1 to 6, R114, R115, R116, and R117 are as defined in claim 9.

11: The method according to claim 1, wherein the compound is represented by formula (200):

wherein

R203 represents hydroxyl or C1-4 alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C1-6 alkyl which is optionally substituted by hydroxyl or C1-6 alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl which is optionally substituted by hydroxyl or C1-6 alkoxy,

R205, R206, R207, and R208, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, or C1-4 alkoxy, and

R209 represents

C1-6 alkyl on which one or more hydrogen atoms are optionally substituted by —R214, -T-R215, or —NR216R217 wherein T represents —O—, —S—, or —NH—; R214 represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R215 represents C1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; R216 and R217, which may be the same or different, represent C1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group; the three- to eight-membered carbocyclic or heterocyclic group represented by R214, R215, R216, and R217 is optionally substituted by C1-6 alkyl, C1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C1-6 alkoxy carbonyl, cyano, cyano C1-6 alkyl, C1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or

a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl, C1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C1-6 alkoxy carbonyl, cyano, cyano C1-6 alkyl, C1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

12: The method according to claim 11, wherein the optionally substituted alkyl group represented by R209 represents —(CH2)p-R214, —(CH2)p-T-R215, or —(CH2)p-NR216R217 in which p is an integer of 1 to 6, R214, R215, R216, and R217 are as defined in claim 1.

13: The method according to claim 1, wherein the compound is represented by formula (300):

wherein

R303 represents hydroxyl or C1-4 alkoxy which is optionally substituted by a halogen atom or a saturated or unsaturated six-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl which is optionally substituted by hydroxyl or C1-6 alkoxy,

R305, R306, R307, and R308, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, or C1-4 alkoxy,

R310 and R311 represent a hydrogen atom, C1-4 alkyl, or C1-4 alkoxy,

R318 represents a hydrogen atom or C1-4 alkyl,

R319 represents

C1-4 alkyl which is optionally substituted by a saturated or unsaturated six-membered carbocyclic group which is optionally substituted by C1-6 alkyl; C1-6 alkoxy; a halogen atom; nitro; trifluoromethyl; C1-6 alkoxy carbonyl; cyano; cyano C1-6 alkyl; C1-6 alkylthio; phenoxy; acetyl; or a saturated or unsaturated five- or six-membered heterocyclic ring and in which, when substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or

a saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl, C1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C1-6 alkoxy carbonyl, cyano, cyano C1-6 alkyl, C1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the four- to seven-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the four- to seven-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

14: The method according to claim 1, wherein the compound is represented by formula (400):

wherein

R405, R406, R407, and R408, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, or C1-4 alkoxy,

R419 represents an unsaturated five- or six-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl, C1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C1-6 alkoxy carbonyl, cyano, cyano C1-6 alkyl, C1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring; when the five- or six-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; and the five- or six-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group.

15: The method according to claim 1, wherein the compound is represented by formula (500):

wherein

X represents CH or N,

when L represents O and M represents —N(—R12)—, Q represents CH2 or NH,

when L represents O and M represents —C(—R10)(—R11)—, Q represents NH,

when L represents S and M represents —N(—R12)—, Q represents CH2,

R503 represents hydroxyl or C1-4 alkoxy which is optionally substituted by a halogen atom; hydroxyl; amino on which one or two hydrogen atoms are optionally substituted by C1-6 alkyl which is optionally substituted by hydroxyl or C1-6 alkoxy; or a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl which is optionally substituted by hydroxyl or C1-6 alkoxy,

R505, R506, R507, and R508, which may be the same or different, represent a hydrogen atom, a halogen atom, C1-4 alkyl, or C1-4 alkoxy, and

R520 represents a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group which is optionally substituted by C1-6 alkyl, C1-6 alkoxy, or a halogen atom.

16: The method according to claim 1, wherein said at least one compound is selected from the group consisting of: (1) N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-N′-phenylacetylthiourea; (2) N-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-N′-[2-(4-fluorophenyl)acetyl]thiourea; (3) N-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-N′-[2-(4-fluorophenyl)acetyl]urea; (4) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-phenyl-acetylurea; (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)methanamide; (10) N-(4-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (11) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; (12) 1-(3-fluoro-4-{6-methoxy-7-[4-(4-methyl-piperazin-1-yl)-butoxy]quinolin-4-yloxy}phenyl)-3-phenylacetylurea; (13) 1-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; (14) 1-{4-[7-(3-chloro-propoxy)-6-methoxyquinolin-4-yloxy]-3-fluorophenyl}-3-phenylacetylurea; (15) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2-methylmalonamide; (16) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-phenylacetylurea; (17) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-3-phenylacetylurea; (18) 1-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-phenylacetylurea; (19) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-3-(2-thiophen-3-ylacetyl)urea; (20) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-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-fluoro-phenyl]-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-fluoro-phenyl]-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-fluoro-phenyl]-3-(2-thiophen-2-ylacetyl)urea; (31) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-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-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]urea; (37) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-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-piperidine-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-piperidine-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-phenylacetylurea; (53) 1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]quinolin-4-yloxy}phenyl)-3-phenylacetylurea; (54) 1-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]phenyl}-3-phenylacetylurea; (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-fluoro-phenyl]-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-dimethoxy-quinolin-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-fluoro-phenyl]-3-(3-o-tolylpropionyl)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-methyl-phenyl]-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-fluoro-phenyl]-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-fluoro-phenyl]-3-[2-(3-fluorophenyl)acetyl]thiourea; (75) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-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-fluoro-phenyl]-3-[2-(2-fluorophenyl)acetyl]thiourea; (81) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluoro-phenyl]-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-fluoro-phenyl]-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-fluoro-phenyl]-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]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (89) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (90) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]thiourea; (91) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]thiourea; (92) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluoro-phenyl]-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-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]malonamide; (99) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-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-dimethoxy-quinolin-4-yloxy)phenyl]malonamide; (103) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2-methoxymalonamide; (104) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-4-yloxy)phenyl]-2,2-dimethylmalonamide; (105) N-(4-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (106) 1-[3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl]-3-phenylacetylurea; (107) 1-(2-chloro-benzoyl)-3-[4-(6,7-dimethoxy-quinolin-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-pentanoylurea; (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-yl acetyl)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]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; (126) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]urea; (127) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]urea; (128) 1-(2-bicyclo[2.2.1]hepto-7-ylacetyl)-3-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]urea; (129) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(2-phenylsulfanylacetyl)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-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]thiourea; (144) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-methoxybenzoyl)thiourea; (145) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-3-(3-trifluoromethyl-benzoyl)thiourea; (146) 1-(2-bromobenzoyl)-3-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]thiourea; (147) 1-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-3-(3-methylsulfanylpropionyl)thiourea; (148) 1-(4-chloro-butyryl)-3-[4-(6,7-dimethoxy-quinolin-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-phenylpropionyl)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-methylthiophen-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-dimethoxy-quinolin-4-yloxy)-2-fluorophenyl]thiourea; (167) 1-(2-butoxyacetyl)-3-[4-(6,7-dimethoxy-quinolin-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; (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-dimethoxy-quinolin-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) methyl 3-{2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenylcarbamoyl]acetylamino}benzoate; (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-dimethoxy-quinolin-4-yloxy)phenyl]malonamide; (219) N-(4-chlorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-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-dimethoxy-quinolin-4-yloxy)-2-methylphenyl]malonamide; (224) N-(2,4-difluorophenyl)-N′-[4-(6,7-dimethoxy-quinolin-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-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (230) N-(3-bromo-5-methyl-2-pyridyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (231) N-(5-chloro-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (232) N-(5-methyl-3-isoxazolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (233) N-(3-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (234) N-(6-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (235) N-(5-methyl-2-pyridyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (236) N-(2-pyridyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (237) N-(1-methyl-1H-5-pyrazolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (238) N-(2,3-dihydro-1,4-benzodioxin-6-yl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (239) N-(3-cyanophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (240) N-[2-(trifluoromethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methan-amide; (241) N-[4-(cyanomethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (242) N-(4-chloro-2-methylphenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (243) N-(2,3-dihydro-1H-5-indenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (244) N-(3-methoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (245) methyl 2-({({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)carbonyl}amino)benzoate; (246) N-(2-benzylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (247) N-(2-bromophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (248) N-(2-chlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (249) N-(4-chlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (250) N-(2-chloro-4-fluorophenyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (251) N-(3-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (252) N-(2-fluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (253) N-[2-(methylsulfanyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (254) N-(4-nitrophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (255) N-(2-phenoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (256) N-(3-methylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (257) N-(4-methylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (258) N-(2,6-dimethylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (259) N-[2-(1H-1-pyrrolyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (260) N-(8-quinolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (261) N-(3-acetylphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (262) N-(5-quinolyl)-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (263) N-(2,6-dichlorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (264) N-(3,4-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (265) N-(2,6-difluorophenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (266) N-(2-methoxyphenyl)-({[4-(6,7-dimethoxy-quinolin-4-yloxy)anilino]carbonyl}amino)methanamide; (267) N-[2-(2-hydroxyethyl)phenyl]-({[4-(6,7-dimethoxyquinolin-4-yloxy)anilino]carbonyl}amino)-methanamide; (268) N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)quinolin-4-yloxy]phenyl}-N′-phenylacetyl-thiourea; (269) N-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)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-phenylacetylthio-urea; (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-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-phenylacetylurea; (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-toluoyl-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-toluoyl-acetyl)-thiourea; (302) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea; (303) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea; (304) 1-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-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-phenylacetyl)-thiourea; (332) 1-{3-fluoro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-thiourea; (333) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-o-toluoyl-acetyl)-thiourea; (334) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-m-toluoyl-acetyl)-thiourea; (335) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-p-toluoyl-acetyl)-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; and (337) 1-{3-fluoro-4-[7-(2-hydroxy-3-morpholin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(2-phenylacetyl)-urea.

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

17-22. (canceled)

23: The method according to claim 1, wherein said malignant tumor is selected from the group consisting of gastric cancer, brain tumors, colon cancer, pancreatic cancer, lung cancer, renal cancer, ovarian cancer, and prostate cancer.