# Patent

## Title
Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor, and medicinal composition containing the same

## 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.

## Background
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 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, or —NR16R17 wherein T represents —O—, —S—, or —NH—; R19 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.
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.
C1-6 alkyl is preferably C1-4 alkyl.
C1-6 alkoxy is preferably C1-4 alkoxy.
C2-6 alkenyl is preferably C2-4 alkenyl.
C2-6 alkynyl is preferably C2-4 alkynyl.
Examples of C1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.
Examples of C1-6 alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.
Examples of C2-6 alkenyl include allyl, butenyl, pentenyl, and hexenyl.
Examples of C2-6 alkynyl 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 C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, preferably a C1-3 alkylene chain. Carbocyclic or heterocyclic groups having this crosslinked structure include bicyclo[2.2.2]octanyl and norbornanyl.
R1 preferably represents a hydrogen atom.
R2 and R3 preferably represents a group other than a hydrogen atom. More preferably, R2 represents unsaturated C1-6 alkoxy, still further preferably methoxy, and R3 represents optionally substituted C1-6 alkoxy.
The substituent of substituted C1-6 alkoxy, which may be represented by R3, is preferably a halogen atom, hydroxyl, amino optionally mono- or disubstituted by optionally substituted C1-6 alkyl, 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 C1-6 alkyl, phenyl, piperazinyl, piperazino, piperidyl, piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, azepanyl, imidazolyl, diazepanyl, and pyrrolidyl.
Optionally substituted alkoxy represented by R3 preferably represents —O—(CH2)m—R13 wherein m is an integer of 1 to 6, R13 is a substituent of the alkoxy group, that is, hydroxyl, a halogen atom, C1-6 alkoxy, C1-6 alkylcarbonyl, C1-6 alkoxy 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 R8 represent a hydrogen atom, or alternatively 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.
Carbocylic group represented by R9, R14, R15, R16, R17, R18, and R19 and R109, R114, R115, R116, R117, R118, R119, R209, R214, 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 R19 and 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 R9 preferably 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 above.
In (—R18)(—R19) represented by R9, preferably, R18 represents a hydrogen atom or C1-6 alkyl, and R18 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.
Preferred examples of R9 include benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, anilino, fluoroanilino, difluoroanilino, chloroanilino, methylanilino, methoxyanilino, naphthyl, thienyl-2-yl-methyl, and thienyl-3-yl-methyl.
Both R10 and R11 preferably represent a hydrogen atom or alkyl, or alternatively any one of R10 and R11 represents alkoxy with the other group representing a hydrogen atom.
R12 preferably 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 (—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 alternatively 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,
compounds of formula (I) 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 alkoxy, R3 represents optionally substituted C1-6 alkoxy, and all of R5, R6, R7, and R8 represent a hydrogen atom or alternatively 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, and
compounds of formula (I) wherein X represents CH or N, Z represents O, L represents S, M represents —N(—R12)—, R1 and R4 represent a hydrogen atom, R2 represents unsubstituted C1-6 alkoxy, R3 represents optionally substituted C1-6 alkoxy, all of R5, R6, R7, and R8 represent a hydrogen atom or alternatively 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.
Examples of preferred compounds according to the present invention include compounds 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.
Preferably, all of R105, R106, R107 and R108 represent a hydrogen atom or alternatively any one of R105, R106, R107 and R108 represents 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 R109 preferably represents —(CH2)p-R114, wherein p is an —(CH2)p-T-R115, or —(CH2)p-NR116R117 integer of 1 to 6 and R114, R115, R116, and R117 are as defined above.
In —N(—R118)(—R119) represented by R109, preferably, R118 represents a hydrogen atom or C1-6 alkyl, and R119 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.
Preferred examples of R109 include benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, naphthyl, and thienyl.
Examples of preferred compounds according to the present invention include compounds of formula (200):




wherein

R203 represents hydroxyl or C1-2 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.
Preferably, all of R205, R206, R207, and R208 represent a hydrogen atom, or alternatively any one of R205, R206, R207, and R208 represents 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 R209 represents —(CH2)p-R214, —(CH2)p-T-R215, or —(CH2)p-NR216R217 wherein p is an integer of 1 to 6, R214, R215, R216, and R217 are as defined above.
In —N(—R218)(—R219) represented by R209, preferably, R218 represents a hydrogen atom or C1-6 alkyl, and R219 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.
Preferred examples of R209 include benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, methylbenzyl, and methoxybenzyl.
Examples of preferred compounds according to the present invention include compounds 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.
Preferably, all of R305, R306, R307, and R308 represent a hydrogen atom, or alternatively any one of R305, R306 R307, and R308 represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.
Preferred examples of R319 include 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, 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.
Preferably, all of R405, R406, R407 and R408 represent a hydrogen atom, or alternatively any one of R405, R406, R407 and R408 represents a group other than a hydrogen atom with all the remaining groups representing a hydrogen atom.
Preferred examples of R419 include 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 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.
Preferably, all of R505, R506, R507, and R508 represent a hydrogen atom, or alternatively any one of R505, R506, R507, and R508 represents 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]-N1-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) (4-hydroxymethyl-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; R51 and R52, which may be the same or different, represent optionally substituted C1-6 alkyl, or alternatively R51 and R52 may 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′-hydroxybenzoic 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 13] (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-phenylacetylurea [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-phenylacetylurea [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.

Starting


No.
Compound structure
compound A





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Ex. No.
Starting compound B
Starting compound C
Mass spectrometric value (m/z)
H1-MNR
Synthesis methoda






 16





476 [M + H]+
(CDCl3, 400 MHz): δ 3.75 (s, 2H), 4.01 (s, 3H), 4.02 (s, 3H), 6.49 (d, J = 5.3 Hz, 1)H, 6.95-7.00 (m, 2H), 7.28-7.48 (m, 5H), 7.41 (s, 1H), 7.50 (s, 1H), 8.01 (s, 1H), 8.18 (t, J = 9.1 Hz, 1H), 8.49 (d, J = 5.3 Hz, 1H), 10.74 (s, 1H)
Ex. 4  


 



 17





476 [M + H]+
(CDCl3, 400 MHz): δ 3.75 (s, 2H), 4.03 (s, 3H), 4.04 (s, 3H), 6.38 (d, J = 5.3 Hz, 1H), 6.97-7.42 (m, 7H), 7.40 (s, 1H), 7.55 (s, 1H), 7.65-7.68 (m, 1H), 8.09 (s, 1H), 8.46 (d, J = 5.3 Hz, 1H), 10.60 (s, 1H)
Ex. 4  


 



 18





492 [M + H]+
(CDCl3, 400 MHz): δ 3.75 (s, 2H), 4.03 (s, 3H), 4.04 (s, 3H), 6.29 (d, J = 5.3 Hz, 1H), 7.17-7.43 (m, 7H), 7.41 (s, 1H), 7.56 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 8.07 (br, 1H), 8.45 (d, J = 5.3 Hz, 1H), 10.62 (s, 1H)
Ex. 4  


 



 19





482 [M + H]+
(DMSO-d6, 400 MHz): δ 11.23 (br, 1H), 10.75 (br, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.22 (m, 1H), 7.52-7.37 (m, 3H), 7.23 (m, 1H), 7.10-7.02 (m, 2H), 6.87- 6.85 (m, 1H), 6.56 (d, J = 5.4 Hz, 1H), 3.94 (s, 6H), 3.77 (s, 2H)
Ex. 3  


 



 20





482 [M + H]+
(DMSO-d6, 400 MHz): δ 11.00 (br, 1H), 10.63 (br, 1H), 8.48 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 14.15 Hz, 1H), 7.52- 7.38 (m, 5H), 7.23 (m, 1H), 7.02 (d, J = 6.1 Hz, 1H), 6.45 (d, J = 5.4 Hz, 1H), 3.95 (s, 6H), 3.77 (s, 2H)
Ex. 3  


 



 21





498 [M + H]+
(DMSO-d6, 400 MHz): δ 10.63 (br, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.01 (s, 1H), 7.59-7.38 (m, 5H), 7.23 (s, 1H), 7.09 (d, J = 4.8 Hz, 1H), 7.02 (d, J = 4.8 Hz, 1H), 6.35 (d, J = 5.4 Hz, 1H), 3.94 (s, 6H), 3.77 (s, 2H)
Ex. 3  


 



 22





476 [M + H]+
(DMSO-d6, 400 MHz): δ 10.96 (br, 1H), 10.50 (br, 1H), 8.31 (d, J = 5.4 Hz, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.38- 7.08 (m, 8H), 6.45 (d, J = 5.1 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.74 (s, 2H)
Ex. 3  


 



 23





494 [M + H]+
(DMSO-d6, 400 MHz): δ 11.03 (br, 1H), 10.61 (br, 1H), 8.47 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 14.1 Hz, 1H), 7.52 (s, 1H), 7.42-7.08 (m, 6H), 6.85 (br, 1H), 6.44 (d, J = 4.9 Hz, 1H), 3.94 (s, 6H), 3.75 (s, 2H)
Ex. 3  


 



 24





510 [M + H]+
(DMSO-d6, 400 MHz): δ 11.08 (br, 1H), 10.62 (br, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.59- 7.57 (m, 1H), 7.52 (br, 1H), 7.42-7.09 (m, 5H), 6.87 (br, 1H), 6.34 (d, J = 5.1 Hz, 1H), 3.93 (s, 6H), 3.75 (s, 2H)
Ex. 3  


 



 25





498 [M + Na]+
(CDCl3, 400 MHz): δ 3.79 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.47 (d, J = 5.1 Hz, 1H), 7.13-7.42 (m, 6H), 7.46 (s, 1H), 7.55 (s, 1H), 7.60 (d, J = 9.0 Hz, 2H), 7.73 (s, 1H), 8.48 (d, J = 5.4 Hz, 1H), 10.47 (s, 1H)
Ex. 3  


 



 26





516 [M + Na]+
(CDCl3, 400 MHz): δ 3.80 (s, 2H), 4.04 (s, 3H), 4.06 (s, 3H), 6.52 (d, J = 5.4 Hz, 1H), 6.96-7.02 (m, 2H), 7.13-7.42 (m, 4H), 7.46 (s, 1H), 7.49 (s, 1H), 7.76 (s, 1H), 8.20-8.26 (m, 1H), 8.51 (d, J = 5.4 Hz, 1H), 10.68 (s, 1H)
Ex. 3  


 



 27





494 [M + H]+
(DMSO-d6, 400 MHz): δ 10.62 (br, 1H), 8.48 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 13.9 Hz, 1H), 7.52-7.11 (m, 8H), 6.93 (br, 1H), 6.45 (d, J = 5.1 Hz, 1H), 3.85 (s, 2H), 3.44 (s, 6H)
Ex. 3  


 



 28





532 [M + Na]+
(CDCl3, 400 MHz): δ 3.79 (s, 2H), 4.06 (s, 3H), 4.07 (s, 3H), 6.34 (d, J = 5.4 Hz, 1H), 7.14-7.54 (m, 7H), 7.59 (s, 1H), 7.70 (s, 1H), 7.84 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 5.4 Hz, 1H), 10.55 (s, 1H)
Ex. 3  


 














 29





464 [M + H]+
(DMSO-d6, 400 MHz): δ 10.97 (br, 1H), 10.47 (br, 1H), 8.47 (d, J = 5.4 Hz, 1H), 7.67-7.65 (m, 2H), 7.50 (s, 1H), 7.44 (d,J = 6.6 Hz, 1H), 7.39 (s, 1H), 7.25-7.23 (m, 2H), 7.01-6.99 (m, 2H), 6.46 (d, J = 5.4 Hz, 1H), 4.00 (s, 2H), 3.98 (s, 6H)
Ex. 3  


 



 30





482 [M + H]+
(DMSO-d6, 400 MHz): δ 11.17 (br, 1H), 10.69 (br, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.23-8.19 (m, 1H), 7.47-7.33 (m, 3H), 7.14 (d, J = 8.8 Hz, 1H), 7.02- 6.89 (m, 3H), 6.55 (d, J = 5.1 Hz, 1H), 3.98 (s, 2H), 3.92 (s, 6H)
Ex. 3  


 



 31





482 [M + H]+
(DMSO-d6, 400 MHz): δ 8.48 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 13.4 Hz, 1H), 7.53-7.33 (m, 4H), 7.01-6.89 (m, 5H), 6.45 (d, J = 5.1 Hz, 1H), 3.97 (s, 2H), 3.95 (s, 6H)
Ex. 3  


 



 32





498 [M + H]+
(DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.54 (br, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.00 (s, 1H), 7.61-7.59 (m, 1H), 7.53 (s, 1H), 7.45-7.33 (m, 3H), 7.01- 6.89 (m, 2H), 6.35 (d, J = 5.1 Hz, 1H), 3.99 (s, 2H), 3.94 (s, 6H)
Ex. 3  


 



 33





512 [M + H]+
(CDCl3, 400 MHz): δ 3.74 (s, 2H), 4.01 (s, 3H), 4.03 (s, 3H), 6.49 (d, J = 5.3 Hz, 1H), 6.86-6.99 (m, 4H), 7.21-7.32 (m, 1H), 7.41 (s, 1H), 7.47 (s, 1H), 8.15 (br, 1H), 8.20 (t, J = 9.5 Hz, 1H), 8.49 (d, J = 5.3 Hz,1H), 10.63 (s, 1H)
Ex. 3  


 



 34





512 [M + H]+
(CDCl3, 400 MHz): δ 3.74 (s, 2H), 4.02 (s, 3H), 4.04 (s, 3H), 6.39 (d, J = 5.3 Hz, 1H), 6.88-7.69 (m, 6H), 7.24 (s, 1H), 7.55 (s, 1H), 8.29 (br, 1H), 8.48 (d, J = 5.3 Hz, 1H), 10.56 (s, 1H)
Ex. 3  


 



 35





512 [M + H]+
(CDCl3, 400 MHz): δ 3.73 (s, 2H), 4.06 (s, 6H), 6.42 (d, J = 5.1 Hz, 1H), 7.03-7.08 (m, 1H), 7.14-7.26 (m, 4H), 7.49 (br, 1H), 7.58 (s, 1H), 7.67-7.72 (m, 1H), 8.13 (br, 1H), 8.51 (d, J =  5.1 Hz, 1H), 10.56 (s, 1H)
Ex. 3  


 



 36





494 [M + H]+
(CDCl3, 400 MHz): δ 3.74 (s, 2H), 4.01 (s, 3H), 4.03 (s, 3H), 6.50 (d, J = 5.3 Hz, 1H), 6.51-7.10 (m, 5H), 7.31-7.35 (m, 1H), 7.42 (s, 1H), 7.47 (s, 1H), 8.18 (t, J = 9.5 Hz, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.89 (s, 1H), 10.74 (s, 1H)
Ex. 3  


 



 37





494 [M + H]+
(CDCl3, 400 MHz): δ 3.74 (s, 2H), 4.03 (s, 3H), 4.04 (s, 3H), 6.39 (d, J = 5.3 Hz, 1H), 7.02-7.68 (m, 7H), 7.41 (s, 1H), 7.55 (s, 1H), 8.26 (s, 1H), 8.47 (d, J = 5.3 Hz, 1H), 10.60 (s, 1H)
Ex. 3  


 



 38





506 [M + H]+
(DMSO-d6, 400 MHz): δ 10.98 (br, 1H), 10.84 (br, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.38-7.04 (m, 6H), 6.84-6.82 (m, 1H), 6.49 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.72 (s, 2H)
Ex. 3  


 



 39





516 [M + Na]+
(CDCl3, 400 MHz): δ 3.72 (s, 2H), 4.04 (s, 3H), 4.05 (s, 3H), 6.47 (d, J = 5.4 Hz, 1H), 7.03-7.09 (m, 1H), 7.15-7.23 (m, 4H), 7.44 (s, 1H), 7.54 (s, 1H), 7.60 (d, J = 9.0 Hz, 2H), 8.49 (d, J = 5.4 Hz, 1H), 8.67 (s, 1H), 10.51 (s, 1H)
Ex. 3  


 



 40





570 [M + H]+
(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)
Ex. 3b 


 



 41








621 [M + H]+
(DMSO-d6, 400 MHz): δ 11.03 (br, 1H), 10.60 (br, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.80 (d, J = 13.6 Hz, 1H), 7.51- 7.07 (m, 5H), 6.85 (br, 3H), 6.43 (d, J = 5.1 Hz, 1H), 4.18-4.16 (m, 2H), 3.95 (s, 3H), 3.58-3.56 (m, 3H), 2.89 (s, 2H), 2.73 (s, 2H), 2.36 (s, 5H), 1.84 (m, 2H), 1.63 (m, 2H)
Ex. 12 


 



 42








619 [M + H]+
(DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.62 (br, 1H), 8.46 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 13.4 Hz, 1H), 7.53 (s, 1H), 7.41-7.33 (m, 5H), 7.19-7.14 (m, 2H), 6.44 (d, J = 5.1 Hz, 1H), 4.19 (m, 2H), 3.95 (s, 2H), 3.75 (s, 2H), 3.29-3.27 (m, 3H), 2.50-2.49 (m, 2H), 1.90-1.85 (m, 3H), 1.69 (m, 9H)
Ex. 12 


 



 43








634 [M + H]+
(DMSO-d6, 400 MHz): δ 11.03 (br, 1H), 10.61 (br, 1H), 8.45 (d, J = 3.9 Hz, 1H), 7.81 (d, J = 13.4 Hz, 1H), 7.50 (s, 1H), 7.41-7.34 (m, 5H), 7.18-7.14 (m, 2H), 6.42 (d, J = 8.1 Hz, 1H), 4.18-4.15 (m, 2H), 3.94 (s, 3H), 3.74 (s, 2H), 3.29-3.28 (m, 4H), 2.50-2.49 (m, 4H), 2.36 (br, 2H), 2.18-2.17 (m, 3H), 1.83 (m, 2H), 1.61 (m, 2H)
Ex. 12 


 



 44








621 [M + H]+
(DMSO-d6, 400 MHz): δ 11.16 (br, 1H), 10.75 (br, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.22 (m, 1H), 7.95 (s, 1H), 7.46- 7.08 (m, 3H), 6.86 (br, 4H), 6.55 (d, J = 5.4 Hz, 1H), 4.19-4.17 (m, 2H), 3.92 (s, 4H), 3.75 (s, 2H), 3.57 (br, 4H), 2.49 (br, 5H), 1.84 (m, 2H), 1.62 (m, 2H)
Ex. 12 


 



 45








619 [M + H]+
(DMSO-d6, 400 MHz): δ 11.16 (br, 1H), 10.76 (br, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.25-8.20 (m, 1H), 7.48 (s, 1H), 7.42-7.34 (m, 4H), 7.19-7.10 (m, 3H), 6.56 (d, J = 5.4 Hz, 1H), 4.19 (br, 2H), 3.93 (s, 3H), 3.75 (s, 2H), 3.34- 3.28 (m, 6H), 2.50-2.49 (m, 5H), 1.91- 1.85 (m, 5H)
Ex. 12 


 



 46








607 [M + H]+
(DMSO-d6, 400 MHz): δ 11.21 (br, 1H), 10.54 (br, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.81 (d, J = 13.5 Hz, 1H), 7.48- 7.06 (m, 5H), 6.51 (br, 3H), 6.31 (d, J = 5.1 Hz, 1H), 4.18-4.13 (m, 2H), 3.94 (s, 3H), 3.57-3.50 (m, 3H), 2.89 (s, 2H), 2.73 (s, 2H), 2.36 (br, 3H), 1.81 (m, 2H), 1.61 (m, 2H)
Ex. 11 


 



 47








605 [M + H]+
(DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.62 (br, 1H), 8.48 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 13.2 Hz, 1H), 7.55 (s, 1H), 7.45-7.35 (m, 5H), 7.19-7.15 (m, 2H), 6.46 (d, J = 5.4 Hz, 1H), 4.18 (br, 2H), 3.96 (s, 3H), 3.75 (s, 3H), 3.51 (br, 1H), 3.29 (m, 5H), 2.50-2.49 (m, 4H), 2.26 (m, 2H), 1.83 (m, 1H), 1.70 (m, 1H)
Ex. 11 


 



 48








591 [M + H]+
(DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.62 (br, 1H), 8.48 (d, J = 5.1 Hz, 1H), 7.81 (d, J = 14.2 Hz, 1H), 7.55 (s, 1H), 7.48-7.34 (m, 5H), 7.18-7.14 (m, 2H), 6.45 (d, J = 4.9 Hz, 1H), 3.96 (s, 3H), 3.75 (s, 2H), 2.50-2.49 (m, 7H), 1.91-1.23 (m, 7H)
Ex. 13 


 



 49








606 [M + H]+
(DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.61 (br, 1H), 8.46 (d, J = 5.4 Hz, 1H), 7.80 (d, J = 13.6 Hz, 1H), 7.52 (s, 1H), 7.43-7.35 (m, 5H), 7.18-7.14 (m, 2H), 6.43 (d, J = 5.1 Hz, 1H), 4.27 (br, 2H), 3.94 (s, 3H), 3.74 (s, 2H), 2.89-2.38 (m, 8H), 1.27-1.39 (m, 5H)
Ex. 13 


 



 50








605 [M + H]+
(DMSO-d6, 400 MHz): δ 11.16 (br, 1H), 10.77 (br, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.23 (m, 1H), 7.50-7.17 (m, 8H), 6.95 (d, J = 5.3 Hz, 1H), 4.26 (br, 2H), 3.93 (s, 4H), 3.75 (br, 2H), 3.50 (m, 1H), 3.29 (m, 3H), 2.94 (m, 1H), 2.67 (s, 1H), 2.49 (m, 3H), 2.32-2.25 (m, 2H), 1.83 (m, 1H), 1.69 (m, 1H)
Ex. 11 


 



 51








620 [M + H]+
(DMSO-d6, 400 MHz): δ 11.10 (br, 1H), 10.76 (br, 1H), 8.50 (d, J = 5.1 Hz, 1H), 8.23 (m, 1H), 7.50-7.14 (m, 8H), 6.93 (d, J = 5.1 Hz, 1H), 4.22 (br, 2H), 3.94 (s, 3H), 3.75 (s, 2H), 3.29 (m, 6H), 2.67 (s, 1H), 2.52-2.49 (m, 7H), 2.32 (s, 1H)
Ex. 11 


 



 52








587 [M + H]+
(DMSO-d6, 400 MHz): δ 11.05 (br, 1H), 10.63 (br, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.81 (d, J = 13.9 Hz, 1H), 7.53 (s, 3H), 7.43-7.27 (m, 8H), 6.44 (d, J = 5.1 Hz, 1H), 4.23 (m, 1H), 3.95 (s, 1H), 3.74 (s, 2H), 3.28-3.26 (m, 4H), 2.89 (s, 1H), 2.73 (s, 1H), 2.50-2.48 (m, 5H), 1.67-1.23 (m, 4H)
Ex. 11 


 



 53








602 [M + H]+
(DMSO-d6, 400 MHz): δ 11.04 (br, 1H), 10.63 (br, 1H), 8.45 (d, J = 5.4 Hz, 1H), 7.95 (d, J = 11.2 Hz, 1H), 7.80 (d, J = 13.9 Hz, 1H), 7.50 (s, 1H), 7.39-7.28 (m, 5H), 6.41 (d, J = 5.1 Hz, 1H), 4.19-4.16 (m, 2H), 3.94 (s, 3H), 3.74 (s, 2H), 3.36-3.27 (m, 7H), 2.89 (s, 1H), 2.73 (s, 1H), 2.32-2.19 (m, 6H), 1.98-1.95 (m, 2H)
Ex. 11 


 



 54








575 [M + H]+
(DMSO-d6, 400 MHz): δ 11.12 (br, 1H), 10.51 (br, 1H), 8.45 (d, J = 5.3 Hz, 1H), 7.80 (d, J = 13.9 Hz, 1H), 7.52 (s, 1H), 7.43-7.28 (m, 8H), 6.41 (d, J = 5.3 Hz, 1H), 4.29 (br, 2H), 3.94 (s, 3H), 3.89 (s, 2H), 3.61-3.56 (m, 4H), 2.52-2.49 (m, 6H)
Ex. 13 


 



 55








593 [M + H]+
(DMSO-d6, 400 MHz): δ 11.10 (br, 1H), 10.75 (br, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.21 (m, 1H), 7.53-7.09 (m, 8H), 6.44 (d, J = 5.3 Hz, 1H), 4.28 (br, 2H), 3.94 (s, 3H), 3.88 (s, 2H), 3.60- 3.51 (m, 4H), 3.25-3.24 (m, 2H), 2.51- 2.48 (m, 4H)
Ex. 13 


 



 56





510 [M + H]+
(DMSO-d6, 400 MHz): δ 12.69 (br, 1H), 12.04 (br, 1H), 8.72 (d, J = 5.9 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 7.1 Hz, 1H), 7.68-7.61 (m, 4H), 7.48-7.43 (m, 4H), 6.79 (d, J = 5.9 Hz, 1H), 4.00 (s, 6H)
Ex. 2  


 



 57





528 [M + H]+
(DMSO-d6, 400 MHz): δ 12.54 (br, 1H), 12.21 (br, 1H), 8.57 (d, J = 5.4 Hz, 1H), 8.23-8.14 (m, 3H), 8.05 (d, J =  7.6 Hz, 1H), 7.86 (d, J = 6.1 Hz, 1H), 7.69-7.52 (m, 3H), 7.48-7.41 (m, 3H), 7.19 (m, 1H), 6.69 (d, J = 5.1 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H)
Ex. 2  


 



 58





492 [M + H]+
(DMSO-d6, 400 MHz): δ 12.26 (br, 1H), 11.89 (br, 1H), 8.55 (d, J = 5.1 Hz, 1H), 8.05 (t, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.29-7.36 (m, 6H), 7.13 (d, J = 9.5 Hz, 1H), 6.64 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.83 (s, 2H)
Ex. 1  


 



 59





508 [M + H]+
(DMSO-d6, 400 MHz): δ 3.92 (s, 3H), 3.95 (s, 3H), 4.04 (s, 2H), 6.54 (d, J = 5.1 Hz, 1H), 7.27-7.50 (m, 7H), 7.74- 7.79 (m, 2H), 8.31 (s, 1H), 8.51 (d, J = 5.1 Hz, 1H), 11.80-11.83 (br, 1H)
Ex. 2  


 



 60





474 [M + H]+
(DMSO-d6, 400 MHz): δ 12.47 (br, 1H), 11.81 (br, 1H), 8.14-8.16 (m, 1H), 7.69 (m, 1H), 7.51 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.25-7.35 (m, 7H), 6.51 (d, J = 6.1 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.82 (s, 2H)
Ex. 1  


 



 61





480 [M + H]+
(DMSO-d6, 400 MHz): δ 12.41 (br, 1H), 11.48 (br, 1H), 8.63 (m, 1H), 7.81-7.84 (m, 2H), 7.59 (s, 1H), 7.44 (s, 1H), 7.34-7.36 (m, 2H), 6.67 (m, 1H), 3.95 (s, 6H), 2.37 (d, J = 6.8 Hz, 2H), 1.69 (m, 3H), 1.19-1.25 (m, 6H), 0.86-1.00 (m, 2H)
Ex. 2  


 



 62





456 [M + H]+
(DMSO-d6, 400 MHz): δ 12.48 (br, 1H), 10.09 (br, 1H), 8.54 (d, J = 6.3 Hz, 1H), 8.09 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.26-7.25 (m, 3H), 6.74 (d, J = 6.1 Hz, 1H), 4.22 (s, 3H), 4.16 (s, 3H), 3.79-3.77 (m, 2H), 3.66- 3.62 (m, 2H), 2.65-2.64 (m, 2H), 1.23- 1.18 (m, 3H)
Ex. 2  


 



 63





508 [M + H]+
(CDCl3, 400 MHz): δ 3.76 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.39 (d, J = 5.1 Hz, 1H), 7.23-7.47 (m, 6H), 7.51 (s, 1H), 7.57 (s, 1H), 7.61-7.64 (m, 1H), 8.00 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 5.4 Hz, 1H)
Ex. 1  


 



 64





520 [M + H]+
(DMSO-d6, 400 MHz): δ 12.62 (br, 1H), 11.64 (br, 1H), 8.51 (d, J = 5.4 Hz, 1H), 8.64 (d, J = 11.5 Hz, 1H), 7.57- 7.42 (m, 4H), 7.16-7.13 (m, 4H), 6.51 (d, J = 5.4 Hz, 1H), 3.96 (s, 8H), 2.91-2.88 (m, 1H), 2.79-7.75 (m, 1H), 2.31 (s, 3H)
Ex. 2  


 



 65





508 [M + H]+
(DMSO-d6, 400 MHz): δ 12.37 (br, 1H), 11.89 (br, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.37-7.23 (m, 6H), 6.63 (d, J = 5.1 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.84 (s, 2H)
Ex. 1  


 



 66





480 [M + H]+
(DMSO-d6, 400 MHz): δ 12.4 (br, 1H), 11.69 (br, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.49-7.00 (m, 9H), 6.56 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.84 (s, 2H)
Ex. 2  


 



 67





488 [M + H]+
(DMSO-d6, 400 MHz): δ 12.42 (br, 1H), 11.73 (br, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.30 (s, 1H), 7.66-7.63 (m, 2H), 7.55 (s, 1H), 7.39 (s, 1H), 7.35-7.19 (m, 8H), 6.34 (d, J = 5.4 Hz, 1H), 3.94 (s, 6H), 3.82 (s, 2H)
Ex. 1  


 



 68





504 [M + H]+
(DMSO-d6, 400 MHz): δ 11.76 (br, 1H), 10.95 (br, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.30 (s, 1H), 7.63 (s, 2H), 7.51 (s, 1H), 7.38-7.22 (m, 6H), 6.31 (d, J = 5.4 Hz, 1H), 3.94 (s, 3H), 3.82 (s, 6H), 3.69 (s, 2H)
Ex. 1  


 



 69





504 [M + H]+
(DMSO-d6, 400 MHz): δ 12.71 (br, 1H), 11.71 (br, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 7.38-7.11 (m, 5H), 7.03 (s, 1H), 6.87 (d, J = 11.5 Hz, 1H), 6.57 (d, J = 5.1 Hz, 1H), 3.95 (s, 9H), 3.83 (s, 2H)
Ex. 1  


 



 70





543 [M + H]+
(DMSO-d6, 400 MHz): δ 12.43 (br, 1H), 11.89 (br, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.07 (s, 2H), 7.55 (s, 1H), 7.42 (s, 1H), 7.35-7.28 (m, 5H), 6.33 (d, J = 5.3 Hz, 1H), 3.95 (s, 6H), 3.83 (s, 2H)
Ex. 1  


 



 71





492 [M + H]+
(DMSO-d6, 400 MHz): δ 12.39 (br, 1H), 11.73 (br, 1H), 8.53 (d, J = 5.4 Hz, 1H), 7.75 (d, J = 9.0 Hz, 2H), 7.51 (s, 1H), 7.41-7.16 (m, 7H), 6.56 (d, J = 5.4 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.83 (s, 2H)
Ex. 2  


 



 72





510 [M + H]+
(DMSO-d6, 400 MHz): δ 12.22 (br, 1H), 11.89 (br, 1H), 8.58 (d, J = 5.4 Hz, 1H), 8.04 (t, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.43-7.11 (m, 7H), 6.68 (d, J = 5.4 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.57 (s, 2H)
Ex. 2  


 



 73





527 [M + H]+
(DMSO-d6, 400 MHz): δ 12.43 (br, 1H), 11.83 (br, 1H), 8.61 (d,J = 5.6 Hz, 1H), 8.15 (s, 1H), 7.73-7.70 (m, 1H), 7.60 (s, 1H), 7.53-7.10 (m, 6H), 6.55 (d, J = 5.1 Hz, 1H), 3.97 (s, 6H), 3.84 (s, 2H)
Ex. 2  


 



 74





510 [M + H]+
(DMSO-d6, 400 MHz): δ 3.88 (s, 2H), 3.91 (s, 3H), 3.95 (s, 3H), 6.64 (d, J = 5.1 Hz, 1H), 7.12-7.22 (m, 4H), 7.35-7.37 (m, 4H), 7.99-8.04 (m, 1H), 8.55 (d, J = 5.3 Hz, 1H), 11.90 (s, 1H), 12.18 (s, 1H)
Ex. 2  


 



 75





510 [M + H]+
(DMSO-d6, 400 MHz): δ 3.87 (s, 2H), 3.94 (s, 3H), 3.95 (s, 3H), 6.49 (d, J = 4.9 Hz, 1H), 7.08-7.23 (m, 3H), 7.34- 7.56 (m, 5H), 8.00-8.03 (m, 1H), 8.50 (d, J = 5.1 Hz, 1H), 11.82 (s, 1H), 12.44 (s, 1H)
Ex. 2  


 



 76





526 [M + H]+
(DMSO-d6, 400 MHz): δ 3.87 (s, 2H), 3.93 (s, 3H), 3.95 (s, 3H), 6.40 (d, J = 5.4 Hz, 1H), 7.09-7.24 (m, 3H), 7.35- 7.54 (m, 4H), 7.65-7.71 (m, 1H), 8.09- 8.13 (m, 1 Hz, 1H), 8.50 (d, J = 5.4 Hz, 1H), 11.82 (s, 1H), 12.38 (s, 1H)
Ex. 2  


 



 77





488 [M + H]+
(DMSO-d6, 400 MHz): δ 2.31 (s, 3H), 3.78 (s, 2H), 3.93 (s, 3H), 3.95 (s, 3H), 6.39 (d, J = 5.1 Hz, 1H), 7.05- 7.27 (m, 5H), 7.41 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.67 (dd, J = 2,4 8.5 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 11.79 (s, 1H), 12.44 (s, 1H)
Ex. 2  


 



 78





522 [M + H]+
(DMSO-d6, 400 MHz): δ 2.30 (s, 3H), 3.77 (s, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 6.53 (d, J = 5.1 Hz, 1H), 7.08- 7.31 (m, 5H), 7.40 (s, 1H), 7.48 (s, 1H), 7.74 (d, J = 8.7 Hz, 2H), 8.49 (d, J = 5.1 Hz, 1H), 11.71 (s, 1H), 12.42 (s, 1H)
Ex. 2  


 



 79





488 [M + H]+
(DMSO-d6, 400 MHz): δ 2.29 (s, 3H), 3.89 (s, 2H), 4.02 (s, 3H), 4.04 (s, 3H), 6.87 (d, J = 6.6 Hz, 1H), 7.12- 7.30 (m, 4H), 7.44 (d, J = 9.0 Hz, 2H), 7.51 (s, 1H), 7.74 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 8.12 (d, J = 6.4 Hz, 1H), 11.77 (s, 1H), 12.49 (s, 1H)
Ex. 2  


 



 80





510 [M + H]+
(DMSO-d6, 400 MHz): δ 12.45 (br, 1H), 11.87 (br, 1H), 8.56 (d, J = 5.6 Hz, 1H), 8.05-8.02 (m, 1H), 7.56-7.18 (m, 8H), 6.57 (d, J = 5.4 Hz, 1H), 3.96 (s, 8H)
Ex. 2  


 



 81





510 [M + H]+
(DMSO-d6, 400 MHz): δ 12.19 (br, 1H), 11.95 (br, 1H), 8.62 (d, J = 5.6 Hz, 1H), 8.07-8.05 (m, 1H), 7.51 (s, 1H), 7.43-7.18 (m, 7H), 6.72 (d, J = 5.4 Hz, 1H), 3.97 (s, 8H)
Ex. 2  


 














 82





522 [M + H]+
(DMSO-d6, 400 MHz): δ 2.29 (s, 3H), 3.77 (s, 2H), 3.93 (s, 3H), 3.95 (s, 3H), 6.39 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.41 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.66 (dd, J = 2.7, 9.0 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 11.78 (s, 1H), 12.44 (s, 1H)
Ex. 2  


 



 83





522 [M + H]+
(DMSO-d6, 400 MHz): δ 3.79 (s, 3H), 3.81 (s, 2H), 3.94 (s, 3H), 3.95 (s, 3H), 6.49 (d, J = 5.1 Hz, 1H), 6.88- 7.03 (m, 2H), 7.20-7.32 (m, 2H), 7.41 (s, 1H), 7.44-7.58 (m, 3H), 8.05 (d, J = 12.4 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 11.71 (s, 1H), 12.55 (s, 1H)
Ex. 2  


 



 84





506 [M + H]+
(CDCl3, 400 MHz): δ 2.36 (s, 3H), 3.77 (s, 2H), 4.05 (s, 6H), 6.46 (d, J = 5.1 Hz, 1H), 7.22-7.34 (m, 5H), 7.41 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.55 (s, 1H), 7.95 (dd, J = 2.4, 11.7 Hz, 1H), 8.37 (s, 1H), 8.51 (d, J = 5.4 Hz, 1H), 12.50 (s, 1H)
Ex. 2  


 



 85





498 [M + H]+
(DMSO-d6, 400 MHz): δ 12.50 (br, 1H), 11.78 (br, 1H), 8.56 (d, J = 5.1 Hz, 1H), 7.56-7.28 (m, 3H), 7.11-7.00 (m, 5H), 6.57 (m, 1H), 3.95 (s, 6H), 3.84 (s, 2H)
Ex. 2  


 



 86





510 [M + H]+
(DMSO-d6, 400 MHz): δ 12.71 (br, 1H), 11.67 (br, 1H), 8.64 (d, J = 5.1 Hz, 1H), 8.52-8.48 (m, 1H), 7.52-7.40 (m, 4H), 7.12-7.04 (m, 3H), 6.59 (d, J = 5.1 Hz, 1H), 3.95 (s, 6H), 3.85 (s, 5H)
Ex. 2  


 



 87





527 [M + H]+
(DMSO-d6, 400 MHz): δ 12.45 (br, 1H), 11.91 (br, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.05-8.03 (m, 1H), 7.54-7.33 (m, 8H), 6.56-6.54 (m, 1H), 4.04 (s, 2H), 3.95 (s, 6H)
Ex. 2  


 



 88





492 [M + H]+
(DMSO-d6, 400 MHz): δ 12.57 (br, 1H), 11.45 (br, 1H), 8.52 (d, J = 5.1 Hz, 1H), 7.79-7.76 (m, 2H), 7.57 (s, 1H), 7.45 (s, 1H), 7.31-7.28 (m, 2H), 6.54 (d, J = 5.1 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.31 (s, 2H), 2.49-2.30 (m, 2H), 1.52-1.08 (m, 9H)
Ex. 2  


 



 89





510 [M + H]+
(DMSO-d6, 400 MHz): δ 12.41 (br,1H), 11.93 (br, 1H), 8.56 (d, J = 5.1 Hz, 1H), 8.15-8.07 (m, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 7.34 (d, J = 13.6 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 5.1 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.31 (s, 2H), 2.45-2.31 (m, 2H), 1.51-1.07 (m, 9H)
Ex. 2  


 



 90





510 [M + H]+
(DMSO-d6, 400 MHz): δ 12.66 (br, 1H), 11.54 (br, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.08 (m, 1H), 7.55-7.43 (m, 4H), 6.54 (d, J = 5.6 Hz, 1H), 3.96 (s, 6H), 3.31 (s, 2H), 2.43-2.30 (m, 2H), 1.48- 1.06 (m, 9H)
Ex. 2  


 



 91





527 [M + H]+
(DMSO-d6, 400 MHz): δ 12.59 (br, 1H), 11.54 (br, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.17-8.15 (m, 1H), 7.70-7.68 (m, 1H), 7.53 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 6.42 (d, J = 5.1 Hz, 1H), 3.94 (s, 6H), 3.31 (s, 2H), 2.42- 2.31 (m, 2H), 1.47-1.05 (m, 9H)
Ex. 2  


 



 92





506 [M + H]+
(DMSO-d6, 400 MHz): δ 12.32 (br, 1H), 11.89 (br, 1H), 8.73 (d, J = 5.9 Hz, 1H), 7.62 (s, 1H), 7.51-7.48 (m, 2H), 7.24- 7.12 (m, 6H), 6.84 (d, J = 6.1 Hz, 1H), 4.01 (s, 6H), 3.78 (s, 2H), 2.28 (s, 3H)
Ex. 2  


 



 93





NDc
(DMSO-d6, 400 MHz): δ 3.92 (s, 5H), 3.95 (s, 3H), 6.65 (d, J = 5.4 Hz, 1H), 7.06-7.50 (m, 7H), 7.99-8.05 (m, 1H), 8.55 (d, J = 5.1 Hz, 1H), 11.94 (s, 1H), 12.12 (s, 1H)
Ex. 2  


 



 94





528 [M + H]+
(DMSO-d6, 400 MHz): δ 3.92 (s, 2H), 3.95 (s, 3H), 3.96 (s, 3H), 6.51 (d, J = 5.1 Hz, 1H), 7.04-7.12 (m, 2H), 7.20- 7.29 (m, 2H), 7.41-7.57 (m, 3H), 7.99- 8.05 (m, 1H), 8.52 (d, J = 5.1 Hz, 1H), 11.87 (s, 1H), 12.39 (s, 1H)
Ex. 2  


 



 95





528 [M + H]+
(DMSO-d6, 400 MHz): δ 12.32 (br, 1H), 11.94 (br, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.02-7.99 (m, 1H), 7.54-7.41 (m, 4H), 7.15-7.11 (m, 3H), 6.49 (d, J = 5.4 Hz, 1H), 3.97 (s, 2H), 3.94 (s, 6H)
Ex. 2  


 



 96





528 [M + H]+
(DMSO-d6, 400 MHz): δ 12.38 (br, 1H), 11.88 (br, 1H), 8.51 (d, J = 4.9 Hz, 1H), 8.02-7.99 (m, 1H), 7.53-7.19 (m, 7H), 6.50 (d, J = 5.1 Hz, 1H), 3.94 (s, 8H) 
Ex. 2  


 



 97





561 [M + H]+
(DMSO-d6, 400 MHz): δ 12.33 (br, 1H), 11.85 (br, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.06-7.93 (m, 4H), 7.63-7.43 (m, 4H), 6.46 (d, J = 5.1 Hz, 1H), 3.94 (s, 8H)
Ex. 2  


 



 98








NDc
(CDCl3, 400 MHz): δ 3.64 (s, 2H), 4.04 (s, 3H), 4.05 (s, 3H), 6.53 (d, J = 5.1 Hz, 1H), 6.87-6.94 (m, 2H), 6.98-7.04 (m, 2H), 7.43 (s, 1H), 7.49 (s, 1H), 8.16-8.24 (m, 1H), 8.31-8.37 (m, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.81 (br, 1H), 9.04 (br, 1H)
Ex. 6  


 



 99








NDc
(CDCl3, 400 MHz): δ 3.62 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.40 (d, J = 5.1 Hz, 1H), 6.87-6.96 (m, 2H), 7.20- 7.34 (m, 2H), 7.43 (s, 1H), 7.58 (s, 1H), 7.76-7.82 (m, 1H), 8.10-8.18 (m, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.72 (br, 1H), 9.38 (br, 1H)
Ex. 6  


 



100








458 [M + H]+
(DMSO-d6, 400 MHz): δ 3.49 (s, 2H), 3.92 (s, 3H), 3.93 (s, 3H), 6.44 (d, J = 5.4 Hz, 1H), 7.04-7.08 (m, 2H), 7.24 (d, J = 9.0 Hz, 2H), 7.28-7.34 (m, 2H), 7.38 (s, 1H), 7.50 (s, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 9.0 Hz, 2H), 8.45 (d, J = 5.4 Hz, 1H), 10.19 (s, 1H), 10.34 (s, 1H)
Ex. 5  


 



101








478 [M + H]+
(CDCl3, 400 MHz): δ 1.24-2.04 (m, 12H), 3.30 (s, 2H), 3.90-4.01 (m, 1H), 4.05 (s, 6H), 6.45 (d, J = 5.4 Hz, 1H), 7.14-7.17 (m, 2H), 7.42 (s, 1H), 7.55 (s, 1H), 7.65-7.68 (m, 2H), 8.48 (d, J = 5.1 Hz, 1H)
Ex. 5  


 



102








NDc
(CDCl3, 400 MHz): δ 3.60 (s, 2H), 4.05 (s, 3H), 4.06 (s, 3H), 6.47 (d, J = 5.4 Hz, 1H), 6.88-6.94 (m, 2H), 7.18 (d, J = 9.0 Hz, 2H), 7.45 (s, 1H), 7.55 (s, 1H), 7.68 (d, J =9.0 Hz, 2H), 8.14- 8.20 (m, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.78 (br, 1H), 8.91 (br, 1H)
Ex. 5  


 



103








524 [M + H]+
(CDCl3, 400 MHz): δ 3.81 (s, 3H), 4.05 (s, 3H), 4.07 (s, 3H), 4.50 (s, 1H), 6.48 (d, J = 5.6 Hz, 1H), 6.87-6.94 (m, 2H), 7.19 (d, J = 9.0 Hz, 2H), 7.52 (s, 1H), 7.55 (s, 1H), 7.70 (d, J = 9.0 Hz, 2H), 8.21-8.29 (m, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.79 (br, 1H), 8.93 (br, 1H)
Ex. 15 


 



104








522 [M + H]+
(CDCl3, 400 MHz): δ 1.73 (s, 6H), 4.05 (s, 3H), 4.05 (s, 3H), 6.44 (d, J = 5.1 Hz, 1H), 6.87-6.94 (m, 2H), 7.18 (d, J = 9.0 Hz, 2H), 7.43 (s, 1H), 7.55 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 8.14- 8.21 (m, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.56 (br, 1H), 8.70 (br, 1H)
Ex. 15 


 



105








472 [M − H]−
(CDCl3, 400 MHz): δ 2.37 (s, 3H), 4.06 (s, 6H), 6.49 (d, J =5.1 Hz, 1H), 6.88 (d, J = 5.1 Hz, 1H), 7.2 (m, 2H), 7.43 (s, 1H), 7.58 (s, 1H), 7.7 (m, 2H), 8.2 (m, 2H), 8.49 (d, J = 5.2 Hz, 1H)
Ex. 10  


 



106


462 [M + H]+
(CDCl3, 400 MHz): δ 8.43 (d, 1H, J =
Ex. 10b
















5.1 Hz), 7.82-7.79 (m, 1H), 7.49-7.08







(m, 12H), 6.36 (d, 1H, J = 5.1 Hz),







3.95 (s, 3H), 3.75 (s, 2H)





a)Synthesized as in Examples described below.


b)Synthesized as described in indicated Synthesis Example.


c)No data




















Ex.




No.
Compound structure
Starting compound A





107










 


108










 


109










 


110










 


111










 


112










 


113










 


114










 


115










 


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117










 


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119










 


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149










 


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151










 


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153










 


154










 


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156










 


157










 


158










 


159










 


160










 


161










 


162










 


163










 


164










 


165










 


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167










 


168










 


169










 


170










 


171










 


172










 


173










 


174










 


175










 


176










 


177










 


178










 


179










 


180










 


181










 


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183










 


184










 


185










 


186










 


187










 


188










 


189










 


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191










 


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196










 


197










 


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200










 


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202










 


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207










 


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233










 


234










 


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244










 


245










 


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247










 


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249










 


250










 


251










 


252










 


253










 


254










 


255










 


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257










 


258










 


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Ex.


Mass spectrometric
Synthesis 



No.
Starting compound B
Starting compound C
value (m/z)
methoda






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





353 [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





506 [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 





a)Synthesized as in Examples described below.






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), 6.50 (ddd, J=1.0, 2.7, 8.5 Hz, 1H), 6.57 (dd, J=2.7, 12.0 Hz, 1H), 7.04 (t, J=8.5 Hz, 1H), 7.45 (s, 1H), 7.58 (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.



No.
Compound structure





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.





No.
Starting compound A
Starting compound B






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.


Synthesis



No.
Starting compound C
Starting Compound D
methoda






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-Diethylamine-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]-3-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-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-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-toluyl-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=5.4 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-1-1)
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 3×104 per 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 3×104 per 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 5th day 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 compound represented by formula (I) or a pharmaceutically acceptable salt thereof:



wherein
X represents CH or N;
Z represents O or S;
L represents O;
M represents
(1-1) —CR10R11— wherein R10 and R11 may be the same or different, and each represents a hydrogen atom, C1-4 alkyl, or C1-4 alkoxy, or
(1-2) —NR12—, wherein R12 represents a hydrogen atom or C1-4 alkyl;

R1, R2, and R3 may be the same or different, and each represents (2-1) a hydrogen atom, (2-2) hydroxyl, (2-3) a halogen atom, (2-4) nitro, (2-5) —NR20R21, wherein R20 and R21 may be the same or different, and each represents a hydrogen atom or C1-6 alkyl optionally substituted by hydroxyl or C1-6 alkoxy, (2-6) C1-6 alkyl, (2-7) C2-6 alkenyl, (2-8) C2-6 alkynyl, or (2-9) C1-6 alkoxy; wherein the (2-6) C1-6 alkyl, the (2-7) C2-6 alkenyl, the (2-8) C2-6 alkynyl, and the (2-9) C1-6 alkoxy are optionally substituted by (3-1) hydroxyl, (3-2) a halogen atom, (3-3) C1-6 alkoxy, (3-4) C1-6 alkylcarbonyl, (3-5) C1-6 alkoxy carbonyl, (3-6) —NR22R23 wherein R22 and R23 may be the same or different, and each represents a hydrogen atom or C1-6 alkyl optionally substituted by hydroxyl or C1-6 alkoxy, or (3-7) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by hydroxyl or C1-6 alkoxy;
R5, R6, R7, and R8 may be the same or different, and each represents (4-1) a hydrogen atom, (4-2) a halogen atom, (4-3) C1-4 alkyl, or (4-4) C1-4 alkoxy; and
R9 represents (5-1) C1-6 alkyl wherein one or more hydrogen atoms on the C1-6 alkyl are optionally substituted by (6-1) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated 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, and the saturated or unsaturated 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 saturated or unsaturated 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, (6-2) -T-R15, wherein T represents O, S, or NH, and R15 represents C1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated 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, and the saturated or unsaturated 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 saturated or unsaturated 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 (6-3) —NR16R17 wherein R16 and R17 may be the same or different, and each represents C1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated 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, and the saturated or unsaturated 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 saturated or unsaturated 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; (5-2) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated 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, and the saturated or unsaturated 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 saturated or unsaturated 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 (5-3) —NR18R19, wherein R18 and R19 may be the same or different, and each represents (7-1) a hydrogen atom, (7-2) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated 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, and the saturated or unsaturated 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 saturated or unsaturated 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
(7-3) C1-6 alkyl optionally substituted by C1-6 alkoxy, C1-6 alkylthio, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated 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, and the saturated or unsaturated 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 saturated or unsaturated 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,
provided that, when X represents CH; Z represents O; L represents O; M represents —NH—; R1, R5, R6, R7, and R8 represent a hydrogen atom; and R2 and R3 represent methoxy, R9 represents neither phenyl, ethoxy, nor pyridin-2-yl.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein Z is O.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R1 is a hydrogen atom.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is C1-6 alkoxy.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is methoxy.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R3 is (8-1) hydroxyl, or (8-2) C1-6 alkoxy wherein the C1-6 alkoxy is optionally substituted by (9-1) hydroxyl, (9-2) a halogen atom, (9-3) —NR22R23 wherein R22 and R23 have the same meanings as defined above, or (9-4) a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group is optionally substituted by C1-6 alkyl wherein the C1-6 alkyl is optionally substituted by hydroxyl or C1-6 alkoxy.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R3 is (10-1) hydroxyl, or (10-2) C1-4 alkoxy, wherein the C1-4 alkoxy is optionally substituted by (11-1) hydroxyl, (11-2) a halogen atom, (11-3) —NR22R23 wherein R22 and R23 have the same meanings as defined above, or (11-4) a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group is optionally substituted by C1-6 alkyl wherein the C1-6 alkyl is optionally substituted by hydroxyl or C1-6 alkoxy.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R3 is methoxy.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein M is —NR12— wherein R12 has the same meaning as defined above.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein M is —CR10R11— and wherein R10 and R11 have the same meanings as defined above.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1,
wherein R9 is C1-6 alkyl wherein one or more hydrogen atoms on the C1-6 alkyl are optionally substituted by (12-1) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated 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, and the saturated or unsaturated 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 saturated or unsaturated 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, (12-2) -T-R15, wherein T and R15 have the same meanings as defined above, or (12-3) —NR16R17, wherein R16 and R17 have the same meanings as defined above.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R9 is —CH2—R24 wherein R24 represents a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group is optionally substituted by C1-6 alkyl, C1-6 alkoxy, or a halogen atom.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R9 is:
(13-1) —NR25R26, wherein R25 represents a hydrogen atom or C1-4 alkyl, and R26 represents
(14-1) C1-4 alkyl optionally substituted by a saturated or unsaturated six-membered carbocyclic group, wherein the saturated or unsaturated six-membered carbocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated six-membered carbocyclic 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 saturated or unsaturated six-membered carbocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or (14-2) a saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated 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, and the saturated or unsaturated four- to seven-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 saturated or unsaturated 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.

14. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1.

15. A method for inhibiting met autophosphorylation comprising administering the compound of claim 1 to a subject in need thereof.

16. The method of claim 15, wherein said subject has a tumor or cancer whose proliferation, invasion or metastasis is mediated by an HGF-met signal.