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HK1043792B - Quinoline derivatives and quinazoline derivatives - Google Patents

Quinoline derivatives and quinazoline derivatives Download PDF

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Publication number
HK1043792B
HK1043792B HK02105360.9A HK02105360A HK1043792B HK 1043792 B HK1043792 B HK 1043792B HK 02105360 A HK02105360 A HK 02105360A HK 1043792 B HK1043792 B HK 1043792B
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Hong Kong
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added
chloroform
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dissolved
dimethoxy
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HK02105360.9A
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Chinese (zh)
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HK1043792A1 (en
Inventor
Kubo Kazuo
Fujiwara Yasunari
Isoe Toshiyuki
Original Assignee
Kyowa Hakko Kirin Co., Ltd.
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Priority claimed from PCT/JP2000/000255 external-priority patent/WO2000043366A1/en
Publication of HK1043792A1 publication Critical patent/HK1043792A1/en
Publication of HK1043792B publication Critical patent/HK1043792B/en

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Description

Quinoline derivative and quinazoline derivative
Background
Technical Field
The present invention relates to quinoline derivatives and quinazoline derivatives having an antitumor effect, and more particularly, to quinoline derivatives and quinazoline derivatives which are effective for the treatment of diseases such as tumors, diabetic retinopathy, chronic joint rheumatism, psoriasis, atherosclerosis, and kaposi's sarcoma.
Background
WO97/17329 describes quinoline derivatives and quinazoline derivatives having an antitumor effect. However, the compound of the present invention is not disclosed in WO97/17329, and the influence on the morphological change of cells is not disclosed.
Summary of The Invention
The inventor finds that a group of quinoline derivatives and quinazoline derivatives not only have an anti-tumor effect, but also have small influence on cell morphology. The giant role of cell morphology is also understood as being the induction of tissue disorders.
The purpose of the present invention is to provide a compound having an antitumor activity and having little influence on cell morphology.
The compounds of the present invention are compounds of formula (I) below, or a pharmaceutically acceptable salt or solvate thereof.
(in the above-mentioned formula,
x and Z each represent CH or N,
R1、R2and R3May be the same or different and represents a hydrogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl, nitro or amino, the radical C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl and C2-6Alkynyl may also be substituted by halogen atom, hydroxy, C1-4Alkoxy radical, C1-4Alkoxycarbonyl, amino (1 or 2 hydrogen atoms of the amino group may be independently replaced by C)1-4Alkyl (the C)1-4The alkyl groups also being substituted by hydroxy or C1-4Alkoxy-substituted), group R12R13N-C(＝O)-O-(R12And R13May be the same or different and represents a hydrogen atom or C1-4Alkyl (the alkyl may also be substituted by hydroxy or C)1-4Alkoxy substituted)) or R14-(S)m-(R14The representation can be C1-4An alkyl-substituted saturated or unsaturated 3-to 7-membered carbocyclic or heterocyclic group, m represents 0 or 1) substitution,
R4represents a hydrogen atom, and is represented by,
R5、R6、R7and R8May be the same or different and represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylthio, nitro or amino groups, but R5、R6、R7And R8Not simultaneously represent a hydrogen atom,
R9and R10May be the same or different and represents a hydrogen atom, C1-6Alkyl or C1-4Alkylcarbonyl group, C1-6Alkyl or C1-4The alkyl moiety of the alkylcarbonyl group may be substituted by a halogen atom, C1-4Alkoxy, amino (amino may be substituted by C)1-4Alkyl substitution, said C1-4Alkyl groups may also be substituted by C1-4Alkoxy substituted) or a saturated or unsaturated 3-to 7-membered carbocyclic or heterocyclic group,
R11is represented by C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl (C)1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl may also be interrupted by halogen atoms or C1-6Alkoxy substituted) or R15-(CH2)n- (n represents an integer of 0 to 4, R)16Represents a saturated or unsaturated 3-to 7-membered carbocyclic or heterocyclic group, which may be substituted with a halogen atom or C1-6Alkyl or C1-6Alkoxy-substituted, in addition bicyclic fused to a further saturated or unsaturated 3-to 7-membered carbocyclic or heterocyclic ring))
The compounds of the present invention are useful for the treatment of tumors, diabetic retinopathy, chronic joint rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, solid tumors, and the like.
Detailed description of the invention
Compound (I)
In the present specification, "C" as a group or as a part of a group1-6Alkyl "and" C1-6Alkoxy radicalThe term "is intended to mean alkyl and alkoxy groups having 1 to 6, preferably 1 to 4, carbon atoms in which the group is straight-chain or branched.
In the present specification, "C" as a group or as a part of a group2-6Alkenyl "and" C2-6The term "alkynyl" refers to alkenyl and alkynyl groups having 2 to 6, preferably 2 to 4, carbon atoms in which the group is straight-chain or branched.
C1-6Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
C1-6Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.
C2-6Examples of alkenyl groups are allyl, butenyl, pentenyl, hexenyl.
C2-6Examples of alkynyl are 2-propynyl, butynyl, pentynyl and hexynyl.
The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The saturated or unsaturated 3-to 7-membered carbocyclic or heterocyclic ring is preferably a 5-to 7-membered, more preferably a 5-or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring.
Examples of saturated or unsaturated 3-to 7-membered carbocyclic groups are phenyl, cycloheptyl, cyclohexyl, cyclopentyl.
The saturated or unsaturated 3-to 7-membered heterocyclic ring contains at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom. Wherein, hetero atom means oxygen atom, nitrogen atom and sulfur atom. Examples of the saturated or unsaturated 3-to 7-membered heterocyclic group include pyridyl, piperidino, piperazinyl, morpholino, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrrolidinyl, pyrazolyl.
R15And R32The saturated or unsaturated heterocyclic groups sometimes indicated may also be reacted withOther saturated or unsaturated heterocycles are fused to form a bicyclic ring, such as naphthyl, indanyl, quinolyl, quinazolinyl.
R1Preferably represents a hydrogen atom.
R2And R3Preferably represents C which may be substituted1-6An alkoxy group.
R1、R2And R3Can represent C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl and C2-6Alkynyl radicals may also be substituted by radicals R14-(S)m-substitution.
R14The carbocyclic and heterocyclic groups which may be represented preferably represent saturated or unsaturated 5-or 6-membered carbocyclic or heterocyclic groups. The carbocyclic group more preferably represents phenyl. The heterocyclic group more preferably means a saturated or unsaturated 5-membered heterocyclic group containing 1 to 4 nitrogen atoms or a saturated or unsaturated 6-membered heterocyclic group containing 1 to 2 hetero atoms selected from nitrogen atoms and oxygen atoms (preferably pyridyl group). More specifically, the hetero atoms constituting the 6-membered heterocyclic group may be 1 nitrogen atom and 1 oxygen atom or 1 or 2 nitrogen atoms.
When m is 0, - (S)m-represents a chemical bond.
R1、R2And R3Substituted C which may represent1-6Alkoxy preferably denotes the radical R31-(CH2)p-O-(R31Represents a halogen atom, a hydroxyl group, C1-4Alkoxy radical, C1-4Alkoxycarbonyl, amino (1 or 2 hydrogen atoms of the amino group may be independently replaced by C)1-4Alkyl (the C)1-4The alkyl groups also being substituted by hydroxy or C1-4Alkoxy-substituted), group R12R13N-C(＝O)-O-(R12And R13Is as defined in formula (I) or a group R14-(S)m-(R14The definition of (A) is the same as that of the formula (I)), p represents an integer of 1 to 6, preferably 1 to 4, more preferably 1 or 2, particularly preferably 1).
Preferred groups of compounds of formula (I) are for example
R1Represents a hydrogen atom, R2And R3Represents unsubstituted C1-4A compound of an alkoxy group (preferably a methoxy group),
R1represents a hydrogen atom, R2Represents substituted C1-4Alkoxy (preferably the radical R)31-(CH2)p-O-)，R3Represents unsubstituted C1-4A compound of an alkoxy group (preferably a methoxy group),
R1represents a hydrogen atom, R2Represents unsubstituted C1-4Alkoxy (preferably methoxy), R3Represents substituted C1-4Alkoxy (preferably the radical R)31-(CH2)p-O-).
Preferred groups of compounds of formula (I) are for example
R5、R6、R7And R8At least one compound representing a halogen atom (preferably a chlorine atom or a fluorine atom),
R5、R6、R7and R8At least one represents C1-4A compound of an alkyl group, wherein,
R5、R6、R7and R8Wherein 2 are methyl groups and the other 2 are hydrogen atoms,
R5、R6、R7and R8At least one represents nitro, amino, C1-4Alkoxy or C1-4A compound of an alkylthio group,
R5、R7and R8Represents a hydrogen atom, R6A compound representing a halogen atom (more preferably a chlorine atom or a fluorine atom),
R5and R6Is represented by C1-4Alkyl (more preferably methyl), R7And R8A compound which represents a hydrogen atom, a compound represented by formula (I),
R5and R8Represents a hydrogen atom, R6And R7Is represented by C1-4A compound of an alkyl group (more preferably a methyl group),
R5、R7and R8Represents a hydrogen atom, R6Is represented by C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylthio, nitro or amino compounds.
R9And R10The saturated or unsaturated 3-to 7-membered carbocyclic group or heterocyclic group as the substituent in (1), preferably a saturated or unsaturated 5-or 6-membered carbocyclic group or heterocyclic group.
R9And R10Preferably represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxymethyl group, a formyl group, an acetyl group, a benzyl group or a phenethyl group.
Preferred groups of compounds of formula (I) are for example
R1、R9And R10A compound representing a hydrogen atom, and
R1represents a hydrogen atom, R9And R10Any one or two of them represent a group other than a hydrogen atom.
R11Group R which may represent15-(CH2)nIn the above formula, n is preferably an integer of 0 to 2, more preferably 0 or 1. R15Preferable examples are, for example, a saturated or unsaturated 6-membered carbocyclic group (more preferably phenyl) which may be substituted and a saturated or unsaturated 6-membered heterocyclic group (more preferably pyridyl) which may be substituted. The hetero atom constituting the 6-membered heterocyclic group may more specifically consist of 1 nitrogen atom, or 1 nitrogen atom and 1 oxygen atom.
Preferred groups of compounds of formula (I) are, for example, those in which X represents N or CH and Z represents CH.
A preferred group of compounds of formula (I) is further exemplified by compounds of formula (Ia).
(in the above-mentioned formula,
x represents a group of a CH or an N,
R21and R22May be the same or different and represents unsubstituted C1-6Alkoxy or a radical R31-(CH2)p-O-(R31Represents a halogen atom, a hydroxyl group, C1-4Alkoxy radical, C1-4Alkoxycarbonyl, amino (1 or 2 hydrogen atoms of the amino group may be independently replaced by C)1-4Alkyl (the C)1-4The alkyl groups also being substituted by hydroxy or C1-4Alkoxy-substituted), group R12R13N-C(＝O)-O-(R12And R13May be the same or different and represents a hydrogen atom or C1-4Alkyl (the alkyl may also be substituted by hydroxy or C)1-4Alkoxy-substituted)) or a radical R14-(S)m-(R14The representation can be C1-4An alkyl-substituted saturated or unsaturated 3-to 7-membered carbocyclic or heterocyclic group, m represents 0 or 1), p represents an integer of 1 to 6),
R23、R24、R25and R26May be the same or different and represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylthio, nitro or amino groups, but R23、R24、R25And R26Not simultaneously represent a hydrogen atom,
R27and R28May be the same or different and represents a hydrogen atom, C1-6Alkyl or C1-4Alkylcarbonyl group, C1-6Alkyl or C1-4The alkyl moiety of the alkylcarbonyl group may be substituted by a halogen atom, C1-4Alkoxy, amino (amino may be substituted by C)1-4Alkyl substitution, said C1-4Alkyl groups may also be substituted by C1-4Alkoxy substituted) or saturated or unsaturated 3E to EA 7-membered carbocyclic group or heterocyclic group,
R29is represented by C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl (C)1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl may also be interrupted by halogen atoms or C1-4Alkoxy substituted) or R32-(CH2)q- (q represents an integer of 0 to 4, R32Denotes a saturated or unsaturated 6-membered carbocyclic or heterocyclic radical which may also be substituted by halogen atoms, C1-4Alkyl or C1-4Alkoxy substituted, in addition, bicyclic fused to another saturated or unsaturated 5-or 6-membered carbocyclic or heterocyclic ring),
R21and R22May both represent unsubstituted C1-6Alkoxy (preferably methoxy).
R21And R22May be any one of unsubstituted C1-6Alkoxy, preferably methoxy, the other representing a group R31-(CH2)p-O-。
Radical R31-(CH2)pin-O-, p preferably represents 1 to 4, more preferably 1 or 2, and particularly preferably 1.
Preferred groups of compounds of the formula (Ia) are for example
R23、R24、R25And R26At least one compound representing a halogen atom (preferably a chlorine atom or a fluorine atom),
R23、R24、R25and R26At least one represents C1-4A compound of an alkyl group, wherein,
R23、R24、R25and R26Wherein 2 are methyl groups and the other 2 are hydrogen atoms,
R23、R24、R25and R26At least one represents nitro, amino, C1-4Alkoxy or C1-4A compound of an alkylthio group,
R23、R25and R26Represents a hydrogen atom, R24A compound representing a halogen atom (more preferably a chlorine atom or a fluorine atom),
R23and R24Is represented by C1-4Alkyl (more preferably methyl), R25And R26A compound which represents a hydrogen atom, a compound represented by formula (I),
R23and R26Represents a hydrogen atom, R24And R25Is represented by C1-4A compound of an alkyl group (more preferably a methyl group),
R23、R25and R26Represents a hydrogen atom, R24Is represented by C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylthio, nitro or amino compounds.
Preferred groups of compounds of formula (Ia) are for example R27And R28A compound representing a hydrogen atom.
In addition, preferred groups of compounds of the formula (Ia) are, for example, R27And R28Any one or two of them represent a group other than a hydrogen atom.
R29R may represent32-(CH2)qIn the above formula, q is preferably an integer of 0 to 2, more preferably 0 or 1. R32Preferable examples are, for example, a phenyl group which may be substituted and a saturated or unsaturated 6-membered heterocyclic group which may be substituted (more preferably, a pyridyl group). The hetero atom constituting the 6-membered heterocyclic group may more specifically consist of 1 nitrogen atom, or 1 nitrogen atom and 1 oxygen atom. R32The saturated or unsaturated 6-membered carbocyclic or heterocyclic group represented may also preferably be bicyclic fused with other saturated or unsaturated 6-membered carbocyclic or heterocyclic rings.
Preferred groups of compounds of the formula (Ia) are for example
X represents a group of a CH or an N,
R21and R22Represents unsubstituted C1-4An alkoxy group,
R23、R25and R26Represents a hydrogen atom, and is represented by,
R24represents a halogen atom, C1-4Alkyl radical, C1-4An alkoxy group or a nitro group, or a salt thereof,
R27and R28Represents a hydrogen atom, and is represented by,
R29is represented by C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl (C)1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl may also be interrupted by halogen atoms or C1-4Alkoxy substituted) or- (CH)2)q-R32(q represents an integer of 0 or 1, R32Represents an optionally halogen atom, C1-4Alkyl or C1-4Alkoxy-substituted phenyl, pyridyl, or naphthyl);
x represents a group of a CH or an N,
R21and R22Represents unsubstituted C1-4An alkoxy group,
R23、R25and R26Represents a hydrogen atom, and is represented by,
R24represents a halogen atom, C1-4Alkyl radical, C1-4An alkoxy group or a nitro group, or a salt thereof,
R27and R28Either or both of which represent a group other than a hydrogen atom,
R29is represented by C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl (C)1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl may also be interrupted by halogen atoms or C1-4Alkoxy substituted) or- (CH)2)q-R32(q represents an integer of 0 or 1, R32Represents an optionally halogen atom, C1-4Alkyl or C1-4Alkoxy substitutionPhenyl, pyridyl or naphthyl) compounds;
x represents a group of a CH or an N,
R21and R22Represents unsubstituted C1-4An alkoxy group,
R23、R25and R26Represents a hydrogen atom, and is represented by,
R24represents a halogen atom, C1-4Alkyl radical, C1-4An alkoxy group or a nitro group, or a salt thereof,
R27represents a hydrogen atom, and is represented by,
R28represents a group other than a hydrogen atom,
R29is represented by C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl (C)1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl, each of which may also be interrupted by halogen atoms or C1-4Alkoxy substituted) or- (CH)2)q-R32(q represents an integer of 0 or 1, R32Represents an optionally halogen atom, C1-4Alkyl or C1-4Alkoxy-substituted phenyl, pyridyl, or naphthyl);
x represents a group of a CH or an N,
R21and R22Any one of (A) represents an unsubstituted C1-4Alkoxy, the other represents a group R31-(CH2)p-O-, preferably R21Represents unsubstituted C1-4Alkoxy radical, R22Represents a group R31-(CH2)p-O-，
R23、R25And R26Represents a hydrogen atom, and is represented by,
R24represents a halogen atom, C1-4Alkyl radical, C1-4An alkoxy group or a nitro group, or a salt thereof,
R27and R28Represents a hydrogen atom, and is represented by,
R29is represented by C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl (C)1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl may also be interrupted by halogen atoms or C1-4Alkoxy substituted) or- (CH)2)q-R32(q represents an integer of 0 or 1, R32Represents an optionally halogen atom, C1-4Alkyl or C1-4Alkoxy-substituted phenyl, pyridyl, or naphthyl);
x represents a group of a CH or an N,
R21and R22Any one of (A) represents an unsubstituted C1-4Alkoxy, the other represents a group R31-(CH2)p-O-, preferably R21Represents unsubstituted C1-4Alkoxy radical, R22Represents a group R31-(CH2)p-O-，
R23、R25And R26Represents a hydrogen atom, and is represented by,
R24represents a halogen atom, C1-4Alkyl radical, C1-4An alkoxy group or a nitro group, or a salt thereof,
R27and R28Either or both of which represent a group other than a hydrogen atom,
R29is represented by C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl (C)1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl, each of which may also be interrupted by halogen atoms or C1-4Alkoxy substituted) or- (CH)2)q-R32(q represents an integer of 0 or 1, R32Represents an optionally halogen atom, C1-4Alkyl or C1-4Alkoxy-substituted phenyl, pyridyl, or naphthyl);
x represents a group of a CH or an N,
R21and R22Any one of (A) represents an unsubstituted C1-4Alkoxy, the other representsRadical R31-(CH2)p-O-, preferably R21Represents unsubstituted C1-4Alkoxy radical, R22Represents a group R31-(CH2)p-O-，
R23、R25And R26Represents a hydrogen atom, and is represented by,
R24represents a halogen atom, C1-4Alkyl radical, C1-4An alkoxy group or a nitro group, or a salt thereof,
R27represents a hydrogen atom, and is represented by,
R28represents a group other than a hydrogen atom,
R29is represented by C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl (C)1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl, each of which may also be interrupted by halogen atoms or C1-4Alkoxy substituted) or- (CH)2)q-R32(q represents an integer of 0 or 1, R32Represents an optionally halogen atom, C1-4Alkyl or C1-4Alkoxy-substituted phenyl, pyridyl, or naphthyl);
x represents a group of a CH or an N,
R21and R22Any one of (A) represents an unsubstituted C1-4Alkoxy, the other represents a group R31-(CH2)p-O-, preferably R21Represents unsubstituted C1-4Alkoxy radical, R22Represents a group R31-(CH2)p-O-，
R23And R26Represents a hydrogen atom, and is represented by,
R24and R25Represents a halogen atom, C1-4Alkyl radical, C1-4An alkoxy group or a nitro group, or a salt thereof,
R27and R28Represents a hydrogen atom, and is represented by,
R29is represented by C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl (C)1-6Alkyl radical, C2-6Alkenyl and C2-6Alkynyl, each of which may also be interrupted by halogen atoms or C1-4Alkoxy substituted) or- (CH)2)q-R32(q represents an integer of 0 or 1, R32Represents an optionally halogen atom, C1-4Alkyl or C1-4Alkoxy-substituted phenyl, pyridyl or naphthyl).
Preferred examples of the compound of the present invention are the compounds described in examples 1 to 186.
Preferred examples of the compound of the present invention include the following compounds.
N- { 2-chloro-4- [ (6, 7-dimethyl-4-quinazolinyl) oxy ] phenyl } -N' -i-butylurea,
N- (4- { [ 7- (phenylmethoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea,
N- (4- { [ 6- (benzyloxy) -7-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea,
N- (2-chloro-4- { [ 7-methoxy-6- (3-morpholinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1-imidazolyl) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -ethylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1, 2, 3-triazol-1-yl) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -ethylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 3- (1H-1, 2, 3-triazol-1-yl) propoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -ethylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (4-methylpiperazino) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -ethylurea,
N- (2-chloro-4- { [ 6-methoxy-7- (2-morpholinoethoxy) -4-quinazolinyl ] oxy } phenyl) -N' -ethylurea,
N- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' -ethylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (dimethylamino) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -ethylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1-imidazolyl) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -propylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1, 2, 3-triazol-1-yl) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -propylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 3- (1H-1, 2, 3-triazol-1-yl) propoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -propylurea,
N- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (dimethylamino) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -propylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1-imidazolyl) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -butylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1, 2, 3-triazol-1-yl) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -butylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 3- (1H-1, 2, 3-triazol-1-yl) propoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -butylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (4-methylpiperazino) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -butylurea,
N- (2-chloro-4- { [ 6-methoxy-7- (2-morpholinoethoxy) -4-quinazolinyl ] oxy } phenyl) -N' -butylurea,
N- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' -butylurea,
N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (dimethylamino) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -butylurea and
n- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (dimethylamino) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -propylurea.
Particularly preferred examples of the compounds of the present invention are the following compounds: 13. n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea,
51. N- (2-chloro-4- { [ 6-methoxy-7- (2-morpholinoethoxy) -4-quinolinyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea,
62. N- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea,
76. N- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } -N' -ethylurea,
117. N- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } -N' -methylurea,
119. N- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea,
135. N- (2-chloro-4- { [ 6-methoxy-7- (3-piperidinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea,
142. N- (2-chloro-4- { [ 6-methoxy-7- (3-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea,
143. N- (2-chloro-4- { [ 6-methoxy-7- (4-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea,
144. N- (2-chloro-4- { [ 6-methoxy-7- (2-morpholinoethoxy) -4-quinolinyl ] oxy } phenyl) -N' -propylurea,
145. N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1, 2, 3-triazol-1-yl) ethoxy ] -4-quinolyl } oxy) phenyl ] -N' -propylurea,
146. N- [ 2-chloro-4- ({7- [ 2- (1H-1-imidazolyl) ethoxy ] -6-methoxy-4-quinolinyl } oxy) phenyl ] -N' -propylurea,
148. N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (4-methylpiperazino) ethoxy ] -4-quinolyl } oxy) phenyl ] -N' -propylurea,
149. N- (2-chloro-4- { [ 7- (2-hydroxyethoxy) -6-methoxy-4-quinolyl ] oxy } phenyl) -N' -propylurea,
151. N- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea,
152. N- [ 2-chloro-4- (6-methoxy-7- { [ 3- (4-methylpiperazinyl) propoxy ] -4-quinolyl } oxy) phenyl ] -N' -propylurea,
153. N- [ 2-chloro-4- (6-methoxy-7- { [ 3- (1H-1, 2, 3-triazol-1-yl) propoxy ] -4-quinolyl } oxy) phenyl ] -N' -propylurea,
157. N- { 2-chloro-4- [ (7- {3- [ (2-hydroxyethyl) (methyl) amino ] propoxy } -6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea,
159. N- { 2-chloro-4- [ (6-methoxy-7- { [ 5- (1H-1, 2, 3-triazol-1-yl) pentyl ] oxy } -4-quinolyl) oxy ] phenyl } -N' -propylurea,
160. N- [ 2-chloro-4- ({7- [ 4- (1H-1-imidazolyl) butoxy ] -6-methoxy-4-quinolinyl } oxy) phenyl ] -N' -propylurea,
162. N- (2-chloro-4- { [ 6-methoxy-7- (2-morpholinoethoxy) -4-quinazolinyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea,
163. N- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea,
164. N- [ 2-chloro-4- ({ 6-methoxy-7- [ 3- (4-methylpiperazino) propoxy ] -4-quinazolinyl } oxy) phenyl ] -N' - (2, 4-difluorophenyl) urea,
165. N- { 2-chloro-4- [ (7- {3- [ (2-hydroxyethyl) (methyl) amino ] propoxy } -6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' - (2, 4-difluorophenyl) urea,
168. N- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinolyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea,
169. N- (2-chloro-4- { [ 6-methoxy-7- (3-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea,
170. N- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1, 2, 3-triazol-1-yl) ethoxy ] -4-quinolyl } oxy) phenyl ] -N' - (2, 4-difluorophenyl) urea,
184. N- (2-chloro-4- { [ 6-methoxy-7- (3-piperidinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' -methylurea,
185. N- (2-chloro-4- { [ 6-methoxy-7- (3-piperidinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' -ethylurea and
186. n- (2-chloro-4- { [ 6-methoxy-7- (4-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea. Very preferred examples of the compounds of the invention are the following compounds:
62. n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea,
142. N- (2-chloro-4- { [ 6-methoxy-7- (3-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea and
169. n- (2-chloro-4- { [ 6-methoxy-7- (3-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea.
The compounds of the present invention can be prepared into pharmaceutically acceptable salts thereof. Preferable examples thereof include alkali metal or alkaline earth metal salts such as sodium salt, potassium salt or calcium salt, hydrohalic acid salts such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate, lower alkylsulfonate such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, arylsulfonate such as benzenesulfonate and p-toluenesulfonate, organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate, acetic acid, malic acid, lactic acid and ascorbic acid, and amino acid salts such as glycinate, phenylalanine, glutamate and aspartate.
In addition, the compounds of the present invention may be prepared as solvates (e.g., hydrates).
Preparation of the Compounds
The compounds of the invention may be prepared, for example, according to scheme 1 and scheme 2.
Scheme 1
The starting compounds necessary for the synthesis of the compounds of the invention are commercially available or can be prepared by conventional methods. For example, 4-chloroquinoline derivatives can be synthesized according to the general method described in org.synth.col.vol.3, 272(1955), Acta chim.hung., 112, 241(1983) or WO 98/47873. The 4-chloroquinazoline derivative can be synthesized by a method generally described in j.am.chem.soc., 68, 1299(1946) or j.am.chem.soc., 68, 1305 (1946).
Alternatively, the 4-chloroquinazoline derivative may be prepared by the following method: first, (1) a benzoic acid ester is reacted with formamide to obtain a quinazolinone derivative (see preparation example 34), and then (2) the quinazolinone derivative is heated in the presence of phosphorus oxychloride using toluene or sulfolane as a solvent (see preparation examples 35 and 36). The quinazolinone derivative is generally synthesized in the presence of a solvent such as benzoate, sodium methoxide, formamide, DMF, or methanol.
(1) Among them, since the reaction is carried out only in the presence of benzoate and formaldehyde, it is advantageous in that the amount of raw materials used is small. Halogenation of the 4-quinazolinone derivatives is generally achieved by heating the quinazolinone derivative with phosphorus oxychloride. In this case, since the quinazoline derivative has high reactivity, the quinazoline derivative is returned to the starting material under the influence of the solvent, and the reaction is not completed in many cases.
(2) In (b), since the reaction is completed in the presence of toluene or sulfolane, it is advantageous in terms of increasing the yield.
Subsequently, after synthesizing a 4- (nitrophenoxy) quinoline derivative or a corresponding quinazoline derivative by allowing a 4-chloroquinoline derivative or a corresponding quinazoline derivative to act on nitrophenol in an appropriate solvent or without a solvent, the 4- (aminophenoxy) quinoline derivative or the corresponding quinazoline derivative is stirred in an appropriate solvent (e.g., N-dimethylformamide) in the presence of a catalyst (e.g., palladium hydroxide-carbon, palladium-carbon) in a hydrogen atmosphere, whereby a 4- (aminophenoxy) quinoline derivative or a corresponding quinazoline derivative can be obtained. Alternatively, 4- (aminophenoxy) quinoline derivatives or corresponding quinazoline derivatives can be obtained by allowing a 4-chloroquinoline derivative or a corresponding quinazoline derivative to act on aminophenol in the presence of a base such as sodium hydroxide.
Alternatively, the 4- (aminophenoxy) quinoline derivative or the corresponding quinazoline derivative can be prepared by: aminophenol was dissolved in an aqueous sodium hydroxide solution, and a 4-chloroquinoline derivative or a corresponding quinazoline derivative dissolved in an organic solvent was subjected to a two-phase reaction in the presence or absence of a phase transfer catalyst (see preparation examples 37 and 38). In this reaction, unreacted phenol and the like and the decomposition product of 4-chloroquinazoline remain in the aqueous layer, and the produced target product is in the organic layer. In addition, it is also advantageous in that the N-alkylaminophenoxy-quinazoline as a by-product can be inhibited.
Scheme 2
The resulting 4- (aminophenoxy) quinoline derivative or the corresponding quinazoline derivative is reacted with an acid chloride or an acid anhydride in the presence of a base, followed by reduction with lithium aluminum hydride or the like, and R may be replaced by9A substituent is introduced (step 1A).
Or reacting the obtained 4- (aminophenoxy) quinoline derivative or the corresponding quinazoline derivative with an aldehyde or ketone to form an imine, and then reducing the imine with sodium cyanoborohydride or the like, or R may be substituted with a substituent9A substituent is introduced (step 1B).
According to known methods, R is9Derivatives having a substituent introduced therein and isocyanate derivatives (O ═ C ═ N-R11) Takes place (step 2) by reacting it with a suitable alkylating agent (R) in the presence of a base (for example sodium hydride)10Hal) (step 3) and the compound of formula (I) can be prepared.
In addition, R is reacted in the presence of a base (e.g., sodium hydride)9And/or R10Urea derivatives being hydrogen atoms with suitable alkylating agents (R)9Hal、R10Hal) and R may also be introduced9And R10(steps 5 and 7).
R9And/or R10The urea derivative which is a hydrogen atom can be produced by the following method: the 4- (aminophenoxy) quinoline derivative or the corresponding quinazoline derivative obtained in scheme 1 is reacted with an isocyanate derivative according to a known method, or triphosgene is added in the presence of a base (e.g., triethylamine) and then the resulting mixture is reacted with an appropriate alkylamine (R)11NH2、R10R11NH) (steps 4 and 6).
Derivatives having a specific substituent at position 7 of the quinoline ring can be prepared, for example, according to scheme 3.
Scheme 3
The nitro group can be introduced by reacting a commercially available 4' -hydroxyacetophenone derivative with an appropriate substituent (e.g., benzyl group) to protect the hydroxyl group, and then reacting with a nitrating agent (e.g., nitric acid-acetic acid).
Subsequently, the nitro group is reduced to give an amino group, and the resulting amino group is reacted with a formate in the presence of a base to form a quinolone ring, which is then reacted with a chlorinating agent (for example, phosphorus oxychloride) to prepare a 4-chloroquinoline derivative.
The obtained 4-chloroquinoline derivative is allowed to act on aminophenol in the presence of a base (for example, sodium hydride) to obtain a 4- (aminophenoxy) quinoline derivative.
The obtained derivative is reacted with an isocyanate derivative (O ═ C ═ N-R) according to a known method29) Acting, or treated with triphosgene, with an aromatic amine or alkylamine (R)29NH2) Acts to enable the synthesis of urea moieties.
Subsequently, the Protecting Group (PG) for the hydroxyl group at the 7-position of the quinoline ring is removed, and the resulting product is reacted with an alkyl halide (R) in the presence of a base22’Hal、R22’Represents R22Alkyl moiety in the case of alkoxy), or with an alcohol derivative (R) according to a known method (e.g. Mitsunobu reaction)22’OH) to produce the compounds of the present application having an alkoxy group at the 7-position of the quinoline ring.
The alkyl halide used in the substitution reaction may be commercially available or may be prepared according to the method described in j.am.chem.soc., 1945, 67, 736, etc.
The alcohol derivative used in the substitution reaction may be commercially available, or may be prepared according to the methods described in j.anibiot (1993), 46(1), 177, ann.pharm.fr.1977, 35, 503, and the like.
Derivatives having a specific substituent at the 6-position of the quinoline ring can be prepared according to scheme 3 using 3' -hydroxyacetophenone derivatives as starting materials.
Derivatives having specific substituents at position 7 of the quinazoline ring may be prepared according to scheme 4.
Scheme 4
The 2-amino-benzoate derivatives can be prepared by esterifying 2-nitro-benzoic acid derivatives synthesized according to the method described in j.med.chem.1977, 20, 146, etc., with, for example, dimethyl sulfate in the presence of a base (e.g., potassium carbonate) and then reducing the nitro group with, for example, iron/acetic acid.
The resulting compound is then reacted with formamide in the presence of a base to form a 4-quinazolinone ring, which is then reacted with a chlorinating agent (e.g., phosphorus oxychloride) to produce a 4-chloroquinazoline derivative.
The obtained 4-chloroquinazoline derivative is allowed to act on an aminophenol derivative in the presence of a base (e.g., sodium hydride), whereby a 4- (aminophenoxy) quinazoline derivative can be obtained.
The obtained derivatives are reacted with isocyanate derivatives (O ═ C ═ N-R) according to known methods29) Acting, or treated with triphosgene, with an aromatic amine or alkylamine (R)29NH2) Acts to enable the synthesis of urea moieties.
Subsequently, the Protecting Group (PG) for the hydroxyl group at the 7-position of the quinazoline ring is removed, and the resulting mixture is reacted with an alkyl halide (R) in the presence of a base22’Hal、R22’Represents R22Alkyl moieties in the case of alkoxy), or according to known methods (e.g. mitsunobu reaction)) With alcohol derivatives (R)22’OH) to produce the compounds of the present application having an alkoxy group at the 7-position of the quinazoline ring.
The alkyl halide and alcohol derivative used in the substitution reaction may be commercially available or may be prepared according to the literature described in the description of scheme 3.
Derivatives having a specific substituent at the 6-position of the quinazoline ring can be prepared according to scheme 4 using 3-hydroxybenzaldehyde derivatives as starting materials.
Use of compound/pharmaceutical composition
The compound of the present invention has an inhibitory effect on tumor growth in vivo (see pharmacological test example 4).
The compounds of the present invention also inhibit the activation of mitogen-activated protein kinase MAPK (refer to pharmacological test examples 1 and 2) caused by the stimulation of vascular endothelial cells by the vascular endothelial growth factor vegf (vascular endothelial growth factor) in vitro. Increased phosphorylated MAPK is confirmed by activation of MAPK by signaling systems downstream of the receptor if vascular endothelial cells are stimulated with VEGF (Abedi, h.and Zachary, i., j.biol.chem., 272, 15442-15451 (1997)). Activation of MAPK is known to play an important role in the proliferation of vascular endothelial cells during angiogenesis (Merenmies, j.et al, Cell Growth & differ., 83-10 (1997); Ferrara, n.and Davis-Smyth, t.endocr.rev., 18, 4-25 (1997)). Therefore, the compounds of the present invention have an angiogenesis inhibitory effect.
Angiogenesis at the lesion site is mainly closely related to diseases such as tumor, diabetic retinopathy, chronic joint rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma and the like, and metastasis of solid tumor (Forkman, J.Nature Med.1: 27-31 (1995); Bicknell, R.R., Harris, A.L.curr.Opin.Oncol.8: 60-65 (1996)). Therefore, the compound of the invention can be used for treating diseases such as tumors, diabetic retinopathy, chronic joint rheumatism, psoriasis, atherosclerosis, Kaposi sarcoma and the like and metastasis of solid tumors.
The compound of the present invention has a small influence on the cell morphology (see pharmacological test example 3). Therefore, the compound of the present invention is very safe when administered to a living body.
According to the present invention, there can be provided a pharmaceutical composition containing the compound of the present invention. The pharmaceutical composition can be used for treating diseases such as tumors, diabetic retinopathy, chronic joint rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma and the like and metastasis of solid tumors.
Also provided in accordance with the present invention is a method of treatment of a disease selected from the group consisting of tumor, diabetic retinopathy, chronic joint rheumatism, psoriasis, atherosclerosis and Kaposi's sarcoma, which comprises co-administering to a mammal a compound of the present invention and a pharmaceutically acceptable carrier.
The compounds of the present invention can be administered to humans and non-human animals by any of oral and non-oral administration routes (e.g., intravenous, intramuscular, subcutaneous, rectal, transdermal). Therefore, the pharmaceutical composition containing the compound of the present invention as an active ingredient can be formulated into an appropriate dosage form according to the administration route.
Specifically, the oral dosage forms include tablets, capsules, powders, granules, syrups and the like, and the non-oral dosage forms include injections, suppositories, tape preparations, ointments and the like.
The above-mentioned various dosage forms can be prepared by a conventional method using a conventional excipient, disintegrant, binder, lubricant, coloring agent, diluent, etc.
Excipients such as lactose, glucose, corn starch, sorbitol, crystalline cellulose, etc., disintegrants such as starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin, etc., binders such as dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, acacia, gelatin, hydroxypropyl cellulose, polyvinylpyrrolidone, etc., lubricants such as talc, magnesium stearate, polyethylene glycol, hardened vegetable oil, etc.
The injection may be prepared by adding a buffer, a pH adjuster, a stabilizer, an isotonic agent, a preservative, and the like, if necessary.
The content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, and is usually 0.5 to 50% by weight, preferably 1 to 20% by weight of the total composition.
The dose is determined as appropriate in each case in consideration of the age, weight, sex, difference in disease, degree of symptoms, etc. of the patient, and is, for example, in the range of 0.1 to 100mg/kg, preferably 1 to 50mg/kg, and is administered 1 time per day or in divided doses.
The compounds of the present invention may be administered in combination with other drugs. Can be administered simultaneously or over time. For example, when a malignant tumor is a treatment target, the tumor is shrunk by the action of the compound of the present invention on vascular endothelial cells of a target blood vessel, and then the tumor can be effectively destroyed by administering an anticancer drug. The kind of the anticancer drug and the administration interval may be determined depending on the kind of cancer and the state of the patient. Diseases other than malignant tumors may also be treated as well.
In addition, according to the present invention, there is further provided a method for inhibiting angiogenesis in a target blood vessel, comprising contacting a compound of the present invention with vascular endothelial cells of the target blood vessel. As the target blood vessel, for example, a blood vessel involved in supplying nutrients to a disease-causing tissue (e.g., tumor tissue, retinopathy tissue, joint rheumatism tissue) is used. The contact of the compound of the present invention with vascular endothelial cells can be carried out by, for example, systemic administration (intravenous administration, oral administration, etc.), local administration (transdermal administration, intra-articular administration, etc.), drug targeting using a carrier (liposome, lipid microsphere, polymeric drug, etc.).
Examples
The present invention will be described with reference to the following examples, but the present invention is not limited thereto.
Preparation example 1: 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline
Sodium hydride (60 w%, 0.72g) was added to dimethyl sulfoxide (10ml), and after stirring at 50 ℃ for 30 minutes, the mixture was returned to room temperature, 4-amino-3-chlorophenol hydrochloride (1.61g) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 4-chloro-6, 7-dimethoxyquinoline (1.00g) was added thereto, and the mixture was stirred at 100 ℃ for 1 night. Water was added to the reaction solution, extraction was performed with chloroform, the chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, methanol was added to the obtained residue, and the precipitated crystals were collected by suction filtration to obtain 0.89g of the title compound with a yield of 60%.
1H-NMR(CDCl3，400MHz)：δ4.05(s，3H)，4.05(s，3H)，4.08(s，2H)，6.44(d，J＝5.4Hz，1H)，6.85(d，J＝8.5Hz，1H)，6.93-6.96(m，1H)，7.15(d，J＝2.7Hz，1H)，7.41(s，1H)，7.54(s，1H)，8.48(d，J＝5.1Hz，1H)
Preparation example 2: 4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethyl Phenylamine
Sodium hydride (60 w%, 0.72g) was added to dimethyl sulfoxide (10ml), and after stirring at 50 ℃ for 30 minutes, the mixture was returned to room temperature, 4-amino-2, 3-dimethylphenol hydrochloride (1.55g) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 4-chloro-6, 7-dimethoxyquinoline (1.00g) was added thereto, and the mixture was stirred at 100 ℃ for 1 night. Water was added to the reaction solution, followed by extraction with chloroform, and then the chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, methanol was added to the obtained residue, and the precipitated crystals were collected by suction filtration to give the title compound (0.94 g) in a yield of 65%.
1H-NMR(CDCl3，400MHz)：δ2.07(s，3H)，2.15(s，3H)，3.62(s，2H)，4.05(s，3H)，4.07(s，3H)，6.25(d，J＝5.4Hz，1H)，6.64(d，J＝8.5Hz，1H)，6.83(d，J＝8.5Hz，1H)，7.42(s，1H)，7.64(s，1H)，8.42(d，J＝5.4Hz，1H)
Preparation example 3: 4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethyl Phenylamine
Sodium hydride (60 w%, 0.36g) was added to dimethyl sulfoxide (10ml), and after stirring at 50 ℃ for 30 minutes, the mixture was returned to room temperature, 4-amino-2, 5-dimethylphenol (1.23g) was added thereto, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 4-chloro-6, 7-dimethoxyquinoline (1.00g) was added thereto, and the mixture was stirred at 100 ℃ for 1 night. Water was added to the reaction solution, followed by extraction with chloroform, and then the chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (1/1) to give the title compound.
Preparation example 4: 3, 5-dichloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] Aniline
Sodium hydride (60 w%, 0.36g) was added to dimethyl sulfoxide (10ml), and after stirring at 50 ℃ for 30 minutes, the mixture was returned to room temperature, and 4-amino-2, 6-dichlorophenol (1.59g) was added thereto and stirred at room temperature for 10 minutes. Subsequently, 4-chloro-6, 7-dimethoxyquinoline (1.00g) was added thereto, and the mixture was stirred at 100 ℃ for 1 night. Water was added to the reaction solution, followed by extraction with chloroform, and then the chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (1/1) to give 0.35g of the title compound in 22% yield.
1H-NMR(CDCl3，400MHz)：δ3.84(s，2H)，4.05(s，3H)，4.08(s，3H)，6.28(d，J＝5.4Hz，1H)，6.74(s，2H)，7.43(s，1H)，7.64(s，1H)，8.48(d，J＝5.4Hz，1H)
Preparation example 5: 4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-nitroaniline
Sodium hydride (60 w%, 0.54g) was added to dimethyl sulfoxide (15ml), and after stirring at 70 ℃ for 30 minutes, the mixture was returned to room temperature, and 4-amino-3-nitrophenol (2.07g) was added thereto and stirred at room temperature for 10 minutes. Subsequently, 4-chloro-6, 7-dimethoxyquinoline (1.50g) was added thereto, and the mixture was stirred at 100 ℃ for 4 hours. Water was added to the reaction solution, followed by extraction with chloroform, and then the chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (1/1) to give the title compound (0.53 g) in a yield of 23%.
Preparation example 6: 1- [ 2-amino-4- (phenylmethoxy) -5-methoxyphenyl ] -1 -ethanones
1- (4-hydroxy-3-methoxyphenyl) -1-ethanone (20g), potassium carbonate (18.3g), tetra-N-butylammonium iodide (4.45g), and benzyl bromide (17.3ml) were dissolved in N, N-dimethylformamide (300ml), and reacted at 100 ℃ for 1 hour. The solvent was removed by distillation under the reduced pressure, water was added to the resulting residue, extraction was performed with ethyl acetate, and the ethyl acetate layer was dried over sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure, and the obtained residue and fuming nitric acid (12.47ml) were dissolved in acetic acid (120ml) and reacted at room temperature for 2 hours. An aqueous sodium hydroxide solution was added thereto at 0 ℃ to adjust the mixture to neutral, followed by extraction with chloroform and drying of the chloroform layer with sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethanol (1160ml) and water (120ml) while it was still hot, and ammonium chloride (19.2g) and zinc (101.7g) were added thereto, followed by heating and refluxing for 3 hours. The residue was then washed with chloroform/methanol (3/1), the solvent was removed by distillation under the reduced pressure, the resulting residue was made alkaline with an aqueous sodium hydroxide solution, extracted with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/ethyl acetate (10/1) to give the title compound (24.95g) in 77% yield (3 steps).
1H-NMR(CDCl3，400MHz)：δ2.51(s，3H)，3.84(s，3H)，5.14(s，2H)，6.12(s，2H)，7.15-7.62(m，7H)
Preparation example 7: 7- (Phenylmethoxy) -6-methoxy-1, 4-dihydro-4-quinolinones
1- [ 2-amino-4- (phenylmethoxy) -5-methoxyphenyl ] -1-ethanone (24.95g) was dissolved in tetrahydrofuran (450ml), and sodium methoxide (24.87g) was added thereto, followed by stirring at room temperature for 1 hour, ethyl formate (37.07ml) was added thereto, followed by stirring at room temperature for 2 hours, water (150ml) was added thereto, and the mixture was stirred overnight. Concentrated sulfuric acid was added at 0 ℃ to adjust pH4, water was added to extract with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol (10/1) to give the title compound (17.16g) in 66% yield.
1H-NMR(DMSO-d6，400MHz)：δ3.84(s，3H)，5.19(s，2H)，5.97(d，J＝7.1Hz，1H)，7.09(s，1H)，7.28-7.51(m，6H)，7.78(d，J＝7.3Hz，1H)，11.50-11.75(br，1H)
Preparation example 8: 7- (benzyloxy) -4-chloro-6-methoxyquinoline
To 7- (benzyloxy) -6-methoxy-1, 4-dihydro-4-quinolinone (17.16g) was added phosphorus oxychloride (14.19ml), and the mixture was refluxed for 1 hour. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in chloroform, an aqueous sodium hydroxide solution was added to make the solution basic, extraction was performed with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (10/1) to give the title compound (3.82 g) in 21% yield.
1H-NMR(CDCl3，400MHz)：δ4.06(s，3H)，5.32(s，2H)，7.30-7.55(m，8H)，8.56(d，J＝4.9Hz，1H)
Preparation example 9: 4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2, 5-dimethylaniline
Sodium hydride (60 w%, 1.17g) was added to dimethyl sulfoxide (25m1), and the mixture was stirred at 60 ℃ for 30 minutes and then returned to room temperature. Subsequently, 4-amino-2, 5-dimethylphenol (4.00g) was added thereto, and after stirring at room temperature for 10 minutes, 7- (benzyloxy) -4-chloro-6-methoxyquinoline (4.36g) was added thereto. After stirring for 22 hours, water was added to the reaction mixture, followed by extraction with chloroform, and then the chloroform layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and methanol was added to the obtained residue to obtain a suspension. The precipitated crystals were collected by suction filtration to give 3.04g of the title compound in 52% yield.
1H-NMR(CDCl3，400MHz)：δ2.05(s，3H)，2.16(s，3H)，3.58(s，2H)，4.06(s，3H)，5.32(s，2H)，6.28(d，J＝5.1Hz，1H)，6.61(s，1H)，6.81(s，1H)，7.28-7.42(m，3H)，7.44(s，1H)，7.49-7.54(m，2H)，7.63(s，1H)，8.39(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 401 (M)++1)
Preparation example 10: n- (4- { [ 7- (phenylmethoxy) -6-methoxy-4-quinolyl ] Oxy } -2, 5-dimethylphenyl) -N' - (2, 4-difluorophenyl) urea
After 4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2, 5-dimethylaniline (300mg) was dissolved in chloroform (5ml), 2, 4-difluorophenyl isocyanate (200. mu.l) was added and the mixture was stirred at 70 ℃ for 1 night. The reaction solution was purified by silica gel chromatography using chloroform/acetone (75/25) to give the title compound 368mg in 88% yield.
1H-NMR(CDCl3，400MHz)：δ2.17(s，3H)，2.26(s，3H)，4.06(s，3H)，5.33(s，2H)，6.29(d，J＝5.1Hz，1H)，6.42(s，1H)，6.76-6.93(m，3H)，6.70(s，3H)，7.30-7.54(m，7H)，7.60(s，1H)，8.04-8.12(m，1H)，8.44(d，J＝5.4Hz，1H)
Preparation example 11: n- (4- { [ 7- (phenylmethoxy) -6-methoxy-4-quinolyl ] Oxygen } -2, 5-dimethylphenyl) -N' - (2-methoxyphenyl) urea
After 4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2, 5-dimethylaniline (300mg) was dissolved in chloroform (5ml), 2-methoxyphenyl isocyanate (0.24ml) was added, and the mixture was stirred at 70 ℃ for 1 night. The reaction solution was purified by silica gel chromatography using chloroform/acetone (75/25) to give the title compound (365 mg) in 89% yield.
1H-NMR(CDCl3，400MHz)：δ2.17(s，3H)，2.28(s，3H)，3.83(s，3H)，4.07(s，3H)，5.33(s，2H)，6.26(s，3H)，6.29(d，J＝5.4Hz，1H)，6.86-7.06(m，4H)，7.12(s，1H)，7.30-7.41(m，3H)，7.46(s，1H)，7.50-7.56(m，3H)，7.61(s，1H)，8.11-8.16(m，1H)，8.43(d，J＝5.4Hz，1H)
Preparation example 12: 4- { [ 7- (Phenylmethoxy) -6-methoxy-4-quinolyl ] oxy } a -2-chloroaniline
Sodium hydride (60 w%, 320mg) was added to dimethyl sulfoxide (3.6ml), and the mixture was stirred at 60 ℃ for 30 minutes and then returned to room temperature. Subsequently, 4-amino-3-chlorophenol hydrochloride (720mg) was added, and after stirring at room temperature for 10 minutes, 7- (benzyloxy) -4-chloro-6-methoxyquinoline (600mg) was added. After stirring at 105 ℃ for 22 hours, water was added to the reaction mixture, followed by extraction with chloroform, and then the chloroform layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and methanol was added to the obtained residue to obtain a suspension. The precipitated crystals were collected by suction filtration to give the title compound 533mg in 66% yield.
1H-NMR(CDCl3，400MHz)：δ4.05(s，3H)，4.08(s，2H)5.32(s，2H)，6.42(d，J＝5.1Hz，1H)，6.84(d，J＝8.5Hz，1H)，6.93(dd，J＝2.4Hz，8.1Hz，1H)，7.14(d，J＝2.4Hz，1H)，7.29-7.42(m，3H)，7.44(s，1H)，7.49-7.53(m，2H)，7.55(s，1H)，8.45(d，J＝5.3Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 497 (M)++1)
Preparation example 13: n- (4- { [ 7- (phenylmethoxy) -6-methoxy-4-quinolyl ] Oxy } -2-chlorophenyl) -N' - (2, 4-difluorophenyl) urea
After 4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2-chloroaniline (260mg) was dissolved in chloroform (10ml), 2, 4-difluorophenyl isocyanate (198mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel chromatography using chloroform/acetone (10/1) to give the title compound 337mg, which was 94% in yield.
1H-NMR(CDCl3，400MHz)：δ4.04(s，3H)，5.32(s，2H)，6.49(d，J＝5.1Hz，1H)，6.86-6.96(m，3H)，7.10-7.17(m，2H)，7.22-7.28(m，1H)，7.28-7.41(m，3H)，7.45-7.53(m，4H)，7.96-8.04(m，1H)，8.27(d，J＝9.0Hz，1H)，8.49(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 562, 564 (M)++1)
Preparation example 14: n- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) Oxy ] phenyl } -N' - (2, 4-difluorophenyl) urea
N- (4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' - (2, 4-difluorophenyl) urea (215mg) was dissolved in dimethylformamide (11ml), and palladium on carbon (215mg) was added to stir under hydrogen atmosphere at room temperature for 1 night. Ethyl acetate (30ml) was added to the reaction solution, which was then filtered through Celite. The solvent was distilled off under reduced pressure to give the title compound 174mg in a yield of 96%.
1H-NMR(DMSO-d6，400MHz)：δ3.94(s，3H)，6.47(d，J＝5.1Hz，1H)，7.01-7.11(m，1H)，7.18-7.36(m，3H)，7.44-7.52(m，2H)，7.95(s，1H)，7.98-8.13(m，1H)，8.23(d，J＝9.5Hz，1H)，6.50(d，J＝5.1Hz，1H)，8.81(s，1H)，9.31(s，1H)
Mass Spectrometry (ESI-MS, m/z): 472 (M)++1)
Preparation example 15: 4- { [ 7- (Phenylmethoxy) -6-methoxy-4-quinolyl ] oxy } a -2, 3-dimethylaniline
Sodium hydride (60 w%, 0.32g) was added to dimethyl sulfoxide (6ml), and after stirring at room temperature for 30 minutes, 4-amino-2, 3-dimethylphenol (1.10g) was added and stirring at room temperature for 10 minutes. Then, 7- (benzyloxy) -4-chloro-6-methoxyquinoline (1.20g) was added thereto, and the mixture was stirred at 110 ℃ for 6 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (6/1) to give the title compound in a yield of 49 g.
1H-NMR(DMSO-d6，400MHz)δ1.87(s，3H)，1.96(s，3H)，3.97(s，3H)，4.78(s，2H)，5.23(s，2H)，6.12(d，J＝5.3Hz，1H)，6.54(d，J＝8.4Hz，1H)，6.69(d，J＝8.4Hz，1H)，7.27-7.51(m，7H)，8.31(d，J＝5.3Hz，1H)
Preparation example 16: n- (4- { [ 7- (phenylmethoxy) -6-methoxy-4-quinolyl ] Oxy } -2, 3-dimethylphenyl) -N' - (2, 4-difluorophenyl) urea
After 4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2, 3-dimethylaniline (260mg) was dissolved in N, N-dimethylformamide (5ml), 2, 4-difluorophenyl isocyanate (121mg) was added thereto, and the mixture was stirred at room temperature for 1 night. Methanol was added, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with methanol and collected by filtration to give the title compound 219mg in a yield of 61%.
1H-NMR(DMSO-d6，400MHz)δ1.99(s，3H)，2.17(s，3H)，3.90(s，3H)，5.24(s，2H)，6.18(d，J＝5.1Hz，1H)，6.95-6.98(m，2H)，7.25-7.63(m，9H)，8.05-8.08(m，1H)，8.34-8.36(m，2H)，8.79(s，1H)
Preparation example 17: 7- (benzyloxy) -4- (3-fluoro-4-nitrophenoxy) -6- Methoxy radicalQuinolines
7- (Phenylmethoxy) -4-chloro-6-methoxyquinoline (300mg) and 3-fluoro-4-nitrophenol (785mg) were dissolved in chlorobenzene (3ml), which was stirred at 130 ℃ for 5 hours. Chloroform and an aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was stirred for 1 hour. The reaction solution was extracted with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the resulting residue was purified by thin layer silica gel chromatography using hexane/ethyl acetate (1/1) to give the title compound in a yield of 197 mg.
1H-NMR(DMSO-d6，400MHz)δ3.83(s，3H)，5.25(s，2H)，6.91(d，J＝5.1Hz，1H)，7.29-7.50(m，9H)，8.18-8.23(m，1H)，8.56(d，J＝5.1Hz，1H)
Preparation example 18: 4- (4-amino-3-fluorophenoxy) -6-methoxy-7-hydroxyquinoline Quinoline (III)
7- (benzyloxy) -4- (3-fluoro-4-nitrophenoxy) -6-methoxyquinoline (190mg) was dissolved in N, N-dimethylformamide (5ml) and triethylamine (1ml), and palladium hydroxide (40mg) was added to the solution, followed by stirring under hydrogen atmosphere at room temperature for 1 night. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/methanol (20/1) to give the title compound in a yield of 56 mg.
1H-NMR(DMSO-d6，400MHz)δ3.87(s，3H)，5.11(s，2H)，6.29(d，J＝5.1Hz，1H)，6.77-6.80(m，2H)，6.93-6.99(m，1H)，7.19(s，1H)，7.40(s，1H)，8.31(d，J＝5.1Hz，1H)，10.03(s，1H)
Preparation example 19: n- (2, 4-difluorophenyl) -N' - { 2-fluoro-4- [ (7-hydroxy) -6-methoxy-4-quinolyl) oxy ] phenyl } urea
After 4- (4-amino-3-fluorophenoxy) -6-methoxy-7-quinolinol (70mg) was dissolved in chloroform (1.5ml) and N, N-dimethylformamide (1ml), 2, 4-difluorophenylisocyanate (43mg) was added thereto and the mixture was reacted at room temperature for 3 hours. Methanol was added to the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/methanol (20/1) to quantitatively obtain the title compound.
1H-NMR(DMSO-d6，400MHz)δ3.94(s，3H)，6.47(d，J＝5.1Hz，1H)，7.04-7.10(m，2H)，7.28-7.34(m，2H)，7.47(s，1H)，8.05-8.15(m，2H)，8.30(s，1H)，8.43(d，J＝5.1Hz，1H)，8.97-9.03(m，2H)，10.10(s，1H)
Preparation example 20: 4-chloro-6-methoxy-7-hydroxyquinoline
7- (benzyloxy) -4-chloro-6-methoxyquinoline (100mg), phenylthiomethane (300. mu.l) and methanesulfonic acid (25. mu.l) were dissolved in trifluoromethanesulfonic acid (1ml), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and to the obtained residue was added an aqueous sodium hydroxide solution to adjust the mixture to neutral, and hexane was added to obtain a suspension. The crystals were collected by suction filtration to give the title compound 53mg in 75% yield.
1H-NMR(DMSO-d6，400MHz)：δ3.98(s，3H)，7.33(s，1H)，7.36(s，1H)，7.47(d，J＝4.9Hz，1H)，8.54(d，J＝4.9Hz，1H)，10.37(br，1H)
Preparation example 21: 4-chloro-6-methoxy-7- (2-methoxyethoxy) quinoline
4-chloro-6-methoxy-7-quinolinol (50mg), potassium carbonate (40mg), tetra-N-butylammonium iodide (9mg), 2-bromoethyl methyl ether (40mg) were dissolved in N, N-dimethylformamide (10ml), and the mixture was stirred at 70 ℃ for 1 night. The solvent was removed by distillation under the reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the resulting residue was purified by chromatography on silica gel using hexane/acetone/dichloromethane (6/2/1) to give the title compound 47mg in 74% yield.
1H-NMR(CDCl3，400MHz)：δ3.49(s，3H)，3.88-3.90(m，2H)，4.04(s，3H)，4.32-4.35(m，2H)，7.35(d，J＝4.9Hz，1H)，7.40(s，1H)，7.43(s，1H)，8.57(d，J＝4.9Hz，1H)
Preparation example 22: 2-chloro-4- { [ (6-methoxy-7- (2-methoxyethoxy) - 4-quinolyl ] oxy } anilines
Sodium hydride (60 w%, 153mg) was added to dimethyl sulfoxide (2ml), and after stirring at 60 ℃ for 30 minutes, the mixture was returned to room temperature, 4-amino-3-chlorophenol hydrochloride (343mg) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 4-chloro-6-methoxy-7- (2-methoxyethoxy) quinoline (254mg) dissolved in dimethyl sulfoxide (2ml) was added thereto, and the mixture was stirred at 110 ℃ for 1 night. Water was added to the reaction solution, followed by extraction with chloroform, and then the chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (7/3) to give the title compound.
1H-NMR(CDCl3，400MHz)：δ3.49(s，3H)，3.89-3.91(m，2H)，4.02(s，3H)，4.09(s，2H)，4.33-4.35(m，2H)，6.43(d，J＝5.4Hz，1H)，6.85(d，J＝8.5Hz，1H)，6.93-6.96(m，1H)，7.15(d，J＝2.7Hz，1H)，7.41(s，1H)，7.52(s，1H)，8.47(d，J＝5.1Hz，1H)
Preparation example 23: 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] benzene Amines as pesticides
Sodium hydride (60 w%, 5.80g) was added to dimethyl sulfoxide (40ml), and the mixture was stirred at 60 ℃ for 30 minutes and then returned to room temperature. Then, 4-amino-3-chlorophenol hydrochloride (13.05g) was added thereto, and after stirring at room temperature for 10 minutes, the mixture was added thereto in accordance with J.Am.chem.Soc.,68，1299(1946)、J.Am.Chem.Soc.， 684-chloro-6, 7-dimethoxyquinazoline (8.14g), which is a chloroquinazoline derivative, was synthesized by a conventional method as described in 1305(1946) and the like. After stirring at 110 ℃ for 30 minutes, water was added to the reaction mixture, followed by extraction with chloroform. Then, the chloroform layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfateAnd (5) drying. The solvent was distilled off under reduced pressure, and methanol was added to the obtained residue to obtain a suspension. The precipitated crystals were collected by suction filtration to give 9.13g of the title compound in a yield of 76%.
1H-NMR(CDCl3，400MHz)：δ4.05-4.08(m，8H)，6.85(d，J＝8.5Hz，1H)，7.00(dd、J＝2.7Hz，8.8Hz，1H)，7.21(d，J＝2.7Hz，1H)，7.32(s，1H)，7.52(s，1H)，8.64(s，1H)
Mass Spectrometry (ESI-MS, m/z): 332 (M)++1)
Preparation example 24: N-benzyl-N- (2, 4-difluorophenyl) amine
2, 4-difluoroaniline (2.37ml) and benzaldehyde (2.36ml) were dissolved in methanol (46ml), and magnesium sulfate (5.59g) and a small amount of acetic acid were added to the solution, followed by stirring at room temperature for 45 minutes. Sodium borohydride (2.64g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Distilling under reduced pressure to remove solvent, adding water and ethyl acetate, stirring, and filtering with diatomaceous earth. The organic layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by chromatography on silica gel using hexane/acetone (30/1) to give the title compound 3.04g in 60% yield.
1H-NMR(CDCl，400MHz)：δ4.34(s，2H)，6.56-6.82(m，3H)，7.25-7.38(m，5H)
Preparation example 25: 4- (Phenylmethoxy) -5-methoxy-2-nitrobenzoic acid methyl ester
Commercially available vanillic acid methyl ester (50g) and potassium carbonate (76g) were dissolved in N, N-dimethylformamide (200ml), and benzyl bromide (33ml) was added dropwise over 10 minutes and stirred at room temperature for 1 night. Water (200ml) was added thereto, and the mixture was extracted with ethyl acetate, and then saturated brine was added to the organic phase to conduct extraction with ethyl acetate. Sodium sulfate was added to the organic phase and dried. The organic phase was then filtered, the solvent was distilled off under reduced pressure, and the resulting residue was dried on a vacuum pump to obtain 68g of a white solid. Then, under ice-cooling conditions, 100ml of acetic acid and 200ml of nitric acid were added, and after stirring for 8 hours, water was added. The resulting solid was collected by filtration, washed well with water, and dried on a vacuum pump to give 74g of the title compound. The yield thereof was found to be 93%.
1H-NMR(CDCl3，400MHz)：3.90(s，3H)，3.98(s，3H)，5.21(s，2H)，7.08(s，1H)，7.31-7.45(m，5H)，7.51(s，1H)
Preparation example 26: 7- (Phenylmethoxy) -6-methoxy-3, 4-dihydro-4-quinazolines
Methyl 4- (benzyloxy) -5-methoxy-2-nitrobenzoate (15.0g) was dissolved in acetic acid (200ml) at room temperature, and iron (powder) (13.2g) was added thereto, and the mixture was heated to 90 ℃ and stirred for 1 hour. The resulting grey solid was filtered through celite and washed with acetic acid. After concentrated hydrochloric acid was added to the mother liquor, the solvent was distilled off under reduced pressure to precipitate a solid. The resulting solid was collected by filtration, washed with ethyl acetate, diethyl ether and dried with a vacuum pump. Then, chloroform and methanol were added to the obtained solid to suspend the solid, and then a 10% aqueous solution of sodium hydroxide was added to dissolve the solid. The mixture was extracted with chloroform, washed with water, and the organic phase was dried over sodium sulfate, followed by filtration of the organic phase and distillation under reduced pressure to remove the solvent, and the resulting residue was dried on a vacuum pump to obtain 9.5g of a crude purified product of methyl 2-amino-4- (phenylmethoxy) -5-methoxybenzoate. The yield thereof was found to be 70%.
The obtained methyl 2-amino-4- (benzyloxy) -5-methoxybenzoate (650mg) was dissolved in N, N-dimethylformamide (15ml) and methanol (3ml), and formamide (0.46ml) and sodium methoxide (373mg) were added thereto, and the mixture was stirred at 100 ℃ overnight. After cooling to room temperature, 10ml of water was added. The reaction solution was neutralized with 1M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, washed with water, diethyl ether and dried on a vacuum pump to give the title compound 566 mg. The yield thereof was found to be 87%.
1H-NMR(DMSO-d6，400MHz)：3.88(s，3H)，5.25(s，2H)，7.23(s，1H)，7.33-7.49(m，6H)，7.97(s，1H)，12.06(br，1H)
Preparation example 27: 7- (benzyloxy) -4-chloro-6-methoxyquinazoline
To 7- (benzyloxy) -6-methoxy-3, 4-dihydro-4-quinazoline (400mg) and diisopropylethylamine (0.3ml), phosphorus oxychloride (515ml) was added, and the mixture was refluxed for 20 minutes. After cooling to room temperature, 10% aqueous sodium hydroxide solution was added, followed by extraction with chloroform. The organic phase was dried over sodium sulfate, the organic phase was filtered, the solvent was then distilled off under reduced pressure, and the resulting residue was dried on a vacuum pump to obtain the title compound (420 mg). The yield thereof was found to be 99%.
1H-NMR(CDCl3，400MHz)：4.08(s，3H)，5.34(s，2H)，7.35-7.51(m，7H)，8.86(s，1H)
Preparation example 28: 5- (Phenylmethoxy) -4-methoxy-2-nitrobenzoic acid methyl ester
Commercially available methyl 3-hydroxy-4-methoxybenzoate (10g) and potassium carbonate (23g) were dissolved in N, N-dimethylformamide (50ml), and benzyl bromide (6.5ml) was added dropwise over 10 minutes and stirred at room temperature for 1 night. 20ml of water was added thereto, and the mixture was extracted with ethyl acetate, and then saturated brine was added to the organic phase to conduct extraction with ethyl acetate. Sodium sulfate was added to the organic phase and dried. The organic phase was then filtered, the solvent was distilled off under reduced pressure, and the resulting residue was dried on a vacuum pump to obtain 8.4g of a white solid. Then, 7.0g of the obtained solid was charged into a flask, and 100ml of acetic acid and 200ml of nitric acid were added under ice-cooling, and after stirring for 8 hours, water was added. The resulting solid was collected by filtration, washed well with water, and dried on a vacuum pump to give 7.9g of the title compound.
1H-NMR(CDCl3，400MHz)：3.89(s，3H)，3.96(s，3H)，5.21(s，2H)，7.15(s，1H)，7.34-7.45(m，6H)
Preparation example 29: 6- (Phenylmethoxy) -7-methoxy-3, 4-dihydro-4-quinazolines Ketones
After methyl 5- (benzyloxy) -4-methoxy-2-nitrobenzoate (15.8g) was dissolved in acetic acid (200ml) at room temperature, iron (powder) (13.9g) was added, and the mixture was stirred at 90 ℃ for 1 hour. The resulting grey solid was filtered through celite and washed with acetic acid. After concentrated hydrochloric acid was added to the mother liquor, the solvent was distilled off under reduced pressure to precipitate a solid. The resulting solid was collected by filtration, washed with ethyl acetate, diethyl ether and dried with a vacuum pump. Then, chloroform and methanol were added to the obtained solid to suspend the solid, and then a 10% aqueous solution of sodium hydroxide was added to dissolve the solid. The mixture was extracted with chloroform, washed with water, and the organic phase was dried over sodium sulfate, followed by filtration of the organic phase and distillation under reduced pressure to remove the solvent, and the resulting residue was dried on a vacuum pump to obtain 10.4g of a crude purified product of methyl 2-amino-5- (phenylmethoxy) -4-methoxybenzoate. The yield thereof was found to be 73%.
The obtained methyl 2-amino-5- (benzyloxy) -4-methoxybenzoate (5.0g) was dissolved in N, N-dimethylformamide (150ml) and methanol (30ml), and formamide (3.5ml) and sodium methoxide (2.8g) were added to the solution, and the mixture was stirred at 100 ℃ overnight. After cooling to room temperature, 10ml of water was added. The reaction solution was neutralized with 1M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, washed with water, diethyl ether and dried on a vacuum pump to give the title compound (3.7 g). The yield thereof was found to be 76%.
1H-NMR(DMSO-d6，400MHz)：3.92(s，3H)，5.21(s，2H)，7.16(s，1H)，7.33-7.49(m，5H)，7.55(s，1H)，7.99(s，1H)，12.06(br，1H)
Preparation example 30: 6- (benzyloxy) -4-chloro-7-methoxyquinazoline
To 6- (benzyloxy) -7-methoxy-3, 4-dihydro-4-quinazolinone (3.5g) and diisopropylethylamine (11.5ml), phosphorus oxychloride (3.1ml) was added and the mixture was refluxed for 20 minutes. After cooling to room temperature, 10% aqueous sodium hydroxide solution was added, followed by extraction with chloroform. The organic phase was dried over sodium sulfate, the organic phase was filtered, the solvent was then distilled off under reduced pressure, and the resulting residue was dried on a vacuum pump to obtain 2.9g of the title compound. The yield thereof was found to be 72%.
1H-NMR(CDCl3，400MHz)：4.07(s，3H)，5.32(s，2H)，7.35-7.53(m，7H)，8.86(s，1H)
Preparation example 31: 4- { [ 7- (phenylmethoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chloroaniline
7- (Phenylmethoxy) -4-chloro-6-methoxyquinazoline (30.0g) and tetrabutylammonium chloride (13.9g) were dissolved in acetone (400ml) and stirred at room temperature. To the solution was added 4-amino-3-chlorophenol hydrochloride (36.0g) dissolved in a 20% aqueous solution of sodium hydroxide (64ml), and the mixture was refluxed for 3 hours. After cooling to room temperature, chloroform and water were added to the reaction mixture, and the mixture was extracted with chloroform, washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. After sodium sulfate was removed, the solvent was distilled off, the obtained residue was washed with methanol, and the obtained solid was dried under reduced pressure by a vacuum pump to obtain 36.6g of the title compound. The yield thereof was found to be 90%.
1H-NMR(DMSO-d6，400MHz)：δ3.96(s，3H)，5.34(s，2H)，6.86(d，J＝8.8Hz，1H)，7.00(dd，J＝2.7Hz，8.8Hz，1H)，7.22(d，J＝2.7Hz，1H)，7.35-7.54(m，7H)，8.53(s，1H)
Preparation example 32: n- (4- { [ 7- (phenylmethoxy) -6-methoxy-4-quinazolinyl ] Oxy } -2-chlorophenyl) -N' -propylurea
4- { [ 7- (Phenylmethoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chloroaniline (12.2g) was dissolved in anhydrous chloroform, and triethylamine (8.4ml) was added thereto, followed by stirring at room temperature. Triphosgene (4.5g) was then dissolved in anhydrous chloroform (12ml) and added dropwise to the mixed solution. After stirring at room temperature for 20 minutes, n-propylamine (4.9ml) was added. Stirring was continued for another 1 hour at room temperature to precipitate a white solid. The solid was collected by filtration and washed with chloroform to give the title compound 9.4 g. The yield thereof was found to be 63%.
1H-NMR(DMSO-d6，400MHz)：δ0.91(t，J＝7.3Hz，3H)，1.44-1.50(m，2H)，3.06-3.09(m，2H)，3.98(s，3H)，5.35(s，2H)，6.97-7.01(m，1H)，7.23(dd，J＝2.7Hz，9.0Hz，1H)，7.37-7.57(m，9H)，8.20(d，J＝9.3Hz，1H)，8.55(s，1H)
Preparation example 33: n- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) Oxy phenyl } -N' -propylurea
N- (4- { [ 7- (benzyloxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea (42.2g) was dissolved in trifluoroacetic acid (200ml), followed by addition of methanesulfonic acid (11.1ml) and stirring at 100 ℃ for 4 hours. After returning to room temperature, trifluoroacetic acid was distilled off under reduced pressure. Chloroform and methanol were added to the remaining mixture, and the mixture was extracted 3 times with a 10% aqueous solution of sodium hydroxide. The aqueous phase was neutralized with concentrated hydrochloric acid to precipitate a solid. The resulting solid was washed with water, methanol and ether in this order, and dried under reduced pressure using a vacuum pump to obtain 20.7g of the title compound. The yield thereof was found to be 60%.
1H-NMR(DMSO-d6，400MHz)：δ0.91(t，J＝7.3Hz，3H)，1.42-1.49(m，2H)，3.06-3.17(m，2H)，3.84(s，3H)，6.65(s，1H)，7.03(m，1H)，7.14(dd，J＝2.7Hz，9.0Hz，1H)，7.20(s，1H)，7.35(d，J＝2.7Hz，1H)，8.05(s，1H)，8.14(dd，J＝2.7Hz，8.8Hz，1H)，8.19(s，1H)
Preparation example 34: 6, 7-dimethoxy-4-quinazolone
To methyl 2-amino-3, 4-dimethoxybenzoate (20.0g, 94.8mmol) was added formamide (150ml) and the mixture was heated to 160 ℃ for 8.5 hours. After cooling the reaction solution, it was filtered, and the resulting precipitate was washed with water (100 ml. times.2 times). The washed precipitate was dried under reduced pressure to obtain 17.85g of the objective product in a yield of 91.5%.
1H-NMR(DMSO-d6，400MHz)：δ4.01(s，3H)，4.02(s，3H)，7.14(s，1H)，7.34(s，1H)，7.61(s，1H)，7.97(s，1H)
Preparation example 35: 4-chloro-6, 7-dimethoxyquinazoline
To 6, 7-dimethoxy-4-quinazolinone (50.1g, 0.24mol) was added sulfolane (250ml) and phosphorus oxychloride (250ml ═ 412.5g, 2.69mol), and the mixture was stirred at 120 ℃ for 1 hour. After cooling to room temperature, excess phosphorus oxychloride was removed by distillation under the reduced pressure, and the residue was poured into ice water (1000ml) and chloroform (1000ml) was added. The aqueous layer was adjusted to pH6.5 with 20% sodium hydroxide, and the aqueous and organic layers were separated. The organic layer obtained by the separation was washed with water (1000ml × 6 times), dried over sodium sulfate, and concentrated under reduced pressure. Tetrahydrofuran (470ml) was added to the residue for reflux, cooled to-5 ℃ to-10 ℃, filtered, and dried to obtain 38.5g of the objective product with a yield of 71.4%.
1H-NMR(DMSO-d6，400MHz)：δ4.09(s，3H)，4.09(s，3H)，7.14(s，1H)，7.34(s，1H)，7.61(s，1H)，7.97(s，1H)
Preparation example 36: 4-chloro-6, 7-dimethoxyquinazoline
To 6, 7-dimethoxy-4-quinazolinone (10.0g, 48.5mmol) were added toluene (100ml) and phosphorus oxychloride (7.4g, 48.6mmol), and the mixture was stirred at 120 ℃ for 6.5 hours. After cooling to room temperature, it was filtered. Washed with toluene (100ml, 50ml) and dried to give 11.5g of the desired product in 91% yield.
Preparation example 37: 4- (4 '-amino-3' -chloro) -phenoxy-6, 7-dimethoxyquinoline Azoline
To 4-amino-3-chlorophenol hydrochloride (14.6g, 81mmol) were added sodium hydroxide (8.5g, 0.21mol) and water (90ml) to dissolve it, and 4-chloro-6, 7-dimethoxyquinazoline (12g, 53mmol) and methyl ethyl ketone (225ml) were added and refluxed for 2 hours. After the reaction solution was cooled to about 50 ℃, chloroform (500ml) and water (500ml) were added thereto, and after stirring for 10 minutes, the organic layer and the aqueous layer were separated. Chloroform (250ml) was further added to the aqueous layer obtained by the separation, and after stirring for 10 minutes, the mixture was separated. The organic layer obtained was concentrated under reduced pressure to give a residue. Methanol (50ml) was added to the residue, and after stirring for 30 minutes, filtration and drying were carried out to obtain 15.6g of the objective product with a yield of 85%.
1H-NMR(DMSO-d6，400MHz)：δ3.95(s，3H)，3.97(s，3H)，5.33(s，2H)，6.85(d，J＝8.8Hz，1H)，6.98(dd，J＝2.8Hz，J＝8.8Hz，1H)，7.20(d，J＝2.8Hz，1H)，7.36(s，1H)，7.51(s，1H)，8.53(s，1H)
Preparation example 38: 4- (4 '-amino-3' -chloro) -phenoxy-6, 7-dimethoxyquinoline Azoline
To 4-amino-3-chlorophenol hydrochloride (1.3g, 7.2mmol) were added 20% aqueous sodium hydroxide (3.5ml) and water (2ml) to dissolve it, and 4-chloro-6, 7-dimethoxyquinazoline (0.8g, 3.6mmol), chloroform (6ml) and tetrabutylammonium bromide (0.58g, 1.8mmol) were added and refluxed for 2 hours. After the reaction solution was cooled, chloroform (10ml) and water (10ml) were added thereto, and after stirring for 10 minutes, the organic layer and the aqueous layer were separated. Chloroform (10ml) was further added to the aqueous layer obtained by the separation, and after stirring for 10 minutes, the organic layer obtained was separated and concentrated under reduced pressure to obtain a residue. Methanol (2ml) was added to the residue, and after stirring for 30 minutes, filtration and drying were carried out to obtain 1.0g of the objective product with a yield of 83%.
Example 1: n- (2, 4-difluorobenzyl) -N' - {4- [ (6, 7-dimethoxy) -4-quinolyl) oxy ] -2-fluorophenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in toluene (5.0ml) and triethylamine (1.0ml) under heating, and then triphosgene (103mg) dissolved in dichloromethane (1.0ml) was added to the solution, followed by heating and refluxing for 3 minutes. 2, 4-difluorobenzylamine (54mg) was then added and the mixture was heated under reflux for 5 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound (123 mg) in 80% yield.
1H-NMR(CDCl3，400MHz)：δ4.02(s，3H)，4.03(s，3H)，4.47(d，J＝5.9Hz，2H)，5.78-5.90(m，1H)，6.46(d，J＝5.4Hz，1H)，6.74-6.99(m，4H)，7.03-7.14(m，1H)，7.35-7.44(m，2H)，7.50(s，1H)，8.16(t，J＝9.0Hz，1H)，8.47(d，J＝5.1Hz，1H)
Mass Spectrometry (FD-MS, m/z): 483 (M)+)
Example 2: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluorobenzene Radical } -N' - (2-fluoroethyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in toluene (10ml) and triethylamine (0.5ml) with heating, and triphosgene (47mg) dissolved in dichloromethane (1.0ml) was added to the solution, and the mixture was refluxed for 5 minutes. 2-fluoroethylamine hydrochloride (42mg) was then added and the mixture was heated under reflux for a further 8 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound in a yield of 72 mg.
1H-NMR(DMSO-d6，400MHz)：δ3.40(m，1H)，3.47(m，1H)，3.93(s，3H)，3.95(s，3H)，4.42(t，J＝4.9Hz，1H)，4.54(t，J＝4.9Hz，1H)，6.51(d，J＝5.4Hz，1H)，6.88(m，1H)，7.05(m，1H)，7.28(dd，J＝2.7Hz，J＝11.7Hz，1H)，7.40(s，1H)，7.49(s，1H)，8.21(m，1H)，8.47(br，1H)，8.48(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 404 (M)++1)
Example 3: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluorobenzene Radical } -N' - (2-pyridylmethyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in toluene (5ml) or triethylamine (1ml), and triphosgene (104mg) dissolved in methylene chloride was added to the solution, followed by refluxing for 5 minutes. Then, 2- (aminomethyl) pyridine (40. mu.l) was added thereto and the mixture was refluxed for 2 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution (1ml) and chloroform (2ml), and the mixture was held on celite and extracted with chloroform. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (8/1) to give the title compound 126mg in 88% yield.
1H-NMR(CDCl3，400MHz)：δ4.07(s，3H)，4.09(s，3H)，4.61(d，J＝5.4Hz，2H)，6.40-6.50(br，1H)，6.61(d，J＝5.9Hz，1H)，6.92-7.01(m，2H)，7.21-7.25(m，1H)，7.36(d，J＝7.8Hz，1H)，7.56(s，1H)，7.68-7.78(m，2H)，7.75(s，1H)，8.27-8.34(m，1H)，8.49(d，J＝6.1Hz，1H)，8.55(d，J＝4.1Hz，1H)
Mass Spectrometry (FD-MS, m/z): 448 (M)+)
Example 4: N-allyl-N' - {4- [ (6, 7-dimethoxy-4-quinolyl) Oxy ] -2-fluorophenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in toluene (5ml) or triethylamine (1ml), and triphosgene (104mg) dissolved in methylene chloride was added to the solution, followed by refluxing with heating for 5 minutes. Subsequently, allylamine (22mg) was added and the mixture was heated under reflux for another 4 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution (1ml) and chloroform (2ml), and the mixture was held on celite and extracted with chloroform. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound 125mg in 98% yield.
1H-NMR(CDCl3，400MHz)：δ3.91-3.96(m，2H)，4.06(s，3H)，4.09(s，3H)，5.14-5.20(m，1H)，5.26-5.33(m，1H)，5.58-5.66(br，1H)，5.86-5.98(m，1H)，6.56(d，J＝5.9Hz，1H)，6.88-7.01(m，2H)，7.23(s，1H)，7.55(s，1H)，7.66(s，1H)，8.26-8.33(m，1H)，8.47(d，J＝5.9Hz，1H)
Mass Spectrometry (FD-MS, m/z): 397 (M)+)
Example 5: n- {4- [ (6, 7-dimethoxy-4-quinoline)Yl) oxy ] -2-fluorobenzene Radical } -N' -propylurea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in toluene (10ml) or triethylamine (2ml), and triphosgene (104mg) dissolved in methylene chloride was added to the solution, followed by heating and refluxing for 5 minutes. Subsequently, propylamine (29mg) was added to the solution, and the mixture was heated under reflux for another 40 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/methanol (10/1) to give the title compound (89 mg) with a yield of 71%.
1H-NMR(CDCl3，400MHz)：δ0.97(t，J＝7.6Hz，3H)，1.55-1.64(m，2H)，3.24-3.29(m，2H)，4.05(s，3H)，4.06(s，3H)，5.11(t，J＝5.4Hz，1H)，6.51(d，J＝5.4Hz，1H)，6.74-6.76(m，1H)，6.91-6.99(m，2H)，7.48(s，1H)，7.52(s，1H)，8.18-8.23(m，1H)，8.49(d，J＝5.6Hz，1H)
Mass Spectrometry (FD-MS, m/z): 399 (M)+)
Example 6: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluorobenzene Radical } -N' - (4-fluorobutyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in toluene (6ml) or triethylamine (1.0ml) under heating, and then triphosgene (104mg) dissolved in dichloromethane (1.0ml) was added to the solution, followed by heating and refluxing for 5 minutes. 4-Fluorobutylamine hydrochloride (55mg) was then added and the mixture was heated under reflux for an additional 2 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and then the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound 80mg in 55% yield.
1H-NMR(CDCl3，400MHz)：δ1.66-1.87(m，4H)，3.33-3.40(m，2H)，4.04(s，3H)，4.05(s，3H)，4.44(t，J＝5.6Hz，1H)，4.56(t，J＝5.7Hz，1H)，4.90(t，J＝5.7H，z，1H)，6.48-6.52(m，2H)，6.93-7.02(m，2H)，7.42(s，1H)，7.51(s，1H)，8.15(t，J＝8.9Hz，1H)，8.50(d，J＝5.1Hz，1H)
Mass Spectrometry (FD-MS, m/z): 431 (M)+)
Example 7: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluorobenzene Radical } -N' - (2-propynyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (150mg) was dissolved in chloroform (10ml) or triethylamine (2ml), and triphosgene (156mg) dissolved in methylene chloride was added to the solution, followed by heating and refluxing for 10 minutes. Propargylamine (53mg) was then added, and the mixture was heated under reflux for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound in a yield of 164 mg.
1H-NMR(DMSO-d6，400MHz)δ2.49-2.51(m，1H)，3.90-3.95(m，8H)，6.52(d，J＝5.1Hz，1H)，6.89-6.92(m，1H)，7.04-7.06(m，1H)，7.26-7.29(m，1H)，7.39(s，1H)，7.49(s，1H)，8.16-8.20(m，1H)，8.46-8.49(m，2H)
Example 8: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluorobenzene Radical } -N' -ethylurea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in toluene (8ml) or triethylamine (1.0ml) by heating, and triphosgene (47mg) dissolved in toluene (1.0ml) was added to the solution, followed by heating and refluxing for 5 minutes. Subsequently, ethylamine hydrochloride (60mg) was added thereto, and the mixture was heated under reflux for 5 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound in a yield of 53 mg.
1H-NMR(CDCl3，400MHz)：δ1.21(t，J＝7.3Hz，3H)，3.34(m，2H)，4.06(s，3H)，4.08(s，3H)，5.64(br，1H)，6.55(d，J＝5.6Hz，1H)，6.89(dd，J＝2.7Hz，J＝11.2Hz，1H)，6.97(m，1H)，7.26(br，1H)，7.54(s，1H)，7.62(s，1H)，8.28(t，J＝9.0Hz，1H)，8.47(d，J＝5.6Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 386 (M)++1)
Example 9: N-butyl-N' - {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluorophenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in toluene (8ml) or triethylamine (1.0ml) by heating, and triphosgene (47mg) dissolved in toluene (1.0ml) was added to the solution, followed by heating and refluxing for 5 minutes. Butylamine (80mg) was then added and the mixture was heated under reflux for an additional 5 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound 117mg in 81% yield.
1H-NMR(CDCl3，400MHz)：δ0.94(t，J＝7.3Hz，3H)，1.40(m，2H)，1.55(m，2H)，3.29(dd，J＝7.1Hz，J＝12.9Hz，2H)，4.06(s，3H)，4.09(s，3H)，5.72(br，1H)，6.56(d，J＝5.9Hz，1H)，6.88(dd，J＝2.7Hz，J＝11.2Hz，1H)，6.97(d，J＝9.0Hz，1H)，7.33(s，1H)，7.55(s，1H)，7.65(s，1H)，8.30(t，J＝9.0Hz，1H)，8.46(d，J＝5.9Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 414 (M)++1)
Example 10: N-tert-butyl-N' - {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluorophenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in chloroform (5ml) or triethylamine (1ml), and triphosgene (104mg) dissolved in methylene chloride was added to the solution, followed by refluxing with heating for 5 minutes. Tert-butylamine (48. mu.l) was then added thereto and heated under reflux for 10 minutes. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (8/2) to give the title compound 117mg in 89% yield.
1H-NMR(CDCl3，400MHz)：δ0.95(t，J＝7.6Hz，3H)，1.18(d，J＝6.6Hz，3H)，1.47-1.55(m，2H)，3.79-3.89(m，1H)，4.04(s，6H)，5.28(d，J＝8.1Hz，1H)，6.48(d，J＝5.4Hz，1H)，6.89-6.98(m，2H)，7.08(d，J＝2.7Hz，1H)，7.42(s，1H)，7.51(s，1H)，8.20-8.24(m，J＝9.0Hz，1H)，8.48(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 414 (M)++1)
Example 11: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoro Phenyl } -N' -isobutyl urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in chloroform (5ml) or triethylamine (1ml), and triphosgene (104mg) dissolved in methylene chloride was added to the solution, followed by refluxing with heating for 5 minutes. Isobutylamine (50. mu.l) was then added and heated at reflux for 10 minutes. The reaction solution was purified by silica gel chromatography using chloroform/acetone (4/1) to quantitatively obtain the title compound.
1H-NMR(CDCl3，400MHz)：δ0.94(d，J＝6.6Hz，6H)，1.77-1.84(m，1H)，3.10-3.13(m，2H)，4.03(s，3H)，4.03(s，3H)，5.58(t，J＝5.4Hz，1H)，6.47(d，J＝5.4Hz，H)，6.88-6.97(m，2H)，7.18(s，1H)，7.41(s，1H)，7.50(s，1H)，8.18-8.23(m，1H)，8.48(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 414 (M)++1)
Example 12: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoro Phenyl } -N' - (1, 2-dimethylpropyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-fluoroaniline (100mg) was dissolved in chloroform (5ml) and triethylamine (1ml), and triphosgene (47mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. 1, 2-dimethylpropylamine (55. mu.l) was then added and stirred at room temperature for 10 minutes. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound (89 mg) in a yield of 65%.
1H-NMR(CDCl3，400MHz)：δ0.93(d，J＝2.2Hz，3H)，0.95(d.J＝2.4Hz，3H)，1.14(d，J＝6.8Hz，3H)，1.72-1.80(m，1H)，3.76-3.84(m，1H)，4.04(s，3H)，4.05(s，3H)，4.91(d，J＝8.5Hz，1H)，6.48(d，J＝5.4Hz，1H)，6.74(d，J＝2.9Hz，1H)，6.91-6.98(m，2H)，7.42(s，1H)，7.51(s，1H)，8.18-8.23(m，1H)，8.49(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 428 (M)++1)
Example 13: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] Phenyl } -N' -propylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (100mg) was dissolved in chloroform (7.5ml) and triethylamine (1ml), and triphosgene (99mg) dissolved in chloroform was added to the solution, followed by further refluxing for 5 minutes. Subsequently, n-propylamine (21mg) was added to the solution, and the mixture was heated under reflux for another 2 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, which was then kept on celite, and the resulting mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/methanol (8/1) to quantitatively obtain the title compound.
1H-NMR(CDCl3，400MHz)：δ0.99(t，J＝7.3Hz，3H)，1.58-1.65(m，2H)，3.24-3.31(m，2H)，4.04(s，3H)，4.05(s，3H)，4.94(t，J＝5.9Hz，1H)，6.48(d，J＝5.1Hz，1H)，6.77(s，1H)，7.11(dd，J＝2.7Hz，9.0Hz，1H)，7.21(d，J＝2.7Hz，1H)，7.43(s，1H)，7.52(s，1H)，8.27(d，J＝9.0Hz，1H)，8.50(d，J＝5.1Hz，1H)
Mass Spectrometry (FD-MS, m/z): 415, 417 (M)+)
Example 14: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] Phenyl } -N' - (4-fluoro-2-methylphenyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (122mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Subsequently, 4-fluoro-2-methylaniline (126. mu.l) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (2/1) to give the title compound (142 mg) in a yield of 79%.
1H-NMR(CDCl3，400MHz)：δ2.37(s，3H)，4.04(s，3H)，4.04(s，3H)，6.31(s，1H)，6.47(d，J＝5.1Hz，1H)，6.97-7.06(m，3H)，7.11-7.14(m，1H)，7.19(d，J＝2.7Hz，1H)，7.41-7.44(m，2H)，7.50(s，1H)，8.35(d，J＝9.0Hz，1H)，8.50(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 482, 484 (M)++1)
Example 15: n- (5-bromo-6-methyl-2-pyridyl) -N' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] phenyl } urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (122mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Subsequently, 6-amino-3-bromo-2-methylpyridine (208mg) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction solution, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (2/1) to give the title compound (155 mg), which was obtained in 77% yield.
1H-NMR(CDCl3，400MHz)：δ2.69(s，3H)，4.06(s，6H)，6.53(d，J＝5.4Hz，1H)，6.56(d，J＝8.5Hz，1H)，7.14-7.17(m，1H)，7.30(d，J＝2.7Hz，1H)，7.44(s，1H)，7.53(s，1H)，7.75(d，J＝8.5Hz，1H)，7.93(s，1H)，8.49(d，J＝9.0Hz，1H)，8.52(d，J＝5.4Hz，1H)，11.92(s，1H)
Mass Spectrometry (ESI-MS, m/z): 543, 545, 547 (M)++1)
Example 16: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] Phenyl } -N' - (5-chloro-2-pyridyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (122mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 2-amino-5-chloropyridine (143mg) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction solution, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (2/1) to give the title compound (148mg) in a yield of 82%.
1H-NMR(CDCl3，400MHz)：δ4.06(s，3H)，4.06(s，3H)，6.53(d，J＝5.1Hz，1H)，6.95(d，J＝8.8Hz，1H)，7.14-7.17(m，1H)，7.31(d，J＝2.7Hz，1H)，7.44(s，1H)，7.53(s，1H)，7.64-7.67(m，1H)，8.28(d，J＝2.7Hz，1H)，8.50-8.53(m，2H)，8.92(s，1H)，12.11(brs，1H)
Mass Spectrometry (ESI-MS, m/z)485, 487, 489: (M)++1)
Example 17: n- (5-bromo-2-pyridyl) -N' - { 2-chloro-4- [ (6, 7) -dimethoxy-4-quinolyl) oxy ] phenyl } urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (122mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 2-amino-5-bromopyridine (192mg) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (2/1) to give the title compound 108mg in 55% yield.
1H-NMR(CDCl3，400MHz)：δ4.06(s，3H)，4.06(s，3H)，6.53(d，J＝5.1Hz，1H)，6.80(d，J＝8.8Hz，1H)，7.14-7.18(m，1H)，7.30(d，J＝2.7Hz，1H)，7.45(s，1H)，7.53(s，1H)，7.77-7.80(m，1H)，8.15(s，1H)，8.39(d，J＝2.4Hz，1H)，8.50(d，J＝9.0Hz，1H)，8.52(d，J＝5.4Hz，1H)，12.09(brs，1H)
Mass Spectrometry (ESI-MS, m/z): 529, 531, 533 (M)++1)
Example 18: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] Phenyl } -N' - (2-methoxyphenyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (100mg) was dissolved in chloroform (10ml), and 2-methoxyphenyl isocyanate (54mg) was added thereto, followed by stirring at 60 ℃ for 1 night. Methanol was added to the reaction mixture, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (6/4) to give the title compound (111 mg) in a yield of 77%.
1H-NMR(CDCl3，400MHz)：δ3.85(s，3H)，4.04(s，3H)，4.05(s，3H)，6.50(d，J＝5.1Hz，1H)，6.89-6.93(m，1H)，6.98-7.03(m，1H)，7.05-7.10(m，1H)，7.14(dd，J＝2.7Hz，9.0Hz，1H)，7.23(d，J＝2.7Hz，1H)，7.35(s，1H)，7.36(s，1H)，7.44(s，1H)，7.52(s.1H)，8.05-8.07(m，1H)，8.34(d，J＝9.0Hz，1H)，8.52(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 480, 482 (M)++1)
Example 19: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] Phenyl } -N' - (2-tolyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (122mg) was dissolved in chloroform (10ml), and o-tolylisocyanate (59mg) was added to stir at room temperature for 1 night. Methanol was added to the reaction solution, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in a small amount of chloroform, and a large amount of diethyl ether was added thereto. The precipitated crystals were collected by filtration to obtain the title compound 59mg in 34% yield.
1H-NMR(CDCl3，400MHz)：δ2.38(s，3H)，4.04(s，3H)，4.05(s，3H)，6.22(s，1H)，6.47(d，J＝5.1Hz，1H)，7.01(s，1H)，7.11-7.14(m，1H)，7.18(d，J＝2.7Hz，1H)，7.25-7.35(m，3H)，7.42(s，1H)，7.46(d，J＝6.8Hz，1H)，7.50(s，1H)，8.37(d，J＝8.8Hz，1H)，8.50(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 464, 466 (M)++1)
Example 20: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] Phenyl } -N' - (5-methyl-2-pyridyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (122mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 2-amino-5-methylpyridine (120mg) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (2/1) to give the title compound in a yield of 69 mg.
1H-NMR(CDCl3，400MHz)：δ2.31(s，3H)，4.06(s，6H)，6.53(d，J＝5.4Hz，1H)，6.76(d，J＝8.3Hz，1H)，7.13-7.16(m，1H)，7.29(d，J＝2.7Hz，1H)，7.43(s，1H)，7.49-7.52(m，1H)，7.54(s，1H)，8.00(s，1H)，8.14(s，1H)，8.52(d，J＝5.1Hz，1H)，8.55(d，J＝9.0Hz，1H)，12.57(brs，1H)
Mass Spectrometry (ESI-MS, m/z): 465, 467 (M)++1)
Example 21: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] Phenyl } -N' - (6-methyl-2-pyridyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (122mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Subsequently, 6-amino-2-methylpyridine (120mg) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (2/1) to give the title compound 73mg in 42% yield.
1H-NMR(CDCl3，400MHz)：δ2.57(s，3H)，4.06(s，6H)，6.54(d，J＝5.4Hz，1H)，6.66(d，J＝8.1Hz，1H)，6.83(d，J＝7.6Hz，1H)，7.15-7.18(m，1H)，7.30(d，J＝2.7Hz，1H)，7.44(s，1H)，7.54-7.59(m，2H)，8.36(s，1H)，8.52(d，J＝5.1Hz，1H)，8.57(d，J＝9.0Hz，1H)，12.45(s，1H)
Mass Spectrometry (ESI-MS, m/z): 465, 467 (M)++1)
Example 22: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] Phenyl } -N' - (4-methoxyphenyl) urea hydrochloride
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (100mg) was dissolved in chloroform (4ml), and 4-methoxyphenyl isocyanate (60. mu.l) was added thereto to conduct a reaction at room temperature over 1 night. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in a small amount of chloroform. To the mixture was added a large amount of diethyl ether, and the precipitated precipitate was collected by suction filtration to give 90mg of N- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] phenyl } -N' - (4-methoxyphenyl) urea in a yield of 67%. This was suspended in 4ml of methanol, a hydrochloric acid-methanol solution was added thereto, and after stirring at room temperature for 4 hours, the solvent was distilled off to obtain the title compound.
1H-NMR(DMSO-d6，400MHz)：δ3.73(s，3H)，4.03(s，3H)，4.05(s，3H)，6.90(d，J＝9.3Hz，2H)，6.97(d，J＝6.6Hz，1H)，7.37-7.41(m，3H)，7.62(s，1H)，7.67(d，J＝2.7Hz，1H)，8.39(d，J＝9.0Hz，1H)，8.49(s，1H)，8.82(d，J＝6.6Hz，1H)，9.49(s，1H)
Example 23: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] Phenyl } -N' - (1-naphthyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (122mg) was dissolved in chloroform (10ml), and 1-naphthylisocyanate (75mg) was added thereto, followed by stirring at room temperature for 1 night. Methanol was added to the reaction solution, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in a small amount of chloroform, and a large amount of diethyl ether was added thereto. The precipitated crystals were collected by filtration to give the title compound 105mg in a yield of 57%.
1H-NMR(CDCl3，400MHz)：δ4.03(s，3H)，4.04(s，3H)，6.44(d，J＝5.4Hz，1H)，6.72(s，1H)，7.10-7.13(m，3H)，7.41(s，1H)，7.48(s，1H)，7.55-7.69(m，4H)，7.88-7.96(m，2H)，8.15(d，J＝7.6Hz，1H)，8.38-8.40(m，1H)，8.48(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 500, 502 (M)++1)
Example 24: n- (2, 4-difluorophenyl) -N' - {4- [ (6, 7-dimethoxy) -4-quinolyl) oxy ] -2, 3-dimethylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (710mg) was dissolved in chloroform (7ml), and 2, 4-difluorophenyl isocyanate (310. mu.l) was added thereto and the mixture was refluxed for 1 hour. A large amount of diethyl ether was added thereto, and the precipitate was separated by suction filtration to give the title compound (735 mg) in a yield of 70%.
1H-NMR(CDCl3，400MHz)：δ2.14(s，3H)，2.27(s，3H)，4.04(s，3H)，4.06(s，3H)，6.27(d，J＝5.4Hz，1H)，6.78-6.89(m，2H)，6.95(s，1H)，7.03(d，J＝8.5Hz，1H)，7.10(s，1H)，7.40-7.45(m，2H)，7.61(s，1H)，8.03-8.12(m，1H)，8.46(d，J＝5.4Hz，1H)
Mass Spectrometry (FAB-MS, m/z): 480 (M)++1)
Example 25: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3 -dimethylphenyl } -N' - (4-fluoro-2-methylphenyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (120mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Subsequently, 4-fluoro-2-methylaniline (126. mu.l) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/methanol (91/9) to give the title compound 160mg in 91% yield.
1H-NMR(CDCl3，400MHz)：δ2.12(s，3H)，2.22(s，3H)，2.25(s，3H)，4.05(s，3H)，4.06(s，3H)，6.24(d，J＝5.1Hz，1H)，6.33(s，1H)，6.42(s，1H)，6.94-7.03(m，3H)，7.43(s，1H)，7.46-7.55(m，2H)，7.60(s，1H)，8.43(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 476 (M)++1)
Example 26: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3 -dimethylphenyl } -N' - (3-fluoro-2-methoxyphenyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (120mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 3-fluoro-o-anisidine (132. mu.l) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/methanol (91/9) to give the title compound 23mg in 13% yield.
1H-NMR(CDCl3，400MHz)：δ2.15(s.3H)，2.32(s，3H)，3.84(d，J＝1.7Hz，3H)，4.05(s，3H)，4.08(s，3H)，6.28(d，J＝5.4Hz，1H)，6.72-6.77(m，1H)，6.96-7.09(m，3H)，7.43(d，J＝8.5Hz，1H)，7.46(s，1H)，7.60(s，1H)，7.62(s，1H)，8.02-8.05(m，1H)，8.46(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 492 (M)++1)
Example 27: n- (5-bromo-6-methyl-2-pyridyl) -N' - {4- [ (6, 7) -dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (120mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Subsequently, 6-amino-3-bromo-2-methylpyridine (208mg) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/methanol (91/9) to give the title compound (103mg) in 52% yield.
1H-NMR(CDCl3，400MHz)：δ2.16(s，3H)，2.42(s，3H)，2.65(s，3H)，4.06(s，3H)，4.08(s，3H)，6.32(d，J＝5.1Hz，1H)，6.64(d，J＝8.8Hz，1H)，7.04(d，J＝8.8Hz，1H)，7.44(s，1H)，7.64(s，1H)，7.74(d，J＝8.8Hz，1H)，7.91(d，J＝8.8Hz，1H)，8.29(s，1H)，8.45(d，J＝5.4Hz，1H)，11.30(brs，1H)
Mass Spectrometry (ESI-MS, m/z): 537, 539 (M)++1)
Example 28: n- (5-chloro-2-pyridyl) -N' - {4- [ (6, 7-dimethoxyl) Yl-4-quinolyl) oxy ] -2, 3-dimethylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (3.00g) was dissolved in chloroform (150ml) and triethylamine (6ml), and triphosgene (2.74g) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 2-amino-5-chloropyridine (2.38g) was added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol (20/1) to give the title compound (3.4 g) in 77% yield.
1H-NMR(CDCl3，400MHz)：δ2.16(s，3H)，2.38(s，3H)，4.06(s，3H)，4.08(s，3H)，6.31(d，J＝5.4Hz，1H)，6.89(d，J＝8.8Hz，1H)，7.04(d，J＝8.8Hz，1H)，7.44(s，1H)，7.62-7.68(m，2H)，7.90(d，J＝8.8Hz，1H)，8.23(d，J＝2.4Hz，1H)，8.45(d，J＝5.4Hz，1H)，8.50(s，1H)，11.23(brs，1H)
Mass Spectrometry (ESI-MS, m/z): 479, 481 (M)++1)
Example 29: n- (5-bromo-2-pyridyl) -N' - {4- [ (6, 7-dimethoxyl) Yl-4-quinolyl) oxy ] -2, 3-dimethylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (120mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 2-amino-5-bromopyridine (192mg) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/methanol (91/9). The solvent was distilled off, and crystals were precipitated with a small amount of methanol and a large amount of ether, which were collected by filtration to obtain the title compound 80mg in 41% yield.
1H-NMR(CDCl3，400MHz)：δ2.16(s，3H)，2.38(s，3H)，4.06(s，3H)，4.08(s，3H)，6.31(d，J＝5.1Hz，1H)，6.96(d，J＝8.5Hz，1H)，7.03(d，J＝8.8Hz，1H)，7.45(s，1H)，7.64(s，1H)，7.75-7.77(m，1H)，7.89(d，J＝8.8Hz，1H)，8.31(d，J＝2.4Hz，1H)，8.45(d，J＝5.4Hz，1H)，8.81(s，1H)，11.17(brs，1H)
Mass Spectrometry (ESI-MS, m/z): 523, 525 (M)++1)
Example 30: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3 -dimethylphenyl } -N' - (2-methoxyphenyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (120mg) was dissolved in chloroform (10ml), and 2-methoxyphenyl isocyanate (60. mu.l) was added thereto, and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction solution, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in a small amount of chloroform, and a large amount of diethyl ether was added thereto. The precipitated crystals were collected by filtration to give the title compound 131mg in a yield of 75%.
1H-NMR(CDCl3，400MHz)：δ2.16(s，3H)，2.32(s、3H)，3.81(s，3H)，4.06(s，3H)，4.08(s，3H)，6.25(s，1H)，6.26(d，J＝5.4Hz，1H)，6.85-6.87(m，1H)，6.97-7.07(m，4H)，7.41(d，J＝8.5Hz，1H)，7.44(s，1H)，7.62(s，1H)，8.15-8.17(m，1H)，8.45(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 474 (M)++1)
Example 31: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3 -dimethylphenyl } -N' - (2-tolyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (120mg) was dissolved in chloroform (10ml), and o-tolylisocyanate (55. mu.l) was added thereto, and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction solution, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in a small amount of chloroform, and a large amount of diethyl ether was added thereto. The precipitated crystals were collected by filtration to obtain 130mg of the title compound in a yield of 70%.
1H-NMR(CDCl3，400MHz)：δ2.12(s，3H)，2.22(s，3H)，2.26(s，3H)，4.05(s，3H)，4.07(s，3H)，6.23-6.28(m，3H)，7.02(d，J＝8.5Hz，1H)，7.14-7.17(m，1H)，7.24-7.29(m，2H)，7.43(s.1H)，7.49(d，J＝8.5Hz，1H)，7.60(s，1H)，7.63(d，J＝7.3Hz，1H)，8.43(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 458 (M)++1)
Example 32: n- (4-chloro-2-tolyl) -N' - {4- [ (6, 7-dimethoxyl) Yl-4-quinolyl) oxy ] -2, 3-dimethylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (120mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Subsequently, 4-chloro-2-methylaniline (130. mu.l) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/methanol (91/9) to give the title compound (136 mg) in a yield of 75%.
1H-NMR(CDCl3，400MHz)：δ2.14(s，3H)，2.18(s，3H)，2.27(s，3H)，4.05(s，3H)，4.07(s，3H)，6.24(d，J＝5.4Hz，1H)，6.33(s，1H)，6.40(s，1H)，7.03(d，J＝8.5Hz，1H)，7.19-7.21(m，2H)，7.42-7.44(m，2H)，7.60(s、1H)，7.65(d，J＝9.0Hz，1H)，8.44(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 492, 494 (M)++1)
Example 33: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3 -dimethylphenyl } -N' - (2-pyridyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (120mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 2-aminopyridine (104mg) was added thereto, and the mixture was refluxed for 1 night. Methanol was added to the reaction solution, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/methanol (91/9) to give the title compound 72mg in 44% yield.
1H-NMR(CDCl3，400MHz)：δ2.16(s，3H)，2.41(s，3H)，4.06(s，3H)，4.08(s，3H)，6.32(d，J＝5.4Hz，1H)，6.92-6.98(m，2H)，7.04(d，J＝8.8Hz，1H)，7.44(s，1H)，7.65(s，1H)，7.67-7.69(m，1H)，7.97(d，J＝8.8Hz，1H)，8.25-8.27(m，1H)，8.45(d，J＝5.1Hz，1H)，8.72(s，1H)，11.77(br，1H)
Mass Spectrometry (ESI-MS, m/z): 445 (M)++1)
Example 34: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3 -dimethylphenyl } -N' - (5-methyl-2-pyridyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (120mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 2-amino-5-methylpyridine (120mg) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction solution, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/methanol (91/9) to give the title compound (122mg) in a yield of 72%.
1H-NMR(CDCl3，400MHz)：δ2.15(s，3H)，2.28(s，3H)，2.39(s，3H)，4.04(s，3H)，4.07(s，3H)，6.32(d，J＝5.4Hz，1H)，6.90(d，J＝8.3Hz，1H)，7.02(d，J＝8.8Hz，1H)，7.43(s，1H)，7.45-7.48(m，1H)，7.64(s，1H)，7.99(d，J＝8.8Hz，1H)，8.06(d，J＝1.5Hz，1H)，8.44(d，J＝5.4Hz，1H)，9.23(s，1H)，11.77(br，1H)
Mass Spectrometry (FD-MS, m/z): 458 (M)+)
Example 35: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3 -dimethylphenyl } -N' - (6-methyl-2-pyridyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (120mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (110mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 6-amino-2-methylpyridine (120mg) was added thereto, and the mixture was refluxed for 1 night. Methanol was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (40/60) to give the title compound 64mg in 38% yield.
1H-NMR(CDCl3，400MHz)：δ2.16(s，3H)，2.44(s，3H)，2.54(s，3H)，4.06(s，3H)，4.08(s，3H)，6.32(d，J＝5.4Hz，1H)，6.61(d，J＝8.3Hz，1H)，6.82(d，J＝7.6Hz，1H)，7.04(d，J＝8.8Hz，1H)，7.44(s，1H)，7.53-7.57(m，1H)，7.65(s，1H)，7.79(s，1H)，7.99(d，J＝8.8Hz，1H)，8.44(d，J＝5.1Hz，1H)，11.76(br，1H)
Mass Spectrometry (FD-MS, m/z): 458 (M)+)
Example 36: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3 -dimethylphenyl } -N' - (4-methoxyphenyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 3-dimethylaniline (100mg) was dissolved in chloroform (4ml), and 4-methoxyphenyl isocyanate (60. mu.l) was added to the solution to conduct a reaction at room temperature for 1 night. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in a small amount of chloroform. A large amount of diethyl ether was added thereto, and the precipitated precipitate was suction-filtered to give the title compound (115 mg) in a yield of 78%.
1H-NMR(CDCl3，400MHz)：δ2.02(s，3H)，2.30(s，3H)，3.76(s，3H)，4.06(s，3H)，4.12(s，3H)，6.46(d，J＝6.3Hz，1H)，6.78(d，J＝9.0Hz，2H)，6.91(d，J＝8.8Hz，1H)，7.39(d，J＝9.0Hz，2H)，7.67(s，1H)，7.69(d，J＝8.8Hz，1H)，7.92(s，1H)，8.20-8.23(m，1H)
Mass Spectrometry (ESI-MS, m/z): 474 (M)++1)
Example 37: n- (2, 4-difluorophenyl) -N' - {4- [ (6, 7-dimethoxy) -4-quinolyl) oxy ] -2, 5-dimethylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylaniline (200mg) was dissolved in chloroform (15ml), and 2, 4-difluorophenyl isocyanate (88. mu.l) was added thereto and the mixture was refluxed for 1 hour. The reaction solution was purified by silica gel chromatography using chloroform/acetone (4/1) to give the title compound 287mg in 97% yield.
1H-NMR(CDCl3，400MHz)：δ2.17(s，3H)，2.26(s，3H)，4.05(s，3H)，4.06(s，3H)，6.31(d，J＝5.4Hz，1H)，6.57(s，1H)，6.81-6.95(m，3H)，7.00(s，1H)，7.43(s，1H)，7.55(s，1H)，7.59(s，1H)，8.05-8.13(m，1H)，8.47(d，J＝5.4Hz，1H)
Mass Spectrometry (FD-MS, m/z): 479 (M)+)
Example 38: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5 -dimethylphenyl } -N' -propylurea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylaniline (150mg) was dissolved in chloroform (13ml) or triethylamine (1.5ml), and triphosgene (151mg) dissolved in chloroform was added to the solution, followed by heating and refluxing for 5 minutes. Subsequently, n-propylamine (33mg) was added to the solution, and the mixture was heated under reflux for another 2 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, which was then kept on celite, and the resulting mixture was extracted with chloroform. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (4/1) to give the title compound 178mg in a yield of 95%.
1H-NMR(CDCl3，400MHz)：δ0.94(t，J＝7.3Hz，3H)，1.51-1.65(m，2H)，2.15(s，3H)，2.26(s，3H)，3.21-3.28(m，2H)，4.05(s，3H)，4.06(s，3H)，4.63-4.69(m，1H)，5.97(s，1H)，6.31(d，J＝5.1Hz，1H)，6.98(s，1H)，7.43(s，2H)，7.58(s，1H)，8.46(d，J＝5.4Hz，1H)
Mass Spectrometry (FD-MS, m/z): 409 (M)+)
Example 39: n- (4-chloro-2-tolyl) -N' - {4- [ (6, 7-dimethoxyl) Yl-4-quinolyl) oxy ] -2, 5-dimethylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylaniline (100mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (92mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Subsequently, 4-chloro-2-methylaniline (44. mu.l) was added thereto, and the mixture was stirred at room temperature for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in a small amount of chloroform, to which a large amount of diethyl ether was added. The precipitated crystals were collected by filtration to give the title compound 118mg in 78% yield.
1H-NMR(CDCl3，400MHz)：δ2.16(s、3H)，2.21(s，3H)，2.23(s，3H)，4.05(s，3H)，4.06(s，3H)，6.28(d，J＝5.4Hz，1H)，6.30(s，1H)，6.32(s，1H)，6.98(s，1H)，7.22-7.23(m，2H)，7.43(s，1H)，7.58(s，1H)，7.59-7.63(m，2H)，8.45(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 492, 494 (M)++1)
Example 40: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5 -dimethylphenyl } -N' - (4-fluoro-2-tolyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylaniline (100mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (92mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Subsequently, 4-fluoro-2-methylaniline (42. mu.l) was added thereto, and the mixture was stirred at room temperature for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in a small amount of chloroform, to which a large amount of diethyl ether was added. The precipitated crystals were collected by filtration to give 108mg of the title compound in 74% yield.
1H-NMR(CDCl3，400MHz)：δ2.15(s，6H)，2.30(s，3H)，4.05(s，3H)，4.06(s，3H)，6.24(s，2H)，6.28(d，J＝5.1Hz，1H)，6.94(s，1H)，6.96-7.00(m，2H)，7.42(s，1H)，7.49-7.52(m，1H)，7.58(s，1H)，7.64(s，1H)，8.44(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 476 (M)++1)
Example 41: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5 -dimethylphenyl } -N' - (3-fluoro-2-methoxyphenyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylaniline (100mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (92mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 3-fluoro-o-anisidine (44. mu.l) was added thereto, and the mixture was stirred at room temperature for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound 126mg in 83% yield.
1H-NMR(CDCl3，400MHz)：δ2.16(s，3H)，2.27(s，3H)，3.83(d，J＝1.7Hz，3H)，4.04(s，3H)，4.07(s，3H)，6.31(d，J＝5.1Hz，1H)，6.74-6.79(m，1H)，6.97-7.03(m，3H)，7.44(s，1H)，7.57(s，1H)，7.60(s，1H)，7.66(s，1H)，8.02-8.04(m，1H)，8.48(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 492 (M)++1)
Example 42: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5 -dimethylphenyl } -N' - (2-tolyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylaniline (100mg) was dissolved in chloroform (10ml), and o-tolylisocyanate (46. mu.l) was added thereto, followed by stirring at room temperature for 1 night. Methanol was added to the reaction mixture, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (2/1) to give the title compound (111 mg) in a yield of 79%.
1H-NMR(CDCl3，400MHz)：δ2.12(s，6H)，2.26(s，3H)，4.03(s，3H)，4.05(s，3H)，6.27(d，J＝5.1Hz，1H)，6.77(s，1H)，6.81(s，1H)，6.91(s，1H)，7.11-7.15(m，1H)，7.22(s，1H)，7.24(s，1H)，7.42(s，1H)，7.59(s，1H)，7.63(d，J＝7.8Hz，1H)，7.68(s，1H)，8.43(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 458 (M)++1)
Example 43: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5 -dimethylphenyl } -N' - (2-methoxyphenyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylaniline (100mg) was dissolved in chloroform (10ml), and 2-methoxyphenyl isocyanate (49. mu.l) was added thereto and the mixture was refluxed for 1 night. Methanol was added to the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (2/1) to quantitatively obtain the title compound.
1H-NMR(CDCl3，400MHz)：δ2.14(s，3H)，2.24(s，3H)，3.75(s，3H)，4.03(s，3H)，4.07(s，3H)，6.31(d，J＝5.1Hz，1H)，6.84-6.87(m，1H)，6.95-7.03(m，3H)，7.06(s，1H)，7.44(s，1H)，7.56(s，1H)，7.61(s，1H)，7.63(s，1H)，8.17-8.20(m，1H)，8.46(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 474 (M)++1)
Example 44: n- (5-bromo-6-methyl-2-pyridyl) -N' - {4- [ (6, 7) -dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylaniline (100mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (92mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 6-amino-3-bromo-2-methylpyridine (69mg) was added thereto, and the mixture was stirred at room temperature for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in a small amount of chloroform, to which a large amount of diethyl ether was added. The precipitated crystals were collected by filtration to give the title compound 80mg in 48% yield.
1H-NMR(CDCl3，400MHz)：δ2.18(s，3H)，2.42(s，3H)，2.65(s，3H)，4.06(s，3H)，4.08(s，3H)，6.34(d，J＝5.4Hz，1H)，6.57(d，J＝8.5Hz，1H)，6.98(s，1H)，7.43(s，1H)，7.62(s，1H)，7.70(s，1H)，7.74(d，J＝8.5Hz，1H)，8.05(s，1H)，8.46(d，J＝5.4Hz，1H)，11.17(br，1H)
Mass Spectrometry (ESI-MS, m/z): 537, 539 (M)++1)
Example 45: n- (2, 6-dimethoxy-3-pyridyl) -N' - {4- [ (6, 7-d) -dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylaniline (100mg) was dissolved in chloroform (10ml) and triethylamine (1ml), and triphosgene (92mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, 3-amino-2, 6-dimethoxypyridine (70mg) was added thereto, and the mixture was stirred at room temperature for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in a small amount of chloroform, to which a large amount of diethyl ether was added. The precipitated crystals were collected by filtration to give the title compound 124mg in a yield of 79%.
1H-NMR(CDCl3，400MHz)：δ2.17(s，3H)，2.27(s，3H)，3.89(s，3H)，3.95(s，3H)，4.06(s，3H)，4.07(s，3H)，6.31(d，J＝5.1Hz，1H)，6.34(d，J＝8.5Hz，1H)，6.36(s，1H)，6.74(s，1H)，6.99(s，1H)，7.44(s，1H)，7.57(s，1H)，7.60(s，1H)，8.20(d，J＝8.3Hz，1H)，8.46(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 505 (M)++1)
Example 46: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5 -dimethylphenyl } -N' - (4-methoxyphenyl) urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2, 5-dimethylaniline (100mg) was dissolved in chloroform (4ml), and 4-methoxyphenyl isocyanate (60. mu.l) was added to the solution to conduct a reaction at room temperature for 1 night. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in a small amount of chloroform. A large amount of diethyl ether was added thereto, and the precipitated precipitate was suction-filtered to give the title compound (110mg) in a yield of 74%.
1H-NMR(CDCl3，400MHz)：δ2.07(s，3H)，2.26(s，3H)，3.76(s，3H)，4.03(s，3H)，4.08(s，3H)，6.39(d，J＝6.1Hz，1H)，6.80(d，J＝9.0Hz，2H)，6.87(s，1H)，7.36(d，J＝9.0Hz，2H)，7.55(br，1H)，7.62(s，1H)，7.67(s，1H)，7.80(s，1H)，8.19(br，1H)，8.27(d，J＝6.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 474 (M)++1)
Example 47: n- {4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-nitro-N-trine Phenyl } -N' -propylurea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-nitroaniline (150mg) was dissolved in chloroform (10ml) and triethylamine (1.5ml), followed by addition of triphosgene (144mg) dissolved in chloroform and heating under reflux for 5 minutes. Subsequently, n-propylamine (31mg) was added to the solution, and the mixture was heated under reflux for another 2 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, which was then kept on celite, and the resulting mixture was extracted with chloroform. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (4/1) to give the title compound (160 mg) with a yield of 86%.
1H-NMR(CDCl3，400MHz)：δ1.01(t，J＝7.5Hz，3H)，1.59-1.69(m，2H)，3.27-3.34(m，2H)，4.05(s，3H)，4.06(s，3H)，4.95-5.01(br，1H)，6.47(d，J＝5.4Hz，1H)，7.43-7.51(m，3H)，8.04(d，J＝2.7Hz，1H)，8.53(d，J＝5.4Hz，1H)，8.81(d，J＝9.3Hz，1H)，9.74-9.79(br，1H)
Mass Spectrometry (FD-MS, m/z): 426 (M)+)
Example 48: n- (2, 4-difluorophenyl) -N' - {4- [ (6, 7-dimethoxy) -4-quinolyl) oxy ] -2-nitrophenyl } urea
4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-nitroaniline (100mg) was dissolved in chloroform (10ml) and triethylamine (1ml), followed by addition of triphosgene (96mg) dissolved in chloroform and heating under reflux for 5 minutes. 2, 4-difluoroaniline (45mg) was then added and the mixture was heated under reflux for an additional 1 night. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, which was then kept on celite, and the resulting mixture was extracted with chloroform. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/acetone (3/1) to give the title compound 81mg in 56% yield.
1H-NMR(CDCl3，400MHz)：δ4.05(s，3H)，4.06(s，3H)，6.50(d，J＝5.1Hz，1H)，6.91-6.98(m，3H)，7.45(s，1H)，7.49(s，1H)，7.50-7.54(m，1H)，7.88-7.97(m，1H)，8.05(d，J＝2.9Hz，1H)，8.54(d，J＝5.1Hz，1H)，8.77(d，J＝9.3Hz，1H)，9.98(s，1H)
Mass Spectrometry (FD-MS, m/z): 496 (M)+)
Example 49: n- {3, 5-dichloro-4- [ (6, 7-dimethoxy-4-quinolyl) Oxy ] phenyl } -N' - (2, 4-difluorophenyl) urea
3, 5-dichloro-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] aniline (53mg) was dissolved in chloroform (5ml), and 2, 4-difluorophenyl isocyanate (34. mu.l) was added thereto and the mixture was refluxed for 1 night. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound 56mg in a yield of 74%.
1H-NMR(CDCl3，400MHz)：δ4.05(s，3H)，4.09(s，3H)，6.26(d，J＝5.4Hz，1H)，6.86-6.93(m，2H)，7.05(s，1H)，7.44(s，1H)，7.46(s，1H)，7.60(s，2H)，7.64(s，1H)，8.01-8.05(m，1H)，8.48(d，J＝5.4Hz，1H)
Mass Spectrometry (FAB-MS, m/z): 520, 522, 524 (M)++1)
Example 50: n- (2, 4-difluorophenyl) -N' - (2-fluoro-4- { [ 6-methoxy) Phenyl-7- (2-morpholinoethoxy) -4-quinolinyl ] oxy) urea
N- (2, 4-difluorophenyl) -N' - { 2-fluoro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } urea (20mg), potassium carbonate (7mg), tetra-N-butylammonium iodide (2mg), and N- (2-chloroethyl) morpholine hydrochloride (10mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 70 ℃ for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/methanol (30/1) to give the title compound 14mg in a yield of 57%.
1H-NMR(CDCl3，400MHz)：δ2.57(t，J＝4.4Hz，4H)，2.88(m，2H)，3.69(t，J＝4.4Hz，4H)，3.94(s，3H)，4.26(t，J＝5.9Hz，2H)，6.43(d，J＝5.1Hz，1H)，6.77-6.95(m，4H)，7.35(s，1H)，7.43(s，1H)，7.96-8.02(m，1H)，8.13-8.17(m，1H)，8.44(d，J＝5.1Hz，1H)
Example 51: n- (2-chloro-4- { [ 6-methoxy-7- (2-morpholinoethoxy) -4-quinolyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' - (2, 4-difluorophenyl) urea (174mg) was dissolved in N, N-dimethylformamide (9ml), and potassium carbonate (64mg), tetra-N-butylammonium iodide (14mg), and N- (2-chloroethyl) morpholine hydrochloride (86mg) were added thereto. After stirring at 70 ℃ for 17 hours, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extraction was performed with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol (20/1) to give the title compound in a yield of 35 mg.
1H-NMR(CDCl3，400MHz)：δ2.60-2.67(m，4H)，2.95(t，J＝6.0Hz，2H)，3.71-3.79(m，4H)，4.01(s，3H)，4.33(t，J＝6.0Hz，2H)，6.50(d，J＝5.1Hz，1H)，6.85-6.97(m，2H)，7.09-7.17(m，2H)，7.22-7.27(m，2H)，7.42(s，1H)，7.50(s，1H)，7.97-8.01(m，1H)，8.28(d，J＝9.0Hz，1H)，8.51(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 585, 587 (M)++1)
Example 52: n- (2, 4-difluorophenyl) -N' - (4- { [ 6-methoxy-7) - (2-morpholinoethoxy) -4-quinolinyl ] oxy } -2, 5-dimethylphenyl) urea Reacting N- (4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy }-2, 5-dimethylphenyl) -N' - (2, 4-difluorophenyl) urea (366mg) was dissolved in N, N-dimethylformamide (6ml), palladium hydroxide (366mg) was added, and the mixture was stirred under hydrogen atmosphere at room temperature for 1 night. The solvent was distilled off under reduced pressure, dissolved in chloroform or methanol, and filtered through celite. The solvent was then distilled off under reduced pressure, and the resulting residue (213mg), potassium carbonate (109mg), tetra-N-butylammonium iodide (12mg), and N- (2-chloroethyl) morpholine hydrochloride (74mg) were dissolved in N, N-dimethylformamide (5ml), followed by stirring at 70 ℃ for 1 night. The solvent was removed by distillation under the reduced pressure, water was added to the resulting residue, extraction was performed with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/methanol (10/1) to give the title compound 106mg in 55% yield.
1H-NMR(CDCl3，400MHz)：δ2.17(s，3H)，2.27(s，3H)，2.64(t，J＝4.6Hz，4H)，2.96(t，J＝6.0Hz，2H)，3.76(t，J＝4.6Hz，4H)，4.03(s，3H)，4.34(t，J＝6.0Hz，2H)，6.31(d，J＝5.4Hz，1H)，6.47(s，1H)，6.81-6.92(m，3H)，7.00(s，1H)，7.43(s，1H)，7.54(s，1H)，7.58(s，1H)，8.05-8.12(m，1H)，8.47(d，J＝5.4Hz，1H)
Example 53: n- (4- { [ 6-methoxy-7- (2-morpholinoethoxy) -4-) Quinolinyl ] oxy } -2, 5-dimethylphenyl) -N' - (2-methoxyphenyl) urea
N- {4- [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2, 5-dimethylphenyl) -N' - (2-methoxyphenyl) urea (363mg) was dissolved in N, N-dimethylformamide (6ml), and palladium hydroxide (363mg) was added to the solution, followed by stirring under hydrogen atmosphere at room temperature for 1 night. The solvent was distilled off under reduced pressure, dissolved in chloroform or methanol, and filtered through celite. The solvent was then distilled off under reduced pressure, and the resulting residue (191mg), potassium carbonate (219mg), tetra-N-butylammonium iodide (12mg), and N- (2-chloroethyl) morpholine hydrochloride (148mg) were dissolved in N, N-dimethylformamide (5ml), followed by stirring at 70 ℃ for 1 night. The solvent was removed by distillation under the reduced pressure, water was added to the resulting residue, extraction was performed with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/methanol (10/1) to give the title compound (101 mg) in 55% yield.
1H-NMR(CDCl3，400MHz)：δ2.17(s，3H)，2.28(s，3H)，2.64(t，J＝4.5Hz，4H)，2.96(t，J＝5.9Hz，2H)，3.76(t，J＝4.6Hz，4H)，3.83(s，3H)，4.04(s，3H)，4.34(t，J＝6.0Hz，2H)，6.30(d，J＝5.4Hz，2H)，6.86-6.90(m，1H)，6.96-7.06(m，3H)，7.16(s，1H)，7.43(s，1H)，7.57(s，1H)，7.59(s，1H)，8.11-8.16(m，1H)，8.46(d，J＝5.4Hz，1H)
Example 54: n- (2-chloro-4- { [ 6-methoxy-7- (2-methoxyethoxy) -4-quinolyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea
Sodium hydride (60 w%, 153mg) was added to dimethyl sulfoxide (2ml), and after stirring at 60 ℃ for 30 minutes, the mixture was returned to room temperature, 4-amino-3-chlorophenol hydrochloride (343mg) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 4-chloro-6-methoxy-7- (2-methoxyethoxy) quinoline (254mg) dissolved in dimethyl sulfoxide (2ml) was added thereto, and the mixture was stirred at 110 ℃ for 1 night. Water was added to the reaction solution, followed by extraction with chloroform, and then the chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography using chloroform/acetone (7/3) to give 332mg of a mixture containing 2-chloro-4- { [ (6-methoxy-7- (2-methoxyethoxy) -4-quinolyl ] oxy } aniline as a main product, 83mg of which was dissolved in chloroform (5ml), 2, 4-difluorophenylisocyanate (32. mu.l) was added thereto, and the mixture was refluxed for 1 night, and the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography using chloroform/acetone (2/1) to give 50mg of the title compound.
1H-NMR(DMSO-d6，400MHz)δ3.75-3.77(m，2H)，3.94(s，3H)，4.27-4.29(m，2H)，6.55(d，J＝5.1Hz，1H)，7.04-7.09(m，1H)，7.25-7.36(m，2H)，7.42(s，1H)，7.50(s，1H)，7.51(s，1H)，8.09-8.15(m，1H)，8.24(d，J＝9.0Hz，1H)，8.49(d，J＝5.4Hz，1H)，8.82(s，1H)，9.31(s，1H)
Example 55: n- (2-chloro-4- { [ 6-methoxy-7- (2-methoxyethoxy) -4-quinolyl ] oxy } phenyl) -N' - (2-methoxyphenyl) urea
Sodium hydride (60 w%, 153mg) was added to dimethyl sulfoxide (2ml), and after stirring at 60 ℃ for 30 minutes, the mixture was returned to room temperature, 4-amino-3-chlorophenol hydrochloride (343mg) was added, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 4-chloro-6-methoxy-7- (2-methoxyethoxy) quinoline (254mg) dissolved in dimethyl sulfoxide (2ml) was added thereto, and the mixture was stirred at 110 ℃ for 1 night. Water was added to the reaction solution, followed by extraction with chloroform, and then the chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by silica gel chromatography using chloroform/acetone (7/3) to give 332mg of a mixture containing 2-chloro-4- { [ 6-methoxy-7- (2-methoxyethoxy) -4-quinolyl ] oxy } aniline as a main product. 83mg of the reaction solution was dissolved in chloroform (5ml), and 2-methoxyphenyl isocyanate (35. mu.l) was added thereto and the mixture was refluxed for 1 night. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/acetone (2/1) to give the title compound (31 mg).
1H-NMR(DMSO-d6，400MHz)δ3.75-3.77(m，2H)，3.90(s，3H)，3.94(s，3H)，4.27-4.29(m，2H)，6.55(d，J＝5.1Hz，1H)，6.89-7.05(m，3H)，7.24-7.27(m，1H)，7.42(s，1H)，7.48(d，J＝2.7Hz，1H)，7.50(s，1H)，8.08-8.11(m，1H)，8.18-8.22(m，1H)，8.49(d，J＝5.4Hz，1H)，8.99-9.03(m，2H)
Example 56: n- (2, 4-difluorophenyl) propanoic acidN' - (4- { [ 6-methoxy-7-) (2-methoxyethoxy) -4-quinolinyl ] oxy } -2, 3-dimethylphenyl) urea
N- (4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2, 3-dimethylphenyl) -N' - (2, 4-difluorophenyl) urea (213mg) was dissolved in N, N-dimethylformamide (5ml) and triethylamine (1ml), and palladium hydroxide (40mg) was added to the solution, followed by stirring under hydrogen atmosphere at room temperature for 1 night. The reaction solution was filtered through celite, and washed with chloroform/methanol. The solvent was distilled off under reduced pressure, and 90mg of 184mg of the obtained residue was dissolved in N, N-dimethylformamide (1.5ml), to which potassium carbonate (32mg), tetra-N-butylammonium iodide (7mg) and 2-bromoethyl methyl ether (32mg) were added, and the mixture was stirred at 70 ℃ for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/acetone (2/1) to give the title compound (110 mg).
1H-NMR(DMSO-d6，400MHz)：δ1.97(s，3H)，2.17(s，3H)，3.31(s，3H)，3.70(t，J＝4.4Hz，2H)，3.90(s，3H)，4.21(t，J＝4.4Hz，2H)，6.18(d，J＝5.1Hz，1H)，6.95-6.98(m，2H)，7.22-7.31(m，1H)，7.34(s，1H)，7.51(s，1H)，7.62(d，J＝8.8Hz，1H)，8.03-8.10(m，1H)，8.36(d，J＝5.1Hz，1H)，8.38(s，1H)，8.79(s，1H)
Example 57: n- (4- { [ 6-methoxy-7- (2-methoxyethoxy) -4-) Quinolinyl ] oxy } -2, 3-dimethylphenyl) -N' - (2-methoxyphenyl) urea
N- (4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2, 3-dimethylphenyl) -N' - (2-methoxyphenyl) urea (161mg) was dissolved in N, N-dimethylformamide (4ml) and triethylamine (1ml), and palladium hydroxide (32mg) was added to the solution, followed by stirring under hydrogen atmosphere at room temperature for 1 night. The reaction solution was filtered through celite, and washed with chloroform/methanol. The solvent was distilled off under reduced pressure, 110mg of 223mg of the obtained residue was dissolved in N, N-dimethylformamide (1.5ml), and potassium carbonate (23mg), tetra-N-butylammonium iodide (5mg) and 2-bromoethyl methyl ether (23mg) were added thereto, followed by stirring at 70 ℃ for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/acetone (2/1) to give the title compound (89 mg).
1H-NMR(DMSO-d6，400MHz)：δ2.00(s，3H)，2.17(s，3H)，3.70(t，J＝4.2Hz，2H)，3.83(s，3H)，3.90(s，3H)，4.22(t，J＝4.2Hz，2H)，6.19(d，J＝5.1Hz，1H)，6.81-6.88(m，2H)，6.94-6.97(m，2H)，7.34(s，1H)，7.51(s，1H)，7.58(d，J＝8.8Hz，1H)，8.07(d，J＝8.8Hz，1H)，8.36(d，J＝5.1Hz，1H)，8.48(s，1H)，8.58(s，1H)
Example 58: n- (2, 4-difluorophenyl) -N' - (4- { [ 6-methoxy-7-) (2-methoxyethoxy-4-quinolinyl ] oxy } -2, 5-dimethylphenyl) urea
N- (4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2, 5-dimethylphenyl) -N' - (2, 4-difluorophenyl) urea (366mg) was dissolved in N, N-dimethylformamide (6ml), and palladium hydroxide (366mg) was added to stir under hydrogen atmosphere at room temperature for 1 night. The solvent was distilled off under reduced pressure, dissolved in chloroform or methanol, and filtered through celite. Subsequently, the solvent was distilled off under reduced pressure, and the obtained residue (213mg), potassium carbonate (109mg), tetra-N-butylammonium iodide (12mg), and 2-bromoethyl methyl ether (40. mu.l) were dissolved in N, N-dimethylformamide (5ml), and stirred at 70 ℃ for 1 night. The solvent was removed by distillation under the reduced pressure, water was added to the resulting residue, extraction was performed with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/methanol (10/1) to give the title compound (124 mg) in 73% yield.
1H-NMR(CDCl3，400MHz)：δ2.17(s，3H)，2.26(s，3H)，3.49(s，3H)，3.90(t，J＝4.8Hz，2H)，4.03(s，3H)，4.34(t，J＝4.8Hz，2H)，6.30(d，J＝5.1Hz，1H)，6.57(s，1H)，6.81-6.95(m，3H)，7.00(s，1H)，7.43(s，1H)，7.55(s，1H)，7.57(s，1H)，8.05-8.14(m，1H)，8.46(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 524 (M)++1)
Example 59: n- (4- { [ 6-methoxy-7- (2-methoxyethoxy) -4-) Quinolinyl ] oxy } -2, 5-dimethylphenyl) -N' - (2-methoxyphenyl) urea
N- (4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2, 5-dimethylphenyl) -N' - (2-methoxyphenyl) urea (363mg) was dissolved in N, N-dimethylformamide (6ml), and palladium hydroxide (363mg) was added to stir under hydrogen atmosphere at room temperature for 1 night. The solvent was distilled off under reduced pressure, dissolved in chloroform or methanol, and filtered through celite. Subsequently, the solvent was distilled off under reduced pressure, and the obtained residue (191mg), potassium carbonate (110mg), tetra-N-butylammonium iodide (12mg), and 2-bromoethyl methyl ether (80mg) were dissolved in N, N-dimethylformamide (5ml), followed by stirring at 70 ℃ for 1 night. The solvent was removed by distillation under the reduced pressure, water was added to the resulting residue, extraction was performed with chloroform, and the chloroform layer was dried over sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/methanol (10/1) to give the title compound (128 mg) in a yield of 76%.
1H-NMR(CDCl3，400MHz)：δ2.17(s，3H)，2.28(s，3H)，3.49(s，3H)，3.83(s，3H)，3.90(t，J＝4.8Hz，2H)，4.04(s，3H)，4.35(t，J＝4.9Hz，2H)，6.30(d，J＝5.4Hz，1H)，6.33(s，1H)，6.86-6.90(m，1H)，6.96-7.06(m，3H)，7.17(s，1H)，7.43(s，1H)，7.56(s，1H)，7.58(s，1H)，8.12-8.17(m，1H)，8.45(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 518 (M)++1)
Example 60: n- (4- { [ 7- (phenylmethoxy) -6-methoxy-4-quinolyl ] Oxygen } -2, 3-dimethylphenyl) -N-(2-methoxyphenyl) urea
After 4- { [ 7- (benzyloxy) -6-methoxy-4-quinolyl ] oxy } -2, 3-dimethylaniline (260mg) was dissolved in N, N-dimethylformamide (5ml), 2-methoxyphenyl isocyanate (116mg) was added and the mixture was reacted at room temperature for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography using chloroform/acetone (2/1) to give the title compound 169mg in a yield of 47%.
1H-NMR(DMSO-d6，400MHz)：δ1.99(s，3H)，2.02(s，3H)，3.83(s，3H)，3.90(s，3H)，5.25(s，2H)，6.18(d，J＝5.3Hz，1H)，6.81-6.87(m，2H)，6.95(d，J＝6.1Hz，1H)，7.29-7.59(m，7H)，8.07(d，J＝6.1Hz，1H)，8.35(d，J＝5.3Hz，1H)，8.48(s，1H)，8.58(s，1H)
Example 61: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' - (2, 4-difluorophenyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (214mg) was dissolved in chloroform (5ml), and 2, 4-difluorophenyl isocyanate (180. mu.l) was added to the solution to conduct a reaction at 70 ℃ for 4 hours. A large amount of diethyl ether was added thereto, and the precipitated precipitate was suction-filtered to give the title compound (146 mg) in a yield of 46%.
1H-NMR(DMSO-d6，400MHz)：δ3.98(s，3H)，3.99(s，3H)，7.03-7.10(m，1H)，7.28-7.37(m，2H)，7.40(s，1H)，7.56(s，2H)，8.08-8.21(m，2H)，8.57(s，1H)，8.80(s，1H)，9.30(s，1H)
Mass Spectrometry (ESI-MS, m/z): 487, 489 (M)++1)
Example 62: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' -propylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (5.13g) was dissolved in chloroform (100ml) and triethylamine (50ml), followed by addition of triphosgene (4.59g) dissolved in chloroform (3ml) and stirring for 30 minutes. Then n-propylamine (2.74g) was added, and the mixture was stirred for another 2 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol (50/1) to give 4.14g of the title compound in a yield of 64%.
1H-NMR(DMSO-d6，400MHz)：δ0.91(t，J＝7.3Hz，3H)，1.41-1.53(m，2H)，3.05-3.12(m，2H)，3.97(s，3H)，3.99(s，3H)，6.99(t，J＝5.4Hz，1H)，7.22(dd，J＝2.7Hz，9.0Hz，1H)，7.38(s，1H)，7.46(d，J＝2.9Hz，1H)，7.54(s，1H)，8.04(s，1H)，8.20(d，J＝9.3Hz，1H)，8.55(s，1H)
Mass Spectrometry (ESI-MS, m/z): 417 (M)++1)
Example 63: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } group -N' -ethylurea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), triphosgene (50mg) dissolved in chloroform was added thereto, and the mixture was stirred at room temperature for 30 minutes. Subsequently, ethylamine hydrochloride (69mg) was added thereto, and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (10mg) in 16% yield.
1H-NMR(DMSO-d6，400MHz)：δ1.07(t，J＝7.3Hz，3H)，3.11-3.14(m，2H)，3.97(s，3H)，3.99(s，3H)，6.10(t，J＝5.4Hz，1H)，7.14(d，J＝9.0Hz，2H)，7.37(s，1H)，7.46(d，J＝9.0Hz，2H)，7.55(s，1H)，8.49(br，1H)，8.53(s，1H)
Mass Spectrometry (ESI-MS, m/z): 369 (M)++1)
Example 64: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } group -N' -propylurea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), triphosgene (50mg) dissolved in chloroform was added thereto, and the mixture was stirred at room temperature for 30 minutes. Propylamine (21. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound in a yield of 30mg, 47%.
1H-NMR(DMSO-d6，400MHz)：δ0.89(t，J＝7.6Hz，3H)，1.41-1.50(m，2H)，3.04-3.08(m，2H)，3.97(s，3H)，3.99(s，3H)，6.15(t，J＝5.9Hz，1H)，7.15(d，J＝8.8Hz，2H)，7.37(s，1H)，7.46(d，J＝9.0Hz，2H)，7.55(s，1H)，8.48(br，1H)，8.53(s，1H)
Mass Spectrometry (ESI-MS, m/z): 383 (M)++1)
Example 65: N-butyl-N' - {4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy phenyl urea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), triphosgene (50mg) dissolved in chloroform was added thereto, and the mixture was stirred at room temperature for 30 minutes. Butylamine (22. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (29mg) in a yield of 43%.
1H-NMR(DMSO-d6，400MHz)：δ0.91(t，J＝7.3Hz，3H)，1.28-1.47(m，4H)，3.07-3.12(m，2H)，3.97(s，3H)，3.99(s，3H)，6.12(t，J＝5.6Hz，1H)，7.15(d，J＝8.8Hz，2H)，7.37(s，1H)，7.46(d，J＝9.0Hz，2H)，7.55(s，1H)，8.47(br，1H)，8.53(s，1H)
Mass spectrum (ESI-M)S，m/z)：397(M++1)
Example 66: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } group -N' -pentylurea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), triphosgene (50mg) dissolved in chloroform was added thereto, and the mixture was stirred at room temperature for 30 minutes. Then, pentylamine (26. mu.l) was added thereto, and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound 21mg in 30% yield.
1H-NMR(DMSO-d6，400MHz)：δ0.89(t，J＝7.1Hz，3H)，1.27-1.47(m，4H)，1.41-1.48(m，2H)，3.06-3.11(m，2H)，3.97(s，3H)，3.99(s，3H)，6.13(t，J＝5.6Hz，1H)，7.15(d，J＝9.0Hz，2H)，7.37(s，1H)，7.46(d，J＝8.8Hz，2H)，7.55(s，1H)，8.47(br，1H)，8.53(s，1H)
Mass Spectrometry (ESI-MS, m/z): 411 (M)++1)
Example 67: n- (sec-butyl) -N, - {4- [ (6, 7-dimethoxy-4-quinazol) Quinolinyl) oxy ] phenyl } urea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), triphosgene (50mg) dissolved in chloroform was added thereto, and the mixture was stirred at room temperature for 30 minutes. Sec-butylamine (23. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (33mg) with a yield of 49%.
1H-NMR(DMSO-d6，400MHz)：δ0.88(t，J＝7.3Hz，3H)，1.08(d，J＝6.6Hz，3H)，1.40-1.47(m，2H)，3.58-3.64(m，1H)，3.97(s，3H)，3.99(s，3H)，5.98(t，J＝8.1Hz，1H)，7.15(d，J＝9.0Hz，2H)，7.37(s，1H)，7.46(d，J＝9.0Hz，2H)，7.55(s，1H)，8.38(s，1H)，8.53(s，1H)
Mass Spectrometry (ESI-MS, m/z): 397 (M)++1)
Example 68: N-propenyl-N' - {4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy phenyl urea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), triphosgene (50mg) dissolved in chloroform was added thereto, and the mixture was stirred at room temperature for 30 minutes. Subsequently, allylamine hydrochloride (31mg) was added, followed by stirring at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound 21mg in 33% yield.
1H-NMR(DMSO-d6，400MHz)：3.73-3.76(m，2H)，3.97(s，3H)，3.99(s，3H)，5.07-5.21(m，2H)，5.84-5.92(m，1H)，6.28(t，J＝5.6Hz，1H)，7.16(d，J＝9.0Hz，2H)，7.38(s，1H)，7.47(d，J＝9.0Hz，2H)，7.55(s，1H)，8.53(s，1H)，8.59(s，1H)
Mass Spectrometry (ESI-MS, m/z): 381 (M)++1)
Example 69: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } group -N' - (2-propynyl) urea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), triphosgene (50mg) dissolved in chloroform was added thereto, and the mixture was stirred at room temperature for 30 minutes. Propargylamine hydrochloride (31mg) was then added, and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (26 mg) with a yield of 41%.
1H-NMR(DMS
O-d6，400MHz)：3.11-3.12(m，1H)，3.89-3.90(m，2H)，3.97(s，3H)，3.99(s，3H)，6.49(t，J＝5.9Hz，1H)，7.17(d，J＝9.0Hz，2H)，7.38(s，1H)，7.48(d，J＝8.8Hz，2H)，7.55(s，1H)，8.53(s，1H)，8.68(s，1H)
Mass Spectrometry (ESI-MS, m/z): 379 (M)++1)
Example 70: n- (2, 4-difluorobenzyl) -N' - {4- [ (6, 7-dimethoxyl) 4-quinazolinyl) oxy phenyl urea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), triphosgene (50mg) dissolved in chloroform was added thereto, and the mixture was stirred at room temperature for 30 minutes. 2, 4-difluorobenzylamine (22. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (32mg) in 41% yield.
1H-NMR(DMSO-d6，400MHz)：3.97(s，3H)，3.98(s，3H)，4.32-4.33(m，2H)，6.66(t，J＝5.9Hz，1H)，7.06-7.10(m，1H)，7.16(d，J＝8.8Hz，2H)，7.19-7.24(m，1H)，7.37(s，1H)，7.40-7.44(m，1H)，7.48(d，J＝9.0Hz，2H)，7.55(s，1H)，8.52(s，1H)，8.69(s，1H)
Mass Spectrometry (ESI-MS, m/z): 467 (M)++1)
Example 71: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } group -N' - (2-pyridylmethyl) urea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), triphosgene (50mg) dissolved in chloroform was added thereto, and the mixture was stirred at room temperature for 30 minutes. Then, 2, 4-difluorobenzylamine (31. mu.l) was added thereto, and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound 31mg in 43% yield.
1H-NMR(DMSO-d6，400MHz)：3.42(s，2H)，3.98(s，3H)，3.99(s，3H)，7.16-7.19(m，2H)，7.22-7.27(m，3H)，7.38(s，1H)，7.57(s，1H)，7.67(d，J＝8.8Hz，2H)，7.88-7.92(m，1H)，8.46-8.48(m，1H)，8.54(s，1H)，8.87(s，1H)，12.19(s，1H)
Mass Spectrometry (FD-MS, m/z): 431 (M)+)
Example 72: n- (2, 4-difluorophenyl) -N' - {4- [ (6, 7-dimethoxy) -4-quinazolinyl) oxy ] phenyl } urea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml), 2, 4-difluorophenyl isocyanate (25. mu.l) was added thereto, and the mixture was refluxed for 1 night. The precipitated crystals were collected by filtration and washed to give the title compound 55mg in a yield of 72%.
1H-NMR(DMSO-d6，400MHz)：3.98(s，3H)，3.99(s，3H)，7.04-7.08(m，2H)，7.24(d，J＝8.8Hz，2H)，7.29-7.35(m，1H)，7.38(s，1H)，7.54(d，J＝9.0Hz，2H)，7.56(s，1H)，8.06-8.14(m，1H)，8.51-8.54(m，1H)，8.54(s，1H)，9.11-9.12(m，1H)
Mass Spectrometry (ESI-MS, m/z): 453 (M)++1)
Example 73: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } group -N' - (4-fluorophenyl) urea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml), p-fluorophenyl isocyanate (23. mu.l) was added, and the mixture was refluxed for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (26 mg) in a yield of 36%.
1H-NMR(DMSO-d6，400MHz)：3.98(s，3H)，3.99(s，3H)，7.11-7.15(m，2H)，7.22(d，J＝8.8Hz，2H)，7.38(s，1H)，7.46-7.50(m，2H)，7.54(d，J＝9.0Hz，2H)，7.56(s，1H)，8.54(s，1H)，8.72(s，1H)，8.75(s，1H)
Mass Spectrometry (ESI-MS, m/z): 435 (M)++1)
Example 74: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } group -N' - (2-methylphenyl) urea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml), o-tolylisocyanate (25. mu.l) was added, and the mixture was refluxed for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (30mg) in 41% yield.
1H-NMR(DMSO-d6，400MHz)：2.26(s，3H)，3.98(s，3H)，3.99(s，3H)，6.93-6.98(m，1H)，7.13-7.19(m，2H)，7.22(d，J＝8.8Hz，2H)，7.38(s，1H)，7.54-7.56(m，3H)，7.83-7.86(m，1H)，7.93(s，1H)，8.54(s，1H)，9.10-9.11(m，1H)
Mass Spectrometry (ESI-MS, m/z): 431 (M)++1)
Example 75: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } group -N' - (2-methoxyphenyl) urea
After 4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (3ml), 2-methoxyphenyl isocyanate (27. mu.l) was added. Reflux with heating for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (34 mg) in a yield of 45%.
1H-NMR(DMSO-d6，400MHz)：3.89(s，3H)，3.98(s，3H)，3.99(s，3H)，6.89-7.05(m，3H)，7.22(d，J＝8.8Hz，2H)，7.38(s，1H)，7.54(d，J＝8.8Hz，2H)，7.56(s，1H)，8.13-8.15(m，1H)，8.23-8.24(m，1H)，8.54(s，1H)，9.40-9.41(m，1H)
Mass Spectrometry (ESI-MS, m/z): 447 (M)++1)
Example 76: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' -ethylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (200mg) was dissolved in chloroform (5ml) and triethylamine (1ml), and triphosgene (179mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Subsequently, ethylamine hydrochloride (246mg) was added thereto, followed by stirring at room temperature for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 159mg in a yield of 65%.
1H-NMR(DMSO-d6，400MHz)：δ1.08(t，J＝7.1Hz，3H)，3.11-3.16(m，2H)，3.97(s，3H)，3.99(s，3H)，6.96(t，J＝5.6Hz，1H)，7.23(dd，J＝2.7Hz，9.0Hz，1H)，7.39(s，1H)，7.47(d，J＝2.7Hz，1H)，7.55(s，1H)，8.02(s，1H)，8.20(d，J＝9.3Hz，1H)，8.56(s，1H)
Mass Spectrometry (ESI-MS, m/z): 403 (M)++1)
Example 77: N-butyl-N' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quina-ne) Azolinyl) oxy ] phenyl } urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (5ml) and triethylamine (1ml), and triphosgene (45mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Butylamine (22. mu.l) was then added and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 30mg in a yield of 46%.
1H-NMR(DMSO-d6，400MHz)：δ0.91(t，J＝7.3Hz，3H)，1.31-1.46(m，4H)，3.09-3.14(m，2H)，3.97(s，3H)，3.99(s，3H)，6.96(t，J＝5.6Hz，1H)，7.23(dd，J＝2.7Hz，9.0Hz，1H)，7.39(s，1H)，7.47(d，J＝2.7Hz，1H)，7.55(s，1H)，8.03(s，1H)，8.20(d，J＝9.0Hz，1H)，8.56(s，1H)
Mass Spectrometry (ESI-MS, m/z): 431 (M)++1)
Example 78: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' -pentylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (5ml) and triethylamine (1ml), and triphosgene (45mg) dissolved in methylene chloride was added to the solution, followed by stirring at room temperature for 30 minutes. Then, pentylamine (26. mu.l) was added thereto, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 33mg in 49% yield.
1H-NMR(DMSO-d6，400MHz)：δ0.90(t，J＝7.1Hz，3H)，1.24-1.34(m，4H)，1.43-1.48(m，2H)，3.08-3.14(m，2H)，3.97(s，3H)，3.99(s，3H)，6.97(t，J＝5.1Hz，1H)，7.23(dd，J＝2.7Hz，9.0Hz，1H)，7.39(s，1H)，7.47(d，J＝2.8Hz，1H)，7.55(s，1H)，8.03(s，1H)，8.20(d，J＝9.0Hz，1H)，8.56(s，1H)
Mass Spectrometry (ESI-MS, m/z): 445 (M)++1)
Example 79: n- (sec-butyl) -N' - { 2-chloro-4- [ (6, 7-dimethoxy- 4-quinazolinyl) oxy ] phenyl } urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (5ml) and triethylamine (1ml), and triphosgene (45mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Sec-butylamine (23. mu.l) was then added and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 34mg in 52% yield.
1H-NMR(DMSO-d6，400MHz)：δ0.89(t，J＝7.6Hz，3H)，1.09(d，J＝6.6Hz，3H)，1.43-1.46(m，2H)，3.58-3.66(m，1H)，3.97(s，3H)，3.99(s，3H)，6.88(d，J＝7.6Hz，1H)，7.22(dd，J＝2.4Hz，9.3Hz，1H)，7.39(s，1H)，7.47(d，J＝2.7Hz，1H)，7.55(s，1H)，7.98(s，1H)，8.23(d，J＝9.0Hz，1H)，8.55-8.56(m，1H)
Mass Spectrometry (ESI-MS, m/z): 431 (M)++1)
Example 80: N-allyl-N' - { 2-chloro-4- [ (6, 7-dimethoxy-4- Quinazolinyl) oxy ] phenyl } urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (5ml) and triethylamine (1ml), and triphosgene (45mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Subsequently, allylamine hydrochloride (21mg) was added thereto, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 45mg in a yield of 72%.
1H-NMR(DMSO-d6，400MHz)：3.76-3.79(m，2H)，3.97(s，3H)，3.99(s，3H)，5.10-5.24(m，2H)，5.85-5.94(m，1H)，7.11(t，J＝5.4Hz，1H)，7.24(dd，J＝2.7Hz，9.0Hz，1H)，7.39(s，1H)，7.49(d，J＝2.7Hz，1H)，7.55(s，1H)，8.14(s，1H)，8.19(d，J＝9.0Hz，1H)，8.56(s，1H)
Mass Spectrometry (ESI-MS, m/z): 415 (M)++1)
Example 81: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' - (2-propynyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (5ml) and triethylamine (1ml), and triphosgene (45mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Propargylamine hydrochloride (21mg) was then added, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and washed to give the title compound 38mg in a yield of 61%.
1H-NMR(DMSO-d6，400MHz)：3.16-3.17(m，1H)，3.93-3.95(m，2H)，3.97(s，3H)，3.99(s，3H)，7.25(dd，J＝2.7Hz，9.0Hz，1H)，7.30(t，J＝5.6Hz，1H)，7.39(s，1H)，7.50(d，J＝2.7Hz，1H)，7.55(s，1H)，8.16(d，J＝9.3Hz，1H)，8.18(s，1H)，8.56(s，1H)
Mass Spectrometry (ESI-MS, m/z): 413 (M)++1)
Example 82: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' - (2, 4-difluorobenzyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (5ml) and triethylamine (1ml), and triphosgene (45mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. 2, 4-difluorobenzylamine (22. mu.l) was then added and stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and washed to give the title compound 48mg in 64% yield.
1H-NMR(DMSO-d6，400MHz)：3.97(s，3H)，3.99(s，3H)，4.33-4.36(m，2H)，7.08-7.12(m，1H)，57.22-7.28(m，2H)，7.39(s，1H)，7.42-7.46(m，1H)，7.49(d，J＝2.7Hz，1H)，7.54(s，1H)，8.18-8.20(m，2H)，8.56(s，1H)
Mass Spectrometry (ESI-MS, m/z): 501 (M)++1)
Example 83: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' - (2-pyridylmethyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (5ml) and triethylamine (1ml), and triphosgene (45mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Then, 2- (methylamine) pyridine (19. mu.l) was added thereto, and the mixture was stirred at 60 ℃ for 1 hour. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 26mg in a yield of 37%.
1H-NMR(CDCl3，400MHz)：3.51(s，2H)，4.07(s，3H)，4.07(s，3H)，7.03-7.10(m，2H)，7.19(dd，J＝2.7Hz，9.0Hz，1H)，7.35(s，1H)，7.36(d，J＝2.7Hz，1H)，7.54(s，1H)，7.76-7.81(m，1H)，8.38-8.43(m，1H)，8.56(d，J＝9.0Hz，1H)，8.64(s，1H)，13.53(s，1H)
Mass Spectrometry (ESI-MS, m/z): 466 (M)++1)
Example 85: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' - (4-fluorophenyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (5ml), and p-fluorophenyl isocyanate (21. mu.l) was added thereto, and the mixture was stirred at 60 ℃ for 1 hour. The precipitated crystals were collected by filtration and washed to give the title compound 57mg in 81% yield.
1H-NMR(DMSO-d6，400MHz)：3.98(s，3H)，3.99(s，3H)，7.13-7.17(m，2H)，7.30(dd，J＝2.4Hz，8.8Hz，1H)，7.40(s，1H)，7.48-7.51(m，2H)，7.55-7.56(m，2H)，8.21(d，J＝9.0Hz，1H)，8.31(s，1H)，8.57(s，1H)
Mass Spectrometry (ESI-MS, m/z): 469 (M)++1)
Example 86: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' - (2-methoxyphenyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (5ml), and 2-methoxyphenyl isocyanate (24. mu.l) was added thereto, followed by stirring at 60 ℃ for 1 hour. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (39 mg) in 54% yield.
1H-NMR(DMSO-d6，400MHz)：3.90(s，3H)，3.98(s，3H)，3.99(s，3H)，6.89-7.05(m，3H)，7.29(dd，J＝2.7Hz，9.0Hz，1H)，7.40(s，1H)，7.54(d，J＝2.7Hz，1H)，7.56(s，1H)，8.09-8.16(m，2H)，8.58(s，1H)，8.96-9.02(m，2H)
Mass Spectrometry (ESI-MS, m/z): 418 (M)++1)
Example 87: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' - (5-chloro-2-pyridyl) urea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (5ml) and triethylamine (1ml), and triphosgene (45mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Then, 2-amino-5-chloropyridine (23mg) was added thereto, and the mixture was stirred at 60 ℃ for 1 hour. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 39mg in a yield of 53%.
1H-NMR(DMSO-d6，400MHz)：3.98(s，3H)，4.00(s，3H)，7.33(dd，J＝2.7Hz，9.3Hz，1H)，7.40(s，1H)，7.43-7.48(m，1H)，7.56(s，1H)，7.60(d，J＝2.7Hz，1H)，7.91(dd，J＝2.7Hz，9.0Hz，1H)，8.35(d，J＝8.8Hz，1H)，8.40(d，J＝2.4Hz，1H)，8.58(s，1H)，10.17(s，1H)
Mass Spectrometry (ESI-MS, m/z): 486 (M)++1)
Example 88: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2- Fluorophenyl } -N' -propyl urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-fluoroaniline (50mg) was dissolved in chloroform (3m1) and triethylamine (0.3ml), followed by addition of triphosgene (47mg) dissolved in chloroform and stirring at room temperature for 30 minutes. Propylamine (20. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound 9mg in 14% yield.
1H-NMR(DMSO-d6，400MHz)：δ0.90(t，J＝7.6Hz，3H)，1.43-1.49(m，2H)，3.05-3.10(m，2H)，3.97(s，3H)，3.99(s，3H)，6.61(t，J＝5.6Hz，1H)，7.05-7.07(m，1H)，7.27-7.31(m，1H)，7.38(s，1H)，7.54(s，1H)，8.14-8.19(m，1H)，8.28-8.29(m，1H)，8.55(s，1H)
Mass Spectrometry (ESI-MS, m/z): 401 (M)++1)
Example 89: N-butyl-N' - {4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] -2-fluorophenyl } urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-fluoroaniline (50mg) was dissolved in chloroform (3ml) or triethylamine (0.3ml), and triphosgene (47mg) dissolved in chloroform was added to the solution, followed by stirring at room temperature for 30 minutes. Butylamine (24. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound in an amount of 25mg, and the yield was 38%.
1H-NMR(DMSO-d6，400MHz)：δ0.91(t，J＝7.3Hz，3H)，1.30-1.47(m，4H)，3.09-3.13(m，2H)，3.97(s，3H)，3.99(s，3H)，6.58(t，J＝5.6Hz，1H)，7.04-7.07(m，1H)，7.28-7.31(m，1H)，7.38(s，1H)，7.54(s，1H)，8.14-8.19(m，1H)，8.26-8.28(m，1H)，8.55(s，1H)
Mass Spectrometry (ESI-MS, m/z): 415 (M)++1)
Example 90: n- (sec-butyl) -N' - {4- [ (6, 7-dimethoxy-4-quinazol) Linyl) oxy ] -2-fluorophenyl } urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-fluoroaniline (50mg) was dissolved in chloroform (3ml) or triethylamine (0.3ml), and triphosgene (47mg) dissolved in chloroform was added to the solution, followed by stirring at room temperature for 30 minutes. Sec-butylamine (25. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound in an amount of 12mg, with a yield of 18%.
1H-NMR(DMSO-d6，400MHz)：0.89(t，J＝7.6Hz，3H)，1.08(d，J＝6.6Hz，3H)，1.39-1.48(m，2H)，3.58-3.64(m，1H)，3.97(s，3H)，3.99(s，3H)，6.51(d，J＝7.6Hz，1H)，7.04-7.08(m，1H)，7.30(dd，J＝2.4Hz，11.7Hz，1H)，7.39(s，1H)，7.54(s，1H)，8.16-8.22(m，2H)，8.56(s，1H)
Mass Spectrometry (ESI-MS, m/z): 415 (M)++1)
Example 91: N-allyl-N' - {4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] -2-fluorophenyl } urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-fluoroaniline (50mg) was dissolved in chloroform (3ml) or triethylamine (0.3ml), and triphosgene (47mg) dissolved in chloroform was added to the solution, followed by stirring at room temperature for 30 minutes. Subsequently, allylamine hydrochloride (30mg) was added, followed by stirring at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound in 18mg, yield 28%.
1H-NMR(DMSO-d6，400MHz)：3.75-3.79(m，2H)，3.97(s，3H)，3.99(s，3H)，5.08-5.22(m，2H)，5.84-5.94(m，1H)，6.72(t，J＝5.9Hz，1H)，7.06-7.08(m，1H)，7.30-7.33(m，1H)，7.39(s，1H)，7.54(s，1H)，8.13-8.18(m，1H)，8.40(s，1H)，8.56(s，1H)
Mass Spectrometry (ESI-MS, m/z): 399 (M)++1)
Example 92: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2- Fluorophenyl } -N' - (2-propynyl) urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-fluoroaniline (50mg) was dissolved in chloroform (3ml) or triethylamine (0.3ml), and triphosgene (47mg) dissolved in chloroform was added to the solution, followed by stirring at room temperature for 30 minutes. Propargylamine hydrochloride (29mg) was then added, and the mixture was stirred at room temperature for 1 night. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with chloroform to give the title compound 21mg in a yield of 33%.
1H-NMR(DMSO-d6，400MHz)：3.15(t，J＝2.4Hz，1H)，3.91-3.94(m，2H)，3.97(s，3H)，3.99(s，3H)，7.07-7.11(m，1H)，7.33(dd，J＝2.4Hz，11.7Hz，1H)，7.39(s，1H)，7.54(s，1H)，8.09-8.15(m，1H)，8.47-8.48(m，1H)，8.56(s，1H)
Mass Spectrometry (ESI-MS, m/z): 397 (M)++1)
Example 93: n- (2, 4-difluorobenzyl) -N' - {4- [ (6, 7-dimethoxyl) 4-quinazolinyl) oxy ] -2-fluorophenyl } urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-fluoroaniline (50mg) was dissolved in chloroform (3ml) or triethylamine (0.3ml), and triphosgene (47mg) dissolved in chloroform was added to the solution, followed by stirring at room temperature for 30 minutes. 2, 4-difluorobenzylamine (28. mu.l) was then added and the mixture was stirred at room temperature for 1 night. The precipitated crystals were collected by filtration and washed to give the title compound 20mg in 26% yield.
1H-NMR(DMSO-d6，400MHz)：3.97(s，3H)，3.99(s，3H)，4.34(d，J＝5.8Hz，2H)，7.07-7.11(m，3H)，7.21-7.27(m，1H)，7.30-7.33(m，1H)，7.39(s，1H)，7.41-7.47(m，1H)，7.54(s，1H)，8.12-8.16(m，1H)，8.46-8.47(m，1H)，8.55(s，1H)
Mass Spectrometry (FD-MS, m/z): 484 (M)+)
Example 94: n- (2, 4-difluorophenyl) -N' - {4- [ (6, 7-dimethoxy) -4-quinazolinyl) oxy ] -2-fluorophenyl } urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-fluoroaniline (50mg) was dissolved in chloroform (3m1), and 2, 4-difluorophenyl isocyanate (29. mu.l) was added and the mixture was stirred at 60 ℃ for 1 night. The precipitated crystals were collected by filtration and washed to give the title compound in 50mg, yield 67%.
1H-NMR(DMSO-d6，400MHz)：3.98(s，3H)，3.99(s，3H)，7.04-7.08(m，1H)，7.13-7.15(m，1H)，7.29-7.40(m，3H)，7.55(s，1H)，8.10-8.23(m，2H)，8.57(s，1H)，8.97-9.04(m，2H)
Mass Spectrometry (ESI-MS, m/z): 471 (M)++1)
Example 95: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2- Fluorophenyl } -N' - (2-methylphenyl) urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-fluoroaniline (50mg) was dissolved in chloroform (3ml), and o-tolylisocyanate (30. mu.l) was added thereto, followed by stirring at 60 ℃ for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (17 mg) in 24% yield.
1H-NMR(DMSO-d6，400MHz)：2.27(s，3H)，3.98(s，3H)，3.99(s，3H)，6.95-6.98(m，1H)，7.12-7.20(m，3H)，7.36-7.39(m，2H)，7.55(s，1H)，7.86(d，J＝7.8Hz，1H)，8.21-8.26(m，1H)，8.35(s，1H)，8.57(s，1H)，9.00-9.02(m，1H)
Mass Spectrometry (ESI-MS, m/z): 449 (M)++1)
Example 96: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2- Fluorophenyl } -N' - (2-methoxyphenyl) urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-fluoroaniline (50mg) was dissolved in chloroform (3ml), and 2-methoxyphenyl isocyanate (32. mu.l) was added thereto, followed by stirring at 60 ℃ for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound 22mg in 30% yield.
1H-NMR(DMSO-d6，400MHz)：3.89(s，3H)，3.98(s，3H)，3.99(s，3H)，6.88-7.04(m，3H)，7.11-7.14(m，1H)，7.35-7.39(m，1H)，7.40(s，1H)，7.56(s，1H)，8.12-8.15(m，1H)，8.19-8.25(m，1H)，8.57(s，1H)，8.75-8.78(m，1H)，9.26-9.29(m，1H)
Mass Spectrometry (ESI-MS, m/z): 465 (M)++1)
Example 97: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -3- Methyl phenyl } -N' -propyl urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -3-methylaniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), and triphosgene (48mg) dissolved in chloroform was added to the solution, followed by stirring at room temperature for 30 minutes. Propylamine (20. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound in a yield of 30mg, 47%.
1H-NMR(DMSO-d6，400MHz)：δ0.89(t，J＝7.5Hz，3H)，1.41-1.50(m，2H)，2.03(s，3H)，3.03-3.08(m，2H)，3.98(s，3H)，3.99(s，3H)，6.13(t，J＝5.4Hz，1H)，7.04(d，J＝8.5Hz，1H)，7.28(dd，J＝2.4Hz，8.5Hz，1H)，7.36(d，J＝2.4Hz，1H)，7.38(s，1H)，7.58(s，1H)，8.39(s，1H)，8.50(s，1H)
Mass Spectrometry (ESI-MS, m/z): 397 (M)++1)
Example 98: N-butyl-N' - {4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] -3-methylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -3-methylaniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), and triphosgene (48mg) dissolved in chloroform was added to the solution, followed by stirring at room temperature for 30 minutes. Butylamine (24. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound 31mg in 47% yield.
1H-NMR(DMSO-d6，400MHz)：δ0.91(t，J＝7.3Hz，3H)，1.29-1.46(m，4H)，2.03(s，3H)，3.07-3.12(m，2H)，3.98(s，3H)，3.99(s，3H)，6.11(t，J＝5.6Hz，1H)，7.05(d，J＝8.8Hz，1H)，7.27(dd，J＝2.3Hz，8.5Hz，1H)，7.36(d，J＝2.4Hz，1H)，7.38(s，1H)，7.58(s，1H)，8.39(s，1H)，8.51(s，1H)
Mass Spectrometry (ESI-MS, m/z): 411 (M)++1)
Example 99: n- (2, 4-difluorophenyl) -N' - {4- [ (6, 7-dimethoxy) -4-quinazolinyl) oxy ] -3-methylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -3-methylaniline (50mg) was dissolved in chloroform (3ml), and 2, 4-difluorophenyl isocyanate (23. mu.l) was added thereto and the mixture was refluxed for 1 night. The precipitated crystals were collected by filtration and washed to give the title compound 59mg in 79% yield.
1H-NMR(DMSO-d6，400MHz)：2.07(s，3H)，3.99(s，3H)，3.99(s，3H)，7.03-7.08(m，1H)，7.14(d，J＝8.5Hz，1H)，7.29-7.37(m，2H)，7.39(s，1H)，7.43(d，J＝2.4Hz，1H)，7.60(s，1H)，8.07-8.14(m，1H)，8.52(s，1H)，9.03-9.05(m，1H)
Mass Spectrometry (ESI-MS, m/z): 467 (M)++1)
Example 100: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -3 -methylphenyl } -N' - (4-fluorophenyl) urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -3-methylaniline (50mg) was dissolved in chloroform (3ml), and p-fluorophenyl isocyanate (22. mu.l) was added thereto and the mixture was refluxed for 1 night. The precipitated crystals were collected by filtration and washed to give the title compound 42mg in 58% yield.
1H-NMR(DMSO-d6，400MHz)：2.07(s，3H)，3.98(s，3H)，3.99(s，3H)，7.10-7.14(m，3H)，7.35(dd，J＝2.4Hz，8.5Hz，1H)，7.39(s，1H)，7.43(d，J＝2.4Hz，1H)，7.46-7.49(m，2H)，7.59(s，1H)，8.51(s，1H)，8.66(s，1H)，8.70(s，1H)
Mass Spectrometry (ESI-MS, m/z): 449 (M)++1)
Example 101: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -3 -methylphenyl } -N' - (2-methoxyphenyl) urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -3-methylaniline (50mg) was dissolved in chloroform (3ml), and 2-methoxyphenyl isocyanate (26. mu.l) was added thereto and the mixture was refluxed for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound 41mg, which was obtained in 55% yield.
1H-NMR(DMSO-d6，400MHz)：δ2.07(s，3H)，3.89(s，3H)，3.99(s，3H)，3.99(s，3H)，6.88-6.97(m，2H)，7.01-7.03(m，1H)，7.12(d，J＝8.5Hz，1H)，7.35(dd，J＝2.4Hz，8.5Hz，1H)，7.39(s，1H)，7.44(d，J＝2.4Hz，1H)，7.60(s，1H)，8.13-8.15(m，1H)，8.23(s，1H)，8.52(s，1H)，9.33(s，1H)
Mass Spectrometry (ESI-MS, m/z): 461 (M)++1)
Example 102: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2 -methylphenyl } -N' -propylurea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-methylaniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), and triphosgene (48mg) dissolved in chloroform was added to the solution, followed by stirring at room temperature for 30 minutes. Propylamine (20. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound in a yield of 30mg, 47%.
1H-NMR(DMSO-d6，400MHz)：δ0.90(t，J＝7.3Hz，3H)，1.42-1.51(m，2H)，2.21(s，3H)，3.04-3.09(m，2H)，3.97(s，3H)，3.99(s，3H)，6.53(t，J＝5.6Hz，1H)，7.02(dd，J＝2.7Hz，8.8Hz，1H)，7.08(d，J＝2.7Hz，1H)，7.37(s，1H)，7.54(s，1H)，7.65(s，1H)，7.85(d，J＝8.8Hz，1H)，8.53(s，1H)
Mass Spectrometry (ESI-MS, m/z): 397 (M)++1)
Example 103: N-butyl-N' - {4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] -2-methylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-methylaniline (50mg) was dissolved in chloroform (3ml) and triethylamine (0.2ml), and triphosgene (48mg) dissolved in chloroform was added to the solution, followed by stirring at room temperature for 30 minutes. Butylamine (24. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound 37mg in 56% yield.
1H-NMR(DMSO-d6，400MHz)：δ0.92(t，J＝7.1Hz，3H)，1.31-1.48(m，4H)，2.21(s，3H)，3.08-3.13(m，2H)，3.97(s，3H)，3.99(s，3H)，6.50(t，J＝5.4Hz，1H)，7.02(dd，J＝2.7Hz，8.8Hz，1H)，7.08(d，J＝2.7Hz，1H)，7.37(s，1H)，7.54(s，1H)，7.64(s，1H)，7.86(d，J＝8.8Hz，1H)，8.53(s，1H)
Mass Spectrometry (ESI-MS, m/z): 411 (M)++1)
Example 104: n- (2, 4-difluorophenyl) -N' - {4- [ (6, 7-dimethoxy) -4-quinazolinyl) oxy ] -2-methylphenyl } urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-methylaniline (50mg) was dissolved in chloroform (3ml), and 2, 4-difluorophenyl isocyanate (23. mu.l) was added thereto and the mixture was refluxed for 1 night. The precipitated crystals were collected by filtration, washed and quantified to give the title compound.
1H-NMR(DMSO-d6，400MHz)：2.29(s，3H)，3.98(s，3H)，3.99(s，3H)，7.03-7.11(m，2H)，7.16(d，J＝2.7Hz，1H)，7.29-7.35(m，1H)，7.38(s，1H)，7.55(s，1H)，7.87-7.90(m，1H)，8.13-8.19(m，1H)，8.36-8.39(m，1H)，8.55(s，1H)，8.92-8.95(m，1H)
Mass Spectrometry (ESI-MS, m/z): 467 (M)++1)
Example 105: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2 -methylphenyl } -N' - (4-fluorophenyl) urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-methylaniline (50mg) was dissolved in chloroform (3ml), and p-fluorophenyl isocyanate (22. mu.l) was added thereto and the mixture was refluxed for 1 night. The precipitated crystals were collected by filtration, washed and quantified to give the title compound.
1H-NMR(DMSO-d6，400MHz)：2.28(s，3H)，3.98(s，3H)，3.99(s，3H)，7.08-7.15(m，4H)，7.38(s，1H)，7.47-7.50(m，2H)，7.55(s，1H)，7.84-7.88(m，1H)，7.98(s，1H)，8.55(s，1H)，9.03-9.05(m，1H)
Mass Spectrometry (ESI-MS, m/z): 449 (M)++1)
Example 106: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2 -methylphenyl } -N' - (2-methoxyphenyl) urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-methylaniline (50mg) was dissolved in chloroform (3ml), and 2-methoxyphenyl isocyanate (26. mu.l) was added thereto and the mixture was refluxed for 1 night. The precipitated crystals were collected by filtration and washed to give the title compound 70mg in a yield of 95%.
1H-NMR(DMSO-d6，400MHz)：2.29(s，3H)，3.90(s，3H)，3.98(s，3H)，3.99(s，3H)，6.87-6.97(m，2H)，7.02-7.04(m，1H)，7.08(dd，J＝2.9Hz，8.8Hz，1H)，7.14(d，J＝2.7Hz，1H)，7.38(s，1H)，7.55(s，1H)，7.84(d，J＝8.8Hz，1H)，8.13-8.15(m，1H)，8.55(s，1H)，8.58(s，1H)，8.61-8.62(m，1H)
Mass Spectrometry (ESI-MS, m/z): 461 (M)++1)
Example 107: n- {4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2 -nitrophenyl } -N' -propylurea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-nitroaniline (50mg) was dissolved in chloroform (10ml) or triethylamine (0.2ml), and triphosgene (43mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Propylamine (18. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound in an amount of 24mg, with a yield of 38%.
1H-NMR(DMSO-d6，400MHz)：δ0.91(t，J＝7.6Hz，3H)，1.45-1.51(m，2H)，3.06-3.09(m，2H)，3.98(s，3H)，4.00(s，3H)，7.40(s，1H)，7.52(br，1H)，7.58(s，1H)，7.67-7.70(m，1H)，8.04-8.06(m，1H)，8.38-8.41(m，1H)，8.57(s，1H)，9.35(s，1H)
Mass Spectrometry (ESI-MS, m/z): 428 (M)++1)
Example 108: N-butyl-N' - {4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] -2-nitrophenyl } urea
4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] -2-nitroaniline (50mg) was dissolved in chloroform (10ml) or triethylamine (0.2ml), and triphosgene (43mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Butylamine (22. mu.l) was then added and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (15 mg) in a yield of 23%.
1H-NMR(DMSO-d6，400MHz)：δ0.91(t，J＝7.3Hz，3H)，1.30-1.49(m，4H)，3.10-3.15(m，2H)，3.98(s，3H)，4.00(s，3H)，7.40(s，1H)，7.51(br，1H)，7.57(s，1H)，7.68(dd，J＝2.9Hz，9.3Hz，1H)，8.05(d，J＝2.9Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.57(s，1H)，9.35(s，1H)
Mass Spectrometry (ESI-MS, m/z): 442 (M)++1)
Example 109: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N-methoxymethyl-N' -propylurea
N- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (100mg) was dissolved in anhydrous tetrahydrofuran (30ml), and sodium hydride (60 wt%, 88mg) was added thereto, followed by stirring at room temperature for 15 minutes. Chloromethyl methyl ether (67. mu.l) was then added thereto, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, water was then added thereto, and extraction was performed with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound in 18mg, yield 18%.
1H-NMR(DMSO-d6，400MHz)：δ0.89(t，J＝7.6Hz，3H)，1.46-1.55(m，2H)，3.20(br，2H)，3.48(s，3H)，4.07(s，3H)，4.08(s，3H)，4.54(br，2H)，7.29(dd，J＝2.7Hz，8.5Hz，1H)，7.37(s，1H)，7.47(d，J＝8.8Hz，1H)，7.50(s，1H)，7.50(d，J＝2.7Hz，1H)，8.66(s，1H)
Mass Spectrometry (ESI-MS, m/z): 461 (M)++1)
Example 110: N-acetyl-N- { 2-chloro-4- [ (6, 7-dimethoxy-4- Quinazolinyl) oxy ] phenyl } -N' -propylurea
N- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (100mg) was dissolved in anhydrous tetrahydrofuran (30ml), and sodium hydride (60 wt%, 88mg) was added thereto, followed by stirring at room temperature for 15 minutes. Acetyl chloride (63. mu.l) was then added and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, water was then added thereto, and extraction was performed with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/acetone to give the title compound 27mg in a yield of 26%.
1H-NMR(DMSO-d6，400MHz)：δ0.98(t，J＝7.3Hz，3H)，1.59-1.68(m，2H)，2.04(s，3H)，3.27-3.36(m，2H)，4.07(s，3H)，4.08(s，3H)，7.31-7.33(m，1H)，7.35(s，1H)，7.41(d，J＝9.0Hz，1H)，7.50-7.51(m，2H)，8.63(s，1H)，9.08(br，1H)
Mass Spectrometry (ESI-MS, m/z): 459 (M)++1)
Example 111: n' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] phenyl } -N-methyl-N-propylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (56mg) was dissolved in chloroform (4ml) and triethylamine (0.3ml), and triphosgene (50mg) dissolved in chloroform was added to the solution, followed by stirring at room temperature for 30 minutes. Subsequently, N-methylpropylamine (26. mu.l) was added, and the mixture was stirred at room temperature for 1 hour. Methanol was added to the reaction solution, purification was performed by HPLC using chloroform/methanol, the solvent was distilled off, and the obtained crystals were washed with hexane to obtain 42mg of the title compound with a yield of 58%.
1H-NMR(DMSO-d6，400MHz)：δ0.99(t，J＝7.3Hz，3H)，1.64-1.74(m，2H)，3.08(s，3H)，3.34(t，J＝7.6Hz，2H)，4.07(s，3H)，4.08(s，3H)，7.00(s，1H)，7.17(dd，J＝2.7Hz，9.3Hz，1H)，7.31(d，J＝2.7Hz，1H)，7.38(s，1H)，7.53(s，1H)，8.41(d，J＝9.0Hz，1H)，8.64(s，1H)
Mass Spectrometry (ESI-MS, m/z): 431 (M)++1)
Example 112: n' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] phenyl } -N-ethyl-N-propylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (80mg) was dissolved in chloroform (3ml) and triethylamine (0.3ml), and triphosgene (72mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 15 minutes. Subsequently, N-ethylpropylamine (44. mu.l) was added, and the mixture was stirred at room temperature for 30 minutes. Methanol was added to the reaction solution, purification was performed by HPLC using chloroform/methanol, the solvent was distilled off, and the obtained crystals were washed with hexane to obtain the title compound (40mg) with a yield of 37%.
1H-NMR(DMSO-d6，400MHz)：δ1.00(t，J＝7.3Hz，3H)，1.28(t，J＝7.1Hz，3H)，1.69-1.74(m，2H)，3.32(t，J＝7.6Hz，2H)，3.43(q，J＝7.1Hz，2H)，4.07(s，3H)，4.07(s，3H)，7.02(s，1H)，7.17(dd，J＝2.9Hz，9.2Hz，1H)，7.31(d，J＝2.7Hz，1H)，7.36(s，1H)，7.53(s，1H)，8.42(d，J＝9.0Hz，1H)，8.63(s，1H)
Mass Spectrometry (ESI-MS, m/z): 445 (M)++1)
Example 113: n' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] phenyl } -N, N-dipropylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (100mg) was dissolved in chloroform (3ml) and triethylamine (0.3ml), and triphosgene (90mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 15 minutes. Then, dipropylamine (62. mu.l) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Methanol was added to the reaction solution, purification was performed by HPLC using chloroform/methanol, the solvent was distilled off, and the obtained crystals were washed with hexane to obtain the title compound (48mg) with a yield of 35%.
1H-NMR(DMSO-d6，400MHz)：δ0.99(t，J＝7.3Hz，6H)，1.66-1.76(m，4H)，3.32(t，J＝7.8Hz，4H)，4.07(s，3H)，4.07(s，3H)，7.03(s，1H)，7.16(dd，J＝2.7Hz，9.3Hz，1H)，7.31(d，J＝2.7Hz，1H)，7.34(s，1H)，7.52(s，1H)，8.43(d，J＝9.0Hz，1H)，8.63(s，1H)
Mass Spectrometry (ESI-MS, m/z): 459 (M)++1)
Example 114: N-butyl-N' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quina-ne) Oxazolinyl) oxy ] phenyl } -N-methylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (80mg) was dissolved in chloroform (3ml) and triethylamine (0.3ml), and triphosgene (72mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 15 minutes. N-methylbutylamine (43. mu.l) was then added and the mixture was stirred at room temperature for 30 minutes. Methanol was added to the reaction solution, purification was performed by HPLC using chloroform/methanol, the solvent was distilled off, and the obtained crystals were washed with hexane to obtain the title compound (26 mg) with a yield of 24%.
1H-NMR(DMSO-d6，400MHz)：δ0.99(t，J＝7.3Hz，3H)，1.38-1.43(m，2H)，1.62-1.66(m，2H)，3.07(s，3H)，3.40(t，J＝7.3Hz，2H)，4.07(s，3H)，4.07(s，3H)，7.00(s，1H)，7.17(dd，J＝2.7Hz，9.3Hz，1H)，7.31(d，J＝2.7Hz，1H)，7.36(s，1H)，7.53(s，1H)，8.41(d，J＝9.3Hz，1H)，8.63(s，1H)
Mass Spectrometry (ESI-MS, m/z): 445 (M)++1)
Example 115: n' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] phenyl } -N- (4-chlorophenyl) -N-methylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (80mg) was dissolved in chloroform (3ml) and triethylamine (0.3ml), and triphosgene (72mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 15 minutes. 4-chloro-N-methylaniline (35. mu.l) was then added and the mixture was heated under reflux for 30 minutes. Methanol was added to the reaction solution, purification was performed by HPLC using chloroform/methanol, the solvent was distilled off, and the obtained crystals were washed with ether to obtain 83mg of the title compound with a yield of 69%.
1H-NMR(DMSO-d6，400MHz)：3.36(s，3H)，4.06(s，3H)，4.07(s，3H)，6.89(s，1H)，7.17(dd，J＝2.7Hz，9.0Hz，1H)，7.23(d，J＝2.7Hz，1H)，7.33-7.35(m，3H)，7.48-7.50(m，3H)，8.41(d，J＝9.0Hz，1H)，8.61(s，1H)
Mass Spectrometry (ESI-MS, m/z): 499 (M)++1)
Example 116: n' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] phenyl } -N, N-diethylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (2ml) and triethylamine (0.5ml), and triphosgene (48mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Then, diethylamine (0.5ml) was added thereto, and the mixture was stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound 37mg in 93% yield.
1H-NMR(CDCl3，400MHz)：δ1.30(t，J＝7.1Hz，6H)，3.44(q，J＝7.1Hz，4H)，4.12(s，3H)，4.20(s，3H)，7.16(dd，J＝2.7Hz，9.0Hz，1H)，7.27(s，1H)，7.31(d，J＝2.7Hz，1H)，7.59(s，1H)，8.15(s，1H)，8.48(d，J＝9.0Hz，1H)，8.81(s，1H)
Mass Spectrometry (ESI-MS, m/z): 431 (M)++1)
Example 117: n- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] Phenyl } -N' -methylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (2ml) and triethylamine (0.5ml), and triphosgene (48mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Subsequently, the mixture was cooled to-78 ℃ and methylamine hydrochloride (130mg) was added thereto, and the mixture was directly warmed and stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound 41mg in 70% yield.
1H-NMR(DMSO-d6，400MHz)：δ2.68(d，J＝4.4Hz，3H)，3.97(s，3H)，3.99(s，3H)，6.86-6.88(m，1H)，7.21(dd，J＝2.7Hz，9.0Hz，1H)，7.37(s，1H)，7.43(d，J＝2.7Hz，1H)，7.53(s，1H)，8.07(s，1H)，8.17(d，J＝9.0Hz，1H)，8.54(s，1H)
Mass Spectrometry (ESI-MS, m/z): 389 (M)++1)
Example 118: n' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) Oxy ] phenyl } -N, N-dimethylurea
2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] aniline (50mg) was dissolved in chloroform (2ml) and triethylamine (0.5ml), and triphosgene (48mg) dissolved in chloroform was added thereto, followed by stirring at room temperature for 30 minutes. Then, the mixture was cooled to-78 ℃ and dimethylamine hydrochloride (250mg) was added thereto, and the mixture was warmed up and stirred at room temperature for 1 night. Methanol was added to the reaction mixture, and the mixture was purified by HPLC using chloroform/methanol to give the title compound (33mg) in 53% yield.
1H-NMR(CDCl3，400MHz)：δ3.11(s，6H)，4.12(s，3H)，4.20(s，3H)，7.05(s，1H)，7.17(dd，J＝2.4Hz，9.3Hz，1H)，7.31(d，J＝2.4Hz，1H)，7.59(s，1H)，8.15(s，1H)，8.46(d，J＝9.3Hz，1H)，8.82(s，1H)
Mass Spectrometry (ESI-MS, m/z): 403 (M)++1)
Example 119: n- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (75mg), potassium carbonate (51mg), and 1, 3-dibromopropane (76. mu.l) were dissolved in N, N-dimethylformamide (4ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 74mg of N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, the yield being 78%. The obtained intermediate (74mg), potassium carbonate (51mg) and morpholine (130. mu.l) were dissolved in N, N-dimethylformamide (4ml), and the mixture was stirred at room temperature for 1 night. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound 49mg in a yield of 63%.
1H-NMR(CDCl3，400MHz)：δ0.89(t，J＝7.44Hz，3H)，1.41-1.50(m，2H)，1.97(t，J＝6.83Hz，1H)，2.33-2.49(m，4H)，3.04-3.09(m，2H)，3.32-3.38(m，4H)，3.52-3.68(m，3H)，4.03(s，3H)，4.23-4.29(m，1H)，4.32(t，J＝5.89Hz，1H)，6.98(t，J＝5.49Hz，1H)，7.21(dd，J＝2.68，9.03Hz，1H)，7.36(s，1H)，7.46(d，J＝2.68Hz，1H)，7.53(d，J＝7.81Hz，1H)，8.03(s，1H)，8.18(d，J＝9.27Hz，1H)，8.54(d，J＝4.39Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 529 (M)+)
Example 120: n- (2-chloro-4- { [ 6-methoxy-7- (2-morpholinoethoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (72mg), potassium carbonate (30mg), and 1, 2-dibromoethane (62. mu.l) were dissolved in N, N-dimethylformamide (4ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 40mg of N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, yield 45%. The obtained intermediate (45mg), potassium carbonate (30mg) and morpholine (80. mu.l) were dissolved in N, N-dimethylformamide (2ml), and stirred at room temperature for 1 night. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound 42mg in a yield of 56%.
1H-NMR(CDCl3，400MHz)：δ0.89(t，J＝7.32Hz，3H)，1.43-1.49(m，2H)，2.32-2.38(m，2H)，2.66(bs，1H)，2.79(t，J＝5.86Hz，1H)，3.04-3.09(m，2H)，3.29-3.36(m，4H)，3.53(m，1H)，3.57-3.59(m，2H)，3.96(s，3H)，4.31(t，J＝5.85Hz，1H)，6.98(m，1H)，7.21-7.23(m，1H)，7.41(s，1H)，7.46-7.47(m，1H)，7.55(d，J＝12.69Hz，1H)，8.03(s，1H)，8.19(d，J＝9.27Hz，1H)，8.55(d，J＝5.37Hz，1H)，
Mass Spectrometry (ESI-MS, m/z): 517 (M)++1)
Example 121: n- (2-chloro-4- { [ 7- (3-hydroxypropoxy) -6-methoxy -4-quinazolinyl ] oxy } phenyl) -N' -propylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (55mg), potassium carbonate (20mg), and 3-bromo-1-propanol (62. mu.l) were dissolved in N, N-dimethylformamide (4ml), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound (25 mg) in a yield of 40%.
1H-NMR(CDCl3，400MHz)：δ0.91(t，J＝7.44Hz，3H)，1.24(bs，1H)，1.43-1.52(m，2H)，1.97(t，J＝6.22Hz，2H)，3.06～3.11(m，2H)，3.56-3.71(m，2H)，3.97(s，3H)，4.27(m，2H)，6.99(t，J＝5.62Hz，1H)，7.23(dd，J＝2.68，9.03Hz，1H)，7.38(d，J＝9.03Hz，1H)，7.47(d，J＝2.68Hz，1H)，7.54(s，1H)，8.05(s，1H)，8.20(d，J＝9.03Hz，1H)，8.55(s，1H)
Mass Spectrometry (ESI-MS, m/z): 461 (M)++1)
Example 122: n- (2-chloro-4- { [ 7- (2-hydroxyethoxy) -6-methoxy -4-quinazolinyl ] oxy } phenyl) -N' -propylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (50mg), potassium carbonate (30mg), 2-bromoethanol (44. mu.l) were dissolved in N, N-dimethylformamide (4ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound 12mg in 22% yield.
1H-NMR(CDCl3，400MHz)：δ0.91(t，J＝7.44Hz，3H)，1.42-1.49(m，2H)，3.06-3.11(m，2H)，3.80-3.83(m，2H)，3.98(s，3H)，4.22(t，J＝4.64Hz，2H)，4.98(t，J＝5.37Hz，1H)，6.99(t，J＝5.37Hz，1H)，7.33(dd，J＝2.69Hz，9.03Hz，1H)，7.39(s，1H)，7.48(d，J＝2.68Hz，1H)，7.55(s，1H)，8.05(s，1H)，8.19(d，J＝9.27Hz，1H)，8.55(s，1H)
Mass Spectrometry (ESI-MS, m/z): 447 (M)++1)
Example 123: n- (2-chloro-4- { [ 6-methoxy-7- (4-pyridylmethoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (80mg), potassium carbonate (138mg) and 4-chloromethylpyridine hydrochloride (41mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 3 hours, water was added to the reaction mixture, extraction was performed with chloroform-propanol (3/1), the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by HPLC to give the title compound 65mg in 66% yield.
1H-NMR(CDCl3，400MHz)：δ0.96(t，J＝7.6Hz，3H)，1.53-1.64(m，2H)，3.25(dd，J＝7.3Hz，12.9Hz，2H)，4.07(s，3H)，5.32(s，2H)，6.66(s，1H)，7.14(dd，J＝2.7Hz，9.0Hz，1H)，7.27(s，1H)，7.29(d，J＝2.7Hz，1H)，7.41(d，J＝5.9Hz，2H)，7.54(s，1H)，8.24(d，J＝9.0Hz，1H)，8.59(s，1H)，8.63(d，J＝6.1Hz，2H)
Mass spectrometry (ESI-MS, m/z); 494 (M)++1)
Example 124: n- [ 2-chloro-4- ({ 6-methoxy-7- [ (5-morpholinopentyl) Oxy ] -4-quinazolinyl } oxy) phenyl ] -N' -propylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (70mg), potassium carbonate (30mg), and pentylidene dibromo (80. mu.l) were dissolved in N, N-dimethylformamide (5ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give 43mg of N- [ 4- ({7- (5-bromopentyl) oxy } -6-methoxy-4-quinazolinyl) oxy ] -2-chlorophenyl ] -N' -propylurea in a yield of 46%. The obtained intermediate (43mg), potassium carbonate (30mg) and morpholine (70. mu.l) were dissolved in N, N-dimethylformamide (4ml), and the mixture was stirred at room temperature for 1 night. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound (30mg) in a yield of 68%.
1H-NMR(CDCl3，400MHz)：δ1.71(t，J＝7.32Hz，3H)，2.28(t，J＝7.20Hz，2H)，2.63(m，2H)，3.08-3.14(m，5H)，3.29～3.30(m，5H)，3.47(bs，1H)，3.73(m，1H)，3.86-3.90(m，2H)，4.36(t，J＝4.65Hz，3H)，4.46(t，J＝4.76Hz，1H)，4.77(s，1H)，4.99(t，J＝6.34Hz，2H)，7.80(m，1H)，8.02(dd，J＝2.68Hz，9.27Hz，1H)，8.18(s，1H)，8.27(d，J＝2.68Hz，1H)，8.34(s，1H)，8.85(s，1H)，9.00(d，J＝9.03Hz，1H)，9.35(s，1H)
Mass Spectrometry (ESI-MS, m/z): 559 (M)++1)
Example 125: n- { 2-chloro-4- [ (6-methoxy-7- { [ 5- (1H-1, 2, 3-triazol-1-yl) pentyl ] oxy } -4-quinazolinyl) oxy ] phenyl } -N' -propyl Urea
Triazole (0.41ml), 1-bromo-5-chloropentane (1.0ml), tetrabutylammonium iodide (10mg) and 3M aqueous sodium hydroxide solution (1ml) were dissolved in acetone (10ml), and stirred at 50 ℃ for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography using chloroform to give an intermediate (390 mg).
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea 80mg), potassium carbonate (138mg) and the above intermediate (52mg) were dissolved in N, N-dimethylformamide (1ml), and stirred at 120 ℃ for 5 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC to give the title compound 41mg in 38% yield.
1H-NMR(CDCl3，400MHz)：δ0.96(t，J＝7.6Hz，3H)，1.50-1.65(m，4H)，1.90-2.08(m，4H)，3.24(dd，J＝7.1Hz，12.9Hz，2H)，4.01(s，3H)，4.17(t，J＝6.6Hz，2H)，4.44(t，J＝7.3Hz，2H)，4.88-4.94(m，1H，6.32(s，1H)，7.14(dd，J＝2.7Hz，9.0Hz，1H)，7.25(s，1H)，7.29(d，J＝2.7Hz，1H)，7.48(s，1H)，7.55(s，1H)，7.70(s，1H)，8.23(d，J＝9.0Hz，1H)，8.58(s，1H)
Mass Spectrometry (ESI-MS, m/z): 540 (M)++1)
Example 126: n' - (2-chloro-4- { [ 6-methoxy-7- (4-pyridylmethoxy) 4-quinazolinyl-oxy } phenyl) -N, N-diethylurea
The starting material (N' - { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N, N-diethylurea 83mg), potassium carbonate (138mg) and 4-chloromethylpyridine hydrochloride (49mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC to give the title compound 57mg in a yield of 56%.
1H-NMR(CDCl3，400MHz)：δ1.26(t，J＝7.3Hz，6H)，3.41(q，J＝7.1Hz，4H)，4.08(s，3H)，5.32(s，2H)，6.98(s，1H)，7.14(dd，J＝2.7Hz，9.0Hz，1H)，7.27(s，1H)，7.29(d，J＝2.7Hz，1H)，7.41(d，J＝5.9Hz，2H)，7.55(s，1H)，8.37(d，J＝9.0Hz，1H)，8.58(s，1H)，8.63(d，J＝5.9Hz，2H)
Mass Spectrometry (ESI-MS, m/z): 508 (M)++1)
Example 127: n- (2-chloro-4- { [ 6-methoxy-7- (4-morpholinobutoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (70mg), potassium carbonate (30mg), and pentylidene dibromo (80. mu.l) were dissolved in N, N-dimethylformamide (5ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 43mg of N- (4- { [ 7- (4-bromobutoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, the yield being 46%. The obtained intermediate (43mg), potassium carbonate (30mg) and morpholine (40. mu.l) were dissolved in N, N-dimethylformamide (4ml), and the mixture was stirred at room temperature for 1 night. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound 23mg in a yield of 53%.
1H-NMR(CDCl3，400MHz)：δ0.99(t，J＝7.32Hz，3H)，1.56-1.62(m，13H)，2.00-2.08(m.2H)，3.26-3.28(m，2H)，4.04(s，3H)，4.24(m，2H)，4.72-4.77(m，1H)，6.65(s，1H)，6.99(s，1H)，7.19-7.26(m，1H)，7.30(s，1H)，7.32-7.34(m，1H)，7.51(s，1H)，8.25(d，J＝9.03Hz，1H)，8.61(s，1H)
Mass Spectrometry (ESI-MS, m/z): 545 (M)++1)
Example 128: n- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (4-methyl)Ribospide Azinyl) ethoxy-4-quinazolinyl } oxy) phenyl-N' -propylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (60mg), potassium carbonate (30mg), and 1, 2-dibromoethane (70. mu.l) were dissolved in N, N-dimethylformamide (4ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 46mg of N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, yield 62%. The obtained intermediate (46mg), potassium carbonate (20mg), and N-methylpiperazine (50 μ l) were dissolved in N, N-dimethylformamide (3ml), and the mixture was stirred at room temperature for 1 night. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound (24 mg) in a yield of 50%.
1H-NMR(CDCl3，400MHz)：δ0.99(t，J＝7.32Hz，3H)，1.61-1.64(m，2H)，2.75(m，2H)，3.00-3.16(m，4H)，3.25-3.16(m，4H)，3.25-3.29(m，2H)，4.02(s，3H)，4.27-4. 35(m，2H)，4.78-4.83(m，2H)，5.33(s，3H)，6.69(s，1H)，7.17(dd，J＝2.68Hz，9.03Hz，1H)，7.31(s，1H)，7.49(s，1H)，8.26(d，J＝9.27Hz，1H)，8.59(s，1H)
Mass Spectrometry (ESI-MS, m/z): 530 (M)++1)
Example 129: n- { 2-chloro-4- [ (7- {2- [ (2-hydroxyethyl) (methyl) Amino-ethoxy-6-methoxy-4-quinazolinyl) oxy-phenyl-N' -propylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (65mg), potassium carbonate (30mg), and 1, 2-dibromoethane (30. mu.l) were dissolved in N, N-dimethylformamide (4ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 36mg of N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, yield 45%. The obtained intermediate (36mg), potassium carbonate (30mg), and N-methylethanolamine (30. mu.l) were dissolved in N, N-dimethylformamide (3ml), and the mixture was stirred at room temperature for 1 night. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound 21mg in 55% yield.
1H-NMR(CDCl3，400MHz)：δ0.98(t，J＝7.32Hz，3H)，1.59(m，2H)，1.94(bs，1H)，3.23(m，2H)，4.03(s，3H)，4.07-4.15(m，4H)，4.76(m，4H)，5.35(s，3H)，7.10-7.17(m，1H)，7.28(s，3H)，7.40(s，1H)，7.54(s，1H)，8.37(d，J＝9.03Hz，1H)，8.64(s，1H)
Mass Spectrometry (ESI-MS, m/z): 504 (M)++1)
Example 130: n- [ 2-chloro-4- ({ 6-methoxy-7- [ 3- (4-methylpiper) Azinyl) propoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -propylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (75mg), potassium carbonate (30mg), and 1, 3-dibromopropane (75. mu.l) were dissolved in N, N-dimethylformamide (4ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 50mg of N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, the yield being 52%. The obtained intermediate (30mg), potassium carbonate (20mg), and N-methylpiperazine (40 μ l) were dissolved in N, N-dimethylformamide (3ml), and the mixture was stirred at room temperature for 1 night. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound (20mg) in a yield of 63%.
1H-NMR(CDCl3，400MHz)：δ0.99(t，J＝7.32Hz，3H)，1.58-1.62(m，2H)，2.25-2.50(m，3H)，2.70-2.85(m，3H)，2.92-2.98(m，3H)，3.25(m，2H)，4.04(s，3H)，4.25(m，2H)，4.83(m，3H)，5.34(s，3H)，6.70(s，1H)，7.21(dd，J＝2.68，9.03Hz，1H)，7.26(s，2H)，7.31(s，1H)，7.49(s，1H)，8.18(d，J＝9.27Hz，1H)，8.59(s，1H)
Mass Spectrometry (ESI-MS, m/z): 544 (M)++1)
Example 131: n' - [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1, 2, 3-triazol-1-yl) ethoxy ] -4-quinazolinyl } oxy) phenyl ] -N, N-diethyl Radical urea
The starting material (N' - { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N, N-diethylurea, 83mg), potassium carbonate (138mg), 2- (1H-1, 2, 3-triazol-1-yl) ethyl 4-methyl-1-benzenesulfonate (59mg) was dissolved in N, N-dimethylformamide (1ml), and stirred at 80 ℃ for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to obtain an intermediate. To a solution of the intermediate and triethylamine (0.027ml) in chloroform (1ml) was added triphosgene (90mg) at 0 ℃ and stirred for 30 minutes. After the reaction mixture was cooled to 0 ℃, diethylamine (0.044ml) was added dropwise and warmed to room temperature over 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC to obtain the title compound 30mg in a yield of 29%.
1H-NMR(CDCl3，400MHz)：δ1.26(t，J＝7.1Hz，6H)，3.41(q，J＝7.1Hz，4H)，4.03(s，3H)，4.53(t，J＝4.9Hz，2H)，4.94(t，J＝5.1Hz，2H)，6.98(s，1H)，7.13(dd，J＝2.7Hz，9.0Hz，1H)，7.26(s，1H)，7.73(s，1H)，7.94(s，1H)，8.38(d，J＝9.0Hz，1H)，8.60(s，1H)
Example 132: 3- { [ 4- (3-chloro-4- { [ (diethylamino) carbonyl ] amino } amino Phenoxy) -6-methoxy-7-quinazolinyl ] oxy } propyl-N, N-diethylamino Formic acid esters
The starting material (N' - { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N, N-diethylurea, 83mg), potassium carbonate (138mg), 3-bromo-1-propanol (0.027ml) was dissolved in N, N-dimethylformamide (1ml), and stirred at 80 ℃ for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to obtain an intermediate. To a solution of the intermediate and triethylamine (0.027ml) in chloroform (1ml) was added triphosgene (90mg) at 0 ℃ and stirred for 30 minutes. After the reaction mixture was cooled to 0 ℃, diethylamine (0.044ml) was added dropwise and warmed to room temperature over 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC to give the title compound 19mg in a yield of 17%.
1H-NMR(CDCl3，400MHz)：δ1.04(t，J＝7.1Hz，6H)，1.22(t，J＝7.3Hz，6H)，3.09(q，J＝7.1Hz，4H)，3.36(q，J＝7.1Hz，4H)，3.75(t，J＝6.3Hz，2H)，3.97(s，3H)，4.29(t，J＝6.1Hz，2H)，6.93(s，1H)，7.10(dd，J＝2.7Hz，9.0Hz，1H)，7.24(d，J＝2.7Hz，1H)，7.27(s，1H)，7.45(s，1H)，8.33(d，J＝9.3Hz，1H)，8.55(s，1H)
Example 133:n- [ 2-chloro-4- ({ 6-methoxy-7- [ 3- (4-pyridyl) Thio) propoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -propylurea
The starting material (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, 80mg), potassium carbonate (138mg), and 4-mercaptopyridine (22mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 60mg in a yield of 72%.
1H-NMR(CDCl3，400MHz)：δ0.91(t，J＝7.6Hz，3H)，1.50-1.60(m，2H)，2.24-2.32(m，2H)，3.11-3.24(m，4H)，3.99(s，3H)，4.25(t，J＝5.9Hz，2H)，4.70-4.80(m，1H)，6.62(s，1H)，7.11(dd，J＝2.7Hz，9.0Hz，1H)，7.11-7.16(m，2H)，7.23(s，1H)，7.25(d，J＝2.7Hz，1H)，7.45(s，1H)，8.19(d，J＝9.0Hz，1H)，8.30-8.34(m，2H)，8.55(s，1H)
Mass Spectrometry (ESI-MS, m/z): 554 (M)++1)
Example 134: n- { 2-chloro-4- [ (6-methoxy-7- {3- [ (1-methyl) methyl ] amino acid sequence -1H-1, 2, 3, 4-tetrazol-5-yl) thio ] propoxy } -4-quinazolinyl) oxy ] Phenyl } -N' -propylurea
The starting material (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, 80mg), potassium carbonate (138mg), and 5-mercapto-1-tetrazole (23mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 71mg in a yield of 85%.
1H-NMR(CDCl3，400MHz)：δ0.91(t，J＝7.3Hz，3H)，1.51-1.56(m，2H)，2.39-2.48(m，2H)，3.17-3.23(m，2H)，3.56(t，J＝7.1Hz，2H)，3.86(s，3H)，3.97(s，3H)，4.27(t，J＝5.9Hz，2H)，4.75-4.82(m，1H)，6.63(s，1H)，7.10(dd，J＝2.7Hz，9.0Hz，1H)，7.24(d，J＝3.7Hz，1H)，7.44(s，1H)，8.19(d，J＝9.0Hz，1H)，8.55(s，1H)
Mass Spectrometry (ESI-MS, m/z): 559 (M)++1)
Example 135: n- (2-chloro-4- { [ 6-methoxy-7- (3-piperidinopropoxy) 4-quinazolinyl-oxy-phenyl) -N' -propylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (500mg), potassium carbonate (857mg), and 1, 3-dibromopropane (0.5ml) were dissolved in N, N-dimethylformamide (5ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 451mg of N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, yield 71%. N- (4- { [ 7- (3-Bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea (70mg), potassium carbonate (54mg), and piperidine (39. mu.l) were dissolved in N, N-dimethylformamide (2ml), and the mixture was stirred at room temperature for 1 night. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol (20/1) to give the title compound 35mg in 50% yield.
1H-NMR(CDCl3，400MHz)：δ0.98(t，J＝7.6Hz，3H)，1.46(br，2H)，1.54-1.66(m，8H)，2.15(br，2H)，2.44(br，2H)，2.55(br，2H)，3.20-3.30(m，2H)，4.04(s，3H)，4.27(t，J＝6.6Hz，2H)，4.77(t，J＝5.9Hz，1H)，6.65(s，1H)，7.17(dd，J＝2.7Hz，9.0Hz，1H)，7.32(d，J＝2.7Hz，1H)，7.33(s，1H)，7.49(s，1H)，8.24(d，J＝9.0Hz，1H)，8.61(s，1H)
Example 136: n- [ 2-chloro-4- ({ 7-methoxy-6- [ 2- (4-methylpiper) Azinyl) ethoxy-4-quinazolinyl } oxy) phenyl-N' -propylurea
N- { 2-chloro-4- [ (6-hydroxy-7-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (500mg), potassium carbonate (857mg), and 1, 3-dibromopropane (0.5ml) were dissolved in N, N-dimethylformamide (5ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 451mg of N- (4- { [ 6- (2-bromoethoxy) -7-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, yield 71%. N- (4- { [ 6- (2-Bromoethoxy) -7-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea (50mg), potassium carbonate (40mg), and N-methylpiperazine (50. mu.l) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound (20mg) in a yield of 44%.
1H-NMR(CDCl3，400MHz)：δ0.98(t，J＝7.3Hz，3H)，1.56-1.65(m，2H)，1.77(br，4H)，2.31(s，3H)，2.53(br，2H)，2.71(br，2H)，2.97(t，J＝6.1Hz，3H)，3.24-3.29(m，2H)，4.04(s，3H)，4.32(t，J＝6.1Hz，2H)，4.83(br，1H)，6.69(s，1H)，7.16(dd，J＝2.7Hz，9.0Hz，1H)，7.30(s，1H)，7.31(s，1H)，7.55(s，1H)，8.25(d，J＝9.0Hz，1H)，8.62(s，1H)
Mass Spectrometry (ESI-MS, m/z): 529 (M)++1)
Example 137: n- [ 2-chloro-4- ({ 7-methoxy-6- [ 3- (4-methylpiper) Azinyl) propoxy ] -4-quinazolinyl } oxy) phenyl ] -N' -propylurea
N- { 2-chloro-4- [ (6-hydroxy-7-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea (500mg), potassium carbonate (857mg), and 1, 3-dibromopropane (0.5ml) were dissolved in N, N-dimethylformamide (5ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 451mg of N- (4- { [ 6- (3-bromopropoxy) -7-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, yield 71%. N- (4- { [ 6- (3-Bromopropoxy) -7-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea (50mg), potassium carbonate (40mg), and N-methylpiperazine (50. mu.l) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound (20mg) in a yield of 44%.
1H-NMR(CDCl3，400MHz)：δ0.98(t，J＝7.6Hz，3H)，1.58-1.64(m，2H)，1.71(br，4H)，2.31(s，3H)，2.53(br，2H)，2.71(br，2H)，2.11-2.17(m，2H)，2.30(s，3H)，2.59-2.62(m，2H)，3.24-3.29(m，2H)，4.0(s，3H)，4.26(t，J＝6.6Hz，2H)，4.80(br，1H)，6.67(s，1H)，7.17(dd，J＝2.7Hz，9.0Hz，1H)，7.31(s，1H)，7.31(s，1H)，7.52(s，1H)，8.25(d，J＝9.0Hz，1H)，8.61(s，1H)
Mass Spectrometry (ESI-MS, m/z): 543 (M)++1)
Example 138: n- (2-chloro-4- { [ 7-methoxy-6- (2-pyridylmethoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea
The starting material (N- { 2-chloro-4- [ (6-hydroxy-7-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea, 80mg), potassium carbonate (138mg) and 2- (chloromethyl) pyridine hydrochloride (41mg) were dissolved in N, N-dimethylformamide (1ml), and stirred at 120 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with ethyl acetate to give the title compound 54mg in 55% yield.
1H-NMR(CDCl3，400MHz)：δ0.91(t，J＝7.6Hz，3H)，1.51-1.58(m，2H)，3.17-3.22(m，2H)，4.02(s，3H)，4.69(br，1H)，5.36(s，2H)，6.57(s，1H)，7.08(dd，J＝2.7Hz，9.0Hz，1H)，7.21-7.29(m，2H)，7.53-7.55(m，2H)，7.66-7.71(m，1H)，8.15(d，J＝9.0Hz，1H)，8.55-8.57(m，2H)
Mass Spectrometry (ESI-MS, m/z): 494 (M)++1)
Example 139: n- (2-chloro-4- { [ 7-methoxy-6- (3-morpholinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea
The starting material (N- (4- { [ 6- (3-propoxy) -7-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, 54mg), potassium carbonate (138mg), and morpholine (0.017ml) were dissolved in N, N-dimethylformamide (1ml), and stirred at 120 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with ethyl acetate to give the title compound 42mg in a yield of 77%.
1H-NMR(CDCl3，400MHz)：δ0.91(t，J＝7.6Hz，3H)，1.47-1.59(m，4H)，1.88-2.00(m，2H)，2.35-2.48(m，4H)，3.20(dd，J＝7.3Hz，12.9Hz，2H).3.62-3.74(m，4H)，3.97(s，3H)，4.15(t，J＝6.3Hz，2H)，4.74-4.80(m、1H)，6.63(s，1H)，7.09(dd，J＝2.7Hz，9.0Hz，1H)，7.24(d，J＝2.7Hz，1H)，7.42(s，1H)，8.18(d，J＝9.0Hz，1H)，8.54(s，1H)
Mass Spectrometry (ESI-MS, m/z): 530 (M)++1)
Example 140: n- { 2-chloro-4- [ (6- {3- (2-hydroxyethyl) (methyl) amino phenyl-N' -propylurea (7-methoxy-4-quinazolinyl) oxy) propyloxy
The starting material (N- (4- { [ 6- (3-bromopropoxy) -7-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea, 51mg), potassium carbonate (68mg), 2- (methylamino) ethanol (15 mg) was dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 25mg in a yield of 48%.
1H-NMR(CDCl3，400MHz)：δ0.95(t，J＝7.6Hz，3H)，1.53-1.62(m，2H)，2.08-2.15(m，2H)，2.30(s，3H)，2.58(t，J＝5.4Hz，2H)，2.68(t，J＝7.1Hz，2H)，3.21-3.26(m，2H)，3.60(t，J＝5.4Hz，2H)，4.02(s，3H)，4.23(t，J＝6.3Hz，2H)，5.06(t，J＝5.6Hz，1Hz)，6.79(s，1H)，7.13(dd，J＝2.7Hz，9.0Hz，1H)，7.27-7.28(m，2H)，7.48(s，1H)，8.21(d，J＝9.0Hz，1H)，8.58(s，1H)
Example 141: n- (2-chloro-4- { [ 6-methoxy-7- (2-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea, 80mg), potassium carbonate (138mg) and 2-chloromethylpyridine hydrochloride (41mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC to give the title compound 81mg in 82% yield.
1H-NMR(CDCl3，400MHz)：δ0.97(t，J＝7.6Hz，3H)，1.54-1.65(m，2H)，3.25(dd，J＝7.1Hz，12.9Hz，2H)，4.05(s，3H)，4.75-4.82(m，1H)，5.42(s、2H)，6.46(d，J＝5.4Hz，1H)，6.67(s，1H)，7.08(dd，J＝2.9Hz，9.0Hz，1H)，7.19(d，J＝2.7Hz，1H)，7.44(s，1H)，7.53(s，1H)，7.56(d，J＝7.8Hz，1H)，7.69(dt，J＝2.0Hz，7.8Hz，1H)，8.25(d，J＝9.0Hz，1H)，8.46(d，J＝5.1Hz，1H)，8.61(d，J＝4.6Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 493 (M)++1)
Example 142: n- (2-chloro-4- { [ 6-methoxy-7- (3-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea, 80mg), potassium carbonate (138mg) and 3-chloromethylpyridine hydrochloride (41mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC to give the title compound 70mg in a yield of 71%.
1H-NMR(CDCl3，400MHz)：δ0.97(t，J＝7.3Hz，3H)，1.54-1.65(m，2H)，3.25(dd，J＝7.3Hz，12.9Hz，2H)，4.02(s，3H)，4.82-4.90(m，1H)，5.30(s，2H)， 6.47(d，J＝5.4Hz，1H)，6.72(s，1H)，7.09(dd，J＝2.7Hz，9.0Hz，1H)，7.19(d，J＝2.7Hz，1H)，7.32(dd，J＝4.9Hz，7.8Hz，1H)7.47(s，1H)，7.52(s，1H)，7.84(d，J＝7.8Hz，1H)，8.26(d，J＝9.3Hz，1H)，8.47(d，J＝5.4Hz，1H)，8.58(d，J＝3.2Hz，1H)，8.75(s，1H)
Mass Spectrometry (ESI-MS, m/z): 493 (M)++1)
Example 143: n- (2-chloro-4- { [ 6-methoxy-7- (4-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea, 80mg), potassium carbonate (138mg) and 4-chloromethylpyridine hydrochloride (41mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC to give the title compound 71mg in a yield of 71%.
1H-NMR(CDCl3，400MHz)：δ0.97(t，J＝7.6Hz，3H)，1.54-1.65(m，2H)，3.25(dd，J＝7.1Hz，12.9Hz，2H)，4.05(s，3H)，4.86-4.92(m，1H)，5.32(s，2H)，6.48(d，J＝4.7Hz，1H)，6.73(s，1H)，7.08(dd，J＝2.7Hz，9.0Hz，1H)，7.19(d，J＝2.9Hz，1H)，7.38(s，1H)，7.41(d，J＝6.1Hz，2H)，7.54(s，1H)，8.26(d，J＝9.0Hz，1H)，8.46(d，J＝5.4Hz，1H)，8.61(d，J＝6.1Hz，2H)
Mass Spectrometry (ESI-MS, m/z): 493 (M)++1)
Example 144: n- (2-chloro-4- { [ 6-methoxy-7- (2-morpholinoethoxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea, 100mg), potassium carbonate (172mg) and 1, 2-dibromoethane (0.086ml) were dissolved in N, N-dimethylformamide (1ml) and stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give an intermediate (N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' -propylurea). The intermediate, potassium carbonate (138mg) and morpholine (0.17ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 2 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound 70mg in 54% yield.
1H-NMR(CDCl3，400MHz)：δ0.91(t，J＝7.6Hz，3H)，1.50-1.59(m，2H)，2.57(t，J＝4.6Hz，4H)，2.88(t，J＝5.9Hz，2H)，3.18-3.23(m，2H)，3.68(t，J＝4.6Hz，4H)，3.94(s，3H)，4.26(t，J＝5.9Hz，2H)，4.98(t，J＝5.3Hz，2H)，6.4 1(d，J＝5.3Hz，1H)，6.74(br，1H)，7.03(dd，J＝2.7Hz，9.0Hz，1H)，7.14(d，J＝2.7Hz，1H)，7.34(s，1H)，7.43(s，1H)，8.42(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 515 (M)++1)
Example 145: n- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1, 2, 3-triazol-1-yl) ethoxy ] -4-quinolinyl } oxy) phenyl ] -N' -propylurea
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea, 80mg), potassium carbonate (138mg), 2- (1H-1, 2, 3-triazol-1-yl) ethyl 4-methyl-1-benzenesulfonate (59mg) was dissolved in N, N-dimethylformamide (1ml), and stirred at 120 ℃ for 5 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform-methanol to give the title compound 92mg in a yield of 92%.
1H-NMR(CDCl3，400MHz)：δ0.97(t，J＝7.6Hz，3H)，1.57-1.63(m，2H)，3.23-3.28(m，2H)，4.01(s，3H)，4.52(t，J＝5.1Hz，2H)，4.81(br，1H)，4.93(t，J＝5.1Hz，2H)，6.47(d，J＝5.4Hz，1H)，6.69(s，1H)，7.08(dd，J＝2.7Hz，9.0Hz，1H)，7.18(d，J＝2.7Hz，1H)，7.37(s，1H)，7.51(s，1H)，7.72(d，J＝1.0Hz，1H)，7.97(d，J＝1.0Hz，1H)，8.26(d，J＝9.0Hz，1H)，8.48(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 497 (M)++1)
Example 146: n- [ 2-chloro-4- ({7- [ 2- (1H-1-imidazolyl) ethoxy ] ethoxy Yl ] -6-methoxy-4-quinolyl } oxy) phenyl ] -N' -propylurea
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea, 80mg), potassium carbonate (138mg) and 2- (1H-1-imidazolyl) ethyl 4-methyl-1-benzenesulfonate (59mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 120 ℃ for 5 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform-methanol to give the title compound 81mg in 82% yield.
1H-NMR(CDCl3，400MHz)：δ0.96(t，J＝7.6Hz，3H)，1.50-1.65(m，2H)，1.90-2.08(m，2H)，3.24(dd，J＝7.1Hz，12.9Hz，2H)，4.01(s，3H)，4.17(t，J＝6.6Hz，2H)，4.44(t，J＝7.3Hz，2H)，4.88-4.94(m，1H)，6.32(s，1H)，7.14(dd，J＝2.7Hz，9.0Hz，1H)，7.25(s，1H)，7.29(d，J＝2.7Hz，1H)，7.48(s，1H)，7.55(s，1H)，7.70(s，1H)，8.23(d，J＝9.0Hz，1H)，8.58(s，1H)
Mass Spectrometry (ESI-MS, m/z): 496 (M)++1)
Example 147: n- (2-chloro-4- { [ 7- (3-hydroxypropoxy) -6-methoxy -4-quinolyl ] oxy } phenyl) -N' -propylurea
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea, 80mg), potassium carbonate (138mg) and 3-bromo-1-propanol (0.027ml) were dissolved in N, N-dimethylformamide (1ml), and stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 94mg in 100% yield.
1H-NMR(CDCl3，400MHz)：δ0.92(t，J＝7.6Hz，3H)，1.45-1.62(m，2H)，2.09-2.18(m，2H)，3.21(dd，J＝7.1Hz，12.9Hz，2H)，3.87(t，J＝5.6Hz，2H)，3.94(s，3H)，4.31(t，J＝6.1Hz，2H)，4.81-4.87(m，1H)，6.42(d，J＝5.1Hz，1H)，6.69(s，1H)，7.03(dd，J＝2.7Hz，9.0Hz，1H)，7.14(d，J＝2.7Hz，1H)，7.36(s，1H)，7.43(s，1H)，8.20(d，J＝9.0Hz，1H)，8.42(d，J＝5.4Hz，1H)
Example 148: n- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (4-methylpiper) Azinyl) ethoxy-4-quinolinyl } oxy) phenyl ] -N' -propylurea
The starting material (N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' -propylurea, 50mg), potassium carbonate (138mg) and 1-methylpiperazine (0.055ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 54mg in 100% yield.
1H-NMR(CDCl3，400MHz)：δ0.92(t，J＝7.3Hz，3H)，1.49-1.62(m，2H)，2.24(s，3H)，2.35-2.70(m，2H)，2.90(t，J＝4.6Hz，2H)，3.21(dd，J＝7.3Hz，12.9Hz，2H)，3.94(s，3H)，4.26(t，J＝6.1Hz，2H)，4.75-4.85(m，1H)，6.41(d，J＝5.1Hz，1H)，6.67(s，1H)，7.04(dd，J＝2.7Hz，9.0Hz，1H)，7.14(d，J＝2.7Hz，1H)，7.34(s，1H)，7.42(s，1H)，8.19(d，J＝9.0Hz，1H)，8.42(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 528 (M)++1)
Example 149: n- (2-chloro-4- { [ 7- (2-hydroxyethoxy) -6-methoxy -4-quinolyl ] oxy } phenyl) -N' -propylurea
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea, 80mg), potassium carbonate (138mg) and 2-bromoethanol (0.021ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 80mg in a yield of 90%.
1H-NMR(CDCl3，400MHz)：δ0.96(t，J＝7.6Hz，3H)，1.54-1.65(m，2H)，3.25(dd，J＝7.1Hz，12.9Hz，2H)，3.99(s，3H)，4.07(t，J＝4.4Hz，2H)，4.28(t，J＝4.6Hz，2H)，6.46(d，J＝5.4Hz，1H)，6.77(d，J＝8.3Hz，1H)，7.08(s，1H)，7.08(dd，J＝2.7Hz，9.0Hz，1H)，7.42(s，1H)，7.49(s，1H)，8.25(d，J＝9.0Hz，1H)，8.48(d，J＝2.9Hz，1H)
Example 150: n- { 2-chloro-4- [ (7- {2- [ (2-hydroxyethyl) (methyl) Amino-ethoxy-6-methoxy-4-quinolyl) oxy-phenyl-N' -propylurea
The starting material (N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' -propylurea, 50mg), potassium carbonate (138mg), and 2- (methylamino) ethanol (0.040ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 53mg in a yield of 106%.
1H-NMR(CDCl3，400MHz)：δ0.97(t，J＝7.6Hz，3H)，1.54-1.65(m，2H)，2.42(s，3H)，2.69(t，J＝5.1Hz，2H)，3.00(t，J＝5.6Hz，2H)，3.26(dd，J＝7.1Hz，12.7Hz，2H)，3.64(t，J＝5.1Hz，2H)，3.99(s，3H)，4.26(t，J＝5.6Hz，2H)，4.66-4.69(m，1H)，6.46(d，J＝5.1Hz，1H)，6.70(s，1H)，7.09(dd，J＝2.7Hz，9.0Hz，1H)，7.19(d，J＝2.7Hz，1H)，7.39(s，1H)，7.47(s，1H)，8.24(d，J＝9.0Hz，1H)，8.47(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 503 (M)++1)
Example 151: n- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea
The starting material (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' -propylurea, 52mg), potassium carbonate (138mg) and morpholine (0.044ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 23mg in 44% yield.
1H-NMR(CDCl3，400MHz)：δ0.92(t，J＝7.6Hz，3H)，1.49-1.60(m，2H)，2.02-2.11(m，2H)，2.40-2.47(m，4H)，2.52(t，J＝7.1Hz，2H)，3.21(dd，J＝7.1Hz，12.9Hz，2H)，3.62-3.69(m，4H)，3.95(s，3H)，4.20(t，J＝6.6Hz，2H)，4.70-4.78(m，1H)，6.41(d，J＝5.1Hz，1H)，6.64(s，1H)，7.04(dd，J＝2.7Hz，9.0Hz，1H)，7.15(d，J＝2.7Hz，1H)，7.37(s，1H)，7.43(s，1H)，8.20(d，J＝9.0Hz，1H)，8.42(d，J＝5.4Hz，1H)
Example 152: n- [ 2-chloro-4- (6-methoxy-7- { [ 3- (4-methylpiper) Azinyl) propoxy ] -4-quinolyl } oxy) phenyl ] -N' -propylurea
The starting material (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' -propylurea, 52mg), potassium carbonate (138mg) and 1-methylpiperazine (0.055ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 41mg in a yield of 76%.
1H-NMR(CDCl3，400MHz)：δ0.92(t，J＝7.6Hz，3H)，1.49-1.64(m，2H)，2.02-2.10(m，2H)，2.23(s，3H)，2.30-2.56(m，8H)，2.52(t，J＝7.3Hz，2H)，3.20(dd，J＝7.1Hz，12.9Hz，2H)，3.94(s，3H)，4.19(t，J＝6.8Hz，2H)，4.83-4.92(m，1H)，6.40(d，J＝5.1Hz，1H)，6.69(s，1H)，7.03(dd，J＝2.9Hz，9.3Hz，1H)，7.14(d，J＝2.7Hz，1H)，7.35(s，1H)，7.42(s，1H)，8.19(d，J＝9.0Hz，1H)，8.42(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 542 (M)++1)
Example 153: n- [ 2-chloro-4- (6-methoxy-7- { [ 3- (1H-1, 2, 3-triazol-1-yl) propoxy ] -4-quinolyl } oxy) phenyl ] -N' -propylurea
Triazole (0.41ml), 1-bromo-3-chloropropane (0.79ml), tetrabutylammonium iodide (10mg) and 3M aqueous sodium hydroxide solution (1ml) were dissolved in acetone (10ml), and stirred at 50 ℃ for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography using chloroform to give an intermediate (327 mg).
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea 80mg), potassium carbonate (138mg) and the above-mentioned intermediate (43mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 54mg in 52% yield.
1H-NMR(CDCl3，400MHz)：δ0.97(t，J＝7.6Hz，3H)，1.54-1.65(m，2H)，2.49-2.58(m，2H)，3.26(dd，J＝7.1Hz，13.2Hz，2H)，4.01(s，3H)，4.15(t，J＝5.9Hz，2H)，4.69(t，J＝6.6Hz，2H)，4.90-5.00(m，1H)，6.46(d，J＝5.1Hz，1H)，6.77(s，1H)，7.08(dd，J＝2.7Hz，9.0Hz，1H)，7.19(d，J＝2.7Hz，1H)，7.36(s，1H)，7.51(s，1H)，7.61(s，1H)，7.67(s，1H)，8.26(d，J＝9.0Hz，1H)，8.47(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 511 (M)++1)
Example 154: n- [ 2-chloro-4- ({7- [ 3- (1H-1-imidazolyl) propoxy ] propan-1 Yl ] -6-methoxy-4-quinolyl } oxy) phenyl ] -N' -propylurea
Imidazole (680mg), 1-bromo-3-chloropropane (0.79ml), tetrabutylammonium iodide (10mg) and 3M aqueous sodium hydroxide solution (1ml) were dissolved in acetone (10ml), and stirred at 50 ℃ for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography using chloroform to give intermediate (1- (3-chloropropyl) -1H-imidazole, 525 mg).
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea 80mg), potassium carbonate (138mg) and the above-mentioned intermediate (42mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 23mg in 23% yield.
1H-NMR(CDCl3，400MHz)：δ0.91(t，J＝7.3Hz，3H)，1.48-1.60(m，2H)，2.27-2.36(m，2H)，3.20(dd，J＝6.8Hz，12.9Hz，2H)，3.97(s，3H)，4.06(t，J＝5.9Hz，2H)，4.21(t，J＝6.8Hz，2H)，6.39(d，J＝5.4Hz，1H)，6.90(s，1H)，6.98-7.04(m，2H)，7.12(d，J＝2.7Hz，1H)，7.30(s，1H)，7.44-7.48(m，2H)，8.22(d，J＝9.0Hz，1H)，8.41(d，J＝5.4Hz，1H)
Example 155: n- { 2-chloro-4- [ (7- {2- [ bis (2-hydroxyethyl) amino ] Ethoxy } -6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea
The starting material (N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' -propylurea, 50mg), potassium carbonate (138mg) and 1-methylpiperazine (0.055ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 46mg in a yield of 92%.
1H-NMR(CDCl3，400MHz)：δ0.92(t，J＝7.3Hz，3H)，1.50-1.60(m，2H)，2.74(t，J＝4.9Hz，4H)，3.04(t，J＝4.9Hz，2H)，3.15-3.24(m，2H)，3.60(t，J＝5.1Hz，4H)，3.94(s，3H)，4.17(t，J＝5.0Hz，2H)，6.41(d，J＝5.4Hz，1H)，6.75(s，1H)，7.04(dd，J＝2.4Hz，8.8Hz，1H)，7.14(d，J＝2.7Hz，1H)，7.38(s，1H)，7.43(s，1H)，8.19(d，J＝9.0Hz，1H)，8.42(d，J＝5.4Hz，1H)
Example 156: n- { 2-chloro-4- [ (7- {3- [ bis (2-hydroxyethyl) amino ] Propoxy } -6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylureaThe starting material (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' -propylurea, 52mg), potassium carbonate (138mg) and diethanolamine (53mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 41mg in a yield of 82%.
1H-NMR(CDCl3，400MHz)：δ0.89(t，J＝7.3Hz，3H)，1.46-1.56(m，2H)，1.97-2.05(m，2H)，2.63(t，J＝5.1Hz，4H)，2.69(t，J＝6.1Hz，2H)，3.19(dd，J＝7.1Hz，13.2Hz，2H)，3.60(t，J＝4.9Hz，4H)，3.94(s，3H)，4.32(t，J＝5.9Hz，2H)，5.27-5.35(m，1H)，6.37(d，J＝5.4Hz，1H)，6.94(s，1H)，7.01(dd，J＝2.9Hz，9.0Hz，1H)，7.10(d，J＝2.7Hz，1H)，7.42(s，1H)，7.53(s，1H)，8.19(d，J＝9.0Hz，1H)，8.35(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 547 (M)++1)
Example 157: n- { 2-chloro-4- [ (7- {3- [ (2-hydroxyethyl) (methyl) Amino-propoxy-6-methoxy-4-quinolyl) oxy-phenyl-N' -propylurea
The starting material (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' -propylurea, 52mg), potassium carbonate (138mg), and 2- (methylamino) ethanol (0.040ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 51mg in 98% yield.
1H-NMR(CDCl3，400MHz)：δ0.91(t，J＝7.6Hz，3H)，1.45-1.59(m，2H)，2.05(t，J＝6.8Hz，2H)，2.24(s，3H)，2.51(t，J＝5.1Hz，2H)，2.59(t，J＝7.1Hz，2H)，3.20(dd，J＝6.8Hz，12.9Hz，2H)，3.57(t，J＝5.4Hz，2H)，3.95(s，3H)，4.22(t，J＝6.3Hz，2H)，5.00-5.08(m，1H)，6.40(d，J＝5.1Hz，1H)，6.79(s，1H)，7.03(dd，J＝2.7Hz，9.0Hz，1H)，7.13(d，J＝2.7Hz，1H)，7.426(s，1H)，7.433(s，1H)，8.19(d，J＝9.0Hz，1H)，8.40(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 517 (M)++1)
Example 158: n- [ 2-chloro-4- ({ 6-methoxy-7- [ 4- (1H-1, 2, 3-triazol-1-yl) butoxy ] -4-quinolyl } oxy) phenyl ] -N' -propylurea
Triazole (0.41ml), 1-bromo-4-chlorobutane (0.93ml), tetrabutylammonium iodide (10mg) and a 3M aqueous solution of sodium hydroxide (1ml) were dissolved in acetone (10ml), and stirred at 50 ℃ for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography using chloroform to give intermediate (1- (4-chlorobutyl) -1H-1, 2, 3-triazole, 314 mg).
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea 80mg), potassium carbonate (138mg) and the above-mentioned intermediate (48mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 42mg in a yield of 40%.
1H-NM R(CDCl3，400MHz)：δ0.96(t，J＝7.3Hz，3H)，1.54-1.65(m，2H)，1.88-1.98(m，2H)，2.14-2.24(m，2H)，3.26(dd，J＝6.6Hz，13.2Hz，2H)，3.99(s，3H)，4.20(t，J＝5.9Hz，2H)，4.55(t，J＝7.1Hz，2H)，5.00-5.06(m，1H)，6.46(d，J＝5.4Hz，1H)，6.80(s，1H)，7.08(dd，J＝2.7Hz，9.0Hz，1H)，7.19(d，J＝2.7Hz，1H)，7.37(s，1H)，7.49(s，1H)，7.68-7.72(m，2H)，8.26(d，J＝9.0Hz，1H)，8.47(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 525 (M)++1)
Example 159: n- { 2-chloro-4- [ (6-methoxy-7- { [ 5- (1H-1, 2, 3-triazol-1-yl) pentyl ] oxy } -4-quinolyl) oxy ] phenyl } -N' -propylurea
Triazole (0.41ml), 1-bromo-5-chloropentane (1.0ml), tetrabutylammonium iodide (10mg) and 3M aqueous sodium hydroxide solution (1ml) were dissolved in acetone (10ml), and stirred at 50 ℃ for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography using chloroform to give intermediate (1- (5-chloropentyl-1H-1, 2, 3-triazole, 390 mg).
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea 80mg), potassium carbonate (138mg) and the above-mentioned intermediate (51mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 33mg in 31% yield.
1H-NMR(CDCl3，400MHz)：δ0.92(t，J＝7.6Hz，3H)，1.47-1.59(m，2H)，1.85-2.03(m，4H)，3.21(dd，J＝6.6Hz，13.2Hz，2H)，3.94(s，3H)，4.11(t，J＝6.3Hz，2H)，4.38(t，J＝7.1Hz，2H)，4.86-4.94(m，1H)，6.41(d，J＝5.4Hz，1H)，6.71(s，1H)，7.03(dd，J＝2.4Hz，9.0Hz，1H)，7.14(d，J＝2.7Hz，1H)，7.31(s，1H)，7.43(s，1H)，7.51(s，1H)，7.64(s，1H)，8.20(d，J＝9.0Hz，1H)，8.41(d，J＝5.4Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 539 (M)++1)
Example 160: n- [ 2-chloro-4- ({7- [ 4- (1H-1-imidazolyl) butoxy [ ] Yl ] -6-methoxy-4-quinolyl } oxy) phenyl ] -N' -propylurea
Imidazole (680mg), 1-bromo-4-chlorobutane (0.93ml), tetrabutylammonium iodide (10mg) and a 3M aqueous solution of sodium hydroxide (1ml) were dissolved in acetone (10ml), and stirred at 50 ℃ for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography using chloroform to give intermediate (1- (4-chlorobutyl) -1H-imidazole, 756 mg).
The starting material (N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' -propylurea 80mg), potassium carbonate (138mg) and the above-mentioned intermediate (48mg) were dissolved in N, N-dimethylformamide (1ml), and stirred at 80 ℃ for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 29mg in 28% yield.
1H-NMR(CDCl3，400MHz)：δ0.96(t，J＝7.3Hz，3H)，1.54-1.65(m，2H)，1.83-1.95(m，2H)，1.98-2.08(m，2H)，3.25(dd，J＝6.8Hz，12.7Hz，2H)，4.00(s，3H)，4.10(t，J＝7.1Hz，2H)，4.20(t，J＝6.1Hz，2H)，5.08-5.16(m，1H)，6.46(d，J＝5.1Hz，1H)，6.83(s，1H)，6.97(s，1H)，7.06(s，1H)，7.08(dd，J＝2.9Hz，9.3Hz，1H)，7.18(d，J＝2.7Hz，1H)，7.37(s，1H)，7.49(s，1H)，7.58(s，1H)，8.26(d，J＝9.0Hz，1H)，8.46(d，J＝5.4Hz，1H)
Example 161: n- (2-chloro-4- { [ 6-methoxy-7- (4-pyridylmethoxy) -4-quinazolinyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea
The starting material (N '- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' - (2, 4-difluorophenyl) urea, 80mg), potassium carbonate (138mg) and 4-chloromethylpyridine hydrochloride (41mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 50mg in 52% yield.
1H-NMR(CDCl3，400MHz)：δ4.03(s，3H)，5.46(s，2H)，7.03-7.11(m，1H)，7.28-7.38(m，1H)，7.47(s，1H)，7.50(d，J＝5.9Hz，2H)，7.56(d，J＝2.7Hz，1H)，7.61(s，1H)，7.95(s，1H)，8.09-8.18(m，1H)，8.19(d，J＝9.0Hz，1H)，8.57(s，1H)，8.63(d，J＝5.9Hz，2H)，8.81(s，1H)，9.30(s，1H)
Example 162: n- (2-chloro-4- { [ 6-methoxy-7- (2-morpholinoethoxy) -4-quinazolinyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea
The starting material (N '- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' - (2, 4-difluorophenyl) urea, 100mg), potassium carbonate (857mg), and 1, 2-dibromoethane (0.085ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give an intermediate (N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' - (2, 4-difluorophenyl) urea). The intermediate, potassium carbonate (138mg) and morpholine (0.05ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 57mg in 46% yield.
1H-NMR(CDCl3，400MHz)：δ2.54-2.63(m，4H)，2.85-2.94(m，2H)，3.66-3.73(m，4H)，3.97(s，3H)，4.25-4.32(m，2H)，6.77-6.88(m，2H)，7.09(s，1H)，7.14(dd，J＝2.7Hz，9.0Hz，1H)，7.257(s，1H)，7.264(s，1H)，7.44(s，1H)，7.90-7.99(m，1H)，8.22(d，J＝9.0Hz，1H)，8.56(s，1H)
Mass Spectrometry (ESI-MS, m/z): 586 (M)++1)
Example 163: n- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinazolinyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea
The starting material (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' - (2, 4-difluorophenyl) urea, 59mg), potassium carbonate (857mg), and morpholine (0.043ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 53mg in a yield of 89%.
1H-NMR(CDCl3，400MHz)：δ2.06-2.16(m，2H)，2.43-2.57(m，4H)，2.56(t，J＝6.8Hz，2H)，3.68-3.75(m，4H)，4.03(s，3H)，4.27(t，J＝6.6Hz，2H)，6.79-6.91(m，2H)，7.14(s，1H)，7.19(dd，J＝2.7Hz，9.0Hz，1H)，7.28(s，1H)，7.29(d，J＝9.0Hz，1H)，7.33(s，1H)，7.49(s，1H)，8.26(d，J＝9.0Hz，1H)，8.61(s，1H)
Mass Spectrometry (ESI-MS, m/z): 600 (M)++1)
Example 164: n- [ 2-chloro-4- ({ 6-methoxy-7- [ 3- (4-methylpiper) Azinyl) propoxy ] -4-quinazolinyl } oxy) phenyl ] -N' - (2, 4-difluorophenyl) Urea
The starting material (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' - (2, 4-difluorophenyl) urea, 59mg), potassium carbonate (138mg) and 1-methylpiperazine (0.055ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 58mg in a yield of 95%.
1H-NMR(CDCl3，400MHz)：δ2.01-2.12(m，2H)，2.23(s，3H)，2.23-2.80(m，8H)，2.51(t，J＝7.1Hz，2H)，3.97(s，3H)，4.20(t，J＝7.2Hz，2H)，6.73-6.87(m，2H)，7.13(dd，J＝2.7Hz，9.0Hz，1H)，7.24(d，J＝2.7Hz，1H)，7.27(s，1H)，7.30(s，1H)，7.44(s，1H)，7.91-8.00(m，2H)，8.21(d，J＝9.0Hz，1H)，8.56(s，1H)
Example 165: n- { 2-chloro-4- [ (7- {3- [ (2-hydroxyethyl) (methyl) Amino-propoxy-6-methoxy-4-quinazolinyl) oxy-phenyl-N' - (2, 4 -difluorophenyl) urea
The starting material (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' - (2, 4-difluorophenyl) urea, 59mg), potassium carbonate (138mg), and 2- (methylamino) ethanol (0.040ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 58mg in 100% yield.
1H-NMR(CDCl3，400MHz)：δ2.06-2.16(m，2H)，2.30(s，3H)，2.57(t，J＝5.1Hz，2H)，2.65(t，J＝6.8Hz，1H)，3.63(t，J＝5.4Hz，2H)，4.02(s，3H)，4.28(t，J＝6.1Hz，2H)，6.79-6.91(m，2H)，7.18(dd，J＝2.7Hz，9.0Hz，1H)，7.28(d，J＝2.7Hz，1H)，7.37(s，1H)，7.48(s，1H)，7.96-8.06(m，2H)，8.26(d，J＝9.0Hz，1H)，8.59(s，1H)
Mass Spectrometry (ESI-MS, m/z): 588 (M)++1)
Example 166: n- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (4-methylpiper) Azinyl) ethoxy-4-quinolinyl } oxy) phenyl-N' - (2, 4-difluorophenyl) Urea
The starting material (N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' - (2, 4-difluorophenyl) urea (50mg), potassium carbonate (138mg), 1-methylpiperazine (0.055ml) was dissolved in N, N-dimethylformamide (1ml), and the solution was stirred at room temperature for 18 hours, water was added to the reaction mixture, extraction was performed with chloroform-propanol (3/1), the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give the title compound 48mg, which was 93% in yield.
1H-NMR(CDCl3，400MHz)：δ2.31(s，3H)，2.40-2.75(m，8H)，2.95(t，J＝6.1Hz，2H)，3.99(s，3H)，4.31(t，J＝5.9Hz，2H)，6.48(d，J＝5.1Hz，1H)，6.85-6.96(m，3H)，7.12(dd，J＝2.7Hz，9.0Hz，1H)，7.15(s，1H)，7.22(d，J＝2.7Hz，1H)，7.40(s，1H)，7.47(s，1H)，7.94-8.03(m，1H)，8.25(d，J＝9.0Hz，1H)，8.49(d，J＝5.1Hz，1H)
Example 167: n- { 2-chloro-4- [ (7- {2- [ (2-hydroxyethyl) (methyl) Amino ] ethoxy } -6-methoxy-4-quinolyl) oxy ] phenyl } -N' - (2, 4- Difluorophenyl) urea
The starting material (N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' - (2, 4-difluorophenyl) urea, 50mg), potassium carbonate (138mg) and 2- (methylamino) ethanol (0.040ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 48mg in a yield of 97%.
1H-NMR(CDCl3，400MHz)：δ2.44(s，3H)，2.71(t，J＝4.9Hz，2H)，3.02(t，J＝5.6Hz，4H)，3.66(t，J＝5.1Hz，2H)，3.97(s，3H)，4.27(t，J＝5.6Hz，2H)，6.46(d，J＝5.4Hz，1H)，6.80-6.93(m，2H)，7.11(dd，J＝2.7Hz，9.0Hz，1H)，7.19(d，J＝2.7Hz，1H)，7.45(s，1H)，7.96-8.04(m，1H)，8.25(d，J＝9.0Hz，1H)，8.48(d，J＝5.1Hz，1H)
Example 168: n- (2-chloro-4- { [ 6-methoxy-7- (3-morpholinopropoxy) phenyl-4-quinolyl-oxy-phenyl-N' - (2, 4-difluorophenyl) urea
The starting material (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinolyl ] oxy } -2-chlorophenyl) -N' - (2, 4-difluorophenyl) urea (50mg), potassium carbonate (138mg), and morpholine (0.044ml) were dissolved in N, N-dimethylformamide (1ml), and the solution was stirred at room temperature for 18 hours, water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1), drying of the organic layer over anhydrous sodium sulfate, distillation under reduced pressure to remove the solvent, and the resulting residue was washed with diethyl ether to give the title compound (32mg) in 64% yield.
1H-NMR(CDCl3，400MHz)：δ2.06-2.16(m，2H)，2.43-2.51(m，4H)，2.56(t，J＝7.3Hz，2H)，3.68-3.74(m，4H)，4.00(s，3H)，4.25(t，J＝6.6Hz，2H)，6.47(d，J＝5.1Hz，1H)，6.84-6.93(m，2H)，7.06(s，1H)，7.12(dd，J＝2.7Hz，9.0Hz，1H)，7.22(d，J＝2.9Hz，1H)，7.42(s，1H)，7.47(s，1H)，7.95-8.04(m，1H)，8.25(d，J＝9.0Hz，1H)，8.48(d，J＝5.4Hz，1H)
Example 169: n- (2-chloro-4- { [ 6-methoxy-7- (3-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' - (2, 4-difluorophenyl) urea (55mg), potassium carbonate (31mg), and 3-methylpyridinyl chloride hydrochloride (22mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 1 hour. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 30mg in a yield of 48%.
1H-NMR(CDCl3，400MHz)：δ4.03(s，3H)，5.31(s，2H)，6.49(d，J＝5.4Hz，1H)，6.77-6.88(m，2H)，7.10-7.16(m，2H)，7.31-7.35(m，1H)，7.48(s，1H)，7.54(s，1H)，7.86(d，J＝7.8Hz，1H)，7.96(s，1H)，8.03-8.10(m，1H)，8.32(d，J＝9.0Hz，1H)，8.42(s，1H)，8.49(d，J＝5.4Hz，1H)，8.59(d，J＝3.9Hz，1H)，8.77(s，1H)
Example 170: n- [ 2-chloro-4- ({ 6-methoxy-7- [ 2- (1H-1, 2, 3-triazol-1-yl) ethoxy-4-quinolinyl } oxy) phenyl-N' - (2, 4- Difluorophenyl) urea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' - (2, 4-difluorophenyl) urea (55mg), potassium carbonate (31mg), 2- (1H-1, 2, 3-triazol-1-yl) ethyl 4-methyl-1-benzenesulfonate (36mg) was dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 1 hour. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 46mg in a yield of 72%.
1H-NMR(CDCl3，400MHz)：δ4.02(s，3H)，4.53(d，J＝4.9Hz，2H)，4.95(d，J＝5.1Hz，2H)，6.47(d，J＝5.1Hz，1H)，6.83-6.92(m，2H)，7.11(dd，J＝2.7Hz，9.0Hz，1H)，7.16(d，J＝2.7Hz，1H)，7.39(s，1H)，7.52(s，1H)，7.58(s，1H)，7.70(s，1H)，7.76(s，1H)，8.00(s，1H)，8.01-8.07(m，1H)，8.29(d，J＝9.0Hz，1H)，8.49(d，J＝5.4Hz，1H)
Example 171: n- (2-methoxy-4- { [ 6-methoxy-7- (3-morpholino) Propoxy) -4-quinazolinyl ] oxy } phenyl) -N' -propylurea
N-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] -2-methoxyphenyl } -N' -propylurea (100mg), potassium carbonate (138mg), and 1, 3-dibromopropane (56mg) were dissolved in N, N-dimethylformamide (5ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 53mg of N- (4- [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-methoxyphenyl) -N' -propylurea, which was obtained in 41% yield. N- (4- { [ 6- (3-Bromopropoxy) -7-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea (50mg), potassium carbonate (60mg), and N-methylpiperazine (100. mu.l) were dissolved in N, N-dimethylformamide (2ml), and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound 22mg in a yield of 42%.
1H-NMR(CDCl3，400MHz)：δ0.97(t，J＝7.6Hz，3H)，1.56-1.60(m，2H)，2.14(br，2H)，2.50(br，4H)，2.58(br，2H)，3.23-3.26(m，2H)，3.74(br，4H)，3.87(s，3H)，4.04(s，3H)，4.27-4.31(m，2H)，4.62-4.64(m，1H)，6.65(s，1H)，6.79-6.85(m，2H)，7.33(s，1H)，7.53(s，1H)，8.10(d，J＝8.5Hz，1H)、8.62(s，1H)
Mass Spectrometry (ESI-MS, m/z): 526 (M)++1)
Example 172: n- (2, 4-difluorophenyl) -N' - (2-methoxy-4- { [ 6) -methoxy-7- (3-morpholinopropoxy) -4-quinazolinyl ] oxy } phenyl) urea
N- (2, 4-difluorophenyl) -N' -4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] -2-methoxyphenyl urea (375mg), potassium carbonate (442mg), and 1, 3-dibromopropane (242mg) were dissolved in N, N-dimethylformamide (5ml), and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the resulting residue to conduct extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 210 mg of N- {4- [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy-2-methoxyphenyl } -N' - (2, 4-difluorophenyl) urea in a yield of 45%. N- (4- { [ 6- (3-Bromopropoxy) -7-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N' -propylurea (130mg), triethylamine (0.5ml), and morpholine (0.5ml) were dissolved in N, N-dimethylformamide (4ml), and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound 81mg in 62% yield.
1H-NMR(CDCl3，400MHz)：δ1.97-2.00(m，2H)，2.39(br，4H)，2.49-2.51(m，2H)，3.58-3.60(m，4H)，3.88(s，3H)，3.98(s，3H)，4.25(t，J＝6.3Hz，2H)，4.27-4.31(m，2H)，4.62-4.64(m，1H)，6.84(dd，J＝2.7Hz，8.8Hz，1H)，7.03-7.07(m，2H)，7.28-7.34(m，1H)，7.38(s，1H)，7.55(s，1H)，8.11-8.17(m，2H)，8.55(s，1H)，8.74(s，1H)，9.18(s，1H)
Mass Spectrometry (ESI-MS, m/z): 596 (M)++1)
Example 173: n- (2-methoxy-4- { [ 6-methoxy-7- (3-morpholino) Propoxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea
The starting material (N- {4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] -2-methoxyphenyl } -N' -propylurea, 80mg), potassium carbonate (138mg) and 1, 3-dibromopropane (0.10ml) were dissolved in N, N-dimethylformamide (1ml) and stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to obtain an intermediate. The intermediate, potassium carbonate (138mg) and morpholine (0.040ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol to give the title compound 74mg in a yield of 71%.
1H-NMR(CDCl3，400MHz)：δ0.95(t，J＝7.6Hz，3H)，1.52-1.69(m，2H)，2.06-2.15(m，2H)，2.43-2.49(m，4H)，2.55(t，J＝7.3Hz，2H)，3.23(dd，J＝6.1Hz，12.9Hz，2H)，3.67-3.72(m，4H)，3.81(s，3H)，4.00(s，3H)，4.24(t，J＝6.8Hz，2H)，6.44(d，J＝5.1Hz，1H)，6.68(d，J＝2.4Hz，1H)，6.76(dd，J＝2.4Hz，8.8Hz，1H)，7.40(s，1H)，7.53(s，1H)，8.12(d，J＝8.8Hz，1H)，8.44(d，J＝5.1Hz，1H)
Example 174: n- (2-methoxy-4- { [ 6-methoxy-7- (4-pyridylmethane) Oxy) -4-quinolyl ] oxy } phenyl) -N' -propylurea
The starting material (N- {4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] -2-methoxyphenyl } -N' -propylurea, 80mg), potassium carbonate (138mg) and 4-chloromethylpyridine hydrochloride (48mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 65mg in 67% yield.
1H-NMR(CDCl3，400MHz)：δ0.95(t，J＝7.3Hz，3H)，1.52-1.69(m，2H)，3.24(dd，J＝7.3Hz，12.9Hz，2H)，3.82(s，3H)，4.06(s，3H)，4.63-4.69(m，1H)，5.32(s，2H)，6.46(d，J＝5.4Hz，1H)，6.68(d，J＝2.7Hz，1H)，6.77(dd，J＝2.4Hz，8.5Hz，1H)，7.37(s，1H)，7.42(d，J＝6.1Hz，2H)，7.59(s，1H)，8.14(d，J＝8.5Hz，1H)，8.43(d，J＝5.4Hz，1H)，8.61(d，J＝6.1Hz，2H)
Example 175: N-ethyl-N' - (4- { [ 6-methoxy-7- (2-morpholino) Ethoxy) -4-quinolyl ] oxy } -2, 5-dimethylphenyl) urea
The starting material (N-ethyl-N' - {4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] -2, 5-dimethylphenyl } urea, 76mg), potassium carbonate (138mg), 1, 2-dibromoethane (0.085ml) was dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give an intermediate (N- (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinolyl ] oxy } -2, 5-dimethylphenyl) -N' -ethylurea). The intermediate, potassium carbonate (138mg), and morpholine (0.044ml) were dissolved in N, N-dimethylformamide (1ml), and stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 72mg in a yield of 73%.
1H-NMR(CDCl3，400MHz)：δ1.10(t，J＝7.3Hz，3H)，2.07(s，3H)，2.16(s，3H)，2.53-2.59(m，4H)，2.88(t，J＝5.9Hz，2H)，3.20-3.30(m，2H)，3.66-3.71(m，4H)，3.96(s，3H)，4.26(t，J＝5.9Hz，2H)，4.73-4.82(m，1H)，6.16(s，1H)，6.23(d，J＝5.4Hz，1H)，6.88(s，1H)，7.35(s，1H)，7.40(s，1H)，7.50(s，1H)，8.38(d，J＝5.1Hz，1H)
Example 176: n- [ 4- ({ 6-methoxy-7- [ 3- (4-methylpiperazino) propane Oxy ] -4-quinolyl } oxy) -2, 5-dimethylphenyl ] -N' -propylurea
The starting material (N- {4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] -2, 5-dimethylphenyl } -N' -propylurea, 80mg), potassium carbonate (138mg), 1, 3-dibromopropane (0.10ml) was dissolved in N, N-dimethylformamide (1ml), and stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give an intermediate (N- (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinolyl ] oxy } -2, 5-dimethylphenyl) -N' -propylurea). The intermediate, potassium carbonate (138mg), and 1-methylpiperazine (0.055ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 33mg in a yield of 31%.
1H-NMR(CDCl3，400MHz)：δ0.91(t，J＝7.6Hz，3H)，1.50-1.58(m，2H)，2.07-2.20(m，2H)，2.12(s，3H)，2.23(s，3H)，2.28(s，3H)，2.33-2.70(m，10H)，3.21(dd，J＝7.3Hz，13.4Hz，2H)，4.00(s，3H)，4.24(t，J＝6.6Hz，2H)，4.64-4.76(m，1H)，5.95-6.05(m，1H)，6.27(d，J＝5.1Hz，1H)，6.95(s，1H)，7.39-7.43(m，2H)，7.54(s，1H)，8.42(d，J＝5.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 536 (M)++1)
Example 177: n- (2, 4-difluorophenyl) -N' - [ 4- ({ 6-methoxy-7) - [ 2- (1H-1, 2, 3-triazol-1-yl) ethoxy ] -4-quinolinyl } oxy) -2, 5-dimethylphenyl ] urea
The starting material (N- (2, 4-difluorophenyl) -N' - {4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] -2, 5-dimethylphenyl } urea (93mg), potassium carbonate (138mg), 2- (1H-1, 2, 3-triazol-1-yl) ethyl 4-methyl-1-benzenesulfonate (52mg) was dissolved in N, N-dimethylformamide (1ml), stirred at 80 ℃ for 5 hours, water was added to the reaction mixture, extracted with chloroform-propanol (3/1), the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by HPLC developed with chloroform/methanol to give 33mg of the title compound, the yield thereof was found to be 30%.
1H-NMR(CDCl3，400MHz)：δ2.10(s，3H)，2.19(s，3H)，4.01(s，3H)，4.51(t，J＝4.9Hz，2H)，4.93(t，J＝5.4Hz，2H)，4.94(s，1H)，6.28(d，J＝5.1Hz，1H)，6.75-6.88(m，2H)，6.90(s，1H)，7.36(s，1H)，7.58(s，1H)，7.60(s，1H)，7.73(s，1H)，7.99(s，1H)，8.08(dd，J＝9.3Hz，15.1Hz，1H)，8.41(d，J＝5.1Hz，1H)
Example 178: n' - (2-chloro-4- { [ 6-methoxy-7- (2-morpholinoethyl) Oxy) -4-quinazolinyl ] oxy } phenyl) -N, N-dimethylUrea
The starting material (N' - { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N, N-dimethylurea, 80mg), potassium carbonate (138mg), 1, 2-dibromoethane (0.085ml) was dissolved in N, N-dimethylformamide (1ml), and stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give an intermediate (N' - (4- { [ 7- (2-bromoethoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N, N-dimethylurea). The intermediate, potassium carbonate (138mg), and morpholine (0.043ml) were dissolved in N, N-dimethylformamide (1ml), and stirred at room temperature for 1 night. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 72mg in a yield of 72%.
1H-NMR(CDCl3，400MHz)：δ2.58-2.66(m，4H)，2.90-2.98(m，2H)，3.08(s，6H)，3.70-3.79(m，4H)，4.02(s，3H)，4.29-4.37(m，2H)，6.97(s，1H)，7.15(dd，J＝2.7Hz，9.0Hz，1H)，7.24-7.26(m，1H)，7.29(s，1H)，7.49(s，1H)，8.36(d，J＝9.3Hz，1H)，8.60(s，1H)
Mass Spectrometry (ESI-MS, m/z): 502 (M)++1)
Example 179: n' - (2-chloro-4- { [ 6-methoxy-7- (4-morpholinobutyl) Oxy) -4-quinazolinyl-oxy } phenyl) -N, N-dimethylurea
The starting material (N' - { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N, N-dimethylurea, 80mg), potassium carbonate (138mg) and 1, 4-dibromobutane (0.12ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give an intermediate (N' - (4- { [ 7- (4-bromobutoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N, N-dimethylurea). The intermediate, potassium carbonate (138mg), and morpholine (0.043ml) were dissolved in N, N-dimethylformamide (1ml), and stirred at room temperature for 1 night. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 47mg in 44% yield.
1H-NMR(CDCl3，400MHz)：δ1.67-1.77(m，2H)，1.93-2.03(m，2H)，2.39-2.50(m，4H)，3.67(s，6H)，3.64-3.75(m，4H)，4.02(s，3H)，4.21(t，J＝6.6Hz，2H)，6.97(s，1H)，7.16(dd，J＝2.7Hz，9.3Hz，1H)，7.26(s，1H)，7.28(s，1H)，7.29(d，J＝2.7Hz，1H)，7.48(s，1H)，8.36(d，J＝9.3Hz，1H)，8.59(s，1H)
Example 180: n' - (2-chloro-4- { [ 6-methoxy-7- (4-pyridylmethoxy) 4-quinazolinyl-oxy } phenyl) -N, N-dimethylurea
The starting material (N' - { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N, N-dimethylurea, 50mg), potassium carbonate (138mg) and 4-chloromethylpyridine hydrochloride (49mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 37mg in a yield of 60%.
1H-NMR(CDCl3，400MHz)：δ3.07(s，6H)，4.07(s，3H)，5.32(s，2H)，6.97(s，1H)，7.15(dd，J＝2.7Hz，9.0Hz，1H)，7.26(s，1H)，7.29(d，J＝2.7Hz，1H)，7.41(d，J＝6.1Hz，1H)，7.55(s，1H)，8.37(d，J＝9.0Hz，1H)，8.58(s，1H)，8.63(d，J＝6.1Hz，1H)
Mass Spectrometry (ESI-MS, m/z): 480 (M)++1)
Example 181: 2- { [ 4- (3-chloro-4- { [ (dimethylamino) carbonyl ] amino } amino Phenoxy) -6-methoxy-7-quinazolinyl ] oxy } acetic acid methyl ester
The starting material (N' - { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N, N-dimethylurea, 50mg), potassium carbonate (138mg) and ethyl bromoacetate (49mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by HPLC using chloroform/methanol to give the title compound 37mg in a yield of 60%.
1H-NMR(CDCl3，400MHz)：δ3.07(s，6H)，3.82(s，3H)，4.06(s，3H)，4.87(s，2H)，6.97(s，1H)，7.14(dd，J＝2.7Hz，9.0Hz，1H)，7.18(s，1H)，7.29(d，J＝2.7Hz，1H)，7.54(s，1H)，8.36(d，J＝9.0Hz，1H)，8.60(s，1H)
Example 182: n' - [ 2-chloro-4- ({ 6-methoxy-7- [ 3- (4-methyl) methyl ] methyl ester Piperazinyl) propoxy ] -4-quinazolinyl } oxy) phenyl ] -N, N-dimethylurea
The starting material (N' - { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N, N-dimethylurea, 400mg), potassium carbonate (966mg), 1, 3-dibromopropane (0.51ml) was dissolved in N, N-dimethylformamide (5ml), and stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 398mg of an intermediate (N' - (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N, N-dimethylurea) in 78% yield. The intermediate (51mg), potassium carbonate (138mg) and 1-methylpiperazine (0.055ml) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 46mg in a yield of 85%.
1H-NMR(CDCl3，400MHz)：δ2.06-2.16(m，2H)，2.29(s，3H)，2.30-2.60(m，10H)，3.07(s，6H)，4.02(s，3H)，4.25(t，J＝6.8Hz，2H)，6.96(s，1H)，7.15(dd，J＝2.7Hz，9.0Hz，1H)，7.29(d，J＝2.7Hz，1H)，7.30(s，1H)，7.48(s，1H)，8.36(d，J＝9.0Hz，1H)，8.59(s，1H)
Mass Spectrometry (ESI-MS, m/z): 529 (M)++1)
Example 183: n' - { 2-chloro-4- [ (7- {3- [ (2-hydroxyethyl) (methyl) Amino-propoxy-6-methoxy-4-quinazolinyl) oxy-phenyl-N, N-dimethyl Radical urea
The starting material (N' - { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N, N-dimethylurea, 400mg), potassium carbonate (966mg), 1, 3-dibromopropane (0.51ml) was dissolved in N, N-dimethylformamide (5ml), and stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the resulting residue was washed with diethyl ether to give 398mg of an intermediate (N' - (4- { [ 7- (3-bromopropoxy) -6-methoxy-4-quinazolinyl ] oxy } -2-chlorophenyl) -N, N-dimethylurea) in 78% yield. The intermediate (51mg), potassium carbonate (138mg), and 2- (methylamino) ethanol (0.040ml) were dissolved in N, N-dimethylformamide (1ml), and stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 49mg in a yield of 97%.
1H-NMR(CDCl3，400MHz)：δ2.01-2.11(m，2H)，2.25(s，3H)，2.52(t，J＝5.1Hz，2H)，2.61(t，J＝7.1Hz，2H)，3.03(s，6H)，3.57(t，J＝5.1Hz，2H)，3.98(s，3H)，4.23(t，J＝6.6Hz，2H)，6.92(s，155 7.10(dd，J＝2.7Hz，9.3Hz，1H)，7.24(d，J＝2.7Hz，1H)，7.31(s，1H)，7.44(s，1H)，8.31(d，J＝9.0Hz，1H)，8.54(s，1H)
Mass Spectrometry (ESI-MS, m/z): 504 (M)++1)
Example 184: n- (2-chloro-4- { [ 6-methoxy-7- (3-piperidinopropoxy) 4-quinazolinyl-oxy-phenyl) -N' -methylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -methylurea (2.0g) was dissolved in N, N-dimethylformamide (50ml), and triphosgene (2.8g), piperidinylpropanol (0.9g), and diethyl azodicarboxylate (1.9g) were added. After stirring at room temperature for 2 hours, triphosgene (2.8g), piperidinylpropanol (0.6g) and diethyl azodicarboxylate (1.9g) were added, and the mixture was further stirred at room temperature for 10 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol (20/1) to give the title compound in a yield of 25 mg.
1H-NMR(DMSO-d6，400MHz)：δ1.37-1.43(m，2H)，1.43-1.53(m，4H)，1.96-2.00(m，2H)，2.29-2.50(m，6H)，2.68(d，J＝4.6Hz，3H)，3.97(s，3H)，4.23(t，J＝6.3Hz，2H)，6.82-6.85(m，1H)，7.23(dd，J＝2.7Hz，9.0Hz，1H)，7.38(s，1H)，7.47(d，J＝2.7Hz，1H)，7.54(s，1H)，8.07(s，1H)，8.17(d，J＝9.0Hz，1H)，8.55(s，1H)
Mass Spectrometry (ESI-MS, m/z): 500 (M)++1)
Example 185: n- (2-chloro-4- { [ 6-methoxy-7- (3-piperidinopropoxy) 4-quinazolinyl-oxy-phenyl) -N' -ethylurea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinazolinyl) oxy ] phenyl } -N' -ethylurea (2.7g) was dissolved in N, N-dimethylformamide (30ml), and triphosgene (3.6g), piperidinylpropanol (1.2g), and diethyl azodicarboxylate (2.4g) were added. After stirring at room temperature for 2 hours, triphosgene (3.6g), piperidinylpropanol (0.8g) and diethyl azodicarboxylate (1.9g) were added, and the mixture was further stirred at room temperature for 10 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was purified by chromatography on silica gel using chloroform/methanol (20/1) to give the title compound (1.5 g) in a yield of 42%.
1H-NMR(DMSO-d6，400MHz)：δ1.08(t，J＝7.0Hz，3H)，1.38-1.41(m，2H)，1.47-1.53(m，4H)，1.95-2.00(m，2H)，2.31-2.46(m，6H)，3.10-3.17(m，2H)，3.97(s，3H)，4.23(t，J＝6.3Hz，2H)，6.96(t，J＝5.6Hz，1H)，7.23(dd，J＝2.7Hz，9.0Hz，1H)，7.37(s，1H)，7.47(d，J＝2.7Hz，1H)，7.54(s，1H)，8.02(s，1H)，8.19(d，J＝9.3Hz，1H)，8.55(s，1H)
Mass Spectrometry (ESI-MS, m/z): 514 (M)++1)
Example 186: n- (2-chloro-4- { [ 6-methoxy-7- (4-pyridylmethoxy) -4-quinolyl ] oxy } phenyl) -N' - (2, 4-difluorophenyl) urea
N- { 2-chloro-4- [ (7-hydroxy-6-methoxy-4-quinolyl) oxy ] phenyl } -N' - (2, 4-difluorophenyl) urea (55mg), potassium carbonate (62mg), and 4- (chloromethyl) pyridine hydrochloride (22mg) were dissolved in N, N-dimethylformamide (1ml), and the mixture was stirred at 80 ℃ for 1 hour. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the obtained residue was washed with diethyl ether to give the title compound 35mg in 55% yield.
1H-NMR(DMSO，400MHz)：3.98(s，3H)，5.41(s，2H)，6.56(d，J＝5.1Hz，1H)，7.04-7.10(m，1H)，7.25-7.37(m，2H)，7.47(s，1H)，7.49-7.52(m，4H)，7.55(s，1H)，8.08-8.15(m，1H)，8.24(d，J＝9.0Hz，1H)，8.49(d，J＝5.4Hz，1H)，8.60-8.63(m，1H)，8.81-8.83(m，1H)，9.30-9.31(m，1H)
Mass Spectrometry (ESI-MS, m/z): 563 (M)++1)
The structures of the compounds described in the examples are shown below.
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
1 CH CH H CH3O CH3O H H F H H H H
2 CH CH H CH3O CH3O H H F H H H H
3 CH CH H CH3O CH3O H H F H H H H
4 CH CH H CH3O CH3O H H F H H H H
5 CH CH H CH3O CH3O H H F H H H H
6 CH CH H CH3O CH3O H H F H H H H
7 CH CH H CH3O CH3O H H F H H H H
8 CH CH H CH3O CH3O H H F H H H H
9 CH CH H CH3O CH3O H H F H H H H
10 CH CH H CH3O CH3O H H F H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
11 CH CH H CH3O CH3O H H F H H H H
12 CH CH H CH3O CH3O H H F H H H H
13 CH CH H CH3O CH3O H H Cl H H H H
14 CH CH H CH3O CH3O H H Cl H H H H
15 CH CH H CH3O CH3O H H Cl H H H H
16 CH CH H CH3O CH3O H H Cl H H H H
17 CH CH H CH3O CH3O H H Cl H H H H
18 CH CH H CH3O CH3O H H Cl H H H H
19 CH CH H CH3O CH3O H H Cl H H H H
20 CH CH H CH3O CH3O H H Cl H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
21 CH CH H CH3O CH3O H H Cl H H H H
22 CH CH H CH3O CH3O H H Cl H H H H
23 CH CH H CH3O CH3O H H Cl H H H H
24 CH CH H CH3O CH3O H CH3 CH3 H H H H
25 CH CH H CH3O CH3O H CH3 CH3 H H H H
26 CH CH H CH3O CH3O H CH3 CH3 H H H H
27 CH CH H CH3O CH3O H CH3 CH3 H H H H
28 CH CH H CH3O CH3O H CH3 CH3 H H H H
29 CH CH H CH3O CH3O H CH3 CH3 H H H H
30 CH CH H CH3O CH3O H CH3 CH3 H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R6 R9 R10 R11
31 CH CH H CH3O CH3O H CH3 CH3 H H H H
32 CH CH H CH3O CH3O H CH3 CH3 H H H H
33 CH CH H CH3O CH3O H CH3 CH3 H H H H
34 CH CH H CH3O CH3O H CH3 CH3 H H H H
35 CH CH H CH3O CH3O H CH3 CH3 H H H H
36 CH CH H CH3O CH3O H CH3 CH3 H H H H
37 CH CH H CH3O CH3O H H CH3 CH3 H H H
38 CH CH H CH3O CH3O H H CH3 CH3 H H H
39 CH CH H CH3O CH3O H H CH3 CH3 H H H
40 CH CH H CH3O CH3O H H CH3 CH3 H H H
X Z R1 R2 R3 R4 R5 R6 R7 R6 R9 R10 R11
41 CH CH H CH3O CH3O H H CH3 CH3 H H H
42 CH CH H CH3O CH3O H H CH3 CH3 H H H
43 CH CH H CH3O CH3O H H CH3 CH3 H H H
44 CH CH H CH3O CH3O H H CH3 CH3 H H H
45 CH CH H CH3O CH3O H H CH3 CH3 H H H
46 CH CH H CH3O CH3O H H CH3 CH3 H H H
47 CH CH H CH3O CH3O H H NO2 H H H H
48 CH CH H CH3O CH3O H H NO2 H H H H
49 CH CH H CH3O CH3O H Cl H Cl H H H
50 CH CH H CH3O H H F H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
51 CH CH H CH3O H H C H H H H
52 CH CH H CH3O H H CH3 CH3 H H H
53 CH CH H CH3O H H CH3 CH3 H H H
54 CH CH H CH3O CH3O(CH2)2O H H Cl H H H H
55 CH CH H CH3O CH3O(CH2)2O H H Cl H H H H
56 CH CH H CH3O CH3O(CH2)2O H CH3 CH3 H H H H
57 CH CH H CH3O CH3O(CH2)2O H CH3 CH3 H H H H
58 CH CH H CH3O CH3O(CH2)2O H H CH3 CH3 H H H
59 CH CH H CH3O CH3O(CH2)2O H H CH3 CH3 H H H
60 CH CH H CH3O H CH3 CH3 H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
61 N CH H CH3O CH3O H H Cl H H H H
62 N CH H CH3O CH3O H H Cl H H H H
63 N CH H CH3O CH3O H H H H H H H
64 N CH H CH3O CH3O H H H H H H H
65 N CH H CH3O CH3O H H H H H H H
66 N CH H CH3O CH3O H H H H H H H
67 N CH H CH3O CH3O H H H H H H H
68 N CH H CH3O CH3O H H H H H H H
69 N CH H CH3O CH3O H H H H H H H
70 N CH H CH3O CH3O H H H H H H H
X Z R1 R2 R3 R1 R5 R6 R7 R8 R9 R10 R11
41 N CH H CH3O CH3O H H H H H H H
72 N CH H CH3O CH3O H H H H H H H
73 N CH H CH3O CH3O H H H H H H H
74 N CH H CH3O CH3O H H H H H H H
75 N CH H CH3O CH3O H H H H H H H
76 N CH H CH3O CH3O H H Cl H H H H
77 N CH H CH3O CH3O H H Cl H H H H
78 N CH H CH3O CH3O H H Cl H H H H
79 N CH H CH3O CH3O H H Cl H H H H
80 N CH H CH3O CH3O H H Cl H H H H
X Z R1 R4 R3 R4 R5 R6 R7 R8 R9 R10 R11
81 N CH H CH3O CH3O H H Cl H H H H
82 N CH H CH3O CH3O H H Cl H H H H
83 N CH H CH3O CH3O H H Cl H H H H
85 N CH H CH3O CH3O H H Cl H H H H
86 N CH H CH3O CH3O H H Cl H H H H
87 N CH H CH3O CH3O H H Cl H H H H
88 N CH H CH3O CH3O H H F H H H H
89 N CH H CH3O CH3O H H F H H H H
90 N CH H CH3O CH3O H H F H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
91 N CH H CH3O CH3O H H F H H H H
92 N CH H CH3O CH3O H H F H H H H
93 N CH H CH3O CH3O H H F H H H H
94 N CH H CH3O CH3O H H F H H H H
95 N CH H CH3O CH3O H H F H H H H
96 N CH H CH3O CH3O H H F H H H H
97 N CH H CH3O CH3O H CH3 H H H H H
98 N CH H CH3O CH3O H CH3 H H H H H
99 N CH H CH3O CH3O H CH3 H H H H H
100 N CH H CH3O CH3O H CH3 H H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
101 N CH H CH3O CH3O H CH3 H H H H H
102 N CH H CH3O CH3O H H CH3 H H H H
103 N CH H CH3O CH3O H H CH3 H H H H
104 N CH H CH3O CH3O H H CH3 H H H H
105 N CH H CH3O CH3O H H CH3 H H H H
106 N CH H CH3O CH3O H H CH3 H H H H
107 N CH H CH3O CH3O H H NO2 H H H H
108 N CH H CH3O CH3O H H NO2 H H H H
109 N CH H CH3O CH3O H H Cl H H CH2OCH3 H
110 N CH H CH3O CH3O H H Cl H H CH3C(＝O)- H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
111 N CH H CH3O CH3O H H Cl H H H CH3
112 N CH H CH3O CH3O H H Cl H H H CH3CH2
113 N CH H CH3O CH3O H H Cl H H H CH3(CH2)2
114 N CH H CH3O CH3O H H Cl H H H CH3
115 N CH H CH3O CH3O H H Cl H H H CH3
116 N CH H CH3O CH3O H H Cl H H H CH3CH2
117 N CH H CH3O CH3O H H Cl H H H H CH3
118 N CH H CH3O CH3O H H Cl H H H CH3 CH3
119 N CH H CH3O H H Cl H H H H
120 N CH H CH3O H H Cl H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
121 N CH H CH3O H H Cl H H H H
122 N CH H CH3O H H Cl H H H H
123 N CH H CH3O H H Cl H H H H
124 N CH H CH3O H H Cl H H H H
125 N CH H CH3O H H Cl H H H H
126 N CH H CH3O H H Cl H H H CH3CH2
127 N CH H CH3O H H Cl H H H H
128 N CH H CH3O H H Cl H H H H
129 N CH H CH3O H H Cl H H H H
130 N CH H CH3O H H Cl H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
131 N CH H CH3O H H Cl H H H CH3CH2
132 N CH H CH3O H H Cl H H H CH3CH2
133 N CH H CH3O H H Cl H H H H
134 N CH H CH3O H H Cl H H H H
135 N CH H CH3O H H Cl H H H H
136 N CH H CH3O H H Cl H H H H
137 N CH H CH3O H H Cl H H H H
138 N CH H CH3O H H Cl H H H H
139 N CH H CH3O H H Cl H H H H
140 N CH H CH3O H H Cl H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
141 CH CH H CH3O H H Cl H H H H
142 CH CH H CH3O H H Cl H H H H
143 CH CH H CH3O H H Cl H H H H
144 CH CH H CH3O H H Cl H H H H
145 CH CH H CH3O H H Cl H H H H
146 CH CH H CH3O H H Cl H H H H
147 CH CH H CH3O H H Cl H H H H
148 CH CH H CH3O H H Cl H H H H
149 CH CH H CH3O H H Cl H H H H
150 CH CH H CH3O H H Cl H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
151 CH CH H CH3O H H Cl H H H H
152 CH CH H CH3O H H Cl H H H H
153 CH CH H CH3O H H CH H H H H
154 CH CH H CH3O H H Cl H H H H
155 CH CH H CH3O H H Cl H H H H
156 CH CH H CH3O H H Cl H H H H
157 CH CH H CH3O H H Cl H H H H
158 CH CH H CH3O H H Cl H H H H
159 CH CH H CH3O H H Cl H H H H
160 CH CH H CH3O H H Cl H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
161 N CH H CH3O H H Cl H H H H
162 N CH H CH3O H H Cl H H H H
163 N CH H CH3O H H Cl H H H H
164 N CH H CH3O H H Cl H H H H
165 N CH H CH3O H H Cl H H H H
166 CH CH H CH3O H H Cl H H H H
167 CH CH H CH3O H H Cl H H H H
168 CH CH H CH3O H H Cl H H H H
169 CH CH H CH3O H H Cl H H H H
170 CH CH H CH3O H H Cl H H H H
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
171 N CH H CH3O H H CH3O H H H H
172 N CH H CH3O H H CH3O H H H H
173 CH CH H CH3O H H CH3O H H H H
174 CH CH H CH3O H H CH3O H H H H
175 CH CH H CH3O H H CH3 CH3 H H H
176 CH CH H CH3O H H CH3 CH3 H H H
177 CH CH H CH3O H H CH3 CH3 H H H
178 N CH H CH3O H H Cl H H H CH3 CH3
179 N CH H CH3O H H Cl H H H CH3 CH3
180 N CH H CH3O H H Cl H H H CH3 CH3
X Z R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11
181 N CH H CH3O H H Cl H H H CH3 CH3
182 N CH H CH3O H H Cl H H H CH3 CH3
183 N CH H CH3O H H Cl H H H CH3 CH3
184 N CH H CH3O H H Cl H H H H CH3
185 N CH H CH3O H H Cl H H H H
186 CH CH H CH3O H H Cl H H H H
Pharmacological test example 1: inhibition of MAPK activation in vascular endothelial cells by VEGF stimulation Determination of Capacity
Human umbilical vein endothelial cells (purchased from Chronic) were cultured in EGM-2 medium (purchased from Chronic) in a 5% carbon dioxide incubator until 50-70% confluence, and the same medium was used at 1.5X 10/well5One was seeded in 96-well plates. After culturing at 37 ℃ for 1 night, the medium was replaced with EBM-2 medium (purchased from Chronic) containing 0.5% bovine fetal serum, and cultured for 24 hours. The analyte dissolved in dimethyl sulfoxide was added to each well, and the cells were further incubated at 37 ℃ for 1 hour. Human recombinant vascular endothelial growth factor (hereinafter abbreviated as "VEGF") was added to a final concentration of 50ng/ml, and cells were stimulated at 37 ℃ for 8 minutes. After removing the medium and washing the cells with phosphate buffered saline (pH7.4), 10. mu.l of solubilization buffer (Tris buffered saline (pH7.4) containing 1% Triton X100, 2mM sodium orthovanadate, 1mM disodium ethylenediaminetetraacetate) was added. The cells were solubilized by shaking at 4 ℃ for 1 hour, and Tri s-buffered physiological saline containing 1% sodium lauryl sulfate was added to the solution in equal amounts and mixed well. Mu.l of the solution was adsorbed on a PVDF filter by dot blotting, and the filter was subjected to immunoblotting using an anti-tyrphostinylacetylPK antibody (purchased from first Chemicals).
Quantifying the amount of phosphorylated MAPK with a densitometer, taking the amount of phosphorylated MAPK produced by addition of VEGF in the absence of the test substance as 100%,the amount of phosphorylated MAPK in the absence of the test substance and VEGF was taken as 0%, and the phosphorylated MAPK ratio in the presence of the test substance was determined. From this phosphorylated MAPK rate, the concentration of the test substance necessary for 50% inhibition of MAPK activation (IC) was calculated50)。
The results are shown in Table 1.
TABLE 1
Compound (I) IC50(nM) Compound (I) IC50(nM) Compound (I) IC50(nM)
1 1.8 45 2.0 85 0.7
4 2.1 46 4.3 86 0.6
5 2.9 47 4.0 87 58.0
7 5.2 48 0.5 89 45.0
8 11.0 49 4.3 90 42.0
9 5.1 50 0.5 92 46.0
10 7.8 52 4.4 93 14.0
11 15.0 53 5.9 94 1.8
13 2.2 54 0.5 95 2.7
14 0.7 55 2.8 96 ＜1
16 2.9 56 5.1 97 518.0
17 11.0 57 6.5 98 450.0
18 0.6 58 5.1 99 8.8
19 0.6 59 5.8 100 5.2
20 8.5 62 16.0 102 150.0
21 3.4 63 70.0 103 53.0
22 0.4 64 42.0 104 5.3
23 5.4 65 36.0 105 2.3
24 0.6 66 21.0 106 ＜1
25 3.9 67 345.0 107 10.2
26 5.3 68 45.0
28 4.0 69 67.0
29 4.4 70 6.8
30 1.7 71 750.0
31 2.5 72 3.9
32 7.3 73 ＜2
33 3.5 74 6.0
34 4.2 75 1.2
35 3.7 76 8.0
36 3.3 77 71.0
37 2.3 78 4.1
40 12.0 79 30.0
41 4.9 80 13.0
42 5.9 82 3.8
43 3.8 83 ＞1000
Pharmacological Experimental example 2: measuring KDR phosphorylation inhibitory activity by ELISA method
Human KDR-transfected NIH3T3 cells (Sawano A et al, Cell Growth)&Difference, 7, 213- & ltwbr/& gt221 (1996), "Flt-1 but not KDR/Flk-1tyrosine kinase is a receptor for plant growth factor, while modified to a vascular growth factor") was cultured in a 5% carbon dioxide incubator with DMEM medium (purchased from GIBCOBRL) containing 10% bovine fetal serum to 50-70% confluence. The resulting cells were cultured in the same medium at 1.5X 104Each well was inoculated into a 96-well plate coated with type 1 collagen and incubated at 37 ℃ for 1 night. The medium was replaced with DMEM containing 0.1% fetal bovine serum, and the analyte dissolved in dimethyl sulfoxide was added to each well and cultured at 37 ℃ for another 1 hour. Human recombinant vascular endothelial growth factor (hereinafter abbreviated as VEGF) was added to a final concentration of 100ng/ml, and the cells were stimulated at 37 ℃ for 2 minutes. Removing the culture medium, washing with phosphate buffered saline (pH7.4)After the cells, solubilization buffer (containing 20mM HEPES (pH7.4), 150mM NaCl, 0.2% Triton X-100, 10% glycerol, 5mM sodium orthovanadate, 5mM disodium ethylenediaminetetraacetate, 2mM Na4P2O7)50 μ l. The cell extract was prepared by shaking at 4 ℃ for 2 hours.
50. mu.l of phosphate buffered saline (pH7.4) containing an anti-phosphotyrosine antibody (PY 20; purchased from TRANSduction laboratories, Inc.) at 5. mu.g/ml was added to a microplate for ELIS (Maxisorp; purchased from NUNC) and allowed to stand at 4 ℃ for 1 night to solidify. After washing the plate, 300. mu.l of blocking solution was added thereto, and the mixture was allowed to stand at room temperature for 2 hours to block the plate. After washing, the cell extract was completely transferred and allowed to stand at 4 ℃ for 1 night. After washing, an anti-KDR antibody (purchased from Santa Cruz) was reacted at room temperature for 1 hour, and after washing again, a peroxidase-labeled anti-rabbit Ig antibody (purchased from Amersham) was reacted at room temperature for 1 hour. After washing, a chromogenic substrate for peroxidase (available from Sumitomo Bakelite) was added to start the reaction. After appropriate color development was obtained, the reaction was stopped by adding a reaction-stopping solution, and the absorbance at 450nm was measured by a microplate reader. The KDR phosphorylation activity of each well was determined by taking the absorbance when VEGF was added without adding the drug as the KDR phosphorylation activity of 100%, and the absorbance when VEGF was added without adding the drug as the KDR phosphorylation activity of 0%. Changing the concentration of the substance to be measured at various levels, determining the inhibition rate of KDR phosphorylation in various occasions, and calculating the concentration (IC) of the substance to be measured for 50% inhibition of KDR phosphorylation50)。
The results are shown in Table 2.
TABLE 2
Compound (I) IC50(nM) Compound (I) IC50(nM) Compound (I) IC50(nM)
62 11.0 103 78.0 146 1.0
63 150.0 104 3.9 147 1.0
64 150.0 105 2.0 148 15.0
65 27.0 106 1.5 149 1.6
66 15.0 107 11.0 150 1.8
67 63.0 108 5.0 151 0.5
68 24.0 110 ＞1000 152 0.8
69 64.0 111 ＞1000 153 1.5
70 32.0 112 ＞1000 154 1.5
71 350.0 113 ＞1000 155 2.1
72 3.5 114 ＞1000 156 0.8
73 1.0 115 ＞1000 157 0.4
74 11.0 116 ＞1000 158 1.6
75 1.4 117 24.0 159 1.9
76 3.5 118 ＞1000 160 0.9
77 6.0 119 3.6 161 3.9
78 3.4 120 3.9 162 1.0
79 18.0 121 12.5 163 1.4
80 2.7 122 5.8 164 0.9
81 4.1 123 8.9 165 0.6
82 8.4 124 1.9 166 2.2
83 840.0 125 2.6 167 2.1
85 0.5 126 ＞1000 168 4.0
86 1.5 127 1.1 169 3.7
87 110.0 131 ＞1000 170 1.1
88 61.0 132 ＞1000 175 4.7
89 24.0 133 8.3 176 3.7
90 57.0 134 5.0 177 2.3
92 63.0 135 1.0 178 ＞1000
93 37.0 136 160.0 179 ＞1000
94 2.3 137 24.0 180 ＞1000
95 3.8 138 40.0 181 ＞1000
96 0.4 139 15.0 182 ＞1000
97 490.0 140 36.0 183 ＞1000
98 330.0 141 14.0 184 0.2
99 25.0 142 2.6 185 0.5
100 13.0 143 3.5 186 6.3
101 3.0 144 1.6
102 105.0 145 0.8
Pharmacological test example 3: nuclear morphometric assay
A375 human melanoma cells (purchased from the financial institute of human cancer) 2X 104Each was inoculated on a culture slide (manufactured by Falcon) and cultured at 37 ℃. After 5 hours, the test substance was added to 10. mu.M and 1. mu.M, and the culture was continued for another 48 hours. After the cells were fixed, a 50. mu.g/ml propidium iodide solution containing ribonuclease (200. mu.g/ml) was added to stain nuclei. The stained nuclei were observed with a fluorescence microscope to analyze the presence or absence of abnormality in the form of nuclei.
The nuclear morphometric change of the test substance was recorded as (2+) when cells with morphometric change were confirmed at 1. mu.M and as (+) when cells with morphometric change were confirmed at 10. mu.M. In addition, when cells showing no morphological change were observed at 10. mu.M, the cells were designated as (-) above.
The results are shown in Table 3.
TABLE 3
Compound number Morphological change Compound number Morphological change
131415161718202122242526282930313233343536 (-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-) 373839404142434445464748495253555859606162 (-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)(-)
Pharmacological test example 4: antitumor effect on human glioma cells (GL07)
Human glioma cells GL07 (purchased from Central laboratory of laboratory animals) were transplanted into nude mice, and the tumor volume reached 100mm3The test compound was administered orally or intraperitoneally at 20mg/kg 1 time a day for 9 days, and vehicle was administered to the control group. When the tumor volume on the day of initiation of administration was 1, the tumor volume on day X of the control group was Cx, and the tumor volume in the test compound-administered group was Tx, and the Tumor Growth Inhibition Ratio (TGIR) was determined to be (1-Tx/Cx) × 100.
The tumor growth inhibition rates of representative examples of the compounds of the present invention are shown in table 4.
TABLE 4
Example number Site of administration TGIR(％) Example number Site of administration TGIR(％) Example number Site of administration TGIR(％)
4 Is administered orally 61 102 Is administered orally 24 147 Is administered orally 34
5 Is administered orally 59 103 Is administered orally 23 148 Is administered orally 54
9 In the abdominal cavity 59 104 Is administered orally 22 149 Is administered orally 47
13 In the abdominal cavity 52 105 Is administered orally 20 150 Is administered orally 22
14 In the abdominal cavity 81 107 Is administered orally 49 151 Is administered orally 44
16 In the abdominal cavity 77 109 Is administered orally 71 152 Is administered orally 44
17 In the abdominal cavity 85 110 Is administered orally 26 153 Is administered orally 53
18 Is administered orally 57 111 Is administered orally 78 154 Is administered orally 34
24 Is administered orally 63 112 Is administered orally 81 155 Is administered orally 29
25 In the abdominal cavity 68 113 Is administered orally 61 156 Is administered orally 24
28 In the abdominal cavity 84 114 Is administered orally 60 157 Is administered orally 44
29 Is administered orally 64 115 Is administered orally 74 158 Is administered orally 39
37 In the abdominal cavity 70 116 Is administered orally 83 159 Is administered orally 40
48 In the abdominal cavity 90 119 Is administered orally 40 160 Is administered orally 43
50 Is administered orally 59 120 Is administered orally 30 161 Is administered orally 39
51 Is administered orally 65 121 Is administered orally 22 162 Is administered orally 40
54 Is administered orally 59 122 Is administered orally 21 163 Is administered orally 52
62 Is administered orally 78 123 Is administered orally 31 164 Is administered orally 55
64 Is administered orally 37 124 Is administered orally 27 165 Is administered orally 44
66 Is administered orally 26 125 Is administered orally 30 166 Is administered orally 27
67 Is administered orally 30 126 Is administered orally 52 167 Is administered orally 28
68 Is administered orally 57 127 Is administered orally 25 168 Is administered orally 42
69 Is administered orally 26 128 Is administered orally 21 169 Is administered orally 55
71 Is administered orally 67 129 Is administered orally 25 170 Is administered orally 64
73 Is administered orally 34 130 Is administered orally 32 171 Is administered orally 13
74 Is administered orally 28 131 Is administered orally 31 172 Is administered orally 42
77 Is administered orally 26 132 Is administered orally 24 173 Is administered orally 21
78 Is administered orally 21 133 Is administered orally 20 174 Is administered orally 19
79 Is administered orally 28 134 Is administered orally 29 175 Is administered orally 17
80 Is administered orally 52 135 Is administered orally 62 176 Is administered orally 22
82 Is administered orally 27 136 Is administered orally 23 177 Is administered orally 35
83 Is administered orally 31 137 Is administered orally 20 178 Is administered orally 28
85 Is administered orally 26 138 Is administered orally 21 179 Is administered orally 33
89 Is administered orally 40 139 Is administered orally 27 180 Is administered orally 45
93 Is administered orally 29 140 Is administered orally 21 181 Is administered orally 21
94 Is administered orally 29 141 Is administered orally 28 182 Is administered orally 31
97 Is administered orally 48 142 Is administered orally 48 183 Is administered orally 22
98 Is administered orally 38 143 Is administered orally 53 184 Is administered orally 48
99 Is administered orally 33 144 Is administered orally 56 185 Is administered orally 59
100 Is administered orally 36 145 Is administered orally 57 186 Is administered orally 47
101 Is administered orally 44 146 Is administered orally 4 8
TGIR (%) ═ tumor proliferation inhibition (%)

Claims (26)

1. A compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof,
in the above-mentioned formula, the compound of formula,
x represents a group represented by the formula (I),
R21and R22Represents unsubstituted C1-4An alkoxy group,
R23、R25and R26Represents a hydrogen atom, and is represented by,
R24represents a chlorine atom, and represents a chlorine atom,
R27and R28Represents a hydrogen atom, and
R29is represented by C1-6Alkyl radical, C2-6Alkenyl, or C1-6Alkynyl.
2. The compound of claim 1, wherein R21And R22Represents a methoxy group.
3. The compound of claim 1 which is N- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } -N' -propylurea.
4. The compound of claim 1 which is N- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } -N' -ethylurea.
5. The compound of claim 1 which is N-butyl-N' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } urea.
6. The compound of claim 1 which is N- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } -N' -pentaurea.
7. The compound of claim 1, which is N- (sec-butyl) -N' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } urea.
8. The compound according to claim 1, which is N-allyl-N' - { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl).
9. The compound of claim 1 which is N- { 2-chloro-4- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl } -N' - (2-propynyl) urea.
10. A compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof,
in the above-mentioned formula, the compound of formula,
x represents a group of a CH or an N,
R21and R22Any one of them represents an unsubstituted C1-4Alkoxy, and the other represents a group R31-(CH2) p-O-wherein R31Represents a hydroxyl group, C1-4Alkoxy radicals in which one or two hydrogen atoms are replaced by hydroxy radicals or C1-4Alkoxy substituted or unsubstituted C1-4Alkyl-substituted or unsubstituted amino, or the radical R14- (S) m-wherein R14Denotes a saturated or unsaturated 5-or 6-membered heterocyclic group, which is substituted by C1-4Alkyl is substituted or unsubstituted, m is 0 or 1; p is an integer from 1 to 6;
R23、R24、R25and R26May be the same or different and represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy or nitro, provided that R is23、R24、R25And R26Not simultaneously represent a hydrogen atom;
R27and R28Represents a hydrogen atom, and
R29represents a halogen atom or C1-4Alkoxy substituted or unsubstituted C1-6Alkyl radical, C2～6Alkenyl or C2-6Alkynyl or represents R32-(CH2) q-, wherein q is an integer of 0 to 4, R32Represents a halogen atom, C1-4Alkyl or C1-4An alkoxy substituted or unsubstituted unsaturated 6-membered carbocyclic or heterocyclic group.
11. The compound of claim 10, wherein m is 0.
12. The compound of claim 10, wherein p is an integer from 1 to 4.
13. The compound of claim 10, wherein R23、R24、R25And R26One represents a halogen atom and the others represent a hydrogen atom.
14. The compound of claim 10, wherein R29Is represented by C1-6An alkyl group.
15. A compound according to claim 10, wherein X represents CH.
16. A compound according to claim 10, wherein X represents CH, m is 0; p is an integer from 1 to 4; r14Represents a saturated or unsaturated 5-or 6-membered heterocyclic group; r23、R24、R25And R26One represents a halogen atom and the others represent a hydrogen atom; r29Is represented by C1-6An alkyl group.
17. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof,
in the above-mentioned formula, the compound of formula,
x represents CH or N; z represents CH;
R1represents a hydrogen atom, R2Represents methoxy, and R3Represents a group R31-(CH2) p-O-wherein R31Represents a hydroxyl group, C1-4Alkoxy radicals in which one or two hydrogen atoms are replaced by hydroxy radicals or C1-4Alkoxy substituted or unsubstituted C1-4Alkyl-substituted or unsubstituted amino, or the radical R14- (S) m-wherein R14Denotes a saturated or unsaturated 5-or 6-membered heterocyclic group, which is substituted by C1-4Alkyl is substituted or unsubstituted, m is 0 or 1; p is an integer from 1 to 6;
R4represents a hydrogen atomIn the case of a hybrid vehicle,
R5、R6、R7and R8May be the same or different and represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, or nitro, with the proviso that R5、R6、R7And R8Not simultaneously represent a hydrogen atom;
R9and R10Represents a hydrogen atom; and
R11represents R15-(CH2)n-, where n represents an integer of 0 to 4, R15Denotes an unsaturated 6-membered carbocyclic or heterocyclic group which is interrupted by a halogen atom, C1-4Alkyl or C1-4Alkoxy groups are substituted or unsubstituted.
18. The compound of claim 17, wherein m is 0.
19. The compound of claim 17, wherein n is 0.
20. The compound of claim 17, wherein p is an integer from 1 to 4.
21. The compound of claim 17, wherein R5、R6、R7And R8One represents a halogen atom and the others represent a hydrogen atom.
22. A compound according to claim 17, wherein X represents CH.
23. A pharmaceutical composition comprising the compound of any one of claims 1 to 2 and 4 to 22, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient.
24. Use of a compound according to any one of claims 1-2 and 4-22, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disease selected from tumour, diabetic retinopathy, chronic joint rheumatism, psoriasis, atherosclerosis and kaposi's sarcoma.
25. A pharmaceutical composition comprising the compound of claim 3 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
26. Use of a compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disease selected from tumour, diabetic retinopathy, chronic joint rheumatism, psoriasis, atherosclerosis and kaposi's sarcoma.
HK02105360.9A 1999-01-22 2000-01-20 Quinoline derivatives and quinazoline derivatives HK1043792B (en)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
JP1485899 1999-01-22
JP14858/99 1999-01-22
JP2669199 1999-02-03
JP26691/99 1999-02-03
JP14249399 1999-05-21
JP142493/99 1999-05-21
JP25362499 1999-09-07
JP253624/99 1999-09-07
PCT/JP2000/000255 WO2000043366A1 (en) 1999-01-22 2000-01-20 Quinoline derivatives and quinazoline derivatives

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HK1043792A1 HK1043792A1 (en) 2002-09-27
HK1043792B true HK1043792B (en) 2005-06-30

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