JPH11158149A - Quinolin derivative and pharmaceutical composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having suppressing activities blood stream in a blood vessel in a diseased part, that is suppression activities of arterialization, anti-tumor activities or the like, providing a low influence on the cell morphological transformation and useful for the treatment of a disease such as tumor and retinopathia diabeticas. SOLUTION: This compound is a compound of formula I [R1 is H, a halogen, a lower alkyl or a lower alkoxy; R2 and R3 are each H, a lower alkyl or the like, with the proviso that when R1 is H, R2 and R3 are not simultaneously H; R4 is a halogen; (m) is an integer of 1-3] or a pharmacologically acceptable salt or solvate thereof, e.g. N-(2,4-difluorophenyl)-N'- 4-[(6,7-dimethoxy-4-quinolyl) oxy]-2-fluorophenyl}urea. The compound of formula I is obtained by allowing a 4-chloroquinoline derivative of formula II to act on nitrophenol, and reducing the obtained product to provide 4-(aminophenoxy)quinoline derivative, and allowing an isocyanate derivative to act on the obtained 4-(aminophenoxy) quinoline derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to quinoline derivatives having an inhibitory effect on angiogenesis in diseased sites, and more particularly, to tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, The present invention relates to a quinoline derivative effective for treating a disease such as Kaposi's sarcoma.

[0002] supply of nutrients and oxygen for the survival and maintenance of the background art cells, processing of metabolic waste is indispensable, it is generally carried out through the vascular blood flow as a function of blood. For this reason, securing blood vessels and blood flow is an important issue at sites where new cell proliferation occurs, and under physiological conditions, angiogenesis occurs in the endometrium and the like, and blood flow due to the formation and development of a new blood vessel network Increase is observed. Even in an abnormal proliferative disease, the development of a vascular network and an increase in blood flow are observed at the pathological site, and it has been pointed out that the disease is closely related to the disease. In the case of a solid tumor or the like, an increase in blood flow is considered to be involved in metastasis and the like.

[0003] An increase in vascular blood flow is mainly caused by local enhancement of angiogenesis at a diseased site. Angiogenesis is a positive regulator (inducer) and a negative regulator (suppressor)
Normally, in adults, angiogenesis is suppressed due to the superiority of inhibitory factors other than the formation of uterine mucosa and corpus luteum and the process of wound healing during reproductive processes. However, angiogenesis associated with pathological conditions is observed in various processes such as the growth and metastasis of solid tumors, the development and progression of Kaposi's sarcoma, diabetic retinopathy, and chronic inflammation such as arteriosclerosis, psoriasis and rheumatoid arthritis. It has been shown to be involved in the exacerbation of the condition (Forkman, J. Nature Med.
1: 27-31, 1995).

[0004] To date, control of blood flow in diseased sites has been known to inhibit angiogenesis-inducing factor signal transduction, basement membrane degrading enzyme inhibition, vascular endothelial cell migration or growth inhibition, lumen formation inhibition, vascular endothelial cell adhesion inhibition, and the like. There are reports on some angiogenesis inhibitors whose mechanism of action is (Bicknell, R., Harris, AL Curr.Opin.Oncol.
8: 60-65, 1996), no effective substance has yet been found that is practically useful as a therapeutic agent for abnormal cell proliferative diseases.

On the other hand, WO 97/17329 discloses that
Quinoline derivatives are described as platelet-derived growth factor inhibitors. However, WO 97/17329 does not disclose the compound of the present invention, as well as the inhibitory effect on vascular blood flow at the diseased site and the effect on cell morphology change.

[0006]

SUMMARY OF THE INVENTION The present inventors have determined that a group of compounds in which a diphenylurea derivative is bonded to the 4-position of the quinoline skeleton via oxygen has an antitumor effect and an inhibitory effect on vascular blood flow at a diseased site. I found it. Accordingly, the present invention has an inhibitory effect on vascular blood flow (ie, an inhibitory effect on angiogenesis) and an antitumor activity at a diseased site,
It is an object of the present invention to provide a compound that preferably has a low effect on cell morphology changes. This effect of increasing the cell morphology can also be considered as a tissue damage-inducing effect.

The compound according to the present invention is a compound of the following formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0008]

Embedded image [In the above formula, R ₁ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group,, R ₂ and R
₃ may be the same or different and each is a hydrogen atom, a lower alkyl group, or a group represented by the formula (II):

[0009]

Embedded image (In the above formula, R ₅ may be the same or different;
Each is a halogen atom or a lower alkyl group;
Is an integer of 1 to 5, and p is an integer of 1 to 4, provided that, when R ₁ is a hydrogen atom, R ₂ and R ₃ do not represent a hydrogen atom at the same time, and R ₄ is , A halogen atom, and m is an integer of 1 to 3. The compounds according to the present invention are useful for treating tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, Kaposi's sarcoma, solid tumors and the like.

[0010]

DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein, the term "lower alkyl" or "lower alkoxy" as a group or part of a group means that the group is straight or branched and has 1 to 6 carbon atoms. Represents 1-4 alkyl groups or alkoxy groups.

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

Examples of lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and the like.

Examples of lower alkoxy include methoxy,
Ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy and the like.

The compound R ₁ is preferably a halogen atom, a lower alkyl group,
Or a lower alkoxy group, more preferably a halogen atom, a methyl group or a methoxy group.

R ₂ and R ₃ may preferably be the same or different and each represent a hydrogen atom, a methyl group,
Represents an ethyl group, an isopropyl group, or the formula (II).

In the formula (II), R ₅ preferably represents a halogen atom (particularly a chlorine atom), and n preferably represents 1
Represents p preferably represents 1.

R ₄ preferably represents a fluorine atom,
m is preferably 1 or 2. When m is 1, R ₄ is preferably in the 4-position, and when m is 2, R ₄ is in the 2- and 4-positions of the benzene ring, or 3
Preferably, it is present at positions 4 and 4.

A preferred group of compounds of formula (I) is:
R ₁ is a halogen atom, a lower alkyl group, or a lower alkoxy group, and R ₂ and R ₃ may be the same or different and are each a hydrogen atom, a lower alkyl group,
Or a compound of formula (II) wherein R ₅ is a halogen atom;
n is 1 and p is 1. ), R ₄ is a fluorine atom, and m is 1 or 2.

A preferred class of compounds according to the invention includes the following compounds: N-benzyl-N- (2,
4-difluorophenyl) -N '-{4-[(6,7-dimethoxy
-4-quinolyl) oxy] -2-fluorophenyldiurea,
N- (2-chlorobenzyl) -N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} urea, N- (4-Chlorobenzyl) -N- (2,4-difluorophenyl) -N '-{4-
[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl diurea, N- (2,4-difluorophenyl) -N '
-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N-methylurea, N- (2,4-difluorophenyl) -N ′-{4-[(6, 7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N-isopropylurea, N- (2,4-difluorophenyl) -N ′-{4-[(6,
7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N, N′-dimethylurea, N- (2,4-difluorophenyl) -N ′-{4-[(6,7-dimethoxy- 4-quinolyl)
Oxy] -2-fluorophenyl} urea, N '-(2,4-difluorophenyl) -N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N- Methylurea, N '-(2,4-difluorophenyl) -N- {4-[(6,7
-Dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N-ethylurea, N- (2,4-difluorophenyl) -N ′-{4-[(6,7-dimethoxy-4-quinolyl) oxy ] -2-fluorophenyl} -N, N'-diethylurea,
N- (3,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}-
N, N'-diethylurea, N- (3,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N-methylurea N- (2,
4-difluorophenyl) -N '-{4-[(6,7-dimethoxy
-4-Quinolyl) oxy] -2-fluorophenyl} -N-ethylurea, N ′-{4-[(6,7-dimethoxy-4-quinolyl)
Oxy] -2-fluorophenyl} -N-ethyl-N- (4-fluorophenyl) urea, N ′-{4-[(6,7-dimethoxy-
4-quinolyl) oxy] -2-fluorophenyl} -N- (4-fluorophenyl) -N-methylurea, N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl ｝-
N '-(4-fluorophenyl) -N, N'-dimethylurea, N- {4-[(6,7-dimethoxy-4-quinolyl) oxy]-
2-fluorophenyl｝ -N, N'-diethyl-N '-(4-fluorophenyl) urea, N- (2,4-difluorophenyl) -N'-｛4-[(6,7-dimethoxy-4 -Quinolyl) oxy] -2-methoxyphenyl {urea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methoxyphenyl} -N-methylurea,
N- (3,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methoxyphenyl}-
N-methylurea, N- (3,4-difluorophenyl)-
N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-
Methoxyphenyl｝ -N-ethylurea, N '-｛4-[(6,
7-dimethoxy-4-quinolyl) oxy] -2-methoxyphenyl {-N-methyl-N- (4-fluorophenyl) urea,
N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-
Methoxyphenyl {-N-ethyl-N- (4-fluorophenyl) urea, N- (3,4-difluorophenyl) -N'-
{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N-methylurea, N- (2,4-difluorophenyl) -N ′-{4-[(6,7 -Dimethoxy-4-quinolyl)
[Oxy] -2-methylphenyl} -N-methylurea, N-
(2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N-ethylurea, N'-(2,4-difluorophenyl ) -N-
{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N-methylurea, N- (2,4-difluorophenyl) -N ′-{4-[(6,7 -Dimethoxy-4-quinolyl)
Oxy] -2-methylphenyl {-N, N'-diethylurea, N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N-ethyl-N- (4-fluorophenyl) -urea, and N '-(2,4-difluorophenyl) -N- {4-[(6,7-dimethoxy-4-quinolyl) oxy]
Phenyl｝ -N-ethylurea.

A further preferred class of compounds according to the invention includes the following compounds: N- (2,4-difluorophenyl) -N '-｛4-[(6,7-dimethoxy-4-quinolyl) Oxy] -2-fluorophenyl} -N-methylurea, N '-(2,4-difluorophenyl) -N- {4-
[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N-ethylurea, N-benzyl-N-
(2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}
Urea, N '-(2,4-difluorophenyl) -N- ｛4-
[(6,7-Dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N-methylurea, N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl ｝ -N-ethyl-N- (4-fluorophenyl) urea, N- (2,4-difluorophenyl) -N ′-｛4-[(6,
7-dimethoxy-4-quinolyl) oxy] -2-methylphenyl｝ -N-ethylurea, N- (2,4-difluorophenyl) -N '-｛4-[(6,7-dimethoxy-4-quinolyl)
[Oxy] -2-fluorophenyl} -N-isopropylurea, N- (2,4-difluorophenyl) -N ′-{4-
[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N, N'-dimethylurea, N- (2,4-
Difluorophenyl) -N '-｛4-[(6,7-dimethoxy-4
-Quinolyl) oxy] -2-methoxyphenyl} -N-methylurea, N ′-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methoxyphenyl} -N-ethyl-N- ( Four-
Fluorophenyl) urea, N- (2,4-difluorophenyl) -N '-｛4-[(6,7-dimethoxy-4-quinolyl)
Oxy] -2-methylphenyl} -N, N'-diethylurea, and N '-(2,4-difluorophenyl) -N-
{4-[(6,7-Dimethoxy-4-quinolyl) oxy] phenyl} -N-ethylurea.

The compound of the formula (I) can be a pharmaceutically acceptable salt thereof. Preferred examples are salts of alkali metals or alkaline earth metals, such as sodium, potassium or calcium salts, hydrofluorides,
Inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, hydrohalide, nitrate, perchlorate, sulfate, phosphate, etc., methanesulfonate, trifluoromethanesulfone Acid salts, lower alkyl sulfonates such as ethanesulfonate, benzenesulfonate, arylsulfonates such as p-toluenesulfonate, fumarate, succinate, citrate, tartrate, Organic salts such as oxalate, maleate, acetic acid, malic acid, lactic acid, and ascorbic acid, and amino acid salts such as glycine, phenylalanine, glutamate and aspartate are included.

The compounds of the general formula (I) can also be solvates (eg hydrates).

Preparation of Compound The compound of the present invention can be prepared, for example, according to the following scheme.

[0024]

Embedded image The required starting materials for the compounds of the present invention are commercially available or
Or it is easily manufactured by a conventional method. For example, a 4-chloroquinoline derivative is disclosed in Org. Synth. Col. Vol. 3, 272 (1
955), Acta Chim. Hung., 112, 241 (1983) and the like.

The above-mentioned quinolone derivative, which is an intermediate, can also be produced by reacting a formic ester with an o-aminoacetophenone derivative in an aprotic solvent in the presence of a suitable base and then adding a protic solvent. it can.

Next, a 4-chloroquinoline derivative is allowed to act on nitrophenol in a suitable solvent or in the absence of a solvent to synthesize a 4- (nitrophenoxy) quinoline derivative. Dimethylformamide)
Stirring under a hydrogen atmosphere in the presence of a catalyst (eg, palladium hydroxide-carbon) gives a 4- (aminophenoxy) quinoline derivative. The compound of the present invention can be produced by treating these with an isocyanate derivative according to a known method, or by treating with an aniline derivative after treatment with triphosgene.

The compound having a substituent on the urea moiety can be produced, for example, according to the following scheme.

[0028]

Embedded image An appropriate aniline compound is converted into an amide derivative by the action of an acid chloride or an acid anhydride in the presence of a base and then reduced (for example, using lithium aluminum hydride), or imine is formed by the action of an aldehyde or ketone. An N-monosubstituted aniline compound is produced by subsequent reduction (for example, using sodium cyanoborohydride or the like) and then treated with an isocyanate derivative in accordance with a known method, or another N-unsubstituted compound treated with triphosgene. The compound of the present invention can be produced by acting an aniline compound. Alternatively, the urea derivative can be produced by reacting an appropriate alkylating agent in the presence of a base.

Use of Compound / Pharmaceutical Composition The compound according to the present invention has an inhibitory effect on vascular blood flow in a diseased site, particularly on a tumor mass (see Test Examples described later).
Here, since an increase in vascular blood flow at a diseased site can be used as an indicator of angiogenesis at a diseased site, suppression of vascular blood flow at a diseased site can be evaluated as suppression of angiogenesis. Therefore, the compounds according to the present invention have an anti-angiogenic effect.

In addition, angiogenesis at a diseased site is deeply linked mainly to diseases such as tumor, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, Kaposi's sarcoma, and metastasis of solid cancer. (Forkma
n, J. Nature Med. 1: 27-31 (1995); Bicknell, R., Ha
rris, AL Curr. Opin. Oncol. 8: 60-65 (1996)).

The compound according to the present invention also has a tumor growth inhibitory effect upon in vivo administration (see the test examples described later). The compounds according to the invention furthermore have the effect of inhibiting arthritis induced by type II collagen and DTH
It has a reaction-suppressing action (see Test Examples described later).

Accordingly, the compounds according to the present invention can be used for diseases requiring suppression of vascular blood flow or suppression of angiogenesis (eg tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, Kaposi Sarcoma, and metastasis of solid cancer).

According to another aspect of the present invention there is provided a pharmaceutical composition comprising a compound according to the present invention. The pharmaceutical composition according to the present invention can be used for treatment of tumor, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, Kaposi's sarcoma, solid cancer and the like.

The pharmaceutical composition containing the compound of the present invention as an active ingredient can be administered orally or parenterally (for example, intravenous administration, intramuscular administration, subcutaneous administration, rectal administration, transdermal administration), It can be administered to humans and non-human animals. Therefore, the pharmaceutical composition containing the compound according to the present invention as an active ingredient is in an appropriate dosage form depending on the administration route.

Specifically, the oral preparations include tablets, capsules, powders, granules and syrups, and the parenteral preparations include injections, suppositories, tapes, ointments and the like. It is.

These various preparations can be produced by a conventional method using commonly used excipients, disintegrants, binders, lubricants, coloring agents, diluents and the like.

As the excipient, for example, lactose, glucose,
Corn starch, sorbitol, crystalline cellulose, etc.
Disintegrators include, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin, and the like, and binders such as dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose , Polyvinylpyrrolidone and the like, and examples of the lubricant include talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil and the like.

[0038] The above-mentioned injection may optionally contain a buffer,
It can be produced by adding a pH adjuster, a stabilizer, an isotonic agent, a preservative and the like.

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

The dose is appropriately determined depending on the individual case in consideration of the patient's age, weight, sex, difference in disease, degree of symptoms, etc., for example, 0.1 to 100 mg / kg,
It is preferably in the range of 1 to 50 mg / kg,
Administer once or several times a day.

[0041]

The present invention will be described below with reference to the following examples, but the present invention is not limited to these examples.

Example 1 N- (2,4-difluorophene)
Nil) -N '-{4-[(6,7-dimethoxy-4-ki
Noryl) oxy] -2-fluorophenyl {urea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Fluoroaniline (2.00 g) was added to toluene (2
Then, 2,4-difluorophenyl isocyanate (1.97 g) was added, and the mixture was heated under reflux for 7 hours. The reaction solution was filtered by suction, and the title compound was purified by 2.5.
2 g, 84% yield. ¹ H-NMR (DMSO-d ₆ , 400 MHz): δ
3.94 (s, 3H), 3.95 (s, 3H), 6.5
5 (d, J = 5.1 Hz, 1H), 7.04-7.12
(M, 2H), 7.30-7.37 (m, 2H), 7.
40 (s, 1H), 7.49 (s, 1H), 8.10 −
8.16 (m, 1H), 8.23-8.31 (m, 1
H), 8.49 (d, J = 5.1 Hz, 1H), 8.9
9 (s, 1H), 9.05 (s, 1H) Mass spectrometry (FD-MS, m / z): 469 (M ⁺ )

Example 2 N '-{4-[(6,7-dimethyl
Toxi-4-quinolyl) oxy] -2-fluorophenyl
} -N- (4-fluorophenyl) -N-methylure
A 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Fluoroaniline (80 mg) was dissolved in toluene (8 m
l) and dissolved in triethylamine (1.0 ml) with heating, triphosgene (78 mg) dissolved in dichloromethane (1.0 ml) was added, and the mixture was heated under reflux for 5 minutes. Then N
-(4-Fluorophenyl) -N-methylamine (70
mg), and the mixture was further heated under reflux for 1 hour. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate.
The residue obtained by distilling off the solvent under reduced pressure was treated with chloroform /
Purification by silica gel chromatography developed with acetone (2/1) gave 97 mg of the title compound, yield 8
Obtained at 3%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.35 (s, 3H), 4.03 (s, 3
H), 4.05 (s, 3H), 6.42 (d, J = 3.
2 Hz, 1 H), 6.46 (d, J = 5.1 Hz, 1
H), 6.87 (dd, J = 2.7, 11.2 Hz, 1
H), 6.95-7.00 (m, 1H), 7.18-
7.23 (m, 2H), 7.35-7.39 (m, 2
H), 7.44 (s, 1H), 7.49 (s, 1H),
8.24 (t, J = 8.8 Hz, 1H), 8.48
(D, J = 5.1 Hz, 1H) Mass spectrometry value (FD-MS, m / z): 465 (M ⁺ )

Example 3 N- (2,4-difluorophene)
Nil) -N ′-{4-[(6,7-dimethoxy-4-ki
Noryl) oxy] -2-fluorophenyl {-N-methyl
Luurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-fluoroaniline (500 mg) was added to toluene (5
0 ml) and triethylamine (1.0 ml) under heating, and triphosgene (237 mg) dissolved in dichloromethane (1.0 ml) was added, followed by heating under reflux for 5 minutes.
Next, N- (2,4-difluorophenyl) -N-methylamine (284 mg) was added, and the mixture was further heated under reflux for 8 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution,
The mixture was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure,
Purify by silica gel chromatography, eluting with chloroform / acetone (2/1) to give the title compound in 4%.
80 mg was obtained in a yield of 62%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.32 (s, 3H), 4.03 (s, 3)
H), 4.04 (s, 3H), 6.42 (d, J = 3.
2 Hz, 1 H), 6.47 (d, J = 5.1 Hz, 1
H), 6.89 (dd, J = 2.7, 11.5 Hz, 1
H), 6.96-7.06 (m, 3H), 7.40-
7.45 (m, 2H), 7.49 (s, 1H), 8.2
1 (t, J = 8.8 Hz, 1H), 8.48 (d, J =
5.4 Hz, 1 H) Mass spectrometry value (FD-MS, m / z): 483 (M ⁺ )

Example 4 N- (3,4-difluorophene)
Nil) -N '-{4-[(6,7-dimethoxy-4-ki
Noryl) oxy] -2-fluorophenyl {-N-methyl
Luurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Fluoroaniline (80 mg) was added to toluene (4 m
l) and dissolved in triethylamine (0.8 ml) with heating, triphosgene (83 mg) dissolved in dichloromethane (0.8 ml) was added, and the mixture was heated under reflux for 5 minutes. Then N
-(3,4-Difluorophenyl) -N-methylamine (43 mg) was added, and the mixture was further heated under reflux for 5.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure,
Purification by thin layer silica gel chromatography developed with chloroform / acetone (8/1) gave 74 mg of the title compound in 61% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.36 (s, 3H), 4.05 (s, 3
H), 4.07 (s, 3H), 6.45 (d, J = 3.
4Hz, 1H), 6.52 (d, J = 5.6Hz, 1
H), 6.91 (dd, J = 2.7, 11.2 Hz,
1H), 6.97-7.02 (m, 1H), 7.13-
7.18 (m, 1H), 7.21 to 7.36 (m, 2
H), 7.51 (s, 1H), 7.58 (s, 1H),
8.25 (t, J = 9.0 Hz, 1H), 8.49
(D, J = 5.4 Hz, 1H) Mass spectrometry (FD-MS, m / z): 483 (M ⁺ )

Example 5 N '-{4-[(6,7-dimethyl
Toxi-4-quinolyl) oxy] -2-fluorophenyl
Ru-N-ethyl-N- (4-fluorophenyl) uree
A 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Fluoroaniline (80 mg) was added to toluene (5 m
l) and dissolved in triethylamine (0.8 ml) with heating, triphosgene (83 mg) dissolved in dichloromethane (0.8 ml) was added, and the mixture was heated under reflux for 5 minutes. Then N
-Ethyl-N- (4-fluorophenyl) amine (42
mg), and the mixture was further heated under reflux for 3 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography, developing with chloroform / acetone (8/1), to obtain the title compound (63 m).
g, 53% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.20 (t, J = 7.1 Hz, 3H);
80 (q, J = 7.1 Hz, 2H), 4.04 (s,
3H), 4.07 (s, 3H), 6.30 (d, J =
3.4 Hz, 1 H), 6.49 (d, J = 5.4 Hz,
1H), 6.87 (dd, J = 2.7, 11.2H
z, 1H), 6.96-7.00 (m, 1H), 7.2
0-7.28 (m, 2H), 7.32-7.36 (m,
2H), 7.51 (s, 1H), 7.55 (s, 1
H), 8.28 (t, J = 9.0 Hz, 1H), 8.4
8 (d, J = 5.4 Hz, 1 H) Mass spectrometry (FD-MS, m / z): 479 (M ⁺ )

Example 6 N- (3,4-difluorophene)
Nil) -N '-{4-[(6,7-dimethoxy-4-ki
Noryl) oxy] -2-fluorophenyl {-N-ethyl
Luurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Fluoroaniline (80 mg) was added to toluene (5 m
l) and dissolved in triethylamine (0.8 ml) with heating, triphosgene (83 mg) dissolved in dichloromethane (0.8 ml) was added, and the mixture was heated under reflux for 5 minutes. Then N
-(3,4-Difluorophenyl) -N-ethylamine (47 mg) was added, and the mixture was further heated under reflux for 2.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure,
Purification by thin-layer silica gel chromatography developed with chloroform / acetone (4/1) gave 82 mg of the title compound in 66% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.20 (t, J = 7.1 Hz, 3H);
80 (q, J = 7.1 Hz, 2H), 4.04 (s, 3
H), 4.06 (s, 3H), 6.30 (d, J = 3.
2 Hz, 1 H), 6.48 (d, J = 5.4 Hz, 1
H), 6.89 (dd, J = 2.4, 11.2 Hz,
1H), 6.96-7.00 (m, 1H), 7.12-
7.16 (m, 1H), 7.18-7.37 (m, 2
H), 7.48 (s, 1H), 7.50 (s, 1H),
8.23 (t, J = 9.0 Hz, 1H), 8.48
(D, J = 5.6 Hz, 1H) Mass spectrometry value (FD-MS, m / z): 497 (M ⁺ )

Example 7 N- (2,4-difluorophene)
Nil) -N '-{4-[(6,7-dimethoxy-4-ki
Noryl) oxy] -2-fluorophenyl {-N-iso
Propylurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Fluoroaniline (80 mg) was added to toluene (5 m
l) and dissolved in triethylamine (0.8 ml) with heating, triphosgene (83 mg) dissolved in dichloromethane (0.8 ml) was added, and the mixture was heated under reflux for 5 minutes. Then N
-(2,4-Difluorophenyl) -N-isopropylamine (48 mg) was added, and the mixture was further heated under reflux for 5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure,
Purification by thin layer silica gel chromatography developed with chloroform / acetone (4/1) gave 57 mg of the title compound in 45% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.15 (d, J = 6.6 Hz, 6H),
4.05 (s, 3H), 4.07 (s, 3H), 4.8
6-4.97 (m, 1H), 6.12 (d, J = 3.
4 Hz, 1 H), 6.51 (d, J = 5.6 Hz, 1
H), 6.87 (dd, J = 2.7, 11.2 Hz,
1H), 6.95-7.01 (m, 1H), 7.03-
7.10 (m, 2H), 7.23-7.36 (m, 1
H), 7.51 (s, 1H), 7.60 (s, 1H),
8.27 (t, J = 8.8 Hz, 1H), 8.48 (d,
J = 5.6 Hz, 1H) Mass spectrometry (FD-MS, m / z): 511 (M ⁺ )

Example 8 N-benzyl-N- (2,4-
Difluorophenyl) -N '-{4-[(6,7-dim
Toxi-4-quinolyl) oxy] -2-fluorophenyl
Ruurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Fluoroaniline (80 mg) was added to toluene (4 m
l) and dissolved in triethylamine (0.8 ml) with heating, triphosgene (83 mg) dissolved in dichloromethane (0.5 ml) was added, and the mixture was heated under reflux for 5 minutes. Then N
-Benzyl-N- (2,4-difluorophenyl) amine (62 mg) was added, and the mixture was further heated under reflux for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developing with chloroform / acetone (10/1) to obtain the title compound (42 mg, yield 30%).

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 4.04 (s, 3H), 4.05 (s, 3)
H), 4.90 (brs, 2H), 6.35 (d, J =
5.4 Hz, 1 H), 6.47 (d, J = 2.7 H)
z, 1H), 6.86-6.94 (m, 2H), 6.9
4-7.04 (m, 2H), 7.04-7.16 (m,
1H), 7.16-7.34 (m, 5H), 7.46.
(S, 1H), 7.50 (s, 1H), 8.28 (t,
J = 9.0 Hz, 1H), 8.49 (d, J = 5.4H)
z, 1H) Mass spectrometry value (FD-MS, m / z): 559 (M ⁺ )

Example 9 N- (2-chlorobenzyl)-
N- (2,4-difluorophenyl) -N '-{4-
[(6,7-dimethoxy-4-quinolyl) oxy] -2
Magnesium sulfate (963 mg) and a small amount of acetic acid were added to methanol (10 ml) in which -fluorophenyl diurea 2,4-difluoroaniline (516 mg) and 2-chlorobenzaldehyde (562 mg) were dissolved, and the mixture was stirred at room temperature overnight. Sodium borohydride (454 mg) was added under ice cooling, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction solution, extracted with dichloromethane,
Dry over anhydrous sodium sulfate. By evaporating the solvent under reduced pressure, N- (2-chlorobenzyl) -N- (2,
252 mg of 4-difluorophenyl) amine were obtained. 4
-[(6,7-dimethoxy-4-quinolyl) oxy]-
2-Fluoroaniline (126 mg) was added to toluene (10
ml) and triethylamine (1 ml), and then dissolved in a small amount of dichloromethane.
31 mg) and heated under reflux for 5 minutes. Next, N- (2-chlorobenzyl) -N- (2,4-difluorophenyl) amine (122 mg) obtained above was added, and the mixture was further heated under reflux for 10 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developing with chloroform / acetone (5/1) to obtain the title compound (75 mg, yield 32%).

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.92 (s, 3H), 3.95 (s, 3)
H), 4.95 (s, 2H), 6.55 (d, J = 5.
4Hz, 1H), 7.05-7.12 (m, 2H),
7.22-7.40 (m, 6H), 7.41 (s, 1
H), 7.47 (s, 1H), 7.50-7.54.
(M, 2H), 8.13 (s, 1H), 8.52 (d,
J = 5.4 Hz, 1H) Mass spectrometry value (FD-MS, m / z): 593 (M ⁺ )

Example 10 N- (4-chlorobenzyl)
-N- (2,4-difluorophenyl) -N '-{4-
[(6,7-dimethoxy-4-quinolyl) oxy] -2
-Methoxysulfate (929 mg) and a small amount of acetic acid were added to methanol (8 ml) in which -fluorophenyl diurea 2,4-difluoroaniline (0.39 ml) and 4-chlorobenzaldehyde (544 mg) were dissolved, and the raw materials disappeared at room temperature. Until it is stirred.
Sodium borohydride (441 mg) was added under ice cooling,
Stir at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was distilled off with hexane / acetone (10%).
Purification by silica gel chromatography developed with 0/1), N- (4-chlorobenzyl) -N- (2,
500 mg of 4-difluorophenyl) amine, yield 5
Obtained at 1%. 4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluoroaniline (80 mg) is dissolved in toluene (5 ml) and triethylamine (0.8 ml) by heating, and then dissolved in dichloromethane (0.8 ml). Triphosgene (83 mg) was added and the mixture was heated under reflux for 5 minutes. Next, the N- (4-chlorobenzyl)-obtained above
N- (2,4-difluorophenyl) amine (76 m
g) was added, and the mixture was further heated under reflux for 4 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate.
The residue obtained by distilling off the solvent under reduced pressure was treated with chloroform /
Purification by thin-layer silica gel chromatography developed with acetone (4/1) gave 58 mg of the title compound in 39% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 4.04 (s, 3H), 4.05 (s, 3)
H), 4.86 (brs, 2H), 6.33 (d, J =
3.4 Hz, 1 H), 6.47 (d, J = 5.1 H)
z, 1H), 6.86-7.04 (m, 4H), 7.
07-7.14 (m, 1H), 7.19-7.30
(M, 4H), 7.47 (s, 1H), 7.49 (
s, 1H), 8.25 (d, J = 8.8 Hz, 1
H), 8.49 (d, J = 5.1 Hz, 1H) Mass spectrometry (FD-MS, m / z): 593 (M ⁺ ).

Example 11 N '-(2,4-difluoro
Phenyl) -N- {4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-fluorophenyl} -N-meth
After dissolving tylurea N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N-methylamine (64 mg) in toluene (6 ml),
2,4-difluorophenyl isocyanate (0.1 m
l) was added and the mixture was heated under reflux for 80 minutes. The reaction solution was purified by silica gel chromatography developed with hexane / acetone / dichloromethane (4/3/1) to give the title compound (95 mg, yield 100%).

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.35 (s, 3H), 4.04 (s, 3
H), 4.07 (s, 3H), 6.32 (d, J = 2.
9 Hz, 1 H), 6.66 (d, J = 5.4 Hz, 1
H), 6.75-6.89 (m, 2H), 7.06-
7.13 (m, 2H), 7.44 (s, 1H), 7.4
8 (s, 1H), 7.44-7.50 (m, 1H),
8.05-8.13 (m, 1H), 8.60 (d, J =
5.1 Hz, 1H) Mass spectrometry value (FD-MS, m / z): 483 (M ⁺ )

Example 12 N '-(2,4-difluoro
Phenyl) -N- {4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-fluorophenyl} -N-E
After dissolving tylurea N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N-ethylamine (80 mg) in toluene (7 ml),
2,4-difluorophenyl isocyanate (0.1 m
l) was added and the mixture was refluxed for 17 hours. Hexane /
Purification by silica gel chromatography developed with acetone / dichloromethane (4/3/1) gave 36 mg of the title compound in 32% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.22 (t, J = 7.1 Hz, 3H);
80 (q, J = 7.1 Hz, 2H), 4.03 (s, 3
H), 4.07 (s, 3H), 6.24 (d, J = 2.
9 Hz, 1 H), 6.65 (d, J = 5.1 Hz, 1
H), 6.73-6.87 (m, 2H), 7.07-
7.13 (m, 2H), 7.43 (s, 1H), 7.4
5 (s, 1H), 7.42-7.46 (m, 1H),
8.05-8.13 (m, 1H), 8.59 (d, J =
5.1 Hz, 1H) Mass spectrometry value (FD-MS, m / z): 497 (M ⁺ )

Example 13 N- {4-[(6,7-dimethyl
Toxi-4-quinolyl) oxy] -2-fluorophenyl
Ru-N '-(4-fluorophenyl) -N, N'-di
Methylurea N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N '-(4-fluorophenyl) urea (289 mg) was converted to N, N-dimethylformamide (2 ml). After the temperature was adjusted to 0 ° C., sodium hydride (60 wt%, 23 mg) was added, and the mixture was stirred at room temperature for 1 hour. Next, methyl iodide (0.038 ml)
Was added and further stirred at room temperature for 10 minutes. Water was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography, developing with chloroform / methanol (50/1), to obtain the title compound (101 mg, yield 73%).

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.20 (s, 3H), 3.24 (s, 3
H), 4.04 (s, 3H), 4.06 (s, 3H),
6.32 (d, J = 5.1 Hz, 1H), 6.65 −
6.76 (m, 2H), 6.87-6.98 (m, 5
H), 7.44 (s, 1H), 7.44 (s, 1H),
8.56 (d, J = 5.4 Hz, 1H) Mass spectrometry (FD-MS, m / z): 479 (M ⁺ )

Example 14 N- (2,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-fluorophenyl} -N,
N'-dimethylurea N- (2,4-difluorophenyl) -N '-{4-
[(6,7-dimethoxy-4-quinolyl) oxy] -2
-Fluorophenyldiurea (193 mg) was added to N, N-
After dissolving in dimethylformamide (2 ml) and adjusting to 0 ° C., sodium hydride (60 wt%, 31 mg) was added, and the mixture was stirred at room temperature for 1 hour. Next, methyl iodide (0.04
8 ml), and the mixture was further stirred at room temperature for 10 minutes. Water was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to chloroform / methanol (50
The residue was purified by thin-layer silica gel chromatography developed in (1) to give 75 mg of the title compound in a yield of 78%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.18 (s, 3H), 3.20 (s, 3
H), 4.06 (s, 3H), 4.08 (s, 3H),
6.40 (d, J = 5.6 Hz, 1H), 6.63 −
6.81 (m, 4H), 6.96-7.05 (m, 2
H), 7.45 (s, 1H), 7.54 (s, 1H),
8.56 (d, J = 5.4 Hz, 1H) Mass spectrometry (FD-MS, m / z): 497 (M ⁺ )

Example 15 N- {4-[(6,7-dimethyl
Toxi-4-quinolyl) oxy] -2-fluorophenyl
Ru-N, N'-diethyl-N '-(4-fluorophene
Nyl) urea N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N '-(4-fluorophenyl) urea (37 mg) was treated with N, N-dimethylformamide ( 1 ml), brought to 0 ° C., added sodium hydride (60 wt%, 13 mg), and added 1 ml at room temperature.
Stirred for hours. Next, ethyl iodide (20 μl) was added, and the mixture was further stirred at room temperature for 10 minutes. Water was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography developed with chloroform / methanol (50/1),
36 mg of the title compound were obtained in a yield of 88%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.13-1.19 (m, 6H), 3.58-
3.69 (m, 4H), 4.05 (s, 3H), 4.0
6 (s, 3H), 6.35 (d, J = 5.4 Hz, 1
H), 6.65-6.73 (m, 2H), 6.80-
6.90 (m, 5H), 7.44 (s, 1H), 7.4
5 (s, 1H), 8.57 (d, J = 5.1 Hz, 1
H) Mass spectrometry value (FD-MS, m / z): 507 (M ⁺ )

Example 16 N- (2,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-fluorophenyl} -N,
N'-diethylurea N- (2,4-difluorophenyl) -N '-{4-
[(6,7-dimethoxy-4-quinolyl) oxy] -2
-Fluorophenyl diurea (100 mg) was added to N, N-
After dissolving in dimethylformamide (2 ml) and adjusting the temperature to 0 ° C., sodium hydride (60 wt%, 15 mg) was added, and the mixture was stirred at room temperature for 1 hour. Next, ethyl iodide (51μ)
l) was added, and the mixture was further stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developing with chloroform / acetone (5/1) to obtain the title compound (66 mg, yield 60%).

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.12-1.19 (m, 6H), 3.56
-3.64 (m, 4H), 4.05 (s, 3H), 4.
07 (s, 3H), 6.41 (d, J = 5.4 Hz, 1
H), 6.64-6.77 (m, 4H), 6.88-
6.94 (m, 2H), 7.45 (s, 1H), 7.4
9 (s, 1H), 8.57 (d, J = 5.4 Hz, 1
H) Mass spectrometry value (FD-MS, m / z): 525 (M ⁺ )

Example 17 N- (3,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-fluorophenyl} -N,
N'-diethylurea N- (3,4-difluorophenyl) -N '-{4-
[(6,7-dimethoxy-4-quinolyl) oxy] -2
-Fluorophenyl diurea (110 mg) was added to N, N-
After dissolving in dimethylformamide (2 ml) and adjusting the temperature to 0 ° C., sodium hydride (60 wt%, 25 mg) was added, and the mixture was stirred at room temperature for 10 minutes. Next, ethyl iodide (60 μ
l) was added and the mixture was further stirred at room temperature for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography, developing with hexane / acetone (1/1), to give the title compound (60 mg, yield 49%).
I got it.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.10-1.18 (m, 6H), 3.57-
3.65 (m, 4H), 4.02 (s, 3H), 4.0
5 (s, 3H), 6.34 (d, J = 5.4 Hz, 1
H), 6.58-6.74 (m, 4H), 6.83-
6.89 (m, 1H), 6.91-7.00 (m, 1
H), 7.42 (s, 1H), 7.50 (s, 1H),
8.55 (d, J = 5.1 Hz, 1H) Mass spectrometry (FD-MS, m / z): 525 (M ⁺ )

Example 18 N- (2,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4
-Quinolyl) oxy] -2-methylphenyl} -N-meth
Cylurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methylaniline (200 mg) was added to toluene (10
ml) and triethylamine (2 ml) under heating, and triphosgene (211 mg) dissolved in dichloromethane (0.5 ml) was added, followed by heating under reflux for 5 minutes. Next, N- (2,4-difluorophenyl) -N-methylamine (277 mg) was added, and the mixture was further heated under reflux for 1 hour. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developing with chloroform / acetone (2/1) to obtain the title compound.
7 mg was obtained with a yield of 82%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 2.02 (s, 3H), 3.32 (s, 3
H), 4.05 (s, 3H), 4.07 (s, 3H),
5.96 (s, 1H), 6.49 (d, J = 5.6H)
z, 1H), 6.94-6.96 (m, 1H), 7.0.
1-7.09 (m, 3H), 7.42-7.49 (m,
1H), 7.55 (s, 1H), 7.58 (s, 1
H), 7.86 (d, J = 8.8 Hz, 1H), 8.4
5 (d, J = 5.6 Hz, 1H) Mass spectrometry value (FD-MS, m / z): 479 (M ⁺ )

Example 19 N- (3,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-methylphenyl} -N-methyl
Luurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methylaniline (80 mg) was dissolved in toluene (4 m
l) and dissolved in triethylamine (0.8 ml) with heating, triphosgene (84 mg) dissolved in dichloromethane (0.5 ml) was added, and the mixture was heated under reflux for 5 minutes. next,
N- (3,4-Difluorophenyl) -N-methylamine (40 mg) was added, and the mixture was further heated under reflux for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developing with chloroform / acetone (3/1) to obtain the title compound (78 mg, yield 63%).

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 2.01 (s, 3H), 3.36 (s, 3H),
4.05 (s, 3H), 4.07 (s, 3H), 6.0
5 (s, 1H), 6.48 (d, J = 5.4 Hz, 1
H), 6.95 (d, J = 2.7 Hz, 1H), 7.03
(Dd, J = 2.7, 8.5 Hz, 1H), 7.10−
7.40 (m, 3H), 7.55 (s, 1H), 7.5
6 (s, 1H), 7.89 (d, J = 8.8 Hz, 1
H), 8.45 (d, J = 5.6 Hz, 1H) Mass spectrometry (FD-MS, m / z): 479 (M ⁺ )

Example 20 N- (4-fluorophenyl)
Ru) -N '-{4-[(6,7-dimethoxy-4-quino
Lyl) oxy] -2-methylphenyl} -N-ethyl
Rare 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methylaniline (93 mg) was dissolved in toluene (10 m
1) After heating and dissolving in triethylamine (1 ml),
Triphosgene dissolved in a small amount of dichloromethane (98 m
g) was added and the mixture was heated under reflux for 5 minutes. Next, N-ethyl-
N- (4-Fluorophenyl) amine (50 mg) was added, and the mixture was further heated under reflux for 8 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developing with chloroform / acetone (5/1) to give the title compound (99 mg, yield 69%).
I got it.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.07 (t, J = 7.1 Hz, 3H);
07 (s, 3H), 3.68 (q, J = 7.1 Hz, 2
H), 3.92 (s, 3H), 3.94 (s, 3H),
6.42 (d, J = 5.4 Hz, 1H), 7.00 −
7.07 (m, 2H), 7.21 (s, 1H), 7.2
7-7.46 (m, 5H), 7.48 (s, 1H),
8.47 (d, J = 5.1 Hz, 1H) Mass spectrometry value (FD-MS, m / z): 475 (M ⁺ )

Example 21 N- (2,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-methylphenyl {-N-ethyl
Luurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methylaniline (100 mg) was dissolved in toluene (8 m
1) After heating and dissolving in triethylamine (1 ml),
Triphosgene (1) dissolved in dichloromethane (1 ml)
05 mg) and heated under reflux for 5 minutes. Then N-
(2,4-Difluorophenyl) -N-ethylamine (60 mg) was added, and the mixture was further heated under reflux for 13 hours.
To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography, developing with chloroform / acetone (5/1), to obtain the title compound.
0 mg was obtained in a yield of 44%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.12 (t, J = 7.1 Hz, 3H), 1.
92 (s, 3H), 3.71 (q, J = 7.1 Hz, 2
H), 3.97 (s, 3H), 3.98 (s, 3H),
5.79 (s, 1H), 6.38 (d, J = 5.4H
z, 1H), 6.86 (d, J = 2.7 Hz, 1H),
6.92-7.03 (m, 3H), 7.30-7.38
(M, 1H), 7.40 (s, 1H), 7.47 (s,
1H), 7.78 (d, J = 8.8 Hz, 1H), 8.
38 (d, J = 5.4 Hz, 1 H) Mass spectrometry value (FD-MS, m / z): 493 (M ⁺ )

Example 22 N '-(2,4-difluoro
Phenyl) -N- {4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-methylphenyl} -N-methyl
Luurea N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N-methylamine (8
0 mg) in toluene (8 ml) with heating.
4-Difluorophenyl isocyanate (40 μl) was added, and the mixture was heated under reflux for 5 minutes. The reaction solution was purified by silica gel chromatography developed with hexane / acetone / dichloromethane (4/3/1) to give the title compound as 1
07 mg, 90% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 2.35 (s, 3H), 3.32 (s, 3
H), 4.06 (s, 3H), 4.08 (s, 3H),
6.17 (s, 1H), 6.58 (d, J = 5.4H)
z, 1H), 6.74-6.89 (m, 2H), 7.1
4-7.23 (m, 2H), 7.40 (d, J = 8.3)
Hz, 1H), 7.53 (s, 1H), 7.55 (s,
1H), 8.06-8.14 (m, 1H), 8.56.
(D, J = 5.4 Hz, 1H) Mass spectrometry value (FD-MS, m / z): 479 (M ⁺ )

Example 23 N- (2,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-methylphenyl {-N, N ′
-Diethylurea N- (2,4-difluorophenyl) -N '-{4-
[(6,7-dimethoxy-4-quinolyl) oxy] -2
-Methylphenyl diurea (52 mg) was dissolved in N, N-dimethylformamide (1 ml), the temperature was adjusted to 0 ° C., sodium hydride (60 wt%, 18 mg) was added, and the mixture was stirred at room temperature for 1 hour. Next, ethyl iodide (27 μl) was added, and the mixture was further stirred at room temperature for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography, developing with chloroform / methanol (50/1), to give the title compound (46 mg, yield 79%).

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.05-1.25 (m, 6H), 2.10
(S, 3H), 3.40-3.80 (m, 4H), 4.
05 (s, 3H), 4.06 (s, 3H), 6.38
(D, J = 5.4 Hz, 1H), 6.60-6.92
(M, 6H), 7.45 (s, 1H), 7.50 (s,
1H), 8.54 (d, J = 5.1 Hz, 1H) Mass spectrometry (FD-MS, m / z): 521 (M ⁺ )

Example 24 N- (2,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-methoxyphenyl} urea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methoxyaniline (40 mg) was dissolved in toluene (5 m
After heating and dissolving in 1), 2,4-difluorophenyl isocyanate (30 μl) was added, and the mixture was heated under reflux for 1.5 hours. The residue obtained by evaporating the solvent under reduced pressure was washed with diethyl ether to give the title compound (27 mg, yield 47).
%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.88 (s, 3H), 4.07 (s, 3
H), 4.08 (s, 3H), 6.56 (d, J = 5.
6 Hz, 1 H), 6.75 (d, J = 2.7 Hz, 1
H), 6.79-6.95 (m, 4H), 7.22-
7.29 (m, 1H), 7.58 (s, 1H), 7.5
5 (brs, 1H), 8.00-8.08 (m, 1
H), 8.22 (d, J = 8.8 Hz, 1H), 8.4
8 (d, J = 5.9 Hz, 1 H) Mass spectrometry value (FD-MS, m / z): 481 (M ⁺ )

Example 25 N '-{4-[(6,7-di
Methoxy-4-quinolyl) oxy] -2-methoxyfe
Nil} -N- (4-fluorophenyl) -N-methyl
Rare 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methoxyaniline (80 mg) was dissolved in toluene (5 m
l) and dissolved in triethylamine (0.8 ml) with heating, triphosgene (83 mg) dissolved in dichloromethane (0.8 ml) was added, and the mixture was heated under reflux for 5 minutes. Then N
-(4-Fluorophenyl) -N-methylamine (3
8 mg), and the mixture was further heated under reflux for 5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography, developing with chloroform / acetone (8/1), to obtain the title compound (70 m).
g, 59% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.35 (s, 3H), 3.65 (s, 3)
H), 4.05 (s, 3H), 4.06 (s, 3H),
6.46 (d, J = 5.6 Hz, 1H), 6.62
(D, J = 2.4 Hz, 1H), 6.79 (dd, J
= 2.7, 9.0 Hz, 1H), 6.89 (s, 1
H), 7.17-7.22 (m, 2H), 7.35-
7.38 (m, 2H), 7.49 (s, 1H), 7.5
5 (s, 1H), 8.28 (d, J = 8.8 Hz, 1
H), 8.46 (d, J = 5.4 Hz, 1H) Mass spectrometry (FD-MS, m / z): 477 (M ⁺ )

Example 26 N- (2,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-methoxyphenyl} -N-meth
Cylurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methoxyaniline (75 mg) was added to toluene (10
ml) and triethylamine (0.5 ml) under heating, and triphosgene (65 mg) dissolved in dichloromethane (0.5 ml) was added, followed by heating under reflux for 5 minutes. Next, N- (2,4-difluorophenyl) -N-methylamine (69 mg) was added, and the mixture was further heated under reflux for 1 hour. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developing with chloroform / acetone (2/1) to obtain the title compound (83).
mg, 73% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.36 (s, 3H), 3.70 (s, 3)
H), 4.05 (s, 3H), 4.07 (s, 3H),
6.49 (d, J = 5.6 Hz, 1H), 6.64
(D, J = 2.4 Hz, 1H), 6.80 (dd, J =
2.4, 8.8 Hz, 1H), 6.94 (s, 1H),
7.10-7.18 (m, 1H), 7.20-7.34
(M, 2H), 7.56 (s, 1H), 7.56 (s,
1H), 8.26 (d, J = 8.8 Hz, 1H), 8.
46 (d, J = 5.6 Hz, 1H) Mass spectrometry (FD-MS, m / z): 495 (M ⁺ )

Example 27 N- (3,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-methoxyphenyl {-N-meth
Cylurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methoxyaniline (80 mg) was dissolved in toluene (5 m
l) and dissolved in triethylamine (0.8 ml) with heating, triphosgene (83 mg) dissolved in dichloromethane (0.8 ml) was added, and the mixture was heated under reflux for 5 minutes. Then N
-(3,4-Difluorophenyl) -N-methylamine (43 mg) was added, and the mixture was further heated under reflux for 7 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography, developing with chloroform / acetone (8/1), to obtain the title compound.
mg, 65% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.36 (s, 3H), 3.70 (s, 3)
H), 4.06 (s, 3H), 4.07 (s, 3H),
6.49 (d, J = 5.6 Hz, 1H), 6.64
(D, J = 2.4 Hz, 1H), 6.80 (dd, J
= 2.4, 8.8 Hz, 1H), 6.94 (s, 1
H), 7.14-7.18 (m, 1H), 7.22-
7.29 (m, 2H), 7.56 (s, 2H), 8.2
6 (d, J = 8.8 Hz, 1H), 8.46 (d, J =
5.6 Hz, 1 H) Mass spectrometry value (FD-MS, m / z): 495 (M ⁺ )

Example 28 N '-{4-[(6,7-di
Methoxy-4-quinolyl) oxy] -2-methoxyfe
Nil} -N-ethyl-N- (4-fluorophenyl) u
Rare 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methoxyaniline (80 mg) was added to toluene (10
ml) and triethylamine (2 ml) under heating, and triphosgene (80 mg) dissolved in dichloromethane (0.5 ml) was added, followed by heating under reflux for 5 minutes. Next, N-ethyl-N dissolved in dichloromethane (0.5 ml)
-(4-Fluorophenyl) amine (51 mg) was added, and the mixture was further heated under reflux for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography, developing with chloroform / acetone (2/1), to obtain the title compound (75%).
mg, yield 63%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.19 (t, J = 7.1 Hz, 3H);
63 (s, 3H), 3.81 (q, J = 7.1 Hz, 2
H), 4.04 (s, 3H), 4.05 (s, 3H),
6.44 (d, J = 5.4 Hz, 1H), 6.60
(D, J = 2.7 Hz, 1H), 6.74 (s, 1
H), 6.79 (dd, J = 2.7, 8.8 Hz, 1
H), 7.18-7.24 (m, 2H), 7.31-
7.36 (m, 2H), 7.47 (s, 1H), 7.5
5 (s, 1H), 8.28 (d, J = 8.8 Hz, 1
H), 8.45 (d, J = 5.4 Hz, 1H) Mass spectrometry (FD-MS, m / z): 491 (M ⁺ )

Example 29 N- (3,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-methoxyphenyl {-N-E
Cylurea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methoxyaniline (80 mg) was added to toluene (10
ml) and triethylamine (2 ml) under heating, and triphosgene (80 mg) dissolved in dichloromethane (0.5 ml) was added, followed by heating under reflux for 5 minutes. Next, N- (3,4-
Difluorophenyl) -N-ethylamine (58 mg)
Was added and the mixture was further heated under reflux for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography, developing with chloroform / acetone (2/1) to obtain the title compound (50 mg, yield 40%).

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 2.00 (t, J = 7.1 Hz, 3H);
67 (s, 3H), 3.80 (q, J = 7.1 Hz, 2
H), 4.05 (s, 3H), 4.06 (s, 3H),
6.45 (d, J = 5.4 Hz, 1H), 6.63
(D, J = 2.4 Hz, 1H), 6.77 (s, 1
H), 6.79 (dd, J = 2.4, 8.8 Hz, 1
H), 7.10-7.15 (m, 1H), 7.19-
7.23 (m, 1H), 7.27-7.35 (m, 1
H), 7.47 (s, 1H), 7.55 (s, 1H),
8.24 (d, J = 8.8 Hz, 1H), 8.46
(D, J = 5.4 Hz, 1 H) Mass spectrometry value (FD-MS, m / z): 509 (M ⁺ )

Example 30 N '-(2,4-difluoro
Phenyl) -N- {4-[(6,7-dimethoxy-4-
After quinolyl) oxy] phenyl} -N-ethylurea N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] phenyl} -N-ethylamine (35 mg) was dissolved by heating in toluene (5 ml), 2 , 4-Difluorophenyl isocyanate (30 μl) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and purified by thin-layer silica gel chromatography developed with chloroform / acetone (8/1) to give the title compound (37 mg, yield 69%).

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.23 (t, J = 7.1 Hz, 3H), 3.8
4 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H),
4.07 (s, 3H), 6.24 (d, J = 2.9H)
z, 1H), 6.57 (d, J = 5.1 Hz, 1H),
6.73-6.89 (m, 2H), 7.33 (d, J =
8.8 Hz, 2H), 7.43 (d, J = 8.8 Hz,
2H), 7.49 (s, 1H), 7.53 (s, 1
H), 8.08-8.16 (m, 1H), 8.45.
(D, J = 2.8 Hz, 1 H) Mass spectrometry value (FD-MS, m / z): 479 (M ⁺ )

Production Example 1 6,7-Dimethoxy-4-quino
Ron 2'-amino-4 ', 5'-dimethoxyacetophenone (300 mg) was dissolved in tetrahydrofuran (6 ml), and sodium methylate (250 mg) was added.
Stirred for 0 minutes. Then, ethyl formate (0.5 ml) was added and the mixture was stirred for 150 minutes. After adding water (3 ml) to the reaction solution and stirring for 30 minutes, 10% hydrochloric acid was added to form a precipitate. The precipitate was collected by filtration with a Puchner funnel and washed with water (3 ml).
× 2), and purified by silica gel column chromatography to give 310 mg of the title compound in a yield of 98%.
I got it.

¹ H-NMR (DMSO-d ₆ , 400 M
Hz): δ 3.82 (s, 3H), 3.86 (s, 3)
H), 5.94 (d, J = 7.3 Hz, 1H), 6.9
6 (s, 1H), 7.44 (s, 1H), 7.76
(D, J = 7.3 Hz, 1H), 11.52 (s, 1
H) Mass spectrometry value (FD-MS, m / z): 205 (M ⁺ )

Production Example 2 4-Chloro-6,7-dimethoxy
Shiquinoline 6,7-dimethoxy-4-quinolone (40.0 g) was added to toluene (400 ml), and the mixture was heated under reflux with a Gene Stark trap for 1 hour. Allow to cool to room temperature, remove Gene Stark trap, and add phosphorus oxychloride (25 ml)
Was added and the mixture was refluxed under heating for 2.5 hours. Cool in a water bath and
% Aqueous hydrochloric acid was added and stirred. The mixture was partitioned with a separating funnel, and the aqueous layer was collected. The organic layer was washed with a 10% hydrochloric acid solution, and the first aqueous layer and the washing aqueous layer were combined. Cold water (100 ml) and ice (100 g) were added to the aqueous layer, and a 10% aqueous sodium hydroxide solution was added to adjust the final pH to 10.0. After extraction with chlorobenzene, washing with saturated saline (300 ml, 200 ml), the solvent was removed under reduced pressure, and the residue was dried under reduced pressure to obtain 33.07 g of the title compound in a yield of 83%. ¹ H-NMR (CDCl ₃ , 500 MHz): δ 4.0
5 (s, 3H), 4.07 (s, 3H), 7.36
(D, J = 4.9 Hz, 1H), 7.41 (s, 1
H), 7.43 (s, 1H), 8.59 (d, J = 4.
9Hz, 1H)

Production Example 3 4- (3-fluoro-4-nito)
Lofenoxy) -6,7-dimethoxyquinoline 4-chloro-6,7-dimethoxyquinoline (10.23
g), 3-fluoro-4-nitrophenol (14.3)
7 g) in monochlorobenzene (100 ml),
Heated to reflux overnight. The solvent was distilled off under reduced pressure, and the residue was washed with toluene, filtered and dried. Next, the crystals were suspended in an aqueous sodium hydroxide solution, filtered and dried, and the title compound was dissolved in 1
4.19 g was obtained in a yield of 90%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 4.05 (s, 3H), 4.13 (s, 3)
H), 6.82 (d, J = 5.9 Hz, 1H), 7.1
1-7.18 (m, 2H), 7.42 (s, 1H),
7.87 (s, 1H), 8.27 (t, J = 8.5H
z, 1H), 8.65 (d, J = 5.9 Hz, 1H)

Production Example 4 4-[(6,7-dimethoxy-
4-quinolyl) oxy] -2-fluoroaniline 4- (3-fluoro-4-nitrophenoxy) -6,7
-Dimethoxyquinoline (4.57 g) in ethyl acetate /
N, N-dimethylformamide / triethylamine (1
00ml / 100ml / 20ml), palladium hydroxide (1.14g) was added, and the mixture was dissolved in a hydrogen atmosphere at room temperature.
Stirred overnight. After filtration through celite, the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.27 g of the title compound quantitatively.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 4.06 (s, 3H), 4.07 (s, 3
H), 6.50 (d, J = 5.6 Hz, 1H), 6.8
0-6.96 (m, 3H), 7.53 (s, 1H),
7.55 (s, 1H), 8.48 (d, J = 5.4H
z, 1H)

Production Example 5 4-[(6,7-dimethoxy-
4-quinolyl) oxy] -2-methoxyaniline 4- (3-fluoro-4-nitrophenoxy) -6,7
-Dimethoxyquinoline (3.50 g) was added to methanol (5
00ml) with heat, and potassium carbonate (2.81g)
Was added, and the mixture was stirred for 1 hour with residual heat. The solvent is distilled off under reduced pressure,
A saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was subjected to ethyl acetate / dimethylformamide / triethylamine (2.
00ml / 10ml / 10ml), palladium hydroxide (0.88g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The solvent was distilled off under reduced pressure, chloroform was added to the residue, and the mixture was filtered through Celite. The filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (3.10 g, yield 9).
Obtained at 4%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 3.85 (s, 3H), 4.06 (s, 3
H), 4.07 (s, 3H), 6.49 (d, J = 5.
4Hz, 1H), 6.63-6.67 (m, 2H),
6.75-6.79 (m, 1H), 7.52 (s, 1
H), 7.59 (s, 1H), 8.46 (d, J = 5.
6Hz, 1H)

Production Example 6 4-[(6,7-dimethoxy-
4-quinolyl) oxy] -2-methylaniline 4-chloro-6,7-dimethoxyquinoline (5.00
g), 4-nitro-3-methylphenol (6.85)
g) was suspended in monochlorobenzene (25 ml) and heated under reflux overnight. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate, filtered and dried. Next, the crystals were suspended in an aqueous sodium hydroxide solution, filtered and dried. A portion (1.36 g) of the thus obtained crystal (6.89 g) was subjected to ethyl acetate / dimethylformamide / triethylamine (25%).
ml / 25 ml / 5 ml), palladium hydroxide (0.34 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtration through celite, the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (1.31 g).
Obtained in 91% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 2.21 (s, 3H), 4.05 (s, 6
H), 6.45 (d, J = 5.6 Hz, 1H), 6.7.
4 (d, J = 8.3 Hz, 1H), 6.87 (dd, J
= 2.7, 8.3 Hz, 1H), 6.91 (d, J =
2.7 Hz, 1 H), 8.45 (d, J = 5.4 Hz,
1H)

Production Example 7 N- {4-[(6,7-dimethoate)
[Xy-4-quinolyl) oxy] -2-fluorophenyl
Ru-N-methylamine acetic anhydride (0.18 ml) and formic acid (0.10 ml)
Stirred at 0 ° C. for 120 minutes. 4-[(6,7-Dimethoxy-4-quinolyl) oxy] -2-fluoroaniline (200 mg) was added, and the mixture was stirred at 60 ° C overnight. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with dichloromethane, and the dichloromethane layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (20 ml), lithium aluminum hydride (48 mg) was added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. Under ice-cooling, water and then ethyl acetate were added to the reaction solution, and the mixture was stirred and filtered through celite. The organic layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was chloroform / acetone (2/1/2).
Purification by thin layer silica gel chromatography developed in 1) gave 87 mg of the title compound in 41% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 2.93 (s, 3H), 4.06 (s, 6)
H), 6.46 (d, J = 5.4 Hz, 1H), 6.6.
9-6.76 (m, 1H), 6.85-6.93 (m, 1H)
2H), 7.46 (s, 1H), 7.56 (s, 1
H), 8.47 (d, J = 5.4 Hz, 1H) Mass spectrometry (FD-MS, m / z): 328 (M ⁺ )

Production Example 8 N- {4-[(6,7-dimethoate)
[Xy-4-quinolyl) oxy] -2-fluorophenyl
Ru-N-ethylamine 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Fluoroaniline (813 mg) was dissolved in chloroform / triethylamine (30 ml / 3 ml), acetyl chloride (0.37 ml) was added, and the mixture was stirred at room temperature for 5 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution,
The mixture was extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (20 ml), and lithium aluminum hydride (0.39 g) was added under ice-cooling.
Heated to reflux for 0 minutes. Under ice-cooling, water and then ethyl acetate were added to the reaction solution, and the mixture was stirred and filtered through celite. The organic layer was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developed with hexane / acetone / dichloromethane (2/1/1) to obtain 766 mg of the title compound in a yield of 86%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.34 (t, J = 7.1 Hz, 3H);
20-3.28 (m, 2H), 4.06 (s, 3H),
4.07 (s, 3H), 6.50 (d, J = 5.6H)
z, 1H), 6.71-6.77 (m, 1H), 6.8
6-6.92 (m, 2H), 7.55 (s, 1H),
7.57 (s, 1H), 8.47 (d, J = 5.6H
z, 1H)

Production Example 9 N- {4-[(6,7-dimethoate)
[Xy-4-quinolyl) oxy] -2-methylphenyl}
-N-methylamine acetic anhydride (0.27 ml), formic acid (0.13 ml)
Stirred at 0 ° C. for 90 minutes. There dichloromethane (1m
4-[(6,7-Dimethoxy-4-quinolyl) oxy] -2-methylaniline (300 mg) suspended in 1) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was treated with tetrahydrofuran (2
0 ml), lithium aluminum hydride (0.15 g) was added under ice cooling, and the mixture was refluxed for 4 hours. below freezing,
Water and then ethyl acetate were added to the reaction solution, followed by stirring and filtration through celite. The organic layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was treated with hexane / acetone / dichloromethane (4/2 /
The residue was purified by silica gel chromatography developed in 1) to give 227 mg of the title compound in a yield of 72%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 2.17 (s, 3H), 2.94 (s, 3
H), 4.05 (s, 3H), 4.05 (s, 3H),
6.43 (d, J = 5.4 Hz, 1H), 6.65
(D, J = 8.8 Hz, 1H), 6.91 (d, J =
2.7 Hz, 1 H), 6.99 (dd, J = 2.9,
8.5 Hz, 1H), 7.42 (s, 1H), 7.60
(S, 1H), 8.44 (d, J = 5.1 Hz, 1H)

Production Example 10 N- {4-[(6,7-dimethyl
Toxi-4-quinolyl) oxy] -2-methylphenyi
Ru-N-ethylamine 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methylaniline (400 mg) was added to chloroform /
It was dissolved in triethylamine (5 ml / 2 ml), acetyl chloride (0.19 ml) was added, and the mixture was stirred at room temperature for 5 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (20 ml), and lithium aluminum hydride (0.20 g) was added under ice-cooling.
Heated to reflux for an hour. Under ice-cooling, water and then ethyl acetate were added to the reaction solution, and the mixture was stirred and filtered through celite. The organic layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography, developing with hexane / acetone / dichloromethane (4/2/1), to obtain 263 m of the title compound.
g, 60% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.35 (t, J = 7.1 Hz, 3H);
17 (s, 3H), 3.24 (q, J = 7.1 Hz, 2
H), 4.05 (s, 3H), 4.05 (s, 3H),
6.45 (d, J = 5.4 Hz, 1H), 6.66
(D, J = 8.8 Hz, 1H), 6.91 (d, J =
2.7 Hz, 1 H), 6.96 (dd, J = 2.7,
8.8 Hz, 1H), 7.46 (s, 1H), 7.60
(S, 1H), 8.44 (d, J = 5.4 Hz, 1H)

Production Example 11 N- (2,4-difluorophenyl)
Enyl) -N-methylamine acetic anhydride (11.0 ml) and formic acid (5.84 ml)
Stirred at 0 ° C. for 120 minutes. 2,4-Difluoroaniline (3.94 ml) was added thereto, and the mixture was stirred at room temperature for 280 minutes. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (150 ml), and lithium aluminum hydride (2.94 g) was added under ice-cooling.
Stirred at room temperature for 40 minutes. Under ice-cooling, water and then ethyl acetate were added to the reaction solution, and the mixture was stirred and filtered through celite. The organic layer was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography, developing with hexane / acetone (30/1), to obtain the title compound in 3.4.
8 g, 63% yield.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 2.86 (s, 3H), 6.58-6.65
(M, 1H), 6.74-6.81 (m, 2H)

Production Example 12 N- (2,4-difluorophenyl)
Enyl) -N-ethylamine 2,4-difluoroaniline (645 mg) and methanol (10%) in which acetaldehyde (0.28 ml) was dissolved.
The mixture was added with magnesium sulfate (1.2 g) and a small amount of acetic acid, and stirred under ice-cooling for 45 minutes. Sodium borohydride (570 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the mixture was stirred and filtered through celite. Extract the organic layer with ethyl acetate,
Dry over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography, developing with hexane / acetone / dichloromethane (20/1/1), to give 205 mg of the title compound in a yield of 2
Obtained at 6%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.28 (t, J = 7.3 Hz, 3H);
16 (q, J = 7.3 Hz, 2H), 6.60-6.8
1 (m, 3H)

Production Example 13 N- (2,4-difluorophenyl)
Enyl) -N-isopropylamine 2,4-difluoroaniline (3.00 g) was dissolved in tetrahydrofuran (150 ml), and 3M sulfuric acid /
Acetone / tetrahydrofuran (7.8 ml / 5.1 m
1/40 ml) was added dropwise. Sodium borohydride (2.65 g) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes.
The solvent was distilled off under reduced pressure, saturated sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developing with hexane / acetone / dichloromethane (10/1/1) to obtain 3.24 g of the title compound in a yield of 81%. Was.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.22 (d, J = 6.3 Hz, 6H);
52-3.64 (m, 1H), 6.59-6.67
(M, 1H), 6.71-6.81 (m, 2H)

Production Example 14 N-benzyl-N- (2,4
-Difluorophenyl ) amine 2,4-difluoroaniline (2.37 ml) and methanol (4.36 ml) dissolved with benzaldehyde (2.36 ml)
Magnesium sulfate (5.59 g) and a small amount of acetic acid were added to 6 ml), and the mixture was stirred at room temperature for 45 minutes. Sodium borohydride (2.64 g) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the mixture was stirred and filtered through celite. Extract the organic layer with ethyl acetate,
Dry over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developing with hexane / acetone (30/1) to obtain 3.04 g of the title compound in a yield of 60%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 4.34 (s, 2H), 6.56-6.82
(M, 3H), 7.25-7.38 (m, 5H)

Production Example 15 N- (3,4-difluorophenyl)
Enyl) -N-methylamine acetic anhydride (4.39 ml) and formic acid (2.08 ml) in 6 parts.
Stirred at 0 ° C. for 90 minutes. 3,4-Difluoroaniline (1.54 ml) was added thereto, and the mixture was stirred at room temperature for 10 minutes. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (50 ml), and lithium aluminum hydride (1.18 g) was added under ice-cooling.
Stirred for hours. Under ice-cooling, water and then ethyl acetate were added to the reaction solution, and the mixture was stirred and filtered through celite. The organic layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was distilled off with hexane / ethyl acetate (10%).
The residue was purified by silica gel chromatography developed in (1) to obtain 1.37 g of the title compound in a yield of 62%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 2.80 (s, 3H), 6.25-6.31
(M, 1H), 6.36-6.43 (m, 1H), 6.
92-7.01 (m, 1H)

Production Example 16 N- (3,4-difluorophenyl)
(Enyl) -N-ethylamine 3,4-difluoroaniline (1.00 g) was dissolved in chloroform / triethylamine (10 ml / 2 ml), acetyl chloride (1.11 ml) was added under ice cooling, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (25 ml), and lithium aluminum hydride (0.59
g) was added and stirred for 30 minutes. Under ice-cooling, add water,
Next, ethyl acetate was added, the mixture was stirred, and filtered through Celite. The organic layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was treated with hexane /
Purify by silica gel chromatography, developing with ethyl acetate (10/1) to give the title compound, 0.87 g,
Obtained in a yield of 71%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ1.25 (t, J = 7.1 Hz, 3H);
09 (q, J = 7.1 Hz, 2H), 6.23-6.3.
1 (m, 1H), 6.35-6.44 (m, 1H),
6.90-7.00 (m, 1H)

Production Example 17 N- (4-Fluorophenyl)
) -N-methylamine acetic anhydride (1.27 ml) and formic acid (0.91 ml)
Stirred at 0 ° C. for 90 minutes. 4-Fluoroaniline (0.43 ml) was added thereto, and the mixture was stirred at room temperature for 10 minutes. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (50 ml), lithium aluminum hydride (685 mg) was added under ice cooling, and the mixture was heated under reflux for 5 minutes. Under ice-cooling, water and then ethyl acetate were added to the reaction solution, and the mixture was stirred and filtered through celite. Extract the organic layer with ethyl acetate,
Dry over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography developed with hexane / ethyl acetate (10/1),
The title compound (380 mg, yield 67%) was obtained.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 2.82 (s, 3H), 6.55-6.61
(M, 2H), 6.87-6.95 (m, 2H)

Production Example 18 N-ethyl-N- (4-fur
(Orophenyl) amine 4-fluoroaniline (300 mg) was added to chloroform /
It was dissolved in triethylamine (5 ml / 2 ml), acetyl chloride (0.39 ml) was added, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (10 ml), and lithium aluminum hydride (0.41 g) was added under ice-cooling.
Heated to reflux for 0 minutes. Under ice-cooling, water and then ethyl acetate were added to the reaction solution, and the mixture was stirred and filtered through celite. The organic layer was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography, developing with hexane / acetone / dichloromethane (10/1/1), to obtain 239 mg of the title compound in a yield of 64%.

¹ H-NMR (CDCl ₃ , 400 MH
z): δ 1.26 (t, J = 7.3 Hz, 3H);
13 (q, J = 7.3 Hz, 2H), 6.55-6.6
3 (m, 2H), 6.86-6.93 (m, 2H)

Production Example 19 N- {4-[(6,7-dimethyl
Toxi-4-quinolyl) oxy] -2-fluorophenyl
Ru-N '-(4-fluorophenyl) urea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Fluoroaniline (150 mg) was added to toluene (1
0 ml), and 4-fluorophenyl isocyanate (0.11 ml) was added thereto, followed by heating under reflux for 10 minutes. The precipitated crystals were collected by filtration and dried to give the title compound (163 mg, yield 75%).

¹ H-NMR (DMSO-d ₆ , 400 M
Hz): δ 3.93 (s, 3H), 3.95 (s, 3
H), 6.54 (d, J = 5.1 Hz, 1H), 6.0.
7-7.19 (m, 3H), 7.31-7.36 (m,
1H), 7.40 (s, 1H), 7.45-7.49.
(M, 2H), 7.49 (s, 1H), 8.22 (t,
J = 9.0 Hz, 1H), 8.49 (d, J = 5.1H)
z, 1H), 8.59 (s, 1H), 9.08 (s, 1
H)

Production Example 20 N- (3,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-fluorophenyl} urea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Fluoroaniline (300 mg) was added to toluene (1
5 ml) and triethylamine (3 ml) with heating, and triphosgene (300 mg) dissolved in dichloromethane (0.5 ml) was added, followed by heating under reflux for 5 minutes. Next, 3,4-difluoroaniline (143 mg) was added, and the mixture was further heated under reflux for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography, developing with chloroform / acetone (3/1), to give 290 mg of the title compound, yield 67%.
I got it.

¹ H-NMR (DMSO-d ₆ , 400 M
Hz): δ 3.94 (s, 3H), 3.95 (s, 3
H), 6.55 (d, J = 5.4 Hz, 1H), 7.0.
8-7.15 (m, 2H), 7.32-7.39 (m,
2H), 7.40 (s, 1H), 7.49 (s, 1
H), 7.65-7.73 (m, 1H), 8.19.
(T, J = 9.1 Hz, 1H), 8.50 (d, J =
5.4 Hz, 1H), 8.66 (s, 1H), 9.26
(S, 1H) Mass spectrometry value (FD-MS, m / z): 469 (M ⁺ )

Production Example 21 N- (2,4-difluorophenyl)
Enyl) -N '-{4-[(6,7-dimethoxy-4-
Quinolyl) oxy] -2-methylphenyl} urea 4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-Methylaniline (200 mg) was added to toluene (10
Then, 2,4-difluorophenyl isocyanate (0.15 ml) was added, and the mixture was heated under reflux for 2 hours. The precipitated crystals were collected by filtration and dried to give the title compound (165 mg, yield 56%).

¹ H-NMR (DMSO-d ₆ , 400 M
Hz): δ 2.29 (s, 3H), 3.94 (s, 3)
H), 3.95 (s, 3H), 6.47 (d, J = 5.
1Hz, 1H), 7.04-7.09 (m, 2H),
7.13 (d, J = 2.7 Hz, 1H), 7.27−
7.33 (m, 1H), 7.39 (s, 1H), 7.5
0 (s, 1H), 7.95 (d, J = 8.8 Hz, 1
H), 8.11-8.18 (m, 1H), 8.38
(S, 1H), 8.46 (d, J = 5.1 Hz, 1
H), 8.93 (s, 1H) Mass spectrometry (FD-MS, m / z): 465 (M ^<+> ).

Production Example 22 N- {4-[(6,7-dimension)
Toxi-4-quinolyl) oxy] phenyl} -N-ethyl
Luamine 4-[(6,7-dimethoxy-4-quinolyl) oxy]
Aniline (100 mg) was dissolved in chloroform / triethylamine (6 ml / 0.5 ml), acetyl chloride (50 μl) was added, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (5 ml), lithium aluminum hydride (52 mg) was added under ice cooling, and the mixture was heated under reflux for 4.5 hours. Under ice-cooling, water and then ethyl acetate were added to the reaction solution, and the mixture was stirred and filtered through celite. Extract the organic layer with ethyl acetate,
The ethyl acetate layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by thin-layer silica gel chromatography, developing with chloroform / acetone (2/1), to obtain 52 mg of the title compound in a yield of 47.
%.

¹ H-NMR (DMSO-d ₆ , 400
MHz): δ 1.35 (t, J = 7.2 Hz, 3H),
3.20 (q, J = 7.1 Hz, 2H), 4.06
(S, 6H), 6.45 (d, J = 5.4 Hz, 1
H), 6.67 (d, J = 9.0 Hz, 2H), 7.0.
1 (d, J = 8.8 Hz, 2H), 7.46 (s, 1
H), 7.60 (s, 1H), 8.45 (d, J = 5.
4Hz, 1H)

Production Example 23 4-[(6,7-dimethoxy)
-4-quinolyl) oxy] aniline 4-chloro-6,7-dimethoxyquinoline (1.84
g) and 4-nitrophenol (3.42 g).
Stirred at 70 ° C. for 50 minutes. After allowing to cool to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography using chloroform / methanol for development to obtain a compound (4.54 g), and a portion (1.00 g) of the compound (N, N-dimethylformamide / ethyl acetate) was obtained. (30 ml / 15 ml), 10% palladium hydroxide-carbon (69 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 17 hours. The reaction solution was filtered through celite, and the filtrate was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 799 mg of the title compound.
Obtained in 78% yield.

¹ H-NMR (CD ₃ OD, 500 MH
z): δ 4.00 (s, 3H), 4.00 (s, 3)
H), 6.47 (d, J = 5.5 Hz, 1H), 6.8
2 (d, J = 8.6 Hz, 2H), 6.96 (d, J =
9.2 Hz, 2H), 7.32 (s, 1H), 7.62
(S, 1H), 8.36 (d, J = 5.5 Hz, 1H) Mass spectrometry value (FD-MS, m / z): 296 (M ⁺ ) The structure of the compound of Examples 1 to 30 is shown. It is as follows.

[0146]

[Table 1]

Pharmacological Test Example 1 Evans blue staining of tumor mass
Evaluation of intratumoral blood flow ratio human glioma cells GL07 (obtained from Central Institute for Experimental Animals) was transplanted into nude mice by color, tumor volume is uniformly average tumor volume of each group when it becomes about 100 mm ³ To be
The test compound was orally administered once a day for 3 days every day for 3 days to the test compound and 10 mg / kg for the control group. After the final administration, 250 μl of 1% Evans blue was intravenously administered, and a tumor mass was removed 30 minutes later. 0.3 g of the removed tumor mass
Tissue was lysed by adding 350 μl of 0.1 NKOH per well and incubating at 37 ° C. overnight. Acetone-
Phosphoric acid mixture was added to elute Evans Blue, 3000 rp
m, and centrifuged for 5 minutes, and the absorbance at 620 nm of the supernatant after centrifugation was measured. The absorbance of Evans blue eluted from the tissue lysate of the control group was C, and the absorbance of the test compound administration group was T, and the tumor blood flow ratio was evaluated as T / C × 100 (%).

Table 2 summarizes the measurement results of the intratumoral blood flow ratio for representative examples of the compounds of the present invention.

[0149]

[Table 2]

Pharmacological Test Example 2 Human glioma cells (GL0
7) Antitumor effect on human glioma cells GL07 (obtained from Central Research Institute for Experimental Animals) was transplanted into nude mice, and when the tumor volume became about 100 mm3, the average of the tumor volume of each group was made uniform.
The test compound was orally administered to the control group at a dose of 10 mg / kg once a day every day for 9 days. X of the control group when the tumor volume on the day of administration was set to 1
The tumor volume on the day was Cx, and the tumor volume in the test compound administration group was Tx
The tumor growth inhibition rate (TGIR) = (1−Tx / Cx) × 100 was determined.

Table 3 shows the results of the tumor growth inhibitory rates for representative examples of the compounds of the present invention.

[0152]

[Table 3]

Pharmacological Test Example 3 Effect on Cell Morphological Change Mouse Leukemia Cell P388 (obtained from ATCC: ATCC
CCL-46) was cultured in an RPMI1640 medium containing 10% fetal calf serum in a 5% carbon dioxide incubator, and cells in the logarithmic growth phase were seeded on a 96-well flat bottom plate at 5000 cells per well. Next, a test substance dissolved in dimethyl sulfoxide was added to each well so that the final concentration became 0.01, 0.1, 1.0, and 10 μM, and the cells were cultured at 37 ° C. for 48 hours. Thereafter, the morphological change of the P388 cells in each well, that is, the enlargement of the cells, was observed using a phase contrast microscope. The cell morphological change of the test substance was changed at 1.0 μM when cells whose morphology was changed at 0.01 μM (4+) and when cells whose morphology was changed at 0.1 μM (3+) were detected. When cells were observed (2+), when cells with morphological changes at 10 μM were observed (+). In addition, when no cells whose morphology was changed at 10 μM were observed, it was indicated as (−). Table 4 summarizes the results of evaluation of cell morphological changes for representative examples of the compounds of the present invention.

[0154]

[Table 4]

Pharmacological Test Example 4 Type II Collagen-Induced Arthritis
Example 1 Effect of the compound of Example 1 on male DBA / 1Jsea mice (7 weeks old) (obtained from Seatec Yoshitomi) were used. 5 ml of a solution containing 0.3% bovine type II collagen (obtained from K-41, Collagen Technical Workshop), 2.5 ml of physiological saline and 7.5 ml of incomplete Freund's adjuvant (obtained from Difco Labs.)
Was prepared by subcutaneously administering 0.1 ml per mouse to the tail of mice twice at intervals of about 4 weeks to induce arthritis. 10 days after the second emulsion administration,
The degree of clinical symptoms (limb swelling) of mice that developed arthritis was scored, and 1 group was assigned to each group so that the average score was equal.
Zero animals were assigned (grouping). The compound of Example 1 was suspended in a saline medium containing 10% each of cremophor and DMSO, and methotrexate (MTX) (obtained from Sigma) was suspended in a physiological saline containing 1% carboxymethylcellulose. 26 days from group date
Gavage was administered once a day using a stomach probe once a day. The dose of the compound of Example 1 was 10 mg / kg, and the dose of MTX was 1 mg / kg.

FIG. 1 shows the transition of the average value of the clinical score from the start of administration to the end of the experiment. It was found that the compound of Example 1 exhibited a similar effect of suppressing arthritis as MTX used as a therapeutic agent for rheumatoid arthritis.

Pharmacological Test Example 5 Delayed type hypersensitivity (DTH reaction)
Effect of the compound of Example 1 on 8 male Crj: BDF1 mice (9 weeks old) (obtained from Charles River Japan Co., Ltd.) were used in each group. 1 as antigen
Each mouse was sensitized by subcutaneously administering 0 μg of ovalbumin (OVA) (obtained from Seikagaku Corporation) together with 1 mg of alum, and 7 days after the sensitization, 10 μg of OVA was added together with 50 μg of alum to the footpad of each mouse. Was administered intradermally to elicit a DTH response. The thickness of the antigen-induced site was measured before and 24 hours after the antigen was induced, and the swelling ratio (%) after the antigen was induced was defined as the degree of DTH reaction. The compound of Example 1 was Cremophor and D
Prednisolone acetate (prednisolone) (obtained from Shionogi & Co., Ltd.) was suspended in a physiological saline solution containing 10% of MSO and a saline solution, respectively. Was administered by gavage. The dose of the compound of Example 1 and prednisolone was 10 mg / kg.

The results are shown in FIG. It was found that the compound of Example 1 exhibited a significant (p <0.05, student's test) DTH reaction inhibitory effect.

[Brief description of the drawings]

FIG. 1 shows the effect of the compound of Example 1 on type II collagen-induced arthritis. ●: group (n = 10) to which a medium (physiological saline containing 10% each of Cremophor and DMSO) was given, Δ: group to which the compound of Example 1 was given (n = 10), □: MTX was given Group (n = 10).

FIG. 2: Example 1 for delayed type hypersensitivity (DTH reaction)
FIG. 3 is a diagram showing the effect of the compound of FIG.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 31/47 ADU A61K 31/47 ADU AED AED (72) Inventor Isao Serizawa 3rd Miyaharacho, Takasaki City, Gunma Prefecture Kirin Brewery Co., Ltd. Inside the drug discovery laboratory

Claims (13)

[Claims] 1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Embedded image [Wherein, R ₁ is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, and R ₂ and R ₃ may be the same or different and are each a hydrogen atom, a lower alkyl group, or a formula Group represented by (II): (In the above formula, R ₅ may be the same or different;
Each is a halogen atom or a lower alkyl group;
Is an integer of 1 to 5, and p is an integer of 1 to 4. However, when R ₁ is a hydrogen atom, R ₂ and R ₃ do not represent a hydrogen atom at the same time, and R ₄ is And m is an integer of 1 to 3. ] 2. R ₁ is a halogen atom, a lower alkyl group,
Or the compound according to claim 1, which is a lower alkoxy group. 3. R ₂ and R ₃ may be the same or different and each is a hydrogen atom, a lower alkyl group, or a compound of the formula (II) wherein R ₅ is a halogen atom and n is 1
And p is 1. The compound according to claim 1, which is 4. A compound according to claim 1, wherein R ₄ is a fluorine atom and m is 1 or 2.
The compound of claim 1, wherein 5. R ₁ is a halogen atom, a methyl group, or a methoxy group, and R ₂ and R ₃ may be the same or different and are each a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a Formula (II) wherein R ₅ is
A halogen atom, n is 1 and p is 1. )
The compound according to claim 1, wherein R ₄ is a fluorine atom, and m is 1 or 2. 6. R ₁ is a hydrogen atom, and R ₂ and R _{3
May be} the same or different and each represents a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a compound of the formula (II) (wherein R ₅ is a halogen atom, n is 1 and p is 1 The compound according to claim 1, wherein R ₄ is a fluorine atom, and m is 1 or 2. 7. N-benzyl-N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} urea, N- (2-chlorobenzyl) -N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} urea, N- (4 -Chlorobenzyl) -N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} urea; N- (2,4 -Difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}-
N-methylurea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}-
N-isopropylurea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}-
N, N'-dimethylurea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}
Urea, N '-(2,4-difluorophenyl) -N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}-
N-methylurea, N '-(2,4-difluorophenyl) -N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}-
N-ethylurea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}-
N, N'-diethylurea, N- (3,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}-
N, N'-diethylurea, N- (3,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}-
N-methylurea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl}-
N-ethylurea, N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-
Fluorophenyl｝ -N-ethyl-N- (4-fluorophenyl) urea, N '-｛4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-
Fluorophenyl {-N- (4-fluorophenyl) -N-methylurea, N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N '-(4-fluoro Phenyl) -N,
N'-dimethylurea, N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N, N'-diethyl-N '-(4-fluorophenyl) urea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methoxyphenyl}
Urea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methoxyphenyl}-
N-methylurea, N- (3,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methoxyphenyl}-
N-methylurea, N- (3,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methoxyphenyl}-
N-ethylurea, N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-
Methoxyphenyl} -N-methyl-N- (4-fluorophenyl) urea, N ′-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-
Methoxyphenyl} -N-ethyl-N- (4-fluorophenyl) urea, N- (3,4-difluorophenyl) -N ′-{4-[(6,7-dimethoxy-4-quinolyl) oxy]- 2-methylphenyl｝ -N
-Methylurea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N
-Methylurea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N
-Ethylurea, N '-(2,4-difluorophenyl) -N- {4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N
-Methylurea, N- (2,4-difluorophenyl) -N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-methylphenyl}-
N, N'-diethylurea, N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-
Methylphenyl {-N-ethyl-N- (4-fluorophenyl) -urea, and N '-(2,4-difluorophenyl) -N- {4-[(6,7-dimethoxy-4-quinolyl) oxy ] Phenyl} -N-ethylurea. Or a pharmaceutically acceptable salt or solvate thereof. (8) N- (2,4-difluorophenyl) -N'-
{4-[(6,7-dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N-methylurea, N '-(2,4-difluorophenyl) -N- {4-[(6,7 -
Dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N-ethylurea, N-benzyl-N- (2,4-difluorophenyl) -N '
-｛4-[(6,7-Dimethoxy-4-quinolyl) oxy] -2-
Fluorophenyl｝ urea, N '-(2,4-difluorophenyl) -N-Ｎ4-[(6,7-
Dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N-methylurea, N '-{4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-fluorophenyl} -N-ethyl-N- (4-fluorophenyl) urea, N- (2,4-difluorophenyl) -N ′-｛4-[(6,7-
Dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N-ethylurea, N- (2,4-difluorophenyl) -N ′-{4-[(6,7-
Dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N-isopropylurea, N- (2,4-difluorophenyl) -N ′-{4-[(6,7-
Dimethoxy-4-quinolyl) oxy] -2-fluorophenyl} -N, N′-dimethylurea, N- (2,4-difluorophenyl) -N ′-{4-[(6,7-dimethoxy-4- Quinolyl) oxy] -2-methoxyphenyl｝-
N-methylurea, N '-｛4-[(6,7-dimethoxy-4-quinolyl) oxy]
-2-methoxyphenyl} -N-ethyl-N- (4-fluorophenyl) urea, N- (2,4-difluorophenyl) -N ′-｛4-[(6,7-
Dimethoxy-4-quinolyl) oxy] -2-methylphenyl} -N, N′-diethylurea, and N ′-(2,4-difluorophenyl) -N- {4-[(6,7-dimethoxy-4 A compound selected from the group consisting of -quinolyl) oxy] phenyl} -N-ethylurea, or a pharmaceutically acceptable salt or solvate thereof. 9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. 10. The pharmaceutical composition according to claim 9, which is used for treatment of a disease that requires suppression of angiogenesis at a diseased site. 11. The pharmaceutical composition according to claim 9, which is used for treating a disease selected from the group consisting of tumor, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, and Kaposi's sarcoma. Stuff. 12. The pharmaceutical composition according to claim 9, which is used for suppressing metastasis of a solid cancer. 13. The pharmaceutical composition according to claim 9, which is used for suppressing angiogenesis at a diseased site.