HK1118538A

HK1118538A - Thienopyridine derivative, or quinoline derivative, or quinazoline derivative, having c-met autophosphorylation inhibiting potency

Info

Publication number: HK1118538A
Application number: HK08109635.4A
Authority: HK
Inventors: 久保和生; 古田孝之; 大泽立志; 三轮笃史
Original assignee: 麒麟医药株式会社
Priority date: 2005-03-28
Filing date: 2006-03-28
Publication date: 2009-02-13

Description

Thienopyridine derivatives, quinoline derivatives and quinazoline derivatives having c-Met autophosphorylation inhibitory activity

Technical Field

The present invention relates to thienopyridine derivatives, quinoline derivatives and quinazoline derivatives having c-Met autophosphorylation inhibitory activity. More particularly, the present invention relates to thienopyridine derivatives, quinoline derivatives and quinazoline derivatives useful for the treatment of malignant tumors.

Background

Growth factors, such as epithelial growth factor, platelet-derived growth factor, insulin-like growth factor, and hepatocyte growth factor (hereinafter abbreviated as "HGF") play an important role in the proliferation of cells. In particular, as liver regeneration factors and kidney regeneration factors, HGF is known to be involved in the regeneration of damaged liver and kidney (Oncogenesis, 3,27(1992))。

however, it has been reported that overexpression of HGF and its receptor (hereinafter abbreviated as "c-Met") has been found in various tumors, such as brain tumor, lung cancer, stomach cancer, pancreatic cancer, colon cancer, ovarian cancer, renal cell carcinoma and prostate cancer (Oncology repeats,5,1013(1998)). In particular, overexpression of c-Met in gastric cancer, and increased serum HGF levels in primarily hard gastric cancer, have been reported (int.j. cancer,55,72, (1993)). Further, HGF is also known to accelerate proliferation and migration of vascular endothelial cells (Circulation,97381(1998), and Clinical Cancer Res,53695, (1999)) and induce cell dispersion and invasion(J.Biol.Chem.，27027780(1995)), and thus it has angiogenic activity. For this reason, HGF-c-Met signaling is thought to be involved in the proliferation, invasion and metastasis of various cancer cells.

NK4, a partial peptide of HGF, is reported to be an HGF receptor antagonist. For example, it has been reported that NK4 inhibits c-Met autophosphorylation of various cancer cells, in addition to cell migration and cell invasion, and has an activity of inhibiting tumor enhancement, possibly by virtue of an activity of inhibiting angiogenesis, in an in vivo cancer transplantation model (Oncogene,17，3045(1998)，Cancer Res.，60，6737(2000)，British J.Cancer，84864(2001), and int.j.cancer,85，563(2000))。

however, since NK4 is a peptide, the use of NK4 as a therapeutic agent requires reliable stability design, design of administration method, and the like in vivo.

On the other hand, low-molecular weight and low-toxicity compounds have been reported to have c-Met autophosphorylation inhibitory activity and to exhibit antitumor activity when orally administered.

The invention has found that certain quinoline derivatives and thienopyridine derivatives have c-Met autophosphorylation inhibition activity and also have an anticancer effect.

It is an object of the present invention to provide compounds having anti-cancer activity.

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

[ chemical formula 1]

Wherein

R¹Represents a hydrogen atom or an optionally substituted unsaturated 5-or 6-membered heterocyclic group,

R²represents a hydrogen atom, and is represented by,

x represents a group selected from the group consisting of CH and N,

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

e is absent or represents a substituent on the phenylene radical, said substituent being selected from a halogen atom, C_1-4Alkyl and C_1-4Alkoxy, and the numbers represent substitutable positions,

j represents S or O, and

t represents an optionally halogen atom, C_1-4Alkyl or C_1-4Alkoxy-substituted phenyl; optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4Alkoxy-substituted unsaturated 5-or 6-membered heterocyclyl; or optionally by halogen atoms, C_1-4Alkyl or C_1-4Alkoxy-substituted unsaturated 9-or 10-membered bicyclic carbocyclic or heterocyclic groups.

According to a second aspect of the present invention, there is provided a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, or a solvate thereof;

[ chemical formula 2]

Wherein

R¹¹And R¹²May be the same or different and represents C_1-4An alkoxy group,

d represents a group of CH or N,

g represents O or S, and G represents O or S,

l is absent or represents a substituent on the phenylene group, the substituent being selected from a halogen atom, C_1-4Alkyl and C_1-4Alkoxy, and the numbers represent substitutable positions,

m represents O or S, and

q represents a bicyclic 9-membered unsaturated heterocyclic group optionally substituted with halogen.

Brief Description of Drawings

FIG. 1 is a graph showing the bone growth plate area (mm) of each group in pharmacological example 9²) Wherein n.s. means that there is no significant difference between the groups.

Detailed Description

Definition of

As used herein, the terms "alkyl" and "alkoxy" as a group or part of a group, respectively, mean straight or branched chain alkyl and alkoxy.

C_1-4Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

C_1-4Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

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

The unsaturated 5-or 6-membered heterocyclic ring contains at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur atoms. The unsaturated 5-or 6-membered heterocyclic ring preferably contains one or two heteroatoms, the remaining ring atoms being carbon atoms. Examples of unsaturated 5-or 6-membered heterocyclic groups include thienyl and imidazolyl.

Unsaturated bicyclic 9-or 10-membered heterocyclic groups contain at least one heteroatom selected from oxygen, nitrogen and sulfur atoms. The unsaturated bicyclic 9-or 10-membered heterocyclic ring preferably contains one to three heteroatoms, the remaining ring atoms being carbon atoms.

Examples of unsaturated bicyclic 9-or 10-membered heterocycles include indolyl, indazolyl, 1H-pyrrolo [2, 3-b ] pyridine and 1H-pyrazolo [3, 4-b ] pyridine.

The term "treatment" as used herein encompasses "prevention".

Compounds of the first aspect

One aspect of the present invention relates to thienopyridine derivatives.

From R¹The unsaturated 5-or 6-membered heterocyclic group represented is preferably an unsaturated 5-membered heterocyclic group, more preferably an imidazolyl group, still more preferably a 1H-imidazol-2-yl group, most preferably of formula (a):

[ chemical formula 3]

Wherein R is³Represents a hydrogen atom or C_1-4Alkyl, preferably methyl.

From R¹The substituent of the heterocyclic group represented by (A) is preferably C_1-4Alkyl, more preferably methyl.

In the formula (I), R is preferred¹Represents optionally substituted by C_1-4Alkyl, preferably methyl, unsaturated 5-membered heterocyclic group, more preferably represents optionally C_1-4Alkyl, preferably imidazolyl substituted by methyl, still more preferably represents optionally C_1-4Alkyl, preferably methyl-substituted 1H-imidazol-2-yl, most preferably a group of formula (a).

Preferably, X represents CH.

Preferably, Z represents O.

Preferably, E isPresence or representation of C in 2-position_1-4Alkoxy, preferably methoxy, or a halogen atom, preferably a chlorine atom or a fluorine atom, in the 3-position.

The unsaturated 5-or 6-membered heterocyclic group represented by T is preferably an unsaturated 5-membered heterocyclic group, more preferably a thienyl group.

The unsaturated 9-or 10-membered bicyclic carbocyclic or heterocyclic group represented by T is preferably an unsaturated 9-membered bicyclic heterocyclic group, more preferably indazolyl.

Preferably, T represents an optionally halogen atom, C_1-4Alkyl or C_1-4Alkoxy-substituted phenyl; optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4Alkoxy-substituted thienyl; optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4An alkoxy-substituted indazolyl group.

X, Z and J is preferably a combination wherein X represents CH, Z represents O and J represents S, or a combination wherein X represents CH, Z represents O and J represents O.

Examples of preferred compounds of formula (I) include the following compounds, wherein:

R¹represents formula (a) wherein R³Represents a hydrogen atom or C_1-4An alkyl group, a carboxyl group,

R²represents a hydrogen atom, and is represented by,

x represents a group represented by the formula CH,

z represents O, and Z represents O,

e is absent or represents a substituent on the phenylene radical, said substituent being selected from a halogen atom, C_1-4Alkyl and C_1-4Alkoxy, the number representing a substitutable position,

j represents S or O, and the compound is represented by,

t represents an optionally halogen atom, C_1-4Alkyl or C_1-4Alkoxy-substituted phenyl; optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4An alkoxy-substituted unsaturated 5-membered heterocyclic group; or optionally by halogen atoms, C_1-4Alkyl or C_1-4An alkoxy-substituted unsaturated 9-membered bicyclic carbocyclic or heterocyclic group.

In the above examples of preferred compounds, R³Represents C_1-4Alkyl, preferably methyl.

In the above examples of preferred compounds, E represents C in the 2-position_1-4Alkoxy, preferably methoxy, or halogen in the 3-position, preferably chlorine or fluorine atom.

In the examples of the above preferred compounds, T represents an optionally halogen atom, C_1-4Alkyl or C_1-4Alkoxy-substituted phenyl; optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4Alkoxy-substituted thienyl; and optionally by halogen atoms, C_1-4Alkyl or C_1-4An alkoxy-substituted indazolyl group. Preferably, T represents an optionally halogen atom, C_1-4Alkyl or C_1-4Phenyl substituted by alkoxy, more preferably represents phenyl optionally substituted by halogen atoms, or optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4Alkoxy-substituted imidazolyl.

Among the compounds of formula (I), preferred compounds are shown below. The numbers in parentheses correspond to example numbers.

(1) N- (3-chloro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) -N- [2- (4-fluorophenyl) acetyl ] thiourea;

(2) n- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) -N- (2-phenylacetyl) urea;

(3) n- [2- (1H-1-indazolyl) acetyl ] -N- (2-methoxy-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) thiourea;

(4) n- [2- (4-fluorophenyl) acetyl ] -N- (4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) thiourea;

(5) n- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) -N- [2- (4-fluorophenyl) acetyl ] thiourea;

(6) n- (4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) -N- (2-phenylacetyl) thiourea;

(7) n- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) -N- (2-phenylacetyl) thiourea;

(8) n- (2-methoxy-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) -N- (2-phenylacetyl) thiourea;

(9) n- (2-methoxy-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) -N- (2-phenylacetyl) urea;

(10) n- [2- (1H-1-indazolyl) acetyl ] -N- (4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) thiourea;

(11) n- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) -N- [2- (1H-1-indazolyl) acetyl ] thiourea;

(12) n- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) -N- [2- (1H-1-indazolyl) acetyl ] urea; and

(13) n- [2- (1H-1-indazolyl) acetyl ] -N- (2-methoxy-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) urea.

In the first aspect of the present invention, examples of the most preferable compounds include the compound of example 1 and the compound of example 9.

Compounds of the second aspect of the invention

According to a second aspect of the present invention, quinoline derivatives and quinazoline derivatives are provided.

R¹¹And R¹²Preferably represents methoxy.

D preferably represents CH.

G preferably represents O.

L is preferably absent or is a halogen atom in the 3-position, preferably a fluorine or chlorine atom, a halogen atom in the 2-position, preferably a fluorine atom, or C in the 2-position_1-4Alkoxy, preferably methoxy.

D. The combination of G and M is preferably a combination in which D represents CH, G represents O and M represents S, or a combination in which D represents CH, G represents O and M represents O.

Q preferably represents formula (b):

[ chemical formula 4]

Wherein the group represented by formula (b) is optionally substituted with a halogen atom, and the number represents a substitutable position;

formula (c):

[ chemical formula 5 ]

Wherein the group represented by formula (c) is optionally substituted with a halogen atom, and the number represents a substitutable position;

formula (d):

[ chemical formula 6 ]

Wherein the group represented by formula (d) is optionally substituted with a halogen atom, and the number represents a substitutable position; or

Formula (e):

[ chemical formula 7 ]

Wherein the group represented by formula (e) is optionally substituted with a halogen atom, and the number represents a substitutable position.

The formulae (b), (c), (d) and (e) are preferably unsubstituted or have as a substituent a halogen atom, preferably a chlorine atom, in the 3-position; a halogen atom, preferably a fluorine atom, in the 4-position; or a halogen atom, preferably a fluorine atom, at the 7-position.

A first example of a preferred compound of formula (II) includes the compounds wherein

R¹¹And R¹²Represents a methoxy group, and a methoxy group,

d represents a group represented by the formula CH,

g represents O, and the compound is represented by,

m represents O or S, and

q represents formula (b), wherein the group represented by formula (b) is optionally substituted with a halogen atom, and the number represents a substitutable position.

In the first instance, L preferably represents a halogen atom, preferably a fluorine atom, at the 3-position.

In a first example, M represents O.

In addition, in the first example, formula (b) is unsubstituted.

A second example of a preferred compound of formula (II) includes the compounds wherein

R¹¹And R¹²Represents a methoxy group, and a methoxy group,

d represents a group represented by the formula CH,

g represents O, and the compound is represented by,

m represents O or S, and

q represents formula (c), wherein the group represented by formula (c) is optionally substituted with a halogen atom, and the number represents a substitutable position.

In a second example, L preferably represents a halogen atom, preferably a fluorine atom, in the 3-position.

In a second example, M preferably represents S.

In a second example, formula (c) is unsubstituted.

A third example of a preferred compound of formula (II) includes the compounds wherein

R¹¹And R¹²Represents a methoxy group, and a methoxy group,

d represents a group represented by the formula CH,

g represents O, and the compound is represented by,

m represents O or S, and

q represents formula (d), wherein the group represented by formula (d) is optionally substituted with a halogen atom, and the number represents a substitutable position.

In a third example, L preferably represents a halogen atom in the 3-position, preferably a fluorine or chlorine atom, C in the 2-position_1-4Alkoxy, preferably methoxy, or a halogen atom in the 2-position, preferably a fluorine atom.

In a third example, M preferably represents O.

In the third instance, formula (d) is preferably unsubstituted or carries a halogen atom, preferably a chlorine atom, as a substituent at the 3-position; a halogen atom, preferably a fluorine atom, in the 4-position; or a halogen atom, preferably a fluorine atom, in the 7-position.

A fourth example of a preferred compound of formula (II) includes the compounds wherein

R¹¹And R¹²Represents a methoxy group, and a methoxy group,

d represents a group represented by the formula CH,

g represents O, and the compound is represented by,

m represents O or S, and

q represents formula (e), wherein the group represented by formula (e) is optionally substituted with a halogen atom, and the number represents a substitutable position.

In a fourth example, L preferably represents a halogen atom, preferably a fluorine atom, in the 3-position or a C atom in the 2-position_1-4Alkoxy, preferably methoxy.

In a fourth example, M preferably represents O.

In a fourth example, M preferably represents S.

In a fourth example, formula (e) is preferably unsubstituted.

Among the compounds of formula (II), preferred compounds are shown below. The numbers in parentheses correspond to example numbers.

(14) N- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl ] -N' - [2- (1H-1-indazolyl) acetyl ] urea;

(15) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl ] -N' - [2- (1H-1-indazolyl) acetyl ] thiourea;

(16) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl ] -N' - [2- (1H-1-indolyl) acetyl ] urea;

(17) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl ] -N' - [2- (1H-1-indazolyl) acetyl ] urea;

(18) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl ] -N' - [2- (1H-1-indazolyl) acetyl ] thiourea;

(19) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-fluorophenyl ] -N' - [2- (1H-1-indazolyl) acetyl ] urea;

(20) n- [2- (3-chloro-1H-1-indazolyl) acetyl ] -N' - [4- { (6, 7-dimethoxy-4-quinolyl) oxy } phenyl ] urea;

(21) n- [2- (3-chloro-1H-1-indazolyl) acetyl ] -N' - [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl ] urea;

(22) n- [ 3-chloro-4- { (6, 7-dimethoxy-4-quinolyl) oxy } phenyl ] -N' - [2- (1H-1-indazolyl) acetyl ] urea;

(23) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl ] -N' - [2- (1H-1-pyrrolo [2, 3-b ] pyridin-1-yl) acetyl ] thiourea;

(24) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-fluorophenyl ] -N' - [2- (4-fluoro-1H-1-indazolyl) acetyl ] thiourea;

(25) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl ] -N' - [2- (4-fluoro-1H-1-indazolyl) acetyl ] thiourea;

(26) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl ] -N' - [2- (4-fluoro-1H-1-indazolyl) acetyl ] thiourea;

(27) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } phenyl ] -N' - [2- (4-fluoro-1H-1-indazolyl) acetyl ] urea;

(28) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-fluorophenyl ] -N' - [2- (4-fluoro-1H-1-indazolyl) acetyl ] thiourea;

(29) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl ] -N' - [2- (4-fluoro-1H-1-indazolyl) acetyl ] urea;

(30) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl ] -N' - [2- (4-fluoro-1H-1-indazolyl) acetyl ] urea;

(31) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl ] -N' - [2- (1H-pyrazolo [3, 4-b ] pyridin-1-yl) acetyl ] thiourea;

(32) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl ] -N' - [2- (7-fluoro-1H-1-indazolyl) acetyl ] thiourea;

(33) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl ] -N' - [2- (7-fluoro-1H-1-indazolyl) acetyl ] urea;

(34) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl ] -N' - [2- (1H-1-pyrazolo [3, 4-b ] pyridin-1-yl) acetyl ] urea; and

(35) n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl ] -N' - [2- (1H-1-pyrazolo [3, 4-b ] pyridin-1-yl) acetyl ] urea.

According to a second aspect of the present invention, there is also provided the following compounds.

(A) N- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl ] -N' - [2- (4-fluorophenyl) acetyl ] thiourea; and

(B) n- { 2-methoxy-4- [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinolinyl ] oxyphenyl } -N' - (2-phenylacetyl) thiourea.

The compound of example 14 and compound a may be the most preferred compounds in the second aspect of the invention.

The compounds of the first aspect of the invention, the compounds of the second aspect of the invention and salts thereof may form pharmaceutically acceptable salts thereof. Preferred examples of such salts include: alkali metal or alkaline earth metal salts, such as sodium, potassium or calcium salts; hydrohalic acid salts, such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide salts; inorganic acid salts such as nitrate, perchlorate, sulfate or phosphate; alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; salts of aromatic sulfonic acids, such as p-toluenesulfonic acid; organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate, acetate, perester, lactate or ascorbate; and amino acid salts such as aminoacetate, phenylalanine, glutamate or aspartate.

The compounds of the first aspect of the invention, the compounds of the second aspect of the invention and salts thereof may form solvates. Such solvates include, for example, hydrates, alcoholates, such as methanolate and ethanolate, and etherates, such as etherate.

KDR inhibitors having KDR autophosphorylation inhibitory activity have been identified for various cancers, including gastric cancer, but have also been reported to cause side effects such as increased blood pressure and renal dysfunction (fill. cancer, 92, S29 (2005)). In addition, KDR inhibitors have also been reported to have significant activity in inducing thickening of bone growth plates in growing-stage animals (Cancer res.65, 4389 (2005)). This fact suggests that the same phenomenon may be induced when administered to patients in the growth phase. For the reasons mentioned above, it is preferred that the compound having inhibitory activity on c-Met autophosphorylation should have low autophosphorylation inhibitory activity, that is, should have high c-Met/KDR selectivity in view of reducing the above-mentioned side effects, when intended for human therapy.

A part of the compounds according to the present invention has a high c-Met autophosphorylation inhibiting activity, but on the other hand, it has a low KDR autophosphorylation inhibiting activity. It is considered that this compound has a low possibility of inducing side effects due to the inhibitory effect on autophosphorylation of KDR. Examples of compounds having high c-Met autophosphorylation inhibitory activity and, on the other hand, low KDR autophosphorylation inhibitory activity include compounds A and B. In actual experiments, compound a did not induce thickening of bone growth plates in animals in growth phase (pharmacological test example 9). On the other hand, in a nude mouse tumor model subcutaneously transplanted with a human gastric cancer cell line expressing c-Met protein at a high level, compound a was administered in a similar manner to that in the bone growth plate thickening induction test described above, and it was confirmed that compound a had anticancer activity (pharmacological test example 5).

When intended for human therapy, it is preferred that the compound having c-Met autophosphorylation inhibiting activity should have an appropriate transfer rate preferably as a therapeutic agent. In the human liver microsome assay, a portion of the compounds according to the invention have an appropriate transfer rate, preferably as a therapeutic agent. Compound a may be exemplified as such a compound (data not shown).

Preparation of the Compounds

The compounds according to the invention can be prepared, for example, according to schemes 1 to 7 below. The starting compounds necessary for the synthesis of the compounds of the invention are commercially available or alternatively can be readily prepared according to conventional methods. The substituents in the schemes are as defined for formula (I), formula (II) and formula (a).

< preparation of 4- (aminophenoxy) thienopyridine derivative (scheme 1) >

[ chemical formula 8 ]

Scheme 1

Me: methyl radical

7-chlorothienopyridine derivatives can be synthesized, for example, according to the conventional methods described in org.Synth.Col. volume 3, 272(1955), Acta Chim.Hung., 112, 241(1983), WO98/47873 or WO 99/24440. Examples of the synthesis of 7-chlorothienopyridine derivatives are shown in scheme 1.

The 3-aminothiophene can be prepared in the following manner: the 3-aminothiophene derivative is first reacted under reflux in a suitable basic solution, for example, an aqueous sodium hydroxide solution, and then the reaction product is acidified. Thienopyridones may be prepared in the following manner: 3-aminothiophene is reacted in a suitable solvent, such as triethyl orthoformate, in the presence of a suitable cyclizing reagent, such as 2, 2-dimethyl-1, 3-dioxane-4, 6-dione, followed by heating the reaction product in a suitable solvent, such as a mixed solution consisting of diphenyl ether and diethyl ether). 7-chlorothienopyridine can be synthesized by reacting thienopyridones in the presence of a chlorinating agent, such as phosphorus oxychloride. 2-iodo-7-chlorothienopyridine can be prepared by reacting 7-chlorothienopyridine in a suitable solvent, such as tetrahydrofuran, in the presence of a base, such as n-butyllithium, and an iodinating agent, such as iodine. The 7-chlorothienopyridine derivative can be prepared in the following manner: activation with a suitable base, e.g. n-butyllithium, in a suitable solvent, e.g. tetrahydrofuran, corresponds to R³By metallation of the activated reagent with a suitable metal salt, e.g. zinc dichlorideDisplacement followed by reaction of the product with 2-iodo-7-chlorothienopyridine in the presence of a suitable catalyst, such as tetrakis (triphenylphosphine) palladium.

Next, a 7- (aminophenoxy) thienopyridine derivative was synthesized in the following manner: the 7- (nitrophenoxy) thienopyridine derivative is synthesized by reacting a nitrophenol derivative with a 7-chlorothienopyridine derivative in an appropriate solvent such as chlorobenzene, and then the 7- (nitrophenoxy) thienopyridine derivative is reacted in an appropriate solvent such as N, N-dimethylformamide under a hydrogen atmosphere in the presence of a catalyst such as palladium hydroxide-carbon, palladium-carbon. The nitro group may also be reduced with zinc, iron, or the like.

Alternatively, the 7- (aminophenoxy) thienopyridine derivative may also be prepared in the following manner: the aminophenol derivative is reacted with the 7-chlorothienopyridine derivative in a suitable solvent, such as dimethyl sulfoxide, in the presence of a base, such as sodium hydride.

The 7-chlorothienopyrimidine derivative can also be synthesized from the same starting materials as in scheme 1 in a similar manner to scheme 3.

< preparation of Compound of formula (I) (scheme 2) >

[ chemical formula 9 ]

Scheme 2

The compounds of formula (I) may be prepared according to scheme 2. The carbonylthiourea compound can be prepared by reacting a 4- (aminophenoxy) thienopyridine derivative with a carbonylthioisocyanate derivative in an appropriate solvent, for example, a mixed solvent consisting of toluene and ethanol. The carbonylthioisocyanate derivative may be commercially available or may be simply prepared by a conventional method. For example, carbonyl thioisocyanate derivatives are prepared by reacting an acid chloride derivative with potassium thiocyanate in a suitable solvent, such as acetonitrile.

Alternatively, the thioisocyanate derivatives may be prepared by reacting 4- (aminophenoxy) thienopyridine derivatives with a thioisocyanating agent, such as di-2-pyridyl thiocarbonate, in a suitable solvent, such as chloroform. The carbonyl thiourea derivatives can be prepared by reacting the resulting thioisocyanate derivatives with amide derivatives in a suitable solvent, such as dimethylformamide, in the presence of a suitable base, such as sodium hydride.

Carbamate derivatives may be prepared by reacting a 4- (aminophenoxy) thienopyridine derivative with a carbamate reagent, such as phenyl chloroformate, in the presence of a suitable base, such as sodium hydride, in a suitable solvent, such as dimethylformamide.

The carbonyl urea derivative can be prepared by reacting the thus-prepared carbamate derivative with an amide derivative in an appropriate solvent, for example, o-xylene.

< preparation of 4-chloroquinoline derivative and 4-chloroquinazoline derivative (scheme 3) >

[ chemical formula 10 ]

Scheme 3

4-chloroquinoline derivatives can be synthesized according to, for example, the conventional methods described in org.synth.col. volume 3, 272(1955), Acta chim.hung., 112, 241(1983) or WO 98/47873. An example of the synthesis of 4-chloroquinoline derivatives is shown in scheme 3.

The quinolone derivative can be prepared by reacting a 2-aminoacetylbenzene derivative with a formic acid ester, such as ethyl formate, in a suitable solvent, such as tetrahydrofuran, in the presence of a base, such as sodium methoxide. 4-chloroquinoline derivatives can be prepared by reacting a carbostyril derivative in the presence of a chlorinating agent, such as phosphorus oxychloride.

The 4-chloroquinazoline derivative can be produced, for example, in the following manner. The quinazoline derivative can be prepared by reacting a 2-aminobenzoate derivative with formamide in the presence of a base such as sodium methoxide in a suitable solvent such as a mixed solvent composed of N, N-dimethylformamide and methanol. 4-chloroquinazoline derivatives can be prepared by reacting quinazolinone derivatives in the presence of a chlorinating agent, such as phosphoryl chloride.

< preparation of aniline derivative having quinoline ring or quinazoline ring (G ═ O) >

[ chemical formula 11 ]

Scheme 4

Aniline derivatives having a quinoline ring or quinazoline ring (G ═ O) can be synthesized, for example, according to scheme 4.

Specifically, a 4- (aminophenoxy) quinoline derivative or a corresponding quinazoline derivative can be prepared in the following manner: reacting a nitrophenol derivative with a 4-chloroquinoline derivative or a corresponding quinazoline derivative in a suitable solvent, such as chlorobenzene, to give a 4- (nitrophenoxy) quinoline derivative or a corresponding quinazoline derivative, and then reacting the product in a suitable solvent, such as N, N-dimethylformamide, under a hydrogen atmosphere in the presence of a catalyst, such as palladium hydroxide-carbon or palladium-carbon. The nitro group may also be reduced with, for example, zinc or iron.

Alternatively, 4- (aminophenoxy) quinoline derivatives or corresponding quinazoline derivatives may be prepared by reacting an aminophenol derivative with a 4-chloroquinoline derivative or a corresponding quinazoline derivative in the presence of a base, such as sodium hydride, in a suitable solvent, such as dimethyl sulfoxide. The 4- (aminophenoxy) quinazoline derivative may also be prepared in the following manner: the aminophenol derivative is dissolved in an aqueous sodium hydroxide solution and the solution is subjected to a two-phase reaction with the 4-chloroquinazoline derivative dissolved in a suitable organic solvent, such as methyl ethyl ketone, in the presence or absence of a phase transfer catalyst, such as tetra-n-butylammonium chloride.

< preparation of aniline derivative having quinoline ring or quinazoline ring (G ═ S) >

[ chemical formula 12 ]

Scheme 5

Aniline derivatives having a quinoline ring or a quinazoline ring (G ═ S) can be prepared, for example, according to scheme 5.

Specifically, a 4- (quinolylthio) aniline derivative or a 4- (quinazolinylthio) aniline derivative (a compound of formula (II) wherein G ═ S) can be prepared by reacting an aminothiophenol derivative with a 4-chloroquinoline derivative or a corresponding quinazoline derivative in a suitable solvent, for example, chlorobenzene. The derivative having a sulfur atom at the 4-position of the quinoline or quinazoline ring can be produced from the derivative according to scheme 7.

< Synthesis of a reagent corresponding to Q in the formula (II) (scheme 6) >

[ chemical formula 13 ]

Scheme 6

The heterofused ring materials corresponding to Q are commercially available or alternatively can be synthesized by conventional methods. As shown in scheme 6, indole derivatives and analogs can be synthesized in the following manner. Specifically, the corresponding indole derivative can be prepared by heating benzaldehyde and hydrazine substituted with halogen or the like at the ortho-position. In addition, the corresponding indole derivatives can be converted into amide compounds as important intermediate compounds in the following manner: indole derivatives are reacted with α -haloacetate compounds, such as methyl bromoacetate, in the presence of a suitable base, such as sodium hydride, to form acetate derivatives, which are then treated with aqueous ammonia.

< preparation of Compound of formula (II) (scheme 7) >

[ chemical formula 14 ]

Scheme 7

Compounds of formula (II), i.e. derivatives with carbonyl ureas or carbonyl thioureas, can be synthesized according to scheme 7.

The compound of formula (II) having carbonyl urea (M ═ O) can be prepared by allowing an aniline compound to form phenyl carbamate, followed by adding an amide as a starting material, and heating the mixture.

Compounds of formula (II) with carbonylthiourea (M ═ S) can be prepared as follows: an aniline compound is reacted with di-2-pyridyl thiocarbamate or the like to produce an isothiocyanate compound, after which an amide is added as a starting material in the presence of a base such as sodium hydride.

Use of compounds

The compounds according to the invention have an activity of inhibiting tumor growth in vivo (see pharmacological test examples 4, 5 and 6).

Furthermore, the compounds according to the invention inhibit in vitro the autophosphorylation of c-Met by: stimulation of human epidermal cancer cells a431 with HGF induced autophosphorylation of c-Met and autophosphorylation of c-Met frequently occurring in HGF independent gastric cancer cells MKN45 (see pharmacological test examples 2 and 3).

Proliferation and activity of different cell types is accelerated by autophosphorylation of tyrosine kinases in the intracellular region under HGF stimulation or in an HGF-independent manner for c-Met in certain cancer cells (j. biochem,119，591，(1996)，Jpn.J.Cancer Res.，88564, (1997), and int.j.cancer,78,750, (1998)). In particular, increased HGF concentration in various cancers, such as blood, overexpression of c-Met, and expression of c-Met mutants in which HGF is independent, have also been reported. c-Met signaling is thought to be involved in the proliferation, invasion and metastasis of various cancer cells (int.j. cancer,55，72，(1993)，Oncology Reports，51013(1998), Proc. Natl. Acad. Sci. USA,884892, (1991), and Cancer,88,1801, (2000)). Further, HGF has also been reported to accelerate the proliferation and migration activity of vascular endothelial cells by c-Met, and accelerate angiogenesis (Circulation,97381(1998) and Clinical Cancer Res,53695, (1999)), HGF is therefore also estimated to be involved in angiogenesis of cancer cells.

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

According to the present invention there is provided a pharmaceutical composition comprising a compound of the first aspect of the invention or a compound of the second aspect of the invention.

The pharmaceutical composition according to the present invention can be used for the treatment of malignant tumors, such as brain tumors, stomach cancers, colon cancers, pancreatic cancers, lung cancers, kidney cancers, ovarian cancers, and prostate cancers.

Furthermore, according to the present invention there is provided a method of treatment of malignant tumours which comprises administering to a mammal, including a human being, to be treated a therapeutically effective amount of a compound of the first aspect of the invention or a compound of the second aspect of the invention in association with a pharmaceutically acceptable carrier.

Furthermore, according to the present invention there is also provided the use of a compound of the first aspect of the invention or a compound of the second aspect of the invention for the manufacture of a therapeutic agent for the treatment of a malignant tumour.

By blocking HGF/c-Met signaling, c-Met autophosphorylation inhibitors can be used to study the role of HGF/c-Met signaling or downstream signaling in, for example, various cancer cells, vascular endothelial cells, epithelial cells, blood cells, and hepatocytes. Recently, antisense technology and siRNA technology have been used in this study. However, these are techniques for controlling protein expression. The effect of inhibition of kinase activity can only be examined by kinase inhibitors. Therefore, the compounds according to the present invention can be used as reagents for studying the effect of c-Met autophosphorylation inhibition in vivo.

Accordingly, the present invention provides c-Met autophosphorylation inhibitors comprising a compound according to the invention.

Further, according to the present invention, there is provided a reagent for studying HGF/c-Met signaling.

Pharmaceutical composition

The compounds according to the invention can be administered orally or parenterally, for example intravenously, intramuscularly, subcutaneously, rectally or transdermally, to humans or non-human animals. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient can be formulated into an appropriate dosage form according to the administration route. Specifically, oral preparations include tablets, capsules, powders, granules and syrups, parenteral preparations include injections, suppositories, tapes and plasters.

These various formulations can be prepared in accordance with conventional methods, for example, using commonly used excipients, disintegrants, binders, lubricants, colorants and diluents.

Excipients include, for example, lactose, glucose, corn starch, sorbitol, and crystalline cellulose. Disintegrants include, for example, starch, sodium alginate, gel powders, calcium carbonate, calcium citrate, and dextrin. Binders include, for example, dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose, and polyvinyl pyrrolidone. Lubricants include, for example, talc, magnesium stearate, polyethylene glycol and hydrogenated vegetable oils.

In preparing injections, if necessary, for example, a buffer, a pH adjuster, a stabilizer, an osmotic agent and a preservative may be added.

The content of the compound according to the present invention in the pharmaceutical composition according to the present invention may vary depending on the dosage form. However, the content is usually 0.5 to 50% by weight, preferably 1 to 20% by weight, based on the entire composition.

The dose can be appropriately determined in consideration of, for example, age, body weight, sex, difference in disease, and severity of individual symptoms of patients, and is preferably 1 to 100 mg/kg. The dose may be administered once daily, or in multiple doses multiple times daily.

The compounds according to the invention may be administered together with other drugs, for example, anticancer agents. In this case, the compounds according to the invention can be administered simultaneously with the other agents, or after or before their administration. The type of therapeutic agent, the interval between administrations, etc., can be determined according to the type of cancer and the symptoms of the patient.

Examples

The invention is further illustrated by the following examples, which are not intended to be limiting.

The starting materials necessary for the synthesis were prepared according to the methods described in WO 97/17329, WO98/47873, WO 00/43366, Japanese patent laid-open Nos. 328782/1997, WO 03/000660 and WO 04/039782. If starting materials are not described in these publications, the preparation of these starting materials is described in the preparation examples.

Example 1: n- (3- (chloro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b)]Pyridine-7- Base of]Oxy } phenyl) -N- [2- (4-fluorophenyl) -acetyl]Thiourea

[ chemical formula 15 ]

4-Fluorophenylacetyl chloride [ raw material B ] (124mg) and potassium thiocyanate (87mg) were dissolved in acetonitrile (3ml), and the mixture was stirred at 50 ℃ for 1 hour. Acetonitrile was removed by evaporation under reduced pressure. Then, saturated aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate was removed by evaporation under reduced pressure and the resulting crude product was dissolved in toluene/ethanol (1/1). 3-chloro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } aniline [ raw material A ] (65mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, the mixture was extracted with chloroform, and the chloroform was removed by evaporation under reduced pressure. The residue was purified by chromatography on silica gel using chloroform/ethanone to give the title compound (70 mg, 71% yield).

¹H-NMR(CDCl₃，400MHz)：δ3.72(s，2H)，3.97(s，3H)，6.61(d，J＝5.6Hz，1H)，7.03(d，J＝1.0Hz，2H)，7.13(t，J＝8.5Hz，2H)，7.17(d，J＝1.2Hz，1H)，7.27-7.31(m，2H)，7.62(dd，J＝2.7Hz，8.8Hz，1H)，7.72(s，1H)，8.00(d，J＝2.7Hz，1H)，8.50(d，J＝5.4Hz，1H)，8.52(s，1H)，12.39(s，1H)

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

Example 2: n- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b]Pyridine-7- Base of]HYDROYL } PHENYL) -N- (2-PHENYLACETYL) UREA

[ chemical formula 16 ]

3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } aniline [ raw material A ] (130mg) was dissolved in dimethylformamide (5 ml). Sodium hydride (23mg) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. Phenyl chloroformate (73. mu.l) was added thereto, and stirred at room temperature for 1 hour. Further, ammonium chloride (5mg) was added thereto, and the mixture was stirred for 10 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Ethyl acetate was removed by evaporation under reduced pressure. The residue was purified by chromatography on silica gel eluting with chloroform/ethyl acetate to give phenyl N- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) carbamate (72mg, 41% yield). Phenyl N- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-B ] pyridin-7-yl ] oxy } phenyl) carbamate (35mg) and 2-phenylacetamide [ raw material B ] (12mg) were dissolved in o-xylene (5ml), and the solution was stirred at 185 ℃ for 4 hours. O-xylene was removed by evaporation under reduced pressure, followed by purification by chromatography on silica gel, and development with chloroform/methanol to give the objective compound (8mg, yield 22%).

¹H-NMR(CDCl₃，400MHz)：δ3.77(s，2H)，3.97(s，3H)，6.54(dd，J＝1.0Hz，5.4Hz，1H)，7.03(d，J＝1.0Hz，1H)，7.17(d，J＝1.0Hz，1H)，7.19-7.45(m，8H)，7.70(s，1H)，7.83(s，1H)，8.49(d，J＝5.4Hz，1H)，10.64(s，1H)

Mass spectrum value (m/z): 500[ M-H ]]^-

Example 3: n- [2- (1H-1-indazolyl) acetyl]-N- (2-methoxy-4- { [2- (1-methyl-) 1H-2-imidazolyl) thieno [3, 2-b]Pyridin-7-yl]Oxy } phenyl) thiourea

[ chemical formula 17 ]

2-methoxy-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } aniline [ raw A ] (24mg) and di-2-pyridyl thiocarbonate (19mg) were dissolved in chloroform (5ml), and the solution was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. Chloroform was removed by evaporation under reduced pressure and the residue was purified by chromatography on silica gel and developed with chloroform/methanol to give 2-methoxy-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl isothiocyanate. 2- (1H-1-indazolyl) acetamide [ raw material B ] (11mg) and sodium hydride (2.8mg) were dissolved in dimethylformamide (2ml), and the mixture was stirred at room temperature for 20 minutes. To this was added a solution of 2-methoxy-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl isothiocyanate dissolved in dimethylformamide (4ml), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Ethyl acetate was removed by evaporation under reduced pressure, and the residue was purified by chromatography on silica gel and developed with chloroform/methanol to give the objective compound (11mg, yield 36%).

¹H-NMR(CDCl₃，400MHz)：δ3.91(s，3H)，3.97(s，3H)，5.20(s，2H)，6.66(d，J＝5.6Hz，1H)，6.79-6.81(m，2H)，7.04(s，1H)，7.17(s，1H)，7.26-7.29(m，1H)，7.44(d，J＝8.5Hz，1H)，7.49-7.51(m，1H)，7.72(s，1H)，7.83(d，J＝8.3Hz，1H)，8.25(s，1H)，8.50(d，J＝5.6Hz，1H)，8.75(d，J＝95Hz，1H)，9.22(s，1H)，12.39(s，1H)

Mass spectrum value (m/z): 568[ M-H]^-

The compounds of examples 4-13 were synthesized according to the methods described in examples 1, 2 and 3. The chemical structural formula, raw materials and synthesis method of the compound are respectively shown in table 1.

[ Table 1]

The data used to confirm the properties of the compounds of examples 4-13 are shown below.

Example 4:n- [2- (4-fluorophenyl) acetyl]-N- (4- { [2- (1-methyl-1H-2-imidazolyl) Thieno [3, 2-b]Pyridin-7-yl]Oxy } phenyl) thiourea

¹H-NMR(CDCl₃，400MHz)：δ3.74(s，2H)，3.96(s，3H)，6.64(d，J＝5.4Hz，1H)，7.03-7.30(m，8H)，7.71-7.73(m，3H)，8.50(d，J＝5.6Hz，1H)，9.48(s，1H)，12.41(s，1H)

Mass spectrum value (m/z): 518[ M + H]⁺

Example 5: n- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b]Pyridine-7- Base of]Oxy } phenyl) -N- [2- (4-fluorophenyl) acetyl]Thiourea

¹H-NMR(CDCl₃，400MHz)：δ3.73(s，2H)，3.97(s，3H)，6.57(d，J＝5.4Hz，1H)，7.03(s，1H)，7.12(t，J＝8.5Hz，2H)，7.17(d，J＝1.0Hz，1H)，7.27-7.31(m，2H)，7.40(d，J＝8.1Hz，1H)，7.72(s，1H)，7.94(d，J＝2.4Hz，11.7Hz，1H)，8.51(d，J＝5.4Hz，1H)，8.71(s，1H)，12.47(s，1H)

Mass spectrum value (m/z): 558[ M + Na ]]⁺

Example 6: n- (4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b]Pyridin-7-yl]Oxygen gas phenyl-N- (2-phenylacetyl) thiourea

¹H-NMR(CDCl₃，400MHz)：δ3.76(s，2H)，3.96(s，3H)，6.64(d，J＝5.4Hz，1H)，7.03(d，J＝1.0Hz，1H)，7.16-7.45(m，8H)，7.71-7.74(m，3H)，8.50(d，J＝5.4Hz，1H)，8.80(s，1H)，12.38(s，1H)

Mass spectrum value (m/z): 500[ M + H ]]⁺

Example 7: n- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b]Pyridine-7- Base of]Oxy } phenyl) -N- (2-phenylacetyl) thiourea

¹H-NMR(CDCl₃，400MHz)：δ3.76(s，2H)，3.97(s，3H)，6.57(d，J＝5.6Hz，1H)，7.03(d，J＝1.2Hz，1H)，7.17(d，J＝1.2Hz，1H)，7.29-7.33(m，3H)，7.37-7.45(m，4H)，7.94(dd，J＝2.4Hz，11.5Hz，1H)，8.48(s，1H)，8.51(d，J＝5.6Hz，1H)，12.49(s，1H)

Mass spectrum value (m/z): 516[ M-H]^-

Example 8: n- (2-methoxy-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b]Pyridine (II) Pyridin-7-yl]Oxy } phenyl) -N- (2-phenylacetyl) thiourea

¹H-NMR(CDCl₃，400MHz)：δ3.75(s，2H)，3.91(s，3H)，3.97(s，3H)，6.66(d，J＝5.4Hz，1H)，6.80(s，1H)，6.81(dd，J＝2.7Hz，8.3Hz，1H)，7.03(d，1.2Hz，1H)，7.17(d，1.0Hz，1H)，7.29-7.33(m，2H)，7.36-7.46(m，3H)，7.70(s，1H)，8.39(s，1H)，8.50(d，J＝5.4Hz，1H)，8.75-8.77(m，1H)，12.59(s，1H)

Mass spectrum value (m/z): 528[ M-H ]]^-

Example 9: n- (2-methoxy-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b]Pyridine (II) Pyridin-7-yl]Amino } phenyl) -N- (2-phenylacetyl) urea

¹H-NMR(CDCl₃，400MHz)：δ3.76(s，2H)，3.92(s，3H)，3.97(s，3H)，6.60(d，J＝5.4Hz，1H)，6.77(s，1H)，6.78(dd，J＝2.7Hz，10.5Hz，1H)，7.03(d，1.2Hz，1H)，7.17(d，1.2Hz，1H)，7.30-7.32(m，2H)，7.37-7.44(m，3H)，7.57(s，1H)，7.70(s，1H)，8.25(d，J＝8.3Hz，1H)，8.48(d，J＝5.4Hz，1H)，10.83(s，1H)

Mass spectrum value (m/z): 512[ M-H [ ]]^-

Example 10: n- [2- (1H-1-indazolyl) acetyl]-N- (4- { [2- (1-methyl-1H-2-imidazole) Yl) thieno [3, 2-b]Pyridin-7-yl]Oxy } phenyl) thiourea

¹H-NMR(CDCl₃，400MHz)：δ3.95(s，3H)，5.23(s，2H)，6.63(d，J＝5.6Hz，1H)，7.02(d，J＝0.7Hz，1H)，7.16-7.27(m，4H)，7.41-7.50(m，2H)，7.69-7.71(m，3H)，7.80(dd，J＝1.0Hz，7.1Hz，1H)，8.20(d，J＝0.7Hz，1H)，8.49(d，J＝5.4Hz，1H)，9.80(s，1H)，12.11(s，1H)

Mass spectrum value (m/z): 562[ M + Na ]]⁺

Example 11: n- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b]Pyridine- 7-yl]Oxy } phenyl) -N- [2- (1H-1-indazolyl) acetyl]Thiourea

¹H-NMR(CDCl₃，400MHz)：δ3.97(s，3H)，5.20(s，2H)，6.57(d，J＝5.4Hz，1H)，7.03(s，1H)，7.17(d，J＝1.0Hz，1H)，7.30-7.38(m，2H)，7.40-7.54(m，3H)，7.70(d，J＝0.7Hz，1H)，7.83(dd，J＝1.0Hz，8.3Hz，1H)，7.9(dd，J＝2.4Hz，11.5Hz，1H)，8.25(d，J＝0.7Hz，1H)，8.50(d，J＝5.6Hz，1H)，9.40(s，1H)，12.21(s，1H)

Mass spectrum value (m/z): 556[ M-H ]]^-

Example 12: n- (3-fluoro-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b]Pyridine- 7-yl]Oxy } phenyl) -N- [2- (1H-1-indazolyl) acetyl]Urea

¹H-NMR(CDCl₃，400MHz)：δ3.97(s，3H)，5.21(s，2H)，6.53(d，J＝4.6Hz，1H)，7.03(d，J＝1.0Hz，1H)，7.16(d，J＝1.2Hz，1H)，7.20-7.30(m，3H)，7.42(d，J＝8.1Hz，1H)，7.51(t，J＝7.3Hz，1H)，7.63-7.67(m，1H)，7.70(s，1H)，7.83(d，J＝8.1Hz，1H)，8.21(s，1H)，8.28(s，1H)，8.48(d，J＝5.4Hz，1H)，10.40(s，1H)

Mass spectrum value (m/z): 540[ M-H ]]^-

Example 13: n- [2- (1H-1-indazolyl) acetyl]-N- (2-methoxy-4- { [2- (1-methyl-) 1H-2-imidazolyl) thieno [3, 2-b]Pyridin-7-yl]Oxy } phenyl) urea

¹H-NMR(CDCl₃，400MHz)：δ3.93(s，3H)，3.97(s，3H)，5.21(s，2H)，6.60(d，J＝5.4Hz，1H)，6.77(s，1H)，6.78(dd，J＝2.4Hz，7.3Hz，1H)，7.03(s，1H)，7.16(d，1.0Hz，1H)，7.27-7.29(m，1H)，7.42(d，J＝8.5Hz，1H)，7.50(t，8.1Hz，1H)，7.69(s，1H)，7.82(d，J＝8.1Hz，1H)，8.13(s，1H)，8.20-8.23(m，2H)，8.48(d，J＝5.4Hz，1H)，10.66(s，1H)

Mass spectrum value (m/z): 552[ M-H ]]^-

Preparation example a: 7-fluoroindazoles

Hydrazine monohydrate (3ml) was added to 2, 3-difluorobenzaldehyde (1.85g), and the mixture was heated at 180 ℃ and stirred for 10 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto, and the organic layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate as a waste water, and the solvent was removed by evaporation under reduced pressure. The residue was purified by chromatography on silica gel and developed with chloroform/acetone to give the objective compound (790mg, yield 45%).

¹H-NMR(CD₃OD，400MHz)：δ7.08-7.12(m，2H)，7.56-7.59(m，1H)，8.10(d，J＝3.4Hz，1H)

Preparation example B: 2- (1H-indazolyl) acetamide

Indazole (6.55g) was dissolved in dimethylformamide (150ml), sodium hydride (60%) was added to the solution under ice bath cooling, and stirred at room temperature for 30 minutes. The mixture was cooled again in an ice bath, methyl bromoacetate (6.1ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. The solvent was then removed by evaporation and the residue was purified by chromatography on silica gel with chloroform/ethyl acetate as eluent to give methyl 2- (1H-indazolyl) acetate (7.5g, 74% yield). Next, methyl 2- (1H-indazolyl) acetate (7.5g) was dissolved in methanol (75ml), 28% aqueous ammonia was added to the solution, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration and washed with methanol to obtain the objective compound (5.6g, yield 81%).

¹H-NMR(CDCl₃，400MHz)：5.07(s，2H)，5.44(brs，1H)，5.81(brs，1H)，7.21-7.26(m，1H)，7.42-7.49(m，2H)，7.78(d，J＝8.1Hz，1H)，8.12(s，1H)

Preparation example C: 4- [ (6, 7-dimethoxy-4-quinolyl) oxy]-3-fluorophenyl isothiocyanate

4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -3-fluoroaniline (3.1g) was dissolved in chloroform (100 ml). Di-2-pyridyl thiocarbamate (2.6g) was added to the solution, and the mixture was stirred at room temperature for 20 minutes. Water was added, and the mixture was extracted with chloroform. The organic phase was washed with saturated brine and then dried over magnesium sulfate. The solvent was removed by evaporation. The obtained crystals were washed with a mixed solution composed of ethyl acetate and hexane (1: 1) and dried by a vacuum pump to obtain the objective compound (3.3g, yield 93%).

¹H-NMR(CDCl₃，400MHz)：4.06(s，3H)，4.06(s，3H)，6.41(d，J＝5.4Hz，1H)，7.10-7.18(m，2H)，7.22-7.27(m，1H)，7.44(s，1H)，7.53(s，1H)，8.52(d，J＝5.1Hz，1H)

Preparation example D: 4- [ (6, 7-dimethoxy-4-quinolyl) oxy]-2-methoxyphenyl isothiocyanate

The title compound (2.2g, yield 61%) was obtained in the same manner as in preparation C except that 4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-methoxyaniline was used as a starting material.

¹H-NMR(CDCl₃，400 MHz)：3.90(s，3H)，4.04(s，3H)，4.06(s，3H)，6.52(d，J＝5.1Hz，1H)，6.71(dd，J＝2.4Hz，8.5Hz，1H)，6.76(d，J＝2.4Hz，1H)，7.17(d，J＝8.5Hz，1H)，7.44(s，1H)，7.49(s，1H)，8.53(d，J＝5.4Hz，1H)

Preparation example E: n-4- [ (6, 7-dimethoxy-4-quinolyl) oxy]-3-fluorophenyl carbamic acid phenyl Esters

4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -3-fluoroaniline (5g) was dissolved in dimethylformamide (100 ml). The solution was cooled with an ice bath and the mixture was stirred at room temperature for 30 minutes. The mixed solution was cooled again in an ice bath, and phenyl chloroformate (3ml) was added thereto and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and then dried over sodium sulfate. The solvent was removed by evaporation, and the obtained crystals were washed with a mixed solution composed of ethyl acetate and hexane (1: 1) and dried by a vacuum pump to obtain the objective compound (3.3g, yield 47%).

¹H-NMR(CDCl₃，400MHz)：4.05(s，3H)，4.07(s，3H)，6.42(d，J＝5.1Hz，1H)，7.20-7.29(m，5H)，7.40-7.44(m，3H)，7.58-7.64(m，2H)，8.51(d，J＝5.4Hz，1H)

Example 14: n- [4- { [6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl]-N’-[2- (1H-1-indazolyl) acetyl]Urea

[ chemical formula 18 ]

Phenyl N-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -3-fluorophenyl carbamate (preparation E) (1.92g) and 2- (1H-indazole) acetamide (preparation B) (1.0g) were added to o-xylene (150ml), and the mixture was stirred at 180 ℃ for 4 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel and developed with chloroform/methanol to give the title compound (1.0g, 40% yield).

¹H-NMR(CDCl₃，400MHz)：4.05(s，3H)，4.06(s，3H)，5.21(s，2H)，6.40(d，J＝5.4Hz，1H)，7.18-7.30(m，3H)，7.41-7.43(m，2H)，7.49-7.53(m，1H)，7.57(s，1H)，7.64-7.67(m，1H)，7.83(d，J＝8.1Hz，1H)8.21(s，1H)，8.32(brs，1H)，8.49(d，J＝5.1Hz，1H)，10.40(brs，1H)

Mass spectrum value (m/z): 514[ M ]⁺-1]

Example 15: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl]- N' - [2- (1H-1-indazolyl) acetyl]Thiourea

[ chemical formula 19 ]

2- (1H-indazole) acetamide (preparation B) (350mg) was dissolved in N, N-dimethylformamide (40 ml). Sodium hydride (60%) (96mg) was added to the solution, and the mixture was stirred for 30 minutes. N-4- [ (6, 7-dimethoxy-4-quinolyl) oxy ] -2-methoxyphenyl isothiocyanate (preparation D) (713mg) was added thereto, and the mixture was stirred for another 2 hours. Water was added to the mixed solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was removed by evaporation, and acetonitrile was added to the residue to conduct crystallization. The resulting crystals were collected by filtration, washed with ethyl acetate and acetonitrile, and dried by vacuum pump to obtain the objective compound (650mg, yield 56%).

¹H-NMR(CDCl₃，400MHz)：δ3.93(s，3H)，4.10(s，3H)，4.17(s，3H)，5.30(s，2H)，6.76-6.86(m，3H)，7.28-7.30(m，1H)，7.46-7.53(m，2H)，7.62(s，1H)，7.88(dd，J＝1.0Hz，7.3Hz，1H)，8.15(s，1H)，8.25(d，J＝1.0Hz，1H)，8.57(t，J＝6.6Hz，1H)，8.87(d，J＝8.8Hz，1H)，9.69(brs，1H)，12.45(brs，1H)

Mass spectrum value (m/z): 542[ M ]⁺-1]

The compounds of examples 16-35 were synthesized according to the methods described in examples 14 and 15. The chemical structural formula, raw materials, synthesis method and data for confirming the compound are shown in table 2.

[ Table 2]

NMR data of the compounds of examples 16 to 35 are shown below.

Example 16: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-chlorophenyl]-N’-[2- (1H-1-indolyl) acetyl]Urea

¹H-NMR(CDCl₃，400MHz)：4.05(s，3H)，4.05(s，3H)，4.97(s，2H)，6.40(d，J＝5.4Hz，1H)，6.69(t，J＝1.5Hz，1H)，7.12(d，J＝3.2Hz，1H)7.21-7.23(m，3H)，7.28-7.32(m，2H)，7.41(s，1H)，7.57(s，1H)，7.63-7.71(m，2H)，8.46(d，J＝5.4Hz，1H)，10.50(s，1H)

Example 17: n- [4- { [6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl]- N' - [2- (1H-1-indazolyl) acetyl]Urea

¹H-NMR(CDCl₃，400MHz)：δ3.92(s，3H)，4.05(s，3H)，4.05(s，3H)，5.21(s，2H)，6.48(d，J＝5.4Hz，1H)，6.75-6.79(m，2H)，7.18-7.29(m，1H)，7.41-7.52(m，3H)，7.54(s，1H)，7.82(d，J＝8.3Hz，1H)，8.15(s，1H)，8.20-8.23(m，2H)，8.48(d，J＝5.1Hz，1H)，10.66(brs，1H)

Example 18: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl]-N’-[2- (1H-1-indazolyl) acetyl]Thiourea

¹H-NMR(CDCl₃，400MHz)：δ4.11(s，3H)，4.17(s，3H)，5.34(s，2H)，6.72(d，J＝6.3Hz，1H)，7.29-7.36(m，2H)，7.47-7.55(m，3H)，7.64(s，1H)，7.83(d，J＝8.1Hz，1H)，8.03(dd，J＝2.4，11.5Hz，1H)，8.15(s，1H)，8.25(d，J＝1.0Hz，1H)，8.61(t，J＝6.3Hz，1H)，9.97(brs，1H)，12.33(brs，1H)

Example 19: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-fluorophenyl]-N’-[2- (1H-1-indazolyl) acetyl]Urea

¹H-NMR(CDCl₃，400MHz)：δ4.03(s，3H)，4.05(s，3H)，5.22(s，2H)，6.51(d，J＝5.4Hz，1H)，6.96-7.01(m，2H)，7.23-7.29(m，1H)，7.42-7.53(m，4H)，7.83(d，J＝8.1Hz，1H)，8.16-8.21(m，2H)，8.30(brs，1H)，8.51(d，J＝5.1Hz，1H)，10.52(brs，1H)

Example 20: n- [2- (3-chloro-1H-1-indazolyl) acetyl]-N' - [4- { (6, 7-dimethoxy-) 4-quinolyl) oxy } phenyl]Urea

¹H-NMR(CDCl₃，400MHz)：δ4.04(s，3H)，4.05(s，3H)，5.16(s，2H)，6.45(d，J＝5.1Hz，1H)，7.16(d，J＝8.8Hz，2H)，7.32-7.41(m，2H)，7.42(s，1H)，7.54(s，1H)，7.56(s，1H)，7.58(d，J＝4.6Hz，2H)，7.78(d，J＝8.3Hz，1H)，8.26(brs，1H)，8.48(d，J＝5.1Hz，1H)，10.29(brs，1H)

Example 21: n- [2- (3-chloro-1H-1-indazolyl) acetyl]-N' - [4- { (6, 7-dimethoxy-) 4-quinolyl) oxy } -3-fluoroPhenyl radical]Urea

¹H-NMR(CDCl₃，400MHz)：δ4.05(s，3H)，4.06(s，3H)，5.16(s，2H)，6.40(d，J＝5.1Hz，1H)，7.21-7.23(m，2H)，7.32-7.43(m，3H)，7.54-7.59(m，2H)，7.64-7.67(m，1H)，7.78(d，J＝8.3Hz，1H)，8.23(brs，1H)，8.49(d，J＝5.1Hz，1H)，10.38(brs，1H)

Example 22: n- [ 3-chloro-4- { (6, 7-dimethoxy-4-quinolyl) oxy } phenyl]-N’-[2- (1H-1-indazolyl) acetyl]Urea

¹H-NMR(CDCl₃，400MHz)：δ4.05(s，3H)，4.06(s，3H)，5.21(s，2H)，6.31(d，J＝5.4Hz，1H)，7.20(d，J＝8.8Hz，2H)，7.29-7.31(m，2H)，7.42-7.46(m，2H)，7.49-7.54(m，1H)，7.58(s，1H)，7.80(s，1H)，7.83(d，J＝8.3Hz，1H)，8.22(brs，1H)，8.27(s，1H)，8.48(d，J＝5.4Hz，1H)，10.37(brs，1H)

Example 23: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl]-N’-[2- (1H-1-pyrrolo [2, 3-b)]Pyridin-1-yl) acetyl]Thiourea

¹H-NMR(CDCl₃，400MHz)：δ4.05(s，3H)，4.05(s，3H)，5.09(s，2H)，6.45(d，J＝5.4Hz，1H)，6.61(dd，J＝3.7Hz，1H)，7.19-7.26(m，2H)，7.37-7.40(m，1H)，7.44(s，1H)，7.55(s，1H)，7.90(dd，J＝2.4，11.5Hz，1H)，8.00(dd，J＝1.5，7.8Hz，1H)，8.03(s，1H)，8.43(dd，J＝1.5，4.6Hz，1H)，8.51(d，J＝5.1Hz，1H)，10.72(s，1H)，12.22(brs，1H)

Example 24: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-fluorophenyl]-N’-[2-(4- fluoro-1H-1-indazolyl) acetyl]Thiourea

¹H-NMR(CDCl₃，400MHz)：δ4.06(s，3H)，4.06(s，3H)，5.20(s，2H)，6.45(d，J＝5.1Hz，1H)，6.92(dd，J＝7.8，9.5Hz，1H)，7.2 1-7.29(m，2H)，7.39-7.49(m，3H)，7.55(s，1H)，7.90(dd，J＝2.7，11.5Hz，1H)，8.32(brs，1H)，8.51(d，J＝5.4Hz，1H)，9.32(s，1H)，12.16(brs，1H)

Example 25: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl]-N’-[2-(4- fluoro-1H-1-indazolyl) acetyl]Thiourea

¹H-NMR(CDCl₃，400MHz)：δ4.03(s，3H)，4.05(s，3H)，5.20(s，2H)，6.61(d，J＝5.1Hz，1H)，6.92(dd，J＝7.8，9.8Hz，1H)，6.99-7.03(m，2H)，7.22-7.24(m，1H)，7.42-7.52(m，3H)，8.30-8.35(m，2H)，8.55(d，J＝5.4Hz，1H)，9.39(s，1H)，12.06(brs，1H)

Example 26: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl]- N' - [2- (4-fluoro-1H-1-indazolyl) acetyl]Thiourea

¹H-NMR(CDCl₃，400 MHz)：δ3.89(s，3H)，4.04(s，3H)，4.05(s，3H)，5.19(s，2H)，6.55(d，J＝5.1Hz，1H)，6.78-6.82(m，2H)，6.91(dd，J＝7.8，9.8Hz，1H)，7.21(d，J＝8.5Hz，1H)，7.42-7.47(m，2H)，7.52(s，1H)，8.31(d，J＝0.7Hz，1H)，8.51(d，J＝5.1Hz，1H)，8.73(d，J＝8.5Hz，1H)，9.17(s，1H)，12.33(brs，1H)

Example 27: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } phenyl]-N' - [2- (4-fluoro- 1H-1-indazolyl) acetyl]Urea

¹H-NMR(CDCl₃，400MHz)：δ4.04(s，3H)，4.05(s，3H)，5.22(s，2H)，6.45(d，J＝5.4Hz，1H)，6.91(dd，J＝7.8，9.8Hz，1H)，7.15(d，J＝9.0Hz，2H)，7.21(d，J＝8.5Hz，1H)，7.42-7.47(m，2H)，7.54(s，1H)，7.57(d，J＝9.0Hz，2H)，8.27(d，J＝0.7Hz，1H)，8.36(s，1H)，8.48(d，J＝5.4Hz，1H)，10.28(s，1H)

Example 28: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-fluorophenyl]-N’-[2-(4- fluoro-1H-1-indazolyl) acetyl]Thiourea

¹H-NMR(CDCl₃，400MHz)：δ4.03(s，3H)，4.05(s，3H)，5.22(s，2H)，6.51(d，J＝5.1Hz，1H)，6.92(dd，J＝7.8，9.5Hz，1H)，6.97-7.02(m，2H)，7.21(d，J＝8.5Hz，1H)，7.43-7.48(m，3H)，8.16-8.21(m，1H)，8.29(m，2H)，8.52(d，J＝5.1Hz，1H)，10.48(s，1H)

Example 29: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl]- N' - [2- (4-fluoro-1H-1-indazolyl) acetyl]Urea

¹H-NMR(CDCl₃，400MHz)：δ3.91(s，3H)，4.05(s，3H)，4.05(s，3H)，5.21(s，2H)，6.48(d，J＝5.4Hz，1H)，6.75-6.80(m，2H)，6.91(dd，J＝7.8，9.8Hz，1H)，7.20(d，J＝8.5Hz，1H)，7.41-7.46(m，2H)，7.54(s，1H)，8.22(s，1H)，8.23(d，J＝8.5Hz，1H)，8.27(d，J＝1.0Hz，1H)，8.49(d，J＝5.1Hz，1H)，10.63(brs，1H)

Example 30: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl]-N’-[2-(4- fluoro-1H-1-indazolyl) acetyl]Urea

¹H-NMR(CDCl₃，400MHz)：δ4.05(s，3H)，4.06(s，3H)，5.21(s，2H)，6.40(d，J＝5.1Hz，1H)，6.92(dd，J＝7.8，9.5Hz，1H)，7.19-7.22(m，3H)，7.42(s，1H)，7.44-7.48(m，1H)，7.57(s，1H)，7.64-7.68(m，1H)，8.28(d，J＝1.0Hz，1H)，8.33(s，1H)，8.49(d，J＝5.1Hz，1H)，10.36(brs，1H)

Example 31: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl]-N’-[2- (1H-pyrazolo [3, 4-b)]Pyridin-1-yl) acetyl]Thiourea

¹H-NMR(CDCl₃，400MHz)：δ4.05(s，3H)，4.05(s，3H)，5.42(s，2H)，6.46(d，J＝5.1Hz，1H)，7.23-7.28(m，2H)，7.37-7.40(m，1H)，7.44(s，1H)，7.55(s，1H)，7.91(dd，J＝2.4，11.5Hz，1H)，8.17(dd，J＝1.5，8.1Hz，1H)，8.22(s，1H)，8.51(d，J＝5.4Hz，1H)，8.63(dd，J＝1.5，4.6Hz，1H)，9.91(s，1H)，12.26(brs，1H)

Example 32: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl]- N' - [2- (7-fluoro-1H-1-indazolyl) acetyl]Thiourea

¹H-NMR(CDCl₃，400MHz)：δ3.89(s，3H)，4.04(s，3H)，4.05(s，3H)，5.38(s，2H)，6.55(d，J＝5.1Hz，1H)，6.77-6.82(m，2H)，7.13-7.18(m，2H)，7.43(s，1H)，7.52(s，1H)，7.56-7.59(m，1H)，8.23(d，J＝2.4Hz，1H)，8.51(d，J＝5.4Hz，1H)，8.73(d，J＝8.8Hz，1H)，9.08(s，1H)，12.37(s，1H)

Example 33: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl]- N' - [2- (7-fluoro-1H-1-indazolyl) acetyl]Urea

¹H-NMR(CDCl₃，400MHz)：δ3.90(s，3H)，4.05(s，3H)，4.05(s，3H)，5.39(s，2H)，6.48(d，J＝5.1Hz，1H)，6.75-6.80(m，2H)，7.14-7.18(m，2H)，7.42(s，1H)，7.55(s，1H)，7.57(d，J＝8.8Hz，1H)，8.05(s，1H)，8.19(d，J＝2.2Hz，1H)，8.24(d，J＝8.58Hz，1H)，8.49(d，J＝5.4Hz，1H)，10.67(s，1H)

Example 34: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl]- N' - [2- (1H-1-pyrazolo [3, 4-H)]Pyridin-1-yl) acetyl]Urea

¹H-NMR(CDCl₃，400MHz)：δ3.49(s，3H)，4.05(s，3H)，4.05(s，3H)，5.40(s，2H)，6.48(d，J＝5.4Hz，1H)，6.74-6.79(m，2H)，7.23-7.27(m，1H)，7.42(s，1H)，7.55(s，1H)，8.16(dd，J＝1.5Hz，8.1Hz，1H)，8.20(s，1H)，8.23(d，J＝8.8Hz，1H)，8.49(d，J＝5.4Hz，1H)，8.52(s，1H)，8.62(dd，J＝1.5Hz，4.6Hz，1H)，10.69(brs，1H)

Example 35: n- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -3-fluorophenyl]-N’-[2- (1H-1-pyrazolo [3, 4-b)]Pyridin-1-yl) acetyl]Urea.

¹H-NMR(CDCl₃，400MHz)：δ4.05(s，3H)，4.06(s，3H)，5.40(s，2H)，6.40(d，J＝5.4Hz，1H)，7.20-7.29(m，3H)，7.42(s，1H)，7.57(s，1H)，7.65-7.68(m，1H)，8.18(dd，J＝1.7Hz，8.1Hz，1H)8.21(s，1H)，8.49(d，J＝5.4Hz，2H)，8.63(dd，J＝1.5Hz，4.6Hz，1H)，10.44(s，1H)

Compound A

[ chemical formula 20 ]

Compound A (N- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl ] -N' - [2- (4-fluorophenyl) acetyl ] thiourea) was synthesized according to the method described in Japanese patent laid-open publication No. 158149/1999 and WO 03/00660 (in particular, the synthesis method described in example 2).

¹H-NMR(CDCl₃，400MHz)：δ3.72(s，2H)，3.89(s，3H)，4.04(s，3H)，4.06(s，3H)，6.55(d，J＝5.4Hz，1H)，6.78-6.82(m，2H)，7.12(t，J＝8.5Hz，2H)，7.30(dd，J＝5.4，8.5Hz，2H)，7.43(s，1H)，7.52(s，1H)，8.43(brs，1H)，8.52(d，J＝5.1Hz，1H)，8.75(d，J＝8.8Hz，1H)，12.53(brs，1H)

Mass spectrum value (m/z): 520[ M ]⁺-1]

Compound B

[ chemical structural formula 21 ]

Compound A (N- { 2-methoxy-4- [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinolyl ] oxyphenyl } -N' - (2-phenylacetyl) thiourea) was synthesized according to the method described in Japanese patent laid-open No. 158149/1999 and WO 03/00660 (in particular, the synthesis method described in example 268).

¹H-NMR(CDCl₃，400MHz)：δ2.12-2.17(m，2H)，2.49(m，4H)，2.58(t，J＝7.3Hz，2H)，3.72(t，J＝4.4Hz，4H)，3.73(s，2H)，3.89(s，3H)，4.02(s，3H)，4.28(t，J＝6.6Hz，2H)，6.54(d，J＝5.1Hz，1H)，6.78-6.81(m，2H)，7.29-7.46(m，6H)，7.51(s，1H)，8.37(brs，1H)，8.50(d，J＝5.1Hz，1H)，8.74(d，J＝8.8Hz，1H)，12.57(brs，1H)

Pharmacological test example 1: determination of human c-Met enzyme inhibitory Activity

A cDNA code for a region around a human c-Met kinase domain was integrated into a pFastBac vector (invitrogen) and a GST tag was inserted therein, followed by conversion into DH10Bac to thereby obtain Bacmid DNA, which was then introduced into SF9 cells (GIBCO). Repeated infection with virus fluid was performed 5 times, and then SF9 cells were disrupted, followed by purification using GSH column to obtain c-Met kinase active protein.

Poly Glu: Tyr ═ 4: 1(SIGMA) was coated on a 96-well immunoplate (442404, NALGE NUNC International K.K.) above. Kinase buffer (50mM HEPES (pH7.5), 25mM NaCl, 0.01mM Na) was added₃VO₄0.01% BSA), test compound and kinase protein, and the mixture was incubated for 10 minutes. ATP (10. mu.M, SIGMA) was then added and the reaction allowed to proceed for 10 minutes. The plate was washed three times with PBST and reacted with each of a primary antibody PY-20(BD-610000, B.D. bioscience) and a secondary antibody GAM (NA-9310V, Abersham) at room temperature for 1 hour. The plates were washed with PBST and then developed with SUMILON (ML-1120T, Sumitomo Badelite Co., Ltd.) to quantitatively determine phosphorylated tyrosines by measuring absorbance at 450 nm. The absorbance of wells without ATP addition was defined as 100% inhibition, the absorbance of wells with test compound medium and ATP addition was defined as 0% inhibition, and IC was calculated based on the concentration difference curve of the test compound₅₀。

As a result, IC of the compounds of examples 1, 14 and 15₅₀(nM) 3.2, 12.5 and 9.6, respectively. The inhibitory activity of the compounds of the other examples was also observed.

Pharmacological test example 2: determination of c-Met-autophosphorylation Using ELISA method Inhibitory Activity of (1)

Human epidermal cancer cells (a431) (available from JCRB) were cultured in RPMI 1640 medium containing 10% fetal bovine serum (available from gibbcobrl) in a 5% carbon dioxide incubator until 50-90% confluence was reached. Collecting cells at 3X 10⁴The amount per well was inoculated into wells containing RPMI medium containing 0.1% fetal bovine serum in 96-well flat-bottom plates, followed by overnight incubation at 37 ℃. The medium was then replaced with fresh RPMI medium containing 0.1% fetal bovine serum. Test compounds dissolved in dimethyl sulfoxide were added to each well and incubated at 37 ℃ for an additional 1 hour. Human recombinant hepatocyte growth factor (hereinafter abbreviated as "HGF") was added to a final concentration of 50ng/ml, and the cells were stimulated at 37 ℃ for 5 minutes. The medium was removed, the cells were washed with phosphate buffered physiological saline (pH7.4), and then 50. mu.l of a solubilizing buffer (20mM HEPES (pH7.4), 150 mM) was added theretoNaCl, 0.2% Triton X-100, 10% glycerol, 5mM sodium orthovanadate. 5mM disodium EDTA and 2mM Na₂P₂O₇). The mixture was shaken at 4 ℃ for 2 hours to prepare a cell extract.

Separately, phosphate buffered saline (50. mu.l, ph7.4) containing 5. mu.g/ml of anti-phospho-tyrosine antibody (PY 20; available from the Transduction laboratory) was added to a microplate for ELISA (Maxisorp; available from NUNC), followed by standing overnight at 4 ℃ to form a solid phase. The plate was washed with water, after which 300. mu.l of blocking solution was added, and then left at room temperature for 2 hours to perform blocking. After washing, the whole cell extract was transferred and the plate was left overnight at 4 ℃. After washing, the anti-HGF receptor antibody was allowed to react for 1 hour at room temperature, and after washing, the peroxidase-labeled anti-rabbit Ig antibody (purchased from Amersham) was allowed to react for 1 hour at room temperature. After washing, a chromophore matrix for peroxidase (available from Sumitomo Bakelite co., Ltd) was added thereto to initiate the reaction. After an appropriate level of color was formed, the reaction was stopped by adding a reaction stop solution, and the absorbance at 450nm was measured with a microplate reader. The c-Met-autophosphorylation inhibitory activity of each well was determined by setting the absorbance when HGF was added without addition of the test compound to 0% of the c-Met-autophosphorylation inhibitory activity, and the absorbance when HGF was added without addition of the test compound and with addition of HGF to 100% of the c-Met-autophosphorylation inhibitory activity. The concentration of the test compound was varied to several levels, the c-Met-autophosphorylation inhibitory activity was determined in each case, and the c-Met-autophosphorylation (IC) inhibiting 50% was calculated₅₀) Desired test compound concentration.

Pharmacological test example 3: determination of c-Met-autophosphorylation Using ELISA method Inhibitory Activity of (2)

The human gastric cancer cell line MKN45 (available from Riken) was cultured in RPMI 1640 medium containing 10% fetal bovine serum (available from gibbcobrl) in a 5% carbon dioxide incubator until 50-90% fusion was achieved. Collecting cells at 3X 10⁴The amount per well was inoculated into wells containing RPMI medium containing 0.1% fetal bovine serum in 96-well flat-bottom plates, followed by overnight incubation at 37 ℃. The medium was then replaced with fresh RPMI medium containing 0.1% fetal bovine serum. Test compounds dissolved in dimethyl sulfoxide were added to each well and incubated at 37 ℃ for an additional 1 hour. The medium was removed, the cells were washed with phosphate buffered saline (pH7.4), and then 50. mu.l of a solubilizing buffer (20mM HEPES (pH7.4), 150mM NaCl, 0.2% Triton X-100, 10% glycerol, 5mM sodium metavanadate, 5mM disodium EDTA and 2mM Na₂P₂O₇). The mixture was shaken at 4 ℃ for 2 hours to prepare a cell extract.

Separately, phosphate buffered saline (50. mu.l, ph7.4) containing 5. mu.g/ml of anti-phospho-tyrosine antibody (PY 20; available from the Transduction laboratory) was added to a microplate for ELISA (Maxisorp; available from NUNC), followed by standing overnight at 4 ℃ to form a solid phase. The plate was washed with water, after which 300. mu.l of blocking solution was added, and then left at room temperature for 2 hours to perform blocking. After washing, the whole cell extract was transferred and the plate was left overnight at 4 ℃. anti-HGF receptor antibody was allowed to react for 1 hour at room temperature after washing, and peroxidase-labeled anti-rabbit Ig antibody (purchased from Amersham) was allowed to react for 1 hour at room temperature after washing. After washing, a chromophore matrix for peroxidase (available from Sumitomo Bakelite co., Ltd) was added thereto to initiate the reaction. After an appropriate level of color was formed, the reaction was stopped by adding a reaction stop solution, and the absorbance at 450nm was measured with a microplate reader. The c-Met-autophosphorylation activity of each well was determined by setting the absorbance without addition of the test compound to 100% of the c-Met-autophosphorylation activity and the absorbance with addition of a large excess of the positive control to 0% of the c-Met-autophosphorylation activity. The concentration of the test compound was varied to several levels, the rate of inhibition of c-Met-autophosphorylation was determined in each case, and the rate of c-Met-autophosphorylation (IC) at which 50% inhibition was observed was calculated₅₀) Desired test compound concentration.

As a result, IC of the compounds of examples 1, 14, 15 and 16₅₀(nM) 32.8, 22.3, 13.2 and 35.9, respectively. In addition, it was confirmed that the compounds of the other examples in addition to these compounds also had inhibitory activity.

Pharmacological test example 4: inhibition of tumor growth in human gastric cancer cell lines MKN45 Preparation activity

A human gastric cancer cell line MKN45 (available from Riken) was transplanted in nude mice. When the tumor volume reaches 100mm³At the time, the nude mice were grouped such that each group included 4 nude mice and even had an average tumor volume. Test compounds suspended in 0.5% methylcellulose were administered orally once daily for 9 days.

Only 0.5% of methylcellulose was administered to the control group in the same manner as the test group. Tumor Growth Inhibition Rate (TGIR) was calculated as follows: tumor Growth Inhibition Rate (TGIR) ═ 1-TX/CX × 100, where CX represents the tumor volume at the X-th day in the control group, TX represents the tumor volume in the test compound-administered group, and the tumor volume on the day of starting administration was set to 1.

As a result, the TGIR values (%) of the compounds of examples 1 and 14 were 63.8 (day 9) and 42.6 (day 10), respectively.

Pharmacological test example 5: inhibition of tumor growth in human cancer-placing cell line NU-GC-4 Preparation activity

A human gastric Cancer Cell line NU-GC-4 (available from Cell Resource for BiomedicalResearch, Institute of Development Aging and Cancer, university of Tohoku) was transplanted into nude mice. When the tumor volume reaches 100mm³At the time, the nude mice were grouped such that each group included 4 nude mice and even had an average tumor volume. Test compounds suspended in 0.5% methylcellulose were administered orally once daily for 9 days.

As a result, the TGIR value (%) of Compound A (25mg/kg) was 78 (day 10).

Pharmacological test example 6: inhibitory Activity on tumor growth of various human tumor cell lines

Human brain tumor Cell line U87-MG (ATCC), human pancreatic Cancer Cell line KP4(Riken), human renal Cancer Cell line Caki-1 (available from Cell Resource Center for biological Research, Institute of Development Aging and Cancer, university of Tohoku) or human lung Cancer Cell line (GC6) (available from Central Laboratories of Experimental animals) were transplanted into nude mice. When the tumor volume reaches 100mm³At the time, the nude mice were grouped such that each group included 4 nude mice and even had an average tumor volume. Test compounds suspended in 0.5% methylcellulose were administered orally once per eye for 9 days.

Pharmacological test example 7: determination of c-Met and KDR enzyme inhibitory Activity

c-Met protein (north continental, lot No.:25735AU, accession number: 14-526) to 10 mg/. mu.l. KDR protein (812-1346AA) was prepared from SF21 insect cells (affinity purified, 12.4. mu.g/. mu.l) according to the Invitrogen protocol (Bac to Bac (trade Mark) baculovirus expression system) and diluted to 248 ng/. mu.l with EDB. 5-fold concentration of reaction buffer (40mM MOPS (pH7.4), 1mM EDTA) (5. mu.l), 10-fold concentration of Compound A (5. mu.l), 250mM NaCl was added under ice bath₂(2.5. mu.l), sterilized distilled water (2.5. mu.l), c-Met protein or KDR protein (5. mu.l) were mixed therein. ATP reaction solution (25mM ATP, 10. mu.ci/. mu.l. gamma. -32P-ATP (1. mu.l), 25mM Mg (OAc) was added₂And 1.25mM Hepes (pH7.4)) (10. mu.l), and the mixture was allowed to react at 37 ℃ for 10 minutes. The reaction was stopped by adding a tris-SDS β -ME sample treatment solution (301780, Daiichi Dagaku Inc. (10. mu.l). The reaction solution was boiled at 95 ℃ for 5 minutes, followed by SDS-PAGE. The gel was filled after migration, and an imaging plate (Fuji film) was applied to the gel for transfer, followed by analysis with typhoon (amersham biosciences). IC was calculated using GraphPad Prism version 4 analytical Software (GraphPad Software, Inc.)₅₀The value is obtained.

As a result, IC of c-Met protein₅₀IC of 15.5nM, KDR protein₅₀Less than 1000nM (Table 3), indicating that Compound A has high c-Met protein inhibitory activity and has low KDR protein inhibitory activity.

[ Table 3]

Receptors	IC₅₀(nM)
Receptors	IC₅₀(nM)	c-Met	15.5
KDR	＞1000	c-Met	15.5

Pharmacological test example 8: enzyme inhibitory Activity of c-Met and KDR in cultured cells Measurement of

The c-Met autophosphorylation inhibition was measured using MKN45 (poorly differentiated gastric cancer cell line in humans, Riken) and A431 (epithelial cancer cell line in humans, JCRB), and the KDR autophosphorylation inhibition activity was measured using HUVEC.

(1) Assay for inhibition of c-Met autophosphorylation

Mixing MKN45 (2.5X 10)⁵Per well) or A431 (8.5X 10)⁵/well) were seeded in wells of a 6-well plate (collagen type I coated plate, 4810-010, IWAKI) containing RPMI (gibco) containing 0.1% fetal bovine serum (JRH Biosciences), 24 hours after which the original medium was replaced with RPMI medium containing 0.1% fetal bovine serum. Thereafter, compound A was added, followed by 37 ℃ and 5% CO₂Incubate for 90 minutes. Cultures were removed without stimulating MKN45, followed by 50ng/ml HGF (294-HG, R)&D system) a 43110 min. Adding solubilized buffer solution (20mM HEPES (pH7.4), 150mM NaCl, 0.2% TritonX-100, 10% glycerol, 5mM sodium orthovanadate, 5mM disodium ethylenediaminetetraacetate and 2mM Na₂P₂O₇) To solubilize the cells well. Immunoprecipitation was performed with C-Met antibody (C12, Santa Culz) (protein G Sepharose (trade Mark) 4 high fluidity, Ameersham biosciences). Treatment was performed with SDS-PAGE and phosphotyrosine antibody PY20(610000, Ameersham Biosciences) for blotting, and ECL (trademark) (RPN2106, Ameersham Biosciences) treatment was performed. The films were quantified using a Scion image and IC determined using Graph Pad Prism 4 th edition analytical Software (Graph Pad Software, Inc.)₅₀The value is obtained.

(2) Determination of the autophosphorylation inhibition of KDR

HUVEC were inoculated into EGM medium (KURABO INDUSTRIES LTD.) to give a cell number of 2X 10⁶A/100-mm petri dish (collagen-coated dish, 4020-010, IWAKI) was inoculated 24 hours later and replaced with EBM medium (KURABO INDUSTRIES LTD.) containing 0.1% fetal bovine serum. Compound a was added and the compound was incubated for 90 minutes. After 5 minutes with 50ng/ml VEGF (100-20, PeproTech, Inc.), the culture was removed. Using the above-described measurement method of C-Met autophosphorylation inhibitory activity, immunoprecipitation was carried out using KDR antibody (Flk-1, C-1158, St. Kraus.) and the residue, followed by determination of KDR autophosphorylation inhibitory activity by SDS-PAGE.

As a result, the c-Met IC of MKN45₅₀11.3nM and A431 9.3 nM. Furthermore, in HUVEC, IC of KDR₅₀Less than 1000nM (Table 4).

The above results show that compound A has high c-Met autophosphorylation inhibition activity but low KDR autophosphorylation inhibition activity, indicating that compound A has high c-Met/KDR selectivity.

[ Table 4]

Receptors (cells)	IC₅₀(nM)
Receptors (cells)	IC₅₀(nM)	c-Met(MKN45)	11.3
c-Met(A431)	9.3	c-Met(MKN45)	11.3
c-Met(A431)	9.3	KDR(HUVEC)	＞1000

Pharmacological test example 9: influence on mouse lower limb growth plate

Nude mice (BALB-nu/nu, female, four-week-old, Charles River Japan, Inc.) were housed in advance for 1 week and were divided into groups such that each group included 8 mice. Compound a (50mg/kg) suspended in 0.5% methylcellulose was administered orally once daily for 4 weeks in compound a group. On the other hand, 0.5% of methylcellulose was administered to the control group in the same manner as in the compound a group.

Animals were sacrificed 29 days after the start of dosing under ether anesthesia. The lower limb bone growth plates near the knee area were removed, fixed in buffered formalin, delimed, and then paraffin embedded. Thin section specimens were stained with HE and knee bone photographs were taken and the thickening of the bone growth plate was quantitatively determined with image analysis software (WinROOF 5 th edition, MITANI CORPORATION) regardless of whether the bone growth plate was thickened. The average of the bone growth plate cross-sectional areas ± SD in the thin-sliced samples is shown in fig. 1.

As a result, there was no significant difference in bone growth plate area in the individual groups of mice, and compound a administration did not induce thickening of the bone growth plate (fig. 1).

Claims

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

[ chemical formula 1]

Wherein

R¹Represents a hydrogen atom or optionally substituted by C_1-4Alkyl radical, C_1-4Unsaturated 5 substituted by alkoxy or halogen atoms-or a 6-membered heterocyclic group,

R²represents a hydrogen atom, and is represented by,

x represents a group selected from the group consisting of CH and N,

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

j represents S or O, and

2. A compound according to claim 1, wherein R¹Represents a hydrogen atom or optionally substituted by C_1-4An alkyl-substituted unsaturated 5-membered heterocyclic group.

3. A compound according to claim 1, wherein R¹Represents a hydrogen atom or optionally substituted by C_1-4An alkyl substituted imidazolyl group.

4. A compound according to claim 1, wherein R¹Represents a hydrogen atom or optionally substituted by C_1-4Alkyl-substituted 1H-imidazol-2-yl.

5. A compound according to claim 1, wherein R¹Represents a hydrogen atom or formula (a):

[ chemical formula 2]

Wherein R is³Represents a hydrogen atom or C_1-4An alkyl group.

6. A compound according to any one of claims 1 to 5 wherein X represents CH.

7. A compound according to any one of claims 1 to 6 wherein Z represents O.

8. A compound according to any one of claims 1 to 7, wherein E is absent or represents C in the 2-position_1-4Alkoxy or a halogen atom at the 3-position.

9. A compound according to any one of claims 1 to 8, wherein J represents S.

10. A compound according to any one of claims 1 to 8 wherein J represents O.

11. A compound according to any one of claims 1 to 10 wherein T represents

Optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4Alkoxy-substituted phenyl;

optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4Alkoxy-substituted thienyl; or

Optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4An alkoxy-substituted indazolyl group.

12. A compound according to claim 1, wherein

R²represents a hydrogen atom, and is represented by,

x represents a group represented by the formula CH,

z represents O, and Z represents O,

j represents S or O, and the compound is represented by,

t represents

optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4An alkoxy-substituted unsaturated 5-membered heterocyclic group; or

Optionally substituted by halogen atoms, C_1-4Alkyl or C_1-4An alkoxy-substituted unsaturated 9-membered bicyclic heterocyclic group.

13. A compound according to claim 12, wherein R³Represents C_1-4An alkyl group.

14. A compound according to claim 12 or 13 wherein E represents C in the 2-position_1-4An alkoxy group.

15. A compound according to claim 14, wherein E represents methoxy at the 2-position.

16. A compound according to claim 12 or 13, wherein E represents a halogen atom in the 3-position.

17. A compound according to claim 16, wherein E represents a chlorine atom in the 3-position.

18. A compound according to any one of claims 12 to 17 wherein J represents S.

19. A compound according to any one of claims 12 to 17 wherein J represents O.

20. A compound according to any one of claims 12 to 19 wherein T represents

21. A compound according to any one of claims 12 to 19, wherein T represents an optionally halogen atom, C_1-4Alkyl or C_1-4Alkoxy-substituted phenyl.

22. A compound according to any one of claims 12 to 19, wherein T represents phenyl optionally substituted by a halogen atom.

23. A compound according to any one of claims 12 to 19, wherein T represents an optionally halogen atom, C_1-4Alkyl or C_1-4An alkoxy-substituted indazolyl group.

24. A compound according to claim 1, selected from the following compounds:

(3) n- [2- (1H-1-oxazolyl) acetyl ] -N- (2-methoxy-4- { [2- (1-methyl-1H-2-imidazolyl) thieno [3, 2-b ] pyridin-7-yl ] oxy } phenyl) thiourea;

25. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof, or a solvate thereof;

[ chemical formula 3]

Wherein

R¹¹And R¹²May be the same or different and represents C_1-4An alkoxy group,

d represents a group of CH or N,

g represents O or S, and G represents O or S,

l is absent or represents a substituent on the phenylene group, the substituent being selected from a halogen atom, C_1-4Alkyl and C_1-4Alkoxy, the number representing a substitutable position,

m represents O or S, and

26. A compound according to claim 25, wherein R¹¹And R¹²Represents methoxy.

27. A compound according to claim 25 or 26, wherein D represents CH.

28. A compound according to any one of claims 25 to 27 wherein G represents O.

29. A compound according to any one of claims 25 to 28, wherein L is absent or represents a halogen atom in the 3-position, a halogen atom in the 2-position or C in the 2-position_1-4An alkoxy group.

30. A compound according to any one of claims 25 to 29 wherein M represents O.

31. A compound according to any one of claims 25 to 29 wherein M represents S.

32. A compound according to any one of claims 25 to 31 wherein

Q represents formula (b):

[ chemical formula 4]

formula (c):

[ chemical formula 5 ]

formula (d):

[ chemical formula 6 ]

Formula (e):

[ chemical formula 7 ]

33. A compound according to claim 25, wherein

R¹¹And R¹²Represents a methoxy group, and a methoxy group,

d represents a group represented by the formula CH,

g represents O, and the compound is represented by,

m represents O or S, and

34. A compound according to claim 33, wherein L represents a halogen atom in the 3-position.

35. A compound according to claim 33 or 34, wherein M represents O.

36. The compound according to any one of claims 33-35, wherein formula (b) is unsubstituted.

37. A compound according to claim 25, wherein

R¹¹And R¹²Represents a methoxy group, and a methoxy group,

d represents a group represented by the formula CH,

g represents O, and the compound is represented by,

m represents O or S, and

38. A compound according to claim 37, wherein L represents a halogen atom in the 3-position.

39. A compound according to claim 37 or 38, wherein M represents S.

40. The compound according to any one of claims 37-39, wherein formula (c) is unsubstituted.

41. A compound according to claim 25, wherein

R¹¹And R¹²Represents a methoxy group, and a methoxy group,

d represents a group represented by the formula CH,

g represents O, and the compound is represented by,

m represents O or S, and

42. A compound according to claim 41, wherein L represents a halogen atom in the 3-position.

43. A compound according to claim 41, wherein L represents C at the 2-position_1-4An alkoxy group.

44. A compound according to claim 41, wherein L represents a halogen atom in the 2-position.

45. A compound according to any one of claims 41 to 44, wherein M represents O.

46. A compound according to any one of claims 41 to 44, wherein M represents S.

47. The compound according to any one of claims 41-46, wherein formula (d) is unsubstituted or has the following substituents: a halogen atom at the 3-position, a halogen atom at the 4-position or a halogen atom at the 7-position.

48. A compound according to claim 25, wherein

R¹¹And R¹²Represents a methoxy group, and a methoxy group,

d represents a group represented by the formula CH,

g represents O, and the compound is represented by,

m represents O or S, and

49. A compound according to claim 48, wherein L represents a halogen atom in the 3-position.

50. A compound according to claim 48, wherein L represents C at the 2-position_1-4An alkoxy group.

51. A compound according to any one of claims 48 to 50, wherein M represents O.

52. A compound according to any one of claims 48 to 50, wherein M represents S.

53. The compound according to any one of claims 48-52, wherein formula (e) is unsubstituted.

54. A compound according to claim 25, selected from the following compounds:

N- [4- { (6, 7-dimethoxy-4-quinolyl) oxy } -2-methoxyphenyl ] -N' - [2- (4-fluorophenyl) acetyl ] thiourea or a pharmaceutically acceptable salt thereof, or a solvate thereof.

56.N- { 2-methoxy-4- [ 6-methoxy-7- (3-morpholinopropoxy) -4-quinolinyl ] oxyphenyl } -N' - (2-phenylacetyl) thiourea or a pharmaceutically acceptable salt thereof, or a solvate thereof.

57. A pharmaceutical composition comprising a compound according to any one of claims 1-56, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

58. The pharmaceutical composition according to claim 57 for use in the treatment of malignant tumors.

59. The pharmaceutical composition according to claim 58, wherein said malignant tumor is selected from the group consisting of gastric cancer, brain tumor, pancreatic cancer, colon cancer, lung cancer, renal cancer, ovarian cancer, and prostate cancer.

60. Use of a compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a malignant tumour.

61. The use according to claim 60, wherein said malignancy is selected from the group consisting of gastric, brain, colon, pancreatic, lung, renal, ovarian and prostate cancer.

62. A method for treating a malignant tumor comprising the steps of: administering to a mammal in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt or solvate thereof.

63. The method according to claim 62, wherein said malignancy is selected from the group consisting of gastric, brain, colon, pancreatic, lung, renal, ovarian and prostate cancer.

64. An inhibitor of autophosphorylation of c-Met comprising a compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt or solvate thereof.

65. An agent for studying HGF/c-Met signaling, comprising a compound according to any one of claims 1-56, or a pharmaceutically acceptable salt or solvate thereof.