JP7568241B2 - New antitumor agents - Google Patents

Description

The present invention relates to compounds having antitumor activity and cancer metastasis inhibitory activity, particularly pyrazole derivatives and pyrimidine derivatives, and to antitumor agents containing said compounds as active ingredients.

Currently, most cancer treatments are focused on drugs that target cell proliferation, and are effective by suppressing the division and proliferation of cancer cells. For example, the standard treatment for pancreatic cancer is gemcitabine, which is used in combination with several anticancer drugs. In recent years, immune checkpoint inhibitors have appeared and have been approved for use in skin cancer and lung cancer. They are proving effective in treating several cancer diseases by blocking the mechanisms that allow cancer cells to avoid cytotoxicity and increasing their own cytotoxic activity.

Cancer often becomes fatal when it metastasizes, but existing anticancer drugs target cell proliferation inhibition and are almost ineffective in suppressing cancer metastasis itself. In addition, there are currently no cancer treatment drugs that target cancer metastasis itself. However, if further metastasis can be suppressed in either early or advanced cancer, the cancer can be removed by surgery, and a significant improvement in prognosis can be expected.

The object of the present invention is to provide a compound having antitumor activity and cancer metastasis inhibitory activity, and an antitumor agent containing the compound as an active ingredient.

Means for Solving the Problems The present inventors have conducted extensive research to solve the above problems and have found that a compound represented by the following formula (1) has antitumor activity and cancer metastasis inhibitory activity, thereby completing the present invention.
That is, the present invention is as follows.
[1] Formula (1):

(Wherein,
Ring A is an optionally substituted 5- or 6-membered ring,
R ¹ and R ⁴ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, or a C _1-6 alkoxy group;
The benzene ring B and the benzene ring C each may further have a substituent.
the benzene ring B-C (R ² ) (R ³ ) group and the benzene ring C are each bonded to a different carbon atom constituting the ring A;
^R2 and ^R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a _C1-6 alkyl group, a halogenated _C1-6 alkyl group or a _C1-6 alkoxy group, or ^R2 and ^R3 together represent an oxo group or a hydroxyimino group.
(hereinafter, sometimes abbreviated as "compound (1)") or a salt thereof.
[1'] Formula (1):

(Wherein,
Ring A is an optionally substituted 5- or 6-membered ring,
R ¹ and R ⁴ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, or a C _1-6 alkoxy group;
The benzene ring B and the benzene ring C each may further have a substituent.
the benzene ring B-C (R ² ) (R ³ ) group and the benzene ring C are each bonded to a different carbon atom constituting the ring A;
^R2 and ^R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a _C1-6 alkyl group, a halogenated _C1-6 alkyl group, or a _C1-6 alkoxy group, or ^R2 and ^R3 together represent an oxo group.
(hereinafter, sometimes abbreviated as "compound (1)") or a salt thereof.
[2] The compound according to [1] or [1'], wherein R ¹ and R ⁴ are each independently a chlorine atom, a bromine atom, or a methoxy group.
[3] The compound according to [1], [1'] or [2], wherein ring A is a pyrazole ring or a pyrimidine ring optionally having a methyl group.
[4] The compound according to any one of [1] to [3] and [1'], wherein R ² and R ³ taken together are an oxo group.
[5] The compound according to any one of [1] to [4] and [1'], in which R ¹ and R ⁴ are each independently a chlorine atom, a bromine atom, or a methoxy group, ring A is a pyrazole ring or a pyrimidine ring optionally having a methyl group, and R ² and R ³ taken together are an oxo group.
[6] The compound according to [5], which is 5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)-2-methylpyrimidine, 4-(4-methoxybenzoyl)-5-(4-methoxyphenyl)-1-methylpyrazole, 4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-methylpyrazole or 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-methylpyrazole.
[7] The compound according to any one of [1] to [6] and [1'], which has an antitumor activity and an inhibitory activity against cancer metastasis.

The present invention provides compounds having antitumor activity and cancer metastasis inhibitory activity, particularly pyrazole derivatives and pyrimidine derivatives, as well as antitumor agents containing the compounds as active ingredients.

FIG. 1 is a diagram illustrating the real-time cell kinetic analysis method (TAXIScan method) used in Test Example 1. 1 is a graph showing the results of Test Example 1. 1 is a graph showing the results of Test Example 2. 1 is a graph showing the results of Test Example 3 (changes in body weight (with the body weight at the time of transplantation set at 1)). 1 is a graph showing the results of Test Example 3 (the number of individuals in which metastasis was observed). 1 is a graph showing the results of Test Example 3 (comparison of the amount of fluorescence from tumors). 1 is a graph showing the results of Test Example 4 (inhibition of migration speed, one of the chemotaxis components). 1 is a graph showing the results of Test Example 4 (directional inhibition of chemotaxis components). 1 is a graph showing the results of Test Example 4 (inhibition of migration speed, one of the chemotaxis components). 1 is a graph showing the results of Test Example 4 (directional inhibition of chemotaxis components).

The definition of each substituent used in this specification is described in detail below. Unless otherwise specified, each substituent has the following definition.

In the present specification, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
In the present specification, examples of the "C _1-6 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.
[0033] As used herein, examples of the "halogenated _C1-6 alkyl group" include the above-mentioned " _C1-6 alkyl group" substituted by 1 to 5 of the above-mentioned "halogen atoms".
In the present specification, examples of the "C _3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.
In the present specification, examples of the "C _1-6 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
In the present specification, examples of the "C _6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.
In the present specification, examples of the "5- to 14-membered aromatic heterocyclic group" include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferred examples thereof include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like;
Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

In the present specification, examples of the "5- or 6-membered ring" include a 5- or 6-membered aromatic or non-aromatic heterocycle containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the "5- or 6-membered aromatic heterocycle" include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine and the like.
Suitable examples of the "5- or 6-membered non-aromatic heterocycle" include tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, and the like.

The definition of each symbol in formula (1) is explained in detail below.

Ring A is an optionally substituted 5- or 6-membered ring.
The "5- to 6-membered ring" of the "optionally substituted 5- to 6-membered ring" is preferably a 5- to 6-membered aromatic heterocycle (e.g., a pyrazole ring, a pyrimidine ring), more preferably a pyrazole ring or a pyrimidine ring.
The "5- to 6-membered ring" of the "optionally substituted 5- to 6-membered ring" may have 1 to 3 substituents at substitutable positions, and when the number of substituents is 2 or more, the respective substituents may be the same or different. The "substituent" is preferably a C _1-6 alkyl group (e.g., a methyl group), more preferably a methyl group.
In another embodiment of the present invention, the "substituent" is preferably an optionally substituted C _1-6 alkyl group (e.g., methyl group, ethyl group, isopropyl group), an optionally substituted C _3-10 cycloalkyl group (e.g., cyclohexyl group), an optionally substituted C _6-14 aryl group (e.g., phenyl, naphthyl), or an optionally substituted 5- to 14-membered aromatic heterocycle (e.g., pyridyl).
Ring A is preferably a 5- or 6-membered aromatic heterocycle (e.g., a pyrazole ring, a pyrimidine ring) optionally having 1 to 3 substituents selected from a C _1-6 alkyl group (e.g., a methyl group), and more preferably a pyrazole ring or pyrimidine ring each optionally having 1 to 3 methyl groups.
In another embodiment of the present invention, ring A is preferably a 5- to 6-membered aromatic heterocycle (e.g., a pyrazole ring, a pyrimidine ring) optionally having 1 to 3 substituents selected from an optionally substituted C _1-6 alkyl group (e.g., a methyl group, an ethyl group, an isopropyl group), an optionally substituted C _3-10 cycloalkyl group (e.g., a cyclohexyl group), an optionally substituted C _6-14 aryl group (e.g., phenyl, naphthyl) and an optionally substituted 5- to 14-membered aromatic heterocycle (e.g., pyridyl), more preferably each selected from (1) a C 1-6 alkyl group (e.g., a methyl group, an ethyl group, an isopropyl group) optionally having 1 to 3 substituents selected from a hydroxyl group and a C _6-14 aryl group (e.g., phenyl), (2) a C _3-10 cycloalkyl group (e.g., a cyclohexyl group), (3) _{a halogen atom (e.g., a chlorine atom, a bromine atom), a cyano group, a nitro group, a C 1-6 alkyl} group (e.g., a methyl group) and a C and (3) a pyrazole ring or a pyrimidine ring, which may have 1 to 3 substituents selected from a C _6-14 aryl group (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from a _1-6 alkoxy group (e.g., methoxy group), and (4) a 5- to 14-membered aromatic heterocycle (e.g., pyridyl).

R ¹ and R ⁴ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group.
R ¹ and R ⁴ are preferably each independently a halogen atom (e.g., a chlorine atom, a bromine atom) or a C _1-6 alkoxy group (e.g., a methoxy group), and more preferably each independently a chlorine atom, a bromine atom or a methoxy group.
In another embodiment of the present invention, R ¹ and R ⁴ are preferably each independently a hydrogen atom, a nitro group, a cyano group, a halogen atom (e.g., a chlorine atom, a bromine atom), an optionally substituted C _1-6 alkyl group (e.g., a methyl group) or an optionally substituted C _1-6 alkoxy group (e.g., a methoxy group), more preferably each independently a hydrogen atom, a nitro group, a cyano group, a halogen atom (e.g., a chlorine atom, a bromine atom), a C _1-6 alkyl group (e.g., a methyl group) or a C _1-6 alkoxy group (e.g., a methoxy group).

The benzene ring B and the benzene ring C may each have 1 to 4 further substituents other than R ¹ and R ⁴ at substitutable positions.
The benzene ring B and the benzene ring C preferably have no further substituents other than ^R1 and ^R4 , respectively.
In another embodiment of the present invention, the benzene ring C may preferably further have a halogen atom (e.g., a chlorine atom) in addition to ^R4 .

The benzene ring BC (R ² ) (R ³ ) group and the benzene ring C are each bonded to separate carbon atoms constituting the ring A.
The benzene ring BC (R ² ) (R ³ ) group and the benzene ring C are preferably bonded to separate adjacent carbon atoms constituting the ring A, respectively.

R ² and R ³ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group, or R ² and R ³ taken together represent an oxo group.
^R2 and ^R3 together preferably represent an oxo group.

In another embodiment of the present invention, ^R2 and ^R3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a _C1-6 alkyl group, a halogenated _C1-6 alkyl group or a _C1-6 alkoxy group, or ^R2 and ^R3 together represent an oxo group or a hydroxyimino group. Preferably, ^R2 and ^R3 each independently represent a hydrogen atom or a hydroxyl group, or ^R2 and ^R3 together represent an oxo group or a hydroxyimino group.

Suitable examples of compound (1) include the following compounds:
[Compound 1-1]
Ring A is a 5- or 6-membered aromatic heterocycle (e.g., a pyrazole ring, a pyrimidine ring) optionally having 1 to 3 substituents selected from a C _1-6 alkyl group (e.g., a methyl group);
R ¹ and R ⁴ are each independently a halogen atom (e.g., a chlorine atom, a bromine atom) or a C _1-6 alkoxy group (e.g., a methoxy group);
The benzene ring B and the benzene ring C have no further substituents other than R ¹ and R ⁴ , respectively;
the benzene ring B-C (R ² ) (R ³ ) group and the benzene ring C are each bonded to separate adjacent carbon atoms constituting the ring A;
^R2 and ^R3 together are an oxo group;
Compound (1).

[Compound 1-2]
Ring A is a pyrazole ring or a pyrimidine ring, each of which optionally has 1 to 3 methyl groups;
R ¹ and R ⁴ are each independently a chlorine atom, a bromine atom, or a methoxy group;
The benzene ring B and the benzene ring C have no further substituents other than R ¹ and R ⁴ , respectively;
the benzene ring B-C (R ² ) (R ³ ) group and the benzene ring C are each bonded to separate adjacent carbon atoms constituting the ring A;
^R2 and ^R3 together are an oxo group;
Compound (1).

[Compound 1-3]
5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)-2-methylpyrimidine,
4-(4-methoxybenzoyl)-5-(4-methoxyphenyl)-1-methylpyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-methylpyrazole, or
4-(4-Chlorobenzoyl)-5-(4-chlorophenyl)-1-methylpyrazole.

[Compound 1-4]
Ring A is a 5- or _6- membered aromatic heterocycle (e.g., a pyrazole ring, a pyrimidine ring) optionally having 1 to 3 substituents selected from an optionally substituted C _1-6 alkyl group (e.g., a methyl group, an ethyl group, an isopropyl group), an optionally substituted C 3-10 cycloalkyl group (e.g., a cyclohexyl group), an optionally substituted C _6-14 aryl group (e.g., phenyl, naphthyl) and an optionally substituted 5- to 14-membered aromatic heterocycle (e.g., pyridyl);
R ¹ and R ⁴ are each independently a hydrogen atom, a nitro group, a cyano group, a halogen atom (e.g., a chlorine atom, a bromine atom), an optionally substituted C _1-6 alkyl group (e.g., a methyl group), or an optionally substituted C _1-6 alkoxy group (e.g., a methoxy group);
The benzene ring B has no further substituents other than R ¹ ;
The benzene ring C may further have a halogen atom (e.g., a chlorine atom) in addition to ^R4 ;
the benzene ring B-C (R ² ) (R ³ ) group and the benzene ring C are each bonded to separate adjacent carbon atoms constituting the ring A;
^R2 and ^R3 are each independently a hydrogen atom or a hydroxyl group, or ^R2 and ^R3 taken together are an oxo group or a hydroxyimino group;
Compound (1).

[Compound 1-5]
Ring A is a pyrazole ring or _pyrimidine ring, each of which optionally has 1 to 3 substituents selected from (1) a C _1-6 alkyl group (e.g., a methyl group, an ethyl group, an isopropyl group) optionally having 1 to 3 substituents selected from a hydroxyl group and a C _6-14 aryl group (e.g., a phenyl group), (2) a C _3-10 cycloalkyl group (e.g., a cyclohexyl group), (3) a C 6-14 aryl group (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from a halogen atom (e.g., a chlorine atom, a bromine atom), a cyano group, a nitro group, a C _1-6 alkyl group (e.g., a methyl group) and a C _1-6 alkoxy group (e.g., a methoxy group), and (4) a 5- to 14-membered aromatic heterocycle (e.g., pyridyl);
R ¹ and R ⁴ are each independently a hydrogen atom, a nitro group, a cyano group, a halogen atom (e.g., a chlorine atom, a bromine atom), a C _1-6 alkyl group (e.g., a methyl group), or a C _1-6 alkoxy group (e.g., a methoxy group);
The benzene ring B has no further substituents other than R ¹ ;
The benzene ring C may further have a halogen atom (e.g., a chlorine atom) in addition to ^R4 ;
the benzene ring B-C (R ² ) (R ³ ) group and the benzene ring C are each bonded to separate adjacent carbon atoms constituting the ring A;
R ² and R ³ are each independently a hydrogen atom or a hydroxyl group, or R ² and R ³ taken together are an oxo group or a hydroxyimino group;
Compound (1).

When compound (1) is a salt, examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and ammonium salts.

Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, and N,N-dibenzylethylenediamine.

Suitable examples of salts with inorganic acids include salts with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, and phosphoric acid.

Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

Suitable examples of salts with basic amino acids include salts with arginine, lysine, and ornithine.

Suitable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid.

Among these salts, pharma- ceutically acceptable salts are preferred. Examples of pharma-ceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid when the compound has a basic functional group; or salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid. When the compound has an acidic functional group, examples of the pharma-ceutically acceptable salts include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.); and ammonium salts.

The method for producing compound (1) is described below. As an example, the method for producing compound (1) is described below, in which ring A is a pyrazole ring or a pyrimidine ring which may have a methyl group or the like, benzene ring B and benzene ring C have no further substituents other than R ¹ and R ⁴ , respectively, benzene ring B-C(R ² )(R ³ ) group and benzene ring C are each bonded to separate adjacent carbon atoms constituting ring A, and R ² and R ³ are each independently a hydrogen atom or a hydroxyl group, or R ² and R ³ are taken together to be an oxo group or a hydroxyimino group.

1) Synthesis of dibenzoylmethane (III) In a nitrogen stream, an anhydrous benzene solution of acetophenone (II) is dropped into an anhydrous benzene suspension of sodium hydride and benzoic acid ester (I), and then heated to reflux. After cooling to room temperature, a 10% aqueous hydrochloric acid solution is added to the reaction solution, and extraction is performed with ethyl acetate. The organic layer is washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is recrystallized from ethanol or subjected to silica gel column chromatography, and dibenzoylmethane (III) is obtained from the ethyl acetate-hexane eluate.
Reference: T. Choshi, S. Horimoto, CY Wang, H. Nagase, M. Ichikawa, E. Sugino, S. Hibino, Chem. Pharm. Bull., 40, 1047-1049 (1992).

2) Synthesis of N,N-dimethylaminomethylene-dibenzoylmethane (IV) In a nitrogen stream, a solution of dibenzoylmethane (III) in dimethylformamide dimethylacetal is heated and refluxed for 6 hours. After cooling to room temperature, water is added to the reaction solution and extracted with ethyl acetate. The organic layer is washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography to obtain N,N-dimethylaminomethylene (IV) from the ethyl acetate-hexane eluate.

3) Synthesis of 5-benzoyl-4-phenyl-2-methylpyrimidine (V)
A suspension of N,N-dimethylaminomethylene (IV), acetamidine, and potassium carbonate in ethanol is heated to reflux for 4 hours. After cooling to room temperature, water is added to the reaction mixture and it is extracted with ethyl acetate. The organic layer is washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography to obtain 5-benzoyl-4-phenyl-2-methylpyrimidine (V) as an oil from the ethyl acetate-hexane eluate.

4) Synthesis of 4-benzoyl-5-phenyl-1-methylpyrazole (VI)
A solution of N,N-dimethylaminomethylene (IV) and methylhydrazine in ethanol is stirred at room temperature for 12 hours. After the reaction is completed, the ethanol is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography to obtain 4-benzoyl-5-phenyl-1-methylpyrazole (VI) from the ethyl acetate-hexane eluate and the subsequent isomer (VII) as the eluate.

Compound (1) has antitumor activity and cancer metastasis inhibitory activity, and an antitumor agent containing compound (1) as an active ingredient can be used as a preventive or therapeutic agent for various malignant tumors (e.g., pancreatic cancer, lung cancer, colon cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, malignant melanoma, gastric cancer, hepatocellular carcinoma, bile duct cancer, oral cancer, esophageal cancer, bladder cancer, nerve tumors, testicular tumors, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, malignant fibrous histiocytoma, chondroma, osteosarcoma, leukemia, lymphoma, mesothelioma).

The antitumor agent containing the compound (1) of the present invention as an active ingredient may contain only the compound (1), or may contain a pharmacologically acceptable carrier (such as an excipient, a binder, a disintegrant, a flavoring agent, an odorant, an emulsifier, a diluent, or a solubilizing agent).
The antitumor agent containing the compound (1) of the present invention as an active ingredient can be obtained by mixing the compound (1) with a pharmacologically acceptable carrier and formulating it into various dosage forms (e.g., tablets, pills, powders, granules, capsules, liquids, emulsions, suspensions, injections, drops, etc.) according to a method known per se as a method for producing pharmaceutical preparations (e.g., a method described in the Japanese Pharmacopoeia, etc.), and can be administered orally or parenterally.

The content of compound (1) in an antitumor agent containing compound (1) of the present invention as an active ingredient varies depending on the dosage form of the antitumor agent, but is usually about 0.001 to 100% by weight, preferably 0.01 to 10% by weight, and more preferably about 0.1 to 1% by weight, based on the total weight of the antitumor agent.

In this specification, parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion, or local administration (intra-articular administration, transdermal administration, ocular administration, pulmonary/bronchial administration, nasal administration, rectal administration, etc.).

The dosage of an antitumor agent containing compound (1) of the present invention as an active ingredient may vary depending on the subject, route of administration, and symptoms, and is not particularly limited. For example, when orally administered to an adult patient with pancreatic cancer (adult, body weight 40 to 80 kg, e.g., 60 kg), compound (1) may be administered at, for example, 0.1 to 1000 mg/kg body weight once a week, preferably 1 to 500 mg/kg body weight once a week, and more preferably 10 to 100 mg/kg body weight once a week. This amount may be administered in divided doses, one to three times a day.

The present invention will be described in more detail below using examples and test examples, but these examples are not intended to limit the present invention.

Example 1
Synthesis of 5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)-2-methylpyrimidine
1) Synthesis of di(4-methoxybenzoyl)methane
A solution of 4-methoxyacetophenone (2.7 g, 18.2 mmol) in anhydrous benzene (10 mL) was added dropwise to a suspension of sodium hydride (0.84 g, 20.9 mmol) and ethyl 4-methoxybenzoate (3.6 g, 20.0 mmol) in anhydrous benzene (40 mL) in a nitrogen stream, and the mixture was heated to reflux for 5 hours. After cooling to room temperature, 10% aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3 times). The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give the dibenzoylmethane derivative (2.83 g, 56%).
mp 126-127 ℃. ¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.92 (6H, s), 6.81 (1H, s), 7.29 (4H, d, J = 8.3 Hz), 7.89 (4H, d, J= 8.3 Hz).

2) Synthesis of N,N-dimethylaminomethylene-di(4-methoxybenzoyl)methane A solution of di(4-methoxybenzoyl)methane (1.0 g, 3.5 mmol) in dimethylformamide dimethyl acetal (6 mL) was heated under reflux in a nitrogen stream for 5 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate (50 mL x 3 times) was performed. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (50 g), and an oily N,N-dimethylaminomethylene derivative (1.09 g, 92%) was obtained from the ethyl acetate-hexane (70:30 v/v) eluate.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.94 (6H, br s), 3.83 (6H, s), 5.85 (1H, s), 6.86 (2H, d, J = 8.8 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.18 (2H, d, J = 8.8 Hz), 7.86 (2H, d, J = 8.8 Hz).

3) Synthesis of 5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)-2-methylpyrimidine (hereinafter sometimes abbreviated as "14-53")
A suspension of N,N-dimethylaminomethylene derivative (2.3 g, 6.78 mmol), acetamidine hydrochloride (0.96 g, 8.13 mmol), and potassium carbonate (1.12 g, 8.13 mmol) in ethanol (40 mL) was heated to reflux for 4 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate (50 mL x 3 times) was performed. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (50 g) to obtain oily 5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)-2-methylpyrimidine (1.88 g, 83%) from the ethyl acetate-hexane (30:70 v/v) eluate.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.86 (3H, s), 3.76 (3H, s), 3.83 (3H, s), 6.81 (2H, d, J = 8.7 Hz), 6.82 (2H, d, J = 8.7 Hz), 7.61 (2H, d, J = 8.7 Hz ), 7.69 (2H, d, J = 8.7 Hz), 8.65 (1H, s).

Example 2
Synthesis of 4-(4-methoxybenzoyl)-5-(4-methoxyphenyl)-1-methylpyrazole (hereinafter sometimes abbreviated as "14-61")
A solution of N,N-dimethylaminomethylene (380 mg, 1.1 mmol) and methylhydrazine (72 mg, 1.6 mmol) in ethanol (3 mL) was stirred at room temperature for 12 hours. After the reaction was completed, ethanol was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g) to obtain an oily substance of 4-(4-methoxybenzoyl)-5-(4-methoxyphenyl)-1-methylpyrazole (137 mg, 38%) from the ethyl acetate-hexane (15:85 v/v) eluate and the next eluate was the isomer 4-(4-methoxybenzoyl)-3-(4-methoxyphenyl)-1-methylpyrazole (109 mg, 30%).
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.82 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 6.88 (2H, d, J = 8.6 Hz), 6.96 (2H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.6 Hz) ), 7.79 (2H, d, J = 8.6 Hz), 7.83 (1H, s).

Example 3
Synthesis of 4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-methylpyrazole
1) Synthesis of di(4-bromobenzoyl)methane
In a nitrogen stream, a solution of 4-bromoacetophenone (4.3 g, 21.8 mmol) in anhydrous benzene (10 mL) was added dropwise to a suspension of sodium hydride (1.0 g, 25.1 mmol) and ethyl 4-bromobenzoate (5.5 g, 24.0 mmol) in anhydrous benzene (40 mL), and the mixture was heated to reflux for 1 hour. After cooling to room temperature, 10% aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3 times). The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain the dibenzoylmethane derivative (4.5 g, 54%).
mp 195-196 ℃. ¹ H-NMR (300 MHz, CDCl ₃ )δ: 6.77 (1H, s), 7.63 (4H, d, J= 8.4 Hz), 7.85 (4H, d, J = 8.4 Hz).

2) Synthesis of N,N-dimethylaminomethylene-di(4-bromobenzoyl)methane A solution of di(4-bromobenzoyl)methane (2.5 g, 6.54 mmol) in dimethylformamide dimethyl acetal (15 mL) was heated under reflux in a nitrogen stream for 6 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate (100 mL x 3 times) was performed. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (50 g), and the N,N-dimethylaminomethylene derivative (1.66 g, 58%) was obtained as an oil from the ethyl acetate-hexane (40:60 v/v) eluate.
^1H -NMR (300 MHz, CDCl ₃ )δ: 2.77 (3H, br s), 3.31 (3H, br s), 7.32-7.51 (8H, m), 7.64 (1H, s).

3) Synthesis of 4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-methylpyrazole
A solution of N,N-dimethylaminomethylene (600 mg, 1.4 mmol) and methylhydrazine (74 mg, 1.6 mmol) in ethanol (4 mL) was stirred at room temperature for 2 hours. After the reaction was completed, ethanol was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (50 g) to obtain an oily product of 4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-methylpyrazole (hereinafter sometimes abbreviated as "14-67") (420 mg, 73%) from the ethyl acetate-hexane (15:85 v/v) eluate, and the next eluate was the isomer 4-(4-bromobenzoyl)-3-(4-bromophenyl)-1-methylpyrazole (hereinafter sometimes abbreviated as "14-68") (95 mg, 16%).
4-(4-Bromobenzoyl)-5-(4-bromophenyl)-1-methylpyrazole: ^1H -NMR (300 MHz, _CDCl3 ) δ: 3.82 (3H, s), 7.27 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.61 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5 Hz), 7.83 (1H, s).
4-(4-Bromobenzoyl)-3-(4-bromophenyl)-1-methylpyrazole: ^1H -NMR (300 MHz, _CDCl3 ) δ: 3.99 (3H, s), 7.47 (2H, d, J = 8.8 Hz), 7.55 (4H, d, J = 8.8 Hz), 7.64 (2H, d, J = 8.8 Hz), 7.73 (1H, s).

4) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-cyclohexylpyrazole (hereinafter sometimes abbreviated as "14-112")
A solution of N,N-dimethylaminomethylene (200 mg, 0.57 mmol), cyclohexylhydrazine hydrochloride (76 mg, 1.09 mmol), and potassium carbonate (236 mg, 1.71 mmol) in ethanol (6 mL) was stirred at 60°C for 1 hour. After completion of the reaction, ethanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude crystals were recrystallized from ethanol to give 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-cyclohexylpyrazole (200 mg, 87%).
¹ H-NMR (300 MHz, CDCl ₃ )δ: 1.21-1.27 (3H, m), 1.59-2.05 (7H, m), 3.90-3.98 (1H, m), 7.28 (2H, d, J = 8.7 Hz), 7.39 (2H, d, J = 8.9 Hz), 7.45 (2H , d, J = 8.9 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.84 (1H, s).

5) Synthesis of 4-chlorophenyl-[5-(4-chlorophenyl)-1-methylpyrazol-4-yl]methanol (hereinafter sometimes abbreviated as "14-120")
A solution of 4-benzoyl-5-phenyl-1-methylpyrazole (VI) (132 mg, 0.40 mmol) and sodium borohydride (30 mg, 0.79 mmol) in methanol (5 mL) was stirred at room temperature for 3 hours. After completion of the reaction, methanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude crystals were recrystallized from methanol to obtain 4-chlorophenyl-[5-(4-chlorophenyl)-1-methylpyrazol-4-yl]methanol (118 mg, 89%).
¹ H-NMR (300 MHz, DMSO-d ₆ )δ: 3.66 (3H, s), 5.41 (1H, d, J = 4.0 Hz), 5.75 (1H, d, J = 4.0 Hz), 7.23 (2H, d, J = 8.5 Hz), 7.25 (1H, s), 7.29 (2H , d, J = 8.5 Hz), 7.46 (2H, d, J = 7.7 Hz), 7.57 (2H, d, J = 7.7 Hz).

6) Synthesis of 4-chlorobenzyl-5-(4-chlorophenyl)-1-methylpyrazole (IX) (hereinafter sometimes abbreviated as "14-121")
Triethylsilane (62 μL, 0.39 mmol) was added dropwise to a solution of 4-chlorophenyl-[5-(4-chlorophenyl)-1-methylpyrazol-4-yl]methanol (112 mg, 0.34 mmol) in trifluoroacetic acid (5 mL) under ice cooling, and the mixture was stirred at room temperature for 10 minutes. After the reaction was completed, trifluoroacetic acid was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate (100 mL x 3 times). The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 4-chlorobenzyl-5-(4-chlorophenyl)-1-methylpyrazole (103 mg, 97%) was obtained as an oil from the ethyl acetate-hexane (20:80 v/v) eluate.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.67 (2H, s), 3.75 (3H, s), 7.00 (2H, d, J = 8.5 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.20 (2H, d, J = 8.5 Hz), 7.35 (1H, s ), 7.43 (2H, d, J = 8.7 Hz).

7) Synthesis of 4-chlorobenzoyl-5-(4-chlorophenyl)-1-methylpyrazole oxime (X) (hereinafter sometimes abbreviated as "14-122")
A suspension of 4-benzoyl-5-phenyl-1-methylpyrazole (VI) (65 mg, 0.20 mmol), hydroxylamine hydrochloride (41 mg, 0.59 mmol) and potassium carbonate (138 mg, 1.0 mmol) in ethanol (3 mL) was heated and stirred at 80°C for 5 hours. After cooling to room temperature, water was added to the reaction solution and extraction with ethyl acetate (100 mL x 3 times) was performed. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 4-chlorobenzoyl-5-(4-chlorophenyl)-1-methylpyrazole oxime (60 mg, 88%) as a diastereomeric mixture (1:3) as an oil from the ethyl acetate-hexane (30:70 v/v) eluate.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.72 (3/4H, s), 3.85 (9/4H, s), 7.10-7.38 (8H, m), 7.51 (1/4H, s), 7.76 (3/4H, s).

Synthesis of raw materials (III) and (IV) Di(4-fluorobenzoyl)methane According to the synthesis method in Example 1-1), methyl 4-fluorobenzoate was reacted with 4-fluoroacetophenone to obtain the target compound in a yield of 52%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.88 (2H, s), 7.14 (2H, d, J = 8.7 Hz), 7.17 (2H, d, J = 8.7 Hz), 8.12 (2H, d, J = 8.7 Hz), 8.15 (2H, d, J = 8.7 Hz).

N,N-Dimethylaminomethylene-di(4-fluorobenzoyl)methane According to the synthesis method of Example 1-2), di(4-fluorobenzoyl)methane was reacted with dimethylformamide dimethyl acetal to obtain the target compound in a yield of 66%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 2.81 (3H, br s), 3.32 (3H, br s),6.88 (4H, t, J = 7.8 Hz), 7.50-7.65 (4H, m), 7.67 (1H, s).

Di(3-chlorobenzoyl)methane According to the synthesis method of Example 1-1), ethyl 3-chlorobenzoate was reacted with 3-chloroacetophenone to obtain the target compound in a yield of 58%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 6.77 (1H, s), 7.44 (2H, t, J = 8.5 Hz), 7.50-7.58 (2H, m), 7.82-7.88 (2H, m),7.94-7.99 (2H, m).

N,N-Dimethylaminomethylene-di(3-chlorobenzoyl)methane According to the synthesis method in Example 1-2), di(3-chlorobenzoyl)methane was reacted with dimethylformamide dimethyl acetal to obtain the target compound in a yield of 57%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.79 (3H, br s), 3.34 (3H, br s), 7.14 (2H, t, J = 7.8 Hz), 7.25 (2H, d, J = 7.8 Hz), 7.41 (2H, d, J = 7.8 Hz),7.52 (2H , br s), 7.69 (1H, s).

Di(2-chlorobenzoyl)methane According to the synthesis method of Example 1-1), methyl 2-chlorobenzoate was reacted with 2-chloroacetophenone to obtain the target compound in a yield of 51%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 7.31-7.42 (3H, s), 7.41-7.53 (4H, s),8.02 (2H, d, J = 8.2 Hz).

N,N-Dimethylaminomethylene-di(2-chlorobenzoyl)methane According to the synthesis method of Example 1-2), di(2-chlorobenzoyl)methane was reacted with dimethylformamide dimethyl acetal to obtain the target compound in a yield of 48%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 2.78 (3H, br s), 3.30 (3H, br s), 7.20 (4H, d, J = 8.2 Hz), 7.51 (4H, br d, J = 7.9 Hz), 7.64 (1H, s).

Di(4-methylbenzoyl)methane According to the synthesis method of Example 1-1), ethyl 4-methylbenzoate was reacted with 4-methylacetophenone to obtain the target compound in a yield of 66%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 6.82 (1H, s), 7.29 (4H, d, J = 8.0 Hz), 7.89 (4H, d, J = 8.0 Hz).

N,N-Dimethylaminomethylene-di(4-methylbenzoyl)methane According to the synthesis method of Example 1-2), di(4-methylbenzoyl)methane was reacted with dimethylformamide dimethylacetal to obtain the target compound in a yield of 98%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 2.27 (6H, s), 2.80-3.20 (6H, br s), 7.03 (4H, d, J = 8.2 Hz), 7.53 (4H, d, J = 8.2 Hz), 7.67 (1H, s).

Di(2-methoxybenzoyl)methane According to the synthesis method of Example 1-1), ethyl 2-methoxybenzoate was reacted with 4-fluoroacetophenone to obtain the target compound in a yield of 45%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 3.94 (6H, s), 6.92-67.10 (4H, m), 7.31 (1H, s), 7.43-7.52 (2H, m), 7.86-7.94 (2H, m).

N,N-Dimethylaminomethylene-di(2-methoxybenzoyl)methane According to the synthesis method of Example 1-2), di(2-methoxybenzoyl)methane was reacted with dimethylformamide dimethyl acetal to obtain the target compound in a yield of 51%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.92 (3H, br s), 3.44 (3H, br s), 3.67 (6H, s),6.49 (2H, d, J = 8.5 Hz), 6.71 (2H, t, J = 8.5 Hz), 7.10 (2H, t, J = 8. 5 Hz), 7.26 (2H, d, J = 8.5 Hz), 7.98 (1H, s).

Example 4
Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-methylpyrazole
1) Synthesis of di(4-chlorobenzoyl)methane
A solution of 4-chloroacetophenone (3.1 g, 20 mmol) in anhydrous benzene (20 mL) was added dropwise to a suspension of sodium hydride (0.9 g, 22.5 mmol) and ethyl 4-chlorobenzoate (4.1 g, 22 mmol) in anhydrous benzene (40 mL) in a nitrogen stream, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, 10% aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3 times). The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain the dibenzoylmethane derivative (2.4 g, 41%).
mp 157.5-159.5 ℃. ¹ H-NMR (300 MHz, CDCl ₃ )δ: 6.77 (1H, s), 7.48 (4H, d, J= 8.9 Hz), 7.93 (4H, d, J = 8.9 Hz).

2) Synthesis of N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane A solution of di(4-chlorobenzoyl)methane (400 mg, 1.36 mmol) in dimethylformamide dimethyl acetal (10 mL) was stirred at room temperature for 4 hours in a nitrogen stream. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate (50 mL x 3 times) was performed. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (50 g), and an oily N,N-dimethylaminomethylene derivative (384 mg, 81%) was obtained from the ethyl acetate-hexane (80:20 v/v) eluate.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.77 (3H, br s), 3.32 (3H, br s), 7.20 (4H, d, J= 8.6 Hz), 7.35-7.60 (4H, m), 7.64 (1H, s).

3) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-methylpyrazole
A solution of N,N-dimethylaminomethylene (380 mg, 1.09 mmol) and methylhydrazine (50 mg, 1.09 mmol) in ethanol (10 mL) was stirred at room temperature for 12 hours. After the reaction was completed, the ethanol was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g) to obtain an oily substance of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-methylpyrazole (197 mg, 55%) and the next isomer (39 mg, 11%) from ethyl acetate-hexane (15:85 v/v) eluate.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.81 (3H, s), 7.33 (2H, d, J= 8.5 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.61 (2H, d, J = 8.5 Hz), 7 .82 (1H, s).

Example 5
According to the method of Example 1, the following pyrimidine derivatives were synthesized.

1) Synthesis of 5-(4-methylbenzoyl)-4-(4-methylphenyl)pyrimidine (hereinafter, may be abbreviated as "5-106") According to the synthesis method of 3) of Example 1, N,N-dimethylaminomethylene-di(4-methylbenzoyl)methane and formamidine acetate were reacted to obtain the target compound in a yield of 85%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.29 (3H, s), 2.36 (3H, s), 7.11 (2H, d, J = 8.0 Hz), 7.17(2H, d, J = 8.0 Hz), 7.54 (2H, d, J = 8.0 Hz), 7.62 (2H, d , J = 8.0 Hz), 8.77 (1H, br s), 9.36 (1H, s).

2) Synthesis of 2-amino-5-(4-methylbenzoyl)-4-(4-methylphenyl)pyrimidine (hereinafter, may be abbreviated as "5-107") According to the synthesis method of 3) of Example 1, N,N-dimethylaminomethylene-di(4-methylbenzoyl)methane and guanidine hydrochloride were reacted to obtain the target compound in a yield of 91%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.28 (3H, s), 2.35 (3H, s), 5.67 (2H, br s), 7.06 (2H, d, J = 8.0 Hz), 7.13 (2H, d, J = 8.0 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.62 (2H, d, J = 8.0 Hz), 8.45 (1H, s).

3) Synthesis of 2-amino-5-(4-chlorobenzoyl)-4-(4-chlorophenyl)pyrimidine (hereinafter, may be abbreviated as "5-102") According to the synthesis method of 3) of Example 1, N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and guanidine hydrochloride were reacted to obtain the target compound in a yield of 97%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 5.73 (2H, br s), 7.25 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.4 Hz), 7.61 (2H, d, J = 8.6 Hz), 8.53 (1H, s).

4) Synthesis of 5-(2-methoxybenzoyl)-4-(2-methoxyphenyl)-2-methylpyrimidine (hereinafter, sometimes abbreviated as "5-109") According to the synthesis method of 3) of Example 1, N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane and acetamidine hydrochloride were reacted to obtain the target compound in a yield of 99%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.85 (3H, s), 3.53 (6H, s), 6.51 (1H, d, J = 8.6 Hz), 6.58 (1H, d, J = 8.6 Hz), 6.88 (1H, dt, J = 0.8, 8.0 Hz), (1H, dt, J = 0.8, 8.0 Hz), 7.17 (1H, dt, J = 0.8, 8.6 Hz), 7.27 (1H, dt, J = 0.8, 8.6 Hz),7.48 (1H, dd, J = 1.8, 7.6 Hz), 7.56 (1H, dd, J = 1.8, 7.6 Hz), 8.81 (1H, s).

5) Synthesis of 5-(2-methoxybenzoyl)-4-(2-methoxyphenyl)pyrimidine (hereinafter, may be abbreviated as "5-108") According to the synthesis method of 3) of Example 1, N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane and formamidine acetate were reacted to obtain the target compound in a yield of 42%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.51 (3H, s), 3.55 (3H, s), 6.54 (1H, d, J = 8.5 Hz), 6.58 (1H, d, J = 8.5 Hz), 6.90 (1H, dt, J = 1.0, 7.4 Hz), (1H, dt, J = 1.0, 7.4 Hz), 7.17-7.32 (2H, m),7.53 (1H, dd, J = 1.6, 7.2 Hz), 7.61 (1H, dd, J = 1.6, 7.2 Hz), 8.89 (1H, s), 9.34 (1H, s).

6) Synthesis of 2-amino-5-(2-methoxybenzoyl)-4-(2-methoxyphenyl)pyrimidine (hereinafter, may be abbreviated as "5-110") According to the synthesis method of 3) of Example 1, N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane and guanidine hydrochloride were reacted to obtain the target compound in a yield of 83%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.57 (3H, s), 3.60 (3H, s), 5.55 (2H, br s), 6.52 (1H, d, J = 8.3 Hz), 6.57 (1H, d, J = 7.8 Hz), 6.85 (1H, dt, J = 0. 8, 7.8 Hz), 6.92 (1H, dt, J = 0.8, 7.8 Hz), 7.14-7.26 (2H, m),7.38 (1H, dd, J = 1.4, 7.3 Hz), 7.46 (1H, dd, J = 1.4, 7.3 Hz), 8.58 (1H, s).

Example 6
According to the method of Example 4, the following pyrazole derivatives were synthesized.

1) Synthesis of 4-benzoyl-1-methyl-5-phenylpyrazole (hereinafter, sometimes abbreviated as "14-60") According to the synthesis method of 3) of Example 4, N,N-dimethylaminomethylene-dibenzoylmethane and phenylhydrazine were reacted to obtain the target compound in a yield of 67%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 3.82 (3H, s), 7.30-7.52 (8H, m), 7.75 (2H, d, J = 8.5 Hz), 7.87 (1H, s).

2) Synthesis of 4-(4-methylbenzoyl)-5-(4-methylphenyl)-1-methylpyrazole (hereinafter, may be abbreviated as "14-63") According to the synthesis method of Example 4, 3), N,N-dimethylaminomethylene-di(4-methylbenzoyl)methane was reacted with methylhydrazine to obtain the target compound in a yield of 56%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 2.40 (6H, s), 3.82 (3H, s), 7.20 (2H, d, J = 8.8 Hz), 7.23-7.29 (4H, m), 7.69 (2H, d, J = 8.8 Hz), 7.84 (1H, s).

3) Synthesis of 4-(4-methylbenzoyl)-3-(4-methylphenyl)-1-methylpyrazole (hereinafter, may be abbreviated as "14-64") According to the synthesis method of 3) of Example 4, N,N-dimethylaminomethylene-di(4-methylbenzoyl)methane was reacted with methylhydrazine to obtain the target compound as an isomer in a yield of 25%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.33 (3H, s), 2.39 (3H, s), 3.95 (3H, s), 7.12 (2H, d, J = 8.8 Hz), 7.18 (2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz ), 7.69 (2H, d, J = 8.8 Hz), 7.70 (1H, s).

4) Synthesis of 4-(4-fluorobenzoyl)-5-(4-fluorophenyl)-1-methylpyrazole (hereinafter, sometimes abbreviated as "14-100F") According to the synthesis method of 3) of Example 4, N,N-dimethylaminomethylene-di(4-fluorobenzoyl)methane was reacted with methylhydrazine to obtain the target compound in a yield of 23%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.82 (3H, s), 7.08 (2H, dd, J = 8.7, 8.7 Hz), 7.15 (2H, dd, J = 8.7, 8.7 Hz), 7.38 (2H, dd, J = 8.7, 5.6 Hz), 7.80 d, J = 8.7, 5.6 Hz), 7.84 (1H, s).

5) Synthesis of 4-(3-chlorobenzoyl)-5-(3-chlorophenyl)-1-methylpyrazole (hereinafter, may be abbreviated as "14-118") According to the synthesis method of Example 4, 3), N,N-dimethylaminomethylene-di(3-chlorobenzoyl)methane was reacted with methylhydrazine to obtain the target compound in a yield of 69%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 3.82 (3H, s), 7.20-7.26 (1H, m), 7.29-7.47 (5H, m), 7.59-7.63 (1H, m), 7.66-7.68 (1H, m),7.87 (1H, s).

6) Synthesis of 4-(2-chlorobenzoyl)-5-(2-chlorophenyl)-1-methylpyrazole (hereinafter, may be abbreviated as "14-119") According to the synthesis method of Example 4, 3), N,N-dimethylaminomethylene-di(2-chlorobenzoyl)methane was reacted with methylhydrazine to obtain the target compound in a yield of 57%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 3.68 (3H, s), 7.11-7.39 (8H, m), 7.91 (1H, s).

7) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)pyrazole (hereinafter, may be abbreviated as "14-123") According to the synthesis method of Example 4, 3), N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane was reacted with hydrazine to obtain the target compound in a yield of 66%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 7.36 (2H, d, J = 8.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.75 (2H, d, J = 8.8 Hz). 7.93 (1H, br s).

8) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-isopropylpyrazole (hereinafter, may be abbreviated as "14-111") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and isopropylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 76%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 1.48 (6H, d, J = 6.6 Hz), 4.40 (1H, sep, J = 6.6 Hz), 7.29 (2H, d, J = 8.7 Hz), 7.39 (2H, d, J = 8.7 Hz), 7.45 (2H, d, J = 8 .7 Hz), 7.73 (2H, d, J = 8.7 Hz). 7.86 (1H, s).

9) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(2-hydroxyethyl)pyrazole (hereinafter, may be abbreviated as "14-113") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and 2-hydroxyethylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 85%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.13 (1H, t, J = 7.7 Hz), 4.00-4.05 (2H, m), 4.14 (2H, t, J = 4.2 Hz), 7.34 (2H, d, J = 8.6 Hz), 7.39 (2H, d, J = 8.6 Hz ), 7.43 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz). 7.87 (1H, s).

10) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-phenylpyrazole (hereinafter, may be abbreviated as "14-117") According to the synthesis method of Example 4, 3), N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and phenylhydrazine were reacted to obtain the target compound in a yield of 98%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 7.20 (2H, d, J = 8.5 Hz), 7.22-7.29 (4H, m), 7.34-7.39 (3H, m),7.42 (2H, d, J = 8.5 Hz), 7.78 (2H, d, J = 8.5 Hz), 8.0 0 (1H, s).

11) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(2-pyridyl)pyrazole (hereinafter, may be abbreviated as "14-116") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and 2-pyridylhydrazine were reacted to obtain the target compound in a yield of 97%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 7.21-7.31 (5H, m),7.41 (2H, d, J = 8.8 Hz), 7.45 (1H, d, J = 7.9 Hz), 7.85 (2H, d, J = 8.6 Hz), 7.75-7.82 (1H, m), 8.0 2 (1H, s), 8.38 (1H, dd, J = 5.3, 2.0 Hz).

12) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(4-methylphenyl)pyrazole (hereinafter, may be abbreviated as "14-129") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and 4-methylphenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 29%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2,36 (3H, s), 7.09-7.13 (4H, m), 7.19 (2H, d, J = 8.7 Hz), 7.26-7.28 (2H, m), 7.42 (2H, d, J = 8.7 Hz), 7.77 (2H, d, J = 8.7 Hz), 7.98 (1H, s).

13) Synthesis of 4-(4-chlorobenzoyl)-1,5-di(4-chlorophenyl)pyrazole (hereinafter, may be abbreviated as "14-130") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and 4-chlorophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 29%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 7.18 (2H, d, J = 8.8 Hz), 7.19 (2H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.33 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.76 (2H, d, J = 8.5 Hz), 8.00 (1H, s).

14) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(2-nitrophenyl)pyrazole (hereinafter, may be abbreviated as "14-132") According to the synthesis method of Example 4, 3), N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and 2-nitrophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 36%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 7.25-7.28 (6H, m), 7.42 (2H, d, J = 8.5 Hz), 7.58-7.62 (2H, m), 7.78 (2H, d, J = 8.5 Hz), 8.02 (1H, s).

15) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(1-naphthyl)pyrazole (hereinafter, may be abbreviated as "14-133") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and 1-naphthylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 78%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 7.09 (4H, s), 7.26-7.29 (1H, m), 7.39-7.46 (3H, m), 7.51-7.61 (3H, m), 7.85 (2H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8. 1Hz), 8.14 (1H, s).

16) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)pyrazole (hereinafter, may be abbreviated as "14-134") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and 4-methoxyphenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 36%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.82 (3H, s), 6.85 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.8 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz), 7 .42 (2H, d, J = 8.4 Hz), 7.77 (2H, d, J = 8.4 Hz), 7.97 (1H, s).

17) Synthesis of 4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)pyrazole (hereinafter, may be abbreviated as "14-139") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and 3,4-dichlorophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 43%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 6.95 (1H, dd, J = 8.7, 2.3 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.37 (1H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz), 7.54 (1H, d, J = 2.3 Hz), 7.76 (2H, d, J = 8.7 Hz), 8.00 (1H, s).

18) Synthesis of 1-benzyl-4-(4-chlorobenzoyl)-5-(4-chlorophenyl)pyrazole (hereinafter, may be abbreviated as "14-115") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-chlorobenzoyl)methane and benzylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 93%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 4.83 (2H, br s), 7.22 (1H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.40-7.44 (4H, m), 7.76 (2H, d, J = 8.4 Hz), (2H, d, J = 8.4 Hz), 7.76 (2H, d, J = 8.6 Hz), 8.04 (1H, s).

19) Synthesis of 4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(4-methylphenyl)pyrazole (hereinafter, may be abbreviated as "14-140") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-bromobenzoyl)methane and 4-methylphenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 55%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.36 (3H, s), 7.09-7.16 (6H, m), 7.43 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.7 Hz), 7.98 (1 H, s).

20) Synthesis of 4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)pyrazole (hereinafter, may be abbreviated as "14-142") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(4-bromobenzoyl)methane and 2-chlorophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 27%.
^1H -NMR (300 MHz, CDCl ₃ )δ: 7.12 (2H, d, J = 8.7 Hz),7.35-7.44 (6H, m), 7.59 (2H, d, J = 8.7 Hz), 7.71 (2H, d, J = 8.5 Hz), 8.05 (1H, s).

21) Synthesis of 4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(2-nitrophenyl)pyrazole (hereinafter, may be abbreviated as "14-143") According to the synthesis method of Example 4, 3), N,N-dimethylaminomethylene-di(4-bromobenzoyl)methane and 2-nitrophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 55%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 7.19 (2H, d, J = 8.6 Hz), 7.23-7.29 (1H, m), 7.41 (2H, d, J = 8.3 Hz),7.57-7.62 (4H, m), 7.70 (2H, d, J = 8.3 Hz), 7.9 7-8.00 (1H, m), 8.01 (1H, s).

22) Synthesis of 4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(1-naphthyl)pyrazole (hereinafter, may be abbreviated as "14-144") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-bromobenzoyl)methane and 1-naphthylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 30%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 7.02 (2H, d, J = 8.6 Hz), 7.23-7.29 (2H, m), 7.42 (1H, t, J = 7.4 Hz),7.50-7.57 (4H, m), 7.62 (2H, d, J = 8.3 Hz), 7 (2H, d, J = 8.3 Hz), 7.93 (2H, d, J = 8.3 Hz), 8.13 (1H, s).

23) Synthesis of 4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(4-cyanophenyl)pyrazole (hereinafter, may be abbreviated as "14-146") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-bromobenzoyl)methane and 4-cyanophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 18%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 7.14 (2H, d, J = 8.3 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.50 (2H, d, J = 8.5 Hz), 7.59 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 6.3 Hz), 7.68 (2H, d, J = 6.3 Hz),8.03 (1H, s).

25) Synthesis of 1-benzyl-4-(4-bromobenzoyl)-5-(4-bromophenyl)pyrazole (hereinafter, may be abbreviated as "14-173") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(4-bromobenzoyl)methane and benzylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 36%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 5.24 (2H, s), 7.05-7.08 (2H, m), 7.15 (2H, d, J = 8.4 Hz), 7.29-7.32 (3H, m), 7.53 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.89 (1H, s).

26) Synthesis of 4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(3,4-dichlorophenyl)pyrazole (hereinafter, may be abbreviated as "14-150") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-bromobenzoyl)methane and 3,4-dichlorophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 45%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 6.95 (1H, dd, J = 8.8, 2.8 Hz), 7.15 (2H, d, J = 8.2 Hz), 7.38 (1H, d, J = 8.8 Hz), 7. 49 (2H, d, J = 8.2 Hz), 7.55 d, J = 2.8 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.68 (2H, d, J = 8.2 Hz), 8.00 (1H, s).

27) Synthesis of 1-(2-chlorophenyl)-4-(4-methylbenzoyl)-5-(4-methylphenyl)pyrazole (hereinafter, may be abbreviated as "14-153") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(4-methylbenzoyl)methane and 2-chlorophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 55%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2,33 (3H, s), 2,41 (3H, s), 7.01 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.0 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.29-7.38 ( 3H, m), 7.42-7.45 (1H, m), 7.77 (2H, d, J = 8.4 Hz), 8.05 (1H, s).

28) Synthesis of 4-(4-methylbenzoyl)-5-(4-methylphenyl)-1-(1-naphthyl)pyrazole (hereinafter, may be abbreviated as "14-155") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(4-methylbenzoyl)methane and 1-naphthylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 30%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.18 (3H, s), 2.42 (3H, s), 6.88 (2H, d, J = 8.4 Hz), 7.03 (2H, t, J = 8.1 Hz), 7.23-7.29 (3H, m), 7.39 (1H, t, J = 8 .1 Hz), 7.49-7.60 (3H, m), 7.82 (2H, d, J = 7.9 Hz), 7.89 (2H, d, J = 7.8 Hz), 8.13 (1H, s).

29) Synthesis of 4-(4-methylbenzoyl)-5-(4-methylphenyl)-1-(4-methoxyphenyl)pyrazole (hereinafter, may be abbreviated as "14-156") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(4-methylbenzoyl)methane and 4-methoxyphenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 55%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2,31 (3H, s), 2,41 (3H, s), 3.80 (3H, s), 6.83 (2H, d, J = 8.7 Hz), 7.07 (2H, d, J = 8.3 Hz), 7.14 (2H, d, J = 8.0 Hz ), 7.18 (2H, d, J = 8.7 Hz), 7.22 (2H, d, J = 8.0 Hz), 7.75 (2H, d, J = 8.3 Hz), 7.97 (1H, s).

30) Synthesis of 1-(4-cyanocyclophenyl)-4-(4-methylbenzoyl)-5-(4-methylphenyl)pyrazole (hereinafter, may be abbreviated as "14-157") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(4-methylbenzoyl)methane and 4-cyanocyclophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 36%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2,35 (3H, s), 2,41 (3H, s), 7.14 (4H, s), 7.23 (2H, d, J = 8.7 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.61 (2H, d, J = 8.7 Hz ), 7.73 (2H, d, J = 8.5 Hz), 8.03 (1H, s).

31) Synthesis of 1-benzyl-4-(4-methylbenzoyl)-5-(4-methylphenyl)pyrazole (hereinafter, may be abbreviated as "14-174") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(4-methylbenzoyl)methane and benzylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 77%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2,38 (3H, s), 2,39 (3H, s), 5.29 (2H, s), 7.08-7.11 (2H, m), 7.18-7.21 (6H, m), 7.29-7.32 (3H, m), 7.70 (2H, d, J = 8.6 Hz), 7.92 (1H, s).

32) Synthesis of 4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)-1-(4-methylphenyl)pyrazole (hereinafter, may be abbreviated as "14-162") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane and 4-methylphenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 34%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2,29 (3H, s), 3.45 (3H, s), 3.65 (3H, s), 6.61 (1H, d, J = 8.4 Hz), 6.62 (1H, d, J = 8.4 Hz), 6.74 (1H, t, J = 7.5 Hz ), 6.83 (1H, t, J = 7.5 Hz), 6.98 (1H, dd, J = 2.0, 7.5 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.10 (2H, d, J = 8.6 Hz), 7.15-7.18 (1H, m), 7.20-7.23 (1 H, m), 7.26-7.29 (1H, m), 8.10 (1H, s).

33) Synthesis of 1-(4-chlorophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole (hereinafter, may be abbreviated as "14-163") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane and 4-chlorophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 41%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.45 (3H, s), 3.64 (3H, s), 6.62 (1H, d, J = 8.4 Hz), 6.63 (1H, d, J = 8.4 Hz), 6.75 (1H, dt, J = 7.5, 1.0 Hz), (1H, dt, J = 7.5, 1.0 Hz), 7.00 (1H, dd, J = 7.5, 1.7 Hz), 7.14-7.29 (7H, m), 8.11 (1H, s).

34) Synthesis of 4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)-1-(4-methoxyphenyl)pyrazole (hereinafter, may be abbreviated as "14-167") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane and 4-methoxyphenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 48%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.47 (3H, s), 3.65 (3H, s), 3.76 (3H, s), 6.60 (1H, d, J = 8.3 Hz), 6.63 (1H, d, J = 8.3 Hz), 6.71-6.78 (3H, m), 6. 83 (1H, t, J = 7.5 Hz), 6.98 (1H, dd, J = 7.5, 1.7 Hz), 7.10-7.28 (5H, m), 8.09 (1H, s).

35) Synthesis of 1-(4-cyanophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole (hereinafter, may be abbreviated as "14-168") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane and 4-cyanophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 90%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.42 (3H, s), 3.64 (3H, s), 3.76 (3H, s), 6.61-6.64 (2H, m), 6.76 (1H, t, J = 7.5 Hz), 6.84 (1H, t, J = 7.5 Hz), 7. 02 (1H, dd, J = 7.5, 1.8 Hz), 7.18-7.25 (2H, m), 7.29-7.34 (3H, m), 7.71 (2H, d, J = 8.7 Hz), 8.15 (1H, s).

36) Synthesis of 1-(3,4-dimethylphenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole (hereinafter, may be abbreviated as "14-169") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane and 3,4-dimethylphenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 48%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 2.16 (3H, s), 2.19 (3H, s), 3.47 (3H, s), 3.65 (3H, s), 6.61 (1H, d, J = 8.3 Hz), 6.63 (1H, d, J = 8.3 Hz), 6.74 (1 H, t, J = 7.6 Hz), 6.80-6.87 (2H, m), 6.93-6.99 (2H, m), 7.10-7.29 (4H, m), 8.10 (1H, s).

37) Synthesis of 1-(4-bromophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole (hereinafter, may be abbreviated as "14-170") According to the synthesis method of 4) of Example 4, N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane and 4-bromophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 55%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.45 (3H, s), 3.64 (3H, s), 6.62 (1H, d, J = 8.3 Hz), 6.64 (1H, d, J = 8.3 Hz), 6.76 (1H, t, J = 7.7 Hz), 6.84 (1H, t , J = 7.7 Hz), 7.00 (1H, dd, J = 7.7, 1.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.18-7.31 (3H, m), 7.38 (2H, d, J = 8.8 Hz), 8.12 (1H, s).

38) Synthesis of 1-(3,4-dichlorophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole (hereinafter, may be abbreviated as "14-172") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane and 3,4-dichlorophenylhydrazine hydrochloride were reacted to obtain the target compound in a yield of 66%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.48 (3H, s), 3.64 (3H, s), 6.62 (1H, d, J = 8.6 Hz), 6.65 (1H, d, J = 8.6 Hz), 6.78 (1H, t, J = 7.5 Hz), 6.84 (1H, t , J = 7.5 Hz), 6.97-7.02 (2H, m), 7.19-7.30 (4H, m), 7.47 (1H, d, J = 2.5 Hz), 8.12 (1H, s).

39) Synthesis of 1-benzyl-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole (hereinafter, may be abbreviated as "14-175") According to the synthesis method of Example 4, 4), N,N-dimethylaminomethylene-di(2-methoxybenzoyl)methane was reacted with benzylhydrazine hydrochloride to obtain the target compound in a yield of 75%.
¹ H-NMR (300 MHz, CDCl ₃ )δ: 3.57 (3H, s), 3.64 (3H, s), 5.11 (2H, q, J = 8.2 Hz), 6.58 (1H, d, J = 8.2 Hz), 6.68 (1H, d, J = 7.5 Hz), 6.76 (1H, d , J = 7.5 Hz), 6.81 (1H, d, J = 7.5 Hz), 6.95-7.02 (3H, m), 7.13-7.24 (6H, m), 8.04 (1H, s).

Test Example 1
Inhibitory effect on pancreatic cancer cell chemotaxis (in vitro)
Using a real-time cell kinetic analysis method based on image analysis (TAXIScan method) (see J Immunol. Methods. 282:1, 2003, J Immunol. Methods. 320:55, 2007, J Immunol. Methods. 404:59, 2014, and BMC cancer.17:234, 2017) (Figure 1), a system was constructed to evaluate the chemotaxis and invasive ability of pancreatic cancer cells, and the compounds synthesized in Examples 1 to 4 were evaluated for their inhibitory effects on the chemotaxis of pancreatic cancer cells. The results are shown in Figure 2.
As can be seen from FIG. 2, the compounds synthesized in Examples 1 to 4 inhibited the chemotaxis of the pancreatic cancer cell line BxPC-3 toward fetal bovine serum, particularly the migration speed, and the migration speed was suppressed to almost the same speed as that of cells without the chemotactic factor.

Test Example 2
Inhibitory effect on pancreatic cancer cell proliferation (in vivo)
^1x106 human pancreatic cancer cell line BxPC-3 was suspended in 100μL of phosphate buffer and inoculated subcutaneously into the back of 5-week-old nude mice. After confirming engraftment 7 days after inoculation, 1mg (equivalent to 40mg/kg body weight) of the compound synthesized in Example 4 was orally administered once a week to each mouse. At the time of administration, 30mg/mL of the compound dissolved in dimethylsulfoxide was diluted with olive oil to 1mg/100μL and forcibly administered orally using a stomach tube.
The results are shown in Figure 3.
As can be seen from FIG. 3, the compound synthesized in Example 4 suppressed the growth of the pancreatic cancer cell line BxPC-3 inoculated into the back of nude mice more than the existing drug gemcitabine.

Test Example 3
Inhibitory effect on pancreatic cancer cell metastasis (in vivo)
GFP-labeled human pancreatic cancer cell line BxPC-3 was subcutaneously transplanted (4.0 x 10 ⁶ in 200 μl PBS) into nude mice (strain name: BALB/c Ajcl-nu/nu; 5-6 weeks old), and the grown tumor tissue was excised, and a mass (4 mm ³ ) cut from the isolated tumor was transplanted into the pancreas of another 16 mice. Two weeks after transplantation, the mice were divided into 4 groups (4 mice/group), and drugs were administered every week. The fluorescence intensity and number of tumors were measured every week from the body surface. After 50 days (approximately 7 weeks), the mice were euthanized, the abdomen was opened, and the fluorescence intensity was measured directly. Statistics were performed using a nonparametric method, and significant differences were examined using the Kruskal-Wallis test, with p<0.05 considered significant.
Group 1: No drug Group 2: Gemcitabine (ip)
Group 3: Compound of Example 4 (Stock solution: 100 mM in DMSO) (po)
Group 4: Gemcitabine (ip) + compound of Example 4 (stock solution: 100 mM in DMSO) (po)
The results (change in body weight (set at the time of transplantation as 1), the number of mice in which metastasis was observed, and a comparison of the amount of fluorescence from the tumor) are shown in FIGS. 4 to 6, respectively.
As can be seen from FIG. 4, all groups except group 1 (no drug) gained weight.
As can be seen from FIG. 5, metastasis was observed after 22 days in group 1 (no drug) and after 36 days in group 2 (administered gemcitabine), whereas no metastasis was observed in group 3 (administered the compound of Example 4) and group 4 (administered gemcitabine + compound of Example 4).
As can be seen from FIG. 6, the amount of fluorescence was significantly lower in Group 4 (administration of gemcitabine+the compound of Example 4) compared to Group 1 (no drug), and tumor growth was suppressed.

Test Example 4
Inhibitory effect on pancreatic cancer cell chemotaxis (in vitro)
The compounds synthesized in Examples 5 and 6 were evaluated for their inhibitory effect on the chemotaxis of pancreatic cancer cells in the same manner as in Test Example 1. The results are shown in Figures 7 to 10.
As can be seen from FIG. 7, the compounds synthesized in Examples 5 and 6 significantly inhibited the migration speed, which is one of the chemotactic components of the pancreatic cancer cell line BxPC-3 to fetal bovine serum.
As can be seen from FIG. 8, the compounds synthesized in Examples 5 and 6 significantly suppressed the directional chemotaxis component of the pancreatic cancer cell line BxPC-3 to fetal bovine serum.
As can be seen from FIG. 9, the compounds synthesized in Examples 5 and 6 significantly inhibited the migration speed, which is one of the chemotactic components of the pancreatic cancer cell line BxPC-3 to fetal bovine serum.
As can be seen from FIG. 10, the compounds synthesized in Examples 5 and 6 significantly suppressed the directional chemotaxis component of the pancreatic cancer cell line BxPC-3 to fetal bovine serum.

The number of people affected by pancreatic cancer in Japan is about 33,000 per year (2010), accounting for 7-9% of all cancers, and the number of deaths is about 30,000 per year (2012). The number of people affected by pancreatic cancer worldwide is about 277,000 per year, accounting for 2.2% of all cancers. The 5-year survival rate (all stages) is about 7% from 1981 to 1990, and about 13% from 2001 to 2007, and although treatment outcomes have improved, it is still poor. During this time, new drugs and surgical methods have progressed, but pancreatic cancer is still far from being conquered. If the present invention is applied clinically, it is expected to have an effect of dramatically improving the prognosis of these patients.
In addition to pancreatic cancer, the in vitro cell kinetic analysis method on which the present invention is based has established a chemotaxis assay system for lung cancer, colon cancer, breast cancer cells, ovarian cancer, and sarcoma cells, and in the future, it will be possible to evaluate the effect of suppressing cancer metastasis in a wide range of cancers, including these cancers. The total number of cancer patients is approximately 980,000 in Japan (estimated in 2015) and 14 million worldwide (estimated in 2012), and the number of deaths is approximately 370,000 in Japan (estimated in 2015) and approximately 8.2 million worldwide per year (estimated in 2012). The therapeutic effect is expected for some of these cancer patients.
In addition, as shown in Figure 2, it is expected that there will be fewer side effects than existing drugs when applied clinically because it has less cytotoxicity than existing drugs, as seen with the existing drug gemcitabine. Currently, there are cases in which cancer treatment requires the abandonment of medication due to side effects, so it is expected that this new drug will have the effect of avoiding the interruption or discontinuation of treatment.

The present invention can provide a compound having antitumor activity and cancer metastasis inhibitory activity, as well as an antitumor agent containing the compound as an active ingredient.

This application is based on patent application No. 2018-059074 filed in Japan, the contents of which are incorporated in their entirety into this specification.

Claims (6)

5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)-2-methylpyrimidine,
4-(4-methoxybenzoyl)-5-(4-methoxyphenyl)-1-methylpyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-methylpyrazole,
4-(4-bromobenzoyl)-3-(4-bromophenyl)-1-methylpyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-cyclohexylpyrazole,
4-chlorophenyl-[5-(4-chlorophenyl)-1-methylpyrazol-4-yl]methanol,
4-chlorobenzyl-5-(4-chlorophenyl)-1-methylpyrazole,
4-chlorobenzoyl-5-(4-chlorophenyl)-1-methylpyrazole oxime,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-methylpyrazole,
5-(4-methylbenzoyl)-4-(4-methylphenyl)pyrimidine,
2-amino-5-(4-methylbenzoyl)-4-(4-methylphenyl)pyrimidine,
2-amino-5-(4-chlorobenzoyl)-4-(4-chlorophenyl)pyrimidine,
5-(2-methoxybenzoyl)-4-(2-methoxyphenyl)-2-methylpyrimidine,
5-(2-methoxybenzoyl)-4-(2-methoxyphenyl)pyrimidine,
2-amino-5-(2-methoxybenzoyl)-4-(2-methoxyphenyl)pyrimidine,
4-benzoyl-1-methyl-5-phenylpyrazole,
4-(4-methylbenzoyl)-5-(4-methylphenyl)-1-methylpyrazole,
4-(4-methylbenzoyl)-3-(4-methylphenyl)-1-methylpyrazole,
4-(4-fluorobenzoyl)-5-(4-fluorophenyl)-1-methylpyrazole,
4-(3-chlorobenzoyl)-5-(3-chlorophenyl)-1-methylpyrazole,
4-(2-chlorobenzoyl)-5-(2-chlorophenyl)-1-methylpyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-isopropylpyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(2-hydroxyethyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-phenylpyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(2-pyridyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(4-methylphenyl)pyrazole,
4-(4-chlorobenzoyl)-1,5-di(4-chlorophenyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(2-nitrophenyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(1-naphthyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)pyrazole,
1-benzyl-4-(4-chlorobenzoyl)-5-(4-chlorophenyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(4-methylphenyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(2-nitrophenyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(1-naphthyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(4-cyanophenyl)pyrazole,
1-benzyl-4-(4-bromobenzoyl)-5-(4-bromophenyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(3,4-dichlorophenyl)pyrazole,
1-(2-chlorophenyl)-4-(4-methylbenzoyl)-5-(4-methylphenyl)pyrazole,
4-(4-methylbenzoyl)-5-(4-methylphenyl)-1-(1-naphthyl)pyrazole,
4-(4-methylbenzoyl)-5-(4-methylphenyl)-1-(4-methoxyphenyl)pyrazole,
1-(4-cyanophenyl)-4-(4-methylbenzoyl)-5-(4-methylphenyl)pyrazole,
1-benzyl-4-(4-methylbenzoyl)-5-(4-methylphenyl)pyrazole,
4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)-1-(4-methylphenyl)pyrazole,
1-(4-chlorophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole,
4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)-1-(4-methoxyphenyl)pyrazole,
1-(4-cyanophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole,
1-(3,4-dimethylphenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole,
1-(4-bromophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole,
1-(3,4-dichlorophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole, and
1-Benzyl-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole
An antitumor agent comprising, as an active ingredient, a compound selected from the group consisting of: The antitumor agent according to claim 1 , which inhibits the chemotaxis of the human pancreatic cancer cell line BxPC-3 at 10 μM in vitro. The antitumor agent according to claim 1 or 2 , which has no cytotoxicity against the human pancreatic cancer cell line BxPC-3 at 10 μM in vitro. 5-(4-methoxybenzoyl)-4-(4-methoxyphenyl)-2-methylpyrimidine,
4-(4-methoxybenzoyl)-5-(4-methoxyphenyl)-1-methylpyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-methylpyrazole,
4-(4-bromobenzoyl)-3-(4-bromophenyl)-1-methylpyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-cyclohexylpyrazole,
4-chlorophenyl-[5-(4-chlorophenyl)-1-methylpyrazol-4-yl]methanol,
4-chlorobenzyl-5-(4-chlorophenyl)-1-methylpyrazole,
4-chlorobenzoyl-5-(4-chlorophenyl)-1-methylpyrazole oxime,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-methylpyrazole,
5-(4-methylbenzoyl)-4-(4-methylphenyl)pyrimidine,
2-amino-5-(4-methylbenzoyl)-4-(4-methylphenyl)pyrimidine,
2-amino-5-(4-chlorobenzoyl)-4-(4-chlorophenyl)pyrimidine,
5-(2-methoxybenzoyl)-4-(2-methoxyphenyl)-2-methylpyrimidine,
5-(2-methoxybenzoyl)-4-(2-methoxyphenyl)pyrimidine,
2-amino-5-(2-methoxybenzoyl)-4-(2-methoxyphenyl)pyrimidine,
4-benzoyl-1-methyl-5-phenylpyrazole,
4-(4-methylbenzoyl)-5-(4-methylphenyl)-1-methylpyrazole,
4-(4-methylbenzoyl)-3-(4-methylphenyl)-1-methylpyrazole,
4-(4-fluorobenzoyl)-5-(4-fluorophenyl)-1-methylpyrazole,
4-(3-chlorobenzoyl)-5-(3-chlorophenyl)-1-methylpyrazole,
4-(2-chlorobenzoyl)-5-(2-chlorophenyl)-1-methylpyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-isopropylpyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(2-hydroxyethyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-phenylpyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(2-pyridyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(4-methylphenyl)pyrazole,
4-(4-chlorobenzoyl)-1,5-di(4-chlorophenyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(2-nitrophenyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(1-naphthyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)pyrazole,
4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)pyrazole,
1-benzyl-4-(4-chlorobenzoyl)-5-(4-chlorophenyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(4-methylphenyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(2-nitrophenyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(1-naphthyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(4-cyanophenyl)pyrazole,
1-benzyl-4-(4-bromobenzoyl)-5-(4-bromophenyl)pyrazole,
4-(4-bromobenzoyl)-5-(4-bromophenyl)-1-(3,4-dichlorophenyl)pyrazole,
1-(2-chlorophenyl)-4-(4-methylbenzoyl)-5-(4-methylphenyl)pyrazole,
4-(4-methylbenzoyl)-5-(4-methylphenyl)-1-(1-naphthyl)pyrazole,
4-(4-methylbenzoyl)-5-(4-methylphenyl)-1-(4-methoxyphenyl)pyrazole,
1-(4-cyanophenyl)-4-(4-methylbenzoyl)-5-(4-methylphenyl)pyrazole,
1-benzyl-4-(4-methylbenzoyl)-5-(4-methylphenyl)pyrazole,
4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)-1-(4-methylphenyl)pyrazole,
1-(4-chlorophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole,
4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)-1-(4-methoxyphenyl)pyrazole,
1-(4-cyanophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole,
1-(3,4-dimethylphenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole,
1-(4-bromophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole,
1-(3,4-dichlorophenyl)-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole, and
1-Benzyl-4-(2-methoxybenzoyl)-5-(2-methoxyphenyl)pyrazole
2. An agent for suppressing cancer metastasis, comprising as an active ingredient a compound selected from the group consisting of: The cancer metastasis inhibitor according to claim 4 , which inhibits the chemotaxis of the human pancreatic cancer cell line BxPC-3 at 10 μM in vitro. The cancer metastasis inhibitor according to claim 4 or 5 , which has no cytotoxicity against the human pancreatic cancer cell line BxPC-3 at 10 μM in vitro.