JP2010031001A - Heterocyclic compound, method for producing the same and use of the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel compound useful as an anticancer agent and/or a tyrosine kinase inhibitor. <P>SOLUTION: The compound represented by general formula (1) or a salt of the same is provided. In the formula, furan is particularly preferable as the ring A. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to heterocyclic compounds or pharmaceutically acceptable salts useful as pharmaceuticals, particularly anticancer agents and / or tyrosine kinase inhibitors. In addition, the present invention provides a method for producing these heterocyclic compounds, a composition of a drug containing them (including a pharmaceutical composition), a use for producing anticancer agents in warm-blooded animals such as humans, and abnormal tyrosine. Novel of certain heterocyclic compounds in the treatment of various diseases involving kinases, such as diseases associated with cell proliferation (especially cancer cell proliferation), angiogenesis and / or increased vascular permeability (increased vascular permeability) It is about use.

Current representative anticancer agents include alkylating agents, antimetabolites, molecular target drugs, platinum complex anticancer agents, plant-derived anticancer agents, anticancer antibiotics, BRM (Biological response modifier), cancer vaccines, cytokines, differentiation inducers And monoclonal antibodies, hormonal anticancer agents and the like.
Among these anticancer agents, those that are biologics take a long time to manufacture, and are accompanied by difficulties in mass production and price. In addition, chemically synthesized anticancer agents, such as anticancer agents using rare metals, are associated with difficulties in price and mass production.
In recent years, in order to solve the problems of these anticancer agents, anticancer agents that can be chemically synthesized at a realistic price have attracted attention, and tyrosine kinase inhibitors as one of these anticancer agents are phosphorylation of amino acids in specific proteins. It is a therapeutic and / or prophylactic agent aiming at inhibiting the growth of cancer by inhibiting the action of tyrosine kinase, which is an enzyme that promotes (for example, inhibiting autophosphorylation of tyrosine kinase). Platelet-derived growth factor (PDGF) receptor, fibroblast growth factor (FGF) receptor, epidermal growth factor (EGF) receptor for tyrosine kinase Many types of bodies have been found (see Non-Patent Document 1). These are also involved in cancer growth signals, but HER2 is a similar factor. In particular, HER2 (Human EGF Receptor-2) gene is a transmembrane receptor glycoprotein gene, and this receptor also has tyrosine kinase activity (see Non-Patent Document 1). In addition, epidermal growth factor (EGF) and angiogenic factors (VEGF (Vascular Endothelial Growth Factor)) are also involved in angiogenesis. In addition, the molecular target drug is also effective as an inhibitor of abl tyrosine kinase activity (such as an inhibitor of Bcr / abl kinase activity, which is a protein that causes chronic myeloid leukemia (CML) and the like). Furthermore, molecular target drugs are preventive agents (hormone-dependent cancers such as LH-RH) that prevent cancer malignancy (acquisition of cancer cells, acquisition of metastasis, etc.) and initiation (transition from normal cells to cancer cells). (Luteinizing hormone-releasing hormone)) preventive agent that prevents the transition to hormone-independent cancer, preventive agent that induces apoptosis of cells that migrate to cancer, preventive agent that prevents the transition to cancer as an antioxidant, etc.) Is also useful.
Tyrosine kinases are also involved in diseases other than cancer, such as diseases related to inflammation or allergy (hay fever, allergic rhinitis, allergic asthma, bronchial asthma, rhinitis, or atopic dermatitis), diabetes, Alzheimer's disease, etc. In addition, the relationship between anticancer drugs and anti-inflammatory drugs has been pointed out. Many of the functions of tyrosine kinase inhibitors are unclear, but in recent years, some of their functions have been elucidated from the chemical structure of these drugs. These tyrosine kinase inhibitors also include small molecule drugs, which make mass production relatively easy. Therefore, many companies are expected to enter the market in the future.
However, current tyrosine kinase inhibitors have many problems. First, the therapeutic results of tyrosine kinase inhibitor-based molecularly targeted drugs currently on the market vary greatly depending on the patient. Secondly, these drugs are prone to drug resistance.
Some anti-cancer drugs are expensive. Therefore, the present invention aims to develop the above-mentioned novel pharmaceutical composition that can be chemically synthesized and has a therapeutic effect equally at a reasonable price regardless of the patient.
Japan Chemical Society, Maruzen, "Chemical Handbook Applied Chemistry 6th Edition", p1401-p1403

  Problem to be solved by the present invention is to create an anticancer agent having excellent anticancer activity and / or tyrosine kinase inhibitory activity regardless of gene differences, and having low toxicity and good solubility and absorbability It was.

  As a result of diligent researches on anticancer agents and / or tyrosine kinase inhibitors, the present inventors have found that certain heterocyclic compounds according to the correct molecular design of the present invention have good antitumor activity, low toxicity, and safety range. The present invention was completed by discovering that it can be a wide range of useful anticancer agents (cancer therapeutic agents, cancer preventive agents, etc.) and / or therapeutic agents and preventive agents for diseases involving tyrosine kinases.

［式中、ｑが０〜３の整数であり、Ｒ^１が水素原子、炭素数１〜６のアルキル基、炭素数３〜８のシクロアルキル基、炭素数２〜６のアルケニル基、炭素数２〜６のアルキニル基、置換されていてもよい炭素数７〜１２のアラルキル基または含窒素化合物基であり、Ｒ^２が水素原子、ハロゲン原子、炭素数１〜６のアルキル基、ハロゲン化されていてもよい炭素数１〜４のアルキル基または炭素数１〜６のアルコキシル基であり、Ｒ^３が水素原子、ハロゲン原子、ニトロ基、カルバモイル基、炭素数１〜６のアルキル基、ハロゲン化されていてもよい炭素数１〜４のアルキル基、炭素数１〜８のアルコキシカルボニル基、置換されていてもよいエチニル基、置換されていてもよいフェニルエチニル基、置換されていてもよいビニル基、置換されていてもよいフェニルビニル基、炭素数３〜６のシクロアルケニル基、炭素数４〜６のシクロアルカンジエニル基、置換されていてもよいチエニル基、置換されていてもよいピリジル基または置換されていてもよい炭素数６〜１４のアリール基であり、Ｒ^４が水素原子または炭素数１〜６のアルキル基であり、Ｒ^５が炭素数１〜６のアルコキシル基、ハロゲン原子、置換されていてもよいエチニル基または炭素数１〜６のアルキル基であり、ＷがＣＯ、ＳＯ_２または酸素原子であり、Ｘが炭素数１〜４のアルキレン基であり、Ｙが酸素原子または硫黄原子であり、Ｚが単結合、酸素原子、ＮＨ、Ｎ（ＣＨ_３）またはＮ（Ｃ_２Ｈ_５）であり、Ａ環はベンゼン、フランまたはチオフェンである。］で表される化合物またはその塩；
［２］一般式（２）

［式中、Ｒ^１が水素原子、炭素数１〜６のアルキル基、炭素数３〜８のシクロアルキル基、炭素数２〜６のアルケニル基、炭素数２〜６のアルキニル基、置換されていてもよい炭素数７〜１２のアラルキル基または含窒素化合物基であり、Ｒ^２が水素原子、ハロゲン原子、炭素数１〜６のアルキル基、ハロゲン化されていてもよい炭素数１〜４のアルキル基または炭素数１〜６のアルコキシル基であり、Ｒ^３が水素原子、ハロゲン原子、ニトロ基、カルバモイル基、炭素数１〜６のアルキル基、ハロゲン化されていてもよい炭素数１〜４のアルキル基、炭素数１〜８のアルコキシカルボニル基、置換されていてもよいエチニル基、置換されていてもよいフェニルエチニル基、置換されていてもよいビニル基、置換されていてもよいフェニルビニル基、炭素数３〜６のシクロアルケニル基、炭素数４〜６のシクロアルカンジエニル基、置換されていてもよいチエニル基、置換されていてもよいピリジル基または置換されていてもよい炭素数６〜１４のアリール基であり、Ｒ^４が水素原子または炭素数１〜６のアルキル基であり、Ｘが炭素数１〜４のアルキレン基であり、Ｙが酸素原子または硫黄原子であり、Ｚが単結合、酸素原子、ＮＨ、Ｎ（ＣＨ_３）またはＮ（Ｃ_２Ｈ_５）である。］で表される化合物またはその塩；
［３］一般式（３）

［式中、Ｒ^１が水素原子、炭素数１〜６のアルキル基、炭素数３〜８のシクロアルキル基、炭素数２〜６のアルケニル基または含窒素化合物基であり、Ｒ^２が水素原子、ハロゲン原子、炭素数１〜６のアルキル基、ハロゲン化されていてもよい炭素数１〜４のアルキル基または炭素数１〜６のアルコキシル基であり、Ｒ^３が水素原子、ハロゲン原子、カルバモイル基、炭素数１〜６のアルキル基、ハロゲン化されていてもよい炭素数１〜４のアルキル基、炭素数１〜８のアルコキシカルボニル基、置換されていてもよいエチニル基、置換されていてもよいフェニルエチニル基、置換されていてもよいビニル基、置換されていてもよいフェニルビニル基、炭素数３〜６のシクロアルケニル基、炭素数４〜６のシクロアルカンジエニル基、置換されていてもよいチエニル基、置換されていてもよいピリジル基または置換されていてもよい炭素数６〜１４のアリール基である。］で表される［１］及至［２］に記載の化合物またはその塩；
［４］一般式（４）

［式中、ｐが１〜３の整数であり、Ｒ^１が水素原子、炭素数１〜６のアルキル基、炭素数３〜８のシクロアルキル基、炭素数２〜６のアルケニル基、炭素数２〜６のアルキニル基、置換されていてもよい炭素数７〜１２のアラルキル基または含窒素化合物基であり、Ｒ^２が水素原子、炭素数１〜６のアルキル基、ハロゲン化されていてもよい炭素数１〜４のアルキル基、ハロゲン原子または炭素数１〜６のアルコキシル基であり、Ｒ^３が水素原子、ハロゲン原子、ハロゲン化されていてもよい炭素数１〜４のアルキル基、炭素数１〜６のアルキル基または炭素数１〜６のアルコキシル基であり、Ｒ^４が水素原子または炭素数１〜６のアルキル基であり、Ｘが炭素数１〜４のアルキレン基であり、Ｙが酸素原子または硫黄原子であり、Ｚが単結合、酸素原子、ＮＨ、Ｎ（ＣＨ_３）またはＮ（Ｃ_２Ｈ_５）である。］で表される化合物またはその塩；
［５］一般式（５）

［式中、ｐが１〜３の整数であり、Ｒ^１が水素原子、炭素数１〜６のアルキル基または炭素数３〜８のシクロアルキル基であり、Ｒ^２が水素原子、ハロゲン原子、炭素数１〜６のアルキル基またはハロゲン化されていてもよい炭素数１〜４のアルキル基であり、Ｒ^３が水素原子、ハロゲン原子、炭素数１〜６のアルキル基またはハロゲン化されていてもよい炭素数１〜４のアルキル基である。］で表される化合物またはその塩；
［６］一般式（６）

［式中、Ｒ^１が水素原子、炭素数１〜６のアルキル基または炭素数３〜８のシクロアルキル基であり、Ｒ^２が水素原子、ハロゲン原子、炭素数１〜６のアルキル基またはハロゲン化されていてもよい炭素数１〜４のアルキル基であり、Ｒ^３が水素原子、ハロゲン原子、炭素数１〜６のアルキル基またはハロゲン化されていてもよい炭素数１〜４のアルキル基である。］で表される前記［４］、［５］に記載の化合物またはその塩；
［７］Ｒ^１は炭素数１〜６のアルキル基であり、Ｒ^２は炭素数１〜６のアルキル基であり、Ｒ^３がハロゲン化されていてもよい炭素数１〜４のアルキル基である前記［４］及至［６］に記載の化合物またはその塩；
［８］Ｒ^１がメチル基またはエチル基であり、Ｒ^２がメチル基またはエチル基であり、Ｒ^３はトリフルオロメチル基である前記［４］及至［６］に記載の化合物またはその塩；
［９］一般式（７）

［式中、Ｒ^１がメチル基またはエチル基であり、Ｒ^２がメチル基である。］で表される化合物またはその塩；
［１０］メチル５−（６−メチル−５−（２−（４−（トリフルオロメチル）フェニル）エチニル）ピリミジン−４−イルアミノメチル）−２−フランカルボキシレートまたはエチル５−（６−メチル−５−（２−（４−（トリフルオロメチル）フェニル）エチニル）ピリミジン−４−イルアミノメチル）−２−フランカルボキシレートから選択される化合物またはその塩；
［１１］前記［１］及至［１０］に記載の化合物またはその塩を含む医薬組成物；
［１２］前記［１］及至［１０］に記載の化合物またはその塩を温血動物において抗細胞増殖効果を得る際に用いる薬剤の製造に使用する用途；
［１３］前記［１］及至［１０］に記載の化合物またはその塩を温血動物の培養細胞において抗癌作用を得る際に用いる薬剤の製造に使用する用途；
［１４］前記［１］及至［１０］に記載の化合物またはその塩であるプロドラッグを含有する医薬組成物；
［１５］チロシンキナーゼ阻害剤である前記［１１］、［１４］に記載の医薬組成物；
［１６］抗癌剤である前記［１１］、［１４］に記載の医薬組成物；
［１７］前記［１］及至［１０］に記載の化合物またはその塩である医薬中間原料およびその使用；
［１８］チロシンキナーゼ阻害剤を製造するための前記［１］及至［１０］に記載の化合物またはその塩である医薬中間原料およびその使用；
［１９］抗癌剤を製造するための前記［１］及至［１０］に記載の化合物またはその塩である医薬中間原料およびその使用；
［２０］温血動物において、前記［１］及至［１０］に記載の化合物またはその塩を有効量投与することを含む、チロシンキナーゼ阻害方法；
［２１］温血動物において、前記［１］及至［１０］に記載の化合物またはその塩を有効量投与することを特徴とする癌の治療方法および／または予防方法；
［２２］温血動物において、前記［１］及至［１０］に記載の化合物またはその塩を有効量投与することを特徴とする、かかる温血動物において血管新生阻害および／または血管透過性減少作用を生じさせる方法などに関する。That is, the present invention
[1] General formula (1)

[Wherein q is an integer of 0 to 3, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number An alkynyl group having 2 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms that may be substituted, or a nitrogen-containing compound group, and R ² is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or halogenated. An alkyl group having 1 to 4 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, and R ³ is a hydrogen atom, a halogen atom, a nitro group, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, or a halogenated group. An optionally substituted alkyl group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 1 to 8 carbon atoms, an optionally substituted ethynyl group, an optionally substituted phenylethynyl group, and an optionally substituted vinyl. Group, substitution Phenyl vinyl group which may be substituted, cycloalkenyl group having 3 to 6 carbon atoms, cycloalkanedienyl group having 4 to 6 carbon atoms, optionally substituted thienyl group, optionally substituted pyridyl group or substituted Or an aryl group having 6 to 14 carbon atoms, R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ⁵ is an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, or a substituted group. An ethynyl group or an alkyl group having 1 to 6 carbon atoms, W is CO, SO ₂ or an oxygen atom, X is an alkylene group having 1 to 4 carbon atoms, and Y is an oxygen atom or a sulfur atom Z is a single bond, an oxygen atom, NH, N (CH ₃ ) or N (C ₂ H ₅ ), and the A ring is benzene, furan or thiophene. Or a salt thereof;
[2] General formula (2)

[Wherein, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or substituted. An aralkyl group having 7 to 12 carbon atoms or a nitrogen-containing compound group, and R ² may be a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an optionally halogenated carbon atom having 1 to 4 carbon atoms. An alkyl group or an alkoxyl group having 1 to 6 carbon atoms, and R ³ is a hydrogen atom, a halogen atom, a nitro group, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, or an optionally halogenated carbon atom having 1 to 4 carbon atoms. An alkyl group having 1 to 8 carbon atoms, an optionally substituted ethynyl group, an optionally substituted phenylethynyl group, an optionally substituted vinyl group, and an optionally substituted phenyl Nyl group, C3-C6 cycloalkenyl group, C4-C6 cycloalkanedienyl group, optionally substituted thienyl group, optionally substituted pyridyl group, or optionally substituted carbon An aryl group having 6 to 14 carbon atoms, R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, X is an alkylene group having 1 to 4 carbon atoms, Y is an oxygen atom or a sulfur atom, Z is a single bond, an oxygen atom, NH, N (CH ₃ ) or N (C ₂ H ₅ ). Or a salt thereof;
[3] General formula (3)

[Wherein, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or a nitrogen-containing compound group, and R ² is a hydrogen atom. , A halogen atom, an alkyl group having 1 to 6 carbon atoms, an optionally halogenated alkyl group having 1 to 4 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, and R ³ is a hydrogen atom, a halogen atom or a carbamoyl group Group, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 4 carbon atoms which may be halogenated, an alkoxycarbonyl group having 1 to 8 carbon atoms, an ethynyl group which may be substituted, Phenylethynyl group which may be substituted, vinyl group which may be substituted, phenylvinyl group which may be substituted, cycloalkenyl group having 3 to 6 carbon atoms, cycloalkanedienyl group having 4 to 6 carbon atoms, substitution Which may be a thienyl group, a pyridyl group which may be substituted or optionally substituted good having 6 to 14 carbon atoms an aryl group. Or a salt thereof according to any one of [1] to [2],
[4] General formula (4)

[In the formula, p is an integer of 1 to 3, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number. An alkynyl group having 2 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms which may be substituted, or a nitrogen-containing compound group, and R ² may be a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a halogenated group A good alkyl group having 1 to 4 carbon atoms, a halogen atom or an alkoxyl group having 1 to 6 carbon atoms, and R ³ is a hydrogen atom, a halogen atom, an optionally halogenated alkyl group having 1 to 4 carbon atoms, carbon An alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, X is an alkylene group having 1 to 4 carbon atoms, and Y Is an oxygen atom or a sulfur atom, and Z is a single atom A bond, an oxygen atom, NH, N (CH ₃ ) or N (C ₂ H ₅ ). Or a salt thereof;
[5] General formula (5)

[Wherein p is an integer of 1 to 3, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, and R ² is a hydrogen atom, a halogen atom, An alkyl group having 1 to 6 carbon atoms or an optionally halogenated alkyl group having 1 to 4 carbon atoms, wherein R ³ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a halogenated group; Or an alkyl group having 1 to 4 carbon atoms. Or a salt thereof;
[6] General formula (6)

[Wherein, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, and R ² is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a halogen atom. An optionally substituted alkyl group having 1 to 4 carbon atoms, and R ³ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an optionally halogenated alkyl group having 1 to 4 carbon atoms. It is. ] The compound or its salt as described in said [4] and [5] represented by these;
[7] R ¹ is an alkyl group having 1 to 6 carbon atoms, R ² is an alkyl group having 1 to 6 carbon atoms, and R ³ is an alkyl group having 1 to 4 carbon atoms which may be halogenated. A compound or a salt thereof according to [4] and [6] above;
[8] The compound or salt thereof according to [4] to [6], wherein R ¹ is a methyl group or an ethyl group, R ² is a methyl group or an ethyl group, and R ³ is a trifluoromethyl group;
[9] General formula (7)

[Wherein, R ¹ is a methyl group or an ethyl group, and R ² is a methyl group. Or a salt thereof;
[10] Methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate or ethyl 5- (6-methyl A compound selected from -5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate or a salt thereof;
[11] A pharmaceutical composition comprising the compound or salt thereof according to [1] to [10] above;
[12] Use of the compound according to the above [1] to [10] or a salt thereof for use in producing a drug used for obtaining an anti-cell proliferative effect in a warm-blooded animal;
[13] Use of the compound according to the above [1] to [10] or a salt thereof for use in producing a drug used for obtaining an anticancer action in cultured cells of a warm-blooded animal;
[14] A pharmaceutical composition comprising a prodrug which is a compound or a salt thereof according to the above [1] to [10];
[15] The pharmaceutical composition according to the above [11], [14], which is a tyrosine kinase inhibitor;
[16] The pharmaceutical composition according to the above [11], [14], which is an anticancer agent;
[17] Pharmaceutical intermediate material which is a compound or salt thereof according to the above [1] to [10] and use thereof;
[18] A pharmaceutical intermediate material which is a compound or a salt thereof according to the above [1] to [10] and a use thereof for producing a tyrosine kinase inhibitor;
[19] Pharmaceutical intermediate material which is a compound or a salt thereof according to [1] to [10] and a use thereof for producing an anticancer agent;
[20] A method for inhibiting tyrosine kinase, comprising administering an effective amount of the compound or salt thereof according to [1] to [10] above in a warm-blooded animal;
[21] A method for treating and / or preventing cancer, comprising administering an effective amount of the compound or salt thereof according to [1] to [10] to a warm-blooded animal;
[22] In a warm-blooded animal, an angiogenesis inhibitory and / or vascular permeability-decreasing action in the warm-blooded animal, wherein an effective amount of the compound or salt thereof described in [1] to [10] is administered. It is related with the method of generating.

Hereinafter, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X in the general formula (1) to general formula (7) of the compound of the present invention or a salt thereof (heterocyclic compound of the present invention) are specifically described. It illustrates and explains in detail about this invention compound. In addition, the range of General formula (1) to General formula (7) is not limited by these specific illustrations.

  In this specification, the generic term “alkyl group” includes both linear and branched alkyl groups. However, when referring to an individual alkyl group such as a “propyl group”, it refers only to a linear alkyl group. Similar rules apply to other generic terms.

  Specific examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among them, a fluorine atom is preferable.

  The “optionally halogenated alkyl group having 1 to 4 carbon atoms” means that a part of a linear or branched alkyl group having 1 to 4 carbon atoms may be replaced with a halogen atom. . Specific examples of the “optionally halogenated alkyl group having 1 to 4 carbon atoms” include, for example, a trifluoromethyl group, a difluoromethyl group, a fluoromethyl group, a 2,2,2-trifluoroethyl group, and the like. Among them, a trifluoromethyl group is preferable.

  The “C1-C6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples of the “alkyl group having 1 to 6 carbon atoms” include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, An isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, and the like can be mentioned. Among them, a methyl group, an ethyl group, an isopropyl group, an isobutyl group, an isopentyl group, a propyl group, a butyl group, a pentyl group, and the like are preferable. A group, an ethyl group and the like are more preferable.

  Specific examples of the “C3-C8 cycloalkyl group” include, for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and the like.

  Specific examples of the “C3-C6 cycloalkenyl group” include groups such as 2-cyclopenten-1-yl and 2-cyclohexen-1-yl.

  Specific examples of the “C 4-6 cycloalkanedienyl group” include, for example, 2,4-cyclopentanedien-1-yl, 2,4-cyclohexanedien-1-yl, 2,5-cyclohexane. And groups such as dien-1-yl.

  Specific examples of the “alkenyl group having 2 to 6 carbon atoms” include, for example, allyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group and 2-hexenyl. Group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, vinyl group, 1-propenyl group and the like.

  Specific examples of the “C 2-6 alkynyl group” include, for example, 2-propynyl group, 2-butynyl group, 3-butynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 2 -A hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, etc. are mentioned.

The “C1-C4 alkylene group” in X in the general formula (1), the general formula (2), and the general formula (4) means a linear or branched alkylene group having 1 to 4 carbon atoms. To do.
Specific examples of the “C 1-4 alkylene group” include, for example, methylene group, ethylene group, methylmethylene group, dimethylmethylene group, ethylmethylmethylene group, isopropylmethylene group, trimethylene group, propylene group, 1- Examples include methyltrimethylene group, 2-methyltrimethylene group, tetramethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, 1-ethylethylene group, 2-ethylethylene group, etc. A methylene group, a methylmethylene group, an ethylene group, a trimethylene group, and a tetramethylene group are preferable, and a methylene group, a methylmethylene group, and an ethylene group are more preferable.

  Specific examples of the “alkoxyl group having 1 to 6 carbon atoms” include, for example, methoxy group, ethoxy group, propoxy group, butoxy group, isopropoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group and the like. Of these, a methoxy group is preferred.

  Specific examples of the “alkoxycarbonyl group having 1 to 8 carbon atoms” include, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl. Group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, benzyloxycarbonyl group and the like.

  The “nitrogen-containing compound group” means a group containing at least one nitrogen atom. Specific examples of the “nitrogen-containing compound group” include, for example, (N, N-dimethylamino) methyl group, (N, N-diethylamino) methyl group, morpholinomethyl group, 2- (N, N-dimethylamino). Ethyl group, 2- (N, N-diethylamino) ethyl group, 2-morpholinoethyl group, 3- (N, N-dimethylamino) propyl group, 3- (N, N-diethylamino) propyl group, 3-morpholinopropyl Group, 4- (N, N-dimethylamino) butyl group, 4- (N, N-diethylamino) butyl group, 4-morpholinobutyl group, N-methylpiperidin-4-yl group, N-ethylpiperidine-4- Yl group, N-propylpiperidin-4-yl group, N-butylpiperidin-4-yl group, N-methylpiperidin-3-yl group, N-ethylpiperidin-3-yl group N-propylpiperidin-3-yl group, N-butylpiperidin-3-yl group, 2-piperidinoethyl group, 2- (pyrrolidin-1-yl) ethyl group, 3-piperidinopropyl group, 3- (pyrrolidine- 1-yl) propyl group, 4-piperidinobutyl group, 4- (pyrrolidin-1-yl) butyl group, piperidinomethyl group, pyrrolidin-1-ylmethyl group, morpholino group, piperidino group, 1-pyrrolidinyl group, 4- (N, N-diethylamino) -2-butynyl group, 4- (N, N-dimethylamino) -2-butynyl group, 4- (pyrrolidin-1-yl) -2-butynyl group, 4- (piperidino) -2-butynyl Group, 4- (morpholino) -2-butynyl group, 4- (4-methylpiperazin-1-yl) -2-butynyl group, 4- (4-ethylpiperazin-1-yl) 2-butynyl group, (N-methylpiperidin-3-yl) methyl group, 2- (N-methylpiperidin-3-yl) ethyl group, 3- (N-methylpiperidin-3-yl) propyl group, 4 -(N-methylpiperidin-3-yl) butyl group, (N-ethylpiperidin-3-yl) methyl group, 2- (N-ethylpiperidin-3-yl) ethyl group, 3- (N-ethylpiperidin- 3-yl) propyl group, 4- (N-ethylpiperidin-3-yl) butyl group, (N-methylpiperidin-4-yl) methyl group, 2- (N-methylpiperidin-4-yl) ethyl group, 3- (N-methylpiperidin-4-yl) propyl group, 4- (N-methylpiperidin-4-yl) butyl group, (N-ethylpiperidin-4-yl) methyl group, 2- (N-ethylpiperidine) -4-I L) ethyl group, 3- (N-ethylpiperidin-4-yl) propyl group, 4- (N-ethylpiperidin-4-yl) butyl group, N-benzylpiperidin-4-yl group, N-benzylpiperidine- 3-yl group, piperidin-3-yl group, piperidin-4-yl group, piperidin-3-ylmethyl group, piperidin-4-ylmethyl group, 2-piperidin-3-ylethyl group, 2-piperidin-4-ylethyl group 3-piperidin-3-ylpropyl group, 3-piperidin-4-ylpropyl group, 4-piperidin-3-ylbutyl group, 4-piperidin-4-ylbutyl group, homopiperidin-1-yl group, 2-homo Piperidin-1-ylethyl group, 3-homopiperidin-1-ylpropyl group, 2- (4-methylpiperazin-1-yl) ethyl group, 3- (4-methyl Rupiperazin-1-yl) propyl group, 4- (4-methylpiperazin-1-yl) butyl group, (4-methylpiperazin-1-yl) methyl group, 2- (4-ethylpiperazin-1-yl) ethyl Group, 3- (4-ethylpiperazin-1-yl) propyl group, 4- (4-ethylpiperazin-1-yl) butyl group, (4-ethylpiperazin-1-yl) methyl group, piperazin-1-ylmethyl Group, 2- (piperazin-1-yl) ethyl group, 3- (piperazin-1-yl) propyl group, 4- (piperazin-1-yl) butyl group, piperazin-1-yl group, homopiperazine-1- Yl group, 2-homopiperazin-1-ylethyl group, 3-homopiperazin-1-ylpropyl group, 2- (N-methylpyrrolidin-3-yl) ethyl group, 3- (N-methylpyrrole) N-yl) propyl group, 4- (N-methylpyrrolidin-3-yl) butyl group, (N-methylpyrrolidin-3-yl) methyl group, N-methylpyrrolidin-3-yl group, 2- ( N-ethylpyrrolidin-3-yl) ethyl group, 3- (N-ethylpyrrolidin-3-yl) propyl group, 4- (N-ethylpyrrolidin-3-yl) butyl group, (N-ethylpyrrolidin-3- Yl) methyl group, N-ethylpyrrolidin-3-yl group, 2- (pyrrolidin-3-yl) ethyl group, 3- (pyrrolidin-3-yl) propyl group, 4- (pyrrolidin-3-yl) butyl group , (Pyrrolidin-3-yl) methyl group, pyrrolidin-3-yl group, 2- (N-methylpyrrolidin-2-yl) ethyl group, 3- (N-methylpyrrolidin-2-yl) propyl group, 4- (N-methylpi Loridin-2-yl) butyl group, (N-methylpyrrolidin-2-yl) methyl group, N-methylpyrrolidin-2-yl group, 2- (N-ethylpyrrolidin-2-yl) ethyl group, 3- ( N-ethylpyrrolidin-2-yl) propyl group, 4- (N-ethylpyrrolidin-2-yl) butyl group, (N-ethylpyrrolidin-2-yl) methyl group, N-ethylpyrrolidin-2-yl group, 2- (pyrrolidin-2-yl) ethyl group, 3- (pyrrolidin-2-yl) propyl group, 4- (pyrrolidin-2-yl) butyl group, (pyrrolidin-2-yl) methyl group, pyrrolidin-2- Yl group, 2- (N-benzyl-N-methylamino) ethyl group, 3- (N-benzyl-N-methylamino) propyl group, 4- (N-benzyl-N-methylamino) butyl group, (N -Benzyl N-methylamino) methyl group, 8-methyl-8-azabicyclo [3.2.1] octane-3-yl group, 3-quinuclidinyl group, 9-methyl-9-azabicyclo [3.3.1] nonane- 3-yl group, 2-pyridyl group, 5-methyl-1,3-thiazol-2-yl group, 4-methyl-1,3-thiazol-2-yl group and the like are mentioned, among them N-methylpiperidine -4-yl group, N-methylpiperidin-3-yl group, 2-morpholinoethyl group, 2-piperidinoethyl group, 2- (N, N-diethylamino) ethyl group, 2- (N, N-dimethylamino) ethyl Group, 2-pyridyl group, 5-methyl-1,3-thiazol-2-yl group and the like are preferable.

  Specific examples of the “aryl group having 6 to 14 carbon atoms” in the “optionally substituted aryl group having 6 to 14 carbon atoms” include, for example, phenyl group, 1-naphthyl group, 2-naphthyl group and the like. Among them, a phenyl group is preferable.

  Specific examples of the “optionally substituted aryl group having 6 to 14 carbon atoms” include, for example, 4-chlorophenyl group, 4-fluorophenyl group, 4- (trifluoromethyl) phenyl group, 2-chlorophenyl group. 3-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-methylphenyl group, 2-methylphenyl group, 3-methylphenyl group, 2- (trifluoromethyl) phenyl group, 3- (tri Fluoromethyl) phenyl group, phenyl group and the like, and 4-chlorophenyl group, 4-fluorophenyl group, 4- (trifluoromethyl) phenyl group and the like are mentioned among others.

  Specific examples of the “aralkyl group having 7 to 12 carbon atoms” in the “optionally substituted aralkyl group having 7 to 12 carbon atoms” include, for example, benzyl group, benzhydryl group, phenethyl group, naphthylmethyl group and the like. Among them, a benzyl group is preferable.

  Specific examples of the “optionally substituted aralkyl group having 7 to 12 carbon atoms” include benzyl group, 4-methoxybenzyl group, 2-nitrobenzyl group, 4-nitrobenzyl group and the like.

  Specific examples of the “optionally substituted thienyl group” include, for example, 2-thienyl group, 3-thienyl, 3-methyl-2-thienyl, etc., among which 2-thienyl group is preferable.

  Specific examples of the “optionally substituted pyridyl group” include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, and the like.

  Specific examples of the “optionally substituted phenylethynyl group” include, for example, 4- (trifluoromethyl) phenylethynyl group, 4-fluorophenylethynyl group, 4-chlorophenylethynyl group, 3- (trifluoromethyl ) Phenylethynyl group, 2- (trifluoromethyl) phenylethynyl group, 3-fluorophenylethynyl group, 2-fluorophenylethynyl group, 3-chlorophenylethynyl group, 2-chlorophenylethynyl group, 4-methylphenylethynyl group, 3 -Methylphenylethynyl group, 2-methylphenylethynyl group, 2,4-difluorophenylethynyl group, 3,5-difluorophenylethynyl group, 4-fluoro-3-methylphenylethynyl group, 2,5-dimethylphenylethynyl group , 3,5-bis (trif Olomethyl) phenylethynyl group, 1,4-dimethylphenylethynyl group, phenylethynyl group, 4-nitrophenylethynyl, 2-nitrophenylethynyl and the like, among which 4- (trifluoromethyl) phenylethynyl group, 4- A fluorophenylethynyl group, a 3-fluorophenylethynyl group, a 4-methylphenylethynyl group, and the like are preferable, and a 4- (trifluoromethyl) phenylethynyl group is more preferable.

  Specific examples of the “optionally substituted phenylvinyl group” include 2- (4- (trifluoromethyl) phenyl) vinyl group, 2- (4-fluorophenyl) vinyl group, 2- (4 -Chlorophenyl) vinyl group, 2-phenylvinyl group, 2- (4-methylphenyl) vinyl group, 2- (3- (trifluoromethyl) phenyl) vinyl group, 2- (2- (trifluoromethyl) phenyl) Vinyl group, 2- (3-fluorophenyl) vinyl group, 2- (2-fluorophenyl) vinyl group, 2- (3-chlorophenyl) vinyl group, 2- (2-chlorophenyl) vinyl group, 2- (3- Methylphenyl) vinyl group, 2- (2-methylphenyl) vinyl group, 2- (2,4-difluorophenyl) vinyl group, 2- (3,5-difluorophenyl) vinyl 2- (4-fluoro-3-methylphenyl) vinyl group, 2- (2,5-dimethylphenyl) vinyl group, 2- (3,5-bis (trifluoromethyl) phenyl) vinyl group, 2- ( And 1,4-dimethylphenyl) vinyl group.

  Specific examples of the “optionally substituted ethynyl group” include, for example, 3,3-dimethyl-1-butynyl, cyclopropylethynyl group, cyclohexylethynyl group, 3,3,3-trifluoro-1-propynyl. Group, ethynyl group, 1-propynyl group, 1-butynyl group, 1-pentynyl group, 1-hexynyl group, 3-cyclopentylpropynyl group, 3-cyclohexylpropynyl group, 3-thienylethynyl group, 2-pyridylethynyl group, 3 -Pyridylethynyl group, 4-pyridylethynyl group, 5-methoxycarbonyl-1-pentynyl group, 5-ethoxycarbonyl-1-pentynyl group and the like can be mentioned.

  Specific examples of the “optionally substituted vinyl group” include, for example, 3,3-dimethyl-1-butenyl, 2- (cyclopropyl) vinyl group, 3,3,3-trifluoro-1-propenyl. Group, vinyl group, 2- (cyclohexyl) vinyl group, 1-propenyl group, 1-butenyl group, 1-pentenyl group, 1-hexenyl group, 3-cyclopentylpropenyl group, 3-cyclohexylpropenyl group, 2- (3- Thienyl) vinyl group, 2- (2-pyridyl) vinyl group, 2- (3-pyridyl) vinyl group, 2- (4-pyridyl) vinyl group, 2- (methoxycarbonyl) vinyl group, 2- (ethoxycarbonyl) And vinyl group, 2-carbamoyl vinyl group, 5-methoxycarbonyl-1-pentenyl group, 5-ethoxycarbonyl-1-pentenyl group, and the like.

  “Optionally substituted aryl group”, “optionally substituted aralkyl group”, “optionally substituted thienyl group”, “optionally substituted pyridyl group”, “optionally substituted” The substituent in the “good phenylethynyl group” and “optionally substituted phenylvinyl group” is not particularly limited, but examples thereof include halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), carbon C1-C6 alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, etc.), C1-C4 alkyl group (eg, trifluoromethyl group, etc.) which may be halogenated, carbon A cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms (eg, vinyl group, allyl group, etc.), an alkynyl group having 2 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms ( , A methoxy group, an ethoxy group, a propoxy group, etc.), an alkoxyl group having 1 to 4 carbon atoms which may be halogenated (eg, 2,2,2-trifluoroethoxy group, trifluoromethoxy group, etc.), a hydroxyl group, An alkoxycarbonyl group having 1 to 6 carbon atoms (eg, methoxycarbonyl group, ethoxycarbonyl group, etc.), carboxy group, acyl group (eg, formyl group, benzoyl group, acetyl group, etc.), nitro group, sulfamoyl group, carbamoyl group, An amino group etc. can be mentioned, Especially, a halogen atom and a C1-C6 alkyl group are preferable. These optional substituents may be substituted at 0 to 5 positions at substitutable positions. Preferably, these optional substituents may be substituted with 0 to 3 substituents at substitutable positions.

  The substituent in the “optionally substituted ethynyl group” and “optionally substituted vinyl group” is not particularly limited. For example, an optionally substituted pyridyl group (eg, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, etc.), optionally substituted thienyl group (eg, 3-thienyl group), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), carbon C1-C6 alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, etc.), C1-C4 alkyl group (eg, trifluoromethyl group, etc.) which may be halogenated, carbon C3-C8 cycloalkyl group, C2-C6 alkenyl group (e.g., vinyl group, allyl group, etc.), C2-C6 alkynyl group, C1-C6 alkoxyl group (e.g., methoxy group) Ethoxy group, propoxy group, etc.), optionally halogenated C1-C4 alkoxyl group (eg, 2,2,2-trifluoroethoxy group, trifluoromethoxy group, etc.), hydroxyl group, C1-C1 6 alkoxycarbonyl groups (eg, methoxycarbonyl group, ethoxycarbonyl group, etc.), carboxy groups, acyl groups (eg, formyl group, benzoyl group, acetyl group, etc.), carbamoyl groups, amino groups, etc. However, an optionally substituted pyridyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkyl group having 1 to 4 carbon atoms that may be halogenated, and 1 to 6 carbon atoms Are preferably an alkoxyl group, a carbamoyl group, or an alkoxycarbonyl group having 1 to 6 carbon atoms. These optional substituents may be substituted at 0 to 3 positions at substitutable positions.

R ^{1 in} general formula (1) to general formula (7) is not particularly limited, but is preferably a hydrogen atom, methyl group, ethyl group, isopropyl group, isobutyl group, isopentyl group, propyl group, butyl group, pentyl. Group, and the like, more preferably a methyl group and an ethyl group. R ¹ may be a protecting group for a carboxy group.

R ^{2 in} general formula (1) to general formula (7) is not particularly limited, but preferably includes a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a fluorine atom, and the like, and more preferably Includes a methyl group and an ethyl group, and most preferably a methyl group.

R ^{3 in} general formula (1) to general formula (3) is not particularly limited, but is preferably a fluorine atom, a chlorine atom, a trifluoromethyl group, a phenyl group, a 1-propynyl group, or 1- (trifluoromethyl). Examples include ethynyl group and 4- (trifluoromethyl) phenylethynyl group. More preferably, a chlorine atom, 4-fluorophenyl ethynyl group, 4- (trifluoromethyl) phenyl ethynyl group, etc. are mentioned, More preferably, 4- (trifluoromethyl) phenyl ethynyl group is mentioned. In addition, as R ³ in the general formula (1) to the general formula (3), an electron-withdrawing group (an electron-withdrawing group, a group having a superconjugate effect, etc.) and / or a group having a π orbital is more preferable. .

R ^{3 in} general formula (4) to general formula (7) is not particularly limited, but preferably includes a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, and more preferably trifluoro. A methyl group is mentioned.

R ^{4 in} general formula (1), general formula (2), and general formula (4) is not particularly limited, but preferably includes a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, and more preferably a hydrogen atom. Atom. R ⁴ may be an amino-protecting group.

R ^{5 in the} general formula (1) is not particularly limited, but preferably includes a methoxy group, an ethoxy group, a propoxy group, a butoxy group, an isopropoxy group, an isobutoxy group, a tert-butoxy group, a sec-butoxy group, and the like. Of these, a methoxy group is preferred. R ⁴ may be a hydroxyl protecting group.

Specific examples of preferred compounds among the compounds of the present invention include:
Methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate, ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate, isopropyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) ) Phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate, isobutyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-yl Aminomethyl) -2-furancarboxylate, isopentyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenol) L) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate, propyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylamino Methyl) -2-furancarboxylate, butyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate, methyl 5- (6-Ethyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate, ethyl 5- (6-ethyl-5- ( 2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate, Tyl 2- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) benzoate, ethyl 2- (6-methyl-5- (2- (4 -(Trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) benzoate, methyl 4- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-yl Aminomethyl) benzoate, ethyl 4- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) benzoate, methyl 5- (2,6-dimethyl- 5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate Ethyl 5- (2,6-dimethyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate, methyl 5- (2- Isopropyl-6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate and ethyl 5- (2-isopropyl-6-methyl- And a compound selected from 5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate or a salt thereof.

Among the compounds of the present invention, more preferred compounds are specifically listed as follows:
Methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate and ethyl 5- (6-methyl-5- And a compound selected from (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate or a salt thereof.

  The compound of the present invention includes (pyrimidin-4-ylaminomethyl) -2-furancarboxylate derivative or a salt thereof, (pyrimidin-4-ylamino-1-ethyl) -2-furancarboxylate derivative or a salt thereof, (pyrimidine- 4-ylamino-2-ethyl) -2-furancarboxylate derivative or salt thereof, 2- (pyrimidin-4-ylaminomethyl) benzoate derivative or salt thereof, 4- (pyrimidin-4-ylaminomethyl) benzoate derivative or The salt is also included.

  The compound of the present invention or a salt thereof may have isomers (optical isomers, geometric isomers, tautomers, etc.), but the present invention may include isomers even when these isomers are used alone. Also included is a mixture of bodies. In addition, the compound of the present invention or a salt thereof may have an asymmetric carbon atom, and optical isomers based on the asymmetric carbon atom may exist. The present invention includes a case where these optical isomers are singly or a mixture of optical isomers.

  The present invention also includes prodrugs of the compounds of the present invention or salts thereof. “Prodrugs” are those that undergo hydrolysis, oxidation, reduction, decarboxylation, etc. under physiological conditions in vivo, that is, reactions with enzymes or non-enzymes (gastric acid, etc.) to form carboxyl groups, amino groups, hydroxyl groups, etc. Or a salt thereof having a group known to those skilled in the art of pharmaceutical technology or organic chemistry. “Prodrugs” are properties or drugs in vivo such as solubility, absorption, stability, duration of action, activity in the target tissue, biodistribution, metabolism and excretion, toxicity, side effects, taste, odor, etc. It may also have a positive effect on kinetic properties.

  In addition, the compound of the present invention may form an acid addition salt or a salt (free base) with a base. The salt of the compound of the present invention is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or acidic amino acid. Salt or the like is used. Specific examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt. Specific examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, methylamine, ethylamine, dimethylamine. A salt with diethylamine or the like is used. Specific examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Specific examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, propionic acid, malonic acid, lactic acid, Salts with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glycolic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid and the like are used. Specific examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and specific examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Etc.

  Furthermore, the present invention also includes various hydrates and solvates and crystalline polymorphic substances of the compound of the present invention or a salt thereof.

[General manufacturing method]
The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with a suitable protecting group at the raw material or intermediate stage, that is, a group that can be easily converted to the functional group. There is. Thereafter, if necessary, the protecting group is removed, and the compound of the present invention, a salt thereof or an intermediate thereof can be obtained as a target product. Examples of such a functional group include an amino group, a carboxyl group, a hydroxyl group and the like. The protecting groups described in Green et al., John Wiley & Sons, "Protective Groups In Organic Synthesis (3rd edition)" can be mentioned, and these may be used as appropriate according to the reaction conditions.

  For general guidance on reaction conditions and reagents see, e.g. See MARCH et al., John Wiley & Sons, “MARCH'S Advanced Organic Chemistry (5th edition)”. The typical production method of the compound of the present invention will be described below.

Hereinafter, unless otherwise specified, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, X, Y and Z are the above-described compounds of the present invention represented by general formula (1) to general formula (7) or salts thereof. It has one of the meanings specified in. The necessary starting compounds are obtained by standard organic chemical methods. The production of these starting compounds is described in the examples below, but is not limited thereto. Other necessary starting compounds are obtained by methods similar to those described therein, and they can be easily produced by those skilled in the art of organic chemistry by applying various known synthetic methods.

  Hereinafter, specific examples of the leaving group represented by L include, for example, a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom, a methanesulfonyloxy group, an ethanesulfonyloxy group, and a propanesulfonyloxy group. , An optionally substituted alkylsulfonyloxy group such as a trifluoromethanesulfonyloxy group or an optionally substituted arylsulfonyloxy group such as a p-toluenesulfonyloxy group, a benzenesulfonyloxy group, and a p-bromobenzenesulfonyloxy group Etc. The same applies hereinafter.

  The compound of the present invention or its salt in general formula (1) to general formula (7) can be produced according to a method known per se or a method analogous thereto, for example, a method represented by the following reaction formula A or reaction formula B Etc. can be manufactured.

［工程Ａ］
本工程は化合物（８）と化合物（９）を反応させ一般式（１）及至一般式（７）に示される本発明の化合物またはその塩を得る工程である。化合物（８）と化合物（９）は、市販されている場合には、市販品をそのまま用いてもよく、また、自体公知の方法またはこれに準じた方法などに従って製造してもよい。
（基）
本反応の脱離基Ｌとしては塩素原子が好ましい。本反応の、Ｒ^４としては水素原子が好ましい。
（溶媒）
本反応は、無溶媒中もしくは反応に影響を及ぼさない溶媒の存在下で実施するのが有利である。これらの溶媒は、反応が進行する限り特に限定されないが、具体的に例示すると、例えばベンゼン、トルエン、キシレン、クロロベンゼンなどの芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン、エチルエーテル、ジイソプロピルエーテル、ジメトキシエタンなどのエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム、四塩化炭素、テトラクロロエタンなどのハロゲン化炭化水素類、アセトン、メチルエチルケトンなどのケトン類、ジメチルスルホキシド（ＤＭＳＯ）などのスルホキシド類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ−ジメチルアセトアミド（ＤＭＡ）、Ｎ−メチル−２−ピロリドン（ＮＭＰ）、ホルムアミドなどのアミド類、メタノール、エタノール、イソプロピルアルコール、プロパノール，ｔｅｒｔ−ブタノールなどのアルコール類、ヘキサン、シクロヘキサン、ペンタンなどのアルカン類、アセトニトリル、酢酸エチル、ジメチルイミダゾリジノン（ＤＭＩ）、ジエチレングリコールジメチルエーテル、ヘキサメチルリン酸トリアミド（ＨＭＰＡ）、水またはこれら二種以上の混合物などが挙げられる。本反応で好ましくはトルエン、Ｎ−メチル−２−ピロリドン（ＮＭＰ）またはＤＭＦの存在下で実施してもよい。
（塩基）
化合物によっては、塩基すなわち有機塩基（好ましくは、ジエチルアミン、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、ジイソプロピルアミン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、Ｎ−エチルピペリジン、Ｎ−メチルモルホリン、モルホリン、ピロリジン、トリメチルアミン、ブチルアミン、トリブチルアミン、アンモニア、ピコリン、２，６−ルチジン、ジアザビシクロ［５．４．０］ウンデク−７−エンなど）又は金属塩塩基（好ましくは、炭酸カリウム、水酸化ナトリウム、炭酸水素ナトリウム、塩基性アルミナ、炭酸水素カリウム、水酸化カリウム、炭酸ナトリウム、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ−ブトキシド、ブチルリチウム、炭酸カルシウムなど）または金属水素化物（水素化ナトリウム、水素化カリウムなど）などの存在下に実施するのが有利な場合がある。本反応で好ましくはトリエチルアミンの存在下で実施してもよい。
（反応条件）
本反応では、化合物（８）と化合物（９）を等モル乃至一方を過剰量用いる。反応は冷却乃至加熱還流下に行い、化合物に応じて適宜設定できる。反応温度は通常０〜１４５℃、好ましくは１０〜１１５℃である。 Production example A

[Step A]
In this step, the compound (8) and the compound (9) are reacted to obtain the compound of the present invention represented by the general formulas (1) to (7) or a salt thereof. When the compound (8) and the compound (9) are commercially available, they may be used as they are, or may be produced according to a method known per se or a method analogous thereto.
(Base)
The leaving group L for this reaction is preferably a chlorine atom. In this reaction, R ⁴ is preferably a hydrogen atom.
(solvent)
This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent that does not affect the reaction. These solvents are not particularly limited as long as the reaction proceeds, but specific examples include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, diethyl ether, tetrahydrofuran (THF), dioxane, ethyl ether, Ethers such as diisopropyl ether and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and tetrachloroethane, ketones such as acetone and methyl ethyl ketone, sulfoxide such as dimethyl sulfoxide (DMSO) Amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), formamide, methanol, ethanol, iso Alcohols such as propyl alcohol, propanol and tert-butanol, alkanes such as hexane, cyclohexane and pentane, acetonitrile, ethyl acetate, dimethylimidazolidinone (DMI), diethylene glycol dimethyl ether, hexamethylphosphate triamide (HMPA), water Or the mixture of these 2 or more types is mentioned. This reaction may be preferably carried out in the presence of toluene, N-methyl-2-pyrrolidone (NMP) or DMF.
(base)
Depending on the compound, a base or organic base (preferably diethylamine, triethylamine, N, N-diisopropylethylamine, diisopropylamine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N -Diethylaniline, N-ethylpiperidine, N-methylmorpholine, morpholine, pyrrolidine, trimethylamine, butylamine, tributylamine, ammonia, picoline, 2,6-lutidine, diazabicyclo [5.4.0] undec-7-ene, etc.) Or a metal salt base (preferably potassium carbonate, sodium hydroxide, sodium bicarbonate, basic alumina, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butyl Kishido, butyl lithium) or a metal hydride (sodium hydride and calcium carbonate, and potassium hydride) it may be advantageous to carry out in the presence of such. This reaction may be preferably carried out in the presence of triethylamine.
(Reaction conditions)
In this reaction, equimolar amounts of compound (8) and compound (9) are used in excess. The reaction is carried out under cooling or heating under reflux and can be appropriately set according to the compound. The reaction temperature is generally 0 to 145 ° C, preferably 10 to 115 ° C.

［工程Ｂ］
本工程は化合物（１０）と化合物（１１）を反応させ一般式（１）及至一般式（７）に示される本発明の化合物またはその塩を得る工程である。化合物（１０）および化合物（１１）は、市販されている場合には、市販品をそのまま用いてもよく、また、自体公知の方法またはこれに準じた方法などに従って製造してもよい。
（基）
本反応の脱離基Ｌとしては臭素原子または塩素原子が好ましい。本反応の、Ｒ^４としては水素原子が好ましい。
（溶媒）
本反応は、無溶媒中もしくは反応に影響を及ぼさない溶媒の存在下で実施するのが有利である。本反応における溶媒は、反応が進行する限り特に限定されないが、前記の溶媒中で実施してもよく、好ましくはジクロロメタン、クロロホルム、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、トルエンまたはＮ−メチル−２−ピロリドン（ＮＭＰ）の存在下で実施してもよい。
（塩基）
化合物によっては、前記の塩基の存在下に実施するのが有利な場合がある。本反応における塩基として好ましくは炭酸カリウム、炭酸水素ナトリウム、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、塩基性アルミナ、炭酸ナトリウム、水酸化ナトリウムまたは水素化ナトリウムの存在下で実施してもよい。
（反応条件）
本反応では、化合物（１０）と化合物（１１）を等モル乃至一方を過剰量用いる。反応は冷却乃至加熱還流下に行い、化合物に応じて適宜設定できる。反応温度は通常約−２０〜１５３℃、好ましくは約−２０〜１１５℃である。 Manufacturing method B

[Step B]
This step is a step of reacting the compound (10) with the compound (11) to obtain the compound of the present invention represented by the general formulas (1) to (7) or a salt thereof. When the compound (10) and the compound (11) are commercially available, they may be used as they are, or may be produced according to a method known per se or a method analogous thereto.
(Base)
The leaving group L for this reaction is preferably a bromine atom or a chlorine atom. In this reaction, R ⁴ is preferably a hydrogen atom.
(solvent)
This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent that does not affect the reaction. The solvent in this reaction is not particularly limited as long as the reaction proceeds, but it may be carried out in the above-mentioned solvent, preferably dichloromethane, chloroform, N, N-dimethylformamide (DMF), toluene or N-methyl-2. -It may be carried out in the presence of pyrrolidone (NMP).
(base)
Depending on the compound, it may be advantageous to carry out in the presence of the aforementioned base. The base in this reaction is preferably carried out in the presence of potassium carbonate, sodium hydrogen carbonate, triethylamine, N, N-diisopropylethylamine, basic alumina, sodium carbonate, sodium hydroxide or sodium hydride.
(Reaction conditions)
In this reaction, equimolar amounts of compound (10) and compound (11) are used in excess. The reaction is carried out under cooling or heating under reflux and can be appropriately set according to the compound. The reaction temperature is generally about -20 to 153 ° C, preferably about -20 to 115 ° C.

（式中、Ｌは脱離基（好ましくはヨウ素原子または臭素原子）を、Ｖはアミノ基誘導体（アミノ基、Ｎ−メチルアミノ基、Ｎ−エチルアミノ基、Ｎ−イソプロピルアミノ基、ｔｅｒｔ−ブトキシカルボニルアミノ基、エトキシカルボニルアミノ基、アセチルアミノ基、メタンスルホニルアミノ基、ベンゼンスルホニルアミノ基など）もしくは脱離基を、ｐは１〜３の整数を示す。Ｖはアミノ基誘導体が好ましい。）
［前工程１］
本工程は化合物（１２）と化合物（１３）とを反応させ、化合物（８）または（１０）を得る工程である。本工程は必要に応じて化合物（８）または（１０）を製造するために工程Ａまたは工程Ｂの前（好ましくは工程Ｂの前）に実施してもよい。本反応は通常、適切な少なくとも１種類以上の金属触媒と塩基の存在下で化合物（１２）と化合物（１３）とを縮合させる。化合物（１２）および化合物（１３）は、市販されている場合には、市販品をそのまま用いてもよく、また、自体公知の方法またはこれに準じた方法などに従って製造してもよい。
（金属触媒）
金属触媒としてはパラジウム触媒および／または銅触媒が用いられ、好ましくはパラジウム触媒と銅触媒を共に用いる。本反応におけるパラジウム触媒としては、具体的に例示すると、例えばジクロロビス（トリフェニルホスフィン）パラジウム、ジクロロビス（ベンゾニトリル）パラジウム、酢酸パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、パラジウム炭素、塩化パラジウムなどが用いられる。好ましくは塩化パラジウム、酢酸パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウムまたはテトラキス（トリフェニルホスフィン）パラジウムを用いてもよい。本反応における銅触媒としては、具体的に例示すると、例えばヨウ化第一銅、塩化第一銅、酸化第一銅、臭化第一銅などが用いられる。好ましくはヨウ化第一銅を用いてもよい。
（溶媒）
本反応は、無溶媒中もしくは反応に影響を及ぼさない適切な溶媒の存在下で実施するのが有利である。本反応における溶媒は、反応が進行する限り特に限定されないが、前記の溶媒中で実施してもよく、好ましくはトルエン、ＴＨＦ、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチル−２−ピロリドン（ＮＭＰ）および／またはアセトニトリルの存在下で実施してもよく、さらに好ましくはトルエン、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、アセトニトリルまたはＮ−メチル−２−ピロリドン（ＮＭＰ）の存在下で実施してもよい。
（塩基）
本反応における塩基は、反応が進行する限り特に限定されないが、前記の塩基で実施してもよく、好ましくはジエチルアミン、トリエチルアミン、ジイソプロピルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、ピリジン、ピロリジンまたはピペリジンの存在下で実施しても良く、さらに好ましくはピリジン、トリエチルアミン、ジイソプロピルアミンまたはピロリジンの存在下で実施してもよい。また、塩基は溶媒も兼ねて用いてもよい。
（反応条件）
本反応では化合物（１２）と化合物（１３）を等モル乃至一方を過剰量用いる。反応は冷却乃至加熱還流下に行い、化合物に応じて適宜設定できる。反応温度は通常約０〜１６０℃、好ましくは約１０〜１４０℃である。
（精製）
生成物は反応液のまま、あるいは粗成物として次の反応に用いることもできるが、常法に従って反応混合物から単離することもできる。
（保護基の脱離）
また、式中、Ｖがｔｅｒｔ−ブトキシカルボニルアミノ基、エトキシカルボニルアミノ基、アセチルアミノ基、メタンスルホニルアミノ基、ベンゼンスルホニルアミノ基などの保護基を有するアミノ基誘導体の場合、［前工程１］の反応後に保護基を脱離してもよい。保護基の脱離は自体公知の方法またはこれに準じた方法（たとえばトリフルオロ酢酸による酸処理、水酸化ナトリウムによる加水分解または還元など）などに従って実施してもよい。 Previous process 1

(Wherein L is a leaving group (preferably iodine atom or bromine atom), V is an amino group derivative (amino group, N-methylamino group, N-ethylamino group, N-isopropylamino group, tert-butoxy group). A carbonylamino group, an ethoxycarbonylamino group, an acetylamino group, a methanesulfonylamino group, a benzenesulfonylamino group, etc.) or a leaving group, p is an integer of 1 to 3. V is preferably an amino group derivative.
[Preprocess 1]
In this step, compound (12) and compound (13) are reacted to obtain compound (8) or (10). This step may be performed before step A or step B (preferably before step B) to produce compound (8) or (10) as necessary. In this reaction, compound (12) and compound (13) are usually condensed in the presence of at least one suitable metal catalyst and a base. When the compound (12) and the compound (13) are commercially available, they may be used as they are, or may be produced according to a method known per se or a method analogous thereto.
(Metal catalyst)
As the metal catalyst, a palladium catalyst and / or a copper catalyst is used, and preferably both a palladium catalyst and a copper catalyst are used. Specific examples of the palladium catalyst in this reaction include dichlorobis (triphenylphosphine) palladium, dichlorobis (benzonitrile) palladium, palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, Palladium carbon, palladium chloride and the like are used. Palladium chloride, palladium acetate, dichlorobis (triphenylphosphine) palladium or tetrakis (triphenylphosphine) palladium may be preferably used. Specific examples of the copper catalyst used in this reaction include cuprous iodide, cuprous chloride, cuprous oxide, and cuprous bromide. Preferably, cuprous iodide may be used.
(solvent)
This reaction is advantageously carried out in the absence of a solvent or in the presence of a suitable solvent that does not affect the reaction. The solvent in this reaction is not particularly limited as long as the reaction proceeds, but it may be carried out in the above solvent, preferably toluene, THF, N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone. (NMP) and / or in the presence of acetonitrile, more preferably in the presence of toluene, N, N-dimethylformamide (DMF), acetonitrile or N-methyl-2-pyrrolidone (NMP). May be.
(base)
The base in this reaction is not particularly limited as long as the reaction proceeds, but may be carried out with the above-mentioned base, preferably in the presence of diethylamine, triethylamine, diisopropylamine, N, N-diisopropylethylamine, pyridine, pyrrolidine or piperidine. It may be carried out in the presence of pyridine, triethylamine, diisopropylamine or pyrrolidine. A base may also be used as a solvent.
(Reaction conditions)
In this reaction, equimolar amounts of compound (12) and compound (13) are used in excess. The reaction is carried out under cooling or heating under reflux and can be appropriately set according to the compound. The reaction temperature is generally about 0 to 160 ° C, preferably about 10 to 140 ° C.
(Purification)
The product can be used in the next reaction as the reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method.
(Removal of protecting group)
In the formula, when V is an amino group derivative having a protecting group such as a tert-butoxycarbonylamino group, an ethoxycarbonylamino group, an acetylamino group, a methanesulfonylamino group, or a benzenesulfonylamino group, The protecting group may be removed after the reaction. The removal of the protecting group may be carried out according to a method known per se or a method analogous thereto (for example, acid treatment with trifluoroacetic acid, hydrolysis or reduction with sodium hydroxide, etc.).

(Modification of previous process 1)
Further, in [Preliminary step 1], the alkynyl metal compound (for example, copper acetylide compound) corresponding to the copper catalyst and the compound (13) may be reacted with the compound (12) in a solvent and / or a base. 8) or (10) is obtained.
(Alternative to previous process 1)
Further, instead of [Pre-Step 1], compound (8) or (10) may be obtained by a Stille reaction. The Stille reaction can be carried out by a conventional method in the presence of a palladium catalyst. As the palladium catalyst used in the Stille reaction, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, or the like is preferable. The reaction is carried out under cooling or heating under reflux and can be appropriately set according to the compound.
(Synthesis of other compounds)
Depending on the compound, the reaction may be carried out according to Heck reaction, Suzuki coupling reaction, Ullmann reaction, Negishi reaction, Wittg reaction, Horner-Emmons reaction, Knoevenagel reaction or a method similar thereto, instead of [Pre-process 1]. . These reactions can be carried out by conventional methods. For example, in the Wittg reaction, an acyl group such as a formyl group, an acetyl group, a propionyl group, or a butyryl group is preferable instead of the leaving group L of the compound (12), and a phosphorus ylide corresponding to the compound (13) is used.

［前工程２］
化合物（９）は、市販されている場合には、市販品をそのまま用いてもよく、また、自体公知の方法またはこれに準じた方法などに従って製造してもよい。化合物（９）の製造は常法により実施できる。例えば、反応式Ｄのように相当するハロゲン化アルキル（例えば、化合物（１１））とＮａＮ_３とを前記の溶媒（例えば、ＤＭＦなど）中で反応（反応は冷却乃至加熱還流下に行い、化合物に応じて適宜設定できる。）させて得られるアジ化物（例えば、化合物（１４））を還元（例えば、Ｌｉｎｄｌａｒ触媒、Ｒｏｓｅｎｍｕｎｄ触媒またはラネーニッケルなどの金属触媒と水素による還元、水素化ホウ素ナトリウムによる還元など）する方法またはこれに準じた方法などに従って製造してもよい。金属触媒による還元反応は前記の溶媒中で実施してもよく、Ｌｉｎｄｌａｒ触媒（Ｐｄ−ＣａＣＯ_３−ＰｂＯ）による還元反応は前記の溶媒（例えば、エタノール、メタノール、イソプロピルアルコール、ヘキサン、ジエチルエーテル、ＴＨＦなど）中で接触水素化してもよい。Ｒｏｓｅｎｍｕｎｄ触媒（Ｐｄ−ＢａＳＯ_４）による還元反応は前記の溶媒（例えば、キシレン、トルエンなど）中で接触水素化してもよい。ラネーニッケルなどの金属触媒による還元反応は前記の溶媒（例えば、エタノール、メタノール、イソプロピルアルコールなど）中で接触水素化してもよい。上記の接触水素化は水素雰囲気条件下または加圧容器（オートクレーブ、耐圧ガラス容器など）を用いて加圧水素条件下で実施してもよい。また、上記の接触水素化（特にラネーニッケルが金属触媒のとき）は、前記の溶媒とともに前記の塩基（例えば、アンモニア水など）の存在下に接触水素化するのが有利な場合がある。水素化ホウ素ナトリウムによる還元反応は前記の溶媒（例えば、エタノール、メタノール、イソプロピルアルコール、ＴＨＦ、ジエチルエーテルなど）中で実施してもよく、好ましくはエタノール中で実施してもよい。また、化合物によっては、Ｇａｂｒｉｅｌ合成、アンモニアやアミンの還元的アルキル化反応（Ｌｅｕｃｋａｒｔ反応、Ｗａｌｌａｃｈ反応など）または相当するイミンまたはニトリルを還元剤（パラジウム炭素やラネーニッケルなどの金属触媒または前記の金属触媒）で処理する方法などに従って製造してもよい。 Previous process 2

[Previous process 2]
Compound (9) may be commercially available as it is, or may be produced according to a method known per se or a method analogous thereto. Compound (9) can be produced by a conventional method. For example, the corresponding alkyl halide as shown in Reaction Formula D (e.g., compound (11)) wherein the solvent and NaN ₃ (for example, DMF, etc.) is reacted (reaction in carried out under cooling to heating under reflux, compound The azide (for example, the compound (14)) obtained by reduction (for example, reduction with a metal catalyst such as Lindlar catalyst, Rosenmund catalyst or Raney nickel and hydrogen, reduction with sodium borohydride, etc.) ) Or a method according to this method. The reduction reaction with a metal catalyst may be carried out in the above solvent, and the reduction reaction with a Lindlar catalyst (Pd—CaCO ₃ —PbO) may be carried out with the above solvent (for example, ethanol, methanol, isopropyl alcohol, hexane, diethyl ether, THF). Etc.) may be catalytic hydrogenation. The reduction reaction with Rosenmund catalyst (Pd—BaSO ₄ ) may be catalytic hydrogenation in the above-mentioned solvent (for example, xylene, toluene, etc.). In the reduction reaction using a metal catalyst such as Raney nickel, catalytic hydrogenation may be carried out in the aforementioned solvent (for example, ethanol, methanol, isopropyl alcohol, etc.). The catalytic hydrogenation may be performed under a hydrogen atmosphere condition or under a pressurized hydrogen condition using a pressurized container (such as an autoclave or a pressure-resistant glass container). The catalytic hydrogenation (especially when Raney nickel is a metal catalyst) may be advantageously carried out in the presence of the base (for example, aqueous ammonia) together with the solvent. The reduction reaction with sodium borohydride may be carried out in the above-mentioned solvent (for example, ethanol, methanol, isopropyl alcohol, THF, diethyl ether, etc.), preferably in ethanol. Further, depending on the compound, Gabriel synthesis, reductive alkylation reaction of ammonia or amine (Leuckart reaction, Wallach reaction, etc.) or the corresponding imine or nitrile is a reducing agent (metal catalyst such as palladium carbon or Raney nickel or the above metal catalyst). You may manufacture according to the method of processing by.

  Moreover, you may implement a reductive reaction in the process in which the compound of this invention, a compound (9), or a compound (11) is manufactured. The reduction reaction may be performed according to a method known per se.

  Moreover, you may implement hydrolysis, esterification, or transesterification in the process which manufactures the compound of this invention, a compound (9), or a compound (11). Hydrolysis, esterification or transesterification may be carried out according to a method known per se.

  Further, amidation may be carried out in the process of producing the compound of the present invention, compound (9) or compound (11). Amidation may be carried out according to a method known per se.

  Many of the intermediates defined herein, for example, compound (8), compound (9), compound (10), compound (12) and compound (14) are novel, and these are other aspects of the present invention. Provided.

  The compound of the present invention thus produced can be purified and / or isolated by known methods such as extraction, chromatography, recrystallization, filtration, vacuum distillation, precipitation, drying and the like.

  In addition, the compound of the present invention can be obtained in the form of the free base by the above production method, or can be obtained in the form of a salt with an acid. The salt may be treated with the appropriate base as described above in a conventional manner. When a salt of the compound of the present invention is intended, for example, an acid addition salt, the obtained salt of the compound of the present invention may be treated with the above-mentioned appropriate acid by a conventional method.

[General evaluation test method]
The compound of the present invention or a salt thereof has anti-cell proliferative activity such as anticancer activity, which is considered to be derived from the receptor tyrosine kinase inhibitory activity of this compound. These characteristics can be evaluated using, for example, one or more of the following methods.
(A) An in vitro assay that measures the ability of a test compound to inhibit the enzyme EGF receptor tyrosine kinase.
Receptor tyrosine kinases were obtained from A-431 cells (derived from human vulvar cancer) in a partially purified form from Carpenter et al . , J. et al. Biol. Chem . , 1979, 254 , 4884, Cohen et al . , J. et al. Biol. Chem . , 1982, 257 , 1523, and Braun et al . , J. et al. Biol. Chem . , 1984, 259 , 2051 in a manner related to that described in Methods. A-431 cells were grown to confluence in Dulbecco's modified Eagle's medium (DMEM) containing 5% fetal calf serum (FCS). The obtained cells were homogenized in hypotonic borate / EDTA buffer (pH 10.1). The homogenate was centrifuged at 400 xg for 10 minutes at 4 ° C. The supernatant was centrifuged at 25,000 xg for 30 minutes at 4 ° C. The pellet material was suspended in 30 mM Hepes buffer (pH 7.4) containing 5% glycerin, 4 mM benzamidine and 1% Triton X-100, stirred at 4 ° C. for 1 hour, and 100,000 × g for 1 hour. Re-centrifuged at 0 ° C. The supernatant containing the solubilized receptor tyrosine kinase was stored in liquid nitrogen. For the test, 40 μl of the enzyme solution thus obtained was added to the following mixture: 400 μl of a mixture of 150 mM Hepes buffer (pH 7.4), 500 μM sodium orthovanadate, 0.1% Triton X-100, 10% glycerin. 200 μl of water, 80 μl of 25 mM DTT, and 80 μl of a mixture of 12.5 mM manganese chloride, 125 mM magnesium chloride and distilled water. Thus, a test enzyme solution was obtained. Each test compound is dissolved in dimethyl sulfoxide (DMSO) to form a 50 mM solution, which is diluted with 40 mM Hepes buffer containing 0.1% Triton X-100, 10% glycerin and 10% DMSO to obtain a 500 μM solution. It was. An equal volume of this solution was mixed with an epidermal growth factor solution (EGF; 20 μg / ml).
[ _Y- ³² P] ATP (3000 Ci / mM, 250 μCi) was diluted to a volume of 2 ml by addition of ATP solution (100 μM) in distilled water. Peptide (Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala- in a mixture of 40 mM Hepes buffer (pH 7.4), 0.1% Triton X-100 and 10% glycerol A 4 mg / ml solution of Arg-Gly) was added in an equal volume.
The test compound / EGF mixture solution (5 μl) was added to the test enzyme solution (10 μl) and the mixture was incubated at 4 ° C. for 30 minutes. ATP / peptide mixture (10 μl) was added and the mixture was incubated at 25 ° C. for 10 minutes. The phosphorylation reaction was stopped by the addition of 5% trichloroacetic acid (40 μl), and bovine serum albumin (BSA; 1 mg / ml, 5 μl) was added. The mixture was left at 4 ° C. for 30 minutes and then centrifuged. An aliquot (40 μl) of the supernatant was placed on a Whatman p81 phosphocellulose filter strip. The filter paper pieces were washed in 75 mM phosphoric acid (4 × 10 ml), blotted dry. Radioactivity present in the filter paper was measured with a liquid scintillation counter (sequence A). This reaction sequence was repeated in the absence of EGF (sequence B) and repeated again in the absence of the test compound (sequence C). Inhibition rate (%) = 100 × {(SC−SB) − (SA−SB) where receptor tyrosine kinase inhibition is SA, the measurement result of sequence B is SB, and the measurement result of sequence C is SC. } / (SC-SB). The extent of inhibition was then measured in the concentration range of test compounds giving IC ₅₀ values.
(B) An in vitro assay that measures the efficacy of test compounds to inhibit the growth of the human nasopharyngeal carcinoma cell line KB by EGF stimulation.
KB cells were seeded into the wells at a density of 1 × 10 ^{4 to} 1.5 × 10 ⁴ cells / well and grown in DMEM supplemented with 5% FCS (activated carbon stripping) for 24 hours. After 3 days of incubation, cell proliferation was determined by the extent to which the MTT tetrazolium dye was metabolized and turned blue. Cell proliferation was then determined in the presence of EGF (10 ng / ml) or in the presence of EGF (10 ng / ml) and a range of test compounds. IC ₅₀ values were then calculated.
(C) Test compound (usually orally administered as a ball milled suspension in 0.5% polysorbate) administered to growth factor TGFα in male rats (400 μg / kg subcutaneously, usually 3 each after administration of test compound) In vivo assay measuring potency to inhibit hepatocyte proliferation stimulation caused by 2 doses at time and 7 hours).
In the control rat group, administration of TGFα causes an average 5-fold stimulation of hepatocyte proliferation.
Cell proliferation in control and test animals was measured as follows:-The next morning after administration of the test compound (or 0.5% polysorbate in the control group), the animals receive bromodeoxyuridine (BrdU; 100 mg / kg ip). . After 4 hours, the animals are sacrificed and the liver is removed. Sections are cut from each liver and BrdU incorporation is measured by a general immunohistological method similar to that described below: Goldsworthy et al . , Chemically Induced Cell Propagation: Implications for Risk Assessment, Wiley-Liss Inc. 1991, p. Pp. 267 and 268 in the 253-284 report. Further studies were performed with a range of doses of test compound to calculate approximate ED ₅₀ values for inhibition of hepatocyte proliferation as measured by inhibition of BrdU incorporation.
The pharmacological properties of the compounds of the present invention vary with structural changes as expected, but generally the activity of the compounds of the present invention is one or more of the tests (a), (b) and (c). It can be demonstrated in a concentration or dosage of the following in: - test (a): - _{IC 50,} for example 0.01～1MyuM;
Test (b): - _{IC 50,} for example 0.1～10MyuM;
Test (c): - _{ED 50,} for example 1 to 100 mg / kg
Ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate has an IC of 0.24 μM in test (a). ₅₀ , with an IC ₅₀ of 0.8 μM in test (b), and an ED ₅₀ of <12.1 mg / kg in test (c);
Methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate is 0.22 μM in test (a). the _{IC 50,} the test _{IC 50} and the test of 0.7μM in (b) (c) with _{ED 50} of <11.8 mg / kg.

  Therefore, the compound of the present invention or a salt thereof has an anti-cell proliferative activity (particularly, an anti-cell proliferative activity selective to malignant cells such as cancer cells), and this property is considered to be derived from its tyrosine kinase inhibitory property. It is done. Therefore, the compound of the present invention or a salt thereof can be used for obtaining a tyrosine kinase inhibitory effect in a warm-blooded animal (for example, human, horse, cow, dog, cat, rat, mouse, rabbit, pig, monkey, etc.). That is, the compound of the present invention or a salt thereof is expected to be useful for the treatment of diseases or medical conditions involving tyrosine kinases.

[General use]
The compounds of the present invention or salts thereof provide a method for the treatment of malignant cell proliferation. The compounds of the present invention or salts thereof are characterized by inhibition of tyrosine kinase enzymes, which are tyrosine kinases that are exemplified by many common warm-blooded cancers, specifically human cancers such as leukemia (chronic myeloid leukemia (CML)). Acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphocytic leukemia, chronic myelomonocytic leukemia (CMML), acute myeloid leukemia, etc.), brain tumors and lung, pancreas, colon, rectum, duodenum, esophagus, tongue, pharynx, Since it is involved in cancers of the stomach, breast, prostate, bladder, uterus and ovary, the compound of the present invention or a salt thereof is expected to have a wide range of anticancer properties. Furthermore, the compounds of the present invention or salts thereof provide a wide range of leukemias, lymphoid malignancies, and tumors (eg, breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovary by providing an anti-cell proliferative effect. It is expected to have activity against carcinomas and sarcomas of tissues such as

  Furthermore, the compound of the present invention or a salt thereof is expected to be effective against other cell proliferative diseases such as psoriasis and rheumatism. Also, diseases associated with abnormal tyrosine kinase enzyme activity include cardiovascular disease, diabetic complications, osteoporosis and Alzheimer's disease. Therefore, the compound of the present invention or a salt thereof can also be used as a prophylactic and / or therapeutic agent for cardiovascular diseases such as restenosis and diabetic complications such as diabetic retinopathy. In addition, diseases mainly caused by allergies or inflammatory reactions, such as hay fever, rhinitis such as allergic rhinitis, asthma such as allergic asthma and bronchial asthma, pneumonia, otitis media, atopic dermatitis, contact dermatitis, epilepsy It can also be used as a therapeutic and / or prophylactic agent for measles, food allergy, conjunctivitis, spring catarrh, fibrosis, osteoarthritis, ulcer, systemic lupus erythematosus, rejection at the time of organ transplantation, and the like.

  Therefore, according to this aspect of the present invention, there is also provided the use of the above-defined compound of the present invention or a salt thereof for the manufacture of a medicament for use in obtaining an anti-cell proliferative effect in a warm-blooded animal (for example, human). The

  According to another aspect of the present invention, an anti-cell proliferative effect is achieved in a warm-blooded animal (eg, a warm-blooded animal having cancer cells, a warm-blooded animal transplanted with stem cells, etc.), such as a human, in need thereof. Also provided is a method of obtaining comprising administering to a warm-blooded animal an effective amount of a compound of the invention as defined above or a salt thereof.

  According to another aspect of the present invention, stem cells (for example, universal cells (iPS cells (artificial pluripotent hepatocytes), ES cells (embryonic hepatocytes), etc.)) and hematopoietic stem cells in warm-blooded animals (for example, humans). , Mesenchymal stem cells, neural stem cells, basal cells, hepatic stem cells, etc.) in the process of culturing (including the process of differentiation of all-purpose cells) to prevent these cells from becoming cancer cells (especially cancer cells) Anti-cell proliferative effect selective for growth, almost no inhibition of proliferation of normal cells (stem cells, etc.)) or for use in the manufacture of drugs used to obtain anti-cell proliferative effects in the process of culturing stem cells Provided.

  Further, according to another aspect of the present invention, there is provided a method for obtaining an anticancer action for preventing stem cells from becoming cancerous in a process of culturing stem cells of warm-blooded animals, for example, a process of culturing human stem cells. There is also provided a method comprising adding an effective amount of a compound of the present invention or a salt thereof as defined above to a culture of stem cells of a blood animal (including media, buffers, etc.).

(Combination with other drugs)
The anti-cell proliferative treatment defined above is applied as a monotherapy, or in addition to the compound of the present invention or a salt thereof, one or more other drugs and / or traditional Chinese medicines etc. You may use things together. Monoclonal antibodies such as trastuzumab (Herceptin ™), rituximab (Rituxan ™), bevacizumab (Avastin ™), cetuximab (Erbitax ™), such as gefitinib (Iressa ™), imatinib mesylate (Glivec ™), Erlotinib (Tarceva ™) and other molecularly targeted drugs (such as tyrosine kinase inhibitors) such as all-trans retinoic acid (ATRA) tretinoin, hexamethylene bisacetamide, retinoic acid (vitamin A Acid)), for example, interferon (IFNα, IFNβ, IFNγ), cytokines such as interleukin (IL-2), etoposide, paclitaxel (Ta sol (trademark)), docetaxel (Taxotere (trademark)), camptotensin, topotecan, irinotecan, vinplastine, vincristine sulfate (oncobin), vinorelbine, vindesine and the like, for example, nitrogen mustard, nitrogen mustard hydrochloride Alkylating agents such as N-oxide, cyclophosphamide (endoxan), ifosfamide, nimustine, nimustine hydrochloride, ranimustine, thiotepa, dacarbazine, lomustine, predonimustine, melphalan, for example, platinum complexes such as nedaplatin, cisplatin, carboplatin, oxaliplatin Systemic anti-cancer agents such as TS-1, Enocitabine, methotrexate, 5-fluorouracil, tegafur (ftafur), UFT, doxy Luridine, carmofur, galocitabine, emitefur, cytarabine, cytarabine ocphosphate, 6-mercaptopurine, thioinosine, azathioprine, hydroxycarbamide, fludarabine, fludarabine phosphate, gemcitabine hydrochloride, pentostatin, 6-mercaptopurine riboside, alkeran, gemcitabine hydrochloride Antimetabolites such as LH-RH agonists (eg, buserelin acetate, goserelin acetate, leuprorelin acetate, etc.), aromatase inhibition (anastrozole, exemestane, etc.), luteinizing hormone agents (eg, medroxyprogesterone), antiestrogens Hormonal anticancer agents such as drugs (tamoxifen, etc.) and antiandrogens (eg, flutamide, bicalutamide, nilutamide, etc.) such as aclarubicin, a Cutinomycin C, actinomycin D (cosmegen), mitomycin C, mitoxantrone hydrochloride, bleomycin hydrochloride, bleomycin sulfate, adriamycin, toyomycin (chromomycin), anthracycline anticancer agents (for example, daunorubicin hydrochloride, doxorubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, Anticancer antibiotics such as amrubicin hydrochloride), anticancer steroids such as testosterone enanthate, chlormadinone acetate, mebithiostane, antiemetics such as dexamethasone, granisetron, ondansetron and topoisomerase inhibitors (Such as irinotecan hydrochloride), hormonal agents (such as prednisolone and prednisone), addiction treatments (such as levofolinate calcium), antibacterial agents (such as Cobi and phosphoric bleomycin), the other anticancer agent (thalidomide, such as procarbazine), and the like used with such.

[General preparations (pharmaceutical production)]
Such combination therapy may be accomplished by simultaneous, sequential or separate administration of the components for treatment. According to this aspect of the present invention there is also provided a formulation comprising a compound of the present invention or a salt thereof and an additional agent as defined above for combination therapy of cancer.

  In addition to the compound of the present invention or a salt thereof, or a pharmaceutical composition containing the compound of the present invention or a salt thereof, other pharmaceutically active compounds can be included. In addition, these pharmaceutical compositions can contain a plurality of the compounds of the present invention or salts thereof. In addition, a pharmaceutical composition containing the compound of the present invention or a salt thereof and a pharmaceutical composition containing a prodrug of the compound of the present invention or a salt thereof can be produced according to a method known per se.

  When the compound of the present invention or a salt thereof is administered as a medicine to a warm-blooded animal such as a human, the dosage form includes injections (including infusions), ointments, suppositories, eye drops, eye ointments, Parenteral administration (transdermal solution, transdermal patch, transmucosal solution, transmucosal patch, inhalant, pellet, etc. (intravenous, subcutaneous, intramuscular, intravascular, organ, intranasal, intradermal) Ophthalmic, intracerebral, intrarectal, intraperitoneal (including intravaginal), intratumoral, proximal to the tumor, or directly into the lesion. Or tablets (including sugar-coated tablets, film-coated tablets) ), Capsules (including soft capsules and microcapsules), granules, pills, syrups, elixirs, fine granules, powders, and the like. The administration form of the compound of the present invention may be either oral administration or parenteral administration, but oral administration in the form of tablets or capsules or parenteral administration in the form of injection is preferred.

  The clinical dose of the compound of the present invention or a salt thereof varies depending on the administration form, administration timing, administration interval, patient age, sex, body weight, sensitivity, symptom level, etc., but is usually effective daily administration. In the case of oral administration, the amount is about 0.001 to 250 mg / kg per body weight, preferably about 0.1 to 100 mg / kg, more preferably about 1 to 50 mg / kg. Divide into 4 doses. In the case of intravenous administration, the daily dose is suitably about 0.001 to 30 mg / kg per body weight, and is administered once a day or divided into multiple times. As an inhalant and a transmucosal agent, about 0.001 to 25 mg / kg per body weight is administered once to several times a day. However, if necessary, an amount outside the above range can be used. The compounds of the invention are formulated for administration by conventional pharmaceutical means.

  Solid preparations for oral administration (tablets, capsules, granules, pills, fine granules, powders, etc.) contain one or more active substances (compounds or salts thereof) and one or more non-active substances. Using an active substance, it is formulated by a method known per se. Inactive substances include excipients (such as lactose, glucose, starch, mannitol, sucrose) and binders (such as mannitol, sorbit, methylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, gum arabic, gelatin, Syrups) and disintegrants (eg starch, microcrystalline cellulose, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, polyethylene glycol, etc.) and lubricants (eg magnesium stearate, calcium stearate, talc, silica etc.) It is done.

  Tablets or pills contain sugar coating (for example, sucrose, gelatin, gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate and / or titanium dioxide, etc. as necessary and the above-mentioned inert substances. Or a film of a gastric or enteric material (which may include a suitable cellulose such as cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate and the inert materials described above). Moreover, you may use a pigment | dye (for example, titanium dioxide etc.) for the film of a tablet or a pill.

  Liquid preparations (injections, solutions, suspensions, emulsions, aerosols, syrups, elixirs, etc.) are prepared using one or more active substances (the compounds of the present invention or salts thereof) and solutions. It is formulated by a known method. Specific examples of the solution include water (distilled water for injection, physiological saline, purified water, etc.), alcohol (ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol, etc.), oil (olive oil, corn oil, sesame oil (castor oil) Etc.), peanut oil, cottonseed oil, liquid paraffin, etc.).

  Furthermore, liquid preparations include solubilizing agents (triethanolamine, sodium carbonate, glutamic acid, aspartic acid, meglumine, etc.), suspending agents or emulsifiers or dispersing aids or wetting agents (gum arabic, tragacanth, sodium carboxymethylcellulose, methylcellulose, Hydroxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, surfactants (polysorbate 80, lecithin, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.), etc. Tonicity agents (sodium chloride, glycerin, mannitol, etc.), pH adjusters (sodium hydroxide, hydrochloric acid, etc.), buffering agents (phosphoric acid and its alkali metal salts, Acid and alkali metal salts thereof), soothing agents (such as benzyl alcohol), preservatives or preservatives (such as methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid), antioxidants or stabilizers (eg, Additives such as ascorbic acid, sodium pyrosulfite and the like may also be included. Generally these additives are mix | blended in the ratio normally used for a liquid formulation.

  An injection is obtained by dissolving the compound of the present invention or a salt thereof and, if necessary, the additive in a solution. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection. The compound of the present invention or a salt thereof in the injection is 0.5 to 50 w / v%, preferably about 1 to 20 w / v%.

  The injection may be warmed, and can be provided as an injection by performing, for example, filtration sterilization, high-pressure heat sterilization, irradiation sterilization, or bactericidal agent blending in the same manner as normal injections. The injection is preferably sterilized by high-pressure heat which is heated for 5 minutes to 30 minutes under the condition of saturated water vapor (100 ° C. to 121 ° C.) at 2 atm. In addition, an injection may be prepared by preparing a sterile injection raw material and dissolving and suspending it in a sterile solution before use.

  Aerosols, syrups, elixirs and the like may contain sweetening agents (such as aspartame), flavoring agents, thickeners, fragrances and the like.

The present invention will be described in detail with reference to Reference Examples, Examples and Formulation Examples below, but the compounds of the present invention are not limited to the compounds described in the following Examples. Moreover, the general manufacturing method of the raw material compound used in an Example is shown in a reference example.
Unless otherwise indicated in the Reference Examples, Examples and Formulation Examples below, the conditions are as follows.
(I) The operation was performed at room temperature. The synthesis reaction may be carried out in an atmosphere of an inert gas such as argon.
(Ii) Evaporation was performed on a rotary evaporator under vacuum, and finishing was performed after removing residual solids such as desiccant by filtration.
(Iii) When stated, the yields are presented for illustration only and are not necessarily the highest achievable.
(Iv) A mass spectrum which is a measurement result of mass spectrometry (MS) is shown by a value of m / z which is a ratio of the mass number (m) of the molecular ion to the charge (z) of the molecular ion.

Reference Example 1.4 Preparation of amino-6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidine:
4-Amino-5-iodo-6-methylpyrimidine and 4-trifluoromethylphenylacetylene cuprous (Cuprous 4-trifluoromethylphenylacetylide) were reacted in pyridine with heating and stirring to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 278.

４−アミノ−６−メチル−５−（２−（４−（トリフルオロメチル）フェニル）エチニル）ピリミジン（２ｇ）、トリエチルアミン（０．７６ｇ）、エチル５−クロロメチル−２−フランカルボキシレート（１．４ｇ）およびジクロロメタン（６０ｍｌ）の混合物を攪拌しながら７２時間加熱還流した。こうして得られた混合物を減圧濃縮して得られた残渣に水を加え洗浄した後、有機相を無水硫酸ナトリウムで乾燥後、有機相を蒸発させて得られた残渣を、カラムクロマトグラフィー（溶出溶媒；クロロホルムおよびメタノールの混合溶媒）により精製して目的物を０．５ｇ得た。プロトン核磁気共鳴分光法（^１Ｈ−ＮＭＲ）及び質量分析法（ＭＳ）などにより目的物が表題化合物であることを確認した。また、ＭＳの測定結果を示す。
マススペクトル：４３０．Example 1. Preparation of ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:

4-amino-6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidine (2 g), triethylamine (0.76 g), ethyl 5-chloromethyl-2-furancarboxylate (1 0.4 g) and dichloromethane (60 ml) were heated to reflux with stirring for 72 hours. The mixture thus obtained was concentrated under reduced pressure and washed with water. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated. The residue was purified by column chromatography (elution solvent). Purified by a mixed solvent of chloroform and methanol) to obtain 0.5 g of the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 430.

Example 2 Preparation of ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
4-amino-6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidine (2 g), triethylamine (0.76 g), ethyl 5-chloromethyl-2-furancarboxylate (1 .4 g) and toluene (60 ml) were heated to reflux with stirring for 10 hours. The mixture thus obtained was concentrated under reduced pressure and washed with water. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated. The residue was purified by column chromatography (elution solvent). Purified by a mixed solvent of chloroform and methanol) to obtain 0.6 g of the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 430.

Example 3 FIG. Preparation of ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 1 was repeated except that ethyl 5-bromomethyl-2-furancarboxylate was used instead of ethyl 5-chloromethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 430.

Example 4 Preparation of ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 2 was repeated except that ethyl 5-bromomethyl-2-furancarboxylate was used instead of ethyl 5-chloromethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 430.

Embodiment 5 FIG. Preparation of ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
4-amino-6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidine (2.8 g), ethyl 5-chloromethyl-2-furancarboxylate (1.8 g), carbonic acid A mixture of potassium (2.1 g) and N, N-dimethylformamide (120 ml) was heated at 70 ° C. with stirring for 15 hours. Water was added to the residue obtained by concentrating the mixture thus obtained under reduced pressure, followed by extraction with chloroform. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated. Elution solvent; mixed solvent of chloroform and methanol) to obtain 1 g of the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 430.

Example 6 Preparation of ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
4-amino-6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidine (2.8 g), ethyl 5-chloromethyl-2-furancarboxylate (1.8 g), carbonic acid A mixture of potassium (2.1 g) and toluene (60 ml) was heated at 70 ° C. with stirring for 4 hours. Water was added to the residue obtained by concentrating the mixture thus obtained under reduced pressure, followed by extraction with chloroform. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated. Elution solvent; mixed solvent of chloroform and methanol) to obtain 0.9 g of the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 430.

Example 7 Preparation of ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 5 was repeated except that ethyl 5-bromomethyl-2-furancarboxylate was used instead of ethyl 5-chloromethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 430.

Example 8 FIG. Preparation of ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 6 was repeated except that ethyl 5-bromomethyl-2-furancarboxylate was used instead of ethyl 5-chloromethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 430.

Example 9 Preparation of ethyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
4-amino-6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidine (2.8 g), ethyl 5-chloromethyl-2-furancarboxylate (1.8 g), carbonic acid A mixture of sodium hydride (1 g) and N, N-dimethylformamide (120 ml) was heated with stirring at 80 ° C. for 12 hours. Water was added to the residue obtained by concentrating the mixture thus obtained under reduced pressure, followed by extraction with chloroform. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated. (Elution solvent; mixed solvent of chloroform and methanol) to obtain 0.8 g of the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 430.

実施例１に記載した方法を反復し、ただしエチル５−クロロメチル−２−フランカルボキシレートの代わりにメチル５−クロロメチル−２−フランカルボキシレートを用いて目的物を得た。プロトン核磁気共鳴分光法（^１Ｈ−ＮＭＲ）及び質量分析法（ＭＳ）などにより目的物が表題化合物であることを確認した。また、ＭＳの測定結果を示す。
マススペクトル：４１６．Example 10 Preparation of methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:

The method described in Example 1 was repeated except that methyl 5-chloromethyl-2-furancarboxylate was used instead of ethyl 5-chloromethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 416.

Example 11 Preparation of methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 2 was repeated except that methyl 5-chloromethyl-2-furancarboxylate was used in place of ethyl 5-chloromethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 416.

Example 12 FIG. Preparation of methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 3 was repeated except that methyl 5-bromomethyl-2-furancarboxylate was used instead of ethyl 5-bromomethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 416.

Example 13 Preparation of methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 4 was repeated except that methyl 5-bromomethyl-2-furancarboxylate was used instead of ethyl 5-bromomethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 416.

Example 14 Preparation of methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 5 was repeated except that methyl 5-chloromethyl-2-furancarboxylate was used in place of ethyl 5-chloromethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 416.

Example 15. Preparation of methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 6 was repeated except that methyl 5-chloromethyl-2-furancarboxylate was used in place of ethyl 5-chloromethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 416.

Example 16 Preparation of methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 7 was repeated except that methyl 5-bromomethyl-2-furancarboxylate was used instead of ethyl 5-bromomethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 416.

Example 17. Preparation of methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 8 was repeated except that methyl 5-bromomethyl-2-furancarboxylate was used in place of ethyl 5-bromomethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 416.

Example 18 Preparation of methyl 5- (6-methyl-5- (2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate:
The method described in Example 9 was repeated except that methyl 5-chloromethyl-2-furancarboxylate was used instead of ethyl 5-chloromethyl-2-furancarboxylate to obtain the desired product. It was confirmed that the target product was the title compound by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) and mass spectrometry (MS). Moreover, the measurement result of MS is shown.
Mass spectrum: 416.

The following are representative dosage forms containing a compound of the present invention or a salt thereof for use in treatment or prevention in humans. The following formulations are obtained by conventional methods known in the pharmaceutical art.
Formulation Example 1 Tablet (Dose per tablet)
(1) 10 mg of the compound obtained in Example 2
(2) Lactose 80mg
(3) Corn starch 40mg
(4) Magnesium stearate 3mg
(5) Croscarmellose sodium 6mg
After the above components are mixed by a conventional method, the resulting center tablet is coated with a sugar coating to obtain a sugar coated tablet.
Formulation Example 2 Capsule (Dose per capsule)
(1) 10 mg of the compound obtained in Example 2
(2) Lactose 160mg
(3) Magnesium stearate 2mg
The above ingredients are mixed by a conventional method and then filled into gelatin capsules to obtain capsules.
Formulation Example 3 Injection (10mg / ml)
(1) Compound 1.0% w / v obtained in Example 2
(2) Sodium phosphate 3.6% w / v
(3) 0.1M sodium hydroxide solution 15.0% v / v
(4) Amount to be 100% water for injection

  Tables 1 to 4 below show the structures of the compounds of the present invention as pharmaceutical compositions and / or pharmaceutical intermediate materials of the present invention. These can be easily synthesized by using the above-described production methods, the methods described in Examples and methods obvious to those skilled in the art of organic chemistry, or variations thereof. The following abbreviations are used in the table. No: An example of the number of the compound manufactured in the Example.

  The compound of the present invention or a salt thereof has anticancer activity and / or tyrosine kinase inhibitory activity, low toxicity, good solubility and absorbability, and therefore depends on cancer and / or tyrosine kinase in warm-blooded animals and the like. It can be used for therapeutic treatment or prophylactic treatment of sex diseases. Tyrosine kinase-dependent diseases include diseases associated with abnormal tyrosine kinase enzyme activity (especially cancer cell proliferation), angiogenesis and / or increased vascular permeability. Furthermore, since the compound of the present invention or a salt thereof or a prodrug thereof specifically inhibits tyrosine kinase, the therapeutic agent and / or prophylactic agent which suppresses the growth of cancer expressing a receptor corresponding to tyrosine kinase. It is also useful.

Claims (13)

General formula (1)

[Wherein q is an integer of 0 to 3, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number An alkynyl group having 2 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms that may be substituted, or a nitrogen-containing compound group, and R ² is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or halogenated. An alkyl group having 1 to 4 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, and R ³ is a hydrogen atom, a halogen atom, a nitro group, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, or a halogenated group. An optionally substituted alkyl group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 1 to 8 carbon atoms, an optionally substituted ethynyl group, an optionally substituted phenylethynyl group, and an optionally substituted vinyl. Group, substitution Phenyl vinyl group which may be substituted, cycloalkenyl group having 3 to 6 carbon atoms, cycloalkanedienyl group having 4 to 6 carbon atoms, optionally substituted thienyl group, optionally substituted pyridyl group or substituted Or an aryl group having 6 to 14 carbon atoms, R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ⁵ is an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, or a substituted group. An ethynyl group or an alkyl group having 1 to 6 carbon atoms, W is CO, SO ₂ or an oxygen atom, X is an alkylene group having 1 to 4 carbon atoms, and Y is an oxygen atom or a sulfur atom Z is a single bond, an oxygen atom, NH, N (CH ₃ ) or N (C ₂ H ₅ ), and the A ring is benzene, furan or thiophene. Or a salt thereof. General formula (2)

[Wherein, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or substituted. An aralkyl group having 7 to 12 carbon atoms or a nitrogen-containing compound group, and R ² may be a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an optionally halogenated carbon atom having 1 to 4 carbon atoms. An alkyl group or an alkoxyl group having 1 to 6 carbon atoms, and R ³ is a hydrogen atom, a halogen atom, a nitro group, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, or an optionally halogenated carbon atom having 1 to 4 carbon atoms. An alkyl group having 1 to 8 carbon atoms, an optionally substituted ethynyl group, an optionally substituted phenylethynyl group, an optionally substituted vinyl group, and an optionally substituted phenyl Nyl group, C3-C6 cycloalkenyl group, C4-C6 cycloalkanedienyl group, optionally substituted thienyl group, optionally substituted pyridyl group, or optionally substituted carbon An aryl group having 6 to 14 carbon atoms, R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, X is an alkylene group having 1 to 4 carbon atoms, Y is an oxygen atom or a sulfur atom, Z is a single bond, an oxygen atom, NH, N (CH ₃ ) or N (C ₂ H ₅ ). Or a salt thereof. General formula (3)

[Wherein, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or a nitrogen-containing compound group, and R ² is a hydrogen atom. , A halogen atom, an alkyl group having 1 to 6 carbon atoms, an optionally halogenated alkyl group having 1 to 4 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, and R ³ is a hydrogen atom, a halogen atom or a carbamoyl group Group, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 4 carbon atoms which may be halogenated, an alkoxycarbonyl group having 1 to 8 carbon atoms, an ethynyl group which may be substituted, Phenylethynyl group which may be substituted, vinyl group which may be substituted, phenylvinyl group which may be substituted, cycloalkenyl group having 3 to 6 carbon atoms, cycloalkanedienyl group having 4 to 6 carbon atoms, substitution Which may be a thienyl group, a pyridyl group which may be substituted or optionally substituted good having 6 to 14 carbon atoms an aryl group. The compound or its salt of Claim 1 to Claim 2 represented by these. General formula (4)

[In the formula, p is an integer of 1 to 3, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number. An alkynyl group having 2 to 6 carbon atoms, an aralkyl group having 7 to 12 carbon atoms which may be substituted, or a nitrogen-containing compound group, and R ² may be a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a halogenated group A good alkyl group having 1 to 4 carbon atoms, a halogen atom or an alkoxyl group having 1 to 6 carbon atoms, and R ³ is a hydrogen atom, a halogen atom, an optionally halogenated alkyl group having 1 to 4 carbon atoms, carbon An alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, X is an alkylene group having 1 to 4 carbon atoms, and Y Is an oxygen atom or a sulfur atom, and Z is a single atom A bond, an oxygen atom, NH, N (CH ₃ ) or N (C ₂ H ₅ ). Or a salt thereof. General formula (5)

[Wherein p is an integer of 1 to 3, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, and R ² is a hydrogen atom, a halogen atom, An alkyl group having 1 to 6 carbon atoms or an optionally halogenated alkyl group having 1 to 4 carbon atoms, wherein R ³ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a halogenated group; Or an alkyl group having 1 to 4 carbon atoms. Or a salt thereof. General formula (6)

[Wherein, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, and R ² is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a halogen atom. An optionally substituted alkyl group having 1 to 4 carbon atoms, and R ³ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an optionally halogenated alkyl group having 1 to 4 carbon atoms. It is. ] The compound or its salt of Claim 4 and Claim 5 represented by these. R ¹ is an alkyl group having 1 to 6 carbon atoms, R ² is an alkyl group having 1 to 6 carbon atoms, and R ³ is an alkyl group having 1 to 4 carbon atoms which may be halogenated. 4. The compound or salt thereof according to claims 4 to 6. 7. The compound or a salt thereof according to claim 4, wherein R ¹ is a methyl group or an ethyl group, R ² is a methyl group or an ethyl group, and R ³ is a trifluoromethyl group. General formula (7)

[Wherein, R ¹ is a methyl group or an ethyl group, and R ² is a methyl group. Or a salt thereof. Methyl 5- (6-methyl-5- (2- (4-trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate or ethyl 5- (6-methyl-5- ( A compound selected from 2- (4- (trifluoromethyl) phenyl) ethynyl) pyrimidin-4-ylaminomethyl) -2-furancarboxylate or a salt thereof. A pharmaceutical composition comprising the compound according to claim 1 or 10 or a salt thereof. The use which uses the compound or its salt of Claim 1 to Claim 10 for manufacture of the chemical | medical agent used when obtaining an anti-cell proliferation effect in a warm-blooded animal. The use which uses the compound or its salt of Claim 1 to Claim 10 for manufacture of the chemical | medical agent used when obtaining an anticancer effect | action in the cultured cell of a warm-blooded animal.