JP7237002B2 - pyrimidine derivative - Google Patents

Description

The present invention relates to novel pyrimidine derivatives. More specifically, it relates to a pyrimidine derivative that has mPGES-1 inhibitory action and is useful as an active ingredient of a medicine for preventing and/or treating diseases such as inflammation, pain, and rheumatoid arthritis.

Prostaglandin E2 (PGE2) is involved in inflammation, pain, fever, etc. via PGE receptors, and inflammation can be suppressed by suppressing PGE2 production. Nonsteroidal anti-inflammatory drugs (NSAIDs) exert anti-inflammatory effects by inhibiting cyclooxygenase (COX) upstream of the prostaglandin biosynthetic pathway, and prostanoids in which COX is involved in the prostaglandin biosynthetic pathway. Since it inhibits all biosynthetic pathways downstream from its production, gastric mucosal damage occurs as a side effect due to suppression of gastric mucus secretion and gastric mucosal blood flow.

COX has two isoenzymes, COX-1 and COX-2. Among these, COX-2 is induced in inflamed tissue by various pro-inflammatory stimuli (eg, cytokines such as interleukin-1β). This COX-2 selective inhibitor suppresses the production of PGI2, which has vasodilatory and platelet aggregation effects, but on the other hand, thromboxane A2 ( Since it does not inhibit TXA2) production, it is thought to increase the risk of thrombosis and increase cardiovascular events.

Downstream of the PGE2 biosynthetic pathway, PGE2 is biosynthesized from PGH2 by prostaglandin E synthase (PGESynthase, PGES). PGES has three types of enzymes: mPGES-1 (microsomal prostaglandin E2 synthase-1), mPGES-2 (microsomal prostaglandin E2 synthase-2), and cPGES (cytosolic PGE synthase). mPGES-1 is a trimeric inducible enzyme whose expression is increased by inflammatory stimuli (Proc. Natl. Acad. Sci. USA, 96, pp.7220-7225, 1999). It is known to be involved in tissue repair and the like.

Inhibitors of mPGES-1 can selectively suppress the final step of the biosynthetic pathway of PGE2 at inflammatory sites (Pharmacol. Rev., 59, pp.207-224, 2007; J. Biol. Chem., 279 , pp.33684-33695, 2004), and is expected as an anti-inflammatory agent that does not cause gastric mucosal damage like non-steroidal anti-inflammatory agents. In addition, mPGES-1 inhibitors are effective for pain, rheumatoid arthritis, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic sclerosis, colon It is expected to be effective for the prevention and/or treatment of malignant tumors such as cancer, or diseases for which suppression of PGE2 production is effective (uses of PGE2, PGES, and mPGES-1, and mPGES-1 inhibitors, etc.) See International Publication WO2015/125842). In addition, mPGES-1 inhibitors are also known to increase the production of other prostanoids along with the suppression of PGE2 production (J. Biol. Chem., 280, pp.16579-16585, 2005).

Known mPGES-1 inhibitors include heterocyclic derivatives disclosed in Patent No. 5601422, substituted pyrimidine compounds disclosed in International Publication WO2015/59618, and triazine compounds disclosed in International Publication WO2015/125842. there is International Publication WO2015/59618 discloses a pyrimidine compound (Example 2) substituted with a p-trifluoromethylphenyl group and a 2-chloro-5-isobutyramidobenzyl group, and International Publication WO2015/125842 discloses Triazine compounds substituted with a p-trifluoromethylphenyl group and a 2-chloro-5-isobutyramidobenzyl group are disclosed (Examples 1-28). International Publication WO2017/073709 discloses a pyrimidine derivative substituted with a phenyl group.

Patent No. 5601422 International publication WO2015/59618 International publication WO2015/125842 International publication WO2017/073709

Proc. Natl. Acad. Sci. USA, 96, pp.7220-7225, 1999 Pharmacol. Rev., 59, pp.207-224, 2007 J. Biol. Chem., 279, pp.33684-33695, 2004 J. Biol. Chem., 280, pp.16579-16585, 2005

An object of the present invention is to provide a novel compound that has mPGES-1 inhibitory action and is useful as an active ingredient of a medicine for preventing and/or treating diseases such as inflammation, pain, or rheumatoid arthritis.

The present inventors conducted intensive research to solve the above problems, and as a result, the pyrimidine derivative represented by the following general formula (1) has a strong inhibitory effect on mPGES-1. The inventors have found that it is useful as an active ingredient of a medicine for the prevention and/or treatment of diseases such as pain or rheumatism, and have completed the present invention.

(式中、Xはカルボニル基又はスルホニル基を示し；R^１は水素原子、ハロゲン原子、アルキル基、アルカノイル基、シアノ基、又はカルボキシル基を示し；R²はアルキル基、置換基を有していてもよい炭素環基、又は置換基を有していてもよい複素環基を示し；R³は水素原子、又は環A上に置換する1ないし3個の置換基(該置換基は、ハロゲン原子、アルキル基(該アルキル基はハロゲン原子で置換されていてもよい)、及びアルコキシ基(該アルコキシ基はハロゲン原子で置換されていてもよい)からなる群から選択される)を示し；R⁴及びR⁵はそれぞれ独立に水素原子、ハロゲン原子、又はアルキル基を示し；R⁶はアルキル基(該アルキル基はヒドロキシ基、ハロゲン原子又はアルコキシ基で置換されていてもよい)、又はアルコキシ基を示し；環Aは複素環ジイル基を示す)で表される化合物又はその塩が提供される。Thus, according to the present invention, the following general formula (1):

(In the formula, X represents a carbonyl group or a sulfonyl group; R ¹ represents a hydrogen atom, a halogen atom, an alkyl group, an alkanoyl group, a cyano group, or a carboxyl group; R ² represents an alkyl group, having a substituent represents a carbocyclic group which may be substituted, or a heterocyclic group which may have a substituent; R ³ is a hydrogen atom, or 1 to 3 substituents substituted on ring A (the substituents are halogen an atom, an alkyl group (which is optionally substituted with a halogen atom), and an alkoxy group (which is optionally substituted with a halogen atom); R ⁴ and R ⁵ each independently represent a hydrogen atom, a halogen atom, or an alkyl group; R ⁶ represents an alkyl group (the alkyl group may be substituted with a hydroxy group, a halogen atom, or an alkoxy group), or an alkoxy group; and ring A represents a heterocyclic diyl group) or a salt thereof.

According to a preferred embodiment of the above invention, the compound represented by the general formula (1) or a salt thereof, wherein X is a carbonyl group; R ⁶ is a branched C _1-6 alkyl group (the alkyl group is a C _1- a compound represented by the above general formula (1) or a _salt thereof; a compound represented by the above general formula (1) wherein both ^R4 and ^R5 are hydrogen atoms; or a salt thereof; ^R3 is a hydrogen atom, or an alkyl group (the alkyl group may be substituted with a halogen atom), and an alkoxy group (the alkoxy group may be substituted with a halogen atom) A compound or a salt thereof represented by the above general formula (1), which is one substituent selected from the group consisting of; R ¹ is a hydrogen atom, an alkyl group, or a cyano group. or a salt thereof; R ² is an optionally substituted saturated or partially saturated monocyclic 3- to 7-membered cyclic hydrocarbon group, an optionally substituted phenyl group, a substituent A saturated or partially saturated monocyclic 3- to 7-membered heterocyclic group (the heterocyclic group contains 1 to 3 ring-constituting heteroatoms) optionally having Good monocyclic aromatic heterocyclic group (the heterocyclic group contains 1 to 3 ring-constituting heteroatoms); Ring A is a monocyclic aromatic heterocyclic diyl group (the heterocyclic group has 1 to 3 or a salt thereof; Ring A is a monocyclic 5- or 6-membered aromatic heterocyclic diyl group (the heterocyclic group is 1 or two ring-constituting heteroatoms) are provided.

From another aspect, according to the present invention, mPGES-1 inhibitor containing the compound represented by the above general formula (1) or a salt thereof; and PGE2 containing the compound represented by the above general formula (1) or a salt thereof Biosynthetic inhibitors are provided.

From yet another aspect, the present invention provides a medicament containing the compound represented by the general formula (1) or a physiologically acceptable salt thereof as an active ingredient. The above medicaments are useful for, for example, inflammation, pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic sclerosis, colon It can be used for the prevention and/or treatment of malignant tumors such as cancer, or diseases for which suppression of PGE2 production is effective.

Further, according to the present invention, use of the above mPGES-1 inhibitor, the above PGE2 biosynthesis inhibitor, or the compound represented by the above general formula (1) or a salt thereof for the production of the above medicament; A method for inhibiting mPGES-1 in vivo, comprising the step of administering an effective amount of the compound represented by the general formula (1) or a physiologically acceptable salt thereof to mammals including humans Method: A method of inhibiting PGE2 biosynthesis in vivo in mammals including humans, comprising administering an effective amount of the compound represented by the above general formula (1) or a physiologically acceptable salt thereof to humans. A method comprising the step of administering to a mammalian animal; and a method of promoting the production of other prostanoids by inhibiting the biosynthesis of PGE2 in vivo in mammals including humans, wherein the general formula (1) A method is provided comprising administering to a mammal, including a human, an effective amount of a represented compound or a physiologically acceptable salt thereof.

The compound represented by the general formula (1) or a salt thereof provided by the present invention exerts a strong inhibitory effect on mPGES-1 and can inhibit the biosynthesis of PGE2. , pain, rheumatoid arthritis, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic sclerosis, malignant tumors such as colon cancer, or It is useful as an active ingredient of a medicine for prevention and/or treatment of diseases for which inhibition of PGE2 production is effective.

In general formula (1) above, X represents a carbonyl group or a sulfonyl group. It is preferred that X is a carbonyl group.
^R1 represents a hydrogen atom, a halogen atom, an alkyl group, an alkanoyl group, a cyano group, or a carboxyl group. As used herein, the term halogen atom includes fluorine, chlorine, bromine, and iodine atoms. A fluorine atom or a chlorine atom is preferable as the halogen atom.

As used herein, the term alkyl group includes linear, branched, cyclic, or a combination thereof, and the number of carbon atoms is not particularly limited. is 1 to 6, particularly preferably 1 to 4. The same applies to the alkyl moieties of other substituents having alkyl moieties (eg, alkoxy groups). R ¹ is preferably a hydrogen atom, an alkyl group, or a cyano group, more preferably a hydrogen atom, a methyl group, or a cyano group, and particularly preferably a hydrogen atom.

R ² represents an alkyl group, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group. As the carbocyclic group, for example, an aromatic hydrocarbon group or a saturated or partially saturated cyclic hydrocarbon group can be used. As the aromatic hydrocarbon group, for example, a phenyl group or a naphthyl group can be used. As the saturated or partially saturated cyclic hydrocarbon group, for example, a saturated or partially saturated monocyclic or bicyclic 3- A 12-membered cyclic hydrocarbon group can be used. Preferably, a phenyl group can be used as the aromatic hydrocarbon group. Also preferably, a saturated monocyclic 3- to 7-membered cyclic hydrocarbon group can be used as the cyclic hydrocarbon group, and more preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group. .

As the heterocyclic group, a saturated or partially saturated heterocyclic group having one or two or more ring-constituting heteroatoms, or an aromatic heterocyclic group having one or two or more ring-constituting heteroatoms can be used. A nitrogen atom, an oxygen atom, a sulfur atom, or the like can be used as the ring-constituting heteroatom. Saturated or partially saturated heterocyclic groups having one or more ring-constituting heteroatoms include, for example, saturated or partially saturated monocyclic 3- to 7-membered heterocyclic groups or bicyclic 8- to 12-membered heterocyclic groups can be used. Saturated or partially saturated monocyclic 3- to 7-membered heterocyclic groups include, for example, 1-aziridinyl group, 1-azetidinyl group, 1-pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group and 2-tetrahydrofuryl group. , 3-tetrahydrofuryl group, thiolanyl group, 1-imidazolidinyl group, 2-imidazolidinyl group, 4-imidazolidinyl group, 1-pyrazolidinyl group, 3-pyrazolidinyl group, 4-pyrazolidinyl group, 1-(2-pyrrolinyl) group, 1 -(2-imidazolinyl) group, 2-(2-imidazolinyl) group, 1-(2-pyrazolinyl) group, 3-(2-pyrazolinyl) group, piperidino group, 2-piperidinyl group, 3-piperidinyl group, 4- piperidinyl group, 1-homopiperidinyl group, 2-tetrahydropyranyl group, morpholino group, (thiomorpholin)-4-yl group, 1-piperazinyl group, 1-homopiperazinyl group, etc. Examples of cyclic 8- to 12-membered heterocyclic groups include 2-quinuclidinyl, 2-chromanyl, 3-chromanyl, 4-chromanyl, 5-chromanyl, 6-chromanyl, 7-chromanyl, 8 -chromanyl group, 1-isochromanyl group, 3-isochromanyl group, 4-isochromanyl group, 5-isochromanyl group, 6-isochromanyl group, 7-isochromanyl group, 8-isochromanyl group, 2-thiochromanyl group, 3-thiochromanyl group, 4 -thiochromanyl group, 5-thiochromanyl group, 6-thiochromanyl group, 7-thiochromanyl group, 8-thiochromanyl group, 1-isothiochromanyl group, 3-isothiochromanyl group, 4-isothiochromanyl group, 5- isothiochromanyl group, 6-isothiochromanyl group, 7-isothiochromanyl group, 8-isothiochromanyl group, 1-indolinyl group, 2-indolinyl group, 3-indolinyl group, 4-indolinyl group, 5-indolinyl, 6-indolinyl, 7-indolinyl, 1-isoindolinyl, 2-isoindolinyl, 4-isoindolinyl, 5-isoindolinyl, 2-(4H-chromenyl), 3-(4H-chromenyl) ) group, 4-(4H-chromenyl) group, 5-(4H-chromenyl) group, 6-(4H-chromenyl) group, 7-(4H-chromenyl) group, 8-(4H-chromenyl) group, 1- isochromenyl group, 3-isochromenyl group, 4-isochromenyl group, 5-isochromenyl group, 6-isochromenyl group, 7-isochromenyl group group, 8-isochromenyl group, 1-(1H-pyrrolidinyl) group, 2-(1H-pyrrolidinyl) group, 3-(1H-pyrrolidinyl) group, 5-(1H-pyrrolidinyl) group, 6-(1H-pyrrolidinyl) group groups, 7-(1H-pyrrolidinyl) groups, and the like, but are not limited to these.

Examples of aromatic heterocyclic groups having one or more ring-constituting heteroatoms include monocyclic aromatic heterocyclic groups such as 2-furyl, 3-furyl, 2-thienyl, and 3-thienyl. group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 5-pyrazolyl group, (1,2,3-oxadiazol)-4-yl group, (1,2,3-oxadiazol)-5-yl group , (1,2,4-oxadiazol)-3-yl group, (1,2,4-oxadiazol)-5-yl group, (1,2,5-oxadiazol)-3-yl group, (1,2,5-oxadiazol)-4-yl group, (1,3,4-oxadiazol)-2-yl group, (1,3,4-oxadiazol)-5- yl group, furazanyl group, (1,2,3-thiadiazol)-4-yl group, (1,2,3-thiadiazol)-5-yl group, (1,2,4-thiadiazol)-3-yl group , (1,2,4-thiadiazol)-5-yl group, (1,2,5-thiadiazol)-3-yl group, (1,2,5-thiadiazol)-4-yl group, (1,3 ,4-thiadiazolyl)-2-yl group, (1,3,4-thiadiazolyl)-5-yl group, (1H-1,2,3-triazol)-1-yl group, (1H-1,2, 3-triazol)-4-yl group, (1H-1,2,3-triazol)-5-yl group, (2H-1,2,3-triazol)-2-yl group, (2H-1,2 ,3-triazol)-4-yl group, (1H-1,2,4-triazol)-1-yl group, (1H-1,2,4-triazol)-3-yl group, (1H-1, 2,4-triazol)-5-yl group, (4H-1,2,4-triazol)-3-yl group, (4H-1,2,4-triazol)-4-yl group, (1H-tetrazole )-1-yl group, (1H-tetrazol)-5-yl group, (2H-tetrazol)-2-yl group, (2H-tetrazol)-5-yl group, 2-pyridyl group, 3-pyridyl group , 4-pyridyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 2-pyrazinyl group, (1,2,3-triazin)-4-yl group , (1,2,3-triazin)-5-yl group, (1,2,4-triazin)-3-yl group, (1,2,4-triazin)-5-yl group, (1,2 ,4-triazin)-6-yl group, (1,3,5-triazin)-2-yl group, 1-azepinyl group, 2-azepinyl group, 3-azepinyl group, 4-azepinyl group, (1,4 -oxazepin)-2-yl group, (1,4-oxazepin)-3-yl group, (1,4-oxazepin)-5-yl group, (1,4-oxazepin)-6-yl group, (1 ,4-oxazepin)-7-yl group, (1,4-thiazepin)-2-yl group, (1,4-thiazepin)-3-yl group, (1,4-thiazepin)-5-yl group, Examples include (1,4-thiazepin)-6-yl group, (1,4-thiazepin)-7-yl group and the like, but are not limited to these.

Condensed polycyclic aromatic heterocyclic groups include, for example, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzo[b]thienyl group, 3-benzo[b]thienyl group, 4-benzo[b]thienyl group, 5-benzo[b ]thienyl group, 6-benzo[b]thienyl group, 7-benzo[b]thienyl group, 1-benzo[c]thienyl group, 4-benzo[c]thienyl group, 5-benzo[c]thienyl group, 1 -indolyl group, 2-indolyl group, 3-indolyl group, 4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group, (2H-isoindol)-1-yl group, (2H-isoindolyl group) indol)-2-yl group, (2H-isoindol)-4-yl group, (2H-isoindol)-5-yl group, (1H-indazol)-1-yl group, (1H-indazole)-3 -yl group, (1H-indazol)-4-yl group, (1H-indazol)-5-yl group, (1H-indazol)-6-yl group, (1H-indazol)-7-yl group, (2H -indazol)-1-yl group, (2H-indazol)-2-yl group, (2H-indazol)-4-yl group, (2H-indazol)-5-yl group, 2-benzoxazolyl group, 4-benzoxazolyl group, 5-benzoxazolyl group, 6-benzoxazolyl group, 7-benzoxazolyl group, (1,2-benzoisoxazolyl)-3-yl group, (1, 2-benzisoxazol)-4-yl group, (1,2-benzisoxazol)-5-yl group, (1,2-benzisoxazol)-6-yl group, (1,2-benzisoxazol) )-7-yl group, (2,1-benzisoxazol)-3-yl group, (2,1-benzisoxazol)-4-yl group, (2,1-benzisoxazol)-5-yl group group, (2,1-benzisoxazol)-6-yl group, (2,1-benzisoxazol)-7-yl group, 2-benzothiazolyl group, 4-benzothiazolyl group, 5-benzothiazolyl group, 6-benzothiazolyl group, 7-benzothiazolyl group, (1,2-benzisothiazol)-3-yl group, (1,2-benzisothiazol)-4-yl group, (1,2-benzisothiazol)-5 -yl group, (1,2-benzisothiazol)-6-yl group, (1,2-benzisothiazol)-7-yl group, (2,1-benzisothiazol)-3-yl group, ( 2,1-benzisothiazol)-4-yl group, (2,1-benzisothiazol)-5-yl group, (2,1-benzisothiazol)-6-yl group, (2,1-benzo isothiazol)-7-yl group, (1,2,3-benzoxadiazol)-4-yl group, (1,2,3-benzoxadiazol)-5-yl group, (1,2, 3-benzoxadiazol)-6-yl group, (1,2,3-benzoxadiazol)-7-yl group, (2,1,3-benzoxadiazol)-4-yl group, ( 2,1,3-benzoxadiazol)-5-yl group, (1,2,3-benzothiadiazol)-4-yl group, (1,2,3-benzothiadiazol)-5-yl group, ( 1,2,3-benzothiadiazol)-6-yl group, (1,2,3-benzothiadiazol)-7-yl group, (2,1,3-benzothiadiazol)-4-yl group, (2, 1,3-benzothiadiazol)-5-yl group, (1H-benzotriazol)-1-yl group, (1H-benzotriazol)-4-yl group, (1H-benzotriazol)-5-yl group, ( 1H-benzotriazol)-6-yl group, (1H-benzotriazol)-7-yl group, (2H-benzotriazol)-2-yl group, (2H-benzotriazol)-4-yl group, (2H- benzotriazol)-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 3 -isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 3-cinnolinyl group, 4-cinnolinyl group, 5-cinnolinyl group, 6-cinnolinyl group, 7 -cinnolinyl group, 8-cinnolinyl group, 2-quinazolinyl group, 4-quinazolinyl group, 5-quinazolinyl group, 6-quinazolinyl group, 7-quinazolinyl group, 8-quinazolinyl group, 2-quinoxalinyl group, 5-quinoxalinyl group, 6 -quinoxalinyl group, 1-phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 2-naphthyridinyl group, 3-naphthyridinyl group, 4-naphthyridinyl group, 2-purinyl group, 6-purinyl group, 7- purinyl group, 8-purinyl group, 2-pteridinyl group, 4-pteridinyl group, 6-pteridinyl group, 7-pteridinyl group, 1-carbazolyl group, 2-carbazolyl group, 3-carbazolyl group, 4-carbazolyl group, 9- carbazolyl group, 2-(α-carbolinyl) group, 3-(α-carbolinyl) group, 4-(α-carbolinyl) group, 5-(α-carbolinyl) group, 6-(α-carbolinyl) group, 7- (α-carbonyl) group, 8-(α-carbonyl) group, 9-(α-carbonyl) group, 1-(β-carbonylyl) group, 3-(β-carbonylyl) group, 4-(β-carbonyl) group group, 5-(β-carbonylyl) group, 6-(β-carbonylyl) group, 7-(β-carbonylyl) group, 8-(β-carbonylyl) group, 9-(β-carbonylyl) group, 1-( γ-carbolinyl) group, 2-(γ-carbolinyl) group, 4-(γ-carbolinyl) group, 5-(γ-carbolinyl) group, 6-(γ-carbolinyl) group, 7-(γ-carbolinyl) group , 8-(γ-carbolinyl) group, 9-(γ-carbolinyl) group, 1-acridinyl group, 2-acridinyl group, 3-acridinyl group, 4-acridinyl group, 9-acridinyl group, 1-phenoxazinyl group, 2 -phenoxazinyl group, 3-phenoxazinyl group, 4-phenoxazinyl group, 10-phenoxazinyl group, 1-phenothiazinyl group, 2-phenothiazinyl group, 3-phenothiazinyl group, 4-phenothiazinyl group, 10-phenothiazinyl group, 1 -phenazinyl group, 2-phenazinyl group, 1-phenanthridinyl group, 2-phenanthridinyl group, 3-phenanthridinyl group, 4-phenanthridinyl group, 6-phenanthridinyl group, 7 -phenanthridinyl group, 8-phenanthridinyl group, 9-phenanthridinyl group, 10-phenanthridinyl group, 2-phenanthrolinyl group, 3-phenanthrolinyl group, 4-phenanthrolinyl group Nanthrolinyl, 5-phenanthrolinyl, 6-phenanthrolinyl, 7-phenanthrolinyl, 8-phenanthrolinyl, 9-phenanthrolinyl, 10-phenanthrolinyl nyl group, 1-thianthrenyl group, 2-thianthrenyl group, 1-indolizinyl group, 2-indolizinyl group, 3-indolizinyl group, 5-indolizinyl group, 6-indolizinyl group, 7-indolizinyl group, 8-indolizinyl group, 1- phenoxathiinyl group, 2-phenoxathiinyl group, 3-phenoxa thiinyl group, 4-phenoxathiinyl group, thieno[2,3-b]furyl group, pyrrolo[1,2-b]pyridazinyl group, pyrazolo[1,5-a]pyridyl group, imidazo[11,2- a]pyridyl group, imidazo[1,5-a]pyridyl group, imidazo[1,2-b]pyridazinyl group, imidazo[1,2-a]pyrimidinyl group, 1,2,4-triazolo[4,3- 8- to 14-membered condensed polycyclic aromatic heterocyclic groups such as a]pyridyl group, 1,2,4-triazolo[4,3-a]pyridazinyl group, but are limited thereto. never.

In the present specification, when a functional group is referred to as "optionally having a substituent", unless otherwise specified, the functional group is unsubstituted or at a chemically possible position. It means that it may have one or more substituents. The type of substituents present in the functional group, the number of substituents, and the substitution position are not particularly limited, and when two or more substituents are present, they may be the same or different. Examples of substituents present in functional groups include alkyl groups, halogen atoms, oxo groups, thioxo groups, nitro groups, nitroso groups, cyano groups, isocyano groups, cyanato groups, thiocyanato groups, isocyanato groups, isothiocyanato groups, and hydroxy groups. , sulfanyl group, carboxy group, sulfanylcarbonyl group, oxalo group, mesooxalo group, thiocarboxy group, dithiocarboxy group, carbamoyl group, thiocarbamoyl group, sulfo group, sulfamoyl group, sulfino group, sulfinamoyl group, sulfeno group, sulfenamoyl group, phosphono group, hydroxyphosphonyl group, hydrocarbon group, heterocyclic group, hydrocarbon-oxy group, heterocyclic-oxy group, hydrocarbon-sulfanyl group, heterocyclic-sulfanyl group, acyl group, amino group, hydrazino group, hydrazono group group, diazenyl group, ureido group, thioureido group, guanidino group, carbamoimidoyl group (amidino group), azide group, imino group, hydroxyamino group, hydroxyimino group, aminooxy group, diazo group, semicarbazino group, semicarbazono group , allophanyl group, hydantoyl group, phosphano group, phosphoroso group, phospho group, boryl group, silyl group, stannyl group, ceranyl group, oxide group and the like, but are not limited thereto.

Such substituents may be substituted with other substituents at any chemically possible position on the substituent. The type of substituent, the number of substituents, and the substitution position are not particularly limited, and when two or more substituents are substituted, they may be the same or different. Examples of such groups include halogenated alkyl groups (e.g., trifluoromethyl group, etc.), hydroxyalkyl groups (e.g., hydroxymethyl group, etc.), halogenated alkyl-carbonyl groups (e.g., trifluoroacetyl group, etc.), halogenated Alkyl-sulfonyl group (e.g., trifluoromethanesulfonyl, etc.), acyl-oxy group, acyl-sulfanyl group, N-hydrocarbon-amino group, N,N-di(hydrocarbon)-amino group, N-heterocyclic- Examples include, but are not limited to, groups such as amino groups, N-hydrocarbon-N-heterocycle-amino groups, acyl-amino groups, di(acyl)-amino groups and the like.

R ² is an optionally substituted saturated or partially saturated monocyclic 3- to 7-membered cyclic hydrocarbon group, an optionally substituted phenyl group, or an optionally substituted Good saturated or partially saturated monocyclic 3- to 7-membered heterocyclic group (the heterocyclic group contains 1 to 3 ring-constituting heteroatoms), or optionally substituted monocyclic aromatic Heterocyclic groups, which heterocyclic groups contain from 1 to 3 ring-constituting heteroatoms, are preferred. R ² is preferably a saturated cyclic hydrocarbon group such as a cyclopentyl group or a cyclohexyl group, a phenyl group, a thienyl group, a pyridyl group, a pyrimidyl group, a thiazolyl group, a pyrazolyl group or a benzothiophene group. is, for example, a methyl group, an isobutyl group, a chlorine atom, a fluorine atom, a cyano group, a trifluoromethyl group, a difluoromethyl group, a methoxy group, a difluoromethoxy group, a trifluoromethoxy group, an ethoxy group, a methoxyethoxy group, an ethoxyethoxy group, One or more substituents selected from trifluoroethoxy groups, isopropoxy groups, methoxypropoxy groups, methylsulfanyl groups, cyclopropyl groups and the like can be mentioned, but are not limited to these.

R ³ represents a hydrogen atom or 1 to 3 substituents on ring A, and the substituents are halogen atoms, alkyl groups (the alkyl groups may be substituted with halogen atoms ), and an alkoxy group (the alkoxy group may be substituted with a halogen atom). A fluorine atom is preferable as a halogen atom substituted for an alkyl group or an alkoxy group. Preferably, R ³ represents one hydrogen atom or one substituent substituted on ring A, and the substituent is a methyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, 2,2,2-trifluoroethoxy group, fluorine atom or chlorine atom. The substitution position of R ³ is not particularly limited, but when R ³ represents one substituent on ring A, the position adjacent to the pyrimidinyl group substituted on ring A In the case of a ring, the substituent is preferably at the ortho position), and further, the substituent is at the adjacent position to the pyrimidinyl group substituted on ring A (ortho position when ring A is a 6-membered ring), Moreover, it is more preferably at the most remote position to the aminomethyl group (in the case where ring A is a 6-membered ring, the para position).

^R4 and ^R5 each independently represent a hydrogen atom, a halogen atom, or an alkyl group. Preferably both ^R4 and ^R5 are hydrogen atoms.
^R6 represents an alkyl group (the alkyl group may be substituted with a hydroxy group, a halogen atom or an alkoxy group) or an alkoxy group. Preferably R ⁶ is a branched or cyclic C _1-6 alkyl group, which may be substituted with _{a C 1-6 alkoxy} group. As R ⁶ , an isopropyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group, a t-butyl group, or the like can be preferably used, and an isopropyl group can be particularly preferably used.

Ring A represents a heterocyclic diyl group. A 4-oxo-pyrimidin-2-yl group substituted by R ¹ and R ² and an aminomethyl group substituted by R ⁴ , R ⁵ and R ⁶ are attached to the heterocyclic diyl group, and the ring ^R3 binds to the top. As the heterocyclic diyl group, a saturated or partially saturated heterocyclic diyl group having 1 or 2 or more ring-constituting hetero atoms, or an aromatic heterocyclic diyl group having 1 or 2 or more ring-constituting hetero atoms can be used. can. A nitrogen atom, an oxygen atom, a sulfur atom, or the like can be used as the ring-constituting heteroatom.

The heterocyclic structures constituting these heterocyclic diyl groups are not particularly limited, and for example, the heterocyclic structures constituting the heterocyclic groups described above can be exemplified. A structure in which one more hydrogen atom is removed from the position can be exemplified. Preferably a monocyclic aromatic heterocyclic diyl group, more preferably a monocyclic 5- or 6-membered aromatic heterocyclic diyl group containing 1 or 2 nitrogen atoms and/or sulfur atoms as ring-constituting heteroatoms ring diyl group, more preferably pyridinediyl group, pyrazinediyl group, pyrimidinediyl group, pyridazinediyl group, pyrrolediyl group, imidazoldiyl group, pyrazoldiyl group, thiazoldiyl group, or isothiazoldiyl group; . A pyridinediyl group, a pyrazinediyl group, or a thiazoldiyl group is particularly preferred.

Examples of compounds of the present invention encompassed by general formula (1) include:
N-{[6-(difluoromethyl)-5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}pyridin-3-yl]methyl} isobutyramide;
N-[(6-{4-[4-(cyclohexylmethoxy)phenyl]-6-oxo-1,6-dihydropyrimidin-2-yl}pyrazin-2-yl)methyl]isobutyramide;
N-[(5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}pyridin-3-yl)methyl]isobutyramide;
N-[(6-ethoxy-5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}pyridin-3-yl)methyl]isobutyramide;
N-[(4-methyl-5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}thiazol-2-yl)methyl]isobutyramide;
N-[(5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}-6-(2,2,2-trifluoroethoxy)pyridine -3-yl)methyl]isobutyramide;
N-[(6-methyl-5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}pyridin-3-yl)methyl]isobutyramide;
N-[(5-{4-[4-(cyclopropylethynyl)phenyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-4-{trifluoromethyl}thiazol-2-yl)methyl ] isobutyramide;
N-[(5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}-4-{trifluoromethyl}thiazol-2-yl)methyl ] isobutyramide;

N-[(5-{4-[4-(cyclopropylethynyl)phenyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-6-methylpyridin-3-yl)methyl]isobutyramide;
N-[(5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}-6-(trifluoromethyl)pyridin-3-yl)methyl ] isobutyramide;
N-[(5-{4-[4-(cyclopropylethynyl)phenyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-6-(trifluoromethyl)pyridin-3-yl)methyl ] isobutyramide;
N-[(5-{6-oxo-4-[4-(trifluoromethoxy)phenyl]-1,6-dihydropyrimidin-2-yl}-6-(trifluoromethyl)pyridin-3-yl)methyl ] isobutyramide
N-[(5-{4-[4-(2-butoxyethoxy)phenyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-6-(trifluoromethyl)pyridin-3-yl) Examples include, but are not limited to, methyl]isobutyramide and the like.

The compound represented by general formula (1) may be in the form of a salt. The salt is not particularly limited and can be appropriately selected depending on the purpose. Examples include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; Examples include organic amine salts, mineral acid salts such as hydrochlorides, sulfates and nitrates, and organic acid salts such as p-toluenesulfonates, maleates and tartrates.

The compound represented by general formula (1) or a salt thereof may exist in the form of a hydrate or solvate. Although the type of solvent that forms the solvate is not particularly limited, examples thereof include ethanol, ethyl acetate, and acetone. The compounds represented by the general formula (1) may exist as optical isomers, diastereoisomers, or geometric isomers depending on the type of substituents. , and mixtures of any isomers are also included within the scope of the present invention.

The compound represented by the general formula (1) or a salt thereof can be easily synthesized from raw material compounds readily available to those skilled in the art by carrying out general chemical reactions widely used by those skilled in the art. Specific methods for preparing the compounds of the present invention are shown in the examples of the present specification. Those skilled in the art can easily produce the compounds of the present invention encompassed by general formula (1) by referring to those synthesis methods.

The compounds of the present invention represented by general formula (1) have mPGES-1 inhibitory activity, and can inhibit PGE2 biosynthesis based on this inhibitory activity. Therefore, the medicament of the present invention, which contains the compound of the present invention represented by general formula (1) or a physiologically acceptable salt thereof as an active ingredient, is effective for treating inflammation, pain, Rheumatoid arthritis, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension such as glaucoma, ischemic retinal disease, systemic sclerosis, malignant tumors such as colon cancer, or suppression of PGE2 production can be used for the prevention and/or treatment of diseases for which is effective.

More specifically, the medicament of the present invention is useful for, for example, inflammatory colitis, irritable bowel syndrome, migraine, headache, low back pain, lumbar spinal canal stenosis, intervertebral disc herniation, temporomandibular disorder, cervico-omo-brachial syndrome, cervical spine. endometriosis, uterine adenomyosis, premature birth, threatened premature birth, dysmenorrhea, overactive bladder, dysuria associated with prostatic hyperplasia, nocturia, urinary incontinence, neurogenic bladder, interstitial cystitis, Bladder Pain Syndrome, Urolithiasis, BPH, Chronic Prostatitis, Pelvic Pain Syndrome, Erectile Dysfunction, Cognitive Disorder, Neurodegenerative Disease, Alzheimer's Disease, Pulmonary Hypertension, Psoriasis, Rheumatoid Arthritis, Rheumatic Fever, Fibromyalgia, Neuralgia, complex regional pain syndrome, myofascial disorder, ischemic heart disease, hypertension, angina pectoris, viral infection, bacterial infection, fungal infection, burns, post-surgery, post-traumatic, post-extraction inflammation/pain , malignant tumor, myocardial infarction, atherosclerosis, thrombosis, embolism, type I diabetes, type II diabetes, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ligaments Ossification, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis , allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids or cancer. For the relationship between mPGES-1 inhibitory action and medical use, see, for example, International Publication WO2015/125842. The disclosure of the above international publication and all of the documents cited therein are incorporated by reference into the disclosure of this specification.

As the medicament of the present invention, the compound represented by the above general formula (1) or a physiologically acceptable salt thereof, which is an active ingredient, may be administered, preferably orally by a method well known to those skilled in the art. Pharmaceutical compositions for oral or parenteral use can be prepared and administered. Pharmaceutical compositions suitable for oral administration include, for example, tablets, powders, capsules, fine granules, liquids, granules, syrups, etc. Pharmaceutical compositions suitable for parenteral administration include: Examples include injections such as intravenous injections and intramuscular injections, drops, inhalants, eye drops, nasal drops, suppositories, transdermal absorption agents, and transmucosal absorption agents. is not limited to

The pharmaceutical composition described above can be produced by a method well known to those skilled in the art using pharmaceutical additives commonly used in the preparation of pharmaceutical compositions in the art. Pharmaceutical additives are not particularly limited, and can be appropriately selected depending on the form of the pharmaceutical composition, the purpose of imparting sustained release properties, and the like. Examples include excipients, binders, extenders, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, corrigents, fragrances, coating agents, diluents, etc. It is not limited to these.

The dosage of the medicament of the present invention is not particularly limited, and is appropriately selected according to the type of disease to be prevented or treated, the purpose of prevention or treatment, the type of active ingredient, the weight and age of the patient, the symptoms, the route of administration, etc. For example, in the case of oral administration, the weight of the active ingredient can be in the range of about 0.01 to 500 mg per day for adults. However, the dosage can be appropriately selected by those skilled in the art, and is not limited to the above range.

EXAMPLES The present invention will be described in more detail below based on examples, but the present invention is not limited by these examples. Table 1 shows the chemical structural formulas of the compounds of the examples.

Reference Example 1: 2-(Difluoromethyl)-5-(isobutylamidomethyl)pyridine-3-carboxamide

To a solution of 1.36 g of 2-(difluoromethyl)-5-(isobutylamidomethyl)pyridine-3-carboxylic acid in 20 mL of methylene chloride, 0.64 mL of oxalyl dichloride and several drops of N,N-dimethylformamide were added and stirred for 3 hours. . Solvent and excess oxalyl dichloride were removed under reduced pressure. Under ice-cooling, the previously prepared acid chloride was slowly added dropwise to a solution obtained by dissolving 3 mL of aqueous ammonia in 10 mL of THF. It was returned to room temperature and stirred for 3 hours. The resulting solid was separated to obtain 562 mg of the title compound.
¹ H-NMR (DMSO- _d6 , δ): 1.04 (6H, d, J = 6.8 Hz), 2.4-2.5 (1H, m), 4.36 (2H, d, J = 6.0 Hz), 7.19 (1H, t,J=54.4Hz), 7.76(1H,s), 7.85(1H,s), 8.17(1H,s), 8.37(1H,t,J=5.6Hz), 8.61(1H,d,J=2.0 Hz)
MS (m/z): 272 (M ⁺ +1).

Reference Example 2: N-{[5-cyano-6-(difluoromethyl)pyridin-3-yl]methyl}isobutyramide

To a solution of 414 mg of 2-(difluoromethyl)-5-(isobutylamidomethyl)pyridine-3-carboxamide in 10 mL of N,N-dimethylformamide, 0.51 mL of triethylamine was added. Under ice-cooling, 0.25 mL of trifluoroacetic anhydride was added dropwise, and the mixture was warmed to room temperature and stirred overnight. Ethyl acetate was added, washed with water three times and saturated brine once, and dried over magnesium sulfate. The solvent was distilled off and the obtained solid was dried under reduced pressure to obtain 300 mg of the title compound.
¹ H-NMR (DMSO- _d6 , δ): 1.04 (6H, d, J = 6.8 Hz), 2.4-2.5 (1H, m), 4.38 (2H, d, J = 6.0 Hz), 7.42 (1H, t,J=53.2Hz),8.34(1H,s),8.39(1H,t,J=5.6Hz),8.80(1H,d,J=2.0Hz)
MS (m/z): 253 (M ⁺ ).

Reference Example 3: N-{[5-carbamimidoyl-6-(difluoromethyl)pyridin-3-yl]methyl}isobutyramide hydrochloride

To a solution of 334 mg of N-{[5-cyano-6-(difluoromethyl)pyridin-3-yl]methyl}isobutyramide in 4 mL of methanol under ice-cooling, 26 μL of a methanol solution of sodium methoxide was slowly added dropwise. Warmed to room temperature and stirred overnight. 78 mg of ammonium chloride was added and refluxed for 5 hours. After cooling to room temperature, insoluble matter was filtered off, and the solvent of the filtrate was distilled off under reduced pressure to obtain 357 mg of the title compound. The obtained compound was used for the next reaction without purification.

Reference Example 4: N-[(6-cyanopyrazin-2-yl)methyl]isobutyramide

6-chloropyrazine-2-carbonitrile 977mg, potassium N-[(trifluoroborate)methyl]isobutyramide 2.9g, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) chloride (551 mg), potassium carbonate (2.9 g), 1,4-dioxane (50 mL) and water (10 mL) were mixed and stirred overnight at 100°C. . It was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The obtained organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was suspended in a 10% hexane-ethyl acetate solution with heating, cooled to room temperature, filtered and dried under reduced pressure to obtain 313 mg of the title compound.
¹ H-NMR (DMSO- _d6 , δ): 1.07 (6H, d, J = 6.8 Hz), 2.4-2.5 (1H, m), 4.52 (2H, d, J = 5.6 Hz), 8.48 (1H, t,J=5.6Hz),8.65(1H,s),9.37(1H,s)
MS (m/z): 204 (M ⁺ ).

Reference Example 5: N-[(6-carbamimidoylpyrazin-2-yl)methyl]isobutyramide hydrochloride

The title compound was obtained in the same manner as in Reference Example 3 using N-[(6-cyanopyrazin-2-yl)methyl]isobutyramide. The obtained compound was used for the next reaction without purification.

Reference Example 6: 5-chloro-2-iodopyridine-3-carbonitrile

1.2 mL of hydroiodic acid was added to a solution of 1.73 g of 2,5-dichloropyridine-3-carbonitrile and 10.49 g of sodium iodide in 40 mL of 2-butanone, and the mixture was heated under reflux overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed twice with water and once with an aqueous sodium sulfite solution, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dried under reduced pressure to obtain 520 mg of the title compound.
¹ H-NMR (CDCl ₃ , δ): 7.78 (1H, d, J = 2.8 Hz), 8.52 (1H, d, J = 3.2 Hz)
MS (m/z): 264 (M ⁺ ).

Reference Example 7: 5-chloro-2-(trifluoromethyl)pyridine-3-carbonitrile

To a solution of 1.17 g of 5-chloro-2-iodopyridine-3-carbonitrile in 35 mL of N,N-dimethylformamide, 2.2 mL of methyl difluoro(fluorosulfonyl)acetate and 3.35 g of copper iodide were added, and the mixture was stirred overnight at 80°C. . After allowing to cool to room temperature, ethyl acetate was added, and the mixture was washed with saturated brine three times. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography and dried under reduced pressure to obtain 693 mg of the title compound.
¹ H-NMR (CDCl ₃ , δ): 8.17 (1H, d, J = 2.4 Hz), 8.85 (1H, d, J = 2.0 Hz)
MS (m/z): 206 (M ⁺ ).

Reference Example 8: N-{[5-cyano-6-(trifluoromethyl)pyridin-3-yl]methyl}isobutyramide

The title compound was obtained in the same manner as in Reference Example 4, except that 5-chloro-2-(trifluoromethyl)pyridine-3-carbonitrile was used.
¹ H-NMR (CDCl ₃ , δ): 1.21 (6H, d, J = 6.8 Hz), 2.46 (1H, sept, J = 6.8 Hz), 4.56 (2H, d, J = 6.0 Hz), 6.0-6.1 (1H,m),8.09(1H,d,J=1.2Hz),8.79(1H,d,J=1.6Hz)
MS (m/z): 271 (M ⁺ ).

Reference Example 9: 2-(5-Chloropyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one

348 mg of 4-(trifluoromethyl)benzaldehyde, 457 mg of ethyl phenylsulfonylacetate and 553 mg of potassium carbonate were added to 15 mL of a methanol solution of 384 mg of 5-chloropyridine-3-carboximidamide hydrochloride, and the mixture was stirred at 50°C for 4 days. The solvent was distilled off, and the resulting residue was washed with an aqueous ammonium chloride solution and chloroform to obtain 638 mg of the title compound.
¹ H-NMR (d ₆ -DMSO, δ): 6.61 (1H, s), 7.81 (2H, d, J = 8.4 Hz), 8.31 (2H, d, J = 8.4 Hz), 8.6-8.7 (2H, m), 9.42 (1H, d, J=1.2Hz)
MS (m/z): 351 (M ⁺ ).

Reference Example 10: 5-chloro-2-ethoxypyridine-3-carboximidamide hydrochloride

8 mg of sodium methoxide was added to 5 mL of a methanol solution of 262 mg of 5-chloro-2-ethoxypyridine-3-carbonitrile, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and the obtained compound was used for the next reaction without purification.

Reference Example 11: 2-(5-Chloro-2-ethoxypyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one

The title compound was obtained in the same manner as in Reference Example 9 using 4-(trifluoromethyl)benzaldehyde and 5-chloro-2-ethoxypyridine-3-carboximidamide hydrochloride.
¹ H-NMR (d ₆ -DMSO, δ): 1.3-1.4 (3H, m), 4.4-4.5 (2H, m), 7.06 (1 H, s), 7.86 (2H, d, J = 8.4 Hz), 8.3-8.4(3H,m),8.43(1H,d,J=2.4Hz),12.56(1H,brs)
MS (m/z): 395 (M ⁺ ).

Reference Example 12: 2-bromo-4-methylthiazole-5-carboximidamide hydrochloride

Under ice-cooling, 10 mL of a toluene solution (1.8 M) of trimethylaluminum was added to a suspension of 1.39 g of ammonium chloride in 25 mL of toluene, and the mixture was stirred at room temperature for 30 minutes. 1.02 g of 2-bromo-4-methylthiazole-5-carbonitrile was added, and the mixture was heated under reflux overnight. The reaction solution was ice-cooled, methanol was added, and the mixture was stirred at room temperature for 30 minutes. The insoluble matter was removed by filtration, and the filtrate was evaporated to give the title compound. The obtained compound was used for the next reaction without purification.

Reference Example 13: 2-(2-bromo-4-methylthiazol-5-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one

The title compound was obtained in the same manner as in Reference Example 9 using 4-(trifluoromethyl)benzaldehyde and 2-bromo-4-methylthiazole-5-carboximidamide hydrochloride.
¹ H-NMR (d ₆ -DMSO, δ): 2.87 (3H, s), 7.24 (1H, s), 7.91 (2H, d, J = 8.4 Hz), 8.35 (2H, d, J = 8.4 Hz) ,12.51(1H,brs)
MS (m/z): 417 (M ⁺⁺ 1).

Reference Example 14: 5-chloro-2-(2,2,2-trifluoroethoxy)pyridine-3-carbonitrile

1.38 g of potassium carbonate was added to 10 mL of a 2,2,2-trifluoroethanol solution containing 865 mg of 2,5-dichloropyridine-3-carbonitrile, and the mixture was stirred overnight at 70°C. Water was added and extraction was performed with ethyl acetate to obtain 1.16 g of the title compound.
¹ H-NMR (CDCl ₃ , δ): 4.87 (2H, q, J = 8.0 Hz), 7.94 (1H, d, J = 2.4 Hz), 8.32 (1H, d, J = 2.4 Hz)
MS (m/z): 236 (M ⁺ ).

Reference Example 15: 5-chloro-2-(2,2,2-trifluoroethoxy)pyridine-3-carboximidamide hydrochloride

The title compound was obtained by the same procedure as in Reference Example 10 using 5-chloro-2-(2,2,2-trifluoroethoxy)pyridine-3-carbonitrile. The obtained compound was used for the next reaction without purification.

Reference Example 16: 2-[5-chloro-2-(2,2,2-trifluoroethoxy)pyridin-3-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidine-4(3H)- on

The title compound was obtained in the same manner as in Reference Example 9 using 4-(trifluoromethyl)benzaldehyde and 5-chloro-2-ethoxypyridine-3-carboximidamide hydrochloride.
¹ H-NMR (d ₆ -DMSO, δ): 5.06 (2H, q, J = 8.8 Hz), 7.10 (1 H, s), 7.85 (2H, d, J = 8.4 Hz), 8.33 (2H, d, J = 8.4Hz), 8.38 (1H, d, J = 2.4Hz), 8.50 (1H, d, J = 3.2Hz), 12.77 (1H, brs)
MS (m/z): 449 (M ⁺ ).

Reference Example 17: 5-chloro-2-methylpyridine-3-carboximidamide hydrochloride

The title compound was obtained by the same procedure as in Reference Example 12 using 5-chloro-2-methylpyridine-3-carbonitrile. The obtained compound was used for the next reaction without purification.

Reference Example 18: 2-(5-Chloro-2-methylpyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one

The title compound was obtained in the same manner as in Reference Example 9 using 4-(trifluoromethyl)benzaldehyde and 5-chloro-2-methylpyridine-3-carboximidamide hydrochloride.
¹ H-NMR (d ₆ -DMSO, δ): 2.63 (3H, s), 7.13 (1H, s), 7.86 (2H, d, J = 8.4 Hz), 8.20 (1H, d, J = 2.4 Hz) ,8.32(2H,d,J=8.0Hz),8.68(1H,d,J=2.4Hz),12.95(1H,brs)
MS (m/z): 365 (M ⁺ ).

Reference Example 19: 2-bromo-4-(trifluoromethyl)thiazole-5-carboxamide

To a solution of 3.32 g of ethyl 2-bromo-4-(trifluoromethyl)thiazole-5-carboxylate in 6 mL of tetrahydrofuran, 30 mL of 25% aqueous ammonia solution was added, and the mixture was stirred overnight. After extraction with ethyl acetate, the extract was washed once with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain 2.90 g of the title compound.
¹ H-NMR (DMSO-d ₆ , δ): 8.12 (1H, brs), 8.31 (1H, brs)
MS (m/z): 274 (M ⁺ -1), 276 (M ⁺ +1).

Reference Example 20: 2-bromo-4-(trifluoromethyl)thiazole-5-carbonitrile

5.9 mL of triethylamine was added to a solution of 2.90 g of 2-bromo-4-(trifluoromethyl)thiazole-5-carboxamide in 50 mL of methylene chloride. Under ice-cooling, 2.9 mL of trifluoroacetic anhydride was added dropwise, and the mixture was warmed to room temperature and stirred overnight. After adding 30 mL of water and stirring for 10 minutes, the mixture was extracted with methylene chloride. The extract was washed once with water and once with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain 1.07 g of the title compound.
MS (m/z): 256 (M ⁺ -1), 258 (M ⁺ +1).

Reference Example 21: 2-chloro-4-(trifluoromethyl)thiazole-5-carbonitrile

The title compound was obtained by the same procedure as in Reference Example 20 using 2-chloro-4-(trifluoromethyl)thiazole-5-carboxamide.
MS (m/z): 212 (M ⁺ ), 214 (M ⁺⁺ 2).

Reference Example 22: 2-bromo-4-(trifluoromethyl)thiazole-5-carboximidamide hydrochloride

To a solution of 293 mg of ammonium chloride in 10 mL of toluene, 2.3 mL of a toluene solution (1.8 M) of trimethylaluminum was added dropwise under ice-cooling, and the temperature was raised to room temperature. After stirring for 30 minutes, 300 mg of 2-bromo-4-(trifluoromethyl)thiazole-5-carbonitrile was added, and the mixture was heated to 120°C and stirred overnight. After cooling to ice-cooling, 15 mL of methanol was added, and the mixture was stirred for 30 minutes. The insoluble matter was filtered through Celite, and the solvent of the filtrate was distilled off under reduced pressure to obtain 396 mg of the title compound. The obtained compound was used for the next reaction without purification.

Reference Example 23: 2-chloro-4-(trifluoromethyl)thiazole-5-carboximidamide hydrochloride

The title compound was obtained by the same procedures as in Reference Example 22 using 2-chloro-4-(trifluoromethyl)thiazole-5-carbonitrile. The obtained compound was used for the next reaction without purification.

Reference Example 24: 2-[2-bromo-4-(trifluoromethyl)thiazol-5-yl]-6-[4-(cyclopropylethynyl)phenyl]pyrimidin-4(3H)-one

280 mg of ethyl phenylsulfonylacetate, 210 mg of 4-(cyclopropylethynyl)benzaldehyde and 510 mg of potassium carbonate were added to a solution of 552 mg of 2-bromo-4-(trifluoromethyl)thiazole-5-carboximidamide hydrochloride in 20 mL of methanol. °C overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure. It was extracted three times with ethyl acetate and washed with water and saturated brine. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography, suspended in diethyl ether and collected by filtration to obtain 489 mg of the title compound.
¹ H-NMR (DMSO-d ₆ , δ): 0.77 (2H, m), 0.92 (2H, m), 1.59 (1 H, tt, J = 8.4 Hz, 4.8 Hz), 7.25 (1 H, s), 7.50 (2H,d,J=8.4Hz),8.12(2H,d,J=8.4Hz),8.31(1H,s)
MS (m/z): 465 (M ⁺ -1), 467 (M ⁺ +1).

Reference Example 25: 2-[2-chloro-4-(trifluoromethyl)thiazol-5-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one

The title compound was obtained in the same manner as in Reference Example 24 using 4-(trifluoromethyl)benzaldehyde and 2-chloro-4-(trifluoromethyl)thiazole-5-carboximidamide hydrochloride.
¹ H-NMR (DMSO-d ₆ , δ): 7.31 (1H, s) 7.73 (2H, m), 7.92 (2H, d, J = 8.0 Hz), 8.31 (1H, s)
MS (m/z): 425 (M ⁺ ).

Reference Example 26: 2-(5-Chloro-2-methylpyridin-3-yl)-6-[4-(cyclopropylethynyl)phenyl]pyrimidin-4(3H)-one

The title compound was obtained by the same procedure as in Reference Example 24 using 5-chloro-2-methylpyridine-3-carboximidamide hydrochloride.
^1H -NMR (DMSO- _d6 , δ): 0.76 (2H, m), 0.91 (2H, m), 1.57 (1H, tt, J = 7.6 Hz, 5.6 Hz), 2.61 (3H, s), 6.98 (1H,s),7.46(2H,d,J=8.4Hz),8.06(2H,d,J=8.4Hz),8.17(1H,d,J=2.4Hz),8.66(1H,d,J= 2.4Hz)
MS (m/z): 361 (M ⁺ ).

Reference Example 27: N-{[5-carbamimidoyl-6-(trifluoromethyl)pyridin-3-yl]methyl}isobutyramide hydrochloride

The title compound was obtained by the same procedures as in Reference Example 22 using N-{[5-cyano-6-(trifluoromethyl)pyridin-3-yl]methyl}isobutyramide. The obtained compound was used for the next reaction without purification.

Example 1: N-{[6-(difluoromethyl)-5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}pyridin-3- yl]methyl}isobutyramide
301 mg of ethyl phenylsulfonylacetate and 230 mg of 4-(trifluoromethyl)benzaldehyde were added to a solution of 357 mg of N-{[5-carbamimidoyl-6-(difluoromethyl)pyridin-3-yl]methyl}isobutyramide hydrochloride in 10 mL of methanol. and 365 mg of potassium carbonate were added, and the mixture was stirred overnight at 55°C. After cooling, it was poured into a saturated ammonium chloride aqueous solution, extracted three times with chloroform, and washed with saturated brine. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain 66 mg of the title compound.
¹ H-NMR (DMSO-d ₆ , δ): 1.05 (6H, d, J = 7.2 Hz), 2.3-2.5 (1 H, m), 4.42 (2H, d, J = 5.6 Hz), 7.2-8.2 ( 4H,m), 8.33(2H,d,J=8.0Hz), 8.40(1H,t,J=6.0Hz), 8.73(1H,d,J=1.6Hz), 13.13(1H,s)
MS (m/z): 466 (M ⁺ ).

Example 2: N-[(6-{4-[4-(Cyclohexylmethoxy)phenyl]-6-oxo-1,6-dihydropyrimidin-2-yl}pyrazin-2-yl)methyl]isobutyramide
Using 4-cyclohexylmethoxybenzaldehyde, the same procedure as in Example 1 was carried out to obtain the title compound.
¹ H-NMR (DMSO- _d6 , δ): 1.0-1.3(11H,m), 1.6-1.9(6H,m), 2.5-2.6(1H,m), 3.88(2H,d,J=6.4Hz ), 4.60(2H,d,J=5.6Hz), 6.94(1H,s), 7.06(2H,d,J=8.8Hz), 8.19(2H,d,J=8.8Hz), 8.53(1H,t ,J=5.6Hz), 8.81(1H,s), 9.55(1H,s), 12.40(1H,s)
MS (m/z): 461 (M ⁺ ).

Example 3: N-[(5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}pyridin-3-yl)methyl]isobutyramide
Potassium N- [(trifluoroborate)methyl]isobutyramide 248 mg, bis(dibenzylideneacetone)palladium(0) 17 mg, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl 28 mg, carbonate 127 mg of sodium was added and stirred overnight at 100°C. After the reaction, the mixture was filtered through celite, the solvent was distilled off, and the obtained residue was washed with water and chloroform to obtain 160 mg of the title compound.
¹ H-NMR (d ₆ -DMSO, δ): 1.07 (6H, d, J = 6.8 Hz), 2.46 (1H, sept, J = 6.8 Hz), 4.40 (2H, d, J = 6.0 Hz), 7.13 (1H,s),7.87(2H,d,J=8.0Hz),8.3-8.5(4H,m),8.64(1H,d,J=1.6Hz),9.27(1H,s),12.95(1H, brs)
MS (m/z): 416 (M ⁺ ).

Example 4: N-[(6-ethoxy-5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}pyridin-3-yl)methyl ] isobutyramide
By the same procedure as in Example 3 using 2-(5-chloro-2-ethoxypyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one, The title compound was obtained.
¹ H-NMR (d ₆ -DMSO, δ): 1.03 (6H, d, J = 6.8 Hz), 1.36 (3H, t, J = 6.8 Hz), 2.3-2.5 (1H, m), 4.29 (2H, d,J=6.0Hz), 4.44(2H,q,J=6.8Hz), 7.03(1H,s), 7.85(2H,d,J=8.4Hz), 8.16(1H,d,J=2.4Hz) ,8.24(1H,d,J=2.0Hz),8.3-8.4(3H,m),12.38(1H,brs)
MS (m/z): 460 (M ⁺ ).

Example 5: N-[(4-methyl-5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}thiazol-2-yl)methyl ] isobutyramide
2-(2-bromo-4-methylthiazol-5-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one (296 mg) in 15 mL of 1,4-dioxane and 3 mL of water , potassium N-[(trifluoroborate)methyl]isobutyramide 294 mg, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino -1,1'-Biphenyl)]palladium(II) chloride (56 mg) and potassium carbonate (294 mg) were added, and the mixture was stirred at 100°C for 3 days. After the reaction, the mixture was filtered through celite and the solvent was distilled off. After adding water and extracting with ethyl acetate, the mixture was purified by silica gel column chromatography to obtain 30 mg of the title compound.
¹ H-NMR (d ₆ -DMSO, δ): 1.08 (6H, d, J = 6.8 Hz), 2.47 (1H, sept, J = 6.8 Hz), 2.81 (3H, s), 4.50 (2H, d, J = 6.0Hz), 7.15 (1H, s), 7.90 (2H, d, J = 8.0Hz), 8.34 (2H, d, J = 8.4Hz), 8.69 (1H, t, J = 6.0Hz), 12.37 (1H, brs)
MS (m/z): 436 (M ⁺ ).

Example 6: N-[(5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}-6-(2,2,2-tri Fluorethoxy)pyridin-3-yl)methyl]isobutyramide
using 2-[5-chloro-2-(2,2,2-trifluoroethoxy)pyridin-3-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one, By performing the same operation as in Example 5, the title compound was obtained.
¹ H-NMR (d ₆ -DMSO, δ): 1.03 (6H, d, J = 6.8 Hz), 2.42 (1 H, sept, J = 6.8 Hz), 4.32 (2H, d, J = 5.6 Hz), 5.05 (2H,q,J=9.2Hz),7.06(1H,s),7.85(2H,d,J=8.4Hz),8.13(1H,d,J=2.4Hz),8.27(1H,d,J= 2.4Hz), 8.32 (2H, d, J = 8.0Hz), 8.35 (1H, t, J = 5.6Hz), 12.62 (1H, brs)
MS (m/z): 514 (M ⁺ ).

Example 7: N-[(6-methyl-5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}pyridin-3-yl)methyl ] isobutyramide
By the same procedure as in Example 5 using 2-(5-chloro-2-methylpyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one, The title compound was obtained.
¹ H-NMR (d ₆ -DMSO, δ): 1.03 (6H, d, J = 6.8 Hz), 2.42 (1H, sept, J = 6.8 Hz), 2.60 (3H, s), 4.32 (2H, d, J=6.0Hz), 7.08(1H,s), 7.8-7.9(3H,m), 8.2-8.4(3H,m), 8.49(1H,d,J=2.0Hz), 12.96(1H,brs)
MS (m/z): 430 (M ⁺ ).

Example 8: N-[(5-{4-[4-(cyclopropylethynyl)phenyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-4-{trifluoromethyl}thiazole-2 -yl)methyl]isobutyramide
2-[2-bromo-4-(trifluoromethyl)thiazol-5-yl]-6-[4-(cyclopropylethynyl)phenyl]-3H-pyrimidin-4-one 489 mg, potassium N-[(trifluoromethyl) Lato)methyl]isobutyramide 435 mg, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) ] 165 mg of palladium (II) chloride, 435 mg of potassium carbonate, 8 mL of 1,4-dioxane and 1.5 mL of water were mixed and stirred at 100°C overnight. It was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography, suspended in diethyl ether and collected by filtration. The obtained crystals were dried under reduced pressure to obtain 154 mg of the title compound.
¹ H-NMR (DMSO- _d6 , δ): 0.77 (2H, m), 0.92 (2H, m), 1.07 (6H, d, J = 7.2 Hz), 1.58 (1H, tt, J = 8.0 Hz, 5.2Hz), 2.45(1H,m), 4.57(2H,d,J=6.0Hz), 7.20(1H,brs), 7.49(2H,d,J=8.4Hz), 8.11(2H,d,J= 6.0Hz), 8.81(1H,t,J=6.0Hz)
MS (m/z): 486 (M ⁺ ).

Example 9: N-[(5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}-4-{trifluoromethyl}thiazole-2 -yl)methyl]isobutyramide
Similar to Example 8 using 2-[2-chloro-4-(trifluoromethyl)thiazol-5-yl]-6-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)-one Worked up to give the title compound.
¹ H-NMR (DMSO- _d6 , δ): 1.08 (6H, d, J = 6.8 Hz), 2.47 (1H, m), 4.58 (2H, d, J = 6.0 Hz), 7.32 (1H, brs) ,7.91(2H,d,J=8.0Hz),8.35(2H,d,J=8.0Hz),8.82(1H,t,J=6.0Hz)
MS (m/z): 490 (M ⁺ ).

Example 10: N-[(5-{4-[4-(cyclopropylethynyl)phenyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-6-methylpyridin-3-yl)methyl ] isobutyramide
2-(5-chloro-2-methylpyridin-3-yl)-6-[4-(cyclopropylethynyl)phenyl]pyrimidin-4(3H)-one 66.2mg, potassium N-[(trifluoroborate)methyl ]isobutyramide 76 mg, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium ( II) 29 mg of chloride, 76 mg of potassium carbonate, 5 mL of 1,4-dioxane and 1 mL of water were mixed and stirred overnight at 100°C. It was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was suspended in diethyl ether, collected by filtration, and dried under reduced pressure to obtain 30 mg of the title compound.
¹ H-NMR (DMSO- _d6 , δ): 0.76 (2H, m), 0.91 (2H, m), 1.03 (6H, d, J = 6.8 Hz), 1.57 (1H, tt, J = 8.4 Hz, 4.8Hz), 2.42(1H,m), 2.58(3H,s), 4.31(2H,d,J=6.0Hz), 6.94(1H,brs), 7.45(2H,d,J=8.4Hz), 7.81 (1H,s),8.05(2H,d,J=8.4Hz),8.31(1H,t,J=6.0Hz),8.48(1H,s)
MS (m/z): 426 (M ⁺ ).

Example 11: N-[(5-{6-oxo-4-[4-(trifluoromethyl)phenyl]-1,6-dihydropyrimidin-2-yl}-6-(trifluoromethyl)pyridine-3 -yl)methyl]isobutyramide
Perform the same procedure as in Reference Example 24 using 4-(trifluoromethyl)benzaldehyde and N-{[5-carbamimidoyl-6-(trifluoromethyl)pyridin-3-yl]methyl}isobutyramide hydrochloride. , to give the title compound.
¹ H-NMR (DMSO-d ₆ , δ): 1.05 (6H, d, J = 6.8 Hz), 2.46 (1H, m), 4.45 (2H, d, J = 6.0 Hz), 7.16 (1H, brs) ,7.85(2H,d,J=8.0Hz),8.14(1H,s),8.28(2H,d,J=7.2Hz),8.47(1H,t,J=6.0Hz),8.78(1H,s) ,13.26(1H,brs)
MS (m/z): 484 (M ⁺ ).

Example 12: N-[(5-{4-[4-(cyclopropylethynyl)phenyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-6-(trifluoromethyl)pyridine-3 -yl)methyl]isobutyramide
The title compound was obtained by the same procedures as in Reference Example 24 using N-{[5-carbamimidoyl-6-(trifluoromethyl)pyridin-3-yl]methyl}isobutyramide hydrochloride.
¹ H-NMR (DMSO-d ₆ , δ): 0.76 (2H, m), 0.91 (2H, m), 1.04 (6H, d, J = 7.2 Hz), 1.57 (1H, tt, J = 8.4 Hz, 4.8Hz), 2.45(1H,m), 4.44(2H,d,J=5.6Hz), 7.01(1H,brs), 7.44(2H,d,J=8.4Hz), 8.02(2H,d,J= 8.0Hz), 8.10(1H,s), 8.44(1H,t,J=6.0Hz), 8.77(1H,s)
MS (m/z): 480 (M ⁺ ).

Example 13: N-[(5-{6-oxo-4-[4-(trifluoromethoxy)phenyl]-1,6-dihydropyrimidin-2-yl}-6-(trifluoromethyl)pyridine-3 -yl)methyl]isobutyramide
Perform the same procedure as in Reference Example 24 using 4-(trifluoromethoxy)benzaldehyde and N-{[5-carbamimidoyl-6-(trifluoromethyl)pyridin-3-yl]methyl}isobutyramide hydrochloride. , to give the title compound.
¹ H-NMR (DMSO- _d6 , δ): 1.04 (6H, d, J = 6.8 Hz), 2.43 (1H, m), 4.45 (2H, d, J = 5.6 Hz), 7.08 (1H, brs) ,7.47(2H,d,J=8.4Hz),8.12(1H,s),8.20(2H,d,J=8.4Hz),8.44(1H,t,J=6.0Hz),8.77(1H,s)
MS (m/z): 500 (M ⁺ ).

Example 14: N-[(5-{4-[4-(2-butoxyethoxy)phenyl]-6-oxo-1,6-dihydropyrimidin-2-yl}-6-(trifluoromethyl)pyridine- 3-yl)methyl]isobutyramide
Using 4-(2-butoxyethoxy)benzaldehyde and N-{[5-carbamimidoyl-6-(trifluoromethyl)pyridin-3-yl]methyl}isobutyramide hydrochloride, the same procedure as in Reference Example 24 was performed. to give the title compound.
¹ H-NMR (DMSO- _d6 , δ): 0.87 (3H, t, J = 7.2 Hz), 1.04 (6H, d, J = 6.8 Hz), 1.32 (2H, qt, J = 7.2 Hz, 7.2 Hz ), 1.49 (2H, tt, J = 6.8Hz, 6.8Hz), 2.45 (1H, m), 3.45 (2H, t, J = 6.4Hz), 3.70 (2H, dd, J = 4.4Hz, 4.4Hz) ,4.15(2H,dd,J=4.4Hz,4.4Hz),4.45(2H,d,J=6.0Hz),6.91(1H,brs),7.03(2H,d,J=8.8Hz),8.02(2H ,d,J=8.4Hz),8.09(1H,s),8.43(1H,t,J=6.0Hz),8.76(1H,s)
MS (m/z): 532 (M ⁺ ).

Test Example 1: mPGES-1 inhibitory activity test Microsomes were prepared from COS-1 cells transiently transfected with a plasmid encoding human mPGES-1 cDNA and used as the mPGES-1 enzyme. The mPGES-1 enzyme was diluted with sodium phosphate buffer (pH 7.2) containing reduced glutathione (2.5 mM) and EDTA (1 mM), and DMSO or a DMSO solution of the test compound (final concentration of DMSO: 1%). was added and pre-incubated for 15 minutes at 4°C. Next, the substrate PGH2 (Prostaglandin H2) was added to a final concentration of 1 μM to initiate the enzyme reaction, incubated at 4° C. for 4 minutes, and then ferric chloride (25 mM) and citric acid (50 mM). ) solution was added to stop the enzymatic reaction. The produced PGE2 (Prostaglandin E2) was measured using a Prostaglandin E2 Express EIA kit (Cayman Chemical). _IC50 values were determined using standard methods. The results are shown in Table 2 below.

Claims (11)

General formula (1) below:

(Wherein, X represents a carbonyl group or a sulfonyl group; ^R1 represents a hydrogen atom, a halogen atom, an alkyl group, an alkanoyl group, a cyano group, or a carboxyl group; ^R2 represents an alkyl group, having a substituent represents a carbocyclic group which may be substituted, or a heterocyclic group which may have a substituent; R ³ is a hydrogen atom, or 1 to 3 substituents substituted on ring A (the substituents are halogen an atom, an alkyl group (which is optionally substituted with a halogen atom), and an alkoxy group (which is optionally substituted with a halogen atom); R ⁴ and R ⁵ each independently represent a hydrogen atom, a halogen atom, or an alkyl group; R ⁶ represents an alkyl group (the alkyl group may be substituted with a hydroxy group, a halogen atom, or an alkoxy group), or an alkoxy group; wherein ring A is a monocyclic aromatic heterocyclic diyl group (the heterocyclic ring contains 1 to 3 ring-constituting heteroatoms) or a salt thereof. 2. The compound represented by the general formula (1) or a salt thereof according to claim 1, wherein X is a carbonyl group. Represented by the general formula (1) according to claim 1 or 2, wherein R ⁶ is a branched C _1-6 alkyl group (the alkyl group may be substituted with a C _1-6 alkoxy group) compound or its salt. ^4. The compound represented by general formula (1) or a salt thereof according to any one of claims 1 to 3, wherein both R4 and ^R5 are hydrogen atoms. R ³ is a hydrogen atom, or from the group consisting of an alkyl group (the alkyl group may be substituted with a halogen atom) and an alkoxy group (the alkoxy group may be substituted with a halogen atom) A compound or a salt thereof represented by the general formula (1) according to any one of claims 1 to 4, which is one selected substituent. 6. The compound represented by general formula (1) or a salt thereof according to any one of claims 1 to 5, wherein ^R1 is a hydrogen atom, an alkyl group or a cyano group. R ² is optionally substituted saturated or partially saturated monocyclic 3- to 7-membered cyclic hydrocarbon group, optionally substituted phenyl group, optionally substituted saturated or partially saturated monocyclic 3- to 7-membered heterocyclic group (the heterocyclic group contains 1 to 3 ring-constituting heteroatoms), or optionally substituted monocyclic aromatic heterocyclic group 7. A compound represented by general formula (1) or a salt thereof according to any one of claims 1 to 6, which is a cyclic group (the heterocyclic group contains 1 to 3 ring-constituting heteroatoms). An mPGES-1 inhibitor comprising the compound represented by the general formula ( 1 ) according to claim 1 or a salt thereof. A PGE2 biosynthesis inhibitor comprising the compound represented by the general formula (1) according to claim 1 or a salt thereof. A medicament containing the compound represented by the general formula ( 1 ) according to claim 1 or a physiologically acceptable salt thereof. Inflammation, pain, rheumatoid arthritis, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, ocular hypertension, ischemic retinal disease, systemic sclerosis, malignant tumors, or inhibition of PGE2 production 11. A medicament according to claim 10 for use in the prevention and/or treatment of indicated diseases.