JP4453320B2 - N-substituted-2-oxodihydropyridine derivatives - Google Patents

Description

  The present invention is useful in the field of medicine. More specifically, the N-substituted-2-oxodihydropyridine derivative of the present invention is used as a neuropeptide Y receptor antagonist as various cardiovascular diseases, nervous system diseases, metabolic diseases, reproductive diseases, gastrointestinal diseases. It is useful as a therapeutic agent for respiratory system diseases, inflammatory diseases or glaucoma.

  Neuropeptide Y (hereinafter referred to as NPY) is a peptide consisting of 36 amino acids and was first isolated from porcine brain by Tatemoto et al. In 1982 [Nature, 296, 659 (1982)]. NPY is widely distributed in the central nervous system and the peripheral nervous system, and controls various functions in the living body as one of the most abundant peptides in the nervous system. In other words, NPY acts as an appetite promoting substance in the center and significantly promotes fat accumulation through secretion of various hormones or the action of the nervous system. Intraventricular continuous administration of NPY is known to induce obesity and insulin resistance based on these actions [International Journal of Obesity, 19: 517 (1995). Endocrinology, 133, 1753 (1993)]. In addition, it is known to have central effects such as depression, anxiety, schizophrenia, pain, dementia and circadian rhythm [Drugs, 52, 371 (1996); The Journal of Neuroscience, 18, 3014 (1998)]. Furthermore, in the periphery, NPY coexists with norepinephrine at the sympathetic nerve endings and is associated with sympathetic nervous system tension. Peripheral administration of NPY is known to cause vasoconstriction and to enhance the effects of other vasoconstrictors, including norepinephrine [British Journal of Pharmacology, vol. 95]. 419 (1988)]. It has also been reported to promote cardiac hypertrophy associated with increased sympathetic nervous system [Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America), 97, 1595 (2000)].

In addition, the involvement of sex hormones and growth hormone secretion, sex and reproductive functions, gastrointestinal motility, bronchoconstriction, inflammation and preference for alcohol has been reported [Life Sciences, 55, 551. The Journal of Allergy and Clinical Immunology, 101, S345 (1998); Nature, 396, 366 (page 1994). 1998)].
NPY has a wide variety of pharmacological actions through receptors partially common to its analogs peptide YY and pancreatic polypeptide. It is known that the pharmacological action by these NPYs is caused by at least five kinds of receptors alone or through interaction [Trends in Neurosciences, 20, 294 (1997). ]].

  As a central action through the NPY Y1 receptor, a significant appetite promoting action has been reported [Endocrinology, 137, 3177 (1996): Endocrinology, 141, 1011. Page (2000)]. In addition, involvement in anxiety and pain has been reported [Nature, 259, 528 (1993); Brain Research, 859, 361 (2000)]. In addition, blood pressure raising action through a powerful vasoconstrictive action has been reported in the periphery [FEBS Letters, 362, 192, (1995): Nature Medicine, 4 Volume 722 (1998)].

  As an action through the NPY Y2 receptor, it is known to inhibit the release of various neurotransmitters in nerve endings [British Journal of Pharmacology, Vol. 102, 41 ( 1991): Synapse, Vol. 2, 299 (1988)]. Further, in the periphery, as a control or direct action of these neurotransmitters, it is involved in contraction of blood vessels or vas deferens [The Journal of Pharmacolology and Experimental Therapeutics (The Journal of Pharmacolology). and Experimental Therapeutics), 261, 863 (1992); British Journal of Pharmacology, 100, 190 (1990)]. In adipose tissue, suppression of lipolytic action is known [Endocrinology, 131, 1970 (1992)]. Furthermore, it has been reported to inhibit ion secretion in the digestive tract [British Journal of Pharmacology, 101, 247 (1990)]. On the other hand, central effects such as memory and anxiety are also known [Brain Research, 503, 73 (1989): Peptides, 19, 359 (1998)].

The NPY Y3 receptor is expressed mainly in the brain stem and heart and has been reported to be involved in the control of blood pressure and heart rate [The Journal of Pharmacology and Experimental. The Journal of Pharmacology and Experimental Therapeutics, 258, 633 (1991); Peptides, 11, 545 (1990)]. Furthermore, it is known to be involved in the secretion of catecholamines in the adrenal gland [The Journal of Pharmacolology and Experimental Therapeutics, Vol. 244, 468 (1988); Life Sciences, 50, PL7 (1992)].
The NPY Y4 receptor has particularly high affinity with pancreatic polypeptides, and pharmacological actions have been reported to inhibit pancreatic exocrine secretion and gastrointestinal motility [Gastroenterology, vol. 85, p. 1411]. (1983)]. Furthermore, it is known in the center that it promotes the secretion of sex hormones [Endocrinology, 140, 5171 (1999)].

  As an action through the NPY Y5 receptor, a fat accumulation action including an appetite promoting effect is remarkable [Nature, 382, 168 (1996); American Journal of Physiology (American Journal of Physics) Physiology), 277, R1428 (1999)]. In addition, central effects such as involvement in convulsions and epilepsy or pain and withdrawal symptoms associated with discontinuation of morphine administration and regulation of circadian rhythm have been reported [Nature Medicine, Vol. 3, 761]. (1997); Proceedings of the National of Science of the United States of America, 96. Proceedings of the National of Science of the United States of America, 96. Proceedings of the National Academy of Sciences of the United States of America. 13518 (1999); The Journal of Pharmacologic and Experimental Therapeutics (The Journal of Pharmaco ogy and Experimental Therapeutics), 284, pp. 633, pp. (1998); The Journal Of Niu Russia Science (The Journal of Neuroscience), 21, pp. 5367 (2001)]. Further, in the periphery, diuretic action and hypoglycemic action have been reported [British Journal of Pharmacology, 120, 1335 (1998); Endocrinology, 139 Volume, 3018 (1998)]. It has also been reported to promote cardiac hypertrophy associated with increased sympathetic nervous system [Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America), 97, 1595 (2000)].

  The function of NPY is expressed by binding NPY receptors present in the central or peripheral nervous system. Therefore, the inhibition of the expression of NPY can be prevented by inhibiting the binding of NPY to the NPY receptor. As a result, substances that antagonize NPY receptor binding to NPY are circulatory organs such as angina pectoris, acute / congestive heart failure, myocardial infarction, hypertension, kidney disease, electrolyte abnormalities, and vasospasm. Systemic diseases such as bulimia, depression, anxiety, convulsions, epilepsy, dementia, pain, alcoholism, withdrawal symptoms associated with drug withdrawal, circadian rhythm modulation, schizophrenia, memory impairment, sleep disorders, cognition Central nervous system diseases such as disorders, such as obesity, diabetes, hormonal secretion abnormalities, gout, fatty liver and other metabolic diseases, such as fertility diseases such as infertility, premature birth, sexual dysfunction, gastrointestinal diseases, respiratory system It can be expected to be useful in the prevention or treatment of diseases, inflammatory diseases, glaucoma, etc. [Trends in Pharmaceutical Scientific Sci nces), 15, 153 (1994); Life Sciences, 55, 551 (1994); Drugs, 52, 371 (1996); The Journal・ The Journal of Allergy and Clinical Immunology, 101, S345 (1998); Nature, 396, 366 (1998); The Journal of・ The Journal of Pharmaceutical Therapies and Experimental Therapeutics, 284, 633 ( (1998); Trends in Pharmaceutical Sciences, 20, 104 (1999); Proceedings of the National Academy of Sciences of the United. States of America (Proceedings of the National Academy of Sciences of the United States of America), Vol. 97, p. 1595 (2000); The Journal of Neurosci. (2001); Pharmacology and Therapeutics (Pharma) ology & Therapeutics), 65, 397 (1995); Endocrinology, 140, 4046 (1999); American Journal of Physiology, 280, 280. (2001); American Journal of Physiology, 278, R1627 (2000); Current Opinion in Clinical Nutrition and Metabolic Care (Current) Opinion in Clinical Nutrition and Metabolic Care) Vol. 2, p. 425 (1 99); Current Rheumatology Reports Vol. 3, p. 101 (2001), American Journal of Respiratory and Critical Care Medicine (American Journal of Respiratory Research) Medicine 165, 1217 (2002)].

Recently, the present inventors have found that certain NPY receptor antagonists are useful in the prevention or treatment of hypercholesterolemia, hyperlipidemia, and arteriosclerosis ( International Publication No. 99/27965 pamphlet).
International Publication No. 01/62738 (Patent Document 1) discloses various imidazoline derivatives, which have excellent NPY receptor antagonism, and further have intracerebral transit or cerebrospinal fluid transit. It is described that it is excellent in pharmacokinetics such as sex. However, this document does not disclose or suggest any compounds of the present invention.

International Publication No. 01/62738 Pamphlet

  An object of the present invention is to provide a novel drug having an NPY antagonism.

［式中、Ａｒ^１及びＡｒ^２は、それぞれ独立して、シアノ基、ハロゲン原子、ニトロ基、低級アルキル基、ハロ低級アルキル基、ヒドロキシ低級アルキル基、シクロ低級アルキル基、シクロ低級アルキル低級アルキル基、低級アルケニル基、低級アルキルアミノ基、ジ低級アルキルアミノ基、低級アルカノイルアミノ基、低級アルキルスルホニルアミノ基、アリールスルホニルアミノ基、水酸基、低級アルコキシ基、ハロ低級アルコキシ基、アリールオキシ基、ヘテロアリールオキシ基、低級アルキルチオ基、カルボキシル基、ホルミル基、低級アルカノイル基、低級アルコキシカルボニル基、カルバモイル基、低級アルキルカルバモイル基、ジ低級アルキルカルバモイル基、低級アルキルスルホニル基、アリールスルホニル基、アリール基及びヘテロアリール基からなる群より選択される置換基を有していてもよい、アリール基又はヘテロアリール基を意味し；Ｒ^１及びＲ^２は、それぞれ独立して、ハロゲン原子、低級アルキルアミノ基、ジ低級アルキルアミノ基、低級アルカノイルアミノ基、水酸基、低級アルコキシ基、ホルミル基、低級アルコキシカルボニル基、低級アルキルカルバモイル基及びジ低級アルキルカルバモイル基からなる群より選択される置換基を有していてもよい、低級アルキル基、シクロ低級アルキル基、シクロ低級アルキル低級アルキル基又は低級アルコキシ基を意味し；Ｒ^３、Ｒ^４及びＲ^５は、それぞれ独立して、水素原子、シアノ基、ハロゲン原子若しくは水酸基を意味するか、又はハロゲン原子、低級アルキルアミノ基、ジ低級アルキルアミノ基、低級アルカノイルアミノ基、水酸基、低級アルコキシ基、ホルミル基、低級アルコキシカルボニル基、低級アルキルカルバモイル基及びジ低級アルキルカルバモイル基からなる群より選択される置換基を有していてもよい、低級アルキル基、低級アルコキシ基若しくは低級アルキルチオ基を意味する］で表される化合物がＮＰＹ拮抗作用、特にＮＰＹ Ｙ５受容体における拮抗作用を有し、また、例えば脳内移行性又は脳脊髄液移行性等の体内動態に優れること、更には当該化合物が極めて優れた安全性を示すことを見出し、本発明を完成した。 The inventors have the general formula (I)

[Wherein, Ar ¹ and Ar ² are each independently a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, or a cyclo lower alkyl lower alkyl group. , Lower alkenyl group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, lower alkoxy group, halolower alkoxy group, aryloxy group, heteroaryloxy Group, lower alkylthio group, carboxyl group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group, arylsulfonyl group, aryl And it may have a substituent group selected from the group consisting of heteroaryl group means an aryl group or a heteroaryl group; R ¹ and R ² are each independently a halogen atom, a lower alkyl amino group A substituent selected from the group consisting of a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group. A lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group; each of R ³ , R ⁴ and R ⁵ independently represents a hydrogen atom, a cyano group, a halogen atom or Means a hydroxyl group, or a halogen atom, a lower alkylamino group, a di-lower alkylamino Optionally having a substituent selected from the group consisting of a lower group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group. Compound having the meaning of an alkyl group, a lower alkoxy group or a lower alkylthio group] has an NPY antagonistic action, particularly an antagonistic action at the NPY Y5 receptor. It was found that the compound has excellent pharmacokinetics and that the compound exhibits extremely excellent safety, and the present invention has been completed.

  The compound (I) of the present invention has an NPY antagonism, particularly an NPY Y5 receptor antagonism, and has excellent pharmacokinetics such as intracerebral transfer or cerebrospinal fluid transfer, and also has high safety. Various diseases involving NPY, such as angina pectoris, acute / congestive heart failure, myocardial infarction, hypertension, kidney disease, electrolyte abnormalities, vasospasm, arteriosclerosis, etc., eg bulimia, depression Central nervous system diseases such as anxiety, convulsions, epilepsy, dementia, pain, alcoholism, withdrawal symptoms associated with drug withdrawal, circadian rhythm modulation, schizophrenia, memory impairment, sleep disorder, cognitive impairment, etc. Obesity, diabetes, hormonal secretion abnormalities, hypercholesterolemia, hyperlipidemia, gout, fatty liver and other metabolic diseases such as infertility, premature birth, reproductive system diseases such as sexual dysfunction, gastrointestinal diseases, respiratory organs Diseases, inflammatory diseases or Glaucoma, etc., for example, atherosclerosis, hypogonadism, hyperandrogenism, polycystic ovary syndrome, hirsutism, gastrointestinal motility disorders, gastroesophageal reflux related to obesity, obesity hypoventilation syndrome (Pickwick) Syndrome), sleep apnea syndrome, inflammation, systemic vasculitis, osteoarthritis, insulin resistance, bronchoconstriction, alcohol preference, metabolic syndrome (syndrome X), Alzheimer's disease, cardiac hypertrophy, Left ventricular hypertrophy, hypertriglyceridemia, low HDL cholesterolemia, eg coronary heart disease (CHD), cerebrovascular disease, stroke, peripheral vascular disease, sudden death and other cardiovascular diseases, gallbladder disease, cancer ( Breast cancer, endometrial cancer, colon cancer), shortness of breath, hyperuricemia, fertility disorder, low back pain or anesthetic hypersensitivity It is.

［式中、Ｒ^１ｐはハロゲン原子、ジ低級アルキルアミノ基、低級アルコキシ基、ホルミル基、低級アルコキシカルボニル基及びジ低級アルキルカルバモイル基並びに保護されていてもよい、低級アルキルアミノ基、低級アルカノイルアミノ基、水酸基及び低級アルキルカルバモイル基からなる群より選択される置換基を有していてもよい、低級アルキル基、シクロ低級アルキル基、シクロ低級アルキル低級アルキル基又は低級アルコキシ基を意味し；Ｒ^３ｐは水素原子、シアノ基、ハロゲン原子若しくは保護されていてもよい水酸基を意味するか、又はハロゲン原子、ジ低級アルキルアミノ基、低級アルコキシ基、ホルミル基、低級アルコキシカルボニル基及びジ低級アルキルカルバモイル基並びに保護されていてもよい、低級アルキルアミノ基、低級アルカノイルアミノ基、水酸基及び低級アルキルカルバモイル基からなる群より選択される置換基を有していてもよい、低級アルキル基、低級アルコキシ基若しくは低級アルキルチオ基を意味する（ただし、Ｒ^１ｐがメチル基の場合、Ｒ^３ｐは水素原子、エチル基及びメトキシ基を意味しない）］で表される化合物等に関する。 In particular, the compound (I) of the present invention is useful as a therapeutic agent for bulimia, obesity, diabetes and the like.
The present invention relates to a compound represented by the general formula (I), a salt or ester thereof, and a production method and use thereof.
Furthermore, the present invention provides an intermediate for producing the compound represented by the general formula (I), that is, the general formula (III-1)

[Wherein, R ^1p represents a halogen atom, a di-lower alkylamino group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a di-lower alkylcarbamoyl group, and an optionally protected lower alkylamino group or lower alkanoylamino group. Represents a lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group which may have a substituent selected from the group consisting of a hydroxyl group and a lower alkylcarbamoyl group; R ^3p represents Means a hydrogen atom, a cyano group, a halogen atom or an optionally protected hydroxyl group, or a halogen atom, di-lower alkylamino group, lower alkoxy group, formyl group, lower alkoxycarbonyl group and di-lower alkylcarbamoyl group and protection Lower alkyla which may be Amino group, lower alkanoylamino group, which may have a substituent selected from the group consisting of hydroxyl group and lower alkylcarbamoyl group, a lower alkyl group, a lower alkoxy group or a lower alkylthio group (wherein, R ^1p Is a methyl group, R ^3p does not mean a hydrogen atom, an ethyl group or a methoxy group)].

The meanings of terms used in the present specification are described below, and the present invention is described in more detail.
“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
“Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group. Tert-butyl group, pentyl group, isopentyl group, hexyl group, isohexyl group and the like.
“Halo lower alkyl group” means the lower alkyl group substituted with one or more, preferably 1 to 3, the same or different halogen atoms at any substitutable position, such as a fluoromethyl group, Examples thereof include a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 1,2-difluoroethyl group, a chloromethyl group, a 2-chloroethyl group, a 1,2-dichloroethyl group, a bromomethyl group, and an iodomethyl group.

“Hydroxy lower alkyl group” means the lower alkyl group substituted with one or more, preferably 1 or 2, hydroxyl groups at any substitutable position, for example, hydroxymethyl group, 2-hydroxyethyl group 1-hydroxy-1-methylethyl group, 1,2-dihydroxyethyl group, 3-hydroxypropyl group and the like.
“Cyclo lower alkyl group” means a cycloalkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
“Cyclo lower alkyl lower alkyl group” means the lower alkyl group substituted with one or more, preferably 1 cyclo lower alkyl group at any substitutable position, such as cyclopropylmethyl group, 2-cyclopropylethyl group, 3-cyclopropylpropyl group, cyclobutylmethyl group, 2-cyclobutylethyl group, 3-cyclobutylpropyl group, cyclopentylmethyl group, 2-cyclopentylethyl group, 3-cyclopentylpropyl group, cyclohexyl A methyl group, 2-cyclohexylethyl group, 3-cyclohexylpropyl group, etc. are mentioned.

The “lower alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 3-butenyl group, 2 -Butenyl group, 1-butenyl group, 1-methyl-2-propenyl group, 1-methyl-1-propenyl group, 1-ethyl-1-ethenyl group, 2-methyl-2-propenyl group, 2-methyl-1 -A propenyl group, 3-methyl-2-butenyl group, 4-pentenyl group, etc. are mentioned.
The “lower alkylamino group” means an amino group monosubstituted with the lower alkyl group, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, sec-butylamino group , Tert-butylamino group and the like.

“Di-lower alkylamino group” means an amino group di-substituted with the same or different lower alkyl group, for example, dimethylamino group, diethylamino group, ethylmethylamino group, dipropylamino group, methylpropylamino group. And diisopropylamino group.
The “lower alkanoyl group” means an alkanoyl group having the lower alkyl group, that is, an alkanoyl group having 2 to 7 carbon atoms, such as acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, Examples include a pivaloyl group.

The “lower alkanoylamino group” means an amino group monosubstituted by the lower alkanoyl group, for example, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, isovalerylamino group. And pivaloylamino group.
The “lower alkylsulfonyl group” means an alkylsulfonyl group having the lower alkyl group, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, sec-butylsulfonyl group, tert -A butylsulfonyl group etc. are mentioned.
“Lower alkylsulfonylamino group” means an amino group mono-substituted by the lower alkylsulfonyl group, such as methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, isopropylsulfonylamino group, butylsulfonylamino group. Group, sec-butylsulfonylamino group, tert-butylsulfonylamino group and the like.

Examples of the “aryl group” include a phenyl group and a naphthyl group.
The “arylsulfonyl group” means an arylsulfonyl group having the aryl group, and examples thereof include a phenylsulfonyl group, a 1-naphthylsulfonyl group, and a 2-naphthylsulfonyl group.
The “arylsulfonylamino group” means an amino group monosubstituted with the arylsulfonyl group, and examples thereof include a phenylsulfonylamino group, a 1-naphthylsulfonylamino group, and a 2-naphthylsulfonylamino group.
The “lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, isobutoxy group. Group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, isohexyloxy group and the like.

“Halo lower alkoxy group” means the lower alkoxy group substituted with one or more, preferably 1 to 3, the same or different halogen atoms at any substitutable position, such as a fluoromethoxy group, Difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 1,2-difluoroethoxy group, chloromethoxy group, 2-chloroethoxy group, 1,2-dichloroethoxy group, bromomethoxy group, iodomethoxy group, etc. Can be mentioned.
The “aryloxy group” means an aryloxy group having the aryl group, and examples thereof include a phenoxy group, a 1-naphthoxy group, and a 2-naphthoxy group.
The “lower alkylthio group” means a linear or branched alkylthio group having 1 to 6 carbon atoms, such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, sec-butylthio group, isobutyl. Examples thereof include a thio group, a tert-butylthio group, a pentylthio group, an isopentylthio group, a hexylthio group, and an isohexylthio group.

The “lower alkoxycarbonyl group” means an alkoxycarbonyl group having the above lower alkoxy group, that is, an alkoxycarbonyl group having 2 to 7 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group. Group, butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group and the like.
The “lower alkyl carbamoyl group” means a carbamoyl group mono-substituted with the lower alkyl group, for example, methyl carbamoyl group, ethyl carbamoyl group, propyl carbamoyl group, isopropyl carbamoyl group, butyl carbamoyl group, sec-butyl carbamoyl group. , Tert-butylcarbamoyl group and the like.

The “di-lower alkylcarbamoyl group” means a carbamoyl group disubstituted with the lower alkyl group, for example, dimethylcarbamoyl group, diethylcarbamoyl group, ethylmethylcarbamoyl group, dipropylcarbamoyl group, methylpropylcarbamoyl group, diisopropyl Examples thereof include a carbamoyl group.
The “heteroaryl group” is a 5-membered or 6-membered single atom containing 1 or 2 or more, preferably 1 to 3 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom. A cyclic aromatic heterocyclic group or a condensed cyclic aromatic heterocyclic group in which the monocyclic aromatic heterocyclic group and the aryl group are condensed, or the same or different monocyclic aromatic heterocyclic groups are condensed with each other For example, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, tetrazolyl group, oxadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl group Pyrazinyl group, pyrimidinyl group, pyridazinyl group, 1,2,4-triazinyl group, 1,3,5-triazinyl group, indolyl group, benzofuranyl group, benzothienyl group, benzoimidazolyl group, benzoxazolyl group, benzisoxazolyl Group, benzothiazolyl group, benzoisothiazolyl group, indazolyl group, purinyl group, quinolyl group, isoquinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, 1,5-naphthyridinyl group, etc. Can be mentioned.

The “heteroaryloxy group” means a heteroaryloxy group having the heteroaryl group, for example, 2-thienyloxy group, 3-thienyloxy group, 2-pyridyloxy group, 3-pyridyloxy group, 4- Examples include a pyridyloxy group, a 3-indolyloxy group, a 4-indolyloxy group, a 5-indolyloxy group, and a 6-indolyloxy group.
The “salt” of the compound represented by the general formula (I) means a pharmaceutically acceptable conventional salt. For example, when it has a carboxyl group or a hydroxyl group, a base addition salt or amino at the carboxyl group or hydroxyl group In the case of having a group or a basic heterocyclic group, salts of acid addition salts in the amino group or basic heterocyclic group can be mentioned.

Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; eg ammonium salt; eg trimethylamine salt, triethylamine salt, dicyclohexylamine salt and ethanolamine. Examples thereof include organic amine salts such as salts, diethanolamine salts, triethanolamine salts, procaine salts and N, N′-dibenzylethylenediamine salts.
Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; for example, maleate, fumarate, tartrate, citrate, ascorbate, Organic acid salts such as trifluoroacetates; for example, sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, and the like.

  As the “ester” of the compound represented by the general formula (I), for example, when having a carboxyl group, it means a pharmaceutically acceptable conventional one in the carboxyl group, for example, methyl group, ethyl group, propyl group , Isopropyl group, butyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, cyclopropyl group, cyclobutyl group, ester with lower alkyl group such as cyclopentyl group, benzyl group, phenethyl group, etc. Ester with aralkyl group, ester with lower alkenyl group such as allyl group, 2-butenyl group, ester with lower alkoxy lower alkyl group such as methoxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, acetoxy Methyl group, pivaloyloxymethyl group, 1-pivaloyloxy Esters with lower alkanoyloxy lower alkyl groups such as ethyl group, esters with lower alkoxycarbonyl lower alkyl groups such as methoxycarbonylmethyl group and isopropoxycarbonylmethyl group, esters with carboxy lower alkyl groups such as carboxymethyl group, 1 -(Ethoxycarbonyloxy) ethyl group, ester with lower alkoxycarbonyloxy lower alkyl group such as 1- (cyclohexyloxycarbonyloxy) ethyl group, ester with carbamoyloxy lower alkyl group such as carbamoyloxymethyl group, phthalidyl group Esters of (5-substituted-2-oxo-1,3-dioxol-4-yl) methyl group such as (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group Etc.

“Treatment agent” means a drug provided for the purpose of treatment and / or prevention of various diseases.
In order to more specifically disclose the compound of the present invention represented by the general formula (I), the various symbols used in the formula (I) will be described in more detail with suitable specific examples.
Ar ¹ and Ar ² are each independently a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group, or a lower alkenyl group. , Lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, lower alkoxy group, halolower alkoxy group, aryloxy group, heteroaryloxy group, lower alkylthio Group, carboxyl group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group, arylsulfonyl group, aryl group and It may have a substituent group selected from the group consisting of Roariru group means an aryl group or a heteroaryl group.

  "Cyano group, halogen atom, nitro group, lower alkyl group, halo lower alkyl group, hydroxy lower alkyl group, cyclo lower alkyl group, cyclo lower alkyl lower alkyl group, lower alkenyl group, lower alkyl amino group, di-lower alkyl amino group , Lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, lower alkoxy group, halolower alkoxy group, aryloxy group, heteroaryloxy group, lower alkylthio group, carboxyl group, formyl group, lower alkanoyl group , A lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, a di-lower alkylcarbamoyl group, a lower alkylsulfonyl group, an arylsulfonyl group, an aryl group, and a heteroaryl group. The “aryl group or heteroaryl group optionally having a substituent” means the above-mentioned unsubstituted aryl group or heteroaryl group, or the above-mentioned aryl having a substituent at any substitutable position. Group or the said heteroaryl group, and the substituent is a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group, a lower group. Alkenyl group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, lower alkoxy group, halolower alkoxy group, aryloxy group, heteroaryloxy group, Lower alkylthio group, carboxyl group, formyl group, lower alkyl One or more from the group consisting of noyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group, arylsulfonyl group, aryl group and heteroaryl group. Preferably, 1 or 2 can be selected.

As the halogen atom of the substituent, for example, a fluorine atom, a chlorine atom, a bromine atom and the like, more preferably a fluorine atom and the like are suitable.
The lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group.
The halo-lower alkyl group for the substituent is, for example, preferably a difluoromethyl group, a trifluoromethyl group.

The hydroxy lower alkyl group for the substituent is, for example, preferably a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethyl group.
The cyclo-lower alkyl group for the substituent is, for example, preferably a cyclopropyl group.
The cyclo-lower alkyl-lower alkyl group for the substituent is, for example, preferably a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group.
The lower alkenyl group for the substituent is, for example, preferably a vinyl group, 1-propenyl group, 2-methyl-1-propenyl group.

The lower alkylamino group for the substituent is, for example, preferably a methylamino group, an ethylamino group.
The di-lower alkylamino group for the substituent is, for example, preferably a dimethylamino group, a diethylamino group.
The lower alkanoylamino group for the substituent is, for example, preferably an acetylamino group, a propionylamino group.
The lower alkylsulfonylamino group for the substituent is, for example, preferably a methylsulfonylamino group, an ethylsulfonylamino group.

The arylsulfonylamino group for the substituent is, for example, preferably a phenylsulfonylamino group.
The lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group.
The halo-lower alkoxy group for the substituent is, for example, preferably a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group.
The aryloxy group for the substituent is, for example, preferably a phenoxy group.

The heteroaryloxy group for the substituent is, for example, preferably a 2-pyridyloxy group, a 3-pyridyloxy group, a 4-pyridyloxy group.
The lower alkylthio group for the substituent is, for example, preferably a methylthio group, an ethylthio group.
The lower alkanoyl group for the substituent is, for example, preferably a formyl group, an acetyl group, a propionyl group.
The lower alkoxycarbonyl group for the substituent is, for example, preferably a methoxycarbonyl group, an ethoxycarbonyl group.

The lower alkylcarbamoyl group for the substituent is, for example, preferably a methylcarbamoyl group, an ethylcarbamoyl group.
The di-lower alkylcarbamoyl group for the substituent is, for example, preferably a dimethylcarbamoyl group, a diethylcarbamoyl group.
The lower alkylsulfonyl group for the substituent is, for example, preferably a methylsulfonyl group, an ethylsulfonyl group.
The arylsulfonyl group for the substituent is, for example, preferably a phenylsulfonyl group.

The aryl group for the substituent is, for example, preferably a phenyl group.
The heteroaryl group for the substituent is, for example, preferably a thienyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyrazinyl group.
As the substituent for Ar ¹ or Ar ² , for example, a halogen atom, a halo lower alkyl group and the like are preferable.
The aryl group for Ar ¹ or Ar ² is preferably, for example, a phenyl group, and the heteroaryl group is preferably, for example, a pyridyl group.

More specifically, as Ar ¹ or Ar ² , for example, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group 2-bromophenyl group, 3-bromophenyl group, 3-bromo-4-fluorophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-triphenyl Fluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-hydroxymethylphenyl group, 3-hydroxymethylphenyl group, 4-hydroxymethylphenyl group, 2-methoxyphenyl group, 3- Methoxyphenyl group, 4-methoxyphenyl group, 2-difluoromethoxypheny Group, 3-difluoromethoxyphenyl group, 4-difluoromethoxyphenyl group, 2-trifluoromethoxyphenyl group, 3-trifluoromethoxyphenyl group, 4-trifluoromethoxyphenyl group, 2-formylphenyl group, 3-formylphenyl Group, 4-formylphenyl group, 2-thienyl group, 4-chloro-2-thienyl group, 5-chloro-2-thienyl group, 4-bromo-2-thienyl group, 5-bromo-2-thienyl group, 4 -Methyl-2-thienyl group, 5-methyl-2-thienyl group, 4-methoxy-2-thienyl group, 5-methoxy-2-thienyl group, 3-thienyl group, 5-chloro-3-thienyl group, 5 -Methyl-3-thienyl group, 5-methoxy-3-thienyl group, 2-pyridyl group, 4-methyl-2-pyridyl group, 5-methyl-2-pyridyl group Group, 4-methoxy-2-pyridyl group, 5-methoxy-2-pyridyl group, 4-chloro-2-pyridyl group, 5-chloro-2-pyridyl group, 3-pyridyl group, 4-methyl-3-pyridyl Group, 5-methyl-3-pyridyl group, 4-methoxy-3-pyridyl group, 5-methoxy-3-pyridyl group, 6-fluoro-3-pyridyl group, 4-chloro-3-pyridyl group, 5-chloro -3-pyridyl group, 6-difluoromethyl-3-pyridyl group, 6-trifluoromethyl-3-pyridyl group, 6-cyclopropyl-3-pyridyl group, 4-pyridyl group, 2-fluoro-4-pyridyl group 2-chloro-4-pyridyl group, 3-chloro-4-pyridyl group, 2-methyl-4-pyridyl group, 3-methyl-4-pyridyl group, 2-methoxy-4-pyridyl group, 3-methoxy- 4-pyridyl Among them, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3-bromophenyl group, 3-bromo-4 -Fluorophenyl group, 4-bromophenyl group, 3-methylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3-trifluoromethoxy Phenyl group, 4-trifluoromethoxyphenyl group, 3-difluoromethoxyphenyl group, 4-difluoromethoxyphenyl group, 2-thienyl group, 4-chloro-2-thienyl group, 5-chloro-2-thienyl group, 4- Bromo-2-thienyl group, 5-bromo-2-thienyl group, 3-pyridyl group, 4- Toxi-3-pyridyl group, 5-methoxy-3-pyridyl group, 6-fluoro-3-pyridyl group, 4-chloro-3-pyridyl group, 5-chloro-3-pyridyl group, 6-difluoromethyl-3- Pyridyl group, 6-trifluoromethyl-3-pyridyl group, 6-cyclopropyl-3-pyridyl group, 2-fluoro-4-pyridyl group and the like are preferable, and 4-fluorophenyl group, 4-chlorophenyl group, 3- Bromo-4-fluorophenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 6-fluoro-3-pyridyl group, 6-difluoromethyl-3-pyridyl group, 6-trifluoromethyl-3 -Pyridyl group, 2-fluoro-4-pyridyl group and the like are preferable.

As a preferable embodiment of Ar ¹ and Ar ² , for example, one of them is an aryl group having a substituent selected from the group consisting of a halogen atom and a halo lower alkyl group, and the other is a halogen atom and a halo lower alkyl group. In particular, for example, any one of them is a 4-fluorophenyl group, a 4-chlorophenyl group, a 3-trifluoromethylphenyl group, or 4 -When it is a trifluoromethylphenyl group and the other is a 6-fluoro-3-pyridyl group; either one is a 4-fluorophenyl group, a 4-chlorophenyl group, a 3-trifluoromethylphenyl group or 4-trifluoro When it is a methylphenyl group and the other is a 2-fluoro-4-pyridyl group; When 4-fluorophenyl group, 4-chlorophenyl group, 3-trifluoromethylphenyl group or 4-trifluoromethylphenyl group and the other is 6-trifluoromethyl-3-pyridyl group; -Fluorophenyl group or 4-chlorophenyl group, and the other is preferably 6-difluoromethyl-3-pyridyl group or the like.

R ¹ and R ² are each independently a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and It means a lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group which may have a substituent selected from the group consisting of di-lower alkyl carbamoyl groups.
Selected from the group consisting of a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group The lower alkyl group, cyclo lower alkyl group, cyclo lower alkyl lower alkyl group or lower alkoxy group optionally having a substituent ”means the above-mentioned unsubstituted lower alkyl group, cyclo lower alkyl group, cyclo lower group. An alkyl lower alkyl group or a lower alkoxy group, or the above-mentioned lower alkyl group, cyclo lower alkyl group, cyclo lower alkyl lower alkyl group or lower alkoxy group having a substituent at any substitutable position. A halogen atom, a lower alkylamino group, From the group consisting of a lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group, one or more, preferably One or two can be selected.

The halogen atom for the substituent is, for example, preferably a fluorine atom.
The lower alkylamino group for the substituent is, for example, preferably a methylamino group, an ethylamino group.
The di-lower alkylamino group for the substituent is, for example, preferably a dimethylamino group, a diethylamino group.
The lower alkanoylamino group for the substituent is, for example, preferably an acetylamino group, a propionylamino group.

The lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group.
The lower alkoxycarbonyl group for the substituent is, for example, preferably a methoxycarbonyl group, an ethoxycarbonyl group.
The lower alkylcarbamoyl group for the substituent is, for example, preferably a methylcarbamoyl group, an ethylcarbamoyl group.
The di-lower alkylcarbamoyl group for the substituent is, for example, preferably a dimethylcarbamoyl group, a diethylcarbamoyl group.

As the substituent for the lower alkyl group, cyclo lower alkyl group, cyclo lower alkyl lower alkyl group or lower alkoxy group of R ¹ , for example, a halogen atom is preferable.
The lower alkyl group for R ¹ is, for example, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group.
The cyclo lower alkyl group for R ¹ is, for example, preferably a cyclopropyl group, a cyclobutyl group.

The cyclo lower alkyl lower alkyl group for R ¹ is, for example, preferably a cyclopropylmethyl group, a 2-cyclopropylethyl group, a cyclobutylmethyl group.
As the lower alkoxy group for R ¹ , for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an isobutoxy group, and the like are preferable.
R ¹ is preferably a lower alkyl group, a cyclo lower alkyl group, a lower alkoxy group or the like which may have the above-described substituent.

More specifically, examples of R ¹ include a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, an ethyl group, a cyclopropyl group, a cyclobutyl group, a 2-fluoroethyl group, and 2,2-difluoroethyl. Group, propyl group, isopropyl group, isobutyl group, methoxy group, difluoromethoxy group, ethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, propoxy group, isopropoxy group, isobutoxy group, etc. Methyl, difluoromethyl, ethyl, 2,2-difluoroethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy and the like are preferred.
Examples of the substituent for the lower alkyl group, cyclo lower alkyl group, cyclo lower alkyl lower alkyl group or lower alkoxy group of R ² include a halogen atom, a lower alkyl amino group, a di-lower alkyl amino group, a hydroxyl group, and a lower alkoxy group. Is preferred.

As the lower alkyl group for R ² , for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, and the like, more preferably a methyl group and the like are suitable.
The cyclo lower alkyl group for R ² is, for example, preferably a cyclopropyl group or a cyclobutyl group.
The cyclo lower alkyl lower alkyl group for R ² is, for example, preferably a cyclopropylmethyl group, a 2-cyclopropylethyl group, a cyclobutylmethyl group.
As the lower alkoxy group for R ² , for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an isobutoxy group, and the like, more preferably a methoxy group and the like are preferable.

As R ² , for example, a lower alkyl group which may have the above substituent, etc., more preferably a methyl group or the like is suitable.
R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom, a cyano group, a halogen atom or a hydroxyl group, or a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, Optionally having a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group, a lower alkyl group, a lower alkoxy group or a lower group; An alkylthio group is meant.

As the halogen atom for R ³ , R ⁴ or R ⁵ , for example, a fluorine atom, a chlorine atom, a bromine atom and the like, more preferably a fluorine atom, a chlorine atom and the like are suitable.
Selected from the group consisting of a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group The lower alkyl group, lower alkoxy group or lower alkylthio group optionally having substituent (s) ”refers to the unsubstituted lower alkyl group, lower alkoxy group or lower alkylthio group, or any substitutable The lower alkyl group having the substituent at the position, the lower alkoxy group or the lower alkylthio group means a halogen atom, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, hydroxyl group, lower Alkoxy group, formyl group, lower Alkoxycarbonyl group, from the group consisting of lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group, same or different one or more, preferably be selected one or two.

The halogen atom for the substituent is, for example, preferably a fluorine atom.
The lower alkylamino group for the substituent is, for example, preferably a methylamino group, an ethylamino group.
The di-lower alkylamino group for the substituent is, for example, preferably a dimethylamino group, a diethylamino group.
The lower alkanoylamino group for the substituent is, for example, preferably an acetylamino group, a propionylamino group.

The lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group.
The lower alkoxycarbonyl group for the substituent is, for example, preferably a methoxycarbonyl group, an ethoxycarbonyl group.
The lower alkylcarbamoyl group for the substituent is, for example, preferably a methylcarbamoyl group, an ethylcarbamoyl group.
The di-lower alkylcarbamoyl group for the substituent is, for example, preferably a dimethylcarbamoyl group, a diethylcarbamoyl group.

As the substituent for the lower alkyl group, lower alkoxy group or lower alkylthio group of R ³ , R ⁴ or R ⁵ , for example, a halogen atom is preferred.
Examples of the lower alkyl group which may have the substituent of R ³ , R ⁴ or R ⁵ include a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, an ethyl group, and a 2-fluoroethyl group. 2,2-difluoroethyl group, propyl group, isopropyl group, isobutyl group and the like, among which methyl group, ethyl group and the like are preferable; as the lower alkoxy group which may have the substituent, Examples include a methoxy group, a difluoromethoxy group, an ethoxy group, a 2-fluoroethoxy group, a 2,2-difluoroethoxy group, a propoxy group, an isopropoxy group, and an isobutoxy group, among which a methoxy group is preferable; Examples of the lower alkylthio group optionally having a group include a methylthio group, an ethylthio group, a propylthio group, an iso A propylthio group, an isobutylthio group, etc. are mentioned, A methylthio group etc. are suitable among these.

As R ³ , R ⁴ or R ⁵ , for example, a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group which may have the above-described substituent, and the like are preferable. Among them, for example, it is preferable that R ³ is a hydrogen atom, a halogen atom or a hydroxyl group, or a lower alkyl group which may have the above substituent, and R ⁴ and R ⁵ are hydrogen atoms at the same time. .

で表される基並びにＲ^３、Ｒ^４及びＲ^５は、それぞれ、式（ｂ）

で表されるＮ−置換−２−オキソジヒドロピリジン環上の存在可能な任意の位置に存在することができる。 In general formula (I), formula (a)

And a group represented by R ³ , R ⁴ and R ⁵ are each represented by the formula (b)

It can be present at any possible position on the N-substituted-2-oxodihydropyridine ring represented by

［式中、Ａｒ^１、Ａｒ^２、Ｒ^１、Ｒ^２及びＲ^３は前記の意味を有する］で表される化合物等が好適である。 Among the compounds represented by the general formula (I), for example, the general formula (I-1)

A compound represented by the formula [wherein Ar ¹ , Ar ² , R ¹ , R ² and R ³ have the above-mentioned meanings] is preferred.

In general formula (I) or (I-1), any ^one of Ar ¹ and Ar ² is an aryl group having a substituent selected from the group consisting of a halogen atom and a halo-lower alkyl group, more preferably a phenyl group. And the other is a heteroaryl group having a substituent selected from the group consisting of a halogen atom and a halo-lower alkyl group, more preferably a 3-pyridyl group or a 4-pyridyl group, and R ¹ has the substituent A lower alkyl group, a cyclo lower alkyl group or a lower alkoxy group, R ² may be a lower alkyl group optionally having the above substituent, more preferably a methyl group, and R ³ is A compound or the like which is a hydrogen atom, a halogen atom or a hydroxyl group, or a lower alkyl group which may have the above substituent is preferred. In addition, in general formula (I), in addition to the above, compounds in which R ⁴ and R ⁵ are hydrogen atoms at the same time are suitable.

The compound of the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers and geometric isomers depending on the mode of the substituents. And stereoisomers, tautomers and mixtures thereof.
Various crystals, hydrates and solvates of the compounds of the present invention also belong to the scope of the present invention.
Furthermore, prodrugs of the compounds of the present invention are also within the scope of the present invention. In general, such prodrugs are functional derivatives of the compounds of the present invention that can be readily converted into the required compounds in vivo. Therefore, in the method for treating various diseases according to the present invention, the term “administration” refers not only to the administration of the specified compound but also to the administration of a compound that is converted into the specified compound in vivo after being administered to a patient. including. Conventional means for selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985, etc., the entire description of which is hereby incorporated by reference. Metabolites of these compounds include active compounds produced by placing the compounds of the invention in a biological environment and are within the scope of the invention.

Specific examples of the compound represented by the general formula (I) include, for example,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl-2-pyridone ,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1- (2,2-difluoroethyl) -5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazoline-2 -Yl] -2-pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-propyl-2-pyridone ,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-isopropyl-2-pyridone ,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- 2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- 2-pyridone,
1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -2 -Pyridone,
5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-propyl-2 -Pyridone,
5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-propyl-2 -Pyridone,
1- (2,2-difluoroethyl) -5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline -2-yl] -2-pyridone,
1- (2,2-difluoroethyl) -5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline -2-yl] -2-pyridone,
3-Chloro-1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
3-Chloro-1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
5-[(4S, 5S) -4- (3-Bromo-4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-difluoro Methyl-2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1- (2,2-difluoroethyl) -5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazoline-2 -Yl] -2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (2-fluoro-4-pyridyl) -5-methyl-4- (4-trifluorophenyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (2-fluoro-4-pyridyl) -5-methyl-4- (4-trifluorophenyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
3-Chloro-1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
5-[(4R, 5S) -4- (4-Fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-methyl-2 -Pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-methyl-2 -Pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1-difluoromethyl-5-[(4S, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1-ethyl-5-[(4R, 5S) -4- (2-fluoro-4-pyridyl) -5-methyl-4- (4-trifluoromethylphenyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-ethyl-5-[(4S, 5S) -4- (2-fluoro-4-pyridyl) -5-methyl-4- (4-trifluoromethylphenyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-ethyl-5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
3-Chloro-1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
3-Chloro-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3-methyl -2-pyridone,
3-Chloro-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1 -Methyl-2-pyridone,
3-Chloro-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1 -Methyl-2-pyridone,
1-ethyl-3-fluoro-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1- (2,2-difluoroethyl) -5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazoline-2 -Yl] -2-pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1,3-dimethyl-2 -Pyridone,
3-chloro-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
3-Chloro-1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-ethyl-3-fluoro-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
5-[(4R, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl-2-pyridone ,
1-ethyl-3-fluoro-5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl]- 2-pyridone,
1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl]- 2-pyridone,
3-Ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
3-Ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
3-Ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3-methoxy -2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
5-[(4R, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-2- Pyridone,
5-[(4S, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-2- Pyridone,
5-[(4R, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-3- Fluoro-2-pyridone,
5-[(4S, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-3- Fluoro-2-pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone ,
5-[(4R, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone ,
1-ethoxy-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1-cyclopropyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-cyclopropyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- 2-pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone ,
5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-methoxy-2 -Pyridone,
5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Methyl-2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Methyl-2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Methoxy-2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Methoxy-2-pyridone,
5-[(5S) -4,4-bis (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (6-cyclopropyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
5-[(4S, 5S) -4- (6-cyclopropyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-2- Pyridone,
5-[(4S, 5S) -4- (4-chlorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone,
5-[(4S, 5S) -4- (6-Fluoro-3-pyridyl) -5-methyl-4- (4-trifluoromethylphenyl) -2-imidazolin-2-yl] -1-methoxy-2 -Pyridone,
5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone ,
1-cyclopropyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-cyclopropyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-ethyl-5-[(5S) -4,4-bis (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
5-[(5S) -4,4-bis (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-difluoromethyl-2-pyridone,
1-cyclopropyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-difluoromethyl-3-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl ] -2-pyridone,
1-difluoromethyl-3-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl ] -2-pyridone,
1-difluoromethoxy-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
5-[(4R, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2- Pyridone,
5-[(4S, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2- Pyridone,
1-difluoromethoxy-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-difluoromethyl-3-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl ] -2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Hydroxy-2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluoro-3-hydroxyphenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl ] -2-pyridone or
1-difluoromethyl-5-[(4S, 5R) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-hydroxymethyl-2-imidazolin-2-yl] -2 -Pyridone and the like, among others,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-propyl-2-pyridone ,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-isopropyl-2-pyridone ,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- 2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- 2-pyridone,
1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -2 -Pyridone,
5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-propyl-2 -Pyridone,
5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-propyl-2 -Pyridone,
3-Chloro-1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
3-Chloro-1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1-difluoromethyl-5-[(4S, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1-ethyl-5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-ethyl-3-fluoro-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
3-Ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
5-[(4R, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-3- Fluoro-2-pyridone,
5-[(4S, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-3- Fluoro-2-pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone ,
5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-methoxy-2 -Pyridone or
1-difluoromethyl-3-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl ] -2-pyridone and the like are preferred.

Next, the manufacturing method of the compound based on this invention is demonstrated.
The compound (I) of the present invention can be produced, for example, by the following production method or the method shown in the examples. However, the production method of the compound (I) of the present invention is not limited to these reaction examples.

［式中、Ａｒ^１ｐ及びＡｒ^２ｐは、それぞれ独立して、シアノ基、ハロゲン原子、ニトロ基、低級アルキル基、ハロ低級アルキル基、シクロ低級アルキル基、シクロ低級アルキル低級アルキル基、低級アルケニル基、ジ低級アルキルアミノ基、低級アルコキシ基、ハロ低級アルコキシ基、アリールオキシ基、ヘテロアリールオキシ基、低級アルキルチオ基、ホルミル基、低級アルカノイル基、低級アルコキシカルボニル基、ジ低級アルキルカルバモイル基、低級アルキルスルホニル基、アリールスルホニル基、アリール基及びヘテロアリール基並びに保護されていてもよい、ヒドロキシ低級アルキル基、低級アルキルアミノ基、低級アルカノイルアミノ基、低級アルキルスルホニルアミノ基、アリールスルホニルアミノ基、水酸基、カルボキシル基、カルバモイル基及び低級アルキルカルバモイル基からなる群より選択される置換基を有していてもよい、アリール基又はヘテロアリール基を意味し；Ｒ^２ｐはハロゲン原子、ジ低級アルキルアミノ基、低級アルコキシ基、ホルミル基、低級アルコキシカルボニル基及びジ低級アルキルカルバモイル基並びに保護されていてもよい、低級アルキルアミノ基、低級アルカノイルアミノ基、水酸基及び低級アルキルカルバモイル基からなる群より選択される置換基を有していてもよい、低級アルキル基、シクロ低級アルキル基、シクロ低級アルキル低級アルキル基又は低級アルコキシ基を意味する］で表される化合物と、一般式（ＩＩＩ）

［式中、Ｒ^１ｐはハロゲン原子、ジ低級アルキルアミノ基、低級アルコキシ基、ホルミル基、低級アルコキシカルボニル基及びジ低級アルキルカルバモイル基並びに保護されていてもよい、低級アルキルアミノ基、低級アルカノイルアミノ基、水酸基及び低級アルキルカルバモイル基からなる群より選択される置換基を有していてもよい、低級アルキル基、シクロ低級アルキル基、シクロ低級アルキル低級アルキル基又は低級アルコキシ基を意味し；Ｒ^３ｐ、Ｒ^４ｐ及びＲ^５ｐは、それぞれ独立して、水素原子、シアノ基、ハロゲン原子若しくは保護されていてもよい水酸基を意味するか、又はハロゲン原子、ジ低級アルキルアミノ基、低級アルコキシ基、ホルミル基、低級アルコキシカルボニル基及びジ低級アルキルカルバモイル基並びに保護されていてもよい、低級アルキルアミノ基、低級アルカノイルアミノ基、水酸基及び低級アルキルカルバモイル基からなる群より選択される置換基を有していてもよい、低級アルキル基、低級アルコキシ基若しくは低級アルキルチオ基を意味する］で表される化合物とを反応させ、一般式（ＩＶ）

［式中、Ａｒ^１ｐ、Ａｒ^２ｐ、Ｒ^１ｐ、Ｒ^２ｐ、Ｒ^３ｐ、Ｒ^４ｐ及びＲ^５ｐは前記の意味を有する］で表される化合物とし、次いで該化合物（ＩＶ）を分子内環化縮合反応に付すことにより、一般式（Ｖ）

［式中、Ａｒ^１ｐ、Ａｒ^２ｐ、Ｒ^１ｐ、Ｒ^２ｐ、Ｒ^３ｐ、Ｒ^４ｐ及びＲ^５ｐは前記の意味を有する］で表される化合物とし、所望により保護基を除去することにより、一般式（Ｉ）で表される化合物を製造することができる。 Manufacturing method 1
Formula (II)

[ ^Wherein , Ar ^1p and Ar ^2p each independently represent a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group, a lower alkenyl group, Di-lower alkylamino group, lower alkoxy group, halo-lower alkoxy group, aryloxy group, heteroaryloxy group, lower alkylthio group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group , Arylsulfonyl group, aryl group and heteroaryl group, and optionally protected hydroxy lower alkyl group, lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, carbo Sill group may have a substituent selected from the group consisting of carbamoyl group and a lower alkylcarbamoyl group, an aryl group or a heteroaryl group; R ^2p is a halogen atom, a di-lower alkylamino group, a lower A substituent selected from the group consisting of an alkoxy group, a formyl group, a lower alkoxycarbonyl group, a di-lower alkylcarbamoyl group and an optionally protected lower alkylamino group, lower alkanoylamino group, hydroxyl group and lower alkylcarbamoyl group; Which may have a lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group], and a compound of the general formula (III)

[Wherein, R ^1p represents a halogen atom, a di-lower alkylamino group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a di-lower alkylcarbamoyl group, and an optionally protected lower alkylamino group or lower alkanoylamino group. Represents a lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group which may have a substituent selected from the group consisting of a hydroxyl group and a lower alkyl carbamoyl group; R ^3p , R ^4p and R ^5p each independently represents a hydrogen atom, a cyano group, a halogen atom or an optionally protected hydroxyl group, or a halogen atom, a di-lower alkylamino group, a lower alkoxy group, a formyl group, Lower alkoxycarbonyl group and di-lower alkylcarbamoyl group Optionally having a substituent selected from the group consisting of a lower alkylamino group, a lower alkanoylamino group, a hydroxyl group and a lower alkylcarbamoyl group, a lower alkyl group, a lower alkoxy group or a lower group. And a compound represented by the general formula (IV):

[Wherein Ar ^1p , Ar ^2p , R ^1p , R ^2p , R ^3p , R ^4p and R ^5p have the above-mentioned meanings], and then the compound (IV) is subjected to intramolecular cyclization condensation By subjecting to reaction, the general formula (V)

[Wherein, Ar ^1p , Ar ^2p , R ^1p , R ^2p , R ^3p , R ^4p and R ^5p have the above-mentioned meanings] The compound represented by (I) can be produced.

  In the above reaction, when an amino group, imino group, hydroxyl group, carboxyl group, etc. that are not involved in the reaction are present in the reactant, the amino group, imino group, hydroxyl group, carboxyl group is appropriately protected for the amino group or imino group. The reaction is carried out after protecting with a group, a protecting group for a hydroxyl group or a protecting group for a carboxyl group, and the protecting group can be removed after the reaction.

  Examples of the “protecting group for amino group or imino group” include benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group, trityl group and the like. Aralkyl group; for example, lower alkanoyl group such as formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group; for example, benzoyl group; for example, arylalkanoyl group such as phenylacetyl group, phenoxyacetyl group; for example, methoxycarbonyl group, ethoxycarbonyl group Lower alkoxycarbonyl groups such as propyloxycarbonyl group and tert-butoxycarbonyl group; for example, aralkyloxycarbonyl such as benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group and phenethyloxycarbonyl group ; Such as trimethylsilyl group, and the like lower alkylsilyl group such as tert- butyldimethylsilyl group and the like, in particular an acetyl group, a pivaloyl group, a benzoyl group, an ethoxycarbonyl group, etc. tert- butoxycarbonyl group are preferred.

  Examples of the “hydroxyl-protecting group” include lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; lower alkoxymethyl groups such as methoxymethyl group and 2-methoxyethoxymethyl group; for example, tetrahydropyranyl group; For example, trimethylsilylethoxymethyl group; for example, aralkyl groups such as benzyl group, p-methoxybenzyl group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, trityl group; for example, formyl group, acetyl group, etc. Acyl group, and the like. In particular, methoxymethyl group, tetrahydropyranyl group, trityl group, trimethylsilylethoxymethyl group, tert-butyldimethylsilyl group, acetyl group and the like are preferable.

  Examples of the “carboxyl-protecting group” include lower alkyl groups such as methyl, ethyl, propyl, isopropyl and tert-butyl groups; lower haloalkyl groups such as 2,2,2-trichloroethyl groups; Lower alkenyl groups such as 2-propenyl group; for example, aralkyl groups such as benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group, trityl group, etc., and particularly methyl group, ethyl group, tert-butyl Group, 2-propenyl group, benzyl group, p-methoxybenzyl group, benzhydryl group and the like are preferable.

The reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III) is usually 0.5 mol to excess of compound (III) with respect to 1 mol of the compound (II). It is carried out using 1 mol to 2 mol.
The reaction is usually carried out in an inert solvent. As the inert solvent, for example, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine and the like, or a mixed solvent thereof is suitable.
The above reaction is preferably performed in the presence of a condensing agent. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3- Ethylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium Hexafluorophosphate, diphenyl phosphate azide, 1,1-carbonyldiimidazole, and the like can be used.

The condensing agent can be used usually in an amount of 1 mol to excess mol, preferably 1 mol to 3 mol, per 1 mol of the compound represented by the general formula (II).
The reaction temperature is usually −20 ° C. to the boiling point of the solvent used for the reaction, preferably 0 ° C. to 60 ° C.
The reaction time is usually 30 minutes to 3 days, preferably 1 hour to 24 hours.
After the completion of the reaction, ordinary treatment can be performed to obtain a crude product of the compound represented by the general formula (IV). The compound represented by the general formula (IV) thus obtained can be purified according to a conventional method or subjected to the following intramolecular cyclization condensation reaction without purification.

The intramolecular cyclocondensation reaction for producing compound (V) from compound (IV) is usually performed in an inert solvent or without solvent.
As the inert solvent, for example, ethanol, propanol, butanol, pentanol, 1,4-dioxane, dimethoxyethane, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, or a mixed solvent thereof is preferable.

The reaction temperature is usually from room temperature to the boiling point of the solvent used in the reaction, preferably from 80 ° C to 190 ° C.
The reaction time is usually 1 hour to 7 days, preferably 2 hours to 3 days.
The cyclization reaction can also be performed in the presence of a dehydrating agent or a catalytic amount of a Lewis acid. Examples of the dehydrating agent include phosphorus oxychloride, phosphorus pentachloride, polyphosphoric acid, thionyl chloride and the like. Examples of the Lewis acid include scandium trifluoromethanesulfonate, yttrium trifluoromethanesulfonate, and lanthanum trifluoromethanesulfonate. And lanthanide trifluoromethanesulfonic acid. At this time, it is preferable to carry out the reaction without solvent or to carry out the reaction in methylene chloride, chloroform, benzene, toluene, xylene or the like or a mixed solvent thereof.

The amount of the dehydrating agent to be used is generally 1 mol to excess mol, preferably 2 to 10 mol, per 1 mol of the compound represented by the general formula (IV). The amount of the Lewis acid used is 1 mol% to 50 mol%, preferably 5 mol% to 30 mol%.
The reaction temperature is usually preferably from room temperature to the boiling point of the solvent used in the reaction.
The reaction time is usually 1 hour to 7 days, preferably 5 hours to 3 days.

The cyclization reaction can also be performed while dehydrating using a Dean-Stark water separator or the like. At this time, it is preferable to perform the reaction in, for example, benzene, toluene, xylene, or a mixed solvent thereof.
The reaction temperature is usually preferably from room temperature to the boiling point of the solvent used in the reaction.
The reaction time is usually 1 hour to 7 days, preferably 2 hours to 3 days.
After the completion of the reaction, ordinary treatment can be performed to obtain a crude product of the compound represented by the general formula (V). The compound represented by the general formula (V) thus obtained is purified according to a conventional method, or without purification, if desired, removal of amino, imino, hydroxyl and carboxyl protecting groups. Can be produced by appropriately combining the compounds of formula (I).

  The method for removing the protecting group varies depending on the kind of the protecting group and the stability of the target compound (I). For example, the method described in the literature [Protective Groups in Organic Synthesis], T.A. W. According to Green (TW Greene, John Wiley & Sons (1981)) or a method analogous thereto, for example, solvolysis using an acid or base, for example, 0.01 mole to large excess of acid, Preferably, trifluoroacetic acid, formic acid, hydrochloric acid or the like, or a method in which an equimolar or large excess base, preferably potassium hydroxide, calcium hydroxide or the like is allowed to act; Chemical reduction using a metal hydride complex or the like, or a palladium-carbon catalyst , Catalytic reduction using Raney nickel catalyst or the like.

［式中、Ａｒ^１ｐ、Ａｒ^２ｐ及びＲ^２ｐは前記の意味を有する］で表される化合物と、一般式（ＶＩ）

［式中、Ｒ^６はアミノ基又は低級アルコキシ基を意味し、Ｒ^１ｐ、Ｒ^３ｐ、Ｒ^４ｐ及びＲ^５ｐは前記の意味を有する］で表される化合物の酸付加塩とを反応させ、一般式（Ｖ）

［式中、Ａｒ^１ｐ、Ａｒ^２ｐ、Ｒ^１ｐ、Ｒ^２ｐ、Ｒ^３ｐ、Ｒ^４ｐ及びＲ^５ｐは前記の意味を有する］で表される化合物とし、所望により保護基を除去することにより、一般式（Ｉ）で表される化合物を製造することができる。 Manufacturing method 2
Formula (II)

[Wherein Ar ^1p , Ar ^2p and R ^2p have the above-mentioned meanings] and a general formula (VI)

[Wherein R ⁶ represents an amino group or a lower alkoxy group, and R ^1p , R ^3p , R ^4p and R ^5p have the above-mentioned meanings] are reacted with an acid addition salt of a compound represented by Formula (V)

[Wherein, Ar ^1p , Ar ^2p , R ^1p , R ^2p , R ^3p , R ^4p and R ^5p have the above-mentioned meanings] The compound represented by (I) can be produced.

As the acid addition salt of compound (VI), for example, hydrochloride and the like are preferable.
The reaction of the compound represented by the general formula (II) and the compound represented by the general formula (VI) is usually performed in an inert solvent, and examples of the inert solvent include alcohols such as methanol and ethanol. , Dimethylformamide, dimethyl sulfoxide and the like, or mixed solvents thereof are preferable.

The reaction temperature is generally −30 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C.
The reaction time is usually 30 minutes to 7 days, preferably 2 hours to 5 days.
After completion of the reaction, when a protecting group is present in the product, after removing the protecting group, or when the protecting group is not present in the product, a normal treatment is performed as it is to produce a compound of the general formula (I). be able to.
Removal of the protecting group, post-treatment, and the like can be performed in accordance with the method described in Production Method 1.

The compound of general formula (I) can be easily isolated and purified by conventional separation means. Examples of such means include solvent extraction, recrystallization, column chromatography, preparative thin layer chromatography, and HPLC.
These compounds can be converted into pharmaceutically acceptable salts or esters by conventional methods, and conversely, conversion of salts or esters to free compounds can also be performed according to conventional methods.

  As the compound represented by the general formula (II), (III) or (VI), for example, a commercially available product is used, or a known method described in a document such as WO 01/62738 or a method analogous thereto, or the following It can be produced by appropriately combining the methods described in the above or the methods described in Examples and Reference Examples as necessary.

［式中、Ｌ^１は水素原子又は脱離基を意味し；Ｐはアミノ基の保護基を意味し；Ｒは嵩高い基を意味し、Ａｒ^１ｐ、Ａｒ^２ｐ及びＲ^２ｐは前記の意味を有する］ Manufacturing method A

[Wherein L ¹ represents a hydrogen atom or a leaving group; P represents an amino-protecting group; R represents a bulky group; Ar ^1p , Ar ^2p and R ^2p have the same meanings as described above] Have]

  This production method is a method for producing the compound represented by the general formula (II). According to this production method, the compound represented by general formula (II) is arylated from the compound represented by general formula (1) to form a compound represented by general formula (2), and then the compound (2) ) Is converted to a sulfinylimide group to obtain a compound represented by the general formula (3), and then the compound (3) is arylated again to obtain a compound represented by the general formula (4). Subsequently, the amino group-protecting group P of the compound (4) and the group represented by -S (= O) -R can be removed.

As the leaving group for L ¹ , for example, a group that forms an amide group such as a methoxy (methyl) amide group with a halogen atom, a lower alkoxy group, or an adjacent carbonyl group is preferable.
Examples of the amino-protecting group represented by P include amino-protecting groups described in Production Method 1, and the method described in Production Method 1 can be applied as the removal method.
The bulky group represented by R means a group constituting a steric hindrance in the molecule of the compound, and examples thereof include secondary or tertiary, more preferably tertiary alkyl groups. More specifically, for example, isopropyl group, sec-butyl group, tert-butyl group and the like can be mentioned, and tert-butyl group and the like are preferable.

In the step of producing compound (2) from compound (1), an organometallic compound such as aryllithium, ^{arylmagnesium} , arylzinc or ^arylcopper having a group represented by Ar ^1p as an aryl group is usually added to compound ( It can be performed by acting on 1).
The reaction is usually carried out using 1 mole to excess moles, preferably 2 moles to 5 moles of the organometallic compound per mole of the compound (1), for example, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc. The reaction is carried out in an inert solvent such as an ether solvent or a mixed solvent thereof.
The reaction temperature is usually −130 ° C. to the boiling point of the solvent used in the reaction, preferably −100 ° C. to room temperature, and the reaction time is usually 30 minutes to 2 days, preferably 1 hour to 1 day.

［式中、Ｒは前記の意味を有する］で表されるスルフィニルアミドを作用させることにより行われる。 When L ¹ is a hydrogen atom, the ketone body (2) can be produced by oxidizing the alcohol body obtained by arylation by a method known per se in the field of organic chemistry.
The step of producing the compound (3) from the compound (2) may be carried out by a known method described in literatures such as Journal of Organic Chemistry (J. Org. Chem), 64, 1278 (1999) or the like. It can be performed by a similar method or the like. That is, usually, in the presence of a Lewis acid such as tetraisopropoxy titanium, tetraethoxy titanium, magnesium sulfate, copper sulfide, etc., the compound (2) has the following formula:

[Wherein R has the above-mentioned meaning].

In the reaction, usually, 1 mol to excess mol, preferably 2 mol to 7 mol, and 0.5 mol to excess mol, preferably 1 mol to 5 mol of sulfinylamide are used with respect to 1 mol of compound (2). The reaction is carried out in an inert solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, toluene, benzene, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, etc. or a mixed solvent thereof.
The reaction temperature is usually 0 ° C. to the boiling point of the solvent used for the reaction, preferably 0 ° C. to 100 ° C., and the reaction time is 30 minutes to 3 days, preferably 1 hour to 24 hours.

The step of producing compound (4) from compound (3) is usually an organic compound such as aryllithium, ^{arylmagnesium} , ^arylzinc , ^arylcopper having a group represented by Ar ^2p as an aryl group with respect to (3). It can be carried out by allowing a metal compound to act on the compound (3).
The reaction is usually carried out at 0.5 mol to excess mol, preferably 1 mol to 3 mol, from -130 ° C to the boiling point of the solvent used in the reaction, preferably 1 mol to 1 mol of compound (3). At −110 ° C. to room temperature, for example, in an inert solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, toluene, benzene, dichloromethane, or a mixed solvent thereof, for 5 minutes to 24 hours, preferably 15 It can be carried out by acting for 2 to 2 hours.

  Alternatively, the compound (3) may be activated by the action of a Lewis acid such as trimethylaluminum, triethylaluminum, triisopropylaluminum, boron trifluoride ether complex, zinc chloride or tin chloride, and then subjected to the organometallic reaction. (4) can be obtained. The reaction is usually carried out in an amount of 0.5 mol to excess mol, preferably 1 mol to 3 mol of the Lewis acid relative to 1 mol of the compound (3) at −100 ° C. to the boiling point of the solvent used in the reaction, preferably − At 78 ° C. to room temperature, for example, in an inert solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, toluene, benzene, dichloromethane, or a mixed solvent thereof, for 5 minutes to 24 hours, preferably 15 minutes. Or it can be performed by allowing it to act for 3 hours.

The reaction between the Lewis acid complex obtained by the above method and the organometallic compound is carried out in an amount of 1 mol to excess mol, preferably 2 mol to 5 mol, relative to the Lewis acid complex solution of compound (3). Can be carried out by reacting in an inert solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, toluene, benzene, dichloromethane, or a mixed solvent thereof.
The reaction temperature is usually −130 ° C. to the boiling point of the solvent used for the reaction, preferably −100 ° C. to room temperature, and the reaction time is usually 30 minutes to 2 days, preferably 1 hour to 24 hours.

Next, the compound represented by the general formula (II) can be produced by removing the protecting group P of the amino group of the compound (4) and the group represented by -S (= O) -R.
The removal of the protecting group P of the amino group varies depending on the kind of the protecting group and the stability of the target compound (II). For example, the method described in the literature [Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis) Synthesis), T .; W. According to Green (TW Greene, John Wiley & Sons (1981)) or a method analogous thereto, for example, solvolysis using, for example, an acid or a base, ie, for example, 0.01 mole to large excess of acid, Preferably, trifluoroacetic acid, formic acid, hydrochloric acid or the like, or a method in which an equimolar or large excess of base, preferably potassium hydroxide, calcium hydroxide or the like is allowed to act; chemical reduction using a metal hydride complex or palladium-carbon catalyst , Catalytic reduction using Raney nickel catalyst or the like.

  Removal of the group represented by —S (═O) —R is carried out by, for example, hydrogen halide such as hydrogen chloride, hydrogen bromide, hydrogen iodide, water, methanol, ethanol, propanol, dioxane, ethyl acetate, acetonitrile, The reaction can be carried out in a solvent such as dimethylformamide or dimethyl sulfoxide or a mixed solvent thereof. The concentration of the hydrogen halide used for the reaction is usually 1N to 20N, preferably 2N to 10N, and the reaction temperature is usually -20 ° C to the boiling point of the solvent used for the reaction, preferably 0 ° C to 40 ° C. .

Through the above series of steps from the production of compound (1) to the production of compound (II), the configuration on the carbon atom to which R ^2p is bonded is retained. Therefore, when Ar ^1p and Ar ^2p of the desired compound are the same, the corresponding optically active compound (II) can be obtained by using a derivative of an optically active amino acid as the compound represented by the general formula (1) of the raw material. Can be manufactured. In addition, even when Ar ^1p and Ar ^2p of the desired compound are different, the reaction from compound (3) to compound (4) exhibits high diastereoselectivity, and therefore the corresponding optically active compound (II) must be produced. Can do.

  In addition, the compound represented by the general formula (1) and the organometallic compound used for the arylation are commercially available products, or a known method, a method described in Examples / Reference Examples, or a method according to them is appropriately combined as necessary. Can be manufactured.

［式中、Ｌ^２は脱離基を意味し；Ｒ^０はエステル残基を意味し；Ｒ^１ｐ、Ｒ^３ｐ、Ｒ^４ｐ及びＲ^５ｐは前記の意味を有する］ Manufacturing method B

[Wherein L ² represents a leaving group; R ⁰ represents an ester residue; R ^1p , R ^3p , R ^4p and R ^5p have the above-mentioned meanings]

This production method is a method for producing a compound represented by the general formula (III). According to this production method, the compound represented by the general formula (III) is reacted with the compound represented by the general formula (5) and the compound represented by the general formula (6) in the presence of a base, It can manufacture by introduce ^| transducing group represented by ^R1p on nitrogen of the pyridone ring of a compound (5), and hydrolyzing the said ester compound.

As the leaving group represented by L ² , for example, a halogen atom, a sulfonate group and the like are preferable.
The ester residue represented by R ⁰ is not particularly limited as long as it is a group that can be hydrolyzed under conditions that do not adversely affect other functional groups not involved in the reaction when hydrolyzed. A lower alkyl group such as an ethyl group and a tert-butyl group, an allyl group, a benzyl group and the like are preferable. These groups may have an appropriate substituent that does not adversely influence the reaction.
As the base used in the reaction, for example, sodium hydride, butyl lithium, potassium carbonate, cesium fluoride and the like are suitable.

The reaction between the compound represented by the general formula (5) and the compound represented by the general formula (6) is, for example, Tetrahedron Letters, 36, 8917 (1995); Synlett. ), Page 845 (1995).
The reaction is usually carried out using 1 mol to excess mol, preferably 2 mol to 5 mol of compound (6) per mol of compound (5), for example, methanol, ethanol, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide. , N-methylpyrrolidone, or a solvent mixture thereof.

The reaction temperature is usually −78 ° C. to the boiling point of the solvent used for the reaction, preferably 0 ° C. to 100 ° C., and the reaction time is usually 5 minutes to 2 days, preferably 30 minutes to 1 day. If desired, an additive such as lithium bromide can be added to this reaction, and the additive is usually used in an amount of 1 mol to excess mol, preferably 2 mol to 5 mol, relative to 1 mol of compound (5). Is done.
A compound represented by the general formula (III) can be produced by converting the obtained ester form into a carboxylic acid by hydrolysis of an ester well known in the field of organic chemistry.

［式中、Ｒ^１ｐ及びＲ^３ｐは前記の意味を有する］で表される化合物は文献未記載の新規化合物である。 As the compound represented by the general formula (5) or (6), for example, a commercially available product is used, or a known method or a method equivalent thereto, or a method described in the following methods or Examples / Reference Examples, etc. It can manufacture by combining suitably.
Formula (III-1)

[Wherein R ^1p and R ^3p have the above-mentioned meanings] are novel compounds not described in any literature.

Specific examples of the compound represented by the general formula (III-1) include, for example,
1-ethyl-2-pyridone-5-carboxylic acid,
1-difluoromethyl-2-pyridone-5-carboxylic acid,
1-propyl-2-pyridone-5-carboxylic acid,
1-isopropyl-2-pyridone-5-carboxylic acid,
1- (2,2-difluoroethyl) -2-pyridone-5-carboxylic acid,
3-chloro-1-methyl-2-pyridone-5-carboxylic acid,
3-chloro-1-ethyl-2-pyridone-5-carboxylic acid,
1-ethyl-3-fluoro-2-pyridone-5-carboxylic acid,
1,3-dimethyl-2-pyridone-5-carboxylic acid,
1-ethyl-3-methyl-2-pyridone-5-carboxylic acid,
1-ethyl-3-methoxy-2-pyridone-5-carboxylic acid,
1-difluoromethyl-3-methyl-2-pyridone-5-carboxylic acid,
1-difluoromethyl-3-ethyl-2-pyridone-5-carboxylic acid,
1-methoxy-2-pyridone-5-carboxylic acid,
1-ethoxy-2-pyridone-5-carboxylic acid,
1-difluoromethoxy-2-pyridone-5-carboxylic acid,
Examples thereof include 1-difluoromethyl-3-methoxy-2-pyridone-5-carboxylic acid and 1-cyclopropyl-2-pyridone-5-carboxylic acid.

  The usefulness of the compound of the present invention as a pharmaceutical is demonstrated, for example, in the following pharmacological test examples.

Pharmacological test example 1 (NPY binding inhibition test)
The cDNA sequence encoding the human NPY Y5 receptor [see International Patent Application WO96 / 16542] was cloned into the expression vectors pcDNA3, pRc / RSV (Invitrogen) and pCI-neo (Promega). The resulting expression vector was treated with the cationic lipid method [Proceedings of the National of Sciences of the United States of the United States of America. (America), 84, 7413 (1987)] to be used to transfect host cells COS-7, CHO and LM (tk-) (American Type Culture Collection), and NPY Y5 receptor-expressing cells. Got.

Membrane preparations prepared from cells expressing the NPY Y5 receptor were assay buffer (10 mM magnesium chloride, 1 mM phenylmethylsulfonylfluoride) together with the test compound and 20,000 cpm [ ¹²⁵ I] peptide YY (manufactured by NEN). In 25 mM Tris buffer, pH 7.4) containing 0.1% bacitracin and 0.5% bovine serum albumin at 25 ° C. for 2 hours, and then filtered through a glass filter GF / C. After washing with 5 mM Tris buffer containing 0.3% BSA, pH 7.4, the radioactivity on the glass filter was determined. Nonspecific binding was measured in the presence of 1 μM peptide YY, and the 50% inhibitory concentration (IC ₅₀ value) of the test compound for specific peptide YY binding was determined [Endocrinology, 131, 2090 (1992). See year)]. The results are shown in Table 1.

  As described above, the compound of the present invention strongly inhibited the binding of peptide YY (NPY and homologous substances) to the NPY Y5 receptor.

Pharmacological test example 2 (competitive test for eating behavior induced by D-Trp ³⁴ NPY)
Under ketamine / xylazine anesthesia (74 and 11 mg / kg intraperitoneal single dose administration), a chronic guide cannula (26 gauge, 26 gauge, 26 ° C), stereotaxically fixed in the third ventricle of male SD rats (7-8 weeks old, 200-300 g). 11 mm in length) was inserted and fixed with a dental resin. The tip position of the guide cannula was 2.2 mm behind the bregma, midline, and 8 mm deep from the skull surface. After a recovery period of about 1 week, D-Trp ³⁴ NPY (dissolved in artificial cerebrospinal fluid containing NPY and its cognate substance, 1 μg / 0.4 μL / head, 0.05% bovine serum albumin) was placed in the third ventricle. Administered. The test compound was suspended in 0.5% methylcellulose aqueous solution 2 hours prior to ^D-Trp 34 NPY administered orally, it was measured food intake 2 hours after administration ^D-Trp 34 NPY.
As a result, the compound of the present invention significantly suppressed the increase in food intake by D-Trp ³⁴ NPY administered into the third ventricle at 10 mg / kg.

Pharmacological test example 3 (pharmacokinetic study)
Test compounds were orally or intravenously administered to SD male rats (7-10 weeks old, 200-400 g) fasted overnight, and about 100 μL of blood was collected from the tail vein at a predetermined time using a heparinized capillary. The blood was centrifuged (4 ° C., 6000 rpm, 10 minutes) to obtain plasma. Three times the amount of ethanol (including internal standard substance) was added to the plasma, stirred, allowed to stand at −20 ° C. for 20 minutes, and then centrifuged (4 ° C., 10,000 rpm, 10 minutes). The supernatant was analyzed by LC / MS / MS, and the plasma concentration was quantified by the relative calibration curve method.
As a result, for example, the compound of Example 1-7 had a bioavailability of 94% and a plasma half-life of 8.5 hours.

Pharmacological test example 4 (brain / cerebrospinal fluid transfer test)
The test compound was orally or intravenously administered to SD male rats (7-10 weeks old, 200-400 g), and whole blood was collected from the abdominal aorta using a heparinized syringe under ether anesthesia at a predetermined time. Thereafter, the skin of the head was incised, and a dental 30G needle was inserted between the cervical vertebrae and further inserted into the subarachnoid space. 50-100 μL of cerebrospinal fluid was collected in a 1 mL syringe through a tube connected to a dental 30G needle, and then the brain was removed. A blood sample was centrifuged (4 ° C., 6000 rpm, 10 minutes), and 3 times the amount of ethanol (including internal standard substance) was added to the plasma and stirred. The brain sample was homogenized by adding 2 mL of water, and a part of the brain sample was added and stirred with 3 times the amount of ethanol (including internal standard substance). Cerebrospinal fluid was stirred after adding 3 times the amount of ethanol (including internal standard substance). The above sample was allowed to stand at −20 ° C. for 20 minutes, then centrifuged (4 ° C., 12,000 g, 10 minutes), and the supernatant was analyzed by LC / MS / MS. The concentration in the brain and cerebrospinal fluid was quantified.
As a result, for example, the compound of Example 1-7 exhibited a brain concentration of 2.48 nmol / g, cerebrospinal fluid concentration of 0.15 μM, and plasma concentration of 3.17 μM 2 hours after oral administration (10 mg / kg). It was.

  The compound represented by the general formula (I) can be administered orally or parenterally, and formulated into a form suitable for such administration, for example, angina pectoris, acute congestive heart failure, Cardiovascular diseases such as myocardial infarction, hypertension, kidney disease, electrolyte abnormalities, vasospasm, arteriosclerosis, such as bulimia, depression, anxiety, convulsions, epilepsy, dementia, pain, alcoholism, drug withdrawal Withdrawal symptoms, circadian rhythm modulation, schizophrenia, memory disorders, sleep disorders, cognitive disorders such as central nervous system diseases such as obesity, diabetes, hormonal secretion abnormalities, hypercholesterolemia, hyperlipidemia, Metabolic diseases such as gout, fatty liver, such as fertility diseases such as infertility, premature birth, sexual dysfunction, gastrointestinal diseases, respiratory diseases, inflammatory diseases or glaucoma, etc., for example, atherosclerosis, Hypogonadism, Androgenism, polycystic ovary syndrome, hirsutism, gastrointestinal motility disorders, gastroesophageal reflux associated with obesity, obesity hypoventilation syndrome (Pickwick syndrome), sleep apnea syndrome, inflammation, systemic vasculitis, deformity Osteoarthritis, insulin resistance, bronchoconstriction, alcohol preference, metabolic syndrome (syndrome X), Alzheimer's disease, cardiac hypertrophy, left ventricular hypertrophy, hypertriglyceridemia, low HDL cholesterolemia, eg coronary Heart disease (CHD), cerebrovascular disease, stroke, peripheral vascular disease, cardiovascular disease such as sudden death, gallbladder disease, cancer (breast cancer, endometrial cancer, colon cancer), shortness of breath, hyperuricemia, It can be used as a treatment for fertility disorders, back pain or anesthetic hypersensitivity. When the compound of the present invention is used clinically, it can be administered after various preparations by adding pharmaceutically acceptable additives according to the administration form. Various additives that are usually used in the pharmaceutical field can be used as the additive at that time, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, Crystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, Polyvinyl pyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glyco Le, cyclodextrin or hydroxypropyl cyclodextrin and the like.

  Examples of dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories; or liquid preparations such as syrups, elixirs or injections, etc. These can be prepared according to conventional methods in the pharmaceutical field. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. In particular, in the case of injections, they may be dissolved or suspended in physiological saline or glucose solution as necessary, and buffering agents and preservatives may be added.

When the compound of the present invention is used, for example, in a clinical setting, the dose and frequency of administration vary depending on the sex, age, body weight, symptom of the patient, and the type and range of the intended treatment effect, but generally orally. In the case of administration, 0.01 to 100 mg / kg, preferably 0.03 to 1 mg / kg per day for an adult, divided into 1 to several times, and in the case of parenteral administration, 0.001 to 10 mg / kg The dose is preferably 0.001 to 0.1 mg / kg, more preferably 0.01 to 0.1 mg / kg divided into 1 to several times.
Ordinary physicians, veterinarians or clinicians can easily determine and handle the effective amount of drug needed to prevent, inhibit or stop disease progression.
These preparations can contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight of the total drug. These formulations may also contain other therapeutically effective compounds.

  The compounds of the present invention can be used in combination with other agents useful for the treatment of metabolic disorders and / or eating disorders. The individual components of such a combination can be administered in divided or single formulations at different times or simultaneously during the treatment period. Thus, the present invention should be construed to include all simultaneous or timed administrations, and administration in the present invention should be construed as such. The range of combinations of the compound of the present invention with other agents useful for the treatment of metabolic disorders and / or eating disorders includes, in principle, combinations with any pharmaceutical preparation useful for the treatment of metabolic disorders and / or eating disorders. Is done.

  Diabetes is caused by complex factors and is characterized by elevated plasma glucose levels (hyperglycemia) in the fasted state. There are two commonly recognized types of diabetes. Type 1 is insulin-dependent diabetes mellitus (IDDM) due to insufficiency of insulin, which is a hormone that controls the utilization of glucose, and type 2 is non-insulin-dependent diabetes mellitus (NIDDM) that exhibits hyperglycemia, which is hyperinsulinemia. (The insulin concentration in plasma is equivalent or rather high compared to non-diabetic patients). Type 1 diabetes is treated by administration of exogenous insulin, usually by injection. However, type 2 diabetes often exhibits a phenomenon of increased insulin resistance that reduces the action of insulin that promotes glucose and fat metabolism in the main insulin-sensitive tissues, namely muscle, liver and adipose tissue. That is, in non-insulin dependent diabetes mellitus (NIDDM) patients, plasma insulin levels are insufficient to overcome significant insulin resistance, even at elevated levels, resulting in patients becoming hyperglycemic. I fall. Therefore, treatment with exogenous insulin alone is difficult.

Insulin resistance, though not yet fully understood, results in inhibition of glucose uptake in the muscle, decreased glucose oxidation, glycogen accumulation, inhibition of lipolysis in adipose tissue and abnormal glucose production and secretion in the liver . Leaving hyperglycemia in diabetes is associated with high morbidity and mortality. Type 2 diabetes increases the risk of cardiovascular complications such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, kidney disease, neuropathy and retinopathy .
Non-insulin dependent diabetes is also associated with cardiac hypertrophy, particularly left ventricular hypertrophy (Devereux, RB, Circulation, 101: 2271-2276 (2000)). Cardiac hypertrophy, such as left ventricular hypertrophy, is caused by a chronic increase in blood pressure or an increase in circulating blood volume. Left ventricular hypertrophy (LVH) is characterized by a thickening of the left ventricular wall, including an increase in the left ventricular mass, an index expressed by the left ventricular mass per body surface area, that is, a numerical value exceeding 131 g / m ² for males, In the case of females, left ventricular hypertrophy is defined by a numerical value exceeding 100 g / m ² (Savage et al., The Framingham Study, Circulation, 75 (1Pt2): 26-33 (1987)).

Left ventricular hypertrophy has been implicated in increasing the incidence of cardiovascular diseases such as congestive heart failure, ischemic heart failure, circulatory and other deaths, sudden death and stroke. Therefore, regression of left ventricular hypertrophy is associated with a reduction in cardiovascular disease. It has been reported that patients with advanced left ventricular hypertrophy have a higher risk of falling into a serious situation than patients with regressed left ventricular hypertrophy.
Current treatments for cardiac hypertrophy, including non-pharmacological techniques such as weight loss, sodium intake restriction and aerobic exercise, can reduce left ventricular mass (Gali, JK et al., American Journal of Genetic Cardiology, 6: 38-49 (1997)).

  Many patients who have insulin resistance but have not progressed to type 2 diabetes also have a risk of developing syndrome X (metabolic syndrome), also called metabolic syndrome Have been exposed. The period of 5 to 10 years until glucose intolerance is reached is accompanied by many hormonal dysfunctions and promotes visceral fat accumulation, hypertension, insulin resistance and hyperlipidemia (Bjornstop, P., Current Topics in Diabetes Research, eds. Belfore, F., Bergman.RN, and Molinath.GM, Front Diabetes, Basel, Karger, 12: 182-192 (1993)). Metabolic syndrome is also characterized by insulin resistance with visceral fat accumulation, hyperinsulinemia, hyperglycemia, syndrome X, hypoHDLemia and hyperVLDLemia. For this reason, although there are unclear points about the causal relationship between various components of the metabolic syndrome, insulin resistance is thought to play an important role (Requen, GM, et al., N). Eng.J.Med.334.374: 381 (1996); Despres, JP, et al., N.Engl.J.Med.334: 952-957 (1996); Wajchenberg, B.L. , Et al., Diabetes / Metabolism Rev. 10: 19-29 (1994)). Patients with metabolic disorders are at risk of progressing to the above-mentioned cardiovascular complications, regardless of progression to diabetes. An association between left ventricular hypertrophy and metabolic syndrome has also been recently reported (Marcus, R. et al. Circulation, 90: 928-936 (1994)); et al. J Hypertens. 13: 433-38 (1995); Paulisso, G et al. , Am J Hypertens. 10: 1250-1256 (1997)).

Type 2 diabetes includes PPAR agonists such as glitazone, biguanides, protein tyrosine kinase 1B inhibitors, dipeptidyl peptidase IV inhibitors, insulin, insulin mimetics, sulfonylureas, meglitinides, α-glucoside hydrolase inhibitors And a wide variety of therapeutic agents such as α-amylase inhibitors.
Administration of sulfonylureas (eg, tolbutamide and glipizide) or meglitinide that stimulates pancreatic β-cells to secrete more insulin, and injection of insulin when these drugs are ineffective, reduces insulin levels in plasma. A concentration high enough to stimulate even insulin resistant tissue is reached. However, it can cause hypoglycemia, where blood sugar levels reach dangerously low levels, and further promote insulin resistance. Biguanides increase the sensitivity of insulin and work to improve hyperglycemia somewhat. The α-amylase inhibitor inhibits the enzymatic degradation of starch or glycogen into maltose, functions to delay sugar absorption in the intestine, and reduces the amount of available sugars. Metformin monotherapy is often used to treat type 2 diabetic patients with obesity and / or dyslipidemia. If metformin does not show adequate efficacy, treatment is continued with sulfonylureas, thiazolidinediones, insulin or α-glucoside inhibitors. However, the two biguanides, phenformin and metformin, also induce lactic acidosis and nausea / diarrhea, respectively. Alpha-glucosidase inhibitors such as acarbose cause intestinal dysfunction.

  Glitazone, also known as thiazolidinedione (eg, 5-benzylthizolidine-2,4-dione), is a recently reported compound as a new mode of action agent for ameliorating many symptoms of type 2 diabetes It is one of the kind. These drugs are agonists of the peroxisome proliferator activated receptor (PPAR) γ-subtype, which essentially increases insulin sensitivity in muscle, liver and adipose tissue in some animal models of type 2 diabetes Partially or completely improve the elevated sugar concentration in plasma without inducing blood glucose. Newer PPAR agonists that are being developed for the treatment of type 2 diabetes and / or dyslipidemia are agonists of one or more of the PPARα, γ and δ subtypes.

However, treatment of diabetes with PPARγ agonists can lead to cardiac hypertrophy or increased heart weight. A recent label revision of the PPARγ agonist Avandia (maleate of rosiglitazone) suggests that patients may present with fluid retention and mass-related symptoms such as edema and congestive heart failure is doing. With regard to cardiac hypertrophy associated with treatment with PPARγ agonists, it can be said that discontinuing drug administration is a typical treatment method.
Methods for treating type 2 diabetes usually include weight adjustment by exercise and diet. Exercising and reducing dietary calorie dramatically improve the pathology of diabetes, but adherence to this method of treatment due to lifestyle habits and overeating that are rarely exercised, especially overeating foods containing saturated lipids. Is very bad. Moreover, weight loss due to exercise enhancement is difficult to do for many diabetics due to the associated medical condition.

Abnormal glucose homeostasis (homeostasis) is also directly or indirectly associated with obesity, hypertension and lipid metabolism disorders. In addition, obesity promotes insulin resistance, and the resulting insulin resistance promotes weight gain. Therefore, therapeutic management of glucose homeostasis, dyslipidemia, obesity and hypertension is extremely important for clinical management and treatment of diabetes.
Obesity, defined as having a weight 20% higher than ideal weight, is a major health concern in Western societies. It is estimated that one out of every three Americans is overweight or obese. Obesity occurs as a result of the energy balance becoming positive due to the calorie intake exceeding the energy consumption. (B. Staels et al., J. Biol. Chem. 270 (27), 15958 (1995); F. Lonquist et al., Nature Medicine 1 (9), 950 (1995)). Some genetic factors have been identified, although some are still not fully understood regarding the molecular factors that regulate food intake and weight balance.

  Epidemiological studies have revealed that overweight and obesity progression are important factors in shortening lifespan. Obesity causes or exacerbates many health problems independently or in conjunction with other diseases. Medical problems associated with serious and life-threatening obesity are type 2 diabetes, hypertension, high insulin, insulin resistance, dyslipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, kidney cancer and colon Includes cancer, osteoarthritis, respiratory complications, specifically non-obstructive sleep apnea syndrome, gallstones, arteriosclerosis, heart disease, heart rhythm abnormalities and arrhythmias (Kopelman, P.G. , Nature 404, 635-643 (2000)). Obesity is also a metabolic disorder and cardiovascular disorders, such as cardiac hypertrophy, especially left ventricular hypertrophy, youth death and stroke mortality, severe increases in morbidity, myocardial infarction, congestive heart failure, coronary heart disease and sudden death And is related.

Visceral obesity is associated with coronary artery disease at a high risk rate, and is associated with hypertension, diabetes occurring in adulthood, and hyperlipidemia as the three main risk factors. Weight loss dramatically reduces these risks. In addition, built-in obesity is associated with abnormal metabolic syndrome (syndrome X) such as impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia and decreased high density lipoprotein (HDL) and increased very low density lipoprotein (VLDL). It is closely related to other diseases (VLDL) that are related to (Montague et al., Diabetes, 2000 , 49: 883-888).
Treatments are encouraged for patients, such as obesity and obesity-related diabetes, to be reduced by increasing exercise to reduce dietary intake or increase energy expenditure. By maintaining a weight loss of 5-10% of body weight, obesity-related diseases such as diabetes, left ventricular hypertrophy, osteoarthritis, and cardiopulmonary dysfunction can also be improved.

  Orlistat (Davidson, MH et al. (1999) JAMA 281: 235-42), dexfenfluramine (Guy Grand, B. et al. (1989) Lancet) as weight loss drugs used in the treatment of obesity 2: 1142-5), sibutramine (Bray, GA et al. (1999) Obes. Res. &: 189-98) and phentermine (Douglas, A. et al. (1983) Int. J. Obes. 7: 591-5). However, these anti-obesity drugs have side effects and their use is limited. Dexfenfluramine was withdrawn from the market because of the suspected side effect of valvular heart disease. Orlistat is restricted in its administration due to gastrointestinal side effects. Sibutramine has been withdrawn from the Italian market due to reports of death from side effects on the heart, and its administration is restricted.

  The term “diabetes” as used herein is insulin-dependent diabetes (ie, also known as IDDM, type 1 diabetes) and non-insulin-dependent diabetes (ie, also known as NIDDM, type 2 diabetes). Includes both. The compositions of the present invention are useful for the treatment of both Type 1 and Type 2 diabetes. The composition is particularly useful for the treatment of type 2 diabetes. The compositions of the present invention are also particularly useful for the treatment and / or prevention of gestational diabetes.

The compound or combination composition of the present invention is effective for the treatment of diabetes. One outcome of treatment is to reduce the elevated glucose concentration. Another outcome of treatment is to reduce elevated insulin levels. Another outcome of treatment is to reduce elevated blood triglyceride levels. Another outcome of treatment is to reduce elevated LDL cholesterol levels. Another outcome of treatment is that low levels of HDL cholesterol can be raised. Another outcome of treatment is to increase insulin sensitivity. Another outcome of treatment is to improve impaired glucose tolerance. Another outcome of treatment is that insulin resistance can be reduced.
The compound or combination composition of the present invention is effective in preventing diabetes.

  As used herein, the term “hypertension” is not known for its cause, or it is known for essential hypertension and its cause that result from one or more causes, such as changes in both the heart and blood vessels. Including secondary hypertension. Causes of secondary hypertension include, but are not limited to obesity, and include causes caused by certain diseases such as kidney disease, hormonal ataxia and oral contraceptives, corticosteroids, and cyclosporine. The term “hypertension” includes hypertension in which both systolic blood pressure and diastolic blood pressure are increased, and the case where diastolic blood pressure is less than 90 mmHg and systolic blood pressure is 140 mmHg or more. One outcome of treatment is to reduce elevated blood pressure.

  A lipid metabolism disorder or lipid metabolism disorder is one or more lipids (eg cholesterol and triglycerides) and / or apolipoproteins (eg apolipoproteins A, B, C and E) and / or lipoproteins (eg lipids into the blood). Includes various conditions characterized by abnormal concentrations of circulating lipids and apolipoproteins, eg, polymer complexes such as LDL, VLDL and IDL. Hyperlipidemia is accompanied by abnormal elevation of lipids, LDL and VLDL cholesterol and / or triglycerides.

  The term “metabolic syndrome”, also known as Syndrome X, is defined by Third Report of the National Cholesterol Education Program Expert Panel on Detection (Evaluation and Treatment of High Blood TP). ES Ford et al., JAMA, vol. 287 (3), Jan. 16, 2002, pp 356-359). For example, a person is defined as having a metabolic disorder syndrome when having three or more symptoms of visceral obesity, hypertriglyceridemia, low HDL cholesterol, hypertension and fasting hyperglycemia. These criteria are defined in ATP-III.

As used herein, “left ventricular hypertrophy” (LVH) is the left ventricular mass index (LVMI = left ventricular mass (g) divided by body surface area (m ² )) and relative wall thickness (RWT = Includes 3 types of left ventricular hypertrophy defined based on 2 × posterior wall thickness / left ventricular diameter at end of diastole). The three types are typically centripetal LVH where the left ventricular mass index is 144 and the relative wall thickness is 0.52, and the left ventricular mass index is 136 and the relative wall thickness is 0.38. This refers to a modified afferent left ventricle as a typical example where the centrifugal LVH and LVMI are 93 and the relative wall thickness is 0.38. A typical value for normal LVMI is 85 and a typical value for normal RWT is about 0.36. The risk of progression to cardiovascular disease in patients with modified afferent left ventricle (LV) is intermediate between those with normal left ventricular structure and those with left ventricular hypertrophy.

One outcome of treating diabetes with minimal hypertrophy or left ventricular hypertrophy is the ability to reduce ventricular mass. Another outcome of diabetes treatment performed with minimal cardiac hypertrophy or left ventricular hypertrophy is that the rate of increase in ventricular mass can be reduced. Another outcome of diabetes treatment performed with minimal cardiac hypertrophy or left ventricular hypertrophy is the ability to reduce left ventricular wall thickness. Another outcome of treating diabetes with minimal cardiac hypertrophy or left ventricular hypertrophy is that it can reduce the rate of increase in left ventricular wall thickness.
As used herein, the term “obesity” refers to a condition in which there is an excess of body fat. The definition of obesity is based on body mass index (BMI) (kg / m ² ) calculated by dividing body weight by the square of height. In Europe and the United States, obesity refers to the health status of a healthy person having a BMI of 30 kg / m ² or more or a person having at least one complication of BMI of 27 kg / m ² or more. Healthy person BMI of less than 25 kg / ^{m 2} or more 30kg / ^{m 2} and subject at risk of obesity, or a BMI of a person having at least one complication of less than 25 kg / ^{m 2} or more 27 kg / ^{m 2} Say that.

In Asians, the risk associated with obesity arises from a lower BMI than in Westerners. In Asian countries, including Japan, obesity is at least one obesity-induced or obese-related complication that requires or can be improved by weight loss, 25 kg / m ² or more This refers to the health status of persons with BMI. In Asian countries, those who are at risk of becoming obese are those who have a BMI of 23 kg / m ² or more and less than 25 kg / m ² .
As used herein, the term “obesity” encompasses all obesity as defined above.

  Comorbidities induced by or associated with obesity include, but are not limited to, diabetes, impaired glucose tolerance, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricemia, ventilation, coronary artery disease, Myocardial infarction, angina pectoris, sleep apnea syndrome, pickwick syndrome, fatty liver, cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disease, osteoarthritis, low back pain, menstrual abnormalities and infertility Infections are included. In particular, comorbidities include hypertension, hyperlipidemia, lipid abnormalities, impaired glucose tolerance, cardiovascular diseases, sleep apnea syndrome, diabetes and other obesity related conditions.

  Treatment of obesity and obesity related diseases means administering a compound or mixture composition of the present invention to reduce or maintain the weight of obese patients. One outcome of treatment is that the weight of an obese patient can begin to decrease relative to the weight of the patient prior to administration of the compound or mixed composition of the invention. The outcome of other treatments is the ability to maintain a reduced weight as a result of diet, exercise or drug therapy. The outcome of other treatments is that it can reduce the onset and / or severity of obesity-related diseases. The outcome of treatment is a reduction in food intake and / or caloric intake. That is, a reduction in the total amount of food intake or a reduction in the intake of special food components such as carbohydrates or fats and / or inhibition of nutrient absorption and / or reduction in metabolic rate. The outcome of treatment is a change in metabolic rate. That is, metabolic rate changes such as preventing metabolic rate reduction or increasing metabolic rate and / or minimizing metabolic resistance, usually resulting from weight loss.

  Prevention of obesity and obesity-related diseases means administering a compound or mixed composition of the invention to reduce or maintain the weight of a person at risk of developing obesity. One outcome of prevention is that the weight of a person at risk of developing obesity can begin to decrease compared to the weight of the patient prior to administration of the compound or mixed composition of the invention. Another preventive outcome is the ability to maintain a reduced weight as a result of diet, exercise or drug therapy. Another outcome of prevention is that the onset of obesity can be prevented if treatment is initiated before a person at risk of becoming obese presents with obesity. Another preventive outcome is that the onset and / or severity of obesity-related diseases can be reduced if treatment is initiated before a person at risk of becoming obese exhibits obesity. Furthermore, if obesity is treated, the onset and progression of obesity-related diseases can be prevented or the severity can be reduced. Such obesity-related diseases include arteriosclerosis, type 2 diabetes, polycystic ovary syndrome, cardiovascular disease, osteoarthritis, skin disease, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia And cholelithiasis, but are not limited thereto.

  “Atherosclerosis” as used herein includes vascular diseases and conditions that are identified and understood by physicians' experience gained through the administration of drugs in the field. Atherosclerosis, coronary heart disease (also known as coronary artery disease or ischemic heart failure), cerebrovascular disease and peripheral vasodilatory disease are all clinical symptoms of atherosclerosis and hence the term Included in “atherosclerosis” and “atherosclerosis”. The onset of coronary heart disease, cerebrovascular disease or intermittent claudication or potentially presenting a combination composition of a therapeutically effective amount of an anti-diabetic agent and a therapeutically effective amount of an anti-obesity agent or It can be administered to prevent or reduce the risk of recurrence. Coronary heart disease events include CHD death, myocardial infarction (eg heart attack) and revascularization procedures. Cerebrovascular disease events are meant to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic stroke. Intermittent claudication is a clinical symptom of peripheral vascular disease. As used herein, the term “atherosclerotic disease event” is meant to include coronary heart disease events, cerebrovascular disease events, and intermittent claudication. A person who has previously suffered from one or more non-fatal atherosclerotic events means that he has the potential for recurrence of that event.

  Circadian rhythm affects physiological parameters. Physiological parameters include rest and activity, sleep and wake cycles, body temperature, hormone concentration rhythm, changes in general physiological functions, and the like. When these parameters shift in synchronicity with daily time courses, circadian rhythms that affect physiological function, ability to perform various tasks and emotional health are modulated. The present invention is useful for the prevention or treatment of not only symptoms related to circadian rhythm, but also mental and physical disorders related to, for example, travel across time zones and shift work.

In another embodiment, the present invention provides for the prevention or prevention of mammalian circadian rhythm disorders, including mammalian syndromes, shift-based disorders, sleep phase regression syndrome, sleep phase progression syndrome and non-24 hour sleep-wake disorder. A method of treatment is provided.
In another embodiment, the present invention provides for re-synchronization (meaning recovery to a normal circadian rhythm, implying synchronization to an environmental light-dark cycle) of a patient having an abnormality in the sleep-wake cycle. Provide a way to shorten.
In another embodiment, the present invention provides a method for mitigating a traveler's jet-lag. The purpose of this aspect is to assist in physiologically adapting the body to changes in sleep and eating patterns when crossing time zones many times.
A preferred embodiment is to provide a method for resetting a patient's biological clock to the patient's current activity / sleep cycle. For example, it is effective when a shift worker changes working hours from night to day or from day to night.

  The present invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and increasing sleep persistence. Furthermore, the present invention provides methods for the prevention and treatment of sleep disorders and sleep disturbances. The present invention further provides a pharmaceutical composition for enhancing or improving sleep quality and for increasing sleep efficiency and sleep sustainability. The present invention may result from psychophysiological causes as a result of psychopathological disorders (especially related to anxiety), drug use and alcohol overdose (especially during withdrawal and abstinence), early childhood onset DIMS, nocturnal myoclonus It is useful for the treatment of sleep disorders, including sleep onset disorders and persistent sleep disorders ("DIMS") that result from leg resting and nonspecific REM (eye movement) disorders found in older people.

  The following outcomes that occur on the patient's body brought about by the present invention may be related to improved sleep quality. Increase in value obtained by dividing patient's sleep time by time to try to sleep, sleep latency (time to fall asleep), decrease in wakefulness during sleep, completely after first sleep Decreased time to wake up, increased total sleep time, increased amount and rate of REM sleep, increased duration and occurrence of REM sleep, decreased REM sleep fragmentation, slow wave sleep (eg, stage 3 or 4) An increase in the amount and ratio, an increase in the amount and ratio of stage 2 sleep, particularly a decrease in the number of wakefulnesses in the early morning, an improvement in consciousness / wakefulness during the daytime, and an increase in sleep sustainability. Secondary outcomes provided by the present invention include enhanced cognitive function and increased memory retention. “Methods to enhance sleep quality” include, but are not limited to, outcomes related to enhanced sleep quality as described above. means.

  The invention further includes insomnia, hypersomnia, sleep apnea syndrome, narcolepsy, nighttime myoclonus, REM sleep disturbance, jet-lag, shift worker sleep disturbance, dysomnia, night phobias, night eating and drinking syndrome, Depression associated with sleep (abnormal sleep behavior), emotional / mood disorders, sleeplessness associated with dysfunction, sleepiness associated with dysfunction, sleep problems associated with sleep disorders associated with aging Useful for the prevention and treatment of sleep disorders and sleep disturbances. Sleep disturbances and sleep disturbances are generally difficult to initiate or sustain sleep, or it is difficult to obtain a restful or sufficient sleep.

In addition, certain drugs may cause a decrease in REM sleep as a side effect, and the present invention can also be used to correct these types of sleep disorders. The present invention may also be useful in the treatment of non-restorative sleep and fibromyalgia with muscle pain or apnea sleep associated with breathing disorders during sleep. It is apparent that the present invention is not limited to sleep disturbances and sleep disturbances, but can be applied to a wide range of pathological conditions caused by a decline in sleep quality.
The combination of the compound of the present invention and the composition thereof or other agents using them is useful for the treatment and prevention of these pathological conditions.

  In the present invention, the target mammal is preferably a human. The present invention is applicable to young and old men and women, but may have greater applicability to older men and women. Furthermore, while the present invention is applied to improve the quality of sleep of healthy people, it can be particularly effective in improving the quality of sleep of people suffering from sleep disorders or sleep disturbances.

The composition according to the present invention is also used for the treatment, prevention or management of hypertension, hypertension related to obesity, hypertension related disorders, cardiac hypertrophy, left ventricular hypertrophy, and disorders such as metabolic disorders, obesity and obesity related disorders. It can be used in combination with other beneficial drugs. Such other drugs can be administered at the same time or sequentially in accordance with conventional methods and in the amounts and routes that are generally used. Where the composition of the invention is administered concurrently with one or more other drugs, it is preferably a pharmaceutical unit dosage form comprising such other drugs and the composition of the invention. However, combination therapy also includes therapies in which a combination drug of the drug of the present invention and one or more other drugs is administered based on various overlapping regimens. Also, when combined with one or more other active ingredients, it is anticipated that the composition according to the invention and the other active ingredients may require a lower dosage compared to when they are taken alone. Is done. Accordingly, the drug compositions of the present invention include compositions that contain one or more other active ingredients in addition to the compositions of the present invention.
Examples of other active ingredients that can be taken in combination with the composition according to the invention and as separate or identical drug compositions include, but are not limited to:

(A) (i) Glitazones (for example, ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555), pioglitazone, rosiglitazone, troglitazone, BRL49653, CLX-09211, 5-BTZD, etc.), and GW-0207, LG (Iii) biguanides such as buformin, metformin, phenformin, (iii) protein tyrosine kinase-1B (PTP-1B) inhibitors, (iv) ) Sulfonyuria such as acetohexamide, chlorpropamide, diabinase, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, glyquidone, glicoramide, tolazamide, and tolbutamide (Vi) meglitinides such as repaglinide and nateglinide, (vi) acarbose, adiposine, camiglybose, emiglitate, migitolitol, voglibose, pradimicin-Q, salvostatin, CKD-711, MDL-25, 637, MDL-73, Α-glucoside hydrolase inhibitors such as 945 and MOR14, (vii) α-amylase inhibitors such as tendamistat, trestatin and Al-3688, (viii) linoglylide, and insulin such as A-4166 Secretion promoters, (ix) fatty acid oxidation inhibitors such as chromoxyl and etomoxil, (x) A2 antagonists such as midaglyzol, isagridol, deliglidol, idazoxan, aeroxan and fluparoxane, (xi) biota, L -100, Novarapide, Insulin Detemir, Insulin Lispro, Insulin Glaldine, Insulin Zinc Suspension (Lente and Ultralente), Lys-Pro Insulin, GLP-1 (73-7) (Insulin Tropine), and GLP-1 (7 -36) -NH ₂₎ such as insulin or insulin analogues drugs such, (xii) JT-501, and farnesyl Gurita Saar (GW-2570 / GI-262579 ) non-thiazolidinediones such as such, (xiii) MK-0767 PPARα / γ dual agonists such as CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-79449, LR-90 and SB219994, (xiv) other insulin sensitizing drugs And (xv) a VPAC2 receptor agonist Antidiabetic drugs, like

  (B) (i) bile acid absorption inhibitors such as cholestyramine, colesevelem, colestipol, dialkylaminoalkyl derivatives of cross-linked dextran, Colestid®, LoChholest®, and Questtran®, ii) atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin and HMG-CoA reductase inhibitors such as ZD-4522, (iii) HMG-CoA synthase inhibitors, (iv) stanol esters , Β-sitosterol, sterol glycosides such as ticueside, and cholesterol absorption inhibitors such as azetidinones such as ezetimibe, (v) abashimibe, eflucimibe, KY505, S Acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitors such as P797, (vi) CETP inhibitors such as JTT705, torcetrapib, CP532,632, BAY63-2149, SC591, SC795, etc. (vii) squalene synthase Inhibitors, (viii) antioxidants such as probucol, (ix) beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, gemcabene, and gemfibrozil, GW7647 (X) GW4064, SR103912, BM170744, LY518874, and other fibric acid derivatives such as Atromid®, Loopid®, and Tricor®. FXR receptor modulators such as (xi) GW3965, T901137, and LXR receptors such as XTCO179628, (xii) lipoprotein synthesis inhibitors such as niacin, (xiii) renin-angiotensin system inhibitors, (xiv) PPARδ moieties Agonists, (xv) BARI acid resorption inhibitors such as BARI1453, SC435, PHA384640, S8921, AZD7706, (xvi) PPARδ agonists such as GW501516 and GW590735, (xvii) triglyceride synthesis inhibitors, (xviii) Microsomal triglyceride transport (MTTP) inhibitors, such as imputapide, LAB687, and CP346086, (xix) transcription modulators, (xx) squalene epoxidase inhibition Lipid reducing agents such as (xxi) low density lipoprotein (LDL) receptor inducers, (xxii) platelet aggregation inhibitors, (xxiii) 5-LO or FLAP inhibitors, and (xxiv) niacin receptor agonists, as well as

  (C) (i) diuretics such as chlorthalidone, chlorthiazide, dichlorophenamide, hydroflumethiazide, indapamide, and thiazides including hydrochlorothiazide, loop diuretics such as bumetanide, ethacrynic acid, furosemide, and tolsemide, amiloride , And aldosterone antagonists such as spironolactone and epilenone, (ii) acebutolol, atenolol, betataxol, bevantrol, bisoprolol, bopindolol, carteolol, carvedilol, ceriprolol, esmolol, indenolol , Metaprolol, nadolol, nebivolol, penbutolol, pindolol, propanolol, sotalol, tertatrol, chilisolol, and timo (Iii) amlodipine, alanidipine, azelnidipine, valnidipine, benidipine, bepridil, cinaldipine, clevidipine, diltiazem, efonidipine, felodipine, galopamil, isradipine, rasidipine, remildipine, lercandipine, Calcium channel blockers such as nilvadipine, nimodipine, nisoldipine, nitrendipine, manidipine, pranidipine, and verapamil, (iv) benazepril, captopril, cilazapril, delapril, enalapril, focinopril, imidapril, rosinopril, mopripr Perindropril, Quanipril, Spirapril, Te Angiotensin converting enzyme (ACE) inhibitors such as nocapril, trandolapril, and zofenopril; (v) neutral endopeptidase inhibitors such as omapatril, cadoxatril and ecadotolyl, fostolyl, sampatrilla, AVE7688, ER4030, (Vi) endothelin antagonists such as tezosentan, A308165, and YM62899, (vii) vasodilators such as hydralazine, clonidine, minoxidil, nicotinyl alcohol, etc. (viii) candesartan, eprosartan, irbesartan, losartan, pratosartan, Angiotensin II receptor antagonists such as tasosartan, telmisartan, valsartan, and EXP-3137, FI6828K, and RNH6270, x) α / β-adrenergic blockers such as nipradilol, arotinolol and amosulalol, (x) α1 blockers such as terazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin, naphthopidyl, indolamine, WHIP164, and XEN010, xi) alpha-2 agonists such as lofexidine, thiamenidine, moxonidine, rilmenidine, and guanobenz, (xii) antihypertensive drugs such as aldosterone inhibitors, and

(D) (i) 5HT (serotonin) transporter inhibitors such as paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine; (ii) NE (norepinephrine) transporters such as GW320659, despyramine, talspram, and nomifensine. Inhibitors, (iii) rimonabant (Sanofisyn Labs), SR-147778 (Sanofisyn Labs), BAY65-2520 (Bayer), and SLV319 (Solvay); 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941 and 6,028,084, and WO96 / 33159, WO98 / 33765, WO98 / 43636, WO98 / 43635, WO01 / 09120, WO01 / 96330, WO98 / 31227, WO98 / 41519, WO98 / 37061, WO00 / 10967, WO00 / 10968, WO97 / 29079, WO99 / 02499 WO 01/58869, WO 02/076949, WO 01/64632, WO 01/64633, WO 03/006007, and WO 03/007887, and EPO application no. CB-1 (cannabininoindo-1 receptor) antagonists / reversers, such as the compounds disclosed in EP-658546, (iv) ghrelin antagonists, such as the drugs disclosed in WO01 / 87335, and WO02 / 08250, (V) Thioperamide, 3- (1H-imidazol-4-yl) propyl N- (4-pentenyl) carbamate, clobenepropit, iodophenpropit, imoproxyphan, GT2394 (Gliatec), and A331440, And the drugs disclosed in WO 02/15905, and O- [3- (1H-imidazol-4-yl) propanol] carbamates (Kiec-Konowicz, K. et al., Pharmazie, 55: 349-55 (2000)). ), Piperidine-containing hysteresis H3-receptor antagonist (Lazewska, D. et al., Pharmazie, 56: 927-32 (2001)), benzophenone derivatives and related compounds (Sasese, A. et al., Arch. Pharm. (Weinheim) 334: 45. -52 (2001)), substituted N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55: 83-6 (2000)), and proxyphane derivatives (Sasse, A. et al., J. Med). Chem., 43: 3335-43 (2000)), (vi) T-226296 (Takeda), SNP-7941 (Synaptic), and WO01 / 82924, WO01 / 87834, WO02 / 51809, WO02 / 06245, WO02 / 076929, WO02 / 076947, WO02 / 04433, WO02 / 51809, WO02 / 083134, WO02 / 09799, WO03 / 004027, and melanin-concentrations such as those disclosed in Japanese Patent Application No. JP132226269 Hormone 1 receptor (MCH1R) antagonist, (vii) MCH2R (melanin-concentrating hormone 2R) agonist / antagonist, (viii) BIBP3226, 2- [1- (5-chloro-3-isopropyloxycarbonylaminophenyl) ethylamino ] -6- [2- (5-Ethyl-4-methyl-1,3-thiazol-2-yl) ethyl] -4-morpholinopyridine, BIBO3304, LY-357897, CP-671906, and GI- 264879A, and U.S. Pat. 6,001,836, and NPY1 (neuropeptide YY1) antagonists such as the drugs disclosed in WO96 / 14307, WO01 / 23387, WO99 / 51600, WO01 / 85690, WO01 / 85098, WO01 / 85173, and WO01 / 89528 (Ix) L-152,804, GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR235, 208, FR-226928, FR240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-3778 LY366377, PD-160170, SR-120562A, SR-120919A, JCF-104, and H409 / 22, and U.S. Pat. 6,140,354, 6,191,160, 6,258,837, 6,313,298, 6,337,332, 6,329,395, and 6,340,683, U.S. Pat. 6,326,375, 6,329,395, 6,337,332, 6,335,345, European patent no. EP-01010691, EP-010449970, and PCT International Patent Application Publication No. WO97 / 19682, WO97 / 20820, WO97 / 20821, WO97 / 20822, WO97 / 20823, WO98 / 27063, WO00 / 107409, WO00 / 185714, WO00 / 185730, WO00 / 64880, WO00 / 68197, WO00 / 69849, WO01 / 09120, WO01 / 14376, WO01 / 85714, WO01 / 85730, WO01 / 07409, WO01 / 02379, WO01 / 23388, WO01 / 33389, WO01 / 44201, WO01 / 62737, WO01 / 62738, WO01 / 09120, WO02 / 20488, WO02 / 22592, WO02 / 48152, WO02 / 49648 and WO02 / 094789, and Norman e t al. , J .; Med. Chem. 43: 4288-4312 (2000), such as NPY5 (neuropeptide YY5) antagonists, (x) recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen). Leptins, (xi) U.S. Pat. 5,552,524, 5,552,523, 5,552,522, 5,521,283, and PCT international patent no. Leptin derivatives such as WO96 / 23513, WO96 / 23514, WO96 / 23515, WO96 / 23516, WO96 / 23517, WO96 / 23518, WO96 / 23519, and WO96 / 23520, (xii) nalmefene (Revex®), 3 Methoxynaltrexone, naloxone, and naltrexone, and opioid antagonists such as the compounds disclosed in WO 00/21509, (xiii) SB-334867-A, and WO 01/96302, WO 01/68609, WO 02/51232, WO 02/51838, And orexin antagonists such as the compounds disclosed in WO 03/023561, (xiv) BRS3 (bombesin receptor subtype 3) agonist, (xv) AR-R15849, GI CCK-A (cholecystokinin-A) antagonists such as compounds disclosed in 817171, JMV-180, A-71378, A-71623, and SR146131, and US Pat. No. 5,739,106, (xvi) GI- 181771 (Glaxo-SmithKline), SR146131 (Sanofisynthelab), butabinzide, and CNTF (ciliary neurotrophic factor) such as PD170292, PD149164 (Pfizer), (xvii) axocaine (Regeneron), and WO94 / CNTF derivatives such as the compounds disclosed in 09134, WO 98/22128, and WO 99/43813, (xviii) NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429 and L- 63,255, and US Patent No. No. 6,358,951, US patent application no. GHS (growth hormone secretagogue receptor) agonists such as those compounds disclosed in 2002/049196 and 2002/022637, and WO01 / 56592, and WO02 / 32888, (xix) BVT933, DPCA37215, IK264, PNU22394, WAY161503, R-1065, and YM348, and U.S. Pat. 3,914,250, and 5HT2c (serotonin receptor, such as the compounds disclosed in WO02 / 36596, WO02 / 48124, WO02 / 10169, WO01 / 66548, WO02 / 44152, WO02 / 51844, WO02 / 40456, and WO02 / 40457. 2c) agonists, (xx) Mc3r (melanocortin 3 receptor) agonists, (xxi) CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), and WO99 / 64679, WO00 / 74679, WO01 / 991752 , WO01 / 74844, WO01 / 70708, WO01 / 70337, WO01 / 91752, WO02 / 059095, WO02 / 059107, WO02 / 059108, WO0 Mc4r (Melanocortin 4 Receptor) agonists, (xxii) sibutramine (Meridia® / Reductil®) and salts thereof, and US Pat. 4,746,680, 4,806,570, and 5,436,272, and U.S. Pat. 2002/0006964, and WO 01/27068, and monoamine reuptake inhibitors such as the compounds disclosed in WO 01/62341, (xxiii) dexfenfluramine, fluoxetine, and US Pat. Serotonin reuptake inhibitors such as the compounds disclosed in US 6,365,633 and WO 01/27060 and WO 01/162341, (xxiv) GLP-1 (glucagon-like peptide 1) agonist, (xxv) topiramate (Topimax ( (Registered trademark)), (xxvi) phytofarm compound 57 (CP644, 673), (xxvii) ACC2 (acetyl-CoA carboxylase-2) inhibitor, (xxviii) AD9677 / TAK677 (Dainippon / Takeda), CL-316, 243, SB418790, BRL-37344, L-79568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW427353, Trecadrine, Geneca D7114, and SR59119A, and US patent applications o. (Xxix) DGAT1 (diacylglycerol acyltransferase 1), a β3 (β-adrenergic receptor 3) agonist such as the compounds disclosed in US Pat. No. 5,705,515, US Pat. No. 5,451,677, and WO 01/74782, WO 02/32897. ) Inhibitors, (xxx) DGAT2 (diacylglycerol acyltransferase 2) inhibitors, (xxxi) FAS (fatty acid synthase) inhibitors such as cerulenin and C75, (xxxii) theophylline, pentoxifylline, zaprinast, silidenafil, amrinone, milrinone PDE (phosphodiesterase) inhibitors such as, cilostamide, rolipram, and silomilast, (xxxiii) KB-2611 (KaroBioBMS), and WO02 / 15845 Thyroid hormone beta agonists such as the compounds disclosed in allowed application number JP20000256190, (xxxiv) phytanic acid, 4-[(E) -2- (5,6,7,8-tetrahydro-5,5,8,8) -Tetramethyl-2-naphthalenyl) -1-propenyl] benzoic acid (TTNPB), and retinoic acid, and UCP-1 (uncoupled protein 1), such as the compounds disclosed in WO 99/00123, 2 or 3 active substances, (Xxxv) del Mar-Grasa, M .; et al. , Obesity Research, 9: 202-9 (2001), acyl-estrogens such as oleoyl-estrone, (xxxvi) glucocorticoid antagonists, (xxxvii) BVT3498, BVT2733, and WO01 / 90091,
11βHSD-1 (11-β hydroxysteroid dehydrogenase type 1) inhibitors such as the compounds disclosed in WO01 / 90090, WO01 / 90092, (xxxviii) SCD-1 (stearoyl-CoA desaturase-1) inhibitors, (Xxxix) isoleucine thiazolidide, valine pyrrolizide, NVP-DPP728, LAF237, P93 / 01, TSL225, TMC-2A / 2B / 2C, FE999011, P9310 / K364, VIP01177, SDZ274-444, and WO03 / 004498, WO03 / 004496, WO03 / 004496 EP1258476, WO02 / 083128, WO02 / 062764, WO03 / 000250, WO03 / 002530, WO03 / 002531, WO03 / 002553, W Dipeptidyl peptidase IV (DP-IV) inhibitors, such as the compounds disclosed in 03/002593, WO 03/000180, and WO 03/000181, (xxxx) tetrahydrolipstatin (Orlistat / Xenical®), Triton WR1339, RHC80267, Lipstatin, Theasaponin, and Diethylumbelliferyl Phosphate, FL-386, WAY-121898, Bay-N-3176, Varilactone, Estelacin, Evelactone A, Evelactone B, and RHC80267, and WO01 / 77094, and the United States Patent No. 4,598,089, 4,452,813, 5,512,565, 5,391,571, 5,602,151, 4,405,644, 4,189,438, and 4,242,453 A lipase inhibitor, such as: (xxxxi) a fatty acid transport inhibitor, (xxxii) a dicarboxylate transport inhibitor, (xxxiii) a glucose transport inhibitor, (xxxiv) a phosphate transport inhibitor, (xxxv) melanotan II Or melanocortin agonists, such as those compounds described in WO 99/64002 and WO 00/746799, (xxxvi) melanin-concentrating hormone antagonists, (xxxvii) galanin antagonists, (xxxviii) CCK agonists, (xxxix) corticotropin-release Hormone agonists, and (xxx x) phosphodiesterase -3B (PDE3B) inhibitors such as anti-obesity agents such as.

  Such combinations include combinations of the composition of the present invention not only with one other active substance, but also with two or more other active substances. There are many examples of combinations of the compositions of the present invention with one, two or more activators selected from lipid-reducing drugs and antihypertensive drugs. A combination of the composition of the present invention with one, two or more activators selected from lipid-reducing drugs and anti-diabetic drugs is beneficial for the treatment, management or prevention of metabolic disorders. In particular, in addition to an antidiabetic agent and / or a lipid-reducing agent, a composition comprising an antiobesity agent and an antihypertensive agent exhibits a synergistic effect in the treatment, management or prevention of metabolic disorders.

  The compound of the present invention has NPY antagonism, particularly NPY Y5 receptor antagonism, and is excellent in pharmacokinetics such as intracerebral transfer or cerebrospinal fluid transfer, and has high safety. Various diseases involved, such as angina pectoris, acute / congestive heart failure, myocardial infarction, hypertension, kidney disease, electrolyte abnormalities, vasospasm, arteriosclerosis, etc., such as bulimia, depression, anxiety Central nervous system diseases such as obesity, convulsions, epilepsy, dementia, pain, alcoholism, withdrawal symptoms associated with drug withdrawal, modulation of circadian rhythm, schizophrenia, memory impairment, sleep disorder, cognitive impairment Metabolic disorders such as diabetes, hormonal secretion abnormalities, hypercholesterolemia, hyperlipidemia, gout, fatty liver, reproductive diseases such as infertility, premature birth, sexual dysfunction, gastrointestinal diseases, respiratory diseases , Inflammatory disease or green Disorders such as atherosclerosis, hypogonadism, hyperandrogenism, polycystic ovary syndrome, hirsutism, gastrointestinal motility disorders, gastroesophageal reflux related to obesity, obesity hypoventilation syndrome (Pickwick) Syndrome), sleep apnea syndrome, inflammation, systemic vasculitis, osteoarthritis, insulin resistance, bronchoconstriction, alcohol preference, metabolic syndrome (syndrome X), Alzheimer's disease, cardiac hypertrophy, Left ventricular hypertrophy, hypertriglyceridemia, low HDL cholesterolemia, eg coronary heart disease (CHD), cerebrovascular disease, stroke, peripheral vascular disease, sudden death and other cardiovascular diseases, gallbladder disease, cancer ( Breast cancer, endometrial cancer, colon cancer), shortness of breath, hyperuricemia, fertility disorder, low back pain or anesthetic hypersensitivity That.

  EXAMPLES The present invention will be described more specifically with reference to examples and reference examples, but the present invention is not limited to these examples.

  In the structural formula, a compound marked with “*” means that the configuration on the asymmetric carbon atom marked with the symbol is substantially a single compound.

Example 1
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl-2-pyridone manufacturing (1) N - [(1S , 2S) -2- amino-2- (4-fluorophenyl) -2- (6-fluoro-3-pyridyl) -1-methylethyl] -1-methyl-2 -Preparation of pyridone-5-carboxamide (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine (50 mg) and 1-methyl-2 -After pyridone-5-carboxylic acid (66 mg) was dissolved in 5 mL of pyridine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (95 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1) to obtain the target compound (100 mg).
(2) 5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl- Preparation of 2-pyridone N-[(1S, 2S) -2-amino-2- (4-fluorophenyl) -2- (6-fluoro-3-pyridyl) -1-methylethyl] -1-methyl-2 -Pyridone-5-carboxamide (100 mg) was dissolved in 2 mL of toluene, ytterbium triflate (15 mg) was added, and the tube was heated at 150 ° C for 6 hours in a sealed tube. Saturated sodium hydrogen carbonate solution was added to the reaction solution, and extracted twice with chloroform. The organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to give the titled compound (64 mg) as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.83 (3H, d, J = 6.5 Hz), 3.60 (3H, s), 4.74 (1H, q, J = 6.5 Hz) 6.57 (1H, d, J = 9.6 Hz), 7.00-7.15 (3H, m), 7.20-7.30 (2H, m), 7.89 (1H, s) , 7.90-8.05 (2H, m), 8.26 (2H, dd, J = 2.4 Hz, 8.0 Hz)

Example 1-1
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Preparation of pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.83 (1H, d, J = 6.5 Hz), 4.76 (1H, q, J = 6.5 Hz), 6.62 (1H, d, J = 9.9 Hz), 7.00-7.15 (3H, m), 7.20-7.30 (2H, m), 7.78 (1 H, t, J = 59.9 Hz), 7. 90-8.10 (2H, m), 8.25-8.35 (2H, m)

Example 1-2
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone manufacturing (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2 implement propanediamine and 1-ethyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.83 (3H, d, J = 6.5 Hz), 1.37 (3H, t, J = 7.2 Hz), 4.07 (2H, q, J = 7.2 Hz), 4.75 (1H, q, J = 6.5 Hz), 6.57 (1H, d, J = 9.6 Hz), 7.00-7.15 (3H, m), 7.20-7.30 (2H, m), 7.89 (1H, s), 7.90-8.00 (2H, m), 8.20-8.30 (2H, m)

Example 1-3
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Preparation of pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2-propanediamine and 1-difluoromethyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, the title compound was obtained as a white solid by dehydration cyclization.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.90 (3H, d, J = 6.5 Hz), 4.70-4.90 (1H, m), 6.63 (1H, d, J = 9.6 Hz), 6.99 (1H, brs), 7.05-7.20 (3H, m), 7.40-7.60 (2H, m), 7.78 (1H, t, J = 59.7 Hz), 8.00-8.20 (2H, m), 8.32 (1 H, s)

Example 1-4
1- (2,2-difluoroethyl) -5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazoline-2 -Il] -2-Pyridone Preparation (1S, 2S) -1- (4-Fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1- (2,2- Difluoroethyl) -2-pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a light brown solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.83 (3H, d, J = 6.3 Hz), 4.41 (2H, dt, J = 3.3 Hz, 13.6 Hz), 4.70− 4.80 (1H, m), 6.00-6.40 (1 H, m), 6.61 (1 H, d, J = 9.6 Hz), 7.00-7.20 (3H, 7.20) -7.40 (2H, m), 7.90-8.10 (2H, m), 8.20-8.40 (2H, m)

Example 1-5
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-propyl-2-pyridone manufacturing (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2 implement propanediamine and 1-propyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.84 (3H, d, J = 5.6 Hz), 0.97 (3H, t, J = 7.6 Hz), 1.80 (2H, sextet, J = 7.6 Hz), 3.98 (2H, t, J = 7.6 Hz), 4.70-4.80 (1H, m), 6.56 (1H, d, J = 9.6 Hz), 7.00-7.10 (3H, m), 7.20-7.30 (2H, m), 7.90-8.00 (2H, m), 8.20-8.30 (2H, m) )

Example 1-6
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-isopropyl-2-pyridone Preparation of (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-isopropyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.84 (3H, d, J = 6.4 Hz), 1.42 (3H, d, J = 4.4 Hz), 1.44 (3H, d, J = 4.4 Hz), 4.75 (1H, q, J = 6.4 Hz), 5.18 (1H, septet, J = 4.4 Hz), 6.56 (1H, d, J = 9.2 Hz) ), 7.00-7.10 (3H, m), 7.20-7.30 (2H, m), 7.90-8.00 (2H, m), 8.27 (2H, d, J = 2.4Hz)

Example 1-7
Optically active 1-difluoromethyl-5-[(5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3) starting from the diamine of Reference Example 3-2 -Pyridyl) -2-imidazolin-2-yl] -2-pyridone The diamine of Reference Example 3-2 and 1-difluoromethyl-2-pyridone-5-carboxylic acid were condensed according to Example 1, followed by dehydration. Cyclization gave the title compound as a light brown solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 7.2 Hz), 4.80-4.90 (1H, m), 6.63 (1H, d, J = 9.6 Hz), 7.10 (2H, t, J = 8.4 Hz), 7.45-7.55 (2H, m), 7.76 (1H, d, J = 7.6 Hz), 7. 78 (1H, t, J = 60.0 Hz), 7.89 (1H, d, J = 7.6 Hz), 8.09 (1H, d, J = 9.6 Hz), 8.31 (1H, s ), 8.53 (1H, s)

Example 1-8
Optically active 1-ethyl-5-[(5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-) starting from the diamine of Reference Example 3-2 Preparation of Pyridyl) -2-imidazolin-2-yl] -2-pyridone The diamine of Reference Example 3-2 and 1-ethyl-2-pyridone-5-carboxylic acid were condensed according to Example 1, followed by dehydration cyclization. This gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.89 (3H, d, J = 6.4 Hz), 1.38 (3H, t, J = 7.2 Hz), 4.07 (2H, q, J = 7.2 Hz), 4.80-4.90 (1H, m), 6.57 (1H, d, J = 9.6H), 7.10 (2H, t, J = 8.4 Hz), 7.45-7.55 (2H, m), 7.76 (1H, d, J = 8.8 Hz), 7.85-7.90 (1H, m), 7.97 (1H, dd, J = 2.0 Hz, 9.6 Hz), 8.27 (1H, d, J = 2.0 Hz), 8.53 (1H, brs)

Example 1-9
Optically active 5-[(5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2 starting from the diamine of Reference Example 3-2 -Imidazolin-2-yl] -1-propyl-2-pyridone The diamine of Reference Example 3-2 and 1-propyl-2-pyridone-5-carboxylic acid were condensed according to Example 1, followed by dehydration cyclization. This gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.89 (3H, t, J = 6.4 Hz), 0.98 (3H, t, J = 7.2 Hz), 1.81 (2H, sixtet, J = 7.2 Hz), 3.99 (2H, t, J = 7.2 Hz), 4.80-5.00 (1H, m), 6.57 (1H, d, J = 9.2 Hz), 7.10 (2H, t, J = 8.8 Hz), 7.45-7.55 (1H, m), 7.76 (1H, d, J = 1H, d, J = 8.0 Hz), 7 .85-7.90 (1H, m), 7.97 (1H, dd, J = 2.8 Hz, 9.2 Hz), 8.24 (1H, d, J = 2.8 Hz), 8.53 ( 1H, d, J = 2.0Hz)

Example 1-10
Optically active 1- (2,2-difluoroethyl) -5-[(5S) -4- (4-fluorophenyl) -5-methyl-4- (6) starting from the diamine of Reference Example 3-2 -Trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -2-pyridone The diamine of Reference Example 3-2 and 1- (2,2-difluoroethyl) -2-pyridone-5-carvone The acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a light brown solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.89 (3H, d, J = 6.4 Hz), 4.42 (2H, dt, J = 4.0 Hz, 14.0 Hz), 4.80− 4.90 (1H, m), 6.21 (1H, tt, J = 4.0 Hz, 55.2 Hz), 6.62 (1H, d, J = 9.6 Hz), 7.10 (2H, t , J = 8.4 Hz), 7.45-7.55 (2H, m), 7.76 (1H, d, J = 8.0 Hz), 7.80-7.90 (1H, m), 8 .03 (1H, dd, J = 2.8 Hz, 9.6 Hz), 8.23 (1H, d, J = 2.8 Hz), 8.50-8.60 (1H, m)

Example 1-11
Optically active 3-chloro-1-ethyl-5-[(5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoro) starting from the diamine of Reference Example 3-2 Production of Methyl-3-pyridyl) -2-imidazolin-2-yl] -2-pyridone The diamine of Reference Example 3-2 and 3-chloro-1-ethyl-2-pyridone-5-carboxylic acid were used in Example 1. Accordingly, the title compound was obtained as a white solid by condensation after dehydration.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.3 Hz), 1.40 (3H, m), 4.14 (2H, m), 7.15 (2H , M), 7.52 (2H, m), 7.78 (1H, d, J = 7.8 Hz), 7.90 (1H, m), 8.21-8.28 (2H, m), 8.51 (1H, brs)

Example 1-12
5-[(4S, 5S) -4- (3-Bromo-4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-difluoro Preparation of methyl-2-pyridone (1S, 2S) -1- (3-bromo-4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl- 2-Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a pale yellow solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.90-1.00 (3H, m), 4.70-4.80 (1H, m), 6.61 (1H, d, J = 9. 6 Hz), 7.00-7.10 (1H, m), 7.20-7.30 (2H, m), 7.60-7.70 (1H, m), 7.77 (1H, t, J = 59.6 Hz), 8.00-8.20 (2H, m), 8.28 (2H, brs)

Example 1-13
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Preparation of pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2-propanediamine and 1-difluoromethyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, the title compound was obtained as a white solid by dehydration cyclization.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.87 (3H, d, J = 7.2 Hz), 4.70-4.80 (1H, m), 6.62 (1H, d, J = 9.6 Hz), 7.06 (2H, t, J = 8.4 Hz), 7.16 (1H, brs), 7.20-7.30 (2H, m), 7.39 (1H, brd, 5.0 Hz), 7.77 (1 H, t, J = 59.6 Hz), 7.88 (1 H, s), 8.05-8.10 (1 H, m), 8.14 (1 H, d, J = 5.0 Hz), 8.30 (1H, brs)

Example 1-14
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone manufacturing (1S, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2 implement propanediamine and 1-ethyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.87 (3H, d, J = 6.8 Hz), 1.37 (3H, t, J = 7.6 Hz), 4.07 (2H, q, J = 7.6 Hz), 4.70-4.80 (1 H, m), 6.56 (1 H, d, J = 9.2 Hz), 7.06 (2 H, t, J = 8.8 Hz), 7.16 (1H, brs), 7.20-7.30 (2H, m), 7.30-7.40 (1H, m), 7.88 (1H, s), 7.96 (1H, dd, J = 2.2 Hz, 9.2 Hz), 8.14 (1H, d, J = 5.2 Hz), 8.25 (1H, d, J = 2.2 Hz)

Example 1-15
1- (2,2-difluoroethyl) -5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazoline-2 -Il] -2-Pyridone Preparation (1S, 2S) -1- (4-Fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2-propanediamine and 1- (2,2- Difluoroethyl) -2-pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a yellow solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.87 (3H, d, J = 6.4 Hz), 4.42 (2H, dt, J = 4.0 Hz, 14.0 Hz), 4.70 − 4.80 (1H, m), 6.21 (1H, tt, J = 14.0 Hz, 55.2 Hz), 6.61 (1H, d, J = 9.6 Hz), 7.08 (2H, t , J = 6.8 Hz), 7.16 (1H, s), 7.20-7.30 (2H, m), 7.38 (1H, d, J = 5.2 Hz), 8.01 (1H , Dd, J = 2.4 Hz, 9.6 Hz), 8.14 (1H, d, J = 5.2 Hz), 8.21 (1H, d, J = 2.4 Hz)

Example 1-16
Optically active 1-difluoromethyl-5-[(5S) -4- (2-fluoro-4-pyridyl) -5-methyl-4- (4-trifluorophenyl) starting from the diamine of Reference Example 3 Preparation of 2-Imidazolin-2-yl] -2-pyridone By condensing the diamine of Reference Example 3 and 1-difluoromethyl-2-pyridone-5-carboxylic acid according to Example 1, followed by dehydration cyclization The title compound was obtained as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.85 (3.0 H, d, J = 6.0 Hz), 4.75 (1.0 H, m), 6.62 (1.0 H, d, J = 10 Hz), 7.19 (1H, brs), 7.39 (1H, brs), 7.49 (2.0 H, d, J = 7.6 Hz), 7.64 (2.0 H, d, J = 7.6 Hz), 8.10-8.17 (2.0 H, m), 8.30 (1.0 H, brs)

Example 1-17
1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone manufacturing (1R, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2 implement propanediamine and 1-ethyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a pale yellow solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.92 (3H, d, J = 6.4 Hz), 1.37 (3H, t, J = 7.6 Hz), 4.07 (2H, q, J = 7.6 Hz), 4.75-4.85 (1H, m), 6.56 (1H, d, J = 9.6 Hz), 6.99 (1H, s), 7.05-7. 15 (3H, m), 7.45-7.55 (2H, m), 7.88 (1 H, s), 7.96 (1 H, dd, J = 2.4 Hz, 9.6 Hz), 8. 10 (1H, d, J = 5.6 Hz), 8.26 (1H, d, J = 2.4 Hz)

Example 1-18
3-Chloro-1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] Preparation of 2-pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 3-chloro-1-ethyl-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.82 (3H, d, J = 6.6 HZ), 1.38 (3H, t, d = 7.2 Hz), 4.12 (2H, q, J = 7.2 Hz), 4.74 (1H, m), 7.02-7.10 (3H, m), 7.26 (2H, m), 7.98 (1H, td, J = 2. 7Hz, 8.4Hz), 8.20-8.27 (3H, m)

Example 1-19
Optically active 5-[(5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2 starting from the diamine of Reference Example 3-2 -Imidazolin-2-yl] -1-methyl-2-pyridone Preparation The diamine of Reference Example 3-2 and 1-methyl-2-pyridone-5-carboxylic acid were condensed according to Example 1, followed by dehydration cyclization. This gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.89 (3H, d, J = 6.8 Hz), 3.61 (3H, s), 4.80-4.90 (1H, m), 6 .57 (1H, d, J = 9.6 Hz), 7.10 (2H, t, J = 8.8 Hz), 7.45-7.55 (2H, m), 7.76 (1H, d, J = 8.0 Hz), 7.85-7.90 (1H, m), 7.98 (1H, dd, J = 2.8 Hz, 9.6 Hz), 8.27 (1H, d, J = 2) .8 Hz), 8.53 (1H, d, J = 2.4 Hz)

Example 1-20
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Preparation of pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, the title compound was obtained as a white solid by dehydration cyclization.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.91 (3H, d, J = 6.4 Hz), 4.75-4.85 (1H, m), 6.62 (1H, d, J = 9.6 Hz), 7.01 (1H, dd, J = 2.4 Hz, 8.4 Hz), 7.09 (2H, t, J = 8.8 Hz), 7.45-7.55 (2H, m ), 7.70-7.80 (1H, m), 7.77 (1H, t, J = 59.6 Hz), 7.88 (1H, s), 8.01 (1H, d, J = 2) .8 Hz), 8.05-8.10 (1H, m), 8.30 (1H, brs)

Example 1-21
Optically active 1-difluoromethyl-5-[(5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl, starting from the diamine of Reference Example 3-1. Preparation of 2-Imidazolin-2-yl] -2-pyridone The diamine of Reference Example 3-1 and 1-difluoromethyl-2-pyridone-5-carboxylic acid are condensed according to Example 1 and then subjected to dehydration cyclization. This gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.90 (3.0 H, d, J = 5.6 Hz), 4.74 (1.0 H, m), 6.61 (1.0 H, d, J = 10 Hz), 6.99 (1.0 H, brs), 7.10 (1 H, brd, J = 5.2 Hz), 7.36 (3.0 H, brs), 7.46 (1.0 H, brs), 8.10 (2.0H, brd, J = 6.0 Hz), 8.29 (1.0H, brs)

Example 1-22
Optically active 1-ethyl-5-[(5S) -4- (2-fluoro-4-pyridyl) -5-methyl-4- (4-trifluoromethylphenyl) starting from the diamine of Reference Example 3 2-Imidazolin-2-yl] -2-pyridone The diamine of Reference Example 3 and 1-ethyl-2-pyridone-5-carboxylic acid were condensed according to Example 1 and then subjected to dehydration cyclization. The compound was obtained as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.85 (3.0 H, d, J = 6.0 Hz), 1.37 (3.0 H, t, J = 7.6 Hz), 4.06 ( 2.0H, q, J = 7.6 Hz), 4.78 (1.0 H, m), 6.56 (1.0 H, d, J = 8.0 Hz), 7.18 (1.0 H, m) ), 7.38 (1.0 H, d, J = 5.6 Hz), 7.47 (2.0 H, d, J = 8.0 Hz), 7.64 (2.0 H, d, J = 8. 4 Hz), 7.97 (1.0 H, dd, J = 9.6 Hz, 2.8 Hz), 8.14 (1.0 H, d, J = 5.2 Hz), 8.27 (1.0 H, d , J = 2.4Hz)

Example 1-23
Optically active 1-ethyl-5-[(5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-, starting from the diamine of Reference Example 3-1. Preparation of 2-imidazolin-2-yl] -2-pyridone By condensing the diamine of Reference Example 3-1 and 1-ethyl-2-pyridone-5-carboxylic acid according to Example 1, followed by dehydration cyclization The title compound was obtained as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.91 (3.0 H, d, J = 6.8 Hz), 1.38 (3.0 H, t, J = 7.2 Hz), 4.07 ( 2.0H, q, J = 7.2 Hz), 4.78 (1.0 H, m), 6.56 (1.0 H, d, J = 9.6 Hz), 7.01 (1.0 H, s ), 7.10 (1.0 H, m), 7.36 (2.0 H, d, J = 8.8 Hz), 7.45 (2.0 H, d, J = 8.0 Hz), 7.96 (1.0 H, dd, J = 9.6 Hz, 2.8 Hz), 8.11 (1.0 H, d, J = 5.6 Hz), 8.27 (1.0 H, d, J = 2.0 Hz) )

Example 1-24
3-Chloro-1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] Preparation of 2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2-propanediamine and 3-chloro-1-ethyl-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.89 (3.0 H, m), 1.39 (3 H, m), 4.12 (2 H, m), 4.75 (1 H, m), 7.0 (1H, brs), 7.10 (3H, brs), 7.49 (2H, m), 8.1 (1H, m), 8.25 (1H, brs), 8.26 (1H) , M)

Example 1-25
1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] Preparation of 2-pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-ethyl-3-fluoro-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.83 (3H, d, J = 5.1 Hz), 1.38 (3H, t, J = 7.2 Hz), 4.12 (2H, q, J = 7.2 Hz), 4.74 (1 H, m), 7.03-7.29 (5 H, m), 7.81 (1 H, d, J = 10.2 Hz), 7.98 (1 H, m), 8.10 (1H, s), 8.28 (1H, brs)

Example 1-26
3-Chloro-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl Preparation of 2-pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 3-chloro-1-methyl-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.82 (3H, brs), 3.31 (3H, s), 4.75 (1H, m), 7.02-7.29 (5H, m ), 7.98 (H, m), 8.21-8.29 (3H, m)

Example 1-27
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3-methyl Preparation of 2-pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-ethyl-3-methyl-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.84 (3.0 H, d, J = 6.8 Hz), 1.37 (3.0 H, t, J = 7.2 Hz), 2.16 ( 3.0H, s), 4.07 (2.0H, q, J = 6.8 Hz), 4.74 (1.0H, q, J = 6.8 Hz), 7.03 (1.0H, dd) , J = 8.0 Hz, 2.4 Hz), 7.05-7.09 (2.0 H, m), 7.24-7.28 (2.0 H, m), 7.85 (1.0 H, m), 7.96-8.01 (1.0 H, m), 8.11 (1.0 H, d, J = 2.4 Hz), 8.27 (1.0 H, d, J = 2.8 Hz) )

Example 1-28
Optically active 3-chloro-5-[(5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-) starting from the diamine of Reference Example 3-2 Preparation of Pyridyl) -2-imidazolin-2-yl] -1-methyl-2-pyridone The diamine of Reference Example 3-2 and 3-chloro-1-methyl-2-pyridone-5-carboxylic acid were used in Example 1. Accordingly, the title compound was obtained as a white solid by condensation after condensation.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.3 Hz), 3.68 (3H, s), 7.12 (2H, t, J = 8.1 Hz) 7.51 (2H, brs), 7.78 (1H, d, J = 8.4 Hz), 7.90 (1H, m), 8.25 (2H, m), 8.55 (1H, s) )

Example 1-29
Optically active 1-ethyl-3-fluoro-5-[(5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoro) starting from the diamine of Reference Example 3-2 Preparation of Methyl-3-pyridyl) -2-imidazolin-2-yl] -2-pyridone The diamine of Reference Example 3-2 and 1-ethyl-3-fluoro-2-pyridone-5-carboxylic acid were used in Example 1. Accordingly, the title compound was obtained as a white solid by condensation after dehydration.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.89 (3H, d, J = 6.6 Hz), 1.40 (3H, t, J = 6.9 Hz), 4.14 (2H, q, J = 7.2 Hz), 7.12 (2H, t, J = 8, 7 Hz), 7.52 (2H, m), 7.77-7.91 (3H, m), 8.15 (1H, s), 8.55 (1H, m)

Example 1-30
1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone Preparation of (1R, 2S) -1- (4-Fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-ethyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.92 (3H, d, J = 6.4 Hz), 1.37 (3H, t, J = 7.6 Hz), 4.07 (2H, q, J = 7.6 Hz), 4.80-4.90 (1 H, m), 6.56 (1 H, d, J = 9.2 Hz), 7.01 (1 H, dd, J = 2.4 Hz, 8 .8 Hz), 7.09 (2H, t, J = 8.4 Hz), 7.45-7.55 (2H, m), 7, 65-7.75 (1H, m), 7.88 (1H) , S), 7.96 (1H, dd, J = 2.4 Hz, 9.2 Hz), 8.01 (1H, d, J = 2.4 Hz), 8.25 (1H, d, J = 2. 0Hz)

Example 1-31
1- (2,2-difluoroethyl) -5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazoline-2 -Il] -2-Pyridone Preparation (1R, 2S) -1- (4-Fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1- (2,2- Difluoroethyl) -2-pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a yellow solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.91 (3H, d, J = 6.0 Hz), 4.42 (2H, dt, J = 4.0 Hz, 13.6 Hz), 4.80− 4.90 (1H, m), 6.21 (1H, tt, J = 4.0 Hz, 55.2 Hz), 6.61 (1H, d, J = 9.6 Hz), 7.01 (1H, dd) , J = 2.0 Hz, 8.0 Hz), 7.09 (2H, t, J = 8.8 Hz), 7.45-7.55 (2H, m), 7.65-7.75 (1H, m), 7.88 (1H, s), 7.95-8.05 (2H, m), 8.21 (1H, d, J = 2.0 Hz)

Example 1-32
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1,3-dimethyl-2 Preparation of pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1,3-dimethyl-2-pyridone-5 The carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.83 (3.0 H, d, J = 6.8 Hz), 2.14 (3.0 H, s), 3.60 (3.0 H, s) , 4.73 (1.0 H, q, J = 6.4 Hz), 7.02 (1 H, dd, J = 2.4 Hz, 8.4 Hz), 7.04-7.08 (2.0 H, m ), 7.23-7.26 (2H, m), 7.84 (1.0 H, d, J = 2.4 Hz), 7.95-7.99 (1.0 H, m), 8.10 (1.0H, d, J = 2.4Hz), 8.26 (1.0H, d, J = 2.4Hz)

Example 1-33
3-Chloro-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl Preparation of 2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 3-chloro-1-methyl-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.90 (3H, d, J = 6.6 Hz), 3.66 (3H, s), 4.76 (1H, m), 7.00-7 .07 (1H, m), 7.10 (2H, t, J = 8.4 Hz), 7.51 (2H, m), 7.72 (1H, m), 8.03 (1H, s), 8.23 (2H, d, J = 7.8 Hz)

Example 1-34
3-Chloro-1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] Preparation of 2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 3-chloro-1-ethyl-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.90 (3H, d, J = 6.6 Hz), 1.39 (3H, t, J = 7.2 Hz), 4.13 (2H, q, J = 7.5 Hz), 4.77 (1 H, m), 7.02 (1 H, dd, J = 2.4 Hz, 8.7 Hz), 7.10 (2 H, t, J = 8.1 Hz), 7.50 (2H, m), 7.73 (1H, td, J = 2.1 Hz, 9.0 Hz), 8.03 (1H, s), 8.23 (2H, d, J = 11.4 Hz) )

Example 1-35
1-ethyl-3-fluoro-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] Preparation of 2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-ethyl-3-fluoro-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.91 (3H, d, J = 6.6 Hz), 1.39 (3H, t, J = 7.2 Hz), 4.13 (2H, q, J = 6.9 Hz), 4.78 (1 H, m), 7.02 (1 H, d, J = 8.7 Hz), 7.10 (2 H, t, J = 8.7 Hz), 7.51 ( 2H, m), 7.73 (1H, td, J = 2.1 Hz, 9.2 Hz), 7.82 (1H, d, J = 10.2 Hz), 8.03 (1H, s), 8. 12 (1H, s)

Example 1-36
Optically active 1-difluoromethyl-5-[(5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5 starting from the diamine of Reference Example 3-4 -Methyl-2-imidazolin-2-yl] -2-pyridone After the condensation of the diamine of Reference Example 3-4 and 1-difluoromethyl-2-pyridone-5-carboxylic acid according to Example 1, a dehydrated ring To give the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.84 (3H, brs), 6.62 (1H, d, J = 9.6 Hz), 6.70 (1H, t, J = 55 Hz), 7 .08 (2H, t, J = 8.7 Hz), 7.27 (2H, m), 7.67 (1H, d, J = 8.4 Hz), 7.78 (1H, t, J = 60 Hz) , 8.05 (2H, m), 8.30 (1H, brs), 8.70 (1H, brs)

Example 1-37
5-[(4R, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl-2-pyridone Preparation of (1R, 2S) -1- (4-Fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-methyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.91 (3H, d, J = 6.4 Hz), 3.61 (3H, s), 4.70-4.80 (1H, m), 6 .57 (1H, d, J = 9.2 Hz), 7.01 (1H, dd, J = 2.4 Hz, 8.4 Hz), 7.09 (2H, t, J = 8.8 Hz), 7. 45-7.55 (2H, m), 7.65-7.75 (1H, m), 7.88 (1H, s), 7.97 (1H, dd, J = 2.8 Hz, 9.2 Hz) ), 8.01 (1H, d, J = 2.8 Hz), 8.25 (1H, d, J = 2.4 Hz)

Example 1-38
Optically active 1-ethyl-3-fluoro-5-[(5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl)-starting from the diamine of Reference Example 3-4 Preparation of 5-methyl-2-imidazolin-2-yl] -2-pyridone Condensation of the diamine of Reference Example 3-4 and 1-ethyl-3-fluoro-2-pyridone-5-carboxylic acid according to Example 1 Thereafter, the title compound was obtained as a white solid by cyclodehydration.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.90 (3H, d, J = 6.6 Hz), 1.39 (3H, t, J = 7.2 Hz), 4.13 (2H, q, J = 7.2 Hz), 4.79 (1H, m), 7.01 (1H, s), 7.11 (1H, d, J = 4.8 Hz), 7.37 (2H, d, J = 8.4 Hz), 7.46 (2H, brs), 7.82 (1H, d, J = 10.2 Hz), 8.12 (2H, brs)

Example 1-39
3-Ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl Preparation of 2-pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 3-ethyl-1-methyl-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.83 (3.0 H, d, J = 6.4 Hz), 1.21 (3.0 H, t, J = 7.2 Hz), 2.55 ( 2.0H, q, J = 7.2 Hz), 3.60 (3.0 H, s), 4.73 (1.0 H, q, J = 6.4 Hz), 7.02 (1.0 H, m ), 7.03-7.08 (2.0H, m), 7.23-7.27 (2.0H, m), 7.84 (1H, d, J = 2.8 Hz), 7.95. -8.00 (1.0H, m), 8.11 (1.0H, d, J = 2.4Hz), 8.26 (1.0H, d, J = 2.4Hz)

Example 1-40
3-Ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl Preparation of 2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2-propanediamine and 3-ethyl-1-methyl-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.91 (3.0 H, d, J = 6.4 Hz), 1.21 (3.0 H, t, J = 7.2 Hz), 2.56 ( 2.0H, q, J = 7.2 Hz), 3.61 (3.0 H, s), 4.80 (1.0 H, m), 6.97 (1.0 H, s), 7.06- 7.11 (3.0 H, m), 7.48 (2.0 H, m), 7.84 (1.0 H, d, J = 2.8 Hz), 8.10 (1.0 H, d, J = 5.6 Hz), 8.12 (1.0 H, d, J = 2.0 Hz)

Example 1-41
3-Ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl Preparation of 2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 3-ethyl-1-methyl-2- Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.91 (3.0 H, d, J = 6.4 Hz), 1.21 (3.0 H, t, J = 7.2 Hz), 2.55 ( 2.0H, q, J = 7.2 Hz), 3.60 (3.0 H, s), 4.76 (2.0 H, q, J = 6.4 Hz), 7.01 (1.0 H, dd) , J = 8.4 Hz, 2.4 Hz), 7.06-7.11 (2.0 H, m), 7.47-7.51 (2.0 H, m), 7.68-7.73 ( 1.0H, m), 7.84 (1.0 H, d, J = 2.4 Hz), 8.00 (1.0 H, d, J = 2.4 Hz), 8.12 (1.0 H, d , J = 2.4Hz)

Example 1-42
Optically active 1-difluoromethyl-5-[(5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5 starting from the diamine of Reference Example 3-5 -Methyl-2-imidazolin-2-yl] -2-pyridone The diamine of Reference Example 3-5 and 1-difluoromethyl-2-pyridone-5-carboxylic acid were condensed according to Example 1 and then dehydrated. To give the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.98 (3H, d, J = 6.6 Hz), 6.63 (1H, d, J = 9.6 Hz), 6.71 (1H, t, J = 55.8 Hz), 7.11 (2H, t, J = 9.0 Hz), 7.49-7.54 (2H, m), 7.66 (1H, d, J = 8.1 Hz), 8.00 (1H, t, J = 60.0 Hz), 8.07-8.11 (1H, m), 8.33 (1H, s), 8.47 (1H, s)

Example 1-43
Optically active 5-[(5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-, using diamine of Reference Example 3-5 as a raw material Preparation of imidazolin-2-yl] -1-ethyl-2-pyridone The diamine of Reference Example 3-5 and 1-ethyl-2-pyridone-5-carboxylic acid are condensed according to Example 1 and then subjected to dehydration cyclization. This gave the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.89 (3H, d, J = 6.6 Hz), 1.37 (3H, t, J = 6.3 Hz), 4.08 (2H, q, J = 7.2 Hz), 6.58 (1H, d, J = 9.9 Hz), 6.71 (1H, t, J = 55.5 Hz), 7.1 (2H, t, J = 9.0 Hz) ), 7.49-7.53 (2H, m), 7.66 (1H, d, J = 8.1 Hz), 7.82 (1H, d, J = 8.1 Hz), 7.98 (1H) , Dd, J = 1.8 Hz, 9.4 Hz), 8.29 (1H, s)

Example 1-44
Optically active 5-[(5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-, using diamine of Reference Example 3-4 as a raw material Preparation of imidazolin-2-yl] -1-ethyl-2-pyridone The diamine of Reference Example 3-4 and 1-ethyl-2-pyridone-5-carboxylic acid are condensed according to Example 1 and then subjected to dehydration cyclization. This gave the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.85 (3H, d, J = 6.3 Hz), 1.36 (3H, t, J = 7.2 Hz), 4.06 (2H, q, J = 6.3 Hz), 6.55 (1H, d, J = 9.6 Hz), 6.70 (1H, t, J = 55.5 Hz), 7.08 (2H, t, J = 9.0 Hz) ), 7.25-7.29 (3H, m), 7.67 (1H, d, J = 8.4 Hz), 7.94-8.04 (1H, m), 8.06 (1H, d) , J = 8.4 Hz), 8.26 (1H, s), 8.70 (1H, s)

Example 1-45
Optically active 5-[(5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-, using diamine of Reference Example 3-5 as a raw material Imidazolin-2-yl] -1-ethyl-3-fluoro-2-pyridone According to Example 1, the diamine of Reference Example 3-5 and 1-ethyl-3-fluoro-2-pyridone-5-carboxylic acid were used. After condensation, the title compound was obtained as a white solid by cyclodehydration.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.6 Hz), 1.39 (3H, t, J = 6.6 Hz), 4.13 (2H, q, J = 7.2 Hz), 6.71 (1H, t, J = 54.3 Hz), 7.11 (2H, t, J = 9.6 Hz), 7.48-7.53 (2H, m), 7.66 (1H, d, J = 8.4 Hz), 7.81-7.89 (2H, m), 8.14 (1H, S), 8.47 (1H, s)

Example 1-46
An optically active 5-[(5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-] starting from the diamine of Reference Example 3-4 Preparation of imidazolin-2-yl] -1-ethyl-3-fluoro-2-pyridone The diamine of Reference Example 3-4 and 1-ethyl-3-fluoro-2-pyridone-5-carboxylic acid were used according to Example 1. After condensation, the title compound was obtained as a white solid by cyclodehydration.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.85 (3H, d, J = 6.6 Hz), 1.39 (3H, t, J = 7.2 Hz), 4.12 (2H, q, J = 6.9 Hz), 6.70 (1H, t, J = 55.2 Hz), 7.05-7.30 (4H, m), 7.68 (1H, d, J = 11.7 Hz), 7.81 (1H, dd, J = 2.4 Hz, 9.0 Hz), 8.06 (1H, dd, J = 1.8 Hz, 8.1 Hz), 8.11 (1H, s), 8.70 (1H, s)

Example 1-47
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone manufacturing (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2 implement propanediamine and 1-methoxy-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a pale yellow solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.83 (3H, d, J = 6.4 Hz), 4.08 (3H, s), 4.75 (1H, q, J = 6.4 Hz) 6.69 (1H, d, J = 9.6 Hz), 7.02 (1H, dd, J = 2.4 Hz, 8.4 Hz), 7.04-7.08 (2H, m), 7. 24-7.27 (2H, m), 7.95-7.99 (2H, m), 8.26 (1H, d, J = 2.8 Hz), 8.47 (1H, d, J = 2) .4Hz)

Example 1-48
5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone Preparation of (1R, 2S) -1- (4-Fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-methoxy-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.92 (3H, d, J = 6.4 Hz), 4.09 (3H, s), 4.81 (1H, q, J = 6.8 Hz) 6.70 (1H, d, J = 9.2 Hz), 7.01 (1H, dd, J = 2.4 Hz, 8.4 Hz), 7.07-7.11 (2H, m), 7. 47-7.51 (2H, m), 7.69-7.74 (1H, m), 7.98 (1H, dd, J = 2.8 Hz, 9.6 Hz), 8.02 (1H, d) , J = 2.8 Hz), 8.51 (1H, d, J = 2.4 Hz)

Example 1-49
1-ethoxy-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone Preparation of (1R, 2S) -1- (4-Fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-ethoxy-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.92 (3H, d, J = 6.8 Hz), 1.40 (3H, t, J = 7.2 Hz), 4.34 (2H, q, J = 6.8 Hz), 4.78 (1 H, brs), 6.70 (1 H, d, J = 9.2 Hz), 7.01 (1.0 H, dd, J = 2.4 Hz, 8.8 Hz) ), 7.08-7.12 (2H, m), 7.47-7.55 (2H, m), 7.70-7.75 (1H, m), 7.99 (1H, dd, J = 2.0 Hz, 10 Hz), 8.02 (1H, d, J = 3.2 Hz), 8.47 (1H, d, J = 2.4 Hz)

Example 1-50
1-cyclopropyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Preparation of pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-cyclopropyl-5-methyl-2-pyridone- The 5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.3 Hz), 1.00-1.10 (2H, m), 1.15-1.24 (2H, m), 3.39-3.50 (1H, m), 4.78-4.85 (1H, m), 6.61 (1H, d, J = 9.6 Hz), 7.05-7. 17 (3H, m), 7.27-7.35 (2H, m), 7.98-7.88 (2H, m), 8.25 (1 H, d, J = 2.6 Hz), 8. 32 (1H, d, J = 0.9Hz)

Example 1-51
1-cyclopropyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- Preparation of 2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-trifluoromethyl-3-pyridyl) -1,2-propanediamine and 1-cyclopropyl-2-pyridone- The 5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.9 Hz), 0.98-1.03 (2H, m), 1.12-1.17 (2H, m), 3.36-3.44 (1H, m), 4.78-4.90 (1H, m), 6.57 (1H, d, J = 6.6 Hz), 7.11 (2H, t, J = 8.4 Hz), 7.45-7.56 (2H, m), 7.77 (1H, d, J = 8.0 Hz), 7.88 (1H, dd, J = 6.6 Hz) 1.6 Hz), 7.99 (1 H, dd, J = 9.7 Hz, 2.4 Hz), 8.22 (1 H, d, J = 2.3 Hz), 8.53 (1 H, s)

Example 1-52
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone manufacturing (1S, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2 implement propanediamine and 1-methoxy-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.82-0.90 (3H, brd), 4.08 (3H, s), 4.71-4.77 (1H, brs), 6.70 (1H, d, J = 9.6 Hz), 7.04-7.08 (2H, m), 7.16 (1H, s), 7.23-7.28 (2H, m), 7.38 (1H, d, J = 6.4 Hz), 7.99 (1H, d, J = 9.6 Hz), 8.14 (1H, d, J = 6.4 Hz), 8.48 (1H, d, J = 2.0Hz)

Example 1-53
5-[(4R, 5S) -4- (4-Fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-methoxy-2 Preparation of pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-trifluoromethyl-3-pyridyl) -1,2-propanediamine and 1-methoxy-2-pyridone-5 The carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.4 Hz), 4.09 (3H, s), 4.78-4.88 (1H, m), 6 .70 (1H, d, J = 9.2 Hz), 7.07-7.11 (2H, m), 7.46-7.54 (2H, m), 7.76 (1H, d, J = 8.0 Hz), 7.88 (1H, d, J = 9.2 Hz), 8.01 (1H, brd, J = 8.0 Hz), 8.50 (1H, d, J = 2.4 Hz), 8.53 (1H, d, J = 2.4 Hz)

Example 1-54
5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone Preparation (1R, 2S) -1- (4-Chlorophenyl) -1- (2-fluoro-4-pyridyl) -1,2-propanediamine and 1-methoxy-2-pyridone-5-carboxylic acid The title compound was obtained as a white solid by dehydration cyclization after condensation according to.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.85-0.87 (3H, brd), 4.08 (3H, s), 4.71-4.75 (1H, m), 6.70 (1H, d, J = 9.6 Hz), 7.04-7.06 (2H, m), 7.16 (1H, s), 7.23-7.27 (2H, m), 7.38 (1H, brd, J = 6.4 Hz), 7.99 (1H, d, J = 9.6 Hz), 8.14 (1H, brd, J = 6.4 Hz), 8.48 (1H, d, J = 2.0Hz)

Example 1-55
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Preparation of methyl-2-pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl-3-methyl- 2-Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a pale yellow solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.81-0.88 (3H, brd), 2.16 (3H, s), 4.72-4.78 (1H, brs), 7.10 -7.09 (3H, m), 7.23-7.28 (2H, m), 7.80 (1H, t, J = 60 Hz), 7.92-8.20 (2H, m), 8 .16-8.19 (1H, brs), 8.25-8.30 (1H, brs)

Example 1-56
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Preparation of methyl-2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl-3-methyl- 2-Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a pale yellow solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.91 (3H, d, J = 6.0 Hz), 2.17 (3H, s), 4.72-4.80 (1H, brs), 7 .02 (1H, dd, J = 2.4 Hz, 8.8 Hz), 7.08-7.12 (2H, m), 7.47-7.54 (2H, m), 7.70-7. 74 (1H, m), 7.81 (1H, t, J = 60 Hz), 7.92-7.97 (1H, brs), 8.01 (1H, d, J = 2.8 Hz), 8. 16-8.21 (1H, brs)

Example 1-57
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Preparation of methoxy-2-pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl-3-methoxy- 2-Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.80-0.88 (3H, brs), 3.90 (3H, s), 4.72-4.80 (1H, brs), 7.02 -7.09 (3H, m), 7.25-7.30 (2H, m), 7.42 (1H, s), 7.83 (1H, t, J = 60 Hz), 7.94-8 .02 (2H, m), 8.26 (1H, brs)

Example 1-58
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Preparation of methoxy-2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl-3-methoxy- 2-Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a pale yellow solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.93 (3H, d, J = 6.0 Hz), 3.91 (3H, s), 4.75-4.83 (1H, brs), 7 .02 (1H, dd, J = 2.8 Hz, 8.8 Hz), 7.08-7.13 (1H, m), 7.42-7.45 (1H, brs), 7.48-7. 53 (2H, m), 7.71-7.74 (1 H, m), 7.84 (1 H, t, J = 60 Hz), 7.94-7.98 (1 H, brs), 8.02 ( 1H, d, J = 3.2Hz)

Example 1-59
Preparation of 5-[(5S) -4,4-bis (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone (2S) -1,1-bis (4-Fluorophenyl) -1,2-propanediamine and 1-methoxy-2-pyridone-5-carboxylic acid were condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid. .
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.87 (30 H, d, J = 6.0 Hz), 4.09 (3 H, s), 4.24 (1 H, m), 6.70 (1 H , D, J = 9.6 Hz), 7.00-7.08 (3H, m), 7.16-7.20 (2H, m), 7.44-7.47 (2H, m), 7 .98 (1H, dd, J = 2.4 Hz, 9.6 Hz), 8.48 (1H, d, J = 2.4 Hz)

Example 1-60
1-difluoromethyl-5-[(4S, 5S) -4- (6-cyclopropyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 Preparation of pyridone (1S, 2S) -1- (6-cyclopropyl-3-pyridyl) -1- (4-fluorophenyl) -1,2-propanediamine and 1-difluoromethyl-2-pyridone-5 The carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a brown solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.3 Hz), 0.90-1.10 (4H, m), 2.07-2.18 (1H, m), 4.80 (1H, q, J = 6.4 Hz), 6.67 (1H, d, J = 9.8 Hz), 7.11 (2H, t, J = 8.6 Hz), 7. 26 (1H, d, J = 7.2 Hz), 7.30 (2H, dd, J = 8.5 Hz, 5.4 Hz), 7.77 (1H, dd, J = 8.2 Hz, 2.6 Hz) 7.83 (1H, t, J = 60.0 Hz), 8.11 (1H, dd, J = 9.7 Hz, 2.5 Hz), 8.36 (1H, d, J = 2.0 Hz), 8.46 (1H, d, J = 1.6Hz)

Example 1-61
5-[(4S, 5S) -4- (6-cyclopropyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-2- Preparation of pyridone (1S, 2S) -1- (6-cyclopropyl-3-pyridyl) -1- (4-fluorophenyl) -1,2-propanediamine and 1-ethyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.5 Hz), 0.92-1.10 (4H, m), 1.42 (3H, t, J = 7.2 Hz), 2.07-2.19 (1 H, m), 4.11 (2 H, q, J = 7.3 Hz), 4.79 (1 H, q, J = 6.4 Hz), 6. 62 (1H, d, J = 9.6 Hz), 7.12 (2H, t, J = 8.7 Hz), 7.23 (1H, d, J = 8.4 Hz), 7.30 (2H, dd) , J = 8.9 Hz, 5.3 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.4 Hz), 8.00 (1H, dd, J = 9.3 Hz, 2.4 Hz), 8.31 (1H, d, J = 2.3 Hz), 8.47 (1H, d, J = 2.5 Hz)

Example 1-62
Of 5-[(4S, 5S) -4- (4-chlorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone Preparation (1S, 2S) -1- (4-Chlorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-methoxy-2-pyridone-5-carboxylic acid The title compound was obtained as a white solid by dehydration cyclization after condensation according to.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.83 (3H, d, J = 4.4 Hz), 4.08 (3H, s), 4.75-4.80 (1H, brs), 6 .69 (1H, d, J = 9.6 Hz), 7.02 (1H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.92-8.00 (2H, m), 8.26 (1H, brs), 8.47 (1H, d, J = 2.4 Hz)

Example 1-63
5-[(4S, 5S) -4- (6-Fluoro-3-pyridyl) -5-methyl-4- (4-trifluoromethylphenyl) -2-imidazolin-2-yl] -1-methoxy-2 Preparation of pyridone (1S, 2S) -1- (6-Fluoro-3-pyridyl) -1- (4-trifluoromethylphenyl) -1,2-propanediamine and 1-methoxy-2-pyridone-5 The carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.97 (3H, d, J = 6.8 Hz), 4.12 (3H, s), 5.18-5.22 (1H, brs), 6 .77 (1H, d, J = 9.2 Hz), 7.14 (1H, d, J = 6.0 Hz), 7.47 (2H, d, J = 8.0 Hz), 7.74 (2H, d, J = 8.0 Hz), 7.91 (1H, d, J = 10.0 Hz), 7.95-8.02 (1H, m), 8.33 (1H, s), 8.77 ( 1H, s)

Example 1-64
5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone manufacturing (1R, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2 implement propanediamine and 1-methoxy-2-pyridone-5-carboxylic acid After condensation according to Example 1, dehydration cyclization gave the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.92 (3H, d, J = 6.8 Hz), 4.09 (3H, s), 4.82 (1H, q, J = 6.4 Hz) , 6.71 (1H, d, J = 9.6 Hz), 7.00 (1H, s), 7.07-7.12 (3H, m), 7.47-7.51 (2H, m) 7.46 (2H, d, J = 8.4 Hz), 8.00 (1H, dd, J = 2.8 Hz, 6.8 Hz), 8.11 (1H, d, J = 5.6 Hz), 8.50 (1H, d, J = 2.4Hz)

Example 1-65
1-cyclopropyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Preparation of pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-cyclopropyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, the title compound was obtained as a white solid by dehydration cyclization.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.91 (3H, d, J = 6.5 Hz), 0.96-1.04 (2H, m), 1.12-1.19 (2H, m), 3.34-3.42 (1H, m), 4.72-4.82 (1H, m), 6.56 (1H, d, J = 9.5 Hz), 7.02 (1H, dd, J = 8.6 Hz, 2.7 Hz), 7.10 (2H, t, J = 8.8 Hz), 7.44-7.54 (2H, m), 7.72 (1H, td, J = 8.6 Hz, 2.4 Hz), 7.97 (1H, dd, J = 9.6 Hz, 2.4 Hz), 8.02 (1H, d, J = 2.4 Hz), 8.21 (1H, d, J = 2.4 Hz)

Example 1-66
1-cyclopropyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Preparation of pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2-propanediamine and 1-cyclopropyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, the title compound was obtained as a white solid by dehydration cyclization.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.90 (3H, d, J = 6.6 Hz), 0.96-1.03 (2H, m), 1.10-1.20 (2H, m), 3.34-3.43 (1H, m), 4.73-4.90 (1H, m), 6.57 (1H, d, J = 9.3 Hz), 6.98 (1H, s), 7.05-7.16 (3H, m), 7.44-7.53 (2H, m), 7.98 (1H, dd, J = 9.5 Hz, 2.6 Hz), 8. 12 (1H, d, J = 5.4 Hz), 8.22 (1H, d, J = 2.4 Hz)

Example 1-67
Preparation of 1-ethyl-5-[(5S) -4,4-bis (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone (2S) -1, 1-bis (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-ethyl-2-pyridone-5-carboxylic acid are condensed according to Example 1 and then subjected to dehydration cyclization to give the title compound. Was obtained as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.4 Hz), 1.37 (3H, t, J = 6.8 Hz), 4.07 (2H, q, J = 6.8 Hz), 4.80-4.90 (1 H, m), 6.56 (1 H, d, J = 9.2 Hz), 7.00-7.10 (2 H, m), 7. 70-7.90 (1H, m), 7.88 (1 H, s), 7.96 (1 H, dd, J = 2.4 Hz, 9.2 Hz), 7.95-8.05 (1 H, m ), 8.13 (1H, d, J = 2.8 Hz), 8.26 (1H, d, J = 2.0 Hz), 8.32 (1H, d, J = 2.0 Hz)

Example 1-68
Preparation of 5-[(5S) -4,4-bis (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-difluoromethyl-2-pyridone (2S) -1 , 1-bis (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl-2-pyridone-5-carboxylic acid after condensation according to Example 1, followed by dehydration cyclization The title compound was obtained as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.4H), 4.80-4.90 (1H, m), 6.61 (1H, d, J = 9.6 Hz), 7.00-7.10 (2H, m), 7.77 (1 H, t, J = 59.6 Hz), 8.00-8.20 (3H, m), 8.25- 8.35 (2H, m)

Example 1-69
1-cyclopropyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Preparation of pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2-propanediamine and 1-cyclopropyl-2-pyridone-5-carboxylic acid After condensation according to Example 1, the title compound was obtained as a white solid by dehydration cyclization.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.86 (3H, d, J = 6.3 Hz), 0.97-1.02 (2H, m), 1.10-1.20 (2H, m), 3.33-3.44 (1H, m), 4.72 (1H, q, J = 6.7 Hz), 6.57 (1H, d, J = 9.5 Hz), 7.07 ( 2H, t, J = 8.7 Hz), 7.16 (1H, s), 7.26 (2H, dd, J = 8.6 Hz, 5.3 Hz), 7.39 (1H, dt, J = 5) .2 Hz, 1.3 Hz), 7.99 (1 H, dd, J = 9.6 Hz, 2.4 Hz), 8.16 (1 H, d, J = 5.6 Hz), 8.21 (1 H, d, J = 2.6Hz)

Example 1-70
1-difluoromethyl-3-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl Preparation of 2-pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl-2-pyridone- The 5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.85 (3H, d, J = 6.4 Hz), 1.23 (3H, t, J = 7.6 Hz), 2.57 (2H, q, J = 7.2 Hz), 4.76-4.83 (1H, brs), 7.03-7.11 (3H, m), 7.24-7.28 (2H, m), 7.81 ( 1H, t, J = 60 Hz), 7.90 (1H, s), 7.95-8.00 (1H, m), 8.20 (1H, s), 8.27 (1H, s)

Example 1-71
1-difluoromethyl-3-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl Preparation of 2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl-3-ethyl- 2-Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.93 (3H, d, J = 6.4 Hz), 1.24 (3H, t, J = 7.2 Hz), 2.57 (2H, q, J = 7.2 Hz), 4.82-4.89 (1H, brs), 7.03 (1H, dd, J = 2.4 Hz, 8.4 Hz), 7.09-7.13 (2H, m ), 7.48-7.52 (2H, m), 7.70-7.75 (1H, m), 7.81 (1H, t, J = 60 Hz), 7.90-7.93 (1H) M), 8.02 (1H, d, J = 2.4 Hz), 8.22 (1H, d, J = 2.0 Hz)

Example 1-72
1-difluoromethoxy-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Preparation of pyridone (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethoxy-2-pyridone-5-carboxylic acid After condensation according to Example 1, the title compound was obtained as a white solid by dehydration cyclization.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.83 (3H, d, J = 6.8 Hz), 4.75 (1H, q, J = 6.4 Hz), 6.74 (1H, d, J = 9.6 Hz), 7.06 (1H, t, J = 70 Hz), 7.02-7.08 (3H, m), 7.23-7.26 (2H, m), 7.95- 7.9 (1H, m), 8.05 (1H, d, J = 9.6 Hz), 8.26 (1H, s), 8.42 (1H, s)

Example 1-73
Optically active 5-[(5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-, using diamine of Reference Example 3-5 as a raw material Preparation of imidazolin-2-yl] -1-methoxy-2-pyridone The diamine of Reference Example 3-5 and 1-methoxy-2-pyridone-5-carboxylic acid are condensed according to Example 1 and then subjected to dehydration cyclization. This gave the title compound as a yellow solid.
¹ HNMR (300 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.6 Hz), 6.71 (1H, t, J = 55.2 Hz), 6.73 (1H, s) , 7.11 (2H, t, J = 9.0 Hz), 7.48-7.53 (2H, m), 7.66 (1H, d, J = 8.1 Hz), 7.83 (1H, d, J = 8.4 Hz), 8.02 (1H, dd, J = 2.4 Hz, 9.6 Hz), 8.48 (1H, s), 8.52 (1H, s)

Example 1-74
1-difluoromethoxy-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Preparation of pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethoxy-2-pyridone-5-carboxylic acid Was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.90 (3H, d, J = 6.8 Hz), 4.75-4.83 (1H, brs), 6.75 (1H, d, J = 10 Hz), 7.01 (1 H, dd, J = 2.4 Hz, 8.8 Hz), 7.07 (1 H, t, J = 70 Hz), 7.07-7.11 (2 H, m), 7. 45-7.53 (2H, m), 7.68-7.72 (1H, m), 8.00 (1H, d, J = 2.4 Hz), 8.04 (1H, d, J = 8) .0Hz), 8.43 (1H, s)

Example 1-75
1-difluoromethyl-3-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl Preparation of 2-pyridone (1R, 2S) -1- (4-fluorophenyl) -1- (2-fluoro-4-pyridyl) -1,2-propanediamine and 1-difluoromethyl-3-ethyl- 2-Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a white solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.91 (3H, d, J = 6.0 Hz), 1.23 (1H, t, J = 7.6 Hz), 2.57 (1H, q, J = 7.6 Hz), 4.73-4.85 (1H, brs), 6.92-7.00 (1H, brs), 7.07-7.14 (3H, m), 7.44- 7.54 (2H, brs), 7.81 (1H, t, J = 60 Hz), 7.91-7.95 (1H, brs), 8.11 (1H, d, J = 5.2 Hz), 8.16-8.24 (1H, brs)

Example 1-76
1-difluoromethyl-5-[(4S, 5R) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-hydroxymethyl-2-imidazolin-2-yl] -2 Preparation of pyridone trifluoroacetate salt (1S, 2R) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -3-hydroxy-1,2-propanediamine and 1-difluoromethyl 2-Pyridone-5-carboxylic acid was condensed according to Example 1, followed by dehydration cyclization to obtain the title compound as a brown solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 3.30-3.40 (2H, m), 5.19 (1H, t, J = 5.6 Hz), 6.74 (1H, d, J = 10.0 Hz), 7.10-7.20 (3 H, m), 7.25-7.35 (2 H, m), 7.81 (1 H, t, J = 59.2 Hz), 7.94 ( 1H, dd, J = 2.4 Hz, 10.0 Hz), 8.00-8.10 (1 H, m), 8.38 (1 H, d, J = 3.2 Hz), 8.78 (1 H, d , J = 2.4Hz)

Example 1-77
Sodium 1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2 Preparation of pyridone-3-olate (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl-3-methoxy The title compound was obtained as a pale yellow solid by deprotecting the product obtained by condensing 2-pyridone-5-carboxylic acid according to Example 1, followed by dehydration cyclization.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.86 (3H, d, J = 6.8 Hz), 4.83 (1H, q, J = 6.4 Hz), 7.05 (1H, dd, J = 3.2, 8.4 Hz), 7.06-7.11 (2H, m), 7.22-7.26 (3H, m), 7.82 (1 H, t, J = 60.0 Hz) ), 7.90 (1H, d, J = 2.0 Hz), 7.95-8.00 (1H, m), 8.27 (1H, d, J = 2.4 Hz)

Example 1-78
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluoro-3-hydroxyphenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl Preparation of 2-pyridone (1S, 2S) -1- (4-Fluoro-3-methoxymethoxyphenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine and 1-difluoromethyl The title compound was obtained as a white solid by deprotecting the product obtained by condensing 2-pyridone-5-carboxylic acid according to Example 1, followed by dehydration cyclization.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.88 (3H, d, J = 6.8 Hz), 4.70-4.80 (1H, m), 6.50-6.70 (2H, m), 6.80-6.90 (1H, m), 6.95-7.10 (2H, m), 7.77 (1H, t, J = 59.6 Hz), 7.95-8. 10 (2H, m), 8.20-8.40 (2H, m)

Example 2
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3-methoxy Preparation of 2-pyridone 1-Ethyl-3-methoxy-2-pyridone-5-carbonitrile (30 mg) was dissolved in 1 mL of methanol, 25% sodium methoxide-methanol solution (6.6 mL) was added, and room temperature was added. For 17 hours. To that solution was added methanesulfonic acid (11 μL) and (1S, 2S) -1- (4-fluorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine (44.5 mg). Methanol solution (1 mL) was sequentially added and stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the object compound (1.8 mg) as a brown solid.
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 0.83 (3.0 H, brd, J = 6.4 Hz), 1.36 (3.0 H, t, J = 7.6 Hz), 3.87 ( 3.0H, s), 4.07 (2.0H, q, J = 7.2 Hz), 4.73 (1.0 H, m), 7.01-7.09 (3.0 H, m), 7.23-7.26 (2.0 H, m), 7.37 (1.0 H, d, J = 2.0 Hz), 7.84 (1.0 H, d, J = 2.0 Hz), 7 .97 (1.0 H, m), 8.27 (1.0 H, brs)

Reference example 1
Preparation of 1-ethyl-2-pyridone-5 -carboxylic acid Methyl 2-pyridone-5-carboxylate (1 g), bromoethane (1.46 mL) and cesium fluoride (2.98 g) were dissolved in 20 mL of dimethylformamide. And stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound methyl ester product (465 mg) as a white solid. The obtained methyl ester was hydrolyzed under basic conditions to give the title compound as a white solid.
¹ HNMR (400 MHz, DMSO-d ₆ , δ ppm): 1.61 (3H, t, J = 7.2 Hz), 3.98 (2H, q, J = 7.2 Hz), 6.38 (1H, d , J = 9.5 Hz), 7.83 (1H, dd, J = 1.5 Hz, 9.5 Hz), 8.43 (1H, d, J = 1.5 Hz)

Reference example 2
Preparation of 1-difluoromethyl-2-pyridone-5-carboxylic acid To an N-methylpyrrolidone solution (200 mL) of methyl 2-pyridone-5-carboxylate (20 g) was added 60% sodium hydride (5.6 g) at 0 ° C. ) And stirred for 15 minutes. Lithium bromide (23 g) and sodium chlorodifluoroacetate were sequentially added, and the mixture was stirred at 120 ° C. for 30 minutes. The reaction mixture was cooled to 0 ° C., saturated aqueous sodium chloride solution and ethyl acetate were added, and the mixture was filtered through celite. The filtrate was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15) to give the title compound methyl ester product (5.09 g) as a yellow solid. The obtained methyl ester was hydrolyzed under basic conditions to give the title compound as a white solid.
¹ HNMR (400 MHz, DMSO-d ₆ , δ ppm): 6.56 (1H, d, J = 9.6 Hz), 7.82 (1H, t, J = 58.8 Hz), 7.86 (1H, dd) , J = 1.6 Hz, 9.6 Hz), 8.24 (1H, d, J = 1.6 Hz)

The compounds of Reference Examples 2-1 to 11-11 were synthesized according to the methods of Reference Examples 1 and 2 above.

Reference Example 2-1
1-propyl-2-pyridone-5-carboxylic acid
¹ HNMR (300 MHz, DMSO-d ₆ , δ ppm): 1.43 (3H, t, J = 7.5 Hz), 1.82 (2H, sixtet J = 7.5 Hz), 3.95 (2H, t, J = 7.5 Hz), 6.19 (1H, d, J = 9.5 Hz), 7.87 (1H, dd, J = 1.6 Hz, 9.6 Hz), 8.21 (1H, d, J = 1.6Hz), 12.40 (1H, s)

Reference Example 2-2
1-isopropyl-2-pyridone-5-carboxylic acid
¹ HNMR (300 MHz, DMSO-d ₆ , δ ppm): 1.66 (6H, d, J = 4.4 Hz), 4.49 (1H, septet, J = 4.4 Hz), 6.19 (1H, d , J = 9.5 Hz), 7.87 (1H, dd, J = 1.6 Hz, 9.5 Hz), 8.14 (1H, d, J = 1.6 Hz), 12.43 (1H, brs)

Reference Example 2-3
1- (2,2-difluoroethyl) -2-pyridone-5-carboxylic acid
¹ HNMR (300 MHz, DMSO-d ₆ , δ ppm): 4.48 (2H, dt, J = 4.5 Hz, 32.0 Hz), 6, 32 (1H, tt, J = 4.5 Hz, 84.0 Hz) 6.48 (1H, d, J = 9.5 Hz), 7.82 (1H, dd, J = 1.6 Hz, 9.5 Hz), 8.45 (1H, d, J = 1.6 Hz), 12.97 (1H, s)

Reference Example 2-4
3-Chloro-1-methyl-2-pyridone-5-carboxylic acid
_{^{1 HNMR (300MHz, DMSO-d}} 6, δppm): 3.57 (3H, s), 7.97 (1H, s), 8.49 (1H, s), 13.04 (1H, brs)

Reference Example 2-5
3-Chloro-1-ethyl-2-pyridone-5-carboxylic acid
¹ HNMR (300 MHz, DMSO-d ₆ , δ ppm): 1.24 (3H, t, J = 7.1 Hz), 4.05 (1H, q, J = 7.1 Hz), 7.98 (1H, s ), 8.50 (1H, s), 13.09 (1H, brs)

Reference Example 2-6
1-ethyl-3-fluoro-2-pyridone-5-carboxylic acid
¹ HNMR (300 MHz, DMSO-d ₆ , δ ppm): 1.23 (3H, t, J = 7.3 Hz), 4.05 (2H, q, J = 7.1 Hz), 7.63 (1H, dd , J = 2.3 Hz, 10.0 Hz), 8.36 (1H, s), 13.05 (1H, brs)

Reference Example 2-7
1,3-dimethyl-2-pyridone-5-carboxylic acid
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 2.13 (3H, s), 3.61 (3H, s), 7.81 (1H, d, J = 2.0 Hz), 8.30 (1H , D, J = 2.0 Hz)

Reference Example 2-8
1-ethyl-3-methyl-2-pyridone-5-carboxylic acid
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 1.34 (3.0 H, t, J = 7.2 Hz), 2.12 (3.0 H, s), 4.07 (2.0 H, q, J = 7.2 Hz), 7.79 (1.0 H, d, J = 2.8 Hz), 8.29 (1.0 H, d, J = 2.8 Hz)

Reference Example 2-9
1-ethyl-3-methoxy-2-pyridone-5-carboxylic acid
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 1.34 (3H, t, J = 7.2 Hz), 3.84 (3H, s), 4.09 (2H, q, J = 7.2 Hz) 7.25 (1H, d, J = 2.4 Hz), 8.05 (1H, d, J = 2.4 Hz)

Reference Example 2-10
1-difluoromethyl-3-methyl-2-pyridone-5-carboxylic acid
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 2.14 (3.0 H, s), 7.77 (1.0 H, t, J = 60 Hz), 7.83-7.84 (1.0 H, m), 8.25 (1.0 H, d, J = 2.0 Hz)

Reference Example 2-11
1-difluoromethyl-3-ethyl-2-pyridone-5-carboxylic acid
¹ HNMR (400 MHz, CDCl ₃ , δ ppm): 1.23 (3.0 H, t, J = 7.2 Hz), 2.58 (2.0 H, q, J = 7.2 Hz), 7.69 (1 .0H, t, J = 60 Hz), 7.71-7.73 (1.0 H, m), 8.30 (1.0 H, d, J = 2.0 Hz)

Reference example 3
Production of optically active (2S) -1- (2-fluoro-4-pyridyl) -1- (4-trifluoromethylphenyl) -1,2-propanediamine

  A tetrahydrofuran solution (180 mL) of N-{(1S) -2- [methoxy (methyl) amino] -1-methyl-2-oxoethyl} carbamate (9.6 g) was separately prepared 1.48M 4-trifluoro. After slowly dropping dropwise into a methylphenylmagnesium bromide-tetrahydrofuran solution (70 mL) at 0 ° C., the reaction solution was stirred at room temperature for 14 hours. After cooling to 0 ° C., an aqueous sodium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure, whereby t-butyl N-[(1S) -2- (4-trifluoromethylphenyl) -1-methyl-2-oxoethyl] carbamate (13 0.4 g) was obtained as an orange solid.

A tetrahydrofuran solution (100 mL) of the ketone body (13.4 g), (R) -2-methyl-2-propanesulfinamide (6.14 g) and titanium tetraethoxide (19.3 g) was heated at 80 ° C. for 18 hours. Stir. The reaction solution was cooled to room temperature and diluted with ethyl acetate, and then a saturated sodium sulfate solution was added with vigorous stirring. Insoluble matters were removed by Celite filtration, and the obtained filtrate was washed successively with saturated sodium bicarbonate and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20), whereby t-butyl N-[(1S) -2-[(R)-(t-butylsulfinyl) imino] -2- (4-Trifluoromethylphenyl) -1-methylethyl] carbamate (10.8 g) was obtained as a pale yellow solid. A 1.0 M trimethylaluminum-hexane solution (5.7 mL) was added to a toluene solution (2 mL) of the sulfinylimine compound (2.0 g), and the mixture was stirred at room temperature for 30 minutes. The resulting solution was mixed with 2-fluoro-4-pyridyllithium solution [4-fluoro-2-bromopyridine (3.18 g) and 1.55 M butyllithium-hexane solution (9.21 mL) in diethyl ether (20 mL) − Was prepared by reacting at −100 ° C. in a tetrahydrofuran (20 mL) solvent] to be slowly added dropwise at −100 ° C. After completion of dropping, the reaction solution was heated to -78 ° C over 1.5 hours. After adding a saturated aqueous sodium sulfate solution, the temperature was raised to room temperature. The obtained reaction solution was dried over anhydrous magnesium sulfate, filtered through celite, and the organic solvent was evaporated under reduced pressure. The obtained residue was washed with isopropyl ether to give optically active t-butyl N-[(1S) -2-[(R)-(t-butylsulfinyl) amino] -2- (4-trifluoromethyl). Phenyl) -2- (2-fluoro-4-pyridyl) -1-methylethyl] carbamate (2.06 g) was obtained as a white solid. The product was treated sequentially with trifluoroacetic acid and 4N hydrogen chloride-dioxane solution to give the optically active title diamine (1.22 g) as a pale yellow oil.
¹ HNMR (400 MHz, CDCl ₃ , δ ppm): 1.01 (3H, d, J = 6.2 Hz), 4.14 (1H, q, J = 6.2 Hz), 7.20 (1H, s), 7.31 (1H, m), 7.56 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz), 8.11 (1H, d, J = 5) .6Hz)

In accordance with the method of Reference Example 3 above, N-{(1S) -2- [methoxy (methyl) amino] -1-methyl-2-oxoethyl} carbamate is reacted with an aryl metal compound to form a ketone body (R ) After reacting with 2-methyl-2-propanesulfinamide, diastereoselective arylation was performed and deprotection was performed to obtain the diamines of Reference Examples 3-1 to 8. The organometallic compounds used in the reaction, the reaction temperature and the solvent are shown in Appendix 1 for the production of ketone bodies and in Table 2 for the diastereoselective arylation of imines, where THF is tetrahydrofuran. Et ₂ O means diethyl ether).

^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３，δｐｐｍ）：１．００（３Ｈ，ｄ，Ｊ＝６．０Ｈｚ），４．００（１Ｈ，ｑ，Ｊ＝６．０Ｈｚ），７．０９（１Ｈ，ｓ），７．２３（１Ｈ，ｍ），７．３０（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ） Reference Example 3-1
Optically active (2S) -1- (2-fluoro-4-pyridyl) -1- (4-chlorophenyl) -1,2-propanediamine

¹ HNMR (400 MHz, CDCl ₃ , δ ppm): 1.00 (3H, d, J = 6.0 Hz), 4.00 (1H, q, J = 6.0 Hz), 7.09 (1H, s), 7.23 (1H, m), 7.30 (2H, d, J = 8.8 Hz), 7.45 (2H, d, J = 8.8 Hz), 8.08 (1H, d, J = 5) .6Hz)

^１ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３，δｐｐｍ）：１．０１（３Ｈ，ｄ，Ｊ＝６．３Ｈｚ），４．１４（１Ｈ，ｑ，Ｊ＝６．３Ｈｚ），７．０３（２Ｈ，ｍ），７．５１（２Ｈ，ｍ），７．６０（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．００（１Ｈ，ｄｄ，Ｊ＝２．２Ｈｚ，８．３Ｈｚ），８．８５（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ）
［α］_Ｄ ^２５（ｃ １．００，エタノール） −１６．３８゜ Reference Example 3-2
Optically active (2S) -1- (4-fluorophenyl) -1- (6-trifluoromethyl-3-pyridyl) -1,2-propanediamine

¹ HNMR (300 MHz, CDCl ₃ , δ ppm): 1.01 (3H, d, J = 6.3 Hz), 4.14 (1H, q, J = 6.3 Hz), 7.03 (2H, m), 7.51 (2H, m), 7.60 (1H, d, J = 8.3 Hz), 8.00 (1H, dd, J = 2.2 Hz, 8.3 Hz), 8.85 (1H, d , J = 2.2Hz)
[Α] _D ²⁵ (c 1.00, ethanol) -16.38 °

Reference Example 3-3
(1S, 2S) -1- (6-Fluoro-3-pyridyl) -1- (3-bromo-4-fluorophenyl) -1,2-propanediamine
¹ HNMR (400 MHz, CDCl ₃ , δ ppm): 1.00 (3H, d, J = 6.3 Hz), 4.05 (1H, q, J = 6.3 Hz), 6.87 (1H, dd, J = 2.7 Hz, 8.4 Hz), 7.08 (1 H, m), 7.35 (1 H, m), 7.70 (1 H, m), 7.96 (1 H, m), 8.39 ( 1H, d, J = 2.7Hz)

^１ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３，δｐｐｍ）：１．０４（３Ｈ，ｄ，Ｊ＝６．３Ｈｚ），４．１４（１Ｈ，ｑ，Ｊ＝６．３Ｈｚ），６．６０（１Ｈ，ｔ，Ｊ＝５５．５Ｈｚ），７．００−７．０４（２Ｈ，ｍ），７．２６−７．４６（２Ｈ，ｍ），７．５６（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．０３（１Ｈ，ｄｄ，Ｊ＝２．０Ｈｚ，８．３Ｈｚ），８．８２（１Ｈ，ｓ） Reference Example 3-4
Optically active (2S) -1- (4-fluorophenyl) -1- (6-difluoromethyl-3-pyridyl) -1,2-propanediamine

¹ HNMR (300 MHz, CDCl ₃ , δ ppm): 1.04 (3H, d, J = 6.3 Hz), 4.14 (1H, q, J = 6.3 Hz), 6.60 (1H, t, J = 55.5 Hz), 7.00-7.04 (2H, m), 7.26-7.46 (2H, m), 7.56 (1 H, d, J = 8.4 Hz), 8.03 (1H, dd, J = 2.0 Hz, 8.3 Hz), 8.82 (1H, s)

^１ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３，δｐｐｍ）：１．０１（３Ｈ，ｄ，Ｊ＝６．３Ｈｚ），４．１２（１Ｈ，ｑ，Ｊ＝６．６Ｈｚ），６．６０（１Ｈ，ｔ，Ｊ＝５５．２Ｈｚ），６．９９−７．０４（２Ｈ，ｍ），７．４９−７．５７（３Ｈ，ｍ），７．９６（１Ｈ，ｄｄ，Ｊ＝１．８Ｈｚ，８．３Ｈｚ），８．７７（１Ｈ，ｓ） Reference Example 3-5
Optically active (2S) -1- (4-fluorophenyl) -1- (6-difluoromethyl-3-pyridyl) -1,2-propanediamine (epimer at position 1 in Reference Example 3-4)

¹ HNMR (300 MHz, CDCl ₃ , δ ppm): 1.01 (3H, d, J = 6.3 Hz), 4.12 (1H, q, J = 6.6 Hz), 6.60 (1H, t, J = 55.2 Hz), 6.99-7.04 (2 H, m), 7.49-7.57 (3 H, m), 7.96 (1 H, dd, J = 1.8 Hz, 8.3 Hz) , 8.77 (1H, s)

^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３，δｐｐｍ）：０．９９（３Ｈ，ｄ，Ｊ＝６．０Ｈｚ），４．０４（１Ｈ，ｑ，Ｊ＝６．４Ｈｚ），６．８３（１Ｈ，ｄｄ，Ｊ＝２．８Ｈｚ，８．４Ｈｚ），７．２６（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．３７（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．９１−７．９６（１Ｈ，ｍ），８．３７（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ） Reference Example 3-6
Optically active (2S) -1- (4-chlorophenyl) -1- (6-fluoro-3-pyridyl) -1,2-propanediamine

¹ HNMR (400 MHz, CDCl ₃ , δ ppm): 0.99 (3H, d, J = 6.0 Hz), 4.04 (1H, q, J = 6.4 Hz), 6.83 (1H, dd, J = 2.8 Hz, 8.4 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.37 (2H, d, J = 8.4 Hz), 7.91-7.96 (1H, m), 8.37 (1H, d, J = 2.4 Hz)

^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３，δｐｐｍ）：０．９９（３Ｈ，ｄ，Ｊ＝６．４Ｈｚ），４．１１（１Ｈ，ｑ，Ｊ＝６．４Ｈｚ），６．８４（１Ｈ，ｄｄ，Ｊ＝２．８Ｈｚ，８．４Ｈｚ），７．５４（２Ｈ，ｄ，Ｊ＝９．２Ｈｚ），７．５７（２Ｈ，ｄ，Ｊ＝９．２Ｈｚ），７．９４−７．９８（１Ｈ，ｍ），８．４０（１Ｈ，ｄ，Ｊ＝２．８Ｈｚ） Reference Example 3-7
Optically active (2S) -1- (6-fluoro-3-pyridyl) -1- (4-trifluoromethylphenyl) -1,2-propanediamine

¹ HNMR (400 MHz, CDCl ₃ , δ ppm): 0.99 (3H, d, J = 6.4 Hz), 4.11 (1H, q, J = 6.4 Hz), 6.84 (1H, dd, J = 2.8 Hz, 8.4 Hz), 7.54 (2H, d, J = 9.2 Hz), 7.57 (2H, d, J = 9.2 Hz), 7.94-7.98 (1H, m), 8.40 (1H, d, J = 2.8 Hz)

^１ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３，δｐｐｍ）：０．８８−１．０４（７Ｈ，ｍ），１．６０−１．９２（４Ｈ，ｂｒ），１．９３−２．０２（１Ｈ，ｍ），４．０１（１Ｈ，ｑ，Ｊ＝６．３Ｈｚ），６．９２−７．０８（３Ｈ，ｍ），７．４１（２Ｈ，ｄｄ，Ｊ＝８．８Ｈｚ，５．４Ｈｚ），７．６７（１Ｈ，ｄｄ，Ｊ＝８．２Ｈｚ，２．６Ｈｚ），８．５７（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ） Reference Example 3-8
Optically active (2S) -1- (6-cyclopropyl-3-pyridyl) -1- (4-fluorophenyl) -1,2-propanediamine

¹ HNMR (300 MHz, CDCl ₃ , δ ppm): 0.88-1.04 (7H, m), 1.60-1.92 (4H, br), 1.93-2.02 (1H, m), 4.01 (1H, q, J = 6.3 Hz), 6.92-7.08 (3H, m), 7.41 (2H, dd, J = 8.8 Hz, 5.4 Hz), 7.67 (1H, dd, J = 8.2 Hz, 2.6 Hz), 8.57 (1H, d, J = 2.5 Hz)

Reference example 4
Preparation of 1-ethyl-3-methoxy-2-pyridone-5-carbonitrile To a chloroform solution (3 mL) of 1-ethyl-3-methoxy-2-pyridone-5-carboxylic acid (245 mg) of Reference Example 2-9 1,1′-Carbonyldiimidazole (263 mg) was added and stirred at room temperature for 30 minutes. A 30% aqueous ammonia solution (6 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with a mixed solution of chloroform and methanol (5: 1). The organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure to obtain an amide compound (232 mg) as a brown solid. The chloroform solution (3 mL) of the amide compound (210 mg) was cooled to −78 ° C., triethylamine (1.49 mL) and trifluoroacetic anhydride (3.21 mL) were sequentially added, and the reaction solution was added for 1.5 hours. The temperature was raised to -30 ° C. After diluting with chloroform and adding saturated sodium bicarbonate, the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 4: 6) to give the title compound (80 mg) as a white solid.
¹ HNMR (400 MHz, CDCl ₃ , δ ppm): 1.38 (3H, t, J = 7.2 Hz), 3.84 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 6.59 (1H, d, J = 2.2 Hz), 7.44 (1H, s, J = 2.2 Hz)

Reference Example 5
Production of 1-methoxy-2-pyridone-5-carboxylic acid (1) Production of methyl 6-chloronicotinate N-oxide 2-Chloro-5-methoxycarbonylpyridine (7.0 g) and urea hydrogen peroxide adduct ( 6.93 g) was suspended in 100 mL of acetonitrile. In an ice bath, trifluoroacetic anhydride (9.92 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium thiosulfate solution were added to the residue. Extraction was performed 5 times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 8) to give the title compound as a light brown solid (8.0 g).
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 3.96 (3H, s), 7.86 (1H, d, J = 8.8 Hz), 7.95 (1H, dd, J = 1.6 Hz) 8.4 Hz), 8.88 (1H, d, J = 2.0 Hz)

(2) Preparation of methyl 1-hydroxy-2-pyridone-5-carboxylate To a dry acetonitrile solution (200 mL) of 2-chloro-5-methoxycarbonylpyridine-N-oxide (12.2 g), anhydrous in an ice bath Trifluoroacetic acid (30 mL) was slowly added and stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, methanol was slowly added to the residue in an ice bath, and the mixture was stirred at room temperature for 15 minutes. After distilling off the solvent under reduced pressure, the residue was dried under vacuum. The resulting solid was purified by recrystallization (acetonitrile-diethyl ether) to give the title compound as a white solid (9.3 g).
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 3.83 (3H, s), 6.52 (1H, d, J = 9.2 Hz), 7.80 (1H, dd, J = 2.4 Hz) 9.2 Hz), 8.51 (1H, d, J = 2.4 Hz)

(3) Production of 1-methoxy-2-pyridone-5-carboxylic acid A solution of methyl 1-hydroxy-2-pyridone-5-carboxylate (1.69 g) and methyl iodide (4.26 g) in dimethylformamide (20 mL) ) Was added sodium hydrogen carbonate (3.36 g) and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and ethyl acetate and distilled water were added to the residue. Extraction was performed 3 times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure. The obtained residue was dried under reduced pressure to obtain the desired product as a pale yellow oil (2.20 g). The obtained methyl ester was hydrolyzed under basic conditions to give the title compound as a white solid (1.22 g).
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 4.07 (3H, s), 6.63 (1H, d, J = 9.6 Hz), 7.94 (1H, dd, J = 2.4 Hz, 9.6 Hz), 8.58 (1H, d, J = 2.4 Hz)

  The compounds of Reference Examples 5-1 and 2 were synthesized according to the method of Reference Example 5.

Reference Example 5-1
1-ethoxy-2-pyridone-5-carboxylic acid
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 1.38 (3.0 H, t, J = 7.2 Hz), 4.31 (2.0 H, q, J = 7.2 Hz), 6.63 ( 1.0H, d, J = 9.6 Hz), 7.93 (1.0 H, dd, J = 2.4 Hz, 9.6 Hz), 8.55 (1.0 H, d, J = 2.0 Hz)

Reference Example 5-2
1-difluoromethoxy-2-pyridone-5-carboxylic acid
¹ HNMR (400 MHz, CD ₃ OD, δ ppm): 6.71 (1.0 H, d, J = 10.0 Hz), 7.07 (1.0 H, t, J = 70 Hz), 7.97 (1. 0H, dd, J = 2.4 Hz, 9.6 Hz), 8.50 (1.0 H, d, J = 2.4 Hz)

Reference Example 6
Preparation of 1-cyclopropyl-2-pyridone-5-carboxylic acid Methyl coumarate (1.52 g) was dissolved in 4 mL of methanol, cyclopropylamine (1.5 mL) was added at room temperature, and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the organic solvent was distilled off under reduced pressure. The obtained solid was suspended in diisopropyl ether and filtered to give the title compound (ester ester, 471 mg) as a white solid. The obtained methyl ester was hydrolyzed under basic conditions to give the title compound as a yellow solid.
_{^{1 HNMR (400MHz, CD 3 OD}} , δppm): 0.91-0.97 (2H, m), 1.12-1.19 (2H, m), 3.34 (1H, m), 6.50 (1H, d, J = 9.9 Hz), 7.92 (1H, dd, J = 9.5 Hz, 2.6 Hz), 8.29 (1H, d, J = 2.6 Hz)

Formulation Example 1
After mixing 20.0 g of the compound of Example 1, 417 g of lactose, 80 g of crystalline cellulose and 80 g of partially pregelatinized starch using a V-type mixer, 3.0 g of magnesium stearate is added and mixed. The mixed powder is tableted according to a conventional method to obtain 3000 tablets each having a diameter of 7.0 mm and a weight of 150 mg.
Content per tablet (150 mg) 5.0 mg of the compound of Example 1
Lactose 104.25mg
Crystalline cellulose 20.0mg
Partially pregelatinized starch 20.0mg
Magnesium stearate 0.75mg

Formulation Example 2
After 10.8 g of hydroxypropylcellulose 2910 and 2.1 g of polyethylene glycol 6000 are dissolved in 172.5 g of purified water, 2.1 g of titanium dioxide is dispersed to prepare a coating solution. A coating liquid is spray-coated on 2500 tablets of Formulation Example 1 prepared separately using Hicoater Mini to obtain a film-coated tablet having a weight of 155 mg.
Content per tablet (155 mg) 150 mg of tablets of Preparation Example 1
Hydroxypropylcellulose 2910 3.6mg
Polyethylene glycol 6000 0.7mg
Titanium dioxide 0.7mg

Claims (41)

Formula (I)

[Wherein, Ar ¹ and Ar ² are each independently a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, or a cyclo lower alkyl lower alkyl group. , Lower alkenyl group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, lower alkoxy group, halolower alkoxy group, aryloxy group, heteroaryloxy Group, lower alkylthio group, carboxyl group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group, arylsulfonyl group, aryl And it may have a substituent group selected from the group consisting of heteroaryl group means an aryl group or a heteroaryl group; R ¹ and R ² are each independently a halogen atom, a lower alkyl amino group A substituent selected from the group consisting of a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group. A lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group; each of R ³ , R ⁴ and R ⁵ independently represents a hydrogen atom, a cyano group, a halogen atom or Means a hydroxyl group, or a halogen atom, a lower alkylamino group, a di-lower alkylamino Optionally having a substituent selected from the group consisting of a group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group. Means an alkyl group, a lower alkoxy group or a lower alkylthio group] , or a salt thereof . The compound according to claim 1 , or a salt thereof, wherein R ⁴ and R ⁵ are simultaneously hydrogen atoms. Formula (I-1)

[Wherein, Ar ¹ and Ar ² are each independently a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, or a cyclo lower alkyl lower alkyl group. , Lower alkenyl group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, lower alkoxy group, halolower alkoxy group, aryloxy group, heteroaryloxy Group, lower alkylthio group, carboxyl group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group, arylsulfonyl group, aryl And it may have a substituent group selected from the group consisting of heteroaryl group means an aryl group or a heteroaryl group; R ¹ and R ² are each independently a halogen atom, a lower alkyl amino group A substituent selected from the group consisting of a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group. it may also be a lower alkyl group, a cyclo-lower alkyl group, a cycloalkyl means a lower alkyl lower alkyl group or a lower alkoxy group; R ³ is a hydrogen atom, a cyano group, or represents a halogen atom or a hydroxyl group, or a halogen atom, a lower alkyl Amino group, di-lower alkylamino group, lower alkanoylamino group, hydroxy acid Optionally having a substituent selected from the group consisting of a group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group, a lower alkyl group, a lower alkoxy group or a lower group The compound according to claim 1 , or a salt thereof . Ar ¹ or Ar ² is an aryl group having a substituent selected from the group consisting of a halogen atom and a halo lower alkyl group, and the other is a substituent selected from the group consisting of a halogen atom and a halo lower alkyl group The compound according to claim 1, 2 or 3, or a salt thereof, which is a heteroaryl group having a group. R ¹ is selected from the group consisting of a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group. The compound according to claim 1, 2 or 3 , or a salt thereof, which is a lower alkyl group, a cyclo lower alkyl group or a lower alkoxy group which may have a selected substituent. R ² is selected from the group consisting of a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group. The compound according to claim 1, 2, or 3 , or a salt thereof, which is a lower alkyl group which may have a selected substituent. R ³ is a hydrogen atom, a halogen atom or a hydroxyl group, or a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkyl 4. The compound according to claim 2 or 3 , or a salt thereof, which is a lower alkyl group which may have a substituent selected from the group consisting of a carbamoyl group and a di-lower alkylcarbamoyl group. Ar ¹ or Ar ² is an aryl group having a substituent selected from the group consisting of a halogen atom and a halo lower alkyl group, and the other is a substituent selected from the group consisting of a halogen atom and a halo lower alkyl group A heteroaryl group having a group, and R ¹ is a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and A lower alkyl group, a cyclo lower alkyl group or a lower alkoxy group which may have a substituent selected from the group consisting of di-lower alkylcarbamoyl groups, R ² is a halogen atom, a lower alkylamino group, a di-lower group; Alkylamino group, lower alkanoylamino group, hydroxyl group, lower alcohol A lower alkyl group which may have a substituent selected from the group consisting of a xyl group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group, and R ³ is a hydrogen atom A halogen atom, a hydroxyl group, or a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower group. The compound according to claim 2 or 3, or a salt thereof, which is a lower alkyl group which may have a substituent selected from the group consisting of alkylcarbamoyl groups. 5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl-2-pyridone ,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1- (2,2-difluoroethyl) -5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazoline-2 -Yl] -2-pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-propyl-2-pyridone ,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-isopropyl-2-pyridone ,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- 2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- 2-pyridone,
1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -2 -Pyridone,
5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-propyl-2 -Pyridone,
5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-propyl-2 -Pyridone,
1- (2,2-difluoroethyl) -5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline -2-yl] -2-pyridone,
1- (2,2-difluoroethyl) -5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline -2-yl] -2-pyridone,
3-Chloro-1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
3-Chloro-1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
5-[(4S, 5S) -4- (3-Bromo-4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-difluoro Methyl-2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1- (2,2-difluoroethyl) -5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazoline-2 -Yl] -2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (2-fluoro-4-pyridyl) -5-methyl-4- (4-trifluorophenyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (2-fluoro-4-pyridyl) -5-methyl-4- (4-trifluorophenyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
3-Chloro-1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
5-[(4R, 5S) -4- (4-Fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-methyl-2 -Pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-methyl-2 -Pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1-difluoromethyl-5-[(4S, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1-ethyl-5-[(4R, 5S) -4- (2-fluoro-4-pyridyl) -5-methyl-4- (4-trifluoromethylphenyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-ethyl-5-[(4S, 5S) -4- (2-fluoro-4-pyridyl) -5-methyl-4- (4-trifluoromethylphenyl) -2-imidazolin-2-yl] -2 -Pyridone,
1-ethyl-5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
3-Chloro-1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
3-Chloro-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3-methyl -2-pyridone,
3-Chloro-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1 -Methyl-2-pyridone,
3-Chloro-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1 -Methyl-2-pyridone,
1-ethyl-3-fluoro-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- Il] -2-pyridone,
1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1- (2,2-difluoroethyl) -5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazoline-2 -Yl] -2-pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1,3-dimethyl-2 -Pyridone,
3-chloro-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
3-Chloro-1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-ethyl-3-fluoro-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
5-[(4R, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl-2-pyridone ,
1-ethyl-3-fluoro-5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl]- 2-pyridone,
1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl]- 2-pyridone,
3-Ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
3-Ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
3-Ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl -2-pyridone,
1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3-methoxy -2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
5-[(4R, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-2- Pyridone,
5-[(4S, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-2- Pyridone,
5-[(4R, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-3- Fluoro-2-pyridone,
5-[(4S, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-3- Fluoro-2-pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone ,
5-[(4R, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone ,
1-ethoxy-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone ,
1-cyclopropyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-cyclopropyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- 2-pyridone,
5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone ,
5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-methoxy-2 -Pyridone,
5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Methyl-2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Methyl-2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Methoxy-2-pyridone,
1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Methoxy-2-pyridone,
5-[(5S) -4,4-bis (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (6-cyclopropyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 -Pyridone,
5-[(4S, 5S) -4- (6-cyclopropyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-2- Pyridone,
5-[(4S, 5S) -4- (4-chlorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone,
5-[(4S, 5S) -4- (6-Fluoro-3-pyridyl) -5-methyl-4- (4-trifluoromethylphenyl) -2-imidazolin-2-yl] -1-methoxy-2 -Pyridone,
5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone ,
1-cyclopropyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-cyclopropyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-ethyl-5-[(5S) -4,4-bis (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone,
5-[(5S) -4,4-bis (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-difluoromethyl-2-pyridone,
1-cyclopropyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-difluoromethyl-3-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl ] -2-pyridone,
1-difluoromethyl-3-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl ] -2-pyridone,
1-difluoromethoxy-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
5-[(4R, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2- Pyridone,
5-[(4S, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2- Pyridone,
1-difluoromethoxy-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- Pyridone,
1-difluoromethyl-3-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl ] -2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -3- Hydroxy-2-pyridone,
1-difluoromethyl-5-[(4S, 5S) -4- (4-fluoro-3-hydroxyphenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl ] -2-pyridone , or 1-difluoromethyl-5-[(4S, 5R) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-hydroxymethyl-2-imidazoline The compound according to claim 1, which is 2-yl] -2-pyridone, or a salt thereof. 1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- The compound according to claim 1, which is pyridone, or a salt thereof. 1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone A compound according to claim 1 or a salt thereof. 5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-propyl-2-pyridone A compound according to claim 1 or a salt thereof. 5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-isopropyl-2-pyridone A compound according to claim 1 or a salt thereof. 1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- The compound according to claim 1, which is 2-pyridone, or a salt thereof. 1-difluoromethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl]- The compound according to claim 1, which is 2-pyridone, or a salt thereof. 1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -2 The compound according to claim 1, which is -pyridone, or a salt thereof. 1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -2 The compound according to claim 1, which is -pyridone, or a salt thereof. 5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-propyl-2 The compound according to claim 1, which is -pyridone, or a salt thereof. 5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-propyl-2 The compound according to claim 1, which is -pyridone, or a salt thereof. 3-Chloro-1-ethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- [Il] -2-pyridone, or a salt thereof. 3-Chloro-1-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- [Il] -2-pyridone, or a salt thereof. 1-difluoromethyl-5-[(4R, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -2- The compound according to claim 1, which is pyridone, or a salt thereof. 1-difluoromethyl-5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone A compound according to claim 1 or a salt thereof. 1-difluoromethyl-5-[(4S, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone A compound according to claim 1 or a salt thereof. 1-ethyl-5-[(4R, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone The compound according to claim 1, or a salt thereof. 1-ethyl-5-[(4S, 5S) -4- (4-chlorophenyl) -4- (2-fluoro-4-pyridyl) -5-methyl-2-imidazolin-2-yl] -2-pyridone The compound according to claim 1, or a salt thereof. 1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] The compound according to claim 1, which is 2-pyridone, or a salt thereof. 1-ethyl-3-fluoro-5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- [Il] -2-pyridone, or a salt thereof. 1-ethyl-3-fluoro-5-[(4S, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazoline-2- [Il] -2-pyridone, or a salt thereof. 3-Ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methyl The compound according to claim 1, which is 2-pyridone, or a salt thereof. 1-difluoromethyl-5-[(4R, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 The compound according to claim 1, which is -pyridone, or a salt thereof. 1-difluoromethyl-5-[(4S, 5S) -4- (6-difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -2 The compound according to claim 1, which is -pyridone, or a salt thereof. 5-[(4R, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-3- The compound according to claim 1, which is fluoro-2-pyridone, or a salt thereof. 5-[(4S, 5S) -4- (6-Difluoromethyl-3-pyridyl) -4- (4-fluorophenyl) -5-methyl-2-imidazolin-2-yl] -1-ethyl-3- The compound according to claim 1, which is fluoro-2-pyridone, or a salt thereof. 5-[(4S, 5S) -4- (4-Fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl] -1-methoxy-2-pyridone A compound according to claim 1 or a salt thereof. 5-[(4R, 5S) -4- (4-fluorophenyl) -5-methyl-4- (6-trifluoromethyl-3-pyridyl) -2-imidazolin-2-yl] -1-methoxy-2 The compound according to claim 1, which is -pyridone, or a salt thereof. 1-difluoromethyl-3-ethyl-5-[(4S, 5S) -4- (4-fluorophenyl) -4- (6-fluoro-3-pyridyl) -5-methyl-2-imidazolin-2-yl ] The compound of Claim 1 which is 2-pyridone, or its salt. Formula (II)

[ ^Wherein , Ar ^1p and Ar ^2p each independently represent a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group, a lower alkenyl group, Di-lower alkylamino group, lower alkoxy group, halo-lower alkoxy group, aryloxy group, heteroaryloxy group, lower alkylthio group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group , Arylsulfonyl group, aryl group and heteroaryl group, and optionally protected hydroxy lower alkyl group, lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, carbo Sill group may have a substituent selected from the group consisting of carbamoyl group and a lower alkylcarbamoyl group, an aryl group or a heteroaryl group; R ^2p is a halogen atom, a di-lower alkylamino group, a lower A substituent selected from the group consisting of an alkoxy group, a formyl group, a lower alkoxycarbonyl group, a di-lower alkylcarbamoyl group and an optionally protected lower alkylamino group, lower alkanoylamino group, hydroxyl group and lower alkylcarbamoyl group; Which may have a lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group], and a compound of the general formula (III)

[Wherein, R ^1p represents a halogen atom, a di-lower alkylamino group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a di-lower alkylcarbamoyl group, and an optionally protected lower alkylamino group or lower alkanoylamino group. Represents a lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group which may have a substituent selected from the group consisting of a hydroxyl group and a lower alkyl carbamoyl group; R ^3p , R ^4p and R ^5p each independently represents a hydrogen atom, a cyano group, a halogen atom or an optionally protected hydroxyl group, or a halogen atom, a di-lower alkylamino group, a lower alkoxy group, a formyl group, Lower alkoxycarbonyl group and di-lower alkylcarbamoyl group Optionally having a substituent selected from the group consisting of a lower alkylamino group, a lower alkanoylamino group, a hydroxyl group and a lower alkylcarbamoyl group, a lower alkyl group, a lower alkoxy group or a lower group. And a compound represented by the general formula (IV):

[Wherein Ar ^1p , Ar ^2p , R ^1p , R ^2p , R ^3p , R ^4p and R ^5p have the above-mentioned meanings], and then the compound (IV) is subjected to intramolecular cyclization condensation By subjecting to reaction, the general formula (V)

[Wherein Ar ^1p , Ar ^2p , R ^1p , R ^2p , R ^3p , R ^4p and R ^5p have the above-mentioned meanings], wherein a protective group is optionally removed General formula (I)

[Wherein, Ar ¹ and Ar ² are each independently a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, or a cyclo lower alkyl lower alkyl group. , Lower alkenyl group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, lower alkoxy group, halolower alkoxy group, aryloxy group, heteroaryloxy Group, lower alkylthio group, carboxyl group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group, arylsulfonyl group, aryl And it may have a substituent group selected from the group consisting of heteroaryl group means an aryl group or a heteroaryl group; R ¹ and R ² are each independently a halogen atom, a lower alkyl amino group A substituent selected from the group consisting of a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group. A lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group; each of R ³ , R ⁴ and R ⁵ independently represents a hydrogen atom, a cyano group, a halogen atom or Means a hydroxyl group, or a halogen atom, a lower alkylamino group, a di-lower alkylamino Optionally having a substituent selected from the group consisting of a group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group. Means an alkyl group, a lower alkoxy group or a lower alkylthio group], or a method for producing a salt thereof . Formula (II)

[ ^Wherein , Ar ^1p and Ar ^2p each independently represent a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group, a lower alkenyl group, Di-lower alkylamino group, lower alkoxy group, halo-lower alkoxy group, aryloxy group, heteroaryloxy group, lower alkylthio group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group , Arylsulfonyl group, aryl group and heteroaryl group, and optionally protected hydroxy lower alkyl group, lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, carbo Sill group may have a substituent selected from the group consisting of carbamoyl group and a lower alkylcarbamoyl group, an aryl group or a heteroaryl group; R ^2p is a halogen atom, a di-lower alkylamino group, a lower A substituent selected from the group consisting of an alkoxy group, a formyl group, a lower alkoxycarbonyl group, a di-lower alkylcarbamoyl group and an optionally protected lower alkylamino group, lower alkanoylamino group, hydroxyl group and lower alkylcarbamoyl group; A lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group which may have a compound represented by the general formula (VI):

[Wherein R ⁶ represents an amino group or a lower alkoxy group, and R ^1p represents a halogen atom, a di-lower alkylamino group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a di-lower alkylcarbamoyl group, and a protected group. Optionally having a substituent selected from the group consisting of a lower alkylamino group, a lower alkanoylamino group, a hydroxyl group and a lower alkylcarbamoyl group, a lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower group. R ^3p , R ^4p and R ^5p each independently represents a hydrogen atom, a cyano group, a halogen atom or an optionally protected hydroxyl group, or a halogen atom, an alkyl group or a lower alkoxy group; Di-lower alkylamino group, lower alkoxy group, formyl group, lower alkoxy group Bonyl group and di-lower alkylcarbamoyl group and optionally substituted, selected from the group consisting of lower alkylamino group, lower alkanoylamino group, hydroxyl group and lower alkylcarbamoyl group, lower An alkyl group, a lower alkoxy group or a lower alkylthio group] is reacted with an acid addition salt of a compound represented by the general formula (V):

[Wherein Ar ^1p , Ar ^2p , R ^1p , R ^2p , R ^3p , R ^4p and R ^5p have the above-mentioned meanings], wherein a protective group is optionally removed General formula (I)

[Wherein, Ar ¹ and Ar ² are each independently a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, or a cyclo lower alkyl lower alkyl group. , Lower alkenyl group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, lower alkoxy group, halolower alkoxy group, aryloxy group, heteroaryloxy Group, lower alkylthio group, carboxyl group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group, arylsulfonyl group, aryl And it may have a substituent group selected from the group consisting of heteroaryl group means an aryl group or a heteroaryl group; R ¹ and R ² are each independently a halogen atom, a lower alkyl amino group A substituent selected from the group consisting of a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group. A lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group; each of R ³ , R ⁴ and R ⁵ independently represents a hydrogen atom, a cyano group, a halogen atom or Means a hydroxyl group, or a halogen atom, a lower alkylamino group, a di-lower alkylamino Optionally having a substituent selected from the group consisting of a group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group. Means an alkyl group, a lower alkoxy group or a lower alkylthio group], or a method for producing a salt thereof . Formula (I)

[Wherein, Ar ¹ and Ar ² are each independently a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, or a cyclo lower alkyl lower alkyl group. , Lower alkenyl group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, lower alkoxy group, halolower alkoxy group, aryloxy group, heteroaryloxy Group, lower alkylthio group, carboxyl group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group, arylsulfonyl group, aryl And it may have a substituent group selected from the group consisting of heteroaryl group means an aryl group or a heteroaryl group; R ¹ and R ² are each independently a halogen atom, a lower alkyl amino group A substituent selected from the group consisting of a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group. A lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group; each of R ³ , R ⁴ and R ⁵ independently represents a hydrogen atom, a cyano group, a halogen atom or Means a hydroxyl group, or a halogen atom, a lower alkylamino group, a di-lower alkylamino Optionally having a substituent selected from the group consisting of a lower group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group. A neuropeptide Y receptor antagonist comprising a compound represented by the above or a salt thereof as an active ingredient. Formula (I)

[Wherein, Ar ¹ and Ar ² are each independently a cyano group, a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, or a cyclo lower alkyl lower alkyl group. , Lower alkenyl group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, lower alkylsulfonylamino group, arylsulfonylamino group, hydroxyl group, lower alkoxy group, halolower alkoxy group, aryloxy group, heteroaryloxy Group, lower alkylthio group, carboxyl group, formyl group, lower alkanoyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group, arylsulfonyl group, aryl And it may have a substituent group selected from the group consisting of heteroaryl group means an aryl group or a heteroaryl group; R ¹ and R ² are each independently a halogen atom, a lower alkyl amino group A substituent selected from the group consisting of a di-lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, and a di-lower alkylcarbamoyl group. A lower alkyl group, a cyclo lower alkyl group, a cyclo lower alkyl lower alkyl group or a lower alkoxy group; each of R ³ , R ⁴ and R ⁵ independently represents a hydrogen atom, a cyano group, a halogen atom or Means a hydroxyl group, or a halogen atom, a lower alkylamino group, a di-lower alkylamino Optionally having a substituent selected from the group consisting of a lower group, a lower alkanoylamino group, a hydroxyl group, a lower alkoxy group, a formyl group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group. A therapeutic agent for bulimia, obesity, or diabetes, comprising as an active ingredient a compound represented by the above formula or a salt thereof : an alkyl group, a lower alkoxy group or a lower alkylthio group;