JP5054996B2 - Novel 1,2,3,4-tetrahydroquinoxaline derivative having glucocorticoid receptor binding activity - Google Patents

Description

  The present invention relates to a novel 1,2,3,4-tetrahydroquinoxaline derivative or a salt thereof useful as a medicine. The derivative has a binding activity to a glucocorticoid receptor and is useful as a glucocorticoid receptor modulator (glucocorticoid receptor agonist and / or glucocorticoid receptor antagonist) having a non-steroidal structure.

The glucocorticoid receptor is a 94 kDa ligand-activated intracellular transcriptional regulator belonging to the nuclear receptor superfamily. This receptor regulates the metabolism of carbohydrates, proteins, fats, etc., suppresses immune and inflammatory responses, activates the central nervous system, regulates cardiovascular functions, and regulates basic and stress-related homeostasis. I am a mediator. Diseases involving glucocorticoid action include diabetes, obesity and other metabolic disorders, arthritis, enteritis, inflammatory diseases such as chronic obstructive pulmonary disease, autoimmune diseases such as collagen disease, asthma, atopic dermatitis, allergies Allergic diseases such as rhinitis and conjunctivitis, central nervous system diseases such as psychosis, Alzheimer, drug use disorders, hypertension, hypercalcemia, hyperinsulinemia, cardiovascular diseases such as hyperlipidemia, neurology / immunity・ Homeostasis-related diseases and glaucoma that cause abnormal endocrine balance are known (
, ).

  Therefore, a compound having a binding activity to the glucocorticoid receptor is considered useful as a preventive and / or therapeutic agent for these diseases.

Examples of the compound having binding activity to the glucocorticoid receptor include in vivo glucocorticoid receptor agonists such as cortisol and corticosterone, dexamethasone, prednisone, prednisone and other synthetic glucocorticoid receptor agonists such as RU486, and the like. Non-selective glucocorticoid receptor antagonists are known (
).

On the other hand, compounds having a 1,2,3,4-tetrahydroquinoxaline structure are disclosed in Patent Document 2, Patent Document 3, and the like. The compound disclosed in Patent Document 2 relates to a protein tyrosine phosphatase inhibitor that requires a carboxy group. On the other hand, Patent Document 3 discloses a very large number of compounds having a 1,2,3,4-tetrahydroquinoxaline structure as antiviral agents. However, there is no specific disclosure of the compound of the present invention in any document.
General Clinical, 54 (7), 1951-2076 (2005) JP 2002-193955 A International Publication No. 04/099192 Pamphlet JP-A-5-148243

  Synthetic studies of new 1,2,3,4-tetrahydroquinoxaline derivatives and finding the pharmacological action of the derivatives are very interesting issues.

  The present inventors have conducted synthetic studies on 1,2,3,4-tetrahydroquinoxaline derivatives having a new chemical structure, and have succeeded in creating many new compounds. Furthermore, as a result of studying the pharmacological action of the derivative, the present inventor found that the derivative has a binding activity to the glucocorticoid receptor and is useful as a pharmaceutical, and completed the present invention.

That is, the present invention relates to a compound represented by the following general formula (1) or a salt thereof (hereinafter referred to as “the present compound”) and a pharmaceutical composition containing them. Further, the preferred invention for its pharmaceutical use relates to a glucocorticoid receptor modulator, and the target disease includes diseases involving glucocorticoid action, that is, metabolic disorders such as diabetes and obesity, arthritis, enteritis, chronic Inflammatory diseases such as obstructive pulmonary disease, autoimmune diseases such as collagen disease, allergic diseases such as asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, central nervous system diseases such as psychosis, Alzheimer, drug use disorders, Examples include cardiovascular diseases such as hypertension, hypercalcemia, hyperinsulinemia, and hyperlipidemia, homeostasis-related diseases that cause abnormal balance of nerves, immunity, and endocrine, glaucoma, and the like. A particularly preferred invention is an invention relating to a prophylactic or therapeutic agent for these diseases.

[R ¹ may have a halogen atom, a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. Good heterocyclic group, hydroxy group, ester of hydroxy group, lower alkoxy group optionally having substituent, lower cycloalkyloxy group optionally having substituent, aryloxy group optionally having substituent A heterocyclic oxy group which may have a substituent, a mercapto group, an ester of a mercapto group, a lower alkylthio group which may have a substituent, a lower cycloalkylthio group which may have a substituent, a substituent Arylthio group which may have, heterocyclic thio group which may have substituent, amino group, lower alkylamino group which may have substituent, lower cycloalkylamino group which may have substituent Have a substituent May be an arylamino group, a heterocyclic amino group which may have a substituent, an amide of an amino group, an amide of a lower alkylamino group which may have a substituent, a lower cycloalkyl which may have a substituent An amide of an amino group, an amide of an arylamino group which may have a substituent, an amide of a heterocyclic amino group which may have a substituent, a formyl group, a lower alkylcarbonyl group which may have a substituent, A lower cycloalkylcarbonyl group which may have a substituent, an arylcarbonyl group which may have a substituent, a heterocyclic carbonyl group which may have a substituent, a carboxy group, an ester of a carboxy group, a carboxy group Amide, optionally substituted lower alkylsulfonyl group, optionally substituted lower cycloalkylsulfonyl group, optionally substituted arylsulfonyl group, An optionally substituted heterocyclic sulfonyl group, sulfonic acid group, ester of sulfonic acid group, amide of sulfonic acid group, nitro group or cyano group;
p represents an integer of 0 to 5;
when p is 2-5, each R ¹ may be the same or different;
R ² represents a halogen atom, a lower alkyl group which may have a substituent, a hydroxy group, an ester of a hydroxy group or a lower alkoxy group which may have a substituent;
q represents an integer of 0 to 2;
when q is 2, each R ² may be the same or different;
R ³ may have a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkylcarbonyl group which may have a substituent, or a substituent. A good lower alkenylcarbonyl group or an optionally substituted arylcarbonyl group;
R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group that may have a substituent, a lower alkenyl group that may have a substituent, or a lower group that may have a substituent. An alkynyl group, an optionally substituted lower cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group;
R ⁴ and R ⁵ may together form a 3-8 membered lower cycloalkane ring which may have a substituent;
R ⁶ may have a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, or a substituent. A lower cycloalkyl group, an aryl group which may have a substituent or a heterocyclic group which may have a substituent;
A represents a lower alkylene group which may have a substituent;
R ⁷ represents OR ⁸ , NR ⁸ R ⁹ , SR ⁸ , S (O) R ⁸ or S (O) ₂ R ⁸ ;
R ⁸ and R ⁹ are the same or different and are a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, Lower cycloalkyl group optionally having substituent, aryl group optionally having substituent, heterocyclic group optionally having substituent, formyl group, lower alkylcarbonyl optionally having substituent Group, optionally substituted lower alkenylcarbonyl group, optionally substituted lower alkynylcarbonyl group, optionally substituted lower cycloalkylcarbonyl group, optionally substituted. Arylcarbonyl group, optionally substituted heterocyclic carbonyl group, carboxy group, optionally substituted lower alkoxycarbonyl group, optionally substituted lower alkenyloxycarbonyl group, substituted A lower alkynyloxycarbonyl group which may have a lower cycloalkyloxycarbonyl group which may have a substituent, an aryloxycarbonyl group which may have a substituent, a heterocyclic ring which may have a substituent Oxycarbonyl group, optionally substituted lower alkylsulfonyl group, optionally substituted lower alkenylsulfonyl group, optionally substituted lower alkynylsulfonyl group, optionally substituted A preferred lower cycloalkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted heterocyclic sulfonyl group, an aminocarbonyl group, an optionally substituted lower alkylaminocarbonyl group, A lower alkenylaminocarbonyl group which may have a substituent, a lower alkynylaminocarbonyl group which may have a substituent, Indicates a good lower cycloalkyl amino carbonyl group optionally, may have an optionally substituted arylaminocarbonyl group or optionally substituted heterocyclic aminocarbonyl group;
When R ⁷ is NR ⁸ R ⁹ , R ⁸ and R ⁹ may be taken together to form a 3- to 8-membered nitrogen-containing heterocyclic ring which may have a substituent;
X represents O or S. same as below. ]

The present invention provides a 1,2,3,4-tetrahydroquinoxaline derivative or a salt thereof useful as a medicine. The compound of the present invention has excellent glucocorticoid receptor binding activity and is useful as a glucocorticoid receptor modulator. In particular, diseases involving glucocorticoid action, that is, metabolic disorders such as diabetes and obesity, arthritis, enteritis, inflammatory diseases such as chronic obstructive pulmonary disease, autoimmune diseases such as collagen disease, asthma, atopic dermatitis, Allergic diseases such as allergic rhinitis and conjunctivitis, central nervous system diseases such as psychosis, Alzheimer, drug use disorder, cardiovascular diseases such as hypertension, hypercalcemia, hyperinsulinemia, hyperlipidemia, It is expected to be useful as a preventive or therapeutic agent for homeostasis-related diseases and glaucoma diseases that cause abnormal immunity / endocrine balance.

  Definitions of terms (atoms, groups, rings, etc.) used in this specification will be described in detail below.

  “Halogen atom” refers to a fluorine, chlorine, bromine or iodine atom.

  The “lower alkyl group” refers to a linear or branched alkyl group having 1 to 8 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl group and the like. .

  The “lower alkenyl group” refers to a straight or branched alkenyl group having 2 to 8 carbon atoms. Specific examples include vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, isopropenyl, 2-methyl-1-propenyl, 2-methyl-2-butenyl group and the like.

  The “lower alkynyl group” refers to a straight chain or branched alkynyl group having 2 to 8 carbon atoms. Specific examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, isobutynyl, isopentynyl group and the like.

  The “lower cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl groups.

  The “lower cycloalkane ring” refers to a cycloalkane ring having 3 to 8 carbon atoms. Specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane ring.

  The “aryl group” is a residue obtained by removing one hydrogen atom from a monocyclic aromatic hydrocarbon having 6 to 14 carbon atoms or a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon. Show. A residue obtained by removing one hydrogen atom from a bicyclic or tricyclic condensed polycyclic hydrocarbon having 6 to 14 carbon atoms is also within the scope of the aryl group. Specific examples include phenyl, naphthyl, anthryl, phenanthryl group, fluorenyl group and the like.

  “Heterocyclic group” means a saturated or unsaturated monocyclic heterocycle having one or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring, or a bicyclic or tricyclic ring A residue obtained by removing one hydrogen atom from a condensed polycyclic heterocycle is shown.

  Specific examples of saturated monocyclic heterocycles include pyrrolidine, pyrazolidine, imidazolidine, triazolidine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, homopiperidine, and homopiperazine rings having a nitrogen atom in the ring, Tetrahydrofuran, tetrahydropyran ring, etc. having an atom in the ring, tetrahydrothiophene, tetrahydrothiopyran ring, etc. having a sulfur atom in the ring, oxazolidine, isoxazolidine, morpholine ring, etc. having a nitrogen atom and an oxygen atom in the ring And thiazolidine, isothiazolidine, and thiomorpholine rings having nitrogen and sulfur atoms in the ring.

  These saturated monocyclic heterocycles are condensed with benzene rings and the like to form dihydroindole, dihydroindazole, dihydrobenzimidazole, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydrocinnoline, tetrahydrophthalazine, tetrahydroquinazoline, tetrahydroquinoxaline, dihydro Benzofuran, dihydroisobenzofuran, chroman, isochroman, dihydrobenzothiophene, dihydroisobenzothiophene, thiochroman, isothiochroman, dihydrobenzoxazole, dihydrobenzoisoxazole, dihydrobenzoxazine, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydrobenzothia Bicyclic or tricyclic condensation such as gin, xanthene, 4a-carbazole and perimidine ring Polycyclic heterocyclic ring may be formed.

  Specific examples of the unsaturated monocyclic heterocycle include dihydropyrrole, pyrrole, dihydropyrazole, pyrazole, dihydroimidazole, imidazole, dihydrotriazole, triazole, tetrahydropyridine, dihydropyridine, pyridine, tetrahydropyridazine having a nitrogen atom in the ring, Dihydropyridazine, pyridazine, tetrahydropyrimidine, dihydropyrimidine, pyrimidine, tetrahydropyrazine, dihydropyrazine, pyrazine ring, etc., dihydrofuran, furan, dihydropyran, pyran ring, etc. having an oxygen atom in the ring Dihydrothiophene, thiophene, dihydrothiopyran, thiopyran ring, etc. possessed by dihydrooxazole, oxazole, dihydroisoxazol having nitrogen and oxygen atoms in the ring , Isoxazole, dihydro-oxazine, oxazine rings and the like, dihydrothiazole having a nitrogen atom and a sulfur atom in the ring, thiazole, dihydro-isothiazole, isothiazole, dihydrothiazine, thiazine ring, and the like.

  In addition, these unsaturated monocyclic heterocycles are condensed with a benzene ring or the like to form indole, indazole, benzimidazole, benzotriazole, dihydroquinoline, quinoline, dihydroisoquinoline, isoquinoline, phenanthridine, dihydrocinnoline, cinnoline, Dihydrophthalazine, phthalazine, dihydroquinazoline, quinazoline, dihydroquinoxaline, quinoxaline, benzofuran, isobenzofuran, chromene, isochromene, benzothiophene, isobenzothiophene, thiochromene, isothiochromene, benzoxazole, benzoisoxazole, benzoxazine, benzothiazole, benzo Isothiazole, benzothiazine, phenoxanthine, carbazole, β-carboline, phenanthridine, acridine, phen Ntororin, phenazine, phenothiazine, may form a 2 fused polycyclic heterocyclic cyclic or tricyclic, such as phenoxazine ring.

  The “lower alkoxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkyl group. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexyloxy, n-heptyloxy, n-octyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy group Etc.

  The “lower alkenyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkenyl group. Specific examples include vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, isopropenyloxy, 2-methyl-1-propenyloxy, 2-methyl-2-butenyloxy and the like.

  The “lower alkynyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkynyl group. Specific examples include ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, isobutynyloxy, isopentynyloxy groups and the like.

  The “lower cycloalkyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower cycloalkyl group. Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy groups.

  The “aryloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aryl group. Specific examples include phenoxy, naphthoxy, anthryloxy, phenanthryloxy groups and the like.

  The “heterocyclic oxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a heterocyclic group.

  The “lower alkylthio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with a lower alkyl group. Specific examples include methylthio, ethylthio, n-propylthio, n-butylthio, n-pentylthio, n-hexylthio, n-heptylthio, n-octylthio, isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio group Etc.

  The “lower cycloalkylthio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with a lower cycloalkyl group. Specific examples include cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio or cyclooctylthio groups.

  The “arylthio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with an aryl group. Specific examples include phenylthio, naphthylthio, anthrylthio, phenanthrylthio groups and the like.

  The “heterocyclic thio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with a heterocyclic group.

  The “lower alkylamino group” refers to a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkyl group. Specific examples include methylamino, ethylamino, propylamino, dimethylamino, diethylamino, ethyl (methyl) amino group, and the like.

  The “lower cycloalkylamino group” is a group in which one or both hydrogen atoms of an amino group are substituted with a lower cycloalkyl group or one hydrogen atom of an amino group is a lower cycloalkyl group and the other hydrogen atom is lower A group substituted with an alkyl group, a lower alkenyl group or a lower alkynyl group is shown. Specific examples include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, dicyclohexylamino, cyclohexyl (methyl) amino, cyclohexyl (vinyl) amino, cyclohexyl (ethynyl) amino groups, and the like. It is done.

  “Arylamino group” means a group in which one or both hydrogen atoms of an amino group are substituted with an aryl group, or one hydrogen atom of an amino group is an aryl group, and the other hydrogen atom is a lower alkyl group or a lower alkenyl group. And a group substituted with a lower alkynyl group or a lower cycloalkyl group. Specific examples include phenylamino, naphthylamino, anthrylamino, phenanthrylamino, diphenylamino, methyl (phenyl) amino, ethyl (phenyl) amino, phenyl (vinyl) amino, ethynyl (phenyl) amino, cyclohexyl (phenyl) An amino group etc. are mentioned.

  The “heterocyclic amino group” is a group in which one or both hydrogen atoms of an amino group are substituted with a heterocyclic group, or one hydrogen atom of an amino group is a heterocyclic group, and the other hydrogen atom is a lower alkyl group, A group substituted with a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group or an aryl group is shown.

  The “lower alkylcarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkyl group. Specific examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl, n-octylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, Examples thereof include tert-butylcarbonyl and isopentylcarbonyl groups.

  The “lower alkenylcarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkenyl group. Specific examples include vinylcarbonyl, propenylcarbonyl, butenylcarbonyl, pentenylcarbonyl, hexenylcarbonyl, heptenylcarbonyl, octenylcarbonyl, isopropenylcarbonyl, 2-methyl-1-propenylcarbonyl, 2-methyl-2-butenylcarbonyl. Groups and the like.

  The “lower alkynylcarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkynyl group. Specific examples include ethynylcarbonyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl, heptynylcarbonyl, octynylcarbonyl, isobutynylcarbonyl, isopentynylcarbonyl group and the like.

  The “lower cycloalkylcarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower cycloalkyl group. Specific examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl or cyclooctylcarbonyl group.

  The “arylcarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with an aryl group. Specific examples include phenylcarbonyl, naphthylcarbonyl, anthrylcarbonyl, phenanthrylcarbonyl group and the like.

  The “heterocyclic carbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a heterocyclic group.

  The “lower alkoxycarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkoxy group. Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, n-pentoxycarbonyl, n-hexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl, isopropoxycarbonyl, isobutoxy Examples include carbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isopentoxycarbonyl group and the like.

  The “lower alkenyloxycarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkenyloxy group. Specific examples include vinyloxycarbonyl, propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl, hexenyloxycarbonyl, heptenyloxycarbonyl, octenyloxycarbonyl, isopropenyloxycarbonyl, 2-methyl-1-propenyloxycarbonyl, Examples include 2-methyl-2-butenyloxycarbonyl group.

  The “lower alkynyloxycarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkynyloxy group. Specific examples include ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, hexynyloxycarbonyl, heptynyloxycarbonyl, octynyloxycarbonyl, isobutynyloxycarbonyl, isopentynyloxycarbonyl group Etc.

  The “lower cycloalkyloxycarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower cycloalkyloxy group. Specific examples include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl, and cyclooctyloxycarbonyl groups.

  The “aryloxycarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with an aryloxy group. Specific examples include phenoxycarbonyl, naphthoxycarbonyl, anthryloxycarbonyl, phenanthryloxycarbonyl groups, and the like.

  The “heterocyclic oxycarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a heterocyclic oxy group.

  The “lower alkylaminocarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkylamino group. Specific examples include methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, ethylmethylaminocarbonyl group and the like.

  The “lower alkenylaminocarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkenylamino group. Specific examples include vinylaminocarbonyl, propenylaminocarbonyl, butenylaminocarbonyl, pentenylaminocarbonyl, hexenylaminocarbonyl, heptenylaminocarbonyl, octenylaminocarbonyl, isopropenylaminocarbonyl, 2-methyl-1-propenylaminocarbonyl, Examples include 2-methyl-2-butenylaminocarbonyl, divinylaminocarbonyl, methyl (vinyl) aminocarbonyl group and the like.

  The “lower alkynylaminocarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkynylamino group. Specific examples include ethynylaminocarbonyl, propynylaminocarbonyl, butynylaminocarbonyl, pentynylaminocarbonyl, hexynylaminocarbonyl, heptynylaminocarbonyl, octynylaminocarbonyl, isobutynylaminocarbonyl, isopentynylaminocarbonyl, Examples include diethynylaminocarbonyl, ethynyl (methyl) aminocarbonyl, ethynyl (vinyl) aminocarbonyl group, and the like.

  The “lower cycloalkylaminocarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower cycloalkylamino group. Specific examples include cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, cycloheptylaminocarbonyl, cyclooctylaminocarbonyl, dicyclohexylaminocarbonyl, cyclohexyl (methyl) aminocarbonyl, cyclohexyl (vinyl) aminocarbonyl, Examples include cyclohexyl (ethynyl) aminocarbonyl group.

  “Arylaminocarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with an arylamino group. Specific examples include phenylaminocarbonyl, naphthylaminocarbonyl, anthrylaminocarbonyl, phenanthrylaminocarbonyl, diphenylaminocarbonyl, methylphenylaminocarbonyl, ethylphenylaminocarbonyl, phenyl (vinyl) aminocarbonyl, ethynyl (phenyl) aminocarbonyl And cyclohexyl (phenyl) aminocarbonyl group.

  The “heterocyclic aminocarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a heterocyclic amino group.

  The “lower alkylsulfonyl group” refers to a group in which a hydroxy group of a sulfonic acid group is substituted with a lower alkyl group. Specific examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, n-butylsulfonyl, n-pentylsulfonyl, n-hexylsulfonyl, n-heptylsulfonyl, n-octylsulfonyl, isopropylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl. , Tert-butylsulfonyl, isopentylsulfonyl group and the like.

  The “lower alkenylsulfonyl group” refers to a group in which a hydroxy group of a sulfonic acid group is substituted with a lower alkenyl group. Specific examples include vinylsulfonyl, propenylsulfonyl, butenylsulfonyl, pentenylsulfonyl, hexenylsulfonyl, heptenylsulfonyl, octenylsulfonyl, isopropenylsulfonyl, 2-methyl-1-propenylsulfonyl, 2-methyl-2-butenylsulfonyl. Groups and the like.

  The “lower alkynylsulfonyl group” refers to a group in which a hydroxy group of a sulfonic acid group is substituted with a lower alkynyl group. Specific examples include ethynylsulfonyl, propynylsulfonyl, butynylsulfonyl, pentynylsulfonyl, hexynylsulfonyl, heptynylsulfonyl, octynylsulfonyl, isobutynylsulfonyl, isopentynylsulfonyl group and the like.

  The “lower cycloalkylsulfonyl group” refers to a group in which a hydroxy group of a sulfonic acid group is substituted with a lower cycloalkyl group. Specific examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl, and cyclooctylsulfonyl groups.

  The “arylsulfonyl group” refers to a group in which a hydroxy group of a sulfonic acid group is substituted with an aryl group. Specific examples include phenylsulfonyl, naphthylsulfonyl, anthrylsulfonyl, phenanthrylsulfonyl groups and the like.

  The “heterocyclic sulfonyl group” refers to a group in which a hydroxy group of a sulfonic acid group is substituted with a heterocyclic group.

  The “3- to 8-membered nitrogen-containing heterocycle” refers to a saturated monocyclic heterocycle containing 1 or 2 nitrogen atoms in the ring. Specific examples include aziridine, azetidine, pyrrolidine, piperidine, imidazolidine, pyrazolidine, piperazine, morpholine ring and the like.

  The “lower alkylene group” refers to a linear or branched alkylene group having 1 to 8 carbon atoms. Specific examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, methylmethylene, ethylmethylene groups and the like.

  “Ester of hydroxy group” refers to an ester formed from a hydroxy group and carboxylic acids and / or a group represented by —OCO—R.

  Here, R has a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, or a substituent. May have a lower cycloalkyl group, an aryl group which may have a substituent, a heterocyclic group which may have a substituent, a lower alkoxy group which may have a substituent, or a substituent. A good lower alkenyloxy group, a lower alkynyloxy group which may have a substituent, a lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, and a substituent An optionally substituted heterocyclic oxy group, an amino group, an optionally substituted lower alkylamino group, an optionally substituted lower cycloalkylamino group, an optionally substituted arylamino group or A heterocyclic amino group which may have a substituent is shown. . Hereinafter, R is the same.

“Ester of mercapto group” refers to a thioester formed from a mercapto group and carboxylic acids and / or a group represented by —SCO—R. Here, R is the same as described above.

The “amide of amino group” refers to an amide formed from an amino group and a carboxylic acid and / or a group represented by —NHCO—R. Here, R is the same as described above.

The “amide of a lower alkylamino group” refers to an amide formed from a lower alkylamino group and a carboxylic acid and / or a group represented by —NR′CO—R. Here, R ′ represents a lower alkyl group which may have a substituent, and R is the same as described above.

The “amide of a lower cycloalkylamino group” refers to an amide formed from a lower cycloalkylamino group and a carboxylic acid and / or a group represented by —NR ″ CO—R. Here, R ″ represents a lower cycloalkyl group which may have a substituent, and R is the same as described above.

The “amide of an arylamino group” refers to an amide formed from an arylamino group and a carboxylic acid and / or a group represented by —NR ′ ″ CO—R. Here, R ′ ″ represents an aryl group which may have a substituent, and R is the same as described above.

The “amide of a heterocyclic amino group” refers to an amide formed from a heterocyclic amino group and a carboxylic acid and / or a group represented by —NR ″ ″ CO—R. Here, R ″ ″ represents a heterocyclic group which may have a substituent, and R is the same as described above.

“Carboxylic acids” refers to R ^a COOH (R ^a is a hydrogen atom, ^a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower group which may have a substituent. An alkynyl group, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heterocyclic group which may have a substituent, etc.) , Unsaturated aliphatic carboxylic acid, aryl carboxylic acid, heterocyclic carboxylic acid and the like. Specific examples include saturated aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, and cyclohexanecarboxylic acid. Unsaturated fatty carboxylic acids such as acrylic acid, propiolic acid, crotonic acid, cinnamic acid, cyclopentenecarboxylic acid and cyclohexenecarboxylic acid; aryls such as benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, and toluic acid Carboxylic acids; heterocyclic carboxylic acids such as furan carboxylic acid, thiophene carboxylic acid, nicotinic acid and isonicotinic acid.

  “Ester of carboxy group” refers to an ester formed from a carboxy group and alcohols or phenols.

  The “ester of sulfonic acid group” refers to an ester formed from a sulfonic acid group and alcohols or phenols.

“Alcohols” means R ^b OH (R ^b is a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, A saturated aliphatic hydroxy compound, an unsaturated aliphatic hydroxy compound, a heterocyclic hydroxy compound, etc., represented by a lower cycloalkyl group which may have a substituent, a heterocyclic group which may have a substituent, etc.) Show. Specific examples include saturated aliphatic hydroxy compounds such as methanol, ethanol, propanol, butanol, isopropanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, benzyl alcohol, phenethyl alcohol; vinyl alcohol, allyl alcohol, propargyl alcohol, cyclo Examples thereof include unsaturated aliphatic hydroxy compounds such as pentenol and cyclohexenol; heterocyclic hydroxy compounds such as hydroxypiperidine and hydroxytetrahydropyran.

“Phenols” refers to aryl hydroxy compounds, heterocyclic hydroxys represented by R ^c OH (R ^c represents an aryl group which may have a substituent, a heterocyclic group which may have a substituent, etc.) Compound etc. are shown. Specific examples include arylhydroxy compounds such as phenol, naphthol, anthrol and phenanthrol; heterocyclic hydroxy compounds such as hydroxypyridine, hydroxyfuran and hydroxythiophene.

  The “amide of carboxy group” refers to an acid amide formed from a carboxy group and amines.

  The “amide of sulfonic acid group” refers to an acid amide formed from a sulfonic acid group and amines.

The “amines” are HNR ^d R ^e [R ^d and R ^e are the same or different, and are a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, A lower alkynyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heterocyclic group and the like; and R ^d and R ^e And may form a saturated cyclic amine together with ammonia, a saturated aliphatic amine compound, an unsaturated aliphatic amine compound, an arylamine compound, a heterocyclic amine compound, a saturated cyclic amine compound, etc. . Specific examples include ammonia; saturated aliphatic amines such as methylamine, ethylamine, propylamine, pentylamine, dimethylamine, diethylamine, ethylmethylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, benzylamine, and phenethylamine. Compound; unsaturated aliphatic amine compound such as allylamine, propargylamine; arylamine compound such as phenylamine, naphthylamine, anthrylamine, phenanthrylamine, diphenylamine, methylphenylamine, ethylphenylamine; furylamine, thienylamine Heterocyclic amine compounds such as pyrrolidylamine, pyridylamine, quinolylamine, methylpyridylamine; aziridine, azetidine, pyrrolidine Piperidine, saturated cyclic amine compounds such as 4-methyl piperidine.

“Optionally substituted lower alkyl group”, “optionally substituted lower alkenyl group” “optionally substituted lower alkynyl group”, “optionally substituted” “Lower alkoxy group”, “lower alkylthio group optionally having substituent”, “lower alkylamino group optionally having substituent”, “lower alkylcarbonyl group optionally having substituent”, “ “Lower alkenylcarbonyl group optionally having substituent”, “lower alkynylcarbonyl group optionally having substituent”, “lower alkoxycarbonyl group optionally having substituent”, “having substituent” May have a lower alkenyloxycarbonyl group "," may have a lower alkynyloxycarbonyl group ",""may have a lower alkylaminocarbonyl group", "" may have a substituent. " Good lower alkenyl “Minocarbonyl group”, “lower alkynylaminocarbonyl group optionally having substituent”, “lower alkylsulfonyl group optionally having substituent”, “lower alkenylsulfonyl group optionally having substituent” , “An optionally substituted lower alkynylsulfonyl group” or “an amide of an optionally substituted lower alkylamino group” is one or more substituents selected from the following group α ¹ “Lower alkyl group”, “lower alkenyl group”, “lower alkynyl group”, “lower alkoxy group”, “lower alkylthio group”, “lower alkylamino group”, “lower alkylcarbonyl group” which may have a group , “Lower alkenylcarbonyl group”, “lower alkynylcarbonyl group”, “lower alkoxycarbonyl group”, “lower alkenyloxycarbonyl group”, “lower alkynyl” “Xycarbonyl group”, “lower alkylaminocarbonyl group”, “lower alkenylaminocarbonyl group”, “lower alkynylaminocarbonyl group”, “lower alkylsulfonyl group”, “lower alkenylsulfonyl group”, “lower alkynylsulfonyl group” or “Amido of lower alkylamino group” is shown.

[Α ¹ group]
Halogen atom, lower cycloalkyl group, aryl group, heterocyclic group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen, lower alkenyloxy group, lower alkynyloxy group, lower cycloalkyloxy Group, aryloxy group, heterocyclic oxy group, mercapto group, ester of mercapto group, lower alkylthio group, lower alkenylthio group, lower alkynylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino group, lower group Alkylamino group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, amide of amino group, amide of lower alkylamino group, amide of lower cycloalkylamino group, amide of arylamino group, heterocyclic amino group Amido, formyl group, lower amine Kill carbonyl group, lower alkenyl carbonyl group, lower alkynyl carbonyl group, lower cycloalkyl carbonyl group, aryl carbonyl group, heterocyclic carbonyl group, carboxy group, carboxy group ester, carboxy group amide, lower alkyl sulfinyl group, aryl sulfinyl group , Lower alkylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, sulfinic acid group, sulfinic acid group ester, sulfinic acid group amide, sulfonic acid group, sulfonic acid group ester, sulfonic acid group An amide group, a nitro group and a cyano group.

“Optionally substituted lower cycloalkyl group”, “optionally substituted aryl group”, “optionally substituted heterocyclic group”, “optionally substituted” Preferred lower cycloalkyloxy group ”,“ aryloxy group optionally having substituent ”,“ heterocyclic oxy group optionally having substituent ”,“ lower cycloalkylthio group optionally having substituent ” ”,“ Arylthio group optionally having substituent ”,“ heterocyclic thio group optionally having substituent ”,“ lower cycloalkylamino group optionally having substituent ”,“ substituent An optionally substituted arylamino group, an optionally substituted heterocyclic amino group, an optionally substituted lower cycloalkylcarbonyl group, and an optionally substituted substituent. "Arylcarbonyl group", "heterocyclic carbonyl group optionally having substituent", "substituent A lower cycloalkyloxycarbonyl group which may have ", an aryloxycarbonyl group which may have a substituent", a "heterocyclic oxycarbonyl group which may have a substituent", May be a lower cycloalkylaminocarbonyl group ”,“ arylaminocarbonyl group optionally having substituents ”,“ heterocyclic aminocarbonyl group optionally having substituents ”,“ may have substituents ” Preferred lower cycloalkylsulfonyl group ”,“ optionally substituted arylsulfonyl group ”,“ optionally substituted heterocyclic sulfonyl group ”,“ optionally substituted lower cycloalkylamino ” amide group "and" amide of an optionally substituted arylamino group "or" amide of heterocyclic amino group which may have a substituent ", 1 selected below, from beta ¹ group Or multiple "Lower cycloalkyl group", "aryl group", "heterocyclic group", "lower cycloalkyloxy group", "aryloxy group", "heterocyclic oxy group", "lower cycloalkyl group" which may have a substituent “Alkylthio group”, “arylthio group”, “heterocyclic thio group”, “lower cycloalkylamino group”, “arylamino group”, “heterocyclic amino group”, “lower cycloalkylcarbonyl group”, “arylcarbonyl group” , “Heterocyclic carbonyl group”, “lower cycloalkyloxycarbonyl group”, “aryloxycarbonyl group”, “heterocyclic oxycarbonyl group”, “lower cycloalkylaminocarbonyl group”, “arylaminocarbonyl group”, “hetero Ring aminocarbonyl group "," lower cycloalkylsulfonyl group "," arylsulfonyl group "," heterocyclic sulfonyl group " Group "refers to" amide of lower cycloalkylamino group "," amide of arylamino group "or" amide of heterocyclic amino group ".

[Β ¹ group]
Halogen atom, lower alkyl group, lower alkyl group substituted by halogen atom, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, hydroxy group, hydroxy group ester, lower alkoxy group, halogen Atom-substituted lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, mercapto group, mercapto group ester, lower alkylthio group, lower alkenylthio group , Lower alkynylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino group, lower alkylamino group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, amino group amide, lower alkylamino Group amide, lower cycl Alkylamino group amide, arylamino group amide, heterocyclic amino group amide, formyl group, lower alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl Group, carboxy group, ester of carboxy group, amide of carboxy group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, sulfinic acid group, sulfinic acid Ester, sulfinic acid group amide, sulfonic acid group, sulfonic acid group ester, sulfonic acid group amide, nitro group, cyano group, lower alkylaminocarbonyloxy group and arylaminocarbonic acid Oxy group.

The “plural groups” in the present invention may be the same or different, and the number is preferably two. Further, a hydrogen atom and a halogen atom are also included in the concept of “group”.

The “glucocorticoid receptor modulator” referred to in the present invention refers to a substance that expresses a pharmaceutical action by binding to a glucocorticoid receptor. Examples include glucocorticoid receptor agonists, glucocorticoid receptor antagonists, and the like.

The “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or the like. , Acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethione Acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid lauryl ester, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid, etc. Salt of organic acid, quaternary ammonium salt with methyl bromide, methyl iodide, bromine ion, chloride ion, Salts with halogen ions such as urine ions, salts with alkali metals such as lithium, sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, metal salts with iron and zinc, salts with ammonia , Triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1,3- Examples thereof include salts with organic amines such as propanediol, procaine and N, N-bis (phenylmethyl) -1,2-ethanediamine.

When geometrical isomers or optical isomers exist in the compound of the present invention, these isomers are also included in the scope of the present invention.

The compound of the present invention may take the form of a hydrate or a solvate.

When proton tautomerism exists in the compound of the present invention, those tautomers are also included in the present invention.

When crystalline polymorphs exist in the compound of the present invention, those crystalline polymorphs are also included in the present invention.

(A) As a preferable example in the compound of the present invention, in the compound represented by the general formula (1) or a salt thereof, a compound or a salt thereof in which each group is a group shown below is exemplified.

In general formula (1),
(A1) R ¹ is a halogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower cycloalkyloxy group, an aryloxy group, or a heterocyclic oxy Group, mercapto group, ester of mercapto group, lower alkylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino group, lower alkylamino group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, Amide of amino group, Amide of lower alkylamino group, Amide of lower cycloalkylamino group, Amide of arylamino group, Amide of heterocyclic amino group, Lower alkylcarbonyl group, Lower cycloalkylcarbonyl group, Arylcarbonyl group, Heterocycle Carbonyl group, carboxy group, cal Esters of xy groups, amides of carboxy groups, lower alkylsulfonyl groups, lower cycloalkylsulfonyl groups, arylsulfonyl groups, heterocyclic sulfonyl groups, sulfonic acid groups, esters of sulfonic acid groups, amides of sulfonic acid groups, nitro groups or cyano Indicates a group;
When R ¹ is a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, an amide of a lower alkylamino group, a lower alkylcarbonyl group or a lower alkylsulfonyl group, the lower alkyl group, the lower alkoxy group, A lower alkylthio group, the lower alkylamino group, an amide of the lower alkylamino group, the lower alkylcarbonyl group or the lower alkylsulfonyl group is a halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, a hydroxy group Ester, lower alkoxy group, lower alkoxy group substituted with a halogen atom, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower alkylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino Group, lower alkylamino Group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, amide of amino group, amide of lower alkylamino group, amide of lower cycloalkylamino group, amide of arylamino group, amide of heterocyclic amino group, Lower alkylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, carboxy group ester, carboxy group amide, lower alkylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic ring One or more groups selected from a sulfonyl group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group, and a cyano group may be substituted.
R ¹ is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, lower cycloalkylamino group, aryl Amino group, heterocyclic amino group, amide of lower cycloalkylamino group, amide of arylamino group, amide of heterocyclic amino group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, lower cycloalkylsulfonyl group, In the case of an arylsulfonyl group or a heterocyclic sulfonyl group, the lower cycloalkyl group, the aryl group, the heterocyclic group, the lower cycloalkyloxy group, the aryloxy group, the heterocyclic oxy group, the lower cycloalkylthio group, The arylthio group, the heterocyclic thio group, the lower cycloa A killamino group, an arylamino group, an heterocyclic amino group, an amide of the lower cycloalkylamino group, an amide of the arylamino group, an amide of the heterocyclic amino group, the lower cycloalkylcarbonyl group, the arylcarbonyl group, The heterocyclic carbonyl group, the lower cycloalkylsulfonyl group, the arylsulfonyl group or the heterocyclic sulfonyl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a hydroxy group, an ester of a hydroxy group, An alkoxy group, a lower alkoxy group substituted with a halogen atom, a lower alkylthio group, an amino group, a lower alkylamino group, an amide of an amino group, an amide of a lower alkylamino group, a lower alkylcarbonyl group, a carboxy group, an ester of a carboxy group, Carboxyamide amide, lower amide One or more groups selected from an alkylsulfonyl group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group and a cyano group may be present as a substituent; and / or
(A2) p represents an integer of 0 to 3;
When p is 2 or 3, each R ¹ may be the same or different; and / or
(A3) R ² represents a halogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group;
And / or
(A4) q represents an integer of 0 to 2;
When q is 2, each R ² may be the same or different; and / or
(A5) R ³ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group or an arylcarbonyl group;
When R ³ is a lower alkyl group or a lower alkylcarbonyl group, the lower alkyl group or the lower alkylcarbonyl group may have one or more groups selected from a halogen atom and an aryl group as a substituent;
When R ³ is an arylcarbonyl group, the arylcarbonyl group is selected from a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a lower alkoxy group, and a lower alkoxy group substituted with a halogen atom or May have multiple groups as substituents; and / or
(A6) R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl or a heterocyclic group;
When R ⁴ or R ⁵ is a lower alkyl group, the lower alkyl group is substituted with a halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, or a halogen atom. Lower alkoxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower alkylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino group, lower alkylamino group, lower cycloalkylamino group, Arylamino group, heterocyclic amino group, amide of amino group, amide of lower alkylamino group, amide of lower cycloalkylamino group, amide of arylamino group, amide of heterocyclic amino group, lower alkylcarbonyl group, lower cycloalkyl Carbonyl group, arylcarbonyl group, heterocyclic carbo One or more groups selected from nyl group, carboxy group, ester of carboxy group, amide of carboxy group, nitro group and cyano group may be substituted.
When R ⁴ or R ⁵ is a lower cycloalkyl group, an aryl or a heterocyclic group, the lower cycloalkyl group, the aryl or the heterocyclic group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, Hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, lower alkylthio group, amino group, lower alkylamino group, amide of amino group, amide of lower alkylamino group, lower alkylcarbonyl group Carboxy group, carboxy group ester, carboxy group amide, lower alkylsulfonyl group, sulfonic acid group, sulfonic acid group ester, sulfonic acid group amide, nitro group and cyano group As a substituent;
R ⁴ and R ⁵ may combine to form a 3-8 membered lower cycloalkane ring; and / or
(A7) R ⁶ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group;
When R ⁶ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group, the lower alkyl group, the lower alkenyl group, the lower alkynyl group or the lower cycloalkyl group is selected from a halogen atom and an aryl group One or more groups may be substituted as substituents; and / or
(A8) A represents a lower alkylene group which may be substituted with a hydroxy group or a halogen atom; and / or
(A9) R ⁷ represents OR ⁸ , NR ⁸ R ⁹ or SR ⁸ ;
R ⁸ and R ⁹ are the same or different and are a hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, formyl group, lower alkylcarbonyl group, lower alkenylcarbonyl group. Lower alkynylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryloxy Carbonyl group, heterocyclic oxycarbonyl group, lower alkylsulfonyl group, lower alkenylsulfonyl group, lower alkynylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, Bruno carbonyl group, a lower alkylaminocarbonyl group, a lower alkenyl amino group, a lower alkynyl aminocarbonyl group, a lower cycloalkylamino group, an arylamino group or a heterocyclic aminocarbonyl group;
R ⁸ or R ⁹ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a lower alkynylcarbonyl group, a lower alkoxycarbonyl group, a lower alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, In the case of a lower alkylsulfonyl group, a lower alkenylsulfonyl group, a lower alkynylsulfonyl group, a lower alkylaminocarbonyl group, a lower alkenylaminocarbonyl group or a lower alkynylaminocarbonyl group, the lower alkyl group, the lower alkenyl group, the lower alkynyl group, The lower alkylcarbonyl group, the lower alkenylcarbonyl group, the lower alkynylcarbonyl group, the lower alkoxycarbonyl group, the lower alkenyloxycarbonyl group, the lower alkynyloxy A carbonyl group, the lower alkylsulfonyl group, the lower alkenylsulfonyl group, the lower alkynylsulfonyl group, the lower alkylaminocarbonyl group, the lower alkenylaminocarbonyl group or the lower alkynylaminocarbonyl group are a halogen atom, a lower cycloalkyl group, Aryl group, heterocyclic group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower alkylthio group, lower cyclo Alkylthio group, arylthio group, heterocyclic thio group, amino group, lower alkylamino group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, amino group amide, lower alkylamino group amide, lower cycloalkyl group Group amide, arylamino group amide, heterocyclic amino group amide, lower alkylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, carboxy group ester, carboxy group amide , A lower alkylsulfonyl group, a lower cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group, and a cyano group May have as a substituent
R ⁸ or R ⁹ is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group A lower cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl group, a lower cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a heterocyclic aminocarbonyl group, the lower cycloalkyl group, the aryl group, the heterocyclic group The lower cycloalkylcarbonyl group, the arylcarbonyl group, the heterocyclic carbonyl group, the lower cycloalkyloxycarbonyl group, the aryloxycarbonyl group, the heterocyclic oxycarbonyl group, the lower cycloalkylsulfonyl group, the aryl The sulfonyl group, the heterocyclic sulfonyl group, the lower cycloalkylaminocarbonyl group, the arylaminocarbonyl group or the heterocyclic aminocarbonyl group are a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a hydroxy group A lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group substituted with a halogen atom, Lower alkenyloxy group, lower alkynyloxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower alkylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino group, lower alkylamino group, Lower cycloalkyl amino Group, arylamino group, heterocyclic amino group, amide of amino group, amide of lower alkylamino group, amide of lower cycloalkylamino group, amide of arylamino group, amide of heterocyclic amino group, lower alkylcarbonyl group, lower Cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, ester of carboxy group, amide of carboxy group, lower alkylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, sulfonic acid group , An ester of a sulfonic acid group, an amide of a sulfonic acid group, one or more groups selected from a nitro group and a cyano group may be substituted.
When R ⁷ is NR ⁸ R ⁹ , R ⁸ and R ⁹ may combine to form a 5- or 6-membered nitrogen-containing heterocycle; and / or
(A10) A compound or a salt thereof, wherein X represents O or S.

That is, in the compound represented by the general formula (1), the above (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8), (a9) and A compound consisting of one or more combinations selected from (a10) or a salt thereof.

(B) As a more preferable example in this invention compound, the compound or its salt in which each group is a group shown below in the compound or its salt shown by General formula (1) is mentioned.

In general formula (1),
(B1) R ¹ is a halogen atom, a lower alkyl group, a hydroxy group, a hydroxy group ester, a lower alkoxy group, a lower alkylthio group, an amino group, a lower alkylamino group, an amino group amide, a lower alkylamino group amide, An alkylcarbonyl group, a carboxy group, an ester of a carboxy group, an amide of a carboxy group, a lower alkylsulfonyl group, a nitro group or a cyano group;
When R ¹ is a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, an amide of a lower alkylamino group, a lower alkylcarbonyl group or a lower alkylsulfonyl group, the lower alkyl group, the lower alkoxy group, A lower alkylthio group, the lower alkylamino group, an amide of the lower alkylamino group, the lower alkylcarbonyl group or the lower alkylsulfonyl group is a halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, a hydroxy group Ester, lower alkoxy group, lower alkoxy group substituted with a halogen atom, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower alkylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino Group, lower alkylamino Group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, amide of amino group, amide of lower alkylamino group, amide of lower cycloalkylamino group, amide of arylamino group, amide of heterocyclic amino group, Lower alkylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, carboxy group ester, carboxy group amide, lower alkylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic ring One or more groups selected from a sulfonyl group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group, and a cyano group may be substituted; and / or
(B2) p represents an integer of 0 to 3;
When p is 2 or 3, each R ¹ may be the same or different; and / or
(B3) q represents 0; and / or
(B4) R ³ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group or an arylcarbonyl group;
When R ³ is a lower alkyl group, the lower alkyl group may have one or more aryl groups as substituents;
When R ³ is an arylcarbonyl group, the arylcarbonyl group may have one or more groups selected from a halogen atom and a lower alkyl group as a substituent; and / or
(B5) R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl or a heterocyclic group;
When R ⁴ or R ⁵ is a lower alkyl group, the lower alkyl group is a halogen atom, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group substituted with a halogen atom, a lower alkylthio group, an amino group, a lower group One or more groups selected from an alkylamino group, an amide of an amino group, an amide of a lower alkylamino group, a lower alkylcarbonyl group, a carboxy group, an ester of a carboxy group, an amide of a carboxy group, a nitro group or a cyano group May have as a substituent;
When R ⁴ or R ⁵ is a lower cycloalkyl group, an aryl or a heterocyclic group, the lower cycloalkyl group, the aryl or the heterocyclic group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, Hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, lower alkylthio group, amino group, lower alkylamino group, amide of amino group, amide of lower alkylamino group, lower alkylcarbonyl group , A carboxy group, an ester of a carboxy group, an amide of a carboxy group, a lower alkylsulfonyl group, a nitro group, or a cyano group may have as a substituent;
R ⁴ and R ⁵ together may form a 3-8 membered lower cycloalkane ring; and / or
(B6) R ⁶ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group;
When R ⁶ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group, the lower alkyl group, the lower alkenyl group, the lower alkynyl group or the lower cycloalkyl group is selected from a halogen atom and an aryl group One or more groups may be substituted as substituents; and / or
(B7) A represents a lower alkylene group; and / or
(B8) R ⁷ represents OR ⁸ , NR ⁸ R ⁹ or SR ⁸ ;
R ⁸ and R ⁹ are the same or different and are a hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, formyl group, lower alkylcarbonyl group, lower alkenylcarbonyl group. Lower alkynylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryloxy Carbonyl group, heterocyclic oxycarbonyl group, lower alkylsulfonyl group, lower alkenylsulfonyl group, lower alkynylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, Bruno carbonyl group, a lower alkylaminocarbonyl group, a lower alkenyl amino group, a lower alkynyl aminocarbonyl group, a lower cycloalkylamino group, an arylamino group or a heterocyclic aminocarbonyl group;
R ⁸ or R ⁹ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a lower alkynylcarbonyl group, a lower alkoxycarbonyl group, a lower alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, In the case of a lower alkylsulfonyl group, a lower alkenylsulfonyl group, a lower alkynylsulfonyl group, a lower alkylaminocarbonyl group, a lower alkenylaminocarbonyl group or a lower alkynylaminocarbonyl group, the lower alkyl group, the lower alkenyl group, the lower alkynyl group, The lower alkylcarbonyl group, the lower alkenylcarbonyl group, the lower alkynylcarbonyl group, the lower alkoxycarbonyl group, the lower alkenyloxycarbonyl group, the lower alkynyloxy A carbonyl group, the lower alkylsulfonyl group, the lower alkenylsulfonyl group, the lower alkynylsulfonyl group, the lower alkylaminocarbonyl group, the lower alkenylaminocarbonyl group or the lower alkynylaminocarbonyl group are a halogen atom, a lower cycloalkyl group, Aryl group, heterocyclic group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, lower alkylthio group, amino group, lower alkylamino group, amide of amino group, lower alkylamino group May have one or more groups selected from amide, lower alkylcarbonyl group, carboxy group, carboxy group ester, carboxy group amide, lower alkylsulfonyl group, nitro group or cyano group as a substituent. ;
R ⁸ or R ⁹ is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group A lower cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl group, a lower cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a heterocyclic aminocarbonyl group, the lower cycloalkyl group, the aryl group, the heterocyclic group The lower cycloalkylcarbonyl group, the arylcarbonyl group, the heterocyclic carbonyl group, the lower cycloalkyloxycarbonyl group, the aryloxycarbonyl group, the heterocyclic oxycarbonyl group, the lower cycloalkylsulfonyl group, the aryl The sulfonyl group, the heterocyclic sulfonyl group, the lower cycloalkylaminocarbonyl group, the arylaminocarbonyl group or the heterocyclic aminocarbonyl group are a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a hydroxy group A lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group substituted with a halogen atom, Lower alkenyloxy group, lower alkynyloxy group, lower alkylthio group, amino group, lower alkylamino group, amino group amide, lower alkylamino group amide, lower alkylcarbonyl group, carboxy group, carboxy group ester, carboxy group Amide, lower a Alkylsulfonyl group which may have one or a plurality of groups selected from a nitro group or a cyano group as substituents;
When R ⁷ is NR ⁸ R ⁹ , R ⁸ and R ⁹ may combine to form a 5- or 6-membered nitrogen-containing heterocycle; and / or
(B9) A compound wherein X represents O or a salt thereof.

That is, in the compound represented by the general formula (1), from the above (b1), (b2), (b3), (b4), (b5), (b6), (b7), (b8) and (b9) A compound or a salt thereof comprising one or more selected combinations.

(C) As a further preferred example of the compound of the present invention, in the compound represented by the general formula (1) or a salt thereof, a compound or a salt thereof in which each group is a group shown below is exemplified.

In general formula (1),
(C1) R ¹ is a halogen atom, lower alkyl group, hydroxy group, hydroxy group ester, lower alkoxy group, lower alkylthio group, amino group, amino group amide, lower alkylamino group amide, lower alkylcarbonyl group, carboxy A group, an ester of a carboxy group, a nitro group or a cyano group;
When R ¹ is a lower alkyl group or a lower alkoxy group, the lower alkyl group or the lower alkoxy group may have one or more groups selected from a halogen atom, a hydroxy group and a lower alkoxy group as a substituent. Well; and / or
(C2) p is 1, 2 or 3;
When p is 2 or 3, each R ¹ may be the same or different; and / or
(C3) q represents 0; and / or
(C4) R ³ represents a hydrogen atom; and / or
(C5) R ⁴ and R ⁵ are the same or different and represent a lower alkyl group; and / or
(C6) R ⁶ represents a hydrogen atom, a lower alkyl group or a lower alkenyl group; and / or
(C7) A represents a lower alkylene group; and / or
(C8) R ⁷ represents OR ⁸ or NR ⁸ R ⁹ ;
R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, an aryl group, an arylcarbonyl group or a heterocyclic carbonyl group;
When R ⁸ or R ⁹ is an aryl group, an arylcarbonyl group or a heterocyclic carbonyl group, the aryl group, the arylcarbonyl group or the heterocyclic carbonyl group is a halogen atom, a lower alkyl group, or a lower alkyl substituted with a halogen atom. Substitute one or more groups selected from a group, a lower alkyl group substituted with a hydroxy group, a lower alkenyl group, an aryl group, a lower alkoxy group, a lower alkylcarbonyl group, an ester of a carboxy group, a nitro group, and a cyano group As a group; and / or
(C9) A compound wherein X represents O or a salt thereof.

That is, in the compound represented by the general formula (1), from the above (c1), (c2), (c3), (c4), (c5), (c6), (c7), (c8) and (c9) A compound or a salt thereof comprising one or more selected combinations.

(D) Particularly preferred examples of the compound of the present invention include a compound represented by the general formula (1) or a salt thereof, and a compound or salt thereof in which each group is a group shown below.

In general formula (1),
(D1) R ¹ represents a halogen atom, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, an amide of an amino group or an amide of a lower alkylamino group; and / or
(D2) p represents 2 or 3, wherein each R ¹ may be the same or different; and / or
(D3) q represents 0; and / or
(D4) R ³ represents a hydrogen atom; and / or
(D5) R ⁴ and R ⁵ are the same or different and represent a lower alkyl group; and / or
(D6) R ⁶ represents a lower alkyl group; and / or
(D7) A represents a lower alkylene group; and / or
(D8) R ⁷ represents OR ⁸ or NR ⁸ R ⁹ ;
R ⁸ represents an aryl group, an arylcarbonyl group or a heterocyclic carbonyl group, wherein the aryl group, arylcarbonyl group or heterocyclic carbonyl group is a halogen atom, a lower alkyl group or a lower alkyl substituted with a halogen atom. Substitute one or more groups selected from a group, a lower alkyl group substituted with a hydroxy group, a lower alkenyl group, an aryl group, a lower alkoxy group, a lower alkylcarbonyl group, an ester of a carboxy group, a nitro group, and a cyano group May have as a group;
R ⁹ represents a hydrogen atom; and / or
(D9) A compound wherein X represents O or a salt thereof.

That is, in the compound represented by the general formula (1), from the above (d1), (d2), (d3), (d4), (d5), (d6), (d7), (d8) and (d9) A compound consisting of one or more selected combinations or a salt thereof.

(E) Preferred examples of R ^{1 in} the compound of the present invention include compounds that satisfy the following conditions or salts thereof.

In the general formula (1), R ¹ is a halogen atom, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, an amide of an amino group or an amide of a lower alkylamino group, and the above (a), (b) or ( A compound or a salt thereof that satisfies any of the conditions of c).

(F) Preferable examples of R ⁴ , R ⁵ and R ^{6 in} the compound of the present invention include compounds that satisfy the following conditions or salts thereof.

In general formula (1), R ⁴ , R ⁵ and R ⁶ are methyl groups, and a compound or salt thereof that satisfies any of the above conditions (a), (b), (c) or (d) .

(G) Preferred examples of R ^{8 in} the compound of the present invention include compounds that satisfy the following conditions or salts thereof.

In the general formula (1), R ⁸ is an aryl group, an arylcarbonyl group or a heterocyclic carbonyl group, the aryl group is a phenyl group, the arylcarbonyl group is a phenylcarbonyl group and / or the heterocyclic carbonyl group is A compound or a salt thereof which is a thiophenecarbonyl group and satisfies any of the above conditions (a), (b), (c) or (d).

(H) Preferred examples of A in the compound of the present invention include compounds that satisfy the following conditions or salts thereof.

  In the general formula (1), A is a methylene group, and a compound or a salt thereof that satisfies any of the above conditions (a), (b), (c) or (d).

(I) As a preferable example in the case where R ¹ in the compound of the present invention is an ester having a hydroxy group, a compound satisfying the following conditions or a salt thereof may be mentioned.

In R ¹ of the general formula (1), an ester of a hydroxy group represents —OCO—R ^a1 , and R ^a1 may have a hydrogen atom, a lower alkyl group which may have a substituent, or a substituent. A good lower alkenyl group, a lower alkynyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a complex which may have a substituent A cyclic group, a lower alkoxy group which may have a substituent, a lower alkenyloxy group which may have a substituent, a lower alkynyloxy group which may have a substituent, a lower group which may have a substituent A cycloalkyloxy group, an aryloxy group that may have a substituent, a heterocyclic oxy group that may have a substituent, an amino group, a lower alkylamino group that may have a substituent, and a substituent. A lower cycloalkylamino group, which may be substituted Is also heterocyclic amino group having also good arylamino group or a substituent and,
More preferably, R ^a1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a lower alkoxy group, a lower alkenyloxy group, a lower cycloalkyloxy group, or an aryloxy group. A heterocyclic oxy group, an amino group, a lower alkylamino group, a lower cycloalkylamino group, an arylamino group or a heterocyclic amino group;
When R ^a1 is a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkenyloxy group or a lower alkylamino group, the lower alkyl group, the lower alkenyl group, the lower alkoxy group, the lower alkenyloxy group or the lower The alkylamino group is a substituent of one or more groups selected from halogen atoms, aryl groups, heterocyclic groups, hydroxy groups, hydroxy group esters, amino groups, lower alkylamino groups, carboxy groups and carboxy group esters. You may have as
When R ^a1 is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower cycloalkylamino group, arylamino group or heterocyclic amino group, The alkyl group, the aryl group, the heterocyclic group, the lower cycloalkyloxy group, the aryloxy group, the heterocyclic oxy group, the lower cycloalkylamino group, the arylamino group or the heterocyclic amino group are halogen atoms; Lower alkyl group, lower alkyl group substituted with a halogen atom, hydroxy group, ester of hydroxy group, lower alkoxy group, mercapto group, lower alkylthio group, formyl group, lower alkylcarbonyl group, carboxy group, carboxy basic ester, One or more groups selected from a nitro group and a cyano group are substituted. A also have to be based,
Particularly preferably, R ^a1 is a lower alkyl group, lower alkenyl group, lower cycloalkyl group, aryl group, heterocyclic group, lower alkoxy group, aryloxy group, lower alkylamino group, lower cycloalkylamino group, arylamino Group or heterocyclic amino group,
When R ^a1 is a lower alkyl group, the lower alkyl group may have one or more groups selected from an aryl group and a lower alkylamino group as a substituent,
When R ^a1 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, an ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, or a carboxy group. It may have one or more groups selected from an ester and a nitro group as a substituent,
When R ^a1 is a heterocyclic group, the heterocyclic group may have one or more groups selected from a halogen atom, a lower alkyl group, a hydroxy group and a lower alkoxy group as a substituent;
When R ^a1 is a lower alkylamino group, the lower alkylamino group may have one or more groups selected from an aryl group, a heterocyclic group and an ester of a carboxy group as a substituent,
When R ^a1 is an arylamino group, the arylamino group is a group optionally having one or more groups selected from a halogen atom, a lower alkyl group, and a lower alkoxy group as a substituent, and the above (A), (b), (c), (d) or a compound satisfying any of the conditions (e) or a salt thereof.

(J) As a more preferable example in the case where R ¹ in the compound of the present invention is an amide having an amino group, a compound satisfying the following conditions or a salt thereof may be mentioned.

In R ¹ of the general formula (1), an amide of an amino group represents —NHCO—R ^b1 , and R ^b1 may have a hydrogen atom, a lower alkyl group which may have a substituent, or a substituent. A good lower alkenyl group, a lower alkynyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a complex which may have a substituent A cyclic group, a lower alkoxy group which may have a substituent, a lower alkenyloxy group which may have a substituent, a lower alkynyloxy group which may have a substituent, a lower group which may have a substituent A cycloalkyloxy group, an aryloxy group that may have a substituent, a heterocyclic oxy group that may have a substituent, an amino group, a lower alkylamino group that may have a substituent, and a substituent. May have a lower cycloalkylamino group and a substituent. It is also heterocyclic amino group which may have an aryl amino group or a substituent,
More preferably, R ^b1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a lower alkoxy group, a lower alkenyloxy group, a lower cycloalkyloxy group, an aryloxy group, A heterocyclic oxy group, an amino group, a lower alkylamino group, a lower cycloalkylamino group, an arylamino group or a heterocyclic amino group;
When R ^b1 is a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkenyloxy group or a lower alkylamino group, the lower alkyl group, the lower alkenyl group, the lower alkoxy group, the lower alkenyloxy group or the lower The alkylamino group is a substituent of one or more groups selected from halogen atoms, aryl groups, heterocyclic groups, hydroxy groups, hydroxy group esters, amino groups, lower alkylamino groups, carboxy groups and carboxy group esters. You may have as
When R ^b1 is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower cycloalkylamino group, arylamino group or heterocyclic amino group, The alkyl group, the aryl group, the heterocyclic group, the lower cycloalkyloxy group, the aryloxy group, the heterocyclic oxy group, the lower cycloalkylamino group, the arylamino group or the heterocyclic amino group are halogen atoms; Lower alkyl group, lower alkyl group substituted with a halogen atom, hydroxy group, ester of hydroxy group, lower alkoxy group, mercapto group, lower alkylthio group, formyl group, lower alkylcarbonyl group, carboxy group, carboxy basic ester, One or more groups selected from a nitro group and a cyano group are substituted. A also have to be based,
Particularly preferably, R ^b1 represents a lower alkyl group, an aryl group, a heterocyclic group, an aryloxy group, a lower alkylamino group or an arylamino group,
When R ^b1 is a lower alkyl group, the lower alkyl group may have one or more amino groups as a substituent,
When R ^b1 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, an ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, or a carboxy group. It may have one or more groups selected from an ester and a nitro group as a substituent,
When R ^b1 is a heterocyclic group, the heterocyclic group may have one or more groups selected from a halogen atom, a lower alkyl group, a hydroxy group and a lower alkoxy group as a substituent.
When R ^b1 is a lower alkylamino group, the lower alkylamino group is a group which may have one or more aryl groups as a substituent, and the above (a), (b), (c), A compound or a salt thereof that satisfies the conditions of either (d) or (e).

(K) As a preferable example when R ¹ in the compound of the present invention is an amide having a lower alkylamino group, a compound satisfying the following conditions or a salt thereof may be mentioned.

In R ¹ of the general formula (1), an amide of a lower alkylamino group represents —NR ^c1 CO—R ^c2 , R ^c1 represents a lower alkyl group which may have a substituent, and the R ^c2 may have a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, or a substituent. Lower cycloalkyl group, aryl group optionally having substituent, heterocyclic group optionally having substituent, lower alkoxy group optionally having substituent, lower alkenyl optionally having substituent An oxy group, a lower alkynyloxy group which may have a substituent, a lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, and a substituent. Heterocyclic oxy group, amino group, optionally substituted lower alkyl Amino group, an optionally substituted lower cycloalkyl group, a heterocyclic amino group which may have an optionally substituted arylamino group or a substituent,
More preferably, R ^c1 represents a lower alkyl group, and R ^c2 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a lower alkoxy group, or a lower alkenyloxy group. A lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, an amino group, a lower alkylamino group, a lower cycloalkylamino group, an arylamino group or a heterocyclic amino group;
When R ^c2 is a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkenyloxy group or a lower alkylamino group, the lower alkyl group, the lower alkenyl group, the lower alkoxy group, the lower alkenyloxy group or the lower The alkylamino group is a substituent of one or more groups selected from halogen atoms, aryl groups, heterocyclic groups, hydroxy groups, hydroxy group esters, amino groups, lower alkylamino groups, carboxy groups and carboxy group esters. You may have as
When R ^c2 is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower cycloalkylamino group, arylamino group or heterocyclic amino group, The alkyl group, the aryl group, the heterocyclic group, the lower cycloalkyloxy group, the aryloxy group, the heterocyclic oxy group, the lower cycloalkylamino group, the arylamino group or the heterocyclic amino group are halogen atoms; A lower alkyl group, a lower alkyl group substituted with a halogen atom, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a mercapto group, a lower alkylthio group, a formyl group, a lower alkylcarbonyl group, a carboxy group, a carboxy basic ester, One or more groups selected from a nitro group and a cyano group are substituted. A also have to be based,
Particularly preferably, R ^c1 represents a lower alkyl group, and R ^c2 represents a lower alkyl group, an aryl group or a heterocyclic group,
When R ^c2 is a lower alkyl group, the lower alkyl group may have one or more amino groups as a substituent,
When R ^c2 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, an ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, or a carboxy group. It may have one or more groups selected from an ester and a nitro group as a substituent,
When R ^c2 is a heterocyclic group, the heterocyclic group may have one or more groups selected from a halogen atom, a lower alkyl group, a hydroxy group and a lower alkoxy group as a substituent,
When R ^c2 is a lower alkylamino group, the lower alkylamino group is a group optionally having one or more aryl groups as a substituent, and the above (a), (b), (c), A compound or a salt thereof that satisfies the conditions of either (d) or (e).

(L) Particularly preferred specific examples of the compound of the present invention include the following compounds or salts thereof.

7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (4-methoxybenzoyloxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one .

7- (5-Fluoro-2-methoxyphenyl) -8- (4-methylbenzoyloxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (4-Fluoro-2-methoxyphenyl) -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on.

8- (5-bromorothiophen-2-ylcarbonyloxymethyl) -7- (4-fluoro-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On.

7- (4-Fluoro-2-methoxyphenyl) -8- (2-methyl-5-nitrophenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (5-Chloro-2-methoxyphenyl) -8- [2- (2-hydroxyethyl) phenoxymethyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one .

8- (5-chloro-2-methylphenoxymethyl) -7- (4-fluoro-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (4-Fluoro-2-methoxyphenyl) -8- (2-methoxy-5-nitrophenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

8- (2-allylphenoxymethyl) -7- (4-fluoro-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (4-Fluoro-2-methoxyphenyl) -8- (2-methoxy-5-methylphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one .

7- (5-chloro-2-methoxyphenyl) -8- (5-fluoro-2-methylphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one .

7- (5-Chloro-2-methoxyphenyl) -8- (2-isopropylphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (4-Fluoro-2-methoxyphenyl) -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

-8-benzoyloxymethyl-7- (5-fluoro-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (5-Fluoro-2-methoxyphenyl) -8-phenoxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (5-Fluoro-2-methoxyphenyl) -8-phenylaminomethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

1-ethyl-7- (5-fluoro-2-methoxyphenyl) -8- (4-methylbenzoyloxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one.

1- (propen-3-yl) -7- (5-fluoro-2-methoxyphenyl) -8- (4-methylbenzoyloxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxaline -2-one.

7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (4-methoxybenzoyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On.

7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one.

8- (3-Fluorobenzoyloxymethyl) -7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On.

7- (2-chlorophenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methylthiophenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (4-Fluoro-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

-7- (5-Chloro-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-5-trifluoromethylphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on.

7- (6-Fluoro-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-5-nitrophenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (5-Benzoyloxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one .

8- (2-methoxyphenylaminomethyl) -7- (2-methoxy-5-trifluoromethylphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (4-amino-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- (5-hydroxymethyl-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one .

8- (5-fluoro-2-methylphenoxymethyl) -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (4-Hydroxy-2-methoxyphenyl) -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one.

7- [4- (2-chlorobenzoyloxy) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [4- (furan-3-ylcarbonyloxy) -2-methoxyphenyl] -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (pyridin-4-ylcarbonylamino) phenyl] -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one.

7- [4- (2-chlorobenzoylamino) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (4-methoxybenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one.

7- (4-acryloyloxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one .

8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-4-methoxycarbonyloxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on.

8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-4-phenoxycarbonyloxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on.

8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-4-phenoxycarbonylaminophenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on.

7- [4- (2-Fluorobenzoyloxy) -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (3-methoxycarbonylbenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H -Quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (2-methylpyridin-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4 -Dihydro-1H-quinoxalin-2-one.

7- [4- (2-acetoxybenzoyloxy) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (2-methylthiobenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (6-methylpyridin-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4 -Dihydro-1H-quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (oxazol-4-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one.

7- [4- (3-acetylbenzoyloxy) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one.

7- [4- (3-Chlorothiophen-2-ylcarbonyloxy) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4 -Dihydro-1H-quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (2-methoxypyridin-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4 -Dihydro-1H-quinoxalin-2-one.

7- [2-methoxy-4- (2-methylthiobenzoyloxy) phenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one.

7- [4- (N-acetyl-N-methylamino) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro -1H-quinoxalin-2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (pyridin-3-ylaminocarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro -1H-quinoxalin-2-one.

7- (2-methoxy-4-phenylaminocarbonyloxyphenyl) -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (morpholin-4-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one.

7- (4-Dimethylaminocarbonyloxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On.

7- (4-hydroxy-2-methoxyphenyl) -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (4-Butyryloxy-2-methoxyphenyl) -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [2-methoxy-4- (2-methylpyridin-3-ylcarbonyloxy) phenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one.

8- (2-methoxyphenylaminomethyl) -7- [2-methoxy-4- (thiazol-4-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one.

8- [N- (5-fluoro-2-methylphenyl) -N- (9-fluorenylmethoxycarbonyl) aminomethyl] -7- (4-hydroxy-2-methoxyphenyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxaline- 2-on.

8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methylphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- (4-Benzoyloxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one .

7- (4-Benzoyloxy-2-methoxyphenyl) -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On.

7- [4- (furan-2-ylcarbonyloxy) -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4- Dihydro-1H-quinoxalin-2-one.

7- [2-methoxy-4- (2-methoxybenzoyloxy) phenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one.

7- [2-methoxy-4- (3-methoxycarbonylbenzoyloxy) phenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro -1H-quinoxalin-2-one.

7- [2-methoxy-4- (3-methylfuran-2-ylcarbonyloxy) phenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3 , 4-Dihydro-1H-quinoxalin-2-one.

7- [4- (3-Benzylureido) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one.

8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (3-phenylureido) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one.

8- (2-methoxyphenylaminomethyl) -7- [2-methoxy-4- (pyridin-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one.

7- [2-methoxy-4- (2-methoxybenzoyloxy) phenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On.

8- (2-methoxyphenylaminomethyl) -7- [2-methoxy-4- (thiophen-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one.

7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On.

  The compound of the present invention can be produced by the following method. In addition, each specific manufacturing method is demonstrated in detail by the item of the manufacture example in the below-mentioned Example. Moreover, these illustrations are for understanding the present invention better and are not intended to limit the scope of the present invention. In the following synthesis route, Hal represents a halogen atom, MOM represents methoxymethyl, and Fmoc represents 9-fluorenylmethoxycarbonyl.

The compound (I)-(a) of the present invention (a compound in which A is a methylene group and X is O in the general formula (1)) can be synthesized according to Synthesis Route 1. That is, the halide (II) corresponding to the compound (I)-(b) of the present invention (a compound in which A is a methylene group, X is O, and R ⁶ is H in the general formula (1)) is converted to N, N-dimethyl. In an organic solvent such as formamide (hereinafter referred to as DMF), tetrahydrofuran (hereinafter referred to as THF), 1,4-dioxane, dichloromethane, and the like in the presence of a base such as cesium carbonate and potassium carbonate, 0 ° C. to 50 ° C. Compound (I)-(a) can be obtained by reacting from time to 24 hours.

The compound (I)-(b) of the present invention (a compound in which A is a methylene group, X is O, R ⁶ is H, R ⁷ is OR ⁸ , NR ⁸ R ⁹ or SR ⁸ in the general formula (1)) is synthesized. It can be synthesized according to route 2. That is, the compound (III) and the corresponding alcohol, carboxylic acid, phenol, amine, thiol, thiophenol and the like (IV) in an organic solvent such as DMF, THF and ethanol in the presence of a base such as potassium carbonate and sodium hydride, Compound (I)-(b) can be obtained by reacting at 0 to 100 ° C. for 1 to 48 hours.

The compound (I)-(c) of the present invention (a compound in which A is a methylene group, X is O, and R ⁷ is OR ⁸ in the general formula (1)) can be synthesized according to Synthesis Route 3. That is, the compound (V) and the corresponding halide (VI) are reacted in an organic solvent such as DMF, THF, or dichloromethane in the presence of a base such as triethylamine or potassium carbonate at 0 to 50 ° C. for 1 to 48 hours. Thus, compound (I)-(c) can be obtained.

The compounds (III) and (V) can be synthesized according to the synthesis route 4. That is, a boronic acid corresponding to compound (VII) or an ester thereof (VIII) in a solvent such as DMF, 1,4-dioxane, ethanol, toluene, water, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, etc. By reacting a base with a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or tetrakis (triphenylphosphine) palladium (0) at 50 to 120 ° C. for 1 to 48 hours, the compound ( IX) is obtained. The obtained compound (IX) is treated in an organic solvent such as diethyl ether and THF in the presence of a reducing agent such as lithium aluminum hydride at −30 ° C. to room temperature for 1 to 24 hours to give compound (V). Obtainable. Furthermore, the obtained compound (V) is methanesulfonyl chloride in an organic solvent such as dichloromethane or THF, in the presence of a base such as triethylamine or diisopropylethylamine (hereinafter referred to as DIEA) at 0 ° C. to room temperature for 30 minutes to 12 hours. By treatment, compound (III) can be obtained.

The above compound (VII) can be synthesized according to synthesis route 5. That is, compound (X) is treated in an organic solvent such as methanol, ethanol or DMF in the presence of a reducing agent such as tin (II) chloride or iron (II) chloride at 50 to 120 ° C. for 1 to 12 hours. Thus, compound (XI) is obtained. The resulting compound (XI) is treated with an acetylating agent such as acetyl chloride or acetic anhydride in an organic solvent such as dichloromethane or THF in the presence of a base such as triethylamine or DIEA at 0 to 50 ° C. for 1 to 12 hours. Thus, compound (XII) is obtained. The compound (XIII) can be obtained by treating the resulting compound (XII) with nitric acid in a solvent such as water in the presence of an acid such as sulfuric acid at −20 ° C. to room temperature for 30 minutes to 12 hours. Compound (XIV) is obtained by treating the obtained compound (XIII) in an organic solvent such as methanol in the presence of an acid such as boron trifluoride diethyl ether complex at 50 ° C. under reflux for 1 to 12 hours. It is done. Compound (XVI) is obtained by reacting the resulting compound (XIV) and the corresponding halide (XV) in the presence of a base such as cesium carbonate or potassium carbonate at 50 to 120 ° C. for 1 to 120 hours. . The resulting compound (XVI) is treated in an organic solvent such as methanol, ethanol or DMF in the presence of a reducing agent such as tin (II) chloride or iron (II) at 50 to 120 ° C. for 1 to 12 hours. Thus, compound (VII) can be obtained.

The compound (I)-(a) of the present invention (a compound in which A is a methylene group and X is O in the general formula (1)) can also be synthesized according to the synthesis route 6. That is, a boronic acid corresponding to compound (XVII) or an ester thereof (VIII) in a solvent such as DMF, 1,4-dioxane, ethanol, toluene, water, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, etc. By reacting a base with a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or tetrakis (triphenylphosphine) palladium (0) at 50 to 120 ° C. for 1 to 48 hours, the compound ( I)-(a) can be obtained.

Furthermore, the compound (I)-(a) of the present invention (a compound in which A is a methylene group and X is O in the general formula (1)) can also be synthesized according to the synthesis route 7. That is, the compound (XVIII) and the corresponding halide (XIX) are mixed with a base such as cesium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium phosphate in a solvent such as DMF, 1,4-dioxane, ethanol, toluene, water and the like. By reacting at 50 to 120 ° C. for 1 to 48 hours in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) chloride or tetrakis (triphenylphosphine) palladium (0), compound (I) — (A) can be obtained.

The compounds (XVII) and (XVIII) can be synthesized according to Synthesis Route 8. That is, the compound (VII) is treated in an organic solvent such as diethyl ether and THF in the presence of a reducing agent such as lithium aluminum hydride at 0 ° C. to 50 ° C. for 1 to 24 hours, thereby obtaining the compound (XX). Obtainable. The obtained compound (XX) and the corresponding halide (II) in an organic solvent such as DMF, THF, 1,4-dioxane, dichloromethane, etc. in the presence of a base such as cesium carbonate and potassium carbonate at 0 ° C. to 50 ° C. Compound (XXI) can be obtained by reacting for 1 to 24 hours. Further, the resulting compound (XXI) was treated with methanesulfonyl chloride in an organic solvent such as dichloromethane or THF in the presence of a base such as triethylamine or DIEA at 0 ° C. to room temperature for 30 minutes to 12 hours. ) Can be obtained. The resulting compound (XXII) and the corresponding alcohol, carboxylic acid, phenol, amine, thiol, thiophenol, etc. (IV) in an organic solvent such as DMF, THF, ethanol, in the presence of a base such as potassium carbonate, sodium hydride, Compound (XVII) can be obtained by reacting at 0 to 100 ° C. for 1 to 48 hours. The obtained compound (XVII) and the corresponding diboron (XXIII) and borane (XXIV) are mixed with a base such as potassium acetate and triethylamine in a solvent such as dimethyl sulfoxide, DMF and 1,4-dioxane [1,1 ′ -By reacting at 50 ° C to 120 ° C for 10 minutes to 48 hours in the presence of a catalyst such as bis (diphenylphosphino) ferrocene] palladium (II) or bis (triphenylphosphine) palladium (II) dichloride, (XVIII) can be obtained.

Compound (I)-(d) of the present invention (in the general formula (1), A is a methylene group, X is O, ^one of R ¹ is OR ¹⁰ , R ¹⁰ is a lower alkyl group which may have a substituent, A lower alkylcarbonyl group which may have a group, an arylcarbonyl group which may have a substituent, a heterocyclic carbonyl group which may have a substituent, a lower alkoxycarbonyl group which may have a substituent, A compound such as an aryloxycarbonyl group which may have a substituent can be synthesized according to Synthesis Route 9. That is, the compound (I)-(e) of the present invention (a compound in which A is a methylene group, X is O, and ^one of R ¹ is OH in the general formula (1)) and the corresponding halide (XXV) are THF, dichloromethane. Compound (I)-(d) can be obtained by reacting in an organic solvent such as DMF in the presence of a base such as triethylamine, DIEA or potassium carbonate at 0 to 100 ° C. for 1 to 24 hours. .

Compound (I)-(f) of the present invention (in the general formula (1), A is a methylene group, X is O, ^one of R ¹ is OCOR ¹¹ , R ¹¹ is a lower alkyl group which may have a substituent, A compound such as an aryl group which may have a group or a heterocyclic group which may have a substituent can be synthesized according to Synthesis Route 10. That is, the present compound (I)-(e) (a compound in which A is a methylene group, X is O, and ^one of R ¹ is OH in the general formula (1)) and the corresponding carboxylic acid (XXVI) are converted to DMF, dichloromethane In organic solvents such as N, N′-dicyclohexylcarbodiimide (hereinafter referred to as DCC), O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate Compound (I)-(f) can be obtained by reacting at room temperature to 50 ° C. for 1 hour to 3 days in the presence of a condensing agent (hereinafter referred to as HATU) and a base such as DIEA.

Compound (I)-(g) of the present invention (in general formula (1), A is a methylene group, X is O, ^one of R ¹ is OCONR ¹² R ¹³ , R ¹² and R ¹³ are the same or different and have a substituent. Or a lower alkyl group that may be substituted, an aryl group that may have a substituent, or the like) can be synthesized according to Synthesis Route 11. That is, the compound (I)-(e) of the present invention (a compound in which A is a methylene group, X is O, and ^one of R ¹ is OH in the general formula (1)) and 1,1′-carbonyldiimidazole (hereinafter, CDI) in an organic solvent such as dichloromethane and THF at room temperature to 50 ° C. for 30 minutes to 12 hours, and further reacted with the corresponding amine (XXVII) to give compound (I)-(g ) Can be obtained.

The compound (I)-(e) of the present invention (a compound in which A is a methylene group, X is O, and one of R1 is OH in the general formula (1)) can be synthesized according to the synthesis route 12. That is, the boronic acid corresponding to the compound (XVII) or its ester (XXVIII) in a solvent such as DMF, 1,4-dioxane, ethanol, toluene, water, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, etc. By reacting a base with a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or tetrakis (triphenylphosphine) palladium (0) at 50 to 120 ° C. for 1 to 48 hours, Compound (I)-(h) can be obtained. The resulting compound (I)-(h) is treated in an organic solvent such as 1,4-dioxane or dichloromethane in the presence of an acid such as hydrogen chloride or trifluoroacetic acid at 0 to 50 ° C. for 1 to 24 hours. Thus, compound (I)-(e) can be obtained.

The compound (I)-(e) of the present invention (a compound in which A is a methylene group, X is O, and one of R 1 is OH in the general formula (1)) can also be synthesized according to the synthesis route 13. That is, the boronic acid corresponding to the compound (VII) or its ester (XXVIII) in a solvent such as DMF, 1,4-dioxane, ethanol, toluene, water, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, etc. By reacting a base with a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or tetrakis (triphenylphosphine) palladium (0) at 50 to 120 ° C. for 1 to 48 hours, the compound ( XXIX) can be obtained. The obtained compound (XXIX) is treated in an organic solvent such as diethyl ether and THF in the presence of a reducing agent such as lithium aluminum hydride at −30 ° C. to room temperature for 1 to 24 hours to give compound (XXX). Obtainable. Further, the resulting compound (XXX) is treated with methanesulfonyl chloride in an organic solvent such as dichloromethane or THF in the presence of a base such as triethylamine or DIEA at 0 ° C. to room temperature for 30 minutes to 12 hours. XXXI) can be obtained. The resulting compound (XXXI) and the corresponding alcohol, carboxylic acid, phenol, amine, thiol, thiophenol and the like (IV) in an organic solvent such as DMF, THF and ethanol in the presence of a base such as potassium carbonate and sodium hydride, The present compound (I)-(i) can be obtained by reacting at 0 to 100 ° C. for 1 to 48 hours. The resulting compound (I)-(i) and the corresponding halide (II) are heated from 0 ° C. in the presence of a base such as cesium carbonate or potassium carbonate in an organic solvent such as DMF, THF, 1,4-dioxane, dichloromethane or the like. The present compound (I)-(h) can be obtained by reacting at 50 ° C. for 1 to 24 hours. The resulting compound (I)-(h) is treated in an organic solvent such as 1,4-dioxane or dichloromethane in the presence of an acid such as hydrogen chloride or trifluoroacetic acid at 0 to 50 ° C. for 1 to 24 hours. Thus, compound (I)-(e) can be obtained.

Compound (I)-(j) of the present invention (in general formula (1), A is a methylene group, X is O, ^one of R ¹ is OR ¹⁰ , R ⁷ is NHR ⁸ , and R ¹⁰ has a substituent) May have a lower alkyl group, a lower alkylcarbonyl group which may have a substituent, an arylcarbonyl group which may have a substituent, a heterocyclic carbonyl group which may have a substituent, or a substituent. A preferred lower alkoxycarbonyl group, a compound such as an aryloxycarbonyl group optionally having substituent (s)), the present compound (I)-(k) (in the general formula (1), A is a methylene group, X is O, ^One of R ¹ is OCOR ¹¹ , R ⁷ is NHR ⁸ , R ¹¹ is a lower alkyl group that may have a substituent, an aryl group that may have a substituent, or a heterocyclic ring that may have a substituent A compound which is a group, etc.) and the compound (I)-(l (In the general formula (1), A is a methylene group, X is O, ^one of R ¹ is OCONR ¹² R ¹³ , R ⁷ is NHR ⁸ , R ¹² and R ¹³ may be the same or different and have a substituent. A compound that is a good lower alkyl group, an aryl group that may have a substituent, or the like) can be synthesized according to synthetic route 14. That is, the halogen compound corresponding to the compound (I)-(m) of the present invention (a compound in which A is a methylene group, X is O, one of R 1 is OH, and R ⁷ is NR ⁸ (Fmoc) in general formula (1)) After reacting compound (XXV), corresponding carboxylic acid (XXVI), and corresponding amine (XXVII) according to the methods of Synthesis Routes 9, 10, and 11, respectively, the reaction product is piperidine in an organic solvent such as DMF or dichloromethane. Compound (I)-(j), compound (I)-(k) and compound (I)-(l) are treated in the presence of a base such as 0 ° C. to 50 ° C. for 5 minutes to 24 hours. Obtainable.

The compound (I)-(m) of the present invention (a compound in which A is a methylene group, X is O, one of R 1 is OH, and R ⁷ is NR ⁸ (Fmoc) in the general formula (1)) is synthesized according to the synthesis route 15 can do. That is, the compound (XXII) and the corresponding amine (XXXII) are reacted in an organic solvent such as DMF, THF, and ethanol in the presence of a base such as potassium carbonate and sodium hydride at 0 to 100 ° C. for 1 to 48 hours. Compound (XXXIII) can be obtained. The resulting compound (XXXIII) and the corresponding boronic acid or its ester (XXVIII) in a solvent such as DMF, 1,4-dioxane, ethanol, toluene, water, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, etc. By reacting the base with a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or tetrakis (triphenylphosphine) palladium (0) at 50 to 120 ° C. for 1 to 48 hours, Compound (I)-(o) can be obtained. The resulting compound (I)-(o) and 9-fluorenylmethoxycarbonyl chloride in a solvent such as 1,4-dioxane and water in the presence of a base such as sodium bicarbonate at 0 ° C. to 50 ° C. for 1 hour The compound (I)-(n) of the present invention can be obtained by reacting for 24 hours. The resulting compound (I)-(n) is treated in an organic solvent such as 1,4-dioxane or dichloromethane in the presence of an acid such as hydrogen chloride or trifluoroacetic acid at 0 to 50 ° C. for 1 to 24 hours. Thus, compound (I)-(m) can be obtained.

Compound (I)-(p) of the present invention (In the general formula (1), A is a methylene group, X is O, ^one of R ¹ is OR ¹⁰ , R ⁷ is OR ⁸ , and R ¹⁰ has a substituent) May have a lower alkyl group, a lower alkylcarbonyl group which may have a substituent, an arylcarbonyl group which may have a substituent, a heterocyclic carbonyl group which may have a substituent, or a substituent. A compound that is a good lower alkoxycarbonyl group, an aryloxycarbonyl group that may have a substituent, or the like) can be synthesized according to Synthesis Route 16. That is, the compound (XXX) is treated in an organic solvent such as 1,4-dioxane or dichloromethane in the presence of an acid such as hydrogen chloride or trifluoroacetic acid at 0 to 50 ° C. for 1 to 24 hours. XXXIV) can be obtained. The resulting compound (XXXIV) and the corresponding halide (XXV) in an organic solvent such as THF, dichloromethane, DMF and the like in the presence of a base such as triethylamine, DIEA, potassium carbonate and the like at 0 ° C. to 100 ° C. for 1 hour to 24 hours. Compound (XXXV) can be obtained by reacting. The resulting compound (XXXV) and the corresponding halide (VI) are reacted in an organic solvent such as DMF, THF or dichloromethane in the presence of a base such as triethylamine or potassium carbonate at 0 to 50 ° C. for 1 to 48 hours. Thus, compound (I)-(q) can be obtained. The resulting compound (I)-(q) and the corresponding halide (II) are heated from 0 ° C. in the presence of a base such as cesium carbonate or potassium carbonate in an organic solvent such as DMF, THF, 1,4-dioxane or dichloromethane. Compound (I)-(p) can be obtained by reacting at 50 ° C. for 1 to 24 hours.

  In order to find the usefulness of the compound of the present invention as a pharmaceutical, a glucocorticoid receptor competition assay kit by a polarized fluorescence method was performed using a glucocorticoid receptor competition assay kit. As a result, the compound of the present invention showed excellent glucocorticoid receptor binding activity. As described above, glucocorticoid receptors are involved in the development of various diseases, and the compounds of the present invention having excellent binding activity to glucocorticoid receptors are expected to be useful as glucocorticoid receptor modulators. The

  The details will be described in detail in the “Pharmacological Test Section” below.

The compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, injections, eye drops and the like, and they can be formulated using a widely used technique.

  For example, oral preparations such as tablets, capsules, granules, powders are lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate and other excipients, stearic acid, magnesium stearate , Lubricants such as talc, binders such as starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, calcium citrate, hydroxypropylmethylcellulose, macrogol, Coating agents such as silicone resins, stabilizers such as ethyl paraoxybenzoate and benzyl alcohol, and flavoring agents such as sweeteners, acidulants and fragrances can be prepared using necessary amounts as necessary. .

  In addition, parenterals such as injections and eye drops are made of isotonic agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol, mannitol, sodium phosphate, sodium hydrogen phosphate, sodium acetate. Buffering agents such as citric acid, glacial acetic acid, trometamol, surfactants such as polysorbate 80, polyoxy40 stearate, polyoxyethylene hydrogenated castor oil 60, stabilizers such as sodium citrate and sodium edetate, benzal chloride PH adjustment of preservatives such as luconium, paraben, benzotonium chloride, paraoxybenzoate, sodium benzoate, chlorobutanol, hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate Agent, benzyl alcohol, etc. If necessary the soothing agent or the like, using the required amount can be prepared.

  The dose of the compound of the present invention can be appropriately selected and used depending on symptoms, age, dosage form and the like. For example, in the case of an oral preparation, 0.01 to 1000 mg per day, preferably 1 to 100 mg can be administered once or divided into several times. In addition, the eye drops are usually administered in a concentration of 0.0001% to 10% (w / v), preferably 0.01% to 5% (w / v) in one or several divided doses. it can.

The production examples, formulation examples and pharmacological test results of the compounds of the present invention are shown below. In addition, these illustrations are for understanding this invention better, and do not limit the scope of the present invention.

Moreover, Fmoc in the chemical structural formula in the production examples represents a 9-fluorenylmethoxycarbonyl group.

[Production example]
Reference example 1
7-Bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound 1)

Methyl 5-amino-2-bromobenzoate (Reference compound 1- (1))
Methyl 2-bromo-5-nitrobenzoate (25.3 g, 97.3 mmol) was dissolved in anhydrous methanol (500 mL), tin (II) chloride (93.3 g, 487 mmol) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool, ethyl acetate (500 mL) and water (100 mL) were added, neutralized with 4N aqueous sodium hydroxide solution, and filtered through celite. The filtrate was concentrated under reduced pressure, ethyl acetate (200 mL) was added, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution (200 mL, twice), water (200 mL) and saturated brine (200 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title reference compound (21.0 g) as a yellow oil. (Yield 94%)

Methyl 5-acetylamino-2-bromobenzoate (Reference compound 1- (2))
Methyl 5-amino-2-bromobenzoate (reference compound 1- (1), 21.0 g, 91.2 mmol) was dissolved in anhydrous dichloromethane (450 mL), and under ice cooling, triethylamine (19.0 mL, 137 mmol) and Acetyl chloride (13.0 mL, 182 mmol) was added dropwise in that order over 30 minutes, and the mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was washed successively with water (200 mL, twice), saturated aqueous sodium hydrogen carbonate solution (200 mL, twice) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was collected by filtration with hexane-ethyl acetate (20: 1) to give the titled reference compound (24.2 g) as a pale yellow solid. (Yield 98%)

Methyl 3-acetylamino-6-bromo-2-nitrobenzoate (reference compound 1- (3))
After adding methyl 5-acetylamino-2-bromobenzoate (reference compound 1- (2), 18.5 g, 68.1 mmol) little by little to concentrated sulfuric acid (150 mL) at 0 ° C., concentrated nitric acid (150 mL) Was added dropwise over 1 hour. After stirring for 30 minutes, the reaction solution was added to ice water (1 L) and extracted with ethyl acetate (500 mL, twice). The organic layer was washed successively with water (1 L, twice), saturated aqueous sodium hydrogen carbonate solution (1 L) and saturated brine (1 L), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (13.4 g) as a yellow solid. (Yield 62%)

Methyl 3-amino-6-bromo-2-nitrobenzoate (reference compound 1- (4))
Methyl 3-acetylamino-6-bromo-2-nitrobenzoate (reference compound 1- (3), 13.4 g, 42.2 mmol) was dissolved in methanol (240 mL), and boron trifluoride diethyl ether complex (24 0.0 mL, 190 mmol) was added, and the mixture was heated to reflux for 2.5 hours. The reaction solution was neutralized with sodium hydrogen carbonate (48 g), and then concentrated under reduced pressure. After adding ethyl acetate (500 mL) and water (700 mL) to the reaction solution and partitioning, the ethyl acetate layer was washed successively with water (700 mL) and saturated brine (700 mL), dried over anhydrous magnesium sulfate, and then the solvent under reduced pressure. Was distilled off to obtain the title reference compound (11.6 g) as an orange solid. (Yield 100%)

Methyl 6-bromo-3-[(2-ethoxycarbonyl) propan-2-yl] amino-2-nitrobenzoate (Reference compound 1- (5))
Methyl 3-amino-6-bromo-2-nitrobenzoate (reference compound 1- (4), 11.6 g, 42.0 mmol), ethyl 2-bromoisobutyrate (60.4 mL, 412 mmol), potassium iodide (7 A mixture of .76 g, 46.2 mmol) and cesium carbonate (56.1 g, 172 mmol) was stirred at 85 ° C. for 4 days. After allowing to cool, ethyl acetate (500 mL) and water (500 mL) were added to the reaction solution for partitioning, and the aqueous layer was extracted with ethyl acetate (300 mL). The organic layers were combined, washed successively with water (1 L, 2 times) and saturated brine (1 L), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (5.08 g) as an orange oil. (Yield 31%)

7-Bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound 1)
Methyl 6-bromo-3-[(2-ethoxycarbonyl) propan-2-yl] amino-2-nitrobenzoate (reference compound 1- (5), 105 mg, 0.26 mmol) in absolute ethanol (4.5 mL) Into the solution, tin (II) chloride (247 mg, 1.30 mmol) was added and heated to reflux for 5 hours. After allowing to cool, ethyl acetate (25 mL) was added to the reaction mixture, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and filtered through celite. After partitioning the filtrate, the aqueous layer was extracted with ethyl acetate (10 mL, twice), and the combined organic layers were washed successively with water (50 mL, twice) and saturated brine (50 mL), and anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (56.3 mg) as a pale yellow solid. (Yield 70%)

Reference example 2
8-Methoxycarbonyl-7- (2-methoxyphenyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 2-1)
7-bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 1, 203 mg, 0.64 mmol), 2-methoxyphenylboronic acid (196 mg, 1 .28 mmol), cesium carbonate (629 mg, 1.92 mmol) and bis (triphenylphosphine) palladium (II) dichloride (45.8 mg, 0.06 mmol) are suspended in anhydrous N, N-dimethylformamide (3 mL). It became cloudy and stirred at 80 ° C. for 2 hours. After cooling, ethyl acetate (30 mL) and water (30 mL) were added and partitioned. The organic layer was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (116 mg) as a pale yellow amorphous product. (Yield 53%)

参考例３
８−ヒドロキシメチル−７−（２−メトキシフェニル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物３−１）
窒素雰囲気下、水素化リチウムアルミニウム（２６．０ｍｇ、０．６４ｍｍｏl）を無水テトラヒドロフラン（０．５ｍL）に懸濁した。０℃で、８−メトキシカルボニル−７−（２−メトキシフェニル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物２−１、１０８ｍｇ、０．３２ｍｍｏl）の無水テトラヒドロフラン（１．５ｍL）溶液を滴下し、同温で３時間攪拌した。反応液に酢酸エチル（３ｍL）及び水（３ｍL）を順次滴下した後、酢酸エチル（３０ｍL）、水（３０ｍL）及び１規定塩酸（５ｍL）を加えて分配した。水層を酢酸エチル（２０ｍL）で抽出した後、有機層を合わせた。有機層を水（５０ｍL、２回）及び飽和食塩水（５０ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記参考化合物（６１．０ｍｇ）を淡黄色アモルファスとして得た。（収率６１％）

Hereinafter, reference compounds 2-2 to 2-5 were obtained according to the production method of reference compound 2-1, using compounds selected from reference compounds 1, 18-3, 18-5 and commercially available compounds.

Reference example 3
8-hydroxymethyl-7- (2-methoxyphenyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 3-1)
Under a nitrogen atmosphere, lithium aluminum hydride (26.0 mg, 0.64 mmol) was suspended in anhydrous tetrahydrofuran (0.5 mL). At 0 ° C., 8-methoxycarbonyl-7- (2-methoxyphenyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 2-1, 108 mg, 0.32 mmol) Solution of anhydrous tetrahydrofuran (1.5 mL) was added dropwise and stirred at the same temperature for 3 hours. Ethyl acetate (3 mL) and water (3 mL) were sequentially added dropwise to the reaction solution, and then ethyl acetate (30 mL), water (30 mL) and 1N hydrochloric acid (5 mL) were added and partitioned. The aqueous layer was extracted with ethyl acetate (20 mL), and then the organic layers were combined. The organic layer was washed successively with water (50 mL, twice) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (61.0 mg) as a pale yellow amorphous product. (Yield 61%)

参考例４
８−クロロメチル−７−（４−フルオロ−２−メトキシフェニル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物４−１）
７−（４−フルオロ−２−メトキシフェニル）−８−ヒドロキシメチル−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物３−２、７０．０ｍｇ、０．２１ｍｍｏL）を無水ジクロロメタン（１ｍL）及び無水テトラヒドロフラン（１．５ｍL）の混合溶媒に溶解し、トリエチルアミン（３５μL、０．２５ｍｍｏL）及び塩化メタンスルホニル（１８μL、０，２３ｍｍｏL）を順次加えた。反応液を室温で一晩攪拌した。反応液に酢酸エチル（３０ｍL）及び水（３０ｍL）加えて分配した。有機層を水（３０ｍL）及び飽和食塩水（３０ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記参考化合物（４９．５ｍｇ）を淡黄色固体として得た。（収率６８％）

Hereinafter, reference compounds 3-2 to 3-5 were obtained according to the production method of reference compound 3-1, using a compound selected from reference compounds 2-2 to 2-5.

Reference example 4
8-chloromethyl-7- (4-fluoro-2-methoxyphenyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 4-1)
7- (4-Fluoro-2-methoxyphenyl) -8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 3-2, 70.0 mg, 0. 21 mmol) was dissolved in a mixed solvent of anhydrous dichloromethane (1 mL) and anhydrous tetrahydrofuran (1.5 mL), and triethylamine (35 μL, 0.25 mmol) and methanesulfonyl chloride (18 μL, 0.23 mmol) were sequentially added. The reaction was stirred at room temperature overnight. The reaction solution was partitioned by adding ethyl acetate (30 mL) and water (30 mL). The organic layer was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (49.5 mg) as a pale yellow solid. (Yield 68%)

Hereinafter, reference compounds 4-2 and 4-3 were obtained according to the production method of reference compound 4-1, using a compound selected from reference compounds 3-3 and 3-4.

Reference Example 5
7-Bromo-8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 5)
Under a nitrogen atmosphere, lithium aluminum hydride (38.5 mg, 1.01 mmol) was suspended in anhydrous tetrahydrofuran (0.5 mL). At 0 ° C., anhydrous tetrahydrofuran (1.5 mL) of 7-bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound 1, 101 mg, 0.323 mmol) ) The solution was added dropwise and stirred at the same temperature for 1 hour. Ethyl acetate (10 mL), water (10 mL) and 1N hydrochloric acid (2 mL) were sequentially added to the reaction solution and partitioned. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (67.4 mg) as an orange amorphous. (Yield 74%)

Reference Example 6
7-Bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 6)
7-bromo-8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 5, 62.7 mg, 0.220 mmol), methyl iodide (68.6 μL, 1.10 mmol) and cesium carbonate (180 mg, 0.552 mmol) were suspended in anhydrous N, N-dimethylformamide (1 mL) and stirred at room temperature for 2.5 hours. The reaction mixture was partitioned by adding ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (45.5 mg) as an orange amorphous. (Yield 69%)

Reference Example 7
7-Bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound 7)
7-Bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 6, 37.5 mg, 0.125 mmol) was added to anhydrous dichloromethane (1 mL). After dissolution, triethylamine (20.9 μL, 0.150 mmol) and methanesulfonyl chloride (10.7 μL, 0.138 mmol) were sequentially added. The reaction was stirred at room temperature overnight. The reaction mixture was partitioned by adding ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (28.7 mg) as an orange amorphous. (Yield 72%)

Reference Example 8
7-Bromo-8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 8-1)
7-bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 7, 801 mg, 2.52 mmol), 5-fluoro-2-methylphenol A mixture of (330 μL, 3.02 mmol) and potassium carbonate (524 mg, 3.79 mmol) was suspended in anhydrous N, N-dimethylformamide (10 mL) and stirred at 80 ° C. overnight. After cooling, ethyl acetate (80 mL) and water (50 mL) were added and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (945 mg) as a colorless solid. (Yield 92%)

Hereinafter, reference compounds 8-2 to 8-4 were obtained according to the production method of reference compound 8-1, using a compound selected from reference compound 7 and a commercially available compound.

Reference Example 9
7-Bromo-8-methoxycarbonyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 9)
7-bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound 1, 102 mg, 0.326 mmol), methyl iodide (100 μL, 1.60 mmol) And cesium carbonate (272 mg, 0.835 mmol) were suspended in anhydrous N, N-dimethylformamide (5 mL) and stirred at room temperature for 2 hours. The reaction mixture was partitioned by adding ethyl acetate (25 mL) and water (25 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (86.0 mg) as a pale yellow solid. (Yield 83%)

Reference Example 10
7- (5-Chloro-2-methoxyphenyl) -8-methoxycarbonyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 10-1)
Under an argon atmosphere, 7-bromo-8-methoxycarbonyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 9, 3.75 g, 11.5 mmol), 5- Of chloro-2-methoxyphenylboronic acid (2.57 g, 13.8 mmol), cesium carbonate (7.49 g, 23.0 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.33 g, 1.16 mmol). The mixture was suspended in anhydrous N, N-dimethylformamide (70 mL) and stirred at 80 ° C. overnight. After allowing to cool, ethyl acetate (300 mL), diethyl ether (150 mL) and water (400 mL) were added and partitioned. The organic layer was washed successively with water (250 mL) and saturated brine (150 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (3.84 g) as a colorless amorphous product. (Yield 86%)

Hereafter, the compound selected from the reference compound 9 and a commercially available compound was used, and the reference compound 10-2 was obtained according to the manufacturing method of the reference compound 10-1.

Reference Example 11
9-chloro-2,2,4-trimethyl-1,4-dihydro-2H-6-oxa-1,4-diazachrysene-3,5-dione (Reference compound 11-1)
7- (5-Chloro-2-methoxyphenyl) -8-methoxycarbonyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 10-1, 3.81 g, 9.80 mmol) was dissolved in anhydrous dichloromethane (30 mL), boron tribromide (7.62 g, 30.4 mmol) was added at −78 ° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water (500 mL), and partitioned by adding ethyl acetate (500 mL). The organic layer was washed with saturated brine (200 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in anhydrous N, N-dimethylformamide (50 mL), 60% sodium hydride (23.1 mg, 0.578 mmol) was added, and the mixture was stirred at 70 ° C. overnight. 60% sodium hydride (31.2 mg, 0.780 mmol) was added, and the mixture was stirred at 80 ° C. overnight. After cooling, ethyl acetate (200 mL), diethyl ether (200 mL) and water (300 mL) were added and partitioned. The organic layer was washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was collected by filtration with ethyl acetate / hexane (1/4, 30 mL) to give the titled reference compound (2.04 g) as a pale yellow solid. (Yield 61%)

Hereinafter, reference compound 11-2 was obtained using reference compound 10-2 according to the production method of reference compound 11-1.

Reference Example 12
7- (5-Chloro-2-hydroxyphenyl) -8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 12-1)
Under a nitrogen atmosphere, lithium aluminum hydride (442 mg, 11.7 mmol) was suspended in anhydrous tetrahydrofuran (10 mL). At −10 ° C., 9-chloro-2,2,4-trimethyl-1,4-dihydro-2H-6-oxa-1,4-diazachrysene-3,5-dione (reference compound 11-1, 1.99 g) A solution of 5.81 mmol in anhydrous tetrahydrofuran (40 mL) was added dropwise and stirred at the same temperature for 10 minutes. Ethyl acetate (1 mL) and water (1 mL) were sequentially added to the reaction solution, and then ethyl acetate (300 mL) and brine (300 mL) were added and partitioned. The organic layer was washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.38 g) as a pale yellow solid. (Yield 69%)

Hereinafter, Reference Compound 12-2 was obtained using Reference Compound 11-2 according to the production method of Reference Compound 12-1.

Reference Example 13
7- (5-Chloro-2-methoxyphenyl) -8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 13-1)
7- (5-Chloro-2-hydroxyphenyl) -8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 12-1, 1.36 g, 3.92 mmol), methyl iodide (244 μL, 3.92 mmol) and potassium carbonate (1.08 g, 7.81 mmol) were suspended in anhydrous N, N-dimethylformamide (20 mL) and stirred at 50 ° C. for 1 hour. did. After standing to cool, ethyl acetate (70 mL), diethyl ether (70 mL) and water (150 mL) were added and partitioned. The organic layer was washed successively with water (100 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.36 g) as a pale yellow amorphous. (Yield 96%)

Hereinafter, reference compound 13-2 was obtained according to the production method of reference compound 13-1, using reference compound 12-2.

Reference Example 14
7- (5-Chloro-2-methoxyphenyl) -8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 14-1)
7- (5-Chloro-2-methoxyphenyl) -8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 13-1, 1.34 g, 3.71 mmol) was dissolved in anhydrous dichloromethane (19 mL), and triethylamine (621 μL, 4.46 mmol) and methanesulfonyl chloride (316 μL, 4.08 mmol) were sequentially added. The reaction was stirred at room temperature overnight. Ethyl acetate (200 mL) was added to the reaction solution, washed with water (200 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.14 g) as a colorless amorphous product. (Yield 81%)

Hereafter, reference compound 14-2 was obtained according to the manufacturing method of reference compound 14-1 using reference compound 13-2.

Reference Example 15
4-Benzoyloxyanisole (Reference compound 15-1)
4-Hydroxyanisole (1.25 g, 10.1 mmol) was dissolved in anhydrous dichloromethane (10 mL), and triethylamine (4.25 mL, 30.5 mmol) and benzoyl chloride (1.40 mL, 12.1 mmol) were sequentially added. The reaction was stirred at room temperature for 4 hours. Chloroform (50 mL) and water (50 mL) were added to the reaction solution and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was collected by filtration with hexane (50 mL) to give the titled reference compound (2.24 g) as a colorless solid. (Yield 98%)

Hereinafter, Reference Compound 15-2 was obtained using Reference Compound 16-3 according to the production method of Reference Compound 15-1.

Reference Example 16
2-Bromo-4-chloro-5-fluoroanisole (Reference compound 16-1)
Mixture of 4-chloro-3-fluoroanisole (124 μL, 1.00 mmol) and N-bromosuccinimide (183 mg, 1.03 mmol) with anhydrous N, N-dimethylformamide (0.5 mL) and anhydrous dichloromethane (1 mL) It melt | dissolved in the solvent and stirred at 40 degreeC for 3 days. After allowing to cool, chloroform (30 mL) and water (30 mL) were added and partitioned. The aqueous layer was extracted with chloroform (30 mL, twice), and then the organic layers were combined. The organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (195 mg) as a colorless solid. (Yield 82%)

Hereinafter, reference compounds 16-2 to 16-3 were obtained according to the production method of reference compound 16-1, using a compound selected from reference compound 15-1 and commercially available compounds.

Reference Example 17
5-Chloro-4-fluoro-2-methoxyphenylboronic acid (Reference Compound 17)
2-Bromo-4-chloro-5-fluoroanisole (Reference compound 16-1, 239 mg, 1.00 mmol) was dissolved in a mixed solvent of anhydrous toluene (2 mL) and anhydrous tetrahydrofuran (0.5 mL), and the solution was at −40 ° C. A 1.6 M hexane solution (750 μL, 1.20 mmol) of n-butyllithium was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Triisopropyl boronate (277 μL, 1.20 mmol) was added dropwise to the reaction solution, and the temperature was raised to −20 ° C. over 10 minutes, and then 2N hydrochloric acid (1 mL) was added. The reaction solution was stirred at room temperature for 20 minutes, and partitioned by adding ethyl acetate (20 mL) and water (20 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the titled reference compound (181 mg) as a colorless solid. (Yield 89%)

Reference Example 18
2- (5,5-Dimethyl [1,3,2] dioxaborinan-2-yl) -4-nitroanisole (Reference compound 18-1)
2-Bromo-4-nitroanisole (100 mg, 0.431 mmol), bis (neopentylglycolate) diboron (151 mg, 0.668 mmol), potassium acetate (129 mg, 1.31 mmol) and dichloride [1,1′- A mixture of bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane complex (1: 1) (35.5 mg, 0.0435 mmol) was suspended in dimethyl sulfoxide (3 mL) and irradiated with microwaves at 80 ° C. for 10 Stir for minutes. After allowing to cool, ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution and partitioned. The organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the titled reference compound (72.5 mg) as a yellow solid. (Yield 85%)

参考例１９
５−シアノ−２−トリフルオロメチルスルホニルオキシアニソール（参考化合物１９−１）
アルゴン雰囲気下、５−シアノ−２−ヒドロキシアニソール（６００ｍｇ、４．０２ｍｍｏｌ）及びトリエチルアミン（１．４０ｍL、１０．０ｍｍｏｌ）の混合物を無水テトラヒドロフラン（２０ｍL）に溶解した。−１０℃で、塩化トリフルオロメタンスルホニル（６４２μＬ、６．０３ｍｍｏl）を滴下し、同温で１時間攪拌した。反応液に酢酸エチル（１００ｍL）及び水（１００ｍL）を加えて分配した。有機層を飽和食塩水（５０ｍL）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記参考化合物（９７９ｍｇ）を無色固体として得た。（収率８７％）

Hereinafter, reference compounds 18-2 to 18-7 were obtained according to the production method of reference compound 18-1, using compounds selected from reference compounds 15-2, 16-2 and 23 and commercially available compounds.

Reference Example 19
5-Cyano-2-trifluoromethylsulfonyloxyanisole (Reference compound 19-1)
Under an argon atmosphere, a mixture of 5-cyano-2-hydroxyanisole (600 mg, 4.02 mmol) and triethylamine (1.40 mL, 10.0 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Trifluoromethanesulfonyl chloride (642 μL, 6.03 mmol) was added dropwise at −10 ° C., and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction solution and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (979 mg) as a colorless solid. (Yield 87%)

Hereinafter, reference compounds 19-2 to 19-4 were obtained using commercially available compounds according to the production method of Reference Compound 19-1.

Reference Example 20
5-Cyano-2- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) anisole (Reference compound 20-1)
Under an argon atmosphere, 5-cyano-2-trifluoromethylsulfonyloxyanisole (reference compound 19-1, 200 mg, 0.711 mmol), bis (pinacolato) diboron (200 mg, 0.788 mmol), potassium acetate (213 mg, 2. 17 mmol), 1,1′-bis (diphenylphosphino) ferrocene (20.0 mg, 0.0361 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane complex (1: 1) A mixture of (29.4 mg, 0.0360 mmol) was suspended in 1,4-dioxane (4 mL) and stirred at 80 ° C. overnight. After allowing to cool, ethyl acetate (100 mL) and water (100 mL) were added and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (123 mg) as a colorless solid. (Yield 67%)

Hereinafter, Reference Compound 20-2 was obtained using Reference Compound 19-4 according to the production method of Reference Compound 20-1.

Reference Example 21
7- (5,5-Dimethyl [1,3,2] dioxaborinan-2-yl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one (Reference Compound 21)
Under an argon atmosphere, 7-bromo-8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 8-1, 98.7 mg, 0.242 mmol), bis (neopentylglycolate) diboron (170 mg, 0.753 mmol), potassium acetate (112 mg, 1.14 mmol) and [1,1′-bis (diphenylphosphino) ferrocene dichloride A mixture of palladium (II) dichloromethane complex (1: 1) (20.7 mg, 0.0253 mmol) was suspended in dimethyl sulfoxide (2 mL), and irradiated with microwaves and stirred at 80 ° C. for 15 minutes. After allowing to cool, ethyl acetate (15 mL) and water (15 mL) were added to the reaction solution and partitioned. The organic layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (first hexane-ethyl acetate, second chloroform). The obtained residue was collected by filtration with hexane (5 mL) to give the titled reference compound (70.2 mg) as a colorless solid. (Yield 65%)

Reference Example 22
8- (5-Fluoro-2-methylphenoxymethyl) -7- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -1,3,3-trimethyl-3 , 4-Dihydro-1H-quinoxalin-2-one (Reference Compound 22)
7-Bromo-8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 8-1, 101 mg, 0. 248 mmol), bis (pinacolato) diboron (156 mg, 0.614 mmol), potassium acetate (75.5 mg, 0.769 mmol), 1,1′-bis (diphenylphosphino) ferrocene (7.2 mg, 0.013 mmol) and A mixture of [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane complex (1: 1) (10.7 mg, 0.0131 mmol) dichloride was suspended in 1,4-dioxane (2 mL). And stirred at 80 ° C. overnight. After cooling, ethyl acetate (15 mL) and water (15 mL) were added and partitioned. The organic layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (first hexane-ethyl acetate, second chloroform-methanol) to give the titled reference compound (87.9 mg) as a colorless amorphous. (Yield 78%)

Reference Example 23
2-Bromo-5-methoxymethoxyanisole (Reference compound 23)
A mixture of 4-bromo-3-methoxyphenol (500 mg, 2.46 mmol), chlorodimethyl ether (281 μL, 3.70 mmol) and potassium carbonate (850 mg, 6.15 mmol) was suspended in anhydrous N, N-dimethylformamide (8 mL). It became cloudy and stirred at 50 ° C. for 1 hour. After cooling, ethyl acetate (150 mL) was added for dilution. The extract was washed successively with water (150 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (421 mg) as a colorless oil. (Yield 69%)

Reference Example 24
8-hydroxymethyl-7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound 24)
7- (4-Hydroxy-2-methoxyphenyl) -8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 3-5, 430 mg, 1.31 mmol) Was dissolved in tetrahydrofuran (10 mL), and triethylamine (365 μL, 2.62 mmol) and 2-methylbenzoyl chloride (222 μL, 1.70 mmol) were sequentially added at 0 ° C. The reaction solution was stirred at the same temperature for 80 minutes and then diluted with ethyl acetate (200 mL). The extract was washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (362 mg) as a colorless solid. (Yield 62%)

Reference Example 25
5-Bromothiophene-2-carbonyl chloride (Reference compound 25)
A mixture of 5-bromothiophene-2-carboxylic acid (300 mg, 1.45 mmol), thionyl chloride (423 μL, 5.80 mmol) and N, N-dimethylformamide (1 drop) was dissolved in chloroform (3 mL) for 1 hour. Heated to reflux. After allowing to cool, the reaction mixture was concentrated under reduced pressure to give the titled reference compound (324 mg) as a pale yellow solid. (Yield 99%)

[Example]
Example 1
8-Benzoyloxymethyl-7- (2-methoxyphenyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound 1-1)
8-hydroxymethyl-7- (2-methoxyphenyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 3-1, 54.2 mg, 0.17 mmol) was anhydrous After dissolving in tetrahydrofuran (1.5 mL), triethylamine (73.0 μL, 0.52 mmol) and benzoyl chloride (30.0 μL, 0.26 mmol) were sequentially added. The reaction was stirred at room temperature for 24 hours. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution and partitioned. The organic layer was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was collected by filtration with ethyl acetate to give the title compound (54.1 mg) as a colorless solid. (Yield 76%)

実施例２
７−（５−フルオロ−２−メトキシフェニル）−８−(５−メチルチオフェン−２−イルカルボニルオキシメチル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物２−１）
８−クロロメチル−７−（５−フルオロ−２−メトキシフェニル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物４−２、５０．９ｍｇ、０．１４ｍｍｏｌ）、５−メチル−２−チオフェンカルボン酸（６２．５ｍｇ、０．４４ｍｍｏｌ）及び炭酸カリウム（７９．９mｇ、０．５８ｍｍｏｌ）を無水Ｎ，Ｎ−ジメチルホルムアミド（１．５ｍL）に懸濁し、８０℃で４．５時間攪拌した。反応液に酢酸エチル（３０ｍL）及び水（３０ｍL）を加え分配した。有機層を水（３０ｍL）及び飽和食塩水（３０ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（５５．０ｍｇ）を無色固体として得た。（収率８５％）

Hereinafter, using a compound selected from Reference Compounds 3-2, 3-3, 24 and 25, Compounds 1-2 to 1-7 were obtained according to the production method of Compound 1-1.

Example 2
7- (5-Fluoro-2-methoxyphenyl) -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound) 2-1)
8-chloromethyl-7- (5-fluoro-2-methoxyphenyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 4-2, 50.9 mg, 0. 14 mmol), 5-methyl-2-thiophenecarboxylic acid (62.5 mg, 0.44 mmol) and potassium carbonate (79.9 mg, 0.58 mmol) were suspended in anhydrous N, N-dimethylformamide (1.5 mL), The mixture was stirred at 80 ° C. for 4.5 hours. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution and partitioned. The organic layer was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (55.0 mg) as a colorless solid. (Yield 85%)

実施例３
７−（４−フルオロ−２−メトキシフェニル）−８−フェノキシメチル−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン(化合物３−１)
８−クロロメチル−７−（４−フルオロ−２−メトキシフェニル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物４−１、４７．１ｍｇ、０．１４ｍｍｏｌ）、フェノール（３７．５ｍｇ、０．４０ｍｍｏｌ）及び炭酸カリウム（７３．０ｍｇ、０．５３ｍｍｏｌ）の混合物を無水Ｎ，Ｎ−ジメチルホルムアミド（１．５ｍL）に懸濁し、８０℃で１９時間攪拌した。放冷後、酢酸エチル（３０ｍL）及び水（３０ｍL）を加えて分配した。有機層を水（３０ｍL）及び飽和食塩水（３０ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（３５．７ｍｇ）を淡黄色固体として得た。（収率６７％）

Hereinafter, using compounds selected from Reference Compounds 4-1 to 4-3, 14-1, 14-2 and commercially available compounds, and according to the production method of Compound 2-1, compounds 2-2 to 2-19 Got.

Example 3
7- (4-Fluoro-2-methoxyphenyl) -8-phenoxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound 3-1)
8-chloromethyl-7- (4-fluoro-2-methoxyphenyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 4-1, 47.1 mg, 0. 14 mmol), phenol (37.5 mg, 0.40 mmol) and potassium carbonate (73.0 mg, 0.53 mmol) were suspended in anhydrous N, N-dimethylformamide (1.5 mL) and stirred at 80 ° C. for 19 hours. did. After cooling, ethyl acetate (30 mL) and water (30 mL) were added and partitioned. The organic layer was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (35.7 mg) as a pale yellow solid. (Yield 67%)

実施例４
７−（５−フルオロ−２−メトキシフェニル）−８−（４−メチルフェニルアミノメチル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物４−１）
８−クロロメチル−７−（５−フルオロ−２−メトキシフェニル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物４−２、５０．７ｍｇ、０．１５ｍｍｏl）、４−メチルアニリン（１９．３ｍｇ、０．１８ｍｍｏl）及び炭酸カリウム（６０．６ｍｇ、０．４４ｍｍｏl）の混合物を無水Ｎ，Ｎ−ジメチルホルムアミド（１ｍL）に懸濁し、８０℃で一晩攪拌した。放冷後、酢酸エチル（３０ｍL）及び水（３０ｍL）を加え分配した。有機層を水（３０ｍL）及び飽和食塩水（３０ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（４８．２ｍｇ）を淡黄色固体として得た。（収率８０％）

Hereinafter, compounds 3-2 to 3-19 were obtained according to the production method of compound 3-1, using compounds selected from reference compounds 4-2, 14-1, 14-2 and commercially available compounds.

Example 4
7- (5-Fluoro-2-methoxyphenyl) -8- (4-methylphenylaminomethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound 4-1)
8-chloromethyl-7- (5-fluoro-2-methoxyphenyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 4-2, 50.7 mg, 0. 15 mmol), 4-methylaniline (19.3 mg, 0.18 mmol) and potassium carbonate (60.6 mg, 0.44 mmol) were suspended in anhydrous N, N-dimethylformamide (1 mL) and at 80 ° C. overnight. Stir. After cooling, ethyl acetate (30 mL) and water (30 mL) were added and partitioned. The organic layer was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (48.2 mg) as a pale yellow solid. (Yield 80%)

実施例５
８−ベンゾイルオキシメチル−７−（５−フルオロ−２−メトキシフェニル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物５−１）
８−ベンゾイルオキシメチル−７−（５−フルオロ−２−メトキシフェニル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物１−３、４２．９ｍｇ、０．０９９ｍｍｏｌ）、よう化メチル（３０．７μL、０．４９ｍｍｏｌ）及び炭酸セシウム（８９．０ｍｇ、０．２７ｍｍｏｌ）の混合物を無水Ｎ，Ｎ−ジメチルホルムアミド（１ｍL）に懸濁し、室温で１．５時間攪拌した。酢酸エチル（１００ｍL）を加え希釈した。水（１００ｍL）及び飽和食塩水（５０ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（３５．０ｍｇ）を無色アモルファスとして得た。（収率７９％）

Hereinafter, compounds 4-2, 14-1, 14-2 and compounds selected from commercially available compounds were used, and compounds 4-2 to 4-11 were obtained according to the production method of compound 4-1.

Example 5
8-Benzoyloxymethyl-7- (5-fluoro-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound 5-1)
8-Benzoyloxymethyl-7- (5-fluoro-2-methoxyphenyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound 1-3, 42.9 mg, 0. 099 mmol), methyl iodide (30.7 μL, 0.49 mmol) and cesium carbonate (89.0 mg, 0.27 mmol) were suspended in anhydrous N, N-dimethylformamide (1 mL) and stirred at room temperature for 1.5 hours. Stir. Ethyl acetate (100 mL) was added for dilution. The extract was washed successively with water (100 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (35.0 mg) as a colorless amorphous product. (Yield 79%)

実施例６
８−（５−フルオロ−２−メチルフェノキシメチル）−７−（２−メトキシ−４−トリフルオロメトキシフェニル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物６−１）
アルゴン雰囲気下、７−ブロモ−８−（５−フルオロ−２−メチルフェノキシメチル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物８−１、４９．７ｍｇ、０．１２２ｍｍｏl）、２−メトキシ−４−トリフルオロメトキシフェニルボロン酸（５８．１ｍｇ、０．２４６ｍｍｏl）、炭酸セシウム（１１９ｍｇ、０．３６ｍｍｏl）及び二塩化ビス（トリフェニルホスフィン）パラジウム（ＩＩ）（１２．０ｍｇ、０．０１７１ｍｍｏｌ）の混合物を無水Ｎ，Ｎ−ジメチルホルムアミド（０．５ｍL）に懸濁し、８０℃で２時間攪拌した。放冷後、酢酸エチル（１００ｍL）及び水（１００ｍL）を加えて分配した。有機層を飽和食塩水（５０ｍL）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（５２．７ｍｇ）を無色アモルファスとして得た。（収率８５％）

Hereinafter, compounds 1-4 to 1-7, 2-1 to 2-6, 2-13, 3-1 to 3-6, 4-1 to 4-4, 22 and compounds selected from commercially available compounds are used. Then, according to the production method of compound 5-1, compounds 5-2 to 5-25 were obtained.

Example 6
8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-4-trifluoromethoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound 6-1)
Under an argon atmosphere, 7-bromo-8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 8-1, 49.7 mg, 0.122 mmol), 2-methoxy-4-trifluoromethoxyphenylboronic acid (58.1 mg, 0.246 mmol), cesium carbonate (119 mg, 0.36 mmol) and bis (triphenylphosphine) palladium dichloride. A mixture of (II) (12.0 mg, 0.0171 mmol) was suspended in anhydrous N, N-dimethylformamide (0.5 mL) and stirred at 80 ° C. for 2 hours. After allowing to cool, ethyl acetate (100 mL) and water (100 mL) were added and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (52.7 mg) as a colorless amorphous product. (Yield 85%)

実施例７
８−（５−フルオロ−２−メチルフェノキシメチル）−７−（２−ニトロフェニル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物７−１）
７−（５，５−ジメチル［１，３，２］ジオキサボリナン−２−イル）−８−（５−フルオロ−２−メチルフェノキシメチル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物２１、６８．２ｍｇ、０．１５５ｍｍｏl）、２−ニトロ−１−ヨードベンゼン（７９．０ｍｇ、０．３１７ｍｍｏl）、炭酸水素ナトリウム（４１．５ｍｇ、０．４９４ｍｍｏl）及びテトラキス（トリフェニルホスフィン）パラジウム（０）（１９．０ｍｇ、０．０１６４ｍｍｏｌ）の混合物をＮ，Ｎ−ジメチルホルムアミド（０．５ｍL）及び水（０．５ｍL）の混合溶媒に懸濁し、マイクロ波を照射して１２０℃で３０分間攪拌した。放冷後、酢酸エチル（１５ｍL）及び水（１５ｍL）を加えて分配した。有機層を飽和食塩水（１５ｍL）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（４２．６ｍｇ）を黄色固体として得た。（収率６１％）

Hereinafter, using compounds selected from Reference Compounds 8-1 to 8-4, 17, 18-1 to 18-5, 20-1, 20-2, and commercially available compounds, and according to the production method of Compound 6-1 Thus, compounds 6-2 to 6-34 and 6-37 to 6-43 were obtained. In addition, a compound selected from Reference Compounds 19-2 and 19-3 and a commercially available compound is used, and the compound selected from Reference Compound 8-1 and a commercially available compound is used after following the production method of Reference Compound 20-1. In accordance with the manufacturing method of compound 6-1, compounds 6-35 and 6-36 were obtained.

Example 7
8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-nitrophenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound 7-1)
7- (5,5-Dimethyl [1,3,2] dioxaborinan-2-yl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one (Reference compound 21, 68.2 mg, 0.155 mmol), 2-nitro-1-iodobenzene (79.0 mg, 0.317 mmol), sodium bicarbonate (41.5 mg, 0.494 mmol) ) And tetrakis (triphenylphosphine) palladium (0) (19.0 mg, 0.0164 mmol) are suspended in a mixed solvent of N, N-dimethylformamide (0.5 mL) and water (0.5 mL). The mixture was irradiated with waves and stirred at 120 ° C. for 30 minutes. After cooling, ethyl acetate (15 mL) and water (15 mL) were added and partitioned. The organic layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (42.6 mg) as a yellow solid. (Yield 61%)

Hereafter, the compound selected from the reference compound 22 and a commercially available compound was used, and the compound 7-2 was obtained according to the manufacturing method of the compound 7-1.

Example 8
7- (5-Amino-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound 8-1)
8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-5-nitrophenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound 6-27, 18.8 mg, 0.0392 mmol) and tin chloride (II) (23.0 mg, 0.121 mmol) were mixed with anhydrous N, N-dimethylformamide (0.25 mL) and absolute ethanol (0.5 mL). And stirred at 80 ° C. overnight. After allowing to cool, the reaction mixture was diluted with ethyl acetate (10 mL), and saturated aqueous sodium hydrogen carbonate solution was added until the pH reached 9. After the precipitated solid was filtered off, the mother liquor was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (8.2 mg) as a brown solid. (Yield 47%)

Hereafter, compound 8-28 was used and compound 8-2 was obtained according to the production method of compound 8-1.

Example 9
8- (5-Fluoro-2-methylphenoxymethyl) -7- (5-hydroxymethyl-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ( Compound 9-1)
8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-5-methoxycarbonylphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ( Compound 6-37, 50.2 mg, 0.102 mmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL), and lithium aluminum hydride (6.8 mg, 0.18 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, ethyl acetate (1 mL) and water (1 mL) were sequentially added to the reaction solution. Further, ethyl acetate (10 mL) and water (10 mL) were added and partitioned. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (29.8 mg) as a pale yellow solid. (Yield 63%)

Hereafter, compound 9-2 was obtained according to the manufacturing method of compound 9-1 using compound 6-42.

Example 10
7- (5-Carboxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound 10-1)
8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-5-methoxycarbonylphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ( Compound 6-37, 50.5 mg, 0.103 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), 4N aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred overnight at room temperature. . Ethyl acetate (15 mL) and 0.25 N hydrochloric acid (20 mL) were added to the reaction solution and partitioned. The organic layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained residue was filtered with chloroform (3 mL) to give the titled compound (20.3 mg) as a pale yellow solid. (Yield 42%)

Hereafter, compound 10-2 was used according to the manufacturing method of compound 10-1, using compound 6-42.

Example 11
8- (5-Fluoro-2-methylphenoxymethyl) -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound 11)
7- (4-Benzoyloxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ( Compound 6-31, 422 mg, 0.761 mmol) was dissolved in a mixed solution of methanol (2 mL) and tetrahydrofuran (2 mL), and 4N aqueous sodium hydroxide solution (0.761 mL, 3.04 mmol) was added. After stirring the reaction solution at room temperature for 40 minutes, water (100 mL) and 1N hydrochloric acid (4 mL) were added. After extraction with ethyl acetate (100 mL), the organic layer was washed successively with water (100 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was collected by filtration with a mixed solution of hexane (10 mL) and ethyl acetate (10 mL) to give the title compound (292 mg) as a colorless solid. (Yield 85%)

Example 12
7- (2-methoxy-4-methoxymethoxyphenyl) -8- [N- (2-methoxyphenyl) -N- (9-fluorenylmethoxycarbonyl) aminomethyl] -1,3,3-trimethyl-3 , 4-Dihydro-1H-quinoxalin-2-one (Compound 12-1)
7- (2-Methoxy-4-methoxymethoxyphenyl) -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound 6- 39, 104 mg, 0.212 mmol) and sodium bicarbonate (22.0 mg, 0.262 mmol) were dissolved in a mixed solution of 1,4-dioxane (1.5 mL) and water (1 mL), and 9-fluorenyl chloride was dissolved. Methoxycarbonyl (60.3 mg, 0.233 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and diluted with ethyl acetate (50 mL). The extract was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (149 mg) as a colorless amorphous. (Yield 99%)

Hereafter, compound 12-2 was obtained according to the manufacturing method of compound 12-1, using a compound selected from compound 6-41 and commercially available compounds.

Example 13
7- (4-hydroxy-2-methoxyphenyl) -8- [N- (2-methoxyphenyl) -N- (9-fluorenylmethoxycarbonyl) aminomethyl] -1,3,3-trimethyl-3, 4-Dihydro-1H-quinoxalin-2-one (Compound 13-1)
7- (2-methoxy-4-methoxymethoxyphenyl) -8- [N- (2-methoxyphenyl) -N- (9-fluorenylmethoxycarbonyl) aminomethyl] -1,3,3-trimethyl-3 , 4-dihydro-1H-quinoxalin-2-one (compound 12-1, 137 mg, 0.192 mmol) was dissolved in 1,4-dioxane (1 mL), and 4N hydrogen chloride / 1,4-dioxane solution (144 μL) was dissolved. 0.576 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and diluted by adding ethyl acetate (100 mL). The extract was washed successively with water (100 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (71.6 mg) as a colorless solid. (Yield 56%)

Hereinafter, compounds 13-2 and 13-3 were obtained according to the production method of compound 13-1, using compounds 5-20 and 12-2.

Example 14
7- (4-Butyryloxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound 14-1)
8- (5-Fluoro-2-methylphenoxymethyl) -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound 11, 25 mg, 0.055 mmol) was dissolved in tetrahydrofuran (1 mL), and triethylamine (20 μL, 0.14 mmol) and butyryl chloride (7.6 μL, 0.073 mmol) were sequentially added. The reaction solution was stirred at room temperature for 1 hour and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (27 mg) as a colorless amorphous. (Yield 92%)

実施例１５
８−（５−フルオロ−２−メチルフェノキシメチル）−７−［２−メトキシ−４−（３−メトキシカルボニルベンゾイルオキシ）フェニル］−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物１５−１）
８−（５−フルオロ−２−メチルフェノキシメチル）−７−（４−ヒドロキシ−２−メトキシフェニル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物１１、２５．３ｍｇ、０．０５６２ｍｍｏｌ）、イソフタル酸モノメチル（２０．５ｍｇ、０．１１４ｍｍｏｌ）、Ｎ，Ｎ−ジイソプロピルエチルアミン（３８．８μＬ、０．２２３ｍｍｏ）及びＯ−（７−アザベンゾトリアゾール−１−イル）−Ｎ，Ｎ，Ｎ，Ｎ−テトラメチルウロニウムヘキサフルオロホスフェート（４３．４ｍｇ、０．１１４ｍｍｏｌ）の混合物を無水Ｎ，Ｎ−ジメチルホルムアミド（０．５ｍｌ）に溶解し、室温で一晩攪拌した。反応液に酢酸エチル（１５ｍL）を加え希釈した。水（１５ｍL）及び飽和食塩水（１５ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（２２．０ｍｇ）を無色固体として得た。（収率６４％）

Hereinafter, compounds 14-2 to 14-62 were obtained according to the production method of compound 14-1, using compounds selected from compounds 8-2, 11, 13-2 and commercially available compounds.

Example 15
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (3-methoxycarbonylbenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one (Compound 15-1)
8- (5-Fluoro-2-methylphenoxymethyl) -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound 11, 25.3 mg, 0.0562 mmol), monomethyl isophthalate (20.5 mg, 0.114 mmol), N, N-diisopropylethylamine (38.8 μL, 0.223 mmol) and O- (7-azabenzotriazole-1) -Yl) -N, N, N, N-tetramethyluronium hexafluorophosphate (43.4 mg, 0.114 mmol) was dissolved in anhydrous N, N-dimethylformamide (0.5 ml) and mixed at room temperature. Stir overnight. Ethyl acetate (15 mL) was added to the reaction solution for dilution. The extract was washed successively with water (15 mL) and saturated brine (15 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (22.0 mg) as a colorless solid. (Yield 64%)

実施例１６
８−（５−フルオロ−２−メチルフェノキシメチル）−７−［２−メトキシ−４−［Ｎ−メチル−Ｎ−（ピリジン−４−イルカルボニル）アミノ］フェニル］−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物１６−１）
８−（５−フルオロ−２−メチルフェノキシメチル）−７−［２−メトキシ−４−（ピリジン−４−イルカルボニルアミノ）フェニル］−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物１４−２１、１３．９ｍｇ、０．０２５１ｍｍｏｌ）、炭酸セシウム（４１．７ｍｇ、０．１２８ｍｍｏｌ）及びよう化メチル（４．７μＬ、０．０７５ｍｍｏｌ）の混合物を無水Ｎ，Ｎ−ジメチルホルムアミド（０．５ｍｌ）に懸濁し、室温で３時間攪拌した。反応液に酢酸エチル（１０ｍL）を加え希釈した。水（１０ｍL）及び飽和食塩水（１０ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（４．６ｍｇ）を黄色アモルファスとして得た。（収率３２％）

Hereinafter, compounds 15-2 to 15-32 were obtained according to the production method of compound 15-1, using compounds selected from compounds 8-2, 11, 13-2 and commercially available compounds.

Example 16
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- [N-methyl-N- (pyridin-4-ylcarbonyl) amino] phenyl] -1,3,3-trimethyl -3,4-Dihydro-1H-quinoxalin-2-one (Compound 16-1)
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (pyridin-4-ylcarbonylamino) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H A mixture of quinoxalin-2-one (compound 14-21, 13.9 mg, 0.0251 mmol), cesium carbonate (41.7 mg, 0.128 mmol) and methyl iodide (4.7 μL, 0.075 mmol) in anhydrous N , N-dimethylformamide (0.5 ml), and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (10 mL) was added to the reaction solution for dilution. The extract was washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (4.6 mg) as a yellow amorphous. (Yield 32%)

実施例１７
７−［４−（３−クロロフェニルアミノカルボニルオキシ）−２−メトキシフェニル］−８−（５−フルオロ−２−メチルフェノキシメチル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物１７−１）
８−（５−フルオロ−２−メチルフェノキシメチル）−７−（４−ヒドロキシ−２−メトキシフェニル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物１１、２０．３ｍｇ、０．０４５１ｍｍｏｌ）を無水ジクロロメタン（０．５ｍL）に溶解し、トリエチルアミン（１３．６μL、０．０９７７ｍｍｏｌ）及びイソシアン酸３−クロロフェニル（６μL、０．０５ｍｍｏｌ）を順次加えた。反応液を室温で１時間攪拌した後、シリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（２２．４ｍｇ）を無色固体として得た。（収率８２％）

Hereafter, compounds 16-2 to 16-5 were obtained according to the production method of compound 16-1, using compounds selected from compounds 14-17 to 14-20 and commercially available compounds.

Example 17
7- [4- (3-Chlorophenylaminocarbonyloxy) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one (Compound 17-1)
8- (5-Fluoro-2-methylphenoxymethyl) -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound 11,20.3 mg, 0.0451 mmol) was dissolved in anhydrous dichloromethane (0.5 mL), and triethylamine (13.6 μL, 0.0977 mmol) and 3-chlorophenyl isocyanate (6 μL, 0.05 mmol) were sequentially added. The reaction solution was stirred at room temperature for 1 hour and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (22.4 mg) as a colorless solid. (Yield 82%)

実施例１８
８−（５−フルオロ−２−メチルフェノキシメチル）−７−［２−メトキシ−４−（モルホリン−４−イルカルボニルオキシ）フェニル］−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物１８−１）
８−（５−フルオロ−２−メチルフェノキシメチル）−７−（４−ヒドロキシ−２−メトキシフェニル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物１１、１５３ｍｇ、０．３４０ｍｍｏｌ）、１，１’−カルボニルジイミダゾール（９５．６ｍｇ、０．５９０ｍｍｏｌ）及び４−ジメチルアミノピリジン（５．２ｍｇ、０．０４３ｍｍｏｌ）の混合物を無水テトラヒドロフラン（３ｍｌ）に溶解し、室温で１時間攪拌した。反応液にモルホリン（５８．３μＬ、０．６６６ｍｍｏｌ）を加え、さらに２時間攪拌した後、シリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（６１．２ｍｇ）を無色固体として得た。（収率３２％）

Hereinafter, compounds 17-2 to 17-17 were obtained according to the production method of compound 17-1, using compounds selected from compounds 8-2, 11, 13-2 and commercially available compounds.

Example 18
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (morpholin-4-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H -Quinoxalin-2-one (Compound 18-1)
8- (5-Fluoro-2-methylphenoxymethyl) -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound 11, 153 mg, 0.340 mmol), 1,1′-carbonyldiimidazole (95.6 mg, 0.590 mmol) and 4-dimethylaminopyridine (5.2 mg, 0.043 mmol) in anhydrous tetrahydrofuran (3 ml). Dissolved and stirred at room temperature for 1 hour. Morpholine (58.3 μL, 0.666 mmol) was added to the reaction mixture, and the mixture was further stirred for 2 hours and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (61.2 mg) as a colorless solid. It was. (Yield 32%)

Hereinafter, compounds 18-2 and 18-3 were obtained according to the production method of compound 18-1, using a compound selected from compound 11 and commercially available compounds.

Example 19
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (N-methyl-N-phenylaminocarbonyloxy) phenyl] -1,3,3-trimethyl-3,4- Dihydro-1H-quinoxalin-2-one (Compound 19)
8- (5-Fluoro-2-methylphenoxymethyl) -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (compound 11, 25.4 mg, 0.0564 mmol) and N-methyl-N-phenylcarbamoyl chloride (20.4 mg, 0.120 mmol) were dissolved in pyridine (1 ml) and stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (28.7 mg) as a pale yellow amorphous product. (Yield 87%)

Example 20
7- (4-Aminoacetylamino-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one Monohydrochloride (Compound 20)
7- (4-tert-Butoxycarbonylaminoacetylamino-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline 2-one (compound 15-31, 10.5 mg, 0.0173 mmol) was dissolved in 1,4-dioxane (0.2 mL), and 4N hydrogen chloride / 1,4-dioxane solution (41.3 μL, 0 .165 mmol) was added. The reaction solution was stirred at room temperature for 4 hours, and then diluted by adding hexane (10 mL). The precipitated solid was collected by filtration to give the title compound (7.8 mg) as a pale yellow solid. (Yield 83%)

Example 21
8- (2-methoxyphenylaminomethyl) -7- [2-methoxy-4- (pyridin-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline- 2-one (compound 21-1)
7- (4-hydroxy-2-methoxyphenyl) -8- [N- (2-methoxyphenyl) -N- (9-fluorenylmethoxycarbonyl) aminomethyl] -1,3,3-trimethyl-3, 4-Dihydro-1H-quinoxalin-2-one (compound 13-1, 30.0 mg, 0.0448 mmol) was dissolved in a mixed solution of tetrahydrofuran (1 mL) and dichloromethane (1 mL), and triethylamine (25 μL, 0.18 mmol) was dissolved. And nicotinic chloride monohydrochloride (12.0 mg, 0.0674 mmol) were added sequentially. The reaction solution was stirred at room temperature for 40 minutes and then purified by silica gel column chromatography (hexane-ethyl acetate). The obtained colorless amorphous was dissolved in N, N-dimethylformamide (1 mL), and piperidine (50 μL) was added. The reaction was stirred at room temperature for 20 minutes and then diluted with ethyl acetate (50 mL). The extract was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (13.0 mg) as a colorless solid. (Yield 52%)

実施例２２
７−［２−メトキシ−４−（２−メチルベンゾイルオキシ）フェニル］−８−(２−メトキシ−５−ニトロフェノキシメチル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物２２）
８−ヒドロキシメチル−７−［２−メトキシ−４−（２−メチルベンゾイルオキシ）フェニル］−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物２３、４０．１ｍｇ、０．０８９８ｍｍｏｌ）、２−メトキシ−５−ニトロフェノール（２２．８ｍｇ、０．１３５ｍｍｏｌ）及びトリ−ｎ−ブチルホスフィン（３３．７μＬ、０．１３５ｍｍｏｌ）の混合物を無水テトラヒドロフラン（１ｍL）に溶解し、１，１’−（アゾジカルボニル）ジピペリジン（３４．０ｍｇ、０．１３５ｍｍｏｌ）を加え室温で攪拌した。２０分後に２−メトキシ−５−ニトロフェノール（２３．１ｍｇ、０．１３７ｍｍｏｌ）、トリ−ｎ−ブチルホスフィン（３３．７μＬ、０．１３５ｍｍｏｌ）及び１，１’−（アゾジカルボニル）ジピペリジン（３３．９ｍｇ、０．１３４ｍｍｏｌ）を追加し、８０分後に２−メトキシ−５−ニトロフェノール（２２．９ｍｇ、０．１３５ｍｍｏｌ）、トリ−ｎ−ブチルホスフィン（３３．７μＬ、０．１３５ｍｍｏｌ）及び１，１’−（アゾジカルボニル）ジピペリジン（３４．０ｍｇ、０．１３５ｍｍｏｌ）を追加した。３時間後に攪拌を終了し、反応液を濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（２２．１ｍｇ）を淡黄色アモルファスとして得た。（収率４１％）

Hereinafter, a compound selected from Compounds 13-1, 13-3 and commercially available compounds is used according to the production method of Compound 14-1, 15-1, 17-1, or 18-1, and then a compound is further added. Compounds 21-2 to 21-24 were obtained using a part of the production method of 21-1.

Example 22
7- [2-Methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxaline-2 -On (compound 22)
8-hydroxymethyl-7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compounds 23, 40. 1 mg, 0.0898 mmol), a mixture of 2-methoxy-5-nitrophenol (22.8 mg, 0.135 mmol) and tri-n-butylphosphine (33.7 μL, 0.135 mmol) dissolved in anhydrous tetrahydrofuran (1 mL) 1,1 ′-(azodicarbonyl) dipiperidine (34.0 mg, 0.135 mmol) was added and stirred at room temperature. After 20 minutes 2-methoxy-5-nitrophenol (23.1 mg, 0.137 mmol), tri-n-butylphosphine (33.7 μL, 0.135 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (33 0.9 mg, 0.134 mmol) and after 80 min 2-methoxy-5-nitrophenol (22.9 mg, 0.135 mmol), tri-n-butylphosphine (33.7 μL, 0.135 mmol) and 1, 1 ′-(azodicarbonyl) dipiperidine (34.0 mg, 0.135 mmol) was added. Stirring was terminated after 3 hours, and the reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (22.1 mg) as a pale yellow amorphous product. (Yield 41%)

[Formulation example]
The typical formulation example of this invention compound is shown below.

1) Tablet (in 150mg)
1 mg of the present compound
Lactose 100mg
Corn starch 40mg
Carboxymethylcellulose calcium 4.5mg
Hydroxypropylcellulose 4mg
Magnesium stearate 0.5mg

A tablet having the above formulation can be coated with 3 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the intended tablet. Moreover, a desired tablet can also be obtained by changing suitably the kind and / or quantity of this invention compound and an additive.

2) Capsule (in 150mg)
Compound of the present invention 5mg
Lactose 135mg
Carboxymethylcellulose calcium 4.5mg
Hydroxypropylcellulose 4mg
Magnesium stearate 1.5mg

Desired capsules can be obtained by appropriately changing the type and / or amount of the compound of the present invention and additives.

3) Eye drops (in 100ml)
Compound of the present invention 100mg
Sodium chloride 900mg
Polysorbate 80 500mg
Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount

Desired eye drops can be obtained by appropriately changing the type and / or amount of the compound of the present invention and additives.

[Pharmacological test]
1. Glucocorticoid receptor (hereinafter referred to as “GR”) binding activity evaluation test
In order to evaluate the binding activity to GR, a receptor competition assay by polarized fluorescence was performed. For the assay, a GR competition assay kit (manufactured by Invitrogen, Cat No. P2816) was used, and the assay was performed according to the plot call attached to this kit. The specific method is described below.

(Preparation of reagents)
GR screening buffer: 10 mM potassium phosphate (pH 7.4), 20 mM sodium molybdate (Na ₂ MoO ₄ ), 0.1 mM ethylenediaminetetraacetic acid (EDTA), 5 mM dithiothreitol (DTT), 0.1 mM stabilized peptide , And 2% dimethyl sulfoxide.

4 × GS1 solution: Fluormone ^™ GS1, which is a fluorescent glucocorticoid ligand, was diluted with a GR screening buffer to prepare a 4 nM solution.

  4 × GR solution: Recombinant human GR was diluted with GR screening buffer to prepare a 16 nM solution.

(Preparation of test compound solution)
The test compound was dissolved in dimethyl sulfoxide and diluted with a GR screening buffer to prepare a 20 μM test compound solution.

(Test method and measurement method)
1) A test compound solution was injected into a 96-well plate at 25 μL per well, and then 4 × GS1 solution and 4 × GR solution were added at 12.5 μL per well.

2) Incubated in the dark at room temperature for 2-4 hours.

3) Using a multimode plate reader Analyst ^™ HT (manufactured by LJL Biosystems), each well using a well containing a GR screening buffer instead of the test compound solution and 4 × GS1 solution as a blank. The fluorescence polarization of was measured.

4) A GR screening buffer was used instead of the test compound solution, and the other operations were the same as in 1-3) described above, and the result was used as a negative control.

5) 2 mM dexamethasone was used in place of the test compound solution, and the other operations were carried out in the same manner as in the above 1-3), and the result was used as a positive control.

(Calculation formula of GR coupling ratio)
The GR binding rate (%) was calculated by the following formula.

表Ｉに示したとおり本発明化合物は優れたGR受容体結合活性を示した。よって、本発明化合物はGR受容体モジュレーターとして使用でき、特にGRが関与する疾患、すなわち、代謝異常疾患、炎症性疾患、自己免疫疾患、アレルギー性疾患、中枢神経系疾患、心血管系疾患、ホメオスタシス関連疾患、緑内障等の予防又は治療剤として有用である。 GR binding rate (%) = 100 × {1- (fluorescence polarization of test compound solution−fluorescence polarization of positive control solution) / (fluorescence polarization of negative control solution−fluorescence polarization of positive control solution)}

(Test results and discussion)
Examples of test results include test compounds (compound 1-4, compound 2-2, compound 2-9, compound 2-16, compound 3-7, compound 3-10, compound 3-15, compound 3-16, compound 3-17, Compound 4-5, Compound 4-7, Compound 4-10, Compound 4-11, Compound 5-1, Compound 5-9, Compound 5-14, Compound 5-18, Compound 5-19, Compound 5-21, Compound 5-22, Compound 5-24, Compound 6-4, Compound 6-8, Compound 6-10, Compound 6-12, Compound 6-15, Compound 6-19, Compound 6-23, Compound 6-27, Compound 6-32, Compound 6-38, Compound 8-2, Compound 9-1, Compound 11, Compound 13-2, Compound 14-2, Compound 14-4, Compound 14-11, Compound 14- 21, Compound 14-22, Compound 14-30 Compound 14-33, Compound 14-35, Compound 14-36, Compound 14-37, Compound 14-44, Compound 15-1, Compound 15-2, Compound 15-4, Compound 15-6, Compound 15-9, Compound 15-11, Compound 15-13, Compound 15-17, Compound 15-22, Compound 15-24, Compound 16-3, Compound 17-5, Compound 17-16, Compound 18-1, Compound 18-2, Table I shows the GR bonding rate (%) of Compound 21-3, Compound 21-5, Compound 21-12, Compound 21-13, Compound 21-22, and Compound 22).

As shown in Table I, the compounds of the present invention showed excellent GR receptor binding activity. Therefore, the compound of the present invention can be used as a GR receptor modulator, and in particular, diseases involving GR, ie, metabolic disorders, inflammatory diseases, autoimmune diseases, allergic diseases, central nervous system diseases, cardiovascular diseases, homeostasis. It is useful as a preventive or therapeutic agent for related diseases and glaucoma.

Claims (21)

A compound represented by the following general formula (1) or a salt thereof.

[R ¹ may have a halogen atom, a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. Good heterocyclic group, hydroxy group, ester of hydroxy group, lower alkoxy group optionally having substituent, lower cycloalkyloxy group optionally having substituent, aryloxy group optionally having substituent A heterocyclic oxy group which may have a substituent, a mercapto group, an ester of a mercapto group, a lower alkylthio group which may have a substituent, a lower cycloalkylthio group which may have a substituent, a substituent Arylthio group which may have, heterocyclic thio group which may have substituent, amino group, lower alkylamino group which may have substituent, lower cycloalkylamino group which may have substituent Have a substituent An arylamino group which may have a substituent, a heterocyclic amino group which may have a substituent, an amide of an amino group, an amide of a lower alkylamino group which may have a substituent, a lower cyclo which may have a substituent Amido of alkylamino group, Amido of arylamino group which may have a substituent, Amide of heterocyclic amino group which may have a substituent, Formyl group, Lower alkylcarbonyl group which may have a substituent A lower cycloalkylcarbonyl group which may have a substituent, an arylcarbonyl group which may have a substituent, a heterocyclic carbonyl group which may have a substituent, a carboxy group, an ester of a carboxy group, a carboxy group An amide, a lower alkylsulfonyl group which may have a substituent, a lower cycloalkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent An optionally substituted heterocyclic sulfonyl group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group or a cyano group;
p represents an integer of 0 to 5;
when p is 2-5, each R ¹ may be the same or different;
R ² represents a halogen atom, a lower alkyl group which may have a substituent, a hydroxy group, an ester of a hydroxy group or a lower alkoxy group which may have a substituent;
q represents an integer of 0 to 2;
when q is 2, each R ² may be the same or different;
R ³ represents a hydrogen atom;
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a methyl group ;
R ⁶ may have a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, or a substituent. A lower cycloalkyl group, an aryl group which may have a substituent or a heterocyclic group which may have a substituent;
A represents a lower alkylene group which may have a substituent;
R ⁷ represents OR ⁸ , NR ⁸ R ⁹ , SR ⁸ , S (O) R ⁸ or S (O) ₂ R ⁸ ;
R ⁸ and R ⁹ are the same or different and are a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, Lower cycloalkyl group optionally having substituent, aryl group optionally having substituent, heterocyclic group optionally having substituent, formyl group, lower alkylcarbonyl optionally having substituent Group, optionally substituted lower alkenylcarbonyl group, optionally substituted lower alkynylcarbonyl group, optionally substituted lower cycloalkylcarbonyl group, optionally substituted. An arylcarbonyl group, an optionally substituted heterocyclic carbonyl group, a carboxy group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkenyloxycarbonyl group, A lower alkynyloxycarbonyl group which may have a group, a lower cycloalkyloxycarbonyl group which may have a substituent, an aryloxycarbonyl group which may have a substituent, a complex which may have a substituent Ring oxycarbonyl group, optionally substituted lower alkylsulfonyl group, optionally substituted lower alkenylsulfonyl group, optionally substituted lower alkynylsulfonyl group, substituted Lower cycloalkylsulfonyl group, optionally substituted arylsulfonyl group, optionally substituted heterocyclic sulfonyl group, aminocarbonyl group, optionally substituted lower alkylaminocarbonyl group A lower alkenylaminocarbonyl group which may have a substituent, a lower alkynylaminocarbonyl group which may have a substituent, A lower cycloalkylaminocarbonyl group which may have, an arylaminocarbonyl group which may have a substituent or a heterocyclic aminocarbonyl group which may have a substituent;
When R ⁷ is NR ⁸ R ⁹ , R ⁸ and R ⁹ may combine to form a 3- to 8-membered nitrogen-containing heterocyclic ring which may have a substituent;
X represents O. ] In the general formula (1), R ¹ is a halogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower cycloalkyloxy group, or an aryloxy group. , Heterocyclic oxy group, mercapto group, ester of mercapto group, lower alkylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino group, lower alkylamino group, lower cycloalkylamino group, arylamino group, Ring amino group, amino group amide, lower alkylamino group amide, lower cycloalkylamino group amide, arylamino group amide, heterocyclic amino group amide, lower alkylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl Group, heterocyclic carbonyl group, cal Boxy group, ester of carboxy group, amide of carboxy group, lower alkylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, sulfonic acid group, ester of sulfonic acid group, amide of sulfonic acid group, nitro A group or a cyano group;
When R ¹ is a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, an amide of a lower alkylamino group, a lower alkylcarbonyl group or a lower alkylsulfonyl group, the lower alkyl group, the lower alkoxy group, A lower alkylthio group, the lower alkylamino group, an amide of the lower alkylamino group, the lower alkylcarbonyl group or the lower alkylsulfonyl group is a halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, a hydroxy group Ester, lower alkoxy group, lower alkoxy group substituted with a halogen atom, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower alkylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino Group, lower alkylamino Group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, amide of amino group, amide of lower alkylamino group, amide of lower cycloalkylamino group, amide of arylamino group, amide of heterocyclic amino group Lower alkylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, ester of carboxy group, amide of carboxy group, lower alkylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, One or more groups selected from a ring sulfonyl group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group, and a cyano group may be substituted.
R ¹ is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, lower cycloalkylamino group, aryl Amino group, heterocyclic amino group, amide of lower cycloalkylamino group, amide of arylamino group, amide of heterocyclic amino group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, lower cycloalkylsulfonyl group, In the case of an arylsulfonyl group or a heterocyclic sulfonyl group, the lower cycloalkyl group, the aryl group, the heterocyclic group, the lower cycloalkyloxy group, the aryloxy group, the heterocyclic oxy group, the lower cycloalkylthio group, The arylthio group, the heterocyclic thio group, the lower cycloa Alkylamino group, arylamino group, heterocyclic amino group, amide of lower cycloalkylamino group, amide of arylamino group, amide of heterocyclic amino group, lower cycloalkylcarbonyl group, arylcarbonyl group, The heterocyclic carbonyl group, the lower cycloalkylsulfonyl group, the arylsulfonyl group or the heterocyclic sulfonyl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a hydroxy group, an ester of a hydroxy group, An alkoxy group, a lower alkoxy group substituted with a halogen atom, a lower alkylthio group, an amino group, a lower alkylamino group, an amide of an amino group, an amide of a lower alkylamino group, a lower alkylcarbonyl group, a carboxy group, an ester of a carboxy group, Carboxy group amide, lower Alkylsulfonyl group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group may have one or a plurality of groups selected from a nitro group and a cyano group as substituents;
p represents an integer of 0 to 3;
when p is 2 or 3, each R ¹ may be the same or different;
R ² represents a halogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group;
q represents an integer of 0 to 2;
when q is 2, each R ² may be the same or different;
R ³ represents hydrogen atom;
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a methyl group ;
R ⁶ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group;
When R ⁶ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group, the lower alkyl group, the lower alkenyl group, the lower alkynyl group or the lower cycloalkyl group is selected from a halogen atom and an aryl group May have one or more groups as substituents;
A represents a lower alkylene group which may be substituted with a hydroxy group or a halogen atom;
R ⁷ represents OR ⁸ , NR ⁸ R ⁹ or SR ⁸ ;
R ⁸ and R ⁹ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a formyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group. Lower alkynylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryloxy Carbonyl group, heterocyclic oxycarbonyl group, lower alkylsulfonyl group, lower alkenylsulfonyl group, lower alkynylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, Amino carbonyl group, a lower alkylaminocarbonyl group, a lower alkenyl amino group, a lower alkynyl aminocarbonyl group, a lower cycloalkylamino group, an arylamino group or a heterocyclic aminocarbonyl group;
R ⁸ or R ⁹ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a lower alkynylcarbonyl group, a lower alkoxycarbonyl group, a lower alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, In the case of a lower alkylsulfonyl group, a lower alkenylsulfonyl group, a lower alkynylsulfonyl group, a lower alkylaminocarbonyl group, a lower alkenylaminocarbonyl group or a lower alkynylaminocarbonyl group, the lower alkyl group, the lower alkenyl group, the lower alkynyl group, The lower alkylcarbonyl group, the lower alkenylcarbonyl group, the lower alkynylcarbonyl group, the lower alkoxycarbonyl group, the lower alkenyloxycarbonyl group, the lower alkynyloxy Cicarbonyl group, the lower alkylsulfonyl group, the lower alkenylsulfonyl group, the lower alkynylsulfonyl group, the lower alkylaminocarbonyl group, the lower alkenylaminocarbonyl group or the lower alkynylaminocarbonyl group are a halogen atom, a lower cycloalkyl group , Aryl group, heterocyclic group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower alkylthio group, lower Cycloalkylthio group, arylthio group, heterocyclic thio group, amino group, lower alkylamino group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, amino group amide, lower alkylamino group amide, lower cycloalkyl Amino group amide, arylamino group amide, heterocyclic amino group amide, lower alkylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, carboxy group ester, carboxy group amide , A lower alkylsulfonyl group, a lower cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group, and a cyano group May have as a substituent
R ⁸ or R ⁹ is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group A lower cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl group, a lower cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a heterocyclic aminocarbonyl group, the lower cycloalkyl group, the aryl group, the heterocyclic group The lower cycloalkylcarbonyl group, the arylcarbonyl group, the heterocyclic carbonyl group, the lower cycloalkyloxycarbonyl group, the aryloxycarbonyl group, the heterocyclic oxycarbonyl group, the lower cycloalkylsulfonyl group, The arylsulfonyl group, the heterocyclic sulfonyl group, the lower cycloalkylaminocarbonyl group, the arylaminocarbonyl group or the heterocyclic aminocarbonyl group are a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, or a hydroxy group. Substituted lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, lower Alkenyloxy group, lower alkynyloxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower alkylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino group, lower alkylamino group, lower Cycloalkyla Mino group, arylamino group, heterocyclic amino group, amide of amino group, amide of lower alkylamino group, amide of lower cycloalkylamino group, amide of arylamino group, amide of heterocyclic amino group, lower alkylcarbonyl group, Lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, ester of carboxy group, amide of carboxy group, lower alkylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, sulfonic acid 1 or a plurality of groups selected from a group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group, and a cyano group may be substituted.
When R ⁷ is NR ⁸ R ⁹ , R ⁸ and R ⁹ may combine to form a 5- or 6-membered nitrogen-containing heterocycle;
The compound or a salt thereof according to claim 1, wherein X represents O. In the general formula (1), R ¹ is a halogen atom, a lower alkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group, an amino group, a lower alkylamino group, an amino amide, or a lower alkylamino group. An amide, a lower alkylcarbonyl group, a carboxy group, an ester of a carboxy group, an amide of a carboxy group, a lower alkylsulfonyl group, a nitro group or a cyano group;
When R ¹ is a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, an amide of a lower alkylamino group, a lower alkylcarbonyl group or a lower alkylsulfonyl group, the lower alkyl group, the lower alkoxy group, A lower alkylthio group, the lower alkylamino group, an amide of the lower alkylamino group, the lower alkylcarbonyl group or the lower alkylsulfonyl group is a halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, a hydroxy group Ester, lower alkoxy group, lower alkoxy group substituted with a halogen atom, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower alkylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino Group, lower alkylamino Group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, amide of amino group, amide of lower alkylamino group, amide of lower cycloalkylamino group, amide of arylamino group, amide of heterocyclic amino group Lower alkylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, ester of carboxy group, amide of carboxy group, lower alkylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, One or more groups selected from a ring sulfonyl group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group, and a cyano group may be substituted.
p represents an integer of 0 to 3;
when p is 2 or 3, each R ¹ may be the same or different;
q represents 0;
R ³ represents hydrogen atom;
R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a methyl group ;
R ⁶ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group;
When R ⁶ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group, the lower alkyl group, the lower alkenyl group, the lower alkynyl group or the lower cycloalkyl group is selected from a halogen atom and an aryl group May have one or more groups as substituents;
A represents a lower alkylene group;
R ⁷ represents OR ⁸ , NR ⁸ R ⁹ or SR ⁸ ;
R ⁸ and R ⁹ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a formyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group. Lower alkynylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryloxy Carbonyl group, heterocyclic oxycarbonyl group, lower alkylsulfonyl group, lower alkenylsulfonyl group, lower alkynylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, Amino carbonyl group, a lower alkylaminocarbonyl group, a lower alkenyl amino group, a lower alkynyl aminocarbonyl group, a lower cycloalkylamino group, an arylamino group or a heterocyclic aminocarbonyl group;
R ⁸ or R ⁹ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a lower alkynylcarbonyl group, a lower alkoxycarbonyl group, a lower alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, In the case of a lower alkylsulfonyl group, a lower alkenylsulfonyl group, a lower alkynylsulfonyl group, a lower alkylaminocarbonyl group, a lower alkenylaminocarbonyl group or a lower alkynylaminocarbonyl group, the lower alkyl group, the lower alkenyl group, the lower alkynyl group, The lower alkylcarbonyl group, the lower alkenylcarbonyl group, the lower alkynylcarbonyl group, the lower alkoxycarbonyl group, the lower alkenyloxycarbonyl group, the lower alkynyloxy Cicarbonyl group, the lower alkylsulfonyl group, the lower alkenylsulfonyl group, the lower alkynylsulfonyl group, the lower alkylaminocarbonyl group, the lower alkenylaminocarbonyl group or the lower alkynylaminocarbonyl group are a halogen atom, a lower cycloalkyl group , Aryl group, heterocyclic group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, lower alkylthio group, amino group, lower alkylamino group, amide of amino group, lower alkylamino A amide of a group, a lower alkylcarbonyl group, a carboxy group, an ester of a carboxy group, an amide of a carboxy group, a lower alkylsulfonyl group, a nitro group or a cyano group as a substituent. Often;
R ⁸ or R ⁹ is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group A lower cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl group, a lower cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a heterocyclic aminocarbonyl group, the lower cycloalkyl group, the aryl group, the heterocyclic group The lower cycloalkylcarbonyl group, the arylcarbonyl group, the heterocyclic carbonyl group, the lower cycloalkyloxycarbonyl group, the aryloxycarbonyl group, the heterocyclic oxycarbonyl group, the lower cycloalkylsulfonyl group, The arylsulfonyl group, the heterocyclic sulfonyl group, the lower cycloalkylaminocarbonyl group, the arylaminocarbonyl group or the heterocyclic aminocarbonyl group are a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, or a hydroxy group. Substituted lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, lower Alkenyloxy group, lower alkynyloxy group, lower alkylthio group, amino group, lower alkylamino group, amino group amide, lower alkylamino group amide, lower alkylcarbonyl group, carboxy group, carboxy group ester, carboxy group amide , Low One or more groups selected from an alkylsulfonyl group, a nitro group or a cyano group may be substituted.
When R ⁷ is NR ⁸ R ⁹ , R ⁸ and R ⁹ may combine to form a 5- or 6-membered nitrogen-containing heterocycle;
The compound or a salt thereof according to claim 1, wherein X represents O. In the general formula (1), R ¹ is a halogen atom, a lower alkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group, an amino group, an amino group amide, a lower alkylamino group amide, a lower alkyl A carbonyl group, a carboxy group, an ester of a carboxy group, a nitro group or a cyano group;
When R ¹ is a lower alkyl group or a lower alkoxy group, the lower alkyl group or the lower alkoxy group may have one or more groups selected from a halogen atom, a hydroxy group and a lower alkoxy group as a substituent. Often;
p represents 1, 2 or 3;
when p is 2 or 3, each R ¹ may be the same or different;
q represents 0;
R ³ represents a hydrogen atom;
R ⁴ and R ⁵ represent a methyl group;
R ⁶ represents a hydrogen atom, a lower alkyl group or a lower alkenyl group;
A represents a lower alkylene group;
R ⁷ represents OR ⁸ or NR ⁸ R ⁹ ;
R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, an aryl group, an arylcarbonyl group or a heterocyclic carbonyl group;
When R ⁸ or R ⁹ is an aryl group, an arylcarbonyl group or a heterocyclic carbonyl group, the aryl group, the arylcarbonyl group or the heterocyclic carbonyl group is a halogen atom, a lower alkyl group, or a lower alkyl substituted with a halogen atom. Substitute one or more groups selected from a group, a lower alkyl group substituted with a hydroxy group, a lower alkenyl group, an aryl group, a lower alkoxy group, a lower alkylcarbonyl group, an ester of a carboxy group, a nitro group, and a cyano group May have as a group;
The compound or a salt thereof according to claim 1, wherein X represents O. In the general formula (1), R ¹ represents a halogen atom, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, an amide of an amino group or an amide of a lower alkylamino group;
p represents 2 or 3, wherein each R ¹ may be the same or different;
q represents 0;
R ³ represents a hydrogen atom;
R ⁴ and R ⁵ represent a methyl group;
R ⁶ represents a lower alkyl group;
A represents a lower alkylene group;
R ⁷ represents OR ⁸ or NR ⁸ R ⁹ ;
R ⁸ represents an aryl group, an arylcarbonyl group or a heterocyclic carbonyl group, wherein the aryl group, arylcarbonyl group or heterocyclic carbonyl group is a halogen atom, a lower alkyl group, or a lower alkyl substituted with a halogen atom. Substitute one or more groups selected from a group, a lower alkyl group substituted with a hydroxy group, a lower alkenyl group, an aryl group, a lower alkoxy group, a lower alkylcarbonyl group, an ester of a carboxy group, a nitro group, and a cyano group May have as a group;
R ⁹ represents a hydrogen atom;
The compound or a salt thereof according to claim 1, wherein X represents O. The compound according to any one of claims 1 to 4, wherein in the general formula (1), R ¹ represents a halogen atom, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, an amide of an amino group or an amide of a lower alkylamino group. Or a salt thereof. The compound or a salt thereof according to any one of claims 1 to 5, wherein, in the general formula (1), R ⁴ , R ⁵ and R ⁶ each represent a methyl group. In the general formula (1), R ⁸ represents an aryl group, an arylcarbonyl group or a heterocyclic carbonyl group, the aryl group is a phenyl group, the arylcarbonyl group is a phenylcarbonyl group, and the heterocyclic carbonyl group is a thiophenecarbonyl. The compound according to any one of claims 1 to 5 or a salt thereof, which represents a group. The compound or a salt thereof according to any one of claims 1 to 5, wherein A represents a methylene group in the general formula (1). In R ¹ of the general formula (1), an ester of a hydroxy group represents —OCO—R ^a1 , and R ^a1 may have a hydrogen atom, a lower alkyl group which may have a substituent, or a substituent. A good lower alkenyl group, a lower alkynyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a complex which may have a substituent A cyclic group, a lower alkoxy group which may have a substituent, a lower alkenyloxy group which may have a substituent, a lower alkynyloxy group which may have a substituent, a lower group which may have a substituent A cycloalkyloxy group, an aryloxy group that may have a substituent, a heterocyclic oxy group that may have a substituent, an amino group, a lower alkylamino group that may have a substituent, and a substituent. An optionally substituted lower cycloalkylamino group, Compound or a salt thereof as claimed in any one of claims 1 to 6 showing a heterocyclic amino group which may have an aryl amino group or a substituent which may have a group. In R ¹ of the general formula (1), an ester of a hydroxy group represents —OCO—R ^a1 , where R ^a1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, an aryl group, or a heterocyclic group. , A lower alkoxy group, a lower alkenyloxy group, a lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, an amino group, a lower alkylamino group, a lower cycloalkylamino group, an arylamino group or a heterocyclic amino group;
When R ^a1 is a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkenyloxy group or a lower alkylamino group, the lower alkyl group, the lower alkenyl group, the lower alkoxy group, the lower alkenyloxy group or the lower The alkylamino group is a substituent of one or more groups selected from halogen atoms, aryl groups, heterocyclic groups, hydroxy groups, hydroxy group esters, amino groups, lower alkylamino groups, carboxy groups and carboxy group esters. May have as:
When R ^a1 is a lower cycloalkyl group, an aryl group, a heterocyclic group, a lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a lower cycloalkylamino group, an arylamino group or a heterocyclic amino group, the lower cyclo The alkyl group, the aryl group, the heterocyclic group, the lower cycloalkyloxy group, the aryloxy group, the heterocyclic oxy group, the lower cycloalkylamino group, the arylamino group or the heterocyclic amino group are halogen atoms; Lower alkyl group, lower alkyl group substituted with a halogen atom, hydroxy group, ester of hydroxy group, lower alkoxy group, mercapto group, lower alkylthio group, formyl group, lower alkylcarbonyl group, carboxy group, carboxy basic ester, Substitution of one or more groups selected from nitro and cyano groups The compound or its salt of Claim 10 which you may have as a group. In R ¹ of the general formula (1), an ester of a hydroxy group represents —OCO—R ^a1 , where R ^a1 represents a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, or a lower alkoxy group. A group, an aryloxy group, a lower alkylamino group, a lower cycloalkylamino group, an arylamino group or a heterocyclic amino group;
When R ^a1 is a lower alkyl group, the lower alkyl group may have one or more groups selected from an aryl group and a lower alkylamino group as a substituent;
When R ^a1 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, an ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, or a carboxy group. One or more groups selected from an ester and a nitro group may be substituted.
When R ^a1 is a heterocyclic group, the heterocyclic group may have one or more groups selected from a halogen atom, a lower alkyl group, a hydroxy group and a lower alkoxy group as a substituent;
When R ^a1 is a lower alkylamino group, the lower alkylamino group may have one or more groups selected from an aryl group, a heterocyclic group and an ester of a carboxy group as a substituent;
The compound according to claim 10, wherein when R ^a1 is an arylamino group, the arylamino group may have one or more groups selected from a halogen atom, a lower alkyl group, and a lower alkoxy group as a substituent. Or a salt thereof. In R ¹ of the general formula (1), an amide of an amino group represents —NHCO—R ^b1 , and the R ^b1 may have a hydrogen atom, a lower alkyl group which may have a substituent, or a substituent. A good lower alkenyl group, a lower alkynyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a complex which may have a substituent A cyclic group, a lower alkoxy group which may have a substituent, a lower alkenyloxy group which may have a substituent, a lower alkynyloxy group which may have a substituent, a lower group which may have a substituent A cycloalkyloxy group, an aryloxy group that may have a substituent, a heterocyclic oxy group that may have a substituent, an amino group, a lower alkylamino group that may have a substituent, and a substituent. Optionally lower cycloalkylamino group, substituent Compound or a salt thereof as claimed in any one of claims 1 to 6 showing an even heterocyclic amino group having also good arylamino group or a substituent having. In R ¹ of the general formula (1), an amide of an amino group represents —NHCO—R ^b1 , and R ^b1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, an aryl group, or a heterocyclic group. , A lower alkoxy group, a lower alkenyloxy group, a lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, an amino group, a lower alkylamino group, a lower cycloalkylamino group, an arylamino group or a heterocyclic amino group;
When R ^b1 is a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkenyloxy group or a lower alkylamino group, the lower alkyl group, the lower alkenyl group, the lower alkoxy group, the lower alkenyloxy group or the lower The alkylamino group is a substituent of one or more groups selected from halogen atoms, aryl groups, heterocyclic groups, hydroxy groups, hydroxy group esters, amino groups, lower alkylamino groups, carboxy groups and carboxy group esters. You may have as
When R ^b1 is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower cycloalkylamino group, arylamino group or heterocyclic amino group, The alkyl group, the aryl group, the heterocyclic group, the lower cycloalkyloxy group, the aryloxy group, the heterocyclic oxy group, the lower cycloalkylamino group, the arylamino group or the heterocyclic amino group are halogen atoms; Lower alkyl group, lower alkyl group substituted with a halogen atom, hydroxy group, ester of hydroxy group, lower alkoxy group, mercapto group, lower alkylthio group, formyl group, lower alkylcarbonyl group, carboxy group, carboxy basic ester, Substitution of one or more groups selected from nitro and cyano groups The compound or its salt of Claim 13 which you may have as a group. In R ¹ of the general formula (1), an amide of an amino group represents —NHCO—R ^b1 , and the R ^b1 represents a lower alkyl group, an aryl group, a heterocyclic group, an aryloxy group, a lower alkylamino group, or an arylamino Indicates a group;
When R ^b1 is a lower alkyl group, the lower alkyl group may have one or more amino groups as substituents;
When R ^b1 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, an ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, or a carboxy group. One or more groups selected from an ester and a nitro group may be substituted.
When R ^b1 is a heterocyclic group, the heterocyclic group may have one or more groups selected from a halogen atom, a lower alkyl group, a hydroxy group and a lower alkoxy group as a substituent;
The compound or salt thereof according to claim 13, wherein when R ^b1 is a lower alkylamino group, the lower alkylamino group may have one or more aryl groups as a substituent. In R ¹ of the general formula (1), the amide of the lower alkylamino group represents —NR ^c1 CO—R ^c2 , the R ^c1 represents a lower alkyl group which may have a substituent, and the R ^c2 may have a hydrogen atom, a lower alkyl group that may have a substituent, a lower alkenyl group that may have a substituent, a lower alkynyl group that may have a substituent, or a substituent. Lower cycloalkyl group, aryl group optionally having substituent, heterocyclic group optionally having substituent, lower alkoxy group optionally having substituent, lower alkenyl optionally having substituent An oxy group, a lower alkynyloxy group which may have a substituent, a lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, and a substituent. Heterocyclic oxy group, amino group, may have a substituent A lower alkylamino group, a lower cycloalkylamino group which may have a substituent, an arylamino group which may have a substituent or a heterocyclic amino group which may have a substituent. Or a salt thereof. In R ¹ of the general formula (1), the amide of the lower alkylamino group represents —NR ^c1 CO—R ^c2 , the R ^c1 represents a lower alkyl group, the R ^c2 represents a hydrogen atom, a lower alkyl group, Lower alkenyl group, lower cycloalkyl group, aryl group, heterocyclic group, lower alkoxy group, lower alkenyloxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, amino group, lower alkylamino group, lower cyclo An alkylamino group, an arylamino group or a heterocyclic amino group;
When R ^c2 is a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkenyloxy group or a lower alkylamino group, the lower alkyl group, the lower alkenyl group, the lower alkoxy group, the lower alkenyloxy group or the lower The alkylamino group is a substituent of one or more groups selected from halogen atoms, aryl groups, heterocyclic groups, hydroxy groups, hydroxy group esters, amino groups, lower alkylamino groups, carboxy groups and carboxy group esters. May have as:
When R ^c2 is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower cycloalkylamino group, arylamino group or heterocyclic amino group, The alkyl group, the aryl group, the heterocyclic group, the lower cycloalkyloxy group, the aryloxy group, the heterocyclic oxy group, the lower cycloalkylamino group, the arylamino group or the heterocyclic amino group are halogen atoms; Lower alkyl group, lower alkyl group substituted with a halogen atom, hydroxy group, ester of hydroxy group, lower alkoxy group, mercapto group, lower alkylthio group, formyl group, lower alkylcarbonyl group, carboxy group, carboxy basic ester, Substitution of one or more groups selected from nitro and cyano groups The compound or its salt of Claim 16 which you may have as a group. In R ¹ of the general formula (1), the amide of the lower alkylamino group represents —NR ^c1 CO—R ^c2 , the R ^c1 represents a lower alkyl group, and the R ^c2 represents a lower alkyl group, an aryl group, or Represents a heterocyclic group;
When R ^c2 is a lower alkyl group, the lower alkyl group may have one or more amino groups as substituents;
When R ^c2 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, an ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, or a carboxy group. One or more groups selected from an ester and a nitro group may be substituted.
When R ^c2 is a heterocyclic group, the heterocyclic group may have one or more groups selected from a halogen atom, a lower alkyl group, a hydroxy group and a lower alkoxy group as a substituent;
The compound or a salt thereof according to claim 16, wherein when R ^c2 is a lower alkylamino group, the lower alkylamino group may have one or more aryl groups as a substituent. 7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (4-methoxybenzoyloxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one ,
7- (5-fluoro-2-methoxyphenyl) -8- (4-methylbenzoyloxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (4-Fluoro-2-methoxyphenyl) -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on,
8- (5-bromorothiophen-2-ylcarbonyloxymethyl) -7- (4-fluoro-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On,
7- (4-Fluoro-2-methoxyphenyl) -8- (2-methyl-5-nitrophenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (5-Chloro-2-methoxyphenyl) -8- [2- (2-hydroxyethyl) phenoxymethyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ,
8- (5-chloro-2-methylphenoxymethyl) -7- (4-fluoro-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (4-Fluoro-2-methoxyphenyl) -8- (2-methoxy-5-nitrophenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
8- (2-allylphenoxymethyl) -7- (4-fluoro-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (4-Fluoro-2-methoxyphenyl) -8- (2-methoxy-5-methylphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ,
7- (5-chloro-2-methoxyphenyl) -8- (5-fluoro-2-methylphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ,
7- (5-chloro-2-methoxyphenyl) -8- (2-isopropylphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (4-fluoro-2-methoxyphenyl) -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
8-benzoyloxymethyl-7- (5-fluoro-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (5-fluoro-2-methoxyphenyl) -8-phenoxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (5-fluoro-2-methoxyphenyl) -8-phenylaminomethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
1-ethyl-7- (5-fluoro-2-methoxyphenyl) -8- (4-methylbenzoyloxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one,
1- (propen-3-yl) -7- (5-fluoro-2-methoxyphenyl) -8- (4-methylbenzoyloxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxaline -2-one,
7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (4-methoxybenzoyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On,
7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one,
8- (3-Fluorobenzoyloxymethyl) -7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On,
7- (2-chlorophenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
8- (5-fluoro-2-methylphenoxymethyl) -7- (2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
8- (5-fluoro-2-methylphenoxymethyl) -7- (2-methylthiophenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (4-Fluoro-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (5-chloro-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-5-trifluoromethylphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on,
7- (6-Fluoro-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
8- (5-fluoro-2-methylphenoxymethyl) -7- (2-methoxy-5-nitrophenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (5-Benzoyloxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ,
8- (2-methoxyphenylaminomethyl) -7- (2-methoxy-5-trifluoromethylphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (4-amino-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- (5-hydroxymethyl-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ,
8- (5-fluoro-2-methylphenoxymethyl) -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (4-hydroxy-2-methoxyphenyl) -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one,
7- [4- (2-chlorobenzoyloxy) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [4- (furan-3-ylcarbonyloxy) -2-methoxyphenyl] -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (pyridin-4-ylcarbonylamino) phenyl] -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one,
7- [4- (2-chlorobenzoylamino) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (4-methoxybenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one,
7- (4-acryloyloxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ,
8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-4-methoxycarbonyloxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on,
8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-4-phenoxycarbonyloxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on,
8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-4-phenoxycarbonylaminophenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- on,
7- [4- (2-Fluorobenzoyloxy) -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (3-methoxycarbonylbenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H -Quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (2-methylpyridin-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4 -Dihydro-1H-quinoxalin-2-one,
7- [4- (2-acetoxybenzoyloxy) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (2-methylthiobenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (6-methylpyridin-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4 -Dihydro-1H-quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (oxazol-4-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one,
7- [4- (3-acetylbenzoyloxy) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H- Quinoxalin-2-one,
7- [4- (3-Chlorothiophen-2-ylcarbonyloxy) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4 -Dihydro-1H-quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (2-methoxypyridin-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4 -Dihydro-1H-quinoxalin-2-one,
7- [2-methoxy-4- (2-methylthiobenzoyloxy) phenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one,
7- [4- (N-acetyl-N-methylamino) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro -1H-quinoxalin-2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (pyridin-3-ylaminocarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro -1H-quinoxalin-2-one,
7- (2-methoxy-4-phenylaminocarbonyloxyphenyl) -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (morpholin-4-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one,
7- (4-Dimethylaminocarbonyloxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On,
7- (4-hydroxy-2-methoxyphenyl) -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (4-butyryloxy-2-methoxyphenyl) -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [2-methoxy-4- (2-methylpyridin-3-ylcarbonyloxy) phenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one,
8- (2-methoxyphenylaminomethyl) -7- [2-methoxy-4- (thiazol-4-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one,
8- [N- (5-fluoro-2-methylphenyl) -N- (9-fluorenylmethoxycarbonyl) aminomethyl] -7- (4-hydroxy-2-methoxyphenyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxaline- 2-on,
8- (5-fluoro-2-methylphenoxymethyl) -7- (2-methylphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- (4-Benzoyloxy-2-methoxyphenyl) -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ,
7- (4-Benzoyloxy-2-methoxyphenyl) -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On,
7- [4- (furan-2-ylcarbonyloxy) -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4 Dihydro-1H-quinoxalin-2-one,
7- [2-methoxy-4- (2-methoxybenzoyloxy) phenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro- 1H-quinoxalin-2-one,
7- [2-methoxy-4- (3-methoxycarbonylbenzoyloxy) phenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro -1H-quinoxalin-2-one,
7- [2-methoxy-4- (3-methylfuran-2-ylcarbonyloxy) phenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3 , 4-dihydro-1H-quinoxalin-2-one,
7- [4- (3-Benzylureido) -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one,
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (3-phenylureido) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one,
8- (2-methoxyphenylaminomethyl) -7- [2-methoxy-4- (pyridin-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one,
7- [2-methoxy-4- (2-methoxybenzoyloxy) phenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2 -On,
8- (2-methoxyphenylaminomethyl) -7- [2-methoxy-4- (thiophen-3-ylcarbonyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one and 7- [2-methoxy-4- (2-methylbenzoyloxy) phenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro- A compound selected from 1H-quinoxalin-2-one or a salt thereof. The pharmaceutical composition containing the compound or its salt of any one of Claims 1-19. A modulator of a glucocorticoid receptor comprising the compound according to any one of claims 1 to 19 or a salt thereof as an active ingredient.