JP4825636B2 - Novel 1,2-dihydroquinoline derivatives having glucocorticoid receptor binding activity - Google Patents

Description

  The present invention relates to a novel 1,2-dihydroquinoline 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 reactions, activates the central nervous system, regulates cardiovascular functions, regulates basic and stress-related homeostasis, etc. It is known to affect. Diseases involving the glucocorticoid receptor include diabetes, metabolic disorders such as obesity, enteritis, inflammatory diseases such as chronic obstructive pulmonary disease, autoimmune diseases such as collagen disease, asthma, atopic dermatitis, allergic Allergic diseases such as rhinitis, central nervous system diseases such as psychosis, Alzheimer, drug use disorders, hypertension, hypercalcemia, hyperinsulinemia, cardiovascular diseases such as hyperlipidemia, neurology / immunity / endocrine Homeostasis-related diseases, glaucoma, and the like that cause abnormal balance are known (Non-patent Document 1, Patent Document 1).

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 (Patent Document 1).

On the other hand, compounds having a 1,2-dihydroquinoline structure are disclosed in Patent Document 2, Patent Document 3, and the like as modulators of steroid receptors. The compounds disclosed in Patent Document 2 and Patent Document 3 have a 1,2-dihydroquinoline structure, but specifically disclose compounds in which various substituents are introduced at the 5-position of the 1,2-dihydroquinoline structure. Not done.
General Clinical, 54 (7), 1951-2076 (2005) JP 2002-193955 A International Publication No. 04/018429 Pamphlet Japanese National Patent Publication No. 10-0510840

  Synthetic studies of novel 1,2-dihydroquinoline derivatives and finding the pharmacological actions of the derivatives are very interesting issues.

  The present inventors have conducted synthetic studies on 1,2-dihydroquinoline 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 inventors have found that the derivative has a binding activity to the glucocorticoid receptor and is useful as a medicine, 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 diseases include diseases involving glucocorticoid receptor, that is, metabolic disorders such as diabetes and obesity, enteritis, chronic obstructive Inflammatory diseases such as lung diseases, autoimmune diseases such as collagen diseases, allergic diseases such as asthma, atopic dermatitis, allergic rhinitis, psychosis, Alzheimer, central nervous system diseases such as drug use disorders, hypertension, high calcium Cardiovascular diseases such as hypertension, hyperinsulinemia, 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.

[Ring X represents a benzene ring or a pyridine ring;
R ¹ represents a halogen atom, an optionally substituted lower alkyl group, a hydroxy group, an optionally substituted lower alkoxy group, an optionally substituted lower alkenyloxy group, or a lower alkylcarbonyl group. Represents an amino 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 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. An aryl group, an optionally substituted lower alkylcarbonyl group, an optionally substituted lower alkenylcarbonyl group, an optionally substituted lower alkynylcarbonyl group, or an optionally substituted substituent. Represents an arylcarbonyl group;
R ⁴ and R ⁵ represent a methyl group;
R ⁶ represents a methyl group;
A represents a lower alkylene group ;
R ⁷ represents OR ⁸ , NR ⁸ R ⁹ , SR ⁸ , S (O) R ⁸ , or S (O) ₂ R ⁸ ;
R ⁸ 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, or a lower cycloalkyl which may have a substituent. Group, aryl group which may have a substituent, heterocyclic group which may have a substituent, formyl group, lower alkylcarbonyl group which may have a substituent, lower group which may have a substituent Alkenylcarbonyl group, optionally substituted lower alkynylcarbonyl group, optionally substituted lower cycloalkylcarbonyl group, optionally substituted arylcarbonyl group, optionally substituted Good heterocyclic carbonyl group, carboxy group, optionally substituted lower alkoxycarbonyl group, optionally substituted lower alkenyloxycarbonyl group, optionally substituted lower alkynyloxy A carbonyl group, a lower cycloalkyloxycarbonyl group which may have a substituent, an aryloxycarbonyl group which may have a substituent, a heterocyclic oxycarbonyl group which may have a substituent, and a substituent Lower alkylsulfonyl group which may have a substituent, lower alkenylsulfonyl group which may have a substituent, lower alkynylsulfonyl group which may have a substituent, lower cycloalkylsulfonyl group which may have a substituent, substituent An arylsulfonyl group which may have a substituent, a heterocyclic sulfonyl group which may have a substituent, an aminocarbonyl group, a lower alkylaminocarbonyl group which may have a substituent, a lower group which may have a substituent Alkenylaminocarbonyl group, optionally substituted lower alkynylaminocarbonyl group, optionally substituted lower cycloalkylamino Carbonyl group, a heterocyclic aminocarbonyl group which may have an optionally substituted arylaminocarbonyl group or a substituent;
R ⁹ 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. A lower cycloalkyl group, an aryl group which may have a substituent, a heterocyclic group which may have a substituent, a formyl group, a lower alkylcarbonyl group which may have a substituent, and a substituent; A lower alkenylcarbonyl group which may have a substituent, a lower alkynylcarbonyl group which may have a substituent, a lower cycloalkylcarbonyl group which may have a substituent, an arylcarbonyl group which may have a substituent, and a substituent An optionally substituted heterocyclic carbonyl group, a carboxy group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkenyloxycarbonyl group, an optionally substituted lower alkyl Nyloxycarbonyl group, optionally substituted lower cycloalkyloxycarbonyl group, optionally substituted aryloxycarbonyl group, optionally substituted heterocyclic oxycarbonyl group, substituent A lower alkylsulfonyl group which may have, a lower alkenylsulfonyl group which may have a substituent, a lower alkynylsulfonyl group which may have a substituent, a lower cycloalkylsulfonyl group which may have a substituent, An arylsulfonyl group which may have a substituent, a heterocyclic sulfonyl group which may have a substituent, an aminocarbonyl group, a lower alkylaminocarbonyl group which may have a substituent, and a substituent Good lower alkenylaminocarbonyl group, optionally substituted lower alkynylaminocarbonyl group, optionally substituted lower cycloalkyl Le aminocarbonyl group, a heterocyclic aminocarbonyl group which may have an aryl amino group or a substituent which may have a substituent;
When R ⁷ is NR ⁸ R ⁹ , R ⁸ and R ⁹ may be combined to form a 3- to 8-membered nitrogen-containing heterocycle that may have a substituent. same as below. ]

  The present invention provides a 1,2-dihydroquinoline derivative or a salt thereof useful as a medicament. 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 receptors, ie, metabolic disorders such as diabetes and obesity, enteropathies, inflammatory diseases such as chronic obstructive pulmonary disease, autoimmune diseases such as collagen disease, asthma, atopic dermatitis, allergies Allergic diseases such as rhinitis, central nervous system diseases such as psychosis, Alzheimer, drug use disorders, hypertension, hypercalcemia, hyperinsulinemia, cardiovascular diseases such as hyperlipidemia, neurology / immunity / endocrine It is useful as a preventive or therapeutic agent for homeostasis-related diseases and glaucoma-related diseases that cause abnormal balance.

  Definitions of terms (atoms, groups, 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 group having 6 to 14 carbon atoms or a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon Indicates. Specific examples include phenyl, naphthyl, anthryl, phenanthryl 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 the saturated monocyclic heterocycle include pyrrolidine, pyrazolidine, imidazolidine, triazolidine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, homopiperidine, homopiperazine ring 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, sulfur 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, cyclooctyloxy groups and the like.

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, and ethyl (methyl) amino groups.

The “lower alkenylamino group” is a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkenyl group, or one hydrogen atom of an amino group is a lower alkenyl group and the other hydrogen atom is a lower alkyl group The group substituted by is shown. Vinylamino, propenylamino, butenylamino, pentenylamino, hexenylamino, heptenylamino, octenylamino, isopropenylamino, 2-methyl-1-propenylamino, 2-methyl-2-butenylamino, divinylamino, methyl (vinyl) amino group Etc.

The “lower alkynylamino group” is a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkynyl group, or one hydrogen atom of an amino group is a lower alkenyl group and the other hydrogen atom is a lower alkyl group Or the group substituted by the lower alkenyl group is shown. Specific examples include ethynylamino, propynylamino, butynylamino, pentynylamino, hexynylamino, heptynylamino, octynylamino, isobutynylamino, isopentynylamino, diethynylamino, ethynyl (methyl) amino, ethynyl (vinyl) amino group Etc.

“Lower cycloalkylamino group”, a group in which one or both of the 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 a lower alkyl A group substituted with a group, a lower alkenyl group, or a lower alkynyl group; Specific examples include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, dicyclohexyl, cyclohexyl (methyl) amino, cyclohexyl (vinyl) amino, cyclohexyl (ethynyl) amino groups, and the like. .

An “arylamino group” is 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 lower alkenyl group. A group substituted by a group, 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.

“Heterocyclic amino group” means a group in which one or both hydrogen atoms of an amino group are substituted with a heterocyclic group, one hydrogen atom of an amino group is a heterocyclic group, and the other hydrogen atom is a lower alkyl group, Or a group substituted with a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, or an aryl group;

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, cyclooctyloxycarbonyl group and the like.

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 cycloaramino 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 alkylsulfinyl group” refers to a group in which hydroxy of the sulfinic acid group is substituted with a lower alkyl group. Specific examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, n-butylsulfinyl, n-pentylsulfinyl, n-hexylsulfinyl, n-heptylsulfinyl, n-octylsulfinyl, isopropylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl , Tert-butylsulfinyl, isopentylsulfinyl group and the like.

The “arylsulfinyl group” refers to a group in which hydroxy of the sulfinic acid group is substituted with an aryl group. Specific examples include phenylsulfinyl, naphthylsulfinyl, anthrylsulfinyl, phenanthrylsulfinyl groups, and the like.

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

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

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

The “lower alkoxycarbonyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkoxycarbonyl group. Specific examples include methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, n-butoxycarbonyloxy, n-pentoxycarbonyloxy, n-hexyloxycarbonyloxy, n-heptyloxycarbonyloxy, n-octyloxycarbonyl. Examples thereof include oxy, isopropoxycarbonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, tert-butoxycarbonyloxy, isopentoxycarbonyloxy groups and the like.

The “aryloxycarbonyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aryloxycarbonyl group. Specific examples include phenoxycarbonyloxy, naphthoxycarbonyloxy, anthryloxycarbonyloxy, phenanthryloxycarbonyloxy groups and the like.

The “lower alkylsulfonyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkylsulfonyl group. Specific examples include methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, n-butylsulfonyloxy, n-pentylsulfonyloxy, n-hexylsulfonyloxy, n-heptylsulfonyloxy, n-octylsulfonyloxy, isopropylsulfonyl Examples include oxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, isopentylsulfonyloxy group and the like.

The “arylsulfonyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with an arylsulfonyl group. Specific examples include phenylsulfonyloxy, naphthylsulfonyloxy, anthrylsulfonyloxy, phenanthrylsulfonyloxy groups, and the like.

The “lower alkylaminocarbonyloxy group” refers to a group in which a hydrogen atom of a formyloxy group is substituted with a lower alkylamino group. Specific examples include methylaminocarbonyloxy, ethylaminocarbonyloxy, propylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, ethyl (methyl) aminocarbonyloxy group and the like.

The “arylaminocarbonyloxy group” refers to a group in which a hydrogen atom of a formyloxy group is substituted with an arylamino group. Specific examples include phenylaminocarbonyloxy, naphthylaminocarbonyloxy, anthrylaminocarbonyloxy, phenanthrylaminocarbonyloxy, diphenylaminocarbonyloxy, methyl (phenyl) aminocarbonyloxy, ethyl (phenyl) aminocarbonyloxy, phenyl ( Vinyl) aminocarbonyloxy, ethynyl (phenyl) aminocarbonyloxy, cyclohexyl (phenyl) aminocarbonyloxy groups and the like.

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 “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 a carboxylic acid.

“Ester of mercapto group” refers to a thioester formed from a mercapto group and carboxylic acids.

“Amino group amide” refers to an amide formed from an amino group and a carboxylic acid.

The “lower alkylamino group amide” refers to an amide formed from a lower alkylamino group and a carboxylic acid.

The “amide of arylamino group” refers to an amide formed from an arylamino group and a carboxylic acid.

The “amide of heterocyclic amino group” refers to an amide formed from a heterocyclic amino group and carboxylic acids.

“Carboxylic acids” means 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, or an aryl which may have a substituent. A saturated aliphatic monocarboxylic acid, a saturated aliphatic dicarboxylic acid, an unsaturated aliphatic carboxylic acid represented by a group, a heterocyclic group which may have a substituent, a lower alkoxy group which has a substituent, etc. , Carbocyclic carboxylic acid, heterocyclic carboxylic acid and the like. Specific examples include saturated aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid; oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, etc. Saturated aliphatic dicarboxylic acids; unsaturated aliphatic carboxylic acids such as acrylic acid, propiolic acid, crotonic acid and cinnamic acid; benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, toluic acid, cyclohexanecarboxylic acid, cyclohexane Examples thereof include carbocyclic carboxylic acids such as dicarboxylic acid; heterocyclic carboxylic acids such as furan carboxylic acid, thiophene carboxylic acid, nicotinic acid and isonicotinic acid. Moreover, the acid anhydrides [(R ^a CO) ₂ O] and acid halides (R ^a COX, X represents a halogen atom) of these carboxylic acids are also included in the “carboxylic acids”.

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

The “ester of sulfinic acid group” refers to an ester formed from a sulfinic acid 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 a saturated aliphatic hydroxy compound represented by R ^b OH (R ^b represents a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, etc.), An unsaturated aliphatic hydroxy compound is shown. Specific examples include saturated aliphatic hydroxy compounds such as methanol, ethanol, propanol, butanol and isopropanol; unsaturated aliphatic hydroxy compounds such as vinyl alcohol; saturated aliphatic substituted with an aryl group such as benzyl alcohol and phenethyl alcohol. A system hydroxy compound etc. are shown.

“Phenols” refers to carbocyclic hydroxy compounds represented by R ^c OH (R ^c represents an aryl group or the like which may have a substituent). Specific examples include phenol, naphthol, anthrol, phenanthrol and the like.

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

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

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

“Amines” refers to HNR ^d R ^e [R ^d and R ^e are the same or different and each represents a hydrogen atom, a lower alkyl group that may have a substituent, an aryl group that may have a substituent, a complex Ammonia, saturated aliphatic amine compound, carbocyclic amine compound, heterocyclic system represented by the following formulas: R ^c and R ^d may form a saturated cyclic amine together. An amine compound, a saturated cyclic amine compound, etc. are shown. Specific examples include ammonia; saturated aliphatic amine compounds such as methylamine, ethylamine, propylamine, pentylamine, dimethylamine, diethylamine, and ethylmethylamine; saturated aliphatic amine compounds having a substituent such as benzylamine; phenyl Carbocyclic amine compounds such as amine, naphthylamine, anthrylamine, phenanthrylamine, diphenylamine, methylphenylamine, ethylphenylamine, cyclohexylamine; furylamine, thienylamine, pyrrolidylamine, pyridylamine, quinolylamine, methylpyridyl Heterocyclic amine compounds such as amines; saturated cyclic amine compounds such as aziridine, azetidine, pyrrolidine, piperidine, 4-methylpiperidine and the like.

“Optionally substituted lower alkyl group”, “optionally substituted lower alkenyl group” “optionally substituted lower alkynyl group”, “optionally substituted” “Lower alkoxy group”, “lower alkylcarbonyl group optionally having substituent”, “lower alkenylcarbonyl group optionally having substituent”, “lower alkynylcarbonyl group optionally having substituent”, “Optionally substituted lower alkoxycarbonyl group”, “optionally substituted lower alkenyloxycarbonyl group”, “optionally substituted lower alkynyloxycarbonyl group”, “substituted group” The “lower alkylaminocarbonyl group optionally having a substituent” and / or the “lower alkylsulfonyloxy group optionally having a substituent” means one or more substituents selected from the following α ¹ group: Even if you have “Lower alkyl group”, “lower alkenyl group” “lower alkynyl group”, “lower alkoxy group”, “lower alkylcarbonyl group”, “lower alkenylcarbonyl group”, “lower alkynylcarbonyl group”, “lower alkoxycarbonyl group” , “Lower alkenyloxycarbonyl group”, “lower alkynyloxycarbonyl group”, “lower alkylaminocarbonyl group”, or “lower alkylsulfonyloxy group”.

[Α ¹ group]
A halogen atom, a lower cycloalkyl group, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with a lower alkyl group, an aryl group substituted with a hydroxy group, an aryl group substituted with a lower alkoxy group, a complex A cyclic group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group substituted with a halogen atom, a lower alkenyloxy group, a lower alkynyloxy group, a lower cycloalkyloxy group, an aryloxy group, a 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, amide of amino group, lower alkylamino group, lower alkyl Amido of amino group, arylami Group, arylamino group amide, heterocyclic amino group, heterocyclic amino group amide, formyl group, lower alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic ring Carbonyl group, carboxy group, ester of carboxy group, amide of carboxy group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group , Lower alkyl sulfinyl group, aryl sulfinyl group, lower alkyl sulfonyl group, aryl sulfonyl group, sulfinic acid group, sulfinic acid group ester, sulfinic acid group amide, sulfonic acid group Esters of a sulfonic acid group, an amide of a sulfonic acid 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 cycloalkylcarbonyl group ”,“ optionally substituted arylcarbonyl group ”,“ optionally substituted heterocyclic carbonyl group ”,“ optionally substituted lower cycloalkyloxy ” “Carbonyl group”, “aryloxycarbonyl group optionally having substituent”, “heterocyclic oxycarbonyl group optionally having substituent”, “arylaminocarbonyl group optionally having substituent”, And / or “optionally substituted heterocyclic aminocarbonyl group” means “lower cycloalkyl group” which may have one or more substituents selected from the following β ¹ group: Aryl group, heterocyclic group, lower cycl "Alkylcarbonyl group", "arylcarbonyl group", "heterocyclic carbonyl group", "lower cycloalkyloxycarbonyl group", "aryloxycarbonyl group", "heterocyclic oxycarbonyl group", "arylaminocarbonyl group", or "Heterocyclic aminocarbonyl group" is shown.

[Β ¹ group]
Halogen atom, lower alkyl group, lower alkyl group substituted with halogen atom, lower alkyl group substituted with hydroxy group, lower alkyl group substituted with lower alkoxy group, lower alkyl group substituted with amino group, lower alkyl Lower alkyl group substituted by amino group, lower alkyl group substituted by carboxy group, lower alkyl group substituted by lower alkoxycarbonyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic ring 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, mercapto Group, mercapto group ester, lower alkyl Ruthio group, lower alkenylthio group, lower alkynylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino group, amino group amide, lower alkylamino group, lower alkylamino group amide, arylamino group, Amido of arylamino group, heterocyclic amino group, amide of heterocyclic amino group, formyl group, lower alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group Carboxy group, amide of carboxy group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group Lower alkyl sulfinyl group, aryl sulfinyl group, lower alkyl sulfonyl group, aryl sulfonyl group, sulfinic acid group, sulfinic acid group ester, sulfinic acid group amide, sulfonic acid group, sulfonic acid group ester, sulfonic acid group amide, A nitro group, a cyano group, an aminocarbonyloxy group, a lower alkylaminocarbonyloxy group, and an arylaminocarbonyloxy group.

  The “plural groups” as used in the present invention may be the same or different, and the number is preferably 1, 2 or 3, particularly 2 Is preferred. Further, a hydrogen atom and a halogen atom are also included in the concept of “group”.

  The “glucocorticoid receptor modulator” as used 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) Ring X represents a benzene ring or a pyridine ring; and / or
(A2) R ¹ represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkenyloxy group, a lower alkylcarbonyl group, an amino 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 is a halogen atom, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with a lower alkyl group, a hydroxy group One or more groups selected from aryl groups substituted with, aryl groups substituted with lower alkoxy groups, hydroxy groups, hydroxy group esters, lower alkoxy groups, aryloxy groups, carboxy groups and carboxy group esters As a substituent; and / or
(A3) 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
(A4) R ² represents a halogen atom, a lower alkyl group, a hydroxy group, an ester of a hydroxy group or a lower alkoxy group; and / or
(A5) q represents an integer of 0 to 2;
When q is 2, each R ² may be the same or different; and / or
(A6) R ³ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a lower alkynylcarbonyl 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 aryl groups as a substituent;
When R ³ is an aryl group or an arylcarbonyl group, the aryl group or the arylcarbonyl group may have one or more groups selected from a halogen atom and a lower alkyl group as a substituent; and / or ,
(A7) R ⁴ and R ⁵ represent a methyl group; and / or
(A8) R ⁶ represents a methyl group; and / or
(A9) A represents a lower alkylene group ; and / or
(A10) R ⁷ represents OR ⁸ , NR ⁸ R ⁹ or SR ⁸ ; and / or
(A11) R ⁸ is a 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 cyclo Alkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group Lower alkylsulfonyl group, lower alkenylsulfonyl group, lower alkynylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, aminocarbonyl group, lower alkyl Represents a killaminocarbonyl group, a lower alkenylaminocarbonyl group, a lower alkynylaminocarbonyl group, a lower cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a heterocyclic aminocarbonyl group; and / or
(A12) R ⁹ is 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, aryloxycarbonyl group, heterocyclic ring Oxycarbonyl group, lower alkylsulfonyl group, lower alkenylsulfonyl group, lower alkynylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, aminocarbonyl group Represents a lower alkylaminocarbonyl group, a lower alkenylaminocarbonyl group, a lower alkynylaminocarbonyl group, a lower cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a heterocyclic aminocarbonyl group; and / or
(A13) R ⁸ or R ⁹ is a lower alkyl group, lower alkenyl group, lower alkynyl group, lower alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxy In the case of a carbonyl group, 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 An alkynyl group, the lower alkylcarbonyl group, the lower alkenylcarbonyl group, the lower alkynylcarbonyl group, the lower alkoxycarbonyl group, the lower alkenyloxycarbonyl group, the lower alkyl A quinyloxycarbonyl 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 each a halogen atom, Alkyl 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, mercapto group, mercapto group ester, lower alkylthio group, lower alkenylthio group, lower alkynylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, amino group, amino group Amide, lower alkylamino group, lower alkylamino group amide, arylamino group, arylamino group amide, heterocyclic amino group, 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, carboxy amide, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group , Aryloxycarbonyl group, heterocyclic oxycarbonyl group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, sulfinic acid group, sulfinic acid group One or more groups selected from esters, amides of sulfinic acid groups, sulfonic acid groups, esters of sulfonic acid groups, amides of sulfonic acid groups, nitro groups, and cyano groups may be substituted; and Or
(A14) 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 ring In the case of oxycarbonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, lower cycloalkylaminocarbonyl group, arylaminocarbonyl group or heterocyclic aminocarbonyl group, the lower cycloalkyl group, aryl group, Heterocyclic group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, lower cycloalkylsulfonyl group Group, arylsulfonyl group, heterocyclic sulfonyl group, lower cycloalkylaminocarbonyl group, arylaminocarbonyl group or heterocyclic aminocarbonyl group is a halogen atom, lower alkyl group, lower alkyl group substituted by halogen atom A lower alkyl group substituted with a hydroxy group, a lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted with an amino group, a lower alkyl group substituted with a lower alkylamino group, or a carboxy group Lower alkyl group, lower alkyl group substituted by lower alkoxycarbonyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, hydroxy group, hydroxy group ester, lower alkoxy group, halogen atom A lower alkoxy group substituted with Lucenyloxy 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, amide of amino group, lower alkylamino group, amide of lower alkylamino group, arylamino group, amide of arylamino group, heterocyclic amino group, amide of heterocyclic amino group, Formyl group, lower alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, carboxy group amide, lower alkoxycarbonyl group, lower alkyl group Nyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, sulfinic acid group Sulfinic acid group ester, sulfinic acid group amide, sulfonic acid group, sulfonic acid group ester, sulfonic acid group amide, nitro group, cyano group, aminocarbonyloxy group lower alkylaminocarbonyloxy group and arylaminocarbonyloxy May have one or more groups selected from the group as substituents; and / or
(A15) When R ⁷ is NR ⁸ R ⁹ , R ⁸ and R ⁹ may be combined to form a 5- or 6-membered nitrogen-containing heterocycle.

That is, in the compound represented by the general formula (1), the above (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8), (a9), Examples thereof include compounds composed of one or more combinations selected from (a10), (a11), (a12), (a13), (a14) and (a15), or salts 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) Ring X represents a benzene ring or a pyridine ring; and / or
(B2) R ¹ represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkenyloxy group, a lower alkylcarbonyl group, an amino group or a nitro group,
When R ¹ is a lower alkyl group or a lower alkoxy group, the lower alkyl group or the lower alkoxy group is a halogen atom, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with a lower alkyl group, a lower alkoxy group One or more groups selected from an aryl group, a hydroxy group, a lower alkoxy group, an aryloxy group, a carboxy group and an ester of a carboxy group substituted with a group may be present as a substituent; and / or
(B3) 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
(B4) R ² represents a halogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group; and / or
(B5) q represents an integer of 0 to 2;
When q is 2, each R ² may be the same or different; and / or
(B6) R ³ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aryl 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 aryl groups as a substituent;
When R ³ is an aryl group or an arylcarbonyl group, the aryl group or the arylcarbonyl group may have one or more groups selected from a halogen atom and a lower alkyl group as a substituent; and / or ,
(B7) R ⁴ and R ⁵ represent a methyl group; and / or
(B8) R ⁶ represents a methyl group; and / or
(B9) A represents a lower alkylene group ; and / or
(B10) R ⁷ represents OR ⁸ , NR ⁸ R ⁹ or SR ⁸ ; and / or
(B11) R ⁸ is a lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, lower alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, lower cycloalkylcarbonyl group Represents an arylcarbonyl group or a heterocyclic carbonyl group; and / or
(B12) R ⁹ is a hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, lower alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, lower cyclo Represents an alkylcarbonyl group, an arylcarbonyl group or a heterocyclic carbonyl group; and / or
(B13) When 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 or a lower alkynylcarbonyl group, the lower alkyl group, the lower alkenyl group, the lower The alkynyl group, the lower alkylcarbonyl group, the lower alkenylcarbonyl group or the lower alkynylcarbonyl group may have one or more groups selected from an aryl group, a hydroxy group and a lower alkoxy group as a substituent; And / or
(B14) When R ⁸ or R ⁹ is a lower cycloalkyl group, aryl group, heterocyclic group, lower cycloalkylcarbonyl group, arylcarbonyl group or heterocyclic carbonyl group, the lower cycloalkyl group, aryl group, A cyclic group, the lower cycloalkylcarbonyl group, the arylcarbonyl group or the heterocyclic carbonyl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, a lower alkoxy group; Lower alkyl group substituted with a group, lower alkyl group substituted with an amino group, lower alkyl group substituted with a lower alkylamino group, lower alkyl group substituted with a carboxy group, lower substituted with a lower alkoxycarbonyl group Alkyl group, lower alkenyl group, lower alkynyl group, aryl group, Ring group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, aryloxy group, mercapto group, lower alkylthio group, amino group, amino group amide, lower alkylamino group, lower group 1 or selected from amide of alkylamino group, formyl group, lower alkylcarbonyl group, carboxy group, amide of carboxy group, lower alkoxycarbonyl group, nitro group, cyano group, aminocarbonyloxy group and lower alkylaminocarbonyloxy group May have multiple groups as substituents; and / or
(B15) When R ⁷ is NR ⁸ R ⁹ , R ⁸ and R ⁹ may be combined to form a 5- or 6-membered nitrogen-containing heterocycle.

  That is, in the compound represented by the general formula (1), the above (b1), (b2), (b3), (b4), (b5), (b6), (b7), (b8), (b9), Examples thereof include compounds consisting of one or more combinations selected from (b10), (b11), (b12), (b13), (b14) and (b15), or salts thereof.

(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.

In general formula (1),
(C1) Ring X represents a benzene ring or a pyridine ring; and / or (c2) R ¹ is a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkenyloxy group, a lower alkylcarbonyl group, an amino group, or Indicates a nitro group;
When R ¹ is a lower alkyl group or a lower alkoxy group, the lower alkyl group or lower alkoxy group is a halogen atom, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with a lower alkyl group, or a lower alkoxy group 1 or a plurality of groups selected from an ester of an aryl group, a hydroxy group, a lower alkoxy group and a carboxy group substituted with may be substituted.
And / or (c3) 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 (c4) R ² represents a halogen atom, a lower alkyl group or a lower alkoxy group; and / or (c5) q is 0 And / or (c6) 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 (c7) R ⁴ and R ⁵ represents a methyl group; and / or (c8) R ⁶ represents a methyl group; and / or (c9) A represents a lower alkylene group ; and / or (c10) R ⁷ represents OR ⁸ or NR ⁸ shows the R ⁹ or SR ^8; and / or (c11) R ⁸ is a lower alkyl group, lower cycloalkyl group, an aryl group, a heterocyclic group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a lower cycloalkylcarbonyl group, an aryl A carbonyl group or a heterocyclic carbonyl group; and / or (c12) where R ⁹ is a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic ring A group, an arylcarbonyl group or a heterocyclic carbonyl group; and / or (c13) when R ⁸ or R ⁹ is a lower alkyl group, the lower alkyl group is one or more selected from a lower alkoxy group and an aryl group And / or (c14) 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 ring The carbonyl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, a lower alkyl group substituted with an amino group, or a lower alkyl substituted with a lower alkylamino group. Group, lower alkyl group substituted with carboxy group, lower alkyl group substituted with lower alkoxycarbonyl group, Primary alkenyl group, lower alkynyl group, aryl group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, aryloxy group, lower alkylthio group, amino group, amide of amino group, lower 1 or selected from alkylamino group, amide of lower alkylamino group, formyl group, lower alkylcarbonyl group, carboxy group, amide of carboxy group, lower alkoxycarbonyl group, nitro group, cyano group and lower alkylaminocarbonyloxy group And / or (c15), and when R ⁷ is NR ⁸ R ⁹ , R ⁸ and R ⁹ are taken together to form a 5- or 6-membered nitrogen-containing heterocycle May be formed.

  That is, in the compound represented by the general formula (1), the above (c1), (c2), (c3), (c4), (c5), (c6), (c7), (c8), (c9), Examples thereof include compounds composed of one or more combinations selected from (c10), (c11), (c12), (c13), (c14) and (c15), or salts thereof.

(D) 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),
(D1) Ring X represents a benzene ring; and / or (d2) R ¹ represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkenyloxy group, an amino group, or a nitro group;
When R ¹ is a lower alkyl group, the lower alkyl group may have one or more halogen atoms as substituents;
When R ¹ is a lower alkoxy group, the lower alkoxy group includes an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with a lower alkyl group, an aryl group substituted with a lower alkoxy group, and a lower alkoxy group. May have one or more selected groups as substituents; and / or (d3) p represents 2 or 3, wherein each R ¹ may be the same or different; and / or (D4) R ² represents a halogen atom, a lower alkyl group or a lower alkoxy group; and / or (d5) q represents 0 or 1; and / or (d6) R ³ represents a hydrogen atom; and / or (D7) R ⁴ and R ⁵ represent a methyl group; and / or (d8) R ⁶ represents a methyl group; and / or (d9) A represents a lower alkylene group; and / or (d10) R ⁷ Is OR ⁸ , NR ⁸ R ⁹ or SR ⁸ ; and / or (d11) R ⁸ represents an aryl group, an arylcarbonyl group or a heterocyclic carbonyl group; and / or (d12) R ⁹ represents a hydrogen atom or a lower alkyl group; And / or (d13) when R ⁸ is an aryl group, arylcarbonyl group or heterocyclic carbonyl group, the aryl group, arylcarbonyl group or heterocyclic carbonyl group is substituted with a halogen atom, a lower alkyl group or a halogen atom. Lower alkyl group, lower alkyl group substituted with hydroxy group, lower alkyl group substituted with amino group, lower alkyl group substituted with lower alkylamino group, lower alkyl group substituted with carboxy group, lower alkoxycarbonyl Group-substituted lower alkyl group, lower alkenyl group, lower alkynyl group, aryl group, hydride Roxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, aryloxy group, lower alkylthio group, amino group, amino group amide, lower alkylamino group, lower alkylamino group amide, A substituent having one or more groups selected from a formyl group, a lower alkylcarbonyl group, a carboxy group, an amide of a carboxy group, a lower alkoxycarbonyl group, a nitro group, a cyano group, and a lower alkylaminocarbonyloxy group; Also good.

  That is, in the compound represented by the general formula (1), the above (d1), (d2), (d3), (d4), (d5), (d6), (d7), (d8), (d9), Examples thereof include compounds consisting of one or more combinations selected from (d10), (d11), (d12) and (d13), or salts thereof.

(E) Further preferred examples of the compound of the present invention include compounds that satisfy the following conditions or salts thereof.

In the general formula (1), ^{R 7} is OR ⁸ and above (a), (b), preferably the compound or a salt thereof satisfies the condition of (c) and / or (d), at that time, ^{R 8} is A compound which is a compound which is a phenyl group, a phenylcarbonyl group or a thiophenecarbonyl group or a salt thereof is particularly preferable.

R ⁸ may have a substituent. When R ⁸ is a phenyl group, the phenyl group is substituted with a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, or a hydroxy group. Lower alkyl group, lower alkyl group substituted with lower alkylamino group, lower alkyl group substituted with carboxy group, lower alkyl group substituted with lower alkoxycarbonyl group, lower alkenyl group, lower alkynyl group, aryl group, Hydroxy group, lower alkoxy group, lower alkylthio group, amino group, amino group amide, lower alkylamino group, lower alkylamino group amide, formyl group, lower alkylcarbonyl group, carboxy group, carboxy group amide, lower alkoxycarbonyl One or more groups selected from a group, a nitro group and a cyano group ( May be substituted with one, two or three groups), when R ⁸ is a phenyl group, the phenyl group are halogen atom, lower alkyl group, a lower alkyl group substituted with a halogen atom, Lower alkyl group substituted by hydroxy group, aryl group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted by halogen atom, aryloxy group, lower alkylthio group, amino group, lower alkylamino group , A lower alkylcarbonyl group, a nitro group and a cyano group may be substituted with one or more groups (especially 1, 2 or 3 groups). In the case of a thiophenecarbonyl group, the thiophene The carbonyl group is a halogen atom, a lower alkyl group, an aryl group, a lower alkoxy group, a lower alkyl group. Group, may be substituted with 1 or more groups selected from amide, and lower alkyl carbonyl group of the amino group (especially two or three groups).

(F) Another preferred example of the compound of the present invention includes a compound that satisfies the following conditions or a salt thereof.

In the general formula (1), R ⁷ is NR ⁸ R ⁹ and a compound or a salt thereof satisfying the above conditions (a), (b), (c) and / or (d) is preferable. ^A compound or a salt thereof, in which ⁸ is a phenyl group, is particularly preferable.

R ⁸ may have a substituent. When R ⁸ is a phenyl group, the phenyl group may be a halogen atom, a lower alkyl group, a lower alkyl group substituted with a hydroxy group, a heterocyclic group, a lower group. One or more groups selected from an alkoxy group, a lower alkylthio group, an amide of an amino group, a lower alkylamino group, an amide of a lower alkylamino group, a lower alkylaminocarbonyloxy group and a cyano group (particularly 1, 2 or 3) Number of groups).

(G) Another preferred example of the compound of the present invention includes a compound satisfying the following conditions or a salt thereof.

In the general formula (1), R ⁷ is SR ⁸ and a compound or a salt thereof satisfying the above conditions (a), (b), (c) and / or (d) is preferable.

(H) Still more preferred examples of the compound of the present invention include compounds that satisfy the following conditions or salts thereof.

  In the general formula (1), the ring X is a benzene ring and satisfies the conditions (a), (b), (c), (d), (e), (f) and / or (g). Compound or salt thereof.

(I) Still more preferred examples of 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 the above conditions (a), (b), (c), (d), (e), (f), (g) and / or (h) Ru include a compound or a salt thereof satisfies.

(J) Still more preferred examples of the compound of the present invention include compounds that satisfy the following conditions or salts thereof.

In the general formula (1), R ³ is a hydrogen atom and the above (a), (b), (c), (d), (e), (f), (g), (h) and / or A compound or a salt thereof that satisfies the condition (i).

(K) Particularly preferred examples of the compound of the present invention include compounds that satisfy the following conditions or salts thereof.

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

5-acetoxymethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5-benzoyloxymethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (2-methoxyphenyl) -5-[(thiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (4-t-butylbenzoyloxymethyl) -6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5-benzoyloxymethyl-6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-Fluoro-2-methoxyphenyl) -5- (3-methoxybenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxybenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methoxybenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(thiophen-2-yl) carbonyloxymethyl)]-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-phenoxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methoxyphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-fluorophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-fluorophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-fluorophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methoxyphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxyphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4,5-difluoro-2-methoxyphenyl) -5- (3-fluorophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-hydroxymethylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (5-chloro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4,5-difluoro-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxy-5-nitrophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- [2- (2-hydroxyethyl) phenoxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methyl-5-nitrophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-allylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- [2- (2-hydroxyethyl) phenoxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (5-fluoro-2-methylphenoxymethyl) -6- (4-hydroxy-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (5-fluoro-2-methylphenoxymethyl) -6- (5-hydroxy-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-hydroxy-2-methoxyphenyl) -5- (4-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (2-methoxyphenyl) -5-phenylaminomethyl-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-phenylaminomethyl-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methoxyphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-fluorophenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-fluorophenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-fluorophenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methoxyphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxyphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4,5-difluoro-2-methoxyphenyl) -5- (2-methoxyphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-hydroxymethylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxy-5-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (5-fluoro-2-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (2-methoxyphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (5-fluoro-2-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (2-methoxyphenyl) -5-phenylthiomethyl-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-phenylthiomethyl-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxyphenylthiomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(5-methylthiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(4-methylthiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
5-[(5-chlorothiophen-2-yl) carbonyloxymethyl] -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(3-methylthiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
5-[(5-bromothiophen-2-yl) carbonyloxymethyl] -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(5-methoxythiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(thiophen-3-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4,5-difluoro-2-methoxyphenyl) -5-[(5-methylthiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (5-methylthiophen-2-ylcarbonyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (4-methoxybenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (2-methyl-5-nitrophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (2-methoxy-5-nitrophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (5-chloro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (5-fluoro-2-methoxyphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (2,5-dimethylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (2-allylphenoxymethyl) -6- (5-chloro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (5-fluoro-2-methylphenoxymethyl) -6- (2-methoxy-5-nitrophenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-allyloxy-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-allyloxy-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-amino-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (2-fluorobenzoyloxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (3-fluorobenzoyloxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (4-fluorobenzoyloxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline and 6- (4-fluoro-2- Methoxyphenyl) -5- (2-methylphenylthiomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline.

  The compound of the present invention can be produced by the following method. Each specific manufacturing method will be described in detail in the section [Manufacturing Examples] in the examples described later. Moreover, these illustrations are for understanding the present invention better and are not intended to limit the scope of the present invention. In addition, hal shown in the following synthetic pathway represents a halogen atom.

Compound (I)-(a) of the present invention (in the general formula (1), A is a methylene group, R ³ is H, R ⁴ , R ⁵ and R ⁶ are methyl groups, R ⁷ is OR ^8a , R ^8a is alkylcarbonyl Group, cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group and the like) and (I)-(b) (in the general formula (1), A is a methylene group, R ³ is an alkylcarbonyl group, cycloalkylcarbonyl) Group, arylcarbonyl group, heterocyclic carbonyl group, etc., R ⁴ , R ⁵ and R ⁶ are methyl groups, R ⁷ is OR ^8a , R ^8a is alkylcarbonyl group, cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group Etc.) can be synthesized according to synthetic route 1. That is, compound (II) is converted into triethylamine, diisopropylethylamine (hereinafter referred to as “THF”) in an organic solvent such as tetrahydrofuran (hereinafter referred to as “THF”), 1,4-dioxane, N, N-dimethylformamide (hereinafter referred to as “DMF”), methylene chloride and the like. In the presence of a base such as DIEA, the compound (I)-(a) or (I) is reacted with the corresponding acid chloride (III)-(a) at 0 ° C. to room temperature for 12 hours to 2 days. )-(B) can be obtained.

The compound of the present invention (I)-(a) (in the general formula (1), A is a methylene group, R ³ is H, R ⁴ , R ⁵ and R ⁶ are methyl groups, R ⁷ is OR ^8a , R ^8a is alkyl) Compounds that are a carbonyl group, a cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl group, etc.) can also be synthesized according to Synthesis Route 2. That is, compound (IV) is reacted with methanesulfonyl chloride in an organic solvent such as methylene chloride or DMF in the presence of a base such as triethylamine or DIEA at 0 ° C. to room temperature for 30 minutes to 3 days. can get. Obtained (IV) and the corresponding carboxylic acid (III)-(b) in an organic solvent such as DMF or methylene chloride in the presence of a base such as potassium carbonate, DIEA or sodium hydride at 50 to 100 degrees for 1 hour. The compound (I)-(a) can be obtained by reacting for 2 days.

Further, the present compound (I)-(a) (in the general formula (1), A is a methylene group, R ³ is H, R ⁴ , R ⁵ and R ⁶ are methyl groups, R ⁷ is OR ^8a , R ^8a is alkyl) Compounds that are a carbonyl group, a cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl group, etc.) can also be synthesized according to Synthesis Route 3. That is, the compound (II) and the carboxylic acid (III)-(b) in an organic solvent such as benzene and toluene, a phosphine such as triphenylphosphine and tributylphosphine, diethyl azodicarboxylate, diisopropyl azodicarboxylate, Compound (I)-(a) can be obtained by reacting at room temperature for 1 to 2 days in the presence of a reagent such as 1 ′-(azodicarbonyl) dipiperidine.

In addition, the present compound (I)-(c) (in the general formula (1), A is a methylene group, R ³ is H, R ⁴ , R ⁵ and R ⁶ are methyl groups, R ⁷ is OR ⁸ , NR ⁸ R) Compound ⁹ or SR ⁸ ) can be synthesized according to Synthesis Route 4. That is, compound (IV) and corresponding alcohol or phenol (V), amine (VI) or thiol or thiophenol (VII) in an organic solvent such as DMF, methylene chloride, potassium carbonate, DIEA, sodium hydride, etc. Compound (I)-(c) can be obtained by reacting at 50 to 100 degrees for 1 hour to 2 days in the presence of a base.

Further, the present compound (I)-(d) (in the general formula (1), A is a methylene group, R ³ is H, R ⁴ , R ⁵ and R ⁶ are methyl groups, R ⁷ is OR ⁸ , R ⁸ is The compound which is an aryl group or the like can be synthesized according to the synthesis route 5. That is, the compound (II) and the corresponding phenol (V) are mixed with phosphine such as triphenylphosphine and tributylphosphine in diethyl benzene and toluene, diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1 ′ Compound (I)-(d) can be obtained by reacting at room temperature for 1 hour to 2 days in the presence of a reagent such as-(azodicarbonyl) dipiperidine.

Compound (I)-(e) of the present invention (in the general formula (1), A is a carbonyl group, ^one of R ¹ is a hydroxy group at the 2-position, R ³ is H, R ⁴ , R ⁵ and R ⁶ are methyl groups , R ⁷ is NR ⁸ R ⁹ , and p ′ is an integer from 0 to 4) and (I)-(f) (in the general formula (1), A is a carbonyl group, and ^one of R ¹ is in position 2) OR ¹⁰ group (R ¹⁰ is lower alkyl group, lower alkylcarbonyl group, etc.), R ³ is H, R ⁴ , R ⁵ and R ⁶ are methyl groups, R ⁷ is NR ⁸ R ⁹ , p ′ is 0 to 4 Compound that is an integer) can be synthesized according to Synthesis Route 4. That is, the compound (VIII) and the corresponding amine (VI) are reacted in an organic solvent such as diethyl ether or THF in the presence of a base such as butyl lithium at 0 ° C. to room temperature for 30 minutes to 2 hours. I)-(e) is obtained. The resulting compound (I)-(e) and the corresponding halogenated compound (IX) are heated in an organic solvent such as DMF or ethanol in the presence of a base such as potassium carbonate or DIEA at room temperature to 100 ° C. for 1 to 24 hours. Compound (I)-(f) can be obtained by reacting.

Compound (II)-(a) (a compound in which ^one of R ¹ is the OR ¹⁰ group at the 2-position and p ′ is an integer of 0 to 4 in the above-mentioned compound (II)) is synthesized according to synthesis route 7. be able to. That is, by treating compound (VIII) in an organic solvent such as diethyl ether or THF in the presence of a reducing agent such as lithium aluminum hydride at 0 to 50 degrees for 1 hour to 1 day, compound (II) -(B) is obtained. Obtained compound (II)-(b) and the corresponding halogenated compound (IX) in an organic solvent such as DMF and ethanol in the presence of a base such as potassium carbonate and DIEA at room temperature to 100 ° C. for 1 to 24 hours Compound (II)-(a) can be obtained by reacting.

Compound (II)-(c) (in the above compound (II), ^one of R ¹ is hydrogen at the 2-position and p ′ is an integer of 0 to 4) can be synthesized according to synthesis route 8. it can. That is, the compound (II)-(b) and trifluoromethanesulfonyl chloride are reacted in an organic solvent such as methylene chloride in the presence of a base such as triethylamine at −30 ° to 0 ° for 30 minutes to 12 hours. (II)-(d) is obtained. The resulting compound (II)-(d) is heated in an organic solvent such as DMF in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium (O), a base such as triethylamine and formic acid at 60 to 100 degrees for 1 hour. The compound (II)-(c) can be obtained by treating for 24 hours.

Compound (VIII) can be synthesized according to synthetic route 9. That is, the corresponding boronic acid (X)-(a) (having a benzyloxy group at the 2-position) and a halogenated compound or triflate compound (XI) in a solvent such as DMF, ethanol, toluene, water, cesium carbonate, In the presence of a base such as sodium carbonate or potassium phosphate and a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or tetrakis (triphenylphosphine) palladium (O), the temperature is from 50 to 120 degrees, from 12 hours to 2 hours. Compound (XII) is obtained by reacting for a day. By treating the obtained compound (XII) in an organic solvent such as methanol, ethanol, 1,4-dioxane, and THF in a hydrogen atmosphere and in the presence of a catalyst such as palladium carbon and platinum dioxide at room temperature for 2 hours to 2 days. Compound (XIII) is obtained. Compound (VIII) can be obtained by treating the obtained compound (XIII) in acetone in the presence of iodine at 80 to 130 degrees for 24 hours to 5 days.

Compound (XIII) in Synthesis Route 9 can also be synthesized according to Synthesis Route 10. That is, by treating compound (XII) in an organic solvent such as methanol, ethanol, 1,4-dioxane, and THF in a hydrogen atmosphere and in the presence of a catalyst such as palladium carbon and platinum dioxide at room temperature for 2 hours to 2 days. Compound (XII)-(a) is obtained. Compound (XIII) can be obtained by refluxing the obtained (XII)-(a) in pyridine for 2 hours to 1 day.

Compound (VIII) can also be synthesized according to Synthesis Route 11. That is, the corresponding boronic acid (X)-(b) (having fluorine at the 2-position) and a halogenated compound or triflate compound (XI) in a solvent such as DMF, ethanol, toluene, water, cesium carbonate, sodium carbonate And bases such as potassium phosphate and the like in the presence of a catalyst such as bis (triphenylphosphine) palladium (II) dichloride or tetrakis (triphenylphosphine) palladium (O) for 12 hours to 2 days at 50 to 120 degrees To give compound (XIV). The compound (XV) is obtained by treating the resulting compound (XIV) with a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or the like at 0 ° C. to room temperature for 1 hour to 1 day. The resulting compound (XV) is treated in an organic solvent such as DMF or THF in the presence of a base such as sodium hydride at room temperature to 100 ° C. for 1 hour to 2 days to obtain compound (XVI). By treating the obtained compound (XVI) in an organic solvent such as methanol, ethanol, 1,4-dioxane and THF in a hydrogen atmosphere and in the presence of a catalyst such as palladium carbon and platinum dioxide at room temperature for 2 hours to 2 days. Compound (XIII) is obtained. Compound (VIII) can be obtained by treating the resulting (XIII) in acetone in the presence of iodine at 80 to 130 degrees for 24 hours to 5 days.

Furthermore, compound (VIII)-(a) (a compound in which ring X is a pyridine ring) can also be synthesized according to synthesis route 12. That is, the corresponding boronic acid (XVII) (having a methoxy group at the 2-position) and the halogenated compound (XI) are mixed with a base such as cesium carbonate or sodium carbonate in a solvent such as DMF, ethanol, toluene, or water, and bis (dichloride) dichloride. Compound (XVIII) is obtained by reacting in the presence of a catalyst such as (triphenylphosphine) palladium (II) or tetrakis (triphenylphosphine) palladium (O) at 50 to 120 degrees for 12 hours to 2 days. . The compound (XVIII) obtained was treated in an organic solvent such as methylene chloride, methanol, ethanol, etc. in the presence of an acid such as boron tribromide or hydrochloric acid at −78 ° C. to 0 ° C. for 1 hour to 12 hours. (XIX) is obtained. The compound (XX) is obtained by treating the resulting compound (XIX) with a base such as sodium hydroxide in a solvent such as water, methanol, ethanol or the like at 0 ° C. to room temperature for 1 hour to 1 day. The obtained compound (XX) is mixed with N, N′-dicyclohexylcarbodiimide, O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethyluro in organic solvents such as DMF and methylene chloride. Compound (XXI) can be obtained by treatment at room temperature to 50 ° C. for 1 hour to 3 days in the presence of a condensing agent such as nickel hexafluorophosphate and a base such as DIEA. Compound obtained by treating the obtained (XXI) in an organic solvent such as methanol, ethanol, 1,4-dioxane, THF and the like in a hydrogen atmosphere and in the presence of a catalyst such as palladium carbon and platinum dioxide at room temperature for 2 hours to 2 days. (XXII) is obtained. Compound (VIII) can be obtained by treating the resulting (XXII) in acetone in the presence of iodine at 80 to 130 degrees for 24 hours to 5 days.

  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, the glucocorticoid receptor is related to the development of various diseases, and the compound of the present invention having an excellent binding activity to the glucocorticoid receptor is useful as a glucocorticoid receptor modulator.

  Details thereof will be described in detail in the section of [Pharmacological test] in the Examples described later.

  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. , Buffers such as citric acid, glacial acetic acid, trometamol, surfactants such as polyoxyethylene sorbitan monooleate, polyoxy 40 stearate, polyoxyethylene hydrogenated castor oil, stabilizers such as sodium citrate and sodium edetate , Benzalkonium chloride, paraben, benzotonium chloride, paraoxybenzoate, sodium benzoate, chlorobutanol, sorbic acid and other preservatives, hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, sodium carbonate, carbonic acid P such as sodium hydrogen Modifier, optionally soothing agent such as benzyl alcohol, it is possible to use the required amount to prepare.

  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.

[Production example]
Reference example 1
2,2,4-Trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference compound 1-1)
Methyl 2- (2-benzyloxyphenyl) -5-nitrobenzoate (Reference compound 1-1- (1))
2-benzyloxyphenylboronic acid (20.2 g, 88.6 mmol), methyl 2-bromo-5-nitrobenzoate (25.4 g, 97.5 mmol), cesium carbonate (57.7 g, 177 mmol) and bis (dichloride) A mixture of (triphenylphosphine) palladium (II) (1.16 g, 1.65 mmol) was suspended in anhydrous N, N-dimethylformamide (300 mL) and stirred at 80 ° C. for 3 days under an argon atmosphere. After allowing to cool, ethyl acetate (500 mL), diethyl ether (300 mL) and water (500 mL) were added and partitioned. The aqueous layer was extracted with a mixture of ethyl acetate (200 mL) and diethyl ether (200 mL), and the organic layers were combined. The organic layer was washed successively with water (500 mL, twice) and saturated brine (300 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 (21.0 g) as a pale yellow oil. (Yield 65%)

8-Aminobenzo [c] chromen-6-one (reference compound 1-1- (2))
Methyl 2- (2-benzyloxyphenyl) -5-nitrobenzoate (reference compound 1-1- (1), 21.0 g, 57.8 mmol) was added to methanol (135 mL) and 1,4-dioxane (90 mL). It melt | dissolved in the liquid mixture, 5% palladium-carbon (2.19g) was added, and it stirred at room temperature overnight under hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was collected by filtration with a mixed solution of ethyl acetate and hexane to give the titled reference compound (8.92 g) as a pale yellow solid. (Yield 73%)

2,2,4-Trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference compound 1-1)
In a pressure tube, 8-aminobenzo [c] chromen-6-one (reference compound 1-1- (2), 8.81 g, 41.7 mmol) was dissolved in acetone (300 mL) and iodine (4.24 g) was dissolved. 16.7 mmol), and the mixture was sealed and stirred at 105 ° C. for 2 days. After cooling, 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 (4.83 g) as a yellow solid. (Yield 40%)

7,8-Difluoro-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference compound 1-2)
Methyl 2- (2,3,4-trifluorophenyl) -5-nitrobenzoate (Reference compound 1-2 (1))
2,3,4-trifluorophenylboronic acid (4.70 g, 26.7 mmol), methyl 2-bromo-5-nitrobenzoate (9.02 g, 34.7 mmol), sodium carbonate (8.49 g, 80. 1 mmol) and tetrakis (triphenylphosphine) palladium (O) (1.55 g, 1.34 mmol) are suspended in toluene (160 mL) -ethanol (40 mL) -water (80 mL) and at 95 ° C. under a nitrogen atmosphere. Stir overnight. After allowing to cool, ethyl acetate (200 mL) and water (200 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 (4.37 g) as a brown oil. (Yield 53%)

2- (2,3,4-trifluorophenyl) -5-nitrobenzoic acid (reference compound 1-2 (2))
Methyl 2- (2,3,4-trifluorophenyl) -5-nitrobenzoate (reference compound 1-2 (1), 4.37 g, 14.1 mmol) in tetrahydrofuran (10 mL) -methanol (30 mL) Dissolved, 1N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred overnight at room temperature. Water (150 mL) and 1N hydrochloric acid (30 mL) were added to acidify, and then ethyl acetate (150 mL) was added to partition. The organic layer was washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the titled reference compound (4.18 g) as a gray solid. (Yield 100%)

3,4-difluoro-8-nitrobenzo [c] chromen-6-one (reference compound 1-2 (3))
60% sodium hydride (2.82 g, 70.5 mmol) was suspended in anhydrous N, N-dimethylformamide (60 mL) and, under ice cooling, 2- (2,3,4-trifluorophenyl) -5-nitro. A solution of benzoic acid (reference compound 1-2 (2), 6.97 g, 23.5 mmol) in anhydrous N, N-dimethylformamide (40 mL) was added dropwise, and the mixture was stirred at 80 ° C. for 24 hours under a nitrogen atmosphere. After allowing to cool, ethyl acetate (400 mL), water (400 mL) and 1N hydrochloric acid (80 mL) were added and partitioned. The organic layer was washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was collected by filtration with chloroform to give the titled reference compound (3.85 g) as a brown solid. (Yield 59%)

8-Amino-3,4-difluorobenzo [c] chromen-6-one (Reference compound 1-2 (4))
3,4-Difluoro-8-nitrobenzo [c] chromen-6-one (reference compound 1-2 (3), 3.75 g, 13.5 mmol) was dissolved in 1,4-dioxane (300 mL). % Palladium-carbon (375 mg) was added, and the mixture was stirred at room temperature in a pressurized (3 kgf / cm ² ) hydrogen atmosphere for 4 days. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained solid was collected by filtration with 1,4-dioxane to give the titled reference compound (2.44 g) as an orange solid. (Yield 73%)

7,8-Difluoro-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference compound 1-2)
In a pressure tube, 8-amino-3,4-difluorobenzo [c] chromen-6-one (reference compound 1-2 (4), 2.30 g, 9.26 mmol) was dissolved in acetone (60 mL). After adding iodine (939 mg, 3.70 mmol) and sealing, the mixture was stirred at 110 degrees for 5 days. After cooling, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give the titled reference compound (0.95 g) as a yellow solid. (Yield 31%)

2,2,4-Trimethyl-1,2-dihydro-6-oxa-1,7-diazacrisen-5-one (reference compound 1-3)
Methyl 2- (2-methoxypyridin-3-yl) -5-nitrobenzoate (Reference compound 1-3- (1))
2-methoxypyridin-3-ylboronic acid (1.00 g, 6.54 mmol), methyl 2-bromo-5-nitrobenzoate (2.21 g, 8.50 mmol), cesium carbonate (6.39 g, 17.6 mmol) And bis (triphenylphosphine) palladium (II) dichloride (230 mg, 0.33 mmol) were suspended in anhydrous N, N-dimethylformamide (15 mL) and stirred overnight at 80 ° C. under a nitrogen atmosphere. After allowing to cool, water (100 mL) was added, and the mixture was extracted with ethyl acetate (80 mL, twice). The organic layer was washed with 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 (1.54 g) as a yellow solid. (Yield 81%)

Methyl 2- (2-hydroxypyridin-3-yl) -5-nitrobenzoate (Reference compound 1-3- (2))
Methyl 2- (2-methoxypyridin-3-yl) -5-nitrobenzoate (Reference compound 1-3- (1), 200 mg, 0.694 mmol) was dissolved in anhydrous dichloromethane (2 mL) at -78 degrees. Boron tribromide (118 μl, 1.25 mmol) was added. The reaction solution was stirred at 0 degree for 3 hours, and the reaction solution was transferred to ice water (30 mL). After partitioning by adding ethyl acetate (50 mL), 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 (102 mg) as a yellow solid. (Yield 54%)

2- (2-Hydroxypyridin-3-yl) -5-nitrobenzoic acid (reference compound 1-3- (3))
Methyl 2- (2-hydroxypyridin-3-yl) -5-nitrobenzoate (Reference compound 1-3- (2), 300 mg, 1.09 mmol) was dissolved in methanol (2 mL) and concentrated hydrochloric acid (5 mL). And refluxed overnight. The solvent was distilled off under reduced pressure to obtain the title reference compound (263 mg) as a yellow solid. (Yield 93%)

8-Nitro-4-azabenzo [c] chromen-6-one (reference compound 1-3- (4))
2- (2-hydroxypyridin-3-yl) -5-nitrobenzoic acid (reference compound 1-3- (3), 50 mg, 0.20 mmol) was dissolved in N, N-dimethylformamide (5 mL), and N , N-diisopropylethylamine (141 μl, 0.81 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate (154 mg, 0.41 mmol). In addition, the mixture was stirred overnight at room temperature. Ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed with water (30 mL) and saturated brine (30 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was collected by filtration with chloroform to give the titled reference compound (35 mg) as a pale yellow solid. (Yield 71%)

8-amino-4-azabenzo [c] chromen-6-one (reference compound 1-3- (5))
8-Nitro-4-azabenzo [c] chromen-6-one (reference compound 1-3- (4), 368 mg, 1.52 mmol) was dissolved in methanol (10 mL), and 5% palladium-carbon (37 mg) was dissolved. In addition, the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained solid was collected by filtration with chloroform to give the titled reference compound (298 mg) as a yellow solid. (Yield 92%)

2,2,4-Trimethyl-1,2-dihydro-6-oxa-1,7-diazacrisen-5-one (reference compound 1-3)
In a pressure tube, 8-amino-4-azabenzo [c] chromen-6-one (reference compound 1-3- (5), 258 mg, 1.21 mmol) was dissolved in acetone (10 mL) and iodine (123 mg , 0.48 mmol) was added and the mixture was sealed and stirred at 105 degrees for 1 day. After cooling, 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 (82.5 mg) as a yellow solid. (Yield 23%)

8-Fluoro-2,2,4,11-tetramethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (reference compound 1-4)
Methyl 2-hydroxy-3-methylbenzoate (reference compound 1-4- (1))
2-Hydroxy-3-methylbenzoic acid (24.9 g, 0.164 mol) was dissolved in methanol (200 mL), sulfuric acid (1.75 mL, 32.8 mmol) was added, and the mixture was refluxed for 7 days. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (300 mL), and methanol was distilled off under reduced pressure. The aqueous layer is extracted with ethyl acetate (500 mL), the organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. This gave the title reference compound (23.0 g) as a light brown oil. (Yield 84%)

2-hydroxy-3-methyl-5-nitrobenzoic acid methyl ester (reference compound 1-4- (2))
Methyl 2-hydroxy-3-methylbenzoate (reference compound 1-4- (1), 22.9 g, 0.138 mol) was dissolved in trifluoroacetic acid (190 mL) and sodium nitrate (12.9 g, 152 mmol) was dissolved. An aqueous solution (90 mL) was added dropwise at -10 degrees over 1 hour. After stirring at 0 degree for 1.5 hours, the reaction solution was poured into ice water (600 mL), and the precipitate was collected by filtration. The filtered product was suspended in methanol (100 mL) and collected by filtration to give the titled reference compound (18.7 g) as a pale red solid. (Yield 64%)

Methyl 3-methyl-5-nitro-2-trifluoromethylsulfonyloxybenzoate (reference compound 1-4- (3))
Methyl 2-hydroxy-3-methyl-5-nitrobenzoate (reference compound 1-4- (2), 6.0 g, 28.4 mmol) was dissolved in tetrahydrofuran (200 mL), and triethylamine (16.7 mL, 120 mmol) was dissolved. , Trifluoromethanesulfonic acid chloride (6.23 mL, 58.5 mmol) was added and stirred at room temperature overnight. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 mL). The organic layer was washed successively with 0.2N aqueous sodium hydroxide solution (200 mL, 2 times) and saturated brine (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 (932 g) as a pale yellow oil. (Yield 96%)

Methyl 2- (2-benzyloxy-4-fluorophenyl) -3-methyl-5-nitrobenzoate (Reference compound 1-4- (4))
Methyl 3-methyl-5-nitro-2-trifluoromethylsulfonyloxybenzoate (Reference compound 1-4 (3), 13.26 g, 38.6 mmol), 2-benzyloxy-4-fluorophenylboronic acid ( A mixture of 14.3 g, 58.1 mmol), potassium phosphate (21.3 g, 100 mmol) and tetrakis (triphenylphosphine) palladium (O) (3.23 g, 2.80 mmol) was added to anhydrous 1,4-dioxane (200 mL). ) And refluxed for 3 days. After allowing to cool, ethyl acetate (500 mL) was added, washed successively with water (500 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 (10.7 g) as a light brown solid. (Yield 70%)

Methyl 5-amino-2- (4-fluoro-2-hydroxyphenyl) -3-methylbenzoate (Reference compound 1-4- (5))
Methyl 2- (2-benzyloxy-4-fluorophenyl) -3-methyl-5-nitrobenzoate (reference compound 1-4- (4), 10.7 g, 27.0 mmol) in methanol (50 mL) and tetrahydrofuran (50 mL) was dissolved, 10% palladium-carbon (1.00 g) was added, and the mixture was stirred at room temperature under a pressurized (3 kgf / cm ² ) hydrogen atmosphere for 3 days. The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was collected by filtration with ethyl acetate to give the titled reference compound (4.79 g) as a light gray solid. (Yield 64%)

8-amino-3-fluoro-10-methylbenzo [c] chromen-6-one (reference compound 1-4- (6))
Methyl 5-amino-2- (4-fluoro-2-hydroxyphenyl) -3-methylbenzoate (Reference compound 1-4- (5), 7.40 g, 26.9 mmol) was dissolved in pyridine (250 mL). , Refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was collected by filtration with hexane-ethyl acetate (1: 1) to give the titled reference compound (6.15 g) as a pale yellow solid. (Yield 94%)

8-Fluoro-2,2,4,11-tetramethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (reference compound 1-4)
In a pressure tube, 8-amino-3-fluoro-10-methylbenzo [c] chromen-6-one (reference compound 1-4- (6)), 6.13 g, 25.2 mmol) was added to acetone (175 mL). After dissolution, iodine (2.56 g, 10.1 mmol) was added and sealed, and then stirred at 110 degrees for 4 days. After allowing to cool, 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 (6.35 g) as a brown solid. (Yield 78%)

Hereinafter, reference compounds 1-5 to 1-20 were obtained using commercially available compounds according to the production method of any one of reference compounds 1-1 to 1-4.

Reference example 2
7-methoxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (reference compound 2-1)
7-hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azacrisen-5-one (reference compound 1-9, 430 mg, 1.40 mmol), methyl iodide (87.2 μl) , 1.40 mmol) and potassium carbonate (387 mg, 2.80 mmol) were suspended in anhydrous N, N-dimethylformamide (7 mL) and stirred at 50 degrees for 3 hours. 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 (384 mg) as a yellow solid. (Yield 85%)

Hereinafter, using a compound selected from Reference Compounds 1-9, 1-18 and 1-19, Reference Compounds 2-2 to 2-6 were obtained according to the production method of Reference Compound 2-1.

Reference example 3
5-hydroxymethyl-6- (2-hydroxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 3-1)
Lithium aluminum hydride (1.48 g, 39.0 mmol) was suspended in anhydrous tetrahydrofuran (30 mL) under an argon atmosphere. A solution of 2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference Compound 1-1, 3.80 g, 13.0 mmol) in anhydrous tetrahydrofuran (40 mL) at 0 degree Was added dropwise and stirred at the same temperature for 1 hour. Ethyl acetate (15 mL) and water (5 mL) were successively added dropwise to the reaction solution, and 0.2N hydrochloric acid (350 mL) was added. After extraction with ethyl acetate (300 mL, 100 mL), the organic layers were combined. The organic layer was washed successively with water (300 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The title reference compound (4.01 g) was obtained as a light brown solid by evaporating the solvent under reduced pressure. (quantitative)

Hereinafter, a compound selected from Reference Compounds 1-2 to 1-8, 1-10 to 1-17, 1-20, and 2-1 to 2-6 is used, according to the production method of Reference Compound 3-1. Reference compounds 3-2 to 3-23 were obtained.

Reference example 4
5-hydroxymethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 4-1)
5-hydroxymethyl-6- (2-methoxyphenyl) -1,2,2,4-tetramethyl-1,2-dihydroquinoline (reference compound 4-2)
5-hydroxymethyl-6- (2-hydroxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 3-1, 4.01 g, 13.6 mmol), methyl iodide (847 μl, A mixture of 13.6 mmol) and potassium carbonate (3.76 g, 27.2 mmol) was suspended in anhydrous N, N-dimethylformamide (70 mL) and stirred at 50 degrees for 4 hours. After allowing to cool, ethyl acetate (200 mL) and diethyl ether (300 mL) were added for dilution. The extract was washed successively with water (500 mL, 300 mL) and saturated brine (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 title reference compound 4-1 (3.01 g, yield 71%) and the title reference compound 4-2 (380 mg, yield 9). %) As a pale yellow solid.

Hereinafter, using a compound selected from Reference Compounds 3-1 to 3-10 and 3-12 to 3-23, according to the production method of Reference Compounds 4-1 and 4-2, Reference Compound 4-3 4-32 was obtained.

Reference Example 5
5-chloromethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 5-1)
5-Hydroxymethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Reference compound 4-1, 2.00 g, 6.46 mmol) was added to anhydrous dichloromethane (32 mL). Dissolve and add triethylamine (1.35 mL, 9.69 mmol) and methanesulfonyl chloride (550 μl, 7.11 mmol) at 0 degrees. The reaction was stirred at room temperature overnight. Ethyl acetate (500 mL), water (200 mL) and saturated brine (200 mL) were added to the reaction solution and partitioned. The aqueous layer was extracted with ethyl acetate (150 mL) and the organic layers were combined. The organic layer was washed with saturated brine (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 (1.07 g) as a pale yellow solid. (Yield 50%)

Hereinafter, a compound selected from the reference compounds 4-3, 4-4, 4-6, 4-11, 4-17, 4-18, 4-20 to 4-27 and 4-32 is used, and the reference compound is used. Reference compounds 5-2 to 5-16 were obtained according to the production method of 5-1.

Reference Example 6
5-hydroxymethyl-6- (2-trifluoromethylsulfonyloxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 6-1)
5-hydroxymethyl-6- (2-hydroxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 3-1, 293 mg, 0.992 mmol) was dissolved in anhydrous dichloromethane (5 mL). At 0 degrees, triethylamine (167 μl, 1.20 mmol) and trifluoromethanesulfonyl chloride (106 μl, 0.996 mmol) were added. The reaction solution was stirred at 0 ° C. for 1 hour, and diluted by adding chloroform (20 mL). The extract was washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), 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 titled reference compound (177 mg) as an orange solid. (Yield 42%)

Hereafter, the reference compound 6-2 was used and the reference compound 6-2 was obtained according to the manufacturing method of the reference compound 6-1.

Reference Example 7
5-hydroxymethyl-6-phenyl-2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 7-1)
5-hydroxymethyl-6- (2-trifluoromethylsulfonyloxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 6-1, 136 mg, 0.318 mmol) was added to anhydrous N, N -Dissolved in dimethylformamide (1.5 mL) and bubbled with argon for 2 min, then tetrakis (triphenylphosphine) palladium (O) (35.6 mg, 0.0308 mmol), triethylamine (221 μl, 1.59 mmol) and formic acid ( 60 μl, 1.6 mmol) was added. The reaction solution was stirred at 60 ° C. for 10 hours, and diluted by adding ethyl acetate (50 mL). The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution (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 (93.0 mg) as a yellow oil. (quantitative)

Hereinafter, Reference Compound 7-2 was obtained using Reference Compound 6-2 in accordance with the production method of Reference Compound 7-1.

Reference Example 8
Methyl 5-amino-2-bromobenzoate (Reference Compound 8)
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 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%)

Reference Example 9
Methyl 3-amino-4-chlorobenzoate (Reference compound 9)
3-amino-4-chlorobenzoic acid (20.9 g, 0.122 mol) and cesium carbonate (79.5 g, 0.244 mol) were suspended in anhydrous N, N-dimethylformamide (500 mL) and methyl iodide (7 .60 mL, 0.122 mol) was added, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. Ethyl acetate (250 mL) and diethyl ether (500 mL) were added to the reaction mixture, and the mixture was washed with water (1 L). The aqueous layer was extracted with ethyl acetate / diethyl ether (2/1) (300 mL, 3 times). The organic layers were combined and then washed sequentially with water (500 mL, 4 times) and saturated brine (300 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title reference compound (21.82 g) as a light brown solid. (Yield 97%)

Reference Example 10
Methyl 5-amino-2-bromo-4-chlorobenzoate (Reference Compound 10)
Methyl 3-amino-4-chlorobenzoate (Reference compound 9, 12.0 g, 64.7 mmol) was dissolved in anhydrous N, N-dimethylformamide (250 mL), cooled to 0 ° C., and then N-bromosuccinimide ( 11.5 g, 64.6 mmol) was added, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. Ethyl acetate (200 mL) and diethyl ether (200 mL) were added to the reaction mixture, and the mixture was washed with 1% aqueous sodium thiosulfate solution (500 mL). The aqueous layer was extracted with ethyl acetate / diethyl ether (1/1) (200 mL). The organic layers were combined, washed successively with water (400 mL, 4 times) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was filtered with hexane (15 mL) to give the titled reference compound (15.74 g) as a light brown solid. (Yield 92%)

Reference Example 11
(2-hydroxyphenyl) methyl acetate (reference compound 11-1)
2-hydroxyphenylacetic acid (302.7 mg, 1.99 mmol) was dissolved in anhydrous methanol (10 mL), sulfuric acid (0.2 mL) was added, and the mixture was stirred at 90 degrees for 6 hours. The reaction solution was concentrated under reduced pressure. The residue was partitioned by adding ethyl acetate (50 mL), 1N aqueous sodium hydroxide solution (5 mL) and saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The title reference compound (242.4 mg) was obtained as a yellow solid by evaporating the solvent under reduced pressure. (Yield 73%)

Hereinafter, using a commercially available compound, Reference Compound 11-2 was obtained according to the production method of Reference Compound 11-1.

Example 1
5- (2-Fluorobenzoyloxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 1-1)
1- (2-Fluorobenzoyl) -5- (2-fluorobenzoyloxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 1 -2)
6- (4-Fluoro-2-methoxyphenyl) -5-hydroxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 4-3, 60.0 mg, 0.183 mmol) was added to anhydrous tetrahydrofuran. (1 mL) and triethylamine (81.0 μl, 0.581 mmol) and 2-fluorobenzoyl chloride (51.0 μl, 0.427 mmol) were added. The reaction was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction solution 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 1-1 (43.0 mg, yield 52%) as a colorless solid, the title compound 1-2 (18.3 mg, Yield 17%) was obtained as a pale yellow oil.

Hereinafter, compounds selected from Reference Compounds 3-11, 4-1 to 4-10, 4-12 to 4-16, 4-18, 4-19, 4-22, 7-1 and 7-2 are used. Then, according to the production method of compounds 1-1 and 1-2, compounds 1-3 to 1-58 were obtained.

Example 2
1-acryloyl-5-benzoyloxymethyl-6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 2-1)
5-Benzoyloxymethyl-6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 1-14, 35.7 mg, 0.0827 mmol) in anhydrous tetrahydrofuran (1 mL) and triethylamine (115 μl, 0.825 mmol) and acryloyl chloride (40.4 μl, 0.497 mmol) were added. The reaction was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction solution for dilution. 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 (3.0 mg) as a pale yellow oil. (Yield 7%)

Hereinafter, using a compound selected from Compounds 1-7, 1-8, 1-25, 3-4, and 10-1, according to the production method of Compound 2-1, compounds 2-2 to 2-6 Got.

Example 3
6- (2-methoxyphenyl) -5-phenoxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (Compound 3-1)
5-chloromethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 5-1, 52 mg, 0.16 mmol), phenol (42 μl, 0.48 mmol) And potassium carbonate (88 mg, 0.64 mmol) was suspended in anhydrous N, N-dimethylformamide (2 mL) and stirred at 80 ° C. for 5 hours. After cooling, ethyl acetate (60 mL) was added for dilution. The extract was washed successively with water (50 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 (24 mg) as a colorless oil. (Yield 39%)

Hereinafter, using a compound selected from Reference Compounds 5-2, 5-3, 5-7 to 5-9 and 5-14 to 5-16, according to the production method of Compound 3-1, 2-3-3-102 was obtained.

Table 45α

Table 45β

Table 45γ

Table 45δ

Table 45ε

Table 45ζ

Table 45η

Table 45θ

Example 4
5-Benzyloxymethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 4-1)
60% sodium hydride (30 mg, 0.75 mmol) was suspended in anhydrous tetrahydrofuran (1 mL), and benzyl alcohol (78 μl, 0.75 mmol) was added at 0 ° C. under an argon atmosphere. After stirring for 30 minutes at room temperature, 5-chloromethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 5-1, 50 mg, 0. 15 mmol) in anhydrous tetrahydrofuran (1.5 mL) was added. The reaction was stirred at 50 degrees for 7 hours. After allowing to cool, ethyl acetate (50 mL) was added. The extract was washed successively with water (50 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 (4.0 mg) as a colorless solid. (Yield 7%)

Hereinafter, Reference Compound 5-2 was used and Compounds 4-2 to 4-6 were obtained according to the production method of Compound 4-1.

Example 5
5-Benzoyloxymethyl-6- (3-hydroxy-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 5-1)
5-benzoyloxymethyl-6- (2-methoxy-3-methoxymethoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 1-28, 228 mg, 0.481 mmol) was converted to 1,4 -It melt | dissolved in dioxane (4 mL), 4N hydrogen chloride / 1, 4- dioxane (1 mL) was added, and it stirred at room temperature for 45 minutes. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (14.0 mg) as a colorless solid. (Yield 7%)

Hereinafter, using a compound selected from Reference Compound 2-6, Compounds 1-38, 13-4 and 13-49 to 13-50, according to the production method of Compound 5-1, compounds 5-2 to 5 -5 was obtained.

Example 6
6- (2-methoxyphenyl) -5-[(pyrrolidin-1-yl) methyl] -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 6-1)
5-chloromethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 5-1, 41.2 mg, 0.126 mmol), pyrrolidine (52.6 μl, 0.630 mmol) and potassium carbonate (34.8 mg, 0.252 mmol) were suspended in anhydrous N, N-dimethylformamide (1 mL) and stirred at 50 degrees for 1 hour. After cooling, ethyl acetate (50 mL) was added for dilution. 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 (36.1 mg) as a colorless solid. (Yield 79%)

Hereinafter, using a compound selected from Reference Compounds 5-1 to 5-10 and 5-14 to 5-16, Compounds 6-2 to 6-86 were obtained according to the production method of Compound 6-1. .

Table 51α

Table 51β

Table 51γ

Example 7
5-acryloyloxymethyl-1-allyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 7-1)
5-acryloyloxymethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 1-7, 50 mg, 0.14 mmol), allyl bromide (111 μl, 1. 28 mmol) and potassium carbonate (78 mg, 0.56 mmol) were suspended in anhydrous N, N-dimethylformamide (2 mL) and stirred at 60 degrees for 4 days. After allowing to cool, ethyl acetate (25 mL) was added for dilution. The extract was washed successively with water (30 mL, twice) 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 (23 mg) as a pale yellow oil. (Yield 41%)

Hereinafter, compounds 7-2 and 7-3 were obtained using compound 1-7 or 9-5 according to the production method of compound 7-1.

Example 8
6- (2-hydroxyphenyl) -5-[(pyrrolidin-1-yl) carbonyl] -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 8-1)
Pyrrolidine (135 μl, 1.62 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and a 1.6 M hexane solution (1.01 mL, 1.62 mmol) of n-butyllithium was added dropwise at 0 degrees. After stirring at the same temperature for 30 minutes, 2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (reference compound 1-1, 80 mg, 0.27 mmol) in anhydrous tetrahydrofuran (3 mL) solution was added dropwise and stirred for an additional 30 minutes. A saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and then diluted with 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 (80.2 mg) as a pale yellow solid. (Yield 82%)

Hereinafter, using the reference compound 1-1, compounds 8-2 to 8-8 were obtained according to the production method of the compound 8-1.

Example 9
6- (2-methoxyphenyl) -5-[(pyrrolidin-1-yl) carbonyl] -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 9-1)
6- (2-hydroxyphenyl) -5-[(pyrrolidin-1-yl) carbonyl] -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 8-1, 65.0 mg, 0.179 mmol) , A mixture of methyl iodide (11.1 μl, 0.178 mmol) and potassium carbonate (49.5 mg, 0.358 mmol) was suspended in anhydrous N, N-dimethylformamide (1.5 mL) and stirred at 50 ° C. overnight. did. After cooling, 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 (42.5 mg) as a colorless solid. (Yield 63%)

Hereinafter, compounds 9-2 to 9-8 were obtained according to the production method of compound 9-1 using a compound selected from compounds 8-2 to 8-8.

Example 10
6- (2-methoxyphenyl) -5-phenylthiomethyl-2,2,4-trimethyl-1,2-dihydroquinoline (Compound 10-1)
5-chloromethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 5-1, 80 mg, 0.24 mmol), thiophenol (148 μl, 1.44 mmol) ) And potassium carbonate (266 mg, 1.92 mmol) were suspended in anhydrous N, N-dimethylformamide (2 mL) and stirred at 50 ° C. overnight. After cooling, ethyl acetate (50 mL) was added for dilution. The extract was washed successively with water (50 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 (53 mg) as a colorless solid. (Yield 55%)

Hereinafter, using the reference compound 5-2, the compounds 10-2 to 10-5 were obtained according to the production method of the compound 10-1.

Example 11
5-Benzylthiomethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 11-1)
5-chloromethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Reference compound 5-1, 80 mg, 0.24 mmol), benzyl mercaptan (85 μl, 0.72 mmol) ) Was dissolved in anhydrous tetrahydrofuran (2 mL) and 60% sodium hydride (38 mg, 0.95 mmol) was added at 0 ° C. under an argon atmosphere. At room temperature, anhydrous N, N-dimethylformamide (0.5 mL) was added and stirred for 4 hours. Ethyl acetate (50 mL) was added to the reaction solution for dilution. 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 (65 mg) as a colorless solid. (Yield 65%)

Hereinafter, compounds 11-2 to 11-3 were obtained according to the production method of reference compound 11-1, using reference compound 5-2.

Example 12
6- (4-Fluoro-2-methoxyphenyl) -5- (4-methylthiobenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 12-1)
5-chloromethyl-6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 5-2, 50.0 mg, 0.145 mmol), 4- Methylthiobenzoic acid (73.2 mg, 0.435 mmol) and potassium carbonate (80.2 mg, 0.580 mmol) were suspended in anhydrous N, N-dimethylformamide (1 mL) and stirred at 80 ° C. for 2.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, 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 title compound (32.4 mg) as a colorless amorphous product. (Yield 47%)

Hereinafter, compounds 12-2 to 12-80 were obtained according to the production method of compound 12-1, using a compound selected from reference compounds 5-2 to 5-3 and 5-5 to 5-16. .

Example 13
5- (3-Aminobenzoyloxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 13-1)
6- (4-Fluoro-2-methoxyphenyl) -5-hydroxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 4-3, 49.7 mg, 0.15 mmol), 3- Aminobenzoic acid (49.0 mg, 0.35 mmol), tri-n-butylphosphine (87.0 μL, 0.35 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (89.4 mg, 0.35 mmol). Dissolved in anhydrous benzene (2 mL) and stirred overnight at room temperature under argon atmosphere. Hexane (3 mL) -ethyl acetate (3 mL) was added to the reaction solution, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (28.0 mg) as a colorless amorphous. (Yield 42%)

Hereinafter, using a compound selected from Reference Compounds 4-1, 4-3 and 4-31, Compounds 13-2 to 13-4 were obtained according to the production method of Compound 13-1.

Example 14
6- (4-Fluoro-2-methoxyphenyl) -5- (2-methoxycarbonylmethylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 14-1)
6- (4-Fluoro-2-methoxyphenyl) -5-hydroxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 4-3, 100.1 mg, 0.31 mmol), 2- Methyl hydroxyphenylacetate (76.1 mg, 0.46 mmol), tri-n-butylphosphine (114 μL, 0.46 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (117 mg, 0.46 mmol) was added to anhydrous benzene ( 2 mL) and stirred at room temperature under an argon atmosphere for 1 hour. Hexane (5 mL) was added to the reaction solution, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (107.1 mg) as a colorless amorphous. (Yield 74%)

Hereinafter, a compound selected from Reference Compounds 4-3 to 4-4, 4-6, 4-17, 4-27 and 4-29 to 4-32 is used, and according to the production method of Compound 14-1. Compounds 14-2 to 14-56 were obtained.

Example 15
6- (4-Benzyloxy-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 15-1)
5- (5-Fluoro-2-methylphenoxymethyl) -6- (4-hydroxy-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 5-3, 20.1 mg , 0.046 mmol), potassium carbonate (16.7 mg, 0.12 mmol), and benzyl bromide (6.6 μL, 0.055 mmol) were dissolved in anhydrous N, N-dimethylformamide (0.5 mL) and dissolved at 40 ° C. at 40 ° C. Stir for minutes. Ethyl acetate (50 mL) was added to the reaction mixture, washed with water (50 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (5.1 mg) as a colorless oil. (Yield 19%)

Hereafter, using compound 5-3 or 5-4, according to the manufacturing method of compound 15-1, compounds 15-2 to 15-18 were obtained.

Example 16
6- (4-Fluoro-2-methoxyphenyl) -5- (4-hydroxybenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 16)
5- (4-Acetoxybenzoyloxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (compound 12-5, 40.9 mg, 0. 0835 mmol) and potassium carbonate (24.0 mg, 0.174 mmol) were suspended in anhydrous methanol (1 mL) and stirred at room temperature for 1.5 hours. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and 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 solid was collected by filtration with hexane to give the titled compound (28.8 mg) as a colorless solid. (Yield 78%)

Example 17
5-Benzoylaminomethyl-6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 17-1)
60% sodium hydride (23.2 mg, 0.580 mmol) was suspended in anhydrous N, N-dimethylformamide (3 mL), and benzamide (70.3 mg, 0.580 mmol) was added at 0 degrees. After stirring at room temperature for 25 minutes, 5-chloromethyl-6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 5-2, 50.0 mg) 0.145 mmol) was added and the mixture was stirred at 50 degrees for 1 hour. Ethyl acetate (100 mL) was added to the reaction mixture, 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 (34.1 mg) as a pale yellow amorphous product. (Yield 55%)

Hereinafter, using reference compound 5-2, compounds 17-2 to 17-4 were obtained according to the production method of compound 17-1.

6- (4-Fluoro-2-methoxyphenyl) -5-phenylaminocarbonyloxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (Compound 18)
6- (4-Fluoro-2-methoxyphenyl) -5-hydroxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 4-3, 50.0 mg, 0.153 mmol) and 4- Dimethylaminopyridine (1.87 mg, 0.0153 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), 1,1′-carbonyldiimidazole (32.3 mg, 0.199 mmol) was added, and the mixture was stirred overnight at room temperature [Solution 1 ].
To a solution of aniline (69.7 μl, 0.765 mmol) in anhydrous tetrahydrofuran (2 mL), a 1.6 M hexane solution (430 μl, 0.688 mmol) of n-butyllithium was added dropwise at 0 degree, and the mixture was stirred at 0 degree for 30 minutes. [Solution 2].
After the reaction solution 2 was cooled to -78 degrees, the reaction solution 1 was added dropwise and stirred at -78 degrees for 30 minutes. A saturated aqueous ammonium chloride solution (5 mL) was added, and the mixture was diluted with ethyl acetate (100 mL). The extract was washed successively with water (100 mL), 0.02 N hydrochloric acid (100 mL), 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 (toluene-ethyl acetate) to give the titled compound (66.0 mg) as a pale yellow amorphous. (Yield 97%)

Example 19
5- (2-carboxymethylphenoxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 19-1)
6- (4-Fluoro-2-methoxyphenyl) -5- (2-methoxycarbonylmethylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 14-1, 84.0 mg, 0 .18 mmol) was dissolved in methanol (2 mL) -tetrahydrofuran (1 mL), 1N aqueous sodium hydroxide solution (0.56 mL) was added, and the mixture was stirred overnight at room temperature. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed successively with 0.01 N hydrochloric acid (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 (74.1 mg) as a colorless solid. (Yield 89%)

Hereinafter, compounds 19-2 to 19-4 were obtained according to the production method of compound 21-1, using a compound selected from compounds 3-51, 3-53 and 14-3.

Example 20
5- (2-Aminophenoxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 20-1)
5- (2-t-Butoxycarbonylaminophenoxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 3-79, 9.6 mg) , 0.019 mmol) was added 4N hydrogen chloride / 1,4-dioxane solution (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was partitioned by adding ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (5.4 mg) as a yellow oil. (Yield 70%)

Hereafter, compound 20-2 was obtained according to the manufacturing method of compound 20-1 using compound 6-86.

Example 21
6- (5-amino-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 21-1)
5- (5-Fluoro-2-methylphenoxymethyl) -6- (2-methoxy-5-nitrophenyl) -2,2,4-trimethyl-1,2-dihydroquinoline (compounds 14-48, 100.4 mg , 0.217 mmol) was dissolved in 4N aqueous sodium hydroxide solution (405 μL, 1.62 mmol) -ethanol (5 mL), zinc (292.9 mg, 4.48 mmol) was added, and the mixture was stirred at 110 ° C. overnight. Ethyl acetate (20 mL) was added to the reaction solution, and insoluble material was removed by filtration. Ethyl acetate (50 mL) was added to the filtrate, 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 residue was purified by silica gel column chromatography (hexane-ethyl acid) to give the title compound (12.1 mg) as a yellow amorphous. (Yield 13%)

Example 22
6- (2-Methoxy-5-phenylacetylphenyl) -5- (4-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 22)
Aluminum chloride (97.0 mg, 0.73 mmol) was added to anhydrous dichloroethane solution (0.5 mL) and cooled to 0 degrees. Phenylacetyl chloride (97 μL, 0.73 mmol), 6- (2-methoxyphenyl) -5- (4-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 13-3 49.7 mg, 0.12 mmol), and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, 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 residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (53.6 mg) as a pale yellow amorphous. (Yield 82%)

Example 23
6- [2-Methoxy-5- (1-hydroxy-2-phenylethyl) phenyl] -5- (4-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 23) )
6- [5- (1-Hydroxy-2-phenylethyl) -2-methoxyphenyl] -5- (4-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (SA22540)
6- (2-methoxy-5-phenylacetylphenyl) -5- (4-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline (Compound 22, 34.0 mg, 0.0623 mmol) ) Was dissolved in THF (0.5 mL) -methanol (0.5 mL), sodium borohydride (6.8 mg, 0.180 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. 1N Hydrochloric acid (0.5 mL) and ethyl acetate (50 mL) were added to the reaction mixture, washed successively with water (50 mL, 2 times) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (31.8 mg) as a colorless amorphous. (Yield 93%)

[Formulation example]
The typical formulation example of this invention compound is shown below.
1) Tablet (in 100mg)
1 mg of the present compound
Lactose 66.4mg
Corn starch 20mg
Carboxymethylcellulose calcium 6mg
Hydroxypropylcellulose 4mg
Magnesium stearate 0.6mg

A tablet of the above formulation can be coated with 2 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 be obtained by changing suitably the kind and / or quantity of this invention compound and an additive.
2) Capsule (in 150mg)
The compound of the present invention 5mg
Lactose 145mg

A desired capsule can be obtained by appropriately changing the mixing ratio of the compound of the present invention and lactose.
3) Eye drops (in 100 ml)
Compound of the present invention 100mg
Sodium chloride 900mg
Polysorbate 80 200mg
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 and additive of the present invention.

[Pharmacological test]
1. Glucocorticoid receptor (hereinafter referred to as “GR”) binding activity evaluation test 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 operation was performed according to the protocol 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 a buffer solution containing 2% dimethyl sulfoxide.
4 × GS1 solution: Fluorone ^™ 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)
After the test compound was dissolved in dimethyl sulfoxide, this solution was 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 or 384-well plate at 25 μL or 10 μL per well, and then 4 × GS1 solution and 4 × GR solution were added at 12.5 μL or 5 μL per well, respectively.
2) Incubate in the dark at room temperature for 2-4 hours.
3) Using a multi-mode 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 the 4 × GS1 solution as a blank The fluorescence polarization of was measured.
4) A GR screening buffer was used in place of the test compound solution, and the other operations were the same as in the above 1-3), and the result was used as a negative control.
5) In place of the test compound solution, 2 mM dexamethasone was used, and the others were carried out in the same manner as in the above 1 to 3), and the result was used as a positive control.

(Calculation formula of GR coupling rate)
The GR bond rate (%) was calculated by the following formula.
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)
As an example of the test results, test compounds (compound 1-19, compound 1-21, compound 1-46, compound 3-21, compound 3-22, compound 3-33, compound 3-44, compound 3-45, compound 3-48, Compound 3-56, Compound 3-57, Compound 3-58, Compound 3-59, Compound 3-61, Compound 3-62, Compound 3-67, Compound 3-68, Compound 3-69, Compound 3-72, Compound 3-74, Compound 3-85, Compound 3-91, Compound 3-94, Compound 3-98, Compound 3-99, Compound 5-3, Compound 5-4, Compound 6-20, Compound 6-24, Compound 6-27, Compound 6-36, Compound 6-37, Compound 6-40, Compound 6-43, Compound 6-45, Compound 6-47, Compound 6-53, Compound 6-57, Compound 6-59, compound 6-7 , Compound 6-76, Compound 6-77, Compound 6-78, Compound 6-79, Compound 12-17, Compound 12-19, Compound 12-20, Compound 12-21, Compound 12-22, Compound 12-25 , Compound 12-33, Compound 12-42, Compound 12-53, Compound 12-54, Compound 12-58, Compound 12-67, Compound 12-69, Compound 12-73, Compound 12-75, Compound 12-76 , Compound 14-1, Compound 14-11, Compound 14-12, Compound 14-13, Compound 14-15, Compound 14-21, Compound 14-40, Compound 14-41, Compound 14-43, Compound 14-45 Table I shows the GR bond percentage (%) of Compound 14-47, Compound 14-48, Compound 15-2, and Compound 15-7).

  As can be seen from 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 (16)

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

[Ring X represents a benzene ring or a pyridine ring;
R ¹ represents a halogen atom, an optionally substituted lower alkyl group, a hydroxy group, an optionally substituted lower alkoxy group, an optionally substituted lower alkenyloxy group, or a lower alkylcarbonyl group. Represents an amino 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 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. An aryl group, an optionally substituted lower alkylcarbonyl group, an optionally substituted lower alkenylcarbonyl group, an optionally substituted lower alkynylcarbonyl group, or an optionally substituted substituent. Represents an arylcarbonyl group;
R ⁴ and R ⁵ represent a methyl group ;
R ⁶ represents a methyl group;
A represents a lower alkylene group ;
R ⁷ represents OR ⁸ , NR ⁸ R ⁹ , SR ⁸ , S (O) R ⁸ or S (O) ₂ R ⁸ ;
R ⁸ 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, or a lower cycloalkyl which may have a substituent. Group, aryl group which may have a substituent, heterocyclic group which may have a substituent, formyl group, lower alkylcarbonyl group which may have a substituent, lower group which may have a substituent Alkenylcarbonyl group, optionally substituted lower alkynylcarbonyl group, optionally substituted lower cycloalkylcarbonyl group, optionally substituted arylcarbonyl group, optionally substituted Good heterocyclic carbonyl group, carboxy group, optionally substituted lower alkoxycarbonyl group, optionally substituted lower alkenyloxycarbonyl group, optionally substituted lower alkynyloxy A carbonyl group, a lower cycloalkyloxycarbonyl group which may have a substituent, an aryloxycarbonyl group which may have a substituent, a heterocyclic oxycarbonyl group which may have a substituent, and a substituent Lower alkylsulfonyl group which may have a substituent, lower alkenylsulfonyl group which may have a substituent, lower alkynylsulfonyl group which may have a substituent, lower cycloalkylsulfonyl group which may have a substituent, substituent An arylsulfonyl group which may have a substituent, a heterocyclic sulfonyl group which may have a substituent, an aminocarbonyl group, a lower alkylaminocarbonyl group which may have a substituent, a lower group which may have a substituent Alkenylaminocarbonyl group, optionally substituted lower alkynylaminocarbonyl group, optionally substituted lower cycloalkylamino Carbonyl group, a heterocyclic aminocarbonyl group which may have an optionally substituted arylaminocarbonyl group or a substituent;
R ⁹ 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. A lower cycloalkyl group, an aryl group which may have a substituent, a heterocyclic group which may have a substituent, a formyl group, a lower alkylcarbonyl group which may have a substituent, and a substituent; A lower alkenylcarbonyl group which may have a substituent, a lower alkynylcarbonyl group which may have a substituent, a lower cycloalkylcarbonyl group which may have a substituent, an arylcarbonyl group which may have a substituent, and a substituent An optionally substituted heterocyclic carbonyl group, a carboxy group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkenyloxycarbonyl group, an optionally substituted lower alkyl Nyloxycarbonyl group, optionally substituted lower cycloalkyloxycarbonyl group, optionally substituted aryloxycarbonyl group, optionally substituted heterocyclic oxycarbonyl group, substituent A lower alkylsulfonyl group which may have, a lower alkenylsulfonyl group which may have a substituent, a lower alkynylsulfonyl group which may have a substituent, a lower cycloalkylsulfonyl group which may have a substituent, An arylsulfonyl group which may have a substituent, a heterocyclic sulfonyl group which may have a substituent, an aminocarbonyl group, a lower alkylaminocarbonyl group which may have a substituent, and a substituent Good lower alkenylaminocarbonyl group, optionally substituted lower alkynylaminocarbonyl group, optionally substituted lower cycloalkyl Le aminocarbonyl group, a heterocyclic aminocarbonyl group which may have an optionally substituted arylaminocarbonyl group or a substituent; and, 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. ] In general formula (1), ring X represents a benzene ring or a pyridine ring;
R ¹ represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkenyloxy group, a lower alkylcarbonyl group, an amino 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 is a halogen atom, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with a lower alkyl group, a hydroxy group One or more groups selected from aryl groups substituted with, aryl groups substituted with lower alkoxy groups, hydroxy groups, hydroxy group esters, lower alkoxy groups, aryloxy groups, carboxy groups and carboxy group esters As a substituent;
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, an ester of 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 a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a lower alkynylcarbonyl 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 aryl groups as a substituent;
When R ³ is an aryl group or an arylcarbonyl group, the aryl group or the arylcarbonyl group may have one or more groups selected from a halogen atom and a lower alkyl group as a substituent;
R ⁴ and R ⁵ represent a methyl group;
R ⁶ represents a methyl group;
A represents a lower alkylene group ;
R ⁷ represents OR ⁸ , NR ⁸ R ⁹ or SR ⁸ ;
R ⁸ is a 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, aryloxycarbonyl group, heterocyclic oxycarbonyl group, lower alkyl Sulfonyl group, lower alkenylsulfonyl group, lower alkynylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, aminocarbonyl group, lower alkylamino A carbonyl group, a lower alkenylaminocarbonyl group, a lower alkynylaminocarbonyl group, a lower cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a heterocyclic aminocarbonyl group;
R ⁹ is 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 cyclo Alkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group Lower alkylsulfonyl group, lower alkenylsulfonyl group, lower alkynylsulfonyl group, lower cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl group, aminocarbonyl group, lower alkyl A killaminocarbonyl group, a lower alkenylaminocarbonyl group, a lower alkynylaminocarbonyl group, a lower cycloalkylaminocarbonyl group, an arylaminocarbonyl 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 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, a lower alkenyloxy group, a lower alkynyloxy group, a lower cycloalkyloxy group, an 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, amide of amino group, low Primary alkylamino group, lower alkylamino group amide, arylamino group, arylamino group amide, heterocyclic amino group, 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, carboxy group amide, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryl Oxycarbonyl group, heterocyclic oxycarbonyl group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, sulfinic acid group, ester of sulfinic acid group Amides of a sulfinic acid 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;
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. A substituted lower alkyl group, a lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted with an amino group, a lower alkyl group substituted with a lower alkylamino group, a lower alkyl group substituted with a carboxy group, Substituted by lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, hydroxy group, hydroxy group ester, lower alkoxy group, halogen atom substituted by lower alkoxycarbonyl group Lower alkoxy group, lower alkenyl group Xyl 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, amide of amino group, lower alkylamino group, amide of lower alkylamino group, arylamino group, amide of arylamino group, heterocyclic amino group, amide of heterocyclic amino group, Formyl group, lower alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, carboxy group, carboxy group amide, lower alkoxycarbonyl group, lower alkenyloxy group Carbonyl group, lower alkynyloxycarbonyl group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, sulfinic acid group, sulfine Esters of acid groups, amides of sulfinic acid groups, sulfonic acid groups, esters of sulfonic acid groups, amides of sulfonic acid groups, nitro groups, cyano groups, aminocarbonyloxy groups, lower alkylaminocarbonyloxy groups and arylaminocarbonyloxy groups May have one or more groups selected from as substituents;
Further, when R ⁷ is NR ⁸ R ⁹ , the compound or a salt thereof according to claim 1, wherein R ⁸ and R ⁹ may be combined to form a 5- or 6-membered nitrogen-containing heterocyclic ring. In general formula (1), ring X represents a benzene ring or a pyridine ring;
R ¹ represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkenyloxy group, a lower alkylcarbonyl group, an amino group or a nitro group;
When R ¹ is a lower alkyl group or a lower alkoxy group, the lower alkyl group or lower alkoxy group is a halogen atom, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with a lower alkyl group, or a lower alkoxy group 1 or a plurality of groups selected from an aryl group, a hydroxy group, a lower alkoxy group, an aryloxy group, a carboxy group and an ester of a carboxy group substituted with
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 a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aryl 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 aryl groups as a substituent;
When R ³ is an aryl group or an arylcarbonyl group, the aryl group or the arylcarbonyl group may have one or more groups selected from a halogen atom and a lower alkyl group as a substituent;
R ⁴ and R ⁵ represent a methyl group;
R ⁶ represents a methyl group;
A represents a lower alkylene group ;
R ⁷ represents OR ⁸ , NR ⁸ R ⁹ or SR ⁸ ;
R ⁸ is a lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, lower alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, lower cycloalkylcarbonyl group, arylcarbonyl A group or a heterocyclic carbonyl group;
R ⁹ is a hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, lower alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, lower cycloalkylcarbonyl group Represents an arylcarbonyl group or a heterocyclic carbonyl group;
When 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 or a lower alkynylcarbonyl group, the lower alkyl group, the lower alkenyl group, the lower alkynyl group, The lower alkylcarbonyl group, the lower alkenylcarbonyl group or the lower alkynylcarbonyl group may have one or more groups selected from an aryl group, a hydroxy group and a lower alkoxy group as a substituent;
When R ⁸ or R ⁹ is a lower cycloalkyl group, an aryl group, a heterocyclic group, a lower cycloalkylcarbonyl group, an arylcarbonyl group or a heterocyclic carbonyl group, the lower cycloalkyl group, the aryl group, the heterocyclic group, The lower cycloalkylcarbonyl group, arylcarbonyl group or heterocyclic carbonyl group is substituted with a halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a lower alkyl group substituted with a hydroxy group, or a lower alkoxy group. A lower alkyl group substituted with an amino group, a lower alkyl group substituted with a lower alkylamino group, a lower alkyl group substituted with a carboxy group, a lower alkyl group substituted with a lower alkoxycarbonyl group, Lower alkenyl group, lower alkynyl group, aryl group, heterocyclic group, Roxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, aryloxy group, mercapto group, lower alkylthio group, amino group, amino group amide, lower alkylamino group, lower alkylamino group One or more selected from amide, formyl group, lower alkylcarbonyl group, carboxy group, amide of carboxy group, lower alkoxycarbonyl group, nitro group, cyano group, aminocarbonyloxy group and lower alkylaminocarbonyloxy group May have a group as a substituent;
Further, when R ⁷ is NR ⁸ R ⁹ , the compound or a salt thereof according to claim 1, wherein R ⁸ and R ⁹ may be combined to form a 5- or 6-membered nitrogen-containing heterocyclic ring. In general formula (1), ring X represents a benzene ring or a pyridine ring;
R ¹ represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkenyloxy group, a lower alkylcarbonyl group, an amino group or a nitro group;
When R ¹ is a lower alkyl group or a lower alkoxy group, the lower alkyl group or lower alkoxy group is a halogen atom, an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with a lower alkyl group, or a lower alkoxy group 1 or a plurality of groups selected from an ester of an aryl group, a hydroxy group, a lower alkoxy group and a carboxy group substituted with 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;
R ² represents a halogen atom, a lower alkyl group or a lower alkoxy group;
q represents 0 or 1;
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;
R ⁴ and R ⁵ represent a methyl group;
R ⁶ represents a methyl group;
A represents a lower alkylene group ;
R ⁷ represents QR ⁸ , NR ⁸ R ⁹ or SR ⁸ ;
R ⁸ represents a lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a lower cycloalkylcarbonyl group, an arylcarbonyl group or a heterocyclic carbonyl group;
R ⁹ represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, an arylcarbonyl group or a heterocyclic carbonyl group;
When R ⁸ or R ⁹ is a lower alkyl group, the lower alkyl group may have one or more groups selected from a lower alkoxy group and an aryl group as a substituent;
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. Group, lower alkyl group substituted with hydroxy group, lower alkyl group substituted with amino group, lower alkyl group substituted with lower alkylamino group, lower alkyl group substituted with carboxy group, substituted with lower alkoxycarbonyl group Lower alkyl group, lower alkenyl group, lower alkynyl group, aryl group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, aryloxy group, lower alkylthio group, amino group, Amido of amino group, lower alkylamino group, lower Substitute one or more groups selected from alkylamide amide, formyl group, lower alkylcarbonyl group, carboxy group, carboxy group amide, lower alkoxycarbonyl group, nitro group, cyano group and lower alkylaminocarbonyloxy group May have as a group;
Further, when R ⁷ is NR ⁸ R ⁹ , the compound or a salt thereof according to claim 1, wherein R ⁸ and R ⁹ may be combined to form a 5- or 6-membered nitrogen-containing heterocyclic ring. In general formula (1), ring X represents a benzene ring;
R ¹ represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkenyloxy group, an amino group or a nitro group;
When R ¹ is a lower alkyl group, the lower alkyl group may have one or more halogen atoms as substituents;
When R ¹ is a lower alkoxy group, the lower alkoxy group includes an aryl group, an aryl group substituted with a halogen atom, an aryl group substituted with a lower alkyl group, an aryl group substituted with a lower alkoxy group, and a lower alkoxy group. May have one or more selected groups as substituents;
p represents 2 or 3, wherein each R ¹ may be the same or different;
R ² represents a halogen atom, a lower alkyl group or a lower alkoxy group;
q represents 0 or 1;
R ³ represents a hydrogen atom;
R ⁴ and R ⁵ represent a methyl group;
R ⁶ represents a methyl group;
A represents a lower alkylene group;
R ⁷ represents OR ⁸ , NR ⁸ R ⁹ or SR ⁸ ;
R ⁸ represents an aryl group, an arylcarbonyl group or a heterocyclic carbonyl group;
R ⁹ represents a hydrogen atom or a lower alkyl group;
When R ⁸ 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, a lower alkyl group substituted with a halogen atom, hydroxy Lower alkyl group substituted with a group, lower alkyl group substituted with an amino group, lower alkyl group substituted with a lower alkylamino group, lower alkyl group substituted with a carboxy group, lower substituted with a lower alkoxycarbonyl group Alkyl group, lower alkenyl group, lower alkynyl group, aryl group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with halogen atom, aryloxy group, lower alkylthio group, amino group, amino group Amido, lower alkylamino group, lower alkylamino Substitution of one or more groups selected from amide of mino group, formyl group, lower alkylcarbonyl group, carboxy group, amide of carboxy group, lower alkoxycarbonyl group, nitro group, cyano group and lower alkylaminocarbonyloxy group The compound or its salt of Claim 1 which you may have as a group. In general formula (1), R < ⁷ > is OR < ⁸ >, The compound or its salt of any one of Claims 1-5. The compound or a salt thereof according to claim 6, wherein R ⁸ represents a phenyl group, a phenylcarbonyl group or a thiophenecarbonyl group. In general formula (1), R < ⁷ > is NR < ⁸ > R < ⁹ >, The compound or its salt of any one of Claims 1-5. The compound or a salt thereof according to claim ^{8, wherein} R ⁸ represents a phenyl group. In general formula (1), R < ⁷ > is SR < ⁸ >, The compound or its salt of any one of Claims 1-5. In general formula (1), the ring X is a benzene ring, The compound or its salt of any one of Claims 1-10. In general formula (1), A is a methylene group, The compound or its salt of any one of Claims 1-11. In the general formula (1), a compound or a salt thereof as claimed in any one of claims. 1 to 12 R ³ is a hydrogen atom. 5-acetoxymethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5-benzoyloxymethyl-6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (2-methoxyphenyl) -5-[(thiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (4-t-butylbenzoyloxymethyl) -6- (2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5-benzoyloxymethyl-6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methoxybenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxybenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methoxybenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(thiophen-2-yl) carbonyloxymethyl)]-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-phenoxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methoxyphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-fluorophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-fluorophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-fluorophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methoxyphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxyphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4,5-difluoro-2-methoxyphenyl) -5- (3-fluorophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-hydroxymethylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (5-chloro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4,5-difluoro-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxy-5-nitrophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- [2- (2-hydroxyethyl) phenoxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methyl-5-nitrophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-allylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- [2- (2-hydroxyethyl) phenoxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (5-fluoro-2-methylphenoxymethyl) -6- (4-hydroxy-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (5-fluoro-2-methylphenoxymethyl) -6- (5-hydroxy-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-hydroxy-2-methoxyphenyl) -5- (4-methylbenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (2-methoxyphenyl) -5-phenylaminomethyl-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-phenylaminomethyl-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methoxyphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-fluorophenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-fluorophenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-fluorophenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methoxyphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxyphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4,5-difluoro-2-methoxyphenyl) -5- (2-methoxyphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-hydroxymethylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxy-5-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (5-fluoro-2-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (2-methoxyphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (5-fluoro-2-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (2-methoxyphenyl) -5-phenylthiomethyl-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-phenylthiomethyl-2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methoxyphenylthiomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(5-methylthiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(4-methylthiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
5-[(5-chlorothiophen-2-yl) carbonyloxymethyl] -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(3-methylthiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
5-[(5-bromothiophen-2-yl) carbonyloxymethyl] -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(5-methoxythiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5-[(thiophen-3-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4,5-difluoro-2-methoxyphenyl) -5-[(5-methylthiophen-2-yl) carbonyloxymethyl] -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (5-methylthiophen-2-ylcarbonyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (4-methoxybenzoyloxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (2-methyl-5-nitrophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (2-methoxy-5-nitrophenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (5-chloro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (5-fluoro-2-methoxyphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-chloro-2-methoxyphenyl) -5- (2,5-dimethylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (2-allylphenoxymethyl) -6- (5-chloro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (5-fluoro-2-methylphenoxymethyl) -6- (2-methoxy-5-nitrophenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-allyloxy-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-allyloxy-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (5-amino-2-methoxyphenyl) -5- (5-fluoro-2-methylphenoxymethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (2-fluorobenzoyloxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (3-fluorobenzoyloxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
5- (4-fluorobenzoyloxymethyl) -6- (4-fluoro-2-methoxyphenyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (4-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (3-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline,
6- (4-fluoro-2-methoxyphenyl) -5- (2-methylphenylaminomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline and 6- (4-fluoro-2- A compound selected from methoxyphenyl) -5- (2-methylphenylthiomethyl) -2,2,4-trimethyl-1,2-dihydroquinoline or a salt thereof. Compound or pharmaceutical compositions containing the salts according to any one of claims 1-14. Compounds or modulators of the glucocorticoid receptor a salt thereof as an active ingredient according to any one of claims 1-14.