JP2012176930A - Novel jak3 inhibitor containing, as active ingredient, thiophene derivative having ureido group and aminocarbonyl group as substituents - Google Patents

Abstract

PROBLEM TO BE SOLVED: To find out a novel JAK3 inhibitor, and to provide a compound with a novel chemical structure having JAK3 inhibiting activity.SOLUTION: The JAK3 inhibitor contains at least one compound represented by general formula (1) and salts thereof as an active ingredient.

Description

  The present invention relates to a novel JAK3 inhibitor containing at least one of a thiophene derivative having a ureido group and an aminocarbonyl group as a substituent or a salt thereof as an active ingredient, and a novel thiophene derivative having a ureido group and an aminocarbonyl group as a substituent, or About its salt. The JAK3 inhibitor of the present invention is expected to be useful as a preventive and / or therapeutic agent for a disease in which JAK3 is involved.

  The JAK family (JAK1 to 3, TYK2) is a tyrosine kinase that is essential for cytokines to exert their biological activities. JAK is activated in the cell after the cytokine binds to the receptor, and activates the transcription factor Stat downstream thereof. JAK1 and JAK2 are widely expressed in vivo, while JAK3 is locally expressed in blood cells. This deficiency of JAK3 causes lymphoid cell differentiation / proliferation in both humans and mice and presents severe combined immunodefiency (SCID) (Japanese Journal of Clinical Immunology, 32, (2) 85 (2009) (Non-Patent Document 1)). This suggests that immunosuppression occurs by blocking signal pathways via JAK3. Therefore, a compound that inhibits JAK3 is expected to have an effect of controlling an immune response and is expected to be useful for the prevention and / or treatment of various autoimmune diseases.

  As compounds that inhibit existing JAK3, compounds having a pyrrolopyrimidine skeleton (Bioorganic & Medicinal Chemistry Letters, 16, 5633 (2006) (Non-patent Document 2)), compounds having a tetracyclic pyridone skeleton (Bioorganic & Medicinal Chemistry) Letters, 12, 1219 (2002) (non-patent document 3)), compounds having an oxindole skeleton (non-patent document 2), and the like are known.

  On the other hand, a thiophene derivative having a ureido group and an aminocarbonyl group as substituents is known as an IKK-2 inhibitor (The Journal of Pharmacology and Experimental Therapeutics, 312, 373 (2005) (Non-patent Document 4)).

  However, it is not known at all that the thiophene derivative having a ureido group and an aminocarbonyl group as substituents according to the present application has inhibitory activity against JAK3.

Japanese Journal of Clinical Immunology, 32, (2) 85 (2009) Bioorganic & Medicinal Chemistry Letters, 16, 5633 (2006) Bioorganic & Medicinal Chemistry Letters, 12, 1219 (2002) The Journal of Pharmacology and Experimental Therapeutics, 312, 373 (2005)

  Finding new JAK3 inhibitors and finding compounds with new chemical structures that have JAK3 inhibitory activity are very interesting challenges.

  As a result of intensive research on the chemical structure of a compound having JAK3 inhibitory activity, the present inventors have found that a thiophene derivative having a ureido group and an aminocarbonyl group as substituents has JAK3 inhibitory activity. I found.

  Furthermore, as a result of synthesizing a large number of novel thiophene derivatives having ureido groups and aminocarbonyl groups as substituents, and intensively researching the pharmacological action of these compounds, it was found that these compounds also have JAK3 inhibitory activity. Was completed.

  That is, the present invention relates to a JAK3 inhibitor containing at least one of a compound represented by the following general formula (1) or a salt thereof (hereinafter also referred to as “the present compound” unless otherwise specified) as an active ingredient.

[Wherein A represents the following general formula (2a), (2b), (2c), (2d), (2e) or (2f);

R ¹ is hydrogen atom, halogen atom, lower alkyl group, lower alkenyl group, phenyl group, hydroxy group, lower alkoxy group, lower alkenyloxy group, phenoxy group, amino group, lower alkylamino group, morpholino group, amide of amino group An amino group sulfonamido, a mercapto group, a lower alkylthio group, a lower alkylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, an aminocarbonyl group or a cyano group; R ² represents a hydrogen atom or a lower alkyl group; R ³ And R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom or a lower alkyl group; R ⁵ represents a hydroxy group or a lower alkoxy group; and when R ¹ is a lower alkyl group, the lower alkyl group is a hydroxy group, From lower alkylcarbonyloxy and morpholino groups May be substituted with one or more groups selected from the group; when R ¹ is a lower alkoxy group, the lower alkoxy group is a halogen atom, a lower alkyl amino group, a morpholino group, 4-fluorophenyl piperazino Optionally substituted by one or more groups selected from the group consisting of a group, a carboxyl group and a lower alkoxycarbonyl group; when R ¹ is an amino group amide, the amino group amide is a hydroxy group, a lower alkoxy group May be substituted with one or more groups selected from the group consisting of a carbonyl group and a cyano group; when R ¹ is an aminocarbonyl group, the aminocarbonyl group is selected from a hydrogen atom, a lower alkyl group and a lower alkoxy group; The lower alkyl group may be substituted with one or more groups selected from the group consisting of May be substituted with one or more groups selected from the group consisting of Le group or a lower alkoxycarbonyl group; p represents 0, 1, 2 or 3; when p is 2 or 3, R ¹ is They may be the same or different. ]
In the JAK3 inhibitor of the present invention, in the general formula (1), A preferably represents the following general formula (2a).

  In the JAK3 inhibitor of the present invention, preferably, in the general formula (1), A represents the following general formula (2a);

R ¹ is hydrogen atom, halogen atom, lower alkyl group, phenyl group, hydroxy group, lower alkoxy group, lower alkenyloxy group, phenoxy group, lower alkylamino group, morpholino group, lower alkylcarbonylamino group, lower alkylsulfonylamino group , A lower alkylthio group, a lower alkylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylaminocarbonyl group, an N-methoxy-N-methylaminocarbonyl group or a cyano group; when R ¹ is a lower alkyl group, The lower alkyl group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkylcarbonyloxy group and a morpholino group; when R ¹ is a lower alkoxy group, the lower alkoxy group is a halogen atom. Atom, lower alkylamino , Morpholino group, 4-fluorophenyl piperazino group may be substituted with 1 or more groups selected from the group consisting of carboxyl group and lower alkoxycarbonyl group; when R ¹ is a lower alkylcarbonyl amino group The lower alkylcarbonylamino group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkoxycarbonyl group and a cyano group; when R ¹ is an aminocarbonyl group, the aminocarbonyl The group may be substituted with one or more groups selected from the group consisting of a hydrogen atom, a lower alkyl group and a lower alkoxy group, and the lower alkyl group is selected from the group consisting of a carboxyl group and a lower alkoxycarbonyl group Optionally substituted by one or more groups selected; p is 0, 1 It indicates 2 or 3; when p is 2 or 3, R ¹ may be the same or different.

The present invention also provides
2-aminocarbonylamino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2,3,4-trimethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-methoxypyridin-3-yl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-isopropylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-ethylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methylthiophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-ethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-trifluoromethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [3-[(2-cyanoacetyl) amino] phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (2-propoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2,4-dimethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-dimethylaminophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-methylthiophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [4- (4-morpholinyl) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (2-hydroxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (3-hydroxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-cyanophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [2- (2-ethoxy-2-oxoethoxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- [2- (2-propen-1-yloxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- (3-carboxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [3-[[(carboxymethyl) amino] carbonyl] phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- [2- (carboxymethoxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-hydroxymethylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-chlorophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5-[(1,1′-biphenyl) -3-yl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (3-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-dimethylaminophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-propionylphenyl) thiophene-3-carboxamide,
It consists of 2-aminocarbonylamino-5- (2-acetyl-4-hydroxyphenyl) thiophene-3-carboxamide and 2-aminocarbonylamino-5- (3-acetyl-4-hydroxyphenyl) thiophene-3-carboxamide A JAK3 inhibitor containing at least one compound selected from the group or a salt thereof as an active ingredient is also provided.

  The JAK3 inhibitor of the present invention is a disease in which JAK3 is involved, such as autoimmune disease, keratitis, conjunctivitis, blepharitis, dry eye syndrome (also called “dry eye”), allergic conjunctivitis, anterior uvea Inflammation, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular macular disease, proliferative vitreoretinopathy, retinitis pigmentosa, central retinal vein occlusion, retinal vein occlusion, uveitis, etc. It is expected to be useful as a preventive and / or therapeutic agent.

The present invention also provides
2-aminocarbonylamino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2,3,4-trimethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-methoxypyridin-3-yl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-isopropylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-ethylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methylthiophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-ethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-trifluoromethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [3-[(2-cyanoacetyl) amino] phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (2-propoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2,4-dimethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-dimethylaminophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-methylthiophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [4- (4-morpholinyl) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (2-hydroxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (3-hydroxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-cyanophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [2- (2-ethoxy-2-oxoethoxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- [2- (2-propen-1-yloxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- (3-carboxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [3-[[(carboxymethyl) amino] carbonyl] phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- [2- (carboxymethoxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-hydroxymethylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-chlorophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5-[(1,1′-biphenyl) -3-yl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (3-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-dimethylaminophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-propionylphenyl) thiophene-3-carboxamide,
It consists of 2-aminocarbonylamino-5- (2-acetyl-4-hydroxyphenyl) thiophene-3-carboxamide and 2-aminocarbonylamino-5- (3-acetyl-4-hydroxyphenyl) thiophene-3-carboxamide A compound selected from the group or a salt thereof is also provided.

  The present invention further provides a pharmaceutical composition containing the compound or salt of the present invention described above.

  The thiophene derivative having a ureido group and an aminocarbonyl group as a substituent, or a salt thereof, which is a compound of the present invention, has excellent JAK3 inhibitory activity. Therefore, the compound of the present invention is used for diseases in which JAK3 is involved, such as autoimmune diseases, keratitis, conjunctivitis, blepharitis, dry eye syndrome (also called “dry eye”), allergic conjunctivitis, anterior uveitis Age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular macular dysfunction, proliferative vitreoretinopathy, retinitis pigmentosa, central retinal vein occlusion, branch retinal vein occlusion, uveitis, etc. It is expected to be useful as a prophylactic and / or therapeutic agent.

  Definitions of terms (atoms, groups, rings, etc.) used in this specification will be described in detail below. Moreover, when the definition of the following words is applied mutatis mutandis to the definition of another wording, the preferable range and especially preferable range of each definition can also apply mutatis mutandis.

“Halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The “lower alkyl group” refers to a linear or branched alkyl group having 1 to 8, preferably 1 to 6 carbon atoms. Specific examples include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, isopropyl group, isobutyl group, sec-butyl group. , Tert-butyl group, isopentyl group and the like.

  The “lower alkenyl group” refers to a straight or branched alkenyl group having 2 to 8, preferably 2 to 6 carbon atoms. Specific examples include vinyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, isopropenyl group, 2-methyl-1-propenyl group, 2-methyl-2-butenyl group and the like. .

  The “lower alkynyl group” refers to a straight or branched alkynyl group having 2 to 8, preferably 2 to 6 carbon atoms. Specific examples include ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octynyl group, isobutynyl group, isopentynyl group and the like.

  The “lower cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.

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

  The “heterocyclic group” is a saturated or unsaturated monocyclic heterocycle having 1 or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring (preferably 1 or 2 A saturated or unsaturated monocyclic hetero 5- or 6-membered ring having 3 to 5 carbon atoms, or a bicyclic or tricyclic fused polycyclic heterocycle (preferably 1 Or a residue obtained by removing one hydrogen atom from a bicyclic or tricyclic fused polycyclic heterocyclic ring having 7 to 13 carbon atoms and having 2 heteroatoms in the ring.

  Specific examples of the `` saturated monocyclic heterocycle '' include a pyrrolidine ring having a nitrogen atom in the ring, a pyrazolidine ring, an imidazolidine ring, a triazolidine ring, a piperidine ring, a hexahydropyridazine ring, a hexahydropyrimidine ring, a piperazine ring, Homopiperidine ring, homopiperazine ring, etc. Tetrahydrothiophene ring, tetrahydrothiopyran ring, etc. that have sulfur atom in the ring, such as tetrahydrofuran ring, tetrahydropyran ring, etc. that have oxygen atom in the ring in the ring Examples thereof include thiazolidine rings, isothiazolidine rings, and thiomorpholine rings having nitrogen and sulfur atoms in the ring, such as oxazolidine ring, isoxazolidine ring, and morpholine ring.

  In addition, the saturated monocyclic heterocycle is condensed with a benzene ring or the like to form a dihydroindole ring, a dihydroindazole ring, a dihydrobenzimidazole ring, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, a tetrahydrocinnoline ring, a tetrahydrophthalazine ring, Tetrahydroquinazoline ring, tetrahydroquinoxaline ring, dihydrobenzofuran ring, dihydroisobenzofuran ring, chroman ring, isochroman ring, dihydrobenzothiophene ring, dihydroisobenzothiophene ring, thiochroman ring, isothiochroman ring, dihydrobenzoxazole ring, dihydrobenzoiso Oxazole ring, dihydrobenzoxazine ring, dihydrobenzothiazole ring, dihydrobenzoisothiazole ring, dihydrobenzothiazine ring, xanthene ring, 4a- Carbazole ring, may form a 2 fused polycyclic heterocyclic cyclic or tricyclic, such as perimidine ring.

  Specific examples of “unsaturated monocyclic heterocycle” include dihydropyrrole ring, pyrrole ring, dihydropyrazole ring, pyrazole ring, dihydroimidazole ring, imidazole ring, dihydrotriazole ring, triazole ring having a nitrogen atom in the ring, Oxygen atoms in the ring such as tetrahydropyridine ring, dihydropyridine ring, pyridine ring, tetrahydropyridazine ring, dihydropyridazine ring, pyridazine ring, tetrahydropyrimidine ring, dihydropyrimidine ring, pyrimidine ring, tetrahydropyrazine ring, dihydropyrazine ring, pyrazine ring Dihydrofuran ring, furan ring, dihydropyran ring, pyran ring, etc. having a sulfur atom in the ring, such as dihydrothiophene ring, thiophene ring, dihydrothiopyran ring, thiopyran ring, etc. Loxazole ring, oxazole ring, dihydroisoxazole ring, isoxazole ring, dihydrooxazine ring, oxazine ring, dihydrothiazole ring having nitrogen and sulfur atoms in the ring, thiazole ring, dihydroisothiazole ring, isothiazole ring, Examples include a dihydrothiazine ring and a thiazine ring.

  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, phenant. Lysine ring, dihydrocinnoline ring, cinnoline ring, dihydrophthalazine ring, phthalazine ring, dihydroquinazoline ring, quinazoline ring, dihydroquinoxaline ring, quinoxaline ring, benzofuran ring, isobenzofuran ring, chromene ring, isochromene ring, benzothiophene ring, Isobenzothiophene ring, thiochromene ring, isothiochromene ring, benzoxazole ring, benzoisoxazole ring, benzoxazine ring, benzothiazole ring, benzoisothiazole ring, benzothiazine ring, phenoxanthine ring A bicyclic or tricyclic condensed polycyclic heterocycle such as a carbazole ring, β-carboline ring, phenanthridine ring, acridine ring, phenanthroline ring, phenazine ring, phenothiazine ring, phenoxazine ring may be formed. .

  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 group, ethoxy group, n-propoxy group, n-butoxy group, n-pentoxy group, n-hexyloxy group, n-heptyloxy group, n-octyloxy group, isopropoxy group, isobutoxy group, A sec-butoxy group, a tert-butoxy group, an isopentoxy group, and the like can be given.

  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 group etc. are mentioned.

  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 a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, a cyclooctyloxy group, 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 group, naphthoxy group, anthryloxy group, phenanthryloxy group 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 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 a methylamino group, an ethylamino group, a propylamino group, a dimethylamino group, a diethylamino group, and an ethyl (methyl) amino group.

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

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

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

“Amino group amide” refers to an amide formed from an amino group and a carboxylic acid. Here, the carboxylic acids are R ^a COOH (R ^a is a hydrogen atom, ^a lower alkyl group which may have a substituent, an 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, a carbocyclic carboxylic acid, a heterocyclic carboxylic acid, and the like. Indicates acid and the like. In addition, acid anhydrides [(R ^a CO) ₂ O] of these carboxylic acids and acid halides (R ^a COX, X represents a halogen atom) are also included in the “carboxylic acids”. Specific examples include saturated aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and vivalic 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; carbocyclic carboxylic acids such as benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, and toluic acid Acids: heterocyclic carboxylic acids such as furan carboxylic acid, thiophene carboxylic acid, nicotinic acid, and isonicotinic acid; acid anhydrides such as acetic anhydride.

  The “lower alkylcarbonylamino group” is a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkylcarbonyl group or one hydrogen atom of an amino group is a lower alkylcarbonyl group and the other hydrogen atom is lower A group substituted with an alkyl group, a lower alkenyl group or a lower alkynyl group is shown. Specific examples include methylcarbonylamino group, ethylcarbonylamino group, n-propylcarbonylamino group, n-butylcarbonylamino group, n-pentylcarbonylamino group, n-hexylcarbonylamino group, n-heptylcarbonylamino group, n -Octylcarbonylamino group, isopropylcarbonylamino group, isobutylcarbonylamino group, sec-butylcarbonylamino group, tert-butylcarbonylamino group, isopentylcarbonylamino group, dimethylcarbonylamino group, methylcarbonyl (methyl) amino group, methyl Examples thereof include a carbonyl (vinyl) amino group and a methylcarbonyl (ethynyl) amino group.

“Amino group sulfonamide” refers to a sulfonamide formed from an amino group and sulfonic acids. Here, the sulfonic acids are R ^a SO ₃ H (R ^a is a hydrogen atom, ^a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. A saturated aliphatic monosulfonic acid, a saturated aliphatic disulfonic acid, an unsaturated aliphatic sulfonic acid, a carbocyclic sulfonic acid, a heterocyclic ring, and the like. Sulfonic acid and the like. The sulfonic acid anhydrides [(R ^a SO ₂ ) ₂ O] and acid halides (R ^a SO ₂ Hal, Hal represents a halogen atom) are also included in the “sulfonic acids”. Examples of sulfonic acids include p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, methanesulfonyl chloride, and the like.

  The “lower alkylsulfonylamino group” is a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkylsulfonyl group or one hydrogen atom of an amino group is a lower alkylsulfonyl group and the other hydrogen atom is lower A group substituted with an alkyl group, a lower alkenyl group or a lower alkynyl group is shown. Specific examples include methylsulfonylamino group, ethylsulfonylamino group, n-propylsulfonylamino group, n-butylsulfonylamino group, n-pentylsulfonylamino group, n-hexylsulfonylamino group, n-heptylsulfonylamino group, n -Octylsulfonylamino group, isopropylsulfonylamino group, isobutylsulfonylamino group, sec-butylsulfonylamino group, tert-butylsulfonylamino group, isopentylsulfonylamino group, dimethylsulfonylamino group, methylsulfonyl (methyl) amino group, methyl A sulfonyl (vinyl) amino group, a methylsulfonyl (ethynyl) amino group, etc. are mentioned.

  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 group, ethylthio group, n-propylthio group, n-butylthio group, n-pentylthio group, n-hexylthio group, isopropylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, isopentyl group. And a ruthio group.

  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 a phenylthio group, a naphthylthio group, an anthrylthio group, a phenanthrylthio group, and the like.

  The “lower alkylsulfonyl group” refers to a group in which a hydroxy group of a sulfonic acid group is substituted with a lower alkyl group. Specific examples include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, n-butylsulfonyl group, n-pentylsulfonyl group, n-hexylsulfonyl group, isopropylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, Examples thereof include a tert-butylsulfonyl group and an isopentylsulfonyl 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 group, ethylcarbonyl group, n-propylcarbonyl group, n-butylcarbonyl group, n-pentylcarbonyl group, n-hexylcarbonyl group, isopropylcarbonyl group, isobutylcarbonyl group, sec-butylcarbonyl group, Examples thereof include a tert-butylcarbonyl group and an isopentylcarbonyl 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 group, naphthylcarbonyl group, anthrylcarbonyl group, phenanthrylcarbonyl group and the like.

  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 group, ethoxycarbonyl group, n-propoxycarbonyl group, n-butoxycarbonyl group, n-pentoxycarbonyl group, n-hexyloxycarbonyl group, n-heptyloxycarbonyl group, n-octyloxycarbonyl. Group, isopropoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, isopentoxycarbonyl 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 a phenoxycarbonyl group, naphthoxycarbonyl group, anthryloxycarbonyl group, phenanthryloxycarbonyl group, and the like.

  The “lower alkylcarbonyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkylcarbonyl group. Specific examples include methylcarbonyloxy group, ethylcarbonyloxy group, n-propylcarbonyloxy group, n-butylcarbonyloxy group, n-pentylcarbonyloxy group, n-hexylcarbonyloxy group, n-heptylcarbonyloxy group, n -Octylcarbonyloxy group, isopropylcarbonyloxy group, isobutylcarbonyloxy group, sec-butylcarbonyloxy group, tert-butylcarbonyloxy group, isopentylcarbonyloxy group and the like can be mentioned.

  The “arylcarbonyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with an arylcarbonyl group. Specific examples include a phenylcarbonyloxy group, a naphthylcarbonyloxy group, an anthrylcarbonyloxy group, a phenanthrylcarbonyloxy group, and the like.

  The “aminocarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with an amino 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 a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, a dimethylaminocarbonyl group, a diethylaminocarbonyl group, and an ethylmethylaminocarbonyl group.

The “lower alkyl group optionally having substituent (s)” or “lower alkenyl group optionally having substituent (s)” may have one or more substituents selected from the following α ¹ group. A preferable “lower alkyl group” or “lower alkenyl group” is shown.

[Α ¹ group]
Halogen atom, lower cycloalkyl group, aryl group, heterocyclic group, hydroxy group, lower alkoxy group, lower alkoxy group substituted by halogen atom, lower alkenyloxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy Group, amino group, lower alkylamino group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, formyl group, lower alkylcarbonyl group, arylcarbonyl group, carboxy group, lower alkoxycarbonyl group, aryloxycarbonyl group, A lower alkylcarbonyloxy group, an arylcarbonyloxy group, a mercapto group, a lower alkylthio group, an arylthio group, a nitro group and a cyano group;

The “aryl group optionally having substituent (s)” or “heterocyclic group optionally having substituent (s)” may have one or more substituents selected from the following β ¹ group: An “aryl group” or a “heterocyclic group” is shown.

[Β ¹ group]
A halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a lower alkenyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, a lower alkoxy group, a lower alkoxy group substituted with a halogen atom, Lower alkenyloxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, amino group, lower alkylamino group, lower cycloalkylamino group, arylamino group, heterocyclic amino group, formyl group, lower alkylcarbonyl group , Arylcarbonyl group, carboxy group, lower alkoxycarbonyl group, aryloxycarbonyl group, lower alkylcarbonyloxy group, arylcarbonyloxy group, mercapto group, lower alkylthio group, arylthio group, nitro group and cyano group.

  The “plural groups” as used in the present invention may be the same or different, and each group represents two or more groups at the substitution site, and the number of substitutions or less. The number is preferably two. Further, a hydrogen atom and a halogen atom are also included in the concept of “group”.

  The “JAK3 inhibitor” in the present invention means a pharmaceutical composition containing at least one of the compounds of the present invention as an active ingredient.

  The “prophylactic and / or therapeutic agent” as used in the present invention means a drug for preventing and / or treating a disease.

  In the present invention, “disease associated with JAK3” is, for example, autoimmune disease, rheumatoid arthritis, psoriasis, osteoarthritis, osteoporosis, spondyloarthritis, keratitis, keratoconjunctivitis, conjunctivitis, blepharitis, dry eyeball Syndrome (also called “dry eye”), allergic conjunctivitis, anterior uveitis, inflammation after anterior surgery of the anterior eye, ocular tissue transplant rejection, age-related macular degeneration (early age-related macular degeneration, atrophic addition) Age-related macular degeneration and / or wet age-related macular degeneration), diabetic retinopathy, diabetic macular edema, neovascular macular disease, idiopathic macular degeneration, proliferative vitreoretinopathy, retinitis pigmentosa, central retinal vein occlusion , Central retinal artery occlusion, branch retinal vein occlusion, branch retinal artery occlusion, inflammation or degeneration due to retinal detachment or trauma, inflammation after posterior eye surgery, retinitis, uveitis, strong Meningitis, optic neuritis, etc. It is.

  In addition, the specific disease mentioned above is for understanding this invention better, and does not limit the scope of the present invention.

  The “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, glucone Acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, Salts with organic acids such as trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid, quaternary ammonium salts with methyl bromide, methyl iodide, etc. , Salts with halogen ions such as bromine ion, chlorine ion and iodine ion, lithium, sodium, potassium Salts with alkali metals such as um, salts with alkaline earth metals such as calcium and magnesium, metals 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-propanediol, procaine, N, N-bis (phenylmethyl)- And salts with organic amines such as 1,2-ethanediamine.

The compounds of the present invention may take the form of hydrates or solvates.
When a geometric isomer or an optical isomer exists in the compound of the present invention, the isomer is also included in the scope of the present invention.

  When proton tautomerism exists in this invention compound, the tautomer is also contained in this invention.

  When a crystal polymorph and a crystal polymorph group (crystal polymorph system) exist in the compound of the present invention, those crystal polymorphs and crystal polymorph groups (crystal polymorph system) are also included in the present invention. Here, the crystal polymorphism group (crystal polymorphism system) means that the crystal form changes depending on the conditions and states (including the formulated state in this state) such as the production, crystallization, and storage of these crystals. Means the individual crystal forms at each stage and the whole process.

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

  (A1) A represents the following general formula (2a), (2b), (2c), (2d), (2e) or (2f); and / or

(A2) R ¹ is a hydrogen atom, halogen atom, lower alkyl group, lower alkenyl group, phenyl group, hydroxy group, lower alkoxy group, lower alkenyloxy group, phenoxy group, amino group, lower alkylamino group, morpholino group, amino An amide of a group, a sulfonamido of an amino group, a mercapto group, a lower alkylthio group, a lower alkylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, an aminocarbonyl group or a cyano group; and / or (a3) R ² is a hydrogen atom And / or (a4) R ³ and R ⁴ are the same or different and represent a hydrogen atom, a halogen atom or a lower alkyl group; and / or (a5) R ⁵ is a hydroxy group or a lower alkoxy group. And / or (a6) R ¹ is lower alkyl The lower alkyl group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkylcarbonyloxy group and a morpholino group; and / or (a7) R ¹ is When it is a lower alkoxy group, the lower alkoxy group is one or more groups selected from the group consisting of a halogen atom, a lower alkylamino group, a morpholino group, a 4-fluorophenylpiperazino group, a carboxyl group, and a lower alkoxycarbonyl group. And / or (a8) when R ¹ is an amide of an amino group, the amide of the amino group is one or more selected from the group consisting of a hydroxy group, a lower alkoxycarbonyl group and a cyano group may be substituted by the group; and / or (a9) when R ¹ is an amino group, The aminocarbonyl group may be substituted with one or more groups selected from the group consisting of a hydrogen atom, a lower alkyl group and a lower alkoxy group, and the lower alkyl group is a group consisting of a carboxyl group or a lower alkoxycarbonyl group. And / or (a10) p represents 0, 1, 2 or 3; and / or (a11) when p is 2 or 3, R1 May be the same or different.

  That is, the compound of the present invention is a compound represented by the general formula (1), wherein (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8) , (A9), (a10) and (a11), or a combination thereof, or a salt thereof.

  (B) A preferred example of A in the compound of the present invention includes a case where A represents the following general formula (2a) in the compound represented by the general formula (1).

  In the present invention, a compound satisfying the combination of the condition (b) and the condition (a) or a salt thereof is preferable.

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

  (C1) A represents the following general formula (2a); and / or

(C2) R ¹ is hydrogen atom, halogen atom, lower alkyl group, phenyl group, hydroxy group, lower alkoxy group, lower alkenyloxy group, phenoxy group, lower alkylamino group, morpholino group, lower alkylcarbonylamino group, lower alkyl Represents a sulfonylamino group, a lower alkylthio group, a lower alkylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylaminocarbonyl group, an N-methoxy-N-methylaminocarbonyl group or a cyano group; and / or (c3) R ^{When 1} is a lower alkyl group, the lower alkyl group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkylcarbonyloxy group and a morpholino group; and / or (c4) when R ¹ is a lower alkoxy group The lower alkoxy group may be substituted with one or more groups selected from the group consisting of a halogen atom, a lower alkylamino group, a morpholino group, a 4-fluorophenylpiperazino group, a carboxyl group and a lower alkoxycarbonyl group. Well; and / or (c5) when R ¹ is a lower alkylcarbonylamino group, the lower alkylcarbonylamino group is substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkoxycarbonyl group and a cyano group And / or (c6) when R ¹ is an aminocarbonyl group, the aminocarbonyl group is substituted with one or more groups selected from the group consisting of a hydrogen atom, a lower alkyl group, and a lower alkoxy group. Further, the lower alkyl group may be a carboxyl group and a lower group. Optionally substituted with one or more groups selected from the group consisting of secondary alkoxycarbonyl groups; and / or (c7) p represents 0, 1, 2 or 3; and / or (c8) p is When 2 or 3, R ¹ may be the same or different.

  That is, in the compound represented by the general formula (1), 1 selected from the above (c1), (c2), (c3), (c4), (c5), (c6), (c7) and (c8) Or the compound which consists of each 2 or more combination, or its salt is more preferable.

  A compound satisfying the combination of the condition (c) and the condition (a) and / or (b) or a salt thereof is also within the scope of the present invention.

  (D) Preferred specific examples of the compound of the present invention include the following compounds or salts thereof.

2-aminocarbonylamino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (2,3,4-trimethoxyphenyl) thiophene-3-carboxamide 2-amino Carbonylamino-5- (4-methoxypyridin-3-yl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-methylphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- ( 2-Isopropylphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-ethylphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-methylthiophenyl) thiophene-3-carboxamide・ 2-aminoca Bonylamino-5- (2-ethoxyphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-trifluoromethoxyphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-acetyl) Phenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- [3-[(2-cyanoacetyl) amino] phenyl] thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-propoxyphenyl) Thiophene-3-carboxamide 2-aminocarbonylamino-5- (2,4-dimethoxyphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (4-dimethylaminophenyl) thiophene-3-carboxamide 2 -Ami Carbonylamino-5- (4-methylthiophenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- [4- (4-morpholinyl) phenyl] thiophene-3-carboxamide 2-aminocarbonylamino-5- [ 4- (1-methyl-1H-pyrazol-4-yl) phenyl] thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-hydroxyphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5 -(3-hydroxyphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-cyanophenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- [2- (2-ethoxy-2) -Oxoethoxy) phenyl] thiophene -3-carboxamide 2-aminocarbonylamino-5- [2- (2-propen-1-yloxy) phenyl] thiophene-3-carboxamide 2-aminocarbonylamino-5- (3-carboxyphenyl) thiophene-3 2-carboxamide 2-aminocarbonylamino-5- [3-[[(carboxymethyl) amino] carbonyl] phenyl] thiophene-3-carboxamide 2-aminocarbonylamino-5- [2- (carboxymethoxy) phenyl] thiophene -3-Carboxamide 2-aminocarbonylamino-5- (2-hydroxymethylphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-methoxyphenyl) thiophene-3-carboxamide 2-aminocarbonyl amino 5- (2-chlorophenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5-[(1,1′-biphenyl) -3-yl] thiophene-3-carboxamide 2-aminocarbonylamino-5- ( 3-acetylphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (4-acetylphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-dimethylaminophenyl) thiophene-3- Carboxamide 2-aminocarbonylamino-5- (2-propionylphenyl) thiophene-3-carboxamide 2-aminocarbonylamino-5- (2-acetyl-4-hydroxyphenyl) thiophene-3-carboxamide 2-aminocarbonyl Amino-5- (3 Of Acetyl-4-hydroxyphenyl) thiophene-3-carboxamide compounds of the present invention are those novel compounds listed in (d), the present invention also provides for the compound or a salt thereof itself. Furthermore, the present invention also provides a pharmaceutical composition containing these compounds or salts thereof.

The compound of the present invention can be produced by the following method. In addition, each specific manufacturing method is demonstrated in detail by the item of the below-mentioned Example [production example]. Moreover, these illustrations are for understanding the present invention better and are not intended to limit the scope of the present invention. In the following synthesis route, R represents an arbitrary substituent, TFA represents trifluoroacetic acid, Hal represents a halogen atom, NaOH represents sodium hydroxide, and Boc ₂ O represents di-tert-dicarbonate. Butyl, NBS stands for N-bromosuccinimide.

(Synthesis route 1)
The compound (I) of the present invention can be synthesized according to Synthesis Route 1. That is, after reacting compound (II) and trichloroacetyl isocyanate in an organic solvent such as acetonitrile at room temperature to 40 ° C. for 1 hour to 6 hours, an ammonia-methanol solution was further added, and 0 ° C. to room temperature for 1 hour. The compound (I) of the present invention can be obtained by reacting for 24 hours.

(Synthesis route 2)
This invention compound (I) is compoundable according to the synthetic pathway 2. That is, boronic acid ester (IV) such as boronic acid or boronic acid pinacol ester corresponding to compound (III) in an organic solvent such as N, N-dimethylformamide, or a mixed solvent of organic solvent and water, cesium carbonate In the presence of a base such as tetrakis (triphenylphosphine) palladium (0) and the like, the compound (I) of the present invention can be obtained by reacting at 70 to 100 ° C. for 1 to 6 hours.

(Synthesis route 3)
The compound of the present invention (I-2a-5; a compound in which A is (2a), R ¹ is COOH and p is 1 in the general formula (1)), (I-2a-6; in the general formula (1) A compound in which A is (2a), R ¹ is CONHCH ₂ COOH and p is 1, and (I-2a-7; in the general formula (1), A is (2a), R ¹ is OCH ₂ COOH and p is 1) and (I-2a-8; in the above general formula (1), A is (2a), R ¹ is CH ₂ OH and p is 1), and can be synthesized according to synthetic route 3. it can. That is, sodium hydroxide or ammonia-methanol solution in an organic solvent such as methanol is added to each of the compounds (I-2a-1) to (I-2a-4), and the temperature is from room temperature to 65 ° C. for 1 hour to 24 hours. The compounds (I-2a-5) to (I-2a-8) of the present invention can be obtained by the reaction.

(Synthesis route 4)
Compound (II) can be produced according to synthetic route 4. That is, boronic acid ester (IV) such as boronic acid or boronic acid pinacol ester corresponding to compound (V) is mixed in a mixed solvent of an organic solvent such as 1,4-dioxane and water, or a mixed solvent of ethanol and toluene. Compound (VI) is obtained by reacting at 70 to 100 ° C. for 1 to 6 hours in the presence of a base such as cesium carbonate and a catalyst such as tetrakis (triphenylphosphine) palladium (0). Further, compound (II) can be obtained by adding trifluoroacetic acid to compound (VI) in an organic solvent such as dichloromethane and reacting at 0 ° C. to room temperature for 1 to 6 hours.

(Synthesis route 5)
Compound (VI-2a-1; Compound (VI) wherein A is (2a), R ¹ is NH ₂ and p is 1), (VI-2a-2; Compound (VI) where A is (2a) , R ¹ is COOR and p is 1), (VI-2a-3; in compound (VI), A is (2a), R ¹ is CH ₂ OH and p is 1) and (VI- 2a-4; Compound (VI) wherein A is (2a), R ¹ is OH and p is 1) can be synthesized according to Synthesis Route 5.

  That is, boronic acid esters (IV-a) to (IV-d) such as boronic acid or boronic acid pinacol ester corresponding to compound (V) are mixed with an organic solvent such as 1,4-dioxane and water or ethanol Compound (VI-) by reacting in a mixed solvent of toluene and toluene at 70 to 100 ° C. for 1 to 6 hours in the presence of a base such as cesium carbonate and a catalyst such as tetrakis (triphenylphosphine) palladium (0). 2a-1) to (VI-2a-4) are obtained.

  Compound (VI-2a-5) is compound (VI-2a-1) and various carboxylic acids in an organic solvent such as N, N-dimethylformamide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride It can be obtained by reacting in the presence of a salt and 1-hydroxybenzotriazole overnight at room temperature.

  Compound (VI-2a-6) can be obtained by adding sodium hydroxide to compound (VI-2a-2) in an organic solvent such as methanol and reacting at room temperature to 65 ° C. for 1 to 24 hours. it can. Further, compound (VI-2a-6) and various amine compounds are present in an organic solvent such as N, N-dimethylformamide in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole. The compound (VI-2a-7) can be obtained by reacting at room temperature overnight.

  Compound (VI-2a-8) is reacted by adding a base such as acetic anhydride and 4-dimethylaminopyridine to an N, N-dimethylformamide solution of compound (VI-2a-3) for 1 to 24 hours. Obtainable.

  Compounds (VI-2a-9) and (VI-2a-10) are prepared by mixing compound (VI-2a-4) and various halogen compounds in a solvent such as tetrahydrofuran or N, N-dimethylformamide, potassium carbonate, cesium carbonate, etc. In the presence of a base at room temperature for 1 to 4 days. Further, compound (VI-2a-11) is a reaction of compound (VI-2a-10) and various amine compounds such as morpholine in an organic solvent such as N, N-dimethylformamide at room temperature to 100 ° C. for 1 day to 4 days. Can be obtained.

(Synthesis route 6)
Compound (V) can be produced according to synthesis route 6. That is, 2,5-dihydroxy-1,4-dithiane (VII) and 2-cyanoacetamide are reacted in an organic solvent such as ethanol with a base such as triethylamine and allowed to react at room temperature to 70 ° C. for 1 to 6 hours. Gives compound (VIII). Compound (VIII) and di-tert-butyl dicarbonate are reacted in an organic solvent such as tetrahydrofuran in the presence of a base such as N, N-diisopropylethylamine at 50 to 100 ° C. for 1 to 4 days. IX) is obtained. Compound (V) can be obtained by reacting compound (IX) and N-bromosuccinimide in an organic solvent such as N, N-dimethylformamide at 0 ° C. to room temperature for 1 to 3 hours.

(Synthesis route 7)
Compound (III) can be produced according to synthetic route 7. That is, compound (VIII) and trichloroacetyl isocyanate are reacted in an organic solvent such as acetonitrile at room temperature to 40 ° C. for 1 hour to 6 hours, and then an ammonia-methanol solution is further added, and 0 ° C. to room temperature for 1 hour. For 24 hours to give compound (X). Compound (III) can be obtained by reacting compound (X) with N-bromosuccinimide in an organic solvent such as N, N-dimethylformamide at 0 ° C. to room temperature for 1 to 3 hours.

  In order to find a new pharmacological action of the compound of the present invention, an inhibitory activity test for JAK3 in the test system for measuring the JAK3 inhibitory activity of the compound of the present invention was carried out, and the effect of the compound of the present invention in these tests was evaluated. The details thereof will be described in detail in the Examples [Pharmacological Tests] section below, but the present inventors have found that the compounds of the present invention have excellent JAK3 inhibitory activity.

  Therefore, the compound of the present invention having JAK3 inhibitory activity is a disease in which JAK3 is involved, such as autoimmune disease, keratitis, conjunctivitis, blepharitis, dry eye syndrome (also called “dry eye”), allergic conjunctivitis, Anterior uveitis, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular macular disease, proliferative vitreoretinopathy, retinitis pigmentosa, central retinal vein occlusion, branch retinal vein occlusion, It is expected to be useful as a preventive and / or therapeutic agent for uveitis and the like.

  The compound of the present invention can be administered orally or parenterally. Examples of dosage forms include oral administration, topical ocular administration (instillation administration, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, subtenon administration, etc.), intravenous administration, transdermal administration, etc. A pharmaceutically acceptable additive can be appropriately selected and used, and can be formulated into a dosage form suitable for the dosage form.

  Examples of the dosage form include tablets, capsules, granules, powders, and the like in the case of oral preparations, and parenterals include injections, eye drops, eye ointments, insertion agents, preparations for intraocular implants, and the like. Can be mentioned.

  For example, in the case of tablets, capsules, granules, powders, etc., excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium Disintegrants such as hydroxypropyl cellulose, ethyl cellulose, gum arabic, starch, partially pregelatinized starch, polyvinyl pyrrolidone, polyvinyl alcohol; stearic acid Lubricants such as magnesium, calcium stearate, talc, hydrous silicon dioxide, hydrogenated oil; refined sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, Le cellulose, ethyl cellulose, a coating agent such as polyvinylpyrrolidone; citric acid, aspartame, ascorbic acid, and suitably selected depending on, for example, required a flavoring agent such as menthol, can be formulated.

  The injection is appropriately selected according to need such as an isotonic agent such as sodium chloride; a buffering agent such as sodium phosphate; a surfactant such as polyoxyethylene sorbitan monooleate; a thickener such as methylcellulose. Can be used and formulated.

  Eye drops include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surface activity such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil Agents: Stabilizers such as sodium citrate and sodium edetate; preservatives such as benzalkonium chloride and paraben can be appropriately selected and used as necessary, and the pH is ophthalmic. There is no particular problem as long as it is within the range acceptable for the preparation, and a pH range of 4 to 8 is desirable.

  The eye ointment can be formulated using a commonly used base such as white petrolatum or liquid paraffin.

  The intercalator can be formulated using a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid, and if necessary, excipients, binders, stable An agent, a pH adjuster, and the like can be appropriately selected and used as necessary.

  Intraocular implant formulations can be formulated using biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, hydroxypropyl cellulose, and excipients as needed , Binders, stabilizers, pH adjusters and the like can be appropriately selected and used as necessary.

  The dose of the compound of the present invention can be appropriately selected according to the dosage form, patient symptoms, age, body weight and the like. For example, in the case of oral administration, 0.01 to 5000 mg, preferably 0.1 to 2500 mg, particularly preferably 0.5 to 1000 mg can be administered in 1 to several times per day. In the case of an injection, 0.00001-2000 mg, preferably 0.0001-1500 mg, particularly preferably 0.001-500 mg can be administered in one to several doses per day. In the case of eye drops, 0.00001 to 10% (w / v), preferably 0.0001 to 5% (w / v), particularly preferably 0.001 to 1% is applied once to several times a day. can do. In the case of an eye ointment, one containing 0.0001 to 2000 mg can be applied. In the case of an insertion agent or an intraocular implant preparation, one containing 0.0001 to 2000 mg can be inserted or implanted.

  Below, the manufacture example of this invention compound, a formulation example, and a pharmacological test are shown. In addition, these illustrations are for understanding this invention better, and do not limit the scope of the present invention.

[Production example]
Representative production examples of the compound of the present invention are shown below.

<Reference Example 1: 2-Aminothiophene-3-carboxamide (Reference Compound 1)>
Ethanol (60 mL) was added to 2,5-dihydroxy-1,4-dithiane (8.8 g, 58 mmol), 2-cyanoacetamide (7.2 g, 86 mmol), triethylamine (3.4 mL, 24 mmol) were added, The mixture was stirred at 50 to 60 ° C. under a nitrogen atmosphere for 2.5 hours. After cooling the insoluble matter after cooling, the filtrate was concentrated and the yellow solid obtained after adding a mixed solvent (60 mL, ethyl acetate / hexane = 1/1) and water (60 mL) to the resulting residue and filtering. This gave the title compound (8.9 g).

<Reference Example 2: 2- (tert-butoxycarbonylamino) thiophene-3-carboxamide (Reference Compound 2)>
2-Aminothiophene-3-carboxamide (Reference compound 1, 10.8 g, 76 mmol) to di-tert-butyl dicarbonate (25 g, 115 mmol), N, N-diisopropylethylamine (29.4 g, 228 mmol), tetrahydrofuran (250 mL) ) Was added and heated to reflux overnight under a nitrogen atmosphere. Di-tert-butyl dicarbonate (25 g, 115 mmol) was further added, and the mixture was heated to reflux for 2 days under a nitrogen atmosphere. After cooling, a portion of tetrahydrofuran was distilled off, and the resulting residue was dissolved in ethyl acetate, washed with hydrochloric acid, water and saturated brine, and then dried over magnesium sulfate. Purification by silica gel column chromatography (moving layer: ethyl acetate / n-hexane = 1/2) gave the title compound (8.7 g) as a pale yellow solid.

<Reference Example 3: 5-Bromo-2- (tert-butoxycarbonylamino) thiophene-3-carboxamide (Reference Compound 3)>
2- (tert-Butoxycarbonylamino) thiophene-3-carboxamide (Reference compound 2, 4.0 g, 17 mmol) was dissolved in N, N-dimethylformamide (40 mL), and N-bromosuccinimide (3. 3 g, 18 mmol) was added and the mixture was stirred for 1.5 hours under ice cooling in a nitrogen atmosphere. Ethyl acetate (150 mL) was added, and the mixture was washed with 1N hydrochloric acid, water and saturated brine, and dried over magnesium sulfate. Purification by silica gel column chromatography (mobile layer: ethyl acetate / n-hexane = 1/1) gave the title compound (4.5 g) as a pale yellow powder.

<Reference Example 4: 2- (tert-butoxycarbonylamino) -5- (2-isopropyloxyphenyl) thiophene-3-carboxamide (Reference compound 4-1)>
5-Bromo-2- (tert-butoxycarbonylamino) thiophene-3-carboxamide (Reference Compound 3, 0.20 g, 0.62 mmol) and 2-isopropyloxyphenylboronic acid (0.17 g, 0.93 mmol), carbonic acid Add cesium (0.30 g, 0.93 mmol), tetrakis (triphenylphosphine) palladium (0) (0.10 g, 0.09 mmol), ethanol (3 mL), toluene (3 mL) at 80 ° C. to 90 ° C. Stir in a nitrogen atmosphere for 1.5 hours. Ethyl acetate was added, washed with water and saturated brine, and dried over magnesium sulfate. Purification by silica gel column chromatography (mobile layer: ethyl acetate / n-hexane = 1 / 3-1 / 2) gave the title compound (71 mg) as a colorless oil.

  Hereinafter, reference compounds 4-2 to 4-34 were obtained according to the production method of Reference Example 4 using the corresponding boronic acid or boronic acid ester commercially available.

Reference Example 5: 2- (tert-Butoxycarbonylamino) -5- [3-[(2-cyanoacetyl) amino] phenyl] thiophene-3-carboxamide (Reference Compound 5-1)>
N, N-dimethylformamide (3 mL) was added to 2- (tert-butoxycarbonylamino) -5- (3-aminophenyl) thiophene-3-carboxamide (Reference compound 4-18, 0.10 g, 0.30 mmol). , Cyanoacetic acid (38 mg, 0.45 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (86 mg, 0.45 mmol), 1-hydroxybenzotriazole (60 mg, 0.45 mmol) were added. Stir overnight at room temperature under a nitrogen atmosphere. The reaction mixture was washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over magnesium sulfate. The resulting yellow solid was collected by filtration to give the title compound (77 mg).

  Reference compound 5-2 was obtained according to the production method of Reference Example 5 using Reference compound 4-18 and malonic acid monoethyl ester.

<Reference Example 6: 2- (tert-butoxycarbonylamino) -5- (3-carboxyphenyl) thiophene-3-carboxamide (Reference Compound 6-1)>
2- (tert-Butoxycarbonylamino) -5- (3-methoxycarbonylphenyl) thiophene-3-carboxamide (Reference compound 4-9, 0.55 g, 1.46 mmol) was added dioxane (5 mL) and methanol (1 mL). In addition, 1N aqueous sodium hydroxide solution (2.9 mL) was added, and the mixture was stirred at 40 ° C. to 45 ° C. under a nitrogen atmosphere overnight. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. The title compound (0.50 g) was obtained as a pale yellow solid by distilling off the solvent.

  Using Reference Compound 4-17, Reference Compound 6-2 was obtained according to the production method of Reference Example 6.

Reference Example 7: 2- (tert-Butoxycarbonylamino) -5- [3-[[(2-methoxy-2-oxoethyl) amino] carbonyl] phenyl] thiophene-3-carboxamide (Reference Compound 7-1)>
N, N-dimethylformamide (3 mL) was added to 2- (tert-butoxycarbonylamino) -5- (3-carboxyphenyl) thiophene-3-carboxamide (Reference compound 6-1, 0.10 g, 0.28 mmol). 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (80 mg, 0.42 mmol), 1-hydroxybenzotriazole (55 mg, 0.42 mmol), glycine methyl ester hydrochloride (55 mg, 0.44 mmol) , Triethylamine (45 mg, 0.44 mmol) was added and stirred overnight at room temperature under a nitrogen atmosphere. Ethyl acetate was added, and the mixture was washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over magnesium sulfate. The title compound (0.11 g) was obtained as a pale yellow solid by distilling off the solvent.

  Hereinafter, reference compounds 7-2 to 7-5 were obtained according to the production method of Reference Example 7 using amine corresponding to Reference Compound 6-2.

<Reference Example 8: 2- (tert-butoxycarbonylamino) -5- (2-propoxyphenyl) thiophene-3-carboxamide (Reference Compound 8-1)>
N, N-dimethylformamide (3 mL) was added to 2- (tert-butoxycarbonylamino) -5- (2-hydroxyphenyl) thiophene-3-carboxamide (Reference compound 4-31, 90 mg, 0.27 mmol), and carbonic acid was added. Cesium (130 mg, 0.40 mmol) and 2-iodopropane (70 mg, 0.40 mmol) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate. The title compound (51 mg) was obtained as a pale yellow oil by purifying the residue obtained by distilling off the solvent by silica gel column chromatography (ethyl acetate / n-hexane = 1/2).

  Reference compounds 8-2 to 8-3 were obtained according to the production method of Reference Example 8 using halogen compounds corresponding to Reference compound 4-31.

<Reference Example 9: 2- (tert-butoxycarbonylamino) -5- [2- (acetyloxymethyl) phenyl] thiophene-3-carboxamide (Reference Compound 9-1)>
N, N-dimethylformamide (2 mL) was added to 2- (tert-butoxycarbonylamino) -5- (2-hydroxymethylphenyl) thiophene-3-carboxamide (Reference compound 4-33, 56 mg, 0.16 mmol), Acetic anhydride (17 μL, 0.17 mmol) and 4-dimethylaminopyridine (22 mg, 0.17 mmol) were added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The title compound (56 mg) was obtained by distilling off the solvent.

  Using Reference Compound 4-32, Reference Compound 9-2 was obtained according to the production method of Reference Example 9.

Reference Example 10: 2- (tert-Butoxycarbonylamino) -5- [2- (2-ethoxy-2-oxoethoxy) phenyl] thiophene-3-carboxamide (Reference Compound 10-1)>
Tetrahydrofuran (3 mL) was added to 2- (tert-butoxycarbonylamino) -5- (2-hydroxyphenyl) thiophene-3-carboxamide (Reference compound 4-31, 50 mg, 0.15 mmol), and potassium carbonate (23 mg, 0 .16 mmol) and ethyl bromoacetate (20 μL, 0.18 mmol) were added and stirred overnight at room temperature under a nitrogen atmosphere. After adding water, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The title compound (68 mg) was obtained as a white solid by distilling off the solvent.

  Reference compound 10-2 was obtained according to the production method of Reference Example 10 using the halogen compound corresponding to Reference compound 4-31.

Reference Example 11: 2- (tert-Butoxycarbonylamino) -5- [2- (3-bromopropoxy) phenyl] thiophene-3-carboxamide (Reference Compound 11)>
N, N-dimethylformamide (5 mL) was added to 2- (tert-butoxycarbonylamino) -5- (2-hydroxyphenyl) thiophene-3-carboxamide (Reference compound 4-31, 50 mg, 0.15 mmol), and carbonic acid was added. Cesium (73 mg, 0.23 mmol) and 1,3-dibromopropane (46 μL, 0.45 mmol) were added and stirred overnight at room temperature under a nitrogen atmosphere. The mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate. The title compound (63 mg) was obtained as a white solid by purifying the residue obtained by distilling off the solvent by silica gel column chromatography (mobile layer; ethyl acetate / n-hexane).

Reference Example 12: 2- (tert-Butoxycarbonylamino) -5- [2- [3- (4-morpholino) propoxy] phenyl] thiophene-3-carboxamide (Reference Compound 12-1)>
2- (tert-Butoxycarbonylamino) -5- [2- (3-bromopropoxy) phenyl] thiophene-3-carboxamide (Reference compound 11, 62 mg, 0.14 mmol) was mixed with N, N-dimethylformamide (3 mL). In addition, morpholine (72 μL, 0.81 mmol) was added and stirred overnight at 50 ° C. under a nitrogen atmosphere. The white solid obtained by concentration was collected by filtration to give the title compound (40 mg).

  Reference compounds 12-2 to 12-3 were obtained according to the production method of Reference Example 12 using the amine corresponding to Reference compound 11.

<Reference Example 13: 2-amino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide (Reference compound 13-1)>
Dichloromethane (2 mL) was added to 2- (tert-butoxycarbonylamino) -5- (2-isopropyloxyphenyl) thiophene-3-carboxamide (Reference compound 4-1, 71 mg, 0.19 mmol), and then trifluoroacetic acid. (1 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. Purification by silica gel column chromatography (mobile layer: ethyl acetate / n-hexane = 1 / 2-2 / 1) gave the title compound (39 mg) as a colorless oil.

  Reference compounds 4-2 to 4-16, 4-20 to 4-32, 5-1, 5-2, 7-1 to 7-5, 8-1 to 8-3, 9-1 and 9- 2, 10-1, 10-2, 12-1 to 12-3 were used, and reference compounds 13-2 to 13-46 were obtained according to the production method of Reference Example 13.

<Reference Example 14: 2-amino-5- (3-methylphenyl) thiophene-3-carboxamide (Reference compound 14-1)>
5-Bromo-2- (tert-butoxycarbonylamino) thiophene-3-carboxamide (Reference compound 3, 0.20 g, 0.62 mmol) to 3-methylphenylboronic acid (0.13 g, 0.93 mmol), cesium carbonate (0.30 g, 0.93 mmol), tetrakis (triphenylphosphine) palladium (0) (0.10 g, 0.09 mmol), ethanol (3 mL), toluene (3 mL) were added, and nitrogen was added at 80 ° C. to 90 ° C. Stir for 1.5 hours under atmosphere. Ethyl acetate was added, washed with water and saturated brine, and dried over magnesium sulfate. Dichloromethane (2 mL) was added to the residue obtained by purification by silica gel column chromatography (mobile bed: ethyl acetate / n-hexane = 1 / 3-1 / 2), trifluoroacetic acid (1 mL) was added at room temperature. Stir for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The title compound (40 mg) was obtained as a colorless solid by washing the residue obtained by distilling off the solvent with chloroform.

  In the following, reference compounds 14-2 to 14-18 were obtained according to the production method of Reference Example 14 using the corresponding boronic acid or boronate ester commercially available.

<Reference Example 15: 2- (Aminocarbonylamino) thiophene-3-carboxamide (Reference Compound 15)>
Acetonitrile (65 mL) was added to 2-aminothiophene-3-carboxamide (Reference compound 1, 1.9 g, 13 mmol), followed by addition of trichloroacetyl isocyanate (1.8 mL, 15 mmol) and 1 at room temperature under a nitrogen atmosphere. Stir for hours. A 2 mol / L ammonia / methanol solution (20 mL) was added dropwise over 30 minutes, and the mixture was stirred overnight at room temperature. The precipitated white solid was collected by filtration to obtain the title compound (1.1 g).

Reference Example 16: 5-Bromo-2- (aminocarbonylamino) thiophene-3-carboxamide (Reference Compound 16)>
N, N-dimethylformamide (15 mL) was added to 2- (aminocarbonylamino) thiophene-3-carboxamide (reference compound 15, 560 mg, 3.1 mmol), and N-bromosuccinimide (600 mg, 3. 4 mmol) was added, and the mixture was stirred for 1 hour under ice cooling in a nitrogen atmosphere and overnight at room temperature. Ethyl acetate was added to the reaction solution, washed with water and saturated brine, and dried over magnesium sulfate. The title compound (537 mg) was obtained by distilling off the solvent.

<Reference Example 17: 2- (tert-Butoxycarbonylamino) -5- (2-propionylphenyl) thiophene-3-carboxamide (Reference Compound 17)>
After adding dioxane (2.5 mL) and water (0.5 mL) to 1- (2-bromophenyl) propan-1-one (0.18 g, 0.82 mmol), potassium acetate (0.12 g, 1.2. 23 mmol), bis (pinacolato) diborane (0.31 g, 1.23 mmol), tetrakis (triphenylphosphine) palladium (0) (0.1 g, 0.082 mmol) were added, and the mixture was stirred at 90 ° C. under a nitrogen atmosphere for 3 hours. did. Ethyl acetate was added, washed with saturated brine, and dried over magnesium sulfate. To the residue obtained by distilling off the solvent, 5-bromo-2- (tert-butoxycarbonylamino) thiophene-3-carboxamide (Reference compound 3, 0.10 g, 0.31 mmol), dioxane (2.5 mL), water (0.5 mL), cesium carbonate (0.15 g, 0.47 mmol), tetrakis (triphenylphosphine) palladium (0) (0.04 g, 0.03 mmol) were added, and a nitrogen atmosphere at 90 ° C. For 1 hour. Ethyl acetate was added, washed with saturated brine, and dried over magnesium sulfate. The title compound (94 mg) was obtained by refine | purifying the residue obtained by distilling a solvent off by silica gel column chromatography.

  Reference compounds 17-2 to 17-3 were obtained according to the production method of Reference Example 17 using various aryl halides, bis (pinacolato) diborane, and Reference Compound 3.

  Hereinafter, reference compounds 18-1 to 18-3 were obtained according to the production method of Reference Example 13 using reference compounds 17-1 to 17-3.

<Example 1: 2-aminocarbonylamino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide (Compound 1-1)>
Acetonitrile (3 mL) was added to 2-amino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide (Reference compound 13-1, 39 mg, 0.14 mmol), and then trichloroacetyl isocyanate (23 μL, 0.2 mL). 19 mmol) was added, and the mixture was stirred at 30 to 40 ° C. for 4 hours. 2 mol / L ammonia / methanol solution (0.16 mL) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. The title compound (28 mg) was obtained by filtering the light yellow solid obtained by adding chloroform to the residue which distilled the solvent off.

  Hereinafter, using reference compounds 13-2 to 13-46, 14-1 to 14-18, and 18-1 to 18-3, according to the production method of Example 1, compounds 1-2 to 1-67 Got.

<Example 2: 2-aminocarbonylamino-5- (3-carboxyphenyl) thiophene-3-carboxamide (Compound 2)>
To 2-aminocarbonylamino-5- (3-methoxycarbonylphenyl) thiophene-3-carboxamide (Compound 1-18, 25 mg, 0.078 mmol) was added 2 mL of methanol, and 1N aqueous sodium hydroxide solution (0.12 mL) was added. The mixture was stirred at 60 to 65 ° C. in a nitrogen atmosphere for 5 hours. 1N Hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. Dioxane (2 mL) was added to the residue obtained by evaporating the solvent, 1N aqueous sodium hydroxide solution (78 μL) and methanol (1 mL) were added, and the mixture was stirred at 60 ° C. to 65 ° C. overnight. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The title compound (7 mg) was obtained by filtering off the yellow solid obtained by distilling off the solvent.

<Example 3: 2-aminocarbonylamino-5- [3-[[(carboxymethyl) amino] carbonyl] phenyl] thiophene-3-carboxamide (Compound 3-1)>
2-Aminocarbonylamino-5- [3-[[(2-methoxy-2-oxoethyl) amino] carbonyl] phenyl] thiophene-3-carboxamide (Compound 1-28, 11 mg, 0.029 mmol) in methanol (1 mL) 1N aqueous sodium hydroxide solution (43 μL) was added, and the mixture was stirred at 40 ° C. to 50 ° C. in a nitrogen atmosphere for 4 hours. 1N Hydrochloric acid (1 mL) was added to acidify the reaction mixture, ethyl acetate and water were added, and the precipitated white solid was collected by filtration to give the title compound (4 mg).

  Hereinafter, compounds 3-2 and 3-3 were obtained according to the production method of Example 3, using Reference Compounds 1-56 and 1-29.

<Example 4: 2-aminocarbonylamino-5- (2-hydroxymethylphenyl) thiophene-3-carboxamide (Compound 4)>
Methanol (1 mL) was added to 2-aminocarbonylamino-5- [2- (acetyloxymethyl) phenyl] thiophene-3-carboxamide (Compound 1-54, 11 mg, 0.03 mmol), and a 2 mol / L ammonia / methanol solution. (0.15 mL, 0.3 mmol) was added, and the mixture was stirred at 50 ° C. in a nitrogen atmosphere for 3.5 hours. Then, 2 mol / L ammonia / methanol solution (0.075 mL) and methanol (1 mL) were further added at 50 ° C. Stir overnight. The title compound (6 mg) was obtained by filtering the white solid obtained by distilling off the reaction solvent.

<Example 5: 2-aminocarbonylamino-5- (2-methoxyphenyl) thiophene-3-carboxamide (Compound 5-1)>
5-Bromo-2- (aminocarbonylamino) thiophene-3-carboxamide (Reference compound 16, 96 mg, 0.36 mmol) to 2-methoxyphenylboronic acid (83 mg, 0.54 mmol), cesium carbonate (177 mg, 0.54 mmol) ), Tetrakis (triphenylphosphine) palladium (0) (42 mg, 0.036 mmol), N, N-dimethylformamide (3 mL) and water (1 mL) were added, and the mixture was stirred at 90 ° C. under a nitrogen atmosphere for 1 hour. Ethyl acetate was added, washed with water and saturated brine, and dried over magnesium sulfate. The title compound (45 mg) was obtained by washing the solid obtained by distilling off the solvent with methanol.

  Hereinafter, Examples 5-2 and 5-3 were obtained according to the production method of Example 5 using Reference Compound 16 and the corresponding boronic acid commercially available.

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

1) Tablet (in 150mg)
1 mg of the present compound
Lactose 100mg
Corn starch 40mg
Carboxymethylcellulose calcium 4.5mg
Hydroxypropylcellulose 4mg
Magnesium stearate 0.5mg
A tablet of the above formulation can be coated with 3 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the intended tablet. Moreover, a desired tablet can also be obtained by changing suitably the kind and / or quantity of this invention compound and an additive.

2) Capsule (in 150mg)
The compound of the present invention 5mg
Lactose 135mg
Carboxymethylcellulose calcium 4.5mg
Hydroxypropylcellulose 4mg
Magnesium stearate 1.5mg
Desired capsules can be obtained by appropriately changing the type and / or amount of the compound of the present invention and additives.

3) Eye drops (in 100 ml)
Compound of the present invention 100mg
Sodium chloride 900mg
Polysorbate 80 500mg
Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount By appropriately changing the type and / or amount of the compound of the present invention and additives, a desired eye drop can be obtained.

[Pharmacological test]
<JAK3 inhibitory activity measurement test>
JAK3 inhibitory activity was measured using QS Assist JAK3_TR-FRET Kit (Carna Biosciences; product number 08-046TX). The specific method is shown below.

(1) Preparation of test compound solution A test compound was dissolved in dimethyl sulfoxide, and then diluted with an assay buffer (Tween 20 and dithiothreitol-containing Tris buffer) to 40 μM.

(2) Preparation of JAK3 enzyme solution The human JAK3 kinase domain was diluted and mixed in the assay buffer according to the instructions of QS SS Assist JAK3_TR-FRET Kit.

(3) Preparation of detection reagent Europium-labeled anti-phosphorylated tyrosine antibody (PerkinElmer) and allophycocyanin-streptavidin (PerkinElmer) were added to the detection buffer (Tween) to final concentrations of 5.3 nM and 33.3 nM, respectively. 20 and EDTA-containing Tris buffer).

(Test method and measurement method)
1) 5 μL of the test compound solution, 5 μL of the JAK3 substrate solution (purchased from Carna Biosciences), and 10 μL of the JAK3 enzyme solution were added to each well of the 384-well plate.

2) Incubated for 1 hour at room temperature.
3) 60 μL of detection reagent was added to each well.

4) Incubated for 30 minutes at room temperature.
5) TR-FRET signal was measured with a plate reader (ARVOsx; PerkinElmer).

(Calculation of JAK3 inhibition rate)
The JAK3 inhibition rate was calculated by the following formula.

JAK3 inhibition rate (%) = 100 × {1− (TR-FRET value of test substance−blank TR-FRET value) / (control TR-FRET value−blank TR-FRET value)}
(Evaluation results)
Examples of evaluation results include test compounds (compounds 1-1, 1-2, 1-9, 1-12, 1-15, 1-19, 1-20, 1-21, 1-23, 1-25, 1-27, 1-33, 1-39, 1-42, 1-43, 1-47, 1-49, 1-50, 1-51, 1-53, 1-56, 1-57, 2, Table 91 shows the inhibition rate of JAK3 at 10 μM of 3-1, 3-2, 4, 5-1, and 5-2).

The inhibition rate of 100% or more was shown as 100%.
As shown in Table 91, the compound of the present invention has excellent JAK3 inhibitory activity. Therefore, the compound of the present invention is expected to be useful as a prophylactic and / or therapeutic agent for diseases in which JAK3 is involved.

Claims (7)

A JAK3 inhibitor comprising as an active ingredient at least one of a compound represented by the following general formula (1) or a salt thereof.

[Wherein A represents the following general formula (2a), (2b), (2c), (2d), (2e) or (2f);

R ¹ is hydrogen atom, halogen atom, lower alkyl group, lower alkenyl group, phenyl group, hydroxy group, lower alkoxy group, lower alkenyloxy group, phenoxy group, amino group, lower alkylamino group, morpholino group, amide of amino group Represents an amino group sulfonamido, mercapto group, lower alkylthio group, lower alkylcarbonyl group, carboxyl group, lower alkoxycarbonyl group, aminocarbonyl group or cyano group;
R ² represents a hydrogen atom or a lower alkyl group;
R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom or a lower alkyl group;
R ⁵ represents a hydroxy group or a lower alkoxy group;
When R ¹ is a lower alkyl group, the lower alkyl group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkylcarbonyloxy group and a morpholino group;
When R ¹ is a lower alkoxy group, the lower alkoxy group is selected from the group consisting of a halogen atom, a lower alkylamino group, a morpholino group, a 4-fluorophenylpiperazino group, a carboxyl group, and a lower alkoxycarbonyl group or May be substituted with multiple groups;
When R ¹ is an amino amide, the amino amide may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkoxycarbonyl group and a cyano group;
When R ¹ is an aminocarbonyl group, the aminocarbonyl group may be substituted with one or more groups selected from the group consisting of a hydrogen atom, a lower alkyl group and a lower alkoxy group, and the lower alkyl group is Optionally substituted with one or more groups selected from the group consisting of carboxyl groups or lower alkoxycarbonyl groups;
p represents 0, 1, 2 or 3;
When p is 2 or 3, R ¹ may be the same or different. ] The JAK3 inhibitor according to claim 1, wherein A in the general formula (1) represents the following general formula (2a).

In the general formula (1), A represents the following general formula (2a);

R ¹ is hydrogen atom, halogen atom, lower alkyl group, phenyl group, hydroxy group, lower alkoxy group, lower alkenyloxy group, phenoxy group, lower alkylamino group, morpholino group, lower alkylcarbonylamino group, lower alkylsulfonylamino group , A lower alkylthio group, a lower alkylcarbonyl group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylaminocarbonyl group, an N-methoxy-N-methylaminocarbonyl group or a cyano group;
When R ¹ is a lower alkyl group, the lower alkyl group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkylcarbonyloxy group and a morpholino group;
When R ¹ is a lower alkoxy group, the lower alkoxy group is selected from the group consisting of a halogen atom, a lower alkylamino group, a morpholino group, a 4-fluorophenylpiperazino group, a carboxyl group, and a lower alkoxycarbonyl group or May be substituted with multiple groups;
When R ¹ is a lower alkylcarbonylamino group, the lower alkylcarbonylamino group may be substituted with one or more groups selected from the group consisting of a hydroxy group, a lower alkoxycarbonyl group and a cyano group;
When R ¹ is an aminocarbonyl group, the aminocarbonyl group may be substituted with one or more groups selected from the group consisting of a hydrogen atom, a lower alkyl group and a lower alkoxy group, and the lower alkyl group is Optionally substituted with one or more groups selected from the group consisting of carboxyl groups and lower alkoxycarbonyl groups;
p represents 0, 1, 2 or 3;
The JAK3 inhibitor according to claim 1, wherein when p is 2 or 3, R ¹ may be the same or different. 2-aminocarbonylamino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2,3,4-trimethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-methoxypyridin-3-yl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-isopropylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-ethylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methylthiophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-ethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-trifluoromethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [3-[(2-cyanoacetyl) amino] phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (2-propoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2,4-dimethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-dimethylaminophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-methylthiophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [4- (4-morpholinyl) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (2-hydroxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (3-hydroxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-cyanophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [2- (2-ethoxy-2-oxoethoxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- [2- (2-propen-1-yloxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- (3-carboxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [3-[[(carboxymethyl) amino] carbonyl] phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- [2- (carboxymethoxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-hydroxymethylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-chlorophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5-[(1,1′-biphenyl) -3-yl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (3-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-dimethylaminophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-propionylphenyl) thiophene-3-carboxamide,
It consists of 2-aminocarbonylamino-5- (2-acetyl-4-hydroxyphenyl) thiophene-3-carboxamide and 2-aminocarbonylamino-5- (3-acetyl-4-hydroxyphenyl) thiophene-3-carboxamide A JAK3 inhibitor comprising as an active ingredient at least one of a compound selected from the group or a salt thereof.   The JAK3 inhibitor according to any one of claims 1 to 4, which is a prophylactic and / or therapeutic agent for a disease associated with JAK3. 2-aminocarbonylamino-5- (2-isopropyloxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2,3,4-trimethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-methoxypyridin-3-yl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-isopropylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-ethylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methylthiophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-ethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-trifluoromethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [3-[(2-cyanoacetyl) amino] phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (2-propoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2,4-dimethoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-dimethylaminophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-methylthiophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [4- (4-morpholinyl) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- [4- (1-methyl-1H-pyrazol-4-yl) phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (2-hydroxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (3-hydroxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-cyanophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [2- (2-ethoxy-2-oxoethoxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- [2- (2-propen-1-yloxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- (3-carboxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- [3-[[(carboxymethyl) amino] carbonyl] phenyl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- [2- (carboxymethoxy) phenyl] thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-hydroxymethylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-methoxyphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-chlorophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5-[(1,1′-biphenyl) -3-yl] thiophene-3-carboxamide;
2-aminocarbonylamino-5- (3-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (4-acetylphenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-dimethylaminophenyl) thiophene-3-carboxamide,
2-aminocarbonylamino-5- (2-propionylphenyl) thiophene-3-carboxamide,
It consists of 2-aminocarbonylamino-5- (2-acetyl-4-hydroxyphenyl) thiophene-3-carboxamide and 2-aminocarbonylamino-5- (3-acetyl-4-hydroxyphenyl) thiophene-3-carboxamide A compound selected from the group or a salt thereof.   A pharmaceutical composition comprising the compound or salt according to claim 6.