JP2008133269A - Novel compound having 1,4-benzothiazin-3-one skeleton or 3,4-dihydroquinolin-2-one skeleton - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To synthesize a novel compound having a 1,4-benzothiazin-3-one skeleton or a 3,4-dihydroquinolin-2-one skeleton and find pharmacological activities of the compound. <P>SOLUTION: A therapeutic agent for a disease, in which vascularization participates, comprising a compound represented by formula [I] or a salt thereof is provided. In the formula, the ring A is an aryl group, an aromatic heterocyclic group or the like; R<SB>1</SB>is a hydrogen atom, a halogen atom, an alkyl group, a halogenoalkyl group or the like; X is S, CH<SB>2</SB>or the like; Y is a hydroxy group, an alkoxy group, NR<SB>2</SB>R<SB>3</SB>or the like; R<SB>2</SB>and R<SB>3</SB>are each a hydrogen atom, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group or the like. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel compound having a 1,4-benzothiazin-3-one skeleton or a 3,4-dihydroquinolin-2-one skeleton useful as a pharmaceutical or a salt thereof. These compounds are therapeutic agents for diseases involving angiogenesis, especially cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal angiopathy, diabetic macular edema, It is useful as a therapeutic agent for psoriasis vulgaris, atherosclerosis, etc.

  Angiogenesis is a phenomenon in which a new blood vessel network is formed from existing blood vessels, and is mainly observed in small blood vessels. Angiogenesis is inherently a physiological phenomenon and is essential for embryonic angiogenesis, but in adults it is usually only at limited times, such as in the endometrium, follicles, and in the wound healing process. Not observed. However, in diseases such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis Angiogenesis is observed and is closely related to the pathological progression of these diseases. Angiogenesis is regulated by the balance between the promoting factor and the inhibitory factor, and it is considered that angiogenesis occurs when the balance is lost (see Non-Patent Document 1 and Non-Patent Document 2).

  Vascular endothelial growth factor (hereinafter referred to as “VEGF”) specifically acts on receptors (Flt-1, KDR / Flk-1, etc.) present on the surface of vascular endothelial cells to proliferate vascular endothelial cells. It is a factor that promotes the construction of capillary networks through migration and tube formation, and plays a very important role in the development of angiogenesis. Therefore, many attempts have been reported to treat diseases involving angiogenesis by inhibiting the VEGF and controlling the occurrence of angiogenesis. Examples of drugs used for such treatment include indoline-2-one derivatives (see Patent Document 1), phthalazine derivatives (see Patent Document 2), quinazoline derivatives (see Patent Document 3), anthranilic acid amide derivatives (Patent Document 4). Reference), 2-aminonicotinic acid derivatives (see Patent Document 5), 4-pyridylalkylthio derivatives (see Patent Document 6), and the like.

  However, these patent documents do not describe a cyclic compound having a 1,4-benzothiazin-3-one skeleton or a 3,4-dihydroquinolin-2-one skeleton.

On the other hand, Patent Document 7 reports a cyclic compound having a 1,4-benzothiazin-3-one skeleton. In Patent Document 7, these are reported as cell growth inhibitors by tyrosine kinase inhibition. However, the patent document does not describe detailed data on the activity, and no attempt has been made to introduce a hydrophilic substituent which is a feature of the compound of the present invention.
Molecular Medicine vol.35 Special issue “Molecular mechanisms of symptoms and pathologies”, Nakayama Shoten, 73-74 (1998) Protein Nucleic Acid Enzyme “Advanced Drug Discovery”, Kyoritsu Shuppan, 1182-1187 (2000) International Publication WO98 / 50356 Pamphlet International Publication WO98 / 35958 Pamphlet International Publication WO97 / 30035 pamphlet International Publication WO00 / 27819 Pamphlet International Publication WO01 / 55114 Pamphlet International Publication WO04 / 078723 Pamphlet International Publication WO00 / 75139 Pamphlet

Synthetic studies of novel compounds having a 1,4-benzothiazin-3-one skeleton or a 3,4-dihydroquinolin-2-one skeleton and finding the pharmacological actions of these compounds are very interesting issues.

  The present inventors have conducted synthetic studies on compounds having a 1,4-benzothiazin-3-one skeleton or a 3,4-dihydroquinolin-2-one skeleton, and have succeeded in creating many new compounds.

  Furthermore, various studies on the pharmacological action of these compounds revealed that these compounds have angiogenesis-inhibiting action and are therapeutic agents for diseases involving angiogenesis, particularly cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retina. And the present invention was completed. The present invention was found to be useful as a therapeutic agent for retinopathy of prematurity, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis, etc.

  That is, the present invention relates to a compound represented by the general formula [I] or a salt thereof (hereinafter referred to as “the present compound” unless otherwise specified) and a pharmaceutical composition containing the present compound. The pharmaceutical use of the compound of the present invention will be described in more detail. The present invention relates to a therapeutic agent for a disease involving angiogenesis which comprises the compound of the present invention as an active ingredient, such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, The present invention relates to therapeutic agents for retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis and the like.

A compound represented by the following general formula [I] or a salt thereof.

[Wherein, ring A represents an aryl group or an aromatic heterocyclic ring;
R ₁ represents a hydrogen atom, a halogen atom, an alkyl group or a halogenoalkyl group;
X represents S or CH ₂ ;
Y represents a hydroxyl group, an alkoxy group or NR ₂ R ₃ ;
R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group;
R ₂ and R ₃ together may form a non-aromatic heterocycle;
Each alkyl group described above is one or more selected from a hydroxyl group, an amino group, a carboxyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylamino group, an aryl group, an aromatic heterocyclic group and a non-aromatic heterocyclic group. May have a substituent;
Each of the above aryl groups is a halogen atom, amino group, nitro group, alkyl group, halogenoalkyl group, alkoxy group, hydroxyalkyl group, alkylcarbonyl group, alkyloxycarbonyl group, alkylamino group, alkylcarbonylamino group, aromatic heterocycle. May have one or more substituents selected from a cyclic group and a non-aromatic heterocyclic group;
Each of the aromatic heterocyclic groups described above has one or more substituents selected from a halogen atom, amino group, alkyl group, halogenoalkyl group, hydroxyalkyl group, alkyloxycarbonyl group, alkylamino group and alkylcarbonylamino group. May have;
Each of the above non-aromatic heterocyclic groups is selected from a halogen atom, amino group, alkyl group, halogenoalkyl group, hydroxyalkyl group, alkyloxycarbonyl group, alkylamino group, alkylcarbonylamino group and non-aromatic heterocyclic group. May have one or more substituents. ]

  The present invention provides a novel compound having a 1,4-benzothiazin-3-one skeleton or a 3,4-dihydroquinolin-2-one skeleton, or a salt thereof useful as a medicine. The novel cyclic compound according to the present invention has an excellent angiogenesis-inhibiting action, and diseases involving angiogenesis, such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retina It is useful as a therapeutic agent for venous occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis, etc.

  Each group used in the claims and specification shall have the following meaning throughout the claims and specification.

  “Halogen atom” means fluorine, chlorine, bromine or iodine.

  “Alkyl” refers to linear or branched alkyl having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and the like.

  “Cycloalkyl” refers to cycloalkyl having 3 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

  “Aryl” refers to a monocyclic aromatic hydrocarbon or a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms. In addition, these monocyclic aromatic hydrocarbons or condensed polycyclic hydrocarbons formed by condensation of a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon and a cycloalkane ring are also “aryl” of the present invention. include. Specific examples of monocyclic aromatic hydrocarbons include phenyl, specific examples of condensed polycyclic aromatic hydrocarbons include naphthyl, anthryl, and phenanthryl. Specific examples of condensed polycyclic hydrocarbons include indanyl, tetrahydronaphthyl, and tetrahydro. Anthryl and the like.

  “Aromatic heterocycle” means a monocyclic aromatic heterocycle having one or more heteroatoms (nitrogen atom, oxygen atom, sulfur atom) in the ring, or a bicyclic or tricyclic condensed polycyclic aroma A group heterocycle is shown.

  Specific examples of monocyclic aromatic heterocycles include aromatic heterocycles having one heteroatom in the ring such as pyrrole, furan, thiophene, pyridine, etc .; imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, etc. Specific examples of fused polycyclic aromatic heterocycles having two or three rings such as an aromatic heterocycle having two nitrogen atoms in a ring such as pyrazine and pyrimidine And condensed aromatic heterocycles such as indole, isoindole, benzimidazole, benzoxazole, benzothiazole, quinoline, isoquinoline, naphthyridine, thianthrene, phenoxatin, and phenanthroline.

  “Non-aromatic heterocycle” means a monocyclic non-aromatic heterocycle having one or more hetero atoms (nitrogen atom, oxygen atom, sulfur atom) in the ring, or a bicyclic or tricyclic condensed polycycle Represents a non-aromatic heterocycle of formula

  Specific examples of monocyclic non-aromatic heterocycles include saturated non-aromatic heterocycles having one hetero atom in the ring, such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, azepane, tetrahydropyran, homopiperazine; , Oxazolidine, thiazolidine, pyrazolidine, piperazine, morpholine, thiomorpholine, homopiperidine, homomorpholine, etc., saturated non-aromatic heterocycle having two heteroatoms in the ring; pyrroline, dihydrofuran, dihydrothiophene, tetrahydropyridine, dihydropyridine An unsaturated non-aromatic heterocyclic ring having one hetero atom in the ring such as dihydropyran and pyran; an unsaturated non-aromatic heterocyclic ring having two hetero atoms such as imidazoline, oxazoline, thiazoline and pyrazoline Bicyclic youth 3 Examples of the fused polycyclic non-aromatic heterocyclic cyclic, chroman, indoline, isoindoline, xanthine and the like.

  “Alkoxy” represents straight-chain or branched alkoxy having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy and the like.

  “Alkylamino” refers to monoalkylamino having 1 to 6 carbon atoms or dialkylamino having 2 to 12 carbon atoms. Specific examples of monoalkylamino include methylamino, ethylamino, hexylamino and the like, and specific examples of dialkylamino include ethylmethylamino, dimethylamino, diethylamino, dihexylamino and the like.

  “Alkylcarbonyl” refers to a straight-chain or branched alkylcarbonyl having 2 to 7 carbon atoms. Specific examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, isopentylcarbonyl and the like. Can be mentioned.

  “Alkyloxycarbonyl” refers to a linear or branched alkyloxycarbonyl having 2 to 7 carbon atoms. Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, n-pentoxycarbonyl, n-hexyloxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, iso Examples include pentoxycarbonyl.

  “Alkylcarbonylamino” refers to monoalkylcarbonylamino having 2 to 7 carbon atoms or dialkylcarbonylamino having 4 to 14 carbon atoms. Specific examples of monoalkylcarbonylamino include methylcarbonylamino, ethylcarbonylamino, hexylcarbonylamino and the like, and specific examples of dialkylcarbonylamino include ethylmethylcarbonylamino, dimethylcarbonylamino, diethylcarbonylamino, dihexylcarbonylamino and the like.

  “Hydroxyalkyl” refers to an alkyl having one or more hydroxyl groups as substituents.

  “Halogenoalkyl” refers to an alkyl having one or more halogen atoms as substituents.

  “Halogenoaromatic heterocycle” refers to an aromatic heterocycle having the same or different halogen atoms as substituents.

  The “halogenoalkyl aromatic heterocycle” refers to an aromatic heterocycle having the same or different halogenoalkyl group as a substituent.

  “Amino aromatic heterocycle” refers to an aromatic heterocycle having one or more amino groups as substituents.

  When the compound of the present invention has a free hydroxy group, amino group, alkylamino group or alkylcarbonylamino group as a substituent, these substituents may be protected with a protecting group. Moreover, also when an aromatic heterocyclic group or a non-aromatic heterocyclic ring has a free nitrogen atom, this nitrogen atom may be protected by the protecting group.

  “Protecting group for free hydroxy group” means a substituted or unsubstituted alkyl group such as methyl group, methoxymethyl group, benzyl group, 4-methoxyphenylmethyl group, allyl group, or unsubstituted alkenyl group; 3-bromotetrahydro Substituted or unsubstituted non-aromatic heterocyclic group such as pyranyl group, tetrahydropyranyl group, tetrahydrofuranyl group; substituted or unsubstituted alkylcarbonyl group such as acetyl group, trifluoroacetyl group, benzoyl group, 4-chlorobenzoyl group Or a substituted or unsubstituted arylcarbonyl group; methoxycarbonyl group, ethoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group ,vinyl Substituted or unsubstituted alkyloxycarbonyl group, unsubstituted alkenyloxycarbonyl group, substituted or unsubstituted aryloxycarbonyl group such as xyloxycarbonyl group, allyloxycarbonyl group, phenyloxycarbonyl group, p-nitrophenyloxycarbonyl group; trimethylsilyl And those commonly used as protecting groups for free hydroxy groups such as substituted silyl groups such as a group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group;

  “Free amino group, free alkylamino group, free alkylcarbonylamino group, aromatic heterocyclic group having a free nitrogen atom or non-aromatic heterocyclic group having a free nitrogen atom” means Unsubstituted alkenyl groups such as allyl groups; hydrocarbonyl groups such as formyl groups; substituted or unsubstituted alkylcarbonyl groups such as acetyl groups, trichloroacetyl groups, trifluoroacetyl groups, benzoyl groups, 4-chlorobenzoyl groups, picolinoyl groups; Substituted or unsubstituted arylcarbonyl group, or unsubstituted aromatic heterocyclic carbonyl group; methoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, diphenyl Methoxycarbonyl group, phenoxycarbo Substituted or unsubstituted alkyloxycarbonyl such as m-nitrophenoxycarbonyl group, or substituted or unsubstituted aryloxycarbonyl group; methylsulfonyl group, benzylsulfonyl group, phenylsulfonyl group, 4-chlorophenylsulfonyl group, tolylsulfonyl group A substituted or unsubstituted alkylsulfonyl group such as 2,4,6-trimethylphenylsulfonyl group, or a substituted or unsubstituted arylsulfonyl group; a free amino group such as a free alkylamino group, a free arylamino group, a free And those commonly used as protecting groups for aromatic heterocyclic groups having a nitrogen atom or non-aromatic heterocyclic groups having a free nitrogen atom.

  The substituted alkyl group, substituted non-aromatic heterocyclic group, substituted alkylcarbonyl group, substituted arylcarbonyl group, substituted alkyloxycarbonyl group, substituted aryloxycarbonyl group, substituted silyl group, substituted alkylsulfonyl group or substituted arylsulfonyl group are: , An alkyl group, a non-aromatic heterocyclic group, an alkyl group each substituted with one or more groups selected from a halogen atom, an alkoxy group, an alkyl group, an aryl group, a halogenoaryl group, an alkoxyaryl group and a nitro group A carbonyl group, an arylcarbonyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, a silyl group, an alkylsulfonyl group or an arylsulfonyl group;

  In the “multiple groups” in the present invention, each group may be the same or different, and preferably represents 2 or 3 groups, more preferably 2 groups.

  Further, the “group” in the present invention includes a hydrogen atom, a halogen atom and an oxo ligand.

  The “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, a salt with an inorganic acid 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, gluconic acid, glucoheptic 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, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid, etc. Salts with organic acids, quaternary ammonium salts such as methyl bromide and methyl iodide, bromine ions, chloride ions, iodine Salts with halogen ions such as 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, Ethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1,3-propanediol And salts with organic amines such as 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.

  Furthermore, when proton tautomerism exists in this invention compound, those tautomers are also included in the scope of the present invention.

  The wavy line in the general formula [I] represents that the solid of the double bond to be bonded is E-form or Z-form.

“R ₂ and R ₃ together form a non-aromatic heterocycle” means that R ₂ and R ₃ together form a non-aromatic heterocycle via a single bond or a heteroatom. It is. Non-aromatic heterocycles formed through a single bond may be those shown in the above specific examples, but typical examples are pyrrolidine ring, piperidine ring, azepane ring, etc. The formed non-aromatic heterocycle may also be the one shown in the above specific examples, but typical examples are morpholine ring, piperazine ring and the like.

(A) As a preferable example in the compound of the present invention, a compound represented by the general formula [I] or a salt thereof in which each group is a group shown below can be mentioned.

(A1) ring A represents a benzene ring or thiophene ring; and / or (a2) ring A may be substituted with a halogen atom; and / or (a3) R ₁ represents a hydrogen atom or a halogenoalkyl group; And / or (a4) X represents S or CH ₂ ; and / or (a5) Y represents a hydroxyl group, an alkoxy group or NR ₂ R ₃ ; and / or (a6) R ₂ and R ₃ are the same or different. And represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group; and / or (a7) R ₂ and R ₃ together And / or (a8) the alkyl group defined above is one or more substituents selected from a hydroxyl group, an alkyloxycarbonyl group, an aryl group and an aromatic heterocyclic group You may have And / or (a9) the aryl group defined above may have one or more substituents selected from a nitro group, an alkyl group, an alkoxy group, a hydroxyalkyl group, an alkylcarbonyl group, and an alkyloxycarbonyl group; And / or (a10) the aromatic heterocyclic group as defined above may have one or more substituents selected from alkyl groups and halogenoalkyl groups; and / or (a11) as defined above. The non-aromatic heterocyclic group may have one or more substituents selected from an alkyl group, an alkylamino group, an alkyloxycarbonyl group, and an aromatic heterocyclic group.

  That is, in the compound represented by the general formula [I], the above (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8), (a9), A compound or a salt thereof comprising one or more combinations selected from (a10) and (a11).

(B) As a more preferable example in the compound of the present invention, a compound represented by the general formula [I] or a salt thereof, in which each group is a group shown below, may be mentioned.

(B1) Ring A represents a benzene ring or a thiophene ring;
When ring A is a benzene ring, the benzene ring may be substituted with a halogen atom; and / or (b2) R ₁ represents a hydrogen atom or a halogenoalkyl group; and / or (b3) X is S or CH _And / or (b4) Y represents a hydroxyl group, an alkoxy group or NR ₂ R ₃ ; and / or (b5) R ₂ and R ₃ are the same or different and represent a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group. , A cycloalkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group; and / or (b6) when R ₂ or R ₃ is an alkyl group, the alkyl group is a hydroxyl group, an alkyloxycarbonyl group , aryl, alkoxyaryl group may have one or more substituents selected from the aromatic heterocyclic groups and halogenoalkyl aromatic heterocyclic group; and / or (b7) R ₂ or R If is an aryl group, the aryl group is a nitro group, an alkyl group, an alkoxy group, a hydroxyalkyl group may have one or more substituents selected from alkyl group and an alkyloxycarbonyl group; and / Or (b8) when R ₂ or R ₃ is an aromatic heterocyclic group, the aromatic heterocyclic group may be substituted with an alkyl group; and / or (b9) R ₂ or R ₃ is a non-aromatic heterocyclic group In the case of a cyclic group, the non-aromatic heterocyclic group may be substituted with an alkyloxycarbonyl group; and / or (b10) R ₂ and R ₃ may combine to form a non-aromatic heterocyclic ring. And / or (b11) when R ₂ and R ₃ together form a non-aromatic heterocyclic ring, the non-aromatic heterocyclic ring is an alkyl group, an alkylamino group, an alkyloxycarbonyl group and an aromatic heterocyclic group; From It may have one or more substituents-option.

  That is, in the compound represented by the general formula [I], the above (b1), (b2), (b3), (b4), (b5), (b6), (b7), (b8), (b9), A compound or a salt thereof comprising one or more combinations selected from (b10) and (b11).

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

(C1) Ring A represents a benzene ring, fluorobenzene ring or thiophene ring; and / or (c2) R ₁ represents a hydrogen atom or a trifluoromethyl group; and / or (c3) X represents S or CH ₂ And / or (c4) Y is hydroxyl, tert-butoxy, hydroxyamino, tert-butoxyamino, pyridin-2-ylmethylamino, pyridin-3-ylmethylamino, pyridin-4-yl Methylamino group, 2-trifluoromethylpyridin-5-ylmethylamino group, benzylamino group, 4-methoxybenzylamino group, n-pentylamino group, 3-methoxycarbonylpropylamino group, N-ethyl-N-pyridine -3-ylmethylamino group, N-ethyl-N-2-hydroxyethylamino group, cyclopropylamino group, Lopentaneamino group, phenylamino group, 3-hydroxymethylphenylamino group, 4-propylphenylamino group, 4-methoxyphenylamino group, 4-methylcarbonylphenylamino group, 4-methoxycarbonylphenylamino group, 4-nitro Phenylamino group, 3,5-dimethoxyphenylamino group, pyridin-2-ylamino group, pyridin-4-ylamino group, 5-methylpyridin-2-ylamino group, piperidin-4-ylamino group, 1-tert-butoxycarbonyl Piperidin-4-ylamino group, 3-dimethylaminopyrrolidin-1-yl group, piperidin-1-yl group, piperazin-1-yl group, 4-methylpiperazin-1-yl group, 4-pyrimidin-2-ylpiperazine -1-yl group, 4-tert-butoxycarbonyl Rupiperazin-1-yl group, morpholin-4-yl group, azepan-1-yl group or 1-hydroxy-3- (1H-indol-3-yl) propan-2-ylamino group is shown.

  That is, in the compound represented by the general formula [I], a compound or a salt thereof comprising one or more combinations selected from the above (c1), (c2), (c3) and (c4).

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

(2E) -tert-butyl 3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylate,
(2E) -tert-butyl 3- (3-fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) Acrylate,
(2E) -tert-butyl 3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylate,
(2E) -tert-butyl 3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylate,
(2E) -tert-butyl 3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) Acrylate,
(2E) -tert-butyl 3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) Methyl) thiophen-3-yl) acrylate,
(2E) -tert-butyl 3- (5-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) thiophen-3-yl) acrylate,
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylic acid,
(2E) -3- (3-fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylic acid,
(2E) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylic acid,
(2E) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylic acid,
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) acrylic acid
(2E) -3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene -3-yl) acrylic acid,
(2E) -3- (5-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) thiophen-3-yl) acrylic acid,
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N- (pyridine-3 -Ylmethyl) acrylamide,
2- (4-((E) -3-oxo-3- (piperidin-1-yl) propen-1-yl) benzylidene) -2H-benzo [b] [1,4] thiazine-3 (4H) -On,
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N- (pyridine-2 -Yl) acrylamide,
Methyl 4-((2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylamide) benzoate ,
(2E) -N-cyclopentyl-3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylamide;
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N-pentylacrylamide,
(2E) -N- (4-methoxyphenyl) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) Phenyl) acrylamide,
(2E) -N- (3- (hydroxymethyl) phenyl) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene ) Methyl) phenyl) acrylamide,
Methyl 4-((2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylamide) butyric acid ,
(2E) -3- (3-Fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N- (Pyridin-3-ylmethyl) acrylamide,
(2E) -N-cyclopropyl-3- (3-fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) Phenyl) acrylamide,
(2E) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N- (pyridin-3-ylmethyl) acrylamide,
(2E) -N-cyclopropyl-3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
3- (4-((E) -3- (azepan-1-yl) -3-oxopropen-1-yl) benzylidene) -3,4-dihydroquinolin-2 (1H) -one,
(2E) -N- (3,5-dimethoxyphenyl) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -3- (4-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) phenyl) -N- (pyridin-4-yl) acrylamide,
(2E) -N- (4-acetylphenyl) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N- (4-propylphenyl) acrylamide,
(2E) -N-tert-butoxy-3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -N-hydroxy-3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N- (pyridin-3-ylmethyl) acrylamide,
(2E) -N-cyclopropyl-3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -N- (5-methylpyridin-2-yl) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N-phenylacrylamide,
(2E) -N- (4-nitrophenyl) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) -N- (Pyridin-3-ylmethyl) acrylamide,
(2E) -N-benzyl-3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl ) Acrylamide,
(2E) -N-ethyl-N- (2-hydroxyethyl) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazine-2- Ylidene) methyl) thiophen-3-yl) acrylamide,
(2E) -N- (4-methoxybenzyl) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) Thiophen-3-yl) acrylamide,
(2E) -N-ethyl-3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl ) -N- (pyridin-3-ylmethyl) acrylamide,
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) -N- ((6- (trifluoromethyl) pyridin-3-yl) methyl) acrylamide,
Tert-butyl 4-((2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene-3 -Yl) acrylamide) piperidine-1-carboxylate,
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) -N- (Piperidin-4-yl) acrylamide hydrochloride,
Tert-butyl 4-((2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene-3 -Yl) acryloyl) piperazine-1-carboxylate,
2-((4-((E) -3-oxo-3- (4- (pyrimidin-2-yl) piperazin-1-yl) propen-1-yl) thiophen-2-yl) methylene) -2H -Benzo [b] [1,4] thiazin-3 (4H) -one,
(2E) -N- (3,5-dimethoxyphenyl) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) Methyl) thiophen-3-yl) acrylamide,
(2E) -N-((S) -1-hydroxy-3- (1H-indol-3-yl) propan-2-yl) -3- (5-((3-oxo-3,4-dihydro -2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) acrylamide,
(2E) -3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene -3-yl) -N- (pyridin-3-ylmethyl) acrylamide,
(2E) -3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene -3-yl) -N- (pyridin-4-ylmethyl) acrylamide,
2-((4-((E) -3- (4-methylpiperazin-1-yl) -3-oxopropen-1-yl) thiophen-2-yl) methylene) -6- (trifluoromethyl) -2H-benzo [b] [1,4] thiazin-3 (4H) -one,
2-((4-((E) -3-morpholino-3-oxopropen-1-yl) thiophen-2-yl) methylene) -6- (trifluoromethyl) -2H-benzo [b] [1 , 4] thiazin-3 (4H) -one,
2-((4-((E) -3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropen-1-yl) thiophen-2-yl) methylene) -6- (tri Fluoromethyl) -2H-benzo [b] [1,4] thiazin-3 (4H) -one,
2-((4-((E) -3-oxo-3- (piperazin-1-yl) propen-1-yl) thiophen-2-yl) methylene) -6- (trifluoromethyl) -2H- Benzo [b] [1,4] thiazin-3 (4H) -one hydrochloride, and (2E) -3- (5-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene ) Methyl) thiophen-3-yl) -N- (pyridin-3-ylmethyl) acrylamide.

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 below-mentioned Example [section of a manufacturing example]. Further, Hal used in the following synthesis route represents a halogen atom.

The compound of the present invention is produced by properly using conditions and the like according to the main synthetic route consisting of the following routes A to D.

The compound (I) of the present invention can be produced according to the synthesis route A. That is, the compound (II) of the present invention and the primary or secondary amine (III) in an organic solvent such as N, N-dimethylformamide (hereinafter abbreviated as DMF), TFP resin (J. Comb. Chem., 2000, 2). , 691-697), water-soluble carbodiimides (WSC) such as O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), and N , N-diisopropylethylamine (hereinafter abbreviated as DIEA), and the like, in the presence of a base at room temperature to 80 ° C. for 1 to 24 hours, compound (I) can be obtained.

Synthesis route A

  The compound (II) of the present invention can be produced according to the synthesis route B. That is, the compound (II) is obtained by reacting the compound (IV) of the present invention with hydrogen chloride in an organic solvent such as dioxane at room temperature for 1 to 24 hours.

Synthesis route B

  The compound (IV) of the present invention can be produced according to the synthesis route C. That is, compound (V) and compound (VI) (for example, tert-butyl acrylate) are present in an organic solvent such as DMF, a catalytic amount of a ligand such as palladium acetate and triphenylphosphine, and a base such as DIEA. The compound (IV) of the present invention can be obtained by reacting at room temperature to 100 ° C. for 1 to 24 hours.

Synthesis route C

  Compound (V) can be produced according to synthetic route D. That is, compound (V) can be obtained by heating and refluxing compound (VII) and aldehyde (VIII) in an organic solvent such as methanol in the presence of a base such as sodium methoxide for 1 to 24 hours.

Synthesis route D

  The compound of the present invention produced by the above synthetic route can be made into the above-mentioned salt, hydrate or solvate form by a widely used technique.

  In order to find the usefulness of the compound of the present invention, a VEGF-induced HUVEC proliferation response evaluation system (HUVEC: vascular endothelial cell derived from normal human umbilical vein), which is a method for evaluating the angiogenesis inhibitory effect of a drug, is used. A cell growth inhibitory effect test was performed, and the angiogenesis inhibitory effect was evaluated. Details thereof will be described in the following Examples [Pharmacological Test Items], and it has been found that the compound of the present invention exhibits an excellent cell growth inhibitory action and has an angiogenesis inhibitory effect.

  As mentioned above, angiogenesis is cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis It is reported that it is deeply related to diseases such as Therefore, the compound of the present invention is highly expected as a therapeutic agent for those diseases involving angiogenesis.

  The compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, injections, ointments, eye drops, eye ointments, 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, A coating agent such as a silicone resin, a stabilizer such as ethyl paraoxybenzoate and benzyl alcohol, a flavoring agent such as a sweetener, an acidulant, and a fragrance can be used 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, preservatives such as chlorobutanol, hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate PH adjusting agents such as Use in accordance with emissions benzyl alcohol soothing agent such as such as required, it may be prepared.

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

[Production example]
Reference example 1
2- (4-Bromobenzylidene) -2H-benzo [b] [1,4] thiazin-3 (4H) -one (Reference compound 1-1)

  Sodium methoxide (28 mL) was added to a methanol solution (10 mL) of 2H-benzo [b] [1,4] thiazin-3 (4H) -one (3.0 g, 18 mmol) and p-bromobenzaldehyde (5.0 g, 27 mmol). % Methanol solution, 18 mL) was added. The reaction was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was collected by filtration. Drying under reduced pressure gave 4.1 g of the title reference compound as a colorless solid (yield 67%).

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 7.03 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.08 (dd, J = 7.8, 1.2 Hz, 1H), 7.20 (dd , J = 7.8, 1.2, 1.2 Hz, 1H), 7.33 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 11.11 (s, 1H)
Hereinafter, using compounds selected from commercially available compounds and known compounds, reference compounds 1-2 to 7 were obtained according to the production method of reference compound 1-1.

2- (4-Bromo-2-fluorobenzylidene) -2H-benzo [b] [1,4] thiazin-3 (4H) -one (Reference compound 1-2)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 7.01 (m, 1H), 7.06 (d, J = 7.9 Hz, 1H), 7.19 (m, 1H), 7.27-7.33 (m, 3H), 7. 54 (d, J = 7.9 Hz, 1H), 7.85 (s, 1H), 11.03 (s, 1H)
3- (4-Bromobenzylidene) -3,4-dihydroquinolin-2 (1H) -one (Reference compound 1-3)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.81 (s, 2H), 7.14 (brt, J = 8.0 Hz, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.28 (brd, J = 7.8 Hz, 1H), 7.45 (brt, J = 7.8 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.60 (brd, J = 8. 0 Hz, 1H), 7.71 (s, 1H), 11.81 (brs, 1H)
3- (2-Bromobenzylidene) -3,4-dihydroquinolin-2 (1H) -one (Reference compound 1-4)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.84 (s, 2H), 7.16 (brt, J = 8.0 Hz, 1H), 7.25-7.34 (m, 3H), 7.40 (brd, J = 8.0) Hz, 1H), 7.46 (brt, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.60 (brd, J = 8.0 Hz, 1H), 7.77 ( s, 1H), 11.81 (s, 1H)
2-((4-Bromothiophen-2-yl) methylene) -2H-benzo [b] [1,4] thiazin-3 (4H) -one (Reference compound 1-5)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 7.04-7.10 (m, 1H), 7.23 (m, 1H), 7.40 (brd, J = 8.0 Hz, 1H), 7.46 (brt, J = 8.0) Hz, 1H), 7.51 (s, 1H), 7.60 (brd, J = 8.0 Hz, 1H), 7.77 (s, 1H), 11.81 (s, 1H)
2-((4-Bromothiophen-2-yl) methylene) -6- (trifluoromethyl) -2H-benzo [b] [1,4] thiazin-3 (4H) -one (Reference compound 1-6)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 7.35-7.40 (m, 2H), 7.66-7.68 (m, 2H), 8.03 (s, 1H), 8.04 (t, J = 0.6 Hz, 1H ), 11.30 (s, 1H)
3-((4-Bromothiophen-2-yl) methylene) -3,4-dihydroquinolin-2 (1H) -one (reference compound 1-7)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.02 (s, 2H), 6.97 (d, J = 1.5 Hz, 1H), 7.17 (ddd, J = 8.3, 8.3, 1.2 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 1.5 Hz, 1H), 7.47 (ddd, J = 8.3, 7.8, 1.H) 2 Hz, 1H), 7.63 (dd, J = 7.8, 1.2 Hz, 1H), 7.84 (s, 1H), 11.88 (s, 1H)
Example 0
(2E) -tert-butyl 3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylate (compound 0- 1)

  2- (4-Bromobenzylidene) -2H-benzo [b] [1,4] thiazin-3 (4H) -one (3.1 g, 9.3 mmol, Reference compound 1-1), palladium acetate (210 mg, 0 The reaction vessel containing .93 mmol) and tri (0-tolyl) phosphine (570 mg, 1.8 mmol) was replaced with nitrogen gas. DMF (50 mL), DIEA (3.3 mL, 19 mmol) and tert-butyl acrylate (6.8 mL, 46 mmol) were added to the reaction vessel, and the mixture was heated and stirred at 60 ° C. overnight. The reaction mixture was cooled to room temperature and filtered through celite using chloroform (100 mL). The filtrate was diluted with chloroform (100 mL), washed twice with saturated brine (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was filtered with water, washed with ethanol, and dried under reduced pressure to obtain 3.4 g of the title reference compound as a yellow solid (yield 96%).

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.48 (s, 9H), 6.61 (d, J = 15.9 Hz, 1H), 7.04 (ddd, J = 8.5, 7.1, 1.2 Hz, 1H), 7.06 (dd, J = 7.1, 1.2 Hz, 1H), 7.21 (ddd, J = 8.5, 7.1, 1.2 Hz, 1H), 7.36 (dd, J = 7.1, 1.2 Hz, 1H), 7.59 (d, J = 15.9 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.81 ( s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 11.10 (s, 1H)
Hereinafter, compounds 0-2 to 7 were obtained according to the production method of compound 0-1, using compounds selected from reference compounds 1-2 to 7, commercially available compounds, and known compounds.

(2E) -tert-butyl 3- (3-fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylate (Compound 0-2)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.49 (s, 9H), 6.69 (d, J = 15.9 Hz, 1H), 7.01 (m, 1H), 7.06 (dd, J = 7.9, 1.2) Hz, 1H), 7.19 (m, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.39 (dd, J = 7.9, 1.2 Hz, 1H), 7.45 (d, J = 1.2 Hz, 1H), 7.57 (d, J = 15.9 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7. 96 (s, 1H), 11.04 (s, 1H)
(2E) -tert-butyl 3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylate (compound 0-3)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.48 (s, 9H), 3.86 (s, 2H), 6.46 (d, J = 15.9 Hz, 1H), 7.14 (t, J = 8.3 Hz, 1H) 7.29 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 8.3 Hz, 1H), 7 .52 (d, J = 15.9 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.61 (S, 1H), 11.80 (s, 1H)
(2E) -tert-butyl 3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylate (compound 0-4)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.42 (s, 9H), 3.96 (s, 2H), 6.38 (d, J = 15.9 Hz, 1H), 7.11 (m, 1H), 7.28-7. 50 (m, 7H), 7.77 (d, J = 15.9 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 11.89 (s, 1H)
(2E) -tert-butyl 3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) acrylate (Compound 0-5)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.48 (s, 9H), 6.43 (d, J = 15.9 Hz, 1H), 7.07 (m, 1H), 7.23 (m, 1H), 7.41 (d, J = 7.3 Hz, 2H), 7.55 (d, J = 15.9 Hz, 1H), 7.95 (s, 1H), 7.96 (s, 1H), 8.26 (s, 1H), 11.07 (s, 1H)
(2E) -tert-butyl 3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl ) Thiophen-3-yl) acrylate (Compound 0-6)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.49 (s, 9H), 6.43 (d, J = 15.9 Hz, 1H), 7.36-7.39 (m, 2H), 7.55 (d, J = 15.9) Hz, 1H), 7.65 (s, 1H), 7.98-8.00 (m, 2H), 8.29 (s, 1H), 11.21 (s, 1H)
(2E) -tert-butyl 3- (5-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) thiophen-3-yl) acrylate (compound 0-7)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.46 (s, 9H), 4.01 (s, 2H), 6.25 (d, J = 15.9 Hz, 1H), 7.16 (m, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.45 (d, J = 15.9 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H) , 7.74 (s, 1H), 7.75 (s, 1H), 7.81 (s, 1H), 11.87 (s, 1H)
Example 1
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylic acid (Compound 1-1)

  (2E) -tert-butyl 3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylate (3.5 g 9.2 mmol, compound 0-1) in dioxane suspension (25 mL) was added 4M hydrogen chloride dioxane solution (25 mL, 100 mmol) and DMF (10 mL). The reaction solution was stirred overnight at room temperature, and the precipitated solid was collected by filtration. When dried under reduced pressure, 2.7 g of the target compound was obtained as a colorless powder (yield 93%).

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 6.63 (d, J = 15.9 Hz, 1H), 7.04 (brt, J = 8.5 Hz, 1H), 7.07 (brd, J = 8.5 Hz, 1H), 7 .21 (brt, J = 8.5 Hz, 1H), 7.36 (brd, J = 7.1 Hz, 1H), 7.63 (d, J = 15.9 Hz, 1H), 7.73 (D, J = 8.6 Hz, 2H), 7.81 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 11.09 (s, 1H), 12.47 (S, 1H)
Hereinafter, compounds 1-2 to 7 were obtained according to the production method of compound 1-1 using compounds selected from compounds 0-2 to 7, commercially available compounds, and known compounds.

(2E) -3- (3-Fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylic acid (compound 1-2)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 6.69 (d, J = 15.9 Hz, 1H), 7.01 (m, 1H), 7.06 (dd, J = 8.2, 1.2 Hz, 1H), 7.18 ( m, 1H), 7.30 (dd, J = 8.2, 1.2 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 0) .9 Hz, 1H), 7.62 (d, J = 15.9 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.96 (s, 1H), 11. 04 (s, 1H), 12.49 (brs, 1H)

(2E) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylic acid (Compound 1-3)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 3.86 (s, 2H), 6.48 (d, J = 15.9 Hz, 1H), 7.14 (t, J = 8.3 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 8.3 Hz, 1H), 7.56 (d, J = 15. 9 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H), 11.81 (S, 1H), 12.34 (s, 1H)
(2E) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylic acid (Compound 1-4)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.96 (s, 2H), 5.60 (brs, 1H), 6.41 (d, J = 15.9 Hz, 1H), 7.11 (m, 1H), 7.27-7. 38 (m, 4H), 7.41 (dd, J = 9.8, 1.2 Hz, 1H), 7.43 (m, 1H), 7.50 (d, J = 8.1 Hz, 1H) ), 7.78 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 15.9 Hz, 1H), 11.89 (s, 1H)
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) acrylic acid (compound 1-5) SA15239

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 6.42 (d, J = 15.9 Hz, 1H), 7.03-7.11 (m, 2H), 7.23 (m, 1H), 7.41 (d, J = 7.8) Hz, 1H), 7.59 (d, J = 15.9 Hz, 1H), 7.95 (s, 1H), 8.00 (s, 1H), 8.25 (s, 1H), 11. 06 (s, 1H), 12.40 (s, 1H)
(2E) -3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene 3-yl) acrylic acid (compound 1-6)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 6.43 (d, J = 15.9 Hz, 1H), 7.37-7.39 (m, 2H), 7.59 (d, J = 15.9 Hz, 1H), 7.67 ( d, J = 8.9 Hz, 1H), 7.9 (d, J = 0.6 Hz, 1H), 8.01 (s, 1H), 8.28 (s, 1H), 11.26 ( s, 1H), 12.42 (s, 1H)
(2E) -3- (5-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) thiophen-3-yl) acrylic acid (Compound 1-7)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.02 (s, 2H), 6.26 (d, J = 15.9 Hz, 1H), 7.16 (m, 1H), 7.31-7.34 (m, 2H), 7. 45 (m, 1H), 7.49 (d, J = 15.9 Hz, 1H), 7.63 (dd, J = 7.8, 1.2 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.81 (s, 1H), 9.70 (brs, 1H), 11.88 (s, 1H)
Example 2
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N- (pyridine-3- Ylmethyl) acrylamide (compound 2-1)

(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylic acid (320 mg, 1.0 mmol , Compound 1-1) in DMF (10 mL) was added diisopropylcarbodiimide (320 μL, 2.0 mmol), dimethylaminopyridine (13 mg, 0.10 mmol) and TFP resin (500 mg), and stirred at room temperature to 80 ° C. for 24 hours. did. The resin was washed twice with 10 mL of DMF, tetrahydrofuran, and methylene chloride in this order, and then dried. Resin (100 mg, theoretical value 0.1 mmol) and 3-aminomethylpyridine (7.0 mg, 0.069 mmol) were added to DMF (1 mL) at room temperature and stirred for 24 hours. After the reaction solution was filtered, the resin was washed with 2 mL of methylene chloride, DMF, and methylene chloride twice in order. The washing solution and the filtrate were combined and concentrated under reduced pressure to obtain 22 mg of the target compound as a yellow solid (yield 54%).

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.44 (d, J = 5.9 Hz, 2H), 6.75 (d, J = 15.9 Hz, 1H), 7.01-7.09 (m, 2H), 7.21 ( m, 1H), 7.33-7.40 (m, 2H), 7.52 (d, J = 15.9 Hz, 1H), 7.69-7.76 (m, 5H), 7.80. (S, 1H), 8.48 (dd, J = 4.9, 1.7 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.75 (t, J = 5.6 Hz, 1H), 11.08 (s, 1H)
Hereinafter, compounds 2-2 to 44 were obtained according to the production method of compound 2-1, using compounds selected from compounds 1-1 to 7, commercially available compounds, and known compounds.

2- (4-((E) -3-oxo-3- (piperidin-1-yl) propen-1-yl) benzylidene) -2H-benzo [b] [1,4] thiazine-3 (4H)- ON (compound 2-2)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.45-1.60 (m, 6H), 3.49-3.57 (m, 2H), 3.60-3.69 (m, 2H), 7.03 (dd, J = 7. 6, 7.6 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 7.20 (ddd, J = 7.6, 7.1, 1.5 Hz, 1H), 7.32-7.36 (m, 2H), 7.51 (d, J = 15.4 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.81 (s) , 1H), 7.85 (d, J = 8.3 Hz, 2H), 11.07 (s, 1H)
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N- (pyridine-2- Yl) acrylamide (compound 2-3)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 7.00-7.15 (m, 4H), 7.21 (ddd, J = 7.8, 7, 8, 1.4 Hz, 1H), 7.35 (d, J = 7.8 Hz) , 1H), 7.67 (d, J = 15.9 Hz, 1H), 7.72-7.83 (m, 6H), 8.25 (d, J = 8.3 Hz, 1H), 8 .36 (ddd, J = 4.9, 1.7, 0.8 Hz, 1H), 10.75 (s, 1H), 11.09 (s, 1H)
Methyl 4-((2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylamide) benzoate ( Compound 2-4)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.84 (s, 3H), 6.92 (d, J = 15.8 Hz, 1H), 7.04 (ddd, J = 8.2, 7.6, 1.2 Hz, 1H), 7.08 (dd, J = 8.2, 1.2 Hz, 1H), 7.21 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 15.8 Hz, 1H), 7.78 (s, 4H), 7.82 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 10.61 (s, 1H), 11.10 (s, 1H)
(2E) -N-cyclopentyl-3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylamide (compound 2 -5)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.38-1.44 (m, 2H), 1.50-1.58 (m, 2H), 1.62-1.70 (m, 2H), 1.80-1.88 (m, 2H), 4.11 (m, 1H), 6.68 (d, J = 15.6 Hz, 1H), 7.03 (dd, J = 7.7, 7.3 Hz, 1H), 7. 07 (dd, J = 8.2, 1.2 Hz, 1H), 7.21 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 15.6 Hz, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8. 3 Hz, 2H), 7.83 (s, 1H), 8.13 (d, J = 7.4 Hz, 1H), 11.08 (s, 1H)
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N-pentylacrylamide (Compound 2 -6)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 0.88 (t, J = 7.0 Hz, 3H), 1.42-1.50 (m, 2H), 1.90-1.95 (m, 4H), 3.13-3-1.18 (M, 2H), 6.68 (d, J = 15.9 Hz, 1H), 7.03 (dd, J = 7.9, 7.3 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 7.21 (dd, J = 7.9, 7.3 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 15.8 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.80 (s, 1H) , 8.15 (t, J = 5.6 Hz, 1H), 11.08 (s, 1H)
(2E) -N- (4-Methoxyphenyl) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl ) Acrylamide (Compound 2-7)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.74 (s, 3H), 6.92 (d, J = 15.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.04 (ddd, J = 8.2, 7.6, 1.2 Hz, 1H), 7.08 (dd, J = 8.2, 1.2 Hz, 1H), 7.21 (ddd, J = 7.6, 7. 6, 1.2 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 15.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.75 (s, 4H), 7.82 (s, 1H), 10.19 (s, 1H), 11.10 (s, 1H)
(2E) -N- (3- (hydroxymethyl) phenyl) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) Methyl) phenyl) acrylamide (compound 2-8)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.50 (d, J = 5.8 Hz, 2H), 5.22 (t, J = 5.8 Hz, 1H), 6.92 (d, J = 15.8 Hz, 1H), 7 .03 (dd, J = 7.9, 7.3 Hz, 1H), 7.08 (dd, J = 8.2, 1.2 Hz, 1H), 7.21 (dd, J = 7.9) , 7.3 Hz, 1H), 7.34-7.41 (m, 2H), 7.60-7.66 (m, 2H), 7.72-7.82 (m, 6H), 8. 58 (d, J = 6.8, 1.5 Hz, 1H), 10.19 (s, 1H), 11.10 (s, 1H)
Methyl 4-((2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylamide) butyric acid ( Compound 2-9)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.69-1.73 (m, 2H), 2.3-2.38 (m, 2H), 3.18-3.22 (m, 2H), 3.60 (s, 3H), 6 .68 (d, J = 15.8 Hz, 1H), 7.04 (dd, J = 7.6, 7.3 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H) , 7.21 (dd, J = 7.6, 7.3 Hz, 1H), 7.36 (dd, J = 7.3 Hz, 1H), 7.45 (d, J = 15.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.81 (s, 1H), 7.82 (d, J = 8.2 Hz, 2H), 8.20-8. 21 (m, 1H), 11.08 (s, 1H)
(2E) -3- (3-Fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N- ( Pyridin-3-ylmethyl) acrylamide (Compound 2-10)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.44 (d, J = 5.8 Hz, 2H), 6.78 (d, J = 15.9 Hz, 1H), 7.01 (m, 1H), 7.01 (dd, J = 7.9, 1.2 Hz, 1H), 7.19 (m, 1H), 7.29-7.32 (m, 2H), 7.38 (dd, J = 7.9, 4.3 Hz) , 1H), 7.51 (d, J = 15.9 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 7.9 Hz, 2H) ), 7.96 (s, 1H), 8.48 (dd, J = 4.6, 1.5 Hz, 1H), 8.54 (d, J = 1.5 Hz, 1H), 8.73. (T, J = 5.8 Hz, 1H), 11.02 (s, 1H)
(2E) -N-cyclopropyl-3- (3-fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl ) Acrylamide (Compound 2-11)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 0.45-0.50 (m, 2H), 0.65-0.70 (m, 2H), 2.78 (m, 1H), 6.63 (d, J = 15.9 Hz, 1H ), 6.90-7.10 (m, 2H), 7.15 (m, 1H), 7.27-7.35 (m, 3H), 7.45 (d, J = 15.9 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 8.25 (d, J = 4.6 Hz, 1H), 11.03 (s, 1H)
(2E) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N- (pyridin-3-ylmethyl) acrylamide (Compound 2-12)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 3.85 (s, 2H), 4.41 (d, J = 5.9 Hz, 2H), 6.62 (d, J = 15.8 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 7.27-7.51 (m, 8H), 7.59 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.71 (s, 1H), 8.46 (dd, J = 4.8, 1.7 Hz, 1H), 8.52 (d, J = 1.7 Hz, 1H), 8. 66 (t, J = 5.9 Hz, 1H), 11.81 (s, 1H)
(2E) -N-cyclopropyl-3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide (Compound 2-13)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 0.42-0.46 (m, 2H), 0.64-0.69 (m, 2H), 2.75 (m, 1H), 3.84 (s, 2H), 6.48 (d , J = 15.9 Hz, 1H), 7.14 (m, 1H), 7.28-7.50 (m, 7H), 7.58 (d, J = 7.6 Hz, 1H), 7 .72 (s, 1H), 8.16 (d, J = 4.6 Hz, 1H), 11.80 (s, 1H)
3- (4-((E) -3- (azepan-1-yl) -3-oxopropen-1-yl) benzylidene) -3,4-dihydroquinolin-2 (1H) -one (compound 2-14 )

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.45-1.50 (m, 4H), 1.60-1.70 (m, 4H), 3.50 (t, J = 6.3 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 3.85 (s, 2H), 7.09 (d, J = 15.6 Hz, 1H), 7.14 (m, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.45 (m, 1H), 7.46 (d, J = 15.6 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.68 (s, 1H), 11.80 (s, 1H)
(2E) -N- (3,5-dimethoxyphenyl) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide (Compound 2-15 )

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 3.70 (s, 6H), 3.86 (s, 2H), 6.22 (s, 1H), 6.77 (d, J = 15.6 Hz, 1H), 6.94 (s, 2H), 7.13 (s, 1H), 7.25-7.80 (m, 9H), 10.13 (s, 1H), 11.80 (s, 1H)
(2E) -3- (4-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) phenyl) -N- (pyridin-4-yl) acrylamide (Compound 2-16)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 3.86 (s, 2H), 6.22 (s, 1H), 6.78 (d, J = 15.6 Hz, 1H), 7.13 (s, 1H), 7.25-7. 80 (m, 12H), 10.92 (s, 1H), 11.80 (s, 1H)
(2E) -N- (4-acetylphenyl) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide (Compound 2-17)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.54 (s, 3H), 3.88 (s, 2H), 6.82 (d, J = 15.9 Hz, 1H), 7.16 (m, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.45 (m, 1H), 7.57-7.63 (m, 4H), 7. 75 (s, 1H), 7.83 (d, J = 8.9 Hz, 2H), 7.96 (d, J = 8.9 Hz, 2H), 10.54 (s, 1H), 11. 82 (s, 1H)
(2E) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N- (4-propylphenyl) acrylamide (Compound 2-18)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 0.88 (t, J = 7.3 Hz, 3H), 1.56 (t, J = 7.3 Hz, 2H), 2.50-2.55 (m, 2H), 3.87 ( s, 2H), 6.78 (d, J = 15.9 Hz, 1H), 7.13 (m, 1H), 7.14 (d, J = 8.6 Hz, 2H), 7.29 ( d, J = 8.2 Hz, 1H), 7.35-7.48 (m, 3H), 7.50-7.63 (m, 6H), 7.74 (s, 1H), 10.11. (S, 1H), 11.81 (s, 1H)
(2E) -N-tert-butoxy-3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide (Compound 2-19)

¹ H-NMR (300 MHz, DMSO-d ₆ )
δ 1.18 (s, 9H), 3.84 (s, 2H), 6.49 (d, J = 15.6 Hz, 1H), 7.10 (m, 1H), 7.25-7. 35 (m, 3H), 7.40-7.50 (m, 4H), 7.57 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 10.54 (brs) , 1H), 11.79 (s, 1H)
(2E) -N-hydroxy-3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide (Compound 2-20)

¹ H-NMR (300 MHz, DMSO-d ₆ )
δ 3.85 (s, 2H), 6.58 (d, J = 16.2 Hz, 1H), 7.13 (m, 1H), 7.27 (d, J = 7.9 Hz, 1H) 7.33 (d, J = 7.9 Hz, 2H), 7.43 (m, 1H), 7.55-7.65 (m, 4H), 7.71 (s, 1H), 10. 12 (brs, 1H), 11.79 (s, 1H)
(2E) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N- (pyridin-3-ylmethyl) acrylamide (Compound 2-21)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.95 (s, 2H), 4.39 (d, J = 5.8 Hz, 2H), 6.57 (d, J = 15.9 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 7.25-7.38 (m, 6H), 7.42-7.48 (m, 2H), 7.61-7.68 (m, 2H), 7.70. (D, J = 15.9 Hz, 1H), 8.46 (d, J = 4.9, 1.8 Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8 .68 (t, J = 5.8 Hz, 1H), 11.87 (s, 1H)
(2E) -N-cyclopropyl-3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide (Compound 2-22)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 0.40-0.46 (m, 2H), 0.64-0.69 (m, 2H), 2.72 (m, 1H), 3.94 (s, 2H), 6.42 (d , J = 15.9 Hz, 1H), 7.10 (m, 1H), 7.23 (s, 1H), 7.24-7.37 (m, 4H), 7.40-7.50 ( m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 15.9 Hz, 1H), 8.19 (d, J = 4.6 Hz, 1H), 11.89 (s, 1H)
(2E) -N- (5-methylpyridin-2-yl) -3- (2-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) phenyl) acrylamide (Compound 2 -23)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.25 (s, 3H), 3.98 (s, 2H), 6.93 (d, J = 15.6 Hz, 1H), 7.10 (m, 1H), 7.25-7. 50 (m, 7H), 7.60-7.67 (m, 2H), 7.82 (d, J = 15.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H) ), 8.16 (d, J = 2.1 Hz, 1H), 10.64 (s, 1H), 11.89 (s, 1H)
(2E) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N-phenylacrylamide (Compound 2-24)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.00 (s, 2H), 6.76 (d, J = 15.6 Hz, 1H), 7.07 (m, 1H), 7.30-7.46 (m, 7H), 7. 50 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 15.6 Hz, 1H), 7.91 ( d, J = 9.2 Hz, 2H), 8.24 (d, J = 9.2 Hz, 2H), 10.20 (s, 1H), 11.88 (s, 1H)
(2E) -N- (4-Nitrophenyl) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide (Compound 2-25)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.00 (s, 2H), 6.77 (d, J = 15.6 Hz, 1H), 7.10 (m, 1H), 7.30-7.46 (m, 6H), 7. 50 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 15.6 Hz, 1H), 7.91 ( d, J = 9.2 Hz, 2H), 8.24 (d, J = 9.2 Hz, 2H), 10.80 (s, 1H), 11.90 (s, 1H)
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) -N- ( Pyridin-3-ylmethyl) acrylamide (Compound 2-26)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.43 (d, J = 5.9 Hz, 2H), 6.55 (d, J = 15.9 Hz, 1H), 7.03-7.10 (m, 2H), 7.23 ( t, J = 8.1 Hz, 1H), 7.36-7.41 (m, 2H), 7.48 (d, J = 15.9 Hz, 1H), 7.72 (d, J = 7) .8 Hz, 1H), 8.01 (s, 1H), 8.13 (s, 1H), 8.48 (dd, J = 4.9, 1.7 Hz, 1H), 8.54 (d , J = 1.7 Hz, 1H), 8.73 (t, J = 5.8 Hz, 1H), 11.07 (s, 1H)
(2E) -N-benzyl-3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) Acrylamide (Compound 2-27)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.40 (d, J = 5.8 Hz, 2H), 6.57 (d, J = 15.9 Hz, 1H), 7.00-7.14 (m, 2H), 7.20− 7.38 (m, 6H), 7.41 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 15.9 Hz, 1H), 7.78 (d, J = 1) .5 Hz, 1H), 8.01 (s, 1H), 8.11 (s, 1H), 8.65 (t, J = 5.8 Hz, 1H), 11.06 (s, 1H)
(2E) -N-ethyl-N- (2-hydroxyethyl) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene ) Methyl) thiophen-3-yl) acrylamide (Compound 2-28)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.07 (t, J = 7.0 Hz, 3Hx1 / 2), 1.16 (t, J = 7.0 Hz, 3Hx1 / 2), 3.38-3.49 (m, 2H), 3.50-3.61 (m, 4H), 4.71 (t, J = 5.2 Hz, 1Hx1 / 2), 4.83 (t, J = 5.2 Hz, 1Hx1 / 2), 7 .00-7.10 (m, 3H), 7.20 (m, 1H), 7.35-7.55 (m, 2H), 7.95-8.05 (m, 2H), 8.15 (S, 1Hx1 / 2), 8.20 (s, 1Hx1 / 2), 11.02 (s, 1H)
(2E) -N- (4-methoxybenzyl) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene -3-yl) acrylamide (compound 2-29)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.73 (s, 3H), 4.32 (d, J = 5.8 Hz, 2H), 6.55 (d, J = 15.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.03-7.11 (m, 2H), 7.23 (m, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.40 ( d, J = 6.7 Hz, 1H), 7.46 (d, J = 15.9 Hz, 1H), 7.77 (s, 1H), 8.00 (s, 1H), 8.10 ( s, 1H), 8.57 (t, J = 5.8 Hz, 1H), 11.06 (s, 1H)
(2E) -N-ethyl-3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) -N- (pyridin-3-ylmethyl) acrylamide (Compound 2-30)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.07 (t, J = 7.0 Hz, 3HX1 / 3), 1.17 (t, J = 7.0 Hz, 3HX2 / 3), 3.18-3.50 (m, 2HX2 / 3) ), 3.57 (q, J = 7.0 Hz, 3HX1 / 3), 4.68 (s, 2HX2 / 3), 4.88 (s, 2HX1 / 3), 7.05-7.60 ( m, 8H), 7.85-8.26 (m, 3H), 8.58 (m, 1H), 11.03 (s, 1H)
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) -N- ( (6- (Trifluoromethyl) pyridin-3-yl) methyl) acrylamide (Compound 2-31)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.53 (d, J = 5.8 Hz, 2H), 6.56 (d, J = 15.9 Hz, 1H), 7.03-7.10 (m, 2H), 7.22 ( t, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 15.9 Hz, 1H), 7.81 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.97 (dd, J = 8.0, 1.5 Hz, 1H), 8.01 (s, 1H), 8. 14 (s, 1H), 8.72 (d, J = 1.5 Hz, 1H), 8.82 (t, J = 5.8 Hz, 1H), 11.06 (s, 1H)
tert-Butyl 4-((2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene-3- Yl) acrylamide) piperidine-1-carboxylate (compound 2-32)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.20-1.38 (m, 2H), 1.39 (s, 9H), 1.72-1.84 (m, 2H), 2.80 (m, 1H), 3.20 (m , 1H), 3.54 (m, 1H), 4.19 (m, 1H), 4.32 (m, 1H), 6.88 (d, J = 7.9 Hz, 1H), 7.06 (T, J = 7.9 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 15.6 Hz, 1H), 7.22 (t , J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 15.6 Hz, 1H), 7.97 (s, 1H) ), 8.02 (s, 1H), 8.19 (s, 1H), 11.03 (s, 1H)
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) -N- ( Piperidin-4-yl) acrylamide hydrochloride (Compound 2-33)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.30-1.52 (m, 2H), 1.90-2.10 (m, 2H), 2.75 (m, 1H), 3.18 (m, 1H), 3.30 (m , 1H), 4.30 (m, 1H), 4.50 (m, 1H), 7.06 (t, J = 7.9 Hz, 1H), 7.10 (d, J = 7.9 Hz) , 1H), 7.19 (d, J = 15.3 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H) ), 7.49 (d, J = 15.3 Hz, 1H), 7.98 (s, 1H), 8.02 (s, 1H), 8.09 (brs, 2H), 8.10 ( br d, 1H), 8.21 (s, 1H), 11.04 (s, 1H)
tert-Butyl 4-((2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene-3- Yl) acryloyl) piperazine-1-carboxylate (compound 2-34)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 1.42 (s, 9H), 3.30-3.41 (m, 4H), 3.50-3.60 (m, 2H), 3.65-3.72 (m, 2H), 7 .06 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 15.3 Hz, 1H), 7.22. (T, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 15.3 Hz, 1H), 7.97 (s , 1H), 8.01 (s, 1H), 8.20 (s, 1H), 11.03 (s, 1H)
2-((4-((E) -3-oxo-3- (4- (pyrimidin-2-yl) piperazin-1-yl) propen-1-yl) thiophen-2-yl) methylene) -2H- Benzo [b] [1,4] thiazin-3 (4H) -one (Compound 2-35)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.60-3.90 (m, 8H), 6.68 (t, J = 4.9 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 7.10 ( d, J = 7.9 Hz, 1H), 7.22 (d, J = 15.3 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 15.3 Hz, 1H), 7.99 (s, 1H), 8.04 (s, 1H), 8.22 (s, 1H), 8.40 (d, J = 4.9 Hz, 2H), 11.03 (s, 1H)
(2E) -N- (3,5-dimethoxyphenyl) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl ) Thiophen-3-yl) acrylamide (Compound 2-36)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.73 (s, 6H), 6.24 (d, J = 2.1 Hz, 1H), 6.66 (d, J = 15.6 Hz, 1H), 6.96 (d, J = 2.1 Hz, 2H), 7.05-7.15 (m, 2H), 7.23 (m, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.58 ( d, J = 15.6 Hz, 1H), 7.81 (s, 1H), 8.03 (s, 1H), 8.18 (s, 1H), 10.20 (s, 1H), 11. 09 (s, 1H)
(2E) -N-((S) -1-hydroxy-3- (1H-indol-3-yl) propan-2-yl) -3- (5-((3-oxo-3,4-dihydro- 2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) acrylamide (Compound 2-37)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.82 (dd, J = 14.4, 7.0 Hz, 1H), 2.98 (dd, J = 14.4, 6.4 Hz, 1H), 3.40-3.50 (m , 2H), 4.12 (m, 1H), 4.80 (m, 1H), 6.56 (d, J = 15.6 Hz, 1H), 6.98 (m, 1H), 7.03. −7.13 (m, 4H), 7.23 (m, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 15.6 Hz, 1H) 7.40 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.74 (s, 1H), 8.00 (s, 1H) , 8.00 (s, 1H), 8.07 (s, 1H), 10.77 (s, 1H), 11.07 (s, 1H)
(2E) -3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene 3-yl) -N- (pyridin-3-ylmethyl) acrylamide (Compound 2-38)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.42 (d, J = 5.8 Hz, 2H), 6.55 (d, J = 15.9 Hz, 1H), 7.35-7.39 (m, 3H), 7.48 ( d, J = 15.9 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.83 (s, 1H), 8.05 (s, 1H), 8.16 (s, 1H), 8.47 (d, J = 4.9 Hz, 1H), 8.53 (s, 1H), 8.72 ( t, J = 5.8 Hz, 1H), 11.27 (s, 1H)
(2E) -3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene 3-yl) -N- (pyridin-4-ylmethyl) acrylamide (Compound 2-39)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 4.43 (d, J = 5.8 Hz, 2H), 6.59 (d, J = 15.9 Hz, 1H), 7.28 (d, J = 6.1 Hz, 2H), 7 .35-7.39 (m, 2H), 7.50 (d, J = 15.9 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.85 (s, 1H), 8.06 (s, 1H), 8.18 (s, 1H), 8.51 (d, J = 6.1 Hz, 2H), 8.72 (t, J = 5.8 Hz, 1H), 11.27 (s, 1H)
2-((4-((E) -3- (4-methylpiperazin-1-yl) -3-oxopropen-1-yl) thiophen-2-yl) methylene) -6- (trifluoromethyl)- 2H-benzo [b] [1,4] thiazin-3 (4H) -one (compound 2-40)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.22 (s, 3H), 2.25-2.40 (m, 4H), 3.50-3.80 (m, 4H), 7.18 (d, J = 15.3 Hz, 1H ), 7.35-7.40 (m, 2H), 7.49 (d, J = 15.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 8.00. (S, 1H), 8.06 (s, 1H), 8.23 (s, 1H), 11.24 (s, 1H)
2-((4-((E) -3-morpholino-3-oxopropen-1-yl) thiophen-2-yl) methylene) -6- (trifluoromethyl) -2H-benzo [b] [1, 4] Thiazin-3 (4H) -one (Compound 2-41)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.50-3.80 (m, 8H), 7.16 (d, J = 15.3 Hz, 1H), 7.35-7.40 (m, 2H), 7.52 (d, J = 15.3 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 8.00 (s, 1H), 8.05 (s, 1H), 8.24 (s, 1H) ) 11.24 (s, 1H)
2-((4-((E) -3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropen-1-yl) thiophen-2-yl) methylene) -6- (trifluoro Methyl) -2H-benzo [b] [1,4] thiazin-3 (4H) -one (Compound 2-42)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 2.65 (bs, 8H), 3.50-3.70 (m, 4H), 3.80-4.00 (m, 1H), 7.16 (d, J = 15.3 Hz, 1H ), 7.35-7.40 (m, 2H), 7.52 (d, J = 15.3 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 8.00. (S, 1H), 8.05 (s, 1H), 8.24 (s, 1H) 11.24 (s, 1H)
2-((4-((E) -3-oxo-3- (piperazin-1-yl) propen-1-yl) thiophen-2-yl) methylene) -6- (trifluoromethyl) -2H-benzo [B] [1,4] thiazin-3 (4H) -one hydrochloride (Compound 2-43)

¹ H-NMR (500 MHz, DMSO-d ₆ )
δ 3.70-4.00 (m, 8H), 7.18 (d, J = 15.3 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.40 ( s, 1H), 7.55 (d, J = 15.3 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 8.00 (s, 1H), 8.04 ( s, 1H), 8.26 (s, 1H), 8.95 (brs, 2H), 11.26 (s, 1H)
(2E) -3- (5-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) thiophen-3-yl) -N- (pyridin-3-ylmethyl) acrylamide (compound 2-44)

¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 4.03 (s, 2H), 4.39 (d, J = 5.8 Hz, 2H), 6.39 (d, J = 15.9 Hz, 1H), 7.12 (s, 1H) 7.16 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.35 (dd, J = 7.9, 4.9 Hz, 1H), 7.37 (d, J = 15.9 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 8.45 (dd, J = 4.9, 1.2) Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.57 (t, J = 5.8 Hz, 1H), 11.86 (s, 1H)
[Production example]
Representative production examples of the compound of the present invention are shown below.

1) Tablet formulation 1 Compound of the present invention in 100 mg 1 mg
Lactose 66.4mg
Corn starch 20mg
Carboxymethylcellulose calcium 6mg
Hydroxypropylcellulose 4mg
Magnesium stearate 0.6mg
A tablet having the above formulation is coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the desired coated tablet. Moreover, a desired tablet can be obtained by changing suitably the kind and quantity of this invention compound and an additive.

2) Capsule Formulation 2 150 mg of the present compound 5 mg
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 drop formulation 3 100 mg of the present compound in 100 mL
Sodium chloride 900mg
Polysorbate 80 200mg
Sodium hydroxide Appropriate hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount By appropriately changing the type and amount of the compound of the present invention and additives, a desired eye drop can be obtained.

[Pharmacological test]
1. Evaluation Test for Angiogenesis Inhibitory Effect As one of the widely used methods for evaluating the angiogenesis inhibitory effect of drugs, a cell growth inhibitory action test using a VEGF-induced HUVEC proliferation reaction evaluation system is disclosed in Cancer Res. 59, 99-106 (1999). Therefore, according to the method described in the above-mentioned literature, the cell growth inhibitory action test of the compound of the present invention was conducted, the cell growth inhibition rate was calculated, and the angiogenesis inhibitory effect of the compound of the present invention was evaluated using it as an index.

(Preparation of test compound solution)
The test compound was dissolved in dimethyl sulfoxide (hereinafter, DMSO), and the resulting solution was diluted with a commercially available phosphate buffer solution (hereinafter, PBS) to prepare a 20 μg / mL test compound solution.

(Preparation of HUVEC suspension)
HUVEC was suspended in F12K medium containing 0.5% fetal bovine serum (hereinafter FBS) to prepare a HUVEC suspension at 2 × 10 4 cells / mL.

(Preparation of VEGF solution)
VEGF was dissolved in PBS containing 0.1% bovine serum albumin, and the resulting solution was diluted with F12K medium containing 0.5% FBS to prepare a 400 ng / mL VEGF solution.

(Test method and measurement method)
1) 100 μL of HUVEC suspension was seeded in each well of a 96-well plate coated with type I collagen (2 × 10 3 cells per well).

2) One day after sowing, 5 μL of the test compound solution was added per well.

3) One hour after the addition of the test compound solution, 5 μL of VEGF solution was added per well.

4) Three days after the addition of the VEGF solution, 10 μL of WST-8 assay reagent (Dojin Chemical) was added per well.

5) After 3 hours, the plate was attached to an absorptiometer (multi-label counter ARVO), and the absorbance of each well suspension (hereinafter referred to as test compound suspension) at 450 nm was measured.

6) In place of the test compound solution, 1.0% DMSO was used, and the others were tested in the same manner as in the above 1-5), and the result was used as a control.

In addition, between each said test process, it incubated in 37 degreeC, 5% carbon dioxide, and 95% oxygen conditions in the incubator.

(Calculation of cell growth inhibition rate)
The cell growth inhibition rate (%), which is an index of the angiogenesis inhibitory effect, was calculated from the formula shown below.

(a formula)
Cell growth inhibition rate (%)
= 100-{(absorbance of test compound suspension-A) / (absorbance of control-A)} × 100
A: Absorbance of only cell suspension (cell + medium) (test results and discussion)
As an example of the test results, Table 1 shows the cell growth inhibition rates (%) of the test compounds (Compound 2-10, Compound 2-12, and Compound 2-26).

  As shown in Table 1, the compound of the present invention exhibited an excellent cell growth inhibitory action. Therefore, the compound of the present invention has an excellent angiogenesis inhibitory effect.

Claims (8)

A compound represented by the following general formula [I] or a salt thereof.

[Wherein, ring A represents an aryl group or an aromatic heterocyclic ring;
R ₁ represents a hydrogen atom, a halogen atom, an alkyl group or a halogenoalkyl group;
X represents S or CH ₂ ;
Y represents a hydroxyl group, an alkoxy group or NR ₂ R ₃ ;
R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group;
R ₂ and R ₃ together may form a non-aromatic heterocycle;
Each alkyl group described above is one or more selected from a hydroxyl group, an amino group, a carboxyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylamino group, an aryl group, an aromatic heterocyclic group and a non-aromatic heterocyclic group. May have a substituent;
Each of the above aryl groups is a halogen atom, amino group, nitro group, alkyl group, halogenoalkyl group, alkoxy group, hydroxyalkyl group, alkylcarbonyl group, alkyloxycarbonyl group, alkylamino group, alkylcarbonylamino group, aromatic heterocycle. May have one or more substituents selected from a cyclic group and a non-aromatic heterocyclic group;
Each of the aromatic heterocyclic groups described above has one or more substituents selected from a halogen atom, amino group, alkyl group, halogenoalkyl group, hydroxyalkyl group, alkyloxycarbonyl group, alkylamino group and alkylcarbonylamino group. May have;
Each non-aromatic heterocyclic group described above is selected from a halogen atom, an amino group, an alkyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkyloxycarbonyl group, an alkylamino group, an alkylcarbonylamino group, and an aromatic heterocyclic group. It may have one or more substituents. ] In general formula [I],
Ring A represents a benzene ring or a thiophene ring;
Ring A may be substituted with a halogen atom;
R ₁ represents a hydrogen atom or a halogenoalkyl group;
X represents S or CH ₂ ;
Y represents a hydroxyl group, an alkoxy group or NR ₂ R ₃ ;
R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group;
R ₂ and R ₃ together may form a non-aromatic heterocycle;
The alkyl group defined above may have one or more substituents selected from a hydroxyl group, an alkyloxycarbonyl group, an aryl group, and an aromatic heterocyclic group;
The aryl group defined above may have one or more substituents selected from a nitro group, an alkyl group, an alkoxy group, a hydroxyalkyl group, an alkylcarbonyl group and an alkyloxycarbonyl group;
The aromatic heterocyclic group defined above may have one or more substituents selected from an alkyl group and a halogenoalkyl group;
The compound according to claim 1, wherein the non-aromatic heterocyclic group defined above may have one or more substituents selected from an alkyl group, an alkylamino group, an alkyloxycarbonyl group, and an aromatic heterocyclic group. Or a salt thereof. In general formula [I],
Ring A represents a benzene ring or a thiophene ring;
When ring A is a benzene ring, the benzene ring may be substituted with a halogen atom;
R ₁ represents a hydrogen atom or a halogenoalkyl group;
X represents S or CH ₂ ;
Y represents a hydroxyl group, an alkoxy group or NR ₂ R ₃ ;
R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group;
When R ₂ or R ₃ is an alkyl group, the alkyl group is one or more selected from a hydroxyl group, an alkyloxycarbonyl group, an aryl group, an alkoxyaryl group, an aromatic heterocyclic group, and a halogenoalkyl aromatic heterocyclic group. May have a substituent;
When R ₂ or R ₃ is an aryl group, the aryl group has one or more substituents selected from a nitro group, an alkyl group, an alkoxy group, a hydroxyalkyl group, an alkylcarbonyl group, and an alkyloxycarbonyl group. Well;
When R ₂ or R ₃ is an aromatic heterocyclic group, the aromatic heterocyclic group may be substituted with an alkyl group;
When R ₂ or R ₃ is a non-aromatic heterocyclic group, the non-aromatic heterocyclic group may be substituted with an alkyloxycarbonyl group;
R ₂ and R ₃ together may form a non-aromatic heterocycle;
When R ₂ and R ₃ together form a non-aromatic heterocyclic ring, the non-aromatic heterocyclic ring is one or more selected from an alkyl group, an alkylamino group, an alkyloxycarbonyl group, and an aromatic heterocyclic group The compound or its salt of Claim 1 which may have a substituent of these. In general formula [I],
Ring A represents a benzene ring, a fluorobenzene ring or a thiophene ring;
R ₁ represents a hydrogen atom or a trifluoromethyl group;
X represents S or CH ₂ ;
Y is a hydroxyl group, tert-butoxy group, hydroxyamino group, tert-butoxyamino group, pyridin-2-ylmethylamino group, pyridin-3-ylmethylamino group, pyridin-4-ylmethylamino group, 2-trifluoro Methylpyridin-5-ylmethylamino group, benzylamino group, 4-methoxybenzylamino group, n-pentylamino group, 3-methoxycarbonylpropylamino group, N-ethyl-N-pyridin-3-ylmethylamino group, N-ethyl-N-2-hydroxyethylamino group, cyclopropylamino group, cyclopentaneamino group, phenylamino group, 3-hydroxymethylphenylamino group, 4-propylphenylamino group, 4-methoxyphenylamino group, 4 -Methylcarbonylphenylamino group, 4-methoxycarbo Ruphenylamino group, 4-nitrophenylamino group, 3,5-dimethoxyphenylamino group, pyridin-2-ylamino group, pyridin-4-ylamino group, 5-methylpyridin-2-ylamino group, piperidin-4-ylamino Group, 1-tert-butoxycarbonylpiperidin-4-ylamino group, 3-dimethylaminopyrrolidin-1-yl group, piperidin-1-yl group, piperazin-1-yl group, 4-methylpiperazin-1-yl group, 4-pyrimidin-2-ylpiperazin-1-yl group, 4-tert-butoxycarbonylpiperazin-1-yl group, morpholin-4-yl group, azepan-1-yl group or 1-hydroxy-3- (1H The compound according to claim 1 or a salt thereof, which represents -indol-3-yl) propan-2-ylamino group. (2E) -tert-butyl 3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylate,
(2E) -tert-butyl 3- (3-fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) Acrylate,
(2E) -tert-butyl 3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylate,
(2E) -tert-butyl 3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylate,
(2E) -tert-butyl 3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) Acrylate,
(2E) -tert-butyl 3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) Methyl) thiophen-3-yl) acrylate,
(2E) -tert-butyl 3- (5-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) thiophen-3-yl) acrylate,
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylic acid,
(2E) -3- (3-fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylic acid,
(2E) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylic acid,
(2E) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylic acid,
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) acrylic acid
(2E) -3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene -3-yl) acrylic acid,
(2E) -3- (5-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) thiophen-3-yl) acrylic acid,
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N- (pyridine-3 -Ylmethyl) acrylamide,
2- (4-((E) -3-oxo-3- (piperidin-1-yl) propen-1-yl) benzylidene) -2H-benzo [b] [1,4] thiazine-3 (4H) -On,
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N- (pyridine-2 -Yl) acrylamide,
Methyl 4-((2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylamide) benzoate ,
(2E) -N-cyclopentyl-3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylamide;
(2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N-pentylacrylamide,
(2E) -N- (4-methoxyphenyl) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) Phenyl) acrylamide,
(2E) -N- (3- (hydroxymethyl) phenyl) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene ) Methyl) phenyl) acrylamide,
Methyl 4-((2E) -3- (4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) acrylamide) butyric acid ,
(2E) -3- (3-Fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) phenyl) -N- (Pyridin-3-ylmethyl) acrylamide,
(2E) -N-cyclopropyl-3- (3-fluoro-4-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) Phenyl) acrylamide,
(2E) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N- (pyridin-3-ylmethyl) acrylamide,
(2E) -N-cyclopropyl-3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
3- (4-((E) -3- (azepan-1-yl) -3-oxopropen-1-yl) benzylidene) -3,4-dihydroquinolin-2 (1H) -one,
(2E) -N- (3,5-dimethoxyphenyl) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -3- (4-((2-oxo-1,2-dihydroquinolin-3 (4H) -ylidene) methyl) phenyl) -N- (pyridin-4-yl) acrylamide,
(2E) -N- (4-acetylphenyl) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N- (4-propylphenyl) acrylamide,
(2E) -N-tert-butoxy-3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -N-hydroxy-3- (4-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N- (pyridin-3-ylmethyl) acrylamide,
(2E) -N-cyclopropyl-3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -N- (5-methylpyridin-2-yl) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) -N-phenylacrylamide,
(2E) -N- (4-nitrophenyl) -3- (2-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) methyl) phenyl) acrylamide,
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) -N- (Pyridin-3-ylmethyl) acrylamide,
(2E) -N-benzyl-3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl ) Acrylamide,
(2E) -N-ethyl-N- (2-hydroxyethyl) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazine-2- Ylidene) methyl) thiophen-3-yl) acrylamide,
(2E) -N- (4-methoxybenzyl) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) Thiophen-3-yl) acrylamide,
(2E) -N-ethyl-3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl ) -N- (pyridin-3-ylmethyl) acrylamide,
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) -N- ((6- (trifluoromethyl) pyridin-3-yl) methyl) acrylamide,
Tert-butyl 4-((2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene-3 -Yl) acrylamide) piperidine-1-carboxylate,
(2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) -N- (Piperidin-4-yl) acrylamide hydrochloride,
Tert-butyl 4-((2E) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene-3 -Yl) acryloyl) piperazine-1-carboxylate,
2-((4-((E) -3-oxo-3- (4- (pyrimidin-2-yl) piperazin-1-yl) propen-1-yl) thiophen-2-yl) methylene) -2H -Benzo [b] [1,4] thiazin-3 (4H) -one,
(2E) -N- (3,5-dimethoxyphenyl) -3- (5-((3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) Methyl) thiophen-3-yl) acrylamide,
(2E) -N-((S) -1-hydroxy-3- (1H-indol-3-yl) propan-2-yl) -3- (5-((3-oxo-3,4-dihydro -2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophen-3-yl) acrylamide,
(2E) -3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene -3-yl) -N- (pyridin-3-ylmethyl) acrylamide,
(2E) -3- (5-((3-oxo-6- (trifluoromethyl) -3,4-dihydro-2H-benzo [b] [1,4] thiazin-2-ylidene) methyl) thiophene -3-yl) -N- (pyridin-4-ylmethyl) acrylamide,
2-((4-((E) -3- (4-methylpiperazin-1-yl) -3-oxopropen-1-yl) thiophen-2-yl) methylene) -6- (trifluoromethyl) -2H-benzo [b] [1,4] thiazin-3 (4H) -one,
2-((4-((E) -3-morpholino-3-oxopropen-1-yl) thiophen-2-yl) methylene) -6- (trifluoromethyl) -2H-benzo [b] [1 , 4] thiazin-3 (4H) -one,
2-((4-((E) -3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropen-1-yl) thiophen-2-yl) methylene) -6- (tri Fluoromethyl) -2H-benzo [b] [1,4] thiazin-3 (4H) -one,
2-((4-((E) -3-oxo-3- (piperazin-1-yl) propen-1-yl) thiophen-2-yl) methylene) -6- (trifluoromethyl) -2H- Benzo [b] [1,4] thiazin-3 (4H) -one hydrochloride, and (2E) -3- (5-((2-oxo-1,2-dihydroquinoline-3 (4H) -ylidene) ) A compound selected from methyl) thiophen-3-yl) -N- (pyridin-3-ylmethyl) acrylamide or a salt thereof. The pharmaceutical composition containing the compound or its salt in any one of Claims 1-5. A therapeutic agent for a disease involving angiogenesis, comprising the compound according to any one of claims 1 to 5 or a salt thereof. Diseases involving angiogenesis are cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris or atherosclerosis The therapeutic agent according to claim 7.