WO2008053861A1

WO2008053861A1 - Novel compound having 1,4-benzoxazin-3-one skeleton

Info

Publication number: WO2008053861A1
Application number: PCT/JP2007/071069
Authority: WO
Inventors: Takahiro Honda; Koushi Fujisawa; Hiroyuki Aono; Masakazu Ban
Original assignee: Santen Pharmaceutical Co., Ltd.
Priority date: 2006-10-30
Filing date: 2007-10-30
Publication date: 2008-05-08
Also published as: JP2008231088A

Abstract

The object is to synthesize and study a novel compound having a 1,4-benzoxazin-3-one skeleton and find a pharmacological activity of the compound. Specifically provided is a compound represented by the formula [I] or a salt thereof [wherein the ring A represents a benzene ring, a thiophene ring, a thiazole ring, a furan ring or the like; R1 and R2 independently represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an aromatic heterocyclic group or the like; X represents a single bond, C=C, CH2-O, O-CH2, NH-CH2, CH2-NH or the like; Y represents a hydroxyl group, an alkyl group, an alkoxy group, NR3R4 or the like; and R3 and R4 independently represent 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.

Description

Specification

1,4 1-benzoxazine 1-new compound with 3-one skeleton

Technical field

[0001] The present invention relates to a novel compound having a 1,4-benzoxazin 3-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, vulgaris It is useful as a therapeutic agent for psoriasis vulgaris and atherosclerosis.

Background art

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 blood vessel formation, but in adults it is usually limited to limited areas such as the endometrium and follicles and the wound healing process. Only observed. However, it is pathological in diseases such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal angiopathy, diabetic macular edema, psoriasis vulgaris, and atherosclerosis Angiogenesis is observed and is closely related to the 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).

[0003] Vascular endothelial growth factor (hereinafter referred to as "VEGF") acts specifically on receptors (Flt_l, KDR / Flk-1, etc.) present on the surface of vascular endothelial cells to It is a factor that promotes the construction of capillary networks through proliferation, migration, and lumen 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 (see Patent Document 4). ), 2 aminonicotinic acid derivatives (see Patent Document 5), 4 pyridylalkylthio derivatives (see Patent Document 6), etc. Raise your power with S.

[0004] However, these patent documents do not describe a cyclic compound having a 1,4 monobenzoxazine-3-one skeleton.

[0005] On the other hand, Patent Document 7 reports a cyclic compound having a 1,4 benzoxazin 3 -on skeleton. In Patent Document 7, it is reported as a cell growth inhibitor by inhibiting tyrosine kinase! However, detailed data on the activity is not described in the patent document, and introduction of a hydrophilic substituent which is a feature of the compound of the present invention has not been attempted.

Non-Patent Document 1: Molecular Medicine vol.35 Special issue “Symptoms: Molecular mechanism of pathology”, Nakayama Shoten, 73-74 (1998)

Non-Patent Document 2: Protein Nucleic acid Enzyme Extra number “Advanced Drug Discovery”, Kyoritsu Shuppan, 1182— 11 87 (2000)

Patent Document 1: International Publication WO98 / 50356 Pamphlet

Patent Document 2: International Publication W098 / 35958 Pamphlet

Patent Document 3: International Publication WO97 / 30035 Pamphlet

Patent Document 4: International Publication WO00 / 27819 Pamphlet

Patent Document 5: International Publication WO01 / 55114 Pamphlet

Patent Document 6: International Publication WO04 / 078723 Pamphlet

Patent Document 7: International Publication WO00 / 75139 Pamphlet

Disclosure of the invention

Problems to be solved by the invention

[0006] Synthesis studies of novel compounds having a 1,4 benzoxazin 3-one skeleton and finding the pharmacological actions of these compounds are very interesting issues.

Means for solving the problem

[0007] The present inventors have conducted a synthetic study of a compound having a 1,4 benzoxazin 3-one skeleton, and have succeeded in creating a large number of new compounds.

[0008] Further, various studies on the pharmacological action of these compounds revealed that these compounds have angiogenesis inhibitory action, and are therapeutic agents for diseases involving angiogenesis, particularly cancer, rheumatoid arthritis, It has been found to be useful as a therapeutic agent for age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, psoriasis vulgaris, atherosclerosis, The present invention has been completed.

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

[0010] A compound represented by the following general formula [I] or a salt thereof.

[Wherein ring A represents a benzene ring, a thiophene ring, a thiazole ring or a furan ring;

The ring A may have one or more substituents selected from a halogen atom, an alkyl group, an alkoxy group and a halogenoalkyl group;

R and R are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or

1 2

Represents an aromatic heterocyclic group;

X represents a single bond, C = C, CH-0, O-CH, NH-CH or CH-NH;

2 2 2 2

Y represents a hydroxyl group, an alkyl group, an alkoxy group or NR R;

3 4

R and R are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group,

3 4

An alkyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group;

R and R may join together to form a non-aromatic heterocycle;

3 4

Each of the above-mentioned alkyl groups includes 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 Each of the above-mentioned aryl groups may be a halogen atom, an amino group, a nitro group, an alkyl group, a halogenoalkynole group, an alkoxy group, a cyclo group or a non-aromatic heterocyclic group. From alkyl groups, hydroxyalkyl groups, alkyl carbonyl groups, alkyloxycarbonyl groups, alkylamino groups, alkylcarbonylamino groups, alkyloxycarbonylamino groups, aromatic heterocyclic groups and non-aromatic heterocyclic groups May have one or more substituents selected;

Each of the above aromatic heterocyclic groups includes a halogen atom, an amino group, an alkyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkyloxycarbonyl group, an alkenoquinamino group, an alkylcarbonylamino group, and an alkyloxycarbonyl group. May have one or more substituents selected from an amino group;

Each of the above non-aromatic heterocyclic groups is selected from a halogen atom, an amino group, an alkyl group, a halogenoalkynole group, a hydroxyalkyl group, an alkyloxycarbonyl group, an alkylamino group, and an alkylcarbonylamino group. You may have a substituent. ] The invention's effect

[0012] The present invention provides a novel compound having a 1,4-benzoxazin 3-one skeleton useful as a pharmaceutical or a salt thereof. The novel cyclic compound according to the present invention has an excellent angiogenesis inhibitory 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 angiopathy, glycouria macular edema, psoriasis vulgaris, atherosclerosis, etc.

BEST MODE FOR CARRYING OUT THE INVENTION

[0013] Each group used in the claims and the specification shall have the following meanings throughout the claims and the specification.

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

“Alkyl” refers to a straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples include methinole, ethinole, n-propinole, n-butinole, n-pentinole, n-hexinole, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and the like.

“Alkenyl” refers to straight-chain or branched alkenyl having 2 to 8 carbon atoms. Specific examples include Bulle, Arinole, 1-propenyl, 3-Butul, 3-Pentul, 4-Hexe. Nyl, 5-heptul, 7-octatur, 1-methylbutyl and the like.

“Cycloalkyl” refers to cycloalkyl having 3 to 8 carbon atoms. Specific examples include cyclopropinole, cyclobutinole, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctyl and the like.

[0018] "Aryl" refers to a monocyclic aromatic hydrocarbon or a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms. In addition, the condensed polycyclic hydrocarbons formed by condensation of these monocyclic aromatic hydrocarbons or bicyclic or tricyclic condensed polycyclic aromatic hydrocarbons and cycloalkane rings are also referred to as “ Included in "Areel". 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, Tetrahydroanthryl and the like can be mentioned.

“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 fused ring Polycyclic aromatic Heterocycle.

[0020] Specific examples of monocyclic aromatic heterocycles include aromatic heterocycles having one hetero atom in the ring, such as pyrrole, furan, thiophene, and pyridine; imidazole, oxazole, thiazole, pyrazole, and isoxazole. Azole aromatic heterocycles such as isothiazole; aromatic heterocycles having two nitrogen atoms in the ring such as pyrazine and pyrimidine, etc. are condensed bicyclic or tricyclic condensed polycyclic aromatic heterocycles Specific examples of these include condensed aromatic heterocycles such as indole, isoindoinole, benzimidazole, benzoxazonole, benzothiazonole, quinoline, isoquinoline, naphthyridine, thianthrene, phenoxatine, and phenanthorin. Can be mentioned.

[0021] "Non-aromatic heterocycle" means a monocyclic non-aromatic heterocycle having one or more heteroatoms (nitrogen atom, oxygen atom, sulfur atom) in the ring, or bicyclic or tricyclic A fused polycyclic non-aromatic heterocycle of

[0022] As specific examples of monocyclic non-aromatic heterocycles, saturated non-aromatics having one hetero atom in the ring such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, homopiperazine, etc. Heterocyclic ring; imidazolidine, oxazolidine, thiazolidine, villa Saturated non-aromatic heterocycle having two heteroatoms in the ring such as zolidine, piperazine, morpholine, thiomorpholine, homopiperidine, homomorpholine; pyrroline, dihydrofuran, dihydrothiophene, tetrahydropyridine, dihydropyridine Unsaturated non-aromatic heterocycle having one heteroatom in the ring such as imidazoline, dihydropyran, pyran, etc .; Unsaturated non-aromatic heterocycle having two heteroatoms such as imidazoline, oxazoline, thiazoline, pyrazoline Specific examples of isotropic bicyclic or tricyclic fused polycyclic non-aromatic heterocycles include chroman, indoline, isoindoline, xanthine and the like.

“Alkoxy” refers to straight-chain or branched alkoxy having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n propoxy, n butoxy, n pentoxy, n hexenoreoxy, 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, etc. Specific examples of dialkylamino include ethylmethylamino, dimethylamino, jetylamino, dihexylamino and the like.

“Alkylcarbonyl” refers to a linear or branched alkylcarbonyl having 2 to 7 carbon atoms. Specific examples include methylcarbonyl, ethylcarbonyl, n-propylcarboninole, n-butinorecanoreponinore, n-pentinorecanoreponinore, n-hexinorecanoreponinore, isopropinorecanoreponinore, isobutinorecanoreponinore, sec butinorecanole pononole, tert butylcarbonyl, isopentylcarbonyl and the like.

[0026] "Alkyloxycarbonyl" refers to a straight or branched alkynoxycarbonyl having 2 to 7 carbon atoms. Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycanoleponinore, n-butoxycanoleponinole, n-pentoxycanoleponinole, n-hexinolexinoreponinore, isopropoxynoreponinore, isobutoxynoreponinore, sec — Butoxycarbonyl, tert butoxycarbonyl, isopentoxycarbonyl and the like.

[0027] "Alkylcarbonylamino" refers to a monoalkylcarbonylamino having 2 to 7 carbon atoms or a dialkylcarbonylamino having 4 to 14 carbon atoms. Monoalkylcarbo Specific examples of nilamino include methylcarbonylamino, ethylcarbonylamino-substituted hexylcarbonylamino, etc. Specific examples of dialkylcarbonylamino include dimethylcarbonylamino, jetylcarbonylamino, dihexylcarbonylamino, etc. Is mentioned.

[0028] "Alkyloxycarbonylamino" refers to a monoalkyloxy power ruponylamino having 2 to 7 carbon atoms or a dialkyloxycarbonylamino having 4 to 14 carbon atoms. Specific examples of monoalkyloxycarbonylamino include methoxycarbonylamidooxycarbonylamino, hexyloxycarbonylamino and the like S, dialkyloxycarbonylamino, ethylmethylcarbonylamino, dimethoxycarbonyl And amino, diethoxycarbonylamino, dihexyloxycarbonylamino and the like.

[0029] "Hydroxyalkyl" refers to an alkyl having one or more hydroxyl groups as substituents.

[0030] "Halogenoalkyl" refers to an alkyl having the same or different one or more halogen atoms as substituents.

[0031] The "halogenoaromatic heterocycle" refers to an aromatic heterocycle having the same or different one or more halogen atoms as substituents.

[0032] The "halogenoalkyl aromatic heterocycle" refers to an aromatic heterocycle having the same or different halogenoalkyl group as a substituent.

[0033] The "amino aromatic heterocycle" refers to an aromatic complex ring having one or more amino groups as a substituent.

[0034] When the compound of the present invention has a free hydroxy group, amino group, alkylamino group or alkyl group sulfonylamino group as a substituent, these substituents may be protected with a protecting group. In addition, when the aromatic heterocyclic group or the non-aromatic heterocyclic ring has a free nitrogen atom, the nitrogen atom may be protected with a protecting group.

[0035] The "protecting group for a free hydroxy group" is a substituted or unsubstituted alkyl group such as a methyl group, a methoxymethyl group, a benzyl group, a 4 methoxyphenylmethyl group, an aryl group, or an unsubstituted alkenyl group; Substituted or unsubstituted non-aromatic heterocyclic groups such as 3-bromotetrahydrobiranyl group, tetrahydrobiranyl group and tetrahydrofuranyl group; substituted or unsubstituted groups such as acetyl group, trifluoroacetyl group, benzoyl group and 4-chlorobenzoyl group Archi Lucalonyl group, or substituted or unsubstituted arylylcarbonyl group; methoxycarbonyl group, ethoxycarbonyl group, isobutoxycarbonyl group, tertbutoxycarbonyl group, benzyloxycarbonyl group, p methoxybenzyloxycarbonyl group, 9-fu A substituted or unsubstituted alkyloxycarbonyl group such as a norelenylmethoxycarbonyl group, a buroxycarbonyl group, an aryloxycarbonyl group, a phenyloxycarbonyl group, or a p-nitrophenyloxycarbonyl group; Unsubstituted alkenyloxycarbonyl group, or substituted or unsubstituted aryloxycarbonyl group; trimethylsilyl group, triethylsilinole group, triisopropylpropylsilyl group, tertbutyldimethylsilinole group, tertbutyldiphenylsilyl group, etc. Substituted silyl groups of It shows what is commonly used as a protecting group for the free hydroxy groups.

[0036] “A free amino group, a free alkylamino group, a free alkylcarbonylamino group, an aromatic heterocyclic group having a free nitrogen atom, or a non-aromatic heterocyclic group having a free nitrogen atom. “Protecting group” means an unsubstituted alkenyl group such as an aryl group; a hydrocarbonyl group such as a formyl group; a substitution such as an acetyl group, a trichloroacetyl group, a trifluoroacetyl group, a benzoyl group, a 4-chlorobenzoyl group, and a picolinol group. Or an unsubstituted alkylcarbonyl group, a substituted or unsubstituted arylylcarbonyl group, or an unsubstituted aromatic heterocyclic carbonyl group; a methoxycarbonyl group, an isobutoxycarbonyl group, a tertbutoxycarbonyl group, 2, 2, 2-trichloro Oral ethoxycarbonyl group, benzyloxycarbonyl group, diphenylenomethoxymethoxyreponinole group, phenoxyca Substituted or unsubstituted alkyloxycarbonyl or substituted or unsubstituted aryloxycarbonyl group such as leponinore group, m-nitrophenoxycanoleponinole group; methylsulfonyl group, benzylsulfonyl group, phenylnonenoreno group, 4 A substituted or unsubstituted alkylsulfonyl group such as a phenylsulfonyl group, a trinolesnorephoninole group, a 2,4,6 trimethylphenylsulfonyl group, or a free or substituted amino group such as a substituted or unsubstituted arylsulfonyl group; , A free alkylamino group, a free arylamino group, an aromatic heterocyclic group having a free nitrogen atom or a non-aromatic heterocyclic group having a free nitrogen atom, which are widely used.

[0037] The above substituted alkyl group, substituted non-aromatic heterocyclic group, substituted alkylcarbonyl group, substituted arylcarbonyl group, substituted alkyloxycarbonyl group, substituted aryloxy force The sulfonyl, substituted silyl, substituted alkylsulfonyl, or substituted arylsulfonyl groups are each selected from a halogen atom, an alkoxy group, an alkyl group, an aryl group, a halogenoaryl group, an alkoxyaryl group, and a nitro group. Or an alkyl group, a non-aromatic heterocyclic group, an alkylcarbonyl group, an aryloxycarbonyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, a silinole group, an ananolyl sulfol group substituted with a plurality of groups. Or an arylsulfonyl group is shown.

The “plural groups” as used in the present invention may be the same or different, and preferably represent 2 or 3 groups, more preferably 2 groups.

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

[0040] The "salt" in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and includes an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salt, acetic acid, fumanoleic acid, maleic acid, konsuccinic acid, citrate, tartaric acid, adipic acid, gnoleconic acid, gnolecoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1, 2-Ethane disulfonic acid, isethionic acid, ratatobionic acid, oleic acid, pamoic acid, polygalatathuronic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, Salts with organic acids such as naphthalene sulfonic acid and sulfosalicylic acid, quaternary ammonium salts such as methyl bromide and methyl iodide, bromine ions, salts Salts with halogen ions such as ions and iodine 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, ammonia Salt with, triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy 1- (methylamino) 2-D-sorbitol, 2-amino-2- (hydroxymethyl) 1, 3— Examples thereof include salts with organic amines such as propanediol, procaine, N, N bis (phenylmethyl) -1,2-ethanediamine.

[0041] When a geometric isomer or an optical isomer exists in the compound of the present invention, these isomers are also included in the scope of the present invention.

[0042] Further, the compound of the present invention takes the form of a hydrate or a solvate! /! [0043] Further, when proton tautomerism exists in the compound of the present invention, such tautomers are also included in the scope of the present invention.

[0044] 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.

[0045] "R and R together form a non-aromatic heterocycle" means that R and R together

3 4 3 4

The formation of a non-aromatic heterocycle via a single bond or a heteroatom. Non-aromatic heterocycles formed through a single bond may be those shown in the above specific examples, but typical examples are pyrrolidine rings, piperidine rings, and azepane rings, and heteroatoms. The non-aromatic heterocycle formed via the ring may be the one shown in the above specific examples, but typical examples include a morpholine ring and a piperazine ring.

[0046] (a) As a preferred example of the compound of the present invention, in the compound represented by the general formula [I], a compound in which each group is a group shown below or a salt thereof is exemplified.

[0047] (al) Ring A represents a benzene ring, a thiophene ring, a thiazole ring or a furan ring; and / or

(a2) the ring A may have one or more substituents selected from a halogen atom and an alkoxy group; and / or

(a3) R and R are the same or different and each represents a hydrogen atom, an alkyl group or an alkenyl group; and

1 2

And / or

(a4) X represents a single bond, C = C, CH-0, O-CH, NH-CH or CH-NH;

2 2 2 2

And / or

(a5) Y represents a hydroxyl group, an alkyl group, an alkoxy group or NR R; and / or

3 4

(a6) R and R are the same or different and are a hydrogen atom, a hydroxyl group, an alkyl group, or a cycloalkyl group.

3 4

Represents an aryl group or an aromatic heterocyclic group; and / or

(a7) R and R may combine to form a non-aromatic heterocycle; and / or

3 4

(a8) Each alkyl group defined above has one or more substituents selected from a carboxyl group, an alkyloxycarbonyl group, an alkylamino group, an aryl group, an aromatic heterocyclic group and a non-aromatic heterocyclic group. May have; and / or

(a9) Each aryl group defined above is a halogen atom, an alkyl group, or a halogenoalkyl. May have one or more substituents selected from a group, an alkoxy group, a cycloalkyl group and a non-aromatic heterocyclic group; and / or

(alO) Each aromatic heterocyclic group defined above has one or more substituents selected from a halogen atom, an amino group, an alkyl group, a halogenoalkyl group, an alkylamino group, and an alkyloxycarbonylamino group. And / or

(al 1) Each non-aromatic heterocyclic group defined above may be substituted with a hydroxyalkyl group.

[0048] That is, in the compound represented by the general formula [I], the above (al), (a2), (a3) (a4)

(a5), (a6), (a7), (a8) (a9) A compound comprising one or more combinations selected from (alO) and (al l) or a salt thereof.

[0049] (b) As a more preferred example of the compound of the present invention, the compound represented by the general formula [I]

V, and compounds in which each group is a group shown below or a salt thereof.

[0050] (bl) Ring A represents a benzene ring, a thiophene ring, a thiazole ring or a furan ring; and / or

(b2) when ring A is a benzene ring, the benzene ring may have one or more alkoxy groups as substituents; and / or

(b3) R represents a hydrogen atom, an alkyl group or an alkenyl group; and / or

(b4) when R is an alkyl group, the alkyl group may have one or more substituents selected from a carboxyl group and an alkyloxycarbonyl group; and / or (b5) R represents a hydrogen atom; And / or

2

(b6) X represents C C; and / or

(b7) Y represents a hydroxyl group, an alkoxy group or NR R; and / or

3 4

(b8) R and R are the same or different and are a hydrogen atom, a hydroxyl group, an alkyl group, or a cycloalkyl group.

3 4

Represents an aryl group or an aromatic heterocycle; and / or

(b9) When R or R is an alkyl group, the alkyl group is an alkylamino group, an aromatic

3 4

Ring groups (the aromatic heterocyclic group may have one or more halogen atoms, halogenoalkyl groups, amino groups or alkyloxycarbonylamino groups as substituents! /,) And non-aromatic heterocyclic rings May have one or more substituents selected from the group; and / or (blO) When R or R is an aryl group, the aryl group is an alkyl group, an alkoxy group, a

3 4

May have one or more substituents selected from a chloroalkyl group and a non-aromatic heterocyclic group; and / or

(bl l) When R or R is an aromatic heterocyclic group, the aromatic heterocyclic group is 1 or

3 4

May have multiple alkyl groups; and / or

(bl2) R and R together may form a non-aromatic heterocycle; and / or

3 4

(bl3) When R and R together form a non-aromatic heterocycle, the non-aromatic heterocycle

3 4

May have one or more hydroxyalkyl groups as substituents.

[0051] That is, in the compound represented by the general formula [I], (bl), (b2), (b3), (b4),

(b5), (b6), (b7), (b8), (b9), (blO), (bl l), (bl2) and a compound comprising each combination of two or more selected from (bl3) Or a salt thereof.

[0052] (c) As a particularly preferred example of the compound of the present invention, the compound represented by the general formula [I]

V, and compounds in which each group is a group shown below or a salt thereof.

[0053] (cl) Ring A represents a benzene ring, a thiophene ring, a thiazole ring or a furan ring; and / or

(c2) When ring A is a benzene ring, the benzene ring may have 1 methoxy group as a substituent; and / or

(c3) R represents a hydrogen atom, a methyl group, a hydroxycarbonylmethyl group, an ethoxycarbonylmethyl group or an aryl group; and / or

(c4) R represents a hydrogen atom; and / or

2

(c 5) X represents C = C; and / or

(c6) Y is a hydroxyl group, a tert-butoxy group, a pyridine-2-ylmethylamino group, a pyridine-3-ylmethylamino group, a pyridine-4-ylmethylamino group, a 2-cyclomethylpyridine-5-methylmethylamino group, a 2-trifluoromethylpyridine-5-methylmethylamino group, or a 2-dimethylamino group. Ethylamino group, hydroxyamino group, 2 morpholine-4-ethylamino group, cyclopropylamino group, 3,5-dimethylphenylamino group, 3,4-dimethoxyphenylamino group, 4-cyclohexylphenyla Mino group, 4 morpholine-4-ylphenylamino group, 7 methyl- [1,8] naphthyridine-2-ylamino group, pyrrolidine 1-yl group, mol Holin 4-yl group, 4 (2-hydroxyethinole) piperazine 1-yl group, 1H-one lu 6-ylamino group, 6-aminoviridine-3-ylmethylamino group, 6-tert-butoxycarbonylaminomino 3-ylmethylamino amino group Indicates a group.

[0054] That is, in the compound represented by the general formula [I], (cl), (c2), (c3), (c4),

A compound comprising one or more combinations selected from (c5) and (c6) or a combination thereof

[0055] (d) Particularly preferred specific examples of the compound of the present invention include the following compounds or salts thereof.

• (E) —tert-butyl 3- (4 — ((Z) — (3oxo3,4dihydro-2H-b] [l, 4] oxazine-2-ylidene) methyl) phenyl) attalylate,

• (E) —tert-butyl 3- (2 — ((Z) — (3oxo3,4 dihydro-2H-b] [l, 4] oxazine 2-ether

• (E) —tert-butyl 3- (5 — ((Z) — (3-4-dihydro-2H-b] [l, 4] oxazine 2- 3-yl) acrylate,

• (E) —tert-butyl 3- (5 — ((Z) — (3-4-dihydro-2H-b] [l, 4] oxazine 2- 2-yl) acrylate,

• (E) — tert-butyl 3-

((Z) — (3-oxo-4-dihydro-2H-b] [l, 4] oxazine 2-ylidene) methyl) furan-3-yl) atarylate,

• (E) — tertbutyl 3- (5— ((Z) — (3 oxo 3, 4 dihydro-2H b] [l, 4] oxazine 2-ylidene) methyl) furan-2-yl) talate,

• (E) — tert-butyl 3-

3- ()-(3-Oxo 3,4-dihydro 2H Nzo [b] [l, 4] oxa, N-2-ylidene) methyl) phenyl) talylate, (E)-tert butyl (E) -3 — (2 — ((Z) — (3 oxo 3, 4 dihydro-2H-zone [b] [l, 4] oxazine 2 lysine) methyl) thiazole-5

G

• (E) —tert-butyl 3- (3 — ((Z) — (3oxo3,4 dihydro-2H-no-b] [l, 4] oxazine-2-ylidene) methyl) phenyl) talylate,

• (E) —tert-butyl 3- (3 — ((Z) — (4-methyl-3-oxo3, 4-dihydro 2H Benzo [b] [1,4] oxazine 2ylidene) methyl) phenyl) talylate, • (E) —tert butyl 3— (5 — ((Z) — (4-methyl-3-oxo3, 4-dihydro-2H) Benzo [b] [1,4] oxazine 2 ylidene) methinole) thiophene 2inole) acrylate,

• (E) —tert butynole 3— (5 — ((Z) — (4 (2 ethoxy-2 oxoethyl) -3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl ) Thiophene 2— Atylate,

• (E) —tert butynole 3— (4-methoxy-3-((Z) — (4-methinole 3-oxo-3,4-dihydro-2H benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl)

• (E) —3— (4 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodazine-2-ylidene) methyl) phenyl) acrylic acid,

• (E) —3— (3 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodazine-2-ylidene) methyl) phenyl) acrylic acid,

• (E) —3— (2 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 1 2-ylidene) methyl) phenyl) acrylic acid,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2-ylidene) methyl) thiophene 3 yl) acrylic acid ,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodazine-2-ylidene) methyl) thiophene 2-yl) Acrylic acid,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) furan 3 yl) acrylic acid ,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) furan 2-yl) Acrylic acid,

• (E) -3- (3-((Z) I (4-Methyl-3oxo3, 4 Dihydro-2H Benzo [b]

[1, 4] oxazine 2 ylidene) methyl) phenyl) acrylic acid,

• (E) -3- (5-((Z) I (4-Methyl-3oxo3, 4 Dihydro-2H Benzo [b]

[1, 4] oxazine 2 ylidene) methyl) thiophene 2yl) acrylic acid, • (E) -3- (5-((Z)-((4-Ethoxy-2-oxoethyl) -3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazine-2-ylidene) methyl) thiophene-2 E) Acrylic acid,

• (E) -3- (4 Methoxy-3-((Z)-(3oxo3,4-dihydro-2-H) benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) acrylic acid,

• (E) -3- (4 Methoxy-1-3 — ((Z)-(4 Methyl-3-oxo3,4 dihydro-2-H benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) acrylic acid, • (E) —3— (2 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 iridine) methyl) thiazole-5 yl) acrylic acid,

• (E) —3— (4 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine—2 ylidene) methyl) phenyl) — N— (Pyridine-3ylmethyl) acrylamide,

• (E) —N— ((2 Dimethylamino) ethyl) -3- (4-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl ) Acrylic amide,

• (E) -N- (2 morpholinoethyl) -3— (4-((Z)-((3 oxo 3, 4 dihydro-2H-benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) Acrylamide,

• (E) —N Cyclopropinol 3- (4 — ((Z)-(3 oxo 3,4 dihydro-1 2H—benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) acrylamide,

• (Z) — 2— (4— ((E) —3—oxo-3— (pyrrolidine-1-yl) prope-1-one-noyl) benzylidene) 2H—benzo [b] [1, 4] oxazine 3 (4H) —one,

• (Z) — 2— (4- ((E) —3 Morpholino 3-oxopropenyl 1-benzyl) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H) ON,

-(Z) -2- (4- ((E) -3- (4- (2 Hydroxyethyl) piperazine 1-yl)-3 -oxopropene 1 heninore) benzylidene) 2H-benzo [b] [1,4] oxazine 3 (4H) -one,

• (E) —3— (4 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 1 2-ylidene) methyl) phenyl) N— (pyridine 2-ylmethyl) acryla Mid,

• (E) —3— (4 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) phenyl) N— (pyridine-4 Ylmethyl) acrylamide,

• (E) —3— (4 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodazine-2-ylidene) methyl) phenyl) N— ((6 Trifluoromethylpyridine 1 3-

• (E) -N- (3,5-Dimethylphenyl) -3— (4-((Z)-(3-Oxo-1,4-dihydro 2H benzo [b] [1, 4] oxazine 2 Ylidene) methyl) phenyl) acrylamide,

• (E) -N- (3, 4-Dimethoxyphenyl) 3— (4— ((Z)-(3-Oxo 3, 4-dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) Methyl) phenyl) acrylamide,

• (E) -N- (4-morpholinophenyl) 3— (4— ((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine 2 ylidene) methyl ) Phenyl) acrylamide,

(E) -N- (7 Methyl-1, 8 Naphthyridin-2-yl) -3— (4-((Z) -one (3 oxo-1,4 dihydro-1,2H benzo [b] [l, 4] oxazine 1-2 ylidene) methyl) phenyl) acrylamide,

• (E) —3— (3 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine—2 ylidene) methyl) phenyl) — N— (Pyridine-3ylmethyl) acrylamide,

• (E) —N— ((2 Dimethylamino) ethyl) -3- (3-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl ) Acrylic amide,

• (E) —N Cyclopropinole 3- (3 — ((Z)-(3 oxo 3, 4 dihydro- 1H— benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) acrylamide, • (Z ) — 2— (3— ((E) — 3 oxo 3— (pyrrolidine 1-yl) propylene 1-ene nore) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H ) On, • (Z) -2- (3- ((E) -3-Mono-reforino 3 oxoprop 1 benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H) ON,

-(Z) -2- (3- ((E) -3- (4- (2 hydroxyethyl) piperazine 1-yl) 3 oxoprop 1 enninore) benzylidene) 2H-benzo [b] [ 1, 4] oxazine 3 (4H) -one,

• (E) —3— (3 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) phenyl) N— (pyridine 2-ylmethyl) acrylamide,

• (E) —3— (3 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) phenyl) N— (pyridine-4 Ylmethyl) acrylamide,

• (E) —3— (3 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) phenyl) N— ((6 Trifluoromethylpyridine 1 3-

• (E) —3— (3 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) phenyl) N— ((6 Black mouth pyridine 3yl) methyl) acryloleamide,

• (E) -N- (3,5-Dimethylphenyl) 3— (3— ((Z)-(3-Oxo 3, 4-dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) Methyl) phenyl) acrylamide,

• (E) -N- (3, 4-Dimethoxyphenyl) 3— (3— ((Z)-(3-Oxo 3, 4-dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) Methyl) phenyl) acrylamide,

• (E) —N-hydroxyl 3— (5 — ((Z)-(3 oxo3,4 dihydrol 2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) thiophene 2 yl) acrylamide, (E) —3— (2 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine—2 ylidene) methyl) phenyl) — N— ( Pyridine—3ylmethyl) acryla • (E) —N— ((2 dimethylamino) ethyl) -3- (2-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl ) Acrylic amide,

• (E) —N Cyclopropinole 3- (2 — ((Z)-(3 oxo 3, 4 dihydro- 1H— benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) acrylamide; ) — 2— (2— ((E) — 3 oxo 3— (pyrrolidine 1-yl) propylene 1-henyl) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H ) On,

• (Z) -2- (2- ((E) 3 morpholino 3 oxoprop 1 benzyl) benzylidene) 2H benzo [b] [1, 4] oxazine 3 (4H) ON,

-(Z) -2- (2- ((E) -3- (4- (2 Hydroxyethyl) piperazine 1-yl)-3 -oxopropene 1 heninoyl) benzylidene) 2H-benzo [b] [1,4] oxazine 3 (4H) -one,

• (E) —3— (2 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 1 2-ylidene) methyl) phenyl) N— (pyridine 2-ylmethyl) acrylamide,

• (E) —3— (2 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) phenyl) N— (pyridine-4 Ylmethyl) acrylamide,

• (E) —3— (2 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) phenyl) N— ((6 Trifluoromethylpyridine 1 3-

• (E) —3— (2 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) phenyl) N— ((6 Black mouth pyridine 3yl) methyl) acryloleamide,

• (E) -N- (3,5 dimethylphenyl) 3— (2— ((Z)-(3 oxo 3, 4 dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl ) Acrylic amide,

• (E) -N- (3,4 Dimethoxyphenyl) 3— (2— ((Z)-(3 oxo 3, 4 dihi Draw 2H—Benzo [b] [1,4] oxazine 2—ylidene) methyl) phenyl) acrylamide,

• (E) -N- (4 morpholinophenyl) 3— (2— ((Z)-(3 oxo 3, 4 dihydro-2H-benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) Acrylamide,

(E) -N- (7 Methyl-1, 8 Naphthyridin-2-yl) -3— (2-((Z) -one (3 oxo-1,4 dihydro-1,2H benzo [b] [l, 4] oxazine 1-2 ylidene) methyl) phenyl) acrylamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) thiophene 3 yl) N— (Pyridine 3-dimethyl) acrylamide,

• (E) —N— ((2 Dimethylamino) ethyl) -3- (5-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl ) Thiophene 3) Acrylamide,

• (E) —N Cyclopropinol 1— (5 — ((Z)-(3 oxo 3,4 dihydro-1 2H—benzo [b] [1, 4] oxazine 2 ylidene) methyl) thiophene 3 yl) acrylamide ,

• (Z) -2- ((4- ((E) —3 oxo 3— (pyrrolidine 1-yl) propeyl 1-ene nore) thiophene 2 yl) methylene) 2H Benzo [b] [l, 4] oxazine 3 (4H) —on,

• (Z) — 2— ((4— ((E) — 3 Monorephorino 1-Propyl 1-Chelene 2) Ino-Methylene) 2H Benzo [b] [l, 4] oxazine 3 (4H ) On,

• (Z) — 2 — ((4 ((E) 3— (4 1 (2 hydroxyethyl) piperazine 1 1 1) 1 3 —oxoprop 1 1 enore) thiophen 2—inore) methylene) 2H—benzo [b] [1, 4] oxazine 3 (4H) —one,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) thiophene 3 yl) N— (Pyridine 2-dimethyl) acrylamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxo Sadine 1 ylidene) methyl) thiophene 3 yl) N— (pyridine 4 dimethyl) acrylamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) thiophene-3 yl) N— ((6 Trifluoromethyl

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) thiophene 3 yl) N— ((6 Black mouth pyridine one 3

• (E) -N- (3,5-Dimethylphenyl) 3— (5— ((Z)-(3-Oxo 3, 4-Dihydro 2H Benzo [b] [1, 4] oxazine 2 Ylidene) methinore) thiophene 3 yl) acrylamide,

• (E) -N- (3, 4-Dimethoxyphenyl) 3— (5— ((Z)-(3-Oxo 3, 4-Dihydr Draw 2H—Benzo [b] [1, 4] oxazine 2-ylidene) methyl) thiophene 3-yl) acrylamide,

• (E) -N- (4-morpholinophenyl) 3— (5— ((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine 2-ylidene) Methyl) thiophene 3-yl) a clinoleamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) thiophene 2 yl) N— (Pyridine 3-dimethyl) acrylamide,

• (E) —N— ((2 Dimethylamino) ethyl) -3- (5-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methinole ) Thiophene 2) Acrylamide,

• (E) —N Cyclopropinol 1— (5 — ((Z)-(3 oxo 3,4 dihydro-1 2H—benzo [b] [1, 4] oxazine 2 ylidene) methyl) thiophene 2 yl) acrylamide ,

• (Z) — 2— ((5— ((E) — 3 oxo 3— (pyrrolidine 1-yl) propylene 1-hen nore) thiophene 2 yl) methylene) 2H Benzo [b] [l, 4] oxazine 3 (4H) — on,

• (Z) — 2— ((5— ((E) — 3 Monorephorino 3 Oxopropene 1) Thiophene-2 Inole) Methylene) 2H Benzo [b] [l, 4] oxazine 3 (4H) ON ,

• (Z) — 2— ((5— ((E) 3— (4— (2 Hydroxyethyl) piperazine 1—yl) 3— oxoprop 1 enoinole) thiophene 2—inole) methylene) 2H— Benzo [b] [1, 4] oxazine 3 (4H) —one,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodazine-2-ylidene) methyl) thiophene 2-yl) N— (pyridine 2-ylmethyl) acrylamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) thiophene 2 yl) N— (Pyridine 4-dimethyl) acrylamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 1 ylidene) methinore) thiophene 2 yl) N— ((6 Trifluoromethyl

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) thiophene 2 yl) N— ((6 Black mouth pyridine one 3

• tert-Butyl 5 — (((E) —3— (5 — ((Z) — (3-Oxo 3, 4— 3, 4-dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methinole) Thiophene 2-inole) acrylamido) methyl) pyridine-2-ylcarbamate,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) thiophene 2 yl) N— ((6 Aminoviridine 1 3

• (E) -N- (3,5-Dimethylphenyl) 3— (5— ((Z)-(3-Oxo 3, 4-Dihydro 2H Benzo [b] [1, 4] oxazine 2 Ylidene) methinole) thiophene 2 inore) acrylamide,

• (E) -N- (3, 4-Dimethoxyphenyl) 3— (5— ((Z)-(3-Oxo 3, 4-Dihi Draw 2H—Benzo [b] [1,4] oxazine 2-ylidene) methyl) thiophene 2-yl) acrylamide,

• (Ε) -Ν- (4-morpholinophenyl) 3— (5— ((Ζ)-(3-Oxo 3, 4-dihydro-2Η-benzo [b] [1, 4] oxazine 2-ylidene) Methinole) thiophene 2-ynole) clinoleamide,

(E) -N- (1H—Indole— 6—yl) —3— (5— ((Z)-(3—Oxo—3, 4—Dihydro-2H Benzo [b] [1, 4 ] Oxazine 2 ylidene) methinole) thiophene 2 yl) acrylamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) furan 3 yl) N— (Pyridine 3-ylmethyl) acryloleamide,

• (E) —N— ((2 Dimethylamino) ethyl) -3- (5-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl ) Fran 3 ill) Acrylamide,

• (E) —N Cyclopropinol 3- (5 — ((Z)-(3 oxo 3,4 dihydro-1 2H—benzo [b] [1, 4] oxazine 2 ylidene) methyl) furan 3 yl) acrylamide, • (Z) -2- ((4- ((E) —3 oxo 3— (pyrrolidine 1-yl) prope 1-ene nore) furan-2-inole) methylene) 2H Benzo [b] [ l, 4] oxazine 3 (4H) ON

• (Z) — 2— ((4— ((E) — 3 Monorephorino 1-Propyl 1-Enyl) Furan 2-Inole) Methylene) 2H Benzo [b] [l, 4] oxazine 3 (4H ) On,

• (Z) — 2 — ((4 ((E) 3— (4 (2 hydroxyethyl) piperazine 1 yl) 3—oxoprop 1 yl) furan 2 yl) methylene) 2H benzo [ b] [1, 4] oxazine 3 (4H) —aged,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) furan 3 yl) N— (Pyridine 2-ylmethyl) acryloleamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxo Sadine 1 ylidene) methyl) furan 3 yl) N— (pyridine 4 ylmethyl) a clinoleamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxo

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 1-2 ylidene) methyl) furan 3 yl) N — ((6 Chloropyridine 1- 3 yl) methyl) attalinoleamide,

• (E) -N- (3,5-Dimethylphenyl) -3— (5-((Z) -one (3-Oxo 3, 4-dihydride) 2H-Benzo [b] [1, 4] Oxazine 2-ylidene) methyl) furan 3-yl) acrylamide,

• (E) -N- (3, 4-Dimethoxyphenyl) 3— (5— ((Z)-(3-Oxo 3, 4-Dihydr Draw 2H—Benzo [b] [1, 4] oxazine 2—ylidene) methyl) furan 3—yl) a clinoleamide,

• (E) -N- (4-morpholinophenyl) 3— (5— ((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine 2-ylidene) Methyl) furan 3-yl) atarylamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) furan 2 yl) N— (Pyridine 3-ylmethyl) acryloleamide,

• (E) —N— ((2 Dimethylamino) ethyl) -3- (5-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methinole ) Fran 2 yl) Acrylamide,

• (E) —N Cyclopropinol 3- (5 — ((Z)-(3 oxo 3,4 dihydro-1 2H—benzo [b] [1, 4] oxazine 2 ylidene) methyl) furan 2 yl) acrylamide, • (Z) — 2— ((5— ((E) — 3 oxo 3— (pyrrolidine 1-yl) propylene 1- enyl) furan-2 yl) methylene) 1 2H Benzo [b ] [l, 4] oxazine 3 (4H) —one • (Z) —2— ((5— ((E) —3 morpholino 1-oxoyl) furan-1 2-inole) methylene) 2H Benzo [b] [l, 4] oxazine 3 (4H ) On,

• (Z) — 2— ((5— ((E) 3— (4— (2 Hydroxyethyl) piperazine 1-yl) 3— oxopropene 1-yl) furan 2-yl) methylene) 2H Benzo [b] [1, 4] oxazine 3 (4H) —

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) furan 2-yl) N— (Pyridine 2-ylmethyl) acrylolamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) furan 2 yl) N— (Pyridine 4-ylmethyl) acryloleamide,

• (E) -N- (3,5-Dimethylphenyl) 3— (5— ((Z)-(3-Oxo 3, 4-Dihydro 2H Benzo [b] [l, 4] oxazine 2 Iridene) Methinore) Furan 2-Inole) Acrylamide,

• (E) -N- (3, 4-Dimethoxyphenyl) 3— (5— ((Z)-(3-Oxo 3, 4-Dihydr Draw 2H—Benzo [b] [1, 4] oxazine 2-ylidene) methyl) furan 2-yl) acryloamide,

• (E) -N- (4-morpholinophenyl) 3— (5— ((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine 2-ylidene) Methyl) furan 2-yl) atarylamide,

(E) —N— ((2 dimethylamino) ethyl) -3- (3-((Z) -one (4-methyl-3 oxo-1, 3, 4 dihydro-1, 2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) phenyl) acrylamide,

• (E) —N Cyclopropylamino-3— (3— ((Z)-(4-Methyl-3-oxo3, 4 dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) Acrylamide,

• (Z) -2- (3- ((E) -4-Methylenol 3-Oxo 3- (Pyrrolidine 1-yl) propenyl) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H) ON • (Z) —4—Methinore 2— (3 — ((E) —3—morpholino 1—oxoprop 1—e: Nore) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H) ON,

• (Z) — 4 methylolene 2— (3 — ((E) —3— (4 (2-hydroxyethyl) piperazine 1 yl) 3 oxoprop 1 benzyl) benzylidene) 2H benzo [b] [1 , 4] oxazine 3 (4H) —one,

• (E) -3- (3- ((Z) — 4 Methyl-3oxo3, 4 Dihydro-2H Benzo [b] [

1, 4] oxadi: —2—ylidenemethyl) phenyl) N— (pyridine 1-clinoleamide,

• (E) -3- (3-((Z) -4-Methyl-3-oxo3,4 dihydro- 1H benzo [b] [1,4] oxazi: 2 ylidenemethyl) phenyl) N- (pyridine-4-ylmethyl) Clinoleamide,

• (E) -3- (3- ((Z)-(4-Methyl-3oxo3, 4 dihydro-2H benzo [b] [1, 4] oxa, 2-ylidene) methinole) phenyl) N— (4 —Morpholinophenyl) Atalinoleamide,

• (E) -3- (5-((Z)-(4-Methyl-3-oxo3,4 dihydro- 1H benzo [b] [1,4] oxa, no 2-ylidene) methyl) thiophene N) N (pyridine 1: 3, de,

• (E) -3- (5- ((Z)-(4-Methyl-3-oxo3,4 dihydro-1H benzo [b]

[1, 4] oxa, N-2-ylidene) methinole) thiophene 2yl) N— (4 morpholinophenyl) acrylamide,

• Ethyl 2 — ((Z) —3 oxo 2— ((5— ((E) —3 oxo 3— (pyridine-3-methylmethylamino) prop 1-enyl) thiophene 2-yl) methylene) 1 2H —Benzo [b] [1, 4] oxazine 4 (3H) —yl) acetic acid,

• (E) -3- (5— ((Z) —4 allyl 1-3 xo 3, 4 dihydro -1H benzo [b] [1, 4] oxazine-2 ylidenemethyl) thiophene-2 yl) N— (pyridine-3—

• (E) —N— ((2 Dimethylamino) ethyl) -3- (5— ((Z) —4 Methylolone 3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidenemethyl) thiophene 3-yl) acrylamide

• (E) —N Cyclopropinole 3— (5— ((Z) —4—Metinole 1—Oxo 3, 4—Dihydro 2H—Benzo [b] [1, 4] oxazine 2—ylidenemethinole) thiophene 3—yl) acrylamide,

• (Z) —4 Methyl 2— ((5— ((E) —3 oxo 3— (pyrrolidine 1-yl) propene 1) thiophen 2 yl) methyl) -2H-benzo [b] [ 1, 4] oxazine 3 (4H) -one,

• (Z) —4 Methyl 2— ((5— ((E) —3 Morpholino 3-oxopropeno 1) -phenophyl 2 yl) methylene) 2H Benzo [b] [l, 4] oxazine 3 (4H) —on,

• (Z) — 4 Methyl 2— ((5— ((E) 3— (4— (2 Hydroxyethyl) piperazine 1 — yl) 3 oxoprop 1-heninore) thiophene 1 2 inore) methylene ) 2H— Benzo [b] [l, 4] oxazine 3 (4H) —one,

• (E) -3- (5— ((Z) —4 Methinole 3 oxo 3, 4 Dihydro-1 2H Benzo [b] [1, 4] oxazine-2 ylidenemethyl) thiophene 2 yl) N— (pyridine-2—

• (E) -3- (5— ((Z) —4 Methinole 1 3 oxo 3, 4 Dihydro 1 2H Benzo [b] [1, 4] oxazine-2 ylidenemethyl) thiophene 2 yl) N— (Pyridine-4

• (E) —3— (4 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) phenyl) N— ((6 Black mouth pyridine 3yl) methyl) acryloleamide,

• (E) —N — ((2 dimethylamino) ethyl) -3- (4-methoxy-3-((Z) — (3 oxo-1,4 dihydro-1,2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) phenyl) acrylamide,

• (E) —N Cyclopropinole 3- (4-Methoxy-3 -— ((Z)-(3-oxo-3,4-dihydro 2H benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) acryla Mid,

• (Z) — 2— (4 Methoxy-3-((E) —3-oxo-3— (pyrrolidine-1-yl) propenyl) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 ( 4H) ON

• (Z) -2- (4-Methoxy-1-3- ((E) -3-Morpholino 3-oxopropeno 1-ene nore) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 ( 4H) ON,

• (Z) -2- (4-Methoxy-3-((E) -3-3- (4 (2-hydroxyethyl) piperazine 1 yl) 3 oxoprop 1 benzyl) benzylidene) 2H Benzo [b] [1 , 4] oxazine 3 (4H) —one,

• (E) -3- (4 Methoxy-3-((Z)-(3oxo3, 4 dihydro- 1H benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) N- (pyridine-2-methyl) ) Acrylamide,

• (E) -3- (4 Methoxy-3 -— ((Z)-(3oxo3,4 dihydro-2H benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) N (pyridine-3-dimethyl) Le) acrylamide,

• (E) -3- (4 Methoxy-3-((Z)-(3oxo3,4 dihydro- 1H benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) N- (pyridine-4-methyl) ) Acrylamide,

(E) -N- (4-Morpholinophenyl) 3— (4-Methoxy-3— ((Z)-(3-Oxo 3, 4 Dihydro-2H Benzo [b] [l, 4] oxazine-2 Ylidene) methyl) phenyl) acrylamide,

• (E) —N— ((2 Dimethylamino) ethyl) -3- (4-Methoxy-3-((Z) —4-Methanol 3 Oxo 3, 4 Dihydro-2H Benzo [b] [l, 4] oxazine-2 Ylidenemethyl) phenyl) attalinoleamide,

• (E) —N Cyclopropynol 3- (4-Methoxy-3- ((Z) -4-Methylol 3-Oxo-3, 4-Dihydro-2H Benzo [b] [l, 4] oxazine-2-ylidenemethyl) phenyl ) Acryloleamide,

• (Z) — 2— (4 Methoxy-3-((E) —3-oxo-3— (Pyrrolidine-1-yl) propylene 1-benzyl) benzylidene) 4 methyl 2H benzo [b] [1, 4] oxazine 3 (4H) —one,

• (Z) -2- (4-Methoxy-1-3-((E) -3-morpholino-1-oxopropenyl 1-benzyl) benzylidene) 4 methyl 2H benzo [b] [1, 4] oxazine 3 (4H) ON

• (Z) -2- (4-Methoxy-3 — ((E) —3— (4 (2-hydroxyethyl) piperazine 1-inore) 3-oxopropene 1-eninole) benzylidene) 4-methyl-2H-benzo [ b] [l, 4] oxazine 3 (4H) —one,

• (E) -3- (4 Methoxy-3 — ((Z) -4 Methylolone 3oxo3, 4 Dihydro-2-H 2 Benzo [b] [1, 4] oxazine 2 ylidenemethyl) phenyl) N— (pyridine 2—

• (E) -3- (4 Methoxy-3 — ((Z) -4 Methylolone 3oxo3,4 Dihydro-1H Benzo [b] [1,4] oxazine 2 ylidenemethyl) phenyl) N— (pyridine 3—

• (E) -N- (4-Morpholinophenyl) 3— (4-Methoxy-3— ((Z) —Methyl-3-oxo 3, 4 Dihydro-2H Benzo [b] [l, 4] oxazine-2 Ylidenemethyl) phenyl) acrylamide,

• (E) -N- (4 morpholinophenyl) 3— (2— ((Z)-(3 oxo 3, 4 dihydro-2H-benzo [b] [1, 4] oxazine 2-ylidene) methinole) thiazole 5—yl) acrylamide,

• (E) -N- (4-morpholinophenyl) 3— (3— ((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine 2 ylidene) methyl ) Phenyl) acrylamide,

• (E) -N- (4-Cyclohexylphenyl) 3— (5— ((Z)-(3-Oxo 3, 4-dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene ) Methinole) thiophene 2) acrylamide and • 2- ((Z) —3 oxo 2— ((5— ((E) —3 oxo 3— (pyridine 3-methylmethylamino) propylene 1-thiophene 2-yl) methylene) 2H-benzo [b ] [1,4] oxazine-4 (3H) -yl) acetic acid.

[0057] The compound of the present invention can be produced by the following method. Each specific manufacturing method will be described in detail in Examples [Production Examples] described later. In addition, Hal used in the following synthesis route represents a halogen atom.

[0058] 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 ammine (III) in an organic solvent such as N, N dimethylformamide (hereinafter abbreviated as DMF), TFP resin, O- (7-azabe Nzotriazole-1-yl) -1, 1, 3, 3, 3-tetramethyluronium water-soluble carpositimide (WSC) such as hexafluorophosphate (HATU), and N, N diisopropylethylamine Compound (I) can be obtained by reacting at room temperature to 80 ° C for 1 to 24 hours in the presence of a base such as DIEA.

[0059] Synthesis route A

[Chemical 2]

[0060] The compound (Π) of the present invention can be produced according to Synthesis route B. That is, the compound (IV) 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.

[0061] Synthesis route B

[Chemical 3]

The compound of the present invention (IV &; Ι ^ ≠ Η) can be produced according to Synthesis route C. That is, the compound of the present invention (IV—b; R = H) and an alkyl halide (V) such as methyl iodide in an organic solvent such as DMF in the presence of a base such as sodium hydride from room temperature to 100 ° C. The compound of the present invention (IV—a; R ≠ H) can be obtained by reacting with C for 1 hour for 24 hours.

[0063] Synthesis route C

[Chemical 4]

IV-b (R! = H) IV-a (R ^ H)

[0064] The compound of the present invention (IV b; R = H) can be produced according to synthetic route D. In other words, compound (VI) and compound (VII) (for example, tert-butyl acrylate) are mixed with a catalytic amount of a ligand such as palladium acetate and triphenylphosphine in an organic solvent such as DMF, and N 2, N diisopropyl. The compound of the present invention (IV—b; R = H) can be obtained by reacting at room temperature to 100 ° C for 1 hour to 24 hours in the presence of a base such as ethylamine (DIEA). In the general formula (I), the compound in which Y is an alkyl group can also be obtained by the corresponding raw material power S, which can be obtained according to Synthesis Route D.

[0065] Synthesis route D

[Chemical 5]

VI VII

IV-b (R! = H)

[0066] Compound (VI) can be manufactured and manufactured according to Synthesis Route E. That is, compound (VI) can be obtained by heating and refluxing compound (VIII) and aldehyde (IX) for 1 to 24 hours in the presence of an acid anhydride such as acetic anhydride and a base such as triethylamine.

[0067] Synthesis route E

[Chemical 6]

The compound of the present invention (IV—b; R = H) can also be produced according to Synthesis route F. In other words, compound (VII) and aldehyde (X) are heated to reflux for 1 to 24 hours in the presence of an acid anhydride such as acetic anhydride and a base such as triethylamine. ) Can be obtained.

[0069] Synthesis route F

[Chemical 7]

[0070] Compound (X) used in synthetic route F can be produced according to synthetic route G. In other words, aldehyde (IX) and t-butyl acrylate (VII) are mixed in organic solvents such as DMF with catalytic amounts of ligands such as palladium acetate and triphenylphosphine, and N, N diisopropyl pyrethylamine (DIEA). Compound (X) can be obtained by reacting in the presence of a base such as) at room temperature to 100 ° C for 1 to 24 hours.

[0071] Synthesis route G

[Chemical 8]

[0072] The compound of the present invention produced by the above synthetic route may be in the form of the aforementioned salt, hydrate or solvate by a widely used technique.

[0073] In order to find the usefulness of the compound of the present invention, a tyrosine kinase of the compound of the present invention was evaluated using an evaluation system for kinase (KDR) inhibitory activity by ELISA, which is a method for evaluating the anti-angiogenic effect of a drug. (KDR) inhibitory effect test was conducted and its angiogenesis inhibitory effect was evaluated. Details thereof will be described in the following [Examples of pharmacological tests]. It has been found that the compound of the present invention has an excellent tyrosine kinase (KDR) inhibitory action and has an angiogenesis inhibitory effect.

[0074] As described 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, rod-shaped It has been reported that it is closely related to diseases such as arteriosclerosis. Therefore, the compound of the present invention is highly expected as a therapeutic agent for those diseases involving angiogenesis.

[0075] 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. [0076] For example, oral preparations such as tablets, capsules, granules, powders and the like are used for excipients such as lactose, mannitol, starch, crystalline cellulose, light anhydrous carboxylic acid, calcium carbonate, calcium hydrogen phosphate, and stearic acid. , Lubricants such as magnesium stearate and talc, binders such as starch and hin, carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, disintegrants such as calcium citrate, hydroxypropylmethylcellulose, macrogol, silicone resin Can be prepared by using a coating agent such as paraethyl benzoate, stabilizers such as benzyl alcohol, and flavoring agents such as sweeteners, acidulants and fragrances as necessary.

[0077] Parenteral agents such as injections and eye drops include isotonic agents such as sodium chloride, concentrated glycerin, propylene glycolone, polyethylene glycol, potassium chloride, sonolebithonole, mannitol, sodium phosphate, hydrogen phosphate Buffering agents such as sodium, sodium acetate, citrate, glacial acetic acid, trometamol, surfactants such as polyoxyethylene sorbitan monolate, polyoxystearate 40, polyoxyethylene hydrogenated castor oil, sodium citrate, edet Stabilizers such as sodium nitrate, benzalkonium chloride, paraben, benzotonium chloride, noroxybenzoic acid ester, sodium benzoate, preservatives such as chlorobutanol, hydrochloric acid, citrate, phosphoric acid, glacial acetic acid, hydroxylated Sodium, sodium carbonate, sodium bicarbonate, etc. Use a pH adjuster, a soothing agent such as benzyl alcohol, etc., as necessary, and prepare with S.

[0078] The present invention provides a method for treating a disease involving angiogenesis, comprising administering to a patient a therapeutically effective amount of a compound of the present invention or a salt thereof.

[0079] The dose of the compound of the present invention can be appropriately selected depending on symptoms, age, dosage form and the like. For example, for oral preparations, 0.01 to 1000 mg / day, preferably 1 to 100 mg per day can be administered in one or several divided doses. In addition, eye drops are usually administered at a concentration of 0.0001% to 10% (w / v), preferably 0.01% to 5% (w / v), once or in several divided doses. Can do.

[0080] [Production example]

Reference example 1 (Z) — 2— (4 Bromobenzylidene) 2H Benzo [b] [1, 4] —Oxazine 1 3 (4H) 1-on (Reference compound 1 1)

[Chemical 9]

[0081] 2H Benzo [b] [l, 4] oxazine 3 (4H) one (12g, 82mmol) and p-bromobenzaldehyde (22g, 120mmol) were added to acetic anhydride (50mU and triethylamine (25mU). The mixture was stirred overnight at ° C. The reaction solution was cooled to room temperature, poured into a 1M aqueous sodium hydroxide solution at ice age, and the precipitated solid was collected by filtration.The collected solid was collected with water (25 mL), acetonitrile (25 mL), The extract was washed with ethyl acetate (25 mL) and dried under reduced pressure to obtain 7.9 g of the title reference compound as a yellow solid (yield 30%).

[0082] 'H-NMROOOMHz, DMSO— d)

6

δ: 11.18 (s, 1Η), 7.85 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.31-7.28 (m, 1H), 7.07— 7.03 (m, 2H) , 7.01— 6.98 (m, 1H), 6.76 (s, 1H).

Hereinafter, reference compounds 1 2 to 8 were obtained using a compound selected from commercially available compounds and known compounds according to the production method of reference compound 11.

[0083] (Z) — 2— (2 Bromobenzylidene) 2H Benzo [b] [l, 4] Oxazine 1 3 (4H) 1-on (Reference compound 1 2)

[Chemical 10]

[0084] H—NMR (300MHz, DMSO—d)

6

δ: 11.31 (s, 1Η), 8.29 (dd, J = 8.0, 1.6 Hz, 1H), 7.73 dd, J = 8 .0, 1.2 Hz, IH), 7.50 (t, J = 7.6 Hz, IH), 7.26 (dd, J = 14.2 Hz, 2H), 7.07 (s, IH), 7.06— 6.98 (m, 3H) .

(Z) 2 — ((4-Bromothiophene 2-yl) methylene) 2H Benzo [b] [l, Oxazine 1 3 (4H) ON (Reference compound 1 3)

[Chemical 11]

[0085] H—NMR (300MHz, DMSO—d)

6

δ: 11.20 (s, IH), 7.83 (s, IH), 7.51 (s, IH), 7.25— 7.22 (m, IH), 7.11 (s, IH), 7.08-7.04 (m, 2H), 7.02— 6.98 (m, IH).

(Z) 2 — ((5 Bromothiophene 2-yl) methylene) 2H Benzo [b] [l, 4] —Oxazine 1 3 (4H) ON (Reference Compound 1 4)

[Chemical 12]

[0086] H—NMR (300MHz, DMSO—d)

6

δ: 11.16 (s, IH), 7.32 (d, J = 3.9 Hz, IH), 7.29 (d, J = 2.8 Hz, IH), 7.27 (d, J = 2.8 Hz, IH), 7.10 (s, IH ), 7.07—7.03 (m, 2H), 7.01-6.97 (m, IH).

(Z) —2— ((4 Bromofuran-2-inole) methylene) 2H Benzo [b] [l, 4] —Oxazin-3 (4H) ON (Reference Compound 1 5)

[Chemical 13]

[0087] H-NMR (300MHz, DMSO-d)

6

δ: 11.25 (s, IH), 8.03 (s, IH), 7.47— 7.44 (m, IH), 7.24 (s, IH), 7. 07-7.03 (m, 2H), 7.01— 6.97 (m, IH ), 6.64 (s, IH).

(Z) —2— ((5 Bromofuran-2-yl) methylene) 2H Benzo [b] [1, 4] -Oxazine 1 3 (4H) ON (Reference compound 1 6)

[Chemical 14]

[0088] H—NMR (300MHz, DMSO—d)

6

δ: 11.23 (s, IH), 7.36— 7.33 (m, IH), 7.14 (d, J = 3.5 Hz, IH), 7.06-7.02 (m, 2H), 7.00— 6.96 (m, IH ), 6.80 (d, J = 3.5 Hz, IH), 6.64 (s, IH).

(Z) 2— (3 Bromo-5 methoxybenzylidene) 2H Benzo [b] [1, 4] Oxazine 1 3 (4H) ON (Reference compound 1 7)

[Chemical 15]

H—NMR (300MHz, DMSO—d)

6

δ: 11.21 (s, IH), 8.27 (d, J = 2.4 Hz, IH), 7.50 (dd, J = 8.8, 2.4 Hz, IH), 7.14-7.ll (m, IH), 7.07— 7.03 (m, 4H), 7.00— 6.97 (m, IH), 3.86 (s, 3H).

(Z) —2— ((5 Bromothiazol-2-yl) methylene) 2H Benzo [b] [1, 4] oxazine 3 (4H) —one (Reference compound 1 8)

[Chemical 16]

[0090] H—NMR (300MHz, DMSO—d)

6

δ: 11.49 (s, 1H), 8.05 (s, 1H), 7.42 (dd, J = 7.6, 1.7 Hz, 1H), 7.16-7.03 (m, 3H), 7.00 (s, 1H).

Reference example 0

(E) -tert-butyl 3- (4-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) talate (compound 0-1 )

[Chemical 17]

[0091] 2— (4 Bromobenzylidene) 2H Benzo [b] [l, 4] oxazine 3 (4H) ON

A reaction vessel containing (7.9 g, 25 mmol, reference compound 11), palladium acetate (510 mg, 2.3 mmol) and tri (o-tolyl) phosphine (1.4 g, 4.5 mmol) was replaced with nitrogen gas. To the reaction vessel, dimethylformamide (120 mL), diisopropylethylamine (360 mL, 2 lOmmol), and tert butyl acrylate (15 mL, lOOmmol) were added and stirred at 100 ° C with heating. The reaction mixture was cooled to room temperature and filtered through Celite acetate (lOOmU. The filtrate was diluted with ethyl acetate (lOOmL), washed with saturated brine (200mU twice, dried over sodium sulfate, and concentrated under reduced pressure). The residue was collected by filtration with hexane ethyl acetate (1: 1), washed with ethyl acetate, and dried under reduced pressure to obtain 7.9 g of the title reference compound as a yellow solid (yield 87%).

[0092] 'H-NMROOOMHz, DMSO— d)

6

δ: 8.77 (s, 1Η), 7.87 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 15.2 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.26 (s, 1H ), 7.21— 7.19 (m, 1H), 7.09-7.04 (m, 2H), 6.95 (s, 1H), 6.91— 6.88 (m, 1H), 6.41 (d, J = 15.8 Hz, IH), 1.53 (s, 9H).

Hereinafter, using the compounds selected from Reference Compounds 12 to 8, commercially available compounds and known compounds, the considered compounds 0 to 2 to 8 were obtained according to the production method of the compound 0 to 1.

(E) -tert-butyl 3- (2-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) acrylate (compound 0-2 )

[Chemical 18]

[0094] H—NMR (300MHz, DMSO—d)

6

δ: 8.13 (s, IH), 7.93 (d, J = 6.1 Hz, IH), 7.91 (d, J = 10.3 Hz, IH), 7.61 (d, J = 6.8 Hz, IH), 7.43 (t , J = 7.4 Hz, IH), 7.34 (t, J = 7.3 Hz, IH), 7.19 (s, IH), 7.04—6.99 (m, 3H), 6.87— 6.82 (m, IH), 6.31 (d, J = 15.8 Hz, IH), 1.49 (s, 9H).

(E) -tert-butyl 3- (5-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) thiophene 3 yl) atelate (compound

0-3)

[Chemical 19]

[0095] H—NMR (300MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.ll (s, IH), 7.83 (s, IH), 7.53 (d, J = 15.8 Hz, IH), 7.27-7.24 (m, IH), 7.09— 7.04 ( m, 2H), 7.05 (s, IH), 7.02— 6.98 (m, IH), 6.37 (d, J = 15.8 Hz, IH), 1.48 (s, 9H).

(E) -tert-butyl 3- (5-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) thiophene 2 yl) talate (compound (9

-o (^^) ^-^ (^ -z-^^ (^-^ ≠ (^ Ci -z- ^ ^ w 'χ] [

-(z)) -s) -ε / ^ ー

• (H6 ^<s ) 6 ^ "X '(HI ^<Ζ Η 8" SI = Γ' P) SS · 9 '(HI' s) S9 · 9 '(HS' ^) 6 · 9 80 · Ζ '( HI 's) 9 · Ζ' (HI ' ^Ζ Η 8 · SI = ΓΡ) Ζ · Ζ' (HI 'ra) i9 · Ζ- 9 · Ζ' (HI 's) 8X · 8' (HI ^) Z '11: 9

(P-OS a ^<z HM00S) ¾MN-H _T

[

(s

— O 呦 ^ WH— 4i ^ (^ — ε—Be ^ / (/ ^ Be ^ ίί ^ — z—Be [Ί] [

-(ζ)) -s) -ε / ^ ー

• (H6 ' ^s ) 6 "X' (Η

X ' ^Ζ Η 8 "SX = Γ' P) SS · 9 '(ΗΧ' ^) 66 · 9— SO · Ζ '(HZ' ra) go · Ζ 60 · Ζ '(HI' s) ZX · Ζ ' (HI 'ra) s · Ζ— S · Ζ' (HI ' ^Ζ Η 6 Έ = Γ' P) S ^ · Ζ '(HI' ΖΗ 6 · ε = Γ 'P) ZS · Ζ' (ΗΧ ' ^Ζ Η 8 "SX = Γ 'Ρ) ΖΖ · Ζ' (HI 's) SZ" 11: 9

( ⁹ P-0SMQ ^<z HM00S) ¾MN-H _T

(1 0

690l.0 / .00Zdf / X3d 6ε T98CS0 / 800Z OAV

H—NMR (300MHz, DMSO d)

6

δ: 11.28 (s, IH), 7.40— 7.35 (m, 2H), 7.24 (d, J = 3.5 Hz, IH), 7

13 (d, J = 3.5 Hz, IH), 7.08— 7.04 (m, 2H), 7.03— 6.98 (m, IH)

, 6.71 (s, IH), 6.23 (d, J = 15.8 Hz, IH), 1.48 (s, 9H).

(E) -tert-butyl 3- (4-methoxy-3- ()-(3-oxo3, 4 dihydro-2

H Benzo [b] [1,4] oxazine 2 ylidene) methyl) phenyl) atarylate (compound 0— 7)

[Chemical 23]

H—NMR (300MHz, DMSO d)

6

δ: 11.17 (s, IH), 8.34 (d, J = 2.0 Hz, IH), 8.31 (s, IH), 7.75 (dd, J = 8.5, 2.1 Hz, IH), 7.63 (d, J = 16.0 Hz, IH), 7.26— 7.23 (m, IH), 7.12 (d, J = 9.0 Hz, IH), 7.08 (s, IH), 7.06— 6.97 (m, 2H), 6.40 (d, J = 16.0 Hz, IH), 3.91 (s, 3H), 1.50 (s, 9H)

(E) —tert-butyl (E) -3— (2 — ((Z) — (3 oxo-3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 lysine) methyl) thiazole-5 yl ) Atarylate (compound 0-8)

[Chemical 24]

[0100] H—NMR (300MHz, DMSO—d)

6

δ: 11.52 (s, 1H), 8.28 (s, 1H), 7.83 (d, J = 15.8 Hz, 1H), 7.61— 7.58 (m, 1H), 7.15— 7.00 (m, 3H), 7.02 ( s, 1H), 6.44 (d, J = 15.8 Hz, 1H), 1.47 (d, J = 13.9 Hz, 9H).

Reference example 2

(E) tert butyl 3- (3 formylphenyl) acrylate (reference compound 2-1) [Chemical formula 25]

[0101] 3 Bromobenzaldehyde (3.5mL, 30mmol), Palladium acetate (340mg, 1.5mmoD, O-Linole) phosphine (910mg, 3. OmmoD, Diisopropinoreethinoreamine (6OmL, 350mmol) Nitrogen gas was bubbled into a solution of dimethylformamide (130 mL), and the inside of the vessel was replaced with nitrogen gas, tert butyl acrylate (20 mL, 140 mmol) was added to the reaction vessel, and the mixture was stirred overnight at 100 ° C. The reaction solution was cooled to room temperature and filtered through celite using ethyl acetate (lOOmL) The filtrate was diluted with ethyl acetate (150mU, washed twice with saturated brine (300mL), dried over sodium sulfate, and dried under reduced pressure. After drying under reduced pressure, the title reference compound (5.2 g) was obtained as a colorless transparent liquid (yield 74%).

[0102] 'H-NMROOOMHz, DMSO— d)

6

δ: 10.03 (s, 1H), 8.25 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.68-7.61 (m, 2H), 6.67 (d, J = 16.0 Hz, 1H), 1.50 (s, 9H).

Example 0 '

(E) — tert butyl 3- (3 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine-2 ylidene) methyl) phenyl) acrylate (compound 0'— 1) [Chemical 26]

[0103] 2H Benzo [b] [l, 4] oxazine 1 3 (4H) —one (1.4 g, 9.7 mmol) and (E) —ter tert-butinole 3— (3 honoreminophenyl) ate (1.7) g, 7.4 mmol, Reference compound 2-1) was added acetic anhydride (4 mL) and triethylamine (2 mU) and stirred at 110 ° C. The reaction mixture was cooled to room temperature and cooled with ice-cold 1 M hydroxide. The precipitated solid poured into an aqueous sodium solution was collected by filtration, washed with water (5. OmL), acetonitrile (5. OmL), ethyl acetate (5.0 mL) and dried under reduced pressure to give 570 mg of the title reference compound. Obtained as a yellow solid (yield 16%).

[0104] 'H-NMROOOMHz, DMSO-d)

6

δ: 11.20 (s, 1H), 8.05 (s, 1H), 8.04 (d, J = 7. O Hz, 1H), 7.69 (d, J = 7.3 Hz, 1H), 7.62 (d, J = 16. 1 Hz, 1H), 7.49 (t, J = 8.1 H z, 1H), 7.33-7.30 (m, 1H), 7.09— 7.03 (m, 2H), 7.02— 6.97 (m, 1H), 6.82 (s, 1H), 6.59 (d, J = 16.1 Hz, 1H), 1.50 (s, 9H).

Example 0 "

(E) —tert-butyl 3- (3 — ((Z) — (4-methyl-3oxo3,4 dihydro-2Hbenzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) talylate (compound 0 "— 1)

[Chemical 27]

(E) -tert-butyl 3- (3-((Z)-(3 oxo 3, 4 dihydro-2H-benzo [b] [l, 4] oxazine-2 ylidene) methyl) phenyl) talate (550 mg, 1.5 mm ol Compound 0'-1) in tetrahydrofuran (3mU solution was added sodium hydride (60%, 90mg, 2.3mmol) and stirred. After stirring at room temperature for 15 minutes, odomethane (0.20mL, 3. 2 mmol) was added and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (10 mL), washed twice with saturated brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was collected by filtration with hexane ethyl acetate (1: 1), washed with ethyl acetate, and dried under reduced pressure to give 450 mg of the title reference compound as a yellow solid (yield 88%).

[0106] 'H-NMROOOMHz, DMSO-d)

6

δ: 8.07 (s, 1H), 8.06 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1 H), 7.62 (d, J = 16.0 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.39— 7.36 (m, 1H), 7.28— 7.25 (m, 1H), 7.18— 7.14 (m, 2H), 6.87 (s, 1H), 6.59 (d, J = 16.0 Hz , 1H), 3.42 (s, 3H), 1.50 (s, 9H).

Hereinafter, using compounds selected from compounds 0-4, 0-7, commercially available compounds and known compounds, compounds 0 "-2 to 4 were obtained according to the production method of compound 0" -1.

[0107] (E) —tert-Butyl 3- (5 — ((Z) — (4-Methyl-3-oxo3,4 dihydro-2 H-benzo [b] [1, 4] oxazine 2-ylidene) methyl) thiophene 2- ) Atarirate (Compound 0 "— 2)

[Chemical 28]

[0108] H—NMR (300MHz, DMSO-d)

6

δ: 7.72 (d, J = 15.8 Hz, 1H), 7.52 (d, J = 3.9 Hz, 1H), 7.50—7.46 (m, 2H), 7.29—7.25 (m, 1H), 7.21—7.13 ( m, 3H), 6.34 (d, J =

15.6 Hz, 1H), 3.41 (s, 3H), 1.49 (s, 9H).

(E) —tert butynole 3— (5 — ((Z) — (4 (2 ethoxy-2-oxoethyl) -3—oxo3,4 dihydro-2H benzo [b] [l, 4] oxazine-2-ylidene) methyl ) Thiophene 2) Atalylate (Compound 0 "— 3)

[Chemical 29]

[0109] H—NMR (300MHz, DMSO—d)

6

δ: 7.73 (d, J = 15.8 Hz, IH), 7.57—7.50 (m, 3H), 7.24—7.13 (m, 4H), 6.37 (d, J = 15.8 Hz, IH), 4.88 (s, 2H) , 4.18 (q, J = 7.2 Hz, 3H), 1.49 (s, 9H), 1.22 (t, J = 7.2 Hz, 2H).

(E) -tert-butyl 3- (4-methoxy-3- ()-(4-methyl-3-oxo3,4 dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) acrylate (compound 0 "- Four)

[Chemical 30]

[0110] H—NMR (300MHz, DMSO—d)

6

δ: 8.33 (d, J = 2.0 Hz, IH), 7.76 (dd, J = 8.4, 2.0 Hz, IH), 7.6 3 (d, J = 16.0 Hz, IH), 7.30— 7.24 (m, 2H), 7. 17— 7. ll (m, 4H), 6.40 (d, J = 16.0 Hz, IH), 3.91 (s, 3H), 3.42 (s, 3H), 1.50 (s, 9H) Example 1

(E) —3— (4— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2-ylidene) methyl) phenyl) acrylic acid (compound 1 1)

[Chemical 31]

[0111] (E) —tert-Butyl 3— (4— ((Z) — (3 oxo 3, 4 dihydro-2H—benzo [b] [l, 4] oxazine-2 ylidene) methyl) phenyl) talylate (6 · To 8 g, 19 mmol, Compound 0-1) was added 4M hydrogen chloride dioxane solution (150 mL, 0.60 mol) and black mouth form (50 mL). The reaction solution was stirred overnight at room temperature. Concentration under reduced pressure yielded 6.8 g of the target compound as a yellow powder (yield 100%).

[0112] ¹ H—NMR (300 MHz, DMSO— d)

6

δ: 12.43 (s, IH), 11.21 (s, IH), 7.93 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 16.0 Hz, IH ), 7.31 (q, J = 3.1 Hz, IH), 7.09-7.04 (m, 2H), 7.01—6.99 (m, IH), 6.81 (s, IH), 6.5 7 (d, J = 16.0 Hz, IH ).

Compound 0—2 to 8, 0′—1, 0 ″ — ;! to 4, Compound 1 2˜, using a compound selected from commercially available compounds and known compounds according to the production method of Compound 11; 13 was obtained.

[0113] (E) —3— (3 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2-ylidene) methyl) phenyl) acrylic acid (compound 1 2)

[Chemical 32]

[0114] H—NMR (300MHz, DMSO—d)

6

δ: 12.48 (s, IH), 11.20 (s, IH), 8.08 (s, IH), 8.01 (d, J = 7.9 Hz, IH), 7.69 (d, J = 7.7 Hz, IH), 7.66 (d , J = 16.0 Hz, IH), 7.50 (dd, J = 7.7, 7.7 Hz, IH), 7.32 (t, J = 4.8 Hz, IH), 7.07— 7.04 (m, 2H), 7.02-6.97 (m, IH), 6.82 (s, IH), 6.59 (d, J = 16.0 Hz, 1 H).

(E) —3— (2— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2-ylidene) methyl) phenyl) acrylic acid (compound 1 3)

[Chemical 33]

[0115] ¹ H—NMR (300 MHz, DMSO— d)

6

δ: 12.51 (s, IH), 11.29 (s, IH), 8.02 (d, J = 7.0 Hz, IH), 7.85 (d, J = 15.8 Hz, IH), 7.80 (d, J = 7.9 Hz, IH ), 7.51 (t, J = 7.1 Hz, IH), 7.39 (t, J = 7.7 Hz, IH), 7.12— 6.98 (m, 4H), 6.98 (s, 1 H), 6.46 (d, J = 15.8 Hz, IH).

(E) —3— (5— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) thiophene 3 yl) acrylic acid (compound 1— Four)

[Chemical 34]

[0116] H—NMR (300MHz, DMSO—d)

6

δ: 12.35 (s, IH), 11.17 (s, IH), 8.09 (s, IH), 7.82 (s, IH), 7.56 (d, J = 16.0 Hz, IH), 7.25-7.23 (m, IH) , 7.08— 6.97 (m, 3H), 7.06 (s, IH), 6.36 (d, J = 16.0 Hz, IH).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) thiophene 2 yl) acrylic acid (compound 1 Five)

[Chemical 35]

[0117] H—NMR (300MHz, DMSO—d)

6

δ: 12.40 (s, IH), 11.23 (s, IH), 7.76 (d, J = 15.6 Hz, IH), 7.51 (d , J = 3.9 Hz, IH), 7.46 (d, J = 3.9 Hz, IH), 7.44— 7.41 (m, IH), 7.12 (s, IH), 7.09-7.05 (m, 2H), 7.03— 7.00 ( m, IH), 6.35 (d, J = 15.6 Hz, IH).

(E) —3— (5— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) furan 3 yl) acrylic acid (compound 1 6 )

[Chemical 36]

[0118] H—NMR (300MHz, DMSO—d)

6

δ: 12.32 (s, IH), 11.25 (s, IH), 8.18 (s, IH), 7.62— 7.59 (m, IH), 7.51 (d, J = 15.8 Hz, IH), 7.46 (s, IH), 7.10— 6.97 (m, 3H), 6.64 (s, IH), 6.55 (d, J = 15.8 Hz, IH).

(E) —3— (5— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) furan 2 yl) acrylic acid (compound 1 7 )

[Chemical 37]

[0119] H—NMR (300MHz, DMSO—d)

6

δ: 11.28 (s, IH), 7.41 (d, J = 15.6 Hz, IH), 7.38— 7.35 (m, IH), 7.22 (d, J = 3.5 Hz, IH), 7.ll (d, J = 3.5 Hz, IH), 7.08— 7.05 (m, 2H), 7.02-6.98 (m, IH), 6.71 (s, IH), 6.26 (d, J = 15.6 Hz, 1 H), 3.57 (s, IH) .

(E) -3- (3-((Z)-(4-Methyl-3 oxo-1,3,4 dihydro-2H benzo [b] [1,4] oxazine 2 ylidene) methyl) phenyl) acrylic acid (compound 1 8 )

[Chemical 38]

lH-NMR (300MHz, DMSO—d6)

δ: 12.48 (s, IH), 8.09 (s, IH), 8.03 (d, J = 8.3 Hz, IH), 7.68 (t, J = 3.9 Hz, IH), 7.63 (s, IH), 7.50 (t , J = 7.7 Hz, IH), 7.39— 7.36 (m, IH), 7.28— 7.25 (m, IH), 7.21— 7.12 (m, 2H), 6.87 (s, IH), 6.59 (d, J = 16.0 Hz, IH), 3.42 (s, 3H).

(E) -3- (5-((Z)-(4-Methyl-3oxo3, 4 dihydro-2H benzo [b] [1,4] oxazine 2-ylidene) methyl) thiophene-2-yl) acrylic acid (Compound 1 9)

[Chemical 39]

lH-NMR (300MHz, DMSO—d6)

δ: 8.32 (s, IH), 7.76 (d, J = 15.8 Hz, IH), 7.50 (dt, J = 9.8, 3.1 Hz, 3H), 7.22 (tt, J = 16.2, 5.4 Hz, 4H) , 6.36 (d, J = 15.8 H z, IH), 3.41 (s, 3H).

(E) -3- (5-((Z) (4 ((2Ethoxy-2-oxoethyl))-3 (oxo-1,3,4) -dihydro-2H benzo [b] [1,4] oxazine-2ylidene) methyl) thiophene 2 — Gil) Acrylic acid (Compound 1 10)

[Chemical 40]

lH-NMR (300MHz, DMSO—d6)

δ: 12.42 (s, IH), 7.77 (d, J = 15.8 Hz, IH), 7.54-7.51 (m, 3H), 7.23 (s, IH), 7.19-7.15 (m, 3H), 6.38 (d, J = 15.8 Hz, IH), 4.88 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).

(E) -3- (4 Methoxy-1-3-((Z)-(3oxo-3,4 dihydro-l 2H benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) acrylic acid (compound 1— 11)

[Chemical 41]

H—NMR (300MHz, DMSO—d)

6

δ: 12.32 (s, IH), 11.18 (s, IH), 8.39 (d, J = 2.0 Hz, IH), 7.72 (dd, J = 8.7, 2.1 Hz, IH), 7.67 (d, J = 15.8 Hz , IH), 7.25 (q, J = 3.1 Hz, IH), 7.13 (d, J = 8.8 Hz, IH), 7.10 (s, IH), 7.07— 6.97 (m, 3H), 6.41 ( d, J = 16.0 Hz, IH), 3.91 (s, 3H)

(E) -3- (4 Methoxy-1-3-((Z)-(4 Methyl-3-oxo-3,4 Dihydro-2-H) Benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) acrylic acid (compound 1 -12)

[Chemical 42]

lH-NMR (300MHz, DMSO—d6)

δ: 12.3 (s, IH), 8.37 (d, J = 2.0 Hz, IH), 7.73 (dd, J = 8.5, 2.1 Hz, IH), 7.67 (d, J = 16.1 Hz, IH), 7.31— 7.24 (m, 2H), 7. 19— 7. 12 (m, 4H), 6.41 (d, J = 16.0 Hz, IH), 3.91 (s, 3H), 3.42 (s, 3H )

(E) -3- (2-((Z)-(3 oxo 34 dihydro-2H benzo [b] [1, 4] oxazine 2 iridine) methyl) thiazole-5 yl) acrylic acid (compound 1 13)

[Chemical 43]

H—NMR (300MHz, DMSO d)

6

δ: 11.52 (s, 1H), 8.27 (s, 1H), 7.86 (d, J = 15.6 Hz, 1H), 7.57 (t, J = 4.7 Hz, 1H), 7.14-7.03 (m, 5H), 6.45 (d, J = 15.8 Hz, 1H) Example 2

(E) —3— (4— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine—2 ylidene) methyl) phenyl) N— (pyridine-3-ylmethyl) Acrylamide (compound 2 1)

[Chemical 44]

(E) —3— (4 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) phenyl) acrylic acid (90 mg, 0.29 A dimethylformamide solution (mmol, Compound 11) (4-N, N dimethylaminopyridine (4 mg), mol / g) (100 mg, 0.15 mmol) was added to 4 mU, and the mixture was stirred at room temperature. The resin was washed with dimethylformamide, tetrahydrofuran and methylene chloride and dried under reduced pressure to obtain a resin (143 mg, calculated value 0.18 mmol). Add dimethylformamide (resin (140 mg, calculated 0.18 mmol) to 3 mU and 3 aminomethyl pyridine (17 mg, 0.16 mmol) at room temperature. The mixture was stirred. The reaction solution was filtered, and the back solution and the washing solution obtained by washing the resin with dimethylformamide and methylene chloride were combined and concentrated under reduced pressure to obtain 45 mg of the target compound as a yellow solid (yield 63%).

[0127] ¹ H— NMR (300 MHz, DMSO— d)

6

δ: 11.21 (s, 1H), 8.78 (t, J = 5.9 Hz, 1H), 8.58 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H ), 7.80 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 16.0 Hz, 1H), 7.46 (dd, J = 7.7, 5.1 Hz, 1H) ), 7.34—7.31 (m, 1H), 7.08—7.03 (m, 2 H), 7.02-6.98 (m, 1H), 6.80 (s, 1H), 6.73 (d, J = 16.0 Hz, 1H), 4.46 (d, J = 5.9 Hz, 2H).

Hereinafter, using a compound selected from Compound 113, a commercially available compound and a known compound, Compound 2-2135 was obtained according to the production method of Compound 2-1.

[0128] (E) —N — ((2 dimethylamino) ethyl) -3— (4 — ((Z) — (3 oxo3, 4 dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl ) Phenyl) acrylamide (Compound 2-2)

[Chemical 45]

H-NMR (500MHz, DMSO—d)

6

δ: 11.19 (s, 1H), 8.05 (t, J = 5.6 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 15.6 Hz, 1H), 7.34 -7.32 (m, 1H), 7.08— 7.03 (m, 2H), 7.01— 6.98 (m, 1H), 6.80 (s, 1 H), 6.72 (d, J = 15.6 Hz , 1H), 3.28 (t, J = 6.2 Hz, 2H), 2.34 (t, J = 6.6 Hz, 2H), 2.15 (d, J = 17.8 Hz, 6H).

(E) — N— (2 morpholinoethyl) 3— (4-((Z)-(3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) attalinoleamide (Compound 2-3) [Chem 46]

H—NMR (300MHz, DMSO—d)

6

δ: 11.17 (s, IH), 8.06 (t, J = 5.6 Hz, IH), 7.91 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 15.8 Hz, IH), 7.34 -7.28 (m, IH), 7.08— 7.02 (m, 2H), 7.01— 6.96 (m, IH), 6.79 (s, 1 H), 6.69 (d, J = 15.6 Hz , IH), 3.57 (t, J = 4.6 Hz, 4H), 3.29 (d, J = 6.6 Hz, 2H), 2.50-2.28 (m, 6H).

(E) —N Cyclopropinole 1— (4 — ((Z)-(3 oxo 3, 4 dihydro-1 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) attalinoleamide (compound twenty four)

[Chemical 47]

H—NMR (500MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.22 (d, J = 4.3 Hz, IH), 7.93 (t, J = 10.2 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 15.6 Hz, IH), 7.34 -7.30 (m, IH), 7.08— 7.02 (m, 2H), 7.00— 6.98 (m, IH), 6.79 (s, 1 H), 6.58 (d, J = 15.6 Hz , IH), 2.79- 2.76 (m, IH), 0.69 (td, J = 6.9, 5.0 Hz, 2H), 0.47 (dt, J = 7.7, 3.4 Hz, 2H).

(Z) —2— (4— ((E) —3-Oxo-3- (pyrrolidine 1 yl) propylene 1 benzylidene) 2H benzo [b] [1, 4] oxazine 3 (4H) ON (compound 2— 5) [Chemical 48]

[0132] H—NMR (500MHz, DMSO—d)

6

δ: 11.19 (s, IH), 7.92 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 15.6 Hz, IH), 7.31— 7.26 (m , IH), 7.07— 7.04 (m, 3H), 7.02-6.98 (m, IH), 6.81 (s, IH), 3.66 (t, J = 6.8 Hz, 2H), 3.41 (t, J = 6.8 Hz, 2H), 1.93 (tt, J = 6.8, 6.8 Hz, 2H), 1.82 (tt, J = 6.8, 6.8 Hz, 2H).

(Z) — 2— (4- ((E) —3 Morpholino 3-oxopropenyl 1-benzyl) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H) ON (compound 2— 6)

[Chemical 49]

[0133] H—NMR (500MHz, DMSO—d)

6

δ: 11.18 (s, IH), 7.92 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 15.3 Hz, IH), 7.31 (d, J = 15.3 Hz, IH), 7.29 -7.26 (m, IH), 7.08— 7.03 (m, 2H), 7.02— 6.98 (m, IH), 6.81 (s, 1 H), 3.74-3.51 (m, 8H) .

(Z) -2- (4- ((E) -3- (4- (2 Hydroxyethyl) piperazine 1-yl) 3-Oxopropene 1 heninole) benzylidene) 2H Benzo [b] [1 , 4] oxazine 3 (4H) ON (compound 2— 7)

[Chemical 50]

H—NMR (500MHz, DMSO—d)

6

δ: 11.18 (s, IH), 7.91 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 15.4 Hz, IH), 7.31 (d, J = 15.6 Hz, IH), 7.29 -7.26 (m, IH), 7.08— 7.04 (m, 2H), 7.03— 6.98 (m, IH), 6.81 (s, 1 H), 4.44 (t, J = 5.4 Hz , IH), 3.70—3.50 (m, 8H), 2.42 (t, J = 6.2 Hz, 4H).

(E) —3— (4— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine—2-ylidene) methyl) phenyl) N— (pyridine— 2 —Ylmethyl) acrylamide (compound 2— 8)

[Chemical 51]

H-NMR (500MHz, DMSO—d)

6

δ: 11.19 (s, IH), 8.74 (t, J = 5.8 Hz, IH), 8.53 (dq, J = 4.9, 0.9 Hz, IH), 7.94 (d, J = 8.2 Hz, 2H), 7.78 (td, J = 7.6, 1.8 Hz, IH), 7.65 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 15.6 Hz, IH), 7.34 -7.32 (m, 2H), 7.30— 7.27 ( m, IH), 7.08— 7.03 (m, 2H), 7.00— 6.99 (m, IH), 6.81 (d, J = 15.6 Hz, IH), 6.80 (s, IH), 4.51 (d, J = (5.8 Hz, 2H).

(E) —3— (4— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) phenyl) N— (pyridine-4-ylmethyl) Acrylamide (compound 2-9)

[Chemical 52]

[[00113366]] HH—— NNMMRR ((550000MMHHzz ,, DDMMSSOO—— dd))

66

δδ :: 1111..1188 ((ss ,, IIHH)), 88..7777 ((tt ,, JJ == 55..99 HHzz ,, IIHH)) ,, 88..5522 ((dddd ,, JJ == 44..44 ,, 11 .. 77 HHzz ,, 22HH)), 77..9944 ((dd ,, JJ == 88..33 HHzz ,, 22HH)) ,, 77..6666 ( (dd ,, JJ == 88..55 HHzz ,, 22HH)), 77 ..5522 ((dd ,, JJ == 1155..99 HHzz ,, IIHH)) ,, 77..3344——77 ..3322 ((mm ,, IIHH)) ,, 77..2299 ((dddd ,, JJ == 44..44 ,, 11..55 HHzz ,, 22HH)) ,, 77..0099--77 ..0044 ((mm ,, 22HH)) ,, 77..0022—— 66..9988 ((mm ,, IIHH)) ,, 66..8811 ((ss ,, 11 HH)) ,, 66. .7766 ((dd ,, JJ == 1155..99 HHzz ,, IIHH)) ,, 44..4455 ((dd ,, JJ == 55..99 HHzz ,, 22HH)).

((EE)) —— 33—— ((44—— ((((ZZ)) — ((33 oxoxo 33 ,, 44 jijihi hydrodoro 22HH bebenzozo [[bb]] [[ll ,, 44] ] Oxoxasa Jidzin 22 Irididene))) Methicyll)) Fuueinyll)) NN —— ((((66 Totrilifluoromethylmethylicylpipyridinidine 33

[Chemical 53]

H—NMR (300MHz, DMSO—d)

6

δ: 11.20 (s, IH), 8.84 (t, J = 5.7 Hz, IH), 8.72 (s, IH), 8.00— 7. 88 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H) , 7.51 (d, J = 15.8 Hz, IH), 7.34-7.31 (m, IH), 7.07— 7.03 (m, 2H), 7.01— 6.97 (m, IH), 6.80 (s, IH), 6.73 (d , J = 15.8 Hz, IH), 4.55 (d, J = 5.7 Hz, 2H).

(E) -N- (3,5-Dimethylphenyl) 1 3— (4— ((Z) — (3-Oxo 3, 4-dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) Methyl) phenyl) acrylamide (compound 2 11)

[Chemical 54]

[0138] H—NMR (500MHz, DMSO—d)

6

δ: 11.19 (s, IH), 10.07 (s, IH), 7.96 (d, J J = 8.6 Hz, 2H), 7.58 (d, J = 15.6 Hz, IH), 7.36— 7.32 (m, 3H), 7.09-7.04 (m, 2H), 7.02— 6.99 (m, IH), 6.87 (d , J = 15.6 Hz, 1 H), 6.82 (s, IH), 6.72 (s, IH), 2.26 (s, 6H).

(E) -N- (3, 4-Dimethoxyphenyl) 1 3— (4— ((Z) — (3-Oxo 3, 4-dihydro) 2H Benzo [b] [1, 4] oxazine 2 Iridene ) Methyl) phenyl) acrylamide (compound 2-12)

[Chemical 55]

H—NMR (500MHz, DMSO—d)

6

δ: 11.21 (s, IH), 10.12 (s, IH), 7.96 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 15.6 Hz, IH ), 7.42 (d, J = 2.2 Hz, IH), 7.36-7.33 (m, IH), 7.23 (dd, J = 8.7, 2.3 Hz, IH), 7.0 9-7.04 (m, 2H), 7.01—6.99 (m, IH), 6.93 (d, J = 8.8 Hz, IH), 6.84 (d, J = 15.9 Hz, IH), 6.82 (s, IH), 3.76 (s, 3H), 3.74 (s, 3H). (E) — N— (4-morpholinophenyl) 3— (4-((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine 2— Iridene) methyl) phenyl) acrylamide (compound 2-13)

[Chemical 56]

H—NMR (500MHz, DMSO—d)

6

δ: 11.20 (s, IH), 10.05 (s, IH), 7.96 (d, J = 8.6 Hz, 2H), 7.67 (d J = 8.6 Hz, 2H), 7.59 (d, J = 9.2 Hz, 2H) , 7.56 (d, J = 15.6 Hz, IH), 7.36-7.32 (m, IH), 7.09— 7.03 (m, 2H), 7.02— 6.98 (m, H), 6.93 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 15.6 Hz, IH), 6.81 (s, IH), 3.74 (t, J = 4.9 Hz, 4H), 3.06 (t, J = 4.9 Hz, 4H).

(E) N— (7 Methyl-1, 8 Naphthyridin-2-yl) -3— (4-((Z)-(3 oxo-1,4 dihydro-1 2H benzo [b] [l, 4] oxazine-1 2 Iridene) methyl) phenyl) atalinoleamide (compound 2-14)

[Chemical 57]

H—NMR (500MHz, DMSO—d)

6

δ: 11.27 (s, IH), 11.22 (s, IH), 8.51 (d, J = 8.8 Hz, IH), 8.41 (d, J = 8.8 Hz, IH), 8.27 (d, J = 8.3 Hz, IH ), 7.99 (d, J = 8.5 H z, 2H), 7.74 (d, J = 15.9 Hz, IH), 7.71 (d, J = 8.5 Hz, 2H), 7.4 2 (d, J = 8.1 Hz, IH ), 7.39—7.36 (m, IH), 7.15 (d, J = 15.9 Hz, IH), 7.08-7.05 (m, 2H), 7.02—6.99 (m, IH), 6.83 (s, IH), 2.68 (s, 3H).

(E) —3— (3— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine—2 ylidene) methyl) phenyl) N— (pyridine-3-ylmethyl) Acrylamide (compound 2-15)

[Chemical 58]

H—NMR (300MHz, DMSO—d)

6

δ: 11.20 (s, IH), 8.77 (t, J = 5.9 Hz, IH), 8.55 (d, J = 1.7 Hz, IH), 8.47 (dd, J = 4.8, 1.7 Hz, IH), 8.05 (s , IH), 7.91 (d, J = 7.5 Hz, IH), 7.72 (d, J = 8.1 Hz, IH), 7.58—7.47 (m, 3H), 7.40 -7.32 (m, 2H), 7.07— 7.04 (m, 2H), 7.02— 6.98 (m, IH), 6.80 (s, 1 H), 6.74 (d, J = 15.8 Hz, IH), 4.45 (d, J = 5.9 Hz, 2H).

(E) —N— ((2 dimethylamino) ethyl) -3- (3-((Z)-(3 oxo 3, 4 dihydro 2H-benzo [b] [1, 4] oxazine 2-ylidene) methyl) Phenyl) acrylamide (compound 2-16)

[Chemical 59]

H—NMR (300MHz, DMSO—d)

6

δ: 11.20 (s, IH), 8.13 (s, IH), 8.02 (s, IH), 7.91 (d, J = 7.3 Hz, 1 H), 7.56-7.45 (m, 3H), 7.34 (d, J = 9.2 Hz, IH), 7.07—6.99 (m, 3H), 6.80 (s, IH), 6.73 (d, J = 15.8 Hz, IH), 3.33—3.31 (m, 4H), 2.24 (s, 6H) .

(E) —N Cyclopropinole 1— (3 — ((Z)-(3 Oxo 3, 4 Dihydro-1 2H Benzo [b] [1, 4] Oxazine 2 Iridene) methyl) phenyl) Atalinoleamide (Compound 2—17)

[Chemical 60]

H—NMR (300MHz, DMSO—d)

6

δ: 11.20 (s, IH), 8.27 (d, J = 4.6 Hz, IH), 8.01 (s, IH), 7.90 (d, J = 7.3 Hz, IH), 7.54-7.46 (m, 3H), 7.35 — 7.32 (m, IH), 7.08— 7.04 (m, 2H), 7.03— 6.98 (m, IH), 6.80 (s, IH), 6.59 (d, J = 15.8 Hz, IH), 2.82-2.72 (m , IH), 0.73— 0.67 (m, 2H), 0.49 (dd, J = 6.2, 3.9 Hz, 2H). ) -2— (3 -— ((£) -3—Oxoso 3-—pyrrolidine-1-yl) propenyl-1-benzylidene) 2H Benzo [b] [1,4] oxazine 3 (4H) ON (compound 2-18 )

[Chemical 61]

[0145] H—NMR (300MHz, DMSO—d)

6

δ: 11.19 (s, IH), 8.10 (s, IH), 8.00 (d, J = 7.5 Hz, IH), 7.66 (d, J

= 7.7 Hz, IH), 7.52 (d, J = 15.6 Hz, IH), 7.49 (d, J = 15.6 Hz, IH), 7.32-7.29 (m, IH), 7.08— 6.98 (m, 4H), 6.84 (s, IH), 3.6 8 (t, J = 6.7 Hz, 2H), 3.41 (t, J = 6.7 Hz, 2H), 1.93 (tt, J = 6. 7, 6.7 Hz, 2H), 1.84 (tt , J = 6.7, 6.7 Hz, 2H).

(Z) -2- (3- ((E) -3-Monolephorinone 3-oxopropylene 1) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H) ON (compound 2-19)

[Chemical 62]

[0146] H—NMR (300MHz, DMSO—d)

6

δ: 11.17 (s, IH), 8.09 (s, IH), 8.04 (d, J = 7.7 Hz, IH), 7.70 (d, J = 7.9 Hz, IH), 7.56 (d, J = 15.6 Hz, IH ), 7.49 (t, J = 7.8 H z, IH), 7.32-7.30 (m, IH), 7.32 (d, J = 15.6 Hz, IH), 7.08—6.9 8 (m, 3H), 6.83 (s, IH), 3.76- 3.54 (m, 8H).

(Z) -2- (3- ((E) -3- (4- (2 Hydroxyethyl) piperazine 1-yl) 3-Oxopropene 1 heninore) benzylidene) 2H Benzo [b] [1 , 4] oxazine 3 (4H) ON (compound 2-20)

[Chemical 63]

[0147] H—NMR (300MHz, DMSO—d)

6

δ: 11.24 (s, IH), 8.15 (s, IH), 7.57- 7.53 (m, IH), 7.50 (s, IH), 7.44 (d, J = 15.4 Hz, IH), 7.15 (d, J = 15.4 Hz, IH), 7.10— 7.06 (m, 2H), 7.02-6.99 (m, IH), 6.65 (s, IH), 4.46 (t, J = 5.2 Hz, IH), 3.74-3.49 (m , 12H), 2.44 (t, J = 6.1 Hz, 2H).

(E) —3— (3— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine—2-ylidene) methyl) phenyl) N— (pyridine— 2 —Ylmethyl) acrylamide (compound 2— 21)

[Chemical 64]

[0148] H—NMR (300MHz, DMSO—d)

6

δ: 11.20 (s, IH), 8.80 (t, J = 5.9 Hz, IH), 8.53 (d, J = 4.0 Hz, IH), 8.07 (s, IH), 7.91 (d, J = 8.1 Hz , IH), 7.78 (td, J = 7.7, 1. 7 Hz, IH), 7.57-7.47 (m, 3H), 7.37— 7.26 (m, 3H), 7.07— 6.98 (m, 3H), 6.82 (d , J = 15.6 Hz, IH), 6.81 (s, IH), 4.52 (d, J = 6.1 Hz, 2H).

(E) —3— (3— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine—2 ylidene) methyl) phenyl) N— (pyridine-4-ylmethyl) Acrylamide (compound 2-22) [Chemical 65]

[0149] H—NMR (300MHz, DMSO—d)

6

δ: 11.20 (s, IH), 8.81 (t, J = 6.0 Hz, IH), 8.52 (d, J = 6.1 Hz, 2H), 8.07 (s, IH), 7.92 (d, J = 6.6 Hz, IH ), 7.59— 7.48 (m, IH), 7.36-7.33 (m, IH), 7.30 (d, J = 6.1 Hz, 2H), 7.08— 7.04 (m, 2H), 7.01-6.98 (m, 3H), 6.81 (s, IH), 6.78 (d, J = 17.2 Hz, IH), 4.46 (d, J = 6.0 Hz, 2H).

(E) —3— (3— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) phenyl) N — ((6 trifluoro Methylpyridine 3

[Chemical 66]

[0150] H—NMR (500MHz, DMSO—d)

6

δ: 11.19 (s, IH), 8.86 (t, J = 5.6 Hz, IH), 8.73 (s, IH), 8.06 (s, 1 H), 8.00 (d, J = 8.1 Hz, IH), 7.91 ( t, J = 7.3 Hz, 2H), 7.60— 7.48 (m, 3H), 7.35— 7.33 (m, IH), 7.09— 6.98 (m, 3H), 6.81 (s, IH), 6.75 (t, J = 7.8 Hz, IH), 4.56 (d, J = 5.6 Hz, 2H).

(E) —3— (3— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2-ylidene) methyl) phenyl) N— ((6 (3- (yl) pyridine) methyl) acrylamide (compound 2-24)

[Chemical 67]

H—NMR (300MHz, DMSO—d)

6

δ: 11.20 (s, IH), 8.79 (t, J = 5.7 Hz, IH), 8.38 (d, J = 2.2 Hz, IH), 8.05 (s, IH), 7.91 (d, J = 7.3 Hz, IH ), 7.79 (dd, J = 8.1, 2.6 Hz, IH), 7.57-7.47 (m, 4H), 7.34 (d, J = 9.2 Hz, IH), 7.07 -7.00 (m, 3H), 6.80 ( s, IH), 6.73 (d, J = 15.6 Hz, IH), 4.45 (d, J = 6.4 Hz, 2H).

(E) -N- (3,5-Dimethylphenyl) 1 3— (3— ((Z) — (3-Oxo 3, 4-dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) Methyl) phenyl) acrylamide (compound 2-25)

[Chemical 68]

'H-NMROOOMHz, DMSO— d)

6

δ: 11.21 (s, IH), 10.10 (s, IH), 8.07 (s, IH), 7.95 (d, J = 7.5 Hz, IH), 7.65-7.50 (m, 4H), 7.36— 7.33 (t, J = 12.5 Hz, 3H), 7.09 -6.99 (m, 3H), 6.88 (m, 2H), 6.82 (s, IH), 6.73 (s, IH), 2.26 (s, 6H)

(E) -N- (3, 4-Dimethoxyphenyl) 1 3— (3— ((Z) — (3-Oxo 3, 4-dihydro) 2H Benzo [b] [1, 4] oxazine 2 Iridene ) Methyl) phenyl) acrylamide (Compound 2-26)

[Chem 69] [

Four

-(ζ))-ζ) -ε- (Ή)

"(HI 's) S6 · Ζ' (ΗΧ 'Ζ Η 9" SX = ΓΡ) · 9' (ΗΧ) 00 · Ζ- SO · Ζ '(HZ' ra) go "Ζ-ΟΧ · Ζ '(HI 's) ZX' L '(HI ^) Z' L-LZ · Ζ '(HI' ^Ζ Η Z Έ = Γ 'Ρ) Χ ^ · Ζ' (ΗΧ ^<Ζ Η Έ Έ = Γ 'Ρ) 9 Ζ '(ΗΧ' ^Ζ Η 9 "SX = ΓΡ) 9 · Ζ '(HI' s) 6S ΌΧ '(HI' ^) ΖΖ" 11: 9

(V-OSWa ^<Z HMOOS) MN-H _T

(zz— z 呦 ^

]. ^> ^-HZ--'ε— ^ One ε)-(z))-s) -ε- ^ α ^^ ι-Ν- (Ή)

• (HS ' ^S ) Z Έ' (HS 's) 9Z Έ' (HI 'S) Z8 · 9' (HI ' ^Ζ Η 6 · SI = Γ' Ρ) 98 · 9 '(ΗΧ' ^Ζ Η 8 · 8 = Γ 'Ρ) 86 9' (ΗΧ ' ^Ζ Η S Έ Ό 9 =

Γ 'ΡΡ) 00 · Ζ' (HZ 'ra) o · Ζ- 80 · Ζ' (ΗΧ ' ^Ζ Η Ζ · Ζ' 8 · 8 = Γ 'ΡΡ) ΖΖ · Ζ' (

HI '^) ςε' ζ-ζε · ζ '(ΗΧ' ^Ζ ν νζ = ΓΡ) · ζ '(ΗΧ' ^Ζ Η Ζ · Ζ = Γ

) SS · Ζ '(HI' ^Ζ "X" 8 = Γ '09) 09 Ζ '(HI' ^Ζ Η 6 "SX = Γ 'Ρ) 89 · Ζ' (HI ' ^Ζ Η 8 · Ζ = ΓΡ) 6 · Ζ '(HI' S) Z0 · 8 '(HI' s) SX '' (HI 's) 0Z "11: 9

( ⁹ P-0SMQ ^<Ζ ΗΜ003) ΉΜΝ-Η _Τ

690l.0 / .00Zdf / X3d 89 T98CS0 / 800Z OAV

H—NMR (300MHz, DMSO—d)

6

δ: 8.75 (t, J = 6.0 Hz, IH), 8.52 (d, J = 1.8 Hz, IH), 8.45 (dd, J = 4.8, 1.7 Hz, IH), 8.04 (d, J = 7.7 Hz, IH ), 7.76 (d, J = 15.6 Hz, IH), 7.68 (d, J = 7.9 Hz, IH), 7.61 (d, J = 6.8 Hz, IH), 7.45 (t, J = 7.1 Hz, IH ), 7.38—7.33 (m, 2H), 7.06 (d, J = 7.9 Hz, IH), 6.98-6.92 (m, 4H), 6.93 (s, IH), 6.59 (d, J = 15.6 Hz, IH) , 4.41 (d, J = 5.9 Hz, 2H)

(E) —N— ((2 dimethylamino) ethyl) -3- (2-((Z)-(3 oxo 3, 4 dihydro 2H-benzo [b] [1, 4] oxazine 2-ylidene) methyl) (Phenyl) acrylamide (Compound 2-29)

[Chemical 72]

H—NMR (500MHz, DMSO—d)

6

δ: 11.27 (s, IH), 8.10 (t, J = 5.5 Hz, IH), 8.05 (dd, J = 7.8, 1.1 Hz, IH), 7.70 (d, J = 15.6 Hz, IH), 7.61 (dd, J = 7.9, 1.2 Hz, IH), 7.47 (td, J = 7.6, 1.1 Hz, IH), 7.39 (td, J = 7.6, 1.0 Hz, IH), 7.12 (d, J = 7.0 Hz, IH), 7.06— 6.97 (m, 4H), 6.60 (d, J = 15.6 Hz, IH), 3.30-3.25 (m, 2H), 2.32 (q, J = 8.7 Hz, 2H), 2. 19-2.12 (m, 6H).

(E) —N Cyclopropinole 1— (2 — ((Z)-(3 Oxo 3, 4 Dihydro 1 2H Benzo [b] [1, 4] Oxazine 2 Iridene) methyl) phenyl) Atalinoleamide (Compound 2—

H—NMR (500MHz, DMSO—d)

6

δ: 11.28 (s, IH), 8.26 (d, J = 4.4 Hz, IH), 8.05 (d, J = 6.8 Hz, IH), 7.70 (d, J = 15.6 Hz, IH), 7.58 (d, J = 6.6 Hz, IH), 7.47 (t, J = 7.1 Hz, IH), 7.39 (t, J = 7.1 Hz, IH), 7.13— 7. ll (m, IH), 7.07-6.96 (m, 4H) , 6.45 (d, J = 15.6 Hz, IH), 2.77— 2.73 (m, IH), 0.68 (dt, J = 7.0, 4.8 Hz, 2H), 0.45 (dt, J = 7.0, 4.8 Hz, 2H).

(Z) —2— (2— ((E) —3 Oxoso-3 (pyrrolidine-1 yl) propylene 1 benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H) ON (compound 2 — 31)

[Chemical 74]

H—NMR (500MHz, DMSO—d)

6

δ: 11.28 (s, IH), 8.06 (dd, J = 7.9, 1.1 Hz, IH), 7.80 (dd, J = 7.8, 1.2 Hz, IH), 7.76 (d, J = 15.4 Hz, IH), 7.48 (td, J = 7.6, 1.1 Hz, IH), 7.39 (td, J = 7.6, 1.0 Hz, IH), 7.14— 7.12 (m, IH), 7.07-6.97 (m, 4H) , 6.88 (d, J = 15.4 Hz, IH), 3.64 (t, J = 6.7 Hz, 2H), 3.39 (t, J = 6.8 Hz, 2H), 1.92 (tt, J = 6.7, 6.7 Hz, 2H) , 1.81 (tt, J = 6.7, 6.7 Hz, 2H).

(Z) -2- (2- ((E) 3-morpholino 3-oxopropene 1-benzyl) benzylide 2H Benzo [b] [1, 4] oxazine 3 (4H) ON (compound 2-32)

[Chemical 75]

H-NMR (500MHz, DMSO d)

6

δ: 11.27 (s, IH), 8.04 (dd, J = 7.9, 1.2 Hz, IH), 7.85 (dd, J = 7.9, 1.2 Hz, IH), 7.80 (d, J = 15.3 Hz, IH) , 7.48 (td, J = 7.6, 1.2 Hz, IH), 7.39 (td, J = 7.6, 1.0 Hz, IH), 7.16 (d, J = 15.0 H z, IH), 7.12 (dd, J = 7.8, 1.4 Hz, IH), 7.06— 6.98 (m, 4H), 3.71 -3.56 (m, 8H).

(Z) -2- (2-((E) -3- (4- (2 Hydroxyethyl) piperazine 1-yl) 3-Oxopropene 1 heninole) benzylidene) 2H Benzo [b] [1 , 4] oxazine 3 (4H) one (compound 2-33)

[Chemical 76]

H-NMR (300MHz, CDCl)

Three

δ: 8.03 (d, J = 7.7 Hz, 2H), 7.96 (d, J = 15.4 Hz, IH), 7.56 (d, J = 7.7 Hz, IH), 7.42 (t, J = 7.0 Hz, IH), 7.33 (t, J = 7.4 Hz, IH), 7.20 (s, IH), 7.05— 6.95 (m, 4H), 6.78 (d, J = 15.4 Hz, IH), 3.75-3.62 (m, 5H), 2.95 (d, J = 7.5 Hz, 2H), 2.88 (t, J = 3.7

Hz, 2H), 2.56 (dd, J = 6.1, 4.3 Hz, 4H).

(E) —3— (2— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine— 2-ylidene) methyl) phenyl) N— (pyridine—2— Ylmethyl) acrylamide (compound 2-34) [Chemical 77]

[0161] H— NMR (500 MHz, DMSO— d)

6

δ: 11.27 (s, IH), 8.78 (t, J = 5.5 Hz, IH), 8.52 (ddd, J = 4.9, 0. 9, 0.5 Hz, IH), 8.05 (dd, J = 7.9, 0.9 Hz, IH), 7.78—7.74 (m, 2 H), 7.65 (dd, J = 7.8, 1.1 Hz, IH), 7.48 (td, J = 7.6, 1.3 Hz, 1 H), 7.41 (td, J = 7.5, 0.8 Hz, IH), 7.31 (d, J = 7.9 Hz, IH), 7.28 (ddd, J = 7.5, 4.9, 1.1 Hz, IH), 7.13— 7. ll (m, IH), 7.06 — 6. 98 (m, 4H), 6.69 (d, J = 15.6 Hz, IH), 4.49 (d, J = 5.5 Hz, 2H). (E) —3— (2— ((Z) — (3 Oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) phenyl) N— (pyridine-4-ylmethyl) acrylamide (compound 2-35)

[Chemical 78]

[0162] H— NMR (500 MHz, DMSO— d)

δ: ΐι. 27 (s, IH), 8.80 (t, J = 6.1 Hz, IH), 8.50 (dd, J = 4. 4, 1.

7 Hz, 2H), 8.04 (dd, J = 7.8, 1.2 Hz, IH), 7.77 (d, J = 15 • 6 Hz

, IH), 7.66 (dd, J = 7.7, 1.1 Hz, IH), 7.49 (td, J = 7.6, 1.3 Hz

, IH), 7.41 (td, J = 7.5, 1.1 Hz, IH), 7.27 (dd, J = 4.4, 1. 7 Hz

, 2H), 7.13-7.10 (m, IH), 7.07— 6.98 (m, 4H), 6.64 (d, J: 15.6

Hz, IH), 4.43 (d, J = 5.6 Hz, 2H).

(E) —3— (2— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) phenyl) N — ((6 trifluoro Methylpyridine 3 Nole) methyl) acrylamide (compound 2-36)

[Chemical 79]

[0163] H—NMR (300MHz, DMSO—d)

6

δ: 11.28 (s, IH), 8.86 (t, J = 6.0 Hz, IH), 8.72 (s, IH), 8.04 (d, J = 7.7 Hz, IH), 7.97 (d, J = 8.3 Hz, IH ), 7.88 (d, J = 8.1 Hz, IH), 7.77 (d, J = 15.6 Hz, IH), 7.65 (d, J = 6.8 Hz, IH), 7.48 (t, J = 6.9 Hz, IH), 7.40 (t, J = 6.9 Hz, IH), 7.13— 6.96 (m, 5 H), 6.61 (d, J = 15.6 Hz, IH), 4.53 (d, J = 5.7 Hz, 2H).

(E) —3— (2— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2-ylidene) methyl) phenyl) N— ((6 (3-yl) methyl) acrylamide (compound 2-37)

[Chemical 80]

[0164] H—NMR (300MHz, DMSO—d)

6

δ: 11.28 (s, IH), 8.78 (t, J = 6.2 Hz, IH), 8.36 (d, J = 2.6 Hz, IH), 8.04 (d, J = 7.3 Hz, IH), 7.79— 7.74 (m , 2H), 7.64 (d, J = 7.2 Hz, IH), 7.49 (d, J = 8.3 Hz, IH), 7.48 (t, J = 6.9 Hz, IH), 7.40 (t, J = 7.1 Hz, IH ), 7.13— 7.10 (m, IH), 7.05— 6.97 (m, 4 H), 6.59 (d, J = 15.8 Hz, IH), 4.42 (d, J = 5.9 Hz, 2H).

(E) -N- (3,5 dimethylphenyl) 1 3— (2— ((Z) — (3 oxo 3, 4 dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl ) Acrylic amide (Compound 2-38) [Chemical 81]

H-NMR (500MHz, DMSO—d)

6

δ: 11.30 (s, IH), 10.10 (s, IH), 8.07 (dd, J = 7.7, 0.9 Hz, IH), 7.85 (d, J = 15.6 Hz, IH), 7.68 (dd, J = 7.8, 0.7 Hz, IH), 7.51 (td, J = 7.6, 1.2 Hz, IH), 7.43 (td, J = 7.6, 1.0 Hz, IH), 7.31 (s, 2H), 7.14-7.12 (m, IH ), 7.07-6.97 (m, 4H), 6.75 (d, J = 15.6 Hz, IH), 6.72 (s, IH), 2.24 (s, 6H).

(E) -N- (3,4 Dimethoxyphenyl) 1 3— (2— ((Z) — (3 oxo 3, 4 dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) (Phenyl) acrylamide (Compound 2-39)

[Chemical 82]

H—NMR (500MHz, DMSO—d)

6

δ: 11.29 (s, IH), 10.14 (s, IH), 8.08 (d, J = 6.7 Hz, IH), 7.85 (d, J = 15.6 Hz, IH), 7.67 (d, J = 7.0 Hz, IH ), 7.51 (t, J = 7.6 Hz, IH), 7.43 (t, J = 5.5 Hz, IH), 7.18— 7.13 (m, IH), 7.06— 6.9 8 (m, 4H), 6.92 (d, J = 8.9 Hz, IH), 6.73 (d, J = 15.6 Hz, IH), 6.63 (d, J = 8.2 Hz, IH), 6.05 (dd, J = 8.4, 2.6 Hz, IH), 3.75 (s , 3H), 3.73 (s, 3H).

(E) — N— (4 morpholinophenyl) 3— (2-((Z)-(3 oxo 3, 4 dihydro-2H-benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) acrylamide ( Compound 2-40)

[Chemical 83]

H—NMR (500MHz, DMSO—d)

6

δ: 11.28 (s, IH), 10.07 (s, IH), 8.08 (d, J = 7.9 Hz, IH), 7.83 (d, J = 15.6 Hz, IH), 7.67 (d, J = 7.0 Hz, IH ), 7.57 (t, J = 4.4 Hz, 2H), 7.50 (t, J = 7.0 Hz, IH), 7.43 (t, J = 7.2 Hz, IH), 7.1 4 (dd, J = 7.0, 2.4 Hz, IH), 7.06—6.99 (m, 4H), 6.93 (dd, J = 7.0, 2.1 Hz, 2H), 6.73 (d, J = 15.6 Hz, IH), 3.73 (q, J = 5.0 Hz , 4H), 3.07-3.03 (m, 4H).

(E) N— (7 Methyl-1, 8 Naphthyridin-2-yl) -3— (2-((Z) -one (3 oxo-1,4 dihydro-1,2H benzo [b] [l, 4] oxazine-one 2 Iridene) methyl) phenyl) acrylamide (compound 2-41)

[Chemical 84]

H—NMR (500MHz, DMSO—d)

6

δ: 11.31 (s, IH), 11.30 (s, IH), 8.47 (d, J = 8.9 Hz, IH), 8.41 (d, J = 8.9 Hz, IH), 8.26 (d, J = 8.2 Hz, IH ), 8.07 (d, J = 7.0 H z, IH), 7.98 (d, J = 15.6 Hz, IH), 7.70 (d, J = 7.0 Hz, IH), 7.5 4 (td, J = 7.6, 1.2 Hz , IH), 7.46 (td, J = 7.6, 0.9 Hz, IH), 7.4 2 (d, J = 7.9 Hz, IH), 7.13 (d, J = 7.9 Hz, IH), 7.05— 6.97 (m, 5H ), 2.67 (s 3H). (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) thiophene 3 yl) N— (pyridine 3 Ylmethyl) acrylamide (compound 2-42)

[Chemical 85]

H—NMR (300MHz, DMSO—d)

6

δ: 11.15 (s, IH), 8.68 (t, J = 6.1 Hz, IH), 8.52 (s, IH), 8.46 (d, J = 3.8 Hz, IH), 7.95 (s, IH), 7.69 (t , J = 3.8 Hz, 2H), 7.45 (d, J = 15.6 Hz, IH), 7.36 (dd, J = 7.9, 4.8 Hz, IH), 7.25— 7.22 (m, IH), 7. ll (s, IH), 7.07— 7.05 (m, 2H), 7.01— 6.97 (m, IH), 6.5 0 (d, J = 15.6 Hz, IH), 4.41 (d, J = 5.9 Hz, 2H).

(E) —N— ((2 dimethylamino) ethyl) -3- (5-((Z)-(3 oxo 3, 4 dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) Thiophene 3-ino) acrylamide (compound 2-43)

[Chemical 86]

H—NMR (500MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.01 (t, J = 5.7 Hz, IH), 7.93 (s, IH), 7.67 (d, J = 1.5 Hz, IH), 7.39 (d, J = 15.6 Hz, IH ), 7.27— 7.24 (m, IH), 7. ll (s, IH), 7.09-7.03 (m, 2H), 7.02— 6.99 (m, IH), 6.51 (d, J = 15.6 Hz, IH), 3.26 (t, J = 6.1 Hz, 2H), 2.33 (t, J = 6.7 Hz, 2H), 2.16 (s, 6H).

(E) —N Cyclopropinole 1— (5 — ((Z)-(3 Oxo 3, 4 Dihydro 1H [B] [l, 4] oxa,: yl) acrylamide

(Compound 2-44)

[Chemical 87]

H—NMR (500MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.20 (d, J = 4.6 Hz, IH), 7.94 (s, IH), 7.65 (s, 1 H), 7.40 (d, J = 15.9 Hz, IH), 7.25— 7.22 (m, IH), 7.12 (s, IH), 7.08-7.05 (m, 2H), 7.01—6.99 (m, IH), 6.37 (d, J = 15.9 Hz, 1 H), 2.80-2.74 (m , IH), 0.67 (td, J = 7.1, 4.9 Hz, 2H), 0.46 (dt, J = 7.1, 4.3 Hz, 2H).

(Z) — 2— ((4— ((E) —3 oxo-3— (pyrrolidine- 1-yl) prope- 1-enylene) thiophene 2-yl) methylene) 2H benzo [b] [l, 4] oxazine 3 (4H) — ON (compound 2— 45)

[Chemical 88]

H—NMR (500MHz, DMSO—d)

6

δ: 11.17 (s, IH), 8.03 (s, IH), 7.86 (s, IH), 7.46 (d, J = 15.4 Hz, IH), 7.27-7.24 (m, IH), 7.09— 7.04 (m, 3H), 7.03—6.99 (m, IH), 6.84 (d, J = 15.4 Hz, IH), 3.63 (t, J = 6.8 Hz, 2H), 3.39 (t, J = 6.8 Hz, 2H), 1.93 ( tt, J = 6.8, 6.8 Hz, 2H), 1.81 (tt, J = 6.8, 6.8 Hz, 2H).

(Z) — 2 ((4— ((E) — 3—Monolephorino 1-Oxylpropyol 2-thiophene 2-yl) methylene) -2H-Benzo [b] [1, 4] oxazine 3 (4H ) ON (compound 2-46)

[Chemical 89]

H—NMR (500MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.05 (s, IH), 7.88 (s, IH), 7.50 (d, J = 15.4 Hz, IH), 7.28-7.24 (m, IH), 7.ll (d, J = 15.4 Hz, IH), 7.07- 7.03 (m, 3H), 7.01-6.99 (m, IH), 3.75- 3.52 (m, 8H).

(Z) — 2 — ((4 ((E) 3— (4 1 (2 hydroxyethyl) piperazine 1 yl) 3—oxoprop 1 heninore) thiophene 2—inole) methylene) 2H-benzo [ b] [1, 4] oxazine 3 (4H) ON (compound 2-47)

[Chemical 90]

H—NMR (500MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.04 (s, IH), 7.88 (s, IH), 7.47 (d, J = 15.4 Hz, IH), 7.27-7.25 (m, IH), 7.ll (d, J = 15.4 Hz, IH), 7.07— 7.04 (m, 3H), 7.03-6.99 (m, IH), 4.44 (t, J = 5.4 Hz, IH), 3.68— 3.5 0 (m, 8H), 2.42 ( t, J = 6.2 Hz, 4H).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) thiophene 3 yl) N— (pyridine 2 Ylmethyl) acrylamide (compound 2-48)

[Chemical 91]

[0175] H—NMR (500MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.72 (t, J = 5.9 Hz, IH), 8.52 (dt, J = 4.7, 0.9 Hz, IH), 7.97 (s, IH), 7.77 (td, J = 7.7, 1.7 Hz, IH), 7.71 (s, IH), 7.46 (d, J = 15.6 Hz, IH), 7.33— 7.23 (m, 3H), 7.12 (s, IH), 7. 09-7.04 (m, 2H ), 7.03—6.99 (m, IH), 6.60 (d, J = 15.6 Hz, IH), 4.50 (d, J = 5.9 Hz, 2H).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) thiophene 3 yl) N— (pyridine 4 Ylmethyl) acrylamide (compound 2-49)

[Chemical 92]

[0176] H—NMR (500MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.74 (t, J = 6.1 Hz, IH), 8.51 (dd, J = 4.4, 1.7 Hz, 2H), 7.97 (s, IH), 7.72 (s, IH) , 7.48 (d, J = 15.9 Hz, IH), 7.28 (dd, J = 4.4, 1.5 Hz, 2H), 7.26— 7.24 (m, IH), 7.13 (s, IH), 7. 10-7.05 (m , 2H), 7.04—6.99 (m, IH), 6.56 (d, J = 15.9 Hz, 1 H), 4.43 (d, J = 6.1 Hz, 2H).

(E) —3— (5— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2-ylidene) methyl) thiophene-3 yl) N— (( 6 Trifunoleolomethinorepyridine—3yl) methyl) acrylamide (compound 2-50)

[Chemical 93]

HH—— NNMMRR ((330000MMHHzz ,, DDMMSSOO—— dd))

66

δδ :: 1111..1188 ((ss ,, IIHH)) ,, 88..8811 ((tt ,, JJ == 55..99 HHzz ,, IIHH)) ,, 88..7711 ((ss ,, IIHH)) ,, 77..9999 ((ss ,, 11 HH)) ,, 77..9977 ((dd ,, JJ == 88..88 HHzz ,, IIHH)) ,, 77..8899 (( dd ,, JJ == 88..11 HHzz ,, IIHH)), 77..7711 ((ss ,, IIHH)) ,, 77..4477 ((dd ,, JJ == 1155..88 HHzz, , IIHH)) ,, 77..2255 ((tt ,, JJ == 44..77 HHzz ,, IIHH)) ,, 77..1133 ((ss ,, IIHH)) ,, 77..0088-- 77..0033 ((mm ,, 22HH)) ,, 77..0011—— 66..9988 ((mm ,, IIHH)) ,, 66..5522 ((dd ,, JJ == 1155..88

HHzz ,, IIHH)) ,, 44..5533 ((dd ,, JJ == 55..33 HHzz ,, 22HH)).

((EE)) —— 33—— ((55—— ((((ZZ)) — ((33) 33 ,, 44 jihihidodororo 22HH bebenzozo [[bb]] [[ll ,, 44] ] Oxixasa Dizin 1 1 1 1 1 2 1 2 3 2 1 2 1 2 3 2 1 2 1 2 3 2 1 2 3 2 1 2 3 2 1 2 1 2 1 2 1 2 1 2 1 2 3 2 1 2 3 1 1

[Chemical 94]

H—NMR (300MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.73 (t, J = 5.7 Hz, IH), 8.36 (d, J = 2.6 Hz, IH), 7.98 (s, IH), 7.77 (dd, J = 8.2, 2.5 Hz , IH), 7.70 (s, IH), 7.50 (d, J = 8.1 Hz, IH), 7.46 (d, J = 15.6 Hz, IH), 7.27— 7.23 (m, IH), 7.12 (s, IH), 7.08— 7.04 (m, 2H), 7.02— 6.98 (m, IH), 6.5 0 (d, J = 15.6 Hz, IH), 4.42 (d, J = 5.7 Hz, 2H).

(E) -N- (3,5-Dimethylphenyl) 1 3— (5— ((Z) — (3-Oxo 3, 4-dihydro) 2H Benzo [b] [1, 4] oxazine 2 Ylidene) methinole) thiophene 3inole) attalinoleamide (compound 2-52)

[Chemical 95]

H—NMR (500MHz, DMSO d)

6

δ: 11.19 (s, IH), 10.06 (s, IH), 8.03 (s, IH), 7.71 (s, IH), 7.54 (d, J = 15.6 Hz, IH), 7.33 (s, 2H), 7.26 (dd, J = 7.0, 2.3 Hz, IH), 7.16 (s, IH), 7.10-7.06 (m, 2H), 7.02—6.99 (m, IH), 6.71 (s, IH), 6.65 (d , J = 15.6 Hz, IH), 2.25 (s, 6H).

(E) -N- (3, 4-Dimethoxyphenyl) 1 3— (5— ((Z) — (3-Oxo 3, 4-dihydro) 2H—Benzo [b] [1, 4] Oxazine 2-ylidene) methinole) thiophene 3-yl) Atalinoleamide (compound 2-53)

[Chemical 96]

H—NMR (500MHz, DMSO d)

6

δ: 11.19 (s, IH), 10.10 (s, IH), 8.01 (s, IH), 7.71 (s, IH), 7.54 (d, J = 15.6 Hz, IH), 7.42 (d, J = 2.2 Hz , IH), 7.27— 7.21 (m, 2H), 7.16 (s, IH), 7.10-7.04 (m, 2H), 7.03—6.99 (m, IH), 6.92 (d, J = 9.0 Hz, IH), 6.63 (d, J = 15.6 Hz, IH), 3.75 (s, 3H), 3.73 (s, 3H).

(E) — N— (4-morpholinophenyl) 3— (5-((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine 2 ylidene) methyl) Thiophene 3-yl) acrylamide (compound 2-54)

[Chemical 97]

H—NMR (500MHz, DMSO d)

6

δ: 11.19 (s, IH), 10.03 (s, IH), 8.00 (s, IH), 7.70 (s, IH), 7.58 (d, J = 9.2 Hz, 2H), 7.53 (d, J = 15.6 Hz , IH), 7.27— 7.25 (m, IH), 7.15 (s, IH), 7.09-7.05 (m, 2H), 7.02— 7.00 (m, IH), 6.92 (d, J = 9.2 Hz, 2H), 6.63 (d, J = 15.6 Hz, IH), 3.74 (t, J = 4.9 Hz, 4H), 3.08 (t, J = 4.9 Hz, 4H).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) thiophene 2 yl) N— (pyridine 3 Ylmethyl) acrylamide (compound 2-55)

[Chemical 98]

H—NMR (300MHz, DMSO d)

6

δ: 11.23 (s, IH), 78 (s, IH), 8.54 (d, J = 2.2 Hz, IH), 8.48 (d, J = 4.8 Hz, IH), 7.71 (d, J = 8.1 Hz, IH ), 7.64 (d, J = 15.6 Hz, 1 H), 7.44 (d, J = 3.7 Hz, IH), 7.40 (d, J = 3.3 Hz, IH), 7.37 (dd, J = 7.7, 4.8 Hz, IH), 7.25— 7.21 (m, IH), 7.10 (s, IH), 7.08— 7.01 (m, 3H), 6.57 (d, J = 15.6 Hz, IH), 4.43 (d, J = 3.9 Hz , 2H)

(E) —N— ((2 dimethylamino) ethyl) -3- (5-((Z)-(3 oxo 3, 4 dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) Thiophene 2-nor) acrylamide (compound 2-56)

[Chemical 99]

H—NMR (500MHz, DMSO—d)

6

δ: 11.20 (s, IH), 8.04 (t, J = 5.6 Hz, IH), 7.57 (d, J = 15.6 Hz, IH), 7.44 (d, J = 4.4 Hz, IH), 7.38 (d, J = 3.9 Hz, IH), 7.27 -7.25 (m, IH), 7.ll (s, IH), 7.09— 7.06 (m, 2H), 7.04— 7.00 (m, 1 H), 6.56 (d, J = 15.4 Hz, IH), 3.27 (t, J = 6.1 Hz, 2H), 2.34 (t, J = 6.5 Hz, 2H), 2.15 (s, 6H).

(E) —N Cyclopropinole 1— (5 — ((Z)-(3 Oxo 3, 4 Dihydro-1 2H Benzo [b] [1, 4] Oxazine 2 ylidene) methyl) thiophene 2 yl) Atalinole Amides (Compound 2-57)

[Chemical 100]

H-NMR (500MHz, DMSO—d)

6

δ: 11.20 (s, IH), 8.20 (d, J = 4.4 Hz, IH), 7.58 (d, J = 15.6 Hz, IH), 7.45 (d, J = 3.9 Hz, IH), 7.38 (d, J = 3.9 Hz, IH), 7.24 -7.21 (m, IH), 7.ll (s, IH), 7.09— 7.06 (m, 2H), 7.03— 7.00 (m, 1 H), 6.40 (d, J = 15.6 Hz, IH), 2.81- 2.74 (m, IH), 0.69 (td, J = 7.1, 4.9 Hz, 2H), 0.46 (dt, J = 7.8, 3.4 Hz, 2H).

(Z) — 2— ((5— ((E) — 3 oxo 3— (pyrrolidine 1-yl) propylene 1-hen nore) thiophene 2-yl) methylene) 2H Benzo [b] [ l, 4] oxazine 3 (4H) — ON (compound 2— 58)

[Chemical 101]

H—NMR (500MHz, DMSO—d)

6

δ: 11.19 (s, IH), 7.65 (d, J = 15.4 Hz, IH), 7.48 (d, J = 3.9 Hz, IH), 7.45 (d, J = 4.4 Hz, IH), 7.39 (dt, J = 5.0, 2.1 Hz, IH), 7.ll (d, J = 5.6 Hz, IH), 7.09— 7.06 (m, 2H), 7.02—6.99 (m, IH), 6.77 (d, J = 15.4 Hz, IH), 3.67 (t, J = 6.7 Hz, 2H), 3.41 (t, J

= 6.7 Hz, 2H), 1.97-1.91 (m, 2H), 1.87— 1.76 (m, 2H).

(Z) — 2— ((5— ((E) — 3 Mono-rephorino 1-oxoyl 2-thiophene 2-yl) methylene) -2H-benzo [b] [1, 4] oxazine 3 (4H) ON (compound 2-59)

[Chemical 102]

H-NMR (500MHz, DMSO—d)

6

δ: 11.19 (s, IH), 7.71 (d, J = 15.1 Hz, IH), 7.50 (d, J = 3.9 Hz, IH), 7.45 (d, J = 4.1 Hz, IH), 7.42—7.40 (m, IH), 7.12 (s, IH), 7.09-7.07 (m, 2H), 7.02—6.99 (m, IH), 6.91 (d, J = 15.1 Hz,] H), 3.71-3.48 (m, 8H).

(Z) — 2— ((5— ((E) 3— (4— (2 Hydroxyethyl) piperazine 1—yl) 3 — oxopropene 1 heninore) thiophene 2 — inore) methylene) 2H—benzo [b] [1, 4] oxazine 3 (4H) ON (compound 2-60)

[Chemical 103]

H—NMR (500MHz, DMSO—d)

6

δ: 11.18 (s, IH), 7.68 (d, J = 15.3 Hz, IH), 7.49 (d, J = 4.0 Hz, IH), 7.45 (d, J = 4.0 Hz, IH), 7.43— 7.41 (m , IH), 7.ll (s, IH), 7.09-7.04 (m, 3H), 7.02—7.00 (m, IH), 4.44 (br s, IH), 3.68—3.45 (m, 8H), 2.64 (t, J = 1.8 Hz, 2H), 2.43 (t, J = 6.1 Hz, 2H).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2-ylidene) methyl) thiophene 2-yl) N— ( Pyridine 2-ylmethyl) Acrylamide (Compound 2 61)

[Chemical 104]

H-NMR (500MHz, DMSO—d)

6

δ: 11.19 (s, IH), 8.70 (t, J = 5.5 Hz, IH), 8.53 (dq, J = 4.7, 0.9 Hz, IH), 7.78 (td, J = 7.8, 1.8 Hz, IH) , 7.64 (d, J = 15.6 Hz, IH), 7.46 (d, J = 3.7 Hz, IH), 7.40 (d, J = 4.0 Hz, IH), 7.33 (d, J = 7.9 Hz, IH), 7.30 — 7.24 (m, 2H), 7. 12 (s, IH), 7.09— 7.06 (m, 2H), 7.04-7.01 (m, IH), 6.64 (d, J = 15.6 Hz, IH), 4.50 (d , J = 5.5 Hz, 2H).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 ylidene) methyl) thiophene 2 yl) N— (pyridine 4 Ylmethyl) acrylamide (compound 2-62)

[Chemical 105]

[0189] H—NMR (500MHz, DMSO—d)

6

δ: 11.19 (s, IH), 8.73 (t, J = 5.5 Hz, IH), 8.52 (dd, J = 4.6, 1.5 Hz, 2H), 7.65 (d, J = 15.6 Hz, IH), 7.46 (d, J = 4.0 Hz, IH), 7.42 (d, J = 4.0 Hz, IH), 7.29 (dd, J = 4.6, 1.5 Hz, 2H), 7.26 -7.23 (m, IH), 7.12 (s, IH), 7.10— 7.05 (m, 2H), 7.04— 7.01 (m, 1 H), 6.59 (d, J = 15.6 Hz, IH), 4.44 (d, J = 5.8 Hz, 2H).

(E) —3— (5— ((Z) (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2-ylidene) methyl) thiophene-2-yl) N— (( 6 Trifnoleolomethinorepyridine 3 yl) methyl) attalinoleamide (Compound 2-63)

[Chem 106]

[[00119900]] HH——NNMMRR ((330000MMHHzz ,, DDMMSSOO——dd))

66

δδ :: 1111..2211 ((ss ,, IIHH)) ,, 88..8800 ((tt ,, JJ == 55..88 HHzz ,, IIHH)) ,, 88..7722 ((ss ,, IIHH)) ,, 77..9988 ((tt ,, JJ == 77..66 HHzz ,, IIHH)) ,, 77..9900 ((dd ,, JJ == 88..44 HHzz ,, IIHH) ) ,, 77..6655 ((dd ,, JJ == 1155..66 HHzz ,, IIHH)) ,, 77..4466 ((dd ,, JJ == 44..00 HHzz ,, IIHH)), , 77..4422 ((dd ,, JJ == 44..00 HHzz ,, IIHH)) ,, 77..2266 --77..2233 ((mm ,, IIHH)) ,, 77..1122 ( (ss ,, IIHH)) ,, 77..0099—— 77..0066 ((mm ,, 22HH)) ,, 77..0033—— 66..9999 ((mm ,, 11 HH)) ,, 66..5555 ((dd ,, JJ == 1155..66 HHzz ,, IIHH)), 44..5544 ((dd ,, JJ == 55..55 HHzz ,, 22HH)).

((EE)) —— 33—— ((55—— ((((ZZ)) —— ((33 oxo 33 ,, 44 jiji hydridoro 22HH bebenzozo [[bb]] [[ll ,, 44 ]] Oxoxasa Jinjin 1 1 2 Irididene)) Methychilur) 1) Chiofoven 1 2) NN —— ((((66 Chloro-Mouth Pipirizidin 1)

[Chemical 107]

H—NMR (300MHz, DMSO—d)

6

δ: 11.21 (s, IH), 8.72 (t, J = 5.7 Hz, IH), 8.37 (d, J = 2.4 Hz, IH), 7.78 (dd, J = 8.3, 2.6 Hz, IH), 7.64 (d , J = 15.4 Hz, IH), 7.51 (d, J = 8.3 Hz, IH), 7.46 (d, J = 4.0 Hz, IH), 7.41 (d, J = 3.9 Hz, IH), 7.26-7.23 (m , IH), 7.12 (s, IH), 7.09— 7.06 (m, 2 H), 7.04-6.99 (m, IH), 6.53 (d, J = 15.4 Hz, IH), 4.43 (d, J = (5.7 Hz, 2H).

tert butyl 5 — (((E) —3— (5 — ((Z) — (3 oxo 3, 4— 3, 4 dihydro-2 H benzo [b] [1, 4] oxazine 2 ylidene) methyl) thiophene 2 Yl) Atarylamide) methyl) pyridine 2-ylcarbamate (compound 2-65)

[Chemical 108]

HH—— NNMMRR ((550000MMHHzz ,, DDMMSSOO—— dd))

66

δδ :: 1111..2200 ((ss ,, IIHH)) ,, 99..7733 ((ss ,, IIHH)) ,, 88..6600 ((tt ,, JJ == 55..77 HHzz ,, IIHH)) ,, 88..1188 ((dd ,, JJ == 11..88 HHzz ,, IIHH)) ,, 77..7766 ((dd ,, JJ == 88..44 HHzz ,, IIHH) ) ,, 77..6677—— 77..6644 ((mm ,, IIHH)) ,, 77..6633 ((dd ,, JJ == 1155..44 HHzz ,, IIHH)) ,, 77 .. 4455 ((dd ,, JJ == 33..99 HHzz ,, IIHH)), 77..4400 ((dd ,, JJ == 33..99 HHzz ,, IIHH)) ,, 77..2255- -77..2222 ((mm ,, IIHH)), 77 .. llll ((ss ,, IIHH)), 77..0033 ((tttt ,, JJ == 1100 ..99, 33 .. 88 HHzz ,, 33HH)) ,, 66..5533 ((dd ,, JJ == 1155..44 HHzz ,, IIHH)) ,, 44..3344 ((dd ,, JJ == 55..77 HHzz ,, 22HH)) ,, 11..4466 ((ss ,, 99HH)).

((EE)) —— 33—— ((55—— ((((ZZ)) —— ((33 oxo 33 ,, 44 jiji hydridoro 22HH bebenzozo [[bb]] [[ll ,, 44 ]] Oxoxasa Jinjin 1 1 2 Irididene)) Methicyll)) Chiojoffen 22 Ill)) NN—— ((((66 Aamimino Nobiliridin 1 1 33

[Chemical 109]

H—NMR (300MHz, DMSO—d)

6

δ: 11.20 (s, IH), 8.44 (t, J = 5.5 Hz, IH), 7.85 (d, J = 1.7 Hz, IH), 7.61 (d, J = 15.4 Hz, IH), 7.45 (d, J = 3.9 Hz, IH), 7.38 (d, J = 3.9 Hz, IH), 7.33 (dd, J = 8.4, 2.4 Hz, IH), 7.24— 7.21 (m, IH), 7. ll (s, IH) , 7.09—6.99 (m, 3H), 6.52 (d, J = 15.4 Hz, IH), 6.43 (d, J = 8.4 Hz, IH), 5.91 (s, 2H), 4.19 (d, J = 5.5 Hz, 2H).

(E) -N- (3,5-Dimethylphenyl) 1 3— (5— ((Z) — (3-Oxo 3, 4-dihydro) 2H Benzo [b] [1, 4] oxazine 2 Iridene) Methinole) Thiophene 2-Inole) Acrylamide (Compound 2-67)

[Chem 110]

H—NMR (500MHz, DMSO—d)

6

δ: 11.21 (s, IH), 10.04 (s, IH), 7.72 (d, J = 15.6 Hz, IH), 7.49 (d, J = 3.7 Hz, IH), 7.46 (d, J = 3.7 Hz, IH ), 7.33 (s, 2H), 7.27 (dt, J = 9.7, 3.7 Hz, IH), 7.14 (s, IH), 7.11— 7.07 (m, 2H), 7.04 -7.02 (m, IH), 6.72 ( s, IH), 6.68 (d, J = 15.6 Hz, IH), 2.26 (s, 6 H).

(E) -N- (3, 4-Dimethoxyphenyl) 1 3— (5— ((Z) — (3-Oxo 3, 4-dihydro) 2H Benzo [b] [1, 4] oxazine 2 Iridene) Mechinore) Chofen 2 Inore) Acrylamide (Compound 2-68)

[Chem 111]

[0195] H—NMR (500MHz, DMSO—d)

6

δ: 11.21 (s, IH), 10.09 (s, IH), 7.71 (d, J = 15.3 Hz, IH), 7.48 (d, J = 4.3 Hz, IH), 7.44 (d, J = 4.0 Hz, IH ), 7.41 (d, J = 2.4 Hz, IH), 7.27-7.25 (m, IH), 7.23 (dd, J = 8.7, 2.3 Hz, IH), 7.1 3 (s, IH), 7. 11-7.07 (m, 2H), 7.04— 7.01 (m, IH), 6.92 (d, J = 8.6 Hz, IH), 6.65 (t, J = 11.9 Hz, IH), 3.76 (s, 3H), 3.73 ( s, 3H). (E) — N— (4-morpholinophenyl) 3— (5-((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine) 2 ylidene) methinole) thiophene 2-inole) acrylamide (compound 2-69)

[Chem 112]

[0196] H— NMR (500 MHz, DMSO— d)

6

δ: 11.20 (s, IH), 10.02 (s, IH), 7.71 (d, J = 15.3 Hz, IH), 7.58 (d, J = 9.2 Hz, 2H), 7.48 (d, J = 3.7 Hz, IH ), 7.40 (d, J = 3.7 Hz, IH), 7.28-7.25 (m, IH), 7.13 (s, IH), 7.11— 7.07 (m, 2H), 7.0 4-7.01 (m, IH), 6.93 (d, J = 9.2 Hz, 2H), 6.66 (d, J = 15.3 Hz, IH), 3.75-3.68 (m, 4H), 3.07- 3.01 (m, 4H).

(E) — N— (IH indole 1-6-yl) 3— (5-((Z)-(3-Oxo 3, 4-dihydr Draw 2H Benzo [b] [1, 4] oxazine 2 Iridene ) Methyl) thiophen 2 Nole) acrylamide (compound 2-70)

[Chem 113]

H—NMR (300MHz, DMSO—d)

6

δ: 11.20 (s, IH), 10.05 (s, IH), 8.02 (s, IH), 7.95 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.57 (d , J = 15.6 Hz, IH), 7.35 -7.30 (m, 3H), 7.09— 7.03 (m, 2H), 7.02— 6.97 (m, IH), 6.90 (d, J = 15.6 Hz, IH), 6.81 ( s, IH), 6.39 (t, J = 2.3 Hz, IH).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 1-2 ylidene) methyl) furan 3 yl) N— ( Pyridine-3-ylmethyl) atrylamide (Compound 2-71)

[Chemical 114]

H—NMR (500MHz, DMSO—d)

6

δ: 11.25 (s, IH), 8.60 (t, J = 6.0 Hz, IH), 8.54 (d, J = 1.7 Hz, IH), 8.47 (dd, J = 4.6, 1.7 Hz, IH), 7.71 (dt , J = 7.8, 2.0 Hz, IH), 7.41-7.34 (m, 3H), 7.29 (s, IH), 7.10—6.99 (m, 4H), 6.66 (s, IH), 6.57 (d, J = 15.6 Hz, IH), 4.43 (d, J = 5.9 Hz, 2H).

(E) —N— ((2 dimethylamino) ethyl) -3- (5-((Z)-(3 oxo 3, 4 dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) Furan 3yl) acrylamide (compound 2-72)

[Chemical 115]

Be 1 (H 1, 4 ^ ^ 'X] [q], HZ— {Λ ^ (^ Ζ- ^^ {Λ (

-1—Be Π — ε— ^ — ε— (a)) —)) — ζ— (ζ)

• (ΗΖ ' ^Ζ Η · ε' Ζ · Ζ = Γ Ρ) 9 Ό '(ΗΖ' ^Ζ Η 6 'Ό · Ζ = Γ' Ρ¾89 Ό '(HI ^) L · — 08 · Ζ' (HI ' ^Ζ Η 9 "SX = ΓΡ) Ζ · 9 '(HI' s) 99 · 9 '(ΗΧ ¾) 66 · 9— Ζ0 · Ζ' (HZ ^) 0" Ζ-ΟΧ • Ζ '(HI' s · Ζ '(ΗΖ' ^) χε · Ζ— · Ζ '(HZ' s) 0X · 8 '(HI' s) Z '11: g

( ⁹ P-0SMQ ^<Ζ ΗΜ003) ΉΜΝ-Η _Τ

[9ΐΐ¾]

(εζ— ζ 呦 ^

'x] [q] /

— HZ— a '¾ ^ ―' S— ^ i S)-(Ζ)) -S)-ε-^^ _o a-Ν-(Ή)

• (Η9 's) 6X · Ζ' (ΗΖ ' ^Ζ Η 9 "9 = Γ' ¾98 · Ζ '(ΗΖ' ^Ζ Η X · 9 = Γ '¾8Ζ Έ' (ΗΧ ' ^Ζ Η 6" SX = Γ' P) 8S 9 '(HI' s) 99 9 (9) () '^) 00 · Ζ -Ζ · Ζ' (HZ 'ra) go' Ζ-60 · Ζ '(HI' s) 8Z · Ζ ' (ΗΧ ' ^Ζ Η 6 "SX = Γ' Ρ) Ζ 8 • Ζ '(HI' ra) SS · Ζ— 8S · Ζ '(HI' s) 98 · Ζ '(HI' s) 60 · 8 '(HI 's) SZ "!!: 9

( ⁹ P-0SMQ ^<Ζ ΗΜ003) ΉΜΝ-Η _Τ

690l.0 / .00Zdf / X3d 98 T98CS0 / 800Z OAV ) 90 `` Ζ-ΟΧ ・ Ζ '(HI' ^Ζ Η Ρ 'QT = Γ' P) SX · L '(HI' ^Ζ Η 'Ql = Γ' Ρ) ^

Ζ '(HI' s) os · ζ '(HI -z-zs · ζ' (HI 'S) SX · 8' (HI 's) z · χχ: 9

( ⁹ P-0SMQ 'ZHM00S) ¾MN-H _T

[6

(9 (H ^)

[t ⁷ 'I], ^-\ λΖ- Λ ^ (^ Z—,, ^ (/ A X ^

• (Η8 '«i) 9S Έ-6Ζ Έ' (ΗΧ 's) S9 · 9' (ΗΧ) 86 · 9 Ζ0 'L' (ΗΖ ¾) 'Ζ-ΟΧ · Ζ' (ΗΤ ' ^Ζ Η 6" SI = Γ 'V) l · Ζ' (ΗΖ ' ^Ζ Η 6 "SX = ΓΡ) 8 · Ζ' (ΗΧ ' ^Ζ Ζ Έ Έ f f'¾) SS · Ζ' (HI 's) 9X · 8' (HI 's) PZ '11: 9

( ⁹ P-0SMQ 'ZHM00S) ¾MN-H _T

[8

(SZ

-z ^) be (H ^) ε—be ^ [Ί] [¾ ^ -nz {Λ ^ {^ y-

Z- ^-1-^ _ο Δ ^ -Ϋ,-fl ^ i-S-(Ά)) →))-Ζ- (Z)

"(HZ ^<Z H 8 '9' 8 '9 = Γ' W) S8 Ί '(HZ' ^Z H 8 9 '8' 9 = Γ«) 6 "X '(ΗΖ' ^Ζ Η 8 '9 = Γ) 0 Έ '(Η

' ^Ζ Η Ζ · 9 = Γ') 1 Έ '(ΗΤ' s) S9 · 9 '(ΗΧ ^<Ζ Η -ei = Γ' Ρ) 68 · 9 '(ΗΧ' ^) 66 · 9— Ζ0 · Ζ UZ 'ra) so · Ζ— 80 · Ζ' (ΗΧ ' ^Ζ Η "SI = f'P) I • Ζ' (HI 's) S · L' (HI 'ra) 0S--SS · Ζ' ( HI 's) SX · 8' (HI 's) g '11: g

( ⁹ p-osi ^ a ^<z HI ^ 00S) ¾MN-H _T

690l.0 / .00Zdf / X3d Z8 T98CS0 / 800i ΟΛ \ m, 2H), 7.02-6.99 (m, IH), 6.65 (s, IH), 4.46 (t, J = 5.2 Hz, IH), 3.74-3.49 (m, 10H), 2.44 (t, J = 6. (1 Hz, 2H).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 1-2 ylidene) methyl) furan 3 yl) N— ( Pyridine-2-ylmethyl) atrylamide (Compound 2-77)

[Chemical 120]

[0204] H—NMR (500MHz, DMSO—d)

6

δ: 11.25 (s, IH), 8.58 (t, J = 5.9 Hz, IH), 8.53 (dq, J = 4.9, 0.9 Hz, IH), 8.12 (s, IH), 7.78 (td, J = 7.7, 1.9 Hz, IH), 7.39 (d, J

= 15.9 Hz, IH), 7.36-7.27 (m, 4H), 7.10— 7.04 (m, 2H), 7.02 -7.00 (m, IH), 6.67 (s, IH), 6.67 (d, J = 15.9 Hz, IH), 4.50 (d, J

= 5.9 Hz, 2H).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 1-2 ylidene) methyl) furan 3 yl) N— ( Pyridine mono (4-methyl)) allylamide (Compound 2-78)

[Chemical 121]

[0205] H—NMR (500MHz, DMSO—d)

6

δ: 11.25 (s, IH), 8.64 (t, J = 5.9 Hz, IH), 8.52 (dd, J = 4.4, 1.7 Hz, 2H), 8.13 (s, IH), 7.41 (d, J = 15.6 Hz, IH), 7.38— 7.35 (m, IH), 7.31 (s, IH), 7.29 (d, J = 6.1 Hz, IH), 7.10— 7.00 (m, 4H), 6.67 (s, IH ), 6.62 (d, J = 15.6 Hz, IH), 4.43 (d, J = 5.9 Hz, 2 H).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxa 3 yl) methyl) attalinoleamide (compound 2-79)

[Chemical 122]

[0206] H—NMR (500MHz, DMSO—d)

6

δ: 11.25 (s, IH), 8.70 (t, J = 6.2 Hz, IH), 7.98 (d, J = 8.1 Hz, IH), 7.90 (d, J = 8.1 Hz, IH), 7.40 (d, J = 15.6 Hz, 2H), 7.36 (dd, J = 6.6, 2.7 Hz, 2H), 7.30 (s, IH), 7.10—6.99 (m, 3H), 6.67 (s, IH), 6.59 (d, J = 15.9 Hz, IH), 4.53 (d, J = 5.9 Hz, 2H).

(E) —3— (5— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methinole) furan-3 inore) N— ((6 black Mouth pyridine-3 Inole) Methyl) acrylamide (Compound 2-80)

[Chemical 123]

[0207] H—NMR (500MHz, DMSO—d)

6

δ: 11.25 (s, IH), 8.62 (t, J = 5.9 Hz, IH), 8.36 (d, J = 2.2 Hz, IH), 8.12 (s, IH), 7.78 (dd, J = 8.3, 2.4 Hz , IH), 7.50 (d, J = 8.3 Hz, IH), 7.39 (d, J = 15.6 Hz, IH), 7.35 (dd, J = 6.7, 4.3 H z, IH), 7.29 (s, IH ), 7.10—6.99 (m, 3H), 6.56 (d, J = 15.6 Hz, 1 H), 6.58-6.45 (m, IH), 4.42 (d, J = 5.9 Hz, 2H).

(E) -N- (3,5-Dimethylphenyl) 1 3— (5— ((Z) — (3-Oxo 3, 4-dihydride) (S8—Z 呦 ^, /

Ί] [¾] ,, -wz-

'ε— ^ —ε) — (z))-s) ε— -Ν- (Ή)

• (HS 's) Z · ε' (Η ε 's) 9Z Έ' (ΗΧ ' ^Ζ Η 9 "SX = Γ' Ρ) 99 · 9 '(HI' s) 69 · 9 '(HI' ^Ζ Η 8 · 8 = Γ 'Ρ) Ζ6 · 9' (HS ¾) 66 "9-εΐ · ΐ '(ΗΧ' ^Ζ Η Ζ · Ζ 'S 8 = Γ' ΡΡ) 8Ζ · Ζ '(HI' s) OS · Ζ '(HI' ra ) SS "Ζ-βε · Ζ '(ΗΧ' Ζ Η Ζ · Ζ = f 'P) Z · Ζ' (ΗΧ 'Ζ Η 9" SX = ΓΡ) Ζ · Ζ' ( HI 'S) ZX · 8' (HI 's) 66 · 6' (HI LZ '11: 9

(P-OSMQ ^<Z HMOOS) ¾MN-H _T

'χ] [¾ /, Hz a ¾ ^ ―' ε- ^ -ε)-(z))-s)-ε- Ι-^^ ^ Λ ^^ → 'ε) -Ν- (Ή)

• (Η9 ^<S ) 9Z 'Ζ' (HI ^<Ζ Η 9 "SI = Γ 'Ρ) 89 9' (HI 's) 69 9' (HS '^) 66" 9-81 HS '^) οε · Ζ— 6S · Ζ' (HI ' ^Ζ Η' SI = ΓΡ) 8 · Ζ '(HI' S) 8X · 8 '(HI' s) 96 · 6 '(HI LZ '11: 9

^{^{(9 P-0SMQ <Ζ ΗΜ003}} ) ΉΜΝ-Η Τ

690l.0 / .00Zdf / X3d 06 T98CS0 / 800Z OAV XZ— ,, ^ Λί ^ ≠ (Be ^ C Z- ^^ \ '!] [¾ /, -WZ-

'ε— ^ —ε) — (z))-s) -ε-

• (ΗΖ ' ^Ζ Η Ζ "S = ΓΡ) Ζ''(ΗΧ' ΖΗ 9" SX = Γ 'P) SS · 9' (HI 's) 99 · 9' (ΗΖ '^) 96' 9-10 · Ζ '(ΗΖ

0 · Ζ— Ζ0 · Ζ '(ΗΧ' ^Ζ Η S Έ = Γ 'Ρ) 8 Χ Ζ' (ΗΧ ' ^Ζ Η 9 "SX = Γ' Ρ) 08 · Ζ

'(HZ' ra) s--0 · Ζ '(ΗΧ' ^Ζ Η S · Ζ = Γ 'Ρ) 89 · Ζ' (ΗΧ ' ^Ζ Η 8 "S =

ΓΡ) 9 · 8 '(HI' s) XS · 8 '(ΗΪ' ^Ζ Η Ζ "S = Γ;) 8Ζ · 8 '(HI ^) QZ" 11: 9

(v-oswa ^<ζ ν νοοε) ΉΜΝ-Η _Τ

(8—2 呦) '/

Four

-(ζ)) -s) -ε- (Ή)

• (Η ' ^Ζ Η 8 = Γ' ¾90 Έ '(Η

' ^Ζ Η 8 · = Γ ；) Ζ Έ' (ΗΧ ' ^Ζ Η 9 "SX = Γ' Ρ) 99 · 9 '(HI' s) 69 · 9 '(HZ' ^Ζ Η 0 · 6 = Γ 'Ρ ) 86 · 9 '(ΗΧ' ^) 66 · 9 SO · Ζ '(HZ' ^) 90 · Ζ— 01 · Ζ

'(HI' s) 0S · Ζ '(HI ¾) 98' Ζ-βε · Ζ '(HI' ^Ζ Η 9 "SI = f'P) 9 · Ζ '(Η

Ζ ' ^Ζ Η 0 · 6 = Γ' P) 8S · Ζ '(HI' s) 9X · 8 '(HI' s) P6 · 6 '(HI' s) 9Z '11: 9

( ⁹ P-0SMQ ^<Z HM00S) ¾MN-H _T [OJZO]

690l.0 / .00Zdf / X3d! ■ 6 T98CS0 / 800Z OAV [οετ ^]

(8-Ζί ^) Be one (H one, 4 ^ ^ 'X] [q] /, HZ— {Λ ^ (^ Ζ- ^^ {Λ (

_{i- ^ C M) -ε- ^ -ε-} (a)) - s)) - z- (ζ)

• (ΗΖ ' ^Ζ Η 0''6 · 9 = ΓΡ) 9 Ό' (ΗΖ ' ^Ζ Η 0 ·' 6 ·

9 = Γ'Ρ¾89 Ό '(ΗΧ' ^) ^ Ύ-61 'Ζ' (ΗΧ ^<Ζ Η 8 "SX = ΓΡ) Ι 9 '(

HI 's) 99 9' (ΗΧ ' ^Ζ Η Έ = Γ' Ρ) 96 9 '(ΗΧ' ^) 66 "9-10 · Ζ '(ΗΖ

S0 "Z-60 · L '(HI ^<Z H z' ε = Γ 'Ρ) 6Χ"Ζ' (ΗΧ ^<Ζ Η 8 "SX = Γ 'P) SZ · Z' (HI '^) 88" Z -6S · Ζ '(HI ^Ζ Η 9 = Γ' Ρ) 9Ζ · 8 '(HI' s) Z '11: g

( ⁹ P-0SMQ ^<z HMOOS) MN-H _T [£ JZ0]

[6

(98— Ζ 呦 ^

• (Η9 's) 9X · Ζ' (HZ

' ^Ζ Η ζ · 9 = f') εε · ζ '(Η' ^) 92 · ε '(HI' ^Ζ Η 9 "SI = Γ 'P) SS · 9' (

HI 's) Z9 9' (ΗΧ ' ^Ζ Η Ζ Έ = Γ' P) S6 9 '(HI' ^) 66 `` 9-10

) S0 "Ζ-60 'Ζ' (ΗΧ ' ^Ζ Η 8' ε = Γ '¾6X"Z' (HI ^<Z H 9 "SI = ΓΡ) · Ζ '(ΗΧ' ^) 88 'L-OV · Ζ '(ΗΧ ^<Z HZ "S = Γ' ¾SX · 8 '(HI' s) Z · χχ: 9

( ⁹ P-0SMQ ^<z HMOOS) MN-H _T [ZJZO]

690l.0 / .00Zdf / X3d 36 T98CS0 / 800Z OAV

H—NMR (500MHz, DMSO—d)

6

δ: 11.22 (s, IH), 7.36— 7.34 (m, IH), 7.32 (d, J = 15.3 Hz, IH), 7.20 (d, J = 3.4 Hz, IH), 7.09— 7.03 (m, 3H) , 7.01— 7.00 (m, IH), 6.76 (d, J = 15.3 Hz, IH), 6.73 (s, IH), 3.64 (t, J = 6.9 Hz, 2 H), 3.40 (t, J = 6.9 Hz , 2H), 1.93 (tt, J = 6.9, 6.9 Hz, 2H), 1.82 (tt, J = 6.9, 6.9 Hz, 2H).

(Z) —2— ((5— ((E) —3 Morpholino 1-oxoyl) furan-2-yl) methylene) -2H-benzo [b] [1, 4] oxazine 3 (4H ) ON (compound 2-88)

[Chemical 131]

H-NMR (500MHz, DMSO—d)

6

δ: 11.22 (s, IH), 7.95 (s, IH), 7.38— 7.35 (m, 2H), 7.23 (d, J = 3.7 Hz, IH), 7.09-7.03 (m, 2H), 7.02— 6.99 (m, 2H), 6.73 (s, IH), 3.72-3.53 (m, 8H).

(Z) — 2— ((5— ((E) 3— (4— (2 Hydroxyethyl) piperazine 1-yl) 3-Oxopropene 1-yl) Furan 2-yl) Methylene) 2H Benzo [ b] [1, 4] oxazine 3 (4H) ON (compound 2-89)

[Chemical 132]

"I '= Γ' PP) XS · 8 '(HI' ^Ζ Η 9" S = f ';) S8 · 8' (HI '^) 9 Ζ '11: 9

(V-OSWa ^<z HMOOS) MN-H _T [8ΪΖ0]

[n n

4 ^ ^ 'i] [q] / —Hz—a' ¾, — 'ε- ^ -ε)-(z)) -s) -ε- (a)

• (HZ ^<Z HX "9 = Γ 'P) 0

S '' (HI ^<Z H "SI = Γ 'P) Z9"9' (HI 's) 69 "9' (HZ '^) 86 · 9— Ζ0 · Ζ'

(HZ 'ra) so "Z-60' L '(HI ^<Z H Έ = Γ' P) 6X 'L' (HS '^) 92 · Ζ— SS · L' (HI 'ra) 6S -LZ' L '(HI ^<Z H 8 "X' 9 'L = Γ' P¾ZZ 'L' (HI ^<Z H 6 • 0 '6' = f '¾P) ZS 8' (HI ^<Z H 0" 9 = Γ), 8 · 8 '(HI ^) QZ "11: 9

(P-OS Q ^<Ζ ΗΜ003) ΉΜΝ-Η _Τ

4 ^ ^ 'i] [q] / —Hz—a' ¾, — 'ε- ^ -ε)-(z)) -s) -ε- (Ή)

"(HZ ' ^Ζ Η X

• 9 = Γ ') z · ζ' (ΗΖ 's -iq) xs · ε' (Η8 'ra) os · ε— S9 · ε' (ΗΧ ' ^Ζ Η -s

= r;) S · '(HI' s) SZ · 9 '(HZ' ^) 66 · 9 10 · Ζ '(HS' ^) εθ · Ζ- 60 ·

L '(HI' ^Ζ Η z · ε = Γ 'ν) ζζ · ζ' (ΗΖ '^) εε · ζ―8ε · ζ' (HI 'S) SZ · χχ: 9

690l.0 / .00Zdf / X3d V6 T98CS0 / 800Z OAV 5 Hz, 2H), 7.41-7.39 (m, IH), 7.33 (d, J = 15.6 Hz, IH), 7.28 (dd, J = 4.5, 1.6 Hz, 2H), 7.20 (d, J = 3.4 Hz, IH), 7.09— 7.04 (m, 2H), 7.00 (q, J = 3.2 Hz, 2H), 6.69 (s, IH), 6.59 (d, J = 15.

6 Hz, IH), 4.44 (d, J = 5.6 Hz, 2H).

(E) -N- (3,5-Dimethylphenyl) 1 3— (5— ((Z) — (3-Oxo 3, 4-dihydro) 2H Benzo [b] [l, 4] oxazine 2 Iridene) methinole) furan 2-inole) acrylamide (compound 2-92)

[Chemical 135]

[0219] H—NMR (500MHz, DMSO—d)

6

δ: 11.28 (s, IH), 10.10 (s, IH), 7.43— 7.41 (m, IH), 7.38 (d, J = 1 5.4 Hz, IH), 7.33 (s, 2H), 7.24 (d, J = 3.4 Hz, IH), 7.11— 7.04 (m, 2H), 7.03-6.99 (m, IH), 6.70 (s, IH), 6.70 (d, J = 15.4 Hz, 3 H), 2.25 (s, 6H ).

(E) -N- (3, 4-Dimethoxyphenyl) 1 3— (5— ((Z) — (3-Oxo 3, 4-dihydro) 2H Benzo [b] [l, 4] oxazine 2 ylidene) methinole) furan 2-inole) acrylamide (compound 2-93)

[Chemical 136]

[0220] H—NMR (500MHz, DMSO—d)

6

δ: 11.27 (s, IH), 10.15 (s, IH), 7.43—7.41 (m, 2H), 7.37 (d, J = 1 5.4 Hz, IH), 7.24 (d, J = 3.7 Hz, IH), 7.20 (dd, J = 8.7, 2.3 H z, IH), 7.11-7.06 (m, 2H), 7.04— 7.00 (m, 2H), 6.92 (d, J = 8.8 Hz, IH), 6.70 (s, IH), 6.67 (d, J = 15.4 Hz, IH), 3.75 (s, 3H), 3.73 (s, 3H).

(E) — N— (4-morpholinophenyl) 3— (5-((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine 2 ylidene) methinole) Furan 2-luamide (Compound 2-94)

[Chemical 137]

H—NMR (300MHz, DMSO—d)

6

δ: 11.27 (s, IH), 10.08 (s, IH), 7.58 (d, J = 9.0 Hz, 2H), 7.43—7.41 (m, IH), 7.37 (d , J = 15.9 Hz, IH), 7. 24 (d, J = 3.7 Hz, IH), 7. 10-7.04 (m, 3H), 7.04— 6.99 (m, 2H), 6 92 (d, J = 9.0 Hz, 2 H), 6.68 (d, J = 15.9 Hz, IH), 3.71 (m, 8H).

(E) —N— ((2 Dimethylamino) ethyl) -3- (3-((Z) -I (4-Methyl-3oxo3, 4 Dihydro-2H Benzo [b] [l, 4] oxazine 2-Nore) Acrylamide (Compound 2-95)

[Chemical 138]

H—NMR (300MHz, DMSO—d)

6

δ: 8.17 (s, IH), 8.03 (s, IH), 7.93 (d, J = 7.5 Hz, IH), 7.56—7.4 6 (m, 3H), 7.40-7. 37 (m, IH), 7. 28— 7. 25 (m, IH), 7. 21— 7. 12 (m, 2H), 6. 86 (s, IH), 6. 73 (d, J = 15.8Hz, IH), 3.43 (s, 3H), 3.39—3.35 (m, 2H), 2.33—2.27 (m, 8H). (E) —N Cyclopropylamino-3— (3— ((Z)-(4-Methyl-3-oxo3, 4--dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) atari Luamide (Compound 2-96)

[Chem 139]

[0223] H—NMR (300MHz, DMSO—d)

6

δ: 8.26 (d, J = 4.6 Hz, IH), 8.01 (s, IH), 7.92 (d, J = 7.0 Hz, 1 H), 7.54-7.46 (m, 3H), 7.40— 7.37 (m, IH ), 7.28— 7.25 (m, IH), 7.19-7.15 (m, 2H), 6.85 (s, IH), 6.60 (d, J = 15.8 Hz, 1 H), 3.42 (s, 3H), 2.81 -2.76 (m, IH), 0.73-0.67 (m, 2H), 0.51-0.45 (m, 2 H).

(Z) -2- (3- ((E) -4 Methinole 1 3 oxo 3-(Pyrrolidine 1 1-yl) Prop 1 Enenore) Benzylidene) 2H-Benzo [b] [1, 4] oxazine 3 (4H) —On (compound 2-97)

[Chemical 140]

[0224] H—NMR (300MHz, DMSO—d)

6

δ: 8.12 (s, IH), 8.03 (d, J = 7.3 Hz, IH), 7.67 (d, J = 8.6 Hz, 1 H), 7.51 (dd, J = 15.9, 8.5 Hz, 2H), 7.38— 7.34 (m, IH), 7.28— 7.25 (m, 1 H), 7.18— 7.14 (m, 2H), 7.07 (d, J = 15.6 Hz, IH), 6.8 9 (s, IH ), 3.68 (t, J = 6.5 Hz, 2H), 3.43 (s, 3H), 3.42— 3.40 (m, 2 H), 1.99-1.90 (m, 2 H), 1.87— 1.78 (m, 2H).

(Z) —4 Methinole 2— (3- ((E) —3 Morpholino 3 Oxoprop 1—Enyl ■ 2H-f [b] [l, 4] oxa:-3 (4H) ON (compound 2-98

[Chem 141]

H—NMR (300MHz, DMSO—d)

6

δ: 8.ll (s, IH), 8.06 (d, J = 7.7 Hz, IH), 7.69 (d, J = 7.5 Hz, 1 H), 7.56 (d, J = 15.6 Hz, IH), 7.49 ( d, J = 7.8 Hz, IH), 7.38— 7.25 (m, 3H), 7.17 (td, J = 7.8, 3.3 Hz, 2H), 6.88 (s, IH), 3.75— 3.61 (m, 8 H), 3.42 (s, 3H).

(Z) — 4 Methynole 2— (3 — ((E) — 3— (4 2 Hydroxyethyl) piperazine 1 yl) 3 oxopro 1 benzyl) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H) ON (compound 2-99)

[Chemical 142]

H—NMR (300MHz, DMSO—d)

6

δ: 8.09 (s, IH), 8.03 (d, J = 8.1 Hz, IH), 7.69 (d, J = 8.1 Hz, 1 H), 7.54 (d, J = 15.4 Hz, IH), 7.49 (t, J = 7.6 Hz, IH), 7.35— 7.29 (m, IH), 7.33 (d, J = 15.8 Hz, IH), 7.09— 6.98 (m, 3H), 6.8 3 (s, IH), 4.52 (brs, IH), 3.70- 3.57 (m, 12H), 3.43 (s, 3H).

(E) -3- (3-((Z) —4-Methyl-3-oxo3,4-dihydro-1 2H-benzo [b] [1,4] oxazine-2 ylidenemethyl) phenyl) N— (pyridine 2-chloramide (Compound 2-100) [Chemical 143]

[0227] H—NMR (300MHz, DMSO—d)

6

δ: 8.80 (t, J = 5.9 Hz, IH), 8.53 (d, J = 3.9 Hz, IH), 8.07 (s, 1 H), 7.92 (d, J = 7.5 Hz, IH), 7.78 (td, J = 7.8, 1.8 Hz, IH), 7.57-7.47 (m, 3H), 7.42— 7.39 (m, IH), 7.33 (t, J = 6.9 Hz, IH), 7.29-7.25 (m, 2H), 7.20— 7.13 (m, 2 H), 6.86 (s, IH), 6.83 (d, J =

15.8 Hz, IH), 4.52 (d, J = 5.9 Hz, 2H), 3.43 (s, 3H).

(E) -3- (3-((Z) -4-Methylenol 3-oxo3, 4-Dihydro- 1H-benzo [b] [1,4] oxazine-2 ylidenemethyl) phenyl) N- (pyridine-4-ylmethyl ) Acrylamide (compound 2-101)

[Chemical 144]

[0228] H—NMR (300MHz, DMSO—d)

6

δ: 8.71 (t, J = 5.7 Hz, IH), 8.53 (d, J = 4.8 Hz, IH), 7.78 (td, J = 7.7, 1.7 Hz, IH), 7.64 (d, J = 15.4 Hz, IH ), 7.48 (d, J = 3.9 Hz, IH), 7.41 (d, J = 3.9 Hz, IH), 7.35— 7.27 (m, 5H), 7.22 -7. 17 (m, 4H), 6.65 ( d, J = 15.6 Hz, IH), 4.50 (d, J = 5.7 Hz, 2H), 3.41 (s, 3H).

(E) -3- (3-((Z)-(4-Methyl-3oxo3, 4 dihydro-2H benzo [b] [1,4] oxazine 2 ylidene) methyl) phenyl) N— (4 monoreforinov Enyl) acrylamide (compound 2-102) [Chemical 145]

[[00222299]] HH——NNMMRR ((330000MMHHzz ,, DDMMSSOO——dd))

66

δδ :: 1100..0077 ((ss ,, IIHH)), 88..0077 ((ss ,, IIHH)) ,, 77..9955 ((dd ,, JJ == 77..55 HHzz ,, IIHH)) ,, 77..6644—— 77 .. 5588 ((mm ,, 44HH)) ,, 77..5522 ((tt ,, JJ == 77..88 HHzz ,, IIHH)) ,, 77 ..4422 ((dddd ,, JJ == 77..11 ,, 22..55 HHzz ,, IIHH)) ,, 77..2299--77..2266 ((mm ,, IIHH)) ,, 77 ..2211—— 77..1144 ((mm ,, 22HH)) ,, 66..9944 ((dd ,, JJ == 99..00 HH zz ,, 22HH)) ,, 66..8877 (( ss ,, IIHH)) ,, 66..8866 ((dd ,, JJ == 1155..66 HHzz ,, IIHH)) ,, 33..7744 ((tt ,, JJ == 44..77 HHzz, , 44HH)) ,, 33..4433 ((ss ,, 33HH)) ,, 33..0077 ((tt ,, JJ == 44..77 HHzz ,, 44HH)).

((EE)) --33-- ((55-((((ZZ)) ichiichi ((44-mechichiruru 33 okikisoso 33 ,, 44 jijihidodororo 22HH bebenzozo [[bb] ] [[11 ,, 44]] Oxoxasadine-22 Irididene)) Methychilur)) Chiofen-22 Ill)) NN —— ((Pipirididine-33——

[Chemical 146]

[0230] H—NMR (300MHz, CDCl)

Three

δ: 8.59 (d, J = 2.0 Hz, IH), 8.55 (dd, J = 4.9, 1.6 Hz, IH), 7.8 0 (d, J = 15.2 Hz, IH), 7.71 (dt, J = 7.9, 2.0 Hz, IH), 7.31— 7.00 (m, 7H), 6.30 (d, J = 15.2 Hz, IH), 6.01 (t, J = 6.1 Hz, IH), 4.61 (d, J = 5.9 Hz, 3H ), 3.48 (d, J = 4.8 Hz, 3H).

(E) -3- (5-((Z)-(4-Methyl-3 oxo-1,3,4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methinole) thiophene 2 yl) N— ( 4 Morpholinophenyl) Atalinoleamide (Compound 2-104)

[Chemical 147]

H—NMR (300MHz, DMSO—d)

6

δ: 10.04 (s, IH), 7.71 (d, J = 15.4 Hz, IH), 7.59 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 3.9 Hz, IH), 7.44 (d, J = 3.9 Hz, IH), 7.33 -7.27 (m, 2H), 7.23— 7.17 (m, 3H), 6.94 (d, J = 8.8 Hz, 2H), 6. 66 (d, J = 15.4 Hz, IH), 3.74 (t, J = 4.8 Hz, 4H), 3.42 (s, 3H), 3.07 (t, J = 4.6 Hz, 4H).

Ethyl 2— ((Z) —3 oxo 2— ((5— ((E) —3 oxo 3— (pyridine 1 3-norethinoreamino) propylene 1-heninore) thiophene 2-inole) methylene) 2H—Benzo [b] [1, 4] oxazine 4 (3H) yl) acetic acid (compound 2—105)

[Chemical 148]

H—NMR (300MHz, DMSO—d)

6

δ: 8.71 (t, J = 5.7 Hz, IH), 8.54 (s, IH), 8.48 (d, J = 4.8 Hz, 1 H), 7.71 (d, J = 7.3 Hz, IH), 7.65 (d, J = 15.4 Hz, IH), 7.49 (d, J = 3.7 Hz, IH), 7.42-7.36 (m, 2H), 7.32— 7.28 (m, IH), 7.19 (s, IH), 7.16-7.12 (m , 2H), 6.57 (d, J = 15.4 Hz, IH), 4.63 (s, 2 H), 4.43 (d, J = 5.7 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H), 1.22 ( t, J = 7.0 Hz, 3H).

(E) -3- (5-((Z) —4 allyl 1-3 xo 3, 4 dihydro-1 2H benzo [b] [1, 4] oxazine-2 ylidenemethyl) thiophene-2 yl) N- (pyridine-3 ylmethyl ) Acrylamide (Compound 2-106) [Chemical 149]

'H-NMROOOMHz, DMSO— d)

6

δ: 8.69 (t, J = 6.0 Hz, IH), 8.54 (s, IH), 8.48 (d, J = 4.6 Hz, 1 H), 7.71 (d, J = 7.7 Hz, IH), 7.64 (d, J = 15.8 Hz, IH), 7.48 (d, J = 3.9 Hz, IH), 7.42-7.25 (m, 2H), 7.19— 7.09 (m, 4H), 6.56 (d, J = 15.6 Hz, IH), 5.95— 5.84 (m, IH), 5.21 (dd, J = 14.4, 7.1 Hz, 3H), 4.67 (s, 2H), 4.43 (d, J = 5.7 Hz, 2H)

(E) —N— ((2 Dimethylamino) ethyl) -3- (5-((Z) 4-Methyl-3oxo3, 4 Dihydro-2H Benzo [b] [l, 4] oxazine 2 Iridenemethyl) thiophene 3-yl) acrylamide (compound 2-107)

[Chemical 150]

H—NMR (300MHz, DMSO—d)

6

δ: 8.05 (t, J = 5.5 Hz, IH), 7.57 (d, J = 15.4 Hz, IH), 7.46 (d, J = 3.9 Hz, IH), 7.38 (d, J = 3.9 Hz, IH), 7.32— 7.26 (m, 2H), 7.22-7.17 (m, 3H), 6.56 (d, J = 15.6 Hz, IH), 3.41 (s, 3H), 3.28 (q, J = 6.2 Hz, 2H), 2.35 (t, J = 6.4 Hz, 2H), 2. 18 (s, 6H). (E) —N Cyclopropinol 3- (5 — ((Z) —4-Methyl-3-oxo3, 4-dihydro-2H -Benzo [b] [1,4] oxazine 2-ylidenemethyl) thiophene-3-yl) acrylamide (Compound 2-108)

[Chemical 151]

H—NMR (300MHz, DMSO—d)

6

δ: 8.20 (d, J = 4.6 Hz, IH), 7.58 (d, J = 15.4 Hz, IH), 7.47 (d, J = 3.9 Hz, IH), 7.38 (d, J = 3.7 Hz, IH), 7.28 (dd, J = 7.0, 2.4 Hz, 2H), 7.22-7.16 (m, 3H), 6.40 (d, J = 15.6 Hz, IH), 3.41 (s, 3H), 2.79-2.73 (m, IH), 0.69 (td, J = 7.1, 4.8 Hz, 2H), 0.48 -0.43 (m, 2H).

(Z) —4 Methyl 2— ((5— ((E) — 3 oxo 3— (pyrrolidine 1-yl) propene 1) thiophene 2-yl) methyl) -2H-benzo [b] [ 1,4] oxazine 3 (4H) one (compound 2-109)

[Chemical 152]

lH-NMR (300MHz, DMSO—d6)

δ: 7.65 (d, J = 15.2 Hz, IH), 7.49— 7.47 (m, 2H), 7.46— 7.43 (m, IH), 7.29-7.25 (m, IH), 7.22— 7.14 (m, 3H), 6.78 (d, J = 15.2 Hz, IH), 3.67 (t, J = 6.8 Hz, 2H), 3.41 (t, J = 6.6 Hz, 5H), 1.9 3 (dd, J = 12.9, 6.7 Hz, 2H) , 1.83 (dd, J = 13.1, 6.3 Hz, 2H).

(Z) —4 Methyl 2— ((5— ((E) —3 Morpholino 3-oxopropene 1) -phen-2-yl) methylene) 2H Benzo [b] [l, 4] oxazine 3 (4H) — ON (compound 2—110)

[Chemical 153]

H—NMR (300MHz, DMSO d)

6

δ: 7.71 (d, J = 15.0 Hz, 1H), 7.50— 7.45 (m, 3H), 7.29— 7.25 (m, 1H), 7.22-7.15 (m, 3H), 7.03 (d, J = 15.0 Hz, 1H), 3.78- 3.52 (m, 8H), 3.41 (s, 3H).

(Z) 4-Methyl-2-((5-((E) 3— (4 (2-hydroxyethyl) piperazine 1 yl) 3-oxopropene 1-enynole) thiophene 1-2-inole) methylene) 2H—Benzo [b] [1,4] oxazine 3 (4H) ON (compound 2—111)

[Chemical 154]

H—NMR (300MHz, DMSO d)

6

δ: 7.68 (d, J = 15.0 Hz, 1H), 7.50— 7.46 (m, 3H), 7.29— 7.25 (m, 1H), 7.22-7.17 (m, 3H), 7.05 (d, J = 15.2 Hz, 1H), 4.47 (t, J = 5.0 Hz, 1H), 3.69-3.50 (m, 8H), 3.41 (s, 3H), 2.47—2.40 (m, 4H).

(E) -3- (5-((Z) 4-Methyl-3oxo3, 4 Dihydro-2H Benzo [b] [1, 4] Oxazine-2 Iridenemethyl) thiophene-2yl) N- (Pyridine-2-ylmethyl) Atalinoleamide (Compound 2-112)

[Chemical 155]

H—NMR (300MHz, DMSO—d)

6

δ: 8.71 (t, J = 5.7 Hz, IH), 8.53 (d, J = 4.8 Hz, IH), 7.78 (td, J = 7.7, 1.7 Hz, IH), 7.64 (d, J = 15.4 Hz, IH ), 7.48 (d, J = 3.9 Hz, IH), 7.41 (d, J = 3.9 Hz, IH), 7.35— 7.27 (m, 4H), 7.22 -7. 17 (m, 3H), 6.65 ( d, J = 15.6 Hz, IH), 4.50 (d, J = 5.7 Hz, 2H), 3.41 (s, 3H).

(E) -3- (5-((Z) 4-Methyl-3oxo3, 4 Dihydro-2H Benzo [b] [1, 4] Oxazine-2 ylidenemethyl) thiophene-2yl) N— (Pyridine-4-ylmethyl ) Atalinoleamide (Compound 2-113)

[Chemical Formula 156]

[0240] H—NMR (300MHz, DMSO—d)

6

δ: 8.75 (t, J = 6.1 Hz, IH), 8.52 (dd, J = 4.5, 1.6 Hz, 2H), 7.6 5 (d, J = 15.4 Hz, IH), 7.48 (d, J = 3.9 Hz, IH), 7.42 (d, J = 3.9 Hz, IH), 7.31-7.14 (m, 7H), 6.59 (d, J = 15.4 Hz, IH), 4.44 (d, J = 6.1 Hz, 2H ), 3.41 (s, 3H).

(E) —3— (4— ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2-ylidene) methyl) phenyl) N— ((6 (3- (yl) pyridine) methyl) Atalinoleamide (Compound 2-114)

[Chemical 157]

[0241] 'H-NMROOOMHz, DMSO— d)

6

δ: 11.20 (s, IH), 8.75 (t, J = 5.7 Hz, IH), 8.37 (d, J = 2.4 Hz IH), 7.93 (d, J = 8.3 Hz, 2H), 7.78 (dd, J = 8.3, 2.6 Hz, IH), 7.64 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 2.0 Hz, IH), 7.48 (d, J = 5.5 Hz, IH), 7.34-7.31 (m, IH), 7.07— 7.03 (m, 2H), 7.02— 6.97 (m, IH), 6.80 (s, IH) , 6.71 (d, J = 15.8 Hz, IH), 4.43 (d, J = 5.7 Hz, 2H).

(E) —N— ((2 dimethylamino) ethyl) -3- (4-methoxy-3-((Z) — (3 oxo-1,4 dihydro-1 2H benzo [b] [l, 4] oxazine 1 2 Ylidene) methyl) phenyl) atalinoleamide (Compound 2 -115)

[Chemical 158]

[0242] H—NMR (300MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.36 (d, J = 2.0 Hz, IH), 8.ll (t, J = 5.5 Hz, IH), 7.55 (dd, J = 8.6, 2.0 Hz, IH), 7.46 (d, J = 15.8 Hz, IH), 7.32-7.28 (m, IH), 7. 14-6.97 (m, 5H), 6.59 (d, J = 15.8 Hz, 1 H), 3.90 (s, 3H) , 3.30 (t, J = 6.5 Hz, 2H), 2.39 (t, J = 6.5 Hz, 2 H), 2.20 (s, 6H).

(E) —N Cyclopropynol 3- (4-Methoxy-3 -— ((Z)-(3-Oxo 3,4-dihydro 2H benzo [b] [1,4] oxazine 2 ylidene) methyl) phenyl) acrylamide (Compound 2-116)

[Chemical 159]

[0243] lH-NMR (300MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.35 (d, J = 2.0 Hz, IH), 8.22 (d, J IH), 7.54 (dd, J = 8.5, 2.1 Hz, IH), 7.46 (d, J = 15.8 Hz, IH), 7.31-7.26 (m, IH), 7.14— 6.97 (m, 5H) , 6.46 (d, J = 15.8 Hz, 1 H), 3.90 (s, 3H), 2.80— 2.73 (m, IH), 0.69 (td, J = 7.0, 4.8 Hz, 2 H), 0.50-0.45 (m , 2H).

(Z) — 2— (4 Methoxy-3-((E) —3-oxo-3- (pyrrolidine-1-yl) propenyl) benzylidene) 2H-benzo [b] [1, 4] oxazine 3 ( 4H) —On (compound 2—117)

[Chemical 160]

lH-NMR (300MHz, DMSO—d)

6

6: 11.17 (s, IH), 8.41 (d, J = 1.8 Hz, IH), 7.70 (d, J = 8.6 Hz, IH), 7.51 (d, J = 15.4 Hz, 1 H), 7.22 (dd, J = 7.0, 2.2 Hz, IH), 7.13-6.97 (m, 5H), 6.87 (d, J = 15.6 Hz, IH), 3.90 (s, 3H), 3.68 (t, J = 6.7 Hz, 2H ), 3.41 (t, J = 6.7 Hz, 2H), 1.99— 1.90 (m, 2H), 1.87-1.78 (m, 2H).

(Z) -2- (4 Methoxy-3-((E) -3 Morpholino-3-oxopropenyl-1-benzylidene) 2H Benzo [b] [1,4] oxazine 3 (4H) ON (Compound 2 — 118)

[Chemical 161]

lH-NMR (300MHz, DMSO—d)

6

δ: 11.16 (s, IH), 8.37 (d, J = 2.0 Hz, IH), 7.77 (dd, J = 8.6, 2.0 Hz, IH), 7.56 (d, J = 15.4 Hz, IH), 7.23 — 7.19 (m, IH), 7. 14 ( d, J = 6.1 Hz, IH), 7.10-6.96 (m, 5H), 3.91 (s, 3H), 3.79—3.47 (m, 8H).

(Z) -2- (4-Methoxy-3-((E) -3- (4 (2-hydroxyethyl) piperazine 1 yl) 3 oxoprop 1 yl) benzylidene) 2H Benzo [b] [1, 4] Oxazine 3 (4H) ON (compound 2—119)

[Chemical 162]

H—NMR (300MHz, DMSO—d)

6

δ: 11.17 (s, IH), 8.37 (d, J = 2.0 Hz, IH), 7.76 (ddj = 8.7, 2.1 Hz, IH), 7.53 (d, J = 15.4 Hz, IH), 7.23— 7.20 (m , IH), 7.16— 6.97 (m, 6H), 4.46 (s, IH), 3.91 (s, 3H), 3.75— 3.50 (m, 8H), 2.47 -2.40 (m, 4H).

(E) -3- (4 Methoxy-3- ((Z)-(3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) N (pyridine-2-ylmethyl) atari Noreamide (Compound 2-120)

[Chemical 163]

H—NMR (300MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.79 (t, J = 5.9 Hz, 1 H), 8.53 (d, J = 5.0 Hz, IH), 8.40 (dj = 1.8 Hz, IH), 7.78 (td, J = 7.7, 1.7 Hz, IH), 7.59-7.48 (m, 2H), 7.36— 7.26 (m, 3H), 7.15— 6.97 (m, 5H), 6.68 (d, J = 15.8 Hz, IH), 4.53 (d, J = 5.9 Hz, 2H), 3.91 (s, 3H). (E) -3- (4 Methoxy-3- ((Z)-(3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) N (pyridine 1-3 ylmethyl) acrylamide (Compound 2-121)

[Chemical 164]

H—NMR (300MHz, DMSO—d)

6

δ: 11.19 (s, IH), 8.76 (s, IH), 8.55 (d, J = 2.2 Hz, IH), 8.47 (d, J = 4.8 Hz, IH), 8.39 (d, J = 2.0 Hz, IH ), 7.72 (d, J = 7.7 Hz, IH), 7.56 (dd, J = 7.8, 2.8 Hz, IH), 7.53 (d, J = 15.8 Hz, IH), 7.37 (dd, J = 7.8, 4.7 Hz , IH), 7.32— 7.29 (m, IH), 7.13 (d, J = 8.3 Hz, IH), 7.12 (s, IH), 7.06— 6.98 (m, 3H), 6.61 (d, J = 15.8 Hz, IH), 4.45 (d, J = 5.9 Hz, 2H), 3.90 (s, 3H).

(E) -3- (4 Methoxy-3- ((Z)-(3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) N (pyridine 4-ylmethyl) atari Noreamide (Compound 2-122)

[Chemical 165]

H—NMR (300MHz, DMSO—d)

6

δ: 11.18 (s, IH), 8.78 (t, J = 6.3 Hz, IH), 8.52 (d, J = 5.7 Hz, 2H), 8.40 (d, J = 2.2 Hz, IH), 7.62— 7.48 (m , 2H), 7.33— 6.97 (m, 8H), 6.64 (d, J = 15.8 Hz, IH), 4.46 (d, J = 5.9 Hz, 2H), 3.91 (s, 3H).

(E) — N— (4-Morpholinophenyl) 3— (4-Methoxy-3— ((Z)-(3-Oxo 3 , 4-dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) phenyl) acrylamide (compound 2-123)

[Chemical 166]

H—NMR (300MHz, DMSO—d)

6

δ: 11.19 (s, IH), 10.01 (s, IH), 8.41 (d, J = 2.2 Hz, IH), 7.72 (dd, J = 8.5, 2.3 Hz, IH), 7.62— 7.57 (m, 2H) , 7.51 (d, J = 15.4 H z, IH), 7.36-7.33 (m, IH), 7.23— 7.20 (m, IH), 7.17— 6.92 (m, 6H), 6.73 (d, J = 15.6 Hz, IH), 3.91 (s, 3H), 3.74 (t, J = 4.7 Hz, 4 H), 3.06 (t, J = 4.5 Hz, 4 H).

(E) —N— ((2 Dimethylamino) ethyl) -3- (4-Methoxy-3-((Z) —4 Methyl-13-xo 3, 4 Dihydro-2H Benzo [b] [l, 4] oxazine 2 Iridenemethi Nole) phenyl) acrylamide (compound 2-124)

[Chemical 167]

H—NMR (300MHz, DMSO—d)

6

δ: 8.34 (d, J = 2.0 Hz, IH), 8.10 (t, J = 5.4 Hz, IH), 7.55 (dd, J

= 8.7, 2.3 Hz, IH), 7.46 (d, J = 15.8 Hz, IH), 7.36— 7.33 (m, IH), 7.27-7.05 (m, 5H), 6.59 (d, J = 15.8 Hz, IH) , 3.90 (s, 3H), 3.42 (s, 3H), 3.30 (t, J = 6.4 Hz, 2H), 2.40 (t, J = 6.5 Hz, 2H), 2.21 (s, 6H).

(E) —N Cyclopropinol 3- (4-Methoxy-3-((Z) —4-Methyl-3-Oxo 3, 4 Dihydro-2H benzo [b] [l, 4] oxazine-2 ylidenemethyl) phenyl) Acrylamide (Compound 2-125)

[Chemical 168]

H—NMR (300MHz, DMSO—d)

6

δ: 8.33 (d, J = 1.8 Hz, IH), 8.22 (d, J = 4.0 Hz, IH), 7.54 (dd, J = 8.7, 2.1 Hz, IH), 7.47 (d, J = 15.8 Hz , IH), 7.34— 7.31 (m, IH), 7.27-7.24 (m, IH), 7.20— 7. ll (m, 4H), 6.47 (d, J = 15.8 Hz, IH), 3.90 (s, 3H ), 3.42 (s, 3H), 2.77 (td, J = 7.4, 3.8 Hz, IH), 0.69 (td, J = 7.0, 4.8 Hz, 2H), 0.50- 0.45 (m, 2H).

(Z) — 2— (4 Methoxy-1-3- ((E) -3-oxo-3— (pyrrolidine-1-yl) propenyl) benzylidene) 4 Methyl-2H benzo [b] [1, 4] oxazine 3 (4H) ON (compound 2-126)

[Chemical 169]

H—NMR (300MHz, DMSO—d)

6

δ: 8.40 (d, J = 2.0 Hz, IH), 7.69 (dd, J = 8.6, 2.0 Hz, IH), 7.5 l (d, J = 15.6 Hz, IH), 7.26 (d, J = 2.2 Hz, IH), 7.24 (d, J = 2.0 Hz, IH), 7.19-7.10 (m, 3H), 6.86 (d, J = 15.6 Hz, IH), 3.90 (s, 4H), 3.68 (t, J = 6.6 Hz, 2H), 3.42 (t, J = 6.6 Hz, 2H), 3.41 (s, 3H), 1.99-1.90 (m, 2H), 1.87— 1.78 (m, 2H).

(Z) -2- (4-Methoxy-1-3- ((E) -3-Morpholino-1-oxopropylene 1-benzene) Benzylidene) 4-Methinole 2H Benzo [b] [1, 4] oxazine 3 (4H) ON (compound 2-127) [Chemical 170]

H—NMR (300MHz, DMSO—d)

6

δ: 8.36 (d, J = 2.2 Hz, IH), 7.78 (dd, J = 8.7, 2.1 Hz, IH), 7.5 6 (d, J = 15.4 Hz, IH), 7.28— 7.23 (m, 2H), 7.17— 7.10 (m, 5H), 3.91 (s, 3H), 3.77-3.54 (m, 8H), 3.41 (s, 3H).

(Z) -2- (4-Methoxy-3-(((E) -3-3- (4 (2-hydroxyethyl) piperazine 1 yl) 3-oxoprop 1 enninore) benzylidene) 4-methyl-2H-benzo [ b] [1, 4] oxazine 3 (4H) ON (compound 2-128)

[Chemical 171]

HH—— NNMMRR ((330000MMHHzz ,, DDMMSSOO—— dd))

66

δδ :: 88..3366 ((dddd ,, JJ == 55..77 ,, 11..88 HHzz ,, IIHH)) ,, 77..8800—— 77..7711 ((mm ,, IIHH) ) ,, 77..5522 ((dd ,, JJ == 1155..55 HHzz ,, IIHH)) ,, 77..2266--77..2211 ((mm ,, 22HH)) ,, 77. 1188—— 77..0044 ((mm ,, 55HH)) ,, 44..4466 ((ss ,, IIHH)) ,, 33..9900 ((ss ,, 33HH)) ,, 33..7733— — 33..5500 ((mm ,, 88HH)) ,, 33..4411 ((ss ,, 33HH)) ,, 22..4444 ((tt ,, JJ == 66 .. 11 HHzz ,, 44HH) ) ..

((EE)) --33-- ((44 Memetoxyxiecy 33—— ((((ZZ)) —— 44 Memethicyl roux 33 oxoxoso 33 ,, 44 1 Jihi-Hyddrolo 1 22HH Bebenzozo [[bb]] [[11 ,, 44]] Oxoxasazidin 22 Iridyldenden methethylyl)) Huefienillu)) NN —— ((Pipyrridinedin 22——)

[Chemical 172]

HH—— NNMMRR ((330000MMHHzz ,, DDMMSSOO—— dd))

66

δδ :: 88..7788 ((tt ,, JJ == 66 .. 11 HHzz ,, IIHH)) ,, 88..5533 ((dd ,, JJ == 44..00 HHzz ,, IIHH)), , 88..3399 ((dd ,, JJ == 11..88 HHzz ,, IIHH)) ,, 77..7788 ((ttdd ,, JJ == 77..77 ,, 11..88 HHzz ,, IIHH)) ,, 77..5599 ((dd ,, JJ == 22 ..00 HHzz ,, IIHH)) ,, 77..5533 ((dd ,, JJ == 1155..88 HHzz ,, IIHH) ) ,, 77..3388—— 77..2244 ((mm ,, 33HH)) ,, 77..2200 --77 .. 1100 ((mm ,, 55HH)) ,, 66..6688 ((dd ,, JJ == 1155..88 HHzz ,, IIHH)) ,, 44..5522 ((dd ,, JJ == 55..99 HHzz ,, 22HH)) ,, 33..9911 ((ss ,, 33HH)) ,, 33..4422 ((ss ,, 33 HH)) ..

((EE)) --33-- ((44 Memetoxyxiecy 33—— ((((ZZ)) —— 44 Memethicyl roux 33 oxoxoso 33 ,, 44 1 Jihi-Hyddrolo 1 22HH Bebenzozo [[bb]] [[11 ,, 44]] Oxoxasadizin 22 Iridyldenden methethylyl)) Huefienillu)) NN —— ((Pipyrridinedin 33——

[Chemical 173]

H—NMR (300MHz, DMSO—d)

6

δ: 8.73 (t, J = 6.1 Hz, IH), 8.55 (d, J = 2.2 Hz, IH), 8.48 (t, J = 2.4 Hz, IH), 8.37 (d, J = 1.8 Hz, IH ), 7.72 (d, J = 7.7 Hz, IH), 7.57 (dd, J = 8.6, 2.0 Hz, IH), 7.54 (d, J = 15.4 Hz, 1 H), 7.40-7.32 (m, 2H), 7.25 (dd, J = 7.5, 2.0 Hz, IH), 7.20— 7. 10 (m, 4H), 6.61 (d, J = 15.8 Hz, IH), 4.46 (d, J = 5.7 Hz, 2H), 3 .90 (s, 3H), 3.42 (s, 3H)

(E) -3- (4 Methoxy-3- ((Z)-(3 oxo 3, 4 dihydro- 1H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) N (pyridine 1-4 methyl) acrylamide (Compound 2-131) [Chemical 174]

H—NMR (300MHz, DMSO—d)

6

δ: 8.78 (t, J = 6.1 Hz, IH), 8.52 (d, J = 6.1 Hz, IH), 8.38 (dd, J = 5.6, 1.6 Hz, IH), 7.73 (dd, J = 8.8, 2.4 Hz, IH), 7.60—7.4 8 (m, 2H), 7.37-7.24 (m, 3H), 7.20—7.05 (m, 5H), 6.65 (d, J = 1 5.8 Hz, IH), 4.46 (d , J = 5.9 Hz, 2H), 3.91 (s, 3H), 3.43 (d, J = 5.3 Hz, 3H).

(E) — N— (4-Morpholinophenyl) 3— (4-Methoxy-3— ((Z) —4-Methyl-3-oxo3, 4 Dihydro-2H Benzo [b] [l, 4] oxazine-2 Ilidenemethyl ) Phenyl) Atalinoleamide (Compound 2-132)

[Chemical 175]

H—NMR (300MHz, DMSO—d)

6

δ: 10.02 (s, IH), 8.39 (d, J = 7.0 Hz, IH), 7.63— 7.50 (m, 3H), 7.41-7.36 (m, IH), 7.28— 7.23 (m, IH), 7.20— 7. 10 (m, 6H), 6.93 (d, J = 8.8 Hz, IH), 6.73 (d, J = 15.6 Hz, IH), 3.92 (s, 3H), 3.7 4 (t, J = 4.5 Hz, 4H), 3.43 (s, 3H), 3.06 (t, J = 4.7 Hz, 4H).

(E) -N- (4 morpholinophenyl) 3— (2-((Z)-(3 oxo 3, 4 dihydro-2H-benzo [b] [1, 4] oxazine 2 ylidene) methinole) thiazole 5 ) Acrylamide (Compound 2-133)

[Chemical 176]

[0260] H—NMR (300MHz, DMSO—d)

6

δ: 11.53 (s, IH), 10.08 (s, IH), 8.23 (s, IH), 7.80 (d, J = 15.2 Hz, IH), 7.58 (d, J = 9.2 Hz, 2H), 7.36— 7.32 (m, IH), 7.17— 7.05 (m, 4H), 6.93 (d, J = 9.2 Hz, 2H), 6.70 (d, J = 15.4 Hz, IH), 3.74 (t, J = 4.7 Hz, 4H), 3.06 (t, J = 4.7 Hz, 4H).

(E) — N— (4-morpholinophenyl) 3— (3-((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine 2-ylidene) methyl ) Phenyl) acrylamide (compound 2-134)

[Chemical 177]

[0261] H—NMR (300MHz, DMSO—d)

6

δ: 10.09 (s, IH), 8.06 (s, IH), 7.93 (d, J = 7.9 Hz, IH), 7.63—7.58 (m, 4H), 7.52 (t, J = 7.7 Hz, IH) , 7.37— 7.34 (m, IH), 7.08— 6.98 (m, 3 H), 6.94 (d, J = 9.2 Hz, 2H), 6.87 (d, J = 15.8 Hz, 1 H), 6.81 (s , IH), 3.74 (t, J = 4.7 Hz, 4H), 3.07 (t, J = 4.7 Hz, 4 H).

(E) N— (4-Cyclohexylphenyl) -3- (5-((Z)-(3-oxo-3,4-dihydro-2H-benzo [b] [1, 4] oxazine 2— Ylidene) methinole) thiophene 2-inole) acrylamide (compound 2-135)

[Chemical 178]

[0262] H—NMR (300MHz, DMSO—d)

6

δ: 11.22 (s, 1H), 10.14 (s, 1H), 7.74 (d, J = 15.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 3.9 Hz, 1H ), 7.46 (d, J = 4.0 Hz, 1H), 7.27 (dd, J = 5.8, 3.6 Hz, 1H), 7. 19— 7.00 (m, 6H), 6.6 7 (d, J = 15.2 Hz, 1H ), 1.83 1.72 (m, 6H), 1.40—1.33 (m, 5H). Example 3

2-((Z) —3 oxo 2— ((5— ((E) —3 oxo 3— (pyridine 1 3-methylmethylamino) propylene 1 thiol 2-yl) methylene) 2H-benzo [b] [1, 4] oxazine 4 (3H) -yl) acetic acid (compound 3 1)

[Chemical 179]

[0263] Ethyl 2— ((Z) — 3 oxo 2— ((5— ((E) — 3 oxo 3— (pyridine 1-ylmethylamino) propylene 1-enyl) thiophene 2-yl) methylene) 1H-Benzo [b] [l, 4] -year-old xazine (4 (3H) -Inole) oxalic acid (7.7 mg, 16 mol, compound 2-105) in dimethylformamide (0 · 30 mU) 4M Aqueous sodium hydroxide solution (0 · 50 mL) was added, and the mixture was stirred at room temperature for 1 hour, the reaction solution was neutralized with 1M hydrochloric acid, and the precipitated solid was collected by filtration. Washing and drying under reduced pressure gave 7. lmg of the target compound as a yellow solid (yield 98%).

[0264] 'H-NMROOOMHz, DMSO— d)

6

δ: 8.71 (t, J = 5.7 Hz, 1H), 8.54 (s, 1H), 8.48 (d, J = 4.8 Hz, 1 H), 7.71 (d, J = 7.3 Hz, 1H), 7.65 (d, J = 15.6 Hz, 1H), 7.49 (d , J = 3.7 Hz, 1H), 7. 42- 7. 36 (m, 3H), 7. 32— 7. 28 (m, 1H), 7. 19 (s, 1H), 7. 16- 7. 12 (m, 3H), 6. 57 (d, J = 15.6 Hz, 1H), 4. 63 (s, 2 H), 4. 43 (d, J = 5.7 Hz, 2H) .

[Production example]

Representative production examples of the compound of the present invention are shown below.

[0265] 1) Tablet

Formula 1 in lOOmg

Compound of the present invention lmg

Lactose 66. 4mg

Corn starch 20mg

Canoleboxymethinorescenorose canolecium 6mg

Magnesium stearate

The tablet with 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. Desired tablets can be obtained by appropriately changing the type and amount of the compound of the present invention and additives.

[0266] 2) Capsule

Formula 2 150 mg

Compound of the present invention 5mg

Lactose 145mg

A desired capsule can be obtained by appropriately changing the mixing ratio of the compound of the present invention and lactose.

[0267] 3) Eye drops

Formula 3 in lOOmL

Compound of the present invention lOOmg

Sodium chloride 900mg

Polysorbate 80 200mg Sodium hydroxide

Hydrochloric acid

Sterilized purified water

By changing the kind and amount of the compound of the present invention and additives as appropriate, the desired instillation IJ can be obtained with the power S.

[0268] [Pharmacological study]

Evaluation test of tyrosine kinase (KDR) activity inhibitory effect

ELISA is known as one of the widely used methods for evaluating the tyrosine kinase (KDR) activity inhibitory effect of drugs. Therefore, the inhibitory effect on tyrosine kinase activity of the compound of the present invention was evaluated using a commercially available kit for measuring kinase (KDR) inhibitory activity by ELISA (Carna Bio).

[0269] (Preparation of test compound solution)

Prepare a 2 mg / ml stock solution by dissolving the test compound (2 mg) in dimethyl sulfoxide (DMSO). This was transferred to a 2 L container and diluted with 8 L DMSO. This solution (compound concentration: 0.4 mg / ml) was diluted 25-fold with Atsy buffer to prepare a test compound solution. As a control, a solvent (4% DMSO / Atsusei buffer) was prepared for the well where no compound was added.

[0270] (Preparation of ATP / substrate solution)

A commercially available ATP / substrate (manufactured by Carna Bio Inc.) was thawed and 250 L was taken, and 1 mL of Atsei noffer was added and stirred to obtain an ATP / substrate solution. The prepared ATP / substrate solution was stored under ice-cooling and returned to room temperature before use.

[0271] (Preparation of enzyme solution)

Seven commercially available tyrosine kinases (KDR) (manufactured by Carna Bio) were removed, and 2.793 mL of assay buffer was added and stirred to obtain an enzyme solution. This enzyme solution was stored under ice-cooling, and returned to room temperature immediately before use.

[0272] (Preparation of blocking buffer)

Dissolve BSA (Sigma, A—7030) in wash buffer (50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.2% Tween—20) to a concentration of 10%. The solution was prepared and stored at -80 ° C. Remove 400 X100BSA solution thawed before use and add to 40 mL of wash buffer to make a blocking buffer.

[0273] (Preparation of detection antibody solution)

Commercially available HRP-labeled antibody (Carna Bio) 40 HL was added to 12 mL of blocking buffer to obtain a detection antibody solution.

[0274] (Test method and measurement method)

1) Add 10 L of test compound solution and 10 L of ATP / substrate solution to each well of ELISA plate (streptavidin-coated 96-well plate, PerkinElmer, 4009-0010), and add 20 enzyme solutions each. The reaction was started at room temperature for 1 hour (compound concentration ^ g / ml, 15 mM Tris-HCl (pH 7.5), 0.01% Tween-20, 20 mM DTT, substrate concentration: 250 nM, 1 ^ M ATP, 5 mg Mg). In addition, the above-mentioned 4% DMSO / Atsusei buffer was added to the well used as a reaction control instead of the compound.

[0275] 2) After completion of the reaction, the solution in the tool was discarded, and immediately the residue in the well was washed 4 times with 200 μL of wash buffer per wellol.

[0276] 3) 200 HL blocking buffer was added to each well and allowed to react at room temperature for 30 minutes.

[0277] 4) The solution in the well was discarded, and 100 L of the detection antibody solution was added to each well and reacted at room temperature for 30 minutes.

[0278] 5) After the reaction, the solution in the well was discarded, and immediately the residue in the well was washed 4 times with 200 μL of wash buffer per wenore.

[0279] 6) 100 L of coloring reagent was added to each well. After reacting at room temperature for 5 minutes, the reaction was stopped by adding 100 L of a color stop solution.

[0280] 7) Absorbance at 450 nm was measured with a plate reader.

[0281] (Calculation of kinase activity inhibition rate)

The inhibition rate of the compound solution-added well was calculated from the absorbance of the reaction-positive control wall to which the enzyme was added as 0% inhibition and the reaction negative control well to which the enzyme buffer was added instead of the enzyme as 100% inhibition. [0282] (Calculation formula)

A; Absorbance of reaction negative control well

B; Absorbance of reaction positive control well

C; Absorbance of compound solution added well

Kinase activity inhibition rate (%)

= 100 [1- (C-A) / (B-A)]

(Test results and discussion)

As an example of the test results, test compounds (compound 2-15, compound 2-16, compound 2-17, compound 2-20, compound 2-21, compound 2-22, compound 2-103 and compound 2-11 7 Table 1 shows the inhibition rate (% inhibition rate) of tyrosine kinase (KDR) activity.

[table 1]

K D R inhibitory activity at 4 μg mL

[0283] As shown in Table 1, the compound of the present invention has excellent tyrosine kinase (KDR) activity inhibition. The effect was shown. Therefore, the compound of the present invention has an excellent angiogenesis inhibitory effect.

Claims

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

[Chemical 1]

[Wherein, ring A represents a benzene ring, a thiophene ring, a thiazole ring or a furan ring; the ring A has one or more substituents selected from a halogen atom, an alkyl group, an alkoxy group and a halogenoalkyl group. May be;

1 2

Represents an aromatic heterocyclic group;

X represents a single bond, C = C, CH-0, O-CH, NH-CH or CH-NH;

2 2 2 2

Y represents a hydroxyl group, an alkyl group, an alkoxy group or NR R;

3 4

R and R may join together to form a non-aromatic heterocycle;

3 4

Each of the above alkyl groups is 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 1 or Each of the above-mentioned aryl groups may be a halogen atom, an amino group, a nitro group, an alkyl group, a halogenoalkynole group, an alkoxy group, a cycloalkyl group, a hydroxyalkyl group, an alkylcarbon group, Having one or more substituents selected from an alkyloxycarbonyl group, an alkylamino group, an alkylcarbonylamino group, an alkyloxycarbonylamino group, an aromatic heterocyclic group and a non-aromatic heterocyclic group Well;

Each of the above aromatic heterocyclic groups includes a halogen atom, an amino group, an alkyl group, a halogenoalkyl group, a hydroxyalkyl group, an alkyloxycarbonyl group, an anolenoquinamino group, an alkyl group. May have one or more substituents selected from a kill carbonylamino group and an alkyloxycarbonylamino group;

Each of the above non-aromatic heterocyclic groups is selected from a halogen atom, an amino group, an alkyl group, a halogenoalkynole group, a hydroxyalkyl group, an alkyloxycarbonyl group, an alkylamino group, and an alkylcarbonylamino group. You may have a substituent. ]

[2] In general formula [I],

Ring A represents a benzene ring, a thiophene ring, a thiazole ring or a furan ring;

The ring A may have one or more substituents selected from a halogen atom and an alkoxy group;

R and R are the same or different and each represents a hydrogen atom, an alkyl group or an alkenyl group;

1 2

X represents a single bond, C = C, CH—〇, O—CH, NH—CH or CH—NH;

2 2 2 2

Y represents a hydroxyl group, an alkyl group, an alkoxy group or NR R;

3 4

R and R are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, an aryl group.

3 4

An aryl group or an aromatic heterocyclic group;

R and R may join together to form a non-aromatic heterocycle;

3 4

Each alkyl group defined above has one or more substituents selected from a carboxyl group, an alkyloxycarbonyl group, an alkylamino group, an aryl group, an aromatic heterocyclic group and a non-aromatic heterocyclic group. Well;

Each aryl group as defined above may have one or more substituents selected from a halogen atom, an alkyl group, a halogenoalkyl group, an alkoxy group, a cycloalkyl group and a non-aromatic heterocyclic group;

Each aromatic heterocyclic group defined above is selected from a halogen atom, an amino group, an alkyl group, a halogenoalkyl group, an alkylamino group, and an alkyloxycarbonylamino group.

May have one or more substituents;

The compound or a salt thereof according to claim 1, wherein each non-aromatic heterocyclic group defined above may be substituted with a hydroxyalkyl group.

[3] In general formula [I],

Ring A represents a benzene ring, a thiophene ring, a thiazole ring or a furan ring; When ring A is a benzene ring, the benzene ring may have one or more alkoxy groups as substituents;

R represents a hydrogen atom, an alkyl group or an alkenyl group;

When R is an alkyl group, the alkyl group may have one or more substituents selected from a carboxyl group and an alkyloxycarbonyl group;

R represents a hydrogen atom;

2

X indicates c = c;

Y represents a hydroxyl group, an alkoxy group or NR R;

3 4

An alkyl group or an aromatic heterocycle;

When R or R is an alkyl group, the alkyl group is an alkylamino group or an aromatic heterocyclic group.

3 4

(The aromatic heterocyclic group may have one or more halogen atoms, halogenoalkyl groups, amino groups or alkyloxycarbonylamino groups as substituents) and non-aromatic heterocyclic groups May have one or more substituents selected from:

When R or R is an aryl group, the aryl group is an alkyl group, an alkoxy group, a cycloaryl group.

3 4

May have one or more substituents selected from an alkyl group and a non-aromatic heterocyclic group; when R or R is an aromatic heterocyclic group, the aromatic heterocyclic group is 1 or Multiple

3 4

May have an alkyl group of

R and R may join together to form a non-aromatic heterocycle;

3 4

When R and R together form a non-aromatic heterocycle, the non-aromatic heterocycle is substituted

3 4

May have one or more hydroxyalkyl groups as groups,

The compound according to claim 1 or a salt thereof.

In general formula [I]:

When ring A is a benzene ring, the benzene ring may have 1 methoxy group as a substituent;

R represents a hydrogen atom, a methyl group, a hydroxycarbonylmethyl group, an ethoxycarbonylmethyl group or an aryl group;

R represents a hydrogen atom; X indicates c = c;

Y is a hydroxyl group, a tert-butoxy group, a pyridine-2-methylmethylamino group, a pyridine-3-ylmethylamino group, a pyridine-4-methylmethylamino group, a 2-chloropyridine-5-methylmethylamino group, a 2-trifluoromethylpyridine-5-ylmethylamino group, a 2-dimethylaminoethylamino group, Hydroxyamino group, 2 morpholine-4-ylethylamino group, cyclopentylamino group, 3,5-dimethylphenylamino group, 3,4-dimethoxyphenylamino group, 4-cyclohexylphenylamino group, 4 morpholine-4 2-ylphenylamino group, 7-methyl- [1, 8] naphthyridine-2-ylamino group, pyrrolidine 1-yl group, morpholine 4-yl group, 4 (2 hydroxyethinole) piperazine 1-yl group, 1H-indole 6-inoreamino group, 6-aminoviridine-3-ylmethylamine Group or 6- tert butoxy Shikarubonirua 3 compound or its salt according to claim 1 showing a Irumechiruamino group.

• (Ε) —tert-butyl 3- (4 — ((Z) — (3oxo3,4dihydro-2H-b] [l, 4] oxazine-2-ylidene) methyl) phenyl) talylate,

• (E) — tert butyl 3- (2— ((Z) — (3 oxo 3, 4 dihydro-2H-b] [l, 4] oxazine 2-ether

• (E) — tert-butyl 3-

3- ()-(3-Oxo 3,4-dihydro 2H Nzo [b] [l, 4] oxa, N-2-ylidene) methyl) phenyl) talylate, (E)-tert butyl (E) -3 — (2 — ((Z) — (3 oxo 3, 4 dihydro-2H-zone [b] [l, 4] oxazine 2 lysine) methyl) thiazole-5 •• ((EE)) —— tteerrtt bubutytill 33 —— ((33 —— ((((ZZ)) —— ((33 thix 33 ,, 44 jihi hydridoro 22HH——bebenzozo [[bb]] [ [ll ,, 44]] Oxoxasadzin 22 Iridyldenden)) Methychilur)) Fuheenillulu)) Atataly relate,

•• ((EE)) —— tteerrtt Bubutytille 33 —— ((33—— ((((ZZ)) —— ((44—Memethicyl Loose 33——Oxoxoso 33 ,, 44——Dijihydrido Loh 22HH Bebenzozo [[bb]] [[11,, 44]] Oxoxasadzin 22 Iridyldenen)) Methicyllu)) Fuheenillulu)) Atari relate, •• ((EE)) —— tteerrtt Bubutytill 33 —— ((55—— ((((ZZ)) —— ((44-Methychilulu 33——Oxoxoso 33 ,, 44——Dijihihydrodoro 22HH Bebenzozo [[bb]] [[ 11 ,, 44]] Oxoxasadzin 22——Iridyldenden)) Methychinorele)) Chiofenen 22——Innorele)) Archive relate,

•• ((EE)) —— tteerrtt bubutchinorelle 33 —— ((55—— ((((ZZ)) —— ((44 et 11 ((22 etetoxyxy 22))ーー 33 OXOXOSO 33 ,, 44 Jijihidodoro 22HH Benbenzozo [[bb]] [[ll ,, 44]] Oxoxasadine--22 Irilidene))

• (E) —tert butynole 3— (4-methoxy-3-((Z) — (4-methyl-3-oxo-3,4-dihydro-2H benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) talate,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) furan 2-yl) Acrylic acid, • (E) -3- (3-((Z) I (4-Methyl-3oxo3, 4 Dihydro-2H Benzo [b]

[1, 4] oxazine 2 ylidene) methyl) phenyl) acrylic acid,

• (E) -3- (5-((Z) I (4-Methyl-3oxo3, 4 Dihydro-2H Benzo [b]

[1, 4] oxazine 2 ylidene) methyl) thiophene 2yl) acrylic acid,

• (E) -3- (5-((Z)-((4-Ethoxy-2-oxoethyl) -3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazine-2-ylidene) methyl) thiophene-2 E) Acrylic acid,

• (E) -3- (4 Methoxy-1-3-((Z)-(3-oxo3,4-dihydro-2-H) benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) acrylic acid

• (E) -3- (4 Methoxy-1-3 — ((Z)-(4 Methyl-3-oxo-3,4 dihydro-2-H benzo [b] [1,4] oxazine-2-ylidene) methyl) phenyl) acrylic acid

• (E) —3— (2 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 2 lysine) methyl) thiazole-5 yl) acrylic acid

-(Z) -2- (4- ((E) -3- (4- (2-hydroxyethyl) piperazine 1-yl)-3 Oxopropene 1) benzylidene) 2H—benzo [b] [1,4] oxazine 3 (4H) —one,

• (E) —3— (4 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine 1 2-ylidene) methyl) phenyl) N— (pyridine 2-ylmethyl) acrylamide,

• (E) —N— ((2 Dimethylamino) ethyl) -3- (3-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl ) Acrylic amide, • (E) —N Cyclopropinol 3- (3 — ((Z)-(3 oxo 3,4 dihydro-l 2H—benzo [b] [1, 4] oxazine 2-ylidene) methyl) phenyl) acrylamide, Z) — 2— (3— ((E) — 3 oxo 3— (pyrrolidine 1-yl) propylene 1-henyl) benzylidene) 2H benzo [b] [1, 4] oxazine 3 ( 4H) ON,

• (Z) -2- (3- ((E) -3-Mono-reforino 3 oxoprop 1 benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H) ON,

• (E) —N Hydroxy 3— (5 — ((Z)-(3 Oxo 3, 4 Dihydro 1H [b] [l, 4] oxazine 2 ylidene) methyl) thiophene 2yl) acrylamide, • (E) —3— (2 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) phenyl) —N— (pyridine-3-ylmethyl) acrylamide,

• (E) —N— ((2 dimethylamino) ethyl) -3- (2-((Z)-(3 oxo 3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl ) Acrylic amide,

• (E) —3— (2 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) phenyl) N— ((6 Black mouth pyridine 3yl) methyl) acryloleamide, • (E) One N— (3,5 Dimethylphenyl) -3— (2-((Z) One (3 oxo-1,4 dihydro 2H benzo [b] [1,4] oxazine 2 ylidene) methyl ) Phenyl) acrylic amide,

• (E) -N- (3,4 Dimethoxyphenyl) 3— (2— ((Z)-(3 oxo 3, 4 dihydro 2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl ) Acrylamide,

• (Z) — 2 — ((4 ((E) 3— (4 1 (2 hydroxyethyl) piperazine 1 1 1) 1 3 —oxoprop 1 1) and thiophen 2—inole) methylene) 2H—benzo [b] [1, 4] oxazine 3 (4H) —one, • (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) thiophene 3 yl) N— (Pyridine 2-dimethyl) acrylamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxazine-2 ylidene) methyl) thiophene 3 yl) N— (Pyridine 4-dimethyl) acrylamide,

• (E) —N Cyclopropinole 3— (5 — ((Z)-(3 Oxo 3, 4 Dihydro 1H— Benzo [b] [1,4] oxazine 2-ylidene) methyl) thiophene-2-yl) acrylamide,

• (Ζ) — 2— ((5— ((E) — 3—oxo 3— (pyrrolidine 1-yl) prope 1-eny nore) thiophene 2 yl) methylene) 2Η Benzo [b ] [l, 4] oxazine 3 (4H) —on,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxo • (E) — N— (3, 5-Dimethylphenyl) 3— (5-((Z)-(3-Oxo 3, 4-Dihydro 2H—Benzo [b] [1, 4] oxazine 2—ylidene) methinole) thiophene 2—yl) acrylamide,

• (E) -N- (3, 4-Dimethoxyphenyl) 3— (5— ((Z)-(3-Oxo 3, 4-Dihydr Draw 2H—Benzo [b] [1, 4] oxazine 2-ylidene) methyl) thiophene 2-yl) acrylamide,

• (E) -N- (4-morpholinophenyl) 3— (5— ((Z)-(3-Oxo 3, 4-dihydro-2H-benzo [b] [1, 4] oxazine 2-ylidene) Methinole) thiophene 2-ynole) clinoleamide,

• (Z) — 2 — ((4 ((E) 3— (4 (2 hydroxyethyl) piperazine 1 yl) 3—oxoprop 1 yl) furan 2 yl) methylene) 2H benzo [ b] [1, 4] oxazine 3 (4H) —aged, • (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) furan 3 yl) N— (Pyridine 2-ylmethyl) acryloleamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxodine-2-ylidene) methyl) furan 3 yl) N— (Pyridine 4-ylmethyl) acryloleamide,

• (E) —3— (5 — ((Z) — (3 oxo 3, 4 dihydro-2H benzo [b] [l, 4] oxo

• (E) —N Cyclopropinole 3— (5 — ((Z)-(3 Oxo 3, 4 Dihydro 1H— Benzo [b] [1, 4] oxazine 2 ylidene) methyl) furan 2 yl) acrylamide, • (Ζ) — 2— ((5— ((E) — 3 oxo 3— (pyrrolidine 1-yl) Prop 1—Eny Nole) Furan 2 Inole) Methylene) 2Η Benzo [b] [l, 4] oxazine 3 (4H) ON

• (Z) —2— ((5— ((E) —3 morpholino 1-oxoyl) furan-1 2-inole) methylene) 2H Benzo [b] [l, 4] oxazine 3 (4H ) On,

• (E) -N- (3,

5—Dimethylphenyl) 3— (5— ((Z)-(3-oxo3, 4-dihydro 2H Benzo [b] [l, 4] oxazine 2 ylidene) methinole) furan 2 Rilamide,

• (E) —N Cyclopropylamino-3— (3— ((Z)-(4—Methyl 3-oxo3, 4 Dihydro 2H benzo [b] [1,4] oxazine 2 ylidene) methyl) phenyl) acrylamide,

• (Z) -2- (3- ((E) -4-Methylenol 3-Oxo 3- (Pyrrolidine 1-yl) propenyl) benzylidene) 2H Benzo [b] [1, 4] oxazine 3 (4H) ON

• (Z) —4—Metinole 1— (3 — ((E) —3—morpholino 1—oxoprop 1—eny nore) benzylidene) 2H benzo [b] [1, 4] oxazine 3 ( 4H) ON,

• (E) -3- (3— ((Z) —4 Methinole 1 3 oxo 3, 4 Dihydro 1 2 H Benzo [b] [1, 4] oxazine 2 ylidenemethyl) phenyl) N— (Pyridine 2 ylmethyl) a ,

• (E) -3- (3— ((Z) —4 Methylolone 3 oxo 3, 4 Dihydro- 1H Benzo [b] [1, 4] oxazine 2 ylidenemethyl) phenyl) N— (pyridine-4-ylmethyl) acrylinoamide ,

• (E) -3- (3-((Z)-(4-Methyl-3oxo3, 4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) N— (4 mono-rephori Nophenyl) acrylamide,

• (E) -3- (5-((Z)-(4-Methyl-3 oxo-1,3,4 dihydro-2H benzo [b] [1, 4] oxazine-2 ylidene) methyl) thiophene-2-yl) N— (Pyridine-3

• (E) -3- (5-((Z)-(4-Methyl-3 oxo-1,3,4 dihydro-2H benzo [b] [1, 4] oxazine 2 ylidene) methinole) thiophene 2 yl) N— (4 morpholinophenyl) acrylamide,

• Ethyl 2 — ((Z) —3 oxo 2— ((5— ((E) —3 oxo 3— (pyridine-3-methylmethylamino) prop 1-enyl) thiophene 2-yl) methylene) 1 2H —Benzo [b] [1, 4] oxazine 4 (3H) —yl) acetic acid, • (E) -3- (5-((Z) —4 allyl 1-3 xo 3, 4 dihydro-1 2H benzo [b] [1, 4] oxazine-2 ylidenemethyl) thiophene 2 yl) N— (pyridine-3—

• (E) —N— ((2 Dimethylamino) ethyl) -3- (5— ((Z) —4 Methylolone 3 oxo 3, 4 Dihydro-2H Benzo [b] [l, 4] oxazine 2 ylidenemethyl) Thiophene 3-yl) acrylamide,

• (E) —N — ((2 Dimethylamino) ethyl) -3- (4-Methoxy-3-((Z) — (3 1,3,4 dihydro-1,2H benzo [b] [l, 4] oxazine-1,2 ylidene) methyl) phenyl) acrylamide,

• (E) —N— ((2 Dimethylamino) ethyl) -3- (4-Methoxy-3-((Z) —4-Methanol 3 Oxo 3, 4 Dihydro-2H Benzo [b] [l, 4] oxazine-2 Ylidenemethyl) phenyl) attalinoleamide, • (E) —N Cyclopropynol 3- (4-Methoxy-3- ((Z) -4-Methylol 3-Oxo-3, 4-Dihydro-2H Benzo [b] [l, 4] oxazine-2-ylidenemethyl) phenyl ) Acryloleamide,

• (Z) — 2— (4 Methoxy-1-3- ((E) -3-oxo3-— (Pyrrolidine-1-yl) propenyl) benzylidene) 4 Methyl 2H Benzo [b] [1, 4] oxazine 3 (4H) —on,

• (E) -N- (4-morpholinophenyl) 3— (3— ((Z)-(3—oxo3, 4-dihydro -2H-benzo [b] [1, 4] oxazine 2 ylidene) methyl) phenyl) acrylamide, • (Ε) -Ν- (4-cyclohexylphenyl) 3— (5— ((Ζ)-(3— Oxo 3, 4-dihydro-2Η-benzo [b] [1, 4] oxazine 2-ylidene) methinore) thiophene 2-yl) acrylamide, and

• 2— ((Z) —3 oxo 2— ((5— ((E) —3 oxo 3— (pyridine 1 3-methylmethylamino) propylene 1-thiophene 2-yl) methylene) 2H-benzo [b ] [

1,4] oxazine 4 (3H) -yl) acetic acid

Or a salt thereof selected from

[6] A pharmaceutical composition comprising the compound according to any one of claims 5 to 5 or a salt thereof.

[7] A therapeutic agent for a disease associated with angiogenesis, comprising the compound according to any one of claims 1 to 5 or a salt thereof.

[8] 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 The therapeutic agent according to claim 7, which is arteriosclerosis.

[9] A method for treating a disease associated with angiogenesis, comprising administering to a patient a therapeutically effective amount of the compound or salt thereof according to any one of claims 1 to 5.

[10] 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 The treatment method according to claim 9, which is arteriosclerosis.