KR20230116511A - Benzoxazinone Derivative and Pharmaceutical Composition Comprising the Same - Google Patents

Abstract

The present invention relates to a benzoxazinone derivative having excellent activity of inhibiting PGE ₂ production through inhibition of microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) and a pharmaceutical composition containing the same as an active ingredient. The benzoxazinone derivatives of the present invention can be effectively used for the treatment or prevention of brain diseases such as inflammation, arthritis, high fever, pain, cancer, stroke or Alzheimer's disease.

Description

Benzoxazinone Derivative and Pharmaceutical Composition Comprising the Same}

The present invention relates to a benzoxazinone derivative and a pharmaceutical composition containing the same, and more specifically, to a microsomal prostaglandin E ₂ synthase-1 (microsomal prostaglandin E synthase-1: mPGES-1) inhibition through inhibition It relates to a benzoxazinone derivative that blocks the production of PGE ₂ and a pharmaceutical composition containing the same as an active ingredient.

Prostanoids are endocrine substances involved in various physiological actions, and one of them, prostaglandin E ₂ : PGE ₂ , is known _to be involved in inflammation.

As a treatment for such inflammation, a COX-2 inhibitor that selectively inhibits only the cyclooxygenase-2 (COX-2) enzyme has been developed. Representative COX-2 inhibitors include Pfizer's Celecox celecoxib (Celebrex ^™ ), G. d. and valdecoxib (Bextra ^™ ) from GD Searle & Company and rofecoxib (Vioxx ^™ ) from Merck. They have been used extensively for arthritis, severe pain and rheumatism.

However, COX-2 inhibitors have been withdrawn from the pharmaceutical market, except for celecoxib, due to cardiovascular side effects, despite reducing gastrointestinal disorder, which is the biggest side effect of non-steroidal anti-inflammatory drugs (NSAIDs). It has been reported that these cardiovascular side effects occur because production of PGH ₂ (prostaglandin H ₂ ), an intermediate, is inhibited, thereby inhibiting not only PGE ₂ but also PGI ₂ (prostacyclin) and TXA ₂ (thromboxane) production.

Therefore, an inhibitor that selectively inhibits microsomal prostaglandin _E synthase-1 (mPGES-1) involved in the production of PGE ₂ by acting on the terminal stage of PGH ₂ is a COX-2 inhibitor. Recognized as a new drug candidate that complements the disadvantages while taking advantage of the advantages, studies targeting mPGES-1 are in progress.

In particular, mPGES-1 inhibition has been proven to be as effective as treatment with NSAIDs in pain and inflammation animal model studies, and is effective in treating inflammation, arthritis, high fever, pain, cancer, stroke, and brain diseases such as Alzheimer's disease. It is expected that there will be

As an inhibitor of mPGES-1, for example, pyridopyrimidine derivatives of the following formula (I) have been proposed (Bioorgnic & Medicinal Chemistry Letters, 2014, 24, 4838-4844).

[Formula I]

However, there is a need to develop mPGES-1 inhibitors with new structures that are more effective and have no side effects.

(Bioorgnic & Medicinal Chemistry Letters, 2014, 24, 4838~4844)

One object of the present invention is to provide a benzoxazinone derivative of Formula II or a pharmaceutically acceptable salt thereof that strongly inhibits the production of PGE ₂ .

Another object of the present invention is to provide a pharmaceutical composition for inhibiting mPGES-1 containing a benzoxazinone derivative of Formula II or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention relates to a benzoxazinone derivative of Formula II below or a pharmaceutically acceptable salt thereof.

[Formula II]

In the above formula,

R ¹ is an aryl group or a C ₃ -C ₁₀ cycloalkyl group;

L is absent or is a C ₁ -C ₆ alkylene group,

R ² is an isopropylcarbonyl group, a methylcarbonyl group or a methylsulfonyl group.

Aryl groups as used herein include both aromatic groups, heteroaromatic groups, and partially reduced derivatives thereof. The aromatic group is a 5- to 15-membered simple or fused ring, and the heteroaromatic group refers to an aromatic group containing at least one oxygen, sulfur, or nitrogen. Representative examples of aryl groups include phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, oxazolyl, thiazolyl, tetrahydronaphthyl, etc., but are not limited thereto.

As used herein, the C ₃ -C ₁₀ cycloalkyl group refers to a simple or fused cyclic hydrocarbon having 3 to 10 carbon atoms, and examples thereof include, but are limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. it is not going to be

As used herein, the C ₁ -C ₆ alkylene group refers to a straight-chain or branched divalent hydrocarbon having 1 to 6 carbon atoms, and includes, for example, methylene, ethylene, propylene, butylene, etc., but is limited thereto. it is not going to be

In one embodiment of the present invention, the benzoxazinone derivative R ¹ is halogen, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ haloalkoxy group, C ₁ -C _{A 6} -membered alkoxycarbonyl group, a carboxy group, a carboxylate group, a C ₃ -C ₁₀ cycloalkyl group and an aryl group unsubstituted or substituted with one or more substituents selected from the group consisting of an aryl group or a C ₃ -C ₁₀ cycloalkyl group. it is a compound

In this case, the C ₃ -C ₁₀ cycloalkyl group and aryl group, which are substituents of the aryl group or C ₃ -C ₁₀ cycloalkyl group, may or may not be substituted with a halogen or C ₁ -C ₆ alkoxy group.

As used herein, the C ₁ -C ₆ alkyl group refers to a straight-chain or branched monovalent hydrocarbon having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, i-propyl, and n-butyl. , i-butyl, t-butyl, n-pentyl, n-hexyl, and the like, but are not limited thereto.

As used herein, the C ₁ -C ₆ haloalkyl group refers to a straight-chain or branched hydrocarbon having 1 to 6 carbon atoms substituted with one or more halogens selected from the group consisting of fluorine, chlorine, bromine and iodine, for example trifluoromethyl, trichloromethyl, trifluoroethyl, and the like, but are not limited thereto.

As used herein, the C ₁ -C ₆ haloalkoxy group refers to a straight-chain or branched alkoxy group composed of 1 to 6 carbon atoms substituted with one or more halogens selected from the group consisting of fluorine, chlorine, bromine and iodine, and Oromethoxy, trichloromethoxy, trifluoroethoxy and the like are included, but are not limited thereto.

As used herein, the C ₁ -C ₆ alkoxycarbonyl group represents a group of the formula -C(=O)R (wherein R is a C ₁ -C ₆ alkoxy group), methoxycarbonyl group, ethoxycarbonyl group Nyl groups and the like are included, but are not limited thereto.

A carboxy group as used herein refers to a group of the formula -COOH.

As used herein, a carboxylate group represents a group of the formula ^-COO- . The carboxylate group may form a salt with a cation such as Na ⁺ .

The C ₁ -C ₆ alkoxy group used herein refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and includes, but is not limited to, methoxy, ethoxy, n-propanoxy, and the like.

In one embodiment of the present invention, the benzoxazinone derivative is selected from the group consisting of R ¹ is fluoro, chloro, bromo, methyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, carboxy, sodium carboxyl with one or more substituents selected from the group consisting of cyclohexyl, monofluorophenyl, difluorophenyl, trifluoromethylphenyl, methoxyphenyl, monochlorophenyl, pyridinyl, fluoropyridinyl and methoxypyridinyl; substituted or unsubstituted phenyl, tetrahydronaphthyl, cyclopropyl or cyclohexyl.

In one embodiment of the present invention, the benzoxazinone derivative is a compound in which L does not exist or is methylene.

In one embodiment of the present invention, the benzoxazinone derivative is a compound wherein R ² is an isopropylcarbonyl group.

In one embodiment of the present invention, the benzoxazinone derivative,

R ¹ is fluoro, chloro, bromo, methyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, carboxy, carboxylate, cyclohexyl, monofluorophenyl, difluorophenyl , phenyl optionally substituted with one or more substituents selected from the group consisting of trifluoromethylphenyl, methoxyphenyl, monochlorophenyl, pyridinyl, fluoropyridinyl and methoxypyridinyl, tetrahydronaphthyl, cyclopropyl or cyclohexyl;

L is absent or methylene;

R ² is an isopropylcarbonyl group.

In one embodiment of the present invention, the benzoxazinone derivative,

R ¹ is a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl group and C ₁ -C ₆ haloalkyl group;

L is absent or methylene;

R ² is an isopropylcarbonyl group.

In one embodiment of the present invention, the benzoxazinone derivative,

R ¹ is a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and C ₁ -C ₆ haloalkyl groups;

L does not exist,

R ² is an isopropylcarbonyl group.

In the present specification, pharmaceutically acceptable salts include both non-toxic inorganic salts and organic salts, and may be acid addition salts or base addition salts. Acid addition salts include, for example, hydrochloride, sulfate, nitrate, phosphate, acetate, adipate, aspartate, benzoate, benzenesulfonate, citrate, camphorate, camphorsulfonate, and diphosphate. salts, ethanesulfonates, fumarates, glutamates, malates, lactates, methanesulfonates, succinates, tartrates, picrates, tosylates and the like. Base addition salts include, for example, alkali metal or alkaline earth metal salts such as lithium, sodium, potassium, magnesium and calcium, ammonium salts, quaternary ammonium salts such as tetramethylammonium and methylamine, dimethylamine, trimethylamine, triethyl amines and amine salts such as ethylamine; and the like.

Representative compounds among the compounds of the present invention are selected from the following groups.

2-chloro-N-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 1);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 2);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 3);

2-Chloro-N-(3-(3-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 4);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 5);

2-chloro-N-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 6);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 7);

2-Chloro-N-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(isobutyramidomethyl)benzamide (Compound 8);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(2-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 9);

2-chloro-N-(3-(3-fluoro-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 10);

2-chloro-N-(3-(2-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 11);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(o-tolyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine- 6-yl)benzamide (Compound 12);

2-chloro-N-(3-(3-chlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 13);

2-chloro-N-(3-(3-chloro-5-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 14);

N-(3-(4-Bromophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro-5-( isobutyramidomethyl)benzamide (Compound 15);

N-(3-(4-(tert-butyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro- 5-(isobutyramidomethyl)benzamide (Compound 16);

2-chloro-N-(3-(4-chlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 17);

2-chloro-N-(3-(4-fluoro-2-(trifluoromethoxy)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 18);

2-chloro-N-(3-(4-fluoro-2-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 19);

2-chloro-N-(3-(3-chloro-4-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 20);

2-Chloro-N-(3-(2,6-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(isobutyramidomethyl)benzamide (Compound 21);

N-(3-(2-Bromophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro-5-( isobutyramidomethyl)benzamide (Compound 22);

2-chloro-N-(3-(2-chlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 23);

2-Chloro-N-(3-(3,5-dichlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 24);

2-Chloro-N-(3-(2,4-dichlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 25);

2-Chloro-N-(3-(4-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 26);

2-chloro-N-(3-(4-chloro-2-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 27);

2-chloro-N-(3-(2-chloro-4-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 28);

N-(3-(4-bromo-2-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2- chloro-5-(isobutyramidomethyl)benzamide (Compound 29);

N-(3-(4-bromo-3-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2- chloro-5-(isobutyramidomethyl)benzamide (Compound 30);

2-Chloro-N-(3-(2,4-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(isobutyramidomethyl)benzamide (Compound 31);

2-chloro-N-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 32);

Methyl 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl) Benzoate (Compound 33);

Methyl 3-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl) Benzoate (Compound 34);

4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoic acid (Compound 35);

3-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoic acid (Compound 36);

Sodium 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl) Benzoate (Compound 37);

5-(acetamidomethyl)-2-chloro-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1, 3]oxazin-6-yl)benzamide (Compound 38);

2-Chloro-5-(methylsulfonamidomethyl)-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 39);

2-Chloro-5-(methylsulfonamidomethyl)-N-(4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 40);

2-Chloro-N-(3-(3,4-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(isobutyramidomethyl)benzamide (Compound 41);

2-chloro-N-(3-(4-chloro-3-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 42);

2-chloro-N-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 43);

2-Chloro-N-(3-(cyclohexylmethyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobutyr amidomethyl)benzamide (Compound 44);

2-Chloro-N-(3-cyclopropyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl )benzamide (compound 45);

2-Chloro-N-(3-(3',5'-difluoro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[ e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 46);

2-Chloro-N-(3-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 47);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3 ,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)benzamide (Compound 48);

2-Chloro-N-(3-(3'-fluoro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 49);

2-Chloro-5-(isobutyramidomethyl)-N-(3-(4'-methoxy-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-di hydro-2H-benzo[e][1,3]oxazin-6-yl)benzamide (Compound 50);

2-Chloro-N-(3-(4'-chloro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[e][1, 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 51);

2-Chloro-N-(3-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[ e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 52);

2-chloro-N-(3-(4-(6-fluoropyridin-3-yl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 53);

2-Chloro-5-(isobutyramidomethyl)-N-(3-(4-(6-methoxypyridin-3-yl)phenyl)-4-oxo-3,4-dihydro-2H-benzo [e][1,3]oxazin-6-yl)benzamide (Compound 54);

2-chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(pyridin-4-yl)phenyl)-3,4-dihydro-2H-benzo[e][ 1,3]oxazin-6-yl)benzamide (Compound 55);

2-Chloro-N-(3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 56);

2-Chloro-N-(3-(4-chloro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5 -(isobutyramidomethyl)benzamide (Compound 57);

2-chloro-N-(3-(4-chloro-3-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 58);

2-Chloro-N-(3-(3-chloro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 59);

2-Chloro-N-(3-(3,4-dichlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 60);

2-Chloro-N-(3-(3,4-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(isobutyramidomethyl)benzamide (Compound 61);

2-Chloro-N-(3-(4-cyclohexylphenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 62);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(5,6,7,8-tetrahydronaphthalen-1-yl)-3,4-dihydro-2H- benzo[e][1,3]oxazin-6-yl)benzamide (Compound 63);

2-Chloro-N-(3-(2-chlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 64);

2-Chloro-N-(3-(3-chlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 65);

2-Chloro-N-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 66);

2-Chloro-N-(3-(2-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 67);

2-Chloro-N-(3-(3-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 68);

2-Chloro-N-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 69);

2-Chloro-N-(3-(4-chloro-3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 70);

2-chloro-N-(3-(3-chloro-4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 71);

2-chloro-N-(3-(2-chloro-6-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(Isobutyramidomethyl)benzamide (Compound 72);

2-Chloro-N-(3-(2,3-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 73);

2-Chloro-N-(3-(2,4-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 74);

2-Chloro-N-(3-(2,6-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 75);

2-Chloro-N-(3-(2,5-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 76);

2-Chloro-N-(3-(2,6-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 77);

2-Chloro-N-(3-(2,4-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 78);

2-chloro-N-(3-(4-fluoro-3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 79);

2-chloro-N-(3-(2-fluoro-4-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 80);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 81);

2-Chloro-N-(3-(3,4-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 82);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 83);

2-Chloro-N-(3-(2,3-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 84);

2-Chloro-N-(3-(3,5-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 85);

N-(3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2- chloro-5-(isobutyramidomethyl)benzamide (Compound 86);

N-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro- 5-(Isobutyramidomethyl)benzamide (Compound 87);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 88);

2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 89);

N-(3-(3-Bromobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro-5-( isobutyramidomethyl)benzamide (Compound 90);

N-(3-(4-bromobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro-5-( isobutyramidomethyl)benzamide (Compound 91);

2-chloro-N-(3-(2-chloro-5-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(Isobutyramidomethyl)benzamide (Compound 92); and

2-Chloro-N-(3-(2-chloro-3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 93).

A method for preparing the benzoxazinone derivative of Formula II of the present invention is shown in Reaction Scheme 1 below. The method described in the reaction scheme below is merely an example of a method typically used, and the reaction reagents, reaction conditions, etc. may be changed as needed.

[Scheme 1]

In Reaction Scheme 1, R ¹ , L and R ² are as defined in Formula II above.

As shown in Reaction Scheme 1, the benzoxazinone derivative of Formula II is obtained by an amide coupling reaction of a compound of Formula III with a compound of Formula IV to obtain a compound of Formula V, and the compound of Formula V is reacted with formaldehyde under an acid catalyst. to obtain a compound of formula VI having a benzoxazinone skeleton, and then reducing the nitro group of the compound of formula VI to obtain a compound of formula VII having an amine group, and then preparing the compound of formula VII and the compound of formula VIII It can be prepared by an amide coupling reaction.

At this time, the amide coupling reaction may be carried out using a conventional amide coupling agent, for example, by adding triphenylphosphite and reacting, or by adding hydroxybenzotriazole (HOBT) and 4-dimethylaminopyridine (DMAP). After reaction, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and optionally triethylamine (TEA) are added to react, or hexafluorophosphate azabenzotriazole tetra It can be carried out by adding methyluronium (HATU) and N,N -diisopropylethylamine (DIPEA) to react.

In addition, toluenesulfonic acid or the like may be used as an acid catalyst used in the reaction of the compound of Formula V with formaldehyde.

In addition, the reduction reaction of the nitro group may be performed by hydrogenation under a Pd/C catalyst.

The compound of Formula II or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent PGE ₂ production inhibitory activity through inhibition of microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) (see Test Example 1). .

Accordingly, the present invention provides a pharmaceutical composition for inhibiting microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) comprising the compound of Formula II or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, specifically It relates to a pharmaceutical composition for the treatment or prevention of brain diseases such as inflammation, arthritis, high fever, pain, cancer, stroke or Alzheimer's disease.

The pharmaceutical composition according to the present invention can be administered orally (eg, ingested or inhaled) or parenterally (eg, injection, deposition, implantation, suppository), and injection is, for example, intravenous , subcutaneous injection, intramuscular injection, or intraperitoneal injection. Depending on the route of administration, the pharmaceutical composition according to the present invention may be formulated into tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, sprays, etc. can be formulated. The above various types of pharmaceutical compositions according to the present invention can be prepared by known techniques using pharmaceutically acceptable carriers commonly used in each formulation. Examples of pharmaceutically acceptable carriers are excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweetening agents, solubilizing agents, bases, dispersing agents, wetting agents. , suspending agents, stabilizers, colorants and the like.

The pharmaceutical composition according to the present invention includes about 0.01 to 95% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof, depending on the type of drug.

The specific dosage of the pharmaceutical composition of the present invention may vary depending on the type, weight, sex, degree of disease, judgment of a doctor, etc. of mammals including humans to be treated. Preferably, in the case of oral administration, 0.01 to 50 mg of the active ingredient per 1 kg of body weight is administered per day, and in the case of parenteral administration, 0.01 to 10 mg of the active ingredient per 1 kg of body weight is administered per day. The total daily dose may be administered at one time or divided into several times depending on the severity of the disease, the doctor's judgment, and the like.

The compound of the present invention exhibits excellent PGE ₂ production inhibitory activity through inhibition of microsomal prostaglandin E ₂ synthetase-1 (mPGES-1). Therefore, the compounds of the present invention can be effectively used in pharmaceutical compositions for the treatment or prevention of brain diseases such as inflammation, arthritis, high fever, pain, cancer, stroke or Alzheimer's disease.

1 is a graph showing the evaluation results of the blood inflammatory factor PGE ₂ performed in an osteoarthritis animal model for Compound 1 of the present invention.
Figure 2 is a graph showing the results of evaluation of the blood inflammatory factor IL-1β performed in an osteoarthritis animal model with respect to Compound 1 of the present invention.
Figure 3 is a graph showing the evaluation results of the blood inflammatory factor TNF-α performed in an osteoarthritis animal model with respect to Compound 1 of the present invention.
Figure 4 is a graph showing the results of evaluation of the anti-pain efficacy performed in a pain animal model for Compound 1 of the present invention.

Hereinafter, the present invention will be described in more detail by examples. These examples are only for explaining the present invention, it is apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1: 2-chloro-N-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1, Synthesis of 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 1)

Example 1-1: Synthesis of N-(3-fluoro-4-(trifluoromethyl)phenyl)-2-hydroxy-5-nitrobenzamide

Add 5-nitrosalicylic acid (2.0g, 10.921mmol), 3-fluoro-4-(trifluoromethyl)aniline (1.51ml, 14.198mmol) and triphenylphosphite (3.93ml, 14.963mmol) to a 50mL flask. , suspended in toluene (33 mL), cooled under reflux, and the mixture was stirred for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered under reduced pressure. The obtained filtrate was washed with dichloromethane and dried in vacuum to obtain N-(3-fluoro-4-(trifluoromethyl)phenyl)-2-hydroxy-5-nitrobenzamide (2.7 g, 90.9%) as crystals. ) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 8.21-8.17 (m, 1H), 7.88-7.84 (m, 1H), 7.61 (s, 1H), 5.03-4.93 (m , 2H), 4.86–4.70 (m, 2H), 4.40–4.32 (m, 2H), 1.38–1.32 (m, 3H).

Example 1-2: 3-(3-fluoro-4-(trifluoromethyl)phenyl)-6-nitro-2,3-dihydro-4H-benzo[e][1,3]oxazine- Synthesis of 4-ones

N-(3-fluoro-4-(trifluoromethyl)phenyl)-2-hydroxy-5-nitrobenzamide (2.335 g, 8.576 mmol), p-formaldehyde (5.666 g, 188.68 mmol) and p -Toluenesulfonic acid monohydrate (0.489g, 2.573mmol) was suspended in toluene (100mL), cooled under reflux, and the mixture was stirred for 24 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate and distilled water. The organic layer was dried over MgSO ₄ and then concentrated under reduced pressure to remove the solvent. 3-(3-fluoro-4-(trifluoromethyl)phenyl)-6-nitro-2,3-dihydro-4H-benzo[e][1, 3]oxazin-4-one (1.925 g, 79.0%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.32-7.29 (m, 1H), 7.01 (s, 1H), 6.78-6.73 (m, 2H), 4.81-4.79 (br, NH, 2H), 4.75 -4.71 (m, 3H), 4.61-4.57 (m, 2H), 4.32-4.24 (m, 2H), 1.33-1.28 (m, 3H).

Example 1-3: 6-amino-3-(3-fluoro-4-(trifluoromethyl)phenyl)-2,3-dihydro-4H-benzo[e][1,3]oxazine- Synthesis of 4-ones

3-(3-fluoro-4-(trifluoromethyl)phenyl)-6-nitro-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (1.924 g , 6.768 mmol), Pd/C (200 mg) was suspended in ethanol (200 ml) and the mixture was stirred at room temperature for 12 hours under hydrogen. After completion of the reaction, Pd/C was filtered using celite, and the organic layer was concentrated under reduced pressure to obtain 6-amino-3-(3-fluoro-4-(trifluoromethyl)phenyl)-2,3-dihydro-4H - Benzo[e][1,3]oxazin-4-one (1.925 g, 79.0%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.48 (br, NH, 1H), 8.40-8.36 (m, NH, 1H), 8.19 (s, 1H), 7.63-7.59 (m, 1H), 7.54 -7.49 (m, 2H), 7.43 (s, 1H), 7.37-7.32 (m, 2H), 4.93 (m, 1H), 4.85-4.80 (m, 2H), 4.65 (m, 1H), 4.37-4.28 (m, 4H), 2.51–2.38 (m, 1H), 1.36–1.31 (m, 3H), 1.05–1.02 (m, 6H).

Example 1-4: 2-chloro-N-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][ Synthesis of 1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide

To a 10 mL flask, add 6-amino-3-(3-fluoro-4-(trifluoromethyl)phenyl)-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (211mg, 0.829mmol) and 2-chloro-5-(isobutyramidomethyl)benzoic acid (177mg, 0.691mmol) were added, suspended in CH ₂ Cl ₂ (4.61ml), and HOBT (140mg, 1.037 mmol) and DMAP (25mg, 0.207mmol) were added and stirred. Subsequently, EDCI (199mg, 1.037mmol) was added at room temperature, stirred for 10 minutes, and Et ₃ N (0.29ml, 2.074mmol) was slowly added dropwise and stirred at room temperature. After completion of the reaction, the organic matter was extracted with ethyl acetate and H ₂ O. The organic layer was dried over MgSO ₄ and then concentrated under reduced pressure to remove the solvent. The residue was prepared by recrystallization or column chromatography to obtain 2-chloro-N-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H- Benzo[e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (170mg, 50.0%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (1H, s), 8.36 (2H, m), 7.88 (2H, m), 7.66 (1H, d, J = 13.2 Hz), 7.49 (3H, m ), 7.36 (1H, d, J = 9.0 Hz), 7.20 (1H, d, J = 9.0 Hz), 5.79 (2H, s), 4.29 (2H, d, J = 5.7 Hz), 2.42 (1H, m ), 1.03 (6H, m).

Example 2: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)benzamide (Compound 2)

The target compound was prepared in the same manner as in Example 1, except that 4-(trifluoromethyl)aniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got it

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.68 (s, 1H), 8.17-8.12 (m, 2H), 7.72-7.69 (m, 2H), 7.52-7.49 (m, 3H), 7.40-7.34 (m, 3H), 7.09-7.06 (m, 1H), 6.94-6.93 (m, 1H), 5.60 (s, 2H), 4.43-4.41 (m, 2H), 2.59-2.58 (m, 1H), 1.18-1.15 ( m, 6H)

Example 3: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)benzamide (Compound 3)

The target compound was prepared in the same manner as in Example 1, except that 3-(trifluoromethyl)aniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.95 (s, 1H), 8.37-8.35 (m, 1H), 7.90-7.87 (m, 1H), 7.79 (s, 1H), 7.68-7.63 (m, 4H), 7.55-7.52 (m, 1H), 7.47-7.45 (m, 2H), 7.39-7.36 (m, 1H), 5.77 (s, 2H), 4.31-4.28 (m, 2H), 2.43-2.39 ( m, 1H), 1.04–1.02 (m, 6H).

Example 4: 2-chloro-N-(3-(3-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 4)

A target compound was obtained in the same manner as in Example 1, except that 3-fluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.37-8.32 (m, 2H), 7.86-7.83 (m, 1H), 7.53-7.48 (m, 2H), 7.44 (s, 1H), 7.37-7.25 (m, 3H), 7.19-7.16 (m, 2H), 5.71 (s, 2H), 4.30-4.28 (m, 2H), 2.41-2.38 (m, 1H), 1.04-1.02 ( m, 6H).

Example 5: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)benzamide (Compound 5)

The target compound was prepared in the same manner as in Example 1, except that 3-(trifluoromethoxy)aniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 8.39-8.35 (m, 2H), 7.87-7.83 (m, 1H), 7.62-7.44 (m, 5H), 7.37-7.31 ( m, 2H), 7.19–7.16 (m, 1H), 5.73 (s, 2H), 4.30–4.28 (m, 2H), 2.48–2.41 (m, 1H), 1.04–1.02 (m, 6H).

Example 6: 2-chloro-N-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1, Synthesis of 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 6)

Except for using 4-fluoro-3-(trifluoromethyl)aniline instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, in the same manner as in Example 1. carried out to obtain the target compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (m, 1H, NH), 8.34-8.32 (m, 2H), 7.86-7.78 (m, 3H), 7.66-7.59 (m, 1H), 7.53- 7.50 (m, 1H), 7.43 (m, 1H), 7.36-7.34 (m, 1H), 7.19-7.16 (m, 1H), 5.72 (m, 2H), 4.30-4.28 (m, 2H), 2.43- 2.38 (m, 2H), 1.04-1.02 (m, 6H).

Example 7: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)benzamide (Compound 7)

The target compound was prepared in the same manner as in Example 1, except that 4-(trifluoromethoxy)aniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (m, 1H, NH), 8.35-8.32 (m, 2H), 7.87-7.83 (m, 1H), 7.55-7.44 (m, 6H), 7.36- 7.34 (m, 1H), 7.18–7.16 (m, 1H), 5.70 (m, 2H), 4.30–4.28 (m, 2H), 2.43–2.38 (m, 2H), 1.04–1.02 (m, 6H).

Example 8: 2-Chloro-N-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 8)

A target compound was obtained in the same manner as in Example 1, except that 3,5-difluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.10 (2H, m), 7.99 (1H, s), 7.68 (1H, s), 7.39 (2H, m), 7.12 (1H, d, J = 8.7Hz ), 6.95 (1H, d, J = 6.6 Hz), 6.76 (1H, m), 5.86 (1H, m), 5.55 (2H, s), 4.46 (2H, d, J = 6.3 Hz), 2.41 (1H , m), 1.19 (6H, m).

Example 9: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(2-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)benzamide (Compound 9)

The target compound was prepared in the same manner as in Example 1, except that 2-(trifluoromethoxy)aniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (1H, s), 8.33 (2H, m), 7.83 (1H, m), 7.47 (7H, m), 7.19 (1H, d, J = 9.0 Hz ), 5.58 (2H, s), 4.29 (2H, d, J = 5.4 Hz), 2.42 (1H, m), 1.04 (6H, m).

Example 10: 2-chloro-N-(3-(3-fluoro-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1, Synthesis of 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 10)

Except for using 3-fluoro-5-(trifluoromethyl)aniline instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, in the same manner as in Example 1. carried out to obtain the target compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (1H, s), 8.36 (2H, m), 7.87 (1H, m), 7.68 (3H, m), 7.52 (1H, d, J = 8.1 Hz ), 7.44 (1H, s), 7.36 (1H, d, J = 8.4 Hz), 7.20 (1H, d, J = 8.7 Hz), 5.78 (2H, s), 4.30 (2H, d, J = 6.0 Hz) ), 2.42 (1H, m), 1.03 (6H, m).

Example 11: 2-chloro-N-(3-(2-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 11)

A target compound was obtained in the same manner as in Example 1, except that 2-fluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (1H, s), 8.34 (2H, m), 7.86 (1H, m), 7.42 (7H, m), 7.19 (1H, m), 5.62 (2H , s), 4.29 (2H, m), 2.28 (1H, m), 1.04 (6H, m).

Example 12: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(o-tolyl)-3,4-dihydro-2H-benzo[e][1,3 Synthesis of ]oxazin-6-yl)benzamide (Compound 12)

A target compound was obtained in the same manner as in Example 1, except that o-toluidine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (1H, s), 8.34 (2H, m), 7.83 (1H, d, J = 8.7 Hz), 7.35 (8H, m), 5.54 (2H, m) ), 4.29 (2H, d, J = 5.4 Hz), 2.42 (1H, m), 2.21 (3H, s), 1.03 (6H, m).

Example 13: 2-Chloro-N-(3-(3-chlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- Synthesis of 5-(isobutyramidomethyl)benzamide (Compound 13)

A target compound was obtained in the same manner as in Example 1, except that 3-chloroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (1H, s), 8.35 (2H, m), 7.86 (1H, m), 7.44 (7H, m), 7.18 (1H, d, J = 8.7Hz ), 5.7 (2H, s), 4.30 (2H, d, J = 6.0 Hz), 2.42 (1H, m), 1.03 (6H, m).

Example 14: 2-Chloro-N-(3-(3-chloro-5-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- Synthesis of 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 14)

The target compound was prepared in the same manner as in Example 1, except that 3-chloro-5-fluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (1H, s), 8.33 (2H, m), 7.44 (6H, m), 7.19 (1H, d, J = 9.0 Hz), 5.72 (2H, s ), 4.29 (2H, d, J = 6.0 Hz), 2.44 (1H, m), 1.03 (6H, m).

Example 15: N-(3-(4-bromophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 15)

A target compound was obtained in the same manner as in Example 1, except that 4-bromoaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (1H, s), 8.34 (2H, m), 7.84 (1H, m), 7.65 (2H, d, J = 8.7 Hz), 7.44 (5H, m ), 7.17 (1H, d, J = 8.7 Hz), 5.68 (2H, s), 4.29 (2H, d, J = 6.0 Hz), 2.43 (1H, m), 1.03 (6H, m).

Example 16: N-(3-(4-(tert-butyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- Synthesis of 2-chloro-5-(isobutyramidomethyl)benzamide (Compound 16)

A target compound was obtained in the same manner as in Example 1, except that 4-(tert-butyl)aniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (1H, s), 8.36 (2H, m), 7.84 (1H, m), 7.44 (2H, d, J = 8.7Hz), 7.17 (1H, d , J = 8.7 Hz), 5.68 (2H, s), 4.29 (2H, d, J = 6.0 Hz), 2.42 (1H, m), 1.03 (6H, m).

Example 17: 2-Chloro-N-(3-(4-chlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- Synthesis of 5-(isobutyramidomethyl)benzamide (Compound 17)

A target compound was obtained in the same manner as in Example 1, except that 4-chloroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (1H, s), 8.36 (2H, m), 7.84 (1H, m), 7.44 (2H, d, J = 8.7Hz), 7.17 (1H, d , J = 8.7 Hz), 5.68 (2H, s), 4.29 (2H, d, J = 6.0 Hz), 2.42 (1H, m), 1.03 (6H, m).

Example 18: 2-chloro-N-(3-(4-fluoro-2-(trifluoromethoxy)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1, Synthesis of 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 18)

Except for using 4-fluoro-2-(trifluoromethoxy)aniline instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, in the same manner as in Example 1. carried out to obtain the target compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.14 (s, 2H), 7.96 (s, 1H), 7.67 (s, 1H), 7.33-7.48 (m, 3H), 7.23-7.29 (m, 8H), 7.10-7.13 (m, 3H), 5.89 (s, 1H), 5.42 (s, 1H), 4.44-4.46 (d, 2H, J = 6.0 Hz), 2.39-2.41 (m, 1H), 1.17-1.20 (d, 6H, J = 18.0 Hz).

Example 19: 2-chloro-N-(3-(4-fluoro-2-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1, Synthesis of 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 19)

Except for using 4-fluoro-2-(trifluoromethyl)aniline instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, in the same manner as in Example 1. carried out to obtain the target compound.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.09-8.20 (m, 1H), 7.95-7.94 (d, 1H, J = 3.0 Hz), 7.64 (s, 1H), 7.32-7.51 (m, 4H), 7.09-7.12 (d, 1H, J = 9.0 Hz), 5.94 (s, 1H), 5.38 (s, 2H), 4.43-4.45 (d, 2H, J = 6.0 Hz), 2.38-2.42 (m, 1H) , 1.16–1.19 (d, 6H, J = 9.0 Hz).

Example 20: 2-Chloro-N-(3-(3-chloro-4-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- Synthesis of 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 20)

The target compound was prepared in the same manner as in Example 1, except that 3-chloro-4-fluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got it

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.10-8.14 (m, 2H), 7.95 (s, 1H), 7.66 (s, 1H), 7.35-7.45 (m, 3H), 7.21-7.29 (m, 8H) ), 7.09–7.12 (d, 1H, J = 9.0 Hz), 5.89 (s, 1H), 5.51 (s, 2H), 4.44–4.46 (d, 2H, J = 6.0 Hz), 2.39–2.43 (m, 1H), 1.17–1.20 (d, 6H, J = 9.0 Hz).

Example 21: 2-chloro-N-(3-(2,6-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 21)

A target compound was obtained in the same manner as in Example 1, except that 2,6-difluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. .

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.12-8.15 (m, 2H), 7.96-7.97 (m, 1H), 7.67 (s, 1H), 7.31-7.43 (m, 4H), 7.01-7.13 (m , 3H), 5.88 (s, 1H), 5.47 (s, 2H), 4.44–4.46 (d, 2H, J = 6.0 Hz), 2.38–2.45 (m, 1H), 1.17–1.20 (d, 6H, J = 9.0 Hz).

Example 22: N-(3-(2-bromophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 22)

A target compound was obtained in the same manner as in Example 1, except that 2-bromoaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (1H, s), 8.34 (2H, m), 7.83 (1H, m), 7.45 (7H, m), 7.18 (1H, d, J = 8.7Hz ), 5.63 (1H, m), 5.48 (1H, m), 4.30 (2H, m), 2.43 (1H, m), 1.04 (6H, m).

Example 23: 2-Chloro-N-(3-(2-chlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- Synthesis of 5-(isobutyramidomethyl)benzamide (Compound 23)

A target compound was obtained in the same manner as in Example 1, except that 2-chloroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (1H, s), 8.35 (2H, m), 7.87 (1H, m), 7.51 (7H, m), 7.20 (1H, m), 5.58 (2H , m), 4.31 (2H, m), 2.50 (1H, m), 1.04 (6H, m).

Example 24: 2-chloro-N-(3-(3,5-dichlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl Synthesis of )-5-(isobutyramidomethyl)benzamide (Compound 24)

A target compound was obtained in the same manner as in Example 1, except that 3,5-dichloroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (m, 1H, NH), 8.35-8.30 (m, 2H), 7.85-7.83 (m, 1H), 7.54-7.49 (m, 4H), 7.42 ( m, 1H), 7.35-7.32 (m, 1H), 7.17-7.14 (m, 1H), 5.73-5.69 (m, 2H), 4.28-4.26 (m, 2H), 2.48-2.38 (m, 1H), 1.02-1.00 (m, 6H).

Example 25: 2-chloro-N-(3-(2,4-dichlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl Synthesis of )-5-(isobutyramidomethyl)benzamide (Compound 25)

A target compound was obtained in the same manner as in Example 1, except that 2,4-dichloroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (m, 1H, NH), 8.35 (m, 1H, NH), 8.28 (m, 1H), 7.82 (m, 2H), 7.55-7.48 (m, 3H), 7.41 (m, 1H), 7.34-7.32 (m, 1H), 7.17-7.15 (m, 1H), 5.60-5.48 (m, 2H), 4.28-4.26 (m, 2H), 2.43-2.38 ( m, 1H), 1.02–0.99 (m, 6H).

Example 26: 2-chloro-N-(3-(4-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 26)

A target compound was obtained in the same manner as in Example 1, except that 4-fluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (1H, s), 8.33 (2H, m), 7.83 (1H, d, J = 6.9 Hz), 7.50 (4H, m), 7.32 (3H, m) ), 7.16 (1H, m), 5.65 (2H, s), 4.30 (2H, d, J = 5.7 Hz), 2.42 (1H, m), 1.03 (6H, m).

Example 27: 2-chloro-N-(3-(4-chloro-2-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- Synthesis of 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 27)

The target compound was prepared in the same manner as in Example 1, except that 4-chloro-2-fluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (1H, s), 8.36 (2H, m), 7.85 (1H, m), 7.66 (1H, m), 7.53 (2H, m), 7.39 (3H , m), 7.19 (1H, m), 5.62 (2H, s), 4.29 (2H, d, J = 6.0 Hz), 2.42 (1H, m), 1.03 (6H, m).

Example 28: 2-Chloro-N-(3-(2-chloro-4-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- Synthesis of 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 28)

The target compound was prepared in the same manner as in Example 1, except that 2-chloro-4-fluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (1H, s), 8.33 (2H, m), 7.85 (1H, d, J = 6.9 Hz), 7.63 (2H, m), 7.45 (4H, m) ), 7.18 (1H, d, J = 9.0 Hz), 5.54 (2H, m), 4.29 (2H, d, J = 6.0 Hz), 2.42 (1H, m), 1.03 (6H, m).

Example 29: N-(3-(4-bromo-2-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl Synthesis of )-2-chloro-5-(isobutyramidomethyl)benzamide (Compound 29)

The target compound was prepared in the same manner as in Example 1, except that 4-bromo-2-fluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (1H, s), 8.33 (2H, m), 7.78 (2H, m), 7.46 (4H, m), 7.33 (1H, d, J = 7.8 Hz ), 7.16 (1H, d, J = 8.7 Hz), 5.59 (2H, s), 4.27 (2H, d, J = 5.7 Hz), 2.42 (1H, m), 1.03 (6H, m).

Example 30: N-(3-(4-bromo-3-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl Synthesis of )-2-chloro-5-(isobutyramidomethyl)benzamide (Compound 30)

The target compound was prepared in the same manner as in Example 1, except that 4-bromo-3-fluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (1H, s), 8.35 (2H, m), 7.83 (2H, m), 7.35 (6H, m), 5.71 (2H, s), 4.29 (2H , d, J = 6.0 Hz), 2.42 (1H, m), 1.03 (6H, m).

Example 31: 2-chloro-N-(3-(2,4-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 31)

A target compound was obtained in the same manner as in Example 1, except that 2,4-difluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (m, 1H, NH), 8.35 (m, 1H, NH), 8.29 (m, 1H), 7.85-7.82 (m, 1H), 7.56-7.42 ( m, 4H), 7.34-7.32 (m, 1H), 7.19-7.15 (m, 2H), 5.58 (m, 2H), 4.28-4.26 (m, 2H), 2.43-2.38 (m, 1H), 1.02- 1.00 (m, 6H).

Example 32: 2-chloro-N-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1, Synthesis of 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 32)

Except for using 2-fluoro-4-(trifluoromethyl)aniline instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, in the same manner as in Example 1. carried out to obtain the target compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (m, 1H, NH), 8.36-8.32 (m, 2H), 7.91-7.83 (m, 2H), 7.71 (m, 2H), 7.52-7.49 ( m, 1H), 7.42 (m, 1H), 7.35-7.33 (m, 1H), 7.20-7.17 (m, 1H), 5.71-5.68 (m, 2H), 4.28-4.26 (m, 2H), 2.43- 2.38 (m, 1H), 1.02–0.99 (m, 6H).

Example 33: Methyl 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H ) -yl) benzoate synthesis (Compound 33)

A target compound was obtained in the same manner as in Example 1, except that methyl 4-aminobenzoate was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (m, 1H, NH), 8.32 (m, 2H), 8.02-7.99 (m, 2H), 7.85-7.82 (m, 1H), 7.56-7.48 ( m, 3H), 7.42 (m, 1H), 7.34-7.32 (m, 1H), 7.18-7.15 (m, 1H), 5.75 (m, 2H), 4.28-4.26 (m, 2H), 3.85 (s, 3H), 2.43–2.38 (m, 1H), 1.02–0.99 (m, 6H).

Example 34: Methyl 3-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazine-3(4H ) -yl) benzoate synthesis (Compound 34)

A target compound was obtained in the same manner as in Example 1, except that methyl 3-aminobenzoate was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (m, 1H, NH), 8.37 (m, NH, 1H), 8.31 (m, 1H), 7.95 (m, 1H), 7.88-7.82 (m, 2H), 7.68-7.57 (m, 2H), 7.52-7.49 (m, 1H), 7.42 (m, 1H), 7.34-7.32 (m, 1H), 7.18-7.15 (m, 1H), 5.72 (m, 2H), 4.28–4.26 (m, 2H), 3.85 (s, 3H), 2.43–2.38 (m, 1H), 1.02–0.99 (m, 6H).

Example 35: 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H) -yl) synthesis of benzoic acid (Compound 35)

Methyl 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazine-3(4H )-yl)benzoate (250 mg, 0.466 mmol) was added, dissolved in THF (20 ml) and MeOH (20 ml), and then LiOH (98 mg, 2.33 mmol) was added to H ₂ O (15 ml). It was added after melting and stirred for 12 hours. After completion of the reaction, after concentration, pH was adjusted to 2 with 2N-HCl, and the resulting solid was filtered to obtain 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo This gave -2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoic acid (210 mg, 0.40 mmol, 86%, white solid).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.00 (m, 1H, OH), 10.67 (m, 1H, NH), 8.36-8.32 (m, 2H), 8.00-7.97 (m, 2H), 7.84- 7.82 (m, 1H), 7.52-7.49 (m, 3H), 7.42 (m, 1H), 7.35-7.32 (m, 1H), 7.18-7.15 (m, 1H), 5.74 (m, 2H), 4.28- 4.26 (m, 2H), 2.43–2.38 (m, 1H), 1.02–0.99 (m, 6H).

Example 36: 3-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H) -yl) synthesis of benzoic acid (Compound 36)

The above methyl 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl ) Benzoate instead of methyl 3-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazine-3(4H A target compound was obtained in the same manner as in Example 35, except that )-yl)benzoate was used.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.21 (m, 1H, OH), 10.67 (m, 1H, NH), 8.38 (m, NH, 1H), 8.31-8.30 (m, 1H), 7.92- 7.85 (m, 3H), 7.66-7.54 (m, 2H), 7.52-7.49 (m, 1H), 7.43 (m, 1H), 7.34-7.31 (m, 1H), 7.17-7.15 (m, 1H), 5.72 (m, 2H), 4.28–4.26 (m, 2H), 2.43–2.38 (m, 1H), 1.02–0.99 (m, 6H).

Example 37: Sodium 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazine-3(4H ) -yl) benzoate synthesis (Compound 37)

4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H) in a 10 mL flask -yl) Benzoic acid (150 mg, 0.287 mmol) was added, dissolved in MeOH (5 ml), and NaOH (12 mg, 0.302 mmol) dissolved in H ₂ O (1 ml) was added and stirred for 12 hours. did Concentrated after completion of the reaction, sodium 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3 (4H)-yl)benzoate (140 mg, 0.257 mmol, 89 %, white solid) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.71 (m, 1H, NH), 8.38 (m, NH, 1H), 8.25 (m, 1H), 7.89-7.86 (m, 2H), 7.82-7.79 ( m, 1H), 7.46-7.41 (m, 2H), 7.30-7.23 (m, 3H), 7.11-7.08 (m, 1H), 5.63 (m, 2H), 4.27-4.25 (m, 2H), 2.43- 2.38 (m, 1H), 1.02–0.99 (m, 6H).

Example 38: 5-(acetamidomethyl)-2-chloro-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e Synthesis of [1,3]oxazin-6-yl)benzamide (Compound 38)

4-(trifluoromethyl)aniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, and 2-chloro-5-(isobutyr of Example 1-4 A target compound was obtained in the same manner as in Example 1, except that 5-(acetamidomethyl)-2-chlorobenzoic acid was used instead of amidomethyl)benzoic acid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 8.12-8.09 (s, 1H), 7.99 (s, 1H), 7.71-7.65 (m, 2H), 7.50-7.47 (m, 2H) , 7.47-7.32 (m, 2H), 7.12-7.09 (m, 1H), 6.01-6.00 (m, 1H), 5.60 (s, 2H), 4.44-4.42 (m, 2H), 2.04 (s, 3H) .

Example 39: 2-chloro-5-(methylsulfonamidomethyl)-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)benzamide (Compound 39)

4-(trifluoromethyl)aniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, and 2-chloro-5-(isobutyr of Example 1-4 A target compound was obtained in the same manner as in Example 1, except that 2-chloro-5-(methylsulfonamidomethyl)benzoic acid was used instead of amidomethyl)benzoic acid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.46 (s, 1H), 8.20-8.19 (m, 1H), 8.10-8.09 (m, 1H), 7.71-7.66 (m, 3H), 7.51-7.48 (m, 2H), 7.42-7.41 (m, 2H), 7.10-7.07 (m, 1H), 6.76-6.75 (m, 1H), 5.60 (s, 2H), 4.29-4.27 (m, 2H), 2.91 (s, 3H).

Example 40: 2-chloro-5-(methylsulfonamidomethyl)-N-(4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)benzamide (Compound 40)

3-(trifluoromethyl)aniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, and 2-chloro-5-(isobutyr of Example 1-4 A target compound was obtained in the same manner as in Example 1, except that 2-chloro-5-(methylsulfonamidomethyl)benzoic acid was used instead of amidomethyl)benzoic acid.

^1H NMR (300 MHz, DMSO) δ 10.69 (s, 1H), 8.34-8.33 (m, 1H), 7.89-7.86 (m, 1H), 7.81 (s, 1H), 7.71-7.69 (m, 4H) , 7.58-7.55 (m, 2H), 7.50-7.47 (m, 1H), 7.21-7.18 (m, 1H), 5.77 (s, 2H), 4.23-4.21 (m, 2H), 2.93 (s, 3H) .

Example 41: 2-Chloro-N-(3-(3,4-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 41)

Except for using (3,4-difluorophenyl)methanamine instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, the same procedure as in Example 1 was carried out. A target compound was obtained.

^1H NMR (300 MHz, DMSO) δ 8.37-8.40 (m, 1H), 8.26-8.27 (d, 1H, J = 3.0 Hz), 7.76-7.79 (m, 1H), 7.33-7.53 (m, 5H) , 7.21 (S, 1H), 7.07–7.10 (d, 1H, J = 9.0 Hz), 5.34 (s, 2H), 4.68 (s, 2H), 4.28–4.30 (d, 2H, J = 6.0 Hz), 2.40–2.45 (m, 1H), 1.01–1.04 (d, 6H, J = 9.0 Hz).

Example 42: 2-Chloro-N-(3-(4-chloro-3-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- Synthesis of 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 42)

Example 1-1 was carried out in the same manner as in Example 1, except that (4-chloro-3-fluorophenyl)methanamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline. Thus, the target compound was obtained.

¹ H NMR (300 MHz, DMSO) δ 8.34-8.36 (m, 1H), 8.25-8.26 (m, 1H), 7.76-7.79 (m, 1H), 7.50-7.61 (m, 2H), ), 7.33- 7.42 (m, 4H), 7.20-7.23 (d, 1H, J = 9.0 Hz), 7.08-7.10 (d, 1H, J = 9.0 Hz), 5.35 (s, 2H), 4.70 (s, 2H), 4.28 −4.29 (d, 2H, J = 3.0 Hz), 2.27–2.40 (m, 1H), 1.01–1.04 (d, 6H, J = 9.0 Hz).

Example 43: 2-chloro-N-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1, Synthesis of 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 43)

Except for using (3-fluoro-5-(trifluoromethyl)phenyl)methanamine instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1, the above Example In the same manner as in 1, the target compound was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (m, 1H, NH), 8.38 (m, 1H, NH), 8.27 (m, 1H), 7.79-7.76 (m, 1H), 7.64-7.58 ( m, 2H), 7.53-7.50 (m, 2H), 7.42 (m, 1H), 7.36-7.33 (m, 1H), 7.12-7.09 (m, 1H), 5.40 (m, 2H), 4.80 (m, 2H), 4.29–4.28 (m, 2H), 2.43–2.38 (m, 2H), 1.04–1.01 (m, 6H).

Example 44: 2-chloro-N-(3-(cyclohexylmethyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5 Synthesis of -(isobutyramidomethyl)benzamide (Compound 44)

A target compound was obtained in the same manner as in Example 1, except that cyclohexylmethanamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.57 (m, 1H, NH), 8.34 (m, 1H, NH), 8.18 (m, 1H), 7.75-7.72 (m, 1H), 7.50-7.47 ( m, 1H), 7.40 (m, 1H), 7.34-7.31 (m, 1H), 7.05-7.03 (m, 1H), 5.24 (m, 2H), 4.27-4.26 (m, 2H), 3.30 (m, 1H), 2.43–2.38 (m, 2H), 1.64–1.61 (m, 6H), 1.21–0.85 (m, 11H).

Example 45: 2-chloro-N-(3-cyclopropyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu Synthesis of thiramidomethyl)benzamide (Compound 45)

A target compound was obtained in the same manner as in Example 1, except that cyclopropylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.56 (m, 1H, NH), 8.34 (m, 1H, NH), 8.18 (m, 1H), 7.75-7.72 (m, 1H), 7.50-7.47 ( m, 1H), 7.40 (m, 1H), 7.33-7.31 (m, 1H), 7.03-7.01 (m, 1H), 5.20 (m, 2H), 4.27-4.25 (m, 2H), 2.66 (m, 1H), 2.43–2.38 (m, 1H), 1.01–0.99 (m, 6H), 0.86–0.79 (m, 2H), 0.68 (m, 2H).

Example 46: 2-Chloro-N-(3-(3′,5′-difluoro-[1,1′-biphenyl]-4-yl)-4-oxo-3,4-dihydro- Synthesis of 2H-benzo[e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 46)

N-(3-(4-Bromophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro-5-( isobutyramidomethyl)benzamide (200 mg, 0.359 mmol), 3,5-difluorophenylboronic acid (73.7 mg, 0.467 mmol), K ₂ CO ₃ (148.9 mg, 1.077 mmol), and Pd (PPh ₃ ) ₄ (21mg, 0.018mmol) was suspended in dioxane:H ₂ O (5.5ml), cooled under reflux, and stirred for 24h. After completion of the reaction, extraction was performed with ethyl acetate and distilled water. The organic layer was dried over MgSO ₄ , filtered under reduced pressure and concentrated to remove the solvent. The residue was prepared by recrystallization or column chromatography to obtain 2-chloro-N-(3-(3',5'-difluoro-[1,1'-biphenyl]-4-yl)-4-oxo- Obtained 3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (35.1 mg, 16.5%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (1H, s), 8.35 (2H, m), 7.85 (1H, d, J = 8.7Hz), 7.41 (9H, m), 5.68 (2H, s ), 4.29 (2H, d, J = 5.7 Hz), 2.43 (1H, m), 1.03 (6H, m).

Example 47: 2-Chloro-N-(3-(4′-fluoro-[1,1′-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 47)

A target compound was obtained in the same manner as in Example 46, except that (4-fluorophenyl)boronic acid was used instead of 3,5-difluorophenylboronic acid in Example 46.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (1H, s), 8.34 (2H, m), 7.84 (1H, m), 7.65 (2H, d, J = 8.7 Hz), 7.44 (5H, m ), 7.17 (1H, d, J = 8.7 Hz), 5.68 (2H, s), 4.29 (2H, d, J = 6.0 Hz), 2.43 (1H, m), 1.03 (6H, m).

Example 48: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4- Synthesis of yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)benzamide (Compound 48)

A target compound was obtained in the same manner as in Example 46, except that (4-(trifluoromethyl)phenyl)boronic acid was used instead of 3,5-difluorophenylboronic acid in Example 46.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (1H, s), 8.36 (2H, m), 7.89 (6H, m), 7.45 (6H, m), 5.75 (2H, s), 4.29 (2H , d, J = 5.7 Hz), 2.43 (1H, m), 1.02 (6H, m).

Example 49: 2-Chloro-N-(3-(3′-fluoro-[1,1′-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 49)

A target compound was obtained in the same manner as in Example 46, except that (3-fluorophenyl)boronic acid was used instead of 3,5-difluorophenylboronic acid in Example 46.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (1H, s), 8.35 (2H, m), 7.83 (2H, m), 7.51 (9H, m), 5.71 (2H, s), 4.30 (2H , d, J = 5.7 Hz), 2.43 (1H, m), 1.03 (6H, m).

Example 50: 2-Chloro-5-(isobutyramidomethyl)-N-(3-(4′-methoxy-[1,1′-biphenyl]-4-yl)-4-oxo-3 Synthesis of ,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)benzamide (Compound 50)

A target compound was obtained in the same manner as in Example 46, except that (4-methoxyphenyl)boronic acid was used instead of 3,5-difluorophenylboronic acid in Example 46.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (1H, s), 8.36 (2H, m), 7.85 (1H, d, J = 8.7 Hz), 7.67 (4H, m), 7.44 (6H, m) ), 7.11 (3H, m), 5.71 (2H, s), 4.29 (2H, d, J = 6.0 Hz), 3.80 (3H, s), 2.42 (1H, m), 1.03 (6H, m).

Example 51: 2-Chloro-N-(3-(4′-chloro-[1,1′-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[e Synthesis of [1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 51)

A target compound was obtained in the same manner as in Example 46, except that (4-chlorophenyl)boronic acid was used instead of 3,5-difluorophenylboronic acid in Example 46.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (m, 1H, NH), 8.39 (m, 1H, NH), 8.35-8.34 (m, 1H), 7.86-7.83 (m, 1H), 7.77- 7.73 (m, 4H), 7.55-7.44 (m, 6H), 7.37-7.34 (m, 1H), 7.19-7.16 (m, 1H), 5.73 (m, 2H), 4.30-4.28 (m, 2H), 2.43-2.39 (m, 2H), 1.04-1.02 (m, 6H).

Example 52: 2-Chloro-N-(3-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro- Synthesis of 2H-benzo[e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 52)

The target compound was obtained in the same manner as in Example 46, except that (2,4-difluoro-phenyl)boronic acid was used instead of 3,5-difluorophenylboronic acid in Example 46.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (m, 1H, NH), 8.36-8.33 (m, 2H), 7.87-7.83 (m, 1H), 7.64-7.60 (m, 3H), 7.52- 7.50 (m, 3H), 7.44 (m, 1H), 7.39-7.34 (m, 2H), 7.25-7.17 (m, 2H), 5.73 (m, 2H), 4.30-4.28 (m, 2H), 2.43- 2.39 (m, 2H), 1.04–1.02 (m, 6H).

Example 53: 2-chloro-N-(3-(4-(6-fluoropyridin-3-yl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1, Synthesis of 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 53)

The target compound was obtained in the same manner as in Example 46, except that (6-fluoropyridin-3-yl)boronic acid was used instead of 3,5-difluorophenylboronic acid in Example 46.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (m, 1H, NH), 8.60 (m, 1H), 8.35-8.31 (m, 3H), 7.86-7.80 (m, 3H), 7.54-7.51 ( m, 3H), 7.44 (m, 1H), 7.37-7.29 (m, 1H), 7.20-7.17 (m, 1H), 5.75-7.74 (m, 2H), 4.30-4.28 (m, 2H), 2.43- 2.38 (m, 2H), 1.04-1.02 (m, 6H).

Example 54: 2-Chloro-5-(isobutyramidomethyl)-N-(3-(4-(6-methoxypyridin-3-yl)phenyl)-4-oxo-3,4-dihydro Synthesis of -2H-benzo[e][1,3]oxazin-6-yl)benzamide (Compound 54)

The target compound was obtained in the same manner as in Example 46, except that (6-methoxypyridin-3-yl)boronic acid was used instead of 3,5-difluorophenylboronic acid in Example 46.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (m, 1H, NH), 8.53 (m, 1H), 8.37-8.34 (m, 2H), 8.07-8.05 (m, 1H), 7.86-7.83 ( m, 1H), 7.76-7.74 (m, 2H), 7.53-7.45 (m, 4H), 7.37-7.34 (m, 1H), 7.19-7.16 (m, 1H), 6.94-6.92 (m, 1H), 5.72 (m, 2H), 4.30–4.28 (m, 2H), 3.90 (s, 3H), 2.43–2.38 (m, 2H), 1.04–1.02 (m, 6H).

Example 55: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(pyridin-4-yl)phenyl)-3,4-dihydro-2H-benzo Synthesis of [e][1,3]oxazin-6-yl)benzamide (Compound 55)

A target compound was obtained in the same manner as in Example 46, except that pyridin-4-ylboronic acid was used instead of 3,5-difluorophenylboronic acid in Example 46.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (1H, s), 8.65 (2H, d, J = 4.8 Hz), 8.35 (2H, m), 7.89 (3H, m), 7.75 (2H, d , J = 5.7 Hz), 7.47 (5H, m), 7.18 (1H, m), 5.75 (2H, s), 4.29 (2H, d, J = 6.0 Hz), 2.42 (1H, m), 1.03 (6H) , m).

Example 56: 2-Chloro-N-(3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 56)

The target compound was prepared in the same manner as in Example 1, except that 4-fluoro-2-methylaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. Got it.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (1H, s), 8.34 (2H, m), 7.83 (1H, m), 7.44 (4H, m), 7.20 (3H, m), 5.60 (1H) , m), 5.44 (1H, m), 4.29 (2H, d, J = 6.0 Hz), 2.42 (1H, m), 2.22 (3H, s), 1.03 (6H, m).

Example 57: 2-chloro-N-(3-(4-chloro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine-6- Synthesis of yl)-5-(isobutyramidomethyl)benzamide (Compound 57)

A target compound was obtained in the same manner as in Example 1, except that 4-chloro-2-methylaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (1H, s), 8.31 (2H, m), 7.83 (1H, m), 7.44 (5H, m), 7.17 (2H, m), 5.61 (1H , m), 5.46 (1H, m), 4.29 (2H, d, J = 6.0 Hz), 2.43 (1H, m), 2.21 (3H, s), 1.03 (6H, m).

Example 58: 2-chloro-N-(3-(4-chloro-3-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- Synthesis of 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 58)

The target compound was prepared in the same manner as in Example 1, except that 4-chloro-3-fluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. Got it.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (1H, s), 8.37 (2H, m), 7.86 (1H, m), 7.67 (1H, m), 7.55 (1H, m), 7.44 (5H , m), 7.34 (2H, m), 7.18 (2H, m), 5.71 (2, m), 4.29 (2H, d, J = 6.0 Hz), 2.46 (1H, m), 1.03 (6H, m) .

Example 59: 2-Chloro-N-(3-(3-chloro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3 Synthesis of ]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 59)

Except for using 3-chloro-4-(trifluoromethyl)aniline instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, the same procedure as in Example 1 was carried out. Thus, the target compound was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (1H, s), 8.37 (2H, m), 7.86 (1H, m), 7.67 (1H, m), 7.55 (1H, m), 7.44 (5H , m), 7.34 (2H, m), 7.18 (2H, m), 5.71 (2H, m), 4.29 (2H, d, J = 6.0 Hz), 2.46 (1H, m), 1.03 (6H, m) .

Example 60: 2-chloro-N-(3-(3,4-dichlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl Synthesis of )-5-(isobutyramidomethyl)benzamide (Compound 60)

A target compound was obtained in the same manner as in Example 1, except that 3,4-dichloroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (1H, s), 8.33 (2H, m), 7.89 (1H, m), 7.73 (2H, m), 7.44 (5H, m), 7.18 (1H) , m), 5.71 (2H, m), 4.30 (2H, d, J = 6.0 Hz), 2.50 (1H, m), 1.03 (6H, m).

Example 61: 2-Chloro-N-(3-(3,4-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 61)

A target compound was obtained in the same manner as in Example 1, except that 3,4-difluoroaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.34 (2H, m), 7.85 (1H, m), 7.44 (5H, m), 7.18 (1H, m), 5.67 (2H, m), 4.29 (2H, d, J = 6.0 Hz), 2.46 (1H, m), 1.03 (6H, m).

Example 62: 2-chloro-N-(3-(4-cyclohexylphenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 62)

A target compound was obtained in the same manner as in Example 1, except that 4-cyclohexylaniline was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.33 (m, NH, 1H), 7.81 (1H, m), 7.52 (2H, m), 7.30 (5H, m) , 7.16 (1H, m), 5.64 (2H, s), 4.29 (2H, d, J = 6.0 Hz), 2.42 (1H, m), 1.79 (5H, m), 1.28 (6H, m), 1.03 ( 6H, m).

Example 63: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(5,6,7,8-tetrahydronaphthalen-1-yl)-3,4-di Synthesis of hydro-2H-benzo[e][1,3]oxazin-6-yl)benzamide (Compound 63)

Except for using 5,6,7,8-tetrahydro-1-naphthylamine instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, In the same manner, the target compound was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.33 (2H, m), 7.81 (1H, m), 7.45 (4H, m), 5.58 (1H, m), 5.38 (1H, m), 4.29 (2H, d, J = 6.0 Hz), 2.79 (2H, m), 2.50 (3H, m), 1.71 (4H, m), 1.03 (6H, m).

Example 64: 2-Chloro-N-(3-(2-chlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- Synthesis of 5-(isobutyramidomethyl)benzamide (Compound 64)

A target compound was obtained in the same manner as in Example 1, except that 2-chlorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (NH, 1H, s), 8.36 (1H, m), 8.26 (NH, 1H, s), 7.82 (1H, m), 7.43 (7H, m) , 7.11 (1H, m), 5.37 (2H, s), 4.77 (2H, d, J = 6.0 Hz), 4.29 (2H, m), 2.42 (1H, m), 1.03 (6H, m).

Example 65: 2-Chloro-N-(3-(3-chlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- Synthesis of 5-(isobutyramidomethyl)benzamide (Compound 65)

A target compound was obtained in the same manner as in Example 1, except that 3-chlorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (NH, 1H, s), 8.36 (1H, m), 8.26 (NH, 1H, s), 7.79 (1H, m), 7.52 (1H, m) , 7.38(6H,m), 7.10(1H,m), 5.35(2H,s), 4.71(2H,d,J = 6.0Hz), 4.29(2H,m), 2.42(1H,m), 1.03( 6H, m).

Example 66: 2-Chloro-N-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- Synthesis of 5-(isobutyramidomethyl)benzamide (Compound 66)

A target compound was obtained in the same manner as in Example 1, except that 4-chlorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (NH, 1H, s), 8.36 (1H, m), 8.26 (NH, 1H, s), 7.77 (1H, m), 7.51 (1H, m) , 7.39(6H, m), 7.08(1H, m), 5.31(2H, s), 4.69(2H, d, J = 6.0 Hz), 4.29(2H, m), 2.42(1H, m), 1.03( 6H, m).

Example 67: 2-chloro-N-(3-(2-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 67)

The target compound was prepared in the same manner as in Example 1, except that (2-fluorophenyl)methylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1. got it

¹ H NMR (300 MHz, DMSO) δ 10.60 (m, NH), 8.34 (m, NH), 8.23 (m, 1H), 7.78-7.76 (m, 1H), 7.51-7.49 (m, 1H), 7.41 -7.35 (m, 4H), 7.24-7.18 (m, 2H), 7.09-7.06 (m, 1H), 5.33 (s, 2H), 4.73 (s, 2H), 4.28-4.27 (m, 2H), 2.48 -2.39 (m, 1H), 1.03-1.00 (m, 6H).

Example 68: 2-chloro-N-(3-(3-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 68)

The target compound was prepared in the same manner as in Example 1, except that (3-fluorophenyl)methylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1. got it

¹ H NMR (300 MHz, DMSO) δ 10.61 (m, NH), 8.35 (m, NH), 8.26-8.25 (m, 1H), 7.78-7.76 (m, 1H), 7.52-7.49 (m, 1H) , 7.41-7.32 (m, 3H), 7.18-7.06 (m, 4H), 5.33 (s, 2H), 4.71 (s, 2H), 4.29-4.27 (m, 2H), 2.48-2.39 (m, 1H) , 1.03–1.00 (m, 6H).

Example 69: 2-chloro-N-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 69)

The target compound was prepared in the same manner as in Example 1, except that (4-fluorophenyl)methylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got it

¹ H NMR (300 MHz, DMSO) δ 10.60 (m, NH), 8.35 (m, NH), 8.25 (m, 1H), 7.78-7.75 (m, 1H), 7.51-7.49 (m, 1H), 7.41 -7.32 (m, 4H), 7.20-7.14 (m, 2H), 7.08-7.05 (m, 1H), 5.29 (s, 2H), 4.67 (s, 2H), 4.28-4.27 (m, 2H), 2.48 -2.39 (m, 1H), 1.03-1.00 (m, 6H).

Example 70: 2-Chloro-N-(3-(4-chloro-3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3 Synthesis of ]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 70)

Except for using 4-chloro-3-(trifluoromethyl)benzylamine instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, in the same manner as in Example 1. carried out to obtain the target compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.27 (NH, 1H, s), 7.84 (1H, m), 7.76 (2H, m) , 7.66(1H,m), 7.52(1H,m), 7.42(1H,m), 7.36(1H,m), 7.10(1H,m), 5.38(2H,s), 4.77(2H,d,J = 6.0 Hz), 4.29 (2H, m), 2.42 (1H, m), 1.03 (6H, m).

Example 71: 2-Chloro-N-(3-(3-chloro-4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- Synthesis of 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 71)

The target compound was prepared in the same manner as in Example 1, except that 3-chloro-4-fluorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.26 (NH, 1H, s), 7.78 (1H, m), 7.54 (2H, m) , 7.38(4H, m), 7.09(1H, m), 5.38(2H, s), 4.68(2H, d, J = 6.0 Hz), 4.29(2H, m), 2.42(1H, m), 1.03( 6H, m).

Example 72: 2-Chloro-N-(3-(2-chloro-6-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- Synthesis of 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 72)

The target compound was prepared in the same manner as in Example 1, except that 2-chloro-6-fluorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (NH, 1H, s), 8.38 (1H, m), 8.21 (NH, 1H, s), 7.74 (1H, m), 7.51 (1H, m) , 7.35 (5H, m), 7.04 (1H, m), 5.23 (2H, s), 4.79 (2H, d, J = 6.0 Hz), 4.28 (2H, m), 2.42 (1H, m), 1.03 ( 6H, m).

Example 73: 2-Chloro-N-(3-(2,3-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl Synthesis of )-5-(isobutyramidomethyl)benzamide (Compound 73)

A target compound was obtained in the same manner as in Example 1, except that 2,3-dichlorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.26 (NH, 1H, s), 7.80 (1H, m), 7.61 (1H, m) , 7.52(1H, m), 7.37(4H, m), 7.12(1H, m), 5.39(2H, s), 4.79(2H, d, J = 6.0 Hz), 4.28(2H, m), 2.42( 1H, m), 1.03 (6H, m).

Example 74: 2-chloro-N-(3-(2,4-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl Synthesis of )-5-(isobutyramidomethyl)benzamide (Compound 74)

A target compound was obtained in the same manner as in Example 1, except that 2,4-dichlorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.37 (1H, m), 8.25 (NH, 1H, s), 7.80 (1H, m), 7.68 (1H, m) , 7.40 (5H, m), 7.09 (1H, m), 5.36 (2H, s), 4.73 (2H, d, J = 6.0 Hz), 4.29 (2H, m), 2.42 (1H, m), 1.03 ( 6H, m).

Example 75: 2-chloro-N-(3-(2,6-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl Synthesis of )-5-(isobutyramidomethyl)benzamide (Compound 75)

A target compound was obtained in the same manner as in Example 1, except that 2,6-dichlorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (NH, 1H, s), 8.39 (1H, m), 8.25 (NH, 1H, s), 7.74 (1H, m), 7.53 (3H, m) , 7.43 (2H, m), 7.36 (1H, m), 7.02 (1H, m), 5.11 (2H, s), 4.90 (2H, d, J = 6.0 Hz), 4.28 (2H, m), 2.42 ( 1H, m), 1.03 (6H, m).

Example 76: 2-Chloro-N-(3-(2,5-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 76)

The target compound was prepared in the same manner as in Example 1, except that 2,5-difluorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.39 (1H, m), 8.23 (NH, 1H, s), 7.78 (1H, m), 7.51 (1H, m) , 7.41 (1H, m), 7.28 (4H, m), 7.10 (1H, m), 5.37 (2H, s), 4.73 (2H, d, J = 6.0 Hz), 4.28 (2H, m), 2.42 ( 1H, m), 1.03 (6H, m).

Example 77: 2-Chloro-N-(3-(2,6-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 77)

The target compound was prepared in the same manner as in Example 1, except that 2,6-difluorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (NH, 1H, s), 8.38 (1H, m), 8.20 (NH, 1H, s), 7.78 (1H, m), 7.41 (4H, m) , 7.10 (3H, m), 5.30 (2H, s), 4.73 (2H, d, J = 6.0 Hz), 4.28 (2H, m), 2.42 (1H, m), 1.03 (6H, m).

Example 78: 2-Chloro-N-(3-(2,4-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 78)

The target compound was prepared in the same manner as in Example 1, except that 2,4-difluorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.37 (1H, m), 8.25 (NH, 1H, s), 7.80 (1H, m), 7.68 (1H, m) , 7.44(2H, m), 7.32(2H, m), 7.13(2H, m), 5.34(2H, s), 4.71(2H, d, J = 6.0 Hz), 4.29(2H, m), 2.42( 1H, m), 1.03 (6H, m).

Example 79: 2-chloro-N-(3-(4-fluoro-3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1, Synthesis of 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 79)

Same as Example 1, except that 4-fluoro-3-(trifluoromethyl)benzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. This was carried out to obtain the target compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.27 (NH, 1H, s), 7.77 (1H, m), 7.43 (4H, m) , 7.09 (1H, m), 5.37 (2H, s), 4.76 (2H, d, J = 6.0 Hz), 4.29 (2H, m), 2.42 (1H, m), 1.03 (6H, m).

Example 80: 2-chloro-N-(3-(2-fluoro-4-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1, Synthesis of 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 80)

Same as Example 1, except that 2-fluoro-4-(trifluoromethyl)benzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. This was carried out to obtain the target compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.25 (NH, 1H, s), 7.74 (2H, m), 7.61 (2H, m) , 7.52 (1H, m), 7.42 (1H, m), 7.36 (1H, m), 7.11 (1H, m), 5.40 (2H, s), 4.85 (2H, d, J = 6.0 Hz), 4.28 ( 2H, m), 2.42 (1H, m), 1.03 (6H, m).

Example 81: 2-chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[ Synthesis of e] [1,3] oxazin-6-yl) benzamide (Compound 81)

The target compound was prepared in the same manner as in Example 1, except that 4-(trifluoromethoxy)benzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.27 (NH, 1H, s), 7.76 (1H, m), 7.47 (7H, m) , 7.10 (1H, m), 5.35 (2H, s), 4.73 (2H, d, J = 6.0 Hz), 4.29 (2H, m), 2.42 (1H, m), 1.03 (6H, m).

Example 82: 2-chloro-N-(3-(3,4-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl Synthesis of )-5-(isobutyramidomethyl)benzamide (Compound 82)

A target compound was obtained in the same manner as in Example 1, except that 3,4-dichlorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.26 (NH, 1H, s), 7.78 (2H, m), 7.65 (2H, m) , 7.51 (1H, m), 7.43 (1H, m), 7.36 (3H, m), 7.10 (1H, m), 5.36 (2H, s), 4.70 (2H, d, J = 6.0 Hz), 4.29 ( 2H, m), 2.42 (1H, m), 1.03 (6H, m).

Example 83: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)benzamide (Compound 83)

The target compound was prepared in the same manner as in Example 1, except that 3-(trifluoromethoxy)benzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.27 (NH, 1H, s), 7.79 (1H, m), 7.51 (2H, m) , 7.35 (5H, m), 7.10 (1H, m), 5.36 (2H, s), 4.75 (2H, d, J = 6.0 Hz), 4.29 (2H, m), 2.42 (1H, m), 1.03 ( 6H, m).

Example 84: 2-Chloro-N-(3-(2,3-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 84)

The target compound was prepared in the same manner as in Example 1, except that 2,3-difluorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.61 (NH, 1H, s), 8.35 (1H, m), 8.23 (NH, 1H, s), 7.76 (1H, m), 7.50 (1H, m) , 7.35 (3H, m), 7.18 (2H, m), 7.08 (1H, m), 5.35 (2H, s), 4.77 (2H, d, J = 6.0 Hz), 4.27 (2H, m), 2.42 ( 1H, m), 1.03 (6H, m).

Example 85: 2-Chloro-N-(3-(3,5-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6 Synthesis of -yl)-5-(isobutyramidomethyl)benzamide (Compound 85)

The target compound was prepared in the same manner as in Example 1, except that 3,5-difluorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1. got it

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.26 (NH, 1H, s), 7.78 (1H, m), 7.51 (1H, m) , 7.43(1H, m), 7.36(1H, m), 7.09(4H, m), 5.38(2H, s), 4.72(2H, d, J = 6.0 Hz), 4.29(2H, m), 2.42( 1H, m), 1.03 (6H, m).

Example 86: N-(3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl Synthesis of )-2-chloro-5-(isobutyramidomethyl)benzamide (Compound 86)

Except for using 4-bromo-2-fluorobenzylamine instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, the same purpose as in Example 1 was carried out. compound was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.25 (NH, 1H, s), 7.76 (1H, m), 7.55 (2H, m) , 7.36 (4H, m), 7.10 (1H, m), 5.35 (2H, s), 4.71 (2H, d, J = 6.0 Hz), 4.29 (2H, m), 2.42 (1H, m), 1.03 ( 6H, m).

Example 87: N-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- Synthesis of 2-chloro-5- (isobutyramidomethyl) benzamide (Compound 87)

A target compound was obtained in the same manner as in Example 1, except that 4-tert-butylbenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (NH, 1H, s), 8.37 (1H, m), 8.26 (NH, 1H, s), 7.77 (1H, m), 7.51 (1H, m) , 7.39(4H, m), 7.26(2H, m), 7.08(1H, m), 5.30(2H, s), 4.66(2H, d, J = 6.0 Hz), 4.39(2H, m), 2.42( 1H, m), 1.03 (6H, m).

Example 88: 2-chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)benzamide (Compound 88)

A target compound was obtained in the same manner as in Example 1, except that 4-trifluoromethylbenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.25 (NH, 1H, s), 7.74 (2H, m), 7.61 (2H, m) , 7.52 (1H, m), 7.42 (1H, m), 7.36 (1H, m), 7.11 (1H, m), 5.40 (2H, s), 4.85 (2H, d, J = 6.0 Hz), 4.28 ( 2H, m), 2.42 (1H, m), 1.03 (6H, m).

Example 89: 2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[ Synthesis of e][1,3]oxazin-6-yl)benzamide (Compound 89)

A target compound was obtained in the same manner as in Example 1, except that 3-trifluoromethylbenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (NH, 1H, s), 8.38 (1H, m), 8.28 (NH, 1H, s), 7.78 (3H, m), 7.65 (4H, m) , 7.52 (1H, m), 7.43 (1H, m), 7.35 (1H, m), 7.11 (1H, m), 5.36 (2H, s), 4.80 (2H, d, J = 6.0 Hz), 4.29 ( 2H, m), 2.42 (1H, m), 1.03 (6H, m).

Example 90: N-(3-(3-bromobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 90)

The target compound was prepared in the same manner as in Example 1, except that (3-bromophenyl)methylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1. got it

¹ H NMR (300 MHz, DMSO) δ 10.61 (m, NH), 8.35 (m, NH), 8.26 (m, 1H), 7.79-7.76 (m, 1H), 7.53-7.49 (m, 3H), 7.42 (m, 1H), 7.33 (m, 3H), 7.09-7.06 (m, 1H), 5.33 (s, 2H), 4.68 (s, 2H), 4.29-4.27 (m, 2H), 2.48-2.39 (m) , 1H), 1.03 (m, 6H).

Example 91: N-(3-(4-bromobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro Synthesis of -5-(isobutyramidomethyl)benzamide (Compound 91)

The target compound was prepared in the same manner as in Example 1, except that (4-bromophenyl)methylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline in Example 1-1. got it

¹ H NMR (300 MHz, DMSO) δ 10.62 (m, NH), 8.37 (m, NH), 8.25 (m, 1H), 7.78-7.75 (m, 1H), 7.56-7.49 (m, 3H), 7.42 (m, 1H), 7.35-7.28 (m, 3H), 7.08-7.05 (m, 1H), 5.30 (s, 2H), 4.66 (s, 2H), 4.28-4.2 (m, 2H), 2.48-2.39 (m, 1H), 1.02 (m, 6H).

Example 92: 2-Chloro-N-(3-(2-chloro-5-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- Synthesis of 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 92)

The target compound was prepared in the same manner as in Example 1, except that 2-chloro-5-fluorobenzylamine was used instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1. got

¹ H NMR (300 MHz, DMSO) δ 10.62 (NH, 1H, s), 8.35 (1H, m), 8.26 (NH, m), 7.82-7.79 (m, 1H), 7.58-7.49 (m, 2H) , 7.43 (m, 1H), 7.37-7.34 (m, 1H), 7.25-7.17 (m, 2H), 7.12 (m, 1H), 5.41 (s, 2H), 4.75 (s, 2H), 4.29 (m , 2H), 2.45–2.41 (m, 1H), 1.03 (m, 6H).

Example 93: 2-Chloro-N-(3-(2-chloro-3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3 Synthesis of ]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 93)

Except for using 2-chloro-3-(trifluoromethyl)benzylamine instead of 3-fluoro-4-(trifluoromethyl)aniline of Example 1-1, in the same manner as in Example 1. carried out to obtain the target compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (NH, 1H, s), 8.35 (1H, m), 8.26 (NH, m), 7.84-7.80 (m, 1H), 7.66 (1H, m) , 7.57(1H,m), 7.51(1H,m), 7.43-7.42(1H,m), 7.37-7.34(1H,m), 7.14-7.12(1H,m), 5.43(2H,s), 4.85 (2H, d, J = 6.0 Hz), 4.29 (2H, m), 2.47–2.39 (1H, m), 1.03 (6H, m).

Test Example 1: mPGES-1 inhibitory activity

Microsomal fraction of A549 human lung cancer cells

A549 human lung cancer cells were cultured in a DMEM medium supplemented with 100 units/mL penicillin-streptomycin and 10% FBS at 37°C in a 5% CO ₂ incubator. After seeding the cells and culturing them in an incubator at 37° C., 5% CO ₂ , the cells were treated with IL-1β (1 ng/mL). After culturing for 48 hours, wash the cells with PBS, react with 2mL of trypsin/EDTA for 5 minutes, add 3mL of DMEM to separate the cells, collect the cells by centrifugation at 1,000 rpm for 5 minutes, and then wash the cells twice with PBS. was washed. The prepared cells were resuspended in homogenization buffer (0.1 M potassium phosphoate buffer, pH 7.4, 2.5 mM glutathione, 0.25 M sucrose), incubated on ice for 10 minutes, and then sonicated (3 × 20 s) to 1,000 g. , 10 minutes and 174000 g, 1 hour, microsomes were fractionated by centrifugation at 4 ° C. The microsomal fraction was resuspended in 50 μL of homogenization buffer, and protein quantification was performed by Bradford assay.

PGE ₂ measurement

After seeding with A549 human lung cancer cells, 24 hours later samples were treated for each concentration. After 1 hour, the cells were treated with 1 ng/mL of IL-1β, cultured for 48 hours, and the culture supernatant was collected. The collected supernatant was measured using the PGE ₂ EIA kit according to the manufacturer's instructions.

The results are shown in Table 1 below.

compound name A549 cells 1 nM 10 nM 100nM 1000 nM IC ₅₀ (nM) GRC27864 - - - - 3.21 One 24.23 64.54 79.85 - 5.94 8 - - 63 79.74 6.45 10 - - 71.12 79.57 6.25 13 - - 70.69 83.88 - 14 - - 80.41 87.67 10.49 15 - - 84.24 86.87 - 22 14.04 34.56 72.06 - 38.33 23 -0.8 37.32 69.92 - 37.52 24 39.57 53.14 79.45 - 4.44 25 13.2 51.28 68.32 - 9.61 26 -5.92 17.75 34.43 - >100 27 15.18 26.66 58.27 - 51.24 28 23.14 37.81 63.96 - 43.91 29 28.48 43.26 66.34 - 31.91 30 -6.3 21.09 57.44 - 76.33 31 4.01 22.33 45.99 - >100 32 -8.97 33.3 63.17 - 53.53 33 -2.75 5.15 7.03 - >100 34 -17.34 0.84 11.62 - >100 35 4.31 10.12 -2.91 - >100 36 -7.68 10.82 27.16 - >100 37 8.01 29.98 12.99 - >100 44 14.98 42.48 78.58 - 22.74 45 6.96 7.49 31.19 - >100 55 12.57 21.86 35.15 - >100 56 40.64 25.4 64.17 - 59.18 57 20.45 55.21 74.2 - 8.27 58 21.66 54.28 63.1 - 8.52 59 40.34 64.84 74.78 - 4.02 60 31.99 71.47 78.96 - 84.19 61 25.21 43.23 70.03 - 27.85 62 23.35 44.16 63.45 - 33.29 63 13.2 55.08 71.07 - 8.55 64 39.59 45.1 59.46 - 48.36 65 24.19 32.15 55.75 - 51.35 66 8.85 12.68 68.44 - 48.36 67 -5.74 36.15 51.86 - 52.87 68 17.98 22.05 50.53 - 98.07 69 17.74 56.39 64.04 - 8.07 70 4.31 33.69 74.13 - 37 71 18.71 15.11 76.9 - 46.59 72 2.73 41.52 40.16 - >100 73 13.74 40.74 69.79 - 32.74 74 14.05 54.49 73.37 - 8.64 75 10.9 18.23 35.31 - >100 76 -5.2 16.8 47.89 - >100 77 -30.6 2.3 17.67 - >100 78 -3.69 25.24 51.63 - 93.22 79 -7.18 12.07 57.57 - 79.81 80 17.87 51.78 82.97 - 9.39 81 -3.64 18.2 65.48 - 61.47 82 -32.74 32.48 93.86 - 21.26 83 30.13 46.07 68.87 - 22.35 84 23.61 39.18 67.56 - 38.09 85 29.76 44.52 62.77 - 33.43 86 14.43 23.02 66.2 - 57.32 87 5.01 27.55 64.74 - 56.27 88 11.49 33.32 81.07 - 30.59 89 2.12 1.1 21.55 - >100 90 -16.8 -2.72 36.22 - >100 91 -12.97 0.22 50.16 - 99.52 92 1.13 15.45 41.35 - >100 93 3.63 43.04 60.54 - 41.77

As can be seen in Table 1, the benzoxazinone derivatives according to the present invention showed excellent PGE ₂ production inhibitory effect. In addition, the compound according to the present invention showed almost the same mPGES-1 enzyme inhibitory effect as the positive control, GRC27864 (compound of Formula I).

Test Example 2: Efficacy test using MIA (Monosodium iodoacetate) induced osteoarthritis guinea pig model

In order to evaluate the efficacy of the compound according to the present invention in osteoarthritis-induced guinea pigs, the following experiment was conducted.

Specifically, a male guinea pig weighing about 500 g ± 20% was supplied from Coretech Co., Ltd. (Gyeonggi-do, Korea) and used after being adapted for 8 days in the laboratory. Water and feed were freely consumed, temperature (23 ± 3 ° C), Humidity (55±15%) and light/dark cycle (12 hours, 08:00 ~ 20:00) were automatically controlled.

Each group used 10 guinea pigs. Anesthetize using Zoletil 50 (VIRBAC, France, 5 mg/kg) and xylazine (xylazine, Rompun ^® , Bayer AG, Germany, 2.5 mg/kg), and clipper the animal. The area around the right knee was shaved. After confirming that a syringe equipped with a 26-gauge needle was placed in the joint cavity using a C-arm (ARCADIS Vric, SIEMENS Co.), 50 μL of MIA at a concentration of 60 mg/mL was administered into the joint cavity. One week after MIA administration, compound 1 of the present invention was added to the excipients (DMSO (10 wt%), Tween 80 (30 wt%), HMPC (same amount as the drug)), and water was added to dissolve the total to 100 wt%. 10 mg/kg and 25 mg/kg were orally administered to the prepared experimental animals, respectively. The positive control group was orally administered 12.5 mg/kg of GRC27864 using the same excipient, and only the excipient was orally administered to the control group. The drug was administered for 4 weeks.

After 4 weeks, blood concentrations of PGE ₂ , IL-1β, and TNF-α were measured using a commercially available ELISA kit. The results are shown in Table 2 and FIGS. 1 to 3 below. ***, ** and * indicate statistical significance compared to the control group, P<0.001, P<0.01, P<0.05 compared to the control group.

ELISA assay analysis item control group GRC27864 (12.5 mpk) Compound 1 (10mpk) Compound 1 (25mpk) PGE ₂ 11031.4±2635.5 7756.9±1860.5 ^** 8689.3±2198.1 6190.2±1177.1 ^*** IL-1β 47.139±14.282 37.408±9.109 43.930±10.583 32.904±7.097 TNF-α 135.574±28.660 97.110±20.595 ^* 112.036±27.822 89.926±22.568 ^**

As a result of comparing the inhibitory ability of inflammatory factors in the control group administered only with vehicle, the GRC27864-administered group and the Compound 1 (25mpk)-administered group, the compound 1 (25mpk)-administered group inhibited inflammatory factors more than the GRC27864 drug-administered group. could confirm that

Test Example 3: Antipain efficacy test using acetic acid induced abdominal contraction mouse model

In order to evaluate the anti-pain effect of the compound according to the present invention on abdominal contraction mice, the following experiment was conducted.

Specifically, male ICR mice weighing about 20 to 25 g were supplied from Orient Bio Co., Ltd. (Gyeonggi-do, Korea) and used after being acclimatized for 7 days in the laboratory. Water and feed were freely consumed, and temperature (20±2℃), humidity (40±60%), and light/dark cycle (12 hours) were automatically controlled.

Based on 10 mice per group, the control group was orally administered with an excipient (200 μL), and the positive control group was orally administered with 25 mg/kg of celecoxib. Compound 1 of the present invention was dissolved in an excipient (10% NMP (N-methyl-2-pyrrolidone), 10% ethanol, 80% polyethylene glycol 400) and orally administered to each mouse at 10 and 50 mg/kg. One hour after drug administration, pain was induced by intraperitoneal injection of 0.7% acetic acid at 10 mg/kg. The number of times of riding was measured for 10 minutes from 10 minutes after administration of acetic acid. The results are shown in FIG. 4 .

In this experiment, it was evaluated that the anti-pain effect of the drug was stronger as the number of riding for 10 minutes decreased. Statistical significance was expressed as ^** P<0.01, ^* P<0.05 compared to the control group. 4, compared to the control group, the GRC27864, celecoxib-administered group, and Compound 1-administered group exhibited significantly lower riding frequency. In particular, Compound 1 exhibited a better pain suppression effect than GRC27864, and celecoxib (25 mg/kg) Compared to the high-dose administration group (50 mg / kg) of Compound 1, a better pain suppression effect was confirmed.

Claims (11)

A benzoxazinone derivative of Formula II or a pharmaceutically acceptable salt thereof:
[Formula II]

In the above formula,
R ¹ is an aryl group or a C ₃ -C ₁₀ cycloalkyl group;
L is absent or is a C ₁ -C ₆ alkylene group,
R ² is an isopropylcarbonyl group, a methylcarbonyl group or a methylsulfonyl group. According to claim 1,
R ¹ is halogen, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkoxycarbonyl group, carboxy group, carboxylate group, C _{A 3} -C ₁₀ cycloalkyl group and an aryl group unsubstituted or substituted with one or more substituents selected from the group consisting of an aryl group or a C ₃ -C ₁₀ cycloalkyl group, a benzoxazinone derivative or a pharmaceutically acceptable salt thereof. According to claim 1,
R ¹ is fluoro, chloro, bromo, methyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, carboxy, carboxylate, cyclohexyl, monofluorophenyl, difluorophenyl , phenyl optionally substituted with one or more substituents selected from the group consisting of trifluoromethylphenyl, methoxyphenyl, monochlorophenyl, pyridinyl, fluoropyridinyl and methoxypyridinyl, tetrahydronaphthyl, cyclopropyl or a benzoxazinone derivative that is cyclohexyl or a pharmaceutically acceptable salt thereof. According to claim 1,
A benzoxazinone derivative in which L is absent or methylene, or a pharmaceutically acceptable salt thereof. According to claim 1,
A benzoxazinone derivative in which R ² is an isopropylcarbonyl group or a pharmaceutically acceptable salt thereof. According to claim 1,
R ¹ is fluoro, chloro, bromo, methyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, carboxy, carboxylate, cyclohexyl, monofluorophenyl, difluorophenyl , phenyl optionally substituted with one or more substituents selected from the group consisting of trifluoromethylphenyl, methoxyphenyl, monochlorophenyl, pyridinyl, fluoropyridinyl and methoxypyridinyl, tetrahydronaphthyl, cyclopropyl or cyclohexyl;
L is absent or methylene;
A benzoxazinone derivative in which R ² is an isopropylcarbonyl group or a pharmaceutically acceptable salt thereof. According to claim 1,
R ¹ is a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl group and C ₁ -C ₆ haloalkyl group;
L is absent or methylene;
A benzoxazinone derivative in which R ² is an isopropylcarbonyl group or a pharmaceutically acceptable salt thereof. According to claim 1,
R ¹ is a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and C ₁ -C ₆ haloalkyl groups;
L does not exist,
A benzoxazinone derivative in which R ² is an isopropylcarbonyl group or a pharmaceutically acceptable salt thereof. The benzoxazinone derivative according to claim 1, characterized in that it is selected from the following compounds or a pharmaceutically acceptable salt thereof:
2-chloro-N-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 1);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 2);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 3);
2-Chloro-N-(3-(3-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 4);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 5);
2-chloro-N-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 6);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 7);
2-Chloro-N-(3-(3,5-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(isobutyramidomethyl)benzamide (Compound 8);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(2-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 9);
2-chloro-N-(3-(3-fluoro-5-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 10);
2-chloro-N-(3-(2-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 11);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(o-tolyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine- 6-yl)benzamide (Compound 12);
2-chloro-N-(3-(3-chlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 13);
2-chloro-N-(3-(3-chloro-5-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 14);
N-(3-(4-Bromophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro-5-( isobutyramidomethyl)benzamide (Compound 15);
N-(3-(4-(tert-butyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro- 5-(isobutyramidomethyl)benzamide (Compound 16);
2-chloro-N-(3-(4-chlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 17);
2-chloro-N-(3-(4-fluoro-2-(trifluoromethoxy)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 18);
2-chloro-N-(3-(4-fluoro-2-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 19);
2-chloro-N-(3-(3-chloro-4-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 20);
2-Chloro-N-(3-(2,6-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(isobutyramidomethyl)benzamide (Compound 21);
N-(3-(2-Bromophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro-5-( isobutyramidomethyl)benzamide (Compound 22);
2-chloro-N-(3-(2-chlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 23);
2-Chloro-N-(3-(3,5-dichlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 24);
2-Chloro-N-(3-(2,4-dichlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 25);
2-Chloro-N-(3-(4-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 26);
2-chloro-N-(3-(4-chloro-2-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 27);
2-chloro-N-(3-(2-chloro-4-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 28);
N-(3-(4-bromo-2-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2- chloro-5-(isobutyramidomethyl)benzamide (Compound 29);
N-(3-(4-bromo-3-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2- chloro-5-(isobutyramidomethyl)benzamide (Compound 30);
2-Chloro-N-(3-(2,4-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(isobutyramidomethyl)benzamide (Compound 31);
2-chloro-N-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 32);
Methyl 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl) Benzoate (Compound 33);
Methyl 3-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl) Benzoate (Compound 34);
4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoic acid (Compound 35);
3-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoic acid (Compound 36);
Sodium 4-(6-(2-chloro-5-(isobutyramidomethyl)benzamido)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl) Benzoate (Compound 37);
5-(acetamidomethyl)-2-chloro-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1, 3]oxazin-6-yl)benzamide (Compound 38);
2-Chloro-5-(methylsulfonamidomethyl)-N-(4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 39);
2-Chloro-5-(methylsulfonamidomethyl)-N-(4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 40);
2-Chloro-N-(3-(3,4-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(isobutyramidomethyl)benzamide (Compound 41);
2-chloro-N-(3-(4-chloro-3-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 42);
2-chloro-N-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 43);
2-Chloro-N-(3-(cyclohexylmethyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobutyr amidomethyl)benzamide (Compound 44);
2-Chloro-N-(3-cyclopropyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl )benzamide (compound 45);
2-Chloro-N-(3-(3',5'-difluoro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[ e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 46);
2-Chloro-N-(3-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 47);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3 ,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)benzamide (Compound 48);
2-Chloro-N-(3-(3'-fluoro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 49);
2-Chloro-5-(isobutyramidomethyl)-N-(3-(4'-methoxy-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-di hydro-2H-benzo[e][1,3]oxazin-6-yl)benzamide (Compound 50);
2-Chloro-N-(3-(4'-chloro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[e][1, 3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 51);
2-Chloro-N-(3-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)-4-oxo-3,4-dihydro-2H-benzo[ e][1,3]oxazin-6-yl)-5-(isobutyramidomethyl)benzamide (Compound 52);
2-chloro-N-(3-(4-(6-fluoropyridin-3-yl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 53);
2-Chloro-5-(isobutyramidomethyl)-N-(3-(4-(6-methoxypyridin-3-yl)phenyl)-4-oxo-3,4-dihydro-2H-benzo [e][1,3]oxazin-6-yl)benzamide (Compound 54);
2-chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(pyridin-4-yl)phenyl)-3,4-dihydro-2H-benzo[e][ 1,3]oxazin-6-yl)benzamide (Compound 55);
2-Chloro-N-(3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 56);
2-Chloro-N-(3-(4-chloro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5 -(isobutyramidomethyl)benzamide (Compound 57);
2-chloro-N-(3-(4-chloro-3-fluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 58);
2-Chloro-N-(3-(3-chloro-4-(trifluoromethyl)phenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 59);
2-Chloro-N-(3-(3,4-dichlorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 60);
2-Chloro-N-(3-(3,4-difluorophenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(isobutyramidomethyl)benzamide (Compound 61);
2-Chloro-N-(3-(4-cyclohexylphenyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 62);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(5,6,7,8-tetrahydronaphthalen-1-yl)-3,4-dihydro-2H- benzo[e][1,3]oxazin-6-yl)benzamide (Compound 63);
2-Chloro-N-(3-(2-chlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 64);
2-Chloro-N-(3-(3-chlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 65);
2-Chloro-N-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-(isobu thiramidomethyl)benzamide (Compound 66);
2-Chloro-N-(3-(2-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 67);
2-Chloro-N-(3-(3-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 68);
2-Chloro-N-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5-( isobutyramidomethyl)benzamide (Compound 69);
2-Chloro-N-(3-(4-chloro-3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 70);
2-chloro-N-(3-(3-chloro-4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(isobutyramidomethyl)benzamide (Compound 71);
2-chloro-N-(3-(2-chloro-6-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(Isobutyramidomethyl)benzamide (Compound 72);
2-Chloro-N-(3-(2,3-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 73);
2-Chloro-N-(3-(2,4-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 74);
2-Chloro-N-(3-(2,6-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 75);
2-Chloro-N-(3-(2,5-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 76);
2-Chloro-N-(3-(2,6-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 77);
2-Chloro-N-(3-(2,4-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 78);
2-chloro-N-(3-(4-fluoro-3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 79);
2-chloro-N-(3-(2-fluoro-4-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine -6-yl)-5-(isobutyramidomethyl)benzamide (Compound 80);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 81);
2-Chloro-N-(3-(3,4-dichlorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-5- (isobutyramidomethyl)benzamide (Compound 82);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 83);
2-Chloro-N-(3-(2,3-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 84);
2-Chloro-N-(3-(3,5-difluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)- 5-(Isobutyramidomethyl)benzamide (Compound 85);
N-(3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2- chloro-5-(isobutyramidomethyl)benzamide (Compound 86);
N-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro- 5-(Isobutyramidomethyl)benzamide (Compound 87);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 88);
2-Chloro-5-(isobutyramidomethyl)-N-(4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[e][1 ,3]oxazin-6-yl)benzamide (Compound 89);
N-(3-(3-Bromobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro-5-( isobutyramidomethyl)benzamide (Compound 90);
N-(3-(4-bromobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-2-chloro-5-( isobutyramidomethyl)benzamide (Compound 91);
2-chloro-N-(3-(2-chloro-5-fluorobenzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl) -5-(Isobutyramidomethyl)benzamide (Compound 92); and
2-Chloro-N-(3-(2-chloro-3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine- 6-yl)-5-(isobutyramidomethyl)benzamide (Compound 93). Microsomal prostaglandin E ₂ synthetase-1 (mPGES-1) comprising the benzoxazinone derivative according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition for inhibition. The pharmaceutical composition according to claim 10, which is for treatment or prevention of inflammation, arthritis, high fever, pain, cancer, stroke or Alzheimer's disease.