Novel compounds with mTORC2 inhibitory activity and their applications

Abstract

This invention relates to a novel compound having mTORC2 inhibitory activity, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient. The novel compound of Chemical Formula 1 of this invention selectively inhibits mTORC2 activity and can therefore be effectively used to prevent, improve, or treat degenerative neurological diseases induced by hyperactivated mTORC2.

Description

[Technical Field]

[0001] The present invention relates to a novel compound having mTORC2 inhibitory activity, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient. [Background technology]

[0002] The mTOR complex exists as mTORC1 (mammalian target of rapamycin complex 1), composed of mTOR, mLST8, DEPTOR, Tti1 / Tel2, RAPTOR, and PRAS40, and mTORC2 (mammalian target of rapamycin complex 2), composed of mTOR, mLST8, DEPTOR, Tti1 / Tel2, RICTOR, mSIN1, and PROTOR1 / 2. Both mTORC1 and mTORC2 share mTOR, a serine / threonine protein kinase belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family, as a catalytic subunit. The two protein complexes act as a signaling hub, integrating signals from inside and outside the cell to regulate cellular metabolism, growth, proliferation, and survival. However, mTORC1 and mTORC2 have distinct characteristics in the composition of the protein complex, substrate specificity, and regulatory mechanisms, and are responsible for specific regions that produce specific cellular responses depending on the type of signal transmitted from above.

[0003] mTORC1 senses the levels of intracellular soluble energy and nutrients and regulates anabolism so that it proceeds only when energy and nutrients are sufficient. Specifically, if intracellular energy and nutrient levels are sufficiently high, mTORC1 phosphorylates 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1) to activate cap-dependent protein synthesis and also activates SREBP (sterol responsive element binding protein) to promote de novo lipid synthesis. Furthermore, mTORC1 inhibits catabolism by phosphorylating ULK1 and TFEB (transcription factor EB) to inhibit autophagy. Therefore, when intracellular energy and nutrient levels are high, mTORC1 promotes anabolism while suppressing catabolism, and conversely, when intracellular energy and nutrient levels are low, it suppresses anabolism and promotes catabolism, thus maintaining an equilibrium between anabolism and catabolism in accordance with the intracellular energy and nutrient levels.

[0004] In contrast to the function of mTORC1, mTORC2 receives signals transmitted from outside the cell and plays a role in guiding cells to survive, proliferate, or interact with each other in the appropriate place and time. Specifically, when the receptor is activated by insulin or growth factors, phosphoinositide 3-phosphorylation enzyme (PI3K) is activated, increasing PIP3 on the cell membrane, and PIP3 activates mTORC2. Once activated, mTORC2 phosphorylates and activates AGC kinase enzymes, including AKT (protein kinase B), SGK (serum and glucocorticoid-inducible kinase), and PKC (protein kinase C). AGC kinases have been shown to regulate cell survival, division, and metabolism. In addition, mTORC2 regulates the cytoskeleton by phosphorylating proteins that regulate actin filament structure, such as PKCα, PKCδ, Rho, and Rac1, thereby determining cell migration and tissue structure.

[0005] Once activated, mTORC2 is activated by phosphorylating Ser473 of AKT. Therefore, the degree of AKT Ser473 phosphorylation serves as an indicator of mTORC2 activity. Activated AKT phosphorylates TSC2 (Tuberous sclerosis complex 2), thereby repressing TSC2. TSC is the negative regulator of mTORC1, and it prevents the action of Rheb, a GTPase that directly binds to and activates mTORC1. Therefore, when TSC is inhibited, mTORC1 is activated. Activated mTORC1 phosphorylates S6K1 (p70S6 Kinase 1) Thr389, and phosphorylated and activated S6K1 promotes cap-dependent translation. Therefore, the degree of pS6K1 Thr389 phosphorylation serves as an indicator of mTORC1 activity.

[0006] The process of Aβ production from amyloid precursor protein (APP) in nerve cells primarily occurs during endocytosis. However, Arc protein is required for γ-secretase, the enzyme that cleaves APP, to bind to endosomes. Metabotropic glutamate receptor 1 / 5-dependent long-term depression (LTD) is mediated by Arc protein production in dendritic spines, and mTORC2 is required for this process. Therefore, mTORC2 hyperactivation in dendritic spines increases Arc protein production and promotes Aβ production. Consequently, mTORC2 inhibitors are useful in the treatment of Alzheimer's disease because they reduce Arc protein production in dendritic spines and suppress Aβ production.

[0007] Autophagy is a cellular physiological process that cleans up damaged or dysfunctional proteins and organelles. mTORC2 inhibits autophagy through the AKT / FoxO3 signaling pathway and mTORC1 activation. Studies have shown that autophagy activity is reduced in the brain tissue of Alzheimer's disease patients, leading to the accumulation of Aβ and tau aggregates generated within nerve cells. These accumulated protein aggregates further activate the mTOR signaling pathway, ultimately promoting nerve cell death. Therefore, mTORC2 inhibitors can prevent nerve cell death by promoting autophagy activity and removing accumulated Aβ and tau aggregates within nerve cells. Huntington's disease and spinocerebellar ataxia are caused by an abnormal increase in the CAG trinucleotide sequence within the Huntington gene and the Ataxin-1 gene, respectively. The Huntington and Ataxin-1 proteins, with their increased polyglutamine repeats, form aggregates within cells, inducing neuronal death (Koyuncu et al. (2017) Int.J.Mol.Sci.18:1568). Therefore, mTORC2 inhibitors may be useful in treating Huntington's disease and spinocerebellar ataxia by promoting autophagy and removing Huntington and Ataxin-1 protein aggregates.

[0008] Increased mTOR signaling or phosphorylation of S6K, a subtransmitter of mTORC1, is associated with increased Aβ and neurofibrillary tangle (NFT) accumulation in the brain tissue of Alzheimer's disease patients, and pathological accumulation of hyperphosphorylated tau is linked to activation of mTOR proteins by S2481 phosphorylation (Li et al. (2005) FEBS J.272:4211-4220). Furthermore, AKT, which activates mTORC1, is increased in the temporal lobe brain of Alzheimer's disease patients, and suppression of mTOR signaling shows physiological and behavioral relief in animal models that accumulate Aβ. Drug-induced and genetically engineered reductions in both Aβ levels are accompanied by decreased activity of the mTOR pathway, and it has been shown that suppression of the mTOR pathway alleviates symptoms in Parkinson's disease (PD) and Huntington's disease (HD), both types of degenerative neurological disorders (Lipton & Sahin (2014) Neuron 84:275-291).

[0009] Based on the above research results, the present invention predicts that novel compounds that suppress Aβ40 and Aβ42 production and promote autophagy will become target proteins for therapeutic agents of degenerative neurological diseases, including Alzheimer's disease. [Overview of the Initiative]

[0010] Problems that the invention aims to solve One example of this application provides a novel compound of chemical formula 1, or a pharmaceutically acceptable salt thereof.

[0011] [ka]

[0012] Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of degenerative neurological diseases comprising a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] Another object of the present invention is to provide a food composition for the prevention or improvement of degenerative neurological diseases, comprising a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] Another object of the present invention is to provide a use for the manufacture of compositions for the prevention, improvement, and / or treatment of degenerative neurological diseases, comprising a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0015] Another object of the present invention is to provide a method for preventing, improving, and / or treating a degenerative neurological disorder, comprising the step of administering an effective amount of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject (individual) in need of prevention, improvement, and / or treatment of a degenerative neurological disorder.

[0016] Another object of the present invention is to provide a method for producing a compound of chemical formula 1.

[0017] Means for solving the problem The inventors of this invention have made diligent efforts to discover a novel compound that can inhibit the activity of mTORC2 and exhibit therapeutic effects against degenerative neurological diseases induced by mTORC2 hyperactivation. As a result, they have discovered that the compound represented by chemical formula 1 herein has excellent inhibitory effects on mTORC2 activity and has the potential to exhibit therapeutic effects against degenerative neurological diseases associated with mTORC2 hyperactivation, thus completing the present invention.

[0018] One example of this application provides a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0019] [ka]

[0020] Definition of Terms The terms used in this specification are briefly explained below.

[0021] As used herein, the term "pharmaceutically acceptable salt" means a salt form of a compound that does not induce serious irritation in the organism to which the compound is administered and does not impair the biological activity and properties of the compound. In the present invention, this can refer collectively to any salt that possesses equivalent biological efficacy and properties of the compound of chemical formula 1 and is preferable in terms of pharmaceutically, biological, or other properties. A pharmaceutically acceptable salt may be an acid addition salt formed by an acid that forms a nontoxic acid addition salt containing a pharmaceutically acceptable anion, such as an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; an organic carbonic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; or an acid addition salt formed by a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. As a specific example, an acid addition salt of the compound in one embodiment can be obtained by reacting a compound in its free base form with a stoichiometric amount of a suitable acid. In this case, the reaction can proceed in water, an organic solvent, or a mixture thereof, and specifically in a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. In addition, depending on the pharmaceutically acceptable form of the salt, each form of salt can be obtained by a normal reaction obvious to those skilled in the art. Furthermore, pharmaceutically acceptable salts may be alkali metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts such as lysine, arginine, guanidine; or organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc.

[0022] As used herein, the term "aryl" refers to a carbocyclyl group (e.g., phenyl) having a shared π-electron system and at least one ring. This term includes monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups.

[0023] As used herein, the term "heteroaryl" refers to a heterocyclic aryl group having a shared π-electron system and at least one ring, including, but not limited to, furan, thiophene, pyrrole, imidazole, oxazole, isoxazole, oxadiazole, tetrazole, thiazole, imidazole, pyrazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

[0024] As used herein, the term "alkyl" means an aliphatic hydrocarbon group. The alkyl group may be a "saturated alkyl" group that does not contain any alkene or alkyne groups, or it may be an "unsaturated alkyl" group that contains at least one alkene or alkyne group. The "alkene" group means a group consisting of at least one carbon-carbon double bond, and the "alkyne" group means a group consisting of at least one carbon-carbon triple bond. For example, "alkyl" may be a saturated or unsaturated alkyl group having a linear, branched, or cyclic structure. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, profene, and butenyl. For example, C1-C4-alkyl groups have 1 to 4 carbon atoms in the alkyl chain and are selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0025] In this specification, alkyl groups are defined as C 1-10 The alkoxy group may be a linear or branched alkyl group, and the alkoxy group is C 1-10 It may be a linear or branched alkoxy group. 1-10 A linear or branched alkyl group, or C 1-10The linear or branched alkoxy groups can be independently of the number of carbon atoms: 1-10 (C1-C10), 1-9 (C1-C9), 1-8 (C1-C8), 1-7 (C1-C7), 1-6 (C1-C6), 1-5 (C1-C5), 1-4 (C1-C4), 1-3 (C1-C3), 1-2 (C1-C2), 1 (C1), 2-10 (C2-C10), 2-9 (C2-C9), 2-8 carbons (C2-C8), 2-7 carbons (C2-C7), 2-6 carbons (C2-C6), 2-5 carbons (C2-C5), 2-4 carbons (C2-C4), 2-3 carbons (C2-C3), 2 carbons (C2), carbon Number of 3 to 10 carbons (C3-C10), 3 to 9 carbons (C3-C9), 3 to 8 carbons (C3-C8), 3 to 7 carbons (C3-C7), 3 to 6 carbons (C3-C6), 3 to 5 carbons (C3-C5), 3 to 4 carbons (C3-C4) ), 3 carbons (C3), 4-10 carbons (C4-C10), 4-9 carbons (C4-C9), 4-8 carbons (C4-C8), 4-7 carbons (C4-C7), 4-6 carbons (C4-C6), 4-5 carbons (C4-C5) ), 4 carbons (C4), 5-10 carbons (C5-C10), 5-9 carbons (C5-C9), 5-8 carbons (C5-C8), 5-7 carbons (C5-C7), 5-6 carbons (C5-C6), 5 carbons (C5), 6 carbons It may be up to 10 carbon atoms (C6-C10), 6-9 carbon atoms (C6-C9), 6-8 carbon atoms (C6-C8), 6-7 carbon atoms (C6-C7), 6 carbon atoms (C6), 7-10 carbon atoms (C7-C10), 7-9 carbon atoms (C7-C9), 7-8 carbon atoms (C7-C8), 7 carbon atoms (C7), 8-10 carbon atoms (C8-10), 8-9 carbon atoms (C8-C9), 9 carbon atoms (C9), 9-10 carbon atoms (C9-C10), or 10 carbon atoms (C10).

[0026] As used herein, the term "halo" or "halogen" may refer to a fluorine group (-F), a chloro group (-Cl), a bromo group (-Br), or an iodine group (-I).

[0027] As used herein, the term "heterocycle" refers to a group in which a cyclic carbon is replaced by oxygen, nitrogen, sulfur, etc., and may optionally contain a double bond. Examples of heterocycles include, but are not limited to, pyrroline, pyrrolidine, tetrahydrofuran, imizolin, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, piperazine, morpholine, and thiomorpholine.

[0028] "Each can be substituted independently" means that if there are two or more substituted hydrogen atoms, each hydrogen atom can be substituted with the same or different substituents.

[0029] Terms other than those described herein can be interpreted as having the meanings that are ordinarily understood by those skilled in the art in which this invention pertains. [Modes for carrying out the invention]

[0030] The following provides a more detailed explanation of this application.

[0031] Compounds of chemical formula 1 One example of this application provides a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0032] [ka] In chemical formula 1, "X" is oxygen, sulfur, or a methylene group or a substituted amine. "R1" is hydrogen, a halo (F, Br, Cl, or I), or a substituted or unsubstituted carbon. 6-10 A substituted or unsubstituted 4- to 12-membered heteroaryl containing an aryl or one or more heteroatoms selected from the group consisting of N, O, and S, "R2" is hydrogen, a halo (F, Br, Cl, or I), or a substituted or unsubstituted carbon. 6-10 aryl, substituted or unsubstituted C 1-6is amino, substituted or unsubstituted 4- to 12-member heterocycloalkyl, or unsubstituted benzylamino, "R3" is hydrogen or halo (F, Br, Cl, or I), "R4" and "R5" are each independently unsubstituted C 1-6 alkoxy, or "R4" and "R5" can form -O(CH) n O- (n is 1 or 2) with two oxygen atoms, The substituted amine may be substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C 1-10 linear or branched alkyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted C 6-10 arylsulfonyl, at this time, the substituted linear or branched alkyl, aryl or arylsulfonyl may be substituted with C 1-5 linear or branched alkyl, The substituted aryl or substituted heteroaryl may be hydroxy (OH), halo (F, Br, Cl, or I), linear or branched alkyl substituted or unsubstituted with 1 to 3 halos, and unsubstituted C 1-10 linear or branched alkyl, and unsubstituted C 1-5 linear or branched alkoxy, and may be substituted with one or more (as used herein, "one or more" substitutions include substitution with two or more of the same substituents, for example, when substituted with two -OCH3) substituents selected from the group consisting of, The substituted amino is C 1-5 linear or branched alkyl, unsubstituted C 3-8 cycloalkyl, C 1-5 linear or branched alkoxy-substituted phenyl group-substituted C 1-5 linear alkyl, unsubstituted thiophenyl group-substituted C 1-5 linear alkyl, C 3-8 cycloalkyl and C 1-5 linear alkyl-substituted sulfonyl, and may be substituted with one or more substituents selected from the group consisting of, Substituted heterocycloalkyls are different from unsubstituted C 6-10 Aryl or unsubstituted C 6-10 Aryl C 1-6 It may be substituted with alkyl, Compounds of chemical formula 1 do not contain the following compounds: a) 2,3-dimethoxydibenz[b,e]oxepin-11(6H)-one; and b) 9-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one.

[0033] In chemical formula 1 of the present invention, "X" may be oxygen, sulfur, or a methylene group, and for example, "X" may be oxygen.

[0034] In Chemical Formula 1 of the present invention, "R1" is hydrogen, halo (F, Br, Cl, or I), substituted or unsubstituted C 6-10 The heteroaryl group may be a substituted or unsubstituted 4- to 10-membered heteroaryl group containing one or more heteroatoms selected from the group consisting of N, O, and S, specifically hydrogen (H), fluoro (F), bromo (Br), substituted or unsubstituted C 6-10 It may also be an aryl or an unsubstituted 4- to 6-membered heteroaryl containing O as a heteroatom.

[0035] The substituted aryl group "R1" can be hydroxy(OH), fluoro(F), chloro(Cl), or substituted or unsubstituted C with 1-3 fluoro groups. 1-3 Linear alkyl and unsubstituted C 1-3It may be substituted with 1 to 3 substituents selected from the group consisting of linear alkoxys, specifically, it may be substituted with one substituent selected from the group consisting of hydroxy (OH), fluoro (F), chloro (Cl), trifluoro (CF3), methyl (CH3), and 1 to 3 methoxy (OCH3) groups.

[0036] The heteroaryl group "R1" may also be furanyl.

[0037] In Chemical Formula 1 of the present invention, "R2" is hydrogen, halo (-F, -Br, -Cl, or -I), substituted or unsubstituted C 6-10 The C6 aryl group may be an aryl group, a substituted or unsubstituted amino group, a substituted or unsubstituted 4- to 6-membered heterocycloalkyl group, or an unsubstituted benzylamino group, specifically, hydrogen (H), fluoro (F), a substituted C6 aryl group, or a substituted or unsubstituted C6 group. 1-6 It may be an alkylamino, a substituted or unsubstituted six-membered heterocycloalkyl, or an unsubstituted benzylamino.

[0038] The substituted aryl group "R2" is chloro(Cl), while the unsubstituted C is C. 1-3 Linear alkyl and unsubstituted C 1-3 It may be substituted with 1 to 3 substituents selected from the group consisting of linear alkoxys, specifically, it may be substituted with one substituent selected from the group consisting of chloro(Cl), methyl(CH3), and 1 to 3 methoxy(OCH3) groups.

[0039] The amino acid substituted with "R2" is C 1-5 Linear or branched alkyl, unsubstituted C5-7 cycloalkyl, C 1-4 C substituted with a phenyl group substituted with a linear or branched alkoxy 1-4 Linear alkyl, C substituted with an unsubstituted thiophenyl group 1-4 Linear alkyl and C 1-4It may be substituted with one to three substituents selected from the group consisting of linear alkyl-substituted sulfonyl groups, specifically, it may be substituted with one substituent selected from the group consisting of two methyl (CH3), cyclohexyl, phenethyl, thiophenylethyl, and methylsulfonyl groups.

[0040] The heterocycloalkyl group substituted with "R2" may also be substituted with an unsubstituted phenyl group.

[0041] The heterocycloalkyl group "R2" may be morpholine, piperidine, or piperazine, specifically unsubstituted morpholine, unsubstituted piperidine, or piperazine substituted with unsubstituted phenyl.

[0042] In Chemical Formula 1 of the present invention, "R3" may be hydrogen or a halo (F, Br, Cl, or I), and more specifically, it may be hydrogen or a fluorocarbon.

[0043] In Chemical Formula 1 of the present invention, "R4" and "R5" are each independently unsubstituted C 1-3 It is an alkoxy, or "R4" and "R5" together with two oxygen atoms -O(CH) n O-(n is 1 or 2) can be formed, specifically, "R4" and "R5" may each be independently methoxy, or "R4" and "R5" may form -O(CH)2O- with the two oxygen atoms.

[0044] More specifically, in chemical formula 1, "X" is oxygen, sulfur, or a methylene group. "R1" stands for hydrogen (H), fluorocarbon (F), bromocarbon (Br), [ka] It is one selected from the group consisting of (in the substituted compound shown, the asterisk (*) indicates the part that is bonded to another group).

[0045] "R2" stands for hydrogen (H), fluorocarbon (F), [ka] It may be one species selected from the group consisting of the following:

[0046] "R4" and "R5" can each be independently a substituted or unsubstituted methoxy, or "R4" and "R5" can form a dioxolane column with two oxygen atoms.

[0047] For example, the compound of chemical formula 1 may be one or more compounds selected from the group consisting of the following compounds. 1) 9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2203); 2[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2204; 3) 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2208); 4) 8-(dimethylamino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2209); 5) 8-(morpholino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2210); 6) 8-(piperidinyl)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2211); 7) 8-(phenylpiperazine-1-yl)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one)(HN2212); 8) 8-(benzylamino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2213); 9)9-(4-chlorophenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2214); 10)9-(4-hydroxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2215); 11)9-(3-furanyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2216); 12)9-(p-tolyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2217); 13) 9-(4-methoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2218); 14)9-(2,4-dimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2219); 15) 9-(3,4,5-trimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2220); 16) 8-(cyclohexylamino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2221); 17) 8-(4-benzylpiperidin-1-yl)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2222); 18)8-((4-methoxyphenethyl)amino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2223); 19)8-((2-(thiophen-2-yl)ethyl)amino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2224); 20) 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2225); 21) 8-(dimethylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2226); 22) 8-(morpholino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2227); 23) 8-(piperidinyl)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2228); 24) 8-(phenylpiperazine-1-yl)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2229); 25) 8-(benzylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2230); 26) 8-(cyclohexylamine)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2231); 27) 8-(4-benzylpiperidin-1-yl)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2232); 28)8-((4-methoxyphenethyl)amino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2233); 29) 8-((2-(thiophen-2-yl)ethyl)amino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2234); 30) 9-bromo-2,3-dimethoxydibenz[b,e]oxepin-11(6H)-one (HN2235); 31) 9-(2,4-dimethoxyphenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one (HN2236); 32) 9-(3,4-dimethoxyphenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one (HN2237); 33) 2,3-dimethoxy-9-(3-methoxyphenyl)dibenzo[b,e]oxepin-11(6H)-one (HN2238); 34) 9-(4-fluorophenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one (HN2239); 35) 8-(4-chlorophenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2240); 36) 8-(p-tolyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2241); 37) 8-(4-methoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2242); 38) 8-(2,4-dimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2243); 39) 8-(3,4,5-trimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2244); 40) 2,3-dimethoxy-9-(4-(trifluoromethyl)phenyl)dibenzo[b,e]oxepin-11(6H)-one (HN2245); 41) N-(9-fluoro-11-oxo-6,11-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-8-yl)methanesulfonamide (HN2301); 42) N-(7-fluoro-11-oxo-6,11-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-8-yl)methanesulfonamide)(HN2302); 43) 2,3-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2303); 44) 9-bromo-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (HN2304); 45) 2,3-dimethoxy-9-(3,4,5-trimethoxyphenyl)dibenzo[b,e]thiepin-11(6H)-one (HN2305); 46) 2,3-dimethoxy-9-(4-methoxyphenyl)dibenzo[b,e]thiepin-11(6H)-one (HN2306); 47) 2,3-dimethoxy-9-(p-tolyl)dibenzo[b,e]thiepin-11(6H)-one (HN2307); 48) 9-(3-furanyl)-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (HN2308); 49) 9-(4-chlorophenyl)-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (HN2309); 50) 10,11-dihydro-5H-benzo[4',5']cyclohepta[1',2':4,5]benzo[1,2-d][1,3]dioxol-5-one (HN2310); 51) 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2311); 52) 8-(cyclopropylamino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2312); 53) 8-(cyclopentylamino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2313); 54) 2-(dimethylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2314); 55) 3-fluoro-7,8-dimethoxy-2-(piperidin-1-yl)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2315); 56) 3-fluoro-7,8-dimethoxy-2-(4-phenylpiperazin-1-yl)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2316); 57) 2-(benzylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2317); 58) 8-(cyclopropylamino)-7-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2318); 59) 8-(cyclopentylamino)-7-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2319); 60) 2-(cyclopropylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2320); 61) 2-(cyclopentylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2321); 62)8-((2,4-dichlorophenethyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one)(HN2322); 63) 9-fluoro-8-((2-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2323); 64) 8,9-difluoro-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (HN2324); 65) 9-fluoro-8-((3-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2325); 66)9-fluoro-8((4-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2326); 67) 9-fluoro-8-((3-methoxyphenethyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2327); 68)8-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one)(HN2328); 69)8-((3,4-dimethoxybenzyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one)(HN2329); 70) 8-Bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2336); and 71) 2,3-dimethoxy-5-tosyl-5,6-dihydro-11H-dibenzo[b,e]azepin-11-one (HN2337).

[0048] Activity of the compound of chemical formula 1 The compound of Chemical Formula 1 of the present invention can inhibit mTORC1 (mammalian target of rapamycin complex 1) activity and / or mTORC2 (mammalian target of rapamycin complex 2) activity, specifically selectively inhibiting mTORC2 activity, and has preventive, ameliorative, and / or therapeutic activity for degenerative neurological diseases.

[0049] The inhibition of mTORC1 activity can be confirmed by measuring the degree to which it inhibits p70S6K Thr389 phosphorylation in human cells, and the inhibition of mTORC2 activity can be confirmed by measuring the degree to which it inhibits AKT Ser473 phosphorylation in human cells. Measurement can be performed by Western blotting, but is not limited to this method.

[0050] In one embodiment of the present invention, it was confirmed that the compound of chemical formula 1 can suppress AKT Ser473 phosphorylation and p70S6K Thr389 phosphorylation simultaneously in human cells, and the compound of chemical formula 1 had mTORC1 and / or mTORC2 inhibitory activity. Furthermore, in one embodiment, it was confirmed that the compound of chemical formula 1 had an even higher inhibitory effect on AKT Ser473 phosphorylation than on p70S6K Thr389 phosphorylation inhibition, and the compound of chemical formula 1 can selectively inhibit mTORC2 activity.

[0051] The compound of chemical formula 1 of the present invention can inhibit mTORC2 complex formation.

[0052] Degenerative neurological disorders refer to diseases that occur in the central nervous system among degenerative disorders, and these disorders are caused by excessive activity of mTORC2.

[0053] Degenerative neurological disorders include Alzheimer's disease, senile dementia, Lewy body dementia, frontotemporal dementia, mild cognitive impairment, Parkinson's disease, Pieck's disease, Huntington's disease, spinocerebellar atrophy, multiple neuronal atrophy, epilepsy, encephalopathy, stroke, cerebral amyloid vasculopathy, Down syndrome, systemic amyloid disease, Niemann-Pick disease, amyotrophic lateral sclerosis, Tourette's syndrome, Friedrich's ataxia, Machado-Joseph's disease, dystonia, and progressive supranuclear palsy. It may be one or more of the group consisting of (Supranuclear Palsy), and in one realized case, the degenerative neurological disorder is Alzheimer's disease.

[0054] In this specification, “prevention” means all actions that suppress or delay the onset of a disease by administering a composition relating to an example; “treatment” means all actions that improve or beneficially alter the symptoms of an individual suspected of having a disease or who has developed a disease by administering a composition relating to an example; and “improvement” can mean all actions that at least reduce parameters related to the state in which a disease is treated, such as the severity of symptoms, by administering a composition relating to an example.

[0055] Due to the activity of the compound of chemical formula 1, the present invention provides a composition for inhibiting mTORC2 activity comprising the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0056] The composition for inhibiting mTORC2 activity may be a pharmaceutical composition or a food composition, but is not limited thereto.

[0057] Furthermore, due to the activity of the compound of chemical formula 1, the present invention provides a composition for the prevention or treatment of degenerative neurological diseases comprising the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0058] The composition may be, but is not limited to, a pharmaceutical composition or a food composition.

[0059] Pharmaceutical composition The present invention provides a composition for the prevention or treatment of degenerative neurological diseases, comprising a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0060] The composition may be a pharmaceutical composition or a food composition.

[0061] Furthermore, the present invention provides a method for preventing, improving, or treating a degenerative neurological disorder, comprising the step of administering an effective amount of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of prevention, improvement, or treatment of a degenerative neurological disorder.

[0062] The method may additionally include a step prior to the administration step to identify subjects who require prevention, improvement, and / or treatment of degenerative neurological disorders.

[0063] Other examples include applications for the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of compositions for the prevention, improvement, or treatment of degenerative neurological diseases.

[0064] The composition may be a pharmaceutical composition.

[0065] A pharmaceutically acceptable salt of the compound of chemical formula 1 may be one or more selected from the group consisting of acid addition salts, metal salts, amino acid salts, and organic salts of the compound of chemical formula 1. Acid addition salts may be formed from inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; organic carbon acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and salicylic acid; or from sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Metal salts may be alkali metal salts or alkaline earth metal salts formed from lithium, sodium, potassium, calcium, magnesium, etc. Amino acid salts may be amino acid salts formed from lysine, arginine, guanidine, etc. The organic salt may be an organic salt formed from dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc.

[0066] The target of administration of the pharmaceutical composition may be one or more mammals selected from among humans, primates such as monkeys, rodents such as mice and rats, livestock such as dogs, cats, pigs, cattle, horses, sheep, and goats, and poultry such as chickens, ducks, geese, quail, and turkeys, or cells, tissues, or cultures thereof derived from these. For example, the target of administration may be a person who needs prevention, improvement, and / or treatment of degenerative neurological diseases, and may be, for example, a human.

[0067] A pharmaceutical composition containing a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be formulated and used in the form of a conventional pharmaceutical preparation. For example, pharmaceutical preparations can be manufactured in various formulations for oral or parenteral administration, and the form of the preparation can be determined in various ways depending on the method of use, method of administration, purpose of administration, etc.

[0068] When manufactured in various formulations for oral or parenteral administration, the formulation can be manufactured using one or more ingredients selected from the group consisting of commonly used fillers, bulking agents, binders, wetting agents, disintegrants, diluents such as surfactants, and excipients.

[0069] Solid formulations for oral administration include tablets, pills, powders, granules, and capsules. Such solid formulations can be manufactured by mixing an active ingredient with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium talc styreneate can also be used. Liquid formulations for oral administration may include suspensions, liquid formulations, oils, and syrups. When formulating into liquid formulations, water and / or liquid paraffin, which are commonly used simple diluents, are used, and optionally, one or more other excipients, such as humectants, sweeteners, fragrances, and preservatives, may be added.

[0070] Parenteral administration can also be carried out via routes such as intravenous, intramuscular, subcutaneous, intraperitoneal, intranasal, transdermal, endothelial, topical, and intrapulmonary administration. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, oils, lyophilized agents, and suppositories. Non-aqueous solvents for the manufacture of non-aqueous solutions, or suspension solvents for the manufacture of suspensions, include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Bases for suppositories include witepsol, macrogol, tween 61, cocoa butter, lauric butter, and glycerogelatin. For intranasal administration, the pharmaceutical composition is diluted and administered by nasal spray, which is absorbed into the nasal cavity via a nebulizer or spray system. Nasal spray formulations or respiratory formulations for nasal spray include aerosols.

[0071] The content of the active ingredient of the compound of chemical formula 1 or its pharmaceutically acceptable salt contained in the pharmaceutical composition shall be, on a weight basis of the whole pharmaceutical composition, 0.01% to 99.9% by weight, 0.01% to 90% by weight, 0.01% to 80% by weight, 0.01% to 70% by weight, 0.01% to 60% by weight, 0.01% to 50% by weight, 0.01% to 40% by weight, 0.01% to 30% by weight, 1% to 99.9% by weight, 1% to 90% by weight, 1% to 80% by weight, 1% to 70% by weight, 1% to 60% by weight, 1% to 50% by weight, and 1% to 40% by weight. The percentage may be %, 1% to 30% by weight, 5% to 99.9% by weight, 5% to 90% by weight, 5% to 80% by weight, 5% to 70% by weight, 5% to 60% by weight, 5% to 50% by weight, 5% to 40% by weight, 5% to 30% by weight, 10% to 99.9% by weight, 10% to 90% by weight, 10% to 80% by weight, 10% to 70% by weight, 10% to 60% by weight, 10% to 50% by weight, 10% to 40% by weight, or 10% to 30% by weight, but is not limited thereto and can be appropriately adjusted depending on the form of the formulation, method of administration, purpose of administration, etc.

[0072] The pharmaceutically effective dose of a pharmaceutical composition containing a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof as the active ingredient varies depending on factors such as the formulation method, administration method, patient's age, weight, sex, medical condition, diet, administration time, administration interval, administration route, excretion rate, and response sensitivity. It is administered or taken once to several times a day, but is not limited to this and can be administered in various doses and methods. For example, the single dose of a pharmaceutical composition is in the range of 0.001 mg / kg to 100 mg / kg, but is not limited to this range.

[0073] As used herein, the term "pharmaceutical effective amount" refers to the amount of active ingredient that produces the desired pharmaceutical effect, and in some cases, to the concentration or dosage of the active ingredient in the pharmaceutical composition required to produce the desired pharmaceutical effect.

[0074] Manufacturing method Another example provides a method for producing the compound of chemical formula 1. A detailed method for producing the compound of chemical formula 1 will be described below.

[0075] Effects of the invention The present invention relates to a novel compound having mTORC2 inhibitory activity, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient. The novel compound of chemical formula 1 of the present invention selectively suppresses mTORC2 activity and can therefore be effectively used to prevent, improve, or treat degenerative neurological diseases (e.g., Alzheimer's disease) induced by hyperactivated mTORC2. [Brief explanation of the drawing]

[0076] [Figure 1-1] The left figure shows the results of Western blot analysis to evaluate the time-dependent mTORC2 inhibitory activity, mTORC1 inhibitory activity, and LC-II activity of the compound in question in primary cultured cerebral nerve cells, along with graphs (right) showing the changes in Akt Ser473 phosphorylation, Akt Thr308 phosphorylation, and LC3-II activity. Specifically, Figure 1a shows the results for HN2210, Figure 1b for HN2213, Figure 1c for HN2304, Figure 1d for HN2308, Figure 1e for HN2313, and Figure 1f for HN2323. [Figure 1-2] Same as above [Figure 1-3] Same as above [Figure 2-1]The images above are confocal scanning microscope images (top) and graph (bottom) showing, in numerical values ​​per 20 μm length of dendritic spine, that the phosphorylation of AKT-S473 (green dots) induced by mTORC2 activation (DHPG) was suppressed by the compound of this application when dendritic spines (PSD95+) of primary cultured hippocampal neurons were treated with DHPG, an mGluR1 / 5 agonist. Specifically, Figure 2a shows the results for HN2209, Figure 2b for HN2210, Figure 2c for HN2213, Figure 2d for HN2216, Figure 2e for HN2304, Figure 2f for HN2305, Figure 2g for HN2308, Figure 2h for HN2309, Figure 2i for HN2313, Figure 2j for HN2323, Figure 2k for HN2325, and Figure 2l for HN2329. [Figure 2-2] Same as above [Figure 2-3] Same as above [Figure 2-4] Same as above [Figure 2-5] Same as above [Figure 2-6] Same as above [Figure 3-1] The images above are confocal scanning microscope images (top) and graphs (bottom) showing the concentration-dependent inhibitory activity of the compound in this study on mGluR1 / 5-dependent mTORC2 activity in dendritic spines (PSD95+) of hippocampal neurons at 25, 50, and 100 nM. Specifically, Figure 3a shows the results for HN2210, Figure 3b for HN2213, Figure 3c for HN2221, Figure 3d for HN2308, and Figure 3e for HN2313. [Figure 3-2] Same as above [Figure 3-3] Same as above [Figure 4] This figure shows the activity of inhibiting binding by treatment with the compound of this application, after expressing and separating mTOR protein and mLST8 protein within the mTOR complex in E. coli and insect cells, and inducing binding in an in vitro test tube. [Figure 5]The results of a Y-maze test were performed on 5xFAD, a model mouse for dementia, after administering the compound of this application (5 mg / kg) for two weeks. The control group was administered DMSO, the commercially available dementia treatment donepezil (1 mg / kg), or rapamycin (5 mg / kg), an inhibitor of mTORC1 and mTORC2, for two weeks. [Figure 6] The results of a water maze test were performed on 5xFAD, a model mouse for dementia, after administering the compound of this application (5 mg / kg) for two weeks. Specifically, Figure 6a shows the number of target crossings by the mice, and Figure 6b shows the time spent in the quadrant zone by the mice. The control group was administered DMSO, the commercially available dementia treatment donepezil (1 mg / kg), or rapamycin (5 mg / kg), an mTORC1 and mTORC2 inhibitor, for two weeks. [Figure 7] This report describes the results of a passive avoidance test conducted on 5xFAD, a model mouse for dementia, after administering the compound of this application (5 mg / kg) for two weeks. The control group was administered DMSO, the commercially available dementia treatment donepezil (1 mg / kg), or rapamycin (5 mg / kg), an mTORC1 and mTORC2 inhibitor, for two weeks. [Figure 8-1] The following are the results of administering the compound of this application to dementia model mice 5xFAD at doses of 0.2 mg / kg, 1 mg / kg, and 5 mg / kg for two weeks, followed by Y-maze tests, underwater maze tests, and passive avoidance tests. Specifically, Figure 8a shows the results of the Y-maze test, Figure 8b shows the results of the underwater maze test and the number of target crossings by the mice, Figure 8c shows the results of the underwater maze test and the time spent in the quadrant zone by the mice, and Figure 8d shows the results of the passive avoidance test. [Figure 8-2] Same as above [Figure 9-1]Figure 9 shows the amyloid plaque removal effect confirmed in brain tissue of 5xFAD dementia model mice administered the compound of this application (5 mg / kg) for two weeks. Specifically, Figure 9a is a confocal scanning microscope image showing the amyloid plaque removal effect by the compound of this application in the hippocampal region, where amyloid plaques are most frequently observed, stained with 6E10 antibody or thioflavin-S; Figure 9b is a graph quantitatively showing the 6E10 antibody signal-positive region in the dentate gyrus (DG); and Figure 9c is a graph quantitatively showing the thioflavin-S signal-positive region in the dentate gyrus. [Figure 9-2] Same as above [Figure 10] This figure shows the tau aggregate removal effect observed in brain tissue of 5xFAD dementia model mice administered the compound of this application (5 mg / kg) for two weeks. Specifically, Figure 10a is a confocal scanning microscope image showing the tau aggregate removal effect by the compound of this application in the hippocampal region, where neurofibrillary tangles (NFTs) are most frequently observed, stained with hyperphosphorylated Tau immunoantibody (AT8) (hyperphosphorylated Tau - green, MAP2 - nerve - red, DAPI - cell nucleus). Figure 10b is a graph quantitatively showing the AT8 antibody signal-positive region in the dentate gyrus. [Figure 11] This figure shows the anti-inflammatory effect observed in brain tissue of 5xFAD, a dementia model mouse, after administration of the compound (5 mg / kg) for two weeks. Specifically, Figure 11a is a confocal scanning microscope image showing the anti-inflammatory effect of the compound by staining the brain inflammation response using IBA-1, an antibody that immunostains activated microglia, and Figure 11b is a graph quantitatively showing the IBA-1 antibody signal-positive region in the dentate gyrus.

[0077] The present invention will be described more specifically below with reference to the following embodiments. However, these are for illustrative purposes only, and the scope of the present invention is not limited by these embodiments. [Examples]

[0078] General steps in compound synthesis and NMR analysis 1.Analytical equipment The instruments used to confirm the structure of the product obtained in this experiment are as follows: Nuclear magnetic resonance spectroscopy ( 1 For 1H NMR, a Bruker MagnetSystem 500' 54 Ascend and a JEOL JNM-ECZ500R were used, with the solvents being CDCl3, MeOH-d4, or DMSO-d6.

[0079] 2.General process General manufacturing method 1: General manufacturing process for Methyl 2-bromomethyl benzoate derivative (2) [ka]

[0080] Step 1: Preparation of Methyl 2-methylbenzoate compound 1 2-Methylbenzoic acid S1 (1 equivalent) was dissolved in DMF, and then K2CO3 (1.5 equivalents) and MeI (1.5 equivalents) were added. The reaction mixture was stirred at room temperature while monitoring with TLC until the reaction was complete. H2O was added to the reaction mixture to terminate the reaction, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compound 1 was obtained by purification using column chromatography with 5% HCl solvent in n-hexane.

[0081] Step 2: Preparation of Methyl 2-bromomethyl benzoate compound 2 After dissolving methyl 2-methylbenzoate 1 (1 equivalent) prepared in step 1 in 1,2-dichloroethane (CCl4 can also be used), N-bromosuccinimide (1.1 equivalents) was added. The mixture was stirred under reflux conditions while monitoring by TLC until the reaction was complete. The reaction mixture was cooled and extracted with CH2Cl2. The organic layer was washed with H2O and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compound 2 was obtained by purification using column chromatography with 5% SiO2 solvent in n-hexane.

[0082] General Manufacturing Method 2: General Manufacturing Process for Dibenzo[b,e]oxepin-11(6H)-one Derivative 6 [ka]

[0083] Step 1: Preparation of Methyl 2-(phenoxymethyl)benzoate compound 4 Methyl 2-bromomethylbenzoate 2 (1 equivalent), prepared by general method 1, was dissolved in DMF, and then phenol compound 3 (1.5 equivalents) and K2CO3 (2 equivalents) were added. The mixture was stirred at room temperature while monitoring by TLC until the reaction was complete. H2O was added to the reaction mixture to terminate the reaction, and the mixture was extracted with SiO2. The organic layer was washed with H2O and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compound 4 was obtained by purification using column chromatography with 5-10% SiO2 solvent in n-hexane.

[0084] Step 2: Preparation of 2-(Phenoxymethyl)benzoic acid compound 5 After dissolving methyl 2-(phenoxymethyl)benzoate 4 (1 equivalent) prepared in Step 1 in MeOH:THF:H2O (1:1:1), KOH (4 equivalents) was added. The mixture was stirred under reflux conditions while monitoring by TLC until the reaction was complete. The reaction mixture was cooled, the solvent was removed under vacuum, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and 1NHCl and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compound 5 was obtained by purification using column chromatography with 5% MeOH solvent in CH2Cl2.

[0085] Step 3: Preparation of ibenzo[b,e]oxepin-11(6H)-one compound 6 After dissolving 2-(phenoxymethyl)benzoic acid 5 (1 equivalent) prepared in step 2 in CH2Cl2, BF3·OEt2 (0.1 equivalent) and trifluoroacetic anhydride (3 equivalents) were added. The mixture was stirred under reflux conditions while monitoring by TLC until the reaction was complete. After cooling the reaction mixture, NaHCO3 was added to terminate the reaction, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compound 6 was obtained by purification by column chromatography.

[0086] General manufacturing method 3: General manufacturing process of Dibenzo[b,e]thiepin-11(6H)-one derivative 10 [ka]

[0087] Step 1: Preparation of Methyl 2-((phenylthio)methyl)benzoate compound 8 Methyl 2-bromomethylbenzoate 2 (1 equivalent), prepared by general method 1, was dissolved in DMF, and then thiol compound 7 (1 equivalent) and K2CO3 (2 equivalents) were added. The mixture was stirred at room temperature while monitoring by TLC until the reaction was complete. H2O was added to the reaction mixture to terminate the reaction, and the mixture was extracted with SiO2. The organic layer was washed with water and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compound 8 was obtained by purification using column chromatography with 10-15% SiO2 solvent in n-hexane.

[0088] Step 2: Preparation of 2-((Phenylthio)methyl)benzoic acid compound 9 After dissolving methyl 2-((phenylthiol)methyl)benzoate 8 (1 equivalent) prepared in Step 1 in MeOH:THF:H2O (1:1:1), KOH (4 equivalents) was added. The mixture was stirred under reflux conditions while monitoring by TLC until the reaction was complete. The reaction mixture was cooled, the solvent was removed under vacuum, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and 1NHCl and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compound 9 was obtained by purification using column chromatography with 5% MeOH solvent in CH2Cl2.

[0089] Step 3: Preparation of Dibenzo[b,e]thiepin-11(6H)-one compound 10 After dissolving 2-((phenylthio)methyl)benzoic acid 9 (1 equivalent) prepared in step 2 in CH2Cl2, BF3·OEt2 (0.1 equivalent) and trifluoroacetic anhydride (3 equivalents) were added. The mixture was stirred under reflux conditions while monitoring by TLC until the reaction was complete. After cooling the reaction mixture, NaHCO3 was added to terminate the reaction, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compound 10 was obtained by purification using column chromatography.

[0090] General manufacturing process 4: General manufacturing process of 10,11-Dihydro-5H-dibenzo[a,d][7]annulen-5-one derivative [ka]

[0091] Step 1: Preparation of Methyl 2-phenethylbenzoate compound 13 Methyl 2-bromomethylbenzoate 2 (1 equivalent) and PPh3 (1.1 equivalents), prepared by general method 1, were dissolved in acetone, and the mixture was stirred overnight under reflux conditions. The reaction mixture was cooled, the precipitate was filtered, and washed with acetone to obtain benzyltriphenylphosphonium bromide salt 11, which was used in the next reaction without further purification.

[0092] 60% NaH (2 equivalents) was added to a THF solution of benzyltriphenylphosphonium bromide salt 11 (1.3 equivalents) at 0°C. After stirring for 1 hour, benzaldehyde 12 (1 equivalent) was added. The reaction was stirred at room temperature while monitoring by TLC until completion. The reaction was terminated by adding saturated NH4Cl aqueous solution and extracted with ELISA. The organic layer was washed with water and dried over anhydrous MgSO4. After removing the solvent under vacuum, the next reaction was carried out without purification. The concentrated mixture was dissolved in MeOH and a catalytic amount of Pd / C was added. After injecting H2 gas and stirring for 3 hours, the catalyst was removed by filtration through Celite. The solvent was removed by vacuum concentration. The target methyl 2-phenethylbenzoate compound 13 was obtained by purification by column chromatography.

[0093] Step 2: Preparation of 2-Phenethylbenzoic acid compound 14 After dissolving methyl 2-phenethylbenzoate compound 13 (1 equivalent) prepared in step 1 in MeOH:THF:H2O (1:1:1), KOH (4 equivalents) was added. The mixture was stirred under reflux conditions while monitoring by TLC until the reaction was complete. The reaction mixture was cooled, the solvent was removed under vacuum, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and 1NHCl and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compound 14 was obtained by purification using column chromatography with 5% MeOH solvent in CH2Cl2.

[0094] Step 3: Preparation of 10,11-Dihydro-5H-dibenzo[a,d][7]annulen-5-one compound 15 After dissolving 2-phenylethylbenzoic acid 14 (1 equivalent) prepared in step 2 in CH2Cl2, BF3·OEt2 (0.1 equivalent) and trifluoroacetic anhydride (3 equivalents) were added. The mixture was stirred under reflux conditions while monitoring by TLC until the reaction was complete. After cooling the reaction mixture, NaHCO3 was added to terminate the reaction, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compound 15 was obtained by purification using column chromatography.

[0095] General method 5: Nucleophilic aromatic substitution [ka]

[0096] To DMSO, p-fluorobenzophenone compound of chemical formula 16 (1 equivalent), K2CO3 (1 equivalent), tetrabutylammonium bromide (0.5 equivalents), and amine compound of chemical formula 17 (3-5 equivalents), prepared by general methods 2-4, were added. The reaction mixture was stirred at 90°C while monitoring by TLC until the reaction was complete. The reaction mixture was cooled, water was added to terminate the reaction, and the mixture was extracted with CH2Cl2. The organic layer was washed with water and dried over anhydrous Na2SO4. After removing the solvent under vacuum, the target compound 18 was obtained by purification using column chromatography.

[0097] General manufacturing method 6: Suzuki cross-coupling reaction [ka]

[0098] Bromobenzofenone compounds of chemical formulas 19-20 (1 equivalent), boronic acid of chemical formula 21 (1.5 equivalents), and K2CO3 (4 equivalents), prepared by general methods 2-4, were dissolved in aq.DMF (H2O:DMF=1:5). Then, Pd(PPh3)4 (0.1 equivalent) was added. The reaction mixture was stirred at 90°C while monitoring by TLC until the reaction was complete. After cooling the reaction mixture, H2O was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with H2O and dried over anhydrous MgSO4. After removing the solvent under vacuum, the target compounds 22-23 were obtained by purification using column chromatography.

[0099] General production method 7: General production of 5,6-dihydro-11H-dibenzo[b,e]azepin-11-one [ka]

[0100] Step 1: Preparation of methyl 2-((4-methylphenyl)sulfonamido)benzoate compound 25 After dissolving methyl 2-aminobenzoate 24 (1 equivalent) in 1,2-Dichloroethane, p-TsCl (1.2 equivalents) and pyridine (3 equivalents) were added. The mixture was stirred at room temperature while monitoring by TLC until the reaction was complete. H2O was added to the reaction mixture to terminate the reaction, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and dried over anhydrous Na2SO4. After removing the solvent under vacuum, the target compound 25 was obtained by purification using column chromatography with 5% siRNA and 50% methylene chloride in n-hexane.

[0101] Step 2: Preparation of methyl 2-((N-benzyl-4-methylphenyl)sulfonamido)benzoate compound 27 In a flame-dried round-bottom flask, methyl 2-((4-methylphenyl)sulfonamido)benzoate 25 (1 equivalent), prepared in Step 1, was dissolved in DMF. Then, 60% NaH (2 equivalents) was added at 0°C, and the mixture was stirred for 30 minutes. After 30 minutes of stirring, benzyl bromide 26 (2 equivalents) was added. The mixture was stirred at room temperature while monitoring by TLC until the reaction was complete. H2O was added to the reaction mixture to terminate the reaction, and the mixture was extracted with SiO2. The organic layer was washed with H2O and dried over anhydrous Na2SO4. After removing the solvent under vacuum, the target compound 27 was obtained by column chromatography using 25% SiO2 solvent in n-hexane.

[0102] Step 3: Preparation of 2-((N-benzyl-4-methylphenyl)sulfonamido)benzoic acid compound 28 After dissolving methyl 2-((N-benzyl-4-methylphenyl)sulfonamido)benzoate 27 (1 equivalent) prepared in step 2 in MeOH:THF:H2O (1:1:1), KOH (4 equivalents) was added. The mixture was stirred under reflux conditions while monitoring by TLC until the reaction was complete. The reaction mixture was cooled, the solvent was removed under vacuum, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and 1NHCl and dried over anhydrous Na2SO4. After removing the solvent under vacuum, the target compound 28 was obtained by purification using column chromatography with 5% MeOH solvent in CH2Cl2.

[0103] Step 4: Preparation of 5,6-dihydro-11H-dibenzo[b,e]azepin-11-one compound 29 After dissolving 2-((N-benzyl-4-methylphenyl)sulfonamido)benzoic acid 28 (1 equivalent) prepared in step 3 in CH2Cl2, BF3·OEt2 (0.1 equivalent) and trifluoroacetic anhydride (3 equivalents) were added. The mixture was stirred under reflux conditions while monitoring by TLC until the reaction was complete. After cooling the reaction mixture, NaHCO3 was added to terminate the reaction, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and dried with anhydrous Na2SO4. After removing the solvent under vacuum, the target compound 29 was obtained by purification using column chromatography with 40% siRNA in n-hexane.

[0104] <Example 1> Preparation of 9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2203) [ka]

[0105] Step 1: Preparation of Methyl 5-fluoro-2-methylbenzoate Following the reaction between 5-Fluoro-2-methylbenzoic acid (100 mg, 0.648 mmol) and iodomethane (0.05 mL, 0.778 mmol) using the manufacturing method of Step 1 of General Manufacturing Method 1, the resulting product was purified by column chromatography using 5% ethyl acetate solvent in n-hexane to obtain Methyl 5-fluoro-2-methylbenzoate 9 (2.6 mg, 85%).

[0106] Step 2: Preparation of Methyl 2-bromomethyl-5-fluorobenzoate Following the reaction between Methyl 5-fluoro-2-methylbenzoate (30 mg, 0.178 mmol) produced in Step 1 and N-Bromosuccinimide (34.7 mg, 0.196 mmol) using the manufacturing method of Step 2 of General Manufacturing Method 1, the mixture was purified by column chromatography using 5% ethyl acetate solvent in n-hexane to obtain Methyl 2-bromomethyl-5-fluorobenzoate (41 mg, 93%).

[0107] Step 3: Preparation of Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-5-fluorobenzoate Following the manufacturing method of Step 1 of General Manufacturing Method 2, Methyl 2-bromomethyl-5-fluorobenzoate (123.1 mg, 0.498 mmol) produced in Step 2 was reacted with sesamol (103.2 mg, 0.747 mmol), and then purified by column chromatography using 10% ethyl acetate solvent in n-hexane to obtain Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-5-fluorobenzoate (87.3 mg, 58%).

[0108] Step 4: Preparation of 2-[(1,3-Benzodioxol-5-yloxy)methyl]-5-fluorobenzoic acid Using the manufacturing method of Step 2 of General Manufacturing Method 2, Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-5-fluorobenzoate (67 mg, 0.22 mmol) produced in Step 3 was reacted to obtain 2-[(1,3-Benzodioxol-5-yloxy)methyl]-5-fluorobenzoic acid (59.5 mg, 93%).

[0109] Step 5: Preparation of 9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one Following the manufacturing method in step 3 of general manufacturing method 2, 2-[(1,3-Benzodioxol-5-yloxy)methyl]-5-fluorobenzoic acid (30 mg, 0.103 mmol) produced in step 4 was reacted, and then purified by column chromatography using 25% ethyl acetate solvent in n-hexane to obtain 9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (26.9 mg, 96%).

[0110] 1 H NMR(500MHz,CDCl3)δ7.65(s,1H),7.63(d,J=2.4Hz,1H),7.33(dd,J=8.2,5. 2Hz,1H),7.22(td,J=8.1,2.5Hz,1H),6.49(s,1H),6.02(s,2H),5.13(s,2H)

[0111] <Example 2> Preparation of [2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2204) [ka]

[0112] Step 1: Preparation of Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]benzoate Following the reaction between methyl 2-(bromomethyl)benzoate (50 mg, 0.218 mmol) and sesamol (45.3 mg, 0.327 mmol) using the manufacturing method of step 2 of general manufacturing method 2, the mixture was purified by column chromatography using 10% ethyl acetate solvent in n-hexane to obtain methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]benzoate (37.4 mg, 59%).

[0113] Step 2: Preparation of 2-[(1,3-Benzodioxol-5-yloxy)methyl]benzoic acid Using the manufacturing method of Step 1 of General Manufacturing Method 2, Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]benzoate (75 mg, 0.261 mmol) produced in Step 1 was reacted to obtain 2-[(1,3-Benzodioxol-5-yloxy)methyl]benzoic acid (47.4 mg, 67%).

[0114] Step 3: Preparation of [2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one Following the reaction with 2-[(1,3-Benzodioxol-5-yloxy)methyl]benzoic acid (29.6 mg, 0.108 mmol) produced in step 2 using the manufacturing method of step 3 of general manufacturing method 2, [2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (28.8 mg, 98%) was obtained by column chromatography using methylene chloride solvent.

[0115] 1 H NMR(500MHz,CDCl3)δ7.94(d,J=7.7Hz,1H),7.68(s,1H),7.54(t,J=7.2Hz,1H),7 .47(t,J=7.6Hz,1H),7.33(d,J=7.4Hz,1H),6.50(s,1H),6.01(s,2H),5.16(s,2H)

[0116] <Example 3> Preparation of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2208) [ka]

[0117] Step 1: Preparation of Methyl 4,5-difluoro-2-methylbenzoate Following the reaction between 4,5-Difluoro-2-methylbenzoic acid (100 mg, 0.581 mmol) and iodomethane (0.043 mL, 0.697 mmol) using the manufacturing method of Step 1 of General Manufacturing Method 1, the product was purified by column chromatography using 5% ethyl acetate solvent in n-hexane to obtain Methyl 4,5-difluoro-2-methylbenzoate (109 mg, 99%).

[0118] Step 2: Preparation of Methyl 2-bromomethyl-4,5-difluorobenzoate Following the reaction between Methyl 4,5-difluoro-2-methylbenzoate (100 mg, 0.537 mmol) produced in Step 1 and N-Bromosuccinimide (104.6 mg, 0.590 mmol) using the manufacturing method of Step 2 of General Manufacturing Method 1, the mixture was purified by column chromatography using 5% ethyl acetate solvent in n-hexane to obtain Methyl 2-bromomethyl-4,5-difluorobenzoate (114.3 mg, 80%).

[0119] Step 3: Preparation of Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-4,5-difluorobenzoate Following the manufacturing method of Step 1 of General Manufacturing Method 2, Methyl 2-bromomethyl-4,5-difluorobenzoate (100 mg, 0.377 mmol) produced in Step 2 was reacted with sesamol (62.4 mg, 0.452 mmol), and then purified by column chromatography using 10% ethyl acetate solvent in n-hexane to obtain Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-4,5-difluorobenzoate 54.5 mg, 45%).

[0120] Step 4: Preparation of 2-[(1,3-Benzodioxol-5-yloxy)methyl]-4,5-difluorobenzoic acid Using the manufacturing method of Step 2 of General Manufacturing Method 2, Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-4,5-difluorobenzoate (30 mg, 0.093 mmol) produced in Step 3 was reacted to obtain 2-[(1,3-Benzodioxol-5-yloxy)methyl]-4,5-difluorobenzoic acid (20.8 mg, 73%).

[0121] Step 5: Preparation of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one Following the manufacturing method in step 3 of general manufacturing method 2, 2-[(1,3-Benzodioxol-5-yloxy)methyl]-4,5-difluorobenzoic acid (40 mg, 0.129 mmol) produced in step 4 was reacted, and then purified by column chromatography using methylene chloride solvent to obtain 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (21.3 mg, 57%).

[0122] 1 H NMR(500MHz,CDCl3)δ7.82(dd,J=10.8,8.0Hz,1H),7.65(s,1H),7.16(dd,J=9.5,7.2Hz,1H),6.50(s,1H),6.03(s,2H),5.09(s,2H)

[0123] <Example 4> Preparation of 8-(dimethylamino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2209) [ka]

[0124] Using the general manufacturing method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (20 mg, 0.068 mmol) from Example 3 was reacted with dimethylamine (0.1 mL), and then purified by column chromatography using methylene chloride solvent to obtain 8-(dimethylamino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (18.4 mg, 86%).

[0125] 1 H NMR(500MHz,DMSO-d6)δ7.57(d,J=15.4Hz,1H),7.52(s,1H),6.97(d,J=8.9Hz,1H),6.71(s,1H),6.13(s,2H),5.18(s,2H),3.00(d,J=1.3Hz,6H)

[0126] <Example 5> Preparation of 8-(morpholino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2210) [ka]

[0127] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (20 mg, 0.068 mmol) from Example 3 was reacted with morpholine (0.03 mL, 0.340 mmol), and then purified by column chromatography using methylene chloride solvent to obtain 8-(morpholino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (24.3 mg, 99%).

[0128] 1H NMR(500MHz,DMSO-d6)δ7.59(d,J=14.4Hz,1H),7.51(s,1H),7.18(d,J=8.5Hz,1 H),6.71(s,1H),6.13(s,2H),5.21(s,2H),3.79-3.74(m,4H),3.23-3.18(m,4H)

[0129] <Example 6> Preparation of 8-(piperidinyl)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2211) [ka]

[0130] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (20 mg, 0.068 mmol) from Example 3 was reacted with piperidine (0.03 mL, 0.34 mmol), and then purified by column chromatography using methylene chloride solvent to obtain 8-(piperidinyl)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (9.0 mg, 37%).

[0131] 1 H NMR(500MHz,MeOD)δ7.64(s,1H),7.61(s,1H),7.01(d,J=8.3Hz,1H),6.57(s,1H),6.06(s,2H),5.15(s,2H),3.26(s,2H),3.18-3.15(m,8H)

[0132] <Example 7> Preparation of 8-(phenylpiperazine-1-yl)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2212) [ka]

[0133] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 3 was reacted with 1-phenylpiperidine (0.047 mL, 0.310 mmol). The mixture was then purified by column chromatography using 5-9% ethyl acetate and 50% methylene chloride solvent in n-hexane to obtain 8-(phenylpiperazine-1-yl)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (43.6 mg, 97%).

[0134] 1 H NMR(500MHz,DMSO-d6)δ7.62(d,J=14.3Hz,1H),7.52(s,1H),7.26(dd,J=16.1,8.0Hz,3H),7. 03(d,J=8.1Hz,2H),6.84(s,1H),6.73(s,1H),6.14(s,2H),5.23(s,2H),3.39(d,J=3.2Hz,4H)

[0135] <Example 8> Preparation of 8-(benzylamino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2213) [ka]

[0136] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 3 was reacted with benzylamine (0.056 mL, 0.517 mmol). The mixture was then purified by column chromatography using 5% ethyl acetate and 50% methylene chloride solvent in n-hexane to obtain 8-(benzylamino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (32.2 mg, 82%).

[0137] 1 H NMR(500MHz,DMSO-d6)δ7.58(d,J=13.1Hz,1H),7.52(s,1H),7.40(d,J=7.0Hz,2H),7.35(t,J=7.7Hz, 2H),7.26(s,1H),6.73(d,J=8.3Hz,1H),6.66(s,1H),6.12(s,2H),5.06(s,2H),4.49(d,J=6.3Hz,2H)

[0138] <Example 9> Preparation of 9-(4-chlorophenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2214) [ka]

[0139] Step 1: Preparation of Methyl 5-bromo-2-methylbenzoate Following the reaction between 5-Bromo-2-methylbenzoic acid (200 mg, 0.930 mmol) and iodomethane (0.07 mL, 1.116 mmol) using the manufacturing method of Step 1 of General Manufacturing Method 1, the mixture was purified by column chromatography using 5% ethyl acetate solvent in n-hexane to obtain Methyl 5-bromo-2-methylbenzoate (218.7 mg, 98%).

[0140] Step 2: Preparation of Methyl 2-bromomethyl-5-bromobenzoate Following the manufacturing method of Step 2 of General Manufacturing Method 1, Methyl 5-bromo-2-methylbenzoate (100 mg, 0.436 mmol) produced in Step 1 was reacted with N-Bromosuccinimide (85.5 mg, 0.480 mmol), and then purified by column chromatography using 5% ethyl acetate solvent in n-hexane to obtain Methyl 2-bromomethyl-5-bromobenzoate (120 mg, 90%).

[0141] Step 3: Preparation of Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-5-bromobenzoate Following the manufacturing method of Step 1 of General Manufacturing Method 2, Methyl 2-bromomethyl-5-bromobenzoate (120 mg, 0.389 mmol) produced in Step 2 was reacted with sesamol (64.5 mg, 0.467 mmol), and then purified by column chromatography using 10% ethyl acetate solvent in n-hexane to obtain Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-5-bromobenzoate (55.2 mg, 63%).

[0142] Step 4: Preparation of 2-[(1,3-Benzodioxol-5-yloxy)methyl]-5-bromobenzoic acid Following the manufacturing method of Step 2 of General Manufacturing Method 2, the Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-5-bromobenzoate (20 mg, 0.054 mmol) produced in Step 3 was reacted to obtain 2-[(1,3-Benzodioxol-5-yloxy)methyl]-5-bromobenzoic acid (24.1 mg, 97%).

[0143] Step 5: Preparation of 9-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one Following the manufacturing method described in step 3 of general manufacturing method 2, 2-[(1,3-Benzodioxol-5-yloxy)methyl]-5-bromobenzoic acid (10 mg, 0.029 mmol) produced in step 4 was reacted, and then purified by column chromatography using 25% ethyl acetate solvent in n-hexane to obtain 9-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one 22 (9.3 mg, 80%).

[0144] Step 6: Preparation of 9-(4-chlorophenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one Following the manufacturing method of General Method 6, 9-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.09 mmol) prepared in step 5 was reacted with 4-chlorophenylboronic acid (21.1 mg, 0.135 mmol), and then purified by column chromatography using 66% methylene chloride solvent in n-hexane. The purified compound was decanted with n-hexane to obtain 9-(4-chlorophenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (31 mg, 94%).

[0145] 1 H NMR(500MHz,CDCl3)δ8.13(d,J=2.0Hz,1H),7.72(dd,J=7.8,2.0Hz,1H),7.69(s, 1H),7.58-7.53(m,2H),7.45-7.39(m,3H),6.51(s,1H),6.03(s,2H),5.19(s,2H)

[0146] <Example 10> Preparation of 9-(4-hydroxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2215) [ka]

[0147] Following the reaction of the 22 compounds (35 mg, 0.105) produced in step 5 using the general manufacturing method 6, the compounds were purified by column chromatography using 5-20% ethyl acetate solvent in n-hexane to obtain 9-(4-hydroxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one.

[0148] 1 H NMR(500MHz,DMSO-d6)δ9.67(s,1H),7.94(d,J=2.0Hz,1H),7.84(dd,J=7.8,2.0Hz,1H),7.57(d,J=7 .9Hz,1H),7.56-7.52(m,2H),7.50(s,1H),6.92-6.82(m,2H),6.72(s,1H),6.13(s,2H),5.26(s,2H)

[0149] <Example 11> Preparation of 9-(3-furanyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2216) [ka]

[0150] Following the manufacturing method of General Method 6, the 22 compounds (30 mg, 0.09 mmol) prepared in step 5 of Practical Example 9 were reacted with 3-furylboronic acid (15.1 mg, 0.135 mmol), and then purified by column chromatography using 2.5% ethyl acetate and 50% methylene chloride solvent in n-hexane. The purified compound was decanted with n-hexane to obtain 9-(3-furanyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (27.7 mg, 96%).

[0151] 1 H NMR(500MHz,CDCl3)δ8.04(d,J=1.9Hz,1H),7.80(dd,J=1.4,0.9Hz,1H),7.68(s,1H),7.64(dd,J=7.7,1.9Hz,1H) ,7.49(t,J=1.7Hz,1H),7.34(d,J=7.8Hz,1H),6.75(dd,J=1.9,0.9Hz,1H),6.50(s,1H),6.02(s,2H),5.15(s,2H)

[0152] <Example 12> Preparation of 9-(p-tolyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2217) [ka]

[0153] Following the manufacturing method of General Method 6, the 22 compounds (30 mg, 0.09 mmol) produced in step 5 of Practical Example 9 were reacted with 4-methylphenylboronic acid (18.3 mg, 0.135 mmol), and then purified by column chromatography using 66% methylene chloride solvent in n-hexane. The purified compound was decanted with n-hexane to obtain 9-(p-tolyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (24.3 mg, 78%).

[0154] 1 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 7.7, 1.9 Hz, 1H), 7.69 (s, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 6.51 (s, 1H), 6.02 (s, 2H), 5.18 (s, 2H), 2.40 (s, 3H)

[0155] <Example 13> Preparation of 9-(4-methoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2218) [Chemical formula]

[0156] Using the production method of General Production Method 6, 22 compound (30 mg, 0.09 mmol) produced in Step 5 of Practical Example 9 was reacted with 4-methoxyphenylboronic acid (20.5 mg, 0.135 mmol), and then purified by column chromatography using a solvent of 3% ethyl acetate in n-hexane and 50% methylene chloride to obtain 9-(4-methoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30.3 mg, 93%).

[0157] 1 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 7.8, 2.0 Hz, 1H), 7.69 (s, 1H), 7.60 - 7.54 (m, 2H), 7.38 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.51 (s, 1H), 6.02 (s, 2H), 5.18 (s, 2H), 3.86 (s, 3H)

[0158] <Example 14> Preparation of 9-(2,4-dimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2219)

Chemical formula

[0159] According to the production method of General Production Method 6, after reacting the 22 compound (35 mg, 0.105 mmol) produced in Step 5 of Practical Example 9 with 2,4-dimethoxyphenylboronic acid (28.0 mg, 0.158 mmol), it was purified by column chromatography using a 5 - 33% ethyl acetate solvent in n-hexane to obtain 9-(2,4-dimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one.

[0160] 1 H NMR (500 MHz, CDCl3) δ8.06 (d, J = 1.8 Hz, 1H), 7.69 (q, J = 1.9 Hz, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.28 (s, 1H), 6.59 - 6.55 (m, 2H), 6.50 (s, 1H), 6.01 (s, 2H), 5.17 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H)

[0161] <Example 15> Preparation of 9-(3,4,5-trimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (HN2220)

Chemical formula

[0162] Following the manufacturing method of General Method 6, the 22 compound (30 mg, 0.09 mmol) produced in step 5 of Practical Example 9 was reacted with 3,4,5-trimethoxyphenylboronic acid (28.6 mg, 0.135 mmol). The mixture was then purified by column chromatography using 12% ethyl acetate and 50% methylene chloride in n-hexane to obtain 9-(3,4,5-trimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (36.2 mg, 95%).

[0163] 1 H NMR(500MHz,CDCl3)δ8.12(d,J=1.9Hz,1H),7.72(dd,J=7.7,2.0Hz,1H),7.69(s,1H),7.40(d ,J=7.8Hz,1H),6.81(s,2H),6.51(s,1H),6.03(s,2H),5.19(s,2H),3.93(s,6H),3.90(s,3H)

[0164] <Example 16> Preparation of 8-(cyclohexylamino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2221) [ka]

[0165] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (20 mg, 0.068 mmol) from Example 3 was reacted with cyclohexylamine (0.04 mL, 0.340 mmol). The mixture was then purified by column chromatography using 17% ethyl acetate solvent in n-hexane to obtain 8-(cyclohexylamino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (22.4 mg, 89%).

[0166] 1 H NMR(500MHz,DMSO-d6)δ7.56(d,J=13.3Hz,1H),7.53(s,1H),6.84(d,J=8.3Hz,1H),6.69(s,1H),6 .12(s,2H),5.15(s,2H),1.94(d,J=11.3Hz,2H),1.71(dd,J=55.1,13.0Hz,4H),1.41-1.29(m,4H)

[0167] <Example 17> Preparation of 8-(4-benzylpiperidin-1-yl)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2222) [ka]

[0168] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (20 mg, 0.068 mmol) from Example 3 was reacted with 4-benzylpiperidine (0.06 mL, 0.340 mmol). The mixture was then purified by column chromatography using 17% ethyl acetate solvent in n-hexane to obtain 8-(4-benzylpiperidin-1-yl)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (13.3 mg, 44%).

[0169] 1H NMR(500MHz,DMSO-d6)δ7.56(d,J=14.5Hz,1H),7.51(s,1H),7.34-7.28(m,2 H),7.22(d,J=7.5Hz,3H),7.13(d,J=8.6Hz,1H),6.71(s,1H),6.13(s,2H),5. 19(s,2H),3.62(d,J=12.4Hz,2H),2.80(t,J=11.4Hz,2H),2.58(d,J=7.0Hz, 2H),1.77-1.72(m,1H),1.69(d,J=13.6Hz,2H),1.36(dd,J=20.9,12.0Hz,3H)

[0170] <Example 18> Preparation of 8-((4-methoxyphenethyl)amino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2223) [ka]

[0171] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (20 mg, 0.068 mmol) from Example 3 was reacted with 1-(4-methoxyphenyl)ethylamine (0.05 mL, 0.340 mmol). The mixture was then purified by column chromatography using 25% ethyl acetate solvent in n-hexane to obtain 8-((4-methoxyphenethyl)amino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (22.9 mg, 80%).

[0172] 11H NMR (500 MHz, DMSO-d6) δ 7.56 (d, J = 13.2 Hz, 1H), 7.53 (s, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H), 6.12 (s, 2H), 5.15 (s, 2H), 3.73 (s, 3H), 3.43 - 3.38 (m, 2H), 2.87 - 2.82 (m, 2H)

[0173] <Example 19> Preparation of 8 - ((2 - (thiophen - 2 - yl)ethyl)amino)-9 - fluoro[2]benzoxepino[3,4 - f]-1,3 - benzodioxol - 11(6H)-one (HN2224)

Chemical Structure

[0174] According to the production method of General Production Method 5, 8,9 - difluoro[2]benzoxepino[3,4 - f]-1,3 - benzodioxol - 11(6H)-one (20 mg, 0.068 mmol) of Example 3 was reacted with 2 - thiopheneethylamine (0.04 mL, 0.340 mmol), and then purified by column chromatography using a 25% ethyl acetate solvent in n - hexane to obtain 8 - ((2 - (thiophen - 2 - yl)ethyl)amino)-9 - fluoro[2]benzoxepino[3,4 - f]-1,3 - benzodioxol - 11(6H)-one (17.2 mg, 64%).

[0175] 1 1H NMR (500 MHz, DMSO - d6) δ 7.56 (d, J = 13.1 Hz, 1H), 7.52 (s, 1H), 7.38 - 7.32 (m, 1H), 6.98 (d, J = 3.7 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.72 - 6.70 (m, 1H), 6.69 (s, 1H), 6.12 (s, 2H), 5.14 (s, 2H), 3.49 (dd, J = 13.2, 7.1 Hz, 2H), 3.14 (t, J = 7.2 Hz, 2H)

[0176] <Example 20> Preparation of 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2225) [ka]

[0177] Step 1: Preparation of Methyl 3,4-difluoro-2-methylbenzoate Methyl 3,4-difluoro-2-methylbenzoate (937.3 mg, 86%) was obtained in the same manner as in Step 1 of Example 3, except that 3,4-difluoro-2-methylbenzoic acid (1.0 g, 5.811 mmol) was used instead of 4,5-difluoro-2-methylbenzoic acid in Step 1 of Example 3.

[0178] Step 2: Preparation of Methyl 2-bromomethyl-3,4-difluorobenzoate Methyl 2-bromomethyl-3,4-difluorobenzoate (1.28 g, 97%) was obtained in the same manner as in Step 2 of Example 3, except that Methyl 3,4-difluoro-2-methylbenzoate (930 mg, 4.995 mmol) prepared in Step 1 was used instead of Methyl 4,5-difluoro-2-methylbenzoate in Step 2 of Example 3.

[0179] Step 3: Preparation of Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-3,4-difluorobenzoate Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-3,4-difluorobenzoate (1.35 g, 87%) was obtained in the same manner as in step 3 of Example 3, except that Methyl 2-bromomethyl-3,4-difluorobenzoate (1.28 g, 4.844 mmol) prepared in step 2 was used instead of Methyl 2-bromomethyl-4,5-difluorobenzoate in step 3 of Example 3.

[0180] Step 4: Preparation of 2-[(1,3-Benzodioxol-5-yloxy)methyl]-3,4-difluorobenzoic acid Using the manufacturing method of Step 2 of General Manufacturing Method 2, Methyl 2-[(1,3-benzodioxol-5-yloxy)methyl]-3,4-difluorobenzoate (1.344 g, 4.171 mmol) produced in Step 3 was reacted to obtain 2-[(1,3-Benzodioxol-5-yloxy)methyl]-3,4-difluorobenzoic acid (1.25 g, 97%).

[0181] Step 5: Preparation of 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (1.07 g, 91%) was obtained in the same manner as in step 5 of Example 3, except that 2-[(1,3-Benzodioxol-5-yloxy)methyl]-3,4-difluorobenzoic acid (1.245 g, 4.039 mmol) prepared in step 4 was used instead of 2-[(1,3-Benzodioxol-5-yloxy)methyl]-4,5-difluorobenzoic acid in step 5 of Example 3.

[0182] 1H NMR(500MHz,CDCl3)δ7.75(ddd,J=8.7, 4.8, 1.7Hz,1H),7.64(s,1H),7.27-7.22(m,1H),6.52(s,1H),6.03(s,2H),5.29(d,J=0.7Hz,2H)

[0183] <Example 21> Preparation of 8-(dimethylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2226) [ka]

[0184] 8-(dimethylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (20 g, 92%) was obtained in the same manner as in Example 4, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (20 mg, 0.069 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 4.

[0185] 1 H NMR(500MHz,DMSO-d6)δ7.63(d,J=8.8Hz,1H),7.49(s,1H),6.97(t,J=9.0Hz,1H),6.69(s,1H),6.11(s,2H),5.27(s,2H),2.96(d,J=1.5Hz,6H)

[0186] <Example 22> Preparation of 8-(morpholino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2227) [ka]

[0187] 8-(morpholino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (32.5 mg, 88%) was obtained in the same manner as in Example 5, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 5.

[0188] 1 H NMR(500MHz,DMSO-d6)δ7.65(d,J=8.4Hz,1H),7.48(s,1H),7.12(t,J=8.6Hz,1H), 6.70(s,1H),6.11(s,2H),5.29(s,2H),3.75(t,J=4.8Hz,4H),3.16(t,J=4.8Hz,4H)

[0189] <Example 23> Preparation of 8-(piperidinyl)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2228) [ka]

[0190] 8-(piperidinyl)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (32.1 mg, 87%) was obtained in the same manner as in Example 6, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 6.

[0191] 1 H NMR(500MHz,DMSO-d6)δ7.63(d,J=8.4Hz,1H),7.48(s,1H),7.10(t,J=8.8Hz,1H),6.70(s, 1H),6.11(s,2H),5.28(s,2H),3.14(t,J=5.3Hz,4H),1.65-1.64(m,4H),1.58-1.57(m,2H)

[0192] <Example 24> Preparation of 8-(phenylpiperazine-1-yl)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2229) [ka]

[0193] 8-(phenylpiperazine-1-yl)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (37.5 mg, 83%) was obtained in the same manner as in Example 7, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 7.

[0194] 1 H NMR(500MHz,DMSO-d6)δ7.67(d,J=8.8Hz,1H),7.49(s,1H),7.25(dd,J=7.3,8.8Hz,2H),7.18(t,J=8.8Hz, 1H),6.99(d,J=8.0Hz,2H),6.81(t,J=7.3Hz,1H),6.71(s,1H),6.12(s,2H),5.31(s,2H),3.34-3.30(m,4H)

[0195] <Example 25> Preparation of 8-(benzylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2230) [ka]

[0196] 8-(benzylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 8, except that 8-(benzylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30.2 mg, 77%) was obtained in the same manner as in Example 8, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 8.

[0197] 1 H NMR(500MHz,DMSO-d6)δ7.54(d,J=8.4Hz,1H),7.48(s,1H),7.35-7.29(m,4H),7.22(d ,J=6.9Hz,2H),6.66(t,J=8.8Hz,2H),6.09(s,2H),5.26(s,2H),4.45(d,J=6.3Hz,2H)

[0198] <Example 26> Preparation of 8-(cyclohexylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2231) [ka]

[0199] 8-(cyclohexylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (29.2 mg, 76%) was obtained in the same manner as in Example 16, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (29.2 mg, 76%) from Example 16.

[0200] 1 H NMR(500MHz,DMSO-d6)δ7.64(d,J=8.8Hz,1H),7.50(s,1H),6.83(t,J=8.8Hz,1H),6.68(s,1H),6.10(s ,2H),5.24(s,2H),1.90(d,J=11.1Hz,2H),1.72(d,J=12.6Hz,2H),1.64-1.57(m,2H),1.36-1.27(m,4H)

[0201] <Example 27> Preparation of 8-(4-benzylpiperidin-1-yl)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2232) [ka]

[0202] 8-(4-benzylpiperidin-1-yl)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (39.1 mg, 84.9%) was obtained in the same manner as in Example 17, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (39.1 mg, 84.9%) from Example 17.

[0203] 1 H NMR(500MHz,DMSO-d6)δ7.61(d,J=8.8Hz,1H),7.48(s,1H),7.28(t,J=7.6Hz,2 H),7.18(t,J=7.6Hz,3H),7.08(t,J=8.6Hz,1H),6.69(s,1H),6.11(s,2H),5.2 7(s,2H),3.53(d,J=12.2Hz,2H),2.75(t,J=11.3Hz,2H),2.56(d,J=6.9Hz,2H) ,1.75-1.71(m,1H),1.67(d,J=13.4Hz,2H),1.34(ddd,J=23.8,11.7,3.2Hz,2H)

[0204] <Example 28> Preparation of 8-((4-methoxyphenethyl)amino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2233) [ka]

[0205] 8-((4-methoxyphenethyl)amino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (36.1 mg, 82.8%) was obtained in the same manner as in Example 18, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 18.

[0206] 1 H NMR(500MHz,DMSO-d6)δ7.66(d,J=8.8Hz,1H),7.51(s,1H),7.18(d,J=8.4Hz,2H),6.86-6.83(m,3H),6 .68(s,1H),6.10(s,2H),5.25(s,2H),3.71(s,3H),3.38(dd,J=14.4,6.3Hz,2H),2.80(t,J=7.6Hz,2H)

[0207] <Example 29> Preparation of 8-((2-(thiophen-2-yl)ethyl)amino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2234) [ka]

[0208] 8-((2-(thiophen-2-yl)ethyl)amino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (34.6 mg, 84%) was obtained in the same manner as in Example 19, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 19.

[0209] 1 H NMR(500MHz,DMSO-d6)δ7.65(d,J=8.4Hz,1H),7.51(s,1H),7.32(dd,J=4.3,1.8Hz,1H),6.95(t,J=4.0Hz,2H),6.84(t ,J=8.6Hz,1H),6.68(s,1H),6.61(s,1H),6.10(s,2H),5.25(s,2H),3.47(dd,J=7,1,13.2Hz,2H),3.09(t,J=7.1Hz,2H)

[0210] <Example 30> Preparation of 9-bromo-2,3-Dimethoxydibenz[b,e]oxepin-11(6H)-one(HN2235) [ka]

[0211] Step 1: Preparation of Methyl 2-[(3,4-dimethoxyphenoxy)methyl]-5-bromobenzoate Methyl 5-bromo-2-(bromomethyl)benzoate (95.8 mg, 0.311 mmol) prepared in Step 2 of Example 9 was reacted with 3,4-dimethoxyphenol (57.5 mg, 0.373 mmol), and then purified by column chromatography using 25% ethyl acetate solvent in n-Hexane to obtain methyl 2-[(3,4-dimethoxyphenoxy)methyl]-5-bromobenzoate (86.5 mg, 73%).

[0212] Step 2: Preparation of 2-[(3,4-dimethoxyphenoxy)methyl]-5-bromobenzoic acid According to the manufacturing method of Step 2 of General Manufacturing Method 2, Methyl 2-[(3,4-dimethoxyphenoxy)methyl]-5-bromobenzoate (40 mg, 0.105 mmol) produced in Step 1 was reacted to obtain 2-[(3,4-dimethoxyphenoxy)methyl]-5-bromobenzoic acid (36.5 mg, 95%).

[0213] Step 3: Preparation of 9-bromo-2,3-Dimethoxydibenz[b,e]oxepin-11(6H)-one Following the reaction of 2-[(3,4-dimethoxyphenoxy)methyl]-5-bromobenzoic acid (37.7 mg, 0.103 mmol) produced in step 2 using the manufacturing method of step 3 of general manufacturing method 2, the product was purified by column chromatography using 9% ethyl acetate and 50% methylene chloride solvent in n-hexane to obtain 9-bromo-2,3-Dimethoxydibenz[b,e]oxepin-11(6H)-one (31.7 mg, 88%).

[0214] 1H NMR(500MHz,CDCl3)δ8.07(d,J=2.1Hz,1H),7.66(dd,J=7.3,2.8Hz,2H),7.24(d,J=8.0Hz,1H),6.50(s,1H),5.12(s,2H),3.94(s,3H),3.92(s,3H)

[0215] <Example 31> Preparation of 9-(2,4-dimethoxyphenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one(HN2236) [ka]

[0216] Following the production method of General Method 6, 9-bromo-2,3-Dimethoxydibenz[b,e]oxepin-11(6H)-one (10 mg, 0.028 mmol) from Example 30 was reacted with 2,4-Dimethoxyphenylboronic acid (7.8 mg, 0.043 mmol). The reaction was then purified by column chromatography using 33% ethyl acetate solvent in n-hexane to obtain 9-(2,4-dimethoxyphenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one (11.5 mg, 90%).

[0217] 1 H NMR(500MHz,CDCl3)δ8.06(d,J=1.6Hz,1H),7.71(s,1H),7.68(dd,J=7.7,1.9Hz,1H),7.35(d,J=7.6Hz,1H),7.25( d,J=8.4Hz,1H),6.57-6.54(m,2H),6.50(s,1H),5.17(s,2H),3.92,(s,3H),3.90(s,3H),3.84(s,3H),3.78(s,3H)

[0218] <Example 32> Preparation of 9-(3,4-dimethoxyphenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one(HN2237) [ka]

[0219] Following the production method of General Method 6, 9-bromo-2,3-Dimethoxydibenz[b,e]oxepin-11(6H)-one (25 mg, 0.072 mmol) from Example 30 was reacted with 3,4-Dimethoxyphenylboronic acid (19.5 mg, 0.107 mmol). The mixture was then purified by column chromatography using 20-33% ethyl acetate solvent in n-hexane to obtain 9-(3,4-dimethoxyphenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one (19.7 mg, 67%).

[0220] 1 H NMR(500MHz,CDCl3)δ8.12(d,J=1.9Hz,1H),7.73(d,J=2.0Hz,1H),7.71(s,1H),7.39(d,J=8.1Hz,1H),7.18(dd,J=8.4,1.9 Hz,1H),7.12(d,J=2.3Hz,1H),6.94(d,J=8.4Hz,1H),6.51(s,1H),5.18(s,2H),3.93(d,J=3.1Hz,6H),3.91(d,J=3.1Hz,6H)

[0221] <Example 33> Preparation of 2,3-dimethoxy-9-(3-methoxyphenyl)dibenzo[b,e]oxepin-11(6H)-one(HN2238) [ka]

[0222] Following the production method of General Method 6, 9-bromo-2,3-Dimethoxydibenz[b,e]oxepin-11(6H)-one (25 mg, 0.072 mmol) from Example 30 was reacted with 3-methoxyphenylboronic acid (16.3 mg, 0.107 mmol). The mixture was then purified by column chromatography using 33% ethyl acetate solvent in n-hexane to obtain 2,3-dimethoxy-9-(3-methoxyphenyl)dibenzo[b,e]oxepin-11(6H)-one (24.5 mg, 91%).

[0223] 1 H NMR(500MHz,CDCl3)δ8.16(d,J=1.9Hz,1H),7.74(dd,J=7.8,2.1Hz,1H),7.71(s,1H),7.41(d,J=7.6Hz,1H),7.35(t,J=8.0Hz,1H),7.2 0(d,J=8.0Hz,1H),7.14(t,J=2.1Hz,1H),6.91(dd,J=8.2,2.5Hz,1H),6.51(s,1H),5.19(s,2H),3.93(s,3H),3.91(s,3H),3.85(s,3H)

[0224] <Example 34> Preparation of 9-(4-fluorophenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one(HN2239) [ka]

[0225] Following the production method of General Method 6, 9-bromo-2,3-Dimethoxydibenz[b,e]oxepin-11(6H)-one (25 mg, 0.072 mmol) from Example 30 was reacted with 4-fluorophenylboronic acid (15.0 mg, 0.107 mmol). The mixture was then purified by column chromatography using 6% ethyl acetate and 90% methylene chloride solvent in n-hexane to obtain 9-(4-fluorophenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one (24 mg, 92%).

[0226] 1 H NMR(500MHz,CDCl3)δ8.11(d,J=1.9Hz,1H),7.71-7.69(m,2H),7.59-7.56(m,2H),7.41(d ,J=8.0Hz,1H),7.13(t,J=8.8Hz,2H),6.51(s,1H),5.19(s,2H),3.93(s,3H),3.91(s,3H)

[0227] <Example 35> Preparation of 8-(4-chlorophenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2240) [ka]

[0228] 8-(4-chlorophenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one was obtained in the same manner as in step 6 of Example 9, except that 8-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (35 mg, 0.105 mmol) from Example 76 was used instead of 9-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one in step 6 of Example 9.

[0229] 1H NMR(500MHz,CDCl3)δ8.03(d,J=8.1Hz,1H),7.70(s,1H),7.64(dd,J=8.1,1.9Hz,1H),7.58- 7.54(m,2H),7.50(d,J=1.8Hz,1H),7.47-7.41(m,2H),6.51(s,1H),6.02(s,2H),5.20(s,2H)

[0230] <Example 36> Preparation of 8-(p-tolyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2241) [ka]

[0231] 8-(p-tolyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (26.0 mg, 72%) was obtained in the same manner as in Example 12, except that 8-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (35 mg, 0.105 mmol) from Example 76 was used instead of 9-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 12.

[0232] 1 H NMR(500MHz,CDCl3)δ8.03(d,J=8.1Hz,1H),7.71(s,1H),7.68(dd,J=8.1,1.8Hz,1H),7.56-7.53(m, 2H),7.52(d,J=1.8Hz,1H),7.28(d,J=7.9Hz,2H),6.52(s,1H),6.02(s,2H),5.21(s,2H),2.41(s,3H)

[0233] <Example 37> Preparation of 8-(4-methoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2242) [ka]

[0234] 8-(4-methoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (29.5 mg, 78%) was obtained in the same manner as in Example 13, except that 8-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (35 mg, 0.105 mmol) from Example 76 was used instead of 9-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 13.

[0235] 1 H NMR(500MHz,CDCl3)δ8.02(d,J=8.1Hz,1H),7.71(s,1H),7.65(dd,J=8.1,1.9Hz,1H),7.61-7.56(m ,2H),7.50(d,J=1.7Hz,1H),7.03-6.98(m,2H),6.52(s,1H),6.03(s,2H),5.21(s,2H),3.87(s,3H)

[0236] <Example 38> Preparation of 8-(2,4-dimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2243) [ka]

[0237] 8-(2,4-dimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25.6 mg, 63%) was obtained in the same manner as in Example 14, except that 8-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (35 mg, 0.105 mmol) from Example 76 was used instead of 9-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 14.

[0238] 1 H NMR(400MHz,CDCl3)δ7.98(d,J=8.3Hz,1H),7.71(s,1H),7.61(d,J=7.8Hz,1H),7.47(s,1H),7.2 9(s,1H),6.59(d,J=9.7Hz,2H),6.51(s,1H),6.02(s,2H),5.19(s,2H),3.87(s,3H),3.82(s,3H)

[0239] <Example 39> Preparation of 8-(3,4,5-trimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2244) [ka]

[0240] 8-(3,4,5-trimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (22.5 mg, 51%) was obtained in the same manner as in Example 15, except that 8-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (35 mg, 0.105 mmol) from Example 76 was used instead of 9-bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 15.

[0241] 1 H NMR(400MHz,CDCl3)δ8.03(d,J=8.1Hz,1H),7.71(s,1H),7.65(d,J=8.0Hz,1H),7.50 (s,1H),6.81(s,2H),6.53(s,1H),6.04(s,2H),5.23(s,2H),3.95(s,6H),3.91(s,3H)

[0242] <Example 40> Preparation of 2,3-dimethoxy-9-(4-(trifluoromethyl)phenyl)dibenzo[b,e]oxepin-11(6H)-one(HN2245) [ka]

[0243] Following the production method of General Method 6, 9-bromo-2,3-Dimethoxydibenz[b,e]oxepin-11(6H)-one (25 mg, 0.072 mmol) from Example 30 was reacted with 4-(trifluoromethyl)phenylboronic acid (20.4 mg, 0.107 mmol). The mixture was then purified by column chromatography using 12% ethyl acetate and 30% methylene chloride in n-hexane to obtain 2,3-dimethoxy-9-(4-(trifluoromethyl)phenyl)dibenzo[b,e]oxepin-11(6H)-one (26 mg, 88%).

[0244] 1 H NMR(500MHz,CDCl3)δ8.19(d,J=1.7Hz,1H),7.78(dd,J=7.7,1.8Hz,1H),7.76-7.6 9(m, 5H), 7.48(d,J=7.8Hz,1H),6.54(s,1H),5.22(s,2H),3.96(s,3H),3.93(s,3H)

[0245] <Example 41> Preparation of N-(9-fluoro-11-oxo-6,11-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-8-yl)methanesulfonamide (HN2301) [ka]

[0246] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 3 was reacted with methanesulfonamide (19.6 mg, 0.206 mmol). The mixture was then purified by column chromatography using 33% ethyl acetate solvent in n-hexane to obtain N-(9-fluoro-11-oxo-6,11-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-8-yl)methanesulfonamide (12 mg, 31%).

[0247] 1 H NMR(500MHz,DMSO-d6)δ10.18(s,1H),7.63(d,J=11.2Hz,1H),7.56(d,J=7.4Hz,1H),7.46(s,1H),6.70(s,1H),6.11(s,2H),5.21(s,2H),3.15(s,3H)

[0248] <Example 42> Preparation of N-(7-fluoro-11-oxo-6,11-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-8-yl)methanesulfonamide (HN2302) [ka]

[0249] N-(7-fluoro-11-oxo-6,11-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-8-yl)methanesulfonamide (12 mg, 31%) was obtained in the same manner as in Example 41, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (30 mg, 0.103 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 41.

[0250] 1 H NMR(500MHz,DMSO-d6)δ10.18(s,1H),7.65(d,J=8.8Hz,1H),7.54(t,J=8.1Hz,1H),7.48(s,1H),6.73(s,1H),6.13(s,2H),5.31(s,2H),3.11(s,3H)

[0251] <Example 43> Preparation of 2,3-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one(HN2303) [ka]

[0252] Step 1: Preparation of methyl 2-(3,4-dimethoxyphenethyl)benzoate Following the reaction of 2-(methoxycarbonyl)benzyl)triphenylphosphonium bromide (115.3 mg, 0.234 mmol) obtained by reacting Methyl 2-(bromomethyl)benzoate (200 mg, 0.873 mmol) with Triphenylphosphine (251.9 mg, 0.959 mmol) with 3,4-dimethoxybenzaldehyde (30 mg, 0.180 mmol), the next reaction was carried out without a purification step. The concentrated mixture was dissolved in 1.8 mL of MeOH, and after reacting with a catalytic amount of Pd / C and H2 gas injection, the mixture was purified by column chromatography using 16-20% ethyl acetate solvent in n-hexane to obtain methyl 2-(3,4-dimethoxyphenethyl)benzoate (44.8 mg, 82%).

[0253] Step 2: Preparation of 2-(3,4-dimethoxyphenethyl)benzoic acid Using the manufacturing method of Step 2 of General Manufacturing Method 4, methyl 2-(3,4-dimethoxyphenethyl)benzoate (42.3 mg, 0.141 mmol) produced in Step 1 was reacted to obtain 2-(3,4-dimethoxyphenethyl)benzoic acid (39.6 mg, 98%).

[0254] Step 3: Preparation of 2,3-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one Following the reaction with 2-(3,4-dimethoxyphenethyl)benzoic acid (20 mg, 0.069 mmol) prepared in step 2 using the manufacturing method of step 3 of general manufacturing method 4, the compound was purified by column chromatography using 9% ethyl acetate and 30% methylene chloride solvent in n-hexane. The purified compound was decanted with n-hexane to obtain 2,3-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (16.2 mg, 86%).

[0255] 1 H NMR(500MHz,CDCl3)δ7.96(dd,J=7.8,1.2Hz,1H),7.76(s,1H),7.42(td,J=7.4,1.4Hz,1H),7.33(td ,J=7.7,1.1Hz,1H),7.22(d,J=7.3Hz,1H),6.66(s,1H),3.96(s,3H),3.94(s,3H),3.21-3.12(m,4H)

[0256] <Example 44> Preparation of 9-bromo-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one(HN2304) [ka]

[0257] Step 1: Preparation of methyl 5-bromo-2-(((3,4-dimethoxyphenyl)thio)methyl)benzoate Following the manufacturing method of Step 1 of General Manufacturing Method 2, methyl 5-bromo-2-(bromomethyl)benzoate (312 mg, 1.01 mmol) produced in Step 2 of Example 9 was reacted with 3,4-dimethoxythiophenol (161.2 mg, 0.947 mmol). The mixture was then purified by column chromatography using 16-20% ethyl acetate solvent in n-hexane to obtain methyl 5-bromo-2-(((3,4-dimethoxyphenyl)thio)methyl)benzoate (236.6 mg, 62%).

[0258] Step 2: Preparation of 5-bromo-2-(((3,4-dimethoxyphenyl)thio)methyl)benzoic acid Using the manufacturing method of Step 2 of General Manufacturing Method 2, methyl 5-bromo-2-(((3,4-dimethoxyphenyl)thio)methyl)benzoate (236 mg, 0.594 mmol) produced in Step 1 was reacted to obtain 5-bromo-2-(((3,4-dimethoxyphenyl)thio)methyl)benzoic acid (223.2 mg, 98%).

[0259] Step 5: Preparation of 9-bromo-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one Following the reaction of 5-bromo-2-(((3,4-dimethoxyphenyl)thio)methyl)benzoic acid (20 mg, 0.052 mmol) produced in step 2 using the manufacturing method of step 3 of general manufacturing method 2, the product was purified by column chromatography using 5% ethyl acetate and 30% methylene chloride solvent in n-hexane to obtain 9-bromo-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (17.8 mg, 93%).

[0260] 1H NMR(500MHz,CDCl3)δ7.82(s,1H),7.78(d,J=2.1Hz,1H),7.56(dd,J=8.1,2.1Hz ,1H),7.09(d,J=8.1Hz,1H),6.75(s,1H),3.98(s,2H),3.95(s,3H),3.92(s,3H)

[0261] <Example 45> Preparation of 2,3-dimethoxy-9-(3,4,5-trimethoxyphenyl)dibenzo[b,e]thiepin-11(6H)-one(HN2305) [ka]

[0262] Following the production method of General Method 6, 9-bromo-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (30 mg, 0.082 mmol) from Example 44 was reacted with 3,4,5-trimethoxyphenylboronic acid (26.1 mg, 0.123 mmol). After purification by column chromatography using 17% ethyl acetate and 50% methylene chloride solvent in n-hexane, decantation with n-hexane was performed to obtain 2,3-dimethoxy-9-(3,4,5-trimethoxyphenyl)dibenzo[b,e]thiepin-11(6H)-one (22 mg, 59%).

[0263] 1 H NMR(500MHz,CDCl3)δ7.87(s,1H),7.82(d,J=2.2Hz,1H),7.63(dd,J=8.0,1.9Hz,1H),7.26(d,J= 8.0Hz,1H),6.75(d,J=4.6Hz,3H),4.06(s,2H),3.95(s,3H),3.90(s,3H),3.90(s,6H)3.87(s,3H)

[0264] <Example 46> Preparation of 2,3-dimethoxy-9-(4-methoxyphenyl)dibenzo[b,e]thiepin-11(6H)-one(HN2306) [ka]

[0265] Following the production method of General Method 6, 9-bromo-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (30 mg, 0.082 mmol) from Example 44 was reacted with 4-methoxyphenylboronic acid (18.7 mg, 0.123 mmol). After purification by column chromatography using 6% ethyl acetate and 50% methylene chloride solvent in n-hexane, decantation with n-hexane was performed to obtain 2,3-dimethoxy-9-(4-methoxyphenyl)dibenzo[b,e]thiepin-11(6H)-one (31.3 mg, 97%).

[0266] 1 H NMR(500MHz,CDCl3)δ7.85(s,1H),7.82(d,J=1.9Hz,1H),7.62(dd,J=7.7,1.9Hz,1H),7.51(d,J=8.8Hz,2H), 7.24(d,J=8.0Hz,1H),6.94(d,J=8.8Hz,2H),6.75(s,1H),4.05(s,2H),3.94(s,3H),3.90(s,3H),3.83(s,3H)

[0267] <Example 47> Preparation of 2,3-dimethoxy-9-(p-tolyl)dibenzo[b,e]thiepin-11(6H)-one(HN2307) [ka]

[0268] Following the production method of General Method 6, 9-bromo-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (30 mg, 0.082 mmol) from Example 44 was reacted with 4-methylphenylboronic acid (16.8 mg, 0.123 mmol). The mixture was then purified by column chromatography using 5% ethyl acetate and 50% methylene chloride solvent in n-hexane to obtain 2,3-dimethoxy-9-(p-tolyl)dibenzo[b,e]thiepin-11(6H)-one (30 mg, 98%).

[0269] 1 H NMR(500MHz,CDCl3)δ7.86(s,1H),7.85(d,J=1.9Hz,1H),7.64(dd,J=8.0,1.9Hz,1H),7.47(d,J=8.0Hz, 2H),7.25(s,1H),7.22(d,J=7.7Hz,2H),6.75(s,1H),4.05(s,2H),3.94(s,3H),3.90(s,3H),2.37(s,3H)

[0270] <Example 48> Preparation of 9-(3-furanyl)-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one(HN2308) [ka]

[0271] Following the production method of General Method 6, 9-bromo-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (30 mg, 0.082 mmol) from Example 44 was reacted with 3-furylboronic acid (13.8 mg, 0.123 mmol). The mixture was then purified by column chromatography using 6% ethyl acetate and 50% methylene chloride in n-hexane to obtain 9-(3-furanyl)-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (24.4 mg, 84%).

[0272] 1 1H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.73 (s, 1H), 7.55 (dd, J = 8.0, 1.9 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.75 (s, 1H), 6.69 (m, 1H), 4.02 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H)

[0273] <Example 49> Preparation of 9-(4-chlorophenyl)-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (HN2309)

Chem.

[0274] Using the production method of General Production Method 6, 9-bromo-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (30 mg, 0.082 mmol) of Example 44 and 4-chlorophenylboronic acid (19.2 mg, 0.123 mmol) were reacted, and then purified by column chromatography using a 5% ethyl acetate and 30% methylene chloride solvent in n-hexane, and decanted with n-hexane to obtain 9-(4-chlorophenyl)-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (29.1 mg, 89%).

[0275] 1 1H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.62 (dd, J = 7.9, 2.1 Hz, 1H), 7.50 (m, 2H), 7.38 (m, 2H), 7.27 (d, J = 8.1 Hz, 1H), 6.75 (s, 1H), 4.02 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H)

[0276] <Example 50> Preparation of 10,11-dihydro-5H-benzo[4',5']cyclohepta[1',2':4,5]benzo[1,2-d][1,3]dioxol-5-one(HN2310) [ka]

[0277] Step 1: Preparation of Methyl 2-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)benzoate After reacting 2-(methoxycarbonyl)benzyl)triphenylphosphonium bromide (170.2 mg, 0.346 mmol) used in Step 1 of Example 43 with piperonal (40 mg, 0.266 mmol), the following reaction was carried out without a purification step. The concentrated mixture was dissolved in 3 mL of MeOH, and after reacting with a catalytic amount of Pd / C and H2 gas injection, the mixture was purified by column chromatography using 5% ethyl acetate solvent in n-hexane to obtain Methyl 2-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)benzoate (68.3 mg, 90%).

[0278] Step 2: Preparation of 2-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)benzoic acid Using the manufacturing method of Step 2 of General Manufacturing Method 4, methyl 2-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)benzoate (61.2 mg, 0.215 mmol) produced in Step 1 was reacted to obtain 2-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)benzoic acid (56.7 mg, 97%).

[0279] Step 3: Preparation of 10,11-dihydro-5H-benzo[4',5']cyclohepta[1',2':4,5]benzo[1,2-d][1,3]dioxol-5-one Following the manufacturing method in step 3 of general manufacturing method 4, 2-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)benzoic acid (50.3 mg, 0.186 mmol) produced in step 2 was reacted, and then purified by column chromatography using 66% methylene chloride solvent in n-hexane to obtain 10,11-dihydro-5H-benzo[4',5']cyclohepta[1',2':4,5]benzo[1,2-d][1,3]dioxol-5-one (46.6 mg, 99%).

[0280] 1 H NMR(500MHz,CDCl3)δ7.98(dd,J=7.8Hz,1H),7.61(s,1H),7.42(t,J=7.4Hz,1H),7.3 2(t,J=7.5Hz,1H),7.20(d,J=7.5Hz,1H),6.66(s,1H),6.01(s,2H),3.22-3.06(m,4H)

[0281] <Example 51> Preparation of 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one(HN2311) [ka]

[0282] Step 1: Preparation of Methyl 4,5-difluoro-2-methylbenzoate The manufacturing method was carried out in the same manner as in Step 1 of Example 3.

[0283] Step 2: Preparation of Methyl 2-bromomethyl-4,5-difluorobenzoate The manufacturing method was carried out in the same manner as in Step 2 of Example 3.

[0284] Step 3: Preparation of Methyl 2-(3,4-dimethoxyphenethyl)-4,5-difluorobenzoate Following the production method of Step 1 of General Method 4, (4,5-difluoro-2-(methoxycarbonyl)benzyl)triphenylphosphonium bromide (885.2 mg, 0.234 mmol), obtained by reacting Methyl 2-bromomethyl-4,5-difluorobenzoate (510.9 mg, 1.927 mmol) produced in Step 2 with Triphenylphosphine (606.7 mg, 2.313 mmol), was reacted with 3,4-dimethoxybenzaldehyde (214.5 mg, 1.291 mmol). The next reaction was carried out without a purification step. The concentrated mixture was dissolved in 13 mL of MeOH, and after reacting with a catalytic amount of Pd / C and H2 gas injection, the mixture was purified by column chromatography using 20% ​​ethyl acetate solvent in n-hexane to obtain Methyl 2-(3,4-dimethoxyphenethyl)-4,5-difluorobenzoate (331.1 mg, 76%).

[0285] Step 4: Preparation of 2-(3,4-dimethoxyphenethyl)-4,5-difluorobenzoic acid Using the manufacturing method of Step 2 of General Manufacturing Method 4, methyl 2-(3,4-dimethoxyphenethyl)-4,5-difluorobenzoate (318.4 mg, 0.946 mmol) produced in Step 3 was reacted to obtain 2-(3,4-dimethoxyphenethyl)-4,5-difluorobenzoic acid (303.3 mg, 99%).

[0286] Step 5: Preparation of 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one Following the reaction of 2-(3,4-dimethoxyphenethyl)-4,5-difluorobenzoic acid (298.9 mg, 0.924 mmol) produced in step 4 using the manufacturing method of step 3 of general manufacturing method 4, the product was purified by column chromatography using 66-100% methylene chloride solvent in n-hexane to obtain 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (275 mg, 97%).

[0287] 1 H NMR(500MHz,DMSO-d6)δ7.83(dd,J=8.3,11.8Hz,1H),7.58(s,1H),7.48(dd, J=7.8, 11.2Hz,1H),6.93(s,1H),3.85(s,3H),3.79(s,3H),3.13-3.08(m,4H)

[0288] <Example 52> Preparation of 8-(cyclopropylamino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2312) [ka]

[0289] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 3 was reacted with cyclopropylamine (0.03 mL, 0.43 mmol). The mixture was then purified by column chromatography using 66-100% methylene chloride solvent in n-hexane to obtain 8-(cyclopropylamino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (24.1 mg, 85%).

[0290] 1 H NMR(500MHz,DMSO-d6)δ7.53(d,J=13.0Hz,1H),7.51(s,1H),7.00(d,J=8.0Hz,1H),6.67( s,1H),6.10(s,2H),5.16(s,2H),2.50-2.48(m,1H),0.80-0.76(m,2H),0.55-0.52(m,2H)

[0291] <Example 53> Preparation of 8-(cyclopentylamino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2313) [ka]

[0292] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 3 was reacted with cyclopentylamine (0.042 mL, 0.43 mmol). After purification by column chromatography using 66-80% methylene chloride solvent in n-hexane, decantation with n-hexane was performed to obtain 8-(cyclopentylamino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (24.7 mg, 80%).

[0293] 1 H NMR(500MHz,DMSO-d6)δ7.53(d,J=13.4Hz,1H),7.51(s,1H),6.79(d,J=8.4Hz,1H),6.67(s,1H),6. 10(s,2H),5.13(s,2H),3.91-3.85(m,1H),2.02-1.96(m,2H),1.73-1.65(m,2H),1.59-1.52(m,4H)

[0294] <Example 54> Preparation of 2-(dimethylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one(HN2314) [ka]

[0295] Following the production method of General Method 5, 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (25 mg, 0.082 mmol) from Example 51 was reacted with dimethylamine (0.1 mL), and then purified by column chromatography using 50% methylene chloride and 3% ethyl acetate solvent in n-hexane to obtain 2-(dimethylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (24.1 mg, 89%).

[0296] 1 H NMR(500MHz,DMSO-d6)δ7.69(d,J=16.4Hz,1H),7.58(s,1H),6.90(s,1H),6.73 (d,J=9.2Hz,1H),3.84(s,3H),3.78(s,3H),3.04(s,4H),2.96(d,J=1.5Hz,6H)

[0297] <Example 55> Preparation of 3-fluoro-7,8-dimethoxy-2-(piperidin-1-yl)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one(HN2315) [ka]

[0298] Following the production method of General Method 5, 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (25 mg, 0.082 mmol) from Example 51 was reacted with piperidine (0.04 mL, 0.41 mmol). The mixture was then purified by column chromatography using 33-50% methylene chloride and 3% ethyl acetate in n-hexane to obtain 3-fluoro-7,8-dimethoxy-2-(piperidin-1-yl)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (29.4 mg, 97%).

[0299] 1 H NMR(500MHz,DMSO-d6)δ7.67(d,J=15.7Hz,1H),7.57(s,1H),6.91(s,1H),6.88(d,J=8.8Hz,1H) ,3.84(s,3H),3.78(s,3H),3.17-3.14(m,4H),3.05(s,4H),1.66-1.61(m,4H),1.58-1.54(m,2H)

[0300] <Example 56> Preparation of 3-fluoro-7,8-dimethoxy-2-(4-phenylpiperazin-1-yl)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one(HN2316) [ka]

[0301] According to the production method of General Production Method 5, after reacting 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (25 mg, 0.082 mmol) of Example 51 with 1-phenylpiperazine (0.037 mL, 0.24 mmol), it was purified by column chromatography using a 25% ethyl acetate solvent in n-hexane to obtain 3-fluoro-7,8-dimethoxy-2-(4-phenylpiperazin-1-yl)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (31.1 mg, 85%).

[0302] 1 H NMR (500 MHz, DMSO-d6) δ 7.71 (d, J = 15.3 Hz, 1H), 7.58 (s, 1H), 7.25 - 7.22 (m, 2H), 7.00 - 6.96 (m, 3H), 6.92 (s, 1H), 6.81 (t, J = 7.3 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.36 - 3.35 (m, 4H), 3.30 - 3.28 (m, 4H), 3.08 (s, 4H)

[0303] <Example 57> Production of 2-(benzylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2317)

Chemical formula

[0304] Following the production method of General Method 5, 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (25 mg, 0.082 mmol) from Example 51 was reacted with benzylamine (0.045 mL, 0.41 mmol). After purification by column chromatography using 25% ethyl acetate solvent in n-hexane, the mixture was decanted with n-hexane to obtain 2-(benzylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (21.9 mg, 68%).

[0305] 1 H NMR(500MHz,DMSO-d6)δ7.70(d,J=13.8Hz,1H),7.56(s,1H),7.37-7.31(m,4H),7.23(t,J=7.3Hz,1H),6.48(d,J =8.8Hz,1H),6.85(s,1H),4.44(d,J=5.4Hz,2H),3.84(s,3H),3.76(s,3H),2.97-2.95(m,2H),2.91-2.89(m,2H)

[0306] <Example 58> Preparation of 8-(cyclopropylamino)-7-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2318) [ka]

[0307] 8-(cyclopropylamino)-7-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (21.8 mg, 77%) was obtained in the same manner as in Example 52, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 52.

[0308] 1 H NMR(500MHz,DMSO-d6)δ7.69(d,J=8.8Hz,1H),7.51(s,1H),7.06(d,J=8.4Hz,1H),6.68( s,1H),6.10(s,2H),5.24(s,2H),2.49-2.47(m,1H),0.78-0.74(m,2H),0.52-0.49(m,2H)

[0309] <Example 59> Preparation of 8-(cyclopentylamino)-7-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2319) [ka]

[0310] 8-(cyclopentylamino)-7-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (22.3 mg, 73%) was obtained in the same manner as in Example 53, except that 7,8-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 20 was used instead of 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one from Example 53.

[0311] 1 H NMR(500MHz,DMSO-d6)δ7.65(d,J=8.8Hz,1H),7.51(s,1H),6.82(t,J=8.6Hz,1H),6.68(s,1H),6. 10(s,2H),5.25(s,2H),3.89-3.83(m,1H),1.99-1.93(m,2H),1.69-1.64(m,2H),1.59-1.54(m,4H)

[0312] <Example 60> Preparation of 2-(cyclopropylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one(HN2320) [ka]

[0313] Following the production method of General Method 5, 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (25 mg, 0.082 mmol) from Example 51 was reacted with cyclopropylamine (0.028 mL, 0.41 mmol). After purification by column chromatography using 25% ethyl acetate solvent in n-hexane, the mixture was decanted with n-hexane to obtain 2-(cyclopropylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (19.2 mg, 68%).

[0314] 1 H NMR(500MHz,DMSO-d6)δ7.68(d,J=13.7Hz,1H),7.58(s,1H),6.89(s,1H),6.81(d,J=8 .8Hz,1H),3.84(s,3H),3.77(s,3H),3.04(s,4H),0.83-0.71(m,2H),0.58-0.47(m,2H)

[0315] <Example 61> Preparation of 2-(cyclopentylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one(HN2321) [ka]

[0316] Following the production method of General Method 5, 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (25 mg, 0.082 mmol) from Example 51 was reacted with cyclopentylamine (0.04 mL, 0.41 mmol). The mixture was then purified by column chromatography using 25% ethyl acetate solvent in n-hexane to obtain 2-(cyclopentylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (24.5 mg, 81%).

[0317] 1 H NMR(500MHz,DMSO-d6)δ7.68(d,J=14.1Hz,1H),7.57(s,1H),6.88(s,1H),6.57(d,J=8.8Hz,1H) ,3.89-3.85(m,1H),3.83(s,3H),3.77(s,3H),3.02(s,4H),2.00-1.93(m,2H),1.73-1.50(m,6H)

[0318] <Example 62> Preparation of 8-((2,4-dichlorophenethyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2322) [ka]

[0319] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 3 was reacted with 2-2,4-dichlorophenyl)ethylamine (0.032 mL, 0.215 mmol). The mixture was then purified by column chromatography using 16-20% ethyl acetate solvent in n-hexane to obtain 8-((2,4-dichlorophenethyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (35.0 mg, 88%).

[0320] 1 H NMR(500MHz,DMSO-d6)δ7.58(d,J=1.9Hz,1H),7.54(d,J=13.0Hz,1H),7.51(s,1H),7.43(d,J=8.1Hz,1H),7.37(dd,J= 2.1、8.2Hz,1H),6.81(d,J=8.4Hz,1H),6.67(s,1H),6.10(s,2H),5.11(s,2H),3.47-3.43(m,2H),3.01(t,J=7.3Hz,2H)

[0321] <Example 63> Preparation of 9-fluoro-8-((2-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2323) [ka]

[0322] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 3 was reacted with 2-methoxybenzylamine (0.056 mL, 0.43 mmol). The mixture was then purified by column chromatography using 20% ​​ethyl acetate in n-hexane to obtain 9-fluoro-8-((2-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (32.2 mg, 92%).

[0323] 1 H NMR(500MHz,DMSO-d6)δ7.56(d,J=13.4Hz,1H),7.50(s,1H),7.25-7.22(m,1H),7.17(d,J=7.7Hz,1H),7.02- 6.98(m,2H),6.88(t,J=6.9Hz,1H),6.63(s,2H),6.09(s,2H),5.03(s,2H),4.42(d,J=5.4Hz,2H),3.86(s,3H)

[0324] <Example 64> Preparation of 8,9-difluoro-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one(HN2324) [ka]

[0325] Step 1: Preparation of Methyl 4,5-difluoro-2-methylbenzoate The manufacturing method was carried out in the same manner as in Step 1 of Example 3.

[0326] Step 2: Preparation of Methyl 2-bromomethyl-4,5-difluorobenzoate The manufacturing method was carried out in the same manner as in Step 2 of Example 3.

[0327] Step 3: Preparation of methyl 2-(((3,4-dimethoxyphenyl)thio)methyl)-4,5-difluorobenzoate Following the manufacturing method of Step 1 of General Manufacturing Method 3, methyl 2-bromomethyl-4,5-difluorobenzoate (500 mg, 1.886 mmol) produced in Step 2 was reacted with 3,4-dimethoxythiophenol (321.1 mg, 1.886 mmol). The mixture was then purified by column chromatography using 16-20% ethyl acetate solvent in n-hexane to obtain methyl 2-(((3,4-dimethoxyphenyl)thio)methyl)-4,5-difluorobenzoate (602.6 mg, 90%).

[0328] Step 4: Preparation of 2-(((3,4-dimethoxyphenyl)thio)methyl)-4,5-difluorobenzoic acid Using the manufacturing method of Step 2 of General Manufacturing Method 3, methyl 2-(((3,4-dimethoxyphenyl)thio)methyl)-4,5-difluorobenzoate (581.8 mg, 1.642 mmol) produced in Step 3 was reacted to obtain 2-(((3,4-dimethoxyphenyl)thio)methyl)-4,5-difluorobenzoic acid (527.3 mg, 94%).

[0329] Step 5: Preparation of 8,9-difluoro-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one Following the manufacturing method in step 3 of general manufacturing method 3, 2-(((3,4-dimethoxyphenyl)thio)methyl)-4,5-difluorobenzoic acid (522.4 mg, 1.535 mmol) produced in step 4 was reacted, and then purified by column chromatography using 50% methylene chloride and 1% ethyl acetate solvent in n-hexane to obtain 8,9-difluoro-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (447.5 mg, 90%).

[0330] 1 H NMR(500MHz,CDCl3)δ7.83(s,1H),7.54(dd,J=7.8, 10.9Hz,1H),7.00(dd,J=7.3,9.9Hz,1H),6.75(s,1H),3.96(s,2H),3.93(s,3H),3.90(s,3H)

[0331] <Example 65> Preparation of 9-fluoro-8-((3-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2325) [ka]

[0332] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 3 was reacted with 3-methoxybenzylamine (0.057 mL, 0.43 mmol). The mixture was then purified by column chromatography using 20% ​​ethyl acetate solvent in n-hexane to obtain 9-fluoro-8-((3-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (25.8 mg, 73%).

[0333] 1 H NMR(500MHz,DMSO-d6)δ7.55(d,J=13.0Hz,1H),7.49(s,1H),7.25-7.22(m,2H),6.94(d,J=7.3Hz,2H),6.81- 6.79(m,1H),6.70(d,J=8.4Hz,1H),6.63(s,1H),6.09(s,2H),5.03(s,2H),4.43(d,J=5.4Hz,2H),3.72(s,3H)

[0334] <Example 66> Preparation of 9-fluoro-8-((4-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2326) [ka]

[0335] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 3 was reacted with 4-methoxybenzylamine (0.056 mL, 0.43 mmol). The mixture was then purified by column chromatography using 20% ​​ethyl acetate solvent in n-hexane to obtain 9-fluoro-8-((4-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (25.5 mg, 72%).

[0336] 1H NMR(500MHz,DMSO-d6)δ7.54(d,J=13.4Hz,1H),7.49(s,1H),7.30(d,J=8.4Hz,2H),7.18(t,J=5.5Hz,1H),6.88( d,J=8.8Hz,2H),6.71(d,J=8.4Hz,1H),6.63(s,1H),6.09(s,2H),5.04(s,2H),4.38(d,J=6.1Hz,2H),3.71(s,3H)

[0337] <Example 67> Preparation of 9-fluoro-8-((3-methoxyphenethyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2327) [ka]

[0338] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 3 was reacted with 2-(3-methoxyphenyl)ethylamine (0.062 mL, 0.43 mmol). The mixture was then purified by column chromatography using 20% ​​ethyl acetate solvent in n-hexane to obtain 9-fluoro-8-((3-methoxyphenethyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (28.7 mg, 79%).

[0339] 1H NMR(500MHz,DMSO-d6)δ7.54(d,J=13.4Hz,1H),7.51(s,1H),7.21(t,J=8.0Hz,1H),6.87-6.85(m,2H),6.82(d,J=8.4Hz,1H), 6.79-6.76(m,1H),6.67(s,1H),6.59(s,1H),6.10(s,2H),5.13(s,2H),3.73(s,3H),3.46-3.40(m,2H),2.87(t,J=7.6Hz,2H)

[0340] <Example 68> Preparation of 8-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2328) [ka]

[0341] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 3 was reacted with 2,4-dimethoxybenzylamine (0.065 mL, 0.43 mmol). The mixture was then purified by column chromatography using 16-20% ethyl acetate in n-hexane to obtain 8-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (31.7 mg, 84%).

[0342] 1H NMR(500MHz,DMSO-d6)δ7.55(d,J=13.4Hz,1H),7.50(s,1H),7.09(d,J=8.4Hz,1H),6.90(s,1H),6.64-6.63(m,2H),6.57 (d,J=2.3Hz,1H),6.46(dd,J=8.4,2.3Hz,1H),6.09(s,2H),5.04(s,2H),4.33(d,J=5.7Hz,2H),3.84(s,3H),3.72(s,3H)

[0343] <Example 69> Preparation of 8-((3,4-dimethoxybenzyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one(HN2329) [ka]

[0344] Following the production method of General Method 5, 8,9-difluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (25 mg, 0.086 mmol) from Example 3 was reacted with 3,4-dimethoxybenzylamine (0.039 mL, 0.258 mmol). The mixture was then purified by column chromatography using 20-25% ethyl acetate in n-hexane to obtain 8-((3,4-dimethoxybenzyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (29.1 mg, 77%).

[0345] 1H NMR(500MHz,DMSO-d6)δ7.54(d,J=13.0Hz,1H),7.49(s,1H),7.16(t,J=6.1Hz,1H),7.03(s,1H),6.91-6.87(m,2) H),6.73(d,J=8.4Hz,1H),6.63(s,1H),6.09(s,2H),5.05(s,2H),4.37(d,J=5.7Hz,2H),3.73(s,3H),3.70(s,3H)

[0346] <Example 70> Preparation of 8-Bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one(HN2336) [ka]

[0347] Step 1: Preparation of Methyl 2-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-bromobenzoate Following the reaction between Methyl 4-Bromo-2-(bromomethyl)benzoate (100 mg, 0.325 mmol) and sesamol (53.8 mg, 0.389 mmol) using the manufacturing method of Step 1 of General Manufacturing Method 2, the product was purified by column chromatography using 33% methylene chloride solvent in n-hexane to obtain Methyl 2-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-bromobenzoate (82.0 mg, 69%).

[0348] Step 2: Preparation of 2-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-bromobenzoic acid Using the manufacturing method of Step 2 of General Manufacturing Method 2, Methyl 2-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-bromobenzoate (76.8 mg, 0.210 mmol) produced in Step 1 was reacted to obtain 2-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-bromobenzoic acid (62.4 mg, 84%).

[0349] Step 3: Preparation of 8-Bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one Following the manufacturing method described in Step 3 of General Manufacturing Method 2, 57.8 mg (0.165 mmol) of 2-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-bromobenzoic acid produced in Step 2 was reacted, and then purified by column chromatography using 50% methylene chloride solvent in n-hexane to obtain 8-Bromo[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (51.6 mg, 94%).

[0350] 1 H NMR(500MHz,CDCl3)δ7.83(d,J=8.3Hz,1H),7.66(s,1H),7.60(dd,J=8.3,1.3Hz,1H),7.50(s,1H),6.50(s,1H),6.02(s,2H),5.10(s,2H)

[0351] <Example 71> Preparation of 2,3-dimethoxy-5-tosyl-5,6-dihydro-11H-dibenzo[b,e]azepin-11-one(HN2337) [ka]

[0352] Step 1: Preparation of methyl 4,5-dimethoxy-2-((4-methylphenyl)sulfonamido)benzoate Following the manufacturing method described in Step 1 of General Manufacturing Method 7, methyl 2-Amino-4,5-dimethoxybenzoate (50 mg, 0.236 mmol) was reacted with p-TsCl (54.2 mg, 0.284 mmol) and pyridine (0.06 mL, 0.710 mmol). The mixture was then purified by column chromatography using 5% ethyl acetate and 50% methylene chloride solvent in n-hexane to obtain methyl 4,5-dimethoxy-2-((4-methylphenyl)sulfonamido)benzoate (85 mg, 98%).

[0353] Step 2: Preparation of methyl 2-((N-benzyl-4-methylphenyl)sulfonamido)-4,5-dimethoxybenzoate Following the manufacturing method described in Step 2 of General Manufacturing Method 7, 4,5-dimethoxy-2-((4-methylphenyl)sulfonamido)benzoate (45 mg, 0.123 mmol) prepared in Step 1 was reacted with benzylbromide (0.03 mL, 0.246 mmol). The mixture was then purified by column chromatography using 25% ethyl acetate solvent in n-hexane to obtain methyl 2-((N-benzyl-4-methylphenyl)sulfonamido)-4,5-dimethoxybenzoate (54.5 mg, 97%).

[0354] Step 3: Preparation of 2-((N-benzyl-4-methylphenyl)sulfonamido)-4,5-dimethoxybenzoic acid Using the manufacturing method described in Step 3 of General Manufacturing Method 7, methyl 2-((N-benzyl-4-methylphenyl)sulfonamido)-4,5-dimethoxybenzoate (54.5 mg, 0.119 mmol) produced in Step 2 was reacted to obtain 2-((N-benzyl-4-methylphenyl)sulfonamido)-4,5-dimethoxybenzoic acid (52.8 mg, 100%).

[0355] Step 4: Preparation of 2,3-dimethoxy-5-tosyl-5,6-dihydro-11H-dibenzo[b,e]azepin-11-one Following the reaction with 2-((N-benzyl-4-methylphenyl)sulfonamido)-4,5-dimethoxybenzoic acid (27.7 mg, 0.063 mmol) produced in step 3 using the manufacturing method of general manufacturing method 7, the product was purified by column chromatography using 40% ethyl acetate solvent in n-hexane to obtain 2,3-dimethoxy-5-tosyl-5,6-dihydro-11H-dibenzo[b,e]azepin-11-one (5.8 mg, 22%).

[0356] 1 H NMR(500MHz,DMSO-d6)δ7.63(s,1H),7.62-7.57(m,2H),7.48(d,J=7.4Hz,1H),7.37(t,J=7.5Hz,1H),7.2 1(s,1H),6.89(d,J=8.1Hz,2H),6.69(d,J=8.2Hz,2H),5.09(s,2H),3.92(s,3H),3.86(s,3H),2.22(s,3H)

[0357] The compounds synthesized in Examples 1 to 71 are shown in Table 1 below.

[0358] [Table 1] TIFF2026511542000086.tif240160TIFF2026511542000087.tif216161TIFF2026511542000088.tif218162TIFF2026511542000089.t if242161TIFF2026511542000090.tif209161TIFF2026511542000091.tif211161TIFF2026511542000092.tif212161TIFF20265115420 00093.tif224161TIFF2026511542000094.tif229162TIFF2026511542000095.tif242162TIFF2026511542000096.tif219161TIFF202 6511542000097.tif220163TIFF2026511542000098.tif219162TIFF2026511542000099.tif186160TIFF2026511542000100.tif145161

[0359] Experimental example: In vitro efficacy evaluation of compounds Experimental Example 1. Evaluation of mTORC1 and mTORC2 inhibitory activity in the mTOR signaling pathway of HeLa cells. The following experiments were performed to evaluate the mTORC1 and mTORC2 inhibitory activities of the compounds synthesized in Examples 1 to 70 in HeLa cells.

[0360] The compounds used in the experiment were HN2203, HN2204, HN2205, HN2208, HN2209, HN2210, HN2211, HN2212, HN2213, HN2214, HN2215, HN2216, HN2217, HN2218, HN2220, HN2221, and HN2220, as listed in Table 1. 222, HN2223, HN2224, HN2225, HN2226, HN2227, HN2228, HN2229, HN2230, HN22 31, HN2232, HN2233, HN2234, HN2235, HN2236, HN2237, HN2238, HN2239, HN2240 , HN2241, HN2242, HN2243, HN2244, HN2245, HN2301, HN2302, HN2303, HN2304, HN2305, HN2306, HN2307, HN2308, HN2309, HN2310, HN2311, HN2312, HN2313, HN Seventy compounds were used: 2314, HN2315, HN2316, HN2317, HN2318, HN2319, HN2320, HN2321, HN2322, HN2323, HN2324, HN2325, HN2326, HN2327, HN2328, HN2329, and HN2336.

[0361] Specifically, HeLa cells were cultured in DMEM (Dulbecco's Modified Eagles Media) medium containing 10% FBS, penicillin (100 units / ml), and streptomycin (100 μg / ml) at 37°C in a 5% CO2 incubator. 4 × 10⁶ cells were placed in a 100 mm culture dish. 5 The cells were planted and cultured, and then subcultured every three days.

[0362] Human HeLa cell line cells 2 × 10 5After inoculating 60 mm culture dishes at a cell / plate density, the cells were cultured for 24 hours. Subsequently, HeLa cells were treated with 70 different compounds at a concentration of 40 μM each for 9 hours. After wiping the HeLa cells twice with cold 1×PBS, the cell membranes were hemolyzed by treating them with 100 μl of RIPA buffer (50 mM Tris-HCl (pH 7.4), 0.25% sodium deoxycholate, 50 mM NaF, 1% NP-40, 150 mM NaCl, 1 mM β-glycerophosphate, 1 mM PMSF, 1 mM NaVO4, 1 μg / ml leupeptin, 1 μg / ml pepstatin A, 10 nM kallikrin A, 10 μg / ml aprotinin, 1 mM EDTA). The supernatant, or cell lysate, was then obtained by centrifugation at 12,000 rpm at 4°C for 10 minutes. The protein concentration of cell lysates was measured using the BCA protein assay kit (Thermo Fisher Scientific), and the same amount of protein was separated by SDS-PAGE.

[0363] Western blot analysis was performed using the following method: Proteins developed by SDS-PAGE were transferred to a PVDF membrane by electroblotting. The membrane was blocked by shaking for 1 hour in TBS-T buffer containing 5% skim milk (20 mM Tris, 137 mM NaCl, 0.1% Tween20). The membrane was washed three times for 5 minutes each with TBS-T buffer, and then reacted overnight at 4°C with a primary antibody diluted in TBS-T buffer containing 5% skim milk or 5% BSA. Subsequently, the membrane was washed three times for 5 minutes each with TBS-T buffer, and then reacted at room temperature for 30 minutes with a secondary antibody diluted in TBS-T buffer containing 5% skim milk. The membrane was washed five times for 5 minutes each with TBS-T buffer containing 5% skim milk, and the protein bands bound to the secondary antibody were detected by chemiluminescence. The primary antibodies used were Akt(Cell signalling, #4691), pAkt(S473)(Cell signalling, #4060), p70S6K(Cell signalling, #S6198), pp70S6K(T389)(Cell signalling, #9205S), and LC3-II(MBL, #PM036). The secondary antibodies used were HRP-conjugated anti-rabbit antibody (Jackson immunoresearch laboratory, #711-035-152) and HRP-conjugated anti-mouse IgG (Jackson immunoresearch laboratory, #515-035-072).

[0364] As an indicator of mTORC2 activity in HeLa cells, the degree of Akt Ser473 phosphorylation was selected as a label. The phosphor-Akt(Ser473) signal level measured by Western blot analysis was normalized by the pan-Akt signal level and then expressed as a percentage relative to a control group treated only with DMSO, the vehicle.

[0365] As an indicator of mTORC1 activity in HeLa cells, the degree of p70S6K Thr389 phosphorylation was selected as a label. The phosphor-p70S6K(Thr389) signal level, measured by Western blot analysis, was normalized to the pan-p70S6K signal level and then expressed as a percentage relative to a control group treated only with DMSO, the vehicle.

[0366] As an indicator of autophagy in HeLa cells, LC3-II formation was selected as the label. The degree of LC3-II signal, measured by Western blot analysis, was normalized by the degree of pan-Akt signal, and then expressed as a percentage relative to a control group treated only with DMSO, the vehicle.

[0367] The experimental results are shown in Table 2 below.

[0368] [Table 2]

[0369] As a result, as shown in Table 2, 29 compounds, HN2203, HN2209, HN2210, HN2213, HN2214, HN2216, HN2217, HN2221, HN2222, HN2225, HN2232, HN2233, HN2301, HN2302, HN2304, HN2305, HN2306, HN2307, HN2308, HN2309, HN2313, HN2315, HN2316, HN2318, HN2319, HN2323, HN2326, HN2328, and HN2329, showed increased mTORC2 activity levels (Akt) after 9 hours following compound treatment at a concentration of 40 μM. We confirmed that the Ser473 phosphorylation was reduced by more than 20% compared to the control group. We also confirmed that 10 compounds, HN2211, HN2231, HN2305, HN2313, HN2316, HN2317, HN2319, HN2321, HN2325, and HN2329, reduced the p70S6K Thr389 phosphorylation, an indicator of mTORC1 activity, by more than 20% after 9 hours of treatment at a 40 μM concentration compared to the control group.

[0370] Specifically, HN2210 reduced AKT Ser473 phosphorylation by 57% and had no effect on S6K Thr389 phosphorylation. LC3-II was increased by 22%. HN2213 reduced AKT Ser473 phosphorylation by 49% but increased S6K Thr389 phosphorylation by 14%. LC3-II was reduced by 33%. HN2216 reduced AKT Ser473 phosphorylation by 36% but increased S6K Thr389 phosphorylation by 21%. HN2308 reduced AKT Ser473 phosphorylation by 56% but had no effect on S6K Thr389 phosphorylation. HN2313 reduced AKT Ser473 phosphorylation by 20% and S6K Thr389 phosphorylation by 46%. LC3-II was increased by 62%. HN2323 reduced AKT Ser473 phosphorylation by 28% and S6K Thr389 phosphorylation by 40%. It also increased LC3-II by 80%. In particular, it was confirmed that 23 compounds, HN2203, HN2209, HN2210, HN2213, HN2214, HN2216, HN2217, HN2221, HN2222, HN2225, HN2232, HN2233, HN2301, HN2302, HN2304, HN2306, HN2307, HN2308, HN2309, HN2315, HN2318, HN2326, and HN2328, can selectively inhibit mTORC2.

[0371] The results show that 35 compounds, as well as the compounds in Examples 1 to 70 that share the same or similar parent organisms, can suppress the activity of mTORC1 and / or mTORC2 in HeLa cells.

[0372] Experimental Example 2. Evaluation of mTORC1 and mTORC2 inhibitory activity in the cerebral cell mTOR signaling pathway. The following experiments were performed to evaluate the time-dependent mTORC2 inhibitory activity, mTORC1 inhibitory activity, and LC-II activity in primary cultured cerebral cells.

[0373] Sixteen compounds were selected and evaluated as subjects for the experiment: HN2209, HN2210, HN2213, HN2216, HN2304, HN2308, HN2309, HN2313, HN2316, HN2318, HN2319, HN2323, HN2325, HN2328, HN2329, and HN2337, which were shown to have excellent mTORC2 inhibitory activity or mTORC1 inhibitory activity and low toxicity in Experimental Example 1.

[0374] Specifically, primary nerve cell cultures were performed from the cerebrum of E16 embryos of white mice (SD, Orient Bio) at 16 weeks of gestation. The left and right hemispheres of the excised brain were separated, and the meninges were removed from the cerebrum. 2+ / Mg 2+ Cells were treated with trypsin in -free HBSS solution. After centrifugation and removal of the supernatant, cells were slowly triturated in neurobasal media to disintegrate them. Clumps of cells that remained unseparated were filtered through a 40 μm nylon mesh. Cells were placed in 35 mm culture dishes coated with 50 μg / ml poly-D-lysine (Sigma, P0899) and 1 μg / ml laminin (Invitrogen, 23017-015) at a rate of 19,000 cells / cm². 2 After inoculation, the cells were cultured in a 5% CO2 incubator using neurobasal complete media supplemented with B27 (Gibco, 17504-044).

[0375] Since the mTORC2 inhibitory activity of the compounds is more strongly expressed in primary cultured cerebral cells compared to HeLa cells, the mTORC2 inhibitory activity in primary cultured cerebral cells was evaluated using the same method as in Experimental Example 1, except that primary cultured cerebral cells were treated with each compound at a concentration of 500 nM or 100 nM for 24 hours. Time-dependent Akt Ser473 phosphorylation, Akt Thr308 phosphorylation, and LC3-II changes were measured by Western blot analysis.

[0376] The experimental results are shown in Figures 1a to 1f and in Table 3 below.

[0377] [Table 3]

[0378] As a result, as shown in Figures 1a to 1f and Table 3, we confirmed that six compounds, HN2210, HN2213, HN2304, HN2308, HN2313, and HN2323, reduce Akt Ser473 phosphorylation, an indicator of mTORC2 activity, and that the HN2210 compound also reduces p70S6K Thr389 phosphorylation, an indicator of mTORC1 activity.

[0379] Specifically, HN2210 reduced AKT Ser473 phosphorylation by approximately 50% from 30 minutes to 6 hours, and by 67% at 24 hours. S6K Thr389 phosphorylation increased by 49% at 3 hours and then decreased by 77% at 24 hours. LC3-II was significantly increased. HN2213 reduced AKT Ser473 phosphorylation by 62% at 24 hours, but S6K Thr389 phosphorylation increased by 37% in a time-dependent manner. LC3-II was significantly increased. HN2304 significantly increased AKT Ser473 phosphorylation from 1 hour to 12 hours and then decreased by 17% at 24 hours. On the other hand, S6K Thr389 phosphorylation was significantly increased from 6 hours to 24 hours. LC3-II was unaffected. HN2308 significantly increased AKT Ser473 phosphorylation from 1 to 12 hours, then decreased it by 54% at 24 hours. However, it had no effect on S6K Thr389 phosphorylation or LC3-II. HN2313 significantly increased AKT Ser473 phosphorylation from 1 to 12 hours, then decreased it by 66% at 24 hours. Meanwhile, S6K Thr389 phosphorylation increased 2-3 times from 1 to 6 hours. LC3-II had no effect. HN2323 significantly increased AKT Ser473 phosphorylation from 1 to 12 hours, then decreased it by 52% at 24 hours. Meanwhile, S6K Thr389 phosphorylation or LC3-II had no effect.

[0380] The results showed that all compounds HN2213, HN2304, HN2308, HN2313, and HN2323 significantly reduced Akt Ser473 phosphorylation, an indicator of mTORC2 activity, while either not reducing or only slightly reducing p70S6K Thr389 phosphorylation, an indicator of mTORC1 activity. Therefore, it was confirmed that compounds HN2213, HN2304, HN2308, HN2313, and HN2323 can be used as selective mTORC2 inhibitors.

[0381] Experimental Example 3.1 Evaluation of mGluR1 / 5-dependent mTORC2 activation inhibition efficacy in dendritic spines of primary cultured hippocampal neurons. Experimental Example 3-1. Evaluation of the efficacy of mGluR1 / 5-dependent mTORC2 activation inhibition in hippocampal neurons. When hippocampal neurons (DIV21) differentiated from primary cultures were treated with DHPG to activate mGluR1 / 5, mTORC2 was activated in the dendritic spines of the neurons. To evaluate the inhibitory ability of compounds on mTORC2, which is activated in a mGluR1 / 5-dependent manner in the dendritic spines of hippocampal neurons, the following experiment was conducted. Fourteen compounds that showed excellent mTORC2 inhibitory activity in Experimental Example 1 were selected and used as the experimental compounds.

[0382] Specifically, hippocampal neurons (DIV21) that had been cultured and differentiated were pretreated with HN2209, HN2210, HN2213, HN2216, HN2304, HN2305, HN2308, HN2309, HN2313, HN2319, HN2323, HN2325, HN2328, and HN2329 at a concentration of 500 nM for 2 hours, and then treated with DHPG for 10 minutes to induce mTORC2 activation. After staining with p-AKT(S473) antibody and PSD95 antibody by immunohistochemistry, the stained spots (puncta) were quantified, and the results are shown in Figures 2a to 2l and Table 4.

[0383] [Table 4]

[0384] As a result, as shown in Figures 2a to 2l and Table 4, we confirmed that 12 compounds, HN2209, HN2210, HN2213, HN2216, HN2304, HN2305, HN2308, HN2309, HN2313, HN2323, HN2325, and HN2329, reduced the increase in p-AKT(S473)+PSD95+p spots induced by DHPG by 68-124%.

[0385] Experimental Example 3-2. IC of a compound that inhibits mGluR1 / 5-dependent mTORC2 activation in hippocampal neuronal dendritic spines. 50 evaluation IC10 inhibits mGluR1 / 5-dependent mTORC2 activation in primary cultured hippocampal neuronal dendritic spines against five compounds: HN2210, HN2213, HN2221, HN2308, and HN2313. 50 To evaluate this, the following experiment was conducted.

[0386] Specifically, hippocampal neurons (DIV21) that had been cultured and differentiated were pretreated with HN2210, HN2213, HN2221, HN2308, and HN2313 at concentrations of 25, 50, and 100 nM for 2 hours, and then treated with DHPG for 10 minutes to induce mTORC2 activation. After staining with p-AKT(S473) antibody and PSD95 antibody by immunohistochemistry, the stained puncta were quantified, and the results are shown in Figures 3a to 3e and Table 5.

[0387] [Table 5]

[0388] As a result, as shown in Figures 3a to 3e and Table 5, HN2210, HN2213, HN2221, HN2308, and HN2313 suppressed mTORC2 activity by more than 50% at a concentration of 25 nM, and therefore the IC50 of HN2210, HN2213, HN2221, HN2308, and HN2313 50 We were able to confirm that it was below 50 nM.

[0389] Experimental Example 4. Evaluation of the inhibitory activity of binding between mTOR protein and mLST8 protein. mLST8 binds to the mTORC-terminal domain (mTOR(CD), aa2179-2549). After binding to mTOR, mLST8 acts as a scaffold, binding to mSin1 and Rictor to complete the mTORC2 complex. To evaluate the mTOR-mLST8 protein binding inhibitory activity of the compounds synthesized in Examples 1 to 70, the following mTOR(CD)-mLST8 binding analysis method was performed to evaluate the inhibitory activity of the compounds on the binding between mLST8 protein and mTOR(CD) protein. Four compounds were used as experimental subjects: HN2210, HN2213, HN2221, and HN2313.

[0390] Specifically, mTOR(CD) protein was overexpressed in E. coli, then labeled with biotin and partially purified. mLST8 protein was overexpressed in insect cells (Sf9 cells), and an mLST8 extract was obtained. mTOR(CD)-biotin and mLST8 extract were shaken at 4°C to induce binding between mTOR(CD)-biotin and mLST8 protein, and then the mTOR(CD)-biotin and mLST8 complex was co-precipitated with avidin agarose beads. The relative amounts of the precipitated mTOR(CD)-biotin protein and mLST8 protein were measured by Western blot analysis and are shown in Figure 4. The four compounds were added during the shaking process of mTOR(CD)-biotin and mLST8 extract.

[0391] As a result, as shown in Figure 4, HN2210 and HN2213 began to inhibit the binding of mTOR(CD) to mLST8 protein by 24% and 19%, respectively, at a concentration of 4 μM, and by 36% and 30%, respectively, at a concentration of 40 μM. HN2313 inhibited the binding of mTOR(CD) to mLST8 protein by 34% at a concentration of 40 μM. On the other hand, HN2221 did not significantly inhibit the binding of mTOR(CD) to mLST8 protein at concentrations of 0.04 to 40 μM.

[0392] The experimental results show that the three compounds HN2210, HN2213, and HN2313, as well as the compounds in Examples 1 to 70 that share the same or similar parent organisms, directly inhibit the binding of mTOR and mLST8, thereby suppressing the formation of the mTORC2 complex.

[0393] In vivo efficacy evaluation of compounds Experimental Example 4. In vivo efficacy evaluation of the compound of chemical formula 1 in 5xFAD mice, an Alzheimer's disease model. To evaluate the effects of HN2210, HN2213, and HN2313 on Alzheimer's disease-related symptoms, particularly 1) memory and cognitive impairment, 2) amyloid plaques, 3) neurofibrillary tangles (NFTs), and 4) brain inflammation, the in vivo efficacy of HN2210, HN2213, and HN2313 was assessed in 5xFAD mice, an Alzheimer's disease model. 5xFAD mice were purchased from Jackson Lab (Cat#034840-JAX) in the United States, crossed once with C57bl6, and F1 heterozygous offspring (Het) were used. After intraperitoneal injection of the compounds into 6-month-old 5xFAD Het mice, behavioral tests were performed. Normal control mice were aged for 6 months using 5xFAD Het mice and littermate mice, and then injected with the same amount of DMSO.

[0394] Experimental Example 4-1. Confirmation of the effect of the Y-maze test on improving short-term memory ability. To confirm the short-term memory-enhancing effects of HN2210, HN2213, and HN2313 compounds in an Alzheimer's disease model, a Y-maze test was performed using 5xFAD-DMSO mice (without compound administration), 5xFAD mice (administered with donepezil, rapamycin, and HN2210, HN2213, and HN2313 compounds), and normal mice as a control group. Donepezil was administered at a dose of 1 mg / kg, and rapamycin, HN2210, HN2213, and HN2313 were administered at a dose of 5 mg / kg, once daily via intraperitoneal injection for two weeks.

[0395] Specifically, the Y-maze experiment was conducted using a Y-shaped maze made of black acrylic material with each arm at a 120° angle. Lighting and a camera were installed on the ceiling, and the surrounding area was shielded with curtains. White mice were measured entering each arm. This was used to analyze short-term memory. To allow the mice to adapt to the environment, they were allowed to acclimate to the experimental space for 30 minutes. The mice were placed at one end of the maze and allowed to move freely for 12 minutes. The measurement time was divided into 8-minute, 10-minute, and 12-minute intervals. When all four paws of a mouse entered the entrance, it was considered that it had entered completely. The number of times the mouse entered each of the three different arms without overlap was measured. The number of times each mouse entered each of the three different arms was divided by the total number of times each mouse entered each arm - 2 to express the percentage. All results were statistically processed using ANOVA, and the results are shown in Figure 5.

[0396] As a result, as shown in Figure 5, in the Y-maze test, the % alternation score, a short-term memory indicator, decreased in 5xFAD-DMSO mice to 75% of the level of the control group (normal mice). In contrast, 5xFAD mice administered HN2210, HN2213, or HN2313 at a dose of 5 mg / kg for 14 days showed an increase in % alternation scores of 1.25, 1.3, and 1.2 times, respectively, compared to 5xFAD-DMSO mice, reaching levels of 93%, 97%, and 90% of the normal control group. On the other hand, administration of donepezil (1 mg / kg) or rapamycin (5 mg / kg) for two weeks did not show a significant increase. From the experimental results, it was confirmed that short-term memory recovered to almost the level of the normal control group in 5xFAD mice administered HN2210, HN2213, and HN2313.

[0397] Experimental Example 4-2. Confirmation of the effect of the Morris underwater maze test on improving spatial perception. To confirm the spatial perception-enhancing effects of HN2210, HN2213, and HN2313 compounds in an Alzheimer's disease model, the Morris water maze (MWM) test was performed using 5xFAD-DMSO mice (without compound administration), 5xFAD mice (administered with donepezil, rapamycin, and HN2210, HN2213, and HN2313 compounds), and a control group of normal mice, in the manner described below.

[0398] Specifically, a 50cm deep tank filled with water (25.0±1.0℃) was divided equally into four sections, and a platform (12cm in diameter) was placed in the middle of one of the sections at a depth of 3mm from the water surface. The training test consisted of a 1-minute free swimming practice without the platform on the first day, and a training test four times a day for four days in which the animals searched for the invisible platform using spatial cues above the tank. The day after the training test, after the tank platform was removed, the time the experimental animals stayed where the platform had been was measured (probe trial). Captured video images were analyzed using a video tracking system (Ethovision underwater maze program, Noldus Information Technology, Wageningen, Netherlands). The analysis included the time spent swimming in the target quarter and the number of times the animals crossed a virtual platform to find the removed platform. The measured experimental results are shown in Figures 6a and 6b.

[0399] As a result, as shown in Figures 6a and 6b, the number of target crossings in 5xFAD-DMSO mice in the Morris water maze test decreased to 15% of the level of normal control mice. In 5xFAD mice administered HN2210, HN2213, or HN2313 at a dose of 5 mg / kg for 14 days, the number of target crossings increased 3.96 times, 4 times, and 5.5 times, respectively, compared to 5xFAD-DMSO mice, reaching levels of 59%, 60%, and 82% of the normal control group. Furthermore, the time spent in the four-segment zone in 5xFAD-DMSO mice decreased to 55% of the level of normal control mice. In 5xFAD mice administered HN2210, HN2213, or HN2313 at a dose of 5 mg / kg for 14 days, the time spent in the four-segment zone increased by 1.74, 1.91, and 1.53 times, respectively, compared to 5xFAD-DMSO mice, reaching levels of 96%, 105%, and 84% of the normal control group. On the other hand, administration of donepezil (1 mg / kg) or rapamycin (5 mg / kg) for two weeks did not show a significant increase in the number of target crossovers or the time spent in the four-segment zone. From the experimental results, it was confirmed that spatial perception in 5xFAD mice administered HN2210, HN2213, and HN2313 recovered to almost the level of the normal control group.

[0400] Experimental Example 4-3. Confirmation of the effect of passive avoidance testing on improving long-term memory capacity. To confirm the long-term memory-enhancing effects of HN2210, HN2213, and HN2313 compounds in an Alzheimer's disease model, a passive avoidance test was conducted using 5xFAD-DMSO mice (without compound administration), 5xFAD mice (administered donepezil, rapamycin, and HN2210, HN2213, and HN2313 compounds), and a control group of normal mice, using the method described below.

[0401] Specifically, mice that had been trained to avoid bright light three times daily were subjected to an electric foot shock (1 mA, 300 g reference) for 3 seconds in a dark room at the same time the following day. After 24 hours, the mice were placed in the same room, and their light avoidance response, i.e., the time it took to move from the bright room to the dark room, was measured. After 24 hours of adaptive training, the mice were placed back into the bright room, and the latency time it took to enter the dark room was measured for 720 seconds. The measured test results are shown in Figure 7.

[0402] As a result, as shown in Figure 7, the waiting time in 5xFAD-DMSO mice in the passive avoidance test decreased to 16% of the level of normal control mice. In 5xFAD mice administered HN2210, HN2213, or HN2313 at a dose of 5 mg / kg for 14 days, the waiting time increased by 5.16 times, 4.52 times, and 5.86 times, respectively, compared to 5xFAD-DMSO mice, reaching levels of 84%, 74%, and 96% of the normal control group. On the other hand, when donepezil (1 mg / kg) or rapamycin (5 mg / kg) was administered for 2 weeks, the waiting time increased to only 38% and 36% of the normal control group, respectively. From the experimental results, it was confirmed that long-term memory recovered to almost the level of the normal control group in 5xFAD mice administered HN2210, HN2213, and HN2313.

[0403] The results from experimental examples 4-1, 4-2, and 4-3 confirmed that memory and cognitive functions, which were reduced in 5xFAD mice compared to the normal group, were restored to normal levels by administration of HN2210, HN2213, and HN2313.

[0404] Experimental Example 4-4. Confirmation of concentration-dependent effects on improving memory and cognitive function. To confirm the concentration-dependent improvement effect of HN2210 on memory and cognitive function in an Alzheimer's disease model, Y-maze tests, Morris water maze tests, and passive avoidance tests were performed using 5xFAD-DMSO mice (without compound administration), 5xFAD mice (administered HN2210 at 0.2 mg / kg, 1 mg / kg, and 5 mg / kg), and a control group of normal mice. HN2210 was administered intraperitoneally once daily for two weeks at doses of 0.2 mg / kg, 1 mg / kg, and 5 mg / kg.

[0405] As a result, as shown in Figure 8a, in the Y-maze test, 5xFAD-DMSO mice showed a decrease in %alternation, a short-term memory indicator, to 70% of the level of normal control mice. In 5xFAD mice administered HN2210 at doses of 0.2 mg / kg, 1 mg / kg, and 5 mg / kg for 14 days, %alternation increased 1.21 times, 1.17 times, and 1.32 times, respectively, compared to 5xFAD-DMSO mice, reaching levels of 85%, 82%, and 93% of the normal control group.

[0406] As shown in Figure 8b, in the Morris water maze test, the number of target crossings in 5xFAD-DMSO mice decreased to 15% of the level of the control group (normal mice), while in 5xFAD mice administered HN2210 at doses of 0.2 mg / kg, 1 mg / kgm, and 5 mg / kg for 14 days, the number of target crossings increased 2.02 times, 4.27 times, and 5.84 times, respectively, compared to 5xFAD-DMSO mice, reaching levels of 30%, 63%, and 86% of the normal control group. Furthermore, as shown in Figure 8c, the time spent in the quadrilateral zone of 5xFAD-DMSO mice decreased to 41% of the level of normal control mice. In contrast, 5xFAD mice administered HN2210 at doses of 0.2 mg / kg, 1 mg / kg, and 5 mg / kg for 14 days showed increased time spent in the quadrilateral zone by 2.14, 2.07, and 2.34 times, respectively, compared to 5xFAD-DMSO mice, reaching levels of 87%, 85%, and 96% of the normal control group.

[0407] Furthermore, as shown in Figure 8d, in the passive avoidance test, the latency of 5xFAD-DMSO mice decreased to 19% of that of the control group (normal mice). In 5xFAD mice administered HN2210 at doses of 0.2 mg / kg, 1 mg / kg, and 5 mg / kg for 14 days, the latency increased 2.97 times, 4.39 times, and 5.16 times, respectively, compared to 5xFAD-DMSO mice, reaching levels of 56%, 83%, and 97% of the normal control group.

[0408] The results from Experimental Example 4-4 confirmed that memory and cognitive functions, which were reduced in 5xFAD mice compared to the normal group, improved to normal levels in a concentration-dependent manner after HN2210 administration.

[0409] Experimental Example 4-5: Confirmation of amyloid plaque removal effect in 5xFAD mouse brains. To confirm the amyloid plaque removal effects of HN2210, HN2213, and HN2313 compounds in Alzheimer's disease model mouse brains, the following tests were conducted using 5xFAD-DMSO mice that were not administered the compounds, 5xFAD mice administered with HN2210, HN2213, and HN2313 compounds, and normal mice as a control group.

[0410] Specifically, brain sections were sectioned in the coronal direction, and one section was selected every five sections from the anterior to posterior parts of the brain. These sections were then stained with 6E10 antibody or thioflavin-S. 6E10 antibody stains all Aβ and amyloid plaques, while thioflavin-S stains only amyloid plaques. DNA was then simultaneously stained with DAPI. The dentate gyrus (DG) region of the hippocampus, where amyloid plaques are abundant, was observed using a confocal scanning microscope and is shown in Figures 9a to 9c.

[0411] As a result, as shown in Figures 9a and 9b, we were able to confirm that the 6E10 signal in dentate gyrus of 5xFAD mice administered HN2210, HN2213, or HN2313 at a dose of 5 mg / kg for 14 days was reduced by 53%, 29%, and 38%, respectively, compared to the 5xFAD-DMSO group.

[0412] Furthermore, as shown in Figures 9a and 9c, we were able to confirm that the thioflavin-S signal in dentate gyrus of 5xFAD mice administered HN2210, HN2213, or HN2313 at a dose of 5 mg / kg for 14 days was reduced by 38%, 28%, and 35%, respectively, compared to the 5xFAD-DMSO group.

[0413] Experimental Example 4-6: Confirmation of tau aggregate removal effect in 5xFAD mouse brains. To confirm the neurofibrillary tangle removal effects of HN2210, HN2213, and HN2313 compounds in the brains of Alzheimer's disease model mice, the following tests were conducted using 5xFAD mice that were not administered the compounds, 5xFAD mice administered with HN2210, HN2213, and HN2313 compounds, and a control group of normal mice.

[0414] Specifically, the AT8 antibody stains the hyperphosphorylated Tau protein that constitutes tau aggregates. Therefore, tau aggregates formed in the hippocampus of 5xFAD mouse brains can be measured by immunostaining using the AT8 antibody. Brain sections were triple-stained with the AT8 antibody, the neuronal label MAP2, and the cell nucleus stain DAPI, and the dentate gyrus region of the hippocampus was observed using a confocal scanning microscope. The results are shown in Figures 10a and 10b.

[0415] As a result, as shown in Figures 10a and 10b, we were able to confirm that the AT8 antibody signal in dentate gyrus of 5xFAD mice administered HN2210, HN2213, or HN2313 at a dose of 5 mg / kg for 14 days was reduced by 61%, 59%, and 49%, respectively, compared to the 5xFAD-DMSO group.

[0416] Experimental Example 4-7: Confirmation of anti-inflammatory effect in the brains of 5xFAD mice. To confirm the anti-inflammatory effects of HN2210, HN2213, and HN2313 compounds in the brains of Alzheimer's disease model mice, tests were conducted using 5xFAD mice that did not receive the compounds, 5xFAD mice that received HN2210, HN2213, and HN2313 compounds, and a control group of normal mice, using the method described below. Specifically, brain inflammation is mediated by microglia activation, and the IBA-1 antibody stains activated microglia. Therefore, inflammation in the hippocampus of 5xFAD mouse brains can be measured by immunostaining using the IBA-1 antibody. Brain sections were double-stained with the IBA-1 antibody and DAPI, which stains cell nuclei, and the dentate gyrus region of the hippocampus was observed using a confocal scanning microscope. The results are shown in Figures 11a and 11b.

[0417] As a result, as shown in Figures 11a and 11b, we were able to confirm that the IBA-1 antibody signal in dentate gyrus of 5xFAD mice administered HN2210, HN2213, or HN2313 at a dose of 5 mg / kg for 14 days was reduced by 50%, 24%, and 50%, respectively, compared to the 5xFAD-DMSO group.

[0418] The results from experimental examples 4-5, 4-6, and 4-7 confirmed that HN2210, HN2213, and HN2313, when administered to 5xFAD mice (an Alzheimer's disease model), reduced amyloid plaques and neurofibrillary tangles and suppressed brain inflammation.

[0419] From the above description, those skilled in the art will understand that the present invention can be implemented in other specific forms without altering its technical concept or essential features. In this regard, the embodiments described above should be understood to be illustrative and not limiting in all respects. The scope of the present invention should be interpreted as encompassing all modified or altered forms derived from the meaning and scope of the claims and their equivalent concepts described below, rather than from the detailed description.

Claims

1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 In chemical formula 1, "X" is O, S, or CH ２ And, "R １ " is hydrogen, halo (F, Br, Cl, or I), substituted or unsubstituted C ６－１０ A substituted or unsubstituted 4- to 12-membered heteroaryl containing an aryl or one or more heteroatoms selected from the group consisting of N, O, and S, "R ２ " is hydrogen, halo (F, Br, Cl, or I), substituted or unsubstituted C ６－１０ aryl, substituted or unsubstituted C １－６ The amino, a substituted or unsubstituted 4- to 12-membered heterocycloalkyl, or an unsubstituted benzylamino, "R ３ " is hydrogen or halo (F, Br, Cl, or I), "R ４ " and "R ５ " are each independently an unsubstituted C １－６ alkoxy, or "R ４ " and "R ５ " can form -O(CH) ｎ O- (where n is 1 or 2) together with two oxygen atoms, The substituted aryl or substituted heteroaryl is a hydroxyl (OH), halo (F, Br, Cl, or I), and one to three halos, or an unsubstituted C. １－１０ Linear or branched alkyl groups, and unsubstituted C １－５ It may be substituted with one or more substituents selected from the group consisting of linear or branched alkoxys. The substituted amino acid is C １－５ Linear or branched alkyl, unsubstituted C ３－８ Cycloalkyl, C １－５ C substituted with a linear or branched alkoxy phenyl group １－５ Linear alkyl, C substituted with an unsubstituted thiophenyl group １－５ Linear alkyl, C ３－８ Cycloalkyl and C １－５ It may be substituted with one or more substituents selected from the group consisting of linear alkyl-substituted sulfonyl molecules. The substituted heterocycloalkyl group is an unsubstituted C ６－１０ Aryl or unsubstituted C ６－１０ Aryl C １－６ It may be substituted with alkyl, The compound of chemical formula 1 does not contain the following compounds: a) 2,3-dimethoxydibenz[b,e]oxepin-11(6H)-one; and b) 9-bromo[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one.

2. The aforementioned "R" １ " is hydrogen, fluorine, brominated or unsubstituted C ６－１０ Unsubstituted C containing O as an aryl or heteroatom ４－６ It is a heteroaryl, The aforementioned "R" １ The substituted aryl in " is substituted with one substituent selected from the group consisting of hydroxy, fluoro, chloro, trifluoro, methyl, and 1 to 3 methoxy atoms. The aforementioned "R" ２ " is hydrogen, fluoro, substituted C ６－１０ aryl, substituted or unsubstituted C １－６ The amino, substituted or unsubstituted six-membered heterocycloalkyl, or unsubstituted benzylamino, The aforementioned "R" ２ The substituted aryl in " is substituted with one substituent selected from the group consisting of chloro, methyl, and 1 to 3 methoxy atoms. The substituted alkylamino is substituted with one substituent selected from the group consisting of two methyl, cyclohexyl, phenethyl, thiophenylethyl, and methylsulfonyl molecules. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl is substituted with an unsubstituted aryl substituent.

3. The aforementioned "R" ４ " and "R ５ " is either methoxy or "R" independently. ４ " and "R ５ " together with two types of oxygen atoms -O(CH) ２ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which forms an O-.

4. The aforementioned "R" １ " is hydrogen, fluorine, bromo, 【Chemistry 2】 It is one species selected from the group consisting of, The aforementioned "R" ２ " is hydrogen (H), fluoro (F), 【Transformation 3】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

5. The compound of chemical formula 1 is selected from the group consisting of the following compounds, as described in claim 1, or a pharmaceutically acceptable salt thereof. 1) 9-Fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 2) [2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one ([2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one}); 3) 8,9-difluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 4) 8-(dimethylamino)-9-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 5) 8-(morpholino)-9-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 6) 8-(piperidinyl)-9-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 7) 8-(phenylpiperazin-1-yl)-9-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 8) 8-(benzylamino)-9-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (8-(benzylamino)-9-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one); 9) 9-(4-chlorophenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (9-(4-chlorophenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one); 10) 9-(4-hydroxyphenyl)[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (9-(4-hydroxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one); 11) 9-(3-furanyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (9-(3-furanyl)[2]benzoxepino[3,4-f]-1,3-oxobenzodioxol-11(6H)-one); 12) 9-(p-tolyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (9-(p-tolyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one); 13) 9-(4-methoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 14) 9-(2,4-dimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (9-(2,4-dimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one); 15) 9-(3,4,5-trimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 16) 8-(cyclohexylamino)-9-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 17) 8-(4-benzylpiperidine-1-yl)-9-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 18) 8-((4-methoxyphenethyl)amino)-9-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 19) 8-((2-(thiophen-2-yl)ethyl)amino)-9-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 20) 7,8-difluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 21) 8-(dimethylamino)-7-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (8-(dimethylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one); 22) 8-(morpholino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (8-(morpholino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-oxobenzodioxol-11(6H)-one); 23) 8-(piperidinyl)-7-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 24) 8-(phenylpiperazin-1-yl)-7-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 25) 8-(benzylamino)-7-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (8-(benzylamino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one); 26) 8-(cyclohexylamine)-7-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 27) 8-(4-benzylpiperidine-1-yl)-7-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (8-(4-benzylpiperidine-1-yl)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one}); 28) 8-((4-methoxyphenethyl)amino)-7-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (8-((4-methoxyphenethyl)amino)-7-fluoro[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one); 29) 8-((2-(thiophen-2-yl)ethyl)amino)-7-fluoro[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 30) 9-bromo-2,3-dimethoxydibenz[b,e]oxepin-11(6H)-one; 31) 9-(2,4-dimethoxyphenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one (9-(2,4-dimethoxyphenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one); 32) 9-(3,4-dimethoxyphenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one (9-(3,4-dimethoxyphenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one); 33) 2,3-dimethoxy-9-(3-methoxyphenyl)dibenzo[b,e]oxepin-11(6H)-one; 34) 9-(4-fluorophenyl)-2,3-dimethoxydibenzo[b,e]oxepin-11(6H)-one; 35) 8-(4-chlorophenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 36) 8-(p-tolyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (8-(p-tolyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one); 37) 8-(4-methoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 38) 8-(2,4-dimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one (8-(2,4-dimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one); 39) 8-(3,4,5-trimethoxyphenyl)[2]benzoxepino[3,4-f]-1,3-benzodioxol-11(6H)-one; 40) 2,3-dimethoxy-9-(4-(trifluoromethyl)phenyl)dibenzo[b,e]oxepin-11(6H)-one; 41) N-(9-fluoro-11-oxo-6,11-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-8-yl)methanesulfonamide (N-(9-fluoro-11-oxo-6,11-dihydro-[1,3]dioxolo[4',5':4,5]benzoo[1,2-b]benzoo[e]oxepin-8-yl)methanesulfonamide); 42) N-(7-fluoro-11-oxo-6,11-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-8-yl)methanesulfonamide (N-(7-fluoro-11-oxo-6,11-dihydro-[1,3]dioxolo[4',5':4,5]benzoo[1,2-b]benzoo[e]oxepin-8-yl)methanesulfonamide); 43) 2,3-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one; 44) 9-bromo-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one; 45) 2,3-dimethoxy-9-(3,4,5-trimethoxyphenyl)dibenzo[b,e]thiepin-11(6H)-one (HN2305); 46) 2,3-dimethoxy-9-(4-methoxyphenyl)dibenzo[b,e]thiepin-11(6H)-one (HN2306); 47) 2,3-dimethoxy-9-(p-tolyl)dibenzo[b,e]thiepin-11(6H)-one (HN2307); 48) 9-(3-furanyl)-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (HN2308); 49) 9-(4-chlorophenyl)-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (HN2309); 50) 10,11-dihydro-5H-benzo[4',5']cyclohepta[1',2':4,5]benzo[1,2-d][1,3]dioxol-5-one (HN2310); 51) 2,3-difluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2311); 52) 8-(cyclopropylamino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (8-(cyclopropylamino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzoo[1,2-b]benzoo[e]oxepin-11(6H)-one) (HN2312); 53) 8-(cyclopentylamino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (8-(cyclopentylamino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzoo[1,2-b]benzoo[e]oxepin-11(6H)-one) (HN2313); 54) 2-(dimethylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2314); 55) 3-Fluoro-7,8-dimethoxy-2-(piperidine-1-yl)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2315); 56) 3-Fluoro-7,8-dimethoxy-2-(4-phenylpiperazin-1-yl)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2316); 57) 2-(benzylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2317); 58) 8-(cyclopropylamino)-7-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (8-(cyclopropylamino)-7-fluoro-[1,3]dioxolo[4',5':4,5]benzoo[1,2-b]benzoo[e]oxepin-11(6H)-one) (HN2318); 59) 8-(cyclopentylamino)-7-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (8-(cyclopentylamino)-7-fluoro-[1,3]dioxolo[4',5':4,5]benzoo[1,2-b]benzoo[e]oxepin-11(6H)-one) (HN2319); 60) 2-(cyclopropylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2320); 61) 2-(cyclopentylamino)-3-fluoro-7,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-one (HN2321); 62) 8-((2,4-dichlorophenethyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (8-((2,4-dichlorophenethyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzoo[1,2-b]benzoo[e]oxepin-11(6H)-one) (HN2322); 63) 9-Fluoro-8-((2-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2323); 64) 8,9-difluoro-2,3-dimethoxydibenzo[b,e]thiepin-11(6H)-one (HN2324); 65) 9-Fluoro-8-((3-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2325); 66) 9-Fluoro-8((4-methoxybenzyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2326); 67) 9-Fluoro-8-((3-methoxyphenethyl)amino)-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (HN2327); 68) 8-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (8-((2,4-dimethoxybenzyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzolo[1,2-b]benzolo[e]oxepin-11(6H)-one) (HN2328); 69) 8-((3,4-dimethoxybenzyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzo[1,2-b]benzo[e]oxepin-11(6H)-one (8-((3,4-dimethoxybenzyl)amino)-9-fluoro-[1,3]dioxolo[4',5':4,5]benzolo[1,2-b]benzolo[e]oxepin-11(6H)-one) (HN2329); and 70) 8-Bromo[2]benzooxepino[3,4-f]-1,3-benzodioxol-11(6H)-one.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound inhibits mTORC1 (mammalian target of rapamycin complex 1) activity or mTORC2 (mammalian target of rapamycin complex 2) activity.

7. A pharmaceutical composition for the prevention or treatment of degenerative neurological diseases, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

8. The pharmaceutical composition according to claim 7, wherein the degenerative neurological disorder is one or more selected from the group consisting of Alzheimer's disease, senile dementia, Lewy body dementia, frontotemporal dementia, mild cognitive impairment, Parkinson's disease, Pieck's disease, Huntington's disease, spinocerebellar ataxia, epilepsy, and stroke.

9. The pharmaceutical composition according to claim 7, wherein the composition selectively inhibits mTORC2 activity.

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