Bicyclic compound and use thereof

Abstract

The present invention relates to a compound derivative bearing a 6-7 bicyclic ring and a use thereof. The compound according to the present invention acts as a protein arginine methyltransferases 5 (PRMT5) inhibitor and thus can be advantageously used to prevent or treat a disease caused by PRMT5.

Description

DESCRIPTION TITLE OF INVENTION BICYCLIC COMPOUND AND USE THEREOF TECHNICAL FIELD The present invention relates to a compound derivative containing a 6-7 bicyclic ring and use thereof. The compound according to the present invention can be effectively used in the prevention or treatment of diseases caused by protein arginine methyltransferases 5 (PRMTS5) by acting as a PRMTS inhibitor. BACKGROUND ART PRMT (protein arginine methyltransferases) are enzymes that transfer methyl groups to arginine in target proteins using the cofactor SAM (S-adenosyl methionine). Up to now, there are a total of 9 PRMT isoforms (PRMT1-9) have been known, and these are largely divided into 3 types. It has been known that PRMTI, 2, 3, 4, 6 and 8—which belong to type I PRMT—cause monomethylation and asymmetric dimethylation of arginine, and PRMT5 and PRMTY belonging to type II PRMT induce monomethylation and symmetric dimethylation of arginine. Meanwhile, PRMT7—which is a type III PRMT—mainly causes monomethylation of arginine. PRMT induces methylation of various substrates present in the nucleus and cytoplasm, thereby regulating important biological processes in cells such as cell proliferation, differentiation and splicing. PRMTS is a major arginine methyl group transfer enzyme among type II PRMTs. It forms a functional complex with methylosome protein 50 (MEP50) to cause methylation of the target protein. PRMTS is involved in the formation of leukemia, lymphoma, glioblastoma, lung cancer and breast cancer by methylating target proteins including histone protein in the nucleus and non-histone protein such as p53, NFkB, PI3K / AKT and CRAF. Specifically, it is well known that cancer formation by PRMTS occurs as the proliferation, differentiation, invasion and migration of tumor cells are promoted. In addition, according to several reports, it is known that the higher the expression of PRMTS is, the poorer the prognosis of cancer patients is. To the contrary, it has been observed that when the expression of PRMTS is inhibited, the proliferation of tumor cells can be suppressed. Meanwhile, it has been recently reported that diseases other than cancer can also be mediated by PRMTS. DISCLOSURE OF INVENTION TECHNICAL PROBLEM An object of the present invention is to provide a novel compound based on a 6-7 bicyclic ring showing excellent PRMTS inhibitory effect, or an optical isomer, a stereoisomer or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, Another object of the present invention is to provide a pharmaceutical composition comprising the above novel compound based on a 6-7 bicyclic ring, or an optical isomer, a stereoisomer or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. SOLUTION TO PROBLEM To achieve the above object, the present invention provides a compound represented by the following Formula 1, or an optical isomer, a stereoisomer or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof: [Formula 1] a2 0 EX ; . SX 7 ° : fg I< a a,b F(R) wherein X" and X? are each independently carbon or nitrogen; Y is carbon, oxygen or nitrogen; Z is carbon; nis an integer of 0 or 1; m is an integer of 0 to 2; === is a single bond or a double bond; R! is -D-R'%; wherein D is a direct bond, -O-, -C(=0)-, -C=C- or -CR!'R'%; R' is hydrogen, halo, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, haloalkylsulfonate, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminocarbonylalkyl, saturated or unsaturated carbocyclyl, saturated or unsaturated heterocyclyl, saturated or unsaturated carbocyclyl-alkyl, or saturated or unsaturated heterocyclyl-alkyl; R'! and R'2 are each independently hydrogen, hydroxy or alkyl; the carbocycle or heterocycle may be substituted with one or more substituents selected from hydroxy, halo, oxo, formyl (-CHO), nitrile, alkyl, alkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyalkyl, haloalkyl, nitrilealkyl, alkylcarbonyl, alkylthiocarbonyl, alkoxycarbonyl, haloalkylcarbonyl, carbocyclyl, carbocyclylcarbonyl, (alkyl)(haloalkyl)amino, (alkyl)(heterocyclyl)amino, heterocyclyl and heterocyclyl-alkyl; R? is hydrogen or alkyl; R? is hydrogen or alkyl; R*, R®, R® and R are each independently hydrogen or alkyl; R® is hydrogen, halo, alkyl, alkoxy or amino; and R’ is hydrogen, halo or alkyl. Unless indicated otherwise, the term “alkyl” used herein, either alone or in combination with additional terms (for example, haloalkyl), refers to a radical of a saturated aliphatic hydrocarbon group having, for example 1 to 7 carbon atoms of a linear or branched chain. For example, the alkyl may include such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, fert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl and 1, 2-dimethylpropyl, but is not limited thereto. Unless indicated otherwise, the term “alkoxy” used herein refers to alkyloxy having, for example 1 to 7 carbon atoms. Unless indicated otherwise, the term “halo” used herein, either alone or in combination with additional terms (for example, haloalkyl), refers to a radical of fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Unless indicated otherwise, the term “haloalkyl” used herein refers to an alkyl defined as above in which one or more of the hydrogen atoms are replaced with one or more same or different halogen atoms. Exemplary haloalkyl may include -CH:Cl, -CH>CF3, -CH2CCls or perfluoroalkyl (e.g., -CF3). Unless indicated otherwise, the term “oxo” used herein refers to the group of =O (that is, oxygen having a double bond). For example, 1-oxo-ethyl group is an acetyl group. Unless indicated otherwise, the term “hydroxyalkyl” used herein refers to an alkyl in which onr or more of the hydgen atoms are replaced with one or more hydroxy (-OH) groups. For example, it may include that the hydgen atoms are replaced with 2 or 3 hydroxy groups. Unless indicated otherwise, the term “saturated or unsaturated carbocyclyl” used herein refers to a radical of a hydrocarbon that is unsaturated or partially or fully saturated, forming a single or fused cyclic ring having, for example 3 to 24 carbon atoms. Specifically, the carbocyclyl may have 3 to 10 carbon atoms. The carbocycle may include a bridged structure or a spiro structure. In addition, the unsaturated carbocycle may include an aromatic hydrocarbon such as aryl. According to one embodiment of the present invention, the carbocycle may be cyclohexane, cyclohexene, cyclopropane, cyclobutane or cyclopentane, but is not limited thereto. Unless indicated otherwise stated, the term “saturated or unsaturated heterocyclyl” used herein refers to 3- to 24-membered hydrocarbon that is unsaturated or partially or fully saturated, forming a single or fused cyclic ring, and having one or more heteroatoms, for example 1 to 8 heteroatoms selected from the group consisting of nitrogen (N), oxygen (O) and sulfur (S) Specifically, the heterocyclyl may be a 4- to 10-membered hydrocarbon having 1 to 3 hetero atoms. The heterocycle may include a bridged structure or a spiro structure. In addition, the unsaturated heterocyclyl may include an aromatic hydrocarbon such as heteroaryl. According to one embodiment of the present invention, the heterocycle may be tetrahydropyridine, dihydropyridine, piperidine, dihydropyran, tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine, morpholine, 3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrole, pyrrolidine, oxazepane, 2-oxa-5-azabicyclo[2.2.1]heptane, pyridyl, tetrahydrofuran, 8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.4]octane, 2-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane, 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine, 3,4,6,7,8,8a-hexahydro- 1H-pyrrolo[1,2]-a]pyrazine, pyrimidine, pyrazole, 2-oxa-7-azaspiro[3.5]nonane or oxetane, but is not limited thereto. According to one embodiment of the present invention, in the above Formula 1, X! and X?2 are each independently CH or N. According to one embodiment of the present invention, in the above Formula 1, Y is CHa, OorNH, whennis 0; and Yis CH or N, whennis 1. According to one embodiment of the present invention, in the above Formula 1, Z is CHz or CH, whenm is 0; Z is CH or C, when m is 1; and Z is C, when m is 2. According to one embodiment of the present invention, in the above Formula 1, === is a single bond or a double bond. According to one embodiment of the present invention, in the above Formula 1, R! is -D-R!%: wherein D is a direct bond, -O-, -C(=0)-, -C=C- or -CR!'R2-, According to one embodiment of the present invention, in the above Formula 1, R' is hydrogen, halo, hydroxy, cyano, C1-Cy alkyl, hydroxy-Ci-Cs alkyl, halo-C;-C alkyl, halo-C1-C7 alkylsulfonate, di(C1-C7alkyl)amino, C;-C7 alkylamino-Ci-Cr alkyl, di(C1-C7 alkyl)amino-C,-C7 alkyl, di(C1-C7 alkyl)aminocarbonyl-C1-C7 alkyl, saturated or unsaturated Cs-Cio carbocyclyl, saturated or unsaturated, 4- to 10-membered heterocyclyl, saturated or unsaturated Cs3-Cio carbocyclyl-Ci-C7 alkyl, or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl. According to one embodiment of the present invention, in the above Formula 1, R!! and R!? are each independently hydrogen, hydroxy or Ci-C7 alkyl. According to one embodiment of the present invention, in the above Formula 1, the carbocycle or heterocycle may be substituted with 1 to 5 substituents selected from hydroxy, halo, oxo, formyl, nitrile, C1-C7 alkyl, C1-C7 alkoxy, hydroxy-Ci-Cs alkyl, hydroxyhalo-Ci-C; alkyl, C1-C7alkoxy-C1-C7 alkyl, halo-Ci-Cs alkyl, nitrile-C1-C7 alkyl, C1-C5 alkylcarbonyl, C1-C7 alkylthiocarbonyl, Ci-C; alkoxycarbonyl, halo-Ci-C; alkylcarbonyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated C3-Cio carbocyclylcarbonyl, (Ci-C; alkyl)(halo-C1-C7 alkyl)amino, (Ci-C7 alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino, saturated or unsaturated, 4- to 10-membered heterocyclyl and saturated or unsaturated, 4- to 10-membered heterocyclyl-Ci-C7 alkyl. According to one embodiment of the present invention, in the above Formula 1, R? is hydrogen or C;-C7 alkyl. According to one embodiment of the present invention, in the above Formula 1, R? is hydrogen or C1-C7 alkyl. According to one embodiment of the present invention, in the above Formula 1, R*, R, R® and R’ are each independently hydrogen or C1-C7 alkyl. According to one embodiment of the present invention, in the above Formula 1, R® is hydrogen, halo, Ci-C7 alkyl, C;-C7 alkoxy or amino. According to one embodiment of the present invention, in the above Formula 1, R® is hydrogen, halo or C;-C7 alkyl. According to one embodiment of the present invention, in the above Formula 1, X' and X? are each independently CH or N; Y is CHa, O or NH, when nis 0; Y is CH or N, when n is 1; Z is CHz or CH, when m is 0; Z is CH or C, when m is 1; Z is C, when m is 2; and === is a single bond or a double bond. According to one embodiment of the present invention, in the above Formula 1, R! is -D-R'%; wherein D is a direct bond, -O-, -C(=0)-, -C=C- or -CR!''R'%-; R'* is hydrogen, halo, hydroxy, cyano, C1-C7 alkyl, hydroxy-Ci-C7 alkyl, halo-C-C alkyl, halo-Ci-Cy alkylsulfonate, di(C1-C7 alkyl)amino, Ci-C- alkylamino-Ci-Cy alkyl, di(C1-C7 alkyl)amino-C;-C7 alkyl, di(Ci-C7 alkyl)aminocarbonyl-Ci-C7 alkyl, saturated or unsaturated C;-Cio carbocyclyl, saturated or unsaturated, 4- to 10-membered heterocyclyl, saturated or unsaturated C3-Cio carbocyclyl-Ci-C7 alkyl, or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl; and R!' and R'? are each independently hydrogen, hydroxy or C;-C7 alkyl. According to one embodiment of the present invention, in the above Formula 1, R' is halo, Ci-C; alkyl, hydroxy-Ci-C; alkyl, halo-Ci-C; alkyl, saturated or unsaturated Cs3-Cio carbocyclyl, saturated or unsaturated, 4- to 10-membered heterocyclyl, or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl, According to one embodiment of the present invention, in the above Formula 1, the carbocycle or heterocycle may be substituted with 1 to 5 substituents selected from hydroxy, halo, oxo, formyl, nitrile, C;-C7 alkyl, C1-C7 alkoxy, hydroxy-Ci-C alkyl, hydroxyhalo-Ci-C7 alkyl, C1-C7alkoxy-Ci-C7 alkyl, halo-C1-C7 alkyl, nitrile-C;-C7 alkyl, Ci-C7 alkylcarbonyl, C1-C7 alkylthiocarbonyl, Ci-C; alkoxycarbonyl, halo-Ci-C; alkylcarbonyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated C3-Cio carbocyclylcarbonyl, (Ci-C; alkyl)(halo-C1-C7 alkyl)amino, (Ci-C7 alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino, saturated or unsaturated, 4- to 10-membered heterocyclyl and saturated or unsaturated, 4- to 10-membered heterocyclyl-C;-C7 alkyl. According to one embodiment of the present invention, in the above Formula 1, the carbocycle or heterocycle may be substituted with 1 to 5 substituents selected from hydroxy, halo, formyl, Ci-C7 alkyl, hydroxy-Ci-C; alkyl, Ci-C7 alkoxy-Ci-C7 alkyl, halo-Ci-C5 alkyl, C\1-C7 alkylcarbonyl, Ci-C7 alkoxycarbonyl, halo-Ci-C7 alkylcarbonyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated C3-Cio carbocyclylcarbonyl, (Ci-Cr alkyl)(halo-C1-C7 alkyl)amino, (Ci-C7 alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino and saturated or unsaturated, 4- to 10-membered heterocyclyl-C;-C7 alkyl. According to one embodiment of the present invention, in the above Formula 1, the heterocycle may be substituted with 1 or 2 substituents selected from hydroxy, halo, formyl, Ci-C7 alkyl, hydroxy-Ci-C; alkyl, Ci-C; alkoxy-Ci-C; alkyl, halo-Ci-C; alkyl, Ci-C7 alkylcarbonyl, C1-C7 alkoxycarbonyl, halo-C;-C alkylcarbonyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated C3-Cio carbocyclylcarbonyl and saturated or unsaturated, 4- to 10-membered heterocyclyl-C;-C7 alkyl. According to one embodiment of the present invention, in the above Formula 1, the carbocycle may be substituted with 1 or 2 substituents selected from halo-C,-C7 alkyl, (Ci-C7 alkyl)(halo-C1-C7 alkyl)amino and (Ci-C7 alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino. According to one embodiment of the present invention, in the above Formula 1, R! is -D-R'%; wherein D is a direct bond; R'? is hydrogen, halo, cyano, C1-C7 alkyl, halo-Ci-C7 alkyl, di(C1-C7 alkyl)amino-C1-C;7 alkyl, saturated or unsaturated, 4- to 10-membered heterocyclyl, saturated or unsaturated C3-Cio carbocyclyl, or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl; and the heterocycle may be substituted with 1 or 2 substituents selected from hydroxy, halo, formyl, Ci-C; alkyl, Ci-C7 alkoxy, hydroxy-Ci-C; alkyl, halo-Ci-C alkyl, nitrile-C1-C7 alkyl, Ci-C; alkylcarbonyl, Ci-C7 alkoxy-Ci-C; alkyl, C-C; alkoxycarbonyl, halo-C;-C7 alkylcarbonyl, and saturated or unsaturated, 4- to 10-membered heterocyclyl. According to one embodiment of the present invention, in the above Formula 1, R? is hydrogen or C1-C7alkyl; R? is hydrogen or C1-Cralkyl; R*, R®, R® and R’ are each independently hydrogen or Ci-C alkyl; R® is hydrogen, halo, Ci-C7 alkyl, Ci-C7 alkoxy or amino; and R’ is hydrogen, halo or C;-C7 alkyl, According to one embodiment of the present invention, in the above Formula 1, === is a single bond. According to one embodiment of the present invention, in the above Formula 1, the heterocycle is a saturated or unsaturated, 4- to 8-membered hydrocarbon having 1 or 2 heteroatoms selected from N and O. According to one embodiment of the present invention, in the above Formula 1, the heterocycle is selected from the group consisting of tetrahydropyridine, dihydropyridine, piperidine, dihydropyran, tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine, morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, oxazepane, 2-oxa-5-azabicyclo[2.2.1]heptane, ~~ pyridyl, tetrahydrofuran, 8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.4]Joctane, 2-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane, 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine, 3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2]-a]pyrazine, pyrimidine, pyrazole, 2-oxa-7-azaspiro[3.5]nonane, and oxetane. According to one embodiment of the present invention, in the above Formula 1, the heterocycle is selected from the group consisting of tetrahydropyridine, dihydropyridine, piperidine, tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine, morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, pyridyl, 8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, pyrazole, and oxetane. According to one embodiment of the present invention, in the above Formula 1, the carbocycle is selected from the group consisting of cyclohexane, cyclohexene, cyclopropane, cyclobutane, and cyclopentane, According to one embodiment of the present invention, in the above Formula 1, D is a direct bond, -O-, -C(=0)- or -C=C-; R!? is halo, C-C; alkyl, hydroxy-Ci-C alkyl, halo-C;-C7 alkyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated, 4- to 10-membered heterocyclyl, or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl; the carbocycle or heterocycle may be substituted with 1 to 5 substituents selected from hydroxy, halo, formyl, Ci-C7 alkyl, hydroxy-Ci-C; alkyl, Ci-C; alkoxy-Ci-C7 alkyl, halo-Ci-C; alkyl, Ci-C7 alkylcarbonyl, C1-C7 alkoxycarbonyl, halo-C;-C alkylcarbonyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated Cs3-Cio carbocyclylcarbonyl, (Ci-C7 alkyl)(halo-Ci-C7 alkyl)amino, (Ci-C7alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino, and saturated or unsaturated, 4- to 10-membered heterocyclyl-C1-Cy alkyl; the heterocycle is selected from the group consisting of tetrahydropyridine, dihydropyridine, piperidine, tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine, morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, pyridyl, 8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, pyrazole, and oxetane; and the carbocycle is selected from the group consisting of cyclohexane, cyclohexene, and cyclopropane, Representative examples of the compound of Formula 1 according to the present invention may include compounds shown in Table 1, but are not limited thereto. [Table 1] No. Compound Name 4-[3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methoxy-2,3-dihydro-1,4 | -benzoxazepin-5-one 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-methoxy-4,5-dihydro-3H -2-benzazepin-1-one 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-hydroxy-4,5-dihydro-3H- 2-benzazepin-1-one 2-[3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(triftuoromethoxy)-4,5-di hydro-3H-2-benzazepin-1-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(trifluoromethyl)-2, | 3-dihydro-1,4-benzoxazepin-5-one 2-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)- | 4,5-dihydro-3H-2-benzazepin-1-one 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-7-ethoxy-4,5-dihydro- 3H-2-benzazepin-1-one [2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3 | H-2-benzazepin-7yl] trifluoromethanesulfonate 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ox0-4,5-dihydro-3H -2-benzazepin-7-carbonitrile 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methyl-2,3-dihydro- 1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-propyl-2,3-dihydro- 1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-isobutyl-2,3-dihydr 0-1,4-benzoxazepin-5-one EE yl)-2,3-dihydro-1,4-benzoxazepin-5-one tert-butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro- | 1,4-benzoxazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydrop yridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one 8-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)- 2-hydroxy-propyl]-2,3-dihydro- 1,4-benzoxazepin-5-one 8-(1-acetyl-4-piperidyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propy 1]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethyl-3,6-dihydro -2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one "4-{(R)-3-(3 A-dihydro- TH-isoquinolin-2-y1)-2-hydroxy-propylJ-8-(1-1sopropyl-3,6-dih | ydro-2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one oman ans og TESTI | ran-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-y 1-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(morpholinomethyl) -2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-piperidylmethyl)- 2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-ylmet hyl)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(dimethylamino)m ethyl]-2,3-dihydro- 1,4-benzoxazepin-5-one 8-(diethylaminomethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propy 1]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methyl-1-piperi dyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-6-azaspiro[ 3. 3]heptan-6-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-methoxyazetidin | -1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one "| #12R)-3-(3,4-dibydro- TH-isoquinolin-2-y1)-2-hydroxy-propyl]-8-{(2-methylmorpholi | n-4-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one i bis RUS droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one Le ot os ears TT yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one a mses Fo | peridyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one o-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(3-hydroxypyrrolid in-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-methylpyrr olidin-1-yl]methyl]-2,3-dihydro- 1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-(hydroxymethyl )-1-piperidyl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methoxy-1-piper idyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,4-oxazepan-4-yl | | 4-1(2R)-3~(3,4-dihydro-1H-1s0quinolin-2-y1)-2-hydroxy-propyl]-8-(1,4-oxazepan-4-yl | | methyl)-2,3-dihydro-1,4-benzoxazepin-5-one "| #1@R)-3-(3 4-dihydro- TH-isoquinotin-2-y1)-2-hydroxy-propyl]-8-{(3-hydroxy-3-meth | yl-pyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-(hydroxymethyl )morpholin-4-ylJmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one 8-[(3,3-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hy droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one Le oa AFA THE yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxy-1-piper idyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-hydroxy-1-piper idyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(hydroxym ethyl)pyrrolidin-1-ylJmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one fr —————T ET] ethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethylpyrrolidin- | 1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(methoxym ethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one methyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one tte tte A | -1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one [8-16 3-diftuoropyrolidin-T-yDmethyl]-4-[(2R)-3-(3 4-dihydro- TH-fsoquinolin-2-yD)-2 -hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one J aS SST THE oxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one a rs ors Ero | -1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-5-azabicyclo [2.2.1]heptan-5-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridylmethoxy)- 2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridylmethoxy)- 2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-fluoro-4-pyridyl )methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 8-[(2,6-dichloro-4-pyridyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hy droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one Leer THT droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(6-fluoro-3-pyridyl )methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl )methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl )methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-y loxy-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydropyran-2- ylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one 8-(cyclohexylmethoxy)-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl 1-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydrofuran-2-y Imethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperi dyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-ethyl-3-piperidy 1)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 8-[(1-acetyl-4-piperidylymethoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydr oxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one a TE y)-2,3-dihydro-1,4-benzoxazepin-5-one iy ethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one Le SFr | | y)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(2-oxopyrrolidin- 1-yl)ethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-pyridyloxy)-2,3- | dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-ox0-3-piperidyl) | oxy]-2,3-dihydro-1,4-benzoxazepin-5-one tert-butyl 4-[[4-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro | | -1,4-benzoxazepin-8-ylJoxy]piperidine-1-carboxylate 8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 8-[(1-acetyl-3-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- | 8-[(1-acetyl-3-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- | propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 8-(1-acetylpyrrolidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy | -propyl]-2,3-dihydro-1,4-benzoxazepin-5-one "| B-[R)-I-acetylpyrrolidin-3-yljoxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-y) 2-hy | droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one TE droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one ET oe TESTE ropyl]-2,3-dihydro-1,4-benzoxazepin-5-one RT n-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 8-[1-(cyclopropanecarbonyl)azetidin-3-ylJoxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin- | 2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one methyl 3-[[4-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro | | -1,4-benzoxazepin-8-ylJoxylazetidin-1-carboxylate “| #1@R)-3-G3 4-diydro- TH-isoquinolin-2-y1)-2-hydroxy-propyl]-8-{(1-methyl-4-piperi | dyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidy 1)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-isopropyl-4-pipe ridyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 8-[(1-cyclopropyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hyd roxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one eee RSF | oxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one TET piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one | -yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethylazetidin-3-y 1)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-isopropylazetidin -3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[ 1-(oxetan-3-yl)azet idin-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethylazetidin-3- | | yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylpyrrolidin -3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(3R)-1-ethylpyrroli din-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-pyridyloxy)-2,3- | dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)- 1-isopropylp yrrolidin-2-yl]methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one SIN dyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidy I)methoxy]-2,3-dihydro- 1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylmorpholi n-2-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-ethylmorpholin- | 2-ylymethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methylpyrrolidi | n-3-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one "| 4-[(2R)-3-(3 4-dihydro- 1H-isoquinolin-2-y1)-2-hydroxy-propyl]-8-[(I-methyl-3-piperl | dyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one ETE] omethyl)-2,3-dihydro-1,4-benzoxazepin-5-one Lo rs FST | 4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidy | 1)oxy]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morp holinomethyl)-3H-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[(1-me thyl-4-piperidyl)oxy]-3H-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2,2-dimethyl-8-(4-pyr idylmethoxy)-3H-1,4-benzoxazepin-5-one 8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-p ropyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one ms | nomethyl)-2,3-dihydro-1,4-benzodiazepin-5-one "| #1@R)-3-(3,4-dihydro-TH-isoquinolin-2-y1)-2-hydroxy-propyl]-I-methyl-8-(3,3,3-4rfl | uoropropyl)-2,3-dihydro-1,4-benzodiazepin-3-one 8-(cyclohexylmethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]- 1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 8-(cyclohexen-1-y1)-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-1 -methyl-2,3-dihydro-1,4-benzodiazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[4-(trifluo | romethyl)cyclohexen-1-yl]-2,3-dihydro- 1,4-benzodiazepin-5-one | tert-butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-ox0-2,3 | -dihydro-1,4-benzodiazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate "[8-(T-acetyl-4-piperidyDoxy]-4-[(ZR)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxy- | | 8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- | propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one ET FE TFFSIEE ropyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one TEE droxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one Fe ——— EE droxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one FF | -4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidy 1)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 8-[(1-cyclobutyl-4-piperidyljoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydr | oxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one [4-[(2R)-3-(3 4-dihydro- 1H-isoquinolin-2-y1)-2-hydroxy-propyl]- -methyl-8-[(I-tetrahy | drofuran-3-yl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one TEE n-3-yl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzodiazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl -3-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl pyrrolidin-3-yl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one ar | pyrrolidin-3-yl)oxy-2,3-dihydro-1,4-benzodiazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl -3-piperidyl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl )ymethoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-piperid yl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one dihydrochloride ET -piperidyl)oxy]-1-methyl-2,3-dihydro- 1,4-benzodiazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyc lo[3.2.1]octan-3-yl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[ (2-methyl | -4-piperidyljoxy]-2,3-dihydro-1,4-benzodiazepin-5-one dihydrochloride 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl )methoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(4-piperidy loxy)-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl- 4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydr oxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-m ethyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one “4-[@R)-3-(3 4-dihydro- IH-isoquinolin-2-y1)-2-hydroxypropyl]-2-methyl-8-[(1-methyl- 4-piperidyl)oxy]-2,3-dihydropyrido[3,2-f][ 1,4]oxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,2-dimethyl-8-[( 1-met hyl-4-piperidyl)oxy]-3H-pyrido[3,2-f][1,4]oxazepin-5-one (28)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxypropyl]-2-methyl-8-[(1-m ethyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxaze pin-5-one 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazep in-1-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzo xazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-2,3-dihydro- 1,4-benzoxazepin-5-one 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro- 1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2,3-dihydropyrido[4,3 -f][1,4]oxazepin-5-one "| 8-chloro-4-{(2R)-3-( 4-dihydro- TH-isoquinolin-2-yD)-2-hydroxy-propy1]-2,3-dihydrop. yrido[3,2-f][1,4]oxazepin-5-one 7-chloro-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro- 3H-2-benzazepin-1-one 7-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro- 3H-2-benzazepin-1-one 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3 | -dihydro-1,4-benzodiazepin-5-one 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-2,3-d ihydro-1,4-benzodiazepin-5-one 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-3H-1 ,4-benzodiazepin-2,5-dione De es RAT TY TR rs | dro-1,4,-benzoxazepin-8-yl]-1-piperidyl]acetonitrile 8-[[1-(2,2-difluoroacetyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl )-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 8-[[1-(2,2-difluoroacetyl)azetidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl )-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxyethyl )-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[ 1-(2-fluoroethyl)- | 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[ 1-(2-fluoroethyl)- | 4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-fluoroethyl)- | | 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-fluoroethyl)- | 4-piperidyl]oxy]-2,3-dihydropyrido[3,2-f][ 1,4]oxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[[ 1-[(3-methyloxetan -3-yl)methyl]-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[[4-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro- | 1,4-benzoazepin-8-yl]oxy]piperidine-1-carbonitrile 8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydr oxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one ITE 0-3H-1,4-benzoxazepin-8-yl]oxy]azetidin-1-carbaldehyde a TIE. 0-3H-1,4-benzoxazepin-8-ylJmethyl]piperazin-1-carbaldehyde TT. | -6-azaspiro[3.3]heptan-6-ylmethyl)-3H-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyc 10[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethyl-2-azaspiro [3.3]heptan-6-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 8-[(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin -2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one [8G acetyl-2-azaspiro[3 3Theptan-6-yT)oxy]-4-[(2R)-3-3,4-dihydro- TH-isoquinolin-2- | yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one I~ ET | ¥D-2.3-dihydro-1 ,4-benzoxazepin-5-one “[4-[@R)-3-(3 4-dihydro- IH-isoquinolin-2-y1)-2-hydroxy-propyl]-8-(piperidine-I-carbo | nyl)-2,3-dihydro-1,4-benzoxazepin-5-one ES Ta | ydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-methylpiperazin- | 1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(pyrro lidin-1-ylmethyl)-3H-1,4-benzoxazepin-5-one 8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- | | 8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- | propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one TE 0-3H-1,4-benzoxazepin-8-yl]oxy]piperidine-1-carbaldehyde TET | xetan-3-yl)piperazin-1-yl]methyl]-3H-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa -7-azaspiro[3 .4]octan-7-ylmethyl)-3H-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-(4-fluoropiperidine- 1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one piperidine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one ei TFS. piperidine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one TT olin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 8-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl )-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-oxa-8-azabicyclo [3.2.1]octan-8-carbonyl}-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-methylmorpholin | -4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-methylmorpholin | -4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morp holinomethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one 8-(3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-2-carbonyl)-4-[(2R)-3-(3,4-dihydr o-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-fluoropiperidine- 1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 8-(2,2-difluoromorpholin-4-carbonyl}-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-h ydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one ydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one EA og FEE TTY eridylmethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one bt dea aul yl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxypropyl]-8-[4-[2-flucroethyl(me thyl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one (28)-4-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-ethanethiol -4-piperidyl)oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (28)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[ 1-(2-fluoroeth yl)azetidin-3-yl]Joxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (28)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[ 1-(2-fluoroeth yl)-4-piperidyl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(3-oxa -8-azabicyclo[3.2.1]octan-8-carbonyl)-3H- 1,4-benzoxazepin-5-one “| 41@R)-3-(3,4-dihydro- [H-isoquinolin-2-y1)-2-hydroxy-propyl]-2,2-dimethyl-8-2-oxa | -5-azabicyclo[2.2.1]heptan-5-carbonyl)-3H-1,4-benzoxazepin-5-one Te a S| olin-4-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one Lae RST 4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one Le Fs TE] | oethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one “[4-[@R)-3-(3 4-dihydro- IH-isoquinolin-2-y1)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-hydr | oxyethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one Heit fin ti rrolo[1,2-a]pyrazine-2-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one a dro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one | 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(5-fluoropyrimidin- | 2-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxyprop yl)-4-piperidylJoxy]-2,3-dihydro-1,4-benzoxazepin-5-one EE dyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one er ——T TET dro-1,4-benzoxazepin-5-one ti i -azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one ETE TI EER pyl]-2,3-dihydro-1,4-benzoxazepin-5-one TEE pyl]-2,3-dihydro-1,4-benzoxazepin-5-one Le Fa ma Sa yl)oxy]-2,3-dihydro-1,4-benzoxazepin-3-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[ 1-(2-hydroxy ethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxy -2-methyl-propyl)-4-piperidylJoxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-morpholinoethyl) -2,3-dihydro-1,4-benzoxazepin-5-one “| 4-[(2R)-3-(3 4-dihydro- 1H-isoquinolin-2-y1)-2-hydroxy-propyl]-8-[1-(2-oxa-6-azaspir | 0[3.3]heptan-6-yl)ethyl]-2,3-dihydro- 1,4-benzoxazepin-5-one TE mF ITE | nyl)-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[ 1-(2-methox yethyl)-4-piperidyl]Joxy]-2-methyl-2,3-dihydro- 1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridyl)-2,3-dihy dro-1,4-benzoxazepin-5-one ddim nie. y1]-2,3-dihydro-1,4-benzoxazepin-5-one Tri FS aT yl]-2,3-dihydro-1,4-benzoxazepin-5-one ee TEE yl)-2,3-dihydro-1,4-benzoxazepin-5-one LTA FH | o-1-pynyl]-2,3-dihydro-1,4-benzoxazepin-5-one ET EET dro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,3-dimethylpyrazo 1-4-y1)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylpyrazol-4- yl)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,5-dimethylpyrazo 1-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxyethyl )-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]Joxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2,2-dimethyl-8-[[(3R) | -1-methyl-3-piperidyl]oxy]-3H-pyrido[3,2-f][ 1,4]Joxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-fluoroethyl)- 3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-hydroxy)-3- | | 4-1@R)-3-(3,4-dihydro- 1H-isoquinolin-2-y1)-2-hydroxy-propyl]-8-[[(1-(2-hydroxy)-3- | piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one Le —— AF RR ethyl-propyl)-4-piperidylJoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-(6-fluoro-2-pyridyl) -2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[ 1-(2-ethoxye thyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[8-2-hydroxy] -8-azabicyclo[3.2.1]octan-3-yl]Joxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroeth yl]-8-azabicyclo[3.2.1]octan-3-ylJoxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one | 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-methoxyethyl )-4-pyridyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(6-methoxy-2-pyrid yl)-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxy propyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-mo | rpholinoethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one T4-[(2R)-3-(3 4-dihydro- IH-isoquinolin-2-y1)-2-hydroxy-propyl]-2,2-dimethyl-8-[1-2- | | 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[1-2- | oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-3H-pyrido[3,2-f][ 1,4]oxazepin-5-one Te yl)-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-][ 1,4]oxazepin-5-one Le TT | | rolo[ 1,2-a]pyrazin-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(2-ox a-6-azaspiro[3.3]heptan-6-ylmethyl}-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(2-oxa-7-azaspiro[3. | 5]nonan-7-ylmethyl)-2,3-dihydro- 1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(2-ox a-7-azaspiro[3.5]nonan-7-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3 -fluoro-1-(2-hydroxyethyl)-4-piperidylJoxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5 | -one dihydrochloride 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R4R)-3-fluoro- | 1-(2-hydroxypropyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride (2R)-4-[(2R)-3-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R, 4R)-3-fluoro-1-(2-hydroxyethyl)-4-piperidylJoxy]-2-methyl-2,3-dihydro-1,4-benzoxaz epin-5-one dihydrochloride 8-[[3,3-difluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoqu inolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][ 1,4]oxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[ 1-(1-piperidyl)ethyl 1-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[ 1-(4-hydroxy-1-pipe ridyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[ 1-(4-methoxy- 1 -pip eridyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[ 1-(3-hydroxy-3-met hyl-pyrrolidin-1-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxy ethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-methoxyethyl )-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]Joxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3S)-1-(oxetan-3-yl )pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2-methyl-8-[ (3S) | -1-methylpyrrolidin-3-yl]Joxy-2,3-dihydro-1,4-benzoxazepin-5-one “4 [(2R)-3-(3 4-dihydro- 1H-isoquinolinon-2-y1)-2-hydroxy-propyl]-8-[3R -tetrahydrof uran-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one BT TE uran-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[ 1-[(2S)-2-hy droxypropyl]-4-piperidylJoxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[1-[(2R)-2-hy droxypropyl]-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 8-[cyclopropyl(hydroxy)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydro xy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one Shh eee ESS xy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one | 2m 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(3R)-1-(oxetan-3-y 1)pyrrolidin-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one | wa 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(2-methoxy ethyl)pyrrolidin-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one | 273 (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2-methyl-8-[(3R )-1-methylpyrrolidin-3-yl]Joxy-2,3-dihydro- 1,4-benzoxazepin-5-one | 274 (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(3R)-1-(2-met hoxyethyl)pyrrolidin-3-ylJoxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one | 778 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-)-2-hydroxy-propyl]-8-[[1-(3,3,3-trifluoro-2- | hydroxy-propyl)-4-piperidylJoxy]-2,3-dihydro-1,4-benzoxazepin-5-one | 775 (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-)-2-hydroxy-propyl]-2-methyl-8-[[ 1-(3, 3,3-trifluoro-2-hydroxy-propyl)-4-piperidyl Joxy]-2,3-dihydro- 1,4-benzoxazepin-5-one | 277 (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxypropyl]-2-methyl-8-[(3R) -1-(oxetan-3-yl)pyrrolidin-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one Since the compounds according to the present invention may have an asymmetric carbon center and an asymmetric axis or an asymmetric plane, they may exist as substantially pure enantiomers, such as R and S enantiomers, as well as all optical and stereoisomeric forms including mixture racemates, and all isomers and compounds thereof are within the scope of the present invention. With respect to a pure enantiomer, the enantiomeric excess of such enantiomer and pharmaceutically acceptable salt thereof represented by Formula 1 may be preferably 60% ee or more, more preferably 95% ee ore more, and most preferably 98% ee or more. The term “ee” refers to an enantiomeric excess. For example, one enantiomer in a particular compound is present as a mixture of enantiomers in the compound in a larger amount than the other enantiomers. Enantiomerically enriched forms may include enantiomeric compounds of a particular compound in which a single enantiomeric concentration in the enantiomeric mixture of the particular compound is at least 50%, more typically at least 60%, 70%, 80%, or 90%, or more (e.g., >95%, >97%, >98%, >99%, >99.5%) with respect to other enantiomers of the compound. Herein, unless stated otherwise, the compound represented by Formula 1 is used as a meaning including all of compound represented by Formula 1, an optical isomer, a stereoisomer, an isotopic variant thereof, and a pharmaceutically acceptable salt thereof. Herein the term “isotopic variant” refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an isotopic variant of a compound may be radiolabeled; hydrogen atom may be selected from hydrogen, deuterium and tritium; and may contain carbon-13 (**C), nitrogen-15 (N) or the like. The compound of Formula 1, or an optical isomer, a stereoisomer or an isotopic variant thereof according to the present invention may form a pharmaceutically acceptable salt. The pharmaceutically acceptable salts include acid or base addition salts and their stereochemical isomers form. The salt may include any salt that maintains the activity of a parent compound in a subject to be administered and does not cause any undesirable effect, but is not limited thereto. The salts include inorganic salts and organic salts, and may be acid addition salts—for example, acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, ethanesulfonic acid, lactic acid, bicarbonic acid, bisulfuric acid, bitartaric acid, oxalic acid, butylic acid, calcium edatate, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid, edetic acid, toluenesulfonic acid, edicylinic acid, ecylinic acid, fumaric acid, gluceptic acid, pamoic acid, gluconic acid, glycollarsanylic acid, methyl nitrate, polygalacturonic acid, hexyllisorcynonic acid, malonic acid, hydrabamic acid, hydrochlorinic acid, hydroiodic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, estolinic acid, mucic acid, naphthenic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, salicylic acid, sulfamine acid, sulfanilic acid, methanesulfonic acid or theoclic acid. In addition, examples of basic salts include alkali and alkaline earth metal salts such as ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts, and calcium salts, salts having organic bases such as benzathine, N-methyl-D-glucamine, and hydrabamine salts, and salts having amino acids such as arginine and lysine. In addition, the salt form may be converted into a free form by treatment with an appropriate base or acid. As used herein, the term “additional salt” may be taken to include solvates obtainable from any of the compound represented by Formula 1 and salts thereof. Examples of these solvates are hydrates or alcoholates. Terms and abbreviations used in the present specification have their original meanings unless stated otherwise. The present invention also provides a method for preparing a compound of Formula 1. Hereinafter, a method of preparing the compound of Formula 1 will be described based on an exemplary reaction scheme for better understanding of the present invention. However, it should be construed that those of ordinary skill in the art may prepare the compound of Formula | by various methods using known compounds based on the structure of Formula 1 or compounds that may be easily prepared therefrom, and be construed that all the methods may be included in the scope of the present invention, That is, the compound of Formula 1 may be prepared by arbitrarily combining several synthesis methods described in the present specification or disclosed in the prior art, and thus the following description related to the method of preparing the compound of Formula 1 is merely illustrative, and if necessary, the order of unit operations may be selectively changed, and the scope of the method of preparing the present invention is not limited thereto. [Reaction Scheme 1] c $ 9 4 of PR od RoR RE 5, RK 0 hi C Ro Khe 2 NN _ RAN RY, i: 3 Lo Lor R “ed 3 Y-2 Jo $ R Acbob 7 CF OORRR [NAIK RAL JN N R xX J) oH Y-z lo ho Aird lo aa R23), (RY) £ © R ER ry 0 -- RA, ¥ vr’ 4 R3), (RY), A; ®), ®), RY, 5.3 . R?3), (rR?) 2 3 4 1a In a general synthesis method, an intermediate 3 can be obtained from the starting material 2 by Schmidt reaction using sodium azide under an acidic condition. From this compound, an intermediate 4 into which oxirane has been introduced is obtained through a substitution reaction, and a final compound la can be obtained through addition reaction of tetrahydroisoquinoline. [Reaction Scheme 2] ’ 50 Rr : ul OR RRR wl ORRR RF ar, Wo EY Py iN Xx ) OH Xx J) OH Y-2 Y-z Z Z a oN 4 ®), ®Y, (R3), "9, 5 1b As another synthesis method, a final compound 1b in which alkyl and alkenyl groups are substituted can be obtained by a Suzuki-coupling reaction under a palladium condition using compound 5 as a starting material. [Reaction Scheme 3] In still another synthesis method, as in Scheme 3, compound 5 is used as a starting material and an intermediate 6 obtained by substituting a bromine group with a hydroxy group using potassium hydroxide under a palladium condition was obtained, and then a final compound 1c—in which the ether group was substituted through a substitution reaction—can be obtained. According to another aspect of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of a disease associated with PRMTS5 inhibition comprising a therapeutically effective amount of the compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable carrier. In addition, prodrugs having various forms that are converted to a compound of Formula 1 as desired in vivo are also within the scope of the present invention. The pharmaceutical composition may further include one or more additives selected from the group consisting of a pharmaceutically acceptable carrier, diluent and adjuvant. As used herein, the term “treatment” refers to the interruption, delay or alleviation of disease progression when used in a subject having a symptom. As used herein, the term “prevention” refers to reduce the possibility of disease or eliminate the possibility of disease. As used herein, the term “pharmaceutical composition” may include other chemical components, such as carriers, diluents, excipients, and the like in addition to the active compounds according to the present invention. Accordingly, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, if necessary. The pharmaceutical composition facilitates administration of the active compound into the organism. A variety of techniques for administering pharmaceutical compositions comprising a compound are known, in which the techniques includes oral, injection, aerosol, parenteral, and topical administration, but not limited thereto. In addition, the pharmaceutical composition may be sterilized, may further include an adjuvant such as a preservative, a stabilizer, a hydrating or an emulsifying accelerator, a salt for osmotic pressure regulation, and / or a buffer, may further include other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating or coating. As used herein, the term “carrier” refers to a compound that facilitates injection of a compound into a cell or tissue. For example, dimethylsulfoxide (DMSO) is a common carrier for easy input of a large amount of organic compounds into cells or tissues of an organism. As used herein, the term “diluent” refers to a compound that stabilizes the biologically active form of the compound of interest, and is diluted in water that dissolves the compound. The salt dissolved in the buffer is used as a diluent in the art. A commonly used buffer is phosphate-buffered saline that imitates the salt form of a human body solution. Since the buffer salt is capable of controlling the pH of the solution at low concentrations, the buffer diluent rarely modifies the biological activity of the compound. As used herein, the term “pharmaceutically acceptable” refers to a property that does not damage biological activity and physical properties of a compound. In addition, the pharmaceutical composition may be a composition for the prevention and / or treatment of diseases associated with PRMTS inhibition. The diseases associated with the PRMTS inhibition may be, for example, cancer, blood disease, autoimmune disease, inflammatory disease or neurodegenerative disease, and may include any disease known to be related to PRMTS. The cancer includes, but is not limted to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma, benign monoclonal gammaglobulinopathy, cholangiocarcinoma, bladder cancer, breast cancer, brain cancer, lymphoma, multiple myeloma, lacrimal gland tumor, bronchial cancer, cervical cancer, craniopharyngioma, colorectal cancer, epithelial carcinoma, epithelial cell tumor, endothelial sarcoma, endometrial cancer, esophageal cancer, Barrett’s adenocarcinoma, Ewing’s sarcoma, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cancer (oral squamous cell carcinoma, OSCC), throat cancer, hematopoietic cancer, hemangioblastoma, inflammatory myofibroblast tumor, immune cell amyloidosis, kidney cancer, liver cancer, lung cancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, prostate cancer, rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, thyroid cancer, urethral cancer, vaginal cancer and vulvar cancer. The brain cancer may include, but is not limited to, meningioma, glioma, medulloblastoma, glioblastoma and brain metastasis cancer. The blood disease may be hemoglobinemia or sickle cell anemia, but is not limited thereto. The autoimmune disease may include, but is not limited to, rheumatoid arthritis, spinal arthritis, gouty arthritis, degenerative joint disease, osteoarthritis, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, juvenile arthritis, asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, psoriasis, eczema, burns, dermatitis, pruritus, enuresis, eosinophilic disease, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis and eosinophilic colitis. The inflammatory disease may include, but is not limited to, acne-related inflammation, aplastic anemia, hemolytic autoimmune anemia, rhinitis, asthma, polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, amyotrophic lateral sclerosis, autoimmune disease, allergic or allergic reaction, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, chronic obstructive pulmonary disease, dermatitis, type I diabetes, type 2 diabetes, psoriasis, eczema, eczema hypersensitivity reaction, burn, dermatitis, pruritus, endometriosis, infection, ischemic heart disease, glomerulonephritis, gingivitis, irritability, migraine, tension headache, postoperative intestinal obstruction, intestinal obstruction during sepsis, idiopathic thrombocytopenia purpura, bladder pain syndrome, peptic ulcer, localized enteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux disease, Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, bypass colitis, Behcet's syndrome, indeterminate colitis, inflammatory bowel syndrome (IBS), lupus, ecchymosis, myasthenia gravis and myocardial ischemia, The neurodegenerative disease may include, but is not limited to, motor neuron disease, Pick’s disease, Alzheimer’s disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinal pigmentation, spinal muscular atrophy and cerebellar degeneration. The pharmaceutical composition may be formulated in various oral or parenteral dosage forms. For example, the pharmaceutical composition may be formulated into any dosage form for oral administration, such as tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules or elixirs. The formulation for oral administration may include, for example, a pharmaceutically acceptable carrier, such as a diluent, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine, or a lubricant, such as silica, talc, stearic acid, magnesium or calcium salt thereof, and / or polyethylene glycol, in addition to the active ingredient, according to the typical configuration of each formulation. In addition, when the formulation for oral administration is a tablet, the formulation may include a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidine, and optionally, may include a disintegrant such as starch, agar, alginic acid or a sodium salt thereof, a boiling mixture, and / or an absorbent, a colorant, a flavoring agent, or a sweetening agent. When the pharmaceutical composition is formulated into a parenteral dosage form, the pharmaceutical composition may be administered by a parenteral administration method such as subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. The pharmaceutical composition may be prepared as a solution or a suspension by mixing an active ingredient—i.e., a compound of Formula 1, or an optical isomer, a stereoisomer or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, with a stabilizer or a buffer in water, and the solution or the suspension may be prepared as a unit dosage form of an ampoule or a vial, In addition, the pharmaceutical composition may be sterilized or further include adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and / or buffers for controlling osmotic pressure, or other therapeutically useful agents, and may be formulated according to a conventional method of mixing, granulating or coating. The active ingredient—i.e.,, a compound of Formula 1, or an optical isomer, a stereoisomer or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof may be included in the pharmaceutical composition in an effective amount of 0.1 to 500 mg / kg (body weight), preferably 0.5 to 100 mg / kg (body weight) per day, with respect to mammals including humans, and the pharmaceutical composition may be divided once or twice a day and administered via an oral or parenteral route. ADVANTAGEOUS EFFECTS OF INVENTION According to the present invention, there are provided compounds based on a 6-7 bicyclic ring which exhibit excellent PRMTS3 inhibitory effect, or optical isomers, stereoisomers or isotopic variants thereof, or pharmaceutically acceptable salts thereof. Therefore, such compounds, or optical isomers, stereoisomers or isotopic variants thereof, or pharmaceutically acceptable salts thereof, can be effectively used to prevent or treat diseases associated with PRMTS inhibition such as cancer, blood diseases, autoimmune diseases, inflammatory diseases or neurodegenerative diseases. In addition, the compounds according to the present invention, or optical isomers, stereoisomers or isotopic variants thereof, or pharmaceutically acceptable salts thereof, may have improved blood-brain barrier permeability, superior efficacy or improved pharmacokinetic properties. MODE FOR THE INVENTION Hereinafter, the present invention is explained in more detail with the following examples. However, it must be understood that the protection scope of the present disclosure is not limited to the examples. Example 1: Synthesis of 4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methoxy-2,3-dihydro-1,4-benz oxazepin-5-one Q n \ <r Lr o— / wt ® 0 oN FCO So To i d Example Synthesis of 8-methoxy-4-(oxyran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 8-Methoxy-3,4-dihydro-2H-1,4-benzoxazepin-5-one (97 mg, 0.5 mmol) was dissolved in dimethylformamide, and 60% sodium hydride (30 mg, 0.75 mmol) was added thereto under ice bath. After the reaction solution was stirred at 0°C for 30 minutes, epibromohydrin (0.056 mL, 0.65 mmol) was slowly added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction was terminated by the addition of methanol. After adding ethyl acetate, the reaction mixture was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the obtained compound was used in the next reaction without additional purification. Example 1-2: Synthesis of 4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methoxy-2,3-dihydro-1,4-benz oxazepin-5-one The starting material obtained in Example 1-1 was dissolved in 3 mL of isopropanol, and tetrahydroisoquinoline (0.06 mL, 0.5 mmol) was added thereto and stirred at 80°C for 12 hours. The temperature was lowered to room temperature temperature, and the oily liquid obtained by concentrating the solvent was purified by flash chromatography to obtain the transparent and sticky solid compound. NMR data about the obtained title compound are as follows: 'H NMR (400 MHz, Methanol-ds) § 7.67 (d, J = 8.8 Hz, 1H), 7.20 — 7.00 (m, 4H), 6.75 (dd, J = 8.8, 2.5 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 4.48 (1, J = 5.0 Hz, 2H), 4.23 (q, J = 8.2, 6.4 Hz, 1H), 3.98 (dd, J = 13.9, 3.6 Hz, 1H), 3.84 (s, 3H), 3.81 — 3.68 (m, 4H), 3.42 (dd, J = 13.9, 7.7 Hz, 1H), 2.97 — 2.85 (m, 4H), 2,69 — 2.60 (m, 2H), Example 2: Synthesis of 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-methoxy-4,5-dihydro-3H-2-ben zazepin-1-one 0 7-Methoxy-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material was used in the same manner as in Example 1 to obtaind the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.42 (d, J = 8.5 Hz, 1H), 6.99 (dd, J = 20.3, 3.4 Hz, 4H), 6.78 (dd, J = 8.7, 2.6 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 4.17 — 4.08 (m, 1H), 3.79 (dd, J = 13.9, 3.8 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 2H), 3.35 — 3.23 (m, 3H), 2.88 — 2.79 (m, 4H), 2.68 (1, J="7.1 Hz, 2H), 2.64 — 2.52 (m, 2H), 2.02 (p, J = 7.0 Hz, 2H). Example 3: Synthesis of 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-hydroxy-4,5-dihydro-3H-2-ben zazepin-1-one 9 (1-Ox0-2,3,4,5-tetrahydro-2-benzazepin-7-yl) acetate as a starting material was used in the same manner as in Example 1 to obtaind the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.56 (d, J = 8.5 Hz, 1H), 7.15 — 7.02 (m, 4H), 6.97 (dd, J = 9.0, 1.9 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 4.32 — 4.22 (m, 1H), 4.14 (dd, J = 9.9, 4.1 Hz, 1H), 4.05 (dd, J= 9.8, 6.0 Hz, 1H), 3.78 (s, 2H), 3.07 (t, J = 6.5 Hz, 2H), 2.98 — 2.86 (m, 4H), 2.86 — 2.78 (m, 3H), 2.73 (dd, J = 13.1, 7.5 Hz, 1H), 2.09 — 1.97 (m, 2H). Example 4: Synthesis of 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)-4,5-dihydro -3H-2-benzazepin-1-one 9 0 NN FaC oH 6-(Trifluoromethoxy)tetralin-1-one as a starting material was used in the same manner as in Example 1 to obtaind the title compound. '"H NMR (400 MHz, Methanol-ds) 8 7.63 (d, J = 8.4 Hz, 1H), 7.21 (dd, J = 8.5, 2.3 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.10 — 6.96 (m, 4H), 4.23 — 4.13 (m, 1H), 3.88 (dd, J = 13.8, 3.6 Hz, 1H), 3.70 (s, 2H), 3.41 — 3.29 (m, 2H), 3.30 — 3.20 (m, 1H), 2.92 — 2.84 (m, 2H), 2.84 — 2.73 (m, 4H), 2.64 —2.52 (m, 2H), 2.15 — 2.04 (m, 2H). Example 5: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(trifluoromethyl)-2,3-dihy dro-1,4-benzoxazepin-5-one re en | oH 0 The title compound was synthesized in the same manner as in Example 1, except that 7-(trifluoromethyl)chroman-4-one was used as a starting material and (R)-(-)-glycidyl nosylate was used instead of epibromohydrin in Example 1-1. 'H NMR (400 MHz, Methanol-d) 8 7.90 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.36 (s, 1H), 7.16 — 7.03 (m, 4H), 4.56 (t, J = 5.1 Hz, 2H), 4.25-4.22 (m, 1H), 4.02 (dd, J = 13.9, 3.5 Hz, 1H), 3.76-3.74 (s, 4H), 3.47 (dd, J = 14.0, 8.0 Hz, 1H), 2.99 — 2.83 (m, 4H), 2.73 — 2.60 (m, 2H). Example 6: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)-4,5-di hydro-3H-2-benzazepin-1-one Q 0 NN FiC | OH 7-(Trifluoromethoxy)-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material was used in the same manner as in Example 5 to obtaind the title compound. 'H NMR (400 MHz, Methanol-ds) § 7.68 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.20 (d, J =2.3 Hz, 1H), 7.16 — 7.02 (m, 4H), 4.29 — 4.20 (m, 1H), 3.94 (dd, J = 13.8, 3.6 Hz, 1H), 3.78 (s, 2H), 3.48 — 3.34 (m, 2H), 3.37 (d, J = 6.7 Hz, 1H), 2.99 — 2.82 (m, 6H), 2.72 — 2.59 (m, 2H), 2.18 (q,J = 6.8 Hz, 2H). Example 7: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-7-ethoxy-4,5-dihydro-3H-2- benzazepin-1-one jo} 7-Ethoxy-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material was used in the same manner as in Example 5 to obtaind the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.52 (d, J = 8.5 Hz, 1H), 7.19 — 7.04 (m, 4H), 6.92 - 6.84 (m, 1H), 6.78 (s, 1H), 4.30 — 4.20 (m, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.91 (dd, J = 13.8, 3.8 Hz, 1H), 3.82 (s, 2H), 3.40 (td, J = 13.6, 12.5, 7.2 Hz, 3H), 3.03 — 2.90 (m, 4H), 2.79 (t, / = 7.1 Hz, 2H), 2.73 — 2.62 (m, 2H), 2.19 — 2.07 (m, 2H), 1.41 (t, J= 7.0 Hz, 3H). Example 8: Synthesis of [2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-be nzazepin-7-yl| trifluoromethanesulfonate F 90 nL F 0 o So NNN | OH (1-Ox0-2,3,4,5-tetrahydro-2-benzazepin-7-yl) trifluoromethanesulfonate as a starting material was used in the same manner as in Example 5 to obtaind the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.74 (d, J = 8.2 Hz, 1H), 7.38 (dd, J = 8.5, 2.4 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.18 — 6.99 (m, 4H), 4.30 — 4.19 (m, 1H), 3.94 (dd, J = 13.8, 3.6 Hz, 1H), 3.78 (s, 2H), 3.46-3.3.4 (m, 3H), 2.98 — 2.83 (m, 6H), 2.71-2.62 (m, 2H), 2.18 (p, J = 6.8 Hz, 2H). Example 9: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-be nzazepin-7-carbonitrile o 7-Cyano-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material was used in the same manner as in Example 5 to obtaind the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.73 (s, 2H), 7.66 (s, 1H), 7.21 — 7.02 (m, 4H), 4.31 — 4.17 (m, 1H), 3.94 (dd, J = 13.9, 3.6 Hz, 1H), 3.77 (s, 2H), 3.57 — 3.34 (m, 3H), 3.01 — 2.81 (m, 6H), 2.70-2.61 (1, J = 5.4 Hz, 2H), 2.17 (p, J = 7.0 Hz, 2H). Example 10: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-methyl-2,3-dihydro-1,4-b enzoxazepin-5-one ly «een ~ een Example 10-1: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-2,3-dihydro-1,4-be nzoxazepin-5-one 8-Bromo-3,4-dihydro-2H-1,4-benzoxazepin-5-one as a starting material was used in the same manner as in Example 5 to obtaind the title compound. 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-methyl-2,3-dihydro-1,4-b enzoxazepin-5-one 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1 ,4-benzoxazepin-5-one (96 mg, 0.22 mmol), methylboronic acid (27 mg, 0.45 mmol), Pd(dppf)Cl2 CHCl (18 mg, 0.022 mmol) and potassium carbonate (91 mg, 0.66 mg) were dissolved in 10 mL of 1,4-dioxane:distilled water (=3:1) solvent and stirred at 100°C. After confirming that the reaction was complete, the reaction solution was concentrated under reduced pressure and filtered with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash column chromatography to obtain the title compound (11 mg). 'H NMR (400 MHz, Methanol-d4) § 7.59 (d, J = 7.9 Hz, 1H), 7.18 — 6.98 (m, 5H), 6.88 (s, 1H), 4.45 (t,J = 5.2 Hz, 2H), 4.23 (p, J = 3.3 Hz, 1H), 3.98 (dd, J = 13.9, 3.6 Hz, 1H), 3.76 (s, 2H), 3.69 (t, J = 5.3 Hz, 2H), 3.43 (dd, J = 13.9, 7.7 Hz, 1H), 2.98 — 2.83 (m, 4H), 2.71 — 2.59 (m, 2H), 2.36 (s, 3H). Example 11: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-propyl-2,3-dihydro-1,4-be nzoxazepin-5-one 0 Oo The title compound was synthesized in the same manner as in Example 10, except that propylboronic acid was used instead of methylboronic acid in Example 10-2, 'H NMR (400 MHz, Methanol-d4) § 7.61 (d, J = 7.9 Hz, 1H), 7.16 — 6.99 (m, 5H), 6.88 (s, 1H), 4.46 (t, J = 5.2 Hz, 2H), 4.25 (dd, J = 8.3, 4.3 Hz, 1H), 3.98 (dd, J = 13.9, 3.7 Hz, 1H), 3.78 (s, 2H), 3.70 (t, J = 5.2 Hz, 2H), 3.45 (dd, J = 13.9, 7.6 Hz, 1H), 2.97-2.88 (m, 4H), 2.73 — 2.65 (m, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.67 (q, J = 7.5 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H). Example 12: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-isobutyl-2,3-dihydro-1,4- benzoxazepin-5-one 0 Oo “Oreo 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1 ,4-benzoxazepin-5-one (100 mg, 0.23 mmol), isobutylboronic acid (47 mg, 0.46 mmol), Pd(dppf)Cl2 (17 mg, 0.023 mmol) and potassium carbonate (95 mg, 0.69 mg) were dissolved in 2 mL of toluene and stirred at 120°C for 2 hours. After confirming that the boronic acid reaction was complete, the reaction solution was concentrated under reduced pressure and filtered with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash column chromatography to obtain the title compound (11 mg). 'H NMR (400 MHz, Methanol-ds) 8 7.62 (d, J = 8.0 Hz, 1H), 7.16 — 7.03 (m, 4H), 7.00 (dd, J = 7.9, 1.6 Hz, 1H), 6.85 (d, J = 1.6 Hz, 1H), 4.46 (t, J= 5.1 Hz, 2H), 4.28 — 4.20 (m, 1H), 3.99 (dd, J=13.9, 3.6 Hz, 1H), 3.76 (s, 2H), 3.70 (t, J= 5.2 Hz, 2H), 3.44 (dd, J = 13.9, 7.6 Hz, 1H), 2.97 — 2.84 (m, 4H), 2.69 — 2.59 (m, 2H), 2.51 (d, J = 7.2 Hz, 2H), 1.96 — 1.83 (m, 1H), 0.93 (d, J = 6.6 Hz, 6H). Example 13: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(3,3,3-trifluoropropyl)-2,3 -dihydro-1,4-benzoxazepin-5-one 0 NOY | FY C0 The title compound was synthesized in the same manner as in Example 12, except that 3,3,3-trifluoropropylboronic acid was used instead of isobutylboronic acid at 100°C. 'H NMR (400 MHz, Methanol-ds) § 7.66 (d, J = 8.0 Hz, 1H), 7.19 — 7.05 (m, 5H), 6.97 (s, 1H), 4.48 (t, J = 5.1 Hz, 2H), 4.28-4.25 (m, 1H), 3.98 (dd, J= 13.8, 3.7 Hz, 1H), 3.81 (s, 2H), 3.71 (t, J =5.3 Hz, 2H), 3.46 (dd, J = 13.9, 7.6 Hz, 1H), 2.96-2.89 (m, 6H), 2.76 — 2.64 (m, 2H), 2.59 — 2.44 (m, 2H). Example 14: Synthesis of tert-butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-ox0-2,3-dihydro-1,4-be nzoxazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate KO NO CYL “0 a > Tout The title compound was synthesized in the same manner as in Example 10, except that tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate was used instead of methylboronic acid in Example 10-2. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.19 — 7.03 (m, SH), 6.26 (s, 1H), 4.49 (t, J = 5.2 Hz, 2H), 4.30 — 4.19 (m, 1H), 4.16 — 4.05 (m, 2H), 4.00 (dd, J = 13.8, 3.8 Hz, 1H), 3.77 (s, 2H), 3.76 — 3.69 (m, 2H), 3.70 — 3.60 (m, 2H), 3.45 (dd, J=14.0,7.7 Hz, 1H), 2.98 — 2.85 (m, 4H), 2.73 — 2.63 (m, 2H), 2.55 (s, 2H), 1.51 (s, 9H). Example 15: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydropyridi n-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one o TW Tert-butyl 4-[4-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-y1)-2-hydroxy-propyl]-5-oxo0-2,3-dihydro-1,4-benzo xazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate obtained in Example 14 was dissolved in methanol, and 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added thereto. The mixture was stirred at room temperature until the reaction was completed, diluted with ethyldiethyl ether, and filtered to obtain the title compound in the form of a white solid dihydrochloride. After addition of water, the title compound in the form of a dihydrochloride was washed with ethyl acetate 3 times. The obtained aqueous layer was basified with sodium hydroxide aqueous solution until the pH reached 14, and ethyl acetate was added again to extract 3 times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound without additional purification. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.17 - 7.01 (m, 5H), 6.32 (s, 1H), 4.49 (t, J = 5.1 Hz, 2H), 4.29 — 4.19 (m, 1H), 4.00 (dd, J = 14.0, 3.6 Hz, 1H), 3.79 — 3.65 (m, 4H), 3.53 (d, J= 3.2 Hz, 2H), 3.45 (dd, J= 13.9, 7.7 Hz, 1H), 3.11 (t, J = 5.8 Hz, 2H), 2.98 — 2.84 (m, 4H), 2.71 — 2.62 (m, 2H), 2.53 (bs, 2H). Example 16: Synthesis of 8-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-4-|(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hyd roxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one oO oO Dihydrochloride of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydropyridin-4-y 1)-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 15 (75 mg, 0.16 mmol) and potassium carbonate (66 mg, 0.48 mmol) were dissolved in 1.5 mL of acetone, and acetic anhydride (0.03 mLm 0.32 mmol) was slowly added thereto at room temperature. The reaction solution was stirred at room temperature and filtered after confirming that the reaction was complete. The filtrate was concentrated under reduced pressure and purified by flash column chromatography to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.69 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.19 — 7.02 (m, 5H), 6.28 (s, 1H), 4.49 (t, J = 5.1 Hz, 2H), 4.31 — 4.19 (m, 3H), 3.98 (dd, J = 13.9, 3.7 Hz, 1H), 3.88 — 3.78 (m, 3H), 3.80 — 3.67 (m, 3H), 3.47 (dd, J = 13.9, 7.5 Hz, 1H), 3.02 - 2.90 (m, 4H), 2.77 — 2.68 (m, 2H), 2.64 (bs, 1H), 2.56 (bs, 1H), 2.18 (d, J= 15.1 Hz, 3H). Example 17: Synthesis of 8-(1-acetyl-4-piperidyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3- dihydro-1,4-benzoxazepin-5-one 00 oS 7 it NON c rf 5 HN } OH 0 o SO EO0 oO Example Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyl)-2,3-dihydro- 1,4-benzoxazepin-5-one Tert-butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzo xazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate obtained in Example 14 was dissolved in methanol, and 5% palladium-charcoal in a catalytic amount was added thereto. The reaction solution was stirred under a hydrogen balloon and filtered through celite. The filtrate was concentrated under reduced pressure, dissolved in a small amount of methanol, and then 4 N hydrochloric acid dissolved in 1,4-dioxane was added thereto, followed by stirring at room temperature for 1 hour. After addition of distilled water, the reaction solution was washed with ethyl acetate. The obtained aqueous layer was basified with sodium hydroxide aqueous solution until the pH reached 14 and extracted with dichloromethane 3 times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound without additional purification. dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyl)-2,3-dihy dro-1,4-benzoxazepin-5-one (50 mg, 0.11 mmol) obtained in Example 17-1 and potassium carbonate (46 mg, 0.33 mg) were dissolved in dichloromethane, and acetic anhydride (0.02 mL, 0.17 mmol) was slowly added thereto. The reaction solution was stirred at room temperature for one day, diluted with dichloromethane, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by flash column chromatography to obtain the title compound (21 mg). 'H NMR (400 MHz, Methanol-d4) § 7.65 (d, J = 8.0 Hz, 1H), 7.18 — 7.02 (m, 5H), 6.95 (s, 1H), 4.69 (d, J= 13.4 Hz, 1H), 4.47 (t, J = 5.2 Hz, 2H), 4.29 — 4.18 (m, 1H), 4.03 (dd, J = 27.3, 14.3 Hz, 2H), 3.80 — 3.65 (m, 4H), 3.44 (dd, J = 14.0, 7.7 Hz, 1H), 3.29 — 3.20 (m, 1H), 2.98 - 2.82 (m, 4H), 2.80 — 2.60 (m, 3H), 2.16 (s, 3H), 1.98 — 1.85 (m, 2H), 1.78 — 1.50 (m, 3H). Example 18: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethyl-3,6-dihydro-2H-p yridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one Q SOTO \ \ OH ~~ oo Dihydrochloride of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydropyridin-4-y 1)-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 15 (75 mg, 0.16 mmol) was dissolved in methanol, and an excess of acetaldehyde was added thereto. While stirring the reaction solution, an excess of sodium cyanoborohydride was added, followed by stirring at room temperature for one day. The reaction was terminated by adding saturated aqueous ammonium chloride solution to the reaction solution, and 1 N sodium hydroxide aqueous solution was added for basification. The reaction mixture was extracted with ethyl acetate 3 times and dried over anhydrous sodium sulfate. The oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash column chromatography to obtain the title compound (10 mg) as a white solid. 'H NMR (400 MHz, Methanol-ds) 3 7.68 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 18.9 Hz, 5H), 6.30 (s, 1H), 4.49 (t, J= 5.1 Hz, 2H), 4.29 — 4.18 (m, 1H), 4.00 (dd, J= 13.7, 3.5 Hz, 1H), 3.77 (s, 2H), 3.73 (t, J = 5.2 Hz, 2H), 3.45 (dd, J = 13.8, 7.6 Hz, 1H), 3.27 (s, 2H), 2.99 — 2.85 (m, 4H), 2.83 (t, J = 5.9 Hz, 2H), 2.71 — 2.59 (m, 6H), 1.21 (t, J = 7.2 Hz, 3H). Example 19: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-isopropyl-3,6-dihydro- 2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one o o The title compound was synthesized in the same manner as in Example 18, except that acetone was used instead of acetaldehyde. 'H NMR (400 MHz, Methanol-ds) § 7.61 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.10 — 6.95 (m, SH), 6.24 (s, 1H), 4.42 (t, J = 5.2 Hz, 2H), 422 — 4.12 (m, 1H), 3.96 — 3.84 (m, 1H), 371 (s, 2H), 3.65 (t, J = 5.2 Hz, 2H), 3.48 — 3.31 (m, 3H), 3.05 — 2.90 (m, 3H), 2.90 — 2.78 (m, 4H), 2.68 — 2.50 (m, 4H), 1.17 (d, J = 6.5 Hz, 6H). Example 20: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(3,6-dihydro-2H-pyran-4- yI)-2,3-dihydro-1,4-benzoxazepin-5-one 0 CUO \ | oH J ort The title compound was synthesized in the same manner as in Example 10, except that 2-(3,6-dihydro-2H-pyran-4-y1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of methylboronic acid. 'H NMR (400 MHz, Methanol-ds) § 7.68 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.20 — 6.98 (m, SH), 6.34 (s, 1H), 4.49 (1, J = 5.1 Hz, 2H), 4.32 (d, J = 3.3 Hz, 2H), 4.29 — 4.19 (m, 1H), 4.00 (dd, J = 13.8, 3.6 Hz, 1H), 3.94 (t, J = 5.5 Hz, 2H), 3.81 — 3.68 (m, 4H), 3.48 — 3.40 (m, 1H), 2.99 — 2.84 (m, 4H), 2.69 — 2.60 (m, 2H), 2.53 (bs, 2H). Example 21: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-yl-2,3- dihydro-1,4-benzoxazepin-5-one o ASS. \' OH 0 0— 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,6-dihydro-2H-pyra n-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 20 was dissolved in methanol, and 5% palladium-charcoal in a catalytic amount was added thereto. The reaction solution was stirred under a hydrogen balloon and filtered through celite. The filtrate was concentrated under reduced pressure and purified by flash chromatography to obtain the title compound as transparent oil. 'H NMR (400 MHz, Methanol-ds) 8 7.65 (d, J = 8.1 Hz, 1H), 7.17 — 7.02 (m, 5H), 6.95 (s, 1H), 4.48 (t, J = 5.2 Hz, 2H), 4.29 — 4.17 (m, 1H), 4.08 — 3.95 (m, 3H), 3.76 (s, 2H), 3.71 (t, J = 5.3 Hz, 2H), 3.63 — 3.52 (m, 2H), 3.44 (dd, J = 13.9, 7.7 Hz, 1H), 2.98 — 2.80 (m, SH), 2.69 — 2.59 (m, 2H), 1.84 — 1.72 (m, 4H). Example 22: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(morpholinomethyl)-2,3-d ihydro-1,4-benzoxazepin-5-one a “Orn 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1 ,4-benzoxazepin-5-one (160 mg, 0.37 mmol), potassium (morpholin-4-yl)methyltrifluoroborate (85 mg, 0.41 mg), palladium acetate(4 mg, 0.0185 mmol), XPhos (18 mg, 0.037 mmol) and cesium carbonate (362 mg, 1.11 mmol) were dissolved in 3 mL of tetrahydrofuran:distilled water (=10:1) solvent, and nitrogen was charged, followed by stirring at 80°C for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and filtered through celite. The obtained solution was concentrated under reduced pressure and purified by flash chromatography to obtain the white title compound (103 mg). 'H NMR (400 MHz, Methanol-ds) § 7.67 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.16 — 7.03 (m, 5H), 4.48 (t, J = 5.1 Hz, 2H), 430 — 4.19 (m, 1H), 3.99 (dd, J = 13.9, 3.6 Hz, 1H), 3.77 (s, 2H), 3.71 (t, J = 4.8 Hz, 6H), 3.55 (s, 2H), 3.46 (dd, J = 13.9, 7.6 Hz, 1H), 2.99 — 2.85 (m, 4H), 2.72 — 2.60 (m, 2H), 2.48 (t, J = 4.7 Hz, 4H). Example 23: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(1-piperidylmethyl)-2,3-di hydro-1,4-benzoxazepin-5-one ~ 0 NN N N SSS eNes The title compound was synthesized in the same manner as in Example 22, except that potassium (piperidin-1-yl)methyltrifluoroborate ~~ was used instead of potassium (morpholin-4-yl)methyltrifluoroborate. 'H NMR (400 MHz, Methanol-ds) § 7.67 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.15 — 7.02 (m, 5H), 4.49 (t, J = 5.1 Hz, 2H), 4.29 — 4.20 (m, 1H), 4.00 (dd, J = 13.8, 3.6 Hz, 1H), 3.76 (s, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.53 (s, 2H), 3.45 (dd, J = 13.8, 7.6 Hz, 1H), 2.96-2.86(m, 4H), 2.71 2.59 (m, 2H), 2.46 (bs, 4H), 1.62 (q, J = 5.6 Hz, 4H), 1.49 (bs, 2H). Example 24: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(pyrrolidin-1-ylmethyl)-2, 3-dihydro-1,4-benzoxazepin-5-one a 0 The title compound was synthesized in the same manner as in Example 22, except that potassium ~~ 1-trifluoroboratomethylpyrrolidine was used instead of potassium (morpholin-4-yl)methyltrifluoroborate. 'H NMR (400 MHz, Methanol-ds) 8 7.69 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.15 - 7.03 (m, 5H), 4.49 (t, J = 5.1 Hz, 2H), 4.27-4.24 (m, 1H), 4.00 (dd, J = 13.9, 3.6 Hz, 1H), 3.81 3.67 (m, 6H), 3.46 (dd, J = 13.9, 7.7 Hz, 1H), 2.95-2.88 (m, 4H), 2.66 (bs, 6H), 1.87 (bs, 4H). Example 25: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(dimethylamino)methyl]- 2,3-dihydro-1,4-benzoxazepin-5-one —N J jo] o_ / OH The title compound was synthesized in the same manner as in Example 22, except that potassium ~~ dimethylaminomethyltrifluoroboronate was used instead of potassium (morpholin-4-yl)methyltrifluoroborate, 'H NMR (400 MHz, Chloroform-d) 8 7.75 (d, J = 8.0 Hz, 1H), 7.18 — 7.07 (m, 4H), 7.06 — 6.95 (m, 2H), 4.51 — 4.39 (m, 2H), 4.17 — 4.06 (m, 2H), 3.93 (d, J = 14.7 Hz, 1H), 3.83 (d, / = 15.0 Hz, 1H), 3.74 - 3.66 (m, 2H), 3.63 (d, J = 14.9 Hz, 1H), 3.56 (dd, J = 14.2, 6.0 Hz, 1H), 3.42 (s, 2H), 3.00 - 2.87 (m, 3H), 2.77 — 2.70 (m, 1H), 2.69 — 2.63 (m, 1H), 2.56 (t, J = 11.3 Hz, 1H), 2.25 (s, 6H). Example 26: Synthesis of 8-(diethylaminomethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3 -dihydro-1,4-benzoxazepin-5-one AoA NYO or OH The title compound was synthesized in the same manner as in Example 22, except that potassium diethylaminomethyltrifluoroboronate ~~ was used instead of potassium (morpholin-4-yl)methyltrifluoroborate. 'H NMR (400 MHz, Chloroform-d) § 7.74 (d, J = 7.9 Hz, 1H), 7.18 — 7.08 (m, 4H), 7.02 (bs, 2H), 4.45 (qt, J = 10.8, 4.6 Hz, 2H), 4.16 — 4.06 (m, 1H), 3.93 (d, / = 14.2 Hz, 1H), 3.83 (d, J = 14.9 Hz, 1H), 3.75 - 3.66 (m, 2H), 3.63 (d, J = 14.9 Hz, 1H), 3.57-3.54 (m, 3H), 3.00 — 2.87 (m, 3H), 2.74 (dd, J= 10.7, 5.3 Hz, 1H), 2.67 (dd, J = 12.5, 3.9 Hz, 1H), 2.61 — 2.47 (m, 5H), 1.04 (t, J=17.1 Hz, 6H). Example vid Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methyl-1-piperidyl)me thyl]-2,3-dihydro-1,4-benzoxazepin-5-one K* A F Br BF K* £ - H 0 sO S220 a — . N_g:F 2 *Y Sen COCO 4-Methyl piperidine (0.054 mL, 0.46 mmol) and potassium (bromomethyl)trifluoroborate (92 mg, 0.46 mmol) were dissolved in 2 mL of tetrahydrofuran, and stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, and 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzo xazepin-5-one (100 mg, 0.23 mmol), palladium acetate (3 mg, 0.011 mmol), XPhos (11 mg, 0.023 mmol), cesium carbonate (225 mg, 0.69 mmol) and 2 mL of tetrahydrofuran:distilled water (=10:1) were added thereto, followed by charging a reaction vessel with nitrogen. The reaction solution was stirred at 80°C for 16 hours, diluted with ethyl acetate, and filtered through celite. The obtained solution was concentrated under reduced pressure and purified by flash chromatography to obtain the white title compound (70 mg). 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.14 — 7.02 (m, 5H), 4.49 (t, J = 5.1 Hz, 2H), 4.29 — 4.19 (m, 1H), 4.00 (dd, J = 13.9, 3.6 Hz, 1H), 3.76 (s, 2H), 3.72 (t, J = 5.2 Hz, 2H), 3.54 (s, 2H), 3.46 (dd, J = 13.8, 7.7 Hz, 1H), 2.98 — 2.83 (m, 6H), 2.72 — 2.60 (m, 2H), 2.07 (d, J = 11.6 Hz, 1H), 1.66 (d, J = 13.0 Hz, 2H), 1.41 (bs, 1H), 1.34-1.19 (m, 2H), 0.96 (d, J = 6.4 Hz, 3H). Example 28: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-6-azaspiro[3.3| hep tan-6-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 0 1 0 Ln N Oro Ooi The title compound was synthesized in the same manner as in Example 27, except that 4 equivalents of potassium carbonate was added, and 2-oxa-6-azaspiro[3.3]heptane oxalate was used instead of 4-methyl piperidine. 'H NMR (400 MHz, Methanol-d4) § 7.67 (d, J = 7.9 Hz, 1H), 7.18 — 7.03 (m, 5H), 6.98 (s, 1H), 4.75 (s, 4H), 4.48 (t, J = 5.1 Hz, 2H), 4.30 — 4.19 (m, 1H), 3.99 (dd, J = 14.0, 3.6 Hz, 1H), 3.78 (s, 2H), 3.71 (t, J = 5.3 Hz, 2H), 3.62 (s, 2H), 3.47-3.43 (m, 5H), 2.95-2.89 (m, 4H), 2.74 — 2.61 (m, 2H). Example 29: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-methoxyazetidin-1-yl) methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 0 OO O~ 3-Methoxyazetidine ~~ hydrochloride (57 mg, 046 mmol), potassium (bromomethyl)trifluoroborate (92 mg, 0.46 mmol) and potassium carbonate (127 mg, 0.92 mmol) were dissolved in tetrahydrofuran:distilled water (10:1), and stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, and 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzo xazepin-5-one (100 mg, 0.23 mmol), palladium acetate(3 mg, 0.011 mmol), XPhos (11 mg, 0.023 mmol), cesium carbonate (225 mg, 0.69 mmol) and tetrahydrofuran:distilled water (=10:1) were added thereto, followed by charging a reaction vessel with nitrogen. The reaction solution was stirred at 80°C for 16 hours, diluted with ethyl acetate, and filtered through celite. The obtained solution was concentrated under reduced pressure and purified by flash chromatography to obtain the white title compound (16 mg). 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.0 Hz, 1H), 7.16 — 7.04 (m, 5H), 7.00 (s, 1H), 4.48 (t, J = 5.1 Hz, 2H), 4.28 — 4.19 (m, 1H), 4.11 — 4.04 (m, 1H), 3.99 (dd, J = 13.9, 3.7 Hz, 1H), 3.77 (s, 2H), 3.74 — 3.67 (m, 3H), 3.61 (1, J = 7.3 Hz, 2H), 3.45 (dd, J = 14.0, 7.6 Hz, 1H), 3.27 (s, 3H), 3.08 (t, J = 7.1 Hz, 2H), 3.00 — 2.84 (m, 4H), 2.71 — 2.61 (m, 2H). Example 30: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(2-methylmorpholin-4-yl )methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2 “ope CEO The title compound was synthesized in the same manner as in Example 29, except that 2-methylmorpholine was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.15 - 7.03 (m, 5H), 4.49 (t, J = 5.1 Hz, 2H), 4.30 - 4.17 (m, 1H), 3.99 (dd, J = 13.8, 3.7 Hz, 1H), 3.88 — 3.79 (m, 1H), 3.77 (s, 2H), 3.75 — 3.61 (m, 4H), 3.54 (s, 2H), 3.46 (dd, J = 13.8, 7.6 Hz, 1H), 2.98 — 2.84 (m, 4H), 2.76 (d, J = 11.4 Hz, 1H), 2.72 - 2.62 (m, 3H), 2.21 - 2.11 (m, 1H), 1.86 (t, J=10.6 Hz, 1H), 1.12 (d, J = 6.3 Hz, 3H). Example 31: Synthesis of 8-[(4,4-difluoro-1-piperidylymethyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy -propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1 Lome CEO The title compound was synthesized in the same manner as in Example 29, except that 4,4-difluoropiperidine hydrochloride was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.15 — 7.03 (m, 4H), 4.49 (t, J = 5.1 Hz, 2H), 4.29 — 4.19 (m, 1H), 4.00 (dd, J = 13.8, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J = 5.2 Hz, 2H), 3.60 (s, 2H), 3.46 (dd, J = 13.8, 7.6 Hz, 1H), 2.99 — 2.84 (m, 4H), 2.71 — 2.64 (m, 2H), 2.59 (t, J = 5.8 Hz, 4H), 2.01 (ddt, J= 19.4, 12.4, 5.6 Hz, 4H). Example 32: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(4-fluoro-1-piperidyl)met hyl]-2,3-dihydro-1,4-benzoxazepin-5-one E ~ Sod N C0 The title compound was synthesized in the same manner as in Example 29, except that 4-fluoropiperidine hydrochloride was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.14 — 7.01 (m, SH), 4.67 (d, J = 48.8 Hz, 1H), 4.48 (t, / = 5.1 Hz, 2H), 4.29 — 4.17 (m, 1H), 3.99 (dd, J = 13.8, 3.6 Hz, 1H), 3.81 — 3.67 (m, 4H), 3.55 (s, 2H), 3.45 (dd, J = 13.9, 7.7 Hz, 1H), 2.99 — 2.83 (m, 4H), 2.72 — 2.54 (m, 4H), 2.50 — 2.35 (m, 2H), 2.00 — 1.76 (m, 4H). Example 33: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(3,5-dimethyl-1-piperidyl )methyl]-2,3-dihydro-1,4-benzoxazepin-5-one Cod EO The title compound was synthesized in the same manner as in Example 29, except that 3,5-dimethylpiperidine was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 3 7.68 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.16 — 6.95 (m, 4H), 4.49 (t, J = 5.2 Hz, 2H), 4.25 (s, 1H), 4.00 (dd, J = 14.0, 3.6 Hz, 1H), 3.75 (d, J = 16.5 Hz, 2H), 3.55 (s, 2H), 3.46 (dd, J = 13.7, 7.7 Hz, 1H), 3.01 — 2.81 (m, 5H), 2.67 (d, J= 5.2 Hz, 2H), 1.75 (d, J= 13.2 Hz, 3H), 1.55 (t, J = 11.0 Hz, 2H), 0.87 (d, J = 6.3 Hz, 6H). Example 34: Synthesis of 8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-ylmethyl)-4-[(2R)-3-(3,4-dihydro-1H-i soquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one Co! Le C0 The title compound was synthesized in the same manner as in Example 29, except that 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole hydrochloride was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.0 Hz, 1H), 7.18 (s, OH), 7.14 — 7.02 (m, 4H), 4.48 (t, J = 5.1 Hz, 2H), 4.24 (s, 1H), 4.00 (dd, J = 13.9, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J = 5.1 Hz, 2H), 3.60 (s, 2H), 3.46 (dt, J = 13.8, 7.6 Hz, 1H), 2.94 (d, J = 5.5 Hz, 2H), 2.89 (d, J = 6.2 Hz, 3H), 2.76 — 2.59 (m, 4H), 2.08 (dd, J = 9.4, 5.4 Hz, 2H), 1.62 (d, J = 41.3 Hz, 4H), 1.47 (s, 2H). Example 35: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxypyrrolidin-1-y 1)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one HO Sr [SCO The title compound was synthesized in the same manner as in Example 29, except that pyrrolidin-3-ol was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 4.2 Hz, 3H), 7.08 (s, 2H), 4.48 (1, J = 5.2 Hz, 2H), 4.37 (s, 1H), 4.24 (s, 1H), 4.00 (dd, J= 13.7, 3.6 Hz, 1H), 3.77 (s, 2H), 3.75 — 3.68 (m, 3H), 3.65 (d, J = 13.0 Hz, 1H), 3.46 (dt, / = 13.8, 7.4 Hz, 1H), 2.94 (d, J = 5.6 Hz, 2H), 2.89 (d, J = 5.4 Hz, 2H), 2.84 — 2.74 (m, 2H), 2.75 — 2.63 (m, 2H), 2.61 — 2.48 (m, 2H), 2.16 (dt, J = 14.3, 7.0 Hz, 1H). Example 36: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-methylpyrrolidin -1-yljmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one “Co ero a. ; Os The title compound was synthesized in the same manner as in Example 29, except that (2R)-2-methylpyrrolidine was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (d, J =4.3 Hz, 3H), 7.07 (s, 2H), 4.49 (t, J = 5.2 Hz, 2H), 4.24 (s, 0H), 4.11 — 3.93 (m, 2H), 3.76 (s, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.46 (dt, J= 13.9, 7.7 Hz, 1H), 3.24 (d, J = 12.9 Hz, 1H), 2.94 (d, J =5.7 Hz, 3H), 2.89 (d, J = 5.7 Hz, 2H), 2.71 — 2.62 (m, 2H), 2.57 — 2.45 (m, 1H), 2.24 (d, J = 9.2 Hz, 1H), 2.03 (dq, J = 14.6, 7.3 Hz, 1H), 1.74 (p, J = 8.1 Hz, 2H), 1.49 (dt, J = 17.6, 8.9 Hz, 1H), 1.21 (d, J = 6.1 Hz, 3H). Example 37: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-(hydroxymethyl)-1-pi peridyljmethyl|-2,3-dihydro-1,4-benzoxazepin-5-one HO Oo The title compound was synthesized in the same manner as in Example 29, except that 3-piperidylmethanol was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 3 7.67 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.12 (d, J =4.2 Hz, 3H), 7.06 (s, 2H), 4.49 (1, J = 5.1 Hz, 2H), 4.24 (s, 1H), 3.99 (dd, J = 14.0, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J = 5.0 Hz, 2H), 3.65 — 3.53 (m, 2H), 3.54 — 3.41 (m, 1H), 3.00 (d, / = 7.1 Hz, 1H), 2.94 (d, J = 5.4 Hz, 2H), 2.88 (1, J = 10.9 Hz, 3H), 2.73 - 2.61 (m, 2H), 2.16 — 1.95 (m, 1H), 1.76 (d, J = 18.7 Hz, 2H), 1.63 (d, J = 12.4 Hz, 1H). Example 38: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(4-methoxy-1-piperidyl) methyl]-2,3-dihydro-1,4-benzoxazepin-5-one Pe] 0 Softer 5) OH The title compound was synthesized in the same manner as in Example 29, except that 4-methoxypiperidine was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) § 7.67 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.15 — 7.01 (m, SH), 4.49 (t, J = 5.2 Hz, 2H), 4.31 — 4.19 (m, 1H), 4.00 (dd, J = 13.8, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J = 4.8 Hz, 2H), 3.55 (s, 2H), 3.46 (dd, J = 13.8, 7.7 Hz, 1H), 3.34 (5, 3H), 3.31 —3.24 (m, 1H), 2.98 — 2.85 (m, 4H), 2.76 (dd, J= 11.1, 3.9 Hz, 2H), 2.71 — 2.62 (m, 2H), 2.25 (, J=10.8 Hz, 2H), 1.99 — 1.87 (m, 2H), 1.67 — 1.52 (m, 2H). Example 39: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,4-oxazepan-4-ylmethyl )-2,3-dihydro-1,4-benzoxazepin-5-one 0 \ y o NN, “ero 0 OH The title compound was synthesized in the same manner as in Example 29, except that 1,4-oxazepane hydrochloride was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) § 7.67 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.15 — 7.03 (m, 5H), 4.48 (t, J= 5.1 Hz, 2H), 4.29 — 4.19 (m, 1H), 3.99 (dd, J= 13.7, 3.6 Hz, 1H), 3.83 (t, J = 6.1 Hz, 2H), 3.79 — 3.65 (m, 8H), 3.46 (dd, J = 13.8, 7.6 Hz, 1H), 2.98 — 2.84 (m, 4H), 2.78 — 2.68 (m, 4H), 2.69 — 2.61 (m, 2H), 1.93 (p, J= 5.8 Hz, 2H). Example 40: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxy-3-methyl-pyr rolidin-1-yl)methyl}-2,3-dihydro-1,4-benzoxazepin-5-one Hox) 0 Yeo 0" The title compound was synthesized in the same manner as in Example 29, except that 3-methylpyrrolidin-3-ol was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.16 — 7.01 (m, 5H), 4.48 (t, J = 5.1 Hz, 2H), 4.30 — 4.19 (m, 1H), 4.00 (dd, J = 14.0, 3.6 Hz, 1H), 3.77 (s, 2H), 3.75 —- 3.61 (m, 4H), 3.46 (dd, J = 13.9, 7.6 Hz, 1H), 2.94 (d, J = 5.6 Hz, 2H), 2.92 — 2.80 (m, 4H), 2.73 — 2.60 (m, 4H), 2.55 (d, J = 10.1 Hz, 1H), 1.95 — 1.85 (m, 2H), 1.36 (s, 3H). Example 41: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[[2-(hydroxymethyl)-1-pi peridyljmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one ~~ ANI VEN Lees CEO The title compound was synthesized in the same manner as in Example 29, except that morpholin-3-ylmethanol was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.66 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.15 — 7.04 (m, SH), 4.48 (t, J= 5.1 Hz, 2H), 4.29 — 4.19 (m, 1H), 4.14 (d, J = 13.3 Hz, 1H), 3.99 (dd, J = 14.0, 3.5 Hz, 1H), 3.91 — 3.84 (m, 1H), 3.83 — 3.75 (m, 3H), 3.75 — 3.63 (m, 4H), 3.64 — 3.50 (m, 2H), 3.46 (dd, J = 13.8, 7.6 Hz, 1H), 3.39 (d, J = 13.9 Hz, 1H), 2.99 - 2.85 (m, 4H), 2.72 — 2.63 (m, 3H), 2.53 (s, 1H), 2.29 (d, J=9.3 Hz, 1H). Example 42: Synthesis of 8-[(3,3-difluoro-1-piperidylymethyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy -propyl]-2,3-dihydro-1,4-benzoxazepin-5-one “Hod ee The title compound was synthesized in the same manner as in Example 29, except that 3,3-difluoropiperidine hydrochloride was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) § 7.68 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.09 (dd, J=21.4,4.6 Hz, 4H), 4.49 (t, J = 5.2 Hz, 2H), 4.31 — 4.20 (m, 1H), 3.99 (dd, J = 14.0, 3.6 Hz, 1H), 3.78 (s, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.63 (s, 2H), 3.46 (dd, J = 13.9, 7.9 Hz, 1H), 3.00 — 2.83 (m, 4H), 2.74 — 2.58 (m, 4H), 2.55 — 2.44 (m, 2H), 1.97 — 1.83 (m, 2H), 1.82 - 1.72 (m, 2H). Example 43: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(3-fluoro-1-piperidyl)met hyl]-2,3-dihydro-1,4-benzoxazepin-5-one { o A "3 o— The title compound was synthesized in the same manner as in Example 29, except that 3-fluoropiperidine hydrochloride was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.15 - 7.02 (m, SH), 4.63 (d, J = 48.0 Hz, 1H), 4.49 (t, J = 5.1 Hz, 2H), 4.30 — 4.19 (m, 1H), 4.00 (dd, J =14.0, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.58 (s, 2H), 3.46 (dd, J= 13.9, 7.7 Hz, 1H), 3.00 — 2.82 (m, 4H), 2.81 — 2.58 (m, 3H), 2.55 — 2.41 (m, 2H), 2.38 (t, J = 9.9 Hz, 1H), 1.94 — 1.78 (m, 2H), 1.70 — 1.51 (m, 2H). Example 44: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxy-1-piperidyl) methyl]-2,3-dihydro-1,4-benzoxazepin-5-one ~r ° x. o— The title compound was synthesized in the same manner as in Example 29, except that piperidin-3-ol hydrochloride was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.16 — 7.01 (m, 5H), 4.48 (t, J = 5.1 Hz, 2H), 4.30 — 4.19 (m, 1H), 3.99 (dd, J= 13.7, 3.6 Hz, 1H), 3.78 (s, 2H), 3.75 — 3.63 (m, 3H), 3.63 — 3.50 (m, 2H), 3.46 (dd, J= 13.9, 7.7 Hz, 1H), 3.00 — 2.82 (m, 5H), 2.77 — 2.61 (m, 3H), 2.12 — 2.04 (m, 1H), 1.99 — 1.88 (m, 2H), 1.82 — 1.70 (m, 1H), 1.65 — 1.50 (m, 1H). Example 45: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-hydroxy-1-piperidyl) methyl]-2,3-dihydro-1,4-benzoxazepin-5-one HOA Tog CO id o— The title compound was synthesized in the same manner as in Example 29, except that piperidin-4-ol was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) § 7.67 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.15 — 7.03 (m, SH), 449 (t, J = 5.0 Hz, 2H), 4.29 — 4.20 (m, 1H), 4.02 — 3.96 (m, 1H), 3.77 (s, 2H), 3.76 — 3.70 (m, 2H), 3.68 — 3.59 (m, 1H), 3.55 (s, 2H), 3.46 (dd, J = 13.8, 7.5 Hz, 1H), 2.98 — 2.86 (m, 4H), 2.86 — 2.76 (m, 2H), 2.70 — 2.63 (m, 2H), 2.28 — 2.15 (m, 2H), 1.92 — 1.82 (m, 2H), 1.66 — 1.53 (m, 2H). Example 46: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(hydroxymethyl) pyrrolidin-1-yljmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one dre The title compound was synthesized in the same manner as in Example 29, except that [(2S)-pyrrolidin-2-yl]methanol was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.66 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16 — 7.03 (m, 5H), 4.48 (t, J = 5.1 Hz, 2H), 4.29 — 4.19 (m, 1H), 4.13 (d, J = 12.8 Hz, 1H), 4.00 (dd, J =14.1,3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J = 5.4 Hz, 2H), 3.60 (dd, J = 11.1, 4.6 Hz, 1H), 3.56 — 3.41 (m, 3H), 3.02 — 2.85 (m, 5H), 2.79 — 2.62 (m, 3H), 2.39 — 2.25 (m, 1H), 2.03 — 1.93 (m, 1H), 1.82 — 1.66 (m, 3H). Example 47: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-(hydroxymethyl) pyrrolidin-1-yljmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one or oO 0 N “Orv os OH The title compound was synthesized in the same manner as in Example 29, except that [(2R)-pyrrolidin-2-yl]methanol was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.66 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.17 - 7.02 (m, 5H), 4.48 (t, J = 5.2 Hz, 2H), 4.24 (s, 1H), 4.14 (d, J= 13.2 Hz, 1H), 3.99 (dd, / = 13.8, 3.5 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J = 4.9 Hz, 2H), 3.60 (dd, J = 11.0, 4.6 Hz, 1H), 3.57 - 3.41 (m, 3H), 3.02 — 2.84 (m, 5H), 2.79 — 2.68 (m, 1H), 2.69 — 2.61 (m, 2H), 2.38 — 2.27 (m, 1H), 2.05-1.92 (m, 1H), 1.83 — 1.66 (m, 3H). Example 48: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(2-ethylpyrrolidin-1-yl)m ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one Coe CY CO0 The title compound was synthesized in the same manner as in Example 29, except that 2-ethylpyrrolidine hydrochloride was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.16 — 7.02 (m, 5H), 4.48 (t, J = 5.2 Hz, 2H), 429 — 4.19 (m, 1H), 4.07 (d, J = 13.2 Hz, 1H), 4.00 (dd, J =14.1, 3.5 Hz, 1H), 3.76 (s, 2H), 3.74 — 3.67 (m, 2H), 3.45 (dd, / = 13.9, 7.7 Hz, 1H), 3.25 (d, J = 12.9 Hz, 1H), 2.99 — 2.81 (m, 5H), 2.70 — 2.60 (m, 2H), 2.41 — 2.29 (m, 1H), 2.27 — 2.15 (m, 1H), 2.09 — 1.99 (m, 1H), 1.91 — 1.80 (m, 1H), 1.79 — 1.65 (m, 2H), 1.57 — 1.45 (m, 1H), 1.43 — 1.26 (m, 2H), 0.96 (t, J= 7.5 Hz, 3H). Example 49: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(methoxymethyl) pyrrolidin-1-yljmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one o- or - The title compound was synthesized in the same manner as in Example 29, except that (2S)-2-(methoxymethyl)pyrrolidine was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.66 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.16 — 7.03 (m, 5H), 4.48 (t, J= 5.3 Hz, 2H), 4.24 (dd, J = 9.6, 5.5 Hz, 1H), 4.16 (d, J = 13.1 Hz, 1H), 4,00 (d,J = 11.2 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J = 6.2 Hz, 2H), 3.52 — 3.42 (m, 3H), 3.43 - 3.36 (m, 1H), 3.36 (s, 3H), 2.99 — 2.85 (m, 5H), 2.84 — 2.74 (m, 1H), 2.71 — 2.60 (m, 2H), 2.35 2.24 (m, 1H), 2.02 — 1.88 (m, 1H), 1.80 — 1.69 (m, 2H), 1.67 — 1.57 (m, 1H). Example 50: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-(methoxymethyl) pyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one C00 The title compound was synthesized in the same manner as in Example 29, except that (2R)-2-(methoxymethyl)pyrrolidine was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 3 7.66 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.15 - 7.02 (m, 5H), 4.48 (t, J = 5.2 Hz, 2H), 4.30 — 4.19 (m, 1H), 4.15 (d, J = 13.4 Hz, 1H), 4.00 (dd, J =13.9, 3.5 Hz, 1H), 3.76 (s, 2H), 3.72 (t, J = 5.2 Hz, 2H), 3.51 — 3.41 (m, 3H), 3.41 — 3.37 (m, 1H), 3.36 (s, 3H), 2.98 — 2.84 (m, 5H), 2.83 — 2.74 (m, 1H), 2.71 — 2.60 (m, 2H), 2.35 — 2.22 (m, 1H), 2.02 — 1.89 (m, 1H), 1.80 — 1.68 (m, 2H), 1.68 — 1.54 (m, 1H). Example 51: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoropyrrolidin-1-yl) methyl]-2,3-dihydro-1,4-benzoxazepin-5-one jie Oey 5) OH Nr uh OS The title compound was synthesized in the same manner as in Example 29, except that 3-fluoropyrrolidine hydrochloride was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.16 — 7.04 (m, 5H), 5.30 — 5.22 (m, 1H), 5.16 — 5.08 (m, 1H), 4.49 (t, J = 5.2 Hz, 2H), 4.30 — 4.19 (m, 1H), 4.00 (dd, J = 13.7, 3.6 Hz, 1H), 3.77 (s, 2H), 3.74 — 3.62 (m, 4H), 3.46 (dd, J = 13.9, 7.7 Hz, 1H), 2.98 — 2.89 (m, 4H), 2.71 — 2.62 (m, 2H), 2.47 (q, J = 8.0 Hz, 1H), 2.32 - 2.13 (m, 2H), 2.10- 1.91 (m, 2H). Example 52: Synthesis of 8-[(3,3-difluoropyrrolidin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydr oxy-propylj-2,3-dihydro-1,4-benzoxazepin-5-one F = 9 TEC The title compound was synthesized in the same manner as in Example 29, except that 3,3-difluoropyrrolidine was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.15 - 7.02 (m, 5H), 4.49 (t, J = 5.0 Hz, 2H), 429 — 4.19 (m, 1H), 4.00 (dd, J = 14.0, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J = 4.9 Hz, 2H), 3.68 (s, 2H), 3.46 (dd, J = 14.0, 7.7 Hz, 1H), 3.00 — 2.91 (m, 3H), 2.92 — 2.85 (m, 3H), 2.79 (t, J = 7.0 Hz, 2H), 2.71 — 2.62 (m, 2H), 2.36 — 2.23 (m, 2H). Example 53: Synthesis of 8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-p ropyl]-2,3-dihydro-1,4-benzoxazepin-5-one MN 6 / Ore oo The title compound was synthesized in the same manner as in Example 29, except that 1-piperazin-1-yl-ethanone was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d,J = 7.9 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.13 (d, J =4.4 Hz, 3H), 7.07 (s, 2H), 4.49 (t, J = 5.1 Hz, 2H), 4.25 (s, 1H), 3.99 (dd, J = 13.9, 3.7 Hz, 1H), 3.79 (s, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.59 (dq, J = 10.4, 5.0 Hz, 7H), 3.47 (dd, J = 13.9, 7.6 Hz, 1H), 2.93 (dd, J = 14.0, 4.7 Hz, 4H), 2.74 — 2.63 (m, 2H), 2.48 (dt, J= 19.1, 5.1 Hz, 5H), 2.11 (s, 3H). Example 54: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(4-methylpiperazin-1-yl) methyl]-2,3-dihydro-1,4-benzoxazepin-5-one w NN 0 / SoC 1 oH oOo Example 54-1: Synthesis of tert-butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-0xo-2,3-dihydro-1,4-b enzoxazepin-8-yl|methyl|piperazin-1-carboxylate The title compound was synthesized in the same manner as in Example 29, except that tert-butyl piperazin-1-carboxylate was used instead of 3-methoxyazetidine hydrochloride. 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(piperazin-1-ylmethyl)-2, 3-dihydro-1,4-benzoxazepin-5-one dihydrochloride Tert-butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-ox0-2,3-dihydro-1,4-benz oxazepin-8-ylJmethyl]piperazin-1-carboxylate obtained in Example 54-1 was dissolved in methanol, and 4 M hydrochloric acid solution dissolved in 1,4-dioxane was slowly added thereto. The reaction solution was stirred at room temperature, diluted with diethyl ether, and filtered to obtain the title compound as a white solid. Example 54-3: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylpiperazin-1-yl) methyl]-2,3-dihydro-1,4-benzoxazepin-5-one The obtained hydrochloride was dissolved in methanol, and an excess of paraformaldehyde and sodium cyanoborohydride were added thereto, followed by stirring at room temperature for 12 hours. The reaction was terminated by adding a saturated aqueous ammonium chloride solution to the reaction solution, and 1 N sodium hydroxide aqueous solution was added for basification. The mixture was extracted with ethyl acetate 3 times and dried over anhydrous sodium sulfate. The pale yellow oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to obtain the title compound. '"H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.09 (dd, J=23.3,5.1 Hz, 5H), 4.48 (t, J = 5.3 Hz, 2H), 4.28 — 4.19 (m, 1H), 4.00 (d, J = 13.6 Hz, 1H), 3.79 - 3.67 (m, 4H), 3.56 (s, 2H), 3.45 (dd, J = 13.8, 7.6 Hz, 1H), 2.98 — 2.84 (m, 4H), 2.66 (d, J = 6.5 Hz, 2H), 2.53 (bs, 6H), 2.31 (s, 3H). Example 55: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(2-oxa-5-azabicyclo[2.2.1] heptan-5-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one o 0 Gov 00 Od The title compound was synthesized in the same manner as in Example 29, except that 2-oxa-5-azabicyclo[2.2.1]Theptane hydrochloride was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16 — 7.02 (m, SH), 4.47 (dd, J = 11.9, 6.9 Hz, 3H), 4.29 — 4.19 (m, 2H), 4.11 (d, J = 7.8 Hz, 1H), 3.99 (dd, J = 14.0, 3.6 Hz, 1H), 3.81 (d, J = 6.1 Hz, 2H), 3.77 (s, 2H), 3.72 (1, J = 5.3 Hz, 2H), 3.65 (d, J=179 Hz, 1H), 3.54 (s, 1H), 3.46 (dd, J = 13.9, 7.6 Hz, 1H), 2.98 — 2.83 (m, 5H), 2.73 — 2.59 (m, 3H), 2.00 — 1.93 (m, 1H), 1.76 (d, J = 10.2 Hz, 1H). Example 56: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridylmethoxy)-2,3-di hydro-1,4-benzoxazepin-5-one o benzoxazepin-5-one 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1 ,4-benzoxazepin-5-one (9.0 g, 21 mmol), hydroxypotassium (4.68 g, 83 mmol), Pd(dba), (180 mg, 0.315 mmol) and rBuXPhos (270 mg, 0.63 mmol) were dissolved in 80 mL of 1,4-dioxane:distilled water (=1:1) solution, and a reaction vessel was charged with nitrogen. The reaction solution was stirred at 100°C for 3 hours, and a hydrochloric acid aqueous solution was added under an ice bath to acidify the reaction solution to pH ~1. The aqueous layer was washed with ethyl acetate 3 times, and sodium hydroxide aqueous solution was added under an ice bath to basify to pH 14, followed by extraction with ethyl acetate 3 times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a white solid without additional purification. Example 56-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridylmethoxy)-2,3-di hydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro- 1,4-benzoxazepin-5-one (100 mg, 0.27 mmol) obtained in Example 56-1 was dissolved in dimethylformamide, and 60% sodium hydride (33 mg, 0.81 mmol) and 3-(chloromethyl)pyridine hydrochloride (66 mg, 0.41 mmol) were added thereto at room temperature. The reaction solution was stirred at room temperature for 3 hours and extracted by adding ethyl acetate and distilled water. The oily liquid obtained by drying the organic layer over anhydrous sodium sulfate and concentrated under reduced pressure was purified by flash chromatography to obtain the title compound (64 mg) as a sticky white solid. '"H NMR (400 MHz, Methanol-da) 8 8.66 (s, 1H), 8.54 (d, J = 4.9 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.50 (t, J = 6.6 Hz, 1H), 7.18 — 7.02 (m, 4H), 6.86 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 2.9 Hz, 1H), 5.22 (s, 2H), 449 (t, J = 5.0 Hz, 2H), 429 — 4.17 (m, 1H), 3.98 (dd, J = 13.8, 3.2 Hz, 1H), 3.83 — 3.67 (m, 4H), 3.43 (dd, J = 13.9, 7.6 Hz, 1H), 2.99 — 2.83 (m, 4H), 2.71 = 2.59 (m, 2H). Example 57: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(4-pyridylmethoxy)-2,3-di hydro-1,4-benzoxazepin-5-one 0 a O50 NJ 0 _ OH The title compound was synthesized in the same manner as in Example 56, except that 4-(chloromethyl)pyridine hydrochloride was used instead of 3-(chloromethyl)pyridine hydrochloride in Example 56-2. 'H NMR (400 MHz, Methanol-da) 8 8.60 — 8.51 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 5.2 Hz, 2H), 7.18 — 7.00 (m, 4H), 6.86 (d, J = 9.0 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 5.25 (s, 2H), 4.48 (t, J = 4.9 Hz, 2H), 4.27 — 4.18 (m, 1H), 3.98 (dd, J = 14.0, 3.6 Hz, 1H), 3.81 — 3.67 (m, 4H), 3.43 (dd, J= 13.9, 7.7 Hz, 1H), 2.99 — 2.83 (m, 4H), 2.71 — 2.60 (m, 2H). Example 58: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(2-fluoro-4-pyridyl)meth oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 0 Qo oreo \ OH re oo’ N_~ F The title compound was synthesized in the same manner as in Example 56, except that (2-fluoro-4-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride in Example 56-2. 'H NMR (400 MHz, Methanol-ds) 8 8.22 (d, J = 5.3 Hz, 1H), 7.71 (dd, J = 8.8, 2.0 Hz, 1H), 7.40 (d,J=5.2 Hz, 1H), 7.18 (s, 1H), 7.12 (t, J = 2.6 Hz, 3H), 7.06 (d, J = 6.8 Hz, 1H), 6.87 (dd, J = 8.9, 2.4 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 5.27 (s, 2H), 4.49 (t, J = 5.1 Hz, 2H), 4.24 (s, 1H), 3.97 (dd, J =13.7, 3.3 Hz, 1H), 3.79 (s, 2H), 3.74 (t, J = 4.7 Hz, 2H), 3.44 (dd, J= 13.9, 7.7 Hz, 1H), 2.93 (dd, J= 11.6, 4.7 Hz, 4H), 2.68 (d, J= 6.4 Hz, 2H). Example 59: Synthesis of 8-[(2,6-dichloro-4-pyridyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy -propyl]-2,3-dihydro-1,4-benzoxazepin-5-one j=4&y =U y UL U-1 4 DCHLOA ALL PI -O-00 2 N ~~ \ OH Sao 5 N Cl The title compound was synthesized in the same manner as in Example 56, except that 2,6-dichloro-4-ethyl-pyridine hydrochloride was used instead of 3-(chloromethyl)pyridine hydrochloride in Example 56-2. 'H NMR (400 MHz, Methanol-ds) § 7.72 (d, J = 8.8 Hz, 1H), 7.53 (s, 2H), 7.23 — 7.06 (m, 2H), 7.06 (s, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.69 (d, J = 3.1 Hz, 1H), 5.23 (s, 2H), 4.64 (s, 2H), 4.50 (d, J=5.6 Hz, 2H), 4.23 (s, 1H), 4.00 (s, 1H), 3.75 (s, 4H), 3.55 — 3.37 (m, 1H), 2.93 (d, J = 5.7 Hz, 2H), 2.88 (d, J = 5.5 Hz, 2H), 2.64 (d, J = 6.2 Hz, 2H). Example 60: Synthesis of 8-[(2,3-difluoro-4-pyridyl)methoxy|-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy -propyl]-2,3-dihydro-1,4-benzoxazepin-5-one oO SO F oc Nn a N__~ The title compound was synthesized in the same manner as in Example 56, except that (2,3-difluoro-4-pyridyl) methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride in Example 56-2. 'H NMR (400 MHz, Methanol-ds) § 8.02 (d, J = 5.0 Hz, 1H), 7.83 — 7.66 (m, 1H), 7.51 (d, J = 5.3 Hz, 1H), 7.26 — 7.06 (m, 3H), 7.06 (d, J = 6.5 Hz, 1H), 6.89 — 6.84 (m, 1H), 6.71 (d, J=2.9 Hz, 1H), 5.34 (s, 2H), 4.48 (d, J = 5.4 Hz, 2H), 4.23 (d, J = 7.0 Hz, 1H), 4.05 — 3.92 (m, 1H), 3.75 (d, J = 10.7 Hz, 4H), 3.43 (dd, J = 14.0, 7.7 Hz, 1H), 2.98 — 2.92 (m, 2H), 2.89 (d, J = 5.3 Hz, 2H), 2.66 (d, J= 6.1 Hz, 2H). Example 61: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-fluore-3-pyridylymeth oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 0 0 ra \ OH Loe FN? The title compound was synthesized in the same manner as in Example 56, except that (6-fluoro-3-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride in Example 56-2. 'H NMR (400 MHz, Methanol-d4) § 8.32 (s, 1H), 8.07 (t, J = 8.3 Hz, 1H), 7.70 (dd, J = 8.8, 2.2 Hz, 1H), 7.20 — 7.03 (m, 5H), 6.85 (d, J = 8.9 Hz, 1H), 6.69 (d, J = 2.7 Hz, 1H), 5.18 (s, 2H), 4.48 (t, J = 5.3 Hz, 2H), 4.23 (s, 1H), 3.98 (d, / = 13.9 Hz, 1H), 3.75 (d, J = 15.5 Hz, 4H), 3.43 (dd, J= 14.0, 7.8 Hz, 1H), 3.03 — 2.82 (m, 4H), 2.66 (d, J= 6.1 Hz, 2H). Example 62: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl)meth oxy]-2,3-dihydro-1,4-benzoxazepin-5-one E 0 Are reo _ OH The title compound was synthesized in the same manner as in Example 56, except that (3-fluoro-4-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride in Example 56-2. 'H NMR (400 MHz, Methanol-da) 8 8.50 (s, 1H), 8.44 (d, J = 5.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.65 (t, J = 5.7 Hz, 1H), 7.16 — 7.02 (m, 4H), 6.87 (d, / = 9.3 Hz, 1H), 6.70 (d, J = 2.9 Hz, 1H), 5.32 (s, 2H), 4.49 (t, J = 5.0 Hz, 2H), 4.27 — 4.18 (m, 1H), 3.98 (dd, J = 13.7, 3.1 Hz, 1H), 3.79 - 3.67 (m, 4H), 3.43 (dd, J = 13.9, 7.6 Hz, 1H), 2.97 — 2.83 (m, 4H), 2.69 — 2.59 (m, 2H). Example 63: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl)meth 0xy]-2,3-dihydro-1,4-benzoxazepin-5-one C0 “ro \ OH F~%.N o— The title compound was synthesized in the same manner as in Example 56, except that (5-fluoro-2-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride in Example 56-2. 'H NMR (400 MHz, Methanol-ds) § 8.49 (s, 1H), 7.68 (dd, J = 15.0, 6.3 Hz, 3H), 7.16 — 7.03 (m, 4H), 6.85 (d, J = 8.9 Hz, 1H), 6.67 (s, 1H), 5.22 (5, 2H), 4.48 (t, J = 5.0 Hz, 2H), 4.28 — 4.16 (m, 1H), 3.98 (d, J = 15.0 Hz, 1H), 3.78 — 3.69 (m, 4H), 3.43 (dd, J = 13.9, 7.7 Hz, 1H), 3.00 — 2.83 (m, 4H), 2.70 — 2.61 (m, 2H). Example 64: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-yloxy- 2,3-dihydro-1,4-benzoxazepin-5-one oN, 9 Cory C0 = o— 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro- 1,4-benzoxazepin-5-one (100 mg, 0.27 mmol) obtained in Example 56-1, potassium carbonate (112 mg, 0.81 mmol) and 4-chlorotetrahydropyran (0.12 mL, 0.81 mmol) were dissolved in dimethylformamide, and stirred at 150°C for 12 hours or longer. The reaction solution was cooled to room temperature, and distilled water was added thereto, followed by extraction with ethyl acetate 3 times. The oily liquid obtained by drying the combined organic layers over anhydrous sodium sulfate and concentrated under reduced pressure was purified by flash chromatography to obtain the title compound as a sticky white solid. 'H NMR (400 MHz, Methanol-ds) § 7.67 (d, J = 8.7 Hz, 1H), 7.17 — 7.02 (m, 4H), 6.78 (d, J = 8.9 Hz, 1H), 6.61 (s, 1H), 4.69 — 4.61 (m, 1H), 4.48 (t, J = 5.0 Hz, 2H), 4.27 — 4.19 (m, 1H), 4.02 ~3.91 (m, 3H), 3.78 (s, 2H), 3.77 — 3.70 (m, 2H), 3.62 (t, J = 10.0 Hz, 2H), 3.43 (dd, J = 13.5, 7.5 Hz, 1H), 2.99 — 2.82 (m, 4H), 2.72 — 2.60 (m, 2H), 2.11 = 2,01 (m, 2H), 1.79 — 1.67 (m, 2H). Example 65: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydropyran-2-ylmet hoxy)-2,3-dihydro-1,4-benzoxazepin-5-one oO Qo SY ore ol ot OH The title compound was synthesized in the same manner as in Example 64, except that tetrahydropyran-2-ylmethyl methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Methanol-ds) § 7.65 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 4.1 Hz, 3H), 7.06 (d, J = 6.6 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.55 (s, 1H), 4.47 (t, J = 5.1 Hz, 2H), 4.23 (s, 1H), 4.05 —3.94 (m, 1H), 3.89 - 3.67 (m, 7\6H), 3.43 (dd, J = 13.9, 7.6 Hz, 1H), 2.92 (dd, J=17.2, 5.3 Hz, 4H), 2.66 (d, J = 6.2 Hz, 2H), 1.89 (d, J = 13.1 Hz, 2H), 1.84 — 1.66 (m, 4H), 1.49 — 1.19 (m, 4H), 1.11 (q, J = 12.1 Hz, 2H). Example 66: Synthesis of 8-(cyclohexylmethoxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3- dihydro-1,4-benzoxazepin-5-one oO oO Yo oS A The title compound was synthesized in the same manner as in Example 64, except that cyclohexylmethyl methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Methanol-ds) § 7.67 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 5.0 Hz, 4H), 7.06 (d, J = 6.8 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 6.59 (s, 1H), 4.46 (d, J = 5.2 Hz, 2H), 4.28 — 4.17 (m, 1H), 3.99 (dd, J = 14.1, 9.2 Hz, 4H), 3.88 — 3.66 (m, 6H), 3.53 (td, J = 10.8, 3.5 Hz, 1H), 3.43 (dd, J = 14.0, 7.6 Hz, 1H), 2.94 (dd, J = 9.6, 4.6 Hz, 4H), 2.74 — 2.57 (m, 2H), 1.92 (d, J = 6.5 Hz, 1H), 1.69 (t, J = 14.9 Hz, 1H), 1.61 (d, / = 10.2 Hz, 3H), 1.51 — 1.41 (m, 1H). Example 67: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydrofuran-2-ylmet hoxy)-2,3-dihydro-1,4-benzoxazepin-5-one oO Cro YY =X... a Ol The title compound was synthesized in the same manner as in Example 64, except that tetrahydrofuran-2-ylmethyl methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Chloroform-d) 8 7.79 (d, J = 8.7 Hz, 1H), 7.20 — 7.10 (m, 3H), 7.04 (d, J = 6.7 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 4.46 (q, J = 5.4 Hz, 2H), 4.30 (t, / = 6.2 Hz, 1H), 4.13 (d, J = 8.1 Hz, 1H), 4.06 — 3.90 (m, 4H), 3.86 (dd, J= 15.1, 8.3 Hz, 2H), 3.77 —- 3.60 (m, 3H), 3.53 (dd, J = 14.1, 6.2 Hz, 1H), 3.02 — 2.87 (m, 4H), 2.84 — 2.51 (m, 3H), 2.31 - 2.05 (m, 1H), 1.98 (q, J = 6.9 Hz, 2H), 1.79 (dt, J = 12.0, 7.2 Hz, 1H), 1.35 — 1.22 (m, 1H). Example 68: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)ox y]-2,3-dihydro-1,4-benzoxazepin-5-one | [] Ny Jed NG “Ho 14 The title compound was synthesized in the same manner as in Example 64, except that (1-methyl-3-piperidyl) methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Methanol-d) 7.68 (dd, J = 8.8, 1.9 Hz, 1H), 7.12 (d, J = 2.9 Hz, 3H), 7.06 (d,J=6.6 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.61 (d, J = 2.9 Hz, 1H), 4.69 — 4.42 (m, 3H), 4.24 (s, 1H), 3.97 (dd, J= 14.5, 3.4 Hz, 1H), 3.78 (s, 2H), 3.74 (d, J = 5.5 Hz, 2H), 3.43 (dd, J = 14.0, 7.6 Hz, 1H), 3.03 — 2.84 (m, 5H), 2.67 (d, J = 6.6 Hz, 3H), 2.37 (d, J= 2.0 Hz, 3H), 2.05 (d, J = 9.8 Hz, 2H), 1.91 (d, J = 16.4 Hz, 3H), 1.66 (d, J = 20.3 Hz, 3H), 0.93 (q, / = 16.5, 10.6 Hz, 2H). Example 69: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(1-ethyl-3-piperidyl)oxy] -2,3-dihydro-1,4-benzoxazepin-5-one ~~ Q AC rr C0 0 \' OH O— The title compound was synthesized in the same manner as in Example 64, except that (1-ethyl-3-piperidyl) methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 8.8 Hz, 1H), 7.17 — 7.02 (m, 4H), 6.78 (dd, J = 8.5,2.5 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 4.48 (t, J= 5.0 Hz, 2H), 4.28 — 4.17 (m, 1H), 4.11 — 3.94 (m, 3H), 3.79 - 3.68 (m, 4H), 3.43 (dd, J = 13.8, 7.6 Hz, 1H), 3.26 (bs, 1H), 3.18 — 3.09 (m, 1H), 3.04 (bs, 1H), 2.99 — 2.91 (m, 2H), 2.92 — 2.84 (m, 2H), 2.71 — 2.59 (m, 2H), 2.54 (bs, 1H), 2.44 (bs, 1H), 2.16 — 2.05 (m, 1H), 1.89 (dd, J= 16.4, 8.7 Hz, 2H), 1.81 — 1.71 (m, 1H), 1.20 (t, J =7.3 Hz, 3H). Example 70: Synthesis of 8-[(1-acetyl-4-piperidylymethoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-p ropyl]-2,3-dihydro-1,4-benzoxazepin-5-one o Aer VEO o Ne— a The title compound was synthesized in the same manner as in Example 64, except that (1-acetyl-4-piperidyl)methyl methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Methanol-ds) 8 7.66 (d, J = 8.8 Hz, 1H), 7.17 — 7.01 (m, 4H), 6.79 - 6.71 (m, 1H), 6.58 (s, 1H), 4.59 (d, J = 13.3 Hz, 1H), 4.53 — 4.41 (m, 2H), 4.27 - 4.17 (m, 1H), 3.98 (d, J= 13.6 Hz, 2H), 3.91 (d, J = 6.3 Hz, 2H), 3.83 - 3.64 (m, 4H), 3.42 (dd, J = 13.9, 7.6 Hz, 1H), 3.21 — 3.12 (m, 1H), 2.98 — 2.82 (m, 4H), 2.75 — 2.60 (m, 3H), 2.13 (s, 3H), 1.92 (dd, J = 25.3, 14.0 Hz, 2H), 1.45 - 1.21 (m, 3H). Example 71: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,2,2-trifluoroethoxy)-2,3 -dihydro-1,4-benzoxazepin-5-one a N reo YE C0 ~%. God The title compound was synthesized in the same manner as in Example 64, except that 2,2,2-trifluoroethyl methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Methanol-ds) 8 7.73 (d, J = 8.8 Hz, 1H), 7.19 — 6.99 (m, 4H), 6.84 (d, J = 9.0 Hz, 1H), 6.69 (s, 1H), 4.61 (q, J = 8.4 Hz, 2H), 4.50 (t, / = 5.1 Hz, 2H), 4.27 - 4.17 (m, 1H), 3.99 (d, J = 13.6 Hz, 1H), 3.81 — 3.67 (m, 4H), 3.43 (dd, J = 13.9, 7.4 Hz, 1H), 3.00 — 2.82 (m, 4H), 2.65 (d, J = 6.2 Hz, 2H). Example 72: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[2-(dimethylamino)ethoxy 1-2,3-dihydro-1,4-benzoxazepin-5-one 0 1 RE C0 oT T ~~ of hn a oo The title compound was synthesized in the same manner as in Example 64, except that 2-chloro-N,N-dimethyl-ethanamine hydrochloride was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 8.6 Hz, 1H), 7.19 — 7.01 (m, 4H), 6.79 (d, J = 9.0 Hz, 1H), 6.62 (s, 1H), 4.48 (t, J = 5.0 Hz, 2H), 4.28 — 4.19 (m, 1H), 4.16 (t, J = 5.5 Hz, 2H), 3.98 (d, J = 13.8 Hz, 1H), 3.82 — 3.69 (m, 4H), 3.43 (dd, J = 13.8, 7.8 Hz, 1H), 2.99 — 2.85 (m, 4H), 2.86 — 2.77 (m, 2H), 2.69 — 2.60 (m, 2H), 2.38 (s, 6H). Example 73: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-morpholinoethoxy)-2,3 -dihydro-1,4-benzoxazepin-5-one 0 oN oF CR Nero o- The title compound was synthesized in the same manner as in Example 64, except that 4-(2-chloroethyl)morpholine hydrochloride was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Chloroform-d) 8 7.78 (d, J = 8.7 Hz, 1H), 7.13 (dd, J = 9.7, 5.6 Hz, 3H), 7.01 (d, J = 6.7 Hz, 1H), 6.69 (d, J = 8.7 Hz, 1H), 6.50 (s, 1H), 4.45 (d, J = 4.7 Hz, 2H), 4.12 (t, J=5.6 Hz, 3H), 3.93 (d, J = 14.1 Hz, 1H), 3.83 (d, J = 14.9 Hz, 1H), 3.73 (d, J = 4.8 Hz, 6H), 3.63 (d,J= 14.8 Hz, 1H), 3.51 (dd, J = 14.1, 6.2 Hz, 1H), 2.93 (dq, J = 13.3, 5.5 Hz, 3H), 2.81 (t, J=5.7Hz, 3H), 2.77 — 2.71 (m, 1H), 2.66 (dd, J = 12.3, 4.0 Hz, 1H), 2.57 (q, J = 6.0, 5.3 Hz, 5H), 1.31 -1.20 (m, 1H). Example 74: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[2-(2-oxopyrrolidin-1-yl)e thoxy]-2,3-dihydro-1,4-benzoxazepin-5-one Q N OTE I \ NoNe~o 4 The title compound was synthesized in the same manner as in Example 64, except that 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Chloroform-d) § 7.79 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 9.0 Hz, 3H), 7.01 (d, J=17.0 Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 6.48 (s, 1H), 4.46 (d, J= 4.8 Hz, 3H), 4.12 (d, J=5.3 Hz, 4H), 3.88 (dd, J = 41.5, 14.5 Hz, 2H), 3.79 — 3.43 (m, 8H), 2.93 (d, J = 16.8 Hz, 3H), 2.70 (dd, J = 32.9, 9.3 Hz, 2H), 2.60 — 2.48 (m, 1H), 2.39 (t, J = 8.1 Hz, 2H), 2.12 — 1.97 (m, 3H), 1.26 (s, 1H). Example 75: Synthesis of 2-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-b enzoxazepin-8-yl]oxy]-N,N-diethyl-acetamide ff 0 ON | In N ~o-r 0 o ~~ ' OH TW vy oo The title compound was synthesized in the same manner as in Example 64, except that [2-(diethylamino)-2-oxo-ethyl] methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Chloroform-d) § 7.79 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 8.9 Hz, 3H), 7.02 (d, J=6.8 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 6.55 (s, 1H), 4.69 (s, 2H), 4.53 — 4.42 (m, 2H), 4.12 (d, J=17.8Hz, 1H), 3.93 (d, J = 14.1 Hz, 1H), 3.83 (d, J = 14.9 Hz, 1H), 3.76 — 3.57 (m, 3H), 3.52 (dd,J=14.1, 6.1 Hz, 1H), 3.39 (dq, J = 14.6, 7.0 Hz, 4H), 2.93 (d, J= 16.7 Hz, 3H), 2.74 (d, J = 5.6 Hz, 1H), 2.66 (d, J = 12.4 Hz, 1H), 2.55 (t, J = 11.3 Hz, 1H), 2.05 (s, 1H), 1.30 — 1.20 (m, 3H), 1.15 (t,J=7.2 Hz, 3H). Example 76: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-0x0-3-piperidyl)oxy]-2 ,3-dihydro-1,4-benzoxazepin-5-one H Oy N N ON 0 Ore C0 A OH on 0 The title compound was synthesized in the same manner as in Example 64, except that (6-0x0-3-piperidyl) methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 8.8 Hz, 1H), 7.17 — 7.02 (m, 4H), 6.82 — 6.75 (m, 1H), 6.62 (s, 1H), 4.48 (t, J = 5.0 Hz, 2H), 4.28 — 4.17 (m, 1H), 4.13 — 4.02 (m, 2H), 4.02 — 3.92 (m, 2H), 3.79 — 3.67 (m, 4H), 3.42 (dd, J = 13.8, 7.6 Hz, 1H), 2.98 — 2.84 (m, 4H), 2.70 — 2.59 (m, 2H), 2.54 — 2.43 (m, 1H), 2.38 (dd, J= 17.1, 13.5 Hz, 2H), 2.08 — 1.97 (m, 1H). Example 77: Synthesis of tert-butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinelin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-b enzoxazepin-8-yl]oxy]piperidine-1-carboxylate Mf NN . o The title compound was synthesized in the same manner as in Example 64, except that tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Methanol-ds) § 7.67 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 19.7 Hz, 4H), 6.79 (d, J =9.0 Hz, 1H), 6.62 (s, 1H), 4.70 — 4.60 (m, 1H), 4.51 — 4.44 (m, 2H), 4.27 — 4.19 (m, 1H), 3.98 (d, J = 14.4 Hz, 1H), 3.85 — 3.64 (m, 6H), 3.45 (d, J = 7.4 Hz, 1H), 2.98 — 2.92 (m, 2H), 2.93 -2.86 (m, 2H), 2.71 — 2.62 (m, 2H), 2.04 — 1.89 (m, 3H), 1.76 — 1.60 (m, 2H), 1.49 (s, 9H). Example 78: Synthesis of 8-[(1-acetyl-4-piperidyl)oxy|-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl 1-2,3-dihydro-1,4-benzoxazepin-5-one o £0 Carrer C0 Example 78-1: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(4-piperidyloxy)-2,3-dihy dro-1,4-benzoxazepin-5-one dihydrochloride Tert-butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-ox0-2,3-dihydro-1,4-benz oxazepin-8-ylJoxy]piperidine-1-carboxylate obtained in Example 77 was dissolved in methanol, and 4 M hydrochloric acid solution dissolved in 1,4-dioxane was slowly added thereto. The reaction solution was stirred at room temperature, diluted with diethyl ether and filtered to obtain the title compound as a white solid. Example 78-2: Synthesis of 8-[(1-acetyl-4-piperidyl)oxy|-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl 1-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3- dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 78-1 was dissolved in dichloromethane, and trimethylamine and acetic anhydride were added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture, saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate 3 times. The oily liquid obtained by drying the combined organic layers over anhydrous sodium sulfate and concentrated under reduced pressure was purified by flash chromatography to obtain the title compound as a white solid. 'H NMR (400 MHz, Methanol-ds) & 7.58 (d, J = 8.8 Hz, 1H), 7.27 — 7.05 (m, 4H), 6.70 (dd, J = 9.0, 2.4 Hz, 1H), 6.54 (d, J = 1.9 Hz, 1H), 4.65 — 4.49 (m, 2H), 4.47 — 4.28 (m, 4H), 3.81 — 3.57 (m, 7H), 3.48 — 3.33 (m, 3H), 3.33 — 3.23 (m, 2H), 3.12 (q, J = 7.4 Hz, 2H), 2.03 (s, 3H), 1.97 — 1.80 (m, 3H), 1.77 — 1.54 (m, 2H). Example 79: Synthesis of 8-[(1-acetyl-3-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl 1-2,3-dihydro-1,4-benzoxazepin-5-one N N N yore 0 No ude Ot The title compound was synthesized in the same manner as in Example 64, except that (1-acetyl-3-piperidyl) methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (diastereomeric mixture, 400 MHz, Methanol-ds) 8 7.72-7.65 (m, 2H), 7.17 — 7.02 (m, 8H), 6.83 — 6.74 (m, 2H), 6.61 (s, 2H), 4.68 — 4.59 (m, 1H), 4.48 (q, J = 4.6 Hz, 5H), 4.23 (s, 2H), 4.10 — 3.93 (m, 4H), 3.86 (dd, J = 14.3, 4.8 Hz, 1H), 3.81 — 3.68 (m, 8H), 3.66 — 3.48 (m, 4H), 3.43 (dd, J = 14.0, 7.7 Hz, 2H), 3.20 (t, J = 11.3 Hz, 1H), 2.99 — 2.84 (m, 8H), 2.71 — 2.59 (m, 4H), 2.17 = 1.95 (m, 9H), 1.93 — 1.77 (m, 3H), 1.70 — 1.52 (m, 2H). Example 80: Synthesis of 8-(1-acetylpyrrolidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-prop yl]-2,3-dihydro-1,4-benzoxazepin-5-one oO o HO, org CO ° Lr in fang The title compound was synthesized in the same manner as in Example 64, except that tert-butyl ~~ 4-methylsulfonyloxypyrrolidine-1-carboxylate ~~ was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Methanol-ds) § 7.70 (dd, J = 8.8, 3.8 Hz, 1H), 7.18 — 7.00 (m, 4H), 6.77 (t, J =8.6 Hz, 1H), 6.60 (dd, J = 5.8, 2.3 Hz, 1H), 5.19 — 5.04 (m, 1H), 4.48 (t, J = 5.0 Hz, 2H), 4.30 — 4.18 (m, 1H), 3.97 (dd, J = 14.0, 3.5 Hz, 1H), 3.92 — 3.59 (m, 7H), 3.54 — 3.37 (m, 2H), 3.00 — 2.84 (m, 4H), 2.73 — 2.59 (m, 2H), 2.35 — 2.23 (m, 1H), 2.25 — 2.15 (m, 1H), 2.09 (d, J = 15.8 Hz, 3H). Example 81: Synthesis of 8-[(3R)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- propyl]-2,3-dihydro-1,4-benzoxazepin-5-one o oa, legato ono 0 The title compound was synthesized in the same manner as in Example 80, except that tert-butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate was used instead of tert-butyl 4-methylsulfonyloxypyrrolidine-1-carboxylate, 'H NMR (400 MHz, Methanol-ds) § 7.70 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 20.4 Hz, 4H), 6.81 — 6.72 (m, 1H), 6.61 (d, J = 5.8 Hz, 1H), 5.13 (d, J = 22.4 Hz, 1H), 4.52 — 4.44 (m, 2H), 4.29 — 4.18 (m, 1H), 3.98 (d, J = 14.1 Hz, 1H), 3.83 — 3.62 (m, 8H), 3.43 (dd, J = 142, 7.5 Hz, 1H), 2.99 — 2.81 (m, 4H), 2.70 — 2.59 (m, 2H), 2.36 — 2.27 (m, 1H), 2.27 — 2.16 (m, 1H), 2.09 (d, J = 15.7 Hz, 3H). Example 82: Synthesis of 8-[(3S)-1-acetylpyrrolidin-3-yl]oxy-4-[ (2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 0, Oreo No up oo The title compound was synthesized in the same manner as in Example 80, except that tert-butyl (3R)-3-methylsulfonyloxypyrrolidine-1-carboxylate was used instead of tert-butyl 4-methylsulfonyloxypyrrolidine-1-carboxylate. 'H NMR (400 MHz, Methanol-d4) 8 7.69 (d, J = 8.6 Hz, 1H), 7.17 — 7.02 (m, 4H), 6.77 (1, J = 7.5 Hz, 1H), 6.61 (d, J=4.8 Hz, 1H), 5.13 (d, J =22.4 Hz, 1H), 4.53 — 4.43 (m, 2H), 4.22 (dd, J =12.1,5.5 Hz, 1H), 3.98 (d, J = 13.4 Hz, 1H), 3.91 — 3.61 (m, 8H), 3.43 (dd, J= 13.9, 7.9 Hz, 1H), 2.99 - 2.82 (m, 4H), 2.70 - 2.58 (m, 2H), 2.37 - 2.26 (m, 1H), 2.26 - 2.16 (m, 1H), 2.09 (d, J=15.6 Hz, 3H). Example 83: Synthesis of 8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl] -2,3-dihydro-1,4-benzoxazepin-5-one fn ors CO oA Example Synthesis of 8-(azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dih ydro-1,4-benzoxazepin-5-one dihydrochloride The material, which is obtained by changing 4-chlorotetrahydropyrane to tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 64, as a starting material was used in the same manner as in Example 78-1 to obtain the title compound. Example 83-2: Synthesis of 8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl] -2,3-dihydro-1,4-benzoxazepin-5-one 8-(Azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2, 3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 83-1 as a starting material was used in the same manner as in Example 78-2 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.71 (d, J = 8.7 Hz, 1H), 7.19 — 7.00 (m, 4H), 6.69 (dd, J = 8.7,2.2 Hz, 1H), 6.49 (d, J = 2.3 Hz, 1H), 5.09 (dt, J = 12.0, 6.5 Hz, 1H), 4.69 — 4.61 (m, 1H), 4.49 (t, J = 5.0 Hz, 2H), 4.42 (dd, J = 11.0, 6.6 Hz, 1H), 4.29 — 4.18 (m, 2H), 4.04 — 3.91 (m, 2H), 3.82 — 3.67 (m, 4H), 3.43 (dd, J = 13.7, 7.7 Hz, 1H), 3.00 — 2.83 (m, 4H), 2.72 — 2.58 (m, 2H), 1.93 (s, 3H). Example 84: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-propanoylazetidin-3-yl )oxy-2,3-dihydro-1,4-benzoxazepin-5-one o “ho rece o 8-(Azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2, 3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 83-1 as a starting material was used in the same manner as in Example 78-2 to obtain the title compound, except that propanoyl chloride was used instead of acetic anhydride. 'H NMR (400 MHz, Methanol-ds) 8 7.71 (d, J = 8.7 Hz, 1H), 7.21 — 7.01 (m, 4H), 6.72 - 6.65 (m, 1H), 6.49 (d, J= 2.4 Hz, 1H), 5.15 — 5.05 (m, 1H), 4.69 — 4.59 (m, 1H), 4.49 (t, J = 5.0 Hz, 2H), 4.46 — 4.38 (m, 1H), 4.28 — 4.17 (m, 2H), 4.03 — 3.90 (m, 2H), 3.85 — 3.68 (m, 4H), 3.44 (dd, J = 13.9, 7.7 Hz, 1H), 3.02 — 2.82 (m, 4H), 2.75 — 2.62 (m, 2H), 2.21 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H). Example 85: Synthesis of 8-[1-(cyclopropanecarbonyl)azetidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2 -hydroxy-propylj-2,3-dihydro-1,4-benzoxazepin-5-one why 2 VO 8-(Azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2, 3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 83-1 as a starting material was used in the same manner as in Example 78-2 to obtain the title compound, except that cyclopropanecarbonyl chloride was used instead of acetic anhydride. 'H NMR (400 MHz, Methanol-da) § 7.71 (d, J = 8.7 Hz, 1H), 7.20 — 7.02 (m, 4H), 6.71 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H), 5.19 — 5.08 (m, 1H), 4.82 — 4.74 (m, 1H), 4.49 (t, J = 5.1 Hz, 2H), 4.45 — 437 (m, 1H), 4.33 (d, J = 9.9 Hz, 1H), 4.29 — 4.16 (m, 1H), 3.97 (d, J = 12.2 Hz, 2H), 3.84 — 3.68 (m, 4H), 3.44 (dd, J = 13.9, 7.7 Hz, 1H), 3.00 — 2.84 (m, 4H), 2.74 — 2.61 (m, 2H), 1.67 — 1.56 (m, 1H), 0.93 — 0.78 (m, 4H). Example 86: Synthesis of methyl 3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-b enzoxazepin-8-yl]oxy]azetidin-1-carboxylate o oo eC o— 8-(Azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2, 3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 83-1 as a starting material was used in the same manner as in Example 78-2 to obtain the title compound, except that methyl chloroformate was used instead of acetic anhydride. 'H NMR (400 MHz, Methanol-ds) 8 7.70 (d, J = 8.8 Hz, 1H), 7.16 — 7.00 (m, 4H), 6.66 (d, J = 8.7 Hz, 1H), 6.46 (s, 1H), 5.10 — 5.00 (m, 1H), 4.54 — 4.35 (m, 4H), 4.28 — 4.16 (m, 1H), 4.06 — 3.90 (m, 3H), 3.78 — 3.70 (m, 4H), 3.69 (s, 3H), 3.41 (dd, J = 14.0, 7.7 Hz, 1H), 2.98 — 2.81 (m, 4H), 2.69 — 2.58 (m, 2H). Example 87: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidyl)ox y]-2,3-dihydro-1,4-benzoxazepin-5-one N’ v0 Toh Cor A, o / 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3- dihydro-1,4-benzoxazepin-5-one dihydrochloride (100 mg, 0.19 mmol) obtained in Example 78-1 was dissolved in methanol, and paraformaldehyde (57 mg, 1.9 mmol) and sodium cyanoborohydride (36 mg, 0.57 mmmol) were added thereto. The reaction solution was stirred at room temperature until the reaction was completed, a saturated aqueous ammonium chloride solution was added, stirred for 30 minutes, and then 1 N sodium hydroxide aqueous solution was added for basification. The mixture was extracted with ethyl acetate 3 times and dried over anhydrous sodium sulfate. The pale yellow oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by flash chromatography to obtain the title compound as a white solid. 'H NMR (400 MHz, Methanol-ds) 8 7.66 (d, J = 8.8 Hz, 1H), 7.16 — 7.00 (m, 4H), 6.76 (dd, J = 8.8,2.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 4.56 — 4.41 (m, 3H), 4.27 - 4.16 (m, 1H), 3.97 (dd, J = 13.9, 3.5 Hz, 1H), 3.79 — 3.63 (m, 4H), 3.41 (dd, J= 13.9, 7.7 Hz, 1H), 2.98 — 2.88 (m, 2H), 2.90 ~ 2.80 (m, 2H), 2.79 — 2.68 (m, 2H), 2.68 — 2.56 (m, 2H), 2.49 — 2.36 (m, 2H), 2.32 (s, 3H), 2.10 —2.01 (m, 3H), 1.90 — 1.76 (m, 2H). Example 88: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy] -2,3-dihydro-1,4-benzoxazepin-5-one —N\ NA | Ae rE 0— The title compound was synthesized in the same manner as in Example 87, except that acetaldehyde was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) § 7.67 (d, J = 8.7 Hz, 1H), 7.17 — 7.03 (m, 4H), 6.81 — 6.74 (m, 1H), 6.60 (s, 1H), 4.61 — 4.51 (m, 1H), 4.47 (t, J = 5.0 Hz, 2H), 4.28 — 4.16 (m, 1H), 4.02 — 3.92 (m, 1H), 3.82 — 3.68 (m, 4H), 3.43 (dd, J = 13.9, 7.7 Hz, 1H), 3.01 — 2.80 (m, 6H), 2.74 - 2.51 (m, 6H), 2.15 — 2.02 (m, 2H), 1.96 — 1.78 (m, 2H), 1.19 (t, J= 7.2 Hz, 3H). Example 89: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-isopropyl-4-piperidyl) oxy]-2,3-dihydro-1,4-benzoxazepin-5-one — o NAN - 9 ! N Ore o— The title compound was synthesized in the same manner as in Example 87, except that acetone was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) § 7.68 (d, J = 8.7 Hz, 1H), 7.16 — 7.01 (m, 4H), 6.78 (d, J = 8.8 Hz, 1H), 6.61 (s, 1H), 4.63 — 4.51 (m, 1H), 4.47 (t, J = 4.9 Hz, 2H), 4.22 (dd, J= 7.8, 4.4 Hz, 1H), 3.97 (d, J = 13.9 Hz, 1H), 3.81 — 3.66 (m, 4H), 3.43 (dd, J = 13.9, 7.6 Hz, 1H), 3.10 — 2.98 (m, 2H), 2.98 — 2.82 (m, 4H), 2.83 — 2.70 (m, 2H), 2.69 — 2.58 (m, 2H), 2.18 — 1.98 (m, 3H), 1.95 1.82 (m, 2H), 1.21 (d, J = 6.5 Hz, 6H). Example 90: Synthesis of 8-[(1-cyclopropyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-p ropyl]-2,3-dihydro-1,4-benzoxazepin-5-one 4 The title compound was synthesized in the same manner as in Example 87 at 60°C, except that (1-ethoxycyclopropoxy)trimethylsilane was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 9.0 Hz, 1H), 7.18 — 7.02 (m, 4H), 6.76 (d, J = 8.8 Hz, 1H), 6.59 (s, 1H), 4.58 — 4.41 (m, 3H), 4.28 — 4.17 (m, 1H), 3.97 (dd, J = 14.0, 3.6 Hz, 1H), 3.83 — 3.66 (m, 4H), 3.42 (dd, J = 14.0, 7.7 Hz, 1H), 3.01 — 2.78 (m, 6H), 2.73 — 2.51 (m, 4H), 2.10 — 1.96 (m, 2H), 1.86 — 1.66 (m, 3H), 0.59 — 0.39 (m, 4H). Example 91: Synthesis of 8-[(1-cyclobutyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-pr opyl]-2,3-dihydro-1,4-benzoxazepin-5-one —n ~ Core C0 A, o— The title compound was synthesized in the same manner as in Example 87, except that cyclobutanone was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 3 7.67 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 21.0 Hz, 4H), 6.77 (d, J=18.9 Hz, 1H), 6.60 (s, 1H), 4.63 — 4.50 (m, 2H), 4.47 (d, J = 5.3 Hz, 2H), 4.29 — 4.18 (m, 1H), 3.97 (d, J = 14.5 Hz, 1H), 3.80 (s, 2H), 3.77 — 3.67 (m, 2H), 3.44 (dd, J = 14.0, 7.5 Hz, 1H), 3.05 — 2.88 (m, SH), 2.86 — 2.74 (m, 2H), 2.71 — 2.63 (m, 2H), 2.56 — 2.35 (m, 3H), 2.22 — 2.11 (m, 2H), 2.11 — 1.93 (m, 4H), 1.92 — 1.74 (m, 4H), Example 92: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(oxetan-3-yl)4-piperi dyljoxy}-2,3-dihydro-1,4-benzoxazepin-5-one 0 Bo NN S ~N 1» LOY oH The title compound was synthesized in the same manner as in Example 87, except that oxetan-3-one was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 8 7.75 — 7.56 (m, 1H), 7.12 (d, J = 3.1 Hz, 3H), 7.06 (d, J = 6.7 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 2.1 Hz, 1H), 4.71 (t, J = 6.7 Hz, 2H), 4.62 (t, J =6.3 Hz, 2H), 4.54 — 4.41 (m, 3H), 4.23 (s, 1H), 4.02 — 3.91 (m, 1H), 3.79 (s, 2H), 3.73 (s, 2H), 3.55(t,J = 6.5 Hz, 1H), 3.43 (dd, J = 14.0, 7.6 Hz, H), 2.93 (dd, J = 11.3, 4.6 Hz, 4H), 2.68 (d, J =6.6 Hz, 2H), 2.61 (s, 2H), 2.28 (t, J = 10.0 Hz, 2H), 2.04 (d, J = 10.2 Hz, 2H), 1.89 (d, J = 36.1 Hz, 2H). Example 93: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(1-methylazetidin-3-yl)ox y-2,3-dihydro-1,4-benzoxazepin-5-one "Or O0 oOo The matetial obtained in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 19.7 Hz, 4H), 6.65 (d, J=8.9 Hz, 1H), 6.44 (s, 1H), 4.86 (t, J = 5.6 Hz, 3H), 447 (1, J = 5.2 Hz, 2H), 429 — 4.17 (m, 1H), 3.98 (dd, J = 13.7, 2.5 Hz, 1H), 3.83 (t, J = 7.5 Hz, 2H), 3.78 — 3.69 (m, 4H), 3.42 (dd, J = 13.9, 7.8 Hz, 1H), 3.28 (dd, J = 8.6, 5.1 Hz, 3H), 2.98 — 2.82 (m, 4H), 2.70 — 2.58 (m, 2H), 2.44 (s, 3H). Example 94: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethylazetidin-3-yl)oxy- 2,3-dihydro-1,4-benzoxazepin-5-one Morn CS "~.. Cit, The matetial obtained in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetaldehyde was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 8 7.57 (d, J = 8.7 Hz, 1H), 7.05 — 6.91 (m, 4H), 6.55 (d, J = 8.7 Hz, 1H), 6.34 (d, J = 2.9 Hz, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.15 — 4.04 (m, 1H), 3.90 — 3.80 (m, 1H), 3.73 (t, J = 7.7 Hz, 2H), 3.66 (s, 2H), 3.61 (t, J = 5.2 Hz, 2H), 3.31 (dd, J= 13.9, 7.7 Hz, 1H), 3.17 (dd, J = 8.8, 4.9 Hz, 4H), 2.87 — 2.73 (m, 4H), 2.60 — 2.47 (m, 4H), 1.96 — 1.85 (m, 3H), 0.92 (t, J= 17.2 Hz, 3H). Example 95: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-isopropylazetidin-3-yl) oxy-2,3-dihydro-1,4-benzoxazepin-5-one “moots TO yc gp oo The matetial obtained in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetone was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 3 7.68 (d, J = 8.7 Hz, 1H), 7.18 — 7.01 (m, 4H), 6.67 (d, J = 8.9 Hz, 1H), 6.46 (s, 1H), 4.88 — 4.78 (m, 1H), 4.48 (t,J = 5.2 Hz, 2H), 428 — 4.17 (m, 1H), 4.02 — 3.93 (m, 1H), 3.86 — 3.65 (m, 6H), 3.42 (dd, J = 13.9, 7.7 Hz, 1H), 3.24 (t, J = 7.0 Hz, 2H), 3.00 —2.83 (m, 4H), 2.72 — 2.60 (m, 2H), 2.57 — 2.46 (m, 1H), 1.01 (d, / = 6.2 Hz, 6H). Example 96: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[1-(oxetan-3-ylyl)azetidin- 3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one To 3 . ro oF o- / ’ The matetial obtained in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that oxetan-3-one was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 8 7.69 (d, J = 8.7 Hz, 1H), 7.19 — 7.02 (m, 4H), 6.67 (d, J = 8.7 Hz, 1H), 6.47 (s, 1H), 4.77 (t, J = 6.9 Hz, 2H), 4.50 (dt, J = 15.6, 5.6 Hz, 4H), 4.25 (d, J = 6.3 Hz, 1H), 4.01 - 3.83 (m, 4H), 3.82 (s, 2H), 3.73 (d, J = 5.0 Hz, 2H), 3.44 (dd, J = 13.9, 7.5 Hz, 1H), 2.95 (s, 4H), 2.69 (d, J = 6.7 Hz, 2H). Example 97: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethylazetidin-3-yl) met hoxy}-2,3-dihydro-1,4-benzoxazepin-5-one o er C0 Ot The matetial obtained by changing tert-butyl 3-methylsulfonyloxyazetidin-1-carboxylate to tert-butyl 3-(methylsulfonyloxymethyl)azetidin-1-carboxylate in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetaldehyde was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) § 7.68 (d, J = 8.7 Hz, 1H), 7.17 — 7.01 (m, 4H), 6.76 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 4.48 (t, J = 5.0 Hz, 2H), 4.27 — 4.17 (m, 1H), 4.14 (d, J = 6.4 Hz, 2H), 3.98 (dd, J = 13.7, 3.5 Hz, 1H), 3.80 — 3.67 (m, 4H), 3.53 — 3.37 (m, 3H), 3.15 (1, J = 7.2 Hz, 2H), 3.01 — 2.89 (m, 3H), 2.90 — 2.80 (m, 2H), 2.70 — 2.61 (m, 2H), 2.57 (q, J = 7.4 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H). Example 98: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(1-methylpyrrolidin-3-yl) o0xy-2,3-dihydro-1,4-benzoxazepin-5-one . 0 note The matetial obtained by changing tert-butyl 3-methylsulfonyloxyazetidin-1-carboxylate to tert-butyl 4-methylsulfonyloxypyrrolidin-1-carboxylate in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound. '"H NMR (400 MHz, Methanol-ds) 7.67 (dd, J = 8.7, 2.0 Hz, 1H), 7.11 (d, J = 3.3 Hz, 3H), 7.05 (d, J =6.7 Hz, 1H), 6.72 (dd, J = 8.8, 2.4 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 4.95 (d, J = 6.9 Hz, 1H), 4.47 (t, J= 5.3 Hz, 2H), 4.22 (d, J = 6.3 Hz, 1H), 3.98 (dd, J = 14.0, 3.4 Hz, 1H), 3.74 (d, J = 9.3 Hz, 4H), 3.42 (dd, J = 14.0, 7.7 Hz, 1H), 3.00 — 2.81 (m, 8H), 2.64 (d, J = 6.2 Hz, 2H), 2.53 -2.45 (m, 1H), 2.41 (s, 3H), 2.07 — 1.93 (m, 2H), 1.32 (d, J = 6.0 Hz, 1H). Example 99: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(3R)-1-ethylpyrrolidin-3- yljoxy-2,3-dihydro-1,4-benzoxazepin-5-one 0 “1 oreo Nn a The matetial obtained by changing rert-butyl 3-methylsulfonyloxyazetidin-1-carboxylate to tert-butyl (3S)-3-methylsulfonyloxypyrrolidin-1-carboxylate in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetaldehyde was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) § 7.61 (d, J = 8.7 Hz, 1H), 7.10 — 6.95 (m, 4H), 6.66 (d, J = 8.9 Hz, 1H), 6.48 (s, 1H), 4.94 (s, 1H), 4.41 (1, J = 5.0 Hz, 2H), 4.21 — 4.11 (m, 1H), 3.90 (d, J = 16.4 Hz, 1H), 3.72 (s, 2H), 3.66 (t, J = 5.1 Hz, 2H), 3.37 (dd, J = 14.0, 7.5 Hz, 1H), 3.03 —2.77 (m, 7H), 2.72 = 2.53 (m, 5H), 2.40 — 2.29 (m, 1H), 1.98 (dd, J = 10.0, 7.6 Hz, 2H), 1.13 (t, J = 7.3 Hz, 3H). Example 100: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(2-pyridyloxy)-2,3-dihydr 0-1,4-benzoxazepin-5-one oO 0) [0] The title compound was synthesized in the same manner as in Example 64, except that cesium carbonate was used instead of potassium carbonate, and 2-fluoropyridine was used instead of 4-chlorotetrahydropyran. '"H NMR (400 MHz, Chloroform-d) & 8.26 (d, J = 5.2 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.22 — 6.94 (m, 7H), 6.73 (d, J = 2.2 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 4.16 — 4.01 (m, 1H), 3.91 — 3.77 (m, 1H), 3.69 (1, J = 14.7 Hz, 2H), 3.52 (d, J = 14.5 Hz, 1H), 3.06 — 2.87 (m, 3H), 2.80 (d, J = 8.8 Hz, 1H), 2.68 — 2.53 (m, 2H), 2.05 (d, J = 11.5 Hz, 1H), 1.63 (d, J =6.0 Hz, 1H), 1.01 — 0.73 (m, 1H). Example 101: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[[(2S)-1-isopropylpyrrolid in-2-yljmethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 3 Lol C0 The matetial obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl (2R)-2-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetone was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 8 7.62 (d, J = 8.7 Hz, 1H), 7.08 — 7.03 (m, 3H), 6.98 (d, J = 6.7 Hz, 1H), 6.78 — 6.69 (m, 1H), 6.56 (d, J= 2.4 Hz, 1H), 4.41 (t, J = 5.1 Hz, 2H), 4.16 (s, 1H), 4.03 (d, J = 5.7 Hz, 2H), 3.94 — 3.85 (m, 1H), 3.73 - 3.62 (m, 4H), 3.37 (dd, J = 13.7, 7.6 Hz, 2H), 3.22 - 3.15 (m, 1H), 2.95 (d, J= 9.3 Hz, 1H), 2.89 — 2.80 (m, 4H), 2.60 (d, J = 6.4 Hz, 2H), 2.08 (t,J=9.4 Hz, 1H), 1.98 — 1.79 (m, 5H), 1.24 (d, J= 6.7 Hz, 5H), 1.19 (d, J= 6.5 Hz, 3H). Example 102: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidyl)me thoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 0 Q ~~ \ OH No o- NO The matetial obtained by changing erz-butyl 3-methylsulfonyloxyazetidin-1-carboxylate to tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.59 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 5.1 Hz, 3H), 7.00 (d, J =17.0 Hz, 1H), 6.80 — 6.60 (m, 1H), 6.51 (d, J=2.6 Hz, 1H), 5.42 (d, J = 1.7 Hz, 1H), 4.39 (t, J = 5.2 Hz, 2H), 4.29 — 4.07 (m, 1H), 4.01 — 3.74 (m, 5H), 3.65 (t, J = 5.0 Hz, 2H), 3.47 (d, J= 7.2 Hz, 2H), 3.32 (d, J = 12.1 Hz, 2H), 3.25 (p, J = 1.7 Hz, 3H), 2.90 (s, 4H), 2.76 (t, J = 12.5 Hz, 2H), 2.71 — 2.57 (m, 6H), 2.05 — 1.92 (m, 4H), 1.55 (d, J = 12.9 Hz, 2H), 1.11 (t, J = 7.0 Hz, 1H). Example 103: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)met hoxy}-2,3-dihydro-1,4-benzoxazepin-5-one ~ NU o aio \ OH (Yoo NO The matetial obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetaldehyde was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) § 7.60 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 4.4 Hz, 4H), 7.00 (d, J =6.0 Hz, 1H), 6.69 (d, J = 8.9 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 4.40 (t,J= 5.1 Hz, 2H), 4.18 (s, 1H), 3.89 (d, J= 5.2 Hz, 3H), 3.79 (s, 2H), 3.66 (t, J= 5.1 Hz, 2H), 3.44 (ddt, J = 21.3, 13.9, 6.9 Hz, 4H), 3.29 (s, 1H), 3.02 (q, J = 7.4 Hz, 2H), 2.91 (s, 4H), 2.81 (t, J = 12.8 Hz, 2H), 2.66 (d, J =7.8 Hz, 2H), 2.03 (d, J = 14.1 Hz, 4H), 1.59 (d, J= 13.0 Hz, 1H), 1.26 (t, J= 7.3 Hz, 5H) Example 104: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylmorpholin-2-yl )methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 0 Q 0 o \ OH Ooo J The matetial obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl 2-(methylsulfonyloxymethyl)morpholine-4-carboxylate in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-da) 8 7.67 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 4.0 Hz, 3H), 7.06 (s, 1H), 6.77 (d, J = 8.9 Hz, 1H), 6.60 (s, 1H), 4.48 (t, J = 4.9 Hz, 2H), 4.23 (s, 1H), 4.12 — 3.86 (m, 5H), 3.80 - 3.66 (m, 5H), 3.56 — 3.35 (m, 1H), 2.91 (dd, J = 20.1, 6.0 Hz, 5H), 2.74 (d, J= 11.8 Hz, 1H), 2.67 — 2.56 (m, 2H), 2.35 (s, 3H), 2.26 — 2.16 (m, 1H), 2.07 (q, J = 9.9, 8.9 Hz, 2H). Example 105: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-ethylmorpholin-2-yl) methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 0 0 a J OH r 0 o Cy The matetial obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl 2-(methylsulfonyloxymethyl)morpholine-4-carboxylate in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetaldehyde was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-d) 8 7.68 (d, J = 8.8 Hz, 1H), 7.12 (s, 3H), 7.07 (s, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.60 (s, 1H), 4.48 (s, 2H), 4.24 (s, 1H), 4.13 — 3.86 (m, 5H), 3.75 (d, J =22.3 Hz, 5H), 3.51 — 3.37 (m, 2H), 2.93 (td, J = 30.3, 29.0, 11.6 Hz, 6H), 2.68 (s, 2H), 2.51 (q, J=7.3 Hz, 2H), 2.20 (d, J = 11.2 Hz, 2H), 2.05 (d, J = 10.7 Hz, 4H), 1.30 (d, / = 9.4 Hz, 4H), 1.15 (t, J =7.3 Hz, 3H). Example 106: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methylpyrrolidin-3-yl) methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 0 CF The matetial obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl 3-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 3.6 Hz, 3H), 7.06 (s, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.58 (s, 1H), 4.47 (t, J = 5.2 Hz, 2H), 4.23 (s, 1H), 3.97 (t, / =7.8 Hz, 3H), 3.74 (d, J = 11.0 Hz, 4H), 3.42 (dd, J= 14.0, 7.7 Hz, 1H), 2.93 (d, J= 5.7 Hz, 2H), 2.89 —2.82 (m, 3H), 2.74 — 2.62 (m, 4H), 2.54 (t, J = 8.2 Hz, 1H), 2.43 (s, 3H), 2.12 (t, J= 11.3 Hz, 1H), 2.05 (d, / =9.8 Hz, 1H), 1.69 (dd, J= 13.2, 6.7 Hz, 1H). Example 107: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(1-methyl-3-piperidyl)me thoxy]-2,3-dihydro-1,4-benzoxazepin-5-one So The matetial obtained by changing tert-butyl 3-methylsulfonyloxyazetidin-1-carboxylate to tert-butyl 3-(methylsulfonyloxymethyl)piperidine-1-carboxylate in Example 83-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.66 (d, J = 8.7 Hz, 1H), 7.16 — 7.09 (m, 3H), 7.05 (d, J = 6.7 Hz, 1H), 6.75 (dd, J = 8.8, 2.4 Hz, 1H), 6.57 (d, J = 2.3 Hz, 1H), 4.47 (t, J = 5.1 Hz, 2H), 4.22 (s, 1H), 3.96 (ddd, J= 15.0, 11.6, 4.5 Hz, 3H), 3.86 (d, / = 7.7 Hz, 1H), 3.76 — 3.69 (m, 4H), 3.42 (dd, J = 13.9, 7.7 Hz, 1H), 3.04 (d, J = 11.3 Hz, 1H), 2.93 (d, J = 6.0 Hz, 3H), 2.87 (d, J = 5.6 Hz, 3H), 2.68 — 2.59 (m, 2H), 2.31 (d, J = 8.8 Hz, 4H), 2.02 (td, J = 11.9, 11.4, 6.9 Hz, 2H), 1.93 - 1.74 (m, 4H), 1.66 (d, J= 13.3 Hz, 1H), 1.20 — 1.09 (m, 1H). Example 108: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-6-fluoro-8-(morpholinomet hyl)-2,3-dihydro-1,4-benzoxazepin-5-one F F Fo 0” — 07 Hy — Cyr N Br: \ Br 3 Br 0 "Boc nS A hy] o— [ N or o Br: A wy gee Tet oe EIN ly oo No Example 108-1: Synthesis of methyl 4-bromo-2-[2-(tert-butoxycarbonylamino)ethoxy]-6-fluoro-benzoate Methyl 4-bromo-2,6-diflucro-benzoate (5.0 g, 19.9 mmol) was dissolved in 50 mL of tetrahydrofura, and 60% sodium hydride (1.03 g, 258 mmol) and tert-butyl N-(2-hydroxyethyl)carbamate (3.7 mL, 23.9 mmol) were slowly added thereto at 0°C, followed by stirring at the same temperature. To the reaction solution saturated aqueous chloroammonium solution and extracted with ethyl acetate 3 times. The oily liquid obtained by drying the combined organic layers over anhydrous magnesium sulfate and concentrating was purified by flash chromatography to obtain the title compound (5.07 g) as transparent liquid. Example 108-2: Synthesis of 8-bromo-6-fluoro-3,4-dihydro-2H-1,4-benzoxazepin-5-one Methyl 4-bromo-2-[2-(tert-butoxycarbonylamino)ethoxy]-6-fluoro-benzoate (5.07 g, 12.9 mmol) obtained in Example 108-1 was dissolved in 20 mL of methanol, and 4 M hydrochloric acid solution dissolved in 1,4-dioxane (20 mL, 80 mmol) was added thereto. The reaction solution was stirred at room temperature, and sodium hydroxide aqueous solution was added under an ice bath to basify, followed by extraction with ethyl acetate 3 times. The oily liquid obtained by drying the combined organic layers over anhydrous magnesium sulfate and concentrating under reduced pressure was purified by flash chromatography to obtain the solid 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-6-fluoro-2,3-dihyd ro-1,4-benzoxazepin-5-one 8-Bromo-6-fluoro-3,4-dihydro-2H-1,4-benzoxazepin-5-one obtained in Example 108-2 as a starting material was used in the same manner as in Example 5 to obtain the title compound. Example 108-4: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-(morpholinomet hyl)-2,3-dihydro-1,4-benzoxazepin-5-one 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-2,3-d ihydro-1,4-benzoxazepin-5-one obtained in Example 108-3 as a starting material was used in the same manner as in Example 22 to obtain the title compound. 'H NMR (400 MHz, Methanol-da) & 7.12 (d, J = 3.8 Hz, 3H), 7.06 (d, J = 9.8 Hz, 2H), 6.95 (s, 1H), 4.43 (t, J = 5.6 Hz, 2H), 4.29 — 4.20 (m, 1H), 4.03 — 3.94 (m, 1H), 3.85 — 3.76 (m, 2H), 3.76 — 3.65 (m, 6H), 3.54 (s, 2H), 3.52 — 3.44 (m, 1H), 3.02 — 2.86 (m, 4H), 2.74 — 2.63 (m, 2H), 2.54 — 2.42 (m, 4H). Example 109: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-[(1-methyl-4-pip eridyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one SNA F / C, Arc 0 \' OH Or 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-hydroxy-2,3-dih ydro-1,4-benzoxazepin-5-one 8-Bromo-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-2,3-d ihydro-1,4-benzoxazepin-5-one obtained in Example 108-3 as a starting material was used in the same manner as in Example 56-1 to obtain the title compound. Example 109-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-[(1-methyl-4-pip eridyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-hydroxy-2,3 -dihydro-1,4-benzoxazepin-5-one as a starting material was used in the same manner as in Examples 77, 78-1 and 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) § 7.09 (d, J = 19.1 Hz, 4H), 6.65 (d, J = 12.2 Hz, 1H), 6.51 (s, 1H), 4.57 — 4.46 (m, 1H), 4.41 (1, J = 5.7 Hz, 2H), 4.28 — 4.16 (m, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.77 (s, 2H), 3.71 (t, J = 5.6 Hz, 2H), 3.45 (dd, J = 13.8, 7.6 Hz, 1H), 3.00 — 2.83 (m, 4H), 2.81 — 2.70 (m, 2H), 2.70 — 2.59 (m, 2H), 2.51 — 2.38 (m, 2H), 2.35 (s, 3H), 2.12 — 1.99 (m, 2H), 1.92 — 1.76 (m, 2H). Example 110: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(1-ethyl-4-piperidyl)oxy] -2,2-dimethyl-3H-1,4-benzoxazepin-5-one o - Br 0 or Br o+~ ECC o 0 WED Cadre Example 110-1: Synthesis of 7-bromo-2,2-dimethyl-chroman-4-one 1-(4-Bromo-2-hydroxyphenyl)ethanone (5.0 g, 23.2 mmol) was dissolved in 20 mL of methanol, and pyrrolidine (5 mL, 60.9 mmol) was added thereto and stirred for 30 minutes under an ice bath. To the reaction solution acetone (2.5 mL, 33.7 mmol) was added, heated to reflux for 4 hours, and water was added to terminate the reaction, followed by extraction with ethyl acetate 3 times. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated, dissolved in ethyl acetate, and filtered through a small amount of silica. The solution was concentrated under reduced pressure to obtain the title compound (4.7 g) as a crystalline solid without additional purification. Example 110-2: Synthesis of 8-bromo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazepin-5-one 7-Bromo-2,2-dimethyl-chroman-4-one (4.7 g, 18.6 mmol) obtained in Example 110-1 was dissolved in 25 mL of methanesulfonic acid, and sodium azide (1.81 g, 27.9 mmol) was slowly added thereto under an ice bath. The reaction solution was stirred at room temperature for 5 hours, and 1 M sodium hydroxide aqueous solution was slowly added while maintaining at 0°C under an ice bath. After basifying the reaction solution to pH 10 or more, ethyl acetate was added thereto and extracted 3 times. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was removed by evaporation under reduced pressure, and then recrystallized from dichloromethane and hexane to obtain the solid title compound. Example 110-3: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1 ,4-benzoxazepin-5-one 8-Bromo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazepin-5-one obtained in Example 110-2 as a starting material was used in the same manner as in Example 5 to obtain the title compound. Example 110-4: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,2-dimethyl-3H -1,4-benzoxazepin-5-one 8-Bromo-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl- 3H-1,4-benzoxazepin-5-one obtained in Example 110-3 as a starting material was used in the same manner as in Example 56-1 to obtain the title compound. Example 110-5: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-piperidyl o0xy)-3H-1,4-benzoxazepin-5-one dihydrochloride The material obtained in Example 110-4 as a starting material was used in the same manner as in Examples 77 and 78-1 to obtain the title compound. 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(1-ethyl-4-piperidyl)oxy| -2,2-dimethyl-3H-1,4-benzoxazepin-5-one The material obtained in Example 110-5 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetaldehyde was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 8 7.58 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 19.8 Hz, 4H), 6.81 (d, J=28.9 Hz, 1H), 6.52 (s, 1H), 4.58 — 4.48 (m, 1H), 4.32 - 4.22 (m, 1H), 4.03 (d, J= 13.7 Hz, 1H), 3.76 (s, 2H), 3.50 (s, 2H), 3.41 (dd, J = 10.0, 3.2 Hz, 1H), 2.97 - 2.90 (m, 2H), 2.91 — 2.76 (m, 4H), 2.71 = 2.59 (m, 2H), 2.59 — 2.41 (m, 4H), 2.14 - 1.98 (m, 2H), 1.94 — 1.78 (m, 2H), 1.43 (s, 3H), 1.34 (s, 3H), 1.16 (t, J= 7.2 Hz, 3H). Example 111: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morpholino methyl)-3H-1,4-benzoxazepin-5-one Cove 0 o£ 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl- 3H-1,4-benzoxazepin-5-one as a starting material was used in the same manner as in Example 22 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) § 7.61 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.17 — 7.02 (m, 4H), 7.00 (s, 1H), 4.34 — 4.24 (m, 1H), 4.06 (dd, J = 13.7, 2.6 Hz, 1H), 3.78 (s, 2H), 3.71 (t,J = 4.7 Hz, 4H), 3.56 (s, 2H), 3.53 — 3.38 (m, 3H), 2.99 — 2.81 (m, 4H), 2.72 — 2.58 (m, 2H), 2.48 (1, J = 4.8 Hz, 4H), 1.43 (s, 3H), 1,33 (s, 3H). Example 112: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-2,2-dimethyl-8-[(1-methyl-4 -piperidyl)oxy]-3H-1,4-benzoxazepin-5-one Cogs oA The material obtained in Example 110-5 as a starting material was used in the same manner as in Example 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.57 (d, J = 8.6 Hz, 1H), 7.17 — 7.02 (m, 4H), 6.81 (d, J = 8.7 Hz, 1H), 6.52 (s, 1H), 4.56 — 4.46 (m, 1H), 4.33 — 4.21 (m, 1H), 4.03 (d, J = 13.3 Hz, 1H), 3.75 (s, 2H), 3.50 (s, 2H), 3.40 (dd, J = 14.0, 8.1 Hz, 1H), 2.98 —- 2.81 (m, 4H), 2.80 — 2.66 (m, 2H), 2.66 — 2.54 (m, 2H), 2.51 - 2.39 (m, 2H), 2.34 (s, 3H), 2.10 — 1.98 (m, 2H), 1.89 — 1.76 (m, 2H), 1.43 (s, 3H), 1.34 (s, 3H). Example 113: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-pyridylm ethoxy)-3H-1,4-benzoxazepin-5-one ETO \ OH No 0-L 0A The material obtained in Example 110-4 as a starting material was used in the same manner as in Example 56-2 to obtain the title compound, except that 4-(chloromethyl)pyridine hydrochloride was used instead of 3-(chloromethyl)pyridine hydrochloride. 'H NMR (400 MHz, Methanol-ds) § 8.56 (d, J = 5.2 Hz, 2H), 7.61 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 5.1 Hz, 2H), 7.17 — 7.00 (m, 4H), 6.90 (d, J = 8.8 Hz, 1H), 6.62 (s, 1H), 5.25 (s, 2H), 4.32 — 4.22 (m, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.76 (s, 2H), 3.50 (s, 2H), 3.41 (dd, J = 13.9, 8.2 Hz, 1H), 2.97 — 2.82 (m, 4H), 2.66 — 2.57 (m, 2H), 1.42 (s, 3H), 1.32 (s, 3H). Example 114: Synthesis of 8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl] -2,2-dimethyl-3H-1,4-benzoxazepin-5-one 0 Mo ros 0 ot The material obtained in Example 110-4 as a starting material was used in the same manner as in Example 83 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) § 7.61 (d, J = 8.6 Hz, 1H), 7.16 — 7.02 (m, 4H), 6.72 (d, J = 8.1 Hz, 1H), 6.44 (s, 1H), 5.15 — 5.05 (m, 1H), 4.69 — 4.59 (m, 1H), 4.47 — 4.37 (m, 1H), 4.33 — 4.19 (m, 2H), 4.10 — 4.00 (m, 1H), 4.01 — 3.92 (m, 1H), 3.76 (s, 2H), 3.50 (s, 2H), 3.40-3.33 (m, 1H), 2.99 — 2.81 (m, 4H), 2.67 — 2.58 (m, 2H), 1.93 (s, 3H), 1.43 (s, 3H), 1.34 (s, 3H). Example 115: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-1-methyl-8-(morpholinomet hyl)-2,3-dihydro-1,4-benzodiazepin-5-one 0 9 OD 0 Example Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-1-methyl-2,3-dihy dro-1,4-benzodiazepin-5-one 8-Bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one as a starting material was used in the same manner as in Example 5 to obtain the title compound. Example 115-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-1-methyl-8-(morpholinomet hyl)-2,3-dihydro-1,4-benzodiazepin-5-one 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3- dihydro-1,4-benzodiazepin-5-one as a starting material was used in the same manner as in Example 22 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.49 (d, J = 8.0 Hz, 1H), 7.15 — 7.08 (m, 2H), 7.09 — 7.03 (m, 1H), 7.01 (d, J = 7.0 Hz, 2H), 4.29 — 4.20 (m, 1H), 3.94 (dd, J = 14.0, 4.0 Hz, 1H), 3.78 (s, 2H), 3.72 (t, J = 4.7 Hz, 4H), 3.65 — 3.57 (m, 2H), 3.55 (s, 2H), 3.50 (t, J = 7.4 Hz, 1H), 3.48 — 3.36 (m, 3H), 3.00 — 2.88 (m, 4H), 2.86 (s, 3H), 2.69 (1, J = 5.4 Hz, 2H), 2.49 (s, 4H). Example 116: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(3,3,3-trifluorop ropyl)-2,3-dihydro-1,4-benzodiazepin-5-one o —N \ OH 0 ~ 1 Pr 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3- dihydro-1,4-benzodiazepin-5-one as a starting material was used in the same manner as in Example 10 to obtain the title compound, except that 3,3,3-trifluoropropylboronic acid was used instead of methylboronic acid. 'H NMR (400 MHz, Chloroform-d) 8 7.59 (d, J = 7.8 Hz, 1H), 7.14 (q, J = 5.6, 5.1 Hz, 3H), 7.09 —- 6.91 (m, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.67 (s, 1H), 4.11 (s, 1H), 3.98 — 3.76 (m, 2H), 3.73 — 3.48 (m, 4H), 3.41 (dt, J=11.8, 6.0 Hz, 1H), 3.30 (dt, / = 10.8, 5.3 Hz, 1H), 2.94 (d, J= 11.3 Hz, 2H), 2.87 (d, J = 8.0 Hz, 5H), 2.84 (s, 1H), 2.75 (s,1H), 2.68 (dd, J = 12.5, 4.2 Hz, 1H), 2.65 — 2.56 (m, 1H), 2.39 (dq, J = 20.0, 10.5 Hz, 2H), 1.00 — 0.78 (m, 2H). Example 117: Synthesis of 8-(cyclohexylmethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-met hyl-2,3-dihydro-1,4-benzodiazepin-5-one Oo 1 2 N 1 3 nN 1 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3- dihydro-1,4-benzodiazepin-5-one as a starting material was used in the same manner as in Example 10 to obtain the title compound, except that cyclohexylmethylboronic acid was used instead of methylboronic acid. 'H NMR (400 MHz, Chloroform-d) 8 7.53 (d, J = 7.8 Hz, 1H), 7.24 — 7.04 (m, 3H), 7.02 (d, J = 6.7 Hz, 1H), 6.78 (d, J= 7.8 Hz, 1H), 6.61 (s, 1H), 4.12 (s, 1H), 3.85 (dd, J = 17.6, 14.1 Hz, 2H), 3.74 - 3.52 (m, 4H), 3.39 (dt, J = 11.7, 5.9 Hz, 1H), 3.33 — 3.21 (m, 1H), 2.95 (s, 1H), 2.82 (s, 2H), 2.77 (d, J =9.0 Hz, 1H), 2.71 — 2.59 (m, 2H), 2.46 (d, J= 7.1 Hz, 2H), 1.68 (d, / = 11.4 Hz, 5H), 1.32-1.13 (m, 5H), 0.93 (q, J = 13.8, 12.4 Hz, 3H). Example 118: Synthesis of 8-(cyclohexen-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methy 1-2,3-dihydro-1,4-benzodiazepin-5-one 0 Qo 2 ASA ! 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3- dihydro-1,4-benzodiazepin-5-one as a starting material was used in the same manner as in Example 10 to obtain the title compound, except that 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of methylboronic acid. 'H NMR (400 MHz, Chloroform-d) 8 7.57 (d, J = 8.0 Hz, 1H), 7.19 — 7.07 (m, 3H), 7.01 (t, J = 6.2 Hz, 2H), 6.86 (s, 1H), 6.17 (s, 1H), 4.12 (d, J = 7.3 Hz, 1H), 3.97 - 3.76 (m, 2H), 3.70 - 3.44 (m, 4H), 3.38 (dt, / =11.9, 6.1 Hz, 1H), 3.27 (dt, J= 10.6, 5.2 Hz, 1H), 2.91 (d, J = 5.3 Hz, 4H), 2.85 (s, 3H), 2.75 (t, J = 7.8 Hz, 1H), 2.70 — 2.56 (m, 2H), 2.40 (s, 2H), 2.25 - 2.18 (m, 2H), 2.17 (s, 1H), 2.05 (s, 1H), 1.78 (q, J = 6.2, 5.3 Hz, 2H), 1.67 (t, J = 5.8 Hz, 2H), 1.30 — 1.20 (m, 1H). Example 119: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[4-(trifluoromet hyl)cyclohexen-1-yl]-2,3-dihydro-1,4-benzodiazepin-5-one oO o ~~ \ OH N Nn F i Fe 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3- dihydro-1,4-benzodiazepin-5-one as a starting material was used in the same manner as in Example 10 to obtain the title compound, except that 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane was used instead of methylboronic acid. 'H NMR (400 MHz, Chloroform-d) & 7.59 (d, J = 7.9 Hz, 1H), 7.19 - 7.07 (m, 3zH), 7.00 (dd, J = 13.6, 7.3 Hz, 2H), 6.84 (s, 1H), 6.11 (d, J = 5.1 Hz, 1H), 4.11 (t, J = 7.1 Hz, 2H), 3.95 — 3.76 (m, 2H), 3.65 (s, 1H), 3.60 (dd, J = 10.0, 4.6 Hz, 3H), 3.39 (dt, / = 10.4, 5.1 Hz, 1H), 3.29 (dq, J = 104, 5.2 Hz, 1H), 2.92 (q, J = 8.0, 6.0 Hz, 4H), 2.85 (s, 3H), 2.75 (dd, J = 10.8, 5.0 Hz, 1H), 2.69 2.58 (m, 2H), 2.57 — 2.43 (m, 2H), 2.42 — 2.24 (m, 1H), 2.23 — 2.14 (m, 1H), 2.05 (s, 1H), 1.69 (qd, J = 11.9, 5.8 Hz, 1H), 1.43 — 1.18 (m, 1H). Example 120: Synthesis of tert-butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo-2,3-dihy dro-1,4-benzodiazepin-8-yl}-3,6-dihydro-2H-pyridine-1-carboxylate Oo 0 9 CO B; CH S N yr" 0 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3- dihydro-1,4-benzodiazepin-5-one as a starting material was used in the same manner as in Example 10 to obtain the title compound, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate was used instead of methylboronic acid. 'H NMR (400 MHz, Chloroform-d) & 7.60 (d, J = 8.0 Hz, 1H), 7.18 - 7.08 (m, 3H), 7.01 (t, J = 8.8 Hz, 2H), 6.84 (s, 1H), 6.08 (s, 1H), 4.21 — 4,04 (m, 3H), 4.01 - 3.75 (m, 2H), 3.74 — 3.52 (m, 5H), 3.48 — 3.35 (m, 1H), 3.36 — 3.24 (m, 1H), 2.92 (s, 2H), 2.85 (s, 3H), 2.74 (s, 1H), 2.72 - 2.56 (m, 2H), 2.52 (s, 2H), 2.05 (s, 1H), 1.49 (s, 7H), 1.31 — 1.21 (m, 2H). Example 121: Synthesis of 8-[(1-acetyl-4-piperidyl)oxy|-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl ]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one ty oe 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3- dihydro-1,4-benzodiazepin-5-one as a starting material was used in the same manner as in Example 56-1 to obtain the title compound Example 121-2: Synthesis of 8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl |-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one The title compound was synthesized in the same manner as in Example 64, except that (1-acetyl-4-piperidyl) methanesulfonate was used instead of 4-chlorotetrahydropyran. 'H NMR (400 MHz, Chloroform-d) § 7.61 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 8.2 Hz, 3H), 7.02 (d, J=6.7 Hz, 1H), 6.51 (d, J = 8.6 Hz, 1H), 6.38 (s, 1H), 4.59 (s, 1H), 4.11 (t, J="7.1 Hz, 2H), 3.99 —3.81 (m, 1H), 3.84 — 3.72 (m, 2H), 3.74 — 3.56 (m, 6H), 3.42 (dd, / = 11.6, 5.8 Hz, 2H), 3.36 — 3.25 (m, 1H), 2.91 (d, J = 8.7 Hz, 3H), 2.81 (s, 3H), 2.75 (s, 1H), 2.69 — 2.53 (m, 2H), 2.13 (d, J =1.5 Hz, 3H), 2.05 (d, J = 1.5 Hz, 1H), 1.98 — 1.77 (m, 5H), 1.44 — 1.15 (m, 2H), 1.09 — 0.81 (m, 1H). Example 122: Synthesis of 8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl] -1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one i Hi 2 vO The material obtained in Example 121-1 as a starting material was used in the same manner as in Example 83 to obtain the title compound. 'H NMR (400 MHz, Chloroform-d) & 7.61 (d, J = 8.4 Hz, 1H), 7.19 — 7.07 (m, 3H), 7.02 (d, J = 6.7 Hz, 1H), 6.44 — 6.16 (m, 2H), 4.97 (t, J = 5.7 Hz, 1H), 4.49 (t, J = 8.0 Hz, 1H), 4.39 (dd, J = 10.9, 6.6 Hz, 1H), 4.28 — 3.99 (m, 4H), 3.95 — 3.72 (m, 2H), 3.75 — 3.50 (m, 4H), 3.52 — 3.26 (m, 2H), 2.93 (q, J = 9.0, 6.9 Hz, 3H), 2.81 (s, 3H), 2.78 — 2.54 (m, 3H), 2.05 (s, 1H), 1.92 (s, 3H), 1.26 (t,J = 7.2 Hz, 1H). Example 123: Synthesis of 8-[(3R)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one [eo] Joe The material obtained in Example 121-1 as a starting material and the intermediate obtained by changing 4-chlorotetrahydropyran to tert-butyl (38)-3-methylsulfonyloxypyrrolidin-1-carboxylate in Example 64 were used in the same manner as in Example 78 to obtain the title compound. '"H NMR (400 MHz, Methanol-ds) 8 7.51 (dd, J = 8.7, 3.2 Hz, 1H), 7.29 — 7.03 (m, 4H), 6.68 — 6.34 (m, 2H), 5.15 (d, J = 22.7 Hz, 1H), 4.27 (s, 1H), 3.99 — 3.84 (m, 3H), 3.79 — 3.57 (m, 6H), 3.55 - 3.39 (m, 2H), 3.01 (d, J = 8.8 Hz, 4H), 2.81 (d, J = 15.8 Hz, 5H), 2.40 — 2.14 (m, 2H), 2.16 — 1.90 (m, 5H), 1.31 (s, 3H). Example 124: Synthesis of 8-[(3S)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one oO The material obtained in Example 121-1 as a starting material and the intermediate obtained by changing 4-chlorotetrahydropyran to tert-butyl (3R)-3-methylsulfonyloxypyrrolidin-1-carboxylate in Example 64 were used in the same manner as in Example 78 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.57 — 7.45 (m, 1H), 7.15 (d, J = 4.5 Hz, 3H), 7.09 (s, 1H), 6.60 (d,J=7.9 Hz, 1H), 6.48 (d, J = 5.6 Hz, 1H), 5.15 (d, J = 22.7 Hz, 1H), 427 (s, 1H), 3.90 (d, J=14.7 Hz, 3H), 3.79 — 3.58 (m, SH), 3.59 — 3.41 (m, 2H), 2.99 (s, 4H), 2.80 (d, J = 23.3 Hz, 5H), 2.31 (s, 1H), 2.23 (s, 1H), 2.18 — 1.98 (m, 4H), 1.96 (s, 1H), 1.28 (d, J = 20.7 Hz, 2H). Example 125: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-1-methyl-8-[(1-methyl-4-pip eridyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one J [74 0=UlNYUT0=1,4=DCNZ0A1a Ze pPil=o 3, oy Co LA oAy I The material obtained in Example 121-1 as a starting material was used in the same manner as in Examples 77 and 78-1 to obtain the title compound. Example Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-4-pip eridyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one The material obtained in Example 125-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-da) 8 7.49 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 4.4 Hz, 3H), 7.08 (s, 1H), 6.62 (d, J = 8.7 Hz, 1H), 6.50 (s, 1H), 4.25 (s, 1H), 4.00 — 3.78 (m, 3H), 3.61 (d, J=5.7 Hz, 2H), 3.52 — 3.38 (m, 2H), 2.89 (d, J = 52.2 Hz, 8H), 2.73 (s, 3H), 2.49 (s, 3H), 2.05 (d, / = 11.4 Hz, 3H), 1.94 (s, 2H). Example 126: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(1-ethyl-4-piperidyl)oxy] -1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one SCD oS FF The material obtained in Example 125-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetaldehyde was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 8 7.50 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 3.0 Hz, 3H), 7.07 (d, J =6.9 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.51 (s, 1H), 4.65 (d, J = 9.6 Hz, 1H), 4.25 (s, 1H), 3.91 (dd, J=13.9, 3.9 Hz, 1H), 3.84 (s, 2H), 3.62 (t, J = 5.8 Hz, 2H), 3.51 — 3.36 (m, 3H), 3.18 - 3.04 (m, 2H), 2.96 (s, 4H), 2.85 (d, J = 12.9 Hz, 6H), 2.73 (t, J = 5.5 Hz, 2H), 2.14 (s, 2H), 2.09 — 1.93 (m, 3H), 1.35 —-1.10 (m, 5H). Example 127: Synthesis of 8-[(1-cyclobutyl-4-piperidyl)oxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-pr opyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one Sy, oe The material obtained in Example 125-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that cyclobutanone was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-da) § 7.41 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 3.0 Hz, 3H), 6.99 (s, 1H), 6.53 (d, J = 8.6 Hz, 1H), 6.41 (s, 1H), 4.47 (s, 1H), 4.15 (d, / = 6.7 Hz, 1H), 3.85 (d, J = 14.6 Hz, 1H), 3.71 (s, 2H), 3.54 (s, 2H), 3.37 (dt, J = 11.7, 6.3 Hz, 2H), 2.92 - 2.81 (m, 4H), 2.75 (s, 3H), 2.68 — 2.54 (m, 4H), 2.32 (s, 2H), 2.06 (s, 2H), 1.97 (d, / = 8.7 Hz, 4H), 1.88 (d, J = 9.6 Hz, 1H), 1.79 — 1.62 (m, 4H). Example 128: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-1-methyl-8-[(1-tetrahydrofu ran-3-yl-4-piperidyl)oxy}-2,3-dihydro-1,4-benzodiazepin-5-one 3 Q 8 > [OF ors \ © 0 N i The material obtained in Example 125-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that tetrahydrofuran-3-one was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 8 7.48 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 4.2 Hz, 3H), 7.06 (s, 1H), 6.60 (d, J = 8.6 Hz, 1H), 6.47 (s, 1H), 4.51 (d, J = 7.7 Hz, 1H), 4.23 (t, J = 5.9 Hz, 1H), 3.93 (tt, J = 12.0, 4.8 Hz, 6H), 3.78 (s, SH), 3.69 — 3.51 (m, 5H), 3.48 - 3.36 (m, 2H), 3.06 (t, J= 7.3 Hz, 1H), 2.94 (d, J= 5.3 Hz, 2H), 2.90 (d, J = 4.6 Hz, 2H), 2.82 (s, 3H), 2.74 —- 2.64 (m, 3H), 2.51 (t,J= 10.1 Hz, 1H), 2.41 (t, J = 9.8 Hz, 1H), 2.16 (dd, J = 13.1, 6.9 Hz, 2H), 2.04 (d, / = 9.5 Hz, 3H), 1.94 — 1.71 (m, 5H). Example 129: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[[1-(oxetan-3-yl) -4-piperidyl]oxy]-2,3-dihydro-1,4-benzodiazepin-5-one So OR bye ¥ The material obtained in Example 125-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that oxetan-3-one was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) 8 7.55 — 7.37 (m, 1H), 7.12 (d, J = 5.1 Hz, 3H), 7.06 (d, J = 6.8 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H), 6.47 (s, 1H), 4.71 (t, J = 6.7 Hz, 2H), 4.62 (t, J = 6.2 Hz, 2H), 4.53 (s, 1H), 4.23 (s, 1H), 3.94 (s, 1H), 3.79 (s, 2H), 3.69 (d, J = 4.9 Hz, 1H), 3.64 — 3.51 (m, 3H), 3.44 (dt, J= 13.1, 6.7 Hz, 2H), 2.93 (dd, J= 11.8, 4.7 Hz, 4H), 2.82 (s, 3H), 2.68 (d, J = 7.8 Hz, 2H), 2.62 (d, J = 12.0 Hz, 2H), 2.29 (t, J = 9.8 Hz, 2H), 2.04 (d, J = 10.2 Hz, 2H), 1.85 (s, 2H). Example 130: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-3-pip eridyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one [0] | vy ory SAAS 1 The material obtained in Example 121-1 as a starting material was used in the same manner as in Example 68 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 3 7.50 (dd, J = 8.6, 1.7 Hz, 1H), 7.12 (t, J = 2.5 Hz, 3H), 7.06 (d,J= 6.6 Hz, 1H), 6.61 (dd, J = 8.5, 2.5 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 4.28 — 4.20 (m, 1H), 4.08 (d, J = 5.3 Hz, 2H), 3.92 (dd, J = 14.2, 3.9 Hz, 1H), 3.78 (s, 2H), 3.62 (dt, J = 8.6, 4.5 Hz, 2H), 3.42 (ddd, J = 21.1, 15.3, 6.7 Hz, 2H), 3.17 (dt, J = 10.1, 4.3 Hz, 1H), 2.99 — 2.87 (m, 5H), 2.87 - 2.81 (m, 3H), 2.67 (1, J = 4.7 Hz, 2H), 2.57 (d, J = 1.8 Hz, 3H), 2.47 (q, J = 8.9 Hz, 1H), 2.14 (dd, J = 12.4, 8.3 Hz, 1H), 2.05 (d, J = 10.0 Hz, 2H), 1.93 — 1.73 (m, 4H), 1.31 (s, 3H). Example 131: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-1-methyl-8-[(1-methylpyrro lidin-3-yl)methoxy|-2,3-dihydro-1,4-benzodiazepin-5-one oO 0 re The material obtained in Example 121-1 as a starting material was used in the same manner as in Example 106 to obtain the title compound. "H NMR (400 MHz, Methanol-ds) 8 7.49 (d, J = 8.5 Hz, 1H), 7.11 (s, 3H), 7.06 (s, 1H), 6.58 (d, J=8.7 Hz, 1H), 6.48 (s, 1H), 4.23 (s, 1H), 4.07 — 3.87 (m, 3H), 3.76 (s, 2H), 3.61 (s, 2H), 3.51 - 3.40 (m, 2H), 2.91 (dd, J = 19.1, 5.4 Hz, 5H), 2.84 (s, 3H), 2.68 (d, J = 8.9 Hz, 5H), 2.56 (d, J = 8.0 Hz, 1H), 2.43 (d, J = 2.1 Hz, 3H), 2.05 (d, / = 9.6 Hz, 3H), 1.71 (d, J= 7.2 Hz, 1H), 1.57 (s, 1H), 0.91 (s, 2H). Example 132: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(1-methylpyrrol idin-3-yl)oxy-2,3-dihydro-1,4-benzodiazepin-5-one | Oo wv The material obtained in Example 121-1 as a starting material was used in the same manner as in Example 98 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) & 7.49 (d, J = 8.5 Hz, 1H), 7.11 (s, 3H), 7.07 (s, 1H), 6.53 (d, J=8.6 Hz, 1H), 6.44 (s, 1H), 4.98 (s, 1H), 4.23 (s, 1H), 3.93 (d, J = 13.8 Hz, 1H), 3.77 (s, 2H), 3.62 (s, 2H), 3.44 (dd, J = 14.5, 7.2 Hz, 2H), 2.91 (dd, J = 18.9, 6.2 Hz, 6H), 2.83 (s, 3H), 2.66 (d, J = 7.7 Hz, 2H), 2.49 (d, J = 8.0 Hz, 1H), 242 (s, 3H), 2.05 (d, J = 10.2 Hz, 3H), 1.31 (s, 4H). Example 133: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-3-pip eridyl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one 0 0 ~N The material obtained in Example 121-1 as a starting material was used in the same manner as in Example 107 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) § 7.48 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 4.7 Hz, 3H), 7.06 (s, 1H), 6.57 (d, J = 8.6 Hz, 1H), 6.47 (s, 1H), 4.22 (s, 1H), 4.00 — 3.84 (m, 4H), 3.76 (s, 2H), 3.61 (d,J= 5.4 Hz, 2H), 3.44 (dd, J = 14.2, 7.8 Hz, 2H), 3.05 (d, J = 12.9 Hz, 1H), 2.93 (d, / = 6.0 Hz, 5H), 2.85 (d, J = 16.2 Hz, 6H), 2.65 (d, J = 7.2 Hz, 2H), 2.30 (dd, J = 10.2, 1.7 Hz, SH), 2.14 (s, 2H), 2.09 — 1.81 (m, 4H), 1.77 (s, 1H). Example 134: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl)meth oxy|-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one HEC LILY Imo )mUIH YUE U1 4" CHAU U IA LL], 3, ~ C2 F oy OH yo Nn N ~ ! The material obtained in Example 121-1 as a starting material was used in the same manner as in Example 56-2 to obtain the title compound, except that (3-fluoro-4-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride. 'H NMR (400 MHz, Methanol-ds) 3 8.50 (s, 1H), 8.44 (d, J = 5.0 Hz, 1H), 7.67 (t, J = 5.8 Hz, 1H), 7.52 (dd, J = 8.7, 2.0 Hz, 1H), 7.20 — 7.00 (m, 4H), 6.68 (dd, J = 8.7, 2.6 Hz, 1H), 6.60 (d, J = 2.8 Hz, 1H), 5.33 (s, 2H), 4.23 (s, 1H), 3.95 — 3.87 (m, 1H), 3.77 (s, 2H), 3.62 (5, 2H), 3.49 — 3.37 (m, 3H), 2.92 (dd, J = 15.9, 5.2 Hz, 4H), 2.84 (d, J = 2.0 Hz, 3H), 2.74 — 2.62 (m, 2H), 1.31 (s, 1H). Example 135: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-piperidyl)oxy ]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; dihydrochloride oO F { 2HCI OO HN ot NE Nos F / 2HCI The intermediate in which Boc is substituted was synthesized by using the material obtained in Example 121-1 as a starting material and changing 4-chlorotetrahydropyran to tert-butyl 3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate in Example 64. The obtained intermediate was dissolved in methanol, and 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added thereto. The reaction solution was stirred at room temperature until the reaction was terminated, diluted with ethyldiethyl ether and filtered to obtain the title compound as a white solid in the form of dihydrochloride. 'H NMR (400 MHz, Methanol-ds) § 7.63 (d, J = 8.5 Hz, 1H), 7.31 (q, J = 7.5 Hz, 3H), 7.24 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.89 (s, 1H), 5.06 (d, J = 44.3 Hz, 2H), 4.74 — 4.58 (m, 1H), 4.49 (td, J = 15.4, 14.0, 7.3 Hz, 2H), 3.93 — 3.86 (m, 1H), 3.80 (d, J = 9.6 Hz, 1H), 3.74 — 3.63 (m, 6H), 3.60 (s, 1H), 3.52 (d, J = 15.3 Hz, 2H), 3.44 — 3.35 (m, 2H), 3.25 — 3.14 (m, 1H), 3.02 (s, 3H), 2.44 — 2.30 (m, 1H), 2.19 (d, J = 15.7 Hz, 1H). Example 136: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(1-ethyl-3-fluoro-4-piperi dyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one F lI Q N ANN ory oC “Aor Ags F 1 The material obtained in Example 135 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetaldehyde was used instead of paraformaldehyde. '"H NMR (400 MHz, Methanol-ds) 8 7.49 (dd, J = 8.6, 1.9 Hz, 1H), 7.12 (d, J = 3.1 Hz, 3H), 7.06 (d, J= 6.7 Hz, 1H), 6.65 (d, J = 8.6 Hz, 1H), 6.53 (d, J = 2.6 Hz, 1H), 4.67 (d, J = 48.8 Hz, 1H), 4.52 (s, 1H), 4.23 (s, 1H), 3.92 (dd, J = 13.7, 3.8 Hz, 1H), 3.78 (s, 2H), 3.62 (s, 2H), 3.45 (dd, J =14.4,7.6 Hz, 2H), 3.14 — 3,02 (m, 1H), 2,94 (d, J = 5.2 Hz, 3H), 2.90 (d, J = 4.6 Hz, 2H), 2.83 (d, J= 1.8 Hz, 3H), 2.68 (t, J = 5.4 Hz, 2H), 2.55 (d, / = 7.2 Hz, 1H), 2.46 (d, J = 8.2 Hz, OH), 2.34 (t,J=10.8 Hz, 1H), 2.21 (s, 1H), 1.77 (dd, J = 12.9, 8.8 Hz, 1H), 1.19 — 1.11 (m, 3H). Example 137: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(8-ethyl-8-azabicyclo[3.2. 1]octan-3-yl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one | (0 “20 oN 8-(8-azabicyclo[3.2.1]octan-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy -propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one dihydrochloride The intermediate in which Boc is substituted was synthesized by using the material obtained in Example 121-1 as a starting material and changing 4-chlorotetrahydropyran to tert-butyl 3-methylsulfonyloxy-8-azabicyclo [3.2.1]octane-8-carboxylate in Example 64. The obtained intermediate was dissolved in methanol, and 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added thereto. The reaction solution was stirred at room temperature until the reaction was terminated, diluted with ethyldiethyl ether and filtered to obtain the title compound as a white solid in the form of dihydrochloride. Example 137-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyclo[3.2. 1]octan-3-yl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one The material obtained in Example 137-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that acetaldehyde was used instead of paraformaldehyde. 'H NMR (400 MHz, Methanol-ds) § 7.66 — 7.39 (m, 1H), 7.12 (d, J = 4.9 Hz, 3H), 7.05 (d, J = 6.7 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 4.80 (dg, J = 10.7, 5.6, 4.9 Hz, 1H), 4.22 (d, J = 8.0 Hz, 1H), 3.94 — 3.87 (m, 1H), 3.77 (s, 2H), 3.69 (s, 2H), 3.61 (dd, J = 7.5, 3.6 Hz, 2H), 3.43 (dt, J = 11.7, 6.2 Hz, 2H), 2.93 (d, J = 5.5 Hz, 2H), 2.89 (d, J = 5.3 Hz, 2H), 2.82 (s, 4H), 2.71 — 2.54 (m, 2H), 2.30 — 2.13 (m, 4H), 2.03 (d, J = 1.6 Hz, 1H), 1.97 — 1.84 (m, 5H), 1.24 (t, J =7.1 Hz, 4H). Example 138: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(2-methyl-4-pip eridyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one; dihydrochloride i o N Pye O Nn 2HCI The intermediate in which Boc is substituted was synthesized by using the material obtained in Example 121-1 as a starting material and changing 4-chlorotetrahydropyran to tert-butyl 2-methyl-4-methylsulfonyloxy-piperidine-1-carboxylate in Example 64. The obtained intermediate was dissolved in methanol, and 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added thereto. The reaction solution was stirred at room temperature until the reaction was terminated, diluted with ethyldiethyl ether and filtered to obtain the title compound as a white solid in the form of dihydrochloride. 'H NMR (400 MHz, Methanol-ds) 8 7.60 (d, J = 8.6 Hz, 1H), 7.32 (q, J = 7.7, 7.1 Hz, 3H), 7.23 (d,J=1.7 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.76 (s, 1H), 4.75 (d, / = 11.8 Hz, 1H), 4.74 — 4.62 (m, 1H), 4.49 (td, J = 15.2, 12.9, 6.6 Hz, 2H), 3.89 (s, 1H), 3.84 — 3.75 (m, 1H), 3.73 — 3.61 (m, 3H), 3.51 (t, J = 17.0 Hz, 3H), 3.44 — 3.36 (m, 2H), 3.20 (q, J = 13.8 Hz, 2H), 3.00 (s, 3H), 2.42 (t, J=13.0 Hz, 1H), 1.80 (q, J = 11.8, 10.8 Hz, 1H), 1.68 — 1.57 (m, 1H), 1.42 (d, J = 6.4 Hz, 2H), 1.37 (d, J = 6.5 Hz, 1H). Example 139: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl)meth oxy|-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one r Q ~~ —o 3 OH JY The material obtained in Example 121-1 as a starting material was used in the same manner as in Example 56-2 to obtain the title compound, except that (5-fluoro-2-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride. 'H NMR (400 MHz, Methanol-d4) § 8.49 (s, 1H), 7.80 — 7.62 (m, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.11 (d,J=3.6 Hz, 3H), 7.06 (s, 1H), 6.65 (d, J = 8.7 Hz, 1H), 6.59 (s, 1H), 5.23 (s, 2H), 4.23 (s, 1H), 3.92 (d, J = 13.8 Hz, 1H), 3.77 (s, 2H), 3.62 (d, J = 5.4 Hz, 2H), 3.44 (dd, J = 13.3, 6.9 Hz, 2H), 2.94 (d, J = 5.5 Hz, 2H), 2.89 (d, J = 5.2 Hz, 2H), 2.82 (s, 3H), 2.71 — 2.60 (m, 2H). Example 140: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(4-piperidyloxy)- 2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride 0 ~ - 2x, oo — oA —- Sg Br OH Br OT""Boc Br oT 2 CIH o NH Br 0 CIH CIH 0° LEO — of I; ry HNN, 0 Lin ir od HO ol OH 0 =. Soyo Example 140-1: Synthesis of methyl 4-bromo-2-[2-(tert-butoxycarbonylamino)propoxy|benzoate Methyl 4-bromo-2-hydroxy-benzoate (3 g, 12.98 mmol), Cs2COs (12.7 g, 51.95 mmol) and [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate (7 mL, 25.98 mmol) were dissolved in acetonitrile, stirred for one day and heated to reflux. The reaction solution was cooled to room temperature, and distilled water was added thereto, followed by dilution with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by flash chromatography to obtain the title compound. Example 140-2: Synthesis of methyl 2-(2-aminopropoxy)-4-bromo-benzoate hydrochloride The material obtained in Example 140-1 as a starting material was dissolved in methanol, and 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added thereto, followed by strring at room temperature. The reaction solution was concentrated under reduced pressure to obtain the title compound without additional purification. Example 140-3: Synthesis of 8-bromo-2-methyl-3,4-dihydro-2H-1,4-benzoxazepin-5-one The material (2.3 g, 8.01 mmol) obtained in Example 140-2 was dissolved in toluene, and triethylamine was added thereto. The reaction solution was stirred and heated to reflux. After confirming that the reaction was complete, the reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure, The concentrate was purified by flash chromatography to obtain the title compound. Example 140-4: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihyd ro-1,4-benzoxazepin-5-one The material obtained in Example 140-3 as a starting material was used in the same manner as in Example 5 to obtain the title compound. 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-hydroxy-2-methyl-2,3-dih ydro-1,4-benzoxazepin-5-one The material obtained in Example 140-4 as a starting material was used in the same manner as in Example 56-1 to obtain the title compound. Example 140-6: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(4-piperidyloxy)- 2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride The material obtained in Example 140-5 as a starting material was used in the same manner as in Examples 77 and 78-1 to obtain the title compound. 'H NMR (400 MHz, Methanol-da) 8 7.66 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.4 Hz, 3H), 7.23 (s, 1H), 6.93 — 6.84 (m, 1H), 6.67 (s, 1H), 4.82 (s, 2H), 4.68 (d, J= 16.0 Hz, 1H), 4.48 (d, J = 10.0 Hz, 2H), 4.01 — 3.83 (m, 3H), 3.70 (d, J = 15.8 Hz, 2H), 3.58 —- 3.36 (m, 8H), 3.26 (d, J = 13.3 Hz, 3H), 3.08 (d, / = 26.7 Hz, 1H), 2.21 (s, 2H), 2.05 (d, J = 14.1 Hz, 3H), 1.76 (s, 1H), 1.34 (dd, J=14.1, 6.4 Hz, 3H). Example 141: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl|-2-methyl-8-[(1-methyl-4-pip eridyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one N Caves Cah 0 The material obtained in Example 140 as a starting material was used in the same manner as in Example 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) & 7.62 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 21.1 Hz, 3H), 6.80 (s, 1H), 6.57 (s, 1H), 4.55 (s, 1H), 4.25 (s, 1H), 4.15 (d, J = 14.1 Hz, 1H), 3.79 (s, 2H), 3.63 (d, J = 14.6 Hz, 1H), 3.49 (q, J = 7.6, 6.7 Hz, 1H), 3.27 — 3.15 (m, 1H), 2.93 (d, J = 13.9 Hz, 3H), 2.84 (s, 2H), 2.71 — 2.61 (m, 2H), 2.56 (s, 2H), 2.42 (s, 2H), 2.06 (s, 2H), 1.88 (s, 2H), 1.31 (dd, J = 16.5, 6.5 Hz, 3H). Example 142: Synthesis of (2R)-8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypro pyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one o a Jn “1 rs 0 The material obtained by changing [2-(fers-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate to [(1S)-2-(ferz-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 as a starting material was used in the same manner as in Example 83 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) § 7.66 (d, J = 8.6 Hz, 1H), 7.19 — 7.02 (m, 4H), 6.70 (d, J = 8.7 Hz, 1H), 6.47 (s, 1H), 5.10 (t, J = 5.4 Hz, 1H), 4.80 (s, 1H), 4.65 (t, J = 8.5 Hz, 1H), 4.42 (dd, J=11.1, 6.7 Hz, 1H), 4.23 (d, J = 10.2 Hz, 2H), 4.14 (d, J = 13.8 Hz, 1H), 3.97 (d, / = 11.3 Hz, 1H), 3.81 (s, 2H), 3.64 (d, J = 15.5 Hz, 1H), 3.50 (dd, J = 15.9, 7.5 Hz, 1H), 3.29 — 3.20 (m, 1H), 2.95 (s, 4H), 2.68 (t, J = 6.9 Hz, 2H), 1.93 (s, 3H), 1.34 (d, J = 6.3 Hz, 4H). Example 143: Synthesis of (2R)-4-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl}-2-methyl-8-[(1-methyl- 4-piperidyl)oxy|-2,3-dihydro-1,4-benzoxazepin-5-one NN © Qo oo 0 The material obtained by changing [2-(terf-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 as a starting material was used in the same manner as in Example 141 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.63 (d, J = 8.8 Hz, 1H), 7.17 — 7.02 (m, 4H), 6.79 (d, J = 8.8 Hz, 1H), 6.57 (s, 1H), 4.79 (s, 1H), 4.56 (s, 1H), 4.24 (s, 1H), 4.14 (d, J= 12.2 Hz, 1H), 3.79 (s, 2H), 3.69 — 3.59 (m, 1H), 3.50 (dd, J = 15.6, 7.6 Hz, 1H), 3.24 (dd, J = 13.8, 8.1 Hz, 1H), 2.98 — 2.80 (m, 6H), 2.63 (dt, J = 24.4, 8.0 Hz, 4H), 2.05 (d, J= 13.3 Hz, 2H), 1.92 (d, / = 18.6 Hz, 2H), 1.33 (d, J = 6.4 Hz, 3H). Example 144: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-pip eridyl)oxy]-2,3-dihydropyrido|3,2-f][1,4]oxazepin-5-one PMB TUN o NN 7 pws o ig g-0 cy A PuEoH Ng 0 2 PMI KY n o "0 oly 5 0, ol ° \ Cory — Qo N o Example Synthesis of 2,6-dichloro-N-(2-hydroxypropyl)-N-[(4-methoxyphenyl)methyl]pyridine-3-carboxamide 2,6-Dichloropyridine-3-carboxylic acid (5.0 g, 26 mmol) was dissolved in dichloromethane, and oxalyl chloride (3.3 mL, 39 mmol) and a catalytic amount of dimethylformamide were added thereto. The reaction solution was stirred at room temperature and concentrated under reduced pressure to obtain 2,6-dichloropyridine-3-carbonyl chloride without additional purification. 1-[(4-Methoxyphenyl)methylamino]propan-2-ol (1.3 g, 7.2 mmol) and KoCO; (22 g, 15.8 mmol) were dissolved in dichloromethane, and 2,6-dichloropyridine-3-carbonyl chloride (1.6 g, 7.6 mmol) dissolved in dichloromethane was slowly added thereto under an ice bath. The reaction solution was stirred at the same temperature for 1 hour, and the reaction was termination by adding water. The reaction solution was extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (2.64 g) as a sticky liquid. Example 144-2: Synthesis of 8-chloro-4-[(4-methoxyphenyl)methyl]-2-methyl-2,3-dihydropyrido[3,2-f][1,4] oxazepin-5-0 ne 2,6-Dichloro-N-(2-hydroxypropyl)-N-[(4-methoxyphenyl)methyl]pyridine-3-carboxami de (2.64 g) obtained in Example 144-1 was dissolved in tetrahydrofuran, and 60% sodium hydride (630 mg, 15.8 mmol) was slowly added thereto under an ice bath. The reaction solution was slowly heated to room temperature, stirred until the starting material completely disappeared, and methanol was added to terminate the reaction. To the reaction mixture, saturated sodium chloride aqueous solution was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by flash chromatography to obtain the title compound (1.35 g) as a sticky liquid. Example 144-3: Synthesis of tert-butyl 4-[[4-[(4-methoxyphenyl)methyl]-2-methyl-5-0x0-2,3-dihydropyrido[3,2-f] [1,4] oxazepin-8-y 1]oxy]piperidine-1-carboxylate The material (500 mg, 1.51 mmol} obtained in Example 144-2, tert-butyl 4-hydroxypiperidine-1-carboxylate (460 mg, 2.26 mmol) and 60% sodium hydride (180 mg, 4.5 mmol) were dissolved in 20 mL of tetrahydrofuran and stirred at 60°C for one day. The reaction solution was extracted with saturated aqueous sodium chloride solution and ethyl acetate, and purified by flash chromatography to obtain the title compound (540 mg). Example 144-4: Synthesis of 2-methyl-8-(4-piperidyloxy)-3,4-dihydro-2H-pyrido[3,2-f][1,4] oxazepin-5-one The material (540 mg) obtained in Example 144-3 was dissolved in 4 mL of trifluoroacetic acid, and the reaction was carried out by the use of a microwave at 120°C for 30 minutes. The reaction solution was diluted with ethyl acetate under an ice bath and basified with K2COs aqueous solution. The reaction mixture was washed with ethyl acetate 3 times, and KOH was added to the aqueous layer to basify the pH to 9 or higher, followed by extraction with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound. 2-methyl-8-[(1-methyl-4-piperidyl)oxy]-3,4-dihydro-2H-pyrido[3,2-f] [1,4] oxazepin-5-one The material obtained in Example 144-4 as a starting material was used in the same manner as in Example 87 to obtain the title compound. Example 144-6: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl|-2-methyl-8-[(1-methyl-4-pip eridyl)oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one The material obtained in Example 144-5 as a starting material was used in the same manner as in Example 5 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) (diastereomeric mixture) § 8.18 (t, J = 7.4 Hz, 2H), 7.17 — 7.01 (m, 8H), 6.57 (dd, J = 9.0, 3.9 Hz, 2H), 5.10 (s, 2H), 4.83 (d, J = 7.4 Hz, 3H), 429 - 4.16 (m, 2H), 4.12 (d, J = 14.1 Hz, 1H), 3.85 (d, J = 14.1 Hz, 1H), 3.78 — 3.66 (m, 8H), 3.68 — 3.53 (m, 3H), 3.21 (dd, J = 13.9, 8.7 Hz, 1H), 2.98 — 2.85 (m, 9H), 2.85 — 2.73 (m, 4H), 2.69 — 2.56 (m, 4H), 2.46 (s, 4H), 2.36 (s, 6H), 2.12 — 2.02 (m, 4H), 1.93 — 1.78 (m, 4H), 1.44 (t, J = 6.7 Hz, 6H). Example 145: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,2-dimethyl-8-[(1-methyl-4- piperidyl)oxy]-3H-pyrido[3,2-f][1,4]oxazepin-5-one N 0 o ~ oA The title compound was synthesized in the same manner as in Example 144, except that 1-[(4-methoxyphenyl)methylamino]-2-methyl-propan-2-ol was used instead of 1-[(4-methoxyphenyl)methylamino]propan-2-ol. 'H NMR (400 MHz, Methanol-ds) § 8.04 (d, J = 8.0 Hz, 1H), 7.17 — 7.02 (m, 4H), 6.62 (d, J = 8.3 Hz, 1H), 5.17 — 5.03 (m, 1H), 4.32 — 4.21 (m, 1H), 4.03 (d, J = 14.1 Hz, 1H), 3.76 (s, 2H), 3.71 - 3.57 (m, 2H), 3.41 (dd, J = 13.8, 8.1 Hz, 1H), 2.97 — 2.84 (m, 4H), 2.85 — 2.73 (m, 2H), 2.71 — 2.58 (m, 3H), 2.55 — 2.41 (m, 2H), 2.37 (s, 3H), 2.13 — 2.01 (m, 2H), 1.91 — 1.80 (m, 2H), 1.45 (d, J = 18.4 Hz, 6H). Example 146: Synthesis of (2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4 -piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one NN © Qo oo 0 The material obtained by changing [2-(terf-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate to [(1R)-2-(fert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 as a starting material was used in the same manner as in Example 141 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) § 7.62 (d, J = 8.5 Hz, 1H), 7.18 — 7.04 (m, 4H), 6.81 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 2.8 Hz, 1H), 4.83 (s, 1H), 4.57 (s, 1H), 4.32 (d, J = 2.0 Hz, 3H), 4.25 (s, 1H), 3.79 (d, J = 13.0 Hz, 3H), 3.68 — 3.58 (m, 2H), 3.47 (dd, J = 15.6, 9.2 Hz, 1H), 2.92 (d, J = 23.0 Hz, 5H), 2.70 (d, J = 6.3 Hz, 2H), 2.63 (s, 2H), 2.46 (d, J = 2.0 Hz, 3H), 2.08 (s, 2H), 1.95 1.87 (m, 2H), 1.29 (d, J = 6.5 Hz, 3H). Example 147: Synthesis of 4-[3~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5- one 9H N os o- 2 SH 0 N 0 ~ 5 ~ ofr 0 o / nn) Over o -“ J} o— Example 147-1: Synthesis of 3,4-dihydro-2H-1,4-benzoxazepin-5-one Chroman-4-one (2.0 g, 14 mmol) was dissolved in 10 mL of concentrated sulfuric acid, and sodium azide (1.1 g, 18 mmol) was slowly added thereto at 0°C. The reaction mixture was slowly heated to room temperature and stirred for 12 hours. The reaction mixture was maintained at 0°C under an ice bath, and 1 M sodium hydroxide aqueous solution was slowly added thereto. After basifying the reaction solution to pH 10 or more, ethyl acetate was added and extracted 3 times. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was removed by evaporating under reduced pressure, and recrystallized with dichloromethane and hexane to obtain the title compound as a white solid. Example 147-2: Synthesis of 4-(oxyran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 3,4-Dihydro-2H-1,4-benzoxazepin-5-one (163 mg, 1 mmol) obtained in Example 147-1 was dissolved in dimethylformamide, and sodium hydride (52 mg, 1.3 mmol) was added thereto under an ice bath. The reaction solution was stirred at 0°C for 30 minutes, and epibromohydrin (0.1 mL, 1.2 mmol) was slowly added thereto and stirred at room temperature for 2 hours. Methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate was added, and washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporating under reduced pressure, and the obtained title compound was used in the next reaction without additional purification. Example 147-3: Synthesis of 4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5- one 4-(Oxyran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 147-2 was dissolved in isopropanol, and tetrahydroisoquinoline (0.13 mL, 1.0 mmol) was added thereto and stirred at 80°C for 12 hours. The temperature was lowered to room temperature temperature, and the oily liquid obtained by concentrating the solvent was purified by flash chromatography to obtain the transparent and sticky solid compound. NMR data about the obtained title compound are as follows. 'H NMR (400 MHz, Methanol-ds) 8 7.69 (dd, J = 7.9, 1.7 Hz, 1H), 7.48 (td, J = 7.8, 1.7 Hz, 1H), 7.20 (t, J= 7.5 Hz, 1H), 7.15 —- 6.99 (m, 5H), 4.46 (t, J = 5.2 Hz, 2H), 4.29 — 4.18 (m, 1H), 3.99 (dd, J=13.9, 3.6 Hz, 1H), 3.68 (td, J=5.1, 1.6 Hz, 2H), 3.44 (dd, J= 13.8, 7.7 Hz, 1H), 2.92 (d, J=15.6Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H), 2.70 — 2.59 (m, 2H). Example 148: Synthesis of 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1- one o Cyr 0 Tetralin-1-one (1.9 g, 14 mmol) as a starting material was used in the same manner as in Example 147 to obtain the title compound, except that 35% hydrochloric acid aqueous solution (30 mL) was used instead of concentrated sulfuric acid in Example 147-1. 'H NMR (400 MHz, Methanol-d4) 3 7.58 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.36 (t, J =17.5 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 7.17 — 7.02 (m, 4H), 4.25 (dt, J = 7.8, 3.7 Hz, 1H), 3.95 (dd, / = 13.8, 3.7 Hz, 1H), 3.48 — 3.36 (m, 3H), 2.94 (d, J = 5.5 Hz, 3H), 2.91 — 2.86 (m, 2H), 2.82 (t,J=17.1 Hz, 2H), 2.66 (h, J= 7.6 Hz, 2H), 2.14 (p, J = 6.8 Hz, 2H). Example 149: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazep in-5-one 0 Oreo IJ) MJ 0) Example 149-1: Synthesis of 4-[[(2R)-oxyran-2-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 3,4-Dihydro-2H-1,4-benzoxazepin-5-one (163 mg, 1 mmol) obtained in Example 147-1 was dissolved in 5 mL of dimethylformamide, and sodium hydride (48 mg, 1.2 mmol) was added thereto under an ice bath. The reaction solution was stirred at 0°C for 30 minutes, and (R)-(-)-glycidyl nosylate (298 mg, 1.15 mmol) was slowly added thereto and stirred at room temperature for 2 hours. Methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate was added, and washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, The solvent was removed by evaporating under reduced pressure, and the 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-2,3-dihydro-1,4-benzoxazep in-S-one 4-[[(2R)-oxyran-2-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 149-1 was used in the same manner as in Example 147-3 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.69 (dd, J = 7.9, 1.7 Hz, 1H), 7.48 (td, J= 7.8, 1.8 Hz, 1H), 7.20 (t, J = 17.5 Hz, 1H), 7.15 — 7.02 (m, 5H), 4.46 (t, J = 5.2 Hz, 2H), 4.29 — 4.19 (m, 1H), 3.99 (dd, J=13.9, 3.6 Hz, 1H), 3.75 (d, J = 2.2 Hz, 2H), 3.74 — 3.63 (m, 2H), 3.44 (dd, J = 13.9, 7.7 Hz, 1H), 2.97 — 2.90 (m, 2H), 2.91 — 2.83 (m, 2H), 2.70 — 2.60 (m, 2H). Example 150: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-2,3-dihydro-1,4-be nzoxazepin-5-one oO 29S eNee oo OH 7-Fluorochroman-4-one as a starting material was used in the same manner as in Examples 147-1 and 149 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) § 7.81 - 7.73 (m, 1H), 7.16 — 7.02 (m, 4H), 6.94 (td, J = 8.5, 2.6 Hz, 1H), 6.81 (dd, J = 9.9, 2.6 Hz, 1H), 4.52 (t, J = 5.0 Hz, 2H), 4.27 — 4.20 (m, 1H), 3.99 (dd, J = 13.9, 3.6 Hz, 1H), 3.81 — 3.71 (m, 4H), 3.44 (dd, J = 13.9, 7.8 Hz, 1H), 2.98 — 2.84 (m, 4H), 2.69 — 2.61 (m, 2H). Example 151: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-2,3-dihydro-1,4-be nzoxazepin-5-one «erry or OH 7-Bromochroman-4-one as a starting material was used in the same manner as in Examples 147-1 and 149 to obtain the title compound. 'H NMR (400 MHz, Methanol-dz) § 7.63 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.4, 1.7 Hz, 1H), 7.26 (d,J=1.6 Hz, 1H), 7.16 - 7.01 (m, 4H), 4.51 (t, J = 5.0 Hz, 2H), 4.27 — 4.17 (m, 1H), 3.99 (dd, J=13.7,3.5 Hz, 1H), 3.74 (d, J = 6.5 Hz, 4H), 3.44 (dd, J = 13.9, 7.8 Hz, 1H), 2.97 — 2.83 (m, 4H), 2.69 — 2.59 (m, 2H). Example 152: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-2,3-dihydropyrido[4,3-f][1, 4]oxazepin-5-one Ns~oH A 2 ii al = J L— Oy — Oh N Ns~o~Ng, Ny 1 3" ==" % YEO Example 152-1: Synthesis of methyl 3-[2-(benzyloxycarbonylamino)ethoxy]pyridine-4-carboxylate Methyl ~~ 3-hydroxypyridine-4-carboxylate (1.0 g, 6.53 mmol), benzyl N-(2-hydroxyethyl)carbamate (1,53 g, 7.84 mmol) and triphenylphosphine (2.06 g) were dissolved in tetrahydrofuran, and diisopropyl azodicarboxylate was slowly added thereto at 0°C. The reaction solution was stirred at room temperature for 12 hours, and the solvent was removed under reduced pressure. The concentrate was purified by flash chromatography under the solvent condition of hexane and ethyl acetate to obtain the title compound. Example 152-2: Synthesis of 3,4-dihydro-2H-pyrido[4,3-f][1,4]oxazepin-5-one Methyl 3-[2-(benzyloxycarbonylamino)ethoxy]pyridine-4-carboxylate obtained in Example 152-1 was dissolved in ethanol at room temperature, and 5% palladium-charcoal was added thereto, followed by stirring under a hydrogen balloon for 24 hours. The reaction solution was filtered through celite and washed with ethanol. The obtained solution was concentrated under reduced pressure and purified by flash chromatography to obtain the title compound (548 mg) as a white crystalline solid. Example 152-3: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido[4,3-f] [1, 4]oxazepin-5-one 3,4-Dihydro-2H-pyrido[4,3-f][1,4]oxazepin-5-one obtained in Example 152-2 as a starting material was used in the same manner as in Example 149 to obtain the title compound. '"H NMR (400 MHz, Methanol-da) 8 8.36 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.75 (d, J = 5.1 Hz, 1H), 7.17 — 7.02 (m, 4H), 4.62 (t, J = 4.7 Hz, 2H), 4.30 — 4.20 (m, 1H), 4.02 (dd, J= 13.9, 3.5 Hz, 1H), 3.82 (t, J = 4.6 Hz, 2H), 3.76 (s, 2H), 3.45 (dd, J = 13.9, 8.0 Hz, 1H), 2.98 — 2.90 (m, 2H), 2.91 — 2.83 (m, 2H), 2.69 — 2.60 (m, 2H). Example 153: Synthesis of 8-chloro-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido [3,2-f][1,4]oxazepin-5-one o LO WENO 8-Chloro-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-5-one as a starting material was used in the same manner as in Example 149 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) & 8.36 (dd, J = 8.1, 1.4 Hz, 1H), 7.26 (dd, J = 8.2, 1.4 Hz, 1H), 7.17 - 7.00 (m, 4H), 4.70-4.67 (m, 2H), 4.24 (q, J = 9.0, 8.0 Hz, 1H), 3.99 (dd, J= 13.9, 3.5 Hz, 1H), 3.89 (t, J = 4.3 Hz, 2H), 3.76 (s, 2H), 3.42 (dd, J = 13.8, 8.1 Hz, 1H), 2.94-2.86 (dd, J = 17.3, 5.4 Hz, 4H), 2.65 (d, J= 6.3 Hz, 2H). Example 154: Synthesis of 7-chloro-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2- benzazepin-1-one o 7-Chloro-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material was used in the same manner as in Example 149 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.55 (d, J = 8.2 Hz, 1H), 7.35 (dd, J = 8.3, 1.9 Hz, 1H), 7.27 (d, J =2.1 Hz, 1H), 7.15 — 7.00 (m, 4H), 4.27 - 4.18 (m, 1H), 3.91 (dd, J = 13.8, 3.6 Hz, 1H), 3.75 (s, 2H), 3.44 — 3.33 (m, 2H), 3.32 — 3.23 (m, 1H), 2.97 — 2.89 (m, 2H), 2.90 — 2.82 (m, 2H), 2.78 (t, J = 7.1 Hz, 2H), 2.68 — 2.59 (m, 2H), 2.11 (p, J = 6.8 Hz, 2H). Example 155: Synthesis of 7-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-4,5-dihydro-3H-2- benzazepin-1-one o «TD 7-Bromo-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material was used in the same manner as in Example 149 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.55 — 7.51 (m, 1H), 7.51 — 7.45 (m, 2H), 7.16 — 7.01 (m, 4H), 4.29 — 4.19 (m, 1H), 3.92 (dd, J = 13.8, 3.6 Hz, 1H), 3.78 (s, 2H), 3.47 — 3.38 (m, 2H), 3.36 —3.34(m, 1H), 2.99 — 2.91 (m, 2H), 2.93 — 2.85 (m, 2H), 2.80 (t, J = 7.1 Hz, 2H), 2.71 — 2.61 (m, 2H), 2.14 (p, J = 6.9 Hz, 2H). Example 156: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-1-methyl-2,3-dihy dro-1,4-benzodiazepin-5-one ore Qu N och Br vd Qu N le @! Br No gu YY oo HH or oes dye H H © H = ere N—” yy ; N—" ZL Example 156-1: Synthesis of 8-bromo-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione 7-Bromo-1H-3,1-benzoxazine-2,4-dione (550 g, 2.27 mol) was dissolved in 2.5 L of distilled water, and triethylamine (230 g, 2.27 mol) and glycine (239 g, 3.18 mol) were added thereto. The reaction solution was stirred at room temperature for 4 hours, concentrated, dissolved again in 3 L of acetic acid, and the mixture was stirred at 140 °C for 8 hours. The reaction solution was diluted with petroleum ether and filtered to obtain the title compound (866 g, 74.7%) as a white solid. Example 156-2: Synthesis of 8-bromo-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-one 8-Bromo-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione (200 g, 784 mmol) obtained in Example 156-1 was dissolved in 4 L of tetrahydrofuran, and LAH (50.6 g, 1.33 mol) was slowly added thereto at 0°C. The reaction solution was stirred at 70°C for 3 hours, and after cooling, 100 mL of distilled water, 100 mL of 15% sodium hydroxide aqueous solution, and additional 100 mL of distilled water were slowly added to terminate the reaction. The mixture solution was dried over anhydrous sodium sulfate, filtered with hot tetrahydrofuran, the solvent was removed under reduced pressure, and recrystallized by adding 500 mL of ethyl acetate to obtain the title compound (177g, 46.8%) as a white solid. Example 156-3: Synthesis of 8-bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one 8-Bromo-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-one (177 g, 734 mmol) obtained in Example 156-2 was dissolved in 1.2 L of methanol, and paraformaldehyde (200 g, 3.67 mol) dissolved in 1.2 L of acetic acid was added thereto. The reaction solution was stirred at 50°C for 1 hour. Sodium cyanoborohydride (231 g, 3.67 mol) was added to the reaction solution, stirred at 50°C for 4 hours, and concentrated by removing the solvent under reduced pressure. The mixture was diluted with 4 L of distilled water and extracted with dichloromethane 2 times. The combined organic layers were washed with saturated aqueous sodium chloride solution 2 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Methanol was added to the obtained concentrate and recrystallized to obtain the title compound (yield: 78%) as a white solid. Example Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-1-methyl-2,3-dihy dro-1,4-benzodiazepin-5-one 8-Bromo-1-methyl-3,4-dihydro-2H- 1,4-benzodiazepin-5-one obtained in Example 156-3 as a starting material was used in the same manner as in Example 149 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 3 7.42 (d, J = 7.7 Hz, 1H), 7.20 — 7.02 (m, 6H), 4.23 (m, 1H), 3.94 (dd, J= 13.8, 3.9 Hz, 1H), 3.76 (s, 2H), 3.63 (q, J = 4.9 Hz, 2H), 3.52 — 3.37 (m, 3H), 2.93 (d,J=5.7 Hz, 2H), 2.92 — 2.80 (m, 5H), 2.73 — 2.59 (m, 2H). Example 157: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-1-ethyl-2,3-dihydr 0-1,4-benzodiazepin-5-one Qo PORN YC NS / Example 157-1: Synthesis of 8-bromo-1-ethyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one 8-Bromo-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-one (100 mg, 0.41 mmol) obtained in Example 156-2 and potassium carbonate (170 mg, 1.23 mmol) were dissolved in dimethylformamide, and iodoethane (0.07mL, 0.82 mmol) was added thereto. The reaction solution was stirred at 60°C for one day. The reaction mixture was cooled to room temperature, diluted with distilled water and extracted with ethyl acetate 3 times. The combined organic layers were washed with saturated aqueous sodium chloride solution 2 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by flash chromatography to obtain the solid title compound. Example 157-2: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-1-ethyl-2,3-dihydr 0-1,4-benzodiazepin-5-one The material obtained in Example 157-1 as a starting material was used in the same manner as in Example 149 to obtain the title compound. '"H NMR (400 MHz, Methanol-da) 8 7.42 (d, J = 8.6 Hz, 1H), 7.17 — 7.09 (m, 5H), 7.06 (d, J = 5.6 Hz, 1H), 4.23 (dt, J = 12.4, 6.4 Hz, 1H), 3.90 (dd, J = 13.8, 4.0 Hz, 1H), 3.79 (s, 2H), 3.61 (d, J=5.9 Hz, 2H), 3.49 (dd, J = 14.4, 6.8 Hz, 2H), 3.41 (t, J = 5.4 Hz, 2H), 3.22 (dt, / = 11.9, 6.8 Hz, 2H), 2.95-2.88 (m, 4H), 2.76 — 2.63 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). Example 158: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-1-ethyl-3H-1,4-be nzodiazepin-2,5-dione Qu N le ®! Br No 0} Oo 7-Bromo-1-ethyl-3,1-benzoxazine-2,4-dione (262 mg, 0.97 mmol) and glycine (73 mg, 0.97 mmol) were dissolved in acetic acid, and heated to reflux for 4 hours. The reaction mixure was cooled to room temperature, diluted with distilled water and filtered. The obtained solid was washed with diethyl ether to obtain the solid title compound (100 mg) without additional purification. Example 158-2: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-1-ethyl-3H-1,4-be nzodiazepin-2,5-dione The material obtained in Example 158-1 as a starting material was used in the same manner as in Example 149 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.72-7.69 (m, 2H), 7.55 (d, J = 8.5 Hz, 1H), 7.17 — 6.99 (m, 4H), 4.24 (p, J = 7.4 Hz, 2H), 4.15 (dd, J = 14.9, 6.0 Hz, 1H), 4.01-3.95 (m, 2H), 3.85 — 3.67 (m, 4H), 3.53 — 3.45 (m, 1H), 2.93-2.86 (m, 4H), 2.63 (d, J = 7.0 Hz, 2H), 1.19 — 1.09 (m, 3H). Example 159: Synthesis of 2-[4-[[4-(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroexy-propyl]-5-oxo-2,3-dihydro-1,4- benzoxazepin-8-yl]|-1-piperidyl]acetonitrile OLY Co 9; OH 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3- dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 78-1 was dissolved in acetonitrile, potassium carbonate and 2-bromoacetonitrile were added thereto, followed by stirring at 90°C for 1 hour. To the reaction mixture, saturated aqueous ammonium chloride aqueous solution was added and extracted with ethyl acetate 3 times. The oily liquid obtained by drying the combined organic layers over anhydrous sodium sulfate and concentrating under reduced pressure was purified by flash chromatography to obtain the title compound as a white solid. 'H NMR (400 MHz, Methanol-dy) § 7.69 (dd, J = 8.7, 2.2 Hz, 1H), 7.16 — 7.09 (m, 3H), 7.06 (d, J=6.6Hz, 1H), 6.81 (dd, J=8.8, 2.7 Hz, 1H), 6.64 (d, J = 2.6 Hz, 1H), 4.76 (dq, J = 7.2, 3.8 Hz, 1H), 4.47 (d, J = 5.4 Hz, 2H), 4.23 (s, 1H), 4.17 — 4.07 (m, 1H), 3.97 (dt, J = 13.8, 3.2 Hz, 1H), 3.86 — 3.65 (m, 6H), 3.61 (t, J = 11.6 Hz, 1H), 3.43 (dd, J = 14.2, 7.6 Hz, 1H), 2.97 — 2.86 (m, 4H), 2.67 (d, J = 6.1 Hz, 2H), 2.04 (t, J = 6.5 Hz, 3H), 1.87 (ddd, J = 23.5, 11.9, 4.2 Hz, 2H), 1.26 (td, J= 7.4, 2.2 Hz, 1H). Example 160: Synthesis of 8-[[1-(2,2-difluoroacetyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hy droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one Ho oh ew The title compound was synthesized in the same manner as in Example 78 except that difluoro-acetic anhydride was used instead of acetic anhydride in Example 78-2. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (dd, J = 8.8, 2.1 Hz, 1H), 7.14 (h, J = 5.8 Hz, 3H), 7.07 (d,J=7.0 Hz, 1H), 6.77 (dd, J = 8.8, 2.9 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 4.52 (s, 1H), 4.47 (d, J=15.4 Hz, 2H), 4.26 (s, 1H), 3.95 (dd, J = 13.9, 3.4 Hz, 1H), 3.86 (s, 2H), 3.77 — 3.65 (m, 4H), 3.46 (dd, J= 14.0, 7.5 Hz, 1H), 2.98 (s, 3H), 2.88 — 2.67 (m, 4H), 2.58 (t, J = 9.5 Hz, 2H), 2.08 — 2.00 (m, 2H), 1.86 (d, J = 11.8 Hz, 2H). Example 161: Synthesis of 8-[[1-(2,2-difluoroacetyl)azetidin-3-yl oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hy droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one Q ~~ a < MN OH 8-(Azetidin-3-yloxy)-4-[(2R})-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2, 3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 83-1 as a starting material was used in the same manner as in Example 160 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.72 (dd, J = 8.7, 2.0 Hz, 1H), 7.14 (d, J = 5.7 Hz, 3H), 7.07 (d, J =6.9 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 6.49 (d, / =2.3 Hz, 1H), 5.21 - 5.14 (m, 1H), 4.88 — 4.77 (m, 1H), 4.60 — 4.37 (m, 4H), 4.25 (d, J = 7.2 Hz, 1H), 4.11 (td, J = 11.8, 10.3, 5.3 Hz, 2H), 3.96 (dd, J = 13.9, 3.2 Hz, 1H), 3.85 (s, 2H), 3.72 (h, J = 7.3, 6.4 Hz, 2H), 3.46 (dd, J = 14.1, 7.6 Hz, 1H), 2.97 (s, 3H), 2.80 — 2.69 (m, 2H). Example 162: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-pi peridyljoxy]-2,3-dihydro-1,4-benzoxazepin-5-one HON 3 ~0 N OLS or 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3- dihydro-1,4-benzoxazepin-5-one dihydrochloride (100 mg, 0.19 mmol) obtained in Example 78-1, potassium carbonate (79 mg, 0.57 mmol) and 2-iodoethanol (15 pL, 0.19 mmol) were dissolved in acetonitrile and stirred. After completion of the reaction, the reaction solution was concentrated and purified by flash chromatography to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) § 7.66 (d, J = 8.9 Hz, 1H), 7.11 - 7.03 (m, 4H), 6.76 (d, J = 8.9 Hz, 1H), 6.59 (s, 1H), 4.51 - 4.46 (m, 3H), 4.18 (s, 1H), 3.98 (d, J= 13.9 Hz, 1H), 3.76 - 3.71 (m, 6H), 3.42 (dd, J = 14.0, 7.9 Hz, 1H), 3.02 - 2.79 (m, 6H), 2.71 — 2.58 (m, 4H), 2.58 — 2.43 (m, 2H), 2.04 (t, J=7.4 Hz, 2H), 1.91 — 1.75 (m, 2H). Example 163: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-fluoroethyl)-4-pipe ridyljoxy]-2,3-dihydro-1,4-benzoxazepin-5-one Q C9 F ry L J \ C. o- / The title compound was synthesized in the same manner as in Example 162 except that 2-fluoroethyl 4-methylbenzenesulfonate was used instead of 2-iodoethanol at 90°C. 'H NMR (400 MHz, Methanol-ds) 8 7.66 (d, J = 8.7 Hz, 1H), 7.17 - 7.01 (m, 4H), 6.76 (d, J = 8.9 Hz, 1H), 6.58 (s, 1H), 4.66 (t, J = 5.0 Hz, 1H), 4.59 — 4.42 (m, 4H), 4.23 (s, 1H), 3.97 (d, J = 13.4 Hz, 1H), 3.84 — 3.66 (m, 4H), 3.42 (dd, J = 13.9, 7.6 Hz, 1H), 3.02 — 2.76 (m, 7H), 2.75 — 2.59 (m, 3H), 2.51 (t, J= 10.2 Hz, 2H), 2.13 — 2.00 (m, 2H), 1.93 — 1.75 (m, 2H). Example 164: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[[1-(2-fluoroethyl)-4-pipe ridyljoxy]-2,3-dihydropyrido|3,2-f][ 1,4] oxazepin-5-one A 9 ry [GY \ 0 " 5 4 o) a 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3- dihydropyrido[3,2-f][1,4]oxazepin-5-one dihydrochloride as a starting material was used in the same manner as in Example 163 to obtain the title compound. 'H NMR (400 MHz, Methanol-dy) § 8.26 (d, J = 8.5 Hz, 1H), 7.19 — 6.97 (m, 4H), 6.55 (d, J = 8.5 Hz, 1H), 5.08 (s, 1H), 4.66 (s, 1H), 4.61 (s, 2H), 4.55 (s, 1H), 4.29 — 4.18 (m, 1H), 3.99 (d, J = 13.9 Hz, 1H), 3.90 — 3.83 (m, 2H), 3.75 (s, 2H), 3.43 — 3.37 (m, 1H), 2.99 — 2.83 (m, 6H), 2.80 (s, 1H), 2.73 (s, 1H), 2.63 (d, J = 6.2 Hz, 2H), 2.55 — 2.43 (m, 2H), 2.14 — 2.03 (m, 2H), 1.90 — 1.77 (m, 2H). Example 165: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl|-8-[[1-[(3-methyloxetan-3-yl) methyl]-4-piperidyl]oxy]}-2,3-dihydro-1,4-benzoxazepin-5-one o 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3- dihydro-1,4-benzoxazepin-5-one (200 mg, 0.443 mmol) obtained in Example 78-1, cesium carbonate (288 mg, 0.886 mmol) and 3-(bromomethyl)-3-methyl-oxetan (110 mg, 0.665 mmol) were dissolved in dimethylformamide, heated to 60°C and stirred. After completion of the reaction, the reaction solution was extracted with saturated aqueous sodium chloride solution and ethyl acetate, and purified by flash chromatography to obtain the title compound (6 mg). 'H NMR (400 MHz, Methanol-ds) 8 7.66 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 3.1 Hz, 3H), 7.06 (d, J = 6.6 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 4.56 — 4.46 (m, 4H), 4.45 (s, 2H), 4.33 (d, J = 5.7 Hz, 2H), 4.23 (s, 1H), 4.01 — 3.92 (m, 1H), 3.80 — 3.69 (m, 4H), 3.42 (dd, J = 14.0, 7.6 Hz, 1H), 2.97 — 2.85 (m, 4H), 2.66 (d, J = 6.7 Hz, 2H), 2.61 (s, 3H), 2.31 (t, J=10.3 Hz, 2H), 2.06 — 1.98 (m, 2H), 1.79 (t, J = 10.2 Hz, 2H), 1.43 (s, 3H). Example 166: Synthesis of 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-0x0-2,3-dihydro-1,4-be nzoazepin-8-yljoxy]piperidine-1-carbonitrile “A, 0 . 1 Lory 0 oa 4 cc PRT 0 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3- dihydro-1,4-benzoxazepin-5-one (200 mg, 0.443 mmol) obtained in Example 78-1, cyanogen bromide (94 mg, 0.886 mmol) and cesium carbonate (433 mg, 1.329 mmol) were dissolved in dimethylformamide, and the reaction was carried out by the use of a microwave at 70°C for 3 hours. After completion of the reaction, the reaction solution was extracted with saturated aqueous sodium chloride solution and ethyl acetate, and purified by flash chromatography to obtain the title compound (14 mg). 'H NMR (400 MHz, Methanol-dy) § 7.68 (dd, J = 8.7, 2.1 Hz, 1H), 7.14 - 7.09 (m, 3H), 7.05 (d, J=6.7 Hz, 1H), 6.79 (dd, J= 8.8, 2.3 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 4.65 (dq, J= 7.1, 3.6 Hz, 1H), 4.51 — 4.43 (m, 2H), 4.23 (d, J = 7.3 Hz, 1H), 3.97 (dt, J = 14.1, 2.9 Hz, 1H), 3.82 — 3.69 (m, 4H), 3.55 — 3.37 (m, 3H), 3.26 (t, J= 9.9 Hz, 2H), 2.93 (d, J = 5.6 Hz, 2H), 2.91 — 2.84 (m, 2H), 2.65 (d, J = 6.3 Hz, 2H), 2.09 (t, J = 10.7 Hz, 2H), 1.94 — 1.81 (m, 2H). Example 167: Synthesis of 8-[(4-acetylpiperazin-1-yl)methylj-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-p ropyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one toy re Example 167-1: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(piperazin-1 -ylmethyl)-3H-1,4-benzoxazepin-5-one; dihydrochloride 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl- 3H-1,4-benzoxazepin-5-one as a starting material was used in the same manner as in Examples 54-1 and 54-2 to obtain the title compound, Example 167-2: Synthesis of 8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-p ropyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one The material obtained in Example 167-1 as a starting material was used in the same manner as in Example 78-2 to obtain the title compound. 'H NMR (400 MHz, Methanol-dy) 8 7.61 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.17 — 7.02 (m, 4H), 7.00 (s, 1H), 4.29 (s, 1H), 4.06 (d, J = 13.6 Hz, 1H), 3.77 (s, 2H), 3.59 (t, / = 10.1 Hz, 6H), 3.48 (s, 2H), 3.43 (dd, J = 14.0, 8.0 Hz, 2H), 2.93 (s, 4H), 2.74 — 2.56 (m, 2H), 2.55 — 2.41 (m, 4H), 2.10 (s, 3H), 1.43 (s, 3H), 1.33 (s, 3H). Example 168: Synthesis of 3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinelin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H- 1,4-benzoxazepin-8-yljoxy]azetidin-1-carbaldehyde og re Example 168-1: Synthesis of 8-(azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dim ethyl-3H-1,4-benzoxazepin-5-one dihydrochloride 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,2-dimethyl -3H-1,4-benzoxazepin-5-one as a starting material was used in the same manner as in Example 83-1 to obtain the title compound. Example 168-2: Synthesis of 3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinelin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H- 1,4-benzoxazepin-8-yljoxy]azetidine-1-carbaldehyde The material (105 mg, 0.2 mmol) obtained in Example 168-1 was dissolved in 2 mL of acetonitrile, and formic acid (38 pL, 1.0 mmol), triethylamine (0.17 mL, 1.2 mL) and HATU(114 mg, 0.3 mmol) were added thereto and stirred at room temperature. After confirming that the reaction was complete, saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate 3 times. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) § 8.03 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.21 — 7.03 (m, 4H), 6.72 (d, J = 8.7 Hz, 1H), 6.45 (s, 1H), 5.19 (s, 1H), 4.68 (t, J = 8.4 Hz, 1H), 4.52 — 4.42 (m, 1H), 4.35 — 4.18 (m, 2H), 4.02 (t, J = 13.6 Hz, 2H), 3.79 (s, 2H), 3.51 (s, 2H), 3.43 — 3.37 (m, 1H), 2.93(d,J= 11.6 Hz, 4H), 2.73 — 2.59 (m, 2H), 1.44 (s, 3H), 1.35 (s, 3H). Example 169: Synthesis of 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H- 1,4-benzoxazepin-8-yl]methyl]piperazine-1-carbaldehyde og oF GF KN of- The material obtained in Example 167-1 as a starting material was used in the same manner as in Example 168-2 to obtain the title compound. 'H NMR (400 MHz, Methanol-d) 3 8.03 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.19 — 7.03 (m, 4H), 7.01 (s, 1H), 4.30 (s, 1H), 4.06 (d, J = 13.8 Hz, 1H), 3.79 (s, 2H), 3.61 (s, 2H), 3.56 (s, 2H), 3.52 — 3.38 (m, 5H), 2.93 (d, J = 11.0 Hz, 4H), 2.75 — 2.60 (m, 2H), 2.49 (d, J=17.2 Hz, 4H), 1.44 (s, 3H), 1.34 (s, 3H). Example 170: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-2,2-dimethyl-8-(2-oxa-6-aza spiro[3.3] heptan-6-ylmethyl)-3H-1,4-benzoxazepin-5-one 1 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl- 3H-1,4-benzoxazepin-5-one as a starting material was used in the same manner as in Example 28 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.60 (d, J = 7.8 Hz, 1H), 7.19 — 7.01 (m, 5H), 6.92 (s, 1H), 4.76 (s, 4H), 4.29 (s, 1H), 4.06 (d, J = 13.8 Hz, 1H), 3.76 (s, 2H), 3.62 (s, 2H), 3.47 (s, 6H), 3.43 — 3.38 (m, 1H), 2.98 — 2.83 (m, 4H), 2.64 (s, 2H), 1.43 (s, 3H), 1.33 (s, 3H). Example 171: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyclo[3.2. 1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one AN oF AP OL, o- Example 171-1: Synthesis of 8-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydrox y-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride The intermediate was synthesized by changing 4-chlorotetrahydropyran to tert-butyl 3-methylsulfonyloxy-8-azabicyclo[3.2.1]octan-8-carboxylate in Example 64. The obtained intermediate as a starting material was used in the same manner as in Example 78-1 to obtain the 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(8-ethyl-8-azabicyclo[3.2. 1Joctan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one The material obtained in Example 171-1 as a starting material was used in the same manner as in Example 88 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 3 7.60 (d, J = 8.7 Hz, 1H), 7.09 — 6.92 (m, 4H), 6.61 (d, J = 8.8 Hz, 1H), 6.42 (s, 1H), 4.56 (d, J = 5.1 Hz, 1H), 4.38 (d, J = 5.3 Hz, 2H), 4.13 (d, / = 7.5 Hz, 1H), 4.00 — 3.87 (m, 1H), 3.65 (d, J = 6.7 Hz, 4H), 3.42 — 3.27 (m, 3H), 2.96 — 2.71 (m, 4H), 2.53 (dd, J = 14.6, 6.8 Hz, 4H), 2.09 (dd, J = 29.8, 11.7 Hz, 4H), 2.01 — 1.78 (m, 4H), 1.09 (t, J = 7.3 Hz, 3H). Example 172: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(2-ethyl-2-azaspiro[3.3]h eptan-6-yl)oxy|-2,3-dihydro-1,4-benzoxazepin-5-one Mn 3 ot Example 172-1: Synthesis of 8-(2-azaspiro[3.3|heptan-6-yloxy)-4-|(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-p ropyl]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride The intermediate was synthesized by changing 4-chlorotetrahydropyran to tert-butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptan-2-carboxylate in Example 64. The obtained intermediate as a starting material was used in the same manner as in Example 78-1 to obtain the title compound. Example Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethyl-2-azaspiro[3.3]h eptan-6-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one The material obtained in Example 172-1 as a starting material was used in the same manner as in Example 88 to obtain the title compound. 'H NMR (400 MHz, Methanol-dy) § 7.65 (dd, J = 8.7, 2.1 Hz, 1H), 7.18 - 6.99 (m, 4H), 6.65 (d, J=8.5 Hz, 1H), 6.44 (d, J= 3.0 Hz, 1H), 4.66 (t, J = 6.8 Hz, 1H), 4.45 (d, J = 5.1 Hz, 2H), 4.33 —4.18 (m, 1H), 3.97 (dt, J = 14.1, 2.9 Hz, 1H), 3.82 — 3.70 (m, 4H), 3.45 - 3.28 (m, 7H), 2.92 (d, J=5.8 Hz, 2H), 2.87 (d, J = 6.0 Hz, 2H), 2,73 (ddd, J = 11.3, 7.0, 3.6 Hz, 2H), 2.63 (d, J = 6.3 Hz, 2H), 2.58 — 2.48 (m, 2H), 2.26 (ddd, / = 13.1, 6.2, 2.4 Hz, 2H), 0.99 (td, J = 7.3, 2.0 Hz, 3H). Example 173: Synthesis of 8-[(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)- 2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one Yo, 00% . i CR 8-(8-Azabicyclo[3.2.1]octan-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hy droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 171-1 as a starting material was used in the same manner as in Example 78-2 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) & 7.70 (dd, J = 8.8, 2.0 Hz, 1H), 7.19 — 6.99 (m, 4H), 6.71 (dd, J=88,2.6 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 4.92 (s, 2H), 4.73 (d, J = 4.9 Hz, 1H), 4.65 — 4.55 (m, 1H), 4.46 (d, J = 5.1 Hz, 2H), 4.32 — 4.17 (m, 2H), 3.97 (dd, J = 13.9, 3.4 Hz, 1H), 3.80 — 3.67 (m, 4H), 3.41 (dd, J = 14.1, 7.6 Hz, 1H), 3.01 — 2.81 (m, 4H), 2.64 (d, J = 6.2 Hz, 2H), 2.32 ~1.91 (m, 9H). Example 174: Synthesis of 8-[(2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy|-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2- hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one boy ht 8-(2-Azaspiro[3.3]heptan-6-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydr oxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 172-1 as a starting material was used in the same manner as in Example 78-2 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.54 (dd, J = 8.9, 2.3 Hz, 1H), 7.12 - 6.87 (m, 4H), 6.53 (dd, J=172,43 Hz, 1H), 6.35 (d, = 2.7 Hz, 1H), 4.57 (q, J = 6.6 Hz, 1H), 4.33 (d, J = 5.1 Hz, 2H), 4.23 — 4.04 (m, 3H), 3.93 (s, 1H), 3.84 (d, J = 11.1 Hz, 2H), 3.75 —- 3.51 (m, 4H), 3.36 — 3.26 (m, 1H), 2.89 — 2.72 (m, 4H), 2.67 (ddt, J = 13.7, 6.7, 3.1 Hz, 2H), 2.61 — 2.46 (m, 2H), 2.22 (ddd, J =10.2, 6.6, 3.2 Hz, 2H), 1.74 (dd, J = 6.7, 2.3 Hz, 3H). Example 175: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-carbonyl)-2, 3-dihydro-1,4-benzoxazepin-5-one Looe ~ Adee ~ Sado Example 175-1: Synthesis of methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-0x0-2,3-dihydro-1,4-benz oxazepine-8-carboxylate 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1 ,4-benzoxazepin-S-one (1.0 equiv), molybdenum hexacarbonyl (1.0 equiv), trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium an (0.1 equiv), tri-tert-butylphosphonium tetrafluoroborate (0.2 equiv) and 1,8-diazabicyclo[5.4.0]Jundec-7-ene (1.5 equiv) were dissolved in methanol:acetonitrile (=1:1) and stirred at 150°C for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate 3 times. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by flash chromatography to obtain the title compound. Example 175-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(pyrrolidin-1-carbonyl)-2, 3-dihydro-1,4-benzoxazepin-5-one Methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-0x0-2,3-dihydro-1,4-benzoxa zepin-8-carboxylate (1.0 equiv) obtaind in Example 175-1, pyrrolidine (5.0 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1 mL) were mixed and heated to 120°C overnight. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate and purified by flash chromatography to obtain the title compound. '"H NMR (400 MHz, Methanol-ds) 7.66 (dd, J = 8.1, 2.2 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 7.04 — 6.85 (m, 4H), 4.39 (t, J = 5.2 Hz, 2H), 4.12 (dt, J = 11.3, 4.9 Hz, 1H), 3.88 (dt, J =13.9,3.1 Hz, 1H), 3.63 (d, / = 11.4 Hz, 4H), 3.48 (t, / = 7.1 Hz, 2H), 3.34 (q, J= 7.3 Hz, 3H), 2.90 — 2.65 (m, 4H), 2.54 (d, J = 5.9 Hz, 2H), 1.84 (dp, J = 33.2, 6.7 Hz, 4H). Example 176: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(piperidine-1-carbonyl)-2, 3-dihydro-1,4-benzoxazepin-5-one I0=1,4=UCNLUX4LLPIR=0=0NL gC N on SN o! Oo The title compound was synthesized in the same manner as in Example 175, except that piperidine was used instead of pyrrolidine in Example 175-2. 'H NMR (400 MHz, Methanol-dy) 3 7.67 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.97 (d, J =20.8 Hz, 5H), 4.41 (d, J = 5.3 Hz, 2H), 4.13 (s, 1H), 3.88 (d, J = 13.9 Hz, 1H), 3.74 — 3.53 (m, 6H), 3.35 (dd, J = 14.0, 7.8 Hz, 1H), 2.79 (dd, J = 18.3, 5.6 Hz, 4H), 2.54 (d, J = 6.3 Hz, 2H), 1.75 — 1.49 (m, 5H). Example 177: Synthesis of 8-(3,3-difluoropyrrolidin-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydrox y-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 0 os ED GD 0 The title compound was synthesized in the same manner as in Example 175, except that 3,3-difluoropyrrolidine was used instead of pyrrolidine in Example 175-2. 'H NMR (400 MHz, Methanol-ds) § 7.80 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.12 (q, J =11.5, 8.0 Hz, 5H), 4.54 (d, J = 5.4 Hz, 2H), 4.27 (s, 1H), 4.05 — 3.95 (m, 1H), 3.89 — 3.72 (m, 5H), 3.64 — 3.39 (m, 4H), 2.96 (s, 4H), 2.72 (d, J = 6.7 Hz, 2H), 2.56 (s, 2H), 2.44 (s, 2H), 2.35 (d,J=2.1 Hz, 3H). Example 178: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-methylpiperazine-1-ca rbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one oO Q N { ) NEN Non NO at 0 The title compound was synthesized in the same manner as in Example 175, except that 1-methylpiperazine was used instead of pyrrolidine in Example 175-2, 'H NMR (400 MHz, Methanol-dy) 8 7.68 (dd, J = 8.0, 2.2 Hz, 1H), 7.22 (t, J = 6.7 Hz, 1H), 7.10 (s, 1H), 7.08 — 6.88 (m, 4H), 4.40 (d, J = 5.5 Hz, 2H), 4.13 (s, 1H), 3.95 — 3.70 (m, 4H), 3.63 (d, J=1.8Hz, 5H), 3.35 (dd, J = 14.1, 7.8 Hz, 1H), 2.81 (d, J = 5.7 Hz, 2H), 2.76 (t, J = 5.7 Hz, 2H), 2.54 (d, J=6.1 Hz, 2H), 2.45 — 2.25 (m, 2H). Example 179: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(pyrrolidin- 1-ylmethyl)-3H-1,4-benzoxazepin-5-one 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl- 3H-1,4-benzoxazepin-5-one as a starting material was used in the same manner as in Example 24 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.62 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.17 — 7.03 (m, 4H), 7.01 (s, 1H), 4.29 (s, 1H), 4.06 (d, J = 13.5 Hz, 1H), 3.76 (s, 2H), 3.72 (s, 2H), 3.49 (s, 2H), 3.43 (dd, J = 13.7, 8.2 Hz, 1H), 2.98 — 2.83 (m, 4H), 2.64 (d, J = 7.2 Hz, 6H), 1.86 (s, 4H), 1.44 (s, 3H), 1.34 (s, 3H). Example 180: Synthesis of 8-[(1-acetyl-4-piperidyl)oxy|-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl 1-2,2-dimethyl-3H-1,4-benzoxazepin-5-one ho ot 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-piper idyloxy)-3H-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 110-5 as a starting material was used in the same manner as in Example 78-2 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 3 7.59 (dd, J = 8.7, 2.5 Hz, 1H), 7.15 - 7.09 (m, 3H), 7.06 (d, J=6.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.57 (s, 1H), 4.72 (dd, J = 8.6, 4.9 Hz, 1H), 4.29 (s, 1H), 4.04 (d, J= 13.8 Hz, 1H), 3.90 — 3.72 (m, 4H), 3.53 (d, J = 17.0 Hz, 4H), 3.40 (dd, / = 13.9, 8.3 Hz, 1H), 2.91 (dd, J = 19.8, 5.2 Hz, 4H), 2.67 — 2.60 (m, 2H), 2.14 (d, J = 2.4 Hz, 3H), 2.11 —1.93 (m, 2H), 1.79 (d, J = 31.6 Hz, 2H), 1.43 (s, 3H), 1.34 (d, J= 2.4 Hz, 3H). Example 181: Synthesis of 4-[[4-[(2R)-3-~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H- 1,4-benzoxazepin-8-ylJoxy]piperidine-1-carbaldehyde Hey . oe The material obtained in Example 110-5 as a starting material was used in the same manner as in Example 78 to obtain the title compound, except that formic acid was used instead of acetic anhydride in Example 78-2. 'H NMR (400 MHz, Methanol-ds) § 8.06 (s, 1H), 7.63 — 7.56 (m, 1H), 7.12 (s, 3H), 7.07 (s, 1H), 6.85 (d, J=9.1 Hz, 1H), 6.58 (s, 1H), 4.77 (s, 1H), 4.28 (s, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.73 (d, J = 32.7 Hz, 5H), 3.57 — 3.37 (m, 6H), 2.89 (s, 2H), 2.64 (d, J = 7.3 Hz, 2H), 2.03 (s, 2H), 1.77 (s, 2H), 1.43 (s, 3H), 1.33 (d, J= 13.9 Hz, 3H). Example 182: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-2,2-dimethyl-8-[[4-(oxetan- 3-yl)piperazin-1-yljmethyl]-3H-1,4-benzoxazepin-5-one 2 The material obtained in Example 167-1 as a starting material was used in the same manner as in Example 92 to obtain the title compound. 'H NMR (400 MHz, Methanol-dy) 8 7.60 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.17 - 7.01 (m, 4H), 6.99 (s, 1H), 4.70 (t, J = 6.8 Hz, 2H), 4.66 — 4.53 (m, 2H), 4.29 (s, 1H), 4.06 (d, J = 13.9 Hz, 1H), 3.77 (s, 2H), 3.59 (s, 2H), 3.53 (t, J = 7.0 Hz, 1H), 3.48 (s, 2H), 3.42 (dd, J = 13.5, 8.3 Hz, 1H), 3.01 — 2.81 (m, 4H), 2.71 — 2.27 (m, 10H), 1.43 (s, 3H), 1.33 (s, 3H). Example 183: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-7-aza spiro[3.4]octan-7-ylmethyl)-3H-1,4-benzoxazepin-5-one 0 0 0K 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl- 3H-1,4-benzoxazepin-5-one as a starting material was used in the same manner as in Example 29 to obtain the title compound, except that 2-oxa-7-azaspiro[3.4]octane was used instead of 3-methoxyazetidine hydrochloride. 'H NMR (400 MHz, Methanol-ds) § 7.49 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 7.04 — 6.90 (m, 4H), 6.86 (s, 1H), 4.51 (p, J = 5.7, 5.2 Hz, 4H), 4.17 (s, 1H), 3.94 (d, J = 13.6 Hz, 1H), 3.64 (s, 2H), 3.53 (s, 2H), 3.36 (s, 2H), 3.31 (dd, J = 13.9, 8.2 Hz, 2H), 2.85 — 2.68 (m, 6H), 2.60 —2.43 (m, 4H), 2.06 (t, J = 7.3 Hz, 2H), 1.32 (s, 3H), 1.22 (s, 3H). Example 184: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(4-fluoropiperidine-1-car bonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 0 go vi CN o Oo The title compound was synthesized in the same manner as in Example 175, except that 4-fluoropiperidine was used instead of pyrrolidine in Example 175-2. 'H NMR (400 MHz, Methanol-d) & 7.80 (dd, J = 7.9, 2.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.17 — 6.97 (m, 5H), 5.00 — 4.76 (m, 1H), 4.52 (d, J = 5.2 Hz, 2H), 4.24 (d, / = 7.1 Hz, 1H), 4.07 —- 3.83 (m, 2H), 3.76 (d, J = 6.6 Hz, 5H), 3.63 — 3.36 (m, 4H), 2.94 (d, J= 5.6 Hz, 2H), 2.89 (d, J = 5.4 Hz, 2H), 2.67 (d, J = 6.0 Hz, 2H), 2.13 1.70 (m, 3H). Example 185: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[3-(trifluoromethyl)piperi dine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one OH LalrDollyl]=4«,0=Ulllyuro=1,2=DciZo oo 5D A N ow AN oe’ Oo The title compound was synthesized in the same manner as in Example 175, except that 3-triflucromethylpiperidine was used instead of pyrrolidine in Example 175-2. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.05 - 6.81 (m, 5H), 4.66 — 4.23 (m, 3H), 4.13 (q, J = 6.1, 5.4 Hz, 1H), 3.88 (dt, J = 14.2, 2.9 Hz, 1H), 3.64 (d, J= 6.5 Hz, 5H), 3.34 (dd, J = 14.1, 7.8 Hz, 1H), 2.97 (dt, J = 45.9, 12.8 Hz, 2H), 2.81 (d, J=5.6 Hz, 2H), 2.77 (d, J = 5.4 Hz, 2H), 2.54 (d, J = 6.3 Hz, 2H), 2.45 — 2.29 (m, 1H), 1.99 (d, J=12.2 Hz, 1H), 1.70 — 1.37 (m, 3H). Example 186: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(trifluoromethyl)piperi dine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one oO re FC a (AN ot 0 The title compound was synthesized in the same manner as in Example 175, except that 4-trifluoromethylpiperidine was used instead of pyrrolidine in Example 175-2. 'H NMR (400 MHz, Methanol-ds) § 7.75 — 7.61 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.05 - 6.83 (m, 5H), 4.62 (d, J = 13.2 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 4.13 (d, J = 6.7 Hz, 1H), 3.88 (dt, J = 14.0, 3.1 Hz, 1H), 3.63 (s, 5H), 3.34 (dd, J = 14.0, 7.7 Hz, 1H), 3.05 (t, J = 13.9 Hz, 1H), 2.88 — 2.67 (m, 5H), 2.53 (d, J = 6.3 Hz, 2H), 2.47 — 2.30 (m, 1H), 2.01 — 1.83 (m, 1H), 1.75 (d, J = 12.8 Hz, 1H), 1.43 (q, J = 13.5, 12.9 Hz, 2H). Example 187: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,6-dimethylmorpholin-4 -carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one oO Q N Aare AN 4 0 2,6-Dimethylmorpholine (33 pL, 1.1 equiv) was dissolved in 1,4-dioxane (1 mL), and 2 M trimethylaluminum toluene solution (134 pL, 1.1 equiv) was added thereto under the condition of nitrogen at 0°C. The reaction mixture was stirred at room temperature for 1 hour, and methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-ox0-2,3-dihydro-1,4-benzoxa zepine-8-carboxylate (100 mg) dissolved in 1,4-dioxane was added thereto. The reaction solution was stirred at 110°C for 3 hours, and the reaction was terminated with a saturated aqueous potassium sodium tartrate solution, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by flash chromatography to obtain the title compound. 'H NMR (400 MHz, Methanol-dy) 3 7.81 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.18 — 7.00 (m, 5H), 4.63 — 4.44 (m, 3H), 4.33 — 4.18 (m, 1H), 4.00 (dt, J = 13.9, 2.8 Hz, 1H), 3.75 (d, J =7.6 Hz, 4H), 3.71 — 3.55 (m, 2H), 3.55 — 3.39 (m, 2H), 2.99 —- 2.80 (m, 5H), 2.62 (dd, J=23.2, 9.1 Hz, 3H), 1.24 (d, J= 6.5 Hz, 3H), 1.09 (dd, J= 17.3, 6.2 Hz, 3H). Example 188: Synthesis of 8-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hy droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one oO SY. GOL OH 0 The title compound was synthesized in the same manner as in Example 187, except that 2-azabicyclo[2.2.1]heptane was used instead of 2,6-dimethylmorpholine. 'H NMR (400 MHz, Methanol-ds) § 7.86 — 7.73 (m, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.24 — 6.99 (m, SH), 4.52 (q, J = 6.0 Hz, 2H), 4.24 (dd, J= 10.3, 5.4 Hz, 1H), 4.12 (s, 1H), 4.00 (dt, J= 14.1, 3.2 Hz, 1H), 3.75 (d, J = 8.9 Hz, 4H), 3.60 — 3.38 (m, 2H), 3.12 (dd, / = 63.7, 10.4 Hz, 1H), 2.99 — 2.84 (m, 4H), 2.76 — 2.56 (m, 3H), 1.89 — 1.66 (m, 4H), 1.59 (d, / =9.9 Hz, 1H), 1.52 (q, J = 10.4, 7.9 Hz, 1H). Example 189: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-oxa-8-azabicyclo[3.2.1] octan-8-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 0 . 3 GL 0 The title compound was synthesized in the same manner as in Example 187, except that 3-oxa-8-azabicyclo [3.2.1]octane was used instead of 2,6-dimethylmorpholine. 'H NMR (400 MHz, Methanol-ds) 8 7.81 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.15 — 7.02 (m, 4H), 4.64 (s, 1H), 4.53 (d, J = 5.3 Hz, 2H), 4.29 — 4.19 (m, 1H), 4.04 - 3.93 (m, 2H), 3.81 (d, J= 11.5 Hz, 1H), 3.77 — 3.66 (m, 6H), 3.59 (d, J= 11.1 Hz, 1H), 3.46 (dd, J = 14.0, 7.8 Hz, 1H), 2.92 (d, J = 5.7 Hz, 2H), 2.87 (d, J = 5.8 Hz, 2H), 2.65 (d, J = 6.2 Hz, 2H), 2.05 (dd, J = 28.2, 10.9 Hz, 4H). Example 190: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-methylmorpholin-4-ca rbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one oO 0 0 S30 OH 0 The title compound was synthesized in the same manner as in Example 187, except that 2-methylmorpholine was used instead of 2,6-dimethylmorpholine. 'H NMR (400 MHz, Methanol-dy) § 7.81 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.17 — 6.92 (m, SH), 4.62 — 4.35 (m, 3H), 4.24 (dq, J = 11.4, 6.7, 6.1 Hz, 1H), 4.08 — 3.68 (m, 6H), 3.65 —3.18 (m, 5H), 2.92 (d, J = 5.6 Hz, 2H), 2.87 (d, J = 5.7 Hz, 2H), 2.66 (t, J = 7.1 Hz, 2H), 1.23 (h,J=6.1, 5.0 Hz, 2H), 1.06 (d, J = 6.2 Hz, 1H). Example 191: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-methylmorpholin-4-ca rbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one Soh 0 oe! The title compound was synthesized in the same manner as in Example 187, except that 3-methylmorpholine was used instead of 2,6-dimethylmorpholine. 'H NMR (400 MHz, Methanol-d) 8 7.81 (d, J = 8.0 Hz, 1H), 7.28 - 6.97 (m, 6H), 4.51 (d, J = 5.2 Hz, 2H), 4.24 (q, J = 7.3, 6.0 Hz, 1H), 3.99 (dd, J = 13.8, 3.3 Hz, 1H), 3.95 — 3.62 (m, 7H), 3.59 -3.39 (m, 3H), 3.06 — 2.72 (m, 4H), 2.67 (d, J = 6.1 Hz, 2H), 1.37 (d, J = 7.0 Hz, 3H). Example 192: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-2,2-dimethyl-8-(morpholino methyl)-3H-pyrido|3,2-f][1,4]oxazepin-5-one NN _ o 0K 8-Chloro-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl- 3H-pyrido[3,2-f][1,4]oxazepin-5-one as a starting material was used in the same manner as in Example 22 to obtain the title compound. 'H NMR (400 MHz, Methanol-dy) § 8.14 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 7.0 Hz, 1H), 7.19 — 7.01 (m, 4H), 4.35 — 4.21 (m, 1H), 4.05 (d, J = 13.8 Hz, 1H), 3.77 (s, 2H), 3.73 (s, 4H), 3.62 (s, 4H), 3.45 (dd, J = 14.0, 8.6 Hz, 1H), 2.92 (s, 2H), 2.89 (s, 2H), 2.66 (q, J = 5.7, 4.1 Hz, 2H), 1.50 (s, 3H), 1.43 (s, 3H). Example 193: Synthesis of 8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta|c]pyrrol-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one © ren ee rh OO =e yard Example Synthesis of potassium;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-0x0-2,3-dihydr 0-1,4-benzoxazepin-8-carboxylate Methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-ox0-2,3-dihydro-1,4-benzoxa zepin-8-carboxylate and potassium trimethylsilanoate were dissolved in tetrahydrofuran and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and used in the next reaction without additonal purification. Example 193-2: Synthesis of 8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta|c]pyrrol-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H- isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one The starting material (100 mg, 1.0 equiv) obtained in Example 193-1, octahydrocyclopenta[c]pyrrole (1.5 equiv), HATU (131 mg, 1.5 equiv) and diisopropylethylamine (120 pL, 3 equiv) were dissolved in methylene chloride and stirred at room temperature for 2 hours. The reaction solution was extracted with methylene chloride, dried over magnesium sulfate and purified by flash chromatography to obtain the title compound. '"H NMR (400 MHz, Methanol-ds) 7.66 (dd, J = 8.0, 2.1 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.08 — 6.89 (m, 5H), 4.41 (q, J=5.7 Hz, 2H), 4.13 (dd, / = 9.8, 5.2 Hz, 1H), 3.88 (dt, / = 14.2, 3.1 Hz, 1H), 3.75 — 3.60 (m, 5H), 3.55 (dd, J= 11.4, 7.9 Hz, 1H), 3.43 — 3.34 (m, 2H), 3.21 (d, / = 2.8 Hz, 2H), 3.18 — 3.07 (m, 1H), 2.89 — 2.73 (m, 4H), 2.73 — 2.46 (m, 4H), 1.73 (ddt, J = 39.4, 20.0, 7.0 Hz, 3H), 1.49 (ddt, J = 33.3, 12.5, 6.8 Hz, 2H), 1.28 (dt, J= 11.8, 5.8 Hz, 1H). Example 194: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(3-fluoropiperidine-1-car bonyl)-2,3-dihydro-1,4-benzoxazepin-5-one x dey )=UHLYUIO=1,24=DCILVALLL I HIT=0O" LoCo Wonk N, A oo o The title compound was synthesized in the same manner as in Example 193, except that 3-fluoropiperidine was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.06 — 6.89 (m, 5H), 4.57 (d, J = 48.2 Hz, 1H), 441 (t, J = 5.1 Hz, 2H), 4.33 — 4.08 (m, 2H), 3.89 (dd, J = 13.8, 3.2 Hz, 1H), 3.64 (d, J = 7.0 Hz, 5H), 3.52 — 3.23 (m, 3H), 3.17 —- 2.95 (m, 1H), 2.90 — 2.71 (m, 4H), 2.54 (d, J = 6.2 Hz, 2H), 1.89 — 1.65 (m, 2H), 1.50 (d, J= 50.2 Hz, 1H). Example 195: Synthesis of 8-(2,2-difluoromorpholin-4-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydro xy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 3 roo Cad o The title compound was synthesized in the same manner as in Example 193, except that 2,2-difluoromorpholine was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2. 'H NMR (400 MHz, Methanol-dy) § 7.70 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.08 — 6.89 (m, 5H), 4.41 (d, J = 5.3 Hz, 2H), 4.14 (d, J = 6.5 Hz, 1H), 4.08 — 3.77 (m, SH), 3.71 — 3.42 (m, 6H), 3.36 (dd, J = 14.1, 7.7 Hz, 1H), 3.23 (d, J = 16.0 Hz, 2H), 2.87 — 2.74 (m, 4H), 2.56 (d, J=6.1 Hz, 28). Example 196: Synthesis of 8-(4,4-difluoropiperidine-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydrox y-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one Fi : bay ° MN Oro YA YO The title compound was synthesized in the same manner as in Example 193, except that 4,4-difluoropiperidine was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (dd, J = 8.0, 2.2 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.06 — 6.91 (m, SH), 4.46 — 4.34 (m, 2H), 4.14 (dd, J = 7.2, 3.9 Hz, 1H), 3.85 (dt, J = 14.0, 3.2 Hz, 1H), 3.75 (s, 1H), 3.70 (s, 2H), 3.62 (s, 2H), 3.42 (m, 3H), 2.93 — 2.78 (m, 4H), 2.59 (d, / =5.9 Hz, 2H), 2.12 — 1.78 (m, 4H). Example 197: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-2,2-dimethyl-8-(1-piperidyl methyl)-3H-pyrido|3,2-f][1,4]oxazepin-5-one I 0 MO ey J NA) OH oe 0K 8-Chloro-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl- 3H-pyrido[3,2-f][1,4]oxazepin-5-one as a starting material was used in the same manner as in Example 23 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) § 8.13 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.19 — 7.01 (m, 4H), 4.29 (s, 1H), 4.06 (d, J = 13.7 Hz, 1H), 3.75 (s, 2H), 3.69 — 3.54 (m, 4H), 3.45 (dd, J=137, 83 Hz, 1H), 3.00 — 2.80 (m, 4H), 2.72 — 2.57 (m, 2H), 2.50 (s, 4H), 1.70 — 1.58 (m, 4H), 1.50 (s, 5H), 1.44 (s, 3H). Example 198: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[methyl(oxetan-3-yl)am ino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 0° Boe ° HN, ECO — Qo edo — Q,olyw00 2HC| TO, bre 0 Example 198-1: Synthesis of tert-butyl N-[4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinelin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4 -benzoxazepin-8-ylJoxy]cyclohexyl]-N-methyl-carbamate The title compound was synthesized in the same manner as in Example 64, except that [4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl] methanesulfonate, cesium carbonate and acetonitrile were used instead of 4-chlorotetrahydropyran, potassium carbonate and dimethylformamide, respectively. 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl|-8-[4-(methylamino)cyclohex 0xy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride Tert-butyl N-[4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-ox0-2,3-dihydro-1,4-be nzoxazepin-8-ylJoxy]cyclohexyl]-N-methyl-carbamate obtained in Example 198-1 was dissolved in methanol, and 4 M hydrochloric acid solution dissolved in 1,4-dioxane was slowly added thereto. The reaction solution was stirred at room temperature, diluted with diethyl ether and filtered to obtain the solid title compound. Example 198-3: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[methyl(oxetan-3-yl)am ino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-(methylamino)cycl ohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 198-2 as a starting material was used in the same manner as in Example 87 to obtain the title compound, except that oxetan-3-one was used instead of paraformaldehyde. '"H NMR (400 MHz, Methanol-dy) 3 7.67 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 3.8 Hz, 3H), 7.06 (d, J = 6.5 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.58 (s, 1H), 4.67 (d, J = 7.1 Hz, 4H), 4.61 (s, 1H), 4.46 (d,J= 5.5 Hz, 2H), 4.23 (d, J= 7.3 Hz, 1H), 4.06 (q, J = 7.3 Hz, 1H), 3.97 (dd, J = 14.0, 3.6 Hz, 1H), 3.78 (s, 2H), 3.73 (d, J = 5.4 Hz, 2H), 3.43 (dd, J = 14.0, 7.6 Hz, 1H), 2.97 — 2.86 (m, 4H), 2.67 (d, J = 6.2 Hz, 2H), 2.47 (t, J = 11.2 Hz, 1H), 2.24 (s, 3H), 2.12 (d, J = 12.0 Hz, 2H), 1.64 (tt, J=23.8, 11.0 Hz, 6H). Example 199: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[2-fluoroethyl(methyl)a mino|cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one FANN —~ i+} oe VO PN. opt 0 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-(methylamino)cycl ohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride (200 mg, 0.362 mmol) obtained in Example 198-2, potassium carbonate (150 mg, 1.086 mmol) and 2-fluoroethyl 4-methylbenzenesulfonate (93 ul, 0.543 mmol) were dissolved in acetonitrile and stirred at 100°C for one day. To the reaction mixture, saturated aqueous ammonium chloride aqueous solution was added and extracted with ethyl acetate 3 times. The oily liquid obtained by drying the combined organic layers over anhydrous sodium sulfate and concentrating under reduced pressure was purified by flash chromatography to obtain the title compound (45 mg). 'H NMR (400 MHz, Methanol-ds) 8 7.67 (dd, J = 8.9, 2.5 Hz, 1H), 7.10 (d, J = 3.5 Hz, 3H), 7.04 (d,J=6.6 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.58 (s, 1H), 4.61 (q, J = 4.0 Hz, 2H), 4.47 (dq, J = 12.2, 4.3, 3.9 Hz, 3H), 4.22 (dq, J= 10.0, 5.8, 5.0 Hz, 1H), 3.97 (dd, J = 13.9, 3.1 Hz, 1H), 3.72 (d, J=9.9 Hz, 4H), 3.45 — 3.35 (m, 1H), 2.86 (td, J = 23.1, 4.6 Hz, 6H), 2.69 — 2.50 (m, 3H), 2.37(d,J=2.5 Hz, 3H), 2.12 (d, J = 12.8 Hz, 2H), 1.75 — 1.56 (m, 6H). Example 200: Synthesis of (2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[(1-ethanethiol-4-pip eridyl)oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one Qe boy ol C0 Example Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(4-piperidyloxy)-2,3-dihy dro-1,4-benzoxazepin-5-one dihydrochloride The material, which is obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate to [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140, as a starting material was used in the same manner as in Example 78-1 to obtain the title compound. Example 200-2: Synthesis of 8-[(1-acetyl-4-piperidyl)oxy|4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl ]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one The material obtained in Example 200-1 as a starting material was used in the same manner as in Example 78-2 to obtain the title compound Example 200-3: Synthesis of (28)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethanethiol-4-pip eridyl)oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one The material obtained in Example 200-2 as a starting material was dissolved in tetrahydrofuran, and Lawesson’s reagent was added thereto. The reaction mixture was stirred at 50°C until the reaction was completed, the reaction solution was cooled to room temperature, distilled water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by flash chromatography to obtain the title compound. '"H NMR (400 MHz, Methanol-ds) 8 8.19 — 8.09 (m, 1H), 7.65 — 7.55 (m, 1H), 7.29 (d, / =9.3 Hz, 2H), 6.89 (dd, J = 32.8, 8.6 Hz, 3H), 5.46 (s, 1H), 4.80 (s, 1H), 4.65 (s, 1H), 4.44 (s, 2H), 4.18 — 4.07 (m, 2H), 3.99 (s, 1H), 3.83 (d, J = 2.4 Hz, 5H), 3.60 — 3.45 (m, 1H), 2.67 (s, 2H), 2.14 -2.00 (m, 3H), 1.95 - 1.80 (m, 2H), 1.35 — 1.20 (m, 3H), 1.03 (d, J = 6.3 Hz, 2H). Example 201: Synthesis of (2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-fluoroethyl)aze tidin-3-yljoxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one he ol or GO Example 201-1: Synthesis of 8-(azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-meth yl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride The intermediate in which Boc is substituted was synthesized by using the material obtained in the same manner as in Examples 140-1 to 140-5 except that [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate was used instead of [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate as a starting material and the method in the same manner as in Example 64 except that tert-butyl 3-hydroxyazetidine-1-carboxylate is used instead of 4-chlorotetrahydropyran. The obtained intermediate was dissolved in methanol, and 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added thereto. The reaction solution was stirred at room temperature until the reaction was terminated, diluted with ethyldiethyl ether and filtered to obtain the title compound (2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-fluoroethyl)aze tidin-3-yljoxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one The materal obtained in Example 201-1 as a starting material, 2-fluoroethyl para-toluenesulfonate and potassium carbonate were dissolved in acetonitrile, and the reaction solution was stirred at 60°C for one day. The reaction mixture was cooled to room temperature, diluted with distilled water, and extracted with ethyl acetate 3 times. The combined organic layers were washed twice with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrate was purified by flash chromatography to obtain the solid title compound. 'H NMR (400 MHz, Methanol-ds) § 7.62 (dd, J = 8.7, 2.5 Hz, 1H), 7.12 (d, J = 3.7 Hz, 3H), 7.06 (d, J = 6.6 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.43 (d, J = 3.2 Hz, 1H), 4.82 (ddd, J = 10.1, 6.6, 3.4 Hz, 1H), 4.55 (q, J = 3.9 Hz, 1H), 4.43 (q, J = 3.9 Hz, 1H), 4.25 (1d, J = 6.8, 3.6 Hz, 1H), 3.90 (t, J=7.4 Hz, 2H), 3.80 (d, J = 14.0 Hz, 3H), 3.62 (dt, / = 15.2, 3.4 Hz, 2H), 3.46 (ddd, J = 15.0, 9.8, 5.3 Hz, 1H), 2.90 (tdd, J = 20.0, 9.1, 4.9 Hz, 7H), 2.68 (dd, J = 6.4, 2.4 Hz, 2H), 1.38 — 1.25 (m, 4H). Example 202: Synthesis of (28)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-fluoroethyl)-4- piperidyl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one Fern Lote The matetial obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate to [(1R)-2-(fert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 as a starting material was used in the same manner as in Example 163 to obtain the title compound. '"H NMR (400 MHz, Methanol-ds) 8 7.61 (dd, J = 8.6, 2.1 Hz, 1H), 7.12 (d, J = 3.2 Hz, 3H), 7.06 (d,J= 6.5 Hz, 1H), 6.79 (d, J= 8.7 Hz, 1H), 6.55 (s, 1H), 4.67 (s, 1H), 4.58 — 4.49 (m, 2H), 4.24 (s, 1H), 3.78 (d, J = 8.0 Hz, 2H), 3.67 — 3.58 (m, 2H), 3.47 (dd, J = 15.6, 9.3 Hz, 1H), 2.93 (d, J = 5.4 Hz, 2H), 2.91 —- 2.81 (m, 4H), 2.80 (s, 1H), 2.73 (t, J = 5.2 Hz, 1H), 2.66 (d, J = 6.4 Hz, 2H), 2.52 (t, J = 10.2 Hz, 2H), 2.05 (d, J = 10.5 Hz, 2H), 1.85 (s, 2H), 1.31 — 1.26 (m, 3H). Example 203: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(3-oxa-8-aza bicyclo[3.2.1]octan-8-carbonyl)-3H-1,4-benzoxazepin-5-one o o Correo 0 of Potassium; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo0-3H-1,4-ben zoxazepine-8-carboxylate as a starting material was used in the same manner as in Example 193 to obtain the title compound, except that 3-oxa-8-azabicyclo [3.2.1]octane was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2, 'H NMR (400 MHz, Methanol-ds) 8 7.62 (d, J = 7.9 Hz, 1H), 7.28 — 7.15 (m, 1H), 7.06 — 6.88 (m, 5H), 4.53 (s, 1H), 4.26 — 4.08 (m, 1H), 3.98 — 3.92 (m, 1H), 3.84 (s, 1H), 3.70 (d, J= 11.0 Hz, 1H), 3.61 (d, J=26.9 Hz, 4H), 3.48 (d, J= 11.0 Hz, 1H), 3.39 (s, 2H), 3.32 (dd, / = 13.7, 8.3 Hz, 1H), 2.84 — 2.72 (m, 4H), 2.58 — 2.48 (m, 2H), 1.33 (s, 3H), 1.23 (s, 3H). Example 204: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-5-aza bicyclo[2.2.1]heptan-5-carbonyl)-3H-1,4-benzoxazepin-5-one 0 C_ over oO o( Potassium; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2,2-dimethyl-5-oxo0-3H-1,4-ben zoxazepine-8-carboxylate as a starting material was used in the same manner as in Example 193 to obtain the title compound, except that 2-oxa-5-azabicyclo[2.2.1]heptane was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2. 'H NMR (400 MHz, Methanol-ds) § 7.67 — 7.55 (m, 1H), 7.30 — 7.16 (m, 1H), 7.07 — 6.86 (m, 5H), 4.24 — 4.10 (m, 1H), 4.02 — 3.89 (m, 1H), 3.85 (dd, = 7.7, 3.4 Hz, 1H), 3.71 (ddd, J = 31.5, 7.7,1.6 Hz, 1H), 3.64 (s, 2H), 3.53 — 3.42 (m, 1H), 3.42 — 3.35 (m, 3H), 3.32 (td, J = 6.5,4.9, 2.5 Hz, 1H), 2.84 — 2.69 (m, 4H), 2.58 — 2.45 (m, 2H), 1.95 — 1.72 (m, 2H), 1.40 — 1.27 (m, 3H), 1.27- 1.17 (m, 3H). Example 205: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(3,5-dimethylmorpholin-4 -carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one O™N— 0 YOO oO o( Potassium; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2,2-dimethyl-5-ox0-3H-1,4-ben zoxazepine-8-carboxylate as a starting material was used in the same manner as in Example 193 to obtain the title compound, except that 3,5-dimethylmorpholine was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2, '"H NMR (400 MHz, Methanol-ds) 8 7.58 (d, J = 7.8 Hz, 1H), 7.13 (dd, J = 7.8, 1.6 Hz, 1H), 7.05 —6.91 (m, 4H), 6.89 (d, J = 1.6 Hz, 1H), 4.16 (q, / = 7.9, 6.8 Hz, 1H), 3.94 (dd, / J= 13.7, 3.7 Hz, 1H), 3.69 — 3.51 (m, 4H), 3.45 — 3.25 (m, 7H), 2.80 (d, J = 5.7 Hz, 2H), 2.77 - 2.71 (m, 2H), 2.52 (dd, J = 6.3, 3.8 Hz, 2H), 1.40 (s, 6H), 1.32 (s, 3H), 1.22 (s, 3H). Example 206: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-1-methyl-4-pip eridyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 0 Boc, ECO LTO ah ~ Raye Boc, 0 HCI Example 206-1: Synthesis of tert-butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-0x0-2,3-dihydro-1,4-be nzoxazepin-8-yl]oxy]-3-fluoro-piperidine-1-carboxylate The title compound was synthesized in the same manner as in Example 64, except that tert-butyl 3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate, cesium carbonate and acetonitrile were used instead of 4-chlorotetrahydropyran, potassium carbonate and dimethylformamide, respectively. Example 206-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(3-fluoro-4-piperidyl)oxy] -2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride Tert-butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-y1)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzo xazepin-8-yl]oxy]-3-fluoro-piperidine-1-carboxylate obtained in Example 206-1 was dissolved in methanol, and 4 M hydrochloric acid solution dissolved in 1,4-dioxane was slowly added thereto. The reaction solution was stirred at room temperature, diluted with diethyl ether and filtered to obtain the solid title compound. Example 206-3: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(3-fluoro-1-methyl-4-pipe ridyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxypropyl]-8-[(3-fluoro-4-piperidyl) oxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 206-2 as a starting material was used in the same manner as in Example 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 8.8 Hz, 1H), 7.18 — 7.06 (m, 3H), 7.06 — 7.01 (m, 1H), 6.82 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 4.79 — 4.43 (m, 4H), 429 — 4.18 (m, 1H), 3.98 (dd, J = 13.9, 3.6 Hz, 1H), 3.78 — 3.64 (m, 4H), 3.42 (dd, J = 13.9, 7.7 Hz, 1H), 3.07 - 2.83 (m, 5H), 2.74 — 2.58 (m, 3H), 2.51 (q, J = 8.2, 7.7 Hz, 1H), 2.36 (s, 4H), 2.24 - 2.15 (m, 1H), 1.77 (dtd, J = 13.1, 9.0, 3.7 Hz, 1H). Example 207: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[[3-fluoro-1-(2-fluoroethy 1)-4-piperidyljoxy]-2,3-dihydro-1,4-benzoxazepin-5-one F gC Fan orb LHe oo F 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(3-fluoro-4-piperidyl) oxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 206-2 as a starting material was used in the same manner as in Example 163 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 3 7.67 (d, J = 8.8 Hz, 1H), 7.17 — 7.02 (m, 4H), 6.82 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 4.65 (dq, J = 5.6, 4.6 Hz, 2H), 4.56 — 4.45 (m, 4H), 4.27-4.17 (m, 1H), 3.98 (dd, J = 13.9, 3.6 Hz, 1H), 3.81 — 3.69 (m, 4H), 3.43 (dd, J=13.9,7.7 Hz, 1H), 2.94 (d, J = 5.4 Hz, 2H), 2.90 — 2.83 (m, 4H), 2.79 (dt, J = 9.4, 5.0 Hz, 2H), 2.76 — 2.71 (m, 1H), 2.68 — 2.62 (m, 2H), 2.53 (dd, J = 11.2, 7.5 Hz, 1H), 2.47 — 2.38 (m, 1H), 2.21 (dd, J = 9.7,4.6 Hz, 1H), 1.76 (dd, J= 11.9, 7.8 Hz, 1H). Example 208: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[[3-fluoro-1-(2-hydroxyet hyl)-4-piperidyljoxy|-2,3-dihydro-1,4-benzoxazepin-5-one PF ~N © HO oH OH LAosAos : 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(3-fluoro-4-piperidyl) oxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 206-2 as a starting material was used in the same manner as in Example 162 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.8 Hz, 1H), 7.17 — 7.00 (m, 4H), 6.81 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 4.67 (dtd, J = 49.2, 8.2, 4.6 Hz, 1H), 4.48 (, J = 5.0 Hz, 3H), 4.23 (s, 1H), 3.98 (dd, J = 13.9, 3.6 Hz, 1H), 3.82 — 3.62 (m, 6H), 3.43 (dd, J = 13.9, 7.6 Hz, 1H), 3.26 — 3.14 (m, 1H), 2.98 — 2.80 (m, 5H), 2.71 — 2.56 (m, 4H), 2.47 (q, J = 8.9, 8.3 Hz, 1H), 2.37 (t, J = 10.4 Hz, 1H), 2.26 — 2.14 (m, 1H), 1.80 — 1.65 (m, 1H). Example 209: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,4-dihydro-1H-pyrrolo[ 1,2-a]pyrazine-2-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one oO EN ole - LN oA o Potassium;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl -5-0x0-3H-1,4-benzoxazepin-8-carboxylate as a starting material was used in the same manner as in Example 193 to obtain the title compound, except that 1,2,3,4-tetrahydropyrrol [1,2-a]pyrazine was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2. 'H NMR (400 MHz, Methanol-ds) 8 7.75 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.21 - 6.96 (m, 5H), 6.65 (s, 1H), 6.08 (d, J = 16.4 Hz, 1H), 5.85 (d, J = 81.0 Hz, 1H), 4.87 (s, 1H), 4.62 (s, 1H), 4.32 (it, J = 8.5, 4.3 Hz, 1H), 4.20 — 3.96 (m, 4H), 3.79 (d, J = 20.8 Hz, 3H), 3.56 — 3.40 (m, 3H), 2.95 (q, J = 5.0, 4.2 Hz, 4H), 2.70 (t, J = 5.6 Hz, 2H), 1.45 (s, 3H), 1.36 (s, 3H). Example 210: Synthesis of 8-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a] pyrazine-2-carbonyl)-4-[ (2R)-3-(3,4-dihydro-1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one oO Ry, cbt Potassium;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl -5-0x0-3H-1,4-benzoxazepin-8-carboxylate as a starting material was used in the same manner as in Example 193 to obtain the title compound, except that 1,2,3,4,6,7,8,8a-octahydropyrrol [1,2-a]pyrazine was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2. 'H NMR (400 MHz, Methanol-ds 8 7.73 (d, J = 7.8 Hz, 1H), 7.26 (dd, J= 7.8, 1.6 Hz, 1H), 7.18 — 6.96 (m, 5H), 4.70 (dd, J = 50.1, 13.0 Hz, 1H), 4.30 (dd, J = 7.5, 3.6 Hz, 1H), 4.07 (d, J = 14.6 Hz, 1H), 3.79 (s, 3H), 3.52 (s, 2H), 3.44 (dd, J = 13.8, 8.4 Hz, 1H), 3.33 (p, J= 1.7 Hz, 4H), 3.23 — 3.05 (m, 2H), 2.98 (d, J = 12.7 Hz, 1H), 2.75 — 2.63 (m, 2H), 2.25 (q, J = 12.1, 11.3 Hz, 2H), 2.13 — 1.98 (m, 2H), 1.88 (dd, J = 48.6, 16.4 Hz, 4H), 1.62 - 1.51 (m, 1H), 1.45 (s, 3H), 1.35 (s, 3H). Example 211: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(5-fluoropyrimidin-2-yl)o xy-2,3-dihydro-1,4-benzoxazepin-5-one oo eH [8 oo” 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro- 1,4-benzoxazepin-5-one (1.0 equiv), 2-chloro-5-flucropyrimidine (1.5 equiv) and cesium carbonate (2 equiv) were dissolved in acetonitrile and heated to reflux overnight. The reaction solution was extracted with ethyl acetate. The separated organic layer was dried over magnesium sulfate, concentrated and purified by flash chromatography to obtain the title compound. 'H NMR (400 MHz, Methanol-d4) § 8.46 (s, 2H), 7.67 (d, J = 8.6 Hz, 1H), 7.08 — 6.92 (m, 4H), 6.89 (dd, J=8.6, 2.4 Hz, 1H), 6.77 (d, J = 2.3 Hz, 1H), 4.39 (t, J= 5.0 Hz, 2H), 4.14 (tt, J= 7.6, 3.6 Hz, 1H), 3.87 (dd, J = 13.9, 3.6 Hz, 1H), 3.70 (d, J = 2.3 Hz, 2H), 3.65 (t, / = 5.1 Hz, 2H), 3.35(dd,J=13.9, 7.6 Hz, 1H), 2.87 — 2.75 (m, J = 4.4, 3.8 Hz, 4H), 2.62 — 2.54 (m, 2H). Example 212: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-p iperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one oe, he 4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-d ihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 78-1 was dissolved in a mixture solution of water and acetonitrile, and 2-methoxirane and sodium hydroxide were added thereto and stirred at room temperature for 1 hour. To the reaction mixture, water was added and extracted with ethyl acetate 3 times. The oily liquid obtained by drying the combined organic layers over anhydrous sodium sulfate and concentrating under reduced pressure was purified by flash chromatography to obtain the title compound as a white solid. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.8 Hz, 1H), 7.17 - 6.97 (m, 4H), 6.76 (dd, J = 8.8,2.5 Hz, 1H), 6.59 (d, / = 2.5 Hz, 1H), 4.49 (dt, J = 18.2, 4.4 Hz, 3H), 4.23 (t, J = 5.4 Hz, 1H), 4.04 — 3.91 (m, 2H), 3.83 — 3.67 (m, 4H), 3.43 (dd, J = 13.9, 7.6 Hz, 1H), 3.00 — 2.83 (m, 6H), 2.69 — 2.41 (m, 6H), 2.05 (d, J= 14.9 Hz, 2H), 1.93 — 1.78 (m, 2H), 1.18 (d, J = 6.2 Hz, 3H). Example 213: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)ox y]-2,3-dihydro-1,4-benzoxazepin-5-one Q N ~ cass CC AIL Example 213-1: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-piperidyl)oxy]-2,3-dih ydro-1,4-benzoxazepin-5-one dihydrochloride The title compound was synthesized in the same manner as in Examples 64 and 78-1, except that tert-butyl (S)-3-methylsulfonyloxypiperidine-1-carboxylate was used instead of 4-chlorotetrahydropyran in Example 64. y]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-piperidyl)oxy]-2,3 -dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 213-1 as a starting material was used in the same manner as in Example 87 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.60 (d, J = 8.8 Hz, 1H), 7.12 — 6.92 (m, 4H), 6.70 (dd, J = 8.8,2.5 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 4.40 (t, J = 5.0 Hz, 3H), 4.15 (q, J = 7.1, 5.2 Hz, 1H), 3.90 (dd, J = 13.9, 3.6 Hz, 1H), 3.76 — 3.53 (m, 4H), 3.36 (dd, J= 13.9, 7.6 Hz, 1H), 2.92 - 2.72 (m, 5H), 2.63 — 2.45 (m, 3H), 2.28 (s, 4H), 2.04 — 1.76 (m, 3H), 1.58 (d, / = 20.6 Hz, 2H). Example 214: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-propanoyl-2,3-dihydro-1, 4-benzoxazepin-5-one 8 aS CSE ge Tops Yh o o Example 214-1: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-N-methoxy-N-methyl-5-oxo -2,3-dihydro-1,4-benzoxazepine-8-carboxamide The title compound was synthesized in the same manner as in Example 193-2, except that N,O-dimethylhydroxyamine hydrochloride was used instead of octahydrocyclopenta[c]pyrrole. 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-N-methoxy-N-methyl-5 -0x0-2,3-dihydro-1,4-benzoxazepin-8-carboxamate (700 mg, equiv) was dissolved in tetrahydrofuran, and 1 M ethylmagnesium bromide (2 mL, tetrahydrofuran solution) was added thereto at 0°C. The reaction solution was stirred at room temperature for 5 hours, extracted with ethyl acetate, dried over magnesium sulfate and purified by flash chromatography to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.74 — 7.59 (m, 2H), 7.50 (d, J = 1.6 Hz, 1H), 7.05 - 6.86 (m, 4H), 4.40 (t, J= 5.1 Hz, 2H), 4.12 (tdd, J = 7.5, 5.4, 3.6 Hz, 1H), 3.88 (dd, J= 13.8, 3.6 Hz, 1H), 3.70 - 3.61 (m, 2H), 3.60 (dt, J= 5.0, 2.5 Hz, 2H), 3.40 — 3.30 (m, 1H), 2.94 (q, J = 7.2 Hz, 2H), 2.89 — 2.69 (m, 4H), 2.58 — 2.52 (m, 2H), 1.07 (t, / = 7.2 Hz, 3H). Example 215: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabi cyclo[3.2.1)octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one LO Fan or 9, o- Example 215-1: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[-8-azabicyclo[3.2.1]octan -3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride The intermediate was synthesized by changing 4-chlorotetrahydropyran to fert-butyl 3-methylsulfonyloxy-8-azabicyclo [3.2.1]octane-8-carboxylate in Example 64. The obtained intermediate was dissolved in methanol, and 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added thereto. The mixture was stirred at room temperature until the reaction was completed, diluted with ethyl diethyl ether and filtered to obtain the title compound as a white solid in the form of divalent dihydrochloride. Example Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabi cyclo[3.2.1)octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[-8-azabicyclo[3.2.1]o ctan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 215-1 as a starting material was used in the same manner as in Example 163 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.68 (d, J = 8.8 Hz, 1H), 7.18 - 6.99 (m, 4H), 6.69 (dd, J = 8.8,2.5 Hz, 1H), 6.50 (d, J= 2.4 Hz, 1H), 4.65 (dt, J= 9.8, 5.0 Hz, 2H), 4.54 (t, J= 5.0 Hz, 1H), 4.47 (t,J = 5.0 Hz, 2H), 4.24 (d, J = 5.7 Hz, 1H), 3.98 (dd, / = 13.9, 3.7 Hz, 1H), 3.74 (dd, J = 11.1, 6.0 Hz, 4H), 3.43 (dd, J = 13.9, 7.6 Hz, 1H), 3.36 (s, 2H), 2.88 (ddd, J = 26.4, 14.4, 5.1 Hz, 5H), 2.76 (t, J= 5.0 Hz, 1H), 2.69 — 2.60 (m, 2H), 2.23 (d, J = 15.2 Hz, 2H), 2.16 — 1.98 (m, 4H), 1.98 — 1.90 (m, 2H). Example 216: Synthesis of 8-(cyclopropanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-2 ,3-dihydro-1,4-benzoxazepin-5-one Qo ALOR g ¥.,, / oH The title compound was synthesized in the same manner as in Example 241, except that cyclopropylmagnesium bromide was used instead of ethylmagnesium bromide in Example 214-2. 'H NMR (400 MHz, Methanol-dy) 8 7.70 (d, J = 1.1 Hz, 2H), 7.54 (d, J = 1.1 Hz, 1H), 7.07 — 6.80 (m, 4H), 4.39 (t, J = 5.1 Hz, 2H), 4.17 - 4.06 (m, 1H), 3.87 (dd, J = 13.8, 3.6 Hz, 1H), 3.69 —3.51 (m, 4H), 3.33 (dd, / = 13.8, 7.7 Hz, 1H), 2.80 (t, J = 6.2 Hz, 2H), 2.73 (dd, J = 8.8, 3.7 Hz, 2H), 2.71 — 2.66 (m, 1H), 2.59 — 2.45 (m, 2H), 1.07 — 0.92 (m, 4H). Example 217: Synthesis of 8-(cyclopentanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2, 3-dihydro-1,4-benzoxazepin-5-one Qos ALENT The title compound was synthesized in the same manner as in Example 241, except that cyclopentylmagnesium bromide was used instead of ethylmagnesium bromide in Example 214-2. 'H NMR (400 MHz, Methanol-ds) 8 7.75 — 7.60 (m, 2H), 7.51 (d, J = 1.5 Hz, 1H), 7.04 — 6.88 (m, 4H), 4.41 (t, J = 5.1 Hz, 2H), 4.13 (tdd, J = 7.5, 5.3, 3.5 Hz, 1H), 3.88 (dd, J = 13.9, 3.6 Hz, 1H), 3.75 — 3.58 (m, 5H), 3.36 (dd, J = 13.9, 7.7 Hz, 1H), 2.87 — 2.70 (m, 4H), 2.61 — 2.49 (m, 2H), 1.86 (dtd, J = 10.2, 7.6, 6.0, 2.9 Hz, 2H), 1.74 (dq, J = 13.3, 7.2 Hz, 2H), 1.66 — 1.51 (m, 4H). Example 218: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(1-methyl-3- piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one m N Cobre CO ., oo The title compound was synthesized in the same manner as in Example 64, except that [rac-(3R)-1-methyl-3-piperidyl] methanesulfonate was used instead of 4-chlorotetrahydropyran. '"H NMR (400 MHz, Methanol-ds) 3 7.67 (d, J = 8.8 Hz, 1H), 7.18 — 7.00 (m, 4H), 6.77 (dd, J = 8.8, 2.5 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 4.49 (dt, J = 14.9, 4.4 Hz, 3H), 4.27 — 4.18 (m, 1H), 3.98 (dd, J = 13.9, 3.6 Hz, 1H), 3.81 — 3.68 (m, 4H), 3.42 (dd, J = 13.9, 7.7 Hz, 1H), 2.94 (t, J = 6.2 Hz, 2H), 2.90 — 2.79 (m, 3H), 2.68 — 2.54 (m, 3H), 2.33 (s, 4H), 2.08 — 1.80 (m, 3H), 1.73 — 1.53 (m, 2H). Example 219: Synthesis of (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-8-[[1-(2-hydroxyethyl) -4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one HO _~ o oe P The material, which is obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140, as a starting material was used in the same manner as in Example 162 to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.62 (d, J = 8.7 Hz, 1H), 7.18 — 7.02 (m, 4H), 6.80 (dd, J = 8.7, 2.5 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.79 (dt, J= 7.2, 3.6 Hz, 1H), 4.56 (s, 1H), 4.30 — 4.20 (m, 1H), 4.15 (dd, J = 13.7, 3.7 Hz, 1H), 3.84 — 3.70 (m, 3H), 3.64 (dd, J = 15.5, 3.4 Hz, 1H), 3.50 (dd, J = 15.5, 7.7 Hz, 1H), 3.26 — 3.18 (m, 2H), 2.93 (dd, J = 15.1, 4.1 Hz, SH), 2.79 — 2.58 (m, 5H), 2.08 (d, J = 9.8 Hz, 2H), 1.89 (s, 2H), 1.32 (s, 3H). Example 220: Synthesis of (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl}-8-|[[1-(2-hydroxy-2-me thyl-propyl)-4-piperidyljoxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one The matetial obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 as a starting material was used in the same manner as in Example 212 to obtain the title compound, except that 2,2-dimethyloxirane was used instead of 2-methoxirane. 'H NMR (400 MHz, Methanol-ds} 8 7.61 (d, J = 8.7 Hz, 1H), 7.17 - 7.02 (m, 4H), 6.77 (dd, J = 8.8, 2.5 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 4.84 — 4.74 (m, 1H), 4.44 (dt, J = 8.0, 4.1 Hz, 1H), 4.29-4.19 (m, 1H), 4.15 (dd, J= 13.7, 3.6 Hz, 1H), 3.78 (d, / = 11.8 Hz, 2H), 3.63 (dd, J = 15.6, 3.4 Hz, 1H), 3.49 (dd, J = 15.6, 7.6 Hz, 1H), 3.23 (dd, J = 13.8, 8.2 Hz, 1H), 2.91 (dt, J = 19.8, 5.5 Hz, 6H), 2.68 — 2.50 (m, 4H), 2.38 (s, 2H), 2.08 — 1.97 (m, 2H), 1.85 — 1.75 (m, 2H), 1.32 (dd, J=17.0, 3.1 Hz, 2H), 1.21 (s, 6H). Example 221: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(1-morpholinoethyl)-2,3-d ihydro-1,4-benzoxazepin-5-one 2 o "X... a 0" Example Synthesis of 8-acetyl-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-be nzoxazepin-5-one The title compound was synthesized in the same manner as in Example 214-2, except that methylmagnesium bromide was used instead of ethylmagnesium bromide. Example 221-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-morpholinoethyl)-2,3-d ihydro-1,4-benzoxazepin-5-one 8-Acetyl-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1, 4-benzoxazepin-5-one (100 mg, equiv), morpholine (66 uL, 3 equiv), sodium cyanoborohydride (48 mg, 3 equiv) and acetic acid (1 drop) were dissolved in 1 mL of methanol and stirred at 80°C for 6 hours. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate and purified by flash chromatography to obtain the title compound. '"H NMR (400 MHz, Methanol-ds) 7.55 (d, J = 8.0 Hz, 1H), 7.05 (dd, J = 8.0, 1.5 Hz, 1H), 7.03 — 6.95 (m, 3H), 6.92 (d, J = 7.2 Hz, 2H), 4.35 (t, J = 5.1 Hz, 2H), 4.11 (dt, J = 9.6, 3.5 Hz, 1H), 3.86 (dd, J = 13.9, 3.6 Hz, 1H), 3.63 (s, 2H), 3.57 (dt, J = 9.6, 4.8 Hz, 6H), 3.31 (dd, J = 13.8, 7.6 Hz, 1H), 3.23 (s, 1H), 2.81 (t, J = 6.1 Hz, 2H), 2.74 (t, J = 5.7 Hz, 2H), 2.60 — 2.48 (m, 2H), 2.48 — 2.33 (m, 2H), 2.25 (dt, J = 10.9, 4.7 Hz, 2H), 1.24 (d, J = 6.6 Hz, 3H). Example 222: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[1-(2-oxa-6-azaspiro[3.3]|h eptan-6-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one 7 Sates The title compound was synthesized in the same manner as in Example 221, except that 2-oxa-6-azaspiro [3.3]heptane was used instead of morpholine in Example 221-2. 'H NMR (400 MHz, Methanol-ds) 8 7.56 (d, J = 8.0 Hz, 1H), 7.05 - 6.91 (m, 5H), 6.88 (d, J = 1.6 Hz, 1H), 4.61 (s, 4H), 4.35 (t, J = 5.1 Hz, 2H), 4.18 — 4.04 (m, 1H), 3.85 (dd, J = 13.9, 3.6 Hz, 1H), 3.65 (d, J = 2.0 Hz, 2H), 3.62 — 3.50 (m, 2H), 3.35 — 3.16 (m, 6H), 2.89 — 2.69 (m, 4H), 2.62 —-2.47 (m, 2H), 1.10 (d, J = 6.5 Hz, 3H). Example 223: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxypro-1-pynyl)-2 ,3-dihydro-1,4-benzoxazepin-5-one o vo_= EO ~N J -y ; 0 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1 ,4-benzoxazepin-5-one ~~ (100 mg, 1.0 equiv), prop-2-yn-l-ol (3 equiv), bis(triphenylphosphine)palladium (II) dichloride (8 mg, 0.05 equiv), copper (I) iodide (5 mg, 0.1 equiv) and triethylamine (97 uL, 3 equiv) were dissolved in N,N-dimethylformamide (1 mL) and stirred at 100°C for 4 hours. The reaction solution was cooled to room temperature, filtered through celite and extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The obtained solution was concentrated under reduced pressure and purified by flash chromatography to obtain the title compound. 'H NMR (400 MHz, Methanol-ds) 8 7.67 (d, J = 8.1 Hz, 1H), 7.23 (dd, J =8.1, 1.6 Hz, 1H), 7.19 — 6.99 (m, 5H), 4.48 (t, J = 5.1 Hz, 2H), 4.42 (s, 2H), 4.31 — 4.18 (m, 1H), 3.98 (dd, J= 13.9, 3.6 Hz, 1H), 3.82 — 3.76 (m, 2H), 3.76 — 3.68 (m, 2H), 3.45 (dd, J = 13.9, 7.6 Hz, 1H), 3.01 — 2.82 (m, 4H), 2.73 - 2.62 (m, 2H). Example 224: Synthesis of (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-methoxyethyl) -4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 0, etd The material, which is obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140, as a starting material was used in the same manner as in Example 163 to obtain the title compound, except that 1-bromo-2-methoxyethane was used instead of 2-fluoroethyl para-toluenesulfonate. 'H NMR (400 MHz, Methanol-ds) 3 7.62 (d, J = 8.7 Hz, 1H), 7.17 - 7.02 (m, 4H), 6.78 (dd, J = 8.7,2.5 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.79 (td, J= 7.0, 3.3 Hz, 1H), 4.50 (t, J= 3.7 Hz, 1H), 4.23 (dt, J = 8.6, 4.0 Hz, 1H), 4.15 (dd, J= 13.8, 3.7 Hz, 1H), 3.77 (s, 2H), 3.68 — 3.45 (m, 4H), 3.37 (s, 2H), 3.23 (dd, J = 13.8, 8.2 Hz, 1H), 2.94 (d, J = 5.3 Hz, 2H), 2.88 (t, J = 5.5 Hz, 4H), 2.66 (dt, J = 13.4, 6.6 Hz, 4H), 2.50 (d, J = 10.2 Hz, 2H), 2.10 — 2.00 (m, 2H), 1.88 — 1.80 (m, 2H), 1.35- 1.30 (m, 3H). Example 225: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-(4-pyridyl)-2,3-dihydro-1, 4-benzoxazepin-5-one —~ CO \ OH 7 oo Ny J The title compound was synthesized in the same manner as in Example 12, except that 4-pyridylboronic acid was used instead of isobutylboronic acid. 'H NMR (400 MHz, Methanol-ds) 8 8.70 — 8.56 (m, 2H), 7.87 (d, J = 8.1 Hz, 1H), 7.81 — 7.69 (m, 2H), 7.60 (dd, J = 8.2, 1.8 Hz, 1H), 7.48 (d, / = 1.8 Hz, 1H), 7.17 — 7.04 (m, 4H), 4.56 (t, J = 5.0 Hz, 2H), 4.27 (d, J = 5.4 Hz, 1H), 4.03 (dd, J = 13.9, 3.6 Hz, 1H), 3.79 (d, J = 7.0 Hz, 4H), 3.48 (dd, J= 13.9, 7.7 Hz, 1H), 2.95 (d, J = 5.2 Hz, 2H), 2.89 (dd, J = 8.9, 3.5 Hz, 2H), 2.68 (dd, J=6.2,2.1 Hz, 7H}. Example 226: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl|-8-[2-(4-pyridyl)ethynyl]-2,3 -dihydro-1,4-benzoxazepin-5-one o ~Tr as NT at oH The title compound was synthesized in the same manner as in Example 223, except that 4-ethynylpyridine was used instead of prop-2-yn-1-ol. 'H NMR (400 MHz, Methanol-ds) § 8.55 — 8.33 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.50 — 7.40 (m, 2H), 7.26 (dd, J = 8.1, 1.6 Hz, 1H), 7.14 (d, / = 1.6 Hz, 1H), 7.09 — 6.83 (m, 4H), 4.39 (t, J = 5.1 Hz, 2H), 4.13 (dddd, J = 9.0, 7.4, 4.6, 2.6 Hz, 1H), 3.87 (dd, J = 13.9, 3.6 Hz, 1H), 3.70 — 3.52 (m, 4H), 3.35 (dd, J = 13.8, 7.7 Hz, 1H), 2.88 — 2.69 (m, 4H), 2.65 — 2.48 (m, 2H). Example 227: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(3-pyridyl)ethynyl]-2,3 -dihydro-1,4-benzoxazepin-5-one 0 NN a=" OH 0 The title compound was synthesized in the same manner as in Example 223, except that 3-ethynylpyridine was used instead of prop-2-yn-1-ol. 'H NMR (400 MHz, Methanol-d) 5 8.67 — 8.56 (m, 1H), 8.43 (dd, J = 5.0, 1.6 Hz, 1H), 7.88 (dt, J=8.0, 1.9 Hz, 1H), 7.61 (d, / = 8.0 Hz, 1H), 7.36 (ddd, J = 8.0, 5.0, 0.9 Hz, 1H), 7.25 (dd, J = 8.1, 1.6 Hz, 1H), 7.13 (d, J = 1.5 Hz, 1H), 7.06 — 6.96 (m, 3H), 6.95 — 6.89 (m, 1H), 4.39 (t, J = 5.1Hz, 2H), 4.11 (ddd, J=7.4, 5.7, 3.4 Hz, 1H), 3.88 (dd, J = 13.9, 3.5 Hz, 1H), 3.70 — 3.52 (m, 4H), 3.32 (dd, J = 13.8, 7.8 Hz, 1H), 2.82 (t, J = 6.2 Hz, 2H), 2.75 (t, J = 5.5 Hz, 2H), 2.57 —- 2.40 (m, 2H). Example 228: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxybu-1-tynyl)-2,3 -dihydro-1,4-benzoxazepin-5-one 0 N o_O 0 The title compound was synthesized in the same manner as in Example 223, except that but-3-yn-2-ol was used instead of prop-2-yn-1-ol, 'H NMR (400 MHz, Methanol-ds) 8 7.66 (d, J = 8.0 Hz, 1H), 7.21 (dd, J =8.1, 1.6 Hz, 1H), 7.16 — 6.94 (m, 5H), 4.70 (q, J = 6.6 Hz, 1H), 4.47 (1, J = 5.1 Hz, 2H), 4.22 (dq, J = 10.1, 5.6, 4.5 Hz, 1H), 3.98 (dd, J = 13.9, 3.5 Hz, 1H), 3.75 (s, 2H), 3.73 — 3.64 (m, 2H), 3.43 (dd, J = 13.9, 7.7 Hz, 1H), 2.92 (d, J = 5.6 Hz, 2H), 2.86 (t, J = 5.6 Hz, 2H), 2.64 (d, J = 6.5 Hz, 2H), 1.50 (d, J = 6.6 Hz, 3H). Example 229: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(methylamino)pro-1-p ynyl]-2,3-dihydro-1,4-benzoxazepin-5-one . N N Arr a “N\ ; 0 The title compound was synthesized in the same manner as in Example 223, except that N-methylprop-2-yn-1-amine was used instead of prop-2-yn-1-ol. 'H NMR (400 MHz, Methanol-ds) 8 7.55 (d, J = 8.1 Hz, 1H), 7.11 (dd, J = 8.1, 1.6 Hz, 1H), 7.06 — 6.89 (m, 5H), 4.36 (t, J = 5.1 Hz, 2H), 4.18 — 4.05 (m, 1H), 3.86 (dd, J = 13.9, 3.6 Hz, 1H), 3.68 — 3.63 (m, 2H), 3.59 (dt, J = 5.0, 2.9 Hz, 2H), 3.52 (s, 2H), 3.33 (dd, J= 13.9, 7.7 Hz, 1H), 2.81 (d,J=5.3 Hz, 2H), 2.75 (dd, J= 8.9, 3.6 Hz, 2H), 2.57 — 2.50 (m, 2H), 2.39 (s, 3H). Example 230: Synt...

Claims

CLAIMS 1. A compound represented by the following Formula 1, or an optical isomer, a stereoisomer or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof’ [Formula 1] 2 » Oo a a, 3 F(R wherein X" and X? are each independently carbon or nitrogen; Y is carbon, oxygen or nitrogen; Z is carbon; nis an integer of 0 or 1; m is an integer of 0 to 2; === is a single bond or a double bond; R! is -D-R'%; wherein D is a direct bond, -O-, -C(=0)-, -C=C- or -CR!'R'%; R' is hydrogen, halo, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, haloalkylsulfonate, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminocarbonylalkyl, saturated or unsaturated carbocyclyl, saturated or unsaturated heterocyclyl, saturated or unsaturated carbocyclyl-alkyl, or saturated or unsaturated heterocyclyl-alkyl; R'! and R'? are each independently hydrogen, hydroxy or alkyl; the carbocycle or heterocycle may be substituted with one or more substituents selected from hydroxy, halo, oxo, formyl (-CHO), nitrile, alkyl, alkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyalkyl, haloalkyl, nitrilealkyl, alkylcarbonyl, alkylthiocarbonyl, alkoxycarbonyl, haloalkylcarbonyl, carbocyclyl, carbocyclylearbonyl, (alkyl)(haloalkyl)amino, (alkyl)(heterocyclyl)amino, heterocyclyl and heterocyclyl-alkyl; RZ is hydrogen or alkyl; R? is hydrogen or alkyl; R*, R%, R® and R are each independently hydrogen or alkyl; R?® is hydrogen, halo, alkyl, alkoxy or amino; and R® is hydrogen, halo or alkyl.

2. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 1, wherein X" and X? are each independently CH or N; Y is CHa, O or NH, when nis 0; Yis CH or N, when nis 1; Z is CH or CH, when m is 0; Z is CH or C, when mis 1; Z is C, when m is 2; and === is a single bond or a double bond.

3. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 1, wherein R! is -D-R'%; wherein D is a direct bond, -O-, -C(=0)-, -C=C- or -CR''R'2-; R! is hydrogen, halo, hydroxy, cyano, Ci-Cy alkyl, hydroxy-Ci-C alkyl, halo-C:-C7 alkyl, halo-C:-C; alkylsulfonate, di(C1-C7alkyl)amino, C;-C7 alkylamino-Ci-C7 alkyl, di(C1-C7 alkyl)amino-C,-C7 alkyl, di(C,-C7 alkyl)aminocarbonyl-C,-C7 alkyl, saturated or unsaturated Cs-Cio carbocyclyl, saturated or unsaturated, 4- to 10-membered heterocyclyl, saturated or unsaturated Cs3-Cio carbocyclyl-C1-Cr alkyl, or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl; and R!! and R'? are each independently hydrogen, hydroxy or Ci-C7 alkyl.

4. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 3, wherein R! is halo, C)-Cy alkyl, hydroxy-Ci-C alkyl, halo-C)-C7 alkyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated, 4- to 10-membered heterocyclyl, or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl, 5 The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 1, wherein the carbocycle or heterocycle may be substituted with 1 to 5 substituents selected from hydroxy, halo, oxo, formyl, nitrile, Ci-C7 alkyl, Ci-C; alkoxy, hydroxy-Ci-C; alkyl, hydroxyhalo-C)-C7 alkyl, Ci1-C7 alkoxy-C1-C7 alkyl, halo-Ci-C7 alkyl, nitrile-Ci-C7 alkyl, Ci-C7 alkylcarbonyl, Ci-C; alkylthiocarbonyl, Ci-C; alkoxycarbonyl, halo-Ci-C7 alkylcarbonyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated Cs-Cio carbocyclylcarbonyl, (C1-C alkyl)(halo-C,-C7 alkyl)amino, (C1-C7 alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino, saturated or unsaturated, 4- to 10-membered heterocyclyl and saturated or unsaturated, 4- to 10-membered heterocyclyl-C;-C7 alkyl.

6. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 5, wherein the carbocycle or heterocycle may be substituted with 1 to 5 substituents selected from hydroxy, halo, formyl, Ci-Cs alkyl, hydroxy-Ci-C7 alkyl, Ci-Cs alkoxy-Ci-C7 alkyl, halo-C1-C7 alkyl, Ci-C7 alkylcarbonyl, C;-C; alkoxycarbonyl, halo-Ci-C; alkylcarbonyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated Cs-Cio carbocyclylcarbonyl, (Ci-C7 alkyl)(halo-Ci-C7 alkyl)amino, (Ci-C7 alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino and saturated or unsaturated, 4- to 10-membered heterocyclyl-Ci-C7 alkyl.

7. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 1, wherein the heterocycle may be substituted with 1 or 2 substituents selected from hydroxy, halo, formyl, C1-C; alkyl, hydroxy-Ci-Cy alkyl, Ci1-Cy alkoxy-Ci-C7 alkyl, halo-C-C alkyl, Ci-C; alkylcarbonyl, C1-C; alkoxycarbonyl, halo-C;-C alkylcarbonyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated C3-Cio carbocyclylcarbonyl and saturated or unsaturated, 4- to 10-membered heterocyclyl-C;-C7 alkyl.

8. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 1, wherein the carbocycle may be substituted with 1 or 2 substituents selected from halo-Ci-C7 alkyl, (Ci-C7 alkyl)(halo-C1-C; alkyl)amino and (Ci-C; alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino, 9. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 1, wherein R! is -D-R!?; wherein D is a direct bond; R! is hydrogen, halo, cyano, Ci-C7 alkyl, halo-C;-C; alkyl, di(C)-C7alkyl)amino-C,-C; alkyl, saturated or unsaturated, 4- to 10-membered heterocyclyl, saturated or unsaturated C3-Cio carbocyclyl, or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl; and the heterocycle may be substituted with 1 or 2 substituents selected from hydroxy, halo, formyl, Ci-C7 alkyl, Ci-C7 alkoxy, hydroxy-Ci-C7 alkyl, halo-Ci-C7 alkyl, nitrile-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C alkoxy-Ci-C7 alkyl, C1-C7 alkoxycarbonyl, halo-C-C7 alkylcarbonyl, and saturated or unsaturated, 4- to 10-membered heterocyclyl.

10. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 1, wherein R? is hydrogen or C1-C7 alkyl; R? is hydrogen or C;-Cy alkyl; R% R® R® and R are each independently hydrogen or Ci-C; alkyl; R® is hydrogen, halo, Ci-Cr alkyl, C1-C7 alkoxy or amino; and R’ is hydrogen, halo or C1-C5 alkyl.

11. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 1, wherein === is a single bond.

12. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to any one of Claims 1 to 11, wherein the heterocycle is a saturated or unsaturated, 4- to 8-membered hydrocarbon having 1 or 2 heteroatoms selected from N and O.

13. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to any one of Claims 1 to 11, wherein the heterocycle is selected from the group consisting of tetrahydropyridine, dihydropyridine, piperidine, dihydropyran, tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine, morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, oxazepane, 2-oxa-5-azabicyclo[2.2.1]Theptane, pyridyl, tetrahydrofuran, 8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.4]octane, 2-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane, 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine, 3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2]-a] pyrazine, pyrimidine, pyrazole, 2-oxa-7-azaspiro[3.5]nonane, and oxetane.

14. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 13, wherein the heterocycle is selected from the group consisting of tetrahydropyridine, dihydropyridine, piperidine, tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine, morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, pyridyl, 8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, pyrazole, and oxetane.

15. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to any one of Claims 1 to 11, wherein the carbocycle is selected from the group consisting of cyclohexane, cyclohexene, cyclopropane, cyclobutane, and cyclopentane.

16. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 13, wherein D is a direct bond, -O-, -C(=0)- or -C=C-; R! is halo, C)-Cy alkyl, hydroxy-Ci-C alkyl, halo-C)-C7 alkyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated, 4- to 10-membered heterocyclyl, or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl; the carbocycle or heterocycle may be substituted with 1 to 5 substituents selected from hydroxy, halo, formyl, C-C alkyl, hydroxy-Ci-Cs alkyl, Ci-Cy alkoxy-Ci-C7 alkyl, halo-Ci-C7 alkyl, Ci-C; alkylcarbonyl, C;-C; alkoxycarbonyl, halo-Ci-C7 alkylcarbonyl, saturated or unsaturated C3-Cio carbocyclyl, saturated or unsaturated C3-Cio carbocyclylcarbonyl, (Ci-Cr alkyl)(halo-Ci-C7 alkyl)amino, (Ci-C; alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino, and saturated or unsaturated, 4- to 10-membered heterocyclyl-Ci-C7 alkyl; the heterocycle is selected from the group consisting of tetrahydropyridine, dihydropyridine, piperidine, tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine, morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, pyridyl, 8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, pyrazole, and oxetane; and the carbocycle is selected from the group consisting of cyclohexane, cyclohexene, and cyclopropane.

17. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to Claim 1, wherein the compound is selected from the group consisting of’ 4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methoxy-2,3-dihydro-1,4-b enzoxazepin-5-one; 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-methoxy-4,5-dihydro-3H-2 -benzazepin-1-one; 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-hydroxy-4,5-dihydro-3H-2 -benzazepin-1-one; 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(triflucromethoxy)-4,5-dih ydro-3H-2-benzazepin-1-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(trifluoromethyl)-2,3- dihydro-1,4-benzoxazepin-5-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)-4, 5-dihydro-3H-2-benzazepin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-7-ethoxy-4,5-dihydro-3 H-2-benzazepin-1-one; [2-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]- 1-oxo-4,5-dihydro-3H- 2-benzazepin-7yl] trifluoromethanesulfonate; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H- 2-benzazepin-7-carbonitrile; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methyl-2,3-dihydro-1 ,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-propyl-2,3-dihydro-1, 4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-isobutyl-2,3-dihydro- 1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,3,3-trifluoropropyl )-2,3-dihydro-1,4-benzoxazepin-5-one; tert-butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-y1)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzo xazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydropy ridin-4-y1)-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-4-[(2R}-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2 -hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(1-acetyl-4-piperidyl}-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxy-propyl] -2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethyl-3,6-dihydro- 2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-(1-isopropyl-3,6-dihy dro-2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,6-dihydro-2H-pyra n-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-yl- 2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(morpholinomethyl)- 2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-piperidylmethyl)-2 ,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-ylmethy 1)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(dimethylamino)met hyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(diethylaminomethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl] -2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methyl-1-piperidy 1methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-6-azaspiro[3.3 Jheptan-6-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-methoxyazetidin- 1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-methylmorpholin- 4-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(4,4-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hyd roxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-fluoro-1-piperidyl )methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3,5-dimethyl-1-pipe ridyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-ylmethyl)-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxypyrrolidin -1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[(2R)-2-methylpyrro lidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[3-(hydroxymethyl)- 1-piperidyl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methoxy-1-piperi dyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,4-oxazepan-4-ylm ethyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxy-3-methyl -pyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-(hydroxymethyl) morpholin-4-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(3,3-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hyd roxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-1-piperidyl Ymethyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(3-hydroxy-1-piperid ylmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-hydroxy-1-piperid ylmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(hydroxymet hylpyrrolidin-1-yl]methyl]-2,3-dihydro- 1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-(hydroxymet hylpyrrolidin-1-yl]methyl]-2,3-dihydro- 1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethylpyrrolidin-1- ylmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[(2S)-2-(methoxyme thyl)pyrrolidin-1-ylJmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[(2R)-2-(methoxyme thyl)pyrrolidin-1-ylJmethyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoropyrrolidin- 1 -yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(3,3-difluoropyrrolidin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-h ydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R}-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydro xy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylpiperazin-1 -yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-5-azabicyclo[ 2.2.1]heptan-5-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridylmethoxy)-2 ,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridylmethoxy)-2 ,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(2-fluoro-4-pyridyl) methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(2,6-dichloro-4-pyridyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hyd roxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(2,3-difluoro-4-pyridylymethoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hyd roxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(6-fluoro-3-pyridyl) methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl) methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl) methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-ylo xy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-(tetrahydropyran-2-yl methoxy)-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(cyclohexylmethoxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl] -2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydrofuran-2-yl methoxy)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidy 1oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-ethyl-3-piperidyl) oxy]-2,3-dihydro-1,4-benzoxazepin-35-one; 8-[(1-acetyl-4-piperidyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydro xy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,2,2-trifluoroethoxy )-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[2-(dimethylamino)et hoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-morpholinoethoxy )-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(2-oxopyrrolidin- 1 -yl)ethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-(2-pyridyloxy)-2,3-di hydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(6-oxo-3-piperidyl)o xy]-2,3-dihydro-1,4-benzoxazepin-5-one; tert-butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-ox0-2,3-dihydro-1,4-benz oxazepin-8-yl]oxy]piperidine-1-carboxylate; 8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-pr opyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(1-acetyl-3-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-pr opyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(1-acetylpyrrolidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy- propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(3R)-1-acetylpyrrolidin-3-yl]Joxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydr oxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(3S)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydr oxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-pr opyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-propanoylazetidin- 3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[1-(cyclopropanecarbonyl)azetidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2- yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; methyl 3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-ox0-2,3-dihydro-1,4-benz oxazepin-8-yl]oxy]azetidin-1-carboxylate; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidy 1)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl) oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-isopropyl-4-piperi dyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(1-cyclopropyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydr oxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(1-cyclobutyl-4-piperidyljoxy]-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydro xy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(oxetan-3-yl)-4-pi peridyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-(1-methylazetidin-3-y 1oxy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-(1-ethylazetidin-3-yl) oxy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-isopropylazetidin- 3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[ 1-(oxetan-3-yl)azetid in-3-ylJoxy-2,3-dihydro- 1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethylazetidin-3-yl Ymethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylpyrrolidin-3 -yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-ethylpyrrolidi n-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-(2-pyridyloxy)-2,3-di hydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-1-isopropylpyr rolidin-2-ylJmethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidy Dmethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl) methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylmorpholin- 2-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-ethylmorpholin-2- yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-methylpyrrolidin- 3-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidy Dmethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-6-fluoro-8-(morpholino methyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-[(1-methyl-4 -piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl) oxy]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morph olinomethyl)-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[(1-met hyl-4-piperidyl)oxy]-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-pyrid ylmethoxy)-3H-1,4-benzoxazepin-5-one; 8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-pr opyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(morpholin omethyl)-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]- 1-methyl-8-(3,3,3-triflu oropropyl)-2,3-dihydro-1,4-benzodiazepin-5-one; 8-(cyclohexylmethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1 -methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 8-(cyclohexen-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1- methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[4-(trifluoro methyl)cyclohexen-1-yl]-2,3-dihydro-1,4-benzodiazepin-5-one; tert-butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-y1)-2-hydroxy-propyl]-1-methyl-5-ox0-2,3-dihydro- 1,4-benzodiazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate; 8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-pr opyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-pr opyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 8-[(3R)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydr oxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 8-[(3S)-1-acetylpyrrolidin-3-ylJoxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydr oxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl- 4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl) oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 8-[(1-cyclobutyl-4-piperidyljoxy]-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydro xy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-tetrahyd rofuran-3-yl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[[ 1-(oxetan- 3-yl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-1-methyl-8-[ (1-methyl- 3-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methylp yrrolidin-3-yl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(1-methylp yrrolidin-3-yl)oxy-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl- 3-piperidyl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl) methoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-piperidyl Yoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one dihydrochloride; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-3-fluoro-4-p iperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicycl 0[3.2.1]octan-3-yl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(2-methyl- 4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one dihydrochloride; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl) methoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(4-piperidyl oxy)-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4 -piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydro xypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-met hyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4 -piperidyl)oxy]-2,3-dihydropyrido[3,2-f][ 1,4]oxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxypropyl]-2,2-dimethyl-8-[(1-meth yl-4-piperidyl)oxy]-3H-pyrido[3,2-f][ 1,4]oxazepin-5-one; (28)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-met hyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepi n-5-one; 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepi n-1-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2,3-dihydro-1,4-benzox azepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-2,3-dihydro-1, 4-benzoxazepin-5-one; 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1, 4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido[4,3-f 1[1,4]oxazepin-5-one; 8-chloro-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2,3-dihydropy rido[3,2-f][1,4]oxazepin-5-one; 7-chloro-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3 H-2-benzazepin-1-one; 7-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3 H-2-benzazepin-1-one; 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3- dihydro-1,4-benzodiazepin-5-one; 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-2,3-di hydro-1,4-benzodiazepin-5-one; 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-3H-1, 4-benzodiazepin-2,5-dione; 2-[4-[[4-(2R)-3-(3,4,-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-ox0-2,3,-dihyd ro-1,4,-benzoxazepin-8-yl]-1-piperidyl]acetonitrile; 8-[[1-(2,2-difluoroacetyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl) -2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[[1-(2,2-difluoroacetyl)azetidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl) -2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxyethyl)- 4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-fluoroethyl)-4- piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-fluoroethyl)-4- piperidyl]oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[[ 1-[(3-methyloxetan- 3-yl)methyl]-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-ox0-2,3-dihydro-1, 4-benzoazepin-8-yl]Joxy]piperidine-1-carbonitrile; 8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydro xy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one; 3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo- 3H-1,4-benzoxazepin-8-ylJoxy]azetidin-1-carbaldehyde; 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo- 3H-1,4-benzoxazepin-8-ylJmethyl]piperazine- 1-carbaldehyde; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa- 6-azaspiro[3.3]heptan-6-ylmethyl)-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicycl 0[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethyl-2-azaspiro[ 3 .3]heptan-6-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin- 2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-y 1)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-carbony 1)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(piperidine- 1-carbony 1)-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(3,3-difluoropyrrolidin-1-carbonyl)-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hy droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-methylpiperazine- 1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(pyrroli din-1-ylmethyl)-3H-1,4-benzoxazepin-5-one; 8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-pr opyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one; 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo- 3H-1,4-benzoxazepin-8-ylJoxy]piperidine-1-carbaldehyde; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[[4-(oxe tan-3-yl)piperazin-1-ylJmethyl]-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa- 7-azaspiro[3.4]octan-7-ylmethyl)-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-fluoropiperidine-1- carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(trifluoromethyl)pi peridine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(trifluoromethyl)pi peridine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,6-dimethylmorpho lin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)- 2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-oxa-8-azabicyclo[ 3.2.1]octan-8-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-methylmorpholin- 4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-methylmorpholin- 4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morph olinomethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one; 8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-carbonyl)-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-fluoropiperidine-1- carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(2,2-difluoromorpholin-4-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hy droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(4,4-difluoropiperidine-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hy droxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-piper idylmethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxypropyl]-8-[4-[methyl(oxetan-3-y 1)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[2-fluoroethyl (meth yl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; (2S)-4-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethanethiol-4 -piperidyl)oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; (2S)-4-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[ 1-(2-fluoroethyl )azetidin-3-yl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; (2S)-4-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[ 1-(2-fluoroethyl )-4-piperidyl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(3-oxa- 8-azabicyclo[3.2.1]octan-8-carbonyl)-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa- S-azabicyclo[2.2.1]heptan-5-carbonyl)-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-(3,5-dimethylmorpho lin-4-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-1-methyl-4 -piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-fluoro ethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-hydro xyethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,4-dihydro-1H-pyrr olo[1,2-a]pyrazine-2-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one; 8-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[ 1,2-a]pyrazine-2-carbonyl)-4-[(2R)-3-(3,4-dihydr o-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(5-fluoropyrimidin-2- yloxy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[ 1-(2-hydroxypropyl )-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidy 1oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3~(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-propanoyl-2,3-dihydr 0-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-a zabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(cyclopropanecarbonyl)-4-[(2R)-3-(3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxy-prop y1]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(cyclopentanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propy 1]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(1-methyl-3-piperidyl Yoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxye thyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxy- 2-methyl-propyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-morpholinoethyl)- 2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[ 1-(2-oxa-6-azaspiro[ 3.3]heptan-6-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxypro-1-pyn yl)-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-methoxye thyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridyl)-2,3-dihyd ro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(4-pyridyl)ethynyl 1-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(3-pyridyl)ethynyl 1-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxybu-1-tynyl )-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(methylamino)pro- 1-pynyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-(3-pyridyl)-2,3-dihyd ro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,3-dimethylpyrazol- 4-y1)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylpyrazol-4-y 1)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,5-dimethylpyrazol- 4-y1)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxyethyl)- 4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][ 1 ,4]oxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[[(3R)-1 -methyl-3-piperidyl]oxy]-3H-pyrido[3,2-f][1,4]oxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-fluoroethyl)-3 -piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[[(1-(2-hydroxy)-3-pi peridyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxy-2-met hyl-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(6-fluoro-2-pyridyl)-2 ,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-ethoxyeth yl)-4-piperidylJoxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-hydroxy]- 8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethy 1]-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-methoxyethyl)- 4-pyridyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(6-methoxy-2-pyridyl )-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyp ropyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-morp holinoethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[ 1-(2-0x a-6-azaspiro[3.3]heptan-6-yl)ethyl]-3H-pyrido[3,2-f][1,4]oxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxypropyl )-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(3,4-dihydro-1H-pyrro lo[1,2-a]pyrazin-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(2-oxa- 6-azaspiro[3.3]heptan-6-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxypropyl]-8-(2-oxa-7-azaspiro[3.5] nonan-7-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(2-oxa- 7-azaspiro[3.5]nonan-7-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-f luoro-1-(2-hydroxyethyl)-4-piperidyl]Joxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1- (2-hydroxypropyl)-4-piperidylJoxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride; (2R)-4-[(2R)-3-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4 R)-3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride; 8-[[3,3-difluoro-1-(2-hydroxyethyl)-4-piperidylJoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquin olin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][ 1,4]oxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxypropyl]-8-[ 1-(1-piperidyl)ethyl]- 2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[ 1-(4-hydroxy-1-piperi dyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[ 1-(4-methoxy- 1-piper idyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[ 1-(3-hydroxy-3-meth yl-pyrrolidin-1-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro- 1 H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-hydroxye thyl)-4-piperidyl]Joxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[ 1-(2-methoxyethyl)- 4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][ 1,4]oxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3S)-1-(oxetan-3-yl) pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3S)- 1-methylpyrrolidin-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolinon-2-yl}-2-hydroxy-propyl]-8-[(3R)-tetrahydrofur an-3-ylJoxy-2,3-dihydro- 1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolinon-2-yl)-2-hydroxy-propyl]-8-[(3S)-tetrahydrofur an-3-ylJoxy-2,3-dihydro- 1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-[(2S)-2-hydr oxypropyl]-4-piperidyl]Joxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-[(2R)-2-hydr oxypropyl]-4-piperidyl]Joxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[cyclopropyl(hydroxy)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydrox y-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[cyclopentyl(hydroxy)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy -propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl}-2-hydroxy-propyl]-8-[(3R)-1-(oxetan-3-yl) pyrrolidin-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(2-methoxyet hylpyrrolidin-3-yl]Joxy-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3R)- 1-methylpyrrolidin-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(2-meth oxyethyl)pyrrolidin-3-yl]Joxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-)-2-hydroxy-propyl]-8-[[1-(3,3,3-trifluoro-2-h ydroxy-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-}-2-hydroxy-propyl]-2-methyl-8-[[1-(3,3, 3-trifluoro-2-hydroxy-propyl)-4-piperidyl]Joxy]-2,3-dihydro- 1,4-benzoxazepin-5-one; and (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(3R)-1 -(oxetan-3-yl)pyrrolidin-3-ylJoxy-2,3-dihydro-1,4-benzoxazepin-5-one.

18. A pharmaceutical composition for the prevention or treatment of a disease associated with protein arginine methyltransferase 5 (PRMTS5) inhibition comprising a therapeutically effective amount of the compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof as defined in any one of Claims 1 to 17 as an active ingredient, together with a pharmaceutically acceptable carrier, 19. The pharmaceutical composition according to Claim 18, wherein the disease associated with PRMTS5 inhibition is selected from cancer, blood disease, autoimmune disease, inflammatory disease and neurodegenerative disease.

20. The pharmaceutical composition according to Claim 19, wherein the cancer is selected from the group consisting of acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma, benign monoclonal gammaglobulinopathy, cholangiocarcinoma, bladder cancer, breast cancer, brain cancer, lymphoma, multiple myeloma, lacrimal gland tumor, bronchial cancer, cervical cancer, craniopharyngioma, colorectal cancer, epithelial carcinoma, epithelial cell tumor, endothelial sarcoma, endometrial cancer, esophageal cancer, Barrett's adenocarcinoma, Ewing’s sarcoma, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cancer (oral squamous cell carcinoma, OSCC), throat cancer, hematopoietic cancer, hemangioblastoma, inflammatory myofibroblast tumor, immune cell amyloidosis, kidney cancer, liver cancer, lung cancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, prostate cancer, rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, thyroid cancer, urethral cancer, vaginal cancer and vulvar cancer, 21. The pharmaceutical composition according to Claim 20, wherein the brain cancer is selected from the group consisting of meningioma, glioma, medulloblastoma, glioblastoma and brain metastasis cancer.

22. The pharmaceutical composition according to Claim 19, wherein the blood disease is hemoglobinemia or sickle cell anemia; the autoimmune disease is selected from the group consisting of rheumatoid arthritis, spinal arthritis, gouty arthritis, degenerative joint disease, osteoarthritis, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, juvenile arthritis, asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, psoriasis, eczema, burns, dermatitis, pruritus, enuresis, eosinophilic disease, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis and eosinophilic colitis; the inflammatory disease is selected from the group consisting of acne-related inflammation, aplastic anemia, hemolytic autoimmune anemia, rhinitis, asthma, polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, amyotrophic lateral sclerosis, autoimmune disease, allergic or allergic reaction, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, chronic obstructive pulmonary disease, dermatomyositis, type I diabetes, type 2 diabetes, psoriasis, eczema, eczema hypersensitivity reaction, burn, dermatitis, pruritus, endometriosis, infection, ischemic heart disease, glomerulonephritis, gingivitis, irritability, migraine, tension headache, postoperative intestinal obstruction, intestinal obstruction during sepsis, idiopathic thrombocytopenia purpura, bladder pain syndrome, peptic ulcer, localized enteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux disease, Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, bypass colitis, Behcet’s syndrome, indeterminate colitis, inflammatory bowel syndrome (IBS), lupus, ecchymosis, myasthenia gravis and myocardial ischemia; and the neurodegenerative disease is selected from the group consisting of motor neuron disease, Pick’s disease, Alzheimer’s disease, AIDS-related dementia, Parkinson’s disease, amyotrophic lateral sclerosis, retinal pigmentation, spinal muscular atrophy and cerebellar degeneration.