Bicyclic compounds and their uses

Abstract

The present invention relates to compound derivatives containing 6-7 bicyclic rings and their use. The compounds according to the present invention act as protein arginine methyltransferase 5 (PRMT5) inhibitors and can therefore be effectively used to prevent or treat diseases induced by PRMT5.

Description

[Technical Field]

[0001] The present invention relates to compound derivatives containing a 6-7 bicyclic ring and their use. The compounds according to the present invention act as protein arginine methyltransferase 5 (PRMT5) inhibitors and can be effectively used for the prevention or treatment of diseases induced by PRMT5. [Background technology]

[0002] PRMTs (protein arginine methyltransferases) are enzymes that transfer methyl groups to arginine in target proteins using the cofactor SAM (S-adenosylmethionine). Nine PRMT isoforms have been identified, which can be broadly divided into three types: type I PRMTs PRMT1, 2, 3, 4, 6, and 8 induce arginine monomethylation and asymmetric dimethylation; type II PRMTs PRMT5 and PRMT9 induce arginine monomethylation and symmetric dimethylation; and type III PRMT PRMT7 induces arginine monomethylation. PRMTs induce methylation of various substrates in the nucleus and cytoplasm, thereby regulating important intracellular biological processes such as cell proliferation, differentiation, and splicing.

[0003] PRMT5 is an important arginine methyltransferase among type II PRMTs. It forms a functional complex with methylosome protein 50 (MEP50) and induces methylation of target proteins. PRMT5 methylates target proteins, including nuclear histone and non-histone proteins such as p53, NFκB, PI3K / AKT, and CRAF, and is therefore associated with the development of leukemia, lymphoma, glioblastoma, lung cancer, and breast cancer. It is well known that PRMT5-mediated oncogenesis is driven by its promotion of tumor cell proliferation, differentiation, invasion, and migration. Several studies have also shown that elevated PRMT5 expression is associated with poorer prognosis in cancer patients. Conversely, inhibition of PRMT5 expression has been shown to suppress tumor cell proliferation.

[0004] On the other hand, recent reports have suggested that diseases other than cancer may also be mediated by PRMT5. Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a novel compound based on a 6-7 bicyclic ring, or an optical isomer, stereoisomer or isotope variant thereof, or a pharmaceutically acceptable salt thereof, which exhibits excellent PRMT5 inhibitory effect.

[0006] Another object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, a novel compound based on the 6-7 bicyclic ring, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof. [Means for solving the problem]

[0007] In order to achieve the above object, the present invention provides a compound represented by the following formula (1):

[0008] [ka] (1) [where, X 1 and X 2 are each independently carbon or nitrogen; Y is carbon, oxygen or nitrogen; Z is carbon; n is an integer of 0 or 1, m is an integer from 0 to 2, TIFF0007609857000002.tif38 is a single or double bond, R 1 -DR 10 wherein D is a direct bond, —O—, —C(═O)—, —C≡C—, or —CR 11 R 12 - and R 10 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 11 and R 12 are each independently hydrogen, hydroxy or alkyl, and the carbocycle or heterocycle is optionally 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 2 is hydrogen or alkyl, R 3 is hydrogen or alkyl, R 4 , R 5 , R 6 and R 7are each independently hydrogen or alkyl; R 8 is hydrogen, halo, alkyl, alkoxy or amino; R 9 is hydrogen, halo, or alkyl; or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

[0009] Unless otherwise stated, the term "alkyl," as used herein, alone or in combination with additional terms (e.g., haloalkyl), refers to the radical of a saturated aliphatic hydrocarbon group, e.g., straight or branched chain, having 1 to 7 carbon atoms. For example, alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.

[0010] Unless otherwise specified, the term "alkoxy" as used herein refers to, for example, alkyloxy having 1 to 7 carbon atoms.

[0011] Unless otherwise stated, the term "halo," as used herein, alone or in combination with an additional term (e.g., haloalkyl), refers to a radical of fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0012] Unless otherwise stated, the term "haloalkyl," as used herein, refers to an alkyl as defined above in which one or more hydrogen atoms have been replaced with one or more of the same or different halogen atoms. Exemplary haloalkyls include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), and the like.

[0013] Unless otherwise specified, the term "oxo" as used herein means a group of =0 (i.e., an oxygen with a double bond). For example, a 1-oxo-ethyl group is an acetyl group.

[0014] Unless otherwise specified, the term "hydroxyalkyl," as used herein, refers to an alkyl in which one or more hydrogen atoms have been replaced with one or more hydroxy (-OH) groups. For example, it includes alkyls in which one or three hydrogen atoms have been replaced with hydroxy.

[0015] Unless otherwise specified, the term "saturated or unsaturated carbocyclyl" as used herein refers to a hydrocarbon radical that is unsaturated, partially, or completely saturated, forming a single or fused cyclic ring, for example, having 3 to 24 carbon atoms. Specifically, the carbocyclyl can have 3 to 10 carbon atoms. The carbocycle can include a bridged or spiro structure. The unsaturated carbocycle can also include an aromatic hydrocarbon, such as an aryl.

[0016] According to one embodiment of the present invention, the carbocycle may be, but is not limited to, cyclohexane, cyclohexene, cyclopropane, cyclobutane, or cyclopentane.

[0017] Unless otherwise specified, the term "saturated or unsaturated heterocyclyl" as used herein refers to a 3- to 24-membered hydrocarbon having one or more heteroatoms selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S), e.g., 1 to 8 heteroatoms, which is unsaturated, partially, or completely saturated, and which forms a single or fused cyclic ring. Specifically, the heterocyclyl may be a 4- to 10-membered hydrocarbon having 1 to 3 heteroatoms. The heterocycle may include a bridged or spiro structure. The unsaturated heterocyclyl may also include an aromatic hydrocarbon such as a heteroaryl.

[0018] According to one embodiment of the present invention, 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, pyrrolidine, oxazepane, 2-oxa-5-azabicyclo[2.2.1]heptane, pyridyl, tetrahydrofuran, 8-azabicyclo[3.2.1]octane, piperidine ... The aryl group may be, but is not limited to, arylazine, 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.

[0019] According to one embodiment of the present invention, in the formula (1), X 1 and X 2 are each independently CH or N.

[0020] According to one embodiment of the present invention, in the formula (1), Y is CH2, O or NH when n is 0, and Y is CH or N when n is 1.

[0021] According to one embodiment of the present invention, in the formula (1), Z is CH2 or CH when m is 0, CH or C when m is 1, and C when m is 2.

[0022] According to one embodiment of the present invention, in the formula (1), TIFF0007609857000003.tif38 is a single or double bond.

[0023] According to one embodiment of the present invention, in the formula (1), R 1 -DR 10wherein D is a direct bond, —O—, —C(═O)—, —C≡C—, or —CR 11 R 12 -It is.

[0024] According to one embodiment of the present invention, in the formula (1), R 10 is hydrogen, halo, hydroxy, cyano, C1-C7 alkyl, hydroxy-C1-C7 alkylhalo-C1-C7 alkyl, halo-C1-C7 alkylsulfonate, di(C1-C7 alkyl)amino, C1-C7 alkylamino-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkyl, di(C1-C7 alkyl)aminocarbonyl-C1-C7 alkyl, saturated or unsaturated C3-C 10 Carbocyclyl, saturated or unsaturated 4-10 membered heterocyclyl, saturated or unsaturated C3-C 10 It is carbocyclyl-C1-C7 alkyl, or saturated or unsaturated 4-10 membered heterocyclyl-alkyl.

[0025] According to one embodiment of the present invention, in the formula (1), R 11 and R 12 are each independently hydrogen, hydroxy, or C1-C7 alkyl.

[0026] According to one embodiment of the present invention, in the formula (1), the carbocyclic or heterocyclic ring is selected from the group consisting of hydroxy, halo, oxo, formyl, nitrile, C1-C7 alkyl, C1-C7 alkoxy, hydroxy-C1-C7 alkyl, hydroxyhalo-C1-C7 alkyl, C1-C7 alkoxy-C1-C7 alkyl, halo-C1-C7 alkyl, nitrile-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkylthiocarbonyl, C1-C7 alkoxycarbonyl, halo-C1-C7 alkylcarbonyl, saturated or unsaturated C3-C 10 Carbocyclyl, saturated or unsaturated C3-C 10It is optionally substituted by 1 to 5 substituents selected from carbocyclylcarbonyl, (C1-C7 alkyl)(halo-C1-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-C1-C7 alkyl.

[0027] According to one embodiment of the present invention, in the formula (1), R 2 may be hydrogen or C1-C7 alkyl.

[0028] According to one embodiment of the present invention, in the formula (1), R 3 is hydrogen or C1-C7 alkyl.

[0029] According to one embodiment of the present invention, in the formula (1), R 4 , R 5 , R 6 and R 7 are each independently hydrogen or C1-C7 alkyl.

[0030] According to one embodiment of the present invention, in the formula (1), R 8 is hydrogen, halo, C1-C7 alkyl, C1-C7 alkoxy or amino.

[0031] According to one embodiment of the present invention, in the formula (1), R 9 is hydrogen, halo, or C1-C7 alkyl.

[0032] According to one embodiment of the present invention, in the formula (1), X 1 and X 2 are each independently CH or N; Y is CH, O, or NH when n is 0, or CH or N when n is 1; Z is CH or CH when m is 0, or CH or C when m is 1, or C when m is 2; TIFF0007609857000004.tif38 is a single or double bond.

[0033] According to one embodiment of the present invention, in the formula (1), R 1 Ha-DR 10 wherein D is a direct bond, —O—, —C(═O)—, —C≡C—, or —CR 11 R 12 - and R 10 is hydrogen, halo, hydroxy, cyano, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, halo-C1-C7 alkylsulfonate, di(C1-C7 alkyl)amino, C1-C7 alkylamino-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkyl, di(C1-C7 alkyl)aminocarbonyl-C1-C7 alkyl, saturated or unsaturated C3-C 10 Carbocyclyl, saturated or unsaturated 4-10 membered heterocyclyl, saturated or unsaturated C3-C 10 carbocyclyl-C1-C7 alkyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl, R 11 and R 12 are each independently hydrogen, hydroxy, or C1-C7 alkyl.

[0034] According to one embodiment of the present invention, in the formula (1), R 10 is halo, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, saturated or unsaturated C3-C 10 It is carbocyclyl, saturated or unsaturated 4- to 10-membered heterocyclyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl.

[0035] According to one embodiment of the present invention, in the formula (1), the carbocyclic or heterocyclic ring is selected from the group consisting of hydroxy, halo, oxo, formyl, nitrile, C1-C7 alkyl, C1-C7 alkoxy, hydroxy-C1-C7 alkyl, hydroxyhalo-C1-C7 alkyl, C1-C7 alkoxy-C1-C7 alkyl, halo-C1-C7 alkyl, nitrile-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkylthiocarbonyl, C1-C7 alkoxycarbonyl, halo-C1-C7 alkylcarbonyl, saturated or unsaturated C3-C10 Carbocyclyl, saturated or unsaturated C3-C 10 It is optionally substituted by 1 to 5 substituents selected from carbocyclylcarbonyl, (C1-C7 alkyl)(halo-C1-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-C1-C7 alkyl.

[0036] According to one embodiment of the present invention, in the formula (1), the carbocyclic or heterocyclic ring is selected from the group consisting of hydroxy, halo, formyl, C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy-C1-C7 alkyl, halo-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkoxycarbonyl, halo-C1-C7 alkylcarbonyl, saturated or unsaturated C3-C 10 Carbocyclyl, saturated or unsaturated C3-C 10 It may be optionally substituted by 1 to 5 substituents selected from carbocyclylcarbonyl, (C1-C7 alkyl)(halo-C1-C7 alkyl)amino, (C1-C7 alkyl)(saturated or unsaturated 4- to 10-membered heterocyclyl)amino, and saturated or unsaturated 4- to 10-membered heterocyclyl-C1-C7 alkyl.

[0037] According to one embodiment of the present invention, in the formula (1), the heterocycle is selected from the group consisting of hydroxy, halo, formyl, C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy-C1-C7 alkyl, halo-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkoxycarbonyl, halo-C1-C7 alkylcarbonyl, saturated or unsaturated C3-C 10 Carbocyclyl, saturated or unsaturated C3-C 10 It may be optionally substituted with one or two substituents selected from the group consisting of carbocyclylcarbonyl and saturated or unsaturated 4- to 10-membered heterocyclyl-C1-C7 alkyl.

[0038] According to one embodiment of the present invention, in the formula (1), the carbocyclic ring may be substituted with one or two substituents selected from the group consisting of halo-C1-C7 alkyl, (C1-C7 alkyl)(halo-C1-C7 alkyl)amino, and (C1-C7 alkyl)(saturated or unsaturated 4- to 10-membered heterocyclyl)amino.

[0039] According to one embodiment of the present invention, in the formula (1), R 1 -DR 10 where D is a direct bond and R 10 is hydrogen, halo, cyano, C1-C7 alkyl, halo-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkyl, saturated or unsaturated 4- to 10-membered heterocyclyl, saturated or unsaturated C3-C 10 carbocyclyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl, wherein the heterocycle is optionally substituted by 1 or 2 substituents selected from hydroxy, halo, formyl, C1-C7 alkyl, C1-C7 alkoxy, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, nitrile-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkoxy-C1-C7 alkyl, C1-C7 alkoxycarbonyl, halo-C1-C7 alkylcarbonyl, and saturated or unsaturated 4- to 10-membered heterocyclyl.

[0040] According to one embodiment of the present invention, in the formula (1), R 2 is hydrogen or C1-C7 alkyl, and R 3 is hydrogen or C1-C7 alkyl, and R 4 , R 5 , R 6 and R 7 are each independently hydrogen or C1-C7 alkyl, and R 8 is hydrogen, halo, C-C alkyl, C-C alkoxy, or amino; R 9 is hydrogen, halo, or C1-C7 alkyl.

[0041] According to one embodiment of the present invention, in the formula (1), TIFF0007609857000005.tif38 is a single bond.

[0042] According to one embodiment of the present invention, in the formula (1), the heterocycle is a 4- to 8-membered saturated or unsaturated hydrocarbon containing one or two heteroatoms selected from nitrogen and oxygen.

[0043] According to one embodiment of the present invention, in the 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]o 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.

[0044] According to one embodiment of the present invention, in the 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.

[0045] According to one embodiment of the present invention, in said formula (1), the carbocyclic ring is selected from the group consisting of cyclohexane, cyclohexene, cyclopropane, cyclobutane, and cyclopentane.

[0046] According to one embodiment of the present invention, in the formula (1), D is a direct bond, —O—, —C(═O)—, or —C≡C—, and R 10 is halo, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, saturated or unsaturated C3-C 10 carbocyclyl, saturated or unsaturated 4- to 10-membered heterocyclyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl, wherein the carbocycle or heterocycle is hydroxy, halo, formyl, C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy-C1-C7 alkyl, halo-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkoxycarbonyl, halo-C1-C7 alkylcarbonyl, saturated or unsaturated C3-C 10 Carbocyclyl, saturated or unsaturated C3-C 10 and the heterocycle may be optionally substituted by 1 to 5 substituents selected from carbocyclylcarbonyl, (C1-C7 alkyl)(halo-C1-C7 alkyl)amino, (C1-C7 alkyl)(saturated or unsaturated 4- to 10-membered heterocyclyl)amino, and saturated or unsaturated 4- to 10-membered heterocyclyl-C1-C7 alkyl, and the heterocycle may be substituted by tetrahydropyridine, dihydropyridine, piperidine, tetrahydropyran, pyrrolidine, and the carbocyclic ring is selected from the group consisting of 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 carbocyclic ring is selected from the group consisting of cyclohexane, cyclohexene, and cyclopropane.

[0047] Representative examples of compounds of formula (1) according to the present invention include, but are not limited to, the compounds shown in Table 1.

[0048] [Table 1] TIFF0007609857000007.tif230130 TIFF0007609857000008.tif236131 TIFF0007609857000009.tif233131 TIFF0007609857000010.tif235131 TIFF0007609857000011.tif231133 TIFF0007609857000012.tif233134 TIFF0007609857000013.tif228132 TIFF0007609857000014.tif230132 TIFF0007609857000015.tif224132 TIFF0007609857000016.tif221132 TIFF0007609857000017.tif227131 TIFF0007609857000018.tif218129 TIFF0007609857000019.tif220131 TIFF0007609857000020.tif213133 TIFF0007609857000021.tif223131 TIFF0007609857000022.tif206132 TIFF0007609857000023.tif226132 TIFF0007609857000024.tif222133 TIFF0007609857000025.tif222132 TIFF0007609857000026.tif218133 TIFF0007609857000027.tif217129 TIFF0007609857000028.tif230134 TIFF0007609857000029.tif225133 TIFF0007609857000030.tif70133

[0049] The compounds according to the present invention may have asymmetric carbon centers and asymmetric axes or planes, and therefore may exist as all optical and stereoisomers, including substantially pure enantiomers such as R and S enantiomers, as well as mixed racemates, and all isomers and compounds thereof are within the scope of the present invention. With respect to pure enantiomers, the enantiomeric excess of such enantiomers of formula (1) and their pharmaceutically acceptable salts may preferably be 60% ee or greater, more preferably 95% ee or greater, and most preferably 98% ee or greater.

[0050] The term "ee" refers to enantiomeric excess. For example, one enantiomer of a particular compound is present in a mixture of enantiomers in a compound in a greater amount than the other enantiomer. Enantiomerically enriched forms can include enantiomeric mixtures of a particular compound in which the concentration of a single enantiomer in the enantiomeric mixture of the particular compound is at least 50% or more, more typically at least 60%, 70%, 80%, or 90% or more, relative to the other enantiomer of the compound (e.g., >95%, >97%, >98%, >99%, >99.5%).

[0051] In this specification, unless otherwise specified, the compound represented by formula (1) is used to mean the compound of formula (1), its optical isomers, stereoisomers, isotopic variants, and pharmaceutically acceptable salts thereof.

[0052] As used herein, the term "isotopic variant" refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such compound. For example, an isotopic variant of a compound can be radiolabeled, e.g., the hydrogen atoms can be selected from hydrogen, deuterium, and tritium, and carbon-13 ( 13 C), nitrogen-15( 15 N), etc.

[0053] The compound of formula (1) according to the present invention, or its optical isomer, stereoisomer, or isotopic variant, can form a pharmaceutically acceptable salt. The pharmaceutically acceptable salt includes an acid or base addition salt and its stereochemical isomer. The salt includes, but is not limited to, any salt that retains the activity of the parent compound in the administered subject and does not cause undesired effects. Salts include inorganic salts and organic salts, such as acid addition salts of 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, esculent acid, lactic acid, bicarbonate, bisulfate, bitartaric acid, oxalic acid, butyric acid, calcium edetate, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid, edetic acid, toluenesulfonic acid, edicylinic acid, ecylinic acid, fumaric acid, and gluceptic acid. The basic salt may be pamoic acid, gluconic acid, glycolylarsanilic acid, methyl nitrate, polygalacturonic acid, hexylresorcylic acid, malonic acid, hydrobamic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactobionic acid, mandelic acid, estronic acid, mucic acid, naphthenic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogen phosphate, dihydrogen phosphate, salicylic acid, sulfamic acid, sulfanilic acid, methanesulfonic acid, or theoclic acid. Examples of the basic salt include alkali and alkaline earth metal salts such as ammonium salt, lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt; salts with organic bases such as benzathine, N-methyl-D-glucamine, and hydrabamine salt; and salts with amino acids such as arginine and lysine. Furthermore, the salt forms can be converted into free forms by treating with an appropriate base or acid. As used herein, the term "addition salt" can be interpreted as including solvates and salts thereof obtained from any of the compounds represented by formula (1). Examples of such solvates include hydrates and alcoholates.

[0054] Terms and abbreviations used herein have their original meaning unless otherwise specified.

[0055] The present invention also provides a method for preparing a compound of formula (1). Below, a method for preparing a compound of formula (1) is described based on an exemplary reaction scheme for better understanding of the present invention. However, it should be understood that a person skilled in the art can prepare a compound of formula (1) by various methods using known compounds based on the structure of formula (1) or compounds that can be easily prepared therefrom, and all methods are within the scope of the present invention. That is, a compound of formula (1) can be prepared by any combination of several synthetic methods described herein or disclosed in the prior art. Therefore, the following description of a method for preparing a compound of formula (1) is merely illustrative, and the order of unit operations can be selectively changed as necessary, and the scope of the preparation method of the present invention is not limited thereto.

[0056] <Reaction Scheme 1>

[0057] [ka]

[0058] In a typical synthesis method, starting material 2 can be converted to intermediate 3 by a Schmidt reaction using sodium azide under acidic conditions. From this compound, intermediate 4 is obtained by a substitution reaction to introduce an oxirane, and the final compound 1a is obtained by addition of tetrahydroisoquinoline.

[0059] <Reaction Scheme 2> [ka]

[0060] Alternatively, the final compound 1b substituted with alkyl and alkenyl groups can be obtained by Suzuki coupling reaction under palladium conditions using compound 5 as the starting compound.

[0061] <Reaction Scheme 3> [ka]

[0062] In yet another synthesis method, compound 5 can be used as a starting material, as shown in Reaction Scheme 3, to obtain intermediate 6 by substituting the bromine group with a hydroxide group using potassium hydroxide under palladium conditions, followed by a substitution reaction to obtain the final compound 1c with the ether group substituted.

[0063] According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating a disease associated with PRMT5 inhibition, comprising, as an active ingredient, a therapeutically effective amount of a compound of formula (1) or its optical isomer, stereoisomer, or isotopic variant, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. Also within the scope of the present invention are prodrugs having various forms that are converted to the compound of formula (1) as desired in vivo. The pharmaceutical composition may further comprise one or more additives selected from the group consisting of pharmaceutically acceptable carriers, diluents, and adjuvants.

[0064] As used herein, the term "treating" means halting, slowing or alleviating disease progression when used in a subject with symptoms.

[0065] As used herein, the term "prevention" means reducing the chance of disease or eliminating the chance of disease.

[0066] As used herein, the term "pharmaceutical composition" may contain, in addition to the active compound according to the present invention, other chemical components, such as carriers, diluents, and excipients. Thus, the pharmaceutical composition may optionally contain a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof. The pharmaceutical composition facilitates administration of the active compound to an organism. Various techniques for administering pharmaceutical compositions containing compounds are known, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. The pharmaceutical composition may be sterilized and may further contain auxiliary agents, such as preservatives, stabilizers, wetting or emulsifying agents, salts for regulating osmotic pressure, and / or buffers, and may further contain other therapeutically valuable substances. The pharmaceutical composition may be formulated according to conventional methods of mixing, granulating, or coating.

[0067] As used herein, the term "carrier" refers to a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier for easily introducing large amounts of organic compounds into cells or tissues of living organisms.

[0068] As used herein, the term "diluent" refers to a compound that is diluted with water to stabilize the biologically active form of the compound of interest and dissolve the compound.Salt dissolved in a buffer solution is used as a diluent in the art.A commonly used buffer solution is phosphate buffered saline, which mimics the salt form of human body fluids.Because buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely alter the biological activity of the compound.

[0069] As used herein, the term "pharmaceutically acceptable" refers to the property of not impairing the biological activity and physical properties of a compound.

[0070] The pharmaceutical composition may also be a composition for preventing and / or treating a disease associated with PRMT5 inhibition, such as cancer, blood disease, autoimmune disease, inflammatory disease, or neurodegenerative disease, and also includes any other disease known to be associated with PRMT5.

[0071] The cancers include acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma, benign monoclonal gammopathy, bile duct carcinoma, bladder carcinoma, breast cancer, brain tumor, lymphoma, multiple myeloma, lacrimal gland tumor, bronchial carcinoma, cervical carcinoma, craniopharyngioma, colorectal cancer, epithelial tumor, ependymoma, endothelial sarcoma, endometrial carcinoma, esophageal carcinoma, Barrett's adenocarcinoma, Ewing's sarcoma, and the like. sarcoma), eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cavity cancer (OSCC), throat cancer, hematopoietic cancer, hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer, liver cancer, lung cancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), neuroblastoma, neurofibroma, neuroendocrine carcinoma, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, prostate cancer, colon cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, thyroid cancer, urethral cancer, vaginal cancer, and vulvar cancer. The brain tumors include, but are not limited to, meningiomas, gliomas, medulloblastomas, glioblastomas, and brain metastases.The brain tumors include, but are not limited to, meningiomas, gliomas, medulloblastomas, glioblastomas, and brain metastases.

[0072] Such blood disorders include, but are not limited to, hemoglobinemia or sickle cell anemia.

[0073] The autoimmune diseases include, but are not limited to, rheumatoid arthritis, spondyloarthritis, gouty arthritis, degenerative joint disease, osteoarthritis, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, juvenile arthritis, asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, psoriasis, eczema, burns, dermatitis, pruritus, nocturnal enuresis, eosinophilic diseases, peptic ulcer, regional enteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis.

[0074] The inflammatory diseases include acne-related inflammation, aplastic anemia, autoimmune hemolytic 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 diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, chronic obstructive pulmonary disease, dermatomyositis, type 1 diabetes, type 2 diabetes, psoriasis, eczema, eczema hypersensitivity reactions, burns, dermatitis, pruritus, endometriosis, infection, ischemic heart disease, glomerulonephritis, gingivitis, hypersensitivity, migraine, tension headache, and postoperative intestinal obstruction. These conditions include, but are not limited to, urinary tract infection, ileus during sepsis, idiopathic thrombocytopenic purpura, painful bladder syndrome, peptic ulcer, regional 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, morphea, myasthenia gravis, and myocardial ischemia.

[0075] Examples of such neurodegenerative diseases include, but are not limited to, motor neuron disease, Pick's disease, Alzheimer's disease, AIDS dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinal pigmentation, spinal muscular atrophy, and cerebellar degeneration.

[0076] The pharmaceutical composition can be formulated into various oral or parenteral dosage forms. For example, it can be formulated into any oral dosage form such as tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc. Such oral dosage forms may contain, in addition to the active ingredient, pharmaceutically acceptable carriers such as diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine, or glidants such as silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol, depending on the typical composition of each formulation.

[0077] When the oral preparation is a tablet, the preparation may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidine, and may optionally further contain a disintegrating agent such as starch, agar, alginic acid or a sodium salt thereof, a boiling mixture and / or an absorbent, a coloring agent, a flavoring agent, or a sweetening agent.

[0078] When the pharmaceutical composition is formulated into a parenteral dosage form, it can be administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In this case, to formulate the pharmaceutical composition into a parenteral administration preparation, the active ingredient, i.e., the compound of formula (1), or its optical isomer, stereoisomer, or isotopic variant, or a pharmaceutically acceptable salt thereof, is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, and such a solution or suspension can be prepared in a unit dosage form such as an ampule or vial.

[0079] The pharmaceutical compositions may be sterilized or may further contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, salts and / or buffers for adjusting osmotic pressure, or other therapeutically useful agents, and may be formulated according to conventional methods of mixing, granulating, or coating.

[0080] The active ingredient, i.e., the compound of formula (1) or its optical isomer, stereoisomer or isotope variant, or a pharmaceutically acceptable salt thereof, may be contained 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 for mammals including humans, and the pharmaceutical composition can be administered orally or parenterally once or twice a day. [Effects of the Invention]

[0081] The present invention provides a 6-7 bicyclic ring-based compound, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, which exhibits excellent PRMT5 inhibitory effect. Therefore, such a compound, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof can be effectively used for the prevention or treatment of diseases associated with PRMT5 inhibition, such as cancer, blood diseases, autoimmune diseases, inflammatory diseases, or neurodegenerative diseases.

[0082] Furthermore, the compound according to the present invention, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof may have improved blood-brain barrier permeability, superior efficacy, or improved pharmacokinetic properties. BEST MODE FOR CARRYING OUT THE INVENTION

[0083] The present invention will now be described in detail with reference to the following examples, but it should be understood that the scope of protection of the present disclosure is not limited to the examples.

[0084] Example 1: Synthesis of 4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methoxy-2,3-dihydro-1,4-benzoxazepin-5-one

[0085] [ka]

[0086] Example 1-1: Synthesis of 8-methoxy-4-(oxiran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0087] 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 in an ice bath. After stirring the reaction solution at 0 °C for 30 minutes, epibromohydrin (0.056 mL, 0.65 mmol) was slowly added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of methanol. After adding ethyl acetate, the mixture was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting compound was used in the next reaction without further purification.

[0088] Example 1-2: Synthesis of 4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methoxy-2,3-dihydro-1,4-benzoxazepin-5-one

[0089] 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, followed by stirring at 80°C for 12 hours. The temperature was lowered to room temperature, and the solvent was concentrated to obtain an oily liquid. The resulting oily liquid was purified by flash chromatography to obtain a transparent, sticky solid compound. The NMR data of the title compound obtained are as follows:

[0090] 1H NMR (400 MHz, Methanol-d4) δ 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 (t, 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, 7.7Hz, 1H), 2.97 - 2.85 (m, 4H), 2.69 - 2.60 (m, 2H).

[0091] Example 2: Synthesis of 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-methoxy-4,5-dihydro-3H-2-benzazepin-1-one

[0092] [ka]

[0093] The title compound was obtained in a similar manner to Example 1 using 7-methoxy-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material.

[0094] 1H NMR (400 MHz, Methanol-d4) δ 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 (t, J = 7.1 Hz, 2H), 2.64 - 2.52 (m, 2H), 2.02 (p, J = 7.0 Hz, 2H).

[0095] Example 3: Synthesis of 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-hydroxy-4,5-dihydro-3H-2-benzazepin-1-one

[0096] [ka]

[0097] The title compound was obtained in a similar manner to Example 1 using (1-oxo-2,3,4,5-tetrahydro-2-benzazepin-7-yl)acetate as a starting material.

[0098] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0099] 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

[0100] [ka]

[0101] The title compound was obtained in a similar manner to Example 1 using 6-(trifluoromethoxy)tetralin-1-one as a starting material.

[0102] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0103] Example 5: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(trifluoromethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0104] [ka]

[0105] The title compound was synthesized in the same manner as in Example 1, except that 7-(trifluoromethyl)chroman-4-one was used as the starting material and (R)-(-)-glycidyl nosylate was used instead of epibromohydrin in Example 1-1.

[0106] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0107] Example 6: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)-4,5-dihydro-3H-2-benzazepin-1-one

[0108] [ka]

[0109] The title compound was obtained using 7-(trifluoromethoxy)-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material in a manner similar to that in Example 5.

[0110] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0111] 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

[0112] [ka]

[0113] The title compound was obtained in a similar manner to that in Example 5 using 7-ethoxy-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material.

[0114] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 7.1 Hz, 2H), 2.73 - 2.62 (m, 2H), 2.19 - 2.07 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H).

[0115] Example 8: Synthesis of [2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-benzazepin-7-yl]trifluoromethanesulfonate

[0116] [ka]

[0117] The title compound was obtained using (1-oxo-2,3,4,5-tetrahydro-2-benzazepin-7-yl)trifluoromethanesulfonate as a starting material in a manner similar to that in Example 5.

[0118] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0119] Example 9: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-benzazepine-7-carbonitrile

[0120] [ka]

[0121] The title compound was obtained in the same manner as in Example 5 using 7-cyano-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material.

[0122] 1H NMR (400 MHz, Methanol-d4) δ 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 (t, J = 5.4 Hz, 2H), 2.17 (p, J = 7.0 Hz, 2H).

[0123] Example 10: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

[0124] [ka]

[0125] 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-benzoxazepin-5-one

[0126] The title compound was obtained in the same manner as in Example 5 using 8-bromo-3,4-dihydro-2H-1,4-benzoxazepin-5-one as a starting material.

[0127] Example 10-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

[0128] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,3-dihydro-1,4-benzoxazepin-5-one (96 mg, 0.22 mmol), methylboronic acid (27 mg, 0.45 mmol), Pd(dppf)Cl₂·CHCl₂ (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 completion of the reaction, the reaction solution was concentrated under reduced pressure and filtered with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash chromatography to give the title compound (11 mg).

[0129] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0130] Example 11: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-propyl-2,3-dihydro-1,4-benzoxazepin-5-one

[0131] [ka]

[0132] 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.

[0133] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0134] 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

[0135] [ka]

[0136] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,3-dihydro-1,4-benzoxazepin-5-one (100 mg, 0.23 mmol), isobutylboronic acid (47 mg, 0.46 mmol), Pd(dppf)Cl (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 completion of the boronic acid reaction, the reaction solution was concentrated under reduced pressure and filtered with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash chromatography to give the title compound (11 mg).

[0137] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0138] 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

[0139] [ka]

[0140] The title compound was synthesized in a similar manner to Example 12, except that 3,3,3-trifluoropropylboronic acid was used instead of isobutylboronic acid at 100°C.

[0141] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0142] Example 14: Synthesis of 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

[0143] [ka]

[0144] The title compound was synthesized in the same manner as in Example 10, except that in Example 10-2, 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.

[0145] 1H NMR (400 MHz, Methanol-d4) δ 7.68 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.19 - 7.03 (m, 5H), 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).

[0146] Example 15: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0147] [ka]

[0148] The tert-butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate obtained in Example 14 was dissolved in methanol, and a 4N solution of hydrochloric acid in 1,4-dioxane was added. The reaction was stirred at room temperature until completion, diluted with ethyl acetate, and filtered to obtain the title compound in the dihydrochloride form as a white solid. After adding water, the title compound in the dihydrochloride form was washed three times with ethyl acetate. The resulting aqueous layer was basified with aqueous sodium hydroxide to pH 14 and extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound without further purification.

[0149] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0150] 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-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0151] [ka]

[0152] The dihydrochloride salt (75 mg, 0.16 mmol) of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 15 and potassium carbonate (66 mg, 0.48 mmol) were dissolved in 1.5 mL of acetone, and acetic anhydride (0.03 mL, 0.32 mmol) was slowly added at room temperature. The reaction solution was stirred at room temperature, and after confirming completion of the reaction, it was filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography to obtain the title compound.

[0153] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0154] 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

[0155] [ka]

[0156] Example 17-1: 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

[0157] tert-Butyl 4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate obtained in Example 14 was dissolved in methanol and a catalytic amount of 5% palladium on carbon was added. The reaction solution was stirred under a hydrogen balloon and filtered through Celite. The filtrate was concentrated under reduced pressure and dissolved in a small amount of methanol. 4N hydrochloric acid dissolved in 1,4-dioxane was added and stirred at room temperature for 1 hour. Distilled water was added to the reaction solution, which was then washed with ethyl acetate. The resulting aqueous layer was basified with aqueous sodium hydroxide to pH 14 and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound without further purification.

[0158] Example 17-2: 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

[0159] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(4-piperidyl)-2,3-dihydro-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. The reaction solution was stirred at room temperature for 1 day, diluted with dichloromethane, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography to give the title compound (21 mg).

[0160] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0161] Example 18: Synthesis of 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

[0162] [ka]

[0163] The dihydrochloride salt (75 mg, 0.16 mmol) of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 15 was dissolved in methanol, and an excess amount of acetaldehyde was added. An excess amount of sodium cyanoborohydride was added to the stirred reaction solution, and the mixture was stirred at room temperature for 1 day. The reaction solution was quenched by adding saturated aqueous ammonium chloride, and basified with 1N aqueous sodium hydroxide. The reaction mixture was extracted three times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting oily liquid was purified by flash chromatography to yield the title compound (10 mg) as a white solid.

[0164] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0165] 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

[0166] [ka]

[0167] The title compound was synthesized in the same manner as in Example 18, except that acetone was used instead of acetaldehyde.

[0168] 1 H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.10 - 6.95 (m, 5H), 6.24 (s, 1H), 4.42 (t, J = 5.2 Hz, 2H), 4.22 - 4.12 (m, 1H), 3.96 - 3.84 (m, 1H), 3.71 (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).

[0169] Example 20: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0170] [ka]

[0171] The title compound was obtained in the same manner as in Example 10, except that 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of methylboronic acid.

[0172] 1H NMR (400 MHz, Methanol-d4) δ 7.68 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.20 - 6.98 (m, 5H), 6.34 (s, 1H), 4.49 (t, 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).

[0173] 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

[0174] [ka]

[0175] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 20 was dissolved in methanol, and a catalytic amount of 5% palladium on carbon was added. 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 give the title compound as a clear oil.

[0176] 1H NMR (400 MHz, Methanol-d4) δ 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, 5H), 2.69 - 2.59 (m, 2H), 1.84 - 1.72 (m, 4H).

[0177] Example 22: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(morpholinomethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0178] [ka]

[0179] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,3-dihydro-1,4-benzoxazepin-5-one (160 mg, 0.37 mmol), potassium (morpholin-4-yl)methyl trifluoroboronate (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, flushed with nitrogen, and then stirred at 80 °C for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and filtered through Celite. The resulting solution was concentrated under reduced pressure and purified by flash chromatography to give the title compound (103 mg) as a white solid.

[0180] 1H NMR (400 MHz, Methanol-d4) δ 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), 4.30 - 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).

[0181] Example 23: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-piperidylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0182] [ka]

[0183] The title compound was synthesized in a similar manner to Example 22, except that potassium (piperidin-1-yl)methyl trifluoroboronate was used instead of potassium (morpholin-4-yl)methyl trifluoroboronate.

[0184] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0185] 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

[0186] [ka]

[0187] The title compound was synthesized in the same manner as in Example 22, except that potassium 1-trifluoroboratemethylpyrrolidine was used instead of potassium (morpholin-4-yl)methyltrifluoroboronate.

[0188] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0189] 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

[0190] [ka]

[0191] 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)methyltrifluoroboronate.

[0192] 1H NMR (400 MHz, Chloroform-d) δ 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, J = 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).

[0193] 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

[0194] [ka]

[0195] 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)methyltrifluoroboronate.

[0196] 1H NMR (400 MHz, Chloroform-d) δ 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, J = 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 = 7.1 Hz, 6H).

[0197] Example 27: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methyl-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0198] [ka]

[0199] 4-Methylpiperidine (0.054 mL, 0.46 mmol) and potassium (bromomethyl)trifluoroboronate (92 mg, 0.46 mmol) were dissolved in 2 mL of tetrahydrofuran and stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature, and 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,3-dihydro-1,4-benzoxazepin-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. The reaction vessel was then flushed with nitrogen. The reaction solution was stirred at 80° C. for 16 hours, diluted with ethyl acetate, and filtered through Celite. The resulting solution was concentrated under reduced pressure and purified by flash chromatography to give the title compound (70 mg) as a white solid.

[0200] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0201] Example 28: Synthesis of 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

[0202] [ka]

[0203] The title compound was synthesized in a similar manner to Example 27, except that 4 equivalents of potassium carbonate were added and 2-oxa-6-azaspiro[3.3]heptane oxalate was used instead of 4-methylpiperidine.

[0204] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0205] 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

[0206] [ka]

[0207] 3-Methoxyazetidine hydrochloride (57 mg, 0.46 mmol), potassium (bromomethyl)trifluoroboronate (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-hydroxypropyl]-2,3-dihydro-1,4-benzoxazepin-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. The reaction vessel was then flushed with nitrogen. The reaction mixture was stirred at 80 °C for 16 h, diluted with ethyl acetate, and filtered through Celite. The resulting solution was concentrated under reduced pressure and purified by flash chromatography to give the title compound (16 mg) as a white solid.

[0208] 1 H NMR (400 MHz, Methanol-d4) δ 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 (t, 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).

[0209] 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

[0210] [ka]

[0211] The title compound was synthesized in the same manner as in Example 29, except that 2-methylmorpholine was used instead of 3-methoxyazetidine hydrochloride.

[0212] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0213] Example 31: Synthesis of 8-[(4,4-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0214] [ka]

[0215] 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.

[0216] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0217] Example 32: Synthesis of 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

[0218] [ka]

[0219] 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.

[0220] 1H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.14 - 7.01 (m, 5H), 4.67 (d, J = 48.8 Hz, 1H), 4.48 (t, J = 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).

[0221] 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

[0222] [ka]

[0223] 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.

[0224] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0225] 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-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0226] [ka]

[0227] 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.

[0228] 1H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J = 8.0 Hz, 1H), 7.18 (s, 0H), 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).

[0229] Example 35: Synthesis of 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

[0230] [ka]

[0231] The title compound was synthesized in a similar manner to Example 29, except that pyrrolidin-3-ol was used instead of 3-methoxyazetidine hydrochloride.

[0232] 1H NMR (400 MHz, Methanol-d4) δ 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 (t, 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, J = 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).

[0233] Example 36: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-methylpyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0234] [ka]

[0235] 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.

[0236] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0237] Example 37: Synthesis of 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

[0238] [ka]

[0239] The title compound was synthesized in the same manner as in Example 29, except that 3-piperidylmethanol was used instead of 3-methoxyazetidine hydrochloride.

[0240] 1H NMR (400 MHz, Methanol-d4) δ 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 (t, 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, J = 7.1 Hz, 1H), 2.94 (d, J = 5.4 Hz, 2H), 2.88 (t, 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).

[0241] 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

[0242] [ka]

[0243] The title compound was synthesized in a similar manner to Example 29, except that 4-methoxypiperidine was used instead of 3-methoxyazetidine hydrochloride.

[0244] 1H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.15 - 7.01 (m, 5H), 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 (s, 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 (t, J = 10.8 Hz, 2H), 1.99 - 1.87 (m, 2H), 1.67 - 1.52 (m, 2H).

[0245] 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

[0246] [ka]

[0247] 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.

[0248] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0249] Example 40: Synthesis of 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

[0250] [ka]

[0251] 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.

[0252] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0253] Example 41: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[2-(hydroxymethyl)-1-piperidyl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0254] [ka]

[0255] 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.

[0256] 1H NMR (400 MHz, Methanol-d4) δ 7.66 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.15 - 7.04 (m, 5H), 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).

[0257] Example 42: Synthesis of 8-[(3,3-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0258] [ka]

[0259] 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.

[0260] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0261] Example 43: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0262] [ka]

[0263] 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.

[0264] 1H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.15 - 7.02 (m, 5H), 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).

[0265] 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

[0266] [ka]

[0267] The title compound was synthesized in a similar manner to Example 29, except that piperidin-3-ol hydrochloride was used instead of 3-methoxyazetidine hydrochloride.

[0268] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0269] 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

[0270] [ka]

[0271] The title compound was synthesized in a similar manner to Example 29, except that piperidin-4-ol was used instead of 3-methoxyazetidine hydrochloride.

[0272] 1H NMR (400 MHz, Methanol-d4) δ 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 = 5.0 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).

[0273] Example 46: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0274] [ka]

[0275] 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.

[0276] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0277] Example 47: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0278] [ka]

[0279] 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.

[0280] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0281] Example 48: Synthesis of 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

[0282] [ka]

[0283] 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.

[0284] 1H NMR (400 MHz, Methanol-d4) δ 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), 4.29 - 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, J = 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).

[0285] Example 49: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0286] [ka]

[0287] 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.

[0288] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0289] 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

[0290] [ka]

[0291] 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.

[0292] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0293] 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

[0294] [ka]

[0295] 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.

[0296] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0297] Example 52: Synthesis of 8-[(3,3-difluoropyrrolidin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0298] [ka]

[0299] 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.

[0300] 1H NMR (400 MHz, Methanol-d4) δ 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), 4.29 - 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).

[0301] Example 53: Synthesis of 8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0302] [ka]

[0303] The title compound was synthesized in a similar manner to Example 29, except that 1-piperazin-1-ylethanone was used instead of 3-methoxyazetidine hydrochloride.

[0304] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0305] 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

[0306] [ka]

[0307] Example 54-1: Synthesis of 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]methyl]piperazine-1-carboxylate

[0308] The title compound was synthesized in the same manner as in Example 29, except that tert-butylpiperazine-1-carboxylate was used instead of 3-methoxyazetidine hydrochloride.

[0309] Example 54-2: Synthesis of 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

[0310] The tert-butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]methyl]piperazine-1-carboxylate obtained in Example 54-1 was dissolved in methanol, and 4 M hydrochloric acid solution in 1,4-dioxane was slowly added. The reaction solution was stirred at room temperature, diluted with diethyl ether, and filtered to give the title compound as a white solid.

[0311] 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

[0312] The resulting hydrochloride salt was dissolved in methanol, and excess paraformaldehyde and sodium cyanoborohydride were added. The mixture was then stirred at room temperature for 12 hours. The reaction was quenched by adding saturated aqueous ammonium chloride, and basified by adding 1N aqueous sodium hydroxide. The mixture was extracted three times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting pale yellow oily liquid was purified by flash chromatography to give the title compound.

[0313] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0314] 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

[0315] [ka]

[0316] The title compound was synthesized in the same manner as in Example 29, except that 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was used instead of 3-methoxyazetidine hydrochloride.

[0317] 1H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16 - 7.02 (m, 5H), 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 (t, J = 5.3 Hz, 2H), 3.65 (d, J = 7.9 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).

[0318] Example 56: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

[0319] [ka]

[0320] Example 56-1: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-one

[0321] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,3-dihydro-1,4-benzoxazepin-5-one (9.0 g, 21 mmol), potassium hydroxide (4.68 g, 83 mmol), Pd(dba)2 (180 mg, 0.315 mmol), and tBuXPhos (270 mg, 0.63 mmol) were dissolved in 80 mL of 1,4-dioxane:distilled water (1:1) solution, and the reaction vessel was flushed with nitrogen. The reaction solution was stirred at 100 °C for 3 h and then acidified with aqueous hydrochloric acid in an ice bath to a pH of ∼1. The aqueous layer was washed three times with ethyl acetate, basified with aqueous sodium hydroxide in an ice bath to a pH of 14, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a white solid without further purification.

[0322] Example 56-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

[0323] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-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 at room temperature. The reaction solution was stirred at room temperature for 3 hours and then extracted with ethyl acetate and distilled water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily liquid. The title compound (64 mg) was purified by flash chromatography to give a sticky white solid.

[0324] 1H NMR (400 MHz, Methanol-d4) δ 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), 4.49 (t, J = 5.0 Hz, 2H), 4.29 - 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).

[0325] Example 57: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

[0326] [ka]

[0327] The title compound was synthesized in the same manner as in Example 56-2, except that 4-(chloromethyl)pyridine hydrochloride was used instead of 3-(chloromethyl)pyridine hydrochloride.

[0328] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0329] Example 58: Synthesis of 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

[0330] [ka]

[0331] The title compound was synthesized in the same manner as in Example 56-2, except that (2-fluoro-4-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride.

[0332] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0333] 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

[0334] [ka]

[0335] The title compound was synthesized in the same manner as in Example 56-2, except that 2,6-dichloro-4-ethyl-pyridine hydrochloride was used instead of 3-(chloromethyl)pyridine hydrochloride.

[0336] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0337] 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

[0338] [ka]

[0339] The title compound was synthesized in the same manner as in Example 56-2, except that (2,3-difluoro-4-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride.

[0340] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0341] Example 61: Synthesis of 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

[0342] [ka]

[0343] The title compound was synthesized in the same manner as in Example 56-2, except that (6-fluoro-3-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride.

[0344] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0345] Example 62: Synthesis of 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

[0346] [ka]

[0347] The title compound was synthesized in the same manner as in Example 56-2, except that (3-fluoro-4-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride.

[0348] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0349] Example 63: Synthesis of 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

[0350] [ka]

[0351] The title compound was synthesized in the same manner as in Example 56-2, except that (5-fluoro-2-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride.

[0352] 1H NMR (400 MHz, Methanol-d4) δ 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 (s, 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).

[0353] 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

[0354] [ka]

[0355] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-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 more. The reaction solution was cooled to room temperature, distilled water was added, and the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily liquid. The title compound was purified by flash chromatography to give a sticky white solid.

[0356] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0357] Example 65: Synthesis of 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

[0358] [ka]

[0359] The title compound was synthesized in a similar manner to Example 64, except that tetrahydropyran-2-ylmethyl methanesulfonate was used instead of 4-chlorotetrahydropyran.

[0360] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0361] 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

[0362] [ka]

[0363] The title compound was synthesized in a similar manner to Example 64, except that cyclohexylmethyl methanesulfonate was used instead of 4-chlorotetrahydropyran.

[0364] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 10.2 Hz, 3H), 1.51 - 1.41 (m, 1H).

[0365] Example 67: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydrofuran-2-ylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

[0366] [ka]

[0367] The title compound was synthesized in a similar manner to Example 64, except that tetrahydrofuran-2-ylmethyl methanesulfonate was used instead of 4-chlorotetrahydropyran.

[0368] 1H NMR (400 MHz, Chloroform-d) δ 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, J = 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).

[0369] Example 68: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[0370] [ka]

[0371] 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.

[0372] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 16.5, 10.6 Hz, 2H).

[0373] 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

[0374] [ka]

[0375] 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.

[0376] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0377] Example 70: Synthesis of 8-[(1-acetyl-4-piperidyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0378] [ka]

[0379] 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.

[0380] 1H NMR (400 MHz, Methanol-d4) δ 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, 7.6Hz, 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).

[0381] 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

[0382] [ka]

[0383] 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.

[0384] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0385] Example 72: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(dimethylamino)ethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[0386] [ka]

[0387] 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.

[0388] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0389] 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

[0390] [ka]

[0391] 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.

[0392] 1H NMR (400 MHz, Chloroform-d) δ 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 = 5.7 Hz, 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).

[0393] Example 74: Synthesis of 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

[0394] [ka]

[0395] The title compound was synthesized in a similar manner to Example 64, except that 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate was used instead of 4-chlorotetrahydropyran.

[0396] 1H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 9.0 Hz, 3H), 7.01 (d, J = 7.0 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).

[0397] 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-benzoxazepin-8-yl]oxy]-N,N-diethyl-acetamide

[0398] [ka]

[0399] 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.

[0400] 1H NMR (400 MHz, Chloroform-d) δ 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 = 7.8 Hz, 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).

[0401] Example 76: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-oxo-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[0402] [ka]

[0403] The title compound was synthesized in the same manner as in Example 64, except that (6-oxo-3-piperidyl)methanesulfonate was used instead of 4-chlorotetrahydropyran.

[0404] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0405] Example 77: Synthesis of 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]oxy]piperidine-1-carboxylate

[0406] [ka]

[0407] 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.

[0408] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0409] Example 78: Synthesis of 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

[0410] [ka]

[0411] Example 78-1: Synthesis of 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

[0412] tert-Butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]piperidine-1-carboxylate obtained in Example 77 was dissolved in methanol, and 4 M hydrochloric acid solution in 1,4-dioxane was slowly added. The reaction solution was stirred at room temperature, diluted with diethyl ether, and filtered to give the title compound as a white solid.

[0413] Example 78-2: Synthesis of 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

[0414] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 78-1 was dissolved in dichloromethane, and triethylamine and acetic anhydride were added, followed by stirring at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as an oily liquid, which was purified by flash chromatography to give the title compound as a white solid.

[0415] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0416] Example 79: Synthesis of 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

[0417] [ka]

[0418] 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.

[0419] 1H NMR (mixed diastereomers, 400 MHz, Methanol-d4) δ 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).

[0420] Example 80: Synthesis of 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

[0421] [ka]

[0422] 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.

[0423] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0424] 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

[0425] [ka]

[0426] The title compound was obtained 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.

[0427] 1H NMR (400 MHz, Methanol-d4) δ 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 = 14.2, 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).

[0428] 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

[0429] [ka]

[0430] 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.

[0431] 1H NMR (400 MHz, Methanol-d4) δ 7.69 (d, J = 8.6 Hz, 1H), 7.17 - 7.02 (m, 4H), 6.77 (t, 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, 7.9Hz, 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).

[0432] 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

[0433] [ka]

[0434] Example 83-1: Synthesis of 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

[0435] The title compound was obtained in the same manner as in Example 78-1, except that in Example 64, the starting material was changed from 4-chlorotetrahydropyran to tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate.

[0436] 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

[0437] The title compound was obtained in the same manner as in Example 78-2 using 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 the starting material.

[0438] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0439] 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

[0440] [ka]

[0441] The title compound was obtained in the same manner as in Example 78-2, except that 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 was used as the starting material, and propanoyl chloride was used instead of acetic anhydride.

[0442] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0443] Example 85: Synthesis of 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

[0444] [ka]

[0445] The title compound was obtained in the same manner as in Example 78-2, except that 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 was used as the starting material, and cyclopropanecarbonyl chloride was used instead of acetic anhydride.

[0446] 1 H NMR (400 MHz, Methanol-d4) δ 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 - 4.37 (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).

[0447] 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-benzoxazepin-8-yl]oxy]azetidine-1-carboxylate

[0448] [ka]

[0449] The title compound was obtained in the same manner as in Example 78-2, except that 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 was used as the starting material, and methyl chloroformate was used instead of acetic anhydride.

[0450] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0451] Example 87: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[0452] [ka]

[0453] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-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 mmol) were added. The reaction solution was stirred at room temperature until the reaction was complete, and saturated aqueous ammonium chloride was added. After stirring for 30 minutes, the mixture was basified by adding 1N aqueous sodium hydroxide. The mixture was extracted three times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting pale yellow oily liquid was purified by flash chromatography to give the title compound as a white solid.

[0454] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0455] 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

[0456] [ka]

[0457] The title compound was synthesized in a similar manner to Example 87, except that acetaldehyde was used instead of paraformaldehyde.

[0458] 1 H NMR (400 MHz, Methanol-d4) δ 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)

[0459] 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

[0460] [ka]

[0461] The title compound was synthesized in the same manner as in Example 87, except that acetone was used instead of paraformaldehyde.

[0462] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0463] Example 90: Synthesis of 8-[(1-cyclopropyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0464] [ka]

[0465] The title compound was synthesized in a similar manner to Example 87, except that (1-ethoxycyclopropoxy)-trimethyl-silane was used instead of paraformaldehyde at 60°C.

[0466] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0467] Example 91: Synthesis of 8-[(1-cyclobutyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0468] [ka]

[0469] The title compound was synthesized in the same manner as in Example 87, except that cyclobutanone was used instead of paraformaldehyde.

[0470] 1H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 21.0 Hz, 4H), 6.77 (d, J = 8.9 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, 5H), 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).

[0471] Example 92: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[0472] [ka]

[0473] The title compound was synthesized in a similar manner to Example 87, except that oxetan-3-one was used instead of paraformaldehyde.

[0474] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0475] Example 93: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one

[0476] [ka]

[0477] The title compound was obtained in the same manner as in Example 87, using the material obtained in Example 83-1 as the starting material.

[0478] 1H NMR (400 MHz, Methanol-d4) δ 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), 4.47 (t, J = 5.2 Hz, 2H), 4.29 - 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).

[0479] 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

[0480] [ka]

[0481] The title compound was obtained in the same manner as in Example 87 using the material obtained in Example 83-1 as the starting material, except that acetaldehyde was used instead of paraformaldehyde.

[0482] 1H NMR (400 MHz, Methanol-d4) δ 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 = 7.2 Hz, 3H).

[0483] 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

[0484] [ka]

[0485] The title compound was obtained in the same manner as in Example 87, except that the material obtained in Example 83-1 was used as the starting material and acetone was used instead of paraformaldehyde.

[0486] 1H NMR (400 MHz, Methanol-d4) δ 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), 4.28 - 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, J = 6.2 Hz, 6H).

[0487] Example 96: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(oxetan-3-yl)azetidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

[0488] [ka]

[0489] The title compound was obtained in the same manner as in Example 87, except that the material obtained in Example 83-1 was used as the starting material and oxetan-3-one was used instead of paraformaldehyde.

[0490] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0491] Example 97: Synthesis of 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

[0492] [ka]

[0493] The title compound was obtained in the same manner as in Example 87, except that the starting material in Example 83-1 was changed from tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl 3-(methylsulfonyloxymethyl)azetidine-1-carboxylate and acetaldehyde was used instead of paraformaldehyde.

[0494] 1H NMR (400 MHz, Methanol-d4) δ 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 (t, J = 7.2Hz, 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).

[0495] Example 98: Synthesis of 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

[0496] [ka]

[0497] The title compound was obtained in the same manner as in Example 87, using the material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl 4-methylsulfonyloxypyrrolidine-1-carboxylate as the starting material in Example 83-1.

[0498] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0499] Example 99: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-ethylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

[0500] [ka]

[0501] The title compound was obtained in the same manner as in Example 87, except that the starting material in Example 83-1 was changed from tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate and acetaldehyde was used instead of paraformaldehyde.

[0502] 1H NMR (400 MHz, Methanol-d4) δ 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 (t, 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).

[0503] Example 100: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-pyridyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one

[0504] [ka]

[0505] 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.

[0506] 1H NMR (400 MHz, Chloroform-d) δ 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 (t, 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).

[0507] Example 101: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[0508] [ka]

[0509] The title compound was obtained in the same manner as in Example 87, except that the starting material in Example 83-1 was changed from tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl (2R)-2-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate and acetone was used instead of paraformaldehyde.

[0510] 1H NMR (400 MHz, Methanol-d4) δ 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, 7.6Hz, 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).

[0511] Example 102: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[0512] [ka]

[0513] The title compound was obtained in the same manner as in Example 87, using the material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 83-1 to tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate as the starting material.

[0514] 1H NMR (400 MHz, Methanol-d4) δ 7.59 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 5.1 Hz, 3H), 7.00 (d, J = 7.0 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).

[0515] Example 103: Synthesis of 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

[0516] [ka]

[0517] The title compound was obtained in the same manner as in Example 87, except that the starting material in Example 83-1 was changed from tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate and acetaldehyde was used instead of paraformaldehyde.

[0518] 1H NMR (400 MHz, Methanol-d4) δ 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)

[0519] 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

[0520] [ka]

[0521] The title compound was obtained in the same manner as in Example 87, using the material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl 2-(methylsulfonyloxymethyl)morpholine-4-carboxylate as the starting material in Example 83-1.

[0522] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0523] 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

[0524] [ka]

[0525] The starting material used in Example 83-1 was tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate, but the resulting material was replaced with tert-butyl 2-(methylsulfonyloxymethyl)morpholine-4-carboxylate. The procedure was the same as in Example 87, except that acetaldehyde was used instead of paraformaldehyde, to obtain the title compound.

[0526] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 9.4 Hz, 4H), 1.15 (t, J = 7.3 Hz, 3H).

[0527] 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

[0528] [ka]

[0529] The title compound was obtained in the same manner as in Example 87, using the material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 83-1 to tert-butyl 3-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate as the starting material.

[0530] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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, J = 9.8 Hz, 1H), 1.69 (dd, J = 13.2, 6.7 Hz, 1H).

[0531] Example 107: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[0532] [ka]

[0533] The title compound was obtained in the same manner as in Example 87, using the material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 83-1 to tert-butyl 3-(methylsulfonyloxymethyl)piperidine-1-carboxylate as the starting material.

[0534] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0535] Example 108: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-(morpholinomethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0536] [ka]

[0537] Example 108-1: Synthesis of methyl 4-bromo-2-[2-(tert-butoxycarbonylamino)ethoxy]-6-fluoro-benzoate

[0538] Methyl 4-bromo-2,6-difluorobenzoate (5.0 g, 19.9 mmol) was dissolved in 50 mL of tetrahydrofuran, and 60% sodium hydride (1.03 g, 25.8 mmol) and tert-butyl N-(2-hydroxyethyl)carbamate (3.7 mL, 23.9 mmol) were slowly added at 0 °C and stirred at the same temperature. A saturated aqueous solution of chloroammonium chloride was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to give an oily liquid, which was purified by flash chromatography to give the title compound (5.07 g) as a clear liquid.

[0539] Example 108-2: Synthesis of 8-bromo-6-fluoro-3,4-dihydro-2H-1,4-benzoxazepin-5-one

[0540] Methyl 4-bromo-2-[2-(tert-butoxycarbonylamino)ethoxy]-6-fluorobenzoate (5.07 g, 12.9 mmol) obtained in Example 108-1 was dissolved in 20 mL of methanol, and 4 M hydrochloric acid solution (20 mL, 80 mmol) dissolved in 1,4-dioxane was added. The reaction solution was stirred at room temperature, basified with aqueous sodium hydroxide solution in an ice bath, and extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily liquid. The resulting oily liquid was purified by flash chromatography to obtain the title compound (870 mg) as a solid.

[0541] Example 108-3: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-2,3-dihydro-1,4-benzoxazepin-5-one

[0542] The title compound was obtained in the same manner as in Example 5 using 8-bromo-6-fluoro-3,4-dihydro-2H-1,4-benzoxazepin-5-one obtained in Example 108-2 as the starting material.

[0543] Example 108-4: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-(morpholinomethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0544] The title compound was obtained in the same manner as in Example 22 using 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 108-3 as the starting material.

[0545] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0546] Example 109: Synthesis of 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

[0547] [ka]

[0548] Example 109-1: Synthesis of 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

[0549] The title compound was obtained in the same manner as in Example 56-1 using 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 108-3 as the starting material.

[0550] Example 109-2: Synthesis of 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

[0551] The title compound was obtained using 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 in a manner similar to that used in Examples 77, 78-1 and 87.

[0552] 1H NMR (400 MHz, Methanol-d4) δ 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 (t, 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).

[0553] 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

[0554] [ka]

[0555] Example 110-1: Synthesis of 7-bromo-2,2-dimethyl-chroman-4-one

[0556] 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 in an ice bath. The mixture was stirred for 30 minutes. Acetone (2.5 mL, 33.7 mmol) was added to the reaction solution, and the mixture was heated to reflux for 4 hours. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined organic layer was 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 give the title compound (4.7 g) as a crystalline solid without further purification.

[0557] Example 110-2: Synthesis of 8-bromo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazepin-5-one

[0558] 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 in an ice bath. The reaction solution was stirred at room temperature for 5 hours, and then 1 molar aqueous sodium hydroxide solution was slowly added while maintaining the temperature at 0°C in an ice bath. The reaction solution was basified to pH 10 or higher, and then extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The solid title compound was obtained by recrystallization from dichloromethane and hexane.

[0559] 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

[0560] The title compound was obtained in the same manner as in Example 5 using 8-bromo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazepin-5-one obtained in Example 110-2 as the starting material.

[0561] 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

[0562] The title compound was obtained in the same manner as in Example 56-1 using 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one obtained in Example 110-3 as a starting material.

[0563] Example 110-5: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-piperidyloxy)-3H-1,4-benzoxazepin-5-one dihydrochloride

[0564] The title compound was obtained in the same manner as in Examples 77 and 78-1, using the material obtained in Example 110-4 as the starting material.

[0565] Example 110-6: 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

[0566] The title compound was obtained in the same manner as in Example 87, except that the material obtained in Example 110-5 was used as the starting material and acetaldehyde was used instead of paraformaldehyde.

[0567] 1H NMR (400 MHz, Methanol-d4) δ 7.58 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 19.8 Hz, 4H), 6.81 (d, J = 8.9 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).

[0568] Example 111: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morpholinomethyl)-3H-1,4-benzoxazepin-5-one

[0569] [ka]

[0570] The title compound was obtained in a similar manner to that in Example 22 using 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 the starting material.

[0571] 1H NMR (400 MHz, Methanol-d4) δ 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 (t, J = 4.8 Hz, 4H), 1.43 (s, 3H), 1.33 (s, 3H).

[0572] 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

[0573] [ka]

[0574] The title compound was obtained in the same manner as in Example 87, using the material obtained in Example 110-5 as the starting material.

[0575] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0576] Example 113: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-pyridylmethoxy)-3H-1,4-benzoxazepin-5-one

[0577] [ka]

[0578] The title compound was obtained in the same manner as in Example 56-2, except that the material obtained in Example 110-4 was used as the starting material and 4-(chloromethyl)pyridine hydrochloride was used instead of 3-(chloromethyl)pyridine hydrochloride.

[0579] 1H NMR (400 MHz, Methanol-d4) δ 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, 8.2Hz, 1H), 2.97 - 2.82 (m, 4H), 2.66 - 2.57 (m, 2H), 1.42 (s, 3H), 1.32 (s, 3H).

[0580] 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

[0581] [ka]

[0582] The title compound was obtained in the same manner as in Example 83, using the material obtained in Example 110-4 as the starting material.

[0583] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0584] Example 115: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(morpholinomethyl)-2,3-dihydro-1,4-benzodiazepin-5-one

[0585] [ka]

[0586] Example 115-1: Synthesis of 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

[0587] The title compound was obtained in the same manner as in Example 5 using 8-bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one as a starting material.

[0588] Example 115-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(morpholinomethyl)-2,3-dihydro-1,4-benzodiazepin-5-one

[0589] The title compound was obtained in a similar manner to that in Example 22 using 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.

[0590] 1 H NMR (400 MHz, Methanol-d4) δ 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 (t, J = 5.4 Hz, 2H), 2.49 (s, 4H).

[0591] Example 116: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(3,3,3-trifluoropropyl)-2,3-dihydro-1,4-benzodiazepin-5-one

[0592] [ka]

[0593] The title compound was obtained in the same manner as in Example 10, except that 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 was used as the starting material and 3,3,3-trifluoropropylboronic acid was used instead of methylboronic acid.

[0594] 1 H NMR (400 MHz, Chloroform-d) δ 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, J = 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).

[0595] Example 117: Synthesis of 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

[0596] [ka]

[0597] The title compound was obtained in the same manner as in Example 10, except that 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 was used as the starting material and cyclohexylmethylboronic acid was used instead of methylboronic acid.

[0598] 1 H NMR (400 MHz, Chloroform-d) δ 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, J = 11.4 Hz, 5H), 1.32 - 1.13 (m, 5H), 0.93 (q, J = 13.8, 12.4Hz, 3H).

[0599] Example 118: Synthesis of 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

[0600] [ka]

[0601] The title compound was obtained in the same manner as in Example 10, except that 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 was used as the starting material and 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of methylboronic acid.

[0602] 1 H NMR (400 MHz, Chloroform-d) δ 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, J = 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).

[0603] Example 119: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[4-(trifluoromethyl)cyclohexen-1-yl]-2,3-dihydro-1,4-benzodiazepin-5-one

[0604] [ka]

[0605] The title compound was obtained in the same manner as in Example 10, except that 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 was used as the starting material and 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane was used instead of methylboronic acid.

[0606] 1 H NMR (400 MHz, Chloroform-d) δ 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, J = 10.4, 5.1 Hz, 1H), 3.29 (dq, J = 10.4, 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).

[0607] 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-dihydro-1,4-benzodiazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

[0608] [ka]

[0609] The title compound was obtained in the same manner as in Example 10, except that 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 was used as the starting material and 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.

[0610] 1 H NMR (400 MHz, Chloroform-d) δ 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).

[0611] 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

[0612] [ka]

[0613] Example 121-1: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

[0614] The title compound was obtained in the same manner as in Example 56-1 using 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.

[0615] 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

[0616] The title compound was obtained in the same manner as in Example 64, except that (1-acetyl-4-piperidyl)methanesulfonate was used instead of 4-chlorotetrahydropyran.

[0617] 1H NMR (400 MHz, Chloroform-d) δ 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, J = 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).

[0618] 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

[0619] [ka]

[0620] The title compound was obtained in the same manner as in Example 83, using the material obtained in Example 121-1 as the starting material.

[0621] 1H NMR (400 MHz, Chloroform-d) δ 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).

[0622] 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

[0623] [ka]

[0624] The title compound was obtained in the same manner as in Example 78 using the substance obtained in Example 121-1 as the starting material and the intermediate obtained by changing 4-chlorotetrahydropyran to tert-butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate in Example 64.

[0625] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0626] 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

[0627] [ka]

[0628] The title compound was obtained in the same manner as in Example 78, using the material obtained in Example 121-1 as the starting material and the intermediate obtained by changing 4-chlorotetrahydropyran to tert-butyl (3R)-3-methylsulfonyloxypyrrolidine-1-carboxylate in Example 64.

[0629] 1H NMR (400 MHz, Methanol-d4) δ 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), 4.27 (s, 1H), 3.90 (d, J = 14.7 Hz, 3H), 3.79 - 3.58 (m, 5H), 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).

[0630] Example 125: Synthesis of 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

[0631] [ka]

[0632] Example 125-1: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzodiazepin-5-one dihydrochloride

[0633] The title compound was obtained in the same manner as in Examples 77 and 78-1, using the material obtained in Example 121-1 as the starting material.

[0634] Example 125-2: Synthesis of 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

[0635] The title compound was obtained in the same manner as in Example 87, using the material obtained in Example 125-1 as the starting material.

[0636] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 11.4 Hz, 3H), 1.94 (s, 2H).

[0637] 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

[0638] [ka]

[0639] The title compound was obtained in the same manner as in Example 87, except that the material obtained in Example 125-1 was used as the starting material and paraformaldehyde was used instead of acetaldehyde.

[0640] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0641] Example 127: Synthesis of 8-[(1-cyclobutyl-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

[0642] [ka]

[0643] The title compound was obtained in the same manner as in Example 87, except that the material obtained in Example 125-1 was used as the starting material and paraformaldehyde was used instead of cyclobutanone.

[0644] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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, J = 8.7 Hz, 4H), 1.88 (d, J = 9.6 Hz, 1H), 1.79 - 1.62 (m, 4H).

[0645] Example 128: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-tetrahydrofuran-3-yl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one

[0646] [ka]

[0647] The title compound was obtained in the same manner as in Example 87, except that the material obtained in Example 125-1 was used as the starting material and tetrahydrofuran-3-one was used instead of paraformaldehyde.

[0648] 1H NMR (400 MHz, Methanol-d4) δ 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, 5H), 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, J = 9.5 Hz, 3H), 1.94 - 1.71 (m, 5H).

[0649] 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

[0650] [ka]

[0651] The title compound was obtained in the same manner as in Example 87, except that the material obtained in Example 125-1 was used as the starting material and oxetan-3-one was used instead of paraformaldehyde.

[0652] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0653] Example 130: Synthesis of 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

[0654] [ka]

[0655] The title compound was obtained in the same manner as in Example 68, using the material obtained in Example 121-1 as the starting material.

[0656] 1H NMR (400 MHz, Methanol-d4) δ 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, 4.5Hz, 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 (t, 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).

[0657] Example 131: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methylpyrrolidin-3-yl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one

[0658] [ka]

[0659] The title compound was obtained in the same manner as in Example 106, using the material obtained in Example 121-1 as the starting material.

[0660] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 9.6 Hz, 3H), 1.71 (d, J = 7.2 Hz, 1H), 1.57 (s, 1H), 0.91 (s, 2H).

[0661] Example 132: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(1-methylpyrrolidin-3-yl)oxy-2,3-dihydro-1,4-benzodiazepin-5-one

[0662] [ka]

[0663] The title compound was obtained in the same manner as in Example 98, using the material obtained in Example 121-1 as the starting material.

[0664] 1H NMR (400 MHz, Methanol-d4) δ 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), 2.42 (s, 3H), 2.05 (d, J = 10.2 Hz, 3H), 1.31 (s, 4H).

[0665] Example 133: Synthesis of 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

[0666] [ka]

[0667] The title compound was obtained in the same manner as in Example 107, using the material obtained in Example 121-1 as the starting material.

[0668] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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, 5H), 2.14 (s, 2H), 2.09 - 1.81 (m, 4H), 1.77 (s, 1H).

[0669] Example 134: Synthesis of 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

[0670] [ka]

[0671] The title compound was obtained in the same manner as in Example 56-2, except that the material obtained in Example 121-1 was used as the starting material and (3-fluoro-4-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride.

[0672] 1H NMR (400 MHz, Methanol-d4) δ 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 (s, 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).

[0673] 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

[0674] [ka]

[0675] Using the material obtained in Example 121-1 as the starting material, a Boc-substituted intermediate was synthesized by replacing 4-chlorotetrahydropyran with tert-butyl 3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate in Example 64. The resulting intermediate was dissolved in methanol, and a 4N solution of hydrochloric acid in 1,4-dioxane was added. The reaction was stirred at room temperature until completion, diluted with ethyl diethyl ether, and filtered to obtain the title compound as a white solid in the form of a dihydrochloride salt.

[0676] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0677] Example 136: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-3-fluoro-4-piperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

[0678] [ka]

[0679] The title compound was obtained in the same manner as in Example 87, except that the material obtained in Example 135 was used as the starting material and acetaldehyde was used instead of paraformaldehyde.

[0680] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 7.2 Hz, 1H), 2.46 (d, J = 8.2 Hz, 0H), 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).

[0681] 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

[0682] [ka]

[0683] Example 137-1: Synthesis of 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

[0684] Using the material obtained in Example 121-1 as the starting material, a Boc-substituted intermediate was synthesized by replacing 4-chlorotetrahydropyran with tert-butyl 3-methylsulfonyloxy-8-azabicyclo[3.2.1]octane-8-carboxylate in Example 64. The resulting intermediate was dissolved in methanol, and a 4N solution of hydrochloric acid in 1,4-dioxane was added. The reaction was stirred at room temperature until completion, diluted with ethyl diethyl ether, and filtered to obtain the title compound as a white solid in the form of a dihydrochloride salt.

[0685] 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

[0686] The title compound was obtained in the same manner as in Example 87, except that the material obtained in Example 137-1 was used as the starting material and acetaldehyde was used instead of paraformaldehyde.

[0687] 1H NMR (400 MHz, Methanol-d4) δ 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 (dq, 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).

[0688] Example 138: Synthesis of 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

[0689] [ka]

[0690] Using the material obtained in Example 121-1 as the starting material, a Boc-substituted intermediate was synthesized by replacing 4-chlorotetrahydropyran with tert-butyl 2-methyl-4-methylsulfonyloxy-piperidine-1-carboxylate in Example 64. The resulting intermediate was dissolved in methanol, and a 4N solution of hydrochloric acid in 1,4-dioxane was added. The reaction was stirred at room temperature until completion, diluted with ethyl diethyl ether, and filtered to obtain the title compound as a white solid in the form of a dihydrochloride salt.

[0691] 1 H NMR (400 MHz, Methanol-d4) δ 7.60 (d, J = 8.6 Hz, 1H), 7.32 (q, J = 7.7, 7.1 Hz, 3H), 7.23 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.76 (s, 1H), 4.75 (d, J = 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).

[0692] Example 139: Synthesis of 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

[0693] [ka]

[0694] The title compound was obtained in the same manner as in Example 56-2, except that the material obtained in Example 121-1 was used as the starting material and (5-fluoro-2-pyridyl)methyl methanesulfonate was used instead of 3-(chloromethyl)pyridine hydrochloride.

[0695] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0696] 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

[0697] [ka]

[0698] Example 140-1: Synthesis of methyl 4-bromo-2-[2-(tert-butoxycarbonylamino)propoxy]benzoate

[0699] Methyl 4-bromo-2-hydroxybenzoate (3 g, 12.98 mmol), CsCO (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 1 day, and heated to reflux. The reaction solution was cooled to room temperature, distilled water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by flash chromatography to obtain the title compound.

[0700] Example 140-2: Synthesis of methyl 2-(2-aminopropoxy)-4-bromo-benzoate hydrochloride

[0701] The starting material obtained in Example 140-1 was dissolved in methanol, and 4N HCl dissolved in 1,4-dioxane was added thereto, followed by stirring at room temperature. The reaction solution was concentrated under reduced pressure to give the title compound without further purification.

[0702] Example 140-3: Synthesis of 8-bromo-2-methyl-3,4-dihydro-2H-1,4-benzoxazepin-5-one

[0703] The material obtained in Example 140-2 (2.3 g, 8.01 mmol) was dissolved in toluene, and triethylamine (4.5 mL, 32 mmol) was added. The reaction solution was stirred and heated to reflux. After confirming the completion of the reaction, it 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.

[0704] Example 140-4: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

[0705] The title compound was obtained in the same manner as in Example 5, using the material obtained in Example 140-3 as the starting material.

[0706] Example 140-5: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-hydroxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

[0707] The title compound was obtained in the same manner as in Example 56-1 using the substance obtained in Example 140-4 as the starting material.

[0708] 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

[0709] The title compound was obtained in the same manner as in Examples 77 and 78-1, using the material obtained in Example 140-5 as the starting material.

[0710] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0711] Example 141: Synthesis of 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

[0712] [ka]

[0713] The title compound was obtained in the same manner as in Example 87, using the material obtained in Example 140 as the starting material.

[0714] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0715] Example 142: Synthesis of (2R)-8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

[0716] [ka]

[0717] The title compound was obtained in the same manner as in Example 83, except that the starting material in Example 140 was changed from [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate.

[0718] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0719] 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

[0720] [ka]

[0721] The title compound was obtained in the same manner as in Example 141, except that the starting material in Example 140 was changed from [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate.

[0722] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 18.6 Hz, 2H), 1.33 (d, J = 6.4 Hz, 3H).

[0723] Example 144: Synthesis of 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

[0724] [ka]

[0725] Example 144-1: Synthesis of 2,6-dichloro-N-(2-hydroxypropyl)-N-[(4-methoxyphenyl)methyl]pyridine-3-carboxamide

[0726] 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. The reaction solution was stirred at room temperature and concentrated under reduced pressure to give 2,6-dichloropyridine-3-carbonyl chloride without further purification. 1-[(4-Methoxyphenyl)methylamino]propan-2-ol (1.3 g, 7.2 mmol) and K2CO3 (2.2 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 in an ice bath. The reaction solution was stirred at the same temperature for 1 hour, and water was added to quench the reaction. The reaction solution was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.64 g) as a viscous liquid.

[0727] Example 144-2: Synthesis of 8-chloro-4-[(4-methoxyphenyl)methyl]-2-methyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one

[0728] 2,6-Dichloro-N-(2-hydroxypropyl)-N-[(4-methoxyphenyl)methyl]pyridine-3-carboxamide (2.64 g) obtained in Example 144-1 was dissolved in tetrahydrofuran, and 60% sodium hydride (630 mg, 15.8 mmol) was slowly added in an ice bath. The reaction solution was slowly heated to room temperature and stirred until the starting material was completely consumed, and methanol was added to quench the reaction. A saturated aqueous solution of sodium chloride was added to the reaction mixture, which was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The reaction concentrate was purified by flash chromatography to give the title compound (1.35 g) as a viscous liquid.

[0729] Example 144-3: Synthesis of tert-butyl 4-[[4-[(4-methoxyphenyl)methyl]-2-methyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-8-yl]oxy]piperidine-1-carboxylate

[0730] The substance obtained in Example 144-2 (500 mg, 1.51 mmol), 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 for 1 day at 60° C. 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).

[0731] Example 144-4: Synthesis of 2-methyl-8-(4-piperidyloxy)-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-5-one

[0732] The material obtained in Example 144-3 (540 mg) was dissolved in 4 mL of trifluoroacetate and reacted at 120 °C for 30 minutes using a microwave. The reaction solution was diluted with ethyl acetate in an ice bath and basified with an aqueous K2CO3 solution. The reaction mixture was washed three times with ethyl acetate, and the aqueous layer was basified to pH 9 or higher by adding KOH, followed by extraction with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound.

[0733] Example 144-5: Synthesis of 2-methyl-8-[(1-methyl-4-piperidyl)oxy]-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-5-one

[0734] The title compound was obtained in the same manner as in Example 87, using the material obtained in Example 144-4 as the starting material.

[0735] Example 144-6: Synthesis of 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

[0736] The title compound was obtained in the same manner as in Example 5, using the material obtained in Example 144-5 as the starting material.

[0737] 1 H NMR (400 MHz, Methanol-d4) (diastereomer mixture) δ 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), 4.29 - 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).

[0738] 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

[0739] [ka]

[0740] 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.

[0741] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0742] 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

[0743] [ka]

[0744] The title compound was obtained in the same manner as in Example 141, using as the starting material the material obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate in Example 140 to [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate.

[0745] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0746] Example 147: Synthesis of 4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0747] [ka]

[0748] Example 147-1: Synthesis of 3,4-dihydro-2H-1,4-benzoxazepin-5-one

[0749] 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 at 0°C. The reaction mixture was slowly heated to room temperature and stirred for 12 hours. While maintaining the temperature at 0°C in an ice bath, 1 M aqueous sodium hydroxide solution was slowly added. The reaction solution was basified to pH 10 or higher, and then extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and recrystallized from dichloromethane and hexane to give the title compound as a white solid.

[0750] Example 147-2: Synthesis of 4-(oxiran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0751] 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 in an ice bath. The reaction solution was stirred at 0°C for 30 minutes, and then epibromohydrin (0.1 mL, 1.2 mmol) was slowly added, followed by stirring at room temperature for 2 hours. Methanol was added to the reaction mixture to quench the reaction, and ethyl acetate was added. The mixture was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting title compound was used in the next reaction without further purification.

[0752] 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

[0753] 4-(oxiran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 147-2 was dissolved in isopropanol, tetrahydroisoquinoline (0.13 mL, 1.0 mmol) was added, and the mixture was stirred at 80° C. for 12 hours. The temperature was lowered to room temperature, and the solvent was concentrated to obtain an oily liquid. The resulting oily liquid was purified by flash chromatography to obtain a transparent, sticky solid compound. The NMR data for the title compound obtained are as follows:

[0754] 1 H NMR (400 MHz, Methanol-d4) δ 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 = 5.6 Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H), 2.70 - 2.59 (m, 2H).

[0755] Example 148: Synthesis of 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one

[0756] [ka]

[0757] The title compound was obtained in the same manner as in Example 147 using tetralin-1-one (1.9 g, 14 mmol) as the starting material, except that 35% aqueous hydrochloric acid (30 mL) was used instead of concentrated sulfuric acid in Example 147-1.

[0758] 1 H NMR (400 MHz, Methanol-d4) δ 7.58 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.5 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, J = 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 = 7.1 Hz, 2H), 2.66 (h, J = 7.6 Hz, 2H), 2.14 (p, J = 6.8 Hz, 2H).

[0759] Example 149: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0760] [ka]

[0761] Example 149-1: Synthesis of 4-[[(2R)-oxiran-2-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0762] 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 in 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, followed by stirring at room temperature for 2 hours. Methanol was added to the reaction mixture to quench the reaction, and ethyl acetate was added. The mixture was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting title compound was used in the next reaction without further purification.

[0763] Example 149-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0764] The title compound was obtained from 4-[[(2R)-oxiran-2-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 149-1 in the same manner as in Example 147-3.

[0765] 1 H NMR (400 MHz, Methanol-d4) δ 7.69 (dd, J = 7.9, 1.7 Hz, 1H), 7.48 (td, J = 7.8, 1.8 Hz, 1H), 7.20 (t, J = 7.5 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).

[0766] Example 150: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-2,3-dihydro-1,4-benzoxazepin-5-one

[0767] [ka]

[0768] The title compound was obtained in the same manner as in Example 147-1 and Example 149 using 7-fluorochroman-4-one as a starting material.

[0769] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0770] Example 151: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0771] [ka]

[0772] The title compound was obtained in the same manner as in Example 147-1 and Example 149 using 7-bromochroman-4-one as a starting material.

[0773] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0774] 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

[0775] [ka]

[0776] Example 152-1: Synthesis of methyl 3-[2-(benzyloxycarbonylamino)ethoxy]pyridine-4-carboxylate

[0777] 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 added slowly 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 using hexane and ethyl acetate to give the title compound.

[0778] Example 152-2: Synthesis of 3,4-dihydro-2H-pyrido[4,3-f][1,4]oxazepin-5-one

[0779] Methyl 3-[2-(benzyloxycarbonylamino)ethoxy]pyridine-4-carboxylate obtained in Example 152-1 was dissolved in ethanol at room temperature, and 5% palladium on carbon was added and stirred under a hydrogen balloon for 24 hours. The reaction solution was filtered through Celite and washed with ethanol. The resulting solution was concentrated under reduced pressure and purified by flash chromatography to give 548 mg of the title compound as a white crystalline solid.

[0780] 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

[0781] The title compound was obtained in the same manner as in Example 149, using 3,4-dihydro-2H-pyrido[4,3-f][1,4]oxazepin-5-one obtained in Example 152-2 as the starting material.

[0782] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0783] 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

[0784] [ka]

[0785] The title compound was obtained in a similar manner to Example 149 using 8-chloro-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-5-one as the starting material.

[0786] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0787] 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

[0788] [ka]

[0789] The title compound was obtained in a similar manner to Example 149 using 7-chloro-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material.

[0790] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0791] 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

[0792] [ka]

[0793] The title compound was obtained in a similar manner to Example 149 using 7-bromo-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material.

[0794] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0795] Example 156: Synthesis of 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

[0796] [ka]

[0797] Example 156-1: Synthesis of 8-bromo-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione

[0798] 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. The reaction solution was stirred at room temperature for 4 hours, concentrated, and redissolved in 3 L of acetic acid. The mixture was stirred at 140 °C for 8 hours. The reaction solution was diluted with petroleum ether and filtered to give the title compound (866 g, 74.7%) as a white solid.

[0799] Example 156-2: Synthesis of 8-bromo-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-one

[0800] 8-Bromo-3,4-dihydro-1H-1,4-benzodiazepine-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 at 0°C. The reaction solution was stirred at 70°C for 3 hours and cooled. The reaction was quenched by slowly adding 100 mL of distilled water, 100 mL of 15% aqueous sodium hydroxide solution, and another 100 mL of distilled water. The mixture was dried over anhydrous sodium sulfate, filtered with hot tetrahydrofuran, and the solvent was removed under reduced pressure. Recrystallization from 500 mL of ethyl acetate afforded the title compound (177 g, 46.8%) as a white solid.

[0801] Example 156-3: Synthesis of 8-bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one

[0802] 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. The reaction solution was stirred at 50°C for 1 hour. Sodium cyanoborohydride (231 g, 3.67 mol) was added to the reaction solution, and the mixture was stirred at 50°C for 4 hours. The solvent was removed under reduced pressure and the mixture was concentrated. The mixture was diluted with 4 L of distilled water and extracted twice with dichloromethane. The combined organic layer was washed twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Methanol was added to the resulting concentrate, and the mixture was recrystallized to give the title compound (yield: 78%) as a white solid.

[0803] Example 156-4: Synthesis of 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

[0804] The title compound was obtained in the same manner as in Example 149 using 8-bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one obtained in Example 156-3 as the starting material.

[0805] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0806] Example 157: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-2,3-dihydro-1,4-benzodiazepin-5-one

[0807] [ka]

[0808] Example 157-1: Synthesis of 8-bromo-1-ethyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one

[0809] 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 (0.07 mL, 0.82 mmol) was added. The reaction solution was stirred at 60 °C for 1 day. The reaction mixture was cooled to room temperature, diluted with distilled water, and extracted three times with ethyl acetate. The combined organic layer was washed twice with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography to give the title compound as a solid.

[0810] Example 157-2: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-2,3-dihydro-1,4-benzodiazepin-5-one

[0811] The title compound was obtained in the same manner as in Example 149, using the material obtained in Example 157-1 as the starting material.

[0812] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0813] Example 158: Synthesis of 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-3H-1,4-benzodiazepine-2,5-dione

[0814] [ka]

[0815] Example 158-1: Synthesis of 8-bromo-1-ethyl-3,4-dihydro-1,4-benzodiazepine-2,5-dione

[0816] 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 mixture was cooled to room temperature, diluted with distilled water, and filtered. The resulting solid was washed with diethyl ether to give the title compound (100 mg) as a white solid without further purification.

[0817] 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-benzodiazepine-2,5-dione

[0818] The title compound was obtained in the same manner as in Example 149, using the material obtained in Example 158-1 as the starting material.

[0819] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0820] Example 159: Synthesis of 2-[4-[[4-(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]-1-piperidyl]acetonitrile

[0821] [ka]

[0822] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 78-1 was dissolved in acetonitrile, and potassium carbonate and 2-bromoacetonitrile were added, followed by stirring at 90°C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily liquid. The title compound was purified by flash chromatography to give a white solid.

[0823] 1H NMR (400 MHz, Methanol-d4) δ 7.69 (dd, J = 8.7, 2.2 Hz, 1H), 7.16 - 7.09 (m, 3H), 7.06 (d, J = 6.6 Hz, 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).

[0824] Example 160: Synthesis of 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

[0825] [ka]

[0826] 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.

[0827] 1H NMR (400 MHz, Methanol-d4) δ 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 = 5.4 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).

[0828] Example 161: Synthesis of 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

[0829] [ka]

[0830] The title compound was obtained in the same manner as in Example 160 using 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 divalent salt obtained in Example 83-1 as the starting material.

[0831] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0832] Example 162: Synthesis of 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

[0833] [ka]

[0834] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-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 μL, 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.

[0835] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0836] Example 163: Synthesis of 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

[0837] [ka]

[0838] The title compound was obtained in the same manner as in Example 162, except that 2-fluoroethyl 4-methylbenzenesulfonate was used instead of 2-iodoethanol at 90°C.

[0839] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0840] Example 164: Synthesis of 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

[0841] [ka]

[0842] The title compound was obtained in a similar manner using 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 in Example 163 as the starting material.

[0843] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0844] 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

[0845] [ka]

[0846] 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), 3-(bromomethyl)-3-methyl-oxetane (110 mg, 0.665 mmol) were dissolved in dimethylformamide and heated with stirring at 60 ° C. After completion of the reaction, the reaction solution was extracted with saturated aqueous sodium chloride and ethyl acetate, and purified by flash chromatography to obtain the title compound (6 mg).

[0847] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0848] Example 166: Synthesis of 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzazepin-8-yl]oxy]piperidine-1-carbonitrile

[0849] [ka]

[0850] 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), cesium carbonate (433 mg, 1.329 mmol) were dissolved in dimethylformamide, and the reaction was carried out using a microwave at 70 ° C. for 3 hours. After completion of the reaction, the reaction solution was extracted with saturated aqueous sodium chloride and ethyl acetate, and purified by flash chromatography to obtain the title compound (14 mg).

[0851] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0852] Example 167: Synthesis of 8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

[0853] [ka]

[0854] 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

[0855] The title compound was obtained in the same manner as in Examples 54-1 and 54-2 using 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 the starting material.

[0856] Example 167-2: Synthesis of 8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

[0857] The title compound was obtained in the same manner as in Example 78-2, using the material obtained in Example 167-1 as the starting material.

[0858] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0859] Example 168: Synthesis of 3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]oxy]azetidine-1-carbaldehyde

[0860] [ka]

[0861] Example 168-1: Synthesis of 8-(azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one dihydrochloride

[0862] The title compound was obtained in the same manner as in Example 83-1 using 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.

[0863] Example 168-2: 3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]oxy]azetidine-1-carbaldehyde

[0864] The material obtained in Example 168-1 (105 mg, 0.2 mmol) was dissolved in 2 mL of acetonitrile, and formic acid (38 μL, 1.0 mmol), triethylamine (0.17 mL, 1.2 mL), and HATU (114 mg, 0.3 mmol) were added and stirred at room temperature. After confirming the completion of the reaction, saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by flash chromatography to obtain the title compound.

[0865] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0866] 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

[0867] [ka]

[0868] The title compound was obtained in the same manner as in Example 168-2, using the material obtained in Example 167-1 as the starting material.

[0869] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0870] Example 170: Synthesis of 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

[0871] [ka]

[0872] The title compound was obtained in a similar manner to that in Example 28 using 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.

[0873] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0874] 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

[0875] [ka]

[0876] 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-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride

[0877] An intermediate was synthesized by changing 4-chlorotetrahydropyran to tert-butyl 3-methylsulfonyloxy-8-azabicyclo[3.2.1]octane-8-carboxylate in Example 64. The obtained intermediate was used as a starting material to obtain the title compound in the same manner as in Example 78-1.

[0878] Example 171-2: 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]-2,3-dihydro-1,4-benzoxazepin-5-one

[0879] The title compound was obtained in the same manner as in Example 88, using the material obtained in Example 171-1 as the starting material.

[0880] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0881] Example 172: Synthesis of 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

[0882] [ka]

[0883] 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-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride

[0884] The intermediate was obtained by changing 4-chlorotetrahydropyran to tert-butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate in Example 64. The obtained intermediate was used as a starting material to obtain the title compound in the same manner as in Example 78-1.

[0885] Example 172-2: Synthesis of 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

[0886] The title compound was obtained in the same manner as in Example 88, using the material obtained in Example 172-1 as the starting material.

[0887] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 13.1, 6.2, 2.4 Hz, 2H), 0.99 (td, J = 7.3, 2.0 Hz, 3H).

[0888] 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

[0889] [ka]

[0890] The title compound was obtained in the same manner as in Example 78-2 using 8-(8-azabicyclo[3.2.1]octan-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 171-1 as the starting material.

[0891] 1 H NMR (400 MHz, Methanol-d4) δ 7.70 (dd, J = 8.8, 2.0 Hz, 1H), 7.19 - 6.99 (m, 4H), 6.71 (dd, J = 8.8, 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).

[0892] 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

[0893] [ka]

[0894] The title compound was obtained in the same manner as in Example 78-2 using 8-(2-azaspiro[3.3]heptan-6-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 172-1 as the starting material.

[0895] 1H NMR (400 MHz, Methanol-d4) δ 7.54 (dd, J = 8.9, 2.3 Hz, 1H), 7.12 - 6.87 (m, 4H), 6.53 (dd, J = 7.2, 4.3 Hz, 1H), 6.35 (d, J = 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, 2.3Hz, 3H).

[0896] Example 175: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0897] [ka]

[0898] Example 175-1: Synthesis of methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxylate

[0899] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,3-dihydro-1,4-benzoxazepin-5-one (1.0 equiv.), molybdenum hexacarbonyl (1.0 equiv.), trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) (0.1 equiv.), tri-tert-butylphosphonium tetrafluoroborate (0.2 equiv.), and 1,8-diazabicyclo[5.4.0]undec-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 three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by flash chromatography to give the title compound.

[0900] Example 175-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0901] Methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxylate (1.0 equivalent) obtained in Example 175-1, pyrrolidine (5.0 equivalents), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1 mL) were mixed and heated overnight at 120° C. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, and purified by flash chromatography to give the title compound.

[0902] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 11.4 Hz, 4H), 3.48 (t, J = 7.1 Hz, 2H), 3.34 (q, J = 7.3Hz, 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).

[0903] 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

[0904] [ka]

[0905] The title compound was obtained in the same manner as in Example 175-2, except that piperidine was used instead of pyrrolidine.

[0906] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0907] Example 177: Synthesis of 8-(3,3-difluoropyrrolidine-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0908] [ka]

[0909] 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.

[0910] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0911] Example 178: Synthesis of 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

[0912] [ka]

[0913] The title compound was obtained in the same manner as in Example 175, except that 1-methylpiperazine was used instead of pyrrolidine in Example 175-2.

[0914] 1H NMR (400 MHz, Methanol-d4) δ 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 = 7.8 Hz, 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).

[0915] 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

[0916] [ka]

[0917] The title compound was obtained in a similar manner to that in Example 24 using 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.

[0918] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0919] Example 180: Synthesis of 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

[0920] [ka]

[0921] The title compound was obtained in the same manner as in Example 78-2 using 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-piperidyloxy)-3H-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 110-5 as the starting material.

[0922] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0923] 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-yl]oxy]piperidine-1-carbaldehyde

[0924] [ka]

[0925] The title compound was obtained in the same manner as in Example 78-2, except that the material obtained in Example 110-5 was used as a starting material and formic acid was used instead of acetic anhydride.

[0926] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0927] 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-yl]methyl]-3H-1,4-benzoxazepin-5-one

[0928] [ka]

[0929] The title compound was obtained in the same manner as in Example 92, using the material obtained in Example 167-1 as the starting material.

[0930] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0931] Example 183: Synthesis of 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

[0932] [ka]

[0933] The title compound was obtained in the same manner as in Example 29, except that 8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one was used as the starting material and 2-oxa-7-azaspiro[3.4]octane was used instead of 3-methoxyazetidine hydrochloride.

[0934] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0935] Example 184: Synthesis of 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

[0936] [ka]

[0937] 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.

[0938] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[0939] Example 185: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(trifluoromethyl)piperidine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0940] [ka]

[0941] The title compound was obtained in the same manner as in Example 175, except that 3-trifluoromethylpiperidine was used instead of pyrrolidine in Example 175-2.

[0942] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0943] Example 186: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(trifluoromethyl)piperidine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0944] [ka]

[0945] The title compound was obtained in the same manner as in Example 175, except that 4-trifluoromethylpiperidine was used instead of pyrrolidine in Example 175-2.

[0946] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0947] Example 187: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,6-dimethylmorpholine-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0948] [ka]

[0949] 2,6-Dimethylmorpholine (33 μL, 1.1 equiv.) was dissolved in 1,4-dioxane (1 mL) and 2 M trimethylaluminum toluene solution (134 μL, 1.1 equiv.) was added at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 1 hour, and methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxylate (100 mg) dissolved in 1,4-dioxane was added. The reaction mixture was stirred at 110° C. for 3 hours, quenched with saturated aqueous potassium sodium tartrate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by flash chromatography to give the title compound.

[0950] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[0951] Example 188: Synthesis of 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

[0952] [ka]

[0953] 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.

[0954] 1 H NMR (400 MHz, Methanol-d4) δ 7.86 - 7.73 (m, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.24 - 6.99 (m, 5H), 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, J = 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, J = 9.9 Hz, 1H), 1.52 (q, J = 10.4, 7.9 Hz, 1H).

[0955] 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]octane-8-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0956] [ka]

[0957] 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.

[0958] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0959] Example 190: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-methylmorpholine-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0960] [ka]

[0961] The title compound was synthesized in a similar manner to Example 187, except that 2-methylmorpholine was used instead of 2,6-dimethylmorpholine.

[0962] 1H NMR (400 MHz, Methanol-d4) δ 7.81 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.17 - 6.92 (m, 5H), 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).

[0963] Example 191: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-methylmorpholine-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0964] [ka]

[0965] The title compound was synthesized in the same manner as in Example 187, except that 3-methylmorpholine was used instead of 2,6-dimethylmorpholine.

[0966] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0967] Example 192: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morpholinomethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one

[0968] [ka]

[0969] The title compound was obtained in a similar manner to that in Example 22 using 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.

[0970] 1H NMR (400 MHz, Methanol-d4) δ 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).

[0971] Example 193: Synthesis of 8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0972] [ka]

[0973] Example 193-1: Synthesis of potassium 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxylate

[0974] Methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxylate and potassium trimethylsilanolate were dissolved in tetrahydrofuran and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and used in the next reaction without further purification.

[0975] Example 193-2: Synthesis of 8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0976] The starting material obtained in Example 193-1 (100 mg, 1.0 equivalent), octahydrocyclopenta[c]pyrrole (1.5 equivalents), HATU (131 mg, 1.5 equivalents), and diisopropylethylamine (120 μL, 3 equivalents) 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 give the title compound.

[0977] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 9.8, 5.2 Hz, 1H), 3.88 (dt, J = 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, J = 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).

[0978] Example 194: Synthesis of 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

[0979] [ka]

[0980] 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.

[0981] 1 H NMR (400 MHz, Methanol-d4) δ 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), 4.41 (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).

[0982] Example 195: Synthesis of 8-(2,2-difluoromorpholine-4-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0983] [ka]

[0984] The title compound was obtained in the same manner as in Example 193-2, except that 2,2-difluoromorpholine was used instead of octahydrocyclopenta[c]pyrrole.

[0985] 1 H NMR (400 MHz, Methanol-d4) δ 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, 5H), 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, 2H).

[0986] Example 196: Synthesis of 8-(4,4-difluoropiperidine-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0987] [ka]

[0988] 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.

[0989] 1H NMR (400 MHz, Methanol-d4) δ 7.68 (dd, J = 8.0, 2.2 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.06 - 6.91 (m, 5H), 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, J = 5.9 Hz, 2H), 2.12 - 1.78 (m, 4H).

[0990] Example 197: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-piperidylmethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one

[0991] [ka]

[0992] The title compound was obtained in a similar manner to that in Example 23 using 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.

[0993] 1H NMR (400 MHz, Methanol-d4) δ 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 = 13.7, 8.3 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).

[0994] Example 198: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[methyl(oxetan-3-yl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[0995] [ka]

[0996] Example 198-1: Synthesis of tert-butyl N-[4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]cyclohexyl]-N-methyl-carbamate

[0997] The title compound was synthesized in the same manner as in Example 64, except that [4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]methanesulfonate was used instead of 4-chlorotetrahydropyran, cesium carbonate was used instead of potassium carbonate, and acetonitrile was used instead of dimethylformamide.

[0998] Example 198-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-(methylamino)cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride

[0999] The tert-butyl N-[4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]cyclohexyl]-N-methyl-carbamate obtained in Example 198-1 was dissolved in methanol, and 4 M hydrochloric acid solution in 1,4-dioxane was slowly added. The reaction solution was stirred at room temperature, diluted with diethyl ether, and filtered to obtain the title compound as a solid.

[1000] Example 198-3: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[methyl(oxetan-3-yl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1001] The title compound was obtained in the same manner as in Example 87, except that in Example 198-2, 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-(methylamino)cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride was used as the starting material, and paraformaldehyde was used instead of oxetan-3-one.

[1002] 1H NMR (400 MHz, Methanol-d4) δ 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).

[1003] Example 199: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[2-fluoroethyl(methyl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1004] [ka]

[1005] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-(methylamino)cyclohexoxy]-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 μL, 0.543 mmol) were dissolved in acetonitrile and stirred at 100 °C for 1 day. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily liquid. The title compound (45 mg) was obtained by flash chromatography.

[1006] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[1007] Example 200: Synthesis of (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

[1008] [ka]

[1009] Example 200-1: Synthesis of 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

[1010] The title compound was obtained by the method of Example 78-1 using the material obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate in Example 140 to [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate as the starting material.

[1011] 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

[1012] The title compound was obtained in the same manner as in Example 78-2, using the material obtained in Example 200-1 as the starting material.

[1013] Example 200-3: Synthesis of (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

[1014] The starting material obtained in Example 200-2 was dissolved in tetrahydrofuran, and Lawesen's reagent was added. The reaction solution was stirred at 50°C until the reaction was complete, and then cooled to room temperature. Distilled water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by flash chromatography to obtain the title compound.

[1015] 1 H NMR (400 MHz, Methanol-d4) δ 8.19 - 8.09 (m, 1H), 7.65 - 7.55 (m, 1H), 7.29 (d, J = 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).

[1016] Example 201: Synthesis of (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

[1017] [ka]

[1018] Example 201-1: Synthesis of 8-(azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride

[1019] The materials synthesized 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, were used as starting materials. The Boc-substituted intermediate was obtained in the same manner as in Example 64, except that tert-butyl 3-hydroxyazetidine-1-carboxylate was used instead of 4-chlorotetrahydropyran. The resulting intermediate was dissolved in methanol, and a 4N solution of hydrochloric acid in 1,4-dioxane was added. The reaction was stirred at room temperature until completion, diluted with ethyl diethyl ether, and filtered to obtain the title compound as a white solid in the form of a dihydrochloride salt.

[1020] Example 201-2: Synthesis of (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

[1021] The starting material, the material obtained in Example 201-1, 2-fluoroethyl p-toluenesulfonate, and potassium carbonate were dissolved in acetonitrile, and the reaction solution was stirred at 60°C for 1 day. The reaction mixture was cooled to room temperature, diluted with distilled water, and extracted three times with ethyl acetate. The combined organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography to obtain the title compound as a solid.

[1022] 1H NMR (400 MHz, Methanol-d4) δ 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 (td, 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, J = 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).

[1023] Example 202: Synthesis of (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

[1024] [ka]

[1025] The title compound was obtained in the same manner as in Example 163, using the material obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate in Example 140 to [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate as the starting material.

[1026] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[1027] Example 203: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-3H-1,4-benzoxazepin-5-one

[1028] [ka]

[1029] The title compound was obtained in the same manner as in Example 193 using potassium; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepine-8-carboxylate as the starting material, except that 3-oxa-8-azabicyclo[3.2.1]octane was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2.

[1030] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[1031] Example 204: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-3H-1,4-benzoxazepin-5-one

[1032] [ka]

[1033] The title compound was obtained in the same manner as in Example 193 using potassium 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepine-8-carboxylate as the starting material, except that 2-oxa-5-azabicyclo[2.2.1]heptane was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2.

[1034] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[1035] Example 205: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,5-dimethylmorpholine-4-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

[1036] [ka]

[1037] The title compound was obtained in the same manner as in Example 193 using potassium; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepine-8-carboxylate as the starting material, except that 3,5-dimethylmorpholine was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2.

[1038] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[1039] Example 206: Synthesis of 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

[1040] [ka]

[1041] Example 206-1: Synthesis of tert-butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]-3-fluoro-piperidine-1-carboxylate

[1042] The title compound was obtained in the same manner as in Example 64, except that tert-butyl 3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate was used instead of 4-chlorotetrahydropyran, cesium carbonate was used instead of potassium carbonate, and acetonitrile was used instead of dimethylformamide.

[1043] 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

[1044] The tert-butyl 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]-3-fluoro-piperidine-1-carboxylate obtained in Example 206-1 was dissolved in methanol, and 4M hydrochloric acid solution in 1,4-dioxane was slowly added. The reaction solution was stirred at room temperature, diluted with diethyl ether, and filtered to obtain the title compound as a solid.

[1045] Example 206-3: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(3-fluoro-1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1046] The title compound was obtained in the same manner as in Example 87 using 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 the starting material.

[1047] 1H NMR (400 MHz, Methanol-d4) δ 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), 4.29 - 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).

[1048] Example 207: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-fluoroethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1049] [ka]

[1050] The title compound was obtained in the same manner as in Example 163 using 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 the starting material.

[1051] 1H NMR (400 MHz, Methanol-d4) δ 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).

[1052] Example 208: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1053] [ka]

[1054] The title compound was obtained in the same manner as in Example 162 using 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 the starting material.

[1055] 1 H NMR (400 MHz, Methanol-d4) δ 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 (t, 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).

[1056] 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

[1057] [ka]

[1058] The title compound was obtained in the same manner as in Example 193, except that potassium; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepine-8-carboxylate was used as the starting material, and 1,2,3,4-tetrahydropyrrole[1,2-a]pyrazine was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2.

[1059] 1 H NMR (400 MHz, Methanol-d4) δ 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 (tt, 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).

[1060] 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-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

[1061] [ka]

[1062] The title compound was obtained in the same manner as in Example 193, except that potassium; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepine-8-carboxylate was used as the starting material, and 1,2,3,4,6,7,8,8a-octahydropyrrole[1,2-a]pyrazine was used instead of octahydrocyclopenta[c]pyrrole in Example 193-2.

[1063] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[1064] Example 211: Synthesis of 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

[1065] [ka]

[1066] 4-[(2R)-3-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-one (1.0 equivalent), 2-chloro-5-fluoropyrimidine (1.5 equivalents), and cesium carbonate (2 equivalents) were dissolved in acetonitrile and heated under reflux overnight. The reaction solution was extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, concentrated, and purified by flash chromatography to give the title compound.

[1067] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[1068] Example 212: Synthesis of 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

[1069] [ka]

[1070] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 78-1 was dissolved in a mixed solution of water and acetonitrile, 2-methyloxirane and sodium hydroxide were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily liquid. The title compound was purified by flash chromatography to give a white solid.

[1071] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[1072] Example 213: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1073] [ka]

[1074] Example 213-1: Synthesis of 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

[1075] The title compound was synthesized in the same manner as in Example 64 and Example 781, except that tert-butyl (S)-3-methylsulfonyloxypiperidine-1-carboxylate was used instead of 4-chlorotetrahydropyran in Example 64.

[1076] Example 213-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1077] The title compound was obtained in the same manner as in Example 87 using 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 the starting material.

[1078] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 20.6 Hz, 2H).

[1079] 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

[1080] [ka]

[1081] 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

[1082] 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.

[1083] Example 214-2: 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

[1084] 4-[(2R)-3-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-N-methoxy-N-methyl-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxamate (700 mg, 1 equivalent) was dissolved in tetrahydrofuran, and 1 M ethylmagnesium bromide (2 mL, tetrahydrofuran solution) was added 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 column chromatography to give the title compound.

[1085] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 7.2 Hz, 3H).

[1086] Example 215: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1087] [ka]

[1088] 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

[1089] This intermediate was synthesized by replacing 4-chlorotetrahydropyran with tert-butyl 3-methylsulfonyloxy-8-azabicyclo[3.2.1]octane-8-carboxylate in Example 64. The resulting intermediate was dissolved in methanol and 4N hydrochloric acid solution in 1,4-dioxane was added. The reaction was stirred at room temperature until completion, diluted with ethyl diethyl ether, and filtered to obtain the title compound as a white solid in the form of a dihydrochloride salt.

[1090] Example 215-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1091] The title compound was obtained in the same manner as in Example 163 using 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 obtained in Example 215-1 as the starting material.

[1092] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[1093] 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

[1094] [ka]

[1095] The title compound was obtained in the same manner as in Example 241, except that cyclopropylmagnesium bromide was used instead of ethylmagnesium bromide in Example 214-2.

[1096] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 13.8, 7.7 Hz, 1H), 2.80 (t, J = 6.2 Hz, 2H), 2.73 (dd, J = 8.8, 3.7Hz, 2H), 2.71 - 2.66 (m, 1H), 2.59 - 2.45 (m, 2H), 1.07 - 0.92 (m, 4H).

[1097] 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

[1098] [ka]

[1099] The title compound was obtained in the same manner as in Example 241, except that cyclopentyl magnesium bromide was used instead of ethyl magnesium bromide in Example 214-2.

[1100] 1H NMR (400 MHz, Methanol-d4) δ 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 (dtdd, 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).

[1101] 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

[1102] [ka]

[1103] The title compound was obtained in the same manner as in Example 64, except that 4-chlorotetrahydropyran was replaced with [rac-(3R)-1-methyl-3-piperidyl]methanesulfonate.

[1104] 1H NMR (400 MHz, Methanol-d4) δ 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).

[1105] 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

[1106] [ka]

[1107] The title compound was obtained in the same manner as in Example 162, using the material obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate in Example 140 to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate as the starting material.

[1108] 1H NMR (400 MHz, Methanol-d4) δ 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, 5H), 2.79 - 2.58 (m, 5H), 2.08 (d, J = 9.8 Hz, 2H), 1.89 (s, 2H), 1.32 (s, 3H).

[1109] Example 220: Synthesis of (2R)-4-[(2R)-3-(3,4-dihydro-1H-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

[1110] [ka]

[1111] The starting material used was the material obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate in Example 140 to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate, and the title compound was obtained in the same manner as in Example 212, except that 2,2-dimethyloxirane was used instead of 2-methyloxirane.

[1112] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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 = 7.0, 3.1 Hz, 2H), 1.21 (s, 6H).

[1113] Example 221: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-morpholinoethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[1114] [ka]

[1115] Example 221-1: Synthesis of 8-acetyl-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[1116] The title compound was obtained in the same manner as in Example 214-2, except that methylmagnesium bromide was used instead of ethylmagnesium bromide.

[1117] Example 221-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-morpholinoethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[1118] 8-Acetyl-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one (100 mg, 1 equivalent), morpholine (66 μL, 3 equivalents), sodium cyanoborohydride (48 mg, 3 equivalents), and acetic acid (1 drop) were dissolved in 1 mL of methanol and stirred for 6 hours at 80° C. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, and purified by flash column chromatography to give the title compound.

[1119] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[1120] 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]heptan-6-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[1121] [ka]

[1122] The title compound was obtained in the same manner as in Example 221-2, except that 2-oxa-6-azaspiro[3.3]heptane was used instead of morpholine.

[1123] 1 H NMR (400 MHz, Methanol-d4) δ 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)

[1124] Example 223: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxyprop-1-ynyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[1125] [ka]

[1126] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,3-dihydro-1,4-benzoxazepin-5-one (100 mg, 1.0 equiv.), prop-2-yn-1-ol (3 equiv.), bis(triphenylphosphine)dichloride(II)palladium (8 mg, 0.05 equiv.), copper(I) iodide (5 mg, 0.1 equiv.), and triethylamine (97 μL, 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 aluminum chloride and ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The resulting solution was concentrated under reduced pressure and purified by flash column chromatography to give the title compound.

[1127] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[1128] 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

[1129] [ka]

[1130] The title compound was obtained in the same manner as in Example 163, except that the starting material was the material obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate in Example 140 to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate, and 1-bromo-2-methoxyethane was used instead of 2-fluoroethyl p-toluenesulfonate.

[1131] 1 H NMR (400 MHz, Methanol-d4) δ 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).

[1132] 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

[1133] [ka]

[1134] The title compound was synthesized in a similar manner to Example 12, except that 4-pyridylboronic acid was used instead of isobutylboronic acid.

[1135] 1 H NMR (400 MHz, Methanol-d4) δ 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, J = 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, 2H).

[1136] 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

[1137] [ka]

[1138] The title compound was synthesized in a similar manner to Example 223, except that 4-ethynylpyridine was used instead of prop-2-yn-1-ol.

[1139] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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).

[1140] 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

[1141] [ka]

[1142] The title compound was synthesized in a similar manner to Example 223, except that 3-ethynylpyridine was used instead of prop-2-yn-1-ol.

[1143] 1H NMR (400 MHz, Methanol-d4) δ 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, J = 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 = 5.1 Hz, 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).

[1144] Example 228: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxybut-1-ynyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[1145] [ka]

[1146] The title compound was synthesized in a similar manner to Example 223, except that but-3-yn-2-ol was used instead of prop-2-yn-1-ol.

[1147] 1H NMR (400 MHz, Methanol-d4) δ 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 (t, 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).

[1148] Example 229: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(methylamino)prop-1-ynyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[1149] [ka]

[1150] The title compound was obtained in a similar manner to that in Example 223, except that N-methylprop-2-yn-1-amine was used instead of prop-2-yn-1-ol.

[1151] 1H NMR (400 MHz, Methanol-d4) δ 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).

[1152] Example 230: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[1153] [ka]

[1154] The title compound was obtained in the same manner as in Example 12, except that 3-pyridylboronic acid was used instead of isobutylboronic acid.

[1155] 1H NMR (400 MHz, Methanol-d4) δ 8.94 - 8.83 (m, 1H), 8.64 - 8.53 (m, 1H), 8.21 - 8.09 (m, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.64 - 7.46 (m, 2H), 7.40 (d, J = 1.8 Hz, 1H), 7.18 - 6.92 (m, 4H), 4.56 (t, J = 5.1 Hz, 2H), 4.31 - 4.23 (m, 1H), 4.03 (dd, J = 13.8, 3.6 Hz, 1H), 3.84 - 3.75 (m, 4H), 3.49 (dd, J = 13.9, 7.7 Hz, 1H), 3.00 - 2.87 (m, 4H), 2.70 (dd, J = 6.3, 2.4 Hz, 2H).

[1156] Example 231: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,3-dimethylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

[1157] [ka]

[1158] The title compound was obtained in the same manner as in Example 12, except that 1,3-dimethylpyrazoleboronic acid was used instead of isobutylboronic acid.

[1159] 1H NMR (400 MHz, Methanol-d4) δ 7.84 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.28 (dd, J = 8.1, 1.8 Hz, 1H), 7.18 - 7.03 (m, 5H), 4.51 (t, J = 5.1 Hz, 2H), 4.30 - 4.22 (m, 1H), 4.00 (dd, J = 13.8, 3.6 Hz, 1H), 3.88 (s, 3H), 3.83 - 3.72 (m, 4H), 3.47 (dd, J = 13.9, 7.6 Hz, 1H), 2.93 (ddd, J = 11.9, 9.3, 4.3 Hz, 4H), 2.74 - 2.62 (m, 2H), 2.40 (s, 3H).

[1160] Example 232: Synthesis of 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

[1161] [ka]

[1162] The title compound was synthesized in a similar manner to Example 12, except that 1-methylpyrazoleboronic acid was used instead of isobutylboronic acid.

[1163] 1H NMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.93 - 7.81 (m, 1H), 7.74 - 7.66 (m, 1H), 7.39 (dd, J = 8.1, 1.7 Hz, 1H), 7.25 (d, J = 1.7 Hz, 1H), 7.16 - 7.02 (m, 4H), 4.50 (t, J = 5.1 Hz, 2H), 4.31 - 4.21 (m, 1H), 4.03 - 3.89 (m, 4H), 3.81 (s, 2H), 3.78 - 3.71 (m, 2H), 3.47 (dd, J = 13.9, 7.6 Hz, 1H), 2.94 (dd, J = 9.5, 4.6 Hz, 4H), 2.72 - 2.66 (m, 2H).

[1164] Example 233: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,5-dimethylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

[1165] [ka]

[1166] The title compound was obtained in the same manner as in Example 12, except that 1,5-dimethylpyrazoleboronic acid was used instead of isobutylboronic acid.

[1167] 1H NMR (400 MHz, Methanol-d4) δ 7.83 - 7.53 (m, 3H), 7.25 (dd, J = 8.1, 1.7 Hz, 1H), 7.11 (ddd, J = 14.4, 6.0, 2.5 Hz, 4H), 4.52 (t, J = 5.1 Hz, 2H), 4.27 (d, J = 9.2 Hz, 1H), 4.01 (dd, J = 13.9, 3.7 Hz, 1H), 3.86 (s, 3H), 3.82 - 3.71 (m, 4H), 3.48 (dd, J = 13.9, 7.6 Hz, 1H), 2.93 (dt, J = 8.6, 4.9 Hz, 4H), 2.73 - 2.64 (m, 2H), 2.46 (s, 3H).

[1168] Example 234: Synthesis of 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

[1169] [ka]

[1170] The title compound was obtained in a similar manner to Example 162 using 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-piperidyloxy)-3H-pyrido[3,2-f][1,4]oxazepin-5-one dihydrochloride as a starting material.

[1171] 1H NMR (400 MHz, Methanol-d4) δ 8.04 (d, J = 8.4 Hz, 1H), 7.16 - 7.00 (m, 4H), 6.61 (d, J = 8.4 Hz, 1H), 5.14 - 5.00 (m, 1H), 4.27 (s, 1H), 4.04 (dd, J = 13.8, 3.6 Hz, 1H), 3.78 - 3.57 (m, 6H), 3.40 (dd, J = 13.7, 8.2 Hz, 1H), 2.97 - 2.79 (m, 6H), 2.66 - 2.53 (m, 4H), 2.48 (s, 2H), 2.12 - 2.02 (m, 2H), 1.89 - 1.76 (m, 2H), 1.48 (s, 3H), 1.43 (s, 3H).

[1172] Example 235: Synthesis of 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

[1173] [ka]

[1174] The title compound was synthesized in the same manner as in Example 144-1 and Example 114-3 to Example 144-6, except that 1-[(4-methoxyphenyl)methylamino]-2-methyl-propan-2-ol was used instead of 1-[(4-methoxyphenyl)methylamino]propan-2-ol in Example 144-1, and tert-butyl 3-hydroxypiperidine-1-carboxylate was used instead of tert-butyl 4-hydroxypiperidine-1-carboxylate in Example 144-3.

[1175] 1H NMR (400 MHz, Methanol-d4) δ 8.04 (d, J = 8.4 Hz, 1H), 7.17 - 7.02 (m, 4H), 6.63 (d, J = 8.4 Hz, 1H), 5.18 (s, 1H), 4.27 (s, 1H), 4.04 (dd, J = 13.8, 3.6 Hz, 1H), 3.76 (s, 2H), 3.71 - 3.56 (m, 2H), 3.39 (dd, J = 13.8, 8.3 Hz, 1H), 2.99 - 2.81 (m, 5H), 2.64 (dd, J = 6.3, 2.8 Hz, 2H), 2.60 (d, J = 6.8 Hz, 1H), 2.52 - 2.35 (m, 2H), 2.33 (s, 3H), 2.02 - 1.84 (m, 2H), 1.75 - 1.58 (m, 2H), 1.47 (s, 3H), 1.42 (s, 3H).

[1176] Example 236: Synthesis of 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

[1177] [ka]

[1178] Example 236-1: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one; dihydrochloride

[1179] The title compound was synthesized in the same manner as in Example 77 and Example 78-1, except that tert-butyl (R)-3-methylsulfonyloxypiperidine-1-carboxylate was used instead of tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate in Example 77.

[1180] Example 236-2: Synthesis of 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

[1181] The title compound was obtained in the same manner as in Example 163 using 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one; dihydrochloride obtained in Example 236-1 as the starting material.

[1182] 1 H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J = 8.8 Hz, 1H), 7.19 - 6.98 (m, 4H), 6.77 (dd, J = 8.8, 2.5 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 4.66 (td, J = 5.0, 2.2 Hz, 1H), 4.57 - 4.41 (m, 4H), 4.23 (tdd, J = 7.5, 5.4, 3.7 Hz, 1H), 3.97 (dd, J = 13.9, 3.7 Hz, 1H), 3.80 - 3.68 (m, 4H), 3.43 (dd, J = 13.9, 7.6 Hz, 1H), 3.06 (d, J = 11.4 Hz, 1H), 2.98 - 2.85 (m, 4H), 2.85 - 2.71 (m, 3H), 2.70 - 2.61 (m, 2H), 2.36 (ddd, J = 21.3, 11.4, 5.6 Hz, 2H), 2.04 (d, J = 8.9 Hz, 1H), 1.86 (dt, J = 8.4, 4.3 Hz, 1H), 1.76 - 1.62 (m, 1H), 1.59 - 1.48 (m, 1H).

[1183] Example 237: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-hydroxy)-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1184] [ka]

[1185] The title compound was obtained in the same manner as in Example 162 using 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one; dihydrochloride obtained in Example 236-1 as the starting material.

[1186] 1 H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J = 8.8 Hz, 1H), 7.19 - 6.99 (m, 4H), 6.78 (dd, J = 8.8, 2.5 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 4.50 (dt, J = 22.5, 4.6 Hz, 3H), 4.24 (tt, J = 7.8, 4.1 Hz, 1H), 3.97 (dd, J = 13.9, 3.7 Hz, 1H), 3.81 (s, 2H), 3.72 (q, J = 5.9 Hz, 4H), 3.44 (dd, J = 13.9, 7.5 Hz, 1H), 3.14 - 3.04 (m, 1H), 2.94 (dt, J = 9.5, 4.8 Hz, 4H), 2.82 (dd, J = 10.8, 5.0 Hz, 1H), 2.67 (dt, J = 17.1, 5.2 Hz, 3H), 2.49 - 2.32 (m, 2H), 2.05 (d, J = 10.2 Hz, 2H), 1.87 (s, 1H), 1.70 (dt, J = 9.5, 4.1 Hz, 1H), 1.64 - 1.51 (m, 1H).

[1187] Example 238: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

[1188] [ka]

[1189] The title compound was obtained in the same manner as in Example 220 using 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 as the starting material.

[1190] 1 H NMR (400 MHz, Methanol-d4) δ 7.66 (d, J = 8.7 Hz, 1H), 7.17 - 6.99 (m, 4H), 6.76 (dd, J = 8.8, 2.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 4.46 (q, J = 11.0, 8.0 Hz, 3H), 4.24 (s, 1H), 3.97 (dd, J = 13.9, 3.7 Hz, 1H), 3.83 - 3.68 (m, 4H), 3.44 (dd, J = 13.9, 7.6 Hz, 1H), 2.93 (dd, J = 13.7, 4.6 Hz, 6H), 2.75 - 2.53 (m, 4H), 2.42 (d, J = 7.6 Hz, 2H), 2.03 (s, 2H), 1.83 (d, J = 9.5 Hz, 2H), 1.22 (s, 6H).

[1191] Example 239: Synthesis of 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

[1192] [ka]

[1193] The title compound was obtained in the same manner as in Example 12, except that 6-fluoro-2-pyridylboronic acid was used instead of isobutylboronic acid.

[1194] 1 H NMR (400 MHz, Methanol-d4) δ 8.03 (q, J = 8.1 Hz, 1H), 7.92 - 7.78 (m, 3H), 7.75 (d, J = 1.7 Hz, 1H), 7.17 - 7.01 (m, 5H), 4.55 (t, J = 5.1 Hz, 2H), 4.33 - 4.21 (m, 1H), 4.02 (dd, J = 13.8, 3.6 Hz, 1H), 3.85 - 3.70 (m, 4H), 3.49 (dd, J = 13.8, 7.7 Hz, 1H), 3.01 - 2.86 (m, 4H), 2.75 - 2.64 (m, 2H).

[1195] Example 240: Synthesis of (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-ethoxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

[1196] [ka]

[1197] The starting material used was the material obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate in Example 140 to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate, and the title compound was obtained in the same manner as in Example 163, except that 1-bromo-2-ethoxyethane was used instead of 2-fluoroethyl p-toluenesulfonate.

[1198] 1 H NMR (400 MHz, Methanol-d4) δ 7.63 (d, J = 8.7 Hz, 1H), 7.16 - 6.99 (m, 4H), 6.79 (dd, J = 8.7, 2.5 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 4.79 (td, J = 6.9, 3.3 Hz, 1H), 4.53 (dp, J = 7.7, 3.7 Hz, 1H), 4.29 - 4.19 (m, 1H), 4.14 (dd, J = 13.9, 3.7 Hz, 1H), 3.79 (s, 2H), 3.68 - 3.58 (m, 3H), 3.58 - 3.43 (m, 3H), 3.24 (dd, J = 13.8, 8.1 Hz, 1H), 2.93 (qd, J = 9.2, 8.7, 4.5 Hz, 6H), 2.76 (t, J = 5.6 Hz, 2H), 2.64 (dt, J = 16.5, 7.0 Hz, 4H), 2.07 (ddd, J = 16.6, 10.3, 6.3 Hz, 2H), 1.93 - 1.81 (m, 2H), 1.32 (d, J = 6.4 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H).

[1199] Example 241: Synthesis of (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

[1200] [ka]

[1201] Example 241-1: Synthesis of (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride

[1202] The Boc-substituted intermediate was synthesized in the same manner as in Example 64, except that the material synthesized in Example 140 by replacing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate with [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate was used as the starting material, and tert-butyl 3-methylsulfonyloxy-8-azabicyclo[3.2.1]octane-8-carboxylate was used instead of 4-chlorotetrahydropyran. The resulting intermediate was dissolved in methanol, and a 4N solution of hydrochloric acid in 1,4-dioxane was added. The reaction was stirred at room temperature until completion, diluted with ethyl diethyl ether, and filtered to obtain the title compound as a white solid in the form of a dihydrochloride salt.

[1203] Example 241-2: Synthesis of (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

[1204] The title compound was obtained in the same manner as in Example 162 using (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 241-1 as the starting material.

[1205] 1 H NMR (400 MHz, Methanol-d4) δ 7.62 (d, J = 8.8 Hz, 1H), 7.19 - 6.99 (m, 4H), 6.79 (dd, J = 8.7, 2.5 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 4.81 - 4.74 (m, 2H), 4.24 (d, J = 5.4 Hz, 1H), 4.15 (dd, J = 13.8, 3.6 Hz, 1H), 3.79 - 3.58 (m, 7H), 3.55 - 3.45 (m, 1H), 3.23 (d, J = 5.5 Hz, 1H), 3.00 - 2.77 (m, 6H), 2.66 (h, J = 5.2 Hz, 2H), 2.15 (s, 4H), 1.97 - 1.80 (m, 4H), 1.33 (d, J = 6.4 Hz, 3H).

[1206] Example 242: Synthesis of (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

[1207] [ka]

[1208] The title compound was obtained in the same manner as in Example 163 using (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained in Example 241-1 as the starting material.

[1209] 1 H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J = 8.7 Hz, 1H), 7.17 - 7.00 (m, 4H), 6.77 (dd, J = 8.7, 2.5 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 4.78 (td, J = 6.9, 3.3 Hz, 1H), 4.73 - 4.62 (m, 1H), 4.54 (t, J = 5.0 Hz, 1H), 4.16 (ddd, J = 23.5, 11.6, 8.0 Hz, 2H), 3.77 (d, J = 9.9 Hz, 3H), 3.63 (dd, J = 15.6, 3.4 Hz, 1H), 3.53 - 3.41 (m, 2H), 3.23 (dd, J = 13.8, 8.2 Hz, 1H), 2.96 - 2.91 (m, 4H), 2.88 (td, J = 6.4, 5.7, 2.7 Hz, 3H), 2.81 (t, J = 5.0 Hz, 1H), 2.70 (dd, J = 12.9, 4.1 Hz, 1H), 2.62 (dt, J = 13.0, 6.5 Hz, 2H), 2.12 - 2.00 (m, 3H), 1.89 - 1.77 (m, 3H), 1.33 (d, J = 6.4Hz, 3H).

[1210] Example 243: Synthesis of 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

[1211] [ka]

[1212] The title compound was obtained in the same manner as in Example 224 using 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 as the starting material.

[1213] 1 H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J = 8.8 Hz, 1H), 7.20 - 7.01 (m, 4H), 6.77 (dd, J = 8.8, 2.5 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.50 (dt, J = 25.8, 4.4 Hz, 3H), 4.30 - 4.19 (m, 1H), 3.97 (dd, J = 13.9, 3.7 Hz, 1H), 3.84 - 3.67 (m, 4H), 3.60 (t, J = 5.5 Hz, 2H), 3.45 (dd, J = 13.9, 7.6 Hz, 1H), 3.38 (s, 3H), 2.93 (dt, J = 11.0, 5.7 Hz, 6H), 2.76 (t, J = 5.5 Hz, 2H), 2.72 - 2.54 (m, 4H), 2.06 (dd, J = 18.1, 11.0 Hz, 2H), 1.93 - 1.82 (m, 2H).

[1214] Example 244: Synthesis of 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

[1215] [ka]

[1216] The title compound was synthesized in a similar manner to Example 12, except that 6-methoxy-2-pyridylboronic acid was used instead of isobutylboronic acid.

[1217] 1 H NMR (400 MHz, Methanol-d4) δ 7.90 (dd, J = 8.3, 1.7 Hz, 1H), 7.84 - 7.69 (m, 3H), 7.52 (d, J = 7.4 Hz, 1H), 7.18 - 7.01 (m, 4H), 6.78 (d, J = 8.2 Hz, 1H), 4.54 (t, J = 5.1 Hz, 2H), 4.33 - 4.21 (m, 1H), 4.03 (s, 4H), 3.82 - 3.71 (m, 4H), 3.49 (dd, J = 13.9, 7.7 Hz, 1H), 3.00 - 2.82 (m, 4H), 2.74 - 2.62 (m, 2H).

[1218] Example 245: Synthesis of (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

[1219] [ka]

[1220] The title compound was synthesized in a similar manner to Example 212 using the material obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate in Example 140 to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate as the starting material.

[1221] 1H NMR (400 MHz, Methanol-d4) δ 7.63 (d, J = 8.7 Hz, 1H), 7.17 - 7.00 (m, 4H), 6.79 (dd, J = 8.7, 2.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 4.82 - 4.77 (m, 1H), 4.56 (s, 1H), 4.24 (tt, J = 8.3, 4.6 Hz, 1H), 4.13 (ddd, J = 13.9, 7.8, 5.4 Hz, 1H), 4.00 (p, J = 6.3 Hz, 1H), 3.79 (s, 2H), 3.64 (dd, J = 15.6, 3.4 Hz, 1H), 3.50 (dd, J = 15.6, 7.6 Hz, 1H), 3.27 - 3.21 (m, 1H), 3.10 - 2.87 (m, 6H), 2.80 - 2.62 (m, 4H), 2.57 (d, J = 6.4 Hz, 2H), 2.17 - 2.04 (m, 2H), 1.94 (s, 2H), 1.33 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.2 Hz, 3H).

[1222] Example 246: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-morpholinoethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one

[1223] [ka]

[1224] Example 246-1: Synthesis of 8-acetyl-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

[1225] 8-Chloro-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one (200 mg, 0.48 mmol), tributyl(1-ethoxyvinyl)tin (0.21 mL, 0.62 mmol), and tetrakis(triphenylphosphine)palladium (28 mg, 0.024 mmol) were dissolved in 4 mL of toluene and the reaction was carried out at 120 °C for 2 hours using a microwave. Concentrated aqueous hydrochloric acid and 1,4-dioxane were added to the reaction solution and stirred at room temperature for 10 minutes. The reaction solution was diluted with ethyl acetate and basified with aqueous sodium hydroxide. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, and purified by flash chromatography to give the title compound.

[1226] Example 246-2: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-morpholinoethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one

[1227] The title compound was obtained in the same manner as in Example 221-2 using 8-acetyl-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 obtained in Example 246-1 as the starting material.

[1228] 1H NMR (400 MHz, Methanol-d4) δ 8.13 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 7.8, 1.2 Hz, 1H), 7.17 - 7.00 (m, 4H), 4.29 (s, 1H), 4.05 (ddd, J = 13.7, 7.3, 3.8 Hz, 1H), 3.77 (s, 2H), 3.70 (t, J = 4.7 Hz, 4H), 3.62 (d, J = 2.4 Hz, 2H), 3.55 - 3.39 (m, 2H), 2.99 - 2.80 (m, 4H), 2.72 - 2.61 (m, 2H), 2.64 - 2.52 (m, 2H), 2.41 (dt, J = 11.0, 4.6 Hz, 2H), 1.50 (d, J = 2.3 Hz, 3H), 1.44 (d, J = 2.2 Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H).

[1229] Example 247: Synthesis of 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

[1230] [ka]

[1231] The title compound was obtained in the same manner as in Example 222 using 8-acetyl-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 obtained in Example 246-1 as the starting material.

[1232] 1H NMR (400 MHz, Methanol-d4) δ 8.13 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.15 - 7.03 (m, 4H), 4.75 (s, 4H), 4.28 (s, 1H), 4.05 (ddd, J = 12.9, 8.5, 3.8 Hz, 1H), 3.76 (s, 2H), 3.61 (d, J = 2.1 Hz, 2H), 3.49 - 3.37 (m, 6H), 2.97 - 2.82 (m, 4H), 2.65 (dd, J = 6.3, 3.8 Hz, 2H), 1.50 (d, J = 2.8 Hz, 3H), 1.44 (d, J = 2.8 Hz, 3H), 1.25 (d, J = 6.6 Hz, 3H).

[1233] Example 248: Synthesis of 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

[1234] [ka]

[1235] The title compound was obtained in a similar manner to Example 212 using 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-...

Claims

1. The following formula (1) 【Chemistry 1】 （１） [In the formula, X 1 and X 2 are each independently CH or N; Y is CH 2 , O or NH when n is 0, and is CH or N when n is 1; Z is CH2 or CH when m is 0, CH or C when m is 1, and C when m is 2; n is an integer of 0 or 1; m is an integer from 0 to 2, 【change】 is a single bond or a double bond, R 1 Is -D-R 10 where D is a direct bond, —O—, —C(═O)—, —C≡C—, or —CR 11 R 12 - and R 10 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 11 and R 12 are each independently hydrogen, hydroxy or alkyl, and the carbocycle or heterocycle is optionally 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 2 is hydrogen or alkyl, R 3 is hydrogen or alkyl, R 4 , R 5 , R 6 and R 7 are each independently hydrogen or alkyl; R 8 is hydrogen, halo, alkyl, alkoxy or amino; R 9 is hydrogen, halo, or alkyl; or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

2. R 1 Is -D-R 10 where D is a direct bond, —O—, —C(═O)—, —C≡C—, or —CR 11 R 12 - and R 10 is hydrogen, halo, hydroxy, cyano, C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl sulfonate, di(C 1 -C 7 Alkyl)amino, C 1 -C 7 Alkylamino-C 1 -C 7 Alkyl, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 Alkyl, di(C 1 -C 7 Alkyl)aminocarbonyl-C 1 -C 7 Alkyl, saturated or unsaturated C 3 -C 10 Carbocyclyl, saturated or unsaturated 4- to 10-membered heterocyclyl, saturated or unsaturated C 3 -C 10 Carbocyclyl-C 1 -C 7 alkyl, or saturated or unsaturated 4-10 membered heterocyclyl-alkyl; R 11 and R 12 are each independently hydrogen, hydroxy or C 1 -C 7 2. The compound of claim 1, wherein R is an alkyl group, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

3. R 10 Ha, Haro, C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, saturated or unsaturated C 3 -C 10 3. The compound according to claim 2, which is carbocyclyl, saturated or unsaturated 4- to 10-membered heterocyclyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

4. The carbocyclic or heterocyclic ring may be selected from the group consisting of hydroxy, halo, oxo, formyl, nitrile, C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, Hydroxy-C 1 -C 7 Alkyl, hydroxyhalo-C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, nitrile-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, C 1 -C 7 Alkylthiocarbonyl, C 1 -C 7 Alkoxycarbonyl, halo-C 1 -C 7 Alkylcarbonyl, saturated or unsaturated C 3 -C 10 Carbocyclyl, saturated or unsaturated C 3 -C 10 Carbocyclylcarbonyl, (C 1 -C 7 Alkyl) (Halo-C 1 -C 7 alkyl)amino, (C 1 -C 7 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 1 -C 7 The compound according to claim 1, which is optionally substituted with 1 to 5 substituents selected from alkyl, or an optical isomer, stereoisomer or isotopic mutant thereof, or a pharma- ceutically acceptable salt thereof.

5. The carbocyclic or heterocyclic ring may be selected from the group consisting of hydroxy, halo, formyl, C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, C 1 -C 7 Alkoxycarbonyl, halo-C 1 -C 7 Alkylcarbonyl, saturated or unsaturated C 3 -C 10 Carbocyclyl, saturated or unsaturated C 3 -C 10 Carbocyclylcarbonyl, (C 1 -C 7 Alkyl) (Halo-C 1 -C 7 alkyl)amino, (C 1 -C 7 alkyl)(saturated or unsaturated 4- to 10-membered heterocyclyl)amino, and saturated or unsaturated 4- to 10-membered heterocyclyl-C 1 -C 7 The compound according to claim 4, which is optionally substituted with 1 to 5 substituents selected from alkyl, or an optical isomer, stereoisomer or isotopic mutant thereof, or a pharma- ceutically acceptable salt thereof.

6. The heterocycle may be selected from the group consisting of hydroxy, halo, formyl, C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, C 1 -C 7 Alkoxycarbonyl, halo-C 1 -C 7 Alkylcarbonyl, saturated or unsaturated C 3 -C 10 Carbocyclyl, saturated or unsaturated C 3 -C 10 Carbocyclylcarbonyl, and saturated or unsaturated 4- to 10-membered heterocyclyl-C 1 -C 7 The compound according to claim 1, which may be substituted by 1 or 2 substituents selected from the group consisting of alkyl, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

7. The carbocycle is halo-C 1 -C 7 Alkyl, (C 1 -C 7 Alkyl) (Halo-C 1 -C 7 (C alkyl)amino, and 1 -C 7 The compound according to claim 1, which may be substituted by 1 or 2 substituents selected from the group consisting of (alkyl)(saturated or unsaturated 4- to 10-membered heterocyclyl)amino, its optical isomer, stereoisomer or isotopic variant, or a pharma- ceutically acceptable salt thereof.

8. R 1 Is -D-R 10 where D is a direct bond; R 10 is hydrogen, halo, cyano, C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 Alkyl, saturated or unsaturated 4- to 10-membered heterocyclyl, saturated or unsaturated C 3 -C 10 carbocyclyl, or saturated or unsaturated 4-10 membered heterocyclyl-alkyl; The heterocycle may be selected from the group consisting of hydroxy, halo, formyl, C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, Hydroxy-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, nitrile-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkoxycarbonyl, halo-C 1 -C 7 The compound according to claim 1, which is optionally substituted by 1 or 2 substituents selected from alkylcarbonyl, and saturated or unsaturated 4- to 10-membered heterocyclyl, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

9. R 2 is hydrogen or C 1 -C 7 is alkyl, R 3 is hydrogen or C 1 -C 7 is alkyl, R 4 , R 5 , R 6 and R 7 are each independently hydrogen or C 1 -C 7 is alkyl, R 8 is hydrogen, halo, C 1 -C 7 Alkyl, C 1 -C 7 alkoxy or amino; R 9 is hydrogen, halo or C 1 -C 7 2. The compound of claim 1, wherein R is an alkyl group, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

10. The above is a single bond, or an optical isomer, stereoisomer, isotopic variant, or pharma- ceutically acceptable salt thereof.

11. The compound according to any one of claims 1 to 10, wherein the heterocycle is a 4-8 membered saturated or unsaturated hydrocarbon containing 1 or 2 heteroatoms selected from nitrogen and oxygen, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

12. The heterocycle may be 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] The compound according to any one of claims 1 to 10, which is selected from the group consisting of 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, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

13. 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. The compound according to claim 12, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 10, wherein the carbocyclic ring is selected from the group consisting of cyclohexane, cyclohexene, cyclopropane, cyclobutane, and cyclopentane, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

15. D is a direct bond, —O—, —C(═O)—, or —C≡C—; R 10 Ha, Haro, C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, saturated or unsaturated C 3 -C 10 carbocyclyl, saturated or unsaturated 4- to 10-membered heterocyclyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl; The carbocyclic or heterocyclic ring may be selected from the group consisting of hydroxy, halo, formyl, C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, C 1 -C 7 Alkoxycarbonyl, halo-C 1 -C 7 Alkylcarbonyl, saturated or unsaturated C 3 -C 10 Carbocyclyl, saturated or unsaturated C 3 -C 10 Carbocyclylcarbonyl, (C 1 -C 7 Alkyl) (Halo-C 1 -C 7 alkyl)amino, (C 1 -C 7 alkyl)(saturated or unsaturated 4- to 10-membered heterocyclyl)amino, and saturated or unsaturated 4- to 10-membered heterocyclyl-C 1 -C 7 It is optionally substituted with 1 to 5 substituents selected from 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; 2. The compound of claim 1, wherein the carbocycle is selected from the group consisting of cyclohexane, cyclohexene, and cyclopropane, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

16. 2. The compound according to claim 1, selected from the following compounds, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof: 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-(trifluoromethoxy)-4,5-dihydro-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-3H-2-benzazepin-7-yl]trifluoromethanesulfonate; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-benzazepine-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-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-tetrahydropyridin-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-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-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-(3,6-dihydro-2H-pyran-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-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(dimethylamino)methyl]-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-piperidyl)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; 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-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-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-piperidyl)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-methylpyrrolidin-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-piperidyl)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-ylmethyl)-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-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-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-hydroxy-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-hydroxy-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-[[(2S)-2-(hydroxymethyl)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-[[(2R)-2-(hydroxymethyl)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-(methoxymethyl)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-[[(2R)-2-(methoxymethyl)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-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-hydroxy-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-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-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-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 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; 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-yloxy-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-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-ylmethoxy)-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-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-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-[(1-acetyl-4-piperidyl)methoxy]-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-(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)ethoxy]-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-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-oxo-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-yl]oxy]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-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; 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; 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; 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; 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-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]azetidine-1-carboxylate; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-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]-2,3-dihydro-1,4-benzoxazepin-5-one; 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; 8-[(1-cyclopropyl-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-cyclobutyl-4-piperidyl)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-(oxetan-3-yl)-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-methylazetidin-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-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)azetidin-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-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-ethylpyrrolidin-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-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-isopropylpyrrolidin-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-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-[(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-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-(morpholinomethyl)-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-(morpholinomethyl)-3H-1,4-benzoxazepin-5-one; 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; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-pyridylmethoxy)-3H-1,4-benzoxazepin-5-one; 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; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(morpholinomethyl)-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-trifluoropropyl)-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-(trifluoromethyl)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-oxo-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-propyl]-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-propyl]-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-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one; 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; 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-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; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-tetrahydrofuran-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-methylpyrrolidin-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-methylpyrrolidin-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)oxy]-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-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-azabicyclo[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-piperidyloxy)-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-hydroxypropyl]-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-methyl-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-methyl-4-piperidyl)oxy]-3H-pyrido[3,2-f][1,4]oxazepin-5-one; (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; 4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one; 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-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; 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; 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-dihydro-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-benzodiazepine-2,5-dione; 2-[4-[[4-(2R)-3-(3,4,-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3,-dihydro-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-oxo-2,3-dihydro-1,4-benzazepin-8-yl]oxy]piperidine-1-carbonitrile; 8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-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-yl]oxy]azetidine-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-yl]methyl]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-azabicyclo[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-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-(pyrrolidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 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; 8-(3,3-difluoropyrrolidine-1-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-(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-(pyrrolidin-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-propyl]-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-yl]oxy]piperidine-1-carbaldehyde; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[[4-(oxetan-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; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(trifluoromethyl)piperidine-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)piperidine-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-dimethylmorpholine-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]octane-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-methylmorpholine-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-methylmorpholine-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-(morpholinomethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one; 8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-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-difluoromorpholine-4-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-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-hydroxy-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-piperidylmethyl)-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-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-fluoroethyl(methyl)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]octane-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-5-azabicyclo[2.2.1]heptane-5-carbonyl)-3H-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,5-dimethylmorpholine-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-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-[[3-fluoro-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-(3,4-dihydro-1H-pyrrolo[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-dihydro-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-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-piperidyl)oxy]-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-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[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-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one; 8-(cyclopentanecarbonyl)-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-hydroxypropyl]-8-[(1-methyl-3-piperidyl)oxy]-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-hydroxyethyl)-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-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-hydroxyprop-1-ynyl)-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-methoxyethyl)-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-dihydro-1,4-benzoxazepin-5-one; 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; 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; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxybut-1-ynyl)-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(methylamino)prop-1-ynyl]-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-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,3-dimethylpyrazol-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-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-dimethylpyrazol-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]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-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-2-methyl-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-ethoxyethyl)-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]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-fluoroethyl]-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-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-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-morpholinoethyl)-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-oxa-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-pyrrolo[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-fluoro-1-(2-hydroxyethyl)-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-[[(3R,4R)-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-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride; 8-[[3,3-difluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-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; 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-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-methoxy-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-(3-hydroxy-3-methyl-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-hydroxyethyl)-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]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-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolinon-2-yl)-2-hydroxy-propyl]-8-[(3R)-tetrahydrofuran-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolinon-2-yl)-2-hydroxy-propyl]-8-[(3S)-tetrahydrofuran-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]-8-[[1-[(2S)-2-hydroxypropyl]-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-[(2R)-2-hydroxypropyl]-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-hydroxy-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-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-(2-methoxyethyl)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-[(3R)-1-methylpyrrolidin-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]-8-[(3R)-1-(2-methoxyethyl)pyrrolidin-3-yl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one; 4-[(2R)-3-(3,4-dihydro-1H-isoquinoline-2-)-2-hydroxy-propyl]-8-[[1-(3,3,3-trifluoro-2-hydroxy-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one; (2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinoline-2-)-2-hydroxy-propyl]-2-methyl-8-[[1-(3,3,3-trifluoro-2-hydroxy-propyl)-4-piperidyl]oxy]-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-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

17. A pharmaceutical composition for preventing or treating a disease associated with protein arginine methyltransferase 5 (PRMT5) inhibition, comprising a therapeutically effective amount of a compound of formula (1) according to any one of claims 1 to 16, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutical acceptable salt thereof, together with a pharma-ceutical acceptable carrier.

18. The pharmaceutical composition according to claim 17, wherein the disease associated with PRMT5 inhibition is selected from cancer, blood disease, autoimmune disease, inflammatory disease and neurodegenerative disease.

19. The cancers include acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma, benign monoclonal gammopathy, bile duct carcinoma, bladder carcinoma, breast cancer, brain tumor, lymphoma, multiple myeloma, lacrimal gland tumor, bronchial carcinoma, cervical cancer, craniopharyngioma, colorectal cancer, epithelial tumor, ependymoma, endothelial sarcoma, endometrial cancer, esophageal cancer, Barrett's adenocarcinoma, Ewing's sarcoma, 19. The pharmaceutical composition according to claim 18, wherein the cancer is selected from the group consisting of cancer of the liver, sarcoma, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cavity cancer (OSCC), pharyngeal cancer, hematopoietic system cancer, hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer, liver cancer, lung cancer, myelodysplastic syndromes (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, calcific cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, thyroid cancer, urethral cancer, vaginal cancer, and vulvar cancer.

20. 20. The pharmaceutical composition of claim 19, wherein the brain tumor is selected from the group consisting of meningioma, glioma, medulloblastoma, glioblastoma, and brain metastasis cancer.

21. 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, tendonitis, psoriasis, eczema, burns, dermatitis, pruritus, nocturnal enuresis, eosinophilic diseases, peptic ulcer, regional enteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis and eosinophilic colitis; The inflammatory diseases include acne-related inflammation, aplastic anemia, autoimmune hemolytic anemia, rhinitis, asthma, polyarteritis nodosa, temporal arteritis, periarteritis nodosa, Takayasu's arteritis, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, chronic obstructive pulmonary disease, dermatomyositis, type I diabetes, type 2 diabetes, psoriasis, eczema, eczema hypersensitivity reaction, burns, dermatitis, pruritus, endometriosis, infection, ischemic heart disease, glomerulonephritis, gingivitis, hypersensitivity, migraine, tension headache, postoperative selected from the group consisting of intestinal obstruction, intestinal obstruction during sepsis, idiopathic thrombocytopenic purpura, painful bladder syndrome, peptic ulcer, regional 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, morphea, myasthenia gravis and myocardial ischemia, 19. The pharmaceutical composition of claim 18, wherein the neurodegenerative disease is selected from the group consisting of motor neuron disease, Pick's disease, Alzheimer's disease, AIDS dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinal pigmentation, spinal muscular atrophy and cerebellar degeneration.

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