Bicyclic compound and use thereof

Abstract

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

Description

Bicyclic compounds and their uses

[0001] The present invention relates to a compound derivative containing a 6-7 bicyclic ring and its use, and the compound according to the present invention acts as a protein arginine methyltransferases 5 (PRMT5) inhibitor and can be usefully used for the prevention or treatment of diseases caused by PRMT5.

[0002] Protein arginine methyltransferases (PRMTs) are enzymes that transfer methyl groups to arginine in target proteins using the cofactor SAM (S-adenosyl methionine). Currently, nine PRMT isoforms (PRMT1-9) are known, which are broadly divided into three types. Type I PRMTs, PRMT1, 2, 3, 4, 6, and 8, induce monomethylation and asymmetric dimethylation of arginine. Type II PRMTs, PRMT5 and PRMT9, are known to induce monomethylation and symmetric dimethylation of arginine. Meanwhile, type III PRMT, PRMT7, primarily induces monomethylation of arginine. PRMTs induce methylation of various substrates present in the nucleus and cytoplasm, thereby regulating important biological processes within cells, such as cell proliferation, differentiation, and splicing.

[0003] PRMT5 is a major arginine methyltransferase among type II PRMTs, forming a functional complex with methylosome protein 50 (MEP50) to induce methylation of target proteins. PRMT5 methylates target proteins, including nuclear histone proteins and non-histone proteins such as p53, NFκ, PI3K / AKT, and CRAF, and is implicated in the formation of leukemia, lymphoma, glioblastoma, lung cancer, and breast cancer. In particular, it is well known that PRMT5-mediated carcinogenesis occurs by promoting tumor cell proliferation, differentiation, invasion, and migration. Furthermore, several reports have shown that higher PRMT5 expression is associated with a poorer prognosis in cancer patients, and conversely, inhibition of PRMT5 expression has been observed to inhibit tumor cell proliferation.

[0004] Meanwhile, it has recently been reported that diseases other than cancer can also be mediated by PRMT5.

[0005] The present invention aims to provide a novel compound based on a 6-7 bicyclic ring, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, which exhibits excellent PRMT5 inhibitory effect.

[0006] In addition, another object of the present invention is to provide a pharmaceutical composition comprising 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 as an active ingredient.

[0007] To achieve the above purpose, the present invention provides a compound of the following chemical formula 1, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof:

[0008] [Chemical Formula 1]

[0009]

[0010]

[0011] In the above chemical formula 1,

[0012] X 1 and X 2 each independently represents carbon or nitrogen;

[0013] Y represents carbon, oxygen or nitrogen;

[0014] Z represents carbon;

[0015] n represents an integer of 0 or 1;

[0016] m represents an integer from 0 to 2;

[0017] represents a single bond or double bond;

[0018] R 1 Silver -DR 10 represents; where D is a direct bond, -O-, -C(=O)-, -C≡C- or -CR 11 R 12 - represents; R 10 represents 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 12each independently represent hydrogen, hydroxy or alkyl; the carbocycle or heterocycle may be substituted with one or more substituents selected from hydroxy, halo, oxo, formyl (-CHO), nitrile, alkyl, alkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyalkyl, haloalkyl, nitrilealkyl, alkylcarbonyl, alkylthiocarbonyl, alkoxycarbonyl, haloalkylcarbonyl, carbocyclyl, carbocyclylcarbonyl, (alkyl)(haloalkyl)amino, (alkyl)(heterocyclyl)amino, heterocyclyl and heterocyclyl-alkyl;

[0019] R 2 represents hydrogen or alkyl;

[0020] R 3 represents hydrogen or alkyl;

[0021] R 4 , R 5 , R 6 and R 7 each independently represents hydrogen or alkyl;

[0022] R 8 represents hydrogen, halo, alkyl, alkoxy or amino;

[0023] R 9 represents hydrogen, halo or alkyl.

[0024]

[0025] Unless otherwise stated, the term “alkyl” used herein, alone or in combination with additional terms (e.g., haloalkyl), means a straight-chain or branched radical of a saturated aliphatic hydrocarbon group having, for example, 1 to 7 carbon atoms. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.

[0026] Unless otherwise stated, the term “alkoxy” herein means alkyloxy, e.g., alkyloxy having 1 to 7 carbon atoms.

[0027] Unless otherwise stated, the term “halo” used herein, either alone or in combination with additional terms (e.g., haloalkyl), means a radical which is F, Cl, Br or I.

[0028] Unless otherwise stated, the term "haloalkyl" as used herein means an alkyl, as defined herein, in which one or more hydrogens are replaced by the same or different halogens. Exemplary haloalkyls include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), and the like.

[0029] Unless otherwise stated, the term "oxo" herein refers to a group of the formula =O (i.e., oxygen with a double bond). Thus, for example, a 1-oxo-ethyl group is an acetyl group.

[0030] Unless otherwise stated, the term “hydroxyalkyl” as used herein includes a group in which one or more hydrogen atoms in the alkyl group are replaced by one or more hydroxyl (-OH), e.g., divalent or trivalent hydroxyl.

[0031] Unless otherwise stated herein, the term “saturated or unsaturated carbocyclyl” refers to a hydrocarbon radical forming a single or fused cyclic ring having (e.g., 3 to 24) carbon atoms, which is unsaturated or partially or fully saturated. Specifically, the carbocyclyl may have 3 to 10 carbon atoms. The carbocycle may include a bridged structure or a spiro structure. In addition, the unsaturated carbocycle may include an aromatic hydrocarbon such as an aryl.

[0032] According to one specific example of the present invention, the carbocyclyl may be, but is not limited to, cyclohexane, cyclohexene, cyclopropane, cyclobutane, or cyclopentane.

[0033] Unless otherwise stated, the term “saturated or unsaturated heterocyclyl” as used herein means a 3 to 24 membered hydrocarbon group forming an unsaturated or partially or fully saturated single or fused cyclic ring having one or more heteroatoms selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S), for example, 1 to 8 heteroatoms. Specifically, the heterocyclyl may be a 4 to 10 membered hydrocarbon group having 1 to 3 heteroatoms. The heterocycle may include a bridged structure or a spiro structure. In addition, the unsaturated heterocyclyl may include an aromatic hydrocarbon such as heteroaryl.

[0034] According to one specific example of the present invention, the heterocyclyl is tetrahydropyridine, dihydropyridine, piperidine, dihydropyran, tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine, morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, pyrrolidine, oxazepane, 2-oxa-5-azabicyclo[2.2.1]heptane, pyridyl, tetrahydrofuran, 8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.4]octane, 2-azabicyclo[2.2.1]heptane, 3-Oxa-8-azabicyclo[3.2.1]octane, 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine, 3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine, pyrimidine, pyrazole, 2-oxa-7-azaspiro[3.5]nonane, or oxetane, but is not limited thereto.

[0035]

[0036] According to one specific example of the present invention, in the chemical formula 1, X 1 and X 2 can each independently be CH or N.

[0037] According to one specific example of the present invention, in the chemical formula 1, Y represents CH2, O or NH when n is 0, and may be CH or N when n is 1.

[0038] According to one specific example of the present invention, in the chemical formula 1, Z represents CH2 or CH when m is 0, represents CH or C when m is 1, and may be C when m is 2.

[0039] According to one specific example of the present invention, in the chemical formula 1, represents a single bond or double bond.

[0040] According to one specific example of the present invention, in the chemical formula 1, R 1 Silver -DR 10 represents; where D is a direct bond, -O-, -C(=O)-, -C≡C- or -CR 11 R 12 -It could be.

[0041] According to one specific example of the present invention, in the chemical formula 1, 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- to 10-membered heterocyclyl, saturated or unsaturated C3-C 10 Carbocyclyl-C1-C7 alkyl, or a saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl.

[0042] According to one specific example of the present invention, in the chemical formula 1, R 11 and R 12 Each can independently be hydrogen, hydroxy or C1-C7 alkyl.

[0043] According to one specific example of the present invention, in the chemical formula 1, the carbocycle or heterocycle 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 10 Carbocyclylcarbonyl, (C1-C7alkyl)(halo-C1-C7alkyl)amino, (C1-C7alkyl)(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-C7alkyl.

[0044] According to one specific example of the present invention, in the chemical formula 1, R 2 may be hydrogen or C1-C7 alkyl.

[0045] According to one specific example of the present invention, in the chemical formula 1, R 3 may be hydrogen or C1-C7 alkyl.

[0046] According to one specific example of the present invention, in the chemical formula 1, R 4 , R 5 , R 6 and R 7 Each may independently be hydrogen or C1-C7 alkyl.

[0047] According to one specific example of the present invention, in the chemical formula 1, R 8may be hydrogen, halo, C1-C7 alkyl, C1-C7 alkoxy or amino.

[0048] According to one specific example of the present invention, in the chemical formula 1, R 9 may be hydrogen, halo or C1-C7 alkyl.

[0049]

[0050] According to one specific example of the present invention, in the chemical formula 1, X 1 and X 2 each independently represents CH or N; Y represents CH2, O or NH when n is 0, and CH or N when n is 1; Z represents CH2 or CH when m is 0, CH or C when m is 1, and C when m is 2; can represent a single bond or a double bond.

[0051]

[0052] According to one specific example of the present invention, in the chemical formula 1, R 1 Silver -DR 10 represents; where D is a direct bond, -O-, -C(=O)-, -C≡C- or -CR 11 R 12 - represents; 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- to 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 12Each can independently represent hydrogen, hydroxy or C1-C7 alkyl.

[0053]

[0054] According to one specific example of the present invention, in the chemical formula 1, R 10 Silver halo, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, saturated or unsaturated C3-C 10 It may represent carbocyclyl, saturated or unsaturated 4- to 10-membered heterocyclyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl.

[0055]

[0056] According to one specific example of the present invention, in the chemical formula 1, the carbocycle or heterocycle 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 10 Carbocyclylcarbonyl, (C1-C7alkyl)(halo-C1-C7alkyl)amino, (C1-C7alkyl)(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-C7alkyl.

[0057]

[0058] According to one specific example of the present invention, in the chemical formula 1, 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 It may be substituted with 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.

[0059]

[0060] According to one specific example of the present invention, in the chemical formula 1, the 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 It may be substituted with 1 or 2 substituents selected from the group consisting of carbocyclylcarbonyl, and saturated or unsaturated 4- to 10-membered heterocyclyl-C1-C7alkyl.

[0061]

[0062] According to one specific example of the present invention, in the chemical formula 1, the carbocyclyl may be substituted with 1 or 2 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.

[0063]

[0064] According to one specific example of the present invention, in the chemical formula 1, R 1 Silver -DR 10 represents; where D represents a direct bond; 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 a saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl; wherein the heterocyclyl may be substituted with 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 a saturated or unsaturated 4- to 10-membered heterocyclyl.

[0065]

[0066] According to one specific example of the present invention, in the chemical formula 1, R 2 represents hydrogen or C1-C7 alkyl; R 3 represents hydrogen or C1-C7 alkyl; R 4 , R 5 , R 6 and R 7 Each independently represents hydrogen or C1-C7 alkyl; R 8 represents hydrogen, halo, C1-C7 alkyl, C1-C7 alkoxy or amino; R 9 may represent hydrogen, halo or C1-C7 alkyl.

[0067]

[0068] According to one specific example of the present invention, in the chemical formula 1, may be a single bond.

[0069]

[0070] According to one specific example of the present invention, in the chemical formula 1, the heterocyclyl may be a 4 to 8-membered saturated or unsaturated hydrocarbon containing 1 or 2 heteroatoms selected from nitrogen and oxygen.

[0071]

[0072] According to one specific example of the present invention, in the chemical formula 1, the heterocyclyl is 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]octane, 2-azabicyclo[2.2.1]heptane, It may be selected from the group consisting of 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.

[0073]

[0074] According to one specific example of the present invention, in the chemical formula 1, the heterocyclyl may be 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.

[0075]

[0076] According to one specific example of the present invention, in the chemical formula 1, carbocyclyl may be selected from the group consisting of cyclohexane, cyclohexene, cyclopropane, cyclobutane, and cyclopentane.

[0077]

[0078] According to one specific example of the present invention, in the chemical formula 1, D represents a direct bond, -O-, -C(=O)-, or -C≡C-; R 10 Silver halo, C1-C7 alkyl, hydroxy-C1-C7 alkyl, halo-C1-C7 alkyl, saturated or unsaturated C3-C 10 Carbocyclyl, saturated or unsaturated 4-10 membered heterocyclyl, or saturated or unsaturated 4-10 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 which may be substituted with 1 to 5 substituents selected from carbocyclylcarbonyl, (C1-C7alkyl)(halo-C1-C7alkyl)amino, (C1-C7alkyl)(saturated or unsaturated 4- to 10-membered heterocyclyl)amino, and saturated or unsaturated 4- to 10-membered heterocyclyl-C1-C7alkyl; The above heterocyclyl 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 above carbocyclyl may be selected from the group consisting of cyclohexane, cyclohexene, and cyclopropane.

[0079]

[0080] Representative examples of compounds of chemical formula 1 according to the present invention include, but are not limited to, those listed in Table 1 below:

[0081]

[0082] [Table 1]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099] The compounds according to the present invention may have an asymmetric carbon center and an asymmetric axis or asymmetric plane, and therefore may exist as all optical and stereoisomers, including substantially pure enantiomers such as R and S enantiomers, as well as mixture racemates, and all of these enantiomers and mixtures are included in the scope of the present invention. With respect to pure enantiomers, the optical purity of such enantiomers represented by formula 1 and pharmaceutically acceptable salts thereof may be preferably 60%ee or higher, more preferably 95%ee or higher, and most preferably 98%ee or higher.

[0100] The term "ee" above refers to enantiomeric excess. For example, one enantiomeric form in a particular compound is present in a mixture of enantiomeric forms in a greater amount than the other enantiomeric forms in the compound. An enantiomeric enriched form can include an enantiomeric mixture of a particular compound in which the concentration of a single enantiomeric form in the enantiomeric mixture of the particular compound is at least 50%, more typically at least 60%, 70%, 80%, or 90%, or greater (e.g., >95%, >97%, >98%, >99%, >99.5%) with respect to the other enantiomeric forms of the compound.

[0101] In this specification, for convenience, unless otherwise specified, the compound of formula 1 is used to mean all compounds of formula 1, optical isomers, stereoisomers, isotopic variants thereof, and pharmaceutically acceptable salts thereof.

[0102] As used herein, the term “isotopic variant” refers to a compound that contains an unusual ratio of isotopes at one or more atoms constituting the compound. For example, an isotopic variant of a compound may be radioactively labeled, for example, a hydrogen atom may be selected from hydrogen, deuterium, and tritium, and a carbon-13 (13 C), nitrogen-15( 15 N) may contain the following.

[0103] The compound of formula 1 according to the present invention, its optical isomers, stereoisomers, or isotopic variants can form pharmaceutically acceptable salts. The pharmaceutically acceptable salts include both acid or base addition salts and stereochemically isomeric forms thereof. The salts include, but are not limited to, any salt that maintains the activity of the parent compound in the subject to which the compound is administered and does not cause undesirable effects. Such salts include inorganic and organic salts, for example, acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, esylic acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium idetic acid, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid, idetic acid, toluenesulfonic acid, edicilinic acid, esylinic acid, fumaric acid, gluceptic acid, pamoic acid, gluconic acid, glycolylarsanilic acid, methylnitric acid, polygalacturic acid, hexylisorcinonic acid, malonic acid, Hydrabamic acid, hydrochloric acid, hydroiodoic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, estolinic acid, mucic acid, napsylic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, salicylic acid, sulfamic acid, sulfanilinic acid, methanesulfonic acid, teoclic acid. In addition, the basic salt form includes, for example, 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, hydrabamine salts, and salts with amino acids such as arginine and lysine. In addition, the salt form can be converted into the free form by treatment with a suitable base or acid.The term "additional salt" includes compounds of formula 1 and solvates with which salts thereof can form. Such solvates are, for example, hydrates and alcoholates.

[0104]

[0105] Terms and abbreviations used in this specification have their original meanings unless otherwise defined.

[0106]

[0107] The present invention also provides a method for preparing a compound of formula 1. Hereinafter, a method for preparing a compound of formula 1 will be described based on an exemplary reaction scheme to help understand the present invention. However, those skilled in the art to which the present invention pertains can prepare the compound of formula 1 by various methods using known compounds or compounds that can be easily prepared therefrom based on the structure of formula 1, and all such methods should be interpreted as being included in the scope of the present invention. That is, the compound of formula 1 can be prepared by arbitrarily combining various synthetic methods described in the present specification or disclosed in the prior art, and therefore, the following description related to the method for preparing the compound of formula 1 merely presents exemplary methods, and the order of unit operations, etc. can be selectively changed as needed, and the scope of the preparation method of the present invention is not limited thereto.

[0108]

[0109] [Reaction Formula 1]

[0110]

[0111]

[0112] A general synthetic method involves obtaining intermediate 3 from starting material 2 through a Schmidt reaction using sodium azide under acidic conditions. From this compound, intermediate 4 with oxirane introduced can be obtained through a substitution reaction, and the final compound 1a can be obtained through an addition reaction of tetrahydroisoquinoline.

[0113]

[0114] [Reaction Formula 2]

[0115]

[0116]

[0117] Another synthetic method is to use compound 5 as a starting material and perform a Suzuki coupling reaction under palladium conditions to obtain the final compound 1b substituted with an alkyl or alkenyl group.

[0118]

[0119] [Reaction Formula 3]

[0120]

[0121]

[0122] Another synthetic method is to obtain intermediate 6 by substituting a bromine group with a hydroxyl group using potassium hydroxide under palladium conditions, similar to reaction scheme 3, using compound 5 as a starting material, and then obtain the final compound 1c with an ether group substituted through a substitution reaction.

[0123]

[0124] According to another aspect of the present invention, a pharmaceutical composition for preventing or treating a disease associated with PRMT5 inhibition is provided, comprising a therapeutically effective amount of a compound of formula 1, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, together with a pharmaceutically acceptable carrier. In addition, various forms of prodrugs that are converted into the compound of formula 1 in vivo as desired are also included in the scope of the present invention. The pharmaceutical composition may further comprise one or more additives selected from the group consisting of pharmaceutically acceptable carriers, diluents, and adjuvants.

[0125]

[0126] As used herein, “treatment” means stopping, delaying or alleviating the progression of a disease when applied to a subject exhibiting symptoms of the disease.

[0127] As used herein, “prevention” means reducing or eliminating the possibility of contracting a disease.

[0128] As used herein, the term "pharmaceutical composition" may include other chemical components, such as carriers, diluents, excipients, etc., in addition to the active compound according to the present invention. Accordingly, the pharmaceutical composition may include pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof, as needed. Such pharmaceutical compositions facilitate administration of the active compound into a living organism. Various techniques for administering pharmaceutical compositions containing compounds are known, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. In addition, the pharmaceutical composition may be sterilized, or may further include auxiliary agents, such as preservatives, stabilizers, wetting agents or emulsifying agents, salts for osmotic pressure control, and / or buffers, and may further include other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating, or coating.

[0129] 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 that facilitates the introduction of many organic compounds into the cells or tissues of living organisms.

[0130] As used herein, a "diluent" is defined as a compound that not only stabilizes the biologically active form of the target compound but also dilutes the compound in water to dissolve it. Salts dissolved in buffers are used as diluents in the art. A commonly used buffer is phosphate-buffered saline, which mimics the salt form of human body fluids. Because buffer salts can control the pH of a solution at low concentrations, buffering diluents rarely alter the biological activity of a compound.

[0131] As used herein, “pharmaceutically acceptable” means a property that does not impair the biological activity and physical properties of the compound.

[0132]

[0133] Additionally, the pharmaceutical composition may be a composition for the prevention and / or treatment of diseases associated with PRMT5 inhibition. Here, the diseases associated with PRMT5 inhibition may include, for example, cancer, blood diseases, autoimmune diseases, inflammatory diseases, or neurodegenerative diseases, and may include any other diseases known to be associated with PRMT5.

[0134] The above cancers include acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, hemangiosarcoma, benign monoclonal gammopathy, cholangiocarcinoma, bladder cancer, breast cancer, brain cancer, lymphoma, multiple myeloma, lacrimal gland tumor, bronchial cancer, cervical cancer, craniopharyngioma, colorectal cancer, epithelial carcinoma, ependymoma, endothelial sarcoma, endometrial cancer, esophageal cancer, Barrett's adenocarcinoma, Ewing's sarcoma, eye cancer, gallbladder cancer, stomach cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cancer (OSCC), throat cancer, hematopoietic system cancer, hemangioblastoma, inflammatory myofibroblastic tumor, immunocytotoxic 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 cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, prostate cancer, rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, thyroid cancer, urethral cancer, vaginal cancer, and vulvar cancer, but are not limited thereto. Brain cancers include, but are not limited to, meningioma, glioma, medulloblastoma, glioblastoma, and brain metastases.

[0135] The above blood disorders may include, but are not limited to, hemoglobinopathies and sickle cell anemia.

[0136] The above autoimmune diseases include, but are not limited to, rheumatoid arthritis, spondyloarthropathy, 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, enuresis, eosinophilic disease, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis.

[0137] The above inflammatory diseases include inflammation associated with acne, aplastic anemia, hemolytic autoimmune anemia, rhinitis, asthma, polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis, crystal 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 reactions, burns, dermatitis, pruritus, endometriosis, infections, ischemic heart disease, glomerulonephritis, gingivitis, hypersensitivity, migraine, tension headache, postoperative ileus, ileus during sepsis, idiopathic thrombocytopenic purpura, Bladder pain syndrome, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal 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.

[0138] Examples of the above neurodegenerative diseases include, but are not limited to, motor neuron disease, Pick's disease, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar degeneration.

[0139]

[0140] The pharmaceutical composition may be formulated into various oral or parenteral dosage forms. For example, it may be any oral dosage form, such as tablets, pills, hard or soft capsules, liquids, suspensions, emulsions, syrups, granules, and elixirs. These oral dosage forms may, in addition to the active ingredient, contain, according to the typical composition of each dosage form, pharmaceutically acceptable carriers, such as diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine, or lubricants such as silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol.

[0141] In addition, when the oral administration formulation is a tablet, it may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and, in some cases, may further contain a disintegrating agent such as starch, agar, alginic acid or its sodium salt, an effervescent mixture and / or an absorbent, a coloring agent, a flavoring agent or a sweetening agent.

[0142] The pharmaceutical composition may be formulated as a parenteral dosage form, in which case it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. At this time, in order to formulate the pharmaceutical composition as a dosage form for parenteral administration, the active ingredient, i.e., the compound of formula 1, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, is mixed in water with a stabilizer or buffer to prepare a solution or suspension, and this solution or suspension can be prepared in a unit dosage form of an ampoule or vial.

[0143] In addition, the pharmaceutical composition may be sterilized or may further contain auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying agents, salts for osmotic pressure control and / or buffers, and may further contain other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating or coating.

[0144] The above-mentioned effective ingredient, i.e., the compound of the above-mentioned chemical formula 1, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, may be included in the pharmaceutical composition in an effective amount of 0.1 to 500 mg / kg (body weight), preferably 0.5 to 100 mg / kg (body weight) per day for mammals including humans, and such pharmaceutical composition may be administered orally or parenterally once a day or in divided doses of two or more times.

[0145] According to the present invention, a compound based on a 6-7 bicyclic ring, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, exhibiting excellent PRMT5 inhibitory effects can be provided. Accordingly, 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.

[0146] Additionally, the compounds according to the present invention, or optical isomers, stereoisomers or isotopic variants thereof, or pharmaceutically acceptable salts thereof, may have improved blood-brain barrier penetration ability, superior efficacy or improved pharmacokinetic properties.

[0147] The present invention will be described in more detail below through examples. However, these examples are intended only to exemplify the invention and are not intended to limit the scope of the invention.

[0148]

[0149] 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

[0150]

[0151]

[0152] Example 1-1: Synthesis of 8-methoxy-4-(oxiran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[0153] 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. The reaction solution was stirred at 0°C for 30 min, then epibromohydrin (0.056 mL, 0.65 mmol) was slowly added, and the mixture was stirred at room temperature for 2 h. Methanol was added to the reaction mixture to quench the reaction, and ethyl acetate was added. The mixture was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and used in the next reaction without further purification.

[0154]

[0155] 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

[0156] The starting material obtained from Example 1-1 was dissolved in 3 mL of isopropanol and tetrahydroisoquinoline (0.06 mL, 0.5 mmol) was added to 80 o The mixture was stirred at C for 12 hours. The temperature was lowered to room temperature, and the solvent was concentrated. The resulting oily liquid was purified by chromatography to synthesize a transparent, sticky solid compound. The NMR data for the synthesized title compound are as follows.

[0157] 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, 7.7 Hz, 1H), 2.97 - 2.85 (m, 4H), 2.69 - 2.60 (m, 2H).

[0158]

[0159] 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

[0160]

[0161]

[0162] The title compound was synthesized using 7-methoxy-2,3,4,5-tetrahydro-2-benzazepin-1-one as the starting material and the same method as in Example 1.

[0163] 1 H 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).

[0164]

[0165] 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

[0166]

[0167]

[0168] The title compound was synthesized by the same method as in Example 1, using (1-oxo-2,3,4,5-tetrahydro-2-benzazepin-7-yl) acetate as the starting material.

[0169] 1 H 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).

[0170]

[0171] 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

[0172]

[0173]

[0174] The title compound was synthesized using 6-(trifluoromethoxy)tedralin-1-one as the starting material and the same method as in Example 1.

[0175] 1 H 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).

[0176]

[0177] 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

[0178]

[0179]

[0180] The title compound was synthesized by the same method as in Example 1, using 7-(trifluoromethyl)chroman-4-one as the starting material and changing epibromohydrin in Example 1-1 to (R)-(-)-glycidyl nosylate.

[0181] 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).

[0182]

[0183] 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

[0184]

[0185]

[0186] The title compound was synthesized using 7-(trifluoromethoxy)-2,3,4,5-tetrahydro-2-benzazepin-1-one as the starting material and the same method as in Example 5.

[0187] 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).

[0188]

[0189] 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

[0190]

[0191]

[0192] The title compound was synthesized using 7-ethoxy-2,3,4,5-tetrahydro-2-benzazepin-1-one as the starting material and the same method as in Example 5.

[0193] 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).

[0194]

[0195] 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

[0196]

[0197]

[0198] The title compound was synthesized using (1-oxo-2,3,4,5-tetrahydro-2-benzazepin-7-yl) trifluoromethanesulfonate as the starting material and by the same method as in Example 5.

[0199] 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).

[0200]

[0201] 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

[0202]

[0203]

[0204] The title compound was synthesized using 7-cyano-2,3,4,5-tetrahydro-2-benzazepin-1-one as the starting material and the same method as in Example 5.

[0205] 1 H 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).

[0206]

[0207] 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

[0208]

[0209]

[0210] 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

[0211] The title compound was synthesized using 8-bromo3,4-dihydro-2H-1,4-benzoxazepin-5-one as the starting material and the same method as in Example 5.

[0212]

[0213] 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

[0214] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one (96 mg, 0.22 mmol), methylboronic acid (27 mg, 0.45 mmol), Pd(dppf)Cl2 . CH2Cl2 (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) and stirred at 100°C. After confirming the 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 obtain 11 mg of the title compound.

[0215] 1H 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).

[0216]

[0217] 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

[0218]

[0219]

[0220] In Example 10-2, the title compound was synthesized by the same method after changing methylboronic acid to propylboronic acid.

[0221] 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).

[0222]

[0223] 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

[0224]

[0225]

[0226] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one (100 mg, 0.23 mmol), isobutylboronic acid (47 mg, 0.46 mmol), Pd(dppf)Cl2 (17 mg, 0.023 mmol), and potassium carbonate (95 mg, 0.69 mg) were dissolved in 2 mL of toluene and stirred at 120°C for 2 hours. After confirming the 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 obtain 11 mg of the title compound.

[0227] 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).

[0228]

[0229] 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

[0230]

[0231]

[0232] In Example 12, isobutylboronic acid was changed to 3,3,3-trifluoropropylboronic acid, and the title compound was synthesized by the same method at 100°C.

[0233] 1 H 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).

[0234]

[0235] 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

[0236]

[0237]

[0238] In Example 10-2, the title compound was synthesized by the same method after changing methylboronic acid to tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate.

[0239] 1 H 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).

[0240]

[0241] 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

[0242]

[0243]

[0244] 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 obtained from Example 14 was dissolved in methanol, and a 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added. The mixture was stirred at room temperature until the reaction was complete, diluted with ethyldiethyl ether, and filtered to obtain the title compound in the form of a dihydrochloride salt as a white solid.

[0245] 2 Water was added to the title compound in the form of hydrochloric acid salt and washed three times with ethyl acetate. The obtained aqueous layer was alkalized with sodium hydroxide aqueous solution until the pH reached 14, and ethyl acetate was added again to extract three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to synthesize the title compound without any additional purification process.

[0246] 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).

[0247]

[0248] 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

[0249]

[0250]

[0251] In Example 15, dihydrochloride (75 mg, 0.16 mmol) 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 and potassium carbonate (66 mg, 0.48 mmol) obtained were dissolved in 1.5 mL of acetone, and acetic anhydride (0.03 mLm 0.32 mmol) was slowly added at room temperature. The reaction solution was stirred at room temperature, and after confirming the completion of the reaction, it was filtered. The filtrate was concentrated under reduced pressure, and the title compound was obtained by flash column chromatography.

[0252] 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).

[0253]

[0254] 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

[0255]

[0256]

[0257] 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

[0258] The 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 obtained in Example 14 was dissolved in methanol, and a catalytic amount of 5% palladium-charcoal was added. The reaction solution was stirred under a hydrogen balloon and filtered through Celite. The filtrate was concentrated under reduced pressure and dissolved again in a small amount of methanol. 4 N hydrochloric acid dissolved in 1,4-dioxane was added, and the mixture was stirred at room temperature for 1 hour. Distilled water was added to the reaction solution, and the mixture was washed with ethyl acetate. The obtained aqueous layer was basified to pH 14 with aqueous sodium hydroxide solution, and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the title compound was obtained without further purification.

[0259]

[0260] 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

[0261] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyl)-2,3-dihydro-1,4-benzoxazepin-5-one (50 mg, 0.11 mmol) and potassium carbonate (46 mg, 0.33 mg) obtained from Example 17-1 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 one day, diluted with dichloromethane, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by flash column chromatography to obtain 21 mg of the title compound.

[0262] 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).

[0263]

[0264] 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

[0265]

[0266]

[0267] The dihydrochloride salt (75 mg, 0.16 mmol) 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 obtained in Example 15 was dissolved in methanol, and an excess of acetaldehyde was added. An excess of sodium cyanoborohydride was added while stirring the reaction solution, and the mixture was stirred at room temperature for one day. A saturated aqueous solution of ammonium chloride was added to the reaction solution to terminate the reaction, and a 1 N aqueous solution of sodium hydroxide was added to make it alkaline. The reaction mixture was extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. The oily liquid obtained by removing the solvent by evaporation under reduced pressure was purified by rapid chromatography to synthesize 10 mg of the title compound as a white solid.

[0268] 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).

[0269]

[0270] 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

[0271]

[0272]

[0273] In Example 18, the title compound was synthesized by the same method after changing acetaldehyde to acetone.

[0274] 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).

[0275]

[0276] 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

[0277]

[0278]

[0279] In Example 10, the title compound was synthesized by the same method after changing methylboronic acid to 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0280] 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).

[0281]

[0282] 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

[0283]

[0284]

[0285] 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 obtained from Example 20 was dissolved in methanol, and a catalytic amount of 5% palladium-charcoal 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 synthesize the title compound as a transparent oil.

[0286] 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).

[0287]

[0288] 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

[0289]

[0290]

[0291] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one (160 mg, 0.37 mmol), potassium (morpholin-4-yl)methyltrifluoroborate (85 mg, 0.41 mg), palladium acetate (4 mg, 0.0185 mmol), XPhos (18 mg, 0.037 mmol) and cesium carbonate (362 mg, 1.11 mmol) were dissolved in 3 mL of tetrahydrofuran:distilled water (=10:1) solvent, and nitrogen was charged to 80 o The mixture was stirred at C for 16 hours. 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 synthesize 103 mg of the white title compound.

[0292] 1 H 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).

[0293]

[0294] 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

[0295]

[0296]

[0297] In Example 22, the title compound was synthesized by the same method, except that potassium (morpholin-4-yl)methyltrifluoroborate was changed to potassium (piperidin-1-yl)methyltrifluoroborate.

[0298] 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).

[0299]

[0300] 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

[0301]

[0302]

[0303] In Example 22, the title compound was synthesized by the same method, except that potassium (morpholin-4-yl)methyltrifluoroborate was changed to potassium 1-trifluoroboratemethylpyrrolidine.

[0304] 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).

[0305]

[0306] 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

[0307]

[0308]

[0309] In Example 22, the title compound was synthesized by the same method, except that potassium (morpholin-4-yl)methyltrifluoroborate was changed to potassium dimethylaminomethyltrifluoroboronate.

[0310] 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).

[0311]

[0312] 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

[0313]

[0314]

[0315] In Example 22, the title compound was synthesized by the same method, except that potassium (morpholin-4-yl)methyltrifluoroborate was changed to potassium diethylaminomethyltrifluoroboronate.

[0316] 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).

[0317]

[0318] 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

[0319]

[0320]

[0321] Dissolve 4-methylpiperidine (0.054 mL, 0.46 mmol) and potassium (bromomethyl)trifluoroborate (92 mg, 0.46 mmol) in 2 mL of tetrahydrofuran and 80 oC 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-hydroxy-propyl]-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, and the reaction vessel was filled with nitrogen. The reaction solution was stirred at 80°C for 16 h, diluted with ethyl acetate, and filtered through Celite. The obtained solution was concentrated under reduced pressure and purified by rapid chromatography to synthesize 70 mg of the white title compound.

[0322] 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).

[0323]

[0324] 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

[0325]

[0326]

[0327] In Example 27, the title compound was synthesized by the same method, adding 4 equivalents of potassium carbonate and changing 4-methyl piperidine to 2-oxa-6-azaspiro[3.3]heptane oxalate.

[0328] 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).

[0329]

[0330] 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

[0331]

[0332]

[0333] 3-Methoxyazetidine hydrochloride (57 mg, 0.46 mmol), potassium (bromomethyl)trifluoroborate (92 mg, 0.46 mmol), and potassium carbonate (127 mg, 0.92 mmol) were dissolved in tetrahydrofuran:distilled water (10:1) and 80 o 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-hydroxy-propyl]-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, and the reaction vessel was filled with nitrogen. The reaction solution was stirred at 80°C for 16 h, diluted with ethyl acetate, and filtered through Celite. The obtained solution was concentrated under reduced pressure and purified by rapid chromatography to synthesize 16 mg of the white title compound.

[0334] 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).

[0335]

[0336] 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

[0337]

[0338]

[0339] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 2-methylmorpholine.

[0340] 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).

[0341]

[0342] 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

[0343]

[0344]

[0345] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 4,4-difluoropiperidine hydrochloride.

[0346] 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).

[0347]

[0348] 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

[0349]

[0350]

[0351] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 4-fluoropiperidine hydrochloride.

[0352] 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).

[0353]

[0354] 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

[0355]

[0356]

[0357] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 3,5-dimethylpiperidine.

[0358] 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).

[0359]

[0360] 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

[0361]

[0362]

[0363] In Example 29, 3-methoxyazetidine hydrochloride was changed to 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole hydrochloride, and the title compound was synthesized by the same method.

[0364] 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).

[0365]

[0366] 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

[0367]

[0368]

[0369] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to pyrrolidine-3-ol.

[0370] 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).

[0371]

[0372] 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

[0373]

[0374]

[0375] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to (2R)-2-methylpyrrolidine.

[0376] 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).

[0377]

[0378] 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

[0379]

[0380]

[0381] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 3-piperidylmethanol.

[0382] 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).

[0383]

[0384] 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

[0385]

[0386]

[0387] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 4-methoxypiperidine.

[0388] 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).

[0389]

[0390] 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

[0391]

[0392]

[0393] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 1,4-oxazepane hydrochloride.

[0394] 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).

[0395]

[0396] 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

[0397]

[0398]

[0399] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 3-methylpyrrolidine-3-ol.

[0400] 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).

[0401]

[0402] 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

[0403]

[0404]

[0405] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to morpholin-3-ylmethanol.

[0406] 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).

[0407]

[0408] 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

[0409]

[0410]

[0411] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 3,3-difluoropiperidine hydrochloride.

[0412] 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).

[0413]

[0414] 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

[0415]

[0416]

[0417] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 3-fluoropiperidine hydrochloride.

[0418] 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).

[0419]

[0420] 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

[0421]

[0422]

[0423] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to piperidin-3-ol hydrochloride.

[0424] 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).

[0425]

[0426] 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

[0427]

[0428]

[0429] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to piperidin-4-ol.

[0430] 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).

[0431]

[0432] 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

[0433]

[0434]

[0435] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to [(2S)-pyrrolidin-2-yl]methanol.

[0436] 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).

[0437]

[0438] 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

[0439]

[0440]

[0441] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to [(2R)-pyrrolidin-2-yl]methanol.

[0442] 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).

[0443]

[0444] 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

[0445]

[0446]

[0447] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 2-ethylpyrrolidine hydrochloride.

[0448] 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).

[0449]

[0450] 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

[0451]

[0452]

[0453] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to (2S)-2-(methoxymethyl)pyrrolidine.

[0454] 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).

[0455]

[0456] 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

[0457]

[0458]

[0459] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to (2R)-2-(methoxymethyl)pyrrolidine.

[0460] 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).

[0461]

[0462] 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

[0463]

[0464]

[0465] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 3-fluoropyrrolidine hydrochloride.

[0466] 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).

[0467]

[0468] 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

[0469]

[0470]

[0471] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 3,3-difluoropyrrolidine.

[0472] 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).

[0473]

[0474] 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

[0475]

[0476]

[0477] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 1-piperazin-1-ylethanolone.

[0478] 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).

[0479]

[0480] 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

[0481]

[0482]

[0483] 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

[0484] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to tert-butyl piperazine-1-carboxylate.

[0485]

[0486] 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 2 hydrochloride

[0487] 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 obtained from Example 54-1 was dissolved in methanol, and a 4 M hydrochloric acid solution dissolved 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 white solid.

[0488]

[0489] 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

[0490] The obtained hydrochloride salt was dissolved in methanol, and an excess of paraformaldehyde and sodium cyanoborohydride were added, followed by stirring at room temperature for 12 hours. The reaction solution was quenched by adding a saturated aqueous ammonium chloride solution, and basified by adding a 1 N aqueous sodium hydroxide solution. 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 obtained pale yellow oily liquid was purified by flash chromatography to synthesize the title compound.

[0491] 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).

[0492]

[0493] 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

[0494]

[0495]

[0496] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride.

[0497] 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).

[0498]

[0499] 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

[0500]

[0501]

[0502] 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

[0503] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one (9.0 g, 21 mmol), hydroxypotassium (4.68 g, 83 mmol), Pd(dba)2 (180 mg, 0.315 mmol), and tBuXPhos (270 mg, 0.63 mmol) were dissolved in 80 mL of a 1,4-dioxane:distilled water (=1:1) solution, and the reaction vessel was filled with nitrogen. The reaction solution was stirred at 100°C for 3 hours, and acidified to pH ~ 1 by adding aqueous hydrochloric acid in an ice bath. The aqueous layer was washed three times with ethyl acetate, alkalized to pH 14 by adding aqueous sodium hydroxide solution in an ice bath, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to synthesize the title compound as a white solid without further purification.

[0504]

[0505] 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

[0506] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-one (100 mg, 0.27 mmol) obtained from 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 extracted by adding ethyl acetate and distilled water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the oily liquid was purified by flash chromatography to synthesize 64 mg of the title compound as a sticky white solid.

[0507] 1 H 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).

[0508]

[0509] 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

[0510]

[0511]

[0512] In Example 56-2, the title compound was synthesized by the same method as in Example 56-2, by changing 3-(chloromethyl)pyridine hydrochloride to 4-(chloromethyl)pyridine hydrochloride.

[0513] 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).

[0514]

[0515] 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

[0516]

[0517]

[0518] In Example 56-2, the title compound was synthesized by the same method as in Example 56-2, except that 3-(chloromethyl)pyridine hydrochloride was changed to (2-fluoro-4-pyridyl)methyl methanesulfonate.

[0519] 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).

[0520]

[0521] 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

[0522]

[0523]

[0524] In Example 56-2, the title compound was synthesized by the same method after changing 3-(chloromethyl)pyridine hydrochloride to 2,6-dichloro-4-ethyl-pyridine hydrochloride.

[0525] 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).

[0526]

[0527] 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

[0528]

[0529]

[0530] In Example 56-2, the title compound was synthesized by the same method as in Example 56-2, except that 3-(chloromethyl)pyridine hydrochloride was changed to (2,3-difluoro-4-pyridyl)methyl methanesulfonate.

[0531] 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).

[0532]

[0533] 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

[0534]

[0535]

[0536] In Example 56-2, the title compound was synthesized by the same method as in Example 56-2, except that 3-(chloromethyl)pyridine hydrochloride was changed to (6-fluoro-3-pyridyl)methyl methanesulfonate.

[0537] 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).

[0538]

[0539]

[0540] 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

[0541]

[0542]

[0543] In Example 56-2, the title compound was synthesized by the same method as in Example 56-2, except that 3-(chloromethyl)pyridine hydrochloride was changed to (3-fluoro-4-pyridyl)methyl methanesulfonate.

[0544] 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).

[0545]

[0546] 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

[0547]

[0548]

[0549] In Example 56-2, the title compound was synthesized by the same method as in Example 56-2, except that 3-(chloromethyl)pyridine hydrochloride was changed to (5-fluoro-2-pyridyl)methyl methanesulfonate.

[0550] 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).

[0551]

[0552] 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

[0553]

[0554]

[0555] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-one (100 mg, 0.27 mmol), potassium carbonate (112 mg, 0.81 mmol), and 4-chlorotetrahydropyran (0.12 mL, 0.81 mmol) obtained from Example 56-1 were dissolved in dimethylformamide and stirred at 150°C for more than 12 hours. The reaction solution was cooled to room temperature, distilled water was added, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the oily liquid was purified by flash chromatography to synthesize the title compound as a sticky white solid.

[0556] 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).

[0557]

[0558] 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

[0559]

[0560]

[0561] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to tetrahydropyran-2-ylmethyl methanesulfonate.

[0562] 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).

[0563]

[0564] 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

[0565]

[0566]

[0567] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to cyclohexylmethyl methanesulfonate.

[0568] 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).

[0569]

[0570] 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

[0571]

[0572]

[0573] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to tetrahydrofuran-2-ylmethyl methanesulfonate.

[0574] 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).

[0575]

[0576] 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

[0577]

[0578]

[0579] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to (1-methyl-3-piperidyl) methanesulfonate.

[0580] 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).

[0581]

[0582] 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

[0583]

[0584]

[0585] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to (1-ethyl-3-piperidyl) methanesulfonate.

[0586] 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).

[0587]

[0588] 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

[0589]

[0590]

[0591] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to (1-acetyl-4-piperidyl)methyl methanesulfonate.

[0592] 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, 7.6 Hz, 1H), 3.21 - 3.12 (m, 1H), 2.98 - 2.82 (m, 4H), 2.75 - 2.60 (m, 3H), 2.13 (s, 3H), 1.92 (dd,J= 25.3, 14.0 Hz, 2H), 1.45 - 1.21 (m, 3H).

[0593]

[0594] 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

[0595]

[0596]

[0597] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to 2,2,2-trifluoroethyl methanesulfonate.

[0598] 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).

[0599]

[0600] 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

[0601]

[0602]

[0603] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to 2-chloro-N,N-dimethyl-ethanamine hydrochloride.

[0604] 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).

[0605]

[0606] 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

[0607]

[0608]

[0609] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to 4-(2-chloroethyl)morpholine hydrochloride.

[0610] 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).

[0611]

[0612] 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

[0613]

[0614]

[0615] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate.

[0616] 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).

[0617]

[0618] Example 75: 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

[0619]

[0620]

[0621] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to [2-(diethylamino)-2-oxo-ethyl] methanesulfonate.

[0622] 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).

[0623]

[0624] 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

[0625]

[0626]

[0627] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to (6-oxo-3-piperidyl) methanesulfonate.

[0628] 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).

[0629]

[0630] 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

[0631]

[0632]

[0633] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate.

[0634] 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).

[0635]

[0636] 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

[0637]

[0638]

[0639] 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 2 hydrochloride

[0640] 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 obtained from Example 77 was dissolved in methanol, and a 4 M hydrochloric acid solution dissolved 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 white solid.

[0641]

[0642] 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

[0643] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one 2 hydrochloride obtained from Example 78-1 was dissolved in dichloromethane, triethylamine and acetic anhydride were added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution 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, concentrated under reduced pressure, and the oily liquid was purified by flash chromatography to synthesize the title compound as a white solid.

[0644] 1 H 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).

[0645]

[0646] 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

[0647]

[0648]

[0649] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to (1-acetyl-3-piperidyl) methanesulfonate.

[0650] 1 H NMR (diastereomeric mixture, 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).

[0651]

[0652] 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

[0653]

[0654]

[0655] The title compound was synthesized by the same method as in Example 78 from the starting material obtained by changing 4-chlorotetrahydropyran to tert-butyl 4-methylsulfonyloxypyrrolidine-1-carboxylate in Example 64.

[0656] 1 H 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).

[0657]

[0658] 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

[0659]

[0660]

[0661] In Example 80, the title compound was synthesized by the same method as in Example 80, except that tert-butyl 4-methylsulfonyloxypyrrolidine-1-carboxylate was changed to tert-butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate.

[0662] 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).

[0663]

[0664] 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

[0665]

[0666]

[0667] In Example 80, the title compound was synthesized by the same method as in Example 80, except that tert-butyl 4-methylsulfonyloxypyrrolidine-1-carboxylate was changed to tert-butyl (3R)-3-methylsulfonyloxypyrrolidine-1-carboxylate.

[0668] 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, 7.9 Hz, 1H), 2.99 - 2.82 (m, 4H), 2.70 - 2.58 (m, 2H), 2.37 - 2.26 (m, 1H), 2.26 - 2.16 (m, 1H), 2.09 (d,J= 15.6 Hz, 3H).

[0669]

[0670] Example 83: Synthesis of 8-(1-acetylasetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0671]

[0672]

[0673] 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 2 hydrochloride

[0674] The title compound was synthesized by the same method as in Example 78-1, using as a starting material the material obtained by changing 4-chlorotetrahydropyran to tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 64.

[0675]

[0676] Example 83-2: Synthesis of 8-(1-acetylasetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[0677] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 83-1 as a starting material.

[0678] 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).

[0679]

[0680] 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

[0681]

[0682]

[0683] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 83-1 as a starting material, but changing acetic anhydride to propanoyl chloride.

[0684] 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).

[0685]

[0686] 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

[0687]

[0688]

[0689] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 83-1 as a starting material, but changing acetic anhydride to cyclopropanecarbonyl chloride.

[0690] 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).

[0691]

[0692] 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

[0693]

[0694]

[0695] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 83-1 as a starting material, but changing acetic anhydride to methyl chloroformate.

[0696] 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).

[0697]

[0698] 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

[0699]

[0700]

[0701] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one 2 hydrochloride (100 mg, 0.19 mmol) obtained from 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 a saturated aqueous ammonium chloride solution was added, stirred for 30 minutes, and then basified by the addition of a 1 N aqueous sodium hydroxide solution. 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 pale yellow oily liquid was purified by rapid chromatography to synthesize the title compound as a white solid.

[0702] 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).

[0703]

[0704] 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

[0705]

[0706]

[0707] In Example 87, the title compound was synthesized by the same method after changing paraformaldehyde to acetaldehyde.

[0708] 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).

[0709]

[0710] 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

[0711]

[0712]

[0713] In Example 87, the title compound was synthesized by the same method after changing paraformaldehyde to acetone.

[0714] 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).

[0715]

[0716] 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

[0717]

[0718]

[0719] In Example 87, paraformaldehyde was changed to (1-ethoxycyclopropoxy)-trimethyl-silane and 60 o The title compound was synthesized by the same method in C.

[0720] 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).

[0721]

[0722] 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

[0723]

[0724]

[0725] In Example 87, the title compound was synthesized by the same method after changing paraformaldehyde to cyclobutanone.

[0726] 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).

[0727]

[0728] 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

[0729]

[0730]

[0731] In Example 87, the title compound was synthesized by the same method after changing paraformaldehyde to oxetan-3-one.

[0732] 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).

[0733]

[0734] 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

[0735]

[0736]

[0737] The title compound was synthesized by the same method as in Example 87 using the material obtained from Example 83-1 as a starting material.

[0738] 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).

[0739]

[0740] 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

[0741]

[0742]

[0743] The title compound was synthesized by the same method as in Example 87, using the material obtained from Example 83-1 as a starting material and changing paraformaldehyde to acetaldehyde.

[0744] 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).

[0745]

[0746] 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

[0747]

[0748]

[0749] The material obtained from Example 83-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 87, except that paraformaldehyde was changed to acetone.

[0750] 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).

[0751]

[0752] 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

[0753]

[0754]

[0755] The material obtained from Example 83-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 87, except that paraformaldehyde was changed to oxetan-3-one.

[0756] 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).

[0757]

[0758] 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

[0759]

[0760]

[0761] The title compound was synthesized by using the starting material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 83-1 to tert-butyl 3-(methylsulfonyloxymethyl)azetidine-1-carboxylate in Example 87, and then changing paraformaldehyde to acetaldehyde by the same method.

[0762] 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= 7.2 Hz, 2H), 3.01 - 2.89 (m, 3H), 2.90 - 2.80 (m, 2H), 2.70 - 2.61 (m, 2H), 2.57 (q,J= 7.4 Hz, 2H), 1.00 (t,J= 7.2 Hz, 3H).

[0763]

[0764] 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

[0765]

[0766]

[0767] The title compound was synthesized by the same method as in Example 87, using as a starting material the material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 83-1 to tert-butyl 4-methylsulfonyloxypyrrolidine-1-carboxylate.

[0768] 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).

[0769]

[0770] 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

[0771]

[0772]

[0773] In Example 83-1, tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate was changed to tert-butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate, and the title compound was synthesized by the same method as in Example 87, except that paraformaldehyde was changed to acetaldehyde.

[0774] 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).

[0775]

[0776] 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

[0777]

[0778]

[0779] In Example 64, the title compound was synthesized by the same method, except that potassium carbonate was changed to cesium carbonate and 4-chlorotetrahydropyran was changed to 2-fluoropyridine.

[0780] 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).

[0781]

[0782] 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

[0783]

[0784]

[0785] In Example 83-1, tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate was changed to tert-butyl (2R)-2-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate, and the title compound was synthesized by the same method as in Example 87, except that paraformaldehyde was changed to acetone.

[0786] 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, 7.6 Hz, 2H), 3.22 - 3.15 (m, 1H), 2.95 (d,J= 9.3 Hz, 1H), 2.89 - 2.80 (m, 4H), 2.60 (d,J= 6.4 Hz, 2H), 2.08 (t,J= 9.4 Hz, 1H), 1.98 - 1.79 (m, 5H), 1.24 (d,J= 6.7 Hz, 5H), 1.19 (d,J= 6.5 Hz, 3H).

[0787]

[0788] 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

[0789]

[0790]

[0791] The title compound was synthesized by the same method as in Example 87, using as a starting material the material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 83-1 to tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate.

[0792] 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).

[0793]

[0794] 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

[0795]

[0796]

[0797] In Example 83-1, tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate was replaced with tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate, and the title compound was synthesized by the same method as in Example 87, except that paraformaldehyde was replaced with acetaldehyde.

[0798] 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)

[0799]

[0800] 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

[0801]

[0802]

[0803] The title compound was synthesized by the same method as in Example 87, using as a starting material the material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 83-1 to tert-butyl 2-(methylsulfonyloxymethyl)morpholine-4-carboxylate.

[0804] 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).

[0805]

[0806] 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

[0807]

[0808]

[0809] The title compound was synthesized by using the starting material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 83-1 to tert-butyl 2-(methylsulfonyloxymethyl)morpholine-4-carboxylate in Example 87, and then changing paraformaldehyde to acetaldehyde by the same method.

[0810] 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).

[0811]

[0812] 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

[0813]

[0814]

[0815] The title compound was synthesized by the same method as in Example 87, using as a starting material the material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 83-1 to tert-butyl 3-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate.

[0816] 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).

[0817]

[0818] 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

[0819]

[0820]

[0821] The title compound was synthesized by the same method as in Example 87, using as a starting material the material obtained by changing tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 83-1 to tert-butyl 3-(methylsulfonyloxymethyl)piperidine-1-carboxylate.

[0822] 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).

[0823]

[0824] 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

[0825]

[0826]

[0827] Example 108-1: Synthesis of methyl 4-bromo-2-[2-(tert-butoxycarbonylamino)ethoxy]-6-fluoro-benzoate

[0828] Methyl 4-bromo-2,6-difluoro-benzoate (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 the mixture was stirred at the same temperature. Saturated aqueous ammonium chloro solution was added to the reaction solution, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated, and the obtained oily liquid was purified by flash chromatography to obtain 5.07 g of the title compound as a transparent liquid.

[0829]

[0830] Example 108-2: Synthesis of 8-bromo-6-fluoro-3,4-dihydro-2H-1,4-benzoxazepin-5-one

[0831] Methyl 4-bromo-2-[2-(tert-butoxycarbonylamino)ethoxy]-6-fluoro-benzoate (5.07 g, 12.9 mmol) obtained from Example 108-1 was dissolved in 20 mL of methanol, and a 4 M hydrochloric acid solution (20 mL, 80 mmol) in 1,4-dioxane was added. The reaction solution was stirred at room temperature, basified by adding aqueous sodium hydroxide solution in an ice bath, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained oily liquid was purified by flash chromatography to obtain 870 mg of the title compound as a solid.

[0832]

[0833] 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

[0834] The title compound was synthesized using 8-bromo-6-fluoro-3,4-dihydro-2H-1,4-benzoxazepin-5-one obtained from Example 108-2 as a starting material by the same method as in Example 5.

[0835]

[0836] 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

[0837] The title compound was synthesized by the same method 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 from Example 108-3 as a starting material.

[0838] 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).

[0839]

[0840] 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

[0841]

[0842]

[0843] 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

[0844] The title compound was synthesized 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 from Example 108-3 as a starting material by the same method as in Example 56-1.

[0845]

[0846] 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

[0847] The title compound was synthesized 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 by the same method as in Examples 77, 78-1 and 87.

[0848] 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).

[0849]

[0850] 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

[0851]

[0852]

[0853] Example 110-1: Synthesis of 7-bromo-2,2-dimethyl-chroman-4-one

[0854] 1-(4-Bromo-2-hydroxy-phenyl)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 and stirred for 30 minutes. Acetone (2.5 mL, 33.7 mmol) was added to the reaction solution, heated under reflux for 4 hours, water was added, and the reaction was quenched. The mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated, dissolved in ethyl acetate again, and filtered through a small amount of silica. The solution was reduced in pressure and concentrated to obtain 4.7 g of the title compound as a crystalline solid without any additional purification.

[0855]

[0856] Example 110-2: Synthesis of 8-bromo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazepin-5-one

[0857] 7-Bromo-2,2-dimethyl-chroman-4-one (4.7 g, 18.6 mmol) obtained from 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 1 molar concentration of sodium hydroxide aqueous solution was slowly added while maintaining it at 0℃ in an ice bath. The reaction solution was alkalized until the pH became 10 or higher, and then extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was removed by evaporation under reduced pressure, and then recrystallized from dichloromethane and hexane to synthesize the title compound as a solid.

[0858]

[0859] 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

[0860] The title compound was synthesized using 8-bromo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazepin-5-one obtained from Example 110-2 as a starting material and by the same method as Example 5.

[0861]

[0862] 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

[0863] The title compound was synthesized 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 from Example 110-3 as a starting material by the same method as in Example 56-1.

[0864]

[0865] 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 2 hydrochloride

[0866] The title compound was synthesized by the same method as in Examples 77 and 78-1 using the material obtained from Example 110-4 as a starting material.

[0867]

[0868] 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

[0869] The title compound was synthesized by the same method as in Example 87, using the material obtained from Example 110-5 as a starting material and changing paraformaldehyde to acetaldehyde.

[0870] 1H NMR (400 MHz, Methanol-d4) δ7.58 (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).

[0871]

[0872] 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

[0873]

[0874]

[0875] The title compound was synthesized 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 by the same method as in Example 22.

[0876] 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).

[0877]

[0878] 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

[0879]

[0880]

[0881] The title compound was synthesized by the same method as Example 87 using the material obtained from Example 110-5 as a starting material.

[0882] 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).

[0883]

[0884] 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

[0885]

[0886]

[0887] The title compound was synthesized by the same method as in Example 56-2, using the material obtained from Example 110-4 as a starting material and changing 3-(chloromethyl)pyridine hydrochloride to 4-(chloromethyl)pyridine hydrochloride.

[0888] 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, 8.2 Hz, 1H), 2.97 - 2.82 (m, 4H), 2.66 - 2.57 (m, 2H), 1.42 (s, 3H), 1.32 (s, 3H).

[0889]

[0890] Example 114: Synthesis of 8-(1-acetylasetidin-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

[0891]

[0892]

[0893] The title compound was synthesized by the same method as in Example 83 using the material obtained from Example 110-4 as a starting material.

[0894] 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).

[0895]

[0896] 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

[0897]

[0898]

[0899] 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

[0900] The title compound was synthesized using 8-bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one as a starting material using the same method as in Example 5.

[0901]

[0902] 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

[0903] The title compound was synthesized 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 by the same method as in Example 22.

[0904] 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).

[0905]

[0906] 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

[0907]

[0908]

[0909] The title compound was synthesized 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 and the same method as in Example 10, except that methylboronic acid was changed to 3,3,3-trifluoropropylboronic acid.

[0910] 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).

[0911]

[0912] 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

[0913]

[0914]

[0915] The title compound was synthesized 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 and the same method as in Example 10, except that methylboronic acid was changed to cyclohexylmethylboronic acid.

[0916] 1H 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, 12.4 Hz, 3H).

[0917]

[0918] 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

[0919]

[0920]

[0921] The title compound was synthesized by the same method as in Example 10 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 and changing methylboronic acid to 2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0922] 1H 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).

[0923]

[0924] 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

[0925]

[0926]

[0927] The title compound was synthesized by the same method as in Example 10 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 the starting material and changing methylboronic acid to 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane.

[0928] 1H 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).

[0929]

[0930] 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

[0931]

[0932]

[0933] The title compound was synthesized by the same method as in Example 10 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 the starting material and methylboronic acid as tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate.

[0934] 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).

[0935]

[0936] 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

[0937]

[0938]

[0939] 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

[0940] The title compound was synthesized 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 by the same method as in Example 56-1.

[0941]

[0942] 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

[0943] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to (1-acetyl-4-piperidyl) methanesulfonate.

[0944] 1 H 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).

[0945]

[0946] Example 122: Synthesis of 8-(1-acetylasetidin-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

[0947]

[0948]

[0949] The title compound was synthesized by the same method as in Example 83 using the material obtained from Example 121-1 as a starting material.

[0950] 1 H 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).

[0951]

[0952] 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

[0953]

[0954]

[0955] The title compound was synthesized by the same method as in Example 78 from an intermediate obtained by using the material obtained from Example 121-1 as a starting material and changing 4-chlorotetrahydropyran to tert-butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate in Example 64.

[0956] 1 H 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).

[0957]

[0958] 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

[0959]

[0960]

[0961] The title compound was synthesized by the same method as in Example 78 from an intermediate obtained by using the material obtained from Example 121-1 as a starting material and changing 4-chlorotetrahydropyran to tert-butyl (3R)-3-methylsulfonyloxypyrrolidine-1-carboxylate in Example 64.

[0962] 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).

[0963]

[0964] 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

[0965]

[0966]

[0967] 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 2 hydrochloride

[0968] The title compound was synthesized by the same method as in Examples 77 and 78-1, using the material obtained from Example 121-1 as a starting material.

[0969]

[0970] 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

[0971] The material obtained from Example 125-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 87.

[0972] 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).

[0973]

[0974] 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

[0975]

[0976]

[0977] The material obtained from Example 125-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 87, except that paraformaldehyde was changed to acetaldehyde.

[0978] 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).

[0979]

[0980] 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

[0981]

[0982]

[0983] The material obtained from Example 125-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 87, except that paraformaldehyde was changed to cyclobutanone.

[0984] 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).

[0985]

[0986] 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

[0987]

[0988]

[0989] The material obtained from Example 125-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 87, except that paraformaldehyde was changed to tetrahydrofuran-3-one.

[0990] 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).

[0991]

[0992] 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

[0993]

[0994]

[0995] The material obtained from Example 125-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 87, except that paraformaldehyde was changed to oxetan-3-one.

[0996] 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).

[0997]

[0998] 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

[0999]

[1000]

[1001] The material obtained from Example 121-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 68.

[1002] 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, 4.5 Hz, 2H), 3.42 (ddd,J= 21.1, 15.3, 6.7 Hz, 2H), 3.17 (dt,J= 10.1, 4.3 Hz, 1H), 2.99 - 2.87 (m, 5H), 2.87 - 2.81 (m, 3H), 2.67 (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).

[1003]

[1004] 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

[1005]

[1006]

[1007] The material obtained from Example 121-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 106.

[1008] 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).

[1009]

[1010] 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

[1011]

[1012]

[1013] The material obtained from Example 121-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 98.

[1014] 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).

[1015]

[1016] 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

[1017]

[1018]

[1019] The material obtained from Example 121-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 107.

[1020] 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).

[1021]

[1022] 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

[1023]

[1024]

[1025] The material obtained from Example 121-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 56-2, except that 3-(chloromethyl)pyridine hydrochloride was changed to (3-fluoro-4-pyridyl)methyl methanesulfonate.

[1026] 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).

[1027]

[1028] 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; 2 hydrochloride

[1029]

[1030]

[1031] Using the material obtained from Example 121-1 as a starting material, a Boc-substituted intermediate was synthesized by the same method as in Example 64, but replacing 4-chlorotetrahydropyran with tert-butyl 3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate. The obtained intermediate was dissolved in methanol, and a 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added. The mixture was stirred at room temperature until the reaction was complete, diluted with ethyldiethyl ether, and filtered to obtain the title compound in the form of a dihydrochloride salt as a white solid.

[1032] 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).

[1033]

[1034] 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

[1035]

[1036]

[1037] The material obtained from Example 135 was used as a starting material, and the title compound was synthesized by the same method as in Example 87, except that paraformaldehyde was changed to acetaldehyde.

[1038] 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).

[1039]

[1040] 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

[1041]

[1042]

[1043] 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 2 hydrochloride

[1044] Using the material obtained from Example 121-1 as a starting material, and changing 4-chlorotetrahydropyran to tert-butyl 3-methylsulfonyloxy-8-azabicyclo [3.2.1]octane-8-carboxylate in Example 64, a Boc-substituted intermediate was synthesized by the same method. The obtained intermediate was dissolved in methanol, and a 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added. The mixture was stirred at room temperature until the reaction was complete, diluted with ethyldiethyl ether, and filtered to synthesize the title compound in the form of a dihydrochloride salt as a white solid.

[1045]

[1046] 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

[1047] The title compound was synthesized by the same method as in Example 87, using the material obtained from Example 137-1 as a starting material and changing paraformaldehyde to acetaldehyde.

[1048] 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).

[1049]

[1050] 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; 2 hydrochloride

[1051]

[1052]

[1053] Using the material obtained from Example 121-1 as a starting material, a Boc-substituted intermediate was synthesized by the same method as in Example 64, except that 4-chlorotetrahydropyran was replaced with tert-butyl 2-methyl-4-methylsulfonyloxy-piperidine-1-carboxylate. The obtained intermediate was dissolved in methanol, and a 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added. The mixture was stirred at room temperature until the reaction was complete, diluted with ethyldiethyl ether, and filtered to obtain the title compound in the form of a dihydrochloride salt as a white solid.

[1054] 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).

[1055]

[1056] 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

[1057]

[1058]

[1059] The material obtained from Example 121-1 was used as a starting material, and the title compound was synthesized by the same method as in Example 56-2 by changing 3-(chloromethyl)pyridine hydrochloride to (5-fluoro-2-pyridyl)methyl methanesulfonate.

[1060] 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).

[1061]

[1062] 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 2 hydrochloride

[1063]

[1064]

[1065] Example 140-1: Synthesis of methyl 4-bromo-2-[2-(tert-butoxycarbonylamino)propoxy]benzoate

[1066] Methyl 4-bromo-2-hydroxy-benzoate (3 g, 12.98 mmol), Cs2CO3 (12.7 g, 51.95 mmol), and [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate (7 mL, 25.98 mmol) were dissolved in acetonitrile and heated to reflux with stirring for one day. The reaction solution was cooled to room temperature, distilled water was added, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and purified by flash chromatography to obtain the title compound.

[1067]

[1068] Example 140-2: Synthesis of methyl 2-(2-aminopropoxy)-4-bromo-benzoate hydrochloride

[1069] The material obtained from Example 140-1 was used as a starting material, dissolved in methanol, and then 4 N HCl dissolved in 1,4-dioxane was added, followed by stirring at room temperature. The reaction solution was concentrated under reduced pressure, and the title compound was obtained without further purification.

[1070]

[1071] Example 140-3: Synthesis of 8-bromo-2-methyl-3,4-dihydro-2H-1,4-benzoxazepin-5-one

[1072] The material obtained from 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 heated to reflux with stirring, and after confirming that the reaction was complete, 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.

[1073]

[1074] 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

[1075] The title compound was synthesized using the same method as in Example 5, using the material obtained from Example 140-3 as a starting material.

[1076]

[1077] 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

[1078] The title compound was synthesized by the same method as in Example 56-1 using the material obtained from Example 140-4 as a starting material.

[1079]

[1080] 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 2 hydrochloride

[1081] The title material was synthesized using the material obtained from Example 140-5 as a starting material by the same method as in Examples 77 and 78-1.

[1082] 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).

[1083]

[1084] 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

[1085]

[1086]

[1087] The material obtained from Example 140 was used as a starting material and the title material was synthesized by the same method as in Example 87.

[1088] 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).

[1089]

[1090] Example 142: Synthesis of (2R)-8-(1-acetyazetidin-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

[1091]

[1092]

[1093] The title compound was synthesized by the same method as in Example 83 from the starting material synthesized by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate.

[1094] 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).

[1095]

[1096] 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

[1097]

[1098]

[1099] The title compound was synthesized by the same method as in Example 141 from the starting material synthesized by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate.

[1100] 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).

[1101]

[1102] 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

[1103]

[1104]

[1105] Example 144-1: Synthesis of 2,6-dichloro-N-(2-hydroxypropyl)-N-[(4-methoxyphenyl)methyl]pyridine-3-carboxamide

[1106] 2,6-Dichloropyridine-3-carboxylic acid (5.0 g, 26 mmol) was dissolved in dichloromethane, and oxalic chloride (3.3 mL, 39 mmol) and a catalytic amount of dimethylformamide were added. The reaction solution was stirred at room temperature, concentrated under reduced pressure, and 2,6-dichloropyridine-3-carbonyl chloride was obtained 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, water was added to terminate the reaction, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (2.64 g) as a sticky liquid.

[1107]

[1108] Example 144-2: Synthesis of 8-chloro-4-[(4-methoxyphenyl)methyl]-2-methyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one

[1109] 2,6-Dichloro-N-(2-hydroxypropyl)-N-[(4-methoxyphenyl)methyl]pyridine-3-carboxamide (2.64 g) obtained from 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 gradually warmed to room temperature and stirred until the starting material completely disappeared, and methanol was added to terminate the reaction. A saturated aqueous sodium chloride solution was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The reaction concentrate was purified by flash chromatography to obtain the title compound (1.35 g) as a sticky liquid.

[1110]

[1111] 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

[1112] The material obtained from 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 60 o The mixture was stirred at C for one day. The reaction solution was extracted with saturated aqueous sodium chloride solution and ethyl acetate, and purified by flash chromatography to obtain the title compound (540 mg).

[1113]

[1114] Example 144-4: Synthesis of 2-methyl-8-(4-piperidyloxy)-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-5-one

[1115] The material obtained from Example 144-3 (540 mg) was dissolved in 4 mL of trifluoroacetic acid and heated at 120° C. using a microwave. o The reaction was carried out at C for 30 minutes. The reaction solution was diluted with ethyl acetate in an ice bath and alkalized with aqueous K2CO3 solution. The reaction mixture was washed three times with ethyl acetate, and the aqueous layer was alkalized to a pH of 9 or higher by adding KOH, and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the title compound.

[1116]

[1117] 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

[1118] The title compound was obtained by the same method as in Example 87 using the material obtained from Example 144-4 as a starting material.

[1119]

[1120] 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

[1121] The title substance was synthesized by the same method as Example 5 using the material obtained from Example 144-5 as a starting material.

[1122] 1 H NMR (400 MHz, Methanol-d4) (diastereomeric 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).

[1123]

[1124] 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

[1125]

[1126]

[1127] In Example 144, the title compound was synthesized by the same method by changing 1-[(4-methoxyphenyl)methylamino]propan-2-ol to 1-[(4-methoxyphenyl)methylamino]-2-methyl-propan-2-ol.

[1128] 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).

[1129]

[1130] 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

[1131]

[1132]

[1133] The title compound was synthesized by the same method as in Example 141 from the starting material synthesized by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 to [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate.

[1134] 1H 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).

[1135]

[1136] Example 147: Synthesis of 4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[1137]

[1138]

[1139] Example 147-1: Synthesis of 3,4-dihydro-2H-1,4-benzoxazepin-5-one

[1140] 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 stirred for 12 hours while slowly warming to room temperature. While maintaining the temperature at 0°C in an ice bath, 1 molar aqueous sodium hydroxide solution was slowly added. The reaction solution was alkalized until the pH became 10 or higher, and then extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was removed by evaporation under reduced pressure, and recrystallized from dichloromethane and hexane to synthesize the title compound as a white solid.

[1141]

[1142] Example 147-2: Synthesis of 4-(oxiran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[1143] 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, then epibromohydrin (0.1 mL, 1.2 mmol) was slowly added, and the mixture was stirred 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 a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the obtained title compound was used in the next reaction without further purification.

[1144]

[1145] 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

[1146] Tetrahydroisoquinoline (0.13 mL, 1.0 mmol) was added to an isopropanol solution containing 4-(oxiran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 147-2, and the mixture was stirred at 80°C for 12 hours. The temperature was lowered to room temperature, and the solvent was concentrated. The obtained oily liquid was purified by flash chromatography to synthesize a transparent, sticky solid compound. The NMR data for the synthesized title compound are as follows.

[1147] 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).

[1148]

[1149] Example 148: Synthesis of 2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one

[1150]

[1151]

[1152] The title compound was synthesized by the same method as in Example 147, using tetralin-1-one (1.9 g, 14 mmol) as the starting material and changing the concentrated sulfuric acid in Example 147-1 to a 35% aqueous hydrochloric acid solution (30 mL).

[1153] 1H 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).

[1154]

[1155] 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

[1156]

[1157]

[1158] Example 149-1: Synthesis of 4-[[(2R)-oxiran-2-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[1159] 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, and the mixture was stirred 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 a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the obtained title compound was used in the next reaction without further purification.

[1160]

[1161] 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

[1162] The title compound was synthesized using 4-[[(2R)-oxiran-2-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one obtained in Example 149-1 by the same method as in Example 147-3.

[1163] 1H 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).

[1164]

[1165] 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

[1166]

[1167]

[1168] The title compound was synthesized using 7-fluorochroman-4-one as a starting material and by the same method as in Example 147-1 and Example 149.

[1169] 1H 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).

[1170]

[1171] 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

[1172]

[1173]

[1174] The title compound was synthesized using 7-bromochroman-4-one as the starting material and by the same method as in Example 147-1 and Example 149.

[1175] 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).

[1176]

[1177] 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

[1178]

[1179]

[1180] Example 152-1: Synthesis of methyl 3-[2-(benzyloxycarbonylamino)ethoxy]pyridine-4-carboxylate

[1181] Methyl 3-hydroxypyridine-4-carboxylate (1.0 g, 6.53 mmol), benzyl N-(2-hydroxyethyl)carbamate (1.53 g, 7.84 mmol), and triphenylphosphine (2.06 g) were dissolved in tetrahydrofuran, and diisopropyl azodicarboxylate was slowly added at 0°C. The reaction solution was stirred at room temperature for 12 hours, and the solvent was removed under reduced pressure. The concentrate was purified by flash chromatography under solvent conditions of hexane and ethyl acetate to synthesize the title compound.

[1182]

[1183] Example 152-2: Synthesis of 3,4-dihydro-2H-pyrido[4,3-f][1,4]oxazepin-5-one

[1184] Methyl 3-[2-(benzyloxycarbonylamino)ethoxy]pyridine-4-carboxylate obtained from Example 152-1 was dissolved in ethanol at room temperature, 5% palladium-charcoal was added, and the mixture was stirred under a hydrogen balloon for 24 hours. The reaction solution was filtered using Celite and washed with ethanol. The obtained solution was concentrated under reduced pressure and purified by flash chromatography to synthesize 548 mg of the title compound as a white crystalline solid.

[1185]

[1186] 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

[1187] The title compound was synthesized by the same method as in Example 149 using 3,4-dihydro-2H-pyrido[4,3-f][1,4]oxazepin-5-one obtained from Example 152-2 as a starting material.

[1188] 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).

[1189]

[1190] 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

[1191]

[1192]

[1193] The title compound was synthesized using 8-chloro-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-5-one as the starting material by the same method as in Example 149.

[1194] 1H 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).

[1195]

[1196] 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

[1197]

[1198]

[1199] The title compound was synthesized using 7-chloro-2,3,4,5-tetrahydro-2-benzazepin-1-one as the starting material and by the same method as in Example 149.

[1200] 1H 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).

[1201]

[1202] 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

[1203]

[1204]

[1205] The title compound was synthesized using 7-bromo-2,3,4,5-tetrahydro-2-benzazepin-1-one as the starting material and the same method as in Example 149.

[1206] 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).

[1207]

[1208] 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

[1209]

[1210]

[1211] Example 156-1: Synthesis of 8-bromo-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione

[1212] 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 re-dissolved in 3 L of acetic acid, and the mixture was stirred at 140°C for 8 hours. The reaction solution was diluted with petroleum ether and filtered to obtain the title compound (866 g, 74.7%) as a white solid.

[1213]

[1214] Example 156-2: Synthesis of 8-bromo-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-one

[1215] 8-Bromo-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (200 g, 784 mmol) obtained from Example 156-1 was dissolved in 4 L of tetrahydrofuran, and LAH (50.6 g, 1.33 mol) was slowly added at 0℃. The reaction solution was stirred at 70℃ for 3 hours, and after cooling, 100 mL of distilled water, 100 mL of 15% sodium hydroxide aqueous solution, and 100 mL of distilled water were slowly added to terminate the reaction. The mixture was dried over anhydrous sodium sulfate, filtered over hot tetrahydrofuran, and the solvent was removed under reduced pressure. 500 mL of ethyl acetate was added and recrystallized to obtain the title compound (177 g, 46.8%) as a white solid.

[1216]

[1217] Example 156-3: Synthesis of 8-bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one

[1218] 8-Bromo-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-one (177 g, 734 mmol) obtained from 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, and the reaction solution was diluted to 50 o The mixture was stirred at C for 1 hour. Sodium cyanoborohydride (231 g, 3.67 mol) was added to the reaction solution, stirred at 50°C for 4 hours, and concentrated by removing the solvent under reduced pressure. The mixture was diluted with 4 L of distilled water and extracted twice with dichloromethane. The combined organic layers were washed twice with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was recrystallized by adding methanol to obtain the title compound as a white solid in a yield of 78%.

[1219]

[1220] 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

[1221] The title compound was synthesized using 8-bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one obtained from Example 156-3 as a starting material by the same method as Example 149.

[1222] 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).

[1223]

[1224] 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

[1225]

[1226]

[1227] Example 157-1: Synthesis of 8-bromo-1-ethyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one

[1228] 8-Bromo-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-one (100 mg, 0.41 mmol) and potassium carbonate (170 mg, 1.23 mmol) obtained from Example 156-2 were dissolved in dimethylformamide, iodoethane (0.07 mL, 0.82 mmol) was added, and the reaction solution was stirred at 60o The mixture was stirred at C for one day. The reaction mixture was cooled to room temperature, diluted with distilled water, and extracted three times with ethyl acetate. The combined organic layers were washed twice with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography to obtain the title compound as a solid.

[1229]

[1230] 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

[1231]

[1232] *The title compound was synthesized using the material obtained from Example 157-1 as a starting material by the same method as Example 149.

[1233] 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).

[1234]

[1235] 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

[1236]

[1237]

[1238] Example 158-1: Synthesis of 8-bromo-1-ethyl-3,4-dihydro-1,4-benzodiazepine-2,5-dione

[1239] 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 under reflux for 4 hours. The reaction mixture was cooled to room temperature, diluted with distilled water, and filtered. The obtained solid was washed with diethyl ether, and 100 mg of the title compound as a white solid was synthesized without further purification.

[1240]

[1241] 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

[1242] The title compound was synthesized using the material obtained from Example 158-1 as a starting material by the same method as Example 149.

[1243] 1 H 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).

[1244]

[1245] 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

[1246]

[1247]

[1248] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one 2 hydrochloride obtained from Example 78-1 was dissolved in acetonitrile, potassium carbonate and 2-bromoacetonitrile were added, and the mixture was stirred at 90° C. for 1 hour. o The mixture was stirred at C. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the oily liquid was purified by flash chromatography to synthesize the title compound as a white solid.

[1249] 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).

[1250]

[1251] 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

[1252]

[1253]

[1254] The title compound was synthesized by the same method as in Example 78-2, except that acetic anhydride was changed to difluoro-acetic anhydride.

[1255] 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).

[1256]

[1257] 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

[1258]

[1259]

[1260] The title compound was synthesized by the same method 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 from Example 83-1 as a starting material.

[1261] 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).

[1262]

[1263] 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

[1264]

[1265]

[1266] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one 2 hydrochloride (100 mg, 0.19 mmol) synthesized 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 synthesize the title compound.

[1267] 1H 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).

[1268]

[1269] 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

[1270]

[1271]

[1272] In Example 162, the title compound was synthesized by the same method at 90°C after changing 2-iodoethanol to 2-fluoroethyl 4-methylbenzenesulfonate.

[1273] 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).

[1274]

[1275] 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

[1276]

[1277]

[1278] The title compound was synthesized by the same method 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 2 hydrochloride as the starting material in Example 163.

[1279] 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).

[1280]

[1281] 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

[1282]

[1283]

[1284] 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), cesium carbonate (288 mg, 0.886 mmol), 3-(bromomethyl)-3-methyl-oxetane (110 mg, 0.665 mmol) obtained from Example 78-1 were dissolved in dimethylformamide and 60 o The mixture was heated and stirred at C. After completion of the reaction, the reaction solution was extracted with saturated aqueous sodium chloride solution and ethyl acetate, and purified by flash chromatography to obtain the title compound (6 mg).

[1285] 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).

[1286]

[1287] Example 166: Synthesis of 4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoazepin-8-yl]oxy]piperidine-1-carbonitrile

[1288]

[1289]

[1290] 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), cyanogen bromide (94 mg, 0.886 mmol), and cesium carbonate (433 mg, 1.329 mmol) obtained from Example 78-1 were dissolved in dimethylformamide and heated at 70° C. using a microwave. oThe reaction was carried out for 3 hours at C. After completion of the reaction, the reaction solution was extracted with saturated sodium chloride aqueous solution and ethyl acetate, and purified by flash chromatography to obtain the title compound (14 mg).

[1291] 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).

[1292]

[1293] 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

[1294]

[1295]

[1296] 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; 2 hydrochloride

[1297] The title compound was synthesized 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 by the same method as in Examples 54-1 and 54-2.

[1298]

[1299] 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

[1300] The title compound was synthesized by the same method as in Example 78-2 using the material obtained from Example 167-1 as a starting material.

[1301] 1 H 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).

[1302]

[1303] 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

[1304]

[1305]

[1306] 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 2 hydrochloride

[1307] The title compound was synthesized 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 by the same method as in Example 83-1.

[1308]

[1309] Example 168-2: 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

[1310] The material obtained from Example 168-1 (105 mg, 0.2 mmol) was dissolved in 2 mL of acetonitrile. To this solution, formic acid (38 μL, 1.0 mmol), triethylamine (0.17 mL, 1.2 mL), and HATU (114 mg, 0.3 mmol) were added, and the mixture was stirred at room temperature. After confirming that the reaction was complete, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by flash chromatography to synthesize the title compound.

[1311] 1H 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).

[1312]

[1313] 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

[1314]

[1315]

[1316] The title compound was synthesized by the same method as in Example 168-2 using the material obtained from Example 167-1 as a starting material.

[1317] 1H 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).

[1318]

[1319] 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

[1320]

[1321]

[1322] The title compound was synthesized 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 by the same method as in Example 28.

[1323] 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).

[1324]

[1325] 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

[1326]

[1327]

[1328] 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 2 hydrochloride

[1329] In Example 64, 4-chlorotetrahydropyran was replaced with tert-butyl 3-methylsulfonyloxy-8-azabicyclo[3.2.1]octane-8-carboxylate, and an intermediate was synthesized by the same method. The obtained intermediate was used as a starting material, and the title compound was synthesized by the same method as in Example 78-1.

[1330]

[1331] 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

[1332] The material obtained from Example 171-1 was used as a starting material and the title compound was synthesized by the same method as in Example 88.

[1333] 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).

[1334]

[1335] 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

[1336]

[1337]

[1338] 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 2 hydrochloride

[1339] In Example 64, 4-chlorotetrahydropyran was replaced with tert-butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate, and an intermediate was synthesized by the same method. The obtained intermediate was used as a starting material, and the title compound was synthesized by the same method as in Example 78-1.

[1340]

[1341] 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

[1342] The material obtained from Example 172-1 was used as a starting material and the title compound was synthesized by the same method as in Example 88.

[1343] 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).

[1344]

[1345] 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

[1346]

[1347]

[1348] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 171-1 as a starting material.

[1349] 1H 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).

[1350]

[1351] 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

[1352]

[1353]

[1354] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 172-1 as a starting material.

[1355] 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, 2.3 Hz, 3H).

[1356]

[1357] 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

[1358]

[1359]

[1360] 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

[1361] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one (1.0 equiv), hexacarbonylmolybdenum (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 h. 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 synthesize the title compound.

[1362]

[1363] 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

[1364] Methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxylate (1.0 equiv), pyrrolidine (5.0 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1 mL) obtained from Example 175-1 were mixed, and 120 o C was heated overnight. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, and purified by flash chromatography to synthesize the title compound.

[1365] 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 = 7.3 Hz, 3H), 2.90 - 2.65 (m, 4H), 2.54 (d, J = 5.9 Hz, 2H), 1.84 (dp, J = 33.2, 6.7 Hz, 4H).

[1366]

[1367] 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

[1368]

[1369]

[1370] In Example 175-2, pyrrolidine was changed to piperidine and the title compound was synthesized by the same method.

[1371] 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).

[1372]

[1373] 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

[1374]

[1375]

[1376] In Example 175-2, pyrrolidine was changed to 3,3-difluoropyrrolidine and the title compound was synthesized by the same method.

[1377] 1 H 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).

[1378]

[1379] 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

[1380]

[1381]

[1382] In Example 175-2, pyrrolidine was changed to 1-methylpiperazine and the title compound was synthesized by the same method.

[1383] 1 H 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).

[1384]

[1385] 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

[1386]

[1387]

[1388] The title compound was synthesized 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 by the same method as in Example 24.

[1389] 1 H 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).

[1390]

[1391] 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

[1392]

[1393]

[1394] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 110-5 as a starting material.

[1395] 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).

[1396]

[1397] 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

[1398]

[1399]

[1400] The starting material obtained from Example 110-5 was used and the title compound was synthesized by the same method as in Example 78-2, except that acetic anhydride was changed to formic acid.

[1401] 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).

[1402]

[1403] 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

[1404]

[1405]

[1406] The title compound was synthesized by the same method as in Example 92 using the material obtained from Example 167-1 as a starting material.

[1407] 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).

[1408]

[1409] 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

[1410]

[1411]

[1412] The title compound was synthesized by the same method as in Example 29 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 and replacing 3-methoxyazetidine hydrochloride with 2-oxa-7-azaspiro[3.4]octane.

[1413] 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).

[1414]

[1415] 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

[1416]

[1417]

[1418] In Example 175-2, pyrrolidine was changed to 4-fluoropiperidine and the title compound was synthesized by the same method.

[1419] 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).

[1420]

[1421] 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

[1422]

[1423]

[1424] In Example 175-2, pyrrolidine was changed to 3-trifluoromethylpiperidine and the title compound was synthesized by the same method.

[1425] 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).

[1426]

[1427] 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

[1428]

[1429]

[1430] In Example 175-2, pyrrolidine was changed to 4-trifluoromethylpiperidine and the title compound was synthesized by the same method.

[1431] 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).

[1432]

[1433] 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

[1434]

[1435]

[1436] Dissolve 2,6-dimethylmorpholine (33 μL, 1.1 equiv) in 1,4-dioxane (1 mL) and 0 o At C, 2M trimethylaluminum toluene solution (134 μL, 1.1 equiv) was added under nitrogen conditions. The reaction mixture was stirred at room temperature for 1 hour, and methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxylate (100 mg) dissolved in 1,4-dioxane was added. The reaction solution was stirred at 110 for 3 hours. oThe mixture was stirred at C and the reaction was quenched with a saturated aqueous potassium sodium tartrate solution, then extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and purified by flash chromatography to synthesize the title compound.

[1437] 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).

[1438]

[1439] 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

[1440]

[1441]

[1442] In Example 187, 2,6-dimethylmorpholine was changed to 2-azabicyclo[2.2.1]heptane and the title compound was synthesized by the same method.

[1443] 1H 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).

[1444]

[1445] 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

[1446]

[1447]

[1448] In Example 187, 2,6-dimethylmorpholine was changed to 3-oxa-8-azabicyclo[3.2.1]octane and the title compound was synthesized by the same method.

[1449] 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).

[1450]

[1451] 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

[1452]

[1453]

[1454] In Example 187, 2,6-dimethylmorpholine was changed to 2-methylmorpholine and the title compound was synthesized by the same method.

[1455] 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).

[1456]

[1457] 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

[1458]

[1459]

[1460] In Example 187, 2,6-dimethylmorpholine was changed to 3-methylmorpholine and the title compound was synthesized by the same method.

[1461] 1 H 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).

[1462]

[1463] 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

[1464]

[1465]

[1466] The title compound was synthesized by the same method as 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 the starting material.

[1467] 1 H 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).

[1468]

[1469] 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

[1470]

[1471]

[1472] 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

[1473] Methyl 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxylate and potassium trimethylsilanolate were dissolved in tetrahydrofuran and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and used in the next reaction without further purification.

[1474]

[1475] 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

[1476] The starting material obtained from Example 193-1 (100 mg, 1.0 equiv), octahydrocyclopenta[c]pyrrole (1.5 equiv), HATU (131 mg, 1.5 equiv), and diisopropylethylamine (120 uL, 3 equiv) were dissolved in methylene chloride and stirred at room temperature for 2 hours. The reaction solution was extracted with methylene chloride, dried over magnesium sulfate, and purified by flash chromatography to synthesize the title compound.

[1477] 1H 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).

[1478]

[1479] 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

[1480]

[1481]

[1482] In Example 193-2, the title compound was synthesized by the same method by changing octahydrocyclopenta[c]pyrrole to 3-fluoropiperidine.

[1483] 1H 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).

[1484]

[1485] 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

[1486]

[1487]

[1488] In Example 193-2, the title compound was synthesized by the same method by changing octahydrocyclopenta[c]pyrrole to 2,2-difluoromorpholine.

[1489] 1H 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).

[1490]

[1491] 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

[1492]

[1493]

[1494] In Example 193-2, the title compound was synthesized by the same method by changing octahydrocyclopenta[c]pyrrole to 4,4-difluoropiperidine.

[1495] 1 H 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).

[1496]

[1497] 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

[1498]

[1499]

[1500] The title compound was synthesized by the same method as 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 the starting material.

[1501] 1 H 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).

[1502]

[1503] 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

[1504]

[1505]

[1506] 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

[1507] In Example 64, the title compound was synthesized by the same method as in Example 64, by changing 4-chlorotetrahydropyran to [4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl] methanesulfonate, potassium carbonate to cesium carbonate, and dimethylformamide to acetonitrile.

[1508]

[1509] 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 2 hydrochloride

[1510] 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 from Example 198-1 was dissolved in methanol, and a 4 M hydrochloric acid solution dissolved 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.

[1511]

[1512] 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

[1513] The title compound was synthesized by the same method as in Example 87 using 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-(methylamino)cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2 hydrochloride obtained from Example 198-2 as a starting material and changing paraformaldehyde to oxetan-3-one.

[1514] 1 H 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).

[1515]

[1516] 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

[1517]

[1518]

[1519] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-(methylamino)cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2 hydrochloride (200 mg, 0.362 mmol), potassium carbonate (150 mg, 1.086 mmol) and 2-fluoroethyl 4-methylbenzenesulfonate (93 μl, 0.543 mmol) obtained from Example 198-2 were dissolved in acetonitrile and 100 o The mixture was stirred at C for one day. A saturated aqueous solution of ammonium chloride 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, concentrated under reduced pressure, and the oily liquid was purified by flash chromatography to synthesize the title compound (45 mg).

[1520] 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).

[1521]

[1522] 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

[1523]

[1524]

[1525] 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 2 hydrochloride

[1526] The title compound was synthesized by the method of Example 78-1 from the starting material synthesized by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 to [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate.

[1527]

[1528] 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

[1529] The title compound was synthesized using the material obtained from Example 200-1 as a starting material in the same manner as in Example 78-2.

[1530]

[1531] 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

[1532]

[1533] The material obtained from Example 200-2 was used as a starting material, dissolved in tetrahydrofuran, and then Laweson's reagent was added and stirred at 50°C until the reaction was complete. The reaction solution was cooled to room temperature, distilled water was added, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and purified by flash chromatography to obtain the title compound.

[1534] 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).

[1535]

[1536] 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

[1537]

[1538]

[1539] 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 2 hydrochloride

[1540] In Example 140, [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate was changed to [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate, and the starting material synthesized in the same manner as in Example 140-5 was used, and in Example 64, 4-chlorotetrahydropyran was changed to tert-butyl 3-hydroxyazetidine-1-carboxylate, and the Boc-substituted intermediate was synthesized in the same manner. The obtained intermediate was dissolved in methanol, and a 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added. The mixture was stirred at room temperature until the reaction was complete, diluted with ethyldiethyl ether, and filtered to synthesize the title compound in the form of dihydrochloride as a white solid.

[1541]

[1542] 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

[1543] Using Example 201-1 as a starting material, 2-fluoroethyl para-toluenesulfonate and potassium carbonate were dissolved in acetonitrile and the reaction solution was stirred at 60 o The mixture was stirred at C for one day. The reaction mixture was cooled to room temperature, diluted with distilled water, and extracted three times with ethyl acetate. The combined organic layers were washed twice with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography to obtain the title compound as a solid.

[1544] 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).

[1545]

[1546] 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

[1547]

[1548]

[1549] The title compound was synthesized using the starting material obtained by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 to [(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate, and the same method as in Example 163.

[1550] 1H 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).

[1551]

[1552] 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

[1553]

[1554]

[1555] The title compound was synthesized by the same method as in Example 193-2 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 and changing octahydrocyclopenta[c]pyrrole to 3-oxa-8-azabicyclo[3.2.1]octane.

[1556] 1H 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).

[1557]

[1558] 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

[1559]

[1560]

[1561] The title compound was synthesized by the same method as in Example 193-2 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 and changing octahydrocyclopenta[c]pyrrole to 2-oxa-5-azabicyclo[2.2.1]heptane.

[1562] 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).

[1563]

[1564] 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

[1565]

[1566]

[1567] The title compound was synthesized by the same method as in Example 193-2 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 and changing octahydrocyclopenta[c]pyrrole to 3,5-dimethylmorpholine.

[1568] 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).

[1569]

[1570] 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

[1571]

[1572]

[1573] 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

[1574] In Example 64, the title compound was synthesized by the same method as in Example 64, except that 4-chlorotetrahydropyran was replaced with tert-butyl 3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate, potassium carbonate was replaced with cesium carbonate, and dimethylformamide was replaced with acetonitrile.

[1575]

[1576] 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 2 hydrochloride

[1577] 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 from Example 206-1 was dissolved in methanol, and a 4 M hydrochloric acid solution dissolved 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.

[1578]

[1579] 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

[1580] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 206-2 as a starting material.

[1581] 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).

[1582]

[1583] 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

[1584]

[1585]

[1586] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 206-2 as a starting material.

[1587] 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).

[1588]

[1589] 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

[1590]

[1591]

[1592] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 206-2 as a starting material.

[1593] 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).

[1594]

[1595] 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

[1596]

[1597]

[1598] The title compound was synthesized by the same method as in Example 193-2 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 and changing octahydrocyclopenta[c]pyrrole to 1,2,3,4-tetrahydropyrrole[1,2-a]pyrazine.

[1599] 1H 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).

[1600]

[1601] 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

[1602]

[1603]

[1604] The title compound was synthesized by the same method as in Example 193-2 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 and changing octahydrocyclopenta[c]pyrrole to 1,2,3,4,6,7,8,8a-octahydropyrrole[1,2-a]pyrazine.

[1605] 1H NMR (400 MHz, Methanol-d4δ 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).

[1606]

[1607] 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

[1608]

[1609]

[1610] 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-one (1.0 equiv), 2-chloro-5-fluoropyrimidine (1.5 equiv), and cesium carbonate (2 equiv) were dissolved in acetonitrile and heated to reflux overnight. The reaction solution was extracted with ethyl acetate, and the separated organic layer was dried over magnesium sulfate, concentrated, and purified by flash chromatography to synthesize the title compound.

[1611] 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).

[1612]

[1613] 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

[1614]

[1615]

[1616] 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 from Example 78-1 was dissolved in a mixture 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, concentrated under reduced pressure, and the oily liquid was purified by flash chromatography to synthesize the title compound as a white solid.

[1617] 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).

[1618]

[1619] 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

[1620]

[1621]

[1622] 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 2 hydrochloride

[1623] In Example 64, 4-chlorotetrahydropyran was changed to tert-butyl (S)-3-methylsulfonyloxypiperidine-1-carboxylate, and then synthesized by the same method, followed by the synthesis of the title compound by the method of Example 78-1.

[1624]

[1625] 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

[1626] The title compound was synthesized by the method of 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 2 hydrochloride obtained in Example 213-1 as a starting material.

[1627] 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).

[1628]

[1629] 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

[1630]

[1631]

[1632] 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

[1633] In Example 193-2, the title compound was synthesized by the same method by changing octahydrocyclopenta[c]pyrrole to N,O-dimethylhydroxyamine hydrochloride.

[1634]

[1635] 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

[1636] 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-carboxamate (700 mg, 1 equiv) 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 h, extracted with ethyl acetate, dried over magnesium sulfate, and purified by flash column chromatography to synthesize the title compound.

[1637] 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).

[1638]

[1639] 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

[1640]

[1641]

[1642] 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 2 hydrochloride

[1643] In Example 64, 4-chlorotetrahydropyran was replaced with tert-butyl 3-methylsulfonyloxy-8-azabicyclo [3.2.1]octane-8-carboxylate, and an intermediate compound was synthesized by the same method. The obtained intermediate compound was dissolved in methanol, and a 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added. The mixture was stirred at room temperature until the reaction was complete, diluted with ethyldiethyl ether, and filtered to synthesize the title compound in the form of a dihydrochloride salt as a white solid.

[1644]

[1645] 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

[1646] The title compound was synthesized 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 2 hydrochloride obtained in Example 215-1 as a starting material.

[1647] 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).

[1648]

[1649] 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

[1650]

[1651]

[1652] In Example 214-2, the title compound was synthesized by the same method by changing ethylmagnesium bromide to cyclopropylmagnesium bromide.

[1653] 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, 3.7 Hz, 2H), 2.71 - 2.66 (m, 1H), 2.59 - 2.45 (m, 2H), 1.07 - 0.92 (m, 4H).

[1654]

[1655] 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

[1656]

[1657]

[1658] In Example 214-2, the title compound was synthesized by the same method by changing ethylmagnesium bromide to cyclopentylmagnesium bromide.

[1659] 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).

[1660]

[1661] 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

[1662]

[1663]

[1664] In Example 64, the title compound was synthesized by the same method after changing 4-chlorotetrahydropyran to [rac-(3R)-1-methyl-3-piperidyl] methanesulfonate.

[1665] 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).

[1666]

[1667] 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

[1668]

[1669]

[1670] The starting material was synthesized by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate, and the title material was synthesized by the same method as Example 162.

[1671] 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).

[1672]

[1673] 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

[1674]

[1675]

[1676] In Example 140, [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate was changed to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate, and the title compound was synthesized by the same method as in Example 212, by changing 2-methyloxirane to 2,2-dimethyloxirane.

[1677] 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).

[1678]

[1679] 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

[1680]

[1681]

[1682] 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

[1683] In Example 214-2, the title compound was synthesized by the same method by changing ethyl magnesium bromide to methyl magnesium bromide.

[1684]

[1685] 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

[1686] 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 equiv), morpholine (66 μL, 3 equiv), sodium cyanoborohydride (48 mg, 3 equiv) and acetic acid (1 drop) were dissolved in 1 mL of methanol and stirred at 80 o The mixture was stirred for 6 hours at C. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, and purified by rapid column chromatography to synthesize the title compound.

[1687] 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).

[1688]

[1689] 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

[1690]

[1691]

[1692] In Example 221-2, morpholine was changed to 2-oxa-6-azaspiro [3.3]heptane and the title compound was synthesized by the same method.

[1693] 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).

[1694]

[1695] Example 223: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxypro-1-phynyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[1696]

[1697]

[1698] 8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one (100 mg, 1.0 equiv), prop-2-pin-1-ol (3 equiv), bis(triphenylphosphine)palladium(II) dichloride (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 for 100 o The mixture was stirred at C for 4 hours. The reaction solution was cooled to room temperature, filtered through Celite, and extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The resulting solution was concentrated under reduced pressure and purified by flash column chromatography to synthesize the title compound.

[1699] 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).

[1700]

[1701] 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

[1702]

[1703]

[1704] In Example 140, [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate was changed to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate, and the title compound was synthesized by the same method as in Example 163, but 2-fluoroethyl para-toluenesulfonate was changed to 1-bromo-2-methoxy-ethane.

[1705] 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).

[1706]

[1707] 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

[1708]

[1709]

[1710] In Example 12, the title compound was synthesized by the same method by changing isobutylboronic acid to 4-pyridylboronic acid.

[1711] 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).

[1712]

[1713] 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

[1714]

[1715]

[1716] In Example 223, pro-2-pin-1-ol was changed to 4-ethynylpyridine and the title compound was synthesized by the same method.

[1717] 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).

[1718]

[1719] 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

[1720]

[1721]

[1722] In Example 223, pro-2-pin-1-ol was changed to 3-ethynylpyridine and the title compound was synthesized by the same method.

[1723] 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).

[1724]

[1725] Example 228: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxybut-1-ethynyl)-2,3-dihydro-1,4-benzoxazepin-5-one

[1726]

[1727]

[1728] In Example 223, pro-2-pin-1-ol was changed to but-3-yn-2-ol and the title compound was synthesized by the same method.

[1729] 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).

[1730]

[1731] Example 229: Synthesis of 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(methylamino)prop-1-phynyl]-2,3-dihydro-1,4-benzoxazepin-5-one

[1732]

[1733]

[1734] In Example 223, pro-2-pin-1-ol was changed to N-methylpro-2-pin-1-amine and the title compound was synthesized by the same method.

[1735] 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).

[1736]

[1737] 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

[1738]

[1739]

[1740] In Example 12, the title compound was synthesized by the same method by changing isobutylboronic acid to 3-pyridylboronic acid.

[1741] 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).

[1742]

[1743] 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

[1744]

[1745]

[1746] In Example 12, the title compound was synthesized by the same method by changing isobutylboronic acid to 1,3-dimethylpyrazolboronic acid.

[1747] 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).

[1748]

[1749] 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

[1750]

[1751]

[1752] In Example 12, the title compound was synthesized by the same method by changing isobutylboronic acid to 1-methylpyrazoleboronic acid.

[1753] 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).

[1754]

[1755] 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

[1756]

[1757]

[1758] In Example 12, the title compound was synthesized by the same method by changing isobutylboronic acid to 1,5-dimethylpyrazolboronic acid.

[1759] 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).

[1760]

[1761] 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

[1762]

[1763]

[1764] The title compound was synthesized by the same method as in 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 2 hydrochloride as the starting material.

[1765] 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).

[1766]

[1767] 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

[1768]

[1769]

[1770] In Example 144-1, 1-[(4-methoxyphenyl)methylamino]propan-2-ol was changed to 1-[(4-methoxyphenyl)methylamino]-2-methyl-propan-2-ol and synthesized using the same method. In Example 144-3, tert-butyl 4-hydroxypiperidine-1-carboxylate was changed to tert-butyl 3-hydroxypiperidine-1-carboxylate and the title compound was synthesized using the same method as in Example 144-6.

[1771] 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).

[1772]

[1773] 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

[1774]

[1775]

[1776] 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; 2 hydrochloride

[1777] In Example 77, tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate was changed to tert-butyl (R)-3-methylsulfonyloxypiperidine-1-carboxylate and synthesized using the same method, and then the title compound was synthesized using the same method as in Example 78-1.

[1778]

[1779] 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

[1780] The title compound was synthesized 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; 2 hydrochloride obtained from Example 236-1 as a starting material.

[1781] 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).

[1782]

[1783] 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

[1784]

[1785]

[1786] The title compound was synthesized 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; 2 hydrochloride obtained from Example 236-1 as a starting material.

[1787] 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).

[1788]

[1789] 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

[1790]

[1791]

[1792] The title compound was synthesized by the same method 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 2 hydrochloride obtained from Example 78-1 as a starting material.

[1793] 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).

[1794]

[1795] 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

[1796]

[1797]

[1798] In Example 12, the title compound was synthesized by the same method by changing isobutylboronic acid to 6-fluoro-2-pyridylboronic acid.

[1799] 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).

[1800]

[1801] 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

[1802]

[1803]

[1804] In Example 140, [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate was changed to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate, and the title compound was synthesized using the same method as in Example 163, except that 2-fluoroethyl para-toluenesulfonate was changed to 1-bromo-2-ethoxy-ethane.

[1805] 1H 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).

[1806]

[1807] 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

[1808]

[1809]

[1810] 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 2 hydrochloride

[1811] In Example 140, [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate was changed to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate as a starting material, and in Example 64, 4-chlorotetrahydropyran was changed to tert-butyl 3-methylsulfonyloxy-8-azabicyclo [3.2.1]octane-8-carboxylate to synthesize a Boc-substituted intermediate by the same method. The obtained intermediate was dissolved in methanol, and a 4 N hydrochloric acid solution dissolved in 1,4-dioxane was added. The mixture was stirred at room temperature until the reaction was complete, diluted with ethyldiethyl ether, and filtered to synthesize the title compound in the form of dihydrochloride as a white solid.

[1812]

[1813] 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

[1814] The title compound was synthesized 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 2 hydrochloride obtained in Example 241-1 as a starting material.

[1815] 1H 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).

[1816]

[1817] 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

[1818]

[1819]

[1820] The title compound was synthesized 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 2 hydrochloride obtained in Example 241-1 as a starting material.

[1821] 1H 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 = 6.4 Hz, 3H).

[1822]

[1823] 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

[1824]

[1825]

[1826] The title compound was synthesized 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 2 hydrochloride obtained in Example 78-1 as a starting material in the same manner as in Example 224.

[1827] 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).

[1828]

[1829] 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

[1830]

[1831]

[1832] In Example 12, the title compound was synthesized by the same method by changing isobutylboronic acid to 6-methoxy-2-pyridylboronic acid.

[1833] 1H 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).

[1834]

[1835] 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

[1836]

[1837]

[1838] The title compound was synthesized using the starting material synthesized by changing [2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate in Example 140 to [(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl] methanesulfonate, and the same method as Example 212.

[1839] 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).

[1840]

[1841] 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

[1842]

[1843]

[1844] 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

[1845] 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 (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 reacted in a microwave at 120°C for 2 h. Concentrated aqueous hydrochloric acid and 1,4-dioxane were added to the reaction solution, and the mixture was 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 synthesize the title compound.

[1846]

[1847] 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

[1848] The title compound was synthesized by the same method 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 from Example 246-1 as a starting material.

[1849] 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).

[1850]

[1851] 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

[1852]

[1853]

[1854] The title compound was synthesized by the same method 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 from Example 246-1 as a starting material.

[1855] 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).

[1856]

[1857] 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

[1858]

[1859]

[1860] The title compound was synthesized 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 2 hydrochloride as a starting material by the same method as in Example 212.

[1861] 1H NMR (400 MHz, Methanol-d4) δ 8.04 (d, J = 8.4 Hz, 1H), 7.15 - 7.02 (m, 4H), 6.60 (d, J = 8.4 Hz, 1H), 5.07 (s, 1H), 4.26 (s, 1H), 4.03 (dd, J = 13.6, 3.6 Hz, 1H), 3.96 (q, J = 6.0 Hz, 1H), 3.75 (s, 2H), 3.71 - 3.57 (m, 2H), 3.41 (dd, J = 13.8, 8.2 Hz, 1H), 2.90 (dd, J = 19.1, 5.4 Hz, 6H), 2.63 (dd, J = 6.2, 3.0 Hz, 2H), 2.53 (s, 1H), 2.41 (d, J = 8.6 Hz, 3H), 2.06 (s, 2H), 1.85 (s, 2H), 1.48 (s, 3H), 1.43 (s, 3H), 1.17 (d, J = 6.2 Hz, 3H).

[1862]

[1863] Example 249: Synthesis of 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

[1864]

[1865]

[1866] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine.

[1867] 1H NMR (400 MHz, Methanol-d4) δ 7.70 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 8.0, 1.6 Hz, 1H), 7.17 - 6.99 (m, 5H), 6.59 - 6.50 (m, 1H), 6.11 - 5.97 (m, 1H), 5.74 (dd, J = 3.5, 1.6 Hz, 1H), 4.48 (t, J = 5.1 Hz, 2H), 4.24 (tdd, J = 7.3, 5.2, 3.5 Hz, 1H), 3.99 (ddd, J = 9.5, 4.3, 2.6 Hz, 3H), 3.77 (d, J = 2.3 Hz, 2H), 3.72 (d, J = 7.3 Hz, 4H), 3.62 (s, 2H), 3.46 (dd, J = 13.9, 7.6 Hz, 1H), 2.96 - 2.91 (m, 2H), 2.91 - 2.83 (m, 4H), 2.67 (dd, J = 6.2, 2.2 Hz, 2H).

[1868]

[1869] Example 250: Synthesis of (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

[1870]

[1871]

[1872] In Example 28, the starting material was changed to (2R)-8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one, and the title compound was synthesized by the same method.

[1873] 1H NMR (400 MHz, Methanol-d4) δ 7.63 (d, J = 7.9 Hz, 1H), 7.17 - 7.01 (m, 5H), 6.95 (d, J = 1.6 Hz, 1H), 4.84 - 4.78 (m, 1H), 4.75 (s, 3H), 4.23 (td, J = 7.9, 4.2 Hz, 1H), 4.15 (dd, J = 13.8, 3.7 Hz, 1H), 3.77 (s, 2H), 3.66 - 3.56 (m, 3H), 3.46 (s, 5H), 3.26 (dd, J = 13.8, 8.1 Hz, 1H), 2.97 - 2.83 (m, 4H), 2.64 (h, J = 7.6 Hz, 2H), 1.31 (d, J = 6.3 Hz, 4H).

[1874]

[1875] Example 251: Synthesis of 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

[1876]

[1877]

[1878] In Example 29, the title compound was synthesized by the same method after changing 3-methoxyazetidine hydrochloride to 2-oxa-7-azaspiro[3.5]nonane oxalate.

[1879] 1H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J = 8.0 Hz, 1H), 7.19 - 6.97 (m, 6H), 4.47 (t, J = 5.1 Hz, 2H), 4.42 (s, 4H), 4.28 - 4.19 (m, 1H), 3.99 (dd, J = 13.9, 3.6 Hz, 1H), 3.78 - 3.67 (m, 4H), 3.51 - 3.40 (m, 3H), 2.93...

Claims

1. A compound of the following chemical formula 1, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, X 1 and X 2 each independently represents carbon or nitrogen; Y represents carbon, oxygen or nitrogen; Z represents carbon; n represents an integer of 0 or 1; m represents an integer from 0 to 2; represents a single bond or double bond; R 1 Silver -DR 10 represents; where D is a direct bond, -O-, -C(=O)-, -C≡C- or -CR 11 R 12 - represents; R 10 represents 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 each independently represent hydrogen, hydroxy or alkyl; the carbocycle or heterocycle may be substituted with one or more substituents selected from hydroxy, halo, oxo, formyl (-CHO), nitrile, alkyl, alkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyalkyl, haloalkyl, nitrilealkyl, alkylcarbonyl, alkylthiocarbonyl, alkoxycarbonyl, haloalkylcarbonyl, carbocyclyl, carbocyclylcarbonyl, (alkyl)(haloalkyl)amino, (alkyl)(heterocyclyl)amino, heterocyclyl and heterocyclyl-alkyl; R 2 represents hydrogen or alkyl; R 3 represents hydrogen or alkyl; R 4 , R 5 , R 6 and R 7 each independently represents hydrogen or alkyl; R 8 represents hydrogen, halo, alkyl, alkoxy or amino; R 9 represents hydrogen, halo or alkyl.

2. In paragraph 1, X 1 and X 2 each independently represents CH or N; Y is CH when n is 0 2 , O or NH, and when n is 1, it represents CH or N; Z is CH when m is 0 2 or CH, and when m is 1, it represents CH or C, and when m is 2, it represents C; represents a single bond or double bond, A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, R 1 Silver -DR 10 , where D represents a direct bond, -O-, -C(=O)-, -C≡C-, or -CR 11 R 12 - represents; R 10 Silver 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 represents alkyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl; R 11 and R 12 are each independently hydrogen, hydroxy or C 1 -C 7 Representing alkyl; A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

4. In paragraph 3, R 10 Silver halo, C 1 -C 7 Alkyl, hydroxy-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, saturated or unsaturated C 3 -C 10 Representing carbocyclyl, saturated or unsaturated 4- to 10-membered heterocyclyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl, A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, The above carbocycle or heterocycle is 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 which may be substituted with 1 to 5 substituents selected from alkyl, A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

6. In paragraph 5, The above carbocycle or heterocycle may be 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 which may be substituted with 1 to 5 substituents selected from alkyl, A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, The above heterocycles are 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 which may be substituted with 1 or 2 substituents selected from the group consisting of alkyl, A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, The above carbocyclyl is halo-C 1 -C 7 Alkyl, (C 1 -C 7 Alkyl)(halo-C 1 -C 7 alkyl)amino, and (C 1 -C 7 which may be substituted with 1 or 2 substituents selected from the group consisting of alkyl)(saturated or unsaturated 4- to 10-membered heterocyclyl)amino, A compound, an optical isomer, a stereoisomer or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, R 1 Silver -DR 10 , where D represents a direct bond; R 10 Silver 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 Represents carbocyclyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl; The above heterocyclyl is 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 which may be substituted with 1 or 2 substituents selected from alkylcarbonyl, and saturated or unsaturated 4- to 10-membered heterocyclyl, A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

10. In paragraph 1, R 2 is hydrogen or C 1 -C 7 Represents alkyl; R 3 is hydrogen or C 1 -C 7 Represents alkyl; R 4 , R 5 , R 6 and R 7 are each independently hydrogen or C 1 -C 7 Represents alkyl; R 8 Silver hydrogen, halo, C 1 -C 7 Alkyl, C 1 -C 7 Represents alkoxy or amino; R 9 Silver hydrogen, halo or C 1 -C 7 Representing alkyl, A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

11. In the first paragraph, is a single bond, A compound, or an optical isomer, stereoisomer, isotope variant or pharmaceutically acceptable salt thereof.

12. In any one of paragraphs 1 to 11, The above heterocyclyl is a 4 to 8 membered saturated or unsaturated hydrocarbon containing 1 or 2 heteroatoms selected from nitrogen and oxygen. A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

13. In any one of paragraphs 1 to 11, The above heterocyclyl is 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]octane, 2-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane, A compound selected from the group consisting of 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. A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

14. In paragraph 13, The above heterocyclyl 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. A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

15. In any one of paragraphs 1 to 11, The above carbocyclyl is selected from the group consisting of cyclohexane, cyclohexene, cyclopropane, cyclobutane, and cyclopentane. A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

16. In paragraph 1, The above D represents a direct bond, -O-, -C(=O)-, or -C≡C-; R 10 Silver halo, C 1 -C 7 Alkyl, hydroxy-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkyl, saturated or unsaturated C 3 -C 10 Represents carbocyclyl, saturated or unsaturated 4- to 10-membered heterocyclyl, or saturated or unsaturated 4- to 10-membered heterocyclyl-alkyl; The above carbocycle or heterocycle may be 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 may be substituted with 1 to 5 substituents selected from alkyl; The above heterocyclyl 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 above carbocyclyl is selected from the group consisting of cyclohexane, cyclohexene, and cyclopropane. A compound, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

17. In paragraph 1, a compound selected from the following compounds, or an optical isomer, stereoisomer or isotope variant thereof, or a pharmaceutically 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 2 hydrochloride; 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 2 hydrochloride; 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 2 hydrochloride; 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-acetyazetidin-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; 4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido[4,3-f][1,4]oxazepin-5-one; 8-Chloro-4-[(2R)-3-(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-benzoazepin-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-hydroxypro-1-phynyl)-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-ethynyl)-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-phynyl]-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 2 hydrochloride; 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 2 hydrochloride; (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 2 hydrochloride; 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 2 hydrochloride; 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-isoquinolinone-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.

18. 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 17, or an optical isomer, a stereoisomer, or an isotope variant thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

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

20. In clause 19, the cancer is acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma, benign monoclonal gammopathy, cholangiocarcinoma, bladder cancer, breast cancer, brain cancer, lymphoma, multiple myeloma, lacrimal gland tumor, bronchial cancer, cervical cancer, craniopharyngioma, colorectal cancer, epithelial carcinoma, ependymoma, endothelial sarcoma, endometrial cancer, esophageal cancer, Barrett's adenocarcinoma, Ewing's sarcoma, eye cancer, gallbladder cancer, stomach cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cancer (OSCC), pharyngeal cancer, hematopoietic system cancer, hemangioblastoma, inflammatory myofibroblastic tumor, immunocytotoxic amyloidosis, kidney cancer, liver cancer, lung cancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD), chronic idiopathic A pharmaceutical composition selected from the group consisting of myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, prostate cancer, rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestinal cancer, soft tissue sarcoma, thyroid cancer, urethral cancer, vaginal cancer and vulvar cancer.

21. A pharmaceutical composition according to claim 20, wherein the brain cancer is selected from the group consisting of meningioma, glioma, medulloblastoma, glioblastoma, and brain metastasis.

22. In claim 19, the blood disease is hemoglobinopathies or sickle cell anemia; and the autoimmune disease is selected from the group consisting of rheumatoid arthritis, spondyloarthropathy, 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, enuresis, eosinophilic disease, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis; The above inflammatory diseases are inflammation associated with acne, aplastic anemia, hemolytic autoimmune anemia, rhinitis, asthma, polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis, crystal 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 reactions, burns, dermatitis, pruritus, endometriosis, infections, ischemic heart disease, glomerulonephritis, gingivitis, hypersensitivity, migraine, tension headache, postoperative ileus, ileus during sepsis, idiopathic thrombocytopenic purpura, selected from the group consisting of bladder pain syndrome, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal 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;A pharmaceutical composition, wherein the neurodegenerative disease is selected from the group consisting of motor neuron disease, Pick's disease, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration.;