BICYCLIC COMPOUND AND USE THEREOF

Abstract

The present invention relates to a 6-6 bicyclic ring-containing compound derivative and use thereof. The compound according to the present invention acts as a PRMT5 inhibitor, and thus can be effectively used in the prevention or treatment of diseases caused by PRMT5.

Claims

1. A compound represented by the following Formula 1, or an optical isomer, a stereoisomer or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof: ##STR00157## wherein X is CH or N; n is an integer from 0 to 2; R.sup.1 is -D-R.sup.9 or ##STR00158## wherein D is a direct bond, —CH.sub.2—, —O— or —C≡C—; R.sup.9 is halo, hydroxy, alkyl, hydroxyalkyl, dialkylaminoalkyl, saturated or unsaturated heterocyclyl, or saturated heterocyclyl-alkyl; the saturated or unsaturated heterocyclyl may be substituted with one or more substituents selected from halo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl and saturated heterocyclyl; R.sup.10 and R.sup.11 are each independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, cycloalkyl-alkyl, alkylcarbonyl, hydroxyalkylcarbonyl, aralkyl, saturated heterocyclyl, saturated or unsaturated heterocyclyl-alkyl, unsaturated heterocyclyl-carbonyl, or saturated heterocyclyl-alkylcarbonyl; or R.sup.10 and R.sup.11 together with nitrogen (N) atom to which they are attached may form saturated or unsaturated heterocyclyl; the saturated or unsaturated heterocyclyl may be substituted with one or more substituents selected from hydroxy, oxo, formyl (—CHO), cyano, alkyl, alkoxy, hydroxyalkyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkylamino, alkylsulfonyl, alkoxyalkyl, aminocarbonyl, alkylcarbonylamino, alkylcarbonylalkylamino, alkoxyalkylalkylamino, dialkylamino, dialkylaminoalkyl, dialkylaminoalkoxy, dialkylaminocarbonyl and 4- to 10-membered, saturated heterocyclyl; R.sup.2 is hydrogen or halo; R.sup.3 is hydrogen, halo or alkyl, or together with carbon (C) atom to which they are attached may form cycloalkyl when n is 2; R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each independently hydrogen or alkyl; and R.sup.8 is hydrogen, halo, alkyl, alkoxy or amino.

2. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.1 is -D-R.sup.9, wherein D is a direct bond, —CH.sub.2—, —O— or —C≡C—; R.sup.9 is halo, hydroxy, C.sub.1-C.sub.7 alkyl, hydroxy-C.sub.1-C.sub.7 alkyl, di(C.sub.1-C.sub.7 alkyl)amino-C.sub.1-C.sub.7 alkyl, 4- to 10-membered, saturated or unsaturated heterocyclyl, or 4- to 10-membered, saturated heterocyclyl-alkyl; the saturated or unsaturated heterocyclyl has 1 to 3 heteroatoms selected from N, O and S; and may be substituted with one or more substituents selected from halo, C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkoxy, halo-C.sub.1-C.sub.7 alkyl, hydroxy-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkoxy-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkylcarbonyl, C.sub.1-C.sub.7 alkoxycarbonyl, and 4- to 10-membered, saturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S.

3. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to claim 2, wherein D is a direct bond; R.sup.9 is halo, hydroxy, C.sub.1-C.sub.7 alkyl or 4- to 10-membered, saturated or unsaturated heterocyclyl; the saturated or unsaturated heterocyclyl has 1 to 3 heteroatoms selected from N, O and S; and may be substituted with 1 to 3 substituents selected from halo, C.sub.1-C.sub.7 alkylcarbonyl and C.sub.1-C.sub.7 alkoxycarbonyl.

4. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to claim 2, wherein D is —CH.sub.2—, —O— or —C≡C—; R.sup.9 is hydroxy-C.sub.1-C.sub.7 alkyl, di(C.sub.1-C.sub.7 alkyl)amino-C.sub.1-C.sub.7 alkyl, 4- to 10-membered, saturated or unsaturated heterocyclyl, or 4- to 10-membered, saturated or unsaturated heterocyclyl-C.sub.1-C.sub.7 alkyl; the saturated or unsaturated heterocyclyl has 1 to 3 heteroatoms selected from N, O and S; and may be substituted with 1 to 3 substituents selected from C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkoxy, halo-C.sub.1-C.sub.7 alkyl, hydroxy-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkoxy-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkylcarbonyl, C.sub.1-C.sub.7 alkoxycarbonyl and 4- to 10-membered, saturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S.

5. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to claim 2, wherein the saturated or unsaturated heterocyclyl is selected from the group consisting of pyridyl, morpholinyl, oxazepanyl, dihydropyridinyl, tetrahydropyridinyl, piperidyl, piperazinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl.

6. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.1 is ##STR00159## R.sup.10 and R.sup.11 are each independently hydrogen, C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.7 cycloalkyl, hydroxy-C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.7 cycloalkyl-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkylcarbonyl, hydroxy-C.sub.1-C.sub.7 alkylcarbonyl, C.sub.6-C.sub.12 aryl-C.sub.1-C.sub.7 alkyl, saturated heterocyclyl, saturated or unsaturated heterocyclyl-C.sub.1-C.sub.7 alkyl, unsaturated heterocyclyl-carbonyl or saturated heterocyclyl-C.sub.1-C.sub.7 alkylcarbonyl; or R.sup.10 and R.sup.11 together with nitrogen (N) atom to which they are attached may form saturated or unsaturated heterocyclyl; the heterocyclyl may be substituted with 1 to 3 substituents selected from hydroxy, oxo, formyl (—CHO), cyano, C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkoxy, hydroxy-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkylcarbonyl, halo-C.sub.1-C.sub.7 alkylcarbonyl, C.sub.1-C.sub.7 alkoxycarbonyl, C.sub.1-C.sub.7 alkylamino, C.sub.1-C.sub.7 alkylsulfonyl, C.sub.1-C.sub.7 alkoxy-C.sub.1-C.sub.7 alkyl, aminocarbonyl, C.sub.1-C.sub.7 alkylcarbonylamino, C.sub.1-C.sub.7 alkylcarbonyl-C.sub.1-C.sub.7 alkylamino, (C.sub.1-C.sub.7 alkoxy-C.sub.1-C.sub.7 alkyl)(C.sub.1-C.sub.7 alkyl)amino, di(C.sub.1-C.sub.7 alkyl)amino, di(C.sub.1-C.sub.7 alkyl)amino-C.sub.1-C.sub.7 alkyl, di(C.sub.1-C.sub.7 alkyl)amino-C.sub.1-C.sub.7 alkoxy, di(C.sub.1-C.sub.7 alkyl)aminocarbonyl and saturated heterocyclyl.

7. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to claim 6, wherein the heterocyclyl is 4- to 10-membered, saturated or unsaturated hydrocarbon having 1 to 3 heteroatoms selected from N, O and S.

8. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to claim 6, wherein the heterocyclyl is selected from the group consisting of pyrrolidinyl, morpholinyl, tetrahydropyranyl, pyridyl, piperazinyl, azetidinyl, piperidyl, tetrahydrofuranyl, oxazolidinyl, 2-oxa-6-azaspiro[3.3]heptan-6yl, thiomorpholinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, diazepanyl, 4,7-diazaspiro[2.5]octanyl, 5,6,8,8a-tetrahydrooxazolo[3,4-a]pyrazinyl, azepanyl, 6,8-dihydro-5H-imidazo[1,2-a]pyrazinyl and oxetanyl.

9. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.2 is hydrogen or halo; R.sup.3 is hydrogen, halo or C.sub.1-C.sub.7 alkyl; or together with carbon (C) atom to which they are attached may form C.sub.3-C.sub.7 cycloalkyl when n is 2; R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each independently hydrogen or C.sub.1-C.sub.7 alkyl; and R.sup.8 is hydrogen, halo, C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkoxy or amino.

10. The compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of: 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-pyrrolidin-1-yl-3,4-dihydroisoquinolin-1-one; 6-(cyclohexylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-morpholino-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(tetrahydropyran-4-ylamino)-3,4-dihydroisoquinolin-1-one; 6-(cyclohexylmethylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 6-(benzylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-pyridyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-pyridyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-pyridylmethylamino)-3,4-dihydroisoquinolin-1-one; 6-[cyclohexyl(methyl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-fluoro-4-pyridyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-propyl-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(6-fluoro-3-pyridyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(2R)-2-methylmorpholin-4-yl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-oxopyrrolidin-1-yl)-3,4-dihydroisoquinolin-1-one; N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinoline-6-yl]-2,2-dimethyl-propanamide; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-oxoazetidin-1-yl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-oxo-1-piperidyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-pyridylmethylamino)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(tetrahydropyran-4-ylmethylamino)-3,4-dihydroisoquinolin-1-one; 6-[(1-acetyl-4-piperidyl)methylamino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(2-hydroxy-2-methyl-propyl)amino]-3,4-dihydroisoquinolin-1-one; N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]pyridine-3-carboxamide; N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]pyridine-4-carboxamide; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3,5-dimethyl-1-piperidyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3,5-dimethylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(tetrahydrofuran-3-ylmethylamino)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidylmethylamino)-3,4-dihydroisoquinolin-1-one; 6-[(1-acetyl-4-piperidyl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-2-morpholino-acetamide; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidylamino)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(hydroxymethyl)-1-piperidyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[3-(hydroxymethyl)-1-piperidyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-hydroxy-1-piperidyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-hydroxy-1-piperidyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-oxazolidin-3-yl-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-methylmorpholin-4-yl)-3,4-dihydroisoquinolin-1-one; N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-2-hydroxy-acetamide; N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]acetamide; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(morpholinomethyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3,4-dihydroisoquinolin-1-one; 3-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxazolidin-2-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[3-(hydroxymethyl)azetidin-1-yl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(2S)-2-methylmorpholin-4-yl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methoxy-1-piperidyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1,1-dioxo-1,4-thiazinan-4-yl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(tetrahydrofuran-3-ylamino)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(oxetan-3-ylamino)-3,4-dihydroisoquinolin-1-one; 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carboxylate; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1,4-oxazepan-4-ylmethyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methyl-3-oxo-piperazin-1-yl)-3,4-dihydroisoquinolin-1-one; tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-piperazin-1-yl-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methylsulfonylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one; methyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carboxylate; 6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(2,2,2-trifluoro acetyl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one; tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperidine-1-carboxylate; [(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-isopropylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one; ethyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carboxylate; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(4-methoxy-1-piperidyl)methyl]-3,4-dihydroisoquinolin-1-one; 6-(1-acetyl-4-piperidyl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 6-[(4-acetylpiperazin-1-yl)methyl]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-propanoylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(2-methylpropanoyl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one; tert-butyl 5-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-hydroxy-3,4-dihydroisoquinolin-1-one; 2-chloro-6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7,8-dihydro-1,6-naphthyridin-5-one; 6-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-piperidylamino)-3,4-dihydroisoquinolin-1-one; tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-1,4-diazepane-1-carboxylate; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methyl-3-oxo-1,4-diazepan-1-yl)-3,4-dihydroisoquinolin-1-one; 6-(4-acetyl-1,4-diazepan-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 6-(5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 6-(4-acetyl-4,7-diazaspiro[2.5]octan-7-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 6-[(1-acetyl-4-piperidyl)methoxy]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methyl-5-oxo-1,4-diazepan-1-yl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-isopropyl-3-oxo-piperazin-1-yl)-3,4-dihydroisoquinolin-1-one; 6-(4-acetyl-2-oxo-piperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carbaldehyde; 2-(4-acetylpiperazin-1-yl)-6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7,8-dihydro-1,6-naphthyridin-5-one; 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-morpholino-7,8-dihydro-1,6-naphthyridin-5-one; N-[1-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-4-piperidyl]-N-methyl-acetamide; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-tetrahydropyran-4-yloxy-3,4-dihydroisoquinolin-1-one; N-[1-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-4-piperidyl]acetamide; 6-[(1-acetyl-3-piperidyl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 7-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3-one; 6-[(1-acetyl-4-piperidyl)oxy]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 6-(1-acetylazetidin-3-yl)oxy-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 1-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-N,N-dimethyl-piperidine-4-carboxamide; 6-[(1-acetylazepan-4-yl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 6-[(1-acetylpyrrolidin-3-yl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carboxamide; 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carbonitrile; 6-(6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3,4-dimethyl-5-oxo-piperazin-1-yl)-3,4-dihydroisoquinolin-1-one; 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one; 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]spiro[3H-isoquinoline-4,1′-cyclopropane]-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-pyrrolidin-1-yl-1-piperidyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(1-piperidyl)-1-piperidyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-morpholino-1-piperidyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(2-methoxyethyl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(dimethylamino)-1-piperidyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(dimethylamino)-1-piperidyl]-4,4-dimethyl-3H-isoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-6-morpholino-3H-isoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-morpholinoethoxy)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-ethyl-4-piperidyl)oxy]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-ethyl-4-piperidyl)methyloxy]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[3-(dimethylamino)-1-piperidyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-[(dimethylamino)methyl]-1-piperidyl]-3,4-dihydroisoquinolin-1-one; 6-[4-(diethylamino)-1-piperidyl]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-[2-(dimethylamino)ethoxy]-1-piperidyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-[2-methoxyethyl(methyl)amino]-1-piperidyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(oxetan-3-yl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-tetrahydropyran-4-ylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one; 6-[4-(diethylamino)-1-piperidyl]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-6-(4-pyrrolidin-1-yl-1-piperidyl)-3H-isoquinolin-1-one; 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-1-oxo-3H-isoquinolin-6-yl]piperazine-1-carbaldehyde; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(dimethylamino)-1-piperidyl]-4,4-dimethyl-3H-isoquinolin-1-one; dihydrochloride; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-tetrahydrofuran-3-ylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one; 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-3,4-dihydroisoquinolin-1-one; 6-(4-acetylpiperazin-1-yl)-2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-1-methyl-propyl]-3,4-dihydroisoquinolin-1-one; 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-1-oxo-3H-isoquinolin-6-yl]piperazine-1-carbaldehyde; hydrochloride; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-ethyl-4-piperidyl)oxy]-4,4-dimethyl-3H-isoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-difluoro-6-morpholino-3H-isoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1-methylpyrrolidin-3-yl)oxy-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1-ethylpyrrolidin-3-yl)oxy-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-methyl-4-piperidyl)oxy]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-(3-hydroxyprop-1-ynyl)-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-[2-(4-pyridyl)ethynyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-[(1-methyl-3-piperidyl)oxy]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-[[1-(2-fluoroethyl)-3-piperidyl]oxy]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-[3-(dimethylamino)prop-1-ynyl]-3,4-dihydroisoquinolin-1-one; 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[[1-(2-methoxyethyl)-4-piperidyl]oxy]-3,4-dihydroisoquinolin-1-one; 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-[[1-(2-methoxyethyl)-4-piperidyl]oxy]-7,8-dihydro-1,6-naphthyridin-5-one; 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-[[1-[(2R)-2-hydroxypropyl]-4-piperidyl]oxy]-7,8-dihydro-1,6-naphthyridin-5-one; 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]oxy]-7,8-dihydro-1,6-naphthyridin-5-one; and 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-7,8-dihydro-1,6-naphthyridin-5-one.

11. A pharmaceutical composition for the prevention or treatment of a disease associated with protein arginine methyltransferase 5 (PRMT5) inhibition comprising a therapeutically effective amount of the compound, or optical isomer, stereoisomer or isotopic variant thereof, or pharmaceutically acceptable salt thereof as defined in claim 1 as an active ingredient, together with a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, wherein the disease associated with PRMT5 inhibition is selected from cancer, blood disease, autoimmune disease, inflammatory disease and neurodegenerative disease.

13. The pharmaceutical composition according to claim 12, wherein the cancer is selected from the group consisting of acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma, benign monoclonal gammaglobulinopathy, cholangiocarcinoma, bladder cancer, breast cancer, brain cancer, lymphoma, multiple myeloma, lacrimal gland tumor, bronchial cancer, cervical cancer, craniopharyngioma, colorectal cancer, epithelial carcinoma, epithelial cell tumor, endothelial sarcoma, endometrial cancer, esophageal cancer, Barrett's adenocarcinoma, Ewing's sarcoma, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cancer (oral squamous cell carcinoma, OSCC), throat cancer, hematopoietic cancer, hemangioblastoma, inflammatory myofibroblast tumor, immune cell amyloidosis, kidney cancer, liver cancer, lung cancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, prostate cancer, rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, thyroid cancer, urethral cancer, vaginal cancer and vulvar cancer.

14. The pharmaceutical composition according to claim 13, wherein the brain cancer is selected from the group consisting of meningioma, glioma, medulloblastoma, glioblastoma and brain metastasis cancer.

15. The pharmaceutical composition according to claim 12, wherein the blood disease is hemoglobinemia or sickle cell anemia; the autoimmune disease is selected from the group consisting of rheumatoid arthritis, spinal arthritis, gouty arthritis, degenerative joint disease, osteoarthritis, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, juvenile arthritis, asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, psoriasis, eczema, burns, dermatitis, pruritus, enuresis, eosinophilic disease, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis and eosinophilic colitis; the inflammatory disease is selected from the group consisting of acne-related inflammation, aplastic anemia, hemolytic autoimmune anemia, rhinitis, asthma, polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, amyotrophic lateral sclerosis, autoimmune disease, allergic or allergic reaction, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, chronic obstructive pulmonary disease, dermatomyositis, type I diabetes, type 2 diabetes, psoriasis, eczema, eczema hypersensitivity reaction, burn, dermatitis, pruritus, endometriosis, infection, ischemic heart disease, glomerulonephritis, gingivitis, irritability, migraine, tension headache, postoperative intestinal obstruction, intestinal obstruction during sepsis, idiopathic thrombocytopenia purpura, bladder pain syndrome, peptic ulcer, localized enteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, bypass colitis, Behcet's syndrome, indeterminate colitis, inflammatory bowel syndrome (IBS), lupus, ecchymosis, myasthenia gravis and myocardial ischemia; and the neurodegenerative disease is selected from the group consisting of motor neuron disease, Pick's disease, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinal pigmentation, spinal muscular atrophy and cerebellar degeneration.

Description

DETAILED DESCRIPTION

[0081] Hereinafter, the present invention is explained in more detail with the following examples. However, it must be understood that the protection scope of the present disclosure is not limited to the examples.

[0082] The abbreviations and terms used in the following Examples are as follows:

[0083] BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

[0084] Cs.sub.2CO.sub.3: cesium carbonate

[0085] NaBH.sub.3CN: sodium cyanoborohydride

[0086] NaOt-Bu: sodium tert-butoxide

[0087] Pd(dppf)Cl.sub.2: 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride

[0088] Pd(dba).sub.2: bis(dibenzylideneacetone)palladium(0)

[0089] Pd.sub.2(dba).sub.3: tris(dibenzylideneacetone)dipalladium(0)

[0090] tBuXphos: 2-di-tert-butylphosphino-2′,4′,6′-trisisopropylbiphenyl

[0091] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0092] Xphos: 2-dicyclohexylphosphino-2′,4′,6′-trisisopropylbiphenyl

Example 1: Synthesis of 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0093] ##STR00009##

Example 1-1: Synthesis of 6-bromo-2-[[(2R)-oxiran-2-yl]methyl]-3,4-dihydroisoquinolin-1-one

[0094] 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one (3.6 g, 15.92 mmol) was dissolved in dimethylformamide, and 60% sodium hydride (828 mg, 20.7 mmol) was added at 0° C. and stirred for 30 minutes. (R)-(−)-glycidyl nosylate (4.95 g, 19.11 mmol) was slowly added to the reaction solution, followed by stirring at room temperature. Methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate was added. The reaction mixture was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and 2 g of the title compound was obtained by flash chromatography.

Example 1-2: Synthesis of 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0095] 6-Bromo-2-[[(2R)-oxiran-2-yl]methyl]-3,4-dihydroisoquinolin-1-one (2 g, 7.09 mmol) was dissolved in 53 mL of isopropanol, and tetrahydrogen isoquinoline (0.89 mL, 7.09 mmol) was added dropwise, followed by stirring at 80° C. After completion of the reaction, the solvent was dried under reduced pressure and purified by flash chromatography to obtain 2.2 g of the title compound.

[0096] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.84 (d, J=8.2 Hz, 1H), 7.57-7.49 (m, 2H), 7.17-7.01 (m, 4H), 4.29-4.20 (m, 1H), 3.91 (dd, J=13.7, 4.0 Hz, 1H), 3.84-3.67 (m, 4H), 3.39 (dd, J=13.6, 7.7 Hz, 1H), 3.04 (t, J=6.8 Hz, 2H), 2.97-2.85 (m, 4H), 2.71-2.59 (m, 2H).

Example 2: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-pyrrolidin-1-yl-3,4-dihydroisoquinolin-1-one

[0097] ##STR00010##

[0098] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one (100 mg, 0.24 mmol) obtained in Example 1, pyrrolidine (0.12 mL, 0.96 mmol), Pd.sub.2(dba).sub.3 (11 mg, 0.01 mmol), NaOt-Bu (35 mg, 0.03 mmol) and BINAP (15 mg, 0.02 mmol) were dissolved in 4 mL of toluene and stirred in a microwave at 120° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was dried under reduced pressure and purified by flash chromatography to obtain 40 mg of the title compound.

[0099] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.76 (d, J=8.7 Hz, 1H), 7.18-7.01 (m, 4H), 6.51 (d, J=8.8 Hz, 1H), 6.36 (s, 1H), 4.28-4.18 (m, 1H), 3.87 (dd, J=14.0, 4.3 Hz, 1H), 3.84-3.61 (m, 4H), 3.36 (d, J=6.0 Hz, 4H), 2.97-2.91 (m, 6H), 2.76-2.61 (m, 2H), 2.14-2.00 (m, 4H).

Example 3: Synthesis of 6-(cyclohexylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0100] ##STR00011##

[0101] The title compound was synthesized in the same manner as in Example 2, except that cyclohexanamine was used instead of pyrrolidine.

[0102] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J=8.3 Hz, 1H), 7.53-7.40 (m, 1H), 7.36 (d, J=1.9 Hz, 1H), 7.12 (qd, J=8.4, 7.3, 4.0 Hz, 3H), 7.05-6.91 (m, 1H), 4.12 (ddt, J=10.1, 7.0, 3.5 Hz, 1H), 3.96-3.68 (m, 5H), 3.62 (d, J=14.9 Hz, 2H), 3.45 (ddd, J=20.6, 13.8, 6.6 Hz, 2H), 3.04-2.78 (m, 6H), 2.77-2.58 (m, 2H), 2.53 (dd, J=12.3, 10.1 Hz, 2H), 1.35-1.10 (m, 4H), 0.99-0.71 (m, 2H).

Example 4: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-morpholino-3,4-dihydroisoquinoline-1-one

[0103] ##STR00012##

[0104] The title compound was synthesized in the same manner as in Example 2, except that morpholine was used instead of pyrrolidine.

[0105] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82 (d, J=8.8 Hz, 1H), 7.17-7.07 (m, 3H), 7.05 (d, J=7.0 Hz, 1H), 6.91 (dd, J=8.7, 2.5 Hz, 1H), 6.78 (d, J=2.5 Hz, 1H), 4.23 (td, J=7.3, 3.8 Hz, 1H), 3.93-3.81 (m, 5H), 3.79-3.64 (m, 4H), 3.40-3.34 (m, 1H), 3.29 (t, J=4.9 Hz, 4H), 3.03-2.96 (m, 2H), 2.92 (d, J=5.5 Hz, 2H), 2.87 (t, J=5.5 Hz, 2H), 2.69-2.58 (m, 2H).

Example 5: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(tetrahydropyran-4-ylamino)-3,4-dihydroisoquinolin-1-one

[0106] ##STR00013##

[0107] The title compound was synthesized in the same manner as in Example 2, except that tetrahydropyran-4-amine was used instead of pyrrolidine.

[0108] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J=8.5 Hz, 1H), 7.23-7.04 (m, 3H), 7.06-6.93 (m, 1H), 6.51 (dd, J=8.6, 2.4 Hz, 1H), 6.31 (d, J=2.3 Hz, 1H), 4.17-3.39 (m, 14H), 2.80-2.48 (m, 4H), 2.04 (d, J=12.7 Hz, 3H), 1.51 (td, J=14.4, 7.4 Hz, 3H).

Example 6: Synthesis of 6-(cyclohexylmethylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0109] ##STR00014##

[0110] The title compound was synthesized in the same manner as in Example 2, except that cyclohexylmethanamine was used instead of pyrrolidine.

[0111] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J=8.5 Hz, 1H), 7.12 (qd, J=8.5, 7.2, 3.9 Hz, 3H), 7.07-6.94 (m, 1H), 6.49 (dd, J=8.6, 2.4 Hz, 1H), 6.28 (d, J=2.4 Hz, 1H), 4.10 (d, J=7.7 Hz, 2H), 3.93-3.57 (m, 5H), 3.48 (dd, J=13.9, 6.0 Hz, 1H), 2.99 (t, J=6.1 Hz, 2H), 2.90 (d, J=6.4 Hz, 4H), 2.78-2.48 (m, 3H), 1.91-1.49 (m, 7H), 1.40-1.12 (m, 3H), 0.98 (q, J=11.8 Hz, 2H).

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

[0112] ##STR00015##

[0113] The title compound was synthesized in the same manner as in Example 2, except that phenylmethanamine was used instead of pyrrolidine.

[0114] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J=8.4 Hz, 1H), 7.41-7.20 (m, 5H), 7.12 (qd, J=8.6, 7.3, 4.0 Hz, 3H), 7.04-6.93 (m, 1H), 6.55 (dd, J=8.6, 2.4 Hz, 1H), 6.34 (d, J=2.3 Hz, 1H), 4.44 (s, 1H), 4.37 (s, 2H), 4.11 (dt, J=10.7, 4.3 Hz, 1H), 3.90-3.74 (m, 2H), 3.66 (qd, J=14.7, 13.7, 6.6 Hz, 3H), 3.46 (dd, J=14.0, 6.0 Hz, 1H), 2.88 (q, J=7.7, 6.4 Hz, 5H), 2.77-2.47 (m, 3H).

Example 8: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-pyridyl)-3,4-dihydroisoquinolin-1-one

[0115] ##STR00016##

[0116] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one (100 mg, 0.24 mmol) obtained in Example 1, 4-pyridylboronic acid (60 mg, 0.48 mmol), Pd((dppf)Cl.sub.2 (20 mg, 0.02 mmol) and K.sub.2CO.sub.3 (100 mg, 0.72 mmol) were dissolved in 3 mL of 1,4-dioxane and 1 mL of H.sub.2O, followed by stirring in a microwave at 120° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was dried under reduced pressure, and the purification was carried out by flash chromatography to obtain 35 mg of the title compound.

[0117] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.69 (d, J=5.1 Hz, 2H), 8.18 (d, J=8.1 Hz, 1H), 7.67-7.42 (m, 4H), 7.13 (dp, J=8.9, 6.4, 4.3 Hz, 3H), 7.05-6.94 (m, 1H), 4.16 (ddt, J=10.2, 7.0, 3.6 Hz, 1H), 4.02-3.71 (m, 4H), 3.64 (d, J=14.6 Hz, 1H), 3.48 (dd, J=13.9, 6.3 Hz, 1H), 3.09 (t, J=6.7 Hz, 2H), 2.93 (tt, J=10.7, 4.8 Hz, 3H), 2.82-2.49 (m, 3H).

Example 9: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-pyridyl)-3,4-dihydroisoquinolin-1-one

[0118] ##STR00017##

[0119] The title compound was synthesized in the same manner as in Example 8, except that 3-pyridylboronic acid was used instead of 4-pyridylboronic acid.

[0120] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J=2.4 Hz, 1H), 8.63 (dd, J=4.8, 1.7 Hz, 1H), 8.18 (d, J=8.1 Hz, 1H), 7.91 (dt, J=8.1, 2.1 Hz, 1H), 7.56 (dd, J=8.0, 1.9 Hz, 1H), 7.47-7.33 (m, 2H), 7.21-7.06 (m, 3H), 7.06-6.91 (m, 1H), 4.16 (dtt, J=14.3, 10.7, 5.4 Hz, 1H), 3.93 (dd, J=14.0, 3.1 Hz, 1H), 3.88-3.73 (m, 3H), 3.68-3.57 (m, 1H), 3.49 (dd, J=14.0, 6.2 Hz, 1H), 3.10 (q, J=8.0, 6.6 Hz, 2H), 2.93 (tt, J=10.3, 4.7 Hz, 3H), 2.80-2.53 (m, 3H).

Example 10: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-pyridylmethylamino)-3,4-dihydroisoquinolin-1-one

[0121] ##STR00018##

[0122] The title compound was synthesized in the same manner as in Example 2, except that 4-pyridylmethanamine was used instead of pyrrolidine.

[0123] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.46 (d, J=5.9 Hz, 2H), 7.69 (d, J=8.5 Hz, 1H), 7.42 (d, J=5.2 Hz, 2H), 7.15-6.95 (m, 4H), 6.53 (dd, J=8.6, 2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.20 (tt, J=7.7, 4.6 Hz, 1H), 3.84 (dd, J=13.8, 4.2 Hz, 1H), 3.77-3.51 (m, 4H), 3.33 (d, J=21.3 Hz, 3H), 2.88 (dt, J=25.3, 6.4 Hz, 6H), 2.66-2.54 (m, 2H).

Example 11: Synthesis of 6-[cyclohexyl(methyl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0124] ##STR00019##

[0125] The title compound was synthesized in the same manner as in Example 2, except that N-methylcyclohexanamine was used instead of pyrrolidine.

[0126] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.76 (d, J=8.8 Hz, 1H), 7.18-6.94 (m, 4H), 6.72 (dd, J=8.9, 2.6 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H), 4.22 (tt, J=7.7, 4.6 Hz, 1H), 3.87 (dd, J=13.7, 4.3 Hz, 1H), 3.79-3.61 (m, 5H), 3.37 (d, J=7.3 Hz, 1H), 3.01-2.87 (m, 5H), 2.71-2.60 (m, 2H), 2.04 (d, J=9.6 Hz, 1H), 1.88 (d, J=12.9 Hz, 2H), 1.81-1.66 (m, 3H), 1.65-1.39 (m, 5H), 1.38-1.17 (m, 3H).

Example 12: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-fluoro-4-pyridyl)-3,4-dihydroisoquinolin-1-one

[0127] ##STR00020##

[0128] The title compound was synthesized in the same manner as in Example 8, except that (2-fluoro-4-pyridyl)boronic acid was used instead of 4-pyridylboronic acid.

[0129] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.30 (d, J=5.3 Hz, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.85-7.73 (m, 1H), 7.72 (s, 1H), 7.67 (d, J=5.3 Hz, 1H), 7.45 (s, 1H), 7.17-7.07 (m, 3H), 7.05 (d, J=6.5 Hz, 1H), 4.27 (dd, J=11.1, 5.3 Hz, 1H), 3.95 (dd, J=13.7, 4.1 Hz, 1H), 3.91-3.73 (m, 4H), 3.43 (dd, J=13.7, 7.8 Hz, 1H), 3.21-3.10 (m, 2H), 2.91 (dt, J=9.6, 5.1 Hz, 4H), 2.74-2.61 (m, 2H).

Example 13: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-propyl-3,4-dihydroisoquinolin-1-one

[0130] ##STR00021##

[0131] The title compound was synthesized in the same manner as in Example 8, except that propylboronic acid was used instead of 4-pyridylboronic acid.

[0132] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.85 (d, J=7.9 Hz, 1H), 7.22-6.99 (m, 6H), 4.26 (h, J=6.3, 5.5 Hz, 1H), 3.91 (dd, J=13.7, 4.2 Hz, 1H), 3.83-3.66 (m, 4H), 3.39 (dd, J=13.7, 7.7 Hz, 1H), 3.06-2.97 (m, 2H), 2.91 (dd, J=14.3, 4.8 Hz, 4H), 2.71-2.60 (m, 2H), 1.67 (hept, J=7.4 Hz, 2H), 1.30 (q, J=6.8, 6.3 Hz, 2H), 0.97 (t, J=7.4 Hz, 3H).

Example 14: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3,4-dihydroisoquinolin-1-one

[0133] ##STR00022##

[0134] The title compound was synthesized in the same manner as in Example 2, except that (2R,6S)-2,6-dimethylmorpholine was used instead of pyrrolidine.

[0135] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.7 Hz, 1H), 7.20-6.98 (m, 4H), 6.90 (dd, J=8.8, 2.5 Hz, 1H), 6.77 (d, J=2.5 Hz, 1H), 4.32-4.11 (m, 1H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.80-3.64 (m, 8H), 3.42-3.34 (m, 1H), 3.01-2.83 (m, 6H), 2.72-2.58 (m, 2H), 2.43 (dd, J=12.2, 10.3 Hz, 2H), 1.25 (d, J=6.2 Hz, 6H).

Example 15: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(6-fluoro-3-pyridyl)-3,4-dihydroisoquinolin-1-one

[0136] ##STR00023##

[0137] The title compound was synthesized in the same manner as in Example 8, except that (6-fluoro-3-pyridyl)boronic acid was used instead of 4-pyridylboronic acid.

[0138] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.53 (d, J=2.6 Hz, 1H), 8.27 (td, J=8.1, 2.6 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.71-7.52 (m, 2H), 7.20 (dd, J=8.6, 2.6 Hz, 1H), 7.14-7.01 (m, 4H), 4.28 (tt, J=8.1, 4.7 Hz, 1H), 3.95 (dd, J=13.7, 4.1 Hz, 1H), 3.90-3.74 (m, 4H), 3.43 (dd, J=13.7, 7.7 Hz, 1H), 3.19-3.07 (m, 2H), 3.00-2.83 (m, 4H), 2.76-2.58 (m, 2H).

Example 16: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(2R)-2-methylmorpholin-4-yl]-3,4-dihydroisoquinolin-1-one

[0139] ##STR00024##

[0140] The title compound was synthesized in the same manner as in Example 2, except that (2R)-2-methylmorpholine was used instead of pyrrolidine.

[0141] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.7 Hz, 1H), 7.20-7.00 (m, 4H), 6.91 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 4.22 (dt, J=8.1, 4.7 Hz, 1H), 4.06-3.94 (m, 1H), 3.88 (dd, J=13.9, 4.2 Hz, 1H), 3.81-3.61 (m, 8H), 3.43-3.35 (m, 1H), 3.06-2.78 (m, 7H), 2.73-2.58 (m, 2H), 2.50 (t, J=11.6 Hz, 1H), 1.25 (d, J=6.3 Hz, 3H).

Example 17: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one

[0142] ##STR00025##

[0143] The title compound was synthesized in the same manner as in Example 2, except that N-methylpiperazine was used instead of pyrrolidine.

[0144] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.8 Hz, 1H), 7.18-7.03 (m, 4H), 6.97-6.85 (m, 1H), 6.79 (s, 1H), 4.34-4.17 (m, 1H), 3.88 (dd, J=13.9, 4.2 Hz, 1H), 3.83-3.66 (m, 4H), 3.58 (t, J=4.8 Hz, 1H), 3.38 (q, J=6.0, 4.6 Hz, 5H), 3.03-2.88 (m, 5H), 2.72-2.65 (m, 2H), 2.63 (t, J=5.1 Hz, 3H), 2.38 (s, 3H).

Example 18: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-oxopyrrolidin-1-yl)-3,4-dihydroisoquinolin-1-one

[0145] ##STR00026##

[0146] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one (100 mg, 0.24 mmol) obtained in Example 1, pyrrolidin-2-one (74 μL, 0.96 mmol), Pd.sub.2(dba).sub.3 (11 mg, 0.01 mmol), Cs.sub.2CO.sub.3 (110 mg, 0.34 mmol) and Xantphos (21 mg, 0.036 mmol) were dissolved in 4 mL of 1,4-dioxane and stirred in a microwave at 120° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was dried under reduced pressure, and the purification was carried out by flash chromatography to obtain 38 mg of the title compound.

[0147] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.95 (d, J=8.6 Hz, 1H), 7.75-7.57 (m, 2H), 7.18-6.97 (m, 4H), 4.24 (q, J=6.4 Hz, 1H), 4.04-3.87 (m, 3H), 3.85-3.66 (m, 5H), 3.58 (t, J=4.7 Hz, 1H), 3.40 (q, J=6.0 Hz, 1H), 3.13-3.01 (m, 2H), 2.90 (dd, J=17.2, 5.2 Hz, 4H), 2.72-2.58 (m, 4H).

Example 19: Synthesis of N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-2,2-dimethyl-propanamide

[0148] ##STR00027##

[0149] The title compound was synthesized in the same manner as in Example 18, except that 2,2-dimethylpropanamide was used instead of pyrrolidin-2-one.

[0150] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.89 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.18-7.00 (m, 4H), 4.25 (tt, J=8.2, 4.7 Hz, 1H), 3.90 (dd, J=13.7, 4.1 Hz, 1H), 3.84-3.66 (m, 4H), 3.39 (dd, J=13.8, 7.6 Hz, 1H), 3.09-2.99 (m, 2H), 2.92 (dq, J=10.8, 6.7, 6.0 Hz, 4H), 2.73-2.61 (m, 2H), 1.32 (s, 9H).

Example 20: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-oxoazetidin-1-yl)-3,4-dihydroisoquinolin-1-one

[0151] ##STR00028##

[0152] The title compound was synthesized in the same manner as in Example 18, except that azetidin-2-one was used instead of pyrrolidin-2-one.

[0153] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.94 (d, J=8.9 Hz, 1H), 7.32 (d, J=7.0 Hz, 2H), 7.17-6.99 (m, 4H), 4.25 (tt, J=7.6, 4.6 Hz, 1H), 3.90 (dd, J=13.8, 4.1 Hz, 1H), 3.85-3.67 (m, 6H), 3.39 (dd, J=13.8, 7.7 Hz, 1H), 3.15 (t, J=4.6 Hz, 2H), 3.09-2.98 (m, 2H), 2.92 (dp, J=8.7, 4.4, 3.3 Hz, 4H), 2.72-2.59 (m, 2H).

Example 21: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-oxo-1-piperidyl)-3,4-dihydroisoquinolin-1-one

[0154] ##STR00029##

[0155] The title compound was synthesized in the same manner as in Example 18, except that piperidin-2-one was used instead of pyrrolidin-2-one.

[0156] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.99 (d, J=8.2 Hz, 1H), 7.33-7.17 (m, 2H), 7.20-6.99 (m, 3H), 3.92 (dd, J=13.8, 4.1 Hz, 1H), 3.87-3.66 (m, 5H), 3.58 (t, J=4.7 Hz, 1H), 3.41 (dd, J=13.8, 7.6 Hz, 1H), 3.12-3.01 (m, 2H), 2.93 (d, J=6.4 Hz, 3H), 2.76-2.62 (m, 2H), 2.55 (t, J=6.2 Hz, 2H), 2.07-1.93 (m, 4H), 1.34 (m, 2H).

Example 22: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-pyridylmethylamino)-3,4-dihydroisoquinolin-1-one

[0157] ##STR00030##

[0158] The title compound was synthesized in the same manner as in Example 2, except that 3-pyridylmethanamine was used instead of pyrrolidine.

[0159] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.56 (d, J=2.2 Hz, 1H), 8.43 (d, J=5.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.41 (dd, J=7.9, 4.9 Hz, 1H), 7.18-7.00 (m, 4H), 6.57 (dd, J=8.7, 2.3 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 4.47 (s, 2H), 4.20 (dq, J=7.8, 4.7, 3.9 Hz, 1H), 3.85 (dd, J=13.8, 4.2 Hz, 1H), 3.76-3.57 (m, 4H), 3.33 (d, J=21.3 Hz, 1H), 2.89 (dq, J=15.4, 6.3 Hz, 6H), 2.68-2.55 (m, 2H).

Example 23: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(tetrahydropyran-4-ylmethylamino)-3,4-dihydroisoquinolin-1-one

[0160] ##STR00031##

[0161] The title compound was synthesized in the same manner as in Example 2, except that tetrahydropyran-4-ylmethanamine was used instead of pyrrolidine.

[0162] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.69 (d, J=8.6 Hz, 1H), 7.20-6.96 (m, 4H), 6.54 (dd, J=8.7, 2.3 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 4.21 (tt, J=7.7, 4.6 Hz, 1H), 3.97 (dd, J=11.4, 4.6 Hz, 2H), 3.86 (dd, J=13.8, 4.2 Hz, 1H), 3.78-3.59 (m, 4H), 3.49-3.33 (m, 4H), 3.05 (d, J=6.8 Hz, 2H), 2.88 (dt, J=19.7, 6.1 Hz, 6H), 2.69-2.57 (m, 2H), 1.89 (dqt, J=14.8, 10.9, 6.0 Hz, 1H), 1.79-1.68 (m, 1H), 1.33 (qd, J=14.6, 13.4, 5.8 Hz, 2H).

Example 24: Synthesis of 6-[(1-acetyl-4-piperidyl)methylamino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0163] ##STR00032##

[0164] The title compound was synthesized in the same manner as in Example 2, except that 1-[4-(aminomethyl)-1-piperidyl]ethanone was used instead of pyrrolidine.

[0165] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.69 (d, J=8.6 Hz, 1H), 7.17-6.94 (m, 4H), 6.55 (dd, J=8.6, 2.3 Hz, 1H), 6.44-6.30 (m, 1H), 4.55 (d, J=13.2 Hz, 1H), 4.21 (tt, J=7.8, 4.6 Hz, 1H), 3.95 (d, J=13.8 Hz, 1H), 3.86 (dd, J=13.8, 4.2 Hz, 1H), 3.79-3.58 (m, 4H), 3.34 (d, J=21.4 Hz, 1H), 3.09 (dd, J=14.0, 4.3 Hz, 3H), 2.89 (dt, J=15.3, 5.9 Hz, 6H), 2.72-2.55 (m, 3H), 2.11 (s, 3H), 1.88 (dd, J=19.9, 13.8 Hz, 3H), 1.40-1.06 (m, 2H).

Example 25: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(2-hydroxy-2-methyl-propyl)amino]-3,4-dihydroisoquinolin-1-one

[0166] ##STR00033##

[0167] The title compound was synthesized in the same manner as in Example 2, except that 1-amino-2-methyl-propan-2-ol was used instead of pyrrolidine.

[0168] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.69 (d, J=8.6 Hz, 1H), 7.28-6.96 (m, 4H), 6.60 (dd, J=8.6, 2.3 Hz, 1H), 6.52-6.31 (m, 1H), 4.21 (dq, J=7.9, 4.8, 4.0 Hz, 1H), 3.87 (dd, J=13.8, 4.2 Hz, 1H), 3.80-3.48 (m, 4H), 3.37 (s, 1H), 3.16 (s, 2H), 2.90 (dd, J=17.7, 5.9 Hz, 6H), 2.73-2.55 (m, 2H), 1.27 (s, 6H).

Example 26: Synthesis of N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]pyridine-3-carboxamide

[0169] ##STR00034##

[0170] The title compound was synthesized in the same manner as in Example 18, except that pyridine-3-carboxamide was used instead of pyrrolidin-2-one.

[0171] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.11 (d, J=2.3 Hz, 1H), 8.75 (d, J=4.9 Hz, 1H), 8.45-8.28 (m, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.79 (d, J=2.1 Hz, 1H), 7.64 (ddd, J=24.1, 8.2, 3.5 Hz, 2H), 7.19-6.99 (m, 4H), 4.27 (tt, J=8.0, 4.6 Hz, 1H), 3.91 (dd, J=13.8, 4.1 Hz, 1H), 3.86-3.67 (m, 4H), 3.40 (dd, J=13.8, 7.6 Hz, 1H), 3.14-2.98 (m, 2H), 2.92 (dt, J=9.5, 4.8 Hz, 4H), 2.78-2.59 (m, 2H).

Example 27: Synthesis of N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]pyridine-4-carboxamide

[0172] ##STR00035##

[0173] The title compound was synthesized in the same manner as in Example 18, except that pyridine-4-carboxamide was used instead of pyrrolidin-2-one.

[0174] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.86-8.65 (m, 2H), 8.05-7.88 (m, 3H), 7.81 (d, J=2.1 Hz, 1H), 7.68 (dd, J=8.5, 2.1 Hz, 1H), 7.18-6.94 (m, 4H), 4.28 (tt, J=8.0, 4.6 Hz, 1H), 3.92 (dd, J=13.8, 4.1 Hz, 1H), 3.87-3.71 (m, 4H), 3.41 (dd, J=13.8, 7.6 Hz, 1H), 3.08 (q, J=8.7, 7.0 Hz, 2H), 2.93 (p, J=5.5, 4.6 Hz, 4H), 2.76-2.65 (m, 2H).

Example 28: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3,5-dimethyl-1-piperidyl)-3,4-dihydroisoquinolin-1-one

[0175] ##STR00036##

[0176] The title compound was synthesized in the same manner as in Example 2, except that 3,5-dimethylpiperidine was used instead of pyrrolidine.

[0177] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.76 (t, J=8.0 Hz, 1H), 7.18-6.98 (m, 4H), 6.86 (dd, J=8.9, 2.6 Hz, 1H), 6.77-6.65 (m, 1H), 4.22 (tt, J=7.7, 4.6 Hz, 1H), 3.86 (ddd, J=11.9, 8.0, 4.0 Hz, 3H), 3.81-3.52 (m, 4H), 3.36 (d, J=7.7 Hz, 1H), 3.04-2.83 (m, 6H), 2.73-2.59 (m, 2H), 2.33 (t, J=12.0 Hz, 2H), 1.84 (d, J=13.0 Hz, 1H), 1.73 (qp, J=10.5, 3.8, 2.8 Hz, 2H), 1.08-0.88 (m, 6H), 0.79 (q, J=12.1 Hz, 1H).

Example 29: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3,5-dimethylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one

[0178] ##STR00037##

[0179] The title compound was synthesized in the same manner as in Example 2, except that 2,6-dimethylpiperazine was used instead of pyrrolidine.

[0180] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.80 (d, J=8.7 Hz, 1H), 7.16-6.98 (m, 4H), 6.89 (dd, J=8.9, 2.5 Hz, 1H), 6.76 (d, J=2.5 Hz, 1H), 4.22 (tt, J=7.9, 4.5 Hz, 1H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.81-3.63 (m, 6H), 3.36 (d, J=7.5 Hz, 1H), 3.03-2.80 (m, 8H), 2.71-2.56 (m, 2H), 2.37 (t, J=11.5 Hz, 2H), 1.18 (d, J=6.3 Hz, 6H).

Example 30: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(tetrahydrofuran-3-ylmethylamino)-3,4-dihydroisoquinolin-1-one

[0181] ##STR00038##

[0182] The title compound was synthesized in the same manner as in Example 2, except that tetrahydrofuran-3-ylmethanamine was used instead of pyrrolidine.

[0183] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.71 (d, J=8.6 Hz, 1H), 7.18-6.97 (m, 4H), 6.55 (dd, J=8.7, 2.3 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H), 4.21 (tt, J=7.8, 4.5 Hz, 1H), 3.88 (dp, J=13.0, 4.8 Hz, 3H), 3.80-3.67 (m, 4H), 3.67-3.54 (m, 2H), 3.33 (d, J=21.3 Hz, 1H), 3.14 (d, J=7.4 Hz, 2H), 2.87 (dt, J=18.1, 6.1 Hz, 6H), 2.68-2.52 (m, 3H), 2.10 (tp, J=11.2, 5.4 Hz, 1H), 1.69 (dq, J=13.4, 7.0 Hz, 1H).

Example 31: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidylmethylamino)-3,4-dihydroisoquinolin-1-one

[0184] ##STR00039##

[0185] 6-[(1-Acetyl-4-piperidyl)methylamino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one (10 mg, 0.02 mmol) obtained in Example 24 was dissolved in 4 mL of methanol:H.sub.2O (1:1) solution, and NaOH was added in excess, heated and stirred under reflux. After completion of the reaction, the reaction mixture was extracted with ethyl acetate to obtain 3 mg of the title compound.

[0186] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.69 (d, J=8.6 Hz, 1H), 7.17-6.97 (m, 4H), 6.53 (dd, J=8.8, 2.3 Hz, 1H), 6.39 (s, 1H), 4.28-4.12 (m, 1H), 3.87 (dd, J=13.8, 4.2 Hz, 1H), 3.78-3.60 (m, 4H), 3.34 (d, J=21.7 Hz, 1H), 3.08 (dd, J=20.6, 9.4 Hz, 4H), 2.97-2.79 (m, 6H), 2.63 (q, J=9.3, 6.6 Hz, 4H), 1.82 (t, J=15.1 Hz, 3H), 1.35-1.20 (m, 3H).

Example 32: Synthesis of 6-[(1-acetyl-4-piperidyl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0187] ##STR00040##

[0188] The title compound was synthesized in the same manner as in Example 2, except that 1-(4-amino-1-piperidyl)ethanone was used instead of pyrrolidine.

[0189] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.71 (d, J=8.6 Hz, 1H), 7.16-6.99 (m, 4H), 6.58 (dd, J=8.7, 2.3 Hz, 1H), 6.45 (d, J=2.2 Hz, 1H), 4.40 (dd, J=13.6, 4.8 Hz, 1H), 4.21 (tt, J=8.0, 4.6 Hz, 1H), 3.88 (ddd, J=18.1, 13.5, 6.8 Hz, 2H), 3.80-3.57 (m, 5H), 3.39-3.24 (m, 1H), 2.99-2.79 (m, 7H), 2.72-2.58 (m, 2H), 2.12 (s, 3H), 2.07-1.97 (m, 2H), 1.51-1.28 (m, 3H).

Example 33: Synthesis of N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-2-morpholino-acetamide

[0190] ##STR00041##

[0191] The title compound was synthesized in the same manner as in Example 18, except that 2-morpholinoacetamide was used instead of pyrrolidin-2-one.

[0192] .sup.1H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.34-7.22 (m, 1H), 7.12 (qd, J=8.6, 7.3, 4.1 Hz, 3H), 7.05-6.91 (m, 1H), 4.13 (ddt, J=10.4, 7.1, 3.7 Hz, 1H), 3.89 (dd, J=14.0, 3.2 Hz, 1H), 3.85-3.76 (m, 5H), 3.76-3.68 (m, 2H), 3.63 (d, J=14.9 Hz, 1H), 3.45 (dd, J=14.0, 6.3 Hz, 1H), 3.16 (s, 2H), 3.06-2.97 (m, 2H), 2.97-2.86 (m, 3H), 2.74 (dd, J=9.8, 5.7 Hz, 1H), 2.64 (q, J=6.5, 4.8 Hz, 4H), 2.59-2.51 (m, 2H).

Example 34: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidylamino)-3,4-dihydroisoquinolin-1-one

[0193] ##STR00042##

[0194] 6-[(1-Acetyl-4-piperidyl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one obtained in Example 32 as a starting material was used in the same manner as in Example 31 to obtain the title compound.

[0195] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.69 (d, J=8.5 Hz, 1H), 7.23-6.96 (m, 4H), 6.56 (dd, J=8.6, 2.3 Hz, 1H), 6.47-6.31 (m, 1H), 4.21 (tt, J=8.2, 4.6 Hz, 1H), 3.87 (dd, J=13.8, 4.2 Hz, 1H), 3.77-3.61 (m, 4H), 3.51-3.44 (m, 1H), 3.37 (s, 1H), 3.12 (dt, J=13.0, 3.8 Hz, 2H), 2.98-2.81 (m, 6H), 2.76 (td, J=12.3, 2.7 Hz, 2H), 2.69-2.56 (m, 2H), 2.10-1.99 (m, 2H), 1.50-1.37 (m, 2H).

Example 35: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(hydroxymethyl)-1-piperidyl]-3,4-dihydroisoquinolin-1-one

[0196] ##STR00043##

[0197] The title compound was synthesized in the same manner as in Example 2, except that 4-piperidylmethanol was used instead of pyrrolidine.

[0198] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.7 Hz, 1H), 7.19-6.97 (m, 4H), 6.87 (dd, J=8.9, 2.5 Hz, 1H), 6.74 (d, J=2.5 Hz, 1H), 4.22 (tt, J=7.6, 4.6 Hz, 1H), 4.02-3.81 (m, 3H), 3.81-3.60 (m, 4H), 3.44 (d, J=6.3 Hz, 2H), 3.36 (d, J=7.4 Hz, 1H), 3.02-2.75 (m, 8H), 2.71-2.57 (m, 2H), 1.91-1.77 (m, 2H), 1.69 (ttt, J=10.2, 6.5, 3.7 Hz, 1H), 1.32 (tt, J=12.5, 6.3 Hz, 2H).

Example 36: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[3-(hydroxymethyl)-1-piperidyl]-3,4-dihydroisoquinolin-1-one

[0199] ##STR00044##

[0200] The title compound was synthesized in the same manner as in Example 2, except that 3-piperidylmethanol was used instead of pyrrolidine.

[0201] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.8 Hz, 1H), 7.17-6.99 (m, 4H), 6.87 (dd, J=8.8, 2.5 Hz, 1H), 6.74 (d, J=2.5 Hz, 1H), 4.21 (td, J=7.5, 3.8 Hz, 1H), 4.00-3.90 (m, 1H), 3.87 (dd, J=13.8, 4.2 Hz, 1H), 3.83-3.76 (m, 1H), 3.76-3.61 (m, 4H), 3.53 (dd, J=10.9, 5.1 Hz, 1H), 3.45 (dd, J=10.9, 7.5 Hz, 1H), 3.36 (d, J=7.4 Hz, 1H), 3.00-2.79 (m, 7H), 2.66-2.58 (m, 3H), 1.89-1.73 (m, 3H), 1.64 (qt, J=12.6, 4.5 Hz, 1H), 1.30-1.16 (m, 1H).

Example 37: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-hydroxy-1-piperidyl)-3,4-dihydroisoquinolin-1-one

[0202] ##STR00045##

[0203] The title compound was synthesized in the same manner as in Example 2, except that 4-hydroxypiperidine was used instead of pyrrolidine.

[0204] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.8 Hz, 1H), 7.20-6.97 (m, 4H), 6.89 (dd, J=8.8, 2.5 Hz, 1H), 6.76 (d, J=2.5 Hz, 1H), 4.22 (tt, J=7.7, 4.7 Hz, 1H), 3.95-3.58 (m, 8H), 3.37 (d, J=7.5 Hz, 1H), 3.13-2.79 (m, 8H), 2.71-2.55 (m, 2H), 1.95 (dq, J=12.6, 4.0 Hz, 2H), 1.59 (dtd, J=13.2, 9.6, 3.8 Hz, 2H).

Example 38: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-hydroxy-1-piperidyl)-3,4-dihydroisoquinolin-1-one

[0205] ##STR00046##

[0206] The title compound was synthesized in the same manner as in Example 2, except that 3-hydroxypiperidine was used instead of pyrrolidine.

[0207] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.8 Hz, 1H), 7.19-6.97 (m, 4H), 6.87 (dd, J=8.8, 2.5 Hz, 1H), 6.74 (d, J=2.5 Hz, 1H), 4.22 (tt, J=7.7, 4.6 Hz, 1H), 3.87 (dd, J=13.8, 4.2 Hz, 1H), 3.82-3.57 (m, 7H), 3.36 (d, J=7.5 Hz, 1H), 3.01-2.77 (m, 8H), 2.69-2.58 (m, 2H), 2.00 (d, J=5.0 Hz, 1H), 1.87 (dh, J=12.8, 4.3 Hz, 1H), 1.63 (dtt, J=14.2, 10.6, 3.9 Hz, 1H), 1.48 (tdd, J=12.0, 9.0, 4.0 Hz, 1H).

Example 39: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-oxazolidin-3-yl-3,4-dihydroisoquinolin-1-one

[0208] ##STR00047##

[0209] The title compound was synthesized in the same manner as in Example 2, except that oxazolidine was used instead of pyrrolidine.

[0210] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.6 Hz, 1H), 7.17-6.97 (m, 4H), 6.49 (dd, J=8.6, 2.4 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 4.27-4.13 (m, 3H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.82-3.61 (m, 5H), 3.47 (t, J=6.4 Hz, 2H), 3.40-3.34 (m, 1H), 3.04-2.81 (m, 7H), 2.70-2.56 (m, 2H).

Example 40: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-methylmorpholin-4-yl)-3,4-dihydroisoquinolin-1-one

[0211] ##STR00048##

[0212] The title compound was synthesized in the same manner as in Example 2, except that 3-methylmorpholine was used instead of pyrrolidine.

[0213] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.7 Hz, 1H), 7.17-7.01 (m, 4H), 6.85 (dd, J=8.8, 2.5 Hz, 1H), 6.72 (d, J=2.5 Hz, 1H), 4.22 (tt, J=7.6, 4.6 Hz, 1H), 4.02 (td, J=12.5, 11.6, 5.3 Hz, 2H), 3.88 (dd, J=13.7, 4.2 Hz, 1H), 3.83-3.60 (m, 7H), 3.40-3.34 (m, 2H), 3.18 (td, J=12.2, 3.8 Hz, 1H), 3.01-2.78 (m, 6H), 2.68-2.58 (m, 2H), 1.16 (d, J=6.6 Hz, 3H).

Example 41: Synthesis of N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-2-hydroxy-acetamide

[0214] ##STR00049##

[0215] The title compound was synthesized in the same manner as in Example 18, except that 2-hydroxyacetamide was used instead of pyrrolidin-2-one.

[0216] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.91 (d, J=8.5 Hz, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.57 (dd, J=8.4, 2.1 Hz, 1H), 7.17-7.09 (m, 3H), 7.06 (d, J=5.8 Hz, 1H), 4.27 (tt, J=8.1, 4.7 Hz, 1H), 4.15 (s, 2H), 3.90 (dd, J=13.8, 4.2 Hz, 1H), 3.85-3.67 (m, 4H), 3.41 (dd, J=13.8, 7.5 Hz, 1H), 3.04 (q, J=8.6, 7.0 Hz, 2H), 2.95 (s, 4H), 2.77-2.66 (m, 2H).

Example 42: Synthesis of N-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]acetamide

[0217] ##STR00050##

[0218] The title compound was synthesized in the same manner as in Example 18, except that acetamide was used instead of pyrrolidin-2-one.

[0219] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.88 (d, J=8.5 Hz, 1H), 7.62 (d, J=2.1 Hz, 1H), 7.45 (dd, J=8.6, 2.1 Hz, 1H), 7.16-6.99 (m, 4H), 4.24 (tt, J=7.6, 4.6 Hz, 1H), 3.90 (dd, J=13.8, 4.1 Hz, 1H), 3.83-3.63 (m, 4H), 3.37 (dd, J=13.7, 7.6 Hz, 1H), 3.07-2.81 (m, 6H), 2.69-2.60 (m, 2H), 2.16 (s, 3H).

Example 43: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(morpholinomethyl)-3,4-dihydroisoquinolin-1-one

[0220] ##STR00051##

[0221] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one (100 mg, 0.24 mmol) obtained in Example 1, potassium (morpholin-4-yl)methyltrifluoroborate (55 mg, 0.26 mmol), palladium acetate (3 mg, 0.012 mmol), XPhos (11 mg, 0.023 mmol) and Cs.sub.2CO.sub.3 (228 mg, 0.70 mmol) were dissolved in 3 mL of tetrahydrofuran:distilled water (=10:1) solvent, filled with nitrogen and stirred at 80° C. for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The obtained solution was concentrated under reduced pressure and purified by flash chromatography to obtain 26 mg of the title compound (white).

[0222] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.91 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.15-7.00 (m, 4H), 4.25 (tt, J=7.8, 4.6 Hz, 1H), 3.91 (dd, J=13.8, 4.2 Hz, 1H), 3.85-3.66 (m, 8H), 3.56 (s, 2H), 3.39 (dd, J=13.7, 7.7 Hz, 1H), 3.09-2.98 (m, 2H), 2.96-2.82 (m, 4H), 2.70-2.61 (m, 2H), 2.47 (t, J=4.6 Hz, 4H).

Example 44: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3,4-dihydroisoquinolin-1-one

[0223] ##STR00052##

[0224] The title compound was synthesized in the same manner as in Example 43, except that 2-oxa-6-azaspiro[3.3]heptane was used instead of potassium (morpholin-4-yl)methyltrifluoroborate.

[0225] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.77 (d, J=8.5 Hz, 1H), 7.19-6.98 (m, 4H), 6.39 (dd, J=8.5, 2.3 Hz, 1H), 6.26 (d, J=2.3 Hz, 1H), 4.86 (s, 4H), 4.24 (tt, J=7.8, 4.5 Hz, 1H), 4.11 (s, 4H), 3.86 (d, J=17.1 Hz, 3H), 3.79-3.59 (m, 2H), 3.37 (dd, J=13.9, 7.3 Hz, 1H), 2.95 (d, J=6.2 Hz, 6H), 2.81-2.64 (m, 2H).

Example 45: Synthesis of 3-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxazolidin-2-one

[0226] ##STR00053##

[0227] The title compound was synthesized in the same manner as in Example 18, except that oxazolidin-2-one was used instead of pyrrolidin-2-one.

[0228] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.95 (d, J=8.6 Hz, 1H), 7.63-7.47 (m, 2H), 7.16-6.97 (m, 4H), 4.52 (t, J=8.0 Hz, 2H), 4.25 (tt, J=7.9, 4.6 Hz, 1H), 4.17-4.06 (m, 2H), 3.91 (dd, J=13.8, 4.1 Hz, 1H), 3.85-3.68 (m, 4H), 3.38 (dd, J=13.7, 7.7 Hz, 1H), 3.10-2.98 (m, 2H), 2.98-2.81 (m, 4H), 2.71-2.58 (m, 2H).

Example 46: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[3-(hydroxymethyl)azetidin-1-yl]-3,4-dihydroisoquinolin-1-one

[0229] ##STR00054##

[0230] The title compound was synthesized in the same manner as in Example 2, except that azetidin-3-ylmethanol was used instead of pyrrolidine.

[0231] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.76 (d, J=8.5 Hz, 1H), 7.19-6.99 (m, 4H), 6.35 (dd, J=8.5, 2.3 Hz, 1H), 6.22 (d, J=2.4 Hz, 1H), 4.22 (tt, J=8.1, 4.7 Hz, 1H), 4.00 (t, J=7.8 Hz, 2H), 3.87 (dd, J=13.8, 4.2 Hz, 1H), 3.79-3.59 (m, 8H), 3.36 (d, J=7.4 Hz, 1H), 2.98-2.80 (m, 7H), 2.69-2.57 (m, 2H).

Example 47: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(2S)-2-methylmorpholin-4-yl]-3,4-dihydroisoquinolin-1-one

[0232] ##STR00055##

[0233] The title compound was synthesized in the same manner as in Example 2, except that (2S)-2-methylmorpholine was used instead of pyrrolidine.

[0234] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.7 Hz, 1H), 7.16-6.99 (m, 4H), 6.88 (dd, J=8.9, 2.5 Hz, 1H), 6.75 (d, J=2.5 Hz, 1H), 4.21 (tt, J=7.7, 4.6 Hz, 1H), 3.98 (dd, J=11.4, 3.3 Hz, 1H), 3.87 (dd, J=13.8, 4.1 Hz, 1H), 3.81-3.56 (m, 8H), 3.34 (d, J=13.4 Hz, 1H), 3.02-2.77 (m, 7H), 2.70-2.55 (m, 2H), 2.48 (dd, J=12.5, 10.6 Hz, 1H), 1.24 (d, J=6.1 Hz, 3H).

Example 48: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methoxy-1-piperidyl)-3,4-dihydroisoquinolin-1-one

[0235] ##STR00056##

[0236] The title compound was synthesized in the same manner as in Example 2, except that 4-methoxypiperidine was used instead of pyrrolidine.

[0237] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.7 Hz, 1H), 7.19-6.99 (m, 4H), 6.87 (dd, J=8.9, 2.5 Hz, 1H), 6.74 (d, J=2.5 Hz, 1H), 4.21 (tt, J=7.8, 4.6 Hz, 1H), 3.87 (dd, J=13.8, 4.1 Hz, 1H), 3.78-3.59 (m, 6H), 3.45 (tt, J=8.2, 3.9 Hz, 1H), 3.38 (s, 4H), 3.08 (ddd, J=12.8, 9.3, 3.2 Hz, 2H), 2.99-2.77 (m, 6H), 2.67-2.55 (m, 2H), 1.99 (dq, J=13.0, 4.6, 3.7 Hz, 2H), 1.60 (dtd, J=12.8, 9.0, 3.6 Hz, 2H).

Example 49: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1,1-dioxo-1,4-thiazinan-4-yl)-3,4-dihydroisoquinolin-1-one

[0238] ##STR00057##

[0239] The title compound was synthesized in the same manner as in Example 2, except that 1,4-thiazinane 1,1-dioxide was used instead of pyrrolidine.

[0240] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.85 (d, J=8.7 Hz, 1H), 7.16-6.99 (m, 4H), 6.96 (dd, J=8.8, 2.6 Hz, 1H), 6.85 (d, J=2.6 Hz, 1H), 4.22 (tt, J=7.8, 4.6 Hz, 1H), 3.97 (t, J=5.1 Hz, 4H), 3.87 (dd, J=13.8, 4.2 Hz, 1H), 3.79-3.62 (m, 4H), 3.40-3.30 (m, 1H), 3.10 (t, J=5.0 Hz, 4H), 3.07-2.76 (m, 6H), 2.67-2.54 (m, 2H).

Example 50: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(tetrahydrofuran-3-ylamino)-3,4-dihydroisoquinolin-1-one

[0241] ##STR00058##

[0242] The title compound was synthesized in the same manner as in Example 2, except that tetrahydrofuran-3-amine was used instead of pyrrolidine.

[0243] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.71 (d, J=8.6 Hz, 1H), 7.18-7.00 (m, 4H), 6.56 (dd, J=8.5, 2.3 Hz, 1H), 6.42 (s, 1H), 4.22 (dp, J=7.6, 4.5 Hz, 1H), 4.14 (q, J=7.0 Hz, 1H), 4.03-3.92 (m, 2H), 3.86 (dq, J=14.1, 5.6, 4.5 Hz, 2H), 3.78-3.59 (m, 5H), 3.36 (d, J=7.3 Hz, 1H), 2.90 (dt, J=18.5, 5.8 Hz, 6H), 2.69-2.56 (m, 2H), 2.29 (dt, J=14.8, 7.4 Hz, 1H), 1.91 (td, J=9.8, 9.1, 5.0 Hz, 1H).

Example 51: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(oxetan-3-ylamino)-3,4-dihydroisoquinolin-1-one

[0244] ##STR00059##

[0245] The title compound was synthesized in the same manner as in Example 2, except that oxetan-3-amine was used instead of pyrrolidine.

[0246] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.72 (d, J=8.5 Hz, 1H), 7.16-7.00 (m, 4H), 6.47 (dd, J=8.6, 2.3 Hz, 1H), 6.31 (d, J=2.3 Hz, 1H), 4.99 (t, J=6.5 Hz, 2H), 4.68 (p, J=6.4 Hz, 1H), 4.56 (t, J=6.1 Hz, 2H), 4.21 (tt, J=7.8, 4.6 Hz, 1H), 3.86 (dd, J=13.8, 4.2 Hz, 1H), 3.76-3.58 (m, 4H), 3.35 (s, 1H), 2.87 (dt, J=22.0, 6.0 Hz, 6H), 2.72-2.55 (m, 2H).

Example 52: Synthesis of 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0247] ##STR00060##

[0248] The title compound was synthesized in the same manner as in Example 2, except that N-acetylpiperazine was used instead of pyrrolidine.

[0249] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82 (d, J=8.7 Hz, 1H), 7.15-6.99 (m, 4H), 6.91 (dd, J=8.8, 2.5 Hz, 1H), 6.78 (d, J=2.6 Hz, 1H), 4.22 (tt, J=7.8, 4.7 Hz, 1H), 3.88 (dd, J=13.8, 4.1 Hz, 1H), 3.79-3.63 (m, 8H), 3.42-3.32 (m, 5H), 3.00-2.79 (m, 6H), 2.71-2.57 (m, 2H), 2.16 (s, 3H).

Example 53: Synthesis of tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carboxylate

[0250] ##STR00061##

[0251] The title compound was synthesized in the same manner as in Example 2, except that tert-butyl piperazine-1-carboxylate was used instead of pyrrolidine.

[0252] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.7 Hz, 1H), 7.15-7.00 (m, 4H), 6.90 (dd, J=8.7, 2.5 Hz, 1H), 6.78 (d, J=2.6 Hz, 1H), 4.22 (tt, J=7.9, 4.6 Hz, 1H), 3.88 (dd, J=13.8, 4.1 Hz, 1H), 3.79-3.62 (m, 4H), 3.57 (t, J=4.9 Hz, 4H), 3.39-3.28 (m, 5H), 3.02-2.79 (m, 6H), 2.69-2.57 (m, 2H), 1.50 (s, 9H).

Example 54: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1,4-oxazepan-4-ylmethyl)-3,4-dihydroisoquinolin-1-one

[0253] ##STR00062##

[0254] The title compound was synthesized in the same manner as in Example 43, except that potassium (1,4-oxazepan-4-yl)methyltrifluoroborate was used instead of potassium (morpholin-4-yl)methyltrifluoroborate.

[0255] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.91 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.29 (s, 1H), 7.16-7.01 (m, 4H), 4.25 (tt, J=8.0, 4.6 Hz, 1H), 3.91 (dd, J=13.7, 4.2 Hz, 1H), 3.87-3.67 (m, 10H), 3.38 (dd, J=13.8, 7.6 Hz, 1H), 3.07-2.97 (m, 2H), 2.96-2.80 (m, 4H), 2.78-2.67 (m, 4H), 2.67-2.58 (m, 2H), 1.92 (p, J=5.9 Hz, 2H).

Example 55: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methyl-3-oxo-piperazin-1-yl)-3,4-dihydroisoquinolin-1-one

[0256] ##STR00063##

[0257] The title compound was synthesized in the same manner as in Example 2, except that 1-methylpiperazin-2-one was used instead of pyrrolidine.

[0258] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.84 (d, J=8.7 Hz, 1H), 7.16-6.98 (m, 4H), 6.87 (dd, J=8.8, 2.5 Hz, 1H), 6.80-6.62 (m, 1H), 4.22 (dh, J=10.4, 5.6, 5.0 Hz, 1H), 3.95 (s, 2H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.81-3.60 (m, 6H), 3.54 (t, J=5.4 Hz, 2H), 3.37 (d, J=7.4 Hz, 1H), 3.04 (s, 3H), 3.02-2.81 (m, 6H), 2.69-2.59 (m, 2H).

Example 56: Synthesis of tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

[0259] ##STR00064##

[0260] The title compound was synthesized in the same manner as in Example 8, except that (1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)boronic acid pinacol ester was used instead of 4-pyridylboronic acid.

[0261] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.91 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.35 (s, 1H), 7.16-6.96 (m, 4H), 6.25 (s, 1H), 4.32-4.20 (m, 1H), 4.11 (s, 2H), 3.92 (dd, J=13.7, 4.1 Hz, 1H), 3.77 (d, J=16.8 Hz, 4H), 3.66 (s, 2H), 3.39 (dd, J=13.7, 7.7 Hz, 1H), 3.10-2.97 (m, 2H), 2.90 (dd, J=18.0, 5.4 Hz, 4H), 2.71-2.61 (m, 2H), 2.57 (s, 2H), 1.51 (s, 9H).

Example 57: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroisoquinolin-1-one

[0262] ##STR00065##

[0263] Tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (44 mg, 0.08 mmol) obtained in Example 56 was dissolved in 4 mL of dichloromethane, and 4 M hydrochloric acid (solution in dioxane) solution was added in excess and stirred at room temperature. After completion of the reaction, the reaction mixture was neutralized with 2 N NaOH solution and extracted with a mixed solution of isopropanol and dichloromethane (1:10) to obtain 19 mg of the title compound.

[0264] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.93 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.38 (s, 1H), 7.17-6.99 (m, 4H), 6.31 (d, J=4.5 Hz, 1H), 4.26 (t, J=5.6 Hz, 1H), 3.92 (dd, J=13.7, 4.1 Hz, 1H), 3.86-3.66 (m, 6H), 3.40 (dd, J=13.7, 7.7 Hz, 1H), 3.30 (d, J=6.0 Hz, 2H), 3.12-2.99 (m, 2H), 2.91 (dd, J=15.5, 5.4 Hz, 4H), 2.76-2.60 (m, 4H).

Example 58: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-piperazin-1-yl-3,4-dihydroisoquinolin-1-one

[0265] ##STR00066##

[0266] Tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carboxylate obtained in Example 53 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

[0267] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.7 Hz, 1H), 7.18-7.00 (m, 4H), 6.96-6.87 (m, 1H), 6.79 (s, 1H), 4.23 (dp, J=8.4, 4.8 Hz, 1H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.82-3.64 (m, 4H), 3.37 (dd, J=11.5, 5.9 Hz, 5H), 3.04 (t, J=5.0 Hz, 4H), 3.01-2.83 (m, 6H), 2.66 (dd, J=6.1, 4.0 Hz, 2H).

Example 59: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methylsulfonylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one

[0268] ##STR00067##

[0269] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-piperazin-1-yl-3,4-dihydroisoquinolin-1-one (18 mg, 0.04 mmol) obtained in Example 58, triethylamine (12 μL, 0.08 mmol) and methanesulfonyl chloride (4 μL, 0.05 mmol) were dissolved in 3 mL of dichloromethane and stirred at room temperature. The reaction was terminated by adding a saturated aqueous solution of ammonium chloride to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was dried under reduced pressure, and purification was carried out by flash chromatography to obtain 7 mg of the title compound.

[0270] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.83 (d, J=8.7 Hz, 1H), 7.18-7.03 (m, 4H), 6.95 (d, J=9.2 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 4.25 (s, 1H), 3.88 (dd, J=13.9, 4.2 Hz, 1H), 3.83-3.65 (m, 4H), 3.51-3.42 (m, 4H), 3.42-3.34 (m, 6H), 3.04-2.85 (m, 8H), 2.75-2.62 (m, 2H).

Example 60: Synthesis of methyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carboxylate

[0271] ##STR00068##

[0272] The title compound was synthesized in the same manner as in Example 59, except that methyl chloroformate was used instead of methanesulfonyl chloride.

[0273] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.7 Hz, 1H), 7.16-7.00 (m, 4H), 6.92 (dd, J=8.8, 2.5 Hz, 1H), 6.84-6.72 (m, 1H), 4.23 (tt, J=7.8, 4.5 Hz, 1H), 3.89 (dd, J=13.8, 4.2 Hz, 1H), 3.83-3.66 (m, 7H), 3.63 (t, J=5.2 Hz, 4H), 3.37 (d, J=14.3 Hz, 4H), 3.10-2.80 (m, 7H), 2.74-2.57 (m, 2H).

Example 61: Synthesis of 6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0274] ##STR00069##

[0275] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroisoquinolin-1-one obtained in Example 57 as a starting material was used in the same manner as in Example 59 to obtain the title compound, except that acetic anhydride was used instead of methanesulfonyl chloride.

[0276] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.92 (d, J=8.2 Hz, 1H), 7.49-7.39 (m, 1H), 7.36 (s, 1H), 7.17-6.98 (m, 4H), 6.28 (d, J=5.0 Hz, 1H), 4.25 (td, J=7.9, 3.7 Hz, 3H), 3.92 (dd, J=13.8, 4.1 Hz, 1H), 3.86-3.67 (m, 6H), 3.39 (dd, J=13.8, 7.7 Hz, 1H), 3.05 (t, J=6.9 Hz, 2H), 2.92 (tt, J=10.5, 4.9 Hz, 4H), 2.73-2.52 (m, 4H), 2.18 (d, J=15.2 Hz, 3H).

Example 62: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(2,2,2-trifluoro acetyl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one

[0277] ##STR00070##

[0278] The title compound was synthesized in the same manner as in Example 59, except that trifluoroacetyl chloride was used instead of methanesulfonyl chloride.

[0279] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.83 (d, J=8.7 Hz, 1H), 7.18-7.01 (m, 4H), 6.95 (d, J=9.1 Hz, 1H), 6.83 (s, 1H), 4.24 (d, J=4.6 Hz, 1H), 3.94-3.65 (m, 9H), 3.49-3.34 (m, 5H), 3.07-2.82 (m, 6H), 2.71-2.58 (m, 2H).

Example 63: Synthesis of tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperidine-1-carboxylate

[0280] ##STR00071##

[0281] Tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (85 mg, 0.16 mmol) obtained in Example 56 was dissolved in methanol (5 mL), and palladium-charcoal was added and stirred while charging hydrogen gas. After completion of the reaction, the reaction mixture was filtered through Celite. The solvent was dried under reduced pressure, and the purification was carried out by flash chromatography to obtain 5 mg of the title compound.

[0282] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.88 (d, J=7.9 Hz, 1H), 7.25 (d, J=7.6 Hz, 2H), 7.20-7.02 (m, 4H), 4.25 (t, J=11.9 Hz, 3H), 3.94-3.81 (m, 2H), 3.74 (tt, J=12.6, 6.5 Hz, 3H), 3.43 (td, J=13.8, 13.0, 7.9 Hz, 1H), 3.12-2.67 (m, 10H), 1.84 (d, J=13.1 Hz, 2H), 1.63 (qd, J=12.5, 4.2 Hz, 3H), 1.50 (s, 9H).

Example 64: Synthesis of [(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-isopropylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one

[0283] ##STR00072##

[0284] The title compound was synthesized in the same manner as in Example 2, except that 4-isopropylpiperazine was used instead of pyrrolidine.

[0285] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.80 (d, J=8.7 Hz, 1H), 7.17-6.99 (m, 4H), 6.95-6.86 (m, 1H), 6.78 (s, 1H), 4.25 (d, J=12.4 Hz, 1H), 3.89 (dd, J=13.8, 4.2 Hz, 1H), 3.82-3.63 (m, 4H), 3.37 (t, J=5.3 Hz, 6H), 3.05-2.82 (m, 6H), 2.78-2.69 (m, 4H), 2.65 (t, J=5.1 Hz, 2H), 1.15 (d, J=6.5 Hz, 6H).

Example 65: Synthesis of ethyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carboxylate

[0286] ##STR00073##

[0287] The title compound was synthesized in the same manner as in Example 2, except that ethyl piperazine-1-carboxylate was used instead of pyrrolidine.

[0288] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.7 Hz, 1H), 7.17-7.00 (m, 4H), 6.98-6.88 (m, 1H), 6.87-6.74 (m, 1H), 4.18 (hept, J=8.1 Hz, 3H), 3.89 (dd, J=13.8, 4.2 Hz, 1H), 3.83-3.54 (m, 7H), 3.37 (d, J=13.3 Hz, 6H), 3.05-2.76 (m, 6H), 2.64 (t, J=5.0 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).

Example 66: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(4-methoxy-1-piperidyl)methyl]-3,4-dihydroisoquinolin-1-one

[0289] ##STR00074##

[0290] The title compound was synthesized in the same manner as in Example 43, except that potassium (4-methoxy-1-piperidyl)methyltrifluoroborate was used instead of potassium (morpholin-4-yl)methyltrifluoroborate.

[0291] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.91 (d, J=7.9 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.15-7.00 (m, 4H), 4.25 (q, J=8.0, 6.7 Hz, 1H), 3.92 (dd, J=13.7, 4.2 Hz, 1H), 3.86-3.67 (m, 4H), 3.57 (s, 2H), 3.46-3.23 (m, 4H), 3.04 (t, J=6.8 Hz, 2H), 2.90 (dd, J=15.8, 5.1 Hz, 4H), 2.83-2.56 (m, 4H), 2.32-2.14 (m, 3H), 1.92 (s, 2H), 1.59 (d, J=11.1 Hz, 2H).

Example 67: Synthesis of 6-(1-acetyl-4-piperidyl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0292] ##STR00075##

[0293] 6-(1-Acetyl-3,6-dihydro-2H-pyridin-4-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one obtained in Example 61 as a starting material was used in the same manner as in Example 63 to obtain the title compound.

[0294] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.89 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.19 (s, 1H), 7.14-7.02 (m, 4H), 4.78-4.60 (m, 1H), 4.25 (s, 1H), 4.07 (d, J=13.7 Hz, 1H), 3.91 (dd, J=13.9, 4.1 Hz, 1H), 3.76 (d, J=16.3 Hz, 4H), 3.39 (dd, J=13.8, 7.6 Hz, 1H), 3.31-3.20 (m, 1H), 3.03 (t, J=7.0 Hz, 2H), 2.98-2.82 (m, 4H), 2.80-2.62 (m, 3H), 2.16 (s, 3H), 2.05 (d, J=9.7 Hz, 1H), 1.98-1.81 (m, 2H), 1.68 (dqd, J=37.9, 12.7, 4.3 Hz, 2H).

Example 68: Synthesis of 6-[(4-acetylpiperazin-1-yl)methyl]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0295] ##STR00076##

[0296] The title compound was synthesized in the same manner as in Example 43, except that potassium (4-acetylpiperazin-1-yl)methyltrifluoroborate was used instead of potassium (morpholin-4-yl)methyltrifluoroborate.

[0297] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.92 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.17-7.02 (m, 4H), 4.27 (h, J=5.8, 4.8 Hz, 1H), 3.91 (dd, J=13.8, 4.2 Hz, 1H), 3.87-3.69 (m, 4H), 3.68-3.50 (m, 6H), 3.42 (dd, J=13.8, 7.4 Hz, 1H), 3.05 (t, J=6.9 Hz, 2H), 2.95 (s, 4H), 2.71 (h, J=7.6, 7.2 Hz, 2H), 2.48 (dt, J=20.9, 5.1 Hz, 4H), 2.10 (s, 3H).

Example 69: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-propanoylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one

[0298] ##STR00077##

[0299] The title compound was synthesized in the same manner as in Example 59, except that propionyl chloride was used instead of methanesulfonyl chloride.

[0300] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82 (d, J=8.7 Hz, 1H), 7.17-7.01 (m, 4H), 6.93 (d, J=8.8 Hz, 1H), 6.80 (s, 1H), 3.89 (dd, J=13.8, 4.2 Hz, 1H), 3.82-3.62 (m, 8H), 3.38 (dd, J=16.1, 5.9 Hz, 6H), 3.05-2.82 (m, 6H), 2.70-2.57 (m, 2H), 2.48 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H).

Example 70: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(2-methylpropanoyl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one

[0301] ##STR00078##

[0302] The title compound was synthesized in the same manner as in Example 59, except that isobutyryl chloride was used instead of methanesulfonyl chloride.

[0303] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82 (d, J=8.7 Hz, 1H), 7.19-7.00 (m, 4H), 6.91 (dd, J=8.8, 2.5 Hz, 1H), 6.79 (d, J=2.5 Hz, 1H), 4.22 (dq, J=7.9, 4.8, 3.9 Hz, 1H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.81-3.63 (m, 8H), 3.43-3.31 (m, 5H), 3.08-2.80 (m, 7H), 2.68-2.57 (m, 2H), 1.14 (d, J=6.6 Hz, 6H).

Example 71: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one

[0304] ##STR00079##

[0305] The title compound was synthesized in the same manner as in Example 59, except that pivaloyl chloride was used instead of methanesulfonyl chloride.

[0306] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.70 (d, J=8.7 Hz, 1H), 7.05-6.88 (m, 4H), 6.80 (dd, J=8.9, 2.5 Hz, 1H), 6.68 (d, J=2.5 Hz, 1H), 4.11 (tt, J=7.9, 4.6 Hz, 1H), 3.82-3.68 (m, 5H), 3.68-3.51 (m, 4H), 3.23 (d, J=5.3 Hz, 5H), 2.90-2.69 (m, 6H), 2.59-2.40 (m, 2H), 1.21 (s, 9H).

Example 72: Synthesis of tert-butyl 5-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0307] ##STR00080##

[0308] The title compound was synthesized in the same manner as in Example 2, except that tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was used instead of pyrrolidine.

[0309] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.6 Hz, 1H), 7.18-6.97 (m, 4H), 6.57 (d, J=8.7 Hz, 1H), 6.49-6.36 (m, 1H), 4.60 (d, J=16.3 Hz, 2H), 4.22 (dt, J=8.0, 4.9 Hz, 1H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.79-3.57 (m, 5H), 3.48-3.35 (m, 3H), 3.20 (t, J=8.5 Hz, 1H), 3.02-2.79 (m, 6H), 2.64 (t, J=5.4 Hz, 2H), 2.07-1.95 (m, 2H), 1.45 (d, J=24.1 Hz, 9H).

Example 73: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3,4-dihydroisoquinolin-1-one

[0310] ##STR00081##

[0311] The title compound was synthesized in the same manner as in Example 2, except that 2-oxa-5-azabicyclo[2.2.1]heptane was used instead of pyrrolidine.

[0312] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.6 Hz, 1H), 7.30-6.99 (m, 4H), 6.65-6.50 (m, 1H), 6.46 (s, 1H), 4.68 (d, J=20.8 Hz, 2H), 4.25 (s, 1H), 3.93-3.80 (m, 4H), 3.72 (tp, J=12.6, 6.6 Hz, 2H), 3.58 (d, J=9.6 Hz, 1H), 3.43-3.35 (m, 3H), 3.19 (d, J=9.7 Hz, 1H), 2.96 (s, 5H), 2.72 (t, J=5.7 Hz, 2H), 2.02 (q, J=10.0 Hz, 3H).

Example 74: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-hydroxy-3,4-dihydroisoquinolin-1-one

[0313] ##STR00082##

[0314] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one (543 mg, 1.31 mmol) obtained in Example 1, KOH (293 mg, 5.23 mmol), t-BuXPhos (56 mg, 0.13 mmol) and Pd(dba).sub.2 (38 mg, 0.07 mmol) were put into a microwave container together with 7 mL of 1,4-dioxane:H.sub.2O (1:1) solution, and heated and stirred at 100° C. for 2 hours. After adding ethyl acetate, the reaction mixture was acidified with 2 N hydrochloric acid. The obtained aqueous layer was basified with a saturated K.sub.2CO.sub.3 solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by evaporation under reduced pressure, and then used in the next reaction without further purification (product: 300 mg).

[0315] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.80 (d, J=8.5 Hz, 1H), 7.23-7.05 (m, 4H), 6.78-6.71 (m, 1H), 6.65 (s, 1H), 4.30 (t, J=6.0 Hz, 1H), 3.99 (s, 2H), 3.85 (dd, J=13.9, 4.4 Hz, 1H), 3.73 (dtd, J=16.8, 11.6, 10.5, 5.7 Hz, 2H), 3.43 (dd, J=13.9, 7.1 Hz, 1H), 3.19-2.92 (m, 6H), 2.92-2.77 (m, 2H).

Example 75: Synthesis of 2-chloro-6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7,8-dihydro-1,6-naphthyridin-5-one

[0316] ##STR00083##

[0317] The title compound was synthesized in the same manner as in Example 1, except that 2-chloro-7,8-dihydro-6H-1,6-naphthyridin-5-one was used instead of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one.

[0318] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.23 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.15-6.99 (m, 4H), 4.24 (qt, J=12.3, 6.0 Hz, 1H), 3.93-3.70 (m, 5H), 3.41 (dd, J=13.8, 7.8 Hz, 1H), 3.16 (t, J=6.8 Hz, 2H), 2.91 (tt, J=10.1, 4.6 Hz, 4H), 2.72-2.59 (m, 2H).

Example 76: Synthesis of 6-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0319] ##STR00084##

[0320] Tert-butyl 5-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 72 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

[0321] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.79 (d, J=8.6 Hz, 1H), 7.31-7.01 (m, 4H), 6.60 (d, J=8.8 Hz, 1H), 6.52-6.37 (m, 1H), 4.71 (d, J=22.1 Hz, 2H), 4.26 (s, 1H), 3.86 (t, J=6.1 Hz, 2H), 3.81-3.42 (m, 5H), 2.98 (s, 5H), 2.75 (q, J=7.1, 6.0 Hz, 2H), 2.27-1.91 (m, 6H).

Example 77: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-piperidylamino)-3,4-dihydroisoquinolin-1-one

[0322] ##STR00085##

Example 77-1: Synthesis of tert-butyl 3-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]amino]piperidine-1-carboxylate

[0323] The title compound was synthesized in the same manner as in Example 2, except that tert-butyl 3-aminopiperidine-1-carboxylate was used instead of pyrrolidine.

Example 77-2: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-piperidylamino)-3,4-dihydroisoquinolin-1-one

[0324] Tert-butyl 3-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]amino]piperidine-1-carboxylate obtained in Example 77-1 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

[0325] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.70 (d, J=8.6 Hz, 1H), 7.19-6.97 (m, 4H), 6.57 (dd, J=8.6, 2.3 Hz, 1H), 6.44 (s, 1H), 4.21 (tt, J=7.9, 4.6 Hz, 1H), 3.86 (dd, J=13.8, 4.2 Hz, 1H), 3.79-3.58 (m, 4H), 3.50 (td, J=9.4, 4.6 Hz, 1H), 3.38-3.30 (m, 1H), 3.26 (d, J=3.7 Hz, 1H), 3.01 (dt, J=13.0, 4.0 Hz, 1H), 2.88 (dt, J=18.9, 6.1 Hz, 6H), 2.65 (td, J=9.8, 8.7, 3.8 Hz, 3H), 2.46 (dd, J=12.2, 9.4 Hz, 1H), 2.12-2.01 (m, 1H), 1.84 (dt, J=13.5, 4.0 Hz, 1H), 1.66 (ddt, J=21.0, 14.0, 7.0 Hz, 1H), 1.54-1.39 (m, 1H).

Example 78: Synthesis of tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-1,4-diazepane-1-carboxylate

[0326] ##STR00086##

[0327] The title compound was synthesized in the same manner as in Example 2, except that tert-butyl 1,4-diazepane-1-carboxylate was used instead of pyrrolidine.

[0328] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.77 (d, J=8.8 Hz, 1H), 7.16-6.98 (m, 4H), 6.73 (d, J=8.8 Hz, 1H), 6.59 (s, 1H), 4.28-4.09 (m, 1H), 3.87 (dd, J=13.8, 4.3 Hz, 1H), 3.79-3.57 (m, 9H), 3.37 (d, J=6.4 Hz, 4H), 3.03-2.78 (m, 6H), 2.73-2.55 (m, 2H), 1.95 (dq, J=19.3, 6.2 Hz, 2H), 1.34 (d, J=44.1 Hz, 9H).

Example 79: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methyl-3-oxo-1,4-diazepan-1-yl)-3,4-dihydroisoquinolin-1-one

[0329] ##STR00087##

[0330] The title compound was synthesized in the same manner as in Example 2, except that 1-methyl-1,4-diazepan-2-one was used instead of pyrrolidine.

[0331] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.7 Hz, 1H), 7.17-6.98 (m, 4H), 6.84 (dd, J=8.9, 2.6 Hz, 1H), 6.72 (d, J=2.5 Hz, 1H), 4.25 (d, J=22.5 Hz, 3H), 3.87 (dd, J=13.8, 4.3 Hz, 1H), 3.82-3.62 (m, 6H), 3.62-3.53 (m, 2H), 3.39-3.31 (m, 1H), 2.93 (d, J=17.9 Hz, 7H), 2.86 (t, J=5.8 Hz, 2H), 2.70-2.56 (m, 2H), 1.90 (p, J=5.3 Hz, 2H).

Example 80: Synthesis of 6-(4-acetyl-1,4-diazepan-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0332] ##STR00088##

Example 80-1: Synthesis of 6-(1,4-diazepan-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0333] Tert-butyl 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-1,4-diazepane-1-carboxylate obtained in Example 78 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

Example 80-2: Synthesis of 6-(4-acetyl-1,4-diazepan-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0334] 6-(1,4-Diazepan-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one obtained in Example 80-1 as a starting material was used in the same manner as in Example 59 to obtain the title compound, except that acetic anhydride was used instead of methanesulfonyl chloride.

[0335] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (dd, J=8.8, 4.3 Hz, 1H), 7.17-7.00 (m, 4H), 6.75 (t, J=7.3 Hz, 1H), 6.66-6.53 (m, 1H), 4.22 (dt, J=8.2, 5.2 Hz, 1H), 3.93-3.61 (m, 11H), 3.49 (q, J=5.2, 4.8 Hz, 2H), 3.41-3.34 (m, 1H), 2.93 (ddt, J=20.0, 10.9, 6.8 Hz, 6H), 2.72-2.56 (m, 2H), 2.15-1.87 (m, 5H).

Example 81: Synthesis of 6-(5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0336] ##STR00089##

[0337] 6-(2,5-Diazabicyclo[2.2.1]heptan-2-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one obtained in Example 76 as a starting material was used in the same manner as in Example 59 to obtain the title compound, except that acetic anhydride was used instead of methanesulfonyl chloride.

[0338] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.6 Hz, 1H), 7.22-7.04 (m, 4H), 6.59 (d, J=8.7 Hz, 1H), 6.52-6.41 (m, 1H), 4.70 (d, J=22.3 Hz, 2H), 4.29 (q, J=6.1, 5.5 Hz, 1H), 3.97 (s, 2H), 3.85 (dd, J=13.8, 4.4 Hz, 1H), 3.80-3.50 (m, 4H), 3.49-3.36 (m, 2H), 3.25 (dd, J=29.9, 9.3 Hz, 1H), 3.14-2.92 (m, 6H), 2.83 (d, J=8.0 Hz, 2H), 2.23-1.89 (m, 5H).

Example 82: Synthesis of 6-(4-acetyl-4,7-diazaspiro[2.5]octan-7-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0339] ##STR00090##

[0340] The title compound was synthesized in the same manner as in Example 2, except that 1-(4,7-diazaspiro[2.5]octan-4-yl)ethanone was used instead of pyrrolidine.

[0341] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.80 (d, J=8.7 Hz, 1H), 7.17-7.00 (m, 4H), 6.94-6.83 (m, 1H), 6.74 (s, 1H), 4.32-4.13 (m, 1H), 3.98-3.61 (m, 7H), 3.47-3.34 (m, 3H), 3.21 (d, J=18.2 Hz, 2H), 3.03-2.76 (m, 6H), 2.70-2.55 (m, 2H), 2.19 (d, J=47.0 Hz, 3H), 1.26-1.05 (m, 4H).

Example 83: Synthesis of 6-[(1-acetyl-4-piperidyl)methoxy]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0342] ##STR00091##

[0343] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-hydroxy-3,4-dihydroisoquinolin-1-one (50 mg, 0.14 mmol) obtained in Example 74, (1-acetyl-4-piperidyl)methyl methanesulfonate (60 mg, 0.28 mmol) and Cs.sub.2CO.sub.3 (140 mg, 0.42 mmol) were dissolved in acetonitrile (4 mL) and stirred at 150° C. in a microwave tube. The reaction mixture was diluted with ethyl acetate, filtered through Celite. The solvent was dried under reduced pressure, and the purification was carried out by flash chromatography to obtain 27 mg of the title compound.

[0344] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.88 (d, J=8.7 Hz, 1H), 7.17-6.98 (m, 4H), 6.90 (d, J=8.8 Hz, 1H), 6.82 (s, 1H), 4.59 (d, J=13.2 Hz, 1H), 4.24 (d, J=6.8 Hz, 1H), 4.07-3.84 (m, 4H), 3.84-3.63 (m, 4H), 3.42-3.34 (m, 1H), 3.18 (t, J=12.6 Hz, 1H), 3.07-2.79 (m, 6H), 2.78-2.58 (m, 3H), 2.13 (s, 3H), 1.92 (dd, J=25.6, 13.3 Hz, 2H), 1.47-1.19 (m, 3H).

Example 84: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-methyl-5-oxo-1,4-diazepan-1-yl)-3,4-dihydroisoquinolin-1-one

[0345] ##STR00092##

[0346] The title compound was synthesized in the same manner as in Example 2, except that 4-methyl-1,4-diazepan-5-one was used instead of pyrrolidine.

[0347] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.80 (d, J=8.7 Hz, 1H), 7.18-6.99 (m, 4H), 6.86 (d, J=9.1 Hz, 1H), 6.73 (d, J=2.5 Hz, 1H), 4.22 (d, J=7.1 Hz, 1H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.80-3.71 (m, 3H), 3.67 (q, J=7.7, 7.0 Hz, 6H), 3.37 (d, J=7.4 Hz, 2H), 3.04-2.90 (m, 7H), 2.87 (d, J=5.4 Hz, 2H), 2.81 (t, J=5.6 Hz, 2H), 2.64 (t, J=5.2 Hz, 2H).

Example 85: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-isopropyl-3-oxo-piperazin-1-yl)-3,4-dihydroisoquinolin-1-one

[0348] ##STR00093##

[0349] The title compound was synthesized in the same manner as in Example 2, except that 1-isopropylpiperazin-2-one was used instead of pyrrolidine.

[0350] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.84 (d, J=8.7 Hz, 1H), 7.17-6.97 (m, 4H), 6.90-6.81 (m, 1H), 6.72 (s, 1H), 4.81 (p, J=6.8 Hz, 1H), 4.31-4.18 (m, 1H), 3.99 (s, 2H), 3.89 (dd, J=13.8, 4.2 Hz, 1H), 3.81-3.65 (m, 4H), 3.62 (t, J=5.3 Hz, 2H), 3.49 (t, J=5.2 Hz, 2H), 3.39 (t, J=9.6 Hz, 1H), 3.05-2.80 (m, 6H), 2.71-2.59 (m, 2H), 1.21 (d, J=6.8 Hz, 6H).

Example 86: Synthesis of 6-(4-acetyl-2-oxo-piperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0351] ##STR00094##

[0352] The title compound was synthesized in the same manner as in Example 18, except that 4-acetylpiperazin-2-one was used instead of pyrrolidin-2-one.

[0353] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.01 (d, J=8.3 Hz, 1H), 7.35 (d, J=17.4 Hz, 2H), 7.16-7.00 (m, 4H), 4.37 (d, J=18.9 Hz, 2H), 4.26 (s, 1H), 4.04-3.87 (m, 4H), 3.87-3.68 (m, 4H), 3.40 (dd, J=13.7, 7.8 Hz, 2H), 3.11-2.99 (m, 2H), 2.92 (dd, J=13.3, 4.8 Hz, 4H), 2.73-2.62 (m, 2H), 2.20 (d, J=8.6 Hz, 3H).

Example 87: Synthesis of 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carbaldehyde

[0354] ##STR00095##

[0355] The title compound was synthesized in the same manner as in Example 2, except that piperazine-1-carbaldehyde was used instead of pyrrolidine.

[0356] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.12 (s, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.19-7.01 (m, 4H), 6.94 (dd, J=8.8, 2.4 Hz, 1H), 6.82 (s, 1H), 4.22 (dt, J=8.1, 5.0 Hz, 1H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.82-3.64 (m, 6H), 3.64-3.55 (m, 2H), 3.43-3.34 (m, 5H), 3.04-2.83 (m, 6H), 2.75-2.55 (m, 2H).

Example 88: Synthesis of 2-(4-acetylpiperazin-1-yl)-6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7,8-dihydro-1,6-naphthyridin-5-one

[0357] ##STR00096##

[0358] 2-Chloro-6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7,8-dihydro-1,6-naphthyridin-5-one (100 mg, 0.27 mmol) obtained in Example 75 and N-acetylpiperazine (100 μL, 1.08 mmol) were dissolved in ethanol and stirred at 110° C. in a microwave tube. The reaction mixture was dried under reduced pressure and purified by flash chromatography to obtain 41 mg of the title compound.

[0359] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.00 (d, J=8.9 Hz, 1H), 7.17-6.95 (m, 4H), 6.76 (d, J=9.0 Hz, 1H), 4.22 (tt, J=7.8, 4.6 Hz, 1H), 3.94-3.61 (m, 10H), 3.42-3.34 (m, 1H), 3.05-2.80 (m, 6H), 2.71-2.54 (m, 2H), 2.17 (s, 3H).

Example 89: Synthesis of 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-morpholino-7,8-dihydro-1,6-naphthyridin-5-one

[0360] ##STR00097##

[0361] The title compound was synthesized in the same manner as in Example 88, except that morpholine was used instead of N-acetylpiperazine.

[0362] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.99 (d, J=8.8 Hz, 1H), 7.16-7.00 (m, 4H), 6.72 (d, J=9.0 Hz, 1H), 4.21 (dq, J=7.9, 4.8, 3.9 Hz, 1H), 3.91-3.58 (m, 10H), 3.42-3.33 (m, 1H), 3.04-2.80 (m, 6H), 2.68-2.57 (m, 2H).

Example 90: Synthesis of N-[1-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-4-piperidyl]-N-methyl-acetamide

[0363] ##STR00098##

[0364] The title compound was synthesized in the same manner as in Example 2, except that N-methyl-N-(4-piperidyl)acetamide was used instead of pyrrolidine

[0365] 1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82-7.73 (m, 1H), 7.17-6.99 (m, 4H), 6.92 (d, J=8.9 Hz, 1H), 6.79 (d, J=3.7 Hz, 1H), 4.60 (t, J=12.4 Hz, 1H), 4.23 (s, 1H), 4.03 (d, J=12.4 Hz, 2H), 3.88 (dd, J=13.9, 4.2 Hz, 1H), 3.81-3.62 (m, 4H), 3.41-3.35 (m, 1H), 3.05-2.76 (m, 10H), 2.64 (d, J=7.4 Hz, 2H), 2.17 (d, J=33.1 Hz, 3H), 2.07-1.62 (m, 5H).

Example 91: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-tetrahydropyran-4-yloxy-3,4-dihydroisoquinolin-1-one

[0366] ##STR00099##

[0367] The title compound was synthesized in the same manner as in Example 83, except that 4-bromotetrahydropyran was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

[0368] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.88 (d, J=8.6 Hz, 1H), 7.17-7.01 (m, 4H), 6.92 (d, J=8.7 Hz, 1H), 6.84 (s, 1H), 4.68 (tt, J=8.4, 4.0 Hz, 1H), 4.23 (q, J=5.7, 5.1 Hz, 1H), 3.92 (ddd, J=29.3, 12.9, 5.2 Hz, 3H), 3.84-3.55 (m, 6H), 3.37 (dd, J=13.7, 7.4 Hz, 1H), 3.07-2.82 (m, 6H), 2.77-2.56 (m, 2H), 2.06 (dq, J=12.5, 3.9 Hz, 2H), 1.74 (dtd, J=12.7, 8.4, 3.7 Hz, 2H).

Example 92: Synthesis of N-[1-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-4-piperidyl]acetamide

[0369] ##STR00100##

[0370] The title compound was synthesized in the same manner as in Example 2, except that N-(4-piperidyl)acetamide was used instead of pyrrolidine.

[0371] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.7 Hz, 1H), 7.23-7.04 (m, 4H), 6.93-6.82 (m, 1H), 6.77 (s, 1H), 4.30 (tt, J=8.2, 4.6 Hz, 1H), 4.00 (s, 2H), 3.95-3.79 (m, 4H), 3.72 (dp, J=17.8, 6.2 Hz, 2H), 3.43 (dd, J=13.9, 6.9 Hz, 1H), 3.12 (t, J=6.2 Hz, 2H), 3.07-2.76 (m, 8H), 1.95 (s, 5H), 1.55 (qd, J=11.8, 3.8 Hz, 2H).

Example 93: Synthesis of 6-[(1-acetyl-3-piperidyl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0372] ##STR00101##

[0373] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3-piperidylamino) 3,4-dihydroisoquinolin-1-one obtained in Example 77 as a starting material was used in the same manner as in Example 59 to obtain the title compound, except that acetic anhydride was used instead of methanesulfonyl chloride.

[0374] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.71 (dd, J=12.4, 8.6 Hz, 1H), 7.22-6.99 (m, 4H), 6.61 (t, J=10.1 Hz, 1H), 6.49 (d, J=6.4 Hz, 1H), 4.22 (t, J=6.2 Hz, 1H), 3.93-3.56 (m, 7H), 3.45-3.13 (m, 4H), 3.02-2.82 (m, 6H), 2.64 (dt, J=19.5, 6.0 Hz, 2H), 2.21-1.97 (m, 3H), 1.92-1.47 (m, 4H).

Example 94: Synthesis of 7-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3-one

[0375] ##STR00102##

[0376] The title compound was synthesized in the same manner as in Example 2, except that 1,5,6,7,8,8a-hexahydrooxazolo[3,4-a]pyrazin-3-one was used instead of pyrrolidine.

[0377] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82 (d, J=8.7 Hz, 1H), 7.17-7.04 (m, 4H), 6.95 (d, J=8.7 Hz, 1H), 6.84 (s, 1H), 4.52 (t, J=8.4 Hz, 1H), 4.25 (dt, J=7.7, 4.8 Hz, 1H), 4.16-3.98 (m, 3H), 3.87 (q, J=14.1 Hz, 4H), 3.73 (dtd, J=19.2, 12.7, 5.3 Hz, 3H), 3.39 (dd, J=13.9, 7.3 Hz, 1H), 3.23 (td, J=12.7, 3.7 Hz, 1H), 3.05-2.66 (m, 10H).

Example 95: Synthesis of 6-[(1-acetyl-4-piperidyl)oxy]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0378] ##STR00103##

[0379] The title compound was synthesized in the same manner as in Example 83, except that (1-acetyl-4-piperidyl) methanesulfonate was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

[0380] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.89 (d, J=8.6 Hz, 1H), 7.17-7.01 (m, 4H), 6.94 (d, J=8.8 Hz, 1H), 6.86 (s, 1H), 4.75 (dt, J=7.7, 3.7 Hz, 1H), 4.23 (p, J=6.9, 6.4 Hz, 1H), 3.96-3.65 (m, 7H), 3.63-3.46 (m, 2H), 3.43-3.34 (m, 1H), 3.08-2.77 (m, 6H), 2.72-2.54 (m, 2H), 2.14 (s, 3H), 2.10-1.92 (m, 2H), 1.89-1.65 (m, 2H).

Example 96: Synthesis of 6-(1-acetylazetidin-3-yl)oxy-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0381] ##STR00104##

Example 96-1: Synthesis of tert-butyl 3-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxy]azetidine-1-carboxylate

[0382] The title compound was synthesized in the same manner as in Example 83, except that tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

Example 96-2: Synthesis of 6-(azetidin-3-yloxy)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0383] Tert-butyl 3-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxy]azetidine-1-carboxylate obtained in Example 96-1 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

Example 96-3: Synthesis of 6-(1-acetylazetidin-3-yl)oxy-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0384] 6-(Azetidin-3-yloxy)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one obtained in Example 96-2 as a starting material was used in the same manner as in Example 59 to obtain the title compound, except that acetic anhydride was used instead of methanesulfonyl chloride.

[0385] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.91 (t, J=7.6 Hz, 1H), 7.24-7.08 (m, 4H), 6.83 (d, J=9.0 Hz, 1H), 6.75 (s, 1H), 5.12 (q, J=5.2 Hz, 1H), 4.73-4.62 (m, 1H), 4.43 (dd, J=11.1, 6.6 Hz, 1H), 4.34 (s, 1H), 4.24 (dd, J=9.9, 3.7 Hz, 1H), 4.11 (d, J=8.5 Hz, 2H), 3.96 (dd, J=11.0, 3.8 Hz, 1H), 3.79 (dddd, J=25.9, 19.1, 13.3, 5.5 Hz, 3H), 3.48 (dd, J=13.9, 6.9 Hz, 1H), 3.23 (s, 2H), 3.13-2.90 (m, 6H), 1.93 (s, 3H).

Example 97: Synthesis of 1-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-N,N-dimethyl-piperidine-4-carboxamide

[0386] ##STR00105##

[0387] The title compound was synthesized in the same manner as in Example 2, except that N,N-dimethylpiperidine-4-carboxamide was used instead of pyrrolidine.

[0388] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.79 (d, J=8.7 Hz, 1H), 7.18-6.98 (m, 4H), 6.90 (d, J=8.8 Hz, 1H), 6.77 (s, 1H), 4.21 (dh, J=19.3, 6.5 Hz, 1H), 3.98 (d, J=12.9 Hz, 2H), 3.88 (dd, J=13.7, 4.3 Hz, 1H), 3.80-3.63 (m, 4H), 3.37 (d, J=7.4 Hz, 1H), 3.17 (s, 3H), 3.03-2.82 (m, 12H), 2.71-2.57 (m, 2H), 1.86-1.74 (m, 4H).

Example 98: Synthesis of 6-[(1-acetylazepan-4-yl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0389] ##STR00106##

Example 98-1: Synthesis of tert-butyl 4-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]amino]azepane-1-carboxylate

[0390] The title compound was synthesized in the same manner as in Example 2, except that tert-butyl 4-aminoazepane-1-carboxylate was used instead of pyrrolidine.

Example 98-2: Synthesis of 6-(azepan-4-ylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0391] Tert-butyl 4-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]amino]azepane-1-carboxylate obtained in Example 98-1 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

Example 98-3: Synthesis of 6-[(1-acetylazepan-4-yl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0392] 6-(Azepan-4-ylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one obtained in Example 98-2 as a starting material was used in the same manner as in Example 59 to obtain the title compound, except that acetic anhydride was used instead of methanesulfonyl chloride.

[0393] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.70 (dd, J=8.5, 3.3 Hz, 1H), 7.19-6.97 (m, 4H), 6.52 (t, J=7.3 Hz, 1H), 6.37 (d, J=5.6 Hz, 1H), 4.24 (p, J=6.8, 6.0 Hz, 1H), 3.85 (s, 3H), 3.77-3.33 (m, 9H), 2.94 (d, J=21.7 Hz, 6H), 2.81-2.64 (m, 2H), 2.15 (d, J=6.0 Hz, 4H), 2.07-1.88 (m, 2H), 1.89-1.47 (m, 2H).

Example 99: Synthesis of 6-[(1-acetylpyrrolidin-3-yl)amino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0394] ##STR00107##

[0395] The title compound was synthesized in the same manner as in Example 2, except that 1-(3-aminopyrrolidin-1-yl)ethanone was used instead of pyrrolidine.

[0396] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.72 (dd, J=8.8, 3.7 Hz, 1H), 7.19-6.96 (m, 4H), 6.59 (t, J=6.3 Hz, 1H), 6.46 (d, J=6.7 Hz, 1H), 4.28-4.05 (m, 2H), 3.96-3.81 (m, 1H), 3.81-3.51 (m, 7H), 3.49-3.35 (m, 2H), 3.00-2.83 (m, 6H), 2.72-2.58 (m, 2H), 2.06 (t, J=11.9 Hz, 5H).

Example 100: Synthesis of 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carboxamide

[0397] ##STR00108##

[0398] The title compound was synthesized in the same manner as in Example 2, except that piperazine-1-carboxamide was used instead of pyrrolidine.

[0399] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.70 (d, J=8.7 Hz, 1H), 7.05-6.87 (m, 4H), 6.79 (d, J=8.9 Hz, 1H), 6.66 (s, 1H), 4.11 (p, J=6.2 Hz, 1H), 3.76 (dd, J=13.8, 4.1 Hz, 1H), 3.60 (d, J=21.1 Hz, 4H), 3.45 (d, J=5.2 Hz, 4H), 3.31-3.17 (m, 7H), 2.94-2.67 (m, 6H), 2.60-2.44 (m, 2H).

Example 101: Synthesis of 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]piperazine-1-carbonitrile

[0400] ##STR00109##

[0401] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-piperazin-1-yl-3,4-dihydroisoquinolin-1-one (100 mg, 0.24 mmol) obtained in Example 58, BrCN (28 mg, 0.26 mmol) and K.sub.2CO.sub.3 (50 mg, 0.36 mmol) were dissolved in chloroform and stirred under heating at 60° C. Ethyl acetate was added to the reaction mixture, 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 purification was carried out by flash chromatography to obtain 9 mg of the title compound.

[0402] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82 (d, J=8.7 Hz, 1H), 7.18-7.03 (m, 4H), 6.93 (d, J=8.9 Hz, 1H), 6.82 (s, 1H), 4.26 (p, J=6.9 Hz, 1H), 3.86 (d, J=9.8 Hz, 3H), 3.73 (qt, J=12.7, 6.5 Hz, 2H), 3.42 (s, 9H), 2.98 (s, 6H), 2.82-2.68 (m, 2H).

Example 102: Synthesis of 6-(6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0403] ##STR00110##

[0404] The title compound was synthesized in the same manner as in Example 2, except that 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was used instead of pyrrolidine.

[0405] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.86 (d, J=8.7 Hz, 1H), 7.18-6.96 (m, 7H), 6.88 (s, 1H), 4.55 (s, 2H), 4.25 (q, J=6.8, 5.9 Hz, 1H), 4.18 (t, J=5.4 Hz, 2H), 3.96-3.82 (m, 3H), 3.83-3.65 (m, 4H), 3.43-3.36 (m, 1H), 3.09-2.84 (m, 6H), 2.67 (t, J=5.2 Hz, 2H).

Example 103: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(3,4-dimethyl-5-oxo-piperazin-1-yl)-3,4-dihydroisoquinolin-1-one

[0406] ##STR00111##

[0407] The title compound was synthesized in the same manner as in Example 2, except that 1,6-dimethylpiperazin-2-one was used instead of pyrrolidine.

[0408] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.84 (d, J=8.6 Hz, 1H), 7.18-6.99 (m, 4H), 6.87 (d, J=8.8 Hz, 1H), 6.74 (s, 1H), 4.24 (q, J=6.3, 5.9 Hz, 1H), 4.12 (d, J=17.3 Hz, 1H), 3.88 (dd, J=14.0, 4.2 Hz, 1H), 3.81 (s, 3H), 3.76 (d, J=6.6 Hz, 2H), 3.70 (h, J=6.7 Hz, 2H), 3.52-3.35 (m, 2H), 3.04 (s, 3H), 3.01 (d, J=7.1 Hz, 2H), 2.94 (s, 4H), 2.70 (t, J=5.4 Hz, 2H), 1.37 (d, J=6.4 Hz, 3H).

Example 104: Synthesis of 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one

[0409] ##STR00112##

Example 104-1: Synthesis of 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one

[0410] ##STR00113##

[0411] The title compound was synthesized in the same manner as in Example 1, except that 6-bromo-4,4-dimethyl-2,3-dihydroisoquinolin-1-one was used instead of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one.

[0412] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.87 (d, J=8.3 Hz, 1H), 7.61-7.49 (m, 2H), 7.17-7.00 (m, 4H), 4.24 (d, J=12.3 Hz, 1H), 3.91 (dd, J=13.8, 4.1 Hz, 1H), 3.75 (s, 2H), 3.63 (d, J=12.8 Hz, 1H), 3.52 (d, J=12.9 Hz, 1H), 3.40 (dt, J=13.2, 6.6 Hz, 1H), 2.98-2.82 (m, 4H), 2.70-2.59 (m, 2H), 1.37 (d, J=3.5 Hz, 6H).

Example 104-2: Synthesis of 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one

[0413] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one obtained in Example 104-1 as a starting material was used in the same manner as in Example 2 to obtain the title compound, except that N-acetylpiperazine was used instead of pyrrolidine.

[0414] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.85 (d, J=8.5 Hz, 1H), 7.17-7.00 (m, 4H), 6.95-6.84 (m, 2H), 4.30-4.18 (m, 1H), 3.90 (dd, J=13.6, 4.3 Hz, 1H), 3.80-3.68 (m, 6H), 3.57 (d, J=12.5 Hz, 1H), 3.49-3.34 (m, 6H), 2.91 (dd, J=15.1, 5.1 Hz, 4H), 2.72-2.57 (m, 2H), 2.17 (d, J=1.7 Hz, 3H), 1.35 (d, J=4.1 Hz, 6H).

Example 105: Synthesis of 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]spiro[3H-isoquinoline-4,1′-cyclopropane]-1-one

[0415] ##STR00114##

Example 105-1: Synthesis of 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]spiro[3H-isoquinoline-4,1′-cyclopropan]-1-one

[0416] The title compound was synthesized in the same manner as in Example 1, except that 6-bromospiro[2,3-dihydroisoquinoline-4,1′-cyclopropane]-1-one was used instead of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one.

Example 105-2: Synthesis of 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]spiro[3H-isoquinoline-4,1′-cyclopropan]-1-one

[0417] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]spiro[3H-isoquinoline-4,1′-cyclopropan]-1-one obtained in Example 105-1 as a starting material was used in the same manner as in Example 2 to obtain the title compound, except that N-acetylpiperazine was used instead of pyrrolidine.

[0418] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.87 (d, J=8.7 Hz, 1H), 7.18-7.00 (m, 4H), 6.90 (d, J=8.8 Hz, 1H), 6.44 (s, 1H), 4.23 (s, 1H), 3.88 (dd, J=14.1, 4.2 Hz, 1H), 3.80-3.64 (m, 6H), 3.55 (q, J=12.8 Hz, 3H), 3.38 (t, J=4.9 Hz, 4H), 3.02-2.84 (m, 4H), 2.65 (d, J=7.4 Hz, 2H), 2.16 (s, 3H), 1.18-0.98 (m, 4H).

Example 106: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-pyrrolidin-1-yl-1-piperidyl)-3,4-dihydroisoquinolin-1-one

[0419] ##STR00115##

[0420] The title compound was synthesized in the same manner as in Example 2, except that 4-pyrrolidin-1-ylpiperidine was used instead of pyrrolidine.

[0421] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.79 (d, J=8.7 Hz, 1H), 7.15-6.99 (m, 4H), 6.90 (d, J=8.9 Hz, 1H), 6.78 (s, 1H), 4.30-4.14 (m, 1H), 4.05-3.81 (m, 3H), 3.72 (d, J=22.4 Hz, 4H), 3.37 (d, J=7.4 Hz, 1H), 3.03-2.71 (m, 11H), 2.71-2.57 (m, 2H), 2.44 (t, J=11.5 Hz, 1H), 2.08 (d, J=13.9 Hz, 3H), 1.88 (d, J=5.4 Hz, 4H), 1.62 (qd, J=12.2, 6.4 Hz, 2H).

Example 107: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(1-piperidyl)-1-piperidyl]-3,4-dihydroisoquinolin-1-one

[0422] ##STR00116##

[0423] The title compound was synthesized in the same manner as in Example 2, except that 1-(4-piperidyl)piperidine was used instead of pyrrolidine.

[0424] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.79 (d, J=8.7 Hz, 1H), 7.16-6.98 (m, 4H), 6.90 (d, J=8.9 Hz, 1H), 6.77 (s, 1H), 4.22 (p, J=6.2 Hz, 1H), 4.02 (d, J=13.0 Hz, 2H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.72 (d, J=22.7 Hz, 4H), 3.37 (d, J=7.4 Hz, 1H), 3.02-2.77 (m, 8H), 2.77-2.55 (m, 7H), 2.02 (d, J=12.1 Hz, 2H), 1.67 (dt, J=14.6, 7.4 Hz, 6H), 1.54 (q, J=6.0 Hz, 2H).

Example 108: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-morpholino-1-piperidyl)-3,4-dihydroisoquinolin-1-one

[0425] ##STR00117##

[0426] The title compound was synthesized in the same manner as in Example 2, except that 4-(4-piperidyl)morpholine was used instead of pyrrolidine.

[0427] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.7 Hz, 1H), 7.20-7.01 (m, 4H), 6.90 (d, J=8.9 Hz, 1H), 6.77 (s, 1H), 4.23 (p, J=6.6, 5.8 Hz, 1H), 3.99 (d, J=13.1 Hz, 2H), 3.86 (dt, J=15.4, 7.7 Hz, 1H), 3.82-3.63 (m, 8H), 3.42-3.34 (m, 1H), 3.01-2.78 (m, 8H), 2.65 (dt, J=18.4, 4.2 Hz, 6H), 2.47-2.37 (m, 1H), 2.08-1.95 (m, 2H), 1.64-1.50 (m, 2H).

Example 109: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(2-methoxyethyl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one

[0428] ##STR00118##

[0429] The title compound was synthesized in the same manner as in Example 2, except that 1-(2-methoxyethyl)piperazine was used instead of pyrrolidine.

[0430] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.79 (d, J=8.6 Hz, 1H), 7.18-7.00 (m, 4H), 6.90 (d, J=9.0 Hz, 1H), 6.78 (s, 1H), 4.23 (d, J=7.9 Hz, 1H), 4.01 (d, J=13.0 Hz, 2H), 3.88 (dd, J=13.9, 4.2 Hz, 1H), 3.80-3.61 (m, 4H), 3.40-3.34 (m, 1H), 3.03-2.78 (m, 8H), 2.72-2.60 (m, 2H), 2.54 (t, J=11.7 Hz, 1H), 2.40 (s, 6H), 2.02 (d, J=12.9 Hz, 2H), 1.59 (tt, J=13.4, 6.8 Hz, 2H).

Example 110: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(dimethylamino)-1-piperidyl]-3,4-dihydroisoquinolin-1-one

[0431] ##STR00119##

[0432] The title compound was synthesized in the same manner as in Example 2, except that N,N-dimethylpiperidin-4-amine was used instead of pyrrolidine.

[0433] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.80 (d, J=8.7 Hz, 1H), 7.17-7.00 (m, 4H), 6.90 (d, J=8.9 Hz, 1H), 6.77 (s, 1H), 4.23 (p, J=6.6 Hz, 1H), 3.96-3.83 (m, 1H), 3.82-3.65 (m, 4H), 3.64-3.47 (m, 4H), 3.41-3.34 (m, 7H), 3.04-2.83 (m, 6H), 2.78-2.58 (m, 7H).

Example 111: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(dimethylamino)-1-piperidyl]-4,4-dimethyl-3H-isoquinolin-1-one

[0434] ##STR00120##

[0435] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one obtained in Example 104-1 as a starting material was used in the same manner as in Example 2 to obtain the title compound, except that N,N-dimethylpiperidin-4-amine was used instead of pyrrolidine.

[0436] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82 (d, J=8.6 Hz, 1H), 7.18-7.00 (m, 4H), 6.95-6.78 (m, 2H), 4.23 (s, 1H), 4.02 (d, J=12.9 Hz, 2H), 3.94-3.85 (m, 1H), 3.76 (s, 2H), 3.56 (d, J=13.0 Hz, 1H), 3.50-3.35 (m, 2H), 3.00-2.78 (m, 6H), 2.66 (d, J=6.4 Hz, 2H), 2.53 (t, J=12.4 Hz, 1H), 2.40 (s, 5H), 2.04 (dd, J=11.7, 5.3 Hz, 3H), 1.60 (q, J=11.7 Hz, 2H), 1.34 (d, J=4.1 Hz, 6H).

Example 112: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-6-morpholino-3H-isoquinolin-1-one

[0437] ##STR00121##

[0438] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one obtained in Example 104-1 as a starting material was used in the same manner as in Example 2 to obtain the title compound, except that morpholine was used instead of pyrrolidine.

[0439] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.85 (d, J=8.6 Hz, 1H), 7.19-7.00 (m, 4H), 6.94-6.81 (m, 2H), 4.24 (d, J=8.1 Hz, 1H), 3.96-3.79 (m, 4H), 3.76 (s, 2H), 3.62-3.36 (m, 3H), 3.29 (d, J=4.6 Hz, 5H), 2.91 (dd, J=17.0, 5.4 Hz, 4H), 2.66 (d, J=7.4 Hz, 2H), 1.35 (d, J=4.1 Hz, 6H).

Example 113: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(2-morpholinoethoxy)-3,4-dihydroisoquinolin-1-one

[0440] ##STR00122##

[0441] The title compound was synthesized in the same manner as in Example 83, except that 4-(2-chloroethyl)morpholine was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

[0442] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.89 (q, J=7.9, 6.5 Hz, 1H), 7.25 (d, J=7.0 Hz, 1H), 7.19-7.02 (m, 3H), 6.95 (dd, J=19.4, 8.9 Hz, 1H), 6.85 (s, 1H), 4.32-4.15 (m, 3H), 3.87 (d, J=11.1 Hz, 2H), 3.71 (dtd, J=18.6, 14.2, 13.7, 4.9 Hz, 8H), 3.58 (t, J=4.9 Hz, 2H), 3.44 (ddd, J=20.9, 15.6, 9.8 Hz, 2H), 3.10-2.92 (m, 4H), 2.80 (dt, J=34.2, 6.6 Hz, 3H), 2.62 (t, J=4.6 Hz, 3H).

Example 114: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-ethyl-4-piperidyl)oxy]-3,4-dihydroisoquinolin-1-one

[0443] ##STR00123##

Example 114-1: Synthesis of tert-butyl 4-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxy]piperidine-1-carboxylate

[0444] The title compound was synthesized in the same manner as in Example 83, except that tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

Example 114-2: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidyloxy)-3,4-dihydroisoquinolin-1-one

[0445] Tert-butyl 4-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxy]piperidine-1-carboxylate obtained in Example 114-1 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

Example 114-3: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-ethyl-4-piperidyl)oxy]-3,4-dihydroisoquinolin-1-one

[0446] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidyloxy)-3,4-dihydroisoquinolin-1-one (93 mg, 0.17 mmol) obtained in Example 114-2, acetaldehyde (50 μL, 0.85 mmol) and NaBH.sub.3CN (55 μL, 0.85 mmol) were dissolved in methanol (4 mL) and stirred at room temperature. Ethyl acetate was added to the reaction mixture, washed with a saturated aqueous K.sub.2CO.sub.3 solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the purification was carried out by flash chromatography to obtain 22 mg of the title compound.

[0447] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.88 (d, J=8.6 Hz, 1H), 7.17-6.97 (m, 4H), 6.92 (d, J=8.7 Hz, 1H), 6.84 (s, 1H), 4.60 (s, 1H), 4.23 (dt, J=8.2, 5.1 Hz, 1H), 3.89 (dd, J=13.7, 4.2 Hz, 1H), 3.74 (d, J=18.5 Hz, 4H), 3.38 (dd, J=13.6, 7.4 Hz, 1H), 3.01 (q, J=7.6, 7.0 Hz, 2H), 2.91 (dq, J=10.7, 5.9, 5.4 Hz, 6H), 2.72-2.52 (m, 6H), 2.17-2.00 (m, 2H), 1.97-1.81 (m, 2H), 1.19 (t, J=7.3 Hz, 3H).

Example 115: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-ethyl-4-piperidyl)methyloxy]-3,4-dihydroisoquinolin-1-one

[0448] ##STR00124##

Example 115-1: Synthesis of tert-butyl 4-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxymethyl]piperidine-1-carboxylate

[0449] The title compound was synthesized in the same manner as in Example 83, except that tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

Example 115-2: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidylmethoxy)-3,4-dihydroisoquinolin-1-one

[0450] Tert-butyl 4-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxymethyl]piperidine-1-carboxylate obtained in Example 115-1 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

Example 115-3: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-ethyl-4-piperidyl) methoxy]-3,4-dihydroisoquinolin-1-one

[0451] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidylmethoxy)-3,4-dihydroisoquinolin-1-one obtained in Example 115-2 as a starting material was used in the same manner as in Example 114-3 to obtain the title compound.

[0452] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.87 (d, J=8.6 Hz, 1H), 7.19-6.97 (m, 4H), 6.88 (d, J=8.8 Hz, 1H), 6.80 (s, 1H), 4.23 (p, J=6.2 Hz, 1H), 3.90 (dd, J=14.6, 4.7 Hz, 3H), 3.84-3.65 (m, 4H), 3.41-3.34 (m, 1H), 3.11-2.96 (m, 4H), 2.96-2.80 (m, 4H), 2.70-2.56 (m, 2H), 2.47 (q, J=7.2 Hz, 2H), 2.05 (t, J=11.8 Hz, 2H), 1.89 (d, J=13.0 Hz, 3H), 1.46 (p, J=10.7, 9.4 Hz, 2H), 1.14 (t, J=7.2 Hz, 3H).

Example 116: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[3-(dimethylamino)-1-piperidyl]-3,4-dihydroisoquinolin-1-one

[0453] ##STR00125##

[0454] The title compound was synthesized in the same manner as in Example 2, except that N,N-dimethylpiperidin-3-amine was used instead of pyrrolidine.

[0455] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.79 (d, J=8.8 Hz, 1H), 7.17-7.02 (m, 4H), 6.89 (d, J=8.9 Hz, 1H), 6.75 (s, 1H), 4.23 (s, 1H), 4.03 (d, J=12.6 Hz, 1H), 3.87 (t, J=12.5 Hz, 2H), 3.73 (d, J=23.1 Hz, 4H), 3.38 (d, J=7.0 Hz, 1H), 3.04-2.75 (m, 8H), 2.65 (d, J=8.0 Hz, 2H), 2.54-2.43 (m, 1H), 2.41 (d, J=1.9 Hz, 6H), 2.08 (d, J=13.6 Hz, 1H), 1.94-1.79 (m, 1H), 1.63 (t, J=13.4 Hz, 1H), 1.50 (q, J=12.3 Hz, 1H).

Example 117: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-[(dimethylamino)methyl]-1-piperidyl]-3,4-dihydroisoquinolin-1-one

[0456] ##STR00126##

[0457] The title compound was synthesized in the same manner as in Example 2, except that N,N-dimethyl-1-(4-piperidyl)methanamine was used instead of pyrrolidine.

[0458] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.7 Hz, 1H), 7.18-6.99 (m, 4H), 6.89 (d, J=8.8 Hz, 1H), 6.76 (s, 1H), 4.22 (d, J=6.5 Hz, 1H), 3.99-3.82 (m, 3H), 3.81-3.62 (m, 4H), 3.37 (d, J=7.3 Hz, 1H), 2.89 (ddd, J=25.6, 19.0, 12.1 Hz, 7H), 2.72-2.58 (m, 2H), 2.30 (d, J=10.2 Hz, 7H), 1.86 (q, J=21.4, 17.7 Hz, 3H), 1.30 (q, J=11.9 Hz, 2H).

Example 118: Synthesis of 6-[4-(diethylamino)-1-piperidyl]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one

[0459] ##STR00127##

[0460] The title compound was synthesized in the same manner as in Example 2, except that N,N-diethylpiperidin-4-amine was used instead of pyrrolidine.

[0461] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.79 (d, J=8.5 Hz, 1H), 7.08 (d, J=20.8 Hz, 4H), 6.91 (d, J=8.7 Hz, 1H), 6.78 (s, 1H), 4.23 (s, 1H), 4.03 (d, J=12.9 Hz, 2H), 3.88 (d, J=14.1 Hz, 1H), 3.75 (s, 4H), 3.39 (s, 2H), 2.88 (ddd, J=33.5, 24.9, 16.2 Hz, 11H), 2.64 (d, J=7.6 Hz, 2H), 1.99 (dt, J=30.8, 14.2 Hz, 3H), 1.75-1.57 (m, 2H), 1.15 (t, J=7.3 Hz, 6H).

Example 119: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-[2-(dimethylamino)ethoxy]-1-piperidyl]-3,4-dihydroisoquinolin-1-one

[0462] ##STR00128##

[0463] The title compound was synthesized in the same manner as in Example 2, except that N,N-dimethyl-2-(4-piperidyloxy)ethanamine was used instead of pyrrolidine.

[0464] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=9.8 Hz, 1H), 7.19-7.00 (m, 4H), 6.90 (d, J=8.9 Hz, 1H), 6.77 (s, 1H), 4.23 (s, 1H), 3.88 (dd, J=13.5, 4.2 Hz, 1H), 3.80-3.67 (m, 7H), 3.60 (s, 1H), 3.38 (d, J=7.2 Hz, 1H), 3.13 (t, J=11.1 Hz, 2H), 2.92 (ddd, J=27.2, 12.7, 6.4 Hz, 6H), 2.76 (t, J=5.8 Hz, 2H), 2.65 (d, J=7.6 Hz, 2H), 2.45 (s, 6H), 2.02 (d, J=12.9 Hz, 2H), 1.92 (s, 1H), 1.66 (d, J=10.3 Hz, 2H).

Example 120: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-[2-methoxyethyl(methyl)amino]-1-piperidyl]-3,4-dihydroisoquinolin-1-one

[0465] ##STR00129##

[0466] The title compound was synthesized in the same manner as in Example 2, except that N-(2-methoxyethyl)-N-methyl-piperidin-4-amine was used instead of pyrrolidine.

[0467] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.78 (d, J=8.7 Hz, 1H), 7.18-7.00 (m, 4H), 6.90 (d, J=8.8 Hz, 1H), 6.77 (s, 1H), 4.22 (s, 1H), 4.00 (d, J=12.8 Hz, 2H), 3.88 (dd, J=13.8, 4.2 Hz, 1H), 3.72 (d, J=21.2 Hz, 4H), 3.53 (t, J=5.8 Hz, 2H), 3.36 (d, J=1.8 Hz, 4H), 3.05-2.78 (m, 8H), 2.78-2.56 (m, 5H), 2.36 (s, 3H), 1.94 (d, J=12.6 Hz, 2H), 1.61 (dt, J=14.6, 10.2 Hz, 2H).

Example 121: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(oxetan-3-yl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one

[0468] ##STR00130##

[0469] The title compound was synthesized in the same manner as in Example 2, except that 1-(oxetan-3-yl)piperazine was used instead of pyrrolidine.

[0470] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.6 Hz, 1H), 7.17-7.01 (m, 4H), 6.91 (d, J=8.9 Hz, 1H), 6.78 (s, 1H), 4.74 (t, J=6.6 Hz, 2H), 4.66 (t, J=6.2 Hz, 2H), 4.23 (p, J=6.7 Hz, 1H), 3.88 (dd, J=13.9, 4.1 Hz, 1H), 3.73 (d, J=22.7 Hz, 4H), 3.56 (p, J=6.3 Hz, 1H), 3.38 (t, J=5.1 Hz, 5H), 3.03-2.82 (m, 6H), 2.70-2.58 (m, 2H), 2.52 (t, J=5.1 Hz, 4H).

Example 122: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-tetrahydropyran-4-ylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one

[0471] ##STR00131##

[0472] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-piperazin-1-yl-3,4-dihydroisoquinolin-1-one obtained in Example 58 as a starting material was used in the same manner as in Example 114-3 to obtain the title compound, except that tetrahydropyran-4-one was used instead of acetaldehyde.

[0473] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.80 (d, J=8.7 Hz, 1H), 7.18-7.01 (m, 4H), 6.91 (d, J=8.8 Hz, 1H), 6.78 (s, 1H), 4.23 (s, 1H), 4.11-3.97 (m, 2H), 3.88 (dd, J=13.6, 4.2 Hz, 1H), 3.81-3.64 (m, 4H), 3.44 (t, J=11.8 Hz, 3H), 3.37 (t, J=4.6 Hz, 4H), 3.05-2.84 (m, 6H), 2.76 (t, J=5.1 Hz, 4H), 2.66 (d, J=7.7 Hz, 2H), 2.56-2.40 (m, 1H), 1.91 (d, J=12.5 Hz, 2H), 1.67-1.50 (m, 2H).

Example 123: Synthesis of 6-[4-(diethylamino)-1-piperidyl]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one

[0474] ##STR00132##

[0475] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one obtained in Example 104-1 as a starting material was used in the same manner as in Example 2, except that N,N-diethylpiperidin-4-amine was used instead of pyrrolidine.

[0476] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82 (d, J=8.6 Hz, 1H), 7.21-6.98 (m, 4H), 6.97-6.78 (m, 2H), 4.23 (s, 1H), 4.03 (d, J=13.0 Hz, 2H), 3.90 (d, J=13.4 Hz, 1H), 3.75 (s, 2H), 3.56 (d, J=12.7 Hz, 1H), 3.49-3.34 (m, 2H), 2.99-2.73 (m, 10H), 2.71-2.58 (m, 2H), 2.02 (dd, J=21.5, 11.5 Hz, 3H), 1.66 (q, J=12.0, 11.5 Hz, 2H), 1.34 (d, J=4.2 Hz, 6H), 1.15 (t, J=7.3 Hz, 6H).

Example 124: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-6-(4-pyrrolidin-1-yl-1-piperidyl)-3H-isoquinolin-1-one

[0477] ##STR00133##

[0478] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one obtained in Example 104-1 as a starting material was used in the same manner as in Example 2, except that 4-pyrrolidin-1-ylpiperidine was used instead of pyrrolidine.

[0479] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.82 (d, J=8.7 Hz, 1H), 7.18-7.01 (m, 4H), 6.94-6.82 (m, 2H), 4.23 (s, 1H), 3.98 (d, J=13.1 Hz, 2H), 3.90 (dd, J=13.9, 4.4 Hz, 1H), 3.76 (s, 2H), 3.56 (d, J=12.6 Hz, 1H), 3.49-3.35 (m, 2H), 2.97-2.77 (m, 9H), 2.69-2.60 (m, 2H), 2.47 (d, J=12.0 Hz, 1H), 2.08 (dd, J=24.5, 11.3 Hz, 3H), 1.88 (d, J=5.8 Hz, 4H), 1.72-1.55 (m, 2H), 1.34 (d, J=4.1 Hz, 6H).

Example 125: Synthesis of 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-1-oxo-3H-isoquinolin-6-yl]piperazine-1-carbaldehyde

[0480] ##STR00134##

[0481] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one obtained in Example 104-1 as a starting material was used in the same manner as in Example 2, except that N-formylpiperazine was used instead of pyrrolidine.

[0482] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.13 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.18-7.00 (m, 4H), 6.99-6.88 (m, 2H), 4.24 (s, 1H), 3.90 (dd, J=14.0, 4.2 Hz, 1H), 3.76 (s, 2H), 3.69 (t, J=5.4 Hz, 2H), 3.62 (t, J=5.0 Hz, 2H), 3.57 (d, J=12.6 Hz, 1H), 3.46 (d, J=12.6 Hz, 1H), 3.43-3.39 (m, 2H), 3.37 (d, J=5.9 Hz, 3H), 2.91 (dd, J=17.2, 5.4 Hz, 4H), 2.71-2.62 (m, 2H), 1.35 (d, J=4.2 Hz, 6H).

Example 126: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(dimethylamino)-1-piperidyl]-4,4-dimethyl-3H-isoquinolin-1-one; dihydrochloride

[0483] ##STR00135##

[0484] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(dimethylamino)-1-piperidyl]-4,4-dimethyl-3H-isoquinolin-1-one (30 mg) obtained in Example 111 was dissolved in 4 mL of 1,4-dioxane, and an excess of 4 M hydrochloric acid in dioxane solution was added and stirred at room temperature. The solvent was removed by evaporation under reduced pressure to obtain 17 mg of the title compound without further purification.

[0485] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.92 (d, J=8.6 Hz, 1H), 7.30 (t, J=8.1 Hz, 3H), 7.23 (s, 1H), 7.15 (s, 2H), 4.75-4.57 (m, 1H), 4.54-4.37 (m, 2H), 4.09 (d, J=13.0 Hz, 2H), 3.88 (s, 1H), 3.83-3.72 (m, 1H), 3.68 (s, 4H), 3.60-3.46 (m, 4H), 3.41 (d, J=13.7 Hz, 2H), 3.17 (t, J=12.5 Hz, 3H), 2.94 (s, 6H), 2.29 (d, J=12.3 Hz, 2H), 2.00 (p, J=12.4, 11.6 Hz, 2H), 1.37 (d, J=8.1 Hz, 6H).

Example 127: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-tetrahydrofuran-3-ylpiperazin-1-yl)-3,4-dihydroisoquinolin-1-one

[0486] ##STR00136##

[0487] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-piperazin-1-yl-3,4-dihydroisoquinolin-1-one obtained in Example 58 as a starting material was used in the same manner as in Example 114-3 to obtain the title compound, except that tetrahydrofuran-3-one was used instead of acetaldehyde.

[0488] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (d, J=8.7 Hz, 1H), 7.18-7.00 (m, 4H), 6.90 (d, J=8.9 Hz, 1H), 6.77 (s, 1H), 4.23 (p, J=6.6 Hz, 1H), 3.93 (ddt, J=26.6, 13.4, 6.3 Hz, 3H), 3.84-3.62 (m, 6H), 3.36 (d, J=5.5 Hz, 4H), 3.05 (p, J=6.9 Hz, 1H), 3.00-2.82 (m, 6H), 2.72 (dt, J=10.7, 5.1 Hz, 2H), 2.67-2.54 (m, 4H), 2.15 (h, J=6.2 Hz, 1H), 2.04 (d, J=9.9 Hz, 1H), 1.91 (dq, J=16.1, 8.1 Hz, 1H)

Example 128: Synthesis of 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-3,4-dihydroisoquinolin-1-one

[0489] ##STR00137##

Example 128-1: Synthesis of 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-3,4-dihydroisoquinolin-1-one

[0490] The title compound was synthesized in the same manner as in Example 1, except that 6-bromo-8-fluoro-3,4-dihydro-2H-isoquinolin-1-one was used instead of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one.

Example 128-2: Synthesis of 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-3,4-dihydroisoquinolin-1-one

[0491] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-3,4-dihydroisoquinolin-1-one obtained in Example 128-1 as a starting material was used in the same manner as in Example 2 to obtain the title compound, except that N-acetylpiperazine was used instead of pyrrolidine.

[0492] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.39 (d, J=2.8 Hz, 1H), 7.16-7.01 (m, 4H), 6.95 (dd, J=12.2, 2.5 Hz, 1H), 4.24 (s, 1H), 3.96-3.87 (m, 1H), 3.84-3.66 (m, 8H), 3.39 (dd, J=13.7, 7.7 Hz, 1H), 3.28 (d, J=5.1 Hz, 2H), 3.22 (d, J=5.4 Hz, 2H), 2.99-2.81 (m, 6H), 2.64 (dd, J=7.0, 2.6 Hz, 2H), 2.16 (d, J=1.9 Hz, 3H).

Example 129: Synthesis of 6-(4-acetylpiperazin-1-yl)-2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-1-methyl-propyl]-3,4-dihydroisoquinolin-1-one

[0493] ##STR00138##

Example 129-1: Synthesis of ethyl 2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2-yl) propanate

[0494] 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one (1 g, 4.42 mmol), ethyl 2-bromo propionate (1.15 mL, 8.85 mmol) and Cs.sub.2CO.sub.3 (2.9 g, 8.85) mmol) were dissolved in 15 mL of acetonitrile and stirred at 70° C. Water was added to the reaction mixture to terminate the reaction, extraction was carried out with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the product was used in the next reaction without further purification.

Example 129-2: Synthesis of 2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2-yl) propanal

[0495] Ethyl 2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2-yl)propanate (1.87 g, 5.73 mmol) obtained in Example 129-1 was dissolved in 60 mL of tetrahydrofuran and stirred while cooling to −78° C. While maintaining the temperature, DIBAL-H in toluene solution (11.5 mL, 11.47 mmol) was slowly added dropwise. After the reaction was terminated with methanol and distilled water, the reaction mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the product was used in the next reaction without further purification.

Example 129-3: Synthesis of 6-bromo-2-[1-(oxiran-2-yl)ethyl]-3,4-dihydroisoquinolin-1-one

[0496] Trimethyl sulfoxonium iodide (8.11 g, 36.86 mmol) was dissolved in 30 mL of DMSO and stirred. NaH (60%, 1.36 g, 34.02 mmol) was added to the reaction mixture and stirred for 15 minutes. 2-(6-Bromo-1-oxo-3,4-dihydroisoquinoline-2-yl)propanal (1.6 g, 5.67 mmol) dissolved in 10 mL of DMSO was added dropwise. Methanol was added to the reaction mixture to terminate the reaction, and ethyl acetate was added thereto. The reaction mixture was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the product was used in the next reaction without further purification.

Example 129-4: Synthesis of 6-bromo-2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-1-methyl-propyl]-3,4-dihydroisoquinolin-1-one

[0497] 6-Bromo-2-[1-(oxiran-2-yl)ethyl]-3,4-dihydroisoquinolin-1-one obtained in Example 129-3 as a starting material was used in the same manner as in Example 1-2 to obtain the title compound.

Example 129-5: Synthesis of 6-(4-acetylpiperazin-1-yl)-2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-1-yl)-2-hydroxyl-1-methyl-propyl]-3,4-dihydroisoquinolin-1-one

[0498] ##STR00139##

[0499] 6-Bromo-2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-1-methyl-propyl]-3,4-dihydroisoquinolin-1-one obtained in Example 129-4 as a starting material was used in the same manner as in Example 2 to obtain the title compound, except that N-acetylpiperazine was used instead of pyrrolidine.

[0500] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.83 (d, J=8.7 Hz, 1H), 7.22-7.02 (m, 4H), 6.92 (d, J=8.8 Hz, 1H), 6.80 (s, 1H), 4.70 (p, J=6.8 Hz, 1H), 4.05 (dt, J=9.0, 4.1 Hz, 1H), 3.96-3.83 (m, 2H), 3.83-3.76 (m, 1H), 3.72 (dt, J=14.6, 5.2 Hz, 4H), 3.61-3.50 (m, 1H), 3.45-3.34 (m, 3H), 3.00 (qd, J=14.2, 13.6, 5.4 Hz, 5H), 2.88 (dt, J=15.6, 5.7 Hz, 1H), 2.84-2.66 (m, 2H), 2.14 (d, J=20.8 Hz, 4H), 1.36 (d, J=7.1 Hz, 3H).

Example 130: Synthesis of 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-1-oxo-3H-isoquinolin-6-yl]piperazine-1-carbaldehyde; hydrochloride

[0501] ##STR00140##

[0502] 4-[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-1-oxo-3H-isoquinolin-6-yl]piperazine-1-carbaldehyde obtained in Example 125 as a starting material was used in the same manner as in Example 126 to obtain the title compound.

[0503] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.16 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.30 (q, J=7.8, 7.3 Hz, 3H), 7.22 (dd, J=12.3, 4.0 Hz, 3H), 4.67 (dd, J=15.5, 10.4 Hz, 1H), 4.55-4.39 (m, 2H), 3.89 (dd, J=12.4, 5.2 Hz, 1H), 3.79 (dt, J=21.1, 5.2 Hz, 5H), 3.67 (d, J=1.6 Hz, 6H), 3.64-3.53 (m, 4H), 3.50 (t, J=5.3 Hz, 2H), 3.43-3.34 (m, 2H), 3.19 (dq, J=17.4, 5.1 Hz, 1H), 1.38 (d, J=8.0 Hz, 6H).

Example 131: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-ethyl-4-piperidyl)oxy]-4,4-dimethyl-3H-isoquinolin-1-one

[0504] ##STR00141##

Example 131-1: Synthesis of tert-butyl 4-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-1-oxo-3H-isoquinolin-6-yl]oxy]piperidine-1-carboxylate

[0505] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-3H-isoquinolin-1-one obtained in Example 104-1 as a starting material was used in the same manner as in Example 83 to obtain the title compound, except that tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

Example 131-2: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-6-(4-piperidyloxy)-3H-isoquinolin-1-one

[0506] Tert-butyl 4-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-1-oxo-3H-isoquinolin-6-yl]oxy]piperidine-1-carboxylate obtained in Example 131-1 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

Example 131-3: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-ethyl-4-piperidyl)oxy]-4,4-dimethyl-3H-isoquinolin-1-one

[0507] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-dimethyl-6-(4-piperidyloxy)-3H-isoquinolin-1-one obtained in Example 131-2 as a starting material was used in the same manner as in Example 114-3 to obtain the title compound.

[0508] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.26 (d, J=8.8 Hz, 1H), 7.09-6.98 (m, 3H), 6.95 (d, J=7.0 Hz, 1H), 6.92-6.86 (m, 1H), 6.76 (dt, J=9.1, 2.4 Hz, 1H), 4.56 (d, J=43.1 Hz, 1H), 4.21-4.06 (m, 2H), 3.91 (dd, J=14.4, 7.7 Hz, 1H), 3.70 (d, J=4.0 Hz, 2H), 3.60 (t, J=4.7 Hz, 1H), 3.54-3.41 (m, 1H), 3.32 (dd, J=14.9, 8.7 Hz, 1H), 3.09 (d, J=11.3 Hz, 2H), 2.86 (hept, J=6.9 Hz, 7H), 2.65 (d, J=6.2 Hz, 2H), 2.40 (q, J=15.4 Hz, 2H), 2.04 (d, J=10.3 Hz, 1H), 1.99-1.83 (m, 3H), 1.27-1.12 (m, 9H).

Example 132: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-difluoro-6-morpholino-3H-isoquinolin-1-one

[0509] ##STR00142##

Example 132-1: Synthesis of 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-difluoro-3H-isoquinolin-1-one

[0510] The title compound was synthesized in the same manner as in Example 1, except that 6-bromo-4,4-difluoro-2,3-dihydroisoquinolin-1-one was used instead of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one.

Example 132-2: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-difluoro-6-morpholino-3H-isoquinolin-1-one

[0511] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,4-difluoro-3H-isoquinolin-1-one obtained in Example 132-1 as a starting material was used in the same manner as in Example 2 to obtain the title compound, except that morpholine was used instead of pyrrolidine.

[0512] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.95 (d, J=8.8 Hz, 1H), 7.30 (q, J=7.8, 7.3 Hz, 3H), 7.25-7.14 (m, 3H), 4.62 (s, 1H), 4.56-4.34 (m, 3H), 4.19 (td, J=12.5, 11.1, 3.9 Hz, 2H), 3.86 (t, J=4.9 Hz, 5H), 3.82-3.65 (m, 3H), 3.37 (d, J=4.8 Hz, 6H).

Example 133: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1-methylpyrrolidin-3-yl)oxy-3,4-dihydroisoquinolin-1-one

[0513] ##STR00143##

Example 133-1: Synthesis of tert-butyl 3-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxy]pyrrolidine-1-carboxylate

[0514] The title compound was synthesized in the same manner as in Example 83, except that tert-butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

Example 133-2: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-pyrrolidin-3-yloxy-3,4-dihydroisoquinolin-1-one

[0515] Tert-butyl 3-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxy]pyrrolidine-1-carboxylate obtained in Example 133-1 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

Example 133-3: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1-methylpyrrolidin-3-yl)oxy-3,4-dihydroisoquinolin-1-one

[0516] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-pyrrolidin-3-yloxy-3,4-dihydroisoquinolin-1-one obtained in Example 133-2 as a starting material was used in the same manner as in Example 114-3 to obtain the title compound, except that paraformaldehyde was used instead of acetaldehyde.

[0517] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.88 (d, J=8.6 Hz, 1H), 7.17-7.00 (m, 4H), 6.86 (d, J=8.7 Hz, 1H), 6.77 (s, 1H), 5.00 (s, 1H), 4.23 (s, 1H), 3.89 (dd, J=13.8, 4.1 Hz, 1H), 3.84-3.64 (m, 4H), 3.41-3.35 (m, 1H), 3.06-2.97 (m, 2H), 2.97-2.81 (m, 7H), 2.70-2.60 (m, 2H), 2.55-2.35 (m, 5H), 2.08-1.93 (m, 1H).

Example 134: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1-ethylpyrrolidin-3-yl)oxy-3,4-dihydroisoquinolin-1-one

[0518] ##STR00144##

[0519] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-pyrrolidine-3-yloxy-3,4-dihydroisoquinolin-1-one obtained in Example 133-2 as a starting material was used in the same manner as in Example 114-3 to obtain the title compound.

[0520] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.88 (d, J=8.6 Hz, 1H), 7.18-7.00 (m, 4H), 6.86 (d, J=8.7 Hz, 1H), 6.77 (s, 1H), 5.01 (d, J=8.3 Hz, 1H), 4.23 (s, 1H), 3.93-3.84 (m, 1H), 3.84-3.66 (m, 4H), 3.41-3.34 (m, 1H), 3.05-2.97 (m, 2H), 2.96-2.84 (m, 6H), 2.70-2.49 (m, 5H), 2.41 (dq, J=14.2, 7.2 Hz, 1H), 2.10-1.89 (m, 2H), 1.17 (t, J=7.3 Hz, 3H).

Example 135: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[(1-methyl-4-piperidyl)oxy]-3,4-dihydroisoquinolin-1-one

[0521] ##STR00145##

[0522] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidyloxy)-3,4-dihydroisoquinolin-1-one obtained in Example 114-2 as a starting material was used in the same manner as in Example 114-3 to obtain the title compound, except that paraformaldehyde was used instead of acetaldehyde.

[0523] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.93-7.81 (m, 1H), 7.16-6.99 (m, 4H), 6.91 (dd, J=8.6, 2.4 Hz, 1H), 6.82 (s, 1H), 4.54 (s, 1H), 4.22 (dd, J=8.4, 4.1 Hz, 1H), 3.89 (dd, J=13.9, 4.1 Hz, 1H), 3.83-3.64 (m, 4H), 3.41-3.34 (m, 1H), 2.99 (t, J=6.9 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 2.86 (t, J=5.9 Hz, 2H), 2.73 (s, 2H), 2.67-2.58 (m, 2H), 2.42 (t, J=10.2 Hz, 2H), 2.33 (d, J=1.7 Hz, 3H), 2.05 (t, J=9.6 Hz, 2H), 1.83 (q, J=9.8, 9.1 Hz, 2H).

Example 136: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-3,4-dihydroisoquinolin-1-one

[0524] ##STR00146##

[0525] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidyloxy)-3,4-dihydroisoquinolin-1-one obtained in Example 114-2 as a starting material was used in the same manner as in Example 114-3 to obtain the title compound, except that oxetan-3-one was used instead of acetaldehyde.

[0526] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.87 (d, J=8.6 Hz, 1H), 7.17-7.02 (m, 4H), 6.91 (d, J=8.6 Hz, 1H), 6.82 (s, 1H), 4.71 (t, J=6.7 Hz, 2H), 4.67-4.52 (m, 3H), 4.24 (d, J=7.8 Hz, 1H), 3.89 (dd, J=13.5, 3.7 Hz, 1H), 3.83-3.65 (m, 4H), 3.55 (p, J=6.8 Hz, 1H), 3.43-3.36 (m, 1H), 3.05-2.97 (m, 2H), 2.97-2.87 (m, 4H), 2.73-2.56 (m, 4H), 2.30 (d, J=10.3 Hz, 2H), 2.05 (d, J=11.0 Hz, 2H), 1.85 (s, 2H).

Example 137: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-(3-hydroxyprop-1-ynyl)-3,4-dihydroisoquinolin-1-one

[0527] ##STR00147##

[0528] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one (83 mg, 0.2 mmol), copper iodide (4 mg, 0.02 mmol), bis(triphenylphosphine) palladium(II) dichloride (7 mg, 0.01 mmol), triethylamine (115 μl, 0.6 mmol) and prop-2-yn-1-ol (35 μl, 0.6 mmol) were dissolved in dimethylformamide and reacted at 80° C. for one day. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was dried under reduced pressure, and the purification was carried out by flash chromatography to obtain 12.5 mg of the title compound.

[0529] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J=8.0 Hz, 1H), 7.39 (dd, J=8.1, 1.6 Hz, 1H), 7.20-7.09 (m, 4H), 7.02 (d, J=6.8 Hz, 1H), 4.51 (s, 2H), 4.22-4.07 (m, 1H), 3.94-3.60 (m, 6H), 3.47 (dd, J=14.0, 6.3 Hz, 1H), 2.98 (p, J=9.2 Hz, 4H), 2.83 (d, J=10.9 Hz, 1H), 2.73 (dd, J=12.5, 3.8 Hz, 1H), 2.63 (t, J=11.2 Hz, 1H).

Example 138: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-[2-(4-pyridyl)ethynyl]-3,4-dihydroisoquinolin-1-one

[0530] ##STR00148##

[0531] The title compound was synthesized in the same manner as in Example 137, except that 4-ethynylpyridine was used instead of prop-2-yn-1-ol.

[0532] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.66-8.60 (m, 2H), 8.08 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.0, 1.6 Hz, 1H), 7.43-7.31 (m, 3H), 7.14 (qd, J=7.8, 6.9, 3.8 Hz, 3H), 7.05-6.98 (m, 1H), 4.21-4.07 (m, 1H), 3.98-3.60 (m, 5H), 3.46 (dd, J=13.9, 6.4 Hz, 1H), 3.07-2.86 (m, 5H), 2.78 (dd, J=10.4, 5.1 Hz, 1H), 2.69 (dd, J=12.5, 3.9 Hz, 1H), 2.63-2.53 (m, 1H).

Example 139: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-[(1-methyl-3-piperidyl)oxy]-3,4-dihydroisoquinolin-1-one

[0533] ##STR00149##

Example 139-1: Synthesis of tert-butyl 3-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxy]piperidine-1-carboxylate

[0534] The title compound was synthesized in the same manner as in Example 83, except that tert-butyl 3-methylsulfonyloxypepyridine-1-carboxylate was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate

Example 139-2: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-(3-piperidyloxy)-3,4-dihydroisoquinolin-1-one dihydrochloride

[0535] Tert-butyl 3-[[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]oxy]piperidine-1-carboxylate obtained in Example 139-1 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

Example 139-3: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-[(1-methyl-3-piperidyl)oxy]-3,4-dihydroisoquinolin-1-one

[0536] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-(3-piperidyloxy)-3,4-dihydroisoquinolin-1-one dihydrochloride obtained in Example 139-2 as a starting material was used in the same manner as in Example 114-3 to obtain the title compound, except that paraformaldehyde was used instead of acetaldehyde.

[0537] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.88 (d, J=8.6 Hz, 1H), 7.18-7.02 (m, 4H), 6.92 (dd, J=8.7, 2.5 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 4.57 (dq, J=7.9, 3.8 Hz, 1H), 4.24 (tt, J=7.5, 4.7 Hz, 1H), 3.89 (dd, J=13.8, 4.2 Hz, 1H), 3.84-3.65 (m, 4H), 3.40-3.35 (m, 2H), 3.04-2.85 (m, 7H), 2.68-2.59 (m, 3H), 2.36 (s, 4H), 2.06-1.84 (m, 2H), 1.67 (ddd, J=17.8, 9.0, 4.3 Hz, 2H).

Example 140: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-[[1-(2-fluoroethyl)-3-piperidyl]oxy]-3,4-dihydroisoquinolin-1-one

[0538] ##STR00150##

[0539] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-(3-piperidyloxy)-3,4-dihydroisoquinolin-1-one dihydrochloride (101 mg, 0.2 mmol) obtained in Example 139-2, potassium carbonate (83 mg, 0.6 mmol) and 2-fluoroethyl 4-methylbenzenesulfonate (52 mg, 0.24 mmol) were dissolved in acetonitrile and stirred at 80° C. for one day. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated oily liquid was purified by flash chromatography to obtain the title compound (5.1 mg).

[0540] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.89 (d, J=8.6 Hz, 1H), 7.24 (qd, J=9.4, 8.8, 4.5 Hz, 3H), 7.15 (d, J=7.0 Hz, 1H), 7.02-6.90 (m, 1H), 6.87 (d, J=2.5 Hz, 1H), 4.72-4.64 (m, 1H), 4.62-4.50 (m, 2H), 4.38 (s, 1H), 4.24 (s, 1H), 3.86-3.70 (m, 3H), 3.52 (dd, J=13.9, 6.5 Hz, 1H), 3.36 (d, J=7.7 Hz, 1H), 3.08 (ddd, J=28.2, 13.0, 6.2 Hz, 6H), 2.90-2.78 (m, 2H), 2.46 (dt, J=28.0, 10.3 Hz, 2H), 2.09-1.85 (m, 4H), 1.75-1.50 (m, 4H).

Example 141: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-[3-(dimethylamino)prop-1-ynyl]-3,4-dihydroisoquinolin-1-one

[0541] ##STR00151##

[0542] The title compound was synthesized in the same manner as in Example 137, except that N,N-dimethylprop-2-yn-1-amine was used instead of pyrrolidin-2-one.

[0543] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.91 (d, J=8.0 Hz, 1H), 7.41 (dd, J=8.1, 1.6 Hz, 1H), 7.36 (d, J=1.5 Hz, 1H), 7.18-7.08 (m, 3H), 7.08-7.02 (m, 1H), 4.26 (tt, J=7.4, 4.6 Hz, 1H), 3.90 (dd, J=13.8, 4.1 Hz, 1H), 3.86-3.67 (m, 4H), 3.45-3.39 (m, 1H), 3.37 (s, 2H), 3.07-2.98 (m, 2H), 2.93 (dp, J=9.5, 5.3, 4.7 Hz, 4H), 2.74-2.63 (m, 2H), 2.41 (s, 6H).

Example 142: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[[1-(2-methoxyethyl)-4-piperidyl]oxy]-3,4-dihydroisoquinolin-1-one

[0544] ##STR00152##

[0545] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(4-piperidyloxy)-3,4-dihydroisoquinolin-1-one obtained in Example 114-2 as a starting material was used in the same manner as in Example 140 to obtain the title compound, except that 1-bromo-2-methoxy-ethane was used instead of 2-fluoroethyl 4-methylbenzenesulfonate.

[0546] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.87 (d, J=8.7 Hz, 1H), 7.16-7.05 (m, 3H), 7.04 (dd, J=6.8, 2.2 Hz, 1H), 6.90 (dd, J=8.7, 2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 4.52 (tt, J=7.7, 3.8 Hz, 1H), 4.28-4.17 (m, 1H), 3.89 (dd, J=13.8, 4.1 Hz, 1H), 3.82-3.63 (m, 4H), 3.56 (t, J=5.5 Hz, 2H), 3.36 (m, 4H), 3.03-2.91 (m, 2H), 2.91 (d, J=5.4 Hz, 2H), 2.84 (dd, J=14.7, 7.2 Hz, 4H), 2.70-2.56 (m, 4H), 2.52-2.42 (m, 2H), 2.04 (ddt, J=10.9, 7.3, 3.6 Hz, 2H), 1.82 (dtd, J=12.2, 8.0, 3.4 Hz, 2H).

Example 143: Synthesis of 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-[[1-(2-methoxyethyl)-4-piperidyl]oxy]-7,8-dihydro-1,6-naphthyridin-5-one

[0547] ##STR00153##

Example 143-1: Synthesis of 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-hydroxy-7,8-dihydro-1,6-naphthyridin-5-one

[0548] The title compound was synthesized in the same manner as in Example 74, except that 2-chloro-6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7,8-dihydro-1,6-naphthyridin-5-one was used instead of 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one.

Example 143-2: Synthesis of tert-butyl 4-[[6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-7,8-dihydro-1,6-naphthyridin-2-yl]oxy]piperidine-1-carboxylate

[0549] 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-hydroxy-7,8-dihydro-1,6-naphthyridin-5-one obtained in Example 143-1 as a starting material was used in the same manner as in Example 114-1 to obtain the title compound.

Example 143-3: Synthesis of 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-(4-piperidyloxy)-7,8-dihydro-1,6-naphthyridin-5-one dihydrochloride

[0550] Tert-butyl 4-[[6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-7,8-dihydro-1,6-naphthyridin-2-yl]oxy]piperidine-1-carboxylate obtained in Example 143-2 as a starting material was used in the same manner as in Example 57 to obtain the title compound.

Example 143-4: Synthesis of 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-[[1-(2-methyloxyethyl)-4-piperidyl]oxy]-7,8-dihydro-1,6-naphthyridin-5-one

[0551] 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-(4-piperidyloxy)-7,8-dihydro-1,6-naphthyridin-5-one dihydrochloride obtained in Example 143-3 as a starting material was used in the same manner as in Example 140 to obtain the title compound, except that 1-bromo-2-methoxy-ethane was used instead of 2-fluoroethyl 4-methylbenzenesulfonate.

[0552] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.10 (d, J=8.6 Hz, 1H), 7.10 (dq, J=7.4, 4.4, 3.3 Hz, 3H), 7.05-6.99 (m, 1H), 6.70 (d, J=8.6 Hz, 1H), 5.17 (tt, J=8.2, 4.0 Hz, 1H), 4.22 (ddd, J=9.7, 7.3, 4.7 Hz, 1H), 3.91-3.73 (m, 3H), 3.72 (s, 2H), 3.56 (t, J=5.6 Hz, 2H), 3.36 (m, 4H), 3.05 (t, J=7.0 Hz, 2H), 2.86 (dt, J=18.5, 6.5 Hz, 6H), 2.69-2.56 (m, 4H), 2.50-2.39 (m, 2H), 2.07 (dtd, J=14.9, 7.5, 3.9 Hz, 2H), 1.84 (dtd, J=12.6, 8.5, 3.5 Hz, 2H).

Example 144: Synthesis of 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-[[1-[(2R)-2-hydroxypropyl]-4-piperidyl]oxy]-7,8-dihydro-1,6-naphthyridin-5-one

[0553] ##STR00154##

[0554] 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-(4-piperidyloxy)-7,8-dihydro-1,6-naphthyridin-5-one dihydrochloride obtained in Example 143-3 as a starting material was used in the same manner as in Example 140 to obtain the title compound, except that (2R)-2-methyloxirane was used instead of 2-fluoroethyl 4-methylbenzenesulfonate.

[0555] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.12 (d, J=8.6 Hz, 1H), 7.16-7.01 (m, 4H), 6.72 (d, J=8.6 Hz, 1H), 5.19 (dt, J=8.2, 4.1 Hz, 1H), 4.23 (dq, J=7.5, 4.6, 3.8 Hz, 1H), 4.03-3.74 (m, 6H), 3.39 (dd, J=13.8, 7.7 Hz, 1H), 3.07 (t, J=6.9 Hz, 2H), 2.95-2.83 (m, 6H), 2.71-2.58 (m, 2H), 2.42 (dq, J=13.2, 8.6, 7.1 Hz, 4H), 2.09 (m, 2H), 1.87 (m, 2H), 1.17 (d, J=6.2 Hz, 4H).

Example 145: Synthesis of 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]oxy]-7,8-dihydro-1,6-naphthyridin-5-one

[0556] ##STR00155##

[0557] 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-(4-piperidyloxy)-7,8-dihydro-1,6-naphthyridin-5-one dihydrochloride obtained in Example 143-3 as a starting material was used in the same manner as in Example 140 to obtain the title compound, except that 2,2-dimethyloxirane was used instead of 2-fluoroethyl 4-methylbenzenesulfonate.

[0558] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.11 (d, J=8.6 Hz, 1H), 7.17-7.06 (m, 3H), 7.04 (dd, J=6.9, 2.4 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 5.14 (tt, J=8.3, 4.0 Hz, 1H), 4.28-4.18 (m, 1H), 3.92-3.76 (m, 3H), 3.74 (s, 2H), 3.38 (dd, J=13.8, 7.7 Hz, 1H), 3.06 (t, J=7.0 Hz, 2H), 2.97-2.82 (m, 6H), 2.65 (d, J=1.7 Hz, 1H), 2.66-2.58 (m, 1H), 2.58-2.48 (m, 2H), 2.37 (s, 2H), 2.05 (dq, J=13.0, 6.8, 5.2 Hz, 2H), 1.83 (dtd, J=12.7, 8.9, 3.5 Hz, 2H), 1.21 (s, 6H).

Example 146: Synthesis of 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-7,8-dihydro-1,6-naphthyridin-5-one

[0559] ##STR00156##

[0560] 6-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-(4-piperidyloxy)-7,8-dihydro-1,6-naphthyridin-5-one dihydrochloride obtained in Example 143-3 as a starting material was used in the same manner as in Example 114-3 to obtain the title compound, except that oxetan-3-one was used instead of acetaldehyde.

[0561] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.11 (d, J=8.6 Hz, 1H), 7.16-7.05 (m, 3H), 7.05-7.00 (m, 1H), 6.70 (d, J=8.6 Hz, 1H), 5.21 (tt, J=7.9, 3.9 Hz, 1H), 4.70 (t, J=6.7 Hz, 2H), 4.61 (t, J=6.2 Hz, 2H), 4.22 (ddd, J=9.5, 7.4, 4.7 Hz, 1H), 3.91-3.73 (m, 3H), 3.73 (s, 2H), 3.53 (p, J=6.4 Hz, 1H), 3.37 (dd, J=13.8, 7.7 Hz, 1H), 3.05 (t, J=7.0 Hz, 2H), 2.91 (t, J=6.2 Hz, 2H), 2.84 (dd, J=8.9, 3.8 Hz, 2H), 2.70-2.56 (m, 4H), 2.29-2.20 (m, 2H), 2.09 (ddt, J=14.0, 7.3, 3.6 Hz, 2H), 1.85 (dtd, J=12.4, 8.4, 3.5 Hz, 2H).

Experimental Example

[0562] Method for Measuring Enzyme Activity

[0563] In vitro assay: PRMT5-MEP50 enzyme complex, cofactor S-adenosylmethionine (SAM) and histone H4 peptide were reacted in vitro, and methylation of arginine (H4R3)—which is the third amino acid of histone H4—was measured in order to measure the enzyme activity of PRMT5.

[0564] Reagents: PRMT5-MEP50 enzyme complex (Catalog No. 51045), blocking buffer (52100-B), histone methyltransferase reaction buffer 2 (4×HMT assay buffer 2, Catalog No. 52170), and primary antibody (primary antibody 4-3, Catalog No. 52150) were purchased from BPS Bioscience (USA). The histone H4 peptide (1-20 amino acids) was custom made by Komabiotech (Korea) and used. S-adenosylmethionine was purchased from NEB (New England Biolabs, USA, Catalog No. B9003S). Plates for coating histone H4 peptide, washing buffer and color development reagent were purchased from the following vendors: Plate (Immobilizer™-Amino Plate, NUNC, Denmark, Catalog No. 436023), carbonate-bicarbonate buffer (Sigma-Aldrich, USA, Catalog No. C.sub.3041), washing buffer (10×TBST, Biosesang, Korea, Catalog No. T2005), TMB ELISA substrate (Abcam, UK, Catalog No. ab210902), horseradish peroxidase (HRP)-conjugated antibody (Abcam, UK, Catalog No. ab6721).

[0565] Experimental procedure: The histone H4 peptide was diluted with carbonate-bicarbonate buffer and prepared to 100 μg/mL, and then dispensed onto the plate per 100 μL and reacted at 37° C. for 1 hour. PRMT5-MEP50 enzyme complex and S-adenosylmethionine were diluted with histone methyltransferase reaction buffer to prepare 5 μg/mL and 2 μM, respectively, and then 20 μL of PRMT5-MEP50 enzyme complex and 25 μL of S-adenosylmethionine were dispensed onto the plate prepared above. 5 μL of the compound diluted with 10% dimethyl sulfoxide solution was added thereto and reacted at room temperature for 2 hours (final volume=50 μL). The concentration of the compound was diluted 1:5 from 10 μM until the lowest concentration of 0.128 nM, and 8 points were used for the test. After preparing the primary antibody by diluting 1:2000 with blocking buffer, 100 μL was added to the plate and reacted at room temperature for 1 hour. After preparing horseradish peroxidase-conjugated antibody by diluting 1:10,000 with blocking buffer, 100 μL was added to the plate and reacted at room temperature for 1 hour. 100 μL of TMB substrate was added and reacted for 3 minutes at room temperature, and 100 μL of 1 N sulfuric acid was then added to terminate the reaction. Then, the absorbance at 450 nm was measured to calculate the IC.sub.50 value of the compound. (+++: 1 to 100 nM, ++: greater than 100 to 1,000 nM, +: greater than 1,000 to 10,000 nM)

TABLE-US-00002 TABLE 2 PRMT5 enzyme IC.sub.50 Compound (nM) Example 1 +++ Example 2 ++ Example 4 +++ Example 5 +++ Example 6 +++ Example 7 +++ Example 8 +++ Example 9 +++ Example 10 +++ Example 11 +++ Example 12 +++ Example 13 +++ Example 14 ++ Example 15 +++ Example 16 +++ Example 17 +++ Example 18 + Example 19 ++ Example 20 ++ Example 21 ++ Example 22 + Example 23 +++ Example 24 +++ Example 25 +++ Example 26 +++ Example 27 ++ Example 28 ++ Example 29 +++ Example 30 +++ Example 31 +++ Example 32 +++ Example 33 +++ Example 34 + Example 35 +++ Example 36 +++ Example 37 +++ Example 38 ++ Example 39 ++ Example 40 + Example 41 +++ Example 42 ++ Example 43 + Example 44 +++ Example 45 ++ Example 46 ++ Example 47 +++ Example 48 +++ Example 49 +++ Example 50 ++ Example 51 ++ Example 52 ++ Example 53 +++ Example 54 +++ Example 55 +++ Example 56 +++ Example 57 +++ Example 58 +++ Example 59 ++ Example 60 ++ Example 61 +++ Example 62 +++ Example 63 ++ Example 64 +++ Example 65 + Example 66 +++ Example 67 + Example 68 +++ Example 69 ++ Example 70 +++ Example 71 +++ Example 72 ++ Example 73 ++ Example 75 ++ Example 76 ++ Example 77 ++ Example 78 +++ Example 79 +++ Example 80 +++ Example 81 +++ Example 82 +++ Example 83 ++ Example 84 ++ Example 85 ++ Example 86 ++ Example 87 +++ Example 88 +++ Example 89 +++ Example 90 +++ Example 91 +++ Example 92 ++ Example 93 +++ Example 94 +++ Example 95 ++ Example 96 ++ Example 97 ++ Example 98 ++ Example 99 ++ Example 101 +++ Example 102 +++ Example 103 +++ Example 104 +++ Example 105 +++ Example 106 +++ Example 107 ++ Example 108 ++ Example 109 ++ Example 110 ++ Example 111 ++ Example 112 ++ Example 113 +++ Example 114 ++ Example 115 ++ Example 116 ++ Example 117 ++ Example 118 ++ Example 119 ++ Example 120 +++ Example 121 ++ Example 122 ++ Example 123 ++ Example 124 +++ Example 125 ++ Example 126 +++ Example 127 +++ Example 128 ++ Example 129 ++ Example 130 + Example 131 +++ Example 132 + Example 133 +++ Example 134 ++ Example 135 ++ Example 136 +++ Example 137 ++ Example 138 ++ Example 139 +++ Example 140 ++ Example 141 ++

[0566] Test for In Vivo Target Inhibitory Activity

[0567] After U87MG tumor cells were implanted subcutaneously in nude mice, a PRMT5 inhibitor was administered orally (25 or 50 mg/kg) 1-2 times daily for one week, and then the degree to which SDMA levels in the tumor decreased was measured.

[0568] Reagents: Bradford's solution (Catalog No. 500-0006) was purchased from Bio-rad (USA). SDMA antibody (Catalog No. 13222s) was purchased from Cell Signaling Technology (USA). SmD3 antibody (Catalog No. ap12451a) was purchased from Abgent (USA), and secondary antibody (Catalog No. ab6721) and TMB substrate (Catalog No. ab210902) were purchased from Abcam (UK).

[0569] Experimental procedure: The tumor tissues transplanted into the mice were excised, the cells were lysed, and then quantified with Bradford's solution. 5-10 μg of protein per sample was diluted with carbonate-bicarbonate buffer and dispensed into a 96-well plate and reacted at room temperature for 2 hours. After washing with phosphate buffered saline (PBST) containing 0.05% Tween-20 3 times, 200 μL of PBST containing 5% bovine serum albumin (BSA-PBST) was added and reacted at room temperature for 2 hours. After washing with PBST 3 times, the SDMA antibody and the SmD3 antibody were diluted in BSA-PBST, and 100 μL of each was dispensed onto the plate and reacted at 4° C. overnight. After washing with PBST 3 times the next day, 100 μL of the secondary antibody diluted in BSA-PBST was added and reacted at room temperature for 1 hour. After washing with PBST 3 times, 100 μL of TMB substrate was added and reacted at room temperature for 10-20 minutes, and 100 μL of 1N sulfuric acid solution was added to terminate the reaction. Then, the absorbance at 450 nm was measured to calculate the degree of SDMA inhibition by the compound. (+++: more than 70%, ++: more than 30% and 70% or less, +: 30% or less)

TABLE-US-00003 TABLE 3 SDMA inhibition Compound (%) Example 4 ++ Example 14 +++ Example 87 ++ Example 135 +++