Bicyclic compounds and their uses

Abstract

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

Description

[Technical field]

[0001] The present invention relates to a compound derivative containing a 6-6 bicyclic ring and its use. The compound according to the present invention acts as a protein arginine methyltransferase 5 (PRMT5) inhibitor, and can be effectively used in the prevention or treatment of diseases induced by PRMT5. [Background technology]

[0002] PRMTs (protein arginine methyltransferases) are enzymes that transfer methyl groups to arginine in target proteins using the cofactor SAM (S-adenosylmethionine). A total of nine PRMT isoforms have been known to date, which are broadly divided into three types. PRMT1, 2, 3, 4, 6, and 8, which belong to type I PRMTs, are known to induce monomethylation and asymmetric dimethylation of arginine, while PRMT5 and PRMT9, which belong to type II PRMTs, are known to induce monomethylation and symmetric dimethylation of arginine. On the other hand, PRMT7, a type III PRMT, mainly induces monomethylation of arginine. PRMTs induce methylation of various substrates present in the nucleus and cytoplasm, thereby regulating important biological processes in cells, such as cell proliferation, differentiation, and splicing.

[0003] PRMT5 is an important arginine methyltransferase among type II PRMTs. It forms a functional complex with methylosome protein 50 (MEP50) and causes methylation of target proteins. PRMT5 is involved in the formation of leukemia, lymphoma, glioblastoma, lung cancer, breast cancer, etc. by methylating target proteins such as p53, NFκB, PI3K / AKT, and CRAF, which are a type of nuclear histone protein and non-histone protein. It is well known that cancer formation by PRMT5 occurs when tumor cell proliferation, differentiation, invasion, and migration are promoted. In addition, several reports have shown that the higher the PRMT5 expression, the worse the prognosis of cancer patients. Conversely, it has been observed that inhibition of PRMT5 expression can suppress tumor cell proliferation. On the other hand, it has been reported recently that diseases other than cancer may also be mediated by PRMT5. Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a novel compound based on a 6-6 bicyclic ring, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof, which exhibits excellent PRMT5 inhibitory effect. Another object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, a novel compound based on said 6-6 bicyclic ring, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof. [Means for solving the problem]

[0005] In order to achieve the above object, the present invention provides a compound represented by the following formula (1): [ka] [Wherein X is CH or N, n is an integer from 0 to 2, R 1 -DR 9 or [ka] where D is a direct bond, -CH 2 -, -O- or -C≡C-; R 9 is halo, hydroxy, alkyl, hydroxyalkyl, dialkylaminoalkyl, saturated or unsaturated heterocyclyl, or saturated heterocyclyl-alkyl, wherein the saturated or unsaturated heterocyclyl is optionally substituted with one or more substituents selected from halo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, and saturated heterocyclyl; R 10 and R 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 10 and R 11 may form, together with the N to which they are attached, a saturated or unsaturated heterocyclyl, said saturated or unsaturated heterocyclyl being optionally 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, thiakylaminoalkoxy, dialkylaminocarbonyl and 4-10 membered saturated heterocyclyl; R 2 is hydrogen or halo, R 3 is hydrogen, halo or alkyl, or when n is 2, may form a cycloalkyl together with the C to which it is attached; R 4 , R5 , R 6 and R 7 are each independently hydrogen or alkyl; R 8 represents hydrogen, halo, alkyl, alkoxy or amino; or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

[0006] As used herein, unless otherwise stated, the term "alkyl," alone or in combination with additional terms (e.g., haloalkyl), refers to the radical of a saturated aliphatic hydrocarbon group having, for example, a straight or branched chain, 1 to 7 carbon atoms. For example, alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.

[0007] As used herein, unless otherwise stated, the term "cycloalkyl," alone or in combination with additional terms (e.g., cycloalkyl-alkyl), refers to a cyclic radical of a saturated aliphatic hydrocarbon group, e.g., having 3 to 7 carbon atoms. For example, cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0008] Unless otherwise specified, the term "aryl" as used herein refers to an aromatic hydrocarbon having 6 to 12 carbon atoms, for example, but not limited to, phenyl and naphthyl. Unless otherwise specified, the term "alkoxy" as used herein means, for example, an alkyloxy having 1 to 7 carbon atoms.

[0009] Unless otherwise stated, the term "halo," as used herein, alone or in combination with additional terms (e.g., haloalkyl), refers to a radical of fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). As used herein, unless otherwise noted, the term "oxo" refers to a =O group (i.e., an oxygen with a double bond). Two oxo groups can be used in place of sulfur (S) to form a sulfonyl group.

[0010] Unless otherwise specified, the term "saturated or unsaturated heterocyclyl" as used herein means a 3-24 membered hydrocarbon having one or more heteroatoms, e.g., 1-8 heteroatoms, selected from the group consisting of nitrogen (N), oxygen (O) and sulfur (S), which is unsaturated or partially or completely saturated and forms a single or fused cyclic ring. Specifically, the heterocyclyl may be a 4-10 membered hydrocarbon having 1-3 heteroatoms. The heterocycle may include a bridged structure or a spiro structure. The unsaturated heterocyclyl may also include an aromatic hydrocarbon such as a heteroaryl.

[0011] According to one embodiment of the present invention, said heterocyclyl may be, but is not limited to, pyridyl, morpholinyl, oxazepanyl, dihydropyridinyl, tetrahydropyridinyl, piperidyl, piperazinyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, 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 or oxetane.

[0012] According to one embodiment of the present invention, in the formula (1), R 1 -DR 9where D is a direct bond, -CH 2 -, -O- or -C≡C-; R 9 is halo, hydroxy, C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 alkyl, 4-10 membered saturated or unsaturated heterocyclyl, or 4-10 membered saturated heterocyclyl-alkyl, the saturated or unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, halo, C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, Halo-C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkyl carbonyl, C 1 -C 7 It may be substituted with one or more substituents selected from alkoxycarbonyl and 4-10 membered saturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S.

[0013] According to another embodiment of the present invention, in the formula (1), R 1 -DR 9 where D is a direct bond and R 9 is halo, hydroxy, C 1 -C 7 alkyl, 4-10 membered saturated or unsaturated heterocyclyl, the saturated or unsaturated heterocyclyl having 1-3 heteroatoms selected from N, O and S, halo, C 1 -C 7 Alkylcarbonyl and C 1 -C7 It may be substituted with 1 to 3 substituents selected from alkoxycarbonyl.

[0014] According to another embodiment of the present invention, in the formula (1), R 1 -DR 9 where D is -CH 2 -, -O- or -C≡C-; R 9 is hydroxy-C 1 -C 7 Alkyl, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 Alkyl, 4-10 membered saturated or unsaturated heterocyclyl, or 4-10 membered saturated or unsaturated heterocyclyl-C 1 -C 7 alkyl, the saturated or unsaturated heterocyclic alkyl having 1 to 3 heteroatoms selected from N, O and S, 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, Halo-C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkyl carbonyl, C 1 -C 7 It may be substituted by 1 to 3 substituents selected from alkoxycarbonyl, and 4- to 10-membered saturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S.

[0015] According to another embodiment of the present invention, in the formula (1), R 1 -DR 9 where D is a direct bond, -CH 2 -, -O- or -C≡C-; R 9is halo, hydroxy, C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 alkyl, a 4- to 10-membered saturated or unsaturated heterocyclyl, or a 4- to 10-membered saturated heterocyclyl-alkyl, wherein the saturated or unsaturated heterocyclyl may be selected from the group consisting of pyridyl, morpholinyl, oxazepanyl, dihydropyridinyl, tetrahydropyridinyl, piperidyl, piperazinyl, tetrahydropyranyl, azetidinyl, and pyrrolidinyl.

[0016] According to another embodiment of the present invention, in the formula (1), R 1 teeth, [ka] and R 10 and R 11 are each independently hydrogen, C 1 -C 7 Alkyl, C 3 -C 7 Cycloalkyl, Hydroxy-C 1 -C 7 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, Hydroxy-C 1 -C 7 Alkyl carbonyl, C 6 -C 12 Aryl-C 1 -C 7 Alkyl, saturated heterocyclyl, saturated or unsaturated heterocyclyl-C 1 -C 7 Alkyl, unsaturated heterocyclyl-carbonyl, or saturated heterocyclyl-C 1 -C 7alkylcarbonyl or R 10 and R 11 may form, together with the N to which it is attached, a saturated or unsaturated heterocyclyl, said heterocyclyl being hydroxy, oxo, formyl (-CHO), cyano, C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, Hydroxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, halo-C 1 -C 7 Alkyl carbonyl, C 1 -C 7 Alkoxycarbonyl, C 1 -C 7 Alkylamino, C 1 -C 7 Alkylsulfonyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, Aminocarbonyl, C 1 -C 7 Alkylcarbonylamino, C 1 -C 7 Alkylcarbonyl-C 1 -C 7 Alkylamino, (C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl)(C 1 -C 7 Alkyl)amino, di(C 1 -C 7 Alkyl)amino, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 Alkyl, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 Alkoxy, di(C 1 -C 7 It may be substituted by 1 to 3 substituents selected from alkyl, aminocarbonyl, and saturated heterocyclyl.

[0017] According to another embodiment of the present invention, in the formula (1), R 1 teeth, [ka] and R 10 and R 11 are each independently hydrogen, C 1 -C 7 Alkyl, C 3 -C 7 Cycloalkyl, Hydroxy-C 1 -C 7 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, Hydroxy-C 1 -C 7 Alkyl carbonyl, C 6 -C 12 Aryl-C 1 -C 7 Alkyl, saturated heterocyclyl, saturated or unsaturated heterocyclyl-C 1 -C 7 Alkyl, unsaturated heterocyclyl-carbonyl, or saturated heterocyclyl-C 1 -C 7 alkylcarbonyl or R 10 and R 11 may form a saturated or unsaturated heterocyclyl together with the N to which it is attached, and the heterocyclyl is a 4-10 membered saturated or unsaturated hydrocarbon having 1-3 heteroatoms selected from N, O, and S.

[0018] According to another embodiment of the present invention, in the formula (1), R 1 teeth, [ka] and R 10and R 11 are each independently hydrogen, C 1 -C 7 Alkyl, C 3 -C 7 Cycloalkyl, Hydroxy-C 1 -C 7 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, Hydroxy-C 1 -C 7 Alkyl carbonyl, C 6 -C 12 Aryl-C 1 -C 7 Alkyl, saturated heterocyclyl, saturated or unsaturated heterocyclyl-C 1 -C 7 Alkyl, unsaturated heterocyclyl-carbonyl, or saturated heterocyclyl-C 1 -C 7 alkylcarbonyl or R 10 and R 11 may together with the N to which it is attached form a saturated or unsaturated heterocyclyl 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.

[0019] According to another embodiment of the present invention, in the formula (1), R 2 is hydrogen or halo, R 3 is hydrogen, halo or C 1 -C7 Alkyl or, if n is 2, C together with the bonded C 3 -C 7 may form a cycloalkyl, R 4 , R 5 , R 6 and R 7 are each independently hydrogen or C 1 -C 7 is alkyl, R 8 is hydrogen, halo, C 1 -C 7 Alkyl, C 1 -C 7 It is alkoxy or amino. Representative examples of compounds of formula (1) according to the present invention include, but are not limited to, the compounds shown in Table 1.

[0020] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0021] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0022] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17]

[0023] [Table 18] [Table 19] [Table 20]

[0024] The compounds according to the present invention may have asymmetric carbon centers and asymmetric axes or planes, and therefore may exist as all optical and stereoisomers, including substantially pure enantiomers, such as R and S enantiomers, as well as mixed racemates, all of which are within the scope of the present invention. With respect to pure enantiomers, the enantiomeric excess of such enantiomers of formula (1) and their pharma- ceutically acceptable salts may preferably be 60% ee or greater, more preferably 95% ee or greater, and most preferably 98% ee or greater.

[0025] The term "ee" refers to enantiomeric excess. For example, one enantiomer in a particular compound is present in a mixture of enantiomers in a compound in a greater amount than the other enantiomer. Enantiomerically enriched forms can include enantiomeric mixtures of a particular compound in which the concentration of a single enantiomer in the enantiomeric mixture of the particular compound is at least 50% or more, more typically at least 60%, 70%, 80%, or 90% or more, relative to the other enantiomer of the compound (e.g., >95%, >97%, >98%, >99%, >99.5%).

[0026] In this specification, unless otherwise specified, the compound represented by formula (1) is used to mean the compound of formula (1), its optical isomers, stereoisomers, isotopic variants, and pharma- ceutically acceptable salts thereof. As used herein, the term "isotopic variant" refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such compound. For example, an isotopic variant of a compound can be radiolabeled, e.g., the hydrogen atoms can be selected from hydrogen, deuterium, and tritium, and carbon-13 ( 13 C), nitrogen-15( 15 N), etc.

[0027] The compound of formula (1) according to the present invention, or its optical isomer, stereoisomer or isotopic variant, can form a pharmaceutically acceptable salt. The pharmaceutically acceptable salt includes acid or base addition salts and their stereochemical isomers. The salt includes, but is not limited to, any salt that maintains the activity of the parent compound in the administered subject and does not cause undesired effects. Salts include inorganic and organic salts, such as acid addition salts, e.g., acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, esculitic acid, lactic acid, bicarbonic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium edetate, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid, edetic acid, toluenesulfonic acid, edicylinic acid, ecylinic acid, fumaric acid, gluceptic acid, and the like. acid), pamoic acid, gluconic acid, glycolyl arsenic acid, methyl nitrate, polygalacturonic acid, hexylresorcylic acid, malonic acid, hydrobamic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactobionic acid, mandelic acid, estronic acid, mucic acid, naphthenic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogen phosphate, dihydrogen phosphate, salicylic acid, sulfamic acid, sulfanilic acid, methanesulfonic acid, and theoclic acid. Examples of the basic salt include alkali and alkaline earth metal salts such as ammonium salt, lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt, salts with organic bases such as benzathine, N-methyl-D-glucamine, and hydrabamine salt, and salts with amino acids such as arginine and lysine. Moreover, said salt forms can be converted to free forms by treating with a suitable base or acid. As used herein, the term "addition salt" can be interpreted as including the solvates and salts thereof obtained from any of the compounds represented by formula (1). Examples of such solvates are hydrates and alcoholates.

[0028] Terms and abbreviations used herein have their original meaning unless otherwise specified. The present invention also provides a method for preparing a compound of formula (1). Hereinafter, a method for preparing a compound of formula (1) will be described based on an exemplary reaction scheme for better understanding of the present invention. However, it should be understood that a person skilled in the art can prepare a compound of formula (1) by various methods using a known compound based on the structure of formula (1) or a compound that can be easily prepared from it, and all methods should be understood to be within the scope of the present invention. That is, a compound of formula (1) can be prepared by any combination of several synthetic methods described in this specification or disclosed in the prior art. Therefore, the following description of the method for preparing a compound of formula (1) is merely illustrative, and the order of unit operations can be selectively changed as necessary, and the scope of the preparation method of the present invention is not limited thereto.

[0029] <Reaction Scheme 1> [ka] The general synthetic method is to obtain intermediate 3, which is an oxirane-introduced intermediate by substitution reaction with starting material 2, and then compound 1a is obtained by addition reaction with tetrahydroisoquinoline. Furthermore, compound 1a can be used as an intermediate to obtain the final compound 1b, which is substituted with an amine group by Buchwald-Hartwig amination reaction under palladium conditions.

[0030] <Reaction Scheme 2> [ka]

[0031] As an alternative synthetic method, the compound 1a can be used as the starting material in a Suzuki-coupling reaction under palladium conditions to give the final compound 1c substituted with an alkyl or alkenyl group.

[0032] <Reaction Scheme 3> [ka]

[0033] As yet another synthetic method, compound 1a can be used as a starting material under palladium conditions using potassium hydroxide to obtain intermediate 4 in which the bromine group is replaced with a hydroxide group, followed by a substitution reaction to obtain final compound 1d in which the ether group is replaced. According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating a disease associated with PRMT5 inhibition, comprising a therapeutically effective amount of a compound of formula (1) or its optical isomer, stereoisomer or isotopic variant, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier, as an active ingredient. Also within the scope of the present invention are prodrugs having various forms that are converted to the compound of formula (1) as desired in vivo. The pharmaceutical composition may further comprise one or more additives selected from the group consisting of pharma- ceutically acceptable carriers, diluents and adjuvants.

[0034] As used herein, the term "treatment" means halting, slowing or alleviating the progression of a disease when used in a subject with symptoms. As used herein, the term "prevention" means reducing the chance of disease or eliminating the chance of disease.

[0035] As used herein, the term "pharmaceutical composition" may include other chemical components such as carriers, diluents, excipients, etc., in addition to the active compound according to the present invention. Thus, the pharmaceutical composition may include a pharma- ceutically acceptable carrier, diluent, excipient, or a combination thereof, as necessary. The pharmaceutical composition facilitates administration of the active compound to an organism. Various techniques for administering pharmaceutical compositions containing compounds are known, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. The pharmaceutical composition may also be sterilized, may further include auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifiers, salts for osmotic adjustment and / or buffers, may further include other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulation, or coating.

[0036] As used herein, the term "carrier" refers to a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier for easily introducing large amounts of organic compounds into cells or tissues of living organisms.

[0037] As used herein, the term "diluent" refers to a compound that is diluted with water to stabilize the biologically active form of the compound of interest and dissolve the compound. Salts dissolved in buffered solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, which mimics the salt form of human body fluids. Buffered diluents rarely alter the biological activity of a compound, because buffer salts can control the pH of the solution at low concentrations.

[0038] As used herein, the term "pharmaceutical acceptable" refers to the property of not impairing the biological activity and physical properties of a compound. The pharmaceutical composition may be a composition for preventing and / or treating a disease associated with PRMT5 inhibition, such as cancer, blood disease, autoimmune disease, inflammatory disease, or neurodegenerative disease, and also includes any other disease known to be associated with PRMT5.

[0039] The cancers include acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma, benign monoclonal gammopathy, bile duct cancer, bladder cancer, breast cancer, brain tumor, lymphoma, multiple myeloma, lacrimal gland tumor, bronchial cancer, cervical cancer, craniopharyngioma, colorectal cancer, epithelial tumor, ependymoma, endothelial sarcoma, endometrial cancer, esophageal cancer, Barrett's adenocarcinoma, Ewing's sarcoma, sarcoma), eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cavity cancer (OSCC), throat cancer, hematopoietic system cancer, hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer, liver cancer, lung cancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), neuroblastoma, neurofibroma, neuroendocrine carcinoma, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, prostate cancer, calcific cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, thyroid cancer, urethral cancer, vaginal cancer, and vulvar cancer. The brain tumors include, but are not limited to, meningiomas, gliomas, medulloblastomas, glioblastomas, and brain metastases.The brain tumors include, but are not limited to, meningiomas, gliomas, medulloblastomas, glioblastomas, and brain metastases.

[0040] Said blood disorders include, but are not limited to, hemoglobinemia or sickle cell anemia. The autoimmune diseases include, but are not limited to, rheumatoid arthritis, spinal arthritis, gouty arthritis, degenerative joint disease, osteoarthritis, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, juvenile arthritis, asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, psoriasis, eczema, burns, dermatitis, pruritus, nocturnal enuresis, eosinophilic diseases, peptic ulcer, regional enteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis.

[0041] The inflammatory diseases include acne-related inflammation, aplastic anemia, autoimmune hemolytic anemia, rhinitis, asthma, polyarteritis nodosa, temporal arteritis, periarteritis nodosa, Takayasu's arteritis, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, chronic obstructive pulmonary disease, dermatomyositis, type I diabetes, type 2 diabetes, psoriasis, eczema, eczema hypersensitivity reaction, burns, dermatitis, pruritus, endometriosis, infection, ischemic heart disease, glomerulonephritis, gingivitis, hypersensitivity, migraine, tension headache, postoperative intestinal obstruction. These conditions include, but are not limited to, ileus, ileus during sepsis, idiopathic thrombocytopenic purpura, painful bladder syndrome, peptic ulcer, regional enteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, bypass colitis, Behcet's syndrome, indeterminate colitis, inflammatory bowel syndrome (IBS), lupus, morphea, myasthenia gravis, and myocardial ischemia.

[0042] Examples of said neurodegenerative diseases include, but are not limited to, motor neuron disease, Pick's disease, Alzheimer's disease, AIDS dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinal pigmentation, spinal muscular atrophy and cerebellar degeneration. The pharmaceutical composition can be formulated into various oral or parenteral dosage forms. For example, it can be formulated into any oral dosage form, such as tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc. Such oral preparations can contain, in addition to the active ingredient, pharma- ceutically acceptable carriers, such as diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine, or glidants, such as silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol, depending on the typical constitution of each preparation.

[0043] When the preparation for oral administration is a tablet, the preparation may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and may further contain a disintegrant such as starch, agar, alginic acid or a sodium salt thereof, a boiling mixture and / or an absorbent, a colorant, a flavoring agent or a sweetener, etc.

[0044] When the pharmaceutical composition is formulated into a parenteral dosage form, it can be administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In this case, in order to formulate the pharmaceutical composition into a parenteral administration preparation, the active ingredient, i.e., the compound of formula (1), or its optical isomer, stereoisomer, or isotopic variant, or a pharma- ceutically acceptable salt thereof, is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, and such a solution or suspension can be prepared as a unit dosage form in an ampoule or vial.

[0045] Moreover, the pharmaceutical compositions may be sterilized or may further contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, salts and / or buffers for adjusting osmotic pressure, or other therapeutically useful agents, and may be formulated according to conventional methods of mixing, granulating or coating. The active ingredient, i.e., the compound of formula (1) or its optical isomer, stereoisomer or isotopic variant, or a pharma- ceutically acceptable salt thereof, may be contained in the pharmaceutical composition in an effective amount of 0.1 to 500 mg / kg (body weight), preferably 0.5 to 100 mg / kg (body weight) per day for mammals including humans, and the pharmaceutical composition may be administered once or twice a day via oral or parenteral routes. Effect of the Invention

[0046] According to the present invention, there is provided a 6-6 bicyclic ring-based compound, or its optical isomer, stereoisomer or isotopic variant, or a pharma- ceutically acceptable salt thereof, which exhibits excellent PRMT5 inhibitory effects. Therefore, such a compound, or its optical isomer, stereoisomer or isotopic variant, or a pharma- ceutically acceptable salt thereof, can be effectively used for the prophylaxis or treatment of diseases associated with PRMT5 inhibition, such as cancer, blood disease, autoimmune disease, inflammatory disease, or neurodegenerative disease.

[0047] In addition, the compound according to the present invention, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof, may have improved blood-brain barrier permeability, superior efficacy, or improved pharmacokinetic properties. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] The present invention will now be described in more detail with reference to the following examples. However, it should be understood that the scope of protection of the present disclosure is not limited to the examples. Abbreviations and terms used in the examples below are as follows: BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Cs 2 CO 3 : Cesium carbonate NaBH 3 CN: Sodium cyanoborohydride NaOt-Bu: Sodium tert-butoxide Pd(dppf)Cl 2 :1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride Pd(dba) 2 : Bis(dibenzylideneacetone)palladium(0) Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) tBuXphos: 2-di-tert-butylphosphino-2',4',6'-trisisopropylbiphenyl Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xphos: 2-dicyclohexylphosphino-2',4',6'-trisisopropylbiphenyl

[0049] Example 1: Synthesis of 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one [ka]

[0050] Example 1-1: Synthesis of 6-bromo-2-[[(2R)-oxiran-2-yl]methyl]-3,4-dihydroisoquinolin-1-one 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 quench the reaction, and ethyl acetate was added. The reaction mixture was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the title compound (2 g) was obtained by flash chromatography.

[0051] 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 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 tetrahydroisoquinoline (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 the title compound (2.2 g). 1 H NMR (400 MHz, Methanol-d 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).

[0052] 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 [ka]

[0053] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-3,4-dihydroisoquinolin-1-one (100 mg, 0.24 mmol) obtained in Example 1, pyrrolidine (0.12 mL, 0.96 mmol), Pd 2 (dba) 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 at 120 °C for 2 h in a microwave. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was dried under reduced pressure, and then purified by flash chromatography to give the title compound (40 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0054] Example 3: Synthesis of 6-(cyclohexylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one [ka]

[0055] The title compound was synthesized in a similar manner to Example 2, except that cyclohexanamine was used instead of pyrrolidine. 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, 6.6Hz, 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).

[0056] Example 4: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-morpholino-3,4-dihydroisoquinolin-1-one [ka]

[0057] The title compound was synthesized in a similar manner to Example 2, except that morpholine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0058] 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 [ka]

[0059] The title compound was synthesized in a similar manner to Example 2, except that tetrahydropyran-4-amine was used instead of pyrrolidine. 1 H 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).

[0060] Example 6: Synthesis of 6-(cyclohexylmethylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one [ka]

[0061] The title compound was synthesized in a similar manner to Example 2, except that cyclohexylmethanamine was used instead of pyrrolidine. 1 H 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).

[0062] Example 7: Synthesis of 6-(benzylamino)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one [ka]

[0063] The title compound was synthesized in a similar manner to Example 2, except that phenylmethanamine was used instead of pyrrolidine. 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).

[0064] 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 [ka]

[0065] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-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 2 (20 mg, 0.02 mmol), K 2 CO 3 (100 mg, 0.72 mmol) in 3 mL of 1,4-dioxane and H 2 The mixture was dissolved in 1 mL of O and stirred in a microwave at 120° C. for 2 h. 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 give the title compound (35 mg). 1 H 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).

[0066] 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 [ka]

[0067] The title compound was synthesized in a similar manner to Example 8, except that 3-pyridylboronic acid was used instead of 4-pyridylboronic acid. 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).

[0068] 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 [ka]

[0069] The title compound was synthesized in a similar manner to Example 2, except that 4-pyridylmethanamine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0070] 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 [ka]

[0071] The title compound was synthesized in a similar manner to Example 2, except that N-methylcyclohexanamine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0072] 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 [ka]

[0073] The title compound was synthesized in a similar manner to Example 8, except that (2-fluoro-4-pyridyl)boronic acid was used instead of 4-pyridylboronic acid. 1 H NMR (400 MHz, Methanol-d 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).

[0074] Example 13: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-propyl-3,4-dihydroisoquinolin-1-one [ka]

[0075] The title compound was synthesized in a similar manner to Example 8, except that propylboronic acid was used instead of 4-pyridylboronic acid. 1 H NMR (400 MHz, Methanol-d 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).

[0076] 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 [ka]

[0077] The title compound was synthesized in a similar manner to Example 2, except that (2R,6S)-2,6-dimethylmorpholine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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 = 6.2Hz, 6H).

[0078] 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 [ka]

[0079] The title compound was synthesized in a similar manner to Example 8, except that (6-fluoro-3-pyridyl)boronic acid was used instead of 4-pyridylboronic acid. 1 H NMR (400 MHz, Methanol-d 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, 7.7Hz, 1H), 3.19 - 3.07 (m, 2H), 3.00 - 2.83 (m, 4H), 2.76 - 2.58 (m, 2H).

[0080] 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 [ka]

[0081] The title compound was synthesized in a similar manner to Example 2, except that (2R)-2-methylmorpholine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0082] 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 [ka]

[0083] The title compound was synthesized in a similar manner to Example 2, except that N-methylpiperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0084] 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 [ka]

[0085] 6-Bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-3,4-dihydroisoquinolin-1-one (100 mg, 0.24 mmol) obtained in Example 1, pyrrolidin-2-one (74 μL, 0.96 mmol), Pd 2 (dba) 3 (11 mg, 0.01 mmol), Cs 2 CO 3 (110 mg, 0.34 mmol) and Xantphos (21 mg, 0.036 mmol) were dissolved in 4 mL of 1,4-dioxane and stirred at 120° C. for 2 h in a microwave. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was dried under reduced pressure, and then purified by flash chromatography to give the title compound (38 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0086] 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 [ka]

[0087] The title compound was synthesized in a similar manner to Example 18, except that 2,2-dimethylpropanamide was used instead of pyrrolidin-2-one. 1 H NMR (400 MHz, Methanol-d 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).

[0088] 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 [ka]

[0089] The title compound was synthesized in a similar manner to Example 18, except that azetidin-2-one was used instead of pyrrolidin-2-one. 1 H NMR (400 MHz, Methanol-d4 ) 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).

[0090] 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 [ka]

[0091] The title compound was synthesized in a similar manner to Example 18, except that piperidin-2-one was used instead of pyrrolidin-2-one. 1 H NMR (400 MHz, Methanol-d 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).

[0092] 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 [ka]

[0093] The title compound was synthesized in a similar manner to Example 2, except that 3-pyridylmethanamine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0094] 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 [ka]

[0095] The title compound was synthesized in a similar manner to Example 2, except that tetrahydropyran-4-ylmethanamine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0096] 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 [ka]

[0097] The title compound was synthesized in a similar manner to Example 2, except that 1-[4-(aminomethyl)-1-piperidyl]ethanone was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0098] 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 [ka]

[0099] The title compound was synthesized in a similar manner to Example 2, except that 1-amino-2-methyl-propan-2-ol was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0100] 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 [ka]

[0101] The title compound was synthesized in a similar manner to Example 18, except that pyridine-3-carboxamide was used instead of pyrrolidin-2-one. 1 H NMR (400 MHz, Methanol-d 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).

[0102] 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 [ka]

[0103] The title compound was synthesized in a similar manner to Example 18, except that pyridine-4-carboxamide was used instead of pyrrolidin-2-one. 1 H NMR (400 MHz, Methanol-d 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).

[0104] 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 [ka]

[0105] The title compound was synthesized in a similar manner to Example 2, except that 3,5-dimethylpiperidine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0106] 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 [ka]

[0107] The title compound was synthesized in a similar manner to Example 2, except that 2,6-dimethylpiperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0108] 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 [ka]

[0109] The title compound was synthesized in a similar manner to Example 2, except that tetrahydrofuran-3-ylmethanamine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0110] 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 [ka]

[0111] The 6-[(1-acetyl-4-piperidyl)methylamino]-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one obtained in Example 24 (10 mg, 0.02 mmol) was dissolved in 4 mL of methanol:H 2 The mixture was dissolved in 1:1 HO solution, added with excess NaOH, heated and stirred at reflux. After completion of the reaction, the reaction mixture was extracted with ethyl acetate to give the title compound (3 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0112] 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 [ka]

[0113] The title compound was synthesized in a similar manner to Example 2, except that 1-(4-amino-1-piperidyl)ethanone was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0114] 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 [ka]

[0115] The title compound was synthesized in a similar manner to Example 18, except that 2-morpholinoacetamide was used instead of pyrrolidin-2-one. 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).

[0116] 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 [ka]

[0117] The title compound was obtained by using 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 in the same manner as in Example 31. 1 H NMR (400 MHz, Methanol-d 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).

[0118] 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 [ka]

[0119] The title compound was synthesized in a similar manner to Example 2, except that 4-piperidylmethanol was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0120] 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 [ka]

[0121] The title compound was synthesized in a similar manner to Example 2, except that 3-piperidylmethanol was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0122] 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 [ka]

[0123] The title compound was synthesized in a similar manner to Example 2, except that 4-hydroxypiperidine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0124] 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 [ka]

[0125] The title compound was synthesized in a similar manner to Example 2, except that 3-hydroxypiperidine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0126] 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 [ka]

[0127] The title compound was synthesized in a similar manner to Example 2, except that oxazolidine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0128] 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 [ka]

[0129] The title compound was synthesized in a similar manner to Example 2, except that 3-methylmorpholine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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, 3.8Hz, 1H), 3.01 - 2.78 (m, 6H), 2.68 - 2.58 (m, 2H), 1.16 (d, J = 6.6 Hz, 3H).

[0130] 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 [ka]

[0131] The title compound was synthesized in a similar manner to Example 18, except that 2-hydroxyacetamide was used instead of pyrrolidin-2-one. 1 H NMR (400 MHz, Methanol-d 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).

[0132] 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 [ka]

[0133] The title compound was synthesized in a similar manner to Example 18, except that acetamide was used instead of pyrrolidin-2-one. 1 H NMR (400 MHz, Methanol-d 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).

[0134] Example 43: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(morpholinomethyl)-3,4-dihydroisoquinolin-1-one [ka]

[0135] The mixture was diluted with 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-3,4-dihydroisoquinolin-1-one (100 mg, 0.24 mmol) obtained in Example 1, potassium (morpholin-4-yl)methyl trifluoroboronate (55 mg, 0.26 mmol), palladium acetate (3 mg, 0.012 mmol), XPhos (11 mg, 0.023 mmol), and Cs 2 CO 3 (228 mg, 0.70 mmol) was 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 resulting solution was concentrated under reduced pressure and purified by flash chromatography to give the title compound (26 mg) as a white solid. 1H NMR (400 MHz, Methanol-d 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).

[0136] 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 [ka]

[0137] The title compound was synthesized in a similar manner to Example 43, except that 2-oxa-6-azaspiro[3.3]heptane was used instead of potassium (morpholin-4-yl)methyltrifluoroboronate. 1 H NMR (400 MHz, Methanol-d 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).

[0138] 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 [ka]

[0139] The title compound was synthesized in a similar manner to Example 18, except that oxazolidin-2-one of pyrrolidin-2-one was used. 1 H NMR (400 MHz, Methanol-d 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).

[0140] 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 [ka]

[0141] The title compound was synthesized in a similar manner to Example 2, except that azetidin-3-ylmethanol was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0142] 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 [ka]

[0143] The title compound was synthesized in a similar manner to Example 2, except that (2S)-2-methylmorpholine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d4 ) 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).

[0144] 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 [ka]

[0145] The title compound was synthesized in a similar manner to Example 2, except that 4-methoxypiperidine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0146] Example 49: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-(1,1-dioxo-1,4-diazinan-4-yl)-3,4-dihydroisoquinolin-1-one [ka]

[0147] The title compound was synthesized in a similar manner to Example 2, except that 1,4-thiazinane-1,1-dioxide was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0148] 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 [ka]

[0149] The title compound was synthesized in a similar manner to Example 2, except that tetrahydrofuran-3-amine of pyrrolidine was used. 1 H NMR (400 MHz, Methanol-d 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).

[0150] 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 [ka]

[0151] The title compound was synthesized in a similar manner to Example 2, except that oxetan-3-amine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0152] 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 [ka]

[0153] The title compound was synthesized in a similar manner to Example 2, except that N-acetylpiperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0154] 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 [ka]

[0155] The title compound was synthesized in a similar manner to Example 2, except that tert-butyl piperazine-1-carboxylate was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0156] 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 [ka]

[0157] The title compound was synthesized in a similar manner to Example 43, except that potassium (1,4-oxazepan-4-yl)methyl trifluoroboronate was used instead of potassium (morpholin-4-yl)methyl trifluoroboronate. 1 H NMR (400 MHz, Methanol-d 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).

[0158] 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 [ka]

[0159] The title compound was synthesized in a similar manner to Example 2, except that 1-methylpiperazin-2-one was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0160] 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 [ka]

[0161] The title compound was synthesized in a similar manner to 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. 1 H NMR (400 MHz, Methanol-d 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).

[0162] 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 [ka]

[0163] 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 4M hydrochloric acid (dioxane solution) was added in excess and stirred at room temperature. After completion of the reaction, the reaction mixture was neutralized with 2N NaOH solution and extracted with a mixed solution of isopropanol and dichloromethane (1:10) to obtain the title compound (19 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0164] 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 [ka]

[0165] The title compound was synthesized using 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 in a manner similar to that in Example 57. 1 H NMR (400 MHz, Methanol-d 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).

[0166] 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 [ka]

[0167] 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. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was dried under reduced pressure, and the product was purified by flash chromatography to obtain the title compound (7 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0168] 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 [ka]

[0169] The title compound was synthesized in a similar manner to Example 59, except that methyl chloroformate was used instead of methanesulfonyl chloride. 1 H NMR (400 MHz, Methanol-d 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).

[0170] 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 [ka]

[0171] The title compound was synthesized in the same manner as in Example 59, except that acetic anhydride was used instead of methanesulfonyl chloride, using 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 the starting material. 1 H NMR (400 MHz, Methanol-d 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).

[0172] Example 62: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-3,4-dihydroisoquinolin-1-one [ka]

[0173] The title compound was synthesized in a similar manner to Example 59, except that trifluoroacetyl chloride was used instead of methanesulfonyl chloride. 1 H NMR (400 MHz, Methanol-d 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).

[0174] 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 [ka]

[0175] 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 while filling with hydrogen gas and stirring. After the reaction was completed, the reaction mixture was filtered through Celite, the solvent was dried under reduced pressure, and the product was purified by flash chromatography to obtain the title compound (5 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0176] 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 [ka]

[0177] The title compound was synthesized in a similar manner to Example 2, except that 4-isopropylpiperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0178] 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 [ka]

[0179] The title compound was synthesized in a similar manner to Example 2, except that ethyl piperazine-1-carboxylate was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0180] 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 [ka]

[0181] The title compound was synthesized in a similar manner to Example 43, except that potassium (4-methoxy-1-piperidyl)methyl trifluoroboronate was used instead of potassium (morpholin-4-yl)methyl trifluoroboronate. 1H NMR (400 MHz, Methanol-d 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).

[0182] 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 [ka]

[0183] The title compound was obtained by using 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 obtained in Example 61 as a starting material in a manner similar to that in Example 63. 1 H NMR (400 MHz, Methanol-d 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, 4.3Hz, 2H).

[0184] 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 [ka]

[0185] The title compound was synthesized in a similar manner to Example 43, except that potassium (4-acetylpiperazin-1-yl)methyl trifluoroboronate was used instead of potassium (morpholin-4-yl)methyl trifluoroboronate. 1 H NMR (400 MHz, Methanol-d 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).

[0186] 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 [ka]

[0187] The title compound was synthesized in a similar manner to Example 59, except that propionyl chloride was used instead of methanesulfonyl chloride. 1 H NMR (400 MHz, Methanol-d 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).

[0188] 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 [ka]

[0189] The title compound was synthesized in a similar manner to Example 59, except that isobutyryl chloride was used instead of methanesulfonyl chloride. 1 H NMR (400 MHz, Methanol-d 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).

[0190] 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 [ka]

[0191] The title compound was synthesized in a similar manner to Example 59, except that pivaloyl chloride was used instead of methanesulfonyl chloride. 1H NMR (400 MHz, Methanol-d 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).

[0192] 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 [ka]

[0193] The title compound was synthesized in a similar manner to Example 2, except that tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0194] 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 [ka]

[0195] The title compound was synthesized in a similar manner to Example 2, except that 2-oxa-5-azabicyclo[2.2.1]heptane was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0196] Example 74: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-hydroxy-3,4-dihydroisoquinolin-1-one [ka]

[0197] 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) 2 (38 mg, 0.07 mmol) in 7 mL of 1,4-dioxane:H 2 The mixture was added to a microwave vessel together with a 1:1 K2O (1:1) solution and stirred at 100°C for 2 hours. Ethyl acetate was added to the reaction mixture, which was then acidified with 2N hydrochloric acid. The resulting aqueous layer was washed with saturated K 2 CO 3 The mixture was basified with a solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure, and then used in the next reaction without further purification (product: 300 mg). 1H NMR (400 MHz, Methanol-d 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).

[0198] 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 [ka]

[0199] 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. 1 H NMR (400 MHz, Methanol-d 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).

[0200] 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 [ka]

[0201] The title compound was obtained by using 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 in a manner similar to that in Example 57. 1 H NMR (400 MHz, Methanol-d 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).

[0202] 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 [ka]

[0203] 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 The title compound was synthesized in a similar manner to Example 2, except that tert-butyl 3-aminopiperidine-1-carboxylate was used instead of pyrrolidine.

[0204] 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 The title compound was obtained by using 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 in a manner similar to that in Example 57. 1 H NMR (400 MHz, Methanol-d 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).

[0205] 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 [ka]

[0206] The title compound was synthesized in a similar manner to Example 2, except that tert-butyl 1,4-diazepane-1-carboxylate was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0207] 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 [ka]

[0208] The title compound was synthesized in a similar manner to Example 2, except that 1-methyl-1,4-diazepan-2-one was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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 = 5.8Hz, 2H), 2.70 - 2.56 (m, 2H), 1.90 (p, J = 5.3 Hz, 2H).

[0209] 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 [ka]

[0210] 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 The title compound was synthesized using 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 in a manner similar to that in Example 57.

[0211] 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 The title compound was obtained in the same manner as in Example 59, except that 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 was used as a starting material, and acetic anhydride was used instead of methanesulfonyl chloride. 1 H NMR (400 MHz, Methanol-d 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).

[0212] 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 [ka]

[0213] The title compound was synthesized in the same manner as in Example 59, except that acetic anhydride was used instead of methanesulfonyl chloride, using 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 obtained in Example 76 as a starting material. 1H NMR (400 MHz, Methanol-d 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).

[0214] 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 [ka]

[0215] The title compound was synthesized in a similar manner to Example 2, except that 1-(4,7-diazaspiro[2.5]octan-4-yl)ethanone was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0216] 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 [ka]

[0217] 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-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 2 CO 3 (140 mg, 0.42 mmol) was dissolved in acetonitrile (4 mL) and stirred in a microwave tube at 150° C. 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 give the title compound (27 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0218] 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 [ka]

[0219] The title compound was synthesized in a similar manner to Example 2, except that 4-methyl-1,4-diazepan-5-one was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0220] 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 [ka]

[0221] The title compound was synthesized in a similar manner to Example 2, except that 1-isopropylpiperazin-2-one was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0222] 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 [ka]

[0223] The title compound was synthesized in a similar manner to Example 18, except that 4-acetylpiperazin-2-one was used instead of pyrrolidin-2-one. 1 H NMR (400 MHz, Methanol-d 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).

[0224] 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 [ka]

[0225] The title compound was synthesized in a similar manner to Example 2, except that piperazine-1-carbaldehyde was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0226] 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 [ka]

[0227] 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 in a microwave tube at 110° C. The reaction mixture was dried under reduced pressure and purified by flash chromatography to give the title compound (41 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0228] 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 [ka]

[0229] The title compound was synthesized in a similar manner to Example 88, except that morpholine was used instead of N-acetylpiperazine. 1 H NMR (400 MHz, Methanol-d 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).

[0230] 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 [ka]

[0231] The title compound was synthesized in a similar manner to Example 2, except that N-methyl-N-(4-piperidyl)acetamide was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0232] 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 [ka]

[0233] The title compound was synthesized in a similar manner to Example 83, except that (1-acetyl-4-piperidyl)methyl methanesulfonate was used instead of 4-bromotetrahydropyran. 1 H NMR (400 MHz, Methanol-d 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).

[0234] 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 [ka]

[0235] The title compound was synthesized in a similar manner to Example 2, except that N-(4-piperidyl)acetamide was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0236] 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 [ka]

[0237] The title compound was synthesized in the same manner as in Example 59, except that acetic anhydride was used instead of methanesulfonyl chloride, using 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 the starting material. 1 H NMR (400 MHz, Methanol-d 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).

[0238] 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 [ka]

[0239] The title compound was synthesized in a similar manner to Example 2, except that 1,5,6,7,8,8a-hexahydrooxazolo[3,4-a]pyrazin-3-one was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0240] 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 [ka]

[0241] The title compound was synthesized in a similar manner to Example 83, except that (1-acetyl-4-piperidyl)methanesulfonate was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate. 1 H NMR (400 MHz, Methanol-d 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).

[0242] 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 [ka]

[0243] 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 The title compound was synthesized in a similar manner to Example 83, except that tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate was used instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

[0244] 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 The title compound was synthesized using 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 in a manner similar to that in Example 57.

[0245] 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 The title compound was synthesized in the same manner as in Example 59, except that acetic anhydride was used instead of methanesulfonyl chloride, using 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 the starting material. 1 H NMR (400 MHz, Methanol-d 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).

[0246] 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 [ka]

[0247] The title compound was synthesized in a similar manner to Example 2, except that N,N-dimethylpiperidine-4-carboxamide was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0248] 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 [ka]

[0249] 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 The title compound was synthesized in a similar manner to Example 2, except that tert-butyl 4-aminoazepane-1-carboxylate was used instead of pyrrolidine.

[0250] 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 The title compound was synthesized using 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 in a manner similar to that in Example 57.

[0251] 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 The title compound was synthesized in the same manner as in Example 59, except that acetic anhydride was used instead of methanesulfonyl chloride, using 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 the starting material. 1 H NMR (400 MHz, Methanol-d 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).

[0252] 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 [ka]

[0253] The title compound was synthesized in a similar manner to Example 2, except that 1-(3-aminopyrrolidin-1-yl)ethanone was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0254] 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 [ka]

[0255] The title compound was synthesized in a similar manner to Example 2, except that piperazine-1-carboxamide was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0256] 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 [ka]

[0257] 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), K 2 CO3 (50 mg, 0.36 mmol) was dissolved in chloroform and stirred at 60° C. Ethyl acetate was added to the reaction mixture, which was then washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, and the organic layer was then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the product was purified by flash chromatography to obtain the title compound (9 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0258] Example 102: Synthesis of 6-(6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-3,4-dihydroisoquinolin-1-one [ka]

[0259] The title compound was synthesized in a similar manner to Example 2, except that 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0260] 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 [ka]

[0261] The title compound was synthesized in a similar manner to Example 2, except that 1,6-dimethylpiperazin-2-one was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0262] 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 [ka]

[0263] 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 [ka]

[0264] 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. 1 H NMR (400 MHz, Methanol-d 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).

[0265] 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 The title compound was synthesized in the same manner as in Example 2, except that 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 was used as a starting material, and N-acetylpiperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0266] Example 105: Synthesis of 6-(4-acetylpiperazin-1-yl)-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]spiro[3H-isoquinolin-4,1'-cyclopropan]-1-one [ka]

[0267] Example 105-1: Synthesis of 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]spiro[3H-isoquinolin-4,1'-cyclopropan]-1-one The title compound was synthesized in the same manner as in Example 1, except that 6-bromospiro[2,3-dihydroisoquinolin-4,1'-cyclopropane]-1-one was used instead of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one.

[0268] 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-isoquinolin-4,1'-cyclopropan]-1-one The title compound was synthesized in the same manner as in Example 2, except that 6-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]spiro[3H-isoquinolin-4,1'-cyclopropane]-1-one obtained in Example 105-1 was used as a starting material, and N-acetylpiperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol- d4 ) 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).

[0269] 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 [ka]

[0270] The title compound was synthesized in a similar manner to Example 2, except that 4-pyrrolidin-1-ylpiperidine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0271] 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 [ka]

[0272] The title compound was synthesized in a similar manner to Example 2, except that 1-(4-piperidyl)piperidine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0273] 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 [ka]

[0274] The title compound was synthesized in a similar manner to Example 2, except that 4-(4-piperidyl)morpholine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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, 4.2Hz, 6H), 2.47 - 2.37 (m, 1H), 2.08 - 1.95 (m, 2H), 1.64 - 1.50 (m, 2H).

[0275] 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 [ka]

[0276] The title compound was synthesized in a similar manner to Example 2, except that 1-(2-methoxyethyl)piperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0277] 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 [ka]

[0278] The title compound was synthesized in a similar manner to Example 2, except that N,N-dimethylpiperidin-4-amine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0279] 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 [ka]

[0280] The title compound was synthesized in the same manner as in Example 2, except that 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 was used as a starting material, and N,N-dimethylpiperidin-4-amine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0281] 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 [ka]

[0282] The title compound was synthesized in the same manner as in Example 2, except that morpholine was used instead of pyrrolidine, using 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. 1 H NMR (400 MHz, Methanol-d 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).

[0283] 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 [ka]

[0284] The title compound was synthesized in a similar manner to Example 83, except for using 4-(2-chloroethyl)morpholine instead of (1-acetyl-4-piperidyl)methyl methanesulfonate. 1 H NMR (400 MHz, Methanol-d 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, 9.8Hz, 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).

[0285] 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 [ka]

[0286] 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 The title compound was synthesized in a similar manner to Example 83, except for using tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

[0287] 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 The title compound was synthesized using 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 in a manner similar to that in Example 57.

[0288] 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 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-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 3 CN (55 μL, 0.85 mmol) was dissolved in methanol (4 mL) and stirred at room temperature. Ethyl acetate was added to the reaction mixture, and saturated K 2 CO 3 After washing with aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and purified by flash chromatography to give the title compound (22 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0289] Example 115: 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 [ka]

[0290] 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 The title compound was synthesized in a similar manner to Example 83, except for using tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

[0291] 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 The title compound was synthesized using 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 in a manner similar to that in Example 57.

[0292] 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 The title compound was synthesized using 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 in the same manner as in Example 114-3. 1 H NMR (400 MHz, Methanol-d 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).

[0293] 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 [ka]

[0294] The title compound was synthesized in a similar manner to Example 2, except that N,N-dimethylpiperidin-3-amine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0295] 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 [ka]

[0296] The title compound was synthesized in a similar manner to Example 2, except that N,N-dimethyl-1-(4-piperidyl)methanamine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0297] 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 [ka]

[0298] The title compound was synthesized in a similar manner to Example 2, except that N,N-diethylpiperidin-4-amine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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 [ka]

[0299] The title compound was synthesized in a similar manner to Example 2, except that N,N-dimethyl-2-(4-piperidyloxy)ethanamine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0300] 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 [ka]

[0301] The title compound was synthesized in a similar manner to Example 2, except that N-(2-methoxyethyl)-N-methyl-piperidin-4-amine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0302] 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 [ka]

[0303] The title compound was synthesized in a similar manner to Example 2, except that 1-(oxetan-3-yl)piperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0304] 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 [ka]

[0305] The title compound was synthesized in the same manner as in Example 114-3, except that 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 was used as the starting material, and tetrahydropyran-4-one was used instead of acetaldehyde. 1 H NMR (400 MHz, Methanol-d 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).

[0306] 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 [ka]

[0307] The title compound was synthesized in the same manner as in Example 2, except that 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 was used as a starting material, and N,N-diethylpiperidin-4-amine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0308] 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 [ka]

[0309] The title compound was synthesized in the same manner as in Example 2, except that 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 was used as a starting material, and 4-pyrrolidin-1-ylpiperidine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0310] 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 [ka]

[0311] The title compound was synthesized in the same manner as in Example 2, except that 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 was used as a starting material, and N-formylpiperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0312] 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 salt [ka]

[0313] 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 4M hydrochloric acid in dioxane solution was added and stirred at room temperature. The solvent was removed by evaporation under reduced pressure to give the title compound (17 mg) without further purification. 1 H NMR (400 MHz, Methanol-d 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).

[0314] 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 [ka]

[0315] The title compound was synthesized in the same manner as in Example 114-3, except that 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 was used as the starting material, and tetrahydrofuran-3-one was used instead of acetaldehyde. 1 H NMR (400 MHz, Methanol-d 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)

[0316] 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 [ka]

[0317] 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 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 The title compound was synthesized in the same manner as in Example 2, except that 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 was used as a starting material, and N-acetylpiperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0318] 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 [ka]

[0319] Example 129-1: Synthesis of ethyl 2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2-yl)propanoate 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one (1 g, 4.42 mmol), ethyl 2-bromopropionate (1.15 mL, 8.85 mmol) and Cs 2 CO 3(2.9 g, 8.85 mmol) was dissolved in 15 mL of acetonitrile and stirred at 70° C. The reaction mixture was quenched with water, extracted 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.

[0320] Example 129-2: Synthesis of 2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-2-yl)propanal 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, cooled to -78°C, and stirred. While maintaining the temperature, DIBAL-H (11.5 mL, 11.47 mmol) in toluene solution was slowly added dropwise. After quenching the reaction with methanol and distilled water, it 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 mixture was used in the next reaction without further purification.

[0321] Example 129-3: Synthesis of 6-bromo-2-[1-(oxiran-2-yl)ethyl]-3,4-dihydroisoquinolin-1-one Trimethylsulfoxonium 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, which was stirred for 15 minutes, and 2-(6-bromo-1-oxo-3,4-dihydroisoquinolin-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 quench the reaction, ethyl acetate was added, and the mixture was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the mixture was used in the next reaction without further purification.

[0322] 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 The title compound was synthesized using 6-bromo-2-[1-(oxiran-2-yl)ethyl]-3,4-dihydroisoquinolin-1-one obtained in Example 129-3 as a starting material in a manner similar to that in Example 1-2.

[0323] Example 129-5: 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 [ka]

[0324] The title compound was synthesized in the same manner as in Example 2, except that 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 was used as a starting material, and N-acetylpiperazine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0325] 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 [ka]

[0326] The title compound was synthesized using 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 in a manner similar to that in Example 126. 1 H NMR (400 MHz, Methanol-d 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).

[0327] Example 131: 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 [ka]

[0328] 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 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, using 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.

[0329] 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 The title compound was synthesized using 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 in a manner similar to that in Example 57.

[0330] 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 The title compound was synthesized using 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 in a manner similar to that of Example 114-3. 1 H NMR (400 MHz, Methanol-d 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).

[0331] 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 [ka]

[0332] 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 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.

[0333] 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 The title compound was synthesized in the same manner as in Example 2, except that 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 was used as a starting material, and morpholine was used instead of pyrrolidine. 1 H NMR (400 MHz, Methanol-d 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).

[0334] 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 [ka]

[0335] 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 The title compound was synthesized in a similar manner to Example 83, except for using tert-butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

[0336] 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 The title compound was synthesized using 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 in a manner similar to that in Example 57.

[0337] 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 The title compound was synthesized in the same manner as in Example 114-3, except that 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 was used as a starting material, and paraformaldehyde was used instead of acetaldehyde. 1 H NMR (400 MHz, Methanol-d 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 = 2.55 - 2.35 (m, 5H), 2.08 - 1.93 (m, 1H).

[0338] 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 [ka]

[0339] The title compound was synthesized using 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 in a manner similar to that in Example 114-3. 1 H NMR (400 MHz, Methanol-d 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).

[0340] 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 [ka]

[0341] The title compound was synthesized in the same manner as in Example 114-3, except that 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 was used as a starting material, and paraformaldehyde was used instead of acetaldehyde. 1 H NMR (400 MHz, Methanol-d 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, 9.1Hz, 2H).

[0342] 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 [ka]

[0343] The title compound was synthesized in the same manner as in Example 114-3, except that 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 was used as the starting material, and oxetan-3-one was used instead of acetaldehyde. 1 H NMR (400 MHz, Methanol-d 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).

[0344] Example 137: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-(3-hydroxyprop-1-vinyl)-3,4-dihydroisoquinolin-1-one [ka]

[0345] 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 1 day. After the reaction was completed, 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 the title compound (12.5 mg). 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).

[0346] 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 [ka]

[0347] The title compound was synthesized in a similar manner to Example 137, except that 4-ethynylpyridine was used instead of prop-2-yn-1-ol. 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).

[0348] 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 [ka]

[0349] 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 The title compound was synthesized in a similar manner to Example 83, except for using tert-butyl 3-methylsorboniloxipepyridin-1-carboxylate instead of (1-acetyl-4-piperidyl)methyl methanesulfonate.

[0350] 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 The title compound was synthesized using 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 in a manner similar to that in Example 57.

[0351] 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 The title compound was synthesized in the same manner as in Example 114-3, except that 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 was used as a starting material, and paraformaldehyde was used instead of acetaldehyde. 1 H NMR (400 MHz, Methanol-d 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).

[0352] 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 [ka]

[0353] 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 1 day. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and the oily liquid concentrated under reduced pressure was purified by flash chromatography to obtain the title compound (5.1 mg). 1 H NMR (400 MHz, Methanol-d 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).

[0354] Example 141: Synthesis of 2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-6-[3-(dimethylamino)prop-1-vinyl]-3,4-dihydroisoquinolin-1-one [ka]

[0355] The title compound was synthesized in a similar manner to Example 137, except that N,N-dimethylprop-2-yn-1-amine was used instead of pyrrolidin-2-one. 1 H NMR (400 MHz, Methanol-d 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).

[0356] 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 [ka]

[0357] The title compound was synthesized in the same manner as in Example 140, except that 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 was used as the starting material, and 1-bromo-2-methoxy-ethane was used instead of 2-fluoroethyl 4-methylbenzenesulfonate. 1 H NMR (400 MHz, Methanol-d 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).

[0358] 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 [ka]

[0359] 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 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.

[0360] 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 The title compound was synthesized using 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 in a manner similar to that in Example 114-1.

[0361] 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 The title compound was synthesized using 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 in a manner similar to that of Example 57.

[0362] Example 143-4: 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 The title compound was synthesized in the same manner as in Example 140, except that 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 was used as a starting material, and 1-bromo-2-methoxy-ethane was used instead of 2-fluoroethyl 4-methylbenzenesulfonate. 1 H NMR (400 MHz, Methanol-d 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).

[0363] 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 [ka]

[0364] The title compound was synthesized in the same manner as in Example 140, except that 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 was used as a starting material, and (2R)-2-methyloxirane was used instead of 2-fluoroethyl 4-methylbenzenesulfonate. 1 H NMR (400 MHz, Methanol-d 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).

[0365] 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 [ka]

[0366] The title compound was synthesized in the same manner as in Example 140, except that 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 was used as a starting material, and 2,2-dimethyloxirane was used instead of 2-fluoroethyl 4-methylbenzenesulfonate. 1 H NMR (400 MHz, Methanol-d 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).

[0367] 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 [ka]

[0368] The title compound was synthesized in the same manner as in Example 114-3, except that 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 was used as a starting material, and oxetan-3-one was used instead of acetaldehyde. 1 H NMR (400 MHz, Methanol-d 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).

[0369] Experimental Example Methods for measuring enzyme activity In vitro analysis: The PRMT5-MEP50 enzyme complex, cofactor S-adenosylmethionine (SAM), and histone H4 peptide were reacted in vitro, and the enzymatic activity of PRMT5 was measured by measuring the methylation of arginine (H4R3), the third amino acid of histone H4. Reagents: PRMT5-MEP50 enzyme complex (catalog no. 51045), blocking buffer (52100-B), histone methyltransferase reaction buffer 2 (4x HMT assay buffer 2, catalog no. 52170), and primary antibody (primary antibody 4-3, catalog no. 52150) were purchased from BPS Biosciences (USA). Histone H4 peptide (1-20 amino acids) was custom-made and used by Komabiotech (Korea). 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: plates (Immobilizer®-Amino plates, NUNC, Denmark, Cat. No. 436023), carbonate-bicarbonate buffer (Sigma-Aldrich, USA, Cat. No. C3041), washing buffer (10×TBST, Biosesang, Korea, Cat. No. T2005), TMB ELISA substrate (Abcam, UK, Cat. No. ab210902), horseradish peroxidase-conjugated antibody (HRP-conjugated antibody, Abcam, UK, Cat. No. ab6721).

[0370] Experimental procedure: Histone H4 peptide was diluted with carbonate-bicarbonate buffer to prepare 100μg / mL, then dispensed into a plate per 100μL and reacted at 37℃ for 1 hour. PRMT5-MEP50 enzyme complex and S-adenosylmethionine were diluted with histone methyltransferase reaction buffer to prepare 5μg / mL and 2μM, respectively, and then 20μL and 25μL of PRMT5-MEP50 enzyme complex and S-adenosylmethionine were dispensed into a pre-prepared plate. 5μL of compound diluted with 10% dimethyl sulfoxide solution was added and reacted at room temperature for 2 hours (final volume = 50μL). Compound concentrations were diluted 1:5 from 10μM to a minimum concentration of 0.128nM, and 8 positions were used for the test. Primary antibody was prepared by diluting 1:2000 with blocking buffer, then 100μL was added to the plate and reacted at room temperature for 1 hour. Horseradish peroxidase-conjugated antibodies were prepared by diluting 1:10,000 in blocking buffer, and 100 μL was added to the plate and reacted at room temperature for 1 hour. 100 μL of TMB substrate was added and reacted at room temperature for 3 minutes, and then 100 μL of 1N sulfuric acid was added to stop the reaction. The absorbance at 450 nm was then measured to determine the IC of the compounds. 50 The values ​​were calculated (+++: 1 to 100 nM, ++: over 100 to 1,000 nM, +: over 1,000 to 10,000 nM).

[0371] [Table 21] [Table 22] [Table 23]

[0372] Testing for in vivo target inhibition activity After U87MG tumor cells were subcutaneously implanted into nude mice, the PRMT5 inhibitor was orally administered (25 or 50 mg / kg) 1-2 times daily for one week, and the degree of reduction in SDMA levels in the tumor was measured.

[0373] Reagents: Bradford solution (cat. no. 500-0006) was purchased from Bio-rad (USA). SDMA antibody (cat. no. 13222s) was purchased from Cell Signaling Technology (USA). SmD3 antibody (cat. no. ap12451a) was purchased from Abgent (USA), secondary antibody (cat. no. ab6721) and TMB substrate (cat. no. ab210902) were purchased from Abcam (UK).

[0374] Experimental procedure: Tumor tissues implanted in mice were excised, cells were lysed, and quantified with Bradford solution. 5-10 μg of protein per sample was diluted with carbonate-bicarbonate buffer, dispensed into a 96-well plate, and reacted at room temperature for 2 hours. After washing three times with phosphate-buffered saline (PBST) containing 0.05% Tween-20, 200 μL of PBST containing 5% bovine serum albumin (BSA-PBST) was added and reacted at room temperature for 2 hours. After washing three times with PBST, SDMA antibody and SmD3 antibody were diluted with BSA-PBST, 100 μL of each were dispensed into the plate, and reacted at 4 °C overnight. The next day, after washing three times with PBST, 100 μL of secondary antibody diluted with BSA-PBST was added and reacted at room temperature for 1 hour. After washing three times with PBST, 100 μL of TMB substrate was added, reacted at room temperature for 10-20 minutes, and the reaction was stopped by adding 100 μL of 1N sulfuric acid solution. The absorbance at 450 nm was then measured, and the degree of SDMA inhibition by the compound was calculated (+++: more than 70%, ++: more than 30% to 70% or less, +: 30% or less).

[0375] [Table 24]

Claims

1. The following formula (1) 【Chemistry 1】 wherein X is CH or N; n is an integer from 0 to 2, R 1 Is -D-R 9 or 【Chemistry 2】 where D is a direct bond, -CH 2 -, -O- or -C≡C-; R 9 is halo, hydroxy, alkyl, hydroxyalkyl, dialkylaminoalkyl, saturated or unsaturated heterocyclyl, or saturated heterocyclyl-alkyl, wherein the saturated or unsaturated heterocyclyl is optionally substituted with one or more substituents selected from halo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, and saturated heterocyclyl; R 10 and R 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 10 and R 11 may together with the N to which they are attached form a saturated or unsaturated heterocyclyl, said saturated or unsaturated heterocyclyl being optionally 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, thiakylaminoalkoxy, dialkylaminocarbonyl and 4-10 membered saturated heterocyclyl; R 2 is hydrogen or halo, R 3 is hydrogen, halo or alkyl, or when n is 2, may form a cycloalkyl together with the C to which it is attached; R 4 , R 5 , R 6 and R 7 are each independently hydrogen or alkyl; R 8 represents hydrogen, halo, alkyl, alkoxy or amino. or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

2. R 1 Is -D-R 9 where D is a direct bond, -CH 2 -, -O- or -C≡C-; R 9 is halo, hydroxy, C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 alkyl, 4- to 10-membered saturated or unsaturated heterocyclyl, or 4- to 10-membered saturated heterocyclyl-alkyl, the saturated or unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, halo, C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, halo-C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, C 1 -C 7 The compound according to claim 1, which may be substituted with one or more substituents selected from alkoxycarbonyl, and 4-10-membered saturated heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

3. D is a direct bond; R 9 is halo, hydroxy, C 1 -C 7 alkyl, 4-10 membered saturated or unsaturated heterocyclyl, said saturated or unsaturated heterocyclyl having 1-3 heteroatoms selected from N, O and S, halo, C 1 -C 7 Alkylcarbonyl and C 1 -C 7 The compound according to claim 2, which may be substituted by 1 to 3 substituents selected from alkoxycarbonyl, or an optical isomer, stereoisomer or isotopic mutant thereof, or a pharma- ceutically acceptable salt thereof.

4. The D is -CH 2 -, -O- or -C≡C-, R 9 is hydroxy-C 1 -C 7 Alkyl, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 Alkyl, 4- to 10-membered saturated or unsaturated heterocyclyl, or 4- to 10-membered saturated or unsaturated heterocyclyl-C 1 -C 7 alkyl, the saturated or unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, halo-C 1 -C 7 Alkyl, Hydroxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, C 1 -C 7 The compound according to claim 2, which is optionally substituted by 1 to 3 substituents selected from alkoxycarbonyl, and 4- to 10-membered saturated heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, or an optical isomer, stereoisomer, or isotopic mutant thereof, or a pharma- ceutically acceptable salt thereof.

5. The compound 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, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

6. R 1 teeth, 【Chemistry 3】 where R 10 and R 11 are each independently hydrogen, C 1 -C 7 Alkyl, C 3 -C 7 Cycloalkyl, hydroxy-C 1 -C 7 Alkyl, C 3 -C 7 Cycloalkyl-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, Hydroxy-C 1 -C 7 Alkylcarbonyl, C 6 -C 12 Aryl-C 1 -C 7 Alkyl, saturated heterocyclyl, saturated or unsaturated heterocyclyl-C 1 -C 7 Alkyl, unsaturated heterocyclyl-carbonyl, or saturated heterocyclyl-C 1 -C 7 alkylcarbonyl or R 10 and R 11 may together with the N to which they are attached form a saturated or unsaturated heterocyclyl, said heterocyclyl being selected from the group consisting of hydroxy, oxo, formyl (-CHO), cyano, C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, Hydroxy-C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, halo-C 1 -C 7 Alkylcarbonyl, C 1 -C 7 Alkoxycarbonyl, C 1 -C 7 Alkylamino, C 1 -C 7 Alkylsulfonyl, C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl, aminocarbonyl, C 1 -C 7 Alkylcarbonylamino, C 1 -C 7 Alkylcarbonyl-C 1 -C 7 Alkylamino, (C 1 -C 7 Alkoxy-C 1 -C 7 Alkyl) (C 1 -C 7 alkyl)amino, di(C 1 -C 7 alkyl)amino, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 Alkyl, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 Alkoxy, di(C 1 -C 7 The compound according to claim 1, which is optionally substituted by 1 to 3 substituents selected from alkyl, aryl, aryloxy ...

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

8. 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. The compound according to claim 6, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

9. R 2 is hydrogen or halo, R 3 is hydrogen, halo or C 1 -C 7 alkyl, or when n is 2, together with the C to which it is attached, C 3 -C 7 may form a cycloalkyl, R 4 , R 5 , R 6 and R 7 are each independently hydrogen or C 1 -C 7 is alkyl, R 8 is hydrogen, halo, C 1 -C 7 Alkyl, C 1 -C 7 2. The compound of claim 1 which is alkoxy or amino, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof.

10. 2. The compound according to claim 1, which is selected from the following compounds, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutically acceptable salt thereof: 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-dihydroisoquinolin-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-diazinan-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-trifluoroacetyl)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-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-(3,4-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-isoquinolin-4,1′-cyclopropan]-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)methoxy]-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 salt; 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; dihydrochloride; 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 preventing or treating a disease associated with PRMT5 inhibition, comprising a therapeutically effective amount of a compound of formula (1) according to any one of claims 1 to 10, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharma- ceutical acceptable salt thereof, together with a pharma-ceutical 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 cancers include acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma, benign monoclonal gammopathy, bile duct carcinoma, bladder carcinoma, breast cancer, brain tumor, lymphoma, multiple myeloma, lacrimal gland tumor, bronchial carcinoma, cervical cancer, craniopharyngioma, colorectal cancer, epithelial tumor, ependymoma, endothelial sarcoma, endometrial cancer, esophageal cancer, Barrett's adenocarcinoma, Ewing's sarcoma, 13. The pharmaceutical composition according to claim 12, wherein the cancer is selected from the group consisting of cancer of the human sarcoma, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, oral cavity cancer (OSCC), pharyngeal cancer, hematopoietic system cancer, hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer, liver cancer, lung cancer, myelodysplastic syndromes (MDS), mesothelioma, myeloproliferative disorder (MPD), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, prostate cancer, calcific cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, thyroid cancer, urethral cancer, vaginal cancer, and vulvar cancer.

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

15. the blood disease is hemoglobinemia or sickle cell anemia; the autoimmune disease is selected from the group consisting of rheumatoid arthritis, spinal arthritis, gouty arthritis, degenerative joint disease, osteoarthritis, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, juvenile arthritis, asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, psoriasis, eczema, burns, dermatitis, pruritus, nocturnal enuresis, eosinophilic diseases, peptic ulcer, regional enteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis and eosinophilic colitis; The inflammatory diseases include acne-related inflammation, aplastic anemia, autoimmune hemolytic anemia, rhinitis, asthma, polyarteritis nodosa, temporal arteritis, periarteritis nodosa, Takayasu's arteritis, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, chronic obstructive pulmonary disease, dermatomyositis, type I diabetes, type 2 diabetes, psoriasis, eczema, eczema hypersensitivity reaction, burns, dermatitis, pruritus, endometriosis, infection, ischemic heart disease, glomerulonephritis, gingivitis, hypersensitivity, migraine, tension headache, postoperative selected from the group consisting of intestinal obstruction, intestinal obstruction during sepsis, idiopathic thrombocytopenic purpura, painful bladder syndrome, peptic ulcer, regional enteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, bypass colitis, Behcet's syndrome, indeterminate colitis, inflammatory bowel syndrome (IBS), lupus, morphea, myasthenia gravis and myocardial ischemia, 13. The pharmaceutical composition of claim 12, wherein the neurodegenerative disease is selected from the group consisting of motor neuron disease, Pick's disease, Alzheimer's disease, AIDS dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinal pigmentation, spinal muscular atrophy and cerebellar degeneration.

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