Isoquinolinone derivatives, preparation methods and uses thereof

Abstract

The present invention relates to isoquinolinone derivatives, methods for preparing the same, and pharmaceutical compositions containing the same as active ingredients for preventing or treating poly(ADP-ribose) polymerase-1 (PARP-1)-related diseases. Isoquinolinone derivatives exhibit excellent PARP-1 inhibitory effects at nanomolar concentrations, and further exhibit excellent cell protective effects (apoptosis inhibitory effects) on ophthalmic diseases or disorders, particularly retinal disorders, and thus can be effectively used as pharmaceutical compositions containing the same as active ingredients for preventing or treating PARP-1-related diseases, for example, ophthalmic diseases or disorders.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for preventing or treating poly (ADP-ribose) polymerase (PARP-1) related diseases. Background Art

[0002] An estimated 42 million people worldwide suffer from blindness, and many more suffer from severe retinal disorders.

[0003] In the Western world, retinal diseases such as diabetic retinopathy, retinitis pigmentosa (RP), wet and dry age-related macular degeneration (ARMD), inflammatory diseases including macular edema, central vein occlusion, uveitis affecting the retina, and proliferative vitreoretinopathy are the leading causes of blindness.

[0004] Particularly in developed countries, the most common retinal disease causing blindness in adults over 60 years old is age-related macular degeneration (AMD), and because the number of patients gradually increases, it is expected that if no effective therapeutic agent is developed, the number of cases of AMD will increase at the same rate.AMD gradually weakens the function of some nerves and the upper epithelial layer of the macula.The clinical manifestations of these diseases include the accumulation of drusen, the hyperplasia of retinal pigment epithelium (RPE) or the degeneration caused by oxidative electrical stimulation, geographic atrophy and choroidal neovascularization.Atrophic AMD is characterized by the atrophy of the outer retina and RPE, and the degeneration of the subadjacent choriocapillaris, accounting for 25% of severe central vision loss cases.Exudative (or "wet") AMD is characterized by CNV growth below RPE and retina, followed by hemorrhage, exudative retinal detachment, discoid scarring and retinal atrophy.Decolorization of the pigment epithelium may also occur.Exudative AMD accounts for 75% of the AMD cases suffering from severe central vision loss.

[0005] Currently, most treatments are most useful for patients with relatively advanced symptoms, and these treatments include laser photocoagulation, photodynamic therapy, and surgery. However, since there is currently no effective treatment in the early stages of the disease, there is an urgent need to develop therapeutic agents.

[0006] Meanwhile, the PARP-1 enzyme is an enzyme that is associated with the signal transduction of DNA damage by its ability to recognize single-strand or double-strand DNA breaks and rapidly bind thereto. There are about 18 proteins in the poly (ADP-ribose) polymerase family, and they show a certain level of homology, but have different functions. Among them, the catalytic activities of PARP-1 and PARP-2 are known to be the only enzymes that are initiated by the occurrence of DNA strand breaks, and the intracellular activation rate of PARP-1 is known to be about 90%, while the intracellular activation rate of PARP-2 is about 10%.

[0007] Specifically, PARP-1 is known to be involved in various DNA-related functions, including gene amplification, cell division, differentiation, apoptosis, DNA base excision repair, and effects on telomere length and chromosome stability. Activated PARP-1 bound to DNA utilizes NAD in various cell nuclei. + Poly(ADP-ribose) is synthesized on target proteins including topoisomerases, histones, and PARP itself.

[0008] Severe single-strand or double-strand DNA damage caused by various stimuli induces PARP-1 hyperactivity. Overactivated PARP-1 synthesizes a large amount of intracellular poly(ADP-ribose), and as a result, NAD used for poly(ADP-ribose) synthesis is + is depleted in cells. As a result, NAD used to produce ATP + The depletion of ADP-ribose causes the depletion of ATP in cells, leading to cell necrosis or death. In addition, the over-synthesized poly (ADP-ribose) can bind to mitochondrial AIF (apoptosis inducing factor) and HK1 (hexokinase 1), and AIF bound to poly (ADP-ribose) moves to the nucleus and fragments DNA in the nucleus, thereby inducing cell necrosis. Furthermore, HK1, whose function deteriorates due to binding to poly (ADP-ribose), causes a decline in mitochondrial function, leading to cell necrosis.

[0009] Thus, it has been confirmed that inhibition of PARP by many low molecular weight PARP inhibitors results in a significant increase in DNA strand breaks and apoptosis. In this regard, PARP inhibitors have been attempted for radiosensitization of hypoxic tumor cells, for specific vascular diseases, septic shock, ischemic injury, and neurotoxicity, and their effectiveness has been demonstrated.

[0010] In recent years, attempts have been made to use PARP inhibitors for hemorrhagic shock, macular degeneration (AMD), damage caused by retinitis pigmentosa, and for rejection of organ transplants such as lungs, hearts, and kidneys, and treatment with PARP inhibitors has been shown to alleviate acute diseases such as pancreatitis, as well as liver and lung damage caused by the mechanism of action of PARP.

[0011] As described above, attempts have been made to treat various diseases using PARP inhibitors, but the effects on diseases other than cancer have not yet been confirmed, and in particular, there has been no significant development of therapeutic agents for ophthalmic diseases.

[0012] Thus, the present inventors developed a novel PARP inhibitor, preferably a PARP-1 inhibitor, and while attempting to develop a compound useful at a therapeutic level for a specific disease such as an ophthalmic disease, confirmed the excellent inhibitory effect on PARP-1 caused by the novel compound according to the present invention. Further, it was confirmed that it has a significant level of excellent cell protective effect (apoptosis inhibitory effect) as a therapeutic agent for ophthalmic diseases or disorders such as retinal diseases, etc. Therefore, it was confirmed that it can be effectively used as a pharmaceutical composition containing the novel compound according to the present invention as an active ingredient for preventing or treating PARP-1-related diseases, preferably ophthalmic diseases or disorders, thereby completing the present invention. Summary of the invention

[0013] Technical issues

[0014] The object of the present invention is to provide an isoquinolinone derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0015] Another object of the present invention is to provide a method for preparing isoquinolinone derivatives.

[0016] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, which comprises an isoquinolinone derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0017] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating ophthalmic diseases or disorders, comprising an isoquinolinone derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0018] Still another object of the present invention is to provide a health functional food for preventing or improving ophthalmic diseases or disorders, which comprises an isoquinolinone derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0019] Technical Solution

[0020] In order to achieve the above object, according to aspects of the present invention, a compound represented by the following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0021] [Chemical formula 1]

[0022]

[0023] In the above chemical formula 1,

[0024] is phenyl, or a 5- to 6-membered heteroaryl group containing one or more heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group may be unsubstituted or substituted with halogen or a straight or branched C 1-6 Alkyl substitution;

[0025] L 1 is unsubstituted or substituted with oxygen (oxo) 1-3 Alkylene;

[0026] Y is a 4- to 8-membered monocyclic or polycyclic heterocycloalkylene or heterocycloalkenylene containing one or more heteroatoms selected from N, O and S;

[0027] L 2 Is a single bond, -NR 2 -, -O-, or a linear or branched C 1-10 Alkylene, R 2 is hydrogen or C 1-6 Alkyl; and

[0028] Z is -H, C 3-8 cycloalkyl, 5 to 8 membered heterocycloalkyl containing one or more heteroatoms selected from N, O and S, phenyl, or 5 to 8 membered heteroaryl containing one or more heteroatoms selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl can each independently be unsubstituted or substituted by halogen, cyano, nitro, unsubstituted or substituted by one or more halogen straight or branched chain C 1-6 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-6 Alkoxy, CO 2 H.C 1-6 Alkoxycarbonyl, and C 1-6 The alkylcarbonylamino group is substituted with one or more substituents.

[0029] According to another aspect of the present invention, as shown in the following reaction scheme 1, a method for preparing a compound represented by the above Chemical Formula 1 is provided, comprising: reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1:

[0030] [Reaction Scheme 1]

[0031]

[0032] In the above reaction scheme, L 1 , Y, L 2 and Z are as defined above, and W is a leaving group.

[0033] According to another aspect of the present invention, provided is a pharmaceutical composition for preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, comprising the compound represented by the above Chemical Formula 1, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0034] According to still another aspect of the present invention, provided is a pharmaceutical composition for preventing or treating an ophthalmic disease or disorder, comprising the compound represented by the above Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0035] According to still another aspect of the present invention, there is provided a health functional food for preventing or improving ophthalmic diseases or disorders, comprising the compound represented by the above Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0036] According to a further aspect of the present invention, there is provided a method for preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, preferably ophthalmic diseases or disorders, comprising: administering to a subject in need thereof a pharmaceutical composition or a health functional food composition comprising a compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0037] According to yet a further aspect of the present invention, provided is a pharmaceutical composition or a health functional food composition comprising a compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof for use in preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, preferably ophthalmic diseases or disorders.

[0038] Beneficial effects

[0039] The isoquinolinone derivatives according to the present invention exhibit excellent PARP-1 inhibitory effects at a concentration of nanomolar units, and further, exhibit excellent cytoprotective effects (apoptosis inhibitory effects) on ophthalmic diseases or disorders, particularly retinal disorders, and thus can be effectively used as a pharmaceutical composition for preventing or treating PARP-1-related diseases, such as ophthalmic diseases or disorders, which comprises the isoquinolinone derivatives as an active ingredient. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 These are images obtained using "1500" showing changes in the thickness of the rat retinal layer after treatment with Example 46 or Example 1 (each with a single intraperitoneal injection of 15 mg / kg) in 8-week-old rats. DETAILED DESCRIPTION

[0041] Hereinafter, the present invention will be described in detail.

[0042] The present invention provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0043] [Chemical formula 1]

[0044]

[0045] In the above chemical formula 1,

[0046] It may be phenyl, or a 5- to 6-membered heteroaryl group containing one or more heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group may be unsubstituted or substituted with halogen or a straight or branched C 1-6 Alkyl substitution;

[0047] L 1 Can be unsubstituted or substituted with oxygen C 1-3 Alkylene;

[0048] Y may be a 4- to 8-membered monocyclic or polycyclic heterocycloalkylene or heterocycloalkenylene containing one or more heteroatoms selected from N, O and S;

[0049] L 2 Can be a single bond, -NR 2 -, -O-, or a linear or branched C 1-10 Alkylene, R 2 is hydrogen or C 1-6 Alkyl; and

[0050] Z can be -H, C 3-8 cycloalkyl, 5 to 8 membered heterocycloalkyl containing one or more heteroatoms selected from N, O and S, phenyl, or 5 to 8 membered heteroaryl containing one or more heteroatoms selected from N, O and S, wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl can each independently be unsubstituted or substituted by halogen, cyano, nitro, unsubstituted or substituted by one or more halogen straight or branched chain C 1-6 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-6 Alkoxy, CO 2 H.C 1-6 Alkoxycarbonyl, and C 1-6 The alkylcarbonylamino group is substituted with one or more substituents.

[0051] In the above chemical formula 1,

[0052] It can be phenyl or pyridine, wherein the phenyl or pyridine can be unsubstituted or substituted by one or more halogens, and a linear or branched C 1-6 Alkyl substitution.

[0053] In the above chemical formula 1,

[0054] Can be

[0055] R 1 M may be methyl, and n may be 0 or 1.

[0056] In the above chemical formula 1,

[0057] Can be

[0058] In the above chemical formula 1,

[0059] Can be

[0060] L 1 C may be unsubstituted or substituted with one or more oxygen 3 Alkylene;

[0061] Y may be a 6- to 8-membered monocyclic or bicyclic heterocycloalkylene group containing one or two nitrogen atoms, or a 6-membered monocyclic heterocycloalkenylene group containing one nitrogen atom;

[0062] L 2 Can be a single bond, -NR 2 -, -O-, or a linear or branched C 1-6 Alkylene, R 2 is hydrogen or methyl; and

[0063] Z can be -H, C 3-6 cycloalkyl, 5- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from N and O, phenyl, or 5- to 8-membered heteroaryl containing one or more heteroatoms selected from N and S,

[0064] wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl groups may be each independently unsubstituted or substituted by -F, -Cl, cyano, nitro, a straight or branched chain C 1-3 Alkyl, unsubstituted or substituted with one or more fluorine straight chain or branched C 1-3 Alkoxy, -CO 2 H.C 1-3 Alkoxycarbonyl, and C 1-3 The alkylcarbonylamino group is substituted with one or more substituents.

[0065] In the above chemical formula 1,

[0066]

[0067] L 1 C may be unsubstituted or substituted with one or more oxygen 3 Alkylene;

[0068] Y may be a 6-membered monocyclic or 8-membered bicyclic heterocycloalkylene group containing one or two nitrogen atoms, or a 6-membered monocyclic heterocycloalkenylene group containing one nitrogen atom;

[0069] L 2 Can be a single bond, -NR 2 -, -O-, or a linear or branched C 1-4 Alkylene, R 2 is hydrogen or methyl; and

[0070] Z can be H, C 3-6 Cycloalkyl, heterocycloalkyl, which is tetrahydrofuranyl or pyrrolidinyl, phenyl, or a heteroaryl selected from pyridinyl, pyrimidinyl and thiazolyl;

[0071] wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl may be each independently unsubstituted or substituted by -F, -Cl, cyano, nitro, methyl unsubstituted or substituted by one or more fluorine, methoxy substituted by one or more fluorine, carboxyl (-CO 2 H), methoxycarbonyl, and methylcarbonylamino.

[0072] In the above chemical formula 1,

[0073] Can be

[0074] L1 can be

[0075] Y can be

[0076] L 2 Can be a single key, and

[0077] Z can be -H,

[0078]

[0079]

[0080]

[0081] Examples of the compound represented by the above Chemical Formula 1 may include the following compounds:

[0082] <1> 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile;

[0083] <2> 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile;

[0084] <3> 6-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile;

[0085] <4> 8-Fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0086] <5> 2-Fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile;

[0087] <6> 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile hydrochloride;

[0088] <7> 4-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile;

[0089] <8> 4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile;

[0090] <9> 7-fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0091] <10> 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile;

[0092] <11> 7-Fluoro-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0093] <12> 7-Fluoro-3-(3-(4-phenylpiperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0094] <13> 7-fluoro-3-(3-(4-(pyrimidin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0095] <14> 7-fluoro-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0096] <15> 7-Fluoro-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0097] <16> 7-fluoro-3-(3-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0098] <17> 3-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-7-fluoroisoquinolin-1(2H)-one;

[0099] <18> Methyl 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoate;

[0100] <19> 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoic acid;

[0101] <20> N-(3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)phenyl)acetamide;

[0102] <21> 5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile;

[0103] <22> 6-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile;

[0104] <23> 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile;

[0105] <24> 8-Fluoro-5-methyl-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0106] <25> 8-Fluoro-5-methyl-3-(3-(4-(pyrimidin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0107] <26> 3-Fluoro-4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile;

[0108] <27> 8-Fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0109] <28> 2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile;

[0110] <29> 8-Fluoro-5-methyl-3-(3-(4-(thiazol-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0111] <30> 8-Fluoro-5-methyl-3-(3-(4-(5-methylthiazol-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0112] <31> (R)-8-Fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0113] <32> (S)-8-Fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0114] <33> 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one;

[0115] <34> 4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile;

[0116] <35> 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile;

[0117] <36> 6-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile;

[0118] <37> 3-Fluoro-4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile;

[0119] <38> 2-Fluoro-4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile;

[0120] <39> 7-Fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0121] <40> 7-Fluoro-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0122] <41> 4-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0123] <42> 8-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one;

[0124] <43> 8-Fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)propyl)isoquinolin-1(2H)-one;

[0125] <44> 8-Fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)propyl)isoquinolin-1(2H)-one;

[0126] <45> 8-Fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one;

[0127] <46> 1′-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile;

[0128] <47> 4-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0129] <48> 7-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one;

[0130] <49> 3-(3-(4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-7-fluoroisoquinolin-1(2H)-one;

[0131] <50> 1′-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile;

[0132] <51> 7-Fluoro-3-(3-(4-(2-fluoro-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one;

[0133] <52> 2-Fluoro-4-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0134] <53> 8-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0135] <54> 4-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0136] <55> 2-Fluoro-4-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0137] <56> 8-Fluoro-3-(3-(4-(2-fluoro-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0138] <57> 1′-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile;

[0139] <58> 4-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0140] <59> 7-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0141] <60> 1′-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile;

[0142] <61> 1′-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile;

[0143] <62> 7-Fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0144] <63> 7-Fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0145] <64> 7-Fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one;

[0146] <65> 8-Fluoro-3-(3-(4-(3-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0147] <66> 3-(3-(4-Benzoylpiperazin-1-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one;

[0148] <67> 8-Fluoro-3-(3-(4-(4-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0149] <68> 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0150] <69> 4-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0151] <70> 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile;

[0152] <71> 6-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile;

[0153] <72> 2-Fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0154] <73> 3-Fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0155] <74> 2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0156] <75> 8-Fluoro-3-(3-(4-(2-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one;

[0157] <76> 5-Fluoro-2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0158] <77> 3-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0159] <78> 3-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one;

[0160] <79> 4-Fluoro-3-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0161] <80> 2-Fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0162] <81> 4-Fluoro-2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0163] <82> 8-Fluoro-3-(3-(4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one;

[0164] <83> 8-Fluoro-3-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one;

[0165] <84> 3-Fluoro-5-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0166] <85> 8-Fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one;

[0167] <86> 8-Fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one;

[0168] <87> 2-Fluoro-5-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0169] <88> 1′-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile;

[0170] <89> 8-Fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one;

[0171] <90> 2-Fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0172] <91> 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile hydrochloride;

[0173] <92> 8-Fluoro-3-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridinyl]-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one;

[0174] <93> 1′-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile;

[0175] <94> 4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0176] <95> 4-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0177] <96> 1′-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile;

[0178] <97> 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile;

[0179] <98> 2-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0180] <99> 6-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile;

[0181] <100> 3-Fluoro-4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0182] <192> 7-fluoro-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0183] <193> 7-Fluoro-5-methyl-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0184] <194> 3-(3-(4-(L-alanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one hydrochloride;

[0185] <195> 3-(3-(4-(L-phenylalanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one;

[0186] <196> 8-Fluoro-5-methyl-3-(3-oxo-3-(4-propylpiperazin-1-yl)propyl)isoquinolin-1(2H)-one;

[0187] <197> 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile;

[0188] <198> 8-Fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0189] <199> 6-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile;

[0190] <200> 5-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)picolinonitrile;

[0191] Oxo-1(2H)-one;

[0192] <201> 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one;

[0193] <202> 8-Fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5-methylisoquinolin-1(2H)-one;

[0194] <203> 6-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile;

[0195] <204> 6-(8-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile;

[0196] <205> 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile;

[0197] <206> 6-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile;

[0198] <207> 6-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile;

[0199] <208> 8-Fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one;

[0200] <209> 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile;

[0201] <210> 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one;

[0202] <211> 8-Fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one;

[0203] <212> 8-Fluoro-3-(3-(3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one;

[0204] <213> 4-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile;

[0205] <214> 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile;

[0206] <215> 7-Fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one;

[0207] <216> 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one;

[0208] <217> 7-Fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one;

[0209] <218> 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile;

[0210] <219> 7-Fluoro-3-(3-(3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one;

[0211] <220> 6-(8-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile;

[0212] <221> 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)benzonitrile;

[0213] <222> 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)nicotinonitrile;

[0214] <223> 7-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl-1,6-naphthyridin-5(6H)-one;

[0215] <224> 7-(3-(4-(3-fluorophenyl)piperazin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0216] <225> 4-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile;

[0217] <226> 5-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)picolinonitrile;

[0218] <227> 7-(3-(4-(2-fluoropyridin-4-yl)piperazin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0219] <228> 7-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0220] <229> 5-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)picolinonitrile;

[0221] <230> 7-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl-1,6-naphthyridin-5(6H)-one;

[0222] <231> 7-(3-(3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0223] <232> 6-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile;

[0224] <233> 7-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0225] <234> 1′-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile;

[0226] <235> 1′-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile;

[0227] <236> 7-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0228] <237> 7-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridinyl]-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0229] <238> 7-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0230] <239> 4-(1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0231] <240> 7-(3-(3,6-dihydro-[4,4′-bipyridinyl]-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0232] <241> 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)benzonitrile;

[0233] <242> 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)nicotinonitrile;

[0234] <243> 5-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)picolinonitrile;

[0235] <244> 7-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-1,6-naphthyridin-5(6H)-one;

[0236] <245> 4-(1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile;

[0237] <246> 4-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile;

[0238] <247> 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)benzonitrile;

[0239] <248> 5-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)picolinonitrile;

[0240] <249> 4-((1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)benzonitrile;

[0241] <250> 4-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)benzonitrile;

[0242] <251> 5-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)picolinonitrile;

[0243] <252> Methyl 4-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)benzoate;

[0244] <253> 7-(3-(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0245] <254> 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)oxy)benzonitrile;

[0246] <255> 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile;

[0247] <256> 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzonitrile;

[0248] <257> 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)(methyl)amino)benzonitrile;

[0249] <258> 5-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)picolinonitrile;

[0250] <259> 4-((1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzonitrile;

[0251] <260> 4-((1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzonitrile;

[0252] <261> 4-((1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile;

[0253] <262> 4-((1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile;

[0254] <263> 3-(3-(4-((4-chlorophenyl)amino)piperidin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one;

[0255] <264> 3-(3-(4-((4-chlorophenyl)amino)piperidin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one;

[0256] <265> 7-fluoro-5-methyl-3-(3-oxo-3-(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)propyl)isoquinolin-1(2H)-one;

[0257] <266> 8-Fluoro-5-methyl-3-(3-oxo-3-(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)propyl)isoquinolin-1(2H)-one;

[0258] <267> Methyl 4-((1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzoate;

[0259] <268> Methyl 4-((1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzoate;

[0260] <269> 8-Fluoro-3-(3-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one;

[0261] <270> 8-Fluoro-3-(3-(4-hydroxypiperidin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one;

[0262] <271> 7-(3-(3-Hydroxy-8-azabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one;

[0263] <272> 8-Fluoro-3-(3-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)propyl)isoquinolin-1(2H)-one;

[0264] <273> 4-((8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)benzonitrile;

[0265] <274> 4-((8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)benzonitrile;

[0266] <275> N-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)azetidin-3-yl)cyclopropanecarboxamide; and

[0267] <276> N-(1-(3-(8-Fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)cyclopropanecarboxamide.

[0268] The compound represented by Chemical Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed from a pharmaceutically acceptable free acid is useful. Acid addition salts can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and alkane dioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; or organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Examples of such pharmaceutically nontoxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, cabacates, fumarates, maliates, butyne-1,4-dioates, ,4-dioate), hexane-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate, etc.

[0269] The acid addition salt according to the present invention can be prepared by conventional methods. For example, the acid addition salt can be prepared by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., adding an organic acid or an inorganic acid thereto to generate a precipitate, and then filtering and drying the generated precipitate, or can be prepared by distilling the solvent and excess acid under reduced pressure, and then drying or crystallizing in an organic solvent.

[0270] In addition, pharmaceutically acceptable metal salts can be prepared by using a base. For example, alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. Here, as metal salts, sodium salts, potassium salts or calcium salts are appropriately prepared from pharmaceutical aspects. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0271] Further, the present invention includes not only the compound represented by the above Chemical Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, isomers, hydrates and the like that can be prepared therefrom.

[0272] As used herein, the term "solvate" refers to a compound of the invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefore include solvents that are volatile, non-toxic, and / or suitable for human administration. Herein, when the solvent is water, it is referred to as a "hydrate".

[0273] As used herein, the term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula, but is structurally or spatially different. Such isomers include structural isomers such as tautomers, R or S isomers with asymmetric carbon centers, stereoisomers such as geometric isomers (trans, cis), and optical isomers (enantiomers). All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0274] In addition, as shown in the following reaction scheme,

[0275] The present invention provides a method for preparing a compound represented by Chemical Formula 1, comprising: reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1:

[0276] [Reaction Scheme 1]

[0277]

[0278] In the above reaction scheme 1, L 1 , Y, L 2and Z are as defined above, and

[0279] W is a leaving group.

[0280] Hereinafter, the preparation method represented by the above Reaction Scheme 1 will be described in detail.

[0281] In the method for preparing the compound represented by Chemical Formula 1 according to the present invention, the step of Reaction Scheme 1 is a step of preparing the compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3. Specifically, this is a step of forming the compound represented by Chemical Formula 1 by reacting the mesylate or carboxyl group of the compound represented by Chemical Formula 2 with the secondary amine of the compound represented by Chemical Formula 3.

[0282] Here, the above steps are not particularly limited as long as they are methods for preparing isoquinolinone derivatives represented by Chemical Formula 1, and are included in the scope of the present invention. However, the compound represented by Chemical Formula 2 may be understood as a compound having a leaving group such as mesylate, tosylate, etc. that is easily reacted with a nucleophilic agent, or a compound having a carboxyl group that can form an amide by reacting with an amine. In addition, the compound represented by Chemical Formula 3 may be understood as a cyclic secondary amine that can undergo a nucleophilic substitution reaction or an amide formation reaction, but these are only examples and are not limited thereto. Therefore, the isoquinolinone derivative as the final product of the present invention is prepared by a nucleophilic substitution reaction of a compound having a leaving group and a cyclic secondary amine having sufficient nucleophilicity to react therewith, or by an amide formation reaction of a carboxyl group and a cyclic secondary amine.

[0283] More specifically, it can be understood with reference to the preparation method of the compound of the embodiment of the present invention, but each reaction condition (reaction conditions such as reaction temperature, time, atmospheric conditions, pressure conditions, etc. that can be thought of by those skilled in the art of organic synthesis) can be modified, and it can be understood that the present invention is not limited thereto. Further, it can be understood that the compounds and derivatives thereof used in each step can include derivatives that can be modified to them other than those disclosed, i.e., derivatives modified by simply modifying, changing or removing substituents, and these are also included in the scope of the present invention.

[0284] Meanwhile, some of the hydrochloride compounds in the following Examples 1-276 mean that all compounds of the present invention can be easily prepared into addition salts (such as hydrochloride, etc.) and pharmaceutically acceptable salts, and these are included in the scope of the present invention.

[0285] As a preferred embodiment of the preparation method, the preparation methods disclosed in the following Examples 1 to 276 can be mentioned, but the present invention is not limited thereto.

[0286] Further, the present invention provides a pharmaceutical composition for preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, which comprises the compound represented by the above Chemical Formula 1, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0287] The compound represented by Chemical Formula 1, its isomer, or pharmaceutically acceptable salt according to the present invention is characterized by inhibiting PARP enzyme, preferably poly (ADP-ribose) polymerase-1 (PARP-1) enzyme (see Experimental Example 1).

[0288] Therefore, it can be effectively used as: a pharmaceutical composition for preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, which contains the compound represented by Chemical Formula 1 according to the present invention, its isomer, or a pharmaceutically acceptable salt as an active ingredient; or a health functional food for preventing or improving poly (ADP-ribose) polymerase-1 (PARP-1) related diseases.

[0289] Here, the compound represented by the above Chemical Formula 1, its isomer, or pharmaceutically acceptable salt exhibits a cytoprotective effect by inhibiting the activity of poly (ADP-ribose) polymerase-1 (PARP-1), and is used for the treatment of diseases by inhibiting the synthesis of poly (ADP-ribose) for intracellular energy depletion, the decline of mitochondrial function, DNA fragmentation caused by nuclear migration of AIF, amplification of apoptotic genes, apoptosis, and DNA base excision repair caused by the increase of poly (ADP-ribose) associated with the activity of poly (ADP-ribose) polymerase 1 (PARP-1). More specifically, poly (ADP-ribose) polymerase-1 (PARP-1) is an enzyme present in the nuclei of various organs including the heart, and is an enzyme that is activated by recognizing damaged DNA and then repairs the damaged DNA through poly ADP ribosylation of several proteins. Among the known poly ADP-ribosylation substrates (receptors or target proteins), the most important factor is PARP-1 itself, and in addition, various nuclear proteins such as histones, DNA topoisomerases, DNA ligases, caspases, p53, and transcription-related factors such as NF-κ are also known. PARP catalyzes the transfer of ADP-ribose from NAD, and at this time nicotinamide is released from NAD. Nicotinamide is converted back to NAD by consuming the energy carrier ATP through another enzyme. Therefore, excessive activation of PARP consumes a large amount of ATP and promotes the decline of cell mitochondrial function, leading to cell damage and cell death. As described above and in the background of the present invention, it can treat diseases such as cancer, tumors, stroke and age-related diseases by inhibiting poly (ADP-ribose) polymerase-1 (PARP) (which is more active in cancer, tumors, etc. than in normal cells), and can also be applied to other diseases through the same mechanism as above (see the background of the present invention).

[0290] Therefore, it can be used as a pharmaceutical composition for preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, which contains the compound represented by the above Chemical Formula 1, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0291] Here, poly (ADP-ribose) polymerase-1 (PARP-1) related diseases may include one or more selected from the following: neurogenic disorders, neurodegenerative diseases, vascular stroke, cardiovascular disorders, macular degeneration, AIDS, arthritis, atherosclerosis, cancer, diabetes, brain tumors, inflammatory bowel disease, muscular dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, nerve attack, peripheral nerve damage, kidney disease, retinal ischemia, septic shock and skin aging, but are not limited thereto, and any disease caused by the induction of intracellular ATP depletion and reduced mitochondrial function caused by high activity of poly (ADP-ribose) polymerase-1 (PARP-1), as well as cell damage or cell death promoted thereby, or independent cell death may also be included in the present invention.

[0292] Meanwhile, the present invention is characterized in that it can be used to treat ophthalmic diseases or disorders, based on the evidence shown in Experimental Example 2 of the present invention.

[0293] Here, the ophthalmic disease or disorder is a disease caused by cell damage or apoptosis caused by high activity of poly (ADP-ribose) polymerase-1 (PARP-1), for example, the ophthalmic disease or disorder may include a disease selected from age-related macular degeneration, Stargardt's macular dystrophy, retinal detachment, hemorrhagic retinopathy, pigmentary retinitis, cone-rod dystrophy, Sorsby's fundus dystrophy, optic neuropathy, inflammatory retinopathy, diabetic retinopathy, diabetic maculopathy, retinal vascular occlusion, retinopathy of prematurity, or retinal damage associated with local ischemia-reperfusion, proliferative vitreoretinopathy, retinal dystrophy, congenital optic neuropathy, uveitis, retinal damage, retinal disorders associated with Alzheimer's disease, retinal disorders associated with multiple sclerosis, retinal disorders associated with Parkinson's disease, retinal disorders associated with viral infection, retinal disorders associated with excessive light exposure (light The invention relates to one or more of a retinal disorder associated with leukemia, myopia, or a retinal disorder associated with AIDS.

[0294] In addition, the present invention provides a method for preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases by administering the compound according to the present invention, its isomer, or pharmaceutically acceptable salt thereof.

[0295] Furthermore, the present invention provides the use of preparing a medicament for preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases by administering the compound according to the present invention, its isomer, or pharmaceutically acceptable salt thereof.

[0296] In addition, the present invention provides a health functional food for preventing or improving poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, which comprises the compound represented by the above Chemical Formula 1, its isomer, or a pharmaceutically acceptable salt as an active ingredient.

[0297] In addition, the present invention provides a health functional food for preventing or improving ophthalmic diseases or disorders, comprising the compound represented by the above Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0298] Here, the health functional food can be prepared and used as a general health functional food by including the compound represented by Chemical Formula 1 of the present invention, its isomer, or a pharmaceutically acceptable salt as an active ingredient, and is included in the scope of the present invention as long as it is a preparation, food form, or administration form known to those skilled in the art. Further, it is included in the health functional food of the present invention as long as it is within the range of being able to be identified as a health functional food.

[0299] As used herein, the term "prevention" may mean any action to inhibit or delay the onset of a neurological disease by administering the pharmaceutical composition according to the present invention to an individual.

[0300] As used herein, the term "treatment" may mean any action to improve or beneficially alter the symptoms of a neurological disease by administering a pharmaceutical composition according to the present invention to an individual.

[0301] The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient, or diluent.

[0302] In the case where the composition of the present invention is used as a medicine, the pharmaceutical composition containing the compound represented by the above Chemical Formula 1, its isomer, or a pharmaceutically acceptable salt thereof can be prepared into various oral or parenteral dosage forms shown below and administered during clinical administration, but the present invention is not limited thereto.

[0303] Examples of preparations for oral administration include tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, lozenges, etc. These preparations contain diluents (e.g., lactose, glucose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and lubricants (e.g., silicon dioxide, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol) in addition to the active ingredient. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone, and in some cases, may contain disintegrants such as starch, agar, alginic acid or its sodium salt, or boiling mixtures, and / or absorbents, colorants, flavoring agents, and sweeteners.

[0304] The pharmaceutical composition containing the compound represented by the above Chemical Formula 1 as an active ingredient may be parenterally administered, and the parenteral administration is performed by injection, eye drops, or eye ointment.

[0305] Here, in order to prepare a preparation for parenteral administration, the compound represented by the above Chemical Formula 1, its stereoisomer, or a pharmaceutically acceptable salt is mixed with a stabilizer or a buffer in water to prepare a solution or suspension, and the solution or suspension can be made into an ampoule or a vial unit dosage form. The composition can be sterilized, and / or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsifiers, salts for regulating osmotic pressure, and / or buffers, and other therapeutically useful substances, and the composition can be prepared by conventional methods such as dispersion, gelation, etc.

[0306] In addition, the dosage of the pharmaceutical compound containing the compound represented by the above Chemical Formula 1 as an active ingredient to the human body may vary according to the patient's age, weight and sex, dosage form, health status and severity of the disease. The dosage may be administered several times a day, preferably once a day or three times a day, at regular intervals, preferably in divided doses of 0.001 to 1,000 mg / kg / day, according to the decision of a doctor or pharmacist, by oral or parenteral routes.

[0307] The pharmaceutical composition of the present invention can be used as a single preparation. In addition, it can be prepared and used as a composite preparation by further including one or more other therapeutic agents.

[0308] On the other hand, the present invention provides a method for preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, comprising: administering an effective amount of a pharmaceutical composition to an individual in need thereof. The pharmaceutical composition means a pharmaceutical composition for preventing or treating poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, which contains a compound represented by the above Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0309] As used herein, the term "administering" means introducing the pharmaceutical composition of the present invention into an individual by an appropriate method, and the pharmaceutical composition of the present invention can be administered by any general route as long as it can reach the target tissue by intraperitoneal administration, intraocular administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, intrauterine dura mater, or intraventricular injection, but is not limited thereto.

[0310] As used herein, the term "subject" refers to any animal, including humans, who suffers from or is likely to develop poly (ADP-ribose) polymerase-1 (PARP-1) related diseases, such as ophthalmic diseases or disorders, and any of the above diseases. Poly (ADP-ribose) polymerase-1 (PARP-1) related diseases can be effectively prevented or treated by administering a pharmaceutical composition to the subject.

[0311] As described above, the isoquinolinone derivative of the present invention, the method for preparing the same, and the pharmaceutical use thereof can be understood, and the effects demonstrated by the present invention will be described below.

[0312] First, the inhibitory activity of PARP-1 (poly [ADP-ribose] polymerase-1) enzyme was evaluated by including various concentrations of the isoquinolinone derivatives according to the present invention.

[0313] Specifically, various concentrations of the isoquinolinone derivative of the present invention were treated using a PARP-1 (poly [ADP-ribose] polymerase 1) activity assay kit, and as a result of measuring absorbance, inhibitory activity of PARP-1 (poly [ADP-ribose] polymerase 1) enzyme in nanomolar units was observed.

[0314] From the above results, it can be found that the isoquinolinone derivatives of the present invention have excellent protective ability against retinal degeneration and can therefore be effectively used as a pharmaceutical composition for treating retinal diseases.

[0315] Example

[0316] Hereinafter, the present invention will be described in detail by examples and experimental examples. However, these examples and experimental examples are given for illustrative purposes only, and the scope of the present invention is not intended to be limited to or by these examples and experimental examples.

[0317] <Example 1> Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

[0318]

[0319] Step 1: Preparation of tert-butyl 4-(4-cyanophenyl)piperazine-1-carboxylate

[0320]

[0321] After dissolving 1-Boc-piperazine (70.0 g, 0.38 mol) and 4-bromobenzonitrile (82 g, 0.45 mol) in toluene (1.5 L), Pd(OAc) was added dropwise. 2 (8.4g, 0.04mol), XPhos (9.0g, 0.02mol) and Cs 2 CO 3 (147 g, 0.45 mol). The mixture was stirred at 100 °C for 15 h and cooled to room temperature. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound tert-butyl 4-(4-cyanophenyl)piperazine-1-carboxylate (90 g, 83%).

[0322] 1 H NMR (300 MHz, CDCl 3 )δ7.53-7.50(m,2H),6.87-6.85(m,2H),3.60-3.57(m,4H),3.33-3.29(m,4H),1.49(s,9H).

[0323] Step 2: Preparation of 4-(piperazin-1-yl)benzonitrile 2HCl

[0324]

[0325] 4N HCl / di 4-(4-cyanophenyl)piperazine-1-carboxylic acid tert-butyl ester (80 g, 0.28 mol) was added to 4-(4-cyanophenyl)piperazine-1-carboxylic acid tert-butyl ester (80 g, 0.28 mol), and the mixture was stirred for 15 hours. The solid produced during the reaction was filtered and washed with EtOAc to obtain the target compound 4-(piperazin-1-yl)benzonitrile 2HCl (72 g, 100%).

[0326] 1 H NMR (300 MHz, DMSO-d 6 )δ9.46(br,1H),7.67-7.64(m,2H),7.11-7.08(m,2H),3.61-3.59(m,4H),3.19(m,4H).

[0327] Step 3: Preparation of methyl 2-bromo-6-fluorobenzoate

[0328]

[0329] After dissolving 2-bromo-6-fluorobenzoic acid (100 g, 456.6 mmol) in DMF (1 L), K 2 CO 3 The mixture was stirred for 30 minutes. MeI (194 g, 1369.8 mmol) was slowly added dropwise to the reaction solution at 0°C, and then stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and Na 2 S 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound methyl 2-bromo-6-fluorobenzoate (107 g, 95%).

[0330] 1 H NMR (300 MHz, CDCl 3 )δ7.40(d,1H,J=8.1Hz),7.31-7.24(m,1H),7.09(t,1H,J=8.6Hz),3.98(s,3H).

[0331] Step 4: Preparation of methyl 2-fluoro-6-(5-hydroxypent-1-yn-1-yl)benzoate

[0332]

[0333] After dissolving methyl 2-bromo-6-fluorobenzoate (107 g, 433 mmol) in acetonitrile (1 L), pent-4-yn-1-ol (51 g, 519.6 mmol), Pd(PPh 3 ) 2 Cl 2 (15.2 g, 21.65 mmol) and CuI (4.12 g, 21.65 mmol). TEA (131.4 g, 1299 mmol) was added dropwise, and the mixture was stirred at 80°C for 15 hours and then cooled to room temperature. The reaction solution was diluted with EtOAc and washed with NH 4 The organic solvent was washed with MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound methyl 2-fluoro-6-(5-hydroxypent-1-yn-1-yl)benzoate (75.1 g, 70%).

[0334] 1 H NMR (300 MHz, CDCl 3)δ7.37-7.30(m,1H),7.25-7.23(m,1H),7.05(t,1H,J=8.9Hz),3.95(s,3H),3.88-3.76(m,2H),2.56(t,2H,J=6.8Hz),1.85(m,2H).

[0335] Step 5: Preparation of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one hydroxypropyl)-1H-isochromen-1-one)

[0336]

[0337] Methyl 2-fluoro-6-(5-hydroxypent-1-yn-1-yl)benzoate (75 g, 299.68 mmol) was dissolved in THF / MeOH / H 2 O (600mL / 200mL / 200mL), then dropwise add LiOH·H 2 O (37.7 g, 899.03 mmol), and then stirred at room temperature for 15 hours. The reaction solution was concentrated by distillation under reduced pressure, then diluted with EtOAc, and 6N HCl was slowly added dropwise to adjust the pH to 1-2. The organic solvent was purified by MgSO 4 The concentrated reaction solution was dissolved in acetone (1.5 L) and AgNO was added dropwise. 3 (9.34 g, 29.97 mmol). The reaction solution was stirred at room temperature for 15 hours and then distilled under reduced pressure to remove the solvent. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one (25 g, 35%).

[0338] 1 H NMR (300 MHz, DMSO-d 6 )δ7.83-7.76(m,1H),7.37(d,1H,J=7.8Hz),7.30(t,1H,J=9.8Hz),6.61( s,1H),4.58(br,1H),3.49-3.44(m,2H),2.57-2.50(m,2H),1.76(m,2H).

[0339] Step 6: Preparation of 8-fluoro-3-(3-hydroxypropyl)isoquinolin-1(2H)-one

[0340]

[0341] 8-Fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one (18.0 g, 81.00 mmol) was dissolved in 7N NH 3 / MeOH (200mL, 1.38mol), the mixture was stirred at 80°C for 15 hours. The reaction solution was cooled to room temperature, and the product thus obtained was concentrated by evaporation under reduced pressure. The obtained solid was recrystallized with MeOH to obtain the target compound 8-fluoro-3-(3-hydroxypropyl)isoquinolin-1(2H)-one (14.8g, 83%).

[0342] 1 H NMR (300 MHz, DMSO-d 6 )δ11.26(br,1H),7.65-7.58(m,1H),7.35(d,1H,J=7.8Hz),7.13-7.06(m,1H), 6.35(s,3H),4.58(br,1H),3.47-3.41(m,2H),2.53-2.48(m,2H),1.77(m,2H).

[0343] Step 7: Preparation of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate

[0344]

[0345] After 8-fluoro-3-(3-hydroxypropyl)isoquinolin-1(2H)-one (19.5 g, 88.14 mmol) was dissolved in DMF (44.0 mL), the mixture was cooled to 0° C. MsCl (15.7 mL, 202.72 mmol) and TEA (49.0 mL, 352.56 mmol) were slowly added dropwise at 0° C., followed by stirring at 25° C. for 15 hours. The reaction solution was diluted with EtOAc and washed with NH 4 The organic solvent was washed with MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized with MeOH to obtain the target compound, 3-(8-fluoro-1-fluoro-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (13 g, 49%).

[0346] 1 H NMR (300 MHz, CDCl 3 )δ11.58(br,1H),7.60-7.53(m,1H),7.28-7.25(m,1H),7.09-7.02(m,1H),6.36 (s, 1H), 4.37 (t, 2H, J = 6.2Hz), 3.05 (s, 3H), 2.79 (t, 2H, J = 7.7Hz), 2.26 (m, 2H).

[0347] Step 8: Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzene Nitrile

[0348]

[0349] After dissolving 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (2.4 g, 8.02 mmol) in acetonitrile (160.0 mL), 4-(piperazin-1-yl)benzonitrile 2HCl (3.1 g, 12.03 mmol) was added dropwise at 25°C. NaHCO 3 (3.37 g, 40.10 mmol) and NaI (3.13 g, 16.04 mmol), and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and NaS 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized from MeOH to obtain the target compound 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile (2.4 g, 77%).

[0350] 1 H NMR (300 MHz, CDCl 3 )δ11.63(br,1H),7.55-7.48(m,3H),7.20(d,1H,J=7.8Hz),7.05-6.98(m,1H),6.89-6.86(m,2H ), 6.23 (s, 1H), 3.58-3.56 (m, 4H), 2.72-2.70 (m, 6H), 2.54 (t, 2H, J = 6.0Hz), 1.94-1.90 (m, 2H).

[0351] <Example 2> Preparation of 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazine-1-yl)picolinonitrile

[0352]

[0353] The target compound was obtained according to Example 1, except that 5-bromo-2-cyanopyridine was used instead of 4-bromobenzonitrile used in Step 1 of Example 1.

[0354] 1 H NMR (300 MHz, CDCl 3)δ8.32(s,1H),7.51-7.49(m,2H),7.22-7.20(m,1H),7.12-7.10(m,1H),7.08-7.05(m,1H) ,6.22(s,1H),3.66-3.64(m,4H),2.72-2.70(m,6H),2.57-2.55(m,2H),1.93-1.91(m,2H).

[0355] <Example 3> Preparation of 6-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazine-1-yl)nicotinonitrile

[0356]

[0357] The target compound was obtained according to Example 1, except that 2-bromo-5-cyanopyridine was used instead of 4-bromobenzonitrile used in Step 1 of Example 1.

[0358] 1 H NMR (300 MHz, CDCl 3 )δ8.40-8.39(m,1H),7.62-7.59(m,1H),7.52-7.49(m,1H),7.21-7.19(m,1H),7.05-6.98(m,1H),6.62 -6.59(m,1H),6.22(s,1H),3.99-3.96(m,4H),2.74-2.65(m,6H),2.56-2.52(m,2H),1.92-1.90(m,2H).

[0359] <Example 4> Preparation of 8-fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0360]

[0361] The target compound was obtained according to Example 1, except that 4-bromotrifluorotoluene was used instead of 4-bromobenzonitrile used in step 1 of Example 1.

[0362] 1 H NMR (300 MHz, CDCl 3 )δ11.47(br,1H),7.54-7.48(m,3H),7.21-7.18(m,1H),7.04-7.01(m,1H),7.00-6.96(m,2H ),6.22(s,1H),3.54-3.51(m,4H),2.73-2.66(m,6H),2.55-2.51(m,2H),1.96-1.90(m,2H).

[0363] <Example 5> Preparation of 2-fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

[0364]

[0365] The target compound was obtained according to Example 1, except that 4-bromo-2-fluorobenzonitrile was used instead of 4-bromobenzonitrile used in step 1 of Example 1.

[0366] 1 H NMR (300 MHz, CDCl 3 )δ7.51-7.50(m,1H),7.39-7.38(m,1H),7.21-7.18(m,1H),7.11-7.01(m,1H),6.62-6.54(m, 2H),6.22(s,1H),3.62-3.61(m,4H),2.70-2.68(m,6H),2.55-2.54(m,2H),1.92-1.91(m,2H).

[0367] <Example 6> Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile hydrochloride

[0368]

[0369] 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile (1.0 g, 2.56 mmol) was dissolved in 4N HCl / dihydroisoquinolin-3-yl. After adding 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile hydrochloride (940.0 mg, 90%).

[0370] 1 H NMR (300 MHz, DMSO-d 6)δ11.35(br,1H),11.22(s,1H),7.68-7.61(m,3H),7.37(d,1H,J=7.8Hz),7.16-7.11(m,3H),6.44(s,1H), 4.10-4.05(m,2H),3.61-3.57(m,2H),3.55(t,2H,J=12.9Hz),3.11-3.07(m,4H),2.57(m,2H),2.12(m,2H).

[0371] <Example 7> Preparation of 4-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile

[0372]

[0373] The target compound was obtained according to Example 1, except that tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate was used instead of 1-Boc-piperazine used in step 1 of Example 1.

[0374] 1 H NMR (300 MHz, CDCl 3 )δ11.44(br,1H),7.54-7.46(m,3H),7.20(d,1H,J=7.8Hz),7.03-6.97(m,1H),6.80-6.77(m,2H),6.22(s,1H),3.51 -3.40(m,6H),2.73(t,2H,J=6.3Hz),2.57(t,2H,J=6.0Hz),2.10-2.07(m,2H),1.92-1.88(m,2H),1.79-1.76(m,2H).

[0375] <Example 8> Preparation of 4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

[0376]

[0377] The target compound was obtained according to Example 1, except that 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0378] 1 H NMR (300 MHz, CDCl 3)δ7.97-7.95(m,1H),7.51-7.48(m,3H),7.34-7.32(m,1H),6.90-6.87(m,2H),6.27 (m,1H),3.57-3.55(m,4H),2.72-2.70(m,6H),2.55-2.53(m,2H),1.94-1.92(m,2H).

[0379] <Example 9> Preparation of 7-fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0380]

[0381] The target compound was obtained according to Example 1, except that 4-bromotrifluorotoluene was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0382] 1 H NMR (300 MHz, CDCl 3 )δ11.54(br,1H),7.97-7.94(m,1H),7.49-7.42(m,3H),7.37-7.30(m,1H),6.97-6.94(m,2H ),6.26(s,1H),3.53-3.50(m,4H),2.72-2.71(m,6H),2.55-2.52(m,2H),1.95-1.90(m,2H).

[0383] <Example 10> Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazine-1-yl)picolinonitrile

[0384]

[0385] The target compound was obtained according to Example 1, except that 5-bromo-2-cyanopyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0386] 1 H NMR (300 MHz, CDCl 3)δ11.70(br,1H),8.34(s,1H),7.96-7.95(m,1H),7.53-7.34(m,3H),7.14-7.13(m,1H), 6.27(s,1H),3.63-3.62(m,4H),2.74-2.73(m,6H),2.56-2.55(m,2H),1.94-1.93(m,2H).

[0387] <Example 11> Preparation of 7-fluoro-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0388]

[0389] The target compound was obtained according to Example 1, except that 1-bromo-3-nitrobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0390] 1 H NMR (300 MHz, CDCl 3 )δ11.53(br,1H),7.95(d,1H,J=9.9Hz),7.77(m,1H),7.67(d,1H,J=7.8Hz),7.47-7.41(m,1H),7.39 -7.18(m,3H),6.26(s,1H),3.56-3.53(m,4H),2.77-2.70(m,6H),2.56(t,2H,J=5.9Hz),1.93(m,2H).

[0391] <Example 12> Preparation of 7-fluoro-3-(3-(4-phenylpiperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0392]

[0393] The target compound was obtained according to Example 1, except that 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1, and 1-phenylpiperazine was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 8 of Example 1.

[0394] 1 H NMR (300 MHz, CDCl 3)δ11.38(br,1H),7.98-7.95(m,1H),7.47-7.42(m,1H),7.36-7.30(m,3H),6.99-6.97(m,2H),6.89-6 .85(m,1H),6.26(s,1H),3.44-3.41(m,4H),2.73-2.67(m,6H),2.54-2.50(m,2H),1.94-1.90(m,2H).

[0395] <Example 13> Preparation of 7-fluoro-3-(3-(4-(pyrimidin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0396]

[0397] The target compound was obtained according to Example 1, except that 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1, and 1-(2-pyrimidinyl)piperazine was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 8 of Example 1.

[0398] 1 H NMR (300 MHz, CDCl 3 )δ8.32-8.30(m,2H),7.98-7.95(m,1H),7.44-7.42(m,1H),7.34-7.31(m,1H),6.50-6.52(m,1H),6.26 (s,1H),4.08-4.02(m,4H),2.73-2.71(m,2H),2.65-2.62(m,4H),2.52-2.50(m,2H),1.93-1.90(m,2H).

[0399] <Example 14> Preparation of 7-fluoro-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0400]

[0401] The target compound was obtained according to Example 1, except that 2-bromopyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0402] 1 H NMR (300 MHz, CDCl 3)δ8.20-8.19(m,1H),7.98-7.95(m,1H),7.49-7.42(m,2H),7.34-7.32(m,1H),6.69-6.66(m,1H),6.63 -6.61(m,1H),6.26(s,1H),3.79-3.76(m,4H),2.69-2.66(m,6H),2.54-2.50(m,2H),1.93-1.91(m,2H).

[0403] <Example 15> Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0404]

[0405] The target compound was obtained according to Example 1, except that 4-bromofluorobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0406] 1 H NMR (300 MHz, CDCl 3 )δ11.53(br,1H),7.99-7.96(m,1H),7.47-7.42(m,1H),7.36-7.33(m,1H),6.97-6.9 4(m,4H),3.36-3.32(m,4H),2.75-2.67(m,6H),2.55-2.51(m,2H),1.92-1.90(m,2H).

[0407] <Example 16> Preparation of 7-fluoro-3-(3-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0408]

[0409] The target compound was obtained according to Example 1, except that 1-bromo-3-(trifluoromethoxy)benzene was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0410] 1 H NMR (300 MHz, CDCl 3)δ11.46(br,1H),7.97(dd,1H,J=9.3Hz,2.7Hz),7.47-7.43(m,1H),7.37-7.22(m,2H),6.86(dd,1H,J=8.3Hz,2.0Hz),6. 76(s,1H),6.70(d,1H,J=7.8Hz),6.26(s,1H),3.46-3.43(m,4H),2.74-2.69(m,6H),2.54(t,2H,J=6.2Hz),1.93(m,2H).

[0411] <Example 17> Preparation of 3-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-7-fluoroisoquinolin-1(2H)-one

[0412]

[0413] The target compound was obtained according to Example 1, except that 1-bromo-3-chlorobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0414] 1 H NMR (300 MHz, CDCl 3 )δ11.41(br,1H),7.97(dd,1H,J=9.3Hz,2.7Hz),7.47-7.42(m,1H),7.37-7.30(m,1H),7.17(t,1H,J=8.1Hz),6.92(s ,1H),6.84-6.81(m,2H),6.26(s,1H),3.44-3.41(m,4H),2.71-2.68(m,6H),2.52(t,2H,J=6.0Hz),1.96-1.88(m,2H).

[0415] <Example 18> Preparation of 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoic acid methyl ester

[0416]

[0417] The target compound was obtained according to Example 1, except that methyl 3-bromobenzoate was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0418] 1 H NMR (300 MHz, CDCl 3)δ11.41(br,1H),7.97(dd,1H,J=9.3Hz,2.4Hz),7.64(s,1H),7.54-7.51(m,1H),7.47-7.42(m,1H),7.37-7.30(m,2H),7.15(dd ,1H,J=8.4Hz,1.8Hz),6.26(s,1H),3.91(s,3H),3.49-3.46(m,4H),2.75-2.68(m,6H),2.53(t,2H,J=6.0Hz),1.95-1.90(m,2H).

[0419] <Example 19> Preparation of 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoic acid

[0420]

[0421] Methyl 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoate (300 mg, 0.708 mmol) was dissolved in THF (3 mL), MeOH (1 mL) and H 2 O (1 mL), LiOH (74 mg, 1.76 mmol) was added and stirred at room temperature for 12 hours. The reaction solution was concentrated by evaporation under reduced pressure, diluted with EtOAc, and then 2N HCl was slowly added dropwise to adjust the pH to 6. The organic solvent was purified by anhydrous MgSO 4 Dried, filtered, then concentrated by evaporation under reduced pressure, and the resulting solid was filtered to give 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoic acid (64 mg, 22%).

[0422] 1 H NMR (300 MHz, DMSO-d 6 )δ11.52(br,1H),7.80-7.76(m,1H),7.67-7.66(m,1H),7.59-7.56(m,1H),7.45(s,1H),7 .35(m,2H),7.21(m,1H),6.44(s,1H),3.20(m,4H),2.51(m,6H),2.39(m,2H),1.84(m,2H).

[0423] <Example 20> Preparation of N-(3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)phenyl)acetamide

[0424]

[0425] Step 1: Preparation of 7-fluoro-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0426]

[0427] 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (1.5 g, 5.01 mmol) and 1-(3-nitrophenyl)piperazine HCl (2.1 g, 7.52 mmol) were dissolved in CH 3 CN (100 mL), and then NaI (1.5 g, 10.02 mmol) was added dropwise at room temperature. 3 (2.1 g, 25.05 mmol) was slowly added dropwise to the reaction solution, which was then stirred at 80°C for 17 hours. The reaction solution was diluted with EtOAc and washed with water, and the organic solvent was washed with anhydrous MgSO 4 After drying, filtering and then concentrating by evaporation under reduced pressure, the obtained residue was separated and purified by silica gel chromatography to obtain the target compound 7-fluoro-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one (1.24 g, 60%).

[0428] 1 H NMR (300 MHz, CDCl 3 )δ11.53(br,1H),7.95(d,1H,J=9.9Hz),7.77(m,1H),7.67(d,1H,J=7.8Hz),7.47-7.41(m,1H),7.39 -7.18(m,3H),6.26(s,1H),3.56-3.53(m,4H),2.77-2.70(m,6H),2.56(t,2H,J=5.9Hz),1.93(m,2H).

[0429] Step 2: Preparation of 3-(3-(4-(3-aminophenyl)piperazin-1-yl)propyl)-7-fluoroisoquinolin-1(2H)-one

[0430]

[0431] After 7-fluoro-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one (400 mg, 0.97 mmol) was dissolved in EtOH (5 mL) at room temperature, Pd / C (40 mg) was slowly added dropwise, and then H 2 The reaction solution was filtered and then concentrated by evaporation under reduced pressure to obtain the target compound 3-(3-(4-(3-aminophenyl)piperazin-1-yl)propyl)-7-fluoroisoquinolin-1(2H)-one (216 mg, 58%).

[0432] 1 H NMR (300 MHz, CDCl 3 )δ11.31(br,1H),7.98(d,1H,J=8.7Hz),7.46-7.42(m,1H),7.36-7.31(m,1H),7.05(t,1H,J=7.8Hz),6.40(d,1H,J=8.4Hz ), 6.30 (m, 1H), 6.25-6.22 (m, 2H), 3.60-3.54 (br, 2H), 3.37 (m, 4H), 2.69 (m, 6H), 2.50 (t, 2H, J = 5.9Hz), 1.93-1.97 (m, 2H).

[0433] Step 3: Preparation of N-(3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzene 4-(2-Methyl)acetamide

[0434]

[0435] 3-(3-(4-(3-aminophenyl)piperazin-1-yl)propyl)-7-fluoroisoquinolin-1(2H)-one (320 mg, 0.84 mmol), DMAP (103 mg, 0.84 mmol) and acetic anhydride (0.24 mL, 2.52 mmol) were dissolved in CH 3 Cl (8.4 mL) was added, and TEA (0.35 mL, 2.52 mmol) was slowly added dropwise to the reaction solution, which was then stirred at 60°C for 7 hours. The reaction solution was diluted with EtOAc and washed with water, and the organic solvent was purified by anhydrous MgSO 4 The mixture was dried, filtered, and then concentrated by evaporation under reduced pressure. The resulting residue was separated and purified by silica gel chromatography to obtain the target compound N-(3-(4-(3-(7-fluoro-1-fluoro-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)phenyl)acetamide (33 mg, 10%).

[0436] 1 H NMR (300 MHz, DMSO-d 6)δ11.51(br,1H),9.79(br,1H),7.78(d,1H,J=7.8Hz),7.69-7.64(m,1H),7.59-7.53(m,1H),7.23(m,1H),7.13-7.08(m,1H),6. 99(d,1H,J=7.8Hz),6.62(d,1H,J=7.8Hz),6.43(s,1H),3.11(m,4H),2.57-2.50(m,6H),2.41(m,2H),2.01(s,3H),1.86(m,2H).

[0437] <Example 21> Preparation of 5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile

[0438]

[0439] The target compound was obtained according to Example 1, except that 5-bromo-2-cyanopyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0440] 1 H NMR (300 MHz, CDCl 3 )δ8.32(s,1H),7.50-7.49(m,1H),1.46-7.38(m,1H),7.11-7.10(m,1H),6.93-6.91(m,1H),6.28 (s,1H),3.66-3.64(m,4H),2.74-2.73(m,6H),2.56-2.55(m,2H),2.42(s,3H),1.93-1.91(m,2H).

[0441] <Example 22> Preparation of 6-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile

[0442]

[0443] The target compound was obtained according to Example 1, except that 2-bromo-5-cyanopyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0444] 1 H NMR (300 MHz, CDCl 3)δ8.32(s,1H),7.50-7.49(m,1H),1.46-7.38(m,1H),7.11-7.10(m,1H),6.93-6.91(m,1H),6.28 (s,1H),3.66-3.64(m,4H),2.74-2.73(m,6H),2.56-2.55(m,2H),2.42(s,3H),1.93-1.91(m,2H).

[0445] <Example 23> Preparation of 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

[0446]

[0447] The target compound was obtained according to Example 1, except that 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in Step 3 of Example 1.

[0448] 1 H NMR (300 MHz, CDCl 3 )δ7.50-7.47(m,2H),7.35-7.33(m,1H),6.95-6.86(m,3H),6.27(s,1H),3.61-3. 60(m,4H),2.72-2.71(m,6H),2.55-2.54(m,2H),2.43(s,3H),1.93-1.92(m,2H).

[0449] <Example 24> Preparation of 8-fluoro-5-methyl-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0450]

[0451] The target compound was obtained according to Example 1, except that 2-bromopyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0452] 1 H NMR (300 MHz, CDCl 3)δ8.18-8.17(m,1H),7.47-7.46(m,1H),7.34-7.33(m,1H),6.91-6.90(m,1H),6.76-6.64(m,2H),6. 26(s,1H),3.79-3.78(m,4H),2.68-2.67(m,6H),2.52-2.51(m,2H),2.42(s,3H),1.93-1.92(m,2H).

[0453] <Example 25> Preparation of 8-fluoro-5-methyl-3-(3-(4-(pyrimidin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0454]

[0455] The target compound was obtained according to Example 1, except that 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1, and 1-(2-pyrimidinyl)piperazine was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 8 of Example 1.

[0456] 1 H NMR (300 MHz, CDCl 3 )δ8.30-8.29(m,2H),7.34-7.33(m,1H),6.91-6.90(m,1H),6.48-6.47(m,1H),6.26(s,1H),4.08-4. 07(m,4H),2.74-2.73(m,2H),2.63-2.62(m,4H),2.52-2.51(m,2H),2.42(s,3H),1.92-1.91(m,2H).

[0457] <Example 26> Preparation of 3-fluoro-4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

[0458]

[0459] The target compound was obtained according to Example 1, except that 4-bromo-3-fluorobenzonitrile was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0460] 1 H NMR (300 MHz, CDCl 3)δ11.79(br,1H),7.35-7.334(m,2H),7.27-7.25(m,1H),7.03-7.01(m,1H),6.95-6.92(m,1H),6.2 7(s,1H),3.50-3.48(m,4H),2.78-2.76(m,6H),2.57-2.55(m,2H),2.42(s,3H),1.93-1.91(m,2H).

[0461] <Example 27> Preparation of 8-fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0462]

[0463] The target compound was obtained according to Example 1, except that 4-bromotrifluorotoluene was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0464] 1 H NMR (300 MHz, CDCl 3 )δ11.51(br,1H),7.48-7.45(m,2H),7.37-7.35(m,1H),6.96-6.88(m,3H),6.28(s,1H), 3.54-3.51(m,4H),2.72-2.70(m,6H),2.55-2.51(m,2H),2.42(m,3H),1.95-1.91(m,2H).

[0465] <Example 28> Preparation of 2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

[0466]

[0467] The target compound was obtained according to Example 1, except that 2-bromobenzonitrile was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0468] 1 H NMR (300 MHz, CDCl 3)δ11.91(br,1H),7.59-7.48(m,2H),7.35(dd,1H,J=8.0Hz,5.0Hz),7.16(d,1H,J=8.1Hz),7.02(t,1H,J=7.7Hz),6.92(dd,1H,J=11 .9Hz, 8.3Hz), 6.28 (s, 1H), 3.52-3.49 (m, 4H), 2.82 (m, 4H), 2.74 (t, 2H, J = 6.2Hz), 2.58 (t, 2H, J = 5.6Hz), 2.43 (s, 3H), 1.92 (m, 2H).

[0469] <Example 29> Preparation of 8-fluoro-5-methyl-3-(3-(4-(thiazol-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0470]

[0471] The target compound was obtained according to Example 1, except that 2-bromothiazole was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0472] 1 H NMR (300 MHz, CDCl 3 )δ11.48(br,1H),7.35(dd,1H,J=7.8Hz,4.8Hz),7.20(d,1H,J=3.3Hz),6.93(dd,1H,J=11.3Hz,8.3Hz),6.57(d,1 H, J=3.6Hz), 6.28 (s, 1H), 3.75 (m, 4H), 2.74-2.67 (m, 6H), 2.53 (t, 2H, J=6.2Hz), 2.43 (s, 3H), 1.97-1.89 (m, 2H).

[0473] <Example 30> Preparation of 8-fluoro-5-methyl-3-(3-(4-(5-methylthiazol-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0474]

[0475] The target compound was obtained according to Example 1, except that 2-bromo-5-methylthiazole was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0476] 1H NMR (300 MHz, CDCl 3 )δ11.46(br,1H),7.37-7.33(m,1H),6.96-6.89(m,1H),6.81(s,1H),6.28(s,1H),3.68-3. 65(m,4H),2.73-2.64(m,6H),2.51(t,2H,J=5.9Hz),2.43(s,3H),2.30(s,3H),1.92(m,2H).

[0477] <Example 31> Preparation of (R)-8-fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

[0478]

[0479] The target compound was obtained according to Example 1, except that 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1, and (R)-3-(4-fluorophenyl)pyrrolidine was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 8 of Example 1.

[0480] 1 H NMR (300 MHz, CDCl 3 )δ12.13(br,1H),7.37-7.30(m,3H),7.01-6.89(m,3H),6.28(s,1H),3.69-3.60(m,1H),3.31-3 .26(m,1H),3.13-3.05(m,1H),2.78-2.46(m,4H),2.42(s,3H),2.14-1.97(m,4H),1.90(m,2H).

[0481] <Example 32> Preparation of (S)-8-fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

[0482]

[0483] The target compound was obtained according to Example 1, except that 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1, and (S)-3-(4-fluorophenyl)pyrrolidine was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 8 of Example 1.

[0484] 1 H NMR (300 MHz, CDCl 3)δ12.16(br,1H),7.37-7.25(m,3H),7.01-6.89(m,3H),6.27(s,1H),3.72-3.60(m,1H), 3.31-3.25(m,1H),3.12-3.05(m,1H),2.77-2.46(m,4H),2.42(s,3H),2.07-1.87(m,6H).

[0485] <Example 33> Preparation of 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[0486]

[0487] The target compound was obtained according to Example 1, except that 1-bromo-4-chlorobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 1, and 2-bromo-3-methyl-6-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid used in step 3 of Example 1.

[0488] 1 H NMR (300 MHz, CDCl 3 )δ11.41(br,1H),7.36-7.33(m,1H),7.20-7.17(m,2H),6.94-6.85(m,3H),6.27(s,1H),3.34-3.3 2(m,4H),2.70-2.69(m,4H),2.53-2.48(m,2H),2.42(s,3H),2.38-2.37(m,2H),1.94-1.90(m,2H).

[0489] <Example 34> Preparation of 4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

[0490]

[0491] Step 1: Preparation of methyl 5-fluoro-2-hydroxy-3-methylbenzoate

[0492]

[0493] 5-Fluoro-2-hydroxy-3-methylbenzaldehyde (24 g, 155.7 mmol) and aminosulfonic acid (22.7 g, 622.8 mmol) were dissolved in distilled water. After adding 2% ethanol (1944 mL), an aqueous solution of sodium dihydrogen phosphate monohydrate (0.25 M, 630 mL) was slowly added dropwise, and an aqueous solution of sodium chlorite (2 M, 80 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 30 minutes, and then Na 2 SO 3 The reaction solution was diluted with EtOAc and washed with 1N HCl and water, and the organic solvent was washed with anhydrous MgSO 4 The mixture was dried, filtered, and then concentrated by evaporation under reduced pressure to obtain a mixed solution of 5-fluoro-2-hydroxy-3-methylbenzoic acid (26 g, 100%). The mixed solution was diluted with methanol (1 L), and sulfuric acid (60 mL) was slowly added dropwise and refluxed for 15 hours. The reaction solution was cooled to room temperature, diluted with EtOAc, and then washed with water. The organic solvent was washed with anhydrous MgSO 4 Dry, filter and then concentrate by evaporation under reduced pressure to obtain the target compound 5-fluoro-2-hydroxy-3-benzoic acid methyl ester (31.28 g, 58%).

[0494] 1 H NMR (300 MHz, CDCl 3 )δ10.78(s,1H),7.35-7.33(m,1H),7.09-7.06(m,1H),3.94(s,3H),2.26(s,3H).

[0495] Step 2: Preparation of methyl 5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

[0496]

[0497] Methyl 5-fluoro-2-hydroxy-3-methylbenzoate (1.0 g, 5.43 mmol) was added to CH 2 Cl 2 (1L), and trifluoromethanesulfonic anhydride (2.3 g, 8.15 mmol) was added dropwise. The mixture was stirred for 10 minutes, and TEA (1.1 g, 10.86 mmol) was added dropwise, and then stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was washed with anhydrous MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was separated and purified by silica gel chromatography to obtain the target compound methyl 5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (1.5 g, 87%).

[0498] 1 H NMR (300 MHz, CDCl 3)δ7.53-7.52(m,1H),7.20-7.17(m,1H),3.94(s,3H),2.43(s,3H).

[0499] Step 3: Preparation of methyl 5-fluoro-2-(5-hydroxypent-1-yn-yl)-3-methylbenzoate

[0500]

[0501] After dissolving methyl 5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (52 g, 164.4 mmol) in acetonitrile (822 mL), pent-4-yn-1-ol (16.6 g, 197.28 mmol), Pd(PPh 3 ) 2 Cl 2 (5.77 g, 8.22 mmol) and CuI (1.57 g, 8.22 mmol). Then, TEA (50.0 g, 493.2 mmol) was added dropwise, and the mixture was stirred at 80°C for 15 hours and then cooled to room temperature. The reaction solution was diluted with EtOAc and washed with NH 4 The organic solvent was washed with MgSO 4 Dry, filter and then concentrate by evaporation under reduced pressure, and purify the residue by silica gel chromatography to obtain the target compound 5-fluoro-2-(5-hydroxypent-1-yn-yl)-3-methylbenzoic acid methyl ester (24.35 g, 59%).

[0502] 1 H NMR (300 MHz, CDCl 3 )δ7.41(d,J=9.0Hz,1H),7.10(d,J=8.7Hz,1H),3.91(s,3H),3.88-3.86(m, 2H), 2.66 (t, J = 6.9 Hz, 2H), 2.46 (s, 3H), 2.08 (m, 1H), 1.90 (t, J = 6.0 Hz, 2H).

[0503] Step 4: Preparation of 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one

[0504]

[0505] Methyl 5-fluoro-2-(5-hydroxypent-1-yn-yl)-3-methylbenzoate (24.35 g, 97.3 mmol) was dissolved in THF / MeOH / H 2 O (320 mL / 80 mL / 80 mL), then LiOH·H 2O (20.4 g, 486.5 mmol), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated by distillation under reduced pressure, then diluted with EtOAc, and 6N HCl was slowly added dropwise to adjust the pH to 1-2. The organic solvent was purified by MgSO 4 The reaction mixture was dried, filtered, and then concentrated by evaporation under reduced pressure. After the concentrated reaction solution was dissolved in acetone (486 mL), AgNO was added dropwise. 3 (6.1 g, 19.46 mmol). The reaction solution was stirred at room temperature for 15 hours and then distilled under reduced pressure to remove the solvent. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one (8.3 g, 36%).

[0506] 1 H NMR (300 MHz, CDCl 3 )δ7.76(d,J=8.4Hz,1H),7.28-7.24(m,1H),6.38(s,1H),3.75(t,J=6.0Hz,2H),2.68(t,J=7.5Hz,2H),2.47(s,3H),2.01-1.94(m,2H).

[0507] Step 5: Preparation of 7-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one

[0508]

[0509] 7-Fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one (5.5 g, 23.28 mmol) was dissolved in 7N NH 3 / MeOH (33 mL), the mixture was stirred at 80°C for 15 hours. The reaction solution was cooled to room temperature, and the product thus obtained was concentrated by evaporation under reduced pressure. The obtained solid was recrystallized from MeOH to obtain the target compound 7-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.9 g, 71%).

[0510] 1 H NMR (300 MHz, DMSO-d 6)δ7.53(d,J=9.3Hz,1H),7.32(d,J=9.3Hz,1H),6.27(s,1H),4.50(br,1H), 4.05-4.03(m,1H),3.06-3.05(m,2H),2.46-2.36(m,5H),1.71-1.64(m,2H).

[0511] Step 6: Preparation of 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate

[0512]

[0513] After 7-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.9 g, 16.58 mmol) was dissolved in DMF (83 mL), the mixture was cooled to 0° C. MsCl (1.7 mL, 21.55 mmol) and TEA (3.5 mL, 24.87 mmol) were slowly added dropwise at 0° C., followed by stirring at 25° C. for 15 hours. The reaction solution was diluted with EtOAc and washed with NH 4 The organic solvent was washed with MgSO 4 Filtered, dried and then concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized with MeOH to obtain the target compound, 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (4.42 g, 85%).

[0514] 1 H NMR (300 MHz, CDCl 3 )δ11.63(br,1H),7.86(d,J=9.0Hz,1H),7.25(d,J=9.0Hz,1H),6.49(s,1H),4.3 5(t,J=5.7Hz,2H),3.05(s,3H),2.84(t,J=5.7Hz,2H),2.54(s,3H),2.27(m,2H).

[0515] Step 7: Preparation of 4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazine-1- Benzonitrile

[0516]

[0517] After dissolving 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (200 mg, 0.64 mmol) in acetonitrile (2 mL), 4-(piperazine-1-yl)benzonitrile 2HCl (249 mg, 0.96 mmol) was added dropwise at 25°C. DIPEA (0.56 mL, 3.2 mmol) was added dropwise, and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and treated with NaS 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized from MeOH to obtain the target compound 4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile (46 mg, 17%).

[0518] 1 H NMR (300 MHz, CDCl 3 )δ11.65(br,1H),7.81-7.80(m,1H),7.51-7.42(m,2H),7.25-7.24(m,1H),6.90-6.87(m,2H ),6.34(s,1H),3.56-3.55(m,4H),2.71-2.70(m,6H),2.51-2.50(m,2H),1.93-1.92(m,2H).

[0519] <Example 35> Preparation of 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile

[0520]

[0521] The target compound was obtained according to Example 34, except that 5-(piperazin-1-yl)picolinonitrile 2HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 7 of Example 34.

[0522] 1 H NMR (300 MHz, CDCl 3)δ12.62(br,1H),8.33(s,1H),7.80-7.78(m,1H),7.53-7.50(m,1H),7.26-7.25(m,1H),7.13-7.12(m,1H ),6.34(s,1H),3.64-3.63(m,4H),2.74-2.71(m,6H),2.56-2.55(m,2H),2.50(s,3H),1.94-1.93(m,2H).

[0523] <Example 36> Preparation of 6-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile

[0524]

[0525] The title compound was obtained according to Example 34, except that 6-(piperazin-1-yl)nicotinonitrile 2HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 7 of Example 34.

[0526] 1 H NMR (300 MHz, CDCl 3 )δ8.40(s,1H),7.84-7.83(m,1H),7.62-7.59(m,1H),7.27-7.26(m,1H),6.63-6.60(m,1H),6.34(s,3H),3 .95-3.94(m,4H),2.76-2.75(m,2H),2.66-2.65(m,4H),2.54-2.52(m,2H),2.50(s,3H),1.93-1.92(m,2H).

[0527] <Example 37> Preparation of 3-fluoro-4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

[0528]

[0529] The target compound was obtained according to Example 34, except that 3-fluoro-4-(piperazin-1-yl)benzonitrile 2HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 7 of Example 34.

[0530] 1 H NMR (300 MHz, CDCl 3)δ11.81(br,1H),7.84-7.81(m,1H),7.39-7.36(m,1H),7.29-7.21(m,2H),7.18-7.05(m,1H),7.02-6.99(m ,1H),6.33(s,1H),3.49-3.47(m,4H),2.76-2.75(m,6H),2.57-2.55(m,2H),2.50(s,3H),1.93-1.91(m,2H).

[0531] <Example 38> Preparation of 2-fluoro-4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

[0532]

[0533] The target compound was obtained according to Example 34, except that 2-fluoro-4-(piperazin-1-yl)benzonitrile 2HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 7 of Example 34.

[0534] 1 H NMR (300 MHz, CDCl 3 )δ7.84-7.83(m,1H),7.40-7.37(m,1H),7.20-7.19(m,1H),6.66-6.63(m,1H),6.56-6.55(m,1H),6. 34(s,1H),3.59-3.58(m,4H),2.70-2.69(m,6H),2.55-2.53(m,2H),2.50(s,3H),1.94-1.93(m,2H).

[0535] <Example 39> Preparation of 7-fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0536]

[0537] The target compound was obtained according to Example 34, except that 1-(4-(trifluoromethyl)phenyl)piperazine 2HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 7 of Example 34.

[0538] 1 H NMR (300 MHz, CDCl 3)δ7.84-7.83(m,1H),7.40-7.37(m,1H),7.20-7.19(m,1H),6.66-6.63(m,1H),6.56-6.55(m,1H),6. 34(s,1H),3.59-3.58(m,4H),2.70-2.69(m,6H),2.55-2.53(m,2H),2.50(s,3H),1.94-1.93(m,2H).

[0539] <Example 40> Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

[0540]

[0541] The target compound was obtained according to Example 34, except that 1-(4-fluorophenyl)piperazine 2HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 7 of Example 34.

[0542] 1 H NMR (300 MHz, CDCl 3 )δ7.85-7.82(m,1H),7.20-7.18(m,1H),6.97-6.94(m,4H),6.32(s,1H),3.35-3. 34(m,4H),2.72-2.71(m,6H),2.53-2.52(m,2H),2.50(s,3H),1.93-1.91(m,2H).

[0543] <Example 41> Preparation of 4-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0544]

[0545] Step 1: Preparation of tert-butyl 4-(4-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0546]

[0547] Dissolve tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-pinacolborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g, 4.85 mmol) and 4-bromobenzonitrile (971.63 mg, 5.43 mmol) in distilled water. alkane (48 mL) and H 2 O (16 mL), then Pd(PPh 3 ) 2 Cl2 (170.25 mg, 0.242 mmol) and K 2 CO 3 (2.01 g, 14.55 mol). The mixture was stirred at 100°C for 15 and cooled to room temperature. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound tert-butyl 4-(4-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.2 g, 87%).

[0548] 1 H NMR (300 MHz, CDCl 3 )δ7.62(d,J=8.1Hz,2H),7.46(d,J=8.1Hz,2H),6.18(br,1H),4.12(m,2H),3.66-3.63(m,2H),2.52(m,2H),1.49(s,9H).

[0549] Step 2: Preparation of 4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile HCl

[0550]

[0551] 4N HCl / di 4-(4-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.2 g, 2.22 mol) was added with 1% d-H-pyridine (15 mL), and the mixture was stirred for 15 hours. The solid produced during the reaction was filtered and washed with EtOAc to obtain the target compound 4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile HCl (837 mg, 90%).

[0552] 1 H NMR (300 MHz, DMSO-d 6 )δ9.50(br,1H),7.72(d,J=9.0Hz,2H),7.55(d,J=9.0Hz,2H),6.57(br,1H),3.79(m,2H),3.31(m,2H),2.74(m,2H).

[0553] Step 3: Preparation of 4-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyrrolidone (4-pyridin-1-yl)benzonitrile

[0554]

[0555] After dissolving 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (150 mg, 0.52 mmol) in DMF (2 mL), 4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile HCl (221 mg, 0.79 mmol) was added dropwise at 25°C. TEA (340 mg, 2.62 mmol) was added dropwise, and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and Na 2 S 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized from MeOH to obtain the target compound 4-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (60 mg, 29%).

[0556] 1 H NMR (300 MHz, CDCl 3 )δ7.63-7.60(m,2H),7.55-7.47(m,3H),7.21-7.18(m,1H),7.02-6.98(m,1H),6.24(s,1H),6.22(s, 1H),3.30-3.28(m,2H),2.84-2.82(m,4H),2.68-2.64(m,2H),2.60-2.56(m,2H),1.96-1.92(m,2H).

[0557] <Example 42> Preparation of 8-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one

[0558]

[0559] The target compound was obtained according to Example 41, except that 4-bromofluorobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 41.

[0560] 1 H NMR (300 MHz, CDCl 3)δ11.00(br,1H),7.54-7.46(m,1H),7.42-7.38(m,2H),7.21-7.18(m,1H),7.04-6.98(m,3H),6.22(s,1H),6 .047(s,1H),3.23-3.21(m,2H),2.81-2.75(m,4H),2.68-2.64(m,2H),2.58-2.54(m,2H),1.96-1.92(m,2H).

[0561] <Example 43> Preparation of 8-fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)propyl)isoquinolin-1(2H)-one

[0562]

[0563] The target compound was obtained according to Example 41, except that 5-bromo-2-fluoropyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 41.

[0564] 1 H NMR (300 MHz, CDCl 3 )δ11.05(br,1H),8.26(s,1H),7.87-7.82(M,1H),7.54-7.48(m,1H),7.21-7.18(m,1H),7.04-6.98(m,1H),6.91-6.88(m,1H),6.23(s ,1H),6.10(s,1H),3.25-3.23(m,2H),2.83-2.81(m,2H),2.76-2.75(m,2H),2.69-2.64(m,2H),2.60-2.55(m,2H),1.96-1.92(m,2H).

[0565] <Example 44> Preparation of 8-fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)propyl)isoquinolin-1(2H)-one

[0566]

[0567] The target compound was obtained according to Example 41, except that 2-bromo-5-fluoropyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 41.

[0568] 1 H NMR (300 MHz, CDCl 3)δ11.00(br,1H),8.41-8.40(m,1H),7.54-7.36(m,3H),7.21-7.18(m,1H),7.03-6.97(m,1H),6.62(s,1H), 6.22(s,1H),3.31-3.29(m,2H),2.86-2.84(m,4H),2.68-2.63(m,2H),2.61-2.59(m,2H),1.97-1.93(m,2H).

[0569] <Example 45> Preparation of 8-fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one

[0570]

[0571] The target compound was obtained according to Example 41, except that 4-bromotrifluorotoluene was used instead of 4-bromobenzonitrile used in step 1 of Example 41.

[0572] 1 H NMR (300 MHz, CDCl 3 )δ10.93(br,1H),7.59-7.46(m,5H),7.21-7.18(m,1H),7.04-6.98(m,1H),6.22(s,1H),6.19(s,1 H),3.26-3.25(m,2H),2.83-2.82(m,4H),2.69-2.64(m,2H),2.59-2.55(m,2H),1.96-1.92(m,2H).

[0573] <Example 46> Preparation of 1′-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile

[0574]

[0575] The target compound was obtained according to Example 41, except that 2-bromo-5-cyanopyridine was used instead of 4-bromobenzonitrile used in Step 1 of Example 41.

[0576] 1 H NMR (300 MHz, CDCl 3)δ11.02(br,1H),8.80(s,1H),7.93-7.89(m,1H),7.54-7.46(m,2H),7.21-7.18(m,1H),7.01-6.97(m,1H),6.92(s ,1H),6.22(s,1H),3.34-3.33(m,2H),2.86-2.85(m,4H),2.68-2.64(m,2H),2.62-2.57(m,2H),1.97-1.93(m,2H).

[0577] <Example 47> Preparation of 4-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0578]

[0579] The target compound was obtained according to Example 41, except that 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0580] 1 H NMR (300 MHz, CDCl 3 )δ11.22(br,1H),7.98-7.94(m,1H),7.64-7.61(m,2H),7.55-7.52(m,2H),7.47-7.42(m,1H),7.36-7.30(m,1H), 6.28-6.25(m,2H),3.29-3.27(m,2H),2.84-2.80(m,4H),2.72-2.67(m,2H),2.61-2.57(m,2H),1.96-1.94(m,2H).

[0581] <Example 48> Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one

[0582]

[0583] The target compound was obtained according to Example 41, except that 4-bromofluorobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0584] 1 H NMR (300 MHz, DMSO-d 6 )δ11.46(br,1H),7.79-7.75(m,1H),7.69-7.64(m,1H),7.58-7.52(m,1H),7.48-7.44(m,2H),7.18-7.12(m ,2H),6.42(s,1H),6.12(s,1H),3.07-3.06(m,2H),2.62-2.61(m,2H),2.56-2.50(m,6H),1.84-1.82(m,2H).

[0585] <Example 49> Preparation of 3-(3-(4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-7-fluoroisoquinolin-1(2H)-one

[0586]

[0587] The target compound was obtained according to Example 41, except that 1-bromo-4-chlorobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0588] 1 H NMR (300 MHz, CDCl 3 )δ11.13(br,1H),7.96-7.94(m,1H),7.47-7.27(m,6H),6.26(s,1H),6.10(s,1 H),3.26-3.24(m,2H),2.82-2.67(m,6H),2.57-2.55(m,2H),1.96-1.94(m,2H).

[0589] <Example 50> Preparation of 1′-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile

[0590]

[0591] The target compound was obtained according to Example 41, except that 2-bromo-5-cyanopyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0592] 1 H NMR (300 MHz, CDCl 3 )δ11.20(m,1H),8.81(s,1H),7.96-7.91(m,2H),7.55-7.52(m,1H),7.47-7.44(m,1H),7.36-7.31(m,1H),6.92(s ,1H),6.27(s,1H),3.56-3.54(m,2H),2.87-2.85(m,4H),2.72-2.68(m,2H),2.63-2.59(m,2H),1.98-1.94(m,2H).

[0593] <Example 51> Preparation of 7-fluoro-3-(3-(4-(2-fluoro-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one

[0594]

[0595] The target compound was obtained according to Example 41, except that 4-bromo-3-fluoro-1-nitrobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0596] 1 H NMR (300 MHz, CDCl 3 )δ11.27(br,1H),8.04-7.92(m,3H),7.62-7.57(m,1H),7.47-7.43(m,1H),7.37-7.31(m,1H),6.27(s,1H), 6.22(s,1H),3.31-3.29(m,2H),2.85-2.80(m,4H),2.73-2.71(m,2H),2.69-2.58(m,2H),2.05-1.61(m,2H).

[0597] <Example 52> Preparation of 2-fluoro-4-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0598]

[0599] The target compound was obtained according to Example 41, except that 4-bromo-2-fluorobenzonitrile was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0600] 1 H NMR (300 MHz, CDCl 3 )δ11.16(br,1H),7.98-7.95(m,1H),7.61-7.56(m,1H),7.47-7.44(m,1H),7.36-7.26(m,3H),6.29(s,1H),6.26(s,1 H),3.30-3.29(m,2H),2.84-2.82(m,2H),2.78-2.76(m,2H),2.72-2.67(m,2H),2.61-2.57(m,2H),1.96-1.92(m,2H).

[0601] <Example 53> Preparation of 8-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one

[0602]

[0603] The target compound was obtained according to Example 41, except that 4-bromo-1-fluorobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0604] 1 H NMR (300 MHz, CDCl 3)δ11.07(br,1H),7.42-7.32(m,3H),7.03-6.88(m,3H),6.27(s,1H),6.04(s,1H),3.2 3-3.22(m,2H),2.81-2.67(m,6H),2.58-2.54(m,2H),2.42(s,3H),1.97-1.93(m,2H).

[0605] <Example 54> Preparation of 4-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0606]

[0607] The target compound was obtained according to Example 41, except that 3-(8-fluoro-5-methyl-1-bromo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0608] 1 H NMR (300 MHz, CDCl 3 )δ11.03(br,1H),7.63-7.60(m,2H),7.54-7.51(m,1H),7.36-7.32(m,1H),6.28(s,1H),6.24(s,1H),3.28-3.27(m ,2H),2.82-2.81(m,4H),2.72-2.67(m,2H),2.60-2.56(m,2H),2.58-2.56(m,2H),2.42(s,3H),1.97-1.93(m,2H).

[0609] <Example 55> Preparation of 2-fluoro-4-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0610]

[0611] The target compound was obtained according to Example 41, except that 4-bromo-2-fluorobenzonitrile was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0612] 1 H NMR (300 MHz, CDCl 3 )δ10.99(br,1H),7.59-7.55(m,1H),7.37-7.32(m,2H),7.28-7.26(m,1H),6.95-6.89(m,1H),6.28-6.27(m,2H ),3.28-3.27(m,2H),2.83-2.78(m,4H),2.72-2.67(m,2H),2.60-2.56(m,2H),2.42(s,3H),1.97-1.93(m,2H).

[0613] <Example 56> Preparation of 8-fluoro-3-(3-(4-(2-fluoro-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one

[0614]

[0615] The target compound was obtained according to Example 41, except that 4-bromo-3-fluoro-1-nitrobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0616] 1 H NMR (300 MHz, DMSO-d 6 )11.22(br,1H),8.03-8.02(m,1H),8.00-7.89(m,1H),7.59-7.54(m,1H),7.37-7.33(m,1H),6.95-6.89(m,1H),6 .29(s,1H),6.21(s,1H),3.29-3.28(m,2H),2.83-2.69(m,6H),2.62-2.57(m,2H),2.43(s,3H),2.04-1.95(m,2H).

[0617] <Example 57> Preparation of 1′-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile

[0618]

[0619] The target compound was obtained according to Example 41, except that 2-bromo-5-cyanopyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0620] 1 H NMR (300 MHz, CDCl 3 )δ11.03(br,1H),8.81(s,1H),7.93-7.90(m,1H),7.54-7.51(m,1H),7.36-7.32(m,1H),6.94-6.92(m,2H),6.28(s ,1H),3.36-3.35(m,2H),2.87-2.86(m,4H),2.72-2.68(m,2H),2.62-2.58(m,2H),2.42(s,3H),1.98-1.94(m,2H).

[0621] <Example 58> Preparation of 4-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0622]

[0623] The target compound was obtained according to Example 41, except that 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0624] 1 H NMR (300 MHz, CDCl 3 )δ11.27(br,1H),7.85-7.82(m,1H),7.63-7.60(m,2H),7.51-7.52(m,2H),7.20-7.18(m,1H),6.34(s,1H ),6.24(s,1H),3.28-3.27(m,2H),2.83-2.70(m,6H),2.61-2.57(m,2H),2.50(s,3H),1.98-1.94(m,2H).

[0625] <Example 59> Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one

[0626]

[0627] The target compound was obtained according to Example 41, except that 4-bromo-1-fluorobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0628] 1 H NMR (300 MHz, DMSO-d 6 )11.14(br,1H),7.87-7.85(m,1H),7.44-7.39(m,2H),7.21-7.18(m,1H),7.04-7.02(m,2H),6.33(s,1H ),6.05(s,1H),3.25-3.24(m,2H),2.82-2.69(m,6H),2.59-2.55(m,2H),2.51(s,3H),1.97-1.93(m,2H).

[0629] <Example 60> Preparation of 1′-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile

[0630]

[0631] The target compound was obtained according to Example 41, except that 2-bromo-5-cyanopyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0632] 1 H NMR (300 MHz, CDCl 3)δ11.06(br,1H),8.82(s,1H),7.94-7.91(m,1H),7.85-7.81(m,1H),7.56-7.53(m,1H),7.21-7.18(m,1H),6.93(s,1H), 6.33(s,1H),3.37-3.36(m,2H),2.87-2.86(m,4H),2.74-2.70(m,2H),2.62-2.60(m,2H),2.51(s,3H),2.17-1.96(m,2H).

[0633] <Example 61> Preparation of 1′-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile

[0634]

[0635] The target compound was obtained according to Example 41, except that 5-bromo-2-cyanopyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-5-methyl-1-bromo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0636] 1 H NMR (300 MHz, CDCl 3 )δ11.25(br,1H),8.23(s,1H),7.89-7.83(m,2H),7.70-7.67(m,1H),7.22-7.19(m,1H),6.35-6.3 4(m,2H),3.33-3.32(m,2H),2.87-2.83(m,4H),2.76-2.72(m,2H),2.51(s,3H),1.99-1.97(m,2H).

[0637] <Example 62> Preparation of 7-fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)propyl)-5-methylisoquinolin-1(2H)-one

[0638]

[0639] The target compound was obtained according to Example 41, except that 2-bromo-5-fluoropyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0640] 1 H NMR (300 MHz, CDCl 3 )δ11.14(br,1H),8.41(s,1H),7.86-7.82(m,1H),7.47-7.34(m,2H),7.20-7.17(m,1H),6.26(s,1H),6.33(s,1 H),3.30-3.28(m,2H),2.85-2.84(m,4H),2.73-2.69(m,2H),2.60-2.56(m,2H),2.50(s,3H),1.99-1.91(m,2H).

[0641] <Example 63> Preparation of 7-fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)propyl)-5-methylisoquinolin-1(2H)-one

[0642]

[0643] The target compound was obtained according to Example 41, except that 5-bromo-2-fluoropyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0644] 1 H NMR (300 MHz, CDCl 3 )δ11.28(br,1H),8.28(s,1H),7.89-7.83(m,2H),7.20-7.18(m,1H),6.91-6.88(m,1H),6.34(s,1H),6.10(s,1 H),3.27-3.26(m,2H),2.85-2.81(m,2H),2.75-2.70(m,4H),2.61-2.56(m,2H),2.50(s,3H),2.04-1.94(m,2H).

[0645] <Example 64> Preparation of 7-fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one

[0646]

[0647] The target compound was obtained according to Example 41, except that 4-bromotrifluorotoluene was used instead of 4-bromobenzonitrile used in step 1 of Example 41, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 41.

[0648] 1 H NMR (300 MHz, CDCl 3 )δ11.17(br,1H),7.87-7.83(m,2H),7.60-7.52(m,4H),7.21-7.18(m,1H),6.34(s,1H),6.20(s,1H),3.2 8-3.27(m,2H),2.83-2.80(m,4H),2.74-2.70(m,2H),2.60-2.56(m,2H),2.50(s,3H),1.98-1.94(m,2H).

[0649] <Example 65> Preparation of 8-fluoro-3-(3-(4-(3-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

[0650]

[0651] Step 1: Preparation of tert-butyl 4-(3-fluorobenzoyl)piperazine-1-carboxylate

[0652]

[0653] 1-Boc-piperazine (1.0 g, 5.37 mmol) was dissolved in CH 2 Cl 2 (54 mL), 3-fluorobenzoic acid (902 mg, 6.443 mmol), HBTU (2.44 g, 6.44 mmol) and Et 3 N (2.24 mL, 16.10 mmol) and stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound tert-butyl 4-(3-fluorobenzoyl)piperazine-1-carboxylate (1.6 g, 99%).

[0654] 1 H NMR (300 MHz, CDCl 3 )δ7.41-7.36(m,1H),7.18-7.10(m,3H),3.72-3.41(m,8H),1.47(s,9H).

[0655] Step 2: Preparation of (3-fluorophenyl)(piperazin-1-yl)methanone HCl

[0656]

[0657] 4N HCl (50 mL) was added to tert-butyl 4-(3-fluorobenzoyl)piperazine-1-carboxylate (1.6 g, 5.19 mmol), and the mixture was stirred for 15 hours. The solid produced during the reaction was filtered and washed with EtOAc to obtain the target compound (3-fluorophenyl)(piperazin-1-yl)methanone HCl (1.28 g, 100%).

[0658] 1 H NMR (300 MHz, DMSO-d 6 )δ7.56-7.53(m,1H),7.33-7.27(m,3H),3.67(br,4H),3.14(br,4H).

[0659] Step 3: Preparation of 8-fluoro-3-(3-(4-(3-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinoline-1 (2H)-Keto

[0660]

[0661] After dissolving 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (200 mg, 0.64 mmol) in acetonitrile (3 mL), (3-fluorophenyl)(piperazin-1-yl)methanone HCl (234 mg, 0.96 mmol) was added dropwise at 25°C. NaHCO 3 (268 mg, 3.19 mmol) and NaI (191 mg, 1.27 mmol), and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and NaS 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized from MeOH to obtain the target compound 8-fluoro-3-(3-(4-(3-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one (2.4 g, 77%).

[0662] 1 H NMR (300 MHz, CDCl 3 )δ7.41-7.33(m,2H),7.21-7.19(m,1H),7.15-7.11(m,2H),6.95-6.88(m,1H),6.28(s,1H),4.10-4. 04(m,2H),3.74-3.72(m,2H),2.76-2.68(m,4H),2.56-2.52(m,4H),2.42(s,3H),1.91-1.90(m,2H).

[0663] <Example 66> Preparation of 3-(3-(4-benzoylpiperazin-1-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[0664]

[0665] The target compound was obtained according to Example 65, except that benzoic acid was used instead of 3-fluorobenzoic acid used in step 1 of Example 65.

[0666] 1 H NMR (300 MHz, CDCl 3 )δ7.41-7.32(m,6H),6.93-6.89(m,1H),6.27(s,1H),4.06-4.05(m,2H),3.77-3. 76(m,2H),2.75-2.71(m,4H),2.55-2.54(m,4H),2.42(s,3H),1.91-1.90(m,2H).

[0667] <Example 67> Preparation of 8-fluoro-3-(3-(4-(4-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

[0668]

[0669] The target compound was obtained according to Example 65, except that 4-fluorobenzoic acid was used instead of 3-fluorobenzoic acid used in Step 1 of Example 65.

[0670] 1 H NMR (300 MHz, CDCl 3)δ7.47-7.42(m,2H),7.37-7.32(m,1H),7.11-7.06(m,2H),6.95-6.89(m,1H),6.27(s,1H),4.05-4.03(m,2H) ,3.78-3.77(m,2H),2.75-2.72(m,2H),2.67-2.65(m,2H),2.55-2.52(m,4H),2.42(s,3H),1.91-1.90(m,2H).

[0671] <Example 68> Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0672]

[0673] Step 1: Preparation of 3-(8-fluoro-1-oxo-1H-isochromen-3-yl)propanoic acid

[0674]

[0675] After 8-fluoro-3-(3-hydroxypropyl)-1H-isochromene-1-one (10.0 g, 42.33 mmol) was dissolved in acetone (420 mL), 2.5 M Jones reagent (68 mL) was slowly added dropwise at 0°C. The reaction solution was stirred at room temperature for 15 hours. The reaction solution was concentrated by evaporation under reduced pressure, diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized from MeOH to obtain the target compound 3-(8-fluoro-1-oxo-1H-isochromen-3-yl)propanoic acid (6.4 g, 61%).

[0676] 1 H NMR (300 MHz, CDCl 3 )δ7.84-7.72(m,2H),7.60-7.55(m,1H),7.39-7.29(m,1H),6.63(s,1H),2.77-2.73(m,2H),2.63-2.61(m,2H).

[0677] Step 2: Preparation of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid

[0678]

[0679] 3-(8-Fluoro-1-oxo-1H-isochromen-3-yl)propanoic acid (1.0 g, 4.23 mmol) was dissolved in 7N NH 3 / MeOH (20 mL), the mixture was stirred at 80 ° C for 15 hours. The reaction solution was cooled to room temperature, and then the product thus obtained was concentrated by evaporation under reduced pressure. The resulting solid was recrystallized from MeOH to obtain the target compound 3- (8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl) propionic acid (840 g, 84%).

[0680] 1 H NMR (300 MHz, CDCl 3 )δ7.61-7.54(m,1H),7.32-7.30(m,1H),7.09-7.03(m,1H),6.30(s,1H),2.65-2.61(m,2H),2.40-2.35(m,2H).

[0681] Step 3: Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzene Formonitrile

[0682]

[0683] After dissolving 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid (80 mg, 0.34 mmol) and 4-(piperazin-1-yl)benzonitrile 2HCl (106 mg, 0.41 mmol) in DMF (25 mL), HBTU (193 mg, 0.51 mmol) was added dropwise. TEA (172 mg, 1.7 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 hours. The reaction solution was washed with CH 2 Cl 2 Dilute and wash with water. The organic solvent is purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile (24 mg, 18%).

[0684] 1 H NMR (300 MHz, CDCl 3 )δ10.36(br,1H),7.53-7.50(m,3H),7.22-7.19(m,1H),7.03-6.97(m,1H),6.85-6.82(m,1H),6.26(s ,1H),3.84-3.83(m,2H),3.64-3.63(m,2H),3.34-3.33(m,4H),2.93-2.92(m,2H),2.83-2.80(m,2H).

[0685] <Example 69> Preparation of 4-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0686]

[0687] The title compound was obtained using 4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0688] 1 H NMR (300 MHz, CDCl 3 )δ10.22(br,1H),7.64-7.61(m,2H),7.49-7.41(m,3H),7.20-7.18(m,1H),7.03-7.00(m,1H),6.24-6.09 (m,2H),4.35(m,1H),4.15(m,1H),3.90(m,1H),3.68(m,1H),2.94(m,2H),2.83-2.80(m,2H),2.55(m,2H).

[0689] <Example 70> Preparation of 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile

[0690]

[0691] The title compound was obtained using 5-(piperazin-1-yl)picolinonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0692] 1 H NMR (300 MHz, CDCl 3 )δ10.57(br,1H),8.30(s,1H),7.56-7.53(m,2H),7.22(m,1H),7.11-6.97(m,2H),6 .30(s,1H),3.88(m,2H),3.71(m,2H),3.50-3.41(m,4H),2.97(m,2H),2.86(m,2H).

[0693] <Example 71> Preparation of 6-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile

[0694]

[0695] The title compound was obtained using 6-(piperazin-1-yl)nicotinonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0696] 1 H NMR (300 MHz, CDCl 3 )δ10.44(br,1H),8.42(s,1H),7.66(d,1H,J=8.7Hz),7.56-7.49(m,1H),7.22(d,1H,J=7.8Hz),7.04-6.98(m,1H) ,6.60(d,1H,J=9.3Hz),6.28(s,1H),3.81-3.78(m,4H),3.68-3.61(m,4H),2.97-2.93(m,2H),2.85-2.83(m,2H).

[0697] <Example 72> Preparation of 2-fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0698]

[0699] The title compound was obtained using 2-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0700] 1 H NMR (300 MHz, CDCl 3 )δ10.43(br,1H),7.56-7.49(m,1H),7.46-7.41(m,1H),7.23-7.20(m,1H),7.04-6.98(m,1H),6.61(d,1H,J=8.7Hz),6.53(d,1H, J=12.6Hz), 6.28(s,1H), 3.85(t,2H,J=5.3Hz), 3.67(t,2H,J=4.9Hz), 3.39(m,4H), 2.95(t,2H,J=5.7Hz), 2.82(t,2H,J=5.7Hz).

[0701] <Example 73> Preparation of 3-fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0702]

[0703] The title compound was obtained using 3-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0704] 1 H NMR (300 MHz, CDCl 3 )δ10.54(br,1H),7.56-7.49(m,1H),7.38(d,1H,J=8.1Hz),7.33-7.29(m,1H),7.22(d,1H,J=8.4Hz),7.05-6.98(m,1H),6.89(t,1H, J=8.6Hz),6.29(s,1H),3.86(t,2H,J=4.8Hz),3.66(t,2H,J=4.8Hz),3.20-3.17(m,4H),2.95(t,2H,J=5.6Hz),2.83(t,2H,J=5.9Hz).

[0705] <Example 74> Preparation of 2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0706]

[0707] The title compound was obtained using 2-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0708] 1 H NMR (300 MHz, CDCl 3 )δ10.32(br,1H),7.60(d,1H,J=7.8Hz),7.52-7.49(m,2H),7.21(d,1H,J=7.8Hz),7.11-6.97(m ,3H),6.26(s,1H),3.90(m,2H),3.69(m,2H),3.19(m,4H),2.94-2.93(m,2H),2.82-2.80(m,2H).

[0709] <Example 75> Preparation of 8-fluoro-3-(3-(4-(2-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0710]

[0711] The title compound was obtained using 1-(2-fluorophenyl)piperazine hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0712] 1 H NMR (300 MHz, CDCl 3 )δ10.42(br,1H),7.52-7.48(m,1H),7.21(d,1H,J=7.8Hz),7.07-6.98(m,4H),6.90(t,1H,J=8.3Hz),6.26(s,1H ), 3.86 (t, 2H, J = 4.7Hz), 3.64 (t, 2H, J = 4.7Hz), 3.07-3.05 (m, 4H), 2.94 (t, 2H, J = 5.7Hz), 2.81 (t, 2H, J = 5.9Hz).

[0713] <Example 76> Preparation of 5-fluoro-2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0714]

[0715] The title compound was obtained using 5-fluoro-2-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0716] 1 H NMR (300 MHz, CDCl 3 )δ10.38(br,1H),7.55-7.48(m,1H),7.32-7.20(m,3H),7.06-6.95(m,2H),6.27(s,1H),3.89(t ,2H,J=4.2Hz), 3.69(t,2H,J=4.5Hz), 3.10(m,4H), 2.94(t,2H,J=5.7Hz), 2.81(t,2H,J=5.6Hz).

[0717] <Example 77> Preparation of 3-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0718]

[0719] The title compound was obtained using 3-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0720] 1 H NMR (300 MHz, CDCl 3)δ10.45(br,1H),7.56-7.49(m,1H),7.38-7.31(m,1H),7.23-7.21(m,1H),7.17-7.08(m,3H),7.05-6.98(m,1H),6.28 (s, 1H), 3.85 (t, 2H, J = 5.1Hz), 3.65 (t, 2H, J = 5.0Hz), 3.24-3.21 (m, 4H), 2.95 (t, 2H, J = 5.9Hz), 2.83 (t, 2H, J = 6.0Hz).

[0721] <Example 78> Preparation of 3-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

[0722]

[0723] The title compound was obtained using 1-(2,4-difluorophenyl)piperazine hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0724] 1 H NMR (300 MHz, CDCl 3 )δ10.08(br,1H),7.52-7.48(m,1H),7.20(d,1H,J=8.4Hz),7.05-6.99(m,1H),6.91-6.80(m,3H),6.23(s,1H) ,3.85(t,2H,J=4.7Hz), 3.61(t,2H,J=4.8Hz), 3.00-2.99(m,4H), 2.92(t,2H,J=5.7Hz), 2.76(t,2H,J=5.9Hz).

[0725] <Example 79> Preparation of 4-fluoro-3-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0726]

[0727] The title compound was obtained using 4-fluoro-3-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0728] 1 H NMR (300 MHz, CDCl 3)δ10.46(br,1H),7.54-7.52(m,1H),7.27-7.21(m,2H),7.16-7.00(m,3H),6.29(s,1H),3 .86(m,2H),3.66(m,2H),3.08-3.05(m,4H),2.96(t,2H,J=5.4Hz),2.83(t,2H,J=5.4Hz).

[0729] <Example 80> Preparation of 2-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0730]

[0731] The title compound was obtained using 2-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0732] 1 H NMR (300 MHz, CDCl 3 )δ10.17(br,1H),7.55-7.48(m,1H),7.21(d,1H,J=7.8Hz),7.13-7.10(m,2H),7.05-6.99(m,2H),6.25(s,1H) ,3.85(t,2H,J=5.3Hz), 3.63(t,2H,J=4.8Hz), 3.15-3.12(m,4H), 2.94(t,2H,J=5.9Hz), 2.79(t,2H,J=5.9Hz).

[0733] <Example 81> Preparation of 4-fluoro-2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0734]

[0735] The title compound was obtained using 4-fluoro-2-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0736] 1 H NMR (300 MHz, CDCl 3)δ10.45(br,1H),7.60-7.49(m,2H),7.21(d,1H,J=7.8Hz),7.06-6.99(m,1H),6.76(m,1H),6.64(dd,1H,J=10.8Hz,2.4Hz) ,6.28(s,1H),3.89(t,2H,J=4.7Hz),3.70(t,2H,J=4.7Hz),3.23-3.17(m,4H),2.95(t,2H,J=5.9Hz),2.82(t,2H,J=5.9Hz).

[0737] <Example 82> Preparation of 8-fluoro-3-(3-(4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0738]

[0739] The title compound was obtained using 4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0740] 1 H NMR (300 MHz, CDCl 3 )δ10.22(br,1H),7.54-7.47(m,1H),7.23-6.98(m,6H),6.24(s,1H),5.97-5.90(m,1H),4.31-4.30(m,1H),4 .11(m,1H),3.88(t,1H,J=5.6Hz),3.64(t,1H,J=5.7Hz),2.94-2.92(m,2H),2.83-2.78(m,2H),2.56(m,2H).

[0741] <Example 83> Preparation of 8-fluoro-3-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0742]

[0743] The title compound was obtained using 4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0744] 1 H NMR (300 MHz, DMSO-d 6)δ11.25(br,1H),7.61-7.57(m,1H),7.40-7.23(m,4H),7.12-7.06(m,2H),6.41-6.37(m,1H),6. 28-6.24(m,1H),4.19-4.13(m,2H),3.68(t,2H,J=5.3Hz),2.82-2.74(m,4H),2.50-2.43(m,2H).

[0745] <Example 84> Preparation of 3-fluoro-5-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0746]

[0747] The title compound was obtained using 3-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0748] 1 H NMR (300 MHz, CDCl 3 )δ10.31(br,1H),7.53-7.49(m,1H),7.41(d,1H,J=7.8Hz),7.21(m,3H),7.05-6.97(m,1H),6.26-6.08(m,2H),4.35( m,1H),4.16(m,1H),3.90(t,1H,J=5.6Hz),3.69(t,1H,J=5.6Hz),2.95-2.93(m,2H),2.86-2.78(m,2H),2.52(m,2H).

[0749] <Example 85> Preparation of 8-fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0750]

[0751] The title compound was obtained by using 6-fluoro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0752] 1 H NMR (300 MHz, DMSO-d 6)δ11.25(br,1H),8.28-8.27(m,1H),8.07-8.03(m,1H),7.61-7.55(m,1H),7.32(t,1H,J=7.8Hz),7.20-7.16(m,1H),7.13 -7.02(m,1H),6.41-6.37(m,1H),6.29-6.24(m,1H),4.19-4.14(m,2H),3.69(m,2H),2.82-2.75(m,4H),2.56-2.43(m,2H).

[0753] <Example 86> Preparation of 8-fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0754]

[0755] The title compound was obtained by using 5-fluoro-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0756] 1 H NMR (300 MHz, CDCl 3 )δ10.27(br,1H),8.42-8.39(m,1H),7.54-7.46(m,1H),7.40-7.32(m,2H),7.20(d,1H,J=7.8Hz),7.03-6.96(m,1H),6.53-6.49(m,1H),6.24 (s,1H),4.35(m,1H),4.16(m,1H),3.90(t,1H,J=5.6Hz),3.67(t,1H,J=5.6Hz),2.94(t,2H,J=6.6Hz),2.85-2.76(m,2H),2.70-2.65(m,2H).

[0757] <Example 87> Preparation of 2-fluoro-5-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0758]

[0759] The title compound was obtained using 2-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0760] 1 H NMR (300 MHz, CDCl 3 )δ10.41(br,1H),7.57-7.50(m,3H),7.21-7.16(m,2H),7.04-6.96(m,1H),6.27(s,1H),6.11-5.97(m,1H),4.32(m ,1H),4.14(m,1H),3.89(t,1H,J=5.7Hz),3.69(t,1H,J=5.7Hz),2.95-2.94(m,2H),2.87-2.80(m,2H),2.50(m,2H).

[0761] <Example 88> Preparation of 1′-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile

[0762]

[0763] The title compound was obtained by using 1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0764] 1 H NMR (300 MHz, CDCl 3 )δ10.35(br,1H),8.80(s,1H),7.95-7.90(m,1H),7.51-7.42(m,2H),7.21-7.18(m,1H),7.03-6.95(m,1H),6.82-6.78(m,1H),6 .25(s,1H),4.41(m,1H),4.23(m,1H),3.90(m,1H),3.70-3.67(m,1H),2.95-2.93(m,2H),2.86-2.80(m,2H),2.70-2.64(m,2H).

[0765] <Example 89> Preparation of 8-fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0766]

[0767] The title compound was obtained using 1-(3-fluorophenyl)piperazine hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0768] 1H NMR (300 MHz, CDCl 3 )δ10.68(br,1H),7.55-7.48(m,1H),7.23-7.17(m,1H),7.04-6.98(m,2H),6.66-6.54(m,3H),6.29(s,1H),3 .84(t,2H,J=4.8Hz), 3.64(t,2H,J=4.8Hz), 3.20-3.15(m,4H), 2.96(t,2H,J=6.0Hz), 2.84(t,2H,J=6.0Hz).

[0769] <Example 90> Preparation of 2-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0770]

[0771] The title compound was obtained using 2-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0772] 1 H NMR (300 MHz, CDCl 3 )δ10.70(br,1H),7.57-7.50(m,1H),7.25-7.22(m,1H),7.05-6.98(m,1H),6.86(s,1H),6.83-6.81(m,1H),6.77-6.73( m,1H),6.31(s,1H),3.84(t,2H,J=4.8Hz),3.67(m,2H),3.24-3.23(m,4H),2.97(t,2H,J=6.6Hz),2.86(t,2H,J=6.3Hz).

[0773] <Example 91> Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile hydrochloride

[0774]

[0775] The title compound was obtained by using 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile instead of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile used in Example 68.

[0776] 1H NMR (300 MHz, DMSO-d 6 )δ11.24(br,1H),7.62-7.59(m,3H),7.33(d,1H,J=7.8Hz),7.13-7.06(m,1H),7. 04-7.01(m,2H),6.40(s,1H),3.61(m,4H),3.39-3.34(m,4H),2.76-2.74(m,4H).

[0777] <Example 92> Preparation of 8-fluoro-3-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridyl]-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0778]

[0779] The title compound was obtained using 2'-fluoro-1,2,3,6-tetrahydro-4,4'-bipyridine hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0780] 1 H NMR (300 MHz, CDCl 3 )δ10.22(br,1H),8.17(d,1H,J=4.8Hz),7.50(m,1H),7.19-7.14(m,1H),7.13(d,1H,J=4.8Hz),7.04-7.00(m,1H),6.83(d,1H,J=6.9Hz),6. 38-6.25(m,2H),4.36(m,1H),4.17(m,1H),3.90(t,1H,J=5.1Hz),3.69(t,1H,J=5.1Hz),2.95-2.93(m,2H),2.83-2.79(m,2H),2.53(m,2H).

[0781] <Example 93> Preparation of 1′-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile

[0782]

[0783] The title compound was obtained by using 1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0784] 1 H NMR (300 MHz, CDCl3 )δ10.44(br,1H),8.71(s,1H),7.75-7.65(m,2H),7.51(m,1H),7.21(d,1H,J=5.4Hz),7.03-6.95(m,1H),6.32-6.19(m,2H) ,4.37(m,1H),4.20(m,1H),3.92(t,1H,J=5.3Hz),3.73(t,1H,J=4.8Hz),2.96-2.94(m,2H),2.88-2.82(m,2H),2.56(m,2H).

[0785] <Example 94> Preparation of 4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0786]

[0787] The target compound was obtained by using 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in Step 1 of Example 68.

[0788] 1 H NMR (300 MHz, DMSO-d 6 )δ11.36(br,1H),7.79-7.76(m,1H),7.64-7.54(m,4H),7.02-6.99(m,2H ),6.45(s,1H),3.62-3.61(m,4H),3.78-3.33(m,4H),2.76-2.73(m,4H).

[0789] <Example 95> Preparation of 4-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0790]

[0791] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0792] 1 H NMR (300 MHz, CDCl 3)δ10.65(br,1H),7.99-7.96(m,1H),7.62-7.60(m,2H),7.47-7.40(m,3H),7.36-7.29(m,1H),6.29(s,1H),6.23-6.08(m,1H),4.3 6-4.35(m,1H),4.16-4.15(m,1H),3.92-3.88(m,1H),3.70-3.66(m,1H),2.97-2.96(m,2H),2.86-2.77(m,2H),2.56-2.55(m,2H).

[0793] <Example 96> Preparation of 1′-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile

[0794]

[0795] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0796] 1 H NMR (300 MHz, CDCl 3 )δ10.42(s,1H),8.86(s,1H),8.06-7.96(m,2H),7.47-7.27(m,3H),6.28(s,1H),5.95(s,1H), 4.04-4.03(m,1H),4.19-4.18(m,1H),3.94-3.91(m,1H),3.70-3.66(m,1H),3.01-2.68(m,6H).

[0797] <Example 97> Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile

[0798]

[0799] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 5-(piperazin-1-yl)picolinonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0800] 1 H NMR (300 MHz, DMSO-d 6 )δ11.37(br,1H),8.41-8.40(m,1H),7.78-7.75(m,2H),7.67-7.62(m,1H),7.57-7.5 4(m,1H),7.37-7.33(m,1H),3.63-3.62(m,4H),3.45-3.41(m,4H),2.76-2.73(m,4H).

[0801] <Example 98> Preparation of 2-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0802]

[0803] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0804] 1 H NMR (300 MHz, DMSO-d 6 )δ7.80-7.17(m,2H),7.67-7.55(m,3H),7.15-7.10(m,2H),6.45(s,1H),3.66-3.65(m,4H),3.12-3.10(m,4H),2.78-2.77(m,4H).

[0805] <Example 99> Preparation of 6-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile

[0806]

[0807] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 6-(piperazin-1-yl)nicotinonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0808] 1 H NMR (300 MHz, DMSO-d 6 )δ7.80-7.17(m,2H),7.67-7.55(m,3H),7.15-7.10(m,2H),6.45(s,1H),3.66-3.65(m,4H),3.12-3.10(m,4H),2.78-2.77(m,4H).

[0809] <Example 100> Preparation of 3-fluoro-4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0810]

[0811] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 3-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0812] 1 H NMR (300 MHz, CDCl 3 )δ10.45(br,1H),8.02-7.98(m,1H),7.37-7.34(m,1H),6.90-6.79(m,3H),6.27(s ,3H),3.87-3.84(m,2H),3.60-3.59(m,2H),3.02-2.93(m,6H),2.79-2.75(m,2H).

[0813] <Example 101> Preparation of 2-fluoro-4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0814]

[0815] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0816] 1 H NMR (300 MHz, DMSO-d 6 )δ11.37(br,1H),7.79-7.75(m,1H),7.67-7.54(m,3H),6.96-6.92(m,1H),6.85-6 .83(m,1H),6.44(s,1H),3.61-3.60(m,4H),3.44-3.39(m,4H),2.77-2.76(m,4H).

[0817] <Example 102> Preparation of 7-fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0818]

[0819] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 6-fluoro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0820] 1 H NMR (300 MHz, CDCl 3 )δ10.58(br,1H),8.19-8.16(m,1H),7.99-7.96(m,1H),7.74-7.73(m,1H) ,7.45-7.44(m,1H),7.35-7.34(m,1H),6.92-6.89(m,1H),6.28(s,1H),6.1 0-5.97(m,1H),4.33-4.32(m,1H),4.14-4.13(m,1H),3.92-3.88(m,1H),3 .70-3.67(m,1H),2.97-2.96(m,2H),2.83-2.81(m,2H),2.54-2.53(m,2H).

[0821] <Example 103> Preparation of 7-fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0822]

[0823] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 5-fluoro-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0824] 1 H NMR (300 MHz, CDCl 3 )δ10.83(br,1H),8.41-8.38(m,1H),7.98-7.96(m,1H),7.45-7.30(m,4H),6.50(s,1H),6.30(s,1H),4.36-4.35(m,1 H),4.17-4.16(m,1H),3.89-3.87(m,1H),3.67-3.65(m,1H),2.98-2.96(m,2H),2.83-2.81(m,2H),2.69-2.64(m,2H).

[0825] <Example 104> Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0826]

[0827] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0828] 1 H NMR (300 MHz, CDCl 3)δ10.71(br,1H),7.98-7.96(m,1H),7.44-7.43(m,1H),7.31-7.25(m,3H),7.03-6.97(m,2H),6.29(s,1H),6.01-5.89(m,1H),4.29-4.28(m ,1H),4.14-4.28(m,1H),4.14-4.10(m,1H),3.88-3.87(m,1H),3.65- 3.64(m,1H),2.96-2.95(m,2H),2.80-2.79(m,2H),2.52-2.51(m,2H).

[0829] <Example 105> Preparation of 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

[0830]

[0831] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1-(4-chlorophenyl)piperazine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0832] 1 H NMR (300 MHz, CDCl 3 )δ10.50(br,1H),8.01-7.97(m,1H),7.47-7.42(m,1H),7.37-7.34(m,1H),7.23-7.20(m,2H),6.83-6.80(m,2H ),6.28(s,1H),3.85-3.82(m,2H),3.62-3.59(m,2H),3.15-3.12(m,4H),2.97-2.93(m,2H),2.80-2.76(m,2H).

[0833] <Example 106> Preparation of 3-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

[0834]

[0835] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1-(2,4-difluorophenyl)piperazine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0836] 1 H NMR (300 MHz, CDCl 3 )δ10.45(br,1H),8.02-7.98(m,1H),7.37-7.34(m,1H),6.90-6.79(m,3H),6.27(s ,3H),3.87-3.84(m,2H),3.60-3.59(m,2H),3.02-2.93(m,6H),2.79-2.75(m,2H).

[0837] <Example 107> Preparation of 4-fluoro-3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0838]

[0839] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-fluoro-3-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0840] 1 H NMR (300 MHz, DMSO-d 6 )δ11.39(br,1H),7.79-7.76(m,1H),7.68-7.63(m,1H),7.58-7.38(m,4H ),6.45(s,1H),3.63-3.62(m,4H),3.01-3.02(m,4H),3.76-3.75(m,4H).

[0841] <Example 108> Preparation of 4-fluoro-2-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0842]

[0843] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-fluoro-2-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0844] 1 H NMR (300 MHz, DMSO-d 6 )δ11.39(br,1H),7.81-7.75(m,2H),7.65-7.64(m,1H),7.58-7.55(m,1H),6.98-6 .94(m,2H),6.45(s,1H),3.65-3.64(m,4H),3.16-3.13(m,4H),2.75-2.74(m,4H).

[0845] <Example 109> Preparation of 2-fluoro-5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0846]

[0847] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0848] 1 H NMR (300 MHz, DMSO-d 6 )δ11.38(br,1H),7.78-7.75(m,1H),7.67-7.64(m,1H),7.57-7.55(m,1H),7.39-7 .34(m,3H),6.44(s,1H),3.60-3.59(m,4H),3.13-3.11(m,4H),2.76-2.75(m,4H).

[0849] <Example 110> Preparation of 5-fluoro-2-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0850]

[0851] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 5-fluoro-2-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0852] 1 H NMR (300 MHz, DMSO-d 6 )δ11.39(br,1H),7.78-7.76(m,2H),7.68-7.63(m,1H),7.59-7.49(m,2H),7.20-7 .15(m,1H),6.46(s,1H),3.66-3.65(m,4H),3.05-3.03(m,4H),2.77-2.76(m,4H).

[0853] <Example 111> Preparation of 4-fluoro-3-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0854]

[0855] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0856] 1 H NMR (300 MHz, CDCl 3 )δ10.59(br,1H),8.00-7.97(m,1H),7.56-7.54(m,2H),7.47-7.43(m,1H),7.36-7.34(m,1H),7.19-7.13(m,1H),6.29(s,1H),6.08-5.94(m ,1H),4.34-4.33(m,1H),4.14-4.13(m,1H),3.90-3.88(m,1H),3.68- 3.64(m,1H),2.98-2.96(m,2H),2.85-2.82(m,2H),2.53-2.52(m,2H).

[0857] <Example 112> Preparation of 5-fluoro-2-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0858]

[0859] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0860] 1 H NMR (300 MHz, CDCl 3 )δ10.36(br,1H),8.01-7.98(m,1H),7.47-7.26(m,5H),6.27(s,1H),5.98-5.94(m,1H),4.35-4.34(m,1H),4.1 3-4.12(m,1H),3.94-3.91(m,1H),3.70-3.66(m,1H),2.96-2.95(m,2H),2.82-2.80(m,2H),2.55-2.54(m,2H).

[0861] <Example 113> Preparation of 3-(3-(4-(2,4-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

[0862]

[0863] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(2,4-difluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0864] 1 H NMR (300 MHz, CDCl 3)δ10.56(br,1H),8.01-7.98(m,1H),7.47-7.42(m,1H),7.36-7.33(m,1H),7.19-7.16(m,1H),6.86-6.80(m,2H),6.28(s,1H),5.92-5.85(m ,1H),4.31-4.30(m,1H),4.11-4.10(m,1H),3.88-3.85(m,1H),3.65- 3.61(m,1H),2.98-2.94(m,2H),2.83-2.76(m,2H),2.52-2.51(m,2H).

[0865] <Example 114> Preparation of 3-fluoro-5-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0866]

[0867] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 3-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0868] 1 H NMR (300 MHz, CDCl 3 )δ10.73(br,1H),7.99-7.96(m,1H),7.48-7.26(m,5H),6.31(s,1H),6.21-6.07(m,1H),4.35-4.34(m,1H),4.1 7-4.16(m,1H),3.91-3.88(m,1H),3.71-3.67(m,1H),2.98-2.97(m,2H),2.87-2.79(m,2H),2.51-2.50(m,2H).

[0869] <Example 115> Preparation of 7-fluoro-3-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0870]

[0871] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0872] 1 H NMR (300 MHz, CDCl 3 )δ10.50(br,1H),8.00-7.97(m,1H),7.43-7.41(m,1H),7.32-7.27(m,2H),7.12-7.10(m,1H),7.04-6.93(m,2H),6.27(s,1H),6.12-5.98(m ,1H),4.31-4.30(m,1H),4.11-4.10(m,1H),3.91-3.87(m,1H),3.67- 3.64(m,1H),2.96-2.94(m,2H),2.84-2.75(m,2H),2.55-2.54(m,2H).

[0873] <Example 116> Preparation of (R)-7-fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0874]

[0875] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and (R)-3-(4-fluorophenyl)pyrrolidine was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0876] 1 H NMR (300 MHz, CDCl 3)δ10.55(br,1H),8.01-7.98(m,1H),7.43-7.42(m,1H),7.35-7.29(m,1H),7.17-7.16(m,2H),7.03-6.98(m,2H),6.25(s,1H),4.1 3-4.07(m,1H),3.89-3.77(m,1H),3.61-3.34(m,3H),3.31-3.30(m,2H),2.69-2.68(m,2H),2.34-2.33(m,1H),2.09-1.97(m,1H).

[0877] <Example 117> Preparation of (S)-7-fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0878]

[0879] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and (S)-3-(4-fluorophenyl)pyrrolidine was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0880] 1 H NMR (300 MHz, CDCl 3 )δ10.55(br,1H),8.01-7.98(m,1H),7.43-7.42(m,1H),7.35-7.29(m,1H),7.17-7.16(m,2H),7.03-6.98(m,2H),6.25(s,1H),4.1 3-4.07(m,1H),3.89-3.77(m,1H),3.61-3.34(m,3H),3.31-3.30(m,2H),2.69-2.68(m,2H),2.34-2.33(m,1H),2.09-1.97(m,1H).

[0881] <Example 118> Preparation of 7-fluoro-3-(3-oxo-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[0882]

[0883] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1-(4-(trifluoromethyl)phenyl)piperazine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0884] 1 H NMR (300 MHz, CDCl 3 )δ10.40(br,1H),8.00-7.97(m,1H),7.51-7.30(m,4H),6.92-6.89(m,2H),6.28(s,1H),3.8 5-3.84(m,2H),3.62-3.61(m,2H),3.29-3.27(m,4H),2.93-2.88(m,2H),2.80-2.77(m,2H).

[0885] <Example 119> Preparation of 3-fluoro-5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0886]

[0887] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 3-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0888] 1 H NMR (300 MHz, CDCl 3 )δ10.68(br,1H),7.99-7.96(m,1H),7.48-7.44(m,1H),7.38-7.35(m,1H),6.87-6.73(m,3H),6.31(s ,1H),3.85-3.84(m,2H),3.64-3.63(m,2H),3.24-3.23(m,4H),2.97-2.96(m,2H),2.84-2.80(m,2H).

[0889] <Example 120> Preparation of 7-fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0890]

[0891] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1-(3-fluorophenyl)piperazine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0892] 1 H NMR (300 MHz, CDCl 3 )δ10.66(br,1H),8.01-7.97(m,1H),7.47-7.46(m,1H),7.43-7.16(m,1H),6.67-6.55(m,2H),6.30(s ,3H),3.85-3.84(m,2H),3.82-3.60(m,2H),3.20-3.17(m,4H),2.98-2.94(m,2H),2.82-2.78(m,2H).

[0893] <Example 121> Preparation of 7-fluoro-3-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridyl]-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[0894]

[0895] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2′-fluoro-1,2,3,6-tetrahydro-4,4′-bipyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0896] 1 H NMR (300 MHz, CDCl 3)δ10.66(s,1H),8.16-8.15(m,1H),7.98-7.95(m,1H),7.47-7.42(m,1 H),7.35-7.33(m,1H),7.13-7.12(m,1H),6.84-6.81(m,1H),6.38-6.22 (m,2H),4.37-4.36(m,1H),4.17-4.16(m,1H),3.92-3.88(m,1H),3.71 -3.67(m,1H),2.97-2.96(m,2H),2.86-2.80(m,2H),2.54-2.53(m,2H).

[0897] <Example 122> Preparation of 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0898]

[0899] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68.

[0900] 1 H NMR (300 MHz, CDCl 3 )δ10.82(br,1H),7.53-7.50(m,2H),7.38-7.34(m,1H),6.93-6.82(m,3H),6.36(s,1H),3.84-3.8 3(m,2H),3.68-3.66(m,2H),3.40-3.34(m,4H),3.00-2.98(m,2H),2.89-2.87(m,2H),2.44(s,3H).

[0901] <Example 123> Preparation of 6-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile

[0902]

[0903] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 6-(piperazin-1-yl)nicotinonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0904] 1 H NMR (300 MHz, CDCl 3 )δ10.73(br,1H),8.41(s,1H),7.67-7.64(m,1H),7.35-7.34(m,1H),6.93-6.87(m,1H),6.61-6.58(m,1H ),6.39(s,1H),3.81-3.80(m,4H),3.67-3.64(m,4H),2.99-2.97(m,2H),2.88-2.86(m,2H),2.43(s,3H).

[0905] <Example 124> Preparation of 5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile

[0906]

[0907] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 5-(piperazin-1-yl)picolinonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0908] 1 H NMR (300 MHz, CDCl 3 )δ10.76(br,1H),8.29(s,1H),7.55-7.52(m,1H),7.39-7.35(m,1H),7.07-7.06(m,1H),6.94-6.87(m,1H),6.37(s ,1H),3.87-3.86(m,2H),3.72-3.70(m,2H),3.42-3.41(m,4H),3.20-2.98(m,2H),2.87-2.85(m,2H),2.44(s,3H).

[0909] <Example 125> Preparation of 8-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[0910]

[0911] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0912] 1 H NMR (300 MHz, CDCl 3 )δ10.56(br,1H),7.33-7.27(m,3H),7.03-6.98(m,2H),6.86-6.85(m,1H),6.31(s,1H),6.01-5.89(m,1H),4.28-4.27(m,1H), 4.11-4.10(m,1H),3.89-3.85(m,1H),3.68-3.65(m,1H),2.98-2.96(m,2H),2.87-2.79(m,2H),2.52-2.51(m,2H),2.42(s,3H).

[0913] <Example 126> Preparation of 2-fluoro-4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0914]

[0915] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0916] 1 H NMR (300 MHz, CDCl 3 )δ10.59(br,1H),7.45-7.34(m,2H),6.94-6.87(m,1H),6.62-6.59(m,1H),6.54-6.50(m,1H),6.35(s,1H), 3.86-3.85(m,2H),3.67-3.66(m,2H),3.38-3.37(m,4H),2.99-2.98(m,2H),2.86-2.84(m,2H),2.43(s,3H).

[0917] <Example 127> Preparation of 2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0918]

[0919] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0920] 1 H NMR (300 MHz, CDCl 3 )δ10.69(br,1H),7.60-7.57(m,1H),7.53-7.48(m,1H),7.37-7.33(m,1H),7.09-7.04(m,1H),6.98-6.89(m,2H),6.3 5(s,1H),3.90-3.87(m,2H),3.72-3.70(m,2H),3.17-3.16(m,4H),3.01-2.97(m,2H),2.86-2.82(m,2H),2.43(s,3H).

[0921] <Example 128> Preparation of 3-fluoro-4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0922]

[0923] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 3-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0924] 1 H NMR (300 MHz, CDCl 3)δ10.38(br,1H),7.38-7.20(m,3H),6.95-6.86(m,2H),6.32(s,1H),3.86-3.85(m,2H), 3.64-3.63(m,2H),3.18-3.17(m,4H),2.97-2.96(m,2H),2.83-2.81(m,2H),2.43(s,3H).

[0925] <Example 129> Preparation of 8-fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[0926]

[0927] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 6-fluoro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0928] 1 H NMR (300 MHz, CDCl 3 )δ10.42(br,1H),8.19-8.16(m,1H),7.73-7.72(m,1H),7.34-7.33(m,1H),6.92-6.90(M,2H),6.32(s,1H),6.10-5.97(m,1H),4.32-4.3 1(m,1H),4.14-4.13(m,1H),3.92-3.88(m,1H),3.71-3.68(m,1H),2.99-2.98(m,2H),2.85-2.83(m,2H),2.53-2.52(m,2H),2.42(s,3H).

[0929] <Example 130> Preparation of 8-fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[0930]

[0931] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 5-fluoro-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0932] 1 H NMR (300 MHz, CDCl 3 )δ10.31(br,1H),8.39(s,1H),7.39-7.33(m,2H),6.93-6.87(m,1H),6.52-6.48(m,1H),6.29(s,1H),4.35-4.34(m,1H),4.1 6-4.15(m,1H),3.90-3.88(m,1H),3.66-3.64(m,1H),2.97-2.95(m,2H),2.85-2.81(m,2H),2.70-2.64(m,2H),2.41(s,3H).

[0933] <Example 131> Preparation of 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[0934]

[0935] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1-(4-chlorophenyl)piperazine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0936] 1 H NMR (300 MHz, CDCl 3 )δ10.52(br,1H),7.37-7.33(m,1H),7.23-7.20(m,2H),6.94-6.87(m,1H),6.82-6.80(m,2H),6.32(s,1H), 3.83-3.82(m,2H),3.62-3.61(m,2H),3.12-3.11(m,4H),2.99-2.95(m,2H),2.84-2.80(m,2H),2.42(s,3H).

[0937] <Example 132> Preparation of 3-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[0938]

[0939] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1-(2,4-difluorophenyl)piperazine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0940] 1 H NMR (300 MHz, CDCl 3 )δ10.91(br,1H),7.38-7.33(m,1H),6.94-6.78(m,4H),6.36(s,1H),3.83-3.8 2(m,2H),3.66-3.65(m,2H),2.98-2.96(m,6H),2.88-2.86(m,2H),2.43(s,3H).

[0941] <Example 133> Preparation of 4-fluoro-3-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0942]

[0943] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-fluoro-3-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0944] 1 H NMR (300 MHz, DMSO-d 6 )δ11.39(br,1H),7.47-7.43(m,4H),7.03-6.98(m,1H),6.38(s,1H),3.63-3.62(m,4H),3.03-3.02(m,4H),2.77-2.78(m,4H),2.38(s,3H).

[0945] <Example 134> Preparation of 4-fluoro-2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0946]

[0947] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-fluoro-2-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0948] 1 H NMR (300 MHz, DMSO-d 6 )δ11.30(br,1H),7.84-7.79(m,1H),7.48-7.44(m,1H),7.03-6.94(m,3H),6.3 8(s,1H),3.66-3.65(m,4H),3.19-3.13(m,4H),2.78-2.72(m,4H),2.38(s,3H).

[0949] <Example 135> Preparation of 2-fluoro-5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0950]

[0951] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0952] 1 H NMR (300 MHz, DMSO-d 6 )δ11.28(br,1H),7.47-7.35(m,4H),7.02-6.95(m,1H),6.37(s,1H),3.61-3.60(m,4H),3.17-3.12(m,4H),2.78-2.77(m,4H),2.37(s,3H).

[0953] <Example 136> Preparation of 5-fluoro-2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0954]

[0955] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 5-fluoro-2-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0956] 1 H NMR (300 MHz, CDCl 3 )δ11.30(br,1H),7.78-7.75(m,1H),7.53-7.47(m,2H),7.20-7.18(m,1H),7.03-6.97 (m,1H),6.38(s,1H),3.66(m,4H),3.15-3.06(m,4H),2.78-2.77(m,4H),2.38(s,3H).

[0957] <Example 137> Preparation of 4-fluoro-3-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0958]

[0959] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0960] 1 H NMR (300 MHz, CDCl 3)δ10.49(br,1H),7.55-7.53(m,2H),7.37-7.33(m,1H),7.19-7.12(m,1H),6.95-6.88(m,1H),4.33-4.32(m,1H),4.15-4 .14(m,1H),3.89-3.86(m,1H),3.69-3.65(m,1H),2.99-2.96(m,2H),2.88-2.85(m,2H),2.52-2.51(m,2H),2.43(s,3H).

[0961] <Example 138> Preparation of 8-fluoro-3-(3-(4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[0962]

[0963] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0964] 1 H NMR (300 MHz, CDCl 3 )δ10.14(br,1H),7.39-7.21(m,3H),7.12(d,1H,J=7.8Hz),7.09-7.05(m,1H),6.96-6.89(m,1H),6.29(s,1H),5.97-5.91(m,1H),4.31 (m,1H),4.10(m,1H),3.89(t,1H,J=5.6Hz),3.64(t,1H,J=5.6Hz),2.97(t,2H,J=5.3Hz),2.83-2.76(m,2H),2.56(m,2H),2.43(s,3H).

[0965] <Example 139> Preparation of 2-fluoro-5-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0966]

[0967] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0968] 1 H NMR (300 MHz, CDCl 3 )δ10.39(br,1H),7.58-7.52(m,2H),7.35(m,1H),7.22-7.16(m,1H),6.95-6.87(m,1H),6.32(s,1H),6.11-5.97(m,1H),4.32 (m,1H),4.14(m,1H),3.89(t,1H,J=5.7Hz),3.69(t,1H,J=5.4Hz),2.99(m,2H),2.87-2.79(m,2H),2.51(m,2H),2.43(s,3H).

[0969] <Example 140> Preparation of 1′-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile

[0970]

[0971] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0972] 1 H NMR (300 MHz, CDCl 3)δ10.52(br,1H),8.80(s,1H),7.92-7.89(m,1H),7.51-7.44(m,1H),7.32(m,1H),6.92-6.79(m,2H),6.32(s,1H),4.4 1(m,1H),4.23(m,1H),3.90(m,1H),3.69(m,1H),2.99-2.97(m,2H),2.87-2.85(m,2H),2.69-2.64(m,2H),2.42(s,3H).

[0973] <Example 141> Preparation of 2-fluoro-4-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[0974]

[0975] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0976] 1 H NMR (300 MHz, CDCl 3 )δ10.69(br,1H),7.60-7.55(m,1H),7.34(m,1H),7.22(d,1H,J=8.1Hz),7.17-7.11(m,1H),6.93-6.89(m,1H),6.34(s,1H),6.27-6.13( m,1H),4.35(m,1H),4.19(m,1H),3.88(t,1H,J=4.5Hz),3.70(t,1H,J=4.5Hz),3.00(m,2H),2.89-2.85(m,2H),2.51(m,2H),2.42(s,3H).

[0977] <Example 142> Preparation of 8-fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[0978]

[0979] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1-(3-fluorophenyl)piperazine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0980] 1 H NMR (300 MHz, CDCl 3 )δ11.19(br,1H),7.38-7.34(m,1H),7.20(q,1H,J=7.6Hz),6.94-6.87(m,1H),6.65-6.52(m,3H),6.39(s,1H),3.81( t,2H,J=4.8Hz), 3.66(t,2H,J=4.7Hz), 3.19-3.12(m,4H), 3.01(t,2H,J=6.3Hz), 2.90(t,2H,J=6.3Hz), 2.44(s,3H).

[0981] <Example 143> Preparation of 2-fluoro-5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[0982]

[0983] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0984] 1 H NMR (300 MHz, CDCl 3 )δ11.36(br,1H),7.40-7.36(m,1H),6.94-6.87(m,1H),6.84(s,1H),6.81(d,1H,J=7.8Hz),6.75-6.71(m,1H) ,6.42(s,1H),3.82(m,2H),3.71(m,2H),3.24-3.22(m,4H),3.01-3.00(m,2H),2.96-2.94(m,2H),2.45(s,3H).

[0985] <Example 144> Preparation of 8-fluoro-3-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridyl]-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[0986]

[0987] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2′-fluoro-1,2,3,6-tetrahydro-4,4′-bipyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0988] 1 H NMR (300 MHz, CDCl 3 )δ10.42(br,1H),8.17(d,1H,J=4.5Hz),7.35-7.33(m,1H),7.13(d,1H,J=3.9Hz),6.95-6.88(m,1H),6.82(d,1H,J=8.4Hz),6.38-6.23( m,2H),4.36(m,1H),4.18(m,1H),3.90(t,1H,J=5.4Hz),3.70(t,1H,J=5.6Hz),2.99(m,2H),2.88-2.82(m,2H),2.53(m,2H),2.43(s,3H).

[0989] <Example 145> Preparation of 1′-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile

[0990]

[0991] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0992] 1 H NMR (300 MHz, CDCl 3)δ10.67(br,1H),8.70(s,1H),7.75-7.45(m,2H),7.36-7.34(m,1H),6.93-6.85(m,1H),6.35-6.19(m,2H),4.38(m,1H),4 .22(m,1H),3.92(t,1H,J=5.6Hz),3.74(t,1H,J=5.6Hz),3.01-2.99(m,2H),2.92-2.86(m,2H),2.56(m,2H),2.43(s,3H).

[0993] <Example 146> Preparation of methyl 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzoate

[0994]

[0995] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(piperazin-1-yl)benzoic acid methyl ester hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[0996] 1 H NMR (300 MHz, CDCl 3 )δ10.97(br,1H),7.97-7.91(m,2H),7.38-7.34(m,1H),6.93-6.87(m,1H),6.84-6.81(m,2H),6.37(s,1H),3.87(s,3H),3 .83(t,2H,J=5.1Hz), 3.67(t,2H,J=4.2Hz), 3.34-3.32(m,4H), 3.00(t,2H,J=6.3Hz), 2.88(t,2H,J=6.3Hz), 2.43(s,3H).

[0997] <Example 147> Preparation of 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzoic acid

[0998]

[0999] The target compound was obtained according to Example 19, except that methyl 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzoate was used instead of methyl 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoate used in Example 19.

[1000] 1 H NMR (300 MHz, DMSO-d 6 )δ11.28(br,1H),7.80-7.77(m,2H),7.48-7.44(m,1H),7.03-6.98(m,3H),6.37(s,1H),3.63-3.33(m,8H),2.78(m,4H),2.38(s,3H).

[1001] <Example 148> Preparation of 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile

[1002]

[1003] The target compound was obtained according to Example 68, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1004] 1 H NMR (300 MHz, CDCl 3 )δ11.03(br,1H),7.47-7.44(m,2H),7.34-7.30(m,1H),6.85-6.78(m,1H),6.71-6.68(m,2H),6.37(s,1H),4.9 3(m,1H),4.40(m,1H),3.54-3.50(m,2H),3.14-3.10(m,1H),3.01-2.87(m,5H),2.41(s,3H),2.01-1.79(m,4H).

[1005] <Example 149> Preparation of 4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[1006]

[1007] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68.

[1008] 1 H NMR (300 MHz, DMSO-d 6 )δ11.40(br,1H),7.65-7.59(m,3H),7,44(d,1H,J=9.9Hz),7.03-7.00(m,2 H),6.45(s,1H),3.63-3.62(m,4H),3.33(m,4H),2.79(m,4H),2.47(s,3H).

[1009] <Example 150> Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1010]

[1011] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1012] 1 H NMR (300 MHz, DMSO-d 6 )δ11.42(br,1H),7.65-7.60(m,1H),7.47-7.39(m,3H),7.19-7.14(m,2H),6.45-6.43(m,1H),6.16- 6.10(m,1H),4.17-4.13(m,2H),3.68(t,2H,J=5.4Hz),2.81-2.78(m,4H),2.50(m,2H),2.46(s,3H).

[1013] <Example 151> Preparation of 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile

[1014]

[1015] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 5-(piperazin-1-yl)picolinonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1016] 1 H NMR (300 MHz, DMSO-d 6 )δ11.41(br,1H),8.42(d,1H,J=2.4Hz),7.77(d,1H,J=8.7Hz),7.64(dd,1H,J=9.3Hz,2.4Hz),7.44(dd,1H,J=9.3 Hz, 2.4Hz), 7.36 (dd, 1H, J = 8.7Hz, 3.0Hz), 6.45 (s, 1H), 3.64 (m, 4H), 3.46-3.41 (m, 4H), 2.79 (m, 4H), 2.48 (s, 3H).

[1017] <Example 152> Preparation of 6-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile

[1018]

[1019] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 6-(piperazin-1-yl)nicotinonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1020] 1 H NMR (300 MHz, DMSO-d 6 )δ11.41(br,1H),8.51(s,1H),7.89(d,1H,J=9.3Hz),7.64(d,1H,J=8.7Hz),7.44(d,1H,J =8.7Hz), 6.94 (d, 1H, J = 9.3Hz), 6.46 (s, 1H), 3.71-3.61 (m, 8H), 2.79 (m, 4H), 2.48 (s, 3H).

[1021] <Example 153> Preparation of 2-fluoro-4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[1022]

[1023] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1024] 1 H NMR (300 MHz, DMSO-d 6 )δ11.39(br,1H),7.66-7.60(m,2H),7.44(d,1H,J=9.6Hz),6.95(d,1H,J=13.5Hz),6.84 (d,1H,J=8.7Hz),6.45(s,1H),3.62(m,4H),3.45-3.42(m,4H),2.79(m,4H),2.48(s,3H).

[1025] <Example 154> Preparation of 3-fluoro-4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[1026]

[1027] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 3-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1028] 1 H NMR (300 MHz, DMSO-d 6)δ11.43(br,1H),7.74(d,1H,J=13.2Hz),7.64(d,1H,J=9.6Hz),7.59(d,1H,J=8.7Hz),7.45(d,1 H, J = 9.3Hz), 7.14-7.08 (m, 1H), 6.46 (s, 1H), 3.64 (m, 4H), 3.15 (m, 4H), 2.78 (m, 4H), 2.48 (s, 3H).

[1029] <Example 155> Preparation of 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

[1030]

[1031] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1-(4-chlorophenyl)piperazine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1032] 1 H NMR (300 MHz, DMSO-d 6 )δ11.43(br,1H),7.64(d,1H,J=9.3Hz),7.44(d,1H,J=9.3Hz),7.26-7.23(m,2H),6.9 7-6.94(m,2H),6.45(s,1H),3.61(m,4H),3.12-3.10(m,4H),2.78(m,4H),2.47(s,3H).

[1033] <Example 156> Preparation of 4-fluoro-3-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[1034]

[1035] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-fluoro-3-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1036] 1 H NMR (300 MHz, DMSO-d 6 )δ7.65-7.62(m,1H),7.50-7.39(m,4H),6.46(s,1H),3.63-3.62(m,4H),3.02-3.01(m,4H),2.78-2.77(m,4H),2.50(s,3H).

[1037] <Example 157> Preparation of 4-fluoro-2-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[1038]

[1039] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-fluoro-2-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1040] 1 H NMR (300 MHz, DMSO-d 6 )δ11.42(br,1H),7.84-7.79(m,1H),7.66-7.63(m,1H),7.46-7.43(m,1H),6.99-6.94(m ,2H),6.46(s,1H),3.66-3.65(m,4H),3.17-3.13(m,4H),2.79-2.78(m,4H),2.48(s,3H).

[1041] <Example 158> Preparation of 2-fluoro-5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[1042]

[1043] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1044] 1 H NMR (300 MHz, DMSO-d 6 )δ11.41(br,1H),7.65-7.62(m,1H),7.45-7.34(m,4H),6.44(s,1H),3.61-3.60(m,4H),3.15-3.14(m,4H),2.78-2.77(m,4H),2.47(s,3H).

[1045] <Example 159> Preparation of 5-fluoro-2-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[1046]

[1047] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 5-fluoro-2-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1048] 1 H NMR (300 MHz, CDCl 3 )δ10.71(br,1H),7.88-7.85(m,1H),7.31-7.19(m,3H),6.98-6.93(m,1H),6.37(s,1H),3.89-3.8 8(m,2H),3.67-3.66(m,2H),3.09-3.08(m,4H),2.99-2.97(m,2H),2.83-2.81(m,2H),2.51(s,3H).

[1049] <Example 160> Preparation of 4-fluoro-3-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[1050]

[1051] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1052] 1 H NMR (300 MHz, DMSO-d 6 )δ11.41(br,1H),7.87-7.85(m,2H),7.65-7.60(m,1H),7.49-7.42(m,2H),6.46-6.44(m,1H),6.15-6 .11(m,1H),4.20-4.14(m,2H),3.67-3.66(m,2H),3.22-3.21(m,2H),2.81-2.79(m,4H),2.47(s,3H).

[1053] <Example 161> Preparation of 5-fluoro-2-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[1054]

[1055] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1056] 1 H NMR (300 MHz, CDCl 3 )δ10.54(br,1H),7.88-7.85(m,1H),7.38-7.18(m,4H),6.37(s,1H),5.98-5.94(m,1H),4.35-4.34(m,1H),4.1 5-4.14(m,1H),3.94-3.91(m,1H),3.91-3.67(m,1H),3.01-3.00(m,2H),2.85-2.82(m,2H),2.51-2.50(m,5H).

[1057] <Example 162> Preparation of 3-(3-(4-(2,4-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

[1058]

[1059] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(2,4-difluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile used in step 3 of Example 68.

[1060] 1 H NMR (300 MHz, CDCl 3 )δ10.77(br,1H),7.88-7.85(m,1H),7.20-7.18(m,2H),6.83-6.80(m,2H),6.37(s,1H),6.93-6.85(m,1H),4.31-4.30(m ,1H),4.11-4.10(m,1H),3.87-3.86(m,1H),3.65-3.64(m,1H),3.01-3.00(m,2H),2.83-2.82(m,2H),2.51-2.50(m,5H).

[1061] <Example 163> Preparation of 3-fluoro-5-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[1062]

[1063] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 3-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1064] 1 H NMR (300 MHz, CDCl 3)δ10.53(br,1H),7.86-7.83(m,1H),7.42-7.39(m,1H),7.20-7.17(m,3H),6.36(s,1H),6.21-6.07(m,1H),4.35-4.34(m ,1H),4.15-4.14(m,1H),3.92-3.88(m,1H),3.70-3.66(m,1H),2.99-2.98(m,2H),2.88-2.81(m,2H),2.79-2.78(m,5H).

[1065] <Example 164> Preparation of 7-fluoro-3-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1066]

[1067] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1068] 1 H NMR (300 MHz, CDCl 3 )δ10.53(br,1H),7.86-7.83(m,1H),7.42-7.39(m,2H),7.20-7.17(m,3H),6.36(s,1H),6.21-6.07(m,1H),4.35-4.34(m ,1H),4.15-4.14(m,1H),3.92-3.88(m,1H),3.70-3.66(m,1H),2.99-2.98(m,2H),2.88-2.81(m,2H),2.79-2.78(m,5H).

[1069] <Example 165> Preparation of 1′-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile

[1070]

[1071] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1072] 1 H NMR (300 MHz, CDCl 3 )δ10.37(br,1H),8.80(s,1H),7.92-7.86(m,2H),7.52-7.49(m,1H),7.45-7.42(m,1H),7.21-7.20(m,1H),6.81-6.78(m,1H),6.34(s,1 H),4.43-4.42(m,1H),4.21-4.20(m,1H),3.93-3.92(m,1H),3.67-3.65(m,1H),2.97-2.96(m,2H),2.82-2.80(m,2H),2.78-2.70(m,2H).

[1073] <Example 166> Preparation of 3-fluoro-5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

[1074]

[1075] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 3-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1076] 1 H NMR (300 MHz, CDCl 3 )δ10.32(br,1H),7.88-7.85(m,1H),7.26-7.19(m,1H),6.88-6.74(m,3H),6.35(s,1H),3.86-3.7 9(m,2H),3.76-3.63(m,2H),3.28-3.26(m,4H),2.98-2.96(m,2H),2.79-2.76(m,2H),2.50(s,3H).

[1077] <Example 167> Preparation of 7-fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1078]

[1079] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 1-(3-fluorophenyl)piperazine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1080] 1 H NMR (300 MHz, CDCl 3 )δ10.54(br,1H),7.88-7.85(m,1H),7.21-7.19(m,2H),6.67-6.55(m,3H),6.36(s,1H),3.8 4-3.83(m,2H),3.61-3.60(m,2H),3.18-3.17(m,4H),2.98-2.96(m,2H),2.82-2.80(m,2H).

[1081] <Example 168> Preparation of 7-fluoro-3-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridyl]-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1082]

[1083] The target compound was obtained according to Example 68, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 68, and 2′-fluoro-1,2,3,6-tetrahydro-4,4′-bipyridine hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 3 of Example 68.

[1084] 1 H NMR (300 MHz, CDCl 3)δ10.64(br,1H),8.17-8.16(m,1H),7.86-7.83(m,1H),7.17-7.12(m,2H),6.84-6.80(m,1H),6.37(s,1H),6.37-6.23(m,1H),4.3 6-4.35(m,1H),4.17-4.16(m,1H),3.92-3.89(m,1H),3.71-3.67(m,1H),3.00-2.99(m,2H),2.87-2.78(m,2H),2.53-2.50(m,5H).

[1085] <Example 169> Preparation of 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile hydrochloride

[1086]

[1087] The target compound was obtained according to Example 6, except that 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile was used instead of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile in Example 6.

[1088] 1 H NMR (300 MHz, DMSO-d 6 )δ11.41(br,1H),8.49(d,1H,J=2.4Hz),7.75(d,1H,J=8.7Hz),7.63(dd,1H,J=9.3Hz,2.4Hz),7.44(dd,1H,J=9.3 Hz, 2.4Hz), 7.36 (dd, 1H, J = 8.7Hz, 3.0Hz), 6.45 (s, 1H), 3.64 (m, 4H), 3.46-3.41 (m, 4H), 2.79 (m, 4H), 2.48 (s, 3H).

[1089] <Example 170> Preparation of 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

[1090]

[1091] Step 1: Preparation of tert-butyl 4-(cyclohexanecarbonyl)piperazine-1-carboxylate

[1092]

[1093] After 1-Boc-piperazine (3.5 g, 22.3 mmol) and cyclohexanecarboxylic acid (2.0 g, 15.6 mmol) were dissolved in DMF (52 mL), HBTU (8.9 g, 22.3 mmol) and TEA (10.9 mL, 78.0 mmol) were slowly added dropwise and stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound tert-butyl 4-(cyclohexanecarbonyl)piperazine-1-carboxylate (3.45 g, 75%).

[1094] 1 H NMR (300 MHz, CDCl 3 )δ3.57-3.31(m,8H),2.44-2.41(m,1H),1.79-1.08(m,19H).

[1095] Step 2: Preparation of cyclohexyl(piperazin-1-yl)methanone

[1096]

[1097] 4N HCl (30 mL) was added to tert-butyl 4-(cyclohexanecarbonyl)piperazine-1-carboxylate (3.45 g, 11.64 mmol), and the mixture was stirred for 15 hours. The solid produced during the reaction was filtered and washed with EtOAc to obtain the target compound cyclohexyl(piperazin-1-yl)methanone HCl (2.52 g, 93%).

[1098] 1 H NMR (300 MHz, DMSO-d 6 )δ9.20(br,1H),3.64(m,4H),3.04(m,4H),2.56(m,1H),1.62(m,5H),1.28(m,5H).

[1099] Step 3: Preparation of 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinoline-1(2H)- ketone

[1100]

[1101] 3-(8-Fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid (60 mg, 0.25 mmol) and cyclohexyl(piperazin-1-yl)methanone HCl (89 mg, 0.37 mmol) were dissolved in CH 2 Cl 2(2.5 mL), HBTU (231 mg, 0.61 mmol) and TEA (0.18 mL, 1.27 mmol) were slowly added dropwise and stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one (56 mg, 53%).

[1102] 1 H NMR (300 MHz, CDCl 3 )δ10.54(br,1H),7.54-7.52(m,1H),7.22(d,1H,J=7.8Hz),7.06-6.99(m,1H),6.28(s,1H),3.69-3.62(m,4H),3.52 -3.45(m,4H),2.94(m,2H),2.82(m,2H),2.47-2.43(m,1H),1.80-1.69(m,4H),1.54-1.50(m,2H),1.28-1.19(m,4H).

[1103] <Example 171> Preparation of 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[1104]

[1105] The target compound was obtained according to Example 170, except that 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1106] 1 H NMR (300 MHz, CDCl 3 )δ10.48(br,1H),7.37(m,1H),6.96-6.90(m,1H),6.32(s,1H),3.70-3.62(m,4H),3.51-3.47(m,4H ),2.97(m,2H),2.82(m,2H),2.43(m,4H),1.80(m,2H),1.69(m,2H),1.60(m,2H),1.24-1.19(m,4H).

[1107] <Example 172> Preparation of 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

[1108]

[1109] The target compound was obtained according to Example 170, except that 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1110] 1 H NMR (300 MHz, CDCl 3 )δ10.30(br,1H),8.00-7.97(m,1H),7.47-7.42(m,1H),7.36-7.34(m,1H),6.27(s,1H),3.70-3.63(m,4H),3.52-3.42(m,4H),2.9 3-2.91(m,2H),2.77-2.75(m,2H),2.50-2.41(m,1H),1.81-1.80(m,2H),1.69-1.68(m,2H),1.58-1.54(m,2H),1.27-1.25(m,4H).

[1111] <Example 173> Preparation of 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

[1112]

[1113] The target compound was obtained according to Example 170, except that 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1114] 1 H NMR (300 MHz, CDCl 3 )δ10.45(br,1H),7.87-7.84(m,1H),7.22-7.19(m,1H),6.35(s,1H),3.70-3.61(m,4H),3.50-3.42(m,4H),2.9 6-2.95(m,2H),2.77-2.76(m,2H),2.51-2.50(m,4H),1.81-1.80(m,2H),1.68-1.67(m,2H),1.26-1.25(m,2H).

[1115] <Example 174> Preparation of 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

[1116]

[1117] The target compound was obtained according to Example 170, except that cyclopentanecarboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170.

[1118] 1 H NMR (300 MHz, CDCl 3 )δ10.42(br,1H),7.53-7.52(m,1H),7.22(d,1H,J=8.4Hz),7.06-6.99(m,1H),6.26(s,1H) ,3.69-3.64(m,4H),3.52-3.45(m,4H),2.92-2.80(m,5H),1.81(m,6H),1.23-1.19(m,2H).

[1119] <Example 175> Preparation of 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[1120]

[1121] The target compound was obtained according to Example 170, except that cyclopentanecarboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1122] 1 H NMR (300 MHz, CDCl 3 )δ10.53(br,1H),7.36-7.34(m,1H),6.96-6.70(m,1H),6.32(s,1H),3.68-3.64(m,4H), 3.52-3.47(m,4H),2.97-2.82(m,5H),2.43(s,3H),1.81-1.71(m,6H),1.25-1.19(m,2H).

[1123] <Example 176> Preparation of 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

[1124]

[1125] The target compound was obtained according to Example 170, except that cyclopentanecarboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1126] 1 H NMR (300 MHz, CDCl 3 )δ10.44(br,1H),8.00-7.97(m,1H),7.45-7.43(m,1H),7.37-7.34(m,1H),6.28(s,1H),3.6 9-3.64(m,4H),3.54-3.43(m,4H),2.94-2.89(m,3H),2.79-2.77(m,2H),1.81-1.65(m,8H).

[1127] <Example 177> Preparation of 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

[1128]

[1129] The target compound was obtained according to Example 170, except that cyclopentanecarboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1130] 1 H NMR (300 MHz, CDCl 3 )δ10.35(br,1H),7.88-7.85(m,1H),7.26-7.22(m,1H),6.34(s,1H),3.71-3.65(m,4H), 3.54-3.44(m,4H),2.97-2.95(m,3H),2.78-2.77(m,2H),2.51(s,3H),1.82-1.80(m,8H).

[1131] <Example 178> Preparation of 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

[1132]

[1133] The target compound was obtained according to Example 170, except that cyclobutanecarboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170.

[1134] 1 H NMR (300 MHz, CDCl 3 )δ10.30(br,1H),7.53-7.51(m,1H),7.22-7.19(m,1H),7.06-6.99(m,1H),6.25(s,1H),3.63(m,4H),3.49-3.3 6(m,4H),3.30-3.24(m,1H),2.92(m,2H),2.79-2.78(m,2H),2.40-2.31(m,2H),2.15(m,2H),2.03-1.89(m,2H).

[1135] <Example 179> Preparation of 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[1136]

[1137] The target compound was obtained according to Example 170, except that cyclobutanecarboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1138] 1 H NMR (300 MHz, CDCl 3 )δ10.51(br,1H),7.37(m,1H),6.96-6.90(m,1H),6.32(s,1H),3.63(m,4H),3.49-3.45(m,2H),3.36(m,2H),3.3 0-3.22(m,1H),2.97(m,2H),2.81(m,2H),2.43(s,3H),2.37-2.28(m,2H),2.18-2.15(m,2H),2.03-1.89(m,2H).

[1139] <Example 180> Preparation of 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

[1140]

[1141] The target compound was obtained according to Example 170, except that cyclobutanecarboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1142] 1 H NMR (300 MHz, CDCl 3 )δ10.51(br,1H),7.99-7.96(m,1H),7.47-7.42(m,1H),7.37-7.31(m,1H),6.27(s,1H),3.65-3.61(m,4H),3.42-3.29(m ,4H),3.26-3.24(m,1H),2.94-2.92(m,2H),2.78-2.74(m,2H),2.36-2.30(m,2H),2.17-2.15(m,2H),1.96-1.88(m,2H).

[1143] <Example 181> Preparation of 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

[1144]

[1145] The target compound was obtained according to Example 170, except that cyclobutanecarboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1146] 1 H NMR (300 MHz, CDCl 3 )δ10.41(br,1H),7.87-7.84(m,1H),7.22-7.19(m,1H),6.35(s,1H),3.66-3.61(m,4H),3.42-3.37(m,4H),3.30-3.2 7(m,1H),2.96-2.95(m,2H),2.76-2.75(m,2H),2.51(s,3H),2.37-2.31(m,2H),2.16-2.15(m,2H),2.03-1.88(m,2H).

[1147] <Example 182> Preparation of 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

[1148]

[1149] The title compound was obtained according to Example 170, except that cyclopropyl(piperazin-1-yl)methanone HCl was used instead of cyclohexyl(piperazin-1-yl)methanone HCl used in step 3 of Example 170.

[1150] 1 H NMR (300 MHz, DMSO-d 6 )δ11.22(br,1H),7.62-7.58(m,1H),7.34(d,1H,J=7.8Hz),7.16-7.07(m,1H),6.39( s,1H),3.65(m,2H),3.48-3.44(m,6H),2.73(m,4H),1.98(m,1H),0.73-0.71(m,4H).

[1151] <Example 183> Preparation of 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[1152]

[1153] The target compound was obtained according to Example 170, except that cyclopropyl(piperazin-1-yl)methanone HCl was used instead of cyclohexyl(piperazin-1-yl)methanone HCl, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1154] 1 H NMR (300 MHz, DMSO-d 6 )δ11.26(br,1H),7.46(m,1H),7.02-6.97(m,1H),6.37(s,1H),3.65(m,2H),3.48(m,6H),2.76(m,4H),2.38(s,3H),1.98(m,1H),0.73(m,4H).

[1155] <Example 184> Preparation of 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

[1156]

[1157] The target compound was obtained according to Example 170, except that cyclopropyl(piperazin-1-yl)methanone HCl was used instead of cyclohexyl(piperazin-1-yl)methanone HCl, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1158] 1 H NMR (300 MHz, CDCl 3 )δ10.50(br,1H),8.00-7.97(m,1H),7.43-7.41(m,1H),7.32-7.27(m,2H),7.12-7.10(m,1H),7.04-6.93(m,2H),6.27(s,1H),6.12-5.98(m ,1H),4.31-4.30(m,1H),4.11-4.10(m,1H),3.91-3.87(m,1H),3.67- 3.64(m,1H),2.96-2.94(m,2H),2.84-2.75(m,2H),2.55-2.54(m,2H).

[1159] <Example 185> Preparation of 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

[1160]

[1161] The target compound was obtained according to Example 170, except that cyclopropyl(piperazin-1-yl)methanone HCl was used instead of cyclohexyl(piperazin-1-yl)methanone HCl, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1162] 1 H NMR (300 MHz, CDCl 3 )δ10.55(br,1H),7.87-7.84(m,1H),7.22-7.19(m,1H),6.36(s,1H),3.71-3.46(m,8H),2.98-2.9 6(m,2H),2.81-2.79(m,2H),2.51(s,3H),1.78-1.72(m,1H),1.02-1.01(m,2H),0.83-0.82(m,2H).

[1163] <Example 186> Preparation of 1′-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile

[1164]

[1165] The target compound was obtained according to Example 170, except that isobutyric acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170.

[1166] 1 H NMR (300 MHz, DMSO-d 6 )δ11.23(br,1H),7.63-7.61(m,1H),7.34(d,1H,J=6.0Hz),7.14-7.08(m,1H) ,6.40(s,1H),3.48-3.34(m,8H),2.88(m,1H),2.73(m,4H),1.00-0.98(m,6H).

[1167] <Example 187> Preparation of 8-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1168]

[1169] The target compound was obtained according to Example 170, except that isobutyric acid was used instead of the cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of the 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1170] 1 H NMR (300 MHz, CDCl 3 )δ10.57(br,1H),7.39-7.35(m,1H),6.96-6.90(m,1H),6.33(s,1H),3.70-3.64(m,4H ),3.53-3.47(m,4H),2.98-2.96(m,2H),2.83(m,3H),2.43(m,3H),1.15-1.13(m,6H).

[1171] <Example 188> Preparation of 7-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

[1172]

[1173] The target compound was obtained according to Example 170, except that isobutyric acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1174] 1 H NMR (300 MHz, CDCl 3 )δ10.49(br,1H),7.99-7.96(m,1H),7.47-7.45(m,1H),7.43-7.36(m,1H),6.28(s,1H),3.7 0-3.63(m,4H),3.51-3.44(m,4H),2.94-2.93(m,2H),2.78-2.77(m,3H),1.14-1.12(m,6H).

[1175] <Example 189> Preparation of 7-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1176]

[1177] The target compound was obtained according to Example 170, except that isobutyric acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1178] 1 H NMR (300 MHz, CDCl 3 )δ10.49(br,1H),7.87-7.83(m,1H),7.21-7.18(m,1H),6.25(s,1H),3.70-3.63(m,4H), 3.51-3.43(m,4H),2.97-2.95(m,2H),2.77-2.76(m,3H),1.59(s,3H),1.14-1.12(m,6H).

[1179] <Example 190> Preparation of 8-fluoro-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[1180]

[1181] The target compound was obtained according to Example 170, except that tetrahydrofuran-2-carboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170.

[1182] 1 H NMR (300 MHz, CDCl 3 )δ10.57(br,1H),7.57-7.50(m,1H),7.25-7.22(m,1H),7.06-6.99(m,1H),6.34-6.31(m,1H),4.63-4.5 5(m,1H),3.94-3.73(m,6H),3.25-3.21(m,4H),2.94-2.92(m,2H),2.85-2.82(m,2H),2.04-1.95(m,4H).

[1183] <Example 191> Preparation of 8-fluoro-5-methyl-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[1184]

[1185] The target compound was obtained according to Example 170, except that tetrahydrofuran-2-carboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1186] 1 H NMR (300 MHz, CDCl 3 )δ10.72(br,1H),7.39-7.35(m,1H),6.97-6.90(m,1H),6.35(s,1H),4.62-4.58(m,1H),3.94-3.7 8(m,6H),3.59-3.47(m,4H),2.98-2.96(m,2H),2.86-2.84(m,2H),2.43(s,3H),2.00-1.94(m,4H).

[1187] <Example 192> Preparation of 7-fluoro-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[1188]

[1189] The target compound was obtained according to Example 170, except that tetrahydrofuran-2-carboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1190] 1 H NMR (300 MHz, CDCl 3 )δ10.45(s,1H),8.00-7.97(m,1H),7.47-7.45(m,1H),7.44-7.31(m,1H),6.30(s,1H),4.61-4.55(m,1H),3.9 3-3.79(m,4H),3.58-3.46(m,4H),2.94-2.93(m,2H),2.78-2.76(m,2H),2.31-2.96(m,2H),2.04-1.94(m,4H).

[1191] <Example 193> Preparation of 7-fluoro-5-methyl-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[1192]

[1193] The target compound was obtained according to Example 170, except that tetrahydrofuran-2-carboxylic acid was used instead of cyclohexanecarboxylic acid used in step 1 of Example 170, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid used in step 3 of Example 170.

[1194] 1 H NMR (300 MHz, CDCl 3 )δ10.45(s,1H),8.00-7.97(m,1H),7.46-7.41(m,1H),6.30(s,1H),4.61-4.55(m,1H),3.93-3.79(m ,4H),3.58-3.46(m,4H),2.94-2.93(m,2H),2.78-2.76(m,2H),2.31-2.36(m,5H),2.04-1.94(m,4H).

[1195] <Example 194> Preparation of 3-(3-(4-(L-alanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one hydrochloride

[1196]

[1197] Step 1: Preparation of 4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazine-1-carboxylic acid Tert-butyl ester

[1198]

[1199] 3-(8-Fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid (300 mg, 1.20 mmol), Boc-piperazine (336 mg, 1.80 mmol) and TBTU (928 mg, 2.88 mmol) were dissolved in CH 2 Cl 2 (12.0 mL), TEA (0.84 mL, 6.0 mmol) was slowly added dropwise to the reaction solution, and then stirred at room temperature for 19 hours. The reaction solution was diluted with EtOAc and washed with water, and the organic solvent was purified by anhydrous MgSO 4 Dried, filtered, and then concentrated by evaporation under reduced pressure.The resulting residue was separated and purified by silica gel chromatography to obtain the target compound (440 mg, 88%).

[1200] 1 H NMR (300 MHz, CDCl 3 )δ10.44(br,1H),7.38-7.33(m,1H),6.96-6.89(m,1H),6.31(s,1H),3.65-3.57(m,4H),3.50-3.44(m,8H),2.43(s,3H),1.47(s,9H).

[1201] Step 2: Preparation of 8-fluoro-5-methyl-3-(3-oxo-3-(piperazin-1-yl)propyl)isoquinolin-1(2H)-one

[1202]

[1203] 4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazine-1-carboxylic acid tert-butyl ester (44 mg, 1.05 mmol) was dissolved in 4N HCl / dihydroisoquinolin-3-yl. After adding 2-nitropropane (3 mL), the mixture was stirred at room temperature for 16 hours. The solid generated during the reaction was filtered to obtain the target compound 8-fluoro-5-methyl-3-(3-oxo-3-(piperazin-1-yl)propyl)isoquinolin-1(2H)-one (304 mg, 82%).

[1204] 1 H NMR (300 MHz, DMSO-d 6)δ11.26(br,1H),7.47(s,1H),7.03-6.97(m,1H),6.37(s,1H),3.71(m,8H),3.10-3.02(m,4H),2.76(s,3H).

[1205] Step 3: Preparation of (S)-(1-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl) tert-Butyl piperazine-1-yl)-1-oxopropan-2-yl)carbamate

[1206]

[1207] 8-Fluoro-5-methyl-3-(3-oxo-3-(piperazin-1-yl)propyl)isoquinolin-1(2H)-one (100 mg, 0.28 mmol), N-Boc-L-alanine (80 mg, 0.42 mmol) and TBTU (218 mg, 0.67 mmol) were dissolved in CH 2 Cl 2 (3.0 mL), TEA (0.2 mL, 1.4 mmol) was slowly added dropwise and stirred at room temperature for 17 hours. The reaction solution was diluted with EtOAc and washed with water, and the organic solvent was washed with anhydrous MgSO 4 The mixture was dried, filtered, and then concentrated by evaporation under reduced pressure. The resulting residue was separated and purified by silica gel chromatography to obtain the target compound (S)-tert-butyl (1-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate (59 mg, 43%).

[1208] 1 H NMR (300 MHz, CDCl 3 )δ11.51(br,1H),7.42-7.38(m,1H),7.00-6.93(m,1H),6.43(s,1H),4.62(m,1H), 3.79-3.51(m,8H),3.03-2.94(m,4H),2.46(s,3H),1.45(s,9H),1.33-1.23(m,3H).

[1209] Step 4: Preparation of 3-(3-(4-(L-alanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinoline-1 (2H)-Ketohydrochloride

[1210]

[1211] 4N HCl / di 3-(3-(4-(L-alanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one hydrochloride (40 mg, 78%) was obtained.

[1212] 1 H NMR (300 MHz, DMSO-d 6 )δ11.27(br,1H),8.20(br,2H),7.47(m,1H),7.04-6.97(m,1H),6.38(s,1 H),4.40(m,1H),3.60-3.34(m,8H),2.78(m,4H),2.39(s,3H),1.31(m,3H).

[1213] <Example 195> Preparation of 3-(3-(4-(L-phenylalanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[1214]

[1215] The target compound was obtained according to Example 194, except that N-Boc-L-phenylalanine was used instead of N-Boc-L-alanine used in step 3 of Example 194.

[1216] 1 H NMR (300 MHz, DMSO-d 6 )δ11.26(br,1H),8.29(br,2H),7.48(m,1H),7.34-7.23(m,5H),7.05-6.98(m,1H),6.35(s,1 H),4.66(m,1H),3.57-3.35(m,8H),3.05(m,1H),2.96-2.93(m,1H),2.72(m,4H),2.38(s,3H).

[1217] <Example 196> Preparation of 8-fluoro-5-methyl-3-(3-oxo-3-(4-propylpiperazin-1-yl)propyl)isoquinolin-1(2H)-one

[1218]

[1219] The target compound was obtained according to Example 194, except that N-Boc-L-proline was used instead of N-Boc-L-alanine used in step 3 of Example 194.

[1220] 1 H NMR (300 MHz, DMSO-d 6 )δ11.29(br,1H),9.85(br,1H),7.50-7.46(m,1H),7.04-6.98(m,1H),6.38(s,1H),4.6 0(m,1H),4.04(m,8H),3.23-3.18(m,2H),2.78(m,4H),2.39(s,3H),1.93-1.76(m,4H).

[1221] <Example 197> Preparation of 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile

[1222]

[1223] Step 1: Preparation of tert-butyl 3-(4-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[1224]

[1225] After dissolving tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 3.77 mmol) and 4-bromobenzonitrile (824 mg, 4.52 mmol) in toluene (13 mL), Pd(OAc) was added. 2 (42 mg, 0.2 mmol), XPhos (90 mg, 0.2 mmol) and Cs 2 CO 3 (1.5 g, 4.52 mmol). The mixture was stirred at 100°C for 15 hours and cooled to room temperature. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered, and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (845 mg, 71%).

[1226] 1 H NMR (300 MHz, CDCl 3)δ7.49(d,J=8.4Hz,2H),6.78(d,J=8.4Hz,2H),4.39(m,2H),3.48(d,J=11.1 Hz, 2H), 3.11 (m, 2H), 2.05-1.97 (m, 2H), 1.78 (d, J = 6.9Hz, 2H), 1.48 (s, 9H).

[1227] Step 2: Preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile 2HCl

[1228]

[1229] 4N HCl / di 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (845 mg, 2.7 mmol) was added with 1% oxane (10 mL), and the mixture was stirred for 15 hours. The solid produced during the reaction was filtered and washed with EtOAc to obtain the target compound 4-(3,8-diazabicyclo[3.2.1]octane-3-yl)benzonitrile 2HCl (645 mg, 83%).

[1230] 1 H NMR (300 MHz, DMSO-d 6 )δ9.34(br,2H),7.63(d,J=6.9Hz,2H),7.01(d,J=7.5Hz,2H),4.15(m,2H),3.80(d,J=12.9Hz,2H),3.20(d,J=12.3Hz,2H),1.95-1.86(m,4H).

[1231] Step 3: Preparation of methyl 2-bromo-6-fluoro-3-methylbenzoate

[1232]

[1233] After dissolving 2-bromo-6-fluoro-3-methylbenzoic acid (99 g, 424.83 mmol) in DMF (1.2 L), K 2 CO 3 (176.2 g, 1.27 mol) and stirred for 30 minutes. MeI (56 mL, 849.67 mmol) was slowly added dropwise to the reaction solution at 0°C, and then stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with Na 2 S 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound methyl 2-bromo-6-fluoro-3-methylbenzoate (93 g, 89%).

[1234] 1 H NMR (300 MHz, CDCl 3 )δ7.29-7.24(m,1H),7.03-6.97(m,1H),3.97(s,3H),2.39(s,3H).

[1235] Step 4: Preparation of methyl 6-fluoro-2-(5-hydroxypent-1-yn-1-yl)-3-methylbenzoate

[1236]

[1237] Methyl 2-bromo-6-fluoro-3-methylbenzoate (72 g, 291.43 mmol) was dissolved in CH 3 CN (970 mL) was then added with pent-4-yn-1-ol (41 mL, 437.14 mmol), Pd(PPh 3 ) 2 Cl 2 (10.2 g, 14.57 mmol) and CuI (5.6 g, 29.14 mmol). TEA (162 mL, 1.16 mol) was added dropwise, and the mixture was stirred at 80°C for 15 hours and then cooled to room temperature. The reaction solution was diluted with EtOAc and washed with NH 4 The organic solvent was washed with MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound methyl 6-fluoro-2-(5-hydroxypent-1-yn-1-yl)-3-methylbenzoate (13 g, 18%).

[1238] 1 H NMR (300 MHz, CDCl 3 )δ7.27-7.19(m,1H),6.97-6.91(m,1H),3.95(s,3H),3.83-3.81(m,2H),2.60(t,J=6.3Hz,2H),2.38(s,3H),1.90-1.84(m,2H).

[1239] Step 5: Preparation of 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one

[1240]

[1241] Methyl 6-fluoro-2-(5-hydroxypent-1-yn-1-yl)-3-methylbenzoate (13 g, 51.94 mmol) was dissolved in THF / MeOH / H 2 O (230 mL / 60 mL / 60 mL), then add LiOH·H 2 O (13.1 g, 311.66 mmol) and stirred at room temperature for 15 hours. The reaction solution was concentrated by distillation under reduced pressure, then diluted with EtOAc, and 6N HCl was slowly added dropwise to adjust the pH to 1-2. The organic solvent was purified by MgSO 4 The reaction mixture was dried, filtered, and then concentrated by evaporation under reduced pressure. After the concentrated reaction solution was dissolved in acetone (260 mL), AgNO was added dropwise. 3 (3.24 g, 10.39 mmol). The reaction solution was stirred at room temperature for 15 hours and then distilled under reduced pressure to remove the solvent. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one (9.9 g, 81%).

[1242] 1 H NMR (300 MHz, CDCl 3 )δ7.48-7.44(m,1H),7.05-6.99(m,1H),6.35(s,1H),3.75(m,2H),2.70-2.65(m,2H),2.40(s,3H),2.03-1.97(m,2H).

[1243] Step 6: Preparation of 8-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one

[1244]

[1245] 8-Fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one (4.1 g, 17.55 mmol) was dissolved in 7N NH 3 / MeOH (100 mL), the mixture was stirred at 80°C for 15 hours. The reaction solution was cooled to room temperature, and the product thus obtained was concentrated by evaporation under reduced pressure. The obtained solid was recrystallized from MeOH to obtain the target compound 8-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.2 g, 78%).

[1246] 1 H NMR (300 MHz, DMSO-d 6)δ11.27(br,1H),7.48-7.44(m,1H),7.02-6.96(m,1H),6.31(s,1H),4.57 (br,1H),3.44(m,2H),2.56-2.50(m,2H),2.38(s,3H),1.82-1.75(m,2H).

[1247] Step 7: Preparation of 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate

[1248]

[1249] After 8-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.2 g, 13.6 mmol) was dissolved in DMF (68 mL), the mixture was cooled to 0° C. MsCl (1.37 mL, 17.68 mmol) and TEA (2.84 mL, 20.4 mmol) were slowly added dropwise at 0° C., followed by stirring at 25° C. for 15 hours. The reaction solution was diluted with EtOAc and washed with NH 4 The organic solvent was washed with MgSO 4 Dried, filtered, then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to obtain the target compound, 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (2.28 g, 54%).

[1250] 1 H NMR (300 MHz, DMSO-d 6 )δ11.36(br,1H),7.49-7.45(m,1H),7.04-6.98(m,1H),6.36(s,1H),4.23(t,J= 6.6Hz, 2H), 3.19 (s, 3H), 2.61 (t, J = 7.8Hz, 2H), 2.39 (m, 3H), 2.10-2.00 (m, 2H).

[1251] Step 8: Preparation of 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-dihydroisoquinolin-3-yl)propyl Azabicyclo[3.2.1]octan-3-yl)benzonitrile

[1252]

[1253] 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (0.1 g, 0.032 mmol) was dissolved in CH 3 CN (20 mL), and then 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile 2HCl (0.13 g, 0.45 mmol) was added at 25°C. NaHCO 3(134 mg, 1.6 mmol) and NaI (96 mg, 0.64 mmol), and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and NaS 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4 Dry, filter and then concentrate by evaporation under reduced pressure, and the resulting residue was recrystallized from MeOH to obtain the target compound 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile (10 mg, 7%).

[1254] 1 H NMR (300 MHz, CDCl 3 )δ11.46(br,1H),7.48-7.45(m,2H),7.36-7.35(m,1H),6.94-6.90(m,1H),6.79-6.76(m,2H),6.27(s,1H), 3.47-3.41(m,4H),2.78-2.74(m,2H),2.59-2.55(m,2H),2.42(s,3H),2.07-1.76(m,6H),1.57-1.56(m,2H).

[1255] <Example 198> Preparation of 8-fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5-methylisoquinolin-1(2H)-one

[1256]

[1257] The target compound was obtained according to Example 197, except that 1-bromo-4-fluorobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 197.

[1258] 1 H NMR (300 MHz, CDCl 3 )δ11.51(br,1H),7.35-7.31(m,1H),6.96-6.87(m,3H),6.79-6.74(m,2H),6.27(s,1H),3.36-3.24(m,4H), 2.77-2.72(m,2H),2.58-2.55(m,2H),2.42(s,3H),2.04-2.03(m,2H),1.93-1.87(m,4H),1.65-1.64(m,2H).

[1259] <Example 199> Preparation of 6-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1260]

[1261] The target compound was obtained according to Example 197, except that 6-bromonicotinonitrile was used instead of 4-bromobenzonitrile used in step 1 of Example 197.

[1262] 1 H NMR (300 MHz, CDCl 3 )δ8.39-8.38(m,1H),7.60-7.57(m,1H),7.34-7.33(m,1H),6.93-6.87(m,1H),6.54-6.52(m,1H),6.28(s,1H),3.97-3.96(m,2H) ,3.56-3.46(m,4H),2.79-2.78(m,2H),2.56-2.55(m,2H),2.43(s,3H),2.04-2.03(m,2H),1.92-1.91(m,2H),1.70-1.68(m,2H).

[1263] <Example 200> Preparation of 5-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)picolinonitrile

[1264]

[1265] The target compound was obtained according to Example 197, except that 5-bromopicolinonitrile was used instead of 4-bromobenzonitrile used in step 1 of Example 197.

[1266] 1 H NMR (300 MHz, DMSO-d 6 )δ11.43(br,1H),8.13(s,1H),7.83-7.74(m,2H),7.45-7.42(m,1H),7.00-6.96(m,1H),6.34(s,1H),3.53- 3.50(m,2H),3.38-3.36(m,2H),3.00-2.97(m,2H),2.60-2.38(m,5H),1.88-1.82(m,4H),1.63-1.61(m,2H).

[1267] <Example 201> Preparation of 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[1268]

[1269] The target compound was obtained according to Example 197, except that 1-bromo-4-chlorobenzene was used instead of 4-bromobenzonitrile used in step 1 of Example 197.

[1270] 1 H NMR (300 MHz, CDCl 3 )δ11.42(s,1H),7.35-7.33(m,1H),7.17-7.14(m,2H),6.39-6.89(m,1H),6.75-6.72(m,2H),6.26(s,1H),3 .44-3.25(m,6H),2.76-2.72(m,2H),2.58-2.54(m,2H),2.42(s,3H),2.04-2.03(m,2H),1.92-1.82(m,4H).

[1271] <Example 202> Preparation of 8-fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5-methylisoquinolin-1(2H)-one

[1272]

[1273] The title compound was obtained according to Example 197, except that 5-bromo-2-fluoropyridine was used instead of 4-bromobenzonitrile used in step 1 of Example 197.

[1274] 1 H NMR (300 MHz, CDCl 3 )δ11.46(br,1H),7.71-7.70(m,1H),7.36-7.31(m,1H),7.23-7.22(m,1H),6.93-6.87(m,1H),6.81-6.77(m,1H),6.26(s,1H), 3.46-3.45(m,2H),3.34-3.33(m,4H),2.78-2.73(m,2H),2.58-2.54(m,2H),2.42(s,3H),2.07-2.04(m,2H),1.92-1.84(m,4H).

[1275] <Example 203> Preparation of 6-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1276]

[1277] The target compound was obtained according to Example 197, except that 6-bromonicotinonitrile was used instead of 4-bromobenzonitrile used in step 1 of Example 197, and 2-bromo-6-fluorobenzoic acid was used instead of 2-bromo-6-fluoro-3-methylbenzoic acid used in step 3 of Example 197.

[1278] 1 H NMR (300 MHz, DMSO-d 6 )δ11.26(br,1H),8.46(s,1H),7.84-7.81(m,1H),7.64-7.57(m,1H),7.36-7.34(m,1H),7.12-7.06(m,1H),6.80-6.77(m,1H),6 .36(s,1H),3.90(m,2H),3.31(m,2H),3.04-3.00(m,2H),2.38-2.24(m,2H),1.83(m,2H),1.68-1.66(m,2H),1.46-1.44(m,4H).

[1279] <Example 204> Preparation of 6-(8-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1280]

[1281] The target compound was obtained according to Example 197, except that 6-bromonicotinonitrile was used instead of 4-bromobenzonitrile used in step 1 of Example 197, and 2-bromo-5-fluorobenzoic acid was used instead of 2-bromo-6-fluoro-3-methylbenzoic acid used in step 3 of Example 197.

[1282] 1 H NMR (300 MHz, DMSO-d 6)δ11.57(br,1H),8.47(d,1H,J=1.8Hz),7.85-7.81(m,1H),7.78-7.74(m,1H),7.69-7.64(m,1H),7.59-7.52(m,1H),6.80(d,1H,J=9.3Hz ),6.43(s,1H),3.91(m,2H),3.34(m,2H),3.10-3.06(m,2H),2.62-2.57(m,2H),2.42-2.37(m,2H),1.84-1.79(m,4H),1.48-1.46(m,2H).

[1283] <Example 205> Preparation of 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1284]

[1285] Step 1: Preparation of methyl 5-fluoro-2-hydroxy-3-methylbenzoate

[1286]

[1287] After 5-fluoro-2-hydroxy-3-methylbenzaldehyde (24 g, 155.7 mmol) and NH 2 SO 3 H (22.7 g, 622.8 mmol) was dissolved in di After 1.9 L of oxane, NaH 2 PO 4 H 2 O aqueous solution (0.25 M, 630 mL), and NaClO was added dropwise at 0 °C 2 Aqueous solution (2M, 80 mL). The mixture was stirred at 0°C for 30 minutes, then Na 2 SO 3 The reaction solution was diluted with EtOAc and washed with 1N HCl and water, and the organic solvent was washed with anhydrous MgSO 4 The mixture was dried, filtered, and then concentrated by evaporation under reduced pressure to obtain a mixed solution of 5-fluoro-2-hydroxy-3-methylbenzoic acid (26 g, 100%). The mixed solution was diluted with methanol (1 L), and sulfuric acid (60 mL) was slowly added dropwise and refluxed for 15 hours. The reaction solution was cooled to room temperature, diluted with EtOAc, and then washed with water. The organic solvent was purified by anhydrous MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure to obtain the target compound methyl 5-fluoro-2-hydroxy-3-methylbenzoate (31.28 g, 58%).

[1288] 1 H NMR (300 MHz, CDCl 3 )δ10.78(s,1H),7.35-7.33(m,1H),7.09-7.06(m,1H),3.94(s,3H),2.26(s,3H).

[1289] Step 2: Preparation of methyl 5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

[1290]

[1291] Methyl 5-fluoro-2-hydroxy-3-methylbenzoate (1.0 g, 5.43 mmol) was added to CH 2 Cl 2 (1L), and Tf 2 O (2.3 g, 8.15 mmol). The mixture was stirred for 10 minutes, and TEA (1.1 g, 10.86 mmol) was added dropwise, and then stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water, and the organic solvent was purified by anhydrous MgSO 4 Dried, filtered, and then concentrated by evaporation under reduced pressure. The resulting residue was separated and purified by silica gel chromatography to obtain the target compound methyl 5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (1.5 g, 87%).

[1292] 1 H NMR (300 MHz, CDCl 3 )δ7.53-7.52(m,1H),7.20-7.17(m,1H),3.94(s,3H),2.43(s,3H).

[1293] Step 3: Preparation of methyl 5-fluoro-2-(5-hydroxypent-1-yn-1-yl)-3-methylbenzoate

[1294]

[1295] Methyl 5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (52 g, 164.4 mmol) was dissolved in CH 3 CN (822 mL), then added pent-4-yn-1-ol (16.6 g, 197.28 mmol), Pd(PPh 3 ) 2 Cl 2(5.77 g, 8.22 mmol) and CuI (1.57 g, 8.22 mmol). TEA (50.0 g, 493.2 mmol) was added dropwise, and the mixture was stirred at 80°C for 15 hours and then cooled to room temperature. The reaction solution was diluted with EtOAc and washed with NH 4 The organic solvent was washed with MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound methyl 5-fluoro-2-(5-hydroxypent-1-yn-1-yl)-3-methylbenzoate (24.35 g, 59%).

[1296] 1 H NMR (300 MHz, CDCl 3 )δ7.41(d,J=9.0Hz,1H),7.10(d,J=8.7Hz,1H),3.91(s,3H),3.88-3.86(m, 2H), 2.66 (t, J = 6.9 Hz, 2H), 2.46 (s, 3H), 2.08 (m, 1H), 1.90 (t, J = 6.0 Hz, 2H).

[1297] Step 4: Preparation of 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one

[1298]

[1299] Methyl 5-fluoro-2-(5-hydroxypent-1-yn-1-yl)-3-methylbenzoate (24.35 g, 97.3 mmol) was dissolved in THF / MeOH / H 2 O (320 mL / 80 mL / 80 mL), then add LiOH·H 2 O (20.4 g, 486.5 mmol) and stirred at room temperature for 15 hours. The reaction solution was concentrated by distillation under reduced pressure, then diluted with EtOAc, and 6N HCl was slowly added dropwise to adjust the pH to 1-2. The organic solvent was purified by MgSO 4 The reaction mixture was dried, filtered, and then concentrated by evaporation under reduced pressure. After the concentrated reaction solution was dissolved in acetone (486 mL), AgNO was added. 3 (6.1 g, 19.46 mmol). The reaction solution was stirred at room temperature for 15 hours and then distilled under reduced pressure to remove the solvent. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one (8.3 g, 36%).

[1300] 1 H NMR (300 MHz, CDCl 3 )δ7.76(d,J=8.4Hz,1H),7.28-7.24(m,1H),6.38(s,1H),3.75(t,J=6.0Hz,2H),2.68(t,J=7.5Hz,2H),2.47(s,3H),2.01-1.94(m,2H).

[1301] Step 5: Preparation of 7-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one

[1302]

[1303] 7-Fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one (5.5 g, 23.28 mmol) was dissolved in 7N NH 3 / MeOH (33 mL), the mixture was stirred at 80°C for 15 hours. The reaction solution was cooled to room temperature, and the product thus obtained was concentrated by evaporation under reduced pressure. The obtained solid was recrystallized from MeOH to obtain the target compound 7-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.9 g, 71%).

[1304] 1 H NMR (300 MHz, DMSO-d 6 )δ7.53(d,J=9.3Hz,1H),7.32(d,J=9.3Hz,1H),6.27(s,1H),4.50(br,1H), 4.05-4.03(m,1H),3.06-3.05(m,2H),2.46-2.36(m,5H),1.71-1.64(m,2H).

[1305] Step 6: Preparation of 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate

[1306]

[1307] After 7-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.9 g, 16.58 mmol) was dissolved in DMF (83 mL), the mixture was cooled to 0° C. MsCl (1.7 mL, 21.55 mmol) and TEA (3.5 mL, 24.87 mmol) were slowly added dropwise at 0° C., followed by stirring at room temperature for 15 hours. The reaction solution was diluted with EtOAc and NH 4 The organic solvent was washed with MgSO 4Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized with MeOH to obtain the target compound, 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (4.42 g, 85%).

[1308] 1 H NMR (300 MHz, CDCl 3 )δ11.63(br,1H),7.86(d,J=9.0Hz,1H),7.25(d,J=9.0Hz,1H),6.49(s,1H),4.3 5(t,J=5.7Hz,2H),3.05(s,3H),2.84(t,J=5.7Hz,2H),2.54(s,3H),2.27(m,2H).

[1309] Step 7: Preparation of 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-dihydroisoquinolin-3-yl)propyl Azabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1310]

[1311] 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (100 mg, 0.32 mmol) was dissolved in CH 3 CN (3.2 mL), and then 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile 3HCl (134 mg, 0.41 mmol) was added dropwise at 25°C. 2 CO 3 (169 mg, 1.59 mmol) and NaI (143 mg, 0.96 mmol), and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and Na 2 S 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4 Dry, filter and then concentrate by evaporation under reduced pressure, and the resulting residue was recrystallized from MeOH to obtain the target compound 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile (9.4 mg, 7%).

[1312] 1 H NMR (300 MHz, DMSO-d 6)δ11.63(br,1H),8.47(d,1H,J=1.8Hz),7.84-7.82(m,1H),7.64-7.61(m,1H),7.46-7.43(m,1H),6.80(d,1H,J=9.3Hz),6.43(s,1H ),3.92(m,2H),3.34(m,2H),3.10-3.06(m,2H),2.63-2.60(m,2H),2.49(s,3H),2.40(m,2H),1.84-1.82(m,4H),1.48-1.46(m,2H).

[1313] <Example 206> Preparation of 6-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1314]

[1315] Step 1: Preparation of 3-(8-fluoro-1-oxo-1H-isochromen-3-yl)propanoic acid

[1316]

[1317] After 8-fluoro-3-(3-hydroxypropyl)-1H-isochromene-1-one (10.0 g, 42.33 mmol) was dissolved in acetone (420 mL), 2.5 M Jones reagent (68 mL) was slowly added dropwise at 0°C. The reaction solution was stirred at room temperature for 15 hours. The reaction solution was concentrated by evaporation under reduced pressure, diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was recrystallized from MeOH to obtain the target compound 3-(8-fluoro-1-oxo-1H-isochromen-3-yl)propanoic acid (6.4 g, 61%).

[1318] 1 H NMR (300 MHz, CDCl 3 )δ7.84-7.72(m,2H),7.60-7.55(m,1H),7.39-7.29(m,1H),6.63(s,1H),2.77-2.73(m,2H),2.63-2.61(m,2H).

[1319] Step 2: Preparation of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid

[1320]

[1321] 3-(8-Fluoro-1-oxo-1H-isochromen-3-yl)propanoic acid (1.0 g, 4.23 mmol) was dissolved in 7N NH 3 / MeOH (20 mL), the mixture was stirred at 80 ° C for 15 hours. The reaction solution was cooled to room temperature, and then the product thus obtained was concentrated by evaporation under reduced pressure. The resulting solid was recrystallized from MeOH to obtain the target compound 3- (8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl) propionic acid (840 g, 84%).

[1322] 1 H NMR (300 MHz, CDCl 3 )δ7.61-7.54(m,1H),7.32-7.30(m,1H),7.09-7.03(m,1H),6.30(s,1H),2.65-2.61(m,2H),2.40-2.35(m,2H).

[1323] Step 3: Preparation of 6-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabi Cyclo[3.2.1]octan-3-yl)nicotinonitrile

[1324]

[1325] After 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoic acid (100 mg, 0.42 mmol) and 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile 2HCl (165 mg, 0.51 mmol) were dissolved in DMF (2 mL), HBTU (243 mg, 0.64 mmol) was added. TEA (0.18 mL, 1.3 mmol) was added dropwise and stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 6-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile (30 mg, 16%).

[1326] 1 H NMR (300 MHz, DMSO-d 6)δ11.25(br,1H),8.43(d,1H,J=1.8Hz),7.87-7.86(m,1H),7.61-7.54(m,1H),7.30(d,1H,J=7.8Hz),7.09-7.03(m,1H),6.83( d,1H,J=9.0Hz),6.38(s,1H),4.64(m,1H),4.50(m,1H),4.12-4.10(m,2H),3.02-2.94(m,2H),2.75(m,4H),1.91-1.58(m,4H).

[1327] <Example 207> Preparation of 6-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1328]

[1329] The target compound was obtained according to Example 206, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206.

[1330] 1 H NMR (300 MHz, CDCl 3 )δ10.99(br,1H),8.36(d,1H,J=1.8Hz),7.63-7.59(m,1H),7.35-7.31(m,1H),6 .87-6.80(m,1H),6.49(d,1H,J=8.7Hz),6.37(s,1H),4.92(m,1H),4.39(m,1H), 4.18(d,1H,J=11.7Hz), 3.93(d,1H,J=12.3Hz), 3.22(d,1H,J=12.0Hz), 3.01-2. 99(m,3H),2.89-2.87(m,2H),2.42(s,3H),1.99-1.94(m,2H),1.85-1.73(m,2H).

[1331] <Example 208> Preparation of 8-fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1332]

[1333] The target compound was obtained according to Example 206, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206, and 3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane 2HCl was used instead of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile 3HCl used in step 3 of Example 206.

[1334] 1 H NMR (300 MHz, CDCl 3 )δ10.95(br,1H),7.34-7.30(m,1H),6.94-6.83(m,3H),6.71-6.66(m,2H),6.35(s,1H),4.88(m,1H), 4.32(m,1H),3.34-3.31(m,2H),3.02-2.94(m,3H),2.84-2.77(m,3H),2.41(s,3H),1.94-1.92(m,4H).

[1335] <Example 209> Preparation of 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile

[1336]

[1337] The target compound was obtained according to Example 206, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206, and 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile 2HCl was used instead of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile 3HCl used in step 3 of Example 206.

[1338] 1 H NMR (300 MHz, CDCl 3 )δ10.91(br,1H),7.47-7.44(m,2H),7.26(m,1H),6.85-6.78(m,1H),6.71-6.69(m,2H),6.37(s,1H ),4.92(m,1H),4.39(m,1H),3.53-3.45(m,2H),3.12-2.80(m,6H),2.40(s,3H),2.05-1.81(m,4H).

[1339] <Example 210> Preparation of 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

[1340]

[1341] The target compound was obtained according to Example 206, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206, and 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane 2HCl was used instead of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile 3HCl used in step 3 of Example 206.

[1342] 1 H NMR (300 MHz, DMSO-d 6 )δ11.29(br,1H),7.45-7.40(m,1H),7.22-7.19(m,2H),7.00-6.93(m,1H),6.84-6.81(m,2H),6.34(s ,1H),4.65(m,1H),4.49(m,1H),3.54-3.46(m,2H),2.82-2.70(m,6H),2.34(s,3H),1.85-1.76(m,4H).

[1343] <Example 211> Preparation of 8-fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1344]

[1345] The target compound was obtained according to Example 206, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206, and 3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane 3HCl was used instead of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile 3HCl used in step 3 of Example 206.

[1346] 1 H NMR (300 MHz, DMSO-d 6)δ11.28(br,1H),7.67(s,1H),7.41(m,2H),6.97-6.91(m,2H),6.32(s,1H),4.64(m,1 H),4.48(m,1H),3.54-3.45(m,2H),2.76-2.71(m,6H),2.32(s,3H),1.87-1.77(m,4H).

[1347] <Example 212> Preparation of 8-fluoro-3-(3-(3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1348]

[1349] The target compound was obtained according to Example 206, except that 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206, and 3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane3HCl was used instead of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile3HCl used in step 3 of Example 206.

[1350] 1 H NMR (300 MHz, DMSO-d 6 )δ11.30(br,1H),8.07(d,1H,J=3.0Hz),7.52-7.46(m,1H),7.44-7.39(m,1H),6.99-6.92(m,1H),6.75-6.71(m,1 H),6.33(s,1H),4.64(m,1H),4.49(m,1H),3.91-3.83(m,2H),2.86-2.76(m,6H),2.33(s,3H),1.91-1.67(m,4H).

[1351] <Example 213> Preparation of 4-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile

[1352]

[1353] The target compound was obtained according to Example 206, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206, and 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile 2HCl was used instead of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile 3HCl used in step 3 of Example 206.

[1354] 1 H NMR (300 MHz, DMSO-d 6 )δ11.41(br,1H),7.60-7.54(m,3H),7.35(d,1H,J=9.9Hz),6.88-6.85(m,2H),6.39(s,1H),4. 65(m,1H),4.49(m,1H),3.65-3.62(m,2H),2.83-2.78(m,6H),2.42(s,3H),1.89-1.73(m,4H).

[1355] <Example 214> Preparation of 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1356]

[1357] The target compound was obtained according to Example 206, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206.

[1358] 1 H NMR (300 MHz, CDCl 3 )δ10.64(br,1H),8.38(s,1H),7.81(d,1H,J=6.9Hz),7.63(d,1H,J=8.7Hz),7.18(d,1H,J=10.2Hz),6.52(d,1H,J=9.0Hz),6.37(s,1H),4.94( m,1H),4.31-4.23(m,2H),3.94-3.90(m,1H),3.26-3.22(m,1H),3.00- 2.98(m,3H),2.81(m,2H),2.50(s,3H),1.98(m,2H),1.87-1.71(m,2H).

[1359] <Example 215> Preparation of 7-fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1360]

[1361] The target compound was obtained according to Example 206, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206, and 3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane 2HCl was used instead of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile 3HCl used in step 3 of Example 206.

[1362] 1 H NMR (300 MHz, DMSO-d 6 )δ11.43(br,1H),7.61(d,1H,J=9.9Hz),7.39(d,1H,J=9.9Hz),7.03-6.98(m,2H),6.80(m,2H),6.41(s ,1H),4.63(m,1H),4.46(m,1H),3.46-3.38(m,2H),2.77-2.64(m,6H),2.43(s,3H),1.86-1.76(m,4H).

[1363] <Example 216> Preparation of 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

[1364]

[1365] The target compound was obtained according to Example 206, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206, and 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane 2HCl was used instead of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile 3HCl used in step 3 of Example 206.

[1366] 1 H NMR (300 MHz, DMSO-d 6)δ11.41(br,1H),7.61(d,1H,J=9.0Hz),7.37(d,1H,J=9.3Hz),7.20-7.17(m,2H),6.81-6.78(m,2H),6 .40(s,1H),4.63(m,1H),4.47(m,1H),3.47(m,2H),2.77-2.67(m,6H),2.42(s,3H),1.81-1.76(m,4H).

[1367] <Example 217> Preparation of 7-fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1368]

[1369] The target compound was obtained according to Example 206, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206, and 3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane3HCl was used instead of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile3HCl used in step 3 of Example 206.

[1370] 1 H NMR (300 MHz, DMSO-d 6 )δ11.41(br,1H),7.64(s,1H),7.60-7.57(m,1H),7.41-7.34(m,2H),6.98-6.95(m,1H),6.39(s,1H ),4.63(m,1H),4.47(m,1H),3.51-3.44(m,2H),2.89-2.64(m,6H),2.42(s,3H),1.85-1.76(m,4H).

[1371] <Example 218> Preparation of 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1372]

[1373] The target compound was obtained according to Example 206, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206.

[1374] 1 H NMR (300 MHz, DMSO-d 6 )δ11.44(br,1H),8.47(s,1H),7.88-7.84(m,1H),7.62-7.59(m,1H),7.39-7.37(m,1H),6.80(d,1H,J=9.3Hz),6.41( s,1H),4.65(m,1H),4.50(m,1H),4.12-4.08(m,2H),2.95-2.91(m,2H),2.79(m,4H),2.43(s,3H),1.91-1.58(m,4H).

[1375] <Example 219> Preparation of 7-fluoro-3-(3-(3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

[1376]

[1377] The target compound was obtained according to Example 206, except that 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206, and 3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane3HCl was used instead of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile3HCl used in step 3 of Example 206.

[1378] 1 H NMR (300 MHz, DMSO-d 6 )δ11.44(br,1H),8.06(d,1H,J=3.0Hz),7.61(d,1H,J=9.3Hz),7.52-7.46(m,1H),7.38(d,1H,J=9.3Hz),6.72-6.69(m, 1H),6.41(s,1H),4.64(m,1H),4.50-4.48(m,1H),3.88-3.82(m,2H),2.81-2.76(m,6H),2.42(s,3H),1.90-1.66(m,4H).

[1379] <Example 220> Preparation of 6-(8-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1380]

[1381] The target compound was obtained according to Example 206, except that 7-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one was used instead of 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one used in step 1 of Example 206.

[1382] 1 H NMR (300 MHz, DMSO-d 6 )δ11.40(br,1H),8.47(d,1H,J=2.1Hz),7.88-7.84(m,1H),7.76-7.72(m,1H),7.64-7.59(m,1H),7.53-7.47(m,1H),6.80(d,1 H,J=9.3),6.42(s,1H),4.65(m,1H),4.51-4.49(m,1H),4.11-4.08(m,2H),2.96-2.92(m,2H),2.76(m,4H),1.88-1.58(m,4H).

[1383] <Example 221> Synthesis of 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)benzonitrile

[1384]

[1385] Step 1: Preparation of tert-butyl 4-(4-cyanophenyl)piperazine-1-carboxylate

[1386]

[1387] After dissolving tert-butyl piperazine-1-carboxylate (70.0 g, 0.38 mol) and 4-bromobenzonitrile (82 g, 0.45 mol) in toluene (1.5 L), Pd(OAc) was added. 2 (8.4g, 0.04mol), XPhos (9.0g, 0.02mol) and Cs 2 CO 3 (147 g, 0.45 mol). The mixture was stirred at 100 °C for 15 h and cooled to room temperature. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound tert-butyl 4-(4-cyanophenyl)piperazine-1-carboxylate (90 g, 83%).

[1388] 1 H NMR (300 MHz, CDCl 3 )δ7.53-7.50(m,2H),6.87-6.85(m,2H),3.60-3.57(m,4H),3.33-3.29(m,4H),1.49(s,9H).

[1389] Step 2: Preparation of 4-(piperazin-1-yl)benzonitrile 2HCl

[1390]

[1391] 4N HCl / di 4-(4-cyanophenyl)piperazine-1-carboxylic acid tert-butyl ester (80 g, 0.28 mol) was added with 1,4-dioxane (1400 mL), and the mixture was stirred for 15 hours. The solid produced during the reaction was filtered and washed with EtOAc to obtain the target compound 4-(piperazin-1-yl)benzonitrile 2HCl (72 g, 100%).

[1392] 1 H NMR (300 MHz, DMSO-d 6 )δ9.46(br,1H),7.67-7.64(m,2H),7.11-7.08(m,2H),3.61-3.59(m,4H),3.19(m,4H).

[1393] Step 3: Preparation of methyl 2-bromonicotinate

[1394]

[1395] After dissolving 2-bromonicotinic acid (10 g, 49.5 mmol) in DMF (165 mL), K 2 CO 3 (20.5 g, 148.5 mmol) and stirred for 30 minutes. MeI (14.1 g, 99.0 mmol) was slowly added dropwise to the reaction solution at 0°C, and then stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and Na 2 S 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4Dry, filter and then concentrate by evaporation under reduced pressure to obtain the target compound 2-bromonicotinic acid methyl ester (9.65 g, 90%).

[1396] 1 H NMR (300 MHz, CDCl 3 )δ8.49-8.47(m,1H),8.09-8.06(m,1H),7.37-7.33(m,1H),3.96(s,3H).

[1397] Step 4: Preparation of 2-(5-hydroxypent-1-yn-1-yl)nicotinate methyl ester

[1398]

[1399] Methyl 2-bromonicotinate (9.65 g, 44.67 mmol) was dissolved in CH 3 CN (220 L) was then added with 4-pentyn-1-ol (4.51 g, 53.60 mmol), Pd(PPh 3 ) 2 Cl 2 (1.57 g, 2.23 mmol) and CuI (425 mg, 2.23 mmol). TEA (13.56 g, 134.01 mmol) was added dropwise and stirred at 80 °C for 15 hours. The mixture was cooled to room temperature and filtered through tetracalcium aluminate, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was diluted with EtOAc and NH 4 The organic solvent was washed with MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 2-(5-hydroxypent-1-yn-1-yl)nicotinate methyl ester (8.0 g, 82%).

[1400] 1 H NMR (300 MHz, CDCl 3 )δ8.68-8.66(m,1H),8.22-8.19(m,1H),7.30-7.27(m,1H),3.94(s,3H) ,3.88-3.86(m,2H),2.69-2.65(m,2H),2.17(br,1H),1.96-1.90(m,2H).

[1401] Step 5: Preparation of 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one

[1402]

[1403] After dissolving methyl 2-(5-hydroxypent-1-yn-1-yl)nicotinate (8.0 g, 36.49 mmol) in THF / MeOH / water (100 mL / 25 mL / 25 mL), LiOH·H 2 O (7.66 g, 182.45 mmol), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated by distillation under reduced pressure, then diluted with EtOAc, and 6N HCl was slowly added dropwise. The organic solvent was purified by MgSO 4 The concentrated reaction solution was dissolved in acetone (25 mL) and AgNO was added. 3 (312 mg). The reaction solution was stirred at room temperature for 15 hours and then distilled under reduced pressure to remove the solvent. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (300 mg, 4%).

[1404] 1 H NMR (300 MHz, DMSO-d 6 )δ8.94-8.92(m,1H),8.45-8.42(m,1H),7.57-7.53(m,1H),6.67(s,1H),4 .59-4.56(m,1H),3.51-3.45(m,2H),2.65-2.60(m,2H),1.84-1.77(m,2H).

[1405] Step 6: Preparation of 3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl methanesulfonate

[1406]

[1407] After 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (300 mg, 1.46 mmol) was dissolved in DMF (7 mL), MsCl (217 mg, 1.90 mmol) was added dropwise at 0 °C and stirred for 30 minutes. TEA (2.21 g, 2.19 mmol) was added dropwise at 0 °C and then stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound methanesulfonic acid-3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl ester (150 mg, 36%).

[1408] 1 H NMR (300 MHz, DMSO-d 6 )δ8.95-8.93(m,1H),8.45-8.43(m,1H),7.58-7.54(m,1H),6.72(s,1H) ,4.32-4.27(m,2H),3.19(s,3H),2.74-2.68(m,2H),2.08-2.04(m,2H).

[1409] Step 7: Preparation of 4-(4-(3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl)piperazin-1-yl)benzene Nitrile

[1410]

[1411] Dissolve 3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl methanesulfonate (150 mg, 0.53 mmol) in CH 3 CN (11 mL), then 4-(piperazin-1-yl)benzonitrile 2HCl (223 mg, 0.8 mmol), NaHCO 3 (223 mg, 2.65 mmol) and NaI (159 mg, 1.06 mmol). The mixture was stirred at 80 °C for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dry, filter and then concentrate by evaporation under reduced pressure, and purify the residue by silica gel chromatography to obtain the target compound 4-(4-(3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl)piperazine-1-yl)benzonitrile (160 mg, 81%).

[1412] 1 H NMR (300 MHz, DMSO-d 6 )δ8.94-8.92(m,1H),8.44-8.41(m,1H),7.57-7.53(m,2H),7.01-6.98(m, 2H),6.69(s,1H),3.32-3.19(m,4H),2.66-2.38(m,6H),1.87-1.82(m,2H).

[1413] Step 8: Preparation of 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)benzonitrile

[1414]

[1415] 4-(4-(3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl)piperazin-1-yl)benzonitrile (160 g, 0.43 mmol) was dissolved in 7N NH3 / MeOH (20mL), the mixture was stirred at 80 ° C for 15 hours. The reaction solution was cooled to room temperature and then concentrated by evaporation under reduced pressure to obtain the product. The resulting solid was recrystallized from MeOH to obtain the target compound 4- (4- (3- (5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl) propyl) piperazin-1-yl) benzonitrile (121 mg, 75%).

[1416] 1 H NMR (300 MHz, CDCl 3 )δ8.86-8.84(m,1H),8.56-8.54(m,1H),7.52-7.49(m,2H),7.34-7.30(m,1H),6.91-6.88(m, 2H),6.53(s,1H),3.59-3.57(m,4H),2.81-2.72(m,6H),2.58-2.54(m,2H),1.96-1.95(m,2H).

[1417] <Example 222> Synthesis of 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)nicotinonitrile

[1418]

[1419] Step 1: Preparation of 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one

[1420]

[1421] Pent-4-yn-1-ol (5.0 g, 59.44 mmol) was dissolved in 1,4-dihydroquinone. After 2-bromonicotinic acid (16 g, 65.38 mmol), CuI (1.13 g, 5.94 mmol), MeONa (3.21 g, 59.44 mmol) and NaOH (2.38 g, 59.44 mmol) were added to 100 ° C. The reaction solution was stirred for 48 hours and filtered through tetracalcium aluminate, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was diluted with EtOAc and NH 4 The organic solvent was washed with MgSO 4 Dry, filter, and then concentrate by evaporation under reduced pressure, and the resulting solid is recrystallized from EtOAc to obtain the target compound 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (2.1 g, 17%)

[1422] 1 H NMR (300 MHz, DMSO-d6 )δ8.94-8.92(m,1H),8.45-8.42(m,1H),7.57-7.53(m,1H),6.67(s,1H),4 .59-4.56(m,1H),3.51-3.45(m,2H),2.65-2.60(m,2H),1.84-1.77(m,2H).

[1423] Step 2: Preparation of 7-(3-hydroxypropyl)-1,6-naphthyridin-5(6H)-one

[1424]

[1425] 7-(3-Hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (2.1 g, 10.23 mmol) was dissolved in 7N NH 3 / MeOH (1000mL), the mixture was stirred at 80 ° C for 15 hours. The reaction solution was cooled to room temperature and then concentrated by evaporation under reduced pressure to obtain the product. The obtained solid was recrystallized from MeOH to obtain the target compound 7- (3-hydroxypropyl) -1, 6- naphthyridine -5 (6H) -one (1.0 g, 48%).

[1426] 1 H NMR (300 MHz, DMSO-d 6 )δ1154(s,1H),8.87-8.86(m,1H),8.43-8.41(m,1H),7.43-7.42(m,1H),6.46(s, 1H),4.59-4.57(m,1H),3.45-3.43(m,2H),2.60-2.50(m,2H),1.81-1.76(m,2H).

[1427] Step 3: Preparation of 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl methanesulfonate

[1428]

[1429] After 7-(3-hydroxypropyl)-1,6-naphthyridin-5(6H)-one (420 mg, 2.06 mmol) was dissolved in DMF (10 mL), MsCl (0.366 mL, 4.74 mmol) was added dropwise at 0°C and stirred for 30 minutes. TEA (1.1 mL, 8.24 mmol) was added dropwise at 0°C and then stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered, and then concentrated by evaporation under reduced pressure, and the obtained solid was recrystallized with MeOH to obtain the target compound, 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl methanesulfonate (53 mg, 9%).

[1430] 1 H NMR (300 MHz, DMSO-d 6 )δ11.60(s,1H),8.87-8.86(m,1H),8.45-8.43(m,1H),7.43-7.72(m,1H),6.49 (s,1H),4.27-4.25(m,2H),3.19(s,3H),2.68-2.63(m,2H),2.09-2.05(m,2H).

[1431] Step 4: Preparation of 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)nicotinonitrile

[1432]

[1433] 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl methanesulfonate (50 mg, 0.177 mmol) was dissolved in CH 3 CN (5 mL), then 6-(piperazin-1-yl)nicotinonitrile 3HCl (69 mg, 0.266 mmol), NaHCO 3 (74 mg, 0.885 mmol) and NaI (53 mg, 0.354 mmol). The mixture was stirred at 80 °C for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)nicotinonitrile (17 mg, 26%).

[1434] 1 H NMR (300 MHz, CDCl 3 )δ8.86-8.85(m,1H),8.57-8.55(m,1H),8.41(s,1H),7.64-7.61(m,1H),7.35-7.33(m,1H),6.64-6.61(m,1H) ,6.55(s,1H),3.96-3.95(m,4H),2.83-2.79(m,2H),2.70-2.68(m,4H),2.58-2.55(m,2H),1.96-1.95(m,2H).

[1435] <Example 223> Preparation of 7-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl-1,6-naphthyridin-5(6H)-one

[1436]

[1437] The title compound was obtained according to Example 222, except that 1-(4-fluorophenyl)piperazine 2HCl was used instead of 6-(piperazin-1-yl)nicotinonitrile 3HCl used in step 4 of Example 222.

[1438] 1 H NMR (300 MHz, CDCl 3 )δ8.85-8.84(m,1H),8.58-8.56(m,1H),7.34-7.31(m,1H),7.00-6.95(m,4H),6.54 (s,1H),3.35-3.34(m,4H),2.79-2.76(m,6H),2.57-2.53(m,2H),1.95-1.94(m,2H).

[1439] <Example 224> Preparation of 7-(3-(4-(3-fluorophenyl)piperazin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one

[1440]

[1441] The title compound was obtained according to Example 222, except that 1-(3-fluorophenyl)piperazine 2HCl was used instead of 6-(piperazin-1-yl)nicotinonitrile 3HCl used in step 4 of Example 222.

[1442] 1 H NMR (300 MHz, CDCl 3 )δ8.85-8.84(m,1H),8.58-8.56(m,1H),7.34-7.18(m,2H),6.73-6.62(m,2H),6.53 (s,1H),3.47-3.43(m,4H),2.80-2.74(m,6H),2.57-2.54(m,2H),1.96-1.95(m,2H).

[1443] <Example 225> Preparation of 4-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile

[1444]

[1445] The target compound was obtained according to Example 222, except that 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile 2HCl was used instead of 6-(piperazin-1-yl)nicotinonitrile 3HCl used in step 4 of Example 222.

[1446] 1 H NMR (300 MHz, CDCl 3 )δ12.01(br,1H),8.86-8.84(m,1H),8.55(d,1H,J=7.8Hz),7.51-7.48(m,2H),7.34-7.30(m,1H),6.83-6.80(m,2H) ,6.53(s,1H),3.50-3.45(m,6H),2.86-2.82(m,2H),2.60-2.58(m,2H),2.09(m,2H),1.94(m,2H),1.82-1.79(m,2H).

[1447] <Example 226> Preparation of 5-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)picolinonitrile

[1448]

[1449] The title compound was obtained according to Example 222, except that 5-(piperazin-1-yl)picolinonitrile 3HCl was used instead of 6-(piperazin-1-yl)nicotinonitrile 3HCl used in step 4 of Example 222.

[1450] 1 H NMR (300 MHz, CDCl 3 )δ8.87-8.85(m,1H),8.56-8.53(m,1H),8.35(s,1H),7.54-7.52(m,1H),7.35-7.33(m,1H),7.14-7. 11(m,1H),6.54(s,1H),3.65-3.64(m,4H),2.76-2.75(m,6H),2.59-2.58(m,2H),1.96-1.95(m,2H).

[1451] <Example 227> Preparation of 7-(3-(4-(2-fluoropyridin-4-yl)piperazin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one

[1452]

[1453] The title compound was obtained according to Example 222, except that 1-(2-fluoropyridin-4-yl)piperazine 3HCl was used instead of 6-(piperazin-1-yl)nicotinonitrile 3HCl used in step 4 of Example 222.

[1454] 1 H NMR (300 MHz, CDCl 3)δ12.12(br,1H),8.87-8.53(m,1H),8.57(d,1H,J=7.8Hz),8.00(d,1H,J=5.4Hz),7.35-7.31(m,1H),6.83(m,1H), 6.78-6.77(m,1H),6.54(s,1H),3.81-3.79(m,4H),2.82-2.78(m,2H),2.69(m,4H),2.58-2.54(m,2H),1.96(m,2H).

[1455] <Example 228> Synthesis of 7-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one

[1456]

[1457] Step 1: Preparation of 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one

[1458]

[1459] After dissolving pent-4-yn-1-ol (2.52 g, 30 mmol) in distilled water, After 2-bromonicotinic acid (8.15 g, 33 mmol), CuI (571 mg, 3.0 mmol), MeONa (1.62 mg, 30 mmol) and NaOH (1.2 mg, 30 mmol) were added to alkane (500 mL). The reaction solution was stirred at 100 ° C for 15 hours and filtered through tetracalcium aluminate, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was diluted with EtOAc and NH 4 The organic solvent was washed with MgSO 4 Dried, filtered, and then concentrated by evaporation under reduced pressure, and the resulting solid was recrystallized from EtOAc to obtain the target compound 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (3.1 g, 50%).

[1460] 1 H NMR (300 MHz, DMSO-d 6 )δ8.94-8.92(m,1H),8.45-8.42(m,1H),7.57-7.53(m,1H),6.67(s,1H),4 .59-4.56(m,1H),3.51-3.45(m,2H),2.65-2.60(m,2H),1.84-1.77(m,2H).

[1461] Step 2: Preparation of 3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl methanesulfonate

[1462]

[1463] After 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (3.77 g, 18.37 mmol) was dissolved in DMF (92 mL), MsCl (4.84 g, 42.25 mmol) was added dropwise at 0°C and stirred for 30 minutes. TEA (7.44 g, 73.48 mmol) was added dropwise at 0°C and then stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered, and then concentrated by evaporation under reduced pressure, and the resulting solid was recrystallized with MeOH to obtain the target compound methanesulfonic acid-3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl ester (2.8 g, 55%).

[1464] 1 H NMR (300 MHz, DMSO-d 6 )δ8.95-8.93(m,1H),8.45-8.43(m,1H),7.58-7.54(m,1H),6.72(s,1H) ,4.32-4.27(m,2H),3.19(s,3H),2.74-2.68(m,2H),2.08-2.04(m,2H).

[1465] Step 3: Preparation of 7-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5H- Pyrano[4,3-b]pyridin-5-one

[1466]

[1467] Dissolve 3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl methanesulfonate (100 mg, 0.353 mmol) in CH 3 CN (20 mL), then 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane 2HCl (146 mg, 0.494 mmol), NaHCO 3 (148 mg, 1.765 mmol) and NaI (106 mg, 0.706 mmol). The mixture was stirred at 80 °C for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4Dry, filter, and then concentrate by evaporation under reduced pressure, and purify the residue by silica gel chromatography to obtain the target compound 7-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5H-pyrano[4,3-b]pyridine-5-one (78 mg, 54%).

[1468] 1 H NMR (300 MHz, CDCl 3 )δ8.88-8.86(m,1H),8.48-8.45(m,1H),7.38-7.36(m,1H),7.17-7.13(m,2H),6.68-6.65(m,2H),6.56(s,1H),3 .32-3.26(m,4H),2.92-2.89(m,2H),2.74-2.69(m,2H),2.50-2.45(m,2H),1.97-1.90(m,4H),1.74-1.71(m,2H).

[1469] Step 4: Preparation of 7-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1, 6-Naphthyridin-5(6H)-one

[1470]

[1471] 7-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5H-pyrano[4,3-b]pyridin-5-one (78 mg, 0.198 mmol) was added to 7N NH 3 (in MeOH, 20 mL), and the mixture was stirred at 80 ° C for 15 hours. The mixture was cooled to room temperature and concentrated. The resulting solid was subjected to column chromatography and then recrystallized from methanol to obtain the target compound 7- (3- (3- (4-chlorophenyl) -3,8-diazabicyclo [3.2.1] octane -8- yl) propyl) -1,6-naphthyridine -5 (6H) -one (34 mg, 44%).

[1472] 1 H NMR (300 MHz, CDCl 3 )δ8.85-8.84(m,1H),8.56-8.54(m,1H),7.31-7.25(m,2H),7.19-7.16(m,2H),6.77-6.74(m,2H),6.51 (s,1H),3.46-3.45(m,2H),3.40-3.29(m,4H),2.82-2.80(m,2H),2.59-2.57(m,2H),2.07-1.84(m,6H).

[1473] <Example 229> Preparation of 5-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)picolinonitrile

[1474]

[1475] The target compound was obtained according to Example 228, except that 5-(3,8-diazabicyclo[3.2.1]octan-3-yl)picolinonitrile 3HCl was used instead of 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane 2HCl used in step 3 of Example 228.

[1476] 1 H NMR (300 MHz, CDCl 3 )δ8.85-8.84(m,1H),8.55-8.53(m,1H),8.13-8.12(m,1H),8.04-8.01 (m,1H),7.64-7.63(m,1H),7.33-7.28(m,1H),7.11-7.10(m,1H),6.54 (s,1H),3.55-3.43(m,4H),2.87-2.83(m,2H),2.60-2.58(m,2H),2.09 -2.08(m,2H),1.95-1.94(m,2H),1.84-1.82(m,2H),1.63-1.62(m,2H).

[1477] <Example 230> Preparation of 7-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl-1,6-naphthyridin-5(6H)-one

[1478]

[1479] The target compound was obtained according to Example 228, except that 3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane 2HCl was used instead of 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane 2HCl used in step 3 of Example 228.

[1480] 1 H NMR (300 MHz, DMSO-d 6)δ11.68(br,1H),8.85-8.84(m,1H),8.40(d,1H,J=7.2Hz),7.42-7.37(m,1H),7.03-6.97(m,2H),6.80-6.76(m,2H),6.47 (s,1H),3.33-3.27(m,4H),2.82-2.79(m,2H),2.67-2.62(m,2H),2.42-2.37(m,2H),1.84-1.80(m,4H),1.64-1.62(m,2H).

[1481] <Example 231> Preparation of 7-(3-(3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one

[1482]

[1483] The target compound was obtained according to Example 228, except that 3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane3HCl was used instead of 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane2HCl used in step 3 of Example 228.

[1484] 1 H NMR (300 MHz, DMSO-d 6 )δ11.72(br,1H),8.85(d,1H,J=4.5Hz),8.41(d,1H,J=8.4Hz),8.06(d,1H,J=3.0Hz),7.45-7.38(m,2H),6.71-6.67(m,1H),6.47(s, 1H),3.70-3.66(m,2H),3.34(m,2H),2.95-2.82(m,2H),2.68-2.63(m,2H),2.43-2.38(m,2H),1.85-1.81(m,4H),1.55-1.53(m,2H).

[1485] <Example 232> Preparation of 6-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile

[1486]

[1487] The target compound was obtained according to Example 228, except that 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile 3HCl was used instead of 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane 2HCl used in step 3 of Example 228.

[1488] 1 H NMR (300 MHz, DMSO-d 6 )δ11.72(br,1H),8.85-8.84(m,1H),8.46(s,1H),8.41(d,1H,J=7.8Hz),7.82(d,1H,J=8.7Hz),7.41-7.38(m,1H),6.79(d,1H,J=8.7Hz) ,6.48(s,1H),3.94-3.91(m,2H),3.36(m,2H),3.09-3.05(m,2H),2.68-2.63(m,2H),2.41-2.39(m,2H),1.84(m,4H),1.48-1.45(m,2H).

[1489] <Example 233> Preparation of 7-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one

[1490]

[1491] The target compound was obtained according to Example 228, except that 3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane3HCl was used instead of 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane2HCl used in step 3 of Example 228.

[1492] 1 H NMR (300 MHz, CDCl 3 )δ8.86-8.84(m,1H),8.57-8.54(m,1H),7.74(s,1H),7.33-7.27(m,2H),6.84-6.81(m,1H) ,6.53(s,1H),3.49-3.33(m,6H),2.84-2.82(m,2H),2.59-2.57(m,2H),2.07-1.65(m,6H).

[1493] <Example 234> Preparation of 1′-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile

[1494]

[1495] Step 1: Preparation of tert-butyl 6-cyano-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate

[1496]

[1497] Dissolve tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-pinacolborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.47 mmol) and 5-bromopicolinonitrile (1.42 g, 7.76 mmol) in dihydropyridinecarbonitrile. alkane (65 mL) and H 2 O (22 mL), then Pd(PPh 3 ) 4 (227 mg, 0.32 mmol) and K 2 CO 3 (2.7 g, 19.41 mmol). The mixture was stirred at 100°C for 15 hours and cooled to room temperature. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 After drying, filtering and then concentrating by evaporation under reduced pressure, the resulting residue was purified by silica gel chromatography to obtain the target compound tert-butyl 6-cyano-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (1.25 g, 68%).

[1498] 1 H NMR (300 MHz, CDCl 3 )δ8.75(s,1H),7.77(m,1H),7.68(m,1H),6.26(br,1H),4.14(m,2H),3.69-3.65(m,2H),2.53(m,2H),1.49(s,9H).

[1499] Step 2: Preparation of 1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile 2HCl

[1500]

[1501] 4N HCl / di 6-cyano-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (1.25 g, 4.38 mmol) was added with 11 mL of oxane, and the mixture was stirred for 15 hours. The solid produced during the reaction was filtered and washed with EtOAc to obtain the target compound 1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carbonitrile 2HCl (0.76 g, 79%).

[1502] 1 H NMR (300 MHz, DMSO-d 6 )δ9.46(br,1H),8.92(m,1H),8.12-8.06(m,2H),6.56(br,1H),3.79(m,2H),3.30(m,2H),2.73(m,2H).

[1503] Step 3: Preparation of 1′-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1′,2′,3′,6′-tetrahydro- [3,4′-Bipyridine]-6-carbonitrile

[1504]

[1505] After dissolving 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl methanesulfonate (50 mg, 0.177 mmol) in DMF (10 mL), 1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile 2HCl (69 mg, 0.266 mmol) was added at room temperature. NaHCO 3 (74 mg, 0.885 mmol) and NaI (53 mg, 0.354 mmol), and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and Na 2 S 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4 Dry, filter and then concentrate by evaporation under reduced pressure, and the resulting residue is recrystallized from MeOH to obtain the target compound 1′-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile (7 mg, 11%).

[1506] 1 H NMR (300 MHz, CDCl 3 )δ11.46(m,1H),8.85-8.82(m,2H),8.56-8.54(m,1H),7.88-7.85(m,1H),7.69-7.66(m,1H),7.34-7.29(m, 1H),6.53(s,1H),6.32(s,1H),3.33-3.32(m,2H),2.88-2.76(m,6H),2.65-2.61(m,2H),1.98-1.97(m,2H).

[1507] <Example 235> Preparation of 1′-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile

[1508]

[1509] The title compound was obtained according to Example 234, except that 6-bromonicotinonitrile was used instead of 5-bromopyridinecarbonitrile used in step 1 of Example 234.

[1510] 1 H NMR (300 MHz, CDCl 3 )δ11.46(s,1H),8.86-8.24(m,2H),8.56-8.54(m,1H),7.93-7.91(m,1H),7.56-7.53(m,1H),7.33-7.32(m,1H),6.93 (s,1H),6.53(s,1H),3.38-3.37(m,2H),2.89-2.88(m,4H),2.79-2.75(m,2H),2.65-2.61(m,2H),2.01-1.99(m,2H).

[1511] <Example 236> Preparation of 7-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one

[1512]

[1513] The title compound was obtained according to Example 234, except that 1-bromo-4-fluorobenzene was used instead of 5-bromopicolinonitrile used in step 1 of Example 234.

[1514] 1 H NMR (300 MHz, CDCl 3 )δ11.46(br,1H),8.85-8.84(m,1H),8.59-8.56(m,1H),7.45-7.42(m,2H),7.33-7.29(m,1H),7.05-6.96(m ,2H),6.53(s,1H),6.05(s,1H),3.26-3.25(m,2H),2.84-2.77(m,6H),2.62-2.57(m,2H),1.97-1.96(m,2H).

[1515] <Example 237> Preparation of 7-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridyl]-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one

[1516]

[1517] The title compound was obtained according to Example 234, except that 4-bromo-2-fluoropyridine was used instead of 5-bromopicolinonitrile used in step 1 of Example 234.

[1518] 1 H NMR (300 MHz, CDCl 3 )δ11.52(br,1H),8.86-8.85(m,1H),8.58(d,1H,J=6.6Hz),8.17(d,1H,J=5.4Hz),7.35-7.30(m,1H),7.24(m,1H),6.96(s,1 H),6.54(s,1H),6.39(m,1H),3.32-3.31(m,2H),2.86-2.84(m,2H),2.80-2.76(m,4H),2.64-2.60(m,2H),2.01-1.97(m,2H).

[1519] <Example 238> Preparation of 7-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one

[1520]

[1521] The title compound was obtained according to Example 234, except that 1-bromo-3-fluorobenzene was used instead of 5-bromopicolinonitrile used in step 1 of Example 234.

[1522] 1 H NMR (300 MHz, CDCl 3 )δ11.55(br,1H),8.84(m,1H),8.58(d,1H,J=8.1Hz),7.34-7.25(m,3H),7.16-7.13(m,1H),6.97-6. 94(m,1H),6.53(s,1H),6.15(m,1H),3.27(m,2H),2.84-2.77(m,6H),2.60-2.58(m,2H),1.98(m,2H).

[1523] <Example 239> Preparation of 4-(1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[1524]

[1525] The title compound was obtained according to Example 234, except that 4-bromobenzonitrile was used instead of 5-bromopicolinonitrile used in step 1 of Example 234.

[1526] 1 H NMR (300 MHz, DMSO-d 6 )δ11.61(s,1H),8.85(d,1H,J=4.2Hz),8.42(d,1H,J=7.8Hz),7.81-7.78(m,2H),7.64-7.61(m,2H),7.43-7 .39(m,1H),6.47(s,1H),6.40(m,1H),3.14(m,2H),2.64-2.58(m,6H),2.46-2.44(m,2H),1.90-1.85(m,2H).

[1527] <Example 240> Preparation of 7-(3-(3,6-dihydro-[4,4′-bipyridyl]-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one

[1528]

[1529] The title compound was obtained according to Example 234, except that 4-bromopyridine was used instead of 5-bromopyridinecarbonitrile used in Step 1 of Example 234.

[1530] 1 H NMR (300 MHz, CDCl 3 )δ11.49-11.48(m,1H),8.86-8.84(m,1H),8.58-8.56(m,3H),7.34-7.29(m,3H),6 .53(s,1H),6.35(s,1H),3.31-3.29(m,2H),2.85-2.59(m,6H),2.00-1.96(m,2H).

[1531] <Example 241> Synthesis of 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)benzonitrile

[1532]

[1533] Step 1: Preparation of pent-4-ynoic acid

[1534]

[1535] After dissolving pent-4-yn-1-ol (10.0 g, 118.9 mmol) in acetone (500 mL), 2.5 M Jones reagent (118 mL) was slowly added dropwise at 0°C. The reaction solution was stirred at room temperature for 15 hours. The reaction solution was concentrated by evaporation under reduced pressure, diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 The resulting residue was dried, filtered and concentrated by evaporation under reduced pressure and washed with Et 2 O was recrystallized to obtain the target compound pent-4-ynoic acid (11.6 g, 100%).

[1536] 1 H NMR (300 MHz, CDCl 3 )δ2.63-2.60(m,2H),2.53-2.52(m,2H),2.00(s,1H).

[1537] Step 2: Preparation of 4-(4-(pent-4-ynyl)piperazin-1-yl)benzonitrile

[1538]

[1539] Pent-4-ynoic acid (5.0 g, 50.97 mmol), 4-(piperazin-1-yl)benzonitrile 2HCl (15.91 g, 61.16 mmol) and HBTU (29.07 g, 76.46 mmol) were dissolved in CH 2 Cl 2 (25 mL), TEA (25.8 g, 254.85 mmol) was added dropwise to the reaction solution at room temperature and stirred for 15 hours. 2 Cl 2 Dilute and wash with water. The organic solvent is purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 4-(4-(pent-4-ynyl)piperazin-1-yl)benzonitrile (11.8 g, 87%).

[1540] 1 H NMR (300 MHz, CDCl 3 )δ7.53-7.50(m,2H),6.87-6.84(m,2H),3.80-3.77(m,2H),3.67-3.63(m,2H),3.85-3.31(m,4H),2.63-2.59(m,4H).

[1541] Step 3: Preparation of 4-(4-(3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propanoyl)piperazin-1-yl)benzene Formonitrile

[1542]

[1543] 4-(4-(pent-4-ynyl)piperazin-1-yl)benzonitrile (2.0 g, 7.48 mmol) was dissolved in CH 3 CN, 2-bromonicotinic acid (2.03 g, 8.23 ​​mmol), CuI (143 mg, 0.75 mmol), MeONa (404 mg, 7.48 mmol) and NaOH (299 mg, 7.48 mmol) were added. The reaction solution was stirred at 80 ° C for 2 days and filtered through tetracalcium aluminate, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was diluted with EtOAc and NH 4 The organic solvent was washed with MgSO 4 Dry, filter and then concentrate by evaporation under reduced pressure and purify the residue by silica gel chromatography to obtain the target compound 4-(4-(3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propanoyl)piperazin-1-yl)benzonitrile (150 mg, 10%).

[1544] 1 H NMR (300 MHz, CDCl 3 )δ8.95(br,1H),8.50-8.47(m,1H),7.54-7.51(m,2H),7.42-7.40(m,1H),6.87-6.84(m,2H),6.49(s ,1H),3.81-3.78(m,2H),3.69-3.65(m,2H),3.39-3.32(m,4H),3.03-2.98(m,2H),2.85-2.80(m,2H).

[1545] Step 4: Preparation of 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)benzene Nitrile

[1546]

[1547] 4-(4-(3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propanoyl)piperazin-1-yl)benzonitrile (160 g, 0.43 mmol) was dissolved in 7N NH 3 / MeOH (20mL), the mixture was stirred at 80 ° C for 15 hours. The reaction solution was cooled to room temperature and then concentrated by evaporation under reduced pressure to obtain the product. The resulting solid was recrystallized from MeOH to obtain the target compound 4- (4- (3- (5-oxygen-5,6-dihydro-1,6-naphthyridin-7-yl) propionyl) piperazin-1-yl) benzonitrile (20 mg, 12%).

[1548] 1H NMR (300 MHz, CDCl 3 )δ11.53(br,1H),8.85-8.84(m,1H),8.43-8.41(m,1H),7.62-7.59(m,2H),7.43-7.39(m,1H ),7.03-7.01(m,2H),6.51(s,1H),3.62-3.61(m,4H),3.39-3.34(m,4H),2.82-2.80(m,4H).

[1549] <Example 242> Preparation of 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)nicotinonitrile

[1550]

[1551] The title compound was obtained according to Example 241, except that 6-(piperazin-1-yl)nicotinonitrile 3HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 2 of Example 241.

[1552] 1 H NMR (300 MHz, CDCl 3 )δ10.38(br,1H),8.86-8.85(m,1H),8.62-8.59(m,1H),8.42-8.41(m,1H),7.69-7.65(m,1H),7.35-7.34(m,1H ),6.63-6.60(m,1H),6.52(s,1H),3.84-3.81(m,4H),3.69-3.57(m,4H),3.02-2.99(m,2H),2.83-2.79(m,2H).

[1553] <Example 243> Preparation of 5-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)picolinonitrile

[1554]

[1555] The title compound was obtained according to Example 241, except that 5-(piperazin-1-yl)picolinonitrile 3HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 2 of Example 241.

[1556] 1 H NMR (300 MHz, CDCl 3)δ10.32(br,1H),8.86-8.85(m,1H),8.61-8.59(m,1H),8.32-8.30(m,1H),7.57-7.54(m,1H),7.36-7.35(m,1H),7.12-7 .08(m,1H),6.53(s,1H),3.90-3.88(m,2H),3.67-3.66(m,2H),3.44-3.33(m,4H),3.01-2.99(m,2H),2.83-2.81(m,2H).

[1557] <Example 244> Preparation of 7-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-1,6-naphthyridin-5(6H)-one

[1558]

[1559] The target compound was obtained according to Example 241, except that 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 2 of Example 241.

[1560] 1 H NMR (300 MHz, CDCl 3 )δ10.59(br,1H),8.85-8.83(m,1H),8.61-8.59(m,1H),7.34-7.33(m,2H),7.05-6.99(m,2H),6.52(s,1H),6.03-5.92(m,1H),4.3 2-4.31(m,1H),4.11-4.10(m,1H),3.92-3.88(m,1H),3.68-3.65(m,1H),3.01-3.00(m,2H),2.86-2.80(m,2H),2.55-2.54(m,2H).

[1561] <Example 245> Preparation of 4-(1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

[1562]

[1563] The target compound was obtained according to Example 241, except that 4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 2 of Example 241.

[1564] 1H NMR (300 MHz, DMSO-d 6 )δ11.53(br,1H),8.84(m,1H),8.44-8.38(m,1H),7.82-7.80(m,2H),7.63-7.60(m,2H),7.43-7.35(m,1H ),6.52-6.49(m,1H),6.42-6.37(m,1H),4.23-4.17(m,2H),3.69(m,2H),2.85-2.81(m,4H),2.57(m,2H).

[1565] <Example 246> Preparation of 4-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile

[1566]

[1567] The target compound was obtained according to Example 241, except that 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile 2HCl was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in step 2 of Example 241.

[1568] 1 H NMR (300 MHz, DMSO-d 6 )δ11.54(br,1H),8.81(d,1H,J=4.5Hz),8.40(d,1H,J=7.8Hz),7.59-7.56(m,2H),7.39-7.35(m,1H),6.92-6.89(m,2H), 6.50(s,1H),4.66(m,1H),4.54-4.53(m,1H),3.70-3.63(m,2H),2.92-2.76(m,6H),1.94-1.92(m,1H),1.78-1.74(m,3H).

[1569] <Example 247> Synthesis of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)benzonitrile

[1570]

[1571] Step 1: Preparation of tert-butyl 4-((4-cyanophenyl)amino)piperidine-1-carboxylate

[1572]

[1573] Dissolve tert-butyl 4-oxopiperidine-1-carboxylate (1.0 g, 5.02 mmol) and 4-aminobenzonitrile (770.8 mg, 6.52 mmol) in CH 2 Cl 2 (13 mL), the mixture was stirred at 80 °C for 15 h and then cooled to 0 °C. NaBH(OAc) was added 3 (3.19 mg, 15.06 mmol) and stirred at room temperature for 16 hours. The reaction solution was washed with CH 2 Cl 2 Dilute and wash with water. The organic solvent is purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound tert-butyl 4-((4-cyanophenyl)amino)piperidine-1-carboxylate (698 mg, 46%).

[1574] 1 H NMR (300 MHz, DMSO-d 6 )δ7.48-7.42(m,2H),6.70-6.60(m,3H),3.81-3.84(m,2H),3.49(br,1H),2.89(m,2H),1.87(m,2H),1.39(s,9H),1.24(m,2H).

[1575] Step 2: Preparation of 4-(piperidin-4-ylamino)benzonitrile 2HCl

[1576]

[1577] 4N HCl / di 4-((4-cyanophenyl)amino)piperidine-1-carboxylic acid tert-butyl ester (698 mg, 2.32 mmol) was added with 1% d-Hydroxypropane (5.8 mL), and the mixture was stirred for 15 hours. The solid produced during the reaction was filtered and washed with Et 2 O to obtain the target compound 4-(piperidin-4-ylamino)benzonitrile 2HCl (585 mg, 92%).

[1578] 1 H NMR (300 MHz, DMSO-d 6 )δ9.04(br,2H),7.46(d,J=8.7Hz,2H),6.70(d,J=9.0Hz,2H),3.62(m,1H),3.27(m,2H),2.98(m,2H),2.04(m,2H),1.63(m,2H).

[1579] Step 3: Preparation of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino Benzonitrile

[1580]

[1581] 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (60 mg, 0.2 mmol) was dissolved in CH 3 CN (4 mL), and then 4-(piperidin-4-ylamino)benzonitrile 2HCl (65 mg, 0.24 mmol) was added at room temperature. NaHCO 3 (84.01 mg, 1.0 mmol) and NaI (59.96 mg, 0.4 mmol), and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and NaS 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4 The resulting residue was dried, filtered and concentrated by evaporation under reduced pressure and washed with Et 2 O was recrystallized to obtain the target compound 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)benzonitrile (11 mg, 13%).

[1582] 1 H NMR (300 MHz, DMSO-d 6 )δ11.41(br,1H),7.60(m,1H),7.42(d,J=8.4Hz,2H),7.34(d,J=7.8Hz,1H),7.12-7.05(m,1H),6.65-6.58(m,3H),6.35(s,1 H),3.34(m,3H),2.86-2.85(m,2H),2.78-2.74(m,2H),2.59-2.55(m,2H),2.42(s,3H),2.07-1.76(m,6H),1.57-1.56(m,2H).

[1583] <Example 248> Preparation of 5-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)picolinonitrile

[1584]

[1585] The title compound was obtained according to Example 247, except that 5-aminopyridinecarbonitrile was used instead of 4-aminobenzonitrile used in step 1 of Example 247.

[1586] 1H NMR (300 MHz, CDCl 3 )δ12.78(br,1H),8.06(s,1H),7.54-7.42(m,2H),7.21-7.18(m,1H),7.05-6.98(m,1H),6.85-6.82(m,1H),6.23(s,1H), 4.94(m,1H),3.51-3.45(m,1H),3.12-3.09(m,2H),2.75-2.71(m,2H),2.57-2.54(m,2H),2.33-2.11(m,6H),1.88(m,2H).

[1587] <Example 249> Preparation of 4-((1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)benzonitrile

[1588]

[1589] The target compound was obtained according to Example 247, except that 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl ester used in step 3 of Example 247.

[1590] 1 H NMR (300 MHz, CDCl 3 )δ12.36(br,1H),7.96(d,J=9.3Hz,1H),7.47-7.31(m,4H),6.58(m,2H),6.25(s,1H),4.50(m,1H),3.47(m,1H ),3.08-3.04(m,2H),2.73-2.71(m,2H),2.53-2.52(m,2H),2.32-2.25(m,2H),2.11-2.04(m,4H),1.88(m,2H).

[1591] <Example 250> Preparation of 4-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)benzonitrile

[1592]

[1593] The target compound was obtained according to Example 247, except that 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 247.

[1594] 1 H NMR (300 MHz, CDCl 3 )δ13.05(br,1H),8.87-8.86(m,1H),8.57(d,1H,J=7.8Hz),7.43-7.41(m,2H),7.36-7.32(m,1H),6.60-6.54(m,3H),4. 57-4.55(m,1H),3.11-3.07(m,2H),2.80(m,2H),2.57-2.55(m,2H),2.34-2.28(m,2H),2.11-2.04(m,4H),1.92(m,2H).

[1595] <Example 251> Preparation of 5-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)picolinonitrile

[1596]

[1597] The target compound was obtained according to Example 247, except that 5-aminopyridinecarbonitrile was used instead of 4-aminobenzonitrile used in step 1 of Example 247, and 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 247.

[1598] 1 H NMR (300 MHz, DMSO-d 6 )δ11.26(br,1H),8.85-8.84(m,1H),8.43-8.41(m,1H),8.06-8.05(m,1H),7.59-7.58(m,1H),7.42-7.41(m,1H),6.96-6 .95(m,2H),6.47(s,1H),3.36-3.35(m,1H),2.91-2.90(m,2H),2.61-2.21(m,4H),2.11-1.86(m,6H),1.59-1.45(m,2H).

[1599] <Example 252> Preparation of methyl 4-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)benzoate

[1600]

[1601] The target compound was obtained according to Example 247, except that methyl 4-aminobenzoate was used instead of 4-aminobenzonitrile used in step 1 of Example 247, and 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 247.

[1602] 1 H NMR (300 MHz, CDCl 3 )δ8.85-8.84(m,1H),8.59-8.56(m,1H),7.86-7.83(m,2H),7.34-7.33(m,1H),6.59-6.56(m,2H),6.53(s,1H),4.42-4. 39(m,1H),3.84(s,3H),3.08-3.04(m,2H),2.80-2.79(m,2H),2.57-2.53(m,2H),2.35-2.28(m,2H),2.17-1.91(m,6H).

[1603] <Example 253> Preparation of 7-(3-(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one

[1604]

[1605] The target compound was obtained according to Example 247, except that 4-(trifluoromethyl)aniline was used instead of 4-aminobenzonitrile used in step 1 of Example 247, and 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl methanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate used in step 3 of Example 247.

[1606] 1 H NMR (300 MHz, CDCl 3 )δ8.86-8.85(m,1H),8.59-8.57(m,1H),7.40-7.33(m,2H),6.63-6.61(m,2H),6.52(s,1H),4.19-4.17 (m,1H),3.07-3.04(m,2H),2.80-2.79(m,2H),2.56-2.53(m,2H),2.35-2.28(m,2H),2.17-1.91(m,6H).

[1607] <Example 254> Synthesis of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)oxy)benzonitrile

[1608]

[1609] Step 1: Preparation of tert-butyl 4-(4-cyanophenoxy)piperidine-1-carboxylate

[1610]

[1611] After dissolving tert-butyl 4-hydroxypiperidine-1-carboxylate (0.6 g, 2.98 mmol) and 4-hydroxybenzonitrile (0.35 g, 2.98 mmol) in THF (9.9 mL), the mixture was cooled to 0°C. PPh 3 (1.17 mg, 4.47 mmol), DIAD (0.98 mL, 4.47 mmol) was slowly added dropwise at 10°C, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound tert-butyl 4-(4-cyanophenoxy)piperidine-1-carboxylate (0.73 g, 81%).

[1612] 1 H NMR (300 MHz, DMSO-d 6 )δ7.76(d,J=7.8Hz,2H),7.15(d,J=7.8Hz,3H),4.72(m,1H),3.67-3.66(m, 2H),3.21-3.14(m,2H),1.94-1.91(m,2H),1.56-1.51(m,2H),1.41(s,9H).

[1613] Step 2: Preparation of 4-(piperidin-4-yloxy)benzonitrile HCl

[1614]

[1615] 4N HCl / di 4-(4-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester (729 mg, 2.41 mmol) was added with 1% d-HEXANE (6 mL) and the mixture was stirred for 15 hours. The solid produced during the reaction was filtered and washed with Et 2 O to obtain the target compound 4-(piperidin-4-yloxy)benzonitrile HCl (408 mg, 71%).

[1616] 1 H NMR (300 MHz, DMSO-d6 )δ8.96(br,1H),7.79(d,J=8.7Hz,2H),7.18(d,J=8.7Hz,2H),4.81(m,1H),3.21(m,2H),3.07(m,2H),2.10(m,2H),1.86(m,2H).

[1617] Step 3: Preparation of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)oxy Benzonitrile

[1618]

[1619] 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (60 mg, 0.2 mmol) was dissolved in CH 3 CN (4 mL), and then 4-(piperidin-4-yloxy)benzonitrile HCl (57 mg, 0.24 mmol) was added at room temperature. NaHCO 3 (84.01 mg, 1.0 mmol) and NaI (59.96 mg, 0.4 mmol), and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and NaS 2 O 3 Aqueous solution and NH 4 The organic solvent was washed with MgSO 4 The resulting residue was dried, filtered and concentrated by evaporation under reduced pressure and washed with Et 2 O was recrystallized to obtain the target compound 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)oxy)benzonitrile (15 mg, 13%).

[1620] 1 H NMR (300 MHz, CDCl 3 )δ12.48(br,1H),7.60-7.46(m,3H),7.20-7.17(m,1H),7.04-6.94(m,3H),6 .20(s,1H),4.66(m,1H),2.68-2.43(m,10H),2.06-2.03(m,2H),1.86(m,2H).

[1621] <Example 255> Synthesis of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile

[1622]

[1623] After dissolving 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid (60 mg, 0.25 mmol), 4-(piperidin-4-yloxy)benzonitrile HCl (73.07 mg, 0.31 mmol) and HATU (145.49 mg, 0.38 mmol) in DMF (0.9 mL) at room temperature, DIPEA (0.13 mL, 0.76 mmol) was slowly added dropwise to the reaction solution and stirred at room temperature for 19 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was purified by anhydrous MgSO 4 Dried, filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain the target compound 4-...

Claims

1. A compound represented by the following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Chemical formula 1 In the above chemical formula 1, yes R 1 is methyl, and n is 0 or 1; L 1 Yes-(CH 2 ) 3 -or-(CH 2 ) 2 C(=O)-; Y is a 4- to 8-membered monocyclic or polycyclic heterocycloalkylene or heterocycloalkenylene containing one or more heteroatoms selected from N, O and S; L 2 Is a single bond, -NR 2 -, -O-, or a linear or branched C 1-10 Alkylene, R 2 is hydrogen or C 1-6 Alkyl; and Z is for C 3-8 cycloalkyl, 5 to 8 membered heterocycloalkyl containing one or more heteroatoms selected from N, O and S, phenyl, or 5 to 8 membered heteroaryl containing one or more heteroatoms selected from N, O and S, wherein the C 3-8 The cycloalkyl, 5- to 8-membered heterocycloalkyl, phenyl and 5- to 8-membered heteroaryl are each independently unsubstituted or substituted with one or more halogens, cyano, nitro, straight or branched chain C 1-6 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-6 Alkoxy, -CO 2 H.C 1-6 Alkoxycarbonyl, and C 1-6 The alkylcarbonylamino group is substituted with one or more substituents.

2. The compound according to claim 1, its stereoisomer, or pharmaceutically acceptable salt, wherein yes 3. The compound according to claim 1, its stereoisomer, or pharmaceutically acceptable salt, wherein yes L 1 Yes-(CH 2 ) 3 -or-(CH 2 ) 2 C(=O)-; Y is a 6- to 8-membered monocyclic or bicyclic heterocycloalkylene group containing one or two nitrogen atoms, or a 6-membered monocyclic heterocycloalkenylene group containing one nitrogen atom; L 2 Is a single bond, -NR 2 -, -O-, or a linear or branched C 1-6 Alkylene, R 2 is hydrogen or methyl; and Z is for C 3-6 cycloalkyl, 5- to 8-membered heterocycloalkyl containing one or more heteroatoms selected from N and O, phenyl, or 5- to 8-membered heteroaryl containing one or more heteroatoms selected from N and S, Wherein C 3-6 The cycloalkyl, 5- to 8-membered heterocycloalkyl, phenyl and 5- to 8-membered heteroaryl are each independently unsubstituted or substituted with one or more fluorine-substituted straight or branched chain C 1-3 Alkyl, unsubstituted or substituted with one or more fluorine straight chain or branched C 1-3 Alkoxy, -CO 2 H.C 1-3 Alkoxycarbonyl, and C 1-3 The alkylcarbonylamino group is substituted with one or more substituents.

4. The compound according to claim 1, its stereoisomer, or pharmaceutically acceptable salt, wherein yes L 1 Yes-(CH 2 ) 3 -or-(CH 2 ) 2 C(=O)-; Y is a 6-membered monocyclic or 8-membered bicyclic heterocycloalkylene group containing one or two nitrogen atoms, or a 6-membered monocyclic heterocycloalkenylene group containing one nitrogen atom; L 2 Is a single bond, -NR 2 -, -O-, or a linear or branched C 1-4 Alkylene, R 2 is hydrogen or methyl; and Z is for C 3-6 Cycloalkyl, heterocycloalkyl selected from tetrahydrofuranyl and pyrrolidinyl, phenyl, or heteroaryl selected from pyridinyl, pyrimidinyl and thiazolyl; Wherein C 3-6 Cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are each independently unsubstituted or substituted by -F, -Cl, cyano, nitro, methyl unsubstituted or substituted by one or more fluorine, methoxy substituted by one or more fluorine, carboxyl (-CO 2 H), methoxycarbonyl, and methylcarbonylamino.

5. The compound according to claim 1, its stereoisomer, or pharmaceutically acceptable salt, wherein yes L 1 yes Y is L 2 Is a single key, And Z is 6. The compound according to claim 1, its stereoisomer, or pharmaceutically acceptable salt, wherein the compound represented by the above Chemical Formula 1 is any one selected from the following compound groups: <1> 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile; <2> 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile; <3> 6-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile; <4> 8-Fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <5> 2-Fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile; <6> 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile hydrochloride; <7> 4-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile; <8> 4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile; <9> 7-fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <10> 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile; <11> 7-Fluoro-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <12> 7-Fluoro-3-(3-(4-phenylpiperazin-1-yl)propyl)isoquinolin-1(2H)-one; <13> 7-fluoro-3-(3-(4-(pyrimidin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <14> 7-fluoro-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <15> 7-Fluoro-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <16> 7-fluoro-3-(3-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <17> 3-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-7-fluoroisoquinolin-1(2H)-one; <18> Methyl 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoate; <19> 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoic acid; <20> N-(3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)phenyl)acetamide; <21> 5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile; <22> 6-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile; <23> 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile; <24> 8-Fluoro-5-methyl-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <25> 8-Fluoro-5-methyl-3-(3-(4-(pyrimidin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <26> 3-Fluoro-4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile; <27> 8-Fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <28> 2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile; <29> 8-Fluoro-5-methyl-3-(3-(4-(thiazol-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <30> 8-Fluoro-5-methyl-3-(3-(4-(5-methylthiazol-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <31> (R)-8-Fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one; <32> (S)-8-Fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one; <33> 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <34> 4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile; <35> 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile; <36> 6-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile; <37> 3-Fluoro-4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile; <38> 2-Fluoro-4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile; <39> 7-Fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <40> 7-Fluoro-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one; <41> 4-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <42> 8-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one; <43> 8-Fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)propyl)isoquinolin-1(2H)-one; <44> 8-Fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)propyl)isoquinolin-1(2H)-one; <45> 8-Fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one; <46> 1′-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile; <47> 4-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <48> 7-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one; <49> 3-(3-(4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-7-fluoroisoquinolin-1(2H)-one; <50> 1′-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile; <51> 7-Fluoro-3-(3-(4-(2-fluoro-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one; <52> 2-Fluoro-4-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <53> 8-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one; <54> 4-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <55> 2-Fluoro-4-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <56> 8-Fluoro-3-(3-(4-(2-fluoro-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one; <57> 1′-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile; <58> 4-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <59> 7-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one; <60> 1′-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile; <61> 1′-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile; <62> 7-Fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)propyl)-5-methylisoquinolin-1(2H)-one; <63> 7-Fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)propyl)-5-methylisoquinolin-1(2H)-one; <64> 7-Fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one; <65> 8-Fluoro-3-(3-(4-(3-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one; <66> 3-(3-(4-Benzoylpiperazin-1-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <67> 8-Fluoro-3-(3-(4-(4-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one; <68> 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <69> 4-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <70> 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile; <71> 6-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile; <72> 2-Fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <73> 3-Fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <74> 2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <75> 8-Fluoro-3-(3-(4-(2-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <76> 5-Fluoro-2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <77> 3-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <78> 3-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one; <79> 4-Fluoro-3-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <80> 2-Fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <81> 4-Fluoro-2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <82> 8-Fluoro-3-(3-(4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <83> 8-Fluoro-3-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <84> 3-Fluoro-5-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <85> 8-Fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <86> 8-Fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <87> 2-Fluoro-5-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <88> 1′-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile; <89> 8-Fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <90> 2-Fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <91> 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile hydrochloride; <92> 8-Fluoro-3-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridinyl]-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <93> 1′-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile; <94> 4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <95> 4-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <96> 1′-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile; <97> 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile; <98> 2-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <99> 6-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile; <100> 3-Fluoro-4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <101> 2-Fluoro-4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <102> 7-Fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <103> 7-Fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <104> 7-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <105> 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one; <106> 3-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one; <107> 4-Fluoro-3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <108> 4-Fluoro-2-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <109> 2-Fluoro-5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <110> 5-Fluoro-2-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <111> 4-Fluoro-3-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <112> 5-Fluoro-2-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <113> 3-(3-(4-(2,4-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one; <114> 3-Fluoro-5-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <115> 7-Fluoro-3-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <116> (R)-7-fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <117> (S)-7-Fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <118> 7-fluoro-3-(3-oxo-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <119> 3-Fluoro-5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <120> 7-Fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <121> 7-Fluoro-3-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridinyl]-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one; <122> 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <123> 6-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile; <124> 5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile; <125> 8-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <126> 2-Fluoro-4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <127> 2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <128> 3-Fluoro-4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <129> 8-Fluoro-3-(3-(6-fluoro-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <130> 8-Fluoro-3-(3-(5-fluoro-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <131> 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <132> 3-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <133> 4-Fluoro-3-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <134> 4-Fluoro-2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <135> 2-Fluoro-5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <136> 5-Fluoro-2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <137> 4-Fluoro-3-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <138> 8-Fluoro-3-(3-(4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <139> 2-Fluoro-5-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <140> 1′-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile; <141> 2-Fluoro-4-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <142> 8-Fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <143> 2-Fluoro-5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <144> 8-Fluoro-3-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridinyl]-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <145> 1′-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile; <146> Methyl 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzoate; <147> 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzoic acid; <148> 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile; <149> 4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <150> 7-Fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <151> 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile; <152> 6-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile; <153> 2-Fluoro-4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <154> 3-Fluoro-4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <155> 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one; <156> 4-Fluoro-3-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <157> 4-Fluoro-2-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <158> 2-Fluoro-5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <159> 5-Fluoro-2-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <160> 4-Fluoro-3-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <161> 5-Fluoro-2-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <162> 3-(3-(4-(2,4-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one; <163> 3-Fluoro-5-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <164> 7-Fluoro-3-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <165> 1′-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile; <166> 3-Fluoro-5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile; <167> 7-Fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <168> 7-Fluoro-3-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridinyl]-1(2H)-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <169> 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile hydrochloride; <170> 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one; <171> 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <172> 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one; <173> 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one; <174> 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one; <175> 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <176> 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one; <177> 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one; <178> 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one; <179> 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <180> 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one; <181> 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one; <182> 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one; <183> 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <184> 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one; <185> 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one; <190> 8-fluoro-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <191> 8-Fluoro-5-methyl-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <192> 7-fluoro-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <193> 7-Fluoro-5-methyl-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one; <195> 3-(3-(4-(L-phenylalanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <196> 8-Fluoro-5-methyl-3-(3-oxo-3-(4-propylpiperazin-1-yl)propyl)isoquinolin-1(2H)-one; <197> 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile; <198> 8-Fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5-methylisoquinolin-1(2H)-one; <199> 6-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile; <200> 5-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)picolinonitrile; <201> 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <202> 8-Fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5-methylisoquinolin-1(2H)-one; <203> 6-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile; <204> 6-(8-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile; <205> 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile; <206> 6-(8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile; <207> 6-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile; <208> 8-Fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <209> 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile; <210> 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <211> 8-Fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <212> 8-Fluoro-3-(3-(3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <213> 4-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile; <214> 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile; <215> 7-Fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <216> 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one; <217> 7-Fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <218> 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile; <219> 7-Fluoro-3-(3-(3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one; <220> 6-(8-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile; <221> 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)benzonitrile; <222> 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)nicotinonitrile; <223> 7-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one; <224> 7-(3-(4-(3-fluorophenyl)piperazin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one; <225> 4-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile; <226> 5-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)picolinonitrile; <227> 7-(3-(4-(2-fluoropyridin-4-yl)piperazin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one; <228> 7-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one; <229> 5-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)picolinonitrile; <230> 7-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl-1,6-naphthyridin-5(6H)-one; <231> 7-(3-(3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one; <232> 6-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)nicotinonitrile; <233> 7-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one; <234> 1′-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carbonitrile; <235> 1′-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile; <236> 7-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one; <237> 7-(3-(2′-fluoro-3,6-dihydro-[4,4′-bipyridinyl]-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one; <238> 7-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one; <239> 4-(1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <240> 7-(3-(3,6-dihydro-[4,4′-bipyridinyl]-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one; <241> 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)benzonitrile; <242> 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)nicotinonitrile; <243> 5-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)picolinonitrile; <244> 7-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-1,6-naphthyridin-5(6H)-one; <245> 4-(1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile; <246> 4-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile; <247> 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)benzonitrile; <248> 5-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)picolinonitrile; <249> 4-((1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)benzonitrile; <250> 4-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)benzonitrile; <251> 5-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)picolinonitrile; <252> Methyl 4-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)benzoate; <253> 7-(3-(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one; <254> 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)oxy)benzonitrile; <255> 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile; <256> 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzonitrile; <257> 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)(methyl)amino)benzonitrile; <258> 5-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)picolinonitrile; <259> 4-((1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzonitrile; <260> 4-((1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzonitrile; <261> 4-((1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile; <262> 4-((1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile; <263> 3-(3-(4-((4-chlorophenyl)amino)piperidin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one; <264> 3-(3-(4-((4-chlorophenyl)amino)piperidin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; <265> 7-fluoro-5-methyl-3-(3-oxo-3-(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)propyl)isoquinolin-1(2H)-one; <266> 8-Fluoro-5-methyl-3-(3-oxo-3-(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)propyl)isoquinolin-1(2H)-one; <267> Methyl 4-((1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzoate; <268> Methyl 4-((1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzoate; <273> 4-((8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)benzonitrile; <274> 4-((8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)benzonitrile; <275> N-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)azetidin-3-yl)cyclopropanecarboxamide; and <276> N-(1-(3-(8-Fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)cyclopropanecarboxamide.

7. A method for preparing a compound represented by the chemical formula 1 of claim 1, the method include: The compound represented by Chemical Formula 2 is reacted with the compound represented by Chemical Formula 3 to prepare the compound represented by Chemical Formula 1, as shown in the following Reaction Scheme 1: Reaction Scheme 1 In the above reaction scheme 1, L 1 , Y, L 2 and Z is as defined in claim 1, and W is a leaving group.

8. Use of the compound represented by Chemical Formula 1 according to claim 1, its stereoisomer, or pharmaceutically acceptable salt in the preparation of a medicament for preventing or treating poly (ADP-ribose) polymerase-1 related diseases.

9. The use according to claim 8, wherein the poly (ADP-ribose) polymerase-1 related disease is one or more selected from vascular stroke, cardiovascular disorder, macular degeneration, AIDS, arthritis, atherosclerosis, cancer, diabetes, brain tumor, inflammatory bowel disease, muscular dystrophy, osteoporosis, chronic pain, acute pain, neuropathic pain, neuropathies, nephropathy, retinal ischemia, septic shock, and skin aging.

10. The use according to claim 9, wherein the arthritis is osteoarthritis.

11. The use according to claim 9, wherein the neuropathology is a neurogenic disorder, a neurodegenerative disease or a peripheral nerve injury.

12. Use of the compound represented by Chemical Formula 1, its stereoisomer, or pharmaceutically acceptable salt according to claim 1 in the preparation of a medicament for preventing or treating ophthalmic diseases or disorders.

13. The use according to claim 12, wherein the ophthalmic disease or disorder is selected from one or more of age-related macular degeneration, Stargardt's macular dystrophy, retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy, Thorsby's fundus dystrophy, optic neuropathy, inflammatory retinopathy, diabetic retinopathy, diabetic maculopathy, retinal vascular occlusion, retinopathy of prematurity, or retinal damage associated with ischemia-reperfusion, proliferative vitreoretinopathy, retinal dystrophy, congenital optic neuropathy, uveitis, retinal damage, retinal disorders associated with Alzheimer's disease, retinal disorders associated with multiple sclerosis, retinal disorders associated with Parkinson's disease, retinal disorders associated with viral infection, retinal disorders associated with excessive light exposure, myopia, or retinal disorders associated with AIDS.

Images