RU2815480C1 - ISOQUINOLINONE DERIVATIVES, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING DISEASES ASSOCIATED WITH POLY(ADP-ribose)POLYMERASE-1, CONTAINING THEM AS ACTIVE INGREDIENT - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to an isoquinolinone derivative of formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

formula 1, in which

L¹ is -(CH₂)₃- or -(CH₂)₂C(=O)-; Y is 4-6-membered monocyclic or 8-membered bicyclic heterocycloalkylene containing one or two nitrogen atoms, or 6-membered monocyclic heterocycloalkenylene containing one nitrogen atom; L² is a single bond, -NHCO-, -NR₂-, -O- or straight or branched C_1-4alkylene substituted with one or more substitutes selected from the group consisting of oxo and amino, R² is hydrogen or methyl; and Z is C_3-6cycloalkyl, heterocycloalkyl, which is tetrahydrofuranyl or pyrrolidinyl, phenyl or heteroaryl selected from pyridyl, pyrimidyl and thiazole; where each said cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of -F, -Cl, cyano, nitro, methyl, unsubstituted or substituted with one or more fluorine, methoxy substituted with one or more fluorine, carboxy(-CO₂H), methoxycarbonyl and methylcarbonylamino. Technical result is development of PARP-1 inhibitor.

EFFECT: disclosed compounds can be effectively used to prevent or treat diseases associated with PARP-1, in particular ophthalmic diseases or disorders.

10 cl, 1 dwg, 4 tbl, 277 ex

Description

Field of technology

The present invention relates to a pharmaceutical composition for the prevention or treatment of diseases associated with poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP-1).

Prior Art

An estimated 42,000,000 people worldwide suffer from blindness, and many more suffer from serious retinal diseases.

In the Western world, the leading causes of blindness are 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, retinal uveitis and proliferative vitreoretinopathy.

In particular, in developed countries, the most common retinal disease causing blindness in adults over 60 years of age is age-related macular degeneration (AMD), and as the number of patients gradually increases, the number of AMD cases is expected to increase at the same rate, if not effective therapeutic agents will be developed. AMD gradually weakens the function of some nerves and the epithelial layers of the macula. Clinical manifestations of these diseases include drusen accumulation, retinal pigment epithelial (RPE) hyperplasia or degeneration due to oxidative electrical stimulation, geographic atrophy, and choroidal neovascularization (CNV). Atrophic AMD is characterized by atrophy of the outer layers of the retina and RPE, and degeneration of the adjacent choriocapillaris, accounting for approximately 25% of cases of severe central vision loss. The exudative (or “wet”) form of AMD is characterized by the development of CNV beneath the RPE and retina and subsequent hemorrhage, exudative retinal detachment, disc-shaped scars, and retinal atrophy. Depigmentation of the pigment epithelium may also occur. Exudative AMD accounts for approximately 75% of AMD cases with severe central vision loss.

Currently, most treatments are most beneficial for patients who are already relatively symptomatic, and these treatments include laser photocoagulation, photodynamic therapy, and surgery. However, since there is currently no effective treatment for the early stages of the disease, immediate development of a therapeutic agent is required.

Meanwhile, the PARP-1 enzyme is an enzyme associated with DNA damage signaling due to its ability to recognize single- or double-strand DNA breaks and quickly bind to them. There are approximately 18 protein species in the poly(ADP-ribose) polymerase family, and they exhibit a certain level of homology but differ in function. These include the catalytic activity of PARP-1 and PARP-2, which are known to be the only enzymes that are activated in response to DNA strand breaks, and the rate of intracellular activation is known to be approximately 90% for PARP-1 and approximately 10% for PARP-1. 2.

In particular, 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 DNA-bound PARP-1 uses NAD ⁺ (nicotinamide adenine dinucleotide) to synthesize poly(ADP-ribose) on target proteins in various nuclei, including topoisomerase, histone, and PARP itself.

Severe single- or double-stranded DNA damage caused by various insults causes PARP-1 hyperactivity. Over-activated PARP-1 synthesizes intracellular poly(ADP-ribose) in large quantities, causing the cell to become depleted of NAD ⁺ , which is used to synthesize poly(ADP-ribose). As a result, depletion of NAD ⁺ , used to produce ATP, causes ATP depletion in the cell, leading to necrosis or cell death. In addition, oversynthesized poly(ADP-ribose) can bind to mitochondrial AIF (apoptosis-inducing factor) and HK1 (hexokinase 1), and poly(ADP-ribose)-bound AIF translocates into the nucleus and fragments DNA in the nucleus, thereby causing cell necrosis. In addition, HK1, whose function is impaired by poly(ADP-ribose) binding, causes a decrease in mitochondrial function, leading to cell necrosis.

Accordingly, PARP inhibition has been confirmed to cause a marked increase in DNA strand breaking and apoptosis through a number of small molecule PARP inhibitors. In this regard, the use of PARP inhibitors in sensitizing hypoxic tumor cells in radiotherapy, specific vascular diseases, septic shock, ischemic injury and neurotoxicity has been attempted and proven to be effective.

In recent years, attempts have been made to use PARP inhibitors in hemorrhagic shock, macular degeneration (AMD), damage caused by retinal pigmentary degeneration, and in the rejection of organ transplants such as lung, heart and kidneys, and treatment with PARP inhibitors has been shown to improve the severity acute diseases such as pancreatitis, and liver and lung damage caused by the PARP mechanism of action.

As described above, there have been attempts to use PARP inhibitors to treat various diseases, but they remain at the level of evidence of effects in diseases other than carcinoma, and in particular there has been no significant development of therapeutics for the treatment of ophthalmic diseases to date.

Accordingly, the inventors of the present invention have developed a new PARP inhibitor, preferably a PARP-1 inhibitor, and in an attempt to develop a compound useful at a therapeutic level for a particular disease, such as an ophthalmic disease, have confirmed the excellent inhibitory effect of the new compound of the present invention on PARP-1. In addition, it has been confirmed to have excellent cytoprotective effect (apoptosis inhibition effect) at a significant level as a therapeutic agent for ophthalmic diseases or disorders such as retinal diseases and others. Thus, it has been confirmed that it can be effectively used as a pharmaceutical composition for the prevention or treatment of diseases associated with PARP-1, preferably ophthalmic diseases or disorders, containing the novel compound of the present invention as an active ingredient, thereby creating the present invention.

Disclosure of the invention

Technical problem

The object of the present invention is to provide isoquinolinone derivatives, isomers thereof or pharmaceutically acceptable salts.

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

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1) containing isoquinolinone derivatives, isomers thereof or pharmaceutically acceptable salts as the active ingredient .

Another aspect of the present invention is to provide a pharmaceutical composition for the prevention or treatment of an ophthalmic disease or disorder containing isoquinolinone derivatives, isomers thereof or pharmaceutically acceptable salts as the active ingredient.

Another aspect of the present invention is to provide a functional health food product for the prevention or relief of an ophthalmic disease or disorder containing isoquinolinone derivatives, isomers thereof or pharmaceutically acceptable salts as the active ingredient.

Solving a technical problem

To solve the above objects, according to one aspect of the present invention there is provided a compound of chemical formula 1 below, a stereoisomer or a pharmaceutically acceptable salt thereof:

Chemical formula 1

In chemical formula 1 above,

is a phenyl or 5-6 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, wherein the phenyl or heteroaryl may be unsubstituted or substituted with halogen or straight or branched C _1-6 alkyl ;

L ¹ represents C _1-3 alkylene, unsubstituted or substituted oxo;

Y is a 4-8 membered monocyclic or polycyclic heterocycloalkylene or heterocycloalkenylene containing one or more heteroatoms selected from the group consisting of N, O and S;

L ² represents a single bond, -NHCO-, -NR ² -, -O- or straight or branched C _1-10 alkylene substituted with one or more substituents selected from the group consisting of oxo and amino, R ² represents is hydrogen or C _1-6 alkyl; And

Z represents -H, C _3-8 cycloalkyl, 5-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, phenyl or 5-8 membered heteroaryl containing one or more than one heteroatom selected from the group consisting of N, O and S, wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl may be independently unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, straight or branched C _1-6 alkyl, unsubstituted or substituted by one or more halogens, straight or branched C _1-6 alkoxy, unsubstituted or substituted by one or more halogens, CO ₂ H, C _1-6 alkoxycarbonyl and C _1-6 alkylcarbonylamino.

According to another aspect of the present invention, as shown in Reaction Scheme 1 below, there is provided a method for preparing a compound of Chemical Formula 1 above, comprising reacting a compound of Chemical Formula 2 with a compound of Chemical Formula 3 to produce a compound of Chemical Formula 1:

Reaction scheme 1

In the Reaction Scheme above, L ¹ , Y, L ² and Z are as defined above, and W represents a leaving group.

According to another aspect of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1), containing a compound of chemical formula 1 above, an isomer thereof or a pharmaceutically acceptable salt as an active ingredient .

According to another aspect of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of an ophthalmic disease or disorder, comprising a compound of chemical formula 1 above, an isomer thereof, or a pharmaceutically acceptable salt as an active ingredient.

According to yet another aspect of the present invention, there is provided a functional health food product for the prevention or relief of an ophthalmic disease or disorder, comprising a compound of Chemical Formula 1 above, an isomer thereof, or a pharmaceutically acceptable salt as an active ingredient.

According to yet another aspect of the present invention, there is provided a method of preventing or treating a poly(ADP-ribose) polymerase-1 (PARP-1)-related disease, preferably an ophthalmic disease or disorder, comprising administering a pharmaceutical composition or functional health food composition containing a compound of the chemical formula 1 above, or a pharmaceutically acceptable salt thereof, as an active ingredient, to a subject in need thereof.

According to another aspect of the present invention, there is provided the use of a pharmaceutical composition or a functional health food composition containing a compound of Chemical Formula 1 above, or a pharmaceutically acceptable salt thereof, in the prevention or treatment of a disease associated with poly(ADP-ribose) polymerase-1 (PARP) -1), preferably an ophthalmic disease or disorder.

Beneficial effects of the invention

The isoquinolinone derivatives of the present invention exhibit excellent PARP-1 inhibitory effect at nanomolar concentrations and further exhibit excellent cytoprotective effect (apoptosis inhibition effect) against ophthalmic diseases or disorders, particularly retinal diseases, and thus can be effectively used as a pharmaceutical composition for the prevention or treatment of diseases associated with PARP-1, for example, ophthalmic diseases or disorders, containing them as an active ingredient.

Brief description of graphic materials

In FIG. 1 is an image showing the change in rat retinal layer thickness, obtained using a Moticam 1500 camera, after treatment with the compound of Example 46 or Example 1 (via a single intraperitoneal injection of each 15 mg/kg) in 8-week-old rats.

Detailed Description of Preferred Embodiments

Next, the present invention will be described in detail.

The present invention provides a compound of chemical formula 1 below, a stereoisomer thereof or a pharmaceutically acceptable salt:

Chemical formula 1

In chemical formula 1 above,

may be phenyl or 5-6 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, wherein phenyl or heteroaryl may be unsubstituted or substituted with halogen or straight or branched C _1-6 alkyl;

L ¹ may be C _1-3 alkylene, unsubstituted or substituted oxo;

Y may be a 4-8 membered monocyclic or polycyclic heterocycloalkylene or heterocycloalkenylene containing one or more than one heteroatom selected from the group consisting of N, O and S;

L ² may be a single bond, -NHCO-, -NR ² -, -O- or straight or branched C _1-10 alkylene substituted with one or more substituents selected from the group consisting of oxo and amino, R ² is hydrogen or C _1-6 alkyl; And

Z may be -H, C _3-8 cycloalkyl, 5-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, phenyl or 5-8 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl may be independently unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, cyano , nitro, straight or branched C _1-6 alkyl, unsubstituted or substituted with one or more halogens, straight or branched C _1-6 alkoxy, unsubstituted or substituted with one or more halogens, CO ₂ H, C _1-6 alkoxycarbonyl and C _1-6 alkylcarbonylamino.

In chemical formula 1 above,

may be phenyl or pyridine, wherein the phenyl or pyridine may be unsubstituted or substituted with one or more halogen or straight or branched C _1-6 alkyl;

In chemical formula 1 above,

may represent

R ¹ may be methyl, and n may be 0 or 1.

In chemical formula 1 above,

may represent

In chemical formula 1 above,

may represent

L ¹ may be C ₃ alkylene, unsubstituted or substituted by one or more oxo;

Y may be a 4-8 membered monocyclic or bicyclic heterocycloalkylene containing one or two nitrogen atoms, or a 6-membered monocyclic heterocycloalkenylene containing one nitrogen atom;

L ² may be a single bond, -NHCO-, -NR ² -, -O- or straight or branched C _1-6 alkylene substituted with one or more substituents selected from the group consisting of oxo and amino, R ² is hydrogen or methyl; And

Z may be -H, C _3-6 cycloalkyl, 5-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O, phenyl or 5-8 membered heteroaryl containing one or more than one heteroatom selected from the group consisting of N and S,

wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl may be independently unsubstituted or substituted with one or more substituents selected from the group consisting of -F, -Cl, cyano, nitro, straight or branched C _1-3 alkyl, unsubstituted or substituted one or more fluorines, straight or branched C _1-3 alkoxy, unsubstituted or substituted with one or more fluorines, -CO ₂ H, C _1-3 alkoxycarbonyl and C _1-3 alkylcarbonylamino.

In chemical formula 1 above,

may represent

L ¹ may be C ₃ alkylene, unsubstituted or substituted by one or more oxo;

Y may be a 4-6 membered monocyclic or 8-membered bicyclic heterocycloalkylene containing one or two nitrogen atoms, or a 6-membered monocyclic heterocycloalkenylene containing one nitrogen atom;

L ² may be a single bond, -NHCO-, -NR ² -, -O- or straight or branched C _1-4 alkylene substituted with one or more substituents selected from the group consisting of oxo and amino, R ² is hydrogen or methyl; And

Z may represent -H, C _3-6 cycloalkyl, heterocycloalkyl, which is tetrahydrofuranyl or pyrrolidinyl, phenyl or heteroaryl selected from pyridyl, pyrimidyl and thiazole;

wherein each cycloalkyl, heterocycloalkyl, phenyl and heteroaryl may be independently unsubstituted or substituted with one or more substituents selected from the group consisting of -F, -O, cyano, nitro, methyl, unsubstituted or substituted with one or more fluoro, methoxy substituted with one or more fluorine, carboxy(-CO ₂ H), methoxycarbonyl and methylcarbonylamino.

In chemical formula 1 above,

may represent

L ¹ may represent

Y may represent

L ² can be a simple connection,

Z may be -H

Examples of the compound of Chemical Formula 1 above may include the following compounds:

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'-bipyridin]-1'(2'H)-yl)propyl)-isoquinoline-1( 2H)-one;

44) 8-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)propyl)-isoquinoline-1( 2H)-on;

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-methylisoquinoline-1(2H)- He;

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'-bipyridin]-1'(2'H)-yl)propyl)-5-methylisoquinoline- 1(2H)-one;

63) 7-fluoro-3-(3-(6-fluoro-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)propyl)-5-methylisoquinoline- 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'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)-isoquinoline -1(2H)-on;

86) 8-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)-isoquinoline -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'-bipyridin]-1(2H)-yl)-3-oxopropyl)-isoquinoline-1(2H )-He;

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'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)isoquinoline- 1(2H)-one;

103) 7-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)isoquinoline- 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'-bipyridin]-1(2H)-yl)-3-oxopropyl)isoquinoline-1(2H) -He;

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'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)-5 -methylisoquinolin-1(2H)-one;

130) 8-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-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-tetrahydropyridine -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'-bipyridin]-1(2H)-yl)-3-oxopropyl)-5-methylisoquinoline-1 (2H)-on;

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]octane-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-tetrahydropyridine -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-tetrahydropyridine -4-yl)benzonitrile;

162) 3-(3-(4-(2,4-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinoline-1(2H)- He;

163) 3-fluoro-5-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-propanoyl)-1,2,3,6-tetrahydropyridine -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'-bipyridin]-1(2H)-yl)-3-oxopropyl)-5-methylisoquinoline-1 (2H)-on;

169) 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-propanoyl)piperazin-1-yl)picolinonitrile dihydrochloride;

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-(cyclobutancarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one;

179) 3-(3-(4-(cyclobutancarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one;

180) 3-(3-(4-(cyclobutancarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one;

181) 3-(3-(4-(cyclobutancarbonyl)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;

186) 8-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one;

187) 8-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one;

188) 7-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one;

189) 7-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)-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;

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

195) 3-(3-(4-(L-phenylalanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one hydrochloride;

196) 8-fluoro-5-methyl-3-(3-oxo-3-(4-propylpiperazin-1-yl)propyl)isoquinolin-1(2H)-one hydrochloride;

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]octane-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-methylisoquinoline-1(2H )-He;

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]octane-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]octane-3- yl)nicotinonitrile;

208) 8-fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinoline-1(2H) -He;

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

210) 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinoline-1(2H) -He;

211) 8-fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinoline- 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-methylisoquinoline- 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]octane-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]octane-3- yl)nicotinonitrile;

215) 7-fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinoline-1(2H) -He;

216) 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinoline-1(2H) -He;

217) 7-fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinoline- 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]octane-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-methylisoquinoline- 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)- He;

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)- He;

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'-bipyridin]-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'-bipyridin]-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;

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

270) 8-fluoro-3-(3-(4-hydroxypiperidin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one;

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

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

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.

The compound of Chemical Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by 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 and so on; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids and so on; 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 and so on. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, cabacate, fumarate, maleate, butine-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate , phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorine benzene sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelat and so on.

The acid addition salt of the present invention can be prepared by a conventional method. For example, an acid addition salt can be prepared by dissolving derivatives of compounds of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and so on, adding organic acid or inorganic acid thereto to obtain a precipitate, and then filtering and drying the resulting precipitate, or can be obtained by distilling the solvent and excess acid under reduced pressure, followed by drying or crystallization from an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be prepared using a base. For example, an alkali metal or alkaline earth metal salt is prepared, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble salt of the compound, and then evaporating and drying the filtrate. Here, from a pharmaceutical point of view, a sodium, potassium or calcium salt as a metal salt is suitably produced. In addition, the corresponding salt is prepared by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).

Moreover, the present invention includes not only the compound of the above Chemical Formula 1 and a pharmaceutically acceptable salt thereof, but also the solvate, isomer, hydrate and so on that can be prepared therefrom.

As used herein, the term “solvate” refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents for this include volatile, non-toxic and/or suitable for human administration solvents. Moreover, when the solvent is water, the solvate is called a “hydrate”.

As used herein, the term “isomer” refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but differing structurally or sterically. Such isomers include structural isomers such as tautomers, R- or S-isomers having an asymmetric carbon atom at the center, 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.

Further, as shown in the Reaction Scheme below, the present invention provides a method for producing a compound of Chemical Formula 1 above, comprising reacting a compound of Chemical Formula 2 with a compound of Chemical Formula 3 to produce a compound of Chemical Formula 1:

Reaction scheme 1

In Reaction Scheme 1 above, , L ¹ , Y, L ² and Z are as defined above, and W represents a leaving group.

Next, the production method illustrated by the above Reaction Scheme 1 will be described in detail.

In the method for producing the compound of Chemical Formula 1 of the present invention, the step shown in Reaction Scheme 1 is a step of producing a compound of Chemical Formula 1 by reacting a compound of Chemical Formula 2 with a compound of Chemical Formula 3. Specifically, it is a step in which the compound of Chemical Formula 1 prepared by reacting the mesylate or carboxyl of a compound of Chemical Formula 2 with a secondary amine of a compound of Chemical Formula 3.

However, the above step is not particularly limited as long as it is a method for producing the isoquinolinone derivative of Chemical Formula 1 and is within the scope of the present invention. However, the compound of Chemical Formula 2 can be considered as having a leaving group that readily reacts with a nucleophile such as a mesylate, tosylate, etc., or a compound having a carboxyl group capable of forming an amide by reacting with an amine. In addition, the compound of Chemical Formula 3 can be considered as a cyclic secondary amine capable of nucleophilic substitution reaction or amide formation reaction, but these are examples only and are not limited to this. Accordingly, the isoquinolinone derivative which is the final product of the present invention is prepared by a nucleophilic substitution reaction involving a compound having a leaving group and a cyclic secondary amine having sufficient nucleophilicity to react therewith, or by an amide formation reaction between a carboxyl and a cyclic secondary amine.

More specifically, this can be understood with reference to the method for preparing the compounds of the Examples of the present invention, but each reaction condition (reaction conditions that may be understood by one skilled in the art of organic synthesis, such as reaction temperature, time, atmospheric conditions, pressure conditions, and so on) hereinafter) may be modified, and it should be understood that the invention is not limited to this. In addition, it should be understood that the compounds and derivatives thereof used in each step may include derivatives other than those disclosed that can be obtained by modifying them, that is, derivatives modified by simple modification, substitution or removal of substituents, and they also included in the present invention.

At the same time, some of the compounds in the form of hydrochlorides from the following Examples 1-276 mean that all the compounds of the present invention can be easily obtained in the form of addition salts such as hydrochloride and so on, and pharmaceutically acceptable salts, and they are included in the scope of the present invention.

As a preferred embodiment of the production method, the production methods disclosed in Examples 1-276 below may be mentioned, but the present invention is not limited to them.

In addition, according to the present invention, there is provided a pharmaceutical composition for the prevention or treatment of a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1), containing a compound of chemical formula 1 above, an isomer thereof or a pharmaceutically acceptable salt as the active ingredient.

The compound of Chemical Formula 1 of the present invention, its isomer or a pharmaceutically acceptable salt is characterized by inhibition of the PARP enzyme, preferably the enzyme poly(ADP-ribose) polymerase-1 (PARP-1) (see Experimental Example 1).

Accordingly, it can be effectively used as a pharmaceutical composition for the prevention or treatment of a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1) containing a compound of chemical formula 1 of the present invention, an isomer thereof or a pharmaceutically acceptable salt as an active ingredient or functional health food product for the prevention or amelioration of poly(ADP-ribose) polymerase-1 (PARP-1) related disease.

In this case, a compound of chemical formula 1 above, its isomer or a pharmaceutically acceptable salt exhibits a cytoprotective effect by inhibiting the activity of poly(ADP-ribose) polymerase-1 (PARP-1) and is used in the treatment of diseases by inhibiting the synthesis of poly(ADP-ribose) ), leading to intracellular energy depletion, decreased mitochondrial function, DNA fragmentation due to translocation of AIF into the nucleus, apoptosis gene amplification, apoptosis and DNA base excision repair caused by increased levels of poly(ADP-ribose) associated with poly(ADP-ribose) activity ribose) polymerase-1 (PARP-1). More specifically, poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme present in the nucleus of cells in various organs, including the heart, and is an enzyme that is activated upon recognition of damaged DNA and subsequently repairs the damaged DNA through poly( ADP)-ribosylation of some proteins. Among the known substrates (acceptor or target protein) of poly(ADP)-ribosylation, the most important factor is PARP-1 itself, and in addition many nuclear proteins are known, such as histones, DNA topoisomerase, DNA ligase, caspase, p53 protein (marker caspase-dependent apoptosis) and transcription factors such as NF-κB, and so on. PARP catalyzes the transfer of ADP-ribose from NAD, and nicotinamide is released from NAD at this time. Nicotinamide is converted back to NAD through the consumption of ATP, an energy source, by another enzyme. Consequently, overactivation of PARP consumes large amounts of ATP and contributes to decreased mitochondrial function in cells, leading to cell damage and death. As described above and in the prior art of the present invention, it can be used to treat diseases such as cancer, tumor, stroke, age-related diseases and so on by inhibiting poly(ADP-ribose) polymerase-1 (PARP-1) , which is more active in cancer, tumors, etc. than in normal cells, and it can also be used in other diseases through the same mechanism as described above (see the prior art of the present invention).

Accordingly, it can be used as a pharmaceutical composition for the prevention or treatment of a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1) containing a compound of chemical formula 1 above, an isomer thereof or a pharmaceutically acceptable salt as the active ingredient.

Here, the poly(ADP-ribose) polymerase-1 (PARP-1) related disease may include one or more than one disease selected from the group consisting of a neurogenic disorder, a neurodegenerative disease, stroke, cardiovascular disease, macular degeneration , AIDS, arthritis, atherosclerosis, cancer, diabetes, brain tumor, inflammatory bowel disease, muscular dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, nerve attack, peripheral nerve injury, kidney disease, retinal ischemia, septic shock and skin aging, but not limited to, and any disease caused by intracellular ATP depletion and decreased mitochondrial function caused by hyperactivity of poly(ADP-ribose) polymerase-1 (PARP-1), and the cell damage or death caused thereby, or independent cell death may be included in the present invention.

At the same time, the present invention is characterized in that it can be used for the treatment of ophthalmic diseases or disorders, which is based on the evidence demonstrated in Experimental Example 2 of the present invention.

Here, the ophthalmic disease or disorder is a disease that results from cell damage or apoptosis caused by hyperactivity of poly(ADP-ribose) polymerase-1 (PARP-1), and, for example, the ophthalmic disease or disorder may include one or more disease selected from age-related macular degeneration, Stargardt macular degeneration, retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy, Sorsby's fundus dystrophy, optic neuropathy, inflammatory retinal disease, diabetic retinopathy, diabetic maculopathy, retinal vascular occlusion, retinopathy prematurity or ischemia-reperfusion injury of the retina, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, uveitis, retinal damage, retinal damage associated with Alzheimer's disease, retinal damage associated with multiple sclerosis, retinal damage associated with Parkinson's disease, retinal damage, associated with viral infections, retinal damage associated with excessive exposure to light, myopia or retinal damage due to AIDS.

In addition, the present invention provides a method for preventing or treating a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1) by administering a compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt.

In addition, the present invention provides the use of a medicament for the prevention or treatment of a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1) by administering a compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt.

Furthermore, the present invention provides a functional health food product for the prevention or relief of poly(ADP-ribose) polymerase-1 (PARP-1)-associated disease comprising a compound of chemical formula 1 above, an isomer thereof, or a pharmaceutically acceptable salt in as an active ingredient.

Further, the present invention provides a functional health food product for the prevention or relief of an ophthalmic disease or disorder containing a compound of Chemical Formula 1 above, an isomer thereof, or a pharmaceutically acceptable salt as an active ingredient.

Here, a functional health food product can be prepared and used as a functional food product that improves overall health by including a compound of Chemical Formula 1 of the present invention, an isomer thereof or a pharmaceutically acceptable salt as an active ingredient and is included within the scope of the present invention when refers to a composition, food product or administration form known to those skilled in the art. Moreover, it is included in the functional health food product of the present invention, provided that it is within the range in which it can be recognized as a functional health food product.

As used herein, the term “prevention” can mean any action of inhibiting or delaying the onset of neurological diseases by administering to a subject a pharmaceutical composition of the present invention.

As used herein, the term “treatment” can mean any action to alleviate or beneficially change the symptoms of neurological diseases by administering to an individual a pharmaceutical composition of the present invention.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent.

In the case where the composition of the present invention is used as a pharmaceutical drug, the pharmaceutical composition containing a compound of Chemical Formula 1 above, an isomer thereof or a pharmaceutically acceptable salt thereof can be formulated into various dosage forms for oral or parenteral administration as shown below, and introduced into clinical use, but the present invention is not limited to this.

Examples of preparations for oral administration include tablets, pills, hard/soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, lozenges, and so on. These preparations contain, in addition to the active ingredient, a diluent (eg lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) and a lubricant (eg silicon dioxide, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). The tablets may also contain a binder such as magnesium aluminosilicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and in some cases may contain a disintegrant such as starch, agar, alginic acid or its sodium salt, or evaporation mixture , and/or absorbent, coloring, flavoring and sweetener.

The pharmaceutical composition containing the compound of Chemical Formula 1 above as an active ingredient can be administered parenterally, and parenteral administration is carried out by injection, eye drops or ophthalmic ointment.

Herein, in order to prepare a preparation for parenteral administration, a compound of Chemical Formula 1 above, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is mixed with a stabilizer or buffer in water to obtain a solution or suspension, and this solution or this suspension can be prepared as a standard dosage form in an ampoule or bottle. The composition may be sterilized and/or contain adjuvants such as a preservative, stabilizer, hydrating agent or emulsifier, osmosis salt, and/or buffer, and other therapeutically useful substances, and the composition may be prepared by conventional methods such as dispersion, gelling education and so on.

In addition, the dose of a pharmaceutical compound containing the compound of Chemical Formula 1 above as an active ingredient for a human body may vary depending on the age, body weight and gender of the patient, dosage form, health status and severity of the disease. The dose may preferably be administered in an amount of 0.001 to 1000 mg/kg/day several times a day, preferably once a day or three times a day in divided doses at regular intervals as recommended by a physician or pharmacist via the oral or parenteral route. .

The pharmaceutical composition of the present invention can be used as a separate preparation. In addition, it can be formulated and used as a complex preparation by the additional inclusion of one or more other therapeutic agents.

In another aspect, the present invention provides a method of preventing or treating a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1), comprising administering a pharmaceutical composition in an effective amount to an individual in need thereof. Pharmaceutical composition means a pharmaceutical composition for the prevention or treatment of a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1) containing a compound of chemical formula 1 described above, an isomer thereof or a pharmaceutically acceptable salt as an active ingredient.

As used herein, the term "administration" means the administration of the pharmaceutical composition of the present invention to an individual by an appropriate route, and the pharmaceutical composition of the present invention may be administered by any conventional route, provided that 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 balloon catheter, or intracerebroventricular injection, but is not limited to.

As used herein, the term “individual” refers to any animal, including a human, who has or may develop a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1), such as an ophthalmic disease or disorder and any of the above diseases. Poly(ADP-ribose) polymerase-1 (PARP-1)-related disease can be effectively prevented or treated by administering a pharmaceutical composition to a subject.

The isoquinolinone derivatives of the present invention, the method of their preparation and their pharmaceutical use can be understood as described above, and the effects demonstrated in the present invention will be described below.

First, the inhibitory activity against the enzyme PARP-1 (poly[ADP-ribose] polymerase-1) was evaluated by incorporating the isoquinolinone derivatives of the present invention at different concentrations.

Specifically, the PARP-1 (poly[ADP-ribose] polymerase 1) activity assay kit was used to treat the isoquinolinone derivatives of the present invention at various concentrations, and the uptake measurement resulted in the PARP-1 (poly[ADP-ribose] inhibitory activity ]polymerase 1) was observed in nanomolar units.

From the above results, it can be concluded that the isoquinolinone derivatives of the present invention have excellent protective ability against retinal dystrophy and thus can be effectively used as a pharmaceutical composition for the treatment of retinal diseases.

Method for carrying out the invention

Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. However, these Examples and Experimental Examples are given for illustrative purposes only, and these Examples and Experimental Examples are not intended to limit the scope of the invention.

Example 1. Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

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

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) ₂ (8, 4 g; 0.04 mol), XPhos (9.0 g; 0.02 mol) and Cs ₂ CO ₃ (147 g; 0.45 mol). 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound dare/i-butyl-4-(4-cyanophenyl)-piperazine-1-carboxylate (90 g; 83%).

^1H NMR (nuclear magnetic resonance) (300 MHz, CDCl ₃ ) δ 7.53-7.50 (m, 2H), 6.87-6.85 (m, 2H), 3.60-3.57 (m, 4H), 3.33-3.29 (m, 4H ), 1.49 (s, 9H).

Step 2: preparation of 4-(piperazin-1-yl)benzonitrile 2HCl

Mixture 4 N. HCl/dioxane (1400 ml) was added to t/?eot-butyl-4-(4-cyanophenyl)-piperazine-1-carboxylate (80 g; 0.28 mol) and the mixture was stirred for 15 hours. The resulting solid was filtered and washed with EtOAc to give the title compound 4-(piperazin-1-yl)benzonitrile 2HCl (72 g; 100%).

^1H NMR (300 MHz, DMSO (dimethyl sulfoxide)-d ₆ ) δ 9.46 (br, 1H), 7.67-7.64 (m, 2H), 7.11-7.08 (m, 2H), 3.61-3.59 (m, 4H), 3.19 (m, 4H).

Step 3: production of methyl 2-bromo-6-fluorobenzoate

After dissolving 2-bromo-6-fluorobenzoic acid (100 g; 456.6 mmol) in DMF (1 L), K ₂ CO ₃ was added at 0° C. and stirred for 30 minutes. Mel (194 g; 1369.8 mmol) was slowly added dropwise to the reaction solution at 0° C., followed by stirring at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with aqueous Na ₂ S ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound methyl 2-bromo-6-fluorobenzoate (107 g; 95%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.40 (d, 1H, J=8.1 Hz), 7.31-7.24 (m, 1H), 7.09 (t, 1H, J=8.6 Hz), 3.98 ( s, 3H).

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

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(PPh3) was added dropwise ₂ Cl ₂ (15.2 g; 21.65 mmol) and CuI (4.12 g; 21.65 mmol). TEA (triethylamine) (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 an aqueous NH ₄ Cl solution. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the title compound methyl-2-fluoro-6-(5-hydroxypent-1-yn-1-yl) benzoate (75.1 g; 70%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37-7.30 (m, 1H), 7.25-7.23 (m, 1H), 7.05 (t, 1H, J=8.9 Hz), 3.95 (s, 3H), 3.88-3.76 (m, 2H), 2.56 (t, 2H, J=6.8 Hz), 1.85 (m, 2H).

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

After dissolving methyl 2-fluoro-6-(5-hydroxypent-1-in-1-yl)benzoate (75 g; 299.68 mmol) in a mixture of THF (tetrahydrofuran)/MeOH/H ₂ O (600 ml/200 ml/200 ml) LiOH⋅H ₂ O (37.7 g; 899.03 mmol) was added dropwise, followed by stirring at room temperature for 15 hours. The reaction solution was concentrated by distillation under reduced pressure and then diluted with EtOAc and 6N was added slowly dropwise. HCl to bring the pH value to 1-2. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure. After dissolving the concentrated reaction solution in acetone (1.5 L), AgNO ₃ (9.34 g; 29.97 mmol) was added dropwise. 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 solution was dried over MgSO ₄ filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the title compound 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one (25 g ; 35%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.83-7.76 (m, 1H), 7.37 (d, 1H, J=7.8 Hz), 7.30 (t, 1H, J=9.8 Hz), 6.61 (s, 1H), 4.58 (br, 1H), 3.49-3.44 (m, 2H), 2.57-2.50 (m, 2H), 1.76 (m, 2H).

Step 6: preparation of 8-fluoro-3-(3-hydroxypropate)isoquinolin-1(2H)-one

After dissolving 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one (18.0 g; 81.00 mmol) in a mixture of 7 N. NH ₃ /MeOH (200 ml; 1.38 mol) 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 give the title compound 8-fluoro-3-(3-hydroxypropyl)isoquinolin-1(2H)-one (14.8 g, 83%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.26 (br, 1H), 7.65-7.58 (m, 1H), 7.35 (d, 1H, J=7.8 Hz), 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).

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

After dissolving 8-fluoro-3-(3-hydroxypropyl)isoquinolin-1(2H)-one (19.5 g, 88.14 mmol) 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 an aqueous NH ₄ Cl solution. The organic solution was dried over MgSO ₄ 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-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate ( 13 g; 49%).

^1H NMR (300 MHz, CDCl ₃ ) δ 11.58 (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=6.2 Hz), 3.05 (s, 3H), 2.79 (t, 2H, J=7.7 Hz), 2.26 (m, 2H).

Step 8: Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

When 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (2.4 g; 8.02 mmol) was barely dissolved in acetonitrile (160.0 ml), 4 -(piperazin-1-yl)benzonitrile 2HCl (3.1 g; 12.03 mmol) at 25°C. NaHCO ₃ (3.37 g; 40.10 mmol) and Nal (3.13 g; 16.04 mmol) were added dropwise and the mixture was heated to 80° C. and stirred for 17 hours. The reaction solution was diluted with EtOAc and washed with aqueous NaS ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to give the target compound 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-3 -yl)propyl)piperazin-1-yl)benzonitrile (2.4 g; 77%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.63 (br, 1H), 7.55-7.48 (m, 3H), 7.20 (d, 1H, J=7.8 Hz), 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=6.0 Hz), 1.94- 1.90 (m, 2H).

Example 2. Preparation of 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile

The title compound was prepared according to Example 1, except that 5-bromo-2-cyanopyridine was used instead of 4-bromobenzonitrile used in Step 1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.32 (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).

Example 3. Preparation of 6-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile

The title compound was prepared according to Example 1, except that 2-bromo-5-cyanopyridine was used instead of 4-bromobenzonitrile used in Step 1 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.40-8.39 (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).

Example 4. Preparation of 8-fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared according to Example 1, except that 4-bromobenzotrifluoride was used instead of 4-bromobenzonitrile used in Step 1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) 5 11.47 (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).

Example 5. Preparation of 2-fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

The title compound was prepared according to Example 1, except that 4-bromo-2-fluorobenzonitrile was used instead of 4-bromobenzonitrile used in Step 1 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 7.51-7.50 (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).

Example 6. Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile hydrochloride

After dissolving 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-piperazin-1-yl)benzonitrile (1.0 g; 2.56 mmol) in a mixture of 4 n. The HCl/dioxane (26.0 mL; 76.83 mmol) mixture was stirred at room temperature for 15 hours. The resulting product was concentrated by evaporation under reduced pressure and filtered to obtain the target compound 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl) hydrochloride -benzonitrile (940.0 mg; 90%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.35 (br, 1H), 11.22 (s, 1H), 7.68-7.61 (m, 3H), 7.37 (d, 1H, J=7.8 Hz), 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=12.9 Hz), 3.11- 3.07 (m, 4H), 2.57 (m, 2H), 2.12 (m, 2H).

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

The title compound was prepared 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.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.44 (br, 1H), 7.54-7.46 (m, 3H), 7.20 (d, 1H, J=7.8 Hz), 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=6.3 Hz), 2.57 (t, 2H, J=6.0 Hz), 2.10-2.07 (m, 2H), 1.92-1.88 (m, 2H), 1.79-1.76 (m, 2H).

Example 8. Preparation of 4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 7.97-7.95 (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).

Example 9. Preparation of 7-fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The target compound was prepared according to Example 1, except that 4-bromobenzotrifluoride 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 Stage 3 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.54 (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).

Example 10. Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl (propyl)piperazin-1-yl)picolinonitrile

The title compound was prepared 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 acid used in Step 3 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.70 (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).

Example 11. Preparation of 7-fluoro-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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 acid used in Step 3 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.53 (br, 1H), 7.95 (d, 1H, J=9.9 Hz), 7.77 (m, 1H), 7.67 (d, 1H, J=7.8 Hz), 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=5.9 Hz), 1.93 (m, 2H).

Example 12. Preparation of 7-fluoro-3-(3-(4-phenylpiperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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-(piperazine-1 -yl)benzonitrile 2HCl used in Step 8 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.38 (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).

Example 13. Preparation of 7-fluoro-3-(3-(4-(pyrimidin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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-pyrimidyl)piperazine was used instead of 4 -(piperazin-1-yl)benzonitrile 2HCl used in Step 8 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.32-8.30 (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).

Example 14. Preparation of 7-fluoro-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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 Stage 3 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.20-8.19 (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).

Example 15. Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The target compound was prepared 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 Stage 3 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.53 (br, 1H), 7.99-7.96 (m, 1H), 7.47-7.42 (m, 1H), 7.36-7.33 (m, 1H), 6.97-6.94 (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).

Example 16. Preparation of 7-fluoro-3-(3-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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-benzoic acid. 6-fluorobenzoic acid used in Step 3 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.46 (br, 1H), 7.97 (dd, 1H, J=9.3 Hz, 2.7 Hz), 7.47-7.43 (m, 1H), 7.37-7.22 ( m, 2H), 6.86 (dd, 1H, J=8.3 Hz, 2.0 Hz), 6.76 (s, 1H), 6.70 (d, 1H, J=7.8 Hz), 6.26 (s, 1H ), 3.46-3.43 (m, 4H), 2.74-2.69 (m, 6H), 2.54 (t, 2H, J=6.2 Hz), 1.93 (m, 2H).

Example 17. Preparation of 3-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-7-fluoroisoquinolin-1(2H)-one

The title compound was prepared 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 acid used in Step 3 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.41 (br, 1H), 7.97 (dd, 1H, J=9.3 Hz, 2.7 Hz), 7.47-7.42 (m, 1H), 7.37-7.30 ( m, 1H), 7.17 (t, 1H, J=8.1 Hz), 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=6.0 Hz), 1.96-1.88 (m, 2H).

Example 18. Preparation of methyl 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoate

The title compound was prepared as in 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 Stage 3 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.41 (br, 1H), 7.97 (dd, 1H, J=9.3 Hz, 2.4 Hz), 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=8.4 Hz, 1.8 Hz), 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=6.0 Hz), 1.95-1.90 (m, 2H).

Example 19. Preparation of 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoic acid

After dissolving methyl 3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzoate (300 mg; 0.708 mmol) in THF ( 3 ml) MeOH (1 ml) and H ₂ O (1 ml), LiOH (74 mg; 1.76 mmol) were added and stirred at room temperature for 12 hours. The reaction solution was concentrated by evaporation under reduced pressure, diluted with EtOAc and then 2 N was added slowly dropwise. HCl to adjust the pH to 6. The organic solution was dried over anhydrous MgSO ₄ , filtered and 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%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.52 (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).

Example 20. Preparation of N-(3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)phenyl)acetamide

Step 1: preparation of 7-fluoro-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)propyl)isoquinolin-1 (2H)-one

After dissolving 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) in CH ₃ CN (100 ml) NaI (1.5 g; 10.02 mmol) was added dropwise at room temperature. NaHCO ₃ (2.1 g, 25.05 mmol) was slowly added dropwise to the reaction solution, followed by stirring at 80°C for 17 hours. The reaction solution was diluted with EtOAc and washed with water, and the organic solution was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure. The resulting residue was separated and purified using 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%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.53 (br, 1H), 7.95 (d, 1H, J=9.9 Hz), 7.77 (m, 1H), 7.67 (d, 1H, J=7.8 Hz), 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=5.9 Hz), 1.93 (m, 2H).

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

After dissolving 7-fluoro-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)propyl)-isoquinolin-1(2H)-one (400 mg; 0.97 mmol) in EtOH (5 ml ) at room temperature, Pd/C (40 mg) was slowly added dropwise, followed by stirring under H ₂ atmosphere for 7 hours. 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%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.31 (br, 1H), 7.98 (d, 1H, 7-8.7 Hz), 7.46-7.42 (m, 1H), 7.36-7.31 (m, 1H), 7.05 (t, 1H, J=7.8 Hz), 6.40 (d, 1H, J=8.4 Hz), 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=5.9 Hz), 1.93-1.97 (m, 2H).

Step 3: Preparation of N-(3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)phenyl)acetamide

After dissolution of 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) in CH ₃ Cl (8.4 ml) at room temperature, TEA (0.35 ml; 2.52 mmol) was slowly added dropwise to the reaction solution followed by stirring at 60°C for 7 hours. The reaction solution was diluted with EtOAc and washed with water, and the organic solution was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure. The resulting residue was separated and purified using silica gel chromatography to obtain the target compound N-(3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1- yl)phenyl)acetamide a (33 mg; 10%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.51 (br, 1H), 9.79 (br, 1H), 7.78 (d, 1H, J=7.8 Hz), 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=7.8 Hz), 6.62 (d, 1H, J=7.8 Hz), 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).

Example 21. Preparation of 5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.32 (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).

Example 22. Preparation of 6-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.32 (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).

Example 23. Preparation of 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) 5 7.50-7.47 (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).

Example 24. Preparation of 8-fluoro-5-methyl-3-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isoquinolin-1 (2H)-one

The title compound was prepared 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 acid used in Step 3 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.18-8.17 (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).

Example 25. Preparation of 8-fluoro-5-methyl-3-(3-(4-(pyrimidin-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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-pyrimidyl) piperazine was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 8 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.30-8.29 (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).

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

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.79 (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), 6.27 (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).

Example 27. Preparation of 8-fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared according to Example 1, except that 4-bromobenzotrifluoride 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 acid used in Step 3 of Example 1.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.51 (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).

Example 28. Preparation of 2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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 acid used in Step 3 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.91 (br, 1H), 7.59-7.48 (m, 2H), 7.35 (dd, 1H, J=8.0 Hz, 5.0 Hz), 7.16 (d, 1H, J=8.1 Hz), 7.02 (t, 1H, J=7.7 Hz), 6.92 (dd, 1H, J=11.9 Hz, 8.3 Hz), 6.28 (s, 1H), 3.52-3.49 (m, 4H), 2.82 (m, 4H), 2.74 (t, 2H, J=6.2 Hz), 2.58 (t, 2H, J=5.6 Hz), 2.43 (s, 3H) , 1.92 (m, 2H).

Example 29. Preparation of 8-fluoro-5-methyl-3-(3-(4-(thiazol-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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 acid used in Step 3 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.48 (br, 1H), 7.35 (dd, 1H, J=7.8 Hz, 4.8 Hz), 7.20 (d, 1H, J=3.3 Hz) , 6.93 (dd, 1H, J=11.3 Hz, 8.3 Hz), 6.57 (d, 1H, J=3.6 Hz), 6.28 (s, 1H), 3.75 (m, 4H), 2.74- 2.67 (m, 6H), 2.53 (t, 2H, J=6.2 Hz), 2.43 (s, 3H), 1.97-1.89 (m, 2H).

Example 30. Preparation of 8-fluoro-5-methyl-3-(3-(4-(5-methylthiazol-2-yl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.46 (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=5.9 Hz), 2.43 (s, 3H), 2.30 (s, 3H), 1.92 (m, 2H).

Example 31. Preparation of (R)-8-fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 12.13 (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 ).

Example 32. Preparation of (S)-8-fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 12.16 (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).

Example 33. Preparation of 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.41 (br, 1H), 7.36-7.33 (m, 1H), 7.20-7.17 (m, 2H), 6.94-6.85 (m, 3H), 6.27 (s, 1H ), 3.34-3.32 (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).

Example 34. Preparation of 4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

Step 1: Preparation of methyl 5-fluoro-2-hydroxy-3-methyl benzoate

After dissolving 5-fluoro-2-hydroxy-3-methylbenzaldehyde (24 g; 155.7 mmol) and sulfamic acid (22.7 g; 622.8 mmol) in dioxane (1944 ml), an aqueous solution of dihydrogen phosphate monohydrate was slowly added dropwise sodium (0.25 M; 630 ml) 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 was added dropwise and stirred for 10 minutes. The reaction solution was diluted with EtOAc and washed with 1 N. HCl and water and the organic solution was dried over anhydrous MgSO ₄ , 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 mixture solution was diluted with methanol (1 L) and sulfuric acid (60 ml) was added slowly dropwise and refluxed for 15 hours. The reaction solution was cooled to room temperature, diluted with EtOAc and then washed with water. The organic solution was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure to obtain the title compound 5-fluoro-2-hydroxy-3-methyl-benzoate (31.28 g; 58%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.78 (s, 1H), 7.35-7.33 (m, 1H), 7.09-7.06 (m, 1H), 3.94 (s, 3H), 2.26 (s, 3H).

Step 2: preparation of methyl 5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl)oxyU benzoate

Methyl 5-fluoro-2-hydroxy-3-methyl-benzoate (1.0 g; 5.43 mmol) was added to CH ₂ Cl ₂ (1 L) and trifluoromethanesulfonic acid anhydride (2.3 g; 8 .15 mmol). The mixture was stirred for 10 minutes and TEA (1.1 g; 10.86 mmol) was added dropwise, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solution was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was separated and purified using silica gel chromatography to obtain the target compound methyl-5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl )hydroxy)benzoate (1.5 g; 87%).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.53-7.52 (m, 1H), 7.20-7.17 (m, 1H), 3.94 (s, 3H), 2.43 (s, 3H).

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

After dissolving methyl 5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl)oxy)-benzoate (52 g, 164.4 mmol) in acetonitrile (822 ml), pent-4-yne-1 was added dropwise -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 then 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 an aqueous NH ₄ Cl solution. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the title compound methyl-5-fluoro-2-(5-hydroxypent-1-yn-yl)-3 -methyl benzoate (24.35 g; 59%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.41 (d, J=9.0 Hz, 1H), 7.10 (d, J=8.7 Hz, 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).

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

After dissolving methyl 5-fluoro-2-(5-hydroxypent-1-ynyl)-3-methyl-benzoate (24.35 g; 97.3 mmol) in THF/MeOH/H ₂ O (320 ml/80 ml/80 ml) LiOH⋅H ₂ O (20.4 g; 486.5 mmol) was added dropwise and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated by distillation under reduced pressure and then diluted with EtOAc and 6N was added slowly dropwise. HCl to bring the pH value to 1-2. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure. After dissolving the concentrated reaction solution in acetone (486 ml), AgNO ₃ (6.1 g; 19.46 mmol) was added dropwise. 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the title compound 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromene-1 -ona (8.3 g; 36%).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.76 (d, J=8.4 Hz, 1H), 7.28-7.24 (m, 1H), 6.38 (s, 1H), 3.75 (t, J=6.0 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.47 (s, 3H), 2.01-1.94 (m, 2H).

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

After dissolving 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one (5.5 g; 23.28 mmol) in a mixture of 7 N. NH ₃ /MeOH (33 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 give the title compound 7-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.9 g; 71%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.53 (d, J=9.3 Hz, 1H), 7.32 (d, J=9.3 Hz, 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).

Step 6: Preparation of 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate

After dissolving 7-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.9 g, 16.58 mmol) 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 added slowly dropwise at 0°C, followed by stirring at 25°C for 15 hours. The reaction solution was diluted with EtOAc and washed with an aqueous NH ₄ Cl solution. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to give the title compound 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl )propylmethanesulfonate (4.42 g; 85%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.63 (br, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.49 (s, 1H), 4.35 (t, J=5.7 Hz, 2H), 3.05 (s, 3H), 2.84 (t, J=5.7 Hz, 2H), 2.54 (s, 3H), 2.27 (m, 2H ).

Step 7: Preparation of 4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)benzonitrile

After dissolving 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate (200 mg; 0.64 mmol) in acetonitrile (2 ml), 4-(piperazine) was added dropwise -1-yl)benzonitrile 2HCl (249 mg; 0.96 mmol) at 25°C. DIPEA (diisopropylethylamine) (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 washed with aqueous NaS ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to give 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%).

^1H NMR (300 MHz, CDCl ₃ ) δ 11.65 (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).

Example 35. Preparation of 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)picolinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 12.62 (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).

Example 36. Preparation of 6-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperazin-1-yl)nicotinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.40 (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).

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

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.81 (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).

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

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 7.84-7.83 (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).

Example 39. Preparation of 7-fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)-phenyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared as in 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 7.84-7.83 (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).

Example 40. Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 7.85-7.82 (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).

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

Step 1: Preparation of tert-butyl 4-(4-cyanophenyl)-3.6-dihydropyridine-1(2H)-carboxylate

After dissolving tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g; 4.85 mmol) and 4-bromobenzonitrile (971.63 mg; 5.43 mmol) in dioxane (48 ml) and H ₂ O (16 ml) Pd(PPh ₃ ) ₂ Cl ₂ (170.25 mg) was added dropwise ; 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound tert-butium-4-(4-cyanophenyl)-3,6-dihydropyridine-1(2H )-carboxylate (1.2 g; 87%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.62 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 6.18 (br, 1H), 4.12 (m, 2H), 3.66-3.63 (m, 2H), 2.52 (m, 2H), 1.49 (s, 9H).

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

Mixture 4 N. HCl/dioxane (15 ml) was added to tert-butyl 4-(4-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.2 g; 2.22 mol) and the mixture was stirred for 15 hours. The resulting solid was filtered and washed with EtOAc to give the title compound 4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile HCl (837 mg; 90%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.50 (br, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.55 (d, J=9.0 Hz, 2H), 6.57 ( br, 1H), 3.79 (m, 2H), 3.31 (m, 2H), 2.74 (m, 2H).

Step 3: Preparation of 4-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile

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) 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 washed with aqueous Na ₂ S ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to give the target compound 4-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-3 -yl)propyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (60 mg; 29%).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.63-7.60 (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).

Example 42. Preparation of 8-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared according to Example 41, except that 4-bromofluorobenzene was used instead of 4-bromobenzonitrile used in Step 1 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.00 (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).

Example 43. Preparation of 8-fluoro-3-(3-(6-fluoro-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)propyl)isoquinoline-1 (2 N)-she

The title compound was prepared according to Example 41, except that 5-bromo-2-fluoropyridine was used instead of 4-bromobenzonitrile used in Step 1 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.05 (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).

Example 44. Preparation of 8-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)propyl)isoquinoline-1 (2 N)-she

The title compound was prepared according to Example 41, except that 2-bromo-5-fluoropyridine was used instead of 4-bromobenzonitrile used in Step 1 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.00 (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).

Example 45. Preparation of 8-fluoro-3-(3-(4-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared according to Example 41, except that 4-bromobenzotrifluoride was used instead of 4-bromobenzonitrile used in Step 1 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.93 (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, 1H), 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).

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

The title compound was prepared according to Example 41, except that 2-bromo-5-cyanopyridine was used instead of 4-bromobenzonitrile used in Step 1 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.02 (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).

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

The title compound was prepared according to Example 41, except that 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2 -dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.22 (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).

Example 48. Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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)-propylmethanesulfonate used in Step 3 of Example 41.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.46 (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).

Example 49. Preparation of 3-(3-(4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-7-fluoroisoquinolin-1(2H)-one

The title compound was prepared 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-dihydroisoquinoline- 3-yl)-propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.13 (br, 1H), 7.96-7.94 (m, 1H), 7.47-7.27 (m, 6H), 6.26 (s, 1H), 6.10 (s, 1H), 3.26-3.24 (m, 2H), 2.82-2.67 (m, 6H), 2.57-2.55 (m, 2H), 1.96-1.94 (m, 2H).

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

The title compound was prepared 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-dihydroisoquinoline- 3-yl)-propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.20 (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).

Example 51. Preparation of 7-fluoro-3-(3-(4-(2-fluoro-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.27 (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).

Example 52. Preparation of 2-fluoro-4-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-1,2,3,6-tetrahydropyridine-4- yl)benzonitrile

The title compound was prepared 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-dihydroisoquinoline- 3-yl)-propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.16 (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, 1H), 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).

Example 53. Preparation of 8-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.07 (br, 1H), 7.42-7.32 (m, 3H), 7.03-6.88 (m, 3H), 6.27 (s, 1H), 6.04 (s, 1H), 3.23-3.22 (m, 2H), 2.81-2.67 (m, 6H), 2.58-2.54 (m, 2H), 2.42 (s, 3H), 1.97-1.93 (m, 2H).

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

The title compound was prepared according to Example 41, except that 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo -1,2-dihydroisoquinolin-3-yl)-propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.03 (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).

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

The title compound was prepared 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)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.99 (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).

Example 56. Preparation of 8-fluoro-3-(3-(4-(2-fluoro-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinoline-1(2H) -she

The title compound was prepared 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)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

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).

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

The title compound was prepared 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)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.03 (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).

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

The title compound was prepared according to Example 41, except that 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo -1,2-dihydroisoquinolin-3-yl)-propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.27 (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).

Example 59. Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

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).

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

The title compound was prepared 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)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.06 (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).

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

The title compound was prepared 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-oxo-1, 2-dihydroisoquinolin-3-yl)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.25 (br, 1H), 8.23 (s, 1H), 7.89-7.83 (m, 2H), 7.70-7.67 (m, 1H), 7.22-7.19 (m, 1H ), 6.35-6.34 (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).

Example 62. Preparation of 7-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)propyl)-5- methylisoquinolin-1(2H)-one

The title compound was prepared 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)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.14 (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, 1H), 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).

Example 63. Preparation of 7-fluoro-3-(3-(6-fluoro-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)propyl)-5- methylisoquinolin-1(2H)-one

The title compound was prepared 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)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.28 (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, 1H), 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).

Example 64. Preparation of 7-fluoro-5-methyl-3-(3-(4-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)isoquinoline-1(2H) -she

The title compound was prepared according to Example 41, except that 4-bromobenzotrifluoride was used instead of 4-bromobenzonitrile used in Step 1 of Example 41, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinoline- 3-yl)-propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 41.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.17 (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), 3.28-3.27 (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).

Example 65. Preparation of 8-fluoro-3-(3-(4-(3-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

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

After dissolving 1-Boc-piperazine (1.0 g; 5.37 mmol) in CH ₂ Cl ₂ (54 ml), 3-fluorobenzoic acid (902 mg; 6.443 mmol), HBTU (hexafluorophosphate O-(benzotriazole) -1-yl)-N,N,N',N'-tetramethyluronium) (2.44 g; 6.44 mmol) and Et ₃ N (2.24 ml; 16.10 mmol) and stirred at room temperature in within 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound, tert-butyl 4-(3-fluorobenzoyl)piperazine-1-carboxylate (1.6 g; 99%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.41-7.36 (m, 1H), 7.18-7.10 (m, 3H), 3.72-3.41 (m, 8H), 1.47 (s, 9H).

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

4 n. 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 resulting solid was filtered and washed with EtOAc to give the title compound (3-fluorophenyl)(piperazin-1-yl)methanone HCl (1.28 g; 100%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.56-7.53 (m, 1H), 7.33-7.27 (m, 3H), 3.67 (br, 4H), 3.14 (br, 4H).

Step 3: Preparation of 8-fluoro-3-(3-(4-3-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

After dissolving 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate (200 mg; 0.64 mmol) in acetonitrile (3 ml), (3-fluorophenyl )(piperazin-1-yl)methanone HCl (234 mg; 0.96 mmol) at 25°C. NaHCO ₃ (268 mg; 3.19 mmol) and NaI (191 mg; 1.27 mmol) were added dropwise and the mixture was heated to 80° C. and stirred for 17 hours. The reaction solution was diluted with EtOAc and washed with aqueous NaS ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , 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%).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.41-7.33 (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).

Example 66. Preparation of 3-(3-(4-benzoylpiperazin-1-yl)propyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared according to Example 65, except that benzoic acid was used instead of 3-fluorobenzoic acid used in Step 1 of Example 65.

^1H NMR (300 MHz, CDCl ₃ ) δ 7.41-7.32 (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).

Example 67. Preparation of 8-fluoro-3-(3-(4-(4-fluorobenzoyl)piperazin-1-yl)propyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared according to Example 65, except that 4-fluorobenzoic acid was used instead of 3-fluorobenzoic acid used in Step 1 of Example 65.

^1H NMR (300 MHz, CDCl ₃ ) δ 7.47-7.42 (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).

Example 68. Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

Step 1: Preparation of 3-(8-fluoro-1-oxo-1H-isochromen-3-yl)propionic acid

After dissolving 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one (10.0 g, 42.33 mmol) in acetone (420 ml), 2.5 M Jones' reagent (68) was slowly added dropwise ml) 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to obtain the title compound 3-fluoro-1-oxo-1H-isochromen-3-yl)propionic acid (6.4 g; 61%).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.84-7.72 (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).

Step 2: Preparation of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid

After dissolving 3-(8-fluoro-1-oxo-1H-isochromen-3-yl)propionic acid (1.0 g; 4.23 mmol) in a mixture of 7 N. 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 give the title compound 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid (840 g; 84%).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.61-7.54 (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).

Step 3: Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

After dissolving 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid (80 mg; 0.34 mmol), 4-(piperazin-1-yl)benzonitrile 2HCl (106 mg; 0.41 mmol) in DMF (25 ml) was added dropwise HBTU (193 mg; 0.51 mmol). TEA (172 mg; 1.7 mmol) was added dropwise and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with CH ₂ Cl ₂ and washed with water. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using 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%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.36 (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).

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

The title compound was prepared by 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.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.22 (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).

Example 70. Preparation of 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile

The title compound was prepared by using 5-(piperazin-1-yl)picolinonitrile hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.57 (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).

Example 71. Preparation of 6-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile

The title compound was prepared by using 6-(piperazin-1-yl)nicotinonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.44 (br, 1H), 8.42 (s, 1H), 7.66 (d, 1H, J=8.7 Hz), 7.56-7.49 (m, 1H), 7.22 ( d, 1H, J=7.8 Hz), 7.04-6.98 (m, 1H), 6.60 (d, 1H, J=9.3 Hz), 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).

Example 72. Preparation of 2-fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared by using 2-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.43 (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=8.7 Hz), 6.53 (d, 1H, J=12.6 Hz), 6.28 (s, 1H), 3.85 (t, 2H, J=5.3 Hz), 3.67 (t, 2H, J=4.9 Hz), 3.39 (m, 4H), 2.95 (t, 2H, J=5.7 Hz), 2.82 (t, 2H, J=5.7 Hz ).

Example 73. Preparation of 3-fluoro-4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared by using 3-fluoro-4-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.54 (br, 1H), 7.56-7.49 (m, 1H), 7.38 (d, 1H, J=8.1 Hz), 7.33-7.29 (m, 1H), 7.22 (d, 1H, J=8.4 Hz), 7.05-6.98 (m, 1H), 6.89 (t, 1H, J=8.6 Hz). 6.29 (s, 1H), 3.86 (t, 2H, J=4.8 Hz), 3.66 (t, 2H, J=4.8 Hz), 3.20-3.17 (m, 4H), 2.95 (t, 2H, J=5.6 Hz), 2.83 (t, 2H, J=5.9 Hz).

Example 74. Preparation of 2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared by using 2-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.32 (br, 1H), 7.60 (d, 1H, J=7.8 Hz), 7.52-7.49 (m, 2H), 7.21 (d, 1H, J=7 ,8 Hz), 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).

Example 75. Preparation of 8-fluoro-3-(3-(4-(2-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared by using 1-(2-fluorophenyl)piperazine hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.42 (br, 1H), 7.52-7.48 (m, 1H), 7.21 (d. 1H, J=7,S Hz), 7.07-6.98 (m, 4H), 6.90 (t, 1H, J=S,3 Hz), 6.26 (s, 1H), 3.86 (t, 2H, J=4.7 Hz), 3.64 (t, 2H, J=4.7 Hz), 3.07 -3.05 (m, 4H), 2.94 (t, 2H, J=5.7 Hz), 2.81 (t, 2H, J=5.9 Hz).

Example 76. Preparation of 5-fluoro-2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared by using 5-fluoro-2-(piperazin-1-yl)benzonitrile hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.38 (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=4.2 Hz), 3.69 (t, 2H, J=4.5 Hz), 3.10 (m, 4H), 2.94 (t, 2H, J=5.7 Hz) , 2.81 (t, 2H, J=5.6 Hz).

Example 77. Preparation of 3-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared by using 3-(piperazin-1-yl)benzonitrile hydrochloride instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.45 (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=5.1 Hz), 3.65 (t, 2H, J=5.0 Hz), 3.24- 3.21 (m, 4H), 2.95 (t, 2H, J=5.9 Hz), 2.83 (t, 2H, J=6.0 Hz).

Example 78. Preparation of 3-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

The title compound was prepared by using 1-(2,4-difluorophenyl)piperazine hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.08 (br, 1H), 7.52-7.48 (m, 1H), 7.20 (d, 1H, J=8.4 Hz), 7.05-6.99 (m, 1H), 6.91-6.80 (m, 3H), 6.23 (s, 1H), 3.85 (t, 2H, J=4.7 Hz), 3.61 (t, 2H, J=4.8 Hz), 3.00-2.99 (m, 4H), 2.92 (t, 2H, J=5.7 Hz), 2.76 (t, 2H, J=5.9 Hz).

Example 79. Preparation of 4-fluoro-3-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared by using 4-fluoro-3-(piperazin-1-yl)benzonitrile hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.46 (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=5.4 Hz), 2.83 (t, 2H, J=5.4 Hz).

Example 80. Preparation of 2-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared by using 2-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.17 (br, 1H), 7.55-7.48 (m, 1H), 7.21 (d, 1H, J=7.8 Hz), 7.13-7.10 (m, 2H), 7.05-6.99 (m, 2H), 6.25 (s, 1H), 3.85 (t, 2H, J=5.3 Hz), 3.63 (t, 2H, J=4.8 Hz), 3.15-3.12 (m, 4H), 2.94 (t, 2H, J=5.9 Hz), 2.79 (t, 2H, J=5.9 Hz).

Example 81. Preparation of 4-fluoro-2-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared by using 4-fluoro-2-(piperazin-1-yl)benzonitrile hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.45 (br, 1H), 7.60-7.49 (m, 2H), 7.21 (d, 1H, J=7.8 Hz), 7.06-6.99 (m, 1H), 6.76 (m, 1H), 6.64 (dd, 1H, J=10.8 Hz, 2.4 Hz), 6.28 (s, 1H), 3.89 (t, 2H, J=4.7 Hz), 3.70 (t , 2H, J=4.7 Hz), 3.23-3.17 (m, 4H), 2.95 (t, 2H, J=5.9 Hz), 2.82 (t, 2H, J=5.9 Hz).

Example 82. Preparation of 8-fluoro-3-(3-(4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared by using 4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.22 (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=5.6 Hz), 3.64 (t, 1H, J=5.7 Hz), 2.94-2.92 ( m, 2H), 2.83-2.78 (m, 2H), 2.56 (m, 2H).

Example 83. Preparation of 8-fluoro-3-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared by using 4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.25 (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=5.3 Hz), 2.82-2.74 (m, 4H), 2.50-2.43 ( m, 2H).

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

The title compound was prepared by 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.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.31 (br, 1H), 7.53-7.49 (m, 1H), 7.41 (d, 1H, J=7.8 Hz), 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=5.6 Hz), 3.69 (t, 1H, J=5.6 Hz), 2.95-2.93 (m, 2H), 2.86-2.78 (m, 2H), 2.52 (m, 2H).

Example 85 Preparation of 8-fluoro-3-(3-(6-fluoro-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)-3-oxopropyl) isoquinolin-1(2H)-one

The title compound was prepared by using 6-fluoro-1',2',3',6'-tetrahydro-3,4'-bipyridine hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.25 (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=7.8 Hz), 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).

Example 86. Preparation of 8-fluoro-3-(3-(5-fluoro-3e,6e-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)isoquinoline- 1(2H)-she

The title compound was prepared by using 5-fluoro-1',2',3',6'-tetrahydro-2,4'-bipyridine hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.27 (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=7.8 Hz), 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=5.6 Hz), 3.67 (t, 1H, J=5.6 Hz), 2.94 (t, 2H, J=6.6 Hz), 2.85-2.76 (m, 2H), 2.70 -2.65 (m, 2H).

Example 87. Preparation of 2-fluoro-5-(1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridine-4- yl)-benzonitrile

The title compound was prepared by 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.41 (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=5.7 Hz), 3.69 (t, 1H, J=5.7 Hz), 2.95-2.94 (m, 2H), 2.87-2.80 (m, 2H), 2.50 (m, 2H).

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

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.35 (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).

Example 89. Preparation of 8-fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared by using 1-(3-fluorophenyl)piperazine hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.68 (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.S Hz), 3.64 (t, 2H, J=4.8 Hz), 3.20-3.15 (m, 4H), 2.96 ( t, 2H, J=6.0 Hz), 2.84 (t, 2H, J=6.0 Hz).

Example 90. Preparation of 2-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared by using 2-fluoro-5-(piperazin-1-yl)benzonitrile hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.70 (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=4.8 Hz), 3.67 (m, 2H), 3.24- 3.23 (m, 4H), 2.97 (t, 2H, J=6.6 Hz), 2.86 (t, 2H, J=6.3 Hz).

Example 91. Preparation of 4-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile hydrochloride

The target 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.

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.24 (br, 1H), 7.62-7.59 (m, 3H), 7.33 (d, 1H, J=7.8 Hz), 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).

Example 92. Preparation of 3-fluoro-3-(3-(2'-fluoro-3,6-dihydro-[4,4'-bipyridin]-1(2H)-yl)-3-oxopropyl)isoquinoline-1( 2H)-she

The title compound was prepared by using 2'-fluoro-1,2,3,6-tetrahydro-4,4'-bipyridine hydrochloride instead of the 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.22 (br, 1H), 8.17 (d, 1H, J=4.8 Hz), 7.50 (m, 1H), 7.19-7.14 (m, 1H), 7.13 ( d, 1H, J=4.8 Hz), 7.04-7.00 (m, 1H), 6.83 (d, 1H, J=6.9 Hz), 6.38-6.25 (m, 2H), 4.36 (m, 1H) , 4.17 (m, 1H), 3.90 (t, 1H, J=5.1 Hz), 3.69 (t, 1H, J=5.1 Hz), 2.95-2.93 (m, 2H), 2.83-2.79 (m , 2H), 2.53 (m, 2H).

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

The title compound was prepared 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.

¹ H NMR (300 MHz. CDCl ₃ ) δ 10.44 (br, 1H), 8.71 (s, 1H), 7.75-7.65 (m, 2H), 7.51 (m, 1H), 7.21 (d, 1H, J=5 ,4 Hz), 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=5.3 Hz) , 3.73 (t, 1H, J=4.8 Hz), 2.96-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.56 (m, 2H).

Example 94. Preparation of 4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.36 (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).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, CDCl ₃ ) δ 10.65 (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), 4.36-4.35 (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).

Example 96. Preparation of 1'-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)ropanoyl)-1',2',3',6'-tetrahydro-[2,4 '-bipyridine]-5-carbonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.42 (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 ).

Example 97. Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.37 (br, 1H), 8.41-8.40 (m, 1H), 7.78-7.75 (m, 2H), 7.67-7.62 (m, 1H), 7.57-7.54 ( 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).

Example 98. Preparation of 2-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.80-7.17 (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).

Example 99. Preparation of 6-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.80-7.17 (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).

Example 100. Preparation of 3-fluoro-4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.45 (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).

Example 101. Preparation of 2-fluoro-4-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.37 (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).

Example 102. Preparation of 7-fluoro-3-(3-(6-fluoro-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)-3-oxopropyl) isoquinolin-1(2H)-one

The title compound was prepared 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 Stage 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.58 (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), 6.10-5.97 (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) .

Example 103. Preparation of 7-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-3-oxopropyl) isoquinolin-1(2H)-one

The title compound was prepared 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 Stage 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.83 (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, 1H), 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).

Example 104. Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared 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 in place of 4-(piperazin-1-yl)benzonitrile 2HC1 used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.71 (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).

Example 105. Preparation of 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.50 (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).

Example 106. Preparation of 3-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.45 (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).

Example 107. Preparation of 4-fluoro-3-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.39 (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).

Example 108. Preparation of 4-fluoro-2-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.39 (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).

Example 109. Preparation of 2-fluoro-5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.38 (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).

Example 110. Preparation of 5-fluoro-2-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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 2HC1 used in Step 3 of Example 68.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.39 (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).

Example 111. Preparation of 4-fluoro-3-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridine-4- yl)-benzonitrile

The title compound was prepared 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 Stage 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.59 (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).

Example 112. Preparation of 5-fluoro-2-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridine-4- yl)-benzonitrile

The title compound was prepared 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 Stage 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.36 (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), 4.13-4.12 (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).

Example 113. Preparation of 3-(3-(4-(2,4-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

The title compound was prepared 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 in place of 4-(piperazin-1-yl)benzonitrile 2HC1 used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.56 (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).

Example 114. Preparation of 3-fluoro-5-(1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-1,2,3,6-tetrahydropyridine-4- yl)-benzonitrile

The title compound was prepared 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 Stage 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.73 (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), 4.17-4.16 (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).

Example 115. Preparation of 7-fluoro-3-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared 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 in place of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.50 (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).

Example 116. Preparation of (R)-7-fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared 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 (H)-3-(4-fluorophenyl)pyrrolidine was used in place of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.55 (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), 4.13-4.07 (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).

Example 117. Preparation of (S)-7-fluoro-3-(3-(3-(4-fluorophenyl)pyrrolidin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared 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 in place of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.55 (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), 4.13-4.07 (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).

Example 118. Preparation of 7-fluoro-3-(3-oxo-3-(4-(4-(trifluoromethyl)phenyl)-piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.40 (br, 1H), 8.00-7.97 (m, 1H), 7.51-7.30 (m, 4H), 6.92-6.89 (m, 2H), 6.28 (s, 1H ), 3.85-3.84 (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).

Example 119. Preparation of 3-fluoro-5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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 2HC1 used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.68 (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).

Example 120. Preparation of 7-fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared 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.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.66 (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).

Example 121. Preparation of 7-fluoro-3-(3-(2'-fluoro-3,6-dihydro-[4,4'-bipyridin]-1(2H)-yl)-3-oxopropyl)isoquinoline-1( 2H)-she

The title compound was prepared 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 Examples 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.66 (s, 1H), 8.16-8.15 (m, 1H), 7.98-7.95 (m, 1H), 7.47-7.42 (m, 1H), 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).

Example 122. Preparation of 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.82 (br, 1H), 7.53-7.50 (m, 2H), 7.38-7.34 (m, 1H), 6.93-6.82 (m, 3H), 6.36 (s, 1H ), 3.84-3.83 (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).

Example 123. Preparation of 6-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.73 (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).

Example 124. Preparation of 5-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.76 (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).

Example 125. Preparation of 8-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinoline-1(2H)- she

The title compound was prepared 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 in place of 4-(piperazin-1-yl)benzonitrile 2HC1 used in Step 3 Examples 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.56 (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).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, CDCl ₃ ) δ 10.59 (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).

Example 127. Preparation of 2-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.69 (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), 6.35 (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).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, CDCl ₃ ) δ 10.38 (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).

Example 129. Preparation of 8-fluoro-3-(3-(6-fluoro-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)-3-oxopropyl) -5-methylisoquinolin-1(2H)-one

The title compound was prepared 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.

1H NMR (300 MHz, CDCl ₃ ) δ 10.42 (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), 4.32-4.31 (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).

Example 130. Preparation of 8-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-3-oxopropyl) -5-methylisoquinolin-1(2H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.31 (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), 4.16-4.15 (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).

Example 131. Preparation of 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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 in place of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.52 (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).

Example 132. Preparation of 3-(3-(4-(2,4-difluorophenyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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 in place of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.91 (br, 1H), 7.38-7.33 (m, 1H), 6.94-6.78 (m, 4H), 6.36 (s, 1H), 3.83-3.82 (m, 2H ), 3.66-3.65 (m, 2H), 2.98-2.96 (m, 6H), 2.88-2.86 (m, 2H), 2.43 (s, 3H).

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

The title compound was prepared 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 .

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.39 (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).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.30 (br, 1H), 7.84-7.79 (m, 1H), 7.48-7.44 (m, 1H), 7.03-6.94 (m, 3H), 6.38 (s, 1H), 3.66-3.65 (m, 4H), 3.19-3.13 (m, 4H), 2.78-2.72 (m, 4H), 2.38 (s, 3H).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.28 (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).

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

The title compound was prepared 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 .

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.30 (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).

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

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.49 (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).

Example 138. Preparation of 8-fluoro-3-(3-(4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinoline-1(2H)- she

The title compound was prepared 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 Examples 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.14 (br, 1H), 7.39-7.21 (m, 3H), 7.12 (d, 1H, J=7.8 Hz), 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=5.6 Hz), 3.64 (t, 1H, J=5.6 Hz), 2.97 (t, 2H, J=5.3 Hz), 2.83-2.76 (m, 2H), 2.56 (m, 2H), 2.43 (s , 3H).

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

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.39 (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=5.7 Hz), 3.69 (t, 1H, J=5.4 Hz), 2.99 (m, 2H), 2.87-2.79 (m, 2H), 2.51 (m, 2H) . 2.43 (s, 3H).

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

The title compound was prepared 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-(piperazine-1 -yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.52 (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), 4.41 (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).

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

The title compound was prepared 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.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.69 (br, 1H), 7.60-7.55 (m, 1H), 7.34 (m, 1H), 7.22 (d, 1H, J=8.1 Hz), 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=4.5 Hz), 3.70 (t, 1H, J=4.5 Hz), 3.00 (m, 2H), 2.89-2.85 (m, 2H), 2.51 (m, 2H), 2.42 (s , 3H).

Example 142. Preparation of 8-fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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 in place of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.19 (br, 1H), 7.38-7.34 (m, 1H), 7.20 (q, 1H, 7-7.6 Hz), 6.94-6.87 (m, 1H), 6.65-6.52 (m, 3H), 6.39 (s, 1H), 3.81 (t, 2H, J=4.8 Hz), 3.66 (t, 2H, 7-4.7 Hz), 3.19-3.12 (m, 4H), 3.01 (t, 2H, J=6.3 Hz), 2.90 (t, 2H, J=6.3 Hz), 2.44 (s, 3H).

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

The title compound was prepared 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 .

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.36 (br, 1H), 7.40-7.36 (m, 1H), 6.94-6.87 (m, 1H). 6.84 (s, 1H), 6.81 (d, 1H, J=7.8 Hz), 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).

Example 144. Preparation of 8-fluoro-3-(3-(2'-fluoro-3,6-dihydro-[4,4-bipyridin]-1(2H)-yl)-3-oxopropyl)-5-methylisoquinoline- 1(2H)-she

The title compound was prepared 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 Stage 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.42 (br, 1H), 8.17 (d, 1H, J=4.5 Hz), 7.35-7.33 (m, 1H), 7.13 (d, 1H, J=3 ,9 Hz), 6.95-6.88 (m, 1H), 6.82 (d, 1H, 7-8.4 Hz), 6.38-6.23 (m, 2H), 4.36 (m, 1H), 4.18 (m, 1H) , 3.90 (t, 1H, J=5.4 Hz), 3.70 (t, 1H, J=5.6 Hz), 2.99 (m, 2H), 2.88-2.82 (m, 2H), 2.53 (m, 2H ), 2.43 (s, 3H).

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

The title compound was prepared 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-(piperazine-1 -yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.67 (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=5.6 Hz), 3.74 (t, 1H, J=5.6 Hz), 3.01-2.99 (m, 2H), 2.92-2.86 (m, 2H), 2.56 (m, 2H), 2.43 (s, 3H).

Example 146. Preparation of methyl 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzoate

The title compound was prepared 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 methyl 4-(piperazin-1-yl)benzoate hydrochloride was used instead of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.97 (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=5.1 Hz), 3.67 (t, 2H, J=4.2 Hz), 3.34-3.32 ( m, 4H), 3.00 (t, 2H, J=6.3 Hz), 2.88 (t, 2H, J=6.3 Hz), 2.43 (s, 3H).

Example 147. Preparation of 4-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)-benzoic acid

The title compound was prepared 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 .

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.28 (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).

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]octane- 3-yl)-benzonitrile

The title compound was prepared 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 Stage 3 of Example 68.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.03 (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), 4.93 (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).

Example 149. Preparation of 4-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)benzonitrile

The title compound was prepared 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.

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.40 (br, 1H), 7.65-7.59 (m, 3H), 7.44 (d, 1H, J=9.9 Hz), 7.03-7.00 (m, 2H), 6.45 (s, 1H), 3.63-3.62 (m, 4H), 3.33 (m, 4H), 2.79 (m, 4H), 2.47 (s, 3H).

Example 150. Preparation of 7-fluoro-3-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinoline-1(2H)- she

The title compound was prepared 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 Examples 68.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.42 (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=5.4 Hz), 2.81-2.78 (m, 4H), 2.50 (m, 2H), 2.46 (s, 3H).

Example 151. Preparation of 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.41 (br, 1H), 8.42 (d, 1H, J=2.4 Hz), 7.77 (d, 1H, J=8.7 Hz), 7.64 (dd , 1H, J=9.3 Hz, 2.4 Hz), 7.44 (dd, 1H, J=9.3 Hz, 2.4 Hz), 7.36 (dd, 1H, J=8.7 Hz, 3.0 Hz ), 6.45 (s, 1H), 3.64 (m, 4H), 3.46-3.41 (m, 4H), 2.79 (m, 4H), 2.48 (s, 3H).

Example 152. Preparation of 6-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)nicotinonitrile

The title compound was prepared 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.

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.41 (br, 1H), 8.51 (s, 1H), 7.89 (d, 1H, J=9.3 Hz), 7.64 (d, 1H, J=8, 7 Hz), 7.44 (d, 1H, J=8.7 Hz), 6.94 (d, 1H, J=9.3 Hz), 6.46 (s, 1H), 3.71-3.61 (m, 8H), 2.79 ( m, 4H), 2.48 (s, 3H).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.39 (br, 1H), 7.66-7.60 (m, 2H), 7.44 (d, 1H, J=9.6 Hz), 6.95 (d, 1H, J= 13.5 Hz), 6.84 (d, 1H, J=8.7 Hz), 6.45 (s, 1H), 3.62 (m, 4H), 3.45-3.42 (m, 4H), 2.79 (m, 4H), 2.48 (s, 3H).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.43 (br, 1H), 7.74 (d, 1H, J=13.2 Hz), 7.64 (d, 1H, J=9.6 Hz), 7.59 (d , 1H, J=8.7 Hz), 7.45 (d, 1H, J=9.3 Hz), 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).

Example 155 Preparation of 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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 in place of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.43 (br, 1H), 7.64 (d, 1H, J=9.3 Hz), 7.44 (d, 1H, J=9.3 Hz), 7.26-7.23 (m, 2H), 6.97-6.94 (m, 2H), 6.45 (s, 1H), 3.61 (m, 4H), 3.12-3.10 (m, 4H), 2.78 (m, 4H), 2.47 (s, 3H ).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.65-7.62 (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).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.42 (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).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.41 (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).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, CDCl ₃ ) δ 10.71 (br, 1H), 7.88-7.85 (m, 1H), 7.31-7.19 (m, 3H), 6.98-6.93 (m, 1H), 6.37 (s, 1H ), 3.89-3.88 (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).

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

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.41 (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).

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

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.54 (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), 4.15-4.14 (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).

Example 162. Preparation of 3-(3-(4-(2,4-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinoline-1(2H )-she

The title compound was prepared 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 2HCl used at Stage 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.77 (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).

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

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.53 (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).

Example 164. Preparation of 7-fluoro-3-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-5-methylisoquinoline-1(2H)- she

The title compound was prepared 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 Examples 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.53 (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).

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

The title compound was prepared 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-(piperazine-1 -yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.37 (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, 1H), 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).

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

The title compound was prepared 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 .

^1H NMR (300 MHz, CDCl ₃ ) δ 10.32 (br, 1H), 7.88-7.85 (m, 1H), 7.26-7.19 (m, 1H), 6.88-6.74 (m, 3H), 6.35 (s, 1H ), 3.86-3.79 (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).

Example 167. Preparation of 7-fluoro-3-(3-(4-(3-fluorophenyl)piperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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 in place of 4-(piperazin-1-yl)benzonitrile 2HCl used in Step 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.54 (br, 1H), 7.88-7.85 (m, 1H), 7.21-7.19 (m, 2H), 6.67-6.55 (m, 3H), 6.36 (s, 1H ), 3.84-3.83 (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).

Example 168. Preparation of 7-fluoro-3-(3-(2'-fluoro-3,6-dihydro-[4,4'-bipyridin]-1(2H)-yl)-3-oxopropyl)-5-methylisoquinoline -1(2H)-she

The title compound was prepared 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 Stage 3 of Example 68.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.64 (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), 4.36-4.35 (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).

Example 169. Preparation of 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazin-1-yl)picolinonitrile dihydrochloride

The title compound was prepared 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 used in Example 6.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.41 (br, 1H), 8.49 (d, 1H, J=2.4 Hz), 7.75 (d, 1H, J=8.7 Hz), 7.63 (dd , 1H, J=9.3 Hz, 2.4 Hz), 7.44 (dd, 1H, J=9.3 Hz, 2.4 Hz), 7.36 (dd, 1H, J=8.7 Hz, 3.0 Hz ), 6.45 (s, 1H), 3.64 (m, 4H), 3.46-3.41 (m, 4H), 2.79 (m, 4H), 2.48 (s, 3H).

Example 170. Preparation of 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

Step 1: Preparation of tert-butyl 4-(cyclohexanecarbonyl)piperazine-1-carboxylate

After dissolving 1-Boc-piperazine (3.5 g; 22.3 mmol) and cyclohexanecarboxylic acid (2.0 g; 15.6 mmol) in DMF (52 ml), HBTU (8.9 g; 22 .3 mmol) and TEA (10.9 ml; 78.0 mmol) and stirred at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound tert-butyl 4-(cyclohexanecarbonyl)piperazine-1-carboxylate (3.45 g; 75 %).

^1H NMR (300 MHz, CDCl ₃ ) δ 3.57-3.31 (m, 8H), 2.44-2.41 (m, 1H), 1.79-1.08 (m, 19H).

Step 2: preparation of cyclohexyl(piperazin-1-yl)methanone

4 n. HCl (30 ml) was added to da/?eda-butyl-4-(cyclohexanecarbonyl)piperazine-1-carboxylate (3.45 g; 11.64 mmol) and the mixture was stirred for 15 hours. The resulting solid was filtered and washed with EtOAc to give the title compound cyclohexyl(piperazin-1-yl)methanone HCl (2.52 g; 93%).

¹ H NMR (300 MHz, DMSO- _d6 ) δ 9.20 (br, 1H), 3.64 (m, 4H), 3.04 (m, 4H), 2.56 (m, 1H), 1.62 (m, 5H), 1.28 (m , 5H).

Step 3: Preparation of 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

After dissolving 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid (60 mg; 0.25 mmol) and cyclohexyl(piperazin-1-yl)methanone HCl (89 mg; 0 .37 mmol) 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl )-8-fluoroisoquinolin-1(2H)-one (56 mg; 53%).

^1H NMR (300 MHz, CDCl ₃ ) δ 10.54 (br, 1H), 7.54-7.52 (m, 1H), 7.22 (d, 1H, J=7.8 Hz), 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).

Example 171. Preparation of 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared according to Example 170 except that 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid

was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.48 (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).

Example 172. Preparation of 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

The title compound was prepared according to Example 170, except that 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid was used instead of 3-(8-fluoro-1-oxo-1, 2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.30 (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), 2.93-2.91 (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).

Example 173. Preparation of 3-(3-(4-(cyclohexanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared according to Example 170 except that 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid

was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.45 (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), 2.96-2.95 (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).

Example 174. Preparation of 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

The title compound was prepared according to Example 170, except that cyclopentanecarboxylic acid was used instead of the cyclohexanecarboxylic acid used in Step 1 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.42 (br, 1H), 7.53-7.52 (m, 1H), 7.22 (d, 1H, J=8.4 Hz), 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).

Example 175. Preparation of 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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-dihydroisoquinoline-3- yl)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.53 (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).

Example 176. Preparation of 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

The title compound was prepared 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)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.44 (br, 1H), 8.00-7.97 (m, 1H), 7.45-7.43 (m, 1H), 7.37-7.34 (m, 1H), 6.28 (s, 1H ), 3.69-3.64 (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).

Example 177. Preparation of 3-(3-(4-(cyclopentanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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-dihydroisoquinoline-3- yl)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.35 (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).

Example 178. Preparation of 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

The title compound was prepared according to Example 170, except that cyclobutanecarboxylic acid was used instead of the cyclohexanecarboxylic acid used in Step 1 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.30 (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), 3.49-3.36 (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).

Example 179. Preparation of 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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-dihydroisoquinoline-3- yl)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.51 (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), 3.30-3.22 (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).

Example 180. Preparation of 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

The title compound was prepared 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)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.51 (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).

Example 181. Preparation of 3-(3-(4-(cyclobutanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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-dihydroisoquinoline-3- yl)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.41 (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), 3.30-3.27 (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).

Example 182. Preparation of 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.22 (br, 1H), 7.62-7.58 (m, 1H), 7.34 (d, 1H, J=7.8 Hz), 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).

Example 183. Preparation of 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.26 (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).

Example 184. Preparation of 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one

The title compound was prepared 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 α-dihydroisoquinolin-3-yl)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.50 (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).

Example 185. Preparation of 3-(3-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.55 (br, 1H), 7.87-7.84 (m, 1H), 7.22-7.19 (m, 1H), 6.36 (s, 1H), 3.71-3.46 (m, 8H ), 2.98-2.96 (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).

Example 186. Preparation of 8-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared according to Example 170, except that isobutyric acid was used instead of the cyclohexanecarboxylic acid used in Step 1 of Example 170.

^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.23 (br, 1H), 7.63-7.61 (m, 1H), 7.34 (d, 1H, J=6.0 Hz), 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).

Example 187. Preparation of 8-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared 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-dihydroisoquinoline-3- yl)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.57 (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).

Example 188. Preparation of 7-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)isoquinolin-1(2H)-one

The title compound was prepared according to Example 170, except that isobutyric acid was used instead of the cyclohexanecarboxylic acid used in Step 1 of Example 170, and 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.49 (br, 1H), 7.99-7.96 (m, 1H), 7.47-7.45 (m, 1H), 7.43-7.36 (m, 1H), 6.28 (s, 1H ), 3.70-3.63 (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).

Example 189. Preparation of 7-fluoro-3-(3-(4-isobutyrylpiperazin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared according to Example 170, except that isobutyric acid was used instead of the cyclohexanecarboxylic acid used in Step 1 of Example 170, and 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinoline-3- yl)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.49 (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).

Example 190. Preparation of 8-fluoro-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared according to Example 170, except that tetrahydrofuran-2-carboxylic acid was used instead of the cyclohexanecarboxylic acid used in Step 1 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.57 (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), 4.63-4.55 (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).

Example 191. Preparation of 8-fluoro-5-methyl-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.72 (br, 1H), 7.39-7.35 (m, 1H), 6.97-6.90 (m, 1H), 6.35 (s, 1H), 4.62-4.58 (m, 1H ), 3.94-3.78 (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).

Example 192. Preparation of 7-fluoro-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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-dihydroisoquinoline-3- yl)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.45 (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), 3.93-3.79 (m, 4H), 3.58-3.46 (m, 4H), 2.94-2.93 (m, 2H), 2.78-2.76 (m, 2H), 2.31-2.96 (m, 2H), 2.04-1.94 (m, 4H).

Example 193. Preparation of 7-fluoro-5-methyl-3-(3-oxo-3-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)propyl)isoquinolin-1(2H)-one

The title compound was prepared 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)propionic acid was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Step 3 of Example 170.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.45 (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).

Example 194. Preparation of 3-(3-(4-(L-alanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one hydrochloride

Step 1: Preparation of tert-butyl 4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazine-1-carboxylate

After dissolving 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid (300 mg; 1.20 mmol), Boc-piperazine (336 mg; 1.80 mmol ) and TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate)(928 mg; 2.88 mmol) in CH ₂ Cl ₂ (12.0 ml) at room temperature TEA (0.84 mL, 6.0 mmol) was slowly added dropwise to the reaction solution, followed by stirring at room temperature for 19 hours. The reaction solution was diluted with EtOAc and washed with water, and the organic solution was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure. The resulting residue was separated and purified using silica gel chromatography to give the title compound (440 mg; 88%).

^1H NMR (300 MHz, CDCl ₃ ) δ 10.44 (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).

Step 2: Preparation of 8-fluoro-5-methyl-3-(3-oxo-3-(piperazin-1-yl)propyl)isoquinolin-1(2H)-one

After dissolution of tert-butyl 4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazine-1-carboxylate (44 mg; 1.05 mmol) in a mixture of 4 n. HCl/dioxane (3 ml) mixture was stirred at room temperature for 16 hours. The resulting solid was filtered to give the target compound 8-fluoro-5-methyl-3-(3-oxo-3-(piperazin-1-yl)propyl)isoquinolin-1(2H)-one (304 mg; 82 %).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.26 (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).

Step 3: Preparation of tert-butyl-(S)-(1-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperazine-1- yl)-1-oxopropan-2-yl)carbamate

After dissolving 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) in CH ₂ Cl ₂ (3.0 ml) at room temperature, TEA (0.2 ml; 1 .4 mmol) and stirred at room temperature for 17 hours. The reaction solution was diluted with EtOAc and washed with water, and the organic solution was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure. The resulting residue was separated and purified using silica gel chromatography to obtain the target compound tert-butyl-(S)-(1-(4-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinoline- 3-yl)propanoyl)piperazin-1-yl)-1-oxopropan-2-yl)carbamate (59 mg; 43%).

^1H NMR (300 MHz, CDCl ₃ ) δ 11.51 (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).

Step 4: Preparation of 3-(3-(4-(L-alanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one hydrochloride

Mixture 4 N. HCl/dioxane (8 ml) was added to tert-butyl-(S)-(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; 0.12 mmol) and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated by evaporation under reduced pressure, and the resulting residue was filtered and washed with EtOAc to obtain the target compound 3-(3-(4-(L-alanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5 hydrochloride -methylisoquinolin-1(2H)-one (40 mg; 78%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.27 (br, 1H), 8.20 (br, 2H), 7.47 (m, 1H), 7.04-6.97 (m, 1H), 6.38 (s, 1H), 4.40 (m, 1H), 3.60-3.34 (m, 8H), 2.78 (m, 4H), 2.39 (s, 3H), 1.31 (m, 3H).

Example 195. Preparation of 3-(3-(4-(L-phenylalanyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one hydrochloride

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.26 (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, 1H), 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).

Example 196. Preparation of 8-fluoro-5-methyl-3-(3-oxo-3-(4-propylpiperazin-1-yl)propyl)isoquinolin-1(2H)-one hydrochloride

The title compound was prepared 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.

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.29 (br, 1H), 9.85 (br, 1H), 7.50-7.46 (m, 1H), 7.04-6.98 (m, 1H), 6.38 (s, 1H) , 4.60 (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).

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]octane-3 -yl)benzonitrile

Step 1: Preparation of tert-butyl 3-(4-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

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) was added Pd(OAc) 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound tert-butyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (845 mg; 71%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.49 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 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=6.9 Hz, 2H), 1.48 (s, 9H).

Step 2: preparation of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile 2HCl

Mixture 4 N. HCl/dioxane (10 ml) was added to tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (845 mg; 2.7 mmol) and the mixture was stirred for 15 hours. The resulting solid was filtered and washed with EtOAc to give the title compound 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile 2HCl (645 mg; 83%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 9.34 (br, 2H), 7.63 (d, J=6.9 Hz, 2H), 7.01 (d, J=7.5 Hz, 2H), 4.15 (m , 2H), 3.80 (d, J=12.9 Hz, 2H), 3.20 (d, J=12.3 Hz, 2H), 1.95-1.86 (m, 4H).

Step 3: Preparation of methyl 2-bromo-6-fluoro-3-methyl benzoate

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) was added at 0° C and stirred for 30 minutes. MeI (56 mL; 849.67 mmol) was slowly added dropwise to the reaction solution at 0°C, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with aqueous Na ₂ S ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound methyl 2-bromo-6-fluoro-3-methylbenzoate (93 g; 89%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.29-7.24 (m, 1H), 7.03-6.97 (m, 1H), 3.97 (s, 3H), 2.39 (s, 3H).

Step 4: Preparation of methyl 6-fluoro-2-(5-hydroxypent-1-yn-1-yl)-3-methylbenzoate

After methyl 2-bromo-6-fluoro-3-methylbenzoate (72 g; 291.43 mmol) was dissolved in CH ₃ CN (970 ml), pent-4-yn-1-ol (41 ml; 437.14 mmol) was added ), 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 an aqueous NH ₄ Cl solution. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the title compound methyl-6-fluoro-2-(5-hydroxypent-1-yn-1-yl) -3-methylbenzoate (13 g; 18%).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.27-7.19 (m, 1H), 6.97-6.91 (m, 1H), 3.95 (s, 3H), 3.83-3.81 (m, 2H), 2.60 (t, J =6.3 Hz, 2H), 2.38 (s, 3H), 1.90-1.84 (m, 2H).

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

After dissolving methyl 6-fluoro-2-(5-hydroxypent-1-in-1-yl)-3-methylbenzoate (13 g; 51.94 mmol) in THF/MeOH/H ₂ O (230 ml/60 ml/60 ml) LiOH⋅H ₂ O (13.1 g; 311.66 mmol) was added and stirred at room temperature for 15 hours. The reaction solution was concentrated by distillation under reduced pressure and then diluted with EtOAc and 6N was added slowly dropwise. HCl to bring the pH value to 1-2. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure. After dissolving the concentrated reaction solution in acetone (260 ml), AgNO ₃ (3.24 g; 10.39 mmol) was added dropwise. 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the title compound 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromene-1 -she (9.9 g; 81%).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.48-7.44 (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).

Step 6: Preparation of 8-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one

After dissolving 8-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one (4.1 g; 17.55 mmol) in a mixture of 7 N. NH ₃ /MeOH (100 ml) this 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 give the title compound 8-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.2 g; 78%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.27 (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).

Step 7: Preparation of 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate

After dissolving 8-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.2 g, 13.6 mmol) 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 added slowly dropwise at 0°C, followed by stirring at 25°C for 15 hours. The reaction solution was diluted with EtOAc and washed with an aqueous NH ₄ Cl solution. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to give the title compound 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl )propylmethanesulfonate (2.28 g; 54%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.36 (br, 1H), 7.49-7.45 (m, 1H), 7.04-6.98 (m, 1H), 6.36 (s, 1H), 4.23 (t, J =6.6 Hz, 2H), 3.19 (s, 3H), 2.61 (t, J=7.8 Hz, 2H), 2.39 (m, 3H), 2.10-2.00 (m, 2H).

Step 8: Preparation of 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octane- 3-yl)benzonitrile

After dissolving 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate (0.1 g, 0.032 mmol) in CH ₃ CN (20 ml), 4-(3 ,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile 2HCl (0.13 g, 0.45 mmol) at 25°C.

NaHCO ₃ (134 mg; 1.6 mmol) and NaI (96 mg; 0.64 mmol) were added and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and washed with aqueous NaS ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to give 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%).

^1H NMR (300 MHz, CDCl ₃ ) δ 11.46 (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).

Example 198. Preparation of 8-fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5-methylisoquinoline-1(2H)- she

The title compound was prepared according to Example 197, except that 1-bromo-4-fluorobenzene was used instead of 4-bromobenzonitrile used in Step 1 of Example 197.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.51 (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).

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]octane-3 -yl)-nicotinonitrile

The title compound was prepared according to Example 197, except that 6-bromonicotinonitrile was used instead of 4-bromobenzonitrile used in Step 1 of Example 197.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.39-8.38 (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).

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]octane- 3-yl)-picolinonitrile

The title compound was prepared according to Example 197, except that 5-bromopicolinonitrile was used instead of 4-bromobenzonitrile used in Step 1 of Example 197.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.43 (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).

Example 201. Preparation of 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-8-fluoro-5-methylisoquinoline-1(2H)- she

The title compound was prepared according to Example 197, except that 1-bromo-4-chlorobenzene was used instead of 4-bromobenzonitrile used in Step 1 of Example 197.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.42 (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).

Example 202. Preparation of 8-fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-5-methylisoquinoline-1 (2H)-she

The title compound was prepared according to Example 197, except that 5-bromo-2-fluoropyridine was used instead of 4-bromobenzonitrile used in Step 1 of Example 197.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.46 (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).

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

The title compound was prepared 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 acid used in Step 3 of Example 197.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.26 (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).

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

The title compound was prepared 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 acid used in Step 3 of Example 197.

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.57 (br, 1H), 8.47 (d, 1H, J=1.8 Hz), 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=9.3 Hz), 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).

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]octane- 3-yl)-nicotinonitrile

Step 1: Preparation of methyl 5-fluoro-2-hydroxy-3-methyl benzoate

After dissolving 5-fluoro-2-hydroxy-3-methylbenzaldehyde (24 g; 155.7 mmol) and NH ₂ SO ₃ H (22.7 g; 622.8 mmol) in dioxane (1.9 L) slowly dropwise an aqueous solution of NaH ₂ PO ₄ ⋅H ₂ O (0.25 M; 630 ml) was added and an aqueous solution of NaClO ₂ (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 was added and stirred for 10 minutes. The reaction solution was diluted with EtOAc and washed with 1 N. HCl and water and the organic solution was dried over anhydrous MgSO ₄ , 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 mixture solution was diluted with methanol (1 L) and sulfuric acid (60 ml) was added slowly dropwise and refluxed for 15 hours. The reaction solution was cooled to room temperature, diluted with EtOAc and then washed with water. The organic solution was dried over anhydrous MgSO ₄ filtered and then concentrated by evaporation under reduced pressure to obtain the title compound methyl 5-fluoro-2-hydroxy-3-methylbenzoate (31.28 g; 58%).

^1H NMR (300 MHz, CDCl ₃ ) δ 10.78 (s, 1H), 7.35-7.33 (m, 1H), 7.09-7.06 (m, 1H), 3.94 (s, 3H), 2.26 (s, 3H).

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

Methyl 5-fluoro-2-hydroxy-3-methylbenzoate (1.0 g; 5.43 mmol) was added to CH ₂ Cl ₂ (1 L) 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, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water, and the organic solution was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure. The resulting residue was separated and purified using silica gel chromatography to give the title compound methyl 5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (1.5 g; 87%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53-7.52 (m, 1H), 7.20-7.17 (m, 1H), 3.94 (s, 3H), 2.43 (s, 3H).

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

After dissolving methyl 5-fluoro-3-methyl-2-(((trifluoromethyl)sulfonyl)oxy)-benzoate (52 g, 164.4 mmol) in CH ₃ CN (822 ml), pent-4-yne-1 was added -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 an aqueous NH ₄ Cl solution. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the title compound methyl-5-fluoro-2-(5-hydroxypent-1-yn-1-yl) -3-methylbenzoate (24.35 g; 59%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.41 (d, J=9.0 Hz, 1H), 7.10 (d, J=8.7 Hz, 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).

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

After dissolving methyl 5-fluoro-2-(5-hydroxypent-1-yn-1-yl)-3-methylbenzoate (24.35 g; 97.3 mmol) in THF/MeOH/H ₂ O (320 ml /80 ml/80 ml) LiOH⋅H ₂ O (20.4 g; 486.5 mmol) was added and stirred at room temperature for 15 hours. The reaction solution was concentrated by distillation under reduced pressure, and then diluted with EtOAc and 6N was added slowly dropwise. HCl to bring the pH value to 1-2. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure. After dissolving the concentrated reaction solution in acetone (486 ml), AgNO ₃ (6.1 g; 19.46 mmol) was added. 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the title compound 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromene-1 -ona (8.3 g; 36%).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.76 (d, J=8.4 Hz, 1H), 7.28-7.24 (m, 1H), 6.38 (s, 1H), 3.75 (t, J=6.0 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.47 (s, 3H), 2.01-1.94 (m, 2H).

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

After dissolving 7-fluoro-3-(3-hydroxypropyl)-5-methyl-1H-isochromen-1-one (5.5 g; 23.28 mmol) in a mixture of 7 N. NH ₃ /MeOH (33 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 give the title compound 7-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.9 g, 71%).

¹ H NMR (300 MHz, DMSO- _d6 ) δ 7.53 (d, J=9.3 Hz, 1H), 7.32 (d, J=9.3 Hz, 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).

Step 6: Preparation of 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate

After dissolving 7-fluoro-3-(3-hydroxypropyl)-5-methylisoquinolin-1(2H)-one (3.9 g, 16.58 mmol) 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 added slowly dropwise at 0° C., followed by stirring at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with an aqueous NH ₄ Cl solution. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to give the title compound 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl )propylmethanesulfonate (4.42 g; 85%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.63 (br, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.49 (s, 1H), 4.35 (t, J=5.7 Hz, 2H), 3.05 (s, 3H), 2.84 (t, J=5.7 Hz, 2H), 2.54 (s, 3H), 2.27 (m, 2H ).

Step 7: Preparation of 6-(8-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-3,8-diazabicyclo[3.2.1]octane- 3-yl)nicotinonitrile

After dissolving 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-propylmethanesulfonate (100 mg; 0.32 mmol) in CH ₃ CN (3.2 ml) dropwise 6-(3,8-diazabicyclo[3,2.1]octan-3-yl)nicotinonitrile 3HCl (134 mg; 0.41 mmol) was added at 25°C. Na ₂ CO ₃ (169 mg; 1.59 mmol) and NaI (143 mg; 0.96 mmol) were added and the mixture was heated to 80° C. and stirred for 17 hours. The reaction solution was diluted with EtOAc and washed with aqueous Na ₂ S ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to give 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%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.63 (br, 1H), 8.47 (d, 1H, J=1.8 Hz), 7.84-7.82 (m, 1H), 7.64-7.61 (m, 1H) , 7.46-7.43 (m, 1H), 6.80 (d, 1H, J=9.3 Hz), 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).

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

Step 1: Preparation of 3-(8-fluoro-1-oxo-1H-isochromen-3-yl)propionic acid

After dissolving 8-fluoro-3-(3-hydroxypropyl)-1H-isochromen-1-one (10.0 g, 42.33 mmol) in acetone (420 ml), 2.5 M Jones' reagent (68) was slowly added dropwise ml) 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 solution was dried over MgSO ₄ , 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)propionic acid (6, 4 g; 61%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.84-7.72 (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).

Step 2: Preparation of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)-propionic acid

After dissolving 3-(8-fluoro-1-oxo-1H-isochromen-3-yl)propionic acid (1.0 g; 4.23 mmol) in a mixture of 7 N. NH ₃ /MeOH (20 ml) this 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 give the title compound 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid (840 g; 84%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.61-7.54 (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).

Step 3: 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

After dissolving 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid (100 mg; 0.42 mmol) and 6-(3,8-diazabicyclo[3.2.1]octane- 3-yl)nicotinonitrile 2HCl (165 mg; 0.51 mmol) in DMF (2 ml) was added HBTU (243 mg; 0.64 mmol). 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using 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%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.25 (br, 1H), 8.43 (d, 1H, J=1.8 Hz), 7.87-7.86 (m, 1H), 7.61-7.54 (m, 1H) , 7.30 (d, 1H, J=7.8 Hz), 7.09-7.03 (m, 1H), 6.83 (d, 1H, J=9.0 Hz), 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).

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]octane- 3-yl)-nicotinonitrile

The title compound was prepared 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.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.99 (br, 1H), 8.36 (d, 1H, J=1.8 Hz), 7.63-7.59 (m, 1H), 7.35-7.31 (m, 1H), 6.87-6.80 (m, 1H), 6.49 (d, 1H, J=8.7 Hz), 6.37 (s, 1H), 4.92 (m, 1H), 4.39 (m, 1H), 4.18 (d, 1H, J=11.7 Hz), 3.93 (d, 1H, J=12.3 Hz), 3.22 (d, 1H, J=12.0 Hz), 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).

Example 208. Preparation of 8-fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinoline-1( 2H)-she

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.95 (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).

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]octane- 3-yl)-benzonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.91 (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).

Example 210. Preparation of 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinoline-1( 2H)-she

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.29 (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).

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

The title compound was prepared 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.

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.28 (br, 1H), 7.67 (s, 1H), 7.41 (m, 2H), 6.97-6.91 (m, 2H), 6.32 (s, 1H), 4.64 (m, 1H), 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).

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

The title compound was prepared 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]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.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.30 (br, 1H), 8.07 (d, 1H, J=3.0 Hz), 7.52-7.46 (m, 1H), 7.44-7.39 (m, 1H ), 6.99-6.92 (m, 1H), 6.75-6.71 (m, 1H), 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).

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]octane- 3-yl)-benzonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.41 (br, 1H), 7.60-7.54 (m, 3H), 7.35 (d, 1H, J=9.9 Hz), 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).

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]octane- 3-yl)-nicotinonitrile

The title compound was prepared 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.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.64 (br, 1H), 8.38 (s, 1H), 7.81 (d, 1H, J=6.9 Hz), 7.63 (d, 1H, J=8.7 Hz), 7.18 (d, 1H, J=10.2 Hz), 6.52 (d, 1H, J=9.0 Hz), 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).

Example 215. Preparation of 7-fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinoline-1( 2H)-she

The title compound was prepared 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.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.43 (br, 1H), 7.61 (d, 1H, J=9.9 Hz), 7.39 (d, 1H, J=9.9 Hz), 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).

Example 216. Preparation of 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinoline-1( 2H)-she

The title compound was prepared 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.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.41 (br, 1H), 7.61 (d, 1H, J=9.0 Hz), 7.37 (d, 1H, J=9.3 Hz), 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).

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

The title compound was prepared 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]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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.41 (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).

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]octane- 3-yl)-nicotinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.44 (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=9.3 Hz), 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).

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

The title compound was prepared 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]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.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.44 (br, 1H), 8.06 (d, 1H, J=3.0 Hz), 7.61 (d, 1H, J=9.3 Hz), 7.52- 7.46 (m, 1H), 7.38 (d, 1H, J=9.3 Hz), 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).

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

The title compound was prepared 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 Stage 1 of Example 206.

^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.40 (br, 1H), 8.47 (d, 1H, J=2.1 Hz), 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, 1H, 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).

Example 221 Synthesis of 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)benzonitrile

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

After tert-butyl-piperazine-1-carboxylate (70.0 g, 0.38 mol) and 4-bromobenzonitrile (82 g, 0.45 mol) were dissolved in toluene (1.5 L), Pd(OAc) ₂ ( 8.4 g; 0.04 mol), XPhos (9.0 g; 0.02 mol) and Cs ₂ CO ₃ (147 g; 0.45 mol). 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound tert-butyl 4-(4-cyanophenyl)piperazine-1-carboxylate (90 g; 83 %).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.53-7.50 (m, 2H), 6.87-6.85 (m, 2H), 3.60-3.57 (m, 4H), 3.33-3.29 (m, 4H), 1.49 (s , 9H).

Step 2: preparation of 4-(piperazin-1-yl)benzonitrile 2HCl

Mixture 4 N. HCl/dioxane (1400 ml) was added to tert-butyl 4-(4-cyanophenyl)-piperazine-1-carboxylate (80 g; 0.28 mol) and the mixture was stirred for 15 hours. The resulting solid was filtered and washed with EtOAc to give the title compound 4-(piperazin-1-yl)benzonitrile 2HCl (72 g; 100%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 9.46 (br, 1H), 7.67-7.64 (m, 2H), 7.11-7.08 (m, 2H), 3.61-3.59 (m, 4H), 3.19 (m , 4H).

Step 3: production of methyl 2-bromonicotinate

After dissolving 2-bromonicotinic acid (10 g; 49.5 mmol) in DMF (165 ml), K ₂ CO ₃ (20.5 g; 148.5 mmol) was added at 0° C. and stirred for 30 minutes. Mel (14.1 g; 99.0 mmol) was slowly added dropwise to the reaction solution at 0°C, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with aqueous Na ₂ S ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure to give the title compound methyl 2-bromonicotinate (9.65 g; 90%).

^1H NMR (300 MHz, CDCl ₂ ) δ 8.49-8.47 (m, 1H), 8.09-8.06 (m, 1H), 7.37-7.33 (m, 1H), 3.96 (s, 3H).

Step 4: production of methyl 2-(5-hydroxypent-1-yn-1-yl)nicotinate

After dissolving methyl 2-bromonicotinate (9.65 g, 44.67 mmol) in CH ₃ CN (220 L), 4-pentin-1-ol (4.51 g, 53.60 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (1.57 g; 2.23 mmol) and Cul (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 celite and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was diluted with EtOAc and washed with aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the target compound methyl 2-(5-hydroxypent-1-yn-1-yl)nicotinate (8, 0 g; 82%).

^1H NMR (300 MHz, CDCl ₃ ) δ 8.68-8.66 (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).

Step 5: Preparation of 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one

After methyl 2-(5-hydroxypent-1-yn-1-yl)nicotinate (8.0 g; 36.49 mmol) was dissolved in THF/MeOH/water (100 ml/25 ml/25 ml), LiOH was added ⋅H ₂ O (7.66 g; 182.45 mmol) and this mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated by distillation under reduced pressure and then diluted with EtOAc and 6N was added slowly dropwise. HCl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure. After dissolving the concentrated reaction solution in acetone (25 ml), AgNO ₃ (312 mg) was added. 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the title compound 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridine-5 -ona (300 mg; 4%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.94-8.92 (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).

Step 6: Preparation of 3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)-propylmethanesulfonate

After dissolving 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (300 mg; 1.46 mmol) in DMF (7 ml), MsCl (217 mg; 1. 90 mmol) at 0°C and stirred for 30 minutes. TEA (2.21 g, 2.19 mmol) was added dropwise at 0°C, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the target compound 3-(5-oxo-5H-pyrano[4,3-b]pyridin-7- yl)propylmethanesulfonate (150 mg; 36%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.95-8.93 (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).

Step 7: Preparation of 4-(4-(3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl)-piperazin-1-yl)benzonitrile

After dissolving 3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)-propylmethanesulfonate (150 mg, 0.53 mmol) in CH ₃ CN (11 ml), 4-(piperazine- 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the target compound 4-(4-(3-(5-oxo-5H-pyrano[4,3- b]pyridin-7-yl)propyl)piperazin-1-yl)benzonitrile (160 mg; 81%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.94-8.92 (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).

Step 8: Preparation of 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)benzonitrile

After dissolving 4-(4-(3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propyl)-piperazin-1-yl)benzonitrile (160 g; 0.43 mmol) in a mixture of 7 n. NH ₃ /MeOH (20 ml) this 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 give the target compound 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)benzonitrile (121 mg; 75%).

^1H NMR (300 MHz, CDCl ₃ ) δ 8.86-8.84 (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).

Example 222 Synthesis of 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)nicotinonitrile

Step 1: Preparation of 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one

After dissolving pent-4-yn-1-ol (5.0 g, 59.44 mmol) in 1,4-dioxane (1.2 L), 2-bromonicotinic acid (16 g, 65.38 mmol), Cul (1.13 g; 5.94 mmol), MeONa (3.21 g; 59.44 mmol) and NaOH (2.38 g; 59.44 mmol). The reaction solution was stirred at 100°C for 48 hours and filtered through celite, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was diluted with EtOAc and washed with aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting solid was recrystallized from EtOAc to give the title compound 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (2.1 g; 17%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.94-8.92 (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).

Step 2: Preparation of 7-(3-hydroxypropyl)-1,6-naphthyridin-5(6H)-one

After dissolving 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (2.1 g; 10.23 mmol) in a mixture of 7 N. NH ₃ /MeOH (1000 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 give the title compound 7-(3-hydroxypropyl)-1,6-naphthyridin-5(6H)-one (1.0 g, 48%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.54 (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).

Step 3: Preparation of 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)-propylmethanesulfonate

After dissolving 7-(3-hydroxypropyl)-1,6-naphthyridin-5(6H)-one (420 mg; 2.06 mmol) 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, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting solid was recrystallized from MeOH to give the title compound, 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl )propylmethanesulfonate (53 mg; 9%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.60 (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).

Step 4: Preparation of 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)nicotinonitrile

After dissolving 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl methanesulfonate (50 mg; 0.177 mmol) in CH ₃ CN (5 ml), 6-(piperazine-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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using 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%).

^1H NMR (300 MHz, CDCl ₃ ) δ 8.86-8.85 (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).

Example 223. Preparation of 7-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.85-8.84 (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).

Example 224. Preparation of 7-(3-(4-(3-fluorophenyl)piperazin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.85-8.84 (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).

Example 225 Preparation of 4-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octane-3- yl)benzonitrile

The target compound was prepared 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 Examples 222.

^1H NMR (300 MHz, CDCl ₃ ) δ 12.01 (br, 1H), 8.86-8.84 (m, 1H), 8.55 (d, 1H, J=7.8 Hz), 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).

Example 226. Preparation of 5-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperazin-1-yl)picolinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.87-8.85 (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).

Example 227. Preparation of 7-(3-(4-(2-fluoropyridin-4-yl)piperazin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one

The title compound was prepared 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.

¹ H NMR (300 MHz, CDCl ₃ ) δ 12.12 (br, 1H), 8.87-8.53 (m, 1H), 8.57 (d, 1H, 7-7.8 Hz), 8.00 (d, 1H, J=5 ,4 Hz), 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).

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

Step 1: Preparation of 7-(3-hydroxypropyl)-5H-pyrano[4.3-b]pyridin-5-one

After dissolving pent-4-yn-1-ol (2.52 g; 30 mmol) in dioxane (500 ml), 2-bromonicotinic acid (8.15 g; 33 mmol), CuI (571 mg; 3.0 mmol) was added ), MeONa (1.62 mg; 30 mmol) and NaOH (1.2 mg; 30 mmol). The reaction solution was stirred at 100°C for 15 hours and filtered through celite, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was diluted with EtOAc and washed with aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting solid was recrystallized from EtOAc to give the title compound 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (3.1 g; 50%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.94-8.92 (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).

Step 2: Preparation of 3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)-propylmethanesulfonate

After dissolving 7-(3-hydroxypropyl)-5H-pyrano[4,3-b]pyridin-5-one (3.77 g, 18.37 mmol) in DMF (92 ml), MsCl (4.84 g; 42.25 mmol) at 0°C and stirred for 30 minutes. TEA (7.44 g; 73.48 mmol) was added dropwise at 0°C, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting solid was recrystallized from MeOH to give the title compound 3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl) propylmethanesulfonate (2.8 g; 55%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 8.95-8.93 (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).

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

After dissolving 3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)-propylmethanesulfonate (100 mg; 0.353 mmol) in CH ₃ CN (20 ml), 3-(4-chlorophenyl) was added -3,8-diazabicyclo[3.2.1]octane 2HCl (146 mg; 0.494 mmol), NaHCO ₃ (148 mg; 1.765 mmol) and Nal (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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound 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; 54%).

^1H NMR (300 MHz, CDCl ₃ ) δ 8.88-8.86 (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).

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

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 7 n. 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 title compound 7-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propyl)-1. 6-naphthyridin-5(6H)-one (34 mg; 44%).

^1H NMR (300 MHz, CDCl ₃ ) δ 8.85-8.84 (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).

Example 229. Preparation of 5-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octane-3- yl)picolinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.85-8.84 (m, 1H), 8.55-8.53 (m, 1H), 8.13-8.12 (w, 1H), 8.04-8.01 (w, 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).

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

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.68 (br, 1H), 8.85-8.84 (m, 1H), 8.40 (d, 1H, 7-7.2 Hz), 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).

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 )-she

The title compound was prepared according to Example 228, except that 3-(5-fluoropyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane 3HCl was used instead of 3-(4-chlorophenyl)-3,8- diazabicyclo[3.2.1]octane 2HCl used in Step 3 of Example 228.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.72 (br, 1H), 8.85 (d, 1H, J=4.5 Hz), 8.41 (d, 1H, J=8.4 Hz), 8.06 ( d, 1H, J=3.0 Hz), 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).

Example 232. Preparation of 6-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)-3,8-diazabicyclo[3.2.1]octane-3- yl)nicotinonitrile

The title compound was prepared 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 .Zoctane 2HCl used in Step 3 of Example 228.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.72 (br, 1H), 8.85-8.84 (m, 1H), 8.46 (s, 1H), 8.41 (d, 1H, J=7.8 Hz), 7.82 (d, 1H, J=8.7 Hz), 7.41-7.38 (m, 1H), 6.79 (d, 1H, J=8.7 Hz), 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).

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 )-she

The title compound was prepared according to Example 228, except that 3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane 3HCl was used instead of 3-(4-chlorophenyl)-3,8- diazabicyclo[3.2.1]octane 2HCl used in Step 3 of Example 228.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.86-8.84 (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).

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

Step 1: Preparation of threot-butyl-6-cyano-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

After dissolving tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2 g; 6. 47 mmol) and 5-bromopicolinonitrile (1.42 g; 7.76 mmol) in dioxane (65 ml) and H ₂ O (22 ml) Pd(PPh ₃ ) ₄ (227 mg; 0.32 mmol) was added dropwise 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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound tert-butyl-6-cyano-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (1.25 g; 68%).

^1H NMR (300 MHz, CDCl ₃ ) δ 8.75 (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).

Step 2: preparation of 1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carbonitrile 2HCl

Mixture 4 N. HCl/dioxane (11 ml) was added to tert-butyl-6-cyano-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (1.25 g; 4 .38 mmol) and the mixture was stirred for 15 hours. The resulting solid was filtered and washed with EtOAc to give the title compound 1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carbonitrile 2HCl (0.76 g, 79%) .

^1H NMR (300 MHz, DMSO- _d6 ) δ 9.46 (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).

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

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' was added ,6'-tetrahydro-[3,4'-bipyridine]-6-carbonitrile 2HCl (69 mg; 0.266 mmol) at room temperature. NaHCO ₃ (74 mg; 0.885 mmol) and NaI (53 mg; 0.354 mmol) were added and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and washed with aqueous Na ₂ S ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from MeOH to obtain the target compound G-(3-(5-oxo-5,6-dihydro-1,6-naphthyridine-7- yl)propyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carbonitrile (7 mg; 11%).

^1H NMR (300 MHz, CDCl ₃ ) δ 11.46 (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).

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

The title compound was prepared according to Example 234, except that 6-bromonicotinonitrile was used instead of 5-bromopicolinonitrile used in Step 1 of Example 234.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.46 (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).

Example 236. Preparation of 7-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one

The title compound was prepared according to Example 234, except that 1-bromo-4-fluorobenzene was used instead of 5-bromopicolinonitrile used in Step 1 of Example 234.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.46 (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).

Example 237. Preparation of 7-(3-(2'-fluoro-3,6-dihydro-[4,4'-bipyridin]-1(2H)-yl)propyl)-1,6-naphthyridine-5(6H) -she

The title compound was prepared as in Example 234, except that 4-bromo-2-fluoropyridine was used instead of the 5-bromopicolinonitrile used in Step 1 of Example 234.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.52 (br, 1H), 8.86-8.85 (m, 1H), 8.58 (d, 1H, J=6.6 Hz), 8.17 (d, 1H, J=5 ,4 Hz), 7.35-7.30 (m, 1H), 7.24 (m, 1H), 6.96 (s, 1H), 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).

Example 238. Preparation of 7-(3-(4-(3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one

The title compound was prepared according to Example 234, except that 1-bromo-3-fluorobenzene was used instead of 5-bromopicolinonitrile used in Step 1 of Example 234.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.55 (br, 1H), 8.84 (m, 1H), 8.58 (d, 1H, J=8.1 Hz), 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).

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

The title compound was prepared according to Example 234, except that 4-bromobenzonitrile was used instead of 5-bromopicolinonitrile used in Step 1 of Example 234.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.61 (s, 1H), 8.85 (d, 1H, J=4.2 Hz), 8.42 (d, 1H, J=7.8 Hz), 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).

Example 240. Preparation of 7-(3-(3,6-dihydro-[4,4'-bipyridin]-1(2H)-yl)propyl)-1,6-naphthyridin-5(6H)-one

The title compound was prepared according to Example 234, except that 4-bromopyridine was used instead of 5-bromopicolinonitrile used in Step 1 of Example 234.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.49-11.48 (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).

Example 241 Synthesis of 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)benzonitrile

Step 1: Preparation of pent-4-ynic acid

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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from Et ₂ O to obtain the title compound pent-4-ynic acid (11.6 g; 100%).

^1H NMR (300 MHz, CDCl ₃ ) δ 2.63-2.60 (m, 2H), 2.53-2.52 (m, 2H), 2.00 (s, 1H).

Step 2: Preparation of 4-(4-(pent-4-inoyl)piperazin-1-yl)benzonitrile

After dissolving pent-4-ynic 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) in CH ₂ Cl ₂ (25 ml), TEA (25.8 g; 254.85 mmol) was added dropwise to the reaction solution and stirred at room temperature for 15 hours. The reaction solution was diluted with CH ₂ Cl ₂ and washed with water. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the target compound 4-(4-(pent-4-inoyl)piperazin-1-yl)benzonitrile (11 .8 g; 87%).

^1H NMR (300 MHz, CDCl ₃ ) δ 7.53-7.50 (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).

Step 3: Preparation of 4-(4-(3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propanoyl)piperazin-1 -yl)benzonitrile

After dissolving 4-(4-(pent-4-inoyl)piperazin-1-yl)-benzonitrile (2.0 g; 7.48 mmol) 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). The reaction solution was stirred at 80°C for 2 days and filtered through celite, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was diluted with EtOAc and washed with aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using 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%).

^1H NMR (300 MHz, CDCl ₃ ) δ 8.95 (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).

Step 4: Preparation of 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)benzonitrile

After dissolving 4-(4-(3-(5-oxo-5H-pyrano[4,3-b]pyridin-7-yl)propanoyl)-piperazin-1-yl)benzonitrile (160 g; 0.43 mmol) in a mixture of 7 n. 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 give the title compound, 4-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)benzonitrile ( 20 mg; 12%).

^1H NMR (300 MHz, CDCl ₃ ) δ 11.53 (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).

Example 242. Preparation of 6-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)nicotinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.38 (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).

Example 243. Preparation of 5-(4-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)piperazin-1-yl)picolinonitrile

The title compound was prepared 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.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.32 (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).

Example 244. Preparation of 7-(3-(4-(4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-1,6-naphthyridin-5(6H)-one

The title compound was prepared 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 .

^1H NMR (300 MHz, CDCl ₃ ) δ 10.59 (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), 4.32-4.31 (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).

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

The title compound was prepared 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.

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.53 (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).

Example 246 Preparation of 4-(8-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octane-3- yl)benzonitrile

The target compound was prepared 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 Examples 241.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.54 (br, 1H), 8.81 (d, 1H, J=4.5 Hz), 8.40 (d, 1H, J=7.8 Hz), 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).

Example 247. Synthesis of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)benzonitrile

Step 1: Preparation of tert-butyl 4-((4-cyanophenyl)amino)piperidine-1-carboxylate

After dissolving 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 hours and then cooled to 0°C. NaBH(OAc) ₃ (3.19 mg; 15.06 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was diluted with CH ₂ Cl ₂ and washed with water. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound, tert-butyl 4-((4-cyanophenyl)amino)piperidine-1-carboxylate ( 698 mg; 46%).

^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.48-7.42 (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).

Step 2: preparation of 4-(piperidin-4-ylamino)benzonitrile 2HCl

Mixture 4 N. HCl/dioxane (5.8 ml) was added to tert-butyl 4-((4-cyanophenyl)-amino)piperidine-1-carboxylate (698 mg; 2.32 mmol) and the mixture was stirred for 15 hours. The resulting solid was filtered and washed with Et ₂ O to give the title compound 4-(piperidin-4-ylamino)benzonitrile 2HCl (585 mg; 92%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.04 (br, 2H), 7.46 (d, J=8.7 Hz, 2H), 6.70 (d, J=9.0 Hz, 2H), 3.62 ( m, 1H), 3.27 (m, 2H), 2.98 (m, 2H), 2.04 (m, 2H), 1.63 (m, 2H).

Step 3: Preparation of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)amino)benzonitrile

After dissolving 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)-propylmethanesulfonate (60 mg; 0.2 mmol) in CH ₃ CN (4 ml), 4-(piperidine-4- ylamino)benzonitrile 2HCl (65 mg; 0.24 mmol) at room temperature. NaHCO ₃ (84.01 mg; 1.0 mmol) and NaI (59.96 mg; 0.4 mmol) were added and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and washed with aqueous NaS ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from Et ₂ O 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%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.41 (br, 1H), 7.60 (m, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.34 (d, J=7.8 Hz, 1H), 7.12-7.05 (m, 1H), 6.65-6.58 (m, 3H), 6.35 (s, 1H), 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).

Example 248. Preparation of 5-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl(propyl)piperidin-4-yl)amino)picolinonitrile

The title compound was prepared according to Example 247, except that 5-aminopicolinonitrile was used instead of 4-aminobenzonitrile used in Step 1 of Example 247.

^1H NMR (300 MHz, CDCl ₃ ) δ 12.78 (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).

Example 249. Preparation of 4-((1-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl(propyl)piperidin-4-yl)amino)benzonitrile

The title compound was prepared according to Example 247, except that 3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2 -dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 247.

^1H NMR (300 MHz, CDCl ₃ ) δ 12.36 (br, 1H), 7.96 (d, J=9.3 Hz, 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).

Example 250. Preparation of 4-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)benzonitrile

The title compound was prepared according to Example 247, except that 3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1 ,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 247.

^1H NMR (300 MHz, CDCl ₃ ) δ 13.05 (br, 1H), 8.87-8.86 (m, 1H), 8.57 (d, 1H, J=7.8 Hz), 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).

Example 251. Preparation of 5-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)picolinonitrile

The title compound was prepared according to Example 247, except that 5-aminopicolinonitrile was used instead of 4-aminobenzonitrile used in Step 1 of Example 247, and 3-(5-oxo-5,6-dihydro-1,6-naphthyridine-7- yl)-propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 247.

^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.26 (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).

Example 252. Preparation of methyl 4-((1-(3-(5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)propyl)piperidin-4-yl)amino)benzoate

The title compound was prepared 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-naphthyridine- 7-yl)-propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 247.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.85-8.84 (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).

Example 253. Preparation of 7-(3-(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)propyl)-1,6-naphthyridin-5(6H)-one

The title compound was prepared 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-naphthyridine -7-yl)-propylmethanesulfonate was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propylmethanesulfonate used in Step 3 of Example 247.

^1H NMR (300 MHz, CDCl ₃ ) δ 8.86-8.85 (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).

Example 254. Synthesis of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)oxy)benzonitrile

Step 1: Preparation of tert-butyl 4-(4-cyanophenoxy)piperidine-1-carboxylate

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. PP3 (1.17 mg; 4.47 mmol) was added, DIAD (diisopropyl azodicarboxylate) (0.98 ml; 4.47 mmol) was added slowly dropwise at 0°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 solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to give the title compound tert-butyl 4-(4-cyanophenoxy)-piperidine-1-carboxylate (0.73 g; 81%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.76 (d, J=7.8 Hz, 2H), 7.15 (d, J=7.8 Hz, 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).

Step 2: Preparation of 4-(piperidin-4-yloxy)benzonitrile HCl

Mixture 4 N. HCl/dioxane (6 ml) was added to tert-butyl 4-(4-cyanophenoxy)-piperidine-1-carboxylate (729 mg; 2.41 mmol) and the mixture was stirred for 15 hours. The resulting solid was filtered and washed with Et ₂ O to give the title compound 4-(piperidin-4-yloxy)benzonitrile HCl (408 mg; 71%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.96 (br, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.18 (d, J=8.7 Hz, 2H), 4.81 ( m, 1H), 3.21 (m, 2H), 3.07 (m, 2H), 2.10 (m, 2H), 1.86 (m, 2H).

Step 3: Preparation of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)piperidin-4-yl)oxy)benzonitrile

After dissolving 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl methanesulfonate (60 mg; 0.2 mmol) in CH ₃ CN (4 ml), 4-(piperidine-4 -yloxy)benzonitrile HCl (57 mg; 0.24 mmol) at room temperature. NaHCO ₃ (84.01 mg; 1.0 mmol) and Nal (59.96 mg; 0.4 mmol) were added and the mixture was heated to 80°C and stirred for 17 hours. The reaction solution was diluted with EtOAc and washed with aqueous NaS ₂ O ₃ and aqueous NH ₄ Cl. The organic solution was dried over MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was recrystallized from Et ₂ O 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%).

^1H NMR (300 MHz, CDCl ₃ ) δ 12.48 (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).

Example 255. Synthesis of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile

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) DIPEA (0.13 ml; 0.76 mmol) was slowly added dropwise to the reaction solution at room temperature. and stirred at room temperature for 19 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solution was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified using silica gel chromatography to obtain the target compound 4-((1-(3-(8-fluoro-1-oxo-1, 2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile (32.3 mg; 30%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.22 (br, 1H), 7.77 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.34 (d, J=7 ,8 Hz, 1H), 7.17-7.07 (m, 3H), 6.39 (s, 1H), 4.78 (m, 1H), 3.94-3.73 (m, 2H), 3.39-3.20 (m, 2H), 2.73 ( m, 4H), 1.99-1.95 (m, 2H), 1.61-1.48 (m, 2H).

Example 256. Preparation of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzonitrile

The title compound was prepared as in Example 255, except that 4-(piperidin-4-ylamino)benzonitrile 2HCl was used instead of 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255.

^1H NMR (300 MHz, CDCl) δ 10.16 (br, 1H), 7.56-7.49 (m, 3H), 7.20-7.16 (m, 1H), 7.06-6.99 (m, 1H), 6.73 (d, J= 8.7 Hz, 2H), 6.24 (s, 1H), 4.63-4.58 (m, 1H), 4.14 (m, 1H), 3.86-3.82 (m, 1H), 3.56 (m, 1H), 3.23-3.15 (m, 1H), 2.99-2.87 (m, 3H), 2.79-2.74 (m, 2H), 2.11-2.07 (m, 2H), 1.4-1.32 (m, 2H).

Example 257. Preparation of 4-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)(methyl)amino)benzonitrile

The title compound was prepared as in Example 255, except that 4-(methyl(piperidin-4-yl)amino)benzonitrile 2HCl was used instead of 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.16 (br, 1H), 7.56-7.49 (m, 3H), 7.20-7.16 (m, 1H), 7.06-6.99 (m, 1H), 6.73 (d, J =8.7 Hz, 2H), 6.24 (s, 1H), 4.93-4.88 (m, 1H), 3.99-3.84 (m, 2H), 3.18-3.10 (m, 1H), 2.96-2.63 (m, 7H ), 1.79-1.44 (m, 4H).

Example 258. Preparation of 5-((1-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)picolinonitrile

The title compound was prepared as in Example 255, except that 5-(piperidin-4-ylamino)picolinonitrile 3HCl was used instead of 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.21 (br, 1H), 8.07 (s, 1H), 7.65-7.60 (m, 2H), 7.35-7.32 (m, 1H), 7.13-6.92 (m , 3H), 6.39 (s, 1H), 4.29-4.24 (m, 1H), 3.92-3.87 (m, 1H), 3.22-3.15 (m, 2H), 2.88-2.69 (m, 4H), 1.99-1.91 (m, 2H), 1.34-1.16 (m, 2H).

Example 259. Preparation of 4-((1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzonitrile

The title compound was prepared according to Example 255 except that 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-ylamino)benzonitrile 2HCl was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255, respectively.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.20 (br, 1H), 7.43-7.34 (m, 3H), 6.96-6.89 (m, 1H), 6.55 (d, J=8.4 Hz, 2H), 6.29 (s, 1H), 4.63-4.58 (m, 1H), 4.14 (m, 1H), 3.86-3.82 (m, 1H), 3.55 (m, 1H), 3.23-3.15 (m, 1H), 2.98- 2.87 (m, 4H), 2.42 (s, 3H), 2.11-2.07 (m, 2H), 1.37-1.32 (m, 2H).

Example 260. Preparation of 4-((1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzonitrile

The title compound was prepared according to Example 255 except that 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-ylamino)benzonitrile 2HCl was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255, respectively.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.54 (br, 1H), 7.87 (d, J=6.9 Hz, 1H), 7.42 (d, J=8.7 Hz, 2H), 7.21 (d, J=9.3 Hz, 1H), 6.55 (d, J=8.7 Hz, 2H), 6.35 (s, 1H), 4.64-4.59 (m, 1H), 4.12-4.10 (m, 1H), 3.86 -3.82 (m, 1H), 3.57 (m, 1H), 3.23-3.15 (m, 1H), 2.98-2.87 (m, 4H), 2.42 (s, 3H), 2.11-2.07 (m, 2H), 1.37 -1.32 (m, 2H).

Example 261. Preparation of 4-((1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile

The title compound was prepared according to Example 255, except that 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid was used instead of 3-(8-fluoro-1- oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Example 255.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.56 (br, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.58-7.33 (m, 1H), 6.96-6.88 (m, 3H), 6.32 (s, 1H), 4.63 (m, 1H), 3.78-3.65 (m, 3H), 3.49-3.45 (m, 1H), 2.99-2.96 (m, 2H), 2.83-2.79 (m, 2H), 2.43 (s, 3H), 1.92-1.86 (m, 4H).

Example 262. Preparation of 4-((1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)oxy)benzonitrile

The title compound was prepared according to Example 255, except that 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid was used instead of 3-(8-fluoro-1- oxo-1,2-dihydroisoquinolin-3-yl)propionic acid used in Example 255.

¹ H NMR (300 MHz, CDCl) δ 10.55 (br, 1H), 7.74 (d, J=9.3 Hz, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.21 (d, J =8.7 Hz, 1H), 6.95 (d, J=9.0 Hz, 2H), 6.35 (s, 1H), 4.64 (m, 1H), 3.87-3.63 (m, 3H), 3.47-3.44 ( m, 1H), 2.98-2.96 (m, 2H), 2.80-2.77 (m, 2H), 2.50 (s, 3H), 1.95-1.88 (m, 4H).

Example 263. Preparation of 3-(3-(4-((4-chlorophenyl)amino)piperidin-1-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinolin-1(2H)-one

The title compound was prepared according to Example 255 except that 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and N-(4-chlorophenyl)piperidine-4 -amine 2HCl was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255, respectively.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.40 (br, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.21-7.18 (m, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.95 (d, J=9.0 Hz, 2H), 6.33 (s, 1H), 4.57 (m, 1H), 3.82-3.78 (m, 1H), 3.48 (m, 2H), 3.07 -3.12 (m, 1H), 2.96-2.88 (m, 5H), 2.74 (m, 2H), 2.50 (s, 3H), 2.11-2.06 (m, 2H).

Example 264. Preparation of 3-(3-(4-((4-chlorophenyl)amino)piperidin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2b)-one

The title compound was prepared according to Example 255 except that 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and N-(4-chlorophenyl)piperidine-4 -amine 2HCl was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255, respectively.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.09 (br, 1H), 7.33 (m, 1H), 7.18 (d, J=7.8 Hz, 1H), 6.92 (m, 1H), 6.51 (d, J=8.4 Hz, 2H), 6.27 (s, 1H), 4.55 (m, 1H), 3.82-3.79 (m, 1H), 3.49 (m, 2H), 3.17 (m, 1H), 2.93 (m , 5H), 2.74 (m, 2H), 2.42 (s, 3H), 2.11-2.07 (m, 2H).

Example 265. Preparation of 7-fluoro-5-methyl-3-(3-oxo-3-(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)propyl)isoquinoline-1(2H)- she

The title compound was prepared as in Example 255 except that 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and N-(4-(trifluoromethyl)phenyl) piperidin-4-amine 2HCl was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255, respectively .

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.60 (br, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.20 (d, J=6.9 Hz, 1H), 6.59 (d, J=8.7 Hz, 2H), 6.35 (s, 1H), 4.61-4.57 (m, 1H), 3.86-3.81 (m, 2H), 3.56 (m, 1H), 3.24-3.15 (m, 1H), 2.97-2.94 (m, 5H), 2.79-2.75 (m, 2H), 2.50 (s, 3H), 2.12-2.09 (m, 2H).

Example 266. Preparation of 8-fluoro-5-methyl-3-(3-oxo-3-(4-((4-(trifluoromethyl)phenyl)amino)piperidin-1-yl)propyl)isoquinoline-1(2H)- she

The title compound was prepared according to Example 255 except that 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and N-(4-(trifluoromethyl)phenyl) piperidin-4-amine 2HCl was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255, respectively .

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.33 (br, 1H), 7.40-7.37 (m, 3H), 6.96-6.89 (m, 1H), 6.59 (d, J=9.0 Hz, 1H), 6.31 (s, 1H), 4.59-4.55 (m, 1H), 3.86-3.84 (m, 2H), 3.56 (m, 1H), 3.24-3.16 (m, 1H), 2.96-2.89 (m, 5H), 2.79-2.77 (m, 2H), 2.42 (s, 3H), 2.12-2.05 (m, 2H).

Example 267. Preparation of methyl 4-((1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzoate

The title compound was prepared according to Example 255 except that 3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and methyl 4-(piperidin-4-ylamino) )benzoate 2HCl was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255, respectively.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.66 (br, 1H), 7.87-7.84 (m, 3H), 7.22-7.19 (m, 1H), 6.54 (d, J=8.4 Hz, 2H), 6.36 (s, 1H), 4.62-4.57 (m, 1H), 4.02-4.00 (m, 1H), 3.85 (m, 5H), 3.60 (m, 1H), 3.24-3.16 (m, 1H), 2.97- 2.89 (m, 5H), 2.80-2.76 (m, 2H), 2.50 (s, 3H), 2.12-2.09 (m, 2H).

Example 268. Preparation of methyl 4-((1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)amino)benzoate

The title compound was prepared according to Example 255 except that 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and methyl 4-(piperidin-4-ylamino) )benzoate 2HCl was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255, respectively.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.38 (br, 1H), 7.85 (d, J=8.7 Hz, 2H), 7.37-7.33 (m, 1H), 6.95-6.89 (m, 1H), 6.54 (d, J=8.4 Hz, 2H), 6.30 (s, 1H), 4.60-4.56 (m, 1H), 4.04-4.01 (m, 1H), 3.85 (m, 5H), 3.60 (m, 1H), 3.24-3.16 (m, 1H), 2.96-2.88 (m, 5H), 2.80-2.76 (m, 2H), 2.42 (s, 3H), 2.12-2.09 (m, 2H).

Example 269. Preparation of 8-fluoro-3-(3-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared according to Example 255 except that 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 8-azabicyclo[3.2.1]octane- 3-ol a HCl was used instead of 3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255, respectively.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.48 (br, 1H), 7.38-7.33 (m, 1H), 6.95-6.89 (m, 1H), 6.32 (s, 1H), 4.75 (m, 1H), 4.18-4.13 (m, 2H), 3.00-2.94 (m, 2H), 2.78-2.71 (m, 2H), 2.43 (s, 3H), 2.01-1.95 (m, 4H), 1.40-1.19 (m, 4H ).

Example 270. Preparation of 8-fluoro-3-(3-(4-hydroxypiperidin-1-yl)-3-oxopropyl)-5-methylisoquinolin-1(2H)-one

The title compound was prepared according to Example 255, except that 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and piperidin-4-ol were used instead of 3-( 8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propionic acid and 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255, respectively.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.26 (br, 1H), 7.48-7.44 (m, 1H), 7.03-6.96 (m, 1H), 6.35 (s, 1H), 4.76-4.74 (m , 1H), 3.94-3.90 (m, 1H), 3.69-3.68 (m, 2H), 3.19-3.13 (m, 1H), 3.04-2.97 (m, 1H), 2.72 (m, 4H), 2.38 (s , 3H), 1.70 (m, 2H), 1.33-1.20 (m, 2H).

Example 271. Preparation of 7-(3-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)propyl)-1,6-naphthyridin-5(6H)-one

The title compound was prepared according to Example 228, except that 8-azabicyclo[3.2.1]octan-3-ol HCl was used instead of 3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane 2HCl used at Stage 3 of Example 228.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.48 (br, 1H), 7.38-7.33 (m, 1H), 6.95-6.89 (m, 1H), 6.32 (s, 1H), 4.75 (m, 1H), 4.18-4.13 (m, 2H), 3.00-2.94 (m, 2H), 2.78-2.71 (m, 2H), 2.43 (s, 3H), 2.01-1.95 (m, 4H), 1.40-1.19 (m, 4H ).

Example 272. Preparation of 8-fluoro-3-(3-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)propyl)isoquinolin-1(2H)-one

Step 1: Preparation of 8-fluoro-3-(3-(3-hydroxy-8-azabicyclo[3.2.1.]octan-8-yl)propyl)-1H-isochromen-1-one

After dissolving 8-azabicyclo[3.2.1]octan-3-ol HCl (222 mg; 1.35 mmol) in CH ₃ CN (210 ml), Na ₂ CO ₃ (552 mg; 5.2 mmol) was added at room temperature . 3-(8-fluoro-1-oxo-1H-isochromen-3-yl)-propylmethanesulfonate (313 mg; 1.04 mmol) and NaI (469 mg; 3.12 mmol) were added to the reaction solution and stirred at 80° C within 18 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solution was dried over anhydrous MgSO ₄ , 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-(3-hydroxy-8-azabicyclo[3.2.1]octane -8-yl)propyl)-1H-isochromen-1-one (97.0 mg; 28%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 7.87-7.80 (m, 1H), 7.41-7.32 (m, 2H), 6.65 (s, 1H), 4.96 (m, 1H), 3.98 (m, 3H ), 2.97 (m, 2H), 2.61-2.57 (m, 2H), 2.10-1.87 (m, 8H), 1.75-1.72 (m, 2H).

Step 2: preparation of 8-fluoro-3-(3-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)propyl)isoquinolin-1(2H)-one

After dissolution of 8-fluoro-3-(3-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)propyl)-1H-isochromen-1-one (97.0 mg; 0.29 mmol ) in a mixture of 7 n. NH ₃ /MeOH (10.0 ml) the mixture was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature and then concentrated by distillation under reduced pressure, and the resulting solid was recrystallized from MeOH to obtain the target compound 8-fluoro-3-(3-(3-hydroxy-8-azabicyclo[3.2.1]octane-8 -yl)propyl)isoquinolin-1(2H)-one (73.0 mg; 75%).

¹ H NMR (300 MHz, DMSO- _d6 ) δ 11.27 (br, 1H), 7.67-7.60 (m, 1H), 7.37 (d, 1H, 7=7.8 Hz), 7.16-7.10 (m, 1H) , 6.40 (s, 1H), 4.35 (m, 1H), 3.99 (m, 3H), 2.93 (m, 2H), 2.50 (m, 2H), 2.10-1.87 (m, 8H), 1.76-1.68 (m , 2H).

Example 273. Preparation of 4-((8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy )benzonitrile

The title compound was prepared according to Example 254, except that tert-butyl-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate was used instead of tert-butyl-4-hydroxypiperidine-1-carboxylate used in Step 1 Example 254.

^1H NMR (300 MHz, CDCl ₃ ) δ 11.48 (br, 1H), 7.57-7.46 (m, 3H), 7.20-7.18 (m, 1H), 7.04-7.00 (m, 1H), 6.97-6.91 (m , 2H), 6.21 (s, 1H), 4.70-4.64 (m, 1H), 3.48-3.47 (m, 2H), 2.72-1.57 (m, 14H).

Example 274. Preparation of 4-((8-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy )benzonitrile

The title compound was prepared according to Example 255, except that 4-((8-azabicyclo[3.2.1]octan-3-yl)oxy)benzonitrile HCl was used instead of 4-(piperidin-4-yloxy)benzonitrile HCl used in Example 255.

^1H NMR (300 MHz, CDCl ₃ ) δ 10.17 (s, 1H), 7.57-7.49 (m, 3H), 7.21-7.18 (m, 1H), 7.05-7.01 (m, 1H), 6.90-6.88 (m , 2H), 6.24 (sm, 1H), 4.87-4.77 (m, 2H), 4.26-4.25 (m, 1H), 2.94-2.68 (m, 4H), 2.19-2.06 (m, 4H), 1.88-1.79 (m, 4H).

Example 275. Preparation of N-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)azetidin-3-yl)cyclopropanecarboxamide

Step 1: Preparation of tert-butyl 3-(cyclopropanecarboxamido)azetidine-1-carboxylate

After dissolving 1-Boc-3-aminoazetidine (600 mg; 3.48 mmol), cyclopropanecarboxylic acid (0.33 ml; 4.18 mmol) and HATU (1.98 g; 5.22 mmol) in DMF (12 ml ) DIPEA (1.8 ml; 10.4 mmol) was slowly added dropwise to the reaction solution and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solution was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting residue was purified using silica gel chromatography to obtain the title compound tert-butyl-3-(cyclopropanecarboxamido)azetidine-1-carboxylate (612 mg; 73% ).

^1H NMR (300 MHz, CDCl ₃ ) δ 6.15 (m, 1H), 4.70-4.63 (m, 1H), 4.27-4.22 (m, 2H), 3.77-3.72 (m, 2H), 1.44 (s, 9H ), 1.40-1.33 (m, 1H), 0.97-0.96 (m, 2H), 0.79-0.76 (m, 2H).

Step 2: Preparation of N-(azetidin-3-yl)cyclopropanecarboxamide HCl

After dissolving tert-butyl 3-(cyclopropanecarboxamido)azetidine-1-carboxylate (610 mg; 2.54 mmol) in a mixture of 4 N. HCl/dioxane (13 ml) this mixture was stirred for 17 hours. The resulting solid was filtered and washed with EtOAc to give the title compound N-(azetidin-3-yl)cyclopropanecarboxamide HCl (300 mg; 67%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 6.45 (m, 1H), 4.68-4.60 (m, 1H), 4.27-4.22 (m, 2H), 3.77-3.72 (m, 2H), 1.40-1.33 ( m, 1H), 0.97-0.96 (m, 2H), 0.79-0.76 (m, 2H).

Step 3: Preparation of N-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)azetidin-3-yl)cyclopropanecarboxamide

After dissolving 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-propionic acid (60 mg; 0.24 mmol), N-(azetidin-3-yl)cyclopropanecarboxamide (85 mg; 0.24 mmol) and HATU (137 mg; 0.36 mmol) in DMF (0.8 ml) DIPEA (0.12 ml; 0.72 mmol) was slowly added dropwise to the reaction solution at room temperature. and the mixture was stirred at room temperature for 19 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solvent was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure, and the resulting residue was purified using silica gel chromatography to obtain the target compound N-(1-(3-(8-fluoro-5-methyl-1-oxo -1,2-dihydroisoquinolin-3-yl)propanoyl)azetidin-3-yl)-cyclopropanecarboxamide (21 mg; 23%).

^1H NMR (300 MHz, CDCl ₃ ) δ 11.30 (br, 1H), 8.73 (d, 1H, J=6.3 Hz), 7.49-7.45 (m, 1H), 7.03-6.97 (m, 1H), 6.34 (s, 1H), 4.46-4.35 (m, 2H), 4.12-4.06 (m, 1H), 3.95-3.90 (m, 1H), 3.73-3.68 (m, 1H), 2.73-2.68 (m, 2H ), 2.46-2.44 (m, 2H), 2.38 (s, 3H), 1.53-1.49 (m, 1H), 0.68-0.66 (m, 4H).

Example 276. Preparation of N-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)cyclopropanecarboxamide

Step 1: Preparation of tert-butyl-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)carbamate

After dissolving 3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-propionic acid (350 mg; 1.40 mmol), tert-butyl-piperidin-4-ylcarbamate ( 337 mg; 1.68 mmol) and HATU (801 mg; 2.1 mmol) in DMF (5.0 ml) at room temperature, DIPEA (0.72 ml; 4.2 mmol) was slowly added dropwise to the reaction solution 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 dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure and the resulting solid was recrystallized from MeOH to give the title compound tert-6util-(1-(3-(8-fluoro-5-methyl-1-oxo -1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)-carbamate (350 mg; 58%).

^1H NMR (300 MHz, CDCl ₃ ) δ 10.49 (m, 1H), 7.37-7.33 (m, 1H), 6.96-6.89 (m, 1H), 6.30 (s, 1H), 4.59-4.54 (m, 1H ), 4.43 (m, 1H), 3.81-3.77 (m, 1H), 3.66 (m, 1H), 3.14-3.07 (m, 1H), 2.95-2.93 (m, 2H), 2.83-2.76 (m, 2H ), 2.42 (s, 3H), 2.02-1.94 (m, 2H), 1.44 (s, 9H), 1.38-1.24 (m, 2H).

Step 2: Preparation of 3-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one HCl

After dissolution of tert-butyl-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)-carbamate (350 mg; 0 .81 mmol) in a mixture of 4 N. HCl/dioxane (12 ml) this mixture was stirred at room temperature for 19 hours. The resulting solid was filtered and washed with EtOAc to give the target compound 3-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one HCl ( 296 mg; 99%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.26 (s, 1H), 8.35 (s, 2H), 7.46-7.45 (m, 1H), 7.03-6.97 (m, 1H), 6.37 (s, 1H) , 4.38 (d, 1H, J=12.3 Hz), 3.97 (d, 1H, J=13.2 Hz), 3.24 (m, 1H), 3.10-3.02 (m, 1H), 2.74 (m, 4H ), 2.65-2.62 (m, 1H), 2.38 (S, 3H), 1.95 (m, 2H), 1.49-1.34 (m, 2H).

Step 3: Preparation of N-(1-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)cyclopropanecarboxamide

After dissolving 3-(3-(4-aminopiperidin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one (100 mg; 0.27 mmol), cyclopropanecarboxylic acid (0 .03 mg; 0.41 mmol) and HATU (155 mg; 0.41 mmol) in DMF (0.9 ml) DIPEA (0.14 ml; 0.81 mmol) was slowly added dropwise to the reaction solution at room temperature. and the mixture was stirred at room temperature for 19 hours. The reaction solution was diluted with EtOAc and washed with water. The organic solution was dried over anhydrous MgSO ₄ , filtered and then concentrated by evaporation under reduced pressure, and the resulting solid was recrystallized from MeOH to give the title compound N-(1-(3-(8-fluoro-5-methyl-1-oxo-1 ,2-dihydroisoquinolin-3-yl)propanoyl)piperidin-4-yl)-cyclopropanecarboxamide (44 mg; 40%).

^1H NMR (300 MHz, DMSO- _d6 ) δ 11.26 (br, 1H), 8.03 (d, 1H, J=6.6 Hz), 7.48-7.44 (m, 1H), 7.03-6.96 (m, 1H) , 6.36 (s, 1H), 4.24-4.20 (m, 1H), 3.88-3.83 (m, 2H), 3.14-3.06 (m, 1H), 2.80-2.73 (m, 5H), 2.38 (s, 3H) , 1.80-1.72 (m, 2H), 1.52 (m, 1H), 1.31-1.18 (m, 2H), 0.64-0.62 (m, 4H).

The chemical structures of the compounds obtained in Examples 1-276 are shown in Table 1 below.

Experimental Example 1: PARP-1 (Poly[ADP-ribose]polymer aza-1) Inhibiting Ability

To evaluate the ability of the compounds of the present invention to inhibit the enzyme PARP-1 (poly[ADP-ribose] polymerase-1), the following experiment was performed.

Specifically, to evaluate the ability of the compounds of Examples 1 to 276 of the present invention to inhibit the PARP-1 enzyme (poly[ADP-ribose] polymerase-1), the activity of the PARP-1 enzyme (poly[ADP-ribose] polymerase-1) was examined as follows using an assay kit purchased from Trevigen, Inc. (catalog number: 4677-096-K). 50 μl of 1× PARP buffer (from Trevigen kit) was dispensed into each well of a histone-coated 96-well plate and then rehydrated for 30 minutes. After removing 1× PARP buffer present in the well, PARP-1 (poly[ADP-ribose] polymerase-1) enzyme (0.5 unit/well) and compounds of Examples 1-276 at a concentration of 1 μM or different concentrations and interacted for 10 minutes. After this, 25 μl of 1× PARP cocktail (biotinylated NAD, activated DNA from Trevigen kit) was added to each well and then reacted at room temperature for 1 hour. After completion of the reaction, each well was washed twice with PBS (7.5 mM Na ₂ HPO ₄ , 2.5 mM NaH ₂ PO ₄ , 145 mM NaCl) containing 0.1% Triton X-100, and twice washed with PBS. Then, 50 μl of streptavidin-HRP (peroxidase-conjugated streptavidin) was added and reacted at room temperature for 1 hour and then washed twice with PBS containing 0.1% Triton X-100 and washed twice with PBS. After removing all PBS, 50 μL of TACS-sapphire substrate was added and reacted at room temperature for 15 min while blocking light. After the reaction was stopped by treating each well with 50 μl of 5% phosphoric acid, absorbance was measured at 450 nM using a Victor 3 microplate reader from PerkinElmer, Inc. to quantify the value. The results are shown in Table 2 below.

The ability to inhibit PARP-1 at 1 nM is indicated by * for values less than 50%; ** for values from 50% to 80%; and *** for values greater than 80%. The measured value is missing if the value is not listed in the table above.

Based on Table 2, it was confirmed that the compounds of the Examples of the present invention exhibit inhibitory activity against the enzyme PARP-1 (poly[ADP-ribose] polymerase-1). Specifically, the compound of Example 47 inhibited the activity of the PARP-1 (poly[ADP-ribose] polymerase-1) enzyme by 80% or more.

Among the Examples in Table 2, IC50 values were measured for some compounds and the results are shown in Table 3 below.

Based on Table 3, it was confirmed that the compounds of Examples 1, 6, 8, 15, 21, 22, 23, 46, 48, 49, 50, 54, 55, 57, 58, 68, 99, 103, 128, 151 , 152, 183, 200, 241, 242, 268, and 272 exhibit 50% inhibitory activity against the enzyme PARP-1 (poly[ADP-ribose] polymerase-1) (IC ₅₀ ) at a concentration of 20 nM or less, confirming that PARP-1 (poly[ADP-ribose] polymerase-1) activity is effectively inhibited at low concentrations.

Accordingly, the isoquinolinone derivatives of the present invention can be effectively used as a new PARP-1 (poly[ADP-ribose] polymerase-1) inhibitor, and can be effectively used as a pharmaceutical composition containing isoquinolinone derivatives as an active ingredient for the prevention or treating diseases associated with PARP-1 (poly[ADP-ribose] polymerase-1), for example, one or more diseases selected from the group consisting of a neurogenic disorder, neurodegenerative disease, stroke, cardiovascular disease, macular degeneration , AIDS, arthritis, atherosclerosis, cancer, diabetes, brain tumor, inflammatory bowel disease, muscular dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, nerve attack, peripheral nerve injury, kidney disease, retinal ischemia, septic shock and skin aging.

Experimental Example 2. Assessment of protection of a retinal pigment epithelial cell line

To evaluate the protective effect of the compounds of the present invention on a retinal pigment epithelial cell line under conditions of induction of apoptosis like dry macular degeneration, the following experiment was performed.

Specifically, ARPE-19 cells, a human retinal pigment epithelial cell line, were cultured in DMEM:F12 medium (Dulbecco's modified Eagle's medium: Ham's F-12 nutrient mixture) containing 10% fetal bovine serum (FBS) and 1 % penicillin/streptomycin. Cells were aliquoted into a well plate so that the number of cells per well was 1×10 ⁴ and incubated at 37°C in a CO ₂ incubator for 12 hours. DMSO (0.1%) (control group) alone or various concentrations of the compounds of Examples 1-276 according to the present invention (experimental groups) were treated in medium mixed with 0.5 mM H ₂ O ₂ (control group), and then the cells additionally cultured at 37°C in a CO ₂ incubator for 6 hours to induce apoptosis.

The degree of apoptosis was measured using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) activity assay method manufactured by Promega, MTS activity level cells under normal environmental conditions was taken as 100%, and the relative degree of cell protection was converted and determined based on the level of MTS activity of the control group under 0.5 mM H ₂ O ₂ treatment conditions.

The MTS activity assay evaluation method is a method for measuring the activity of NADH dehydrogenase in the mitochondria of cells, and NADH dehydrogenase reduces MTS to produce colored formazan. This method can quantify living cells as well as cell proliferation and apoptosis. After treating the retinal pigment epithelial cell line with the above-mentioned noxious stimulus, 15 μl of the MTS Activity Assay Kit from Promega was added to each well and then reacted at 37° C. in a CO ₂ incubator for 2 hours. The wells in which the interactions occurred were quantified by measuring absorbance at 450 nM using a Victor 3 microplate reader from PerkinElmer, Inc., and the results are shown in Table 4 below.

Based on Table 4, it was confirmed that the compounds of Examples 1, 6, 8, 21, 22, 23, 46, 50, 54, 55, 57, 58, 68, 99, 103, 128, 151, 152, 165, 200 204, 228, 237, 241, 242, 247, 268 and 272 have _{an EC50H2O2 -} induced human retinal pigment epithelial cell line of less than 150 nM, thereby demonstrating an excellent protective effect on retinal cells.

Accordingly, the isoquinolinone derivatives of the present invention effectively inhibit dry macular degeneration-like apoptosis at a concentration of nanomolar units and thus can be effectively used as a pharmaceutical composition containing isoquinolinone derivatives as an active ingredient for the prevention or treatment of ophthalmic diseases or disorders, for example, one or more than one disease selected from the group consisting of age-related macular degeneration, Stargardt macular degeneration, retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy, Sorsby's fundus dystrophy, optic neuropathy, inflammatory disease retinal, diabetic retinopathy, diabetic maculopathy, retinal vascular occlusion, retinopathy of prematurity or retinal ischemia-reperfusion injury, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, uveitis, retinal damage, retinal damage associated with Alzheimer's disease, retinal damage associated with multiple sclerosis, retinal damage associated with Parkinson's disease, retinal damage associated with viral infections, retinal damage associated with excessive exposure to light, myopia or retinal damage due to AIDS.

Experimental Example 3: Evaluation of rat retinal layer protection in dry macular degeneration-like cells

To evaluate the inhibitory effect (protective effect) of the compounds of the present invention on the reduction of rat retinal layer thickness in dry macular degeneration-like cells, the following experiment was conducted.

Specifically, 8-week-old rats were intraperitoneally injected with 50 mg/kg sodium iodate (SI) to degenerate the retinal pigment epithelium and photoreceptor cell layer to create a simulated animal model of dry macular degeneration. Retinal degeneration was observed 1 week after SI administration.

After a single intraperitoneal administration of the compound of Example 46 or Example 1 at a concentration of 15 mg/kg in a rat model of dry macular degeneration, their inhibitory effect (protective effect) on reducing the thickness of the retinal layer in rats was assessed.

To quantify the reduction in retinal thickness, eyes removed from rats were fixed in a 4% glutaraldehyde solution for 3 hours and then embedded in paraffin. After preparing 5-μm-thick tissue fragments, the fragments were stained with hematoxylin-eosin (H&E) solution and photographed using an optical microscope to measure the thickness of the retinal outer nuclear layer (ONL). As a result, the thickness (µm) of the retinal ONL of the control group was calculated and taken as 100% (n is 3 times). Olympus CX31 and Motic BA 600 microscopes were used for observation, a Moticam 1500 camera was used for photography, and the Image J program was used for measurements. The results are presented in Fig. 1.

In FIG. 1 is an image showing the change in rat retinal layer thickness, obtained using a Moticam 1500 camera, after treatment with the compound of Example 46 or Example 1 (via a single intraperitoneal injection of each 15 mg/kg) in 8-week-old rats.

Based on FIG. 1, by comparing the outer nuclear layer (ONL) of the retina, it was confirmed that retinal degeneration occurred in the vehicle group as opposed to the control group, but the retina was protected when treated with the compound of Example 46 or Example 1. Thus, it can be established that that the compound of the example has excellent protective ability against retinal dystrophy.

Accordingly, the isoquinolinone derivatives can be effectively used as a pharmaceutical composition containing the isoquinolinone derivatives as an active ingredient for the prevention or treatment of ophthalmic diseases or disorders, for example one or more than one disease selected from the group consisting of age-related macular degeneration, macular degeneration Stargardt, retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod dystrophy, Sorsby fundus dystrophy, optic neuropathy, inflammatory retinal disease, diabetic retinopathy, diabetic maculopathy, retinal vascular occlusion, retinopathy of prematurity or ischemia-reperfusion injury of the retina, proliferative retina itreoretinopathy , retinal dystrophy, hereditary optic neuropathy, uveitis, retinal damage, retinal damage associated with Alzheimer's disease, retinal damage associated with multiple sclerosis, retinal damage associated with Parkinson's disease, retinal damage associated with viral infections, retinal damage associated with excessive exposure to light, myopia or retinal damage due to AIDS.

Claims (293)

1. A compound of chemical formula 1 below, a stereoisomer thereof or a pharmaceutically acceptable salt: chemical formula 1 , where in chemical formula 1 above, L ¹ represents -(CH ₂ ) ₃ - or -(CH ₂ ) ₂ C(=O)-; Y is a 4-6 membered monocyclic or 8-membered bicyclic heterocycloalkylene containing one or two nitrogen atoms, or a 6-membered monocyclic heterocycloalkenylene containing one nitrogen atom; L ² represents a single bond, -NHCO-, -NR ² -, -O- or straight or branched C _1-4 alkylene substituted with one or more substituents selected from the group consisting of oxo and amino, R ² represents is hydrogen or methyl; And Z represents C _3-6 cycloalkyl, heterocycloalkyl, which is tetrahydrofuranyl or pyrrolidinyl, phenyl or heteroaryl selected from pyridyl, pyrimidyl and thiazole; wherein each said cycloalkyl, heterocycloalkyl, phenyl and heteroaryl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of -F, -Cl, cyano, nitro, methyl, unsubstituted or substituted with one or more fluorine, methoxy substituted with one or more fluorine, carboxy(-CO ₂ H), methoxycarbonyl and methylcarbonylamino. 2. A compound, its stereoisomer or a pharmaceutically acceptable salt according to claim 1, where L ¹ represents or ; 3. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of chemical formula 1 above is any compound selected from the following groups of compounds: 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'-bipyridin]-1'(2'H)-yl)propyl)-isoquinoline-1( 2H)-one; 44) 8-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)propyl)-isoquinoline-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-methylisoquinoline-1(2H)- He; 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'-bipyridin]-1'(2'H)-yl)propyl)-5-methylisoquinoline- 1(2H)-one; 63) 7-fluoro-3-(3-(6-fluoro-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)propyl)-5-methylisoquinoline- 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'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)isoquinoline- 1(2H)-one; 86) 8-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)isoquinoline- 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'-bipyridin]-1(2H)-yl)-3-oxopropyl)-isoquinoline-1(2H )-He; 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'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)isoquinoline- 1(2H)-one; 103) 7-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)isoquinoline- 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'-bipyridin]-1(2H)-yl)-3-oxopropyl)isoquinoline-1(2H) -He; 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'-bipyridin]-1'(2'H)-yl)-3-oxopropyl)-5- methylisoquinolin-1(2H)-one; 130) 8-fluoro-3-(3-(5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-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-tetrahydropyridine -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'-bipyridin]-1(2H)-yl)-3-oxopropyl)-5-methylisoquinoline-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]octane-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-tetrahydropyridine -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-tetrahydropyridine -4-yl)benzonitrile; 162) 3-(3-(4-(2,4-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinoline-1(2H)- He; 163) 3-fluoro-5-(1-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-propanoyl)-1,2,3,6-tetrahydropyridine -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'-bipyridin]-1(2H)-yl)-3-oxopropyl)-5-methylisoquinoline-1 (2H)-one; 169) 5-(4-(3-(7-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-propanoyl)piperazin-1-yl)picolinonitrile dihydrochloride; 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-(cyclobutancarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoroisoquinolin-1(2H)-one; 179) 3-(3-(4-(cyclobutancarbonyl)piperazin-1-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinolin-1(2H)-one; 180) 3-(3-(4-(cyclobutancarbonyl)piperazin-1-yl)-3-oxopropyl)-7-fluoroisoquinolin-1(2H)-one; 181) 3-(3-(4-(cyclobutancarbonyl)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; 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 hydrochloride; 196) 8-fluoro-5-methyl-3-(3-oxo-3-(4-propylpiperazin-1-yl)propyl)isoquinolin-1(2H)-one hydrochloride; 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]octane-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-methylisoquinoline-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]octane-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]octane-3- yl)nicotinonitrile; 208) 8-fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinoline-1(2H) -He; 209) 4-(8-(3-(8-fluoro-5-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)propanoyl)-3,8-diazabicyclo[3.2.1]octane-3- yl)benzonitrile; 210) 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-8-fluoro-5-methylisoquinoline-1(2H) -He; 211) 8-fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinoline- 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-methylisoquinoline- 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]octane-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]octane-3- yl)nicotinonitrile; 215) 7-fluoro-3-(3-(3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinoline-1(2H) -He; 216) 3-(3-(3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-7-fluoro-5-methylisoquinoline-1(2H) -He; 217) 7-fluoro-3-(3-(3-(6-fluoropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)-5-methylisoquinoline- 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]octane-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-methylisoquinoline- 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)- He; 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)- He; 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'-bipyridin]-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'-bipyridin]-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. 4. A method for producing a compound of Chemical Formula 1 according to claim 1, comprising reacting a compound of Chemical Formula 2 with a compound of Chemical Formula 3 to produce a compound of Chemical Formula 1, as shown in Reaction Scheme 1 below: where in reaction scheme 1 above, , L ¹ , Y, L ² and Z are as defined in claim 1, and W represents a leaving group. 5. A pharmaceutical composition for the prevention or treatment of a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1), containing an effective amount of a compound of chemical formula 1 according to claim 1, its isomer or a pharmaceutically acceptable salt as an active ingredient, a pharmaceutically acceptable carrier, excipient or diluent. 6. The pharmaceutical composition according to claim 5, wherein the compound of chemical formula 1 above, a stereoisomer thereof or a pharmaceutically acceptable salt is characterized by the prevention or treatment of a disease associated with poly(ADP-ribose) polymerase-1 (PARP-1) through cytoprotective effects . 7. The pharmaceutical composition according to claim 5, wherein poly(ADP-ribose) polymerase-1 (PARP-1)-related disease is a disease that results from cell damage or apoptosis caused by hyperactivity of poly(ADP-ribose) polymerase-1 (PARP-1). 8. The pharmaceutical composition according to claim 5, wherein the poly(ADP-ribose) polymerase-1 (PARP-1)-related disease is one or more diseases selected from the group consisting of a neurogenic disorder, a neurodegenerative disease, stroke, cardiovascular disease, macular degeneration, AIDS, arthritis, atherosclerosis, cancer, diabetes, brain tumor, inflammatory bowel disease, muscular dystrophy, osteoarthritis, osteoporosis, chronic pain, acute pain, neuropathic pain, nerve attack, peripheral damage nerves, kidney disease, retinal ischemia, septic shock and skin aging. 9. A pharmaceutical composition for the prevention or treatment of an ophthalmic disease or disorder, containing an effective amount of a compound of chemical formula 1 according to claim 1, an isomer or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, excipient or diluent. 10. The pharmaceutical composition according to claim 9, wherein the ophthalmic disease or disorder is one or more than one disease selected from the group consisting of age-related macular degeneration, Stargardt macular degeneration, retinal detachment, hemorrhagic retinopathy, retinitis pigmentosa, cone-rod degeneration , Sorsby's fundus dystrophy, optic neuropathy, inflammatory retinal disease, diabetic retinopathy, diabetic maculopathy, retinal vascular occlusion, retinopathy of prematurity or retinal ischemia-reperfusion injury, proliferative vitreoretinopathy, retinal dystrophy, hereditary optic neuropathy, uveitis, retinal damage, retinal damage , retinal damage associated with Alzheimer's disease, retinal damage associated with multiple sclerosis, retinal damage associated with Parkinson's disease, retinal damage associated with viral infections, retinal damage associated with excessive exposure to light, myopia, or retinal damage associated with AIDS.

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