RU2793331C1 - 1,3,4-oxadiazole homophthalimide derivative compounds as histone deacetylase 6 inhibitor and the pharmaceutical composition comprising the same - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions relates to pharmaceutical chemistry and includes a compound with formula (I), (II), specific compounds indicated in the claims, their use, as well as a pharmaceutical composition and an inhibition method based thereon. In formula (I) X₁ - X₄ independently refer to CR₀ or N, where at least two of X₁ - X₄ are CR₀, R₀ is independently H or halogen, R₁ is linear or branched -C₁-₅ haloalkyl, R₂ and R₃ are all independently H, halogen,

, 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3-7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S , 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

,

,

,

,

, phenyl, indolyl or

, K is O or S, Y is CR_a R_b, NR_c or a single bond, R_a and R_b are all independently hydrogen or -C _1-7 alkyl or R_a and R_b are bonded to each other and form a 3- 7-membered cycloalkyl, ring A is phenylene, n is 0 or 1, other substituents are as defined in the claims. In formula (II), X₁ - X₄ are independently CR ₀ or N, where at least two of X₁ - X₄ are CR ₀, where R₀ is H, R ₁ is linear or branched -C _1-5 haloalkyl , R₂ and R₃ are all independently H, K is O, Y is NR_c, R_c is -C_1-7 alkylphenyl, -C_1-7 alkylheteroaryl, in which case heteroaryl is 5- or 6-membered heteroaryl , containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, or -C _1-7 alkyl-OC _1-7 alkyl, where one H atom of the group is -C_1-7 alkylheteroaryl, in this case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, may be substituted by the following substituent: heteroaryl-C_1-5 haloalkyl, in which case heteroaryl is 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, ring A is phenylene, n is 0 or 1.

EFFECT: 1,3,4-oxadiazole derivatives having the properties of a highly selective HDAC6 inhibitor.

12 cl, 2 tbl, 1 ex

Description

The field of technology to which the invention belongs

The present invention relates to 1,3,4-oxadiazole homophthalimide derivatives having inhibitory activity against histone deacetylase 6 (HDAC6), their stereoisomers, their pharmaceutically acceptable salts, their use in the preparation of a medicament, a pharmaceutical composition containing them, a therapeutic a method using the composition, and a method for their preparation.

State of the art

In cells, post-translational modification, such as acetylation, serves as a very important regulatory module for many biological processes and is also tightly regulated by a number of enzymes. As the main protein that forms chromatin, histone acts as an axis around which DNA coils, and this promotes DNA condensation. In addition, the balance between histone acetylation and deacetylation plays a very important role in gene expression.

As an enzyme to remove the acetyl group of their lysine residue of a histone protein that forms chromatin, histone deacetylase (HDAC) is known to be associated with gene silencing and induce cell cycle arrest, angiogenic inhibition, immunoregulation, apoptosis, etc. (Hassig et al. , Curr Opin Chem Biol 1997, 1, 300-308). In addition, inhibition of HDAC enzyme functions has been reported to induce the expression of apoptosis in cancer cells themselves by reducing the activity of cancer cell survival-related factors and activating cancer cell death-related factors in the body (Warrell et al., J. Natl. Cancer Inst. 1998, 90, 1621-1625).

There are 18 HDACs known to humans and they are divided into four classes according to homology with yeast HDACs. In this case, the eleven HDACs using zinc as a cofactor can be divided into three groups: class I (HDAC1, 2, 3, 8), class II (IIa: HDAC4, 5, 7, 9; IIb: HDAC6, 10), and class IV (HDAC11). In addition, seven class III HDACs (SIRT 1-7) use NAD+ as a cofactor instead of zinc (Bolden et al., Nat. Rev. Drug Discov. 2006, 5(9), 769-784).

Various HDAC inhibitors are currently in pre-clinical or clinical development, but only non-selective HDAC inhibitors have hitherto been known to be anti-cancer agents. Vorinostat (SAHA) and romidepsin (FK228) are approved as a therapeutic agent for cutaneous T-cell lymphoma, and panobinostat (LBH-589) is approved as a therapeutic agent for multiple myeloma. However, it is known that non-selective HDAC inhibitors at high doses usually lead to side effects such as fatigue, nausea, etc. (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). Side effects have been reported to be caused by class I HDAC inhibition. Due to side effects and the like, non-selective HDAC inhibitors have been restricted in drug development in fields other than anti-cancer agents. (Witt et al., Cancer Letters 277 (2009) 8.21).

In addition, it has been reported that selective inhibition of class II HDACs does not result in the toxicity that occurs with inhibition of class I HDACs. When developing selective HDAC inhibitors, it would be desirable to eliminate side effects such as toxicity and the like caused by non-selective inhibition of HDACs. Accordingly, there is a possibility that selective HDAC inhibitors can be developed as an effective therapeutic agent for various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701).

It is known that HDAC6 of one of the classes IIb HDACs is mainly found in the cytoplasm and contains the protein tubulin and thus is involved in the deacetylation of a number of nonhistone substrates (HSP90, cortactin, etc.) (Yao et al., Mol. Cell 2005, 18 , 601-607). HDAC6 contains two catalytic domains in which the C-terminal zinc finger domain can bind to the ubiquinated protein. It is known that HDAC6 contains a variety of non-histone proteins as a substrate and therefore plays an important role in various diseases such as cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative disorders, etc. (Santo et al., Blood 2012 119 : 2579-2589; Vishwakarma et al., International Immunopharmacology 2013, 16, 72-78; Hu et al., J. Neurol. Sci. 2011, 304, 1-8).

Structural features shared by various HDAC inhibitors include cap groups, linker, and zinc binding groups (ZBGs), as shown in the following structure of vorinostat. Many researchers have studied enzyme inhibitory activity and selectivity with respect to structural modification of the cap groups and the linker. In addition to these groups, the zinc binding group is known to play a more important role in inhibitory activity and enzyme selectivity (Wiest et al., J. Org. Chem. 2013 78: 5051-5065; Methot et al., Bioorg. Med. Chem. Lett. 2008, 18, 973-978).

Most of these zinc binding groups consist of hydroxamic acid or benzamide, due to which hydroxamic acid derivatives have a strong inhibitory effect on HDAC, but are characterized by low bioavailability and strong off-target activity. Benzamide contains aniline and is therefore problematic because benzamide can form toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, online publication).

Accordingly, unlike non-selective inhibitors characterized by side effects, it is necessary to develop a selective HDAC inhibitor that contains a zinc binding group, with improved bioavailability but without side effects, for the treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative disorders, etc. . P.

[Prior Art Literature]

(Patent Document 1) International Patent Publication No. WO 2011/091213 (publicized on Jul. 28, 2011): ACY-1215

(Patent Document 2) International Patent Publication No. WO 2011/011186 (publicized on Jan. 27, 2011): Tubastatin

(Patent Document 3) International Patent Publication No. WO 2013/052110 (publicized on Apr. 11, 2013): Sloan-K

(Patent Document 4) International Patent Publication No. WO 2013/041407 (publicized on Mar. 28, 2013): Cellzome

(Patent Document 5) International Patent Publication No. WO 2013/134467 (publicized on Sep. 12, 2013): Kozi

(Patent Document 6) International Patent Publication No. WO 2013/008162 (publicized on Jan. 17, 2013): Novartis

(Patent Document 7) International Patent Publication No. WO 2013/080120 (publicized on Jun. 06, 2013): Novartis

(Patent Document 8) International Patent Publication No. WO 2013/066835 (publicized on May 10, 2013): Tempero

(Patent Document 9) International Patent Publication No. WO 2013/066838 (publicized on May 10, 2013): Tempero

(Patent Document 10) International Patent Publication No. WO 2013/066833 (publicized on May 10, 2013): Tempero

(Patent Document 11) International Patent Publication No. WO 2013/066839 (publicized on May 10, 2013): Tempero

Detailed description of the invention

Technical task

The object of the present invention is to provide 1,3,4-oxadiazole homophthalimide derivatives having selective inhibitory activity against HDAC6, their stereoisomers or their pharmaceutically acceptable salts.

Another object of the present invention is to provide a process for the preparation of 1,3,4-oxadiazole homophthalimide derivatives, their stereoisomers or their pharmaceutically acceptable salts.

Another object of the present invention is to provide a pharmaceutical composition containing 1,3,4-oxadiazole homophthalimide derivatives having selective HDAC6 inhibitory activity, their stereoisomers or their pharmaceutically acceptable salts.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diseases associated with HDAC6 activity, including cancer, inflammatory diseases, autoimmune diseases, neurological diseases or neurodegenerative disorders, containing homophthalimide derivatives of 1,3,4-oxadiazole, their stereoisomers or their pharmaceutically acceptable salts.

Another object of the present invention is to provide a method for the prevention or treatment of diseases associated with HDAC6 activity, comprising administering a therapeutically effective amount of a pharmaceutical composition containing 1,3,4-oxadiazole homophthalimide derivatives, their stereoisomers, or their pharmaceutically acceptable salts.

Another object of the present invention is to provide a method for selectively inhibiting HDAC6 by administering 1,3,4-oxadiazole homophthalimide derivatives, their stereoisomers or their pharmaceutically acceptable salts to mammals, including humans.

Another object of the present invention is the use of homophthalimide derivatives of 1,3,4-oxadiazole, their stereoisomers or their pharmaceutically acceptable salts for the prevention or treatment of diseases associated with HDAC6 activity.

Another object of the present invention is the use of 1,3,4-oxadiazole homophthalimide derivatives, their stereoisomers or their pharmaceutically acceptable salts for the preparation of a medicament for the prevention or treatment of diseases associated with HDAC6 activity.

Technical solution

The present inventors have discovered 1,3,4-oxadiazole homophthalimide derivatives having histone deacetylase 6 (HDAC6) inhibitory activity and used them to prevent or treat diseases associated with HDAC6 activity, and thus completed the present invention.

Homophthalimide derivatives of 1,3,4-oxadiazole

The present invention relates to 1,3,4-oxadiazole homophthalimide derivatives having the following chemical formula I, their stereoisomers, or their pharmaceutically acceptable salts:

Chemical formula I]

Where

X ₁ - X ₄ are all independently CR ₀ or N,

where each R ₀ is independently hydrogen, halogen, linear or branched -C _1-7 alkyl or linear or branched -OC _1-7 alkyl, where at least two of X ₁ - X ₄ are CR ₀ ,

R ₁ means linear or branched -C _1-5 haloalkyl,

, 3- - 7-членный гетероциклоалкил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S, 3- - 7-членный гетероциклоалкенил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S, 5- или 6-членный гетероарил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S,

-C_1-7 алкил, 3-7-членный циклоалкил, 3- - 7-членный циклоалкенил, циклопента-1,3-диен, фенил, индолил,

или

,R ₂ and R ₃ are all independently H, halogen,

, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3- to 7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S,

-C _1-7 alkyl, 3-7 membered cycloalkyl, 3--7 membered cycloalkenyl, cyclopenta-1,3-diene, phenyl, indolyl,

or

,

-C_1-7 алкил, 3-7-членный циклоалкил, 3-7-членный циклоалкенил, циклопента-1,3-диен, фенила, индолила,

или

может быть замещен с помощью R₄,{wherein at least one hydrogen of said 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from a group comprising N, O or S, a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group comprising N, O or S,

-C _1-7 alkyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, cyclopenta-1,3-diene, phenyl, indolyl,

or

can be substituted with R ₄ ,

, -C_1-7 алкил-C(=O)-R₅, -C_1-7 алкил-C(=O)-O-R₆, -C_1-7 алкил-R₇, -C_1-7 алкил-O-R₈, -NR₉R₁₀, -C(=O)-NR₁₁R₁₂ или -C_1-7 алкил-NR₁₃R₁₄,R ₄ is halogen, -C _1-7 alkyl, -C _1-7 haloalkyl, -OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-C _1-7 alkyl-OH, -C(=O)-OC _1-7 alkyl, -S(=O) ₂ -C _1-7 alkyl, 3- - 7-membered cycloalkyl, 3- - 7-membered halocycloalkyl, 3- - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

, -C _1-7 alkyl-C(=O)-R ₅ , -C _1-7 alkyl-C(=O)-OR ₆ , -C _1-7 alkyl-R ₇ , -C _1-7 alkyl- OR ₈ , -NR ₉ R ₁₀ , -C(=O)-NR ₁₁ R ₁₂ or -C _1-7 alkyl-NR ₁₃ R ₁₄ ,

where R ₅ means -C _1-7 alkyl, 3 - - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5 - or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered cycloalkyl, cyclopenta-1,3-diene or phenyl,

R ₆ is -C _1-7 alkyl, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered cycloalkyl, cyclopenta-1,3-diene or phenyl,

R ₇ is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, a 3- to 7-membered cycloalkyl, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, cyclopenta-1,3-diene or phenyl,

R ₈ is -C _1-7 alkyl, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered cycloalkyl, cyclopenta-1,3-diene or phenyl,

R ₉ and R ₁₀ are all independently H or -C _1-7 alkyl,

R ₁₁ and R ₁₂ are all independently H or -C _1-7 alkyl, and

R ₁₃ and R ₁₄ are all independently H or -C _1-7 alkyl},

R _x and R _y are all independently -C _1-7 alkyl, -C _1-7 alkyl-NR ₁₅ R ₁₆ , H, -C _1-7 alkyl-OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-heteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C( =O)-heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C(=O)-cycloalkyl [in this in the case cycloalkyl is a 3- to 7-membered cycloalkyl], -C _1-7 alkyl-O-heterocycloalkyl [in this case heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] or -C _1-7 alkylcycloalkyl [in this case, cycloalkyl is a 3- to 7-membered cycloalkyl],

или

, и{where at least one hydrogen of the group is -C _1-7 alkyl, -C _1-7 alkyl-OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-heteroaryl [ in this case, heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O, or S], -C(=O)-heterocycloalkyl [in this case, heterocycloalkyl is 3- - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C(=O)-cycloalkyl [in this case, cycloalkyl is 3--7-membered cycloalkyl], - C _1-7 alkyl-O-heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S] or -C _1-7 alkylcycloalkyl [ in this case, cycloalkyl is a 3- to 7-membered cycloalkyl] may be substituted by the following substituent: -C _1-7 alkyl, halogen, -OC _1-7 alkyl, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms , selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms, selected from the group including N, O or S, 3- to 7-membered cycloalkyl, -S(= O) ₂ -C _1-7 alkyl, -CF ₃ ,

or

, And

R ₁₅ and R ₁₆ are all independently H or -C _1-7 alkyl},

K means O or S,

Y means CR _a R _b , NR _c or single bond,

или

, иR _a and R _b are all independently hydrogen, -C _1-7 alkyl, 3--7 membered cycloalkyl, -C _1-7 alkyl-OC _1-7 alkyl, -C _1-7 alkyl-NR ₁₇ R ₁₈ , 3- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _1-7 alkyl-C(=O)-C _1-7 alkyl or -C _1-7 alkyl-C(=O)-OC _1-7 alkyl, or R _a and R _b are bonded to each other and form a 3- to 7-membered cycloalkyl, {where at least one hydrogen of the group C _1-7 alkyl, 3- - 7-membered cycloalkyl, -C _1-7 alkyl-OC _1-7 alkyl, -C _1-7 alkyl-NR ₁₇ R ₁₈ , 3- - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group, comprising N, O or S, -C _1-7 alkyl-C(=O)-C _1-7 alkyl or -C _1-7 alkyl-C(=O)-OC _1-7 alkyl may be substituted by the following substituent: -C _1-7 alkyl, halogen, -OC _1-7 alkyl, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 5- or 6-membered heteroaryl, containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3--7-membered cycloalkyl, -S(=O) ₂ -C _1-7 alkyl, -CF ₃ ,

or

, And

R ₁₇ and R ₁₈ are all independently H or -C _1-7 alkyl},

R _c is hydrogen, -C _1-7 alkyl, -C _1-7 alkyl heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S ], -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] - C _1-7 alkyl-OC _1-7 alkyl, -C _1-7 alkyl-NR ₁₉ R ₂₀ , -C _1-7 alkylcycloalkyl [in this case cycloalkyl is a 3- to 7-membered cycloalkyl], 3- to 7 -membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered cycloalkyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group including N, O or S, cyclopenta-1,3-diene, phenyl, -C(=O)-heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group, including N, O or S], -C(=O)-cycloalkyl [in this case cycloalkyl is a 3- to 7-membered cycloalkyl], -C(=O)-heteroaryl [in this case heteroaryl is 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C(=O)-phenyl, -C(=O)-C _1-7 alkyl, -C(= O)-C _1-7 alkyl-OC _1-7 alkyl or -C(=O)-C _1-7 alkyl-NR ₂₁ R ₂₂ ,

или

, и{where at least one hydrogen of the group is -C _1-7 alkyl, -C _1-7 alkyl heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S ], -C _1-7 alkyl-OC _1-7 alkyl, -C _1-7 alkyl-NR ₁₉ R ₂₀ , -C _1-7 alkylcycloalkyl [in this case, cycloalkyl is a 3- to 7-membered cycloalkyl], 3 - - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3- - 7-membered cycloalkyl, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from a group comprising N, O or S, cyclopenta-1,3-diene, phenyl, -C(=O)-heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C(=O)-cycloalkyl [in this case, cycloalkyl is a 3- to 7-membered cycloalkyl], -C(=O)-heteroaryl [in this case, heteroaryl is 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C(=O)-phenyl, -C(=O)-C _1-7 alkyl, - C(=O)-C _1-7 alkyl-OC _1-7 alkyl or -C(=O)-C _1-7 alkyl-NR ₁₉ R ₂₀ may be substituted by the following substituent: -C _1-7 alkyl, halogen, -OC _1-7 alkyl, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C(=O)-OC _1-7 alkyl, 5- or 6 -membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, heteroaryl-C _1-5 haloalkyl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], 3--7-membered cycloalkyl, -S(=O) ₂ -C _1-7 alkyl, -CF ₃ ,

or

, And

R ₁₉ and R ₂₀ are all independently H or -C _1-7 alkyl},

означает фенилен или 5- или 6-членный гетероарилен, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S,

means phenylene or a 5- or 6-membered heteroarylene containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

halogen is F, Cl, Br or I, and

n is 0 or 1.

In the present specification, the terms used in defining the substituents of the 1,3,4-oxadiazole homophthalimide derivatives of the present invention, their stereoisomers, or their pharmaceutically acceptable salts are as follows.

In the present invention, the term "substitution" means that the hydrogen atom bonded to the carbon atom of the compound is replaced by another substituent, and the substitution position is not limited to a specific position if the hydrogen atom is substituted, i.e., is the position where the substituent can be substituted . If there are two or more substituents, the two or more substituents may be the same or different.

In the present invention, the term "halogen" means an element of the halogen group, and includes, for example, fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

In the present invention, the term "alkyl" means a linear or branched saturated hydrocarbon containing the specified number of carbon atoms unless otherwise indicated.

In the present invention, the term "haloalkyl" means that at least one hydrogen atom associated with a linear or branched saturated hydrocarbon having a given number of carbon atoms is replaced by a halogen, unless otherwise indicated.

In the present invention, the term "heterocycloalkyl" means a cyclic saturated hydrocarbon containing 1 to 3 heteroatoms selected from the group consisting of N, O, or S. Examples of heterocycloalkyl include, without limitation, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolidonyl, piperidonyl, morpholidinyl, imidazolidinyl, pyrazolidinyl, oxetanyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, oxazolidinonyl and thiazolidinonyl.

In the present invention, the term "heterocycloalkenyl" includes at least one double bond and means a cyclic unsaturated hydrocarbon containing 1 to 3 heteroatoms selected from the group consisting of N, O or S. Examples of heterocycloalkenyl include, without limitation, tetrahydropyridinyl, dihydrofuranyl, and 2,5-dihydro-1H-pyrrolyl.

In the present invention, the term "heteroaryl" means a heterocyclic aromatic group containing 1 to 3 heteroatoms selected from the group consisting of N, O, or S. Examples of heteroaryl include, without limitation, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

In the present invention, the term "cycloalkyl" means a cyclic saturated hydrocarbon containing a given number of carbon atoms. Examples of cycloalkyl include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

In the present invention, the term "halocycloalkyl" means that at least one hydrogen atom associated with a cyclic saturated hydrocarbon containing a given number of carbon atoms is replaced by a halogen, unless otherwise indicated.

In the present invention, the term "cycloalkenyl" means a cyclic unsaturated hydrocarbon that contains a given number of carbon atoms and includes at least one double bond. Examples of cycloalkenyl include, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

In the present invention, the term "single bond" means that the atom is not contained in the corresponding position. For example, if Y is a single bond in an X-Y-Z structure, X and Z are directly bonded to each other to form an X-Z structure.

" означает положение присоединения атома, который связан с остальной частью молекулы или с остальной частью фрагмента молекулы в химической структуре.In the present invention, in addition to the indicated substituents "

" means the attachment position of an atom that is bonded to the rest of the molecule or to the rest of the molecule fragment in the chemical structure.

означает структуру , сконденсированную путем использования двух общих с другим кольцом атомов, и два общих/сконденсированных атома углерода являются двумя последовательными атомами. Например,

означает фенилен или 5- или 6-членный гетероарилен, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S. "5- или 6-членный гетероарилен" указанного

означает фуранилен, пирролилен, тиофенилен, тиазолилен, изотиазолилен, имидазолилен, триазолилен, тетразолилен, пиразолилен, оксазолилен, изооксазолилен, пиридинилен, пиразинилен, пиридазинилен, пиримидинилен, триазинилен и т. п., который содержит от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S. В этом случае указанный фенилен и указанный гетероарилен сконденсированы путем обобщения двух атомов углерода с другим кольцом (кольцом, содержащим Y химической формулы I, обладающим структурой

). В этом случае два атома углерода, сконденсрованные путем обобщения в фенилен или 5- или 6-членный гетероарилен, являются двумя последовательными атомами углерода, образующих другое кольцо (кольцо, содержащее Y химической формулы I). В качестве примера, если

означает фенилен, химическая формула I может содержать структуру

.In the present invention

means a structure fused by using two atoms in common with another ring, and the two shared/fused carbon atoms are two consecutive atoms. For example,

means phenylene or a 5- or 6-membered heteroarylene containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S. "5- or 6-membered heteroarylene" of the specified

means furanylene, pyrrolylene, thiophenylene, thiazolylene, isothiazolylene, imidazolylene, triazolilene, tetrazolylene, pyrazolylene, oxazolylene, isooxazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, triazinylene, etc., which contains from 1 to 3 heteroatoms selected from the group, including N, O or S. In this case, said phenylene and said heteroarylene are fused by generalization of two carbon atoms with another ring (a ring containing Y of the chemical formula I having the structure

). In this case, the two carbon atoms condensed by generalization to phenylene or a 5- or 6-membered heteroarylene are two consecutive carbon atoms forming another ring (the Y-containing ring of chemical formula I). As an example, if

means phenylene, the chemical formula I may contain the structure

.

One embodiment of the present invention is a compound having the above chemical formula I, where:

X ₁ - X ₄ are all independently CR ₀ or N,

where R ₀ means hydrogen, halogen or -OC _1-7 alkyl,

R ₁ is -C _1-5 haloalkyl,

, 3- - 7-членный гетероциклоалкил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S, 3- - 7-членный гетероциклоалкенил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S, 5- или 6-членный гетероарил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S,

фенил, индолил,

или -C_1-7 алкил,R ₂ and R ₃ are all independently H, halogen,

, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3- to 7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S,

phenyl, indolyl,

or -C _1-7 alkyl,

фенила, индолила,

или -C_1-7 алкила может быть замещен с помощью R₄,{wherein at least one hydrogen of said 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

phenyl, indolyl,

or -C _1-7 alkyl may be substituted with R ₄ ,

, -C_1-7 алкил-C(=O)-R₅, -C_1-7 алкил-C(=O)-O-R₆, -C_1-7 алкил-R₇, -C_1-7 алкил-O-R₈, -NR₉R₁₀, -C(=O)-NR₁₁R₁₂ или -C_1-7 алкил-NR₁₃R₁₄,R ₄ is halogen, -C _1-7 alkyl, -C _1-7 haloalkyl, -OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-C _1-7 alkyl-OH, -C(=O)-OC _1-7 alkyl, -S(=O) ₂ -C _1-7 alkyl, 3- - 7-membered cycloalkyl, 3- - 7-membered halocycloalkyl, 3- - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

, -C _1-7 alkyl-C(=O)-R ₅ , -C _1-7 alkyl-C(=O)-OR ₆ , -C _1-7 alkyl-R ₇ , -C _1-7 alkyl- OR ₈ , -NR ₉ R ₁₀ , -C(=O)-NR ₁₁ R ₁₂ or -C _1-7 alkyl-NR ₁₃ R ₁₄ ,

where R ₅ means -C _1-7 alkyl or 3 - - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

R ₆ means -C _1-7 alkyl,

R ₇ is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S or a 3- to 7-membered cycloalkyl,

R ₈ means -C _1-7 alkyl,

R ₉ and R ₁₀ are all independently H or -C _1-7 alkyl,

R ₁₁ and R ₁₂ are all independently H or -C _1-7 alkyl, and

R ₁₃ and R ₁₄ are all independently H or -C _1-7 alkyl},

R _x and R _y are all independently -C _1-7 alkyl, -C _1-7 alkyl-NR ₁₅ R ₁₆ , H, -C _1-7 alkyl-OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-heteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C( =O)-heterocycloalkyl [in this case heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] or -C(=O)-cycloalkyl [in this case cycloalkyl is a 3- to 7-membered cycloalkyl],

или

, и{where at least one hydrogen of the group is -C _1-7 alkyl, -C _1-7 alkyl-OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-heteroaryl [ in this case, heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O, or S], -C(=O)-heterocycloalkyl [in this case, heterocycloalkyl is 3- - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] or -C(=O)-cycloalkyl [in this case, cycloalkyl is 3--7-membered cycloalkyl] may be substituted by the following substituent: -C _1-7 alkyl, halogen, -OC _1-7 alkyl, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 5- or 6 -membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered cycloalkyl, -S(=O) ₂ -C _1-7 alkyl, -CF ₃ ,

or

, And

R ₁₅ and R ₁₆ are all independently H or -C _1-7 alkyl},

K means O or S,

Y means CR _a R _b , NR _c or single bond,

R _a and R _b are all independently hydrogen, -C _1-7 alkyl, 3--7 membered cycloalkyl, -C _1-7 alkyl-OC _1-7 alkyl, -C _1-7 alkyl-NR ₁₇ R ₁₈ , or R _a and R _b are bonded to each other and form a 3- to 7-membered cycloalkyl,

или

, и{wherein at least one hydrogen of the group -C _1-7 alkyl, 3- to 7-membered cycloalkyl, -C _1-7 alkyl-OC _1-7 alkyl or -C _1-7 alkyl-NR ₁₇ R ₁₈ may be substituted the following substituent: -C _1-7 alkyl, halogen, -OC _1-7 alkyl, 3- - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 5- or 6- membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered cycloalkyl, -S(=O) ₂ -C _1-7 alkyl, -CF ₃ ,

or

, And

R ₁₇ and R ₁₈ are all independently H or -C _1-7 alkyl},

R _c is hydrogen, -C _1-7 alkyl, -C _1-7 alkyl heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S ], -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] - C _1-7 alkyl-OC _1-7 alkyl, -C _1-7 alkyl-NR ₁₉ R ₂₀ , -C _1-7 alkylcycloalkyl [in this case cycloalkyl is a 3- to 7-membered cycloalkyl], 3- to 7 -membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered cycloalkyl, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group including N, O or S, cyclopenta-1,3-diene, phenyl, -C(=O)-heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group, including N, O or S], -C(=O)-cycloalkyl [in this case cycloalkyl is a 3- to 7-membered cycloalkyl], -C(=O)-heteroaryl [in this case heteroaryl is 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C(=O)-phenyl, -C(=O)-C _1-7 alkyl, -C(= O)-C _1-7 alkyl-OC _1-7 alkyl or -C(=O)-C _1-7 alkyl-NR ₂₁ R ₂₂ ,

или

, и{where at least one hydrogen of the group is -C _1-7 alkyl, -C _1-7 alkyl heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S ], -C _1-7 alkyl-OC _1-7 alkyl, -C _1-7 alkyl-NR ₁₉ R ₂₀ , -C _1-7 alkylcycloalkyl [in this case, cycloalkyl is a 3- to 7-membered cycloalkyl], 3 - - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3- - 7-membered cycloalkyl, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from a group comprising N, O or S, cyclopenta-1,3-diene, phenyl, -C(=O)-heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C(=O)-cycloalkyl [in this case, cycloalkyl is a 3- to 7-membered cycloalkyl], -C(=O)-heteroaryl [in this case, heteroaryl is 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C(=O)-phenyl, -C(=O)-C _1-7 alkyl, - C(=O)-C _1-7 alkyl-OC _1-7 alkyl or -C(=O)-C _1-7 alkyl-NR ₁₉ R ₂₀ may be substituted by the following substituent: -C _1-7 alkyl, halogen, -OC _1-7 alkyl, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C(=O)-OC _1-7 alkyl, 5- or 6 -membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, heteroaryl-C _1-5 haloalkyl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], 3--7-membered cycloalkyl, -S(=O) ₂ -C _1-7 alkyl, -CF ₃ ,

or

, And

R ₁₉ and R ₂₀ are all independently H or -C _1-7 alkyl},

означает фенилен или 5- или 6-членный гетероарилен, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S,

means phenylene or a 5- or 6-membered heteroarylene containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

halogen is F, Cl, Br or I, and

n is 0 or 1.

Also a specific embodiment of the present invention is a compound having the above chemical formula I, where:

X ₁ - X ₄ are all independently CR ₀ or N,

R ₀ means hydrogen or halogen,

R ₁ is -C _1-5 haloalkyl,

, 3- - 7-членный гетероциклоалкил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S, 3- - 7-членный гетероциклоалкенил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S, 5- или 6-членный гетероарил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S,

, фенил, индолил,

или

,R ₂ and R ₃ are all independently H, halogen,

, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3- to 7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S,

, phenyl, indolyl,

or

,

, фенила, индолила,

или

может быть замещен с помощью R₄,{wherein at least one hydrogen of said 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

, phenyl, indolyl,

or

can be substituted with R ₄ ,

, -C_1-7 алкил-C(=O)-R₅, -C_1-7 алкил-R₇, -C_1-7 алкил-O-R₈, -NR₉R₁₀ или -C(=O)-NR₁₁R₁₂,R ₄ is halogen, -C _1-7 alkyl, -C _1-7 haloalkyl, -OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-C _1-7 alkyl-OH, -C(=O)-OC _1-7 alkyl, -S(=O) ₂ -C _1-7 alkyl, 3- - 7-membered cycloalkyl, 3- - 7-membered halocycloalkyl, 3- - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

, -C _1-7 alkyl-C(=O)-R ₅ , -C _1-7 alkyl-R ₇ , -C _1-7 alkyl-OR ₈ , -NR ₉ R ₁₀ or -C(=O)- NR ₁₁ R ₁₂ ,

where R ₅ is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

R ₇ is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S or a 3- to 7-membered cycloalkyl,

R ₈ means -C _1-7 alkyl,

R ₉ and R ₁₀ are all independently -C _1-7 alkyl, and

R ₁₁ and R ₁₂ are all independently H or -C _1-7 alkyl},

R _x and R _y are all independently -C _1-7 alkyl or -C _1-7 alkyl-NR ₁₅ R ₁₆ ,

{where R ₁₅ and R ₁₆ are all independently -C _1-7 alkyl},

K means O

Y means CR _a R _b , NR _c or single bond,

R _a and R _b are all independently hydrogen or -C _1-7 alkyl, or R _a and R _b are bonded to each other to form a 3- to 7-membered cycloalkyl,

R _c is hydrogen, -C _1-7 alkyl, -C _1-7 alkyl heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S ], -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] - C _1-7 alkyl-OC _1-7 alkyl or -C _1-7 alkyl-NR ₁₉ R ₂₀ ,

{where at least one hydrogen of the group is -C _1-7 alkyl, -C _1-7 alkyl heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S ], -C _1-7 alkyl-OC _1-7 alkyl or -C _1-7 alkyl-NR ₁₉ R ₂₀ may be substituted by the following substituent: -C _1-7 alkyl, -OC _1-7 alkyl, 3- - 7 -membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, heteroaryl-C _1-5 haloalkyl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] or -C(=O)-OC _1-7 alkyl, and

R ₁₉ and R ₂₀ are all independently -C _1-7 alkyl},

означает фенилен,

means phenylene,

halogen is F or Br, and

n is 0 or 1.

A more preferred embodiment of the present invention is a compound having the above chemical formula I, wherein:

X ₁ - X ₄ are all independently CR ₀ or N,

R ₀ means hydrogen or F,

R ₁ means CF ₂ H,

, 3- - 7-членный гетероциклоалкил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S, 3- - 7-членный гетероциклоалкенил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S, 5- или 6-членный гетероарил, содержащий от 1 до 3 гетероатомов, выбранных из группы, включающей N, O или S,

, фенил, индолил,

или

,R ₂ and R ₃ are all independently H, F, Br,

, 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3- to 7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S,

, phenyl, indolyl,

or

,

, фенила, индолила,

или

может быть замещен с помощью R₄,{wherein at least one hydrogen of said 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, 3- to 7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

, phenyl, indolyl,

or

can be substituted with R ₄ ,

, -C_1-7 алкил-C(=O)-R₅, -C_1-7 алкил-R₇, -C_1-7 алкил-O-R₈, -NR₉R₁₀ или -C(=O)-NR₁₁R₁₂,R ₄ is F, -C _1-7 alkyl, -C _1-7 haloalkyl, -OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-C _1-7 alkyl-OH, -C(=O)-OC _1-7 alkyl, -S(=O) ₂ -C _1-7 alkyl, 3- - 7-membered cycloalkyl, 3- - 7-membered halocycloalkyl, 3- - 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

, -C _1-7 alkyl-C(=O)-R ₅ , -C _1-7 alkyl-R ₇ , -C _1-7 alkyl-OR ₈ , -NR ₉ R ₁₀ or -C(=O)- NR ₁₁ R ₁₂ ,

where R ₅ is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

R ₇ is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S or a 3- to 7-membered cycloalkyl,

R ₈ means -C _1-7 alkyl,

R ₉ and R ₁₀ are all independently -C _1-7 alkyl, and

R ₁₁ and R ₁₂ are all independently H or -C _1-7 alkyl},

R _x and R _y are all independently -C _1-7 alkyl or -C _1-7 alkyl-NR ₁₅ R ₁₆ ,

{where R ₁₅ and R ₁₆ are all independently -C _1-7 alkyl},

K means O

Y means CR _a R _b , NR _c or single bond,

R _a and R _b are all independently hydrogen or -C _1-7 alkyl, or R _a and R _b are bonded to each other to form a 3- to 7-membered cycloalkyl,

R _c is hydrogen, -C _1-7 alkyl, -C _1-7 alkyl heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S ], -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] - C _1-7 alkyl-OC _1-7 alkyl or -C _1-7 alkyl-NR ₁₉ R ₂₀ ,

{where at least one hydrogen of the group is -C _1-7 alkyl, -C _1-7 alkyl heterocycloalkyl [in this case, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S], -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S ], -C _1-7 alkyl-OC _1-7 alkyl or -C _1-7 alkyl-NR ₁₉ R ₂₀ may be substituted by the following substituent: -C _1-7 alkyl, -OC _1-7 alkyl, 3- - 7 -membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, heteroaryl-C _1-5 haloalkyl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] or -C(=O)-OC _1-7 alkyl, and

R ₁₉ and R ₂₀ are all independently -C _1-7 alkyl},

означает фенилен,

means phenylene,

halogen is F or Br, and

n is 0 or 1.

In a specific embodiment of the present invention, the compound having the above chemical formula I may be the compound having the following chemical formula I-1:

Chemical formula I-1]

Where

X ₁ - X ₄ , R ₁ - R ₃ , Y, K and n are the same as defined for the chemical formula I.

The present invention relates to 1,3,4-oxadiazole homophthalimide derivatives having the following chemical formula II, their stereoisomers, or their pharmaceutically acceptable salts:

Chemical formula II]

Where

A, X ₁ - X ₄ , R ₁ - R ₃ , Y, K and n are the same as defined for the chemical formula I.

A specific embodiment of the present invention is a compound having the above chemical formula II, where:

X ₁ - X ₄ are all independently CR ₀ or N,

R ₀ means hydrogen,

R ₁ means CF ₂ H,

R ₂ and R ₃ are H,

K means O

Y means NR _c ,

R _c means -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] or -C _1-7 alkyl-OC _1-7 alkyl,

{where at least one hydrogen of the group is -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S] or -C _1-7 alkyl-OC _1-7 alkyl may be substituted by the following substituent: heteroaryl-C _1-5 haloalkyl [in this case, heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S]},

означает фенилен,

means phenylene,

halogen is F, and

n is 1.

In a specific embodiment of the present invention, the compound having the above chemical formula II may be the compound having the following chemical formula II-1:

Chemical formula II-1]

Where

X ₁ - X ₄ , R ₁ - R ₃ , Y, K and n are the same as defined for the chemical formula I.

The present invention relates to the 1,3,4-oxadiazole homophthalimide derivatives described in the following Table 1, their stereoisomers, or their pharmaceutically acceptable salts.

The 1,3,4-oxadiazole homophthalimide derivatives of the present invention may contain at least one asymmetric carbon and thus may be present as a racemate, a racemic mixture, one enantiomer (optical isomer), a mixture of diastereoisomers, and the corresponding diastereoisomers thereof. . Stereoisomers can be separated by methods of the related art, for example, column chromatography, HPLC, etc. Alternatively, the corresponding stereoisomers of 1,3,4-oxadiazole homophthalimide derivatives of the present invention can be stereospecifically synthesized using a well-known group of optically pure starting materials and/or reagents.

In the present invention, the term "pharmaceutically acceptable" means that is physiologically acceptable and usually does not lead to an allergic reaction such as gastrointestinal disease and dizziness or other similar reactions when administered to a human, and the term "salt" means a salt prepared by a conventional method in the form an acid addition salt formed by the pharmaceutically acceptable free acid, and a method for preparing the pharmaceutically acceptable salt is generally known to those skilled in the art. Pharmaceutically acceptable salts include, for example, inorganic ion salts derived from calcium, potassium, sodium, magnesium, and the like; inorganic acid salts derived from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, hydroiodic acid, perchloric acid, sulfuric acid, and the like; organic acid salts derived from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid , galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, etc.; sulfonic acid salts derived from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like; amino acid salts derived from glycine, arginine, lysine, and the like; amine salts obtained from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; and the like, but the types of salts used in the present invention are not limited to the listed salts. In the present invention, preferred salts include salts of hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.

Method for obtaining homophthalimide derivatives of 1,3,4-oxadiazole

The present invention relates to a process for the preparation of 1,3,4-oxadiazole homophthalimide derivatives, their stereoisomers or their pharmaceutically acceptable salts.

In the present invention, the preferred method for preparing 1,3,4-oxadiazole homophthalimide derivatives, their stereoisomers, or their pharmaceutically acceptable salts is as shown in Reaction Schemes 1 to 14, and even the present invention also includes a method of preparation modified to the extent obvious for experts in this field of technology.

Reaction Scheme 1

In the above reaction scheme 1, A, X ₁ - X ₄ , R ₁ - R ₃ , Y and n are the same as described for the chemical formula I. In particular, in the above reaction scheme 1, A is phenyl, X ₁ - X ₄ are all independently CH, CF or N, L ₂ is methylene (CH ₂ ), B is N, R ₁ is CF ₂ H, R ₂ and R ₃ are H, Y is methylene (CH ₂ ) or C (C _1-7 alkyl) ₂ , Halo is halo and n is 0 or 1.

The above Reaction Scheme 1 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-1-1 is reacted with a compound of chemical formula 1-1-2 or chemical formula 1-1-3 and get compounds of chemical formula 1-1-4, having the structure of 1,3,4-oxadiazole.

In the present invention, the compounds obtained by the above reaction schemes include 1, 2, 12, 65, etc.

Reaction Scheme 2

In the above reaction scheme 2, A, X ₁ - X ₄ and R ₁ - R ₃ are the same as described for the chemical formula I. In particular, in the above reaction scheme 2, A is phenyl, X ₁ - X ₄ all independently are CH, CF or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R ₂ and R ₃ are H, Y is CR _a R _b (R _a and R _b form cyclobutane), Halo is halo; and alkyl is C _1-7 alkyl.

The above Reaction Scheme 2 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-2-1 is introduced into a substitution reaction with a compound of chemical formula 1-2-2 to obtain compounds of chemical formula 1 -2-3 and then introduced into the hydrolysis reaction and get the compounds of the chemical formula 1-2-4. Then, the compound of the chemical formula 1-2-4 is reacted with urea to obtain the compounds of the chemical formula 1-2-5, and then it is subjected to a substitution reaction with the compound of the chemical formula 1-1-2 to obtain the compounds of the chemical formula 1-2-6.

In the present invention, the compounds obtained by the above reaction schemes include 3, 4, 5, 106, 107, etc.

Reaction Scheme 3

In the above reaction scheme 3, A, X ₁ - X ₄ , R ₁ - R ₃ and R _a - R _b are the same as described for the chemical formula I. In particular, in the above reaction scheme 3, A is phenyl , X ₁ - X ₄ are all independently CH, CF or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R ₂ and R ₃ are all independently H or halogen, R _a and R _b are C _1-7 alkyl, Halo is halo, and alkyl is C _1-7 alkyl.

The above Reaction Scheme 3 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-2-1 is introduced into a substitution reaction with a compound of chemical formula 1-3-1 to obtain compounds of chemical formula 1 -3-2 and then introduced into the hydrolysis reaction and get the compounds of the chemical formula 1-3-3. Then, the compound of the chemical formula 1-3-3 is reacted with urea to obtain the compounds of the chemical formula 1-3-4, and then it is subjected to a substitution reaction with the compound of the chemical formula 1-1-2 to obtain the compounds of the chemical formula 1-3-5.

In the present invention, the compounds obtained by the above reaction schemes include 6, 7, 8, 23, 51, 152, etc.

Reaction Scheme 4

In the above reaction scheme 4, A, X₁ - X₄, R₁ - R₃ and R_c are the same as described for the chemical formula I. In particular, in the above reaction scheme 4, A is phenyl, X₁ - X₄ all independently mean CH, CF or N, L₂ means methylene (CH₂), R₁ means CF₂H, R₂ and R₃ all independently are H or halogen, R_c means C_1-7 alkylheterocycloalkyl, C_1-7 alkylphenyl or C_1-7 alkyl, Halo means halogen and alkyl is C_1-7 alkyl.

Reaction Scheme 4 above shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-4-1 is reacted with a compound of chemical formula 1-4-2 to give compounds of chemical formula 1-4- 3 and then subjected to a displacement reaction with a compound of chemical formula 1-4-4 to obtain compounds of chemical formula 1-4-5. Then, the compound of the chemical formula 1-4-5 is reacted with potassium hydroxide to obtain the compounds of the chemical formula 1-4-6, and then subjected to a substitution reaction with the compound of the chemical formula 1-3-1 to obtain the compounds of the chemical formula 1-4-7. The compound of the chemical formula 1-4-7 is reacted with an aqueous solution of hydrochloric acid to obtain compounds of the chemical formula 1-4-8, and then subjected to a substitution reaction with a compound of the chemical formula 1-1-2 to obtain compounds of the chemical formula 1-4-9.

In the present invention, the compounds obtained by the above reaction schemes include 9, 10, 11, 13, 66, 86, 97, etc.

Reaction Scheme 5

In the above reaction scheme 5, A, X₁ - X₄, R₁ -R₃ and R_c are the same as described for the chemical formula I. In particular, in the above reaction scheme 5, A is phenyl, X₁ - X₄ all independently mean CH or N, L₂ means methylene (CH₂), R₁ means CF₂H, R₂ and R₃ all independently are H or halogen, R_c means C_1-7 alkylheterocycloalkyl, C_1-7 alkyl-O-C_1-7 alkyl, C_1-7 alkyl, C_1-7 alkyl-N(C_1-7 alkyl)₂ or C_1-7 alkylheteroaryl, Halo means halogen, alkyl is C_1-7 alkyl, OMs is mesylate, PG is a protecting group, m is 2, and P and Q are hydrogen.

The above reaction scheme 5 shows the procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and the compound of the chemical formula 1-5-1, which is obtained according to the reaction scheme 4 and in which a protective group is introduced, is introduced into a substitution reaction with compound of chemical formula 1-1-2 to give compounds of chemical formula 1-5-2, and then the protecting group is removed to give compounds 14, 67, etc. of chemical formula 1-5-3. Then, the compound of the chemical formula 1-5-3 is subjected to a displacement reaction with the compound of the chemical formula 1-3-1, and the compounds of the chemical formula 1-5-4 are obtained.

Also, the compound of the chemical formula 1-5-3 is introduced into a substitution reaction with the compound of the chemical formula 1-5-5, in which the protective group is introduced, and the compounds of the chemical formula 1-5-6 are obtained, and then the protective group is removed and the compounds of the chemical formula 1 are obtained -5-7. Then, a reductive amination reaction is carried out with a compound of chemical formula 1-5-8, and compounds of chemical formula 1-5-9 are obtained.

In the present invention, the compounds obtained by the above reaction schemes include 15, 16, 17, 18, 19, 20, 21, 22, 70, 71, 72, 73, etc.

Reaction Scheme 6

In the above reaction scheme 6, A, X ₁ - X ₄ , R ₁ - R ₃ and R _x - R _y are the same as described for the chemical formula I. In particular, in the above reaction scheme 6, A is phenyl , X ₁ - X ₄ are all independently CH or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R ₂ and R ₃ are all independently H or -NR _x R _y , R _x and R _y bonded to each other to form a ring together with their associated nitrogen atom {in this case, the formed ring may further contain one N or O heteroatom, and at least one hydrogen of the formed ring to which R _x and R _y are bonded and bonded to the atom nitrogen, may contain as a substituent C _1-7 alkyl, C(=O)-C _1-7 alkyl, 3--7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S , N(C _1-7 alkyl) ₂ , C _1-7 alkyl-C(=O)-3- - 7-membered heterocycloalkyl [in this case, heterocycloalkyl contains from 1 to 3 heteroatoms selected from the group consisting of N, O or S], C(=O)-C _1-7 alkyl, C _1-7 alkyl-OC _1-7 alkyl, C(=O)-OC _1-7 alkyl, 3- to 7-membered cycloalkyl, C _{1 -7} alkyl-3- - 7-membered cycloalkyl, halogen, 5- or 6-membered heteroaryl [in this case, heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of N, O or S], C(=O) -NH-C _1-7 alkyl, C(=O)-N(C _1-7 alkyl) ₂ or S(=O) ₂ -C _1-7 alkyl}, Y is C(C _1-7 alkyl) ₂ , n is 1 and Halo means halo.

The above Reaction Scheme 6 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-6-1 is introduced into a C-N coupling (Buchwald reaction) with a compound of chemical formula 1-6-2 to obtain compounds of chemical formula 1-6-3.

In the present invention, the compounds obtained by the above reaction schemes include 24, 27, 28, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 46 , 47, 48, 49, 50, 52, 56, 57, 58, 117, 153, etc.

Reaction Scheme 7

In the above reaction scheme 7, A, X ₁ - X ₄ , R ₁ - R ₃ , Y and n are the same as described for the chemical formula I. In particular, in the above reaction scheme 7, A is phenyl, X ₁ - X ₄ are all independently CH or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R ₂ and R ₃ are all independently H or 3- to 7-membered heterocycloalkyl [in this case heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of N, O or S], Y is C(C _1-7 alkyl) ₂ , n is 1, Halo is halogen, alkyl is C _1-7 alkyl, PG is protective group, m is 2 P and Q is C _1-7 alkyl, or P and Q are bonded to each other to form a ring together with their associated carbon atom, where the formed ring may further contain one N or O heteroatom.

The above Reaction Scheme 7 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-6-1 is introduced into a C-N coupling (Buchwald reaction) with a compound of chemical formula 1-7-1 containing a protective group, and compounds 25, 79, etc. of the chemical formula 1-7-2 are obtained. Then the protecting group is removed and compounds of chemical formula 1-7-3 are obtained, and a reductive amination reaction and an acylation reaction are carried out with a compound of chemical formula 1-5-8 and compounds 26, 30, 80, 81, 136, 141, 142, 147 are obtained , 148, 149, 150, etc. of the chemical formula 1-7-4.

Reaction Scheme 8

In the above reaction scheme 8, A, X ₁ - X ₄ , R ₁ - R ₃ , Y and n are the same as described for the chemical formula I. In particular, in the above reaction scheme 8, A is phenyl, X ₁ - X ₄ are all independently CH or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R ₂ and R ₃ are all independently H or a 3- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, Y is C(C _1-7 alkyl) ₂ , n is 1, Halo is halogen, PG is a protecting group, P and Q are all independently H, C _1-7 alkyl or 3- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, or P and Q are bonded to each other to form a ring together with their associated carbon atom, where the formed ring may additionally contain one N or O heteroatom.

The above Reaction Scheme 8 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-6-1 is introduced into a C-C coupling (Suzuki reaction) with a compound of chemical formula 1-8-1 containing a protective group, and compounds 41, 53, 120, 154, etc. of the chemical formula 1-8-2 are obtained. A reduction reaction is carried out and compounds of chemical formula 1-8-3 are obtained, and then the protecting group is removed to obtain compound 122 and the like of chemical formula 1-8-4. Then, the compounds of the chemical formula 1-5-8 are added to the compound of the chemical formula 1-8-4 and subjected to a reductive amination reaction, and the compounds of the chemical formula 1-8-5 are obtained.

In addition, the protective group is removed from the compound of the chemical formula 1-8-2, and the compounds of the chemical formula 1-8-6 are obtained, and then introduced into the reductive amination reaction and the acylation reaction, and the compounds 42, 43, 124, 155, etc. are obtained by chemical formulas 1-8-7. Then, a reduction reaction is carried out with a compound of the chemical formula 1-8-7, and compounds of the chemical formula 1-8-5 are obtained.

In the present invention, the compounds obtained by the above reaction schemes include 44, 54, 55, 59, 60, 61, 62, 63, 64, 68, 69, 127, 128, 134, 135, 143, 144, 145, 146 , 151, 156 etc.

Reaction Scheme 9

In the above reaction scheme 9, A, X ₁ - X ₄ , R ₁ , R ₂ , Y and n are the same as described for the chemical formula I. In particular, in the above reaction scheme 9, A is phenyl, X ₁ - X ₄ are all independently CH or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R ₂ is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, or 3- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, Y is C(C _1-7 alkyl) ₂ , Halo is halogen, and n is 1.

The above Reaction Scheme 9 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-6-1 is introduced into a C-C coupling (Suzuki reaction) with a compound of chemical formula 1-9-1 to obtain compounds of chemical formula 1-9-2.

In the present invention, the compounds obtained by the above reaction schemes include 74, 82, 83, 84, 85, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, 105, 108, 109 , 110, 111, 112, 113, 114, 115 etc.

Reaction Scheme 10

In the above reaction scheme 10, A, X ₁ - X ₄ , R ₁ - R ₃ and R _c are the same as described for the chemical formula I. In particular, in the above reaction scheme 10, A is phenyl, X ₁ - X ₄ are all independently CH or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R ₂ and R ₃ are H, R _c is -C _1-7 alkyl-OC _1-7 alkyl, -C _1-7 alkylphenyl or -C _1-7 alkyl-5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, and Halo means halogen.

The above Reaction Scheme 10 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-4-1 is reacted with a compound of chemical formula 1-10-1 to obtain compounds of chemical formula 1- 10-2 and then introduced into the cyclization reaction and get the compounds of the chemical formula 1-10-3. Then, a substitution reaction is carried out with a compound of the chemical formula 1-1-2, and compounds 75, 77, 78, etc. of the chemical formula 1-10-4 are obtained.

Reaction Scheme 11

In the above reaction scheme 11, A, X ₁ - X ₄ , R ₁ - R ₃ and R _c are the same as described for the chemical formula I. In particular, in the above reaction scheme 11, A is phenyl, X ₁ - X ₄ are all independently CH or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R ₂ and R ₃ are H, R _c is -C _1-7 alkyl-OC _1-7 alkyl and Halo means halogen.

The above Reaction Scheme 11 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-10-3 is introduced into a substitution reaction with a compound of chemical formula 1-11-1 to obtain compounds of chemical formula 1 -11-2 is then reacted with hydrazine to give compounds of chemical formula 1-11-3, and then reacted with difluoroacetic anhydride to give compound 76 and the like of chemical formula 1-11-4.

Reaction Scheme 12

In Reaction Scheme 12 above, A, X ₁ -X ₄ , R ₁ , R ₂ and R _c are the same as described for chemical formula I. In particular, in Reaction Scheme 12 above, A is phenyl, X ₁ - X ₄ are all independently CH or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R ₂ is H, phenyl or 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from a group comprising N, O or S, R _c means -C _1-7 alkyl and Halo means halogen.

The above Reaction Scheme 12 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-10-4 is introduced into C-C coupling (Suzuki reaction) with a compound of chemical formula 1-9-1 to obtain compounds of chemical formula 1-12-1.

In the present invention, the compounds obtained by the above reaction schemes include 87, 88, 89, 90, 91, 92, etc.

Reaction Scheme 13

In the above reaction scheme 13, A, X ₁ - X ₄ , R ₁ , R _a and R _b are the same as described for the chemical formula I. In particular, in the above reaction scheme 13, A is phenyl, X ₁ - X ₄ are all independently CH or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R _a and R _b are -C _1-7 alkyl, Halo is halogen, alkyl is C _1-7 alkyl, PG is a protecting group, m is 2, and P and Q are all independently hydrogen, C _1-7 alkyl, or C _1-7 haloalkyl.

Reaction Scheme 13 above shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-3-2 is introduced into a C-N coupling (Buchwald reaction) with a compound of chemical formula 1-7-1 containing a protecting group, and compounds of chemical formula 1-13-1 are obtained, and then introduced into a hydrolysis reaction, and compounds of chemical formula 1-13-2 are obtained. Then, the compound of the chemical formula 1-13-2 is reacted with urea and the compounds of the chemical formula 1-13-3 are obtained, and then it is introduced into the substitution reaction with the compound of the chemical formula 1-1-2, and the compound 116, etc. of the chemical formula 1- is obtained. 13-4. In addition, the protecting group is removed from the compound of the chemical formula 1-13-4, and the compounds of the chemical formula 1-13-5 are obtained, and then the reductive amination reaction and the substitution reaction are carried out, and the compounds of the chemical formula 1-13-7 are obtained.

In the present invention, the compounds obtained by the above reaction schemes include 118, 119, 129, 130, 131, 132, 133, 137, 138, 139, 140, etc.

Reaction Scheme 14

In Reaction Scheme 14 above, A, X ₁ -X ₄ , R ₁ , R _a and R _b are the same as described for chemical formula I. In particular, in Reaction Scheme 14 above, A is phenyl, X ₁ - X ₄ are all independently CH or N, L ₂ is methylene (CH ₂ ), R ₁ is CF ₂ H, R _a and R _b are -C _1-7 alkyl and Halo is halogen.

The above Reaction Scheme 14 shows a procedure for the synthesis of 1,3,4-oxadiazole having a heterocyclic ring structure, and a compound of chemical formula 1-3-5 is introduced into a C-C coupling (Suzuki reaction) with a compound of chemical formula 1-14-1 to obtain compound 121, etc. of the chemical formula 1-14-2. Then, an oxidation reaction is carried out with a compound of chemical formula 1-14-2 to obtain compound 123, etc. of chemical formula 1-14-3, and then 2,2,2-trifluoroacetamide is used to obtain compound 125, etc. of chemical formula 1-14-3. Then, the trifluoroacetyl substituent is removed, and compound 126, etc. of the chemical formula 1-14-5 is obtained.

Use in medicine of homophthalimide derivatives of 1,3,4-oxadiazole

The present invention relates to the medical use of 1,3,4-oxadiazole homophthalimide derivatives, their stereoisomers or their pharmaceutically acceptable salts.

One embodiment of the present invention is a pharmaceutical composition for the prevention or treatment of diseases associated with histone deacetylase 6 activity, comprising a compound having the following chemical formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof, as an effective ingredient.

Chemical formula I

The above chemical formula I is the same as defined above.

One embodiment of the present invention is a pharmaceutical composition for the prevention or treatment of diseases associated with histone deacetylase 6 activity, comprising a compound having the following chemical formula II, stereoisomers thereof, or pharmaceutically acceptable salts thereof, as an effective ingredient.

Chemical formula II

The above chemical formula II is the same as defined above.

The pharmaceutical composition of the present invention selectively inhibits histone deacetylase 6 and thus exhibits a marked effect in the prevention or treatment of diseases associated with histone deacetylase 6 activity.

In the present invention, diseases associated with histone deacetylase 6 activity include at least one selected from the group consisting of infectious diseases; neoplasm; endocrinopathy; nutritional and metabolic diseases; mental and behavioral disorders; neurological diseases; adnexal eye diseases; circulatory diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissues; diseases of the musculoskeletal system and connective tissue; and malformation or deformity, and chromosomal aberration.

Said pharmaceutically acceptable salts are the same as those described for the pharmaceutically acceptable salts of the 1,3,4-oxadiazole homophthalimide derivatives of the present invention.

For administration, the pharmaceutical composition of the present invention may further comprise at least one type of pharmaceutically acceptable carrier in addition to the 1,3,4-oxadiazole homophthalimide derivatives of the present invention, their stereoisomers, or their pharmaceutically acceptable salts. As a pharmaceutically acceptable carrier, the following may be used: saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerin, ethanol, and a mixture of at least one such component, and the addition of other conventional additives such as as antioxidants, buffer solutions, bacteriostatic agents, and the like. In addition, such a pharmaceutical composition can be formulated into injection dosage forms such as aqueous solutions, suspensions, emulsions, and the like, pills, capsules, granules, or tablets such diluents, dispersing agents, surfactants, binders and lubricants are further added to them. Thus, the composition of the present invention may be patches, liquids and solutions, pills, capsules, granules, tablets, suppositories, and the like. or according to the method disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and the composition can be formulated into different preparations in accordance with each disease or component.

The composition of the present invention can be administered orally or parenterally (for example, administered intravenously, subcutaneously, intraperitoneally or locally) in accordance with the prescribed method, in which its dose varies in a certain range depending on body weight, age, sex, health status and the patient's diet, time of administration, method of administration, rate of elimination, severity of disease, etc. 1000 mg/kg, preferably 5 to 100 mg/kg, and it can be administered once a day or several times a day by dividing the daily dose of the compound.

In addition to the 1,3,4-oxadiazole homophthalimide derivatives of the present invention, their stereoisomers, or their pharmaceutically acceptable salts, said pharmaceutical composition of the present invention may further contain at least one effective component that has the same or similar medical impact.

The present invention relates to a method for preventing or treating diseases associated with histone deacetylase 6 activity, comprising administering a therapeutically effective amount of the 1,3,4-oxadiazole homophthalimide derivatives of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

As used herein, the term "therapeutically effective amount" means an amount of the 1,3,4-oxadiazole homophthalimide derivatives of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof, which is effective in preventing or treating diseases associated with histone deacetylase 6 activity.

In the present invention, the term "prevention" means delaying the onset of a disease, disorder, or pathological condition. If the onset of a disease, disorder, or pathological condition is delayed by the expected period of time, the warning can be considered complete.

In the present invention, the term "treatment" means partial or complete reduction, amelioration, alleviation, suppression or delay of the onset of a certain disease, disorder and/or pathological condition, reduction of its severity or attenuation of at least one symptom or sign thereof.

The method for preventing or treating diseases associated with histone deacetylase 6 activity of the present invention includes not only treating the diseases themselves before symptoms appear, but also suppressing or eliminating symptoms by administering 1,3,4-oxadiazole homophthalimide derivatives as provided in the present invention. When treating a disease, the preventive or therapeutic dose of some active ingredient may vary depending on the nature and severity of the disease or pathological condition and the route of administration of the active ingredient. The dose and its frequency may vary depending on the age, body weight and responses of the individual patient. A suitable dose and application can be easily selected by those skilled in the art, of course, taking into account such factors. In addition, the method for preventing or treating histone deacetylase 6 activity-associated diseases of the present invention may further comprise administering a therapeutically effective amount of an additional active agent that is useful in treating the disease, together with the 1,3,4-oxadiazole homophthalimide derivatives of the present invention. of the present invention, wherein the additional active agent may exhibit a synergistic effect or an additional effect together with the 1,3,4-oxadiazole homophthalimide derivatives of the present invention.

The present invention also relates to the use of the 1,3,4-oxadiazole homophthalimide derivatives of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof, for the prevention or treatment of diseases associated with histone deacetylase 6 activity.

The present invention also relates to the use of the 1,3,4-oxadiazole homophthalimide derivatives of the present invention, their stereoisomers or their pharmaceutically acceptable salts for the preparation of a medicament for the treatment of diseases associated with histone deacetylase 6 activity. For the preparation of a medicament, the 1,3,4-oxadiazole homophthalimide derivatives of the present invention can be mixed with a suitable excipient, diluent, carrier, etc., and can be administered in a complex preparation together with other active agents and thus have synergistic impact.

Furthermore, the present invention relates to a method for selectively inhibiting HDAC6 by administering the 1,3,4-oxadiazole homophthalimide derivatives of the present invention, their stereoisomers, or their pharmaceutically acceptable salts to mammals, including humans.

In the present invention, the term "mammal including humans" means mammals such as monkey, cow, horse, dog, cat, rabbit, rat, mouse, and the like, and preferably includes humans.

In the present invention, the term "suppression" means the reduction or delay of a given pathological condition, symptom, disorder or disease, or a significant decrease in biological activity or the basic activity of a biological process.

The provisions noted for the use, composition and therapeutic method proposed in the present invention are equally applicable, if they do not contradict each other.

Beneficial effects

In the context of the present invention, 1,3,4-oxadiazole homophthalimide derivatives, stereoisomers thereof, or pharmaceutically acceptable salts thereof can selectively inhibit HDAC6 and thus exhibit surprisingly superior effects in preventing or treating histone deacetylase 6 related diseases.

Best Mode for Carrying out the Invention

Below, the present invention is described in more detail using the following examples and experimental examples. However, the following examples and the like are given only to illustrate the present invention, and therefore the scope of the present invention is not limited to them.

Synthesis of compound 1, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione

[Step 1] Synthesis of Compound 1

1,3-Dioxoisoindoline-2-potassium (0.100 g, 0.540 mmol) and 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.157 g, 0.540 mmol) was dissolved in N,N-dimethylformamide (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 2 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then ethyl acetate (20 ml) and hexane (10 ml) were added to the resulting concentrate and stirred and the precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (0.160 g, 83.2 %) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.23 (d, J=2.2 Hz, 1H), 8.30 (dd, J=44.4, 12.6 Hz, 1H), 7.94 ~ 7.90 (m, 2H), 7.81 ~ 7.77 (m, 2H), 7.52 ~ 7.49 (m, 1H), 7.07 (s, 0.25H), 6.94 (s, 0.5H), 6.81 (s, 0.25H), 5.12 (s, 2H).; LRMS (ES) m/z 357.2 (M ⁺ + 1).

Synthesis of compound 2, 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)isoindoline-1,3-dione

[Step 1] Synthesis of Compound 2

1,3-Dioxoisoindoline-2-potassium (0.100 g, 0.540 mmol), 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.166 g, 0.540 mmol) and potassium carbonate (0.112 g, 0.810 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 2 h, and then the reaction was completed by lowering the temperature to room temperature . Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.100 g, 49.6%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 ~ 7.75 (m, 6H), 5.12 (s, 2H), 7.53 (t, J=7.7 Hz, 1H), 7 .05 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 5.01 (s, 2H).

Synthesis of compound 3, 2'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1'H-spiro[cyclobutan-1,4'-isoquinoline] -1',3'(2'H)-dione

[Step 1] Synthesis of methyl 2-(1-(methoxycarbonyl)cyclobutyl)benzoate

Methyl 2-(2-methoxy-2-oxoethyl)benzoate (3.000 g, 14.409 mmol) was dissolved in N,N-dimethylformamide (30 mL) at 0°C followed by sodium hydride (60.00%, 1.441 g, 36.021 mmol) was added to the resulting solution and stirred at the same temperature for 30 min. 1,3-dibromopropane (2.909 g, 14.409 mmol) was added to the reaction mixture, and further stirred at room temperature for 8 hours. Water was poured into the resulting reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (2.220 g, 62.1%) as a colorless oil.

[Step 2] Synthesis of 2-(1-carboxycyclobutyl)benzoic acid

Methyl 2-(1-(methoxycarbonyl)cyclobutyl)benzoate (2.220 g, 8.942 mmol) obtained in Step 1 and sodium hydroxide (3.576 g, 89.415 mmol) were dissolved in methanol (25 ml)/water (25 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. The solvent was removed from the reaction mixture under reduced pressure; an aqueous solution of hydrochloric acid, and then extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (1.900 g, 96.5%, white solid).

[Step 3] Synthesis of 1'H-spiro[cyclobutane-1,4'-isoquinoline]-1',3'(2'H)-dione

2-(1-Carboxycyclobutyl)benzoic acid (0.820 g, 3.724 mmol) obtained in step 2 was stirred in dichlorobenzene (10 ml), then irradiated with microwave radiation, then heated at 175°C for 1 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (0.660 g, 88.1%) as a white solid.

[Step 4] Synthesis of Compound 3

1'H-Spiro[cyclobutane-1,4'-isoquinoline]-1',3'(2'H)-dione (0.150 g, 0.745 mmol) obtained in step 3, 2-(4-(bromomethyl)- 3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.229 g, 0.745 mmol) and potassium carbonate (0.206 g, 1.491 mmol) were dissolved in N,N-dimethylformamide (5 ml) at 80°C , then the resulting solution was stirred at the same temperature for 2 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.100 g, 31.4%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 ~ 8.18 (m, 1H), 7.85 ~ 7.72 (m, 4H), 7.47 ~ 7.43 (m, 1H), 7.38 (t, J=7.9 Hz, 1H), 7.04 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 5 .33(s, 2H), 2.99~2.91(m, 2H), 2.50~2.30(m, 4H).; LRMS (ES) m/z 428.4 (M ⁺ + 1).

Synthesis of compound 4, 2'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1'H-spiro[cyclobutan-1,4 '-isoquinoline]-1',3'(2'H)-dione

[Step 1] Synthesis of Compound 4

1'H-Spiro[cyclobutan-1,4'-isoquinoline]-1',3'(2'H)-dione (0.150 g, 0.745 mmol), 2-(6-(bromomethyl)pyridin-3-yl) -5-(difluoromethyl)-1,3,4-oxadiazole (0.216 g, 0.745 mmol) and potassium carbonate (0.206 g, 1.491 mmol) were dissolved in N,N-dimethylformamide (5 ml) at 80°C, then the resulting solution stirred at the same temperature for 2 hours, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.070 g, 22.9%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J=2.2, 0.9 Hz, 1H), 8.33 (dd, J=8.2, 2.2 Hz, 1H) , 8.22 ~ 8.20 (m, 1H), 7.87 ~ 7.84 (m, 1H), 7.77 ~ 7.73 (m, 1H), 7.48 ~ 7.44 (m, 2H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.44(s, 2H), 3.04~2 .97(m, 2H), 2.55~2.27(m, 4H).; LRMS (ES) m/z 411.3 (M ⁺ + 1).

Synthesis of compound 5, 2'-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,4'-isoquinoline]-1' ,3'(2'H)-dione

[Step 1] Synthesis of Compound 5

1'H-Spiro[cyclobutane-1,4'-isoquinoline]-1',3'(2'H)-dione (0.150 g, 0.745 mmol), 2-(4-(bromomethyl)phenyl)-5-( difluoromethyl)-1,3,4-oxadiazole (0.215 g, 0.745 mmol) and potassium carbonate (0.206 g, 1.491 mmol) were dissolved in N,N-dimethylformamide (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 2 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.100 g, 32.8%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 ~ 8.17 (m, 1H), 8.02 ~ 8.00 (m, 2H), 7.81 ~ 7.79 (m, 1H), 7.73 ~ 7.68 (m, 1H), 7.60 ~ 7.57 (m, 2H), 7.45 ~ 7.41 (m, 1H), 7.03 (s, 0.25H), 6.90(s, 0.5H), 6.77(s, 0.25H), 5.24(s, 2H), 2.94~2.87(m, 2H), 2.47~2, 25(m, 4H).; LRMS (ES) m/z 410.3 (M ⁺ + 1).

Synthesis of compound 6, 2-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of methyl 2-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate

Methyl 2-(2-methoxy-2-oxoethyl)benzoate (3.270 g, 15.705 mmol) was dissolved in N,N-dimethylformamide (30 mL) at 0°C followed by sodium hydride (60.00%, 1.884 g, 47.116 mmol) was added to the resulting solution and stirred at the same temperature for 30 min. Iodomethane (2.933 mL, 47.116 mmol) was added to the reaction mixture, and further stirred at room temperature for 12 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 15%) and concentrated to give the title compound (3.000 g, 80.8%) as a colorless oil.

[Step 2] Synthesis of 2-(2-carboxypropan-2-yl)benzoic acid

Methyl 2-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate (3.000 g, 12.697 mmol) obtained in Step 1 and lithium hydroxide (3.041 g, 126.973 mmol) were dissolved in a mixture of methanol ( 15 ml)/water (15 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. an aqueous solution of hydrochloric acid and carried out extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (2.500 g, 94.6%) as a white solid.

[Step 3] Synthesis of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

2-(2-Carboxypropan-2-yl)benzoic acid (2.500 g, 12.007 mmol) obtained in step 2 was stirred in 1,2-dichlorobenzene (10 ml), then irradiated with microwave radiation, then heated at 175°C in for 1 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (1.700 g, 74.8%) as a white solid.

[Step 4] Synthesis of Compound 6

4,4-Dimethylisoquinoline-1,3(2H,4H)-dione (0.100 g, 0.529 mmol) obtained in step 3, 2-(4-(bromomethyl)phenyl)-5-(difluoromethyl)-1,3, 4-oxadiazole (0.153 g, 0.529 mmol) and potassium carbonate (0.146 g, 1.057 mmol) were dissolved in N,N-dimethylformamide (10 ml), then the resulting solution was stirred at 80°C for 2 h and then further stirred at room temperature. temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.120 g, 57.1%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 ~ 8.22 (m, 1H), 8.04 ~ 8.02 (m, 2H), 7.65 ~ 7.63 (m, 1H), 7.59 ~ 7.57 (m, 2H), 7.50 ~ 7.42 (m, 2H), 7.04 (s, 0.25H), 6.91 (s, 0.5H), 6, 78 (s, 0.25H), 5.24 (s, 2H), 1.63 (s, 6H).; LRMS (ES) m/z 398.3 (M ⁺ + 1).

Synthesis of compound 7

[Step 1] Synthesis of Compound 7

4,4-Dimethylisoquinoline-1,3(2H,4H)-dione (0.200 g, 1.057 mmol), 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4- oxadiazole (0.325 g, 1.057 mmol) and potassium carbonate (0.292 g, 2.114 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 3 h, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; / = 0 to 30%) and concentrated to give the title compound (0.100 g, 22.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (dd, J=7.9, 1.4 Hz, 1H), 7.83 ~ 7.78 (m, 2H), 7.68 ~ 7, 65(m, 1H), 7.52~7.50(m, 1H), 7.47~7.45(m, 1H), 7.40~7.38(m, 1H), 7.04( s, 0.25H), 6.91 (s, 0.5H), 6.78 (s, 0.25H), 5.33 (s, 2H), 1.66 (s, 6H); LRMS (ES) m/z 416.4 (M ⁺ + 1).

Synthesis of compound 8, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione

[Step 1] Synthesis of Compound 8

4,4-Dimethylisoquinolin-1,3(2H,4H)-dione (0.200 g, 1.057 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4 -oxadiazole (0.307 g, 1.057 mmol) and potassium carbonate (0.292 g, 2.114 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 3 h and then the reaction completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; / = 0 to 30%) and concentrated to give the title compound (0.180 g, 42.7%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (dd, J=2.2, 0.8 Hz, 1H), 8.33 (dd, J=8.2, 2.2 Hz, 1H) , 8.24 (dd, J=7.9, 1.3Hz, 1H), 7.68 ~ 7.65 (m, 1H), 7.53 ~ 7.51 (m, 1H), 7.47 ~ 7.43(m, 2H), 7.05(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.42(s, 2H ), 1.69 (s, 6H).; LRMS (ES) m/z 399.4 (M ⁺ + 1).

Synthesis of compound 9, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(2-(piperidin-1-yl) ethyl)quinazoline-2,4(1H,3H)-dione

[Step 1] Synthesis of 2-amino-N-(tert-butyl)benzamide

2H-Benzo[d][1,3]oxazine-2,4(1H)-dione (15.300 g, 93.790 mmol), 2-methylpropan-2-amine (8.232 g, 112.548 mmol) and N,N-dimethylpyridine- 4-amine (DMAP, 1.146 g, 9.379 mmol) was dissolved in N,N-dimethylformamide (100 ml) at room temperature, then the resulting solution was stirred at the same temperature. Water (20 ml) was added to the reaction mixture and stirred, then the precipitated solid was filtered off, then washed with water and then dried to give the title compound (9.500 g, 52.7%) as a light brown solid.

[Step 2] Synthesis of methyl-(2-(tert-butylcarbamoyl)phenyl)carbamate

2-Amino-N-(tert-butyl)benzamide (9.500 g, 49.412 mmol) obtained in step 1, methyl chloroformate (7.003 g, 74.118 mmol) and sodium hydroxide (1.00 M solution, 98.825 ml, 98.825 mmol) were dissolved in 1,4-dioxane (50 ml) at room temperature, then the resulting solution was stirred at the same temperature for 3 hours. 1M aqueous hydrochloric acid (100 ml) was added to the reaction mixture and stirred, then the precipitated solid was filtered off, washed with water and then dried to give the title compound (8.700 g, 70.3%) as a white solid.

[Step 3] Synthesis of 3-(tert-butyl)quinazoline-2,4(1H,3H)-dione

Methyl-(2-(tert-butylcarbamoyl)phenyl)carbamate (8.400 g, 33.560 mmol) obtained in step 2 and potassium hydroxide (18.829 g, 335.597 mmol) were dissolved in ethanol (100 ml) at 80°C, then obtained the solution was stirred at the same temperature for 12 hours, and then the reaction was terminated by lowering the temperature to room temperature. A 2M hydrochloric acid aqueous solution (20 ml) was added to the reaction mixture and stirred, then the precipitated solid was filtered off, then washed with water and then dried to give the title compound (6.000 g, 81.9%) as a beige solid.

[Step 4] Synthesis of 3-(tert-butyl)-1-(2-(piperidin-1-yl)ethyl)quinazolin-2,4(1H,3H)-dione

3-(T-butyl)quinazoline-2,4(1H,3H)-dione (3.000 g, 13.745 mmol) obtained in step 3 was dissolved in N,N-dimethylformamide (30 ml) at 0°C, then the hydride sodium (60.00%, 1.374 g, 34.363 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 1-(2-Chloroethyl)piperidine hydrochloride (3.037 g, 16.494 mmol) was added to the reaction mixture and further stirred at room temperature for 12 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (1.700 g, 37.5%) as a yellow solid.

[Step 5] Synthesis of 1-(2-(piperidin-1-yl)ethyl)quinazolin-2,4(1H,3H)-dione hydrochloride

3-(T-butyl)-1-(2-(piperidin-1-yl)ethyl)quinazolin-2,4(1H,3H)-dione (1.700 g, 5.160 mmol) obtained in step 4 and hydrochloric acid (4.00 M solution in dioxane, 12.901 ml, 51.603 mmol) was mixed at room temperature, then the resulting mixture was refluxed for 12 hours and cooled to room temperature. Then, the solvent was removed from the reaction mixture under reduced pressure, then the resulting product was used without further purification (1.500 g, 93.8%, white solid).

[Step 6] Synthesis of Compound 9

1-(2-(Piperidin-1-yl)ethyl)quinazolin-2,4(1H,3H)-dione hydrochloride (0.180 g, 0.581 mmol) from step 5, 2-(6-(bromomethyl)pyridine-3 -yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.219 g, 0.755 mmol) and potassium carbonate (0.161 g, 1.162 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then, the resulting solution was stirred at the same temperature for 30 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 80%) and concentrated to give the title compound (0.200 g, 71.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 ~ 7.43 (m, 1H), 8.29 (dd, J=8.2, 2.2 Hz, 1H), 8.20 (dd, J=7.9, 1.6 Hz, 1H), 7.68 ~ 7.65 (m, 1H), 7.45 ~ 7.43 (m, 1H), 7.32 ~ 7.28 (m, 1H), 7.25~7.21(m, 1H), 7.04(s, 0.25H), 6.91(s, 0.5H), 6.79(s, 0.25H), 5 .47 (s, 2H), 4.28 ~ 4.24 (m, 2H), 2.62 ~ 2.58 (m, 2H), 2.50 ~ 2.45 (m, 4H), 1.53 ~ 1.49 (m, 4H), 1.39 ~ 1.38 (m, 2H).; LRMS (ES) m/z 483.6 (M ⁺ + 1).

Synthesis of compound 10 2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 10

1-(2-(piperidin-1-yl)ethyl)quinazolin-2,4(1H,3H)-dione hydrochloride (0.200 g, 0.646 mmol), 2-(4-(bromomethyl)-3-fluorophenyl)-5- (difluoromethyl)-1,3,4-oxadiazole (0.258 g, 0.839 mmol) and potassium carbonate (0.178 g, 1.291 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution was stirred at this the same temperature for 30 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 80%) and concentrated to give the title compound (0.200 g, 62.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (dd, J=7.9, 1.5 Hz, 1H), 7.81 ~ 7.78 (m, 2H), 7.73 ~ 7, 68(m, 1H), 7.43~7.40(m, 1H), 7.34~7.25(m, 2H), 7.04(s, 0.25H), 6.91(s, 0.5H), 6.78(s, 0.25H), 5.41(s, 2H), 4.31~4.27(m, 2H), 2.64~2.61(m, 2H) , 2.60~2.45(m, 4H), 1.57~1.52(m, 4H), 1.44~1.41(m, 2H).; LRMS (ES) m/z 458.0 (M ⁺ + 1).

Synthesis of compound 11, 3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1-(2-(piperidin-1-yl)ethyl)quinazolin-2,4 (1H,3H)-dione

[Step 1] Synthesis of Compound 11

1-(2-(Piperidin-1-yl)ethyl)quinazolin-2,4(1H,3H)-dione hydrochloride (0.190 g, 0.613 mmol), 2-(4-(bromomethyl)phenyl)-5-(difluoromethyl) -1,3,4-oxadiazole (0.230 g, 0.797 mmol) and potassium carbonate (0.170 g, 1.227 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution was stirred at the same temperature in for 30 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 80%) and concentrated to give the title compound (0.150 g, 50.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (dd, J=7.9, 1.5 Hz, 1H), 8.04 ~ 7.99 (m, 2H), 7.69 ~ 7, 63(m, 3H), 7.30~7.22(m, 2H), 7.03(s, 0.25H), 6.90(s, 0.5H), 6.78(s, 0, 25H), 5.32(s, 2H), 4.29~4.25(m, 2H), 2.62~2.58(m, 2H), 2.55~2.48(m, 4H) , 1.57 ~ 1.52 (m, 4H), 1.44 ~ 1.40 (m, 2H).

Synthesis of compound 12, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H 4H)-dione

[Step 1] Synthesis of Compound 12

4,4-Dimethylisoquinolin-1,3(2H,4H)-dione (0.200 g, 1.057 mmol), 2-(2-(bromomethyl)pyrimidin-5-yl)-5-(difluoromethyl)-1,3,4 -oxadiazole (0.308 g, 1.057 mmol) and potassium carbonate (0.219 g, 1.586 mmol) were dissolved in N,N-dimethylformamide (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h, and then the reaction completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.150 g, 35.5%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 2H), 8.24 (dd, J=7.9, 1.5 Hz, 1H), 7.71 ~ 7.67 (m, 1H), 7.55~7.53(m, 1H), 7.48~7.44(m, 1H), 7.08(s, 0.25H), 6.95(s, 0.5H) , 6.82 (s, 0.25H), 5.55 (s, 2H), 1.72 (s, 6H).; LRMS (ES) m/z 400.3 (M ⁺ + 1).

Synthesis of compound 13, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(4-methoxybenzyl)quinazolin-2,4 (1H,3H)-dione

[Step 1] Synthesis of 3-(tert-butyl)-1-(4-methoxybenzyl)quinazoline-2,4(1H,3H)-dione

3-(T-butyl)quinazoline-2,4(1H,3H)-dione (2.800 g, 12.829 mmol) was dissolved in N,N-dimethylformamide (30 ml) at 0°C, then sodium hydride (60.00% , 1.026 g, 25.657 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 1-(Chloromethyl)-4-methoxybenzene (2.210 g, 14.112 mmol) was added to the reaction mixture and further stirred at room temperature for 12 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 15%) and concentrated to give the title compound (3.400 g, 78.3%) as a yellow solid.

[Step 2] Synthesis of 1-(4-methoxybenzyl)quinazoline-2,4(1H,3H)-dione

3-(T-butyl)-1-(4-methoxybenzyl)quinazoline-2,4(1H,3H)-dione (3.400 g, 10.047 mmol) obtained in step 1 and hydrochloric acid (6.00 M solution in H ₂ O, 10.047 ml, 60.282 mmol) was mixed in 1,4-dioxane (15 ml) at room temperature, then the resulting mixture was refluxed for 12 h and cooled to room temperature. Then, the precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (2.250 g, 79.3%) as a white solid.

[Step 3] Synthesis of Compound 13

1-(4-Methoxybenzyl)quinazolin-2,4(1H,3H)-dione (2.250 g, 7.970 mmol) from step 2, 2-(6-(bromomethyl)pyridin-3-yl)-5-( difluoromethyl)-1,3,4-oxadiazole (3.006 g, 10.361 mmol) and potassium carbonate (2.203 g, 15.940 mmol) were dissolved in N,N-dimethylformamide (30 ml) at 80°C, then the resulting solution was stirred at the same temperature for 3 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (3.200 g, 81.7%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (d, J=1.6 Hz, 1H), 8.37 (dd, J=8.2, 2.2 Hz, 1H), 8.27 (dd, J=7.9, 1.5Hz, 1H), 7.63 ~ 7.59 (m, 1H), 7.53 (d, J=8.2Hz, 1H), 7.26 ~ 7.22(m, 4H), 7.07(s, 0.25H), 6.94(s, 0.5H), 6.89~6.87(m, 2H), 6.81(s, 0.25H), 5.60(s, 2H), 5.36(s, 2H), 3.79(s, 3H).

Synthesis of compound 14, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)quinazolin-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 14

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(4-methoxybenzyl)quinazolin-2,4(1H,3H )-dione (1.000 g, 2.035 mmol) and cerium ammonium nitrate (3.347 g, 6.104 mmol) were dissolved in acetonitrile (10 ml)/water (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 3 h. The precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (0.680 g, 90.0%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ T11.59 (s, 1H), 9.09 (dd, J=2.2, 0.8 Hz, 1H), 8.37 (dd, J=8, 3, 2.3 Hz, 1H), 7.95 (dd, J=8.2, 1.3 Hz, 1H), 7.73 ~ 7.69 (m, 1H), 7.67 (s, 0 .25H), 7.61(dd, J=8.3, 0.8Hz, 1H), 7.54(s, 0.5H), 7.41(s, 0.25H), 7.26~ 7.22(m, 2H), 5.32(s, 2H).

Synthesis of compound 15, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-((1-methylpiperidin-4-yl) methyl)quinazoline-2,4(1H,3H)-dione

[Step 1] Synthesis of tert-butyl-4-((3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2,4 -dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)piperidine-1-carboxylate

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)quinazolin-2,4(1H,3H)-dione (0.680 g, 1.831 mmol), tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (0.645 g, 2.198 mmol) and potassium carbonate (0.506 g, 3.663 mmol) were dissolved in N,N-dimethylformamide (15 ml ) at 80°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.500 g, 48.0%) as a white foamy solid.

[Step 2] Synthesis of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(piperidin-4-ylmethyl)quinazolin- 2,4(1H,3H)-dione

tert-Butyl-4-((3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-2,4-dioxo-3, 4-dihydroquinazolin-1(2H)-yl)methyl)piperidine-1-carboxylate (0.500 g, 0.879 mmol) obtained in step 1 and trifluoroacetic acid (0.337 ml, 4.397 mmol) were dissolved in dichloromethane (10 ml) at room temperature temperature, then the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, and then extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (0.200 g, 48.5%, yellow oil).

[Step 3] Synthesis of Compound 15

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(piperidin-4-ylmethyl)quinazolin-2,4(1H ,3H)-dione (0.100 g, 0.213 mmol) obtained in step 2, formaldehyde (0.013 g, 0.427 mmol) and sodium triacetoxyborohydride (0.090 g, 0.427 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.037 g, 35.9%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 ~ 9.16 (m, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 8.27 (dd, J=7.9, 1.5 Hz, 1H), 7.74 ~ 7.72 (m, 1H), 7.51 ~ 7.48 (m, 1H), 7.32 ~ 7.28 (m, 1H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.51(s, 2H), 4.13~4 .11(m, 2H), 3.29~3.15(m, 3H), 2.48(s, 3H), 2.29~2.26(m, 2H), 1.81~1.70 (m, 4H).; LRMS (ES) m/z 483.6 (M ⁺ + 1).

Synthesis of compound 16, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-((1-(oxetan-3-yl )piperidin-4-yl)methyl)quinazolin-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 16

3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(piperidin-4-ylmethyl)quinazolin-2,4(1H ,3H)-dione (0.100 g, 0.213 mmol), oxetan-3-one (0.025 ml, 0.427 mmol) and sodium triacetoxyborohydride (0.090 g, 0.427 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.040 g, 35.7%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (dd, J=2.2, 0.8 Hz, 1H), 8.35 (dd, J=8.2, 2.2 Hz, 1H) , 8.29 (dd, J=7.9, 1.5Hz, 1H), 7.73 ~ 7.70 (m, 1H), 7.51 ~ 7.48 (m, 1H), 7.33 ~7.26(m, 2H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.53(s, 2H ), 4.67 ~ 4.60 (m, 4H), 4.16 ~ 4.11 (m, 1H), 3.45 ~ 3.40 (m, 1H), 2.85 ~ 2.75 (m , 2H), 2.02 ~ 1.74 (m, 4H), 1.60 ~ 1.50 (m, 2H).; LRMS (ES) m/z 525.6 (M ⁺ + 1).

Synthesis of compound 17 (1H,3H)-dione

[Step 1] Synthesis of Compound 17

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)quinazolin-2,4(1H,3H)-dione (0.150 g, 0.404 mmol), 1-bromo-2-methoxyethane (0.112 g, 0.808 mmol) and potassium carbonate (0.112 g, 0.808 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 3 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.080 g, 46.1%) as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (dd, J=2.2, 0.7 Hz, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H) , 8.25 (dd, J=7.9, 1.5Hz, 1H), 7.72 ~ 7.68 (m, 1H), 7.49 ~ 7.43 (m, 2H), 7.30 ~ 7.26(m, 1H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.52(s, 2H ), 4.37 (t, J=5.8 Hz, 2H), 3.74 (t, J=5.8 Hz, 2H), 3.36 (s, 2H).; LRMS (ES) m/z 430.5(M ⁺ + 1).

Synthesis of compound 18, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dion

[Step 1] Synthesis of Compound 18

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)quinazolin-2,4(1H,3H)-dione (0.150 g, 0.404 mmol), iodomethane (0.050 ml, 0.808 mmol) and potassium carbonate (0.112 g, 0.808 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.080 g, 51.4%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 ~ 9.20 (m, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 8.26 ~ 8, 24 (m, 1H), 7.76 ~ 7.71 (m, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.32 ~ 7.26 (m, 2H), 7 .06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.28 (s, 2H), 3.64 (s, 3H). ; LRMS (ES) m/z 386.5 (M ⁺ + 1).

Synthesis of compound 19 2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 19

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)quinazolin-2,4(1H,3H)-dione (0.150 g, 0.404 mmol), 3-chloro-N,N-dimethylpropane-1-amine hydrochloride (0.096 g, 0.606 mmol) and potassium carbonate (0.195 g, 1.414 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.060 g, 32.5%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.22 ~ 9.21 (m, 1H), 8.35 (dd, J=8.2, 2.3 Hz, 1H), 8.28 (dd, J=7.9, 1.6 Hz, 1H), 7.75 ~ 7.71 (m, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.41 ~ 7.36 (m, 2H), 7.32 ~ 7.30 (m, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H ), 5.53 (s, 2H), 4.24 (t, J=7.5 Hz, 2H), 2.48 (t, J=7.0 Hz, 2H), 2.31 (s, 6H ), 2.01 ~ 1.93 (m, 2H).; LRMS (ES) m/z 457.6 (M ⁺ + 1).

Synthesis of compound 20, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(2-morpholinoethyl)quinazolin-2,4 (1H,3H)-dione

[Step 1] Synthesis of Compound 20

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)quinazolin-2,4(1H,3H)-dione (0.150 g, 0.404 mmol), 4-(2-chloroethyl)morpholine hydrochloride (0.113 g, 0.606 mmol) and potassium carbonate (0.195 g, 1.414 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution was stirred at this the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.070 g, 35.8%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.22 (d, J=1.8 Hz, 1H), 8.35 (dd, J=8.2, 2.2 Hz, 1H), 8.28 (dd, J=7.8, 1.6Hz, 1H), 7.75 ~ 7.71 (m, 1H), 7.51 ~ 7.48 (m, 1H), 7.33 ~ 7.28 (m, 2H), 7.06 (s, 1H), 6.93 (s, 1H), 6.80 (s, 1H), 5.52 (s, 2H), 4.33 (t, J= 7.2 Hz, 2H), 4.33 (t, J=7.2 Hz, 2H), 3.68 (t, J=4.6 Hz, 4H), 2.71 (t, J=7, 2 Hz, 2H), 2.58 (t, J=4.5 Hz, 4H).; LRMS (ES) m/z 485.5 (M ⁺ + 1).

Synthesis of compound 21, 1-(2-(1H-pyrazol-1-yl)ethyl)-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)- yl)methyl)quinazoline-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 21

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)quinazolin-2,4(1H,3H)-dione (0.150 g, 0.404 mmol), 1-(2-bromoethyl)-1H-pyrazole (0.106 g, 0.606 mmol) and potassium carbonate (0.112 g, 0.808 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution stirred at the same temperature for 12 hours, and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.030 g, 16.0%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.23 ~ 9.22 (m, 1H), 8.38 (dd, J=8.2, 2.3 Hz, 1H), 8.23 (dd, J=7.9, 1.4Hz, 1H), 7.61~7.52(m, 3H), 7.33(dd, J=2.2, 0.6Hz, 1H), 7.26 ~ 7.22 (m, 1H), 7.07 (s, 0.25H), 7.03 (d, J=8.5 Hz, 1H), 6.94 (s, 0.5H), 6, 81(s, 0.25H), 6.14~6.12(m, 1H), 5.49(s, 2H), 4.59~4.52(m, 4H).; LRMS (ES) m/z 466.5 (M ⁺ + 1).

Synthesis of compound 22 2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 22

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)quinazolin-2,4(1H,3H)-dione (0.150 g, 0.404 mmol), 2-chloro-N,N-dimethylethane-1-amine hydrochloride (0.087 g, 0.606 mmol) and potassium carbonate (0.195 g, 1.414 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.040 g, 22.4%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (dd, J=2.2, 0.8 Hz, 1H), 8.35 (dd, J=8.2, 2.2 Hz, 1H) , 8.28 ~ 8.25 (m, 1H), 7.80 ~ 7.73 (m, 1H), 7.50 ~ 7.48 (m, 1H), 7.33 ~ 7.29 (m, 2H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.5H), 5.52(s, 2H), 4.31(t , J=7.5 Hz, 2H), 2.66 (t, J=7.5 Hz, 2H), 2.36 (s, 6H).; LRMS (ES) m/z 443.5 (M ⁺ + 1).

Synthesis of compound 23, 6-bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1, 3(2H,4H)-dione

[Step 1] Synthesis of methyl 4-bromo-2-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate

Methyl 4-bromo-2-(2-methoxy-2-oxoethyl)benzoate (9.500 g, 33.088 mmol) was dissolved in N,N-dimethylformamide (50 mL) at 0°C followed by sodium hydride (60.00%, 3.970 g, 99.265 mmol) was added to the resulting solution and stirred for 30 minutes. Iodomethane (6.180 mL, 99.265 mmol) was slowly added to the reaction mixture and stirred further at room temperature for 12 hours. aqueous hydrochloric acid (20 ml) and stirred, then the precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (7.290 g, 69.9%) as a white solid.

[Step 2] Synthesis of 4-bromo-2-(2-carboxypropan-2-yl)benzoic acid

Methyl 4-bromo-2-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate (7.290 g, 23.131 mmol) obtained in Step 1 and potassium hydroxide (12.978 g, 231.311 mmol) were dissolved in methanol (30 ml)/water (60 ml) at 100°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then 1 N sodium hydroxide was poured into the resulting concentrate. an aqueous solution of hydrochloric acid, and then extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (6.000 g, 90.3%, white solid).

[Step 3] Synthesis of 6-bromo-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

4-Bromo-2-(2-carboxypropan-2-yl)benzoic acid (7.460 g, 25.983 mmol) obtained in step 2 and urea (1.717 g, 28.581 mmol) were mixed in chlorobenzene (30 ml), then irradiated with microwave radiation, then heated at 150°C for 45 min and then the reaction was completed by lowering the temperature to room temperature. The solid that precipitated was filtered off, then washed with hexane and then dried to give the title compound (5.500 g, 79.0%) as a yellow solid.

[Step 4] Synthesis of Compound 23

6-Bromo-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (1.400 g, 5.222 mmol) obtained in step 3, 2-(6-(bromomethyl)pyridin-3-yl)-5- (difluoromethyl)-1,3,4-oxadiazole (2.272 g, 7.833 mmol) and potassium carbonate (1.443 g, 10.443 mmol) were dissolved in N,N-dimethylformamide (30 ml) at 80°C, then the resulting solution was stirred at this the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (2.200 g, 88.3%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J =2.2, 0.8 Hz, 1H), 8.36 (dd, J =8.2, 2.2 Hz, 1H) , 8.13 (d, J =8.4 Hz, 1H), 7.68 (d, J =1.8 Hz, 1H), 7.62 (dd, J =8.4, 1.9 Hz, 1H), 7.47 (dd, J =8.2, 0.8 Hz, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s , 0.25H), 5.42(s, 2H), 1.70(s, 6H).

Synthesis of compound 24, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-morpholinoisoquinoline-1, 3(2H,4H)-dione

[Step 1] Synthesis of Compound 24

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.470 g, 0.985 mmol), morpholine (0.170 ml, 1.970 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.057 g, 0.098 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.090 g, 0.098 mmol) and cesium carbonate (0.963 g, 2.954 mmol) were dissolved in toluene (5 ml) at 65°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 70%) and concentrated to give the title compound (0.220 g, 46.2%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (dd, J=2.2, 0.8 Hz, 1H), 8.37 (dd, J=8.3, 2.3 Hz, 1H), 7.92 (d, J=8.9 Hz, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.43 (s, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.06 (dd, J=8.9, 2.5 Hz, 1H), 5, 26 (s, 2H), 3.76 (t, J=4.8 Hz, 4H), 3.38 (t, J=4.8 Hz, 4H), 1.61 (s, 6H).

Synthesis of compound 25, tert-butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl -1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazine-1-carboxylate

[Step 1] Synthesis of Compound 25

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.893 g, 1.871 mmol), tert-butylpiperazine-1-carboxylate (1.046 g, 5.613 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.108 g, 0.187 mmol) , tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ , 0.171 g, 0.187 mmol) and cesium carbonate (1.829 g, 5.613 mmol) were dissolved in toluene (5 ml) at 65°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 70%) and concentrated to give the title compound (0.300 g, 27.5%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J=2.2, 0.8 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H) , 8.11 (d, J=8.9 Hz, 1H), 7.41 (dd, J=8.2, 0.8 Hz, 1H), 7.05 (s, 0.25H), 6, 92 (s, 0.5H), 6.92 ~ 6.90 (m, 1H), 6.83 (d, J=2.4Hz, 1H), 6.79 (s, 0.25H), 5 .40 (s, 2H), 3.63 (t, J=5.2 Hz, 4H), 3.39 (t, J=5.2 Hz, 4H), 1.67 (s, 6H), 1 .49 (s, 9H).; LRMS (ES) m/z 583.6 (M ⁺ + 1).

Synthesis of compound 26 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 26

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), 1-isopropylpiperazine (0.060 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol), tris(dibenzylideneacetone ) dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.087 g, 52.8%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J=2.2, 0.7 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H) , 8.10 (d, J=8.9 Hz, 1H), 7.42 ~ 7.39 (m, 1H), 7.06 (s, 0.25H), 6.94 ~ 6.91 (m , 1H), 6.92 (s, 0.5H), 6.84 (d, J=2.4 Hz, 0.25H), 6.80 (s, 1H), 5.40 (s, 2H) , 3.43 (t, J=5.1Hz, 4H), 2.78 ~ 2.69 (m, 5H), 1.68 (s, 6H), 1.12 ~ 1.10 (m, 6H ).

Synthesis of compound 27 -yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 27

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), piperidine (0.040 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.080 g, 52.9%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J=1.5 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 8.08 (d, J=8.9 Hz, 1H), 7.41 (dd, J=8.2, 0.7 Hz, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.93 ~ 6.90 (m, 1H), 6.83 (d, J=2.4Hz, 1H), 6.80 (s, 0.25H), 5.41 (s , 2H), 3.42 ~ 3.40 (m, 4H), 1.71 ~ 1.68 (m, 12H).; LRMS (ES) m/z 458.0 (M ⁺ + 1).

Synthesis of compound 28, 6-(azetidin-1-yl)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4, 4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 28

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), azetidine (0.027 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.050 g, 35.1%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (dd, J=2.2, 0.8 Hz, 1H), 8.32 (dd, J=9.2, 1.3 Hz, 1H) , 8.07 (d, J=8.6 Hz, 1H), 7.41 (dd, J=8.2, 0.8 Hz, 1H), 7.06 (s, 0.25H), 6, 93 (s, 0.5H), 6.80 (s, 0.25H), 6.42 (dd, J=8.7, 2.2 Hz, 1H), 6.29 (d, J=2, 2 Hz, 1H), 5.41 (s, 2H), 4.07 (t, J=7.4 Hz, 4H), 2.50 ~ 2.46 (m, 2H), 1.70 (s, 6H).

Synthesis of compound 29, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4-methylpiperazine -1-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin- 1-yl)isoquinoline-1,3(2H,4H)-dione-2,2,2-trifluoroacetate

tert-Butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-1,3 -dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazine-1-carboxylate (0.300 g, 0.515 mmol) and trifluoroacetic acid (0.394 ml, 5.149 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 5 hours. The solvent was removed from the reaction mixture under reduced pressure, then the resulting product was used without further purification (0.300 g, 97.7%, yellow oil).

[Step 2] Synthesis of Compound 29

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.178 g, 0.298 mmol) obtained in step 1 and N,N-diisopropylethylamine (0.052 ml, 0.298 mmol) were dissolved in dichloromethane (10 ml), then the resulting solution was stirred at room temperature for 30 min and then formaldehyde (0.018 g, 0.597 mmol) and sodium triacetoxyborohydride (0.126 g, 0.597 mmol) were added and further stirred at the same temperature for 12 h. To the reaction mixture water was poured out and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/hexane=0 to 10%) and concentrated to give the title compound (0.090 g, 60.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.6 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.05 (s, 0.25H), 6.93 ~ 6.90 (m, 1H), 6.92 (s, 0.5H), 6.83 (d, J=2.4 Hz, 1H), 6.80 (s, 0.25H), 5.39 (s, 2H), 3.43 (t, J=5.1 Hz, 4H), 2.63 (t, J=5.1 Hz, 4H), 2.38 (s, 3H), 1.66 (s, 6H). ; LRMS (ES) m/z 497.5 (M ⁺ + 1).

Synthesis of compound 30, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4-( oxetan-3-yl)piperazin-1-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 30

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.182 g, 0.305 mmol) and N,N-diisopropylethylamine (0.053 ml, 0.305 mmol) were dissolved in dichloromethane (10 ml), then the resulting solution stirred at room temperature for 30 min and then added oxetan-3-one (0.044 g, 0.610 mmol) and sodium triacetoxyborohydride (0.129 g, 0.610 mmol) and further stirred at the same temperature for 12 h. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/hexane=0 to 10%) and concentrated to give the title compound (0.100 g, 60.9%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=2.0 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 8.10 (d, J=8.9 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.06 (s, 0.25H), 6.94 ~ 6.91 (m, 1H), 6.92 (s, 0.5H), 6.84 (d, J=2.2 Hz, 1H), 6.80 (s, 0.25H), 5.40 (s, 2H), 4.74 ~ 4.65 (m, 4H), 3.59 ~ 3.56 (m, 1H), 3.45 (t, J=4.9 Hz, 4H), 2.53 (t, J= 4.9 Hz, 4H), 1.67 (s, 6H).; LRMS (ES) m/z 539.7 (M ⁺ + 1).

Synthesis of compound 31, (S)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(3-(dimethylamino) pyrrolidin-1-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 31

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), (S)-N, N-dimethylpyrrolidin-3-amine (0.054 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then obtained the solution was stirred at the same temperature for 12 hours, and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.079 g, 49.2%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J=2.2, 0.7 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H) , 8.08 (d, J=8.7Hz, 1H), 7.41 ~ 7.38 (m, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H ), 6.80 (s, 0.25H), 6.59 (dd, J=8.9, 2.3Hz, 1H), 5.40 (s, 2H), 3.63 ~ 3.57 ( m, 2H), 3.45 ~ 3.43 (m, 1H), 3.27 (t, J=8.8 Hz, 2H), 2.95 ~ 2.85 (m, 1H), 2.35 (s, 6H), 2.31 ~ 2.27 (m, 1H), 2.05 ~ 1.99 (m, 1H), 1.68 (s, 6H).; LRMS (ES) m/z 511.6 (M ⁺ + 1).

Synthesis of compound 32, (R)-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(3-(dimethylamino) pyrrolidin-1-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 32

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), (R)-N, N-dimethylpyrrolidin-3-amine (0.054 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then obtained the solution was stirred at the same temperature for 12 hours, and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.050 g, 31.2%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J=2.2, 0.7 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H) , 8.08 (d, J=8.7Hz, 1H), 7.41 ~ 7.38 (m, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H ), 6.80 (s, 0.25H), 6.59 (dd, J=8.9, 2.3Hz, 1H), 5.40 (s, 2H), 3.63 ~ 3.57 ( m, 2H), 3.45 ~ 3.43 (m, 1H), 3.27 (t, J=8.8 Hz, 2H), 2.95 ~ 2.85 (m, 1H), 2.35 (s, 6H), 2.31 ~ 2.27 (m, 1H), 2.05 ~ 1.99 (m, 1H), 1.68 (s, 6H).; LRMS (ES) m/z 511.6 (M ⁺ + 1).

Synthesis of compound 33, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4-( 2-oxo-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)isoquinolin-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 33

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), 2-(piperazin-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (0.093 g, 0.471 mmol), 4.5-bis( diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.100 g, 53.6%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J=2.2, 0.8 Hz, 1H), 8.30 (dd, J=8.2, 2.3 Hz, 1H) , 8.08 (d, J=8.9 Hz, 1H), 7.40 (dd, J=8.3, 0.8 Hz, 1H), 7.06 (s, 0.25H), 6, 92 ~ 6.90 (m, 1H), 6.92 (s, 0.5H), 6.82 (d, J=2.4 Hz, 1H), 6.80 (s, 0.25H), 5 .40 (s, 1H), 3.51 ~ 3.42 (m, 8H), 3.20 (s, 2H), 2.75 (t, J=4.4Hz, 4H), 1.98 ~ 1.85 (m, 4H), 1.67 (s, 6H); LRMS (ES) m/z 594.7 (M ⁺ + 1).

Synthesis of compound 34 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 34

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), 1-(piperazin-1-yl)ethan-1-one (0.060 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos , 0.018 g, 0.031 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.090 g, 54.6%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J=2.2, 0.7 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H) , 8.13 (d, J=8.8 Hz, 1H), 7.40 ~ 7.38 (m, 1H), 7.06 (s, 0.25H), 6.94 ~ 6.91 (m , 1H), 6.93 (s, 0.5H), 6.84 (d, J=2.4 Hz, 1H), 6.80 (s, 0.25H), 5.40 (s, 2H) , 3.83 ~ 3.81 (m, 2H), 3.70 ~ 3.67 (m, 2H), 3.46 ~ 3.39 (m, 4H), 2.17 (s, 3H), 1 .68 (s, 6H); LRMS (ES) m/z 525.6 (M+ + 1).

Synthesis of compound 35 1-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 35

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), 1-(2-methoxyethyl)piperazine (0.068 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol ), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.100 g, 58.9%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 ~ 9.19 (m, 1H), 8.31 (dd, J=8.3, 2.2 Hz, 1H), 8.09 (d, J=8.9Hz, 1H), 7.40(d, J=8.3Hz, 1H), 7.06(s, 1H), 6.93~6.90(m, 1H), 6, 93(s, 1H), 6.80(s, 1H), 5.40(s, 2H), 3.58~3.56(m, 2H), 3.47~3.42(m, 3H) , 3.39 (s, 3H), 2.70 ~ 2.65 (m, 6H), 1.67 (s, 6H).; LRMS (ES) m/z 541.7 (M ⁺ + 1).

Synthesis of compound 36 yl)methyl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 36

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), 1-(tert-butyl)piperazine (0.067 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol ), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.088 g, 52.0%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 ~ 9.19 (m, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 8.10 (d, J=8.9Hz, 1H), 7.41(d, J=8.2Hz, 1H), 7.06(s, 0.25H), 6.94~6.91(m, 1H), 6.92(s, 0.5H), 6.84~6.83(m, 1H), 6.80(s, 0.25H), 5.41(s, 2H), 3.42(t, J=5.0 Hz, 4H), 2.77 (t, J=5.0 Hz, 4H), 1.68 (s, 6H), 1.14 (s, 9H).; LRMS (ES) m/z 539.7 (M ⁺ + 1).

Synthesis of compound 37 yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 37

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), N,N-dimethylpiperidin-4-amine (0.060 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at this the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.080 g, 48.5%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 ~ 9.19 (m, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 8.08 (d, J=8.9Hz, 1H), 7.41(d, J=8.3Hz, 1H), 7.06(s, 0.25H), 6.93~6.91(m, 1H), 6.93 (s, 0.5H), 6.84 (d, J=2.4 Hz, 1H), 6.80 (s, 0.25H), 5.40 (s, 2H), 3.99 ~ 3.95 (m, 2H), 2.98 ~ 2.92 (m, 2H), 2.45 ~ 2.36 (m, 9H), 2.02 ~ 1.99 (m, 2H), 1 .67 (s, 6H); LRMS (ES) m/z 525.6 (M ⁺ + 1).

Synthesis of compound 38, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-((2-(dimethylamino)ethyl)( methyl)amino)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 38

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), N1,N1,N2-trimethylethane-1,2-diamine (0.048 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then obtained the solution was stirred at the same temperature for 12 hours, and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.110 g, 70.2%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (dd, J=2.2, 0.7 Hz, 1H), 8.31 (dd, J=8.3, 2.3 Hz, 1H) , 8.07 (d, J=9.0 Hz, 1H), 7.40 ~ 7.38 (m, 1H), 7.06 (s, 1H), 6.93 (s, 1H), 6, 80 (s, 1H), 6.72 (dd, J=9.0, 2.5 Hz, 1H), 6.63 (d, J=2.5 Hz, 1H), 5.40 (s, 2H ), 3.58 (t, J=7.5 Hz, 2H), 3.10 (s, 3H), 2.53 (t, J=7.5 Hz, 2H), 2.33 (s, 6H ), 1.67 (s, 6H).; LRMS (ES) m/z 499.6 (M ⁺ + 1).

Synthesis of compound 39, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(4-ethylpiperazin-1-yl)- 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 39

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), 1-ethylpiperazine (0.054 g, 0.471 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g, 0.031 mmol), tris(dibenzylideneacetone ) dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.080 g, 49.9%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (dd, J=2.2, 0.8 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H) , 8.09 (d, J=8.9 Hz, 1H), 7.41 (dd, J=8.7, 1.2 Hz, 1H), 7.06 (s, 0.25H), 6, 94 ~ 6.91 (m, 1H), 6.93 (s, 0.5H), 6.84 (d, J=2.4 Hz, 1H), 6.80 (s, 0.25H), 5 .40 (s, 2H), 3.43 (t, J=5.1 Hz, 4H), 2.63 (t, J=5.1 Hz, 4H), 2.51 (q, J=7, 2 Hz, 2H), 1.67 (s, 6H), 1.15 (t, J=7.2 Hz, 3H).; LRMS (ES) m/z 511.6 (M ⁺ + 1).

Synthesis of compound 40, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(2-oxa -6-azaspiro[3.3]heptan-6-yl)isoquinolin-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 40

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), 2-oxa-6-azaspiro[3.3]heptane (0.031 g, 0.314 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.018 g , 0.031 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.029 g, 0.031 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.049 g, 31.5%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J=2.2, 0.8 Hz, 1H), 8.33 (dd, J=8.2, 2.2 Hz, 1H) , 8.09 (d, J=8.6 Hz, 1H), 7.42 (dd, J=8.3, 0.8 Hz, 1H), 7.06 (s, 0.25H), 6, 93 (s, 0.5H), 6.80 (s, 0.25H), 6.44 (dd, J=8.7, 2.3 Hz, 1H), 6.33 (d, J=2, 2 Hz, 1H), 5.40 (s, 2H), 4.90 (s, 4H), 4.21 (s, 4H), 1.67 (s, 6H); LRMS (ES) m/z 496.6 (M ⁺ + 1).

Synthesis of compound 41, tert-butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl -1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[Step 1] Synthesis of compound 41

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.700 g, 1.467 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1( 2H)-carboxylate (0.544 g, 1.760 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl ₂ , 0.107 g, 0.147 mmol) and sodium carbonate (0.311 g, 2.933 mmol) was dissolved in 1,2-dimethoxyethane (8 ml)/water (4 ml) at 90°C, then the resulting solution was stirred at the same temperature for 12 h, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 70%) and concentrated to give the title compound (0.450 g, 52.9%) as a brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 ~ 9.19 (m, 1H), 8.35 (dd, J=8.2, 2.2 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.48 ~ 7.45 (m, 3H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s , 0.25H), 6.23 (br s, 1H), 5.44 (s, 2H), 4.16 ~ 4.13 (m, 2H), 3.70 (t, J=5.6 Hz , 2H), 2.59 (s, 2H), 1.71 (s, 6H), 1.52 (s, 9H).; LRMS (ES) m/z 580.5 (M ⁺ + 1).

Synthesis of compound 42, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(1-methyl -1,2,3,6-tetrahydropyridin-4-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(1, 2,3,6-tetrahydropyridin-4-yl)isoquinolin-1,3(2H,4H)-dione-2,2,2-trifluoroacetate

tert-Butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-1,3 -dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.450 g, 0.776 mmol) and trifluoroacetic acid (0.595 ml, 7.764 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 2 hours. The solvent was removed from the reaction mixture under reduced pressure, then the resulting product was used without further purification (0.460 g, 99.8%, brown oil) .

[Step 2] Synthesis of Compound 42

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(1,2,3,6 -tetrahydropyridin-4-yl)isoquinolin-1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.200 g, 0.337 mmol) obtained in step 1, formaldehyde (0.020 g, 0.674 mmol), N , N-diisopropylethylamine (0.059 ml, 0.337 mmol) and sodium triacetoxyborohydride (0.143 g, 0.674 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.080 g, 48.1%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (dd, J=2.2, 0.8 Hz, 1H), 8.33 (dd, J=8.2, 2.2 Hz, 1H) , 8.19 ~ 8.17 (m, 1H), 7.48 ~ 7.42 (m, 3H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6 .80 (s, 0.25H), 6.24 ~ 6.22 (m, 1H), 5.41 (s, 2H), 3.27 ~ 3.25 (m, 2H), 2.81 ~ 2 .79(m, 2H), 2.69~2.67(m, 2H), 2.48(s, 3H), 1.70(s, 6H).; LRMS (ES) m/z 494.6 (M ⁺ + 1).

Synthesis of compound 43, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(1-( oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)isoquinolin-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 43

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(1,2,3,6 -tetrahydropyridin-4-yl)isoquinolin-1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.200 g, 0.337 mmol), oxetan-3-one (0.049 g, 0.674 mmol), N, N-diisopropylethylamine (0.059 ml, 0.337 mmol) and sodium triacetoxyborohydride (0.143 g, 0.674 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.030 g, 16.6%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (dd, J= 2.2, 0.8 Hz, 1H), 8.33 (dd, J= 8.2, 2.2 Hz, 1H) , 8.19 ~ 8.17 (m, 1H), 7.48 ~ 7.42 (m, 3H), 7.06 (s, 0.25H), 6.92 (s, 0.5H), 6 .80 (s, 0.25H), 6.23 (t, J =3.5Hz, 1H), 5.42 (s, 2H), 4.76 ~ 4.70 (m, 4H), 3, 74~3.67(m, 1H), 3.13~3.12(m, 2H), 2.65(s, 4H), 1.69(s, 6H).; LRMS (ES) m/z 536.6 (M ⁺ + 1).

Synthesis of compound 44, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(1-methylpiperidine -4-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 44

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(1-methyl-1,2 ,3,6-tetrahydropyridin-4-yl)isoquinolin-1,3(2H,4H)-dione (0.050 g, 0.101 mmol) was dissolved in methanol (5 ml) at room temperature, then 10%-Pd/C was added slowly (5 mg) and stirred for 12 h with the supply of hydrogen from an attached balloon at the same temperature. The reaction mixture was filtered through a pad of celite to remove solids, then the solvent was removed from the resulting solids-free filtrate under reduced pressure. The resulting concentrate was then purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.018 g, 35.9%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J=1.8, 1.3 Hz, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H) , 8.19 (d, J=8.5Hz, 1H), 7.44 (dd, J=8.2, 0.8Hz, 1H), 7.38 ~ 7.33 (m, 2H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.43(s, 2H), 3.18~3.15( m, 2H), 2.70 ~ 2.65 (m, 1H), 2.28 ~ 2.22 (m, 2H), 2.05 ~ 1.90 (m, 4H), 1.69 (s, 6H).; LRMS (ES) m/z 496.8 (M ⁺ + 1).

Synthesis of compound 45, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4-pentylpiperazine -1-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 45

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), 1-pentylpiperazine (0.049 g, 0.314 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol), tris(dibenzylideneacetone ) dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were dissolved in toluene (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.010 g, 8.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (dd, J=2.2, 0.8 Hz, 1H), 8.33 (dd, J=8.3, 2.3 Hz, 1H) , 8.11 (d, J=8.9 Hz, 1H), 7.42 (dd, J=8.3, 0.8 Hz, 1H), 7.06 (s, 0.25H), 6, 95 ~ 6.92 (m, 1H), 6.93 (s, 0.5H), 6.84 (d, J=2.4 Hz, 1H), 6.80 (s, 0.25H), 5 .41 (s, 2H), 3.46 (t, J=4.8 Hz, 4H), 2.68 ~ 2.67 (m, 4H), 2.45 ~ 2.43 (m, 2H), 1.69(s, 6H), 1.39~1.32(m, 6H), 1.00~0.95(m, 3H).; LRMS (ES) m/z 553.6 (M ⁺ + 1).

Synthesis of compound 46 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 46

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), 1-cyclohexylpiperazine (0.053 g, 0.314 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol), tris(dibenzylideneacetone ) dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were dissolved in toluene (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.020 g, 16.9%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J=2.2, 0.8 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H) , 8.10 (d, J=8.9 Hz, 1H), 7.41 ~ 7.38 (m, 1H), 7.06 (s, 0.25H), 6.94 ~ 6.91 (m , 1H), 6.93 (s, 0.5H), 6.84 (d, J=2.4 Hz, 1H), 6.80 (s, 0.25H), 5.41 (s, 2H) , 3.41 (t, J=5.1Hz, 4H), 2.75 (t, J=5.1Hz, 4H), 2.60 ~ 2.55 (m, 2H), 2.45 ~ 2.35(m, 1H), 2.05~1.82(m, 2H), 1.68(s, 6H), 1.29~1.24(m, 2H).; LRMS (ES) m/z 565.7 (M ⁺ + 1).

Synthesis of compound 47 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 47

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), 1-cyclopropylpiperazine (0.040 g, 0.314 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol), tris(dibenzylideneacetone ) dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were dissolved in toluene (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.020 g, 18.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 ~ 9.19 (m, 1H), 8.32 (dd, J =8.2, 2.2 Hz, 1H), 8.10 (d, J =8.9Hz, 1H), 7.41(d, J =8.2Hz, 1H), 7.06(s, 0.25H), 6.94~6.91(m, 1H), 6.93 (s, 0.5H), 6.84 (d, J =2.4 Hz, 1H), 6.80 (s, 0.25H), 5.41 (s, 2H), 3.38 (t, J =5.1Hz, 4H), 2.80 (t, J=5.1Hz, 4H), 1.71 ~ 1.67 (m, 7H), 0.53 ~ 0.49 ( m, 4H).; LRMS (ES) m/z 523.6 (M ⁺ + 1).

Synthesis of compound 48 methyl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 48

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), 1-(cyclohexylmethyl)piperazine (0.057 g, 0.314 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were dissolved in toluene (5 ml) at 80°C, then the resulting solution was stirred at the same temperature in for 12 h and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.030 g, 24.7%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J=2.2, 0.7 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H) , 8.10 (d, J=8.9 Hz, 1H), 7.42 ~ 7.40 (m, 1H), 7.06 (s, 0.25H), 6.94 ~ 6.91 (m , 1H), 6.93 (s, 0.5H), 6.83 (d, J=2.4 Hz, 1H), 6.80 (s, 0.25H), 5.41 (s, 2H) , 3.41 (t, J=5.1 Hz, 4H), 2.57 (t, J=5.1 Hz, 4H), 2.21 (d, J=7.2 Hz, 2H), 1 .83 ~ 1.71 (m, 4H), 1.67 ~ 1.71 (m, 6H), 1.60 ~ 1.55 (m, 1H), 1.32 ~ 1.27 (m, 4H) , 1.00 ~ 0.80 (m, 2H). ; LRMS (ES) m/z 579.6 (M ⁺ + 1).

Synthesis of compound 49 )-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 49

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), 3,3-difluoroazetidine hydrochloride (0.041 g, 0.314 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol), tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were dissolved in toluene (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.020 g, 19.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J=5.5, 4.1 Hz, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H) , 8.15 (d, J=8.6 Hz, 1H), 7.43 (dd, J=8.2, 0.8 Hz, 1H), 7.06 (s, 0.25H), 6, 93 (s, 0.5H), 6.80 (s, 0.25H), 6.52 (dd, J=8.6, 2.3 Hz, 1H), 6.41 (d, J=2, 2 Hz, 1H), 5.41 (s, 2H), 4.39 (t, J=11.6 Hz, 4H), 1.68 (s, 6H).; LRMS (ES) m/z 490.3 (M ⁺ + 1).

Synthesis of compound 50, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4-( pyrimidin-2-yl)piperazin-1-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 50

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), 2-(piperazin-1-yl)pyrimidine (0.052 g, 0.314 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were dissolved in toluene (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 hours and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.020 g, 17.0%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J=2.2, 0.8 Hz, 1H), 8.37 (d, J=4.8 Hz, 2H), 8.33 (dd, J=8.2, 2.2 Hz, 1H), 8.13 (d, J=8.9 Hz, 1H), 7.43 ~ 7.40 (m, 1H), 7.06 ( s, 0.25H), 6.97 (dd, J=8.9, 2.5 Hz, 1H), 6.93 (s, 0.5H), 6.87 (d, J=2.4 Hz , 1H), 6.80 (s, 0.25H), 6.58 (t, J=4.8 Hz, 1H), 5.41 (s, 2H), 4.04 (t, J=5, 3 Hz, 4H), 3.52 (t, J=5.3 Hz, 4H), 1.68 (s, 6H) .; LRMS (ES) m/z 561.5 (M ⁺ + 1).

Synthesis of compound 51, 7-bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1, 3(2H,4H)-dione

[Step 1] Synthesis of methyl 5-bromo-2-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate

Methyl 5-bromo-2-(2-methoxy-2-oxoethyl)benzoate (6.260 g, 21.803 mmol) was dissolved in N,N-dimethylformamide (50 mL) at 0°C followed by sodium hydride (60.00%, 2.616 g, 65.410 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. Iodomethane (4.072 mL, 65.410 mmol) was added to the reaction mixture, and further stirred at room temperature for 18 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 10%) and concentrated to give the title compound (5.300 g, 77.1%) as a colorless oil.

[Step 2] Synthesis of 5-bromo-2-(2-carboxypropan-2-yl)benzoic acid

Methyl 5-bromo-2-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate (5.300 g, 16.817 mmol) obtained in Step 1 and potassium hydroxide (9.435 g, 168.169 mmol) were dissolved in methanol (30 ml)/water (60 ml) at 100°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then 1 N sodium hydroxide was poured into the resulting concentrate. an aqueous solution of hydrochloric acid, and then extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (4.800 g, 99.4%, white solid).

[Step 3] Synthesis of 7-bromo-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

5-Bromo-2-(2-carboxypropan-2-yl)benzoic acid (4.800 g, 16.718 mmol) obtained in step 2 and urea (1.105 g, 18.390 mmol) were mixed in chlorobenzene (30 ml), then irradiated with microwave radiation, then heated at 150°C for 1 h and then the reaction was completed by lowering the temperature to room temperature. The precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (4.480 g, 99.9%) as a white solid.

[Step 4] Synthesis of Compound 51

7-Bromo-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (4.480 g, 16.710 mmol) obtained in step 3, 2-(6-(bromomethyl)pyridin-3-yl)-5- (difluoromethyl)-1,3,4-oxadiazole (7.270 g, 25.064 mmol) and potassium carbonate (4.619 g, 33.419 mmol) were dissolved in N,N-dimethylformamide (50 ml) at 80°C, then the resulting solution was stirred at this the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (4.500 g, 56.4%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 ~ 9.05 (m, 1H), 8.37 (dd, J=8.3, 2.3 Hz, 1H), 8.16 ( d, J=2.2Hz, 1H), 7.95 ~ 7.93(m, 1H), 7.75(d, J=8.5Hz, 1H), 7.68(s, 0.25H ), 7.63 (d, J=8.3 Hz, 1H), 7.55 (s, 0.5H), 7.42 (s, 0.25H), 5.30 (s, 2H), 1 .61 (s, 6H).

Synthesis of compound 52, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-morpholinoisoquinoline-1, 3(2H,4H)-dione

[Step 1] Synthesis of Compound 52

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), morpholine (0.027 ml, 0.314 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were dissolved in toluene (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.015 g, 14.8%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 ~ 9.20 (m, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 7.72 (d, J=2.8 Hz, 1H), 7.43 ~ 7.40 (m, 2H), 7.26 ~ 7.25 (m, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.41 (s, 2H), 3.89 (t, J=4.9Hz, 4H), 3.26 ~ 3, 23 (m, 4H), 1.67 (s, 6H); LRMS (ES) m/z 484.6 (M ⁺ + 1).

Synthesis of compound 53, tert-butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl -1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[Step 1] Synthesis of Compound 53

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (1.000 g, 2.095 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1( 2H)-carboxylate (0.777 g, 2.514 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl ₂ , 0.153 g, 0.210 mmol) and sodium carbonate (0.444 g, 4.191 mmol) was dissolved in 1,2-dimethoxyethane (10 ml)/water (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 80%) and concentrated to give the title compound (0.490 g, 40.3%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=2.0 Hz, 1H), 8.36 (dd, J=8.2, 2.2 Hz, 1H), 8.24 (s, 1H), 7.71 (dd, J=8.2, 2.0 Hz, 1H), 7.51 ~ 7.45 (m, 2H), 7.06 (s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 6.17(s, 1H), 5.45(s, 2H), 4.16~4.11(m, 2H), 3.67(t, J=5.6Hz, 2H), 2.60~2.56(m, 2H), 1.67(s, 6H), 1.51(s, 9H).

Synthesis of compound 54, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(1-methylpiperidine -4-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of tert-butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4- dimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)piperidine-1-carboxylate

tert-Butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-1,3 -dioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.490 g, 0.845 mmol) was dissolved in methanol (10 ml) at room temperature, then slowly 10%-Pd/C (50 mg) was added and stirred for 12 h with the supply of hydrogen from an attached balloon at the same temperature. The resulting product was used without further purification (0.480 g, 97.6%, colorless oil).

[Step 2] Synthesis of 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin- 4-yl)isoquinoline-1,3(2H,4H)-dione-2,2,2-trifluoroacetate

tert-Butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-1,3 -dioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)piperidine-1-carboxylate (0.488 g, 0.839 mmol) obtained in step 1 and trifluoroacetic acid (0.642 ml, 8.390 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 2 hours. The solvent was removed from the reaction mixture under reduced pressure, then the resulting product was used without further purification (0.490 g, 98.1%, yellow oil).

[Step 3] Synthesis of Compound 54

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.150 g, 0.252 mmol) obtained in step 2, formaldehyde (0.015 g, 0.504 mmol), N,N-diisopropylethylamine (0.044 ml, 0.252 mmol) and sodium triacetoxyborohydride (0.107 g, 0.504 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.050 g, 40.1%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.14 (dd, J=2.2, 0.8 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H) , 8.06 (d, J=2.1 Hz, 1H), 7.58 (dd, J=8.2, 2.1 Hz, 1H), 7.45 (d, J=31.8 Hz, 1H), 7.44 (dd, J=8.0, 1.0 Hz, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s , 0.25H), 5.40 (s, 2H), 3.62 (d, J=12.0 Hz, 2H), 2.88 ~ 2.81 (m, 6H), 2.27 ~ 2, 25(m, 2H), 2.06~2.03(m, 2H), 1.67(s, 6H).; LRMS (ES) m/z 496.6 (M ⁺ + 1).

Synthesis of compound 55, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(1-( oxetan-3-yl)piperidin-4-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 55

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.150 g, 0.252 mmol), oxetan-3-one (0.036 g, 0.504 mmol), N,N-diisopropylethylamine (0.044 ml, 0.252 mmol) and sodium triacetoxyborohydride (0.107 g, 0.504 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.030 g, 22.2%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J=2.2, 0.8 Hz, 1H), 8.33 (dd, J=8.2, 2.3 Hz, 1H) , 8.11 (d, J=2.0 Hz, 1H), 7.56 (dd, J=8.3, 2.0 Hz, 1H), 7.47 ~ 7.43 (m, 2H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.42(s, 2H), 4.69~4.67( m, 4H), 3.55~3.52(m, 1H), 2.93~2.90(m, 2H), 2.70~2.60(m, 1H), 1.99~1, 98(m, 2H), 1.90~1.87(m, 4H), 1.68(s, 6H).; LRMS (ES) m/z 538.6 (M ⁺ + 1).

Synthesis of compound 56, 1-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-1,3 -dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-N-methylpiperidine-4-carboxamide

[Step 1] Synthesis of Compound 56

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), N-methylpiperidine-4-carboxamide (0.030 g, 0.210 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol), 4.5 -bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.030 g, 26.6%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 ~ 9.20 (m, 1H), 8.33 (dd, J=8.2, 2.2 Hz, 1H), 8.11 ~ 8, 10(m, 1H), 7.42~7.40(m, 1H), 7.06(s, 0.25H), 6.94~6.92(m, 1H), 6.93(s, 0.5H), 6.84 (d, J=2.4Hz, 1H), 6.80 (s, 0.25H), 5.60 ~ 5.55 (m, 1H), 5.41 (s , 2H), 4.00 ~ 3.97 (m, 2H), 3.02 ~ 2.96 (m, 2H), 2.87 ~ 2.85 (m, 3H), 2.42 ~ 2.38 (m, 1H), 2.19 ~ 1.88 (m, 4H), 1.68 (s, 6H).

Synthesis of compound 57, 1-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-1,3 -dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-N, N-dimethylpiperidine-4-carboxamide

[Step 1] Synthesis of Compound 57

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), N, N-dimethylpiperidine-4-carboxamide hydrochloride (0.040 g, 0.210 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol), 4 ,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were dissolved in toluene (10 ml) at 80°C, then the resulting solution was stirred at this the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.020 g, 17.3%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J=2.2, 0.6 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H) , 8.08 (d, J=8.9 Hz, 1H), 7.40 (dd, J=8.3, 0.5 Hz, 1H), 7.06 (s, 0.25H), 6, 94 ~ 6.91 (m, 1H), 6.93 (s, 0.5H), 6.84 (d, J=2.4 Hz, 1H), 6.80 (s, 0.25H), 5 .41 (s, 2H), 4.00 ~ 3.96 (m, 2H), 3.12 (s, 3H), 3.05 ~ 2.98 (m, 5H), 2.80 ~ 2.75 (m, 1H), 1.97 ~ 1.83 (m, 4H), 1.67 (s, 6H).; LRMS (ES) m/z 553.6 (M ⁺ + 1).

Synthesis of compound 58, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-((1S, 4S)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)isoquinolin-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 58

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), (1S,4S)-2-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride (0.045 g, 0.210 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were dissolved in toluene ( 10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.050 g, 41.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 ~ 9.20 (m, 1H), 8.33 (dd, J=8.2, 2.3 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6, 80 (s, 0.25H), 6.63 (dd, J=8.8, 2.4 Hz, 1H), 6.49 (d, J=2.3 Hz, 1H), 5.41 (s , 2H), 4.67 (s, 2H), 3.69 ~ 3.66 (m, 1H), 3.58 ~ 3.50 (m, 3H), 2.92 (s, 3H), 2, 50 ~ 2.04 (m, 2H), 1.67 (s, 6H).; LRMS (ES) m/z 573.6 (M ⁺ + 1).

Synthesis of compound 59 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperidin- 4-yl)isoquinoline-1,3(2H,4H)-dione-2,2,2-trifluoroacetate

tert-Butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-1,3 -dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-1-carboxylate (1.340 g, 2.304 mmol) and trifluoroacetic acid (1.764 ml, 23.039 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, then the resulting product was used without further purification (1.300 g, 94.7%, brown oil).

[Step 2] Synthesis of Compound 59

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.200 g, 0.336 mmol) obtained in step 1 and N,N-diisopropylethylamine (0.058 ml, 0.336 mmol) were dissolved in dichloromethane (10 ml), then the resulting solution was stirred at room temperature for 30 h and then acetaldehyde (0.030 g, 0.672 mmol) and sodium triacetoxyborohydride (0.142 g, 0.672 mmol) were added and further stirred at the same temperature for 12 h. To the reaction mixture water was poured out and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.080 g, 46.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 ~ 9.17 (m, 1H), 8.33 (dd, J=8.2, 2.2 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.45 ~ 7.41 (m, 2H), 7.36 ~ 7.33 (m, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.42 (s, 2H), 3.53 ~ 3.49 (m, 2H), 2.92 ~ 2.86 (m , 2H), 2.77 ~ 2.76 (m, 1H), 2.53 ~ 2.47 (m, 2H), 2.24 ~ 2.20 (m, 2H), 2.02 ~ 1.98 (m, 2H), 1.67 (s, 6H), 1.33 ~ 1.30 (m, 3H).; LRMS (ES) m/z 510.6 (M ⁺ + 1).

Synthesis of compound 60 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 60

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.200 g, 0.336 mmol) and N,N-diisopropylethylamine (0.058 ml, 0.336 mmol) were dissolved in dichloromethane (10 ml), then the resulting solution stirred at room temperature for 30 h and then added acetone (0.039 g, 0.672 mmol) and sodium triacetoxyborohydride (0.142 g, 0.672 mmol) and further stirred at the same temperature for 12 h. Water was poured into the reaction mixture and extraction was carried out with dichloromethane . The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.050 g, 28.4%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 ~ 9.18 (m, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 8.21 (d, J=8.1Hz, 1H), 7.45 ~ 7.43(m, 2H), 7.35(dd, J=8.1, 1.5Hz, 1H), 7.06(s, 1H ), 6.93(s, 1H), 6.80(s, 1H), 5.42(s, 2H), 3.69~3.50(m, 3H), 2.87~2.82( m, 3H), 2.53 ~ 2.49 (m, 2H), 2.09 ~ 2.06 (m, 2H), 1.67 (s, 6H), 1.42 ~ 1.38 (m, 6H).; LRMS (ES) m/z 524.6 (M ⁺ + 1).

Synthesis of compound 61, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(1-( oxetan-3-yl)piperidin-4-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 61

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.200 g, 0.336 mmol) and N,N-diisopropylethylamine (0.058 ml, 0.336 mmol) were dissolved in dichloromethane (10 ml), then the resulting solution stirred at room temperature for 30 h and then added oxetan-3-one (0.048 g, 0.672 mmol) and sodium triacetoxyborohydride (0.142 g, 0.672 mmol) and further stirred at the same temperature for 12 h. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.100 g, 55.4%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 ~ 9.18 (m, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 8.20 (d, J=8.1Hz, 1H), 7.45(d, J=8.2Hz, 1H), 7.38~7.33(m, 2H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.43(s, 2H), 4.73~4.67(m, 4H), 3.58~3, 54(m, 1H), 2.96~2.93(m, 2H), 1.70~1.60(m, 1H), 2.09~2.00(m, 2H), 1.93~ 1.88 (m, 4H), 1.67 (s, 6H); LRMS (ES) m/z 538.6 (M ⁺ + 1).

Synthesis of compound 62, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(1-( (tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)isoquinolin-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 62

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.200 g, 0.336 mmol) and N,N-diisopropylethylamine (0.058 ml, 0.336 mmol) were dissolved in dichloromethane (10 ml), then the resulting solution stirred at room temperature for 30 h and then tetrahydro-2H-pyran-4-carbaldehyde (0.077 g, 0.672 mmol) and sodium triacetoxyborohydride (0.142 g, 0.672 mmol) were added and further stirred at the same temperature for 12 h. the reaction mixture was poured into water, and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.060 g, 30.8%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 ~ 9.18 (m, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.40 (d, J=1.3 Hz, 1H), 7.36 (dd, J= 8.2, 1.6 Hz, 1H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.43(s , 2H), 4.16~4.11(m, 2H), 3.46~4.41(m, 2H), 3.05~2.85(m, 1H), 2.69~2.68 (m, 1H), 2.48 ~ 2.47 (m, 2H), 2.34 ~ 2.28 (m, 2H), 2.08 ~ 2.05 (m, 2H), 1.93 ~ 1 .90(m, 2H), 1.73~1.70(m, 2H), 1.67(s, 6H), 1.42~1.39(m, 2H).; LRMS (ES) m/z 580.6 (M ⁺ + 1).

Synthesis of compound 63 2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 63

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.200 g, 0.336 mmol) and N,N-diisopropylethylamine (0.058 ml, 0.336 mmol) were dissolved in dichloromethane (10 ml), then the resulting solution stirred at room temperature for 30 h and then added 2-oxaspiro[3.3]heptan-6-one (0.075 g, 0.672 mmol) and sodium triacetoxyborohydride (0.142 g, 0.672 mmol) and further stirred at the same temperature for 12 h Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.020 g, 10.3%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J=2.2, 0.8 Hz, 1H), 8.34 (dd, J=8.2, 2.3 Hz, 1H) , 8.18 (d, J=8.1 Hz, 1H), 7.44 (dd, J=8.2, 0.8 Hz, 1H), 7.37 (d, J=1.4 Hz, 1H), 7.32 (dd, J=8.2, 1.4 Hz, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s , 0.25H), 5.42(s, 2H), 4.74~4.63(m, 8H), 4.16~4.12(m, 1H), 3.15~3.13(m , 2H), 2.68 ~ 2.61 (m, 3H), 2.47 ~ 2.45 (m, 2H), 2.30 ~ 2.28 (m, 2H), 1.68 (s, 6H ) .; LRMS (ES) m/z 578.6 (M ⁺ + 1).

Synthesis of compound 64 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 64

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.200 g, 0.336 mmol) and N,N-diisopropylethylamine (0.058 ml, 0.336 mmol) were dissolved in dichloromethane (10 ml), then the resulting solution stirred at room temperature for 30 h and then cyclobutanone (0.047 g, 0.672 mmol) and sodium triacetoxyborohydride (0.142 g, 0.672 mmol) were added and further stirred at the same temperature for 12 h. Water was poured into the reaction mixture and extraction was carried out with dichloromethane . The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.100 g, 55.6%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 ~ 9.18 (m, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 7.34 (dd, J= 8.2, 1.6 Hz, 1H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.43(s , 2H), 3.43~3.38(m, 2H), 2.99~2.93(m, 1H), 2.72~2.68(m, 1H), 2.24~2.01 (m, 8H), 1.98 ~ 1.71 (m, 4H), 1.68 (s, 6H).; LRMS (ES) m/z 536.6 (M ⁺ + 1).

Synthesis of compound 65, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)isoquinolin-1,3(2H,4H)-dione

[Step 1] Synthesis of 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

2-(6-(Bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (3.000 g, 10.342 mmol) and sodium azide (1.009 g, 15.513 mmol) were dissolved in N, N -dimethylformamide (5 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (2.310 g, 88.6%, white solid).

[Step 2] Synthesis of (5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methanamine

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.500 g, 5.948 mmol) obtained in step 1 was dissolved in methanol (20 ml) at room temperature temperature, then 10%-Pd/C (100 mg) was slowly added and stirred for 12 h with hydrogen supplied from an attached cylinder at the same temperature. The reaction mixture was filtered through a pad of celite to remove solids, then the solvent was removed from the resulting filtrate under reduced pressure, and then the resulting product was used without further purification (1.300 g, 96.6%, brown solid).

[Step 3] Synthesis of Compound 65

(5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methanamine (1.235 g, 5.458 mmol) from step 2 and isochromene-1,3-dione (0.590 g, 3.639 mmol) was dissolved in toluene (10 ml) at 100°C, then the resulting solution was stirred at the same temperature for 12 h, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.150 g, 11.1%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.22 ~ 9.21 (m, 1H), 8.36 (dd, J=8.2, 2.2 Hz, 1H), 8.25 (d, J=7.3 Hz, 1H), 7.67 ~ 7.63 (m, 1H), 7.52 ~ 7.50 (m, 1H), 7.38 ~ 7.36 (m, 1H), 7 .06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.45 (s, 2H), 4.20 (s, 2H). ; LRMS (ES) m/z 371.4 (M ⁺ + 1).

Synthesis of compound 66 -2,4(1H,3H)-dione

[Step 1] Synthesis of 2-amino-N-(tert-butyl)-5-fluorobenzamide

6-Fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (5.000 g, 27.606 mmol), 2-methylpropan-2-amine (2.423 g, 33.127 mmol) and N, N-dimethylpyridin-4-amine (DMAP, 0.337 g, 2.761 mmol) was dissolved in N,N-dimethylformamide (30 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (2.700 g, 46.5%) as a yellow solid.

[Step 2] Synthesis of methyl-(2-(tert-butylcarbamoyl)-4-fluorophenyl)carbamate

2-Amino-N-(tert-butyl)-5-fluorobenzamide (2.700 g, 12.842 mmol) obtained in step 1, methyl chloroformate (1.456 g, 15.410 mmol) and sodium hydroxide (1.00 M solution in H ₂ O, 25.684 ml, 25.684 mmol) was dissolved in 1,4-dioxane (20 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. aqueous hydrochloric acid (10 ml) and stirred, then the precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (2.570 g, 74.6%) as a white solid.

[Step 3] Synthesis of 3-(tert-butyl)-6-fluoroquinazolin-2,4(1H,3H)-dione

Methyl-(2-(tert-butylcarbamoyl)-4-fluorophenyl)carbamate (2.570 g, 9.579 mmol) obtained in step 2 and potassium hydroxide (5.374 g, 95.792 mmol) were dissolved in ethanol (50 ml) at 80°C , then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. Water (10 ml) was added to the reaction mixture and stirred, then the precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (1.520 g, 67.2%) as a white solid.

[Step 4] Synthesis of 3-(tert-butyl)-6-fluoro-1-(4-methoxybenzyl)quinazoline-2,4(1H,3H)-dione

3-(T-butyl)-6-fluoroquinazolin-2,4(1H,3H)-dione (1.520 g, 6.434 mmol) obtained in step 3 was dissolved in N,N-dimethylformamide (20 ml) at 0°C , then sodium hydride (60.00%, 0.386 g, 9.651 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 1-(Chloromethyl)-4-methoxybenzene (1.310 g, 8.364 mmol) was added to the reaction mixture and further stirred at room temperature for 18 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (1.660 g, 72.4%) as a white solid.

[Step 5] Synthesis of 6-fluoro-1-(4-methoxybenzyl)quinazoline-2,4(1H,3H)-dione

3-(T-butyl)-6-fluoro-1-(4-methoxybenzyl)quinazoline-2,4(1H,3H)-dione (1.660 g, 4.658 mmol) obtained in step 4 and hydrochloric acid (4, 00 M solution in dioxane, 23.288 ml, 93.154 mmol) was mixed at 100°C, then the resulting reaction mixture was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. Water (10 ml) was added to the reaction mixture and stirred, then the precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (1.250 g, 89.4%) as a white solid.

[Step 6] Synthesis of Compound 66

6-Fluoro-1-(4-methoxybenzyl)quinazolin-2,4(1H,3H)-dione (1.250 g, 4.163 mmol) from step 5, 2-(6-(bromomethyl)pyridin-3-yl) -5-(difluoromethyl)-1,3,4-oxadiazole (1.570 g, 5.411 mmol) and potassium carbonate (1.151 g, 8.325 mmol) were dissolved in N,N-dimethylformamide (20 ml) at 90°C, then the resulting solution stirred at the same temperature for 12 hours, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (1.600 g, 75.4%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.25 ~ 9.24 (m, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.94 (dd, J=8.1, 3.1Hz, 1H), 7.54 (d, J=8.2Hz, 1H), 7.34 ~ 7.30 (m, 1H), 7.23 ~ 7.19 (m, 3H), 7.07 (s, 0.25H), 6.94 (s, 0.5H), 6.90 ~ 6.88 (m, 2H), 6.81 (s, 0.25H ), 5.60 (s, 2H), 5.35 (s, 2H), 3.80 (s, 3H).; LRMS (ES) m/z 510.6 (M ⁺ + 1).

Synthesis of compound 67 -dion

[Step 1] Synthesis of Compound 67

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-fluoro-1-(4-methoxybenzyl)quinazolin-2,4 (1H,3H)-dione (1.600 g, 3.141 mmol) and cerium ammonium nitrate (5.165 g, 9.422 mmol) were dissolved in acetonitrile (20 ml)/water (20 ml) at room temperature, then the resulting solution was stirred at this the same temperature for 12 hours. The precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (0.900 g, 73.6%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 ~ 9.08 (m, 1H), 8.38 (dd, J=8.3, 2.3 Hz, 1H), 7.69 ( s, 0.25H), 7.67~7.61(m, 3H), 7.56(s, 0.5H), 7.43(s, 0.25H), 7.31~7.28( m, 1H), 7.12 ~ 6.99 (m, 1H), 5.31 (s, 2H).; LRMS (ES) m/z 390.5 (M ⁺ + 1).

Synthesis of compound 68, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(1-ethylpiperidin-4-yl)- 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 68

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.120 g, 0.202 mmol) and N,N-diisopropylethylamine (0.035 ml, 0.202 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then acetaldehyde (0.018 g, 0.403 mmol) and sodium triacetoxyborohydride (0.085 g, 0.403 mmol) were added to the resulting solution and stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to give the title compound (0.023 g, 22.4%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (dd, J=2.2, 0.7 Hz, 1H), 8.33 (dd, J=8.2, 2.2 Hz, 1H) , 8.09 (d, J=2.0 Hz, 1H), 7.60 (dd, J=8.2, 2.0 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.45 (dd, J=8.2, 0.6 Hz, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s , 0.25H), 5.42 (s, 2H), 3.52 (d, J=11.7 Hz, 1H), 2.94 ~ 2.88 (m, 2H), 2.82 ~ 2, 75(m, 1H), 2.59~2.53(m, 2H), 2.21~2.18(m, 2H), 2.02~2.00(m, 2H), 1.68( s, 6H), 1.34 ~ 1.30 (m, 3H).; LRMS (ES) m/z 510.6 (M ⁺ + 1).

Synthesis of compound 69 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 69

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.120 g, 0.202 mmol) and N,N-diisopropylethylamine (0.035 ml, 0.202 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then acetone (0.030 ml, 0.403 mmol) and sodium triacetoxyborohydride (0.085 g, 0.403 mmol) were added to the resulting solution and stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0 to 10%) and concentrated to give the title compound (0.040 g, 37.9%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 ~ 9.16 (m, 1H), 8.34 ~ 8.31 (m, 1H), 8.06 (s, 1H), 7.63 ~ 7.62(m, 1H), 7.52~7.50(m, 1H), 7.45~7.43(m, 1H), 7.06(s, 0.25H), 6.93( s, 0.5H), 6.80(s, 0.25H), 5.42(s, 2H), 3.54~3.51(m, 3H), 2.83~2.80(m, 3H), 2.45~2.35(m, 2H), 2.08~2.02(m, 2H), 1.67(s, 6H), 1.38~1.36(m, 6H) .; LRMS (ES) m/z 524.6 (M ⁺ + 1).

Synthesis of compound 70 1H,3H)-dione

[Step 1] Synthesis of Compound 70

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-fluoroquinazolin-2,4(1H,3H)-dione (0.100 g, 0.257 mmol), iodomethane (0.032 ml, 0.514 mmol) and potassium carbonate (0.071 g, 0.514 mmol) were dissolved in N,N-dimethylformamide (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.030 g, 29.0%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.22 ~ 9.21 (m, 1H), 8.36 (dd, J=8.2, 2.2 Hz, 1H), 7.94 (dd, J=8.0, 3.0 Hz, 1H), 7.53 ~ 7.43 (m, 2H), 7.28 ~ 7.25 (m, 1H), 7.06 (s, 0.25H) , 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.52 (s, 2H), 3.65 (s, 3H).; LRMS (ES) m/z 404.4 (M ⁺ + 1).

Synthesis of compound 71, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-yl)methyl)-6-fluoro 1-yl)ethyl)quinazolin-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 71

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-fluoroquinazolin-2,4(1H,3H)-dione (0.100 g, 0.257 mmol), 1-(2-chloroethyl)piperidine (0.076 g, 0.514 mmol) and potassium carbonate (0.124 g, 0.899 mmol) were dissolved in N,N-dimethylformamide (5 ml) at 80°C, then the resulting solution stirred at the same temperature for 12 hours, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 50%) and concentrated to give the title compound (0.020 g, 15.6%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J=2.2, 0.8 Hz, 1H), 8.33 (dd, J=8.2, 2.2 Hz, 1H) , 7.91 (dd, J=8.1, 3.0Hz, 1H), 7.49 ~ 7.33 (m, 3H), 7.06 (s, 0.25H), 6.93 (s , 0.5H), 6.80 (s, 0.25H), 5.50 (s, 2H), 4.28 (t, J=7.4 Hz, 2H), 2.64 (t, J= 6.3 Hz, 2H), 2.55 ~ 2.45 (m, 4H), 1.58 ~ 1.53 (m, 4H), 1.47 ~ 1.40 (m, 2H).; LRMS (ES) m/z 501.5 (M ⁺ + 1).

Synthesis of compound 72 2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)piperidine-1-carboxylate

[Step 1] Synthesis of Compound 72

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-fluoroquinazolin-2,4(1H,3H)-dione (0.283 g, 0.727 mmol), tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (0.427 g, 1.454 mmol) and potassium carbonate (0.201 g, 1.454 mmol) were dissolved in N,N-dimethylformamide (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.166 g, 38.9%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.16 ~ 9.15 (m, 1H), 8.35 (dd, J=8.1, 2.1 Hz, 1H), 7.93 (dd, J=8.0, 3.1Hz, 1H), 7.50 ~ 7.44 (m, 2H), 7.23 ~ 7.20 (m, 1H), 7.06 (s, 0.25H) , 6.93(s, 0.5H), 6.80(s, 0.25H), 5.50(s, 2H), 4.14~4.08(m, 4H), 2.65~2 .60 (m, 2H), 2.05 ~ 2.03 (m, 1H), 1.68 ~ 1.65 (m, 2H), 1.45 (s, 9H), 1.27 ~ 1.25 (m, 2H).; LRMS (ES) m/z 587.5 (M ⁺ + 1).

Synthesis of compound 73 4-yl)methyl)quinazolin-2,4(1H,3H)-dione

[Step 1] Synthesis of 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-fluoro-1-(piperidin-4- ylmethyl)quinazolin-2,4(1H,3H)-dione-2,2,2-trifluoroacetate

tert-Butyl-4-((3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-fluoro-2,4- dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)piperidine-1-carboxylate (0.166 g, 0.283 mmol) and trifluoroacetic acid (0.217 ml, 2.830 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, then the resulting product was used without further purification (0.160 g, 94.2%, brown oil).

[Step 2] Synthesis of Compound 73

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-fluoro-1-(piperidin-4-ylmethyl)quinazolin-2 ,4(1H,3H)-dione-2,2,2-trifluoroacetate (0.160 g, 0.266 mmol) obtained in step 1, formaldehyde (0.016 g, 0.533 mmol), sodium triacetoxyborohydride (0.113 g, 0.533 mmol) and N , N-diisopropylethylamine (0.046 ml, 0.266 mmol) was dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.080 g, 60.0%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 ~ 9.16 (m, 1H), 8.38 (dd, J=8.2, 2.1 Hz, 1H), 7.96 (dd, J=7.9, 3.0 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.48 ~ 7.45 (m, 1H), 7.38 ~ 7.37 (m, 1H), 7.07 (s, 0.25H), 6.94 (s, 0.5H), 6.81 (s, 0.25H), 5.51 (s, 2H), 3, 78 ~ 3.77 (m, 2H), 3.77 ~ 3.76 (m, 1H), 3.60 ~ 3.50 (m, 2H), 2.76 (s, 3H), 2.65 ~ 2.55(m, 2H), 2.13~2.06(m, 2H), 1.90~1.85(m, 2H).; LRMS (ES) m/z 501.5 (M ⁺ + 1).

Synthesis of compound 74, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(furan-2-yl)-4, 4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 74

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), furan-2-ylboronic acid (0.053 g, 0.471 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, 0.023 g, 0.031 mmol) and sodium carbonate (0.067 g, 0.629 mmol) were dissolved in 1,2-dimethoxyethane (6 ml)/water (3 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.003 g, 20.6%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (dd, J=2.2, 0.8 Hz, 1H), 8.36 (dd, J=8.2, 2.2 Hz, 1H) , 8.27 (dd, J=8.3, 0.3 Hz, 1H), 7.82 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.3, 1 .6 Hz, 1H), 7.59 (dd, J=1.8, 0.7 Hz, 1H), 7.47 (dd, J=8.2, 0.8 Hz, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.89 (dd, J=3.4, 0.7 Hz, 1H), 6.80 (s, 0.25H), 6.58~6.57(m, 1H), 5.45(s, 2H), 1.76(s, 2H).

Synthesis of compound 75, 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-3-(2-methoxyethyl)quinazolin-2,4(1H,3H)-dione

[Step 1] Synthesis of 2-amino-N-(2-methoxyethyl)benzamide

2H-Benzo[d][1,3]oxazine-2,4(1H)-dione (10.000 g, 61.301 mmol), 2-methoxyethane-1-amine (4.604 g, 61.301 mmol) and triethylamine (8.544 ml, 61.301 mmol) was dissolved in ethanol (50 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (9.800 g, 82.3%) as a colorless oil.

[Step 2] Synthesis of 3-(2-methoxyethyl)quinazoline-2,4(1H,3H)-dione

2-Amino-N-(2-methoxyethyl)benzamide (1.500 g, 7.723 mmol) obtained in step 1 and 1,1'-carbonyldiimidazole (CDI, 1.252 g, 7.723 mmol) were dissolved in tetrahydrofuran (20 ml) at room temperature. temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (1.300 g, 76.4%) as a white solid.

[Step 3] Synthesis of Compound 75

3-(2-Methoxyethyl)quinazoline-2,4(1H,3H)-dione (0.100 g, 0.454 mmol) obtained in step 2 was dissolved in N,N-dimethylformamide (10 ml) at 0°C, then the hydride sodium (60.00%, 0.027 g, 0.681 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-(4-(Bromomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.131 g, 0.454 mmol) was added to the reaction mixture, and further stirred at room temperature for 2 h. water and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.050 g, 25.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (dd, J=7.9, 1.4 Hz, 1H), 8.11 (dd, J=6.7, 1.8 Hz, 2H) , 7.59 ~ 7.55 (m, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.29 ~ 7.25 (m, 1H), 7.06 ~ 7.04 (m, 1H), 7.06 (s, 0.25H), 6.92 (s, 0.5H), 6.79 (s, 0.25H), 5.48 (s, 2H), 4, 45 (t, J=5.7 Hz, 2H), 3.77 (t, J=5.7 Hz, 2H), 3.42 (s, 3H).; LRMS (ES) m/z 429.3 (M ⁺ + 1).

Synthesis of compound 76 (1H,3H)-dione

[Step 1] Synthesis of methyl 6-((3-(2-methoxyethyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)nicotinate

3-(2-Methoxyethyl)quinazoline-2,4(1H,3H)-dione (0.300 g, 1.362 mmol) was dissolved in N,N-dimethylformamide (10 ml) at 0°C, then sodium hydride (60.00% , 0.109 g, 2.724 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. Methyl 6-(bromomethyl)nicotinate (0.313 g, 1.362 mmol) was added to the reaction mixture and further stirred at room temperature for 2 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.300 g, 59.6%) as a colorless oil.

[Step 2] Synthesis of 6-((3-(2-methoxyethyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)nicotinohydrazide

Methyl 6-((3-(2-methoxyethyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)nicotinate (0.090 g, 0.244 mmol) from Step 1, and hydrazine monohydrate (0.237 ml, 4.873 mmol) was dissolved in ethanol (20 ml) at 80°C, then the resulting solution was stirred at the same temperature for 12 h, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then the resulting product was used without further purification (0.090 g, 100.0%, white solid).

[Step 3] Synthesis of Compound 76

6-((3-(2-Methoxyethyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)nicotinohydrazide (0.090 g, 0.244 mmol) obtained in step 2, 2,2 -difluoroacetic anhydride (0.091 ml, 0.731 mmol) and imidazole (0.050 g, 0.731 mmol) were dissolved in dichloromethane (10 ml) at 45° C., then the resulting solution was stirred at the same temperature for 12 h and then the reaction was terminated by lowering the temperature up to room temperature. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.030 g, 28.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 ~ 9.30 (m, 1H), 8.36 (dd, J=8.2, 2.2 Hz, 1H), 8.26 (dd, J=7.9, 1.6Hz, 1H), 7.62 ~ 7.58 (m, 1H), 7.49 (d, J=8.2Hz, 1H), 7.28 ~ 7.20 (m, 2H), 7.07 (s, 0.25H), 6.94 (s, 0.5H), 6.81 (s, 0.25H), 5.58 (s, 2H), 4, 43 (t, J=5.7 Hz, 2H), 3.76 (t, J=5.7 Hz, 2H), 3.40 (s, 3H); LRMS (ES) m/z 430.4 (M ⁺ + 1).

Synthesis of compound 77 -dion

[Step 1] Synthesis of 2-amino-N-phenethylbenzamide

2H-Benzo[d][1,3]oxazine-2,4(1H)-dione (3.000 g, 18.390 mmol), 2-phenylethane-1-amine (2.674 g, 22.068 mmol) and N,N-dimethylpyridine- 4-amine (DMAP, 0.225 g, 1.839 mmol) was dissolved in N,N-dimethylformamide (30 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (4.000 g, 90.5%) as a brown oil.

[Step 2] Synthesis of methyl-(2-(phenethylcarbamoyl)phenyl)carbamate

2-Amino-N-phenethylbenzamide (4.000 g, 16.645 mmol) obtained in step 1, methyl chloroformate (1.887 g, 19.974 mmol) and sodium hydroxide (1.00 M solution in H ₂ O, 33.290 ml, 33.290 mmol) were dissolved in 1,4-dioxane (30 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. an aqueous solution of hydrochloric acid and carried out extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.790 g, 15.9%) as a colorless oil.

[Step 3] Synthesis of 3-phenethylquinazoline-2,4(1H,3H)-dione

Methyl-(2-(phenethylcarbamoyl)phenyl)carbamate (0.790 g, 2.648 mmol) obtained in step 2 and potassium hydroxide (1.486 g, 26.480 mmol) were dissolved in ethanol (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.500 g, 70.9%) as a white solid.

[Step 4] Synthesis of Compound 77

3-Phenethylquinazolin-2,4(1H,3H)-dione (0.150 g, 0.563 mmol) obtained in step 3 was dissolved in N,N-dimethylformamide (10 ml) at 0°C, then sodium hydride (60.00 %, 0.034 g, 0.845 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-(6-(Bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.196 g, 0.676 mmol) was added to the reaction mixture and further stirred at room temperature for 2 h. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.130 g, 48.5%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (dd, J=2.2, 0.8 Hz, 1H), 8.35 (dd, J=5.9, 2.4 Hz, 1H) , 8.29 (dd, J=7.9, 1.3Hz, 1H), 7.62 ~ 7.58 (m, 1H), 7.37 ~ 7.26 (m, 8H), 7.08 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 5.56 (s, 2H), 4.44 ~ 4.40 (m, 2H ), 3.10 ~ 3.06 (m, 2H).; LRMS (ES) m/z 475.9 (M ⁺ + 1).

Synthesis of compound 78 -dion

[Step 1] Synthesis of Compound 78

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)quinazolin-2,4(1H,3H)-dione (0.060 g, 0.162 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.052 g, 0.178 mmol) and potassium carbonate (0.045 g, 0.323 mmol) were dissolved in N,N-dimethylformamide (10 ml), then the resulting solution was stirred at 50° C. for 18 hours and then further stirred at room temperature for 18 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 80%) and concentrated to give the title compound (0.050 g, 53.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J=2.2 Hz, 1H), 9.23 (d, J=2.1 Hz, 1H), 8.39 ~ 8.36 (m, 2H), 8.28 (dd, J=8.0, 1.2Hz, 1H), 7.63 ~ 7.61 (m, 1H), 7.56 ~ 7.51 (m, 2H ), 7.31~7.28(m, 2H), 7.07(s, 0.5H), 6.95~6.94(m, 1H), 6.82~6.81(m, 0 .5H), 5.61 ~ 5.60 (m, 4H), 2.18 (s, 6H).

Synthesis of compound 79, tert-butyl 1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[Step 1] Synthesis of Compound 79

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.500 g, 1.048 mmol), tert-butyl-4,7-diazaspiro[2.5]octane-4-carboxylate (0.334 g, 1.571 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 0.096 g, 0.105 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.061 g, 0.105 mmol) and cesium carbonate (1.024 g, 3.143 mmol) were dissolved in toluene (5 ml) at 80°C , then the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.230 g, 36.1%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.16 (d, J=1.8 Hz, 1H), 8.29 (dd, J=8.2, 2.2 Hz, 1H), 8.07 (d, J=8.9 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.05 (s, 0.25H), 6.92 (s, 0.5H) , 6.86 (dd, J=9.0, 2.3 Hz, 1H), 6.79 (s, 0.25H), 6.76 (d, J=2.3 Hz, 1H), 5, 37 (s, 2H), 3.73 (t, J=5.2 Hz, 2H), 3.38 (t, J=5.2 Hz, 2H), 3.15 (s, 2H), 1, 65(s, 6H), 1.47(s, 9H), 1.08~1.07(m, 2H), 0.87~0.86(m, 2H).

Synthesis of compound 80, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4-methyl -4,7-diazaspiro[2.5]octan-7-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4, 7-diazaspiro[2.5]octan-7-yl)isoquinolin-1,3(2H,4H)-dione-2,2,2-trifluoroacetate

Tert-butyl 7-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-1,3- dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (0.230 g, 0.378 mmol) and trifluoroacetic acid (0.289 ml, 3.779 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, then the resulting product was used without further purification (0.220 g, 93.5%, brown oil) .

[Step 2] Synthesis of Compound 80

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4,7-diazaspiro[2.5 ]octan-7-yl)isoquinolin-1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.100 g, 0.161 mmol) from step 1, N,N-diisopropylethylamine (0.028 ml, 0.161 mmol), formaldehyde (0.010 g, 0.321 mmol) and sodium triacetoxyborohydride (0.068 g, 0.321 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.050 g, 59.6%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=2.2 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 8.09 (d, J=8.9 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.05 (s, 0.25H), 6.96 (s, 0.5H) , 6.88 (dd, J=9.2, 2.2Hz, 1H), 6.80 ~ 6.78 (m, 1.25H), 5.41 (s, 2H), 3.47 ~ 3 .39(m, 2H), 3.17(s, 2H), 3.15~3.12(m, 2H), 2.45(s, 3H), 1.69(s, 6H), 0, 87 (t, J=5.7 Hz, 2H), 0.61 (t, J=5.8 Hz, 2H).

Synthesis of compound 81 )pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 81

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4,7-diazaspiro[2.5 ]octan-7-yl)isoquinolin-1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.100 g, 0.161 mmol), acetyl chloride (0.023 ml, 0.321 mmol), and N,N-diisopropylethylamine (0.084 ml, 0.482 mmol) was dissolved in dichloromethane (5 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 100%) and concentrated to give the title compound (0.060 g, 67.8%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 ~ 9.17 (m, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.41 (d, J=8.1Hz, 1H), 7.05(s, 0.25H), 6.92(s, 0.5H), 6.86(dd, J=9.0, 2.4Hz, 1H ), 6.79 (s, 0.25H), 6.76 (d, J=2.4Hz, 1H), 5.39 (s, 2H), 4.00 ~ 3.80 (m, 2H) , 3.47 ~ 3.43 (m, 2H), 3.20 (s, 2H), 2.23 (s, 3H), 1.66 (s, 6H), 1.14 ~ 1.08 (m , 4H).

Synthesis of compound 82, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-8-(furan-2-yl)-4, 4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of 2-bromo-6-(carboxymethyl)benzoic acid

Diisopropylamine (27.691 ml, 186.003 mmol) was dissolved in tetrahydrofuran (300 ml) at -78°C, then n-butyllithium (2.50 M solution, 74.401 ml, 186.003 mmol) was added to the resulting solution and stirred at the same temperature for 1 h and then stirred at room temperature for 10 min. 2-Bromo-6-methylbenzoic acid (10.000 g, 46.501 mmol) and dimethyl carbonate (7.830 ml, 93.002 mmol) were added to the reaction mixture at -78°C and further stirred at room temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with ethyl acetate. 1 N sodium hydroxide was added to the aqueous solution layer. an aqueous solution of hydrochloric acid (10 ml) and carried out extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous magnesium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (7.700 g, 63.9%, yellow oil).

[Step 2] Synthesis of methyl 2-bromo-6-(2-methoxy-2-oxoethyl)benzoate

2-Bromo-6-(carboxymethyl)benzoic acid (7.700 g, 29.723 mmol) obtained in step 1, dimethyl sulfate (11.247 g, 89.169 mmol) and potassium carbonate (12.324 g, 89.169 mmol) were dissolved in 1,4-dioxane ( 150 ml) at room temperature, then the resulting solution was stirred at 80°C for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then 1 N sodium hydroxide was poured into the resulting concentrate. an aqueous solution of hydrochloric acid, and then extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous magnesium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (8.500 g, 99.6%, yellow oil).

[Step 3] Synthesis of methyl 2-bromo-6-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate

Methyl 2-bromo-6-(2-methoxy-2-oxoethyl)benzoate (8.500 g, 29.605 mmol) obtained in step 2 and sodium hydride (60.00%, 0.059 g, 1.480 mmol) were dissolved in N, N-dimethylformamide (200 ml) at 0°C, then iodomethane (2.212 ml, 35.526 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate and then extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous magnesium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate/hexane=0 to 10%) and concentrated to give the title compound (3.600 g, 38.6%) as a white solid.

[Step 4] Synthesis of 2-bromo-6-(2-carboxypropan-2-yl)benzoic acid

Methyl 2-bromo-6-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate (3.600 g, 11.423 mmol) obtained in step 3 and potassium hydroxide (6.409 g, 114.228 mmol) were dissolved in a mixture of methanol (15 ml)/water (30 ml) at room temperature, then the resulting solution was refluxed for 18 h and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, and 1 N sodium chloride was added to the resulting concentrate. an aqueous solution of hydrochloric acid and stirred and the precipitated solid was filtered off, then washed with water and then dried to give the title compound (3.250 g, 90.3%) as a light yellow solid.

[Step 5] Synthesis of 8-bromo-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

2-Bromo-6-(2-carboxypropan-2-yl)benzoic acid (3.250 g, 11.320 mmol) obtained in step 4 and urea (0.680 g, 11.320 mmol) were mixed in 1,2-dichlorobenzene (20 ml) at room temperature, then the resulting mixture was irradiated with microwave radiation, then heated at 150°C for 45 min, and then the reaction was completed by lowering the temperature to room temperature. The precipitated solid was filtered off, then washed with hexane and then dried, then the resulting filtrate was recrystallized from hexane at -10°C and filtered to give a solid. The solid was then washed with hexane and dried to give the title compound (2.670 g, 88.0%) as a light yellow solid.

[Step 6] Synthesis of 8-bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1 ,3(2H,4H)-dione

8-Bromo-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (2.000 g, 7.460 mmol) obtained in step 5, 2-(6-(bromomethyl)pyridin-3-yl)-5- (difluoromethyl)-1,3,4-oxadiazole (2.380 g, 8.206 mmol), potassium carbonate (3.093 g, 22.379 mmol) and potassium iodide (0.124 g, 0.746 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature, then the resulting solution was stirred at 80°C for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then a saturated sodium hydrogen carbonate aqueous solution was poured into the resulting concentrate, and then extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous magnesium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=10 to 40%) and concentrated to give the title compound (1.640 g, 46.1%) as a yellow solid.

[Step 7] Synthesis of Compound 82

8-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.200 g, 0.419 mmol) obtained in step 6, furan-2-ylboronic acid (0.056 g, 0.503 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II )dichloride (Pd(dtbpf)Cl ₂ , 0.014 g, 0.021 mmol) and cesium carbonate (0.410 g, 1.257 mmol) were mixed in 1,4-dioxane (3 mL)/water (1 mL) at room temperature, then the resulting the mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=10 to 30%) and concentrated to give the title compound (0.046 g, 23.6%) as a light yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.6 Hz, 1H), 8.32 (dd, J=8.2, 2.0 Hz, 1H), 7.70 -7.66 (m, 1H), 7.60 (dd, J=8.0, 1.2 Hz, 1H), 7.53-7.50 (m, 2H), 7.42 (d, J =8.2 Hz, 1H), 7.06-6.80 (m, 1H), 6.52 (d, J=1.2 Hz, 2H), 5.40 (s, 2H), 1.76 (s, 6H).; LRMS (ES) m/z 465.2 (M ⁺ + 1).

Synthesis of compound 83, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-8-morpholinoisoquinoline-1, 3(2H,4H)-dione

[Step 1] Synthesis of Compound 83

8-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.068 g, 0.142 mmol) obtained in step 6, compound 82, tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ , 0.013 g, 0.014 mmol), 4,5-bis(diphenylphosphino)-9 ,9-dimethylxanthene (Xantphos, 0.008 g, 0.014 mmol) and cesium carbonate (0.139 g, 0.427 mmol) were dissolved in 1,4-dioxane (2 ml) at room temperature, then the resulting solution was stirred at 80°C for 18 h and then the reaction was terminated by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0 to 40%) and concentrated to give the title compound (0.005 g, 7.3%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (d, J=1.5 Hz, 1H), 8.35 (dd, J=8.2, 2.2 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.13 (d , J=8.0 Hz, 1H), 7.07-6.81 (m, 1H), 5.44 (s, 2H), 3.97-3.95 (m, 4H), 3.24- 3.23 (m, 4H), 1.71 (s, 6H); LRMS (ES) m/z 484.3 (M ⁺ + 1).

Synthesis of compound 84 -yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 84

8-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol) obtained in step 6, compound 82, pyridin-4-ylboronic acid (0.046 g, 0.377 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.010 g, 0.016 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were mixed in 1,4-dioxane (3 ml)/water (1 ml) at room temperature , then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=10 to 60%) and concentrated to give the title compound (0.042 g, 28.1%) as a gray solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.14 (d, J=1.5 Hz, 1H), 8.60-8.59 (m, 2H), 8.29 (dd, J=8, 2, 2.2 Hz, 1H), 7.72-7.64 (m, 2H), 7.39 (d, J=8.7 Hz, 1H), 7.23-7.21 (m, 3H ), 7.05-6.80 (m, 1H), 5.30 (s, 2H), 1.76 (s, 6H).; LRMS (ES) m/z 476.3 (M ⁺ + 1).

Synthesis of compound 85 -yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 85

8-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol) obtained in step 6, compound 82, pyridin-3-ylboronic acid (0.046 g, 0.377 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.010 g, 0.016 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were mixed in 1,4-dioxane (3 ml)/water (1 ml) at room temperature , then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate/hexane=10 to 60%) and concentrated to give the title compound (0.047 g, 31.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.16 (dd, J=2.1, 0.6 Hz, 1H), 8.59 (dd, J=4.9, 1.4 Hz, 1H) , 8.53 (d, J=1.7 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.74-7.65 (m, 3H), 7.40-7.33 (m, 3H), 7.30-7.27 (m, 1H), 7.06-6.80 (m, 1H), 5.31 (s, 2H), 1, 78(s, 6H).; LRMS (ES) m/z 476.2 (M ⁺ + 1).

Synthesis of compound 86 1H,3H)-dione

[Step 1] Synthesis of 2-amino-5-bromo-N-(tert-butyl)benzamide

6-Bromo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (8.000 g, 33.054 mmol), 2-methylpropan-2-amine (2.901 g, 39.665 mmol) and N, N-dimethylpyridin-4-amine (DMAP, 0.404 g, 3.305 mmol) was dissolved in N,N-dimethylformamide (30 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 h. Water ( 20 ml) and stirred, then the precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (5.500 g, 61.4%) as a white solid.

[Step 2] Synthesis of methyl-(4-bromo-2-(tert-butylcarbamoyl)phenyl)carbamate

2-Amino-5-bromo-N-(tert-butyl)benzamide (4.300 g, 15.858 mmol) obtained in step 1, methyl chloroformate (1.498 g, 15.858 mmol) and N,N-diisopropylethylamine (4.143 ml, 23.787 mmol) was dissolved in dichloromethane (50 ml) at room temperature, then the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (2.280 g, 43.7%) as a yellow solid.

[Step 3] Synthesis of 6-bromo-3-(tert-butyl)quinazoline-2,4(1H,3H)-dione

Methyl-(4-bromo-2-(tert-butylcarbamoyl)phenyl)carbamate (2.280 g, 6.926 mmol) obtained in step 2 and potassium hydroxide (3.886 g, 69.261 mmol) were dissolved in ethanol (20 ml) at 80° C, then the resulting solution was stirred at the same temperature for 12 h and then the reaction was completed by lowering the temperature to room temperature Hydrochloric acid (20 ml) was added to the reaction mixture and stirred, then the precipitated solid was filtered off, then washed with hexane and then dried and obtained the title compound (1.830 g, 88.9%) as a white solid.

[Step 4] Synthesis of 6-bromo-3-(tert-butyl)-1-methylquinazoline-2,4(1H,3H)-dione

6-Bromo-3-(tert-butyl)quinazoline-2,4(1H,3H)-dione (1.830 g, 6.159 mmol) obtained in step 3 was dissolved in N,N-dimethylformamide (20 ml) at 0° C, then sodium hydride (60.00%, 0.369 g, 9.238 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. Iodomethane (0.575 ml, 9.238 mmol) was added to the reaction mixture, and further stirred at room temperature for 18 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (1.440 g, 75.1%) as a colorless oil.

[Step 5] Synthesis of 6-bromo-1-methylquinazoline-2,4(1H,3H)-dione

6-Bromo-3-(tert-butyl)-1-methylquinazolin-2,4(1H,3H)-dione (1.300 g, 4.178 mmol) from step 4 and hydrochloric acid (6.00 M solution in H2O , 17.407 ml, 104.441 mmol) was dissolved in 1,4-dioxane (25 ml) at 100°C, then the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (0.980 g, 92.0%) as a white solid.

[Step 6] Synthesis of Compound 86

6-Bromo-1-methylquinazolin-2,4(1H,3H)-dione (0.980 g, 3.842 mmol) from step 5, 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl )-1,3,4-oxadiazole (1.226 g, 4.226 mmol) and potassium carbonate (1.062 g, 7.684 mmol) were dissolved in N,N-dimethylformamide (20 ml) at 45°C, then the resulting solution was stirred at the same temperature for 18 h and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (1.600 g, 89.7%) as a white solid.

LRMS (ES) m/z 465.4 (M ⁺ + 1).

Synthesis of compound 87, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(furan-2-yl)-1- methylquinazoline-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 87

6-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.100 g, 0.215 mmol), furan-2-ylboronic acid (0.036 g, 0.323 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II, 0.014 g, 0.022 mmol) and cesium carbonate ( 0.105 g, 0.323 mmol) was mixed in a mixture of 1,4-dioxane (9 ml)/water (3 ml), then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.020 g, 20.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (d, J=1.6 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.37 (dd, J =8.2, 2.2 Hz, 1H), 8.05 (dd, J=8.7, 2.2 Hz, 1H), 7.53 ~ 7.51 (m, 2H), 7.31 ( d, J=8.8 Hz, 1H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 6.75(dd , J=3.4, 0.7 Hz, 1H), 6.53 (dd, J=3.4, 1.8 Hz, 1H), 5.55 (s, 2H), 3.68 (s, 3H).; LRMS (ES) m/z 452.2 (M ⁺ + 1).

Synthesis of compound 88, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(furan-3-yl)-1- methylquinazoline-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 88

6-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.100 g, 0.215 mmol), furan-3-ylboronic acid (0.036 g, 0.323 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II, 0.014 g, 0.022 mmol) and cesium carbonate ( 0.105 g, 0.323 mmol) was mixed in a mixture of 1,4-dioxane (9 ml)/water (3 ml), then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.030 g, 30.9%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.23 ~ 9.22 (m, 1H), 8.37 ~ 8.34 (m, 2H), 7.86 ~ 7.81 (m, 2H), 7.30~7.28(m, 1H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 6.77( dd, J=1.9, 0.9 Hz, 1H), 5.55 (s, 2H), 3.67 (s, 3H).

Synthesis of compound 89 2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 89

6-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.100 g, 0.215 mmol), (2-fluorophenyl)boronic acid (0.045 g, 0.323 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II, 0.014 g, 0.022 mmol) and cesium carbonate (0.105 g, 0.323 mmol) was mixed in a mixture of 1,4-dioxane (9 ml)/water (3 ml), then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min and then the reaction was terminated by lowering the temperature up to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.020 g, 19.4%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (d, J=1.8 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.37 (dd, J =8.3, 2.2 Hz, 1H), 7.98 (dt, J=8.6, 2.0 Hz, 1H), 7.54 ~ 7.49 (m, 2H), 7.41 ~ 7.35(m, 2H), 7.28~7.26(m, 1H), 7.24~7.17(m, 1H), 7.06(s, 1H), 6.93(s, 1H), 6.80 (s, 1H), 5.56 (s, 2H), 3.70 (s, 3H).; LRMS (ES) m/z 480.2 (M ⁺ + 1).

Synthesis of compound 90 2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 90

6-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.100 g, 0.215 mmol), (3-fluorophenyl)boronic acid (0.045 g, 0.323 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II, 0.014 g, 0.022 mmol) and cesium carbonate (0.105 g, 0.323 mmol) was mixed in a mixture of 1,4-dioxane (9 ml)/water (3 ml), then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min and then the reaction was terminated by lowering the temperature up to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.030 g, 29.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (dd, J=2.2, 0.8 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.37 (dd, J=8.2, 2.2 Hz, 1H), 7.97 (dd, J=8.7, 2.3 Hz, 1H), 7.54 (dd, J=8.2, 0 .7 Hz, 1H), 7.46 ~ 7.44 (m, 1H), 7.38 ~ 7.33 (m, 1H), 7.12 ~ 7.07 (m, 1H), 7.06 ( s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.57(s, 2H), 3.70(s, 3H).

Synthesis of compound 91, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methyl-6-(pyridin-3-yl )quinazoline-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 91

6-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.100 g, 0.215 mmol), pyridin-3-ylboronic acid (0.040 g, 0.323 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II, 0.014 g, 0.022 mmol) and cesium carbonate ( 0.105 g, 0.323 mmol) was mixed in a mixture of 1,4-dioxane (9 ml)/water (3 ml), then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.025 g, 25.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (d, J=2.2 Hz, 1H), 8.93 (d, J=2.4 Hz, 1H), 8.66 (dd, J =4.6, 1.3 Hz, 1H), 8.51 (d, J=2.2 Hz, 1H), 8.38 (dd, J=8.4, 2.4 Hz, 1H), 7 .55 (d, J=8.2Hz, 1H), 7.46 ~ 7.40 (m, 2H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.57 (s, 2H), 3.71 (s, 3H).; LRMS (ES) m/z 463.2 (M ⁺ + 1).

Synthesis of compound 92, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methyl-6-(pyridin-4-yl )quinazoline-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 92

6-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.100 g, 0.215 mmol), pyridin-4-ylboronic acid (0.040 g, 0.323 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II, 0.014 g, 0.022 mmol) and cesium carbonate ( 0.105 g, 0.323 mmol) was mixed in a mixture of 1,4-dioxane (9 ml)/water (3 ml), then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.030 g, 30.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.23 (d, J=1.6 Hz, 1H), 8.72 ~ 8.71 (m, 2H), 8.58 (d, J=2, 2 Hz, 1H), 8.37 (dd, J=8.2, 2.2 Hz, 1H), 8.04 (dd, J=8.7, 2.3 Hz, 1H), 7.59 ~ 7.53 (m, 3H), 7.42 (d, J=8.7 Hz, 1H), 7.06 (s, 1H), 6.93 (s, 1H), 6.80 (s, 1H ), 5.56 (s, 2H), 3.71 (s, 2H).

Synthesis of compound 93, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-8-(5-methylfuran -2-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 93

8-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol) obtained in step 6, compound 82, 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane ( 0.078 g, 0.377 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.010 g, 0.016 mmol) and cesium carbonate (0.307 g, 0.943 mmol) was mixed in a mixture of 1,4-dioxane (3 ml)/water (1 ml) at room temperature, then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.020 g, 13.3%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (dd, J=2.1, 0.7 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H) , 7.67-7.63 (m, 1H), 7.56-7.51 (m, 2H), 7.43 (d, J=8.2 Hz, 1H), 7.06-6.80 (m, 1H), 6.44 (d, J=3.1 Hz, 1H), 6.09 (dd, J=2.1, 1.0 Hz, 1H), 5.40 (s, 2H) , 2.31 (s, 3H), 1.74 (s, 6H); LRMS (ES) m/z 479.2 (M ⁺ + 1).

Synthesis of compound 94 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 94

8-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol) obtained in step 6, compound 82, (6-methoxypyridin-3-yl)boronic acid (0.058 g, 0.377 mmol), [1,1'-bis(di-tert -butylphosphino)ferrocene]palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.010 g, 0.016 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were mixed in 1,4-dioxane (3 ml)/water (1 ml) at room temperature, then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.016 g, 10.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (d, J=1.6 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.71-7.67 (m, 1H), 7.61 (dd, J=8.0, 1.3 Hz, 1H), 7.55- 7.52 (m, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.29-7.27 (m, 1H), 7.06-6.80 (m, 1H) , 6.75 (d, J=8.5 Hz, 1H), 5.33 (s, 2H), 3.98 (s, 3H), 1.78 (s, 6H); LRMS (ES) m/z 506.2 (M ⁺ + 1).

Synthesis of compound 95, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-8-(furan-3-yl)-4, 4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 95

8-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), furan-3-ylboronic acid (0.042 g, 0.377 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd( dtbpf)Cl ₂ , 0.010 g, 0.016 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were mixed in a mixture of 1,4-dioxane (3 ml)/water (1 ml) at room temperature, then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the product, then the resulting product was repurified by chromatography (SiO ₂ plate, 20×20×1 mm; ethyl acetate/hexane aqueous solution=25%) and concentrated to give the title compound (0.046 g, 31.5%) as a light brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.5 Hz, 1H), 8.33 (dd, J=8.2, 2.2 Hz, 1H), 7.64 (t, J=7.7Hz, 1H), 7.56 (dd, J=8.0, 1.3Hz, 1H), 7.52 ~ 7.52 (m, 1H), 7.45 ~ 7.42 (m, 2H), 7.36 (dd, J=7.5, 1.3Hz, 1H), 7.06 ~ 6.80 (m, 1H), 6.48 ~ 6.47 ( m, 1H), 5.32 (s, 2H), 1.76 (s, 6H).; LRMS (ES) m/z 465.0 (M ⁺ + 1).

Synthesis of compound 96, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-8-(3,5-dimethylisooxazol-4-yl )-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 96

8-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.150 g, 0.314 mmol), (3,5-dimethylisooxazol-4-yl)boronic acid (0.053 g, 0.377 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium (II) dichloride (Pd(dtbpf)Cl ₂ , 0.010 g, 0.016 mmol) and cesium carbonate (0.307 g, 0.943 mmol) were mixed in 1,4-dioxane (3 ml)/water (1 ml) at room temperature, then, the resulting mixture was irradiated with microwave radiation, then heated at 100° C. for 20 minutes, and then the reaction was terminated by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.092 g, 59.3%) as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.13 (d, J=1.6 Hz, 1H), 8.32 (dd, J=8.2, 2.0 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.20 (d , J=7.0 Hz, 1H), 7.06 ~ 6.80 (m, 1H), 5.34 (s, 2H), 2.24 (s, 3H), 1.99 (s, 3H) , 1.77 (d, J=5.4 Hz, 6H); LRMS (ES) m/z 494.2 (M ⁺ + 1).

Synthesis of compound 97 1H,3H)-dione

[Step 1] Synthesis of 2-amino-4-bromo-N-(tert-butyl)benzamide

7-Bromo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (10.000 g, 41.317 mmol), 2-methylpropan-2-amine (3.626 g, 49.581 mmol) and N, N-dimethylpyridin-4-amine (DMAP, 0.505 g, 4.132 mmol) was dissolved in N,N-dimethylformamide (30 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water ( 20 ml) and stirred, then the precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (7.700 g, 68.7%) as a white solid.

[Step 2] Synthesis of methyl-(5-bromo-2-(tert-butylcarbamoyl)phenyl)carbamate

2-Amino-4-bromo-N-(tert-butyl)benzamide (7.700 g, 28.397 mmol) obtained in step 1, methyl chloroformate (2.683 g, 28.397 mmol) and N,N-diisopropylethylamine (7.419 ml, 42.595 mmol) was dissolved in dichloromethane (30 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (3.720 g, 39.8%) as a brown solid.

[Step 3] Synthesis of 7-bromo-3-(tert-butyl)quinazoline-2,4(1H,3H)-dione

Methyl-(5-bromo-2-(tert-butylcarbamoyl)phenyl)carbamate (3.720 g, 11.300 mmol) obtained in step 2 and potassium hydroxide (6.340 g, 113.005 mmol) were dissolved in ethanol (30 ml) at 80° C, then the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, and then extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (2.000 g, 59.6%, brown oil).

[Step 4] Synthesis of 7-bromo-3-(tert-butyl)-1-methylquinazoline-2,4(1H,3H)-dione

7-Bromo-3-(tert-butyl)quinazoline-2,4(1H,3H)-dione (2.000 g, 6.731 mmol) obtained in step 3 was dissolved in N,N-dimethylformamide (30 ml) at 0° C, then iodomethane (0.629 ml, 10.096 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. Sodium hydride (60.00%, 0.404 g, 10.096 mmol) was added to the reaction mixture, and further stirred at room temperature for 18 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (2.000 g, 95.5%) as a white solid.

[Step 5] Synthesis of 7-bromo-1-methylquinazoline-2,4(1H,3H)-dione

7-Bromo-3-(tert-butyl)-1-methylquinazolin-2,4(1H,3H)-dione (2.000 g, 6.427 mmol) obtained in step 4 and hydrochloric acid (6.00 M solution in H ₂ O, 16.068 ml, 96.407 mmol) was dissolved in 1,4-dioxane (20 ml) at 100°C, then the resulting solution was stirred at the same temperature for 18 h, and then the reaction was completed by lowering the temperature to room temperature. The precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (1.500 g, 91.5%) as a brown solid.

[Step 6] Synthesis of Compound 97

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol) obtained in step 5, pyridin-4-ylboronic acid (0.039 g, 0.314 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II ) dichloride (Pd(dtbpf)Cl ₂ , 0.014 g, 0.021 mmol) and cesium carbonate (0.102 g, 0.314 mmol) were mixed in a mixture of 1,4-dioxane (6 ml)/water (2 ml), then the resulting mixture was irradiated with a microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.040 g, 40.2%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.22 (d, J= 1.5 Hz, 1H), 8.36 (dd, J =8.2, 2.2 Hz, 1H), 8.12 (d, J= 8.6 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.45 ~ 7.42 (m, 2H), 7.06 (s, 0, 25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.51(s, 2H), 3.63(s, 3H).

Synthesis of compound 98, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(furan-2-yl)-1- methylquinazoline-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 98

7-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.100 g, 0.215 mmol) obtained in step 6, compound 97, furan-2-ylboronic acid (0.036 g, 0.323 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium( II) dichloride (Pd(dtbpf)Cl ₂ , 0.014 g, 0.022 mmol) and cesium carbonate (0.105 g, 0.323 mmol) were mixed in a mixture of 1,4-dioxane (10 ml)/water (3 ml), then the resulting mixture was irradiated microwave radiation, then heated at 100°C for 20 min and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.020 g, 20.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 (d, J =1.7 Hz, 1H), 8.36 (dd, J =8.2, 2.2 Hz, 1H), 8.25 (d, J =8.6 Hz, 1H), 7.60 ~ 7.50 (m, 4H), 7.06 (s, 0.25H), 6.94 ~ 6.92 (m, 1H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 6.59 (dd, J=3.3, 1.7 Hz, 1H), 5.54 (s, 2H) , 3.72 (s, 3H); LRMS (ES) m/z 452.4 (M ⁺ + 1).

Synthesis of compound 99 2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 99

7-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.100 g, 0.215 mmol) obtained in step 6, compound 97, (2-fluorophenyl)boronic acid (0.045 g, 0.323 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium (II) dichloride (Pd(dtbpf)Cl ₂ , 0.014 g, 0.022 mmol) and cesium carbonate (0.105 g, 0.323 mmol) were mixed in 1,4-dioxane (10 ml)/water (3 ml), then the resulting mixture irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.023 g, 22.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 ~ 9.23 (m, 1H), 8.37 ~ 8.32 (m, 2H), 7.54 ~ 7.42 (m, 5H), 7.32 ~ 7.21(m, 2H), 7.07(s, 0.25H), 6.94(s, 0.5H), 6.81(s, 0.25H), 5.56( s, 2H), 3.69 (s, 3H).; LRMS (ES) m/z 480.4 (M ⁺ + 1).

Synthesis of compound 100, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methyl-7-(pyridin-3-yl )quinazoline-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 100

7-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.100 g, 0.215 mmol) obtained in step 6, compound 97, pyridin-3-ylboronic acid (0.040 g, 0.323 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium( II) dichloride (Pd(dtbpf)Cl ₂ , 0.014 g, 0.022 mmol) and cesium carbonate (0.105 g, 0.323 mmol) were mixed in a mixture of 1,4-dioxane (10 ml)/water (3 ml), then the resulting mixture was irradiated microwave radiation, then heated at 100°C for 20 min and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.026 g, 26.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) 9.22 (s, 1H), 8.93 (s, 1H), 8.73 (d, J =4.3 Hz, 1H), 8.38 ~ 8, 35(m, 2H), 7.98~7.96(m, 1H), 7.62~7.42(m, 4H), 7.07(s, 1H), 6.94(s, 1H) , 6.81 (s, 1H), 5.56 (s, 2H), 3.73 (s, 3H).; LRMS (ES) m/z 463.4 (M ⁺ + 1).

Synthesis of compound 101, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methyl-7-(pyridin-4-yl )quinazoline-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 101

7-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.100 g, 0.215 mmol) obtained in step 6, compound 97, pyridin-4-ylboronic acid (0.040 g, 0.323 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium( II) dichloride (Pd(dtbpf)Cl ₂ , 0.014 g, 0.022 mmol) and cesium carbonate (0.105 g, 0.323 mmol) were mixed in a mixture of 1,4-dioxane (10 ml)/water (3 ml), then the resulting mixture was irradiated microwave radiation, then heated at 100°C for 20 min and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.030 g, 30.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 ~ 9.20 (m, 1H), 8.77 (dd, J =4.4, 1.6 Hz, 1H), 8.38 ~ 8, 35(m, 1H), 7.58~7.52(m, 4H), 7.46(d, J =1.4Hz, 1H), 7.07(s, 0.25H), 6.94 (s, 0.5H), 6.81 (s, 0.25H), 5.55 (s, 2H), 3.73 (s, 3H).; LRMS (ES) m/z 463.4 (M ⁺ + 1).

Synthesis of compound 102, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(furan-3-yl)-4, 4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 102

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol) obtained in step 6, compound 97, furan-3-ylboronic acid (0.035 g, 0.314 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.014 g, 0.021 mmol) and cesium carbonate (0.102 g, 0.314 mmol) were mixed in 1,4-dioxane (30 mL)/water (10 mL), then the resulting the mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.034 g, 34.9%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J =2.2, 0.8 Hz, 1H), 8.35 (dd, J =8.2, 2.2 Hz, 1H) , 8.26(dd, J =7.6, 1.2Hz, 1H), 7.89(dd, J =1.5, 0.9Hz, 1H), 7.59~7.56(m , 3H), 7.47 (dd, J = 8.2, 0.8 Hz, 1H), 7.07 (s, 0.25H), 6.94 (s, 0.5H), 6.81 ( s, 0.25H), 6.79 (dd, J =1.9, 0.9 Hz, 1H), 5.45 (s, 2H), 1.15 (s, 6H).; LRMS (ES) m/z 465.4 (M ⁺ + 1).

Synthesis of compound 103, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(2-fluorophenyl)-4,4- dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 103

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol) obtained in step 6, compound 97, (2-fluorophenyl)boronic acid (0.044 g, 0.314 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene ]palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.014 g, 0.021 mmol) and cesium carbonate (0.102 g, 0.314 mmol) were mixed in 1,4-dioxane (30 mL)/water (10 mL), then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.035 g, 33.9%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (dd, J =2.2, 0.6 Hz, 1H), 8.37 ~ 8.32 (m, 2H), 7.72 ~ 7, 71(m, 1H), 7.66~7.63(m, 1H), 7.53~7.42(m, 3H), 7.32~7.29(m, 1H), 7.25~ 7.20(m, 1H), 7.07(s, 0.25H), 6.94(s, 0.5H), 6.81(s, 0.25H), 5.42(s, 2H) , 1.76 (s, 6H).; LRMS (ES) m/z 493.4 (M ⁺ + 1).

Synthesis of compound 104 -yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 104

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol) obtained in step 6, compound 97, pyridin-3-ylboronic acid (0.039 g, 0.314 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.014 g, 0.021 mmol) and cesium carbonate (0.102 g, 0.314 mmol) were mixed in 1,4-dioxane (30 mL)/water (10 mL), then the resulting the mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.010 g, 10.0%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J =1.6 Hz, 1H), 8.93 (dd, J =2.3, 0.7 Hz, 1H), 8.72 (dd, J =4.8, 1.6Hz, 1H), 8.39 ~ 8.35 (m, 2H), 7.97 ~ 7.94 (m, 1H), 7.71 ~ 7.69 (m, 2H), 7.50 ~ 7.45 (m, 2H), 7.07 (s, 0.25H), 6.94 (s, 0.5H), 6.81 (s, 0.25H ), 5.47 (s, 2H), 1.78 (s, 6H).; LRMS (ES) m/z 476.3 (M ⁺ + 1).

Synthesis of compound 105 -yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 105

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol) obtained in step 6, compound 97, pyridin-4-ylboronic acid (0.039 g, 0.314 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.014 g, 0.021 mmol) and cesium carbonate (0.102 g, 0.314 mmol) were mixed in 1,4-dioxane (6 ml)/water (2 ml), then the resulting the mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.040 g, 40.2%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J =2.2, 0.7 Hz, 1H), 8.75 (d, J =6.0 Hz, 1H), 8.38 ~ 8.33 (m, 2H), 7.74 ~ 7.70 (m, 2H), 7.56 ~ 7.55 (m, 2H), 7.48 (dd, J = 8.2, 0, 6 Hz, 1H), 7.07 (s, 0.25H), 6.94 (s, 0.5H), 6.81 (s, 0.25H), 5.45 (s, 2H), 1, 78(s, 6H).; LRMS (ES) m/z 476.4 (M ⁺ + 1).

Synthesis of compound 106, 6'-bromo-2'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1'H-spiro[ cyclobutane-1,4'-isoquinoline]-1',3'(2'H)-dione

[Step 1] Synthesis of methyl 4-bromo-2-(1-(methoxycarbonyl)cyclobutyl)benzoate

Methyl 4-bromo-2-(2-methoxy-2-oxoethyl)benzoate (2.500 g, 8.707 mmol) was dissolved in N,N-dimethylformamide (30 mL) at 0°C followed by sodium hydride (60.00%, 1.045 g, 26.122 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 1,3-dibromopropane (1.758 g, 8.707 mmol) was added to the reaction mixture, and further stirred at room temperature for 18 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (1.100 g, 38.6%) as a white solid.

[Step 2] Synthesis of 4-bromo-2-(1-carboxycyclobutyl)benzoic acid

Methyl 4-bromo-2-(1-(methoxycarbonyl)cyclobutyl)benzoate (1.100 g, 3.362 mmol) obtained in step 1 and potassium hydroxide (1.886 g, 33.622 mmol) were dissolved in methanol (10 ml)/water (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The reaction mixture was poured 1 N. aqueous hydrochloric acid solution (20 ml) and stirred, then the precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (0.840 g, 83.5%) as a white solid.

[Step 3] Synthesis of 6'-bromo-1'H-spiro[cyclobutane-1,4'-isoquinoline]-1',3'(2'H)-dione

4-Bromo-2-(1-carboxycyclobutyl)benzoic acid (0.840 g, 2.808 mmol) obtained in step 2 and urea (0.186 g, 3.089 mmol) were mixed in N,N-dimethylformamide (10 ml), then irradiated with microwave radiation, then heated at 150°C for 45 min and then the reaction was completed by lowering the temperature to room temperature. The precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (0.700 g, 89.0%) as a white solid.

[Step 4] Synthesis of Compound 106

6'-Bromo-1'H-spiro[cyclobutane-1,4'-isoquinoline]-1',3'(2'H)-dione (0.500 g, 1.785 mmol) obtained in step 3, 2-(6 -(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.518 g, 1.785 mmol) and potassium carbonate (0.370 g, 2.677 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 90°C, then the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.440 g, 50.4%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J =2.1 Hz, 1H), 8.36 (dd, J =8.2, 2.2 Hz, 1H), 8.09 (d, J =8.4 Hz, 1H), 8.00 ~ 7.98 (m, 1H), 7.62 (dd, J =8.4, 1.8 Hz, 1H), 7.48 ( d, J =8.2 Hz, 1H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.45(s , 2H), 3.06~2.99(m, 2H), 2.55~2.45(m, 2H), 2.44~2.29(m, 2H).

Synthesis of compound 107, 6'-bromo-2'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1'H-spiro[ cyclohexane-1,4'-isoquinoline]-1',3'(2'H)-dione

[Step 1] Synthesis of methyl 4-bromo-2-(1-(methoxycarbonyl)cyclohexyl)benzoate

Methyl 4-bromo-2-(2-methoxy-2-oxoethyl)benzoate (2.500 g, 8.707 mmol) was dissolved in N,N-dimethylformamide (30 mL) at 0°C followed by sodium hydride (60.00%, 1.045 g, 26.122 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 1,5-dibromopentane (2.002 g, 8.707 mmol) was added to the reaction mixture, and further stirred at room temperature for 18 hours. Water was poured into the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (1.000 g, 32.3%) as a colorless oil.

[Step 2] Synthesis of 4-bromo-2-(1-carboxycyclohexyl)benzoic acid

Methyl 4-bromo-2-(1-(methoxycarbonyl)cyclohexyl)benzoate (1.000 g, 2.815 mmol) obtained in step 1 and potassium hydroxide (1.579 g, 28.151 mmol) were dissolved in methanol (10 ml)/water (10 ml) at 80°C, then the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The reaction mixture was poured 1 N. aqueous hydrochloric acid (20 ml) and stirred, then the precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (0.894 g, 97.1%) as a white solid.

[Step 3] Synthesis of 6'-bromo-1'H-spiro[cyclohexane-1,4'-isoquinoline]-1',3'(2'H)-dione

4-Bromo-2-(1-carboxycyclohexyl)benzoic acid (0.890 g, 2.720 mmol) obtained in Step 2 and urea (0.180 g, 2.992 mmol) were mixed in N,N-dimethylformamide (10 ml), then irradiated with microwave radiation, then heated at 150°C for 45 min and then the reaction was completed by lowering the temperature to room temperature. The precipitated solid was filtered off, then washed with hexane and then dried to give the title compound (0.347 g, 41.4%) as a white solid.

[Step 4] Synthesis of Compound 107

6'-Bromo-1'H-spiro[cyclohexane-1,4'-isoquinoline]-1',3'(2'H)-dione (0.370 g, 1.201 mmol) obtained in step 3, 2-(6 -(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.348 g, 1.201 mmol) and potassium carbonate (0.249 g, 1.801 mmol) were dissolved in N,N-dimethylformamide (10 ml) at 90°C, then the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.200 g, 32.2%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 ~ 9.17 (m, 1H), 8.35 (dd, J =8.2, 2.2 Hz, 1H), 8.09 (d, J= 8.4 Hz, 1H), 7.77 (d, J =1.8 Hz, 1H), 7.59 (dd, J =8.4, 1.8 Hz, 1H), 7.47 ( dd, J =8.2, 0.5 Hz, 1H), 7.07(s, 0.25H), 6.94(s, 0.5H), 6.81(s, 0.25H), 5 .37(s, 2H), 2.17~2.14(m, 2H), 2.07~1.80(m, 6H), 1.79~1.66(m, 2H).

Synthesis of compound 108, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(3-fluorophenyl)-4,4- dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 108

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), (3-fluorophenyl)boronic acid (0.035 g, 0.251 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd (dtbpf)Cl ₂ , 0.007 g, 0.010 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were mixed in 1,4-dioxane (1.5 ml)/water (0.5 ml) at room temperature, then the resulting the mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0 to 40%) and concentrated to give the title compound (0.066 g, 64.0%) as a light brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.3 Hz, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.35 (dd, J =8.2, 2.1 Hz, 1H), 7.89 (dd, J=8.2, 2.0 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7 .50 ~ 7.43 (m, 3H), 7.34 (d, J=10.1 Hz, 1H), 7.11 ~ 6.81 (m, 2H), 5.47 (s, 2H), 1.75 (s, 6H); LRMS (ES) m/z 493.3 (M ⁺ + 1).

Synthesis of compound 109, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(2-fluorophenyl)-4,4- dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 109

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), (2-fluorophenyl)boronic acid (0.035 g, 0.251 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd (dtbpf)Cl ₂ , 0.007 g, 0.010 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were mixed in 1,4-dioxane (1.5 ml)/water (0.5 ml) at room temperature, then the resulting the mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0 to 40%) and concentrated to give the title compound (0.057 g, 55.2%) as a light brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.8 Hz, 1H), 8.43 (s, 1H), 8.35 ~ 8.33 (m, 1H), 7 .91 ~ 7.88 (m, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.52 ~ 7.46 (m, 2H), 7.38 ~ 7.35 (m , 1H), 7.28~7.16(m, 2H), 7.07~6.81(m, 1H), 5.46(s, 2H), 1.75(s, 6H).; LRMS (ES) m/z 493.3 (M ⁺ + 1).

Synthesis of compound 110 -yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 110

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), pyridin-4-ylboronic acid (0.031 g, 0.251 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd( dtbpf)Cl ₂ , 0.007 g, 0.010 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were mixed in 1,4-dioxane (1.5 ml)/water (0.5 ml) at room temperature, then the resulting mixture irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=10 to 60%) and concentrated to give the title compound (0.047 g, 47.2%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=2.0 Hz, 1H), 8.72 (d, J=4.6 Hz, 2H), 8.55 (d, J =2.0 Hz, 1H), 8.35 (dd, J=8.2, 2.2 Hz, 1H), 7.96 (dd, J=8.2, 2.1 Hz, 1H), 7 .67 (d, J=8.2 Hz, 1H), 7.59 (d, J=4.9 Hz, 2H), 7.49 (d, J=8.2 Hz, 1H), 7.06 ~ 6.80 (m, 1H), 5.47 (s, 2H), 1.75 (s, 6H).; LRMS (ES) m/z 476.2 (M ⁺ + 1).

Synthesis of compound 111 -yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of compound 111

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), pyridin-3-ylboronic acid (0.031 g, 0.251 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd( dtbpf)Cl ₂ , 0.007 g, 0.010 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were mixed in 1,4-dioxane (1.5 ml)/water (0.5 ml) at room temperature, then the resulting mixture irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=10 to 60%) and concentrated to give the title compound (0.042 g, 42.2%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (d, J=2.0 Hz, 1H), 8.90 (d, J=1.3 Hz, 1H), 8.64 (d, J =4.1 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 7.96 ~ 7 .89 (m, 2H), 7.65 (d, J=8.2 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.43 ~ 7.39 (m, 1H), 7.06~6.80(m, 1H), 5.45(s, 2H), 1.74(s, 6H).; LRMS (ES) m/z 476.4 (M ⁺ + 1).

Synthesis of compound 112, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(furan-3-yl)-4, 4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 112

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), furan-2-ylboronic acid (0.028 g, 0.251 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd( dtbpf)Cl ₂ , 0.007 g, 0.010 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were mixed in 1,4-dioxane (1.5 ml)/water (0.5 ml) at room temperature, then the resulting mixture irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0 to 40%) and concentrated to give the title compound (0.050 g, 51.4%) as a brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.8 Hz, 1H), 8.37 ~ 8.34 (m, 2H), 7.84 (s, 1H), 7 .80 (dd, J=8.2, 2.0 Hz, 1H), 7.55 ~ 7.52 (m, 2H), 7.47 (d, J=8.2 Hz, 1H), 7, 06 ~ 6.78 (m, 2H), 5.46 (s, 2H), 1.72 (s, 6H).; LRMS (ES) m/z 465.2 (M ⁺ + 1).

Synthesis of compound 113, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(furan-2-yl)-4, 4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of compound 113

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), furan-3-ylboronic acid (0.028 g, 0.251 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd( dtbpf)Cl ₂ , 0.007 g, 0.010 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were mixed in 1,4-dioxane (1.5 ml)/water (0.5 ml) at room temperature, then the resulting mixture irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0 to 40%) and concentrated to give the title compound (0.050 g, 51.4%) as a light brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, J=1.7 Hz, 1H), 8.52 (d, J=1.9 Hz, 1H), 8.35 (dd, J =8.2, 2.2 Hz, 1H), 7.98 (dd, J=8.3, 2.0 Hz, 1H), 7.56 ~ 7.46 (m, 2H), 7.47 ( d, J=8.2 Hz, 1H), 7.06 ~ 6.78 (m, 2H), 6.53 ~ 6.52 (m, 1H), 5.46 (s, 2H), 1.72 (s, 6H).; LRMS (ES) m/z 465.3 (M ⁺ + 1).

Synthesis of compound 114, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(5-methylfuran -2-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 114

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (0.052 g, 0.251 mmol), [ 1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.007 g, 0.010 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were mixed in a mixture of 1.4 -dioxane (1.5 ml)/water (0.5 ml) at room temperature, then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0 to 40%) and concentrated to give the title compound (0.053 g, 52.9%) as a light brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.7 Hz, 1H), 8.46 (d, J=1.9 Hz, 1H), 8.35 (dd, J =8.2, 2.1 Hz, 1H), 7.92 (dd, J=8.3, 2.0 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7 .47 (d, J=8.2Hz, 1H), 7.06 ~ 6.80 (m, 1H), 6.67 (d, J=3.2Hz, 1H), 6.10 ~ 6, 09 (m, 1H), 5.46 (s, 2H), 2.39 (s, 3H), 1.71 (s, 6H); LRMS (ES) m/z 479.2 (M ⁺ + 1).

Synthesis of compound 115, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(1H-indol-4-yl)- 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 115

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.210 mmol), (1H-indol-4-yl)boronic acid (0.040 g, 0.251 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II )dichloride (Pd(dtbpf)Cl ₂ , 0.007 g, 0.010 mmol) and cesium carbonate (0.205 g, 0.629 mmol) were mixed in 1,4-dioxane (1.5 ml)/water (0.5 ml) at room temperature temperature, then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.045 g, 41.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.22 (d, J=1.7 Hz, 1H), 8.62 (d, J=1.9 Hz, 1H), 8.49 (brs, 1H ), 8.34 (dd, J=8.2, 2.1 Hz, 1H), 8.05 (dd, J=8.2, 2.0 Hz, 1H), 7.65 (d, J= 8.2 Hz, 1H), 7.48 ~ 7.44 (m, 2H), 7.32 ~ 7.24 (m, 3H), 7.06 ~ 6.80 (m, 1H), 6.75 ~ 6.74 (m, 1H), 5.49 (s, 2H), 1.79 (s, 6H).; LRMS (ES) m/z 514.3 (M ⁺ + 1).

Synthesis of compound 116, tert-butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl -1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)piperazine-1-carboxylate

[Step 1] Synthesis of tert-butyl 4-(4-(1-methoxy-2-methyl-1-oxopropan-2-yl)-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

Methyl 5-bromo-2-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate (4.990 g, 15.833 mmol), tert-Butylpiperazine-1-carboxylate (3.834 g, 20.583 mmol), bis (tri-tert-butylphosphine)palladium (0.0.809 g, 1.583 mmol) and cesium carbonate (12.897 g, 39.583 mmol) were dissolved in toluene (20 ml) at 100°C, then the resulting solution was stirred at the same temperature for 18 h and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate/dichloromethane=0 to 30%) and concentrated to give the title compound (2.020 g, 30.3%) as a yellow solid.

[Step 2] Synthesis of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(2-carboxypropan-2-yl)benzoic acid

tert-Butyl 4-(4-(1-methoxy-2-methyl-1-oxopropan-2-yl)-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.000 g, 4.756 mmol) obtained in step 1, and potassium hydroxide (2.668 g, 47.561 mmol) was dissolved in methanol (30 ml)/water (30 ml) at 80°C, then the resulting solution was stirred at the same temperature, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then 1 N sodium hydroxide was poured into the resulting concentrate. an aqueous solution of hydrochloric acid, and then extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (1.500 g, 80.4%, white solid).

[Step 3] Synthesis of tert-butyl 4-(4,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)piperazine-1-carboxylate

5-(4-(T-butoxycarbonyl)piperazin-1-yl)-2-(2-carboxypropan-2-yl)benzoic acid (1.500 g, 3.822 mmol) from step 2 and urea (0.253 g, 4.204 mmol) was dissolved in N,N-dimethylformamide (20 ml), then the resulting solution was stirred at 150°C for 18 h, then further stirred at the same temperature for 18 h, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 30%) and concentrated to give the title compound (0.530 g, 37.1%) as a yellow solid.

[Step 4] Synthesis of Compound 116

tert-Butyl 4-(4,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)piperazine-1-carboxylate (0.420 g, 1.125 mmol) obtained in step 3 , 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.359 g, 1.237 mmol) and potassium carbonate (0.311 g, 2.249 mmol) were dissolved in N, N-dimethylformamide (10 ml) at 90°C, then the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.400 g, 61.0%) as a yellow foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J =2.2, 0.8 Hz, 1H), 8.34 (dd, J= 8.2, 2.2 Hz, 1H) , 7.73 (d, J= 2.8 Hz, 1H), 7.45 ~ 7.40 (m, 2H), 7.28 ~ 7.27 (m, 1H), 7.07 (s, 0 .25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.45(s, 2H), 3.62~3.59(m, 4H), 3, 24~3.22(m, 4H), 1.66(s, 6H), 1.50(s, 9H).

Synthesis of compound 117, 2'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6'-(4-ethylpiperazin-1-yl )-1'H-spiro[cyclobutane-1,4'-isoquinoline]-1',3'(2'H)-dione

[Step 1] Synthesis of Compound 117

6'-Bromo-2'-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1'H-spiro[cyclobutan-1, 4'-isoquinoline]-1',3'(2'H)-dione (0.138 g, 0.282 mmol) obtained in step 4, compound 106, 1-ethylpiperazine (0.064 g, 0.564 mmol), palladium (II, 0.006 g, 0.028 mmol), ruphos (0.013 g, 0.028 mmol) and potassium carbonate (0.230 g, 0.705 mmol) were dissolved in toluene (10 ml) at 100°C, then the resulting solution was stirred at the same temperature for 18 h and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.020 g, 13.6%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J =1.8 Hz, 1H), 8.32 (dd, J =8.2, 2.3 Hz, 1H), 8.08 (d, J =8.9 Hz, 1H), 7.42 (d, J =8.2 Hz, 1H), 7.19 (d, J =2.3 Hz, 1H), 7.06 (s , 0.25H), 6.95 (dd, J =9.7, 3.0 Hz, 1H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5, 42(s, 2H), 3.51~3.48(m, 4H), 3.03~2.96(m, 2H), 2.68~2.63(m, 4H), 2.55~ 2.21(m, 6H), 1.17~1.13(m, 3H).; LRMS (ES) m/z 523.3 (M ⁺ + 1).

Synthesis of compound 118, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(4-methylpiperazine -1-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperazin- 1-yl)isoquinoline-1,3(2H,4H)-dione-2,2,2-trifluoroacetate

tert-Butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-1,3 -dioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)piperazine-1-carboxylate (0.400 g, 0.687 mmol) and trifluoroacetic acid (0.526 ml, 6.866 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, then the resulting product was used without further purification (0.400 g, 97.7%, yellow oil).

[Step 2] Synthesis of compound 118

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.200 g, 0.335 mmol) obtained in step 1, formaldehyde (0.020 g, 0.671 mmol), sodium triacetoxyborohydride (0.142 g, 0.671 mmol) and N,N-diisopropylethylamine (0.058 ml, 0.335 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.110 g, 66.1%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J =2.1 Hz, 1H), 8.32 (dd, J =8.2, 2.2 Hz, 1H), 7.71 (d, J =2.8 Hz, 1H), 7.43 ~ 7.37 (m, 2H), 7.25 (dd, J =8.7, 2.8 Hz, 1H), 7.06 ( s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.42 (s, 2H), 3.30 (t, J = 5.0 Hz , 4H), 2.61 (t, J =5.0 Hz, 4H), 2.36 (s, 3H), 1.64 (s, 6H).; LRMS (ES) m/z 497.4 (M ⁺ + 1).

Synthesis of compound 119 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of compound 119

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione-2,2,2-trifluoroacetate (0.200 g, 0.335 mmol), acetone (0.039 g, 0.671 mmol), sodium triacetoxyborohydride (0.142 g, 0.671 mmol) and N, N- diisopropylethylamine (0.058 ml, 0.335 mmol) was dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.130 g, 73.9%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 ~ 9.19 (m, 1H), 8.33 (dd, J =8.2, 2.3 Hz, 1H), 7.72 (d, J =2.8Hz, 1H), 7.44~7.38(m, 2H), 7.26(dd, J =8.7, 2.8Hz, 1H), 7.06(s, 0 .25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.42 (s, 2H), 3.32 (t, J =5.0 Hz, 4H) , 2.81 ~ 2.78 (m, 1H), 2.75 (t, J =5.0 Hz, 4H), 1.65 (s, 6H), 1.13 (d, J=6.5 Hz, 6H).; LRMS (ES) m/z 525.4 (M ⁺ + 1).

Synthesis of compound 120, tert-butyl-4-(3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methyl-2 ,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[Step 1] Synthesis of Compound 120

7-Bromo-3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methylquinazolin-2,4(1H,3H) -dione (0.729 g, 1.570 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H) -carboxylate (0.728 g, 2.356 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.102 g, 0.157 mmol) and cesium carbonate (0.767 g, 2.356 mmol) was mixed in a mixture of 1,4-dioxane (9 ml)/water (3 ml), then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 80%) and concentrated to give the title compound (0.700 g, 78.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.24 ~ 9.20 (m, 1H), 8.35 (dd, J =8.2, 2.2 Hz, 1H), 8.21 (d, J =8.3Hz, 1H), 7.50(dd, J =8.2, 0.8Hz, 1H), 7.35~7.31(m, 1H), 7.24(d, J =2.2Hz, 1H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 6.25~6.20( m, 1H), 5.53(s, 2H), 4.16~4.11(m, 2H), 3.70~3.65(m, 2H), 2.62~2.58(m, 2H), 1.63(s, 3H), 1.52(s, 9H).

Synthesis of compound 121, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(3,6-dihydro-2H-thiopyran -4-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of compound 121

7-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (1.000 g, 2.095 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.711 g , 3.143 mmol), [1,1'-bis (di-tert-butylphosphino) ferrocene] palladium (II) dichloride (Pd (dtbpf) Cl ₂ , 0.137 g, 0.210 mmol) and cesium carbonate (1.024 g, 3.143 mmol) was mixed in a mixture of 1,4-dioxane (9 ml)/water (3 ml), then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 20 min, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 70%) and concentrated to give the title compound (0.840 g, 80.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, J =1.4 Hz, 1H), 8.34 ~ 8.33 (m, 1H), 8.22 (d, J =2, 1 Hz, 1H), 7.70 ~ 7.63 (m, 1H), 7.50 ~ 7.47 (m, 2H), 7.03 (s, 0.25H), 6.93 (s, 0 .5H), 6.80 (s, 0.25H), 6.40 ~ 6.35 (m, 1H), 5.44 (s, 2H), 3.38 ~ 3.37 (m, 2H), 2.92~2.90(m, 2H), 2.80~2.75(m, 2H), 1.70(s, 6H).; LRMS (ES) m/z 497.0 (M ⁺ + 1).

Synthesis of compound 122, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methyl-7-(1,2,3 ,6-tetrahydropyridin-4-yl)quinazolin-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 122

tert-Butyl-4-(3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methyl-2,4-dioxo -1,2,3,4-tetrahydroquinazolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.720 g, 1.271 mmol) and trifluoroacetic acid (0.973 ml, 12.708 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (0.700 g, 94.9%, white solid).

LRMS (ES) m/z 467.3 (M ⁺ + 1).

Synthesis of compound 123, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(1-oxid -3,6-dihydro-2H-thiopyran-4-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 123

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(3,6-dihydro-2H-thiopyran-4-yl )-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (0.730 g, 1.470 mmol) and 3-chloroperbenzoic acid (77.00%, 0.329 g, 1.470 mmol) were dissolved in dichloromethane (10 ml) at 0°C, then the resulting solution was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 70%) and concentrated to give the title compound (0.300 g, 39.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J =2.1, 0.7 Hz, 1H), 8.36 (dd, J =8.2, 2.2 Hz, 1H) , 8.27 (d, J= 2.0 Hz, 1H), 7.71 (dd, J =8.3, 2.2 Hz, 1H), 7.53 (d, J =8.3 Hz, 1H), 7.48 (dd, J =8.2, 0.7 Hz, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s , 0.25H), 6.07 ~ 6.05 (m, 1H), 5.45 (s, 2H), 3.63 ~ 3.54 (m, 2H), 3.30 ~ 3.20 (m , 2H), 3.00 ~ 2.97 (m, 1H), 2.85 ~ 2.80 (m, 1H), 1.71 (s, 6H).; LRMS (ES) m/z 513.3 (M ⁺ + 1).

Synthesis of compound 124, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(1-isopropyl-1,2,3 ,6-tetrahydropyridin-4-yl)-1-methylquinazolin-2,4(1H,3H)-dione

[Step 1] Synthesis of Compound 124

3-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-methyl-7-(1,2,3,6-tetrahydropyridine -4-yl)quinazolin-2,4(1H,3H)-dione-2,2,2-trifluoroacetate (0.450 g, 0.775 mmol), acetone (0.090 g, 1.550 mmol), sodium triacetoxyborohydride (0.329 g, 1.550 mmol ) and N,N-diisopropylethylamine (0.135 ml, 0.775 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.200 g, 50.7%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (dd, J =2.2, 0.8 Hz, 1H), 8.33 (dd, J =8.2, 2.2 Hz, 1H) , 8.18 (d, J =8.3 Hz, 1H), 7.49 (dd, J =8.3, 0.8 Hz, 1H), 7.32 (dd, J =8.3, 1 .5 Hz, 1H), 7.25 (d, J =38.7 Hz, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s , 0.25H), 6.28~6.27(m, 1H), 5.51(s, 2H), 3.65(s, 3H), 3.48~3.46(m, 2H), 3.12 ~ 3.09 (m, 1H), 2.98 ~ 2.95 (m, 2H), 2.74 ~ 2.72 (m, 2H), 1.22 (d, J =6.6 Hz, 6H).; LRMS (ES) m/z 509.4 (M ⁺ + 1).

Synthesis of compound 125, N-(4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl- 1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-oxido-3,6-dihydro-2H-1λ ⁶ -thiopyran-1-ylidene)-2,2,2-trifluoroacetamide

[Step 1] Synthesis of Compound 125

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(1-oxido-3,6 -dihydro-2H-thiopyran-4-yl)isoquinolin-1,3(2H,4H)-dione (0.157 g, 0.306 mmol), 2,2,2-trifluoroacetamide (0.069 g, 0.613 mmol), iodobenzene diacetate (0.148 g , 0.459 mmol), magnesium oxide (0.049 g, 1.225 mmol) and rhodium(II) acetate dimer (0.014 g, 0.031 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 h. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.100 g, 52.4%) as a violet oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (s, 1H), 8.38 (dd, J =8.2, 2.2 Hz, 1H), 8.26 (d, J =2, 1 Hz, 1H), 7.68 (dd, J = 8.3, 2.2 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.49 (dd, J = 8.3, 0.7Hz, 1H), 7.07(s, 0.25H), 6.94(s, 0.5H), 6.81(s, 0.25H), 6.05~6 .03 (m, 2H), 5.46 (s, 2H), 4.58 ~ 4.56 (m, 1H), 4.22 ~ 4.19 (m, 1H), 3.84 ~ 3.82 (m, 1H), 3.68 ~ 3.64 (m, 1H), 3.28 ~ 3.26 (m, 2H), 1.76 (s, 6H).; LRMS (ES) m/z 624.3 (M ⁺ + 1).

Synthesis of compound 126, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(1-imino-1-oxido-1 ,2,3,6-tetrahydro-1λ ⁶ -thiopyran-4-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 126

N-(4-(2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-1,3- dioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-oxido-3,6-dihydro-2H-1λ ⁶ -thiopyran-1-ylidene)-2,2,2-trifluoroacetamide (0.100 g, 0.160 mmol) and potassium carbonate (0.066 g, 0.481 mmol) were dissolved in methanol (5 ml) at room temperature, then the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, then into the resulting concentrate water was poured out, and then extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.010 g, 11.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 ~ 9.31 (m, 1H), 8.49 ~ 8.45 (m, 1H), 8.31 ~ 8.22 (m, 1H), 7.74 ~ 7.69 (m, 1H), 7.56 ~ 7.42 (m, 2H), 7.17 (s, 1H), 7.07 (s, 1H), 6.92 (s, 1H), 6.08~6.07(m, 1H), 5.56(s, 2H), 4.30~4.25(m, 1H), 4.05~4.01(m, 1H) , 3.94 (s, 1H), 3.71 ~ 3.67 (m, 1H), 3.50 ~ 3.47 (m, 1H), 3.26 ~ 3.22 (m, 2H), 1 .68 (s, 6H); LRMS (ES) m/z 528.22 (M ⁺ + 1).

Synthesis of compound 127 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 127

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.208 mmol) and triethylamine (0.058 ml, 0.415 mmol) were dissolved in dichloromethane (4 ml) at 0°C, then acetic anhydride (0.029 ml, 0.312 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=40 to 90%) and concentrated to give the title compound (0.042 g, 38.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.6 Hz, 1H), 8.35 (dd, J=8.2, 2.2 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.54 ~ 7.45 (m, 3H), 7.06 ~ 6.81 (m, 1H), 5.44 (s, 2H), 4, 83 (d, J=11.4 Hz, 1H), 3.98 (d, J=11.7 Hz, 1H), 3.21 (td, J=13.0, 2.2 Hz, 1H), 2.90 ~ 2.84 (m, 1H), 2.70 ~ 2.63 (m, 1H), 2.16 (s, 3H), 1.95 (t, J=14.7 Hz, 2H) , 1.73 ~ 1.66 (m, 8H).; LRMS (ES) m/z 524.4 (M ⁺ + 1).

Synthesis of compound 128, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(1-( methylsulfonyl)piperidin-4-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 128

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.208 mmol) and triethylamine (0.058 ml, 0.415 mmol) were dissolved in dichloromethane (4 ml) at 0°C, then methanesulfonyl chloride (0.024 ml, 0.312 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=30 to 70%) and concentrated to give the title compound (0.036 g, 31.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.6 Hz, 1H), 8.35 (dd, J=8.2, 2.2 Hz, 1H), 8.11 (d, J=1.9 Hz, 1H), 7.56 ~ 7.46 (m, 3H), 7.06 ~ 6.81 (m, 1H), 5.45 (s, 2H), 3, 99 (d, J=11.9 Hz, 2H), 2.85 ~ 2.72 (m, 6H), 2.03 ~ 2.00 (m, 2H), 1.95 ~ 1.88 (m, 2H), 1.70 (s, 6H).; LRMS (ES) m/z 560.4 (M ⁺ + 1).

Synthesis of compound 129, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(4-ethylpiperazin-1-yl)- 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 129

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.116 g, 0.240 mmol), acetaldehyde (0.021 g, 0.481 mmol) and sodium triacetoxyborohydride (0.102 g, 0.481 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the obtained the solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.060 g, 48.9%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (dd, J =2.2, 0.8 Hz, 1H), 8.33 (dd, J=8.2, 2.2 Hz, 1H) , 7.71(d, J =2.8Hz, 1H), 7.43~7.37(m, 2H), 7.25(dd, J =8.7, 2.8Hz, 1H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.42(s, 2H), 3.33(t, J= 5.1 Hz, 4H), 2.70 (t, J =5.1 Hz, 4H), 2.56 ~ 2.54 (m, 2H), 1.16 (t, J= 7.2 Hz, 3H).;LRMS (ES) m/z 511.3 (M ⁺ + 1).

Synthesis of compound 130, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(4-propylpiperazine -1-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 130

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), propionaldehyde (0.024 g, 0.415 mmol) and sodium triacetoxyborohydride (0.088 g, 0.415 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.050 g, 46.0%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (dd, J =2.2, 0.6 Hz, 1H), 8.33 (dd, J =8.2, 2.2 Hz, 1H) , 7.71(d, J =2.8Hz, 1H), 7.44~7.38(m, 2H), 7.25(dd, J =8.7, 2.8Hz, 1H), 7.06 (s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 3.32 (t, J= 5.1 Hz, 4H), 2 .68 (t, J =5.0 Hz, 4H), 2.40 ~ 2.40 (m, 2H), 1.66 (s, 6H), 1.65 ~ 1.57 (m, 2H), 0.94 (t, J=7.4 Hz, 3H); LRMS (ES) m/z 525.5 (M ⁺ + 1).

Synthesis of compound 131 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 131

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), isobutyric aldehyde (0.030 g, 0.415 mmol) and sodium triacetoxyborohydride (0.088 g, 0.415 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.060 g, 53.7%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (dd, J =2.2, 0.8 Hz, 1H), 8.33 (dd, J =8.2, 2.2 Hz, 1H) , 7.71(d, J =2.8Hz, 1H), 7.43~7.37(m, 2H), 7.25(dd, J =8.8, 2.8Hz, 1H), 7.06(s, 0.25H), 6.93(s, 0.5H), 6.80(s, 0.25H), 5.42(s, 2H), 3.28(t, J = 5.0 Hz, 4H), 2.58 (t, J =5.0 Hz, 4H), 2.17 ~ 2.15 (m, 2H), 1.90 ~ 1.85 (m, 1H), 1.66(s, 6H), 0.94~0.91(m, 6H).; LRMS (ES) m/z 539.5 (M ⁺ + 1).

Synthesis of compound 132 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 132

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), 3-methylbutanal (0.036 g, 0.415 mmol) and sodium triacetoxyborohydride (0.088 g, 0.415 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then, the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.060 g, 52.4%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J =2.2 Hz, 1H), 8.32 (dd, J =8.2, 2.3 Hz, 1H), 7.70 (d, J =2.8 Hz, 1H), 7.43 ~ 7.37 (m, 2H), 7.24 (dd, J =8.7, 2.8 Hz, 1H), 7.06 ( s, 0.25H), 6.93 (s, 0.5H), 6.80 (s, 0.25H), 5.41 (s, 2H), 3.33 (t, J = 5.0 Hz , 4H), 2.73 (t, J =5.0 Hz, 4H), 2.51 ~ 2.47 (m, 2H), 1.66 (s, 6H), 1.48 ~ 1.46 ( m, 2H), 0.94 ~ 0.91 (m, 6H).; LRMS (ES) m/z 553.4(M ⁺ + 1).

Synthesis of compound 133, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(4-( 2,2,2-trifluoroethyl)piperazin-1-yl)isoquinolin-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 133

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.130 g, 0.269 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.081 g, 0.350 mmol) and potassium carbonate (0.074 g, 0.539 mmol) were dissolved in acetonitrile (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.100 g, 65.7%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J =2.2, 0.8 Hz, 1H), 8.35 (dd, J =8.2, 2.2 Hz, 1H) , 7.73 (d, J =2.8 Hz, 1H), 7.45 ~ 7.40 (m, 2H), 7.27 ~ 7.25 (m, 1H), 7.06 (s, 1H ), 6.93 (s, 1H), 6.80 (s, 1H), 5.43 (s, 2H), 3.32 (t, J =5.0 Hz, 4H), 3.07 (dd , J =19.1, 9.5 Hz, 2H), 2.88 (t, J =5.0 Hz, 4H), 1.67 (s, 6H).; LRMS (ES) m/z 565.5 (M ⁺ + 1).

Synthesis of compound 134 4-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 134

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.208 mmol), 2-hydroxyacetic acid (0.032 g, 0.415 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.158 g, 0.415 mmol) and N,N-diisopropylethylamine (0.181 ml, 1.038 mmol) were dissolved in N,N-dimethylformamide (4 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, then the resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=30 to 80%) and concentrated and the product was obtained, then the resulting product was repurified by chromatography (SiO ₂ plate, 20×20×1 mm; ethyl acetate=100%) and concentrated to give the title compound (0.036 g, 32.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.6 Hz, 1H), 8.35 (dd, J=8.2, 2.2 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.54 ~ 7.46 (m, 3H), 7.06 ~ 6.81 (m, 1H), 5.44 (s, 2H), 4, 80 (d, J=11.4 Hz, 1H), 4.24 ~ 4.15 (m, 2H), 3.76 ~ 3.64 (m, 2H), 3.16 (td, J=13, 1, 2.3 Hz, 1H), 2.94 ~ 2.80 (m, 2H), 1.99 (d, J=12.8 Hz, 2H), 1.77 ~ 1.66 (m, 8H ).; LRMS (ES) m/z 540.5 (M ⁺ + 1).

Synthesis of compound 135, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(1-( 2,2,2-trifluoroethyl)piperidin-4-yl)isoquinolin-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 135

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.208 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.072 g, 0.312 mmol) and N,N-diisopropylethylamine (0.109 ml, 0.623 mmol) were dissolved in dichloromethane ( 4 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium chloride was poured into the reaction mixture, then extraction was carried out with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer from it and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=10 to 50%) and concentrated to give the title compound (0.032 g, 27.3%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.8 Hz, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.56 (dd, J=8.2, 2.0 Hz, 1H), 7.48 ~ 7.44 (m, 2H), 7.06 ~ 6.80 (m, 1H), 5.44 (s, 2H), 3.12 (d, J=11.6 Hz, 2H), 3.05 (q, J=9.7 Hz, 2H), 2.62~2.61(m, 1H), 2.56~2.49(m, 2H), 1.90~1.85(m, 4H), 1.69(s, 6H).; LRMS (ES) m/z 564.5 (M ⁺ + 1).

Synthesis of compound 136 4,4-diethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of methyl 4-bromo-2-(3-(methoxycarbonyl)pentan-3-yl)benzoate

Methyl 4-bromo-2-(2-methoxy-2-oxoethyl)benzoate (3.000 g, 10.449 mmol) and sodium hydride (60.00%, 1.672 g, 41.796 mmol) were dissolved in N,N-dimethylformamide (150 ml ) at 0°C, then iodoethane (3.360 ml, 41.796 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous magnesium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 10%) and concentrated to give the title compound (2.800 g, 78.1%) as a white solid.

[Step 2] Synthesis of 4-bromo-2-(3-carboxypentan-3-yl)benzoic acid

Methyl 4-bromo-2-(3-(methoxycarbonyl)pentan-3-yl)benzoate (2.800 g, 8.158 mmol) obtained in Step 1 and potassium hydroxide (4.577 g, 81.580 mmol) were dissolved in a mixture of methanol (25 ml)/water (50 ml) at room temperature, then the resulting solution was stirred at 100° C. for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. In the resulting reaction mixture was poured 1 N. an aqueous solution of hydrochloric acid and carried out extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous magnesium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (2.550 g, 99.2%, white solid).

[Step 3] Synthesis of 6-bromo-4,4-diethylisoquinoline-1,3(2H,4H)-dione

4-Bromo-2-(3-carboxypentan-3-yl)benzoic acid (2.550 g, 8.091 mmol) obtained in step 2 and urea (0.486 g, 8.091 mmol) were dissolved in N,N-dimethylformamide (150 ml) at room temperature, then the resulting solution was stirred at 150° C. for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 10%) and concentrated to give the title compound (0.301 g, 12.6%) as a white solid.

[Step 4] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)-4 -methylpiperazine-1-carboxamide

6-Bromo-4,4-diethylisoquinoline-1,3(2H,4H)-dione (0.300 g, 1.013 mmol) obtained in step 3, 2-(6-(bromomethyl)pyridin-3-yl)-5- (difluoromethyl)-1,3,4-oxadiazole (0.353 g, 1.216 mmol), potassium carbonate (0.420 g, 3.039 mmol) and potassium iodide (0.017 g, 0.101 mmol) were dissolved in N,N-dimethylformamide (5 ml) at room temperature, then the resulting solution was stirred at 100° C. for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, and extraction was performed with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 20%) and concentrated to give the title compound (0.419 g, 81.9%) as a light yellow solid.

[Step 5] Synthesis of Compound 136

N-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)-4-methylpiperazin-1- carboxamide (0.100 g, 0.198 mmol) obtained in step 4, 1-acetylpiperazine (0.028 ml, 0.237 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.018 g, 0.020 mmol), 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.011 g, 0.020 mmol) and cesium carbonate (0.129 g, 0.396 mmol) were dissolved in 1,4-dioxane (4 ml) at room temperature, then the resulting solution was stirred at 100° C for 18 h and then the reaction was completed by lowering the temperature to room temperature. A saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=60 to 100%) and concentrated to give the title compound (0.034 g, 31.1%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.6 Hz, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 8.17 (d, J=8.9 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.06 ~ 6.80 (m, 2H), 6.73 (d, J= 2.4 Hz, 1H), 5.44 (s, 2H), 3.84 (t, J=5.3 Hz, 2H), 3.71 (t, J=5.2 Hz, 2H), 3 .46 (t, J=5.2Hz, 2H), 3.41 (t, J=5.3Hz, 2H), 2.38 ~ 2.32 (m, 2H), 2.18 (s, 3H), 1.92~1.87(m, 2H), 0.64(t, J=7.4Hz, 6H).; LRMS (ES) m/z 553.5 (M ⁺ + 1).

Synthesis of compound 137, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4-( 2,2,3,3-tetrafluoropropyl)piperazin-1-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 137

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate (0.071 g, 0.269 mmol) and potassium carbonate (0.057 g, 0.415 mmol) were dissolved in acetonitrile (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, and then extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.060 g, 48.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (dd, J =2.2, 0.7 Hz, 1H), 8.33 (dd, J =8.2, 2.2 Hz, 1H) , 8.13(d, J =8.9Hz, 1H), 7.44~7.41(m, 1H), 7.06(s, 0.25H), 6.95~6.92(m , 1H), 6.93 (s, 0.5H), 6.85 (d, J = 2.4 Hz, 1H), 6.80 (s, 0.25H), 6.18 (t, J = 4.7 Hz, 0.25H), 6.04 (t, J =4.9 Hz, 0.5H), 5.91 (t, J =4.9 Hz, 0.25H), 5.42 ( s, 2H), 3.42 (t, J =5.1 Hz, 4H), 3.03 (t, J =14.1 Hz, 2H), 2.86 (t, J =5.0 Hz, 4H), 1.69 (s, 6H).; LRMS (ES) m/z 597.5 (M ⁺ + 1).

Synthesis of compound 138, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(4-(2,2-difluoropropyl) piperazin-1-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 138

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), 2,2-difluoropropyl trifluoromethanesulfonate (0.057 g, 0.249 mmol) and potassium carbonate (0.057 g, 0.415 mmol) were dissolved in acetonitrile (10 ml) at room temperature. temperature, then the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, and then extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.050 g, 43.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J =2.2, 0.7 Hz, 1H), 8.33 (dd, J= 8.2, 2.2 Hz, 1H) , 8.11 (d, J =8.9 Hz, 1H), 7.42 (dd, J =8.2, 0.6 Hz, 1H), 7.06 (s, 0.25H), 6, 94 ~ 6.91 (m, 1H), 6.93 (s, 0.5H), 6.84 (d, J =2.4 Hz, 1H), 6.80 (s, 0.25H), 5 .41(s, 2H), 3.42(t, J =5.1Hz, 4H), 2.81~2.74(m, 6H), 1.75~1.65(m, 9H).

Synthesis of compound 139 2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 139

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), 2,2-difluorobutyl trifluoromethanesulfonate (0.065 g, 0.269 mmol) and potassium carbonate (0.057 g, 0.415 mmol) were dissolved in acetonitrile (10 ml) at room temperature. temperature, then the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, and then extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.050 g, 42.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J =2.2, 0.8 Hz, 1H), 8.33 (dd, J =8.2, 2.3 Hz, 1H) , 8.11 (d, J =8.9 Hz, 1H), 7.42 (dd, J =8.2, 0.8 Hz, 1H), 7.06 (s, 0.25H), 6, 93 (dd, J =8.9, 2.5 Hz, 1H), 6.93 (s, 0.5H), 6.84 (d, J=2.4 Hz, 1H), 6.80 (s , 0.25H), 5.41(s, 2H), 3.42(t, J =5.1Hz, 4H), 2.81~2.74(m, 6H), 2.05~1, 99 (m, 2H), 1.68 (s, 6H), 1.06 (t, J =7.5 Hz, 3H).

Synthesis of compound 140, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-6-(4-(2,2,3, 3,4,4,4-heptafluorobutyl)piperazin-1-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 140

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), 2,2,3,3,4,4,4-heptafluorobutyl trifluoromethanesulfonate (0.089 g, 0.269 mmol) and potassium carbonate (0.057 g, 0.415 mmol ) was dissolved in acetonitrile (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, and then extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.040 g, 29.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (dd, J =2.2, 0.8 Hz, 1H), 8.33 (dd, J =8.2, 2.3 Hz, 1H) , 8.12 (d, J = 8.9 Hz, 1H), 7.42 (dd, J = 8.3, 0.8 Hz, 1H), 7.06 (s, 0.25H), 6, 94 (dd, J =8.5, 2.9 Hz, 1H), 6.93 (s, 0.5H), 6.85 (d, J =2.4 Hz, 1H), 6.80 (s , 0.25H), 5.42 (s, 2H), 3.43 (t, J =5.0 Hz, 4H), 3.14 (t, J =15.6 Hz, 2H), 2.88 (t, J =5.0 Hz, 4H), 1.68 (s, 6H).; LRMS (ES) m/z 665.4 (M ⁺ + 1).

Synthesis of compound 141, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4-( 2,2,2-trifluoroethyl)piperazin-1-yl)isoquinolin-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 141

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.063 g, 0.269 mmol) and potassium carbonate (0.057 g, 0.415 mmol) were dissolved in acetonitrile (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, and then extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.070 g, 59.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (dd, J =2.2, 0.8 Hz, 1H), 8.32 (dd, J =8.2, 2.2 Hz, 1H) , 8.10 (d, J =8.9 Hz, 1H), 7.41 (dd, J =8.2, 0.7 Hz, 1H), 7.06 (s, 0.25H), 6, 94 ~ 6.91 (m, 1H), 6.93 (s, 0.5H), 6.84 (d, J =2.4 Hz, 1H), 6.80 (s, 0.25H), 5 .40 (s, 2H), 3.43 (t, J =5.0 Hz, 4H), 3.11 ~ 3.03 (m, 1H), 2.87 (t, J =5.0 Hz, 4H), 1.67 (s, 6H).; LRMS (ES) m/z 564.52 (M ⁺ + 1).

Synthesis of compound 142, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-diethyl-6-(4-ethylpiperazine -1-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 142

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-diethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.198 mmol), 1-ethylpiperazine (0.027 g, 0.237 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.018 g, 0.020 mmol), 4,5-bis(diphenylphosphino )-9,9-dimethylxanthene (Xantphos, 0.011 g, 0.020 mmol) and cesium carbonate (0.129 g, 0.396 mmol) were dissolved in 1,4-dioxane (3 ml) at room temperature, then the resulting solution was stirred at 100°C in for 18 h and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, and extraction was carried out with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to give the product, then the resulting product was repurified by chromatography (SiO ₂ plate, 20×20×1 mm; methanol/dichloromethane=5%) and concentrated to give the title compound (0.019 g, 17.8%) as a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.10 (d, J=1.6 Hz, 1H), 8.41 (dd, J=8.3, 2.1 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.37 ~ 7.07 (m, 2H), 6.95 (d, J= 2.0 Hz, 1H), 5.39 (s, 2H), 3.48 (t, J=4.9 Hz, 4H), 2.66 (t, J=4.8 Hz, 4H), 2 .53 (q, J=7.2 Hz, 2H), 2.27 ~ 2.22 (m, 2H), 2.06 ~ 2.01 (m, 2H), 1.18 (t, J=7 .2 Hz, 3H), 0.62 (t, J=7.3 Hz, 6H).; LRMS (ES) m/z 539.5 (M ⁺ + 1).

Synthesis of compound 143, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(1-propylpiperidine -4-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 143

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.208 mmol) and propionaldehyde (0.018 g, 0.312 mmol) were dissolved in dichloromethane (4 ml) at room temperature, then sodium triacetoxyborohydride (0.088 g, 0.415 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure . The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to give the title compound (0.042 g, 38.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 8.12 (s, 1H), 7.57 (d , J=8.1 Hz, 1H), 7.45 (t, J=7.7 Hz, 2H), 7.06 ~ 6.80 (m, 1H), 5.43 (s, 2H), 3 .12 (d, J=11.0 Hz, 2H), 2.65 ~ 2.61 (m, 1H), 2.38 (t, J=7.7 Hz, 2H), 2.14 ~ 2, 05 (m, 2H), 1.88 ~ 1.87 (m, 4H), 1.68 (s, 6H), 1.63 ~ 1.55 (m, 2H), 0.93 (t, J= 7.3Hz, 3H).; LRMS (ES) m/z 524.5 (M ⁺ + 1).

Synthesis of compound 144, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-7-(1-isobutylpiperidine-4-yl)- 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 144

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.208 mmol) and isobutyric aldehyde (0.022 g, 0.312 mmol) were dissolved in dichloromethane (4 ml) at room temperature, then sodium triacetoxyborohydride (0.088 g, 0.415 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure . The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to give the title compound (0.055 g, 49.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (s, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.13 (s, 1H), 7.56 (d , J=8.0 Hz, 1H), 7.46 ~ 7.44 (m, 2H), 7.06 ~ 6.80 (m, 1H), 5.43 (s, 2H), 3.01 ( d, J=10.6 Hz, 2H), 2.61 ~ 2.57 (m, 1H), 2.13 (d, J=7.0 Hz, 2H), 2.05 ~ 1.99 (m , 2H), 1.83 ~ 1.79 (m, 5H), 1.69 (s, 6H), 0.93 (d, J=6.1 Hz, 6H).; LRMS (ES) m/z 538.3 (M ⁺ + 1).

Synthesis of compound 145 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 145

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.208 mmol) and cyclobutanone (0.016 g, 0.228 mmol) were dissolved in dichloromethane (4 ml) at room temperature, then sodium triacetoxyborohydride (0.066 g, 0.312 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to give the title compound (0.053 g, 47.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.12 (s, 1H), 7.56 (d , J=8.1 Hz, 1H), 7.44 (t, J=7.5 Hz, 2H), 7.05 ~ 6.79 (m, 1H), 5.42 (s, 2H), 3 .04 ~ 3.03 (m, 2H), 2.77 ~ 2.73 (m, 1H), 2.60 ~ 2.59 (m, 1H), 2.07 ~ 2.05 (m, 2H) , 1.95 ~ 1.69 (m, 10H), 1.67 (s, 6H).; LRMS (ES) m/z 536.3 (M ⁺ + 1).

Synthesis of compound 146, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(1-( tetrahydrofuran-3-yl)piperidin-4-yl)isoquinolin-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 146

N-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoroaniline (0.500 g, 1.482 mmol) and dihydrofuran-3(2H)-one ( 0.191 g, 2.224 mmol) was dissolved in dichloromethane (4 ml) at room temperature, then sodium triacetoxyborohydride (0.628 g, 2.965 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction the mixture was then extracted with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to give the title compound (0.062 g, 7.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.16 (d, J=2.0 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.55 (dd, J=8.2, 1.9 Hz, 1H), 7.44 (t, J=8.7 Hz, 2H), 7 .05 ~ 6.79 (m, 1H), 5.41 (s, 2H), 3.96 ~ 3.88 (m, 2H), 3.82 ~ 3.71 (m, 2H), 3.17 (d, J=11.3 Hz, 1H), 3.11 ~ 3.08 (m, 1H), 2.97 (d, J=12.2 Hz, 1H), 2.65 ~ 2.64 ( m, 1H), 2.26 ~ 2.22 (m, 2H), 2.10 ~ 2.07 (m, 1H), 1.97 ~ 1.86 (m, 5H), 1.66 (s, 6H).; LRMS (ES) m/z 552.5 (M ⁺ + 1).

Synthesis of compound 147 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 147

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), butyaldehyde (0.030 g, 0.415 mmol) and sodium triacetoxyborohydride (0.088 g, 0.415 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.060 g, 53.7%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (dd, J =2.1, 0.6 Hz, 1H), 8.33 (dd, J =8.2, 2.2 Hz, 1H) , 8.11 (d, J = 8.9 Hz, 1H), 7.41 (dd, J = 8.3, 0.5 Hz, 1H), 7.06 (s, 0.25H), 6, 95 ~ 6.92 (m, 1H), 6.93 (s, 0.5H), 6.84 (d, J =2.4 Hz, 1H), 6.80 (s, 0.25H), 5 .42 (s, 2H), 3.45 ~ 3.43 (m, 4H), 2.65 ~ 2.63 (m, 4H), 2.44 (t, J = 7.5 Hz, 2H), 1.68(s, 6H), 1.57~1.54(m, 2H), 1.41~1.36(m, 2H), 0.98~0.95(m, 3H).; LRMS (ES) m/z 539.5 (M ⁺ + 1).

Synthesis of compound 148, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(4-propylpiperazine -1-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 148

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), propionaldehyde (0.016 g, 0.269 mmol) and sodium triacetoxyborohydride (0.088 g, 0.415 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.050 g, 46.0%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (dd, J =2.2, 0.6 Hz, 1H), 8.32 (dd, J =8.2, 2.2 Hz, 1H) , 8.11 (d, J =9.1 Hz, 1H), 7.41 (dd, J =8.2, 0.6 Hz, 1H), 7.06 (s, 0.25H), 6, 94 ~ 6.92 (m, 1H), 6.93 (s, 0.5H), 6.84 (d, J =2.4 Hz, 1H), 6.80 (s, 0.25H), 5 .41(s, 2H), 3.44(t, J =5.0Hz, 4H), 2.64(t, J =4.8Hz, 4H), 2.42~2.38(m, 2H), 1.68(s, 6H), 1.61~1.55(m, 2H), 0.96(t, J =7.4Hz, 3H).; LRMS (ES) m/z 525.5 (M ⁺ + 1).

Synthesis of compound 149 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 149

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), isobutyric aldehyde (0.019 g, 0.269 mmol) and sodium triacetoxyborohydride (0.088 g, 0.415 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.050 g, 44.8%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 ~ 9.20 (m, 1H), 8.33 (dd, J =8.2, 2.2 Hz, 1H), 8.11 ~ 8, 09(m, 1H), 7.41(d, J =8.2Hz, 1H), 7.06(s, 0.25H), 6.94~6.92(m, 1H), 6.93 (s, 0.5H), 6.84 (d, J =2.4Hz, 1H), 6.80 (s, 0.25H), 5.43 (s, 2H), 3.43~3, 40(m, 4H), 2.60~2.55(m, 4H), 2.18~2.16(m, 2H), 1.86~1.81(m, 1H), 1.68( s, 6H), 0.98 ~ 0.96 (m, 6H).; LRMS (ES) m/z 539.5 (M ⁺ + 1).

Synthesis of compound 150 2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 150

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-6-(piperazin-1-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.207 mmol), 4,4-difluorocyclohexan-1-one (0.036 g, 0.269 mmol) and sodium triacetoxyborohydride (0.088 g, 0.415 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.090 g, 72.3%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J =1.5 Hz, 1H), 8.33 (dd, J= 8.2, 2.2 Hz, 1H), 8.12 (d, J =8.8 Hz, 1H), 7.42 (d, J =8.3 Hz, 1H), 7.06 (s, 0.25H), 6.94 (dd, J =8, 8, 2.5 Hz, 1H), 6.93 (s, 0.5H), 6.85 (d, J =2.4 Hz, 1H), 6.80 (s, 0.25H), 5, 42(s, 2H), 3.44~3.40(m, 4H), 2.77~2.73(m, 4H), 2.55~2.45(m, 1H), 2.00~ 1.40 (m, 8H), 1.69 (s, 6H); LRMS (ES) m/z 601.5 (M ⁺ + 1).

Synthesis of compound 151 4-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 151

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4,4-dimethyl-7-(piperidin-4-yl)isoquinoline -1,3(2H,4H)-dione (0.100 g, 0.208 mmol), 1-chloro-2-methoxyethane (0.028 ml, 0.312 mmol) and potassium carbonate (0.057 g, 0.415 mmol) were dissolved in acetonitrile (4 ml) at room temperature, then the resulting solution was stirred at 80° C. for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, then water was poured into the resulting concentrate, and extraction was performed with dichloromethane, then filtered through a plastic filter to remove a solid residue and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0 to 5%) and concentrated to give the product, then the resulting product was repurified by chromatography (SiO ₂ plate, 20×20×1 mm; methanol/dichloromethane aqueous solution=3%) and concentrated to give the title compound (0.010 g, 8.9%) as an orange solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, J=2.1 Hz, 1H), 8.34 (dd, J=8.2, 2.2 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.57 (dd, J=8.2, 1.9 Hz, 1H), 7.46 (t, J=8.0 Hz, 2H), 7 .06 ~ 6.80 (m, 1H), 5.44 (s, 2H), 3.60 (t, J=5.6 Hz, 2H), 3.39 (s, 3H), 3.18 ( d, J=11.4 Hz, 2H), 3.20 ~ 2.64 (m, 3H), 2.21 (t, J=10.6 Hz, 2H), 1.96 ~ 1.87 (m , 4H), 1.69 (s, 6H).; LRMS (ES) m/z 506.2 (M ⁺ + 1).

Synthesis of compound 152, 6-bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-4,4-dimethylisoquinoline-1, 3(2H,4H)-dione

[Step 1] Synthesis of Compound 152

6-Bromo-4,4-dimethylisoquinolin-1,3(2H,4H)-dione (1.700 g, 6.341 mmol), 2-(2-(bromomethyl)pyrimidin-5-yl)-5-(difluoromethyl)-1 ,3,4-oxadiazole (2.399 g, 8.243 mmol) and potassium carbonate (1.753 g, 12.681 mmol) were dissolved in N,N-dimethylformamide (20 ml) at 80°C, then the resulting solution was stirred at the same temperature for 18 h and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (1.900 g, 62.7%) as a yellow foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 2H), 8.13 (d, J =8.4 Hz, 1H), 7.70 (d, J =1.6 Hz, 1H ), 7.63 (dd, J = 8.4, 1.7 Hz, 1H), 7.08 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 5.55(s, 2H), 1.73(s, 6H).

Synthesis of compound 153, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-4,4-dimethyl-6-(4-methylpiperazine -1-yl)isoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 153

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.100 g, 0.209 mmol), 1-methylpiperazine (0.047 ml, 0.418 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.019 g, 0.021 mmol), 4,5-bis(diphenylphosphino )-9,9-dimethylxanthene (Xantphos, 0.012 g, 0.021 mmol) and cesium carbonate (0.204 g, 0.627 mmol) were dissolved in toluene (5 ml) at 80°C, then the resulting solution was stirred at the same temperature for 18 h and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.010 g, 9.4%) as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 2H), 8.13 ~ 8.10 (m, 1H), 7.08 (s, 0.25H), 6.96 ~ 6, 93 (m, 1H), 6.94 (s, 0.5H), 6.87 (d, J =2.4 Hz, 1H), 6.82 (s, 0.25H), 5.55 (s , 2H), 3.48~3.45(m, 4H), 2.68~2.64(m, 4H), 2.43(s, 3H), 1.71(s, 6H).; LRMS (ES) m/z 498.5 (M ⁺ + 1).

Synthesis of compound 154, tert-butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-4,4-dimethyl -1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[Step 1] Synthesis of Compound 154

6-Bromo-2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-4,4-dimethylisoquinoline-1,3(2H, 4H)-dione (0.800 g, 1.673 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1( 2H)-carboxylate (0.672 g, 2.175 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)dichloride (Pd(dtbpf)Cl ₂ , 0.109 g, 0.167 mmol) and cesium carbonate (0.818 g, 2.509 mmol) was mixed in a mixture of 1,4-dioxane (9 ml)/water (3 ml), then the resulting mixture was irradiated with microwave radiation, then heated at 100°C for 25 min and then the reaction was terminated by lowering the temperature up to room temperature. Water was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0 to 50%) and concentrated to give the title compound (0.381 g, 39.2%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 2H), 8.22 (d, J =2.5 Hz, 1H), 7.49 ~ 7.43 (m, 2H), 7 .08 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 6.22 (s, 1H), 5.55 (s, 2H), 4.15 ~ 4.09 (m, 2H), 3.70 ~ 3.66 (m, 2H), 2.59 (s, 2H), 1.72 (s, 6H), 1.50 (s, 9H).

Synthesis of compound 155, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-(1-ethyl-1,2,3 ,6-tetrahydropyridin-4-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-4,4-dimethyl-6-(1, 2,3,6-tetrahydropyridin-4-yl)isoquinolin-1,3(2H,4H)-dione

tert-Butyl-4-(2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-4,4-dimethyl-1,3 -dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.381 g, 0.656 mmol) and trifluoroacetic acid (0.503 ml, 6.562 mmol) were dissolved in dichloromethane (10 ml) at room temperature, then the resulting solution was stirred at the same temperature for 5 hours. The solvent was removed from the reaction mixture under reduced pressure, then a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, and then extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting product was used without further purification (0.241 g, 76.4%, yellow oil).

[Step 2] Synthesis of Compound 155

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-4,4-dimethyl-6-(1,2,3,6 -tetrahydropyridin-4-yl)isoquinolin-1,3(2H,4H)-dione (0.241 g, 0.502 mmol) obtained in step 1, acetaldehyde (0.056 ml, 1.003 mmol) and sodium triacetoxyborohydride (0.213 g, 1.003 mmol) was dissolved in dichloromethane (20 ml) at room temperature, then the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extraction was carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.150 g, 58.8%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 2H), 8.20 (d, J =8.2 Hz, 1H), 7.50 ~ 7.47 (m, 2H), 7 .08 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 6.25 (s, 1H), 5.56 (s, 2H), 3.40~3.39(m, 2H), 2.95~2.92(m, 2H), 2.77~2.72(m, 4H), 1.72(s, 6H), 1, 25 (t, J =7.2 Hz, 3H).

Synthesis of compound 156, 2-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl) pyrimidin-2-yl)methyl)-6-(1-ethylpiperidin-4-yl) 4,4-dimethylisoquinoline-1,3(2H,4H)-dione

[Step 1] Synthesis of Compound 156

2-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)methyl)-6-(1-ethyl-1,2,3,6-tetrahydropyridine -4-yl)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (0.125 g, 0.246 mmol) was dissolved in methanol (10 ml) at room temperature, then 10%-Pd/C ( 10 mg) and stirred for 18 h with the supply of hydrogen from an attached balloon at the same temperature. The reaction mixture was filtered through a pad of celite to remove solids, then the solvent was removed from the resulting solids-free filtrate under reduced pressure. The resulting concentrate was then purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0 to 10%) and concentrated to give the title compound (0.100 g, 79.7%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 2H), 8.19 (d, J =8.1 Hz, 1H), 7.42 (d, J =1.4 Hz, 1H ), 7.36 (dd, J =8.2, 1.5 Hz, 1H), 7.08 (s, 0.25H), 6.95 (s, 0.5H), 6.82 (s, 0.25H), 5.55(s, 2H), 3.40~3.37(m, 2H), 2.78~2.72(m, 3H), 2.39~2.33(m, 2H), 2.18~2.15(m, 2H), 1.99~1.95(m, 2H), 1.71(s, 6H), 1.30~1.26(m, 3H) .; LRMS (ES) m/z 511.4 (M ⁺ + 1).

Protocol for the study and analysis of the activity of the compounds proposed in the present invention

<Example 1> Detection of HDAC enzyme inhibition activity (in vitro)

The selective HDAC inhibitor is important for the selectivity of HDAC1 inhibition, which is the cause of side effects, and therefore, HDAC1/6 enzyme selectivity and cell selectivity (HDAC1: histone acetylation/HDAC6: tubulin acetylation) were found.

1. Experimental technique

The ability of a test substance to inhibit the HDAC enzyme was determined using the HDAC1 Fluorimetric Drug Discovery Assay Kit (Enzolifesciences: BML-AK511) and recombinant human HDAC6 (Calbiochem: 382180). For the HDAC1 assay, samples were processed at concentrations of 100, 1000, and 10,000 nM. For HDAC6 testing, samples were processed at concentrations of 0.1, 1, 10, 100, and 1000 nM. After this treatment of the samples, the reaction was carried out at 37°C for 60 min, then treated with a developer and then reacted at 37°C for 30 min, then the fluorescence intensity was determined (excitation at 390 nm, emission at 460 nm) using FlexStatin3 (Molecular device).

2. Results of the experiment

Its results are shown in the following table 2.

Table 2. Results of the HDAC enzyme inhibition activity study

Compound HDAC6 IC ₅₀ (µM) HDAC1 IC ₅₀ (µM) 1 0.057 >10 2 0.561 >10 3 0.318 >10 4 0.032 >10 5 0.513 >10 6 0.647 >10 7 0.145 >10 8 0.030 >10 9 0.126 >10 10 0.455 >10 eleven 1.021 >10 12 0.083 >10 13 0.225 >10 14 0.053 >10 15 0.196 >10 16 0.257 >10 17 0.165 >10 18 0.132 >10 19 0.249 >10 20 0.159 >10 21 0.273 >10 22 0.210 >10 23 0.065 >10 24 0.021 >10 25 0.158 >10 26 0.022 >10 27 0.043 >10 28 0.024 >10 29 0.018 >10 thirty 0.046 >10 31 0.029 >10 32 0.025 >10 33 0.034 >10 34 0.027 >10 35 0.026 >10 36 0.024 >10 37 0.015 >10 38 0.024 >10 39 0.018 >10 40 0.022 >10 41 0.134 >10 42 0.035 >10 43 0.038 >10 44 0.019 >10 45 0.156 >10 46 0.121 >10 47 0.049 >10 48 0.342 >10 49 0.041 >10 50 0.052 >10 51 0.038 >10 52 0.040 >10 53 0.427 >10 54 0.042 >10 55 0.020 >10 56 0.046 >10 57 0.032 >10 58 0.014 >10 59 0.056 >10 60 0.022 >10 61 0.035 >10 62 0.061 >10 63 0.033 >10 64 0.025 >10 65 0.133 >10 66 0.216 >10 67 0.062 >10 68 0.020 >10 69 0.019 >10 70 0.059 >10 71 0.150 >10 72 0.310 >10 73 0.098 >10 74 0.049 >10 75 0.368 >10 76 0.079 >10 77 0.141 >10 78 0.040 >10 79 0.113 >10 80 0.017 >10 81 0.011 >10 82 0.092 >10 83 0.098 >10 84 0.079 >10 85 0.050 >10 86 0.040 >10 87 0.023 >10 88 0.021 >10 89 0.054 >10 90 0.041 >10 91 0.033 >10 92 0.035 >10 93 0.143 >10 94 0.116 >10 95 0.059 >10 96 0.088 >10 97 0.061 >10 98 0.047 >10 99 0.149 >10 100 0.037 >10 101 0.033 >10 102 0.030 >10 103 0.059 >10 104 0.020 >10 105 0.010 >10 106 0.048 >10 107 0.148 >10 108 0.211 >10 109 0.107 >10 110 0.015 >10 111 0.017 >10 112 0.050 >10 113 0.043 >10 114 0.077 >10 115 0.059 >10 116 0.200 >10 117 0.022 >10 118 0.022 >10 119 0.021 >10 120 0.081 >10 121 0.036 >10 122 0.023 >10 123 0.017 >10 124 0.038 >10 125 0.043 >10 126 0.032 >10 127 0.017 >10 128 0.070 >10 129 0.026 >10 130 0.030 >10 131 0.062 >10 132 0.069 >10 133 0.076 >10 134 0.012 >10 135 0.100 >10 136 0.055 >10 137 0.089 >10 138 0.096 >10 139 0.683 >10 140 0.535 >10 141 0.052 >10 142 0.081 >10 143 0.021 >10 144 0.034 >10 145 0.037 >10 146 0.058 >10 147 0.069 >10 148 0.032 >10 149 0.095 >10 150 0.051 >10 151 0.033 >10 152 0.125 >10 153 0.118 >10 154 0.414 >10 155 0.185 >10 156 0.056 >10

As shown in the above Table 2, from the results of the study of HDAC1 and HDAC6 inhibition activity, it can be concluded that the 1,3,4-oxadiazole homophthalimide derivatives of the present invention, their stereoisomers, or their pharmaceutically acceptable salts have not only excellent inhibitory activity on against HDAC6, but also with excellent selective inhibitory activity against HDAC6 - HDAC1.

Claims (120)

1. The compound described by the following chemical formula I, its stereoisomers or its pharmaceutically acceptable salts: [Chemical Formula I]

, where X ₁ -X ₄ are all independently CR ₀ or N, where at least two of X ₁ -X ₄ are CR ₀ , where each R ₀ is independently hydrogen or halogen, R ₁ means linear or branched -C _1-5 haloalkyl, R ₂ and R ₃ are all independently H, halogen,

, 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3-7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S , 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

,

,

,

,

, phenyl, indolyl or

, where one and two hydrogen atoms of the specified 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3-7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group, comprising N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

,

,

,

,

, phenyl, indolyl or

, can be substituted with R ₄ , R ₄ is halogen, -C _1-7 alkyl, -C _1-7 haloalkyl, -OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-C _1-7 alkyl-OH, -C(=O)-OC _1-7 alkyl, -S(=O) ₂ -C _1-7 alkyl, 3-7 membered cycloalkyl, 3-7 membered halocycloalkyl, 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

, -C _1-7 alkyl-C(=O)-R ₅ , -C _1-7 alkyl-R ₇ , -C _1-7 alkyl-OR ₈ , -NR ₉ R ₁₀ or -C(=O)- NR ₁₁ R ₁₂ , where R ₅ means 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, R ₇ is a 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, or a 3-7 membered cycloalkyl, R ₈ means -C _1-7 alkyl, R ₉ and R ₁₀ are all independently H or -C _1-7 alkyl and R ₁₁ and R ₁₂ are all independently H or -C _1-7 alkyl, R _x and R _y are all independently -C _1-7 alkyl or -C _1-7 alkyl-NR ₁₅ R ₁₆ , where R ₁₅ and R ₁₆ are all independently -C _1-7 alkyl, K means O or S, Y means CR _a R _b , NR _c or single bond, R _a and R _b are all independently hydrogen or -C _1-7 alkyl or R _a and R _b are bonded to each other to form a 3-7 membered cycloalkyl, R _c means hydrogen, -C _1-7 alkyl, -C _1-7 alkylheterocycloalkyl, in this case, heterocycloalkyl is a 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _{1- 7} alkyl-OC _1-7 alkyl or -C _1-7 alkyl-NR ₁₉ R ₂₀ , where one hydrogen atom of the group is -C _1-7 alkyl, -C _1-7 alkylheterocycloalkyl, in this case, heterocycloalkyl is a 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _1-7 alkylphenyl or -C _1-7 alkylheteroaryl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, may be substituted by the following substituent: -C _1-7 alkyl, -OC _1-7 alkyl, 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C(=O)-OC _{1 -7} alkyl or heteroaryl-C _1-5 haloalkyl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, and R ₁₉ and R ₂₀ are all independently H or -C _1-7 alkyl,

means phenylene, halogen is F, Cl, Br or I and n is 0 or 1. 2. The compound described by the chemical formula I, its stereoisomers or its pharmaceutically acceptable salts according to claim 1, where X ₁ -X ₄ are all independently CR ₀ or N, where at least two of X ₁ -X ₄ are CR ₀ , where R ₀ means hydrogen or halogen, R ₁ is -C _1-5 haloalkyl, R ₂ and R ₃ are all independently H, halogen,

, 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3-7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S , 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

,

,

,

,

, phenyl, indolyl or

, where one and two hydrogen atoms of the specified 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3-7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group, comprising N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

,

,

,

,

, phenyl, indolyl or

, can be substituted with R ₄ , R ₄ is halogen, -C _1-7 alkyl, -C _1-7 haloalkyl, -OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-C _1-7 alkyl-OH, -C(=O)-OC _1-7 alkyl, -S(=O) ₂ -C _1-7 alkyl, 3-7 membered cycloalkyl, 3-7 membered halocycloalkyl, 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

, -C _1-7 alkyl-C(=O)-R ₅ , -C _1-7 alkyl-R ₇ , -C _1-7 alkyl-OR ₈ , -NR ₉ R ₁₀ or -C(=O)- NR ₁₁ R ₁₂ , where R ₅ means 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, R ₇ is a 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, or a 3-7 membered cycloalkyl, R ₈ means -C _1-7 alkyl, R ₉ and R ₁₀ are all independently -C _1-7 alkyl and R ₁₁ and R ₁₂ are all independently H or -C _1-7 alkyl, R _x and R _y are all independently -C _1-7 alkyl or -C _1-7 alkyl-NR ₁₅ R ₁₆ , where R ₁₅ and R ₁₆ are all independently -C _1-7 alkyl, K means O or S, Y means CR _a R _b , NR _c or single bond, R _a and R _b are all independently hydrogen or -C _1-7 alkyl or R _a and R _b are bonded to each other to form a 3-7 membered cycloalkyl, R _c means hydrogen, -C _1-7 alkyl, -C _1-7 alkylheterocycloalkyl, in this case, heterocycloalkyl is a 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _{1- 7} alkyl-OC _1-7 alkyl or -C _1-7 alkyl-NR ₁₉ R ₂₀ , where one hydrogen atom of the group is -C _1-7 alkyl, -C _1-7 alkylheterocycloalkyl, in this case, heterocycloalkyl is a 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _1-7 alkylphenyl or -C _1-7 alkylheteroaryl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, may be substituted by the following substituent: -C _1-7 alkyl, -OC _1-7 alkyl, 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C(=O)-OC _{1 -7} alkyl or heteroaryl-C _1-5 haloalkyl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, and R ₁₉ and R ₂₀ are all independently H or -C _1-7 alkyl,

means phenylene, halogen is F, Cl, Br or I and n is 0 or 1. 3. The compound described by the chemical formula I, its stereoisomers or its pharmaceutically acceptable salts according to claim 1, where X ₁ -X ₄ are all independently CR ₀ or N, where at least two of X ₁ -X ₄ are CR ₀ , R ₀ means hydrogen or halogen, R ₁ is -C _1-5 haloalkyl, R ₂ and R ₃ are all independently H, halogen,

, 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3-7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S , 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

,

,

,

, phenyl, indolyl,

or

, where one and two hydrogen atoms of the specified 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3-7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group, comprising N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

,

,

,

, phenyl, indolyl,

or

, can be substituted with R ₄ , R ₄ is halogen, -C _1-7 alkyl, -C _1-7 haloalkyl, -OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-C _1-7 alkyl-OH, -C(=O)-OC _1-7 alkyl, -S(=O) ₂ -C _1-7 alkyl, 3-7 membered cycloalkyl, 3-7 membered halocycloalkyl, 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

, -C _1-7 alkyl-C(=O)-R ₅ , -C _1-7 alkyl-R ₇ , -C _1-7 alkyl-OR ₈ , -NR ₉ R ₁₀ or -C(=O)- NR ₁₁ R ₁₂ , where R ₅ is a 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, R ₇ is a 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S or a 3-7 membered cycloalkyl, R ₈ means -C _1-7 alkyl, R ₉ and R ₁₀ are all independently -C _1-7 alkyl and R ₁₁ and R ₁₂ are all independently H or -C _1-7 alkyl, R _x and R _y are all independently -C _1-7 alkyl or -C _1-7 alkyl-NR ₁₅ R ₁₆ , where R ₁₅ and R ₁₆ are all independently -C _1-7 alkyl, K means O Y means CR _a R _b , NR _c or single bond, R _a and R _b are all independently hydrogen or -C _1-7 alkyl or R _a and R _b are bonded to each other to form a 3-7 membered cycloalkyl, R _c means hydrogen, -C _1-7 alkyl, -C _1-7 alkylheterocycloalkyl, in this case, heterocycloalkyl is a 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _{1- 7} alkyl-OC _1-7 alkyl or -C _1-7 alkyl-NR ₁₉ R ₂₀ , where one hydrogen atom of the group is -C _1-7 alkyl, -C _1-7 alkylheterocycloalkyl, in this case, heterocycloalkyl is a 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _1-7 alkylphenyl or -C _1-7 alkylheteroaryl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, may be substituted by the following substituent: -C _1-7 alkyl, -OC _1-7 alkyl, 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, heteroaryl-C _1-5 haloalkyl, in in this case heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, or -C(=O)-OC _1-7 alkyl, and R ₁₉ and R ₂₀ are all independently -C _1-7 alkyl,

means phenylene, halogen is F or Br and n is 0 or 1. 4. The compound described by the chemical formula I, its stereoisomers or its pharmaceutically acceptable salts according to claim 1, where X ₁ -X ₄ are all independently CR ₀ or N, where at least two of X ₁ -X ₄ are CR ₀ , R ₀ means hydrogen or F, R ₁ means CF ₂ H, R ₂ and R ₃ are all independently H, F, Br,

, 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3-7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group including N, O or S , 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

,

,

,

, phenyl, indolyl,

or

, where one and two hydrogen atoms of the specified 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 3-7-membered heterocycloalkenyl containing from 1 to 3 heteroatoms selected from the group, comprising N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

,

,

,

, phenyl, indolyl,

or

, can be substituted with R ₄ , R ₄ is F, -C _1-7 alkyl, -C _1-7 haloalkyl, -OC _1-7 alkyl, -C(=O)-C _1-7 alkyl, -C(=O)-C _1-7 alkyl-OH, -C(=O)-OC _1-7 alkyl, -S(=O) ₂ -C _1-7 alkyl, 3-7 membered cycloalkyl, 3-7 membered halocycloalkyl, 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group including N, O or S,

, -C _1-7 alkyl-C(=O)-R ₅ , -C _1-7 alkyl-R ₇ , -C _1-7 alkyl-OR ₈ , -NR ₉ R ₁₀ or -C(=O)- NR ₁₁ R ₁₂ , where R ₅ is a 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, R ₇ is a 3-7 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, or a 3-7 membered cycloalkyl, R ₈ means -C _1-7 alkyl, R ₉ and R ₁₀ are all independently -C _1-7 alkyl and R ₁₁ and R ₁₂ are all independently H or -C _1-7 alkyl, R _x and R _y are all independently -C _1-7 alkyl or -C _1-7 alkyl-NR ₁₅ R ₁₆ , where R ₁₅ and R ₁₆ are all independently -C _1-7 alkyl, K means O Y means CR _a R _b , NR _c or single bond, R _a and R _b are all independently hydrogen or -C _1-7 alkyl or R _a and R _b are bonded to each other to form a 3-7 membered cycloalkyl, R _c means hydrogen, -C _1-7 alkyl, -C _1-7 alkylheterocycloalkyl, in this case heterocycloalkyl is a 3-7 membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _{1- 7} alkyl-OC _1-7 alkyl or -C _1-7 alkyl-NR ₁₉ R ₂₀ , where one hydrogen atom of the group is -C _1-7 alkyl, -C _1-7 alkylheterocycloalkyl, in this case, heterocycloalkyl is a 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, may be substituted by the following substituent: -C _1-7 alkyl, -OC _1-7 alkyl, 3-7-membered heterocycloalkyl containing from 1 to 3 heteroatoms selected from the group including N, O or S, heteroaryl-C _1-5 haloalkyl, in in this case heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, or -C(=O)-OC _1-7 alkyl, and R ₁₉ and R ₂₀ are all independently -C _1-7 alkyl,

means phenylene, halogen is F or Br and n is 0 or 1. 5. The compound described by the following chemical formula II, its stereoisomers or its pharmaceutically acceptable salts: [Chemical Formula II]

, where X ₁ -X ₄ are all independently CR ₀ or N, where at least two of X ₁ -X ₄ are CR ₀ , where R ₀ means hydrogen, R ₁ means linear or branched -C _1-5 haloalkyl, R ₂ and R ₃ are all independently H, K means O Y means NR _c , R _c means -C _1-7 alkylphenyl, -C _1-7 alkylheteroaryl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S, or -C _1-7 alkyl-OC _1-7 alkyl, where one hydrogen atom of the group -C _1-7 alkylheteroaryl, in which case heteroaryl is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O or S, may be substituted by the following substituent: heteroaryl-C _1-5 haloalkyl, in this case heteroaryl is a 5- or 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O or S,

means phenylene, halogen is F, Cl, Br or I and n is 0 or 1. 6. The compound described in the following table, its stereoisomers or its pharmaceutically acceptable salts:

7. Pharmaceutical composition having inhibitory activity against HDAC6, where the composition contains a therapeutically effective amount of a compound according to any one of paragraphs. 1-6, its stereoisomers or its pharmaceutically acceptable salts as an effective component and a pharmaceutically acceptable carrier. 8. The pharmaceutical composition according to claim 7, wherein said pharmaceutical composition is for the prevention or treatment of diseases associated with histone deacetylase 6 activity. 9. The pharmaceutical composition according to claim 8, where the diseases associated with the activity of histone deacetylase 6 are at least one selected from the group consisting of infectious diseases; neoplasm; endocrinopathy; nutritional and metabolic diseases; mental and behavioral disorders; neurological diseases; adnexal eye diseases; circulatory diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissues; diseases of the musculoskeletal system and connective tissue; and malformation or deformity, and chromosomal aberration. 10. The method of inhibition of histone deacetylase 6, including the introduction of a therapeutically effective amount of a compound according to any one of paragraphs. 1-6, its stereoisomers or its pharmaceutically acceptable salts. 11. The use of a compound according to any one of paragraphs. 1-6, its stereoisomers or its pharmaceutically acceptable salts for inhibiting histone deacetylase 6. 12. The use of a compound according to any one of paragraphs. 1-6, its stereoisomers or its pharmaceutically acceptable salts for the preparation of a medicament for inhibition of histone deacetylase 6.